摘要:

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ISSN:0365-6217    

DOI:10.1039/AR94542FP001

出版商:RSC    

年代:1945

数据来源: RSC

摘要:

ANNUAL REPORTSON THEPROGRESS OF CHEMISTRY.GENERAL AND PHYSICAL CHEMISTRY.1. RECENT ADVANCES IN INFRA-RED SPECTROSCOPY.THE past ten years have seen a remarkable advance in infra-red spectroscopy,particularly in its application to chemical problems. Earlier work, summar-ised in previous reports,l was somewhat physical in character, and centredmainly on the determination of the vibration frequencies and moments ofinertia of simple molecules, together with the exploration of underlyingspectroscopic theory and the intricacies of molecular dynamics.2 It wasoften possible to derive from the results other information bearing upon themolecular structure or thermodynamic properties of the substances involved,and with relatively simple molecules containing not more than five or sixatoms highly accurate structural data could thus be obtained.The scopeof such work was obviously limited, however, since the large majority ofmolecules are too heavy t o give vibrational bands which have a resolvablerotational fine structure, and the molecular complexity and general lack ofsymmetry make it impossible to assign the vibration frequencies completelyand unambiguously.The possibility of other kinds of chemical application was foreshadowedby the correlation of certain absorption bands with particular atomic group-ings, especially those measurements on hydroxylic compounds in which thedisplacement of the characteristic vibration frequency of the O-H link wascorrelated with the existence of hydrogen bonds. It was clear, however,that an essentially different experimental approach would be necessary ifthe bigger molecules generally encountered in chemistry were to be studiedwith advantage, and that this might involve as a first step the empiricalcorrelation of the spectra of a large number of molecules in carefully chosenrelated series.Ten years ago the compilation of such a background ofreference seemed impossible, mainly because of the technical difficulties ofmeasuring the spectra with reasonable speed. Using instruments of greaterresolving power, such as grating spectrometers, progress was even slower.These problems, accentuated by the needs of the war, have led to a numberof striking technical developments, as a result of which it is now possibleto measure the spectra rapidly, using instruments which require neitherAnn.Reports, 1941, 38, 46; 1938, 35, 37; 1936, 33, 53; 1935, 32, 53.a G. Herzberg, “ Infra-red and Raman Spectra,” van Nostrand, 19456 GENERAL AND PHYSICAL CHEMISTRY.elaborate laboratory facilities nor particular operational skill.3 The maincause of this progress has been the vast improvement in the methods ofdetecting infra-red radiation? although many new appropriate accessorieshave simultaneously become available. As a result, the emphasis haspassed rapidly to a wide range of chemical application^,^ many of which canbe classified as qualitative or quantitative analysis, or as structural diagnosis.Further advances on the instrumental side are certain to be made in thenear future, so that infra-red spectroscopy now ranks among the otheruseful standard physicochemical techniques.I n order to obtain a correct perspective, as well as to appreciate theparticular uses of different kinds of instrument, the experimental develop-ments must be outlined more specifically and a t rather greater length thanis usual in a report of this kind.The main difficulty in earlier work lay inthe detection and accurate measurement of the small amount of radiationavailable a t these longer wave-lengths ; especially when radiation from aaource was first spread out by some dispersing system. The most commonmethod employed a thermocouple, working with a sensitive galvanometer.The comparative insensitivity of the couples available made it neccssary touse highly sensitive galvanometers of long period and capricious stability,which implied a slow and tedious measurement of the spectrum, readingsbeing taken at successive wave-lengths point by point.Amplification bythermal or photocell relays of different kinds 5 led $0 some improvementin the technique, but i t remained essentially one for a limited number ofresearch laboratories. By contrast, a wide variety of detectors is nowavailable, so far superior to the older ones that minute amounts of infra-redradiation can be detected from emitters a t great distance and with com-parative ease.A detector can be characterised by three main properties, namely, (1)sensitivity, (2) speed of response, and (3) “ blackness,” i.e., the ability toabsorb perfectly radiation of any wave-length.Three main kinds have nowbeen developed, namely, thermocouples,6 bolometers, and the so-calledselective receivers. As mentioned below, the warming of a gas consequentupon the absorption of radiation can also be used with marked success.As regards thermocouples, the use of new alloys and new methods of mount-ing in a vacuum have led to much greater sensitivity, greater speed ofN. Wright, Id. Eng. Chern. Anal., 1941, 13, 1; R. 13. Barnes, U. Liddel, andV. Z. Williams, ibid., 1943, 15, 659; R. B. Barnes, R. S. McDonald, V. Z. Williams,and R. F. Kinnaird, ibid., 1915,16, 77; H. W. Thompson and D. H. Whiffen, J., 1945,268; G. B. B. M. Sutherland and H. W. Thompson, Trans. Faraday Soc., 1945, 41,174; R.R. Brattain and 0. Beecli, J . Appl. Physics, 1942, 13, 699; R. R. Brattain,Petroleum World, Feb. 1943; W. H. Awry, J. Opt. Soc., 1941, 31, 633; E. D. McAlister.G. L. Matheson, and W. J. Sweeny, Rev. Sci. Instr., 1941, 12, 314; L. G. Smith, ibid.,1942, 13, 54; E. Lehrer and K. F. Luft, 2. techn. Physik, 1942, 23, 169.H. W. Thompson, Endeavour, Oct. 1945.6 E. B. Moss, J. Sci. Instr., 1935, 12, 141.L. C. Roess and E. N. Dacus, Rev. Sci. lnstr., 1945, 16, 164, 172; also the Hilger-Schwarz couple, Brit. PatTHOMPSON : RECENT ADVANCES IN MFRA-RED SPECmOSCOPY. 7response, and by proper compensation to almost complete stability asregards small local fluctuations of temperature. By amplifying the outputvoltage from such thermocouples by means of electro-optical devices it hasbeen possible to build spectrometers with which the spectrum between1 and 25 p can be scanned rapidly, and by coupling a recorder to the scanningmechanism to record the energy as a function of wave-length.I n this way,rapid automatically-recording prism spectrometers have been developedwith which an absorption spectrum between 1 and 25 p can be measuredin about half an hour. Moreover, in such instruments the galvanometerscan be sufficiently robust to be handled conveniently in ordinary laboratories,and the old difficulties largely disappear. I n " single-beam " spectrometersof this kind the record is usually the " fall-off " curve of the emitter, withtroughs in the background due to absorption of the substance under examin-ation.Wave-length calibration can be made either by absolute calculationsfrom the dimensions of the instrument, or by using standard absorptionlines of water vapour,' carbon dioxide, ammonia or other substances. Inorder to simplify the measurement of records some attempts have beenmade to alter the widths of the spectrometer slits continuously as thespectrum is being traversed, so as to give a flat base line on the record.This is not easy, however, to achieve in practice.The traces obtained with the above single-beam spectrometers areadequate for most practical purposes. They suffer, however, from twominor disadvantages. First, it is necessary to measure on the record thevalues of the galvanometer throws a t all wave-lengths with respect to thevalues of these throws for the source itself when there is no absorption.When a large number of spectra are being measured over a wide range ofwave-lengths, it would save much time and computation if the record gavethe percentage absorption directly, although some quick computationaldevices have been suggested.* Secondly, unless the spectrometer and ex-ternal path of the entrant beam of radiation are evacuated or cleared ofwater vapour and carbon dioxide, absorption bands occur in the blank tracedue to these substances.I n some regions these bands are so intense andcomplex that they obscure the fine details of the absorption bands of thesubstance being examined. The difficulties can be greatly reduced byevacuation of the spectrometer or by the use of drying agents, but in eithercase there are experimental inconveniences.In an attempt to obviate these shortcomings of the single-beam insfru-ments, double-beam spectrometers have been de~eloped.~ I n these, twoequal beams of radiation pass through the spectrometer simultaneously andafter emerging fall upon two separate thermocouples. One beam is used asa blank, and the other contaiiis the absorbing substance. The spectralR.A. Oetjen, C. L. Kao, and H. 31. Randall, Rev. Sci. Instr., 1942, 13, 515.H. A. Willis and A. R. Philpots, Trans. paraday SOC., 1946, 41, 187; R. M.Q J. D. Hardy and A. I. Ryer, Physical Rev., 1939,55, 1112 ; G. B. B. M. SutherlandFuoss and D. J. Mead, Rev. Sci. Instr., 1945, 16, 223.and H.W. Thompson, ref. (3); E. Lehrer and K. F. Luft, ref. (3)8 GENERAL AND PHYSICAL CHEMISTRY.record can then be obtained in two ways. Hardy and Ryer, and Lehrerand Luft, used a variable-diaphragm shutter in the blank beam, whichcould be adjusted continuously as the spectrum was being traversed so asto maintain the radiation in both beams the same. The extent of closingthe shutter could be geared to a pen and a direct reading of the absorptionthus obtained. In the method of Hardy and Ryer this procedure involvedanticipation of the motion of a galvanometer spot, and in regions wherethere are sharp absorption bands the spectrum had to be traversed veryslowly if accurate records were to be obtained. Lehrer and Luft avoidedthis difficulty to some extent by means of a photoelectric control.Analternative method is to amplify the voltages from the two thermocouplesseparately and measure their ratio on a quick-acting potentiometric recorder,the balance of which is found by a photoelectric mechanism. The potentio-metric recorder must have a rapid response, consistent with the rate ofscanning of the spectrum, and it must give a conveniently large displacementof the pen in about one second; it must also be capable of being actuatedby a current of about one milliamphe, since this may be the greatest currentwhich can be obtained by direct-current amplification of the very smallvoltages obtained from the thermocouple.These difficulties have been successfully overcome, and the double-beamspectrometers have already proved valuable in studying the absorptionspectra of molecules containing those atomic groupings which give rise toabsorption bands in the region of 3 p and 6-7 p, such as amides and amino-compounds, and hydroxy-compounds.l* There is no doubt, however, thatthe use of direct-current amplifiers of high gain with low input voltage isstill a troublesome undertaking, and complete elimination of moving-coilgalvanometers would be a further advance in building spectrometers forgeneral industrial use in locations where vibrations may be unavoidable.This could be achieved by using alternating-current amplifiers workinga t reasonable audio-frequencies.A pulsating voltage from a thermocouplecan be obtained in two ways, either by means of a periodic shutter placedin front of the entrance slit of the spectrometer, or by feeding the outputto a commutator.I n either case a large degree of amplification is thenrequired. Both methods have now been used successfully,ll but eachinvolves some difficulty. If the commutator is used, erratic contactpotentials are not easily avoided and may mask the very low voltages beingdetermined. If an interrupted beam is used, the chopping frequency mustnot exceed a value consistent with the speed of response of the thermo-couple. The latter condition at present implies the use of very lowfrequencies, say five cycles per second, since the most sensitive thermo-couples have time constants little less than one-quarter of a second.Amplification a t this frequency, for a high gain, is difficult, and troublesarise owing to various kinds of electrical noise in the circuit.If faster thermocouples could be constructed without serious loss oflo R.E. Richards, t o be published soon.l1 E.g., L. C. Roess, Rev. Sci. Instr., 1945, 16, 172THOMPSON : RECENT ADVANCES IN INFRA-RED SPECTROSCOPY. 9sensitivity, some of the difficulties might be avoided. A very promisingalternative a t present, however, is the use of bolometers which, althoughintrinsically less sensitive, have an extremely high rate of response. Theuse of a bolometer for detecting radiation depends on the fact that itsresistance alters with temperature, so that if a steady voltage is appliedacross it, periodic irradiation will produce a small fluctuating output voltage,which can be amplified.Owing to the rapid response (low time constant),higher frequency can be used for the interrupter, and the high resistanceof the bolometer makes i t possible to use a fairly conventional tunedelectronic amplifier. Earlier bolometers were of questionable value com-pared with the best thermocouples since their temperature coefficients ofresistance were small, but other kinds are now becoming available whichhave both greater sensitivity and speed of response (some milliseconds).Some of these are made from films of mixed metallic oxides, and are calledthermistors.12 Apart from their other advantages, they are robust and inuse are not affected by stray disturbances of temperature since the amplifiercan be tuned to the frequency of the interrupter, and erratic readings dueto thermal drift or vibration of a galvanometer disappear.It is certainthat the bolometer will replace the thermocouple in many infra-red instru-ments, and there are some signs that the practical limit may soon be reachedfor the detection of infra-red radiation, judged on the basis of the electricalnoise inherent in the instruments involved. It is still possible, on the otherhand, that by using the detector at very low temperatures a further im-provement may be obtained. A minor defect of the existing bolometers isthat they may not be perfectly " black " for all spectral ranges, but thereseems no reason why this cannot be achieved if suitable surface coatingsare applied.I n spite of these marked improvements leading to the rapid measurementof spectra, there are some circumstances in which an even quicker 13 scan-ning would be advantageous.Several years ago Baker and Robb attemptedto use a cathode-ray oscillograph for this purpose. This possibility has nowbeen developed further. As indicated already, an intermittent beam ofradiation passing through a spectrometer and falling upon a bolometergives rise to an alternating voltage output. The latter can be amplified,rectified, and fed to one pair of plates of a cathode-ray tube so as to causea displacement of the spot-say, vertically-and the amount of the dis-placement will be a measure of the intensity of the incident radiation, Ifthe prism is rotated and its motion is geared to a potentiometer, a timebase can be constructed for the oscillograph, so as to move the spot horizon-tally during the scanning operation.If now the screen of the oscilloscopehas a long persistence of glow, the beginning of the trace will still be visiblewhen the end of the traverse is reached, and by means of a cam a quickfly-back can be arranged, followed by a repeat, so that effectively thespectrum remains continuously on the screen. The success of this applic-l2 Bell Telephone Laboratories, e.g., B e l l Telephone Record, 1940, 19, 106.lS E. B. Baker and C. D. Robb, Reu. Sci. Instr., 1943, 14, 356, 359, 362.A 10 GENERAL AND PHYSICAL CHEMISTRY.ation hinges primarily on the use of a bolometer of rapid response, althoughthe electronic amplifying circuits are rather elaborate.In this way,however, E. F. Daly and G. B. B. M. Sutherland l4 have been able to projecta useful spectral range on to the screen, and improvements in this kind ofspectrometer may be expected soon. The instrument may revolutionisecertain types of analysis and structural diagnosis where it is desirable toobtain a quick survey of the spectrum or to estimate qualitatively or semi-quantitatively a particular component or impurity. It should also be mostuseful in observing continuously any alterations in a spectrum brought aboutby physical and chemical changes.It is well knownthat some czsium photoelectric cells are feebly sensitive to infra-red radiationjust beyond the visible.Other substances are now known to becomephoto-conductive when exposed to selected infra-red wave-lengths. Thusa layer of thallium oxysulphide l5 (" thalofide ") has a peak sensitivitynear 1 t ~ . , and lead sulphide l6 is sensitive between 2 and 3 p. If it is requiredto study the absorption of a substance having some key band within thenarrow spectral range to which the receiver is sensitive, no further spectraldispersion is needed, and by virtue of the high resistance of the cells theeffect can be amplified electronically after interrupting the beam periodicallyin the usual way. It seems likely that other similar receivers may soonbecome available for other spectral regions, and these should be particularlyvaluable for industrial applications.This progress with the various methods of detection has stimulatedimprovements in the accessories used with spectrometers, and in theexperimental methods as a whole.Synthetic crystals of the alkali halidesare now available l7 for use as prisms or windows of absorption cells, andthese are superior to natural samples as regards both transmission and size.Synthetic fluorides of calcium and lithium l8 are also available, and providea better dispersing material than rock salt for the range 2-9 p. Silverchloride sheet l9 is also available for windows of cells, since it transmitsuniformly to about 30 p and if protected with suitable reagents does notdeteriorate markedly in light. Another new material which promises tohave wide application for absorption cells and windows, and perhaps alsofor prisms in the region of very long wave-lengths, is a clear orange-colouredglassy solid obtained from a melt of mixed thallium halides.20 Althoughthis substance has a high refractive index and reflects some 20% of theradiation incident upon it, the transmission is smooth to about 50 p, andthe material is not attacked by water or atmospheric contaminants.SeveralFor some purposes, the selective receivers can be used.l4 Nature, 1946, 157, 547.1 5 T. W. Case, Physical Rev., 1920, 15, 289; J . Opt. SOC. Amer., 1922, 6, 398.l6 German development.17 The Harshaw Chemical Co., Cleveland, Ohio; H. C. Kremers, Ind. Eng. Chem.,18 N. Wright, Rev. Sci. Instr., 1944, 15, 22.l9 R. M. FUOSB, ibicE., 1945, 16, 154.1940, 32, 1478.2o German developmentTHOMPSON : RECENT ADVANCES IN INFRA-RED SPEWROSCOPY.11of the new substances just mentioned make it possible to examine very thinaqueous layers over wide ranges in the infra-red, and this should stimulatefurther work on substances such as proteins and amides. Several labora-tories have described new designs for absorption cells,21 and in view of thegrowth of quantitative analysis much attention has been paid to theaccurate control and measurement of cell thickness.22 Cells for use a thigher temperatures have also been described,23 and a range of solventssuitable for use with different kinds of solute in different spectral regionshas been examined.24 Some alternative laboratory sources of infra-redradiation have been explored,25 but the Nernst filament and Globar rodremain the most convenient.A number of reasons have made it desirable to measure the spectra ofsubstances in the solid state.With clear or semi-transparent films thisoffers no problem, but with amorphous powders much difficulty may befound owing to irregular scattering of the incident radiation. If the powdersare ground to a fine paste with paraffin or other liquids having a goodinfra-red transmission, and the particle size is controlled with respect tothe wave-lengths being studied, good spectra can be obtained.26The use of infra-red spectroscopy in analysis is based upon very simpleprin~iples.~~ A molecule of n atoms has in general (372 - 6) normalmodes of vibration. Some, or all, of these will involve a changing molecularelectric moment and be permitted to appear as fundamentals in the infra-red spectrum; many will occur as combinations or overtone bands.Thefundamental frequencies of the vibrations will depend in magnitude uponthe nuclear masses and force constants of the bonds, i.e., upon the potentialenergy function. I n consequence, no two molecules other than a pair ofoptical enantiomorphs will have the same set of frequencies, and the infra-red spectrum will be a characteristic property of the molecule-a finger-print-and can be used for its identification. I n the case of two closely alliedmolecules containing similar atomic groupings, some of the frequencies willbe the same in the two molecules, but in principle there should be some regionof the spectrum where differences occur.This is nearly always borne outby the facts, for while a few very similar molecules such as a group ofhigher homologues cannot easily be differentiated, many others differingonly slightly in structure show marked spectral dissimilarities.21 L. Gildart and N. Wright, Rev. Sci. Instr., 1941, 12, 204; E. S. Barr, ibid., p. 396.22 D. C. Smith and 33. C. Miller, J. Opt. SOC., 1944, 34, 130; G. B. B. M. Sutherlandand H. A. Willis, Trans. Paraday SOC., 1945, 41, 181; R. R. Gordon and H. Powell,J . Sci. Instr., 1945, 22, 12.z3 R. E. Richards and H. V?. Thompson, Trans. Faraday SOC., 1945, 41, 183; L. G.Smith, Rev. Sci. Instr., 1942, 13, 66.24 P. Torkington and H. W. Thompson, Trans.Paraday SOC., 1945, 41, 184.25 L. G. Smith, Rev. Sci. Instr., 1942, 13, 63.z6 R. E. Richards and H. W. Thompson, unpublished; J. Lecomte, Cahiers dePhysique, 1943, hTo. 17.27 H. W. Thompson, Analyst, 1945, 'SO, 443; G. B. B. M. Sutherland and H. W.Thompson, Trans. Faraduy SOC., 1945, 41, 19712 GENERAL AND PHYSICAL CHEMISTRY.The complete identity of the spectrum of a synthetic product with thatof a natural extract can be regarded as almost certain proof of the identityof the two samples, and this may become very important in testing synthesesof new organic and biologically interesting substances such as penicillin. Weare often more concerned, however, with the analysis of mixtures of fairlysimple substances. It is firstnecessary to know qualitatively what substances are present, or a t anyrate to be sure that no unsuspected component has absorption bands whichinterfere with or mask the key absorption bands of the component underconsideration.If independent methods give this information, the infra-redspectrum can be used to show that no other unsuspected substances arepresent. The spectrum of each of the pure substances must be known, andall the observed absorption bands must be accounted for by reference tothese. Any bands which cannot be correlated in this way will imply thepresence of an unsuspected component. It should be noted that failure todetect a small amount of a particular component in the infra-red spectrumis not necessarily proof of its absence, since in complex mixtures it mayhappen that the only strong bands of a particular component are maskedby overlapping bands of others.The sensitivity of the method dependsupon several factors and can only be assessed by reference to each individualcase. I n some cases 0.01% of a component can be detected, but in others5% might be missed.When the components of a mixture are known, quantitative analysiscan be attempted by methods based upon the theoretical absorption laws,or by empirical calibration. The key wave-lengths to be used for eachcomponent will be selected on the basis of (a) intrinsic intensity of thebands, (b) freedom from overlap with bands of other components. Incomplex cases it- is often essential to compromise between these two factors.It may sometimes be preferable to use a relatively feeble absorption bandfor determining one particular component rather than a more intense onewhich is partly overlaid by a band of some other substance, and by a correctchoice of cell thickness or concentration the percentage absorption can oftenbe brought into a range of convenient measurement.Unless particular intermolecular interactions occur, the spectrum of amixture is obtained by simple superposition of those of the components.I n terms of the standard absorption law, the extinction coefficient of asubstance can be defined by the equation,1 1 Eih = - .log T O = - . d )CiL I CiLSuch analyses usually involve two stages.where d: = log ( I , I ) .If in a mixture the optical densities are additive,dX = d: + d: + ...+ dnA= L(C1E2 + CZEB(\ + ... + C,E,h)The values of E can be determined from the spectra of the pure components.I n order to carry out an analysis for n components, it will be necessary tTHOMJ?SON : RECENT ADVANCES IN INFRA-RED SPECTROSCOPY. 13determine the optical densities at each of n wave-lengths, at each of whichthe values of E have been determined for the pure components. Thesystem of linear homogeneous equations can then be solved for the con-centrations cl, c2 ... c,. The accuracy which can be obtained will dependupon several factors, such as overlapping of bands, and care in solving thesystem of linear equations, since these may be not quite self-consistent.28A more fundamental problem, however, is to decide upon a correct measureof the optical densities, whether in fact we should take peak heights as ameasure of the intensities of some integrated band area.While there isstill some uncertainty on this point,29 experience has shown that in manycases at least the percentage absorption at the band peaks can be safelyused, unless there is some effect such as intermolecular association leadingto excessive and unsymmetrical broadening, or if the absorption band showsa rotational structure which varies abnormally with pressure or con-centration. In this work, too, allowance must be made for the absorptionby the cell itself, and by the solvent, if this is not zero. J. R. Nielsen andD. C. Smith 30 have set out the relevant mathematical formulation in somedetail.When the standard absorption laws are not applicable, empirical calibra-tion can be set up for the analysis by reference to mixtures of knowncomposition, examined under fixed experimental conditions.Many examplesof this kind have been described.31The number of examples of infra-red analysis is now large, althoughmuch of the work has remained unpublished during the war, and muchremains shrouded by industrial secrecy. The first published work on thismethod was that of W. S. Benedict, K. Morikawa, R. B. Barnes, and H. S.who analysed isotopic mixtures of the deutero-methanes and-ethanes, and perhaps the biggest general application hitherto has occurredin studying mixtures of hydrocarbons with special reference to fuels.33This field is well suited to the method, since the spectra of isomers boilingat almost the same temperature often show pronounced differences, and itis at once possible to examine fractions from distillation columns.Thedifferent isomeric octanes, for instance, have characteristic spectral features.It is worth emphasising the point that, although other methods based onphysical properties such as refractive index or density can be used for such28 R. R. Brattain, R. S. Rasmussen, and A. M. Cravath, J. Appl. Physics, 1943,2Q J. R. Nielsen, V. Thornton, and E. B. Dale, Rev. Mod. Physics, 1944, 16, 307.30 I n d . Eng. Chem. Anal., 1943, 15, 609.31 E.g., R. B. Barnes, U. Liddel, and V. 2. Williams, ref. (3).32 J. Chem. Physics, 1937, 5, 1.33 J.R. Nielsen, Oil and Gas J., Jan. 1942; R. A. Oetjen, H. M. Randall, andW. E. Anderson, Rev. Mod. Physics, 1944, 16, 260; R. A. Oetjen and H. M. Randall,ibid., p. 265; R. R. Brattain, Petroleum World, Feb. 1943; R. C. Gore and J. B.Patberg, Ind. Eng. Chern. Anal., 1941, 13, 768; L. J. Brady, ibid., 1944, 16, 422;J. Lecomte and P. Lambert, Publ. Sci. Min. de Z’Air, 1939,42; G. B. B. M. Sutherlandand H. W. Thompson, to be published shortly.14, 418; D. L. Fry, R. E. Nusbaum, and H. M. Randall, ibid., 1946, 17, 15014 GENERAL AND PHYSICAL CHEMISTRY,analyses, they may lead to serious error unless it is known with certaintywhat the components of the fractions really are. Mere boiling point is noreliable guide in such fractionations where azeotropes can arise.Theinfra-red spectrum usually characterises the components beyond doubt.The maximum number of components which can be tolerated in a mixturevaries in different cases and also according to the sensitivity and accuracyrequired. A simple routine spectrometer was originally designed 34 for theanalysis of mixtures of butane and isobutane, needed in the production ofsynthetic octanes, but it is now used for the analysis of many mixtures ofthe lower hydrocarbon gases such as arise in cracking operations, and it wasapplied to the control of butadiene production in the manufacture ofsynthetic rubber.I n the chemical industry as a whole the applications cover a wide range.The individual isomers in cresylic acid can be determined quickly,35 andthe composition of coal-tar acids in general can be examined more satis-factorily than by other methods. The analysis of the complex mixture ofstereoisomeric benzene hexachlorides formed in the manufacture of the newinsecticide ' ' Gammexane " (666) proved comparatively easy,36 particularlyfor the determination of the important y-isomer.Mixtures of nitroparaffinshave been analysed by J. R. Nielsen and D. C. Smith.37 The method hasbeen much applied to the detection of impurities in chemical products suchas the halogenated paraffins,38 or other intermediates. Other mixtureswhich have been examined include acetic anhydride-acetic acidF9 sub-stituted anilines and tol~idines,~~ t e r p e n e ~ , ~ ~ cyclohexanone and cyclo-h e ~ a n e , ~ ~ and various intermediates for the plastics industry.Mixtures ofsynthetic and natural rubber have been examined in this way.43 It isprobable that the infra-red spectrum may come to be regarded as a standardof purity for pharmaceuticals, and for organic solvents and other reagents.It is natural that infra-red analysis should also have been applied infollowing the rate of chemical reactions when other methods are less con-venient. Most applications of this kind so far concern the polymerisationof unsaturated compounds to form polymers or plastics. In such processeswe may follow either the disappearance of a band due to the unsaturatedlinkage, or the appearance of a new band due to the polymer. This method34 R. R. Brattain and 0. Beeck, J. Appl. Physics, 1942, 13, 699.36 D.H. Whiffen and H. W. Thompson, J., 1945, 268; Trans. Paraday SOC., 1945,s6 D. H. Whiffen, P. Torkington, and H. W. Thompson, ibid., p. 206; H. W.37 Ind. Eng. Chem. Anal., 1944, 16, 609.38 N. Wright, ref. (3).30 I. F. Trotter and IS. W. Thompson, Analyst, 1945, 70, 443.40 D. H. Whiffen, P. Torkington, and H. W. Thompson, Trans. Paraday SOC., 1945,*l G. B. B. M. Sutherland, ibid., p. 207.42 R. B. Barnes, U. Liddel, and V. Z. Williams, ref. (3).43 R. B. Barnes, V. Z. Williams, A. R. Davis, and P. Giesecke, I n d . Eng. Chem.41, 200.Thompson, ref. (27).41, 203.Anal., 1944, 16, 9THOMPSON : RECENT ADVANCES IN INFRA-RED SPECTROSCOPY. 15has been used in studying the polymerisation of styrene44 and in othersimilar reactions.Obviously, too, when some reaction is being followed bymeans of a single overall change of pressure, whilst in reality several processesare occurring simultaneously, the infra-red spectrum a t different stages ofthe reaction may be very informative, and its value in this connection maybe greatly enhanced if the cathode-ray tube recorder can be used to givea continuous picture of the reaction as it proceeds. It has hitherto beenusual to measure the spectra of samples taken from the reaction mixturea t successive stages of the reaction. For industrial production and for thecontrol of flow lines it would be more advantageous if the analysis couldbe made continuously and without the use of elaborate prism spectrometers,I ' I r - -I 0 I I I9 I IFIG.1. FIG. 2.or even without a dispersing system a t all. This can be done by filteringout from a beam of infra-red radiation some band which will include thekey wave-length for the substance being estimatedt5 and instruments havenow been devised for this purpose, applicable to the analysis of both gasesand liquids.Several alternative designs are possible, two of which are illustrated inFigs. 1 and 2. I n Pig. 1 N , and N , are two nichrome filaments which emitradiation through the test cell Q and through two separate tubes P and R,each of these chambers being provided with windows which transmit thewave-lengths desired. Effectively, two separate beams of radiation fall uponthe thermocouples T,,T, which can be arranged in some form of balanced44 R.B. Barnes, U. Liddel, and V. Z . Williams, ref. (3).4s A. H. Pfund, Science, 1939, 90, 326; A. H. Pfund and G. L. Gemmill, Bull.Johns Hopkins Hospital, 1940, 67, No. 1, 6116 GENERAL AND PHYSICAL CHEMZSTRY.circuit. If, for example, it is required to determine carbon dioxide in air,tube P is filled with pure carbon dioxide, R being empty. When Q is empty,the gas in P will absorb the band of carbon dioxide at 4.25 p completely,and the thermocouple circuit will now need to be rebalanced. When thetest sample containing carbon dioxide is now introduced into Q, energy willbe removed from the beam R, but owing to the already complete extinctionin P this beam will suffer no change. Hence the balance will again bedisturbed and the extent of the disturbance will give a measure of thecontent of carbon dioxide in Q.This arrangement can be improved andmade more selective by the use of filters, and bolometers can replace thethermocouples if desired. An instrument of this kind has been used byN. Wright and L. W. Herscher 4s for the analysis of streams of styrenewith ethylbenzene, or butadiene with butene.Two beams of radiationfrom the heaters N,, N2 pass through the cells A and B and fall uponchambers C , and C,, which are separated by a membrane condenser acrosswhich a direct-current voltage is applied. Cell A is maintained empty andB is for the test sample. The gas to be determined is first introduced atequal concentrations into C , and C2. Radiation will therefore be absorbedby these cells equally.If the gas to be determined now enters B, chamberC, will become less heated, and if the beams are chopped alternately by arotating shutter X , a fluctuating voltage will be supplied from the condenser,and this voltage can be increased by a tuned amplifier sufficiently to operatea recorder. The presence of other contaminants in B will not affect thedetermination of the gas in C , and C2 unless their absorption bands overlapthose of the gas being determined, since the bands of the contaminants wouldnot be absorbed by the gas in C, in any case. When overlapping of bandsdue to many components arises, it can be mitigated and the selectivity ofthe whole arrangement increased by inserting additional filters. Theoptimum conditions of working for this instrument depend upon a numberof factors which have to be carefully considered, but it promises to be verywidely used in the continuous control of gas streams.A somewhat simplerform of infra-red analyser has been described by D. J. Mead and R. M.FUOSS,~~ and used for the analysis of mixtures of liquids.The use of infra-red spectra for structural diagnosis49 is based uponslightly different principles from those used in analysis. As alreadyexplained, the magnitudes of the vibration frequencies of a molecule aredetermined by the nuclear masses and force constants, and are in realitya characteristic set for the particular molecule considered. Some of thevibrations, however, are effectively controlled by motions of atoms formingone particular link or group, and in such cases the frequencies may persistalmost unchanged in different molecules in which the group is present.A second form of detector 47 is used in Fig.2.46 J. Opt. SOC., 1946, 36, 195.48 Rev. Sci. Instr., 1945, 16, 53.49 H. W. Thompson, J., 1944, 183; R. B. Barnes, R. C. Gore, U. Liddel, and V. Z.4 7 K. F. Luft, 2. techn. Physik, 1943, 24, 97.Willianu, “ Infra-red Spectroscopes,” Rheinhold, 1944THOMPSON : RECENT ADVANCES IN INFRA-RED SPECTROSCOPY. 17With linkages involving hydrogen where the light atom oscillates against amuch heavier residue, it is not surprising that the mass of this residuehardly affects the vibration frequency, and bands characteristic of thestretching of C-H, 0-H, N-H, S-H links are well defined.Other linkagessuch as CIC, (3x0, or CZN also show fairly characteristic absorption bands,and it now seems that some larger groups of atoms forming a structuralunit may give rise to a set of frequencies which persist through series ofrelated molecules. I n order that such rules for structural correlation canbe built up, it will be necessary to measure the spectra of a large numberof compounds chosen in the first instance in related series, and much surveywork of this kind has been begun. Thus, the spectra of esters and ketones 50reveal a number of bands which can be correlated with the CH,.CO or othergroupings, and olefins of the type CR1R2:CHR, show bands in the regionof 10 which vary in position according to whether the radicals are hydrogenatoms or alkyl groups.51 The latter result can be applied to study the typesof unsaturated compound formed in the cracking of hydrocarbons. Insome cases the small variations in frequency of a particular link or groupin different molecules are determined by the other groups to which the maingroup is attached.For example, the stretching vibration band of thecarbonyl group gives rise to a band near 6 p, but its exact position dependson whether the group is present as a ketone, aldehyde, carboxylate ion, oramide, and upon the nature of the neighbouring radicals, saturated orunsaturated alkyl groups or aryl radicals.52 J. J. Fox and A. E. Martin 53have also shown how the frequencies of C-H bonds depend upon theparticular grouping in which they occur.If more examples can be foundof such electronic influences, the correlations should be extremely valuablenot only in the determination of the molecular structure of organic molecules,but also in leading to a fuller understanding of the electronic nature of thelinkages concerned.Many of the diagnostic rules have been applied to current problems inindustrial research laboratories and remain unpublished. A typical case ofan unknown impurity in a sample of adiponitrile has been quoted,S4 wherea small amount of the contaminant was diagnosed and then extracted.The method has been much used for studying macro-molecules of all kinds.556o H. W. Thompson and P. Torkington, J., 1945, 640; J. Lecomte, J . Physique,1945, 5, 1; J .Phys. Radium, 1942, 8, 196.51 M. Tuot, J. Lecomte, and S. Lorillard, Compt. rend., 1940, 211, 586; H. W.Thompson, J., 1944, 183; P. Torkington and H. W. Thompson, Proc. Roy. Xoc., 1945,A , 184, 3.52 Unpublished work of several laboratories. See also a series of papers byJ. Lecomte, Compt. rend., 1941-1945, and Bull. SOC. chirn., 1942-1944.63 Proc. Roy. SOC., 1938, A , 167, 257; 1940, A , 175, 208.64 H. W. Thompson, ref. (27).6 6 R. B. Barnes, U. Liddel, and V. Z. Williams, Ind. Eng. Chem. Anal., 1943, 15,83; W. C . Sears, J. Appl. Physics, 1941,12, 35; A. J. Wells, ibid., 1940,11, 137; H. W.Thompson and P. Torkington, Proc. Roy. SOC., 1945, A , 184, 3, 21; Trans. FaradaySoc., 1945, 41, 246; H. W. Thompson, “ Discussion on Macromolecules,’’ Chem.SOC.,to be published shortly18 GENERAL AND PHYSICAL CHEMISTRY.The spectra of hydrocarbons which were measured as reference data foranalytical work provided many correlation rules which can be used indealing with hydrocarbon-like structures such as polythene and rubber.The occurrence of methyl groups in polythene, first suggested by Fox andMartin,56 has now been confirmed by independent absorption bands.57The possibility of distinguishing spectroscopically between olefinic structuresof the types =CH:CH, and *CH:CH- makes it possible to estimate the extentto which a diene condenses with another olefin by either 1 : 2- or 1 : 4-addition. Thus when butadiene condenses to form " Buna," 1 : 4-additiongives a straight chainwhereas 1 : 2-addition will lead to pendent vinyl groups.The resultsconfirm that under different experimental conditions of polymerisationthe proportions vary. This criterion may also become useful in settlingthe old problem of the presence of isopropenyl and isopropylidene groupsin some terpene derivatives. Other hydrocarbon-type polymers which havebeen examined include polyisobutene, polystyrene, methyl rubber, hydro-rubber, and the interpolymers of butadiene with styrene and isoprene. Theeffect of stretching on the spectrum of rubber has been e~amined,~8 andpolarised infra-red radiation has been used to investigate oriented polymers.59Many other polymers and interpolymers of vinyl derivatives have beenstudied in the same way, including the acetate, acrylates, chloride, andcyanide, and differences in the spectra of many of the products can some-times be interpreted in terms of structural differences.Work with thephenolic resins has given some indications of the types of cross linkageprevalent in such products, and the preliminary results suggest that a moredetailed examination of the hydrogen-bonding relationships by means of thebands near 3 p would be profitable.60 Cellulose ethers and esters have alsobeen examined. It is possible to determine the content of the individualacyl groups in cellulose esters, but most of the results on cellulose deriva.tivesstill await the compilation of more reference data before they can be fullyinterpreted. Other substances which have been measured include poly-esters, poly-amides, and silicon polymers. The spectra of some amino-acidshave been measured by N.Wright,61 and of some proteins by A. M. Ruswelland R. C. Gore.62 It seems likely that processes such as the denaturationof proteins may be followed by spectral changes, and the structural alter-ations may thereby in some measure be inferred.Attempts have also been made to follow the changes brought about bythe special treatment of macro-molecules , such as vulcanisation or plastic-66 Proc. Roy. Soc.. 1940, A , 175, 208.67 H. W. Thompson and P. Torkington, ref. (55).68 D. Williams and B. Pale, J. Appl. Physics, 1944, 15, 585.69 H. W. Thompson and P. Torkington, ref. (55).60 R. E. Richards, unpublished work.J. Biol. Chem., 1939, 127, 137.62 J . Physical Chem., 1942, 46, 575THOMPSON : RECENT ADVANCES IN INFRA-RED SPECTROSCOPY. 19isation. Vulcanisation by sulphur and other reagents,G3 and by sulphurchloride,64 brings about spectral changes, and efforts have been made tocorrelate them with the formation of C-S or S-S bonds, or with otherstructural changes. Similarly, the oxidation of rubber and of polythenehas been studied; polar groups such as C O can be detected and estimatedin hydrocarbon residua, even though present in very small amount.65 I nall these cases, however, the background of reference data is insufficient.The spectra of samples of coal 66 and of coal extracts show special featuresof interest, and some promising deductions have been made about thepresence of key groups.The infra-red spectra of dyes and paints G7 havebeen discussed. General accounts of other applications have been publishedby J. Lecomte.68The other recent work in this field can only be reviewed briefly. Anumber of papers have extended spectroscopic theory and our generalunderstanding of the vibrational and rotational levels of molecules. D. M.Dennison's earlier review of this subject 69 has been followed by a secondpart.70 The interaction of vibrational and rotational energy has beenconsidered by several authors,71 and a striking experimental verification ofsome earlier' predictions by Nielsen has been found in two vibration bandsof allene.72 The normal vibrations of molecules with internal torsion havebeen examined by B. L.Crawford and E. B. Wilson,73 and in a generalarticle J. Duchesne 74 has reviewed critically the potential energy functionsof molecules. A. G. Meister, F. F. Cleveland, and M. J. Murray 75 havetabulated the selection rules in the infra-red and Raman spectra for vibrationsof molecules belonging t o different symmetry groups. J. W. Linnett 76 hasdiscussed the force constants of various kinds of bond.Attempts to analyse the spectra of molecules with a view to assign thevibrational frequencies or to obtain moments of inertia have been carriedout in more cases, including nitr~rnethane,~~ nitrodeuteromethane,78N. Shepperd and G. B. B. M. Sutherland, Trans. Faraday SOC., 1945, 41, 261.64 P. Torkington and H. W. Thompson, ibid., p. 276.6 5 H.W. Thompson, ref. (55).G6 C. G. Cannon and G. B. B. M. Sutherland, ibid., p. 279.67 J. Stearus, Amer. Dyestufls Rep., 1944, 33, 1, 16.6 8 Cours. Confer. Paris, Centre Perf. Tech., Non. 1943; Bull. SOC. Franp. Electr.,6B Rev. Mod. Physics, 1931, 3, 280.70 Ibid., 1940, 12, 175.7l H. H. Nielsen, Physical Rev., 1940, 62, 151, 161; J . Chem. Physics, 1941, 9,847 ; 1943,11, 160; TV. H. Shaffer, Rev. Mod. Physics, 1944,16,245; J. Chem. Physics,1848, 10, 1 ; 1944, 12, 504; W. H. Shaffer and R. C. Herman, ibid., 1945, 12, 83;W. H. Shaffer and W. Silver, ibid., 1941, 9, 599, 607; 1940, 8, 919; W. Silver, ibid.,10, 559, 565.1942, 2, 1 ; Bull. SOC. Philomath., Paris, 1942, 124, 68.7 2 H. W. Thompson and G. P. Harris, Trans. Faraday SOC., 1944, 40, 295.73 J.Chem. Physics, 1941, 9, 323.7 6 Amer. J. Physics, 1943, 11, 239.7 7 A. J. Wells and E. B. Wilson, J . Chem. Physics, 1941, 9, 314.7 8 T. P. Wilson, ibid., 1943, 11, 361.74 Mem. SOC. Roy. LiZge, 1943, 1, 429.7g Trans. Faraduy Xoc., 1945, 41, 22320 GENERBL AND PHYSICAL CHEMISTRY.p r ~ p y l e n e , ~ ~ propaneY8O methylamine,81 acetaldehyde, and deuteroacet-aldehyde, 82 cyczohexane, 83 pyridine, 84 cyclobutane, butadiene, 86 furan,87and thiophen.88 A very important analysis has been made by W. S.Gallaway and E. F. Barker 89 of the spectra of ethylene and tetradeutero-ethylene, which claims to fix the carbon-carbon bond length in thesemolecules with high precision. There is still some doubt, however, aboutthe correctness of their vibrational assignments. A comparison of thespectra of the vinyl halides and vinyl cyanide has led to a very satisfactoryvibrational assignment for these molecules.g0 The rotational contour ofsome bands of the fluoroethylenes has also been measured,gl and the changesin some of the vibration frequencies of these molecules resulting from theintroduction of fluorine atoms is particularly noteworthy.More papers havedealt with measurements on the hydrogen bond, but these must be reservedfor a future report. The effect of temperature upon the shapes of someabsorption bands of hydrocarbons has been examined by W. H. Avery andC. F. Ellis.92Although it is not intended to discuss the Raman spectra in this report,the account would not be complete without reference to the new rapidmethod of measuring Raman spectra using large spectrometers and photo-electric cells as detect0rs.~3 If this method of recording the spectra fulfilsits present promise, it may well open up a new chapter in the applicationof such measurements.H.W. T.2. FRICTION AND LUBRICATION.When there is relative motion between surfaces which are separated bya liquid layer of appreciable thickness, the resistance to motion is due tothe viscosity of the interposed layer. This type of lubrication, which occursin well-designed journal bearings, is essentially a problem in hydro-dynamics; the friction is very small and since the surfaces are completelyseparated by the lubricant film there is no wear of the moving parts. It79 E.B. Wilson and A. J. Wells, J . Chem. Physics, 1941, 9, 319.80 V. L. Wu and E. F. Barker, ibid., p. 487.81 R. G. Owens and E. F. Barker, ibid., 1940, 8, 229.82 J. C. Morris, ibid., 1943, 11, 230. 83 R. S. Rasmussen, ibid., p. 249.84 J. Turkevich and P. C. Stevenson, ibid., p. 328; 1944, 12, 300.S 5 T. P. Wilson, ibid., 1943, 11, 369.8 6 R. S. Rasmussen, D. D. Tunnicliff, and R. R. Brattain, ibid., p. 432.8 7 L. W. Pickett, ibid., 1942, 10, 660; H. W. Thompson and R. B. Temple, Trans.8 8 Idem, ibid. J . Chem. Physics, 1942, 10, 88.Qo P. Torkington and H. W. Thompson, J . , 1944, 597, 303; Trans. Paraday SOC.,1945, 41, 240; Proc. Roy. SOC., 1945, A , 184, 21.Q1 P. Torkington and H. W. Thompson, Trans. Paraday SOC., 1945, 41, 236.O2 J . Chem.Physics, 1942, 10, 10.O3 R. H. Rank, R. J. Pfister, and P. D. Coleman, J. Opt. SOC., 1942, 32, 390; R. H.Rank, R. J. Pfister, and J. Grimm, ibid., 1943, 33, 31; R. H. Rank, R. W. Scott, andM. R. Fenske, Ind. Eng. Chem. Anal., 1942,14, 816; R. F. Straum, ibid., 1945,17, 318.Faraday SOC., 1945, 41, 27BOWDEN AND TABOR : FRICTION AND LUBRICATION. 21is clear, however, that in many practical cases fluid lubrication is impossible.At the beginning and end of a reciprocating stroke and in many slidingmechanisms it is difficult to maintain a thick continuous film of lubricantand even in rotating parts the thick film may break down and only a surfacefilm of lubricant may remain. The friction in such cases is influenced bythe nature of the underlying surfaces as well as the chemical constitution ofthe lubricant, and (Sir) W.B. Hardy 1 referred to such a state as “ boundarylubrication.’’ I n practice, boundary lubrication is of great importance, andthe nature of the surface film will determine whether serious wear or seizurewill take place.Theory of Friction.Before we can form any picture of the nature of this thin-film lubric-ation it is necessary to know something of the origin of the frictional forcebetween clean unlubricated solids. It is a matter of considerable ex-perimental difficulty to prepare and to maintain metal and other surfaceswhich are quite free from oxide and other adsorbed films (see later), and,since most friction measurements have been carried out in air, the surfacesare necessarily contaminated in this way.The early view of Coulomb 2 thatthe frictional force between solids is due to the interlocking of surfaceasperities, so that the frictional work represents the work required to liftone surface irregularity or high spot over another, is still held by someworker^.^have postulated that friction is due to an interaction between the surfacefields of force of the two solids, so that the friction may be regarded as apurely surface effect due to the molecular attraction between the two solids.In recent years, our knowledge of the surface structure and surface con-tour of solids has advanced considerably. Instruments have been de-veloped 6 ~ 7 ~ 8 ~ 9 which amplify the movement of a tracer needle as it passesslowly over the surface.These instruments will record surface irregularitiesas small as 0.05-0-1 micron. Although they can be very useful in moretechnical applications, they do not reveal much of the fine cracks, pits, orsharp steps in the surface, since their sensitivity is limited by the diameterof the tracer point, which in general cannot be much less than 5p. How-ever, more sensitive physical methods have been introduced recently.R. D. Heidenreich and L. A. Mattheson,lo using the electron microscopestereoscopically, have shown that it can reveal surface irregularities whichare of the order of 0.015-3p. R. C . Williams and R. W. G. Wyckhoff l1On the other hand, Hardy,l G. A. Tomlinson,4 and B. Derjaguin“ Collected Works,” Cambridge University Press, 1936.Mem.Math. Phys. Acad. Roy. Sci., 1785, 161.E.g., J. J. Bikerman, Rev. Mod. Physics, 1944, 16, 53.Phil. Mag., 1929, 905.E. J. Abbot, S. Bousky, and D. E. Williamson, Mech. Eng., 1938, 60, 205.Anon., Engineering, 1941, 151, 356.See, e.g., the Talysurf Surface Finish Measuring Instrument, Messra. Taylor &Anon., Engineering, 1945, 159, 427.2. Physik, 1934, 8, 66.Hobson.lo J. Appl. Physics, 1944, 15, 423. l1 Ibid., p. 71222 GENERAL AND PHYSICAL CHEMISTRY.have sputtered thin metallic films on to surfaces from an oblique angle.Small isolated peaks 30 A. high cast a “shadow” which may then bedetected by the electron microscope, although the irregularity itself is notvisible. Improved optical interference methods have also been used.12) 13,143 15S.Tolansky 14 has introduced an important modification by silvering theoptical flat and half silvering the surface in order to get multiple reflectionof the incident light. The fringes are then extremely sharp and a t highmagnification can reveal differences in height of less than 40 A. and changesof face angle as small as 0.016 minute of arc. He used this method tostudy the cleavage surface of mica and showed that small steps were present,the heights of which were integral values of the molecular length (20a.).The (100) face of a natural quartz crystal also showed minute steps of afew molecules in height (100 A. high). Similar measurements have beenmade of the detailed topography of a diamond crystal surface.16The effectiveness of the ordinary optical microscope for the study ofsurface contour can also be considerably increased by protecting the surfaceirregularities with an electrodeposit and cutting a taper section at a veryoblique angle on the surface.17 Irregularities as small as 0 .1 ~ can bedetected in this technique, which also has the advantage of revealing thestructure of the solid immediately below the surface. Electron-diffractionmethods 18,19 also give valuable information about the structure of thesurface films and surface layers of solids. It is evident that metal surfaceswhich have been prepared by the usual methods will be covered with avisible oxide film up to 100 A. thick 2 0 , 2 1 9 2 2 and a layer of altered metal.H. C. V a ~ h e r , ~ ~ using X-ray back reflection methods, has shown that thedeformed layer on steel, polished in the usual metallographic way, is 2pthick, while copper finished on a fine emery paper showed a deformed layer20p thick.It is clear that the metal surfaces normally employed both in practiceand in laboratory experiments on friction will normally be very complexand will consist of (a) surface irregularities which are very large comparedwith molecular dimensions, ( b ) an oxide film, and (c) an altered layer inthe metal itself.When two such surfaces are placed together, they will besupported on the summits of the surface irregularities, and the real areaof contact, i.e., the area over which the surfaces are within molecular range,12 T. P. Hoare and B.Chalmers, Tin Res. and Dev. Council, Pubn. A21, 1935.13 J. F. Kayser, Met. Treatment, 1943, 10, 153.1 4 Proc. Roy. SOC., 1945, A , 184, 41.l8 S. Tolansky, Nature, 1946, 157, 5831 7 H. R. Nelson, Conf. Friction and Surface Finish, MIT., 1940, 217.l5 C . Timms, J . Sci. Instr., 1945, 22, 245.G. P. Thomson and W. Cochrane, “Theory and Practice of Electron Diffraction,”l9 B. Chalmers and A. G. Quarrel, “ Physical Examination of Metals,” Arnold, 1941*O W. H. J. Vernon, F. Wormwell, and T. J. Nurse, J., 1939, 621.21 W. E. Campbell and U. B. Thomas, Trans. Amer. Electrochem. SOC., 1939, 76, 303.22 U. R. Evans, “ Metallic Corrosion, Passivity and Protection,” Arnold, 1937.23 J. Res. Nut. Bur. Stand., 1942, 29, 1’77.London, 1939.[see also refs.(94)-(102)]BOWDEN AND TABOR : FRICTION AND LUBRICATION. 23will be small. This means that, even with comparatively lightly loadedsurfaces, the local pressure a t the region of contact will be high and mayeasily exceed the yield point of the metal or other solid so that plastic flowand deformation occurs a t the point of contact. Measurements of theelectrical conductivity z4, 25 between metals in contact support this viewand show that the area of intimate contact is indeed very small, is com-paratively little influenced by the size of the surfaces, and is determinedmainly by the applied load and the yield point of the metal. Apparently,the summits of the irregularities on which the solids are supported flowplastically, and are crushed down until their cross section is sufficient t oenable them to support the applied load.Beyond this region of intensepressure there will be local elastic deformation of the solids. Except underthe lightest loads, there will be partial breakdown of the surface films andtrue metal to metal contact occurs; this is particularly true if there issome slight movement as if the surfaces are sliding. According to the viewsof Bowden and his co-workers, this local adhesion and pressure welding ofthe surfaces a t the points of contact plays a major part in the friction ofmetals and many other solids. The frictional resistance is due primarilyto the shearing of these metallic junctions and to the work of dragging orploughing the surface irregularities of the harder metal through the softerone.26 Examination of the surfaces after sliding 26$ 273 28 shows that they aretorn and distorted to a depth which is very great compared with moleculardimensions, so that friction cannot be regarded as a purely surface effect.The bulk properties of the solids, such as their relative hardness and, athigh sliding speeds, their relative melting point or softening point, play animportant part.The physical processes occurring during sliding areobviously complex, but as an approximation the frictional force F maybe written F = 8 + P , where S is the shearing term and P the ploughingterm. I n general, it follows that S = As, where A is the real area ofcontact and s the shear strength of the metal; and P = A’p where A‘ isthe cross sectional area of the torn track and p the pressure necessary tocause plastic flow of the metal.Experiments with sliders of different shapesand hardness 26p28,29 show that P is usually small compared with S, andunder the conditions where it can be neglected P = As. The real area ofcontact A is determined primarily by the load W , and W = p A . HenceP = Ws/p, and the coeficient of friction p = P/W = s / p = shear strength/flow pressure.A somewhat similar expression which includes a term for surface rough-ness has also been derived by H. Ernst and M. E. Merchant 30 and applied24 R. Holm, Wiss. Verofl. Siemens-Konz., 1929, 7 (2), 217; 1931, 10, (4), 1; “Dietechnische Physik der elektrischen Kontakte,” Springer, 1941.2s F. P.Bowden and D. Tabor, Proc. Roy. SOC., 1939, A, 169, 391.26 F. P. Bowden, A. J. W. Moore, and D. Tabor, J. Appl. Physics, 1943, 14, 80.27 F. P. Bowden and A. J. W. Moore, Nature, 1945, 155, 451.28 F. P. Bowden, Proc. Roy. SOC. N.S.W., 1945, 78, 187 (Liversidge Lectures).29 F. P. Bowden and D. Tabor, Nature, 1942, 150, 197.30 Conf. Friction and Surface Finish, MIT., 1940, 7624 GENERAL AND PHYSICAL CHEMISTRY.to the cutting of metals.31 The nature and distribution of the small weldedjunctions which are formed and broken during sliding have been deter-mined by Bowden, Moore, and Tabor,Z6 using the taper section technique.When copper is slid on clean steel, small particles are detached and adherestrongly to the steel surface. The shearing usually occurs in the copper,but the strength of the bond is such that occasionally the steel itself isdragged up above the general surface level, or plucked out altogether.Thisis a clear example of a hard metal being worn away by a softer one. Thereis also a marked deformation and hardworking of the metal to a considerabledepth beneath the torn surface. More recent work27 using the methodof electrographic surface analysis 32933 has shown that this localised metallicadhesion occurs even with lubricated surfaces. Experiments with a copperslider passing once over lubricated platinum, for example, have shown thatthe amount of copper adhering to the platinum surface may be cu. g.per mm.2 of track. The copper is not spread uniformly, but is distributedas a number of small discrete particles where local adhesion has occurred ;this is most pronounced on the high spots of the surfaces.If the surfacesare unlubricated, the amount of metallic pick up under similar conditionsmay be greater by a factor of 100 or more. If one of the surfaces is naturallyor artificially radioactive, it provides a very sensitive method for detectingpick up. Sackman, Burwell, and Irvine3* have used curved sliders ofcopper-beryllium alloy and of steel on a radioactive copper-beryllium alloyand have shown by Geiger counter methods that adhesion occurred on theslider under clean and lubricated conditions. This method can be used todetect quantities as small as 10-5 microg. J. N. Gregory,35 using radioactivelead and a photographic technique, has also shown that localised metallicadhesion and welding occurs through the lubricant film.This localisedwelding occurs a t very low sliding speeds where the temperature rise isnegligibly small. It is a " cold " welding brought about by the high localpressure a t the point of contact; at greater speeds and loads, however, thefrictional heat may raise the local surface temperature to a high value, sothat a softening or even a melting may occur a t the points of contact.The occurrence of these high temperatures may be demonstrated bymeasuring the thermal e.m.f. developed between rubbing surfaces of dis-similar metals.36 Earlier work has shown 37,38 that extremely high localtemperatures may readily be reached between metal surfaces undermoderate conditions of load and speed,39 even in the presence of lubricantfilms. When the surfaces are non-conducting, this method is no longer31 M.E. Merchant, J. Appl. Physics, 1945, 16, 267, 318.32 D. L. Masters, Metallurgia, 1943, 29, 101.33 M. S. Hunter, J. R. Churchill, and R. B. Mears, Met. Prog., 1942, 42, 1070.34 B. W. Sackman, J. T. Burwell, and J. W. Irvine, J . Appl. Physics, 1944,15,459.35 Nature, 1946, 157, 443.36 E. G. Herbert, Proc. Inst. Mech. Eng., 1926, 2, 289.37 F. P. Bowden and K. E. W. Ridler, Proc. Roy. SOC., 1936, A , 154, 640.38 T. U. Matthew, J . Roy. Tech. Coll. Qlasgow, 1940, 4, 360.30 H. Blok, Inst. Mech. Eng., Discussion on Lubrication, 1937, 2, 14BOWDEN AND TABOR : FRICTION AND LUBRICATION. 25applicable, but it is clear that for such surfaces, under any given loadand speed, the temperature rise will be higher than for conducting surfaces.If one of the surfaces is transparent, the incidence of high surface temper-atures may be directly observed by visual or photographic Ifpolished surfaces of glass or quartz are used, and the apparatus is so arrangedthat a clear image of the rubbing surfaces can be seen, it is found that anumber of tiny stars of light appear a t the interface between the rubbingsurfaces.These correspond to local hot spots, and experiments suggestthat the temperature at which they first become visible to the eye, asreddish stars, is about 500". They may be observed with metals sliding onglass, when the speed is as low as one or two feet per second.At higherloads or speeds, the points of light become whiter and brighter, correspondingto an increase in the temperature of the hot spots. It is clear that thesehigh local temperatures may greatly facilitate the formation of weldedjunctions between sliding surfaces, and will play an important part inthe adhesion and frictional behaviour of the rubbing solids. The r81eof these high surface temperatures in the process of polishing has beende~cribed.~~Intimacy of Contact.-It is clear that if the frictional force is essentiallydue to the formation and shearing of metallic junctions it will depend onthe intimacy of contact between the metal surfaces. Under most experi-mental conditions, metal surfaces are covered with a thin oxide layer andother contaminating films.During sliding, these films are torn, and manyof the surface irregularities penetrate through them so that a certain amountof intimate metallic contact does occur. We should, however, expect thatif the surface contaminations are removed the intimacy of contact betweenthe surfaces will be increased with a corresponding increase in the friction.This effect will be more marked the more effectively the surface films areremoved. Mechanical and chemical methods are relatively ineffective,* andsurfaces cleaned by even the most stringent normal laboratory methodsrarely give a coefficient of friction above about p = 1. If the surfaces areheated in a vacuum, the surface films are partially destroyed and there isan increase in f r i ~ t i o n .~ ~ , ~ ~ Unless the contaminant film is completelydestroyed, however, the effect is not very marked and the results are variable.By using high-melting metals, F. P. Bowden and T. P. Hughes44 wereable to outgas the surfaces very thoroughly in a high vacuum a t temperatureswell over 1000". They found that the results so obtained were reproducible,and the coefficient of friction extremely high. For example, for outgassed40 F. P. Bowden, M. A. Stone, and G. K. Tudor, Proc. Roy. SOC. (in the press);F. P. Bowden and M. A. Stone, Experientia, 1946, 2, 186.*l F. P. Bowden and T. P. Hughes, ibid., 1937, A, 160, 575.42 W. Claypoole and D. B. Cook, J . Franklin Inst., 1942, 233, 453.43 J. M. Macaulay, J . Roy.Tech. Coll. Glasgow, 1935, 353.4 4 Proc. Roy. SOC., 1939, A, 1'42, 263.4 5 R. schnurmann, Proc. Physical Xoc., 1941, 53, 638.* See, however, the marked adhesion between platinum surfaces cleaned by chemicalmethods,42 and the adhesion of freshly cleaved mica.426 GENERAL AND PHYSICAL CHEMISTRY.nickel or tungsten p increased from about 0.3 to between 5 and 6. In asimilar way, the presence of contaminants or lubricant films reduces theintimacy of contact between the sliding surfaces, and so results in a decreasein the frictional force. A quantitative formulation of these factors hasrecently been given by Bowden and Tabor.29Intermittent Motion.-The friction between metal surfaces depends onthree main factors. The first is the intimacy of contact, which determinesthe extent to which the adhesion between the surfaces is truly metallic,as discussed above.The second is the flow-pressure p , which determinesthe area of real contact between the surfaces. The third is the shear strengthof the metals, which determines the strength of the metallic junctions formed.If any experimental variations arise which alter one or more of these factors,there will be a corresponding alteration in the frictional force. To a certainextent, therefore, the friction will depend on the experimental conditionsunder which it is measured. For example, a t extremely slow speeds ofsliding, these factors vary in such a way that the resultant strength of themetallic junctions formed is often higher than that occurring a t higherspeeds of sliding.This means that the static friction is often higher thanthe kinetic f r i ~ t i o n . ~ 6 ~ * ~ ~ ~ ~ ~ 49 If, therefore, one of the sliding surfaces has acertain degree of elastic freedom, the motion may not be continuous, butmay be intermittent and proceed by a process of " stick-slip ". The " stick "corresponds to the static friction between the surfaces, and the " slip " tothe lower kinetic friction during the slip itself. This type of motion clearlydepends on the mechanical properties of the system, such as the naturalfrequency, the moment of inertia, and the damping of the moving parts.50It will also be influenced by the 'velocity of the main forward motion andby the friction-speed characteristics of the surfaces under consideration.51Since many moving systems possess an appreciable degree of elastic freedom,and since the static friction is often higher than the kinetic friction formetal surfaces, this type of intermittent motion is of frequent occurrencein practice.Even when the moving parts are extremely rigid, the surfaceirregularities may be capable of microscopic elastic deformation of theorder of 10-5 cm, as S. Khaikin, L. Lissovsky, and A. Solomonovitch 52 haverecently shown, using quartz crystals to measure the minute displacementsinvolved. I n such cases, the elasticity of the surface irregularities them-selves may, in the limit, be sufficient to set up vibrations or intermittentmotion in the moving parts.A fourth factor which appears to have some influence on the friction46 F.Morgan, M. Muskat, and D. W. Reed, J. Appl. Physics, 1941, 12, 743; J. B.4 7 S. Khaikin, L. Lissovsky, and A. Solomonovich, J. Physics (U.X.S.R.), 1940, 2,4 8 J. R. Bristow, Nature, 1942, 149, 169.49 B. Chalmers, P. G . Forrester, and E. F. Phelps, ?roc. Roy. SOC. (in the press):60 F. P. Bowden, L. Leben, and D. Tabor, Engineer (London), 1939, 168, 214.51 H. Blok, J . SOC. Aut. Eng., 1940, 46, 54.62 J. Physics (U.S.S.R.), 1939, 1, 455.Sampson, F. Morgan, D. W. Reed, and M. Muskat, ibid., 1943, 14, 689.253BOWDEN AND TABOR : FRICTION AND LUBRICA!L’ION. 27of metal surfaces is the degree of surface fini~h.~395~9~5 Although this effectmay be explained in terms of Coulomb’s theory,3 it may also be explainedin terms of the variation of the ploughing and shearing terms produced bya change in the geometry of the rubbing surfaces.With unlubricated metal surfaces, the friction obeys Amontons’s lawsince a change in load W produces a corresponding change in the area ofreal contact A , where A = W / p .If we neglect the ploughing term andassume a mean value S for the shear strength of the junctions, the frictionalforce is given by F = AB = Wi/p, which is directly proportional to theload. Similarly, the friction of unlubricated metal surfaces is not markedlyaffected by temperat~re.3~3 447 45 The shear strength s decreases with temper-ature, but there is a corresponding increase in the area of contact as themetal softens. Since both B and p are strength properties of the metals,they vary in a similar way with temperature, so that the term B/p is notsensibly dependent on the temperature.If, however, the heating is carriedout in a vacuum and leads to a partial removal of adsorbed layers, the effectof temperature is more complicated and less reprodu~ible.~~9~~Metallic Film Lubrication and the Theory of Bearing Alloys.-A com-pletely different situation arises when two hard rubbing metal surfaces areseparated by a thin film of a softer metal such as indium, lead, or copper.56If the metallic film is plated on to a hard flat surface and the second surfaceconsists of a hard spherical slider, the area of contact is determined largelyby the thickness of the film and the geometry of the surfaces.The under-lying hard surfaces, which support the load, are deformed comparativelylittle, so that further increases in the load have relatively little influence onthe area of contact between the slider and the metallic film. This givesa small area of contact A which is almost independent of load. Providedthe metallic film remains intact, so that little or no metallic contact occursthrough it, the shearing occurs within the soft metallic film. This gives asmall value of i5, so that the frictional force which is given by F = As issmall and almost independent of the load.29 Experiments show, in fact, thatAmontons’s law does not hold, and that extremely low coefficients may beobtained a t the higher loads; with indium films on tool steel, for example,p may be as low as 0.02.If, however, very heavy loads are used, the filmbreaks down, contact occurs between the slider and the underlying metal,and the friction rises. With metallic films, the friction decreases steadilyas the temperature is raised, and reaches a minimum when incipient meltingbegins. This is because the area of contact remains essentially constant,whilst the shear strength of the metallic film steadily decreases. Oncemelting is complete, there is a rise in friction, which is greater if the moltenmetal fails to wet the underlying surface. Thin metallic film lubrication hasbeen used by Z. J. Attlee, J. T. Wilson, and J. C. Filmer 57 to lubricate the53 J. Pr6vost, Mdcanique, 1939, 23, 139.ti4 C. A. Congwer, Conf. Friction and Surface Finish, MIT., 1940, 239.56 J.T. Burwell, J. SOC. Aut. Eng., 1842, 50, 450.6 6 F. P. Bowden andD.Tabor, J . AppZ. Physics, 1943,14,141. 6 7 Ibid., 1940,11,61128 GENERAL AND PHYSICAL CHEMISTRY.steel ball bearings of a rotating-anode X-ray tube. Thin metallic films havealso been used successfully in deep-drawing operations 58 and it is possiblethat they will find increasing use as lubricants under extreme conditions.Earlier accounts of bearing alloys have suggested that an essentialcharacteristic of a bearing alloy is that it should possess a duplex structureconsisting of hard crystals embedded in a softer matrix.59 The function ofthe hard crystals is to resist wear, and that of the softer constituents topermit a more uniform distribution of the load, by allowing any of the hardcrystals that are heavily loaded to sink into the matrix. It is also suggestedthat the hollows worn in the softer material serve as reservoirs for thelubricating oi1.60 Although many successful bearing alloys do possess astructure of this type, recent investigations show that this picture of themechanism of bearing alloys is inadequate.First, even with bearings ofthis type (white-metal bearing alloys) experiments show 61 that the hardparticles are impressed into the surface of the alloy by the sliding processand the frictional and wear properties are determined essentially by thoseof the matrix material itself. Secondly, with many modern bearing alloysthe surface layer does not possess a duplex structure at all, but consists ofa single pure Thirdly, another very wide class of bearing alloys(copper-lead type) consists of a hard matrix (copper) in which numeroussmall particles of a soft phase (lead) are dispersed.In this case the hardcopper is the continuous phase and cannot “ sink ” into the lead, Invest-igations show 56 that in bearing alloys of this type a thin film of the softermetal is extruded by the sliding process and acts as a thin metallic-filmlubricant on the surface of the harder matrix.Non-metals.-Very little work has been carried out on the friction ofnon-metallic substances.(i) Crystalline solids. R. Hutchison 63 has investigated the friction ofcrystalline substances, such as sodium and potassium halides, sulphur,paraffin-wax, and quartz on like crystals and on metals.Similar work hasbeen done by E. Hut~hinson.~~ In general, the friction coefficient is in-dependent of load and speed, but with extremely soft materials such asparaffin-wax the behaviour is essentially like that of a liquid under shear,the friction increasing rapidly with speed of sliding. The frictional behavioiiris associated more with the physical characteristics of the solids than withtheir chemical structure. In nearly all cases when non-metallic crystalsslide on a clean metal surface, there is a small but definite deposit of crystalon the surface. However, with diamond on a hard metal, there is nopick-up and the friction is extremely small, about p = 0.05. Other measure-68 A. J.W. Moore and D. Tabor, C.S.I.R. (Australia), Lubricants and BearingsSect., 1943, Report A96.LD H. N. Bassett, “ Bearing MetaIs and Alloys,” Arnold, 1937.6o C. H. Desch, “ Metallography,” Longinans Green, 1937.61 D. Tabor, J . Appl. Physics, 1945, 16, 325.62 A. Bregman, Iron Age, 1942, 150 (7), 65; (€9, 41.63 Private communication, 1938.64 Thesis (Cambridge) 1946, “ Adsorption and Lubrication a t Crystal Surfaces.BOWDEN AND TABOR : FRICTION AND LUBRICATION. 29ments on the friction of diamonds, sapphires, and jewel pivots have beencarried out by W. Claypoole,65 G. F. Shotter,66 and V. S t ~ t t . ~ ~Hutchison has also extended the earlier work of F. P. Bowden andT. P. Hughes 68 on the frictional properties of ice surfaces. The latterworkers found that a t a few degrees below the melting point of ice thestatic friction is of the same order as for other solid bodies, whilst the kineticfriction is an order of magnitude lower.This effect was explained as beingdue to a surface melting of the ice by frictional heating. Hutchison hasobtained similar results for benzophenone, dinitrobenzene, and sodiumhyposulphite (dithionite). With benzophenone, p fell from 0.2 a t slowspeeds of sliding to 0.03 at high speeds. In confirmation of the earliertheory of surface melting, it was again found that the friction was increasedby (a) increasing the thermal conductivity of the sliding surface, ( b ) decreas-ing the bulk temperature of the rubbing bodies.Some interesting experiments on the frictional properties of freshlycleaved mica surfaces, and of the effect of surface-active materials on thefriction, have been described by B.Derjaguin and 17. Lazarev 69 and otherRussian workers.(ii) Non-crystalline solids. The main recent investigations on non-crystalline materials have been on glass and on rubber. G . W. Hammerand G. Martin 70 showed that in a vacuum the friction of glass is increased,and their observations are consistent with Hardy’s and P. E. Shaw andE. W. L. Leavey’s 71 earlier work, which showed that there .is markedadhesion and tearing of the glass surfaces. F. L. Roth, R. L. Driscoll, andW. L. Holt 72 have investigated the frictional properties of rubber onground steel and on plate-glass surfaces, They find that the static frictionis lower than the kinetic friction and that, in general, rougher surfaces givesmaller coefficients of friction than smooth surfaces.In general, the frictionof a rubber compound depends more on the nature of the rubber matrixthan on the compounding ingredients and fillers.The frictional properties of natural fibres are of interest tothe manufacturers of textiles. Recent measurements by a number ofworkers on the friction of wool fibres have shown that for dry wool thefriction against the scales is higher than in the direction of the scale~.~~9 749 75This “ directional friction ” effect has been used to explain the feltingproperties of woollen fabrics.76 E. H. Mercer and M. Lipson 77 have shown(iii) Fibres.6s Trans. Amer. SOC. Mech. Eng., 1936, 61, 323.6 6 Inst.Mech. Eng., Discussion on Lubrication, 1937, 2, 140.67 Ibid., p. 145.70 Science, 1939, 90, 179.72 J . Res. N a t . Bur. Stand., 1942, 28, 439.73 M. Lipson, Nature, 1945, 158, 268.76 C. S. Whewell, L. Rigelhaupt, and A. Selim, ibid., 1944, 154, 772.76 E. H. Mercer, ibid., 1945, 155, 573; see also J. B. Speakman and E. Stott,J . Textile Inst., 1931, 22, ~ 3 3 9 .77 Ibid., 1946, 157, 134.Proc. Roy. SOC., 1939, A , 172, 280.J . Physical Chem. (U.S.S.R.), 1934, 5, 416; Kolloid-Z., 1934, 69, 11.71 Phil. Mag., 1930, 10, 809.74 L. Bohm, ibid., 155, 54730 GENERAL AND PHYSICAL CHEMISTRY.that certain agents reduce the felting by reducing the difference betweenthe pro-scalar and anti-scalar coefficients of friction, and this effect has beenexplained as being due in some cases to a destruction of the overlappingratchet-like edges of the scales by the chemical agent usecl.78 The effectof pH on the frictional properties of fibres has been used by R.E. D. Clark 79to determine the end point in acid-alkali titrations.Tribo-electricity and its R61e in Friction.-It has long been known thatwhen solids are rubbed on one another electrical charges may be left onthe rubbing surfaces. The earlier work in this field was mainly concernedwith the practical application of this phenomenon to the production of highvoltages, and with the development of a theory that would explain theorigin of these tribo-electric charges. A good review of the work carriedout until 1936 on frictional electricity is given by W.HI. Ward.80pointed out many years ago, that the electricalcharges appearing at the surfaces of rubbing solids will make some contribu-tion to the frictional force observed. Recently, R. Schnurmann andE. Warlow-navies 81 have emphasised the importance of the electrostaticcomponent of sliding friction, particularly when the boundary layer hasdielectric properties, and they have explained the intermittent motion whichoccurs between sliding surfaces in terms of charging and discharging. Theseconclusions agree in part with those of P. E. Shaw and his co-workers, whohave made extensive measurements of electrostatic phenomena. In a paperwith Leavey in 1932, Shaw suggested 82 that tribo-electricity and frictionare two aspects of the same phenomenon; when two surfaces are separated,both take up an electrostatic charge, and when two surfaces slide over oneanother the frictional work is expended in overcoming the electrostaticattraction and in deforming the surface structure, Few workers in thefield, however, believe that the tribo-electric charges can play an appreciablepart in the mechanism of metallic friction, though they may play a largepart in the friction of non-metallic materials.It is clear, as HardyLubricated Surfaces.A systematic investigation of boundary lubrication was first undertakenby Hardy,l who measured the static friction between surfaces, using homo-logous series of paraffins, fatty acids, and alcohols as lubricants.He foundthat the coefficient of friction depended on the nature of the underlyingsurface, but that in all cases it decreased linearly with the chain length ofeach family of compounds.This led to the theory that friction is due tothe surface fields of force and that the effectiveness of a lubricant in reducingthe friction is determined by the extent to which the lubricant film canmask the fields of force of the underlying surfaces.7 8 E. H. Mercer and A. L. G. Rees, Nature, 1946, 157, 589.7e J . SOC. Chem. Ind., 1940, 59, 216.81 Proc. Physical SOC., 1942, 54, 14.82 P. E. Shaw, Phil. Mag., 1930, 9, 628; with C. S. Jex, Proc. Roy. SOC., 1926, A,111, 339; 1928, A , 118, 97, 108; with E. W. L. Leavey, ibid., 1932, A , 138, 502.Rep. Prog. Physics, 1937, 247BOWDEN AND TABOR : FRICTION AND LUBRICATION.31Later workers on static friction ha,ve not fully confirmed these r e s ~ l t s . ~ ~ Measurements of the kinetic friction also show that, although the frictiondecreases with chain length, the reduction is not linear 85786 and the frictioncoefficient reaches a steady low value of about 0.1. In particular, carefulmeasurements by electrographic 27 and radioactive methods 34935 show thateven with the best boundary lubricants the surfaces are torn to a depthwhich is large compared to the dimensions of a molecule, and there is acertain amount of metallic transfer through the lubricant film. It wouldseem that, as for unlubricnted surfaces, the friction cannot be regardedentirely as a surface effect, but must also be dependent upon the bulkproperties of the solids.Film Thickness and Structure.-I.Langmuir 87 was the first to show thata monolayer of a fatty acid deposited from the Langrnuir trough is sufficientto redlzce the friction of glass surfaces from about p = 1.0 for clean glassto about p = 0.1. Numerous workers have confirmed the importance ofthe first monolayer in reducing the friction. In particular, mention may bemade of the recent work of B. V. Derjaguin,88 E. N. Dacus, E. F. Coleman,and L. C. R o ~ s s , ~ ~ T. P. Hughes and G. WhittinghamYgo J. J. F r e ~ i n g , ~ ~T. I s e m ~ r a , ~ ~ and F. P. Bowden, J. N. Gregory, and D. Tabor.93 Isemurafound a slight decrease in friction with increasing film thickness. On theother hand, Bowden and Leben,86 working on built-up layers of stearic acidvarying from 1 to 53 molecular layers, found that a monolayer of stearicacid on steel produced the same low coefficient of friction as a multilayer53 molecules thick.However, the single film was soon worn away, and,for effective lubrication capable of withstanding considerable wear, it wasfound necessary to have present a layer of lubricant several molecules thickin order to replenish the surface with fresh lubricant. Recently Derjaguin 88and Dacus, Coleman, and Roess B9 have described apparatus for investigatingthe " life " of thin lubricant films. With some metals, particularly the noblemetals, a monolayer of fatty acid is insufficient to provide adequate lubric-ation, and for platinum, for example, a stearic acid film must be at least7 molecules thick to produce a low coefficient of friction.These frictional measurements have been co-ordinated with a study ofthe structure of thin lubricant films on solid surfaces.Using electron-diffraction techniques, C. A. M u r i ~ o n , ~ ~ L. T. A n d r e ~ s , ~ ~ and 0. Beeck, J. W.Givens, and A. E. Smith 96 have found that those lubricants which are most83 J. Sameshima, H. Akamatu, T. Isemura et al., '' Studies in the Oiliness of Liquids,"Bull. Chem. SOC. Japan, 1936-39 (10 papers) ; J. Sameshima et al., Rev. Physical Chem.Japan, 1940, 14, 55.A. Fogg, Proc. Physical SOC., 1940, 52, 239.8 5 W. G. Beam and F. P. Bowden, Phil. Trans., 1935, A , 234, 329.8 6 F. P. Bowden and L.Leben, ibid., 1940, A , 239, 1.8 7 Trans. Faraday Soc., 1920, 15, 62.89 J. Appl. Physics, 1944, 15, 813.91 Proc. Rog. SOC., 1942, A , 181, 23.93 Nature, 1945, 156, 97.96 Trans. Faraduy SOC., 1936, 32, 607.8 8 See Chem. Abs., 1942, 7280'.92 Bull. Chem. SOC. Japan, 1940, 15, 467.g4 Phil. Mag., 1934, 17, 201.s6 Proc. Roy. SOC., 1940, A, 177, 90.Trans. Faraday SOC., 1942, 38, 932 GENERAL AND PHYSICAL CHEMISTRY.completely oriented on the solid surface are also those which have the bestlubricating properties. Similar investigations on the structure of surfacefilms of fatty acids, alcohols, soaps, graphitic deposits, etc., by L. H. Germer,97J. J. Trillat, and H. M o ~ z , ~ ~ E. Havings and J. de Wae1,99 R. 0. Jenkins,loOK. Tanaka,lol and G .I. Finchlo2 have tended to agree with these con-clusions. Interesting studies of a similar nature using X-rays have also beendescribed by G. L. Clark, R. R. Sterrett, and B. H. Lincoln.103 However,it would seem that in some cases the degree of orientation of the lubricantfilm bears little relation to its intrinsic lubricating properties.104The friction between metal surfaces may be profoundly modified andgreatly reduced by the presence of thin films of adsorbed vapours 443105 aswell as by liquid and solid lubricant films. In some cases, a similar effectmay be produced by adsorbed layers of gases, and this observation hasformed the basis of a number of interesting experiments on the effect ofinterfacial potential on the friction of metal surfaces in solutions of electro-1ytes.lo63 log Later work has shown that these effects correspond tothe stages a t which adsorbed gaseous layers of hydrogen and oxygen areformed a t the surfaces.For example, G. C. Barker 1 1 O has found anapproximately linear relation between the amount of hydrogen and oxygenadsorbed a t a platinum surface and the coefficient of friction, oxygen beingmore effective than hydrogen in reducing the friction. Similar, though morecomplicated, effects have been observed between metals and non-metallicThe effect of surface films on the friction of metal surfaces has an interest-ing parallel in the work of Fkhbinder and his associates on the reductionof the strength properties of solids by surface-active materials.I n earliers~~fa~s~111,112,113,114,115Q7 J . Appl. Physics, 1938, 9, 143 ; L. H. Germer and K. U. Storks, Proc. Nat. Acad.,Q8 Cornpt. rend., 1935, 200, 1299.QQ Rec. Trav. chim., 1937, 56, 375; Chem. Weekblad, 1937, 34, 694.loo Phil. Mag., 1934, 17, 457.lol Mem. Coll. Sci. Kyoto, 1938, A , 21, 85; 1939, A 22, 377.lo2 Trans. Faraduy SOC., 1935, 31, 1051.lo3 Ind. Eng. Chem., 1936, 28, 1318.lo4 D. Tabor, Dissertation, Cambridge 1939, “ The Area of Contact between Station-lo5 H. Donandt, Reib. u. Verschleiss, 1939 (see Chem. Abs., 1942, 34664).loG T. A. Edison, “Handbook of Electrical Telegraphy,” 1874, I, 474.lo7 K. R. Koch, Ann. Physik, 1879, 7 , 92.lo* M. Krouchkoll, Cornpt. rend., 1882, 95, 177; Ann. Chim. Phys., 1889, 17,lo9 K. Waitz, Ann.Physik, 1883, 20, 285.110 Private communication, 1939.ll1 W. Barrett, Nature, 1880, 21, 483.112 A. Johnsen and K. Rahbek, 2. techn. Physik, 1921, 2, 11; J . Inet. Elect. Eng.,113 K. Rottgardt, 2. techn. Physik, 1923, 4, 1.114 J. Waszik, ibid., 1924, 5, 29.1937, 23, ,390; J . Chem. Physics, 1938, 6, 280; Physical Rev., 1939, 55, 648.ary and Moving Surfaces.’’182.1923, 61, 713.H. M. Barlow, J . Inst. Elect. Eng., 1924, 62, 133BOWDEN AND TABOR : FRICTION AND LUBRICATION. 33papers 116,117 he found that the yield value of metal wires is markedlyreduced by solutions of surface-active materials such as alcohols or fattyacids, for both polycrystalline and single crystal specimens. A similarreduction of Young’s modulus was observed in the elastic deformation ofmica sheets.118 Recently Rehbinder has determined the variation of surfacehardness of pyrites, immersed in sodium chloride solutions, when a varyingpotential is applied between the specimen and the s o l ~ t i o n .~ l ~ In theseexperiments a relation very similar.to the variation of the surface tensionof a mercury-electrode interface with potential was found. These effects areattributed to a penetration by the surface-active materials into the micro-cracks produced on the surface of the solid specimen by deformation, givingrise to a “ wedging pressure ” analogous to that observed earlier l2O9 121 forthin liquid layers between solid surfaces. This explanation is confirmed bythe fact that with metals the decrease in strength-properties is accompaniedby a marked decrease in electrical condu~tivity.1~~ Although the explanationis not quantitative, it is clear that these effects have a significant bearingon the friction of lubricated surfaces.Effect of Speed.-The earlier work of Beare and Bowden 85 on the kinetiofriction of lubricated surfaces showed that pk was sensibly constant over arange of speeds from 60 to 600 cm./sec., and T.Sasaki 122 finds pk independentof sliding speeds up to 100 cm./sec. More recently, Beeck, Givens, andSmiths6 have found that for low speeds the friction is independent of thesliding speed, but that with lubricants containing polar compounds thereis a marked decrease in friction a t a certain critical velocity. This wasattributed to the action of the polar molecules in drawing in a “ wedge ”of oil between the surfaces, and so producing quasi-hydrodynamic lubrication.The effect may also be explained in terms of the formation of a viscous filmof metallic soap formed by chemical reaction between the polar bodies andthe metal surface.93In some cases, the static friction is higher than the kinetic, underconditions of boundary lubrication (see Muskat et ~ 1 .~ ~ ) . Here, if therecording system has an appreciable degree of elastic freedom, the motionwill be intermittent. With “ good ” boundary lubrication this is notgeneral, and usually the friction is low and the motion is smooth.Effect of Temperature.-The effect of temperature on the lubricatingproperties of boundary lubricants is of general interest and importance. Inmany parts of an engine high temperatures may be reached in the runningparts, and it is necessary to know the way in which this will affect the116 P.Rehbinder and E. Wenstrom, Bull. Acad. Sci. U.R.S.S., Sdr. phys., 1937,4, 531.117 P. Rehbinder, V. I. Lichtman and V. M. Maslennikov, Compt. rend. Acad. Sci.U.R.S.S., 1941, 32, 125.11* P. Rehbinder and G. Logghinov, ibid., 30, 491.ll9 P. Rehbinder and E. Wenstrom, Acta Physicochim. U.R.S.S., 1944, 19, 36.120 B. Derjaguin and E. Obuchow, ibid., 1936, 5, 1.lZ1 B. Derjaguin and M. Kussakov, Bull. Acad. Sci. U.R.S.S., S h . chim., 1936,5, 741.122 Bull. Chem. SOC. Japan, 1938, 13, 134.REP.-VOL. XLII. 34 GENERAL AND PHYSICAL CHEMISTRY.lubricant.For small temperature variations a t room temperature, there ispractically no change in the f r i ~ t i 0 n . q ~ ~ ~ At temperatures up to loo", &I.Briault 124 and F. Charron 125 found an increase in friction with temperaturein some cases, but not in others. D. Tabor 126 pointed out in 1940 thatin general there is a well-defined transition temperature (specific to eachlubricant) at which the lubricant breaks down with a corresponding increasein friction and wear. Provided the heating has not been sufficient to causeappreciable oxidation of the lubricant, these changes are reversible oncooling, and the transition temperature T was considered to correspond toa disorientation or desorption of the adsorbed film of lubricant on thesurfaces.For pure paraffins and alcohols, the transition is sharp and well defined,and occurs at the bulk melting point of the compound.86 For fatty acids,the transition temperature depends on the load, speed, and experimentalconditions, but it is usually considerably higher than the bulk melting pointof the fatty Treating the phenomenon as an equilibriumadsorption process, Frewing 128 has used the frictional measurements todetermine the heat of adsorption of fatty acids and esters on steel surfaces.A different interpretation has, however, been given by Bowden, Gregory,and Tabor g3 (see below).For temperatures above 200" in air, the maineffect of temperature is that of oxidation. At an early stage, the oxidationproducts so produced may provide improved lubri~ation.1~~ At highertemperatures, however, or after prolonged heating, gumming, corrosion, andthe production of other deleterious products will cause a deterioration inthe lubricating properties.These effects are not reversible on cooling, andare due to chemical changes in the oils and sometimes the surfaces t,hemselves.127, 128Nature of Underlying Surface and the Importance of Soap Formation.Apart from a few earlier measurements by Hardy 1 and Same~hima,*~little work of a systematic nature has hitherto been carried out on the effectof the underlying metal on the lubricating properties of given boundarylubricants. G . M. Panchenkov and K. V. Konstantinova130 in 1939 de-scribed the effect of various metal substrates on the lubricating propertiesof certain organic compounds, and the investigation was extended over awider field by Hughes and Whittingham in 1942.More recently Bowden,Gregory, and Tabor g3 have investigated the frictional properties of fattyacids on an extensive series of metals, using similar metals for both of thesliding surfaces. One of the most striking results is that, for unreactivemetals such as nickel, platinum, silver, and glass, fatty acids are scarcely123 W. E. Campbell, Trans. Amer. SOC. Mech. Eng., 1939, 61, 633.124 Pub. Sci. Tech. Ministhe Air, France, 1934, 46, 29.125 Ibid., 1935, 131, 18; 1940, 169, 26.126 Nature, 1940, 145, 308.128 J. J. Frewing, Proc. Roy. Xoc., 1944, A, 182, 270.129 F. P. Bowden, L. Leben, and D. Tabor, Tmns. Furuday SOC., 1939, 35.900.130 J . Tech. Physik, U.S.S.R., 1939, 9, 537.lZ7 D. Tabor, ibid., 1941, 147, 609BOWDEN AND TABOR : FRICTION AND LUBRICATION. 35more effective as lubricants than saturated hydrocarbons. On the otherhand, those metals that are most readily attacked chemically by the fattyacid are most effectively lubricated ; whilst the less reactive metals, suchas iron and aluminium, require a higher concentration of fatty acid to givelubrication. (The chemical reactivity of the metals in air is determinedlargely by their oxides, as was pointed out by R. Dubrisay 131 and later byC. F. Prutton et al.132) This a t once leads to a modification of the oldertheory that lubrication is due to an adsorbed monolayer, and suggests thatfatty acids are most effective as boundary lubricants only when they canreact with the surfaces to form a metallic soap ; i.e., the lubrication is ejj’ected,not by the adsorbed fatty acid itself, but by the metallic soap formed on the metalsurface. This view has been confirmed by several experiments on thelubricating properties of metal soaps.The results show that in many casesthe frictional properties of a fatty acid R-CO,H on a metal surface M arethe same as those obtained with a soap (R-CO,),M on any type of surface.93Further, the transition temperature T a t which lubrication breaks downcorresponds approximately to the softening point of the metallic soap. Thishas been confirmed by electron-diffraction experiments which show that thetransition temperature corresponds approximately to the temperature a twhich the soap film loses its high degree of lateral o r i e n t a t i ~ n .~ ~ ~ ~ ~ ~ Thereis therefore a marked similarity between the frictional behaviour of metallicsoaps and of thin metallic films deposited on hard substrates. Lubricationis effective until the lubricant film softens and melts. The behaviour is alsosimilar to that of long-chain fatty acids on unreactive metal surfaces, andof long-chain hydrocarbons on any surfaces, since these lubricate until themelting point of the film is reached. With soap films, however, the soften-ing point is often appreciably higher than thl: mAting point of the corres-ponding fatty acid or hydrocarbon, so that they will lubricate satisfactorilyto a much higher temperature. Further, a single monolayer of soap is fre-quently sufficient to lubricate the surfaces.For these reasons fatty acids,when used on reactive metal surfaces, generally provide good boundarylubrication up to relatively high temperatures. If, however, the adsorptionof the lubricant film to the solid surface is weak, and there is prosent asuperincumbent layer of oil, the lubricant film may dissolve in the excessof oil a t a temperature lower than its softening or melting p0int.~3 Suchan effect may lead to a reduction of the transition temperature.Frewing’s 128 observations are not consistent with this view, since he hasshown that esters lubricate to temperatures well above their bulk meltingpoints on steel surfaces, and has estimated their heats of adsorption fromtheir lubricating properties.Esters, however, do not lubricate above theirbulk melting points on copper and cadmium surfaces, and Frewing’s resultshave been attributed to the anomalous behaviour of steeL93 Furtherinvestigations are needed to clarify this point.The Mechanism of Boundary Lubrication.-Boundary lubrication has beenexplained in terms of surface fields of force,l dipole moments of the lubric-131 Compt. rend., 1940, 210, 533. 132 I n d . Eng. Chem., 1945, 37, 9036 GENERAL AND PHYSICAL CHEMISTRY.ant,l33~1~~ surface. tension effects,l353 1369 1379 1389 139 and a modification ofCoulomb’s theory of surface a~perities.~ Since, however, some surfacedamage always occurs to a depth that is large compared with the dimensionsof a molecule, it would seem that boundary lubrication cannot be consideredas a purely surface effect.There is a continuous formation and shearingof metallic junctions through the lubricant film. When the lubricatedsurfaces are placed in contact, plastic flow of the metals occurs until thearea is large enough to support the applied load. The pressure, however,will not be uniform over the whole region of contact ; a t some points it willbe very much higher, and a t these points a local breakdown of the lubricantfilm may occur. The extent of the breakdown will naturally depend on thenature of the lubricant film. Further, if the sliding speeds are appreciable,it will be aided by local high temperatures developed during sliding.As aresult of the partial breakdown of the lubricant film, metallic junctions,large compared with the size of a molecule, are formed between the surfaces.The resistance to motion is then due in part to the force necessary to shearthese junctions. There will also be some resistance to sliding by thelubricant itself, and we may writewhere A is the area which supports the applied load, c( is the fraction of thisarea over which breakdown of the film has occurred, s, is the shear strengthof the junctions a t the metal-metal contact, and s is the shear strength ofthe lubricating film.93 With a good lubricant, the area over which metalliccontact occurs may be very small indeed. Nevertheless, the shear strengthof these junctions may be so high compared with that of the lubricant thatthey may be responsible for an appreciable part of the resistance to motion.The main purpose of the lubricant film is, therefore, to reduce the amountof metallic contact between the surfaces by interposing a layer that is noteasily penetrated and that possesses a relatively low shear strength.Thispurpose is served effectively by thin metallic films of soft metals 56 and bythin films of certain metallic soaps. There are, however, two main differ-ences in the frictional behaviour of thin soap films and thin metallic films.First, even on rough surfaces, a single molecular layer of soap may provideeffective boundary lubrication, whereas metal films must be appreciablythicker (ca. 10-6 cm.).56 It is for this reason that Amontons’s law holds forlubricated surfaces, but not for metallic film lubrication.Secondly, thegreater portion of the resistance to motion with thin metallic films is duet o shearing within the film itself; with lubricated surfaces, an appreciable133 R. Heinze, M. Marder et al., Oel u. KohZe, 1941, 37, 8.134 E. H. Kadmer, Petroleum Refiner, 1945, 24, 321.136 J. H. Wells and J. E. Southcombe, J . Xoc. Chem. Ind., 1920, 34, 5 1 ~ .136 D. P. Barnard and R. E. Wilson, I d . Eng. Chem., 1922, 14, 682.13’ J. J. Trillat and R. VaillB, J. Chem. Physics, 1936, 33, 742.13* P. Lecomte du Noiiy, Compt. rend., 1940, 210, 101.J. L. Culbertson and F. A. Hedman, J . Phy8iUd Chem., 1937, 41 485BOWDEN AND TABOR : FRICTZON AND LUBRICATION.37part of the friction is generally due to the shearing of metallic junctionsformed through the lubricant film.Extreme Pressure hbrication.The recent development of extreme pressure lubricants has been broughtabout by the failure of conventional mineral oil lubricants t o functioneffectively a t the high pressures and temperatures developed in certainmechanisms, such as hypoid gears, heavy machining operations, etc. Duringthe last ten years, a large number of organic compounds containing " active "elements such as sulphur, phosphorus, and chlorine have been used for thispurpose. Full reviews of the numerous chemicals used are given byJ. Byers,140 M. G. Van Voorhis,l41 and W. A. Wright,142 and a review of themore common extreme pressure additives is given by E.A. Evans andJ. S. Elliot.143 I n a later paper,144 Evans discusses the chemical processesinvolved in the preparation of these compounds.The earlier work was concerned mainly with the empirical preparationof additives which functioned effectively in. practical operations. Morerecent work has been directed to elucidating the mechanism by which theseextreme pressure lubricants function. Hughes and Whittingham,go andmore recently J. N. Gregory145 and W. Davey,lP6 have found that thinsulphide and chloride films are effective in reducing the friction and wearbetween steel and copper surfaces. Campbell 123 showed that relativelythick films of sulphide reduce the friction between steel and copper surfaces,particularly in the presence of paraffin oil, and E.B. Greenhill 14' showedthat the presence of a small quantity of fatty acid in the paraffin oil produceda very much larger reduction in friction. These results explain the wideuse of sulphurised fatty oils as extreme pressure lubricants.The film-forming properties of organic sulphur compounds have beeninvestigated by G. L. Simard, H. W. Russell, and H. R. Nelson,14* usingelectron-diffraction methods. I n particular, they find that a lubricantcontaining free sulphur forms an oxide layer on iron surfaces. They havealso examined the film-forming action of a lubricant containing lead naphth-enate and free sulphur, and find that in many cases the sulphide film isformed. Using a specimen of sulphurised oil prepared with radioactivesulphur, G.L. Clark, S. G. Gallo, and B. H. Lincoln 149 have demonstratedthe formation of a film on various metals and on glass, though the actualcomposition of the film was not investigated.Similar experiments have been carried out on compounds containingchlorine. In particular, Gregory 145 has shown that chloride films are very140 Nat. Pet. News, 1936, 33, 79.142 Ibid., 1945, 37, R34.144 Ibid., 1943, 29, 333.146 C.S.I.R. (Australia), 1945, Ser. no. A , 134, No. 49.146 J . Inst. Petroleum, 1945, 31, 73, 154.ld7 C.S.I.R. (Australia), 1944, Ser. no. A , 97, No. 36.148 I n d . Eng. Chem., 1941, 33, 1352.141 Ibid., 1940, 32, R66.143 J . Inst. Petroleum, 1941, 27, 165.149 J . Appl. Physics, 1943, 14, 42838 GENERAL AND PHYSICAL CHEMISTRY.effective in reducing the friction between steel and copper surfaces in theabsence of moisture.Furthermore, chlorine compounds are effective onlywhen the formation of the metal chloride, by chemical reaction with themetal surface, is possible.It is clear from the results of these workers that the sulphur and thechlorine type of extreme pressure lubricants function by forming a sulphideor metallic chloride on the surface of the rubbing metals. Under the highpressures and temperatures developed between the rubbing surfaces, thecompounds break down, and the " active " portion of the molecule com-bines with the metal surface. These surface films are capable of preventingintimate metallic contact between the surfaces and so reduce the amount ofseizure and wear.That is to say, in terms of equation (1) they produce asmall value of u. With sulphide films, the shear strength s is not, appar-ently, very low, so that although the ability to withstand seizure is greatlyincreased the friction is not appreciably lowered unless fatty acids are alsopresent. With chloride films, however, both s and a are low, so that boththe friction and the probability of seizure are greatly reduced.Interesting confirmation of this general mechanism of film formation hasbeen furnished by 0. Beeck, J. W. Givens, and E. C. Williams I5O in theirwork on the wear-reducing properties of lubricants containing phosphorus.They showed that these compounds, under the action of high runningpressures and temperatures, form phosphide films on the metal surfaces,which then alloy with the metals themselves, producing a low-meltingeutectic.The surface asperities are thereby removed by " chemical "polishing and subsequent wear is very greatly reduced. These workers havesuggested a similar mechanism for the action of lubricants containing sulphur.The Lubrication of Internal Combustion Engines.It has been customary in the past to examine the conditions oflubrication and wear in a running engine by long- or short-range benchtests. In these tests, the engine is run, under close control of the run-ning conditions, and the total energy lost in friction estimated, whilstmeasurements may be made of the oil consumption, compression ratio,piston and cylinder-head temperatures, etc.151, 1 5 2 9 1537 1549 155 After therun is completed, the wear of the piston ring and cylinder liner, and theamount of scuffing and corrosion, are measured. In addition, an ex-amination is made of any physical or chemical changes that may have160 Proc.Roy. SOC., 1940-41, A, 177, 103.1 5 1 H. Wright Baker, Inst. Mech. Eng., 1934, 1i7, 217; 1937, 135, 35-67; Proc.Inst. Automobile Eng. 1932-3, 27, 109; 1934-5, 29, 312.G. F. Mucklow, Inst. Mech. Eng., 1932, 123, 349.153 A. H. Gibson, ibid., 1926, 221; Phil. Mag., 1924, 47, 883.154 Saharo and Sato, Tokyo Imp. Univ. Aeronautical Res. Inst. Report No. 5;L. C. Tyte, Inst. Mech. Eng. Symposium on Modern Aids t o the Investigation ofMaterials, 1944, 16.166 W. L. Bride, J. Inst.Mech. Eng., 1943, 150, 134; 1944, 151, 338BOWDEN AND TABOR : FRICTION AND LUBRICATION. 39occurred in the lubricant. For refined chemical analysis, colorimetric lS6 orradioactive tracer methods 1493 157 may be used.It is, of course, evident that the friction and wear behaviour of a runningengine will be profoundly influenced by the nature of the lubricant, andthe rubbing surfaces, as well as by the running conditions themselves.Experiments also show that it depends markedly on the surface finish of thecylinder and piston ring, since this determines the ease with which thesurfaces are run in a t an early stage of 0peration.15~ A tapered ring hasbeen found advantageous for the same reason.159 More recently, it has beensuggested that the surface finish of the cylinder liner may determine theextent to which the surface will retain a thin film of oil whilst the engine isrunning.l6O> 161The wear which occurs in a running engine may be conveniently dividedThe most outstand-ing research on corrosive wear has been carried out by C.G . Williams,l62who has shown that this type of wear is the predominant factor in engineswhich are frequently started and stopped, and is due to the depositionon the cylinder walls of acids and moisture resulting from the productsof combustion. This work has been generally confirmed by otherw0rkers,16~, 1G43 165, 166 and there is general agreement that a significantreduction of corrosive wear may be obtained by using corrosion-resistantcoatings on the cylinder walls, such as chr~rne-plating,~~~ surface harden-ing,16B etc.Some anti-corrosive coatings may also reduce the amount ofabrasive wear.A more direct investigation of the abrasive wear between the piston ringand cylinder-wall of an internal combustion engine has recently been. into two categories, corrosive wear and abrasive wear.166 H. A. Everett and G. H. Keller, Inst. Mech. Eng., General Discussion on Lubric-ation, 1937, Vol. I, 451-6, 627-8; H. A. Everett and F. C. Stewart, Penna. StateCollege Eng. Expt. Sta., 1935, Ser. Bull. No. 44, 52 pp. ; G. H. Keller, Automotive Ind.,1935, 72, 484.16' S. W. Ferris, U.S. Patent No. 2,315,845.168 W. H. Spencer, Steel, 1938, 103, No. 23, 60; M. M. Roensch, J. SOC. Aut. Eng.,1940, 46, 2 2 1 ~ ; F.Bremer, Korrosion u. Metallschutx, 1941, 17, 208.169 A. Taub, Inst. Mech. Eng., General Discussion on Lubrication, 1937, Vol. I,572-6; J . Inst. Mech. Eng., 1939, 141, 87; 429; &l. Andreev, Teoriga i Prakt. Met.,160 A. Cyril Yeates, Inst. Mech. Eng., General Discussion on Lubrication, 1937,161 Anon., Iron A g e , 1941, 148, 57; E. L. Hemingway, ibid., 1942, 149, 40; AlC2 Collected Researches on Cylinder Wear, Inst. Auto. Engrs., Auto Research163 H. Kjolsen, Ingenwyen, 1936, 45, iv, 52, 71; Chisn. et Ind., 1937, 38, 255.16* Inst. Mech. Eng., General Discussion on Lubrication, 1937, Vol. I, Group 11.165 V. S. Prever, Ind. Meccanica, 1935, 17, 489.166 R. A. Collacott, Power and Works Engineer, 1942, 51.16' H. Van Der Horst, Metal Ind.(N.Y.), 1940, 38, 76; Automobile Engineer, 1941,16* F. P. Peters and E. F. Cone, Metals and Alloys, 1941, 13, 713.1937, NO. 5, 59-71.VOl. I, 595.Composite, " Metals and Alloys," 1942, 15, 322, 326.Committee, ~ 9 4 0 .31, 405; Metal Finishing, 1942, 40, 6940 QENERAL AND PHYSICAL CHEMISTRY.undertaken by workers who have investigated the effect of the metallurgicalstructure of the rings and cylinder on the wear.169, 170, 171, 172, 1739 174 Mostof the workers in this field have emphasised the difficulty of applying ideal-ised experimental wear data to the practical case of a running engine, sincethe laboratory tests are usually carried out under conditions which are veryfar indeed from those which apply to a running engine. This difficultyhas long been felt in engine research, and for this reason special interestattaches to the work of R.Poppingal75 and of J. S. Courtney-Pratt andG . K. These workers have nieasured, by a cathode ray technique,the electrical resistance between the piston ring and cylinder wall of arunning engine. At the top and bottom dead-centre, the resistance is verylow, indicating that there is appreciable metallic contact, or at best aregime of boundary lubrication. At the centre of the stroke, the resistanceis high, implying that the conditions are largely those of fluid lubrication.These results are in agreement with those of C. A. Bouman177 and~ t h e r s , l ~ ~ , 179 though different views have been expressed by otherworkers.f80~ls1, 182s 1839 184 However, the electrical measurements show thatthere is intermittent contact between the surfaces a t all stages of the cycleso that a t no part of the stroke are the surfaces separated by an unbrokenfilm of lubricant.This technique provides an analytical method of in-vestigating the lubricating conditions which operate while the engine isrunning and the way in which these conditions are affected by the temper-ature, viscosity, compression ratio, and other variables.The effect of temperature on the lubrication of a running engine isextremely important. High temperatures, which are readily reached, notonly reduce the viscosity of the oil, but lead to a deterioration of itslubricating properties.126, 127 In addition, persistent high temperatures lead168 H.J. Young, Inst. Mech. Eng., General Discussion on Lubrication, 1937, Vol.170 J. G. Pearce, Inst. Mech. Eng., General Discussion on Lubrication, 1937, Vol.171 A. Wallichs and J. Gregor, Biesserei, 1933, 20, 517, 548.17a E. Soehnchen and E. Piwowarsky, Arch. Eisenhiittenw., 1933, 7 , 371.173 Paul S. Lane, Metal Progress, 1941, 39, 315.174 August Gimmy, Automobiltech. Z., 1939, 42, 334.176 Automobiltech. Z . , 1941, 44, No. 10, 247; 1941, 44, No. 11, 272 (R.T.P. Trans-lation Nos. 1505 and 1603, Ministry of Aircraft Production).176 C.S.I.R. (Australia), 1944, Bulletin No. 179; Engineering, 1946, 161, 69 ; Inst.Mech. Eng., Paper and Discussion, Nov. 30, 1945 (to be published shortly).17? Inst. Mech. Eng., General Discussion on Lubrication, 1937, Vol. I, 426-431.lI8 H.A. Everett, J. Soc. Aut. Eng., 1943, 51, 1 6 5 ~ .17$ R. A. Castleman, Physical Rev., 1936, 49, 410, 886.180 H. R. Ricardo, Automobile Engineer, 1922, 12, 304.lS1 T. E. Stanton, Aeronautical Research Committee, 1924, Report No. 931.lSa S. W. Sparrow and M. A. Thorne, National Advisory Cttee. for Aeronautics,lE3 C. J. Hawkes and G. F. Hardy, Trans. North East Coast Inst. Eng. and Ship-la4 M . P. Taylor, J. SOC. Aut. Eng., 1936, 38, 200.I, 599-606; Proc. Inst. Auto. Engrs., 1935-6, 30, 69.I, 546-549.1927, Report No. 262, Pt. 2.builders, 1936, 52, 143BOWDEN AND TABOR : FRICTION AND LUBRICATION. 41to oxidation and polymerisation of the lubricant. Oxidation gives rise tothe formation of acidic products which may, a t a very early stage, impartimproved boundary lubricating properties to the 0il.129,185 At a later stage,however, these acidic products lead to corrosive wear of the cylinder wallsand piston rings.Oxidation combined with polymerisation causes anincrease in the viscosity of the lubricating oil and the formation of productswhich are insoluble in the bulk of the oil. These products appear in theform of sludge or as gum-like deposits which give rise to sticking of thepiston rings and valve stems.186, 18'9 l88, 1B9 Thus oxidation and polymeris-ation lead to increased ring and cylinder wear, ring sticking, and theaccumulation of sludge.The Use of Additives and Polymers.-It is now common practice toadd substances in small proportions to the lubricating oil, in order tocounteract the effect of oxidation.Such additive agents include a widerange of substances.lW Earlier examples are hydroxy-aromatic compoundssuch as phenols and naphthols and their derivatives; nitrogen com-pounds such as amines ; organic compounds containing sulphur, chlorine,or phosphorus ; and organometallic compounds.The additive may interfere with the oxidation reaction thus retardingthe effect of oxidation, while, in addition, the inhibitor may render themetallic surface passive to corrosion. Additives containing hydroxyl oramino-radicals, such as phenylnaphthylamine, usually react with oxygen,causing a delay period in the oxidation of the lubricating oil, and compoundssuch as tributyl phosphite and tritolyl phosphate react with the metalpresent to form a protective coating.Various organic sulphur compoundsare thought to act in both ways, that is, as anti-oxidants and as metalpassifiers. In addition, some of the additives may possess detergent pro-perties; that is to say, they may tend to take up sludge and carboniferousdeposits and so reduce the amount of ring sticking.Some of the more recent anti-oxidants which have been used as additivesfor lubricating oil are : (1) Zinc salt of diisopropylsalicylic acid (" ZincDips ").191 (2) Polycarboxylic acids of high molecular weight formed bycondensing alkylenes with maleic acid or anhydride followed by saponific-a t i ~ n . l ~ ~ (3) Calcium pheny1~tearate.l~~ (4) Sulphonate salt, as ofpetroleum sulphonic acid and a multivalent metal (e.g., calcium) andarylamine, e.g., phenylnaphthylamine.lS4 ( 5 ) Chelated barium salt of anle5 C.H. Barton, Inst. Mech. Eng., General Discussion on Lubrication, 1937, Vol. I,lS6 C. F. Prutton, Inst. Spokesman, 1941, 5, No. 9, 5-8.407-413.H. W. Brownsdon, Inst. Mech. Eng., General Discussion on Lubrication, 1937,lee H. R. Luck, T. A. Rogers, and A. G. Cattaneo, J. Soo. Aut. Eng., 1943, 51, 38.lE9 33. W. J. Mardles and J. E. Ramsbottom, Inst. Mech. Eng., General DiscussionVol. 11, 2 5 6 2 6 0 .on Lubrication, 1937, Vol. 11, 354-366.M. W. Webber, Petroleum, 1945, 8, No. 4, 76.lgl U.S.P. 2,258,591. lg2 U.S.P. 2,124,628; B.P. 488,597.lg3 B.P. 509,097. 19* U.S.P. 2,270,577.B 42 GENERAL AND PHYSICAL CHEMISTRY.alkylated phenol disulphide (I).lS5 (6) Alkylated p-cres01.1~6 (7) Trichloro-benzene, hexachlorodiphenyl oxide, and inhibitor (trichlorotolyl phosphiteC,H,l R R/ \ / /7\-/-cH2-<7)/-\ T3&s- L/\O-Ba-O/ \O-CH2-O/(1.1 (11.)or phosphate).lS7 (8) Pormols (II).lS8 (9) Sulphurised cracked wax.199(10) pp'-Dichlorodiphenyl disulphide.200 (1 1) Reaction product of tritolylphosphite and octylphenoxyethanol.201 (12) A blend of basic calciumphenylstearate, a solubiliser such as lauryl alcohol or thiol, and athioamide, e.g., thiobenzanilide.202 (13) A combination of additives such as" Zinc Dips " combined with calcium hydro~ypetronate.~~3I n the operation of aero-engines, as distinct from automobile engines,another source of trouble is the formation of a stable foam in the lubricatingoil, particularly a t high altitudes.The presence of foam may cause apartial stoppage in the flow of oil through the supply channels and mayalso cause considerable loss of oil by leakage through the breathing outlets.The use of addition agents to keep foaming down to a minimum hasbeen known for some time. The higher alcohols, such as octyl alcohol, havebeen used in small proportions in industry to prevent heavy foaming duringchemical reactions.204 Anti-foaming additives have been used successfullyin lubricating but there is not much information available on theactual additives in use. The use of silicones has been claimed,206 andthey are likely to be used extensively for this purpose. Other anti-foaming additives which have been proposed are potassium oleate in sul-phurised sperm oi1,206a and compounds such as barium diethylhexyl orditetradecyl dithiophosphates.206b The latter compounds are made byreaction between phosphorus pentasulphide and branched-chain alcohols ormixtures of alcohols and ketones a t 90--100".In many types of moving mecha,nisms lubricated with petroleum oils,the dependence of the viscosity of the oil on the temperature is often aserious disadvantage.For this reason, considerable attention has recentlybeen aroused by the development of polymers containing silicon, which showextremely small variations of viscosity with temperature. These compoundsare, in general, long-chain or ring polymers derived mainly from diorgano-silanediols, with a wide range of physical properties ranging from liquids of195 U.S.P.2,139,766. lo6 U.S.P. 2,202,825. 197 U.S.P. 2,204,620.198 U.S.P. 2,250,188. lg9 U.S.P. 2,215,132. U.S.P. 2,153,432.201 U.S.P. 2,280,450. 202 U.S.P. 2,252,793. 203 U.S.P. 2,373,411.204 Ind. Eng. Chem. (News Edn.), 1935, 16, 389 ; Ann. Reports on Applied Chemistry,205 H. A. Ambrose and C. E. Trautman, J. SOC. Aut. Eng., 1945, 53, 373.206 Nat. Pet. News, 1945, 37, No. 49, 9 4 5 ~ .2060 U.S.P. 2,377,654.1938, 23, 122.206b U.S.P. 2,368,000BOWDEN AND TABOR : FRICTION AND LUBRICATIOX. 43viscosity lower than that of water to those possessing the consistency of thickgreases. These polymers are relatively non-volatile and are extremelyresistant to decomposition and oxidation.They are serviceable up to tem-peratures of over 250" and may possess pour-points lower than - 70".The boundary lubricating properties and wear-resisting characteristics ofsilicones are in general poor, and for this reason they have been used ashydraulic fluids and for mechanisms working mainly under conditions offluid lubrication. However, by suitable chemical modifications, siliconeproducts have recently been prepared which have slightly better boundarylubricating properties than straight mineral oils. Silicones and other syn-thetic polymers such as polyethylene oxides should find increasing use in anumber of practical applications. With most polymers the viscosity de-creases with increasing rate of shear, and in some cases there may be apermanent increase in viscosity due to a breakdown of the polymer.Ifthis occurs to a marked degree, it may impose a limitation on their practicaluse. A recent review of the use of silicones as lubricants is given by T. A.Kauppi and W. W. Pedersen.206Chemical Decomposition by Friction.Although a considerable amount of qualitative work has been done onchemical decomposition produced by friction, little is known concerning themechanism by which these reactions take place. The earlier work wasconcerned with the decomposition of solids (mainly endothermic) by highpressure 2077208 and by grinding in a mortar with a 209 where the solidis subjected to both pressure and shear. Carey Lea 208 investigated thedecomposition of solids such as AgCl+ Ag, HgO ---+ Hg, KMnO, +MnO,, and was able to show that decomposition by pressure was facilitatedby a shearing motion.During the shearing, frictional heat is developed,but he considered that this heat played little or no part in the decomposition.L. H. Parker 210 suggested that, when solids are ground together, reactionsof the type HgC1, + 2KI -+ HgI, + 2KC1 take place owing to the localor surface melting of the solid which results from the stress. In theseexperiments dry salts must be used since the presence of minute traces ofwater vapour affects the results ~onsiderably.20~~210I n a series of papers, P. W. Bridgman 211 has described experiments inwhich he subjected many compounds to hydrostatic pressures up to50,000 kg./cm.(or 50,000 atm.) combined with a shearing stress up to theplastic flow pressure of the material. Under these extreme conditionsmany compounds decomposed explosively, e.g., iodoform, silver nitrate,207 W. Spring, Bull. Soc. chim., 1885, 44, 166; 1886, 46, 299; Z.physika1. Chem.,208 M . Carey Lea, Phil Mug., 1891, 34, 46; 1893, 36, 351; 1894, 37, 31, 470.209 E. P. Perman, Chem. News, 1903, 88, 197; 1907, 96, 3.*lo J., 1914, 105, 1504; 1918, 113, 396.211 Physical Rev., 1935, 48, 825; J . Geol., 1936, 44, 653; Proc. Amer. Acad., 1937,1888, 2, 532, 536.71, 387; Amer. J . Sci., 1938, 36, 8144 GENERAL AND PHYSICAL CHEMISTRY.lead dioxide. Reactions between copper and sulphur, and silicon andmagnesium oxide, also took place with explosive violence.Two phenomena which are of importance in connection with frictionaldecomposition are (i) the effect of pressure on the melting point of solids,212$ 213and (ii) the production of local high-temperature flashes at surface boundarieswhen two solids are rubbed together.26~37~40~214~215 In discussing the effectof pressure on the melting point of solids, Johnston and Adams 212 havepointed out that the application of a uniform pressure to a solid-liquidphase has a comparatively slight effect on the melting point and, in fact,usually raises it by ca.10-30" per 1000 atm. On the other hand, in asystem where there is a non-uniform pressure on the solid-liquid phase, i.e.,where there is an excess pressure on the solid phase, a lowering of the meltingpoint is always obtained.213 Non-uniform compression may be visualised,for example, in the grinding of solids in a mortar with a pestle.Thisgrinding results in a melting of the surface layers a t the crystal boundarieswhere the reaction occurs. The liquid formed by melting flows into inter-stitial spaces and in this way becomes subjected to a smaller pressure thanthe adjacent solid particles. The reaction products are then removedduring the grinding, and fresh surfaces of the reactants are continuallyexposed.It has also been suggested that the decomposition is due to the frictionalheat developed when two surfaces rub together. Many experimental findingssupport this concl~sion.~~~ 40$ 41 The reduction of polishing powders suchas red lead and lead dioxide and the decomposition of calcium carbonatewhen these powders are used to polish metal surfaces has been ascribed tohot spots produced during the polishing.41~214When metals such as iron, copper, and nickel are polished or rolled,oxidation of the metal surface occurs.216% 2179 2189 2191 220 The extent of thewear of the rubbing surfaces is closely bound up with this oxidation.Ina nitrogen 216 or carbon dioxide 217 atmosphere, the wear is considerablydecreased. The oxidation in air may be accelerated by the localised surfaceh e a t h ~ g . ~ ~ , ~ ~ K. Dies 217 has also associated wear with high temperaturesproduced at the points of metallic contact. It is possible that the mechan-ical deformation and breakdown of the protective oxide film also acceleratesthe surface attack.The theory proposed by Fink and Hoffmann 216 is that212 J. Johnston, J . Amer. Chem. SOC., 1912, 34, 788; J. Johnston and L. H. Adams,21s See also H. Jeffreys, Phil. Mag., 1935, 19, 840.216 J. D. Bernal, Trans. Faraday Soc., 1938, 34, 834, 1008.216 M. Fink and U. Hoffiann, Chem. Abs., 1933,27, 1598; 1935, 29,432; 2. anorg.217 Chern. Abs., 1939, 33, 4180; 1943, 37, 5680;218 See also F. Wunderlich, ibid., 1942, 36, 3465.21s K. Lippacher, ibid., 1943, 37, 6226.220 S. Dobinski, Phil. Mag., 1937, 23, 397; see, however, E. Plessing, Physikal. Z.,Amer. J . Sci., 1913, 55, 205.J. M. Macaulay, J . Roy. Tech. Coll. Glasgow, 1931, 2, 378.Chem., 1934, 210, 100; see also F. Roll and W. Palewka, ibid., 221, 177.1944, 38, 708.1939, 40, 233BOWDEN AND TABOR : FRICTION AND LUBRIOATION.45during polishing or rolling chemically active centres are produced on themetal which readily oxidize in air, and this oxidation may penetrate to aconsiderable depth causing scaling of the outer layer.218The initiation of some solid and liquid explosives by friction is thoughtto be due to the development of localised hot spots. The temperature ofthese hot spots is sufficient to bring about a thermal decomposition of theexplosive in the neighbourhood of the hot spots, and this decomposition willdevelop by a process of self-heating into a detonation. Direct experimentalevidence for this view has been obtained by Bowden, Stone, and Tudor 40with liquid explosives such as nitroglycerin.They found that, when thiswas rubbed between solids, the incidence of explosion was determinedmainly by the thermal conductivity of the solids and by their melting points.Explosion resulted only if the melting point was above 480". Below 480"explosion of nitroglycerin could not be obtained, even under severe conditionsof load and speed.Impact experiments on solid explosives (mainly initiating explosives) byW. Taylor and A. Weale 221 have led them .to postulate a tribochemicalmechanism as the cause of initiation in solid explosives. Under the suddenlyapplied pressure of the impact (1 100 atm. in the case of mercury fulminate)the explosive crystals are subjected to normal stress forcing them into moreintimate contact and to tangential stresses tending to shear the crystalsapart. As a result of normal stress, the molecular fields of the surfacemolecules are thrust together and linkages formed.These are almostimmediately ruptured under the tangential stresses, with the result that thesurface molecules are left in highly activated states.222i 223 Experiments onliquid and plastic explosives have shown that in certain cases the initiationby gentle impact may in fact be a thermal one, due to the adiabatic heatingof small entrapped bubbles 224 and, under heavy impact, by a viscous heatingof the explosive.225, 226The effect of grinding on the transformation of the yellow modificationof lead oxide into the red modification has been studied in some228, 2293 230, 231 Clark and his co-workers 230 found changes in theX-ray diffraction patterns and in the catalytic activity of yellow ortho-221 Proc.Roy. SOC., 1932, A, 138, 92; Trans. Paraday Soc., 1938, 34, 995.222 See review by M. F. R. Mulcahy and A. Yoffe, Aust. Chem. Inst. J . Proc., 1945,223 L. R. Carl, J. Franklin Inst., 1943, 235, 553; 1940, 230, 75, 355.224 F. P. Bowden, M. F. R. Mulcahy, R. G. Vines, and A. Yoffe, Nature, 1946,225 T. M. Cherry, C.S.I.R. (Australia), Lubricants and Bearings Sect., 1945, Report2 z 6 F. Eirich and D. Tabor, ibid., Report A121.227 0. W. Brown, S. V. Cook, and J. C. Warner, J. Physical Chem., 1922, 26, 477.228 M. Leblanc and E. Eberius, 2. physikaE. Chem., 1932, A, 160, 69.229 G. Tammann and E. Jenckel, 2. anorg. Chem., 1930, 192, 245.230 G.L. Clark and R. Rowan, J . Amer. Chem. SOC., 1941, 63, 1302; G. L. Clark231 M. Peterson, ibid., 1941, 63, 2617.62, 198.157, 105.A116.and S. F. Kern, ibid., 1942, 04, 163746 GENERAL AND PHYSICAL CHEMISTRY.rhombic lead oxide when subjected to grinding, and conclude that it isconverted into a distorted red tetragonal modification of the oxide. Thepresence of small traces of water vapour appears to have a profound effectin facilitating this tran~formation.~3l It is evident that a considerableamount of work remains to be done before we have a clear understandingof the mechanism of tribochemical or frictional decomposition. At presentthe evidence shows that in certain cases the decomposition is in reality athermal one, due to the high localised temperature flashes produced duringthe rubbing of solid surfaces.We wish to thank Messrs.G. C. Barker, J. A. Burns, J. S. Courtney-Pratt,E. B. Greenhill, A. J. W. Moore, E. D. Tingle, A. Yoffe and other membersof the Research Laboratory on the Physics and Chemistry of Rubbing Solids,Department of Physical Chemistry, Cambridge, for assistance in preparingthis review, and Mr. R. I. Lewis for help with the section on additives.F. P. B.D. T.3. CRYSTALLOGRAPHY.(i) Introduction and General.From a statement now issuedl it is clear that during the recent waryears X-ray crystallography has achieved one of its greatest triumphs in thecomplete elucidation of the structure of penicillin. Details are not yetavailable, apart from the statement that a full electron distribution of therubidium salt of penicillin I1 has been obtained.This implies a full structuredetermination. Although the molecule is not unduly large, containing about25 atoms other than hydrogen, this result is significant of the rapidly growingpower of the X-ray method. The fact that it has been obtained in such ashort time from a recently isolated natural product emphasises the importanceof the X-ray method as a research tool in structural organic chemistry,especially where instability of the molecule or unusual groupings make theusual degradative processes difficult to interpret and entirely independentconfirmation of a structure is badly wanted. Further details of this workare awaited with great interest.During the .year a number of very detailed and complete structuredeterminations by the X-ray method have been published, mainly in thefield of organic structures, and the space available in this Report has beendevoted mainly to outlining the results obtained.Of these determinationsthe work on cholesteryl iodide, geranylamine hydrochloride, and dibenzylis particularly interesting because three-dimensional Fourier series methodshave been extensively employed. It has, of course, long been apparent thatsuch methods must yield far more detailed and accurate information aboutatomic distributions than the ordinary two-dimensional projection method.The latter method is very suitable for planar molecules, such as found in thearomatic hydrocarbons, but when the molecule has a more complicated shape1 “ Chemistry of Penicillin,” Nature, 1946, 156, 766ROBERTSON : CRYSTALLOGRAPHY.47no projection of it is likely to yield a clear picture of all the atomic positions.One difficulty in applying the three-dimensional method lies in the veryformidable amount of numerical calculation required. It is noteworthythat in one of the examples mentioned (dibenzyl) the help of a professionalcomputing service was required. With the provision of more facilities inthis direction and the development of mechanical aids we may expect thethree-dimensional method to be more frequently employed in the future.A far more serious obstacle to such work lies in the initial determinationof the structure; because it must be remembered that in the general caseany Fourier series method is only a means of refining a structure whoseco-ordinates are already approximately known? There is, however, onedirect method of approach which can have a very widespread applicationto complex organic structures.This method depends on the presence a t oneor more points in the structure of atoms whose atomic number is muchhigher than the atomic numbers of the remaining atoms. I n effect thisconverts the unknown phase differences of the X-ray reflections into differ-ences of amplitude, which can be measured; or, in terms of the Pattersonanalysis, it produces a set of vectors, between the heavy atom and each ofthe other atoms, so prominent that they outweigh the confusing mass ofother secondary vectors between the light atoms themselves.The result issome approach to a direct picture of the molecular structure, without anyassumptions based on chemical theory. This powerful method is beingsteadily developed and has been applied to the first two structures mentionedabove, vix., cholesteryl iodide and geranylamine hydrochloride. Fororganic structures in general the halogens, especially iodine, are likely toprovide the most useful heavy atoms; for acids, salts with heavy metalsare possible.The usual indirect method of approach to a crystal structure starts witha model based on what is known of the chemical structure. The orientationof this model in the crystal unit cell must be found by trial, and, afterapproximate agreements have been obtained for the intensities, the Fourierseries method can be applied.The dibenzyl structure was obtained in thisway, and was refined as far as possible by means of two-dimensional pro-j cctions before the three-dimensional analysis was applied.When the Fourier series method is used at its full power, as in theseexamples, the accuracy obtainable is undoubtedly high, provided that acomplete series based on carefully determined intensities has been used. Itappears that the atomic co-ordinates may be obtained to within &O.Ol or*0.02 A.* With this order of accuracy the results should ultimately be ofgreat importance in the development of valency theory. On the other hand,when it is only desired to establish the structure of a molecule in the chemicalsense of finding the relative spatial positions for all the atoms, there isno need to push the work so far, and somewhat less complete series andSee, e.g., D. Macewan and C.A. Beevers, J . Sci. Instr., 1942, 19, 150.For a discussion of principles see J. M. Robertson, J., 1945, 249.A. D. Booth, Nature, 1945, 156, 5148 GENERAL AND PHYSICAL CHEMISTRY.less accurate intensities will suffice. Cholesteryl iodide is a case in point,where the accuracy is sufficient to provide an unambiguous view of thestructure, but not sufficient for a detailed discussion of bond lengths.Two interesting new modifications of the Fourier series method haverecently been devised by A. D. Booth.5 These are called the method ofsection-projections and the method of projected sections and they possessadvantages which are intermediate between the standard two-dimensionaland three-dimensional methods, without requiring such formidable com-putations as are needed in the latter.By the use of section-projections amolecule may sometimes be separated from its companions in the unit celland so lead to a projection which is free from overlapping effects. Theprojected sections, on the other hand, have been devised mainly to reducethe amount of computation involved in making a complete set of ordinarysectional syntheses.Other work published during the year includes a detailed analysis of thecoronene structure, which shows interesting bond length variations withinthe molecule ; the complete analysis of diphenylene, which confirms that thecompound is actually dibenzcyclobutadiene ; and detailed work on certainamino-acids and on adipic acid.Amongst inorganic structures the mostinteresting work is that of Powell and Bartindale on hexamethylisocyanido-ferrous chloride trihydrate, which yields a beautiful projection and givesdetailed information about the structure of the ferrocyanides.The year has also been notable for the publication of a number ofimportant books and monographs on structural crystallography and crystalchemistry. C. W. Bunn has covered the subject of chemical crystallographyin an eminently practical manner, dealing Grst with optical and X-raypowder methods for the identification of substances, and then, in the longersection of the book, with the determination of atomic positions.Thevarious methods of analysis are fully discussed and illustrated with manyexamples of structure determinations. Much of this is new ground whichhas not previously been covered in any book. The widespread applicationsof the subject to chemical problems in general are very well brought out.The more specialised application of X-ray methods to metallurgicalproblems has been fully treated in a book by A. Taylor.’ Brief introductorychapters on the standard methods and principles and the crystal structuresof metals are followed by a full account of applications to metallographicproblems. The subjects covered include the determination of phaseboundaries, defect lattices, electron compounds, superlattices, order-disordertheory, the examination of binary and ternary systems, and an account ofrecent X-ray work on the iron-carbon system.The determination of grainsize by optical and X-ray methods and the study of grain orientation arenext described, and there is a brief account of the X-ray study of refractoryTrans. B’amday SOC., 1945, 41, 434.“ Chemical Crystallography,” Oxford University Press, 1946.“ An Introduction to X-Ray Metallography,” Chapman and Hall, Ltd., London,1945ROBERTSON : CRYSTALLOGRAPHY. 49materials. Much of the ground covered can only be found otherwise inmany scattered original papers, so the book ought to prove extremelyuseful.The much wider field of structural inorganic chemistry is covered in thesurvey given by A.F. Wells.8 The modern basis of this subject dependsvery largely on X-ray crystallographic studies. It is now realised that thefinite molecules studied by the classical methods of chemistry are only asmall part of the subject, which must be extended to include the infinitethree-dimensional arrays of atoms which constitute solids. This extensionof the field of inorganic chemistry forms the main thesis of the book. Aftera general introduction dealing with atomic structure, interatomic forces,the spatial arrangement of atoms in relation to bond type, and other relevantmatters, it goes on to treat the subject in a systematic manner in whichthe results of crystal chemistry figure very largely. The arrangement isaccording to the usual groups; hydrogen (including the acids and certainstructures involving the hydrogen bond), the halogens, oxygen and sulphur(three chapters), nitrogen and phosphorus, carbon, silicon, and boron.Finally, two short chapters deal with the stereochemistry of certain metalsand the crystal structure of metals and alloys.Again, this book bringstogether and systematises a great deal of otherwise scattered material andi t thus represents an important contribution to the literature of the subject.Many papers have also appeared recently on the more physical aspectsof crystallography, and on the structure of metals and alloys, mineralstructures, fibre structures and other less completely crystalline materials,but a review of the work in these fields is not included in the present Report.(ii) Inorganic Structures.The Iron-Carbon Bond in the Ferrocyanides.-A very interesting crystalstructure determination has been carried out by H.M. Powell andG. W. R. Bartindale 1 on hexamethylisocyanidoferrous chloride trihydrate,Fe(CNMe),C1,,3H20. The hexagonal crystal has only one molecule of thiscomposition per unit cell, and so the iron atom must occupy a special position,taken as the origin of the xy co-ordinates. Its contribution to the structureamplitudes is sufficient t o determine the phase constants and enable a directand very striking Fourier projection of the structure to be made on the basalplane of the hexagonal cell. The atoms are all beautifully resolved, but acurious ambiguity is discovered.The structure contains certain two-foldand three-fold positions which one would expect to find occupied by thetwo chlorine ions and the three water molecules respectively. Actually, theelectron-density peaks show that the reverse is true, Le., the chlorine appearsto be where the water was expected and vice versa. I n the isomorphousbromide compound similar and even more striking discrepancies occur.The explanation must be that there is a random distribution of the twohalogen ions among the three-fold positions, and, of the three watera “ Structural Inorganic Chemistry,” Oxford University Press, 1945.J . . 1945, 79950 GENERAL AND PHYSICAL CHEMISTRY.molecules, two must occupy the two-fold positions, and the remaining onebe distributed a t random among the three-fold positions.Each of the three-fold positions therefore holds statistically $Cl and QH,O. This curiousdisorder effect is due to the general architecture of the structure, whichpermits a more compact grouping of the chlorine ions with respect to thepositive ion, and consequently a lower potential energy, if the disorderedarrangement is adopted.The complex ion Fe(CNMe),++ (I) is found to be an octahedral arrange-ment with Fe-C distances of 1-85 A., indicating about 50% double-bondcharacter. The FeCNMe arms have a bend of about 7" at the nitrogenatom, confirming resonance of the two types Fe::C::N:Me and Fe:C:::N:Me.The C-N distance is 1.18 A. and the N-Me, 1-47 A.Me -/Me N+++The octahedral complexes are packed as closely together in the structureas normal separation between the methyl groups (3.70 and 3-91 A.) willallow.With this arrangement, holes are left in the structure of sufficientsize to accommodate either chlorine ions or water molecules, and these areoccupied in the random manner indicated above.8uZphides.-New determinations of the structures of a number of sulphidecompounds have recently been made. Potassium thioferrite,2 KFeS,, ismonoclinic (pseudohexagonal) and consists of chains of (FeS,),, iron beingat the centre of almost regular tetrahedra of sulphur atoms. The iron-sulphur distances are 2.20 and 2-28 A., and the tetrahedron edges 3.62-3.74 A. Potassium occupies interstices in the structure, and is surrounded inan irregular way by eight sulphur atoms, a t distances of from 3.33 to 3-48 A.Sodium thiochromitle,2 NaCrS,, has a rhombohedra1 layer lattice, andconsists of hexagonal layers of Cr, S, Na, S, Cr, etc., piled on each other inclose packing.The Na-S distance is 2.78 A., and Cr-S, 2.44 A. Thestructure resembles the NaCl type, if we disregard the difference betweenNa and Cr.The structure of chalcopyrite,3 CuFeS,, given by L. Pauling and L. 0.J. W. Boon and C . H. MacGillavry, Rec. Trav. chim., 1942, 61, 910; see alsoJ. W. Boon, Rec. Trav. chim., 1944, 63, 69.W. Rudorf€ and K. Stegemann, 2. anorg. Chem., 1943, 251, 376ROBERTSON : CRYSTALLOGRAPHY. 51Brockway4 has been confirmed, and AgFeS, is shown.to have the samestructure. I n these, as in potassium thioferrite, nearly regular tetrahedraof sulphur atoms exist.These chains of sulphur tetrahedra must remainintact during the reactions MFeS, + CuFeS, and KFeS, + AgFeS,,which can occur in the crystalline state, but certain other problems con-cerning the mechanism of these reactions remain obscure.The compounds NaBiS, and KBiS, are cubic and are reported to havethe NaCl type of s t r u ~ t u r e . ~ Apparently two sodium (or potassium) andtwo bismuth ions occupy in a random manner the four sodium positions inthe NaCl structure, while the other four chlorine positions are occupied bythe sulphur ions. The compounds appear to be stable in this structuretype even after prolonged heating, unlike LiFeO, and Li,Ti0,.6 Accordingto this investigation the Bi*++ ion has a radius of between 1.10 and 1.20 A,Sulphur Trioxide.-An interesting account of the crystal structure of they-modification, or ice-like form, of sulphur trioxide has now become avail-able.' From single-crystal measurements it is found that the orthorhombiccell contains twelve units of SO,, which are combined to give four puckeredring molecules of S30, as in (11).Here the sulphuratoms are situated a t the centres of slightly distortedtetrahedra of oxygen atoms, with S-0, 1-60 A. ; S O ,1-40 A. ; 0-0 (tetrahedron edge), 2.45 A. ; although nogreat precision is claimed for the atomic positions.The smallest intermolecular distances are about 2.9-3-0 A. This form of molecule is rather closely relatedto that found for P,01,,8 from which it may be derivedby the removal of one central atom and one oxygen atom and a slightmodification of the remaining positions. This structure for the y-modifica-tion of SO, is in agreement with recent Raman and infra-red investigations.Other Structures.--Other work which may be briefly mentioned includesa confirmation of the phosphorus pentabromide structure 9 as Dz-Pbcmwith four units of PBr, per unit cell, consisting of almost regular tetrahedralPBr,+ ions (P-Br distance, 2.2 A.) and the fifth bromine as a separate Br-ion a t 4.3~., as previously found by H.M. Powell and D. Clark.10I n tungsten hexachloride l1 the space-group is Cii and the structure is ahexagonally close-packed chlorine lattice slightly deformed so as to group thesix chlorine atoms octahedrally around a tungsten atom with W-Cl, 2.24 A.Potassium tetrachlorozincate, K2ZnCl4,l2 proves to be a very complicatedstructure with twelve molecules per unit cell in the space-group C&Pma.0Oys/ 8 ~ 0/ b dNo\s/ (f > ('I.)4 2.Krist., 1932, 82, 188.7 R. Westrik and C. H. MacGillavry, Rec. Trav. chim., 1941, 60, 794.8 G. C. Hampsonand A. J. Stosick,J. Amer. Chem. SOC., 1938, 60, 1814; H. C. J.de Decker and C. H. MacGillavry, Rev. Trav. chim., 1941, 60, 153.9 M. van Driel and C. H. MacGillavry, ibid., 1943, 62, 167.J. W. Boon, Rec. Trav. chim., 1944, 63, 32.E. Kordes, 2. Krist., 1935, 92, 139.Nature, 1940, 145, 071.J. A. A. Ketelaar and G. W. van Oosterhout, Rec. Trav. chim., 1943, 62, 197.l2 H. P.Klug and G. W. Sears, J. Arner. Chem. SOC., 1945, 67, 87852 GENERAL AND PHYSICAL CHEMISTRY.The crystal structures of cadmium cyanide and gold cyanide are discussedby G. Shdanov and E. Schugam.13 In gold cyanide the lattice is built upof chains of Au-C-N-Au- in which covalent bonds predominate.X-Ray measurements have been made on czsium fluosulphonate,l4CsSO,F, which has the scheelite type of structure; and on potassiumberyllium fluoride, K2BeF4, strontium orthosilicate, Sr,SiO,, and bariumorthosilicate, Ba,SiO,, l5 which are all isomorphous with potassium sulphate.The structural crystallography and optical properties of the variousforms of silicon carbide have been discussed,l6 and a preliminary noteindicating a full structure determination of the interesting ferromagneticmineral cubanite, %uFe,S,, has appeared.17 In this structure each metalatom appears to be surrounded by four sulphur atoms in almost undistortedtetrahedral co-ordination, and the sulphur atoms are similarly eachsurrounded by four metal atoms.There is an indication that the iron atomsare bonded to one another in pairs, in addition to their links with the sulphuratoms.(iii) Organic Structures.The Structure of Cholesteryl Iodide.-The very great part played bycrystallography in the elucidation of the chemistry of the sterols is wellknown, The early measurements and ideas put forward by J. D. Bernallwere rapidly followed by an immense amount of purely chemical work,2 andthe structure of the sterol skeleton (I) is now well established.The X-ray26!2627analysis of the crystal structure of cholesteryl iodide (I) now given by C. H.Carlisle and D. Crowfoot (Mrs. Hodgkin) is of outstanding importanceboth to crystallography and to chemistry. In crystallography cholesteryliodide is probably the most complicated organic structure which has yet13 Acta Physicochim. U.R.X.S., 1945, 20, 247, 253.l4 El. Siefert, 2. Krist., 1942, 104, 385.16 H. O'Daniel and L. Tscheischwili, ibid., p. 348.16 N. W. Thibault, Amer. Min., 1944, 29, 327; L. S. Ramsdell, ibid., p. 431.l7 M. J. Buerger, J . Amer. Chem. SOL, 1945, 67, 2056.1 Nature, 1932, 129, 277; Chem. and Ind., 1932, 51, 466; see also J. D. Bernal,2 See Ann. Reports, 1933, 30, 198; 1934, 31, 206; 1936, 33, 341; 1938, 35, 281;3 Proc. Roy.SOC., 1945, A, 184, 64.D. Crowfoot, and I. Fankuchen, Phil. Trans., 1940, A, 239, 135.1939, 36, 286; 1940, 3'7, 332; 1943, 40, 122ROBERTSON : CRYSTALLOGRAPHY. 53been fully analysed, and the analysis has been accomplished very largely bythe use of recently developed direct methods which do not involve anychemical theory. From the chemical point of view, the determination ofall the atomic positions with reasonable accuracy is of great importance asa verification of theory and in settling various outstanding points of stereo-chemical detail.The iodide was found to exist in two polymorphic modifications A andB, of closely related crystal structure, both monoclinic, PZ,, with twomolecules per unit cell. The analysis, carried out on both these crystals,depends on the fact that the phase constants of the X-ray reflections arelargely controlled by the contributions of the iodine atoms.As the twoiodine atoms (one on each molecule) occupy general positions in the unitcell, the analysis is not so straightforward as that of platinum phthalo-cyanine,4 but the general principles are the same. The position of theiodine atoms was first determined with considerable accuracy by a two-dimensional Patterson synthesis on the (010) plane. The phase anglesderived from these positions were then attached to the measured structurefactors and Fourier projections of the electron density were made on the(010) plane. In the projections so obtained from both crystals the outlinesof the sterol ring system and attached side chain were clearly visible.Itwas now apparent, however, that in the B crystal form the orientation ofthe molecule is more favourable for projection as there is less overlappingof the atom centres. The position of nearly every atom could be seen.More detailed work was therefore confined to the B form.To proceed further requires the use of three-dimensional methods, as thesterol molecule is far from being a planar structure. Line syntheses weretherefore constructed parallel to the b axis and passing as nearly as possiblethrough the projected centres of the atoms so far resolved. Here a complic-ation arises, because the phase angles derived from the two iodine positionsnecessarily introduce a centre of symmetry which does not exist in the realstructure.(This complication does not arise in the projections mentionedabove, because they actually possess centres of symmetry.) In threedimensions, the result of the calculation is to show the molecule as a wholesuperimposed upon a spurious mirror image of itself. To select the trueatomic positions it is now necessary to make use of our knowledge of normalcarbon-carbon bond distances and valency angles. It will be noted thatonly at this late stage of the analysis is any previous knowledge of chemicalstructure used, and this knowledge is of the kind that might be derivedmerely from a study of the structure of diamond.Once the atomic positions are sorted out in this manner it is possible toconstruct a very satisfactory model of the molecule, and further refinementcan proceed by well-tried methods of successive approximation. The finalresults are expressed by three very striking sections showing the electron-density distribution in planes parallel to the (010) and passing through themolecule at different levels.From these sections, combined with the lineJ. M. Robertson and (Miss) I. Woodward, J., 1940, 3654 GENERAL AND PHYSICAL CHEMISTRY.syntheses mentioned above, it is possible to estimate all the 84 co-ordinateswhich govern the structure.The accuracy claimed for the final atomic positions is not high, owingto a number of causes, e.g., intensity inaccuracies, spurious diffraction effectsresulting from the heavy atom, and incompleteness of the excessively lengthycalculations involved. A more serious and fundamental limitation isimposed by the general weakness of the X-ray reflections from planes ofsmall spacing, which may indicate some degree of disorder in the structure.Nevertheless, the results are quite sufficient to determine completely thestructure in the chemical sense, and to decide which atom is attached towhich, and the relative orientations of the atoms in space.The interatomicdistances and valency angles found are C-I, 2.08 A. ; C-C, 1.47-1.60 A.,mean 1 . 5 5 ~ . ; ' c=c, 1.30A.; <c-c-c, 91-129" 30', mean 108" 36';(C-C-C, 124" 45', 125" 33'.The molecular structure is in excellent agreement with present chemicalviews.5 The ring system is non-planar, with methyl groups attached a tC,, and C13.C3 is rather ill-defined in the electron-density maps owing tothe proximity of the heavy iodine atom, but the data definitely favour thecarbon-iodine bond being cis to methyl at C,, (the " trans " form ofL. Ruzicka, M. Furter, and M. W. Goldberg 6). Apart from the distortioncaused by the double bond (which is good evidence for its position), therings have the Sachse trans-configuration.Chemical evidence on the stereochemical relations involved in theattachment of the side chain a t C17 appears to be conflicting.' The X-rayevidence, however, is very definitely in favour of the side chain being cis tomethyl at C13. The arrangements of the carbon atoms about the bondCl3-C1, and also about C17-C,o are trans in form.In general, the staggeredtrans-configuration is followed throughout the chain and ring systems ofthe molecules.*Abnormal Bond Distances in Geranylamine Hydrochloride and Dibenzy1.-Perhaps the most complete structural analysis of a complex organic crystalso far achieved has now been described by G. A. Jeffrey9 for the hydro-chloride of geranylamine, CloH1,*NH,,HC1. A preliminary note about thisstructure has already been reported upon.1° The work is remarkable notso much for the complexity of the molecule as for the thoroughness of theX-ray analysis. The atomic positions were derived from preliminaryPatterson syntheses followed by full-scale three-dimensional Fourierayntheses in the form of sections through the two principal monocliniccrystal planes, (010) and (001).Some of the final results are illustrated in5 0. Rosenheim and H. King, Chem. and Id., 1932, 51, 464; H. Wieland andE. Duane, 2. physiol. Chem., 1932, 210, 268.f~ Helv. Chim. Acta, 1938, 21, 498.L. Ruzicka, M. Goldberg, and H. Wirz, ibid., 1935, 18, 998; H. Wieland andE. Duane, 2. physiol. Chem., 1933, 216, 98; V. Caglioti and G. Giacomello, Gazzetta,1939, 69, 245.C. W. Bum, Proc. Roy. SOG., 1942, A , 180, 67.Ibicl., 1945, A, 183, 388. lo Ann. Reports, 1943, 40, 96ROBERTSOX : CRYSTALLOGRAPHY. 55Fig. 1 in the form of superimposed sectional summations on the (010) plane,the contour lines denoting density increments of one electron per A.3, excepton the chlorine atom where the scale is two electrons per A .~ . (The zeroand first contours have been omitted in the diagram.) From this and othersimilar maps all the 36 atomic parameters for the carbon, nitrogen, andchlorine atoms have been measured directly from the maximum of each peak.The experimental data in this work consisted of structure factors derivedfrom visual estimates of intensities from 1060 planes, including all thosewithin range of Cu-Kcc radiation. This represents about 88 structure factorsFIG. 1 .-Projection of the gernnylanaine hydrochloride molecule and Fourier sections on(010). (G. A. Jeffrey, from Proc. Roy. SOC., 1945, A , 183, 391.)per atom of the asymmetric unit and appears to constitute a record forcompleteness of data. Various tests have been applied to ascertain thelimits of experimental error, and these are finally estimated at 3 0.04~.and & 4" for the bond lengths anti valency angles.Within these limits the two isoprene units in the molecule are identical,most of the bond lengths are normal (carbon-carbon single bonds, 1.52-1.55 A., carbon-carbon double bonds, 1.32 A., carbon-nitrogen, 1-48 A.), andthe valency angles have about the expected values. There is, however, oneoutstanding exception.The C,-C, bond (Fig. 1) linking the two isopreneunits has a length of 1.44 or 1.45 A., and is thus shorter than a normal singlebond by an amount two or three times the probable experimental error. A56 GENERAL AND PHYSICAL CHEMISTRY.the system is not conjugated in the usual sense, this contraction is verydifficult to explain in terms of current theory.It is suggested that thehybrid character of the bond may be the result of a hyperconjugation processin which the a-methylenic C-H electrons become partly localised in thecentral bond, as indicated in (11).H H-CH=C+C-CH=C- I ! ! I(11.1 MeH H MeOne important stereochemical feature of the structure 'concerns theorientation of this central bond relative to the planes of the isoprene unitswhich it joins. This appears to be governed by a balance of the stericrepulsions between c6.. . . . C, (3-28 A.) and between c6.. . . . C, (methyl)(3.24 A.). As only intramolecular forces are involved here, the resultshould apply generally and may have an important bearing on the stereo-chemistry of long-chain polymers.I n the structure as a whole, the molecules are so arranged that eachnitrogen atom is a t nearly equal distances (3-17-3-24 A.) from each of fourchlorine neighbours.Thepeak value of the electron density becomes progressively less for every atomas we pass along the chain away from the nitrogen atom.Similar thoughrather less pronounced effects have been noticed in other structures, e.g.,anthracene,ll as we pass along the molecule away from the meso carbonatoms. They may bedue to a variation in the thermal motion of different parts of the molecule;but the possibility of their being spurious and due to the incomplete con-vergence of the Fourier series used cannot be excluded.The interesting result mentioned above regarding the contraction of thecentral bond in the geranylamine molecule immediately raises the questionas to whether this is a general property of all similarly linked systems.Abrief note has now appeared giving the bare results of an equally comprehen-sive three-dimensional investigation of the structure of dibenzyl.12 Anearlier two-dimensional investigation of this structure l3 succeeded indefining the orientation and general shape of this molecule in the crystalwith considerable precision, but the resolution was not sufficient to yieldany very precise measurements of the length of the central -CH,-CH,- bondsituated between the benzene rings. The new determination makes thislength 1.48 0-01 A., thus indicating a contraction similar to thoughsmaller than that found in geranylamine.The explanation, in terms of ahyperconjugation process, is presumably the same.Other interesting results obtained from this new analysis of dibenzyll1 J. M. Robertson, Proc. Roy. SOC., 1933, A , 140, 79.l2 G. A. Jeffrey, Nature, 1945, 156, 82.l3 J. M. Robertson, Proc. Roy. SOC., 1934, A , 146, 473; 1935, A, 150, 348.One peculiar feature of the structure is clearly evident in Fig. 1.The explanation of these effects is rather obscureROBERTSON : CRYSTALLOGRAPHY. 57show that the sides of the benzene rings vary in length from 1-36 to 1-39 A.As the experimental error is estimated to be only 0.01 A., it seems possiblethat some of these variations may be real. All the angles associated withthe benzene rings are found to be 120" 1".Finally, the C-CH, bondlengths immediately adjacent to the rings are given as 1-50 & 0.01 A,, thusindicating a fairly large contraction from the standard single bond value of1.54 A.It is clearthat, if measurements of this order of accuracy can be established generally,much interesting work remains to be done in the detailed examination ofthe structures of simple compounds.Meanwhile, the anomalous reactivity of certain 1 : 5-dienes has beenfurther examined in a combined chemical and crystallographic study ofmethyl and ethyl A1 : 5-hexadiene-l : 1 : 3 : 3 : 4 : 4 : 6 : 6-octacarboxylates byL. Bateman and G. A. Jeffrey.14 The properties of these compounds hadpreviously been studied very fully by C. K. Ingold, M. M. Parekh, andC.W. Shoppee.15 It is now suggested that their anomalous behaviour maybe due to a similar but more extensive chain hyperconjugation than thatin geranylamine hydrochloride. X-Ray data are given for the octamethyland octaethyl esters mentioned above, as well as for the hexamethyl andhexaethyl ester diacids, the hexaethyl ester diacid chloride, the dihydro-octamethyl ester, methyl and ethyl cyczopentane hydroxy-acid ester, thedimer of methyl ay-dicarbomethoxyglutaconate, and the dimers of ethyla-dicarbethoxyglutaconate, but these data only go as far as cell dimensionsand space-group determinations, with. the object of deciding between cis,trans, and cyclic structures.Coronene.-In elucidating the structures so far described full use hasbeen made of the three-dimensional Fourier series methods.For moleculeswith complicated shapes this represents the only feasible way of refining thestructure. The main drawback of the method lies in the excessive amountof numerical computation involved, which makes its use prohibitive in somecases. There are certain special structures, however, for which an almostcomparable accuracy may be achieved by the careful use of two-dimensionalmethods. The aromatic hydrocarbon coronene, for which the full structuredetermination is now available,16 is a good example.I n the two-dimensional projection on the (010) plane a very high degreeof resolution is obtained, the great plane of the molecule being inclined atabout 44" to this projection plane. The accuracy of such work is difficultto assess in general, but in this case a rather careful examination has beenmade by conducting parallel investigations on hypothetical structures withknown atomic positions.The general conclusion is that for the coronenestructure the bond length measurements, after averaging in groups as shownA full discussion of these results is awaited with interest.l4 J . , 1945, 21 1 ; L. Bateman and H. P. Koch, ibid., p. 216.l5 J . , 1930, 142.l6 J. M. Robertson and J. G. White, J., 1945, 607. See also Ann. Reports, 1944,41, 6958 GENERAL AND PHYSIOAL CHEMISTRY.in Fig. 2, are probably accurate to about 5 0.01 A., and that the positionof individual atoms may have maximum errors of between 0.02 and 0.03 A.The results, given in Fig.2, show an interesting variation in bond lengthin different parts of the molecule. For the central ring and spokes it is1-43a., whereas the outer bonds appear to alternate between 1.385 and1.415 A., depending on their situation. These variations are large enoughto be significant, and they represent the first definite measurements ofvariable carbon-carbon bond lengths for any condensed ring aromatic hydro-carbon. They can be given a rough qualitative explanation in terms of thet tIE 7.385 FFIG. 2.-Dimensions of the coronene molecule. (From J . , 1945, p. 612, Fig. 5.)twenty stable valency bond structures which can be written for coroneneby assessing the double-bond character for each set of links and making useof L. Pauling and L. 0.Brockway’s empirical curve relating double-bondcharacter and distance.17 However, both in this treatment and in the moredetailed calculations carried out by C. A. Coulson l8 there is difficulty indistinguishing between the lengths of one set of outer bonds (1.415 A.) andthe bonds of the inner ring (1.43 A.). Much further work clearly remainsto be done in examining other aromatic systems, both experimentally andtheoretically, before final conclusions can be reached.DiphenyEene.-The results of an electron-diffraction study of this moleculehave already been discussed in these Rep0~ts.l~ A full account of thecrystal structure now available 20 confirms the previous conclusion that thel7 J. Amer. Chem. SOC., 1937, 59, 1223.2o J. Waser and C. S. Lu, J.Amer. Chem. SOC., 1944, 88, 2035.18 Nature, 1944, 154, 797.Ann. Reports, 1943, 40, 92ROBERTSON : CRYSTALLOGRAPHY. 59compound is indeed dibenzcyclobutadiene, as originally suggested by W. C.Lothrop's synthesis.21 The crystal structure is a peculiar one, with sixmolecules of diphenylene in the monoclinic space group P2,/a. The symmetryrequirements in this space-group demand that a t least two of these moleculesmust have exact centres of symmetry in special positions, which is strongpreliminary evidence for the coplanar molecule (111) already indicated bythe electron-diffraction results. Exact conclusions regarding the remainingfour niolecules are more difficult to reach, but the analysis is somewhatsimplified by the observation that the (hkO) reflections are nearly all absentexcept when h = 3n, which indicates some form of triplet grouping alongthe a axis (19.60 A.).It was finally possible to achieve a fairly detailedanalysis, with Fourier projections showing reasonably good resolution ofmany of the atoms. Owing to the complexity of the crystal structure ahigh order of accuracy is not claimed, but most of the atomic positions areknown to within 0.1 A. The structure (111) is definitely con-firmed and the dimensions found by electron diffraction(hexagon sides, 1-41 A., and lateral connecting links of the fourring, 1.46 A.) appear to be consistent, within the experimentallimits, with the X-ray results.The full implications of the interesting fact that there are two crystallo-graphically independent types of molecule in the unit cell have not quitebeen worked out.Although it is perhaps improbable, the possibility existsthat the dimensions or the shapes of these two kinds of molecule may beslightly different. In fact, some of the X-ray results seem slightly to favoursuch a conclusion. In this connection a careful study of the environmentof the two crystallographically different kinds of molecule in the unit cellis required, and the appropriate diagrams are given in the original paper.21Other crystals displaying two crystallographically distinct kinds of moleculeare to be found in the stilbene, tolan, and trans-azobenzene series.22 Thesestructures are not strictly analogous to diphenylene, as they are four-moleculecrystals with apparently exact symmetry centres in each molecule, but theyhave the same interesting possibilities of variable dimensions and differentenvironments for the two kinds of molecule.Amino-acids.-Even the simple amino-acids usually present crystalstructure problems of considerable complexity.Several such structureshave in the past been studied carefully as part of a general programme ofinvestigation of the amino-acids and proteins.23 Recently, crystalline copperand nickel salts of several of the acids have been prepared for X-ray in-vestigation, with the hope that the heavy-metal atoms would facilitate thework and enable more or less direct Fourier series methods to be employeda t an early stage. In two structures recently reported this technique has()<)21 J.Waser and C. S . Lu, J , Amer. Chem. SOC., 1941, 63, 1187 ; 1942, 64, 1698.22 J. 31. Robertson and (Miss) I. Woodward, Proc. Roy. SOC., 1937, A , 162, 568;1938, A , 164, 436; J. J. de Lange, J. M. Robertson, and (Miss) I. Woodward, ibid.,1939, A , 171, 398.23 J . Amer. Chem. SOC., 1939, 61, 1087; Ann. Reports, 1939, 36, 17960 GENERAL AND PHYSICAL CHEMISTRY.proved very successful. Copper dl-a-aminobutyrate and nickel aminoacetatedihydrate 24 are both found to belong to the monoclinic space group P2Jcwith two molecules per unit cell. The metal atoms must therefore be onthe special two-fold centro-symmetrical positions, and their co-ordinates arefixed. I n the Patterson projection of these structures the only significantpeaks will correspond to vectors with a metal atom a t one end; in otherwords, the Patterson projections will have very much the same appearanceas the corresponding Fourier projections. The situation is closely similarto that found in the metal phthalocyanine structure^.^^In the case of copper dl-a-aminobutyrate a clear projection on the acplane determines all the x and x co-ordinates of the atoms.The presumablysquare and necessarily coplanar co-ordination of the amino-nitrogen andcarboxyl oxygen atoms around the copper atom is indicated diagramaticallyin (IV). In addition, hydrogen bridges appear to connect the amino-nitrogen atoms to the carboxyl oxygen atoms of other neighbouring molecules,as shown by the dotted lines. As only one projection of the structure isavailable the y co-ordinates of the atoms cannot be determined and so noinformation on real interatomic distances is yet available.The analysis has proceeded much further for nickel aminoacetatedihydrate, Ni(NH2.CH2.C02)2,2H,0.24 The monoclinic cell dimensions aremore nearly equal, and three independent projections of the structure havebeen made along the three crystallographic axes.Unfortunately, theorientation of the molecule in the unit cell is such that some of the parametersof the light atom’s cannot be determined directly. For example, the nitrogenatom is unresolved in all the projections. By assuming values for a fewof the better known interatomic distances it is possible, however, to deducethe whole structure with a good deal of certainty.It is found to consistof distorted octahedral complexes of nickel atoms bound to two glycineresidues and two water molecules. As in the previous compound, thenickel atom makes a coplanar and almost square co-ordination to twooxygen atoms of different carboxyl groups and to two amino-nitrogenatoms, the distances being 2-08 and 2-09 A. In addition the nickel atomforms covalent bonds (2.12 A.) to the two water molecules which are situateda t the remaining vertices of the octahedron. The glycine residues arenearly flat, with dimensions closely similar to those previously found by24 A. J. Stosick, J. Amer. Chem. Soc., 1945, 67, 362, 365.*5 J. M. Robertson and (Miss) I. Woodward, J . , 1937, 219; 1940, 36ROBERTSON : CRYSTALLOGRAPHY. 61G. Albrecht and R. B. Corey.23 Each of the water molecules in the octa-hedral complexes is further connected by two moderately strong hydrogenbridges (2.72 A.) to carboxyl oxygen atoms of neighbouring complexes.The outer oxygen atoms of the carboxyl groups also form one fairly strong(2.96 4.) hydrogen bridge and one very weak (3.13 A.) bridge to the nitrogenatoms of the amino-groups of neighbouring complexes.Although it has been possible to deduce these structures very fully froma study of the Fourier projections, it is quite clear that with such structuresthe maximum amount of information can be obtained only by the use ofthree-dimensional Fourier methods. For the more complex amino-acidsand proteins, and indeed for all structures where the molecular codgurationdeparts markedly from the simple planar form, the use of three-dimensionalmethods is necessary.Adipic Acid.-A fairly complete account of the crystal structure ofadipic acid has now become available.26 The two centro-symmetricalmolecules in the monoclinic unit cell (space group P2,/a) lie along the caxis. Adjacent carboxyl groups are centro-symmetrically related andconnected by hydrogen bridges of length 2-65 A. The structure has beenrefined by means of two Fourier projections [along the (101) and the b axis]and all the parameters are given. It is, however, rather difficult to estimatethe accuracy of the bond-length determinations from this paper. Thevalues reported are C-0, 1-38 A. ; C=O, 1.28 A. ; G-C, 1.49, 1.52, 1.51 A.(reading outwards from the carboxyl group). The mean zigzag angle inthe carbon chain is 113", and the chain is reported to depart by a few degreesfrom the planar zigzag form. It is difficult to say whether the departuresfrom the standard carbon-carbon bond length of 1-54 A. are significantThey are, however, almost identical with the values reported earlier forsuccinic and it is pointed out that a fairly large number of independentstructure determinations lead to values for normal single bonds that aresomewhat less than 1-54 A . ~ * It is quite clear, however, that none of thiswork has an accuracy as high as that now obtained for dibenzyl or coronene(pp. 58, 59), and further investigation is needed.Other Organic Structures.-Certain geometrically isomeric piperazinederivatives containing two quaternary nitrogen atoms have recently beenprepared 29 and an X-ray examination by H. M. Powell has established theconfigurations in this series. The usual correlation between low meltingpoint, high solubility, and &-configuration has been shown to hold. Bymaking use of the high scattering power of the iodine atom, an electrondensity projection was obtained for trans-NN'-di-(P-chloroethyl)-NN'-di-2 6 C. H. MacGillavry, Rec. Traw. chim., 1941, 60, 605.2 7 H. 5. Verweel and C. H. MacGilIavry, Nature, 1938, 142, 161; 2. Krist., 1939,102, 60.28 Ann. Reports, 1938, 35, 196; also C. W. Bunn, Trans. Paraday SOC., 1939, 35,482; C. H. MacGillavry, 2. Krist., 1938, 98, 407; F. J. Llewellyn, E. G. Cox, andT. H. Goodwin, J . , 1937, 883; T. H. Goodwin and R. Hardy, Proc. Roy. SOC., 1938,A , 164, 369.29 W. E. Hanby and H . N. Rydon, J., 1945, 83362 GENERAL AND PHYSICAL CHEMISTRY.methylpiperazinium di-iodide (triclinic) in which the resolution is sufficientto establish the trans-configuration quite clearly.The triphenyls of bismuth, arsenic, and antimony have been examined byJ. Wet~el,~O and he has determined the structure of the bismuth compound inconsiderable detail. 0-03 A.The crystal structure of adamantane (s-tricyclodecane, CloH16) has beendetermined by W. Nowacki.31 This very interesting compound crystallisesin the cubic system, space group T;-F33m, with four molecules per unitcell, and the structure establishes the tetrahedral distribution of valencybonds for the carbon atoms. The carbon-carbon bond length is 1-54~.,and the distance between the carbon atoms on adjoining molecules is 4.15 A.The whole structure is closely similar to that of he~amethylenetetramine.~~Amongst complex compounds of biological interest, preliminary X-ray datahave been given for gliotoxin,33 crepin,3* deoxycorticosterone acetate,35 and17-isodeoxycorticosterone acetate.36 Some very striking single crystalmeasurements have been made on a tobacco necrosis virus derivative byD. Crowfoot and G . M. J. Schmidt.3' The molecular weight of this sub-stance is about 1,850,000, yet it gives single crystals measuring severalmillimetres across. These are triclinic, a = 179 A., b = 219 A., c = 243 A.,and the angles do not differ much from 90". The crystal structure suggeststhat the molecules are spherical, of radius 80-100 A. The extreme size ofthe unit cell makes it possible to apply a new type of examination withmonochromatic X-rays, known as the " still " photograph method. Whenthe crystal is stationary the cell dimensions are such that large numbers ofcrystal planes are correctly oriented for reflection and these are character-istically arranged on the photographic plate in series of concentric circles orellipses. Much information can be obtained from a detailed study of thesephotographs, which require a far shorter exposure time than the otherusual methods. Reflections from planes with spacings as small as 2 . 8 ~ .have been observed.The crystalline phases of soap have received detailed X-ray examinationin a series of papers by M. J. Buerger and and diffraction datahave also been given for a series of mono glyceride^.^^The bismuth-carbon distance is given as 2.30J. M. R.F. P. BOWDEN. J. M. ROBERTSON.D. TABOR. H. W. THOMPSON.so 2. Krist., 1942, 104, 305.32 R. G. Rickinson and A. L. Raymond, J . Amer. Chem. SOC., 1923, 45, 22;s1 Helv. Chim. Acta, 1945, 28, 1233.R. Brill, H. G. Grimm, C. Hermann, and C . Peters, Ann. Physilc, 1939, 34, 393.R. Crowfoot and 13. W. Rogers-Low, Nature, 1944, 153, 651.34 B. W. Rogers, Brit. J. Exp. Path., 1944, 25, 212.35 W. Nowacki, Helv. Chim. Acta, 1944, 27, 1622.s6 Idem, ibid., 1945, 28, 1373.38 M. J. Buerger, L. B. Smith, F. V. Ryer, and J. E. Spike, Proc. Nut. Acud. Sci.,1945, 31, 226; K. W. Gardiner, M. J. Buerger, and L. B. Smith, J. Physical Chem.,1945, 49, 417; M. J. Buerger, Amer. Min., 1945, 30, 551.s9 L. J. Filer, S. S. Sidhu, €3. F. Daubert, and H. E. Longenecker, J . Amer. Chem.SOC., 1944, 66, 1333.a 7 Nuadre, 1945, 155, 504

ISSN:0365-6217    

DOI:10.1039/AR9454200005

出版商:RSC    

年代:1945

数据来源: RSC

摘要:

INORGANIC CHEMISTRY.I. INTRODUCTION AND GENERAL.THIS year's Report on Inorganic Chemistry provides a survey of five specificfields which appear to be dominant a t the present time, and in which rapiddevelopments appear likely in the near future. Exhaustive discussion ofthe large number of available recent papers has been avoided, attentionbeing confined largely to papers of fundamental interest, and to work show-ing notable advances in t'echnique. A few important papers which cannotappropriately be included elsewhere are discussed below.The supposed effects of drying on the physical properties of liquids havefrequently been the subject of discussion, and the appearance of yet anotherpaper proving the invalidity of earlier observations is of considerableinterest. It has been shown that dinitrogen tetroxide, N204, reacts withphosphoric oxide a t room temperature, oxygen and the compound P205,2N0being slowly formed; the liberation of oxygen accounts for the supposedincrease of vapour pressure stated by previous workers to result fromintensive drying of the tetroxide.A small fraction of the liquid tetroxide,distilled from the main bulk after reaction with phosphoric oxide, gavenormal vapour pressures when examined under " dry " conditions. Di-nitrogen trioxide also reacts with phosphoric oxide with formation ofP20,,2N0, and the consequent enrichment of the vapour in N204 =+ 2N0,accounts satisfactorily for the rise of vapour density previously ascribed toa drying process. These observations, together with those of other workerswho have examined other physical properties, lead to the general conclusionthat physical properties of a material are not influenced by intensive drying.A useful contribution to the chemistry of solutions in non-aqueoussolvents is provided by a long paper by G.Jander and G. S ~ h o l z , ~ dealingwith solutions in anhydrous hydrogen cyanide. The feeble dissociation ofliquid hydrogen cyanide itself may be represented by 2HCN (H,CN)+ +(CN)-, so that " acid analogues " in the hydrogen cyanide solvo-system, asin the water system, are substances affording solvated hydrogen ions." Base analogues " in hydrogen cyanide, however, are compounds givingcyanide ions on dissociation. The degree of dissociation of typical acidand base analogues (the latter largely comprising substituted ammoniumcyanides formed by dissolving amines in hydrogen cyanide) have beendetermined by cryoscopic measurements, and the production of salts bytheir " neutralisation " reactions studied.Solvolysis reactions of salts andacyl halides are also described. " Amphoteric " behaviour is typified by atitration with liquid hydrogen cyanide solutions of ferric chloride and tri-ethylammonium cyanide ; the first additions of base cause precipitation ofsolvated ferric cyanide, but excess of the base dissolves the precipitateE. M. Stoddart, J., 1945, 448.2. physikal. Ghem., 1943, 192, 163.a Idem, J . , 1938, 145964 INORGANIC CHEMISTRY.slowly, triethylammonium ferricyanide being formed in solution.Sulphurtrioxide behaves as a potential acid analogue in hydrogen cyanide, with whichi t appears to combine to form a tribasic acid, S(OH),(CN),. Sulphuric acidis thought to give S(OH),(CN),.Continued interest in the simpler derivatives of phosphine and arsine isevident. A simple preparative method for the monosodium derivatives,NaPH, and NaAsH,, has been described-; an ethereal solution containingphosphine or arsine in substantial excess is treated with a solution of sodiumtriphenylmethyl, the required sodium derivative being obtained as a whiteprecipitate. If the hydride is led into a solution of sodium triphenylmethyl,reaction proceeds beyond formation of the monosodium compound, and theproduct is heavily contaminated with Na,PH and Na,P (or correspondingarsenic compounds).The pure monosodium compounds are spontaneouslyinflammable in air, the arsine derivative being notably less stable than itsanalogue. Both compounds afford easy access to alkyl-phosphines and-arsines by treatment with corresponding alkyl halides. Evidence wasobtained for the existence of a magnesium compound, MgBrOPH,, formedby the action of phosphine on ethylmagnesium bromide, but the productwas not isolated. Excess of arsine, bubbled through a solution of lithiumin liquid ammonia a t - 70°, affords LiAsH2,4NH, as a yellowish-whitecrystalline solid ; on warming, this decomposes successively intoLiAsH,,2NH3 and Li,AsH. The thermal decomposition reactions of thecompounds KPH,, NaPH,, and LiPH,,4NH3 have also been studied.6A recent paper on the preparation and properties of chromous iodide 7is noteworthy on account of the elegance of the techniques described forthe manipulation of this substance, which is highly reactive towards airand water.The iodide is prepared by the action of iodine vapour onmetallic chromium a t 700-850" ; it forms a brownish-red crystalline sublim-ate. The colour was suspected to be due to adsorbed or dissolved iodine(the chloride and bromide both being colourless), but since it remainedunchanged in the presence of mercury vapour a t 500" it was finally deducedto be that of chromous iodide itself. The manipulative techniques adopted,including that used for the pyknometric determination of the density ofthe solid by immersion in xylene, are described in detail in the originalpaper.Reactions involved in the oxidation of cobaltous and manganoushydroxides by air have recently been described.Cobaltous hydroxide,precipitated by sodium hydroxide from cobaltous chloride solution, inpresence of the mothor-liquor containing excess of alkali, is not oxidised toany considerable extent by a current of air at room temperature. If thesolid product is washed, air-dried, and heated in air to expel combined water,oxidation proceeds much farther during the heating, and the oxygen contentH. Albers and W. Schuler, Ber., 1943, 76, 23.C. Legoux, Bull. SOC. chim., 1940, 7, 549.P. Fireman, J . Amer. Chern. Soc., 1945, 67, 1447.Idem, ibid., p. 545. ' F. Hein and G.Biihr, 8. anorg. Chem., 1943, 251, 241WELCH : INTRODUCTION AND GENERAL 65may a t one stage exceed that corresponding with the oxide c0304 ; expulsionof the whole of the water, however, is accompanied by liberation of thisexcess of oxygen, the final product being anhydrous Co304. The oxidationof cobaltous hydroxide in the boiling mother-liquor proceeds much fartherthan a t lower temperatures, particularly in presence of a substantial excessof alkali, and the air-dried oxidised material may contain more oxygenthan corresponds with Co,O,; this oxide is again obtained after expulsionof water. Oxidation of a suspension of freshly precipitated manganoushydroxide a t the boiling point affords mangano-manganic oxide, Mn304,directly; a t room temperature a product is obtained containing rathermore oxygen than this oxide.The stability relationships of ferrous hydroxide have been clarified by adetermination of its heat of combustion to or-ferric oxide.s The valueobtained shows that the hydrogen pressure associated with the equilibrium3Fe(OH), + Fe30, + H, + 2H20 is considerable, even at room temper-ature ; ferrous hydroxide is therefore inherently unstable with respect tohigher iron oxides, even in the absence of oxygen.The freshly preparedhydroxide is white, but a greenish tinge is developed on washing, owing toreduction of water. The dry material is pyrophoric, slow oxidation afford-ing ferroso-ferric oxide; a- and y-ferric oxide are formed by oxidation a thigher temperatures.Some recent work on calcium polysulphides lo merits brief reference.When a suspension of calcium sulphide and sulphur is heated, hydrogensulphide is evolved, and calcium polysulphides (CaSIL, where n is between4 and 5), calcium hydrosulphide, and calcium thiosulphate are formed, bythe following reactions : 2CaS + 2H20 4 Ca(SH), + Ca(OH),; Ca(SH), + (n - 1)s _c, CaS, + H2S ; Ca(OH), + 2H2S 4 Ca(SH), + 2H,O ; CaS, + 3H20 -+ CaS203 + 3H2S.Reaction of polysulphide with oxygen alsoproduces thiosulphate : CaS, + 1-50,---+ CaS,03 + (n - 2)s. Evapor-ation of solutions of polysulphides affords oxysulphides of the typeCaS3,2Ca(OH),.Some reviews of particular interest which are now available cover thefollowing topics : the atomic-weight determinations by 0. Honigschmidand his collaborators during the past thirty years; 11 the chemistry of thealkali metals; l2 the chemistry of indium; l3 the inter-relationships of thechemistry of carbon and silicon; l4 reactions in silicate systems containingwater ; l6 the effect of purity on the properties of metals ; J.6 and outstandingrecent developments in inorganic chemistry genera1ly.l'R. Fricke and S.Rihl, Naturwiss., 1943, 31, 326; 2. anorg. Chem., 1943,251,414.lo A. A. Sanfourche, Bull. SOC. chim., 1943, 10, 472.l1 0. Honigschmid, Angew. Chem., 1940, 53, 177.l2 W. Klemm, Chem.-Ztg., 1940, 64, 253.l3 F. Ensslin, Chemie, 1942, 55, 347.l4 R. Schwarz, ibid., 1943, 56, 268.lS W. Noll, ibid., 1944, 57, 90.l6 F. Weibke, Angew. Chem., 1940, 53, 313.l 7 W. Klemm, Chenaie, 1943, 56, 1.REP.-VOL.XLII. 66 INORGANIC CHEMISTRY.2. VALENCY AND THE CONSTITUTION OF SOME INORGANIC MOLECULES.Recent contributions to the theory of valency in which inorganic com-pounds are implicated include an important paper l8 on the occurrence ofthe so-called co-ordinate link. Early valency theory had supported thefollowing structural formuh for nitric acid, phosphorus oxychloride,sulphuryl chloride, and perchloric acid :c1 0 IIII cl\ / O H-O-Cl=O0 I\ O I c l / s ~ o 0H-O-N/< CI--proc1I n later developments of the theory of the chemical bond, co-ordinate linkswere substituted for the double bonds in these formulse, and the followingstructures became widely accepted :? c1c1-P-, 0c1Cl 0c1 0H-O-CI+ 0J.0>s!:0 I1 H-O-N:0Still more recent work has brought to light a number of facts which thesestructures are inadequate to explain.There is good reason for supposingthat the length of a co-ordinate bond should approximate to that of thecorresponding single covalent bond. Evidence has now accumulated thatin structures of the general types shown above, the length of the non-metalt o oxygen bond (briefly termed " oxy-bond ") is considerably less than thatof a single bond of the corresponding type, and is in most cases approximatelyequal to, or even less than, the corresponding double-bond length. Theavailable bond-length data, in fact, suggest strongly that oxy-bonds are notco-ordinate links, but are more accurately represented as double covalentbonds. In their recent paper, Sutton et al.have made a careful analysis ofdipole-moment data (including results of ingeniously planned measurementson a number of compounds not previously studied), and of relevant thermaldata, for compounds containing oxy-bonds with phosphorus, sulphur,selenium, and chlorine; this analysis leads to the same general conclusionas considerations of bond length, and there can be little doubt that co-ordinate links are of much less frequent occurrence than has often beenassumed. Clearly the first, and older, series of structures shown abovemust be accepted in preference to the second series.Some other conclusions reached in the same paper merit brief reference.It appears to be generally true that abnormally strong bonds are abnormallyshort.Co-ordinate links, when they do occur, are relatively weak; thisoccurrence is sometimes favoured by the resonance-energy increase of asystem into which they bring the possibility of more component structures,G . M. Phillips, J. S . Hunter, and L. E. Sutton. J.. 1946. 146WELCH : VALENCY AND CONSTITCTION OF SOME INORGANIC MOLECULES. 67as in the case of ozone, described as a resonance hybrid to which the fourstructures shown below are the principal contributors.O N 0 O 0(Predominant.)+ +Some light is also cast on the chemistry of the halogen oxy-acids, whichapparently exist because the atoms of halogens other than fluorine are ableto utilise d orbitals to form double bonds with oxygen; fluorine is unlikelyto give oxy-acids other than hypofluorous acid, the existence of whichseems possible.Additive compounds of the boron halides are among the simplest examplesof molecules clearly involving donor-acceptor (or co-ordinate) linkings, andtheir study allows the general properties of such linkings to be examined ina relatively simple molecular environment.The compound of dimethylether and boron trifluoride has already been studied in considerable detail,2and the work has now been extended by the recording of some thermal andother physical properties of the 1 : 1 additive compounds of methyl cyanidewith boron trichloride and trifl~oride.~ Both these substances dissociatecompletely into their components in the vapour state, although cryoscopicmolecular-weight determinations on benzene solutions of CH,*CN,BF, reveallittle dissociation.Detailed discussion of the valency relationships in thesecompounds awaits the results of X-ray examination of their structures inthe solid state.The revival of “bridged” structures for diborane and other boronhydrides4 has renewed active interest in this group of compounds, thestructures of which have so far defied entirely satisfactory elucidation. Ina recent contribution on this ~ u b j e c t , ~ a new type of chemical bond ispostulated to occur between boron atoms in the hydrides ; this “ protonateddouble bond ” comprises a double bond of the normal covalent type, withtwo protons embedded in the electron cloud between the bonded atoms;these atoms bear single negative charges, compensatingH - H for the charges on the protons (I).An alternative formul-ation of this bond type in terms of resonance, consistent‘H with the views of Longuet-Higgins and Bell: is possible;moreover, the bond bears many of the essential featuresof the mode of linking proposed by E. Wiberg for the boron-boron bond indiborane, and discarded in favour of earlier resonance structures. The diboranemolecule may be visualised, according to Pitzer’s views, as an ethylenea A. W, Laubengayer and G . R. Finlay, J. Amer. Chem. Xoc., 1943, 65, 884; S. H.Bauer, G. R. Finlay, and A. W. Laubengayer, ibid., p. 889; 1945, 67, 339; Ann.Reports, 1943, 40, 90.\BHfB’(1.)*/ =+A. W. Laubengayer and D. S. Sears, J . Amer. Chem.SOC., 1945, 67, 164.4 See, e.g., H. C . Longuet-Higgins and R. P. Bell, J., 1943, 250; Ann. Reports,6.K. S. Pitzer, J. Amer. Chem. Soc., 1945, 67, 1126.1943, 40, 62.Ber., 1936, 69, 281668 INORGANIC CHEMISTRY.molecule in which two protons have been removed from the carbon atomnuclei and inserted in the spread-out electron cloud of the carbon-carbondouble bond ; the same moleculaz orbitals are said to be appropriate in bothcases, although in diborane the electron cloud is more concentrated roundthe protons. The general properties of the boron-boron linking are satis-factorily accounted for on this basis, and an extension of the theory leads togeneral structural principles which are in accord with the somewhat irregularformulation of the higher boron hydrides.The available physical data forthe hydrides are claimed also to support the principles enunciated. Thereis an evident need for more extended and accurate physical measurementson the boron hydrides (particularly the higher hydrides), and until suchmeasurements provide a secure basis for discussion, speculation on finedistinctions of bond type seems unwise. I n the case of diborane it doesseem clear that an ethane-like model must be discarded in favour of someform of bridged structure, but it is doubtful if information available atpresent justifies detailed discussion of the exact nature of the bridge.Other “ bridged ” structures must clearly exist in the various types ofpolynuclear complexes, in many of which the mode of linking between themetal-atom nuclei is not clearly established. Interesting suggestions regard-ing the constitution of binuclear complexes have recently been made.’Up to the present, halogen bridges such as those in the dimeric moleculesof the aluminium halides have usually been represented in the form (11),although the occurrence of some form of resonance has been tacitly assumed.It is likely that this resonance involves structures of type (111) or (IV); 8(11.) (111.) W.)such structures would give higher interatomic distances for the M-X bridgebonds than normal M-X bonds not incorporated in the bridge, a deductionsupported by the Al-Cl distances in dimeric aluminium chloride.9 Theinteresting feature of structures of type (IV) is that they allow atoms withodd numbers of electrons to attain even-numbered electron configurationswithin the complexes; instead of two metal atoms of valency n, eachcomplex contains one of valency n - 1 and one of valency n + 1, resonancebetween the two possible alternative structures of type (IV) preventingspecific association of either of these valencies with one or other of themetal atoms.Odd-electron atoms bridged by structures of types (11) and(111) would introduce two unpaired electron spins into the complex andrender it paramagnetic; the fact that many complexes in which thesestructures are permissible are actually diamagnetic is accounted for iftype-(IV) structures are assumed.7 K. A. Jensen and R. W. Asmussen, 2. anorg. Chem., 1944,252, 234.8 Cf.ref. (7) and K. A. Jensen, “ Om de koordinativt firegyldige metallers storiokemi,”9 K. J. Palmer and N. Elbott, J. Arner. Chern. Soc., 1938, 60, 1852.Copenhagen, 1937, p. 58WELCH : VALENCY AND CONSTITUTION OF SOME INORGANIC MOLECULES. 69Bridges formed by nitro-, carbonyl, and cyanide groups are thought toinvolve resonance structures (V)-(VII), the second structure of (VI) in-volving a subsidiary resonance shown in (VIII). It is interesting to notethat (VIII) accounts for the observed structure and diamagnetism of theiron carbonyl Fe,(CO), without a direct bonding of the two iron atoms.1°(VII.) (VIII. )Clearly all these proposed bridge structures must still pass the more stringenttests of quantum-mechanical treatment and of physical measurements, butthey offer interesting lines of development in the structural chemistry ofpol ynuclear compounds.The constitution of the compound K,Ni(CN),, prepared by the action* * - -N :C: N : : C : :Ni: : C : : N :.. ....* . * * - - ..- * -: NC+: N : : C : Ni : C : : N :C+N :(XI.).. ..- .. + .. 4-+ . * -....* . -..r- ..N .. . . r i 1- ..C: N : : : C : Ni: C : : : N :CN(X.1a . 4-.... .. ....of excess of potassium on K,Ni(CN), in liquid- ammonia solution,ll presents an interestingproblem. It has recently been pointed out l2that the radical Ni( CN)a- is isoelectronic withnickel carbonyl ; the canonical structures(1X)-(XI) are therefore advanced. The double-bonded structure (IX), in which the nickel atombears no formal charge, is thought to be themost satisfactory, and consequently to con-tribute to the greatest extent to the supposedresonance structure of the ion.10 Cf.H. M. Powell and R. V. G. Ewens, J . , 1939, 286; Ann. Reports, 1939,36,167.l1 J. W. Eastos and W. M. Burgess, J . Amer. Chena. SOC., 1942, 64, 1187.l2 C. L. Deasy, ibid., 1945, 07, 16270 INORGANIC CHEMISTRY.The resonance structures (XII) and (XIII) are proposed for the Ni(CN);-ion in K,Ni(CN),, similarly prepared by the action of potassium, in liquidammonia solution, on K,Ni(CN), in excess. Like structure (IX) for the. - - 2- [: k : : C : : N: .. : : C : : N :I [ : N : : : C : Ni: .. C : : : N :Iz-(XII.)previou..CN :-.. ....II CiN c.... ....(XIII.)compound, structure (XII) is preferred (and presumably ontributesto the larger extent to the resonance structure) because the electropositivenature of the nickel atom should result in relatively low stability for struc-tures in which nickel bears a negative formal charge. The developmentof the structural chemistry of these complexes, and of other related onesthat may yet be isolated, is awaited with interest.3. SOME ASPECTS OF THE CHEMISTRY OF COMPLEX COMPOUNDS.I n the 'study of the chemistry of complex compounds a distinct changeof emphasis is noticeable in recent work; although new types of complexand new co-ordinating groups are still being examined, much more attentionis now being given to the quantitative aspect of complex formation andstability, and data are accumulating which should soon lead to a morecomprehensive understanding of complexes generally, and of the valencyrelationships governing their structure.A careful quantitative investigation of the stability of chelate complexesof bivalent copper A group of 21 complexesof copper with o-hydroxy-aromatic aldehydes (substituted salicylaldehydes)and p-diketones was selected for study.The method adopted was to carryout electrometric titrations with alkali on solutions (in 50% dioxan-water)containing known concentrations of copper, chelating agent, and excessacid. From the pH and concentration values, equilibrium constants werecalcula.ted for the general reactionhas given interesting results.\c-0- 'c-07-C/ +*cu++ * -cH ' ::cu=,=O %= O.''where cu represents one equivalent of copper, and the hature of the bondsshown as dotted lines is open to discussion.With a 4-co-ordinate complextwo equilibrium constants, relating to the successive attachment of twochelate groups, must apply, but in the absence of data sufficiently accuratefor a precise comparison of these constants, an average value was derived1 M. Calvin and K. W. Wilson, J . Amer. Chem. SOC., 1945,67, 2003WELCH : SOME ASPECTS OF THE CHEMISTRY OF COMPLEX COMPOUNDS. 71for each chelating agent.the chelate grouping, formulated as follows :The dissociation of the acidic hydrogen atom of\C-0 \C-0--c/ \H A T --C/ + H+\C= 0.:' \c=o/ /shows a formal resemblance to the dissociation of the chelated metal com-plex, and a comparison of the respective equilibrium constants shows .thatthe two processes are approximately parallel, so long as similar groups areattached to the three-carbon system of the chelate ring.When the attachedgroups differ in type (e.g., in acetylacetone and salicylaldehyde, the doublebond in the latter case forming part of an aromatic ring), the relationbetween the two constants is abnormal. It appears from this result thatthe " enolate resonance," between (I) and (11), which is largely affected bythe environment of the three-carbon system, plays a much more funda-mental part in the bonding of copper in the complex than it does in thebonding of hydrogen in the free chelating agent. It is suggested that thebonding in the complex involves participation of low-lying vacant orbitalsof the metal atom, homopolar metal-oxygen bonds being formed; onepossibility is the formation of a completely conjugated six-membered ring,as in (111).A promised further paper dealing in more detail with thevalency questions involved in this type of structure is awaited with interest.The reactions of a series of amines with the cis- and trans-forms of thecobalt complex [Co en2C1,]C1 (en = ethylenediamine) have been examinedin detail., I n aqueous solutions of this salt, amines with strong donorproperties generally displace one of the chlorine atoms from the complex,affording salts of the [Co en,(NH,R)CI]" ion; substitution by the amine ofthe second chlorine atom was not observed in any of the cases examined.Some weakly basic amines do not enter the complex to give stable salts, butcause disproportionation to [Co en,]"' salts, or rearrangement from thetrans- to the cis-form.In isolated cases, products of other types, including[Co en,(NH,R)OH]Cl,, [Co en,(H,O)OH]CI,, and [Co en,(OH)CI]Cl, are ob-tained. A survey of the observed reactions leads to the important generalconclusion that the type of complex ion formed by a particular amine isnot primarily dependent on its basicity ; this suggests that resonance effects,such as those already discussed above for chelate complexes of copper, mayplay a part in determining the stability of the amine complexes of cobalt.a J. C. Bailar, jun., and L. B. Clapp, J .Amer. Chem. SOC., 1945, 67, 17172 INORGANIC CHEMISTRY.Study of the equilibria involved in the formation of metal-amminecomplexes has usually been limited to determination of equilibrium con-stants for overall reactions of the general type M + nA =+ [MAn], theindividual constants for the successive additions of co-ordinated addendahaving been neglected. J. B j e r r ~ m , ~ emphasising the importance of theseindividual " formation constants " (distinguished from the " complexityconstant " for the overall reaction), has shown how they may be derivedfrom accurate pH data. Bjerrum's method has now been applied* tocomplexes of cadmium, zinc, nickel, and cupric copper with ethylenediamineand propylenediamine, and of silver with ethylamine and diethylamine.Cadmium, zinc, and nickel all form complexes with three molecules ofdiamine per metal atom, but with copper only two diamine molecules enterthe complex.The silver complexes contain not more than two monoaminemolecules ; data for other silver complexes containing one amine moleculefail to reveal any parallelism between the formation constants and thedissociation constants of the amines, the participation of specific valencyeffects again becoming apparent.The use of surface-active catalysts in reactions involving complexes hasuntil recently received little attention,6 but there is now evidence thatactivated carbon may be employed with considerable practical advantagein the preparation of certain cobaltammines ; hexamminocobaltic chloride,[CO(NH,)~]CI,, previously prepared by relatively cumbersome methods, maybe obtained from cobaltous chloride, ammonia solution, ammonium chloride,and air at atmospheric pressure and temperature, if activated carbon isemployed as a catalyst.Several useful catalysed reactions of cobalt andchromium complexes have been examined more recently. The catalystsselected, vix., activated carbon, Raney nickel, and silica gel, are all effectivein promoting formation of bonds between nitrogen and chromium or cobalt,silica gel being less efficient than the other two, and carbon being preferableto Raney nickel on practical grounds. The reaction [Co en2C1,]C1 + 2NH,(aq.) + [Co en2(NH,),]C1, is normally slow and incomplete, the mainreaction product being [Co en,(NH,)Cl]Cl, ; in presence of charcoal thereaction proceeds rapidly to completion.The preparation of [Cr en,]Cl, isusually difficult because of the need to use anhydrous materials, watermolecules co-ordinated to chromium resisting displacement by amines underordinary conditions ; in presence of charcoal, however, the complex isreadily formed from hydrated chromic chloride and aqueous ethylenediamine.Charcoal also has a very marked catalytic action on the interchange ofammonia and nitro-groups in cobalt complexes ; thus [Co en,(NH,)Cl]"3 " Metal Ammine Formation in Aqueous Solution," Copenhagen, 1941.4 G. A. Carlson, J. P. McReynolds, and F. H. Verhoek, J . Amer. Chem. SOC., 1945,67, 1334.6 For earlier work, see R. Schwarz and W. Krlinig, Ber., 1923, 56, 208; N.Shilovand B. Nekrasov, 2. physikal. Chem., 1925, 118, 79; B. Nekrasov, J. Russ. Phys.Chem. SOC., 1926, 58, 207; I. I. Shukoff and 0. P. Shipulina, liolloid-Z., 1929, 49, 126.6 5. Bjerrum, ref. (3).7 J. C. Bailar, jun., and J. B. Work, J . Amer. Chem. SOC., 1945, 67, 176WELCH: SOME ASPECTS OF THE CHEMlSTRY OF COMPLEX COMPOUNDS. 73reacts smoothly with sodium nitrite, the [Co en,(NH,)(NO,)]" formed a troom temperature reacting further, on warming, to give [Co en,(NO,),]'.Even [Co(NH,),]"' reacts with sodium nitrite on heating the solution withcharcoal, and [Co(NH,),(NO,),] is formed ; the same product is obtainedby the catalysed reaction of [CO(NO~)~]"' or [Co(NH,),(NO,),] with liquidammonia, indicating that the non-electrolytic [Co(NH,),(NO,),] is the stableend-product of ammonia and nitro-group interchange in this series of com-plexes.I n the original paper several other catalysed reactions are con-sidered, and evidence is presented that the use of charcoal in reactions ofoptically active cobaltammines does not influence the sign of the rotationof the products. It is evident that the judicious use of catalysts mayconsiderably facilitate access to complex compounds previously preparedby laborious methods, and thus aid the wider development of theirchemistry.The constitution of the group of complexes typified by the carbonato-tetra- and -penta-amminocobaltic ions has been uncertain since the time ofWerner. At first, the latter complex, [CO(NH,)~CO,]*, was thought tocontain a carbonato-group anchored to the cobalt atom by a single bond,one available valency of the CO, group being left free.Later, some evidencewas obtained that known carbonato-pentammine salts all contained onemolecule of water as part of the structure of the complex ion, and Wernerthen proposed the peculiar " betoxine " formula (IV) forOH these salts. The carbonato-group was thought to be abicarbonato-group attached to a basic hydroxyl groupX outside the complex. I n the original or some modifiedform this structure was accepted for a considerable time.Recently it has been pointed out that the complex ion may be regarded asanalogous to a zmitter-ion, such as that of glycine, the only formal differencebeing that the cobalt complex bears a net positive charge :O.CO,H [ C<NHd.](IV.)'0-TO-H 0-E-0-0 0of. +NH,*CH,*CO,H += +NH,*CH,*CO*O- + HSThis structure obviates the need for a molecule of water of constitution.It has now been confirmed that this water is, in fact, not essential to thestability of the complex, the hydrate of carbonatopentamminocobalticnitrate undergoing dehydration, under suitable conditions, without decom-position.8 In the original paper, considerable physical evidence is adducedfor the dipolar-ion structure of the carbonatopentamminocobaltic ion, andthis type of structure is considered to exist in other complexes of generallysimilar character.The application of the spectrophotometer in the identification and study* A.B. Lamb and K.J. Mysels, J . Amer. Chem. Soc., 1945,67, 468.c 74 INORGANIC CHEMISTRY.of coloured complexes in solution is illustrated by recent work on cericsulphate compIex ions.g The equilibrium involved in the formation of asingle species of complex may be represented, in general, as mA + nB[A,B,]. Spectrophotometric measurements on solutions containing vary-ing concentrations of A and B enable the light absorption of the [A,B,]complex to be determined accurately, and although the actual concen-tration of A,B, is not directly deducible unless the extinction coefficient isknown, values of m and n can be derived from the variation in opticaldensity with the concentrations of A and B. Measurements with solutionsof ceric perchlorate and sodium sulphate show that, a t concentrations upto 0 .0 1 ~ ~ a complex is present containing one ceric ion and one sulphateion ; in more concentrated solutions other complexes, containing moresulphate, appear to exist. I n this case the results obtained themselvesallow an estimate to be made of the extinction coefficient of the complex,from which concentration values, and values of the equilibrium constantfor the dissociation of the complex, can be derived. Although the inform-ation they give is sometimes limited, physical methods for the study ofdissolved complexes are of considerable value, and the use of the spectro-photometer is a welcome addition to the available experimental techniques.Similar photometric methods, supplemented by pH determinations andconductometric and polarographic measurements, have been used in a studyof the t'artrate and citrate complexes of nickel and bivalent copper.1° Inall cases the complexes contain metal atoms and organic acid groups in a1 : 1 ratio; the tartrate and citrate complexes, respectively, are consideredto have structures (V) and (VI), or corresponding six-co-ordinate structureseach containing two more water molecules.Both types of complex behaveas monobasic acids, the addition of alkali resulting in removal of an acidicr 1hydrogen atom (thought to be that shown in heavy type in the formula),and increase of the net negative charge on the complex by one unit. Someof the complexes show further reactions with alkali at high pH values.So little is known about the behaviour of complexes in electrode reactionsthat a recent paper on the polarographic reduction of cobaltammines l1merits brief reference.A wide range of complexes containing co-ordinatedammonia, ethylenediamine, water, chlorine, and hydroxyl, nitro-, andnitrito-groups, was studied, 0 . 1 ~ and N-potassium sulphate, and 0.1N-SOdiUmacetate being used as supporting electrolytes. I n every case reduction takesplace in two successive steps; the half-wave potential of the first dependson the complex used, but the second step has a substantially constant@ R. L. Moore and R. C. Anderson, J . Amer. Chem. SOC., 1946,67, 167.lo M. Bobtelsky and J. Jordan, ibid., p. 1824.l1 J. B. Willis, J. A. Friend, and D. P. Mellor, ibid., p. 1680WELCII: SOME ASPECTS OF THE CHEMISTRY OF COMPLEX COMPOUNDS. 75potential through the whole range.The first step is associated with thereduction of cobalt from the tervalent to the bivalent state, with consequentdisruption of the complex, and formation of [Co(H,O),]", and the second stepwith reduction of the aquated cobaltous ions to the metal. The half-wavepotential of the first step is related to the stability of the complex, and it isclear that polarographic measurements may supply yet another techniquefor studying stability in complexes generally.Studies on the preparation of new complexes include a paper on thehydrazine complexes of chromous iodide,12 which were investigated in thehope of stabilising the bivalent state of chromium by co-ordination.Earlierworkers l3 had claimed the existence of a compound formulated as[Cr(N2H4),]I,, stated to be stable in air, but repetition of their preparativemethods gave only a basic, polynuclear compound of evidently complicatedconstitution. Treatment of anhydrous chromous iodide with anhydroushydrazine was found to give a viscous, cherry-red solution which appearedto be stable in dry air, but reacted vigorously with moisture. Attempts toremove excess of hydrazine from the solution by distillat>ion in a high vacuumgave a solid residue, thought to be inhomogeneous, of the approximatecomposition CrI2,3N,H,. Removal of the hydrazine over sulphuric acid ina vacuum afforded a new, stable complex, [Cr(N,H,),]I, ; prolonged keepingover sulphuric acid, after preliminary evaporation of most of the excess ofhydrazine, gave a solid of the composition CrI,,4N,H4.Evidence is adducedthat [Cr(N,H,),]I, is correctly formulated with six-co-ordinate chromium,the hydrazine groups being attached by single bonds, but no indication isgiven of the constitution of the other compounds. Treatment of theviscous solution with alcohol gave a rose-coloured solid formulated asCr,(OEt),I,(N,H,),, which was not further examined.Complexes of rhodium continue to afford a fruitful field of study toF. P. Dwyer and R. S. Nyholm, their latest communication l4 dealing withcomplexes of tervalent rhodium halides with ethyl sulphide. The chloride,bromide, and iodide of the type RhX3,3Et,S have all been prepared byheating the trihalides with an ethyl-alcoholic solution of ethyl sulphide ;co-ordination is sluggish, however, and the complexes dissociate readily.An apparently binuclear compound, ( RhBr3,2Et,S),, was occasionallyisolated in addition to RhBr3,3Et,S.Potassium argentocyanides and cuprocyanides, and the correspondingcomplex acids, have received some attention.15 The compoundK3Ag(CN),,3H,0, in 0-Oh-solution, is completely dissociated into KAg(CN)and potassium cyanide, an interesting confirmation that covalencies greaterthan two are not favoured by univalent silver.A potentiometric titrationmethod indicates that HAg(CN),, HCu(CN),, and HCu,(CN), are all relativelystrong acids. Like H,Ag( CN),, the acid H,Cu(CN),, corresponding withF. Hein and G.Biihr, 2. anorg. Chern., 1943, 252, 55.W. Traube and W. Passarge, Ber., 1913, 46, 1505.14 J. Proc. Roy. Xoc. N.S.W., 1945, 78, 67.16 (Mlle.) J. Brigando, Compt. rend., 1942, 214, 90876 INORGANIC CHEMISTRY.the well-known potassium salt, K3Cu(CN),,3H20, is unstable in aqueoussolution, even a t 0"; it is thought to dissociate successively into H,CU(CN)~and HCU,(CN)~.Further development of the chemistry of carbonyls by W. Hieber andhis collaborators is shown by work on carbonyl halides of osmium.16 Thetetracarbonyl dichloride, [Os(CO),Cl,], is prepared by heating osmium tri-chloride with carbon monoxide a t 120-160°, under 200 atm. pressure; itis a solid, purifiable by sublimation, and is relatively unreactive towardswater and hydrochloric acid.Similar reactions with Os2Br9 and an oxy-iodide of osmium, respectively, give the corresponding bromide and iodide,the iodide being distinctly more reactive than the chloride. The compound[Os( CO),Br],, a corresponding iodide, and osmium tri- and di-carbonyldi-bromides and -iodides, are obtained by appropriate change of conditions,or by thermal degradation of the preceding compounds.4. ORGANOSILICON COMPOUNDS :. VOLATILE HALIDES AND THEIRDERIVATIVES,Continued interest in organosilicon compounds lends importance to anentirely new method of preparing simple alkyl and aryl silicon halides.1I n the past these compounds have almost always been prepared by theaction of Grignard reagents on silicon halides. The new method consists inpassing the vapour of an alkyl or aryl halide (RX) over heated silicon,generally in the presence of a catalyst, or in heating the liquid halide withsilicon and catalyst in an autoclave. The product comprises a mixture ofalkyl or aryl silicon compounds, the composition of which is stronglydependent on the reaction conditions.Under conditions favourable tohigh yields the principal reaction is 2RX + Si --+ R,SiX,, the dialkyl(or diaryl) silicon dihalide being the predominant product ; small quantitiesof RSiX, and R3SiX, and even of R,Si and Six,, are also formed. Whenconditions are such that pyrolysis of free hydrocarbon radicals is favoured,the products include incompletely substituted monosilanes of the typeSiHRX,. Metallic copper appears to be the best catalyst in the preparationof alkyl silicon halides, whereas silver is preferable in the case of aryl com-pounds ; copper may be incorporated as a silicon-copper alloy, by reductionof added cuprous chloride by the silicon itself, or by the use of sintered,compacted pellets of copper powder and finely powdered silicon.I n a subsequent investigation of the reaction between methyl chlorideand silicon-copper,2 the function of the metal catalyst has been more closelyexamined. A series of ingeniously devised experiments affords evidencethat cuprous chloride and methylcopper are the primary reaction products ;in a subsequent change the cuprous chloride is reduced by silicon, copperbeing regenerated and an active intermediate containing silicon (possibly a16 W.Hieber and H. Stallmann, Ber., 1942, 75, 1472.1 E. G. Rochow, J . Amer. Chem. Soc., 1945, 67, 963.D. T. Hurd and E. G. Rochow, ibicE., p. 1057WELCH : ORGANOSILICON COMPOUNDS. 77silicon-chlorine radical) being produced. Finally, the intermediate reactswith methylcopper, cuprous chloride, or free methyl radicals until a stablequadrivalent silicon compound is formed. The metal catalyst thus operatesby making the halogen from the organic halide readily available for reactionwith silicon, and by prolonging the life of the alkyl radicals in the formof metal alkyls readily susceptible to reaction with silicon-containingintermediates.affords another example of thesame type of reaction. Chlorobenzene and silicon react only sluggishly inthe absence of a catalyst; the product is a complex mixture containingchlorinated diphenyls as well as some phenylchlorosilanes, the yield of thelatter being very small.Better yields are obtained with silicon-copper,provided that an " aged " alloy, rendered friable by intergranular oxidation,is used ; the hard, brittle, unoxidised silicon-copper gives very poor results.Other silicon alloys with nickel, antimony, platinum, and silver were tried;silicon-silver was found to give the best yields of phenylchlorosilaneswith the minimum of unwanted pyrolysis products. The alloy used con-tained 10% of silver and was prepared by pressing the mixed powdersand heating in hydrogen a t 900"; it was then heated a t 400" in a stream ofchlorobenzene vapour.The products contained almost all the reactedchlorobenzene as phenyltrichlorosilane and diphenyldichlorosilane, in mole-cular proportions of about 1 : 3. Before distillation of the liquid product itwas necessary to remove, by filtration, small quantities of aluminium chlorideformed from aluminium present as impurity in the silicon; even smallamounts of aluminium chloride, present during distillation, catalyse a dis-proportionation reaction of phenylchlorosilanes to silicon tetrachloride andbenzene." Rearrangement " reactions in covalent halides and related compoundswere commented on in last year's Report: and a recent paper gives furtherinformation on these interesting processes, with special reference to com-pounds of Group IV elements.On being heated in presence of potassiumchloride and partly hydrolysed aluminium chloride, chloroform and bromo-form undergo rearrangement to mixtures of the original compounds withthe two possible chlorobromides, the halogen atoms being randomly dis-tributed among the available CH groups. Methylene chloride rearrangesin a similar fashion with methylene bromide or iodide. In neither case wasmigration of hydrogen atoms detected. Silicon trichlorothiocyanate,SiCl,SCN, disproportionates into the tetrachloride and tetrathiocyanatewhen the vapour is passed through a tube at 600°, and the results showthat the equilibrium 4SiC1,SCN 3SiC1, + Si(SCN), is established, theequilibrium constant (in terms of mo1.-fractions) being 0.11 ; the reality ofthe equilibrium was verified by a rearrangement reaction with silicon tetra-chloride and tetrathiocyanate, from which a mixture of products of closelyThe synthesis of phenylchlorosilanesE.G. Rochow and W. F. Gilliam, ibirE., p. 1772.Ann. Reports, 1944, 41, 88.G . S. Forbes and H. 33. Anderson, J . Amer. Chem. Soc., 1945, 67, 191178 INORGANIC CHEMISTRY.similar composition was obtained. Partial rearrangement of silicon iso-cyanate and thiocyanate was obtained after heating in a sealed tube a t 140"for 40 hours, the product apparently containing the new compound silicontriisocyanatothiocyanate, Si(NCO),SCN ; isolation of this compound in apure state is considered possible, in spite of relatively rapid rearrangementon distillation. Evidence was obtained for the occurrence of germaniumtrichloroisocyanate, GeCl,NCO, in the products of rearrangement of german-ium tetrachloride and tetraisocyanate in a hot tube a t 500"; this newcompound decomposes extensively on distillation.When chlorine orbromine is passed over stannous oxide or fluoride a t 550-600", the halogen-ation of the stannous compound is followed by rapid disproportionationwhich prevents isolation of stannic oxyhalides or mixed halides : 2Sn0 +2Br, --+ SnO, + SnBr,, 2SnF, + 2C1, --+ SnF, + SnC1,. I n general, itis evident that rearrangement reactions become increasingly more facilewith carbon, silicon, germanium, and tin tetrahalides and pseudo- halides,ease of rearrangement also increasing from chlorides to iodides. Rearrange-ment is favoured, in fact, by increasing atomic volume of the atoms con-cerned, and by decreasing electronegativity of the halogen or pseudo-halogen group.The isolation of chlorothiocyanates of phosphorus and silicon, and ofphosphorus chloroisocyanate, provides further examples of mixed pseudo-halogen derivatives of non-metals.The compounds SiCl,SCN, POCl,SCN,and PC1,NCO were prepared by the action of silver thiocyanate (or iso-cyanate) on the corresponding chlorides, in benzene or carbon disulphidesolution. Definite evidence was obtained for the existence of PCl(NCO),,but very rapid rearrangement makes its isolation in the pure state difficult(see below). It is noteworthy that the mixed halogeno-thiocyanates con-taining more than one SCN group in the molecule have not been obtained;since substitution of one SCN for chlorine raises the boiling point of thecompound by about 64", it seems likely that introduction of two or moreSCN groups would ,raise the boiling point to such an extent that rapidrearrangement would prevent detection of the compounds by any simpledistillation process.I n general, chlorothiocyanates are more rapidly pre-pared, but less stable to rearrangement, than chloroisocyanates. Mixedhalides or pseudo-halides of silicon are more stable than those of tervalentphosphorus, these, in turn, being less stable than corresponding phosphoryland thiop hosphor yl compounds.Other derivatives of the same type, described more recently, includeailicon trimethoxythiocyanate, Si(OMe),SCN,7s phosphorus dichlorothio-cyanate, PCl,SCN,8 and phosphorus chlorodiisocyanate, PCl(NC0),.8 Thefirst compound is prepared by the action of methyl alcohol on silicontetrathiocyanate, and is fairly stable, although slow deposition of a soliddecomposition product occurs on long storage.No evidence was obtainedfor the production of other methoxythiocyanates in the same reaction,H. H. Anderson, J. Amer. Chem. SOC., 1945,67, 223.Idem, ibid., p. 2176. 1 Idem, ibi&., p. 869WELCH : ORGANOSILICON COWOUNDS. 79although all three possible methoxyisocyanates are known ; this confirmsthat introduction of more than one thiocyanate group into the same mole-cule is difficult. The phosphorus compounds are prepared and isolated bythe action of phosphorus trichloride on silver thiocyanate or isocyanate,followed by special distillation procedures designed to minimise rearrange-ment reactions among the products.Brief mention has been made8 of the existence of the three mixedsilicon isocyanatothiocyanates, prepared by thermal rearrangement reactionsof silicon tetraisocyanates and tetrathiocyanate.Clearly, the pseudo-halide chemistry of silicon and phosphorus, in particular, is rapidly beingmapped out, and extension of the field to other elements should soonfollow.Recent, work on the fluorination of volatile inorganic halides by theconventional Swarts method has resulted in the isolation of a new siliconoxyfluoride, Si,OF,, and of two oxyfluorochlorides, Si,OF,Cl, and Si,OF,Cl,.loThe reaction of hexachlorodisiloxane with antimony trifluoride yielded allthree compounds, together with traces of other products not yet identified(possibly Si,OF,Cl and Si30,F,), and silicon tetrafluoride. The three com-pounds have been fully characterised by their physical properties ; hexa-fluorodisiloxane is gaseous under normal conditions, its boiling point being- 23.3". The compounds all undergo hydrolysis by water or alkalinesolutions ; an attempt to prepare an oxyfluosilicate by passing hexafluoro-disiloxane into potassium fluoride solution was unsuccessful, although " awhite precipitate of no definite composition " is said to have been obtained.The oxyfluorochloride Si,OF,Cl, is thought to have the constitutionF,Si*O*SiCl,, as there are reasons for supposing that once fluorination ofone silicon atom has been initiated, substitution by fluorine is completedon that atom before the second silicon atom is attacked.Pure vanadium tetrachloride has recently been prepared l1 by passingchlorine over ferrovanadium (containing 90% of vanadium) a t 200", andfractionally distilling the product through an all-glass column.Accuratevalues of the principal physical constants have been determined. Purevanadium trichloride was prepared from the tetrachloride by heating a t140" for one week, in a stream of carbon dioxide. The trichloride wasused, in a specially devised all-glass apparatus, for a study of the equi-librium 2VCl,(s) + Cl,(g) =+ 2VCl,(g), for which the mean value of Kp a t160" was found to be 1480 (pressures in mm.).Measurements of the freezingpoint of solutions of vanadium tetrachloride in carbon tetrachloride revealextensive polymerisation to double molecules, which is to be expected inview of the odd number of electrons in the VCl, molecule; the equilibriumconstant of the reaction V,Cl, T- WCl, a t - 25" is 18-2 x 1V (con-centrations in g.-mol. per 1000 g. of carbon tetrachloride). An electron-O G. s. Forbes and H. H. Anderson, J . Amer. Chenz. SOC., 1944, 66, 1703; Ann.10 H. S. Booth and R. A. Osten, J. Amer. Chem. SOC., 1945, 67, 1092.l1 J. H. Shone and M. G. Powell, ibid., p. 76.Reports, 1944, 41, 8980 INORGANIC CHEMISTRY.diffraction study of the vanadium tetrachloride molecule 12 in the gasphase shows that the structure is tetrahedral, the configuration not beingaffected, apparently, by the presence of the odd, unshared electron.The hydrolysis of sulphur chlorides gives rise to a complex mixture ofproducts, including sulphur dioxide, sulphur, hydrogen sulphide, polythionicacids, sulphuric acid, and hydrogen chloride; the mechanism by whichthese products are formed has recently been discussed.13 The course of thehydrolysis reaction, and the mode of reaction of sulphur chlorides withpotassium iodide solution, lend support to the view that the initial step inthe hydrolysis reaction involves formation of hydrogen sulphide (or di-sulphide) and hypochlorous acid : SC1, + 2H,O --+ H,S + 2HC10 ; S,C1, + 2H,O --+ H,S, + 2HC10.In subsequent reactions the hypochlorousacid oxidises the hydrogen sulphide or disulphide to the other productsfound experimentally.If such a mechanism can be established, sulphurmust be regarded as the electronegative constituent in sulphur chloridemolecules, and these compounds must be formally considered as chlorinesulphides. Certain reactions of organic derivatives of sulphur chlorides areadvanced in support of the proposed formulation.Considerable attention is being given to the chemistry and structuralrelations of the numerous additive compounds of volatile inorganic halides,particularly those of boron. In a recent study of the acceptor propertiesof the boron atom in boron trichloride, the systems SO,-BC1, and H,S-BCl,have been examined by thermal analysis,14 the apparatus used incorporatingimprovements in a design described earlier.15 Sulphur dioxide and borontrichloride were found to be immiscible a t low temperatures (- 78" andbelow), and no evidence of additive-compound formation was obtained.With hydrogen sulphide the freezing point-composition curve showed abroad maximum a t about 50 mols.-% of boron trichloride, indicating theexistence of a compound H,S,BCl,, melting a t -35.3".Trimethylamine oxide, NMe,O, which has strong electron-donor pro-perties, also forms a very stable boron trifluoride adduct, Me3N0,BF3,16which is soluble in water without decomposition.It is also stated thattrimethylamine oxide forms additive compounds with silicon tetrachlorideand phosphorus trichloride, the formulze of which have not yet been estab-lished ; valency relationships in these compounds should be of considerableinterest.The boron halide adducts referred to above and on p.67 appear to becorrectly formulated with a donor-acceptor bond between the boron andthe oxygen, nitrogen, or sulphur atoms; the existence of a class of borontrihalide additive compounds of quite different constitution is therefore ofconsiderable interest. It has been shown l7 that the compound CH,*COF,BF,,12 W. N. Lipscomb and A. G. Whittaker, J . Amer. Chem. SOC., 1945,67, 2019.l3 H. Bohme and E. Schneider, Ber., 1943, 76, 483.14 D. R. Martin, tJ. Amer. Chem. SOC., 1945, 67, 1088.l5 H. S . Booth and D. R. Martin, ibid., 1942, 64, 2198; Ann. Reports, 1942, 39, 92.l6 A.B. Burg and J. H. Bickerton, J . Amer. Chem. SOC., 1945, 67, 2261.1' F. Seel, 2. anorg. Chem., 1943, 250, 331WELCH : SOME HETEROGENEOUS EQUILIBRIA. 81formed by direct combination of acetyl fluoride and boron trifluoride, is tobe regarded as the acetyl salt of fluoboric acid, [CH,*CO]+[BF,]-; this con-stitution is established by electrical conductivity measurements on liquidsulphur dioxide solutions of the compound, and by a number of its chemicalreactions. There is also crystallographic evidence that the compoundNOF,BF3, previously regarded as a molecular compound, should be classifiedas a nitrosyl borofluoride, [NO]+[BF4]-.18 A similar constitution has beenassigned l9 to additive compounds of antimony pentachloride with acetyland benzoyl chlorides, formulated as [R*CO]+[SbCl,]-.Fully ionic charactercannot, however, be assumed for the compound NOCl,SbCl,, which appearsto be a resonance hybrid involving contributions by both ionic and molecular-compound types of structure. The compound SOCl2,2SbC1, has little ioniccharacter, its solution in liquid sulphur dioxide having a relatively very lowelectrical conductivity. In the original paper l9 interesting details are givenof the technique used in the manipulation of the compounds, and oftheoretical considerations bearing on their unusual constitution.Solvates formed by titanium and stannic tetrahalides with liquid sulphurdioxide have been examined.20 Titanium tetrachloride and tetrabromideand stannic bromide all give solid solvates containing half a molecule ofsulphur dioxide per halide molecule.Each of the three systems gives apair of liquid layers a t temperatures slightly above the quadruple point,and in each case the denser of these layers corresponds in composition withthe solid solvate. Compounds of boron trichloride and silicon tetrachloridewith sulphur trioxide, having the compositions BC13,2S03 and SiCl,,SO,,respectively, have also been described ; 21 they are white crystalline solidsprepared by adding liquid sulphur trioxide to the cooled chlorides.5. SOME HETEROGENEOUS EQUILIBRIA.Applications of phase-rule methods to systems involving inorganic com-pounds of special interest continue to yield fruitful results. The selectionof systems discussed below is intended to show the trend of recent inves-tigations, and numerous studies on binary and ternary systems of well-known types have not been included.Developments in the investigation of relatively simple systems are wellillustrated by recent work on part of the iron-oxygen system, in which thestability relationships of wiistite, the non-stoicheiometric iron-oxide phaseapproximating in composition to ferrous oxide, have been examined inconsiderable detai1.l The general method adopted, frequently used forsystems of this kind, consisted in determining a t known temperatures theratios of carbon dioxide to carbon monoxide in equilibrium with a par-ticular pair of solid phases (corresponding, e.g., with establishment of the18 I.L. Klinkenberg, Chem.Weekblad, 1938, 35, 197.lD F. Xed, 2. anorg. Chem., 1943, 252, 24.2o P. A. Bond and W. E. Belton, J . Amer. Chem. SOC., 1945, 67, 1691.21 G. P. Lutschinski, J . Gem. Chem. RUSG., 1941, 11, 884.1 L. S. Darken and R. W. Gurry, J. AWT. Chem. SOC., 1946, 67, 139882 INORGANIC CHEMISTRY.equilibrium FeO + CO Fe + CO,), or with wustite alone; since wiistiteexists as a homogeneous solid phase over appreciable ranges of composition,carbon dioxide and monoxide mixtures of corresponding composition rangescoexist with wiistite -as the only solid phase. The measurements a t theiron-wiistite phase boundary were made by holding a strip of pure iron ina known small temperature gradient, in a stream of carbon monoxide anddioxide containing the gases in an accurately predetermined ratio ; a tequilibrium the strip showed a sharp boundary between oxidised and reducedzones, the position of this boundary in the temperature gradient showingaccurately the temperature at which the gas mixture used was in equi-librium with wiistite and iron.A generally similar method was employedfor measurement with wustite and magnetite as solid phases. Data for thecomposition of wustite itself, within the homogeneity range, were obtainedby passing carbon monoxide and dioxide, in predetermined proportions,over ferric oxide or pure iron held a t an accurately known temperature,and analysing the solid phase after attainment of equilibrium ; establish-ment of true equilibrium was verified by approach from both sides, the pairsof results showing excellent agreement.The wustite composition data foreach of the temperatures used (1 100-1400") were plotted against theC02/C0 ratio, and the usually linear plots extrapolated to the CO,/COvalues corresponding with equilibrium a t the wiistite-iron and wustite-magnetite phase boundaries; by this means composition data for theboundaries of the field of existence of wustite were secured, and an importantsection of the iron-oxygen phase diagram was accurately constructed. Impor-tant thermodynamic properties of the system were also derived. A notablegeneral conclusion reached in the course of this work is that thermal diffusionmay vitiate accurate measurements of gas composition in heterogeneousequilibria, unless careful precautions are taken.Systems involving vanadium oxides and typical slag-forming oxides haverecently been studied2 by methods developed largely by R.Schenck andhis collaborators. I n general, a metal oxide undergoing decomposition orreduction gives rise to a system containing two solid phases (oxide + loweroxide, or oxide + metal), in which the equilibrium oxygen pressure is fixedat a given temperature, in accordance with the phase rule. When the oxideis completely converted into a lower oxide, and thus disappears from thesystem, it is replaced by another solid phase comprising the reduction productof the lower oxide; a t this point an abrupt decrease of equilibrium oxygenpressure indicates the changed composition of the solid phases present, andexperimental observation of the oxygen pressure change usually enablesthe stoicheiometric composition of the individual phases to be deduced.Ifsolid solutions or non-stoicheiometric phases occur as intermediate steps inthe reduction, the corresponding oxygen pressure changes are gradualinstead of abrupt, and they enable an estimate to be made of the com-position ranges of stability of the phases in question. It is usually incon-venient to measure oxygen pressures directly, and the reduction is usually2 J. KlBrding, 2. anorg. Chem., 1944. 252. 190WELCH : SOME HETEROGENEOUS EQUILIBRIA. 83effected by carbon monoxide or hydrogen, the CO,/CO or H,O/H, ratio inthe equilibrium gas providing a direct measure of the oxygen pressure ofthe oxide system.If a '' foreign oxide," not involved in the direct reduc-tion equilibria, is added to the solid phase, the oxygen pressure may remainunchanged, or it may increase or decrease; if it increases, formation ofmixed crystals cr of a solid compound between the foreign oxide and thelower oxide is indicated, but if it decreases, compound or mixed-crystalformation involves the higher oxide undergoing reduction. Clearly if bothoxides form compounds or mixed crystals with the foreign oxide, thedirection of oxygen-pressure change depends on the relative stability of thetwo compounds. The study of equilibrium oxygen pressures over oxidesystems is thus capable of affording detailed information on the chemical(and thermodynamical) relationships of the solid oxides.I n the case of the vanadium oxides, reductions of the pentoxide inpresence of calcium, magnesium, and manganous oxides, silica, alumina,and calcium silicates and aluminates were carried out at 600-700".Theexistence of three stable calcium vanadates, CaO,V,O,, 2Ca0,V,05, and3CaO,V,O,, was confirmed, and their stabilities were compared ; a new solidphase, CaVO,, shown by X-ray analysis to have a perovskite structure, wasfound. Minor effects, corresponding probably with mixed-crystal formation,were observed with the other oxides, but no other stable compounds wereidentified. It is concluded that calcium vanadate formation dominatesslagging processes in which vanadium oxides participate.A thorough study has recently been made of the equilibrium reactionbetween anhydrous ferrous chloride and hydrogen sulphide in the temper-ature range 340460".3 As expected, the principal equilibrium is FeCl, +H,S =+ FeS + 2HC1, which is established relatively quickly, but there isa further slow reaction, FeS + xH,S FeS, +s + xH,, in which theferrous sulphide phase gains sulphur in excess of the stoicheiometric amount,forming pyrrhotite.This secondary reaction accounts satisfactorily for theproportion of hydrogen found to occur in the gas phase a t equilibrium. Inthe temperature range studied, the composition of the equilibrium sulphidephase approximates to FeS,.,,.The interconversion of the oxides and sulphides of iron, important inthe usual process for removing hydrogen sulphide from fuel gases, hasrecently been studied in some detail.* The initial product of the reactionof hydrogen sulphide with any form of ferric oxide (hydrated or otherwise)is an unstable monohydrate of ferric sulphide, Fe,S3,H,0 ; a t temperaturesabove 20" and in presence of hydrogen sulphide, this decomposes into amixture of FeS, and a highly magnetic sulphide formulated as Fe8Sg (i.e.,FeS,.,,).When Fe,S,,H,O, Fe8Sg, or precipitated ferrous sulphide, in theform of a moist solid, is oxidised by oxygen at temperatures below 50",or-Fe,O,,H,O is obtained; oxidation of FeS, is difficult. In aqueous sus-pensions the course of the reaction is evidently different, for oxidation ofJ. J. Lukes, C. F. Prutton, and D. Turnbull, J . Amer. Chem. SOC., 1945, 67, 697.R.H. Griffith and A. R. Morcom, J., 1945, 78684 INORGANIC CHEMISTRY.suspensions of the ferric sulphide hydrate or of precipitated ferrous sulphideaffords y-Fe,O,,H,O. All the sulphides give a mixture of ferric sulphatewith an oxide (mainly y-Fe,O,) on oxidation a t high temperatures. Therates of the various reactions, and their dependence on the porosity of thesolid materials, have been studied, but data for the various equilibriumconstants have not been obtained so far.Phase relations between lead sulphide, lead monoxide, and lead sulphateare of practical interest in view of their importance in the smelting of leadores, and certain features of the Pb-O-S system have been examinedr e ~ e n t l y . ~ The equilibrium sulphur dioxide pressure for the reaction PbS +2Pb0 += 3Pb + SO,, which has previously been measured only over lowertemperature ranges, reaches one atmosphere at 920".This reaction, andthe reaction PbSO, + PbS =+ 2Pb + 2SO,, proceed a t appreciable speedonly a t temperatures a t which the mixtures are molten (i.e., above about800" and 850", respectively). At and above 920", a t atmospheric pressure,formation of metallic lead is very rapid, because the system has high fluidityand the dissociation pressure for the first reaction equals or exceeds that ofthe atmosphere. It appears that reduction of lead sulphate to the metalby interaction with the sulphide is necessarily preceded by formation of abasic sulphate, the reaction in fact proceeding in two stages : 7PbS0, +PbS 4(Pb0,PbS04) + 4SO,, 4(Pb0,PbS04) + 6PbS =$ 14Pb + 10S0,.Although lead sulphide and lead monoxide readily react together, rapidheating allows determination of melting points in the binary system PbO-PbS, which has a simple eutectic melting a t 790".Interesting methods have been used in the study of equilibria betweenchromium halides, in the gas phase, and iron,6 which are of practical im-portance in methods of coating iron surfaces with chromium. The vola-tilities of chromium halides in an inert gas (nitrogen) and in hydrogen-hydrogen chloride mixtures were determined by an entrainment method,and from the results, combined in some cases with previous information,all the essential equilibrium data were derived.The equilibrium constantfor the principal " chromising " reaction, CrC1, (gas) + Fe (mixed crystals)+ FeCl, (gas) + Cr (mixed crystals) is found to be approximately unitya t $79-930".The entrainment method used in this investigation allowsan experimental approach t o many systems which would otherwise bediflicult to study, and a discussion of its application, given in the originalpaper, is of general interest.The chemistry of the carbides of chromium is now much clearer as aresult of carefully planned equilibrium ~tudies.~ The existence of threecarbides, Cr7C3, Cr,C, and Cr3C2, is established, the supposed carbide Cr,C2being a mixture of Cr7C, and Cr,C. Equilibrium data, obtained by measure-6 E. J. Kohlmeyer and W. Monzer, 2. anorg. Chem., 1943, 252, 74.6 C.Wagner and V. Stein, 2. physikal. Chem., 1943, 192, 129.7 F. S. Boericke, U.S. Bur. Mines, Rept. Invest., 1944, No. 3747; K. K. Kelley,F. S. Boericke, G. E. Moore, E. H. Huffman, and W. M. Bangert, U.S. Bur. Mines,Tech. Paper, 1944, No. 662WELCH : SOME HETEROGENEOUS EQUILIBRIA. 85ment of carbon monoxide pressures in a closed system, were obtained forthe four reactions 3Cr203 + 13C 2Cr3C, + 9C0, 5Cr203 + 27Cr,C, =i+13Cr7C3 + 15C0, 5Cr203 + 14Cr,C, =$ 27Cr,C + 15C0, and Cr203 + 3Cr,C14Cr + 3C0, and these data enable the principal thermodynamicalproperties of the equilibria and of the participating phases to be evaluated.Low-temperature specific heats for the carbides were also determined. Allthe carbides are found to be stable, at temperatures below their meltingpoints, with respect to decomposition into chromium and carbon, lowercarbide and carbon, or chromium and higher carbide; Cr7C3 is also stablewith respect to Cr,C2 and Cr,C.The measurements allow useful conclusionsto be drawn regarding methods for decarburising ferrochrome.Modern methods of study of metal-oxygen systems are typified byrecent publications on oxides of tungsten * and ~ a n a d i u m . ~ Many of thelower oxides, particularly of transition metals, form non-stoicheiometricphases which are stable within appreciable ranges of composition ; theexperimental problem lies in the identification of the successive phases inthe system, and the establishment of their composition limits of stability.The vanadium oxides were examined by preparing mixtures of vanadiumwith one of its oxides, covering in 15 uniform steps the whole net com-position range between V and VO,.,, the upper limit of investigation.These mixtures were heated in a vacuum at suitable temperatures (1200-1600°), and the products examined, largely by powder X-radiograms, aftercooling.At low oxygen contents the system consists of a solution of oxygenin metallic vanadium, the dissolved oxygen deforming the cubic body-centred lattice of the metal towards a tetragonal structure-an effect show-ing it close analogy to the solid solution of carbon in iron. Experimentaldifficulties prevented determination of the limit of solubility of oxygen invanadium. Preparations having the net composition V00.2 were unusuallyvolatile a t high temperatures, material subliming on to the upper part ofthe alumina crucible and on to the silica tube used for heating.Composi-tions between VO,., and VO,., gave results suggesting the existence of aphase, as yet not clearly identified, lying between the vanadium-oxygensolid solutions and the known “ VO phase,” which exists in the rangeVO,., to VO,.,. At the composition VO,.,, and above, the corundumlattice of V,O, appears. An interesting feature of the system is that theVO phase disproportionates on slow cooling, affording a mixture of vanadium(containing dissolved oxygen) and a higher oxide not yet identified; in thisrespect the VO phase resembles wiistite, which a t low temperatures isunstable with respect to iron and magnetite.Studies of the kind justdescribed illuminate the frequently discordant results of early investigators,who had no knowledge of the widespread occurrence of non-stoicheiometryin solids, and show that there is a large field for the application of modernexperimental methods to quite simple systems.41, 92.8 0. Glemser and H. Sauer, 2. anorg. Chem., 1943, 252, 144; Ann. Reports, 1944,W. Klemm and L. Grimm, 2. anorg. Chem., 1942, 250, 4286 INORGANIC CHEMISTRY.The possible existence of higher oxides of platinum, as yet unexamined,is indicated by the relatively high stability of osmium tetroxide, OsO,, andby the supposed existence of a corresponding iridium compound.1° It issignificant, therefore, that a t high temperatures platinum loses weight a t agreater rate in an atmosphere containing oxygen than in an inert atmosphere,evidently owing to volatilisation of an oxide or oxides.Measurements haverecently been made of the rate of loss in weight of platinum a t 1200" inoxygen a t different partial pressures, and from the results, values of thepartial vapour pressures of possible platinum oxides have been calculated. l1These values give concordant equilibrium constants for the reaction Pt +&no, + PtO, if the three oxides PtO,, PtO,, and PtO, are assumed tovolatilise in different oxygen-pressure ranges (up to 275 min., 275-850 mm.,and above 850 mm., respectively, a t 1200"). Sharply distinct segments ofthe pPtOn-pO, curves correspond with these three pressure ranges.The collection and determination of basic thermodynamic informationfor systems of metallurgical, as well as purely chemical, interest have forsome time been an important feature of the work of K.I<. Kelley and hiscollaborators at the Pacific Experiment Station of the U.S. Bureau ofMines, and Kelley's compilations l2 are of fundamental value to inorganicchemists. Much of the work done relates to heterogeneous equilibria, thelatest publication available l3 dealing with reactions of nitrogen dioxideand the decomposition of the nitrates of manganese, calcium, barium, andaluminium, for which all important data are given. Collection of basicinformation of this kind allows useful general surveys to be made of importantclasses of rea~ti0ns.l~Recent work on ternary systems of conventional type includes aninteresting study of the system Al,0,-S0,-H,0,15 in which phase relation-ships a t relatively low temperatures (down to - 22") were examined.Anew crystalline sulphite, A1,0,,3S0,,xH20, was isolated and characterised.Further data on the same system are available from an investigation of thereaction of superheated water with more basic aluminium sulphites.16Considerable interest also attaches to studies on the solubility in water ofsalts and salt mixtures a t temperatures substantially above inwhich phase changes at the critical temperature of water have beenelucidated.10 L. Wohler and W. Witzmann, 2. Elektrochem., 1908, 14, 106; (Sir) W. Crookes,l1 A. Schneider and U.Esch, 2. Elektrochem., 1943, 49, 55.l2 U.S. Bur. Mines, Bull. Nos. 350 (1932), 371 (1934), 383, 384 (1935), 393, 394l3 K. K. Kelley, U.S. Bur. Mines, Rept. Invest., 1944, No. 3776.l4 See, e.g., a discussion on the reducibility of metallic oxides and sulphides, byl5 W. Fischer and E. Burger, 2. anorg. Chem., 1943, 257, 355.l7 A. Benrath, ibid., 1943, 252, 86.Proc. Roy. SOC., 1912, A , 86, 461.(1936), 406, 407 (1937), 434 (1940).H. J. T. Ellingham, J . SOC. Chem. Ind., 1944, 63, 125.Idem, ibid., p. 369WELCH : " SUB-COMPOUNDS " AND INORGANIC FREE RADICALS. 876. " SUB-COMPOUNDS " and INORGANIC FREE RADICALS.Spectroscopists have for a considerable time assumed the existence,under special conditions, of molecules of extremely simple types, many ofwhich are unfamiliar to chemists on account of the apparently anomalousvalencies associated with their constituent atoms.Most of these moleculesare diatomic; some (such as CO and H,) are known to chemists as stableentities; others (such as CH and OH) have been accepted as intermediateproducts of short life involved in the mechanisms of known chemicalreactions ; many, however, have not been identified as participants innormal chemical processes. The wide variety of diatomic units known bytheir band spectra is evident from works on the spectroscopy of mo1ecules.lMany such units, moreover, are thought to exist as important constituentsof stellar atmospheres, and preliminary calculations have been made on theequilibria governing their coexistence a t the high temperatures existing instars.2 These diatomic molecules usually contain atoms exhibiting abnor-mally low formal valencies, and most of them may be classed (with otherlower-valency molecules of anomalous types, not necessarily diatomic) as( ( sub-compo~nds.~~ Although so many of the possible sub-compounds haveeluded detection and characterisation by chemical means, evidence of theirimportance in chemical processes, particularly at high temperatures, isaccumulating from scattered sources, and brief discussion of the subject inthese Reports is felt to be timely.A review dealing with a selection ofsuboxides has already a~peared.~The existence of a lower oxide of silicon has been assumed by manyinvestigators over a considerable period,* and a commercial material(" Monox '7 marketed early in the present century was regarded as siliconmonoxide.More recently, X-ray examination of this substance has indic-ated that it consists of silica and silicon in intimate admixture.5 Themore important characteristics of silicon monoxide were not realised,apparently, until 1940, when a useful contribution to the subject appeared.It was found that when silicon is heated a t 1450" with the requisite quantityof silica, dehydrated kaolin (A1,03,2Si0,), beryl ( 3BeO,Al20,,6Si0,) , or zircon(ZrSiO,), in an evacuated tube, the silicon and silica are volatilised com-pletely from the reaction zone, and appear in cooler parts of the apparatusas a brown sublimate having the net composition SiO; in the case of thesilicates a residue of alumina, alumina and beryllia , or zirconia, respectively,remains in the heated region.The condensed material has the propertiesof an intimate mixture of silicon and silica, and it is inferred that siliconSee, e.g., G. Herzberg, " Molecular Spectra and Molecular Structure," translatedK. Wurm, Chem.-Ztg., 1940, 64, 261.C. A. Zapffe, J. Arner. Ceram. SOC., 1944, 2'7, 293.H. N. Baumann, jun., Trans. Electrochem. SOC., 1941, 80, 95.E. Zintl, W. Brauning, H. L. Grube, W. Krings, and W. Morawietz, 2. anorg.by J. W. T. Spinks, New York, 1939, pp. 482-494.4 See reviews and bibliographies in refs. (3), (7).Chem., 1940, 245, 188 INORGANIC CHEMISTRY.monoxide is formed in the vapour phase in the initial reaction, but dispro-portionates rapidly on condensation (2SiO + Si + SiO,).This inabilityof the sub-compound to exist as subh in the solid state is characteristic,and attempts to condense or isolate sub-compounds are generally unsuccess-ful because of very rapid reversal of the equilibria involved in their formation.Recognition of this general property leads to a better understanding ofsub-compound chemistry ; earlier failures to isolate sub-compounds aresatisfactorily explained, and it becomes evident that such materials mayplay an important part in high-temperature processes involving oxidationand reduction.Formation of silicon monoxide is not confined to reactions betweensilicon and silica (or a silicate) ; oxides of niobium and tantalum are reducedon heating with the calculated quantity of silicon, the monoxide " sublim-ing " and leaving a residue of substantially pure niobium or tantalum.6The condensed " silicon monoxide " (silicon and silica) is itself an effectivereducing agent, as might be expected from its content of finely dispersedsilicon; dolomite and a zinc ore give magnesium and zinc, respectively, onheating with the condensed product.Calcium phosphate is reduced tophosphorus, but the yield is poor.Although silicon monoxide is not stable, apparently, as a condensedphase, its existence in dilute solution is indicated by recent work on silicon-oxygen equilibria in molten steel.', Previously the reaction betweensilica and molten iron had been examined on the basis of a single equilibrium,SiO, + 2Fe += 2Fe0 + Si, but a careful re-investigation of the equi-librium under laboratory conditions shows that a consistent equilibriumconstant for this reaction cannot be obtained. If two successive reductionsteps are postulated, SiO, + Fe =+ FeO + SiO, SiO + Fe FeO + Si,the experimental data can be interpreted quite satisfactorily. These datagive, moreover, a considerable amount of preliminary thermodynamicalinformation on reactions involving silicon monoxide ; the standard free-energy change for the reaction SiO, + Si + 2Si0, a t 1600°, is calculatedto be + 10,000 g.-cals., the equilibrium constant a t this temperature being0.067.It is found that a t high oxygen contents silicon present in a molten-steel bath is to a large extent combined as silicon monoxide, a conclusionwhich has an important bearing on certain aspects of equilibria in moltensteel. Clearly, similar considerations may apply to equilibria involvingother alloying and impurity elements in steel, and in metal systemsgenerally.Boron monoxide, BO, appears to exist under similar conditions tosilicon monoxide.9 Boron trioxide is too volatile for its reaction with borona t high temperatures to be examined in simple apparatus.There isevidence, however, for the occurrence of the interesting reaction A1,03 + B-+ 2AlO + BO, material corresponding with the disproportionation pro-7 C. A. Zapffe and C. E. Sims, Iron Age, 1942,149, 29, 34.0 E. Zintl, W. Morawietz, and E. Gastinger, 2. anorg.Chem., 1940, 245, 8.Idem, Amer. Inst. Min. Met. Eng., Tech. Publ. No. 1498 (1942)WELCH : (' SUB-COMPOUNDS " AND INORGANIC FREE RADICALS. 89ducts of aluminium and boron monoxides being obtained as a sublimatewhen alumina and boron are heated in a vacuum a t 1300". At highertemperatures ( lsOoO), a mixture of zirconium dioxide and boron loses boronand oxygen in an approximately 1 : 1 ratio, indicating volatilisation ofboron monoxide, but no zirconium is lost. Aluminium monoxide wasapparently being studied by E. Zintl at the time of his death,1° but nodetails of the work have been made available so far.Detailed attention has not hitherto been given to labile suboxides otherthan those just described, but there is evidence that others exist.3 Theunusual volatility of lower oxides apparently present in the systemstitanium-oxygen 11 and vanadium-oxygen 12 may be accounted for by theexistence of suboxide molecules in the vapour phase.The stability relation-ships and chemistry of sulphur monoxide, which fits well into sub-compoundchemistry generally, have been reviewed recently. l3 Subsulphides appearto merit further study; silicon monosulphide, SiS, is well known,14 andband spectra of other similar species have been 0bserved.l High volatilityof what appears to be a titanium subsulphide has also been noted.15Several sub-halides are known, and although a sub-chloride (CaCl), sub-fluoride (CaF), and sub-iodide of calcium (CaI) were studied 16 as long agoas 1909, little attention has been given to them since.These compounds ofcalcium, although apparently isolable in the solid state by rapid quench-ing, show the characteristic sub-compound property of easy reversion tothe dihalides and free calcium, from which they are prepared.Sub-iodides of cadmium and zinc, presumably CdI and ZnI, are obtainedas greenish-yellow and black powders, respectively, on heating the metalswith the requisite quantity of iodine at 1000" for ten hours, in a steel bomb,and then cooling rapid1y.l'Aluminium monofluoride, AlF, affords an interesting example of a sub-fluoride, to which attention has recently been directed.lB It was earliershown that aluminium in presence of a metal fluoride can be volatilised a t800-1000", a t a pressure of several rnm.,l9 although the vapour pressure ofaluminium in this temperature range is extremely small. Klemm and Voss,suspecting the existence of a volatile aluminium sub-fluoride to which thisunusual volatility of the metal could be attributed, heated suitable mixturesof anhydrous aluminium fluoride and aluminium in close proximity to awater-cooled silica thimble, in an evacuated tube.At temperatures oflo See obituary notice by H. W. Kohlschutter, Ber., 1942, 75, 66.11 P. Ehrlich, 2. anorg. Chem., 1941, 247, 53.l2 Seep. 85.l3 P. W. Schenk, Chem.-Ztg., 1943, 67, 257, 273.l4 F. Wust and A. Schiiller, Stahl u. Eisen, 1903, 23, 1128; W. Hempel and vonW. Biltz, P. Ehrlich, and K. Meisel, ibid., 1937, 234, 97.Haasy, Z . anorg. Chem., 1900, 23, 32.l6 L.Wshler and G. Rodewald, ibid., 1909, 61, 54.17 K. Siddiqi, Current Sci., 1943, 12, 147.l8 W. Klemm and E. Voss, 2. anorg. Chem., 1943, 251, 233.l9 C. B. Willmore, U.S.P. 2,184,705 (1939)90 INORQANIO CHEMISTRY.650-670" (measured outside the evacuated tube, inside which a somewhatlower temperature prevailed on account of the large temperature gradientin the apparatus), a black sublimate was obtained; a t higher temperaturesthe sublimate in the hotter zones of condensation became white, and above750" the whole sublimate was white. The black sublimate became whiteon heating in argon at 600". Both types of sublimate were shown, byX-ray examination, to contain aluminium fluoride, but in the black materialonly one or two lines of the fluoride pattern appeared weakly. The whitesublimate had a composition lying between AIF, and A1F (in a typicalcase, AlFl.,&, the excess of fluorine over that required by the sub-fluorideformula being ascribed to direct sublimation of some aluminium fluoridefrom the reacting mixture. On repeated resublimation of the white materialwith excess of aluminium, the composition progressively approached AIF(e.g., AlFp36, A1F1.22, AIF1.,,, and AlF,.,, in a series of successivesublimations). The black sublimate, however, always contained morefluorine than a white sublimate from the same experiment, and the com-position was not appreciably changed by resublimation with aluminium.From these results the formation of a volatile sub-fluoride, AlF, which dis-proportionates (3A1F =+ All?, + 2A1) on condensation, appears to be fullyestablished. Klemm and Voss consider that the differences between theblack and the white sublimate can be accounted for by different temperaturecoefficients for the processes of A1F formation and AlF, vaporisation,and by condensation of AlF, in a poorly crystallised or vitreous form a tthe lower temperatures. Further investigations, with closer control oftemperatures throughout the system, and measurement of the rate oftransfer of material to the sublimate, appear to be necessary before theseexplanations can be unreservedly accepted.Another indication of the part played by sub-compounds, this time of aquite distinct and novel type, in reactions of practical interest, is affordedby recent work on the transfer of iron from the molten metal to the gasphase.20 It is suggested that reactions between iron oxide and iron carbide,occurring in the metal surface, result in the release of a gaseous materialof composition FeCO, which subsequently decomposes into iron and carbonmonoxide. Further investigation of this supposed compound is clearlynecessary.The few examples cited above illustrate the varied branches of inorganicchemistry which are involved in the interesting field of lower-valency com-pounds. Clearly, many early conclusions relating to supposed compoundsof this type, often abandoned since as incorrect, need to be reviewed again.Many supposed solid " sub-compounds " have been identified as intimatemixtures of elements with compounds exhibiting more normal valencies,but these mixtures may, in fact, be the disproportionation products of truesub-compounds stable a t high temperatures or under other special con-ditions. Clearly, many sub-compound molecules may be correctly regardedas free radicals.20 E. J. Kohlmeyer and H. Spandau, Arch. Eisenhuttenwesen, 1944, 18, 1WELCH : " SUB-CORIPOUNDS " AND INORGANIC FREE RADICALS. 91Mention may be made of a recent investigation on the imine radical,21NH, which is formed in the decomposition of azoimide by non-luminousactive nitrogen; the radical was identieed by its reactions with hydrogenand benzene, in which ammonia and aniline, respectively, are formed.A. J. E. WELCH.2 1 I<. Stewart, Trans. Faraday SOC., 1945, 41, 663

ISSN:0365-6217    

DOI:10.1039/AR9454200063

出版商:RSC    

年代:1945

数据来源: RSC

摘要:

ORGANIC CHEMISTRY.1. INTRODUCTION.THE section on General Methods deals with ion exchange resins, chromato-graphy, reduction, and phosphorylation.Within the last twenty years ultra-violet absorption spectrometry hasbecome a valuable tool for purposes of both qualitative and quantitativeanalysis, as well as in physicochemical studies, such as the determination ofequilibria and reaction rates. Purely structural applications have, however,remained perhaps the most important and have played an invaluable partin many recent investigations on natural and synthetic products, includingvitamins, hormones, and plant pigments. Some of the more theoretical aspectsof the subject have been dealt with in the physicochemical sections of pre-vious Reports, but no comprehensive summary has been hitherto availableof the well-defined empirical relationships between the ultra-violet lightabsorption and the constitution of organic compounds.It is hoped, there-fore, that the present survey will supply a real need. Experimental methodsof determining extinction curves, and in the interpretation of the results,are first brieff y discussed. Selective absorption in the region easily accessiblewith quartz instruments (> 2000 A.) depends on the presence of atoms orgroups containing " mobile " electrons, i.e., electrons of comparativelylow excitation energies. The most important type of mobile electrons metwith in organic compounds is the unsaturation electrons of multiple bonds, andthe vague classical concepts of chromophore and auxochrome are convenientlyre-defined to refer respectively to covalently unsaturated and covalentlysaturated groups.Single chromophores and auxochromes usually give riseto bands in the Schumann region or on the edge of the quartz ultra-violet,but the interaction between two or more of such groups generally results ina displacement of absorption towards higher wave-lengths. Conjugationis strongest when the groups are in vicinal positions, and ultra-violet lightabsorption is still most useful when dealing with compounds containingclassical conjugated systems. The wave-length positions and intensitiesof the maxima depend on the nature of the chromophores and auxochromespresent and on their number, increasing with the latter and eventuallyresulting in visible colour.The more important empirical relationshipsare thus outlined, and their interpretation in terms of electronic mobilityand their correlation with chemical reactivity are indicated. Sufficientdata are now available to make ultra-violet light absorption a convenientcriterion of identity for mahy classes of organic compounds, to allow thereliable prediction of spectral properties, and to judge the compatibility ofthose observed with assigned structures.Recent developments in knowledge of the characteristic reactionsof free neutral radicals have led to a great clarification of outlook in regardto mechanisms of oxidation, and it is now thought that most, though prob-ably not all, organic oxidation processes are chain reactions in which transienINTRODUCTION.93uncharged radicals pa,rticipate. The autoxidation of hydrocarbons has beenstudied intensively by many workers during the past decade in view of itstechnical importance in connection with the chemistry of fats, and with therubber, paint, and varnish industries. Unconjugated olefins, and the sidechains of aromatic hydrocarbons, are, at moderate temperatures, undoubtedlyattacked first a t active methylene groups to give hydroperosides,R”CH*O*OH, several of which have been isolated by R. Criegee, H. Hock,E. H. Farmer, and others. In the case of olefins the initial point of attackis the methylene group adjacent to the double bond. These hydroperoxidessubsequently break down to other products, and in so doing catalyse theattack of oxygen on the original hydrocarbon, thus rendering the wholeautoxidation process autocatalytic.Strong evidence has been forthcomingto indicate that the initiating step in the autoxidation of hydrocarbons is ahomolytic dehydrogenation by a neutral radical, or equivalent catalyst,acting thus :Re + R”CH, + R-H + R”CH*giving a hydrocarbon radical, R”CH-, which then combines with oxygenby the repetitive chain process :R’’CH0 + 0, --+ R”CHaO*O* ‘IR”CH.00 + R”CH, -+ R”CH*O*OH + R”CH*It has been suggested that secondary radicals, such as *OH and R”CH*O*,from hydroperoxide decomposition may function as initiating catalysts(Re). Inhibitors of autoxidation are now thought to be substances whichcombine rapidly with free radicals, for it has been shown that they are notnecessarily substances which rapidly destroy hydroperoxide molecules.Conjugated diolefins, in contrast, seem to add on oxygen in the 1 : 4 positions,giving cyclic peroxides, which, however, can function as catalysts for otherautoxidations.T. P. Hilditch and his colleagues have shown, however,that at elevated temperatures the primary attack of oxygen on an olefinmay be upon the double bond, and this is possibly a hydroxylation ratherthan a peroxidation process. The oxidising reactions of lead tetra-acetatecan be explained consistently as reactions of the two radicals, acetate,Me*CO*O*, and methyl, *Me, which are formed successively by the thermaldecompositions :Pb(O*CO*Me)4 + Pb(O*CO*Me), + 2*O*CO*Me*O*CO*Me -+ CO, + *MeBoth these radicals have dehydrogenating properties.The more activeradical, methyl, is believed to be concerned in oxidations employing leadtetra-acetate in hot solutions, though only the acetate radical may be con-cerned in the selective glycol fission process discovered by R. Criegee.Hydrogen peroxide has been shown to yield free neutral hydroxyl radicals,both by photochemical decomposition and by “ reduction activation ”by a single electron donor, such as a ferrous salt : Fe++ + HOoOH --+Fe+++ + HO. + (:OH)-. The consequent oxidation reactions of hydrogenperoxide are thus hydroxylationa due to the hydroxyl radical, which, a94 ORGANIC CHEMISTRY.shown by J. H. Baxendale, M. G. Evans, and G. S. Park, will add on to olefins,and SO may bring about their chain polymerisation.Fenton’s reaction-the oxidation of a-hydroxy-acids with hydrogen peroxide and a ferroussalt-as well as many typical reactions of the inorganic and organic per-acids can be explained easily as reactions of free hydroxyl radicals. Manyanalogues of these processes can be traced in the organic chemistry of sul-phur. Several quinones have been shown to undergo reversible reductionin two stages, and may give, by gain of one electron, reactive “ semi-quin-ones ” which can play important r6les as “ potential mediators ” in manyother oxidation processes. On these grounds both P. A. Schaffer andL. Michaelis have suggested that the oxidations of both organic and inorganiccompounds can proceed a t measurable speeds only in steps of one electroneach.This generalisation accords with the finding of W. A. Waters thatmany inorganic oxidising agents, such as chromic acid, potassiumpermanganate, and periodic acid, can act upon organic compounds by thehomolytic dehydrogenating mechanismOx* + H*R + 0x.H + *Rbut should as yet be viewed with caution, since some oxidations, e.g., thoseinvolving nitrous acid or selenium dioxide, may proceed by heterolytic stages.The increasing importance of furan and its derivatives is reflected in theallocation of one section of this Report to this topic. Studies have beenmade on the preparation of furans from carbohydrates, unsaturated diketones,ethylenic ethynylcarbinols, acetylenic acetals, acetylenic and ethylenicdiols, long chain cco-diols, 78-ethylenic alcohols, and y-bromo-alcohols ;where the formation of both a tetrahydrofuran and a tetrahydropyranring is possible, the former appears to be obtained preferentially.Several3 : 4-diaminotetrahydrofurans have been prepared from 3 : 4-dicarbethoxy-furans, and in the course of this work the 0-analogue of p-biotin has beensynthesised. Furan mercurials have proved to be of particular value forthe introduction of certain substituents, such as iodine and arsenic, into thefuran ring, and for the elimination of carboxyl groups in the 2- and 5-positions. A considerable amount of information has accumulated on thehydrogenation of furans, and by a suitable choice of catalyst and control ofconditions it is now possible, for example, to obtain furfuryl alcohol, tetra-hydrofurfuryl alcohol, 2-methylfuran, or 2-methyltetrahydrofuran fromfurfuraldehyde, although a satisfactory method has yet to be found for thepreparation of tetrahydrofurfuraldehyde, even by an indirect route.Elim-ination of side chains in furans by passage of the vapour over heated metalsor other catalysts is a process which is of particular interest from the indus-trial viewpoint, since it has recently been shown that in this way it is possibleto obtain good yields of furan from furfuraldehyde, and tetrahydrofuranfrom tetrahydrofurfuryl alcohol. Similar treatment of 2-cyanotetrahydro-furan and of methyl tetrahydrofuroate gives 2 : 3-dihydrofuran. Theseobservations are of some importance in view of the extensive studies whichhave been made on the conversion of furan derivatives by treatment witIHTRODUCTION.95ammonia or hydrogen sulphide into pyrroles and thiophens, processes whichin the absence of ample and cheap supplies of furan and tetrahydrofuranwould be only of academic interest. Improved results have also been claimedin the production of piperidine from tetrahydrofurfuryl alcohol. Ring fissionof furans, particularly of the tetrahydro-derivatives, may lead to the form-ation of valuable aliphatic compounds, and the optimum conditions for manyof these reactions have’ been carefully studied. Reagents which will bringabout this fission include hydrogen, carbon monoxide, hydrogen halides,acyl halides, and acetic anhydride.With unsymmetrically substitutedcompounds, the reaction may theoretically occur in two ways : A+ RCH( OX)*CH2*CH2*CHY*R’------+ B R CHY CH ,*CH ,*CH ( OX) OR’R(,?R’ +xyB\O/AIn some instances, however, the scission takes place almost entirely in onedirection.In continuation of last year’s Report on nucleosides and nucleotides anaccount is now presented of the chemistry of the adenine nucleotides func-tioning as coenzymes in biological systems. They fall into two classes :(a) derivatives of adenosine-5‘-phosphoric acid, which contain labile PJTO-phosphoryl residues by virtue of which they are active in phosphate transfer,and (b) dinucleotides in which adenosine-5’-phosphoric acid is united througha pyrophosphoryl linkage with a moiety containing either quaternarilybound nicotinamide or an alloxazine residue.These residues confer redoxproperties upon the molecules, and condition their activity as coenzymesof hydrogen transfer. The investigation of these coenzymes provides astriking example of the mutually beneficial way in which organic and bio-logical chemistry may interact; knowledge of the chemistry of thesecompounds has greatly furthered the insight gained during the last decadeinto vital processes, whilst in the constitutional investigations extensiveuse was made of biological test methods to determine the nature of fissionproducts produced in degradation reactions.This Report also includes a small section on the chemistry of pyrazineand its derivatives; it was originally planned to include similar sectionsdealing with other “ minor ” heterocyclic systems which have not hithertofound a place in these Reports, but these have had to be deferred.In report-ing upon the chemistry of such heterocyclic systems it has been consideredexpedient to present a representative account of the subject as a wholerather than limit it to a statement of recent developments.R. A. BASTER.E. A. BRAUDE.R. LYTHGOE.G. T. KEWBOLD.F. S. SPRENG.W. A. WATERS.1,. N. OWEN96 ORaANIC CHEMISTRY.2. GENERAL METHODS.1. Ion Exchange Resins.-Ion exchange processes have long been used forsoftening water; the use of zeolites and related substances was limited toreplacing calcium and magnesium by sodium cations. Hydrogen exchangewas impracticable since the zeolites are decomposed by acids; it becamepossible with the introduction of exchangers of the .sulphonated coal type.The development in this country of synthetic resin ion exchangers hasgreatly increased the scope of ion exchange reactions 2 and these reactionsare being increasingly applied in various commercial processes involvingorganic materials.In the belief that the technique will become of valuein certain other branches of organic chemistry, a short account of the re-latively few published reports of the use of ion exchangers in this field isappended.The firstis a cation exchanger and usually consists of a sulphonated phenol-form-aldehyde resin which can be re-activated by washing with a dilute solutionof acid.The second type usually consists of a polyamine-formaldehydetype resin and it allows the removal of an acid from solution. The resincan be reactivated and the acid recovered by washing with an alkali. Thistype of resin is not a true “ anion exchanger ” but rather an “ acid adsorbent.”I n addition, carbonaceous cation exchangers of the sulphonated coal typeare available which also allow the use of the hydrogen cycle exchange.The use of ion exchange resins for the removal of impurities in sugarjuice before crystallisation has constituted a major advance in sugartechn~logy.~ A very ingenious use of ion exchangers is described by D. T.Englis and H. A. Fiess 5 in the preparation of a high quality fructosesyrup from an aqueous solution of the polysaccharides of Jerusalem arti-chokes.The solution, which contains a relatively high percentage ofpotassium salts, was treated with a hydrogen exchange resin which increasedthe acidity of the solution to such an extent that hydrolysis was subse-quently effected without the addition of mineral acid. After hydrolysis,acid was removed by treatment with an acid adsorbent, followed by con-centration to a syrup.J. R. Matchett, R. R. Legault, C. C. Nimmo, and G. K. Notter describeexperiments leading to the recovery of tartaric acid from waste naturalsources such as the pomace from grape juice manufacture, and the slopfrom brandy making. The process consists in passing the slop through abed of acid-regenerated cation exchanger which frees the tartaric acid,Two types of synthetic resin ion exchangers are available.B.A. Adams and G. L. Holmes, J. SOC. Chem. Ind., 1935,54, 1.F. J. Myers, Ind. Eng. Chem., 1943, 35, 858.* F. J. Myers quoted by C. S. Cleaver, R. A. Hardy, and H. G. Cassidy, J . Amer.Chem. SOC., 1945, 87, 1344.F. N. Rawlings and R. W. Shafor, Sugar, 1942, 37, I, 26; F. W. Weitz, ibid.,1943, 38, I, 26; W. Meyer, Centr. Zuckerind., 1943, 51, 37; 0. Spengler and F. Todt,2. Wirts. Zuckerind., 1942, 152.Ind. Eng. Chem., 1942, 34, 864. Ibid., p. 486BAXTER AND SPRING : GENERAL METHODS. 97followed by treatment of the solution with an acid-adsorbent which pre-ferentially adsorbs the tartaric acid. The latter is recovered by washingthe resin with sodium carbonate eolution, and is finally converted into theinsoluble calcium salt.A new method for the separation of basic amino-acids from proteinhydrolysates has been described by R.J. Block.' The protein (bloodfibrin) was hydrolysed with hydrochloric acid, and the protein hydrolysate(amino-acid hydrochlorides) freed from 'excess of mineral acid and thenstirred with an acid-binding resin. After removal of this resin the solutionof amino-acids was treated with a cation exchange resin, from which thebasic amino-acids were regenerated by subsequent washing with dilutehydrochloric acid. From the solution of hydrochlorides so obtained, lysine,arginine, and histidinc were isolated by standard procedures. A method forthe separation of acidic amino-acids (glutamic and aspartic acids) fromprotein hydrolysates has also been developed by R.K. Cannan.8 Thehydrolysate is treated with a basic resin which binds the acidic amino-acidsbut not the neutral or basic amino-acids. The resin is then washed withhydrochloric acid which elutes the acidic amino-acids, and from the acidsolution, glutamic acid, as its hydrochloride, and aspartic acid, as its coppersalt, are readily isolated. Separation of amino-acid mixtures by meansof ion exchange resins has also been claimed by K. Freudenberg, H. Walch,and H. Molter? A study of the behaviour of various amino-acids on ionexchange resins has been made by D. T. Englis and H. A. Fiess,l0 and byC. S. Cleaver, R. A. Hardy, and H. G. Cassidy.ll The latter authorsinvestigated the infiuence of various factors upon the exchange processincluding type of resin, resin particle size, length of adsorption column,hydrogen -ion concentration of the solution, and concentration of the amino-acid solution.p-Alanine can best be prepared from its hydrochloride by passing asolution of the latter through a bed of an acid-binding resin followed byconcentration of the effluent.12A simplification of the preparation and purification of glucose- 1 -phosphate(Cori ester) is claimed by R.M. McCready and W. Z. Hassid.13 The essentialstep in the new procedure is that the reaction mixture obtained by thephosphorylation of starch followed by removal of inorganic phosphate istreated with a cation exchange resin. The effluent is then run through anacid-adsorbing resin which holds the glucose- 1 -phosphate but allows thepassage of dextrins, proteins, and weak organic acids.The acid-adsorbentresin was washed with aqueous ammonia, the Cori ester being isolated fromthe effluent as its dipotassium salt.Proc. SOC. Exp. Bwl. Med., 1942, 51, 252.Naturwiss., 1942, 30, 87; see also F. Turba, M. Richter, and F. Kuchar, ibid.,J. Biol. Chern., 1944, 152, 401.1943, 31, 508.10 I n d . Eng. Chem., 1944, 36, 604.l2 S. R. Buc, J. H. Ford, and E. C. Wise, ibid., p. 94.l3 Ibid., 1944, 66, 560.11 J . Amer. Chem. SOC., 1945, 67, 1343.REP.-VOL. XLII. 98 ORGANIC CHEMISTRY.An attractive procedure for the isolation of alkaloids from crude totaquine(the product obtained by alkaline precipitation of an acid extract of cinchonabark) by means of a cation exchange has been described by N.Applezweig l4who stresses the potential value of the new technique in alkaloid chemistryand reports its successful application in the isolation of atropine, scopol-amine, and morphine. When a solution of quinine in 1% sulphuric acid istreated with a cation exchange resin, the alkaloid is removed from solution;it can be liberated from the exchanger by washing with ammoniacal alcohol,a treatment which also reactivates the resin.A new method for the deacetylation of sugar acetates is described byW. W. Binkley, M. G. Blair, and M. L. Wolfrom; l5 in the case of inositolhexa-acetate saponification was effected with sodium hydroxide and thesolution passed over a column of cation exchanger resin which removedsodium ions; the effluent was then passed over a column of acid-bindingresin which removes acetic acid.Evaporation of the final effluent gaveinositol.2. Chromatography.-Reference has been made in previous Reports l6to the employment of chromatographic methods in the separation of mix-tures of amino-acids. T. Wieland and H. Fremerey l7 have applied thepartition-chromatography method of A. J. P. Martin and R. L. M. Syngeto effect a separation of copper complexes of amino-acids by partitionbetween two phenol-water phases on a silica gel column. In this way aseparation of alanine from valine and of leucine from valine and proline wasachieved, V. Prelog and P. Wieland l9 have claimed the resolution of anunsymmetrical tervalent nitrogen compound, Troger’s base,2o using thechromatographic technique of G.M. Henderson and H. G. Rule; 21 theadsorbent consisted of d-lactose activated by drying and grinding. G. T.Newbold and F. S. Spring,22 using a chromatographic method, have effected aready separation of two alcohols, a-euphorbol and euphol, from euphorbium.Several new applications of chromatography to specific problems incarbohydrate chemistry have been reported. Using the previously men-tioned method of A. J. P. Martin and R. L. M. Synge,18 D. J. Bel123 hasquantitatively separated 2 : 3 : 4 : 6-tetramethyl glucose from 2 : 3 : 6-trimethyl glucose by partition between organic solvents and water held ina column of silica gel.Separation of dimethyl glucoses from tri- and tetra-methyl glucose can also be effected. Using activated alumina as adsorbent,J, K. N. Jones2* has achieved a quantitative separation of tetramethylmethylglucosides from trimethyl methylglucosides. The same methodallows a partial separation of a constant-boiling mixture of trimethyl methyl-Z-arabofuranoside and trimethyl methyl-d-xylopyranoside ; the separationl4 J . Amer. Chem. SOC., 1945, 67, 1990. l6 Ibid., 1945, 67, 1791.l7 Ber., 1944, 77, 234. Ann. Reports, 1944, 41, 127; 1942, 39, 237.Biochem. J., 1941, 35, 1358; 1943, 37, 79, 86, 92.Helv. Chim. Acta, 1944, 27, 1127.*O J . Trdger, J . p r . Chem., 1887, 36, 227.22 Ibid., 1944, 249.21 J., 1939, 1568.24 Ibid., p. 333. 23 Ibid., p. 473BAXTER AND SPRING : GENERAL METHODS.99was complicated by the fact that separation of the a- and p-forms of thetwo glycosides occurred. The chromatographic separation of tetramethylglucose has been used in the assay of end-groups in polysa~charides.~~E. A. Tulley, D. D. Reynolds, and W. L. Evans 26 have used a chromato-graphy technique in the purification of a sugar acetate. Using magnewl,a synthetic hydrated magnesium acid silicate, as adsorbent and employingthe brush technique of L. Zechmeister 27 with aqueous alkaline permanganateas the brush reagent, W. H. McNeely, W. W. Binkley, and M. L. Wolfrom 28have achieved many clear-cut separations of mixtures of sugar acetates ;of these may be mentioned the separation of p-maltose octa-acetate fromsucrose octa-acetate.W. W. Binkley, M. G. Blair, and M. L. Wolfrom29in an analytical study of various molasses have isolated inositol (as itshexa-acetate) and d-mannitol (as its hexa-acetate) by chromatographicmethods. The method developed by W. S. ReichY3O in which separation ofmixtures of monosaccharides is achieved by conversion into a mixture ofthe (coloured) p-phenylazobenzoyl esters followed by chromatographicseparation of the latter, has been extended.31 J. K. Mertzweiler, D. M.Carney, and F. F. Farley 32 have also used the method to separate mixturesof the p-phenylazobenzoyl esters of 2 : 3-dimethy1, 2 : 3 : 6-trimethyl, and2 : 3 : 4 : 6-tetramethyl glucose. B. W. Lew, M. L. Wolfrom, and R. M.Goepp33 report a new method for the chromatography of carbohydratesand related polyhydroxy-compounds in which the adsorbents are clays suchas Florida clay and the developers comprise such solvents as alcohols,ethers, and pyridine. Water was the eluting agent and the brush techniquewas employed to detect zones.Separations such as sorbitol from d-glucose,d-mannitol, and dulcitol were achieved.3. Reduction.-L. W. Covert and H. Adkins34 first reported that Raneynickel, prepared by treatment of a nickel-aluminium alloy with aqueoussodium hydroxide followed by washing, is extremely reactive ; for examplethe authors observed that, when the catalyst is mixed a t room temperaturewith nitrobenzene in an open beaker, the nitrobenzene is reduced to a mix-ture of azo- and azoxy-benzene. J.Bougault, E. Cattelain, and P. Chabrier 35demonstrated that Raney nickel catalyst, prepared in the usual manner,retains hydrogen. Although the nature of the retention was not established,it was shown that the catalyst is capable of effecting a variety of reactionssuch as direct reduction of ethylenic bonds and the decomposition of an2 5 F. Brown, S. Dunstan, T. G. HalsaII, E. L. Hirst, and J. K. N. Jones, Nature,26 J . Amer. Chem. SOC., 1943, 65, 575.27 Bull. SOC. Chim. biol., 1936, 15, 1885; 1940, 22, 458; J , Amer. Chem. 80% 1946,28 Ibid., 1945, 67, 527.30 Compt. rend., 1939, 208, 589, 748; Biochem. J . , 1939, 33, 1000.31 G. H. Coleman, A. G. Farnham, and A. Miller, J . Amer. Chem. SOC., 1942, 84,32 Ibid., p. 2367.34 Ibid., 1932, 54, 4116.1945, 156, 786.67, 1919, 1922.29 lbid., p.1789.1501 ; G. H. Coleman and C. M. McCIoskey, ibid., 1943, 65, 1588.33 Ibid., 1945, 67, 1865.35 Bull.Soc. chim., 1938, 5, 1699100 ORGANIC CHEMISTRY.aqueous solution of potassium permanganate. Later,36 the same authorsshowed that Raney nickel, without addition of gaseous hydrogen, quantit-atively converts thioglycollanilide, HS*CH,*CO*NHPh, using aqueous oralcoholic solutions, into acetanilide and that similar treatment of thioglycollicacid, HS*CH,-CO,H, and dithioglycollic acid, ( SCH2C0,H),, gives acetic acid.A simple method of rendering benzene and toluene free from thiophen andmethylthiophen by treatment with Raney nickel is also reported. Theseearly observations have been considerably extended by R.Mozingo and hiscollaborators 37 who show that Raney nickel catalyst without gaseoushydrogen, at a moderate temperature and in the presence of a solventsuch as alcohol, removes sulphur from a variety of organic compoundsaccording to the scheme :Ni(H) R0S.R’ ~-> RH + R’H.As an example diphenyl sulphide in aqueous alcohol was refluxed withRaney nickel for 4+ hours (the authors observe that the time and tem-perature of reaction are probably in excess of those necessary) to give a68% yield of benzene. A similar ease of hydrogenolysis was observed inthe case of sulphones and sulphoxides, diphenyl sulphone, Ph*SO,*Ph , anddiphenyl sulphoxide, Ph*SO*Ph, giving 65% and 76% yields of benzenerespectively. H. R. Snyder and G. W. Cannon 38 report that with certainethers of ethylenedithiol two types of cleavage may occur when they aretreated with Raney nickel.In addition to the normal reaction leading to theformation of ethane, carbon-carbon cleavage occurs to a certain extentwith formation of methane :The method was used by V. du Vigneaud, R. Mozingo, and their collaboratorsto convert biotin methyl ester into dethiobiotin methyl ester.39 An interest-ing case of hydrogenolysis effected by Raney nickel has been described byM. L. Wolfrom and J. V. Karabinos40 who have developed a method forthe reduction of carbonyl compounds to the corresponding methylenecompounds. The carbonyl compound is first converted into the thioacetal(thioketal) which is then subjected to hydrogenolysis in dilute alcoholaolution with Raney nickel :Using this method acetophenone, benzophenone, benzaldehyde, and heptan-%one are converted into ethylbenzene, diphenylmethane, toluene, andR.Mozingo, D. E. Wolf, S . A. Harris, and K. Folkers, J . Amer. Chem. Soc.,s6 Bull. SOC. chim., 1940, 7 , 781.1943, 65, 1013.s8 IbicE., 1944, 66, 155.4 0 J . Amer. Chem. SOC., 1944, 66, 909.89 Ann. Reports, 1943, 40, 175BAXTER AND SPRING: GENERAL METHODS. 101heptane respectively and in the same way the diethyl thioacetal of aldehydo-d-glucose -penta-acetate is converted into l-deoxy-d-glucitol penta-acetate.Further examples of the application of Raney nickel catalyst withoutthe addition of gaseous hydrogen are given by R. Mozingo, C. Spencer, andK.Folkers 41 who show that, using the general reaction conditions outlinedabove for sulphides, ethylenic bonds are saturated, e.g., conversion of eugenolinto dihydroeugenol (75%), and carbonyl compounds are reduced to thecorresponding alcohols, e.g., conversion of acetone, ethyl acetoacetate, cycb-pentanone, and benzylideneacetone into isopropyl alcohol (78%), ethylP-hydroxybutyrate (96 yo), cycbpentanol (61 %), and 4-phenyl-2-butanol(79%) respectively. Benzaldehyde gives toluene (78%) and not benzylalcohol, indicating that the latter undergoes hydrogenolysis under theseexperimental conditions. Benzene rings, aliphatic acids, and esters are notreduced under these conditions.Raney (nickel-aluminium) alloy added to an alkaline solution of acarbonyl compound has been used by B.Whitman, 0. Wintersteiner, andE. Schwenk42 to reduce oestrone to a mixture of ct- and p-oestradiols.D. Papa, E. Schwenk, and B. Whitman 43 have found that this method whenapplied to phenyl ketones, Ph*CO*R, results in reduction to the correspondinghydrocarbon, Ph*CH,*R. On the other hand, ketones of the typePh*[CH,];CO*R, where x is 1 or greater, give the corresponding carbinol.In the case of ketones which are not soluble in aqueous alkali, the reactioncan be carried out in the presence of toluene or alcohol. The authorssuggest that the reduction is due to the liberation of hydrogen which is thenactivated by the presence of the nickel catalyst since reduction of thecarbonyl group also occurs using aluminium in conjunction with a previouslyprepared Raney nickel catalyst.If the nickel catalyst is omitted and thealkaline solution treated with aluminium, no reduction occurs or amorphousproducts are produced.44Reduction by means of nickel-aluminium alloy in the presence of alkalihas been further studied by E. Schwenk, D. Papa, B. Whitman, andH. Ginsberg 45 who show that using this technique various groups attachedto the aromatic nucleus are displaced by hydrogen. For example, halogenis displaced, bromobenzene giving benzene (100 yo) and m-chlorobenzoicacid giving benzoic acid (100%). Simultaneous replacement of halogenby hydrogen and reduction of carbonyl to methylene was observed in variouscompounds, p-chlorobenzaldehyde yielding toluene (60%) and p-bromo-acetophenone yielding ethylbenzene (67 %) .Reductive displacement ofthe sulphonic acid group occurs for example in o- and m-sulphobenzoic acidswhich gave 40% and 50% yields of benzoic acid respectively. Alkoxylgroups are displaced from disubstituted benzene derivatives when they aresituated in the o- and p-positions with respect to a m-directive group. Forexample, quantitative displacement of the methoxyl group occurs with o-4l J. Amer. C k m . SOC., 1944, 66, 1859.42 J . Biol. Chem., 1937, 118, 792.4 4 E. Schwenk and D. Papa, ibid., 1945,10, 232.4 5 J . Org. Chem., 1942, 7, 507.45 Ibid., 1944, 9, 1102 ORGANIC CHEMISTRY.and p-methoxybenzoic acids, but the m-isomer is recovered unchanged. Aninteresting case is provided by p-nitroanisole which gives a mixture of aniline(20%) and p-anisidine (70%) ; elimination of the methoxyl group can onlyoccur prior to the reduction of the (m-directive) nitro-group to the (o-p-directive) amino-group.Other alkoxy groups are similarly displacedprovided that a m-directive group is located in the.p- (or o - ) position. Aquantitative method for the estimation of halogen in organic compoundsbased upon the replacement reaction has been describedSP6 Various re-ductions of ethylenic compounds by means of nickel-aluminium alloy inthe presence of alkali have been reported,d7 oleic acid giving stearic acid(100%) and maleic acid giving succinic acid (90%). An acetylenic com-pound, phenylpropiolic acid, undergoes complete reduction to p-phenyl-propionic acid.In a study of reduction by means of sodium in liquid ammonia, A.J.Birch48 shows that in a number of benzene and naphthalene derivativesthe course of reduction is very considerably modified by the addition of analcohol. Thus with sodium a- and p-napththoxides, sodium in liquid am-monia effected little reduction, but addition of lert-amyl alcohol as a protonsource gave good yields of dihydro-derivatives (5 : 8-dihydro-a-naphtholand p-tetralone respectively). Reduction and demethylation of methoxy-alkylbenzene derivatives occur when they are treated with sodium in liquidammonia in the presence of an alcohol, whereas treatment with metal andliquid ammonia alone merely leads to demethylati~n.~~ The methoxyalkyl-benzenes when treated with sodium in liquid ammonia in the presence ofalcohol give a small quantity of the corresponding phenol (simple demethyl-ation) together with a difficultly separable mixture of starting material andreduction products.The reduction products were characterised as dihydro-derivatives since treatment of the reaction product with mineral acid gavean ap-unsaturated ketone produced thus :Hydrogenolysis of a number of vinylcarbinols by means of sodium and analcohol in liquid ammonia has also been studied by A. J.Reductions by alkali metals and liquid ammonia have also been studiedby C. M. Knowles and G. W. Watt.51 Quinoline is reduced to a dihydro-derivative which, it is suggested, is the 1 : 4-compound. Reduction of4 6 E. Schwenk, D. Papa, and H.Ginsberg, Ind. Eng. Chem. Anal., 1943, 15, 576.4 7 E. Schwenk, D. Papa, B. Whitman, and H. Ginsberg, J. Org. Chem., 1944,4 8 J., 1944, 430. '' I(. Freudenberg, W. Lautsch, and G. Piazolo, Ber., 1941, 74, 1886.I0 J . , 1945, 809.I1 J . Amer. Chem. SOC., 1943, 85, 410.9, 175BAXTER AND SPRING GENERAL METHODS. 103nitroparaffins by sodium in liquid ammonia is also described ; 52 the reactionis slow and incomplete and yields the corresponding alkylhydroxylamine~.~~A very interesting modification in the technique of the Wolff-Kishnerreduction of carbonyl to methylene compounds is reported by M. D. Soffer,M. B. Soffer, and K. W. Sherk.54 The essential part of the modification isthe use of a high-boiling solvent such as a glycol to obviate the use of itbomb-tube or high-pressure apparatus.As an example may be quoted theprocedure for the reduction of propiophenone to n-propylbenzene (79%).Sodium is dissolved in an excess of diethylene glycol, hydrazine hydrateand the ketone are added, and the mixture is refluxed for 49 hours.H. Houber 55 claims high yields of primary amines by the catalyticreduction of basic nitriles in the presence of ammonia and Raney nickel.Using this method secondary amine formation is negligible and reduction israpid. Perchloric acid is found to be an effective activator for certain reduc-tions using a palladium-barium sulphate catalyst. Using this catalyst andacetic acid as solvent, ethyl benzoylacetate is reduced to ethyl p-phenylpro-pionate in the presence of perchloric acid.56 Using similar conditionsreduction of a p-arylallcanolamine, e.g., Ph*CH( OH)*CHMe*MH,, gives thecorresponding p-arylalkylamine, Ph*CH,*CHMe*NH,.It has been shown by R.Mozingo and associates 57 that hydrogenationof carbon-carbon double bonds can be effected in some sulphur-containingcompounds, using a supported palladium catalyst. Thus thiophen and2-bromothiophen are reduced to tetrahydrothiophen, and the successfulreduction of certain biotin intermediates and other sulphides is described.4. PhosphoryZation.-The known phosphorylation procedures have beenreviewed by F. R. Atherton, H. T. Openshaw, and A. R. Todd,58 who dis-cuss the limitations of existing methods for the phosphorylation of alcohols(particularly carbohydrates) and amines, and state the chief requirementsto be met by a convenient method.In seeking such a method, the authorshave prepared and examined the reactions of dibenzyl chlorophosphonate(11). L. Zervas 59 had previously prepared this acid chloride but reportedthat it was so unstable as to be of little use. The method of preparationnow used is treatment of phosphorus trichloride with benzyl alcohol in thepresence of dimethylaniline to give dibenzyl hydrogen phosphite (I), whichis treated with chlorine in carbon tetrachloride solution, a method developedby H. McCombie, B. C. Saunders, and G. J. Stacey.60 The solution ofdibenzyl chlorophosphonate in carbon tetrachloride thus obt'ained is normallyused directly without isolat,ion of the ester since the latter decomposed ons2 G.W. Watt and C. M. Knowles, J. Org. Chem., 1943, 8, 540.63 For a general review of the reduction of nitroparaffins to the corresponding64 J . Amer. Chenz. SOC., 1945, 67, 1435.65 Ibid., 1944, 66, 876.66 K. Rosenmund, E. Karg, and F. K. Marcus, Be?., 1942, 75, 1850.5 7 J. Amer. Chem. SOC., 1945, 67, 2092.li9 Naturwiss., 1939, 27, 31T.hydroxylamines see H. B. Hass and E. F. Riley, Chew&. Reviews, 1943, 32, 390.J . , 1945, 382.6o J., 1945, 380104 ORQANIC CHEMISTRY.attempted distillation. The solution in an inert solvent reacts readilywith amines, or with alcohols in the presence of pyridine, and the productscan be debenzylated by the standard hydrogenolysis procedure. Thus withalcohol in the presence of pyridine, dibenzyl ethyl phosphate was obtained,hydrogenolysis of which gave ethyl dihydrogen phosphate.The chloro-phosphonate (11) does not react readily with phenols but reacts readily(Ph*CH,*O),P*OH --+ (Ph*CH,*O),POCl(1.1 P a /with sodium phenoxides. More recently D. Deutsch and 0. Ferne 61 haveindependently developed a phosphorylation technique also employingdibenzyl chlorophosphonate. I?. R. Atherton, H. T. Openshaw, and A. R.Todd 62 have described a new method for the phosphorylation of amines inwhich dibenzyl phosphite reacts with carbon tetrachloride in the presenceof a strong primary or secondary amine. The reaction appears to occur intwo stages in the first of which the carbon tetrachloride reacts with thephosphite to give a trichloromethyl phosphonate, the base acting as hydrogenchloride acceptor :(Ph*CH,*O),PH + CCl, + B -+ (Ph*CH,*O),P*CCl3 + B,HC1146 ORGANIC CHEMISTRY.reaction mechanisms which may be involved, but one can discriminatebroadly between the rapid oxidations which can be effected a t room temper-ature, usually in the presence of light or catalysts, and many slower oxidationswhich can be effected only a t higher temperatures or by using the reagentin large excess. Into the first category come reactions with polyphenols,x-hydroxy-acids, and olefins, and into the second, oxidations of saturatedfatty thio-ethers, and aromatic azo-compounds.Evidence is now accumulating to indicate that the rapid reactions ofhydrogen peroxide involve the presence, in aqueous solution, of the transientfree hydroxyl radical, *OH.As mentioned in these Reports for 194397it' is considered by N. A. Milas, P. F. Kurz, and W. P. Anslow that the photo-chemical hydroxylations of ally1 alcohol, crotonic acid, and maleic acidby hydrogen peroxide are reactions of free hydroxyl radicals :H202 --%+ 2 *OHCH,:CH*CH2*OH + 2 *OH --+ CH2( OH)*CH( OH)*CH,-OHsince the radiant energy supplied is amply sufficient to split the weak0-0 bond. Since a similar cis addition of two hydroxyl groups to olefinscan be effected much more easily by catalysing the peroxide reaction with alittle osmium tetroxide, vanadium pentoxide, or, less effectively, chromiumt r i o ~ i d e , ~ ~ * loo* lol it is possible that in these cases too the free hydroxylradical is concerned, its immediate precursor being a relatively unstableper-acid.More stable per-acids, such as perbenzoic acid, do not easilyoxidise olefinic substances such as ethyl fumarate or ethyl maleate whichare attacked by the Milas reagents,lm, lo2 which will even oxidise benzeneto phenol, toluene to cresols, and naphthalene to naphthols.99 Since thiscatalysed hydroxylation can also be effected by means of anhydrous tert.-butyl hydroperoxide lo3 it is evident that organic hydroperoxides Alk-O-OH,and perhaps also their inorgamic per-esters, must also be looked upon assources of active hydroxyl radicals. The fact that chromium trioxideaccelerates the decomposition of aqueous hydrogen peroxide 104 tends tosupport this view of the action of the catalyst. The possibility that thehydroxylation catalysed by osmium tetroxide proceeds via addition of thetetroxide to the double bond cannot be ruled out in all cases, though, asF.S. Spring has pointed O U ~ , ~ ' it is discounted by the fact that hydrogenperoxide plus a little osmium tetroxide will hydroxylate ap-unsaturatedketones, whilst osmium tetroxide in dry ether is inert to these substances.96 H. D. Dakin, J. Biol. Chem., 1908, 4, 63, 227; 1909, 5, 409; cf. H. D. Dakin,o 7 Ann. Reports, 1943, 40, 107.9a J . Amer. Chenz. SOC., 1937, 59, ,543.100 N. A. Yilas, S. Sussmann, and H. S. Mason, ibid., 1939, 61, 1845.101 N. A. Milas and L. S. Maloney, ibid., 1940, 62, 1841.l o 2 Cf. J. Boeseken, Rec. Trav. ciiirn., 1926, 45, 838.lo3 N.A. Milas and S. Sussmann, J. Arner. Chem. SOC., 1936,58, 1302.lo4 M. Bobtelsky, A. Glasner, and I,. Bobtelsky-Chaikin, ibid., 1945, 67, 916.Oxidations and Reductions in the Animal Body," London, 1922.99 N. A. Milas, ibid., p. 2342WATERS : MECHANISMS OF OXIDATION. 147W. Treibs 1°5 has shown that hydrogen peroxide with a vanadate cata-lyst will rapidly oxidise cyclic ketones to aldehydic acids, and has suggestedthat this action involves the addition of two hydroxyl groups to the enolicforms of the ketones :OHoxidat.ive 3 pgg GF fission of a-glycol v \ HThis view is probably an over-simplification of the mechanism of this reaction,since crystalline addition products of anhydrous hydrogen peroxide andvarious cyclic ketones have been isolated 106% lo7 (e.g., XIV).These may bedehydrated by cold sulphuric acid to unstable cyclic peroxides (XV) orpossibly (XVI) lo7 whilst warm sulphuric acid converts the ketone-hydrogenperoxide complex into a lactone.HO,,O*OH 0(XIV.) (XVI.)M. Stoll and W. Scherrer lo6 have suggested that this change, which is ofcourse the normal action of Caro’s acid on a ketone (compare p. 140), proceedsvia an epoxide as follows,the final ring fission being brought about by a prototropic change :Definite evidence for the participation of the neutral hydroxyl radicalin reactions of hydrogen peroxide has been obtained from studies of decom-positions and oxidations catalysed by mild reducing agents, such as ferroussalts. In 1931 F. Haber and R.Willstatter,lo8 in an attempt to explain themechanism of enzyme oxidation, suggested that ferric compounds couldcatalyse many dehydrogenations by abstracting one electron from a H-Rbond :Fe+++ + H-R + Fe++ + H+ + Re105 Ber., 1939, 72, 7, 1194.107 N. A. Milas, S. A. Harris, and P. C. Pangiotakos, J . Amer. Chern. SOC., 1939,108 Ber., 1931, 64, 2644.Helv. Chirn. Acta, 1930, 13, 142.01, 2430148 ORGANIC CHEMISTRY.The action of the enzyme cablase in decomposing hydrogen peroxide wasrepresented as followsfollowed by the chain processFe++' + HO-OH _c, Fe++ + H+ + 00-OH . . (i)*O-OH (-0-0:)- + H+ . . . . . . . . . (ii)(-0-0:)- + HO-OH + (*O-O*) + H-0. + ( : O H ) - . (iii) i H-O*+HO-OH+HO~H+~O-OH . . . . . (iv)This scheme was amended in 1934 by F.Haber and J. Weiss.lo9 Theypointed out that ferrous salts were much more effective catalysts for thedecomposition of hydrogen peroxide than ferric salts, and consequentlyformulated the primary reaction asFe++ + HO-OH --+ Fe+++ + H-0. + (:O-H)- . (v)Fe++ + -0-H -+ Fe+++ + (:O-H)- . . . . (vi)and introduced, a.s the chief chain-breaking reaction,Flow experiments showed that the kinetics of the iron-sa,lt-catalysed decom-position of hydrogen peroxide accorded with the Haber-Weiss scheme overa wide range of pH. However, ferric salts do catalyse the decompositionof hydrogen peroxide, though slowly, so that the primary reaction of theHaber-Willstatter scheme does occur. R. Kuhn and A. Wassermann 110have shown that the reduction of ferric ions to ferrous ions by decomposinghydrogen peroxide can be demonstrated by complex formation with act'-dipyridyl or phenanthroline. The resulting complexes have low but stillobservable catalytic activity.J. H.Baxendale, M. G. Evans, and G. S. Park ll1 have, in a paper ofimportant technical as well as theoretical value, recently given a conclusiveexperimental proof of the Haber-Weiss theory. On the addition of ferrousions, oxygen-free aqueous hydrogen peroxide immediately brings about thechain polymerisations of methyl acrylate, methacrylic acid, methyl meth-acrylate, vinyl cyanide, and styrene, both in solution and in the form ofemulsified droplets. I n the presence of the monomeric olefin no oxygen iaevolved from the hydrogen peroxide, and the stoicheiometry of the reaction,with ferrous salt in initial excess, changes from the oxidation of 2 equivalentsof ferrous ion per mol. of hydrogen peroxide [i.e., an overall reaction2Fe++ + H202 + 2Fe+++ + 2(:OH)- due to the occurrence of reactions(v) and (vi) in quick succession] to oxidation of 1 equivalent of ferrous ionper mol.of peroxide [i.e., reaction (v) alone], for the free hydroxyl radicalsare removed very rapidly by the addition reaction (I%)HO* + CH2=CHR 4 HO--CH2-6HR . . . (vii)and thus start a polymerisation chain, which continues :HO*CH,*eHR + CH2:CHR -+ HO*CH2*CHR*CH,*6HR etc.lo9 Proc. Roy. SOC., 1934, A , 147, 333.ll1 Tran8. Faraday SOC., 1946, 42, 155.110 Annalen, 1933, 503, 203WATERS : MECHANISMS O F OXIDATION. 149until terminated by the union of two radicals, for example ByHO*[CH,*CHR],L*CH2*bHR + *OH --+ HO*[CH,*CHR],, + ,*OH .(viii)J. H. Baxendale, M. G. Evans, and G. S. Park estimate that reaction (vii)between methyl acrylate and hydroxyl radicals is about 5 times as fast asthe reaction between hydroxyl radicals and ferrous ions [reaction (vi)], whilstvinyl cyanide is attacked by hydroxyl still more rapidly. Even ethyleneitself is attacked by hydrogen peroxide-ferrous sulphate mixture.It is generally known that the chain polymerisation of olefins, CH,:CHR,cannot be performed reproducibly in the presence of air, since oxygen actsas an (' inhibitor '' of the free-radical reaction. When studying the reactionsdescribed above, it was found that oxygen could be absorbed by the reactingsystem, though only when ferrous ions, hydrogen peroxide, and monomericolefin were all present.This suggests that oxygen acts as a chain-terminator :HO*[CH,*CHR],* + 0, -+ HO*[CH,*CHR],*O*O* . (ix)HO*[CH,-CHR], - ,*CH,.CHR*O*O* + Fe++ --+HO*[CH,-CHR],, - ,*CH,*CR:O + (:OH)- + Fe+++This action is undoubtedly significant also in the autoxidation of olefinsin the presence of hydroperoxides which can, by thermal decomposition,generate free hydroxyl radicals. Whilst reaction (ix) is an addition of mole-cular oxygen to an ethylenic bond, the immediate reaction product is ahydroperoxide radical, which may (as indicated on pp. 132-140) thenabstract hydrogen from a reactive methylene group. In the case of styrene,with which the spontaneous autoxidation is accompanied by polymerisation,S.Medvedev and P. Zeitlin 112 have shown that the autoxidation andpolymerisation chains must involve the same radicals, for the ratio (amountoxidised) /(amount polymerised) is a constant, independent of the reactiontime, the temperature, and the presence of inhibitors.Ferrous salts are by no means the only reducing agents which can liber-ate hydroxyl radicals from hydrogen peroxide. J. H. Baxendale, M. G .Evans, and G. S. Park ll1 have found Cr", Cu', Ti+++ and Mn++ cations,and also metallic mercury, to be effective polymerisation catalysts, whilstR. G. R. Bacon113 and L. B. Morgan 11* have described many furtherapplications of this (' reduction activation " of peroxidic compounds, suchas potassium persulphate, in emulsion polymerisation.Sulphites, thio-sulphates, sulphides, organic thiols, hydroxylamine, quinol, and pyrogallol,and also clean metals such as copper, iron, and silver must all be regarded assubstances capable of giving electrons singly to hydrogen peroxide, accordingt o the generalised equationJ. Weiss 115 has discussed the application of the hydroxyl radical theory tothe metal-catalysed decomposition of hydrogen peroxide, and also to thellS Trans. Faraday SOC., 1946,43,140.115 Ibid., 1935,31, 1647.Red + HO-OH --+ Ox + KO* + (:OH)-; where Red += Ox + e112 Acta Physicochim. U.R.S.S., 1945,20,3.114 Ibid., p. 169150 ORGANIC CHEMISTRY.action of peroxidase enzymes.l16 As would be expected of reactions involvingthe neutral *OH radical, H.Wieland and W. Francke 117 have shown thatmany of the low-temperature oxidations involving hydrogen peroxide areaccelerated enormously upon the addition of a little ferrous salt, and there-after proceed at a steady rate, though the reacting solution contains through-out both ferrous and ferric ions. Oxidations of arsenites and phosphites,as well as of formic acid, a-hydroxy-acids, and a-amino-acids all show thisbehaviour, though the initial accelerated oxidation is not evident with aro-matic substances such as quinol, pyrogallol, and p-phenylenediamine, theoxidations of which can be catalysed equally well by ferrous and by ferricsalts. This has led J. Weiss 116 to discriminate between two types ofcatalysed oxidations.I n Type A reactions, which are exemplified by the hydrogen peroxide-formic acid system, the oxidisable substance is attacked only by the com-plete system (H,O, + Fe"), and oxidation stops when all the-iron is in theferric state, though excess of hydrogen peroxide may still be present.Theactive oxidising agent is the neutral hydroxyl radical, and only short reactionchains may be involved, e.g. :*OH + H*CO*OH + H0.H + *CO*OH*CO*OH + HO*OH + HO*CO*OH + *OHHO*CO*OH =+ H,O + CO,} chainwith *CO*OH + *OH --+ H,O + CO, chain breakingI n Type B reactions, which are exemplified by iodide anion and by thephotographic developers, the oxidisable substance is attacked by the Fe+++cation, and the function of the hydrogen peroxide may consist in the repeatedrapid re-oxidation of the ferrous cation to the ferric state.Fenton's reaction l18-the oxidation of a-hydroxy-acids at 0" with hydro-gen peroxide in the presence of a trace of a ferrous salt-is obviously a processof Type A , and can be written either asHOH OHR--$-CO,H + *OH ---+ R-vLCO,H + H,O?HR-(YCO,H + HO-OH ras/ R-Y-CO,H + *OH __+ R-CO-CO,HOH OHor as 1 H HOH 0.R-(Y-CO,H + *OH + R-V-CO,H + H,OH + HO-OH11% J .Physical Chern., 1937, 41, 1107.118 H. J. H. Fenton, J . , 1894, 65, 899; 1899, 75, 1 ; 1900, 77,69.11' Annalen, 1927,457, 1 ; 1929,478,1, 19WATERS : MECHANISMS OF OXIDATION. 151according to whether or not the initial dehydrogenation can be believed toattack R C-H or an O-H link.*In accordance with this theory, J.H. Baxendale, M. G. Evans, and G. 8.Park ll1 have shown that the addition of a monomeric olefin, such as iso-propenyl cyanide or methyl acrylate, greatly reduces the rate of oxidationof glycollic acid by Fenton’s reagent, thus proving that the entity (hydroxylradical) responsible for starting the chain oxidation of glycollic acid is thesame as that responsible for initiating polymerisation of the olefin.I n accordance with this recent evidence, the hydroxylation of olefinsby the inorganic per-acids may be represented as a chain processRO-OH -+ RO* + =OH- H-GH--CH=CH- + *OH + 8Hin which the formation of an epoxide is an obvious alternative as a secondstage :-CH-GH- -CH--GH-f l +- Ph-CO-OH + *OH - I -O-i-H + Ph-CO-O-/-OHThe slower reactions of hydrogen peroxide, for which a large excess of thereagent is usually employed, may also be reactions of hydroxyl radicals,but not chain processes in which a second active radical, capable of attackinghydrogen peroxide molecules, is concerned.It is significant that all thereactions of hydrogen peroxide indicate that the free hydrosyl radical isincapable of attacking the C-H bond of a paraffin chain a t room temperatures.Oxidations of thio-ethers, tervalent arsenic or antimony compounds,etc., may also be represented as radical addition processes, for the oxidisableatom can, at least temporarily, increase its electrovalency shell :Hydroxylations of olefins, apparently anaslogous to those effected by theFenton and the Milas reagents, can also be carried out by using a cold aqueoussolution of a chlorate and a trace of osmium tetroxide or vanadium pentoxideas a catalyst.llg$ l 2 O $ 121 G.Braun 122 considers that this chlorate oxidation1111 K. A. Hofma,nn, 0. Erhardt, and 0. Schneider, Ber., 1913,46,667.120 N. A. Milas and E. M. Terry, J. Amer. Chem. SOC., 1925,47, 1412.lzl J. W. E. Glatfield and S. Woodruff, ibid., 1927, 49, 2309.1z2 Ibid., 1929, 51, 228.* This is at present a moot point, which is of significance also in connection with themechanism of oxidation of alcohols (compare W. A. Waters, Trans. Faraduy SOC.,1946, 42, 194). The alternative radicals, >CH-0- and >&OH, would certainly betautomeric, and the removal of the second hydrogen from either form to give thestable structure >CO would undoubtedly be so facile that it might be quite impossibleto characterise the primary radical152 ORGANIU CHEMISTRY.of olefins invariably gives cis-glycols, in contrast to perbenzoic acid oxidation,which often yields trans-glycols on account of the trans addition of water tothe intermediate epoxide.There is some evidence to suggest that chloratehydroxylation requires solutions of low pH, and that it may involve freehypochlorous acid as a possible source of hydroxyl radicals :HO-Cl + e -+ C1- + *OHChlorate reagents are also convenient for effecting the smooth oxidation ofquinols to quinones.l23Isolated experiments also indicate that active radicals are possibly pro-duced by the ‘‘ reductive activation ” of both bromates 12* and iodates,12jbut it may be unwise to speculate too much upon old evidence.Oxidations Involving Sulphur Compounds.The autoxidation of aqueous solutions of sulphites was one of the firstreactions to be explained successfully by the Haber-Willstatter theory ofone-electron transfer.lo** 126 In this, cupric salts are particularly activecatalysts, and have a noticeable effect in concentrations as low as 10-13molar.CU++ + SO,= --+ Cu’ 4- (*SO,)-(*SO,)- + 0, --+ (*OOSO,)-(*O*O*SO,)- + (HSO,)- --+ (HO-O-SO,)- + (*SO,)-giving, in (HS0,)-, the anion of Caro’s acid, which is it sufficiently powerfuloxidiser to convert sulphites directly into sulphates by hydroxylation.(HO*OeSO,)- + SO,= --+ (O*SO,)= + (HO*S03)-Evidence for the participation of the (*SO,)- radical-ion in this processis afforded by the fact that, in the absence of oxygen, copper sulphate andsodium sulphite react to give cuprous oxide and sodium dithionate.l27Persulphate radicals, (.O-O*SO,)-, are evidently formed since the reactingsystem can induce autoxidations of arsenites, nitrites, and alcohols, aldehydes,and other organic substances, many of which can be used a6 “ stabilisers ”of sulphite solutions.The action of photographic developers is of interest in this connection.They consist essentially of buffered solutions of easily oxidisable polyphenolsor amino-phenols, together with a large excess of sodium sulphite.Theinitial reduction of the sensitised silver salt is undoubtedly due to the organiccomponent, which, giving a semi-quinone radical, is then reduced again byThe chain process can be written asE.M. Terry and N. A. Milas, J . Amer. Chem. SOC., 1926,48, 2647; W. Baker and(Miss) I. Munk, J., 1940, 1092; cf. K. A. Hofmann, Ber., 1912,45, 3329.12‘ F. Wachholtz, 2. Elektrochem., 1927, 33, 545.126 H. Wieland and F. G. Fischer, Ber., 1926, 59, 1171.12E H. J. L. Backstrom, 2. physikal. Chern., 1934, B, 34, 122.12’ H. Baubigny, Compt. rend., 1912, 154, 701 ; Ann. Chim. Phys., 1910, 20, 12;1914,1, 201WATERS : MECHANISMS OF OXIDATION. 153the sulphite, and so acts as a '' potential mediator " to the whole system,though it is the sulphite which is the main reducing agent in the end.12*Ag+ + HO*C,H,*OH --+ Ag+ + H+ + *O*C,H,*OH-O*C,H,-OH + (SO,)= -+ (:O*C,H,*OH)- + (*SO,)-(*SO3)- + (:OH)- + *O*C,H,*OH --+ (HS0,)- + (:O*C,H,*OH)-The final reaction involves the mutual destruction of two radicals, and henceeach component of the developer can be regarded as acting as an anti-oxidantfor the other.Many other reactions undoubtedly involve the oxidised sulphite radical-ion.Thus nuclear sulphonation of phenols can be eEected by blowing airthrough their solutions in ammonium sulphite in the presence of a trace ofa copper salt ,129 and similar reactions have been reported with heterocycliccornpo~nds.~30 This action of the (*SO,)- radical is analogous to the alkyl-ation of quinones, etc., with lead tetra-acetate (p. 144). Again, quinonescan be substituted directly by thiols, with simultaneous reduction toquin01s.l~~ The " peroxide-catalysed " additions of sulphites to olefins 132also show the chemical importance of this radical-ion.Thiol radicals, RS*, formed by peroxide catalysts, are undoubtedlyresponsible for the similar " abnormal " addition of thiols to olefins.Theseradicals probably take part in many oxidation reactions involving sulphurcompounds, notably in biochemical processes in which the equilibriumRS: += RS* + e may often be involved as an essential potential mediatoreven when sulphur compounds do not appear as final reaction products.92In this connection copper porphyrins and other " trace-metal " compoundsmay play an essential part in initiating radical formation.K.Ziegler and K. Giinicke 133 have shown that thiophenol can markedlyaccelerate the autoxidation of olefins once radical formation has been initi-ated by the addition of a trace of triphenylmethyl, though phenyl disulphide,Ph*S*S*Ph, has no catalytic action. The essential reaction involving thetkiol is therefore hydrogen abstraction by the thiol radicalPh*S* + HR + Ph*SH + *Rrather than the activation of oxygen by it. At higher temperatures, however,organic disulphides can dissociate thermally to thiol radicals, and can be usedas selective dehydrogenators. J. J. Ritter and (Miss) E. D. Sharpe 13*for instance have shown that tetralin can be smoothly oxidised to naphthal-ene by distilling it a t 250" with isoamyl disulphide through a fractionatingcolumn.isoAmylthio1 gradually distils over, and can easily be collected inCf. A. Weissbcrger, D. S. Thomas, and J. E. Lu Valle, J. Amer. Chenz. Xoc.,1943,65, 1489.lze (Mlle.) Y . Garreau, Bull. ,Sot. chim., 1934, 1, 1563; Compt. rend., 1936, 203,1073.130 H'. McIlwain, J., 1937, 1704.131 J. M. Snell and A. Weissberger, J . Amer. Chem. SOC., 1939, 61, 450.13' M. S. Kharasch, E. M. May, and F. R. Mayo, J . Org. Chem., 1938,3, 175.133 Annalen, 1942, 551, 213. lS4 J . Amer. Chem. SOC., 1937, 59, 2361154 OHQANIC CEiEM1STK.Y.dilute hydrogen peroxide and so immediately re-oxidised for further use.This reaction has been shown to involve the production of transient hydro-carbon radi~a1s.l~~ It is probable that dehydrogenations by sulphur orselenium have a similar mechanism, though in a heterogeneous system.136The fact that thiols can dehydrogenate reactive methylene groups may havean important bearing upon the mechanism of vulcanisation of rub-ber.136, 13’% l38 Thiols, such as thiobenzthiazole, C,H,<S >C*SH, and di-sulphides, such as tetramethylthiuram disulphide, Me,N*CS*S*S*CS*NMe,,are technically valuable “ accelerators ” of the vulcanisation process.Theymay act as Bources of thiol radicals which dehydrogenate active methylenegroups in the rubber molecule, and thus promote the cross-linking of hydro-carbon chains, either by dimerisations :RS- + >CH,+ R*SH + >CH*w2>CH* + >CH*CH<or by union with sulphur, giving thio-ethers or polysulphides :2>CH* + * S o + >CH*S*CH<whilst from the free sulphur there may again be formed fresh active thiolradicals which could continue the chain process :>CH* + *S* ---+ >CH*S*The close connection between the autoxidisability of rubber and its degreeof vulcanisation 139 is an indication that radicals of similar types are involvedin both.Attention may be directed to the fact that thiol radicals (R-S) can evid-ently dehydrogenate some C-H links, whereas hydroxyl or alkoxy (R-0)radicals apparently cannot.This may be associated with the fact thatlthe bond energy of disulphide links is apparently higher than that of peroxidelinks.*Reactiom of Quinones.It is now well-established that the reversible oxidation-reduction re-actions of many quinones and quinonoid dyes take place in two successivestages, which may be representedQH, + QH- + H+ ; QH- + QH + eQH eQ- + H + ; Q- +=Q + esince the independent existence of semi-quinonoid radicals, QH (e.g., XVII) ,135 W; A.Waters, Trans. Faraday SOC., 1946,42, 184.136 E. H. Farmer, ibid., 1942, 38, 345.13’ Idem, ibid., p. 360.138 E. H. Farmer and S. E. Michael, J., 1942, 513.139 S. Horrabin, R. G. A. New, and D. Taylor, Trans. Faraday SOC., 1946,42,262.* Pauling (“ The Nature of the Chemical Bond,” p. 63) gives S-S 64 kg.-cal. and0-0 35 kg.-cal. though both these values may be much too low (compare J. L. Bollaxidand G. Gee, Trans. Paraday SOC., 1946,42,244)WATERS : MECHANISMS OF OXIDATION. 155which are often deeply coloured, has been conclusively established bothmagnetically and electrochemically. 140Compounds of this group include most of the important oxidation-reduction indicators, and also such biochemically important substances as.. - pyocyanine and riboflavin.As well as being important onaccount of their colour changes, several of these semi-quin- :P: onoid systems are important as " potential mediators "Me\//\/Me which, by two successive, reversible, stages of one-electronI I] transfer can bring about oxidations or reductions which,M e / \ \ f \ ; M e though thermodynamically possible, are otherwise exceed-: 0 : ingly slow ; 141, 142 e.g., 2Ti+++ + I, --+ 2Tiff++ + 21-.P. A. Schaffer in 1936 142 pointed out that oxidations and (XVII.) reductions involving simultaneous two-electron changes, suchas Tl' --+ Tl+++, or I, --+ 21-, were generally slow, whereas all oxidationsor reductions involving one-electron changes seemed to be rapid, and ascribedthe catalytic powers of quinonoid dyes to their abilities to accept electronssingly.He pointed out in particular the significance of this view in con-nection with autoxidation and with biological respiration involving the reduc-tion of free oxygen to hydrogen peroxide. L. Michaelis 143 has gone furtherto propound a " principle of compulsory univalent oxidation " accordingto which oxidations of organic compounds can proceed a t a measurablespeed only in steps of one electron each. He postulates the productionof transient radicals in all oxidations, and considers that an oxidation orreduction process is slow when the formation of this intermediate radicalinvolves a high energy increment.Rapid oxidation can occur if, owing toresonance, the formation of the radical involves comparatively little energy.Consequently it is to the resonance-stabilisation of semi-quinone radicals,and to the formation of dimeric quinhydrone complexes, that one can ascribethe potential mediating powers of quinonoid dyestuffs.The preceeding pages will have shown that, in broad outline, the Michaelisprinciple of compulsory univalent oxidation is applicable over a very widefield of organic chemistry, but it may still be premature to accept it, withoutexperimental confirmation, for all oxidation reactions.The Schaffer-Michaelis theory of one-electron transfer was developedfor reactions of quinones in aqueous solution, in which acid-base ionisation,QH Q- + H', was immediate.There is, however, a considerableamount of evidence to suggest that in non-electrolytes quinones can oxidiseby hydrogen atom transfer :Q+H-R---+*QH+*R140 L. Michaelis, Chem. Reviews, 1935, 16, 243; L. Michaelis and M. P. Schubert,ibid., 1938, 22, 437 ; cf. A. E. Remick, " Electronic Interpretations of Organic Chem-istry,', Chap. VIII. (Wiley, New York, 1943.)141 P. A. Schaffer, J. Amer. Ghem. SOC., 1933,55,2169.142 J. Physical Chem., 1936,40, 1021.Trans. Electrochem. SOC., 1937, 71, 107; Ann. Rev. Biochem., 1938, 7, 1 ; J .Amer. Chem. Xoc., 1937, 59, 1246156 ORGANIC CHEMISTRY.E.Clar and F. John 144 introduced phenanthraquinone in boiling nitrobenz-ene, and chloranil in boiling xylene, as convenient reagents for the smoothdehydrogenation of hydroaromatic hydrocarbons, and the same methodhas since had extended application by R. Criegee 145 and by R. T. Arnoldand C. J. The latter workers point out that as a cheap, clean,dehydrogenating agent, chloranil, which can easily be made by oxidisingquinone in concentrated hydrochloric acid with perhydrol, is often superiorto selenium, which reacts only at much higher temperatures.R. Criegee 145 showed that quinones reacted with tetralin to give quinoltetralyl ethers, RO*C,H,*OH, which broke down at higher temperatures todihydronaphthalene and quinols. W. A. Waters 135 has shown that quinonesare partial inhibitors of the autoxidation of tetralin, and considers that thisis due to the facile combination of a-tetralyl and semi-quinone radicals,which leads to enhanced chain-breaking in the oxidation cycle, but pointsout that initially the quinone must be considered as abstracting atomichydrogen from the tetralin.Other Oxidising Agents.It has been impossible to consider in this report the mechanisms of actionof many oxidising agents commonly used in organic chemistry.There isoften no experimental evidence to substantiate theories that can be advancedon paper.Potassium perrnungunate, for instance, is usually regarded as the simplesthydroxylating agent for olefins, but attack on C-H bonds, e.g., of aromaticside chains, is one of its general uses.Many oxidations by permanganate,as for instance the volumetric permanganate-oxalate reaction, are essentiallychain processes in which radicals must presumably be formed, and freehydrocarbon radicals are evidently produced when permanganate is made tooxidise tetralin. It would be premature, however, to classify potassiumpermanganate and lead tetra-acetate or benzoyl peroxide as reagents of anentirely similar type.Selenium dioxide may perhaps be an exception to the Michaelis rule,though from all its reactions with organic compounds 14' scarcely any evidencecan be adduced for its mode of action, H. L. Riley 14* has suggested thatunstable intermediate compounds of selenium are often formed, but haspointed out that subsequently there must occur a very complicated stagewhich brings about the combination of carbon and oxygen as a C-0 group.N.N. Melnikov and M. S. Rokitskaya 149 have shown that selenium dioxidereacts with alcohols to form alkyl selenites, which at 300" decompose told4 Ber., 1930, 63, 2967.146 J . Amer. Chem. SOC., 1939, 61, 1407; cf. ibid., 1940, 62, 983.14' For reviews, see G. R. Waitkins and C. W. Clark, Chem. Reviews, 1945, 36,l48 Sci. J . Roy. Coll. Science, 1935, 5, 7 ; S. Austin, L. de V. Moulds, and H. L.14e J . Qen. Chem. RUGS., 1937, 7, 1532.145 Ibid., 1936, 69, 2758.235.RiIey, J . , 1935, 901OWEN : FURANS.aldehydes, selenium, and water.perhaps be similar :The attackI I ,OH I L/?! _------------ t, I /157on methylene groups may>CH2 + SeO, + >C/ /,S;? -+ >CO +Se+H,O\O/l--------------The fact that the oxidations of methyl and carbinol groups, as in acetoneand alcohol, stop a t the aldehyde stage rather discounts dehydrogenationhypotheses, since aldehydes are usually attacked by free radical reagentsfar more easily than is methyl.In considering the mechanisms of these and other oxidations, the theorieewhich have been described on the preceding pages may serve to indicatenew lines of approach for future crucial experiments.The rapidity of de-velopment of this whole field has been remarkable, for the very conceptof the intervention of transient free radicals in simple organic reactionsin solution was startlingly novel but ten years ago.W. A.W.5 . FURANS.The chemistry of furan has undergone a remarkable expansion withinthe last 25 years, owing in the main to an increasing realisation of the potenti-alities awaiting investigation within this field. It is not intended in thisReport to give any account of the multitudinous uses to which furan deriv-atives have been applied in the commercial production of solvents, pre-servatives, fungicides, dyestuffs, etc., particularly since brief reviews of suchindustrial applications are already available.lY Rather has an attempt beenmade to survey some of the more important reactions which have been studied,both from the point of view of the formation of furan derivatives, and alsowith regard to their synthetic uses, such as the preparation of aliphaticcompounds by ring scission.Formation.-Although considerable interest has recently been shown inthe preparation of furans from acetylene (see p.lSO), the principal source isstill to be found in the naturally occurring pentosans,2 such as those presentin oat-hulls, which when subjected to acid hydrolysis yield pentoses, andfinally furfuraldehyde, from which most of the other derivatives can beprepared. Other materials of carbohydrate nature may also serve assources of furans, but it is only recently that a thorough investigation hasbeen made into the optimum conditions for the preparation of 5-hydroxy-methylfurfuraldehyde from sucrose.have obtained a 54% yield by the use of 0.25% aqueous oxalic acid a t 130"under pressure, the yield being based on the fructose portion of the molecule,since the glucose portion takes no part in the reaction.4 This is probablyW.N. Haworth and W. G. M. JonesP. N. Peters, I n d . Eng. Chem., 1936,28, 755; 1939,31, 178.A. Wacek, Angew. Cheve., 1941, 54, 453.Compare A. D. Braun, Biokhimiya, 1939,4, 276; B. L. Scallet with J. H. Gardner,J., 1944, 667.J. Amer. Ghem. SOC., 1945, 67. 1934158 ORGANIC CHEMISTRY.due to the fact that fructose has a much greater tendency than glucose toreact in the furanose form (I), which by successive dehydrations can readilypass into 5-hydroxymethylfurfuraldehyde (11). They have also shown thatglucose (111) will undergo the reaction, provided it is pretreated with dilutealkali to facilitate the formartion of the 1 : 2-enediol (IV), which by loss ofwater can give (V), a postulated intermediate in the above scheme.HO- OHHO~CH,! )-OH 4 HOTOH --+0 \CH,*OH HO-CH,! ,LCH.OH HOGH,QO!/CHO 0(11.)(I?.) \ (1.)HO*VH-YH*OH HO vH-vH*OHOH OH OH OH(111.) (IV.)HO*CH,*VH YH*CHO + HO*CH,*yH $XCH*OHOptimum conditions have also been worked out for the preparation of5-chloromethylfurfuraldehyde by the action of hydrogen chloride onsucr~se.~ M.L. Wolfrom, E. G. Wallace, and E. A. Metcalf have shownthat acid treatment of 2 : 3 : 4 : 6-tetramethyl d-1 : 2-glucoseen gives5-methoxymethylfurfuraldehyde. The electronic interpretation of suchreactions has been discussed by H. S. Isbell.6Carbohydrates, however, can be utilised in another way for the pre-paration of furan derivatives.The condensation of glucose or mannose with1 : 3-diketones, HA*CO*CH,*CO*R’, in the presence of zinc chloride gives avariety of substituted 5-tetrahydroxybutylfurans (VI), the constitutionsof which have been proved by oxidative degradation with lead tetra-acetate 79 s or periodic acid to give 5-formylfurans (VII), which on furtheroxidation with silver oxide yield substituted furoic acids (VIII). Other- C0.R’ -- CO*R’ --CO*R’+ OHC~!, )IR + HO,C/!~)/R HO*CH2*[CH*OH]3*[o)1R 0(VI.) \ (VII.) (VIII.)-CO,H/\CO.Rt -1 \HO(),o.h3 OH H0,C[O)1C02H(X.1sugars do not readily take part in this condensation.stated to undergo no reaction with acetylacetone,s but JonesGlucose was originallyhas shownJ . Amer. Chem. SOC., 1942, 64, 265.J. Res.Nut. Bur. Stand., 1944, 32, 45.S. Muller and I. Varga, Ber., 1939, 72, 1993; I. Varga, Chem. Abs., 1941,35,1034.8 T. Szeki and E. Laszlo, Ber., 1940, 73, 924. J. K. N. Jones, J., 1945, 116OWEN : FURANS. 169that it readily gives (VI; R = R’ = Me), which rearranges with lossof water in boiling dilute acid solution to form the pyran derivative (IX;R = R’ = Me). The product (VI; R = Me, R’ = OH) from ethyl aceto-acetate behaves similarly. Furan-2 : 3 : 5-tricarboxylic acid (X) can beobtained by permanganate oxidation of the condensation product (VI ;R = CH,*CO,Et, R’ = OEt) from glucose and ethyl acetonedicarboxylate.8This direct oxidation of the methylene group in the side chain a t C, is unusual,since the oxidation of alkylfurans usually results in extensive degradation.It is possible that the necessary stability is secured by the prior formationof carboxyl groups a t C, and C,, since E.V. Brownlo has shown that5-methylfuroic acid, unlike 2 : 5-dimethylfuran, can be oxidised to furan-2 : 5-dicarboxylic acid by ferricyanide. If this is so, oxidation of (VIII)to (X) should be possible.S. Archer and M. G . Pratt l1 have investigated the condensation of ethylbromopyruvate with ethyl P-ketosuberate (XI ; R = [CH,],*CO,Et).If C-alkylation occurs, as originally postulated by H. Sutter l2 for a similarcondensation between ethyl bromopyruvate and ethyl oxalacetate, theproduct would be ethyl 3 : 5-dicarbethoxyfuran-2-valerate, but i t is clearthat the reaction proceeds by O-alkylation, since it gives the isomeric 3 : 4-di-carboxylate (XII; R = [CH,],*CO,Et).The acid obtained on saponific-ation is identical with that prepared by K. Hofmann l3 by an applicationof a reaction studied by K. Alder and H. F. Rickert.14 The latter authorsshowed that whilst the adduct (XIII) from furan and maleic anhydride isreconverted into its components on heating, the ester (XIV; R = H),obtained by semihydrogenation of tlhe adduct from furan and ethyl acetyl-enedicarboxylate, loses ethylene and gives ethyl furan-3 : 4-dicarboxylate(XII; R = H).”R*CO*CH,*CO,Et (XI.) R*F:CH*CO,Et Rlo Iowa State Coll. J . Xci., 1937, 12, 227.l1 J . Amer. Chem. SOC., 1944, 66, 1656.l2 Annulen, 1932, 499, 54; compare T. Reichstein, A. Griissner, K.Schindler, andE. Hardmeier, Helv. Chim. Acta, 1933, 16, 276.lS J . Amer. Chem. SOC., 1944, 68, 51. * W. Nudenberg and L. W. Butz ( J . Amer. Chem. SOC., 1944,86, 307) have obtained3 : 6-epoxycyclohexene, the parent compound of (XIV), by condensation of furan withethylene under high pressure, thus demonstrating the reversibility of the second typeof reaction.l4 Ber., 1937, 70, 1354160 ORGANIC CHEMISTRY.By condensation of furan-2-valeric acid with ethyl acetylenedicarboxyl-ate, followed by semihydrogenation, the ester (XIV; R = [CH2],*C02H)is obtained, which on pyrolysis gives (XI; R = [CH2],*C0211). Similarly,furan-2-pentanol gives (XI1 ; R = [CH,],*CH,*OH), an important inter-mediate in the synthesis of O-heterobiotin (see p. 165).The investigations of R.E. Lutz on the preparation of heavily substitutedfurans have been ~0ntinued.l~ By reductive cyclisation of an unsaturateddiketone (XV), the furan (XVI) can be prepared, the saturated diketone(XVII) probably being an intermediate product. l6 The reverse reaction,oxidative fission, may be accomplished by treatment of some furans with anitric acid-acetic acid mixture. This usually gives the cis-form of theunsaturated diketone, and by the application of these reactions it has beenpossible to prepare certain &-compounds which are difficult to obtain bydirect isomerisation of the trans-form. For example, trans-dibenzoyl-methylethylene (XV; R = Ph, R’ = Me) is converted in high yield into2 : 5-diphenyl-3-methylfuran (XVI; R = Ph, R’ = Me), which on oxidativescission gives the pure ~is-is0rner.l~ The effect of mesityl groups on thestability of the furan ring is exemplified by the resistance of 2 : 5-dimesityl-furan (XVI; R = C9Hll, R’ = H) towards fission with nitric acid.l*Although it has not been found possible to isolate free 3-hydroxyfurans,probably owing to their tautomerism with 3-ketodihydrof~ran.s,~~ the3-acetoxy-derivatives (XVIII), prepared from the unsaturated diketonea(XV) by the action of acetyl chloride, react with a Grignard reagent togive (XIX), from which, by treatment with the appropriate halides, several3-alkoxy- and 3-acyloxy-compounds (XX) have been obtained.20It has recently been shown21 that substituted furans can readily beprepared from ethylenic ethynylcarbinols (XXI), obtained by the condens-ation of ap-unsaturated aldehydes with acetylene.Compare T.S. Stevens, Ann. Reports, 1941, 38, 315.R. E. Lutz and C. J. Kibler, J . Amer. Chem. SOC., 1939, 61, 3007; R. E. Lutzand W. G. Reveley, ibid., 1941, 63, 3180; R. E. Lutz and W. P. Boyer, ibid., p. 3189.l7 R. E. Lutz and C. E. McGinn, ibicl., 1942, 64, 2585.R. E. Lutz and C. J. Kibler, ibid., 1940, 62, 1520.lQ E. P. Kohler, F. H. Westheimer, and 31. Tishler, ibid., 1936, 58, 264; E. P.2o R. E. Lutz, C. E. McGinn, and P. S. Bailey, ibid., 1943, 65, 843; R. E. Lutz and*l I. M. Heilbron, E. R. H. Jones, Peter Smith, and B. C. L. Weedon, J . , 1946, 54.Kohler and D. W. Woodward, ibid., p. 1933.C. E. McGinn, ibid., p. 849OWEN : FURANS.161On treatment with acids, these carbinols rearrange22 to give products(XXII) which when steam distilled in the presence of mercuric chloride givefurans (XXIII). Propenylethynylcarbinol (XXI ; R = Me, R’ = H)gives a 55% yield of 2 : 5-dimethylfuran (XXIII; R = Me, R’ = H),*and from 4-ethyloct-4-en-1-yn-3-01 (XXI; R = Pr, R’ = Et) a 64% yieldof 5-methyl-3-ethyl-2-propylfuran (XXIII ; R = Pr, R’ = Et) can beobtained. This process can be regarded either as a direct intramolecularhydration to (XXIV), followed by isomerisation, or as a normal hydrationof the acetylenic linkage to give (XXV), followed by cyclodehydration.1 : 4-Diketones (XXVI) are formed simultaneously.R’*C-CH*OH R’*((==FH ,/RCH CiCH‘%_3R*CH CiCH II 1(XXI.) I ‘\OH(XXII.)R*CO*CHR’*CH,*CO*Me (XXVI.)R’RInlMe‘0’(XXIIT. )The tautomerism exhibited by hydroxy-aldehydes and hydroxy- ketones 23is well exemplified by y- hydroxycarbonyl compounds (XXVII), whichexist almost entirely in the form of 2-hydroxytetrahydrofurans (XXVIII).On treatment with meth anolic hydrogen chloride, the corresponding‘‘ furanosides ” (XXIX) are formed, whilst dehydration gives 2 : 3-dihydro-furans (XXX).The latter react readily with water to regenerate thehydroxyfurans. The simplest member of this series (XXVIII ; R = R’ = H)has recently been prepared by two new routes, vix. the oxidation of pent-ane-1 : 2 : 5-trio1 with lead tetra-acetate or periodic acid,M and the hydrogen-ation of butyne-1 : 4-diol (see below). J. R.Stevens and G. A. Stein25R(0)<Ek --+ R r l < R ’(XXVIII.) (XXIX.)R*CH( OH)*CH,*CH,*CO*R‘ 6-(XXVII.) \o/ OMeRQR’ (XXX.)22 E. R. H. Jones, Ann. Reports, 1944, 41, 175.z3 L. N. Owen, ibid., p. 140.24 R. Paul, Gompt. rend., 1941, 212, 492; 1942, 215, 303; Bull. SOC. chim., 1941, 8,911.z6 J . Amer. ChemSoc., 1940,62,1045; U.S.P. 2,123,653; see also D.R.-P. 705,034;723,052.* 2 : 5-Dimethylfuran is obtained industrially as a by-product in the preparationof acetaldehyde from acetylene (Reports Appl. Chem., 1938, 23, 142) or by the pyrolysisof acetone at 700” (U.S.P. 2,098,592).REP.-VOL. XLII. 162 ORGANIC CHEMISTRY.have obtained 3-chloro-2-ethoxy-2-methyltetrahydrofuran (XXXI) by theaction of boiling acid-ethanol on chloroacetobutyrolactone (XXXII) :CH,*CH,*CCl*CO*Me c1 I + [CH,(OH)*CH,*CHCl*CO*Me] --+ Me(XXXII.) (XXXI.)\O/<OEt co 0---A closely related instance has been encountered by I.M. Heilbron, E. R. H.Jones, and H. P. Koch 26 who have shown that semihydrogenation of theacetylenic acetal (XXXIII) gives, instead of the expected ethylenic compound(XXXIV), 2-ethoxy-5-methyl-5-ethyl-2 : 5-dihydrofuran (XXXV).I'YC( OH)*CiC*CH( OEt), + Me (XXXIII.)Reference was made in a recent Report 22 to the formation of di- andtetra-h ydrofurans from acetylenic glycols under conditions of hydration,halogenation, hydrogenation, etc. The commercial production of but-2-yne-1 : 4-diol (XXXVI), by the condensation of acetylene with formaldehyde inthe presence of a copper or silver acetylide catalyst,27, 28 has led to a renewedinterest in its hydrogenation products, but-2-ene-1 : 4-diol (XXXVII)and butane-1 : 4-diol (XXXVIII), since dehydration of these glycols overacid catalysts 29 gives dihydro- and tetrahydro-furan, respectively.It hasalso been shown that hydrogenation of butynediol a t 100" over a palladiumcatalyst, on an acid carrier, gives 2-hydroxytetrahydrof~ran.~~?--- (7 H,CH2*OH CH2*OH --+(XXXVI.) (XXXVII.) 4- Ha0I=={\O'?H=--Xp HZ 7H2-?H2CH2*OH CH2*OH -+ CH2*OH CH2*OH(XXXVIII.)I 4- HaoA striking example of t,,e different behaviour of cis- ank tram-unsaturateddiols has been provided by J. R. Johnson and 0. H. whohave shown that whereas trans-2 : 5-dimethylhex-3-ene-2 : 5-diol with 15%sulphuric acid gives only 2 : 5-dimethylhexa-1 : 3 : 5-triene, the cis-isomergives an excellent yield of 2 : 2 : 5 : 5-tetramethyldihydrofuran.E.Beati and G. Mattei 32 have studied the conditions for the dehydrationof pentane-1 : 4-diol to 2-methyltetrahydrofuran, whilst C. S. Marvel andE. H. Dunlap 33 have shown that reduction of ethyl aa'-dipropylsuccinate26 J., 1942, 735.28 Ind. Eng. Chem. (News), 1945, 23, 1516, 1840, 1846.28 B.P. 508,548, 510,949; U.S.P. 2,251,835, 2,251,895.31 J . Amer. Chem. SOC., 1940, 82, 2615.s3 J. Amer. Chem. SOC., 1939, 61, 2714.2' l3.R.-P. 721,004.30 U.S.P. 2,333,216.32 Ann. Chim. appl., 1940, 30, 21OWEN : FURANS. 163over copper chromite at 260" gives 3 : 4-dipropyltetrahydrofuran, the expected1 : 4-diol undergoing dehydration under these conditions.The latter ob-servation is of interest, inasmuch as copper chromite a t high temperaturesfrequently favours the reductive scission of the tetrahydrofuran ring (seep. 167).Long chain ao-diols were originally considered 34 to give 2-alkyltetra-hydropyrans on dehydration with sulphuric acid, but more recently 3 5 9 3 6 ithas been shown that the main product of this reaction is the 2-alkyltetra-hydrofuran (XXXIX). It would therefore appear that the alleged formationHO*[CH,l?I*OH + (01.[CH21n-s*Me (XXXIX.)of tetrahydropyran from pentane-1 : 5-diol under these conditions 37 isprobably erroneous; the physical constants of the product suggest, in fact,that it is 2-methyltetrahydrofuran7 and a further investigation of thisdehydration would be of interest.Preferential formation of the five-membered ring system is also to be found in the dehydration of pentane-1 : 2 : 5-tri01,~~ which gives tetrahydrofurfuryl alcohol,* and in the isomeris-ation of y8-unsaturated alcohols by treatment with concentrated sulphuricacid ; pent-4-en-1-01, for example, gives an 88% yield of 2-methyltetra-hydr~furan.~~ Closely related is the dehydrobromiiiation of 4 : Ei-dibromo-pentanol, which forms only tetrahydrofurfuryl bromide.38 Ring closure byremoval of hydrogen halide has also been studied by C. L. Wilson,40 whohas shown that 1 : 5-dibromopentan-2-01 (XL) gives approximately equalamounts of tetrahydrofurfuryl bromide and y-bromopropylethylene oxide,whereas 1 -chloro-5- bromopentan-2-01 (conveniently prepared from the oxideby treatment with hydrochloric acid) gives mainly tetrahydrofurfurylchloride, which indicates that removal of hydrogen bromide is more facilethan that of hydrogen chloride :$L)CH2Cl Br*[CH,],*CH( OH)*CH,Cl34 A.Franlre and A. Kroupa, fionatsh., 1930, 56, 340.s b Idem, ibid., 1936, 69, 167.36 J. K. Juriev, V. I. Gusev, V. A. Tronova, and P. P. Yurilin, J. Gen. Chein. Russia,37 N. Demjanov, J. Russ. Phys. Chem. SOG., 1890, 22, 388.38 R. Paul, Ann. Chim., 1832, 18, 303; see also ref. 97.39 R. Paul and H. Normant, Bull. SOC. chiin., 1944, 11, 365.* Further dehydration of the latter, however, over alumina at 300-350" gives a70% yield of dihydropyran (U.S.P. 2,365,623 ; Org. Synth., 1943, 23, 25 ; C.H. Klhoand J. Turkevich, J . Amer. Chem. SOG., 1945,67, 498) which is known t o be more stableat high temperatures than thc expected 2-methylenetetrahydrofuran (R. Paul, Bull.SOC. chim., 1935, 2, 745).1941, 11, 344.40 J., 1945, 48164 ORGANIC CHEMISTRY.Cycliaation of py-dibromoalcohols, CH,Br*CHBr*CH,*CH(OH)*R, yields4- bromo-2-alkyltetrahydrofurans,411 42 which on further dehydrobrominationwith alcoholic alkali give 2-alkyl-2 : 5-dihydrofurans (XLI).Amino-derivatives.-Comment was made in an earlier Report 43 on thedifficulty which has been experienced in the preparation of simple amino-furans in which the amino-group is directly attached to the nucleus. The fewcompounds of this type which have been described are very unstable, andit has been suggested that this is due to tautomeric change into the imino-form.It would therefore be anticipated that aminotetrahydrofurans wouldnot show such instability, particularly if the amino-group were in the 3-or 4-position; this is true of the three such compounds known, all of whichwere prepared by cyclisation of 2-aminopolyalkyl-1 : 4-diols. No diamineshad been obtained before the recent work of K. Hofmann and A. Bridg-water. These authors 45 have converted 2-methylfuran-3 : 4-dicarboxylicacid (I) via the acid chloride and azide into 3 : 4-di(carbethoxyamino)-2-methylfuran (11) 46 which is hydrogenated in acetic acid solution over apalladium-barium sulphate catalyst to give the tetrahydro-derivative (111).When this is boiled with 10% aqueous barium hydroxide it yields the bicycliccompound (IV) instead of the expected diamine (V).The latter is formedonly under more drastic conditions, by heating with barium hydroxide underpressure at 140°, and it can be reconverted into (IV) by treatment withcarbonyl chloride in sodium bicarbonate solution. This cyclisation wouldbe expected to occur only with a cis-disposition of amino-groups a t C, andC,, and it is significant that the conditions of hydrogenation were such as tofavour the formation of a cis-compound./\NH NH/\NH NH(VI.) (V. 1 W.)This simple method of preparation is of particular interest in view of theclose relationship of the new ring system to that present in p-biotin, and by a41 0. Kiun-Houo, Ann.Chim., 1940,13, 175; D.R.-P. 696,725.4a E. D. Amstutz, J. Org. Chenz., 1944, 9, 310.43 R. D. Haworth, Ann. Reporb, 1939,36, 310.44 M. Kohn and A. Ostersetzer, Monatsh., 1916, 37, 47; S. Kanao and S. Inagawa,J. Pharm. SOC. Japan, 1928,48, 238. 3-Arylarninotetrahydrof~rans~ prepared from the3-chloro-compound, are described in U.S.P. 2,278,202. 2-Amino- and 3-amino-tetra-hydrofuran are mentioned as typical amines in U.S.P. 2,150,422, but there is no evidencethat they have actually been prepared.45 J. Amer. Chem. SOC., 1945, 67, 738, 1165. 4~ Compare G. Stork, ibid., p. 884OWEN: FDRANS. 166;further application of these reactions47 it has been possible to prepare theO-analogue of p-biotin. For this purpose, 3 : 4-dicarbethoxyfuran-2-pentanolwas synthesised by the method already discussed on p.160, and convertedby the above process into (VI; R = CH,*OH); this on oxidation withchromic acid gave O-heterobiotin (VI; R = CO,H), which differs from@-biotin only in having a tetrahydrofuran in place of a tetrahydrothiophenring. This result has beenconfirmed by R. Duschinsky, L. A. Dolan, D. Flower, and S. H. Rubin.,*The Hofmann method of synthesis, described above, should obviouslybe applicable also to the preparation of monoaminotetrahydrofurans.MercuriaZs.-The ease with which furan and its derivatives can bemercurated, coupled with the great reactivity of the mercuri-group so intro-duced, renders these compounds of particular value for synthetic purposes.Mercuration occurs most readily in the 2- and 5-positions.By controlledtreatment of furan with mercuric chloride and sodium acetate, 2-chloro-mercurifuran (I) is obtained; under more vigorous conditions the 2 : 5-di-and 2 : 3 : 4 : 5-tetra-chloromercurifurans are formed.49 It has been shownthat an alkyl group a t C, or C , orientates the chloromercuri-group into acontiguous 2- or 5-position, if available ; thus, 3-isopropylfuran gives 2-chloro-merc~ri-3-isopropylfuran.~~ Furfuryl alcohol gives 5-chloromercurifurfurylalcohol,s1 and methyl 5-bromofuroate undergoes mercuration in the 4-positionto give (II).62 A chloromercuri-group can also be introduced by replace-ment of a carboxyl residue, provided that this is in the 2- or 5-position,by treatment of the sodium salt of the acid with mercuric chloride.49, 53 Themercuri-chlorides are readily decomposed by acid, the group being replacedby hydrogen, and it is only necessary to treat a furan-2- or-5-carboxylic acidwith mercuric chloride in order to bring about a smooth decarboxylation,since the free hydrochloric acid produced during mercuration is sufficient tobring about the subsequent decomposition.49* 60 Some further typicalreactions involving the replacement of a chloromercuri-group are shownbelow.For simplicity, 2-chloromercurifuran (I) has been chosen as theexample, but alkyl-, hydroxymethyl-, halogeno-, and carbomethoxy-derivatives behave in the same way. Of particular interest is the reactionwith arsenic t r i ~ h l o r i d e , ~ ~ ~ 54 which can be controlled to give furyldichloro-,difurylchloro-, and trifuryl-arsines, compounds which have not been success-The product showed high yeast growth activity.4 7 K.Hofmann, J. Amer. Chem. SOC., 1944, 66, 157; 1945, 67, 421, 1459.4 8 Arch. Biochem., 1945, 6 , 480.4 9 H. Gilman and G. F. Wright, J. Amer. Chem. SOC., 1933, 55, 3302; compare50 H. Gilman, N. 0. Callowny, and R. R. Burtner, J. Amer. Chem. SOC., 1935, 57,6 1 W. J. Chute, W. M. Orchard, and G. F. Wright, J . Org. Chem., 1941, 6, 157.5 2 W. W. Beck and C. S. Hamilton, J . Amer. Chem. SOG., 1938,80, 620.s3 H. Gilman and R. J. Vanderwal, Rec. Trav. chim., 1933,52,267; H. Gilman andR. R. Burtner, J. Amer. Chem. Soc., 1933, 55, 2903; W. G. Lowe and C. S. Hamilton,.ibid., 1935, 57, 2314.H. Gilman and N.0. Calloway, ibid., p. 4197; R. Paul, Compt. Tend., 1935, 200, 1481.906.S4 Idem, ;bid., p. 1081166 ORGANIC CHEMISTRY.fully prepared by any other route. Conversion of (I) into the bisfurylmercury(I11 ; R = H) can be effected by hydrazine, diazomethane, sodium iodide, orIII'0'ClHg-- -BAl lICO,MeFurfurylchloride\O/(11.)thiosulphate.49~ 51 The product (I11 ; R = CH,*OH), from 5-chloromercuri-furfuryl alcohol, on oxidation with potassium permanganate gives bis-(5-formylfuryl-2)-mercury (I11 ; R = CHO), which when treated with mercuricchloride in boiling ethanol gives 5-chloromercurifurfuraldehyde ( IV).51The chloromercuri-derivatives are useful for the characterisation of furans,and can be quantitatively estimated by titration with iodine.Furan-3-mercurials generally undergo the same reactions as their 2-isomerides,but not so readily.Reduction.-The rules which apply to the hydrogenation of benzenoidcompounds are generally applicable to furan derivatives, with the reservationthat the ease of fission of the latter may lead under vigorous conditions to theformation of open-chain 559 56 Hydrogenation of the furannucleus usually proceeds very readily under pressure in the presence of Raneynickel a t 150", but a noteworthy exception has been encountered by W. N.Haworth, W. G. M. Jones, and L. F. wig gin^,^' who have failed to reducemethyl furan-2 : 5-dicarboxylate. The corresponding acid requires atemperature of 235" for hydrogenation to occur, and gives a polymerisedproduct ; by boiling with methanolic hydrogen chloride this is convertedinto the monomeric ester, from which a poor overall yield of tetrahydrofuran-2 : 5-dicarboxylic acid is obtained on saponification.Polymer formation alsooccurs in the hydrogenation of 5-hydroxymethylfuroic acid, but the sametechnique of depolymerisation through the ester gives a good yield of themonomeric tetrahydro-acid. In this case, however, polymerisation can beentirely avoided by the use of methyl 5-hydroxymethylfuroate, whichhydrogenates smoothly over Raney nickel a t 140".If the molecule contamins an easily reducible side chain, this also is hydro-65 Compare H. E. Burdick and H. Adkins, J . Amer. Chem. Xoc., 1934, 56, 438;5 6 G. Natt.n, R. Rigamonti, and E.Beati, Chim. e Z'Ind., 1941, 23 117.6 7 J., 1945, 1." Organic Chemistry " (ed. Gilman), 2nd. edition, p. 779OWEN : FURANS. 167genated under the conditions necessary to reduce the nucleus. Furfuryl-ideneacetone, for example, gives 2- (3'-hydroxybutyl)tetrahydrofuran j8, 59whilst 5-hydroxymethylfurfural gives 2 : 5-bishydroxymethyltetrahydro-furan.57Reduction of the nucleus can be avoided by the use of mild conditionsor less active catalysts. W. Huber 60 has shown that fury1 cyanide, pre-ferably in the presence of ammonia, gives furfurylamine when hydrogenatedover Raney nickel a t room temperature. The same amine can be preparedby the controlled hydrogenation of furfuraldehyde in methanolic ammonia,61and also from furfuraldoxime ; 62 under more drastic conditions, tetrahydro-furfurylamine is formed.63 It has been shown 58 that the hydrogenation offurfurylideneacetaldehyde (I) over Raney nickel to 2-(3'-hydroxypropy1)-tetrahydrofuran (11) proceeds in two stages, the side chain being reduceda t 80", and the nucleus a t 175"; heptane-1 : 3 : 7-trio1 is said Lo be obtainedas a by-product, but there is no evidence to support this formulation ratherthan that of the 1 : 4 : 7-isomer, the formation of which would not be sodifficult to explain.The reduction of furfuraldehyde to furfuryl alcohol and to tetrahydro-furfuryl alcohol has been extensively 55, 569 64, 65 The me of anickel-cobalt catalyst has been recommended for the first stage.Thiscatalyst possesses enhanced activity for side-chain reductions, and undermore vigorous conditions can be used for the preparation from furfuraldehydeof 2-methylfuran and 2-methyltetrahydrofuran.56 I n the benzenoid series,copper chromite is recognised to be particularly effective for the preferentialreduction of side chains, but when applied to furan compounds the temper-ature must be carefully controlled to avoid scission of the heterocyclic ring.For example, furfuraldehyde is rapidly and almost quantitatively reducedto furfuryl alcohol over copper chromite a t 150" under high pressure,j5 butif the temperature is raised it gives a mixture of pentanedi~ls.~~ C.L.Wilson,66,67 however, has shown that 2-methylfuran can be obtained in80% yield by the hydrogenation of furfuraldehyde in the vapour phaseover copper chromite a t 280".Mention must also be made of the applica-tion by A. M. Berkenheim and T. F. Dankova 68 of the general method of5 8 A. Hhz, G. Meyer, and G. Schucking, Ber., 1943, 76, 676.13* W. Huber, ibid., 1944, 66, 876. '' E. J. Schwoegler and H. Adkins, ibid., 1939, 61, 3499; U.S.P. 2,109,159; Org.6 2 R. Paul, Bull. Xoc. chim., 1937,4, 1121.63 U.S.P. 2,338,655. U.S.P. 2,201,347.65 I. B. Rapoport and B. Rapoport, J. Appl. Chenr. Russia, 1938, 11, 723.'I3 J . , 1945, 61.68 J. Gen. Chem. Russia, 1939, 9, 924.R. D. Kleene, J. Amer. Chem. SOC., 1941, 63, 3539.Synth., 1943, 23, 68.6 7 Compare ref. 85168 ORGANIC CHEMISTRY,reducing aldehydes by treatment with formaldehyde and alkali. In thisway they have prepared furfuryl alcohol in 90% yield from furfuraldehyde.It is usually not possible to effect reduction of the nucleus without affect-ing unsaturated centres in the side chain, unless these are suitably protected.The preparation of tetrahydrofurfural has proved to be particularly difficult)and a satisfactory method has yet to be discovered.The hydrogenation offurfuraldehyde diethylacetal or diacetate, followed by removal of theprotecting groups, gives only a very poor yield, and in the experience ofrecent workers is ~nreliable.~B$ 69 Small amounts have been obtained bycatalytic dehydrogenation of tetrahydrofurfuryl alcohol, and by oxidationof the octahydropinacol(II1) with lead tetra-acetate : 69~-~*cH(oH)cH(oH)~J \O ,,J + QHO(111.)'0'No aldehyde was obtained by reduction of 2-cyanotetrahydrofuran withstannous chloride, reduction of barium tetrahydrofuroate with bariumf ~ r m a t e , ~ ~ oxidation of tetrahydro€urfuryl alcohol, or saponification of2 - dic hlor o me t h yl t e t r ah y dr o f uran .70Elimhalion of Bide Chains.-C.L. Wilson 66, 71 has shown that a ttemperatures above 200°, preferably a t 280", furfuraldehyde vapour is de-composed into furan and carbon monoxide on contact with a catalyst con-taining nickel or cobalt. An interesting observation is that the yield offuran may be raised to 65% by the introduction of a limited quantity ofhydrogen (about 2/3 mol. per mol. of aldehyde); as would be anticipated,a small amount of 2-methylfuran is also formed under these conditions, but,apart from that required for this minor reaction, all the hydrogen issuesunchanged.The added hydrogen also has the effect of greatly prolongingthe effective life of the catalyst, which otherwise deteriorates rapidly.Nitrogen or carbon dioxide is ineffective. Nickel gauze is the most suitablecatalyst for continuous operation, since it has a long active life and gives a50% yield of furan, together with 8% of 2-methylfuran. Monel metal gives65% of furan with only 2% of 2-methylfurnn, but unfortunately deterioratesmuch more rapidly. The conversion of furfuraldehyde into furan is alsoreported to occur over lime a t high temperature^.^^in whichfurfuryl alcohol, passed over Raney nickel a t 150") is shown to give a mixtureof furfuraldehyde, furan, and 2-methylfuran.The reactions involved areshown below, the hydrogen necessary for the production of the 2-methylfuranbeing derived from the dehydrogenation of furfuryl alcohol :Closely related to the above are the experiments of R.69 C. L. Wilson, J., 1945, 52.70 H. Paillard and R. Szasz, Helv. Chim. Acta, 1943, 26, 1856. 'l B.P. 553,175.7 2 U.S.P. 2,337,027. 7' Bull. SOC. chim., 1938, 5, 1692; 1941, 8, 607OWEN : FURANS. 169The side chain in tetrahydrofurfuryl a,lcohol, also, is eliminated whenthe vapour is passed over various nickel catalysts, preferably nickel gauze,a t about 260°.69, 74 The principal product is tetra,hydrofuran, accompaniedby carbon monoxide and hydrogen in approximately equimolecular amounts.I n this reaction the addition of hydrogen is unnecessary; presumably thehydrogen formed during the pyrolysis is capable of preventing deactivationof the catalyst.By-products include tetrahydrofuryl tetrahydrofurfurylether (I) and 2 : 3-dihydrofuran (11). The formation of (11) is not readilyexplicable, since it has been proved by direct experiment that tetrahydrofuranis not dehydrogenated to dihydrofuran over nickel. The ether (I) canobviously arise by condensation of dihydrofuran with tetrahydrofurfurylalcohol. The dihydrofuran content of the crude tetrahydrofuran obtainedis usually about 4%, but may be increased to 38% by the use of a cupro-nickel catalyst. This substance is also formed 75 when the vapour of either2-cyanotetrahydrofuran (111) or methyl tetrahydrofuroate (IV) is passedover a dehydrating catalyst a t 300--400", the reaction proceeding by lossof hydrogen cyanide, or of carbon monoxide and methanol, respectively.A t higher temperatures, cyclopropanealdehyde is produced at the expenseof dihydrofuran, from which it is probably formed by rearrangement :i-71'0'I ) C H O +-(11.)Nuclear Transformations.-Brief mention was made in an earlier Report l5of the conversion of furan derivatives into pyrroles and thiophens.Theseinvestigations have been continued by several workers, and sufficientinformation has now been acquired to render possible the evaluation ofthe reactions for preparative purposes, and to give some insight into theprobable mechanisms involved.Treatment of furan, in the vapour phase, with ammonia or with alkyl-or aryl-amines, a t 400-450" over alumina or alumina-chromia, gives 25-30% yields of pyrrole or N-substituted pyrr01es.~~ Although at first sightthese results appear to be unsatisfactory, account must be taken of the recentwork, discussed in the previous section, which has led to tlhe ready avail-ability of furan.C. L. Wilson 77 has investigated the nature of the high-boiling by-products which are formed during the preparation of pyrrole by74 B.P. 550,105.76 D.R,.-P. 706,095.75 C. L. Wilson, J . , 1945, 58.7 7 J., 1945, 63.F 170 ORGANIC CHEMISTRY.this method, and has shown that indole, carbazole, and pyrrocoline (I) arepresent. He considers that these are probably formed by/\--- interaction of pyrrole with itself, since the yield is independentI 1-7 of the concentration of unchanged furan present in the reaction N/N\/ mixture.As yet, however, there is no direct evidence for such con-('') Tetrahydrofurancan be converted into pyrrolidine or A7-substituted pyrrolidines in yields ofup to 56%. Less favourable results a.re observed when the nucleus carriesa C-alkyl substituent, 78 and such homologues of furan and tetrahydrofurangive yields of only 10-12% and 27-34% respectively. The presence ofan efficient dehydration catalyst is essential, and, in view of the readinesswith which the furan ring undergoes scission, it is probable that themechanism involved is one of amination to give a y-amino-alcohol, followedby dehydrati~n.~~ Thus the conversion of furan into pyrrole may be re-presented as proceeding through the intermediate formation of 4-amino-butadien- 1-01 :densations under the conditions employed.I n [ TE+ ifI---CH --++ H*O\\O/ I I CH-OH CH*NH,whereas tetrahydrofuran would give 4-aminobutanol, andiS-lI \ /NHthence pyrrolidine.are obtainable by Only very s m h yields of thiiphen or its homologuessimilar reactions in which hydrogen sulphide is used in place of ammonia, butthe method is excellent for the preparation of tetrahydro-derivatives (thio-phans).2 : 5-Dimethyltetrahydrofuran, for example, gives a 68% yield of2 : 5-dimethylthi0phan.'~ In these cases, also, it is probable that themechanism is similar, since it has been shown that 4-hydroxybutanethiolreadily gives thiophan over alumina a t 400".C.H. Kline and J. Turkevich 8o have studied the vapour phase reactionbetween tetrahydrofurfuryl alcohol and ammonia over alumina a t 400".The products contained only 3% of pyridine and 9% of piperidine, butaccording to G. Natta, G. Mattei, and E. Bartolett,i 81 it is possible bythe use of alumina-chromia or phosphate catalysts to obtain, under optimumconditions, a 67-70% yield of pyridine. These authors consider that theprobable sequence of reactions is amination, dehydration, and dehydrogen-ation, which presumably may take place by either of the routes shownon the next page.It is reported, however, that a mixture of pyridine and piperidine canbe obtained from dihydropyranYa0 a.nd, since dihydropyran is known to beformed when the vapour of tetrahydrofurfuryl alcohol is dehydrated overalumina, it is not improbable that it is an intermediate in the reaction underdiscussion.7 8 J.K. Juriev, V. A. Tronova, and Z. Y. Bukshpan, J. Gen. Chem. Russia, 1941,11,1128.79 G. Natt,a, G. Mattei, and E. Bartoletti, Chim. e l ' l n d . , 1942, 24, 81.80 J . Amer. Chenz. SOC., 1944, 66, 1710.81 Ital. P. 382,819; Chem. Zentr., 1942, I, 2930OWEN : FURANS. 171Pyridine is not formed from furfuryl alcohol *O or from furfurylamine 82under these conditions, but furfurylamine in the liquid phase readilyp 3 2 - - p 3 2 -IfH,O (yH -H,O /\!OJCH2*OH 3 CH2 YHoOH -+ ,NH, CH,*OH NHtakes up two mols. of hydrogen over Raney nickel a t 140", presumably togive the tetrahydro-amine, and a third mol.slowly a t 200". The productthen contains a small amount of pyridine, but the major constituent isN-tetrahydrofurfurylpiperidine (11).Piperidine can be obtained from furfuraldehyde or its hydrogenationproducts by treatment a t 200" under high pressure with ammonia and excessof hydrogen, in the presence of a cobalt catalyst.83Ring Fission.-One of the most promising applications of furan deriv-atives is to be found in the formation of various aliphatic compounds by ringfission, a few examples of which have already been mentioned. I n general,the method is most satisfactory when applied to tetrahydrofurans. Tetra-hydrofuran itself (I) was an important intermediate in the German industryduring the recent war,28 and was chiefly used for the preparation of adipicacid by reaction with carbon monoxide in the presence of a nickel carbonylcatalyst, and for the manufacture of butadiene by dehydration in the vapourphase over a phosphate catalyst.84 Similarly, 2-methyltetrahydrofuran hasbeen used for the preparation of penta-1 : 3-diene.85CH,:CH*CH:CH, , --? H02C*[CH2]4*CO,HCl*[CH,],*OH 7 91.1 Cl*[CH2],*OAcAliphatic 1 : 4-dibromides can be conveniently prepared by the actionof hydrogen bromide in acetic acid a t 130".86 A simpler method, which isrecommended by S.Fried and R. D. Kleene,s7 is to pass the anhydroushydrogen halide into the tetrahydrofuran until the calculated amount hasbeen absorbed, the temperature being allowed to rise to 150" during thestrongly exothermic reaction.According to these authors, the reactivityof the hydrogen halides is in the order HI>HBr>HCl, and with hydrogen82 C. L. Wilson, J . Amer. Chem. SOC., 1945, 67, 693.83 D.R.-P. 695,472. 84 B.P. 506,038. 85 U.S.P. 2,273,484.8% R. Paul, Bull. SOC. chim., 1938,5, 1053.81 J . A w r . Chem. Soc., 1940, 62, 3258; 1941, 63, 2691; compare G. B. Heisig,ibid., 1939, 61, 626172 ORGANIC CHEMISTRY.chloride it is advisable to carry out the reaction in the presence of zincchloride, the yield even then being rather poor. This is supported by theobservation that tetrahydrofuran-2 : 5-dicarboxylic acid fails to react withhydrogen chloride, but with hydrogen bromide a t 125" it gives a 60% yieldof meso-ad-dibromoadipic acid.57 It is evident that the initial product ofring fission is likely to be a halogenohydrin, which then reacts with a furthermol.of hydrogen halide to give the dihalide, and it has often been possibleto show the presence of the intermediate, and in some reactions to isolateit. Thus, when 2 : 5-bisacetoxymethyltetrahydrofuran (11) is treatedwith hydrogen bromide in acetic acid, the main product, 2 : 5-dibromo-1 : 6-&acetoxyhexane, is accompanied by a small amount of 2-bromo-1 : 5 : 6-triacetoxyhexane, evidently derived from the intermediate (111) , 57 whilstJ. K. Juriev, K. M. Minatschev, and K. A. Samurskaja 88 have obtained a55% yield of 4-chlorobutanol by the action of hydrogen chloride on tetra-AcO*CH,!OICH,OAc = AcO*CH,*CHBr * [ CH,] ,CH( OH)*CH,*OAc(111.) i (11.1A&H- .1"" H W ' O-AcO*CH,*CH( OAc) [ CH,] ,* CH (0 Ac) * CH,* 0 AcAcO*CH,*CHBr [CH,],*CHBr*CH,*OAchydrofuran (I).With an unsymmetrically substituted tetrahydrofuran,two intermediate products are possible, but C. L. Wilson4O has shownthat tetrahydrofurfuryl alcohol (IV), treated with hydrogen bromide a tloo", gives almost entirely 1 : 5-dibromopentan-2-01, with only traces of4 : 5Ac,O-ZnCI, [olCH2*OH (IV.)Cl*[CH,],*CH( OAc)*CH,*OAc + AcO*[CH,],*CHCl*CH,*OAc'4 /-> AcO* [CH,],*CH( OAC) *CH,*OAciibrom~pentanol.~~ This preferential fission of the 1 : 5-linkage is alsoshown if the reaction is carried out with hydrogen bromide in acetic acid,when the sole product is 1 : 5-dibromo-2-acetoxybutane; a further exampleis found in the formation of 6-bromo-a-bydroxyvaleric acid (VI) as an inter-s~ J .CTen. Chem. Russia, 1939, 9, 1710.89 See also R. Paul, Bull. SOC. chim., 1933, 53, 417; 1945, 12, 388OWEN : FURANS. 173mediate in the conversion of tetrahydrofuran-2-carboxylic acid or its ester(V) into a8-dibromovalericBr*[CH,],*CH(OH)*CO,Et --+ Br*[CH2I3-CHBr*COzEtAcC1 lo/CO,Et -> Cl*[CH,],*CH( OAc)*CO,Et(VII.)AcO*[CH2],*CH(OAc)*C02Et I=/J. B. Cloke and F. J. PilgrimQ1 have studied the action of acyl halideson tetrahydrofuran (I) and have shown that 8-halogenobutyl esters can beprepared by this method. Acetyl chloride gives a 50% yield of 6-chlorobutylacetate, accompanied by a considerable amount of higher-boiling ethers, butby the use of a minute quantity of zinc chloride in the reaction mixture theyield of the desired ester may be raised to 70% ; a large quantity of catalyst,however, is deleterious, and may reduce this figure to 10%.According toL. M. Smorgonskii and Y. L. G~ldfarb,~, acetyl bromide is particularlyeffective, and these authors have also extended the reaction to aracyl chlorides.Similar results have been obtained with 2 : 5-dimethyltetrahydrofuran.With unsymmetrically substituted compounds, it was at first thought 93that the scission took place preferentially in a manner similar to that en-countered with hydrogen halides, but more recently ,* it has been shown thattetrahydrofurfuryl alcohol (IV) with acetyl chloride gives a mixture ofproducts, in which the secondary chloride preponderates.Since the con-stituents cannot readily be separated, the estimation is based on hydrolysisto the mixed chloro-diols, and determination of 1 : 2-diol by titration withperiodic acid. Preferential scission of the 1 : 5-linkage does appear to occiir,however, with ethyl tetrahydrofuroate (V), which with acetyl chloride givesan 85 yo yield of ethyl 8-chloro- a-acetoxyvalerate (VII) Replacement of thehalogen atom in products of the above types by an acetyl group, followed bysaponification, gives triols or dihydroxy-acids, the overall yield being betterthan that obtained by direct hydration of the tetrahydrofurans.90393 Analternative procedure is to cleave the ring with acetic anhydride containingzinc c h l ~ r i d e .~ ~ , ~ ~ This gives good results when the nucleus carries a sidechain containing a hydroxyl or carboxyl group, e.g. (IV) and (V); other-wise, however, dehydration occurs during the reaction, and unsaturatedproducts are obtained. Acetolysis can also be effected by an acetic anhydride-acetic acid-sulphuric acid reagent,57 which has been used for the conversionof 2 : 5-bisacetoxymethyltetrahydrofuran (11) into 1 : 2 : 5 : 6-tetra-acetoxy-90 R. Paul, Compt. rend., 1941, 212, 398.0 1 J. Amer. Chem. Soc., 1939, 61, 2667.@a J. Gen. C h m . Rucl&a, 1940,10, 1113.94 Idem, Bull. SOC. chim., 1941, 8, 369, 911.R. Paul, Compt. rend., 1940,211, 645174 ORQANIU CHEMISTRY.hexane, and for the preparation of etjhgl 2 : 5 : 6-triacefoxyhexoate fromethyl ~-acetoxymethyltetrahydrofuran-2-carboxylate (VIII).--AoO*CH,(0)CO,Et 4 AcO*CH,*CH( OAc) [CH,],*CH( OAc) *CO,Et(vr 11.)The h ydrogenolysis of tetrahydrofurfuryl alcohol (IV) over copperchromite gives only pentane- 1 : 5-dio1, whilst from furfuraldehyde a mixtureof the 1 : 2-, 1 : 4-, and 1 : 5-diols is obtained.56 The claim that furfurylalcohol under these conditions gives the 1 : 2- and 1 : 4-diols is, however,not in accord with the observations of H. Adkins and R. Connor,95 and ofL. E. Schniepp and H. H. Geller,96 who regard the product as a mixture of1 : 2- and 1 : 5-diols.Hydrogenolysis of halides, by treatment in dry ether with an alkalimetal, results in the formation of unsaturated alcohols. 3-Bromotetra-hydrofuran (IX) , for example, gives allyl~arbinol,~~ whilst pent-4-en-1-01 canbe obtained in 90% yield from tetrahydrofurfuryl chloride (X).97An interesting method for the preparation of long chain di-, tri-, andtetra-ketones has been described by K.Alder and C. H. Schmidt.982-Methylfuran condenses readily with methyl vinyl ketone to give 2-methyl-5-7-ketobutyIfuran (XI), which undergoes the expected scission on boilingwith acid alcohol to give nonane-2 : 5 : 8-trione. Hydrogenolysis of (XI)gives a mixture of nonane-2 : 5- and -2 : 8-diones :MJl II*[CH,],*CO*Me (XI.)f ‘O’\Me*(CO*[CH,],),*CO*Me Me C 0 [ CH ,] gC 0 Me +Me*[CH,],*CO*[CH,],*CO~MeFuran itself condenses with methyl vinyl ketone’ to give 2 : 5-di-y-ketobutyl-furan (XII), which by acid scission yields dodecane-2 : 5 : 8 : ll-tetraone,whilst on hydrogenolysis dodecane-2 : 5 : ll-trione is obtained :--Me*CO*[CH,] 2./!,0)l*[CH,]2*CO*Me (XII.) y\Me*(CO*[CH,],),*CO*Me Me*CO*[CH,],*CO*[CH,],*CO*MeL. N. 0.9 5 J. Amer. Chem. SOC., 1931, 53, 1091.9 7 R. Paul and H. Norrnant, Bull. SOC. chim., 1943,10,484.g6 Ibid., 1945, 67, 54.@ * Ber., 1943,76, 183LYTHGOE : CHEMISTRY OF ADENINE NUCLEOTIDE COENZYMES. 1756. CHEMISTRY OF ADENINE NUCLEOTIDE COENZYMES.~Certain adenosine-5’-phosphoric acid derivatives are active biologicallyas coenzymes of phosphate transfer, and adenine dinucleotides as coenzymesof hydrogen transfer. Phosphate esters seem particularly suited to act ascoenzymes; for example cocarboxylase is known to be aneurin pyrophos-phate and an Z-tyrosine codecarboxylase is probably identical with pyridoxalph~sphate.~Adenosine-Ei’-phosphoric Acid Derivatives Active in Phosphate Transfer.as phos-phate donors by virtue of their labile phosphate content, removal of which isaccompanied by liberation of large amounts of free energy, available as energysource for cellular activities ; the adenosine derivatives of lesser phosphoricacid content act as phosphate acceptors for resynthesis of the polgphosphates.Muscle AdenyEic Acid.-G. Emden and M.Zimmermann in 1927isolated from muscle extracts an acid recognised by the following propertiesas differing from the isomeric yeast adenylic acid (adenosine-3’-phosphate)in the location of the phosphoryl residue : (a) Yeast adenylic acid is notdeaminated by G.Schmidt’s muscle adenylic deaminase. ( b ) Acidicdephosphorylation of the muscle acid takes place more slowly than with theyeast acid and the yield of furfural obtained in W. S. Hoffman’s method *for the determination of pentose is less; these differences are paralleled bythe characteristics of the corresponding d-ribose-3- and -5-phosphoric acids.9( c ) The muscle acid forms a deep blue soluble copper complex (Klimek-Parnas test) lo and increases the acidity of boric acid in the Boesekentest ; these properties indicate the presence of a cis-1 : 2-glycol grouping.Muscle adenylic acid has the ultra-violet absorption spectrum of an adenine-9-glycoside ; it can be dephosphorylated to adenosine enzymically anddeamiiiated to inosinic acid enzymically or by use of nitrous acid; it istherefore adenosine-5’-phosphoric acid (I, R = NH,).The constitutionI n biological systems the adenosine polyphosphates fiinctionf Cf. C. Lutwak-Mann, Biol. Rev. Camb. Phil. Xoc., 1939, 14, 399.2 K. Lohmann and P. Schuster, Naturwiss., 1937, 25, 26.3 J. C. Gunsalus, W. D. Bellamy, and W. W. Umbreit, J. Biol. Chem., 1944, 155,685 ; J. Baddiley and E. F. Gale, Natzwe, 1045,155, 727.4 For recent reviews on biochemical aspects, see €1. M. Kalckrtr, Biol. Rev. Camb.Phil. Xoc., 1942,17, 28; F. Lipmann, Advances in Enzymology, New York, 1941,1, 100;D. M. Needham, Ann. Reports, 1941,38,241.2. physiol. Chem., 1927,167, 114.G. Emden and G. Schmidt,, ibid., 1929,181, 130.l b i d . , 1928,179 243.8 J .Biol. Chern., 1927, 73, 15.9 P. A. Levene and S. A. Harris, ibid., 1933,101,419.10 Biochem. Z., 1932, 252, 392; 2. physiol. Chem., 1933, 217, 75.l 1 Ber., 1913,46,2612.12 J. M. Gulland and E. R. Holiday, J., 1936, 765176 ORGANIC CHEMISTRY.of the inosinic acid (I, R = OH) suggested earlierlater work.has been confirmed byI H H HH02C~-!$-((-CH,*O*P03H2 H H HH H H 1“’“ I CHN\/\N/Inosinic acid gives on acid hydrolysis a ribosephosphoric acid, oxidisable toa phosphoribonic acid (11) which forms only a y-lactone ; l4 additional evid-ence that the ribosephosphoric acid is a 5-phosphate is given by P. A.Levene and E. T. Stiller’s synthesis : l5 &Ribose -+ 2 : S-mono-R (1.1 (11.)MeOH-Me,CO- -_ flu1 POCI, acetone methylribofuranoside - -+ 2 : 3-monoacetone methylribofur-anoside-5-phosphat e ---1-+ d-ribose-5 -p hosphoric acid.Partial synthesisof inosinic acid by a route demonstrating the position of the phos-Dil acid pmdlnephoryl group has been effected.16 Partial syntheses of muscle adenylicacid have been carried out by T. Jachimowicz l7 who phosphorylatedadenosine without protecting the hydroxyl groups a t C, and CX; by P. A.Levene and R. S. Tipson l8 starting from 2’ : 3’-monoacetone adenosine;and by the same authors l8 and by H. Bredereck, E. Berger, and J. Ehren-berg starting from 2’ : 3’-diacetyladenosine; the last workers used di-phenylphosphoryl chloride as phosphorylating agent. The yield of muscleadenylic acid from all these syntheses was very low; they serve as con-firmations of structure rather than as methods of preparation. Hydrolysisof adenosine triphosphate occurring in muscle,20, 21 or obtained enzymicallyfrom adenosine,22 remains the most convenient way so far published ofobtaining muscle adenylic acid.Crystalline acridine salts of this acid havebeen described by T. Wagner-Jauregg 23 and by R. S. T i p ~ o n . ~ ~Adenosine Di- and Tri-phosphates.-Adenosine triphosphate (ATP) wasisolated from muscle extracts in 1929 by K. Lohmann25 and by C. H.Fiske and Y. Subbarow; 26 according to K. Lohmann 27 this nucleotideis the parent of the adenylic acid from muscle, which is an artefact formedduring the isolation process and does not occur free in that source. ATPl3 P.A. Levene and W. A. Jacobs, Ber., 1911,44,746.l4 P. A. Levene and T. Mori, J . Biol. Chem., 1929,81,215.l5 Ibid., 1934,104, 299.l6 P. A. Levene and R. S. Tipson, ibicl., 1935,111, 313.l7 Biochem. Z., 1937, 292, 356. 18 J . Biol. Chem., 1937, 121, 131.2O S. E. Kerr, J . Biol. Chem., 1941,139, 131.21 M. V. Buell, ibid., 1943,150, 389.22 P. Ostern, T. Baranowski, arid J. Terszakowed, 2. physiol. Chem., 1938, 251,23 Ibid., 1936, 239, 188. t4 J . Biol. Chem., 1937,120,621.25 Naturwiss., 1929,17, 624. 26 Science, 1939,70, 381.2’ Biochem. Z., 1931,233, 460,Ber., 1940, 73, 269.268LYTHGOE : CHEMISTRY OB ADENINE NUCLEOTIDE COENZYMES. 177(Cl,,H16013N5P3) gives on hydrolysis with dilute alkali muscle adenylicacid and inorganic pyrophosphate; with dilute acid 1 mol.of adenine and2 mols, of orthophosphoric acid are liberated rapidly, the third phosphorusatom appearing as d-ribo~e-5-phosphate.~~ Whereas dephosphorylationof the latter occurs only slowly, the first 2 mols. of phosphoric acid are liber-ated from ATP a t about the same speed as from inorganic pyrophosphate(7-15 mins. in N-HCl a t 100°),287 2o and determination in this way of the) which is thus 2 : 1 for ATP forms acid-labile phosphorusacid-stable phosphorus ratio P,/P~ (=- -one of the most important ways of characterising this and other adenosinepolyphosphates,28 characteristic melting points being in general lacking inthis series.The structure of muscle adenylic acid being known from earlier work,it remained to determine the location of the acid-labile phosphoryl residues.Evidence (although not conclusive in so complex a molecule) was obtainedindicating that the cis-1 : 2-glycol grouping is not involved, ATP giving apositive response to the Klimek-Parnas and Boeseken tests just as doesadenylic acid.28329 Linkage to the adenine residue as suggested by H.K.Barrenscheen and W. Filz 30 seems excluded, since contrary to the findingsof these authors ATP can be deaminated by nitrous acid to an inosine tri-phosphate (ITP) 28, 313 32 and thus the only functional grouping of the aden-ine residue, vix., the amino-group, must be unsubstituted. Basicity deter-minations with phenolphthalein as indicator, and by electrometric titra-tion,28933 show ATP to possess three primary and one secondary acidicgroupings, which led K.Lohrnann to propose for it the structure (111).o---/ OH OH OH 1 H H I l lCH-?-~--/ --CH,. o -P- o -P- o *P*O H I H H H + + + 0 0 0(111.)CH-?z?!;- 1---O-- -CH,*O-P*O*P*OH 9" 0"1 H H H + + NH20 0I tK. Lohmann 34 later showed that in absence of Mg" ions (washed) crab-muscle pulp removes from ATP only one of the acid-labile phosphoryl28 K. Lohmann, Biochem. Z., 1932,254,381.29 H. K. Barrenscheen and T. Jachimowicz, ibid., 1937, 292, 350.30 Ibid., 1932,250,281 ; H. K. Barremcheen, K. Brsun, and W. Filz, ibid., 1933,265,31 W. Kiessling, ibid., 1934, 273, 103.32 A. Kleinzeller, Bwchem. J., 1942, 36, 729.33 K. Makino, Biocham,. Z . , 1935,278, 161.141.34 Ibicl., 1935, 282, 104, 120178 ORGANIC CHEMISTRY.residues.The product, adenosine diphosphate (ADP), has the compositionC,,H,,010N,P2 ; it resembles ATP in that it can be deaminated to an inosine-diphosphate (IDP), or hydrolysed by acid to adenine, d-ribose-5-phosphoricacid, and phosphoric acid. ADP also is active as a cophosphorylase; ithas a ratio PL/Ps = 1 : 1. ADP contains 2 primary and 1 secondary acidicgroupings and must therefore be represented by (IV); this supports struc-ture (111) for ATP. Other workers 2 9 y 3 5 have, however, claimed that it ispossible by use of certain enzyme preparations to remove the acid-stable(5’) phosphoryl residue from ATP, leaving the acid-labile grouping intact.36This claim is incompatible with the Lohmann formula and, if substantiated,would indicate that the acid-labile phosphoryl groupings are attached toone of the secondary hydroxyls of the ribofuranoside residue as in (V).35OH OH,Po0 *POOHI I/ J .J.0NH2 (V.)Structures of this type have recently been shown to be highly improbableby the use of both enzymatic 37 and chemical 38 methods. Earlier work,39 inwhich it had been shown that the structures of certain nucleosides andnucleotides could be determined by titration with sodium metaperiodate,was extended to the study of ATP; the consumption by the latter of 1 mol.of metaperiodate proved conclusively the presence of an unsubstitutedu-glycol grouping in the molecule as required by t,he Lohmann stricture(111). It therefore seems certain that ADP and ATP are correctly describedas adenosine-Ej’-di- and -tri-phosphates.Improved methods have been described recently for the preparation ofATP from rabbit muscle 2o and by enzymatic synthesis from adenosine,22and for the preparation of ADP40 and IDP32 by the action of purifiedmyosin preparations on the respective triphosphates.The composition ofATP has been verified by recent analytical data 2o and by the preparationof crystalline acridine salts,23 and its mononucleotide nature has been estab-35 T. Satoh, J. Biochem. Japan, 1936,21, 19.3 6 Cf. W. L. Liebknecht, B9:ochern. Z . , 1939,303,96.3 7 31. Dainty, A. Kleinzeller, A. X. C. Lawrence, M. Miall, D. M. Needham, and S.Shen, J. Gen. Physiol., 1944, 27, 355; J. M. Gulland and E. O’F. Walsh, J., 1945,169.38 B.Lythgoe and A. R. Todd, hrature, 1945,155, 695.39 I d e m , J., 1944, 592.40 M. N. Ljubimova and D. Pevsner, Biochimia, 1941, 6, 178; K. Bailey, Biochem.J . , 1942, 36, 121LYTHGOE : CHEMISTRY OF ADENINE NUCLEOTIDE COENZYMES. 179O--:C,H,N5*CH-?L I--lished by molecular weight determination^.^^ On the other hand, the exist-ence of a diadenosine pentaphosphate with a ratio PL/P, = 3 : 2 postulatedby certain workers 42 seems doubtful; it is 41, 34 probably a mixture of ADPand ATP formed as a result of autolytic decomposition.Di(adenosine-5’-phosphoric Acid) .-Isolated from yeast by W. Kiesslingand 0. M e y e r h ~ f , ~ ~ this adenine dinucleotide is active as a cophosphorylase ;it can accept 2 mols. of phosphoric acid from phosphopyruvic acid to give adiadenosine tetraphosphate.A diadenosine triphosphoric acid is formedby removal of one of the two acid-labile phosphoryl residues from thetetraphosphate by washed crab muscle. Diadenosine tetraphosphate hasthe ratio PL/P, = 1 : 1 and contains 4 primary and 1 secondary acidicgroupings. It is readily split by very dilute alkali giving ATP and a com-pound, probably muscle adenylic acid. This suggests a phosphate linkagebetween the two nucleotides of the same type as the internucleotidic linksin nucleic acids, and structure (VI) was suggested for the compound.0OH OH OH--i-(.H,.O.P*O*P***P*OH I l lAdenine Nucleotides Active as Coenzymes of Xydrogen Transport.46The chemistry of these coenzymes, present in minute concentrationbut of primary importance in the metabolism of the living cell, has become4l K.Lohmann and P. Schuster, Biochem. Z . , 1937,294, 183.42 P. Ostern, ibid., 1934, 270, 1; P. Ostern and T. Baranowski, ibid., 1935, 281,43 Biochem. Z., 1938, 296,410. 44 J. Biol. Chem., 1943, 148, 255.45 2. physiol. Chem., 1941,267,264.4 6 For reviews dealing with biochemical aspects, see C. A. Bnumann and F. J.Stare, Physiol. Rev., 1939, 19, 363; D. E. Green, “Mechanisms of Biological Oxid-ations,” Cambridge, 1940, p. 36 ; F. Schlenk, “ Symposium on Respiratory Enzymes,”Wisconsin, 1941, p. 104.157; F. Beattie, T. H. Milroy, and R. W. F. Strain, Biochem. J . , 1934,28, 84180 ORGANIC CHEMISTRY.known during the last decade matii1l;y owing to the investigations of threegroups of workers; those of IT.von Euler in Stockholm, 0. Warburg inBerlin, and P. Karrer in Zurich. As a result, the structure of cozymase(codehydrogenase I ; diphosphopyridine nucleotide, DPN) may be con-sidered as fairly well established; the evidence on which this structureis based will be reviewed here, aiid the present position regarding the struc-ture of codehydrogenase I1 (triphosphopyridine nucleotide, TPN) and ofriboflavin-adenine dinucleotide will be summarised. Features of the out-standing researches here recorded have been the contributions made by thestudies of synthetic model substances, the successful employment of ultra-violet absorption spectroscopy and of manometric micromethods in inter-preting the reactions of the coenzymes, and the extensive use of biologicaltest methods, especially in determining the nature of fission productsobtained from the coenzymes by degradation reactions.Di- and Tri-phosphop yridine NucZeotides.-Chemical investigation ofhydrogen transport coenzymes commenced with the work of H.von Eulerand K. M y r b a ~ k . ~ ~ These workers purified extensively the constituent ofHarden and Young’s 48 complex “ coenzyme of alcoholic fermentmation ’’ nowknown as DPN. As test method in the purification process they usedmeasurement of the stimulation produced in the fermentation of glucoseby washed yeast. Hydrolysis of their most active preparations from yeastgave adenine, a pentose, and phosphoric acid, and up to 1935 the coenzymewas regarded as a mononucleotide. While this work was in progress 0.Warburg and W.Christian 49 were investigating a different 50 though closelyrelated coenzyme (TPN), present in horse erythrocytes, which was necessaryfor the oxidation of glucose-6-phosphate to 6-phosphogluconic acid by mole-cular oxygen in a system containing the appropriate specific protein (apo-enzyme; “ Zwischenferment ”) and 0. Warburg’s 51 “ old flavoprotein.”In 1935 they succeeded (with A. Griese 52) in isolating this coenzyme pureand establishing its mode of action. TPN has the compositionCZ1Hz8O1,N7P3 ; on acid hydrolysis its molecule yields 1 molecule of adenineand 1 molecule of nicotinamide; 3 phosphoryl residues are liberated as in-organic phosphate on treatment with alkali ; and 2 pentose units are probablypresent (furfural estimations).The amino-group of the adenine residue isfree, undergoing deamination under van Slyke conditions to which nicotin-amide is inert. Investigation of themechanism of coenzyme action of TPN by separate study of the constituentreactions manometrically and by ultra-violet absorption methods was neces-4 7 Z.physio1. Chem., 1931,198, 236; 203,143 ; Naturwiss., 1929,17,291; K. Myrbiickand H. Hellstrom, 2. physiol. Chem., 1932, 212, 7 ; K. Myrback, ibid., 1935, 233, 95.4 * A. Harden and W. J. Young, Proc., 1905, 21, 189.‘9 Biochern. Z., 1931,242,206; 1933,266,377; 1934,274, 119; 1935,275,464.6O H. von Euler, E. Adler, F. Schlenk, and G. Gather, 2. physiol. Chem., 1935,51 0.Warburg and W. Christian, Biochem. Z . , 1932, 254, 438; 1933, 263, 228;5 2 Ibid., 1935, 282, 157.TPN is therefore a dinucleotide.233, 120.1936,287, 291, 440LYTHGOE : CHEMISTRY OF ADENINE NUCLEOTIDE COENZYMES. 181sary before the manner in which the degradation fragments are united in themolecule was revealed. Equivalent amounts of TPN and glucose-6-phos-phate react anaerobically in presence of apoenzyme according to the equationTPN + R-COH + H20 = R*CO,H + TPN-H, (1). The dihydrocoen-zyme (isolated from the reaction product as calcium salt) can also be obtainedfrom TPN by reduction with sodium hyposulphite in presence of bicarbonate :TPN + Na,S,O, + 2H20 = 2NaHS0, + TPN-H,The dihydrocoenzyme is not autoxidisable, hence if in reaction (l), conductedin presence of molecular oxygen, less than 1 equivalent of coenzyme is used,the substrate is only partially oxidised, reaction ceasing when all TPN isconverted into dihydro-TPN.Dihydro-TPN, however, can react with flavo-protein anaerobically, the alloxazine ring of the latter undergoing reduction :Since the dihydroflavoprotein is autoxidisable :FH2 + 0, = F + H202a small quantity of coenzyme is able to oxidise large quantities of substratein the complete Warburg system, being continually regenerated from itsdihydro-derivative; L e . , TPN owes its coenzyme activi'y to its redoxproperties.TPN is very unstable to alkaline hydrolysis, but relatively stable towardsacid. It shows an absorption band at 260 mp to which both adenine and nico-tinamide residues contribute ; on catalytic hydrogenation the pyridinenucleus is reduced, giving a hexahydro-derivative, devoid of catalyticactivity (" irreversible hydrogenation "), in which the 260 mp band hasdiminished in intensity to the adenine value." Reversible hydrogenation "of TPN to dihydro-TPN alters the intensity of the 260 mp band only slightly,but a further characteristic band at 346 mp appears ; this change is reversedon addition of flavoprotein (regeneration of TPN). The pH-stabiIityproperties of dihydro-TPN are the reverse of those of the oxidised form;it is relatively stable to alkali, but decomposes immediately on acidification(irreversible addition of acid to the pyridine nucleus 53) ; the 345 mp bandvanishes and is replaced by another a t 295 mp.On catalytic hydrogenationthe dihydro-TPN takes up 2 mols. of hydrogen giving the " irreversible "hexahydro-derivative ; this stepwise formation of the latter shows that di-hydro-TPN owes its production to a partial hydrogenation of the pyridinering; hence the centre of biological activity in the coenzyme molecule isnicotinamide, a fact of importance in connection with the vitamin activityof the latter.54The properties of TPN and dihydro-TPN described above are character-istic of a group of compounds containing nicotinamide linked in a particularmanner; in order to elucidate the nature of this linkage, search for modelsubstances with a redox behaviour similar to that of the coenzyme was com-1938, 21, 223.TPN-H, + F = FH, + TPN63 p.Karrer, F. W. Kahnt, R. Epstein, W. Jaffi?, arid T. Ishii, Helv. Chim. Acta,6 4 Ann. Rev. Biochem., 1941, 10, 352; 1943, 12, 326182 ORGANIC CIXEMISTRY.menced by P. Karrer and 0. Warburg.55, 56 Nicotinamide itself is not hydro-genated by sodium hyposulphite .(Na,S,O,) ; trigonelline (VII) , however,forms a dihydro-derivative with this reagent. It was then found 57 thatnicotinamide methiodide (VIII), which shows ultra-violet absorption closelysimilar to that of TPN, takes up 1 mol. of hydrogen in presence of sodiumhyposulphite,C,H,0N2+I- + Na,S,O, + 2H,O = C7H,,0N, + HI + 2NaHS0,the reduced form showing analogous properties to those of dihydro-TPN(failure to autoxidise ; oxidisation by flavoprotein ; spectroscopic properties ;pH-stability).Other derivatives (IX, X) in which linkage of nicotinamideis effected by either of its other two functional groups (0 or NH, of the carb-oxyamide group) proved ineffective as redox models; 55 in the coenzymenicotinamide is evidently bound as a quaternary pyridinium compound.Me (VII.) Me (VIII.) (IX.1 (X.1The equations of reduction of coenzyme and model (VIII) show liberation of3 mols. of acid; the third, liberated from the model substance as hydrogeniodide, must be set free from the coenzyme as the hydroxyl of a phosphorylgroup, hence TPN is a quaternary pyridinium p h ~ s p h a t e . ~ ~ Facile reduc-tions of quaternary pyridinium compounds were already well known, andcomparison with dihydropyridines of established structure showed that re-duction of (VIII) gave mainly the 1 : 2- or 1 : 6-dihydro-derivative (XI orXII); clear cut decision between these two alternatives has not yet beeneffected.57, 58h e(XII.)A //IICO*NH,H N’IR(XIII.)Reversible reduction of the coenzyme is therefore represented by, e.g.:I OH + 2H ___, +- R-O-P-OR’ I P- R-O*P-OR’ + J.0 065 Biochem. Z., 1936, 285, 297.5 6 0. Warburg and W. Christian, ibid., 1936,287,291.6’ P. Karrer, G. Schwarzenbach, F. Benz, and U. Solmsen, HeZv. Chim. Acta,6 8 P. Karrer, G. Schwartzenbach, and G. Utzinger, ibid., 1937,20, 720.1936, 19, 811LYTHGOE : CHEMISTRY OF ADENINE NUCLEOTIDE COENZYMES. 183These reductions have been shown 57, 59 to proceed by addition of 1 atomof hydrogen at a time via a radical of tshe semiquinone type with a strongnegative potential (XIII).I n further experiments, P.Karrer and co-workers 6o found, in N-glucosido-1 : 2-dihydronicotinamide (XV, R = H) and tetra-acetyl-N-glucosido-nicotinamide bromide (XIV), subst,ances which in respect of redox behaviourand spectroscopic and pH-stability properties were the closest hithertoavailable models for the behaviour of TPN. (XIV) was prepared by con-densing acetobromoglucose with nicctinamide in dioxan ; reduction of (XIV)with sodium hyposulphite a t pH 7-5 gave the dihydro-derivative (XV,R = Ac) which was deacetylated to (XV, R = H)I l / / o n H o qCH-~-~-~--CH,*OAc !/'ZL*Gq cH-i--'-- I - -CH,*ORH OAcH H H O R H H(XIT'.) P V . 1Attempts to prepare N-pentosidonicotinamide derivatives analogous to(XIV) and (XV) were only partially successful, as the compounds were difficultto purify.P. Karrer had been led to the hypothesis that a n N-pentosido-pyridinium phosphate residue exists in the coenzyme molecule by thelability to alkali of already known N-glycosidopyridinium compounds,61whereas AT-glycosides, which would arise on partial reduction, are more,stable to alkali generally.62 The model experiments described, togetherwith the isolation of nicotinamide nucleoside from DPN described below,have demonstrated the correctness of this hypothesis.The important progress made on DPN in the meantime indicated a closerelationship of this coenzyme with TPN. Reinvestigation of the productsof hydrolysis of DPN undertaken with purer material than hitherto availableshowed the presence of nicotinamide 5 6 3 639 643 65 as well as adenine; thatDPN is active in hydrogen transport, recognised by H.von Euler et aE.66and by 0. Warburg and W. Christian 5 6 3 67 independently, became under-standable in the light of the results obtained with TPN; by virtue of itsj9 E. Adler, H. Hellstrom, and H. von Euler, 2. physiol. Chem., 1936, 242, 225.6o P. Karrer, B. H. Ringier, J. Buchi, H. Fritzsche, and U. Solmssen, I-lelv. Chim.61 P. Karrer, A. Widmer, and J. Staub, ibid., 1924,7, 519.6 2 Alkali-labile N-glycosides have, however, been described by R. Kuhn andActa, 1937, 20, 55.R. Strobele, Ber., 1937, 70, 747, 753.64 Idem, ibid., 1936, 240, 113.6 6 0.Warburg and W. Christian, Biochem. Z., 1935,275,464.'66 H. von Euler, E. Adler, and H. Hellstrom, Svensk Kem. Tidskr., 1936, 47, 290;13' Bioclwn. Z., 1936, 268, 81.H. von Euler, H. Albers, and F. Schlenk, 8. physiol. Chem., 1935,257, 1.H. von Euler and E. Adler, 2. physiol. Chem., 1936, 238, 233184 ORGANIU CHEMISTRY.nicotinamide content DPN transfers hydrogen in H. von Euler’s enzymesystem from diphosyhoglyceraldehyde to acetaldehyde, the former beingoxidised to phosphoglyceric acid and the latter reduced to ethylPure DPN, C,1H,7014N7P2,69, 70 contains 1 adenine and 1 nicotinamideunit ; by a modified Bial’s reaction 71 the presence of 2 pentose units can bedetected.72 The amino-group of the adenine is free; a deaminocozymasehas been described, resulting from the action of nitrous acid on DPN.73DPN is therefore a dinucleotide, differing from TPN only in apoenzymespecificity and in having 1 phosphoryl group less.Dihydro-DPN 749 759 76has been obtained analytically pure as the sodium salt by P. Ohlmeyer; 77both reduced and oxidised foriiis of DPN show redox behaviour and spectro-scopic and pH-stability characteristics identical with those of the TPNanalogues; 563 599 74 hence, as in TPN, the nicotinamide fragment of DPNmust be linked as a pentosidopyridinfum phosphate. Titration with alkali 7Oand cataphoretic experiments 78 show DPN to be a monobasic acid (with avery weakly basic grouping due to the adenine part); dihydro-DPN is di-basic.77 These results, as well as showing the presence of the pyridiniumphosphate zwitterion, indicate a pyrophosphate linkage in the molecule.The presence of such a link, originally suggested by E.Adler, H. Hellstrom,and H. von E ~ l e r , ~ ~ was confirmed by later experiments of H. von Eulerand co-worker~.~~ Brief treatment of DPN with hot alkali destroys thecoenzyme activity completely, liberating nicotinamide and a fragmentcontaining acid-labile phosphorus in the same sense as ADP or ATP, and likethese showing cophosphorylase activity in biological systems. This frag-ment, isolated pure as the barium salt, was shown by R. Vestin, F. Schlenk,and H. von Euler *O to be identical with ADP. (IV) the structure of whichwas already known. On the bases of the foregoing evidence, H. von Eulerand F.Schlenk 70 proposed structure (XVI) for DPN.One of the pentose units of DPN must from the foregoing evidence be&ribose; H. von Euler, P. Karrer, and E. Usteri have demonstrated thepresence of this in DPN by isolating the phenylosazone after hydrolysisof the coenzyme successively with dilute acid and a phosphatase preparation.The yield, however, was very small and would not exclude the presence of adifferent sugar as the second pentose unit. Conclusive evidence that6 8 0. Warburg and W. Christian, Biochem. Z . , 1939, 303, 40.69 H. von Euler and F. Schlenk, Svensk Kern. Tidskr., 1936,48, 135.70 Idem, 2. physiol. Chenz., 1937, 246, 64.7 2 F. Schlenk, J . Biol. Chem., 1942,146, 619.7 3 F. Schlenk, H. Hellstrom, and H. von Euler, Ber., 1938, 71, 1471.7 4 H.von Euler, E. Adler, and H. Hellstrom, 2. physiol. Chem., 1936, 241, 239.75 E. Adler and H. von Euler, Svensk Vet. Akad. Arkiv Kemi, 1937,12B, 36.7 6 D. L. Drabkin, J . Biol. Chem., 1945,157, 563.7 8 0. Meyerhof and W. Mohle, ibid., 1937,294,249.79 R. Vestin and H. von Euler, 2. physiol. Chem., 1936, 245, 1 ; F. Schlenk, H. vonEuler, H. Heiwinkel, W. Gleim, and H. Nystrom, ibid., 1937, 247, 23; R. Vestin andH. von Euler, ibid., p. 43.‘1 W. Mejbaum, ibid., 1939, 258, 117.7 7 Biochem. Z., 1938,297,66.Bey., 1937, 70, 1369.81 Helv. China. Acta, 1942, 25, 323LYTHGOE : CHEMISTRY OF ADENINE NUCLEOTIDE COENZYMES. 185/--0- although devoid of coenzyme activity, can bed-ribose was present in the nicotinamide part of the molecule as ~ l ! as in thendenylic acid part was obtained in 1942 when F.Schlenk 72 isolated from th186 ORGANIC CHEMISTRY.activity be isolated ; 86, 87 this is evidence against structure (XVIII). More-over, the reversible enzymatic transformation TPN JI DPN describedby various worlcers,881 g9 and the claim that DPN can be converted to TPNby phosphoryl chloride in ether,gO further emphasise that structurally TPNdiffers from DPN in no way except in the possession of a third phosphorylresidue, and also show that the structure (XVIII) should in all probabilitybe modified in regard to the location of the latter. The third phosphorylgroup may, for example, be linked to the adenylic acid part of the moleculein the same way as the phosphcryl group in yeast adenylic acid givingstructure (XIX).87 To settle this point a redetermination of the basicityof TPN seems desirable, the existing data 52, 91 on this point not being satis-factory ; isolation of larger fission fragments might also clarify the problem.It would be of interest to apply the metaperiodate oxidation method 38, 39to TPN; since (XVIII) should consume 2 mols.but (XIX) only 1 mol. ofthe reagent, decision between these two alternatives should be possible bythis method.0- OHOH0 0 0NH20- OH(XIX.)H H H0 0PO3H2Flavin-adenine Din~cleotide.~~-This coenzyme which is not, strictlyspeaking, a dinucleotide forms the prosthetic group of a wide variety of8 6 H. von Euler, F. Schlenk, H. Heiwinkel, and B. Hogberg, 2. physiol.Chem.,1938,256,208.8 7 F. Schlenk, B. Hogbcrg, and S. Tingstam, Svensk Vet. Akad. Arkiv Kemi,1939,13A, 11.8 8 H. von Euler and E. Adler, 2. physiol. Chem., 1938, 252, 41 ; H. von Euler andE. Bauer, Ber., 1938, 71, 411.E. Adler, S. Elliott, and L. Elliott, Enzymologia, 1940, 8, 80.F. Schlenk, h’aturwiss., 1937, 25, 668. O1 H. Theorell, ibid., 1934, 275, 19.O 2 For reviews dealing with biochemical aspects, see D. E. Green, “Mechanismsof Biological Oxidations,” Cambridge, 1940, p. 74; T. R. Hogness in “ Symposium onRespiratory Enzymes,” Wisconsin, 1941, p. 134LYTHGOE : CHEMISTRY OF ADENINE NUCLEOTIDE COENZYMES. 187flavoproteins; it is active in hydrogen transport in biological systems byvirtue of the redox properties of the riboflavin residue.Chemical investig-ation of FAD dates from the isolation from liver, kidney, and yeast by 0.Warburg and W. Christiang3 of the pure barium salt, C2,H3,0,,H,P,Ba,of the coenzyme. These workers, having effected separation of the apo-enzyme of the d-alanine oxidase 94 from the coenzyme by acidification withhydrochloric acid in presence of ammonium sulphate, were able to use theoxidase system as test method in their purification process; the equationsof the oxidation are :CH3*CH(NH2)*CO2H + FAD + H2O 1 CH,*CO*CO,H + NH, + FAD-Hp,FAD-H2 + 0, = FAD + H202Reduction of FAD to the dihydro-derivative can be effected by sodiumhyposulphite at pH 7.5, and like the similar reductions of the nicotinamidecoenzymes probably proceeds stepwise via a radical of the semiquinonetype.95 Unlike the dihydronicotinamide coenzymes, dihydro-FAD is aut-oxidisable. The evidence a t present available indicates a structure (XX).Hydrolysis of FAD gives 1 mol.of adenine; this must have been combinedin such a way that the amino-group is unsubstituted (dearnination). Theultra-violet absorption spectrum of FAD follows that of riboflavin closely,OH OHI I H H HJ . J / QH OH OH 10 0O*P*O*P*O*CH,-l --l--/-CH,Iand on alkaline photolysis lumiflavin is liberated from the coenzyme a t thesame rate as from riboflavin itself. E. P. Abraham 96 showed that by care-fully controlled hydrolysis with dilute alkali, resulting in complete loss ofd-amino-oxidase activity, FAD gave adenosine-5’-phosphoric acid, identifiedbiologically by its cophosphorylase activity, whilst after similar treatmentof FAD with dilute acid riboflavin-5’-phosphoric acid could be detected byvirtue of its activity as the prosthetic group of 0.Warburg’s “ old flavo-protein.” P. Karrer and H. Frank9’ have shown that the phosphorylresidues occupy terminal positions on the sugar chains since no formalde-hyde is produced on oxidation of PAD with periodic acid. The ready fissionof FAD into the two constituent nucleotides, which probably proceedsenzymatically 93 as well as by action of acid and alkali, has raised the question93 Biochem. Z . , 1938, 298, 150.94 H. A. Krebs, Biochem. J . , 1935, 29, 1620, 1951; N. B. Das, ibid., 1936, 30, 1080,96 Cf. E. Haas, Biochem. Z . , 1937, 290, 291.96 Riochem.J . , 1939, 33, 543.1617; F. B. Straub, Nature, 1938,141,603.97 Helv. Chini. Acta, 1940, 23, 948188 ORUANIC CHEMISTRY.of the status of riboflavin-5'-phosphate 98 as coenzyme of hydrogen transfer.Whilst it seems likely that its isolation from some enzyme systems is a resultof the breakdown of P A D , present evidence indicates that in others, e.g.,cytochrome-c red~ctase:~ ribofiavin-5'-phosphate is the true prostheticgroup and not merely an artefact.B. L.7. PYRAZINE AND ITS DERIVATIVES.Pyrazine bases occur in fuse1 oil ; the hornologues which have been isolatcdtetramethyl-,2 2 : 5-diethyl-,2 from this source include 2 : 5-dimethyl-,l~and methyltriethyl 3-pyrazine.Synthesis of Pyrazine Homologues.A. Reactions Involving the Self-condensation of u- Amino-carbon91 Com-pounds.-The most widely employed method for the synthesis of pyrazinehomologues is by the self-condensation of a-amino-carbonyl compoundsusually in the presence of an oxidising agent.(a) a-Amino-ketones are relatively easily prepared in the form of theirhydrochlorides either by the method developed by V.Meyer which consistsin the reduction of isonitrosoketoiies in acid solution or by the phthalimido-ketone method of S. Gabriel.5 A typical pyrazine synthesis is that of 2 : 5-di-2Me*CO*CH:N*OH \ SnCl,/HCI'(111.)mefhylpyrazine (11) ; successive treatment of aminoacetone hydrochloride(I) with sodium hydroxide and mercuric chloride gives 2 : B-dimethyl-9s P. Karrer, Helv. Chim. Acta, 1935, 18, 69, 426; H.Theorell, Biochem. Z . , 1934,9x1 E. Haas, E. L. Horecker, and T. R. Hogness, J. Biol. Chem., 1940, 136, 747.272, 155; R. Kuhn, H. Rudy, and F. Weygand, Ber., 1936,69,2034.1 E. C. Morin, Compt. rend., 1888,106,360; P. Brandes and C. Stoehr, J. p r . Chem.,2 A. C. Chapman and F. A. Hatch, J . SOC. Chem. Ind., 1929, 98; T. Taira, J. Agric.P. Schorigin, W. Issaguljanz, \I7. Below, and S. Alexandrowa, Ber., 1033, 66,S. Gabriel and G. Pinkus, ibid., 1893, 26, 2197; H. Gutknecht, ibid., 1879, 12,S. Gabriel and J. Colman, ibid., 1902, 35, 3805; S. Gabriel and T. Posner, ibid.,1896,54,481; E. Bamberger and A. Einhorn, Ber., 1897,30,224.Chem Xoc. Japan, 1936, 12, 576.1087.2290.1894, 27, 1141; S. Gabriel, ibid., 1908, 41, 1127NEWBOLD AND SPRING : PYRAZINE AND ITS DERIVATIVES.189pyrazine (11). The mechanism of this general preparative method is notclearly established ; treatment of aminoacetone hydrochloride with alkaligives a product, C,Hl,N,, which when heated with hydrochloric acid is re-converted into the parent aminoacetone hydrochloride. This product doesnot appear to be the dihydropyrazine (111) since it cannot be oxidised to2 : 5-dimethylpyrazine nor can it be reduced to 2 : 5-dimethylpipera~ine.~The method has been used to prepare 2 : 5-diisopropylpyrazineY7 2 : 5-di-ethylpyrazine (the requisite a-amino-ketone salt being obtained by thephthalimido-ketone route),8 tetrarnethylpyra~ine~~ 2 : 5-dimethyl-3 : 6-di-propylpyrazine,g~ 10 2 : 5-dimethyl-3 : 6-diisobutylpyrazine, l1 2 : 5-dimethyl-3 : 6-diamylpyrazine,12 2 : 5-diphenylpyrazine,13 and 3 : 6-diaryl-2 : 5 4 -methylpyrazines.14 Tetraphenylpyrazine has been obtained by thereduction of benzil monoxime 15 (and benzil dioxime Is) with sodium amal-gam, and tetramethylpyrazine has been obtained by the reduction of iso-nitrosolaevulic acid.A variant of this method has been employed by F.B. Ahrens and G.Meissner who obt’ain 2 : 5-dimethylpyrazine in poor yield by the electrolyticreduction of isonitrosoacetone in sulphuric acid followed by treatment of thesolution with alkali and mercuric chloride. Catalytic reduction of isonitroso-acetophenone in neutral solution gives 2 : 5-diphenylpyrazine, the finaloxidation being effected by atmospheric oxygen,lg and catalytic reductionof bend monoxime and dioxime gives tetrapheiiylpyrazine.20 The form-ation of 3 : 6-di-p-phenylethyl-2 : 5-dimethylpyrazine as one of the productsof a catalytic reduction of benzylidenedimetyl monoxime has been observedby 0.Diels and W. Poetsch.21 Other variants have been described.22 Tetra-methylpyrazine is obtained in very high yield by the reduction of the iso-nitroso-derivative of methyl ethyl ketone with zinc dust and alkali,23 amethod also employed by R. Campbell, R. D. Haworth, and W. K. Perkh2*(b) A remarkable rearrangement of oximes leading to their conversion’ M. Conrad and K. Hock, ibid., 1899, 32, 1199.’ H. Kiinne, ibid., 1895, 28, 2158; H. Gutknecht, ibid., 1879, 12, 2290.lo F. P. Treadwell, ibid., 1881, 14, 2036; H.Kunne, Zoc. cit.; 8. Gabriel andl1 E. Lang, ibid., 1885,18, 1364.l3 S. Gabriel, ibicE., 1908,41, 1127 ; E. Braun and V. Meyer, ibid., 1888, 21, 19.lo M. Tiffeneau, J. LBvy, and E. Ditz, BUZZ. SOC. chim., 1935, 2, 1845.l6 E. Braun and V. Meyer, Ber., 1888, 21, 1269.l 7 K. Thal, ibid., 1892, 25, 1718.l9 W. H. Hartung, J. Amer. Chenz. SOC., 1931, 53, 2248; W. H. Hartung, J. C.2o C. F. Winans and H. Adkins, ibid., 1933, 55, 2051.21 Ber., 1921, 54, 1585.22 F. Knoop, F. Ditt, W. Heckstedon, J. Maier, W. Merz, and R. Hiiile, 2. physiol.23 0. Wallach, Nach. Ges. Wiss. Gottinyen, 1927, 238.S. Gabriel, Ber., 1908, 41, 1127.E. Kolehorn, ibid., 1904, 3’7, 2474.T. Posncr, ibid., 1894, 27, 1037; G. Kalischer, ibid., 1895, 28, 1513.12 L. Behr-Bregowski, ibid., 1897, SO, 1515.N.Polonowska, ibid., 1888, 21, 488.Ibid., 1897, 30, 532.Munch, W. A. Deckert, and F. Crossley, ibid., 1930, 52, 3317.Chern., 1936, 234, 30.24 J . , 1926, 32190 ORGANIC CHEMISTRY.into a-amino-ketones (and thence into pyrazines) is described by P. W. Neberand co-worker~.~~ The oxime is converted into its toluenesulphonate whichwhen treated with potassium ethoxide in alcohol gives an amino-ketal whichis readily converted into the corresponding amino-ketone hydrochloride thusaffording a pyrazine synthesis :R*CH2*C*Me R*CH*C( OEt),*Me R*CH*CO*Me - I NH,,HCl II - IN*OH NH2(c) Certain pyrazine bases can be obtained by the action of ammoniaupon a-halogenated ketones. 3-Chlorobutan-2-one gives a good yield oftetramethylpyrazine 26 as does p-bromolaevulic acid 27 (and p-hydroxy-levulic acid), whilst o-bromoacetophenone gives the dihydro-derivativeof 2 : 5-diphenyIpyrazine, diphenacyIamine,28 and 2 : 6-diphenylpyrazineand its dihydro-derivative.29 Treatment of bromoacetaldehyde withammonia gives a poor yield of pyrazine.30( d ) a-Amino-acids or their esters can be used as starting materialsfor pyrazine syntheses.Thus A. Neuberg31 reduced alanine ester withsodium amalgam in the presence of hydrochloric acid and treated the reactionproduct (the hydrochloride of a-aminopropaldehyde 32) with alkali andmercuric chloride to obtain 2 : 5-dirnethylpyrazine. A more valuable methodis that developed by H. D. Dakin and R. West 33 in which an cc-amino-acidis treated with acetic anhydride and pyridine34 to yield the acetamido-ketone (IV) which on hydrolysis with mineral acid followed by treatmentwith alkali and mercuric chloride yields the pyrazine (V).Using this(IV.1 w.1method alanine is converted into tetramethylpyrazine, and phenylalanineand tyrosine yield (V, R = Ph-CH,) and (V, R = p-OH*C6H,*CH2)respectively.( e ) The most efficient synthesis of the parent pyrazine is that describedby L. Wolff and R. M a r b ~ r g . ~ ~ Treatment of chloroacetal with ammonia26 P. W. Neber and A. V. Friedelsheim, Annulen, 1926, 449, 109; P. W. Neber andH. Uber, ibid., 1928,467, 52; P. W. Neber and A. Burgard, ibid., 1932, 493, 281; P. W.Neber and G . Huh, ibid., 1935, 515, 283; P. W. Neber, A. Burgard, and W.Thier, ibid.,1936, 528, 277.26 M. Dbmhtre-Vladesco, Bull. SOC. chim., 1891, 6, 820.2 7 L. Wolff, Ber., 1887, 20, 425.2Q F. Tutin, J., 1910, 97, 2495; S. Gabriel, Ber., 1913, 46, 3861.30 A. E. Tschitschibabin and M. N. Schtschukina, ibid., 1929, 62, 1075.31 Ibid., 1908, 41, 956.32 E. Fischer, ibid., p. 1019; E. Fischer and Kametaka, Annalen, 1909, 365, 10.33 J . Biol. Chem., 1928, 78, 745, 757.34 Cf. P. A. Levene and R. E. Steiger, ibid., 1927, 74, 689; 1928, 79, 95.35 Annalen, 1908, 363, 169.28 S. Gabriel, ibid., 1908,41, 1130NEWBOLD AND SPRING: PYRAZINE AND ITS DERIVATIVES. 191yields diacetalylamine (VI) which on heating with hydrochloric acid gives2 : 6-dihydroxymorpholine (VII) which when treated with hydroxylaminehydrochloride yields pyrazine (VIII) .Acid hydrolysis of aminoacetalNHNH / \(OEt),CH CH( OEt), \ /CH2 VH2HOCH CH*OH / \ 4 HzQ 7%(VIII.) 0 (VII.)followed by treatment of the product with alkali and an oxidising agentgives p y r a ~ i n e , ~ ~ which is also obtained in small yield by the catalyticdehydrogenation of ethanolamine.37B. Other Methods.-Pyrazine bases can be obtained by decarboxylationof pyrazinecarboxylic acids.38 Although condensation of 1 : 2-diamineswith 1 : 2-dicarbonyl compounds has found little application in the pyrazineseries it is claimed that diacetyl and ethylenediamine react to give a dihydro-pyrazine which on oxidation with Fehling's solution yields 2 : 3-dimethyl-p y r a ~ i n e . ~ ~ Condensation of ethylenediamine with benzil' also gives adihydropyrazine derivative which on distillation is converted into 2 : 3-di-phenylpyrazine.40 Treatment of glucose with ammonia gives a mixture ofbases including pyrazine, 2-methyl-, 2 : 5-dimethyl-, and 2 : 6-dimethyl-p y r a ~ i n e s , ~ ~ and 2 : 5-bistetrahydroxybutylpyrazine is obtained by theaction of ammonia upon fructose.42 2 : 5-Dimethylpyrazine is said to bereadily obtained by distillation of glycerol with certain ammonium salts.43According to R.Leuclcart,44 treatment of benzoin with ammonium formategives a nearly quantitative yield of tetraphenylpyrazine. Using form-amide instead of ammonium formate, A. Novelli 45 obtained 4 : 5-diphenyl-glyoxaline as major product together with a small amount of tetraphenyl-pyrazine; this reaction is said to be general for aromatic acyloins.Whenbenzoin is heated with ammonium acetate in acetic acid solution, a mixtureof tetraphenylpyrazine and 4 : 5-diphenyl-2-methylglyoxaline is obtained.4636 S. Gabriel and G. Pinkus, Ber., 1893, 26, 2207; 1908, 41, 960; L. Wolff, ibid.,37 J. G. Aston, T. E. Peterson, and J. H'olowchak, J . Amer. Chent. SOC., 1934,56, 153.38 S. Gabriel and A. Sonn, Ber., 1907, 40, 4850; C. Stoehr, J . p r . Chem., 1894,38 E'. Jorre, Diss., Kiel, 1897.4 0 A. T. Mason, J., 1889, 55, 99; 1893, 63, 1297.41 P. Brandes and C . Stoehr, J . p r . Chem., 1896,54, 481 ; C. Tanret, Bull. SOC. c h h . ,1885, 44, 103; 1897, 17, 801; Compt. rend., 1885,100, 1540.42 Lobry de Bruyn, Rec. Trav. chim., 1899, 18, 72, 81 ; R.Stolte, Biochem. Z . , 1908,4 3 C . Stoehr, Ber., 1891, 24, 4105; J . p r . Chem., 1893, 47, 439; 1895, 51, 449;D.R-P. 73,704; 75,298; A. Etard, Compt. rend., 1881, 92, 460; M. Dennstedt, Ber.,1892, 25, 259.1893, 26, 1830; 1888, 21, 1483.49, 392.12, 499.44 J . p r . Chem., 1890,41, 330; J . Org. Chem., 1938,2,328.4b Anal. Asoc. Quim. Argentina, 1939, 27, 161.46 D. Davidson, M. Weiss, and M. Jelling, J . Org. Chem., 1937, 2, 328192 ORGANIC CHEMISTRY.Only a very small yield of tetraphenylpyrazine is obtained by the action ofliquid ammonia upon ben~il,*'?~~ but K. Bulow48 has shown that thispyrazine is obtained in reasoiiable yield by the action of formamide uponbenzaldehyde. Treatment of a-benzil dioxime with potassium ferrocyanideyields tetrapheiiylpyrazine dioxide which on reduction with zinc dustand acetic acid gives tetraphenylpyrazine.49Properties of Pyraxine and its Homobgues.-Pyrazine and its homologuesare monoacidic bases, neutral to litmus.The lower homologues are volatilecompounds boiling without decomposition and are miscible in all proportionswith water. They are insoluble in alkaline solutions and can be precipitatedfrom aqueous solution by the addition of alkali. They are hygroscopicand readily form crystalline hydrates. The parent pyrazine has b. p.115"/730 mm. and separates from a concentrated aqueous solution as prisms,m. p. 55°.50 Very characteristic of pyrazine and its lower homologues aretheir great volatility and tendency to sublime even at room temperature inclosed vessels.Pyrazines possess a characteristic odour comparable withthat of the higher pyridine bases. They are weaker bases than pyridine,the introduction of aromatic substituents decreasing the basic strength ;thus, 2 : 5-diphenylpyrazine is soluble in concentrated hydrochloric acidbut it is precipitated from this solution on dilution with water.51 2 : 5-Di-methylpyrazine, probably the most fully examined me-mber of the series, hasbeen characterised by the preparation of a monohydrochloride, a picrate,an aurichloride, and a mon~methiodide.~~ When suitably reduced, thepyrazines are converted into the corresponding piperazines ; 53* 52 conversely,piperazines can be oxidised to the corresponding pyyrazines.61 Towardsoxidising agents the pyrazine nucleus resembles that of pyridine ; pyrazinehomologues are readily oxidised to pyrazinecarboxylic acids.2 : 5-Di-methylpyrazine can be oxidised stepwise t o 2-methylpyrazine-5-carboxylic ,acid and thence to pyrazine-2 : 5-dicarboxylic a ~ i d , 5 ~ and oxidation ofquinoxaline gives pyrazine-2 : 3-dicarboxylic acid.55 Methyl groups attachedto the pyrazine ring are reactive and condense with aldehydes to yieldstyryl derivatives ; 56 thus 2 : 5-dimethylpyrazine condenses with benz-aldehyde in the presence of zinc chloride to give the styryl derivatives (IX)4 7 W. B. Leslie and G. W. Watt, J . Org. C'he?it., 1942, '7, 73.4 8 Ber., 1893, 26, 1830.49 E. Durio and M. Bissi, Gazzetta, 1930, 60, 899 ; K. v . Auwers and V. Meyer, Ber.,1888, 21, 806.L.Wolff, ibid., 1893, 26, 721.61 C. Stoehr, J . pr. Chem., 1893,47, 439.5 2 Idem, Ber., 1891, 24, 4105.63 L. Wolff, ibid., 1893, 26, 722, 725; M. Godchot and M. Mousseron, Bull. SOC.chim., 1932, 51, 349; Compt. rend., 1930, 190, 798; F. B. Kipping, J., 1929,2889.54 C. Stoehr, J. pr. Chem., 1893, 47, 447, 476; 1894, 49, 397; 1895,51, 463; 1896,54, 490.55 S. Gabriel and A. Sonn, Ber., 1907, 40, 4852 ; J. W. Sausville and p. E. SPoerri,J. Amer. Chem. SOC., 1941, 63, 3153.66 R. Franke, Ber., 1905, 38, 3724NEWBOLD AND SPRING : PYRAZINE AND ITS DERIVATIVES. 193and (X). 2 : 6-Dimethylpyrazine has zero dipole moment; 57 electrondiffraction studies on pyrazine indicate a C-N link of 1.35 A.58Pyrazinecarboxylic acids can be obtained by oxidation of pyrazinehomologues or of quinoxalines.Pyrazine-2 : 3-dicarboxylic acid (and its5 : 6-disubstituted derivatives) can be obtained by condensation of hydrogencyanide tetramer with 1 : 2-dicarbonyl compounds followed by hydrolysisMe( I p = C H * P h Ph*CH=CH( N/ \CH=CH*PhN(X.)of the intermediate dicyanide (XI) .59obtained by reduction of the isonitroso-derivatives of @-keto-esters.Pyrazinecarboxylic esters have beenThus,N f & (XI.)H,N-CH-CN CHOHN=C-CN--+-I- bHO \N/Ireduction of the isonitroso-derivative of ethyl acetoacetate (XII) followedby treatment with alkali and an oxidising agent gives ethyl 2 : Fi-dimethyl-pyrazhe-3 : 6-dicarboxylate (XIII, R = Et). The reduction has beenaccomplished by stannous chloride and hydrochloric acid 60 and by catalyticmethods.s1 C.Gastaldi has developed a method for the preparation of the(XII.) (XIII.)acid (XIII, R = H) in which the bisulphite compound of isonitrosoacetoneis treated successively with potassium cyanide and hydrochloric acid to give3 : 6-dicyano-2 : 5-dimethylpyrazine (XIV) .62 Alkaline hydrolysis of thedicyanide does not convert it into the corresponding dicarboxylic acid but1 (XV.) (XVI.)yields 2-hydroxy-3 : 6-dimethylpyrazine-5-carboxylic acid (XV). Con-version of the dicyanide (XIV) into the corresponding acid has been achieved67 A. E. van Arkel and J. L. Snoek, Rec. Trav. chirn., 1933, 52, 719, 1013.68 V. Schomaker and L. Pauling, J. Amer. Chem. SOC., 1939,81, 1769.m Grhchkevitsch-Trochimovski, Rocz.Chem., 1928, 8, 165; L. E. Hinkel, G. 0.Richards, and 0. Thomas, J., 1937, 1432; R. P. Linstead, E. G. Noble, and J. M.Wright, ibid., p. 911.6o S. Wleugel, Ber., 1882, 15, 1050; S. Gabriel and T. Posner, ibid., 1894, 27, 1141;V. Cerchez and C. Colesui, Bull. SOC. chim., 1931, 49, 1291.O1 H. AdkinsandE. W. Reeve, J. Amer. Chem. Xoc., 1938, 60, 1328.62 Gazzetta, 1921, 51, 233.REP.-VOL. XLII. 194 ORGANIC CHEMISTRY.by C. Gastaldi and G. Princivalle 63 by acid hydrolysis to the diamide (XVI)which with nitrous acid gave the required acid. Pyrazine-2 : 5-dicarboxylicacid has been obtained by the action of ammonia upon dihydroxymaleicacid.&4 H. E. Fierz-David and E. Ziegler 65 have shown that, after couplingacetoacetanilide with a diazonium salt solution, reduction of the productwith alkaline hydrosulphite gives the anilide corresponding to (XIII).Properties of Pyraxinecarboxylic Acids.-Pyrazinecarboxylic acids givered-violet colourations when treated with aqueous ferrous sulphate.Theionisation constants of pyrazinemonocarboxylic acid and pyrazine-2 : 3 4 -carboxylic acid are 1.2 x 103 and 1.7 x (first ionisation constant)respectively.66 Pyrazine-2 : 3-dicarboxylic acid has been converted intophthalein-like compounds. Thus with resorcinol, (XVII) is obtained ;this dissolves in alkali to give a blood-red-coloured solution which on dilutionwith water shows an orange-green fluore~cence.~~ Pyrazine-2 : 3-dicarboxy-amide (XVIII) when treated with two molecular proportions of alkalinehypobromite solution undergoes an intramolecular rearrangement and giveslumazine (XIX).68 2 : 3-Dicyanopyrazine has been converted into phthalo-cyanine-like compounds when heated with suitable metallic reagents.69(XVIII.) (XIX.)Although antipellagra activity without the vasodilator effect of nicotinicacid is claimed for pyrazinecarboxylic acid and pyrazine-2 : 3-dicarboxylicacid,70 both acids were ineffective in the treatment of black tongue.'l Bothacids also appear to act as growth factors for Proteus vulgaris and Strepto-bacterium plantarium, but they act only in much greater concentration thandoes nicotinic acid.72 A series of alkyl-substituted pyrazine-carboxyamides63 Bazzetfa, 1928, 58, 412.135 Helv. Chim. Acta, 1928, 11, 776.G 6 J. W. Sausville and P. E. Spoarri, J . Amer. Chem. SOC., 1941, 83, 3153.6 7 S. C. De and P. C. Dutta, Ber., 1931,64, 2606.68 S. Gabriel and A. Sonn, ibid., 1907, 40, 4855; R. A. Baxter and F. S. Spring,64 H. J. H. Fenton, J., 1905, 87, 806.J., 1945, 229.R. P. Linstead, E. G. Noble, and J. M. Wright, J . , 1937, 911.70 C . E. Bills, F. G. McDonald, and T. D. Spies, Sth. Med. J., 1939, 32, 793.71 W. J. Dann, H. I. Kohn, and P. Handler, J . Nutrition, 1940, 20, 477.7 2 E. F. Moller and L. Birkofer, Ber., 1942, 75, 1108NEWBOLD AND SPRING: PYRAZINE AND ITS DERIVATIVES. 195and -hydrazides have been prepared as potential analeptics 73 and the pre-paration of NN’-dibenzyl- and NN’-diaryl-pyrazine-2 : 3-dicarboxyamidesis described with a view to their employment as antispasm0dics.~4 Pyrazinoylderivatives of sulphanilamide 75 have also been described.Amino-pyraxines.-Treatment of pyrazine-2 : 3-dicarboxyamide withone molecular proportion of alkaline hypobromite solution gives Z-amino-pyrazine-3-carboxylic acid which on heating yields aminopyrazine ; 68the latter has also been obtained by a normal Hofma.nn reaction uponpyrazine~arboxyarnide.~~ The dihydrazide of pyrazine-2 : 5-dicarboxylicacid has been degraded to the corresponding diisocyanate, but this compoundproved remarkably resistant to hydrolysis as did the corresponding diurethaneobtained via the dia~ide.~’ Aminopyrazine was not obtained by treatmentof pyrazine with potassium amide in liquid but 2 : Ei-dimethyl-pyrazine has been aminated using sodamide to give 2-amino-3 : 6-dimethyl-p y r a ~ i n e . ~ ~ Lumazine, which can be obtained either as described abovefrom pyrazinedicarboxyamide or by treatment of glyoxal with 4 : 5-diamino-2 : 6-dihydro~ypyrimidine,~~ and substituted lumazines (XX) can behydrolysed using either acid or alkaline conditions t o give aminopyrazines(XXI) and 2-aminopyrazine-3-carboxylic acids (XXII) respectively : 81(=.) (XXI.) (XXII.)The amino-acids (XXII) are smoothly decarboxylated when heated togive the corresponding aminopyrazines (XXI). Sulphanilyl derivativesof various aminopyrazines have been much investigated particularly in theUnited States. Single large doses of sulphapyrazine (XXITI) 66,82 given tomice infected with p-hemolytic streptococci are claimed to be considerablymore effective than similar doses of sulphathiazole, sulphapyridine, or sulph-anilamide and equally effective as a similar dose of s~lphadiazine.~~ The73 D.R.-P. 632,257; Canad. P. 378,818; U.S.P. 2,149,279.74 J. H. Billman and J. L. Rendall, J . Amer. Chem. SOC., 1944,66, 540.‘5 T. C. Daniels and H. Iwamoto, ibid., 1941, 63, 257.76 5. A. Hall and P. E. Spoerri, ibid., 1940, 82, 664.77 P. E. Spoerri and A. Erickson, ibid., 1938, 60, 400.79 A. E. Tschitschibabin and M. N. Schtschukins, J . Russ. Phys. Chem. SOC.. 1930,F. W. Bergstrom and R. A. Ogg, ibid., 1931, 53, 245.62, 1189; R. R. Joiner and P. E. Spoerri, J . Amer. Chem. SOC., 1941,63,1929.R. Kuhn and A. H. Cook, Ber., 1937,70, 761.J Weijlard, M. Tishlor, and A. E. Erickson, J. Amer. Chern. SOC., 1945,67,802.82 G. W. Raiziss, L. W. Clemence, and M. Freifelder, ibid., 1941, 63, 2739; R. C.Ellblgson, ibid., p. 2524; H. J. Robinson, H. Siegel, and 0. Graessle, J . Pharmacol.,1943, 79, 354; G. I. Trevett, Bull. Johns Hopkins Hosp., 1944, 74, 299.83 W. H. Schmidt and C. L. Sesler, J. Phamacol., 1943, 77, 277196 ORGANIC CHEMISTRY.absorption, distribution, and excretion of sulphapyrazine in man is de-scribed,84 and a comparative study of its efficiency in the treatment ofpneumococcal infections is made.86$ 86~y~roxy-~yraxines.-2-Hydroxy-3 : 6-dimethylpyrazine was obtained byC . Gastaldi 62 by decarboxylation of 2-hydroxy-3 : 6-dimethylpyrazine-5-carboxylic acid (XV), and a similar synthesis of 2-hydroxy-3 : 6-diphenyl-pyrazine is recorded. A synthesis of 5 : 6-di- and 3 : 5 : 6-tri-substituted-2-hydroxypyrazines has been developed by Y. A. Tota and R. E. Elderfield.87It consists in the condensation of an a-amino-ketone with an a-halo-acid halidefollowed by treatment of the+ P H 2 0 B rMeCOMe.AH*NH,,HCl CO*Brproduct with ammonia, thus :BrCauo, MeCO - I Me*CHTishler, and A. E. Erickson have shown that More recently, J. Weijlard, Mdrastic alkaline hydrolysis of lumazine or 2-aminopyrazine-3-carboxylic acidgives 2-hydroxypyrazine-3-carboxylic acid, decarboxylation of which yieldshydroxypyrazine :/N\/NH\p IPhenylglyoxal or functionally related compounds can cyclise, given anappropriate source of nitrogen, to give either 2-hydroxy-3 : 6-diphenyl-pyrazine or 2-benzoyl-5-phenylglyoxaline.88 Hydroxypyrazines are ampho-teric. 2-Hydroxy-3 : 6-dimethylpyrazine couples with diazonium salts toyield crystalline 5-arylazo-derivatives, and 2-hydroxy-3 : 6-dimethyl-pyrazine-5-carboxylic acid also couples with loss of carbon dioxide to givethe s$me azo-derivatives. 89 The formation of certain quaternary ammoniumsalts from 2-hydroxy-3 : 6-dimethylpyrazine and their conversion intocyarline dyes is claimed by C. Gastaldi and E. Princivalle.goG. T. N.F. S. S.84 M. Hamburger, J. M. Ruegsegger, N. L. Brookens, and E. Eakin, Amer. J.Med.85 L. H. Schmidt, J. M. Ruegsegger, C. L. Sesler, and M. Hamburger, J . Pharmacol.,86 For other sulphanilyl derivatives of aminopyrazines see R. C. Ellingson, R. L.8 7 J . Org. Chem., 1942, 7 , 313.88 H. Muller and H. v. Pechmann, Ber., 1889, 22, 2557; A. Pinner, ibid., 1906,38, 1531 ; C. Engler and E. Hassenkamp, ibid., 1885,18, 2240; S. Minovivi, ibid., 1899,32, 2206; F. R. Japp and N. H. J. Miller, J., 1887, 30; F. R. Japp and J. Knox, ibid.,1905, 701 ; M. Busch and W. Foerst, J. pr. Chem., 1928,119, 287.8Q C. Gastaldi and E. Princivalle, Cfazxetta, 1928, 58, 679; E. Princivalle, ibid., 1930,80, 298.90 Ibid., p. 412; Annuli Chim. Appl., 1936, 26, 450.Sci., 1942, 204, 186.1941, 73, 468; Amer. J . med. Sci., 1941, 202, 432.Henry, and F. G. McDonald, J. Amer. Chem. SOG., 1945, 67, 1711

ISSN:0365-6217    

DOI:10.1039/AR9454200092

出版商:RSC    

年代:1945

数据来源: RSC

摘要:

BIOCHEMISTRY.1. THE INTEGRATION OF THE INTERMEDIARY METABOLISM OFCARBOHYDRATES, FATS, AND AMINO-ACIDS.THE existence of a clearing-house common to intermediates in the oxidativemetabolism of carbohydrates, fats, and proteins has long been suspected,but its demonstration appears to have been brought substantially nearer byrecent work. Although many gaps remain and some stages are still highlycontroversial, a provisional description on the basis of known mechanism isnow possible.The Metabolism of Pyruvate.F. Knoop predicted 15 years ago that pyruvate “ represented thebridge across which the most varied classes of foodstuffs could be inter-converted.” If the various products arising from the multiple metabolicreactivity of pyruvate are included, this statement still holds good.Pyruvatearises on either of the main pathways of carbohydrate breakdown hithertodescribed, on the one hand through the well-known phosphorylated inter-mediates of the Embdcn-Meyerhof series, or alternatively aerobically throughthe presumably stepwise oxidation and decarboxylation of hexose 6-phosphateby a coenzyme II-catalysed system,2 independent of fermentation 39 andrelatively insensitive to poisons such as iodoacetate and f l ~ o r i d e . ~ ~ Anon-phosphorylating mode of carbohydrate breakdown originally advancedfor brain and embryonic tissues 7 now seems to have been insecurelyfounded, and typical phosphorylative mechanisms have since been clearlydemonstrated in these tissues.8 But in moulds and some bacteria loapparently non-phosphorylating pathways of hexose degradation exist,which may lead to the formation of p y r ~ v a t e .~The great reactivity of pyruvate in cells and tissues is illustrated by thelist of such reactions compiled by E. S. G. Barron l1 which includes 151 Ahrens Vortrage, 1931, 9, 18.2 0. Warburg and W. Christian, Biochem. Z., 1937, 292, 287 ; F. Lipmann, Nature,1936, 138, 588; F. Dickens, ibid., p. 1057; Biochem. J., 1938, 32, 1626, 1645.S. B. Barker, E. Shorr, and M. J. Malam, J . Biol. Chem., 1939, 129, 33.S. Spiegelman and M. Nozawa, Arch. Biochem., 1945, 6, 303.E. Stetz, “Advances in Enzymology,” Interscience Press, N.Y., 1945, 5, 129.C. A. Ashford, Biochem. J., 1934, 28, 2229.7 J. Needham and H. Lehmann, ibid., 1937,31,1210,1913 ; J.Needham and W. W.Nowinski, ibid., p. 1165.8 M. F. Utter, H. G. Wood, and J. M. Reiner, J. Biol. Chem., 1945, 161, 197;0. Meyerhof and E. Perdigon, Enzymologiu, 1940, 8, 353; J. R. Klein, J . Biol. Chem.,1944, 153, 295 ; Fed. Proc., 1945, 4, 94.F. F. Nord and R. P. Mull, “Advances in Enzymology,” Interscience Press, N.Y.,1945, 5, 165.lo C. R. Brewer and C . H. Werkman, Enzymologiu, 1940, 8, 325.11 “Advances in Enzymology,” Interscience Press, N.Y., 1943, 3, 149198 BIOCHEMISTRY.different enzyme systems yielding a wide variety of products from pyruvatein animal tissues, yeast, bacteria, fungi, and plants. Some of the morerecently investigated pathways will be considered later in this review, afterthe primary oxidation of pyruvate has been discussed.Oxidation of Pyruvate in Bacteria.Acetone preparations of Lactobacillus delbrueckii oxidise pyruvate toacetyl phosphate and carbon dioxide in presence of inorganic phosphate,diphosphoaneurin, a bivalent metal (Mn, Mg, Co), and alloxazine dinu-cleotide.12 In gonococci, however, oxidation of pyruvate requires thecytochrome system,13 and there is now evidence that, in some systems whichoxidise pyruvate, phosphate is not a component: E.S. G. Barron (un-published ; cited in 11) found that thoroughly washed M . piltonemis requiredno added phosphate, and in careful studies P. K. Stumf l4 has recently shownthat, although Lipmann’s findings with preparations of L. delbrueckii couldbe fully confirmed, similar extracts of Proteus vulgaris and Esch.wli do notappear to require inorganic phosphate for their activity. The productsformed are in both these cases acetic acid and carbon dioxide, and the lack ofevidence of acetyl phosphate formation could not be explained by thebreakdown of this substance by hydrolysis as soon as it was formed. Theextracts contained acetyl phosphatase, the enzyme specifically responsiblefor this hydrolysis which has also been found to occur in skeletal and heartmuscle ;I5 but, although this dephosphorylation is considerably inhibitedby O.lM-phosphate, even in presence of this concentration of inorganicphosphate no acetyl phosphate accumulated in Stumpf’s experiments,and in any case the activity of the acetyl phosphatase was too low to be theexplanation of the non-occurrence of acetyl phosphate as the primary product.The new enzyme system therefore differs from the pyruvate oxidase studiedby Lipmann in that it appears to catalyse a non-phosphorylative oxidation;it resembles Lipmann’s enzyme in that it requires diphosphoaneurin and abivalent metal (in this case, Mn, Mg, Fe, Ni, Zn, or Co), and it is specific forpyruvate among the keto-acids tested.Nature of the Primary Product in Pyruvate Oxidation.The existence of these two types of bacterial pyruvate oxidase may beconsidered in relation to the mechanism of pyruvate oxidation in general.Many attempts to explain the metabolic reactions of pyruvate, acetate, andacetoacetate appear to necessitate the assumption of the existence of a high-energy C, intermediate, which in the past has frequently been referred to as“ nascent acetic acid,” although the unsatisfactory nature of such a term hasl2 Ann.Reports, 1940,37,417; 1944,41, 235; F. Lipmann and L. C. Tuttle, J . Biol.l3 E. S . G . Barron, ibid., 1936, 113, 695.14 Ibid., 1945, 159, 529.15 F. Lipmmn, Proc. Div. BWE. Chern., 108th Meeting, h e r . Chem. SOC. (1944).Cham., 1945,158, 505; M. F. Utter, F. Lipmann, and C. H. Werkman, ibid., p. 521DICEENS : THE INTERMEDIARY METABOLISM OF CARBOHYDRATES, ETC. 199long been admitted. The discovery by Lipmann of acetyl phosphate as aprimary stage in pyruvate oxidation led a t first to the rather uncriticalassumption by several workers that acetyl phosphate, with its high-energyphosphate bond,l6 was always the reactive intermediate. While this maybe true in some systems, evidence is accumulating of examples in which theproperties of acetyl phosphate are not necessarily adequate to account forthe experimental findings.I n the first place, evidence of acetyl phosphateformation in animal tissues is still lacking. Acetylations in which pyruvatemay be a primary source of acetyl groups occur with choline l7 and sul-phanilamide.18 Acetylation in the former system has been shown l9 to bebrought about by cell-free extracts of choline acetylase (the synthesisingenzyme system prepared from nervous tissue, which requires adenosinetriphosphate as primary energy source) and potassium ions, and is furtheractivated by I ( -)-glutamate.However, the system still appea.rs to becomplex, and the intermediate mechanism remains undecided. Acetylationof sulphonamides occurs aerobically in liver slices 2O and in liver homo-genates and extracts.z1 It also proceeds anaerobically a t a similar rateprovided adenosine triphosphate is supplied ; the amounts formed aredoubled by the addition of acetate to the system ; acetoacetate and pyruvateare about half as active in this respect as acetate, while acetoin causes someincrease over the acetate formation without added substrate. I n this systemacetyl phosphate was not active as an acetylating agent and it is assumedthat what is necessary is a complex of the acetyl donator, amino-compound,and adenosine triphosphate a t one and the same enzyme, rather than anintermediate formation of acetyl phosphate.21Though S.Ochoa, L. A. Stocken, and R. A. Petersz2 were unable todemonstrate in brain preparations the utilisation of acetyl phosphate or itsability to phosphorylate adenylic acid, the rate of breakdown by acetylphosphatase in such preparations is not known. There is, however, someevidence (vide infra) that acyl phosphates of fatty acids may be concerned infat metabolism in animal tissues.Since inorganic phosphate is indispensable for the oxidation of pyruvateby Lipmann’s preparation, the assumption has been made that the primaryreaction is an additive reaction of pyruvate and phosphate.23 If this is so,the enzyme concerned in the oxidation of this addition compound is pre-sumably different from that of Stumpf’s bacterial non-phosphorylating oxidasesystem.The finer points of these reactions remain to be investigated : forl6 F. Lipmaan, “Advances in Enzymology,” 1941, 1, 99.l7 P. J. G. Mann and J. H. Quastel, Nature, 1940, 145, 856; cf. ref. 18.l8 P. Handler and W. A. Perlzweig, Ann. Rev. Biochem., 1945, 14, 618.lS D. Nachmansohn and H. M. John, J . Biol. Chem., 1945, 158, 157; Fed. Proc.2o J. R. Klein and J. S. Harris, J . Biol. Chem., 1938,124, 613.21a F. Lipmann, Fed. PTOC., 1945, 4, 97; J . BioZ. Chem., 1945, 160, 173.21b B. Shapiro and E. Wertheimer, Nature, 1945, 156, 690.22 Ibid., 1939,144, 760; cf. Ann. Reporb, 1940,37,417.t 8 See Ann. Reporb, 1944,41, 236.1945, 4, 93200example the nature offormulated by equationTOi HBIOCHEMISTRY.the actual dehydrogenation, which Lipmann 24(I) might perhaps be represented by some suchc o 2I ' - 2H +I IMe*C*4H --+ MeCOHypotheticaladditioncompound.enol-Pyruvic acid.reaction as is shown in equation (11) in the non-phosphorylating oxidation,in which it is assumed that dehydrogenation of enol-pyruvate might yield amolecule of carbon dioxide plus one of keten or some other similar highlyreactive C, compound.This type of oxidative decarboxylation was originallysuggested ten years ago by H. Weil-Malherbe 25u to explain the similar reactionof a-ketoglutaric acid and the decarboxylative r61e of dipho~phoaneurin.~~~C. Martius 26 has quite recently adopted a view very similar to that outlinedabove in which the primary product of the dehydrogenation of pyruvate iswritten as a radical, -CH2-CO-.It is evident that such hypotheses mightexplain the remarkable reactivity of pyruvate in biological systems alreadymentioned ; e.g., the keten-like intermediate could be hydrolysed orphosphorylysed to acetic acid or acetyl phosphate; by the addition of 2Hit could yield acetaldehyde; diacetyl could be formed by condensation withacetaldehyde, and reduction of the product might be a source of acetoin;"amino-compounds could be acetylated ; acetoacetate formation from acetateor fatty acid oxidation could proceed via keten formation. The incorpor-ation of acetate into glycogen, higher fatty acids, or cholesterol, could beexplained by a similar mechanism. Two molecules might unite to formsuccinate.Keten could be the reactant with oxaloacetate in the formationof components of the tricarboxylic acid cycle. In the discussion of some ofthese reactions which follows, the term '' reactive C, compound " will be usedsince a more precise description appears unjustified at present. Alternativesto keten which have been suggested include, besides acetyl phosphate, acetyldiphosphoaneurin 26 and glyoxylic a~id,~'a but the last forms oxalate withtissue enzymes.27bOxidative Metabolism of Pyruvate in Animal Tissues.It is generally considered that in animal tissues simple decarboxylationof pyruvate to acetaldehyde is not on the pathway of pyruvate metabolism,I4 F. Lipmann, Cold Harbor Xymposia on Quant.Biol., 1937, 7 , 248.25a Nature, 1936, 138, 551.2 627a R. H. Barnes and A. Lerner, Proc. SOC. Exp. B i d . Med., 1943,52, 216.276 S. Ratner, V. Nocite, and D. E. Green, J . Biol. Chem., 1944, 152, 119.* Cf. references 27a, b.Zsb Idem, ibid., 1940, 145, 106.2. physiol. Chem., 1943, 279, 96DICKENS : THE INTERMEDIARY METABOLISM OF CARBOHYDRATES, ETC. 201since acetaldehyde is apparently not vigorously metabolised by skeletalmuscle 28 or some other animal tissues which metabolise pyruvate. On theother hand, decarboxylation of this kind occurs readily in a number ofbacteria, yeasts, plants, moulds, and protozoa, some of which have beenstated not to oxidise pyruvate.ll An enzyme from sheep’s heart which iscatalysed by diphosphoaneurin and apparently decarboxylates pyruvate toacetaldehyde (or a-ketoglutarate to succinic semialdehyde), with simultaneouscondensation to acetoin, has been described by Green and co-workers.292CH3*CO*C0,H + CH,*CO*CH(OH)*CH, + 2C02Acetaldehyde is believed to be the primary product of ethanol metabolismin animals, and acetaldehyde injected into rats is rapidly metabolised and,a t least in part, is converted into acetoin ; yet injected dl-acetoin disappearsonly slowly.30 The reason for the apparently different behaviour of theacetoin formed in vivo is not at all understood a t present, but it may beconnected with its optical configuration.* Homogenised brain tissue meta-bolises added acetaldehyde almost quantitatively to acetoin, the rate beinglowered in brain tissue from aneurin-deficient animals (rats and pigeons) ; inthis case the acetoin was not further o ~ i d i s e d .~ ~However, S. Ochoa 31 has shown that his purified preparation from cat’sheart of a-ketoglutarate dehydrogenase failed completely to catalyse theanaerobic decarboxylation of E-ketoglutarate, or to cause a t a sufficient ratethe aerobic oxidation of succinic semialdehyde; nor did the latter competewith a-ketoglutarate as substrate for the oxidation. The balance of evidenceis likewise against a two stage process (decarboxylation followed by oxidation)in the oxidation of pyruvate by animal tissues, but the matter is stilluncertain.From the pioneer work of Peters and co-workers the essential r61e ofdiphosphoaneurin in pyruvate oxidation by animal tissues has been madeabundantly clear, this being the first case in which the action of a vitaminin vitro was dem~nstrated.~~ Pyruvate oxidase of brain tissue has acomponent requiring an essential SH group and is readily inactivated byhalogenoacetates, dichlorodiethyl sulphone, and arsenicals,33, 34 or by exposure. 2 8 H.A. Krebs, “Advances in Enzymology,” Interscience Press, N.Y., 1943, 3, 191.2Q D. E. Green, W. W. Westerfeld, B. Vennesland, and W. E. Knox, J. Biol. Chem.,1941, 140, 683; W. W Westerfeld, E. Stotz, and R. L. Berg, ibicl., 1942, 144, 657;R. L. Berg and W. W. Westerfeld, ibid., 1944, 152, 113.30 E. Stotz, W. W. Westerfeld, and R. L. Berg, ibid., 1944, 152, 41; R. L. Berg,E. Stotz, and W. W. Westerfeld, ibid., p.51.31 Ibid., 1944,155, 87.32 See Ann. Reports, 1940, 37, 417; 386; 1939, 36, 339.33 R. A. Peters, H. Rydin,,and R. H. S. Thompson, Biochem. J., 1936, 29, 63 ; R. A.Peters, Nature, 1936, 138, 327; Current Science, 1936, 5, 212; “Perspectives inBiochemistry,” Cambridge, 1937, p. 41; R. A. Peters and R. W. Wakelin, reportprivately circ. in U.K. and U.S., 1941; R. A. Peters, L. A. Stocken, and R. H. s.Thompson, Nature, 1945, 156, 616.34 E. S. G. Barron and T. P. Singer, J. Biol. Chem., 1944,157 221.* Cf. reference 6.Q 202 BIOUHEMISTRY.to high pressures of oxygen.35 Barron l3 had earlier shown that gonococcalpyruvate oxidase was inhibited by oxygen. There is reason to believe that thisstage in carbohydrate metabolism is one of the most susceptible of all to inter-ference by toxic agents of the type mentioned, and is no doubt the seat ofaction of a variety of metabolic poisons, some of which may be importantpharmacologically. hf.Rlichaelis and J. H. Quastel 36 had earlier pointed outthe susceptibility of brain pyruvate oxidation to narcotics which probablyreacted with the flavoprotein component. This system in brain requires,like the bacterial systems, a bivalent metal (Mn or Mg) in addition to diphos-phoaneurin and inorganic ph~sphate,~’ but it is not yet possible to sayexactly what enzymes are involved, and in several animal tissues the evidencefavours a complicated mechanism of the type of the tricarboxylic acid cycle.The Tricarboxylic (isoCitrate) Cycle.The importance now widely assigned to this cycle, not only in the oxid-ation of pyruvate (or triose) arising in carbohydrate metabolism, but also inintermediary metabolism of fatty acids and amino-acids, warrants somedescription additional to those previously given in these Reports,3* althoughInter-relationship of metabolism of carbohydrate, fat, and protein through thetricarboxylic acid cycle.(Carbohydrate) + Phosphopyruvate .1 (Fatty acid)/ .1 + Acetate Acetoacetatev JI(Amino-acid) +Oxalocitraconate ( 1 ) +--/ loxaloacetate Malate J cis- Aconitate11(Amino-acid)11Fumarate11 11isoCitrate + Citrate Succinate11 + cozOxalosuccinate a-Ketoglutarate +co: Succinicsemialdehyde 11(Amiw-acid)for a full consideration of the literature up to 1943 reference should be madeto the review of H.A. Krebs.28 The cycle, slightly modified to accord with35 F. Dickens, Biochem. J., 1946, 40, 145, 171; P. 3. G. Mann and J. H. Quaatel,ibid., p. 139.36 Ibi&., 1941, 35, 518.37 S. Ochoa, Nature, 1939,144, 834; I. Banga, S. Ochoa, and R. A. Peters, Biochem.38 Ann. Reports, 1937, 34, 416-9; 1941, 38, 260-1.J . , 1939, 33, 1980; C. Long, ibid., 1943, 37, 215; 1945, 39, 143DICKENS : THE INTERMEDIARY METABOLISM OF CARBOHYDRATES, ETC. 203recent work, is shown in the scheme on p. 202. This system has the greatmerit of explaining how, for each complete course of one cycle, a molecule ofpyruvate could be completely oxidised to carbon dioxide and water by asystem of reactions almost all of which (at least in pigeon muscle tissue, themain material used in working out the cycle) have been shown to occur a t asufficiently rapid rate.It further explains how, in presence of malonate toinhibit direct reduction via succinic dehydrogenase, oxaloacetate might beconverted to succinate by an oxidising route, thus explaining the observedformation of succinate and the oxidative regeneration of C, catalyticallyactive dicarboxylic acids. Fortunately carbon dioxide fixation is consideredto be slight or absent in minced pigeon mu~cle,3~ so that for this material theinterpretation of the experimental evidence is not complicated by this factor.In pigeon-liver preparations, on the other hand, use has been made of theability to fix carbon dioxide in the formation of a-ketoglutarate from pyruvatein presence of bicarbonate containing isotopic 41 thus establishing,from the fact that the fixed C is located in the C0,H adjacent to the COgroup of the a-ketoglutarate, that a symmetrical intermediate such as citratecould not be involved in the primary condensation of pyruvate andoxaloacetate.Nature of the Interaction of Pyruvate and Oxaloacetate.Originally Wood et aL40b suggested that oxalomesaconic acid might be theprimary condensation product, but it is more probable41 that the cis-isomeride, oxalocitraconic acid, conforming to the cis-aconitate, which is thenext stage, would be the primary product.It is not known whether oxid-ation is subsequent to this stage or precedes it.* In fact this stage is theleast understood of the whole cycle.C.Martius, who with F. Knoop42 first described the smooth chemicalconversion of oxaloacetate and pyruvate in weakly alkaline solution to aproduct which on oxidation with hydrogen peroxide gave citric acid, hasmade a detailed study of this reaction.43 The simplest assumption, an aldolcondensation which may be catalysed by an enzyme similar to aldolase,would yield oxalocitramalic acid,H02C*CH2*C( OH) (CO,H)*CH,*CO*CO,Hwhich has been purified as the la~tone.~* However, this substance in spiteof the ease of its formation cannot be the intermediate in the citric acidsynthesis since (a) it is not oxidised nor does it yield citric acid in the presence39 E. A. Evans, junr., Harvey Lectures, 1944, 39, 273.406 E. A.Evans, junr., and L. Slotin, J . B w l . Chem., 1940,136, 301; 1941,141, 439,406 H. G. Wood, C. H. Werkman, A. Hemingway, and A. R. Nier, ibid., 1941, 139,4Oe See Ann. Reports, 1941, 38, 257-61.,il H. A. Krebs, Biochem. J., 1942, 36, Proc. ix.4a 8. physwl. Chem., 1936, 242, 1.44 Idem, Habilitation Dissertation, Tubingen, 1937.* Cf. reference 28.377; 1942,142, 31.43 C. Martius, ibicE., 1943, 279, 96204 BIOCHEMISTRY.of suitable enzymes, arid (b) its accumulation cannot be demonstrated underenzymic conditions which should favour its detection. The alkali-labilecondensation product obtained by F. L. Breusch 45 was probably identicalwith oxalocitramalate, and thus is not connected with citric acid synthesisin V ~ V O . ~ It is concluded that oxidation of the pyruvate is probably coupledwith condensation to a C, compound. .Since neither acetate, acetaldehyde,nor monoacetyl phosphate could be substituted for pyruvate in this synthesis,the formation was assumed of an active C, compound resembling the ketenradica1,43 as has been discussed above.The oxolocitraconic acid is assumed to be oxidatively decarboxylated tocis-aconitic acid, this substance being readilyand isocitrate through the action of theaconitase :isocitrate cis-aconitate- H,O7- + HZO(1.1According to K.P. Jacobson 46 reaction (I) isinterconvertible with citratewidely distributed enzyme,+ Ha0 citrate7 - HZO(11.1catalysed by a-aconitase andreaction (11) by p-aconitase, these two enzymes always -being associated,though in variable proportions, in animal and vegetable tissues.However,C. MartiusY4’ who showed that the cis-isomeride was that concerned in thesereactions, considered that a single enzyme catalysed both equilibria, and theevidence to the contrary is not yet convincing.The dehydrogenation of isocitrate to a-ketoglutarate has recently beenshown48ajb to be a two-stage reaction; the primary reversible dehydro-genation, by a coenzyme I1 system present in dialysed extract of an acetone-precipitated pig’s heart preparation, requires no manganese and yieldsoxalosuccinic acid. The secondary stage, the decarboxylation by oxalo-succinic carboxylase, a specific carboxylase requiring manganese ions andpresent in similar extracts of pig’s heart, is also reversible in its action.Thereaction constants are :Stage I : (isocitrate) (Co. II-oxidized)(oxalosuccinate) (Co. II-reduced) = 0.3.( oxalosuccinate)(a-ketoglutarate) (CO,) Stage I1 : = 0.5 x lo3.or for the overall reaction :(isocit.) (Co. II-oxid.)/(CO,) (a-ketoglut.) (Co. 11-red.) = 1.3 x 10-4Thus a new system for the fixation of carbon dioxide which yields isocitricacid is revealed by these experiments. The rate of carbon dioxide fixation46 8. physiol. Chem., 1937,250,262; Biochem. Z . , 1937,295, 101; Biochem. J., 1939,33, 1757 ; Enzymologia, 1942,10, 165.F. L. Breusch and P. Kaza, ibid., 1944, 11, 165.4 6 Ibid., 1940, 8, 327. 47 2. physwl. Chem., 1938, 257, 29.484 S. Ochoa, J . Biol. Chem., 1945, 159, 243; O E b S.Ochoa and E. Weisz-Tabori,ibid., p. 246DICKENS : THE INTERMED-Y METABOLISM OF CARBOHYDRATES, ETC. 205is increased : (a) by removal of the oxidised Co. I1 as it is formed, which maybe accomplished by its re-reduction by the simultaneous presence of thehexose monophosphate-dehydrogenase system, ( b ) by the removal of iso-citrate by addition of aconitase.Since the isocitrate dehydrogenase is part of a coenzyme I1 catalysedsystem, the reoxidation by a cytochrome system of reduced coenzyme pre-sumbably requires the cytochrome c reductase of E. Haas et ~ 1 . ~ ~ or a similarflavin intermediate carrier. Very recently this reaction has also been shownto occur in extracts of pig’s heart.50 It would appear therefore that acoupling of coenzyme I systems with this coenzyme I1 system might beconceived as proceeding through the cytochrome system and suitable cyto-chrome c reductases :Co.II-H, + cyt. c + Co. I1 + cyt. c-H,Cyt. c-H, + Co. I -+ Co. I-H, + cyt. c.This is a point of some importance in the tricarboxylic acid cycle, since, ashas been frequently pointed out,cf- l1 Krebs’s scheme of transfer of electronsfrom isocitrate to oxsloacetate involves two systems of which the former isbelieved to be catalysed by Co. I1 and the latter by Co. I, so that a directinteraction of the two systems does not seem likely. Possibly Ochoa’sobser.vation may supply a way out of this difficulty. In this connexionE. S. G. Barron l1 has pointed out that the isocitrate dehydrogenase systemis not widely distributed in nature, and the introduction of this system limitsthe tissues to which the cycle could be applicable.F. L.Breusch,46 throughout a severe critic of the importance of this cyclein carbohydrate metabolism, has stated that only in kidney tissue doescitrate formation from pyruvate and oxaloacetate occur with sufficientrapidity, and there only when an excess of the two reactants is present. Heregards the cycle as being mainly concerned in the metabolism of P-keto-acidsarising in fatty acid oxidation (see below). Earlier criticism 459 51 that addedcitrate did not increase the respiration of minced muscle has been answeredby H. A. Krebs 28 as being due to the inhibition of respiration by excess ofcitrate which suppresses the ionisation, and therefore the catalytic effect, ofmagnesium.It is still uncertain how far the cycle could explain the carbohydrateoxidation in tissues other than pigeon muscle, the tissue mainly used inKrebs’s experiments, and probably also in heart muscle.52 Usually only afew of the component reactions have been studied in other tissues.Inaddition to “deionising ” effects of the kind just mentioned, there aredifficulties in interpretation due to the impermeability of cells to some of thecomponents of the cycle. For example, malonate probably penetrates49 E. Haas, B. L. Horecker, and T. R. Hogneas, J . BioZ. Chem., 1940,136, 747.50 S. Ochoa, ibid., 1945,160, 273.51 F. J. Stare, M. A. Lipton, and J. M. Goldinger, ibid., 1941,141, 981 ;68 D.H. Smyth, Bbchem. J., 1940, 34, 1046.Q. Thomag,Entymologia, 1939, 7, 231206 BIOCHEMTSTRY.intact animal tissues with difficulty;63 and, although yeast cells are almostimpermeable to succinate and citrate,S4 the free succinic acid has been foundto penetrate the cell quite readily; hence intact yeast cells are readily ableto oxidise the free acid but not its salts.55 Malonate has virtually no effecteither on the whole respiration or on the oxidation of acetate in yeast cells,but malonic acid is inhibitory.55 Since with animal tissues the use of freeacids is generally impossible, it is important that these considerations shouldbe kept in mind when the applicability of metabolic cycles to intact cells ofanimal tissues is being discussed. This factor has often been overlooked inin the past, and indeed presents a formidable problem in practice.The Metabolism of Acetate in Animal Tissues : Earlier Views.Although in the intact 56 or eviscerated 57 animal, as in the isolatedperfused heart,58 acetate is rapidly metabolised, it is remarkable that slicesor homogenates of most animal tissues oxidise added acetate rather feebly.An exception is kidney cortex, in which acetate disappearance may reachalmost the same rate as pyruvate oxidation.59$ 6o I n liver 60 and brain 609it is very slow.Various condensative mechanisms have been sug-gested e2, 59, 63, 64$ 6o none of which can yet be said to be convincing as amechanism of acetate metabolism. More recently, F. Lynen 557 65 fromexperiments with impoverished yeast suggested that acetate condenses withoxaloacetate and is then metabolised via the tricarboxylic acid cycle.Thiswould explain the inhibition of acetate oxidation by m a l ~ n a f e , ~ ~ , 60 andmight be capable of application to animal tissues a t least in a modified form.28There is now experimental support for the view that in some animaltissues acetate may be converted into acetoacetate as a first stage in itsaerobic metabolism, and it will be necessary to discuss this before returningthe tricarboxylic route of fatty acid oxidation.Interconversion of Acetate and Acetoacetate.Liver slices fairly readily convert added acetate into acetoacetate andp-hydroxybutyrate 66, 67 in a ratio determined largely by the effect of the53 G.D. Greville, Biochem. J., 1936, 30, 877.54 F. Lynen and N. Neciullah, Annulen, 1939, 541, 203.55 F. Lynen, ibid., 1943, 554, 40.566 T. B. McManus, C. B. Bender, and 0. F. Garrett, J . Dairy Sci., 1943, 20, 13.57 J. A. Dye and R. W. Marstens, Fed. PTOC., 1943, 2, 11.58 J. Barcroft, R. McNally, and A. Phillipson, Nature, 1943, 151, 304.59 K. A. C. Elliott, h1. B. Benoy, and Z. Baker, Biochem. J., 1935,29, 1936; I(. A. C.60 A. Kleinzeller, ibid., 1943, 3'9, 674.61 K. A. C. Elliott, D. B. M. Scott, and B. Libet, J . Biol. Chem., 1942, 146, 251.62 E. Toenniessen and E. Brinkmann, 2. physiol. Chem., 1930, 187, 137; 1938,63 H. Weil-Malherbe, Biochem. J., 1937, 31, 299.64 H. A. Krebs and W. A. Johnson, ibid., p. 772.65 Annulen, 1942, 552, 270.67 M. Jowett and J.H. Quastel, &id., 2143, 2169.66a G. Lusk, J . Biol. Chern., 1921, 49, 452.Elliott, M. E. Greig, and M. B. Benoy, ibid., 1937, 31, 1003.252, 169.86 N. L. Edson, Biochern. J., 1935, 29, 2082DICKENS : THE INTERMEDIARY METABOLISM OF CARBOHYDRATES, ETC. 207state of oxygenation on the cozymase-catalysed P-hydroxybutyrate dehydro-genase system of Green et aE.68 Until recently, opinion was divided as towhether acetoacetate was hydrolysed to acetate before being oxidised.Among those who originally supported this view was A. L. Lehninger,69as bwho demonstrated the chemical and enzymic cleavage to two molecules ofacetate. The yields were small and irregular with animal tissues (kidney,muscle), but in Esch. coli the activity was higher.The isolation fromliver tissue of acetic acid as the 2 : 4-dinitrophenylhydrazide 7O was con-firmed.71 However, W. C. Staclie et aL7, did not observe this hydrolysis inliver slices; it seems too slow in animal tissues to be intermediary inoxidation.Tracer studies with acetate containing isotopic C in the carboxyl haveclearly established the transfer of this C to the acetone compounds formed.73-76Fasted rats fed with this isotopic acetate contained excess 13C in the carboxylof the acetoacetate, while NaH13C0, was not fixed in the acetone compounds.73But the most convincing evidence was provided by similar experiments withcarboxyl-labelled acetate added to tissue slices.74* 75 I n liver it was foundthat 41-45% of the acetoacetate arose from the labelled acetate, the re-mainder being endogenous and accompanied by considerable formation ofacetate from tissue constituents.The respiratory carbon dioxide producedhad approximately the same 13C content as the acetoacetate, indicating thatprobably the whole of the acetate utilized by liver tissue passed through theintermediate stage of acetoacetate. It seems likely that in such reactions" active " acetate, arising oxidatively from acetate, is involved.76 The factthat more of the l3C found its way into the CO,H than into the CO groupof the acetoacetate suggests that the union of two different C, moleculesmight be concerned, one of ordinary acetate and one more reactive, possiblyacetyl phosphate. I n kidney and heart tissue, intermediates did notaccumulate during the oxidation of acetate.In kidney tissue some 13Cpasses into the non-volatile ether-soluble fraction, in conformity with theassumption that the further metabolism of acetate in this tissue passesthrough the tricarboxylic acid cycle, as will now be considered. In hearttissue ketonicsubstances do not appear to be intermediates in acetateoxidation. Evidence is given to show that the results cited above werenot due to fixation of liberated 13C0,.74, 756 8 D. E. Green, J. G. Dewan, and L. F. Leloir, Biochem. J., 1937, 31, 934.6Da J . Biol. Chem., 1941, 140, lxxvi.696 Idem, ibid., 1942, 143, 147.70 R. P. Cook and K. Harrison, Biochem. J., 1936, 30, 1640.7 1 A. L. Lehninger, J. Biol. Chem., 1943, 149, 43.72 W.C. Stadie, J. A. Zapp, junr., and F. D. M'. Lukens, ibid., 1941, 137, 75.73 M. E. Swendseid, R. H. Barnes, A. Hemingway, and A. 0. Nier, ibid., 1942, 142,74 S. Weinhouse, G. Medes, and N. F. Floyd, ibid., 1945, 158, 411.76 G. Medes, S. Weinhouse, and N. F. Floyd, Fed. Proc., 1945,4, 98.78 S. Weinhouse and G. Medes, Abstracts 108th Meeting, Amer. Chem. SOC., p. 47B47.(New York, 1944)208 BIOCHEMISTRY.Oxidative Mechanism of Acetate and Acetoacetate MetabolGm.F. L. Breusch 76a9b and H. Wieland and C. Rosenthal77 have recentlyindependently suggested that acetoacetate condenses with oxaloacetate toform citrate :CH,*CO*CH,*CO,H + H0,C*CO*CH2*C02H + H,O + citric acid + aceticacid (I).CH,*CO*CH,*CO,H + 2H02C*CO*CH2*C02H + H20 -+ 2 citric acid (11).These authors based their theory on the higher yields of citrate found whenthe two keto-acids were added to tissues than with either keto-acid alone.Breusch earlier favoured reaction (I) but later,78 because of the higher yieldsof citrate then obtained, agreed with Wieland and Rosenthal that reaction(11) more correctly represented the course of the condensation, at least foracetoacetate; with higher p-keto-acids the yields were smaller, and areaction of the type; R*CO*CH,*CO,H + H0,CCOGH2*C02H + H,O --+R*C02H + citric acid (111) represents the course of degradation of ap-keto-acid to a fatty acid with two less C-atoms.This would have greatimportance in explaining the fact that acetic acid has not been shown toarise during oxidation of higher fatty acids a t anything approaching the levelexpected from the original p-oxidation theory of K n o ~ p .~ ~ Unfortunately,the evidence presented, particularly by Breusch, is very incomplete, beingbased almost entirely on the yields of citrate obtained by incubation ofmuscle, kidney, heart, or brain (lung or pancreas did not react) withthe various p-keto-acids and oxaloacetate. Nevertheless Breusch hasnamed the condensing enzyme " citrogenase " ; a suggestion rightly con-sidered to be premature by Marti~s,4~ who has, however, been able toconfirm that acetoacetate and oxaloacetate together gave regularly about50% more citrate than either substance alone in presence of ox or pigheart .43Breusch reports the enzyme system to be stable in solution and ex-tractable from tissues by dilute sodium bicarbonate, though destroyed byheat.It is also inactivated by 0*002~-As,0,, but is unaffected by 0.005 M-iodoacetate or fluoride. The pH optimum is " in the alkaline region " 76bor pH 7-5,78 and cat and pigeon tissues form up to 6 mg. citric acid/g. moisttissue/hr. from added p-keto-acid and oxaloacetate. A number of keto-acidsand other substrates were tested in presence of oxaloacetate : acetoacetate,benzoylacetate, and acetonedicarboxylate yielded citrate ; butyrate,crotonate, and p-phenylpropionate did not. a- and y-Keto-acids are stated76@ Science, 1943, 97, 490; 76b Enzymologia, 1944, 11, 169.7 7 Annalen., 1943, 554, 241.7 8 F. L. Breusch and H . Keskin, Enzymologia, 1944, 11, 243.70 W.H. Hurtley, Qua.rt. J . Med., 1915, 9, 301 ; H. D. Dakin, J. Biol. Chem., 1909,6, 373. See also refs. 67, 72DICKENS : THE INTERMEDIARY METABOLISM OF CARBOHYDRATES, ETC. 209to condense with only about one tenth of the rapidity of p-keto-acids. Of alarge number of p-keto-acids tested, some did not react. The kidney tissueof the cat is, according to Breusch, the only tissue with which any considerablecondensation of pyruvate with oxaloacetate occurs, but this is a t variancewith the work of others,sO and like many of Breusch’s statements is notsupported by adequate published experimental evidence.H. Wieland and C. Rosenthal 77 found, in experiments with rabbitkidney, that the oxygen uptake was increased by about 6--12% by theseparate addition of acetoacetate or oxaloacetate, but by more than 40%when both substances were added together.By addition of barium ions 81(excess of magnesium ions has the same effect S2) the further metabolism ofcitrate is inhibited, and Wieland and Rosenthal found amounts of citrate upto 80% of those calculated according to reaction (11) from the amount ofacetoacetate added. These experiments were all performed aerobically withmechanically sliced rabbit kidney. Only a small yield of citrate was obtainedwith either substrate alone. Acetate incubated with kidney and oxaloacetategave only about half the yield obtained from acetoacetate plus oxaloacetate ;hence it was concluded that the metabolism of acetate probably proceeds viaacetoacetate, and not vice versa.Somewhat similar results were obtainedwith ox heart, but the reaction failed in liver tissue. The authors considerthat it cannot be excluded that the whole carbohydrate metabolism, at leastin kidney and heart, may pass through acetoacetate, rather than wiapyruvate, as the stage which condenses with oxaloacetate to form citrate.They suggest (without ezperimental investigation) that if this were so theappearance of acetonic compounds in diabetes might be connected with thelack of the enzyme responsible for the condensation to “ pro-citric acid ” theprecursor of the citrate formed. H. A. Krebs and L. V. Eggleston *& pre-viously suggested that insulin may act catalytically in the tricarboxylicacid cycle, In this connexion it may be pointed out that very recently astriking effect has been reported 83 of hormones in vivo and in vitro on thehexokinase reaction : glucose + adenosine triphosphate --+ glucose 6-phosphate + adenosine diphosphate.This primary reaction in the break-down of glucose or its synthesis to glycogen is inhibited by anterior pituitaryextract, and the resulting inhibition is counteracted by insulin. Yeasthexokinase, unlike that of muscle, liver, kidney, heart, and brain, is notinhibited by pituitary extract. The full publication of these importantobservations is awaited with great interest.H. Wieland and C. Rosenthal 77 assume, on the basis of earlier work 653 81on yeast, that a preliminary condensation of acetoacetate with oxalo-acetate occurs, to form a “pro-citric acid ” (I or 11), which may80 Hallman, Acta physiol.Scund., 1940, 2, Suppl. IV.8 1 R. Sonderhoff and M. Diffner, Annalen, 1938,536,41.82 A. I. Virtanen and J. Sundman, Bwchern. Z., 1942,313, 236.P2fl Biochern. .J., 1938, 32, 913.83 W. H. Price C . F. Cori, and S. P. Colowick, J . Biol. Chem., 1945,160, 633210 BIOCHEMISTRY.possibly itself condense with a second molecule of acetoacetate to yield(111) :HO,C*CH, *C ( OH) CO,H(I.) (" citroylacetic acid ")RO,C.CH,*CO*CH, I---" H0,C*CH2*CO*C0,H+ 1 \ HO,C*CH,*C( OH)*CO,HH0,C*CH,*CO*CH3 % H0,C *CH *C O*CH,(11.) (" a-acetylcitric acid ")HO,C*CH,*CO*CH, -+ (I) --+HO,C*CH,*C( OH)(C02H)*CH2*CO~CH(C0,H)*CH(C0,H)*CH2*C0,Compound (111) might be split as shown by the broken line to give two mols.of citric acid.This would explain why acetate formation was not observed;alternatively the C,-fraction split off from (I) or (11) on hydrolysis might be" active " acetic acid, which would then react differently from the freesubstance.In yeast, possibly a similar condensation of acetate with aldehyde mayoccur, the CH,*CO*CHR*CHO which results corresponding to acetoacetatein the above reactions."The combination of oxaloacetate and acetoacetate is apparently a simpleadditive reaction : yet Wieland and Rosenthal 77 found that oxygen wasnecessary for the formation of citrate in kidney tissue. In nitrogen virtuallyno synthesis occurred. They concluded, therefore, that the enzymicsynthesis was coupled with an aerobic process which is dependent on theoxygen pressure but is otherwise of an unknown nature.Similarly in yeastno citrate was formed from oxaloacetate and acetate except in presence ofoxygen.H. A. Krebs and L. V. Eggleston 84 made almost complete balance sheetsof the metabolite interchange occurring in sheep heart muscle during incuba-tion with acetoacetate. The rate of acetoacetate removal (Qac. ac.) was about15 aerobically and 6 in nitrogen; only the aerobic removal was inhibited bymalonate, indicating that succinic dehydrogenase plays a part in the aerobicprocess only. When fumarate, oxaloacetate, or a-ketoglutarate was addedboth the aerobic and the anaerobic removal of acetoacetate were increased toa similar level, and the malonate inhibition was largely negatived.Virtuallyall the metabolised acetoacetate was recovered as p-hydroxybutyrate,resulting mainly from the dismutations :Acetoacetate + a-Ketoglutarate = p-Hydroxyglutarate + Succinate + CO,Acetoacetate + Malate = p-Hydroxybutyrate + Oxaloacetate.It was concluded that in the experiments of Breusch and of Wieland andRosenthal, described above, the citrate formed arose from oxaloacetate,which added alone is in part reduced and in part oxidised to citrate and othercompounds. When acetoacetate is added, it is partly reduced to (3-hydroxy-(111.) (" citroylcitric acid ")134 Biochem. J . , 1945, 39, 408DICKENS : THE INTERMEDIARY METABOLISM OF CARBOHYDRATES, ETC. 211butyrate at the expense of some reoxidation of malate to oxaloacetate, thusmaking more oxaloacetate available for citrate formation.84I n considering these opposed interpretations, it should be rememberedthat Wieland and Rosenthal specifically stated that their reaction did notoccur anaerobically.Hence it remains to be seen if in oxygen there mightnot be quite a different outcome of experiments of the type made by Krebsand Eggleston. It is true that the latter authors have far more compre-hensive data, and a similar application of the “ balance sheet ” principle toWieland and Rosenthal’s experiments would be highly desirable. Never-theless, the failure of Krebs and Eggleston a43 a5 and of H. Weil-Malherbea6to observe the condensation of oxaloacetate and acetoacetate may prove tohave been due to their adoption of anaerobic conditions and to the use byWeil-Malherbe of hand-cut (and therefore presumably less damaged) kidneyslices, in which material acetoacetate consumption is probably nearlymaximal *7 even without added C,-acids.I n support of the oxidative nature of the condensation of oxaloacetatewith acetoacetate (or a product derived from it oxidatively), are two recentstudies.F. E. Hunter and L. F. Leloir88 found that dog kidney tissueparticles, which did not oxidise citrate, yielded very little citrate upon theaddition of acetoacetate + oxaloacetate, .unless some a-ketoglutarate or asubstance which yields a-ketoglutarate (glutamate or glutathione) wasadded. Citrate then appeared in good yield (about 2 mols. of citrate foreach mol.of acetoacetate metabolised) and the reduction of acetoacetate tohydroxybutyrate accounted for only a small part of the acetoacetate whichdisappeared during the synthesis. I n this system, the simultaneous oxid-ation of a-ketoglutarate is necessary for citrate formation, but the oxidationcan here be either aerobic or dismutative. It was thought that the oxidationof a-ketoglutarate was in some way coupled with the formation of an activeC, intermediate from the acetoacetate, but acetyl phosphate addition didnot yield any citrate.Finally, J. M. Buchanan et u Z . , ~ ~ who used CH3J3C0,H andCH,*13CO*CH2*13C02H to study the intermediate metabolism of thesesubstances in homogenised guinea pig kidney, were able to show that notonly did the components of the tricarboxylic acid cycle greatly stimulate theconsumption of acetoacetate, but the isolated acids (a-ketoghtaric, succinic,fumaric) contained excess of 13C which could not be accounted for by assimi-lation of 13C0,. The amounts recovered showed that the tricarboxylic acidcycle is in fact an important metabolic pathway for the oxidative metabolismof acetoacetate as well as of acetate.These results seem to prove that areaction similar t o that proposed by Wieland and Rosenthal undoubtedlydoes account for a considerable part of the metabolism of these two acidsunder the conditions adopted.Nature, 1944, 154, 209. 86 Ibid., 1944, 153, 435.87 J. M. Buchanan, W. Sakami, S. Gurin, and D. W. Wilson, J. Bwl. Chem., 1946,159, 695.88 Ibid., 1946, 169, 2962 12 BIOCHEMISTRY.In addition, the fact that 90% of the 13C excess is present in the carboxylof a-ketoglutarate which is remote from the keto-group suggests that cis-aconitate or isocitrate, or both, are intermediates, and not a symmetricalmolecule such as citrate.The last therefore arises by a side-reaction,presumably catalysed by aconitase. The authors favour the view thatacetoacetate provides a reservoir of available reactive C, compound,according to the theories already discussed.The Metabolism of Higher Fatty Acids.During the past year important new evidence of the essential correctnessof Knoop’s p-oxidation theory has been obtained by the use of fatty acidscontaining isotopic carbon. At the same time an explanation has beenprovided of many of the diEculties which led to the assumption of alternativepaths,*9 such as multiple alternate o ~ i d a t i o n , ~ ~ ~ 679 72 and w-oxidation,w oracetopyruvate formationYs4 so that at present these theories seem no longeressential at least for liver slices.The puzzling facts that no acetate accumu-lation is demonstrable during oxidation of the higher fatty acids, and thatthe yield of acetonic compounds exceeds that predicted by the classical Knooptheory, are now accounted for by the demonstration that p-oxidation isfollowed by condensation of acetate, or other C, fraction, to form aceto-acetate ; a suggestion previously advan~ed,~la* b but only recently proveddirectly.S. Weinhouse, G. Medes, and N. F. Floyd 92* found that when liver slicesderived from fasting rats were incubated with n-octanoic acid, containingl3C in the carboxyl, the resulting acetoacetate contained excess of 13C equallydistributed between the keto- and the carboxyl group.As the authors state,this seems to be unequivocal evidence that the ketonic compounds areformed by random condensation of pairs of similar C, units arising from thep-oxidation of the fatty acid :CH3*[CH,]4*CO*CH2*C*02H -+ CH3*[CH2],*C02H + CH3*C*0,H2 CH3*C*02H --+ CH,*C*O*CH,*C*O,H.The above experiments do not decide the fate of the n-butyric acid whichremains after splitting off two acetate residues from n-octanoic acid; thiscould be either (A) cleavage into two molecules of acetate followed by theirresynthesis to acetoacetate or (B) direct P-oxidation to acetoacetate.Thiswas settled 93 by similar experiments with carboxyl-labelled n- butyratewhich showed that mainly route (A) was followed, but that to a lesser extentdirect p-oxidation did occur. The butyrate was not diluted by endogenousbutyrate, which is therefore either not formed or else completely oxidised89 See Ann. Reports, 1935, 32, 4 1 4 4 1 7 .90 E. J. Witzemann, “Advances in Enzymology,” Interscience Press, N.Y ., 1942,910 E. M. MacKay, R. H. Barnes, H. 0. Came, and A. N. Wick, J . BioZ. Chem., 1940,916 E. M. MacKay, A. N. Wick, H. 0. C m e , and C. P. Barnes, ibid., 1941,138,63.Ibid., 1944, 153, 689.O3 G. Medes, S.’Weinhouse, and N, F. Floyd, ibid., 1945, 157, 36.2, 266.135, 157.oab Ibid., 1944, 155, 143DICEENS : THE INTERMEDIARY METABOLISM OF CARBOHYDRATES, ETC.213under these conditions. All the excess 13C of the respiratory carbon dioxidecould be accounted for as having been metabolised via the ketonic compounds.To a slight extent butyrate may be rnetabolised by an unknown reactionresulting in the presence of 13.8y0 of the utilised 13C in the residual non-volatilecarbon compounds. Since the two routes of butyrate oxidation discussedabove lead to different distributions of isotopic C, it may be calculated from thedistribution actually observed that about 64-78y0 of the acetoacetate arisesby route (A) (disruptive p-oxidation and resynthesis) and about 22-36% byroute (B) (direct p-oxidation). A less likely possibility is that all the butyratemight first pass through the stage of acetoacetate which then splits into C,fractions, but the interconversion of these into acetoacetate would have to beslow, otherwise all the latter substance would be brought to the same isotopicdistribution ?3When fed together with glucose to rats, propionate and butyrate 94 werestated to yield liver glycogen, while acetate was not, except in so far as itgave rise to carbon dioxide which was assimilated into carb~hydrate.~~The last conclusion is denied by V.Lorber, N. Lifson, and H. G. Wood, whofound after preliminary experiments g6 that by pathways other than carbondioxide fixation the 13C of carboxyl-labelled acetate,97 p r o ~ i o n a t e , ~ ~ orbutyrate 98 enters the glucose molecule of liver glycogen in positions 3 and 4.The same positions are those occupied by fixed carbon of carbon dioxide.99Space does not allow discussion of the synthesis of higher fatty acids looor cholesterol lo1 from acetate, nor can details be included of enzyme systemswhich oxidise fatty acids lo2 possibly viu the acyl phosphate.lo3Similarly, the developments linking the intermediate acids of the tri-carboxylic acid cycle with amino-acid metabolism, by means of transamin-ations and oxidative deamination,l" can only be mentioned here.Butevidence is steadily accumulating to show the participation of these reactionsin the interconversion of amino-acids by animal tissues.F. D.94 But see H. J. Deuel, junr., C. Johnston, M. G. Morehouse, H. S.Rollman, and95 J. M. Buchanan, A. B. Hastings, and R. B. Nesbett, ibid., 1943,150, 413.96 N. Lifson, V. Lorber, and H. G. Wood, Fed. Proc., 1945, 4, 47.O 7 V. Lorber, N. Lifson, and H. G. Wood, J . Biol. Chem., 1945,161,411.98 H. G. Wood, N. Lifson, and V. Lorber, unpublished, cited in ref. 97.g9 Idem, J . Biol. Chem., 1945, 159, 475.loo D. Rittenberg and K. Bloch, ibid., 1944, 154, 311 ; Arch. Biochem., 1945, 4, 101.Io1 K. Bloch, E. Borek, and D. Rittenberg, Fed. Proc., 1945, 4, 84.lo2 See J. M. Muiioz and L. F. Leloir, J . Biol. Chem., 1943,147, 355; 1944,153,53;-4. L. Lehninger, ibid., 1944, 154, 309; 1945, 157, 363; also E. L. Cosby, and J. B .Sumner, Arch. Biochem., 1945, 8, 259.R. J. Winzler, J . Biol. Chem., 1945, 157, 135.lo3 A.L. Lehninger, Zoc. cit., ref. 102.lo4 See P. P. Cohen, Fed. Proc., 1942, 1, 73; A. E. Braunstein and S. M. Bychkov,Nature, 1939, 144, 751 ; Biochimia, 1940, 5, 261 ; A. E. Braunstein and R. M. Asarkh,J. Biol. Chem., 1945,157,421. Cf. M. Blanchard, D. E. Green, V. Nocito, and S . Ratner,ibid., 1944, 155, 421; L. F. Leloir and D. E. Green, Arch. Biochem., 1945, 4, 96; F.Schlenk and A. Fisher, ibid., 8, 337; H. C. Lichstein and W. W. Umbreit, J. Biol.Chem., 1946,161, 311 ; F. Schlenk and E. E. Snell, ibid., 157, 425214 BIOCHEMISTRY,2. BIOCHEMISTRY OF THE ADRENAL CORTEX.In the biochemical section of the Annual Reports the last review con-cerning the adrenal glands appeared in 1936.l It is characteristic of thedevelopment of biochemistry that since that date three reviews of theorganic chemistry of adrenal steroids have appeared 2s 39 and only now doesthe subject return, for review of functional aspects, to the biochemicalsection.The Results of Removal of the Adrenal Glands.For adequate consideration of the action of adrenal steroids, the chiefeffects of experimental removal of the adrenal glands must be briefly reviewed.References to the original literature will be found in recent publica-t i o n ~ .~ ~ 6, 8, 9 3 lo, l 1 3 l2 Although species variations are encountered thefollowing summary of the results of adrenalectomy, based on observationswith the dog, cat, and rat, may be taken as relevant to the more commonlyinvestigated species, though some elasmobranch fishes, and the opossum,exhibit interesting variations from the normal picture.llUnless the contrary is indicated the influence of removal of the wholeadrenal gland (medulla plus cortex) may be attributed largely or solely t oabsence of the cortical portion.Among the most striking effects of adrenalectomy is diminution or dis-appearance of appetite (anorexia).In its turn anorexia may significantlyinfluence metabolic functions, and hi studies on the effects of adrenalectomyit is important to appreciate the possible complications introduced in this way.For instance, restriction in food intake can depress the rate of absorption ofmaterial from the gut and can also reduce the width of the proximal epiphy-seal cartilage in the tibia of young rats, both of which effects also followadrenalectomy.Since the anorexia of adrenalectomy can often be combattedby the administration of sodium chloride, attempts may sometimes thusbe made to dissect the direct from the indirect effects of removal of adrenalhormones.(a) The Metabolism of Electrolyte and Water.-In the dog, death mayfollow adrenalectomy in little more than a week, and the development of thecondition of adrenal deficiency thus induced is associated with important1 C. P. Stewart and J. Stewart, Ann. Reports, 1936,33, 395.2 R. K. Callow, ibid., 1938, 35, 281.3 F. S. Spring, ibid., 1940, 37, 332.5 (a) R. F. Loeb, Bull. N . Y . Acud. Med., 1940,16, 347; (b) idem, Harvey Lectures,1942, 37, 100; (c) idem, “ Glandular Physiology and Therapy,” American Medical Ass.,Chicago, 1942, p.287.6 (a) E. C . Kendall, Arch. Path, 1941, 32, 474; (b) idem, “ Glandular Physiology andTherapy,” h e r . Med. Ass., Chicago, 1942, p. 273 ; (c) idem, Endocrinology, 1942,30,853.7 J. J. P f f i e r , Advances in Enzymology, 1942, 2, 325.13 F. A. Hartman, Endocrinology, 1942, 30, 861.9 (a) D. J. Ingle, ibid., 1942, 31, 419; ( b ) a m , in Amer. Ass. Advancement of10 T. Reichstein and C. W. Shoppee, Vitamins and Hormones, 1943,1,346.11 W. W. Swingle and J. W. Remington, Physiol. Rev., 1944 24,89.l2 L. J. Soffer, J . Mount Sinai Hospital, 1946,11,263.4 Idem, ibid., 1943, 40, 147.Science, Washington, D.C., 1944, p. 83YOUNG : BIOCHEMISTRY OF THE ADRENAL CORTEX. 216changes in the concentration in the body of Na+, a characteristic inorganicconstituent of extracellular fluids, and of K+, a prominent inorganic constitu-ent of the interior of muscle and other cells.Na+ (together with C1-) is lostin excessive amounts in the urine, and the concentration of these ions in thebody fluids (and also in the tissues) falls to a subnormal level. Water thenpasses from the blood into the cells of the body, with the result that the contentof dry matter of the blood rises. At the same time the urinary excretion ofK+ is greatly diminished and K+ therefore accumulates to an abnormaldegree in the tissue fluids. Kidney function is depressed generally and,although Na+ and C1- constitute an exception, the excretion of most urinaryelectrolytes, and often of nitrogenous substances also, is subnormal. Theabnormalities in electrolyte metabolism are initially associated with diuresis ;nevertheless the ability of the animal to excrete administered water may laterbe greatly depressed, and there is usually an exaggerated susceptibility towater intoxication.Oliguria may be a terminal symptom of fatal adrenalinsufficiency.The fall in plasma volume, associated with a passage of water from theblood into the tissues, contributes to a lowering of the blood pressure and adiminution in the rate of blood flow. This in its turn may enhance the failureof the kidney to excrete K', an effect which thus may become exacerbated.Nevertheless the accumulation of K+ cannot be regarded as the sole cause ofdeath, because a rise in blood K+ equal to that found in adrenalectomisedanimals is compatible with life in normal or in treated adrenalectomisedanimals.ll Likewise the depletion of sodium cannot be regarded as the solecause of death from adrenal failure.ll(b) Carbohydrate MetaboEism.-In the adrenalectomised rat the glycogenstores, which may not be unduly low in a well-fed animal, disappear at anabnormally fast rate during a short period of starvation.Anorexia, whichmay be a prominent feature of adrenal insufficiency, contributes greatly tothe depression of glycogen storage, while a diminished formation of sugar fromprotein (see below) conduces to the same end. Glycogen formation fromadministered carbohydrate becomes slow, and subnormal in amount, whilean excessively high respiratory quotient may indicate that an unusuallylarge proportion of the available carbohydrate is undergoing oxidation.Experimental diabetes may be reduced in intensity as the result of removalof the adrenal glands.The hypoglyczmic action of a small dose of administered insulin becomesgreatly exaggerated, and, particularly in the terminal stages of adrenalinsufficiency, a spontaneous fall of blood sugar may occur.Despite theprofound influence of adrenalectomy on the metabolism of glucose andglycogen it is not possible to ascribe the resulting death solely to the abnormali-ties in carbohydrate metabolism.(c) Protein Metabolism.-In adrenal insufficiency protein catabolism isdiminished and consequently there is decreased production of carbohydratefrom protein.It is of particular interest that this is associated with afall in liver arginase activity. Since urinary excretion may be subnormal216 BIOCHEMISTRY.particularly during starvation , the concentration of non-protein nitrogen inthe blood may rise despite the diminished protein catabolism in the tissues.Plasma protein concentration may rise in association with the decrease inblood volume, but the plasma albumin fraction is diminished and the rise intotal plasma protein content is to be ascribed to a predominating increase inthe globulin fraction.(d) Fat MetaboEisrn.-Adrenalectomy has a less clear-cut influence on fatmetabolism than on the metabolisms of carbohydrate and protein.13 Lessfat is stored in the livers of adrenalectomised animals than is usual, and thedevelopment of fatty livers which, in normal animals, follows the adminis-tration of-a high-fat diet and of certain poisonous substances, does not occurin the absence of the adrenal cortex.It is possible that the rate of oxidationof fat is depressed in adrenal insufficiency, but it is difficult to obtain un-equivocal evidence of this. Experimental ketonuria may be diminished inintensity as the result of removal of the adrenal glands, but this effect mayin part be the result of a rise in the kidney threshold for ketonic substances.(e) Resistance to Stress.-The adrenalectomised animal is abnormallysensitive to alterations in environmental conditions, and may die as theresult of changes (rise or fall) in environmental temperature or pressure whichare not fatal to intact animals.Likeyise adrenalectomised animals areabnormally easily killed by many toxic substances, by numerous sorts ofdietary deficiencies, and by many types of experimental “ shock,” e.g.,haemorrhage, surgical trauma, and bacterial infection.The muscles of adrenalectomised rats are particularly easily fatiguedwhen stimulated to activity, this fatigue being associated to some extentwith the development of hypoglyczmia, the excessive diminution in thestores of muscle glycogen, and possibly with circulatory changes, all ofwhich are found in adrenalectomised animals.(f) Sex GZands.-The recognition of a clinical condition in which anadrenal tumour or adrenal cortical hyperplasia is associated with the appear-ance of masculinising features in female patients and, according to somethough not all clinicians, the occasional development of female traits in themale, emphasised the possibility that experimental adrenslectomy mightexert an outstanding influence on the sex glands.Although testicular andovarian degeneration have been described as sequels of adrenalectomy themost striking observations have been in human patients with Addison’sdisease-the condition, in the human being, of adrenal hypofunction. InAddison’s disease the excretion by female patients of androgens (neutral17-keto-steroids) may be subnormal or even nil,149 15, 16, 17 while axillary1s D. J. Ingle, J. Clin. Endocrinol., 1943, 3, 603.14 R. K. Callow, Proc.Roy. SOC. Med., 1938, 31, 841.16 (a) R. W. Fraser, A. P. Forbes, F. Albright, H. Sulkowitch, and E. C. Reifenstein,J . Clin. Endocrinol., 1941, 1, 234; (b) F. Albright, P. H. Smith, and R. W. Fraser,Amer. J. Med. Sci., 1942, 204, 625; (c) F. Albright, Harvey Lectures, 1943, 38, 123.16 0. Wintersteiner, “ Glandular Physiology and Therapy,” Amer. Med. Ass., Chicago,1942, p. 327.17 E. J. Kepler, G. A. Peters, and H. L. Mason, J . Clin. Endocrinol., 1943, 3, 497YOUNG: BIOCHEMISTRY OF THE ADRENAL CORTEX. 217hair, the existence of which is believed to depend on androgens secreted bythe adrenal cortex, is usually lackirig.l5, 16( g ) Miscellaneous Observations.-In adrenalectomised rats the rate ofabsorption of glucose from the gut is depressed; that of long-chain fattyacids is also diminished, but not that of short-chain fatty acids such as butyricacid.The theory of Verzar, that the secretions of the adrenal cortex areessentially concerned in the processes leading to the phosphorylation ofcarbohydrate or fat, was originally based on observations concerning thesubnormal rate of intestinal absorption (presumably through phosphorylatedintermediates) in adrenalectomised animals, but the theory suffered seriousembarrassment with the demoiistration that treatment with sodium chloriderestores the rate of glucose absorption to normal in the adrenalectomisedrat.ll9 l8 Verzar, however, believes that disturbances in the phosphorylationof glycogen in vitro by preparations of muscle from adrenalectomised ratscan be restored by the addition of adrenal cortical steroids, and he maintainshis viewpoint regarding the particular importance of the adrenal cortex inphosphorylation mechanisms.l9 This idea has, however, not gained generalacceptance.20The basal metabolic rate may be initially unchanged but may laterbe diminished in adrenalectomised animals. In rats, cytochrome oxidaseactivity and cytochrome-c concentration may both fall as a result of removalof the adrenal glands.21Chronic adrenal insufficiency inhibits normal growth in the young ratand prevents the normal regression of the thymus gland. Adrenalectomisedmice show a lyrnphocytosis with a decrease in polymorphonuclear lym-phocytes22 and, when exposed to conditions of stress, do not show thelymphocytopenia exhibited by normal mice.23Conditions which modify the Survival of Adrenalectomised Animals.Since the classical work of Swingle and Pfiffner it has been possible toprepare extracts of the adrenal cortex, the frequent parenteral administrationof which allows the adrenalectomised animal to survive indefinitely.It ispossible, however, to prolong the survival of adrenalectomised animals nottreated with adrenal extracts under some conditions, notably by the adminis-tration of a diet high in Na+ and low in K+. Untreated dogs may also surviveadrenalectomy for the period of pregnancy or of pseudopregnancy, while inhibernating animals the season of the year influences the length of survivalafter adrenalectomy, the animals generally surviving the period of torpor.Evelyn Anderson, “ Essays in Biology in Honor of Herbert M.Evans,” California,U.S.A. : Univ. Calif. Press, 1943, p. 33.l9 C. Montigel and F. Verzar, Helv. Physiol. Pharrn. Acta, 1943, 1, 115.*O N. Stillman, C. Entenman, E. Anderson, and I. L. Chaikoff, Endocrinology, 1942,21 S. R. Tipton, ibid., 1944, 34, 181.22 A. White and T. F. Dougherty, ibid., 1945, 36, 16.2s F. Elmadjian and G. Pincus, ibid., 1945, 37, 47.31, 481218 BIOCHEMISTRY.In adrenalectomised cats the administration of certain anterior pituitaryextracts may prolong survival.The Preparation and Properties of Physiologically Active Adrenal Extracts.(a) Assay of Adrenal Cortical Extrack-The above considerationsemphasize the importance of maintaining a strict control of dietary andenvironmental conditions in animals employed for the assay of adrenalcortical substances capable of maintaining the life of the fully adrenalec-tomised animal.The maintenance of the adrenalectomised dog 24 and rat 25in good health have both been employed as a criterion of activity of adrenalextracts, while the maintenance of a normal electrolyte balance in adrenal-ectomised dog has also been utilised.26Since the diversity of the effects of adrenalectomy are paralleled by thevariety of the qualitatively different actions of the substances isolated fromthe gland it is not surprising to find that methods of assay based on criteriaother than that of life maintenance in adrenalectomised animals often fail toyield concordant results. Nevertheless such tests have been of great valuein elucidating the nature of the complex action of crude adrenal corticalextracts.Two such methods of assay of particular importance have been the" Everse-de Fremery " work test,27 based on the height of the contractiveresponse in the stimulated calf muscles of the extract-treated adrenalec-tomised rat, and the " Ingle " work test, which utilises the total amount ofwork the muscle of the trea.ted adrenalectomised rat is capable of yielding onstimulation to exhaustion.2* As will be seen later these two methods of assaydetermine different types of adrenal cortical substances.A widely used method is that based on the ability of adrenal preparationsto protect the adrenalectomised rat against the otherwise lethal effects of alow environmental temperature ; 29 this method is proving of particular valuefor the assay of adrenal substances in urine.Another useful method utilizesthe ability of adrenal extracts to raise the liver glycogen content of fastingadrenalectomised or normal rats.30 The polarographic estimation of adrenalsteroids, in which no biological test is necessary, may become of especialimportance,31 while colorimetric methods of assay are also being developed.32J. J. Pfiffner, W. W. Swingle, and H. M. Vass, J . BWZ. Chem., 1934,104, 701.26 G. F. Cartland and M. H. Kuizenga, Anzer. J . Physiol., 1936,117, 678.28 (a) G. W. Thorn, L. L. Engel, and H. Eisenberg, J. Exp. Med., 1938, 68, 161;21 J. W.R. Everse and P. de Fremery, Acta Brev. Need., 1932, 2, 152.28 (a) D. J. Ingle, Amer. J . Physiol., 1936, 116, 633; ( b ) idem, Endocrinology, 1944,*@ (a) G. Widstrom, Acta Med. Scund., 1935, 87, 1; ( b ) H. Selye and V. Schenker,Proc. SOC. Exp. BWZ. Med., 1938, 39, 518.(a) R. M. Reinecke and E. C. Kendall, Endocrinology, 1942,31, 573 ; (b) idem, ;bid.,1943, 32, 605; (c) H. V. Bergman and D. Klein, ibid., 1943, 33, 174; (d) R. E. Olson,S. A. Thayer, and L. J. Kopp, ibid., 1944, 35, 464; ( e ) R. E. Olson, F. A. Jacobs,D. Richert, S. A. Thayer, L. J. Kopp, and N. J. Wade, ibid., 1944, 35, 430.( b ) G. W. Thorn and L. L. Engel, ibid., 1938,68, 299.34, 191.s1 J. K. Wolfe, E. B. Hershberg, and L. F. Fieser, J . Bbl. Chem., 1940, 136, 653.32 N.C. Talbot, A. H. Saltzman, R. L. Wixom, and J. K. Wolfe, ibid., 1946,160, 635YOUNG: BIOCHEMISTRY OF THE ADRENAL CORTEX. 219Among the tests for adrenal cortical substances which have been adaptedfor the purpose of assay are the inhibition of the hypoglycmnic action ofadministered insulin in normal or adrenalectomised starving animals,33 theexacerbation of an existing diabetes in partially depancreatisedthe production of glycosuria in the normal intact rat,35 and the enhancementof the depressed glycosuria in adrenalectomised-phloridzinised rats.36(b) The Isolation of “ Life Maintaining ” Adrenal Cortical Ster-oids.’, 37, 38-In the review the term “ life maintaining,” applied toadrenal substances, connotes ability of the substance, on repeated parenteraladministration in suitable dosage, t o prolong indefinitely and in good healththe life of an adrenalectomised animal.Although the methods employed inthe preparation of such active adrenal steroids vary substantially, certaincommon principles underlie most of the methods in use. Preliminaryextraction of fresh whole adrenal gland with ethanol or acetone is followedby removal of the solvent by low-temperature distillation. The activematerial is then extracted from the aqueous residue by benzene, chloroform,or other fat solvent. Further purification often depends on the fact that inthe distribution of an active extract between ether, benzene, or light petro-leum on the one hand, and aqueous solvents on the other, the distributioncoefficient of the active material is 1 to 3 or 4 in favour of the aqueousphase. Traces of adrenaline or of adrenaline decomposition products areremoved by fractionation processes employing weakly acidic or alkalineextractants. The neutral water-soluble material obtained as the result ofthese manipulations constitutes the whole adrenal cortical extract oftenemployed clinically.Further fractionation with neutral organic solvents such as ethyl acetateor benzene yields a variety of crystalline products.Interaction with sub-stances which condense with ketones (e.g., Girard’s reagent) yields productsfrom which active crystalline substances may be obtained by fractionalhydrolysis with acid. Chromatographic fractionation of acetyl derivatives,followed by hydrolysis under mild conditions (e.g., aqueous methanolicpotassium bicarbonate at 20’) of the separated acetyl derivatives has beenextensively and successfully employed by Reichstein and his colleagues.1°33 ( a ) H. Selye and C.Dosne, Proc. SOC. Exp. Biol. Med., 1939, 42, 680; ( b ) J. F.Grattan and H. Jensen, J . Biol. Chem., 1940,135, 511 ; (c) J. F . Grattan, H. Jensen andD. J. Ingle, Amer. J . Physiol., 1941, 134, 8.34 (a) C. N. H. Long, E. G. Fry, and K. W. Thompson, ibid., 1938,123, 130; ( b ) D. J.Ingle, Proc. SOC. Exp Biol. Med., 1940,44, 176; idem, Amer. J . Physiol., 1941,132,670;( c ) E. C. Kendall, Endocrinology, 1943, 30, 853.35 ( a ) D. J. Ingle, ibid., 1941, 29, 649; (b) idem, Amer. J . Physiol., 1941, 133, 337P;( c ) D. J. Ingle, R.Sheppard, J. F. Evans and M . H. Kuizenga, Endocrinology,1945, 37, 341.36 B. B. Wells and A. Chapman, Proc. Staff Meetings Mayo Clin., 1940, 15, 493.37 ( a ) M . H . Kuizenga and G. F. Cartland, Endrocrinology, 1939, 24, 526; ( b ) M. H.Kuizenga in “ The Chemistry and Physiology of Hormones” Amer. A s s . Advancerncnt ofScience, Washington, D.C., 1944, p. 57.38 M. H. Kuizenga, J. W. Nelson, S. C. Lyster, and D. J. Ingle, J . Biol. Chem., 1945,160, 16220 BIOCHEMISTRY.Whatever methods of fractionation are employed there is obtained aseries of crystalline physiologically active steroids, numerous inactivecrystalline substances, and a syrup (" amorphous fraction ") which maypossess much of the total physiological activity present at this stage butwhich has so far failed to yield crystalline material.Altogether 27 crystalline steroids of known constitution have beenobtained from adrenal tissues.listed 21 which had beenisolated by 1938.R. K. CallowTable I gives an additional six.TABLE I.Steroids Isolated from the Adrenal Cortex since 1939.Alphabeticaldesignationby ReichsteinSubstance. et aE.l0 Isolators. Remarks.Ad-Pregnene-20 : 21-diol-3 : 1 l-dione T T. Reichstein andJ. von EuwssA4-Pregnene-17(p) : 20 : 21-triol- U T. Reichstein andJ. von Euw 40A4-Androstene-3 : 17-dione I J. von Euw and Androgenic. Pos-T. Reichstein 41 sibly a decom-position pro-duct of (IV).aEZoPregnane-3(p) : 11(p) : 17(/l) : 21- V J. von Euw and Stereoisomer at C,tetrol-20-one T.Reichatein 42 of Reichstein'sA substance.1°Oestrone - D. Beall O3 Oestrogenic.A4-Pregnene- 17( 8) -01- 3 : 20-dione - J. J. Pfiffner and Weak androgen.(1 7-hydroxyprogesterone, VIII) H. B. North44 No progesta-3 : 11 -dionetional activity.(c) Physiologically Active Adrenal Steroids.-Since a t least six crystallinesteroids extracted from the adrenal gland (seven if progesterone be included)are active in prolonging the life of the adrenalectomised animal, and, sinceno single known substance combines all the recognised types of physiologicalactivity possessed by adrenal extract, a term such as " the adrenal corticalhormone " is at present otiose.The chemistry of the six adrenal steroids active in prolonging life (I-VI)has recently been adequately re~iewed.~, *, lo, 37 Three of them have beenprepared artificially (" partially synthesised ") from other naturallyoccurring steroids by T.Reichstein and his colleagues. 1 l-Deoxycorti-costerone (V), in the form of its C,, acetate, has been a commercial productfor 7-8 years 2, 3, 41 lo7 3' while recently the partial syntheses of ll-de-hydrocorticosterone (111) 45 and of corticosterone (I) have also beenaccomplished.T. Reichstein and J. von Euw, Helv. Chim. Acla, 1939, 22, 1222.40 Idem, ibid., 1941, 24, 2473.I1 5. von Euw and T. Reichstein, ibid., 1941, 24, 879.p 2 Idem, ibicl., 1942, 25, 988.43 D. Beall, Nature, 1939, 144, 76; J. Endocrinol., 1940, 2, 81.44 J. 5. Pfiffner and H. B. North, J. Biol. Chem., 1940, 132, 459; 1941, 139, 855.45 A.Lardon and T. Reichstein, Helv. Chim. Acta, 1943, 26, 747.4 6 J. von Euw, A. Lardon and T. Reichstein, ibid., 1944, 27, 1287YOUNG : BIOCHEMISTRY OF THE ADRENAL CORTEX. 221Because of its high activity the amorphous fraction is of particular interest.I n physiological activity it more closely resembles (V) and (VI) than (I) andother active steroids carrying an oxygen atom at C,,, but its life-maintainingactivity is much greater than that of (V), though the latter is the most active of(1.)Corticosterone(Ad-Pregnene-ll( 9 ) : 21-diol-5: 20 dione)(111.)1 1 -Dehydrocorticosterone(Ad-Pregnene-21-01-3 : 11 : 20-trione)CH2.0H(V-)1 1-Deoxycorticosterone(A4-Pregnene-21-ol-3 : 20-dione)(11.)17-Hydroxycorticosterone(A4-Pregnene-11(p) : 17@) : 21-triol-3 : 20-dione)7H2.DHW.)17-Hydroxy- 11 -dehydrocorticosterone(A4-Pregnene-17(,9) : 21-diol-3 : 11 : 20trione)7H2*OH(VI.)17-Hydroxy - 1 1 -deoxycorticosterone(Aq-Pregnene-l7(B) : 21-diol-3 : 20-dione)the isolated crystalline compounds in this respect.Elementary analysis ofthe amorphous fraction suggests the presence of C2,0, steroids [cf. CZlO, for(I) and (VI) and C210, for (V)]. In keeping with its higher oxygen contentthis fraction is more soluble in water, but unlike (V) it loses activity ontreatment with acidic or alkaline reagents, being unstable even towardspotassium bicarbonate. Moreover, its physiological activity differs signi-ficantly in some respects from that of both (V) and (I), and there can be n222 BIOCHEMISTRY.doubt that this fraction contains active substances of hitherto unrecognizedconstitution.Adrenal glands from different species of animal yield different pro-portions of the various active fractions.Table I1 gives the approximateyields of the active crude and crystalline fractions from ox, pig, and sheepadrenal glands.TABLE 11.Approximate Yields from 1000 kg. of Whole Adrenal Gland.7, 10,37,38Yield (mg., =% x 10’) fromadrenals of-Fraction or substance.A. Soluble in benzene : little soluble in water1. Crude crystalline mixture of (I + 111) ......2. Crystalline (I) .......................................3. Crystalline (111) ....................................4. Crystalline (V) ....................................5.Crystalline (VI) ....................................B. Soluble in water; little soluble in benzene(I1 + IV + amorphous fraction) ...............1. Crude crystalline mixture of (I1 + IV) ......2. Crystalline (11) ....................................3. Crystalline (IV) ....................................4. Amorphous fraction ..............................Neutral fraction soluble in ethyl acetate .........(I + I11 + v + VI) ..............................ox.21,1005,8001,570672336271310,6501,3401684502,460Pig.28,90016,8003,360Sheep.16,6006,0001,57011,5203,8001,3704901,8009,6401,79009001,340Administration of Adrenal Steroids.For experimental and clinical use the active steroids are usually con-verted into esters, which are more active on parenteral administration thanare the free substances.Thus 11-deoxycorticosterone (V) is now employedalmost without exception as its C21-acetate. With corticosterone thediethylacetate (presumably a t C21) is four times as active as the freesubstance.4’Corticosterone (I) and 11 -dehydrocorticosterone (111) are as effectiveorally in the rat as they are by parenteral administration; 48 this is also trueof the amorphous fraction, but 1 l-deoxycorticosterone is much less effectiveby mouth than it is by subcutaneous injection.489 49 There is evidence that11-deoxycorticosterone is destroyed in the gut of the rat.49The most economical way of using 1 1-deoxycorticosterone acetateclinically is by the subcutaneous implantation of tablets of the crystallinecompound.50Physiological Action of Adrenal Steroids.Five of the methods described above (p.218) which have been developedfor the assay of adrenal preparations have also been applied extensively to47 M. H. Kuizenga and G. F. Cartland, Endocrinology, 1940, 27, 647.M. H. Kuizenga, J. W. Nelson and G. F. Cartland, Amer. J. PhysioE., 1940,130, 1.4B (a) H. Fraenkel-Conrat, Proc. SOC. Exp. Biol. Med., 1942, 51, 300; (b) R. A. c l e ghorn, A. P. W. Clarke, and W. F. Greenwood, Endocrinology, 1943, 32, 170.so (a) G. W. Thorn, S. S. Dorrance, and E. Day, Ann. I n t . Med., 1942,16, 1053; (b)D. M. Dunlop, Brit. Med. J., 1943, i, 557; (c) E. P. McCullagh, L. A. Lewis and%’. L.Shively, J.Clin. Endocrinol., 1943, 3, 493YOUNG : BIOCHEMISTRY OF THE ADRENAL CORTEX. 223individual crystalline adrenal steroids and their derivatives. The fivemethods are based on (a) ability to maintain the adrenalectomised dog orrat in good health (“ life-maintenance ” test) ; 24 25 26 (b) the “ Everse-deFremery ” work test ; 27 (c) the “ Ingle ” work test ; 28 (d) ability to influencecarbohydrate metabolism (i.e., to raise the liver-glycogen content 30 ordiminish the insulin sensitivity 33 of starving rats, or to exert a “ diabeto-genic ” action in partially depancreatised 34 or normal 35 animals) ; ( e )activity in influencing the retention of Na+ and C1- in the normal animal.51In Table 111, which is based on the mean of the results in the literature, theactivities of six crystalline adrenal steroids, and of the amorphous fraction,are compared with respect to results with these five methods of assay.FromTable I11 the following conclusions may be drawn : (1) the data with the “ life-TABLE 111.Comparative Physiological Activities of Adrenal Preparations.(The figures, which are based on the mean of the data in the literature, indicatethe order which the seven preparations occupy with respect to activity in any giventest, the most active substance being designated 1, and the least active 7.)“ Life-main-tenance ”Substance. test.(a) Corticosterone group.Corticosterone (I) 317-Hydroxycortico- 41 l-Dehydrocortico- 4sterone (11)sterone (111)corticosterone (IV)sterone group.corticosterone (VI)17-Hydroxy- 1 1 -dehydro- 4(b) 11 -Deoqcortico-11 -Deoxycorticosterone ( V ) 217-Hydroxy- 1J -deoxy- 7(c) Amorphous fraction I“ Everse-deFremery ”work test.36?5132‘ Ingle ”worktest.3141665Influence Naf and C1-on carbo- retentionhydrate in normalmetabolism.dog.3 31 nil(excretion)31 nil(excretion)5 16 ?? 2maintenance ” test approximately parallel those with the (‘ Everse-deFremery ” work test; (2) results with the “ Ingle ” work test parallel thoseconcerning influence on carbohydrate metabolism; (3) the presence of anoxygen atom (hydroxyl or ketonic oxygen) a t C,, of the steroid nucleusgreatly increases activity both with respect to the “ Ingle ” work test andwith respect to influence on carbohydrate metabolism ; (4) the presence of atertiary hydroxyl group a t C,, diminishes activity in the “ life-maintenance ”test and in the Na+ and C1- retaining tests.In (11) and (IV) potency toinduce retention of Na+ and C1- is not only lost but is replaced by ability tofacilitate the excretion of these ions by the kidney of the intact dog.61 (IX)and (X), produced artificially by the removal of the elements of water from6 1 (a) G . W. Thorn, L. L. Engel, and R. A. Lewis, Science, 1941, 94, 348; ( b ) M. J.Clinton and G. W. Thorn, ibid., 1942, 96, 343; ( c ) M. Clinton, jun., G. W. Thorn,H. Eisenberg, and K. E. Stein, Endocrinology, 1942, 31, 678224 BIOCHEMISTRY.cortic~sterone,~~ are active in the " Everse-de Fremery " test, (X) beingcomparable in activity with (V), while (IX) is only 4-i as active as (V).52Another artificial product (XI), in which the C,, hydroxyl of corticosteronehas been replaced by a hydroxyl group at Cl2,= has less potency in the" Everse-de Fremery " test than corticosterone, and exerts no obviousinfluence on carbohydrate metabolism.63Me Me I ICO(VII.) (VIII.)Progesterone 17-Hydroxyprogesterone( A4-Pregnene-3 : 20-dione) (A4-Pregnene- 17(p)-ol-3 : 20-dione)7H2*OH vH2.0Hco coMe :\?$/--0 A//\/ OH\/\(IX.) (X-1Anhydrocorticosterone (1 ) Anhydrocorticosterone (2)( A4: 9-Pregnadiene-2 l-ol- 3 : 20-dione) ( A4:l1-Pregnadiene-21-01-3 : 20-dione)(XI.1(A4-Pregnene-12(p) : 21-diol-3 : 20-dione)Progesterone (VII) is active in maintaining the life of the adrenal-and induces retention of Naf52 C.W. Shoppee and T. Reichstein, Helv. Chim. Acta, 1943, 26, 1316.6t H. G. Fuchs and T. Reichstein, ibid., 1943, 26, 511.5' R. Gaunt, W. 0. Nelson, and E. Loomus, Proc. SOC. Ezp. Biol. Med., 1938,39, 319.56 (a) J. A. Wells and R. R. Greene, Endocrinology, 1939, 25, 183 ; (b) F. E. Emeryectomised ferret,54 rat,55 mouse,s6 andand P. A. Greco, ibid., 1940, 27, 473.C. A. Pfeiffer and C. W. Hooke, Amer. J. Physwl., 1940,131,441.6 7 (a) E. L. Corey, ibid., 1940, 129, P.340; (b) idem, ibid., 1941, 132, 446YOUNG : BIOCHEMISTRY OF THE ADRENAL CORTEX. 225and C1- in the adrenalectomised rat.58 It has, however, no obvious activityin the “ Ingle ” test (rat) s9 and in the anti-insulin test in the same anima1,32bbut raises the blood-sugar level and liver-glycogen content of the fastingnormal ferret,60 of the young rabbit,61 and of the adrenalectomised ~at.~’bThus in some species progesterone reacts physiologically like those adrenalsteroids possessing an oxygen atom a t Cll.17-Hydroxyprogesterone (VIII)exerts no obvious effect in the (‘ Ingle ” work test lo and fails to exhibitactivity also in the “ life-maintenance ’’ test in rats.lO Here again theintroduction of the tertiary hydroxyl group a t C1, diminishes “ life-main-tenance ” activity.It is not possible to give here details of the active doses of all the sub-stances in all the various tests, but average figures from the literature % 379 48, 62may be mentioned.E’or maintenance in good health the adrenalectomiseddog requires, by the subcutaneous route, about 0.15 mg./kg./day of corti-costerone, about 0.015 mg. /kg./day of 11 -deoxycorticosterone, and about0-005 mg. /kg./day of 11-deoxycorticosterone acetate. For the rat thecorresponding figures are about 3-5 mg. /kg./day, 0.80 mg./kg./day, and 0.55mg./kg./day respectively, although there is no good agreement in theliterature concerning such data for the rat.On the basis of the results discussed above it is convenient to divide theactive adrenal steroids into two groups; the first (the “ corticosteronegroup ”) having an oxygen atom at Cll, and the second (the “ deoxycorti-costerone group ”) having no oxygen atom in this position. The membersof the first group are particularly potent in the “ Ingle ” work test and ininfluencing carbohydrate metabolism generally, while those of the secondexert little influence on carbohydrate metabolism but are highly active in the“ life-maintenance ” test and in bringing about retention of Na+ and C1-.The amorphous fraction falls physiologically into the “ deoxycorticosteronegroup .”Since most, if not all, of the many recognised effects which follow removalof the adrenal cortical tissues are neutralised by the administration of adrenalextracts, it is possible here t o consider only a few of the more outstandingfeatures of the results of administration of excess of adrenal steroids toadrenalectomised or to normal animals.M-Substances of the deoxycorti-costerone group, together with the amorphous fraction, are the most activein this connexion.The retention of water and of Na+ and C1- under theinfluence of adrenal substances, together with the excretion of K+, are prob-ably the result of an action on the kidney tubules.65 The loss of K+ from(a) Water and EZectroZyteI8 G. W. Thorn and L. L. Engel, J . E x p . Med., 1938, 68, 299.sv D. J. Ingle, Proc. SOC. E x p . Biol. Med., 1940, 44, 450.61 A. B. Corkill and J. F. Nelson, Aust. J. Exp. Biol. Med. Sci., 1941, 19, 211.62 H. L. Mmon, Endocrinology, 1939, 25, 405.R. Gaunt, J. W. Remington, and E. Edelmann, ibid., 1939, 41, 429.G . W. Thorn, J. Mount S i n a i Hosp., 1942, 8, 1177.J. A. Anderson, J. Clirt. Endocrinol., 1943, 3, 615.86 R.Chambers and G. Cameron, Amer. J. Physiol., 1944,141, 138.REP .-VOL . XLII. 226 BIOCHEMISTRY.the body after repeated large doses of deoxycorticosterone acetate (1-4 mg .in the rat) may be sufficient to bring about cardiac lesions.66 The retentionof water produced initially by adrenal steroid administration is associatedwith an increase in plasma v0lume,~7 and the blood pressure may rise.68Prolonged treatment may result in p ~ l y u r i a , ~ ~ which appears to be a com-pensatory mechanism for the excretion of the retained electrolytes and water.Posterior pituitary extract and adrenal preparations to some extent appear toact antagonistically with respect to water elimination by the kidney.70(b) Metabolism. 71-Substances of the corticosterone series are here mostactive.The administration of suitable adrenal extracts leads to a rise in theliver glycogen content of starving normal rats,30, 71, 72 of starving hypophy-sectomised rats,73 and in the isolated perfused liver.7* Likewise a diabeticcondition is induced or exacerbated in a partially depancreatised rat,34 in anormal rat with an adequate food and in a hypophysectomised-phloridzinised rat.36 The control of glycosuria in the diabetic conditioninduced by treatment with adrenal steroids may require the administrationof large doses of in~ulin.~, 35When the fasting rat (normal or adrenalectomised) is treated withadrenal steroids it is primarily the glycogen stores of the liver which rise,although the muscle glycogen may secondarily increase.71 The control ofmuscle glycogen level appears to be directly influenced by anterior pituitaryextracts 75s 76 and only indirectly by the secretion of the adrenal cortex, thelatter acting with the intermediation of liver glycogen.When adrenal steroids induce a rise in the glycogen stores, or induce orexacerbate a diabetic condition,34, 35, 36* 71, 72, 73 the nitrogen excretion of thetreated animal rises, and it is to be assumed that glyconeogenesis fromprotein is a contributary factor in the accumulation of the extra glycogen or66 (a) D.C. Darrow and H. C. Miller, J . Clin. Invest., 1942,21,601; ( b ) D. C. Damow,e7 M. Clinton, jun., and G. W. Thorn, Johns Hopkins Hosp. Bull., 1943,72, 255.68 ( a ) G. A. Perera, A. I. Knowlton, A.Lowell, and R. F. Loeb, J. Amer. Med. ASSOC.,1944, 125, 1030; (b) J. R. Leatham and V. A. Drill, Endocrinology, 1944, 35, 112; (c)G. A. Perera, J. Amer. Med. Assoc., 1945, 129,537; ( d ) N. M. Gaudino, Rev. SOC. argent.Biol., 1944, 20, 470.69 (a) M. G. Mulinos, C. L. Spingarn, and M. E. Lojkin, Amer. J. Physiol., 1941,135,102; ( b ) J. W. Ferrebee, D. Parker, W. H. Carnes, M. K. Gerity, D. W. Atchley, andR. F. Loeb, A m r . J . Physiol., 1941,135, 230; ( c ) C. A. Winter and W. R. Ingram, ibid.,1943,139, 710; (d) A. S. Harned and W. 0. Nelson, Fed. Proc., 1943, 2, 19.70 ( a ) J . A. Anderson and W. R. Murlin, J. Pedkzt., 1942, 21, 326; (b) R. Gaunt,Trans. N.Y. A d . Sci., 1944, 6, 179; ( c ) ident, Endocrinology, 1944, 34, 400.7 1 (a) C.N. H. Long, B. Katzin, and E. G. Fry, ibid., 1940, 26, 309; (b) C. N. €I.Long, Cold Spring Harb. Symp. Qwtnt. Biol., 1942, 10, 91 ; ( c ) idem, Endocrinology, 1942,30, 870; ( d ) J. Tepperman, F. L. Engel, and C. N. H. Long, {bid., 1943,32,373.73 R. G. Sprague, Proc. Stafs Meet. Mayo Clin., 1940, 15, 291.78 C. N. H. Long and B. Katzin, Proc. SOC. Exp. Biol. Med., 1938, 38, 516.74 ( a ) E. L. Corey and S. W. Britten, Amer. J. Physiol., 1941, 131, 783; ( b ) S. W.76 L. L. Bennett and R. Z . Perkins, Endocrinology, 1945,36, 24.' 6 W. H. Price, C. F. Cori, and S. P. Colowick, J. Bbl. Chem., 1945,160, 633.Proc. SOC. Exp. BWE. Med., 1944,55, 13.Britten and E. L. Corey, ibid., p. 790YOUNG: BIOCHEMISTRY OF THE ADRENAL CORTEX. 227glucose. Nevertheless in carefully controlled experiments it has becomeclear that if the classical data relating to the conversion of protein to carbo-hydrate (100 g.of protein yield 58 g. of carbohydrate) be adopted, it is notpossible to account for all of the extra carbohydrate which appears as theresult of adrenal treatment.6, 9, 3% ~9 359 7' It appears probable that theadrenal steroids diminish the rate of utilization of carbohydrate by theperipheral tissues % 34, 7 8 9 79 and that this is an important factor in the antag-onism to the hypoglycaemic action of insulin exerted by many adrenalsteroids. Since the respiratory quotient is depressed as the result of theadministration of adrenal steroids 9, 34) 35, 71, 78, 79 it appears probable thatthe depression of carbohydrate oxidation thus induced is associated with anincreased combustion of fat.C.N. H. Long 71 has suggested that adrenal substances may stimulatethe conversion of tissue proteins to amino-acids, the hepatic deamination ofthe latter giving rise to the accumulated glycogen. It is perhaps of particularsignificance that D. J. Ingle,gl 35 has recently found that when an adrenal steroiddiabetes is induced in normal rats the administration of large doses of insulin,sufficient to bring the hyperglycaxnia and glycoauria under control, does notreduce urinary nitrogen excretion to the normal level. It therefore seemsunlikely that the enhanced rate of formation of carbohydrate from protein,induced by pituitary substances, can be secondary to inhibition of carbo-hydrate oxidation brought about by such treatment.If the adrenal cortical secretions directly stimulate the breakdown ofintracellular protein it is apparently paradoxical that the presence of theadrenal cortex or of its secretions is necessary for the manifestation of thefull growth-promoting activity of anterior pituitary extract,*O particularlyin view of the fact that the administration of excess of adrenal steroids (Iand IV) inhibits the growth of young *l It may be pointed out, how-ever, that the incorporation of exogenous amino-acids into the tissues may beassisted by a limited stimulation of the catabolism of tissue protein,B2although undue enhancement of protein catabolism would obviously preventor depress growth.C.N.H. Long 71 has pointed out that, if the primary action of adrenalsteroids is to catalyse the breakdown of protein in the cell, the action of thesesteroids on electrolyte balance might follow as secondary effects, sinceintracellular proteolysis would liberate K+ previously held in association withnegatively charged protein ions 83 and the excretion of the K+ by the kidneymight be expected to bring about the retention of Na+ in order to maintainosmotic pressure. Nevertheless, as this author himself points out, deoxy-77 G. W. Thorn and M. Clinton, J . Clin. Endocrinol., 1943,3, 335.78 Q. W. Thorn, G. F. Koepf, R. A. Lewis, andE. F. Olsen, J . Clin. Invest., 1940,19,70 J. A. Russell, Amer. J. Physiol., 1943, 140, 98.8o E. G. Fry and C. N. H. Long, Ann.N . Y . A d . Sci., 1943,43, 383.82 F. G. Young, Biochem. J., 1945, 39, 515.83 P. J. Boyle and E. J. Conway, J . Physwl., 1941,100, 1.813.B. B. Wells and E. C. Kendall, Proc. StaJ Meet. Mayo Clin., 1940, 15, 324228 BIOCHEMISTRY.corticosterone, which has little influence on the metabolism of carbohydrateand protein, is particularly active with respect to electrolyte balance andthere can be little doubt that this adrenal steroid exerts a direct action on thekidney. We must therefore assume that the main action of the deoxy-corticosterone series of steroids is complementary to that of the corticosteroneseries, the action of the latter on tissue proteins resulting in the liberationinto the intercellular fluids of K+, the excretion of which by the kidney isfacilitated by the steroids of the deoxycorticosterone series.It should benoted that steroids of the corticosterone series strikingly increase the activityof the liver with respect to the action of the enzyme arginase 84 which isintimately associated with the disposal of the products of the deaminationof amino-acids. Whether this is a direct action of the steroids, or an indirectone, mediated by the products of proteolyeis in the peripheral tissues, is notcertain. There can be little doubt, however, that the substances of thecorticosterone series exert more than one type of activity in the body, sinceas well as stimulating the catabolism of protein, with consequent accumu-lation of glycogen in the liver, they inhibit the action of insulin and theoxidation of carbohydrates in the muscular tissues.(c) Action on Lymphoid Tissue and Antibody Titre.-It has long beenrecognized that the thymus fails to degenerate to the normal extent in animalssuffering from adrenal deficiency, and it has now been shown that the adminis-tration of adrenal steroids of the corticosterone series causes rapid regressionof the thymus in rats,85 together with an absolute lymphopenia.86 Since anincreased production of antibodies has been demonstrated in animals treatedwith adrenal extract, but not with deoxycorticosterone acetate, it seemsprobable that it is adrenal substances of the corticosterone series that controlthe release of antibody from the lymphocytes.86> 87(d) Influence on Resistance to Stress.-The results of the majority ofinvestigations designed to reveal any activity of adrenal preparations ininducing increased resistance to stress in normal animals have been negative.Nevertheless the resistance of normal rats to peptone shock,80 to reducedatmospheric and to high environmental temperat~re,~~ can beraised by treatment under some conditions with adrenal preparations, butonly in the experiments concerning the effects of high environmental tempera-ture did deoxycorticosterone acetate exert any significant action.s0Control of the Secretory Activity of the Adrenal Cortex.The activity of the adrenal cortex is under the control of the anterior lobeof the pituitary gland through one of its secretions, adrenocorticotropin.slH. Fraenkel-Conrat, M.E. Simpson, and H. M. Evans, J . Biol. Chem., 1943,147,99.D. J. Ingle, Proc. SOC. Exp. Biol. Med., 1940, 44, 174.T. F. Dougherty and A, White, Endocrinology, 1944, 36, 1.(a) T . F. Dougherty, A. White, and J. H. Chase, Proc. Soc. Exp. Biol. Med., 1944,D. J. Ingle, Amer. J . Physiol., 1944, 142, 191.G. W. Thorn, 35. Clinton, B. M. Davis, and R. A. Lewis, Endocrinology, 1945,36,381.V. Hermanson and F. A. Hartman, Amer. J . Physiol., 1946,144, 108.H. G. Swam, Physiol. Rev., 1940, 20, 493.56, 28; ( b ) T. F. Dougherty, J. H. Chase, and A. White, ibid., 1945, 58, 135YOUNG : BIOCHEMISTRY OF THE ADRENAL CORTEX. 229Most of the effects of the administration of adrenal extracts can be reproducedin animals with intact adrenal glands by the administration of pituitaryadrenocorticotropin.Atrophy of the adrenal glands occurs in normal rats(but not in hypophysectomised animals) as the result of the administration oflarge doses of adrenal cortical extract,92 and it seems probable that thesecretions of the adrenal cortex act on the anterior pituitary gland to depressthe release of adrenocorticotropin. In this way a simple automatic controlof adrenal activity is achieved.There is no evidence that the secretion of adrenal steroids is under directnervous control,93, 94 but the intravenous infusion of physiological amounts ofadrenaline induces an immediate, lasting, and substantial increase in the basaloutput of adrenal cortical substances in the eviscerated dog or cat.94 Thusnervous influences may directly affect the secretion of adrenal corticalsteroids via the secretion of adrenaline by the adrenal medulla.The Biological Precursors of Adrenal Xteroids.For some years it has been assumed, without direct evidence, thatadrenal steroids, together with other physiologically active substancesderived from a perhydrocyclopentenophenanthrene nucleus, are formed inthe body from cholesterol.Since, however, i t has been known for evenlonger that the animal body can synthesize cholesterolg5 there seems noobvious reason why it should not also synthesise steroid hormones directly.Recently the biological conversion of cholesterol to pregnanediol has beenclearly demonstrated in a pregnant woman,96 so it is clear that shorteningof the hydrocarbon side-chain a t C17 of the cholesterol molecule can takeplace in vivo.C. N. H. Long and his colleagues 97 have shown that in therat a single dose of pure adrenocorticotropin reduces the adrenal cholesterolcontent to *-$ of its original value within 3 hours. Later (24 hours after theadministration) the adrenal cholesterol content is normal or high.97, 98Adrenaline also induces a rapid fall of adrenal cholesterol 99 and a fall alsooccurs under the influence of many different types of stress.lo0¶ lol Since theadministration of adrenocorticotropin and adrenaline, and the imposition ofconditions of stress, are all circumstances in which the rate of secretion ofadrenal steroids is greatly enhanced there can be little doubt that in such92 D.J. Ingle, Arner. J. Physiol., 1938, 124, 369.O3 W. E. MacFarland, J . Exp. Zool., 1944, 95, 345.R4 ( a ) M. Vogt, J . Physiol., 1944, 103, 317; ( b ) idem, ibid., 1945, 104, 60.s5 (a) H. J . Channon, Biochem. J., 1925, 19, 424; ( b ) K. Bloch and D. Rittenberg,O6 K. Bloch, ibid., 1945, 157, 661.O 7 G. Sayers, M. A. Sayers, E. G. Fry, A. White, and C. N. H. Long, Y a l e J . of Biol.O 8 R. A. Carreyett, Y. M. L. Golla, and M. Reiss, J . Physiol., 1945, 104, 210.99 C. N. H. Long and E. G. Fry, Proc. SOC. Exp. BioZ. Med., 1945, 59, 67.loo (a) N. V. Bekauri, A. A. Danilov, and E. A. Moisseev, Compt. rend. Acad. Sci.U.R.S.S., 1944, 43, 238; ( b ) L. Levin, Endocrinology, 1945,37, 34; (c) G. Sayers, M. A.Sayers, Tsan-Ying Liang, and C.N. H. Long, ibid., 1945, 37, 96.J . Biol. Chern., 1942, 143, 297.and Med., 1944, 16, 361.lol G. Popjak, J . Path. Bact., 1944, 56, 485230 BIOUHEMISTRY .instances the rapidly disappearing cholesterol is converted, at least in part,to adrenal steroids. It is of particular interest that under some conditionsthe disappearance of adrenal cholesterol is accompanied by the appearanceof substances in the adrenal tissue which react with phenylhydrazine.101The possibility that aldehydic or ketonic substances are formed intermediarilyin the conversion of adrenal cholesterol to adrenal steroids must be thusconsidered.Another interesting possibility is that the androgens secreted normallyby the adrenal cortex are by-products in the conversion of cholesterol tocorticosterone and similar substances.16 The increased production ofandrogens in the adrenal-genital syndrome l6 might then be considered toresult from a pathological derangement of the normal process.On the otherhand the isolation from urine of androstane-3 : ll-diol-17-one (XIII) (orpossibly the corresponding 1 l-keto-compound) lo2 suggests the possibilitythat urinary androgens may arise as degradation products of adrenal steroidsof the corticosterone series. In any case the estimation of urinary androgens(neutral 17-keto-steroids) is of particular value clinically as an indication ofnormal or abnormal functioning of the adrenal cortical tissues.l4, l5, lo3Me(XII.) (XIII.)Pregnanediol Androstane-3(a) : 1 l(fi)-diol-l7-one(Pregnane-3(a) : 20(a)-diol)The Fate of Secreted Adrenal Androgens.Secreted adrenal steroids are partly destroyed in the tissues,104 partlyexcreted in the urine in a physiologically active form,lo5 and partly excretedin the urine as inactive catabolic products.ls9 lo6 The urine from patientsloa H.L. Mason, J. Biol. Chem., 1945, 158, 719.LOa (a) N. H. Callow, R. K. Callow, and C. W. Emmens, J. Endocrinol., 1945, 2, 88;(b) N. B. Talbot and A. M. Butler, J. Clin. Endocrinol., 1942, 2, 724; ( c ) G. P ~ C U E ,ibid., 1943, 3, 301 ; ( d ) M. M. Hoffman, McGiZZ Med. J., 1944, 13, 177; (e) N. H. Callowand A. C. Crooke, Lancet, 1944, 248,464.l o 5 (a) E. H. Venning, M. M. Hoffman, and J. S. L. Browne, J. BWZ. Chem., 1943,148, 455; (b) R. A. Shipley, R.I. Dorfman, and B. N. Horwitt, Amer. J. Physiol., 1943,139, 742; (c) E. H. Venning, M. M. Hoffman, and J. S. L. Browne, Endocrinology, 1944,35, 49; ( d ) R. I. Dorfman, B. N. Horwitt, R. A. Shipley, and W. E. Abbott, ibid., 1944,35, 15; ( e ) R. I. Dorfman, B. N. Horwitt, and R. A. Shipley, ibid., 1944,35, 121.lo6 (a) W. K. Cuyler, C. Ashley, and E. C. Hamblen, ibid., 1940, 2'9, 177; (b) U.Westphal, 2. physiol. Chem., 1942, 273, 13; (c) M. M. Hoffman, V. E. Kazmin, andJ. S. L. Browne, J. Bwl. Chern., 1943, 147, 259; (d) W. R. Fish, B. N. Horwitt, andR. I. Dorfman, Science, 1943, 97, 227 ; ( e ) B. N. Horwitt, R. I. Dorfman, R. A. Shipley,and W. R. Fish, J. Biol. Chm., 1944,155,213.lo* M. Vogt, J. Physwl., 1943, 102, 341MORGAN THE SPECIFIC ELOOD-GROUP SUBSTANCES.231who have had surgical operations and in whom the secretion of adrenalsteroids is much enhanced is surprisingly rich in substances possessingadrenal steroid activity. 106The administration of deoxycorticosterone is followed by the excretion ofpregnane-3 : 20-diol (XII) in the urine in many species.lo6 If the reductionof the primary alcoholic group a t C,, in deosycorticosterone precedes thechanges in ring A of this compound, progesterone will be formed inter-mediarily in the transformation to pregnanediol. Such a process mightaccount for the slight progestational activity of deoxycorticosteroneacetate.106a, lo7F. G. Y.3. THE SPECIFIC BLOOD-GROUP SUBSTANCES.At the beginning of this century Landsteiner and his pupils discoveredthat human bloods can be divided into four main serological groups, A, B,AB, and 0, based on the presence or absence of the agglutinable substancesA and B within the erythrocyte.The occurrence or absence of these specificsubstances in the red-cells was determined by means of agglutination testsemploying the agglutinins anti-A and anti-B which occur naturally in theserum of group B and A persons respectively. For many years group 0erythrocytes were considered to be cells devoid of the agglutinable sub-stances A and B and were recognised by the absence of these biologicallyimportant factors and not by the possession of a specific and characteristicagglutinogen of their own. Heredity studies of the blood groups demon-strated that the A- and B-factors were each inherited as simple Mendeliandominants and, according to Bernstein's theory, which postulates theexistence of three allelic genes, A, B, and 0, and is now generally accepted,erythrocytes of the genotype 00 could possess st specific O-factor corres-ponding to the A and B agglutinogens.The recognition of the O-factorhad to await the discovery of a reliable and specific anti-0 serum, for thisagglutinin occurs only rarely in man. The modern technique of bloodtransfusion that has evolved from Landsteiner's original discovery is nowregarded as an established and safe medical procedure, but until quiterecently practically nothing was known as to the nature of the substancespresent in the erythrocytes belonging to the different blood groups which wereresponsible for the characteristic and specific immunological behaviour of theerythrocytes.The reason is in no small measure due to the difficulty ofobtaining, in quantities suitable for chemical investigation, the specific A-, B-,and O-substances. An observation by F. Schiff,l that commercial peptonecontained a blood group A-factor and could serve as a readily availablesource of this blood group substance, enabled a chemical investigation to belo' (a) J. van Heuverswyn, V. J. Collins, W. L. Williams, and W. U. Gardner, Proc.SOC. E x p BioZ. Med., 1939, 41 552; ( b ) J. M. Robson, J . Physiol., 1939, 96, 21P; (c)J. H. Leatham and R. C. Crafts, Endocrinology, 1940,27 283; ( d ) R. D. Lawrence, Brit.Med. J., 1943, i, 12; (e) G.W. Raleigh and H. F. Philipsborn, jun., Arch. Path., 1944,87, 213.Zentr. Bakt. Par., 1930 98, 94232 BIOCHEMISTRY.undertakem2 B. Brahn, F. Schiff,and F. Weinman ; and F. Schiff showed that commercial pepsin was alsoa good source of the blood group A-substance. A particularly rich supply ofthis material was discovered in hog gastric mucin 6s during a study of theglycoproteins occurring in gastric mucosa, and a polysaccharide that possessedintense A-activity and contained N-acetylglucosamine and galactose inequimolecular quantities was isolated but was considered to be only about75% pure because of its positive Ehrlich diazo-reaction. K. Landsteinerand R. A. Harte extended the examination of the active polysaccharideand showed that it contained a component rich in amino-acids.With aview to obtaining results which could be employed subsequently as a basisfor the elaboration of a method for the isolation of the blood group sub-stances from human erythrocytes, tissues, and fluids, W. T. J. Morgan andH. K. King9 devised two methods by which the A-substance could be re-covered from hog gastric mucin without employing conditions of acidity andalkalinity too far removed from neutrality and which could be carried outa t normal temperatures. The undegraded A-substance obtained by thesemethods shows a high viscosity (yj 2.8 a t a concentration of 0-57< in saline).A typical analysis of the substance gave C, 45; H, 6.0; N, 6.0; Ac, 10%.Examination of the material at pH 4.0 and 8.0 in the Tiselius electrophoresisapparatus showed the preparation to be essentially homogeneous.Hydr-olysis of the A-substance with mineral acid gives about 50% of reducing sugars,30-33% of glucosamine, 5.0% of a-amino-N (van Slyke), and 2.5% ofm-amino-acid-N.8,In most of the earlier work the activity of the A-substance isolated fromdifferent sources was determined by the hsmolytic inhibition test, with theresult that any destruction of another important serological property of thenative A-substance, its power to inhibit iso-agglutination, was overlooked,It was observed,s however, that treatment of the crude A-substance withformamide a t 150" for 1 hour gave a purified material which showed only afraction of its original power to inhibit iso-agglutination, whereas its capacityto inhibit the hzemolysis of sheep cells by an anti-A rabbit serum was actuallyincreased beyond the original value.These and other observations indicatedthat if the specific blood group substances are to be obtained in their " native "state a carefully controlled isolation procedure, such as one of those describedby W. T. J. Morgan and H. K. King,g must be employed. The A-substanceprepared by these methods is similar in composition to that described byK. Landsteiner and R. A. Harte but differs from it in a number of importantphysical and immunological properties. The material has high serologicalactivity as determined by the inhibition of iso-agglutination, shows the highviscosity that is so characteristic of native gastric mucin, and forms anSubsequently, F.Schiff and G. Weiler ;W. F. Goebel, J. Exp. Med., 1938, 68, 221.Klin. Woch., 1932, 11, 1592.K. Landsteiner and H. W. Chase, J . Exp. &led., 1936, 63, 813.K. Meyer, E. Smyth, and J. Palmer, J . Biol. Chem., 1937,119, 73.J . Exp. Med., 1940, 71, 651.Biochem. Z . , 1931, 235, 454.6 Deut. med. Woch., 59, 199.9 Biochem. J., 1943, 37, 640MORGAN : THE SPECIFIC BLOOD-GROUP SUBSTANCES. 233elastic gel on the addition of borate buffer at pH 8.5. These properties arerapidly lost on heating in neutral, acid, or alkaline solution a t 100". Treat-ment of the active substance with O.O~N-N~,CO, a t 100" for a few minutescauses the complex to break up in such a manner that at least two-thirds of i tpasses through a cellophane membrane.The amino-acid components arelargely retained by the membrane and are still associated with a carbohydratestructure.lo The indiffusible material is hvorotatory -20°), electro-phoretically homogeneous, and practically non-reducing, and shows only asmall fraction of the original serological activity. The diffusate, on the otherhand, shows strongly reducing properties without further acid hydrolysis andgives an immediate colour with Ehrlich's reagent. The development of animmediate colour with p-dimethylaminobenzaldehyde under these conditionssuggests that an oxazole ring structure is formed in a similar manner to thechange which is known to occur when iV-acetylglucosamine and other N -derivatives of glucosamine are similarly treated with dilute alkali.11-14 Itseems probable that the alkali-labile linkages in the A-substance are thoseglycoside linkages which join C atom 1 of the N-acetylglucosamine to othercomponents of the A-complex.The extreme alkali lability of the substanceis a characteristic property and was not encountered during the examinationof several complex polysaccharide substances which are known to containhexosamine molecule^.^ M. Stacey l5 has stated that the A-substanceisolated from commercial pepsin contains d-mannose and Z-fucose in additionto d-galactose and AT-acetylglucosamine, but details of this work are not yetpublished.A preliminary qualitative examination l6 of the amino-acids present inthe A-substance has been made by the chromatographic method describedby R.Consden, A. H. Gordon, and A. J. P. Martin.17 At least 15 amino-acids are present as components of the complex and it seems probable thatthreonine and hydroxyproline are present in higher concentrations than arenormally found in proteins. The isolation ofthreonine from A-substance has been described by K. Freudenberg, H. Walsh,and H. Molter.lsSeveral workers 19-25 have attempted to isolate the blood group10 H. K. King and W. T. J. Morgan, Biochenz. J., 1944,38, X.l 1 W. T. J. Morgan and L. A. Elson, ibid., 1034, 28, 988.l2 Idem, ibid., 1936, 30, 909.13 Idem, Chem. and Ind., 1938, 1191.l 4 T. White, J., 1940, 428.l6 i V . T. J. Morgan, Brit. Med. Bull., 1944, 2, 165.1 7 Biochent.J., 1944, 38, 224.19 F. Schiff and L. Adelsbergor, 2. Immun. Forsch., 1924, 40, 335.20 B. Brahn and F. Schiff, Klin. Woch., 1926, 1455.21 K. Landsteiner and J. van der Scheer, J . Exp. Med., 1925, 42, 123.23 H. Dold and R. Rosenburg, K l i n . Woch., 1928, 394.23 C. Hallauer, Schweiz. med. Woch,., 1929, 121 ; 2. Immun. Forsch., 1929, 63, 287;i&id., 1932, 76, 119; ibid., 1934, 83, 114.24 F. Ottensooser, ibid., 1932, 77, 140.Cystine appears to be absent.l5 Chem. cincl l l i d . , 1943, 110.Is Naturwiss., 1942, 30, 87.Biochimia, 1940, 5, 547.H 234 BIOCHEMISTRY.agglutinogens from human erythrocytes by extracting them with simpleaqueous reagents or with organic solvents, but without success. Substanceshave been frequently obtained, however, which though devoid of antigenicpower show intense blood group specificity.C. Hallauer 23 described theisolation of specific non-antigenic substances from all three (A, B, and 0)blood groups. Apart from the conclusion based on a few qualitative teststhat the specific substances are largely carbohydrate, the chemical nature ofthe preparations was not determined. The composition of the materialisolated, which is very similar for each of the blood group substances, was C,43-46; H, 7-1-85; N, 6.8-7-9; P, 15-21 %. The high phosphorus content,if present in organic combination, is of considerable interest, but no furtherdetails have yet been given. More recently A. V. Stepanov, A. Kusin, Z.Makajeva, and P. Kosjakov 25 have obtained similar materials fromerythrocytes.The possibility of obtaining the specific blood group substances from othersources has been investigated.E. Witebsky and N. C. Klendshoj 26 haveisolated a material showing group B specificity from gastric juice. Thesubstance contained 1.5% of N and gave 75% of reducing sugars after acidhydrolysis. A similar polysaccharide substance was also obtained 27 bythese workers from the gastric juice of secretors (persons who secrete theirblood group substance in a water-soluble form) belonging to group 0. Theserologically active material contained 2.8% of N and gave 40% of reducingsugars after acid hydrolysis. Owing to lack of material a more detailedexamination of the specific substances was not possible. As a result of thedetection of the specific blood group substances in human urine,28 attemptshave been made 29 to isolate the blood group substances from this source.Apolysaccharide material which contained galactose, aminohexose, and 10%N-acetyl was isolated and shown to possess intense blood group A-specificity.Treatment of the polysaccharide with alkali to remove some of the acetylgroups resulted in the loss of serological activity whereas re-acetylation bymeans of keten restored the A-specificity.Specific blood group substances showing A-, B-, and O-specificity have beenobtained from human saliva.30 The material obtained from secretors be-longing to groups A, B, and 0 showed little difference chemically and con-tained about 5.5% of N, 26y0 of a-amino-acid N, and 23% of glucosamine;it gave 4 5 4 8 % of reducing sugars after acid hydrolysis.An A-specificsubstance obtained from horse saliva appeared to be similar to the humanA-su bstance .The concentration of the blood group substances in saliva, and gastricjuice is high when compared31 with that of many other tissue fluids andsecretions, but even here the active substance represents only a small part of2 6 J. Exp. Med., 1940, 72, 663.2 8 K. Yosida, 2. ges. exp. Med., 1928,63, 331.29 K. Freudenberg and H. Eichel, Annalen, 1934, 510, 240; ibid., 1935, 518, 97.30 K. Landsteiner and R. A. Harte, J. Biol. Chern., 1941,140, 673.31 A. S. Weiner " Blood groups and blood transfusion " (1943).27 Ibid., 1941, 73, 655MORGAN : THE SPECIFIC BLOOD-GROUP SUBSTANOES. 235the total solid matter of the secretions which are, moreover, diiZcult toobtain in useful quantities.The examination 32 of pseudo-mucinousovarian cyst fluids obtained from secretors revealed that these fluids are aconvenient and potent source of the group specific substances A, B, and 0.The A- and O-substances were found 1% 33 to be closely similar in chemicalcomposition in spite of the different serological specificity. Analysis showedthem to contain C, -5; H, 6.6-6.8; N (Dumas), 5.9-6.2%. Bothsubstances behaved as did the hog mucin A-substance on treatment withEhrlich’s reagent after they had been heated with dilute alkali for a fewminutes. The production of a reddish-purple coloration from A-, B-, and 0-substances under these conditions appears to be a characteristic property ofthis biologically important group.The removal of the amino-acids from the specific blood group substanceswith retention of full specificity has not yet been accomplished, and it seems,probable that the con6guration of the amino-acid-containing componentcontributes to, or is entirely responsible for, the serological specificity ofthe blood group substances.The products of acid hydrolysis were verysimilar for A- and O-substances lo, 33 and about 46% of the total N is presentin a-amino-acids and at least 81 yo in a-amino-groups. Both substances gaveabout 33% of glucosamine and 48% of reducing substances after hydrolysiswith dilute acid.The immunological properties of the A-, B-, and O-substances have beenstudied in some detail,349 353 363 379 39 and their conversion to active antigeniccomplexes is reported.36, 379 38 A method €or the quantitative determinationof the amount of blood group agglutinin in normal and immune sera has beendescribed .40It has been recorded 273 329 419 42 that saliva and gastric juice obtained fromsecretors belonging to groups A and B inhibit the action of anti-0 agglutininon human 0 cells.The purified A-substance from hog gastric mucin is soactive in this respect that the O-substance itself is not noticeably more activein inhibiting the action of anti-0 serum on 0 cells.33 The results of theseexperiments indicate that the homogeneous A-substance possesses both A-and O-specificity. The A-substance isolated from ovarian cyst fluid, on theother hand, fails to inhibit the agglutination of group 0 cells by anti-0 serumand therefore possesses A-specificity only.No significant differences in the,3a W. T. J. Morgan and R. van Heyningen, Brit. J. Exp. Path., 1944,25, 6.33 Idem, andM. B. R. Waddell, ibid., 1945,26, 387.34 E. Witebsky, N. C. Klendshoj, and C. McNeil, Proc. Sac. Exp. B i d . Med., 1944,55,35 A. S. Weiner, R. Soble, and H. Polivka, ibid., 1945, 58, 311.38 W. T. J. Morgan and W. M. Watkins, Bvit. J . Exp. Path., 1944, 25, 221.37 S. G. Rainsford and W. T. J. Morgan, Lancet, 1946, 154.38 W. T. J. Morgan, Brit. J . Exp. Path., 1943, 24, 41.*9 Idem and W. M . Watkins, ibid., 1945, 26, 247.40 E. A. Kabat and A. E. Bezer, J . Exp.Med., 1945,82, 207.4 1 H. Sasaki, 2. Immun. Forsch., 1932, 77, 101.4 1 F. Schiffand H. Saeaki, Klin. Woch., 1932,11, 1426.167236 BIOCHEMISTRY.chemical composition of the A-substances isolated from hog mucin orovarian cyst fluids has yet been reported. It will be of considerable interestto know whether, in the A-substance of animal origin, it is the amino-acid-containing component or the polysaccharide that is responsible for the0 -specificity.During the last few years there has been a very rapid increase in know-ledge of the chemical and immunological properties of the specific bloodgroup substances. As yet, however, we know nothing of the chemical natureof the M and N agglutinogens and of the recently discovered Rhesus group ofblood group factors.An almost inexhaustible field of immunochemicalinvestigation on the different blood group and tissue antigens awaitsexploration.W. T. J. M.4. HYALURONIC ACID AND HYALURONIDASE.K. Meyer and J. W. Palmer reported the isolation from vitreous humorof a sulphur-free polysaccharide which contained a uronic acid, an amino-sugar, and possibly a pentose. Somewhat later 2, the same polysaccharidewas obtained from umbilical cord. This material contained 3.2% N, 11.5%Ac, and 45% hexuronic acid; it gave viscous aqueous solutions and yieldedreducing sugar after acid hydrolysis equivalent to 62.2% glucose and 40.3%hexosamine. The equivalent weight was 441. The amino-sugar wasisolated and identified as glucosamine hydrochloride. Oxidation of thepolysaccharide gave saccharic acid, which was isolated as acid potassiumsalt and identified by its crystal habit and by formation of the typicalthallium salt.Mucic acid was not found. The sugar acid is, therefore,glucuronic acid and not galacturonic acid. The analytical figures for thepolysaccharide acid, which was later called hyaluronic acid, agree closelywith those calculated for an anhydride of acetylhexosamine and hexuronicacid containing 2 or 3 molecules of water. In the presence of variousproteins the hyaluronic acid is precipitated from solution by acetic acid as a“mucoid,” similar in many ways to the mucoids obtained from naturalsource^.^ Hyaluronic acid has also been isolated from Group A and Chzemolytic streptoc~cci,~ from synovial fluid,6 from fowl sarcoma,’ and fromSkin.81An electrophoretic examination lo$ l1 of synovial fluids and vitreous bodyhas revealed that the hyaluronic acid present is not combined with protein1 J .BWZ. Chem., 1934,107, 629.‘I C. T. Morner, 2. physiol. Chem., 1894,18, 233.Ibid., 1936, 114, 689.K. Meyer, Symposia on Quantitative Biology, 1938, VI, 91.P. E. Kendall, J. W. Palmer, and.M. Heidelberger, J . BWZ. Chem., 1937, 118, 61.K. Meyer, E. M. Smyth, and M. H. Dawson, ibid., 1939,128, 319.E. A. Kabat, ibid., 1939, 130, 143.A. Claude, PTOC. SOC. Exp. Biol. Med., 1940, 43, 684.K. Meyer, J. Biol. Chem., 1940, 138, 491.lo H. Hesselvik, 2. physiol. Chem., 1938, 254, 144.l 1 G. Blix, Actaphyswl. Scad., 1940, 1, 29MORGAN : HYALURONIC ACID AND HYALURONIDASE.237but most probably exists as a salt with inorganic bases. The results of aninvestigation on the molecular shape and size of native hyaluronic acid havebeen published by G. Blix and 0. Snellman,12 who considered carefully theobservations of earlier workers on the preparation of undegraded hyaluronicacid and, in view of the degradation brought about by mild oxidants,13carried out the isolation procedure in an atmosphere of nitrogen. The Nvalues of 12 preparations of sodium hyaluronate from vitreous humor variedbetween 3-01 and 3.47 yo. The uronic acid content showed wider variation ;from 42.7 to 49.7%. The S content of the different preparations was usuallyless than 0.1 yo. Optical examinations for investigating the streaming doublerefraction and viscosity of the material were carried out in a Kundt’s 14, l5rotation apparatus with an inner rotating cylinder. It has been shown thatfor particles of high polymers, whose length is very much greater than theirthickness, the change in the angle of extinction with the velocity gradientenables values for the length of the particles to be obtained which agreewith those obtained from ultracentrifugation data.The relative viscosityof sodium hyaluronate is markedly influenced by electrolytes,16, 175 l* a valueof 9-45 for a 0.15% solution in water falling to 2.69 in O-lON-NaC1.ll Thehyaluronate solutions show a positive double refraction of flow, are poly-disperse, and possess an average particle length of about 4800 A.for materialobtained from vitreous humor and synovial fluid. Lower values, from 1000-2000 A., were obtained for preparations made without the exclusion of air.The greatest particle lengths, about 7000 A,, were recorded for hyaluronateobtained from umbilical cord. Values of this order are almost beyond theupper limits that can be determined by the apparatus employed; neverthe-less it seems probable that minimum molecular weights of the native hyal-uronates are of the order 200,000--500,000. The viscosity and birefringenceof hyaluronic acid dissolved in 0-1N-NaOH decrease a t room temperature.The particle length of the. alkali-degraded material was estimated a t about1300 A., a value, assuming an unbranched chain, corresponding to a mole-cular weight of 50,000.The same preparation was examined at a concen-tration of 0.25% for sedimentation and diffusion constants, and from thedata obtained (S = 1-78 x and D = 3.75 x lo-’) the average mole-cular weight was estimated as about 37,000. Blix and Snellman concludethat hyaluronic acid in its native state has a long chain structure and a mole-cular weight of 200,000--500,000 and that the difference in chain lengthfound in material obtained from different tissues indicates that the hyaluronicacid exists in its native state in different degrees of polymerisation. Althoughthe results are not incompatible with the presence of short side chaiiis, thesedimentation and diffusion constants do not support the idea of a branched12 Arkiv Kemi, Min.GeoE., 1945, 19, 1.13 B. Skanse and L. Sundblad, Acta physiol. Scand., 1943, 6, 3.14 0. Snellman and Y. Bjornstahl, Kolloid Beih., 1941, 52, 403.15 A. L. von Muralt and J. T. Edsall, J. Biol. Chem., 1930, 89, 315, 351.16 J. Madinaveitia and T. H. H. Quibell, Biochem. J., 1940, 34, 625.17 W. van B. Robertson, M. W. Ropes, and W. Bauer, J. Biol. Chem., 1940,133, 261,18 D. McClean, Biochem. J., 1941, 35, 159238 BIOCHEMISTRY.chain structure for hyaluronic acid. It has been shown that the action ofascorbic acid on hyaluronic acid is catalysed by copper and that this actioncan be inbibited by sodium diethyldithiocarbamate. The action of reducingagents 2o on hyaluronic acid and the influence of some environmental condi-tions 21 on the activity of hyaluronidase are recorded.K.Meyer, R. Dubos, and E. M. Smyth22 first reported the hydrolyticaction of enzymes obtained from pneumococcus on hyaluronic acid isolatedfrom vitreous humor, umbilical cord, and streptococcus. Enzymes were alsoobtained from culture filtrates of CZ. wekhii 1 7 9 23 and from group A haemo-lytic streptococci which hydrolysed hyaluronic acid with the formation ofabout 70% of the theoretical reducing power calculated from the N-acetyl-glucosamine and glucuronic acid content of the hyaluronic acid preparationand expressed as equivalents of glucose. Similar observations were madeusing partially purified enzymes.18924Some years before hyaluronic acid was discovered a number of investi-gations concerned with the capacity of a substance in testis extract, and incertain bacterial filtrates, to increase tissue permeability 259 269 27 were made,the results of which have contributed considerably to later studies whichhave dealt with the action of various enzyme preparations on hyalur*onicacid.E. Chain and L. A. Duthie 28 were the first to demonstrate that testisextracts and other preparations which contain “ spreading or diffusing factor ”decrease the viscosity of synovial fluid and vitreous humor and liberatereducing substances, and as a result of these observations suggested that“ spreading or diffusing factor’’ is probably identical with the mucinase(hyaluronidase) which hydrolyses the viscous polysaccharides in these fluids.Quantitatively good agreement was found when spreading activity andhyaluronidase activity of testis and leech extracts 29 were compared.Bacterial filtrates, especially those from CZ.wekhii and the pneumococcusand certain snake venoms,30 showed a somewhat. bigger spread in the skinthan would have been expected from the hyaluronidase activity, butChain and Duthie consider that this inconsistency is accounted for bythe fact that the injection of toxic bacterial filtrates and snake venomsis always followed by considerable oedema, due to capillary damage.Furthermore, since the spread in the skin caused by hyaluronidase can19 A. Pirie, Brit. J . Exp. Path., 1942, 23, 277.20 C. W. Hale, Biochern. J., 1944, 38, 362.21 Idem, ibid., 1944, 38, 368.23 K. Meyer, G. L. Hobby, E. Chaffee, and M.H. Dawson, J . Exp. Med., 1940, 71,24 K. Meyer, E. Chaffee, G. L. Hobby, andM. H. Dawson, ibid., 1941,73,309.25 F. Duran-Reynals, Compt. rend. SOC. Biol., 1929, 99, 6 ; J . Exp. Med., 1929,50, 327; D. C. Hoffman and F. Duran-Reynals, ibid., 1931,53,387; F. Duran-Reynals,ibid., 1933, 58, 161 ; ibid., 1939,69, 69.22 J . Biol. Chem., 1937, 118, 71.137.z 6 D. McClean, J . Path. Bact., 1930,33, 1045; 1931,34,459; 1936,42, 477.27 J. Madinaveitia, Bwchem. J., 1938, 32, 1806; 1939, 33, 347, 1470.2 8 Nature, 1939, 144, 977 ; Brit. J . Exp. Path., 1940, 21, 324.2o A. Claude, J . Exp. Med., 1937,66, 363.30 G. Favilli, Nature, 1940, 145, 866MORGAN : HYALURONIC AUID AND HYALURONIDASE. 239be influenced by non-specific irritants, it need not be represented correctlyby the viscosimetric determination of hyaluronidase.The degree of hydro-lysis of hyeluronic acid was determined by measuring the liberation of reducingsubstances and of N-acetylglucosamine and by the fall in viscosity. Otherworkers,31 however, consider it is not justifiable to assay skin-diffusing factorsby merely measuring their hyaluronidase activity. Another method ofassaying hyaluronidase, which depends on the destruction by the enzyme ofthe power of a substrate-protein complex to form a typical mucin clot on theaddition of acetic acid, has been developed. The conclusion is reached thatall three methods of assay, (a) diffusing activity, ( 6 ) viscosimetry, and ( c )mucin clot prevention, measure the activity of the same agent.l7? 327 33Guinea pigs can be used in place of rabbits for assaying hyaluronidaseactivity.34 The reduction of the viscosity of hyaluronic acid and the liber-ation of reducing substances and N-acetylglucosamine by bacterial enzymescan be completely neutralized by appropriate antisera which also inhibitdiffusion in the skin.18The results of a more detailed study of the action of partially purifiedhyaluronidase preparations obtained from leeches, bull testes, and culturefiltrates of CZ.welchii have recently been published.35 The leech hyaluroni-dase, acting on hyaluronic acid obtained from vitreous humor at 37" and pH4.6, gave 26% reduction, calculated as glucose by the method of Hagedornand Jensen. The same enzyme acting on hyaluronic acid derived from thecapsule of group A hzmolytic streptococci 36 (a substance considered to beidentical with the material obtained from vitreous humor) gave 50% reduction,corresponding to the amount expected on the assumption that the hyaluronicwas broken down to disaccharide units. On the other hand, hyaluronic acidderived from both these sources gave 70% reduction after hydrolysis withhyaluronidase derived from pneumococci.The purified hyaluronidaseobtained from CZ. welchii gave 60% of reducing substances when acting onsynovial fluid hyaluronic acid, and yielded hydrolysis products which gave areddish-purple colour with p-dimethylaminobenzaldehyde reagent after theyhad been kept at room temperature with dilute alkali. The reactive substancesgave negative reactions for glycuronic acid and were shown to be mono-saccharides, one of which behaved as if it were N-acetylglucosamine while theother was absorbed much more strongly on charcoal than N-acetylglucos-amine and contained 3.4% of N.The hydrolysis products arising throughthe action of leech and partially purified testicle hyaluronidase on theother hand gave a positive test for glucuronic acid and consisted of oneor more oligo-saccharides which show a strong absorption on charcoal andare not eluted by ephedrine. By the action of another enzyme in testiculars1 J. Madinaveitia, A. R. Todd, A. L. Bacharach, and M. R. Chance, Nature, 1940,3a C. V. Seastone, J . Exp. Med., 1939,70, 361.33 D. McClean, Biochern. J., 1943, 37, 169.34 J.H. Humphrey, ibid., p. 177.35 L. Hahn, Arkiv Kemi, Min. Geol., 1945, 19A, 1 ; 21A, 1.36 G. K. Hirst, J . Exp. Med., 1941, 73, 493.146, 197240 BIOCHEMISTRY.preparations the oligosaccharide could be hydrolysed to monosacchar-ides. The products obtained from hyaluronic acid by means of testishyaluronidase, but not those derived by means of leech hyaluronidase,behaved on treatment with dilute alkali a t room temperature like the materialderived by the action of Cl. welchii hyaluronidase, and gave with p-dimethyl-aminobenzaldehyde reagent a strong reddish-purple colour. It appears,therefore, that leech, testis, and CZ. welchii hyaluronidases give differenthydrolysis products when they act on the same hyaluronic acid. Additionalevidence 3’ of similar differences has also been obtained.Testicularhyaluronidase, unlike the streptococcal enzyme, leaves material, not diffus-able through cellophane, which will still adaptively enhance the production ofhyaluronidase by streptococci if added to growth media for the organisms.Reviews covering the subject have been p~blished.~8# 391 40W. T. J. M.5 . CYTOCHEMISTRY.been the subject of several reviews.l> 2, 3, *3 5, 6,will be discussed here.The chemical components of the cell nucleus and cytoplasm have recentlyOnly the salient pointsThe Cytoplasm.Considerable interest has centred recently round the pentose poly-nucleotides of the cell cytoplasm. The pentose polynucleotide of yeast has,of course, been known for a long time but similar material has also beenisolated from beef pancreas and sheep liver,g and from dog liver, intestine,and kidney.1° The pentose of the polynucleotide from yeast l1 and fromsheep liver has been proved conclusively to be ribose, but the general andrather unsatisfactory term ribonucleic acid is usually applied indiscriminatelyto pentose polynucleotides from all sources.Ribonucleic acid in the cell cytoplasm gives a negative Feulgen test(p.244) and, in the caae of rapidly proliferating cells, shows a high absorptionin the ultra-violet a t a wave-length of 260 mp which is characteristic of the37 H. J. Rogers, Biochem. J . , 1945, 39, 435.38 K. Wallenfels, Angew. Chem., 1941, 234.40 L. Hahn, Fermentfwsch.., 1944,17, 417.F. Duran-Reynals, Bact.Rev., 1942, 6, 197.A. E. Mirslry, Advances in Enzymology, 1943, 3, 1.J. N. Davidson and C . Waymouth, Nut. Abs. Rev., 1944, 14, 1.J. P. Greenstein, Advances in Protein Chemistry, 1944, 1, 209.J. Brachet, “ Embryologie Chimique,” Liege, 1944.E. Stedman, Edin. Med. J., 1944, 51, 353; Bwchem. J., Proc. Biocliem. SOC., 10thJ. N. Davidson, Edin. Med. J . , 1945, 52, 344; Biochem. J . , Proc. Biochem. SOC.,j H. S. Loring, Ann. Rev. Biockem., 1944, 13, 296.Nov., 1945.10th Nov., 1945.8 E. Jorpes, Acta Med. Xcand., 1928,68, 253; Biochem. J . , 1934, 28,2102.9 J. N. Davidson and C . Waymouth, ibid., 1944, 38, 375, 379.lo A. M. Brues, M. M. Tracey, and W. E. Cohn, J . Biol. Chem., 1944,155, 619.l 1 J. M. Gulland and G. R. Barker, J . , 1943, 625DAVIDSON : CYTOCHEMISTRY. 241conjugated double bonds of pyrimidines and purines.12 Histochemically itis revealed in the cell cytoplasm as material which is deeply basophilic, i.e.,which readily takes up such stains as pyronine or toluidine blue. It can bedissolved out of the cytoplasm, which then loses its basophilic properties, bytreatment with the enzyme ribonuclease which breaks down ribonucleic acidbut not deoxyribonucleic acid.l3 Nuclear staining is unaffected by suchtreatment.This is the basis of a useful histochemical test (the Rrachet test)which has been extensively employed for the detection of ribonucleicacid,l4, 1 5 3 1% 1 7 3 18, 2% 21 and may even be used to assess roughly theribonucleic acid content of different tissues.Results obtained by thismeans 14, 21 agree well with direct pentose estimations on fresh tissue,22 esti-mations made on the extracted nucleic acids,23 and ultra-violet absorptionmeasurement^.^^ The concentration of ribonucleic acid is low in brain,.muscle, and heart, and in endocrine glands such as the thyroid or the isletcells of the pancreas. It is high in all tissues in which protein synthesisis vigorous for purposes either of secretion or of cell multiplication, e.g., thepancreas, the salivary glands, the gastric and intestinal mucosa, the Mal-pighian layer of the skin, oocytes in course of vitellogenesis, the imaginaldiscs of insects, and embryonic tissues. It is high in the Nissl's granules ofnerve cells, in the young cells (e.g., lymphoblasts) of the hzemopoieticsystern,14, 25 and in simple organisms capable of rapid proliferation, e.g.,yeasts, bacteria, and plant viruses.The basophily of such cells, and therefore their ribonucleic acid content,may depend on the physiological state of the organ concerned.Thus theribonucleic acid content of glandular tissues diminishes after prolongedstimulation by electrical means or by pilocarpine,26, 27 whereas in thegranules of the anterior pituitary i t increases during pregnancy or after12 T. Caspersson, Skand. Arch. Physiol., 73 Suppl. No. 8 ; J . Roy. Microscop. SOC.,1940, 60, 8 ; T. Caspersson and J. Schultz, Nature, 1938,142, 294; ibid., 1939,143, 602.l 3 J. Brachet, ConLpt. rend. SOC. Biol., 1940, 133, 88, 90; Arch. Biol., 1940, 51, 151,167.l * 5.Brachet, ibid., 1941, 53, 207.l5 J. Desclin, Compt. rend. SOC. Bwl., 1940, 133, 457.l6 T. S. Painter and A. N. Taylor, Proc. Nat. A d . Sci., 1942, 28, 311.l i J. Gersh and D. Bodian, Biol. Symposia, 1943, 10, 163.l 8 5. N. Davidson and C. Waymouth, Proc. Roy. SOC. Edin., 1944, 62, 96.l9 J. S. Mitchell, 21st Ann. Rep. Brit. Emp. Cancer Campaign, 1944, p. 62,2O G. J. Roskin and A. S. Ginsburg, Compt. rend. Acad. Sci. U.R.S.S., 1944, 43, 122;21 J. J. Biesele, Cancer Research, 1944,4, 529, 737 ; J. J. Biesele, H. Poyner, and T. S.22 J. Brachet, Enzymologia, 1941, 10, 87.23 J. N. Davidson and C. Waymouth, Biochem. J., 1944, 38, 39.24 T. Caspersson, Naturwiss., 1941, 29, 33.25 T. Caspersson, H. Landstrom-Hydh, and L. Aquilonius, Chromosoma, 1941, 2,111; H.Landstrom-Hydh, Acta physiol. Scand., 1943, 6, Suppl. 17; H'. Landstrom-HydBn, T. Caspersson, and G. Wohlfart, 2. mi1cr.-anat. Porsch., 1941, 49, 534.G. J. Roskin and G. Kharlova, ibid., 1944,44, 389.Painter, Univemity of Texas Publications, 1942, No. 4243.26 J. Verne, Bull. Hist. appl., 1927, 55, 569.27 E. Riea, 2. Zellforsch,., 1935, 22, 523242 BIOOHEMISTRY .administration of o e ~ t r o n e . ~ ~ In nerve cells the ribonucleic acid content ofthe cytoplasm varies with the degree of excitation.25Pentose polynucleotide exists in the cell cytoplasm as phospholipin-ribonucleoprotein complexes of two different sizes.28 The " large particles "(0-5-2*0p diameter) can easily be seen under the microscope. They includethe mitochondria and the secretory or zymogen granules of liver and pancreas.The " small particles " or " microsomes " (50-200 mp diameter) are sub-microscopic but can be shown in the dark field microscope as highly re-fringent small bodies in continuous Brownian movement.They form thechromophilic ground substance of the cell, constituting up to 25% of its totaldry substance.I n the liver cell, glycogen is also present in particulate form.29The particulate components of the cytoplasm can be isolated from cellularextracts by a process of differential centrifugation employing high and lowspeeds alternately.28, 30 The particles from liver, pancreas, and leukamiccells have been most extensively investigated. They contain protein richin -SH groupings,31 pentose polynucleotide,28 lipoid material (some two-thirdsof which is phospholipin including acetal phospholipin 28y 30), inositol,28sterols, and vitamin A.30 Analytical figures from different laboratories vary,but it is generally agreed that the total fat content is higher in the smallparticles (40--45%, Claude ; 28 42-51 %, Bensley 30) than in the largeparticles (20-27%, Claude ; 28 32-38y0, Bensley 30), The phosphoruscontent is 1.1-1-7% in the large particles and about 1.5% in the smallparticles except in particles from pancreas, embryo, and tumour cells whichhave a higher phosphorus content (2.1 yo).2*Nearly all the phospholipin of the cytoplasm,30 and, in the adult cell,nearly all the ribonucleic acid, 31 is present in these particles.In certainrapidly proliferating cells or tissues such as amphibian ,eggs in course ofdevelopment, chick embryos, young oocytes, and yeast, the particles accountfor only 2 0 4 0 % of the total ribonucleic acid content. The remainderoccurs as " free " ribonucleic acid which is not brought down by tbe ultra-centrif~ge.3~Succinic dehydro-genase and cytochrome oxidase are found in granules from liver 31* 32 (butnot in the interparticulate fluid 30), y e a ~ t , ~ and heart muscle.33 Phosphataseis found in particles from kidney 34 and liver.4 Liver particles also containThe enzyme content of the particles is important.28 A. Claude, Science, 1943, 97, 451; Biol. Symposia, 1943, 10, 111; J . Exp. Med.,aQ A. Lazarow, Science, 1942, 95, 49; Biol.Symposia, 1943, 10, 1; Arch. Bwchem.,1944, 80, 19.1945, '7, 337.R. R. Bensley, Science, 1942, 96, 389.31 5. Brachet and H. Chantrenne, Acta Bwl. Belg., 1942, 4,451; R. Jeener andJ. Brachet, ibid., 1941,1, 476; 1942,2, 273.3a A. Lazarow and E. S. G. Barron, Anat. Rec., 1941,79, Suppl. 41 ; E. S. G. Barron,Bwl. Symposia., 1943, 10, 27.33 K. G. Stern, Cold S p r i n g Harbor Symp. Qwtnt. Biol., 1939, 7, 312.34 E. A. Kabat, Science, 1941, 93, 43DAVIDSON : CYTOCHEMISTRY. 243amylase, cathepsin, dipeptidase, ribonuclease, and adenyl deaminase, butthese enzymes are also present in the interparticulate fluid.4* 31 Both largeand small particles contain flavoproteins (as does the interparticulate fluid),SObut one flavoprotein, the d-amino-acid oxidase, is found in the liver in thelarge particles only.28Brachet has pointed out that the cytoplasmic ribonucleoprotein particlesconstitute excellent organs for protein synthe~is.~~ 35 They contain enzymesof the protease type which play a part in protein .synthesis together withoxidation-reduction systems which may be able to provide the energynecessary for such an endothermic reaction.Moreover the particles areabundant and the concentration of cytoplasmic ribonucleic acid is par-ticularly high in cells in which protein synthesis is vigorous.Claude28 has put forward the suggestion that the cytoplasmic particlesare endowed with the power of self-duplication, a property which appears tobe a feature of systems composed of polynucleotide associated with protein.It is found for example in the genes and in the filterable viruses. While plantviruses appear t o consist of simple ribonucleoproteins, the animal virusesare phospholipin-nucleoprotein complexes containing either ribonucleic acid(Rous sarcoma virusF6 equine encephalomyelitis virus 37), or deoxyribonucleicacid (rabbit papilloma virus,38 vaccinia elementary bodies,38* 39 influenzavirus40).The similarity between the cytoplasmic particles and the animalviruses, and possible relationships, have been commented on by severalauthors.41Phospholipin-ribonucleoprotein complexes with thromboplastic activityhave been isolated from lung tissue.42 In liver tissue the liponucleoproteinsconstitute storage material. Fasting is accompanied by a fall in liver weightrelative to total body weightys a loss in granular material from the cytoplasm,43a decrease in cytoplasmic volume, a fall in the total ribonucleic acid (but notin the deoxyribonucleic acid) content of the livery7, and a fall in phospholipinand protein.44 A similar loss of cytoplasmic particles follows administrationof a protein-poor diet.4435 J.Brachet, Ann. Soc. Roy. Zool. Belg., 1942, 73, 93.36 A. Claude, Science, 1938, 87, 467; 1939, 90, 213; 1940, 91, .77.37 A. R. Taylor, D. G. Sharp, D. Beard, and J. W. Beard, J . Infect. Dis., 1943,38 A. R. Taylor, D. Beard, D. G. Sharp, and J. W. Beard, ibid., 1942, 71, 110.S9 C. L. Hoagland, G. L. Lavin, J. E. Smadel, andT. M. Rivers, J . Ezp. Med., 1940,40 A. R. Taylor, J .Bwl. Chem., 1944,153, 675.4 1 H. G. Du Buy and M. W. Woods, Phytopathol., 1943, 33, 766; C. D. Darlington,Nature, 1944, 154, 164; A. Haddow, ibid., 1944, 154, 194; P. Koller, ibid., 1943, 151,244; J. W. Beard, Proc. Inst. Med. Chicago, 1945, 15, No. 13; V. R. Potter, Science,1945,101,609.72, 31.72, 139.48 E. Chargaff, A. Bendich, and S. S. Cohen, J . Biol. Chem., 1944,156, 161.p3 W. Berg, 2. mikr.-anut. Forsch., 1927, 12, 1.44 H. W. Kosterlitz, Nature, 1944, 154, 207; H. W. Kosterlitz and R. M. Campbell,Nut. Abs. Rev., 1946, 15, 1244 BIOCHEMISTRY.The Nucleus.Several methods of obtaining cell nuclei have been described. With theexception of that of BehrensF5 in which powdered freeze-dried tissue isallowed to sediment out in columns of organic solvents of graded density,most methods involve treatment of the finely divided tissue with a weak acid,e.g., citric acid, and isolation of the nuclei by differential centrifugation.46-50From avian erythrocytes, nuclei have been obtained by laking with water,51by freezing and thawing,52 -or by treatment with lysolecithin 53 or saponin.54Nuclei have also been obtained from cells which have been disrupted by sonicvibrations.55The cell nucleus contains deoxyribonucleic acid and basic proteins of thehistone type. Lipin is present in amounts similar to those in whole tissue,49but the phospholipin-cholesterol ratio is unusually low.*’ Glycogen isabsent from the nuclei of liver cells.49 Pigments may be present, e.g.,xanthophyll in chicken erythrocyte nuclei.The enzymes which have been reported in isolated liver cell nuclei includeargina~e,4~, 49 cytochrome oxidase, esterase, alkaline phosphatase (in par-ticularly high concentration), and acid phosphatase, but little or no catalase orsuceinic dehydrogena~e.~~ Esterase and peptidase 56 have been found int henuclei of oocytes, and acid phosphatase in those of chicken erythrocyte^.^^Phosphatase has been demonstrated histochemically in the chromosome~.58~ 59E.Stedman and (Mrs.) E. Stedman 6o have reported the discovery in thenucleus of an acidic protein, “ chromosomin,” which may comprise some30-70% of the total nuclear material. They suggest that the chromosomesconsist of compressed cylindrical spirals of chromosomin with a central coreof nucleic acid which also fills the interstices between the coils and con-stitutes the nuclear sap.6, 6oThe discovery of chromosomin may necessitate a revision of the usualinterpretation of the Feulgen nuclear reaction.61 This test depends upon thefact that the hydrolysis products of deoxyribonucleic acid will restore thecolour to a solution of basic fuchsin which has been decolourised with sulphur45 M. Behrens, 2.physwl. Chem. 1938, 253, 185; 1939, 258, 27.46 G. Crossman, Science, 1937, 85, 250.4 7 C. A. Stoneburg, J. Bwl. Chem., 1939, 129, 189.4 5 A. Marshak, J . Qen. Physiol., 1941, 25, 275.A. L. Dounce, J . Biol. Chem., 1943,147, 685; 1943,151, 221.50 D. M. Ziegler, Anat. Rec., 1945, 91, 169.5 1 D. Ackermann, 2. physiol.Chem., 1904-5, 43, 299.52 0. Warburg, ibid., 1910, 70, 413.53 M. Laskowski, Proc. SOC. Exp. Biol. N.Y., 1942, 49, 354.54 A. L. Dounce and T. H. Lan, Science, 1943,97,584.55 C. A. Zittle and R. A. O’Dell, J. Biol. Chem., 1941, 140, 899.J. Brachet, Compt. rend. SOC. Biol., 1938,127, 1455.5 7 A. L. Dounce and D. Seibel, Proc. SOC. Exp. Biol. N . Y., 1943, 54, 22.6 8 E. N. Wilber, J. Exp. Biol., 1942, 19, 11.59 J. F. Danielli and D. G. Catcheside, Nature, 1945,156,294.60 Ibid., 1943,152, 267, 503, 556; 1944,153, 500.61 R. Feulgen and H. Rossenbeck, 2. physiol. Chem., 1924,135, 203DAVIDSON : CYTOCHEMISTRY. 245dioxide. Stedman maintains that when this test is applied to tissue sectionsthe fully coloured stain is developed in the nucleus and is then taken up bychromosomin, so that, although deoxyribonucleic acid can be detected in thenucleus, it cannot of necessity be located in the chromosomes. Chromosomescan in fact be stained by " developed nucleal stain " prepared by interactionof Feulgen's reagent with hydrolysed deoxyribonucleic acid.62 While thisview has been vigorously contested,63 it would appear that the original simpleinterpretation of the Feulgen technique may be inadequate-aDeoxyribonucleic acid exists in the nucleus in combination with basicproteins of the histone type as material which is usually referred to loosely as" chromatin." Such deoxyribonucleoprotein can be extracted from cellnuclei by concentrated sodium chloride solutions and precipitated by dilutionwith water,65 or it can be isolated in threads by a process of differentialcentrifugation.66 Chromatin prepared in the latter way from liver cells isreported to stimulate cellular proliferation and to accelerate the healing ofexperimental wounds.67On the basis of histochemical tests and pentose estimations on isolatednuclei Brachet has concluded that 10% of the nucleic acid of the nucleus isribonucleic acid.l*~ 22 Some of this is present in the nucleolus (vide infra),but a small amount is reported in the genetically inert chromatin fractiontermed the heterochromatin, which consists therefore of histone, deoxyri-bonucleic acid, and small amounts of ribonucleic acid. The remainder of thechromatin is the gene-bearing euchromatin, which is composed of deoxyri-bonucleic acid together with higher proteins of the globulin G8 Therelationship, if any, of these proteins to chromosomin is not yet clear.The Nucleolus.Evidence that the nucleolus contains ribonucleic a,cid and not deoxyri-bonucleic acid is given by ( a ) a negative Feulgen test,69 ( b ) strong absorptiona t 260mp 69 which is diminished by treatment with ribonuclease,70 (c) apositive Brachet test,14 and (d) positive histochemical tests for pent~ses.'~The ribonucleic acid appears to be combined with histone and to bear arelationship to the cytoplasmic ribonucleoproteins. The nucleolus is large inthose cells where a strongly basophilic cytoplasm, indicating a high ribo-nucleic acid content, is associated with active protein synthesis, and is small62 H. C. Choudhuri, Nature, 1943, 153, 475.63 H. G. Callan, ibid., 1943, 152, 503; H. N. Barber and H. G. Callan, ibid., 1944,153, 109; T. Caspersson, ibid., 1944, 153, 499; R. E. Stowell, Stain Technology, 1945,20, 45.64 J. G. Cam, Xature, 1945, 156, 143.65 A. E. Mirsky and A. W. Pollister, Proc. Nut. Acud. Sci., 1942, 28, 344.6(i A. Claude and J. S. Potter, J. Exp. Med., 1943, 77, 345.6 i A. Marshak and A. C. Walker, Proc. SOC. Exp. Biol. N . Y., 1944, 58, 62.6 8 T. Caspersson and L. Santesson, Acta Radiol., Suppl., No. 46.61 T. Caspersson and 5. Schultz, Nature, 1938,142, 294; ibid., 1939, 143, 602; Proc.70 J. Gersh, quoted by Mirsky (1).71 Brit. J . Exp. Path., 1942, 23, 285, 296, 309, Brit. J . Radiol., 1943, 16, 339.Nat. Acad. Sci., 1940, 26, 507246 BIOOHEMISTRY.in, or apparently absent from, cells where cytoplasmic growth does notO C C U ~ . ~ ~ ~ G6Growth and Cell Division.In primitive organisms, such as the sea urchin egg, nuclear deoxyri-bonucleic acid is apparently synthesised entirely a t the expense of an initiallyabundant store of cytoplasmic ribonucleic acid.4 In higher organisms bothtypes of nucleic acid are synthesised on a large scale, but a balance appearsto be preserved between the two types. Thus in the sheep embryo, althoughribonucleic acid is present in high concentration in most tissues, the ratio ofribonucleic acid to deoxyribonucleic acid for any one tissue is of the same orderin the embryo as in the corresponding adult tissue.23 At the same time it ispossible that some, at least, of the nuclear deoxyribonucleic acid is syn-thesised by way of cytoplasmic ribonucleic acid perhaps even in the chromo-s0mes.3~ On the basis of ultra-violet absorption measurements on the cyto-plasm of the cells of human tumours exposed to X - or gamma-rays, J. S.Mitchell has suggested that ribonucleotides are formed in the cytoplasm fromunknown precursors and are reduced in the nucleus to deoxyribonucleotideswhich are finally polymerized to deoxyribonucleic acid.71The nature of the chemical changes occurring during the process ofmitotic division have been followed both by ultra-violet absorption methodsin conjunction with the quartz microscope 25 and by histochemical tech-nique.12 During prophase deoxyribonucleic acid accumulates in the chromo-8omes reaching a peak concentration at metaphase. At the same time ribonu-cleic acid decreases in the cytoplasm and the nucleolus and, according toBrachet, becomes concentrated in the chromosomes and the spindle.12 Attelophase the deoxyribonucleic acid concentration of the chromosomesdecreases while ribonucleic acid reappears in the cytoplasm and the nucleolusis reformed. Caspersson holds that the heterochromatin controls thesynthesis of histones which together with ribonucleic acid form the nucleolus,while the euchromatin is responsible for the production of higher proteins ofthe globulin type. Some of the histones of the nucleolus diffuse to thenuclear membrane where they stimulate the formation of cytoplasmicribonucleic acid and 68On the other hand Stedman regards the histones as regulators of mitosis.In resting nuclei sufficient histone is present to combine with all the deoxyri-bonucleic acid. When the histone content is low, as in the rapidly pro-liferating cells of embryonic or tumour tissue, nucleic acid is available tocombine with chromosomin forming a self-reproducing 72J. N. D.J. N. DAVIDSON.F. DICKENS.W. T. J. MORGAN.F. G. YOTTNC,.72 E. Stedman and (Mrs.) E. Stedman, Nuture, 1943, 152, 666

ISSN:0365-6217    

DOI:10.1039/AR9454200197

出版商:RSC    

年代:1945

数据来源: RSC

摘要:

ANALYTICAL CHEMISTRY.1. THE PROTEIN AMINO-ACIDS.RECENT theoretical studies of protein structure, and the increasing interestin protein hydrolysates for clinical use, have within the last few years evokeda wide extension of the analytical methods available for estimating theindividual amino-acids. It is hoped that, by reviewing the most recentwork together with a background of less immediately recent “source”papers, it may be possible to provide a fairly comprehensive summary of thetechniques which have been most effectively used during the last ten years.These techniques are, however, of comparatively little value, unless it isreasonably certain that the amino-acids present after hydrolysis correspondqualitatively and quantitatively to the units originally present.Investig-ations on the unhydrolysed protein have thus 9 considerable significancerelevant to the subsequent analysis of the hydrolysate. In this field, infra-red spectrography has been applied to the estimation in proteins of residueswith distinctive groupings- such as those of arginine and proline.The danger of misconception arising from qualitative changes on hydroly-sis is exemplified by the isolation, from protein hydrolysates, of lanthionine ;this has been shown to be in most cases, and probably in all, a secondaryformation from cysteine residues which are the true protein constituent^.^Effective chemical stability in an amino-acid formed by hydrolysis is not initself evidence that the acid will be liberated unchanged from the corres-ponding radical in the parent protein, since it has been shown * that cystine,serine, and threonine, when combined in proteins, are destroyed by hydrolysisconditions which do not affect them in the free st,ate.Similarly, it is knownthat whole protein is more readily racemised by alkalis than are free amino-acids. For some purposes (e.g., if the hydrolysate is to be analysed by iso-topic, biological, or enzymatic methods which are specific as between opticalisomers) racemization must be regarded as a qualitative transformation.There is evidence that ordinary acid hydrolysis conditions will not normallyinduce serious racemization except after a period several times longer than isrequired for hydrolysis only; the amino-acid most readily racemized ishi~tidine.~ 9 65 Racemization during hydrolysis is, however, reported as asource of error in the enzymatic estimation of glutamic acid.62Quantitative errors may arise by more far-reaching decomposition duringhydrolysis, forming breakdown products which are not of amino-acid nature,A.M. Buswell and R. C. Gore, J . Physical Chem., 1942,46, 575.M. J. Horn, D. €3. Jones, and S. 5. Ringel, J. Biol. Chem., 1941,138, 141.E.g., A. Schoberl, Biochem. Z., 1942, 313, 214.€3. H. Nicolet, L. A. Shinn, and L. J. Saidel, J. Biol. Chem., 1942, 142, 609.A. H. Schein and C. P. Berg; through Dairy Sci. Abs., 1944,5, 197248 ANALYTICAL CHEMISTRY.and are not subsequently determined. indicatethat, as in the case of racemization, there will generally be a reasonablelatitude between the duration required for hydrolysis only, and that requiredfor serious decomposition.The emphasis thus laid on hydrolysis conditions,however, is reflected in a tendency for analysts to prepare a number ofhydrolysates from any one protein, using different agents which are severallymost suitable for each of the different amino-acids expected; e.g., ifcystine is to be estimated, maximum yield with minimum humin formationis achieved by hydrolysis with equal parts of 20% hydrochloric and 90%formic acids. For production of tryptophan, which is unstable to acids,alkalis or trypsin have previously been employed, and, to obtain it in acolourless hydrolysate suitable for colorimetric examination, papain hasbeen used for the hydrolysis of ~ a s e i n .~Actual analysis of the. hydrolysate, especially by techniques of theclassical type depending on solubility differences, is frequently complicatedby inter-effects (e.g., mutual solubility and co-precipitation) between theconstituent amino-acids ; so that a procedure suitable for one amino-acidin a particular hydrolysate may be ineffective for the same acid in anothermixture with different proportions of the same or other amino-acids. It istherefore often desirable, before proceeding to the determination of anysingle acid, to simplify its " background " by a preliminary sorting of thetotal amino-acids into groups.39 The newer methods for this purpose aretherefore now reviewed, though it will be understood that some of thesemay also be applicable, in suitable circumstances, to the estimation ofindividual amino-acids.Among methods utilizing solubility differences, the separation of thecopper salts with different solvents has continued to find wide application,and B.W. Town lo has usefully summarized his series of papers on thistechnique. A critique of the Foreman separation of the dicarboxylic acidswith lime (or baryta) and ethanol has been published.ll Mutual solubilityeffects arising when phosphotungstic acid is used to precipitate the basicamino-acids have been investigated by D. D. van Slyke and others.12 The" partition chromatogram" technique of A. J. P. Martin and R. L. M.Synge 13 must strictly be included among differential solubility methods,though the manipulation is more akin to chromatography.The Martin andSynge column, however, not being in itself adsorptive of the amino-acids,serves only as an inert mechanical support to a solvent. When the amino-acids dissolved in a second immiscible solvent are made to flow along thecolumn, partition occurs between the " mobile " and the " static " liquidA number of studies 59 6,6 R. Borchers and C. P. Berg, J . Biol. Chenb., 1942, 142, 693.7 J. M. R. Beveridge and C. C. Lucas, ibid., 1944, 155, 547.8 E.g., R. J. Block and D. Bolling, Arch. Biochem., 1945, 6, 277.9 M. J. Horn and D. B. Jones, J. BioZ. Chem., 1945,157, 153.10 Biochem. J., 1941, 35, 419.11 K. Bailey, A. C. Chibnall, M. W. Rees, and E. F. Williams, ibid., 1943, 37, 361.12 D.D. van Slyke, A. Hiller, and R. T. Dillon, J . Biol. Chem., 1942,146, 137.l 3 Biochem. J., 1941, 35, 91, 1358; 1943, 37, 79, 86, 313; 1945, 39, 363KELLETT : THE PROTEIN AMINO-ACIDS. 249phase; and the total effect approximates to that of a large number of two-solvent separations, in the same way that the equivalent of a large series ofsuccessive distillations is effected in the operation of a fractional distillationcolumn. The amino-acids are thus separated into isolable bands, which aremade visible by an indicator of appropriate pH range, incorporated in thecolumn. A specially suitable indicator, not readily leached out, has beendescribed.l* Martin and Synge found the acetyl derivatives of the amino-acids most convenient in this application, but the copper salts of the un-acetylated acids have also been used; the separated bands are then directlyvisible by their blue colour, and are quantitatively assessed by iodimetrictitration of their copper content.15 The partition chromatogram principleis raised to a higher power in the " two-dimensional chromatogram,') 16, 23in which the solid support is cellulose (filter-paper), and the static liquidphase is the moisture inherent in it.After capillary irrigation with oneimmiscible mobile-phase solvent, the paper sheet is rotated in its ownplane through QO", and irrigated with a different mobile phase. By thistwofold treatment, 22 amino-acids in only 400 pg. of wool protein hydrolysatewere qualitatively separated into distinct spots, which were made visible incharacteristic colour by spraying the paper with ninhydrin solution andheating.The co-ordinates of location of each spot, being determined bytwo different constants (vix., partition coefficients in two different water-solvent systems) of the amino-acid concerned, are characteristic of eachamino-acid .Applications of true chromatography have been somewhat limited. J. L.Wachtel and H. G. Cassidy l7 found that charcoal as an adsorbent tended todecompose the amino-acids, both by aminolysis and more fundamentally.Bleaching earth has been more successfully used for selective adsorption ofthe diamino-acids ; l8 and glutamic and aspartic acids were isolated on acid-washed alumina, and separated from one another by fractional elution withsuitably buffered acidic solutions.l 9 Ion-exchange resins of the Amberlitetype have been similarly applied to separation of the basic acids by R. J.Block,20 and this variant seems so far the most likely to be useful inpractice.21An electrolytic separation of the basic acids was effected by A. A.Albanese,22 who claimed that this method, owing to the minimum of rnanipu-lation involved, avoided many risks of nitrogen loss (e.g., by adsorption onprecipitates) which other methods incur. It. I,. M. Synge 23 has electrolyseda mixture containing monoamino-acids, a diamino-acid, aspartic acid, andethanolamine, placed in a trough hollowed in a block of silica jelly stiffened'' H. F. Liddell and H. K. Rydon, Biochem. J . , 1944, 38, 68.l 5 T.Wieland and H. Fremerey, Ber., 1944, 77, 234.l6 R. Consden, A. H. Gordon, and A. J. P. Martin, Biochem. J., 1944, 38, 224.l7 J. Amer. Chem. SOC., 1943, 65, 665. l6 F. Turba, Ber., 1941, 74, 1829.l9 F. Turba and M. Richter, ibid., 1942, 75, 340.2o PTOC. SOC. Exp. Biol. Med., 1942, 51, 252; through Chem. Abs., 1943, 37, 899.21 Cf. R. K. Cannan, J. Biol. Chem., 1944,152, 401.22 Ibid., 1940, 134, 467. 23 Biochem. J., 1945, 39, 358, 363250 ANALYTICAL CHEMISTRY.with paper pulp and buffered at pH6. The migration of ions towardselectrodes a t the ends of the block is traced by pressing a sheet of paper onto the block and “ developing ” by spraying with ninhydrin and heating;when ionophoresis through the block has proceeded sufficiently far, the printsof separate bands of ions can be recognised on the sheet.The strong baseethanolamine moves rapidly towards the cathode, the diamino-acid lysinemore slowly, and the monoamino-acids most slowly ; the dicarboxylic acid,aspartic, migrates towards the anode. The basic acid ornithine also movestowards the cathode rapidly enough to separate it from the monoamino-acids. With the guidance of the paper “print,” segments of the blockcontaining the separated components can be cut out for further treatment.Specific methods for the estimation of individual amino-acids may bereviewed under five heads : (A) solubility methods, (B) colorimetric andother chemical reactions, (C) microbiological, (D) enzymatic, and (E) iso-topic dilution.(A) Solubility Methods.Advances have been made in the search for precipitants of higherspecificity. M.Bergmann Z4, 25 observed that the introduction of organicmolecules into the co-ordinated envelopes of certain chromium diamminesincreased their specificity as amino-acid precipitants. Thus, althoughReinecke’s salt (ammonium tetrathiocyanatodiamminochromate) precipitatesboth proline and hydroxyproline, yet only proline is precipitated if the twoammonia molecules are replaced by two of aniline ; whereas the trioxalato-chromate complex is specific for glycine. Salts of various amino-acids with‘‘ dioxanilic ” and ‘‘ dioxpyridic ” acids, in which the co-ordinated envelopescontain respectively pyridine and aniline with oxalate residues, have sub-sequently been described.26 The use of naphthalene- p-sulphonic acid andflavianic acid as precipitants has prompted an extensive examination ofother sulphonic acids of possibly higher specificity, chiefly derived fromanthraquinone, diphenylamine, and a~obenzene.~’ Both these types ofprecipitant have been applied in the new technique of the “ solubilityproduct method.” In this procedure, no attempt is made a t quantitativeprecipitation of the complex (amino-acid with precipitant) in an absolutesense ; the concentration of the amino-acid ion in a solution is calculated fromthe extent to which a weighed addition of the complex dissolves, first againstthe common-ion effect of the amino-acid originally present, and then whenthis effect is increased by the addition of a weighed amount of pure amino-acid.If the solubility product [amino-acid ion] [precipitant ion] has not24 J . Biol. Chem., 1935, 110, 471.26 M. Bergmann and S. W. Fox, ibid., 109, 317.26 M. Bergmann, ibid., 1938, 122, 569.27 W. H. Stein, G. Stamm, C - Y . Chou, and M. Bergmann, ibid., 1942,143,121. Someadvantages in the use of flavianic (dinitronaphtholsulphonic) acid to precipitate arginineas the monoflavianate instead of the more usual diilavimate are noted by Beveridge andLucas (ref. 39)KELLETT : THE PROTEIN AMINO-ACIDS. 251identical values a t the two different concentrations involved, a factor isintroduced into the calculation to correct for this.28* 299 30(B) Colorimetric and other Chemical Reactions.Only a selection can be given from numerous papers describingestimations based on chemical, including colorimetric, reactions. Many ofthese papers, however, have full bibliographies of earlier and alternativemethods.Clycine and alanine have been determined by their reaction with nin-hydrin, yielding respectively formaldehyde and a~etaldehyde.~~ Theformer aldehyde is subsequently estimated colorimetrically with chromo-tropic (1 : 8-dihydroxynaphthalene-3 : 6-disulphonic) acid, and the latterwith p-hydroxydiphenyl.Valine and leucine, after aminolysis with nitrous acid, have been deter-mined by oxidation of their isopropyl groups to acetone with chromic acidunder pressure .32Xerine and threonine (and other p-hydroxy-a-amino-acids if present) areconverted into aldehydes by treatment with periodic acid.The form-aldehyde produced from serine can be estimated with dimedon 33 or colori-metrically with chromotropic acid.34 The production of acetaldehyde fromthreonine is much influenced by conditions, and is hardly to be relied uponas quantitative ; when formaldehyde is simultaneously formed, the acet-aldehyde can be simply isolated by volatilization in a stream of air.35 Aserious drawback in these methods is the danger of secondary reactionsbetween the aldehydes and unchanged amino-acid~.~~ An unpublishedmodification giving quantitative results is, however, mentioned by R. L. M.S ~ g e . ~ ~Papers have been published on the elaboration of the Sullivancolorimetric reaction with sodium P-naphthaquinone-4-sulphonate 3' andthe modification of the Vassel method using p-aminodimethylaniline.3*Estimation of cystine from the sulphur content of the mercaptide precipi-tated by cuprous oxide may be unreliable, since methionine has been foundin such a precipitate even after rigorous purification.39Cystine.28 M.Bergmann and W. H. Stein, J . Biol. Chem., 1939,128, 217; 129, 609.29 H. R. Ing and M. Bergmann, ibirE., p. 603.30 S. Moore and W. H. Stein, ibid., 1943,150, 113.31 B. Alexander and A. M. Seligmann, ibid., 1945,159,9 ; 160,51.32 J. Roche and M. Mo~~rgue, Coinpt. rend. Xoc. biol., 1943,137, 766; through Chem.35 B. H. Nicolet and L. A. Shim, J . Biol. Chem., 1941,139, 687.34 M. J. Boyd and M. L. Logan, i b d . , 1942,148,279.35 A. J.P. Martin and R. L. M. Synge, Biochem. J . , 1941,35, 294.s 6 A. Neuberger, ibid., 1944,38, 309.3 7 F. A. Csonka, H. Lichtenstein, and C. A. Denton, J . Biol. Chem., 1944,156, 571 ;38 D. K. Mechan, ibid., 1943,151, 643.39 J. M. R. Beveridge and C. C. Lucas, Bwchem. J., 1944, 38, 88.Abs., 1945, 39, 3313.R. J. Evans, ibid., p. 373252 ANALYTICAL CHEMISTRY.Methionine. Interference by cystine when methionine is determinedby the McCarthy-Sullivan colour reaction with nitroprusside has beenin~estigated.~~ A chemical determination has been described by E. F.Beach and D. M. T e a g ~ e , ~ l based on demethylation with hydriodic acid,forming homocysteine. Under the experimental conditions, homocysteinepasses into a thiolactone ring which does not ’form a cuprous mercaptide;cystine can therefore be removed in this form, after which the thiolactonering is opened with sodium hydroxide, and further treatment with cuprousoxide then precipitates only the homocysteine equivalent to the originalmethionine.Estimation of methionine by means of its periodide has beendescribed by T. F. Lavine; 42 this compound is stable to thiosulphate,which can therefore be used to remove excess of iodine before decomposingthe periodide with acid and titrating the iodine thus liberated. Otheramino-acids which form periodides are allowed for by a blank in which themethionine present is oxidised with potassium iodate to its sulphoxide,which does not form a periodide.Phenylalanine can be estimated by a method 43 based, like the earlierKapeller-Adler method, on the presence of the nitratable benzene ring.Nitration yields the dinitro-compound, which is reduced to the diamine,and this gives a red colour with sodium @-naphthaquinone-4-sulphonate.Other nitratable rings present (tyrosine and tryptophan) are eliminated bypermanganate oxidation.Tyrosine is still most conveniently estimated by hlillon’s reaction, forwhich satisfactory conditions have been worked out by J .W. H. L ~ g g . ~ ~Tryptophan estimation by colorimetric means has been reviewed byM. X. Sullivan and W. C. Hess 45 (cf. Horn and Jones 9).Glutamic acid on heating under pressure a t pH 3-4 undergoes ring-closure to pyrrolidonecarboxylic acid, and a van Slyke determination oftotal amino-nitrogen before and after ring closure has been proposed as ameasure of the glutamic acid present.46 An alternative chemical treatmentof glutamic acid is its oxidation with chloramine-.r to p-cyanopropionic acidand subsequent hydrolysis to succinic acid, which is then estimated by itsoxygen absorption in the presence of succin~xidase.~~A rginine estimation by the Weber-Sakaguchi colour reaction witha-naphthol and a hypohalite solution has been critically discussed by A.A.Albanese and J. E. F r a n k s t ~ n . ~ ~Improved conditions for the Koessler-Hanke colour reactionwith diazotized sulphanilic acid have been described by H. T. MacPhers~n.~~Histidine.W. White and F. C. Koch, J . Biol. Chem., 1945,158, 535.4 1 Ibid., 1942, 142, 277.4 2 Ibid., 1943, 151, 281.43 W.C. Hess and M . X. Sullivan, Arch. Biochem., 1944, 5, 165.4 4 Biochem. J., 1937, 31, 1422; 1938, 32, 775.4 5 J . Biol. Chem., 1944, 155, 441.4:i H. S . Olcott, $bid., 153, 71.4 7 P. P. Cohen, Biochem. J., 1939, 33, 551.4 8 J . Biol. Chem., 1945, 159, 185. 4 9 Riochem. J . , 1942, 38, 59KELLETT : THE PROTEIN AMINO-AO'CDS. 253(C) Microbiological Methods.Microbiological assays for most of the commoner amino-acids have nowbeen described, utilizing LactobaciZEus spp. 50 or Leuconostoc mesenteroides. 51Quantitative assessment may be either by a turbidimetric measure of thegrowth of the organism, or by titration of the acid liberated in its metabolism.Using Streptococcus fcecalis, a uniform routine method allowing of a completeanalysis for histidine, arginine, lysine, leucine, isoleucine, valine, methionine,threonine, tryptophan, and phenylalanine on 1.5 g.of sample has beendescribed.52 Considerable evidence is now available as to the specificityof this type of estimation. Complete specificity as between optical isomersis by no means invariable, since d- and Z-aspartic acids are equally wellutilized by L. DeEbruckii, though this organism responds to serine only inthe Z-form.53 d-Leucine and 1-glutamic acid s5 can a t least partly replacethe natural isomers. There is also evidence that amino-acids may be oftenpartly replaced by the corresponding deaminated (a-hydroxy- or a-keto-)compounds.54, 55 These observations may perhaps be correlated with theconclusion that d-glutamic acid is not utilized as such by the organism;comparison of its irregular " delayed " response curve with the regular curvegiven by glutamine suggests that the acid is utilized only after conversioninto the amine, which may be to some extent formed also from the deaminatedor optically isomeric c0mpounds.5~ As regards glutamic acid, this resultmight perhaps be expected, since the unit is probably present in proteins asglutamine more often than as glutamic acid; but it does not appear that thesame explanation will apply to aspartic acid, which is not readily replaced incultures by asparagine.56Attention has been directed to allowances for error due to the presenceof undefined growth-stimulants either in the basal medium 57 or in thehydrolysate under examination.58 There would also appear to be aomedanger of the test organism varying in its response to certain amino-acids,since it has been reported 59 that L.arabinosus in the course of culture canreadily develop a strain capable of entirely dispensing with histidine or anyobvious source of histidine such as indole or anthranilic acid. A morehelpful kind of variation is exhibited by Neurosporn crassa, which normallycan be cultured in a medium containing only inorganic salts and a sourceof organic carbon, with the addition of biotin; by ultra-violet irradiation or'O E.g., S. Shankman, M. S. Dunn, and L. B. Rubin, J . Biol. Che-m., 1943,150, 305,477; 151,511." E.g., M. S. Dunn, M. N. Camien, S. Shankman, and L. B.Rockland, ibid., 1946,159, 653.5 2 J. L. Stokes, M. Gunness, M. Dwyer, and M. C. Caswell, ibid., 160, 35.53 J. L. Stokes and M. Gunness, ibid., 157, 561.5 4 D. M. Hegsted, ibid., p. 741.5 5 L. R. Hac, E. E. Snell, and R. J. Williams, ibid., 159, 273.56 L. R. Hac and E. E. Snell, ibid., p. 291.'' E. J. chu and R. J. Williams, ibid., 1944, 155, 9.5 8 E. C. Wood, Nature, 1945, 155, 632.59 L. D. Wright and H. R. Skeggs, J . Biol. Chem., 1945,159, 615254 ANALYTIUAL OHEMISTRY.other means, however, mutant strains, having specific requirements for asingle additional orgavic compound, can be generated. The productionof a strain to the growth of which lysine is essential, and the bio-assayof lysine by the use of this organism, have been described by A.H.Doermann.60(D) Enzymatic Methods.A promising development from the bio-assay is the use of enzymepreparations isolated from the micro-organisms. From cultures of variouscoliform bacteria, decarboxylase preparations have been obtained which arespecific respectively to lysine, tyrosine, glutamic acid, histidine, and orni-thine; and mixtures containing these acids have been analysed by mano-metric estimation of the carbon dioxide liberated from each by its appro-priate enzyme.61, 62 Arginine decarboxylase has also been obtained,though not as yet separated from the lysine enzyme.63 The enzymes aresomewhat sensitive to inhibition by inorganic salts and various organiccompounds, e.g., hydroxylamine. They appear to be entirely specific asbetween optical isomers ; this is consistent with the reason suggested under(C) for non-specificity in certain microbiological assays, since the productionof a substance such as glutamine from any one of several precursors is ofcourse not possible by a decarboxylase alone.It is remarkable, however,that the enzymes do appear to some extent effective against hydroxy-derivatives of their normal substrates, whether substituted in the aliphaticchain (hydroxylysine, p-hydroxyglutamic acid) or benzene ring (dihydroxy-phenylalanine) ; but the converse is not true, since tyrosine decarboxylasedoes not act on phenylalanine.(E) Isotopic Dilution.H. H. Ussing’s proposal to estimate the quantity of any oneamino-acid from its effect in diluting a measured addition of the same acidin which one of the elements is present as an isotope, has been applied byG.L. Foster and his co-workers G5* 661 67 to aspartic and glutamic acids,leucine, glycine, lysine, arginine, phenylalanine, and tyrosine. Deuteriumwas the label element chosen by Ussing, but the American workers havepreferred 15N, determining the proportion of this isotope in the pure amino-acid as added, and again as subsequently re-isolated, by the mass spectro-graph. The isohopic preparation as added being necessarily synthetic andtherefore racemic, while the acids in the hydrolysate (except glycine) areoptically active, a somewhat laborious series of crystallizations is required,to ensure that the re-isolated acid consists only of the naturally-occurringstereoisomer ; this course is, however, found more practicable than either*O J .Biol. Chem., 160, 95.81 E. F. Gale and H. M. R. Epps, Biochem. J., 1944, 38, 232, 242.62 E. F. Gale, ibid., 1945, 39, 42, 46.64 Nature, 1939, 144, 977.d B D. Rittenburg and G. L:Foster, ibid., 1940,133, 737.67 D. Shernin, ibid., 1945, 199,1439.6s E. S. Taylor and E. F. Gale, ibid., p. 52.6 5 G. L. Foster, J. Biol. Chem., 1945, 159, 431GASKM : ORGANIC REAGENTS IN INORGANIC ANALYSIS. 255of the alternatives, uiz., quantitative racemization of the acid in the hydroly-sate, or resolution of the racemic isotope preparation before addition. Amarked advantage of the method is that isotope concentration is a verysharp criterion of the purity of the isolated amino-acid, since 5% con-tamination by another amino-acid causes a difference of 5% in the isotopeconcentration, but can cause only a much smaller change in properties suchas nitrogen content or optical rotation which are common to the contaminantand the compound being isolated. E.G . K.2. ORGANIC REAGENTS IN INORGANIC ANALYSIS.As the title of this section indicates, attention has been devoted to thequantitative use of organic reagents in inorganic analysis, and no attempthas been made to cover the whole field of their application in analyticalpractice. This section of the subject appears to have been dominated bythe modern ability to obtain mechanical measurement of colour, either theabsorption or the transmission; hence many more reagents are described asgiving suitable colour reactions than as being suitable for gravimetric work.This insistence on colour has been carried to some lengths, for methods aredescribed where coloured precipitates are actually maintained in a dispersedstate to enable a colour measurement to be made.At other times colourstandards are used, prepared from a different substance.The devotion to colour in its turn has been governed by the desirabilityfor speed in the examination of large numbers of similar samples and also bythe necessity for the determination of minute amounts of an element wherethe colour reaction is the most sensitive test. Fortunately a number ofcomparisons have been made between methods already established and thenewer colour methods, and on the whole it may be said that the latter are notinferior.Although it is the sincere hope of the Reporter that he has not omittedany important contribution in the last year or two to this section of analysis,it should be nevertheless pointed out that the scope of organic reagents,even in inorganic analysis, is very wide and difEcult to arrange in anythinglike a systematic survey.It would have been preferable to have made thevarious headings refer to the reagents, but for reference purposes it has beenconsidered that headings under the names of the elements determined aremore satisfactory and this order has been followed. Lead, copper, and ironhave easily attracted the most attention, followed by bismuth, cobalt,tungsten, boron, beryllium, nickel, zinc, and cadmium, and these elementshave been reviewed under separate headings.Then follow two groups ofelements, the first being those less frequently encountered, and the second amiscellaneous group which have not attracted much attention.Lead.-Mention of lead almost inevitably draws attention to “ dithi-zone,’’ and considerable work has been done with this reagent. In a com-prehensive study P. A. Clifford 1 has enumerated the metals reacting withJ. Assoc. 08. Agric. Chem., 1943, 26, 26256 ANALYTICAL CHEMISTRY.dithizone and has listed certain of the important properties of the metalliccomplexes. He has shown that interference from the complexes of bismuthand tin in the final photometric measurements can be detected, and hasindicated a possible method whereby bismuth and lead may be simultaneouslydetermined. At the same time, a procedure for the separation of smallquantities of lead from a possible interfering element, thallium, was outlined.Applying the method to the examination of urine, Clifford showed that theresults were quite comparable with those of other established methodsrequiring much larger quantities of the original material ; the possibleerrors in the method were examined and eliminated.It has been pointed out that in micro work the bismuth interferencemay be eliminated by extraction of the bismuth complex a t pH 2, and thattitanium and aluminium can interfere with the photometric measurements.This extraction of bismuth may be lengthy, and to avoid it, K.Bambachand R. E. Burkey recommend that the normal acid (‘ stripping ” be re-placed by an aqueous (‘ stripping ” a t pH 3.4, whereby, unless excessivebismuth is present, the lead is completely separated. Using dithizone, thelead in numerous toilet preparations has been successfully determined *and the method has proved of value in the examination of soil, plants, andfood.The blue-violet insoluble precipitate formed with lead salts and carminicacid in acid solution has been proposed as a sensitive test for detecting afew pg. of lead. E. A. Leibmann has examined the reactions of diphenyl-carbazide with lead, and V. I. Kuznetsov 8 proposes testing for quadrivalentlead with paper impregnated with anthraquinone- 1 -azo-4-dimethylamine.Electrolytically deposited lead dioxide may be dissolved in an acetic solutionof tetramethyldiaminodiphenylmethane and the resulting blue colour usedfor the determination of the lead.gCopper.-Numerous reagents have been discussed in recent literaturefor use in the determination of copper.Substituted amides of dithio-carbonic acid l o can be used satisfactorily for its detection, and rapidity inthe quantitative determination of the metal in aluminium alloys can beobtained by the colorimetric method using diethyldithiocarbarnate.ll9 12, l3Extraction of a copper solution with chloroform containing 8-hydroxy-quinoline will, at the appropriate pH, remove the copper-oxine complexJ. Schultz and M. A. Goldberg, Ind. Eng. Chem. Anal., 1945, 15, 155.Ibid., 1942, 14, 904F. H.Buckwalter, Proc. Sci. Sect. Toilet Goods Assoc., 1943-44, No. 1, 22.0. Braadlie and H. Bargh, Tidskr. Kjemi Berg., 1942,2,88 ; Chem. Zentr., 1943.11,J. V. Dubsky, Chem. Listy, 1940, 34, 91; Chern. Zentr., 1941, I, 1576.J . Appl. Chem. U.S.S.R., 1943, 16, 238.M. Fields, New Zealand J . Sci. Tech., 1942, 23B, 224.345.’ Lab. Prakst. U.S.S.R., 1941, 16, No. 10-11, 23.lo E. Geiger and H. G. Muller, Helv. Chim. Acta, 1943, 26, 996.l1 F. W. Haywood, Analyst, 1943, 68, 206.l2 S. Bertoldi, Alluminio, 1943, 12, 37 ; Chem. Zentr., 1944, I, 452.l3 R. F. Partridge, Ind. Eng. Chem. Anal., 1946, 17, 422GASKIN : ORGANIC REAGENTS IN INORGANIC ANALYSIS. 257and the absorption maximum of this extract has been measured.14 H.T.Liem l5 has suggested that Quinosol or Superol can, with advantage, replace8-hydroxyquinoline in the determination of copper, aluminium, and zinc.Attention has been paid to the separation of copper from zinc and cadmium ;apart from interference by silver and gold, 8-hydroxyquinolinecarboxylicacid is a suitable reagent for this purpose.16 With copper and cadmiumonly present, the quinaldic acid separation, originally proposed by P. Rayand M. K. B0se,17 has been shown to be reasonably satisfactory.ls, l9 Ob-jections to the method have not been supported by spectrographic examin-ation 2o of the separated metals, the copper containing only 0~05-0~07~0 ofcadmium, and the cadmium only 0.3% of copper.Two methods 21, 22 are available for using isonitroso-3-phenylpyrazolone,interference from cadmium being prevented by addition of ammoniumtartrate, which addition also prevents co-precipitation of a number ofelements.Highly coloured cuprous complexes are formed with o-phenanthroline and its derivative^,^^ and the first named can be used forthe spectrophotometric determination in the vbsence of interfering elements.=Salicylaldoxime 25 is used for copper in steel, and in nickel-plating baths 26the dithizone method is useful. If the dithizonates are extracted a t pH 3,the transmittance of the copper dithizonate may be measured spectrophoto-metrically, provided interference from silver, mercury, bismuth, and stannoustin is eliminated with acid potassium iodide. Gold, platinum, and palla-dium, which might interfere, are fortunately rarely en~ountered.~~ Com-plexes formed between metal thiocyanates, including copper, and a-naphthylamines are quantitatively precipitated,28 and the copper thiocyanate-pyridine complex can be extracted with cblor~form.~~ The o-toluidinecomplex is regarded as the best for a colorimetric determination.Dithio-oxamide (rubeanic acid) forms a precipitate with a copper solution, but theprecipitate can be dispersed with gum arabic and colorimetric measurementsobtained, provided interference due to the colour of the reagent be elimin-ated.3O Curves relating copper concentration and colour have been obtained14 T. Moelier, Ind. Eng. Chem. Anal., 1943, 15, 346.15 Pharm. Tjdschr. Nederl. Indie, 1942, 19, 13.16 J.R. Gilbreath and H. M. Haendler, Ind. Eng. Chem. Anal., 1942,14, 866.1 7 Z . anal. Chem., 1933, 95, 400.19 C. E. Pritchard and R. C. Chirnsido, ibid., p. 244.2o A. K. Majumdar, J . Indian Chem. SOC., 1944, 21, 24.21 V. Hovorka and J. Vorisek, Chem. Listy, 1942,36, 73; Chem. Zentr., 1942,11, 573.22 V. Hovorka and J. Vorisek, Chem. Listy, 1943, 37, 5; Chem. Zentr., 1943, I, 1700.23 M. L. Moss. M. G. Mellon, and G. F. Smith, I d . Eng. Chem. Anal., 1942,14, 931.2' M. L. Moss and M. G. Mellon, ibid., 1943,15, 116.2 6 M. Jean, Bull. SOC. chim., 1943, 10, 201.26 B. B. Knapp, Proc. Amer. Electroplaters SOC., 1944, June, 109.27 G. H. Bendix and D. Grabenstetter, Ind. Eng. Chem. Anal., 1943, 15, 649.2 * F. B. Ubeda and R. Alloza, Anal. Fis.Quim., 1941, 37, 350.29 L. A. Gulyaeva and E. S. Itkina, J . Appl.,Chem. U.S.S.R., 1944,17, 252.30 A. Ringbom and F. Sundman, Finska Kem. Medd., 1942, 51, 42; Chem. Zentr.,l8 A. K. Majumdar, Analyst, 1943, 88, 242.1943, I, 761.REP.-VOL. XLTI. 258 ANALYTICAL CHEMISTRY.for this reagent.31 R. J. Sherman 32 has described a solution of 5-bromo-2-aminobenzoic acid in sodium hydroxide which gives good quantitativeprecipitation with copper of a complex which can be washed, dried, andweighed.I7ron.--o-Phenanthro1ine7 ax’-dipyridyl, and sulphosalicylic acid are allsatisfactory reagents for the colorimetric determination of iron. J. P.Mehlig and H. R. Hulett 33 recommend spectrophotometric measurement ofthe colour produced by ferrous ion with either o-phenanthroline or its nitro-derivative.Factors affecting the development of the colour34 are theorder in which the reagents are added, the speed of the addition, the presenceof phosphate, the temperature, and the time allowed for development of thecolour ; the addition of a buffer, sodium citrate, a t a temperature exceeding20” is advantageous. As little as 0-05 pg. of iron can be detected with thisreagent or aa’-di~yridyI.~~ Certain derivatives of o-phenanthroline are notpreferred in place of the parent sub~tance.~3The production of coloured ferrous complexes with either aa’-dipyridylor aa’a’’-tripyridyl may be accomplished by using a wide range of reducingagents.36 K. Buch 37 considers hydrazine sulphate good for this purposeand recommends the addition of an ammonium acetate buffer when formingthe colour.Sulphosalicylic acid was proposed by E. I. Nikitina,38 and H.Pfeiffer 39 records its satisfactory use.Of the five reagents, sulphosalicylic acid , salicylic acid, thiocyanate,aa‘-dipyridyl and o-phenanthroline, the last is regarded as the most satis-factory and reliable,40 a finding which is confirmed by a comparative study 41of this reagent and the A.O.A.C. thiocyanate method. The thiocyanateappears slightly less reliable, chiefly because of the instability of the reagentand the difficulty of reproducing the colour-concentration curve. Despitethe technical difficulties of the production and storage of the reagent, thetitanium chloride titration is reliable and easy to use, and results obtainedby it agree well with the colorimetric figures.The colour of iron withthioglycollic acid is also regarded as more stable than the thiocyanate co10ur,42although the latter is more reliable after a definite time interval.An iron colour used in the analysis of minerals and brasses, sensitiveeven in the presence of fluorides, phosphates, tartrates, citrates, and oxalates,is obtained with ferric iron and disodium 1 : 2-dihydroxybenzene-3 : 5-31 E. J. Center and R. M. Macintosh, Ind. Eng. Chem. Anal., 1945,17, 239.a2 J . SOC. Chem. Ind., 1942, 61, 164.83 Ind. Eng. Chem. Anal., 1942‘, 14, 869.34 S. L. Bandemer and P. J. Schaible, ibid., 1944, 16, 317.36 H. Borei, Biochem. Z . , 1943, 314, 359.36 M. L. Moss and M. G. Mellon, I d .Eng. Chem. Anal., 1942, 14, 862.57 Finska Kern. Medd., 1942, 51, 22; Chem. Zentr., 1943, I, 700.* 8 Zavod. Lab., 1940, 9, 629; Khim. Referat. Zhur., 1941, 4, No. 1, 84.a, 2. anal. Chem., 1943, 126, 81.do B. Bencze, Mezogazdasagi Kututaeok, 16, 61 ; Chem. Zentr., 1943, 11, 548.E. J. Benne and A. J. Snyder, J . Assoc. Off. Agric. Chena., 1944, 27, 526.H. van Dam, Ing. china., 1942, 26, 131 ; Chem. Zentr., 1943, I, 2323GASKIN : ORGANIC REAGENTS IN INORGANIC ANALYSIS. 259disulphonate.43 A linear relationship between concentration and colourreading between 0 and 10 pg. has been demonstrated with nitroso-R-salt.44A rapid method depends on the brown colour formed in slightly acid ironsolution with dimethylglyoxime and hydrazine hydr~chloride,~~ and ironcan be removed from a solution, before nickel and cobalt determinations,with hexamethylenetetramine and triethan~lamine.~~Bismuth.-The grouping NR*CS*S*C( SH):N found in thiodiazoledithioland phenyldithiodiazolonethiol is responsible for the formation of colouredprecipitates with the metals of the hydrogen sulphide If theappropriate bismuth complex is peptised with gum acacia, accurate figuresfor bismuth are given by colour rnea~urements.~~~ 49 When phenyldithio-diazolone is used there is considerable interference from other metals, 50and the bismuth complex is best formed from the potassium salt of thereagent in the presence of gum acacia.If the gum is omitted, the precipitatecan be weighed as such. M. Kuras 51 has also noted the reactions of thesulphide-group metals with mercaptoazoles, with particular reference tobismuth.The capacity of these compounds to form metallic salts is thiazole>imidazole > oxazole .s2As already mentioned, T. MoellerI4 has determined the optimum pHrange for the extraction of various metals with chloroform containingoxine, and H. G. Haynes 53 describes complete separation of the bismuthcomplex at pH 52-54 by using oxine alone.I n the absence ofzinc, manganese, and antimony, phenylarsonic acid can be used a t pH 5.1-5.3, and separation from a number of metals is possible if potassium cyanideis added.54 Similarly, the same reagent can be used if the solution isbuffered, preferably with ammonium acetate.55 a-Picoline methiodide i i asuitable reagent for detecting bismuth.56 Small amounts (0.0008-0-0018 yo)in copper have been determined with dithi~one,~' a reagent whose value forthis purpose has already been mentioned under " lead.''BeryZZium.--p-Nitrobenzeneazoresorcinol was first proposed as a spottest for beryllium by A.S. Komarovskii and N. S. P o l u e k t ~ v , ~ ~ but it hasbeen suggested not to be reliable for less than O-8y0 of beryllium.59Substituted arsonic acids have proved of value.43 J. IT. Yo0 and A. L. Jones, I n d . Eng. Chem. A w l . , 1944, 16, 111.4 4 C. P. Sideris, H. Y. Young, and H. H. Q . Chun, ibid., p. 276.4 5 P. van Stein, Clxmist-Analyst, 1945, 34, 15.4 7 A. K. Majumdar, J. I n d i a n Chem. SOC., 1942, 19, 396.48 Idem, Sci. and Cult., 1942, 7, 458.4 O Idem, J .I n d i a n Chem. Xoc., 1944, 21, 240.5 1 Chem. Obzor., 1941, 16, 17; Chem. Zentr., 1941, 11, 84.62 M. Kuras, Chem. Obzor., 1942, 17, 41; Ghem. Zentr., 1944, I, 39.53 AnuZyst, 1945, 70, 129.64 A. K. Majumdar, J. I n d i a n Chem. SOC., 1944, 21, No. 4, 119.6s Idem, ibid., p. 157.66 K. Whelan and F. J. Welcher, J . Chem. Educ., 1943, 20, 246.s7 Y. Yao, I n d . Eng. Chem. Anal., 1945, 1'7, 114.s8 Mikrochem., 1934, 14, 315.4 6 A Kundert, ibid., p. 8.6o Idem, ibid., p. 347.F. Kulcsar, Eng. Min. J . , 1943, 144, No. 12, 103.REP.-VOL. XLII I 260 ANALYTICAL CHEMISTRY.W. Stross and G. H. Osborn 60 subsequently elaborated a photometric method,using the same reagent and, despite the presence of alumina, were able tocorrelate colour measurement (photometrically) with beryllium content overthe range 0.005-18% Be.The colour comparison could not be madevisually. The same authors further extended the use of the reagent to theanalysis of minerals,c1 and F. Kulcsar 62 uses it to detect beryllium in copperbase alloys.It has been found possible to determine 0.005~0 of beryllium by measuringthe fluorescence of the complex formed between the BeO, ion and morin(1 : 2 : 3 : 5-tetrahydroflavonol), aluminium causing no interferen~e.~~ Thesame author separates chromatographically beryllium, aluminium, andmagnesium with quinalizarin.Boron.-The quinalizarin method for the determination of boron in steelshas been developed and found to give good res~Its,6~ accurate determinationshaving been obtained over the range 0~0005-0~003~0 of boron.g5 It ispossible to apply the method to corrosion-resistant steels containing 0.001-0.005 % of the element, intensities being measured photoelectrically.66 Arelated method 67 for the analysis of plant ashes uses alizarin-S, and in plantand fertiliser ashes 0.1 pg.of boron can be detected with certainty if chromo-trope-2B is the reagent.68. A delicate test for boron, in the absence offluorides, can be made with Solway purple (C.I. 1073) in concentratedsulphuric acid together with a very dilute solution of l-amino-4-hydroxy-anthraquinone in the same a ~ i d . 6 ~ Colorimetric determination, usingpentamethylquercetin, has been proposed, the necessary colour standardsbeing potassium chromate solutions.70Tungsten.-Cost and scarcity of the reagent cinchonine have beenfa6tors encouraging the search for an alternative, and rhodamine-B 'l andP-naphthaquinoline 72 are recommended.F. W. Box 73 considers thatneither cinchonine nor rhodamine-B will effect complete precipitation oftungstic oxide, and in the common methods cinchonine is slightly inferiorwhere amounts between 0.019 and 0.2 g. of tungsten are to be determined.J. H. Yoe and A. L. Jones, as a result of work continued over a number of6o J . SOC. Chem. Ind., 1944, 63, 249,61 Metallurgia, 1944, 30, No. 175, 3.62 Chemist-Analyst, 1945, 34, 28, 29, 39.63 G. Venturello, Ric. Sci., 1942, 13, 726; Chem. Zentr., 1943, I, 2519.64 G. A. Rudolph and L. c'. Flickinger, Steel, 1943, 112, No.14, 114, 131-139, 149.6 6 L. C. Flickinger, Proc. Conf. Natl. Open Hearth Cmm. Iron Steel Div. Amer.6 6 S. Weinberg,.K. L. Proctor, and 0. Milner, Ind. Eng. Chem. Anal., 1945,17, 419.67 D. Dickinson, Analyst, 1943, 68, 106.6 8 A. Stettbacher, Mitt. Lebensm. Hyg., 1943, 34, No. 1-2, 90.69 F. A. Radley, Analyst, 1944, 69, 47.' 0 K. Neelakantam and S. Rangaswami, Proc. Indian Acad. Sci., 1943, 18A, 171.7 1 J. T. Oats, Eng. Min. J . , 1943,144, No. 4, 72,7 2 B. A. Platunov and N. M. Kirillova, Uchenye ZapGki Leningrad Gosudarst Univ.,73 Analyst, 1944, 69, 272.Inst. Mining Met. Eng., 1944, 27, 197.Ser. Kkim. Nauk., 1940, No. 5, (54), 269; Khim. Referat. Zhur., 1941, 4, No. 4, 73GASKIT : ORUANIC REAGENTS IN INORaANIU ANALYSIS. 261years by many analysts, have shown that in the hands of a skilledanalyst anti- 1 : 5-di- (p-methoxyphenyl) -5 - hydroxyamino- 3- oximino- 1 -pen-tene gives good gravimetric results for tungsten in ores and alloy^.^^^ 75Toluene-3 : 4-dithiol produces a bluish-green complex with a few pg.oftungsten, and green complexes with molybdenum and rhenium. The colourof the latter can be suppressed by stannous chloride, and tungsten has beenthus satisfactorily determined in steel. 76Nickel.-In addition to its normal use, dimethylglyoxime can be usedfor colorimetric determinations of nickel in a number of ways, of which asolution of the complex in pyridine is suitable for minute am0~nt.s.'~ Treat-ment of the nickel solution with bromine,781 79 or bromine andbefore the addition of ammoniacal dimethylglyoxime also produces satis-factory colours.Aniline molybdate forms an insoluble double salt withnickel salts,81 a useful reaction, and the insoluble compound of nickel anddiguanide sulphate can be dissolved in a known sulphuric acid and theexcess acid titrated.82Coba2t.-For some time now, or-nitroso- p-naphthol has been the acceptedreagent for this metal, but recently the p-nitroso-a-naphthol has beendescribed as being more sensitive, and a detailed method, bot!h for the pre-paration of the rea.gent and for its use, has been described.83 The insolublecobalt complex is dissolved in benzene to provide a solution suitable for acolorimetric method. 84 By destroying other metal complexes with nitricacid, a rapid photometric determination of cobalt in steels is possible usingnitro~o-R-salt,~~ a reagent which has also found application in the analysisof sintered metal carbides.g6 Cobalt in parts per million can be detected andmeasured by the colour formed with tripyridyl (2 : 6-di-2-pyridylpyridinehydrochloride), provided copper, nickel, and iron be first separated andcyanide and dichromate be absent.87Zinc and Cadmium.-Sodium anthranilate,*8 in the presence of a smallamount of mineral acid, or anthranilic acid, is a suitable reagent for thedetermination of these metals.Precipitation is effective at 100°,89 and thesolution of anthranilic acid recommended is 0.5 mol. in a litre of N-sodiumi4 Virginia J . Sci., 1943, 3, 301.75 I n d .Eng. Chem. Anal., 1944, 16, 45.7 7 E. Passamaneck, I n d . Eng. Chem. Anal., 1945, 17, 257.H. Seaman, ibid., 1944, 16, 354.79 A. M. Mitchell and M. G. Mellon, ibid., 1945, 17, 380.G. R. Makepeace and C. H. Craft, ibid., 1944,16, 375.81 E. Pozzi-Escot, Anal. Quint. Labs. Invest. Cient. Ind., Peru, Oct. 1943, 9.8 2 A. K. Majumdar, J . Indian Chem. SOC., 1943, 20, 289.83 W. Jung, C. E. Cardini, and M. Fuksman, Anal. Asoc. Q u h . Argentina, 1943, 31,84 C. E. Cardini, W. Jung, and M. Fuksman, ibid., p. 191.8 G H. E. Cox, Analyst, 1944, 69, 235.s7 M. L. Moss and M. G. Mellon, I n d . Eng. Chem. Anal., 1943, 15, 74.8 8 H. Funk, 2. anal. Chem., 1942,123, 241 ; Chem. Zentr., 1942, I, 2805.7 ° C. C. Miller, Analyst, 1944, 69, 109.122.F.W. Haywood and A. A. R. Wood, J . SOC. Chem. Ind., 1943, 62, 37.P. Wenger, Helv. Chim. Acta, 1942, 25, 1499262 AXALYTIUAL CYHEMISTRY.hydroxide.g0 In a buffered acetic acid solution zinc can be separated frommixtures containing magnesium and aluminium, or from solution containhgeither of these metals, with 8-hydro~yquinaldine.~~ Small quantities ofzinc are identified with d i t h i ~ o n e . ~ ~ As in the determination of copper,8-hydroxyquinoline can be replaced by Quinosol and Superol. l 5 For cadmiumalone, F. Feigl and L. I. Mirandag3 have employed the red compoundproduced when a cadmium salt is mixed with the complex formed by aa'-dipyridyl and ferrous sulphate. This red compound is suitable for gravi-metric work and can be weighed as such; alternatively, the cadmium iseventually determined with mercaptobenzothiazole.Gallium, Germanium, Hafnium, Indium, Niobium, Osmium, Selenium,Tantalum, Titanium, Thorium, Uranium, and Zirconium.-Substitutedarsonic compounds, already mentioned for bismuth, frequently appear asreagents for some of the above elements.Thus, in a comprehensive reviewof the possible reagents for thorium, P. Wenger and R. Duckett 94 recommendphenylarsonic acid and record that quadrivalent, cerium and zirconiumbehave similarly. The p-hydroxy-derivative of this reagent has been criticallyreviewed as a reagent for zirconium.g5 The precipitates are difficult to collectin certain conditions of acidity ; nevertheless, under the correct conditions,a large number of metals are separated by one precipitation, thoriumrequiring two.The determination is possible in the presence of titaniumonly if the amount of that element is small, and tungsten and tin both tendto co-precipitate. 5-Chlorobromamine acid has also been proposed foruse with z i r c ~ n i u m . ~ ~ If a mixture of o-aminophenylarsonic acid andsalicylaldehyde is added to an acetic acid solution of a selenium salt an intenseyellow colour is produced sensitive to one part of selenium in 2,000,000.The colour is formed by all elements precipitated by arsonic acid, e.g.,titanium and thorium, and only o-aminoarsonic acids and o-hydroxyaldehydescan produce the rea~tion.~' The same author 98 has examined the colourreactions of thorium, uranium, and other metals with four complex reagentscontaining arsenic. The cupferron test is suitable for the micro-determin-ation of ~ranium.~9After the separation by distillation and chloroform extraction of thechlorides of osmium and germanium, two organic reagents are available forthe determination of the elements.Osmium has been shown to react readilywith thiourea to form red complexes suitable for colorimetric measurements,as little as 2-5 p.p.m. having been found in a meteorite,l and quinineD. Gunev, Khim. Indust., 1942, 20, 170; Chem. Zentr., 1942, 11, 1157.91 L. L. Morritt and J. K. Walker, Ind. Eng. Chem. Anal., 1944,16, 387.s2 R. Vanossi, Anal. SOC. Cient. Argentina, 1942, 134, 73.93 Anal. Assoc. Quim. Brazil, 1943, 2, 131.s 5 A. Claasen, Rec. Trav.chim., 1942, 61, 299; Chem. Zentr., 1942, I , 3124.s 6 J. H. Yoe and L. G. Overholser, Ind. Eng. Chem. Anal., 1943,15, 73.S 7 V. I. Kuznetsov, J . Gen. Chem. U.S.S.R., 1944, 14, 897.98 Compt. rend. Acud. Sci. U.R.S.S., 1941, 31, 898 (in English).99 P. M. Isakov, J. Appl. Chem. U.S.S.R., 1943,16, 326.E. E. Sandell, Ind. Eng. Chem. Anal., 1944, 16, 342.O4 Helv. Chim. Acta, 1942, 25, 1110QASKM : ORQANIU REAGENTS IN INORGANIC ANALYSIS. 263tannate will precipitate germanium present aa tetrachloride in chloroformor carbon tetra~hloride.~ It has also been found that germanium is com-pletely precipitated with 5 : 6-benzoquinoline as a complex oxalate whichcan be ignited to the oxide and ~ e i g h e d . ~F. Feigl and P. E. Barbosa 5 describe an unusual reagent prepared bymixing an aqueous solution of ethylenediamine with a large excess of silverchromate.The ionic equilibrium in a saturated solution of the resultingcomplex can be disturbed by hydrogen ions, by metal ions forming complexeswith ethylenediamine, and by acid and acid salts, with only trace solubility,which are strong absorbents for the diamine. This last reaction is shownby the appropriate compounds of molybdenum, t'ungsten, tantalum, andniobium, by amorphous silica and zeolites, but not by crystalline silica.Niobium in weak acid solution, and tantalum in sulphuric acid, producecolours with pyrogallol suitable for the determination of the elements.6Gallium has been separated from aluminium with 5 : 7-dibromo-8-hydroxy-quinoline, since aluminium does not form a complex with the reagent.'The precipitate can be ignited with oxalic acid and weighed as the oxide.T. Moeller * has described the use of 8-hydroxyquinoline for indium andmentions the interfering elements, whilst 1 -phenyl-3-methylpyrazoline hasshown promise with hafni~m.~An existing method for the determination of titanium with oxine hasbeen re-examined, and reasons given for errors in the results.lO The separ-ation by this reagent of the metal from aluminium is possible at pH 5-6-6.5in oxalic acid solution, but not in malonic acid, The detection of titaniumwith sodium 1 : 8-dihydroxynaphthalene-3 : 6-disulphonate under prescribedconditions is regarded as more sensitive than the hydrogen peroxide orthymol test.llCalcium, Magnesium, Mercury, Phosphorus, Potassium, Titanium, andVanadium.-Recent work on organic reagents for the above elements hasnot been extensive, but some of the methods described are of interest.Thepolarographic method combined with an organic reagent has proved valuablein the determination of both calcium and magnesium. Small amounts ofcalcium are precipitated with a known amount of picrolonic acid, and theexcess acid is measured polarographically in the filtrate from the calcium. l2High results in the amperometric titration were found to be due to absorp-R. Vanossi, Anal. Asoc. Quim. Argentina, 1944, 32, 164.Idem, Anal. Asoc. Cient. Argentina, 1945, 139, 29.H. H. Willard and C. W. Zuehlke, Ind. Eng. Chem. Anal., 1944,16, 322.Minist.Agr. Dept. Nac. Producao Min. Lab. Producao Min. (Brazil), 1942, Bol. No.M. S. Platonov and N. F. Krivoshlykov, Trudy Vsesoyuz Konf. Anal.Khirn., 1943,E. Gastingsr, 2. anal. Chem., 1944, 126, 373.E. L. Wallace and A. R. Armstrong, Virginia J. Xci., 1943, 3, 292.5, 72.2, 359.a Ind. Eng. Chern. Anal., 1943, 15, 270.lo A. Claasen and J. Visser, Rec. Tvav. chim., 1941, 80, 715.l1 R. Vanossi, Anal. Asoc. Quim. Argentina, 1944, 32, 5 .l2 G. Cohn and I. M. Kolthoff, J. BWZ. Chem., 1943,147,705264 ANALYTICAL CHEMISTRY.tion of the picrolonic acid by the filter paper, for which sintered-glass crucibleswere successfully substituted. l3 It is possible to measure the concentrationof oxine with the polarograph, and such measurements made before and afterthe addition of a magnesium salt give good figures for magnesium in suchmaterials as tap water and plant ash.14 Magnesium in water has also beendetermined by making use of the magnesium lake formed with Titan-yellow,the amount of which lake, suitably dispersed, can be measured spectro-photometrically.Vanadium has been detected in steel by the yellow colour formed withthe reagent obtained by adding phosphoric acid to an alcoholic solution ofbenzidine until the precipitate redissolves,16 and in rocks by treating achloroform solution containing the vanadium with oxine followed by sodiumazide.17 The oxine produces a reddish colour which changes to green withthe azide. The precipitation of vanadium by cupferron in various con-centrations of sulphuric acid is possible, but the method does not separatetitanium and aluminium, and in the presence of aluminium, both vanadiumand aluminium are precipitated by the addition of a neutral electrolyte.l*A. Steigmann has devised a specific test for mercuric chloride usingspeciaIIy prepared membranes treated with dithizone,lg and quantitativeprecipitation is obtained with the metal thiocyanate and a-naphthylamine.26A variation of the normal cobaltinitrite method for potassium involvesthe determination of the nitrogen in the cobaltinitrite precipitate withphenoldisulphonic acid,Z0 and a reagent suitable for both detection anddetermination of the metal is 4 : 6-dinitroben~ofuroxan.~~J. G. N. G.J. G. N. GASKIN.E. G. KELLETT.1s G. Cohn and I. M. Kolthoff, J. BioZ. Chem., 1943, 148, 711.12 K. G. Stone and N. H. Furman, Ind. Eng. Chem. Anal., 1944,16,596.15 E. E. Ludwig and C. R. Johnson, ibid., 1942,14, 895.la E. Trepka-Bloch, 2. anal. Chem., 1943,125, 276.1' R. Vanossi, Anal. Asoc. Cient. Argentina, 1943, 135, 97.18 M. G. Raeder andT. Aakre, Kgl. Norske Videnskab. Selskab. Porh., 1942, 16,19 J . SOC. Chena. Ind., 1943,82,43.20 E. M. Emmert, Proc. Amer. SOC. Hort. Sci., 1944, 45, 311.21 H. Rathburg and A. Scheurer, Die Chemie, 1943, 56, 123; Chem. Zentr., 1943, II,75 (in English) ; Chem. Zentr., 1943,II, 2184.152

ISSN:0365-6217    

DOI:10.1039/AR9454200247

出版商:RSC    

年代:1945

数据来源: RSC

摘要:

INDEX OF AUTHORS’ NAMES.Aakre, T., 264.Abbot, E. J., 21.Abbott, W. E., 230.Abraham, E. P., 187.Ackermann, D., 244.Acree, S. F., 106.Adams, B. A., 96.Adams, L. H., 44.Adams, R., 129.Adelsberger, L., 233.Adkins, H., 99, 166, 167174, 189, 193.Adler, E., 180, 183, 184186.Ahrens, F. B., 189.Akamatu, H., 31.Albanese, A. A., 249, 252.Albers, H., 64, 183.Albert, A., 129.Albrecht, G., 61.Albright, F., 216.Alder, K., 159, 174.Alexa, V., 127.Alexander, B., 251.Alexandrowa, S., 188.Alexayeva, E., 138.Alloza, R., 257.Allsopp, C. B., 106.Ambrose, H. A., 42.Amstutz, E. D., 164.Anderson, E., 217.Anderson, H. H., 77, 78, 79.Anderson, J. A., 225, 226.Anderson, L. C., 112.Anderson, R. C., 74.Anderson, W. E., 13.Andreev, M., 39.Andrews, L.J., 115.Andrews, L. T., 31.Anslow, G. A., 105.Anslow, W. P., 146.Applezweig, N., 98.Aquilonius, L., 241.Archer, S., 159.Arends, B., 106, 127.Arkel, A. E. van, 193.Armfield, F. A., 137, 139,Armstrong, A. R., 263.Arnold, H., 123.Arnold, L. B., 109.Arnold, R. T., 156.Asarkh, R. M., 213.Ashford, C. A., 197.Ashley, C., 230.Asmussen, R. W., 68.Aston, J. G., 191.Atchley, H. W., 226.141.Atherton, D., 134.Atherton, F. R., 103. 104.Attlee, Z. J., 27.Ault, R. G., 129.Austin, J. E., 129.Austin, S., 156.Auwers, K. v., 192.Avery, W. H., 6, 20.Bacharach, A. L., 239.Bacon, R. G. R., 149.Baddiley, J., 175.Biickstrom, H. J. L., 152.Bahr, G., 64, 75.Baer, E., 144, 145.Baeyer, A. von, 140.Bailar, J.C., jun., 71, 72.Bailey, K., 178, 248.Bailey, K. C., 139.Bailey, P. S., 160.Baker, E. B., 9.Baker, H. W., 38.Baker, W., 152.Baker, Z., 206.Baly, E. C. C., 112.Bambach, K., 256.Bamberger, E., 188.Bandemer, S. L., 258.Bandow, F., 109.Banga, I., 202.Bangert, W. M., 84.Baranowski, T., 176, 170.Barber, H. N., 245.Barbosa, P. E., 263.Barbulescu, F., 127.Barcroft, J., 206.Barker, E. F., 20.Barker, G. C., 32.Barker, G. R., 240.Barker, S. B., 107.Barlow, H. M., 32.Barnard, D. P., 36.Barnes, C. P., 212.Barnes, R. B., 6, 13, 14, 15,Barnes, R. H., 112, 200,Barrenscheen, H. K., 177.Barrett, W., 32.Barron, E. S. G., 197, 198,Bartindale, G. W. R., 49.Bartoletti, E., 170.Barton, C. H., 41.Bass, H. B., 103.Bassett, H.N., 28.Bastron, H., 115, 121.Bateman, L., 67, 110, 113.26616, 17.207, 212.201, 202, 205, 242.Baubigny, H., 152.Bauer, E., 186.Bauer, S. H., 67.Bauer, W., 237.Baumann, C. A., 179.Baumann, H. N., jun., 87.Baxendale, J. H., 94, 148,Baxter, J. G., 116.Baxter, R. A., 194.Bayliss, N. S . , 118.Beach, E. F., 252.Beall, D., 220.Beard, D., 243.Beard, J. W., 243.Beare, W. G., 31, 33.Beati, E., 162, 166.Beattie, F., 179.Beck, W. W., 165.Becker, B., 185.Beeck, O., 6, 14, 31, 33, 38.Beevers, C. A., 47.Rehr-Bregowski, L., 189.Behrens, M., 244.Beiles, R. G., 123.Bekauri, N. V., 229.Belkengren, R., 112.Bell, D. J., 98.Bell, R. P., 67.Bell Telephone Labora-Bellamy, W. D., 175.Below, W., 188.Belton, W.E., 81.Bencze, B., 258.Bender, C. B., 206.Bendich, A., 243.Bendix, G. H., 257.Benedict, W. S., 13.Benne, E. J., 258.Bennett, L. L., 226.Benoy, M. B., 206.Benrath, A., 86.Bensley, R. R., 242.Benz, F., 182.Berg, C. P., 247, 248.Berg, R. L., 201.Berg, W., 243.Berger, E., 176.Bergh, H., 256.Bergman, H. V., 218.Bergmann, M., 250, 251.Bergmann, W., 142.Bergstrom, F. W., 195.Berkenheim, A. M., 167.Berlenbach, B. E., 129.Bernal, J. D., 44, 52.Bertoldi, S., 266.149, 151.tories, 9266 INDEX OF AUTHORS’ NAMES.Branch, G. E. K., 127, 129. Beveridge, J. M. R., 248,Bezer, A. E., 235.Bickerton, J. H., 80.Bielecki, J., 113.Biesele, J. J., 241.Bigeleisen, J., 105.Bikerman, J. J., 21.Billman, J.H., 195.Bills, C. E., 194.Biltz, W., 89.Binkley, W. W., 98, 99.Biquard, D., 112, 125.Birch, A. J., 102.Birkofer, L., 194.Bissi, M., 192.Bjerrum, J., 72.Bjornstahl, Y., 237.Blair, M. G., 98, 99.Blanchard, M., 213.Blix, G., 236, 237.Bloch, K., 213, 229.Block, R. J., 97, 248, 249.Blok, H., 24, 26.Bloomfield, G. F., 131, 133,Blout, E. R., 121, 127, 129.Bobtelsky, M., 74, 146.Bobtelsky-Chaikin, L., 146.Bodendorf, K., 142.Bodian, D., 241.Boeseken, J., 146, 175.Bohme, H., 80.Boericke, F. S., 84.Bohm, L., 29.Bolland, J. L., 132.Bolling, D., 248.Bomke, H., 107.Bond, P. A., 81.Booker, H., 117.Boon, J. W., 50, 51.Booth, A. D., 47, 48.Booth, H. S., 79, 80.Borchers, R., 248.Borei, H., 258.Borek, E., 213.Boryniec, A., 129.Bose, M.K., 257.Bougault, J., 99.Bouman, C. A., 40.Bousky, S., 21.Bowden, F. P., 23, 24, 25,26, 27, 29, 31, 33, 34, 45.Bowden, K., 114, 117.Bowen, E. J., 109.Box, F. W., 260.Boyce, J. C., 107.Boyd, M. J., 251.Boyer, W. P., 160.Boyle, P. J., 227.Braadlie, O., 256.Brachet, J., 240, 241, 242,243, 244, 245, 246.Brady, L. J., 13.Briiuning, W., 87.Brahn, B., 232, 233.251.136.Butenandt, A., 121.Brandes, P., 188, 191.Brattain, R. R., 6, 13, 14,Braude, E. A., 105, 110,Brauer, R. W., 105.Braun, A. D., 157.Braun, E., 115, 189.Braun, G., 151.Braun, K., 177.Braunschtein, A. E., 213.Bredereck, H., 176.Bregman, A., 28.Bremer, F., 39.Breusch, F. L., 204, 205.208, 209, 210.Brewer, C. R., 197.Briault, RI., 34.Bride, W.L., 38.Bridgman, P. W., 43.Bridgwater, A., 164.Brigando, (Mlle) J., 75.Brigham, H. R., 109.Brill, R., 62.Brinkmann, E., 206.Bristow, J. R., 26.Britten, S. W., 226.Brockway, L. O., 51, 58.Brode, W. R., 105, 106,129.Brookens, N. L., 196.Brooker, L. G. S., 111.Brown, E. V., 159.Brown, F., 99.Brown, H. C., 143.Brown, 0. W., 45.Brown, R. I?., 144.Brown, W. G., 110.Browne, J. S. L., 230.Brownsdon, H. W., 41.Brues, A. M., 240.Buc, S. R., 97.Buch, K., 268.Buchanan, J. M., 211, 213.Buchi, J., 183.Buckles, R. E., 127.Buckwalter, F. H., 256.Buchnor, E., 145.Buell, M. V., 176.Biilow, K., 192.Ruerger, M. J., 52, 62.Bukshpan, 2. Y., 170.Bunn, C. W., 48, 54, 61.Burawoy, A., 115, 118, 127.Burdick, H.E., 166.Burg, A. B., 80.Burgard, A., 190.Burger, E., 86.Burgess, W. M., 69.Burkey, R. E., 256.Burr, G. O., 107, 112, 136.Burtner, R. R., 165.Burwell, A. W., 142.Burwell, J. T., 24, 27.Bury, C. R., 111.Buswell, A. M., 18, 247.20.117, 122.Butler, A. M., -230.Butz, L. W., 115, 121, 159.Bychkov, S. M., 213.Byers, J., 37.Caglioti, V., 54.Cagniant, P., 129.Callan, H. G., 245.Callow, N. H., 230.Callow, R. K., 214, 216,Calloway, N. O., 165.Calloway, T. C., 127.Calvin, M., 70, 111, 127.Cameron, G., 225.Camien, M. N., 253.Campbell, R., 189.Campbell, R. M., 243.Campbell, W. E., 22, 34, 37.Cannan, R. K., 97, 249.Canning, G., 118.Cannon, C. G., 19.Cannon, G. W., 100.Cardini, C. E., 261.Carl, L.R., 45.Carlisle, C. H., 52.Carlson, G. A., 72.Carne, H. O., 212.Carnes, W. H., 226.Carney, D. M., 99.Carr, E. P., 106, 107.Cam, J. G., 245.Carreyett, R. A., 229.Cartland, G. F., 218, 219,Case, T. W., 10.Caspersson, T., 241, 245.Cassidy, H. G., 96, 97, 249.Castille, A., 114.Castleman, R. A., 40.Caswell, M. C., 253.Catcheside, D. G., 244.Cattaneo, A. G., 41.Cattelain, E., 99.Center, E. J., 258.Cerchez, V., 193.Chabrier, P., 99.Chaffee, E., 238.Chaikoff, I. L., 217.Chain, E., 238.Chalmers, B., 22, 26.Chambers, R., 225.Chance, M. R., 239.Chang, F. C., 144.Chang, S. T., 114.Channon, H. J., 229.Chantrenne, H., 242.Chapman, A. C., 188.Chargaff, E., 243.Charlampowiczowna, B.,Oharron, F., 34.Chase, H.W., 232.Chase, J. H., 228.Buu-Ho~, 129.220, 230.222.129INDEX OF AUTHORS’ NAMES. 267Cherry, T. M., 45.Cheyney, La V. E., 129.Chibnall, A. C., 248.Child, C. L., 118.Chirnside, R. C., 257.Chou, C. Y., 250.Choudhuri, H. C., 245.Christian, W., 180, 183, 184,Chu, E. J., 253.Chun, H. H. Q., 259.Churchill, J. R., 24.Chute, W. J., 165.Claasen, A., 262, 263.Clapp, L. B., 71.Clapp, R. C., 144.Clar, E., 123, 156.Clark, C. W., 156.Clark, D., 51.Clark, G. L., 32, 37, 45.Clark, H., 112.Clark, R. E. D., 30.Clarke, A. P. W., 222.Claude, A., 236, 238, 242:Claypoole, W., 25, 29.Cleaver, C. S., 96, 97.Cleghorn, R. A., 222.Clemence, I,. W., 195.Clemo, G. R., 129.Cleveland, F. F., 19.Clifford, P.A., 255.Cline, C. H., 163.Clinton, M., jun., 223, 226227, 228.Cloke, J. B., 173.Clow, A., 112.Cochrane, W., 22.Cohen, P. P., 213, 252.Cohen, S. L., 121.Cohen, S. S., 243.Cohn, G., 263.Cohn, W. E., 240.Coleman, E. F., 31.Coleman, G. H., 99, 127.Coleman, P. D., 20.Colesui, C., 193.Collacott, R. A., 39.Collins, C. J., 156.Collins, V. J., 231.Colman, J., 188.Colowick, S. P., 209, 226.Condit, P. C., 139.Cone, E. F., 39.Congwer, C. A., 27.Connor, R., 174.Conrad, M., 189.Conrad-Billroth, H., 124.Consden, R., 233, 249.Conway, E. J., 227.Cook, A. H., 127, 136, 195.Cook, D. B., 25.Cook, J. W., 142.Cook, R. P., 207.Cook, S. V., 45.Cope, A. C., 117.187, 197.243, 245.Zorey, E. L., 224, 226.Zorey, R. B., 61.Zori, C.F., 209, 226.Zorkill, A. B., 225.Zornubert, M., 112.Cosby, E. L., 213.CIoulson, C. A., 58.Zourtney-Pratt, J. S., 40.Covert, L. W., 99.Cox, E. G., 61.Cox, H. E., 261.Craft, C. H., 261.Crafts, R. C., 231.Craig, D. P., 129.Cravath, A. M., 13.Crawford, B. L., 19.Criegee, R., 93, 132, 141,144, 145, 156.Cristol, S. J., 115.Crooke, A. C., 230.Crookes, (Sir) W., 86.CrossIoy, F., 189.Crossman, G., 244.Crowfoot, D., 52, 62.Csokh, P., 105.Csonka, F. A., 251.Culbertson, J. L., 36.Custers, J. F. H., 105.Cuyler, W. K., 230.Cymerman, J., 113.Dacus, E. N., 6, 31.Dainty, M., 178.Dakin, H. D., 146, 190, 208.Dale, B., 18.Dale, E. B., 13.Daly, E. F., 10.Dam, H. van, 258.Danielli, J. F., 244.Daniels, T.C., 195.Danilov, A. A., 229.Dankova, T. F., 167.Dann, W. J., 194.Darken, L. S., 81.Darlington, C. D., 243.Darrow, D. C., 226.Das, N. B., 187.Daubert, B. F., 62.Daudt, W. H., 144.Davey, W., 37.Davidson, D., 191.Davidson, J. N., 240, 241.Davis, A. R., 14.Davis, B. M., 228.Davis, R. E., 115, 121.Dawson, M. H., 236, 238.Day, E., 222.De, S. C., 194.Deasy, C. L., 69.De Boer, J. H., 105.De Borst, C., 125.Deckert, W. A., 189.Dede, L., 127.De Decker, H. C. J., 51.De Fremery, P., 218.De Gaouck, V., 127.De Lange, J. J., 59.DBmbtre-Vladesco, M., 190.Dernjanov, N., 163.Denison, G. H., jun., 139.Dennison, D. M., 19.Dennstedt, M., 191.Denton, C. A., 251.Derjaguin, B. V., 21, 29, 31,Desch, C. H., 28, 112.Desclin, J., 241.Deuel, H.J., jun., 213.Deutsch, A., 129.Deutsch, D., 104.De Wael, J., 32.Dewan, J. G., 207.Dickens, F., 197, 202.Dickinson, D., 260.Dickinson, R. G., 62.Diels, O., 189.Dies, K., 44.Diffner, M., 209.Dillon, R. T., 248.Dimroth, K., 105.Dimroth, O., 143.Dingwall, A., 105.Dirking, H., 113.Ditt, F., 189.Ditz, E., 189.Dobinski, S., 44.Doermann, A. H., 254.Dolan, L. A., 165.Dold, H., 233.Donandt, K., 32.Dorfman, R. I., 230.Dorner, O., 112.Dorrance, S. S., 222.Dosne, C., 219.Dougherty, T. F., 217, 228.Dounce, A. L., 244.Drabkin, D. L., 184.Driel, M. van, 51.Drill, V. A., 226.Driscoll, R. L., 29.Duane, E., 54.Dubos, R., 238.Dubrisay, It., 35.Dubsky, J. V., 256.Du Buy, H. G., 243.Duchesne, J., 18.Duckett, R., 262.Duftschmid-Hinrichs, H.,Dimlap, E.H., 162.Dunlop, D. M., 222.Duncan, A. B. F., 118.Dunn, M. S., 253.Du Nouy, P. L., 36.Dunstan, S., 99.Duran-Reynals, F., 238,Durio, E., 192.Duschinsky, R., 165.Duthie, L. A., 238.Dutta, P. C., 194.Du Vigneand, V., 100.I333.125.240268 INDEX OF AUTHORS’ NAMES.Dwyer, F. P., 76.Dwyer, M., 263.Dye, J. A., 206.Eager, V. W., 129.Eakin, E., 196.Eastes, J. W., 69.Eberius, E., 45.Ecker, H., 105.Eckerson, B. A., 105.Eckhardt, H. J., 121.Edelmann, E., 225.Edison, T. A., 32.Edsall, J. T., 237.Edson, N. L., 206.Egerton, (Sir) A. C. G., 141.Eggleston, L. V., 209, 210,Ehrenberg, J., 176.Ehrlich, P., 89.Eichel, H., 234.Einhorn, A., 188.Eirich, F., 45.Eisenberg, H., 218, 223.Eisner, H., 105.Eistert, B., 106, 111.Elderfield, R.E., 196.Ellingham, H. J. T., 86.Ellingson, R. C., 195, 196.Elliot, J. S., 37.Elliott, K. A. C., 206.Elliott, L., 186.Elliott, N., 68.Elliott, S., 186.Ellis, C. F., 20.Elmadjian, F., 217.E l Ridi, M. S., 116.Elson, L. A., 233.Emden, G., 175.Emery, F. E., 224.Emmens, C. W., 230.Emmert, E. M., 264.Engel, F. L., 226.Engel, L. L., 218, 223, 225.Engler, C., 196.Englis, D. T., 96, 97.Ensslin, F., 65.Entenman, C., 217.Epps, H. M. R., 254.Epstein, L. F., 105.Epstoin, R., 181.Erhardt, O., 151.Erickson, A., 195, 196.Ernsberger, M. L., 129.Ernst, H., 23.Esch, U., 86.Etard, A., 191.Euler, H., 116.Euler, H.von, 180, 183,184, 185, 186.Euw, J. von, 220.Evans, E. A., 37.Evans, E. A., jun., 203.Eva.ns, H. M., 228.Evans, J. F., 219.Evans, L. K., 116, 117.211.Evans, M. G., 94, 148, 149,Evans, R. J., 251.Evans, U. R., 22.Evans, W. L., 99.Everett, H. A., 39, 40.Everse, J. W. R., 218.Ewald, L., 139.Ewens, R. V. G., 69.Fankuchen, I., 52.Farley, F. F., 99.Farmer, E. H., 93, 131, 132,135, 136, 138, 143, 164.Farnham, A. G., 99.Fartmann, B., 109.Favilli, G., 238.Feigl, F., 262, 263.Felder, E., 111.Fenske, M. R., 20.Fenton, H. J. H., 150, 194.Ferguson, L. N., 127.Ferne, O., 104.Ferrebee, J. W., 226.Ferris, S. W., 39.Feulgen, R., 244.Fields, M., 256.Fierz-David, H. E., 194.Fieser, L. F., 144, 218.Fiess, H. A., 96, 97.Filer, L.J., 62.Filmer, J. C., 27.Filz, W., 177.Finch, G. I., 32.Finckh, B., 110.Fjndley, T. W., 136.Fink, M., 44.Finlay, G. R., 67.Fireman, P., 64.Fischer, E., 190.Fischer, F. G., 152.Fischer, H. 0. L., 144.Fischer, W., 86.Fish, W. R., 230.Fisher, A., 213.Fiske, C. H., 176.Flexser, L. A., 105.Flickinger, L. C., 260.Florentin, D., 105.Flower, D., 165.Floyd, N. F., 207, 212.Flygare, H., 132.Foerst, W., 196.Forster, G., 124.Forster, T., 105, 109, 111.Fogg, A., 31.Folkers, K., 100, 101.Forbes, A. P., 216.Forbes, G. S., 77, 79.Ford, J. H., 97.Forrester, P. G., 26.Foster, G. L., 254.Faox, J. J., 17, 18.Fox, S. W., 250.Fraenkel-Conrat, H., 222,161.228.France, H., 128.Francke, W., 150.Frank, H., 187.Franke, A., 163.Franke, R., 192.Frankston, J.E., 252.Eraser, R. W., 216.Freifelder, M., 195.Fremerey, H., 98, 249.French, H. S., 121, 125.Preudenberg, K., 97, 102,233, 234.Frewing, J. J., 31, 34, 35.Fricke, R., 65.Fried, S., 171.Friedelsheim, A. V., 190.Friend, J. A., 74.Fritzsche, H., 183.Fromel, W., 109.Fromherz, H., 105, 123.Fry, D. L., 13.Fry, E. G., 219, 226, 227,Fuchs, H. G., 224.Fuksman, M., 261.Funk, H., 261.FUOSS, R. M., 7, 10, 16.Furman, N. H., 264.Furter, M., 54, 121.229.Gabriel, S., 188, 189, 190,191, 192, 193, 194.Ganicke, K., 136, 139, 153.Gale, E. F., 175, 254.Gallaway, W. S., 20.Gallo, S. G., 37.Gardiner, K. W., 62.Gardner, J. H., 157.Gardner, W. U., 231.Garreau, (Mlle.) Y., 153.Garrett, 0.F., 206.Gastaldi, C., 193, 194, 196.Gastinger, E., 88, 263.Gaudino, N. M., 226.Gauditz, I. L., 105.Gaunt, R., 224, 225, 226.Geddes, A. L., 105.Gee, G., 132.Geiger, E., 256.Geller, H. H., 174.Gemmill, G. L., 15.Gens, C. M., 125.George, P., 139, 140.Gerity, M. K., 226.Germer, L. H., 32.Gersh, J., 241,245.Ghosh, B., 105.Giacomello, G., 54.Gibb, T. R. P., 106.Gibson, A. H., 38.Giesecke, P., 14.Gilbreath, J. R., 257.Gildart, L., 11.Gillam,A. E., 105, 115, 116,Gilliam, W. F., 77.117, 118, 121, 124INDEX OF AUTHORS’ NAMES. 269Gilman, H., 166.Gimmy, A., 40.Ginsberg, H., 101, 102.Ginsburg, A. S., 241.Givens, J. W., 31, 33, 38.Gladstone, M. T., 143.Glasner, A., 146.Glatfield, J.W. E., 151.Gleim, W., 184.Glemser, O., 85.Glickman, S. A., 117.Godchot, M., 192.Goebel, W. F., 232.Goepp, R. M., 99.Gofstein, R. M., 127.Gold, M. H., 129.Goldberg, M. A,, 256.Goldberg, M. W., 54.Goldfarb, Y. L., 173.Goldinger, J. M., 205.Goldschmid, O., 105.Golla, Y. M. L., 229.Goodeve, C. F., 118.Goodeve, J. W., 112.Gooding, C. M., 112.Goodwin, T. H., 61.Gordon, A. H., 233, 249.Gordon, R. R., 11.Gore, R. C., 13, 16, 18, 247.Gouveia, A. J. A., 127.Grabenstetter, D., 257.Graessle, O., 195.Graff, M. M., 106.Graham, H., 118.Grammaticakis, P., 125,127.Granick, S., 105.Grattan, J. F., 219.Greco, P. A., 224.Green, D. E., 179, 186, 200,201, 207, 213.Greene, R. R., 224.Greenhill, E. B., 37.Greenstein, J.P., 240.Greenwood, W. F., 222.Gregor, J., 40.Gregory, J. N., 24, 31, 34,Greville, G. D., 206.Grieg, M. E., 206.Grieneisen, H., 106.Griese, A., 180.Griffith, R. H., 83.Grignard, V., 113.Grimm, H. G., 62.Grimm, J., 20.Grimm, L., 85.Grischkevitsch - Trochimov -Grosheintz, J. M., 144.Grossmann, P., 121.Grube, H. L., 87.Griin, A., 142.Grussner, A., 159.Grumez, M., 127, 129.Grundmann, C., 116.Grunfeld, M., 113.37.ski, 193.Giinther, G., 180.Gulland, J. M., 175, 178Gulyaeva, L. A,, 257.Gunev, D., 262.Gunness, M., 253.Gunsalus, J. C., 175.Gunstone, F. D., 134.Gurin, S., 211.Gurry, R. W., 81.GUSBV, V. I., 163.Gutknecht, H., 188, 189.Haas, E., 187, 188, 205.Haasy, von, 89.Haber, F., 147, 148.Hac, L.R., 253.Haddow, A., 243.Haendler, H. M., 257.Harle, R., 189.Hahn, L., 239, 240.Halban, H., 105, 106.Hale, C. W., 238.Hall, S. A., 195.Hallauer, C., 233, 234.Hallman, 209.Halsall, T. G., 99.Hamblen, E. C., 230.Hamburger, M., 196.Hamilton, C. S., 165.Hammer, G. W., 29.Hammett, L. P., 105.Hammick, P. L., 112.Hampson, G. C., 51.Hanby, W. E., 61.Handler, P., 194, 199.Hantzsch, A., 112.Harberts, C. L., 125.Harden, A., 180.Hardmeier, E., 159.Hardy, G. F., 40.Hardy, J. D., 7.Hardy, R., 61.Hardy, R. A., 96, 97.Hardy, (Sir) W. B., 21, 30,Harned, A. S., 226.Harris, E. J., 141.Harris, G. P., 19.Harris, J. S., 199.Harris, S. A., 100, 147,Harrison, K., 207.Harshaw Chemical Co., 10,Hart, M. J., 129.Karte, R.A., 232, 234.Hartman, F. A., 214, 228.Hartmann, H., 109.Hartmann, M., 137.Kartung, W. H., 189.Hartwig, S., 125.Hassan, A., 127.Hassenkamp, E;, 196.Hassid, W. Z., 97.Kastings, A. B., 213.Batch, F. A,, 188.240.34.175.Hausser, K. W., 109, 114,Havinga, E., 32.Hawkes, C. J., 40.Haworth, R. D., 164, 189.Haworth, W. N., 157, 166.Haynes, H. G., 259.Haywood, F. W., 256, 261.Hecksteden, W., 189.Hedman, F. A., 36.Heertjes, P. M., 126.Hegsted, D. M., 253.Heidelberger, M., 236.Heidenreich, R. D., 21.Heilbron, (Sir) I. M., 113,114, 115, 116, 118, 123,160, 162.Heilmeyer, L., 105.Hein, F., 64, 75.Heinze, R., 36.Heisig, G. B., 171.Heiwinkel, H., 184,185,186.Hellstrom, H., 180,183,184.Helmrich, N.L., 112.Hemingway, A., 203, 207.Hemingway, E. L., 39.Hempel, W., 89.Henderson, G. M., 98.Henderson, J. L., 132.Henri, V., 113, 116, 121,Henry, R. L., 196.Herbert, E. G., 24.Herdle, L. E., 129.Herman, R. C., 19.Hermann, C., 62.Hermanson, V., 228.Herold, W., 105, 112, 118,HBros, M., 105.Hhros, R., 105.Herscher, L. W., 16.Hershberg, E. B., 144, 218.Hertel, E., 110.Herzberg, G., 5, 87, 112.Herzfeld, K. F., 111.Hess, W. C., 252.Hesselvik, H., 236.Heuverswyn, J. van, 231.Hey, D. H., 124, 131, 133,Heyningen, R. van, 235.Heyroth, I?. F., 129.Heywood, B. J., 121.Hibbert, H., 125.Hieber, W., 76.Hilditch, T. P., 93, 134.Hiller, A., 248.Hillmer, A., 125.Hinkel, L. E., 193.Hinz, A., 167.Hirasawa, N., 106.Hirst, E.L., 99, 129.Hirst, G. K., 239.Hoagland, C. L., 243.Hoare, T. P., 22.127, 129.124.124.144270 INDEX OF AUTHORS’ NAMES.Hobby, G. L., 238.Hoch, J., 127.Hock, H., 93, 132, 136, 137,Hock, K., 189.Hodgson, H. H., 105, 106.Hogberg, B., 186.Honigschmid, O., 65.Hoffer, M., 114.Hoffman, D. C., 238.Hoffman, M. M., 230.Hoffman, W. S., 175.Hoffmann, U., 44.Hofmann, K., 110,159,164,Hofmann, K. A,, 151, 152.Hogness, R. T., 114.Hogness, T. R., 186, 188,Holden, M. E. T., 121.Holiday, E. R., 175.Holm, R., 23.Holman, R. T., 135.Holmes, G. L., 96.Holowchak, J., 191.Holt, W. L., 29.Hooke, C. W., 224.Horecker, B. L., 188, 205.Horn, M. J., 247, 248.Horrabin, S., 154.Horwitt, B. N., 230.Houber, H., 103.Houston, J., 118.Hovorka, V., 257.Howe, J.P., 118.Huber, W., 167.Huckel, E., 109.Huffman, E. H., 84.Hughes, E. C., 129.Hughes, T. P., 25, 29, 31,Huh, G., 190.Hulett, H. R., 258.Hulst, L. J. N., 125.Humphrey, J. H., 239.Hunter, F. E., 211.Hunter, J. S., 66.Hunter, M. S., 24.Hurd, D. T., 76, 77.Hurtley, W. H., 208.Hutchinson, E., 28.Hutchison, R., 28.Inagawa, S., 164.Ing, H. R., 251.Ingle, D. J., 214, 216, 218,219, 225, 227, 228, 229.Ingold, C. K., 57.Ingram, W. R., 226.Institution of MechanicalEngineers, 39.Irvine, J. W., 24.Isakov, P. M., 262.Isbell, H. S., 158.Isemura, T., 31.Ishii, T., 181.140.165.205.34, 37.Issaguljanz, W., 188.Itkina, E. S., 257.Ivanov, K., 138, 139, 141.Iwamoto, H., 195.Izmailski, V.A., 113.Jachimowicz, T., .176, 177.Jacobs, F. A., 218.Jacobs, W. A., 176.Jacobson, K. P., 204.Jaff6, W., 181.Jander, G., 63.Japp, F. R., 196.Jean, M., 257.Jeener, R., 242.Jeffrey, G. A., 54, 56, 57,Jeffreys, H., 44.Jelling, M., 191.Jenckel, E., 45.Jencks, P. J., 106.Jenkins, R. O., 32.Jensen, H., 219.Jensen, K. A., 68.Jex, C. S., 30.John, F., 156.John, H. M., 199.Johnsen, A., 32.Johnson, A. W., 116, 118.Johnson, C. R., 264.Johnson, J. R., 129, 162.Johnson, 0. H., 162.Johnson, W. A., 206.Johnston, C., 213.Johnston, J., 44.Joiner, R. R., 195.Jones, A. L., 259, 260.Jones, D. B., 247, 248.Jones, D. G., 127.Jones, E. R. H., 105, 113,114, 115, 116, 117, 118,160, 161, 162.Jones, H.O., 112.Jones, J. K. N., 98, 99, 158.Jones, R. N., 105, 112, 123,Jones, T. G. H., 115.Jones, W. G. M., 157, 166.Jonsson, C. V., 109.Jordan, J., 74.Jorpes, E., 240.Jorre, F., 191.Jowett, M., 206.Jung, W., 261.Juriev, J. K., 163, 170, 172.Kabat, E. A., 235, 236, 242.Kadmer, E. H., 36.Kahnt, F. W., 181.Kalckar, H. M., 175.Kalischer, G., 189.Kametaka, 190.Kamiyama, M., 107.Kanao, S., 164.Kane, S. S., 143.Kao, C. L., 7.113.128.Kara, P., 204.Karabinos, J. V., 100.Karasch, M. S., 115.Karg, E., 103.Karrer, P., 116, 117, 180,181, 182, 183, 184, 185,187, 188.Karush, F., 105.Kasha, M., 112.Kasparek, E., 125.Katzin, B., 226.Kauppi, T. A., 43.Kayser, J. F., 22.Kazmin, V. E., 230.Keller, G. H.; 39.Keller, H., 106.Kelley, K.K., 84, 86.Kendall, E. C., 214, 218,Kendall, F. E., 236.Kennedy, T., 121.Kepler, E. J., 216.Kern, S. F., 45.Kerns, D. M., 112.Kerr, S. E., 176.Keskin, H., 208.Ketelaar, J. A. A., 51.Khaikin, S., 26.Kharasch, M. S., 143, 153.Kharlova, G., 241.Kibler, C. J., 160.Kiessling, W., 177, 179.King, G., 136.King, H., 54.King, H. K., 232, 233.Kinnaird, R. F., 6.Kipping, F. B., 192.Kirillova, N. M., 260.Kistiakowski, G. B., 109.Kiun-Houo, O., 164.Kjolsen, H., 39.Klarding, J., 82.Kleene, R. D., 167, 171.Klein, D., 218.Klein, J. R., 197, 199.Kleinzeller, A., 177, 178,Klemm, W., 65, 85, 89.Klendshoj, N. C., 234, 235.Klevens, H. B., 107.Kline, C. H., 170.Klinkenberg, I. L., 81.Klotz, I.M., 105, 118.Klug, H. P., 61.Klussmann, E., 116.Knapp, B. B., 257.Knell, M., 145.Knoop, F., 189, 197, 203,Knowles, C. M., 102, 103.Knowlton, A. I., 226.%ox, J., 196.Knox, W. E., 201.Koch, F. C., 252.Koch, H. P., 57, 110, 121,132, 135, 162.219, 227.206.208INDEX OF AUTHORS’ NAMES. 27 1Koch, K. R., 32.Koepf, G. F., 227.Kohler, E. P., 160.Kohlmeyer, E. J., 84, 90.Kohlschutter, H. W., 89.Kohn, El. I., 194.Kohn, M., 164.Koller, P., 243.Kolshorn, E., 189.Kolthoff, I. M., 263.Komarovski, A. S., 259.Kon, G. A. R., 121.Konstantinova, K. V., 34.Kopp, L. J., 218.Kordes, E., 51.Koritskaya, O., 138.Kortum, G., 110.Kosjakov, P., 234.Kosterlitz, H. W., 243.Kovner, M. A., 109.Kraft, L., 144, 145.Krebs, H.A. 187, 201, 202,203, 205, 206, 209, 210,211.Kremers, H. C., 10.Krings, W., 87.Krivoshlykov, N. F., 263.Kronig, W., 72.Krouchkoll, M., 32.Kroupa, A., 163.Kuchar, F., 97.Kiinne, E., 189.Kuhn, R., 109, 114, 116!127, 129, 148, 183, 188,195.Kuhn, W., 112, 115.Kuizenga, M. H., 218, 219:Kulcsar, F., 259, 260.Kumler, W. D., 125.Kundert, A., 259.Kuras, M., 259.Kurz, P. F., 146.Kusin, A., 234.Kussakov, M., 33.Kuznetsov, V. I., 256, 262.222.Lahey, F. N., 115.Lamb, A. B., 73.Lambert, A., 124.Lambert, P., 13.Lan, T. H., 244.Landsteiner, K., 232, 233.Landstrom-HydBn, H., 241.Lane, P. S., 40.Lang, E., 189.Lang, S., 132, 137, 140.Langer, T., 127.Langmuir, I., 31.Lardon, A., 220.Lardy, G. C., 114, 115.Larsen, R.G., 137, 139,141.Laskowski, M., 244.Laszlo, E., 158.Laubengayer, A. W., 67.Lauer, W. M., 135.Lautsch, W., 102.Lavin, G. L., 243.Lavine, T. F., 252.Lawrence, A. S. C., 178.Lawrence, R. D., 231.Lazarev, V., 29.Lazarow, A., 242.Lea, M. C., 43.Leatham, J. H., 226, 231.Leavey, E. W. L., 29, 30.Leben, L., 26, 31, 34.Leblanc, M., 45.Lebok, F., 110.Lecomte, J., 13, 17, 19.Lederle, E., 118.Le FPvre, R. J. W., 127.Legault, R. R., 96.Legoux, C., 64.Lehmann, H., 197.Lehmann, H. L., 112.Lehninger, A. L., 207, 213.Lehrer, E., 6, 7.Leibmann, E. A,, 256.Leloir, L. F., 207, 211, 213.Lennard-Jones, J. E., 108.Leonard, N. J., 144.Le Page, G. A., 179.Lerner, A,, 200.Leslie, W. B., 192.Leszczynski, C., 110.Leuckart, R., 191.Levene, P.A., 175,176,185Levin, L., 229.LBvy, J., 189.Lew, B. W., 99.Lewis, G. N., 105, 109, 111112, 129.Lewis, L. A., 222.Lewis, R. A., 223, 227, 2243Ley, H., 106, 112, 113, 125Liang, T. Y., 229.Lichstein, H. C., 213.Lichtenstein, H., 251.Lichtman, V. I., 33.Liddel, U., 6, 13, 14, 15, 16Liddell, H. F., 249.Liebknecht, W. L., 178.Liem, H. T., 257.Lifschitz, J., 112.Lifson, N., 213.Lincoln, B. H., 32, 37.Lindenbaum, S. L., 115.Linnett, 5. W., 19.Linsert, O., 121.Linstead, R. P., 130, 143,Linstrom, C. F., 106.Lipkin, D., 109.Lipmann, F., 175, 197, 198,199, 200.Lippacher, K., 44.Lipscomb, W. N., 80.Lipson, M., 29.Lipton, M. A., 205.190.17.193, 194.Lishmund, R. E., 109.Lissovsky, L., 26.Lister, M.W., 112.Litmanovitsch, M., 105,106.Ljubimova, M. N., 178.Llewellyn, F. J., 61.Lobry de Bruyn, 191.Loeb, R. F., 214, 226.Logan, M. L., 251.Logghinov, G., 33.Lohmann, K., 175,176,177,Lohr, H., 114.Lojlrin, M. E., 226.Long, C., 202.Long, C. N. H., 219, 226,227, 229.Longenecker, H. E., 62.Longuet-Higgins, H. C., 67.Loofbourow, J. R., 129.Loomis, E., 224.Lorber, V., 213.Lorillard, S., 17.Loring, H. S., 240.Lowe, W. G., 165.Lowell, A., 226.Lowry, T. M., 109, 114,127.Lu, C. S., 58, 59.Lucas, C. C., 248, 251.Luck, H. R., 41.Ludlam, E. B., 109.Ludwig, E. E., 264.Luft, K. F., 6, 16.Lugg, J. W. H., 252.Luhrmann, H., 110.Lukens, F. D. W., 207.Lukes, J. J., 83.Lundberg, W.O., 135.Lusk, G., 206.Luszczak, A., 105.Luthy, A., 114.Lutschinski, G. P., 81.Lutwak-Mann, C., 175.Lutz, K., 111.Lutz, R. E., 160.LuValle, J. E., 153.Lynas-Gray, J. I., 121.Lynen, F., 206.Lyster, S. C., 219.Lythgoe, B., 178.McAlister, E. D., 6.Macaulay, J. M., 25, 44.Macbeth, A. K., 129.McClean, D., 237, 238, 239.McCleland, N. M., 112.McCloskey, C. M., 99.McCombie, H., 103.McCombie, J. T., 113, 115,MacConkey, C. A. H., 127.McCready, R. M., 97.McCullagh, E. P., 222.McCullough, J. D., 105.McDonald, F. G., 194, 196.McDonald, R. S., 6.179.116272 INDEX OF AUTHORS’ NAMES.Macewan, D., 47.MacFarland, W. E., 229.MacGillavry, C. H., 50, 51McGinn, C. E., 160.McGookin, A., 127.McIlwain, H., 153.Macintosh, R.M., 258.MacKay, E. M., 212.McLean, M., 142.Maclean, M. E., 106.McManus, T. B., 206.McMurry, H. L., 109.McNally, R., 206.McNeely, W. H., 99.McNeil, C., 235.MacPherson, H. T., 252.McReynolds, J. P., 72.Madinaveitia, J., 237, 238Magel, T. T., 105, 109.Maier, J., 189.Majumdar, A. K., 257, 259,Makajeva, Z., 234.Makepeace, G. R., 261.Makino, K., 177.Malam, M. J., 197.Maloney, L. S., 146.Manchen, F., 127.Mankad, B. N., 106.Mann, P. J. G., 199, 202.Marburg, R., 190.Marchlewslti, L., 129.Marcus, F. K., 103.Marder, M., 36.Mardles, E. W. J., 41.Marshak, A., 244, 245.Marstens, R. W., 206.Martin, A. E., 17, 18.Martin, A. J. P., 98, 233,248, 249, 251.Martin, D. R., 80.Martin, G., 29.Martius, C., 200, 203, 204Martynoff, M., 129.Marvel, C.S., 162.Masaki, K., 112.Maslennikov, V. M., 33.Mason, A. T., 191.Mason, H. L., 216, 225,230Mason, H. S., 146.Masters, D. L., 24.Matchett, J. R., 96.Matheson, G. L., 6.Mattei, G., 162, 170.Mattheson, L. A., 21.Matthew, T. U., 24.Mattoon, R. W., 105.Maxwell, R. D., 127.May, E. M., 153.Mayer, J., 129.Mayer-Pitsch, E., 125, 127.Mayneord, W. V., 123.Mayo, F. R., 142, 153.61.239.261.208.Mama, F. P., 105.Mead, D. J., 7, 16.Mears, R. B., 24.Mechan, D. K., 251.Medes, G., 207, 212.Medvedev, S. S., 138, 141Mehlig, J. P., 258.Mehta, C. M., 106.Meisel, K., 89.Meisenheimer, J., 112.Meissner, G., 189.Meister, A. G., 19.Mejbaum, W., 184.Mellon, M. G., 257, 258,261,Mellor, D.P., 74.Melnikov, N. N., 156.Menczel, S., 129.Mercer, E. H., 29, 30.Merchant, M. E., 23, 24.Merkel, E., 129.Merritt, L. L., 262.Mertzweiler, J. K., 99.Merz, W., 189.Metcalf, E. A., 158.Metcalf, W. S., 118.Meunier, P., 105.Meyer, G., 167.Meyer, K., 232,236, 238.Meyer, V., 189, 192.Meyer, W., 96.Meyerhof, O., 179, 184, 197.Miall, M., 178.Michael, S. E., 132, 154.Michaelis, L., 94, 105, 155.Michaelis, M., 202.Migliardi, C., 105.Mikhailova, E., 138.Milas, N. A., 146, 147, 151,Miller, A., 99.Miller, C. C., 261.Miller, E. C., 11.Miller, E. S., 105, 112.Miller, H. C., 226.Miller, N. H. J., 196.Milner, O., 260.Milroy, T. H., 179.Minatschev, K. M., 172.Minovivi, S., 196.Miranda, L. I., 262.Mirsky, A.E., 240, 245.Mitchell, A. M., 261.Mitchell, J. S., 241, 246.Mohla, W., 184.Moller, E. F., 194.Moeller, T., 257, 259, 263.Morner, C. T., 236.Mohler, H., 105, 112, 114,Moisseev, E. A., 229.Molter, H., 97, 233.Mondain-Monval, P., 141.Montagne, M., 127.klontigel, C., 217.Monzer, W., 84.149.152.115, 123.Moore, A. J. W.. 23, 24, 28.Moore, G. E., 84.Moore, R. L., 74.Moore, S., 251.Morawietz, W., 87, 88.Morcom, A. R., 83.Morehouse, M. G., 213.Morf, R., 116.Morgan, F., 26.Morgan, L. B., 149.Morgan, W. T. J., 232, 233,Mori, T., 176.Morikawa, K., 13.Morin, E. C., 188.Morris, J. C., 20.Morton, R. A., 105, 106,127, 129.Moss, E. B., 6.Moss, M. L., 257, 258, 261.Motz, H., 32.Moulds, L. de V., 156.Moureu, H., 127.Mourgue, M., 251.Mousseron, M., 192..Mozingo, R., 100, 101, 103.Mucklow, G.F., 38.Muller, H., 196.Muller, R., 125.Mulcahy, M. F. R., 45.Mulinos, M. G., 226.Mull, R. P., 197.Muller, H. G., 256.Muller, S.: 158.Mulliken, R. S., 109, 110.Munch, J. C., 189.Munk, (Miss) I., 152.Muiioz, J. M., 213.Muralt, A. L. von, 237.Murison, C. A., 31.Murlin, W. R., 226.Murray, M. J., 19.Muskat, M., 26.Mustafa, A., 137.Myers, F. J., 96.Myrbiick, K., 180.Mysels, K. J., 73.Nachmansohn, D., 199.Naik, K. G., 106.Natta, G., 166, 170.Neber, P. W., 190.Neciullah, N., 206.Needham, D. M., 175, 178.Needham, J., 197.Neelakantam, K., 260.Nekrasov, B., 72.Nelson, H. R., 22, 37.Nelson, J. F., 225.Nelson, J.W., 219, 222.Nelson, W. O., 224, 226.NeRbett, R. B., 213.Neuberg, A., 190.Yeuberger, A., 251.Yeumann, M., 141.Seuwirth, A., 132.235INDEX OF AUTHORS’ NAMES. 273Neuworth, M. B., 105.New, R . G. A., 154.Newbold, G. T., 98.Newsome, P. T., 109.Nicolet, B. H., 247, 251.Nielsen, H. H., 19.Nielson, J. R., 13, 14.Nier, A. O., 207.Nier, A. R., 203.Nikitina, E. I., 258.Nimmo, C. C., 96.Noble, E. G., 193, 194.Nocite, V., 200, 213.Noll, W., 65.Nord, F. F., 197.Normant, H., 163, 174.North, H. B., 220.Notter, G. K., 96.Novelli, A., 191.Nowacki, W., 62.Nowinski, W. W., 197.Nozawa, M., 197.Nudenberg, W., 115, 159.Nurse, T. J., 22.Nusbaum, R. E., 13.Nyholm, R. S., 75.Nystrom, H., 184.Oats, J. T., 260.Obuchow, E., 33.Ochoa, S., 199, 201, 202,O’Connor, R.T., 106.O’Daniel, H., 52.O’Dell, R. A., 244.Oetjen, R. A., 7, 13.Ogg, R. A., 105.Ohlmeyer, P., 179, 184.Olcott, H. S., 252.Olsen, E. F., 227.Olson, R. E., 218.Oosterhout, G. W. van, 51.Openshaw, H. T., 103, 104.Orchard, W. M., 165.Osborn, G. H., 260.O’Shaughnessy, M. I., 128.Osten, R . A,, 79.Ostern, P., 176, 179.Ostersetzer, A., 164.Ostrogovich, G., 129.Ottensooser, F., 233.Overholser, L. G., 262.Owen, L. N., 161.Owens, R. G., 20.Paddock, E., 121.Pagnot, C., 136.Paillard, H., 168.Painter, T. S., 241.Palewka, W., 44.Palmer, J., 232.Palmer, J. W., 236.Palmer, K. J., 68.Panchenkov, G. M., 34.Pangiotakos, P. C., 147.Papa, D., 101, 102.204, 205.Parekh, M.M., 57.Park, G. S., 94, 148, 149,Parker, D., 226.Parker, L. H., 43.Partridge, R. F., 256.Passamaneck, E., 261.Passarge, W., 75.Patberg, J. B., 13.Patterson, J. W., 123.Patterson, R. F., 125.Paul, R., 161, 163, 165, 167,168, 171, 172, 173, 174.Pauling, L., 50,58, 111, 154,193.Pearce, J. G., 40.Pechmann, H. V., 196.Pedersen, W. W., 43.Pedlow, G. W., jun., 145.Penfold, A. R., 121.Perdigon, E., 197.Perera, G. A., 226.Perkin, W. H., 189.Perkins, R. Z., 226.Perlzweig, W. A., 199.Pcrman, E. P., 43.Pestemer, M., 105, 127.Peters, C., 62.Peters, F. N., 157.Peters, F. P., 39.Peters, G. A., 216.Peters, R. A., 199, 201, 202,Peterson, M., 45.Peterson, T. E., 191.Petrovski, I. J., 123.Pevsner, D., 178.Pfeiffer, C.A., 224.Pfeiffer, H., 258.Pfiffner, J. J., 214,218, 220.Pfister, R. J., 20.Pfund, A. H., 15.Phelps, E. F., 26.Philipsborn, H. F., jun.,Phillips, G. M., 66.Phillipson, A., 206.Philpots, A. R., 7.Piazolo, G., 102.Pickett, L. W., 20, 107, 121,Pilgrim, F. J., 173.Pilz, H., 132.Pincus, G., 217, 230.Pinkus, G., 188, 191.Pinner, A., 196.Piper, J. D., 129.Pirie, A., 238.Pitzer, K. S., 67.Piwowarsky, E., 40.Platonov, M. S., 263.Platt, J. R., 107.Platunov, B. A., 260.Plessing, E., 44.Podyapolskaya, A. G., 138,Poetsch, W., 189.151.231.128.141.Polivka, H., 235.Pollister, A. W., 245.Polonowska, N., 189.Poluektov, N. S., 259.Polya, J. B., 127.Poppinga, R., 40.Porret, D., 118.Posner, T., 188, 189, 193.Potter, J.S., 245.Potter, V. R., 243.Povenz, F., 106.Powell, H., 11.Powell, H. M., 49, 51, 61,Powell, M. G., 79.Poyner, H., 241.Pozzi-Escot, E., 261.Pratt, M. G., 159.Prelog, V., 98.Prever, V. S., 39.PrBvost, J., 27.Price, C. C . , 145.Price, J. R., 129.Price, W. C., 1G7, 118.Price, W. H., 209, 226.Prichotko, A., 118, 123.Princivalle, G . , 194, 196.Pritchard, C. E., 257.Proctor, K. L., 260.Proskauer, E., 106.Prutton, C. F., 35, 41, 83.Pummerer, R., 113.Purvis, J. E., 112.69.Quanquin, B., 141.Quarrel, A. G., 22.Quastel, J. H., 199, 202,206.Quibell, T. H. H., 237.R,abinowitch, E., 105, 118.Radley, F. A., 260.Radulescu, D., 127, 129.Raeder, M. G., 264.Rahbek, K., 32.Rainsford, S. G., 235.Raiziss, G.W., 195.Raleigh, G. W., 231.Ramart-Lucas. P., 106, 109,112, 113, 125, 127, 129.Ramshottom, J. E., 41.Ramsdell, L. S., 52.Randall, H. M., 7, 13.Rangaswami, S., 260.Rank, B., 144, 145.Rank, R. H., 20.Raphael, R. A., 115, 116.Rapoport, B., 167.Rapoport, I. B., 167.Rapson, W. S., 123.Rasmussen, R. S., 13, 20.Rathburg, H., 264.Ratner, S., 200, 213.Rawlings, F. N., 96.Ray, P., 257.Raymond, A. L., 62274 INDEX OF AUTHORS’ NAMES.Rebenstorf, M. A., 144.Reed, P. W., 26.Rees, A. L. G., 30, 118.Rees, M. W., 248.Reeve, E. W., 193.Rehbinder, P., 33.Reich, W. S., 99, 104.Reichstein, T., 116, 159,Reifenstein, E. C., 216.Reinecke, R. M., 218.Reiner, J. M., 197.Reiss, M., 229.Remick, A. E., 155.Remington, J.W., 214,225.Remington, W. R., 128.Rendall, J. L., 195.Reuter, M. A., 129.Reveley, W. G., 160.Reynolds, D. D., 99.Ricardo, H. R., 40.Richards, G. O., 193.Richards, R. E., 8, 11, 18.Richert, D., 218.Richter, D., 131.Richter, M., 97, 249.Rickert, D. F., 159.Rideal, E. K., 139, 140.Ridler, I(. E. W., 24.Rieche, A., 118.Riegel, B., 131.Rieke, C. A., 110.Ries, E., 241.Rigamonti, R., 166.Rigelhaupt, L., 29.Rihl, S., 65.Riley, E. F., 103.Riley, H. L., 156.Ringbom, A., 257.Ringel, S. J., 247.Ringier, B. H., 183.Rittenberg, D., 213, 229,Ritter, J. J., 153.Rivers, T. M., 243.Robb, C. D., 9.Robertson, A., 138,139,140.Robertson, J. M., 47, 53,Robertson, W. van B., 237.Robeson, C. D., 116.Robinson, H.J., 195.Robson, J. M., 231.Roche, J., 251.Rochow, E. G., 76, 77.Rockland, L. B., 253.Rodebush, W. H., 128.Rodewald, G., 89.Roduta, F. L., 137.Roe, E. M. F., 123.Roensch, M. M., 39.Roess, L. C., 6, 8, 31,Rogers, B. W., 62.Rogers, H. J., 240.Rogers, T. A., 41.Rogcre-Lom-, R . U7., 62.214, 220, 224.254.56, 57, 59, 60.Rokitskaya, M. S., 156.Roll, F., 44.Rollman, H. S., 213.Ropes, M. W., 237.Rosenherg, A., 127.Rosenburg, R., 233.Rosenheim, O., 54, 121.Rosenmund, K., 103.Rosenthal, C., 208,209, 210,Roskin, G. J., 241.Rossenbeck, H., 244.Roth, F. L., 29.Rottgardt, K., 33.Rowan, R., 45.Rubin, L. B., 253.Rubin, S. H., 165.Rudolph, G. A., 260.Rudorff, W., 50.Rudy, H., 188.Ruegger, A., 117.Ruegsegger, J.M., 196.Ruehle, A. E., 129.Rule, H. G., 98.Ruppol, E., 114.Rusoff, I. I., 107, 112.Russell, H. W., 37.Russell, J. A., 227.Rust, F. F., 133.Rutschmann, J., 117.Ruzicka, L., 54, 121, 140.Rydin, H., 201.Rydon, H. N., 61, 349.Ryer, A. I., 7.Ryer, F. V., 62.Sackman, B. W., 24.Sackter, E.: 121.Saharo, 38.Saidel, L. J., 247.Sakami, W., 211.Salmon-Legagneur, F., 113.Saltzman, A. H., 218.Sameshima, J., 31, 34.Sampson, J. B., 26.Samurskaja, K. A., 172.Sandell, E. E., 262.Sanfourche, A. A., 65.Santesson, L., 245.Sasaki, H., 236.Sasaki, T., 33.Sato, 38.Satoh, T., 178.Sauer, H., 85.Saunders, B. C., 103.Sausville, J. W., 192, 194.Savinova, V., 138.Sayers, G., 220.Sayers, M. A., 229.Scallet, B.L., 157.Scanlan, J. T., 136.Schaffer, P. A., 94, 155.Schaihle, P. J., 258.Scheer, J. van der, 233.Scheibe, G., 106, 109, 112,113, 115, 121, 124, 125.211.Schein, A. H., 247.Schenck, R., 82.Scheilk, P. W., 89.Schenker, V., 218.Schemer, W., 140, 147.Scheurer, A., 264.Schiff, F., 231, 232, 233,Schindler, K., 159.Schinzel, M., 110.Schlenk, F., 179, 180, 183,184, 185, 186, 213.Schmidt, C. H., 174.Schmidt, G., 175.Schmidt, G. M. J., 62.Schmidt, L. H., 196.Schmidt, W. H., 195.Schneider, A., 86.Schneider, E., 80.Schniepp, L. E., 174.Schnurmann, R., 25, 30.Schoberl, A., 247.Schonberg, A., 137.Schontag, A., 109.Scholz, G., 63.Schomaker, V., 193.Schorigin, P., 105, 188.Schorning, P., 125.Schtschukina, 35.N., 190,Schubert, M. P., 155.Schucking, G., 167.Schuller, A., 89.Schugam, E., 52.Schuler, W., 64.Schultz, J., 241, 245, 256.Schuster, P., 175, 179.Schaartz, H. M., 123.Schwarz, R., 65, 72.Schwarzenbach, A., 11 1.Schwarzenbach, G., 11 1,Schweizer, R., 143.Schwenk, E.. 101, 102.Schwoegler, E. J., 167.Scott, D. B. M., 206.Scott, R. W., 20.Seaman, H., 261.Sears, D. S., 67.Sears, G. W., 51.Sears, W. C., 17.Seastone, C. V., 239.Seel, F., 80, 81.Seib, A., 139.Seibel, D., 244.Seiberth, M., 137.Seitz, G., 109.Seligmann, A. M., 251.Selim, A., 29.Selye, H., 218, 219.Sesler, C. L., 195, 196.Shaffer, W. H., 19.Shafor, R. W., 96.Shankman, S., 253.Shapiro, B., 199.Sharp, n. G., 243.235.195.182INDEX OF AUTHORS’ NAMES.275Sharpe, (Miss) E. D., 153.Shaw, P. E., 29, 30.Shdanov, G., 52.Shemin, D., 254.Shennan, R. J., 258.Sheppard, R., 219.Sheppard, S. E., 105, 109.Shepperd, N., 19.Sherk, K. W., 103.Shifrin, F. S., 109.Shilov, N., 72.Shim, L. A., 247, 251.Shipley, R. A., 230.Shipulins, 0. P., 72.Shively, F. L., 222.Shoppee, C. W., 57, 214Shorr, E., 197.Short, L. N., 129.Shotter, G. F., 29.Shukoff, I. I., 72.Siddiqi, K., 89.Sideris, C. P., 259.Sidhu, S. S., 62.Siefert, H., 52.Siegel, H., 195.Siegel, U., 110.Silver, W., 19.Simard, G. L., 37.Simons, J. H., 79.Simonsen, J. C., 121.Simpson, D. M., 114.Simpson, M. E., 228.Sims, C. E., 88.Singer, T. P., 201.Sinha, S. P., 105.Sjoberg, B., 118.Skanse, B., 237.Skau, E.L., 106.Skeggs, H. R., 253.Sklar, A. L., 109, 111.Slotin, L., 203.Sluys-Veer, F. C., 121.Smadel, J. E., 243.Smakula, A., 105, 114, 115,Smith, A. E., 31, 33.Smith, D. C., 11, 14.Smith, F. L., 141.Smith, G. F., 257.Smith, J. C., 142.Smith, L. B., 62.Smith, L. G., 6, 11.Smith, P., 160.Smith, P. H., 216.Smorgonskii, L. M., 173.Smyth, D. H., 205.Smyth, E. M., 232, 236,Snell, E. E., 213, 253.Snell, J. M., 153.Snellman, O., 237.Snoek, J. L., 193.Snyder, A. J., 258.Snyder, H. R., 100,Soble, R., 235,224.127, 129.238.Soehnchen, E., 40.Soffer, L. J., 214.Soffer, M. B., 103.Soffer, M. D., 103.Solmssen, U., 182, 183.Solomonovitch, A., 26.Soloviev, S., 105.Sonderhoff, R., 209.S o w , A., 191, 192, 194.Sorge, J., 123.Southcombe, J.E., 36.Spandau, H., 90.Sparrow, S. W., 40.Speakman, J. B., 29.Specker, H., 125.Spencer, C., 101.Spencer, W. H., 39.Spengler, O., 96.Spiegelman, S., 197.Spiers, C. W. F., 129.Spies, T. D., 194.Spike, J. E., 62.Spingarn, C. L., 226.Spinks, A., 118.Spinks, J. W. T., 87.Spoerri, P. E., 192,194,195.Sprague, R. G., 226.Spring, F. S., 98, 121, 146,Spring. W., 43.Stacey, G. J., 103.Stacey, M., 233.Stadie, W. C., 207.Stallmann, H., 76.Stamm, G., 250.Stanton, T. E., 40.Stare, F. J., 179, 205.Staub, J., 183.Steadman, L. T., 105.Stearus, J., 19.Stedman, E., 240, 244, 246.Stedman, (Mrs.) E., 244,Stegemann, K., 50.Steiger, R. E., 190.Steigmann, A., 264.Stein, G.A., 161.Stein, K. E., 223.Stein, P. van, 259.Stein, V., 84.Stein, W. H., 250, 251.Stepanov, A. V., 234.Stephens, H. N., 132, 137.Stern, E. S., 105.Stern, K. G., 242.Sternfeld, E. S., 115.Sterrett, R. R., 32.Stettbacher, A., 260.Stetz, E., 197.Stevens, J. R., 161.Stevens, T. S., 160.Stevenson, P. C., 20.Stewart, A., 214.Stewart, C. P., 214.Stewart, E. T., 123.Stewart, F. C., 39.194, 214.246.Stewart, K., 91.Stiller, E. T., 121, 176.Stillman, N., 217.Stimson, M. M., 129.Stocken, L. A., 199, 201.Stoddart, E. M., 63.Stoehr, C., 188, 191, 192.Stokes, J. L., 253.Stoll, M., 140, 147.Stoke, R., 191.Stone, K. G., 264.Stone, M. A., 25, 45.Stoneburg, C. A., 244.Stork, G., 164.Storks, K. U., 32.Stosick, A.J., 51, 60.Stott, E., 29.Stott, V., 29.Stotz, E., 201.Stowell, R. E., 245.Straight, L. A., 125.Strain, R. W. F., 179.Strasser, O., 124.Straub, F. B., 187.Streum, R. F., 20.Strobele, R., 183.Stross, W., 260.Stubbs, A. L., 127, 129.Stuckey, R. E., 129.Stucklen, H., 106, 107.Stumf, P. K., 398.Subbarow, Y., 176.Suga, T., 107.Sugden, T. M., 107.Sulkowitch, H., 216.Sullivan, M. X., 252.Sully, B. D., 138.Sumner, J. B., 213.Sundblad, L., 237.Sundman, F., 257.Sundman, J., 209.Sundralingam, A., 131, 132,Susemihl, W., 137.Sussmann, S., 146.Sutherland, G. B. B. M.,6, 7, 10, 11, 13, 14, 19.Sutton, D. A., 131. 132, 135,136.Sutton, L. E., 66.Swain, G., 121.Swan, G. A., 129.Swam, H. G., 228.Sweeny, W.J., 6.Swendseid, M. E., 207.Swern, D., 136.Swingle, W. W., 218.Synge, R. L. M., 98, 248,249, 251.Szasz, R., 168.Szeki, T., 158.Tabor, D., 23, 24, 26, 27,28, 31, 32, 34, 45.Taira, T., 188.Talbot, N. B., 218, 230.136276 INDEX OF AUTHORS’ NAMES.Tammann, G., 45.Tanaka, K., 32.Tanret, C., 191.Tasker, H. S., 112.Taub, A., 39.-Taylor, A., 48.Taylor, A. N., 241.Taylor, A. R., 243.Taylor, D., 154.Taylor, E. S., 254.Taylor, H. S., 13.Taylor, M. P., 40.Taylor, W., 45.Teague, D. M., 252.Temple, R. B., 20.Tepperman, J., 226.Terry, E. M., 151, 152.Terszakowed, J., 176.Thal, K., 189.Thaler, L., 123.Thayer, S. A., 218.Theorell, H., 134, 186, 188.Thibault, N. W., 52.Thier, W., 190.Thomas, D. S., 153.Thomas, O., 193.Thomas, Q., 205.Thomas, U.B., 22.Thompson, H. W., 6, 7, 11,13, 14, 16, 17, 18, 19, 20.Thompson, K. W., 219.Thompson, R. H. S., 201.Thomson, G. P., 22.Thorn, G. W., 218,222,223,225, 226, 227, 228.Thorne, M. A., 40.Thornton, V., 13.Thorpe, R. E., 137, 139,Tiffeneau, M., 189.Tingstam, S., 186.Tipson, R. S., 176.Tipton, S. R., 217.Tishler, M., 160, 195, 196.Todd, A. R., 103, 104, 178Todt, F., 96.Toenniessen, E., 206.Tolansky, S., 22.Tolbert, B. M., 129.Tomlinson, G. A., 21.Torkington, P., 11, 14, 17Tota, Y. A,, 196.Toutakin, P., 141.Town, B. W., 248.Tracey, M. M., 240.Traube, W., 75.Trautman, C. E., 42.Treadwell, F. P., 189.Treibs, W., 147.Trepka-Bloch, E., 264.Trevett, G. I., 195.Trieber, E., 105.Trillat, J.J., 32, 36.Trivedi, R. K., 106.141.239.18, 19, 20.Trivelli, G., 116.Troger, J., 98.Tronova, V. A., 163, 170.Trotter, I. F., 14.Tsai, L. S., 114.Tscheischwili, L., 52.Tschitschibabin, A. E., 190,Tsuzuki, Y., 106.Tudor, G. K., 25, 40, 45.Tulley, E. A., 99.Tunnicliff, 9. D., 20.Tuot, M., 17.Turba, F., 97, 249.Turkevich, J., 20, 163, 170.Turnbull, D., 83.Turnbull, N. H., 129.Tutin, F., 190.Tutte, W. T., 107.Tuttle, L. C., 198.Twyman, F., 106.Tyte, L. C., 38.195.Ubbelohde, A. R., 141.Ubeda, F. B., 257.Uber, H., 190.Uemura, T., 106.Ufimtzev, V. N., 113.Umbreit, W. W., 175, 179,Ussing, H. H., 254.Usteri, E., 184.Utter, M. F., 197, 198.Utzinger, G., 182.213.Vacher, H.C., 22. .Vaill6, R., 36.Van der Horst, H., 39.Vanderwal, R. J., 165.Vanossi, R., 262, 263, 264.Van Slyke, D. D., 248.Van Voorhis, M. G., 37.Varga, I., 158.Vass, H. M., 218.Vaughan, W. E., 133.Vennesland, B., 201.Venning, E. H., 230.Venturello, G., 260.Verhoek, F. H., 72.Verne, J., 241.Vernon, W. H. J., 22.Verweel, H. J., 61.Verzar, F., 217.Vestin, R., 184.Villiger, V., 140.Vines, R. G., 45.Virtanen, A. I., 209.Visser, J., 263.Vogt, M., 229, 230.Vorisek, J., 257.Voss, E., 89.Wacek, A., 157.Wachholtz, F., 152.Wachtel, 3. H., 249.Waddell, M. B. R., 235.Wade, N. J., 218.Wagner, C., 84.Wagner, J., 124.Wagner-Jauregg, T., 176.Waitkins, G. R., 156.Waitz, K., 32.Wakelin, R. W., 201.Walch, H., 97.Walker, A.C., 245.Walker, J. K., 262.Walker, M. I<., 106.Walker, 0. J., 105, 118.Wallace, E. G., 158.Wallace, E. L., 263.Wallach, O., 189.Wallenfels, K., 240.Wallichs, A., 40.Walling, C., 142.Walls, H. J., 109.Walsh, A. D., 107, 141.Walsh, E. O’F., 178.Walsh, H., 233.Walter, G. F., 106, 128.Walther, W., 145.Warburg, O., 180, 182, 183,184, 187, 197, 244.Ward, W. H., 30.Warlow-Davies, E., 30.Warner, J. C., 45.Waser, J., 58, 59.Wassermann, A., 115, 127,Waszik, J., 32.Waterman, E. I., 125.Waters, W. A., 94, 131, 132,133, 138, 140, 144, 145,151, 154, 156.148.Watltins, W. M., 235.Watt, G. W., 102, 103, 192.Waymouth, C., 240, 241.Weale, A., 45.Webber, M. W., 41.Weedon, B. C. L., 114, 115,Weibke, I?., 65.Weijlard, J., 195, 196.Weil-Malherbe, H., 200,Weiler, G., 232.Weinberg, S., 260.Weiner, A. S., 234, 235.Weinhouse, S., 207, 212.Weinman, F., 232.Weiss, J., 148, 149, 150.Weiss, M., 191.Weissberger, A., 106, 153.Weisz-Tabori, E., 204.Weitz, F.W., 96.Welcher, F. J., 259.Wells, A. F., 49.Wells, A. J., 17, 19, 20.Wells, B. B., 219, 227.Wells, J. A., 224.Wenger, P., 261, 262.117, 160.206, 211.Wells, J. H., 36INDEX OF AUTHORS' NAMES. 277Wenstrom, E., 33.Werkman, C. H., 197, 198,Wertheimer, E., 199.West, R., 190.West, T. F., 118, 121.Westerfeld, W. W., 201.Westheimer, F. H., 160.Westphal, U., 230.Westrik, R., 51.Wetzel, J., 62.Weygand, F., 188.Whelan, K., 269.Whewell, C. S., 29.Whiffen, D. H., 6, 14.White, A., 217, 228, 229.White, J. G., 57.White, T., 233.White, W., 252.Whitman, B., 101, 102.Whitmore, F. C., 145.Whittaker, A. G., 80.Whittingham,G., 31, 34,37,Wihaut, J. P., 129.Wiberg, E., 67.Wick, A. N., 212.Widmer, A., 183.Widstrom, G., 218.Wiegand, C., 129.Wieland, H., 54, 131, 150152, 208, 209, 210, 211Wieland, P., 98.Wieland, T., 98, 249.Wiggins, L. F., 166.Willard, H. H., 263.Williams, C. G., 39.Williams, D., 18.Williams, E. C., 38.Williams, E. F., 248.Williams, R. C., 21.Williams, R. J., 253.Williams, V. Z., 6, 13, 14Williams, W. L., 231.Williamson, B., 128.203.15, 16, 17.Williamson, D. E., 21.Willis, H. A., 7, 11.Willis, J. B., 74.Willmer, E. N., 244.Willmore, C. B., 89.Willstatter, R., 147.Wilson, C. L., 163, 167, 168,Wilson, D. W., 211.Wilson, E. B., 19, 20.Wilson, 5. T., 27.Wilson, K. W., 70.Wilson, R. E., 36.Wilson, T. P., 19, 20.Winans, C. F., 189.Windaus, A., 121.Wingchen, H., 112.Winter, C. A., 226.Wintersteiner, O., 101, 216.Winzler, R. J., 213.Wirz, H., 54.Wise, E. C., 97.Witebsky, E., 234, 235.Wittig, G., 109.Witzemann, E. J., 212.Witzmann, W., 86.Wixom, R. L., 218.Wizinger, R., 129.Wleugel, S., 193.Wohler, L., 86, 89.Wohlfart, G., 241.Wolf, D. E., 100.Wolf, E., 112.Wolf, G., 123.Wolf, K. L., 105, 112, 124.Wolfe, J. K., 218.Wolfrom, M. L., 98, 99, 100,Woo, S. C., 114.Wood, A. A. R., 261.Wood, E. C., 253.Wood, H. G., 197,203, 213.Wood, W. C., 118.Woodruff, S., 151.169, 171, 172.Wolff, L., 190, 191, 192.158.Woods, M. W., 243.Woodward, D. W., 160.Woodward, I., 53, 59, 60.Woodward, R. B., 117, 121.Work, J. B., 72.Wormwell, F., 22.Wright, G. F., 165.Wright, J. M., 193, 194.Wright, L. D., 253. .Wright, N., 6, 10, 11, 14,Wright, W. A., 37.wu, v. L., 20.Wiirgher, E., 117.Wiist, F., 89.Wunderlich, F., 44.Wurm, K., 87.Wyckhoff, R. W. G., 21.Yao, Y., 259.Yeates, A. C., 39.Yee, L. S., 144.Yoe, J. H., 259, 260, 262.Yoffe, A., 45.Yosida, K., 234.Young, F. G., 227.Young, H. A., 132.Young, H. J., 40.Young, H. Y., 259.Young, W. G., 115.Young, W. J., 180.Yurilin, P. P., 163.Zapffe, C. A., 87, 88.Zapp, J. A., jun., 207.Zechmeister, L., 99, 117.Zeitlin, P., 149.Zervas, L., 103.Ziegler, D. M., 244.Ziegler, E., 194.Ziegler, K., 139, 153.Zimmermann, M., 175.Zintl, E., 87, 88, 89.Zittle, C. A., 244.Zuehlke, C. W., 263.16, 18

ISSN:0365-6217    

DOI:10.1039/AR9454200265

出版商:RSC    

年代:1945

数据来源: RSC

摘要:

INDEX O F SUBJECTS.Acetaldehyde, spectrum of, infra-red, 20.Acetic acid, infra-red analysis of, inmixtures with its anhydride, 14.interconversion of, with acetoacetic acid,206.lead salt, oxidation by, 93, 143.metabolism of, in tissues, 206.oxidation in, 208.Acetic acid, amino-, nickel salt, di-hydrate, crystal structure of, 60.Acetoacetic acid, condensation of, withoxaloacetic acid, 208.interconversion of, with acetic acid, 206.metabolism of, oxidation in, 208.Acetophenone, p-bromo-, reduction of, toAcetyl phosphatase, 198.Acetylene, preparation of furans from, 157.Acetylenedxarboxylic acid, ethyl ester,condensation of, with furan-2-valericacid, 160.Acids, fatty, and their esters, heat offilms, structure of, 32.frictional properties of, on metals, 34.higher, metabolism of, 212.ethylbenzene, 101.phosphate, properties of, 199.adsorption of, on steel, 34.synthesis of, from acetate, 213.Aconitase, 204.Acrylic acid, methyl ester, polymerisationof, 148.Adamantane, crystal structure of, 62.Adenine nucleotide co-enzymes, 95, 175.transport, 179.Adenosine diphosphate, 178.preparation of, 178.preparation of, 178.Adenosine-6’-phosphoric acid, derivatives,phosphate transfer by, 175.Adenylic acid, muscle, 175, 177.Adipic acid, crystal structure of, 61.nucleotides as co-enzymes of hydrogentriphosphate, 176.preparation of, 171.structure of, 48.Adiponitrile, impurity in, 17.Adrenals, biochemistry of, 214.cholesterol in, 229.removal of.See Adrenalectomy.yield of sterols from, 222.Adrenal cortex, biochemistry of, 214.extracts, assay of, 218.secretory activity of, control of, 228.steroids, administration of, to adrenal-ectomised or normal animals, 225.biological precursors of, 229.fate of, in body, 230.isolation of, 219.physiological action of, 222.278Adrenal extracts, preparation and pro-Adrenalectomy, results of, 214.Adrenaline, effect of, on adrenal chole-Adrenocorticotropin, 228.effect of, on adrenal cholesterol, 229.Aero-engines, foam formation in lubricat-Alanine, separation of, from valine, 98.#.?-Alanine, preparation of, 97.Alcohols, catalytic action of, in reductionAlizarin-S, boron detn.with, 260.Alkali halides, crystals, as prisms, 10.Alkaloids, isolation of, from totaquine, 98.Alkylbenzenes, autoxidation of, 136.Alkyl 1 : 4-dibromides, preparation of,Alloys, bearing, theory of, 27, 28.Aluminium, detn.of, with quinosol orseparation of, from gallium, 263.Aluminium alloys, detn. in, of copper, 256.Aluminium monofluoride, 89.halides, structure of, 68.nitrate, decomposition of, 86.monoxide, 89.sulphites, 86.Amines, cobalt complexes with, 71.phosphorylation of, 104.Amino-acids, basic, separation of, frombehaviour of, on ion exchange resins, 97.crystal structure of, 59.detn. of, 248.by isotopic dilution, 254.colorimetrically , 25 1.enzymatically, 254.microbiologically, 253.from protein hydrolysis, 247.from wool protein hydrolysates, separ-ation of, 249.in blood group A substance, 233.intermediary metabolism of, 197.separation of, 98.electrolytically, 249.spectra of, infra-red, 18.190.condensation of, 188.oximes, 190.102.perties of, 218.sterol, 229.ing oil in, 42.processes, 102.films, structure of, 32.metals, chemistry of, 65.171.superol, 257.protein hydrolysates, 97.a-Amino-acids, pyrazine syntheses from,a-Amino-carbonyl compounds, self-Aminofurans, 164.z-Amino-ketones, formation of, fromAmmonia, reduction by alkali metals inINDEX OF SUBJECTS.279Amontons’ law, 27.Amplifiers, alternating-current, 8.Analeptics, pyrazines as, 194.Analysis, chromatographic, 98.inorganic, organic reagents for, 255.spectroscopic, infra-red, 11.Analytical chemistry, 247.Androgens, detn.of, in urine, 230.of adrenal cortex, 230.Androstane-3 : 1 l-diol- 17-One, isolation of,from urine, 230.Anhydrocorticosterones, structure of, 224.Aniline molybdate, nickel detn. with, 261.Anilines, substituted, infra-red analysis of,Animal viruses, constitution of, 243.Anisole, p-nitro-, conversion of, to anilineAnnellation, 123.Anorexia in adrenalectomy, 214.Anthranilic acid, sodium salt, cadmiumand zinc detn. with, 261.Anthraquinone - 1 - azo - 4 - dimethylamine,lead detection with, 256.Antibodies, release of, controlled byadrenal substances, 228.Anti-foaming agents in lubricating oil, 42.Antimony triphenyl, crystal structure of,Anti-oxidants for lubricating oils, 41.Antispasmodics, pyrazines as, 195.Arginine, detn. of, 252.Arsenic trihydride, metallic derivatives of,Artichokes, Jerusalem, fructose syrupAscaridole, 142.Atomic weights, determination of, 65.Autoxidation, 13 1.inhibitors of, 93.Auxochromes, definition of, 117.interaction of, with chromophores, 117.ultra-violet absorption of, 118.Azoimide, decomposition of, by activeBacteria, filtrates, spreading or diffusingoxidation of pyruvic acid by, 198.Barium nitrate, decomposition of, 86.orthosilicate, crystal structure of, 52.Basophily of ribonucleic acid, 241.Bathochromic effect, 117.Bearing alloys, 27, 28.Beer’s law, validity of, 107.Benzaldehyde, reduction of, to toluene,Benzaldehyde, p-chloro-, reduction of, toBenzene, purification of, from thiophen,spectrum of, absorption, ultra-violet,Benzene, bromo-, reduction of, to benzene,14.and p-anisidine, 102.62.64.triphenyl, crystal structure of, 62.from, 96.nitrogen, 91.factor in, 238.101.toluene, 101.100.122.101.Benzene, trichloro-, in lubricating oil, 42.nitro-, catalytic reduction of, 99.dinitro-, friction of, 29.Benzeneazoresorcinol, p-nitro-, berylliumdetection with, 259.Benzene-3 : 5-disulphonic acid, 1 : 2-di-hydroxy-, disodium salt, iron detn.with, 258.Benzofuroxan, 4 : 6-dinitro-, potassiumdetection and detn.with, 264.Benzoic acid, 5-bromo-Z-amino-, copperdetn. with, 258.m-chloro-, reduction of, to benzoic acid101.formate, 191.Benzoin, reaction of, with ammoniumBenzophenone, friction of, 29.5 : 6-Benzoquinoline, germanium detn.p-Benzoquinone, spectrum of, absorption,Benzoylacetic acid.ethyl ester, reductionBeryllium, detn. of, reagents for, 259.O-,%Biotin, 94, 165.Biotin methyl ester, conversion of, intodethiobiotin methyl ester, 100.2 : 5 - Bisacetoxymethyltetrahydrofuran,conversion of, into 1 : 2 : 5 : 6-tetra-acetoxyhexane, 173.reaction of, with hydrogen bromide,172.with, 263.ultra-violet, 121.of, to ethyl /3-phenylpropionate, 103.Bis-( 5 -formylfuryl-2) -mercury, 166.Bisfurylmercury, 166.2 : 5 - Bishydroxymethyltetrahydrofuran,Bismuth, detn of, reagents for, 259.Bismuth triphenyl, crystal structure of,Black tongue, treatment of, with pyrazine-Blood, groups, 231.group A factor, 231.transfusion, technique of, 231.Bolometers, 6, 9.Bonds, protonated double, 67.Boron, detn.of, reagents for, 260.Boron trichloride, sulphur trioxide com-halides, additive compounds of, 67, 80.hydrides, structure of, 67.monoxide, 88.Brass, detn. in, of iron, 258.Bromoform, rearrangement of, in presenceButadiene, condensation of, to Buna, 18.production of, 171.spectrum of, absorption, infra-red, 20.Butadienes, nitro-, spectra of, absorption,Butanes, isomeric, infra-red analysis of,cycbButane, spectrum of, infra-red, 20.Butane-1 : g-diol, dehydration of, 162.167.separation of, from lead, 256.62.carboxylic acids, 194.pound of, 81.of catalysts, 77.ultra-violet, 113.ultra-violet, 115.14280 INDEX OF SUBJEClTS.Butanethiol, 4-hydroxy-, conversion of,But-2-ene-1 : 4-di01, dehydration of, 162.5-Butylfurans, 5-tetruhydroxy-, 158.2-Butyltetrahydrofuran, 3'-hy droxy -, 167.But-2-yne-1 : 4-di01, production of, andits hydrogenation products, 162.Butyric acid, liver glycogen from, 213.dl-Butyric acid, a-amino-, copper salt,crystal structure of, 60.Cadmium, detn.of, reagents for, 261.separation of, from copper and zinc,Cadmium cyanide, crystal structure of, 52.subiodide, 89.Casium fluosulphonate, X-ray structureCalcium, detn. of, reagents for, 263.Calcium fluoride, crystals, as prisms, 10.into thiophan, 170.257.of, 52.subhalides, 89.nitrate, decomposition of, 86.polysulphides, 65.vanadates, 83.furans from, 158.intermediary metabolism of, 197.metabolism of, in adrenalectomy, 215.Carbon, active, catalytic action of, inCarbonatopentamminocobaltic salts,Carbonyl chromophore, effect of auxo-compounds, reduction of, to methyleneCarbohydrates, chromatography of, 99.complex formation, 72.structure of, 73.chromes on, 11 8.compounds, 100, 103.Carboxylase, oxalosuccinic, 204.Carminic acid, lead detection with, 256.Carotenoids, spectra of, absorption ultra-Casein, hydrolysis of, by papain, 248.Catalase, hydrogen peroxide decompositionCatalysts for furan production, 168.for furfuraldehyde reduction, 167.for preparation of silicon alkyl and arylhalides, 76.palladium, 103.polymerisation, 149.Raney nickel, 99, 100, 101,- 103.surface-active, in complex formation,reduction, 99.violet, 113, 116.by, 148.72.Catalytic oxidation, 146, 150.Catechol, reaction of phosphorus oxy-Cells, photo-electric, absorption, 11.chloride with, 104.physiological, cytoplasm of, 240.division of, and growth, 246.nuclei, 244.nucleoli, 245.proliferation of, stimulation of, bychromatin, 245.Cellulose esters and ethers, spectra of,infra-red, and structure, 18.Ceric sulphate, complexes of, 74.Chalcopyrite, crystal structure of, 50.Charcoal, decomposition by, of amino-acids, 249.Chloranil, dehydrogenation by, in xylene,156.Chlorates, oxidation by, in presence ofcatalysts, 151.Chloride films as lubricants, 37.5-Chlorobromamine acid, zirconium detn.with, 262.Chloroform, rearrangement of, in presenceof catalysts, 77.Chlorophosphonic acid, dibenzyl ester,preparation and reactions of, 103.A1:4-Cholestadien-3-one, spectrum of,absorption, ultra-violet, 12 1.Cholesterol, synthesis of, from acetate,in the body, 229.Cholesteryl iodide, crystal structure of,47, 52.Chromatin, 245.Chromatogram, partition, 248, 249.two-dimensional, 2 4 9.Chromatography, 98.Chromium carbides, 84.213.halides, equilibrium of, with iron, 84.trioxide, catalytic action of, in hydrogenfour or more conjugated, ultra-violetinteraction of, with auxochromes, 117.single, ultra-violet absorption of, 112.three conjugated, ultra-violet absorptiontwo conjugated, ultra-violet absorptiontwo cumulated, ultra-violet absorptiontwo isolated, ultra-violet absorption of,ultra-violet absorption of, 110, 11 1.peroxide decomposition, 146.Chromophores, definition of, 117.absorption of, 116.of, 115.of, 114.of, 115.113.Chromosomin, 244.Chromous iodide, hydrazine complexes of,preparation and properties of, 64.Cinchonine, tungsten detn.with, 260.Citric acid, formation of, from aceto-acetate and oxalogcetate, 208.GoCitric dehydrogenase, 205.Citrogenase, 208.Coal, and its extracts, spectra of, infra-red,Coatings, corrosion-resistant, in engines,Cobalt, detn. of, reagents for, 261.Cobalt organic compounds, complex, withCobal tammines, polarographic reductionCobaltous hydroxide, oxidation of, 64.Codehydrogenases, structure of, 180.Co-enzymes, adenine nucleotide, 175.of hydrogen transport, 179.Colour, measurement of, 256.75.19.39.amines, 71.of, 74INDEX OF SUBJECTS.281Compounds, complex, chemistry of, 70.of, 73.Co-ordinate link, 66.Cophosphorylase, yeast, 179.Copper as catalyst in preparation of siliconorganic halides, 76.detn. of, in steel, 257.reagents for, 256.separation of, from cadmium and zinc,257.slid on lubricated platinium, 24.slid on steel, 24.surface film on, 22.Copper chromite, catalytic action of, 167.citrate, complexes of, 74.organic compounds, chelate, with alde-tartrate, complexes of, 74.structure of, 48.coloured, spectrophotometer in studyhydes and diketones, 70.Cori ester. See Glucose l-phosphate.Coronene, crystal structure of, 57.Corticosterone, structure of, 221.Corticosterone, 7-hydroxy-, structure of,Cozymase, structure of, 180.Crepin, crystal structure of, 62.Cresylic acid, infra-red analysis of, 14.Crystals, friction of, 28.Crystallography, 4 6.Cubanite, crystal structure of, 52.Cupric salts as autoxidation catalysts, 152.Cystine, detn.of, 251.Cytochemistry, 240.Cytochrome c reductase, 205.Cytoplasm, 240.enzymes of, 242.particulate components of, 242.self-duplication of particles of, 243.221.Decalin, autoxidation of, 141.trans-Decaly19-hydroperoxide, 141.Decarboxylase, specificity of, for amino-1 1 -Dehydrocorticosterone, structure of,11 -Dehydrocorticosterone, 17-hydroxy-,Dehydrogenase, isocitric, 205.succhic, in cytoplasm, 242.Deoxycorticosterone acetates, crystal1 l-Deoxycorticosterone, structure of, 221.1 l-Deoxycorticosterone, 17-hydroxy-,Deoxyribonucleic acid, in cell nucleus, 244.Detectors for infra-red analysis, 6, 15, 16.Deuteracetaldehyde, spectrum of, infra-Deuterethanes, isotopic, infra-red analysisDeuterium as label element for amino-Deuteromethanes, isotopic, infra-redacids, 254.221.structure of, 221.structure of, 62.structure of, 221.synthesis of, in organism, 246.red, 20.of, 13.acids, 254.analysis of, 13.Deuteromethane, nitro-, spectrum of,Di(adenosine-5’-phosphoric acid), 179.Diamond, friction of, on metals, 28, 29.trans-Dibenzoylmethylethylene, cyclis-ation of, to 2 : 5-diphenyl-3-methyl-furan, 160.Dibenzyl, crystal structure of, 47, 56.Diborane, structure of, 67.3 : 4-Di(carbethoxyamino)-2-methylfuran,164.a-Dicarbethoxyglutaconic acid, ethyl ester,dimers, crystal structure of, 57.ay-Dicarbomethoxyglutaconic acid, methylester, dimer, crystal structure of, 57.a-Dicarbonyl compounds, ultra-violetabsorption of, 114.Dienes, conjugated, autoxidation of, 142.Diethyl dithiocarbamate, copper detn.with, 256.peroxide, thermal decomposition of, 141.sulphide, complexes of, with rhodiumhalides, 75.trans - NN’- Diethyl- NN’ - cfimethylpiper-azinium diiodide, trans-di-p-chloro -,61.2 : 5-Diethylpyrazine, 189.Diguanide sulphate, nickel detn.with, 261.Dihydrodiphosphopyridine nucleotide,Dihydrofarnesene hydroperoxide, 132.Dihy droflavin-adenine dinucleotide, 1 86.Dihydrofuran, 162.2 : 3-Dihydrofuran, 94, 169.Dihydrotriphosphopyridine nucleotide,Diketones, preparation of, 174.j3-Djketones, copper complexes with, 70.antz - 1 : 5 - Di - ( p - methoxyphenyl) - 5 -hydroxyambo-3-oximino- l-pentene,tungsten detn.with, 261.2 : 5-Dimethyl-3 : 6-diamylpyrazine, 188.2 : 5 - Dimethyl - 3 : 6 - diisobutylpyrazine,189.2 : 5-Dimethyl-3 : 6-dipropylpyrazine, 189.2 : 5-Dimethylfuran, formation of, fromDimethylglyoxime, nickel detn. with, 261.with hydrazine hydrochloride, iron detn.2 : 5-Dimethylpyrazine, properties of,3 : 6-Dimethylpyrazine, 2-amino-, 195.Dimethylsemiquinone, spectrum of, ab-sorption, ultra-violet, 121.2 : 5-Dimethyltetrahydrofuran, conversionof, into 2 : 5-dimethylthiophan, 170.2 : 5-Dimethylthiophan, formation of,from 2 : 5-&methyltetrahydrofuran,170.Diphenyl oxide, hezachloro-, in lubricatingoil, 42.sulphide, conversion of, into benzene,100.infra-red, 19.surface structure of, 22.184.181.propenylethynylcarbinol, 16 1.with, 259.192.synthesis of, 188282 INDEX OF SUBJECTS.Diphenyl disulphide, pp’-dichloro-, insulphone, conversion of, into benzene,sulphoxide, conversion of, into benzene,Diphenylcarbazide, lead detection by, 256.Diphenylene, crystal structure of, 58.structure of, 48.3 : 6 - Di - - phenylethyl- 2 : 5 - dimethyl -pyrazine, from benzylidenediacetyloxime, 189.2 : B-Diphenyl-3-rnethylfura11, formationof, from trans-dibenzoylmethyl-ethylene, 160.lubricating oil, 42.100.100.Diphenylmethane hydroperoxide, 137.Equations, extinction coefficient, 12.Equilibria, heterogeneous, 81.Ergosterol peroxide, 142.Esters, spectra of, infra-red, 17.2-Ethoxy-5-methyl-5-ethyl-2 : 5-dihydro-2-Ethoxy-2-methyltetrahydrofuran, 3-Ethylbenzene, autoxidation of, 138.Ethylene, spectrum of, infra-red, 20.Ethylenes, fluoro-, spectra of, infra-red,Ethylenediamine, silver chromate complex,Ethylenedithiol ethers, cleavage of, withfuran, 162.chloro-, 162.hydroperoxide, 137.20.as reagent for metals, 263.Diphosphopyridine nucleotide, 183.2 : 5-Diisopropylpyrazine, 189.Diisopropylsalicylic acid, zinc salt, inlubricating oil, 41.au’-Dipropylsuccinic acid, ethyl ester,hydrogenation of, 162.3 : 4-Dipropyltetrahydrofuran, 163.aa’-Dipyridyl, ferrous sulphate complex,cadmium detn. with, 262.Dithiocarbonamides, copper detectionDithioglycollic acid, conversion of, intoDithio-oxamide.See Rubeanic acid,Dithizone, bismuth detn. with, 259.iron detn. with, 258.with, 256.acetic acid, 100.copper detn. with, 257.lead detn. with, 255.zinc detection with, 262.Dodecane-2 : 5 : 8 : ll-tstraone, 174.Dodecane-2 : 5 : 1 l-trione, 174.Drying, effect of, on physical properties,Dyes, quinonoid, oxidation-reduction rc-63.actions of, 154.spectra of, absorption, infra-red, 19.ultra-violet, 129.Elaidic acid, autoxidation of, 135.Electricity, frictional, 30.Electrons, mobile, 108.u Electrons, 109.T Electrons, 108.Encephalomyelitis virus, equine, 243.Energy, rotational and vibrational, inter-Engines, internal-combustion, abrasivemetallurgical structure in, in relation toof cytoplasm, 242.oxidation by, 147.action of, 19.lubrication of, 38.wear, 40.and corrosive wear of, 39.Enzymes, in cell nucleus, 244.Epoxides, formation of, from olefins, 136.-chromes on, li9.‘aP-Ethylenic compounds, ultra-violetabsorption of, 113.4-Ethyloct-4-en- l-yn-3-01, conversion of,into 5-methyl-3-ethyl-2-propylf11ran,161.Euchromatin, 245.Eugenol, conversion of, into dihydro-Euphol, separation of, from euphorbium,a-Euphorbol, separation of, from euphor-Explosives, liquid and solid, initiation of,Extinction coefficient, equation for, 12.Extinction curves, detn. of, 107.eugenol, 101.98.bium, 98.by friction, 45.Fats, intermediary Jlcetabolism of, 197.metabolism of, in adrenalectomy, 216.Fenton’s reaction, 94.Ferrous chloride, anhydrous, equilibriumhydroxide, heat of combustion of, to U-of, with hydrogen sulphide, 83.ferric oxide, 65.Feulgen nuclear reaction, 244.Fibres, natural, friction of, 29.Films, surface, structure of, 22.thickness and structure of, 31.Flavin-adenine dinucleotide, 186.Flavoproteins, 243.Flow-pressure between metals, 26.Fluoboric acid, acetyl derivative, 81.Formols in lubricating oil, 42.5-Formylfurans, 158.Fourier series method, 47.Friction, 20.chemical decomposition by, 43.initiation of explosives by, 45.kinetic and static, 26.kinetic, using lubricants, 31.sliding, electrostatic component of, 30,speed of, in lubrication, 33.static, between surfaces, using lubri-cants, 30.theory of, 21.Fructose syrup from Jerusalem artichokes,96INDEX OF SUBJECTS.283Furan, spectrum of, infra-red, 20.Furans, 157.conversion of, into pyrroles and thio-phens, 169.hydrogenation of, 94, 166.preparation of, 94.from acetylene, 157.ring fission in, 95, 171.Furan mercurials, 165.Furan-2 : 5-dicarboxylic acid, 159.Furan-2 : 3 : 5-tricarboxylic acid, 159.Furan-2-valeric acid, condensation of,with ethyl acetylenedicarboxylate,160.Furfuraldehyde, catalytic decompositionof, 168.hydrogenation of, with copper chromiteand nickel-cobalt catalysts, 167.hydrogenolysis of, 174.Furfuryl alcohol, catalytic decompositionof, 168.preparation of, from furfuraldehyde, 168.Furfurylamine, preparation of, 167.Furfurylideneacetaldehyde, hydrogenationFurfurylideneacetone, hydrogenation of,Fury1 cyanide, hydrogenation of, 167.Furylchloroarsines, 165.Fuse1 oil, pyrazines in, 188.Gallium, separation of, from aluminium,263.Gammexane, production of, infra-rodanalysis of benzene hexachloridesformed in, 14.Gases, GLms, effect of, on metallic friction,32.Gastric juice, blood group substances in,234.Geranylamine hydrochloride, crystalstructure of, 47, 54.Germanium, detn.and separation of,reagents for, 262, 263.Germanium trichloroisocyanate, 78.Glass, friction of, 29.lubricated by fatty acid film, 31.Gliotoxin, crystal structure of, 62.Globsr rod, 11.Glucose, absorption of, from intestines inadrenalec tomy, 217.Glucose l-phosphate, preparation andpurification of, 97.N - Glucosido - 1 : 2 - dihydronicotinamide,183.Glutamic acid, detn.of, 252.by enzymes, 247.Glycerol, distillation of, with ammoniumsalts, 191.Glycine, detn. of, 251.Glycogen, liver and muscle, effect on, ofa-Glycols, oxidation of, with lead tetra-of, 167.167.action of ammonia on, 191.adrenal steroids, 226.with periodic mid, 146.acetate, 144.Glycollic acid, oxidation of, in presence ofGold cyanide, crystal structure of, 52.Growth, animal, effect on, of adrenaIHafnium, detn. of, with l-phenyl-3-Halogen oxy-acids, chemistry of, 67.Halogens, detn. of, in organic compounds,6-Halogenobutyl esters, preparation of,a-Halogeno-ketones, action of ammoniaHeat, frictional, decomposition by, 44.0 - Hetero bio tin, 1 65.Heterochromatin, 245.Heterocyclic compounds, spectra of, ab-sorption, nltra-violet, 128.A1:3-cycloHexadiene, spectrum of, ab-sorption, ultra-violet, 120.A1Z5 -Hexadiene- 1 : 1 : 3 : 3 : 4 : 4 : 6 : 6 -octacarboxylic acid, ethyl and methylesters, crystal structure of, 57.Hexafluorodisiloxane, 79.Hexamethylisocyanidoferrous chloride tri-hydrate, 48, 49.Hexamethylenetetramine, with triethanol-amine, iron removal with, in analysis,259.Hexamminocobaltic chloride, preparationof, with active carbon as catalyst, 72.n-Hexane, as solvent in spectroscopy, 107.spectrum of, absorption, in solution andin gas phase, 109.cycZoHexane, infra-red analysis of, mixedwith cyclohexanone, 14.spectrum of, infra-red, 20.cycZoHexanediones, spectra of, absorption,ultra-violet, 120.cycZoHexanone, infra-red analysis of,mixed with cyclohexane, 14.Hexaphenylethane, oxidation of, inpresence of pyrogallol, 139.Hcxatrienes, spectra of, absorption, ultra-violet, 114.Al-Hexene, autoxidation of, 132.cycZoHexene peroxide, 13 2.Hexoic acid, 2 : 5 : 6-kihydroxy-, 2 : 5 : 6-triacetyl derivative, ethyl ester, 174.Hexolrinase, action of, in presence ofhormones, 209.Histidine, detn.of, 252.Histones in nucleolus, 246.Hormones, detn. of, in natural products,effect of, on hexokinase reaction, 209.Hyaluronic acid, 236.Hyaluronidase, 23 6.Hydrocarbons, aromatic: spectra of, ab-autoxidation of, 93, 131.cracking of, infra-red spectroscopy of,17.olefins, 151.steroids, 227.methylpyrazoline, 263.102.173.on, 190.105.detn.of, 239.sorption, ultra-violet, 122284 INDEX OF SUBJECTS.Hydrocarbons, hydroaromatic, dehydro-genation of, 156.mixed, infra-red analysis of, 13.saturated, autoxidatioii of, 141.salts, crystal structure of, 52.solutions in, 63.Hydrocyanic acid, cadmium and goldHydrogen peroxide, decomposition of,sulphide, equilibrium of, with ferrouscatalysts for, 149.oxidation by, 93, 145.chloride, 83.Hydro-peroxides, 131.a-Hydroxy-acids, oxidation of, 94.with hydrogen peroxide and ferroussalts, 150.o-Hydroxyaldehydes, aromatic, coppercomplexes with, 70.y-Hydroxycarbonyl compounds, tauto-rnerism of, 161.3-Hydroxyfurans, and their acetyl deriv-atives, 160.Hydroxyl radicals in oxidation withhydrogen peroxide, 146.Hyperchromic effect, 117.Hyperconjugation, 110.Ice, friction of surfaces of, 29.Imine radical, 91.Immunology of blood group substances,Jndane hydroperoxide, 137.Indicators, oxidation-reduction, 155.Indium, chemistry of, 65.detn.of, reagent for, 263.Influenza virus, 243.Infra-red analysers, 16.rays. See under Rays.spectroscopy, 5.in analysis, 11.in structure diagnosis, 16.255.235.Inhibitors for autoxidation, 139.Inorganic analysis, organic reagents in,chemistry, 63.compounds, crystal structure of, 49.Inosine &phosphate, preparation of, 178.Inosinic acid, 176.Inositol, separation of, from molasses, 99.Inositol hezaacetate, deacetylation of, 98.Iodoform, decomposition of, by fric LionIon exchangers, resin, 96.Iron, coating of, with chromium, 84.detn. of, reagents for, 258.equilibrium of, with oxygen, 81.molten, transfer of, to gaseous phase,Iron carbonyl, diamagnetism and structureoxides and sulphides, interconversion of,salts as catalysts for hydrogen peroxideIsoagglutination, inhibition of, by bloodunder pressure, 43.90.of, 69.83.decomposition, 148.group A substance, 232.Isocyclic systems, ultra-violet absorptionJewel pivots, friction of, 29.of, 120.Ketones, cyclic, oxidation of, by hydrogenperoxide and vanadium catalyst,147.oxidative ring fission of, 140.,8-Ketosuberic acid, ethyl ester, con-densation of, with ethyl bromo-pyruvate, 159.Kidneys, cytoplasm, phosphatase in, 242.Kidney cortex, oxidation of acetate by,206.spectra of, infra-red, 17.Lactobacillus, amino-acid assays with, 253.Lactobacillus delbriickii, oxidation of pyru-Lanthionine from protein hydrolysis, 247.Lead, detn.of, reagents for, 255.equilibrium of, with oxygen and sulphur,84.separation of, from bismuth, 256.from thallium, 256.Lead tetraacetate, oxidation with, 93, 143.oxide, yellow, change of, into red form,effect of grinding on, 45.dioxide, decomposition of, by frictionunder pressure, 44.sulphide, sensitivity of, to infra-redrays, 10.Lead ores, smelting of, 84.Leech extracts, spreading or diffusingfactor in, 238.Leucine, detn. of, 251.separation of, from proline and valine,98.Leuconostoc mesenteroides, amino -acidassays with, 263.Light, extinction curves for, 107.Linoleic acid, autoxidation of, 135.methyl ester, autoxidation of, 134.Linolenic acid, autoxidation of, 135.Lithium arsenides and phosphides, 64.fluoride, crystals, as prisms, 10.Liver, acetate conversion in, 206.acetylation of sulphonamides in, 199.arginase of, effect of adrenal steroids on,cytoplasm, enzymes in, 242.glycogen in, 242.effect on, of adrenal steroids, 226.pentose polynucleotide from, 240.Lubricants, boundary, effect of temper-ature on, 33.extreme pressure, 37.life of thin f3ms of, 31.metal soaps as, 35.structure of thin films of, 31.and polymers, 41.-anti-foaming agents for, 42.boundary, 21, 30, 35.vate by, 198.228.Lubricating oils, addition to, of additivesLubrication, 20INDEX OF SUBJECTS.286Lubrication, engine, effect of temperatureon, 40.extreme pressure, 37.metal film, 27.of internal combustion engines, 38.speed of friction in, 33.Lumazine, hydrolysis of, to amino-pyrazines, 196.Lungs? phospholipin-ribonucleoproteinswith thromboplastic activity from,243.Lymphocytosis in adrenalectomy, 21 7.Lymphopenia, due to adrenal steroids,Lysine, detn. of, with Neurospora crassa,Magnesium, detn. of, reagents for, 264.Magnesium bromophosphide, 64.Magnesol, 99.Maleic acid, reduction of, to succinic acid,102.spectrum of, absorption, ultra-violet,115.p-Maltose octaacetate, separation of, fromsucrose octa-acetate, 99.Manganese nitrate, decomposition of,86.Mangano-manganic oxide, 65.Manganous hydroxide, oxidation of, 64.d-Mannitol, separation of, from molasses,Melting point, effect of pressure on, 44.p-Menthene, autoxidation of, 132.Mercurials, furan, 94.Mercurifurans, 165.Mercurifuran, 2-chloro-, 165.Mercurifurfuraldehyde, 5-chloro-, 166.Mercurifurfuryl alcohol, 6-chloro-, 165.Mercuri-3-isopropylfuran, 2-chloro-, 165.Mercury, detection of, with dithizone, 264.Metabolism, acetic, in tissues, 206.acetic and acetoacetic, 208.carbohydrate, fat, and protein, tri-carboxylic acid cycle in, 202.carbohydrate, in adrenalectomy, 215.effect of adrenal steroids on, 226.electrolytes and water, in adrenal-ectomy, 214.fat, in adrenalectomy, 216.fatty acids, 212.intermediary, of amino-acids, carbo-hydrates, and fats, 197.protein, in adrenalectomy, 215.pyruvic acid, 197.Metals, polishing of, oxidation in, 44.properties of, pure, 65.shear strength of, 26.Metal-ammines, complex, 72.Metal films, lubrication with, 27, 36.Metal surfaces, effect of, on lubricant228.254.99.properties, 34.films on, 22.fhish of, 27.friction of, effect of gas and vapoiirfilms on, 32.Metal surfaces, frictional properties offatty acids on, 34.intimacy of contact between, 25.outgassing of, 25.rubbing, potential between, 24.Metal wires, effect on, of surface-activematerials, 33.Metallurgy, X-ray methods in, 48.Methacrylic acid, polymerisation of, andits methyl ester, 148.Methane, nitro-, spectrum of, infra-red, 19.Methionine, detn.of, 252.Methoxyalkylbenzenes, reduction and de-methylation of, 102.5-MethoxymethyIfurfuraIdehyde, form-ation of, from 2 : 3 : 4 : 6-tetramethyld-1 : 2-glucoseen, 158.Methyl chloride, reaction of, with silicon-copper, 76.cyanide, additive compounds of, withboron halides, 67.hydroperoxide, thermal decompositionof, 141.radicals in high temperature oxidation,144.Methylamine, spectrum of, infra-red, 20.Methylene chloride, rearrangement of, ingroups, dehydrogenation of, by thiols,a-Methylenic activity towards olefins, 133.5-Methyl-3-e thyl-2 -propylfuran, formationof, from 4-ethyloct-4-en-l-yn-3-01,161.presence of catalyst, 77.154.Methylfurfural, 5-hydroxy-, hydrogenationof, 167.5-Methylfurfuraldehyde, 5-hydroxy-, pre-paration of, from sucrose, 157.5-Methylfuroic acid, oxidation of, 159.5-Methylfuroic acid, 5-hydroxy-, methylester, hydrogenation of, over Raneynickel, 166.2-Methyltetrahydrofuran, 162.5 - Methyltetrahydrofuran - 2 - carboxylicacid, 5-hydroxy-, 5-acetyl derivative,ethyl ester, conversion of, into ethyl2 : 5 : 6-triacetoxyhexoate, 174.sheets, elastic deformation of, 33.Mica, friction of, 29.Microscope, electron, 21.Microsomes, 242.Minerals, detn.in, of iron, 258.Mitochondria, 242.Mitosis, chemistry of, 246.Mixtures, spectra of, 12.Molasses, inositol and d-mannitol from,Molecular structure and ultra-violet ab-Molecules, rotational and vibrational levelsMolybdenum, toluene-3 : 4-dithiol complexMonel metal, catalytic action of, 168.Monox, 87.Morin, beryllium detn.with, 260.99.sorption, 110.of, 19.with, 261286 INDEX OF SUBJEUTS.Mucin, hog gastric, blood group Asubstance from, 232.Muscle, heart, enzymes in, 242.Muscle adenylic acid, 175, 177.Naphthalene-3 : 6-disulphonic acid, 1 : 8-dihydroxy-, sodium salt, titaniumdetection with, 263.fi-Naphthequinoline, tungsten detn. with,260.a-Naphthol, p-nitroso-, cobalt detn. with,261.Nernst filament, 11.Neurospora crassa, culture of, for lysineassay, 253.Nickel, catalytic, Raney, 99, 100, 101, 103.action of, in complex formation, 72.hydrogenation with, 166.detn. of, reagents for, 261.electroplating of, copper detn. in bathsNickel citrate, complexes of, 74.tartrate, complexes of, 74.Nickel-cobalt, catalytic action of, 167.Nickel gauze, catalytic action of, 168.Nicotinamide methiodide, hydrogenationof, by sodium hyposulphite, 182.Niobium, detn.of, reagents for, 263.Nitric acid, structure of, 66.Nitriles, basic, reduction of, with ammoniaand Raney nickel, 103.Nitrogen, heavy, as label element foramino-acids, 254.Nitrogen dioxide, reactions of, 86.tetroxide, reaction of, with phosphoricoxide, 63.for, 257.Nitroglycerin, frictional initiation of, 45.Nitroparaffis, reduction of, 102.Nitroso-R-salt, cobalt detn. with, 261.iron detn. with, 259.Nitrosyl borofluoride, 81.Nonanediones, preparation of, 174.Oat-hulls, furans from, 157.Octahydroanthraquinone hydroperoxide,isooctane, thermal decomposition of, 142.n-Octanoic acid, fission of, incubated with(Estrone, reduction of, to oestradiols, 101.Oils, fatty sulphurised, as lubricants, 37.Olefins, autoxidation of, 93, 131.effect of thiophenol on, 153.hydroperoxides, decomposition of, 136.hydroxylation of, by per-acids, 151.a-methylenic dehydrogenation of, 133.polymerisation of, 149.Oleic acid, autoxidation of, and its ethylmethyl ester, autoxidation of, 134.potassium salt, in sulphurised sperm oil,reduction of, to stearic acid, 102.Oliguria in adrenalectomy, 215.Optical density, measurement of, 13.137.liver, 212.ester, 135.hydroperoxide, 132.in lubricating oil, 42.Organic chemistry, 92.Organic compounds, constitution andultra-violet absorption spectra of, 92,105.Organic reagents in inorganic analysis,255.Oscillograph, cathode-ray, 9.Osmium, detn.and separation of, reagentsOsmium carbonyl halides, 76.tetroxide, catalysis by, of hydroxylation,for, 262.146.stability of, 86.from, 235.ultra-violet, 114.Outgassing of metal surfaces, 25.Ovarian cyst fluid, blood group substancesOxalic acid, spectrum of, absorption,Oxaloacetic acid, condensation of, withOxalocitraconic acid, 203.Oxalocitramalic acid, 203.Oxalosuccinic acid, 204.Oxalosuccinic carboxylase, 204.Oxidase, d-amino-acid, in cytoplasm, 243.acetoacetic acid, 208.with pyruvic acid, 203.cytochrome, in cytoplasm, 242.pyruvic, 198.in brain tissue, 201.of, 155.mechanism of, 92, 130.of sulphur compounds, 152.with hydrogen peroxide, 145.with lead tetra-acetate, 143.Oxidation, compulsory univalent, principleOximes, rearrangemont of, to a-amino-Oxine, bismuth separation with, 259.Ozone, structure of, 67.Paints, spectra of, infra-red, 19.Palladium, catalytic, 103.Papilloma virus, 243.Paraffins, combustion of, 141.Paraffins, nitro-, infra-red analysis of, 14.Penicillin, crystal structure of, 46.Penta-1 : 3-dieneY preparation of, 171.Pentamethylquercetin, boron detn.with,Pentane-1 : 4-dio1, dehydration of, 162.Pentane-1 : 5-diol, dehydration of, 163.Pentane- 1 : 2 : 6-trio1, dehydration of, 163.Pentanol, 4 : 5-dibromo-, dehydrobromin-Pentan-2-01, 1 : 5-dibromo-, 172.Pent-4-011- 1-01, isomerisation of, 163.Pentosans, furans from, 157.Pentose polynucleotides of cell cytoplasm,Pepsin, blood group A substance from, 232.Perchloric acid as activator in catalyticketones, 189.magnesium detn.with, 264.titanium detn. with, 263.260.oxidation of, 161.ation of, 163.240.reduction, 103.structure of, 66INDEX OF SUBJEOTS, 287Periodic acid, oxidation with, 145.Peroxides, formation of, from olehs, 13 1.Phenanthraquinone, dehydrogenation by,o-Phenanthroline, copper detn. with, 267.Phenols, nuclear sulphonation of, 163.Phenyl chromophore, effect of auxo-chromes on, 124.Phenylalanine, detn. of, 252.Phenylarsonic acid, and o-amino-, and p -hydroxy-, as reagents for metals, 262.Phenylchlorosilanes, 77.Phenyldithiodiazolonethiol, bismuth detn.with, 259.1 -Phenyl-3 -methylpyrazoline, hafniumdetn. with, 263.Phenylpropiolic acid, reduction of, to /?-phenylpropionic acid, 102.3-Phenylpyrazolone, isonitroso-, copperdetn.with, 257.Phosphatase, acetyl, 198.in cytoplasm, 242.Phosphide films as lubricants, 38.Phospholipin-ribonucleoproteins withthromboplastic activity, 243.Phosphoruspentabromide, crystal structureof, 61.chloroisocyanates and chlorothio-cyanates, 78.trihydride, metallic derivatives of, 64.trioxide, reaction of, with nitrogentetroxide, 63.oxychloride, structure of, 66.Phosphorylation, 103.Photographic developers, action of, 152.a-Picoline methiodide, bismuth detectionPicrolonic acid, calcium detn. with, 263.Pigments, detn. of, in natural products,Piperidme, formation of, from dihydro-in nitrobenzene, 156.iron detn.with, 258.bismuth separation with, 259.with, 259.105.pyran, 170.from furfuraldehyde, 17 1.from tetrahydrofurfuryl alcohol, 95.cortex activity, 228.Pituitary, anterior, control by, of adrenalPlant ash, detn. in, of boron, 260.Plant viruses, constitution of, 243.Platinum, lubricant film for, 31.lubricated, copper slid on, 24.Platinum oxides, 86.Polishing, high surface temperatures in,Polishing powders, reduction of, 44.Polyisobutylene, spectrum of, infra-red,Polyenes, autoxidation of, 142.Polymerisation of unsaturated compounds,Polysaccharides, end-group assay of, 99.Polystyrene, spectrum of, infra-red, andPolythene, oxidation of, 19.spectrum of, infra-red, and structure, 18.25.and structure, 18.infra-red spectroscopy of, 14.StIZICtLLm, 18.Potassium, detection and detn.of, re-Potassium argentocyanides, 76.agents for, 264.52.beryllium fluoride, crystal structure of,cuprocyanides, 75.nickel cyanides, structure of, 69, 70.permanganate, oxidation by, 156.tetrachlorozincate, crystal structure of,thioferrite, crystal structure of, 50.51.Powders, amorphous, spectra of, 11.Precipitants for amino-acids, 250.Pregnane-3 : 20-diol in urine after deoxy-A4 - Pregnene - 12(,8) : 21 - diol- 3 : 20 - &one,Progesterone, structure of, 224.Progesterone, 17-hydroxy-, structure of,Propane, spectrum of, infra-red, 20.Propenylethynylcarbinol, conversion of,Propionic acid, liver glycogen from, 213.Proportionality factors in absorptionisoPropylbenzene hydroperoxide, 137.Propylene, spectrum of, infra-red, 20.2-Propyltetrahydrofuran, 3’-hydroxy-,Proteins, hydrolysis of, amino-acids from,metabolism of, in adrenalectomy, 216.spectra of, infra-red, and structure,Proteus vulgaris, growth factors for,Pyocyanine, 155.Pyrazine, and its derivatives, 188.Pyrazine, 2 : 3-dicyano-, phthalocyanine-Pyrazines, properties of, 192.Pyrazines, amino-, 195.hydroxy-, 196.Pyrazinecarboxylic acids, 193.antipellagra activity of, 194.decarboxylation of, 191.properties of, 194.spectrum of, infra-red, 20.chloride solution, 33.with, 263.corticosterone administration, 231.224.224.into 2 : 6-dimethylfuran, 161.spectroscopy, 107.167.247.18.194.chemistry of, 95.synthesis of, 190.like compounds from, 194.Pyridine, formation of, from dihydropyran,Pyrites, surface hardness of, in sodiumPyrogallol, niobium and tantalum detn.Pyrroles, formation of, from furans, 169.Pyrrolidine, formation of, from tetra-Pyruvic acid, condensation of, with170.hydrofuran, 170.oxaloacotic acid, 203.metabolism of, 197.oxidation of, by bacteria, 198.in tissues, 200.to acetylcholine, 145288 INDEX OF SUBJECTS.Pyruvic acid, bromo-, ethyl ester, con-densation of, with ethyl 13-keto-suberate, 159.Pyruvic oxidase, 198.in brain tissue, 201.Quartz, surface structure of, 22.Quinaldic acid, copper separation with,Quinaldine, 8-hydroxy-, zinc detn.with,Quinalizarin, boron detn.with, 260.Quinine tannate, germanium detn. with,Quinols, oxidation of, to quinones, 152.Quinoline, reduction of, 102.Quinoline,gallium separation with, 263.indium detn. with, 263.copper separation with, 257.257.262.262.5 : 7 - dibromo - 8 - hydroxy -,8-hydroxy-, copper detn. with, 256, 257.Quinolinecarboxylic acid, 8-hydroxy-,Quinones, reaction of, with tetralin, 156.reduction of, 94.oxidation-reduction reactions of, 154.Quinonoid dyes, oxidation-reduction re-Quinosol, aluminium, copper, and zincRacemization during protein hydrolysis,Radicals, free, inorganic, 87.Raman spectra. See under Spectra.Rays, infra-red, detection of, 6.Reactions, rearrangement, 77.Reagents, organic, in inorganic analysis,Receivers, selective, 6, 10.Reductase, cytochrome c , 205.Reduction, catalytic, 99.Resins, ion exchange, 96.actions of, 154.detn.with, 257, 262.247.255.for separation of amino-acids, 249.phenolic, spectra of, infra-red, andstructure, 18.Resonance structure of molecules, 11 1.Respiratory quotient, effect on, of adrenalRhenium, toluene-3 : 4-dithiol complexRhodamine-B, tungsten detn. with, 260.Rhodium halides, complexes of, withRiboflavin, 155.Riboflavin-5'-phosphate as co-enzyme ofRibonucleic acid, 240.detection of, 241.in cell nucleolus, 245.in cell nucleus, 245.steroids, 227.with, 261.ethyl sulphide, 75.hydrogen transfer, 188.Rocks, detection in, of vanadium, 264.Rubber, and its derivatives, spectra of,friction of, 29.natural and synthetic, infra-red analysisinfra-red, and structure, 18.of mixtures of, 14.Rubber, oxidation of, 19.vulcanisation of, thiols as acceleratorsfor, 154.Rubeanic acid, copper detn.with, 257.Salicylaldoxime, copper detn. in steel with,Salicylic acid, iron detn. with, 258.Saliva, blood group substances in, 234.Sapphires, friction of, 29.Sarcoma, fowl, hyaluronic acid from, 236.Sarcoma virus, 243.Selenium, detn. of, reagent for, 262.Selenium dioxide, oxidation by, 156.Self-dnplication of cytoplasmic particles,Serhe, detn. of,'251.Sex glands, effect of adrenalectomy on,Silica gel, catalytic action of, in complexSilicates, systems of, containing water,Silicon, polymers, spectra of, infra-red, andSilicon alloys as catalysts in preparationSilicon alkyl and aryl halides, 76.257.243.216.formation, 72.65.structure, 18.of phenylchlorosilanes, 77.carbide, crystal structure of, 52.tetrachloride, sulphur trioxide compoundof, 81.chlorothiocyanates, 78.trichlorothiocyanate, disproportionationof, in heated tube, 77.isocyanato thiocyanates, 79.organic compounds, 76.monoxide, 87.oxyfluoride and oxyfluorochlorides, 79.monosulphide, 89.triisocyanatothiocyanate, 78.trimethoxythiocyanate, 78.Silicones as lubricants, 42, 43.Silver as catalyst in preparation of siliconSilver chloride, sheet, for windows ofnitrate, decomposition of, by frictionorganic halides, 76.absorption cells, 10.under pressure, 43.Skin, hyaluronic acid from, 236.Soaps, crystal structure of, 62.films, lubrication with, and with metalfilms, 36.structure of, 32.ammonia, 102.metal, as lubricants, 35.Sodium, reduction with, in liquidSodium arsenide and phosphide, 64.hyposulphite, friction of, 29.a- and fl-naphthoxides, reduction of,thiochromite, crystal structure of, 50.Solids, m.p. of, effect of pressure on, 44.surface structure of, 21.Solubility, amino-acid separation by, 248,Solutions in non-aqueous solvents, 63.102.250INDEX OF SUBJECTS. 289Solvents for ultra-violet absorption spectro-non-aqueous, chemistry of solutions in,Solway purple, boron detection with, 260.Sorbitol, separation of, from dulcitol,Spectra, absorption, ultra-violet, andstructure of organic compounds,105.scopy, 106.63.d-glucose, and d-mannitol, 99.interpretation of, 108.molecular, measurement of, 5.Raman, measurement of, 20.Spectrometers, double-beam, 7.for gas analysis, 14.prism, automatic, 7.single-beam, 7.analysis, 92.technique of, 106.in analysis, 11.in structure diagnosis, 16.with hyaluronidaso, 238.lubricating oil, 41.detection in, of vanadium, 364.detn.in, of boron, 260.Spectrometry, absorption, ultra-violet, inSpectroscopes, vacuum, 106.Spactroscopy, absorption, ultra-violet,infra-red, 5.Spreading or diffusing factor, identity of,Stearic acid, calcium phenyl ester, inSteel, copper slid on, 24.of cobalt, 261.of copper, 257.of tungsten, 261.esters on, 34.88.heat of adsorption of fatty acids andmolten, silicon-oxygen equilibrium in,surface film on, 22.Steroids, adrenal cortex, isolation of,Sterols, spectra of, absorption, ultra-violet,Streptobacterium plantarium, growth fac-Streptococci, haemolytic, hyaluronic acidStreptococcus fcecalis, amino-acid assaysStress resistance, effect of adrenal steroids219.121.tors for, 194.from, 236.with, 253.on, 228.Strontium orthosilicate, crystal structureof, 52.Structure, diagnosis of, by infra-redspectroscopy, 16.Styrene, polymerisation of, 148.infra-red spectroscopy of, 15.Sub-compounds, 87.Sucrose, 5-hydroxymethylfurfuraldehydefrom, 157.Sucrose octaacetate, separation of, from13-maltose octa-acetate, 99.Sugar acetates, deacetylation of, 98.in adrenalectomy, 2 16.purification of, 99.Sugar juice, purification of, by ionexchange resins, 96.Sulphapyrazine, effect of, on pneumococcaland streptococcal infections, 195, 196.Sulphides, crystal structure of, 50.Sulphide flms as lubricants, 37.Sulphites, autoxidation of, 152.Sulphobenzoic acids, conversion of, toSulphonamides, acetylation of, in liver,Sulphosalicylic acid, iron detn.with, 258.Sulphur chlorides, hydrolysis of, 80.benzoic acid, 101.199.compounds, oxidation of, 152.organic compounds, film-forming pro-monoxide, 89.trioxide, crystal structure of, 61.Sulphuryl chloride, structure of, 66.Superol, aluminium, copper, and zinoSurfaces, contour and structure of, 21, 22.perties of, 37.detn. with, 257.zinc detn.with, 262.lubricated, 30.sliding, friction of, 23.Surface-active materials, effect of, onSurvival, conditions of, in adrenalectomy,Synovial fluid, hyaluronic acid from, 236.Tantalum, detn. of, reagents for, 263.Tar, coal, infra-red analysis of acids in, 14.Tartaric acid, recovery of, from naturalTemperature, transition, in lubricants, 34.Terpenes, infra-red analysis of, 14.Testis extracts, spreading or diffusingTetra - acetyl - N - glucosidonicotinamideTetradeuterethylene, spectrum of, infra-Tetrahydrofuran, 162, 169.conversion of, into adipic acid orreaction of, with acyl halides, 173.Tetrahydrofuran, 3-bromo-, conversion of,2-cyano-, catalytic dehydration of, 169.2-hydroxy-, 162.2-hydroxy-, 161.strength of solids, 32.217.wastes, 96.factor in, 238.bromide, 183.red, 20.butadiene, 17 1.into pyrrolidine, 170.into allylcarbinol, 174.Tetrahydrofurans, ring fission of, 171.Tetrahydrofurans, 3 : 4-diamino-, 94.Tetrahydrofuran-2-carboxylic acid, con-version of, into a8-dibromovalericacid, 173.Tetrahydrofurqic acid, ethyl ester, re-action of, with acetyl chloride, 173.methyl ester, catalytic dehydration of,169.Tetrahydrofurfural, preparation of, 168.Tetrahydrofurfuryl alcohol, 163.catalytic decomposition of, 169.dehydrogenation of, 168290 INDEX OF SUBJECTS.Tetrahydrofurfuryl alcohol, hydrogeno-lysis of, 174.reaction of, with acetyl chloride, 173.with ammonia over catalysts, 170.with hydrogen bromide, 172.Tetrahydrofurfuryl chloride, conversion of,into pent-4-en-1-01, 174.Tetrahydrofurfurylamine, formation of,N-Tetrahydrofurfurylpiperidine, 171.Tetrahydrofuryl tetrahydrofurfuryl ether,Tetraketones, preparation of, 174.Tetralin, autoxidation of, 137.oxidation of, to naphthalene, 153.reaction of, with quinones, 156.Tetramethyldiaminodiphenylmethane,2 : 2 : 5 : 5-Tetramethyldihydrofuran, 162.Tetramethyl glucose, separation of, forend-group assay of polysaccharides,99.2 : 3 : 4 : 6-Tetramethyl glucose, separationof, from 2 : 3 : 6-trimethyl glucose,98.2 : 3 : 4 : 6-Tetramethyl d-1 : 2-glucoseen,conversion of, to 5-methoxymethyl-furfuraldehyde, 158.Tetramethyl methylglucosides, separationof, from trimethyl methylglucosides,98.Tetramethylpyrazine, 189.Tetramethylthiuram disulphide as vul-Tetraphenylpyrazine, 189, 191.Thallium halides, mixed melt of, forwindows of absorption cells, 10.oxysulphide, sensitivity of, to infra-redrays, 10.Thermistors, 9.Thermocouples, 6.Thiobacillus thio-oxidans, adenosine-3'-tri-Thiobenzthiazole as vulcanisation acceler-Thiocyanates, iron detn.with, 258.Thiodiazoledithiol, bismuth detn. with,Thio-others, oxidation of, 151.Thioglycollanilide, conversion of, intoThioglycollic acid, conversion of, intoThiols, dehydrogenation of methyleneThiol radicals, formation of, by peroxideThiophan, formation of, frqm 4-hydroxy-Thiophen, reduction of, 103.spectrum of, infra-red, 20.Thiophen, 2-bromo-, reduction of, 103.Thiophens, formation of, from furans, 169.Thiourea, osmium detn.with, 262.Thorium, detn. of, reagents for, 262.halides, 163.167.169.lead detn. with, 256.canisation accelerator, 154.phosphate from, 179.ator, 164.259.acetanilide, 100.acetic acid, 100.groups by, 154.catalysts, 153.butanethiol, 170.Threonine, detn. of, 251.Thymus, effect of adrenal steroids on,Tin tetrahalides, sulphur dioxide solvateswith, 81.Titanium, detection and detn. of, and itsseparation from aluminium, 263.Titanium tetruhalides, sulphur dioxidesolvates with, 81.Titan-yellow, magnesium detn. with, 264.Tobacco viruses, necrosis, crystal structureToilet preparations, detn. in, of lead, 256.Toluene, purification of, from methyl-thiophen, 100.Toluene - 3 : 4 - dithiol, molybdenum,rhenium, and tungsten detn.with,261.Toluidines, substituted, infra-red analysisof, 14.o-Toluidine, copper detn. with, 257.Totaquine, alkaloids from, 98.TriaryImethanes, peroxides, 137.Tribo-electricity in friction, 30.Trifurylarsines, 165.Trigonelline, hydrogenation of, by sodiumhyposulphite, 182.Triketones, preparation of, 174.Trimethoxythiocyanic acid, siliconderivative, 78.Trimethylamine oxide, boron trifluorideadduct, 80.2 : 3 : 6-Trimethyl glucose, separation of,from 2 : 3 : 4 : 6-tetramethyl glucose,98.Trimethyl mcthyl-Z-arabofuranoside, sep-aration of, from trimethyl methyl-d-xylopyranoside, 98.Trimethyl methylglucosides, separation of,from tetramethyl methylglucosides,98.Triphosphopyridine nucleotide, 180, 185.Trogor's base, resolution of, 98.Tripyridyl, cobalt detn. with, 261.aa'a"-Tripyridyl, iron detn. with, 258.Tryptophan, detn. of, 252.from protein hydrolysis, 248.Tungsten, detn. of, reagents for, 260.Tungsten hezuchloride, crystal structureI'yrosine, detn. of, 252.Umbilical cord, hyaluronic acid from, 236.Uranium, detn. of, cupferron test for,Urine, assay of adrenal substances in, 218.detn. in, of androgens, 230.human, blood group substances in, 234.from blood group A substance, 233.effect of adrenalectomy on, 217.228.subsulphide, 89.of, 62.of, 51.oxides, 86.262.of lead, 256.Vaccinia virus, 243.Valency, 66INDEX OFValeric acid, 6-bromo-a-hydroxy-, 172.6-chloro-a-hydroxy-, a-acetyl derivative,ethyl ester, 173.Valine, detn. of, 251.Vanadium, detection of, reagents for, 264.Vanadium tri- and tetru-chlorides, 79.equilibrium of, with slag-formingVapours, films, effect of, on metallicfriction, 32.Vinyl cyanide, polymerisation of, 148.cyanide and halides, spectra of, infra-Vinylacetylene, spectrum of, absorptionVinylcarbinols, reduction of, 102.Virusee, constitution of, 243.Vitamins, detn. of, in natural products,Vitreous humor, hyaluronic acid from,Vulcanisation, infra-red spectroscopy of,oxides, 85.oxides, 82.red, 20.ultra-violet, 113.105.236.19.thiols as accelerators for, 154.Water, detn. in, of magnesium, 264.IUBJECTS. 291Wear, abrasive and corrosive, in runningWelding, cold, in lubricant films, 24.Wool fibres, friction of, 29.Wool proteins, hydrolysates, amino-acidsWoollen fabrics, felting of, 29.Wounds, healing of, accelerated bychromatin, 245.Wiistite, etability of, 81.p-Xylene hydroperoxide, 137.Yeast, cophosphorylase from, 179.cytoplasm, enzymes in, 242.pentose polynucleotide of, 240.engines, 39.from, 249.Zeolites as softeners, 96.Zinc, detn. of, and its separation fromcopper, 257.reagents for, 261.Zinc subiodide, 89.Zinc Dips. See Diisopropylsalicylic scid,zinc salt.Zirconium, detn. of, reagents for, 262.Zymogen granules in liver and pancrees,242

ISSN:0365-6217    

DOI:10.1039/AR9454200278

出版商:RSC    

年代:1945

数据来源: RSC