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QUARTERLY REVIEWS FLASH PHOTOLYSIS AND KINETIC SPECTROSCOPY By R. G. W. NORRISH Sc.D. F.R.I.C. F.R.S. and B. A. THRUSH M.A. PH.D. (DEPARTMENT OF PHYSICAL CHEMISTRY THE UNIVERSITY CAMBRIDGE) THE recognition of the importance of short-lived intermediates such as atoms and free radicals in many chemical reactions and photochemical processes has done much to stimulate interest in rapid reactions where detectable quantities of these species are present and their reactions can be studied directly. I n this type of work two main problems arise those of initiation and of observation. The reaction must be started so homogene- ously that the chemical processes themselves and not their propagation through space are rate-determining. For certain reactions this can be achieved by rapid mixing or by adiabatic compression including the use of shock waves.Flow systems are generally more useful than static systems where the time of mixing is the limiting factor. This limit is much more serious for gases 1 where it is more difficult to obtain adequate turbulent mixing than for liquids where reaction times as short as one millisecond can be observed.2 Among the methods used for premixed systems those in which reaction is initiated by contact with a heated surface are seriously limited by the incidence of heterogeneous processes and of the temperature gradient which must always be present. is one of the most interesting systems of this type. Adiabatic compression has been used to obtain rapid homogeneous heating but this method unfortunately has been applied mainly to combustion reactions which are so rapid as to require ;I higher rate of production of reaction centres than can be realised by this method resulting in an insufficisntly homogeneous system.Direct mechani- cal compression is now being superseded as a technique by the use of shock waves 5 and their corollary in combustion-detonation waves.6 I n these systems considerable temperature rises can occur in times as short as see. but difficulties arise in observing processes occurring in a rapidly The Paneth mirror technique Johnston Discuss. Paraday SOC. 1954 17 14. Hartridge and Roughton Proc. Roy. SOC. 1923 A 104 376. Paneth Be7,. 1929 62 1335. Jost " Third Symposium on Combustion " Williams and Wilkins Baltimore 1949 p. 424. 5 Greene J. L4mer. Ghern. SOC. 1954 76 2127. 6 Berets Greene and Kist;iakowsky ibid.1950 72 1080. K 149 150 QUARTERLY REVIEWS moving wave-front and there is uncertainty about the rate of transfer of energy from translation t o other degrees of freedom. Spectroscopic methods where practicable are the best for following rapid reactions The use of a thermocouple,7 resistance thermometer or interferometer 8 to follow reactions is restricted to relatively simple systems and the mass-spectrometer 9 10 appears to provide the best alternative to optical spectroscopy. Although this method is very sensitive sampling of the system without serious disturbance of the reaction presents a con- siderable problem. Also the need to prevent further reaction in the time between sampling and ionisation limits the beam current and hence the time resolution. Great strides are however being made at present to overcome these difficulties.The development of the high-intensity flash-discharge lamp was due in the first instance to Edgerton and his co-workers l1 who worked with energies of up to 400 J per flash. Photochemical systems require much higher energies and lamps capable of dissipating 10,000 J corresponding to about 3 x einsteins of ultraviolet light were made by Norrish and Porter 12 l 3 who first applied these tubes to chemical systems. These high light intensities make it possible t o obtain appreciable photochemical changes in times which are comparable with the lives of the radicals or excited molecules formed Part of the light absorbed will appear as kinetic energy of the photolysis products as will the heat liberated by radical reactions or degraded from excited molecules in collisions.Reactions in solution are sufficiently isothermal owing to the thermal capacity of the solvent but in the gas phase a large excess of an inert non-absorbing gas must be added if it is desirable to maintain approximately isothermal con- ditions. On the other hand this temperature rise provides a useful method of initiating explosions homogeneously over a relatively large volume. The flash discharge also provides an excellent method of following fast eactions as it can be used as a source to photograph the absorption spectrum of the system with high dispersion in a very short time. Absorption spectro- scopy is probably the most satisfactory method of following these reactions since while it does not disturb the system it provides a measure of the concentration of the species observed.Its value is however limited as many important reaction intermediates particularly atoms of the non- metallic elements do not absorb in the accessible region of the spectrum (2200-7000 8) or have unidentifiable continuous spectra ; fortunately most diatomic radicals and aromatic species have strong and characteristic electronic transitions in this range. Of the other regions of the spectrum the vacuum-ultraviolet is rendered very difficult experimentally by the strong continuous absorption which many species show in this region. I n Garvin Guinn and Kistiakowsky Discuss. Faraday SOC. 1954 17 32. Burnett Deas and Melville ibid. p. 173. Eltenton J . Chem. Phys. 1942 10 403. l o Ingold and Lossing ibid. 1953 21 368. l1 Murphy and Edgerton J .Appl. Phys. 1941 12 848. l2 Norrish and Porter Nature 1949 164 658. l3 Porter Proc. Roy. Soc. 1950 A 200 284. NORRISH AND THRUSH FLASH PHOTOLYRIS 151 the infrared the main limitations are the absence of intense light sources and the poor response time of most detectors. Emission spectra since they are determined by the populations of upper electronic states can only be observed in high-temperature systems and because they are frequently affected by anomalous excitation conditions tlhe use of light emission as a measure of the concentration of the emitter is limited. Experimental Methods Whilst the exact form of apparatus used in flash-photolysis experiments depends to a large extent on the nature of the problem an arrangement similar to that shown in Fig. 1 has been used in most cases either for the entire problem or in a preliminary search for the spectra present.13 system FIG.1 Typical flash -photo ly s is apparatus. The reactants are placed in a cylindrical quartz vessel normally 50 em. long and 2 em. in diameter. The photolytic flash tube is placed alongside the reaction vessel on to which the light is concentrated by a cylindrical reflector coated with magnesium oxide. This flash lamp is a krypton-filled quartz tube having the same length as the reaction vessel; the main dis- charge occurs between heavy tungsten electrodes placed at the ends and connected to a bank of condensers. After the condensers have been charged to the required voltage the discharge is initiated by applying a triggering pulse to a small central electrode. Alternatively the trigger pulse can be applied to a spark-gap in series with the flash tube ; in this case no voltage is applied to the lamp until it is triggered thus making it possible to operate at high voltages with low filling pressures.In these circumstances the flash duration is reduced at the expense of luminous efficiency. A lower-energy flash lamp of different shape but basically similar design is used to photograph the absorption spectrum of the system through the full length of the reaction vessel. and 1 see. after the photolytic flash by an electronic timer which is initiated This lamp is triggered between l4 Norrish Porter and Thrush Proc. Roy. Soc. 1953 A 216 165. 152 QUARTERLY REVIEWS photoelectrically by the light from this flash. flash-discharge lamps are summarised in Table 1.The performances of typical TABLE 1 Photolytic . . . . . . 9 9 9 . . . . . . . . . . . . Spectroscopic (Hilger E.l Spectroscopic (Hilger E.3 instrument) . . . . . instrument) . . . . . 50 50 100 30 15 Capacity ( P P ) 30 40 480 25 10 Voltage (W 6 10 4 4 10 Energy (J) 540 2000 3840 200 500 Effective duration (ccsec.) 70 120 2000 50 30* * Used with spark gap. With an apparatus of the type described above it is necessary to perform a separate experiment for each point on a radical- concentration-time curve. As an alternative photomultiplier cells recording on a cathode-ray oscillo- graph have been used in some cases to follow the change of light emission or absorption with time. For combustion work a high-pressure xenon arc has been used as background source and this light is observed by two photomultiplier cells which are mounted in place of the spectrograph plate- h01der.l~ In this way it has been possible to follow concentration changes and measure electronic excitation temperatures with a time resolution of 2 psec.on the more intense spectra. For the study of recombination of iodine atoms a very simple photo- electric apparatus has been used.16 In this case a tungsten-filament bulb used in conjunction with a liquid filter and a photomultiplier cell was sufficient to monitor the I absorption from which the iodine-atom concen- tration could be deduced. Though the iodine absorbed only about 10% of the monitoring light it was possible to measure its concentration to better than 1%. If a photographic technique had been used the reproducibility of the plates would probably have been insufficient to show even the con- tinuous I absorption.In this case a spiral flash tube is coiled round the reaction vessel to give a high light intensity and a filter is used to remove the light which would be absorbed by the iodine without producing dissociation. Radical-concentration Measurements.-Whilst the actual observation and identification of the transient absorption spectra of atoms or free radicals in many systems is of interest in itself and these spectra have in some cases yielded valuable information about the structure of the radicals con- cerned it is important from a kinetic viewpoint to obtain values for the absolute concentrations of the species present or failing this t o find a sound 15 Norrish Porter and Thrush " Fifth Symposium on Combustion " Reinhold l6 Christie Norrish and Porter Proc.Roy. SOC. 1953 A 216 152. New York 1955 p. 651. NORRISK AND THRUSH FLASH PHOTOLYSIY 153 method of comparing the relative amounts of a radical present under differ- ent conditions. If we wish to obtain the absolute concentration of a free radical it is necessary to know the identity of all the species present and to have sufficient information to obtain a material balance. So far this has only been possible with C10 and the aromatic triplets although an upper limit can be set to the concentration of particular radicals in other systems. In the work on the recombination of iodine atoms their concen- tration was inferred from the amount of iodine decomposed. If the absolute concentration of the radical cannot be determined it is in theory possible to compare concentrations under different conditions since the number of absorbing molecules is proportional to the integral of the extinction co- efficient witah respect to frequency over the whole of the band system used.For a completely diffuse spectrum this integral can easily be determined but the range of temperature is usually sufficiently limited for the extinction coefficient a t one wavelength to be an adequate measure of concentration. For discrete spectra very high resolution which is not available in flash experiments is needed to determine the true line contour and hence this integral. Under the conditions of constant temperature and pressure the apparent intensity of any spectral line will be determined only by the number of molecules in the absorbing path.In many of the systems studied even to a large extent in explosions the radical concentrations change very much more rapidly than the pressure or temperature and it can be assumed that if the same apparent intensity is observed in the same system a t different times by using path lengths in the ratio 2 1 the concentratioiis at these times will be in the ratio 1 2. By this means,14 it is possible to measure half-lives and establish a relative concentration scale without knowing the absolute concentration at any point. Unfortunately pressure broadening prevents comparison of amounts of the species present a t differ- ent total pressures as for example in the work described below on excited oxygen. Free Radicals and Excited Molecules Several completely new radical spectra have been obtained by flash photolysis ; in other cases spectra have been observed in absorption for the first time or obtained with much greater intensity thus yielding new information about molecular structure and stability.Though it is generally believed that the " hydrocarbon flame bands " are due to the HCO radical this cannot be regarded as proved and the dis- covery by Ramsay l7 of bands at longer wavelengths due to this radical in the flash photolysis of aldehydes is of great interest. By analysis of these bands l8 the structure of this radical has been determined showing that it has a bent lower and a linear upper state. Other spectra of polyatomic species which have been obtained for the first time by flash photolysis are those ascribed to HS,19 and N,2O as well as many spectra of aromatic radicals Ramsay J .Chem. Pirys. 1953 21 960. Herzberg and Ramsay Proc. Roy. Xoc. 1955 A 233 34. Porter Discuss. Faraday SOC. 1950 9 60. 20Thrush Proc. Roy. SOC. 1956 235 143. 154 QUARTERLY REVIEWS and triplet states which are discussed in a later section. The absorption spectra of C321 and NH222 were also first observed by this technique. Flash photolysis provides an easy method of observing many diatomic- radical spectra in absorption. Of these Porter l3 obtained the absorption spectrum of C10 for the first time and was thus able to determine its dis- sociation energy and vibration frequencies. He was also able to determine the vibration frequencies of SH and SD. l9 Other diatomic-radical spectra obtained in absorption for the first time or much more strongly include those of C2 CH CN,l4 CS,13 and SO.The first named is of some interest as both the Mulliken and Swan bands which arise from the lowest singlet (lC,+) and lowest triplet ( 3111,) states have been obtained in absorption by explosions and it cannot be regarded as certain whether C has a singlet or a triplet ground state ; at present evidence appears to favour the former although the two states clearly have closely similar energies. The C10 Radical.-The C10 radical has probably been studied in more detail by flash photolysis than any other species. Its spectrum was first detected in emission from flames containing chlorine by Pannetier and Gaydon 23 and it was obtained in absorption by Porter l3 who determined its dissociation energy and with Wright 24 studied the mechanism of forma- tion and removal of this radical in systems containing small amounts of chlorine and rendered isothermal by a great excess of oxygen and some- times nitrogen.In these experiments the primary photochemical act is clearly to produce chlorine atoms but the reaction c1 + 0 = c10 + 0 . * (1) is far too endothermic to occur. The C10 formation must therefore proceed in the following way c1 + 0 = c1-0-0 . * (2) (2-0-0 + c1 = 2c10 . * (3) In this scheme the C10 formed is not conceived as the stable molecule of this formula but a loosely bound intermediate whose stability could be judged from experiments in which part of the oxygen was replaced by nitrogen ; these showed that the formation of C10 by reactions (2) and (3) above was 46 times as fast as the recombination of chlorine atoms with nitrogen as the third body.It was slso found that the amount of C10 formed was independent of temperature in the range 25-300". The rate of removal of the ClO radical by reaction (4) was found by plate photometry c10 + c10 = c1 + 0 . * (4) to be of the second order constant over the same temperature range and independent of chlorine oxygen or nitrogen pressure. Porter and Wright were only able to obtain the rate constant of this reaction in terms of the unknown extinction coefficient of C10 since the chlorine decomposition was not measurable. Fortunately C10 is a much stronger absorber than 21 Norrish Porter and Thrush Natuye 1952 169 582. 2 2 Herzberg and Ramsay J. Chern. Phys. 1952 20 347. 23 Pannetier and Gaydon Nature 1948 161 262. 2 4 Porter and Wright Discuss.Faraday SOC. 1953 14 23. NORRISH AND THRUSH FLASH PHOTOLYSIS 155 chlorine and in excess of an inert gas it is almost completely converted into C10 and 0 by the flash (Fig. 2) most of the ClO formed being decomposed by the flash. By assuming that the amount of C10 formed was the differ- ence between the C10 decomposed and the ClO formed Lipscomb Norrish and Thrush 25 have obt,ained values for the extinction coefficient of C10 and the rate constant for its removal. In the absence of ClO, they found that C10 radicals reacted a t approximately one collision in 7000 and the slopes of their graphs were in good agreement with those of Porter and Wright. There is an apparent inhibition of this reaction by C10 which has been tentatively interpreted in terms of an equilibrium c1,0 = c10 + c10 - ( 5 ) The bimolecular C10 removal is unusual for a radical-radical reaction in having a very low frequency factor Porter and Wright having found that it has no activation energy.Excited Molecular States.-In the experiments with chlorine dioxide Lipscomb Norrish and Thrush 25 observed the absorption spectra of oxygen molecules in the electronic ground state with up to eight quanta of vibra- tional energy immediately after flashing (Fig. 2). As they used between 300- and 2000-fold excess of nitrogen to eliminate the temperature rise this provides clear evidence for the formation of vibrationally excited molecules in a chemical reaction. Oxygen molecules with a similar energy distribution are also formed in experiments with nitrogen dioxide diluted with a great excess of nitrogen and it is thought that the oxygen is formed by the analogous reactions N O + h v =NO + O .(6) 0 + NO = NO + 0,” . * (7) c10 + k v = c10 + 0 . - (8) 0 + c10 = c10 + o,* * - (9) Reactions 7 and 9 are 46 and 61 kcal. exothermic respectively and the vibrational-energy distribution of the oxygen formed is such that there are approximately equal numbers of molecules in the levels v” = 5 6 and 7 and many fewer with 11’’ = 8 which is the highest level observed and has an excitation energy of 33.6 kcal./mole. The formation of excited oxygen in these systems is of interest since they are almost the only cases where it can be shown that the energy liberated in a simple reaction shows consider- able deviations from both the Maxwell-Boltzmann distribution law and equipartition in that the oxygen vibration is receiving an unexpectedly high proportion of the energy liberated.Since 0 has no electric dipole moment and this energy can consequently only be lost exceedingly slowly by radiation measurement of the half-life of the vibrationally excited oxygen provides a new method of studying the degradation and transfer of vibra- tional energy in collisions ; it has the advantage over sound dispersion and fluorescence measurements that it is applicable to the higher vibrational levels of the ground state which are of particular interest in high-temperature reactions especially combustion. In general the measurements so far made 25 Lipscomb Norrish and Thrush Proc. ROY. XOC. 1956 A 233 45.5 156 QUARTERLY REVIEWS confirm the work witlh sound dispersion stressing the efficacy of resonant transfer to molecules with similar vibration frequencies and of removal by free radicals.Aromatic Molecules.-In aromatic systems we have to consider the possi- bilities that the excited state will fluoresce decompose or undergo a radia- tionless conversion by collision to form a relatively long-lived phosphorescent state In some cases magnetic susceptibility measurements 26 have shown that these phosphorescent states of polynuclear aromatic molecules are triplets and this nomenclature will be adopted for all long-lived excited states of such molecules even where the susceptibilities have not been measured. Absorption spectra of triplet states have been observed by flash photolysis for a. large number of polynuclear aromatic molecules in the gas phase by Porter and Wright,27 in solution by Porter and Windsor,28 and in rigid glasses by McClure and H a n ~ t .~ ~ The radiationless conversion of the excited singlet state into a triplet occurs remarkably freely with almost all polynuclear aromatic compounds ; for instance in dilute hexane solution for several hydrocarbons it approaches 50% with a flash of moderate energy. It is however probable with a substance like anthracene which has a very high extinction coefficient and a short fluorcscent life that many of the molecules are raised to the excited singlet state more than once during the flash. The formation and decay of the triplet together with the depletion and reappearance of the singlet state of anthracene in hexane are shown in Fig. 3 ; in this case the rate of disappearance of the triplet is of the first order and independent of the initial anthracene concentration over a wide range.I n the absence of oxygen the rate constant is about 12,000 sec.-l in n-hexane and for a number of solvents of widely different character the first-order rate constants were found to be roughly inversely proportional to the square root of the viscosity ; in the more rigid solvents and glasses however the rate tends to the radiative phosphorescence value which is of the order of 10 sec.-l. In the gas phase the lives of the triplet states were too short to be measured with the apparatus used. The mechanism of deactivation of the triplet state cannot be regarded as satisfactorily explained and the viscosity relationship given above is probably fortuitous ; it does not fit any of the current theories of reactions in solution.It appears that this process is a radiationless transition which is inhibited by the intermolecular forces determining the viscosity of the solvent. Aromatic Radicals.-In contrast to the pol ycyclic aromatic molecules which give triplet states derivatives of benzene yield free radicals such as C,H,*CH,* C,H,-NH* C,H,*O* and C,H,*S* on photolysis. These have been observed in the gas phase by Porter and Wright 30 and in solution by 26 Lewis CaIvin and Kasha J. Chem. Phys. 1949 17 804 ; Evans Nature 1955 27 Porter and Wright Trans. Faraday SOC. 1955 51 1205. as Porter and Windsor Discuss. Paraday SOC. 1954 17 178. 2B McClure and Hanst J. Chem. Phys. 1955 23 1772. so Porter and Wright Trans. Faraday Soc. 1955 51 1469. 176 777.FIG. 2 Spectra of chlorine dioxide and i t s products of photolysis showing formation and decay of C10 and vibrationally excited oxygen. [Reproduced with modification. by permission from Proc. Roy. SOP. 1956 A 233 457.1 FIG. 3 S'eries of triplet spectra of anthracene in hexane. [ Kcproduced by pertiii4oxi. froni Dismss. Puiutlay Soc. 19.54 17 181.1 FIG. 7 Intensity of OH (1,O) and ( 2 O ) bands during course of explosion. Original mixture P(H,) = 10 mm. ; P(0,) = 5 mm. ; P(N0,) = 0.75 mm. [Reproduced by permission from Proc. Roy. Soe. 1952 A 210 447.1 FIG. 8 Radical spectra in ucc.tylene-oxy!/en-nitroyen dioxide explosions. ( a ) CH ; ( b ) NH ; ( c ) C " Swan " bands ; ( d ) ,F2 " Mullilien " bands ; [Reproduccd by permission from Proc. Roy. Soc.1953 A 216 182.1 ( e ) ( f ) and ( 9 ) CN " violet bands. FIG. 15 The effect of tetraethyl-lead o n the induction period. 4 mm. C,H,,*O*NO + 3.3 mm. C,H + 15 mm. 0 + x mm. PbEt,. Plash energy 1000 J. [Reproduced by permission from Proc. Roy. SOC. 1956 A 234 182.1 3 3 k'1G. 17 Spectra u. timc. 4 tttrn. C,H,,*O.NO -1 3.3 7nwt. C2H -t 20 m7n. 0,. Flash energy 1000 ,J. [lteproduccd by permission fiuiii f'ruc. ftoy. Soc. 1956 A 234 182.1 NOlERlSli AND THRUSH FLASH I'HOTOLYSIS 257 Yortcr and IYintlsor. 31 Their formation can be distinguished from that of a triplet state by several criteria the same radical is produced by the photolysis of more than one substance for instance the spectrum attributed t'o the benzyl radical is obtained from toluene benzyl chloride benzylamine ethylbenzene etc.but not from benzylidene chloride or benzotrichloride. Further tlhe compound photolysed shows a permanent decomposition which does not usually occur if a triplet state is observed. I n rigid media at low temperatures these radicals can be trapped almost indefinitely whereas under these conditions triplet states show lives which are normally less than one second ; for this reason flash photolysis has not yet been used to study radicals in these systems. It is interesting that acetophenone benzo- pheiione and 1 -methylnaphthalene form triplet states rather than radicals. Atomic Reactions Flash photolysis has provided a very convenient method of studying the recombination of iodine atoms arid it has been used by several groups of workers 16 32 3 3 7 34 to extend the measurements originally made with a steady-state system by Rabinowitch and his colleague^.^^ I n all the more recent work similar techniques have been used the concentration of iodine molecules being monitored by a photocell using a tungsten-filament lamp and a suitable filter.The photocell output is displayed on the Y-plate of a cathode-ray oscillograph which is triggered by the flash which decomposes the iodine. Dissociations of the order of 80% can readily be obtained although smaller values are normally used so as to limit the temperature rise. The recombination of the iodine atoms is measured by the reappear- ance of the iodine absorption. For the different inert gases the rate of recombination was found to be proportional to the square of the iodine-atom concentration arid t o the inert-gas pressiire.Typical bimolecular plots of the reciprocal of the iodine-atom pressure against time are shown in Fig. 4 and all the workers found that the second-order law was obeyed quite well over a ten-fold concentration range. The absolute rates determined by the various authors differed however by more than their estimated experi- mental errors and for this reason the reaction in the presence of the inert gases has been investigated over a very wide range of conditions by Christie Harrison Norrish and Porter.34 They examined all the possible sources of error and corrected for the concentration gradient in the reaction vessel ; this is due to the temperature gradient which is produced as the heat absorbed from the flash is removed by conduction. The apparent rate constant of the recombination increased linearly with the ratio of I to inert-gas pressure (see Fig.5) owing to the high efficiency of I as a third body for the iodine atom recombination the values of the rate constants being given in Table 2. These rates stress the stability of I as an intermediate and for the inert Porter arid Windsor unpublished work. 3 2 Marshall and Davidson J . Chem. Phys. 1953 21 650. 3 3 Russell and Simons Proc. Roy. SOC. 1953 A 217 271. 3 4 Christie Harrison Norrish and Porter ibid. 1955 A 231 446. 35 Rabinowitch and Wood J . Chem. Phys. 1936 4 497. 158 QUARTERLY REVIEWS 200 mm. 80- 0 5 ro ?5 FIG. 4 Bimolecular plots of iodine recomb,ination in argon. [Reproduced by permission from Proc. Roy. Xoc. 1953 A 216 158.1 Time (millisec.) 2-0 3.0 4.0 5.0 ;;32k;n;t;a cmr.? mo/ecu/es-z s e c 3 F I G .6 T’uriation of iodine recombination rute constant with [I,]/[M]. [Reproduced by permission from Proc. Roy. Soc. 1955 A 231 449.1 NORRISH AND THRUSH FLASH PHOTOLYSIY 159 gases agree moderately well both with the simple Bodenstein expression 36 and with Wigner's 37 more elaborate theory. The apparent fall in the rate at low iodine pressures is not so easily explained and it has been suggested that a metastable iodine molecule with a different absorption spectrum is formed in the three-body collision involving an inert-gas molecule and that this is only deactivated by collision with another iodine molecule. The effectiveness as third bodies of a wider range of other gases has been studied by Russell and S i m ~ n s ~ ~ who also showed that for a range of substances the rate constant a t 127" was 0.4 times that at 20".For a large number of molecules they showed that the logarithms of the third-order rate constants varied linearly with the boiling points apparently owing to the importance of van der Waals forces in relation to both properties. For helium hydrogen and water this relation does not hold. The Study of Combustion by Flash Photolysis There are two desiderata concerning the initiation of an explosive re- action the first that a sufficient temperature should be generated for the propagation of the reaction chains ; the second that an adequate concentra- tion of atoms or free radicals should be formed to act as initiators of the chains. We have seen above that unless suitable precautions are taken to keep the system isothermal by the addition of inert gas flash photolysis leads to very high temperatures in the absorbing system and it is just this possibility of administering a thermal shock that makes the method valuable as a tool in the study of ignition processes.The system however must be capable of absorbing the light energy of the flash-so that unless one of the reactants has a suitable chromophoric group within the range 2200-6000 A a sensitiser must be used. This is the case with mixtures of oxygen with hydrogen,38 carbon monoxide aliphatic paraffins,39 and acetylene,14 where nitrogen dioxide has proved to be an excellent initiator though other sub- st'ances such as chlorine are efficient. Nitrogen dioxide has two advantages it absorbs over the whole range of the available spectrum and this absorption contributes directly to a considerable temperature rise while in the ultraviolet region direct] dis- sociation occurs according to the equation giving rise to oxygen atoms which readily form initiating centres for the NO -t- h~ = NO + 0 36 Bodenstein 2.phys. Chenz. 1922 100 118. 37 Wigner J . Chem. P?~ys. 1937 5 720. 38 Norrish and Porter Proc. Roy. Xoc. 1952 A 210 439. 39 Norrish Porter and Thrush ibid. 1955 A 227 423. 160 QUABTEHLY HEVIEWS reaction chains leading to ignition. With chlorine iiiit'iation may be achieved by free radicals derived from C1 atoms generated by the flash e.g. Pentyl nitrite has recently been used as a sensitiser by Erhard and Norrish in the study of knock and antiknock.40 Certain other combustible substances such as aromatic hydrocarbons butadiene aldehydes and ketones are themselves sufficiently strong light- absorbers for explosions with oxygen to be produced directly without the use of a photosensitiser.The great advantage of flash photolysis is that by its use it is possible to generate approximately homogeneous explosions. Thus if the reaction tube is one metre long we virtually have a " flame front " one metre thick and free radicals with suitable absorption spectra are readily visible spectro- scopically by means of the spectroflash lamp triggered at suitable intervals after the initiating flash. In this way the waxing and waning of diatomic and triatomic radicals over a period of 1-3 milliseconds during and after the ignition can be followed and in some cases their reactions with each other can be deduced.Thus it has been possible to obtain in absorption the spectra of several radicals previously known only in emission and by suitable methods of photometry to follow changes in their relative concen- trations though unfortunately their absolute concentrations cannot yet be deduced. A further limitation which may well be overcome by the vacuum- spectrograph is that the resonance lines of C H and 0 atoms cannot be observed owing to the limitation imposed by atmospheric transmission. Thus only a partial picture of the reactions constituting an explosion is at present objectively possible but sufficient results have been obtained to provide considerable support for the belief that our intuitive deductions about the chain reactions of combustion and explosion are basically right.The Explosion of Hydrogen and Oxygen.-Fig. 6 shows the decay of the OH spectrum in mixtures of different pressures of hydrogen with nitrogen dioxide observed by Norrish and Porter,38 and since the stoicheiometric equation for the reaction is it will be seen by inspection that the disappearance of OH is faster the greater the H is in excess of the stoicheiomet'ric ratio evidence for the elementary reaction postulated in the H,-0 reaction. A second elementary reaction of the hydrogen-oxygen reaction is proved by the initial generation of the OH spectra which can only arise from the oxygen atoms generated in the photolysis of NO CH + C1 = CH + HC1 H + NO = H,O + NO H + OH = H,O + H 0 -j- H = OH + H A third elementary process in the same reaction is displayed by the fact that the rate of disappearance of OH when there is no excess of H to remove Erhard and Norrish Proc.Roy. SOC. 1956 A 284 178. NORRISH AND THR'CJSTI FTIASEI PHOTOTAYSTS 161 it is greatly reduced by increasing pressure of inert gas (Nz) showing how its removal by diffusion to the wall is hindered by increase of pressure. In Pig. 7 is shown a record of an explosion of 2H -t 0 sensitised by NO, in which the explosion as demonstrated by the growth and decay of OH 1 7.0 r-5 2.0 2.5 FIG. 6 Time (mi//;sec. 1 OH intensity against time effect of P(H,) ; P(N0,) = 2 mm. curves show P(H,) (mm.). Figures on the [Reproduced by permission from Proc. Roy. Soc. 1952 A 210 450.1 can be clearly followed in both the 1,0 and 2,O bands. An induction period of about 0.8 millisec.is seen while the disappearance of the radical takes about 7 millisec. This work on hydrogen and oxygen is to be regarded as only preliminary to much that can be done by studying the reaction in more detail by the more refined apparatus now available. The Explosion of Acetylene and Oxygen.-Fig. 8 shows the absorption spectra of some of the diatomic radicals obtained when mixtures of acetylene are exploded with NO as sensitiser. All the carbon radicals appear when the acetylene oxygen ratio is in excess of 1 1 and with the exception of the weak appearance of CN do not occur when the oxygen is in excess of this mixture ratio. Under these conditions however a strong generation of OH occurs. Figs. 9-11 show three sets of results obtained by the two- path method Fig. 9 the variation of OH with time for various mixture strengths Fig.10 the carbon radicals with acetylene in slight excess and Pig. 11 the OH radical with oxygen in slight excess. Prom curves such as these Fig. 12 has been constructed in which the maxima of the curves of the various radicals are plotted against mixture strengths. Counting the oxygen of the NO as 0 we see an almost exact switch from oxygen to carbon radicals at the ratio C,H 0 = 1. At this point the only radicals in evidence are OH CN and NH and the last-named is confined closely to this specific mixture strength. It seems reasonable to ascribe its production to the reaction OH + CN = CO + NH 162 QUARTERLY REVIEWS 0 7.0 2-0 3-0 4.0 Time (rni//isec.) FIG. 9 OH concentration (logayithmic scale) against time eflect of P(C,H,) ; P(0,) = 10 mm.P(N0,) = 1-5 mm. Numbers on the cuyves are P(C,H,). [Reprodnced by permission from Proc. Roy. Soc. 1953 A 216 173.1 These results may be compared with those of Bone and Drugman 41 who noted the importance of the stoicheiometric equation according to which the carbon is burned preferentially to the hydrogen. With excess of acetylene they obtained carbon deposition in their explosions ; with excess of oxygen water was produced. C,H + 0 = 2CO + H ;L 40 0 0 FIU. 10 P(N0,) = 1.5 mm. [Reproduced by permission from Proc. Roy. SOC. 1953 A 216 175.1 Radical concentrations against time P(C,H,) = 13 mm. P(0,) = 10 mm. 41 Bone and Drugman J . 1906 89 660. NORRISH AND THRUSH FLASH PHOTOLYSIS I63 FIG. 11 P(N0,) = 1.5 mm. [Reproduced by permission from Proc. Rcy. Soc.1953 A 216 174.1 OH and CN concentrations against time P(C,H,) = 10 mm. P(0,) = 10 mni. It may be concluded that the apparent induction period seen for ex- ample in Fig. 10 is really a period of developing reaction and that the carbon radicals seen t o arise so suddenly at its end are really the product of after-cracking of the excess of acetylene while in Fig. 11 the great develop- ment of OH is really the after-burning of hydrogen in excess of oxygen. FIG. 12 Maximum radical concentrations against P(C,H,) ; P(0,) = 10 mm. P ( N O ) = 1.5 mm. [Reproduced by permission from Proc. Roy. Soc. 1953 A 216 172.1 164 QUARTERLY REVIEWS Certainly there is evidence that the temperature has risen to a high value near the end of the induction period for the vibrational temperature of the NO y bands seen at the end is of the order of 2000" K.While the carbon radicals all arise simultaneously the appearance of OH both in carbon-rich and. in oxygen-rich systems always precedes them. This seems to be the only radical which has so far been seen in the rapid chain reactions which culminate in ignition. At the same time it will be seen that the peak of the OH curve in Fig. 11 definitely occurs at a later time than that of the CN and thus if the peak of the CN marks the explosion the displaced peak of the OH must represent a later reaction-in accord with the hypothesis of the after-burning of hydrogen. Other Hydrocarbons.-The explosions of ethylene ethane and methane have been studied by Norrish Porter and Thrush in a similar way.39 The occurrence of the diatomic radicals is similar in all these cases to that of acetylene but there are quantitative differences in the stoicheiometry of the mixtures which give equivalent spectroscopic results.I n this work continuous spectra and the spectrum of C were studied in more detail. The continuum which is present a t comparatively long times after the explosion is undoubtedly due to absorption by carbon particles but a second continuum which has an intense maximum a t 3900 A and whose occurrence in time follows closely that of the carbon radicals is attributed to a carbon molecule in approximate thermal equilibrium with them and whose concen- tration must form a considerable fraction of the free carbon generated by the explosion. It seems probable that further evidence on the production of free carbon will be derived from experiments of this kind.Photoelectric Recording of Emission and Absorption Spectra during Ex- plosion.15-With the object of following continuously the kinetics of the approximately homogeneous explosions engendered by the photoflash the photographic plate was replaced by two photomultiplier cells carried on a carriage interchangeable with the plate holder and so mounted that they could be adjusted to receive any narrow wavelength region of the spectrum through narrow slits placed in front of them. The outputs of the photocells were fed through suitable amplifying circuits to a double-beam oscillograph and by this means the growth and decay of any suitable narrow part of the spectrum of OH CN CH etc. could be recorded photographically. Changes in the absorption of a particular radical during explosion were observed by the light from a continuous-running xenon arc which was focused through the reaction mixture 011 to the slit of the spectrograph the time base of the oscillograph being triggered by the scattered light of the initiating photoflash.Changes in light emission spectra of radicals could be observed directly the time base being triggered by the photoflash as before. Fig. 13 shows the OH emission from a 2H + 0 explosion initiated by NO, for the wavelength range of the OH (0,O) band region. It is charac- terised by a remarkable peak of not more than 2 or 3 psec. duration. Similar peaks of short duration were observed in the acetylene-oxygen explosion for the C, CH CN and OH radicals. By observing the corresponding NORRISH AND THRUSH FLASH PHOTOLYSIS 165 8 1 7 inillisec FIG.13 OH ernimion H,-02-N0 = 8-2-0.8 mm. [Reproduced,-by permission from Fifth_Symnposiutn o n Combtistion Reinhold New York 1955 p. 655.1 changes in absorption it was found that these peaks are superimposed as a strong emission which is not reversed by the xenon arc and in Fig. 14 idealised pictures of the oscillograph records of absorption and emission are 700%' 1 1 I I Time (mi//isec.) FIG. 14 Light emitwiov and absorption with reversal temperatures C2H,-0,-N02 = 14-10-1 -5 mna. [Reproduced by permission from Natzirr 1953 172 71 .] 166 QUARTERLY REVIEWS given from which the temperature in different stages in the explosion can be calculated. 42 The temperature corresponding to the emission characterised by these short-lived peaks is some thousands of degrees greater than the thermodynamically expected temperatures of the explosions and it has been proved by Thrush *3 that while the main part of the explosion is homo- geneous detonation waves travel a short distance to the ends of the reaction vessel the emission peak being caused by the impact of one of these on the vessel window nearest the spectrograph.In this way it has been shown conclusively that detonation waves resulting from slight inhomogeneity in the extremely rapid energy release of' the explosion are readily betrayed by the oscillograph. Knock and Antiknock.-By combining the photoelectric and the photo- graphic techniques Erhard and Norrish *O were able to study the role of tetraethyl-lead in its action as antiknock. Mixtures of acetylene and oxygen with pentyl nitrite as sensitiser in suitable mixture ratios were found to give strong indication of detonation when exploded by the photoflash after an apparent induction period of 20-150 pee.depending on the composition of the mixture and the energy of the initiating flash the explosion was characterised by one or more sharp peaks of emission by the OH or CN radicals. With similar mixtures containing 0-5-1 yo of tetraethyl-lead the apparent induction periods were increased by some 200-300% while the incidence of detonation was greatly reduced or completely eliminated Fig. 15. Parallel with these observations photographic records of the absorption spectra showed that appearance of the OH and other radicals characteristic of ignition is delayed by the presence of tetraethyl-lead the dominant inter- mediate species during the apparent induction period being PbO which is rapidly reduced t o atomic lead at the onset of the explosion.The sequence of events is shown photographically in Figs. 16 and 17 taken respectively with and without the addition of tetraethyl-lead. Taken in conjunction with previously existing evidence it may be concluded that the role of tetraethyl-lead is t o increase the delay before the second stage in the two- stage ignitions and that gaseous PbO is formed during the process by reaction with the oxygenated intermediates formed in the precombustion period and known t o be conducive to knock. The PbO may be then further active in chain termination by reacting preferentially with the propagating radicals in this way the rate of energy release is reduced the PbO is converted into lead vapour and conditions favourable to slow combustion and the absence of detonation are achieved.It is established that the seat of the reaction of tetraethyl-lead arid its products is in the homogeneous gas phase. Flash Photolysis coupled with Chemical Analysis Most photochemical work in the past with concentrated light sources has been carried out with intensities of the order 10-10 einstein per cm.3 per second by means of the high-powered flash lamps used in flash photo- Iysis intensities lo7 times greater than this lasting about second 4 2 Norrish Porter and Thrush Nature 1963 1'72 71. 4 3 Thrush Proc. Roy. SOC. 1956 A 233 147. NORRISH AND THRUSH FLASH PHOTOLPSIS 167 niay be achieved. Under such conditions the final products may well be different from those resulting from the use of low conventional intensities.For in the latter case excited specic>s or radicals izre fornied a t a very low concentration and in general their continuing reactions are with fresh molecules of reactant while in the former the concentration of free radicals is so high that radical-radical reactions may become of predominant importance. It thus becomes of interest to study the variation of final reaction pro- ducts with intensity by using ordinary methods of chemical analysis. For this purpose the lamp may be made of quartz tubing about 10 mm. in diameter about 50 em. long wound in a spiral to fit closely round the reaction vessel which is about 6-7 em. in length and 2-2.5 em. in diameter. I n the photolysis of acetaldehyde vapour the products a t low intensity are methane and carbon monoxide with very little hydrogen and practically no ethane.To account for this Leermakers 44 postulated a chain mech- anism involving the ncetyl radical in which the chief operative reactions were ( l a ) C)H,CHO + hv ( l b ) CH,*CHO + hv (2) CH + CH,*CHO (3) CHO + CH,-CHO (4) CHO + CH,*CHO ( 5 ) CH,.CO (7) CH + CHO (6) CH3 + CH (8) CHO + CHO = CH + CO = CH + CHO = CH + CH,.CO = CO + H + CH,*CO = CO + CH + CHO = CH + CO = C,HG = CH4 + CO = 2CO + H Since ethane was absent from the products Blacet and Blaedel 45 replaced reaction 6 by a recombination of acetyl radicals to form diacetyl which was detected in roughly the expected amount. If however a sufficiently high concentration of methyl radicals could be generated by reaction l b the incidence of reactions 6 and 7 should predominate over reaction 2 since the rates of the former are proportional to the second power of the con- centration of radicals and that of the latter to the first power The consequence of this is that a t very high intensity ethane should make its appearance and the above scheme leads under these conditions to the fcdlowing limitiiig relationship between the products This was investigated by Khan Norrish and Porter 40 using the flash dis- charge and a normal method of gas analysis and was found to be indeed very closely true.I n this work the reaction was kept isothermal by the addition of excess of carbon dioxide. Similar studies wit'h acet,one and 4 4 Loermakers J . Amer. Chem. Xoc. 1934 56 1537. 4 5 Blacet and Blaedel ibid.1940 62 3374. 46 Khan Norrish and Porter Pmc. Roy. Xoc. 1953 A 219 312. 168 QUARTERLY REVIEWS diacetyl showed but little change of product a t high intensity a result to be expected from the established mechanism of these processes which are not chain reactions owing to the absence of the reactive aldehydic hydrogen atom and hence the impossibility of propagating reactions analogous to 2 above. The decomposition of keten by light of very high intensity was studied in a similar way by Knox Norrish and Porter.*' At low flash intensities in the presence of a large excess of inert gas the products are mainly carbon monoxide and ethylene as found under normal photolysis conditions. As the intensity is increased or the inert -gas pressure decreased hydrogen and acetylene are formed in increasing amounts until eventually they with some carbon become the major products.The progressive change is caused by the increasing adiabatic nature of the photolysis. By analysis of the pro- ducts formed under different conditions of reaction it is possible to follow the course of the reactions and to conclude that carbon formation takes place by successive dehydrogenation of C2 hydrocarbons by Rice-Herzfeld mechanisms and final polymerisation to graphite. It is of interest that in excess of methane the photolysis of keten a t high light intensity leads almost exclusively to ethane and carbon monoxide. One of the main limitations at the present stage of the work is that it is not possible to use monochromatic radiation while maintaining sufficiently high intensities or to make direct measurements of quantum yield. There is nevertheless a wide field of reaction worthy of exploration by the analytical method from which we may hope to glean information about radical-radical reactions. 47 Knox Norrish and Porter J . 1952 1477.

ISSN:0009-2681    

DOI:10.1039/QR9561000149

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

NUCLEAR METHYLATION OF FLAVONES AND RELATED COMPOUNDS By A. C. JAIN M.Sc. PH.D. A.R.I.C. and T. R. SESHADRI M.A. PH.D. F.R.I.C. (DEPARTMENT OB CHEMISTRY UNIVERSITY OF DELHI DELHI- 8) IN the study of organic compounds methylation of hydroxyl and amino- groups is a common laboratory technique and several reagents are employed for this purpose. On the other hand substitution of a hydrogen atom of the aromatic nucleus by a methyl group is rarer. The term " nuclear methylation " has been used for the latter process This process also takes place fairly freely in Nature. Occurrence (i) Chrmnes.-Though C-alkylation of a benzene ring is found in a large variety of natural products examples among chromone derivatives are comparatively few and most of these have only recently been isolated. Three such compounds eugenitin isoeugenitol and is~eugenitin,~ were obtained by Schmid and his co-workers from the alkali-soluble phenolic constituents of the flowers of the wild cloves of Java (Eugenia caryophylhata).When eugenitin was subjected to alkali fission it yielded acetone and 2-methylphloroglucinol 1 -methyl ether (IV). Itls methyl ether (V) on the same treatment gave 6-hydroxy-2 4-dimethoxy-3-methylacetophenone (VI) showing thereby that eugenitin was 5-hydroxy-7-methoxy-2 6- dimethylchromone (I). When treated with hydriodic acid eugenitin under- went simultaneous demethylation and isomerisation forming a dihydroxy- dimethylchromone which on alkali fission yielded C-methylphloroglucinol and on complete methylation a methyl ether different from 5-O-methyl- eugenitin (V). This chromone was later found to be isoeugenitol (11).When subjected to partial methylation the chromone gave its 7-methyl M e O m M e M e m e --L M e V . Me\ I I - Me\ Me \ Me0 ij HO ij H (V) ( I ) (I V) t I M e O o O H Me\ COMe W W M e - M e m M e Me0 HO ij HO ij Schmid Helv. Chim. Acta 1949 32 813. Schmid and Bolleter ibid. 1949 32 1358. Idem ibid. 1950 33 1770. 169 170 QUARTERLY REVIEWS ether (111) which proved to be the same as natural isoeugenitin. The constitutions of these compounds have been further confirmed by synthesis by Schmid and B~lleter,~ as well as by Mukerjee Seshadri and Varadarajan (see below). They all contain only one C-methyl group in the benzene ring of the chromone either in the 6- or tihe %position. Penfold6 isolated a yellow crystalline substance from the oil of Backhousicc angustifolia Benth.which he named angustifolionol. It has been recently examined by Birch Elliott and Penfold.' They obtained acetone and ,$, -t R e M e - MeO&H Me\ COMe Me\ Me\ 02H- Me\ C02Me H 0 O t - i HO HO 0 HO HO (XI (VII) a R=Me (vlll) (I xs % 6-dihydroxy-4-methoxy-3 5-dimethylbenzoic acid (VIII) as its alkali- fission products which showed that angustifolionol is 5-hydroxy-7-methoxy- 2 6 8-trimethylchromone (VIIa). The acid (VIII) was synthesised froiii metlhyl 2 4 6-trihydroxy-3 5-dimethylbenzoate (IX) by a process involv- ing partial inethylation and ester hydrolysis. The structure of angusti- folionol (VIIa) has been supported by its synthesis from 3 5-dimethyl- phloracetophenone (X) by chromone condensation [to give (VIIb)] and partial methylation,s and also by other methods given later.(ii) F2avones.-The natural flavones include only one nuclear-methylated compound strobochrysin. This was isolated along with a number of compounds from the heart-wood of Pinus strobus by Lindstedt and Mi~iorny.~ Its struc- Me\ " O W HO (j ture as 6-methylchrysin (XI) was established by alkali- 'I) degradation to C-methylphloroglucinol and benzoic acid as well as by synthesisg lo described below. (iii) FEavonoZs.-Pinoquercetin and pinomyricetin have recently been reported to occur aniong tlhe components of the colouring matter of Ponderosa pine bark.ll Alkali fission of their complete methylation products yielded the same ketone identified by synthesis as 6-hydroxy-2 4 co-trimethoxy- 3-methylacetophenone (XIV) ; in addition the former gave veratric acid and the latter tri-O-methylgallic acid.Pinoquercetin is therefore 6-methyl- quercetin (XII) and pinomyricetin is 6-methylmyricetin (XIII). The former had earlier been synthesised by Jain and Seshadri.12 b R=H 4 Schmid and Bolleter Helv. Chim. Acta. 1950 33 p. 917. 6 Penfold J. Proc. Roy. SOC. New South Wales 1923 57 300. 7 Birch Elliott and Penfold Austral. J . Chem. 1954 7 169. Mukerjee Seshadri and Varadarajan Proc. I n d i a n Acad. Sci. 1953 37 A 131. Birch Elliott Mukerjee Penfold Rajagopalan Seshadri and Varadarajan ibid. 1955 8 409. 9 Lindstedt and Misiorny Acta Chem. Scnnd. 1951 5 1. lo Mukerjee and Seshadri Proc. Indian Acad. Sci. 1953 38 A 208. l1 Kurth Ramanathan and Venkataraman Current Sci. 1955 24 157 ; J . Sci. l2 Jain and Seshadri J . S c i .I n d . Res. India 1954 13 B 539. I n d . Res. I n d i a 1956 15 B 139. JAIN AND SESHADRI NUCLEAR METHYLATION O F FLAVONEY 171 (xi I> oclil) (X I v) (iv) FZavanones.-Two C-methylated flavanones matteucinol and de- methoxymatteucinol were quite early known to occur in Nature. They were isolated from the leaves of Matteucia orientalis by Munesada.13 When fused with alkali these each gave the same phenol 2 4-dimet,hylphloro- glucinol (SVII) and in addition the first yielded 4-methoxycinnamic acid and the second cinnamic acid. Thus the stlructures of matteucinol and demethoxymatteucinol are 5 7-dihydroxy-4’-methoxy-6 8-dimethyl -(XV) and 5 7-dihydroxy-6 8-dimethyl-flavanone (XVI) respectively. l4 These constitutions were confirmed by synthesis from the degradation products mentioned above using the Friedel-Crafts reaction.The natural samples are optically active and their melting points are different from those of the synthetic compounds but become identical apfter racemisation. Mat- teucinol (XV) has also recently been obtained from the ethereal extract of the leaves of Rhododendron simsii by Arthur and Hui.lG otv (XV I I) (XV I) Erdtmanl’ isolated a new colourless compound strobopinin from the heartwood of Pinus strobus which was later found to contain an isomeric compound cryptostrobin.l8 The former has also been found recently by Lindstedt in Pinus monticoEa. l9 With both compounds alkali-fusion yielded 2-methylphloroglucinol and oxidation with potassium permanganate gave benzoic acid. The molecular composition (C16H1404) coupled with these observations indicated that these are 6- (XVIII) and 8-methyl (XIX) derivatives of 5 7-dihydroxyflavanone.The structures were later con- firmed by synthesis involving condensation of methylphloroglucinol with cinnamoyl chloride a mixture of the two substances being obtained in poor yield. However the exact structure-as to which is the 6- and which the 8-methyl derivative-is still undecided. 2o Another C-methylated flavanone farrerol has recently been reported 13Munesada J . Pharm. SOC. Japan 1924 505 185. l4 Fujise Sci. Papers I n s t . Phys. Chem. Res. (Tokyo) 1929 11 111. l5 Fujise and Nishi Ber. 1933 66 929 ; J . Pharm. Soc. Japan 1934 55 1020 ; Fujise and Kubota Ber. 1934 67 1905. 16Arthur and Hui J. 1954 2783. Erdtman Svensk kem. Tidskr. 1944 56 2. Alvarez-Nbvoa Erdtman and Lindstedt Acta Chem.Scund. 1950 4 390. Lindstedt ibid. 1949 3 1147. 2o Lindstedt and Misiorny ibid. 1951 5 11. 172 QUARTERLY REVIEWS to occur in the leaves of Rhododendron furrerue; it is 4'-deniethylmatt8euciiilol (cf. XV).2On HydrozyJlavanones.-The heartwood of Pinus strobus yields also a colour- less compound belonging to this category and it has been named strobo- banksin. Alkali-fission to 2-methylphloroglucinol oxidation with perman- ganate to benzoic acid and easy dehydrogenation by palladium and cinnamic acid to a flavonol showed it to be 3 5 7-trihydroxy-6- or -$-methyl- flavanone (XX a or b) though its exact constitution is unsettled.20 b R-Me,RL H Anhydro- bases of FZuvylium Xa1ts.-Brockmann and Haase21 isolated from " dragon's blood " resin of East Indian origin a coloured substance dracorubin.The same compound was also obtained by HesseZ2 from the blood-red resin of the fruit-bearing parts of the palm Draczna dracobluma along with a minor component dracorhodin. The close relation between these two pigments was indicated by the conversion of dracorubin picrate into rlracorhodin on treatment with alkali. 2 3 Dracorhodin when subjected to alkali-fission yielded acetophenone and C-methylphloroglucinol b-methyl ether. This indicated that it was the anhyclro- base (XXI ) of 7- hydroxy- 5 -methoxy- 6 -methylflavylium hydroxide (XXII) and bhis constitution was confirmed by synthesis 2 3 3 24 from aceto- phenone and 4 6-clihydroxy-2-methoxy-3-inethylbenzaldehyde (XXIV). Me0 (X x I) 1 Me0 OH Me0 (XX I I) -3 Me0 (XX I I 1) (XX I V) 20a Arthur J.1955 3909. 21 Rrockmann and Haase Ber. 1936 69 1950. 2 2 Hesse Annalen 1936 524 14. 23 Brockmann and Junge Ber. 1943 76 751. 2,1 Robertson and M7halley J. 1950 1882. JAIN AND SESHADRl NUCLEAR METHYLATION OP FLAVONES 173 The aldehyde was prepared in a pure stlate by the hydrolysis of the anil of methyl 3-formyl-2 6-dihydroxy-4-methoxy-5-methylbenzoate (XXIII) with simultaneous decarboxylation of the resulting acid. 24 Dracorubin C32H2405 has a more complex structure which has been clucidated by Robert,son and Whalley. 25 On alkali-fission 26 it gave aceto- phenone and draconol C2,H2,06 while oxidation with alkaline hydrogen peroxide 27 produced dracoic acid C,,H,,O,. The latter has been shown to be 7 - hydroxy- 5 -methoxyflavan-8 - carboxylic acid (XXVIII) undergoing decarboxylation to 7-hydroxy-5-methoxyflavan (XXX) which can be ob- tained by Clemmensen reductSon of alpinetin (XXIX).Dracoic acid itself has been synthesised from noralpinetin (XXV) as shown in the above formula -(x x.x I Me0 H2 ( X X X I b) The phenol draconol is considered to have the structure (XXXI a or b) partly by analogy with dracorhodin (XXI) and partly because the properties of its partial methyl ether were reminiscent of a l-hydroxy- xanthone structure (resistance to fusion with alkali formation of perchlorate 25 Robertson and Whalley J. 1950 1876 3117. 26 Brockmann and Haase Ber. 1937 70 1733. 27 Brockmann Haase and Freieusehner Ber. 1944 77 270. 174 QUARTERLY REVIEWS ferric reaction colour solubilities and behaviour with boroacetic anhydride). Since dracorubin yields draconol (XXXI a or b) by the loss of acetophenone with the si.multaneous formation of the carbonyl and 1 -hydroxy-group of the xanthone residue Robertson and Whalley z5 gave the structure of dracorubin as either (XXXII) or (XXXIII).Other types of C-methyl-jlavonoids.-Besides the above mentioned C- methylated benzo-4-pyrones there are others which though they have C-methyl groups in the benzene ring do not seem to arise by nuclear methylation and so are not considered in this Review. For example lichexanthone (XXXIV) present in the lichen Parmelia formomnn ; 28 ravenelin (XXXV) a metabolic product of Helminthosporium turcium and Ti. ravenelii ; 29 eleutherinol (XXXVI) the first natural naphthopyrone found in Eleuthera bulbosa ; 30 31 and 2-methyl-anthracjuinone and -naphth- aquinone derivatives occurring widely in Nature.31(r (xxx I V) (X x XV) (x x xv I) However rottlerin 32 (XXXVII) the phenolic crystalline component of the Indian colouring matter and anthelmintic drug " kamala " (Mallotus philippinensis) could be included among C-methylated compounds. It is a chalcone derivative having a C-methylphloracetophenone unit. Here G-methylation is in the substituent group and not in the main chalcone skeleton. C0CH:CHPh HO HO (XXXVI I) Synthesis (i) Methylation with methyl iodide and methanolic potassium hydroxide was the earliest method for the preparation of nuclear methylated flavon- 28 Asahina and Nagami Bull. Chem. SOC. Japan 1942 17 202; Aghoramurthy and 29 Raistrick Robinson and White Biochem. J. 1936 30 1303. 30 Schmid Ebnother and Meijer Helv. Chim.Acta 1950 33 1751 ; 1952 35 910 31 Birch and Donovan Austral. J . Chent. 1953 6 373. 31a Aghoramurthy and Seshadri J . S c i . I n d . Res. India 1954 13 A 114. 3 2 Perkin and Perkin Ber. 1886 19 3109 ; Hummel and Perkin J. SOC. Chem. Ind. 1895 14 460 ; Perkin ibid. 1900 19 519 ; McGookin and Robertson J. 1937 748 ; 1938 309 ; 1939 1579 1587 ; 1948 113 ; Brockmann and Maier Annalen 1938 535 149. Seshadri J . Sci. I n d . Res. India 1953 12 By 73 350. 928. JAIN AND SESHADRI NUCLEAR METHYLATION OF E'LAVONES 175 Sodium methoxide can also be used in place of potassium hydroxide,38 and sometimes has a marked advantage. This method invari- ably leads to the production of a mixture containing the simple methyl ethers (partial as well as complete) along with the methyl ethers of nuclear methylated products.But the separation of C-methyl compounds is not very difficult because of their markedly lower solubility in organic solvents. For example quercetin (XXXVIII) generally yields a mixture of 3 7 3' 4'- tetramethyl ethers of quercetin (XXXIXa) and 6-methylquercetin (XL) as well as quercetin pentamethyl ether (XXXIXb). Of all these the C- methylated compound is the most sparingly soluble in ether as well as in methyl alcohol and can thus be easily separated.12 37 (XXXIX) a;R=H; b,R=Me (X L) Though it was known even towards the end of the last century that nuclear methylation of geni~tein~~ 34 (XLI) li~teolin~~ (XLII) and ksmpferol 35 (XLIII) took place in the fused benzene ring [alkali-fission yielded C-methylphloroglucinol p-methyl ether (IV)] the exact location of the C-methyl group could not be established.It is only recently that a number of chromone derivatives of definite constitution have been syn- thetically obtained (see p. 178) and by comparison with them the nuclear methylation products have been uniformly shown to be 6-methyl derivatives (see ref. 39). 33 Perkin and Newbury J. 1899 75 836. 34Perkin and Horsfall J. 1900 77 1311 1317. 35 Ciamician and Silber Ber. 1899 32 861. 3Q Waliaschko Arch. Pharm. 1909 247 453. 37 Perkin J. 1913 103 1635. 38 Baker and Robinson J. 1926 2713. 8fi Jain and Seshadri J . Sci. I d . Res, Ilzdia 1955 14 A 227 for collected references. 176 QUARTERLY REVIEWS It was earlier considered that the demethylation of these C-methylated methyl ethers with hydriodic acid yielded the corresponding hydroxy-6- methyl compounds,34 but it is now known that this is not invariably so.With simple chromone and flavone derivatives a mixture results owing to partial isomeric change during demethylation and the isomers have to be separated.5~ lo 40 For example 6-methyl-luteolin 7 3’ 4’-trimethyl ether (XLIV) gives a mixture of 6-methyl-luteolin (XLV) and 8-methyl-luteolin (XLVI) .40 Under ordinary conditions chromonols flavonols 12 41 42 and isoflavones 43-45 do not suffer this isomeric change. But it is possible that under drastic conditions even these can be made to do If instead of hydriodic acid aluminium chloride in dry benzene is used for demethyl- ation in most cases there is little isomeric change ; even here under more drastic conditions a change can be brought This subject of ring isomeric change in flavonoids has been recently reviewed by Mukerjee and Seshadri.48 OMQ M e O w O M c ( X LI V) Me \ HO ij + Nuclear methylation can be achieved satisfactorily with 5 7-dihydroxy- chromones. For example noreugenin (XLVII) forms eugenitin lo 49 (XLVIII) ; isoeugenitol (XLIX) gives angustifolionol * (L) ; chrysin (LI) gives strobochrysin 7-methyl ether lo (LII) ; quercetin (XXXVIII) gives pinoquercetin 3 7 3’ 4’-tetramethyl ether l2 (XL) (see p. 175) ; and genistein (XLI) gives 6-methylgenistein 7 4’-dimethyl ether 33 34 38 50 (LIII). However the method is not suitable for the nuclear methylation of the simpler 7-hydroxychromone derivative^.^^ The reasons for this as well as the mechanism of nuclear methylation have been explained by Jain 40 Bannerjee and Seshadri J.Sci. I n d . Res. India 1954 13 By 598. 4 1 Jain and Seshadri Proc. I n d i a n Acad. Sci. 1954 40 A 249. 4 2 Idem J. S c i . I n d . Res. India 1953 12 B 564. 43 Seshadri and Varadarajan Proc. I n d i a n Acad. Sci. 1953 37 A 145 608 614 4 4 Whalley J . Amer. Chem. SOC. 1953 ‘75 1059. 45 Iengar Mehta Seshadri and Varadarajan J. Sci. I n d . Res. I n d i a 1954 13 B 413 Donnelly Philbin and Wheeler Chem. and Ind. 1954 163 ; Baker Dunstan 47 Whalley Chem. and Ind. 1953 277; J. 1953 3366. 48 Mukerjee and Seshadri Chem. and Ind. 955 271. 49 Whalley J. Amer. Chem. SOC. 1952 74 794. 5O Mehta and Seshadri J. 1954 3823. 526. 166. Harborne Ollis and Winter ibid. 1953 277. JAIN AND SESHADRI NUCLEAR METHYLATION OF FTdA4VONE8 177 and S e ~ h a d r i . ~ ~ It has been shown that the minimum requirement for nuclear methylation is the existence of a resorcinol-carbonyl unit (LIV) capable of undergoing tautomeric change into a #I-diketonic structure (LV) which is the reactive structure for nuclear methylation.(XLVI I) (XLVI 1 1 ) (X LI X) l-1 (ii) The second method of nuclear methylation is a two-stage process consisting of an aldehyde synthesis followed by reduction. The method most commonly used for the first stage is a Duff reaction which introduces an aldehyde group into the reactive 8-position and if this is not available into the 6-position. The second stage involves catalytic reduction with the calculated amount of hydrogen. This method is very satisfactory for the preparation of 8-methyl derivatives of 5 7-dihydroxy- and 7-hydroxy- flavonoids.It was applied earlier in simple cases [e.g. conversion of H O m M e H a M e -t tvleO&Me Me \ OHC \ I I - Me \ HO 0 HO (j HO (j (Lx I) (LxI 1) (U 7-hydroxyflavone (LVI) into its 8-methyl derivative (LVIII) through the intermediate aldehyde (LVII)] by Rangaswami and Seshadri 51 and has recently been used by others for the preparation of 8-methylquercetin 3 3’ 4’-trimethyl ether (LX) from quercetin trimethyl ether l2 (LI.X) anti 61 Rangaswami and Seshadri Proc. Indiun Acad. Sci. 1939 9 A 7. 178 QUARTERLY REVIEWS also for the synthesis of angustifolionol (L) through t’he stages (LXI) and (iii) An unambiguous method for tlhe synthesis of 8-methyl derivatives is to eniploy 2-hydroxy-4 6-dimethoxy-3-methylacetophenone (LXIIIa) or its cu-methoxy-derivative (LXIIIb) for chromone and flavone conden- sations yielding 5 7-dimethoxy-8-methyl compounds.For example the ketone (LXIIIa) on ring closure with sodium acetate and acetic anhydride yields 5 7-dimethoxy-2 8-dimethylchromone (isoeugenitin monomethyl ether) 4 9 (LXIV). The corresponding flavone [8-methylchrysin dimetlhyl ether (LXVa)] and the ether (LXVb) have been prepared in two ways by preparation of the diketone (LXVI) and its cyclisation,1°9 40 and by the preparation of the chalcone (LXVII) and its oxidation with selenium di~xide.~ 9 40 For flavonols Allan-Robinson condensation and chal- cone condensation followed by oxidation with selenium dioxide are sntis- factory. 1 2 7 4 1 9 4 2 7 5 2 For the preparation of 8-methylisoflavone derivatives (LXII) .8 (LXIX) benzyl2-hydroxy-4 6-dimethoxy-3-methylphenyl ketone (LXVIII) with the required subst’ituents in the phenyl group has been subjected to the usual methods of isoflavone ring closure vix.heating with acetic anhydride and fused sodium acetate or condensation with sodium and ethyl f0rmate.~37 4 5 7 53 When 8-methylflavonol and isoflavone methyl ethers having 3-methoxy- and 3-phenyl substituents respectively are demethylated by hydriodic acid under ordinary conditions they do not undergo isomeric change but only demethylation. On the other hand 8-methylchromone and flavone methyl ethers [e.g. 5 7-dimethoxy-2 8-dimethylchromone 54 (LXIV) and 8- methylchrysin diniethyl ether (LXXI)] give mixtures of hydroxy-6- and -8-methyl-chromones and -flavones [eugenitol (LXX) and isoeugenitol (XLIX) ; 8- (LXXII) and 6-rnethylchrysin (LXXIII)].The proportions 5 2 Linclstedt and Misiorny Acta Chem. Xcand. 1951 5 1213. 5 3 Karmarkar Shah and Venkataraman Proc. Indian Acad. A’ci. 1952 36 A 652. 5 4 Mukerjee and Seshadri CJLem. and Ind. 1955 1009. JAIN AND SRSHADRI NUCLEAR METHYLATION OF FLAVONES 179 however vary ; in chromones the 8-methyl derivative is predominantly the major product while in flavones both are obtained in almost equal quantities. The isomerisation is avoided by demethylation with aluminium chloride in benzene under ordinary conditions. lo 40 (iv) If in the above synthesis the hydroxy-ketones (LXXIV; R = H OMe Ph or substituted phenyl group) are employed instead of the methyl ethers a mixture is obtained containing the 6- and 8-methyl derivatives of the hydroxy-chromones -flavones etc.The proportion of the isomers varies from case to case. In simple chromone condensations the 6-methyl compound (eugenitol) (LXXV) constitutes the major product lo and the 8-methyl isomer (XLIX) the minor; 5 4 in flavones these are in almost equal amount ; lo 409 45 in flavonols the major product (75%) is the 8-methyl compound 12 41 42 (LXXVI) ; and in isoflavones when a high-temperature reaction such as heating with acetic anhydride and fused sodium acetate is used the products are almost completely 8-methyl compounds (LXXVII) whereas in the low-temperature reactions 5 5 (ethoxalyl chloride or acetyl chloride in pyridine a t 0" being used) 6-methyl derivatives (LXXVIII) are the most prominent products. 50 Obviously the comparative reactivity of the hydroxyl groups situated ortho or para to the C-methyl group in the ketone used for ring closure depends on the temperature and other conditions.H O N 6 OH HO@JAe H 0 m p M e \ CO.CH,R Me\ HO HO ij HO f (LXX I V) (LXXV) (LXXVI) Biogenesis Though considerable thought has been given to biological methylation and useful experimental results have becn o5tnined we are still far from having information adequate for us to n-ork out precise details of biogenesis. Consequently any mechanism suggested lins to be tentative and in the nature of a working hypothcsis. In discussing the biogenesis oE nuclear-inethylated flavonoids the follow- ing points have to be considered. A number of these compounds carry a &methyl group [engenitin (I) strobochrysin (XI) and dracorhodin (XXI)]. 55 Baker Harborne and Ollis J . 1953 1860.180 QUARTERLY REVIEWS However there are representatives [isoeugenitol (11) and isoeugenitin (111)] which have an 8-methyl group and examples containing methyl groups in both the 6- and the 8-position [matteucinol (XVa) farrerol demethoxy- matteucinol (XVI) and angustifolionol (VIIa)]. In a number of cases the accompanying hydroxyl groups have undergone partial methylation [eugeni- tin (I) isoeugenitin (111) and dracorhodin (XXI)] and there are others in which no O-methylation has taken place [strobochrysin (XI) pinoquercetin (XII) and pinomyricetin (XIII)]. Complete O-methylation is not found in any of these. Further in a large number of plant sources C-methyl com- pounds occur along with simpler compounds not containing the C-methyl group. For example in the flowers of Eugenia caryo- Me phyllata eugenin (LXXIX) has no C-methyl group in the benzene ring whereas three other components mentioned earlier (I 11 and 111) contain either a 6- or (Lxx'x) an 8-methyl group.Similarly in the heartwood of Pinus strobus strobochrysin (XI) and chrysin (LI) occur together. From the above facts it seems that C-methylation takes place after the main carbon skeleton is formed but before O-methylation. The role of formaldehyde or its equivalent as biological methylating agent has been studied for a considerable time and has been discussed in two recent reviews one by Geissman and Hinreiner 56 and the other by Challenger.57 A point which strongly supports this hypothesis was braught out by Seshadri 58 in connection with the biogenesis of lichen acids. It is the occurrence of a single carbon atom in all states of oxidation -CH, -CH,.OH -CHO and -CO,H which is readily explained as arising from the initial -CH,*OH group formed by the condensation of formaldehyde and undergoing reduction to CH and oxidation to the other groups.An alternative may be that transmethylating agents provide methyl groups ; this is also discussed in the above-mentioned reviews. Both reagents are electrophilic (cationoid) but they may react in different ways and under .different conditions. The following two possibilities can be envisaged for the formation of C-monomethyl compounds. The first would be C-methylation of the fully formed 5 7-dihydroxyflavonoids. The predominantly reactive position seems to be position 8 and this conclusion is supported by the conversion of chrysin (LI) into chrysin-&aldehyde 59 (LXXX) and more recently of quercetin 3 3' 4'-trimethyl ether (LIX) into the 8-aldehyde and then into the 8-methyl quercetin derivative l2 (LX) (see p.177). Hawever experi- ments on nuclear methylation by means of methyl iodide 39 indicate that the 6-position is predominently reactive with this reagent and this has been explained as due to the capacity of the system to react in the isomeric diketonic form (see p. 177). This methylation is probably analogous to the action of transmethylating agents. Even with formaldehyde or its equivalent if the 8-position is protected by some means say enzymic HO ij Geissman and Hinreiner Bot. Rev. 1952 18 77. 67 Challenger Quart. Rev. 1955 9 255. 58 Seshadri Proc. I n d i a n Acad. Xci. 1944 20 A 1. 5e Seshadri and Varadarajan ibid.1949 30 A 342. JAIN AND SESI-IADRI NUC'LERR METHYLATICK OF FLAVONES 181 adsorption the 6-position can function. This is suggested by the synthesis of angustifolionol (VIIa) from isoeugenitol (XLIX) even by the aldehyde method (see pp. 177 178). Hence the fully formed pyrone derivative can undergo nuclear methylation either in the 8- or in the 6-position by the mechanisms available in plants. The second possibility would be C-methylation prior to ring-closure. In connection with the biogenesis of the chromones of Eugeaia caryophyllatu Mukerjee et aL5 suggested that thc 8-methyl group arose directly by the nuclear methylation of the 5 7-dihydroxychromone by means of the form- aldehyde equivalent whereas the 6-methyl compound was the result of the nuclear methylation at the earlier diketonic stage noreugenone (LXXXI) subsequent ring closure giving preferentially the 6-methyl derivative (LXXXII).This was based on the general results of pyrone ring-closure available at that time But more recently it has been shown that both 6- and 8-methyl compounds are produced simultaneously in varying pra- portions 54 under the same conditions and this supports Schmid and Bol- leter's suggestion that eugenitin (I) and isoeugenitin (111) arise from the same precursor by ring closure in the two possible ways. HOJ OH I_F H o ~ ~ C t - i & O C H 3 Me \ COCH.$OCH HO HO 0 ( U X X I u HO 0 (LXX I) For evolution of 6 8-dimethyl compounds such as matteucinol farrerol demethoxymatteuciiiol (XVI) and angustifolionol (VIIa) two (XVL routes are possible (i) methylation in the %position of the 6-methyl compound ; and (ii) methylation in the 6-position of the 8-methyl compound.Both these are possible in Nature. In the laboratory the aldehyde method works satisfactorily in both cases (see p. 177) but the method using methyl iodide is applicable only to the 8-methyl compound since the new methyl group a1 ways enters the 6-position. Thus angustifolionol is readily formed by methylation of isoeugenitol (XLIX) and not of eugenitol8 (LXXXII). A further possibility is dialkylation a t an earlier stage before the chromone ring is closed. Definite information has not been available on this reaction. The action of formaldehyde is known to be complex involving more than one molecule of phloroglucinol. 6o Monoalkylation of phlor- acetophenone 61 (LXXXIIIa) and phloroisobutyrophenone 6 2 (LXXXIIIb) with methyl iodide by the potassium carbonate-acetone method is fairly easy.The former yields 2-hydroxy-4 6-dimethoxy-3-methylacetophenone 60 Boehm Annulen 1903 329 269. G 1 Curd and Robertson J. 1933 457. 6 2 Hems and Todd J . 1940 1208. M 182 QUARTERLY REVIEWS (LXXXIVa) and the latter forms baeckeol (LXXXIVc) (2-hydroxy-4 6- dimethoxy-3-methylisobutyrophenone) which is a phenolic constituent of the essential oils from certain species of Myrtucez 63 Further C-methylation does not take place under these conditions.61 Jain and Seshadri 64 therefore subjected C-methylphloracetophenone (LXXXIVb) to methylation under conditions found t o be the most satisfactory for resacetophenone ; excess of both methyl iodide and methanolic alkali were added in one lot and the mixture was refluxed for several hours.It was however found to yield a C-polymethylated product 4-acetyl-5-hydroxy-2 2 6 6-tetramethyl- cyclohex-4-ene-1 3-dione (LXXXVa). The same product was also obtained directly from phloracetophenone (LXXXIIIa). An analogous structure is found in leptospermone (LXXXVb) which occurs in the oil of Leptosper.l-num javescens G57 66 it was obtained from phloroisovalerophenone (LXXXIIIc) by t,he above method in good ~ields.6~9 66 R O O O H \ C o d OH OR (UXXI I I) a . R=Me (LXXXIV) a. R=R'= Me (LXXXV) a R=Me b R- Prl. b R=H R'= Me b R=Bd C R = B ~ c R=Me,R'= Prl C R=H d R=H Therefore in subsequent experiments restricted quantities of alkali (one two and three equivalents) were used always with an excess of methyl iodide in order to avoid st,rongly alkaline ~onditions.~~ 3 5-Dimethyl- phloracetophenone (LXXXVIa) could be obtained only in poor yields.The monomethylphloracetophenone (LXXXIVb) is comparatively easy to obtain in satisfactory yields and similarly the higher methylation products (tri- and tetra-) (see also Riedl and Risse 67). It therefore appears that the dimethyl compound is rapidly consumed in further reaction. Another possibility suggested by Riedl and Risse,G7 is the formation of a gem.- dimethyl derivative e.g. 5-acetylfilicinic acid (LXXXVII) competing wit>h the formation of the 3 5-dimethyl compound These conclusions are further supported by two earlier observations ( a ) formation of methyl 3 Fi-dimethyl- (LXXXVI) b. a,R=Me R = H H O / Me(&-,R 0 1 4 :QoMe (LXXXVI I) C I R = OMe phloroglucinolcarboxylate (LXXXVIc) in a low yield when silver phloro- glucinolcarboxylate (LXXXIIIe) was heated in a sealed tube with methyl 63 Penfold et al.J. Proc. Roy. SOC. New South Wales 1922 56 87 ; 1925 59 351 ; 64 Jain and Seshadri Proc. Indian Acad. Sci. 1955 42 A 279. 6 5 Penfold J . Proc. Roy. Xoc. New South Wales 1921 55 51. 6 6 Briggs et al. J. 1938 1193 ; 1945 706; 1948 383. 67 Riedl and Risse Annalen 1954 585 209. 1936 '71 291. JAIN AND SESHADRI NUCLEAR METHYLATION OF FLAVONES 183 iodide,G8 and ( b ) the formation of 4-formyl-5-hydroxy-2 2 6 6-tetramethyl- cyclohex-4-ene-1 3-dione (LXXXVc) from formyl-3 5-dimethylphloro- glucinol (LXXXVIb) by treatment wit,h methyl iodide and methanolic potassium h y d r o ~ i d e .~ ~ That carbonyl derivatives of phloroglucinol readily undergo C-poly- methylation even in Nature is borne out by the occurrence of a large number of C-polymethylated ketones. Important examples are leptospermone (LXXXVb) and butyrylfilicinic acid 7O (LXXXVIII). Angustione (XCI) and dehydroangustione (XC or its tautomer) occurring in the oil of Back- housia angust~foZia,71 could also come under this category if stages (a) reduc- tion of a keto-group (b) dehydration and ( c ) further reduction of a double bond are envisaged as in (LXXXIX) to (XCI).64 6 0 ( WXXVl I I) (uo(p) H Me CH2 - lt&H * Me20:*, 0 COMe 0 ( XC 0 ( X d Me 0 A number of compounds found in male and female ferns have two such nuclear methylated phloroglucinol units e.g. aspidin 70 (XCII) albaspidin 72 (XCIII) and flavaspidic acid 69 i 2 (XCIV).Some compounds such as protokosin (XCV) a-kosin (XCVIa) and /?-kosin (XCVIb) present in the anthelmintic drug k o ~ s s o ~ ~ and y-aspidin 71 (XCVII) are in lower states of methylation. Aspidinol (XCVIII) is a C-monomethyl derivative of phlorobutyrophenone also found in and usnic acid (XCIX) is a unique example in which two C-methylphloracetophenone units have combined to yield a dibenzofuran derivative. 7 5 A survey of the above-mentioned compounds supports the view that 68 Herzig Wenzel and Altmann Monatsh. 1901 22 219. 69 Herzig and Wenzel ibid. 1905 26 1366. 70 Boehm Annalen 1898,302,171 ; 1899,307,250 ; 1901,318,230 ; 1903,329 321. 7 1 Gibson Penfold and Simonsen J. 1930 1184 ; Cahn Gibson Penfold and Robinson J. 1931 286 ; Birch J. 1951 3026 ; Ensor and Wilson Chena.and Ind. 1955 1010 ; Chan and Hassall J. 1955 2860 ; Birch and Elliott Chem. and Ind. 1956 124; Austral. J. Chem. 1956 9 95. 7 2 Robertson and Sandrock J. 1933 1617 ; McGookin Robertson and Simpson J. 1953 1828; Riedl Annalen 1954 585 32. 73 Hems and Todd J. 1937 562 ; Birch and Todd J. 1952 3102. 7 4 Karrer and Widmer Helv. Chim. Acta 1920 3 392 ; Robertson and Sandrock J. 1933 819. 75 Curd and Robertson J. 1937 898 ; Barton Deflorin and Edwards Chem. and Ind. 1955 1039 ; J. 1956 530 ; Schopf and Ross Naturwiss. 1938 47 772 ; Annalen 1941 546 1. 184 QUARTERLY REVIEWS in general single methyl groups enter the 3- and the 5-position of the phloroglucinol nucleus at an early stage and that the gem-dimethyl groups are formed by further methylahion. Isolation though in poor yield of .HO& M&H . Me*& *Me Pr'CO\ CH / OPr' PrCO\ CH /COPr R'O OH HO OH (XCVI) a R=Me.R'= H b,R=H R'=Me (XCV I I) (XCVIII) OH HO Me OH UClW 3 5-(2i7_netliylphloracetophenone (LXXXVIa) during nuclear methylation of phloracetopheiione 6 4 3 6 7 therefore indicates the possibility of dialkylatiori before pyrone ring-closure in the evolution of G 8-dimethylchromone derivatives.

ISSN:0009-2681    

DOI:10.1039/QR9561000169

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

RAMAN SPECTRA OF INORGANIC COMBOUNDS By L. A. WOODWARD M.A. PH.D. (INORGANIC CHEMISTRY LABORATORY OXFORD) Introduction Description of Raman Effect.-In I925 Raman announced 1 his discovery of the molecular light-scattering effect which is now known by his name. Since then it has established itself as one of the recognised methods for the detection of molecular species and the investigation of their structure. When a beam of light traverses a transparent medium free from dust par- ticles and the like the frequency being chosen so as not to lie in an absorp- tion region most of the light passcs through unaffected ; but (as was known before Raman's work) some is scattered by the molecules. The total inten- sity of this scattering is very small relative to the incident intensity and varies from material to material.For liquids and light in the visible region the total scattered intensity may be of the order of of the incident. Long before Raman's discovery the inverse proportionality t o the fourth power of the wavelength had been made the basis of the well-known explana- tion of the blue of the sky. I n this so-called classical or Rayleigh scattering the wavelength or frequency of the light remains unchanged so that with a monochromatic primary beam the spectrum of the scattered light consists merely of the same single line as does that of the incident light. Raman found that the scattered spectrum also contains new lines whose frequency displacements relative to the primary line are characteristic of the molecular species involved. Thus for any particular substance a similar pattern of lines (the R'aman spectrum) is always found no matter what the incident frequency.In practice visible or ultraviolet light is used and the frequency chosen to avoid regions of absorption. Raman spectra can be observed for all states of aggregation solid liquid and gas. Most work has been done with liquids for which in general the Raman effect is of the order of a thousand times less intense than the Rayleigh scattering which is itself only feeble. Simple Account of Molecular Light-scattering.-The frequency shifts of the Raman lines relative to the primary line (Raman frequencies) are found to be equal to frequencies of vibrational or rotational transitions of the scattering molecules. The vibrational shifts (order lo2 or lo3 cm.-l) are large enough to be observed conveniently with prism spectrographs and have been most widely studied.The pure rotational shiftts give Raman lines lying so close to the relatively much stronger Rayleigh line that their observation is impracticable except for molecules of relatively low mament of inert,ia and may require the high resolving power of a grating instrument. 1 Raman and Krishnan Nature 1928 121 501 ; Raman Indian J. Phys. 1928 2 387; Raman and Krishnan ibid. p. 399. 185 186 QUARTERLY REVIEWS In what follows we shall unless otherwise stated be considering only vibrational Raman spectra. A very simple account of molecular light-scattering can be given as follows. In Rayleigh scattering the incident light quantum (energy hvo) collides with a molecule and is simply scattered without change of frequency.I n the Raman effect on the other hand the collision induces the molecule t o undergo a transition. If for example this is a vibrational transition from n = 0 to n = 1 corresponding to the frequency vW the light quantum is scatbered with correspondingly diminished energy h(v0 - vW) i.e. shows a frequency shift dv = v towards the red. If however the molecule happens to be in the state n = 1 when the quantum collides with it the transition 1 -+ 0 may be induced in which case the quantum will be scattered with correspondingly enhanced energy i.e. will show a shift of the same mag- nitude as before but in the opposite sense. The two Raman lines are known respectively its the Stokes line and the anti-Stokes line for the fre- quency involved. At ordinary temperatures the ratio of the numbers of molecules with n = 1 and n = 0 will usually be small so that anti-Stokes lines will be considerably weaker than the corresponding Stokes lines.In fact anti-Stokes lines are not normally observed except for relatively low values of v,. The name " Stokes line " is taken over from usage in connection with fluorescence ; but fluorescence is in principle quite different from the Ramaii effect. In fluorescence the exciting light must be absorbed by the molecule involved which is thereby raised to an excited electronic state having a " half-life " of the order of lo-* see. or longer. At the end of this time the excited molecule may fluoresce ie. may re-radiate a part of its excitation energy thereby emitting light of frequency lower than that of the original light. I n the Raman effect on the contrary the incident light is chosen so as to be incapable of being absorbed by the scattering molecule and there is therefore no question of re-radiation from an excited state.Rather must we say that the effect of the incident radiation is to perturb the molecule and so induce it to undergo a vibrational (or rotational) transition the frequency of the light being correspondingly altered in the scattering act. Accordingly it is found that fluorescence can be quenched by the addition of suitable agents which are able to rob the excited molecules of their energy by collisions before they can re-radiate. Such quenching is impossible for the Raman effect. The fact that Raman shifts are equal to frequencies of transitions such as are observable in infrared absorption spectroscopy has led to statements to the effect that the Raman effect brings infrared spectra into the more convenient region of the visible or ultraviolet.Such statements however are loose and misleading. The mechanisms of Raman scattering and infra- red absorption are quite different and consequently information can often be obtained from the one type of spectrum which cannot be obtained from the other. Recent Advances in Technique.-It is not an object of this Review to give a detailed account of experimental arrangements. Some of the more BETHELL AND GOLD THE STRUCTURE OF CARBONIUM IONS 187 Doering and Zeiss's model 28 2c has been expressed in a different termin- ology. It is effectively based on the same picture in that the leaving group is supposed to occupy a solvation site on one side of the plane of the car- bonium ion.With a stable carbonium ion the anion is replaced by a solvent molecule during the life of the ion producing a symmetrical carbonium ion (and racemisation) ; an unstable carbonium ion is attacked by solvent before the anion has separated. The distinctive feature of the scheme is the hypothesis that only two sites (one on each side of the plane containing the carbonium valencies) are considered to be involved in the solvation of the carbonium ion. Furthermore it is speculated that the two solvent mole- cules (or one solvent molecule and one leaving group) are held covalently (see formula 8). In all discussions of these phenomena it is possible to replace the concept of " life-time '' of the carbonium ion by the equivalent one of rate constants for the replacement of the shielding ion by a solvent molecule and for the attack of solvent on the carbonium ion as is done by Doering and Zeiss.Xteric Acceleration.-The formation of a planar carbonium ion from a molecule of tetrahedral configuration implies an opening-out of the remain- ing bonds from an initial (tetrahedral) angle of around 109" to one of 120". Thus any congestion existing between the groups attached to the central atom will be alleviated during ionisation. An effect of this kind is likely to be observed in the values of the equilibrium constants for the formation of triarylcarbonium ions with bulky ortho-substituents.16 18 It is also to be expected that the solvolysis of organic halides having a congested structure would be faster than that of similarly constituted but non-congested structures since a t the transition state of ionisation the bonds will have opened out to somewhere between 109" and 120".Such behaviour has been reported in solvolyses of a number of bulky tertiary alkyl compounds e.g. tri-ter.t.-butyl halides,38 but it must be borne in mind that alternative explanations of this steric acceleration are sometimes pos- sible e.g. hyperconjugation or the formation of bridged carbonium ions.40 l7 Bridgehead Carbonium Ions.- Just as the steric compressions between groups attached to the central carbon atom in certain tertiary halides can be relieved during ionisation and lead to faster solvolysis so structures which prevent the increase in bond angles which is the conconiitant of ionisation should show diminished reactivity in unimolecular reactions.Such be- haviour has been observed in bicyclic halides in which the halogen is attached to a bridgehead carbon atom. Thus refluxing l-apocamphanyl chloride (9) with aqueous-ethanolic potassium hydroxide or silver nitrate failed to remove the hal0gen.~1 The bromotriptycene (10) showed a similar lack of reactivity despite the presence of three phenyl groups. In a favourable 38 E.g. Bartlett and M. S. Swain J . Arner. Chem. SOC. 1956 77 2801 ; H. C. FZrown J. 1956 1248. Hughes Ingold and Shiner J. 1953 3827. *O Ingold ref. 20 p. 417 ; cf. H. C. Brown and I-Cornblum J . Arner. Chern. SOC. 1954 76 4510. *l Bartlett and Knos ibid. 1939 61 3184. 188 QUARTERLY REVIEWS slight the spectrum of a mixture is the simple superposition of the spectra of the components.Since in general only comparatively sharp lines are involved these spectra remain distinct and recognisable despite fortuitous coincidences. We have here a useful method for qualitative analysis. Moreover the intensity with which a Raman line appears is in general directly proportional to the volume concentration of the scattering species and so intensity measurements can form the basis of quantitative analytical determinations. The method has the advantage that it does not consume any of the sample. Applications of these kinds do not require any detailed knowledge of the mechanism of Raman scattering though a deeper insight into chemical problems may often be obtained by taking into account the relation of Raman spectra to molecular structure (see p. 192). As an alternative to conventional chemical analysis the Raman effect has been most useful for mixtures of hydrocarbons.Of the comparatively few applications in the inorganic field we may mention the quantitative analysis of mixtures of sodium nitrate and nitrite in aqueous sol~tion.~ Ranian spectra have occasionally been used as a guide in preparative work ; for instance to determine the most favourable conditions for the preparation of chlorotrimethylsilane from silicon tetrachloride by the Grignard reac- tion.lO Another example is the confirmation of the completion of the reaction SeF + SeO = ZSeOF by the disappearance of the lines due to SeF and the appearance of the SeOF spectrum.ll Mixed Halide Formation etc.-It is in cases where ordinary chemical methods are not applicable that the Raman effect has made its most signifi- cant contributions in detecting and estimating molecular species.We refer to systems involving labile chemical equilibria between species which either cannot be isolated at all or at least not without disturbing the equilibria involved. Here the Raman method is especially useful since (provided only that the compounds are not photochemically unstable) its application leaves the system completely unaffected. As a first example we may take the investigations mostly carried out by Delwaulle and Francois,12 of mixed halide formation. The Raman spectrum of a mixture of carbon tetrachloride and carbon tetrabromide or of a mixture of the corresponding halides of silicon is found (as expected) to consist of a simple superposition of the two components but mixtures of stannic chloride and stannic bromide give Raman spectra containing new lines l3 not attributable to either constituent.By comparison with the spectra of the isolable compounds SiCl,Br SiCl,Br, SiClBr, and the carbon analogues the new lines have been shown to be due to the formation of corresponding mixed halides in labile equilibrium with one another and with the stannic chloride and bromide from which they are instantaneously formed. These mixed halides cannot be isolated by such processes as distillation etc. Stamm Ind. Eng. C?iem. Anal. 1945 17 318. lo Goubeaix Siebert and Wiriterwerb Z . ariorq. Chem. 1949 259 240. l1 Rolfe and Woodward Trans. Faraday Xoc. 1956 51 778. l2 Delwaulle and Francois J. Chim. phys. 1949 46 80. WOODWSRD RAMAN SPECTRA OF INORGANIC COMPOUNDS 189 Ranian spectra also show that siniilar labile compounds are formed on mixing SnCI and snI,,13 SnBr and SnTa,l3 or TiCl and TiBr4.14 I n this respect germanium appears t o occupy an interesting intermediate position between silicon and tin.Whereas no mixed halide formation is observed for silicon,l5 and the reaction is instantaneous for tin Delwaulle Frangois Delhaye- Buisset and Delhaye l3 report that with a mixture of germanium tetra- chloride and tetrabromide there is a slow formation of mixed halides which can be followed by taking successive Raman spectra. ' The presence of the species PC1,Br and PClBr in mixtures of phosphorus trichloride and tribromide has likewise been shown l6 by the Raman method and a similar result has been obtained l 7 with a mixture of the trichloride and tribromide of arsenic.When PFC1 and PFBr are mixed new Raman lines appear l7 owing to the formation of the compound PPCIBr. No mixed halide formation is found however for a mixture of arsenic trichloride and trifluoride l 7 it appears that the facility of exchange shown by chlorine and bromine is not shared by fluorine. It is also interesting that the spec- trum of a mixture of POCl and POBr is simply the superposition of the spectra of these two compounds,1s showing that exchange of the halogen atoms does not occur at ordinary temperatures. I n the same way it has recently been shown 1 9 9 2o that analogous mixed halide formation occurs with the trichloride and tribromide of boron. Rough intensity determinations indicate 2o that the equilibrium constant a t ordinary temperature for BCI + BBr + BC1,Br + BClBr is approxim- ately 8.The simplest cases of mixed halide formation however are encountered with the mercuric compounds. Equilibria of the kind HgX + HgY + 2HgXY where X or Y is C1 Br I or CN have been investigated in alcoholic solution.21 Measurements of the intensities of the Raman lines have given tlhe value 2.0 & 0.2 for the equilibrium constant of HgCl + HgBr + 2HgClBr at 15". The corresponding value for HgBr + Hg(CN) + 2HgBr(CN) is found to be about 10 times smaller. Increase of molecular complexity due t o association can also be detected by the Raman effect. A very simple example is furnished by nitric oxide. As is to be expected for the diatomic molecule NO only one Raman line is found for the gas. If it is borne in mind however that NO is an " odd iiiolecule " it is interesting that the liquid shows extra lines,, indicating the presence of dimers (NO),.l3 Delwaulle Franpois Delhaye-Buisset and Delhaye J . Phys. Radium 1954,15,206. l4 Delwaulle and Franpois Compt. rend. 1945 220 173. l5 Idem ibid. 1944 219 335. l6 Delwaulle ibid. 1947 224 389 ; Theimer Acta Phys. Austriaca 1947 1 188. l7 Delwaulle and Franqois J . Chim. phys. 1949 46 80. l8 Idem G'ontpt. rend. 1945 220 817. l9 Long and Dollimore J. 1954 4457. 2o Goubeau Richter and Recher Z. nnorg. Chem. 1955 278 12. 21 Delwaulle C'ompt. repid. 1939 208 999 ; Delwaullo and Franqois Bull. SOC. chint. 2 2 Vodar Jardillier and Mayence Conapt. rend. 1946 222 1343 ; Smith Keller 1940 7 369. and Johnston J . Chern. Phys. 1951 19 189. 190 QUARTERLY REVIEWS Ionic Equilibria in Solution.-Raman spectroscopy is just as applicable to charged species as to neutral molecules and has proved a very direct and elegant method for the study of ionic equilibria in solution.Soon after its discovery the Raman effect was used 23 t o show the incompleteness of the ionisation of nitric acid in aqueous solution. All metal nitrates in solution have the same Raman spectrum which is evidently characteristic of the NO,- ion Dilute solutions of nitric acid show the same spectrum; but as the concentration is increased new lines due to the undissociated HNO molecule appear while at the same time the lines due to the nitrate ion diminish in intensity. This system has been the subject of a number of subsequent investigations amongst which special mention may be made of the quantitative measurements by Redlich and Bigeleisen.24 These workers determined the concentration of nitrate ions in nitric acid solutions by comparison of the intensity of the principal NO,- line with its intensity in sodium nitrate solutions assumed completely ionised. They found that the maximum concentration of NO,- in nitric acid solutions occurs when the acid is about 7 ~ . The value of the dissociation constant obtained by extrapolation to zero concentration shows reasonable agreement with deduc- ttions from other evidence. The same met,hod has been applied to solutions of perchloric acid 25 and has shown as expected that this is a considerably stronger acid than nitric. The two stages of ionisation of sulphuric acid have been followed as a function of concentration by means of Raman spectra 26 and the method has also been applied to iodic acid 27 and phos- phoric acid.28 A feeble band which appears in the Raman spectJrum of very concentrated solutions of hydrochloric acid in water has been attri- buted 29 to undissociated HC1 molecules.Interesting results have been obtained by Ingold Millen and Poole 30 on the behaviour of nitric acid in very acidic solvents like pure sulphuric acid. It had been observed by Chhdin 31 that a Raman line at Av = 1400 crn.-l very weakly present in the spectrum of anhydrous nitric acid is enhanced in intensity by the addition of anhydrous sulphuric acid. At the same time another line at about 1050 cm.-l appears. As he had also found that two lines of practically these frequencies were the sole observable features of the Raman spectrum of solid dinitrogen pentoxide Chhdin concluded that the effect of the addition of anhydrous sulphuric acid to anhydrous nitric acid was to produce dinitrogen pentoxide by de- hydration.Ingold Millen and Poole however showed that the Raman frequency 1400 cm.-l can be produced without 1050 cm.-l by the addition 23 Rao Proc. Roy. SOC. 1930 A 127 279. 2 4 Redlich and Bigeleisen J . Amer. Chem. SOC. 1043 65 1883. 25 Redlich Holt and Bigeleisen ibid. 1944 66 13. 26 Woodward and Horner Proc. Roy. SOC. 1934 A 144 129 ; Rao Indian J . Phys. 27 Idem ibid. 1942 16 71. 28 Idem ibid. 1943 17 357. 29 Karetnikov Zhur. E’iz. Khinz. 1954 28 1331. 30 Ingold Millen and Poole J. 1950 2576. 31 Chedin Ann. Chim. 1937 8 243. 1940 14 143. WOODWBRD RAMAN SPECTRS OF INORGANIC COMPOUNDS 191 of either anhydrous selenic acid or anhydrous perchloric acid to nitric acid.In these cases the 1400 cm.-l frequency is accompanied by others which have been shown to be characteristic of the hydrogen selenate ion HSe0,- and the perchlorate ion ClO,- respectively. In the mixture of nitric acid with sulphuric acid therefore the frequency 1050 cm.-l is to be attributed to the HSO,- ion and not to the same species as 1400 cm.-l. The latter is in fact the characteristic frequency of the nitronium ion NO,+ and Ingold Millen and Poole’s results show that in these very acidic media nitric acid ionises thus HNO + ZH,S04 = NO,+ + 2HS0,- + H,O+ and similarly for perchloric and selenic acids. The appearance of a line a t 1050 cm.-l along with 1400 cm.-l in the spectrum of solid dinitrogen pentoxide is due to the fortuitous circumstance that 1050 cm.-l is also the principal Raman frequency of the nitrate ion.The spectrum shows in fact that in the solid state dinitrogen pentoxide is to be formulated 32 as the nitronium salt (NO,+)(NO,-). The Raman spectrum of dinitrogen pentoxide in solution in nitric acid likewise consists 33 entirely of the frequencies of NO,+ and NO,- so that in this solvent the nitronium salt is simply ionised. Millen has further shown 32 that the solid of composition NClO obtained from the system HNO + HClO gives the nitronium ion frequency 1400 cm.-l together with the known frequencies characteristic of the perchlorate ion and is therefore to be formulated as (NO,+)(ClO,-). Other solids which have similarly been shown to be nitronium salts include (NO,+)(HS,O,-) and (N02+)2(S2072-) both derived from the system N,O + SO + H,O and (NO,+)(SO,F-) derived from the system N,O + HS0,F.Solutions of dinitrogen trioxide in sulphuric acid show 34 the frequency characteristic of HSO,- and also a new one at about 2300 cm.-l which must be due to the nitrosonium ion NO+ since it appears (along with the frequencies of ClO,-) in the spectrum of nitrosonium perchlorate. 35 Reverting to aqueous solutions it has been concluded from measurements by various other methods that certain “ strong ” electrolytes e.g. thallous hydroxide are incompletely dissociated into ions ; and the question arises as to whether the undissociated part consists of covalently linked molecules or electrostatically bound ion-pairs.Here the Raman method can give in- formation ; in the former case a corresponding vibrational Raman spectrum will be expected whereas in the latter case (as has been shown theoreti- cally 36) the effect will be relatively very weak and probably unobservable. In fact for thallous hydroxide no Raman spectrum characteristic of the undissociated part could be observedY3 so that this probably consists of ion-pairs (Tl+)(OH-). A very simple example of the use of Raman spectra for the detection of itn ionic species is the verification by Woodward 37 tlhat the mercurous ion in aqueous solution has the formula HgZ2+. If it were Hg+ it could obviously 32 Millen J . 1950 2606. 33 Ingold arid Millen J. 1950 2G12. a4 Millen J. 1950 2600. 35 Angus and Leckie Proc. Roy. SOC. 1935 A 150 615. 36 George Rolfe and Woodward Trans.Faraday SOC. 19.53 49 375. 192 QUARTERLY REVIEWS give no vibrational Raman effect. The same method applied to thallous 37 and argentous 38 ions shows that in neither case can an appreciable proportion be present in the double form. A few examples must here suffice of the many applications of the Raman effect for the detection of complex ions. In presence of excess of bromide ion in aqueous solution Cd2+ gives a Raman pattern 39 which is clearly to be attributed to the complex ion CdBr42- since it is analogous to the pattern for the isoelectronic neutral molecule SnBr,. Similarly in presence of excess of iodide ion the spectrum of Cd142- is obtained.40 When both Br- and I- are simultaneously present the spectrum obtained 41 depends upon their relative concentrations ; the observations which are analogous to those for mixtures of stannic chloride and bromide (p.188) provide evidence for the presence of the mixed halide complex anions CdBr312- CdBr2IZ2- and CdBr132-. Similar results are obtained for the halide complex ions HgBr,2- and HgI,2- and the corresponding mixed halide species.41 In fact one line is observed. Elementary Theory of Molecular Light-scattering Jn the field of organic chemistry where most of the molecules contain many atoms much of the study of the relation between Raman spectra and molecular structure has necessarily been of an empirical character. In- organic chemistry offers a variety of comparatively simple molecules and ions for which valuable structural information can be obtained by the application of the theory of Raman scattering.We may note in passing that vibrational frequencies as determined from Raman spectra may be used for the calculation of force constants. In general however the number of observable frequencies is insufficient for the complete determination of the force field and although additional in- formation can sometimes be obtained by the use of isotopic substitution approximate assumptions are usually necessary. This subject has been discussed in a Quarterly Review 42 by Linnett who sums u p thus “ For many polyatomic molecules we are by no means sure what sort of force field is best.’’ We shall not pursue this question flirther here nor shall we do more than mention that the Raman effect is helpful in giving vibra- tional frequency values for use in the calculation of entropies etc.by the well-known statistical methods. We wish rather to direct attention to the important fact that for molecules possessing some symmetry it is possible without any knowledge of frequencies or force constants to obtain from Raman spectra clear-cut decisions between different proposed models. The method requires the determination only of the number of fundamentals permitted in the Raman effect and their states of polarisation. It is even more powerful when used along with information from infrared absorption. 37 Woodward Phil. Mag. 1934 18 823. 38 Waters and Woodward J. 1954 3250. 39 Delwaulle FranCois and Wiemann Compt. rend. 1939 208 1818. 4O Idem ibid. p. 184. 4l Itolfe Sheppard and Woodward Trans. Faraday XOC. 1954 50 1275 ; Delwaulle 4 2 Linnett Quart.Rev. 1947 1 73. Bull. Soc. chim. 1955 p. 1294. WOODWARD RAMAN SPECTRA OF INORGANIC COMPOUNDS 193 Undoubtedly the most useful theory of molecular light-scattering is that put forward by P l a c ~ e k ~ ~ which starts with a classical description and then translates this into the language of wave-mechanics. The chemist interested in the important rules of selection and polarisation can gain valuable insight (at least for fundamental frequencies) from a purely classical and largely non-mathematical treakment such as is outlined in the following sections. (The occasional parentheses will serve to remind the reader that the phe- nomena being considered are essentially quantum-mechanical.) Molecular Polarisability Ellipsoid.-A molecule may be regarded as an assemblage of positively charged nuclei embedded in a cloud of negative electricity.I n the equilibrium configuration the electrical centres of the positive and negative parts may be coincident (when the molecule will possess no permanent dipole moment) or not (when a permanent moment will be present). I n either case the application of an electric field will give rise to an induced electric dipole moment. If the field oscillates with a frequency sufficiently large in comparison with nuclear vibration frequencies only the electron cloud (of relatively very small inertia) will be able to " follow " and the heavy nuclei will remain practically unaffected. The relation between the applied field strength E and the induced dipole moment M can be written as M = ME where a is the polarisability of the molecule.I n t,he simplest case of a n isotropic molecule their directions are identical i.e. a is a scalar. I n general however the application of a field in a certain direction induces a moment in a different direction. I n general therefore a is a tensor. Let N, M y N be the components of the induced moment relative to a co-ordinate system fixed in space and in the molecule and let the corresponding components of the applied field be E, By E,. The fact that each component of E in general makes a contribution to each component of M can be expressed as follows Both E and M are vectors. The nature of a may be visualised as follows. The tensor a is thus defined by the set of nine coefficients ax, ccXy etc. which may be shown to reduce to six because aXw = ayx my,,= azy and a, = a,. Now in order to represent cc in a more " pictorial " way we may make use of the six coefficients to form the equation of an ellipsoid V i X .and henceforward we may identify this ellipsoid with the polarisability. A rotation of the co-ordinate system relative to the molecule will cause changes in the coefficients in the ellipsoid equation and the new set will form the polarisability tensor referred to the new axes. I n particular when the co-ordinate axes ( X Y 2) are chosen to coincide with the three principal axes of the ellipsoid the equation reduces to the form Q,,X2 + CcyyY2 + x,,z2 + 2a,,xy + 2~,,YZ + 2~ZXZX = 1 4 3 Placzek " Handbuch der Radiologie " 1934 6/2 205. 194 QUARTERLY REVIEWS A X 2 + BY2 + CZ2 = 1. Thus with this special choice of axes only the three " diagonal " coefficients axx = A ayy = B and azz = C are differ- ent from zero.Pure Rotational Raman Effect.-For a linear molecule one axis of the polarisability ellipsoid obviously lies along the line of the nuclei and the other two are equal. When the molecule rotates it does so about an axis at right angles to the line of the nuclei and so the ellipsoid returns to an identical position after each half revolution. Thus each component of a (relative to space-fixed axes) varies with frequency 2v, where Y is the rotational frequency of the molecule. Irradiation of the molecule with light of frequency YO may be regarded as equivalent t o the application of an oscillating electric field. The consequent induced dipole moment is given by RE where now a varies with frequency 2vT and E with frequency YO.Regarded classically therefore aE represents moments oscillating with the frequencies YO 2v and these will radiate the Stokes and anti-Stokes Raman lines respectively. (In terms of quantum theory this means that only rot,ational transitions with AJ = & 2 are Raman-active. This is the pure rotational selection rule for linear molecules. For non-linear molecules the result is less simple.) Normal Vibrations and their Symmetry Properties.-The nuclei may be regarded as mass-points in a potential field due to the bonding. When they are slightly displaced from their equilibrium positions and then released they perform vibrations which in general have complicated forms. It may be shown however that any such vibration is the superposition of a limited number of so-called normal vibrations in general with different amplitudes and phases.Each normal mode is such that in the absence of other normal modes every nucleus performs simple harmonic oscillations in a straight line about its equilibrium position and that all these individual oscillations are in phase. Thus each normal vibration may be regarded as the simple harmonic oscillation of a so-called normal co-ordinate so constructed as to express all the individual displacements of the nuclei involved. Each normal vibration has its own frequency. Two (or three) of these frequencies may be identical the modes are then said t o show 2-fold (or 3-fold) degeneracy. The equilibrium nuclear configuration may have symmetry elements such as a plane of symmetry etc. To each such element there is a symmetry operation such as reflection in the plane etc.which produces a nuclear configuration indistinguishable from the original. The complete set of symmetry operations characterising any molecule is expressed shortly by the symbol of the point group to which the equilibrium configuration belongs. The symmetry of the molecule determines the symmetry of the potential field and hence also the symmetry types of the normal vibrational modes. Thus consider a molecule slightly distorted in the particular manner des- cribed by the normal co-ordinate Q and perform upon it any chosen sym- metry operation characterising the undistorted molecule The operation will transform q into the new distortion qt while leaving the pokential energy unchanged. Since the potential energy for a distortion is proportional to the They are called the principal values of a.WOODWARD RAMAN SPECTRA OF INORGANIC COMPOUNDS 195 square of the co-ordinate it follows that qt must have been €ormed from q in one or other of the three following ways. I n this case the operation gives a distorted configuration identical with that from which we started. The corresponding normal mode is said to be symmetric with respect to the symmetry operation in question. A mode which is symmetric with respect to every symmetry operation of the molecule is said to be totally symmetric. An example is the mode of frequency v1 shown in Fig. 1. First qt = q. I -J + - FIG. 1 Normal vibratiom of linear synimetl.ica1 AB,. The plus and minus signs iiidicate displacements in oppositle senses normal to the plane of the figure. Secondly qt = - q Here we obtain a distorted configuration in which the displacement of every nucleus is equal in magnitude to but opposite in sign from what it was before.The mode is then said to be antisymmetric with respect to the symmetry operation. A mode which is antisymmetric with respect to any operation is called an antisymmetric mode even though it may be symmetiric with respect to others. An example is the mode of frequency Y in Pig. 1. This is antisymmetric with respect to the plane of symmetry normal to the line of nuclei but is symmetric with respect t o planes passing through this line. Thirdly qt may be a linear combination of two (or three) normal co- ordinates which are then degenerate. Degeneracy only arises where the symmetry element is a d2 rotational axis and the symmetry operation is a rotation through an appropriate angle about it.A very simple example of 2-fold degeneracy is that of the two bending modes shown in Pig. 1. Here the line of the nuclei in the equilibrium configuration is a rotational axis of infinite order i.e. rotation about it through any angle 8 is a sym- inetry operation. In the end-on view shown in Fig. 2 the displacement of any chosen nucleus is represented by d in the mode of normal co-ordinate ql and d in that of q,. Rotation through 0 is seen to transform d into d, which is compounded of d cos 0 and d sin 0. This is a simple instance of a FIG. 2 196 QUARTERLY REVIEWS general behaviour shown by more complicated structures and for axes of finite orders. The Derived Polarisability Tensor.-If the nuclei are displaced the polarisability of the molecule will in general change.Considering in par- ticular the distortion described by the normal vibrational co-ordinate q and confining ourselves to very small amplitndes we may write to a first approximation a = CI.0 + (a%W,q where the zero subscripts indicate values at the equilibrium configuration. This is a convenient way of expressing the fact that a relation of this kind holds for each of the six coefficients defining Q. For the electric moment M induced by an applied field E we can now write Light incident upon the molecule may be regarded as an electric field oscillating with frequency YO. The first term on the right-hand side of the last equation represents a moment also oscillating with frequency YO. This gives rise to Itayleigh scattering.For a given amplitude of E ( i . e . a given incident intensity) it is clear that the intensity etc. of the Rayleigh scatter- ing are determined by the properties of the tensor M,. The second term contains the product of two time-dependent factors q which oscillates with the frequency Y, of the nuclear vibration and E which oscillates with the frequency YO of the incident light. The term there- fore represents electric moments oscillating with the frequencies YO vV which give rise to Raman scattering (Stokes and anti-Stokes lines of the fundamental vibration frequency vW). For a given incident light intensity the Raman intensity will be determined by (acc/aq) and the amplitude of q. (This result is expressed in terms of classical theory the amplitude of q being regarded as continuously variable.In quantum theory where vibra- tional states are characterised by the integral quantum number n the corresponding result is that the probability of the transition n -+ n + 1 increases as n increases. It also follows that for simple harmonic vibrations and in the approximation considered here only transitions with An = 1 are permitted overtones and combination tones being forbidden. This is quite well borne out in practice and consequently Raman spectra are relatively simple as compared with infrared absorption spectra.) At a given temperature the presence of q in the second term of the ex- pression for M merely gives rise to a numerical factor. It follows therefore that the properties of the Raman radiation (intensity state of polarisation etc.) are determined by (aalaq) in just the same manner as the correspond- ing properties of the Rayleigh radiation are determined by cco (see above).Like ao (aa/aq) is a tensor each of its coefficients is the partial derivative of the corresponding coefficient of a. We shall speak of (acx/dq) as the derived polarisability tensor do for the normal vibration defined by q. Its coefficients being rates of change of the corresponding coefficients of a The derived tensor however is not so easy to picture as is a. itself. WOODWARD RAMAN SPECTRA OF INORGANIC COMPOUNDS 197 may be zero or negative. It cannot therefore in general be represented by an ellipsoid. Degree of Depo1arisation.-Because of its greater simplicity we will first discuss Rayleigh scattering. Consider irradiation by natural light along the y-axis (see Fig.3) and scattering a t right angles along the x-axis. The co-ordinate system x y x is fixed in space and the orientation of the scatter- ing molecule will for the present be supposed to be fixed also. The incident light may be regarded as consisting of two oscillating electric vectors E and Ez of equal amplitude each of which will in general induce component moments ME Mu M directed along the three axes. Since an oscillating dipole does not radiate in its own axial direction only My and M will contribute to the scattering along the x-axis producing respectively the plane-polarised components of intensities i and I (see Pig. 3). It is easily seen that for an isotropic molecule (polarisability ellipsoid a sphere) i = 0 FIG. 3 and the scattering is completely polarised.For non-isotropic molecules (i $= 0) the ratio ill is called the degree of depolarisation and is designated by the symbol p. Coming now to Raman scattering we have seen that its properties depend upon in just the same way as those of Rayleigh scattering depend upon cco. Thus p for a Raman line is determined by the nature of the appropriate derived polarisability tensor and by the orientation of the scattering molecule. Raman Effect in Crystals.-In fluids the scattering molecules will have random orientations in space. Only by the use of a sufficiently large single crystal is it possible to maintain a definite orientation relative to the direc- tions of irradiation and observation. Hence it appears that the study of crystals should offer the most favourable opportunities for obtaining in- formation about molecular structure.It must be borne in mind however that molecules in a crystal are necessarily subject to strong interactions ; and these may give rise to considerable complications as compared with other states. Thus the Raman spectrum of a compound in the crystalline state will contain lattice frequencies which have no counterpart in the spectrum of the free molecule. Moreover there are two factors which may cause a single frequency of the free molecule to give rise to more than one in the N 198 QUaRTERLY REVIEWS crystal. First if the vibrational mode concerned is degenerate for the free molecule the degeneracy may be removed by the crystal field. Secondly in the usual cases where the unit cell contains more than one molecule a single molecular mode may give rise to more than one frequency on account of intermolecular coupling.It would be too much to suggest that the Raman effect can a t present compete with X-ray diffraction as a method for the elucidation of crystal structure. Nevertheless in favourable cases Raman spectra can provide interesting auxiliary information for example as to the arrangement of hydrogen nuclei. The method presents considerable experimental diffi- culties as it requires the measurement of degrees of depolarisation for a single crystal placed successively in suitable different orientations relative to the directions of irradiation and scattering. Examples of the successful use of this method are the determination of the orientation of water mole- cules in hydrated crystals 44 and of ammonium ions in ammonium For a short account of the theory reference may be made to an article by Mathieu 46 a full treatment is given in the book 47 by the same author.Degrees of Depolarisation €or Fluids.-In fluids it may be assumed that all orientations of the scattering molecules are equally probable so that experimental determinations of p give an average value. The theoretical expression for this is most conveniently expressed in terms of the two invariants of the tensor involved. These are quantities whose values are unaffected by any change of orientation relative to the co-ordinate system. Considering first the polarisability ellipsoid cco which is concerned with Rayleigh scattering the mean-value invariant a is defined by a = &(a, + a:IJy + azz). Since it is a n invariant its value may be seen in particular to be +(A + B + C) where A B C are the principal values.Hence roughly speaking we may say that a is a measure of the overall " size " of the polarisability ellipsoid. The other invariant the anisatropy y is defined by Considering again the special case when the co-ordinate axes coincide with the principal axes of the ellipsoid we see that Hence roughly speaking we may say that y is a measure of the departure of the shape of the ellipsoid from spherical. The result of averaging over all orientations of the scattering molecule may be written p = 6y2/(45a2 + 7y2) I n accordance with the conclusion reached earlier if the ellipsoid is a sphere y 2 = $[(a, - aJ2 + (ayy - %A2 + ( M z z - Xc,,)2 + 6(Cczg2 + ayz2 + az.,,2)J. y2 = 4[(A - B)2 + ( B - C)2 + (C - D)2] 4 4 Couture " Contrib.Etude Structure mol. Vol. commem. Victor Henri " 1947-48 4 6 I d e m J . Chim. phys. 1952 49 226. 46 Mathieu I n d . chim. belg. 1953 18 219. 47 I d e m " Spectres de Vibration et Symmetries des Molecules et des Cristaux " p. 105 ; Couture-Mathieu and Mathieu Acta Cryst. 1952 5 571. Hermann Paris 1946. WOODWARD RAMAN SPECTRA OF INOROAKIC COMPOUNDS 199 (i.e, y 2 = 0) then p = 0 and the Rayleigh scattering is completely polarised. Jn no circumstances can a2 be zero and so for all molecules p must always be lesa than 6/7. Moreover in no case can the intensity vanish altogether Rayleigh scattering is never forbidden. Coming now to Ra.man scattering we are concerned with the derived tensor a’ in place of Q,. Although the derived tensor cannot be represented by an ellipsoid it nevertheless possesses a mean-value invariant a’ and an anisotropy invariant y’ which are exactly analogous to those of a,.Hence for the degree of depolarisation of a Raman line we may write However owing to the differences in character between a’ and ao important differences arise for Raman scattering as compared with Rayleigh scatter- ing. Thus any of the coefficients of a’ may be zero or negative with the result that either a’ or y’ or both may vanish. If both vanish simultaneously the intensities i and I are both zero i.e. the Raman line is forbidden. If y‘ alone vanishes then p = 0 and the line is completely polarised. If a’ alone vanishes then p has the maximum value of 6/7 and the line is said to be depozarised. In all other cases p is between 0 and 6/7 and the line is said to be pobrised.Rules of Selection and Polarisation.-From the above discussion it is clear that these rules for the Raman effect are determined by the properties of the a’ tensor. These are in turn determined by the symmetry properties of the vibrational modes and of the polarisability ellipsoid both of which depend ultimately on the symmetry of the equilibrium nuclear configuration of the molecule. This is the basis of the method whereby it is possible to decide between alternative proposed structures having different symmetries. The conclusions so reached do not involve any knowledge of frequency values or force constants. The total number of vibrational fundamentals of a molecule cmtlaining N nuclei is 3N - 6 if the molecule is non-linear or 3N - 5 if linear.The numbers of fundamentals belonging to the various symmetry classes (totally symmetric antisymmetric or degenerate) are determined by the symmetry of the equilibrium nuclear configuration. We now wish to see how the symmetry class of a vibration determines the behaviour of its fundamental in the Raman effect. For this purpose we must first refer back to the definitions of the invari- ants given above. Remembering that each coefficient of a’ is related to the corresponding coefficient of a by equations of the kind C C ‘ ~ ~ = (aa,,/aq), we note that a’ = (aa/aq) but that 1’’ $I (ay/aq)o. Now deformation of a molecule in the manner described by q may affect the polarisability ellipsoid in two different ways. First it may cause an alteration in the “ size ” as expressed by a = +(A + B + C) ; and secondly it may cause the orientation of the ellipsoid to change.A change of orienta- tion will produce changes in the coefficients such that although the “ size ” as measured by a will remain unaffected and so (au/aq) = u’ will be zero nevertheless the anisotropy y’ of the derived tensor (which as noted above 200 QUARTERLY REVIEWS is not equal to the derivative of the anisotropy y of the tensor a) will in general have a value different from zero. Consider in particular a vibration that is anttisymmetric with respect to some symmetry operation characteristic of the molecule in its equilibrium configuration. When the molecule is slightly deformed in the manner described by the normal co-ordinate q its mean-value invariant is clearly a + (aa/aq),q which we will write a + a’q.The result of performing the symmetry operation upon the deformed molecule is to cause q to become - q. But the operation obviously gives an ellipsoid of exactly the same “ size ” as before (although in general with its axes differently oriented). Its mean-value invariant is thus unaffected despite the fact that q has been changed to - q. Therefore we have a + a’q = a - a’q whence a’ = 0. But since the orientation of the ellipsoid is in general affected by q the other invariant y’ will not necessarily vanish. Hence the Raman line will not in general be forbidden ; but since a’ = 0 it must have p = 6/7. We have thus proved the polarisation rule that all permitted Raman lines of antisymmetric modes are depolarised. A simple linear AB molecule (e.g. SO,) illustrated in Fig.4 where the arrows represent the nuclear displacements for the co-ordinate q. This mode is seen to be antisymmetric with respect to the and indicated by the dotted line. Reflection of the distorted molecule in this plane reverses the displacement of each nucleus and it is clear that the effect on the ellipsoid is to leave its “ size ” unaffected (a’ = 0) but to change its orientation (7’ + 0). I n the course of the vibration the ellipsoid merely oscillates. The corresponding Raman fundamental is permitted as a line with p = 6/7. A molecule may have further special symmetry properties which will cause an anti- symmetric vibration to be forbidden in the Raman effect. This will be so when in the course of the vibration the ellipsoid in addition to remaining unaltered in “ size ” also remains unaltered in orientation.This arises for example in the-asymmetric vibration (v3) of the linear AB molecule (e.g. HgC1,) shown in Fig. 1 The line of the nuclei is here a rotational axis of the ellipsoid and in the course of the vibration the axes obviously remain unchanged in direction whence y’ = 0. Since as for all antisymmetric modes a’ = 0 also the Raman line must be forbidden. This last example is a special case of a more general selection rule which states that all vibra- tions which are antisymmetric with respect to a centre of symmetry are forbidden in the Raman effect. It may be shown that for a molecule possessing a centre of symmetry no vibration can be permitted in both Raman and infrared absorption spectra. In certain cases however a vibration may be forbidden in both.Coming now t o degenerate vibrations consider for example the 2-fold degeneracy of the modes whose normal co-ordinates are q1 and qz. The I I example is the normal vibration of the non- I I plane of symmetry normal to the figure plane + FIG. 4 Antisymmetric mode of non- linear symmetrical AB,. The proof follows exactly as above. WOODWARD RAMAN SPECTRA OF INORGANIC COMPOUNDS 201 symmetry operation concerned must be rotation through an appropriate angle 6 about an axis. We perform the operation on the molecule distorted by q and the result (cf. Fig. 2) is to change this into q1 cos 8 + q sin 8. Writing (aa/8q1) = a’ and (aa/aq,) = a’, we have for the mean-value invariant of the ellipsoid a + a’,ql cos 8 + af,q2 sin 6. If we had rotated the distorted molecule through - 6 which is necessarily also a symmetry operation of the undistorted molecule we should have arrived at the value a + aflql cos 8 - a’,q sin 8.But the symmetry operations obviously leave the “ size ” of the ellipsoid unchanged whence a f 2 = 0. By a similar argument it follows that a’ = 0 also. The Raman line for the degenerate modes is therefore depolarised. The same conclusion can be reached for %fold degenerate modes. The general rule of polarisation therefore runs all Raman lines of antisymmetric and degenerate modes are depolarised. Only modes which are totally symmetric can have p less than 6/7. Under special symmetry conditions a Raman line may be completely polarised ( p = 0). For this we must have both f = 0 and a’ $1.0 which can only occur for a vibration in the course of which the polarisability ellipsoid remains spherical throughout and merely oscillates in size.Ex- amples are the totally symmetric “ breathing ” modes of regular tetrahedral molecules like Pa or SnCl and of regular octahedral molecules like SF, In infrared absorption the derivative ( a ~ / a q ) ~ where [ I is the electric dipole moment plays a part analogous to that of (acc/aq) for the Raman effect. Consequently the selection rules are quite different and for the investigation of molecular structure the two kinds of spectra are comple- mentary. Molecular Structure Some Results The number of inorganic species whose Raman spectra have been in- vestigated is very large. A complete bibliography 48 is available up to 1943 and many examples are discussed in the valuable books of Kohl- rausch 49 and H e r ~ b e r g ~ ~ published respectively in 1943 and 1945.Data are sometimes incomplete and conclusions doubtful. It will not be possible here to attempt anything like a complete survey space will permit only of the mention of a few of the clearer examples in order to give an idea of the kind of results that can be obtained. References will be mostly to work since about 1945. Rotational Raman Spectra.-For a molecule to show a pure rotational spectrum in absorption it must possess a permanent electric dipole moment ; in the Raman effect this condition is not necessary and early in the history of the effect Rasetti 51 photographed the pure rotational Raman spectra of some non-polar diatomic molecules including N,”and 0,. Corresponding results 48 Hibben “ The Raman Effect and its Chemical Applications ” Reinhold Publishing 40 Kohlrausch “ Ramanspektren ” Becker and Erler Leipzig 1943.50 Herzberg “ Infra-red and Raman Spectra of Polyatomic Molecules ” Van 51 Rasetti 2. Physik 1930 61 598. Corporation New York 1939 ; together with Glockler Rev. Mod. Phys. 1943,15 111. Nostrand Co. New York 1945. 202 QUARTERLY REVIEWS were also obtained for CO by Houston and Lewis.52 The spectra are in agreement with the selection rule AJ = $ 2 (see above) which leads t o I Av I = 4B(J + 4) where B is the usual rotational constant. Tor N, successive rotational lines alternate in intensity those for even J being the stronger. From this it follows that the nitrogen nuclei conform to Bose statistics. For O, lines of odd J do not appear at all showing that the oxygen nuclei have zero spin.More recently Andrychuk 53 has obtained the pure rotational spectrum of F,. Here lines corresponding to odd J are the stronger which provides proof that the fluorine nuclei obey Fermi statistics. Interest in pure rotational Raman spectra has been revived by the recent elegant work of Stoicheff and others in Canada. Stoicheff 54 has described an apparatus with which pure rotational spectra of gases at ordinary pressure can be photographed in the second order of a 21-foot grating the resolving power being as high as lo5. With this apparatus aecurate rotational constants can be measured and results have been pub- lished for N,55 and the linear C,N,.56 Until recently comparatively little has been done upon the less intense rotational structure of vibrational Raman bands.The problems of such high-resolution work have been discussed in a recent paper by Welsh Stansbury Romanko and Feldman. 57 Accurate rotational constants have been determined 58 from the structure of the v3 band of NH,. The v band 59 and the Y band 6o of CH have also been analysed. Vibrational Raman Spectra.-As pointed out on p. 199 it is possible to decide between molecular models of different symmetries by determining the number of permitted fundamentals and the number of these which are polarised. In practice a permitted fundamental may be so weak as to escape observation. On the other hand though overtones are usually ex- tremely feeble and unobservable one may possibly appear and be mistaken for a fundamental. Also a fundamental may give rise to a doublet if there is a fortuitous near-coincidence with an overtone or combination tone of the same symmetry class (so-called Fermi resonance 6l).If p is only slightly less than 6/7 it may be difficult to decide whether a line is polarised or not. Despite occasional difficulties of these kinds the method has provided much valuable information. In the Raman effect unlike infrared absorption the presence of a dipole moment is not necessary for the appearance of the single Diatomic species. 5 2 Houston and Lewis Proc. Nut. Acad. Xci. 1931 17 229. 53 Andrychuk Canad. J . Phys. 1951 29 151. 5 4 Stoicheff ibid. 1954 32 330. 5 5 Idem ibid. p. 630. 56 Moller and Stoicheff ibid. p. 635. 57 Welsh Stansbury Romanko and Feldman J . Opt. Soc. Amer. 1955 45 68 Gumming and Welsh J. Chem. Phys.1953 21 1119. 59 Stoicheff Cumming St. John and Welsh ibid. 1952 20 498. 6o Feldman Romanko and Welsh Canad. J. Phys. 1955 33 138. 61 Fermi 2. Physilc 1931 71 250. 338. WOODWARD RAMAN SPECTRA OF INORGANIC COMPOUNDS 203 vibrational fundamental. Homonuclear diatomic molecules (type A,) in- vestigated recently by this method are F,53 and C1,.6 Molecules of type AB include ClP 63 and BrCl.64 Notable amongst charged species of this type is the nitrosonium ion NO+.34 359 65 For types A and AB, if linear and symmetrical (point group Dcoh) the selection rules permit only v1 as a single polarised line (cf. Fig. 1). For less symmetrical shapes all three fundamentals are permitted. Familiar examples of linear symmetrical molecules are CO and CS ; yet for neither does the Raman spectrum consist of the expected single polarised line.For CO a doublet is found G6 owing to Fermi resonance between v1 and the fortuitously nearly equal 2v2. For liquid CS a similar doublet occurs f37 for the same reason and the forbidden v has also been detected The selection rule for the free molecule evidently loses its strict validity because of molecular interactions in the liquid. This account of complications occurring for such simple molecules may perhaps give the impression that all conclusions from Raman spectra about molecular symmetry are necessarily dubious. Such however is by no means the case. This is known from X-ray evidence to be linear and as it is isoelectronic with CO a symmetrical structure might be expected. The Raman spectrum however shows G9 two widely separated polarised lines both too strong to be explained as other than fundamentals.This at once excludes the symmetrical structure. The two Raman lines coincide in frequency with infrared absorptions show- ing again that the molecule cannot have a centre of symmetry. Its struc- ture must be N-N-0. For this all three fundamentals are permitted in the Raman effect. The third is evidently too weak to have been observed so far. Examples of linear symmetrical molecules of type AB recently investigated are the halides of zinc in non-ionising solvents. 70 If a molecule AB is symmetrical but bent all three fundanientals are permitted (two polarised). This is found for example with SCl,,' and the ion N0,-J3 On the other hand the spectra show that the ions N3-,7* NO2+,S0 and BO,-75 are linear and symmetrical.Species of type ABC may be either linear (Cmv 3 lines 2 polarised) or bent (G 3 lines all polarised). Linear examples whose Raman spectra Triatornic species. as a very feeble line. An interesting example is N,O. 6 2 Stammreich Sala and Forneris A m i s Acud. Brazil Cienc. 1953 25 375. 63 Jones Parkinson and Burke J . Chem. Phys. 1950 18 235. 6 4 Stammreich and Forneris ibid. 1953 21 944. 6 5 Gerding J. Phys. Radium 1954 15 406. 6 6 Langseth and Nielsen 2. phys. Chem. 1932 B 19 427. 67 Giulotto and Caldirola ibid. 1941 B 49 34. 68 Wood and Collins Phys. Rev. 1932 42 386. 69 Cabannes and Rousset J . Phys. Radium 1940 1 210. 70 Delwaulle Compt. rend. 1955 240 2132 ; Bull. SOC. chim. 1955 1294. 7 1 Wagner 2. phys. Chem. 1943 A 193 55. 7 2 Stammreich Forneris and Sone J . Chem.Phys. 1955 23 972. 7 3 Langseth and Walles 2. phys. Chem. 1934 B 27 209. 7 4 Langseth Nielsen and Sorensen ibid. p. 100. 7 5 Nielsen and Ward J . Chem. Phys. 1937 5 201. 204 QUARTERLY REVIEWS have been studied include ClCN 76 77 and BrCN,’6 78 as well as mixed halides like ClHgBr to which reference has already been made.2l A number of molecules (ONCl etc.) are known from other evidence to be non-linear ; but if we except isotopically substituted species like DOH etc. none appears as yet to have been investigated by the Raman method. The only molecule of type A t o have been investi- gated is P4. For both the tetrahedral model (T,) and the plane square (D4h) three fundamentals are permitted one being polarised. Nevertheless a distinction is in principle possible because for the first model the polarised line should have p = 0 whereas for the second it should have p $= 0.I n fact three lines are observed,7s of which two are depolarised and the other has p = 0 within the limits of experimental accuracy. The Raman evidence thus favours the tetrahedral model in accordance with the conclusion reached by other methods. For species of type AB a discrimination is possible between the sym- metrical planar (D3h) and pyramidal (CSv) structures. For the former 3 lines are permitted (one polarised) whereas for the latter 4 are permitted (2 polarised). A planar example is BE’,. It is true that only two of the three permitted fundamentals have so far been observed ; but convincing evidence as to structure is afforded by the observation that one of the fundamentals shows no isotopic splitting due to 1°B and l1B.In the corresponding vibrational mode therefore the boron atom must remain a t rest. This is only possible for the ‘‘ breathing ” mode of the symmetrical planar structure. Other planar species are C032- 81 and Spectra characteristic of the pyramidal model are given by the Group V halides e.g. the recently investigated NF3,82 and the ions C103- BrO,- and I03-.83 The interesting molecule ClF has been founds4 to give a t least five Raman lines a result which rules out the above types of structure. Micro- wave evidence has recently shown this molecule to be T-shaped (C2v)7 for which six Raman fundamentals are permitted C2N furnishes an example 8 5 of a linear symmetrical molecule of type A,B2 (Dcoh). Here three fundamentals are permitted in the Raman effect two being polarised.The spectrum of H,02 shows *6 a larger number of lines indicating a less symmetrical shape. The results for this molecule as also for H,S 87 and S2C12,88 have been interpreted in terms of a zigzag ABBA 78 Idem ibid. 1943 A 193 55. Tetru-atomic species. 7 6 West and Farnsworth J . Chem. Phys. 1933 1 402. 77 Wagner 2. phys. Chem. 1941 By 48 309. 79 Venkateswaran Proc. Indian Acad. Sci. 1935 A 2 260 ; 1936 A 4 345. 8o Yost DeVault Anderson and Lassettre J . Chem. Phys. 1938 6 424. 81 Kujumzelis 2. Physik 1938 109 586 ; Bacchus and Kastler Compt. rend. 1945 82Pace and Pierce J . Chem. Phys. 1955 23 1248. a3 Shen Yao and Wu PJzys. Rev. 1937 51 235. 8 4 Jones Parkinson and Murray J . Chem. Phys. 1949 17 501. 85 Langseth and Moller Acta Chem. S c a d .1950 4 725. Simon and Kriegsmann Naturwiss. 1955 42 12. 87 Feher and Baudler 2. Elektrochem. 1941 47 844. 88 Gerding and Westrik Rec. Trav. chim. 1941 60 701 for interpretation see also Bernstein and Powling J . Chem. Phys. 1950 18 1018 ; Luft and Todhunter ibid. 1953 21 2225. 220 398. WOODWARD RAMAN SPECTRA OF INORGANIC COMPOUNDS 205 model twisted so that the two B-A bonds are not in the same plane (C 6 lines 4 polarised) rather than the planar cis-form (C2v 6 lines 3 polarised) but the Raman data appear to be inadequate to establish the former definitely. The type ABC may be planar Y-shaped (C2v 6 lines 3 polarised e.g. COC1 89 and FNO or pyramidal (C 6 lines 4 polarised). The difference in the number of polarised lines has been used9l to prove the pyramidal shape of SOC1,.Other molecules of this kind that have been investigated recently include SOF 92 and SeOF,.ll The solid of composition POC13,SbC1 is found 93 to show none of the Raman lines of either POC1 or SbCl and it is therefore supposed to have the ionic form (POCl,+) (SbC1,-) involving a positive ion which is isoelectronic with SOC1,. Most molecules and ions of type AB have been found to show the characteristic pattern (4 lines 1 completely polarised) of the regular tetrahedral shape (TJ. Examples are all the tetrahalides of Group IV elements and the corresponding complex halide ions of elements of Groups I1 and 111. Recently studied ions include ZnBr,2- and zn142-,94 BF4-,Q5 A1H4-,96 A1C14-,S7 GaBr,-,98 InBr4-,99 and TlBr,-. loo A complex ion of plane square shape whose Raman spectrum has been obtained is AuC1,-.The result lo1 is in harmony with expectation (D4h 3 lines 1 polarised). In view of the prevalence of such highly symmetrical shapes for species of types AB, it is interesting that SeF shows lo2 a larger number of lines indicating lower symmetry. This molecule has a valency shell of 10 elec- trons (compared with 8 for symmetry Td) and it is evident that the " lone pair " plays a stereochemical r61e. The observed Raman spectrum indi- cates that the type here is either AB,B' (C2J or ABB' (C3J. Similar results have very recently been obtained for SF4.103 The spectrum of fused TeCl has also been investigated lo4 and interpreted in terms of ionisation to give pyramidal TeCl3+ ; but this interpretation leaves some weaker lines unexplained. Type A2B3 is represented by carbon suboxide C302 recent work upon Penta-atomic species.89 Nielsen Burke Woltz and Jones J. Chern. Phys. 1952 20 596. Dodd Rolfe and Woodward Trans. Paraday Soc. 1956 52 145. 91 McDowell ibid. 1953 49 371 ; Allen and McDowell J . Chem. Phys. 1955 9 2 Bender and Wood ibid. p. 1316. 93 Maschka Gutmann and Sponer Monatsh. 1955 86 52. 9 4 Delwaulle Compt. rend. 1955 240 2132. 9 5 Edwards Morrison Ross and Schultz J. Amer. Chern. Soc. 1956 77 266. 9 6 Lippincott J. Chem. Phys. 1949 17 1351. O7 Gerding and Houtgraaf Rec. Trav. chirn. 1953 72 21. 98 Woodward and Nord J. 1955 2655. O9 Woodward and Bill J. 1955 1699. loo Delwaulle Compt. rend. 1954 238 2522. lol Goulden Maccoll and Millen J. 1950 1635. lo2 Rolfe Woodward and Long Trans. Faraday Soc. 1953 49 1388. lo3 Dodd Woodward and Roberts ibid.in the press. lo4 Gerding end Houtgraaf Rec. Trav. chirn. 1954 73 737. 23 209. 206 QUARTERLY REVIEWS which 105 has been interpreted on the basis of a linear structure (Dmh 3 fundamentals 2 polarised). Other 5-atomic types are ABC, which may either have a %fold axis (C3v 6 lines 3 polarised ; e.g. SiIBr l3 and VOCl 106) or be planar (C 9 lines 3 polarised e.g. nitric acid 0,NOH lo') ; and AB,C (Czv 9 lines 4 polarised) examples being SiC1212,108 S02C12,109 and SO2F2.llo Some AB molecules are found to have Raman spectra according with the trigonal bipyramidal shape (Z& 6 lines 2 polarised). Solid PCl, on the other hand gives more lines,l12 interpretable in terms of the ionic structure (PCl,+) (Pel,-). Recent investigations of the interesting molecules BrF 113 and IF 114 show with considerable certainty that the shape in both cases involves a tetragonal pyramid (C4u).The number of lines and the number polarised are in agreement with the requirements (9 lines 3 polarised) for this model. From a recent consideration 115 of the selection and polarisation rules for the four N-H stretching modes and from the observation that the intensities are temperature-dependent it has been concluded that the solid contains only trans-molecules but that in the liquid other rotational isomers are also present. Group VI hexafluorides (type AB,) give the ex- pected spectrum 116 for the regular octahedral model (Oh 3 lines 1 polar- ised). It so happens that a plane hexagonal model (&) would give the same result. A distinction (hardly necessary in view of other evidence) is possible because for 0 (unlike Doh) the polarised line must have p = 0 and also because the infrared selection rules differ.In view of the extra electron of the rhenium atom as compared with molybdenum it is interesting that the recently observed Raman spectrum of ReF 117 is (like that of MOP,) in accordance with the regular octahedral structure. As expected the same symmetry is found for the ions SnCls2- 118 and SbCI,-.119 It has also been reported for SeC1,2- 120-a remarkable result in view of the lo5 Long Murfin and Williams Proc. Roy. SOC. 1954 A 223 251 ; but compare Rix J. Chem. Phys. 1954 22 429. lo6 Eichoff and Weigel 2. anorg. Chem. 1954 275 267. lo' Cohn Ingold and Poole J. 1952 4272 ; Frhjacques Compt. rend. 1952 234 lo8 Delwaulle Buisset and Delhaye J .Amer. Chem. SOC. 1952 '74 5768. log Cabannes and Rousset Ann. Physique 1933 19 229. I1O Bender and Wood J. Chem. Phys. 1955 23 1316. 111 Siebert 2. anorg. Chem. 1951 265 303. 112 Gerding and Houtgraaf Rec. Trav. chinz. 1955 74 5. 113 Stephenson and Jones J. Chem. Phys. 1952 20 1830. 114 Lord Lynch Schumb and Slowinski J . Amer. Chem. SOC. 1950 72 522. 115 Wagner and Bulgozdy J . Chem. Phys. 1951 19 1210. 116 Yost Steffens and Gross ibid. 1934 2 311 ; Burke Smith and Nielsen ibid. 11' Gaunt Trans. Faraday SOC. 1954 50 209. 119 Redlich Kurz and Rosenfeld 2. phys. Chena. 1932 B 19 231. lZo Redlich Kurz and Stricks Sitzungsber. Akad. Wiss. Wien Abt. 2b 1937,146 447. Hexa-atomic species. Examples are liquid PCl and SbCl,.lll An example of type AzB4 is hydrazine.Hepta-atomic species. 1769. 1952 20 447. Mathieu and Cornevin J. Chim. phys. 1939 36 271. WOODWARD RAMAN SPECTRS O F INORGANJC COMPOUNDS 207 structural difference between SeF and the Group IV tetrahalides (see above). Raman spectra show that in the solid 32 and in nitric acid solution 33 this exists as the ions NO,+ and NO,-. The spectrum of the undissociated N,O molecule has not been elucidated. A unique position is occupied by S (sulphur as solid and in solution) whose Raman spectrum can be interpreted 1 2 1 in terms of the puckered octagon model (D4d 7 lines 2 polarised). One compound of type AB has been studied namely iodine hepta- fluoride.l14 Seven Raman lines are observed of which two are polarised. Consideration of the selection rules for various models leads to the conclusion that the shape is most probably a pentagonal bipyramid (D,& 7 lines 2 polarised as observed).The type A$ can be briefly exemplified by the contrasted molecules C2C16 and B2H6. For the former an ethane-like structure may be assumed the rules of selection and polarisation are then for the staggered form (Qd) 6 lines permitted 3 polarised ; and for either the eclipsed form (D3h) or for free rotation about the C-C bond Experiment 122 shows 3 polarised and 3 depolarised lines. Thus unless we make the un- likely assumption that three depolarised lines have escaped observation the spectrum establishes that the molecule has the staggered configuration. On the interesting question of the structure of B2H6 the Raman effect has given valuable evidence. As was first shown by Bell and Longuet- Higgins,l23 the observations exclude an ethane-like model and favour a bridge structure H2BH2BH (D2h 9 lines 4 polarised).Molecules such as Ga2C16 are probably similarly bridged. Xpecies with more than 8 atoms. With increasing number of nuclei the spectra tend to become less simple; but useful information on structure can still be obtained especially where there is high symmetry. Thus for the nona-atomic species Ni(CO) the presence of just two completely polarised lines 125 a t once establishes the regular tetrahedral configuration (T 8 lines 2 with p = 0). By way of contrast the spectrum l26 of the Pt(CN),2- ion supports a plane square configuration (D4h 7 lines 2 with 0 < p < 6/7). Conclusion. Not all the observed Raman spectra even of species be- longing to the types referred to above are as yet completely understood.Nevertheless it is hoped that the examples quoted will have served to show that for the investigation of molecular symmetry Raman spectroscopy is a widely applicable method capable of furnishing valuable independent evidence to supplement that obtained in other ways. An example of type A,B5 is dinitrogen pentoxide. Octa-atomic species. 9 lines 3 polarised. l 2 1 Bernstein and Powling J . Chem. Phys. 1950 18 1018. 1 2 2 Hamilton and Cleveland ibid. 1944 12 249. 123 Bell and Longuet-Higgins Proc. Roy. Soc. 1945 A 183 357 ; see also Lord and Nielsen J . Chem. Phys. 1951 19 1. 124 Gerding Haring and Renes Rec. Trav. chim. 1953 72 78. 1 2 5 Crawford and Horwitz J . Chem. Phys. 1948 16 147. 126Mathieu and Comevin J . Chirn. phys, 1939 36 271 308.

ISSN:0009-2681    

DOI:10.1039/QR9561000185

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

SILYL colvIPouNDs By ALAN G. MACDIARMID M.Sc. PH.D. (JOHN HARRISON LABORATORY OF CHEMISTRY UNIVERSITY OF PENNSYLVANIA) A SILICON HYDRIDE may be defined as a compound which contains at least one Si-H bond A comparatively large number of substances fall into this category and it is convenient to make sub-divisions into classes according as they contain FSiH =SiH, or -SiH groupings. This Review deals specifically with those compounds which contain at least one -SiH or " silyl " group and they are therefore formally inorganic analogues of methyl compounds. There are just over fifty substances of this type known a t present. Until the vacuum-system technique was introduced by Stock during the years 1914-1920 it had not been possible satisfactorily to study volatile compounds which were unstable in air such as the silicon hydrides.Some silyl compounds had been reported in the latter part of the nineteenth century 1 but the physical and chemical properties given could not be accepted with great confidence since their state of purity was always in doubt. Stock and his co-workers re-investigated these compounds and prepared many new ones between 1916 and 1923. Little further work was carried out in the field until 1938 when Emelhs and his co-workers again began to study silyl compounds in addition to other silicon hydrides. Recently investigators in the United States 2-4 have begun to take an inter- est in this class of compound. The types of compounds involved fall into three main categories (i) The unsubstituted parent silicon hydrides which may contain one or more silyl groups and possibly -SiH2- groups as well e.g.SiH,*SiH2*SiH3. (ii) Partially substituted silicon hydrides which contain one or more un- substituted silyl groups and in which there is no direct Si-Si linkage e.g. SiH,*O*SiH,. (iii) Partially substituted silicon hydrides which contain one or more unsubstituted silyl groups and at least one Si-Si linkage e.g. SiH,*SiH,Br. By far the greatest number of compounds known are in the second category. Preparation properties and reactions of silyl compounds (1) The Parent Silicon Hydrides.-A series of silicon hydrides are known corresponding to the simple saturated hydrocarbons of general formula SinH2n+2. Those so far isolated are SiH, Si2HG Si,H, rz-Si,H,, Si,H,, 1 (a) Wohler and Buff Annalen 1857 103 218. ( 6 ) Mellor " Comprehensive Treatise on Inorganic and Theoretical Chemistry " Longmans Green and Co.London 1925 p. 216. 2 Sujishi and Witz Report No. 1 Office of Ordnance Research Control DA-11-OLL. Ord. 1264 (March 1954). Idem J . Amer. Chem. SOC. 1954 76 4631. 4Burg and Kuljian ibid. 1950 72 3103. 208 MACDIARMID SILYL COMPOUNDS 209 and Si,H,,. The last two compounds have only been obtained as a mixture of isomer^.^ A mixture of all the known silicon hydrides may be obtained by the action of dilute hydrochloric acid on magnesium silicide,6 7 and fairly pure silane SiH, may be prepared in good yields by the reaction of magnesium silicide with ammonium bromide in liquid ammonia. With specially prepared magnesium silicide high yields of disilane Si,H, are obtained.8 Pure silane and also disilane are most conveniently prepared by the reduction of the corresponding completely chlorinated compound with lithium aluminium hydride.10 All the saturated silicon hydrides are colourless gases or liquids.Their most important physical constants are given in Table 1 . 6 7 11-13 Preparation. Physical properties. TABLE 1 Compound SiH . . . . . . . Si,H . . . . . . Si,Hlo . . . . . . Si,H12 . . . . . . Si,H, . . . . . . Si,H . . . . . . M.p. - 185" - 132.5 - 117.4 - 84.3 - - B.p. - 111.9" - 14.6 52-9 107.4 > 100 > 100 0.68 (- 185") 0.686 ( - 25") 0.743 (0') 0.825 (0') Reactions. The thermal stability of the silicon hydrides is less than that of the analogous carbon compounds and decreases with increasing molecular weight l4 although the stability of the higher hydrides is actually greater than was originally thought.' At comparatively low temperatures the higher silicon hydrides decompose to give a mixture of lower volatile silicon hydrides and solid unsaturated hydrides all of which decompose completely into silicon and hydrogen a t 500°,14-17 e-g.Si,H, -+ Si,H + SiH -t 2(SiH) Si,H -+ SiH + (SiH) + &H SiH also (SiH) -+ Si + H ti Stock " Hydrides of Boron arid Silicon " Cornell Univ. Press Ithaca New York 1933 p. 21. Stock and Somieski Ber. 1916 49 111. Johnson and Hogness J . Amer. Chem. SOC. 1934 56 1252. Johnson and Isenberg ibid. 1935 57 1349. 7 Emelkus and Maddock J. 1946 1131. lo Finholt Bond Wilzbach and Schlesinger ibid. 1947 69 2692. l1 Wintgen Ber. 1919 52 724. 1 2 Stock Stiebler and Zeidler Ber. 1923 56 1695. lS Stock op. cit. ref. 5 p. 32. 1 4 Idem ibid.pp. 23 24. 1 Emelhs and Reid J. 1939 1021. 1 6 Stockland Kgl. Norske Videnskab. Selskabs. Skrifter 1950 No. 3 1-159. 17 Hogness Wilson and Johnson J . Amer. Chem. Xoc. 1936 58 108. 210 QUARTERLY REVIEWS Silane is also decomposed into solid hydrides by an electric discharge or by ultraviolet irradiation. 18 All the parent silicon hydrides are spontaneously inflammable and ex- plosive in air,20 with the exception of pure silane which can be mixed with oxygen under certain conditions of temperature pressure etc. without inflammation. 2 l None of the silicon hydrides reacts with pure water or with slightly acidified water but in the presence of even a minute trace of alkali they are rapidly and completely hydrolysed to hydrogen and silicate. 22 23 All the silicon hydrides are strong reducing agents.They reduce aqueous solutions of KMnO t o MnO, Hg2+ to Hg+ and Hg Cu2+ to copper hydride etc. The free halogens react vigorously with all silicon hydrides-sometimes explosively-one or more of the hydrogen atoms being replaced by halo- gen.3 23 The reaction of hydrogen halides with silane is discussed in the following section,24 and that with disilane on p. 212. All the silicon hydrides except silane react readily with carbon tetrachloride or chloroform in the presence of aluminium chloride catalyst 25 They do not alter solutions of Ni2+ Cr3+ or Pb2+.6y 23 + 4CHC1 + Si,H,Cl + 4CH,C1 (2) Compounds containing Elements of Group VII or Pseudo-halogens.- (A) Compounds containing no Si-Si Linkage.-Preparation. The silyl hal- ides with the exception of the fluoride which has not been investigated in this type of reaction may be prepared by the action of the gaseous hydrogen halide on silane at slightly elevated temperatures in the presence of the appropriate aluminium halide catalyst as indicated by the general equation 2 3 9 2 4 7 26 A1 X SiH +HX 4 SiH,X +H Silyl halides may also be prepared by the interaction of a higher silicon halide and silane in the presence of the appropriate aluminium halide ~atalyst,2~ e.g.SiH,Cl + SiH -+ 2SiH,C1 Silyl chloride is more conveniently prepared by reduction of silicon tetrachloride with formaldehyde on an alumina catalyst at elevated tem- peratures 27 while an alternative preparation of the bromide involves the reaction of silane with solid bromine at low temperat~res.~ Silyl fluoride is prepared by the action of silyl chloride on antimony trifluoride.28 Schwarz and Heinrich 2.anorg. Chem. 1935 221 277. l9 Emelkus and Stewart Trans. Paraday SOC. 1936 32 1577. 2o Stock op. cit. ref. 5 pp. 20 22. 21 Emelbus and Stewart J. 1935 1182. 22 Stock and Somieski Ber. 1918 51 989. 2 3 Stock op. cit. ref. 5 pp. 25 26. 24 Emelkus Maddock and Reid J. 1941 353. 25 Stock and Stiebler Ber. 1923 56 1087. 26 Stock and Somieski Ber. 1919 52 695. 27 Glemser and Lohman 2. anorg. Chem. 1954 275 260. 28 Emelbus and Maddock J. 1944 293. MACDIARMID SILYL COMPOUNDS 211 The silyl iso-pseudo-halides SiH,*NC SiH,*NCS may be prepared by the act'ion of silyl iodide vapour on the appropriate silver SiH,I 4- AgNC -+ SiH,.NC + AgI When this reaction is carried out with silver cyanate the desired silyl deriva- tive is not obtained and only silicon tetraisocyanate is formed.29 The silyl halides and silyl isothiocyanate are colour- less gases or liquids at room temperatures but the isocyanide is a solid which readily sublimes to form long colourless crystals.Both silyl fluoride and isothiocyanate are considerably associated in the liquid state. 28 29 The most important physical constants are given in Table 2. e.g. Plr ysical properties. TABLE 2 Compound M.p. 1 B.p. 1 d (liquid)(g./ml.) Si133F28 . . . . . . SiH3ClZ6 . . . . . . SiH,Br30 . . . . . SiH3NCZS . . . . . SiH,NCS29 . . . . . s i ~ ~ 1 2 4 . . . . . . - - 118.1" - 94 - 57.0 32.4 - 51.8 - 98.6" - 30.4 1.9 45-4 49.6 84.0 - 1.145 (- 113") 1.533 (0.0") 2-05 (10.1O) - 1.05 (20") Reaction$. All the silyl halides have a tendency to disproportionate a t room temperature^.^^.28 This is discussed fully later (p. 222). Silyl isocyanide decomposes very slowly at room temperature during 1-2 years with the liberation of silane and hydrogen cyanide while the isothiocyanate decomposes during 2-3 weeks at room temperature silane and hydrogen being formed. 29 Silyl bromide is spontaneously inflammable in air,30 whereas the chlor- ide,26 iodide,24 and isccyanide and isothiocyanate 29 are not although they will all burn when ignited. All the halides and pseudo-halides (with the exception of the fluoride which has not been tested) are hydrolysed instan- tlaneously by water to disilyl ether (disiloxane) and the hydro-acid e.g. 2SiH,I + H,O + (SiH,),O + 2HI They are all completely and rapidly hydrolysed by aqueous alkali with the liberation of hydrogen.29 31-33 All the hydrogen atoms in the silyl halides can be successively replaced by halogen by prolonged treatment with the appropriate hydrogen halide and aluminium halide catalyst.23 24 Silyl chloride does not undergo a true Wurtz-type reaction 34 whereas silyl iodide does react to give large yields of disilane 24 2SiH31 + 2Na + SiH,*SiH + 2NaI 29 MacDiarmid J .Inorg. Nuclear Chenz. 1956 2 88. 30 Stock and Somieski Eer. 1917 50 1739. 31 Maddock Ph.D. Thesis London 1941. 3 2 Stock Somieski and Wintgen Ber. 1917 50 1754. 33 Stock and Somieski Ber. 1923 56 132. 3 4 Stock op. cit. ref. 5 p. 34. 212 QUARTERLY REVIEWS Other reactions such as the interaction of silyl halides and pseudo- halides with ammonia phosphine amines non-metals metals organo- metallic compounds silver salts etc.are more appropriately discussed in following sections since the halides and more particularly silyl iodide are the chief reagents in the syntheses of silyl compounds. (B) Compounds containing Si-Si Linkages. 35-Preparation. Disilanyl chloride SiH3*SiH,C1 and disilanyl bromide which are formally the in- organic analogues of ethyl chloride and bromide may be prepared by the interaction of disilane with the hydrogen halide in the presence of the appro- priate aluminium halide catalyst. More completely substituted compounds such as Si2H4C1 and Si2H,Cl3 are also formed in these reactions but they cannot be separated and are themselves mixtures of isomers. Compounds such as Si3H4Cl4 and Si3H,C1 are formed in the reaction between chloroform or carbon tetrachloride and trisilane in the presence of aluminium chloride.Because of the formation of isomers it is not pos- sible to separate any pure compounds.25 The compounds have not been thoroughly investigated. Disilanyl bromide melts a t - 100" and both this compound and the chloride readily disproportionate. This property is discussed more fully in a later section.35q They are completely decomposed by aqueous alkali with the liberation of hydrogen. (3) Compounds containing Elements of Group V1.-(A) Compounds containing no Si-Si Linkage.-Preparation. Silyl alcohol (silanol) SiH,*OH has never been isolated and appears to have only a transitory existence. It has been detected in the hydrolysis products of silyl chloride and bromide but it very rapidly condenses to form disilyl ether.32 Silyl mercaptan (silanethiol) SiH,*SH is formed in an equilibrium reaction between disilyl sulphide and hydrogen sulphide a t room temperatures 36 (SiH,),S + H,S + 2SiH3-SH Disilyl ether (disiloxane) (SiH,),O is formed by hydrolysis of many silyl compounds such as the halides p~eudo-halides,~~ quaternary ammonium salts,38 disilyl sulphide and ~ e l e n i d e .~ ~ The last two compounds are formed by the interaction of silyl iodide with mercuric sulphide and silver selenide respectively 36 e.y.9 2SiH31 + HgS -+ (SiH,),S + HgI A mixed alkyl silyl ether ethyl silyl ether is reported to be formed by ethyl alcohol with [SiH,*N(CH,),]Cl but it has not been isolated in the pure state. 40 Properties. The compounds are all colourless gases or liquids The most important physical constants are given in Table 3.Properties and reactions. 35 Stock and Somieski Ber. 1920 53 759. 35a See p. 223. 36 Emeleus MacDiarmid and Maddock J . Inorg. Nuclear Chem. 1955 1 194. 37 See p. 212. 40 ( a ) E-melhus and Miller J . 1939 819; ( b ) Miller P1i.D. Thesis London 38 See p. 215. 38 See p. 213. 1939. MACDIARMID SILYL COMPOUNDS 213 Compound TABLE 3 M.p. 1 B.p. 1 (1 (g./nil.) SiH,+3H36 . . . . . (SiH3),S36 . . . . (SiH3),032 . . . . . (SiH,),Se36 . . . . . N - 134" - 141 - 50-0 - 68.0 - 0,881 ( - 80') 0.9294 (10.0") 1.36 (80") Reactions. Silanethiol has not been examined in detail. It begins to decompose slowly even at - 78" to produce disilyl sulphide and hydrogen sulphide. 36 Disilyl ether is not spontaneously inflammable in air although it will burn when ignited. 32 7 33 The sulphide is spontaneously iiiflarnmable in moist but not in dry air.36 Disilyl ether is very stable thermally and may be heated to 300-400 O without much decomposition 33 while the sulphide suffers only slight thermal decomposition when held at 100-125 O for several hours.36 The selenide is stable at room temperatures but decom- poses slightly when held near its boiling point for 2-3 hours.36 Both disilyl sulphide and selenide are instantaneously hydrolysed by water to disilyl ether e.g.(SiH,),S + H,O --+ (SiH,),O + 13,s and all the compounds are decomposed by aqueous alkali with liberation of hydrogen. 36 The ether reacts explosively with chlorine even at low temperatures to give a mixture of silicon tetrachloride and (SiC13)20.32 With solid iodine a t room teinpera- t,ures the following reaction occurs (M = 0 S or Se) 36 Disilyl ether sulphide and selenide all react wit>h halogens.(SiH,),M + I -+ ZSiH,I + M The sulphicie and selenide both react with hydrogen iodide to give silyl e.g. (SiH,),Se + 2HI + 2SiH,I + H,Se Methyl iodide reacts neither with the sulphide nor with the selenide to form " onium " type compounds and no sulphoniuni compound is formed by disilyl sulphide and silyl iodide.36 The sulphide does not form an addi- tion compound with either mercuric chloride or iodide. With the former the reaction proceeds quantitatively 36 (SiH,),S + HgCl + ZSiH,Cl + HgS Complex reactions occur between disilyl sulphide and ammonia or tri- niethylamine to yield silane and unidentified solids. 36 (B) Compound containing Si-Si Linkages.- Only one compound in tthis category is known vix.(SiH3*SiH2),0,35 and even this has not been coni- pletely characteriseri. It is formed by the hydrolysis o f disilanyl chloride or bromide e.g. SSiH,*SiH,Br + H,O + (SiH,.SiH,),O + ZHSr It is 8 colourless liquid which can be volatilised without decomposition. When dissolved in benzene it instantaneously reduces silver nitrate. 0 214 QUARTERLY REVIEWS (4) Compounds containing Elements of Group V.-(A) Nitrogen Com- pounds.-Preparation. The mono- and di-silylamines SiH,*NH and (SiH,),NH are formed in the reaction between silyl chloride and excess of ammonia but they have not been obtained in the pure state since they are comparatively unstable 4 1 Trisilylamine (SiH,),N may be prepared by the action of excess of silyl chloride on ammonia 41 3SiH3C1 + NH -+ (SiH,),N + 3HC1 The alkyl-substituted amines such as (SiH,),NMe (SiH,),NEt SiH,*NMe are formed readily in the reaction between silyl chloride or bromide anti the appropriate amine a t room temperature 3 7 4o e.g.SiH,Br + NHMe -+ SiH,*NMe + HBr Quaternary ammonium type compounds such as [ (SiH,),NMe,]Cl (SiH,*NMe,)Cl (SiH,*NMe,)I and (SiH,*NEt,)I are formed in instantaneous reactions at room or reduced temperatures between the appropriate silyl halide and amine,40 42 e.g. SiH,I + NMe -+ (SiH,.NMe,)I An addition compound with a formula approximating to SiH,I,(NMe,) can be prepared by the action of silyl iodide on excess of trirneth~lamine.~~ Properties. The simple amines and alkyl-substituted amines are all colourless gases or liquids and the quaternary and addition compounds are colourless solids.Physical constants where available are given in Table 4. (S,H3)3N41 . . . . . (SIH,),NM~~~ . . . . SiH3NMeZ3. 40 . . . . (SiH3),NEt40 . . . . TABLE 4 - 105.6" - 3-4 - 127 Compound 52" 32.3 65.9 - 0.895 ( - 106') - - - Reactions. The compounds SiH,*NH and (SiH,),NH in the gaseous state to form (SiH,),N and ammonia. also decomposes to some extent as shown below (SiH,),NH + SiH + (*SiH,*NH*) rapidly condense The disilylamine Trisilylamine is spontaneously inflammable in air and is vigorously decom- posed by water to give silica ammonia and hydrogen.41 The alkyl-substituted amines are comparatively stable although SiH,*NMe decomposes at a measurable rate at its melting point.3 Hydrogen chloride reacts with (SiH,),NMe (SiH,),NEt and also (SiH,),N to form silyl chloride,40 41 e.g.(SiH,),N*CH + 3HC1 -+ 2SiH3C1 + CH,*NH,,HCI No alkylsilylamine hydrochloride is formed in this type of reaction. The amines form addition compounds of varying degrees of stability 4 1 Stock and Somieski Ber. 1921 54 740. 4 2 Aylett EmelBus and Maddock J. Inorg. Nuclear Chem. 195.5 1 187. MACDIARMID SILYL COMPOUNDS 215 with boron hydrides and their derivatives such as (SiH,),N-B,H5 (SiH,)MeN*B,H, SiH,*NMe,,BMe3 and (SiH,),N,BCI which subsequently decomposes to give (SiH,),NBGl (SiH,),N + BCI -+ (SiH,),NBCl + SiH,Cl These compounds have in general been completely characterised. 3 9 The quaternary ammonium type compounds containing only one silyl group are stable and decompose only slowly in air while dimethyldisilyl ammonium chloride is unstable and decomposes readily.40 42 A solution of (SiH,-NMe,)Cl in acetone conducts ele~tricity,~~ as does also a solution of (SiH,*NMe,)I in acetonitrile.However the addition com- pound SiH,T,(NMe,) does not conduct an electric current in this s~lvent.~z I n contrast to the action of hydrogen chloride on the alkylsilylamines hydrogen iodide does not react with (SiH,*NMe,)T or even with Si H,I (NMe,) . 43 The compound (SiH,*NMe,)CI is an excellent " silylating " agent and can be used to introduce silyl groups into such substances as ethyl alcohol water etc40 (B) Phosphorus Compounds. - Preparation. Monosilylphosphine SiH,*PH can be prepared by heating a mixture of silane and phosphine,44 while trisilylphosphine (SiH,),P iododisilylphosphine (SiH,),PI di-iodo- silylphosphine SiH,*PI, and tetrasilylphosphonium iodide [ (SiH,),P]I are found amongst the products of the reaction between silyl iodide and white phosphorus.42 Trisilylphosphine and iododisilylphosphine have not yet been isolated in the pure state. No simple alkylsilylphosphines have been reported but there are sev- eral alkylsilylphosphonium compounds known such as [ SiH,*PMe,]I [SiH,*PEt,]I [SiH,*PHMe,]Br [SiH,*PHMe,]I and [SiH,*PH,Me]Br. These are all formed by direct reaction between the appropriate silyl halide and alkylphosphine at or below room temperatures.2 42 Very little is known about silylphosphorus compounds and only SiH,*PI has been characterised t o any extent. This substance boils at 190" but decomposes a t measurable rate at room tem- peratures. 42 The compound SiH,*PH reacts with ammonium hydroxide t o produce silane phosphine and hydrogen,44 and (SiH,),P yields phosphine on hydrolysis.The phosphonium compounds are all white solids some of which e.g. (SiH,*PHMe,)Br and (SiH,*PH,Me,)Br are largely dissociated even at low temperatures. Silyltriethylphosphonium iodide (SiH,.PEt,)I is a very stable solid at room temperatures and its solution in acetonitrile conducts an electlric current. 42 (C) Arsenic Compounds. 42-Prepamtion. Monosilylarsine SiH,*AsH, iododisilylarsine (SiH,),AsI and di-iodosilylarsine SiH,-AsI, have been Properties and reactions. 43 Aylett Ph.D. Thesis Cambridge 1954. 44 Fritz 2. Naturforsch. 1953 8b 776, 216 QUARTERLY REVIEWS reported amongst the products of the reaction between silyl iodide and arsenic. Disilylarsine (SiH,),AsH 43 and trisilylarsine (SiH,),As are formed by the reaction of silyl iodide with K,As but they have not been obtained in the pure state.No alkylsilylarsines are known but the quaternary arsoniuin com- pound (SiH,-AsMe,)I is formed by direct reaction between silyl iodide and trimethylarsine. Tetrasilylarsonium iodide [ (SiH,),As]I is formed by the action of silyl iodide on mercuric arsenide. Di-iodosilylarsine SiH,*AsI, is the only silyl- arsenic compound which has been characterised to any extent. It melts a t 4" and boils a t 201" ; it begins to decompose rapidly at about 80". Trisilylarsine boils at 97-98' and arsine is formed when it is hydrolysed with aqueous alkali. Little is known of the other substances apart from (SiH,-AsMe,)I which melts at 8.1-9-6" and has a high dissociation pressure at low temperatures.(5) Compounds containing Elements of Group 1V.-Preparation. Several compounds have been reported in which an alkyl or a phenyl group is attached to a silyl group. In general they can be synthesised by reaction of silyl chloride with an organo-metallic compound 26 or by reducing a trichloride in which all the chlorine atoms are attached to the silicon with LiAlH4.10 2SiH,Cl + ZnMe - 2SiH3Me + ZnC1 LiAlH SiC1,Me I__ SiH,Me Properties and reactions. The latter method is the one most commonly used e.g. Properties. All the compounds are colourless liquids or g;Lses. Their chief physical constants are given in Table 5. TABLE 5 Conipouritl Si€13CH32G . . . . . SiH3CH2.CH310 . . . SiH3.[CH,]2-CH310 . . . SiH,-[CH2]3*CH310 . . . SiH3-C,H,l0 . . . . . B.1). - 57" - Id 23" 55 120 d (g./1111.) 0.62 ( - 57") - 0.6434 (20') 0.6764 (20') 0.8681 (20') Reactions.All these cornpounds are very stable. They are not spon- taneously inflammable in air and they react very slowly with water but somewhat more rapidly with aqueous alkali. No measurable decomposition occurs on prolonged storage in a sealed container at room temperatures.10 26 With silylmethane and presumably with the other alkyl derivatives a hydrogen atom may be replaced by a chlorine or iodine atom when the compound is heated with the appropriate hydrogen halide and aluminium CH,*SiH + HC1 $ CH,-SiH,CI + H halide catalyst,26t 45 e 4 . 7 A1 C1 4 5 Emelbus and Onyszchuk private communication December 1954. MACDIARMID SILYL COMPOUNDS 217 (6) The Free Silyl Radical.-There is no definite evidence for the existence of' the free silyl radical.The fact that SiH,I undergoes a Wurtz type of reaction with sodium to give high yields of disilane 24 might be due to the existence of short-lived silyl radicals ; e.g. (i) SiH,I + Na -+ SiH + NaI (iia) BSiH -.+ Si2H,3 or (iib) SiH + Na -+ NaSiH followed by NaSiH + SiH,I -+ Si,H + NaI However this reaction could probably proceed without the formation of free radicals merely by the combination of two adjacent SiH,I molecules as they react on the surface of the sodium. Recent experiments on the pyrolysis of silane and disilane with the subsequent passage of the hot gases over films of metals and non-metals gave no indication of the existence of free silyl radicals.46 (7) Silyl Metallic Compounds.-There is some very slight evidence that silyl iodide may combine with metals to form analogues of the methyl organo-metallic compounds.This was indicated in the preceding section when it was suggested that silyl iodide may react with sodium to form disilane through the intermediate formation of NaSiH,. It has been observed that silyl iodide reacts with metallic zinc to give a solid product-possibly SiH3*ZnI. 24 However the reaction has recently been re-examined and no trace of this compound was obtained.43 A solid substance possibly SiH,-HgI,24 has been reported as being formed in the reaction between silyl iodide and mercury but no details of its properties have been given. It has also been reported that magnesium dissolves in a solution of silyl iodide in diisopentyl ether.24 It appears likely that an unstable Grignard-type compound may be formed in this reaction although no Grignard compound could be isolated from the reaction of silyl bromide with magnesium.46a Theoretical aspects of silyl chemistry (1) MeEting Point.-There are fourteen pairs of analogous silyl and methyl compounds whose melting points are known. In six cases the silyl compound melts at a lower temperatiire than the methyl compound and in eight cases at a higher temperature. If t'he melting points of the silicon compounds are plotted against those of their respective carbon analogues there is a very general linear trend but the points do not fall on or near any sort of line or curve. Consequently there is no simple relationship between the melting points of these substances. Nevertheless several interesting comparisons may be made between the silyl and methyl compounds.For instance in the XH compounds the replacement of a hydrogen by a halogen atom has a smaller effect on tjhe melting pointl of the silicon than on t,hat of the carbon compound if the 4 0 Emelkus Kuoheii and Maddock private commmiication December 1054. 465 Von Artsdalen and Gavis J. Amer. Chem. SOC. 1952 74 3196. 218 QUARTERLY REVIEWS halogen is chlorine; if it is bromine the effects are approximately equal; and if it is iodine the effect is greater in the silicon derivative. Another noticeable trend is that the melting points of silyl chloride bromide and iodide increase regularly with increasing molecular weight. This effect is not observable in the methyl compounds. The insertion of an oxygen or sulphur atom between silicon atoms in Si,H raises the melting point much less than their insertion between carbon atoms in C,H,.For instance the difference in melting points of C,H and (CH,),O is 45.2" while the difference for Si,H and (SiH,),O is only 11-5". Also the difference in melting points of C2H6 and (CH,),S is 100.5" while that between Si,H and (SiH,),S is only 62". It is not surprising that no simple relationship exists between the melting points of corresponding silyl and methyl compounds since this property depends largely on the crystal structure which could vary greatly between analogous compounds because of the larger size of the silicon atom and the different molecular structure of some silyl derivatives. (2) Boiling Point.-There are twenty-one pairs of analogous silyl and methyl compounds whose boiling points are known.If the boiling points of the silicon derivatives are plotted against those of their respective carbon analogues there is a general linear trend over the group as a whole and a very close linearity within each sub-group of compounds (see Fig. 1). In all three sub-groups where there are three or more members of similar formula type a very close linear relationship is observed. From this it follows automatically that the molar heats of vaporisation must also bear a linear relationship to each other since the Troutoii constants for silyl and methyl compounds are generally similar. -1000' ' I -90" -30' 30" 90" o XNCS O X N C H 2 2 5 'ZNCH3 3 XSH. o o X N -90" -30" 30" 90" Bo;//i7g point o f si/y/ compound FIG. 1 60" -40" -140' 72 5" 75" 25 " -25" Boiling points of silyl (X = SiH,) and methyl (X = CH,) compounds.MACDIARMID SILYL COMPOUNDS 219 B.p. (SiH,Y) - B.11. (SiH,) FIG. 2 Boiling points of silyl (--) and methyl (- - - -) compounds. ~A~ B.p. (CH,Y) - B.p. (CH,) I n Fig. 2 the boiling points of the carbon compounds are plotted in order of increasing value and those of the silicon derivatives are then added in the same order. It can be seen that all silyl compounds boil at a higher temperature than their methyl analogues except the halogen and pseudo- halogen compounds (except that silyl iodide boils 2.9" above methyl iodide). The (algebraic) difference between the boiling points of the silyl and methyl halides becomes less with increasing atomic weight of the halogen. From Table 6 it can be seen that replacement of a hydrogen in SiH or CH by a halogen raises the boiling point much less in the silicon compound than in the carbon analogue.This effect becomes less noticeable as the TABLE 6 F . . . . . c 1 . . . . . B r . . . . . I . . . . . 13.3" 81.5" 113.8" 157.3" 82.7" 137.2" 165.8" 203.8" 69.4" 55.7" 52.0" 46.5" atomic weight of the halogen increases. Also from Table 7 it is apparent that the replacement of a hydrogen in SiH or CH by an aliphatic or aromatic group raises the boiling point much less in the silicon than in the carbon compound. This effect becomes m r e noticeable as the molecular 220 QUARTERLY REVIEWS weight of the substituted group increases i.e. the reverse of the trend not,ed with the halogens. TABLE 7 Y CH . . . . C,H . . . . C,H . . . . C,H . . . . C,H . . . . B.p. (SiH,Y) - l3.p.(SiH4) 64.9" 97.9" 134-9" 166.9' 231-9" 72.6" 119.1" 160.4" 197.5" 271-9" A 17.7" 21.2" 25-5" 30.6" 40.0" From Table 8 it can be seen that the insertion of an oxygen sulphur or selenium atom between the silicon atoms in Si,H raises the boiling point far less than when they are inserted between the carbon atloms in C,H,. The effect becomes Ze.ss iioticeahle as tlhe atomic weight of the substituted atom increases. TABLE 8 l3.p (S,H,Y) - B.p. (Si2H8) B.1). (C2H,Y) - B.p. (C,H,) o . . . . . s . . . . . S e . . . . . - 0.70 73.5" 99.7" 65.0" 126.2" 146.9" 65.7" 52.7" 47.2" The boiling point of a substance depends on the magnitude of the inter- molecular attractive forces acting between its molecules. These forces clepend on a number of factors such as the molecular weight of the species molecular structure dipole moment degree of hydrogen bonding etc.Their effects may reinforce or oppose one another and it is therefore difficult to predict what the net effect on the intermolecular attractive forces and hence on the boiling point will be when one atom in a compound is replaced by a different atom or group. Consequently it is not surprising to find that silyl fluoride chloride bromide isocyanide and isothiocyanate boil at lower temperatures than their methyl analogues even though their molecular weights are greater. This may well be related to the fact that the dipole moments of simple halogenated silanes are generally smaller than those of the corresponding carbon compounds 47 and hence the intermolecular attractive forces might also be less. (3) Methods of Preparation of Silyl Compotcnds.-There are two general methods of preparation which appear to have great potential value.(A) " Conversion series." The vapour of a simple silyl compound is allowed to react with a silver salt and double decomposition ensues. This type of reaction (carried out under different experimental conditions) has already been used for the preparation of several organo-silicon ileriva- 47 ( a ) Brockway and Coop Trans. Paraday SOC. 1938 34 1429; ( b ) Lewis and Smyth J . Arner. Chern. A ~ O C . 1939 61 3036 ; ( c ) Spauschus Mills Scott and MacKenzie ibid. 1930 72 1377. MACDIARMID SILYL COMPOUNDS 22 1 49 The modified “ conversion series ” proposed for silyl compounds is given below. It is postulated that treatment of a compound with the appropriate silver salt will bring about a conversion into any compound later in the series but into none earlier therein.(SiH,),Te + SiH,I + (SiH,),Se --+ (SiH3),S -+ SiH,Br -+ SiH,Cl -+ SiH,*NC -+ SiH,*NCS -+ SiH,*NCO + (SiH,),O -+ SiH,F This postulate has so far been tested successfully in six reactions,29 36 vix. the conversion of silyl iodide into the selenide isocyanide isothiocyan- ate and isocyanate that of the isothiocyanate into the isocyanate and the non-conversion of the isocyanide into the chloride. No silyl isocyanate has yet been isolated from the above reactions since it is apparently very unstable and decomposes rapidly to the tetraisocyannte Si(NCO)4. Thernio- dynamic calculations 50 using Si-M (M being the attached element) bond energies where available,51 52a and the free energies of formation of the silver salts 52b substantiate the order of compounds in the series.These calculations are not exact in that it is necessary to assume that the entropy change between the silyl reactant and product is zero but they are completely general and in contrast to those of some investigator^,^^ they apply regard- less of the mechanism of the reactions. Another conversion series using mercuric salts may well exist and four reactions have already been studied. 36 Thermodynamic calculations give results similar to those of the silver salts.50 Somewhat similar reactions occur with some alkyl iodides and salts of the heavy metals.53 The silyl compound in the form of liquid or vapour is allowed to react wit,h the appropriate hydro-acid. The “ acid replacement series ” proposed for silyl compounds is given below.It is postulated that treatment of any substance in the series with the appropriate hydro-acid will bring about a conversion into any compound later in the series but into none earlier therein. SiH,H -+ (SiH,),Se + (SiH,),S + SiH31 -+ (€3) ‘’ Acid repZacemen,t seyies.” SiH,Br + SiH,Cl + SiH,F + (SiH,),O This postulate has so far been tested successfully in twelve reactions viz. the conversion of silane into silyl halides thak of silyl halides and pseudo- halides into disilyl ether that of disilyl sulphide and selenide into disilyl ether and that of disilyl sulphide and selenide into silyl iodide. Thermo- dynamic calculations again substantiate the order of the compounds given in the ~eries.5~ 48Eaborn J. 1950 3077. 49 (a) Anderson and Fischer J.Org. Chem. 1954 19 1296 ; ( b ) Aiidersori and Varjta 50 MacDiarmid unpublished work. 51 Gilman and Dunn Chenz. Rev. 1953 52 77. 5 2 ( a ) Sidgwick “ The Chemical Elements and Their Compounds ” Oxford Univ. Press 1950 p. xxxi ; (6) Latimer “ Oxidation Potentials ” 2nd edn. Prentice-Hall Inc. 1952 p. 190. ibid. p. 1300. 5 3 Kerrer “ Organic Chemistry ” Elsevier Press New York 1938 pp. 66 168. 222 QUARTERLY REVIEWS (4) The Electron-attracting Character oj’ the Silyl Group.-From theoretical considerations supported by physical and chemical observations it may be shown that the silyl group when joined to many atoms or groups may act a,s a powerful electron acceptor. At first sight it would appear that the silyl radical should act as a less powerful electron acceptor than the methyl group since the electronegativity of silicon (1.8) is less than that of carbon (2.5).However it has recently been shown that n bonds may play a considerable part in the bonding of atoms with one or inore lone pairs of electrons to atoms with vacant d-orbitals. This often occurs in bonds between silicon and e1ement)s of Groups V VI and VII where there is an overlap between a vacant silicon d orbital and a pn orbital on an atom to which the silicon is already bound by a u b0nd.~~1 5 4 9 5 5 The n bond is usually stronger the more electronegatiwe the donor atom. Consequently the silicon actually attracts electrons more strongly than would be expected from simple electronegativity data. This effect cannot take place with carbon since it has no 3d orbitals. The shortening 56-58 of silicon-halogen and silicon-oxygen bond lengths is consistent with this concept although other causes have been suggested.59 The small dipole moments of simple halogenated silanes also support this viewpoint.47 The infrared absorption spectrum of (SiH,),N indicates that this molecule is planar in contrast to that of (CH,),N which is pyrimidal. This could be explained if there were some resonating bonding structures present such as H,Si.tN(SiH,),.60 Further evidence for this type of bonding is given by the infrared spectrum of SiH,*NCS which indicates a linear molecule whereas CH,*NCS is non-linear.61 This is consistent with a structure such as H,Si.frN=C=S. Chemical support for the n-bonding concept is given by the unexpected properties of many organo-silicon c o m p ~ u n d s ~ ~ ~ 5 5 and also by the un- substituted silyl derivatives which will be discussed in the following sections.( 5 ) Silyl Halides.-All the silyl halides tend to disproportionate as shown 24 28 2SiH,X -+ SiH,X + SiH The effect is greatest in the fluoride and becomes progressively less on pass- ing to the chloride then to the bromide and finally to the iodide in which it is negligible. 54 Craig Maccoll Nyholm Orgel and Sutton. J. 1954 344. 65 Stone and Seyferth J . Inorg. Nuclear Chem. 1955 1 112. 5 6 ( a ) Pauling “ The Nature of the Chemical Bond ” 2nd edn. Coriiell IJiiiv. Press Ithaca New York 1948 p. 164 ; ( b ) Dailey Mays and Townes Phys. Rev. 1949 76 136 ; (c) Mays and Dailey J . Chem. Phyls. 1952 26 1695 ; ( d ) Sheridan and Gordy ibid. 1951 19 965. 57 Huggins J . Amer. Chem.SOC. 1953 75 4126. 58 Schomaker and Stevenson ibid. 1941 63 37. 59 ( a ) Pitzer ibid. 1948 70 2140; ( b ) Mulliken ibid.. 1950 72 4493. 6o Hedberg and Stosick Abstracts of the XI1 International Congress of Pure arid 61 MacDiarmid and Maddock J . Inorg. Nuclear Chern. 1955 1 411. 61a Lord Robinson and Schumb (J. Amer. Chem. SOC. 1956 78 1327) report that (SiH,),O is a linear molecule ; this is further evidence of T bonding in silyl compounds. Applied Chemistry New Yorls September 10-13 1951 p. 543. MACDIARMID SILYL COMPOUNDS 223 The two known disilanyl halides disproportionate as shown 35 2SiH,*SiH,X + Si,H,X + Si,H where X is either chlorine or bromine. The effect is most noticeable in the chloride and the rates of disproportionation are greater than in the simple silyl compounds.Thermodynamically the reactions may proceed at least to a measurable extent because of the entropy changes involved in the redistribution of the hydrogen and halogen atoms although this will be modified by the variation of Si-X bond lengths in the products and The rate of disproportionation will be decided by the mechanism of the reaction and the magnitude of the activation energy involved. Three possible mechanisms are given below in which SiH,F is used as an example. A similar argument would apply to the other silyl halides. (1) SiH,F -+ SiH + F 6 2 F + SiH,F -+ SiH,F + H H + SiH + SiH (2) SiH,F + SiH,+ + F- F- + SiH,F -+ SiH,F + H- H- + SiH,+ + SiH ( 3 ) 2SiH,F -+ (SiH,F+SiH,F)* + SiH,F + SiH Mechanisms (1) and (2) are unsuitable because they suggest that the rate of disproportionation should be greater the smaller the silicon-halogen covalent bond energy (mechanism l) or the smaller the ionic bond energy (mechanism 2).It would appear that the activation energy needed for homolytic or heterolytic fission of the silyl halide would be the rate-con- trolling factor in these mechanisms. If this were the case the rate would increase from the fluoride to the iodide since this is the direction of decreasing covalent 51 and ionic 48 bond strengths. Experimental data show that the disproportionation rate is the reverse of that given by this treatment. In addition no hydrogen fluoride is found amongst the products of the dis- proportionation as might be expected if free hydrogen or fluorine atoms or ions were involved. This fact would also tend to discourage any other mechanism involving free hydrogen or fluorine atoms.Mechanism (3) satisfies the experimental data if it is assumed that the silicon-halogen n bond could also act in an intermolecular f a ~ h i o n ~ and so cause the formatlion of the activated complex shown below. This could readily break down to give SiH and SiH,F, H F H H,SitF + SiH,F + H-Si SikF H H H I / / I .’**. /’ \ Since the strength of the n bond decreases with decreasing electronegativity 62 Sharbaugh Heath Thomas and Sheridan Ndure 1953 171 87. 224 QUARTERLY REVIEWS of the halogen the ease of formation of the activated complex would decrease on going from the fluoride t o iodide with a consequence decrease in the rate of disproportionation. The fact that disilanyl halides disproportionate at a greater rate than the simple silyl halides could also be explained by t'his treatment.With silyl chloride for example there will always be a tendency for the intra- molecular n bonding to reduce any intermolecular z bonding by increasing the negative charge on the silicon atom e.g. H3SifC1 + SikCl + H,Si-Cl+SitCl However in SiH,*SiH,Cl the silyl group is not attached directly to the halogen atom and hence it is not affected by the increase of negative charge caused by the intramolecular z bond. Therefore the silyl group can accept an intermolecular n bond much more easily than in the case of silyl chloride and consequently the disproportionation proceeds much more rapidly e-g. H3 H3 H C l H H H H I / 41 I H H I *'... / I I H3Si.SitC1 + SiH,SitCl + H3Si-Si Si-Si_tCl H H H H The activated complex could then readily break down to give SiH,*SiH and SiH,Cl*SiH,Cl.It would appear that the disproportionation productl should be the 1 2-dichlorodisilane and not 1 1-dichlorodisilane. Although the fluoride and iodide have not yet been prepared it would seem safe to predict from the discussion above that the former would dis- proportionate very rapidly and t,he latter very slowly. On developing the argument further it becomes apparent that the halides of the next higher homologues e.g. SiH,*SiH,*SiH,C1 might be expected to disproportionate a t an even greater rate. I n this case the number of silicon atoms per molecule to which the intermolecular n bond may be attached is greater. (6) Xilyl Derivatives of the Pseudo-halogen Acids.-There is a t present very little evidence to indicate whether the compounds SiH,*NC and SiH,*NCS are the normal or iso-derivatives.Until there is evidence to the contrary it seems reasonable to assume that they are iso-compounds by comparison with their methyl analogues since the reaction of methyl iodide with silver cyanide produces the iso-derivative. 6 3 Hydrolysis cannot be used to distinguish the isomers as with the carbon compounds since the cyanide group is removed instantaneously from the silyl group by treatment with water. It is not slowly hydrolysed while still attached to the group to give substances similar to CH,*C0,NH4 or CH,*NH,.29 The infrared spectra of SiH,*NC' a i d SiH,*NCS caniiot be used directly to determino whether the compounds are the normal or iso-deriv a t' ives. 63 Gauthier Ann. Chirn. Phys. 1869 17 203.MACDIARMTD SILYL COMPOUND8 225 However infrared data indicate that the thiocyanate is a (linear) symmetri- cel-top molecule which is more consistent with its being the iso- rather than the normal derivative. The fact that silyl isothiocyanate is associated in the liquid state may be due to the presence of intermolecular n bonding 29 as suggested for the vapour association of SiH,-NMe,. ( 7 ) Sdyl Derivatiztes containing Grozp VI Elements.-The reactions of (SiH,),O (SiH,),S and (SiH,),Se are not at all like those of their methyl analogues presumably because the n bonding (back-co-ordination) t o the silicon is so strong that the central atom has lost most if not all of its powers of co-ordination. Structures such as H,SitM-SiH are probably in- vo1ved.61a The compounds no longer show any tendency to form oxonium sulphonium or selenoniuin compounds of the type [(SiH,),RS]I where R is an alkyl or silyl group.Even compounds containing only one silyl group such as [SiH,*SMe,]I are not formed.31 Substances which might forni these compounds or other addition compounds G4 either do not react at all e.g. SiH,I and (SiH,),S or if they do react they do not give the product expected by analogy with carbon chemistry e.g. I or HI and (SiH,),S or (SiH,),Se give only SiH,I. Addition compounds of (SiH,),S with HgC1 or HgI, which are known with the methyl analogue,G5 are not formed with the silyl derivatives. ' The hydrolysis of disilyl sulphide and selenide to form the ether is char- acteristic of silyl compounds but it is interesting to note that a gelatinous intermediate compound is first formed which then rapidly decomposes to give the hydrolysis products.36 The intermediate probably has one or more water molecules co-ordinat,ect to the silicon e.g. Hydrogen sulphide could t'heri split off with the formation of SiH,*OH which could then condense to give the ether. The experimental parachor value of disilyl sulphide iiidicates that the Si-S bond probably possesses a considerable amount of n-bonding character. The parachor of silyl compounds might serve as an empirical physical method for determining the presence of back-co-ordination in these sub- stances. 13 (8) Condensation Reactions.-Coinpounds which have at least one silyl 6* (a) Steinkopf and Muller Ber. 1923 56 1928 ; (b) Siclgwick op. cit. ref. 52a 6 5 ( a ) Smiles Proc. 1899 15 240; (b) Phillips J.1901 79 250. 66 MacDiarmid J . Inorg. Nuclear Chenb. in thk press. pp 955 958. 226 QUARTERLY REVIEWS group and one hydrogen atom attached to a central atom frequently undergo spontaneous condensation e .g . 2SiH,.OH -+ (SiH,),O + H,O 2SiH,*SH + (SiH,),S + H,S 2(SiH,),NH + 2(SiH,),N + NH 3SiH,*NH + (SiH,),N + 2NH3 2SiH3*PH + (SiH,),P 3- 2PH 3SiH,*AsH + (SiH,),As + 2AsH Rapid Slow Rapid Rapid Slow Slow In many systems spontaneous condensation is thermodynamically possible but it takes place infinitesimally slowly e.g. the free-energy change for the reaction below under standard conditions is - 19.6 kcal. 2CH,*OK -+ (CH,),O + K20 The problem is essentially kinetic and not thermodynamic in character once it has been established either theoretically or experimentally that the changes are thermodynamically possible.It seems probable that the Group V or VI atom could form an intermolecular n bond t o the silicon of an adjacent molecule and so produce very easily activated complexes in which the silicon atoms of two molecules are already joined to the same oxygen sulphur nitrogen phosphorus or arsenic atom. The ease with which this could occur would decrease on descending Group V or Group VI since the n-bonds would become progressively weaker. With carbon tjhe effect would be non-existent. This is illustrated below for (SiH,),O. €1 H O I $ 1 I [ - -“I ] H,SitO + SiH + H,Si-O-tSiH + H,Si-0-SiH + H,O The water could be split out from the activated complex as indicated by the broken line. For a Group V element the condensation could proceed in two stages e.g* J H H,Sitk + SiH -+ + (SiH,),NH + NH H HNH I TI H HNH Ammonia could split off a t the broken line as shown and the (SiH,),NH could then combine with another SiH,*NH molecule in a similar manners (9) Silyl Compounds containing Group V Elements.- Silyl compounds containing elements of Group V may be divided into two groups-the simple amine type and those which can be formulated as quaternary ammonium salts.The most outstanding property common to both groups is the inert- ness-either partial OF complete-of the lone pair of electrons on the nitrogen phosphorus or arsenic atoms: MACDIARMID SILYL COMPOUN.DS 227 Physical properties of the amines such as the planarity of (SiH,),N the association of the vapour of SiH,*NMe, and the non-association of the vapour of (SiH,),NMe have been explained by using the n-bonding ~oncept.~ The chemistry of (SiH,),N is readily understood if it is assumed that the lone pair of electrons on the nitrogen can no longer be donated to other atoms.This explains why it will not combine with the hydrogen halides or silyl chloride to form quaternary ammonium type salts although atomic models 66a of the (SiH,),N grouping indicate that sterically it is capable of existence. It also shows why the basic properties of the following series of compounds towards B(CH,) increase as shown (SiH,),N < (SiH,),NMe < SiH,*NMe < NMe Addition compounds are formed with the last two but not with the first two. BF and BCl form only very weak addition compounds with (SiH,),N and strong ones with (CH,),N.4 The fewer the number of silyl groups present in the molecule the fewer will be the possible resonance structures involving the n-bond and the greater will be the donor properties of the lone-pair electrons on the nitrogen.Compounds formed by a 1 1 combination of silyl halide and tertiary amines have been formulated in this Review as quaternary ammonium salts since there is no evidence to the contrary but rather some good evidence for this type of structure e.g. the good electrical conductance of solutions of ( SiH,*NMe,)Cl and (SiH,-NMe,)I in organic solvents. However trimethylamirie adducts with di- tri- and tetra-chlorosilane are known,67 and the possibility that the compounds formed with mono- chlorosilane etc, are also simple co-ordination compounds involving a five- co-ordinated silicon atom cannot be dismissed lightly.Consider the two alternative structures below for this type of compound ( SiH,Cl,-y),NMe ( a ) (SiH,Cl,-,,NMe,)+Cl- ( b ) Structure (b) will be most favoured when there are no chlorine atoms inside the cation since the presence of chlorine atoms attached to the silicon would increase the electron-attracting powers of the cation as a whole and consequently reduce the chance of ionisation. Structure (b) will therefore be most favoured with SiH,Cl (or any silyl halide) and consequently silyl halide adducts with tertiary amines are the most likely to have the quater- nary ammonium type structure A similar type of argument should apply t o phosphonium and arsonium compounds although the results of some investigators have led them to formulate phosphorus compounds containing hydrogen e.g.(SiH,=PH,Me)Br as addition compounds. No stable ammonium type compound has yet been obtained in which there is more than one silyl group. As with the simple amines more than one silyl group would probably decrease the lability of electrons on the nitrogen atom to a point where transfer to the halogen atom could take place only with difficulty. The compounds ( SiH,*NMe,)Cl and (SiH,*NMe,)I GGa Courtauld Atomic Models Griffin and Tatlock and Co. London. G7 Burg J . Amer. Chem. SOC. 1954 76 2674. 228 QUARTERLY REVIEWS follow the same trend in stability as their methyl analogues L e . the iodides are more stable than the chlorides.43 Whereas the tetramethylammonium compounds become less stable as nitrogen is replaced successively by phosphorus and arsenic the tetrasilyl compounds appear to become more stable (the tetrasilyl phosphorus and arsenic compounds can be prepared but not the nitrogen analogue).Again this could be related to the decrease in TC bonding as the electroiiegativity of the Group V element decreases with a consequent increase in the lability of their lone-pair electrons. In the mixed salts such as [SiH,*M(CH,),]I the former trend overcomes the latter and the compounds become less stable as M is replaced by nitrogen phosphorus and arsenic. (10) The SiEicon-Hydrogen Bond.-The Si-€I bond in unsubstituted silyl compounds reacts in many circumstances where the C-H bond will not e.g. it is readily hydrolysed and reacts with halogen acids. Other reactions which have so far been investigated only for completely substituted silyl compounds are also e.g.the interaction of acyl halides in the absence of catalyst with trisubstituted silanes R,SiH + R1*COC1 -+ R,SiCl + RWHO The Si-H bond is thermodynamically able to undergo many reactions partly because i t is weaker than t!he C-H bond (79-9 as compared to 98.1 Imal./m~le),~~ and partly because the bonds which silicon forms with other elements are all stronger than those formed by carbon wit)h the exception of the Xi-S bond.51 52a The rapidity with which an Si-H bond reacts as compared t o a C-H bond depends primarily on the following factors all of which greatly affect the ease of formation of the activated complex.51 (i) The silicon atom can increase its co-ordination number from four to either five or six and conse- quently can allow the relatively easy formation of the intermediate com- plex.(ii) The silicon atom is sterically more vulnerable to attack-more so than the carbon atom in the methyl group since the silicon is almost half as large again as the carbon atom. (iii) The polarity of the Xi-H bond is relatively large and is in the reverse direction from that of the C-H bond and is actually more similar to the C-Br link. It is therefore reactive to i-rucleophilic polar reagents and from (i) and (ii) above it would be expected to react more rapidly than the C-Br bond e.g. 6+ 6- 8- d + s+ s- Si - H C - H C-Br Electromgativity . 1.8 2.1 2.5 2-1 2.5 2.8 n . . . . . + 0.3 - 0.4 + 0.3 (1 1) The t%!yE Group-Compounds containing the silyl group are gener- ally much more reactive than their methyl analogues in reactions in which the group itself preserves its identity and suffers no attack on its hydrogen atoms.This is very noticeable in the instantaneous hydrolysis of most silyl compounds to give disilyl ether and in their rapid reaction with silver salts. In addition silyl halides react rapidly with amines even at low temperatures whereas their carbon analogues generally need heating. MACDIARMID SILYL CO3lPOUNT)S 229 The rapidity of the reactions is dependent primarily on three factors which greatly affect the ease of formation of the activated complex.51 The first two are identical with (i) and (ii) in the preceding section and the third is dependent on the fact that the bonds formed by silicon with other elements are usually highly polar in character-at least much more so than in the case of carbon. Since most of the reactions involve polar reagents the intermediate complex can be formed much more easily. (12) Conclusion.-In general silyl compounds are of similar formula type to their methyl analogues but they do not necessarily have similar molecular structures. They are usually more reactive than the correspond- ing methyl compounds not because of an inherent thermodynamic insta- bility but because of the smaller electronegativity and greater co-ordination number of silicon which effect greater ratea of reaction.

ISSN:0009-2681    

DOI:10.1039/QR9561000208

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

PEPTIDES METHODS OF SYNTHESIS AND TERMINAL-RESIDUE STUDIES By H. D. SPRINGALL M.A. D.PHIL. F.R.I.C. and H. D. LAW B.A. (UNIVERSITY COLLEUE OF NORTH STAFFORDSHIRE KEELE STAFFORDSHIRE) Introduction THE very great biological importance of the macromolecular proteins ( M > N 10,000) and the closely related natural peptides ( M < - 10,000) has made the study of their structure of outstanding interest. This study is of extreme technical difficulty because of the intractable nature of the substances they are for example non-volatile insoluble in the normal organic solvents of low dielectric constant and are often of a very fragile nature. Purified proteins and peptides can be hydrolysed by acids alkalis and enzymes to mixtures of ol-amino-acids +NH,*CHR*CO,- in yields accounting for virtually the whole of the parent compound.There are nineteen different natural cc-amino-acids of frequent occurrence and a num- ber of rarer examples their R-side chains varying widely in complexity and reactivity. With all these amino-acids other than glycine the a-carbon atom is asymmetric and the compounds occur in almost all cases in the L-con- figuration. * The amino-acids are less fragile than the proteins and natural peptides but are otherwise very intractable being crystalline solids melting with decomposition at indefinite very high temperatures insoluble in organic solvents. These awkward properties which result from the ion-dipole structure of these compounds have impeded investigation. Nevertheless specialised techniques have been devised permitting the synthesis of all the common and most of the uncommon natural cc-amino-acids.The fundamental problem of the manner of the linkage between the c(.-amino-acid residues in proteins has been intensively studied and work in many fields biological physical and chemical during the last half- century has established the correctness of the hypothesis due to Fischer and to Hofmeister,2 that the linkage is of the amide type and that the fundamental structural feature of the molecules of the natural substances is the polypeptide chain The nineteen common examples are listed in Table 1. Y' ?2 Y3 F + N H;CH CO-N H -CH-CO.NH.CH.CO......N H-CH-CO; 1 E. Fischer and E. Fourneau Ber. 1901 34 2868. See also E. Fischer Ber. ( a ) 1902 35 1095; (b) 1903 36 2094. F Hofmeister Eryebn. Physiol. 1902 1 759. * For the internationd rules on designation of the stereochemistry of amino-acids see J.1952 3522. 230 SPRINGALL AND LAW PEPTIDES 231 These structures are always written conventionally as above the +NH,*CHR'*CO* and the *NH*CHRn*C02- residue are called respectively N-terminal and C-terminal. Peptides are named as amino-acyl substitution products of the C-terminal residue. TABLE 1 R H Me P r' Bu' Bus H2 Ph.CH2 HS*CH2 -02C*CH - C H,.S-S C H I +N H McS-CH2-CH H H,N*C.N H *C H2-C H,*CH AH Name of amino-acid +NH,*CHR.CO,- Glycine Alanine Valine Leucine Isoleucine Proline Phony la1 anine Cysteine Cystine Methionine Tryptophan Arginine Histidine Lysine Aspartic acid * Glutaniic acid * Serine Threonine Tyrosine Reactivity Neutral non-polar 9 9 9 9 S -cont,aining 9 9 ,? Neutral polar 7 9 7 9 Y 9 Y * The carboxyl groups in the side chains of aspartic and glutamic acid frequently occur in Nature as the corresponding amides (asparagine and glutamine).The classical pattern of the elucidation of the structure of a naturally occurring organic compound is the following sequence of operations isola- tion proof of purity niolecular-weight determination analysis degradation synthesis comparison of synthetic and natural specimens Satisfactory techniques for the study of polypeptide chains by stepwise degradation to and synthesis from a-amino-acid units are essential requisites for the organic chemical investigation of protein and peptide structure. Such is the complexity of the substances and such the technical difficulty imposed by their peculiar properties that it is only comparatively recently 232 QUARTERLY REVIEWS that any individual protein or larger natural peptide has been available in sufficient purity to permit the reasonable interpretation of the results of cc-amino-acid analysis and polypeptide clegradat,ion and t'o give a clearly defined objective for synthetic work.The most complex natural product of this class for which all tlhe stages of the classical pattern of investigation have yet been successfully carried out is the peptide pituitary hormone oxytocin a nonapeptide amide. Of the substances of high molecular weight only for insulin monomer (31 6000) and cc-corticotropin ( M 4500) has the investigation been carried as far as the successful completion of degradative studies resulting in the determination of the complete structural formulz and opening the way for synthetic attacks.Despite the unavailability until recently of suitable purified proteins and natural peptides their synthesis and stepwise degradation have been act'ively studied for many years Iny using model substances. The syntmhetlic studies were initiated first. Synthesis of peptides The aim of peptide synthesis is to permit the building normally from the natural optically active cc-amino-acids of polypeptide chains of any desired length containing any desired range of component residues in any desired order racemisation of the components must be avoided. These are exacting requirements especially in view of the ion-dipolar properties of the amino-acids and peptides and completely satisfactory procedures have yet to be devised. (For reviews see Fruton Methods based on Y*NH*CHRWO*X + NH2*CHR2*C02Z " XYZ " Methods.-Fischer,l having achieved the first peptide synthesis in 1901 by preparing glycylglycine by partial hydrolysis of diketopiperazine in 1902-03 devised a scheme which generalised gives a plan of attack on the problem of stepwise synthesis of peptides which has formed the basis of most subse- quent work.The stages in the general synthesis of a dipeptide from the component amino-acids are (1) Synthesis of the " carboxyl component " in which the amino-group is protected and the carboxyl group modified for greater reactivity and S h a p i r ~ . ~ ) 'NHiCHR'CO; NHjCHR'CqNa a Y.NH-CHR'.C02H 3 Y NH.CHR'.COX +X (2) Synthesis of the " amino-wmponent " in which the amino-group is free and the carboxyl group masked i- N H,CH R2COi -%OE ZOH N H2-C H R2C02Z (3) Condensation followed by removal of Y and 7; Y-N H CH RI COX + N ~ C H R~.CO,Z Y.N H-CH R~-CO-NHCHR~-CO$ - + N H,. c H R' .CO. N H .CH R~-CO; J. S. Fruton Adv. Protein C'hem. 1949 5 1. R. L. Shapiro Chena. and Ind. 1952 1119. SPRINGALL AND LAW PEPTIDES 233 Provided that selective methods are available for the removal of the prot,ecting groups Y and Z the process can be extended so that in principle the protected polypeptide Y - N HCHR'CO. N H .CH R~-CO. - N H . c H R" CO,Z can be prepared and the last protecting groups Y and Z are then removed in a final stage. Reasonably suitable groups Z and X were already known and were early applied. Fischer used (i) Z = Na condensing the amino-component with the carboxyl component under Schotten-Baumann conditions and removing Z by acidification and (ii) Z = Me or Et condensing the amino-component as ester in an organic solvent with the carboxyl component in the presence of an organic base the Z group then being removed by careful hydrolysis e.g.by alkali in aqueous d i ~ x a n . ~ These esters can be prepared under mild conditlions but are not very reactive in the subsequent condensation and Fischer lb turned to the use of acid chlorides (X = Cl). These compounds though very reactive in the condensation have the dis- advantage of requiring strenuous conditions for their preparation. In 1902 Curtius 7 introduced his azide method (X = NJ the most attractive of t,he early methods. The group is readily introduced in aqueous media by the successive action of hydrazine and nitrous acid on the ester and is sufficiently reactive in the condensation which is usually performed on the amino-component! ester in an organic solvent.Suitable groups Y susceptible to specific removal in the later stages were much more difficult to find this proved the main initial problem so much so that thirty years elapsed before any large measure of success was achieved. (The emphasis of research has changed somewhat in recent years towards the study of new X and to a smaller extent Z groups.) The Y groups originally tried were carbethoxyl (Fischer) and benzoyl (Curtius) but all attempts to remove these groups by hydrolysis from the protected peptide led to the simultaneous hydrolysis of the peptide bond. At this stage (1903) Fischer and Otto * devised an alternative to the XYZ approach the cc-chloro-acyl chloride method of peptide synthesis.The method is only applicable to peptides with unreactive side chains R and has other drawbacks and though Fischer in 1907 used it to prepare an eighteen-residue p~lypeptide,~ it is of historical interest only. Fischer then turned again to the study of the potentially much more versatile XYZ method seeking Y groups which could be removed by other than hydrol-ytic means. In 1915 he lo found that a N-toluenesulphonyl group could be removed by reductive fission with hot hydriodic acid. The For the group X Fischer used ethoxyl initially. 5 Cf. (Sir) C. R. Harington and T. H. Mead Biochena. J . 1935 29 1602. 6 E. Fischer Ber. 1905 38 605. 7 T. Curtius Ber. 1902 35 3226. 8 E. Fischer and K. Otto Ber. 1903 36 2100. @ E. Fischer Ber.1907 40 1754. lo Idem. Ber. 1915 48 93. 234 QUARTERLY REVIEWS successful application of this discovery to peptide synthesis delayed by war and Fischer's death in 1919 was made in 1926 by Schoenheimer.11 The drastic conditions were a handicap to the reduction method in its original form.* The reductive removal of Y groups was studied by Bergmann and Zervas l3 who in 1932 achieved an advance of the highest importance by introducing the benzyloxycarbonyl group CH,Ph*O*CO* (often written CBz derived from the older terminology carbobenzyloxy) the group is removed by catalytic hydrogenation. This discovery opened a new phase in peptide synthesis. In its original form the process was not available for the prepara- tion of peptides containing cystine (or cysteine) because of the poisoning of hydrogenation catalysts by sulphur.This difficulty has been overcome in three ways two of which were quickly announced (i) Harington and Mead 5 in 1935 used phosphonium iodide ; (ii) Sifferd and du Vigneaud l4 in the same year showed that the benzyloxycarbonyl group could be removed gently and without side reactions by sodium in liquid ammonia ; (iii) much more recently ( 1952) Ben-Ishai and Berger 15 and independently Boissonnas and Preitner,16 have found that hydrogen bromide in cold acetic acid is a very good reagent for this purpose. The last method is very valuable when it is desired to remove the benzyloxycarbonyl group specifically from a compound Ph*CH,.O.CO* N H .CH R I .CO * N H * CH R2.C0$ to prepare the free amino-compound for use in further synthesis and when the group Z (e.g.benzyl see below) is liable to hydrogenolysis. Several modifications to the benzyloxycarbonyl group have been studied recently usually with a view to improving the solubility relations melting points and yields e.g. the 4-bromo- l7 and 4-nitro-benzyloxycarbonyl group,l89 l9 and the allyloxycarbonyl system.20 No extensive use has yet been made of the first and the last of these modifications but the nitro- derivative has been used l9 in devising an important technique for the preparation of the hitherto inaccessible arginyl peptides (see below). Ehrensvard 21 described a more distant variant of the benzyloxycarbonyl group the phenylthiocarbonyl group PhS*CO* removable by hydrolysis and 11 R. Schoenheimer 2. physiol. Chem. 1926 154 203. l2V. du Vigneaud and 0.K. Behrens J . BioZ. Chem. 1937 117 27. l3 M. Bergmann and L. Zervas Ber. 1932 65 1192. l4 R. H. Sifferd and V. du Vigneaud J . Biol. Chem. 1935 108 753. l6 D. Ben-Ishai and A. Berger J . Org. Chem. 1952 17 1564. l6 R. A. Boissonnas and G. Preitner Helv. Chim. Acta 1952 35 2240 (see also l7 D. M. Charming P. B. Turner and G. T. Young Nature 1951 167 487. ref. 39). F. H. Carpenter and D. T. Gish J . Amer. Chem. SOC. 1952 74 3818 ; 1953 75 950. 1s D. T. Gish and F. H. Carpenter ibid. p. 5872. zo C. M. Stevens and R. Watanabe ibid. 1050 72 725. 21 G. C. H. Ehrensvgrd Nature 1947 159 500. * In 1937 du Vigneaud and Behrens12 found that the N-toluenesulphonyl group could be smoothly removed from nitrogen by reduction with sodium in liquid ammonia, SPRINGALL AND LAW PEPTIDES 236 precipitation with cold aqueous-alcoholic lead acetate.The method has been severely criticised,22 however on the grounds that the removal pro- cedure leads to extensive formation of hydantoins. Though since 1932 studies of the Y group have largely centred on the benzyloxycarbonyl group several quite different systems have also been investigated. King et ~ 1 . ~ 3 and Sheehan et ~ 1 . 2 4 independently introduced and have since developed the use of the phthaloyl protecting group which is gently remov- able by hydrazine as phthalazide. (Schumann and Boissonas 25 suggested the use of phenylhydrazine.) Holley and Holley,26 advocate the use of (i) the chloroacetyl group removable by treatment with o-phenylenediamine and neutral hydrolysis cm> H (I) a) [to give (I)] and (ii) the o-nitrophenoxyacetyl group removable after reduc- tion by neutral hydrolysis [to give (II)].These are processes of consider- able promise. In 1953 Waley 27a and in 1954 King et al. 27b utilised in peptide synthesis the fact that the formyl group readily introduced by the direct action of formic acid on an amino-acid can be removed by treatment with hydrogen chloride in cold alcohol. (For a review of Y groups see ref. 28.) Y-X Groups joined in a Cyclic System. The first (1926) of these was the azlactone (oxnzolone) method due to Bergmann et al. 2*a who used compounds of type (111). Though important in its day this method has not been much used since the discovery of the benzyloxycarbonyl method. More likely to be of importance in the future is a series of newer methods based on the general tautomeric heterocyclic system (IV) where A and B may be oxygen or sulphur.These 4-substituted 2-hydroxy(or memapto)- oxazol-5-ones (or -thiazolones) have been much studied during the past 12 years mainly as a result of research on penicillin. They react with 22 A. Lindenmann N. H. Khan and K. Hofmann J . Amer. Chem. sbc. 1952 74 2 3 F. E. King and D. A. A. Kidd. Nature 1948 162 776 ; J. 1949 3316. s 4 J. C. Sheehan and V. S. Frank J . Amer. Chem. SOC. 1949 71 1856. 2 5 I. Schumann and R. A. Boissonnas Helv. Chim. Acta 1953 35 2235. z 6 R. W. Holley and A. D. Holley J . Amer. Chem. SOC. 1952 '74 3069. 27 (a) S. G. Waley Chem. and Ind. 1953 107 ; (b) F. E. King J W. Clark-Lewis D. A. A. Kidd and G. R. Smith J. 1954 1039. 28 R. A. Boissonnas and G. Preitner Helv. Chim. Acta 1953 36 875.Z E a M Bergmanil I?. Stern and C. Witte Annulen 1926 449 227. 476. 236 QUARTERLY REVIEWS amino-esters in the presence of triethylamine to yield open-chain com- pounds which can be decomposed to give peptide esters CH R I CH R I HN’ ‘C0.NH+CHR2*C02Et Hr’‘Co + NHiCHR2CqEt -+ tAe- +NHEt3 A=C-b CHR’ H2N’ ‘CO*NH*CHR2.C0,Et +CAB + NEt The first work of this kind was that of Heilbron and Cook and Levy,29 in 1949-50 working with A = B = S and achieving the decomposition witlli dry methanolic hydrogen chloride. With R1 other than H there is a danger of racemisation at position 4 and a tendency for the decomposition to regenerate the original mercaptothiazolone and amino-acid ester (see however Davis and Levy 30). Leggett Bailey 31 has obtained encouraging results wit,h the series A = B = 0 and A = S B = 0 while Khorana 32 has studied the series These methods t)hough promising (especially that with A = B = S and A = B = 0) have not yet been extensively used.Modern Work on X Groups. In nearly all work up to 1950 on stepwise peptide synthesis either acid chlorides (X = C1) or azides (X = N3) were used. Recently several important new X groups of a rather different type have been introduced. The system R*CO*X may be regarded as the mixed anhydride of the acids R*CO,H and HX and one of the most promising new lines consists in the replacement of the “ classical ” HX acids hydrochloric and hydrazoic by oxy-acids HO*X’ i.e. using the mixed anhydride Y*NH*CHRWO*O*X’ (for a review see ref. 33). Such a compound can react with the amino-component NH,*CHR**CO,Z in two ways to form (1) the desired dipeptide protected by both Y and Z together with HOX’ or (2) the “ moiiomers ” Y*NH*CHR1*CO,H and X’*NH*CHR2*C02Z.This makes critical the choice of suitable (a) X’ groups and ( b ) physical conditions. The first account (1934) of such X groups was by Bergmann et nl. 34 who used compounds of type (V) specifically anhydrides of benzylocarbonyl- A - 0 B = S . Ph-CH2*0 * C0.N H *CH (v) \c60 aspartic (n = 1) and -glutaniic acid (n = 2 ) . These react with amino- esters in organic solvents to give either or both of the possible products a- and p-aspartyl or cc- and y-glutamyl peptides depending on the conditions 29 (Sir) I. X. Heilbron J. 1949 2099 ; A. H. Cook and A. L. Levy J. 1950 64G 30 A. C. Davis and A. L. Levy J. 1951 2419. 3 1 J. Leggett Bailey J.1950 3461. 32 H. G. Khorana Chem. and Ind. 1951 129. 3 3 G. W. Kenner Chem. SOC. Special Publ. No. 2 1955 p. 103. 3 4 M. Bergmann and L. Zervas Ber. 1932 65 1192. 651. SPRINGALL AND LAW PEPTIDES 237 and on the nature of R2. Because of the ambiguity of the ring opening in the peptide coupling reaction these particular mixed anhydrides are not now used directly in peptide synthesis (though they have very important indirect uses-see below). Wieland and Seh1-ing,~5 in 1950 devised the first reasonably successful synthesis based on intermolecular mixed anhydrides using X = OBz ( i ~ mixed anhydrides with benzoic acid). They found that this system gave predominantly the desired protected dipeptide. Vaughan and his collaborators 36 have studied the variation of yields of the alternative products in the reaction between Y*NH*CHRWO*O*CO*R' and amines as a function of R' and recommend for peptide synthesis R' = Bui or OEt ie.mixed anhydrides with isovaleric acid or ethyl hydrogen carbonate. (The latter grouping was studied and advocated inde- pendently by Boissonnas 37 in 1951.) These two anhydride systems have been much used. With mixed anhydrides involving carboxylic components and incor- porating the system *CO.NH**CHR1*CO*OGO* there is grave danger of raceiii- isation at the a-position (marked with an asterisk) (see Vaughan 3 9 especially if the component is a peptide derivative Y*NH*CHR*CO*NH**CHR1*CO*OX' instead of a simple henzyloxycarbonylamino-acid compound. This is probably due 33 to the intervention of the reactions They usually give high yields.Mixed anhydrides with esters of inorganic polybasic acids capable of reaction in non-aqueous solvents with amino-acid esters have been recently discovered. This X group was introduced by Anderson Welcher and Young 39 in 1951 in the form of &ethyl chlorophosphite and was improved in the next year 40 by the use of tetraethyl pyrophosphite (EtO),P*O*P(OEt), as a source of the *O-P( OEt) fragment and of diethyl phosphite as a solvent for the reaction ; this con- stituted a very powerful method though one somewhat liable to racemise the carboxyl component. [Vaughan 41 suggested the corresponding group X = O*As(OEt), and Sheehan and Prank 4 2 have used a quinquevalent phosphorus derivative where X = *O*PO( O*CH,Ph),.] Some mixed anhydrides with polybasic inorganic acids having ionisable 35 T.Wieland and R. Sehring Annalen 1950 569 122. 36 J. R. Vaughan J . Amer. Chem. SOC. 1951 '93 3547 ; J. R. Vaughan and R. L. 1952 74 676. 37 R. A. Boissonnas Helv. Chim. Acta 1951 34 874. 38 J. R. Vaughan J . Amer. Chem. SOC. 1952 74 6137 ; J. R. Vaughan and J. A. Eichler ibid. 1953 75 5556. 39 G. W. Anderson A. D. Welcher and R. W. Young ibid. 1951 73 501 ; cf. G. W. Anderson J. Blodinger R. W. Young and A. D. Welcher ibid. 1952 74 5304 ; G. ?V. Anderson and R. W. Young ibid. p. 5307. The most important class have X = O*P(OEt),. Osato ibid. p. 5553; 40 G. W. Anderson J. Blodinger and A. D. Welcher ibid. p. 5309. 41 J. R. Vaughan ibid. 1951 73 1389. 4 2 J. C. Sheehan and V. S. Frank ibid. 1950 '72 1312. 238 QUARTERLY REVIEWS hydrogen atoms after anhydride formation have been examined recently since such compounds Y*NH*CHRWO*O*X"*OH are soluble in water and permit the peptide coupling reaction to proceed directly with an amino-acid (or peptide) in aqueous alkali ( i e .with Z = Na or another metal). This avoids the use of esterified amino-components and the necessity of subse- quent hydrolysis during which losses may occur.439 44 The first method (1949) of this kind was that of Chantrenne,45 who used X = *O*P*O(OPh)OH ; though his procedure for the introduction of the grouping was rather cumbersome and yields were not very high the method is of interest in that employing phosphoric esters and operating in water it may well be related to peptide biosynthesis. The second and more practicable synthesis of this type is due to Kenner and his ~ollaborators,~6 who employed X = *O*SO,-.This group is intro- duced by treating the lithium salt of the potential carboxyl component with the complex of sulphur trioxide and NN-dimethylformamide. The coupling Nl-$.CHR'.COi Li' + -C$S-O-CH=NMef - NHiCHR'*CDO*SO; Li+ t OHC-NMe reaction can be carried out with the free arnino-component in aqueous dimethylformamide but there is danger of (a) loss of yield by hydrolysis of the mixed anhydride and ( b ) racemisation. Both these difficulties can be avoided by working in anhydrous dimethylforrnamide and coupling to an amino-acid (or peptide) ester. Kenner and his ~ollaborators,~7 seeking X -groups capable of reacting with free amino-acids and peptides in aqueous solution but resistant to hydrolysis and to racemisation have developed an observation by Wieland et aZ.,48 that aryl thiolester groups will act as X groups X = *SPh (the use of cyanomethyl esters X = *O*CH,*CN has also been studied 49).Wieland used phenyl thiolesters prepared by the action of thiophenol on compounds Y*NH*CHR1*CO*O*COZEt. Kenner uses p-nitrophenyl thiolesters which because the p-nitro-group increases the acidity of the parent thiol react much faster with amino-compounds than do unsubstituted thiols and permit reaction in cold neutral aqueous dioxan. Preparation of the p-nitrophenyl thiolesters by the Wieland procedure gave a completely racemised product so an ingenious new method was devised employing tri-p-nitrophenyl phosphotrithioite in dimethylformamide which gives the tliiolesters of benzyloxycarbonylamino-acids (and -peptides) quantitatively and un - racemised-nor is there racemisation in the subsequent coupling reaction.This is a most promising line especially as the aryl thiolester group is 43 J. I. Harris and J. S. Fruton J. Biol. Chem. 1951 191 143. 4 4 C. W. Roberts J. Amer. Chem. Xoc. 1954 76 6203. 4 5 H. Chantrenne Nature 1949 164 576 ; Biochim. Biophys. Acta 1950 4 484. 46 G. W. Kenner and R. J. Stedman J. 1952 2069. 4 7 J. A. Farrington G. W. Kenner and J. M. Turner Chem. and Ind. 1955 601. 48 T. Wieland W. Schafer and E. Bokelmann AnnuZen 1951 573 99. 49 R. Schwyzer B. Iselin and M. Feurer Angew. Chem. 1954 66 747 ; Helv Chim. Acta 1955 38 83 1508, SPRINGALL AND LAW PEPTIDES 239 stable to hydrogen bromide in acetic acid which removes benzyloxycarbonyl groups. This is of importance in the preparation of cyclic peptides (see below).Sheehan and Hess 50 have condensed free carboxyl components with free amino-components in aqueous tetrahydrofuran in the presence of dicyclo- hexylcarbodi-imide which is converted into dicydohexylurea in the process. Khorana who had previously 51a noted the reaction of carbodi-imides with the carboxyl group of amino-acids and peptides in degradation experiments reports 51b that in independent studies of the synthetic procedure he finds that the products are contaminated by acylureas. The process has the advantage of aqueous conditions and freedom from racemisation. Methods based on X’*NH*CHR2*C02Z.-A variation on the general XU Z method has been developed recently. In this an X’ group which in the mixed oxyacid anhydride of the carboxyl component Y *NH*CHR’*CO*OX’ might promote peptide formation by the methods indicated above is instead linked amide-wise to the amino-group of the second component and allowed to react with a free carboxyl group in the first component Y.N He CH R’ C02H + X’- N H-C H R2-C0,Z -a Y.NH.CHR’-CO.NH. CH R?C02Z The first and still the most important example of this procedure was due to Anderson Welcher and Young,3g who in 1951 showed that their diethyl phosphite group could be used either as an orthodox mixed anhydride (see above) or as the amide (Et0)2P*NH*CHR2*C02Z (Vaughan used his diethyl arsenite grouping 41 similarly). By this modified procedure,4O with tetraethyl pyrophosphite the course of the condensation can be changed from an orthodox XYZ method [X = OX’ = *OP(OEt) ; “ anhydride pro- cedure ”] to an X’*NH*CHR2*C02Z method [X’ = *P(OEt) ; “ amide pro- cedure”] by varying the order in which the reagents are added to the diethyl phosphite medium.The great advantage of the “ amide procedure,” in this very important case is that in it the danger of racemisation at the C-terminal a-position of a peptide carboxyl component is reduced it is present if the corresponding “ anhydride procedure ’’ is used. (Because of tlhis du Vigneaud et aL52 used the “ amide procedure ” at two critical stages of the oxytocin synthesis; see below.) Goldschmidt and his school since 1952 have introduced two new groups related to the X’-N type ; these involve the use as the second component of compounds of the types (a) 53 a-cyanato-esters OCN*CHR2*C02Et and i b ) 5 4 following phosphorazo-compounds of type (VI).These are pB N * C H R2 *C02Et (v I) ‘ N H * CH R2 *C02Et 50 J. C. Sheehan and G. P. Hess J . Amer. Chem. SOC. 1955 77 1067. 51H. G. Khorana ( a ) J. 1952 2081; ( b ) Chem. and Ind. 1955 1087. 5 2 V. du Vigneaud C. Ressler J. M. Swan C. W. Roberts and P. G. Katsoyannis 5s S. Goldschmidt and M. Wick Annalen 1952 575 217. 64 S. Goldschmidt and H. Lautenschlager ibid. 1953 580 68 6 6 0. Suss {bid. 1951 572 96 J . Amer. Chem. SOC. 1954 76 3115. 240 QUARTERLY REVIEWS interesting new departures but the methods are not yet reliable in the matter of racemisation. North and Young 56 have studied racemisation of the carboxyl component in the synthesis of acetyl-L-leucylglycine ester in relation to the group X. The use of the small acetyl Y group makes the test very severe.They found extensive racemisation with X = C1 O*COBui and 0-P(OEt), and in the '' arnide-procedure " with X' = (EtO),P or phosphorazo. Coiifiguration was retained with the Curtius grouping (X = NJ. Modern Work on Z-Groups.-Bergmann,57 in 1936 wishing to ut,ilise the favourable solubility relations of the amino-esters and to avoid the hydrolysis (prone to side reactions 43y 44) needed with methyl and ethyl esters con- sidered the possibility of using benzyl esters and found that this group could be removed by catalytic hydrogenation. du Vigneaud and Behrens l2 showed in 1937 that such benzyl esters were also liable to reductive fission by sodium in liquid ammonia. Early developments were held up by poor yields in the preparation of the benzyl esters. Preparative methods have however been greatly improved recently,58 and the use of benzyl esters in this way is now extremely promising ; for example it permits a very clean final stage removal of Y and Z 4 4 with N-benzyloxycarbonyl-peptide benzyl esters.Use of Amino-Acids with Reactive Side Chains in Peptide Synthesis.- These amino-acids give rise to special problems in pept]ide synthesis. (i) Acidic side chains. (a) Glutamic acid. The difficulties arise when this substance is to be used as a carboxyl Component it is important Do be able to use either the a- or the y-carboxyl group unequivocally since both a- and y-glutamyl peptides are known in Nature. Peptide formation through the y-carboxyl group has been achieved by using benzyloxycarbonylglutamic anhydride which as Bergmann et al. 59 showed when treated with benzyl alcohol gives largely the a-monobenzyl ester leaving the y-carboxyl group free for reaction.This ester is obtained purer (Sachs and Brand 59a) from dibenzyl glutamate by partial reduction with hydrogen iodide in acetic acid to the a-monoester followed by N-benzyl- oxycarbonylation. Probably the best route to peptides using the a-carboxyl group of glutamic acid comes from an observation by King and his co-workers 6o several years ago that phthaloylglutamic anhydride on treatment with benzyl (or methyl) alcohol gives the y-ester leaving the a-carboxyl group free for reaction. 5sM. B. North and G. T. Young Chem. and Ind. 1955 1597. 57 See M. Bergmann L. Zervas and W. F. ROSS J. Biol. Chem. 1935 111 245. 58 H. K. Miller and H. Waelsch J. Amer. Chem. SOC. 1952 74 1092 ; D.Ben-Ishai and A. Berger J . Org. Chem. 1952 1'7 1564 ; B. F. Erlanger and R. M. Hall J . Amer. Chem. SOC. 1954 76 5781 ; J. D. Cipera and R. V. V. Nicholls Ghem. and Ind. 1955 16. 59 M. Bergmann L. Zervas and L. Salzmann Rer. 1933 66 1288. 59aH. Sachs and E. Brand J. Amer. Chem. SOC. 1953 75 4610. 6o F. E. King and D. A. A. Kidd J. 1949 3315 ; F. E. King €3. S Jackson and D. A. A. Kidd J . 1951 243. SPRINGALL AND LAW PEPTIDES 241 Le Quesne and Young 61 explored other routes leading to cc- and y- glut8aniyl peptides. They treated bensyloxycarbonyl glut amic anhydride with ethyl alcohol anti separntctl the resulting mixture of a- anti y-rnono- ethyl esters into its components by fractional extraction with aqueous alkali. They also prepared the y-monoethyl ester (by cold alcoholic hydro- gen chloride) and converted this into the y-azide for use in the synthesis of model peptides (Hegedus 63 had independently prepared the y-azide).Sachs and Brand 6 3 found however that the y-azide gave mixtures of a- and y-peptides. The y-amide of glutamic acid glutamine is of frequent occurrence in proteins and natural peptides and its incorporation in peptide synthesis is most important. Difficulties arise especially when it is necessary to use a glutamine residue as a carboxyl component. These have recently been overcome by Swan and du V i g n e a ~ d ~ ~ and independently by R ~ d i n g e r ~ ~ using the following processes which involve several stages previously studied by Harington and Moggridge.C6 N-Toluene-p-sulphonylglutamic acid on treatment with phosphorus pentachloride yields 5-oxo-l-toluene-p-sul- phonylpyrrolidine-2-carbonyl chloride (VII).This is used as the carboxyl component in a peptide synthesis giving the acylamino-acid (VIII) which on ring-opening with aqueous ammonia yields the toluenesulphonylglutaminyl peptide. The protecting group is then removed by sodium in liquid ammonia. This follows from the observation that by using controlled low temperatures it is possible to act upon glutamine hydrazide (available from the methyl ester) with nitrous acid without affecting the y-amide grouping. This makes it possible to use the benzyloxycarbonyl-azide method for glutamine peptides. ( b ) Aspartic acid. The problems here are similar to those encountered with glutamic acid. Unequivocal reaction through the P-carboxyl group can be achieved from the cc-benzyl ester prepared 59 by the action of the alcohol on benzyl- oxycarbonylaspartic anhydride.An equally clear-cut general route to reaction through the a-carboxyl group does not appear to have been described.68 61 W. J. le Quesne and G. T. Young J. 1950 1954 1959. 6 2 B. Hegedus Helv. Chim. Acta 1948 31 737. 63 H. Sachs and E. Brand J . Amer. Chem. SOC. 1954 76 1815. 6 4 J. M. Swan and V. du Vigneaud ibid. p. 3110. 6 6 J. Rudinger CoZZ. Czech. Ghem. Comm. 1954 19 235 244; J. Rudinger and 6 6 (Sir) C. R. Harington and R. C. G. Moggridge J. 1940 706. 67 $1. Sonciheimer and R. W. Holley J . Amer. Chena. SOC. 1954 76 2816. 6* W. I>. John and G. T. Young J. 1954 2870. Another route to glutamine peptides has been recently announced.6 H. Czurbova ibid. p. 286. 242 QUARTERLY REVIEWS The ,8-amide asparagine can be brought into normal peptide synthesis (du Vigneaud) either as an amino-c~mponent,~~ or as a carboxyl component in the presence of tetraethyl pyrophosphite without complicating reactions at the /3-po~ition.6~ The conditions for the isomerisation of esters of ct- and /?-asparty1 (and a- and y-glutamyl) peptides under alkaline hydrolysis have been stu~Iied.7~ (ii) Basic side chains.Complications arise if lysine is to be used as the cc-amino-component. It is then necessary to block the &-amino- group specifically. This was achieved by Bergmann Zervas and R o s s ~ ~ as early as 1935 using ae-dibenzenzyloxycarbonyl-lysyl chloride ; they took advantage of the tendency of a-benzyloxycarbonylamino-acid chlorides to lose benzyl chloride with the formation of hydroxyoxazolones yielding (IX) (a) Lysine.Ph- CHi OC0.N He[$ H2l4 CH HY’ ‘50 oc-0 N 0 2 * N H C * t j H HN4 qH21 Ph.CH;O*CO*N H .C He COX - (Ix) - (XI which can be readily hydrolysed to NB-benzyloxycarbonyl-lysine. (This pro- cess has been adapted by Synge 7 l for the ad-diamino-acid ornithine this substance though not a protein constituent is found in some natural peptides. ) “ Of the protein amino-acids arginine presents perhaps the greatest difficulties in peptide synthesis ’’ (Fruton 3). The main reason for this is the strongly basic 6-guanidino-group. This can be sufficiently masked by nitration to permit peptide coupling to the a-amino-group and the substituent nitro-group can be later removed with some difficulty by hydrogenation (Bergmann et al.72). Satisfactory means for the introduction of arginine into peptide synthesis as the carboxyl component have been much more difficult to find. The logical development in this connection from the discovery of the usefulness of nitro-arginine is the preparation of the substances of type (X). This route was impracticable for years because of the impossibility of converting Na-benzyloxycarbonyl-N&-nitroarginine into the corresponding acyl chloride or azide owing to complicating side reactions involving the guanidino- group. In 1953 however Hofmann Rheiner and Peckham 73 found that the mixed anhydride with ethyl carbonate could be formed and condensed with amino-acid esters. A different approach was realised by Gish and Carpenter l9 in the same year. They utilised the fact that the guanidino-group because of its strong basicity retains the positively charged unreactive guanidinium form under 69 V.du Vigneaud C. Ressler J. M. Swan C. W. Roberts and P. G. Katsoyannis J . Amer. Chem. SOC. 1954 ‘76 3115. 7 O A. R. Battersby and J. C. Robinson J . 1955 259. 7 1 R. L. M. Synge Biochem. J . 1948 42 99. 7 2 M. Bergmann L. Zervas and H. Rinke 2. physiol. Chem. 1934 224 40. 73 K. Hofmann A. Rheiner and W. D. Peckham J . Amer. Chem. SOC. 1953 75 (b) Arginine. 6083; 1956 78 238. SPRINGALL AND LAW PEPTIDES 243 alkaline conditions strong enough to break up the a-amino-carboxyl ion- dipole. The synthesis is carried out under carefully controlled alkaline CI-+H N x- +H*N\\C*NH * +c.NH H,N' I H2N' $HJ3 p 3 3 N Hi C H -C02Na N 0 i C,H,.CHiOCO- N H- CH COC I conditions i.e.with the salt (XI). This is converted into the Na-4-nitro- benzyloxycarbonyl derivative (yields in this case are much better than in the normal unsubstituted benzyloxycarbonyl method) with which thionyl chloride gives the chloride (XII). This reacts as a normal carboxyl com- ponent with amino-esters in dimethylformamide containing triethylamine. This process was later used by du Vigneaud Gish and Katsoyannis,T4 in the probable synthesis of the peptide hormone arginine-vasopressin (see below). The basic glyoxaline ring system does not interfere with the use of histidine methyl ester as an amino-component. Until 1954 however no satisfactory process had been found for using histidine as a carboxyl component owing to substitution and ring-opening side reactions Holley and Sondheimer,75 by a simple modification of standard procedure have succeeded in isolating Na- benzyloxycarbony1-L- histidine azide in good yield and in condensing it with amino-esters in ether ; careful hydrolysis and catalytic hydrogenation gave fully optically active L-histidyl peptides.Thiol and Disulphide Side Chains.-Preparative chemistry involving cystine (Cy*S*S*Cy) and cysteine (Cy=SH) has been clarified largely by the work of du Vigneaud and his collaborators during the past 25 years mainly by the use of the sodium-liquid ammonia reagent in which the following reactions have been achieved ( c ) Histidine. ( 1 ) 7 6 cy.s*s.cy ( l a ) 7 7 Reaction (1) can be (2) 7 6 Cy*SH + CH,PhCl (3) 78 Cy*S.CH,Ph (4) l2 p-C,H,Me-SO,.NHR (6) l4 CH,Ph*O*CO*NHR (6) l2 R*CO,*CH,Ph + 2Cy-SH (as Cy*SNa) reversed by aeration in aqueous solution.-+ Cy*S*CH,Ph -+ Cy-SH + PhMe + NH,R +p-C,H,Me.SH + NHzR + CO + PhMe --+ RCO,H + PhMe Reactions 1 la 2 and 3 make it possible to start from cysteine or cystine prepare the stable X-benzylcysteine carry out synthetic work with this and finally regenerate the cysteine or cystine residue at will. Cyclic Peptides.-Several natural peptides are cyclic without free terminal 7 4 V. du Vigneaud D. T. Gish and P. G. Katsoyannis J . A m e r . Chem. Soc. 7 6 R. W. Holley and E. Sondheimer ibid. p. 1326. 76 V. du Vigneaud L. F. Audrieth and H. S. Loring ibid. 1930 52 4500. 7 7 V. du Vigneaud and R. R. Sealock J . Pharmacol. Exp. Therap. 1934 54 433 ; 78 H. S. Loring and V. du Vigneaud J . BioZ. Chem. 1935 111 385. 1954 '76 4751. S. Gordon and V.du Vigneaud Proc. SOC. Exp. Biol. Med. 1953 84 723. 244 QUARTERLY REVIEWS a-amino- or a-carboxy-groups e.g. gramicidin-S a cyclic decapeptide containing a single thirty-atom ring system. Attempts to synthesise such cyclic peptiides have beeii iiiade and several cyclic tripeptides ~btained,'~ by methods depending on the idea that a peptide derivative of the type NH,*CHR1*CO***NH*CHRn*CO*X a t very high dilution is more likely to lose HX intramolecularly than intermolecularly. Such cyclotripeptides must have their amide groups in the unnatural cis-conformation. It is not until five residues are present that the natural trans-amide conformation can be retained on cyclisation. Kenner and his collaborators have therefore applied their methods to the synthesis of cyclic pentapeptides and recently announced 8o the successful preparation of cycloglycyl-L-leucylglycyl-L-leucylglycyl.The open-chain benzyloxycar- bonyl-pentapeptide was prepared by the sulphuric anhydride method and was converted into the p-nitrophenyl thiolester. The benzyloxycarbonyl group was removed without affecting the aryl thiolester group by hydrogen bromide in acetic acid and the resulting thiolester hydrobromide kept a t room temperature for 18 hours in an aqueous suspension of magnesium oxide. The cyclised pentapeptide was obtained after purification by counter-current distribution in 44% yield-a very remarkable achievement. cycloHexaglycy1 has been prepared during polyinerisation studies by Bamford and his colleagues 81 (see below). Examples of Syntheses of Natural Peptides.-The first important natural peptide to be synthesised was glutathione.This substance was isolated by Hopkins 8 2 in 1921 and its structure was determined by degradative studies notably by Quastel Stewart and Tunni~liffe,~~ and Kendall Mason and McKenzie ,8 as y -L-glutamyl-L- c ysteylglycine. The first synthesis was due to Harington and Mead,5 who used benzyl- oxycarboriylamino-acyl chloride-ethylamino-ester condensations working with cystyl and unprotected cysteyl residues and removing the benzyl- oxycarbonyl groups by phosphonium iodide. In 1936 du Vigneaud and Miller 85 carried out a second synthesis based on the same type of condensation but using cysteyl residues protected by S-benzylation which was effected in the sodium-liquid ammonia reagent. 79 R. A. Boissonnas and I. Schumann Helw.Chim. Acta 1952 35 2229 ; M. Winitz and J. S. Fruton J. Amer. Chem. Soc. 1953 75 3041 ; H. Brockman H. Tummes and F. A. von Metzsch Naturwiss. 1954 41 37 ; J. C. Sheehan and W. L. Richardson J. Amer. Chem. SOC. 1954 76 6329. J. A. Farrington G. W. Kenner and J. M. Turner Chem. and I n d . 1955 602. *1 D. G. H. Ballard C. H. Bamford and F. J. Weymouth Proc. Roy. SOC. 1954 A 227 155 ; D. G. H. Ballarcl and C. H. Bamford Chem. SOC. Special Publ. No. 2 1955 p. 25. 88 (Sir) F. G. Hopkins Biochem. J. 1921 15 286. s3 J. H. Quastel C. P. Stewart and H. E. Tunnirliffe ibid. 1923 17 580. s 4 E. C. Kendall H. L. Mason and B. F. McKenzie J. Bid. Chern. 1929 84 657 ; 85 V. du Vigneaud and G. L. Miller ibid. 1936 118 469. 1030 88 409. SPRINGALL AND LAW PEPTIDES 245 This reagent was also used for the reductive removal of both the benzyl- oxycarbonyl and the X-benzyl group.Hegedus 62 has described another synthesis using a bznzyloxycarbonyl- aminoacylazide procedure and recently Rudinger and Sorm 86 have used anhydro-X-benzyl-N-carboxycysteine and Goldschmidt and Jutz 87 the cyanato- and the phosphorazo-method in further glutathione syntheses. A more complex natural peptide to which a synthetic approach has been made is the antibacterial substance gramidicin-S. This was isolated by Gause and Brazhnikova 88 in 1943. Degradative structural studies (Consden Gordon Martin and Synge sg) and molecular-weight measure- ments indicat'e that the substance is the cyclodecapeptide (XIII). Harris and Work go succeeded in preparing the corresponding open- chain pentapeptide by using the orthodox benzyloxycarbonylamino-azide route.Schumann and Boissonnas91 also report the preparation of this pentapeptide using the mixed anhydride with ethyl hydrogen carbonate throughout ; it appears very probable that considerable racemisation occurred in this synthesis. Erlanger Sachs and Brand 9 2 have succeeded in the remarkable task of preparing the corresponding open-chain decapeptide L-valyl-L-ornithyl-L- leuc yl-D - phenylalanyl-L- pr olyl-L-valyl- L- ornithyl-I,-leuc yl-D - phenylalan yl -I,- proline. They used the carbonate mixed anhydride method for dipeptide intermediates only reserving the azide route for higher peptides to avoid iacemisation. It would be very interesting to see if this decapeptide could be cyclised by the new Kenner procedure. The most remarkable achievement so far attained in this field is the synthesis of the peptide pituitary hormone oxytocin by du Vigneaud and his collaborator^,^^^ g4 announced in 1953 and fully reported in 1954 (for a review see ref.95). The isolation of the pure natural product and the degradative studies J. Rudinger and 3'. sorm CoZZ. Czech. Chem. Comm. 1951 16 214. S. Goldschmidt and C. Jutz Chem. Ber. 1953 86 1116. 88 G. F. Grause and M. G. Brazhnikova " Sovyetskii Gramitsidin i Lecheniye Ran " 89 R. Consden A. H. Gordon A. J. P. Martin and R. L. M. Synge Biochem. J. 2d. P. G. Sergier MOSCOW 1943. 1946 40 xliii; 1947 41 596. J. I. Harris and T. S. Work ibid. 1950 46 196 582. 911. Schumann and R. A. Boissonnas Helv. Chim. Acta 1952 35 2237. 92 B. F. Erlanger H. Sachs and E. Brand J . Amer. Chem.Soc. 1954 78 1806. 93 V. du Vigneaud C. Ressler J. M. Swan C. W. Roberts and P. G. Katsoyannis ibid. 1953 75 4879. 9 * C. Ressler and V. du Vigneaud ibid. 1954 76 3107; J. M. Swan and V. du Vigneaud ibid. p. 3110 ; P. G. Katsoyannis and V. du Vigneaud ibid. p. 3113 ; V. du Vigneaud C. Ressler J. M. Swan C. W. Roberts and P. G. Katsoyannis ibid. p. 3115. 95 V. du Vigneaud Chem. SOC. Special Publ. No. 2 1955 p. 49. Q 246 QUARTERLY REVIEWS carried out in du Vigneaud's laboratory indicated that the substance is a nonapeptide amide containing a 20-atom " loop " closed by a cystine disul- phide bridge (XIV). The three peptide derivatives (all in the L-configura- tion) S-benzyl-N-carbobenzyloxycysteyltyrosine (XV) N-toluene-p-sul- phonylisoleucylglutaminylasparagine (XVI) and S-benzylcysteylprolyl- leucylglycine amide (XVII) were prepared a wide range of techniques being NHZ CH,-C,H,*OH CH,.CH.co.NH.dH.CO.NH.CH.cH~~~~ I S I CO C ~ z ~ ~ ~ ~ N H ~ ~ ~ ~ ~ ~ ~ N H I I NH (x!v) I S I CH2-C0.NH I I co CH2-N CH*C0.NH*CH*CO*NH*CH2-C0.NH I CHZ-cH,> Bui CH2Ph*O-CO-NH CH,*C,H4*OH I I (XV) CH,.CH.CO.NHCHCO,H TosylNHBCHCHMeEt I I I co S*CH2Ph S*CH2Ph NH I (XW H02CCH-NH*COCH*[CH2-J2*C0.NH I CHZ I I I I CH*NH CO I CH2-N (XVII) I )CH-CO*NH*CHC0.NH.CH2-CO*NH2 used.Peptide linkage between the last two was effected by the tetraethyl pyrophosphite " amide procedure ". The N-toluene-p-sulphonyl and the X-benzyl group of the resulting protected heptapeptide were removed and the X-benzyl group replaced all in the sodium-liquid ammonia reagent and the product was condensed (again by the tetraethyl pyrophosphite " amide procedure ") with the dipeptide (XV).Protecting groups were removed as before and the disulphide bridge was formed by aeration. The identity of the synthetic material with the natural hormone was rigorously proved by physical chemical and biological tests.* Chim. Acta 1955 38 1491. I Bui CHZ-CHZ 950R. A. Boissonnas St. Guttmann P.-A. Jaquenoud and J.-P. Waller Helv g 5 b J. Rudinger J. Honzl and M. Zaorat Coll. Czech. Chem. Comm. 1956 21 202. * A second synthesis has just been announced 954 which makes extensive use of N and .OCO,Et groups and of removal of benzyloxycarbonyl groups by hydrobromic acid in acetic acid. A third is due to Rudinger and his collaborators.'J5~ SPRINGALL AJSD LAW PEPTIDES 247 The probable synthesis of two other peptide pituitary hormones closely related to oxytacin has been announced from du Vigneaud’s laboratory namely lysine-vasopressin 96 (differing from oxytocin in having phenyl- alanine for isoleucine and lysine for leucine) and arginine-vasopressin 7 4 (differing from lysine-vasopressin in having arginine for lysine).Full details are not yet available (cf. du Vigneaud 97). The 20-atom “loop ” of a-amino-acid residues closed by the cystine disulphide bridge is also an important feature of the insulin monomer ( M 6000) elucidated by degradative studies by Sanger et aLg8 It is possible now to think of planning a synthetical attack upon this important protein molecule (see Harington and du Vigneaud 99). Polymerisation Techniques in Polypeptide Synthesis.-Stepwise synthesis of peptides becomes increasingly difficult as the number of amino-acid residues in the polypeptide increases.Polypeptides of high molecular weight (- 10,000) have however been synthesised by polymerisation techniques starting with monomers based on either single amino-acids or di- or tri-peptides. Such processes are not likely to lead to proteins or natural higher peptides because in these substances the peptide chains comprise wide ranges of‘ kinds of a-amino-acids and the various residues are arranged along the chains in highly specific and complicated orders. Polymerisation syntheses have most usually been applied to single kinds of amino-acid residues giving polypeptide chains comprising residues of only one kind (e.g. polyglycyl- glycine) . Even when co-polymerisation techniques are invoked permitting the incorporation of several kinds of residues in a polymer there is no control of the order in which they are assembled along the resulting chain.Polymer- isation based on di- or tri-peptide monomers only permits the assembly of two or three kinds of residues in the simplest possible order. Despite this limitation polymerisation techniques have been of great importance in the preparation of polypeptide model substances of high molecular weight which closely resemble fibrous proteins. The study of the physical proper- ties of these polymers especially their X-ray diffraction and infrared absorp- tion has greatly helped the elucidation of the structure of the native proteins. The following polymerisation processes have been used (for a review up to 1951 see Katchalski loo).(a) Methods based on amino-acid monomers. Leuchs lol (1906-08) O 6 V. du Vigneaud H. C. Lawler and E. A. Popenoe J . Amer. Chem. SOC. 1953 97 V. du Vigneaud Chem. SOC. Special Publ. No. 2 1955 p. 66. 98 F. Sanger and H. Tuppy Biochem. J. 1951 49 481 ; F. Sanger and E. 0. P. Thompson ibid. 1953 53 353 366 ; A. P. Ryle F. Sanger L. F. Smith and R. Kitai (bid. 1955 60 541 ; H. Brown F. Sanger and R. Kitai ibid. p. 556. 99 (Sir) Charles Harington Chem. Xoc. Special Publ. No. 2 1955 p. 64; V. du T’igneaud ibid. p. 65. loo E. Katchalski Adv. Protein Chem. 1951 6 123. lol H. Leuchs Ber. 1906 39 857 ; H. Leuchs and W. Manasse Ber. 1907 40 3235; H. Leuchs and W. Geiger Ber. 1908 41 1721. 75 4880. 248 QUARTERLY REVIEWS obtained a polyglycine by the annexed route via anhydro-N-carboxygly- cine ; the first step giving " anhydro-N-carboxyglycine " (2rhydroxyoxazol- 5-one) is effected by heat and the second in the presence of an amine and a trace of water.The process was further studied by Curtius lo2 and by Wessely lo3 and their collaborators and was being developed by Robinson Goldsworthy and Springall in 1938-39. Woodward and Schramin lo4 later used the method to produce co-polymers of leucine and phenylalanine. Since 1948 this method has been developed largely by workers of Courtauld's research group into the most important of the polymerisation techniques. A standard procedure for working in nitrobenzene solution has been de- vised,loS and the kinetics of the reaction have been studied.1°6 Initiation of polymerisation of anhydro-N-carboxyainino-acids by alkali halides (in- stead of organic bases) leads to polymerisation by a different mechanism and yields cyclic peptides (see Bamford and his collaborators *l).Bresler and Selezneva lo7 have reported a novel preparation of a poly- alanine by treating lactamide with sodium n H0.CHMe.C0.NH2 -*"" [.CH MeC0.N ti.], and Noguchi lo8 has found that amino-acids N-substituted by the Ehrens- vard phenylthiocarbonyl group 21 can be made to undergo polycondensation with the elimination of thiophenol and carbon dioxide nPhS-CO-NH-CHR'*C02H - [-NH*CHR'-CO*] + nPhSH + L O 2 (b) Methods based on di- and tri-peptide monomers. In 1906 Fischer 109 noted that when glycylglycylglycine methyl ester is heated it yields by elimination of methyl alcohol the hexapeptide pentaglycylglycine methyl ester.Similar results were obtained on using alanylglycylglycine ester. Pacsu and Wilson 110 showed that on prolonged heating the reaction goes further to give polypeptides by repetition of the tripeptide sequence. The kinetics of the process have been studied by Rees Tong and Young.lll l 0 2 T. Curtius and W. Sieber Ber. 1922 55 1543. l o 3 F. Wessely 2. physiol. Chem. 1926 157 91 ; F. Wessely and F. Sigmund ibid. lo4 R. B. Woodward and C. H. Schramm J . Amer. Chem. Soc. 1947 69 1551. l o 5 W. E. Hanby S. G. Waley and J. Watson J. 1950 3009. 106 S. G. Waley and J. Watson Proc. Roy. SOG. 1949 A 199 499 ; D. G. H. Ballard lo7 S. E. Bresler and N. A. Selezneva Zhur. obshchei Khim. 1950 20 356. 108 J. Noguchi and T. Hayakawa J . Amer. Chem. Xoc. 1954 76 2846. 109 E. Fischer Ber. 1906 39 471.1l0 E. Pacsu and E. Wilson jun. J. Org. Cherrt. 1942 7 117 126. 111 P. S. Rees D. F Tong and G. T. Young J. 1954 662. 1927 159 102; 170 167. and C. H. Bamford ibid. 1954 A 223 495. SPRIRGALL AXD LAW PEPTIDES 249 Magee and Hofmann l 1 2 found that when the hydrazide of glycylglycyl- glycine is treated with nitrous acid the corresponding azide is produced in good yield without complicating side reaction at the free N-terminal a- amino-group. Treatment of the azide with alkali leads by the elimination of hydrazoic acid to polycondensation. Polycondensations corresponding to those with the above tripeptide derivatives have recently been observed with dipeptide chlorides 113 and under the influence of the enzyme cathepsin-C with dipeptide amides,llP while Noguchi 108 and Hayakawa successfully applied their method to dipeptide as well as amino-acid monomers.A synthetic polymer material which though not containing the polypep- tide system nevertheless has remarkable resemblances to some proteins is the p l y -N-vinylpyrrolidone (XVIII) synthesised during the war by H2C-CH H2k t0 --c ‘ty’ CH H2C4 Reppe.l15 This substance has been successfully used as a blood-plasma protein substitute in blood transfusion and in prolonging the effect of e.g. insulin and penicillin. Degradation of peptides terminal residue studies The sequence of the amino-acid residues in polypeptide chains has a profound effect on physical and physiological properties. The sequences in nat’ural substances are highly specific follow no known laws and must be determined experimentally.There are indications that the N-terminal are more important than the C-terminal sequences for biological activity. The residue sequence in a single polypeptide chain of any length could in principle be determined by the repeated application of a single efficient process for the removal and identification of either the N - or the C-terminal residue. In practice it is not feasible to carry out the complete stepwise degradation of a long polypeptide chain in this way even employing both N- and C-residue studies because of the cumulative effect of incomplete reaction. Such a polypeptide must first be partially hydrolysed to oligo- peptides these separated and individually subjected to sequence determina- tion and the results pieced together to give the structure of the original long chain.A further difficulty often arising is that the molecules of many proteins are composed of several long polypeptide chains cross-linked e.g. by -S-S-bridges. In such cases the cross linkages must be broken and the individual long polypeptide chains separated as a first step to degradative 112 M. Z. Magee and K. Hofmann J. Arner. Chem. SOC. 1949 71 1515. 114 J. S. Fruton W. R. Hearn V. M. Inpam D. S. Wiggans and M. Winitz J. Biol. 115 See B.I.O.S. Final Report No. 354 1945 item 22. M. Frankel Y. Liwschitz and A. Zilka ibid. 1954 76 2814. Chem. 1953 264 891. 250 QUARTERLY REVIEWS studies. These necessary and very difficult preliminary tasks are outside the scope of the present discussion which is confined to terminal residue studies.ll6 The chemical methods involve (i) modification of the terminal residue to differentiate it and if possible to render labile the amide bond joining it to the adjacent residue ; (ii) breaking of this amide bond ; and (iii) isolation and identification of the modified terminal residue.Only if the conditions in stage (ii) can be such that the other peptide bonds are unaffected can the process be repeated on the same specimen. The conditions in stage (i) must not cause any peptide bond fission or promote rearrangement of residues in the chain. Yields should be quantitative. These requirements are difficult to meet. The development of methods has so far been more successful for N- than for C-terminal residues. The enzymic methods depend on the existence of exopeptidases,l17 en- zymes catalysing specifically the hydrolysis from peptides of terminal resi- dues.These are classified according to their N - or C specificity as amino- or carboxy-peptidases. Their use gives in principle the most attractive method of terminal-residue identification. No preliminary chemical modi- fication of the peptide is needed and the cleavage of the terminal residue is done under the mildest conditions and is progressive as the enzyme oper- ates on the shortened residual peptide. The difficulties are practical for such work the enzyme should be quite homogeneous free from any other enzymes or even inactive proteins. This is in general extremely difficult to achieve. Moreover the enzyme should be rigidly specific to N - or to C-terminal residues and should show (i) no endopeptidase 117 activity (hydrolysis of peptide bonds remote from the chain ends) (ii) no tendency to promote transpeptidation (synthesis of new peptide bonds) (iii) no R-side-chain specificity (the rate of hydrolysis of the terminal residue should be independent of its nature).No actual amino- or carboxy-peptidase preparations are completely satisfactory in all these respects least so with regard to side-chain specificity though modern techniques have permitted the production of carboxy- and more recently amino-peptidase in a highly homogeneous pure form. N-Terminal Residue Studies.-The two most important current methods are chemical Sanger’s N-2 4-dinitrophenyl (DNP) method and Edman’s phenylthiohydantoin (phenyl isothiocyanate) method. The recent isolation of amino-peptidase in a state of high purity (Smith and his co-workers 11*) makes its use in N-terminal residue studies likely to become important.(a) DNP method When an amino-group is exposed t o the action of l-fluoro-2 4- 116 Reviews S. W. Fox A d v . Protein Chem. 1945 2 155 ; F. Sanger ibid. 1952 7 2 ; P. Desnuelle Adw. Enzymology 1953 14 278 ; H. Fraenkel-Conrat J. I. Harris and A. L. Levy in “Methods of Biochemical Analysis ” ed. D. Glick Interscience Publ. New York 1954 Vol. 11 p. 359 ; &I. Rovery and P. Desnuelle Bull. Xoc. China. biol. 1954 36 No. 1 p. 95 ; M. Jutisz ibid. p. 109. These are of two types chemical and enzymic. (a) Chemical methods involving total hydrolysis in stage (ii). 117 See H. Neurath and G. W. Schwert Chem. Rev. 1950 46 69. P. H. Spackman E. L. Smith and D. M. Brown J. Bid. Chem. 1956 212 255 ; E. L. Smith and D.PI. Spackman ibid. p. 271. SPRINGALL AND LAW PEPTIDES 251 dinitrobenzene (FDNB) under mild alkaline conditions it reacts almost quantitatively to form the bright yellow 2 4-dinitrophenyl (DNP) deriva- tive. The resulting Ar-N bond is very stable under acid hydrolytic con- d i t i o n ~ . ~ ~ ~ (Probable forerunners of the DNP method were the use in peptide acylation of l-chloro-2 4-dinitrobenzene 120 and 2 3 4-trinitrotoluene,~~~ which require strenuous conditions and do not give quantitative results.) When a peptide is treated with l-fluoro-2 4-dinitrobenzene and later hydrolysed then any side-chain reactions being neglected the resulting mixture consists of the dinitrophenyl derivative of the N-terminal amino- acid together with the other component amino-acids. The dinitrophenyl- amino-acid is usually separated by extraction with an organic solvent identified (by control hydrolysis and partition chromatography if necessary) and estimated by means of its strong ultraviolet absorption at - 350 mp.Reactive R-side-chains may cause complications. In these chains amino-groups give dinitrophenyl derivatives thiol groups react in a com- plex manner (in sequence work involving cystine-cysteine residues these must be kept in the disulphide cystine state or further oxidised to cysteic acid CySO,H) phenolic hydroxy-groups give dinitrophenoxy-derivatives which are fortunately colourless and the cyclised side-chain and amino- system in dinitrophenylproline shift the strong absorption region to -390 mp. Porter and Sanger,lz2 and Levy and Chung,lZ3 have studied the condi- t'ions and corrections needed for the preparation and hydrolysis of dinitro- phenyl-peptides.Sanger and Tuppy 124 have described the separation and clstimation procedure (two-dimensional paper chromatography) developed for the successful insulin sequence investigation ; and Levy 125 has given ;m account of a somewhat different technique employing the same principle later used on a-corticotropin. The outstanding successes of the dinitrophenyl method are in the sequence tleterminations in insulin B-chain 126 (30 residues) A-chain 127 (21 residues) oxytocin 12* (9 residues) and a-corticotropin lz9 (39 residues). This is closely related to the dinitrophenyl method. The peptide is acylated by the radioactive p-iodo- phenylsulphonyl group p-1311-C6H4*SOz* introduced as the chloride.The (B) p-Iodophenylsulphonyl method. 130 119 F. Sanger Biochem. J. 1945 39 507. 1 2 0 E. Abderhalden and W. Stix 2. physiol. Chem. 1923 129 143. 121 G. Barger and F. Tutin Biochem. J. 1918 12 402. 122 R. R. Porter and F. Sanger ibid. 1948 42 287 ; R. R. Porter in " Methods of RIedical Research " ed. R. W. Gerard Year Book Publ. Chicago 1950 Vol. 111 p. 256. 123A. L. Levy and D. Chung J . Amer. Chem. Xoc. 1955 77 2899. 12* F. Sanger and H. Tuppy Biochem. J. 1951 49 463. 125 A. L. Levy Nature 1954 174 126. 1 2 6 F. Sanger and H. Tuppy Biochem. J. 1951 49 481. lZ7 F. Sanger and E. 0. P. Thompson ibid. 1953 53 353 366. lZ8 H. Tuppy Biochim. Biophys. Acta 1953 11 449. l 2 8 C. H. Li I. I. Geschwind R. D. Cole I. D. Raacke J. I. Harris and J. S. Dixon 130 S. Udenfrieiid and S.I?. Velick J . Biol. Chem. 1951 190 733 ; 13* R. E. Bowman J . 1950 1349. h-ature 1955 176 687. 191 233. 252 QUARTERLY REVIEWS resulting sulphonamide is stable to acid hydrolysis and the acyl derivative of the N-terminal amino-acid can be detected by its radioactivity and estim- ated by the isotope-dilution procedure. However the method seems t o give rather low results. N-Terminal amino-groups can be dimethylated by treatment with aqueous formaldehyde and simultaneous catalytic hydro- genation. 131 After hydrolysis the NN-dimethylamino-acid can be separated by partition chromatography the lack of reaction with ninhydrin being used for detection.132 Several techniques involving the drastic step of cleaving the N-C bond in the N-terminal residue have been described. The following reagents have been used hypobromous acid ; 133 nitrous acid ; 83 nitrosyl chloride ; 134 ninhydrin then hydrogen peroxide-vana- dium pentoxide.135 Side reactions usually occur.Extensive use of these methods seems unlikely. (cc) Phenylthiohydantoin (PTH) method. Edman 136 showed that when a peptide is treated with phenyl isothiocyanate at pH 9 the phenylthiocarbamoyl (PTC) derivative of the N-terminal amino- group is formed. On treatment with hydrogen chloride in nitromethane or better acetic acid or with 0-1N-hydrochloric acid at 750,137 the N-terminal residue is cleaved specifically from the peptide as the 5-R1-3-phenyl-2- thiohydantoin. The reactions are virtually quantitative. The cyclisation may be followed by the shift of the ultraviolet absorption maximum from 240 (phenylthiocarbamoyl-peptide) to 270 mp (phenylthiohydantoin).138 ( y ) Methylation method. (6) Deamination methods. (b) Xtepwise chemical methods. PhNCS + NHiCHRk0.N H-C HR2.C0- N H.CHRm-C02Na Ph-NH-CS-N H -CH R k 0 . N H .CHR*CO*.*.*- N H-C H dLCq2Na The thiohydantoin and the shortened peptide can be separated by partition between organic and aqueous solvents. The thiohydantoin may be identified by hydrolysis by baryta 136 or acid 139 to the amino-acid or by direct paper chromatography spots being located by suppression of the l32V. M. Ingram J . Biol. Chern. 1953 202 193. 133 S. Goldschmidt E. Wiberg F. Nagel and K. Martin Annalen 1927 456 1 ; 134 R. Consden A. H. Gordon and A. J. P. Martin Biochem. J. 1947 41 590. 135 F. Turba in " The Chemical Structure of Proteins " ed. G. E. W.Wolst.enholme 1 3 6 P. Edman Acta Chem. Scand. 1950 4 283 ; 1953 '7 700. 13' M. Ottesen and A. Wollenberger Nature 1952 170 801 ; Compt. rend. Frau. 138 B. Dahlerup-Peterson K. Linderstrcam-Lang and M. Ottesen Actu Chem. Scand. 139 A. L. Levy Biochim. Biophys. Acta 1954 15 589. S. Goldschmidt and K. Strauss ibid. 1929 471 1 ; Ber. 1930 63 1218. and M. P. Cameron Churchill London 1953 p. 142. Lab. Carlsberg 1953 28 463. 1952 6 1135. SPRISGALL -4ND LAW PEPTIDES 253 starch-iodine colour,l or by the colour reaction with Grote’s solution. 141 The residual shortened peptide may be subjected to a second degradation. A general Edman procedure applicable to all common amino-acids save perhaps cystine on a microscale has been worked out by Fraenkel-Conrat and Harris.142 Notable achievements of the method are in the sequence determinations on o ~ y t o c i n l ~ ~ arginine- and lysine-vasopressin 144 (each of 9 residues) ~ - ~ 2 9 and /?-corti~otropin,l~~ and ~orticotropin-A,~~6 (each of 39 residues) Fox and his collaborators 147 have used the phenyl isothiocyanate (and isocyanate) reaction followed by complete hydrolysis of the phenylthio- carbamoyl-peptide to the thiohydantoin and residual amino-acids.The latter are subjected to bioassay in which the thiohydantoin is inert. Com- parison with a bioassay on the hydrolysate of the unsubstituted peptide identifies the N-terminal residue. The process seems rather laborious but has been used in studies on various corticotropin fractions 147 and on 1 ysoz yme. 148 Replace- ment of Edman’s phenyl isothiocyaiiate by the coloured 4-dimethylamino- 3 5-dinitrophenyl isothiocyanate has been investigated ; 149 so has the use of 3 - unsubst it ut ed derivatives.50 The forerunner of the Edman procedure was the early use of phenyl isocyanate which reacts with a peptide to form the phenylcarbamoyl deriva- tive from which t4he ilr-terminal residue is removed as the 3-phenylhydantoin (0) Ot’her methods based on thiohydantoins and hydantoins. ( XIX) .151 CHR‘ ~ t $ \co 0 1 + +NH;CHR~-CO; OC- NPh CHR’ HY’ ‘70 ,R‘ OC-N-CH 140 J. Sjoquist Acta Chem. Scand. 1953 7 447. 141 W. A. Landmann M. P. Drake and W. F. White J . Amer. Chem. SOC. 1953 142 H. Fraenkel-Conrat and J. I. Harris ibid. 1954 76 6058. 143 V. du Vigneaud C. Ressler and S. Trippett J . Biol. Chem. 1953 205 949. 144 E. A. Popenoe and V. du Vigneaud ibid.p. 133. 145 P. H. Bell J . Amer. Chem. SOC. 1954 76 5565. 146 W. F. White and W. A. Landmann ibid. 1955 77 1711. 147 S. W. Fox T. L. Hurst and K. F. Itscher ibid. 1951 73 3573 ; S. W. Fox 14* D. de Fontaine and S. W. Fox ibid. p. 3701. 149 W. S. Reith and N. M. Waldron Biochem. J. 1954 56 116. 150 D. T. Elmore and P. A. Toseland J. 1954 4533. IS1 M. Bergmann A. Miekeley and E. Kann Annalen 1927 458 56 ; E. Abder- halden and H. Brockmann Biochem. Z. 1930 225 386. 75 3638. T. L. Hurst and C. Warner ibid. 1954 76 1154. 254 QUARTERLY REVIEWS The generation from peptides of hydantoins 3-substituted by other groups (e.g. the coloured p-phenylazophenyl and 4-dimethylamino-3 5- dinitrophenyl group 153) has also been studied. The N-terminal and the adjacent residue can be split from an ethoxycarbonyl peptide as the 3-hydantoinylacetic acid derivative (XX) .l 54 The final identification of the N-terminal residue seems ambiguous however.Levy 155 noted that when salts of N-dithiocarboxy-peptides were acidified the R1- residue tends to be split off as the 4-R1-2-mercaptothiazol-5-one (XXI) which could be extracted by organic solvents for regeneration and identifica- tion of the amino-acid. (7) Methods based on mercapto- and hydroxy-thiazolones. CH R' HY' 'FO sc-s I . o(x 1) (XXII) H Kenner and Khorana I56 carried out a similar process via the 4-R1-2- hydroxythiazol-5-one. (6) Methods based on tetrahydro-oxoquinoxalines. Holley and Holley lS7 treated peptides with methyl 4-fluoro-3-nitrobenzoate reduced the product catalytically and cleaved the N-terminal residue by cold hydrochloric acid as the quinoxaline derivative (XXII).A similar process has been carried out on dinitrophenyl-peptides. 58 None of these chemical methods other than the Edman method has been widely used. (c) Enzymic method. The recent isolation of highly purified amino- peptidase froin pig kidney 118 may well open a new phase in the study of N-terminal residues. The enzyme does show marked side-chain specificity e.g. glycine serine and glutamic acid are split off very slowly but has already been used on corticotropin-A.159 This work has shown the critical importance of the N-terminal sequence €or the biological activity of this hormone. C-Terminal Residue Studies.-The most important method is that based on the use of carboxypeptidase. Many chemical methods have been described none of them is yet really satisfactory; probably the most promising is the modern version of the Schlack-Kumpf thiohpdantoin process.152 F. Turba ref. 135 p. 143. 153 G. G. Evans and W. S. Reith Biochem. J. 1954 56 111. 154 F. Wesseley K. Schlogl and G. Korger Nature 1952 169 708; Monatsh. 1952 83 1157. 155 A. L. Levy J. 1950 404 ; J. LBonis and A. L. Levy Bull. SOC. Chim. biol. 1951 33 779 ; J. LBonis and A. L. Levy Compt. rend. Trav. Lab. Carlsberg 1954 29 57 87; A. L. Levy and Si-Oh Li ibid. p. 127. 156 H. G. Khorana and G. W. Kenner J. 1952 2076. 15' R. W. Holley and A. D. Holley J . Amer. Chem. SOC. 1952. 74 1110. 15* M. Jutisz Bull. SOC. Chim. biol. 1954 36 p. 108. lSB W. F. White and W. A. Landmann J . Amer. Chem. SOC. 1955 7'7 1711 ; K. Hofmann and A. Johl ibid.p. 2914; Mi. F. White ibid. p. 4691. SPRINGALL AND LAW PEPTIDES 255 Enzymic method. Highly purified crystalline carboxypeptidase from ox pancreas has been available for some years.lGO Dangers of contamina- tion by endopeptidases have been overcome by the observation 161 that carboxypeptidase activity is not affected by diisopropyl phosphorofluoridate which inhibits the activity of pancreatic endopeptidases. This enzyme gives the best current method for specific cleavage of a C-terminal residue (for reviews see refs. 117 162) ; subsequent identification of the residue is made either on the free amino-acid or on its dinitrophenyl derivative. It has the drawback of marked side-chain specificity. Fission is fastest with aromatic Rn-side-chain residues is very slow with basic or acidic residues and does not occur with proline; moreover the enzyme is without action on C-terminal residues in the amide form as in oxytocin and the vasopressins.The enzyme has been used in studies of residue sequence on e.g. insulin,163 a- 129 and @-corticotropin,14j corticotropin-A,146 and tobacco mosaic virus.ls4 In all cases studied so far the loss of the C-terminal residue does not impair biological activity l G 2 ChemicaE methods. ( a ) Thiohydantoin method. Schlack and Kumpf 165 showed that when an acylpeptide is treated with hot acetic anhydride and ammonium thiocyanate it is converted into the corresponding 1 -acylpep- tidyl-5-Rn-2-thiohydantoin (XXIII) in - SO:/ yield ; lysis without significant fission of peptide bonds CH as the 5-Rn-2-thiohydantoin which is extracted by .*'-N H-13H.co * Y' 'F0 SC- NH an organic solvent and identified.Waley and the process and reduced the scale hydrolysing the extracted R"-thiohydantoin to the free amino-acid and identifying it by paper chromatography. Kenner Khorana and Stedman 16i improved the first step avoiding the very vigorous acetic anhydride treatment by the use of diphenyl phosphor- isothjocyanatidate (PhO),PO*NCS in dimethylformamide. They followed the hydrolysis of the thiohydantoin spectroscopically [max. a t 260 (l-acyl system) and 278 mp (l-unsubstituted system)]. C-Terminal serine and pro- line seem resistant to this treatment.l6* A somewhat analogous process in- volving mild treatment with diary1 carbodi-imides R*N:C:N*R and the sep- aration of the R" residue as the open chain R*NH*CO*NH*CHR"*CO*NH*R* has been studied.51q Here however poor yields cause contamination of products.(p) Methods depending on the separation of the Rn-residue as R"C0.R'. the R" residue can be split by brief alkaline hydro- Rn-1 7" Wafson and Tibbs,166 improved the later stages of (XXI I I) 160 M. L. Anson J . Gen. Physiol. 1937 20 663. 161 H. Neurath and J. A. Gladner Biochim. Biophys. Acta 1952 9 335. 162 J. I. Harris Chem. SOC. Special Publ. No. 2 1955 p. 71. 163 J. Lens Biochim. Biophys. Acta. 1949 3 367 ; J. I. Harris J . Amer. Chem. Soc. 16* J. I. Harris and C. A. Knight Nature 1952 170 613. 165 P. Schlack and W. Kumpf 2. physiol. Chem. 1926 154 125. 166 S. G. Waley and J. Watson J. 1951 2394 ; J. Tibbs Nature 1951 168 911. 16' G. W. Kenner H. G. Khorana and R. J. Stedman J. 1953 673. 168 R.A. Turner and G. Schmerzler Biochim. Biophys. Acta 1954 13 553. 1952 74 2944. 256 QUARTERLY REVIEWS The earliest stepwise methods were of this class (R1 = CHPh, via .-CO*NH*CHR"*CPh,*OH from PhMgBr and the peptide ester,l69 R1 = H via .. .CO*NH*CHRn*NH2 ( a ) from Curtius rearrangement l 7 O of the azide ..CO-NH*CHR"*CO*N and ( b ) recently from a Lossen reaction l7l with .-CO*NH*CHR"*CO*NH*OH) but yields are very poor. Boissonnas has described 172 an elegant microscale technique for R1 = H via .-CO*NH*CHR"*OMe which is obtained on anodic decarboxylation and methoxylation of the acyl peptide. Chibnall and Fromageot and their co-workers showed that treatment of peptide esters 173 in tetrahydro- furan with lithium borohydride or free peptides 174 in 4-ethylmorpholine with lithium aluminium hydride converted the terminal carboxyl group into an alcohol group apparently without affecting the peptide bonds.Subsequent hydrolysis yields the R"-residue as the amino-alcohol NH2*CHR"*CH2*OH and all other residues as the free amino-acids. The amino-alcohols do not give the ninhydrin test and can be identified by partition chromatography of the dinitrophenyl derivatives. 175 Lithium aluminium hydride seems liable to cause some cleavage of pep- tide bonds and the borohydride appears preferable. 176 An interesting route for liberating the amino-alcohol stepwise has been investigated recently,177 178 This depends on the acid-catalysed N-0 migration of acyl groups as illustrated. Complications arise through N-0 migration at serine residues and through reductive chain fission with higher peptides the low solubility of which necessitates high reaction tempera- tures.177 ( y ) Reductive (a-amino-alcohol) method.Fa-' 8" 7"-' r * * CO. N H CH. CO. N H CH CH,- OH . .. C0.N H*CHCO*OCH.$H. N H 8" -' 7; nu . . . -r,!-! ctf -OH + ..U,C. a c. '2 -. 169 F. Bettzieche and R. Menger 2. physiol. Chem. 1926 161 37 ; F. Bettzieche 170 M. Bergmann and L. Zervas J . BioE. Chem. 1936 113 341. 171 T. Wieland in " The Chemical Structure of Proteins " ed. G. E. W. Wolsten- holme and M. P. Cameron Churchill London 1953 p. 146. 172 R. A. Boissonnas Nature 1953 171 304 ; Helv. Chim. Acta 1952 35 2226; see also R. A. Turner and G. Schmerzler J . Amer. Chem. SOC. 1954 76 949. 173 A. C. Chibnall and M. W. Rees Biochem. J . 1951 48 xlvii ; " The Chemical Structure of Proteins " ed.G. E. W. Wolstenholme and M. P. Cameron Churchill London 1953 p. 70. 174 C. Fromageot M. Jutisz D. Meyer and L. PBnasse Biochim. Biophys. Acta 1950 6 283 ; C. Fromageot and M. Jutisz " The Chemical Structure of Proteins " ed. G. E. W. Wolstenholme and M. P. Cameron Churchill London 1953 p 82. 175 M. Jutisz M. Privat de Garilhe M. Suquet and C. Fromageot BUZZ. Soc. Chim. biol. 1954 36 117 ; W. Grassmann H. Hormann and H. Endres Chem. Ber. 1953 86 1477 ; 2. physiol. Chem. 1954 296 208. ibid. p. 178. 176 J. L. Bailey Biochem. J. 1955 60 170. 177 J. C. Crawhall and D. F. Elliott Biochem. J . 1955 61 264; D. F. Elliott 178 J. Leggett Bailey i b d . 1955 60 153. ibid. 1952 50 542. SPRIFGSLL AKD LAW PEPTIDES 257 (8) Hydrazinolysis and ammonolysis. Akabori et aZ.,179 noting that hydrazine cleaves amide bonds R*CO*NHR' + R*CO*NH*NH + NH,R' hut does not attack free carboxyl groups studied the hydrazinolysis of pep- tides.This should yield the C-terminal residue as the free amino-acid m d all the other residues as the amino-acid hydrazides thus permitting the identification of the C-terminal residue (though at the expense of the rest of the specimen). In practice the drastic attack of hot hydrazine is not always so clear-cut it appears la0 that several amino-acids are corn- pletely destroyed. The corresponding reaction with ammonia has been investigated lSo and found liable to similar limitations due to destructive degradation. The authors are indebted t'o Dr. G. T. Young for valuable comments. 179 S. Akabori K. Ohno and K. Narita Bull. Chem. SOC.Japan 1952 22 214; K. Ohno J . Biochem. (Japan) 1953 40 621 ; S. Akabori K. Ohno T. Ikenaka A. Nagata and I. Haruna Proc. Japap Acad. 1953 29 561. lE0 R. MT. Chambers and F. H. Carpenter J . Amer. Chern. SOC. 1955 77 1527.

ISSN:0009-2681    

DOI:10.1039/QR9561000230

出版商:RSC    

年代:1956

数据来源: RSC