ISSN:0069-3030    

DOI:10.1039/OC97370FX001

出版商:RSC    

年代:1973

数据来源: RSC

ISSN:0069-3030    

DOI:10.1039/OC97370BX003

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

2 Physical Methods Part (i) Organic Mass Spectrometry By R. A. W. JOHNSTONE The Robert Robinson Laboratories The University LiverpoolL69 3BX and F. A. MELLON Agricultural Research Council Unit of Invertebrate Chemistry and Physiology University of Sussex Brighton. BNI 9QJ This our final Report continues the practice adopted in the two previous ones of covering selected areas of mass spectrometry of general interest to organic chemists. A good impression of trends in mass spectrometry can be obtained from the Proceedings of the 6th International Mass Spectrometry Conference,' which should be available in the near future as Volume 6 of Advances in Mass Spectrometry. 1 Theoretical Aspects In earlier Reports,' we have emphasized the limitations of the over-simplified quasi-equilibrium theory equation k = v[(E -Eo)/EIN-',when used for any- thing other than simple teaching or illustrative purposes.This emphasis was simply a reiteration of earlier objections to this equation3 which often seem to have been conveniently overlooked without tacit or implicit justification. The equation is useful for illustrating mass spectrometric fragmentation effects in a quali-quantitative sense. There has been a decline in the use of the simple equation in recent literature possibly because all the parameters which can be varied have now been examined. Nevertheless the equation has been used to calculate tables of estimated kinetic shifts although the authors readily admit the drawbacks. Since the rate given by the equation needs to be folded with the energy distribution function for the ions and the latter is an unknown quantity it is doubtful whether the calculated values provide even an approximate guide to the kinetic shift.Because there is no one rate of ion decomposition all mass spectrometric frag- mentations will yield a spread of rates from zero to about lot4(bond vibration ' Held in Edinburgh. September 1973. * R. A. W. Johnstone and F. A. Mellon Ann. Reports (B) 1972,69 7. See for example A. G. Harrison 'Topics in Organic Mass Spectrometry'. ed. A. L. Burlingame Wiley-Interscience New York 1970 Vol. 8 p. 128. S. Benezra and M. M. Bursey Org. Mass Spectrometry 1973 7 241. 7 R. A. W.Johnstoneand F. A. Mellon frequency) and therefore an ‘observed’ kinetic shift depends on the ability of the instrument to measure the corresponding ion currents.Apart from the ion flight time the sensitivity of the instrument is very important. Measurement of a kinetic shift by obtaining the appearance potentials of normal and metastable ions is considered later. With the decline of interest in the simple QET equation there has been an increase in the number of applications of molecular orbital theory to mass spectrometry. The methods used in these calculations vary from the extremely nai‘ve to the more sophisticated CNDO and INDO approaches but as yet the highly sophisticated ub initio SCF IBMOL and Xa-SW methods which have shown great reliability with inorganic ions have not been used. Perhaps someone with access to the programs could be persuaded to carry out a few calculations.At the simplest MO level for cleavage of a substituent from the para position of 4-styrylquinolines the calculated bond order for the frontier electron correlated linearly with log I where I = the total abundance of the substituent and M -substituent ions;’ it would be interesting to know whether similar correla- tions are obtained between log I and say ionization potentials. At a more sophisticated level extended Huckel theory was used to calculate electron densities and bond orders for oestrone as the neutral molecule and ground-state and excited-state molecular ion.6 These calculations showed that in all the con- figurations considered for the molecular ion the electronic charge was delocalized over the whole structure and more so than in the neutral molecule.These findings are in keeping with earlier qualitative theoretical conclusion^,^ and suggest that net charges are unrelated to fragmentation. However bond densities in the molecular ion did allow a prediction of the gross features of the mass spectrum of oestrone and it was concluded that ionization weakened some bonds near positions of high electron density in the outer molecular orbitals of the ion.6 Just such an argument has been used previously in an attempt to de-polarize the ‘charge localization’ and ‘product stability’ extremes.’ Unfortunately the reliability of the calculations must be questioned because the outermost molecular orbital of oestrone is predicted to be associated largely with the carbonyl function in ring D whereas photoelectron spectroscopy suggests that the outer orbital should be 7r-type and associated mostly with the aromatic ring (c$ the ionization potentials of phenol 8.54 eV,9 and cyclopentanone 9.25 eV’’).It may be that like CNDO calculations extended Huckel theory gives a better guide to charge distributions and not to orbital energies although it has been claimed this is not the case for one Huckel treatment.’ I H. Gusten L. Klasinc and D. Stefanovic Org. Mass Spectrometry 1973 7 1. G. Loew M. Chadwick and D. Smith Org. Mass Spectrometry 1973 7 1241. M. J. S. Dewar Tetrahedron Suppl. 1963,19,89; T. W. Bentley and R. A. W. Johnstone Adv. Phys. Org. Chem. 1970 8 154. R. A.W. Johnstone ‘Mass Spectrometry for Organic Chemists’ Cambridge University Press 1972 pp. 3945. R. A. W. Johnstone and F. A. Mellon J.C.S. Faraday II 1973 69 36. lo D. Chadwick D. C. Frost and L. Weiler J. Amer. Chem. SOC., 1971 93 4320. I’ P. A. Cox S. Evans A. F. Orchard N. V. Richardson and P. J. Roberts Faraday Discuss. Chem. SOC. 1972 No. 54 p. 26. Physical Methods-Part (i) Organic Mass Spectrometry 9 INDO and CNDO calculations have been carried out on substituted phenyl- acetates and the calculated bond orders were interpreted as suggesting bond formation between the carbonyl oxygen and an ortho-fluorine and hence a ‘lower frequency factor’ for elimination of C,H,O from the molecular ion. l2 Although it is not clear in the paper,12 the authors appear to have used the CNDO and INDO density matrix Ppv to obtain the bond order.In looking for bond formation this approach can lead to unreliable results because Ppv is derived from the electron densities at the atoms (p v) and does not take into account the degree of positive overlap (Spv)between them. l3 It would be interesting to know if the same result was obtained from a population analysis13 obtained by multiplying and summing the correct off-diagonal elements of the density and overlap integral matrices i.e. ~Pp~.Spv.’~ As has been found in many other applications of INDO and CNDO techniques,15 the predicted ordering of 71-and a-levels seems unreal. From a further application of INDO it was suggested that scrambling of hydrogen atoms in the molecular ion of ethane took place uia a diborane-type bridge structure (1) with hydrogen atoms on opposite sides of the C-C bond rather than when they are on the same side as in structure (2).16 H H H H,H ,/NH\\ H\ / ‘\ I I /’ c-c c-c / ‘ I’ \H /\ H ‘H H H INDO calculations also predict near co-planarity for the aryl rings in two para-arylacetophenones and therefore the enhanced resonance stabilization nay account for the low abundance of C,H,O ions in their mass spectra.” Finally an attempt has been made to evaluate mass spectrometric fragmentation in terms of the total energies of the fragments as calculated by CNDO and hence the lowest energy for fragmentation.Given Hammond’s postulate’ * the approach seems valid within the limitations of CNDO at which point it is perhaps wise to recall Dewar’s warning on the use of molecular orbital methods to predict small energy changes uiz.the accuracy to be expected from estimating a small energy change as the difference between two large inaccurate energies can only be low. l9 12 C. E. Parker J. R. Has M. M. Bursey and L. G. Pederson Org. Mass spectrometry 1973 7 1189. 13 R. S. Mulliken J. Chem. Phys. 1955 23 1841; ibid. 1962,36 3428. I4 J. A. Pople and D. L. Beveridge ‘Approximate Molecular Orbital Theory’ McGraw- Hill New York 1970 p. 43. 15 J. E. Bloor and D. L. Breen J. Phys. Chem. 1968,72,716; see also ref. 11 and R. A. W. Johnstone and F. A. Mellon J.C.S. Furaduy IZ 1973 69 1155. 16 C. E. Parker M. M. Bursey and L.G. Pederson Org. Mass Spectrometry 1973 7 1077. 17 C. E. Twine. C. E. Parker and M. M. Bursey Org. Muss. Spectrometry 1973 7 1179. I8 G. S. Hammond J. Amer. Chem. Soc. 1955,77 334. 19 M. J. S. Dewar in ‘Aromaticity‘ Special Publication No. 21 The Chemical Society London 1967 p. 199. R.A. W.Johnstone and F. A. Mellon We add to this a reiteration of the poor energies generally obtained using standard CNDO methods. l5 Before leaving this discussion of theoretical models of mass spectrometric fragmentation it is worth emphasizing that almost all applications of simple and full quasi-equilibrium theory equations have explicitly or implicitly assumed that the density of states does not include excited ionic species i.e. that a short time after ionization the molecular ion has converted excess of electronic excitation energy into excess of vibrational energy shared amongst all the oscillators and rotamers and therefore that fragmentation occurs from a vibrationally and rotationally excited ground-state ion.The first experimental body-blow to this cosy assumption has been dealt by the observation from photoelectron-mass spectrometric coincidence techniques that ions in the first excited-state of the C,F cation decompose without prior internal conversion to the ground- state ion.” 2 Ionization and Appearance Potentials These potentials are of considerable value in giving thermochemical data and in providing information on the energetics of mass spectral fragmentations. There is still confusion in the literature over both the significance and the use of adiabatic and vertical ionization potentials and this has led to frustration manifesting itself in print.21 Quite simply for most thermochemical arguments the adiabatic potential should be used.The confusion arises over the data available in the literature because it is not certain exactly what the various mass spectrometric methods measure. Earlier measurements of ionization and appearance potentials using a mass spectrometer have frequently given considerably higher values than have similar measurements made in photo-ionization studies and this led to a belief that the electron-impact methods measured some nebulous ‘vertical’ ionization potential. That some of these differences were due simply to instru- mental insensitivity and the poor methods of evaluating ionization efficiency curves was made apparent in a recent paper.” There is therefore reason to believe that given a sufficiently sensitive method of gathering ionization efficiency data and a proper means of evaluating the data ionization potentials measured by electron or photon impact would be identical and adiabatic ones.The literature has been further confused by another use of the term ‘vertical’ ionization potential in photoelectron spectroscopy. This vertical potential is the name given to the position of a maximum on a band in the photoelectron spectrum and is of dubious significance since it measures a maximum arising from many overlapping processes in polyatomic molecules and alters with changes in the resolving power of the instr~ment.’~ It is by no means certain and is probably highly doubtful that electron-impact and photoelectron ‘vertical’ ionization potentials are equivalent.2o I. G. Simm C. J. Danby and J. H. D. Eland J.C.S. Chem. Comm. 1973,832. * See ref. 27 p. 1205 for example. *’ R. A. W. Johnstone and F. A. Mellon J.C.S. Furaday fI 1972,68 1209. ” D. W. Turner C. Baker A. D. Baker and C. R. Brundle ‘Molecular Photoelectron Spectroscopy’ Wiley-Interscience London and New York 1970 p. 284. Physical Methods-Part (i) Organic Mass Spectrometry 11 Because the difference between photoelectron adiabatic and vertical ionization potentials can vary from zero to about 0.5 eV and different methods of measuring electron-impact ionization potentials can easily have this range also it is not surprising there is confusion in the literature.At present it seems the only values to be reasonably certain of are the photo-ionization and photoelectron adiabatic ionization potentials and the electron-impact potentials obtained with sensitive apparatus and mono-energetic electrons24 or proper mathematical deconvolution of ionization efficiency data.25 As if this confusion is not sufficient there is an added one associated with the term ‘accurate’. Frequently in the literature values for ionization potentials obtained by electron-impact methods are claimed to be ‘accurate’ to say k0.2eV as the result of several determinations. Whilst it can be appreciated that the values obtained are reproducibleto within those limits i.e.the experimental work has been carried out diligently there is no guarantee that the results are accurate. In other words several determinations of an ionization potential could be repro-ducible within close limits but the absolute value obtained could be inaccurate simply because the methods used to acquire and evaluate data are inadequate. The popular ‘semi-log’ method appears to be particularly suspect in this regard,26 and even within a series of compounds relative ionization potentials are unlikely to be accurate (cf:bandshapes for first ionization potentials of benzene and aniline for example). . The usefulness of ionization and appearance potential measurements has again been re~iewed.~’ The differences in appearance and ionization potentials for primary fragmentation of a series of stereoisomers of 1.3-oxathians were found to correlate well with conformational energy differences indicating release of energy due to non-bonded interactions.28 Almost mono-energetic electron beams have been used to measure the ionization potentials of C3H3 and C3H5 C4H,radicals from various sources and hence the heats of formation of the corresponding cations.24 From these values and measurements of the heats of formation of these ions from organic compounds it was concluded that the C3H ion seemed always to have a cyclopropenyl structure and the C3H,ion to have an ally1 structure.27 On the basis of appearance potentials of benzoyl ions from a variety of pre- cursors it has been claimed that excited states of benzoyl ions could be detected.29 The existence of the excited states was deduced from the high values found for the heats of formation of benzoyl ions from different precursor ions.The high results l4 F. P. Lossing Canad. J. Chem. 1972,50 3973. l5 See for example J. D. Morrison J. Chem. Phys. 1953 21 1767; R.E.Winters J. H. Collins and W. L. Courchene ibid. 1966,45 1931 ;J. Vogt and C. Pascual Internat. J. Mass Spectrometry Ion Phys. 1972 9,441 ; G.D.Flesch and H. J. Svec ibid. p. 106; and reference 35. 26 J. L.Occolowitz and B. J. Cerimele in ‘Abstracts of the 20th Annual Conference on Mass Spectrometry and Allied Topics’ ASTM Committee E-14 Dallas June 1972 p. 95. 2’ J. Jalonen and K.Pihlaja Org. Mass Spectrometry 1973 7 1203. ’* J. Jalonen P. Pasanen and K. Pihlaja Org. Mass Spectrometry 1973 7,949. F. Benoit Org. Mass Spectrometry 1973 7 1407. 12 R. A. W.Johnstone and F. A. Mellon were not attributed to experimental error because only a small spread was found in the heats of formation of C6H cations from various sources. It must be pointed out that the heats of formation for C6H ions obtained in this study although consistent are more than 1 eV greater than the currently accepted best values obtained by photoionization methods3' and are 1 eV greater than values obtained using the IE/EDD method.22 Further in measurements made three years ago,31 the appearance potentials by the IE/EDD method for C,H,CO ions from acetophenone and methyl benzoate were 0.94 and 0.53 eV respectively lower than the values reported in the present worktg and lead to the suspicion that the semi-log method of evaluating the ionization efficiency data has failed spectacularly.Efforts have been made to get some idea of the extent of kinetic shift by com- parison of the appearance potentials of normal ions and the longer-lived meta- stable ions.32 The maximum lifetime of a normal ion is very close to the lifetime of a metastable ion in most mass spectrometers so that a sensitive measurement of the appearance potential of a normal ion should not be expected to differ much from that of a metastable. Recent data33 on appearance potentials of some normal and metastable ions using the sensitive IE/EDD method did not provide evidence for any measurable kinetic shift in fragmentations where they had previously been reported.32 A new method has been described for measuring double and triple ionization potentials from the kinetic-energy loss distributions in reactions of the type m+ + N -+ m2+ + N + e- and gives values which compare favourably with ocher literature values.34 A new method has been proposed for mathematical analysis of ionization efficiency curves obtained with a conventional mass spectrometric ion source. The method takes account of the effective electron energy distribution in the ion source at the time of the experiment and does not need any arbitrary normalization procedures because both co-ordinates have the same units of energy.35 3 Ionization Methods There have been two developments in ionization methods which could become very important in the future.The first of these is an atmospheric-pressure ionization source in which ionization is induced in a stream of gas at atmospheric pressure and the ions produced are allowed into the mass spectrometer through '13 H. M. Rosenstock J. T. Larkins and A. J. Walker Internat. J. Mass Spectrometry Ion Phys. 1973 11 309; Yu. Sergeev M. E. Akopyan and G. I. Vilesov Optika i Spek-' troskopiya 1972 32 230. F. A. Mellon Ph.D. thesis Liverpool University 197 1. 32 J. H. Beynon J. A. Hopkinson and G. R. Lester Internat. J. Mass Spectrometry Ion Phys. 1969 2 291; P. Brown Org. Mass Spectrometry 1970 3 639. 33 T. W. Bentley R. A. W. Johnstone and B.N. McMaster J.C.S. Chem. Comm. 1973 510. 34 R. G. Cooks,T. Ast and J. H. Beynon Internat. J. Mass Spectrometry Ion Phys. 1973 11 490. 35 R. A. W. Johnstone and B. N. McMaster J.C.S. Chem. Comm. 1973 730. Physical Methods-Part (i) Organic Mass Spectrometry 13 a small apert~re.~~.~’ The primary source of electrons is a radioactive 63Ni foil and the positive ions are formed by a complex series of ion-molecule reactions; the source appears to be very similar in its principle of operation to the radioactive sources once very widely used in gas chr~matography.~~ Samples can be intro-duced directly into the gas stream in suitable solvents and therefore the source can be used for biological fluids without prior work-up or the preparation of derivatives.Using a computer to process the data and with multiple single- or many-ion scanning corresponding sensitivities of 5-10 picogram or 25 picogram could be attained. For example nicotine was detected in smokers non-smokers and room air.37 The second ion source uses an electrohydrodynamic ionization technique.39 The interaction of a small conducting liquid meniscus with a strong electrostatic field leads to a high potential gradient and ionization similar to that involved in field desorption. Although the technique has as yet been applied only to liquid metals the authors indicate their intention of using it for labile organic compounds. With the relatively little-used photo-ionization method differences in the fragmentation behaviour of stereoisomers have been readily dete~ted.~’ Field desorption (FD) continues to build up an impressive range of mass spectra of organic compounds which are thermally labile or of low volatility.Recently indirect infrared heating of the field anode has been used to yield more abundant molecular ions relative to fragment ions?’ Pyrolysis of sub-microgram quantities of DNA on the high-temperature activated tungsten emitter of an FD source gave a mass spectrum showing ions for all five bases in the molecule as well as ions corresponding to nucleosides nucleotides and dinu~leotides.~~ High-resolution mass measurements and computer analysis of fragmentation patterns were used to assign ion composition and the possibility of using this technique for sequencing is under investigation.Underivatized nucleosides and nucleotides have also been examined by conventional FD and high-resolution measure- ment~.~~ The need for optimal adjustment of the ion source to obtain good high-resolution data and the importance of a suitable solvent for applying the compound to the emitter were dem~nstrated.~~ Abundances of quasi-molecular and fragment iGns in FD mass spectra of glycosides allowed a differentiation between z-and P-isomer~.~~ The remarkably successful handling by FD of 36 E. C. Horning M. G. Horning D. I. Carroll I. Dzidic and R. N. Stillwell Analyr. Chem. 1973,45 936. 37 E. C. Horning M. G. Horning D. I. Carroll I. Dzidic and R. N. Stillwell Life Sci. 1973 13 1331 and references therein.38 For a description see for example H. P. Burchfield and E. E. Storrs ‘Biochemical Applications of Gas Chromatography’ Academic Press New York and London 1962 p. 58. 39 B. N. Colby and C. A. Evans Anafyt. Chem. 1973,45 1884. 40 Z. M. Akhtar C. E. Brion and L. D. Hall Org. Mass Spectrometry 1973 7 647. 4’ H. U. Winkler and H. D. Beckey Org. Mass Spacrrometry 1973 7 1007. 42 H.-R. Schulten H. D. Beckey A. J. M. Boerboom and H. L. C. Menzelaar Analyr. Chem. 1973,452358. 43 H.-R. Schulten and H. D. Beckey Org. Mass Spectromerry 1973 7 861. 44 W. D. Lehmann H.-R. Schulten and H. D. Beckey Org. Mass Spectrometry 1973,7 1103. 14 R. A. W.Johnstone and F. A. Mellon molecules which prove intractable by conventional ionization methods is illustrated by the success in obtaining mass spectra of and high-resolution data on disodium deoxyfluoro-D-glucose 6-pho~phates.~~ Field ionization (FI) mass spectroscopy together with high-resolution mass measurements and electron-impact mass spectroscopy has been used to analyse a crude mixture of alkaloids from Erythrina seeds;several new alkaloids were tentatively identified.46 The detection of multiply-charged ions in FI mass spectra has been used to derive kinetic data for ionic decomposition^.^^ Like FD and FI methods chemical ionization (CI)continues to find increasingly wide use both conventionally and for ‘difficult’ organic compounds.CI mass spectra of underivatized oligopeptides were obtained by introduction of the sample on the end of a probe directly into the reactant gas plasma.These spectra showed quasi-molecular ion peaks sometimes weak and good ‘sequence’ peaks.48 It was suggested that the 100ng of sample required was a considerable gain in sensitivity over electron-impact methods requiring extensive prior derivatization of the peptide with concomitant loss of sample. For sequencing work the CI method was superior to FD in that it gave more abundant sequence ions. Temperature effects in the CI mass spectra of amino-acids and peptides have been investigated4’ and show the expected increase in fragmentation with increase in ion source temperature. As with photo-ionization FD and FI several stereochemical and conformational effects have been observed in CI spectra. The quasi-molecular ions of steroidal 1,2- and 1,3-amino-alcohols eliminated H20 but only when the N-0 distance was too great for hydrogen-bonding.” Considerable differences were observed between the CI mass spectra of epimeric pairs.Other investigations have shown that CI fragmentations can occur at sites remote from that of protonation.” CI mass spectra have been obtained for biogenic amines which do not give good results under electron-impact i~nization.~~ Finally mention should be made of the increased interest in negative ion mass spectroscopy. Following an earlier passing comment of ours2 regarding the then current small interest in and general usefulness of negative ion mass spectroscopy there has been a vigorous reaction from one group of workerss3 to the extent of formulating axioms to describe negative ion fragmentation.similar to those used by proponents of charge-localization (see earlier comments on p. 8). As the 45 H.-R. Schulten H. D. Beckey E. M. Bessell A. B. Foster M. Jarman and J. H. Westoal J.C.S. Chem. Comm. 1973,416. “ D. E. Games A. H. Jackson and D. S. Millington Tetrahedron Letters 1973 3063. ‘’ H. D. Beckey M. D. Mighaed and F. W. Rollgen Internat. J. Mass Spectrometry Ion Phys. 1973 10 471. 48 M. A. Baldwin and F. W. McLafferty Org. Mass Spectrometry 1973 7 1353. 49 M. Meot-Ner and F. H. Field J. Amer. Chem. SOC.,1973 95 7207. ’’ P. Longevialle G. W. A. Milne and H. M. Fales J. Amer. Chem. SOC.,1973 95 6666. ’’ R.L. Foltz A. F. Fentiman C. A. Mitscher and H. D. Showalter J.C.S. Chem.Comm. 1973,872. 52 G. W. A. Milne H. M. Fales and R. W. Colburn Analyt. Chem. 1973 45 1952. 53 R. G. Alexander D. B. Bigley and J. F. J. Todd Org. Mass Spectrometry 1973 7 643. Physical Methods-Part (i) Organic Mass Spectrometry 15 authors themselves suggest there is not yet a wide range of results with which to test the axioms adequately and it is therefore unfitting to comment on their value. If the axioms do yield an empirical rationalization for negative ion mass spectra they will be useful. 4 Chromatographic-Mass SpectrometricMethods With the increasing use of high-speed liquid chromatography have come attempts to couple this apparatus to a mass spectrometer and possible interfacing systems are being reported. In one procedure a stopped-flow technique enabled the solvent from small liquid samples from the liquid chromatographic apparatus to be evaporated at the tip of a probe which was then driven by a motor into the ion source and heated to vaporize the organic residue.54 Satisfactory mass spectra were obtained in this way but a cycle time is required of 3-5 minutes during which the liquid chromatograph is stopped.As a preliminary investigation into the direct coupling of a liquid chromatograph with a mass spectrometer 10 microlitres of solutions were introduced into a CI source through a 2mm capillary The ideal solvent requires a combination of volatility good reagent gas activity in the CI source and few interfering peaks in the mass spectrum (presumably it should also be a good eluent for the liquid chromato- graph !)and various solvents were tried.CI spectra of high specificity were obtained but increased source pumping speeds will be necessary before direct coupling can be made. A good deal of interesting work has been carried out with coupled gas chromatographic-mass spectrometric (g.c.-ms.) systems which are now in widespread routine use following their ready commercial accessibility. Much of this work is covered in Sections 5 and 6 and only instrumental topics are covered here. Of general interest is the demonstration that higher resolution and sensitivity can be achieved using open tubular capillary columns rather than packed columns.56 This point is also mentioned in the course of an excellent review of integrated g.c.-m.s.technol~gy.~~ Readers might like to be reminded of the usefulness of packed capillary columns which have better resolutions than ordinary packed columns and allow a higher sample loading than open capillary columns.58 A system of flow-programming has been described which by use of an auxiliary helium supply and vent achieves maximum separator yield for differing flow rates from the gas chromatographic apparatus.5g 54 R. E. Lovins S. R. Ellis G. D. Tolbert and C. R. McKinney Analyt. Chem. 1973,45 1553. ” M. A. Baldwin and F. W. McLafferty Org. Mass Spectrometry 1973 7 11 1 I. ” B. F. Maume and J. A. Luyten J. Chromatog. Sci. 1973 11 607. ’’ R. Ryhage Quart. Rev. Biophys. 1973,6 3 11. For leading references see C. A. Cramers J.Rijks and P. Bocek J. Chromatog. 1972 65 29. ’’ M. A. Grayson R. L. Levy and C. J. Wolf Analyr. Chem. 1973,45,806. 16 R. A. W.Johnstoneand F. A. Mellon Defects in resolution on coupling a gas chromatographic apparatus to a mass spectrometer were shown to arise in the connecting lines and not in the separator itself.60 The defects were not simply due to inadequate heating of the lines. 5 Computers Computers are increasingly used in mass spectrometry to acquire and process data to control mass spectrometers to compare incoming data with established 'libraries' and to make structural assignments. That the computer has not yet shrugged off the mass spectroscopist is evident from the highly successful inter- active systems in which an operator 'converses with' or alters the operating mode of a computer according to changing requirements.Data acquisition by computer has been extended to the growing field of multiple ion detection (MID). The utility of MID for monitoring g.c. effluents is well-established. In MID only selected ions from the known mass spectrum of a compound are looked for in the ionized effluent from the g.c. column. This technique of detecting selected ions is more rapid than whole scans of all the ions in a spectrum and has an inherently greater sensitivity since only the more abundant ions need be considered. For example if the mass spectrum of a compound has four abundant characteristic ions the mass Spectrometer can be set to cycle round and continuously monitor the abundances of just those ions ; when the compound emerges from the g.c.column and is ionized those four characteristic ions tire sensed even at very low levels. Because quantitative information is required only for known compounds it is not important that most of the information contained in the total spectrum is not used. In this way accurate identification and estimation can be made of small quantities of for example pesticides in soil or drugs in metabolic fluids. In conventional MID methods the selected peaks are examined by altering the ion-accelerating voltage in controlled jumps and recording the ion abundance data on a pen or galvano- meter recorder. It is this process which has been simplified through the use of computers. The computer is used to control the changes in ion-accelerating voltage and to monitor the resulting MID The information can be displayed instantly on a cathode ray tube6' and exact masses can be 'typed' into the computer which then sets the correct accelerating voltages in the ion source.It proved possible to monitor up to eight selected fragment ions in one application and assays of picogram quantities of myoinositol deuteriated alanine and glucose were made.62 On a less sophisticated level a computer was used to monitor selected ion abundances without controlling the ion-accelerating voltage.63 Such a use of the computer was used also to identify individual ion current profiles 'O F. Bruner P. Ciccioli and S. Zelli Analyr. Chem. 1973 45 1002. '* K. Elkin L. Pierrou U. G.Ahlbor B. Holmstadt and J.-E. Lindgren J. Chromafog. 1973 81,47. 62 W. F. Holmes W. H. Holland B. L. Shore D. M. Bier and W. R. Sherman Analyr. Chem. 1973,45,2063. 63 P. D. Klein J. R. Haufman and W. J. Eider Analyr. Chem. 1973 45 308. Physical Methods-Part (i) Organic Mass Spectrometry 17 which would have overlapped on a conventional data record of composite profiles.64 This same system was also 'interactive' in that the operator could modify the instructions to the computer according to changing requirements. As an alternative to MID of selected ions in a mass spectrum magnetic scanning of a limited range of the total mass spectrum has been used with computerized data acquisition and processing to assay The relative merits of single-ion monitoring and repetitive magnetic scanning have been assessed using cholestene as the test substance.Which technique is to be used must ultimately depend on the amount of information already obtained or the amount required. Single-ion monitoring which is approximately a thousand times more sensitive than repetitive scanning was recommended for detection of trace quantities and repetitive scanning for the location of drug metabolites.66 In this respect an electronic resetting device operating during a scan has led to considerable signal enhancement compared with a normal scan and suggests that the above figures for relative sensitivities may need re~ision.~' Apart from simple data processing a computer can be used to recognize a compound by comparing its mass spectrum with those held in a library or file and finding the best match(es).There are two main requirements to make this library searching fast and efficient namely that a minimum of information be stored and that the search and computation time should be short. To some extent these criteria are interdependent. By coding only the most intense peak in every section of 14 mass units throughout a mass spectrum and using only a minimum of ion abundance information the 7000 mass spectra in one collection could be searched in only 10seconds ;'* this latter paper concludes with a timely warning on the use of library search methods. Information theory has led to the adoption of a statistical search and match technique which gave a high percentage of correct identifications even when matching was confined to only 8peaksin the spectrum.69 The variability of mass spectra was highlighted by these authors who noted that the differences between mass spectra of the same compound run on different instruments were sometimes greater than the variations in spectra of geometrical isomers run on the same instrument.Further developments of a search and retrieval system using two out of every 14 ion peaks and available by telephone have been This system will accept instructions to search for molecular weights and complete or partial molecular formulae besides the usual library searching to match spectra. Attempts have been made to classify the pharmacological activity of drugs according to their mass spectra and preliminary findings were that some drugs " J.T. Watson D. R. Pelster B. J. Sweetman J. C. Frohlich and J. A. Oates Anulyt. Chem. 1973,45 2071. 65 L. Baczynskyj D. J. Duchamp J. F. Zieserl and U. Axen Analyt. Chem. 1973,45,479. 66 D. M. Desiderio and B. S. Middleditch Analyt. Chem. 1973 45 806. " R. P. Page A. V. Nowak and R. Wertzler Anulyt. Chem. 1973,45 994. 68 S. L. Grotch Analyt. Chem. 1973,45 2. 69 S. Farbman R. I. Reed D. H. Robertson and M. E. F. Silva Internat. J. Muss Spectro-metry Ion Phys. 1973 12 123. 70 S. R. Heller H. M. Fales. and G. W. A. Milne Org. Muss Spectrometry 1973.7 107. 18 R. A. W.Johnstone and F. A. Mellon could be classified as sedatives or tranquilizers when the mass spectra were fed into a suitably ‘trained’ computer pr~gram.~ A mass spectral computer-processing technique known as the self-training interpretive and retrieval system (STIRS) has been developed to use nine data classes for library searching and matching.72 These classes include information on ion series primary and secondary losses of neutral particles characteristic ions and fingerprint ions.The system compared well with other matching techniques and appeared to be surprisingly independent of errors in the spectro- scopic data in some cases. 6 Chemical Biochemical and Biomedical Uses There has been informal discussion as to the reality of the word ‘biomedical’ since medicine is always associated with biological systems and as to whether it is any different from biomedical. As used here we imply the interaction of medicine and biology in a gross sense i.4.large-scale effects and associated natural or in- duced metabolic functioning as opposed to the molecular (biochemical) investiga- tion of living systems. For example the estimation of ethanol in a toper would be biomedical :the chemistry of the metabolism of the ethanol would be biomedical. Mass spectrometric methods of peptide and protein sequencing are now becoming more routine and especially when the quantity of material available is not a problem these methods can compete favourably with the Edman degra- dation. Each of the methods mass spectrometric and Edman has its advantages and disadvantages which can be classified mainly under the headings of time involved sensitivity cost ‘difficult’ amino-acids and branching or looping of the peptide chain.Most probably the two methods will gradually come to complement each other as demonstrated by the sequence determination on somatostatin a hypothalamic polypeptide which inhibits the secretion of somatotropin.’ Initially Edman degradation of the complete polypeptide became difficult at the sixth cycle and therefore somatostatin was cleaved with trypsin into three peptides two of which were sequenced by the Edman method and the third by mass spectrometry. A discussion of permethylation methods preferred for use for the ‘difficult’ amino-acid residues methionyl histidyl and arginyl contains recommended procedures for dealing with peptides containing them.74 The methods described are now standard and widely used but for the methionine- and histidine-containing peptides it is recommended that very short permethylation times be used rather than exact equivalents of methyl iodide7’ K.-L.H. Ting R. C. T. Lee G. W. A. Milne M. Shapiro and A. M. Guarino Science 1973,180,417. 72 K.-S. Kwok,R. Venkataraghavan and F. W. McLafferty J. Amer. Chem. SOC.,1973 95 4185. 73 N. Ling R. Burgus J. Rivier W. Vale and P. Brazeau Biochem. Biophys. Res. Comm. 1973,50 127; R. Burgus N. Ling M. Butcher and R. Guillemin Proc. Nat. Acad. Sci. U.S.A. 1973,70 684. 74 H. R. Morris R. J. Dickinson and D. H. Williams Biochem. Biophys. Res. Comm. 1973 51 247. 75 M. L. Polan W. J. McMurray S. R. Lipsky and S. Lande Biochem. Biophys. Res. Comm. 1970 38 1 127 J.Amer. Chem. SOC.,1972,94 2847. Physical Methods-Part (i) Organic Mass Spectrometry 19 to prevent sulphonium and ammonium salt formation. In a criticism of the latter method the authors included a further publication7’ which they mis- rep~rted’~.~~ as implying the use of stoicheiometric quantities of methyl iodide. The earlier p~blication~~ in fact recommended short reaction times and not the use of stoicheiometric quantities of methyl iodide. Since two groups of workers have now found that short reaction times for permethylation do not give salt formation with methionine and histidine it can probably be accepted as a routine procedural detail in the presence of these residues. The application of low- and high-resolution mass spectrometry chemical ionization metastable peak measurement and fractional evaporation mass spectral methods to the analysis of mixtures of peptides has been des~ribed.’~ It was concluded that high-resolution mass data were necessary for the unequivocal assignment of some peptide sequences although statements to the contrary have appeared earlier.’’ Dipeptides isolated from urine and identified by g.c.-m.s. have indicated a break-down in collagen in a patient suffering from undiagnosed purpura.80 The C-terminal amino-acids in peptides have been identified by mass spectro- metry after conversion to thiohydantoins and trimethylsilylation.8 The application of mass spectrometry to the analysis of saccharides and associated substances continues to increase.The elucidation of sequences of monosaccharide units in N-arylglycosylamine acetates and in acetates of 2-phenyI-1,2,3-triazole derivatives has been done in this way.” The analysis of glucuronides by mass spectrometry of the trimethylsilyl derivatives allowed identification of the sugar and agly~one.’~ Aldosylaldonates have been per- methylated and analysed by g.c.-ms. whereby 1 --+ 3 1 -+4 and 1 -* 6 linked residues could be distinguished even though there was no molecular ion (electron- impact i~nization).’~ After acetylation and methylation amino-sugar-containing glycosphingo-lipids were analysed. 85 In a new variation of g.c.-m.s. methods for distinguishing the stereoisomers of chiral alcohols and amines drimanoyl and chrysanthemoyl derivatives were used to give readily separable diastereoisomers.86 H.R. Morris in ‘Mass Spectrometry’ ed. D. H. Williams (Specialist Periodical Reports) The Chemical Society London 1973 Vol. 2 p. 162. 77 G. Marino L. Valente R. A. W. Johnstone F. M. Tabrizi and G. C. Sodini J.C.S. Chem. Comm. 1972 357. H.-K. Wipf P. Irving M. McCannish R. Venkataragharen and F. W. McLafferty J. Amer. Chem. Soc. 1973,% 3369. 79 H. R. Morris D. H. Williams and R. P. Ambler Biochem. J. 1971 125 189. R. A. W. Johnstone T. J. Povall J. D. Baty J.-L. Pousset C. Charpentier and A. Lemonnier Clin. Chim. Acta 1974 52 137. M. Rangarajan R. E. Ardrey and A. Darbre J. Chromafog.,1973,87 499. 82 0.S. Chizhov N. N. Malysheva and N. K. Kochetkov Izvest. Akad. Nauk S.S.S.R. Ser. khim.1973 1030; Carbohydrnre Res. 1973,28 21. 83 S. Billets P. S. Lietman and C. Fenselau J. Medicin. Chem. 1973 16 30. J. N. C. Whyte. Canad. J. Chem. 1973,51 3197. W. Stoffel and P. Hanfland Z. physiol. Chem. 1973 354,21. 86 C. J. W. Brooks M. T. Gilbert and J. D. Gilbert Anafyf. Chem. 1973,45 896. 20 R. A. W.Johnstone and F. A. Mellon Oestrogens have been analysed in normal human placental tissue at term and in 1-50 microlitres of urine during pregnan~y.~’ Similarly urinary acid meta- bolites have been identified and estimated by g.c.-m.s.88 Triglyceride mixtures from a variety of sources from cow’s milk to coconut oil were successfully ~eparated.~’ 7 Metastables Research on metastable ions continues apace. If all ions which arise through fragmentation in regions of the mass spectrometer other than the ion source are designated as metastables then this section should include collisional activation” and -E mass spectra.” Collisional activation spectra are formed by increasing the pressure in a field- free drift region of the mass spectrometer until ion-neutral collisions result with addition of internal energy to the ions.The extra energy may be sufficient to cause fragmentation and this can be studied by conventional methods of meta- stable peak measurement. Such collision-induced metastables9’ have been studied in an instrument having a reversed Nier-Johnson geometry by direct analysis of daughter ions (DADI). The ion decomposition pathways resulting from collisional activation resembled conventional mass spectra and provided extra information on ions in normal spectra.The relative abundances of most product ions in collisionally activated spectra appear to be dependent on structure rather than internal energy;90 the structures of ions from different precursors were compared. The so-called -E mass spectra are formed by generating negative ions from positive ions in the electrostatic analyser of a double-focusing instrument. If the polarities of the analyser are reversed negative ions thought to arise from the process m+ + N -+m- + N2+are transmitted. Two variations on methods of investigating metastable ions have been proposed. One technique uses the electrostatic analyser region of a double-focusing mass spectrometer to obtain DADI spectra,93 and the other uses a similarly modified instrument to present consecutive metastable transitions on a single chart record.94 8 Conclusion The increasing use of mass spectrometry in biochemical and biomedical fields has given added impetus to the development of computer processing and of new ” J.Jakowski H.-S. Ervast and H. Adlercreutz J. Steroid Biochem. 1973 4 181; H. Adlercreuz and D. H. Hunneman ibid. p. 233. T. A. Witten S. P. Levine M. T. Killian P. J. R. Boyle and S. P. Markey Clinical Chem. 1973 19 963. ’’ T. Murata and S. Takahashi Analyt. Chem. 1973,45 1816. 90 F. W. McLafferty P. F. Bente R. Kornfeld S.-C. Tsai and I. Howe J. Amer. Chem. SOC.,1973 95 2120; F. W. McLafferty R. Kornfeld W. F. Haddon K. Levsen I.Sakai P. F. Bente S.-C. Tsai and H. D. R. Schuddemage ibid. p. 3886. 91 T. Keough J. H. Beynon and R.G. Cooks J. Amer. Chem. SOC. 1973 95 1695. 92 K. R. Jennings Internat. J. Mass Spectrometry Ion Phys. 1968 1 227. 93 J. H. Miller J. Ross,J. Rustenburg and G. L. Wilson Analyt. Chem. 1973 45 627. 94 J. H. Miller and G. L. Wilson Internat. J. Mass Spectrometry Ion Phys. 1973 12 225. Physical Methods-Part (i ) Organic Mass Spectrometry ionization techniques. With advances in these fields the need for prior preparation or derivatization of biological samples can be greatly reduced. The establishment of a firm base for the understanding of mass spectrometric fragmentation mechanisms is a slower process but is being tackled through a variety of sophisticated theoretical and instrumental methods.Finally in a light-hearted vein we have been intrigued by the steady prolifera- tion of jargon in the form of abbreviations applied to or resulting from mass spectrometry. Without thinking too hard we append a list of some of the abbreviations we have come across this year. The prize for the first correct solution is an Honorary Fellowship in the Faculty of Sciences of Llareggub University.” PI PE EI CI FD FI GC MS IE EDD IP AP STIRS HSLC QUISTOR TLC MID LRP HRP API QET INDO CNDO MO EHT CRT DAD1 -E BNI 9QJ L69 3BX ADIOS ’’ Entries to The Dean 0. Dr. Williams c/o Dr. H. van’t Klooster Dept. of Analytical Chemistry Utrecht University The Netherlands.

ISSN:0069-3030    

DOI:10.1039/OC9737000007

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

2 Physical Methods Part (ii) Nuclear Magnetic Resonance By I. H. SADLER Department of Chemistry University of Edinburgh West Mains Road Edinburgh EH9 UJ The field of n.m.r. spectroscopy is so wide that it is impossible in a Report of this size to cover all aspects of the subject. This Report concentrates therefore almost exclusively on chemically induced dynamic nuclear polarization which receives little attention in other reports and pulse Fourier-transform spectroscopy which in recent years has become the routine method for the examination of low-abundance nuclei. A limited number of papers of general interest have been covered in detail rather than making an attempt to be comprehensive. Papers concerned solely with compilation of chemical shifts or coupling constants or with the application of well established procedures have been largely excluded.A small miscellaneous section is mainly devoted to shift reagents. For all other aspects the reader is referred to the second and third volumes of the Specialist Periodical Reports on Nuclear Magnetic Resonance edited by R. K. Harris which follow the layout of the first volume. 1 Chemically Induced Dynamic Nuclear Polarization A monograph’ devoted almost entirely to CIDNP presents some theoretical material and covers a large number of applications also including several dia- grams and figures not available elsewhere. A chapter on chemically induced dynamic electron polarization (CIDEP) is also included. A review2 describes the origin of CIDNP in a qualitative manner and surveys published work.The possibility of simplifying the analysis of CIDNP spectra by the use of lanthanide shift reagents has been in~estigated.~ The fluorinated chelates [Eu(fod),] and [Pr(fod),] can successfully be used to shift the resonance lines of products possessing atoms bearing lone electron pairs although increasing concentrations of shift reagent rapidly reduce signal intensities. At reagent :sub-strate molar ratios greater than ca. 0.05 signals are quenched. Intensities of pro-ducts which complex less well are reduced less so that certain lines may be ’ ‘Chemically Induced Magnetic Polarization,’ ed. A. R. Lepley and G. L. Closs Wiley New York 1973. * D. Bethel1 and M. R. Brinkman Ado. Phys. Org. Chem. 1973,10 53. J.Bargon J. Amer. Chem. SOC.,1973 95 941. 22 Physical Methods-Part (ii) Nuclear. Magnetic Resonance selectively removed. Similarly coinciding emission and absorption lines of different products which may lead to zero signal may be separated to reveal both polarizations. During reactions line positions approach the original chemical shifts partly owing to a decrease in the reagent :substrate ratio. Systems that produce shift-reagent poisons e.g. acids as reaction products are to be avoided. High-field CIDNP continues to prove useful in the study of the mechanisms of reactions. Some examples showing interesting or unusual features are reported here. Decomposition4 of benzoyl-P-bromopropionyl peroxide in bromotri- chloromethane produces after decarboxylation of the P-bromopropionyloxyl radical a singlet radical pair which yields polarized P-bromoethyl benzoate (1) as a recombination product and unpolarized 1,2-dibromoethane (2) as a transfer product (Scheme 1).The same result is obtained for the ester (1) using chloro- benzene in place of bromotrichloromethane. These results consistent with 0 S II BrCH,CH,Cyp PhCO; eH,CH,Br -+ eH,CH,Br I I PhCO BrCCI, 0 .t + kH,CH,Br PhCO,CH,CH,Br BrCH,CH,Br + 'CCI €A unpolarized H C-CH \/ Br A Absorption; E Emission; S Singlet radical pair; T Triplet radical pair; F Radical pair formed by diffusive encounter. Scheme i Kaptein's rule,5 imply that the two pairs of methylene protons in the bromo- ethyl radical have hyperfine couplings of opposite signs and are not equivalent thus supporting the linear structure (3).A popular alternative the bridged radical (4) can be excluded as a ground state for the bromoethyl radical since this would have equivalent methylene groups which would show the same polarization in the ester (1) and also result in a polarized signal for (2). This study does not however rule out participation by bromine in the decarboxylation step. During a kinetic study of the reaction of aniline with isoamyl nitrite in carbon tetrachloride at 55-60 "Ctwo time-separated maxima were observed6 for the 'J. M. Hargis and P. B. Shevlin J.C.S. Chem. Comm. 1973 779. ' R. Kaptein Chem. Comm. 1971 732. I. P. Gragerov A. F. Levit L. A. Kiprianova and A. L.Buchachenko Org. Magn. Resonance 1973.5. 445. I. H. Sadler emission signals of benzene and also for those of chlorobenzene. This implies that these products are generated by two consecutively formed phenyl radical sources which is consistent with a previously proposed' mechanism outlined in Scheme 2. PhNH + C,H,,ONO -P PhNHNO PhN=NOH Ph-N=N-0-N=N-Ph / -Nz I 5 Ph-N=N-0' 'Ph -+ Ph' -+ PhX X = H or C1 E I Ph-N=N-OPh PhO' 'Ph -+ Ph' -+ PhX Scheme 2 Detailed investigations of the reactions occurring during Grignard-reagent formation have been reported. Polarization observed for the main product RMgX and the hydrocarbon by-products R(H) and R(-H) are shown to arise from a radical pair 2R formed by diffusive encounters of radicals formed prior to Grignard-reagent formation.A comparison of the CIDNP spectra obtained' during the ferric salt-catalysed reaction between isopropylmagnesium bromide and isopropyl bromide the reaction with both reagents deuteriated at C-2 and the reactions with only one reagent deuteriated shows that polarization arises only for the hydrocarbon products propene and propane derived from the alkyl halides. Product analysis indicates that similar quantities of these hydrocarbons are also formed from the Grignard reagent indicating that this compound must react via a non-radical pathway. On the basis of CIDNP signals obtained during the reaction of p-chlorobenzenediazoniumfluoroborate with t-butylmagnesium chloride it has been proposed" that the reduction and addition reactions proceed via the same mechanism and are competitive.Polarizations obtained' for the photo-Fries rearrangement of p-cresyl p-chlorobenzoate to 2-hydroxy-4-methyl-4'-chlorobenzophenone show that the product is formed by cage recombination of a singlet radical pair. The enhance- ment factor for the polarization of the methyl protons was in agreement with the ' I. P. Gragerov and A. F. Levit Zhur. org. Khim. 1968.4 10; ibid. 1969 5 310. H. W. H. J. Bodewitz C. Blornberg and F. Bickelhaupt Tetrahedron 1973 29 719. R. B. Allen R. G. Lawler and H. R. Ward J. Amer. Chem. Soc. 1973.95 1692. lo V. I. Savin I. D. Ternyachev and Y. P. Kitaev Org. Magn. Resonance 1973,s. 449. ' ' W. Adam J. A. de Sanabia and H. Fischer J.Org. Chem. 1973.38,257 1. Physical Methods-Part (ii) Nuclear Magnetic Resonance theoretical value for an exclusive radical-pair route. The related photo-Claisen rearrangement has provided an opportunity to examine the difference in be-haviour of singlet and triplet radical-pair recombinations resulting from the difference in sign of the spin-density distribution in the radicals involved. During the photolysis of p-cresyl P-methallyl ether (5) the polarization (A) of the p-methyl protons in the meta-product (9) was opposite to the polarizations (E) of the corresponding protons in the ortho-product (8) and the para-product (7). This initially surprising result is interpretedI2 in Scheme 3. The spin-density Scheme 3 distribution in the singlet radical pairs suggests that these are likely to undergo recombination resulting in starting material (5) and products (7) and (8).Triplet radical pairs cannot form these products in view of the unfavourable spin pairing but have the correct phase for meta coupling to give the biradical(6) which under- goes spin inversion and bond reorganization to allow the formation of product (9). The possibility of the formation of (9) by other routes was eliminated. This system is unusual in that it allows in principle at least the observation of CIDNP W. Adam H. Fischer H.-J. Hansen H. Heimgartner H. Schmid and H.-R. Waespe Angew. Chem. Internat. Edn. 1973 12 662. I. H. Sadler effects of cage recombination with accompanying escape reactions although in practice escape products were detected.CIDNP can be extremely valuable in the detection of short-lived or unstable reaction products. The photoreduction of acetaldehyde (10) and the photo- cleavage of acetoin (12) appear to proceed through a radical pair formed by diffusive encounters or in the triplet state (Scheme 4). Polarized resonances due T.F 2MeCHO 3 MekHOH kOMe & MeCHOHCOMe J MkHOH + kOMe + AfE bisproportionation EtOH + (11) Scheme 4 to vinyl alcohol (1 1) are obtained’ although these regions are free of resonances after the reaction. Linewidths suggest that this intermediate has a lifetime not shorter than one second. The enol of acetone has similarly been detectedl4 during the photoreduction of acetone in propan-2-01 and that of acetophenone” during the photodecomposition of acetophenone in phenol.In these studies detection was possible as a consequence of the large signal enhancements. Detailed analyses of the CIDNP spectra obtained during the photolysis of pivalaldehydel6 and propionaldehyde’ have been given including the effect of solvent on the primary photochemical steps. CIDNP spectra have also been observed’* for the methyl triplet (AIE)of propyl acetate formed during the thermal decomposition of 2-hydroperoxy-2-methyltetrahydrofuran.Polarization is not normally observed during hydroperoxide decompositions owing to the small proton hyperfine coupling to an electron localized on oxygen. Decarboxylation of the initially formed radical generates an alkyl radical from which polarization may be observed.Emission signals are obtained” for the proton bound to nitrogen in the amide formed during the thermal decomposition of ethyl azido- formate in decalin that are consistent with an abstraction-recombination process. ‘H and 19Femission signals respectively have been obtained during the reaction l3 B. Blank and H. Fischer Helv. Chim. Acta 1973 56 506. I4 G. P. Laroff and H. Fischer Helv. Chim. Acta 1973 56 201 1. Is S. M. Rosenfeld R. G. Lawler and H. R. Ward J. Amer. Chem. SOC.,1973 95 946. H. E. C. Chen A. Groen and M. Cocivera Canad. J. Chem. 1973 51 3032. H. E. C. Chen S. P. Vaish and M. Cocivera Chem. Phys. Letters 1973 22 576. Is A. V. Ignatenko A. V. Kessenikh V. G. Glukhovtsev and M. A. Nadtochii Org. Magn.Resonance 1973,5 219. l9 M. R. Brinkman D. Bethell and J. Hayes Tetrahedron Letters 1973 989. Physical Methods-Part (ii) Nuclear Magnetic Resonance of benzenediazonium fluoroborate6*20 and of the p-fluoro-derivative” with alkoxide ions although the proposed rationalization in terms of one-electron transfer from the alkoxide ion to the diazonium cation must be reconsidered in view of material presented later. Evidence for the formation of the biradical(l3) during the thermal decomposition of a variety of possible precursors is furnished’ by the observation of emission signals from the biradical dimers (14) and (1 5). \ / 1 The application of CIDNP to the determination of the signs of hyperfine coupling constants (avalues) is of particular value since although the magnitudes of these parameters are directly available from e.s.r.spectra their signs are not always readily obtained by this technique. Photochemical decomposition of the corresponding diaroyl peroxides in carbon tetrachloride indicates” that the fluorine a values of the pentafluorophenyl radical are positive for the ortho and *O N. N. Bubnov B. Y. Medvedev L. A. Poljakova K. A. Bilevitch and 0. Y. Okhlobystin Org. Magn. Resonance 1973 5 437. * W. R. Roth and G. Erker Angew. Chem. Infernat. Edn. 1973,12,503,505; W. R. Roth M. Heiber and G. Erker ibid. 504. 22 H. D. Roth and M. L. Kaplan J. Amer. Chem. SOC.,1973 95 262. I. H. Sadler meta positions but negative for the para position with aFo> aFm> aFP,and that the fluorine a values for both 0-and p-fluorophenyl radicals are both positive with uFo> aFp.Such results are in accord with a radical having no appreciable n-character.A similar of the photochemical decomposition of diphenyl-diazomethane and its di-p-fluoro-derivative in 0-and in m-fluorobenzyl chlorides confirms that for a benzyl radical the fluorine a value is positive for ortho-substitution but negative for meta-substitution by fluorine. CIDNP of nuclei other than 'H and "F are being increasingly studied. The low-abundance nuclei '3C and ''N have a number of advantages. Their hyperfine coupling constants can be considerably larger the nuclear relaxation times longer and the spectra are generally simpler and easier to interpret in detail than those of protons.Polarizations of both these nuclei have been observed24 during the thermal decomposition of diazoaminobenzene (16) in cycloheptanone enhancement factors being in the region of 20000 for the quaternary C atoms in the diphenylamine and biphenyl formed no 3C polarization being observable in the starting material. The use of diazoaminobenzene enriched with ''N in the central position yielded ''N polarization in the starting material only. Diazo- aminobenzene enriched at the terminal positions showed no polarization in the starting material but large polarizations with enhancement factors of at least loo00 for aniline (A) and diphenylamine (E). Such results are consistent with the reversible decomposition of diazoaminobenzene to give a phenylamino-phenyl- diazo radical pair in which the latter must be a localized a-radical in view of the apparently much greater hyperfine coupling to the radical site.A similar study25 of the azo-coupling reaction of benzenediazonium fluoroborate with alkaline solutions of phenol in methanol indicated that the coupling process is unlikely Ph-N=N-NH-Ph Ph-NZN' HNPh Ph -dimerization Ph' +-Ph' HNPh -.) PhNHPh to be that of a combination of a radical pair formed by one-electron transfer from the phenoxide ion to the diazonium cation as had previously been proposed.26 Strong approximately equal polarizations of the quaternary carbon (' 3C) and both nitrogen atoms ("N) of the starting diazo-compound implied that the Ph-NZN' radical was not involved (in view of the triazene study referred to above) and that in the radical responsible the electron must be strongly delocalized 23 M.R.Brinkman D. Bethell and J. Hayes J. Chem. Phys. 1973 59 3431. 24 E. Lippmaa T. Saluvere T. Pehk and A. Olivson Org. Magn. Resonance 1973,5,429. '' E. Lippmaa T. Pehk T. Saluvere and M. Magi Org. Mugn. Resonance 1973,5441. 26 N. N. Bubnov K. A. Bilevitch 1. A. Poljakova and 0.Y. Okhlobystin J.C.S. Chem. Comm. 1972 1058. Physical Methods-Part (ii) Nuclear Magnetic Resonance with practically equal hyperfine coupling constants to both nitrogen atoms. A possible scheme is proposed in which an unstable diazoanhydride Ph-N=N-0-N=N-Ph forms a Ph-N=N-0' (N2)Ph' radical pair in which spin selection occurs. Reaction of the polarized phenylazoxy-radical with methanol regenerates a polarized diazonium ion which may undergo coupling.Since the reaction is very fast and the nuclear relaxation times relatively long + Ph-N2-O' + MeOH -+ PhN + 'CH,OH + OH-practically all the polarization is carried over to the coupling product even though the last stage is a heterolytic process. The suggestion that this strongly delocalized radical is a phenylazoxy-radical is however in conflict with e.s.r. data for another radical assigned2' the same formula in which the electron appears to be largely confined to the oxygen atom. It is clear that the use of 15N CIDNP is going to be of great value in the study of reactions of this type of compound and of azo- compounds in general. Comparison of the results2* of 13C and proton CIDNP studies on the de- composition of acetylbenzoyl peroxide shows that for the benzoyl radical the sign of the I3C a values for C-1 and C-2 (C-6) of the ring are positive and negative respectively.A detailed of the thermal decomposition of the diazacyclo- hexanone (17) in perchlorinated solvents in the presence and in the absence of added alkyl iodide reveals that a singlet carbene (18) is first formed which reacts to give a singlet radical pair. Intersystem crossing to the triplet state and cage and escape reactions occur at comparable rates and the reaction product (19) is polarized largely in secondary reactions involving diffusive encounters of free radicals. A free-radical pathway for the rearrangement of the oxime (20)to the thio-oxime (21) is proposed30 on the basis of polarized I3C resonances of the C-1 and C(=N) atoms in the product.It cannot however be too strongly emphasized that the observation of CIDNP effects alone does not rule out the existence of alternative non-radical routes for product formation as a recent rearrangement study3 has shown. '' J. I. G. Cadogan R. M. Paton and I. C. Thomson. Chem. Comm. 1969 614. 2a A. V. Kessenikh P. V. Petrovskii and S. V. Rykov Org. Magn. Resonance. 1973 5 227. 19 G. A. Nikiforov S. A. Markaryan I. G. Plekhanova B. D. Sviridov S. V. Rykov V. V. Ershov A. L. Buchachenko T. Pehk T. Saluvere. and E. Lippmaa Org. Magn. Resonance 1973 5 339. 'O C. Brown R. F. Hudson and A. J. Lawson J. Amer. Chem. Soc. 1973.95 6500. 3' W. D. Ollis. I. 0.Sutherland and Y. Thebtaranoth. J.C.S. Chem. Comm. 1973 654. I. H. Sadler (20) Ar = C,H or 3-FC6H (21) 2 Pulsed Fourier-transform Spectroscopy Theoretical Aspects.-A computer program has been devised3' on the basis of the Bloch equations to simulate the behaviour of systems of non-coupled species in multipulse and Fourier-transform n.m.r. experiments. The effect on the magnetization vectors may be calculated for any sequence of pulses and delays. Such a program is useful for the evaluation of errors in the choice of experimental parameters such as pulse angle phase and timing which are critical when measurements of physical quantities such as relaxation times are attempted. It is also valuable in the design of new experiments.Computer simulation may indicate possible difficulties and whether a proposed new experiment may have any real advantage over existing experiments. Amongst the examples considered the conventional repetitive pulse-delay Fourier-transform sequence the measure- ment of spin-lattice (TI)and spin-spin (T,) relaxation times and the time-shared n.m.r. experiment. In addition to obtaining good agreement with experimental results it is shown that systematic noise in the conventional Fourier-transform sequence may be eliminated without loss in sensitivity by alternating the phases of consecutive pulses by 180". The effect of using a finite pulse power is also ex- amined. The advantage of the Bloch-equation approach is that quite complex pulse sequences can be treated without using large amounts of computer time.The major drawback is that tightly coupled spins cannot be examined. A second program devised3 on the basis of the Schrodinger equation has been developed to examine these systems; however the complexity of pulse sequences capable of being examined by this approach is quite restricted. The effect of the decoupling power level on the lineshape and Overhauser enhancement on a system AX is examined and the results suggest that in systems when the dipolar contribution (TI,&to the spin-lattice relaxation time (TI)is much greater than the effective spin-spin relaxation time (Tr),as is often satisfied in practice it should be possible by suitable choice of a very low decoupling power to obtain a nuclear Overhauser enhancement without decoupling thus providing an inexpensive alternative to gated de~oupling.~~ The effect of a finite pulse power for a 90" pulse on non-first- order spin systems the time development of the Overhauser enhancement and the effect of selective and non-selective 180" pulses in a 180°-o-900 sequence on AX and AB systems are also examined.Criteria are also establi~hed~~~~~ which must be met if accurate T2 values are to be obtained using the Carr-Purcell sequence and its variations. 32 P. Meakin and J. P. Jesson J. Magn. Resonance 1973 10 290. " P. Meakin and J. P. Jesson J. Magn. Resonance 1973 11 182. 34 0.A. Gansow and W. Schittenhelm J. Amer. Chem. SOC. 1971,93,4294. '' R. L. Vold R. R. Vold and H.E. Simon J. Magn. Resonance 1973 11 283. Physical Methods-Part (ii) Nuclear Magnetic Resonance 31 The saturation behaviour of spin systems in pulsed experiments has been inve~tigated~~ theoretically and compared with slow-passage continuous-wave experiments with particular reference to intensity measurements. Uncoupled spin systems (e.g. 3C resonance with simultaneous proton decoupling) show saturation behaviour qualitatively similar to that observed in slow-passage experiments. The maximum signal per unit time may be obtained for a pulse interval of T1and pulse angle of 69" if TI = T2 and any residual transverse magnetization is destroyed before a repeat pulse. Considerable differences in relative line intensities may be expected if a high pulsing rate is employed or if large differences in Tl values exist.In strongly coupled spin systems (e.g. proton and fluorine resonance) however relative signal intensities from pulse experi- ments are considerably less sensitive to saturation than those from slow-passage experiments in which inhomogeneous saturation occurs. Provided spin-lattice relaxation is dominated by an external dipolar process such as would be caused by dissolved oxygen a pulsed experiment will cause homogeneous saturation thus giving correct relative line intensities for a coupled system and is particularly suited for accurate measurements. In such cases it is advisable not to degas the samples and also to add a paramagnetic impurity to enhance external relaxation and equalize the relaxation rate.Except in the two-spin-; system intramolecular dipolar relaxation leads to slightly inhomogeneous saturation. General Techniques.-In the conventional pulsed Fourier-transform experiment the sample resonances are excited by a series of equally spaced radiofrequency pulses of constant width and amplitude. This is equivalent to simultaneously supplying a set of closely spaced frequencies of approximately equal power intensities throughout the spectrum. Fourier analysis of the excitation sequence yields amplitudes and phases of the closely spaced frequencies. Conversely the excitation could be Fourier-synthesized from the frequency spectrum. A method has been described3' for sample resonance excitation equivalent to simultaneously providing a range of frequencies having any pre-specified power-intensity dis- tribution.This is accomplished by computing the Fourier synthesis of the desired frequency distribution and using the function so obtained to amplitude- or width-modulate a sequence of radiofrequency pulses. The n.m.r. spectrum is obtained by Fourier transformation of the response of the spin system to this excitation. This capability has a number of advantages. Strong residual solvent lines may be selectively suppressed or removed while observing all the other spectral lines by choosing a frequency distribution which has zero intensity in the appropriate region and uniform intensity elsewhere. Unlike alternative solvent resonance elimination methods phase anomalies are not introduced into the final spectrum.Simultaneous homonuclear decoupling of one or more resonances may be carried out by specifying very high ( x 300) power intensities at selected positions in the frequency distribution. This has a practical advantage over the use of a conventional decoupler which requires to be frequency-locked 36 R. R. Ernst and R. E. Morgan Mol. Phys. 1973,26,49. 37 B. L. Tomlinson and H. D. W. Hill J. Chem. Phys. 1973 59 1775. 32 I. H. Sadler to the magnetic field and can only irradiate one frequency or frequency band at medThis technique should permit greater flexibility than has previously been possible in standard n.m.r. experiments and should allow extra freedom in the design of new experiments. Resolution enhancement in a conventional pulsed Fourier-transform experi- ment is normally carried out by multiplying the accumulated free induction decay [FID) by an exponentially increasing function before Fourier transformation.This procedure increases the weighting of the FID as a function of time resulting in narrower lines at the expense of the signal to noise ratio. This technique has been succ%ssfully applied * to resolve ’B-’ ’B and B-I H couplings in the ’B n.m.r. spectra of boron hydrides which normally show unresolved broad bands. A more abrupt FID weighting procedure has been found suitable39 in the case of non-proton-decoupled ’3C decays which normally show an initial decay followed by a series of beats. If only the beat pattern is transformed i.e. giving a zero weighting to the initial decay a highly resolved spectrum is obtained.The usual baseline distortions introduced into the final spectrum by truncation of the FID are negligible as this takes place between the end of the initial decay and the development of the first beat. Alternative methods4’ of resolution enhancement involve the subtraction of a ‘broadened’ spectrum from a normal one. The broad- ening may be achieved in a non-selective manner by multiplying a normal FID by an exponentially decreasing function as in signal to noise enhancement procedures or in a selective fashion by the use of a paramagnetic ion which binds selectively to a particular site in the molecule broadening only some of the resonances. In the latter case the difference spectrum obtained identifies signals from nuclei close to the binding site.These methods have been of value in the proton n.m.r. studies of proteins. INDOR spectroscopy in which the intensity of a single line is monitored while sweeping a second irradiating field through the remainder of the spectrum is a valuable tool for the analysis of complex spectra but is unfortunately confined to continuous wave (CW)operation. Two methods have been presented by which the same information may be obtained in a pulsed Fourier-transform experiment. In each case a single resonance spectrum obtained in the usual pulse-transform manner is subtracted from the spectrum of the sample in which the populations of the pair of levels associated with a particular transition are disturbed from the equilibrium distribution but otherwise obtained under the same conditions.The methods differ in the way in which the populations are altered. In one meth~d,~’ referred to as Fourier transform pseudo INDOR spectroscopy (FT$I) a weak irradiating field is applied continuously at the transition frequency. In the other method,42 referred to as selective population inversion (SPI) the ‘observing’ 38 A. 0.Clouse D.C. Moody R. R. Reitz T. Roseberry and R. Schaeffer J. Amer. Chem. SOC.,1973 95 2496. 39 W. B. Moniz and S. A. Sojka J. Magn. Resonance 1973 12 214. 40 I. D. Campbell C. M. Dobson R. J. P. Williams and A. V. Xavier J. Magn. Resonance 1973 11 172. 41 J. Feeney and P. Partington J.C.S. Chem. Comm. 1973 61 1. 42 K. G. R.Pachler and P. L. Wessels J. Magn. Resonance 1973 12 337. Physical Methods-Part (ii) Nuclear Magnetic Resonance pulse is immediately preceded by a selective 180"pulse at the transition frequency thereby inverting the populations of the connected levels only. This pre-pulse must be short compared with the 7''values of the nuclei yet of sufficiently low power not to perturb other levels. In such experiments the frequencies of the lines and the signs of their intensities in the difference spectrum so obtained are identical with those in the normal CW INDOR spectrum in which the same transition has been monitored. This follows since the progressive or regressive nature of a pair of transitions is apparent regardless of which of the pair is irradiated.The actual intensity changes however need not be the same. Spin-lattice relaxation times (Tl) are most commonly measured using the 'inversion-recovery' pulse sequence (T-180-~-90) which requires a delay (T)of about five times the longest TI in order that the spin system attains Boltzmann equilibrium before repetition of the initial 180" pulse. A new sequence43 elimin- ates this delay and also removes the necessity of producing precise 90" pulses (Scheme 5). Initially a homogeneity-spoiling pulse (HSP) ensures that the net lHSPt 1 Scheme 5 magnetization (M)is in the z-direction i.e.no transverse magnetization is present. A 90" pulse follows which shifts the net magnetization into the x-y plane and a second HSP rapidly dephases the nuclear spins (p),resulting in zero magnetization in all directions.The spin system is then allowed to relax partially during a delay (z) resulting in a new magnetization along the z-axis which is sampled with a 43 G. G. McDonald and J. S. Leigh. J. Magti. Resonance 1973 9. 358. 34 1. H. Sadler second 90"pulse and the FID signal acquired. The sequence (HSP-~C~HSP-T-~O) may then be repeated immediately. The peak intensities (A,) are given by A = A [l -exp (-z/T1)],where A represents the corresponding intensity for the spin system at equilibrium. Excellent agreement was obtained for the Tl values for H-4 and H-7 in tryptophan determined by this sequence and by the inversion- recovery technique the latter procedure taking about four times as long for a given number of transients.This sequence should therefore be particularly valuable in the measurement of I3C TI-values. This scheme is also suitable for the elimination of residual solvent resonance when obtaining proton spectra of dilute samples in deuterium oxide. A chemical method44 has been used for the removal of oxygen from samples to be used for TI determinations where conven- tional degassing techniques proved inadequate. Carbon-13 Techniques and Results.-A comprehensive book45 on I3C magnetic resonance covering the literature up to mid-1970 is now available. All chemical shift data have been referred to TMS as is now general practice. Since much of the work was written before the commercial availability of Fourier-transform n.m.r. spectrometers continuous-wave techniques are covered more extensively than pulsed methods.This book complements the other available on 13C n.m.r. I3Cmagnetic resonance is now used continually as an aid in molecular struc- ture determination in all branches of organic chemistry particularly in areas concerning natural products with complex molecular skeletons. The use of single-frequency off-resonance decoupling allows in principle at least the identi- fication of methyl methylene methine and quaternary carbon atoms from the residual splitting it being normally assumed that these carbon resonances appear as quartets triplets doublets and singlets respectively. However caution should be exercised in the interpretation of such spectra since a triplet is only guaranteed from a methylene group where the two protons have the same chemical shift.Otherwise the multiplet pattern depends upon the position of irradiation with respect to the proton4' resonances. Two lines are obtained if the irradiation lies mid-way between the proton resonances three lines are obtained if irradiation is on one of the proton resonances and four lines are obtained if irradiation is elsewhere. In this latter instance the two centre lines are often very close together and the patterns are often somewhat indistinct for a rigid or semi-rigid -CH2CH2-fragment.48 Such effects may be expected for complex natural products and once recognized may be diagnostically useful. Unusual effects are also sometimes observed49 when there is strong coupling between two or more 44 J.Homer A. R. Dudley and W. R. McWhinnie J.C.S. Chem. Comm. 1973 893. 45 J. B. Stothers 'Carbon-13 N.M.R. Spectroscopy,' Academic Press New York 1973. 46 G. C. Levy and G. L. Nelson 'Carbon-13 N.M.R. for Organic Chemists' Wiley New York 1972. 47 E. Wenkert D. W. Cochran E. W. Hagaman F. C. Schael N. Neuss A. S. Katner P. Potier C. Kan M. Plat M. Koch M. Mehri J. Poisson N. Kunesch and Y. Pollard J. Amer. Chem. SOC.,1973 95 4990. 48 I. H. Sadler unpublished observation. 49 R. A. Newmark and J. R. Hill J. Amer. Chem. Soc. 1973,95,4435. Physical Methods-Part (ii) Nuclear Magnetic Resonance 35 protons with the same chemical shift but bonded to different carbon atoms in a molecule. In such cases an effect is observed similar to ‘virtual coupling’ in proton n.m.r.spectra. The olefinic carbon atom in fumaric acid appears as a quintet whose line intensities and positions depend upon the position and intensity of the irradiating frequency. This arises because the effective 13C-’H coupling constant becomes reduced to approximately the same size as the ‘H-’H coupling constant and the carbon atom appears similarly coupled to both protons. In a complex single-frequency off-resonance-decoupled spectrum the quaternary carbons may not be readily identified owing to their reduced intensity resulting from their longer relaxation times and smaller nuclear Overhauser enhancements. By the use of low power for proton noise decoupling quaternary 13C n.m.r. signals may be increased relative to those from hydrogen-bearing carbon atoms which are considerably reduced broadened or eliminated.This may be achieved directly” by the use of a low decoupling power (ca. 0.1 W) centred on and distributed over the entire proton spectrum or indirectly5 by employing narrow- band (ca.300 Hz) proton decoupling at the more usual power levels applied well upfield (6-8p.p.m.) from tetramethytsilane as in an off-resonance experiment. In such experiments it is possible to obtain a significant signal from a methylene carbon atom if the two bonded protons have the same chemical shift ;this situation is easily recognized but is not as common as might be supposed and the technique is particularly valuable in the case of relatively rigid asymmetric molecules.Resonances from protonated carbon atoms can often be assigned by selective proton-decoupling experiments or graphically52 from a series of off-resonance- decoupled spectra. This latter method has recently been shown applicable53 to molecules such as 1-nitronaphthalene that have very complex non-first-order proton spectra providing that analysis of the proton spectrum is possible. In alkyl-substituted aromatic and heteroaromatic molecules it is possible5* to distinguish between carbon atoms two or three bonds distant from the alkyl protons and ring carbon atoms more than three bonds away since the former under selective irradiation of the aromatic protons show residual splitting due to long-range l3C-IH coupling with the alkyl protons. Thus C-1 C-2 and C-6 in toluene and the quaternary carbons in tris-(3-methylphenyl)phosphinemay be readily assigned.The assignment of signals from quaternary carbon atoms is however usually less readily accomplished. For the sesquiterpenoid lactone melampodin this has been achieved55 by observing small but definite intensity increases which occur in selectively decoupled spectra where the decoupling frequency is centred on protons separated from the quaternary atom by two or by three bonds rather than on more distant protons. In large isotropically re-50 I. H. Sadler J.C.S. Chem. Comm. 1973. 809. E. Wenkert A. 0. Clause D. W. Cochran and D. Doddreil J. Amer. Chem. Soc. 1969,91 6879; A. Allerhand R. F. Childers and E. Oldfield Biochemistry 1973 12 1335 and references therein.’* B. Birdsail and J. Feeney J.C.S. Perkin 11 1972 1643. ’’ J. W. Emsley J. C. Lindon and D. Shaw J. Mugn. Resonance 1973 10 100. ’’ S. Ssrensen M. Hansen and H. J. Jakobsen J. Mugn. Resonance 1973 12 342. ’’ N. S. Bhacca F. W. Wehrli and N. H. Fischer J. Org. Chem. 1973,38 3618. 36 I. H. Sadler orientating molecules assignment can sometimes be made from Tl values since in such molecules quaternary carbon atoms are largely or completely relaxed by the intramolecular dipole-dipole mechanism. Since the nearest protons are generally those bound to a-carbon atoms the relaxation rate will be very roughly proportional to the number of a-carbon atoms. This te~hnique,'~ in conjunction with shielding arguments has allowed unambiguous assignments in the alkaloids codeine and brucine.Tl values have also been used for the assignment of proton- ated carbon atoms (see below). In some circumstances assignments may be made by careful visual examination of undecoupled 13Cn.m.r. spectra. The carbon atoms a and P to the substituents in symmetrically ortho-disubstituted benzenes show characterization patterns which may be used as finger prints.57 In anthracene benzocyclobutane 43-benzoxepin indane and naphthalene the fine structure of thedoublet components that result from the one-bond I3C-lH coupling leads to broad multiplets for the a-carbon atom and distinct doublets sometimes sharply split into further doub- lets for the P-carbon atom. Where the chemical shift difference between the a-and b-protons is smaller than 10 Hz however the pattern for the P-carbon atom becomes indistinguishable from that of the a-carbon atom.In theory complete analysis of the region would lead to the same conclusion. However this is often tedious and difficult and not always possible; in such cases 'finger prints' are extremely valuable. The chemical shift parameters58 devised by Grant and Paul from the study of a series of predominantly linear alkenes and used for 3C resonance assignments have been reviseds9 to include also highly branched alkanes and are particularly suitable for predicting shifts in olefin polymer sequences. No additional param- eters have been introduced and most deviations between calculated and measured values are considerably less than 1 p.p.m.Further analysis60v61 of the spectra of methyldecalins has led to a new and simpler set of substituent and conformational parameters6' applicable to aliphatic hydrocarbons in general although it is not always possible specifically to assign resonances closer than 2 p.p.m. Parameters for the prediction of carbon shifts in a fragment XCH,CH,Y have beendeduced62 for a series of 15 different substituents. On the basis of a set of predictive rules,63 a Fortran IV computer program entitled AMINE has been compiled64 to deduce the structures of alicyclic amines from their empirical formulae and fully proton- decoupled 13C n.m.r. spectra. Tests on over a hundred amines show that the program is accurate and selective even for large amines with many millions of 56 F.W. Wehrli J.C.S. Chem. Comm. 1973 380. 57 H. Giinther H. Schmickler and G. Jikeli J. Magn. Resonance 1973 11 344. '* D. M. Grant and E. G. Paul J. Amer. Chem. Soc. 1964,86 2984. 59 C. J. Carman A. R. Tarpley and J. H. Goldstein Mncromolecules 1973 6 719. 6o D. K. Dalling and D. M. Grant J. Amer. Chem. Soc. 1972 94 5318. 61 D. K. Dalling D. M. Grant and E. G. Paul J. Amer. Chem. SOC.,1973,95 3718. 62 G. E. Maciel L. Simeral P. L. Elliott and K. Cribley J. Phys. Chem. 1972 76 1466; L. Simeral and G. E. Maciel J. Phys. Chem. 1973 77 1590. " H. Eggert and C. Djerassi J. Amer. Chem. SOC.,1973 95 3710. 64 R. E. Carhart and C. Djerassi J.C.S. Perkin 11 1973 1753. Physical Methods-Part (ii) Nuclear Magnetic Resonance 37 structural isomers.A list of sources of predictive rules for other classes of organic compounds is also given. Numerous papers have been concerned with the measurement of 3C chemical shifts or I3C-lH coupling constants and relatively few with 13C-13C coupling constants. The effect of deuteriation on 13C chemical shifts and 13C-1H(2D) coupling constants of a number of organic compounds has been e~amined.~’ Upfield shifts of up to 1.4p.p.m. are observed for the deuteriated carbon atom. Isotope effects on shifts correlate with hybridization and electron withdrawal at the deuteriated carbon within a comparable series of compounds. Coupling constants are within 1 Hz of the predicted value [J(C H)/J(C D) = yH/yD]. The incorporation of deuterium atoms does not appear to alter the I3C-lH coupling constants.The correlation between hybridization and directly bonded 3C-1 H and 13C-13C coupling constants is an accepted method for the estimation of s-character of a C-H or C-C bond most studies having been restricted to alicyclic hydrocarbons. The determination66 of 3C-1 H coupling constants for carbonyl compounds in the bicyclo[2,2,l]heptane series shows that compared with alicyclic and monocyclic ketones coupling constants are increased for bridgehead carbon atoms o! to the carbonyl group. It is proposed that this is due to a change in hybridization resulting from a hyperconjugative interaction between the carbonyl group and a strained a-bond of the molecular skeleton. The ring-current effect important in proton studies has received comparatively little attention in 3C n.m.r.Since the absolute value of this effect a few p.p.m. at the most from proton n.m.r. is independent of the nucleus involved its importance for nuclei with wide chemical shift ranges might be expected to be minimal. Comparison of systems where ring currents may be present with geometrically similar systems with no ring current such as [12]paracyclophane with cyclopenta- de~ane~~ or bridged annulenes with corresponding ‘no ring current’ molecules,6* shows that a diamagnetic ring current does in some cases have a small effect on I3Cchemical shifts but that in most cases it is masked by other factors such as the immediate electronic environment and paramagnetic contributions to shielding that affect the shifts more strongly.There appears to be little evidence for a paramagnetic ring-current effect on the I3C resonances of biphenylene and related additivity rules accounting satisfactorily for the resonance positions. These results contrast strongly with those from proton resonance where ring currents when present dominate shifts. Thus I3C resonance cannot be used as a probe for the magnetic properties of cyclic n-electron systems. This is clearly evident” in the bridged systems (22)-(25). Proton spectra show that 65 H. N. Colli V. Gold and J. E. Pearson J.C.S. Chem. Comm. 1973,408; E. Breitmaier G. Jung W. Voelter and L. Pohl Tetrahedron 1973 29 2485. 66 N. H. Werstuik R. Taillefer R. A. Bell and B. Sayer Canad. J. Chem. 1973 51 3010.67 R. H. Levin and J. D. Roberts Tetrahedron Letters 1973 135. 68 H. Gunther H. Schmickler H. Konigshofen K. Recker and E. Vogel Angew. Chem. Internat. Edn. 1973 12 243. 69 A. J. Jones P. J. Garrett and K. P. C. Vollhardt Angew. Chem. Internat. Edn. 1973 12. 241. ’’ H. Gunther H. Schmickler U. H. Brinker K. Nachtkamp J. Wassen and E. Vogel Angew. Chem. Internat. Edn. 1973 12. 760. I. H. Sadler (22)and (24)are clearly olefinic whereas (23) and (25) are delocalized [14]annulenes. Maximum agreement of "C resonances however emphasizes the stereochemical similarities in pairing (22) with (23) and (24) with (25). Thus '3C resonance is here more strongly influenced by ring size strain and conformation. An erroneous suggestion7'that (24) is homoaromatic arises from incorrect ''C assignments.Increasing use of 13C n.m.r. is being made in the elucidation of biosynthetic pathways by the incorporation of 'C-enriched precursors. Comparison of line intensities in the spectra of products obtained with and without labelled precur- sors indicates the sites of incorporation. Primary and secondary pathways have been deduced for the formation of prodigiosin from Serratia marcescens using labelled amino-acid~,~' and similarly for streptovaricin from Streptornyces spectabilis using carboxy-labelled pr~pionate.'~ A new pathway for the bio- synthesis of mollisin from Mollisia caesia has been deduced from 13C-'3C coupling of resonances where doubly labelled acetate was used.74 Since the pre- paration of '3C-enriched materials leaves considerably larger quantities of '2C-enriched materials it has been proposed7' that "C labelling may become a cheaper method than 13C labelling.In such cases identification would be by missing lines rather than by enhancement. Variable-temperature ''C studies have provided (a)evidence76 for the presence of crown conformations in cyclo-octane and its derivatives (b)evidence77 for the valence-tautomeric equilibrium in the 1,6-methano[ lolannulene system (26)*(27) although observation of the individual tautomers was not possible and (c) an estimation78 of the free energy of activation (10.8kcal mol- ') of the 71 E. Wenkert E. W. Hagaman L. A. Paquette R. E. Wingard and R. K. Russel J.C.S. Chem. Comm. 1973 135. 12 H. H. Wasserman R.J.. Sykes P. Peverada C. K. Shaw R. J. Cushley and S. R. Lipsky J. Amer. Chem. SOC.,1973 95 6874. 73 B. Milavetz K. L. Rinehart J. P. Rolls and W. J. Haats J. Amer. Chem. SOC.,1973 95 5793. 74 H. Seto L. W. Cary and M. Tanabe J.C.S. Chem. Comm. 1973 867. 75 S. B. W. Roeder J. Magn. Resonance 1973 12 343. 76 F. A. L. Anet and J. T. Basus J. Amer. Chem. SOC.,1973 95 4424. 77 H. Gunther H. Schmickler W. Bremser F. A. Straube and E. Vogel Angew. Chem. Internat. Edn. 1973 12 570. 78 S. Masamume A. V. Kemp-Jones J. Green D. L. Rabenstein M. Yasunami K. Tabase and T. Nozoe J.C.S. Chem. Comm. 1973 283. Physical Methods-Part (ii) Nuclear Magnetic Resonance (27) (26) R = Me or CN degenerate rearrangement of tropolone derivatives (28).The use7' of a probe de- signed to take 20 mm diameter spinning sample tubes in a field of 14.2 kG shows that a given signal to noise may be achieved in about one twentieth of the time required on commercial instruments employing 12 mm tubes operating above 20 kG.This is of particular value in the study of concentration-limited materials such as non-degraded natural biopolymers. If a full Overhauser enhancement is obtained the lowest acceptable concentration is about 2 mM if an acceptable spectrum is to be obtained in 10h of accumulation. Numerous single-carbon resonances were observed for the first time in the aromatic carbon region of hen egg-white lysozyme. Further details have been presented" concerning the method for obtaining enhanced high-resoltion n.m.r.spectra of low-abundance nuclei (e.g. 'jC "N) in the presence of high-abundance nuclei (e.g. 'H) in solids. Carbon-13 Relaxation Studies.-A well presented review has appeared concerning I3C spin-lattice relaxation studies and their value in organic chemistry.8' The concepts of the rotating-frame and spin-lattice relaxation mechanisms are dis- cussed in a non-mathematical fashion. Methods for the measurement of TI values and for the differentiation of relaxation mechanisms are examined along with applications to the determination of molecular structure molecular tum- bling and rotational and segmental motion. The review is strongly recommended. A comprehensive study8* of spin-lattice relaxation in benzene and its deriva- tives has been reported.Some of this work appeared as preliminary communi- cations and was described in last year's Report. New results are given here. The general assumption that intermolecular '3C-'H dipole4ipole contributions to 13C relaxation are negligible was shown to be true even for non-protonated carbon atoms in toluene by studying dilute solutions of toluene in perdeuterio- toluene. These yielded the same values as were obtained with neat toluene. '' A. Allerhand R. F. Childers and E. Oldfield J. Magn. Resonance 1973 11 278; Biochemistry 1973 12 1335. 8o A. Pines M. G. Gibby and J. S. Waugh J. Chem. Phys. 1973,59 569. G. C. Levy Accounts Chem. Res. 1973 6 161. 82 G. C. Levy J. D. Cargioli and F. A. L. Anet J. Amer. Chem. Soc. 1973.95 1527. I.H. Sadler Shorter T values for carbon atoms para to essentially symmetrical substituents indicate preferred rotation of the molecule about an axis bisecting the substituent and the ring. This sometimes allows the assignment of resonances of protonated carbons where chemical shift arguments are inadequate. In 3-bromobiphenyl (29) for example rotation is anticipated to occur largely about the long axis and the C-3-C-6 axis with the former slightly preferred. On this basis assignments were made for the protonated carbon atoms (TIvalues in seconds). This behavi- our was paralleled in 3-nitrobiphenyl (30) where assignments are possible on (29) (30) chemical shift arguments alone. The self-association of phenol and aniline was also studied shorter Tl values obtained in more concentrated solutions resulting from the slower tumbling rate of the aggregated molecules.A similar study has been reported for ni~otinamide.~~ I3C relaxation for all the protonated carbons in camphor whether part of the rigid bicyclic skeleton or of a rapidly rotating methyl group occursE4 by both dipole-dipole and spin-rotation mechanisms. The former process is the major contributor below 42 “C and the latter process above that temperature molecular motion being essentially isotropic. TI values have been usedE5 to probe the ease of internal rotation of methyl groups in a series of 2,2,3,4,4-pentamethylphosphetans. In some cases pseudoequatorial methyl carbon atoms have relaxation times shorter than the more hindered corresponding pseudoaxial methyl carbon atoms indicating that shorter TI values should not automatically always be taken as implying steric crowding.3C spin-lattice relaxation times have also been used to investigate internal motions in n-alkanes,86 free and complexed polyether antibiotic^,^' gramicidin-S,88 helix and random-coiI states of homo polypeptide^,^' membrane^,^' micel-les,’ phyt01,’~ synthetic polymers,’ and histidine side-chains in protein^.'^ 83 B. Birdsall J. Feeney and P. Partington J.C.S. Perkin 11 1973 2145. 84 J. Grandjean P. Laszlo and R. Price Mol. Phys. 1973 25 695. 85 G. A. Gray and S. E. Cremer J. Magn. Resonance 1973 12 5. 86 N. J. M. Birdsall A. G. Lee Y. K. Levine J. C. Metcalf P. Partington and G. C. K. Roberts J.C.S. Chem. Comm.1973 757; Y. K. Levine J. Magn. Resonance 1973 11 421. 87 M. C. Fedarko J. Magn. Resonance 1973 12 30. 88 A. Allerhand and R. A. Komoroski J. Amer. Chem. Soc. 1973 95 8228. 89 A. Allerhand and E. Oldfield Biochemistry 1973 12. 3428. 90 Y. K. Levine N. J. M. Birdsall A. G. Lee and J. C. Metcalf Biochemistry 1972 11 1416; J. D. Robinson N. J. M. Birdsall A. G. Lee and J. C. Metcalf ibid.. p. 2907. 91 E. Williams B. Sears A. Allerhand and E. H. Cordes J. Amer. Chem. SOC. 1973 95 487 1. 92 R. A. Goodman E. Oldfield and A. Allerhand J. Amer. Chem. Sac. 1973 95 7553. 93 J. Schaefer Macromolecules 1973,6 882; D. D. Davis and W. P. Slichter ibid. p. 728; G. C. Levy J. Amer. Chem. Sac. 1973,956117. 94 D. T. Browne G. L. Kenyon E. L. Packer H.Sternlicht and D. M. Wilson J. Amer. Chem. SOC. 1973 95. 1316. Physical Methods-Part (ii ) Nuclear Magnetic Resonance 41 Other Nuclei.-The observation of deuterium n.m.r. at natural abundance is about 100times more difficult than that of '3Cn.m.r. owing mainly to the lower natural abundance. However the shorter T values are advantageous for spectra accumulation and it has been shown possibleg5 to obtain natural-abundance 2H n.m.r. spectra while employing proton noise decoupling. As expected the spectra show single resonances for the different deuterium atoms. Very little nuclear Overhauser enhancement is obtained consistent with a dominant quadrupolar relaxation although only a small line broadening is obtained. As with '3C n.m.r.deuterium coupling is negligible. Spectra of acetaldehyde benzaldehyde n-butyl alcohol ethanol ethylbenzene and pyridine have been obtained chemical shifts comparing very closely with the corresponding proton chemical shifts. Natural-abundance deuterium n.m,r. spectra can be expected to be particularly advantageous in molecules such as steroids or polycyclic aromatic molecules where the corresponding proton spectra are very complex. ''N chemical shifts for glycine alanine valine ornithine phenylalanine aspartic acid leucine tyrosine and glutamic acid have been measuredg6 using enriched materials. In no case was any significant difference found between the chemical shifts of the fully protonated form and the zwitterion. These results also agreed well in all but two instances with previously published resultsg7 for amino- acid methyl ester hydrochlorides indicating that nitrogen shifts were relatively insensitive to the state of the carboxy-group.29Si spin-lattice relaxation has been examined9* in tetramethylsilane (19 s) diphenylsilane (26 s) dimethylphenylsilane (46 s) hexamethyldisiloxane (39.5 s) tetraethyl orthosilicate (135 s) and a series of polydimethylsiloxanes. For tetra- methylsilane and hexamethyldisiloxane relaxation occurs largely by the spin- rotation mechanism whereas diphenylsilane and tetraethyl orthosilicate relax almost entirely by a dipole-dipole process. Both mechanisms are significant for the other compounds. Dipole-dipole interactions between 29Si nuclei and directly bonded protons are ca.10 times less effective than analogous 13C-'H interactions resulting in the long relaxation times. In contrast to 13Crelaxation intermolecular 29Si-' H dipole-dipole interactions can contribute up to 20 % of the relaxation of a 29Si nucleus. Localized motions along segments of the chain of linear polydimethylsiloxanes result in 29Si relaxation rapidly becoming in- dependent of chain length and viscosity for molecular weights above ca. 500. Relaxation times can be significantly reduced sometimes to as low as 5 s by the presence of paramagnetic species such as dissolved oxygen or by the addition of relaxation reagents such as tris(acety1acetonato)chromium or the corresponding iron complex. Such treatment also suppresses the negative nuclear Overhauser effect (NOE).The observationg9 of a substantial NOE for triphenylsilane and a small NOE for phenylsilane is attributed to a lower barrier to internal rotation 95 J. M. Briggs L. F. Farnell and E. W. Randall J.C.S. Chem. Comm. 1973 70. 96 J. A. Sogn W. A. Gibbons. and E. W. Randall Biochemistry 1973 12 2100. 97 P. S. Pregosin E. W. Randall and A. I. White Chem. Comm. 1971 1602. 98 G. C. Levy J. D. Cargioli P. C. Juliano and T. D. Mitchell J. Amer. Chem. Soc. 1973 95 3445. 99 R. K. Harris and B. J. Kimber J.C.S. Chem. Comm. 1973 255. I. H. Sadler about the silicon-carbon bond in the latter. In view of its resonance frequency lying at the extreme low-frequency end of the 29Si chemical shift range tetraethyl orthosilicate has been proposed'" as a standard to which shifts should be referenced.In practice tetramethylsilane [82.6 p.p.m. relative to (EtO),Si] will be used experimentally as its relaxation time is much shorter. Prior to this year only three studies of 77Se resonance all continuous wave had appeared. The sensitivity of the nucleus in natural abundance is only about three times that of 13C; however the 1H-77Se Overhauser effect will be positive. A recent Fourier-transform study'" of the 77Se resonances of 2-substituted selenophens have been measured and span a range of ca. 100p.p.m. either side of the parent heterocycle. The substituents included the four halogens methyl formyl acetyl carboxy and acetoxy. Two-bond couplings to hydrogen are 4548 Hz three- and four-bond couplings being less than 10 Hz.Two modifications have been described for XL-100spectrometers which allow the observation of nuclei other than those for which an appropriate r.f. unit is provided. The firstlo2 uses the decoupler frequency synthesizer to provide appropriate frequencies for the 'H field-frequency lock signal in order that the field may be varied from the standard value. In this way nuclei such as 23Na 27Al,"V 63Cu and 79Br all of natural abundance greater than SO% may be observed with the r.f. unit provided for I3C observation. A drawback is that decoupling facilities are lost. A second modificati~n'~~ uses the decoupler to provide the observing radio-frequency and allows the observation of about forty different nuclei whose resonant frequencies lie in the range 9.6-32 MHz at 23.5 kG.3 MiscellaneousStudies Two reviews'04 and a book' O5 have appeared concerning lanthanide shift reagents. These continue to be used widely in the simplification of spectra and for the assignment of resonances particularly for mixtures of diastereoisomers.'O6 Chiral shift reagents have been used to estimate the optical purity'07 of 2-methylpiperidine and to distinguish' O8 between enantiomers of sterically hindered asymmetrically ring-substituted cis-p-alkylstyrenes. Optical purity of a-deuteriated primary alcohols was examined' O9 using [Eu(dpm),] (dpm = Me,C.CO-CH-CO-CMe,) after conversion into their camphanic esters. The loo G. C. Levy J. D. Cargioli G. E. Maciel J. J. Natterstad E. B.Whipple and M. Ruta J. Magn. Resonance 1973 11 352. lo' S. Gronowitz I. Johnson and A.-B. Hornfeldt Chem. Scripra 1973 3 94. lo* P. D. Ellis H. C. Walsh and C. S. Peters J. Magn. Resonance 1973 11,426. Io3 C. S. Peters R. Codrington H. C. Walsh and P. D. Ellis J. Magn. Resonance 1973 11 431. '04 B. C. Mayo Chem. SOC.Rev. 1973 2. 49; A. F. Cockerill. G. L. 0. Davies. R. C. Harden and D. M. Rackham Chem. Rev. 1973 73 553. '05 'Nuclear Magnetic Resonance Shift Reagents'. ed. R. E. Sievers Academic Press New York 1973. lo' C. Kruk A. A. M. Roof A. van Wageningen and H. Cerfontain Rec. Trav. chim. 1973 92 1015. lo' R. R. Fraser J. B. Stothers and C. T. Tan J. Magn. Resonance 1973 10 95. lo* C. S. C. Yang and R. S. H. Liu Tetrahedron Letters 1973 481 1.'09 H. Gerlach and B. Zaglalak J.C.S. Chem. Comm. 1973 274. Physical Methods-Part (ii) Nuclear Magnetic Resonance 43 observation' lo that [Eu(fod),] (fod = Me,C.COCHCO-C,F,) causes shifts in the proton spectra of cis-azo-compounds but leaves the trans-isomers virtually unaffected provides a convenient distinguishing test. In aqueous solution praseodymium chloride has been used to simplify proton spectra of mono-saccharides"' and the perchlorate has been used for sequence analysis"2 of hexa- and hepta-peptides at 300 MHz. A method for studying exchanging systems has been described.' ' Increasing the proportion of shift reagent and hence the chemical shift separation causes the signals from the N-methyl protons of trimethyl carbamate Me,NCO,Me to change from a single resonance through coalescence to separate resonances at constant temperature.From the variation in lineshape and separation with mole fraction of shift reagent a value for the free energy of activation (15.5 kcal mol-') for rotation about the N-C(0) bond was obtained in good agreement with the literature value. Lanthanide reagents are also used to infer detailed substrate geometries usually on the assumption that the induced shift A6 is given by an expression of the type A6 = K(3 cos2 4 -l)r-3. This expression should however be used with caution since it is only valid for axially symmetric 1 1 shift reagent (L)-substrate (S) complexes where the shift is due exclusively to a pseudocontact (dipolar) interaction. However the magnetic axis is not necessarily along the metal-substrate axis1l4 and not all 1 1 complexes are axially symmetric.''5 Effective axial symmetry may sometimes result from rapid rotation about the metal-substrate axis in which case it is necessary to average calculated shifts over all molecular conformations before comparisons are made with observed values.''6 The use of static models can lead to errors in spectral assignments.1 :2 Complexes which have no axial symmetry are frequently present,' "*''* and even higher complexes have been observed.' Appreciable contact contri- butions to shifts have been demonstrated''9 in some cases particularly for europium reagents and also in 13C studies. It is therefore surprising that good agreement with the above expression is obtained so frequently.This is however usually achieved using the position of the lanthanide atom as a variable parameter that is adjusted to give the best possible fit of the data which may cover up 'lo S. R. Wilson and R. B. Turner J.C.S. Chem. Comm. 1973 557. I I S. J. Angyal Carbohydrate Res. 1973 26 27 1. M. Anteunis and J. Gelan J. Amer. Chem. SOC. 1973.95 6502. I I3 S. R. Tanny M. Pickering and I. S. Springer J. Amer. Chem. SOC.,1973 95. 6227. R. E. Cramer and R. Dubois J. Amer. Chem. Soc. 1973 95 3801. 'Is J. J. Uebel and R. M. Wing J. Amrr. Chem. Soc. 1972 94 8910. I l6 R. M. Wing J. J. Uebel and K. K. Anderson J. Amer. Chem. SOC.,1973 95 6046; I. M. Armitage L. D. Hall A. G. Marshal and L. G. Werbelow ibid. p. 1437. D. F. Evans and M.Wyatt J.C.S. Chem. Comm. 1973 399; J. W. ApSimon. H. Beierbeck and A. Fruchier J. Amer. Chem. SOC., 1973 95 939. I" R. Porter T. J. Marks and D. F. Shriver J. Amer. Chem. SOC. 1973 95 3548. I19 J. W. ApSimon H. Beierbeck and J. K. Saunders Canad. J. Chem. 1973 51 3874; J. Reuben J. Magn. Resonance 1973 11 103; K. Tori Y. Yoshima M. Kainosho and K. Ajisaka Tetrahedron Letters 1973 1573; 0.A. Gansow P. A. Loeffler R. E. Davis M. R. Willcott and R. E. Lenskinski J. Amer. Chem. SOC.,1973.95 3389 3390; G. E. Hawkes C. Marzin S. R. Johns and J. D. Roberts ibid. p. 1661. 44 I. H. Sadler deficiencies in the method particularly as the lanthanide-complexing site distance is longer than X-ray studies of crystalline complexes suggest. For a further discussion of the basis of the use of these reagents the reader is referred elsewhere.'2o It is noteworthy that positions of equilibria between substrate conformations have been altered"' by the presence of lanthanide shift reagents.As an alternative to the use of the above equation for structural analysis an approach has been proposed'22 based on the r-6 dependence of relative line- widths obtainable by the use of relaxation reagents such as [Gd(fod),] which rests on a firmer theoretical basis.123 The suggested procedure involves the addition of a shift reagent e.g.[Eu(fod),] to induce large shifts between resonances followed by a relaxation reagent [Gd(fod),] to broaden the lines. In this way broadening of up to several hundred Hz may be obtained which would be impossible without the expanded scale provided by the shift reagent.Minor linewidth corrections may be necessary to allow for slight broadening due to the shift reagent and to incompletely collapsed multiplets. Linewidth ratios are expected to be much less sensitive to the presence of multiple species than shift ratios and although shifts may be measured more accurately than linewidths the r-6 dependence allows significant error in the measured linewidth without sacrificing acceptable accuracy in the determination of the relative values for r. A detailed account of the preparation and applications of the macrocyclic shift reagents has been given.' 24 Their advantages and disadvantages together with the way in which they complement the lanthanide reagents are discussed.The observation of intramolecular nuclear Overhauser effects continues to be used in stereochemical problems. l2 It is particularly important to ensure that enhancements observed are valid where the different resonances to be saturated are no more than a few Hz apart.126 In strongly coupled spin systems it has been shownI2' that selective NOE experiments in which a single transition is saturated provide a better method for investigating relaxation mechanisms and molecular structure than the more general experiment where an entire multiplet is saturated. Analyses for ABX and A,X spin systems are given and compared with experiment. The intermolecular nuclear Overhauser effect (INOE) is rather less frequently encountered.In this experiment the solvent spins are saturated and the solute spins observed. Equations have been devised and solutions obtained for the intensity increases expected for the AX spin system with intramolecular dipolar relaxation and different intermolecular dipolar interactions at the sites of the A and X spins.l2* Using tetramethylsilane as solvent intensity increases of 37 and 16% are obtained for A and X spins in the AX system of 1,1,2-trichloroethane. 120 M. I. Foreman in 'Nuclear Magnetic Resonance' ed. R. K. Harris (Specialist Periodical Reports) The Chemical Society London 1973 Vol. 2 p. 378; 1974 Vol. 3 Ch. 10. l2 T. Sat0 and K. Goto J.C.S. Chem. Comm. 1973 494. 122 G. N. La Mar and J. W. Faller J. Amer. Chem. SOC.,1973 95 3817. 1. Solomon Phys.Rev. 1955 99 559. 124 J. E. Maskasky and M. E. Kenney J. Amer. Chem. SOC.,1973 95 1443. 125 R. A. Bell and J. K. Saunders Topics Stereochem. 1973 7 I. 12' A. J. Bellamy and W. Crilly J.C.S. Perkin If 1973 122. 12' N. R. Krishna P. P. Yang and S. L. Gordon J. Chem. Phys. 1973 58 2906. lz8 N. R. Krishna and S. L. Gordon J. Chem. Phys. 1973 58. 5687. Physical Me (hods- Part (ii ) Nuclear Magnetic Resonance 45 Comparison with theory allowed estimation of the fraction of internal relaxation. This approach offers some advantage over the intramolecular experiment in that all the lines of the coupled spin system can be observed and complex lineshape variations due to inhomogeneity effects are absent. It is likely that such studies applied to biological systems would lead to information about intermolecular interactions and molecular conformation of the molecules.A new technique for the observation of high-resolution n.m.r. spectra of rapidly flowing chemical systems has been developed'29 in which the problems posed by the relatively long relaxation times ofnuclei are overcome. It has been used to examine unstable Meisenheimer complexes formed immediately after mixing of reagents and should find application in the observation of other short- I ived intermediates. The following aspects and applications of n.m.r. have been reviewed the solvent dependence of coupling constants :'30 dynamic magnetic resonance :' ' the determination of mechanistic information from lineshapes for intramolecular exchange ;'32 n.m.r.in carbohydrate chemistry ;* 33 carbocations ;'34 phosphorus ~tudies:'~' and rate processes in boron compounds.'36 A book devoted to techniques,' 37 one on general aspects of n.m.r. spectr~scopy,'~~ and one con- cerned with the use of n.m.r. for quantitative analysis'39 have appeared. 129 C. A. Fyfe M. Cocivera and S. W. H. Damji J.C.S. Chem. Comm. 1973 743. I3O M. Barfield and M. D. Johnston Chem. Rev. 1973 73 53. 13' N.M. Sergeev Russ. Chem. Rev. 1973 42 339. 13' J. P. Jesson and P. Meakin Accounts Chem. Res. 1973 6 269. 133 G. Kotowycz and R. U. Lemieux Chem. Rev. 1973 73,669. G. A. Olah Angew. Chem. Internat. Edn. 1973 12 173. 135 G. Mavel Ann. Reports N.M.R. Spectroscopy 1973 5B 1. '36 H. Beall and C. H. Bushweller Chem.Rev. 1973 73,465. 13' W. McFarlane and R. F. M. White 'Techniques of High Resolution Nuclear Magnetic Resonance Spectroscopy' Butterworths London 1973. 13' J. W. Akitt 'N.M.R. and Chemistry' Chapman and Hall London 1973. I39 F. Kasler. 'Quantitative Analysis by N.M.R. Spectroscopy' Academic Press London 1973.

ISSN:0069-3030    

DOI:10.1039/OC9737000022

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

2 Physical Methods Part (iii) X-Ray Crystallography By M. B. HURSTHOUSE Chemistry Department Queen Mary College Mile End Road London El 4NS and S. NEIDLE Department of Sioph ysics Kings College Drury Lane London WC2 5RL 1 Introduction As in previous years the large volume of published work in the field of organic chemical crystallography necessitates that this survey be highly selective. In choosing the papers for inclusion attempts have been made not only to highlight those structures which are novel or relevant to theoretical and mechanistic studies currently in progress but also to give a broad indication of the distribution of crystallographic effort amongst the various areas of organic chemistry. Fortunately the gaps left by the restricted coverage are adequately filled by two other surveys.Volume 1 of the Specialist Periodical Report ‘Molecular Structure by Diffraction Methods’ published in late 1973 covers the literature (for both organic and inorganic structures) for the period from January 1971 to March 1972. Four volumes of the compilation ‘Molecular Structures and Dimensions’ have now appeared giving virtually complete coverage of the litera- ture up to mid-1972. Volume 2 of the Specialist Report and Volume 5 of ‘Mole- cular Structures and Dimensions’ should both have appeared by the time this Report is in print. 2 BondingStudies The structures of two stable free radicals have been reported. The verdazyl ring in 2,4,6-triphenylverdayl (1) is non-planar the methylene carbon atom being displaced by 0.59 A from the plane of the four nitrogen atoms.’ An earlier e.s.r.study had indicated approximately equal sharing of the unpaired electron among the four nitrogen atoms and this is confirmed by the delocalization in the N,CN portion of the ring. The crystal structures of the free radical (2) and its diamagnetic analogue (3) have been compared.2 The approximate molecular * D. E. Williams Acta Cryst. 1973 B29 96. ’ W. Wong and S. F. Watkins J.C.S. Chem. Comm. 1973 888. 46 Physical Methods-Part (iii) X-Ray Crystallography symmetry of both is C,and in neither is the five-membered ring planar probably owing to the steric effect of the methyl groups. The most striking difference between the two molecules is in the dihedral angle between the phenyl group and the mean plane of the five-membered ring.This is 29" in (2) and 71" in (3) although it is not clear how the cause of this difference is apportioned between packing and electronic effects. Three papers describe structures containing carbanions stabilized by bis- N-ligand co-ordinated Li+ ions. In both triphenylmethyl-lithium tetramethyl- ethylenediamine3" and fluorenyl-lithium bis-quin~clidine~~ the position of the lithium ion which presumably is an indication of the location of the charge on the anions is asymmetric with respect to the symmetry ofthe organic species. In a third structure which contains the naphthalene dianion the lithium ions sit over the long bisector of the naphthalene skeleton (one above and one below the plane each associated with one ring only) and are moved out towards the C-24-3 (or C-6-C-7) bond which has a length of 1.34A only.3' The structures of ylides continue to attract attention.Triphenylphosphonium cyclopentadienylide is quite unreactive for an ylide. The structure analysis shows considerable n-delocalization within the cyclopentadiene ring and a rather small amount (ca. 20 %) of double-bond character in the P-C bond which has a length of 1.718A.4 The predominant structure is thus considered to be (4). In 2,2,3,3 4,4-hex~uoro(triphenylphosphoranylidene)cyclob~tane,~ the C-P distance (1.713A)is very similar to that in compound (4),and the results generally imply that the structure is predominantly (5). (a)J . J. Brookes and G.D. Stucky. J. Amer. Chem. Soc. 1972,94,7333; (6)J. J. Brooks. W. Rhine and G. D. Stucky ibid. p. 7339; (c)ibid. p. 7347. H. L. Ammon G. L. Wheeler and P. H. Watts jun. J. Amer. Chem. Sor. 1973,95,6158. M. A. Howells R. D. Howells N. C. Baenziger and D. J. Burton J. Amer. Chem. Soc. 1973 95 5366. M. B. Hursthouse and S. Neidle The crystal-structure analysis of the Wittig salt (3,7-dimethylocta-2,6-dienyl)-triphenylphosphonium bromide shows the P-C bond to the octadienyl chain to have a length of 1.805A slightly less than for a normal P-C(sp3) single bond.6 Crystallographic studies have been combined with CND0/2 calculations to investigate the structures and charge separations in 4,4-dicyano-2,3-diphenyl-triafulvene and 2,3-diphenyl~yclopropenone.~ The structures can be represented by (6) and (7) respectively with a slightly larger negative charge on 0 in the cyclopropenone than on the C(CN) group in the fulvene.0-Ph h, PhA Ph Charge-transfer complexes continue to attract attention. Crystals of the com- plex [(riboflavin)(quinol)(HBr),(H,O),] are black and the quinol molecules and bromide ions both donate charge to the riboflavin molecules which are probably in the semiquinone state.' It is considered that the interaction with the donors is not confined to a specific region of the isoalloxazine nuclei. A number of papers are concerned with studies on the aromaticity of non-benzenoid n-systems. Crystal-structure analyses of a number of substituted 1,2,4-triazoles show that the aromaticity is decreased as the H atoms are replaced the least aromatic systems being thiols such as (8),in which form (9) is a significant contributor.' The tropone molecule studied at -60 "C is approximately planar but shows pronounced bond alternations." The lengths of the formally single and double bonds fall into the ranges 1.415-1.459 and 1.327-1.365 A respec-tively.The increased accuracy of crystal-structure determination arising from the use of diffractometers and study of non-heavy-atom derivatives is being exploited to investigate the distribution of bonding electron density in molecules. One particularly neat use of this facility has been made in the accurate analysis of the ' J. Hjortas Acfa Crysf. 1973 B29 767.' H. L. Ammon J. Amer. Chem. Soc. 1973,95 7093. C. A. Bear J. M. Waters and T. N. Waters J.C.S. Perkin II 1973 1266. R. C. Seccombe and C. H. L. Kennard J.C.S. Perkin IZ 1973 1. lo M. J. Barrow 0.S. Mills and G. Filippini J.C.S. Chem. Comm. 1973.66. Physical Methods-Part (iii) X-Ray Crystallography 49 structures of 2,2’-anhydro-1-/3-arabino-furanosyluracil (10) and 2,5’-anhydro- 2’,3’-isopropylidenecyclouridine(1 l).’ The analysis has not only provided evidence of a shift of electron density from two bonding orbitals on N-3 of the uracil ring in (10) to the lone-pair orbital when a hydrogen bond is formed but also an explanation for two anomalous coupling constants in the I3C n.m.r. spectrum of (1 1). H 3 Strained Molecules and Conformational Studies Intramolecular strain can arise either from excessive steric repulsions or the formation of small rings.1,2,3,3-Tetrachloro-4,5-dimethylspiro[2,3]hexa-1,4-diene molecules contain spiro-linked cyclobutene and cyclopropene rings (12). ’ The double bonds are both localized and in fact are a little shorter than normal (1.302 and 1.31 1 A).However all the bond lengths in the ring are slightly shorter than in related compounds and it is suggested that the rings contain some degree of aromaticity. Other highly strained molecules which contain cyclobutyl rings are the photodimer (14) of ‘basketene’ (13) in which the C-C bond lengths are’ 1.52-1.57 8 and 2,3,6,7,7,8-hexamethyl-( **-1,5-diphenyl)tetracyclo[3,3,0,0’ 03*6]octan-4-one (15).14 In this molecule the C-3-C-6 and C-6-C-5 bonds are unusually long (1.602 and 1.608A)for a small ring and it is one of these bonds which shifts in the rearrangement reactions which this type of ring system under- goes.Another feature of interest in this structure is that the C-4 atom is only 2.145 8 away from the mid-point of the bond C-1-C-2 compared with 2.33 8 in related compounds. This also is believed to be significant in the rearrangement mechanisms. L. T. J. Delbaere M. N. G. James and R. Lemieux J. Amer. Chem. SOC.,1973,95,7866. ** R.J. Guttormson and B. E. Robertson Acta Cryst. 1973 B29 173. N.J. Jones W. D. Deadman and E. LeGoff Terrahedron Letters 1973 2087. l4 C.G.Biefeld H. A. Eick and H. Hart Tetrahedron Letters 1973,4507. M.B. Hursthouse and S.Neidle The effects on bond lengths and angles of molecular overcrowding are also the subject of many investigations. A redetermination of the structure of octachloro- pentafulvene (16) shows that the central C=C bond length 1.365A is not c1 CI strongly affected by the strain arising from theCl- -C1 repulsions this beingrelieved by the twist of 37" about the central bond." Another molecule showing over- crowding is 2-methylhexahelicene.' A number of unusually short C-C bonds are found on the periphery of the helix whilst those in the helix core are lengthened a pattern found in other fused aromatics. The medial rings are also significantly distorted into a boat conformation. A boat distortion of a benzene ring is also found in the molecule of 4-~arboxy[8]paracyclophane(17).' In the molecular structure of hexa-o-phenylene (18) the benzene rings are slightly distorted in a twist form.'' Within the twelve-membered ring all the angles are enlarged to 129.3' because of intramolecular repulsion.A neutron diffraction study of the ten-membered ring compound cyclodecane- 1,6-trms-diol has provided ex-perimental verification of short transannular H--H contacts (ca. 1.95A) in the ring.Ig These interactions cause significant deviations of the methylene groups involved from local CZvsymmetry. In the fifteen-membered ring compound cyclopentasarcosyl(19) the ring contains a succession of three cis amide groups and another succession of two trans amide groups.2o Three of the groups deviate significantly from planarity.Variable temperature n.m.r. studies indicate that the conformation found in the crystal is also predominant in solution. (18) H. L. Ammon G. L. Wheeler and I. Agranat Tetruhedron 1973,29 2695. I6 G. W. Frank D. T. Hefelfinger and D. A. Lightner Actu Cryst. 1973 B29 223. I7 M.G. Newton T. J. Walter and N. L. Allinger J. Amer. Chem. SOC.,1973 95 5652. H. Irngartinger Actu Cryst. 1973 B29 894. l9 0.Ermer J. D. Dunitz and I. Bernal Actu Cryst. 1973 B29 2278. *O K.Titlestad P. Groth and J. Dale J.C.S. Chem. Comm. 1973,646. Physical Methods-Part (iii) X-Ray Crystallography 4 Heterocyclic Systems Perhydropyrido-oxazepines (20)are formed from condensations of substituted 3-(2-piperidyl)propan-l-olswith formaldehyde.trans-Isomers have been found to undergo an unusual dimerization on crystallization from the liquid state which is reversed on dissolution.21 The dimer (22)contains a fourteen-membered ring and its formation is believed to involve an intermediate such as (21).Another novel heterocyclic system (25)involving a bridged ring has been formed by the reaction of the hindered diketo-sulphide (23) with hydrazine.22 Compound (24) is stable in the crystal but in benzene in the presence of oxygen it undergoes a remarkable transformation to (25). A number of other sulphur-containing heterocyclics have been studied. The S-0 distances in (26)are very short 1.875 and 1.878A,23 and are equivalent to the Se-0 distances in the analogous 21 D. A. Whiting R. Cahill and T.A. Crabb I.C.S. Chem. Comm. 1972 1307. '' E. Cuthbertson A. D. U. Hardy and D. D. MacNicol I.C.S. Chem. Comm. 1973,597 23 E. C. Llaguno and I. C. Paul Tetrahedron Letters 1973 1565. M. B. Hursthouse and S. Neidle selenium compound. The interactions are somewhat greater than similar systems where the N atoms are replaced by carbon atoms. The reaction of tetramethyl- cyclobutane-1,3-dione with P,S produces a number of sulphur-containing species. One of the minor products for which the crystal-structure analysis has been reported is the spiro-compound (27).," Another report provides the first detailed structural information on a three-membered ring composed entirely of heteroatoms which is present in the molecule bis-( I ,1,3,3-tetramethylbutyI)-thiadiaziridine 1,l-dioxide (28).25 The S-N bond is quite short (1.62A) but the N-N bond is longer than in any analogous distance.A bridging SO group is also found in the compound (29) formed by reaction of endo-2-chloro-sulphane with potassium t-butoxide in the presence of lY3-diphenylisobenzo- furan.2 Ph I 5 Reaction Mechanisms and Products In this section a few examples are given of the use of X-ray analysis to characterize a reaction product (structure and stereochemistry) or as an aid to the interpreta- tion of the mechanism of a particular reaction. Thus the analysis of the product of bromination of semibullvalene (30) shows that stereoselective cis,exo-l,4 addition has o~curred,~ in contrast to bullvalene itself where kinetically controlled trans-1,4addition takes place.Similarly analysis of the product from the cycloaddition of 2-ethyl-3-methylisoquinolinium perchlorate and cyclopentadiene shows that the reaction is also stereospecific.28 24 C. D. Shirrell and D. E. Williams Acta Crysf. 1973 B29,2128. 25 L. M. Trefonas and L. D. Cheung J. Amer. Chem. SOC.,1973,95 636. 26 C. B. Quinn J. R. Wiseman and J. C. Calabrese J. Amer. Chem. SOC.,1973. 95 6121. 2' L. A. Paquette G. H. Birnberg J. Clardy and B. Parkinson J.C.S. Chem. Comm. 1973 129. C. K. Bradsher F. H. Day A. T. McPhail and P. S. Wong J.C.S. Chem. Comm. 1973 156. 53 Physical Methods-Part (iii)X-Ray Crystallography Direct photolysis of 5-acetyl-3,3-dimethyl-3H-pyrazole (31) yields 7-acetyl- 3,5,5,9,9-pentamethy1-1,6-diazabicyclo[4,3,O]nona-3,7-dien-2-one (32).*' The re- action is believed to occur via formation of a vinylketen which then reacts further 0 with the starting material.The irradiation of exo-3-aza-4-ketobenzotricyclo-[4,2,1,02-5]non-7-ene (33) in methanol gives exo-2-methoxy-3-aza-4-keto-7,8-benzobicyclo[4,2,1]nonene (34) the reaction involving ring-expansion of the fi-lactam moiety in (33) and the incorporation of a molecule of rnethan01.~' The structure of the product was determined by use of n.m.r. lanthanide shift reagents and confirmed by X-ray analysis. (33) An example of the use of X-ray analysis to study a solid-state photochemical reaction is provided by work on 1,l'-trimethylenebisthymine (35).3 This molecule forms a compound (36) intramolecularly and the structure adopted by (35) does not lead immediately to an explanation for the geometry of (36) which is cis-syn.29 A. C. Day A. N. McDonald B. F. Anderson T. J. Bartezak and 0. J. R. Hodder J.C.S. Chem. Comm. 1973 247. 30 H. L. Ammon P. H. Mazzocchi W. J. Kopecky jun. H. J. Tarnburin and P. H. Watts J. Amer. Chem. SOC.,1973 95 1968. 31 J. K. Frank and I. C. Paul J. Amer. Chem. SOC.,1973 95 2324. M. B. Hursthouse and S. Neidle The great enhancement of the reaction rate of a substrate promoted by an enzyme suggests that the latter may impose restrictions on the conformation of the former to produce a favourable geometry. Similar effects may occur if 0 0 PJ0 0 cffo Q0 0 0X-NH the conformation of a compound is restricted by ‘over-methylation’.Such a situation occurs with the reaction rate of lactonization in o-hydroxyhydro- cinnamic acid when methyl groups are substituted both on the ring and the side- chain and the structure analysis of the over-methylated lactone pentamethyl- hydrocoumarin and the alcohol analogue of pentamethyl-o-hydroxyhydro-cinnamic acid shows that the conformation of the acid has been restricted by the presence of a ‘trialkyl lock’ similar to that in the la~tone.~~ Finally the structure analysis of the pyrolysis product (38) of ethylene-1,l- bis(triphenylphosphonium)-2,2-bis(phenylamide) (37) shows that an unprece-dented phenyl migration has occurred from a four-co-ordinate phosphorus to a two-co-ordinate nitrogen atom.33 Ph,P \/ $Ph p\c/ PPh I I C c NH \N-Ny ‘N-Ph I I I I Ph Ph Ph Ph 6 Natural Products and Biologically Active Molecules Many natural products studied have absolute configurational assignments made on the basis of Bijvoet anomalous scattering differences and these often serve to provide key assignments in whole families of compounds.A disquieting report34 that a rigorous exciton analysis of the c.d. spectra of 1,s-disubstituted 32 J. M. Karle and I. L. Karle J. Amer. Chem. Soc. 1972 94 9182. 3’ F. K. Ross Lj. Manojlovic-Muir W. C. Hamilton F. Ramirez and J. F. Pilot J. Amer. Chem. SCC.,1972,94 8738. 34 J. Tanaka C. Katayama F. Ogura H. Tatemitsu. and M. Nakagawa J.C.S. Chem. Comm. 1973 21. Physical Methods-Part (iii) X-Ray Crystallography 55 9,lO-bridged 9,lO-dihydroanthracenes does not agree with their Bijvoet X-ray assignments suggested that the whole basis of absolute configurational deter- minations by X-ray methods might be in error with serious implications for much of organic chemistry.However it has been pointed o~t~~.~~ that flaws in the exciton analysis make the above conclusions no longer tenable and that there is no discrepancy between the X-ray and the c.d. method. A number of sesquiterpenoids have been examined. The y-lactone ring in parthemollin (39) of previously uncertain stereochemistry has been found to be cis ;this has established the complete stereochemistry or the related xanthano- lides. The stereochemistry of the biological divinyloxiran-dihydro-oxepin rearrangement has been defined with reference to the structures of miscandenin (40)and dihydromikanolide (41).38 The trans double bond in (41) has a torsion angle of -163" a considerable distortion from ideality.Other germacranolides reported include enh~drin,~ with a cis,trans configuration of double bond and epoxide ring relative to the ten-membered macrocycle and the potent cytotoxic agent molephantin (42).40 Molephantin has a novel unsaturation pattern and 0 (39) 0 is the first germacranolide found to contain a dienone ring system. The structure of euparotin4' has been determined and the conformation of the cycloheptane 35 S. F. Mason J.C.S. Chem. Cornrn. 1973 239. 36 A. M. F. Hezemans and M. P. Groenewege Tetrahedron 1973,29 1223.'' P. Sundararaman R. S. McEwen and W. Herz Tetrahedron Letters 1973 3809. '' P. J. Cox G. A. Sim J. S. Roberts and W. Herz J.C.S. Chem. Cornrn. 1973,428. 39 G. Kartha K. T. Go and B. S. Joshi J.C.S. Chem. Cornrn. 1972 1327. 40 K. H. Lee H. Furukawa M. Kosuka H. C. Huang P. A. Luhan and A. T. McPhail J.C.S. Chem. Comm. 1973 476. A. T. McPhail and G. A. Sim Tetrahedron 1973,29 1751. 56 M. B. Hursthouse and S. Neidle ring in this and other perhydroazulene sesquiterpenes has been surveyed; in general the ring can be described as closer to a twist chair (C,) than a chair (C,) form. (-)-Arktolone (43)42 has a fused cyclopropane ring adjacent to the car- bony1 group; this results in a hyperconjugative effect between the two groups in spite of the geometry here deviating from ideality.For maximum interaction it is considered that the plane containing the carbonyl group and the adjacent ring carbons should bisect the three-membered ring. In spite of the carbonyl oxygen deviating by 29.6" from the ideal orientation the conjugation still shortens the linking C(sp3)-C(sp2)bond to 1.436 A. (+)-2,5-Diepi-fi-cedrene (44)43has the two five-membered rings trans-fused whereas in P-cedrene itself they are cis. This has induced considerable internal strain. The diterpene alcohol pachydictyol A (49 isolated from a species of marine algae also possesses the perhydroazulene ring previously unknown among diterpene~."~It has been suggested that pachydictyol A has been derived biogenetically as a sesquiterpene to which an isoprene unit has been added.Amongst higher terpenoids investigated is the diterpene barbatusin (46)"' which has the unusual feature of a methylcyclopropyl ring at C-13. Ring c is qo (43) H' (44) (45) described as in a half-chair conformation with considerable distortions from planarity about the conjugated 1,4-diketone group ; torsion angles here are as 42 F. H. Allen 0.Kennard and J. Trotter Acta Cryst. 1973 B29 1451. 43 B. Karlsson A. M. Pilotti and A. C. Wiehager Acru Cryst. 1973 B29 1710. 44 D. R. Hirschfeld W. Fenical G. H. Y. Lin R. M. Wing P. Radlick and J. J. Sims J. Amer. Chem. SOC.,1973 95 4049. 43 A. H. J. Wang I. C. Paul R. Zelnik I(.Mizuta and D. Lavie J. Amer.Chem. SOC. 1973 95 598. Physical Methods-Par t (iii) X-Ray Crystallography 57 large as 32.4". In view of the reactivity of the cyclopropane molecule barbatusin may be considered to be an intermediate in the biosynthesis of some naturally occurring quinoid diterpenes. New skeletal classes of triterpenes continue to be reported ; baccharis oxide (47)46has an oxide bridge between C-3 and C-10 in ring A. Short-range steric strain due to close angular substituents as well as ring-junction strain is con- sidered to be responsible for considerable deviations from ideality of many of the bond lengths and angles. Repulsions between 1,3-diaxial substituents are also concluded to be responsible for the pronounced flattening and twisting observed for the trans-fused rings c and D.The crystal structure of the physiologically important hormonal steroid cortisol$' as its methano solvate has been established and the structure com- pared4' with five other corticosteroids of known conformation in order to attempt a correlation between conformational differences and biological activity. It was noted that the degree of bowing towards the a-face is related to the varia- tion in anti-inflammatory activity in these compounds. The ring-D-bridged steroid 14a 17a-etheno-15,16-di(trifluoromethyl)pregna-4,15-diene-3,20-dione (48)"' has a conformation in which ring A is said to be intermediate between a half-chair and a sofa and the geometry of the bicyclic system of ring D is very similar to that of norbornadiene.Other steroidal derivatives analysed include (23R)-23-hydroxy-3a,5a-cycloergost-7-en-6-one (49)," with a cis A/B ring junction and the 17-spirobicyclomethyI-steroidNic 11 (50).' (47) @H ..-c OH **(j 46 F. Mo Acta Cryst. 1973 B29 1796. 4' P. J. Roberts J. Coppola N. W. Isaacs and 0. Kennard J.C.S. Perkin II 1973 774. 48 C. M. Weeks W. L. Duax and M. E. Wolff J. Amer. Chem. SOC.,1973,95 2865. 49 G. I. Birnbaum Acta Cryst. 1973 B29 54. M. B. Hursthouse and S. Neidle J.C.S. Perkin II 1973 781. 51 M. Begley L. Crombie P. J. Ham and D. A. Whiting J.C.S. Chem. Comm. 1973,821. M. B. Hursthouse and S. Neidle Among the many alkaloids investigated have been a number of novel structures. The anticholinergic agent dihydroisohistrionicotoxin (5 1y2 has the unique combination of a spiro-alkaloid moiety and two unsaturated side-chains one with an allene group and the other a vinylacetylene.The cis-butenynyl chain is quite planar and the C-13-C-14 single bond is of length 1.43A. The allene moiety deviates slightly from linearity. The neuromuscular blocking compound d-tubocuranine (52),53 which is a curare alkaloid has been found to have only one quaternary nitrogen atom. The molecular conformation is thought to be consistent with a one-site attach- ment to a receptor site thus blocking the possible binding of acetylcholine molecules. The large hydrophobic grouping would appear to be an effective block. 12s-Tetrahydroaustamide (53)54 and cytochalasin E (54)" are both fungal metabolites.The former has the diketopiperazine ring in a boat con- formation. -3C I1 CH Several studies have served to interrelate various members of alkaloid families. Thus the knowledge of the structure and absolute configuration of (+)-coron- aridine (55)56 has enabled configurational assignments to be made for a number '* I. L. Karle J. Amer. Chem. SOC.,1973 95 4036. 53 P. W. Codding and M. N. G. James Acta Cryst. 1973 B29 935. " J. Coetzer and P. S. Steyn Acta Cryst. 1973 B29 685. " G. Biichi Y. Kitaura S. S. Yuan H. E. Wright J. Clardy A. L. Demain T. Glinsukon N. Hunt and G. N. Wogan J. Amer. Chem. SOC.,1973,95 5423. " J. P. Kutney K. Fuji A. M. Treasurywala,J. Fayos J. Clardy A. I. Scott and C. C. Wei J. Amer. Chem. SOC.,1973 95 5407. Physical Methods-Part (iii) X-Ray Crystallography 59 of the Iboga alkaloids.Lythrumine (56)57 has an unusual skeleton which has now been found in lythraceae alkaloids from both North America and Japan. Among the sugar analyses reported are those of 2,6-anhydro-/?-~-fructo-furanose (57)58 and 1,2:4,5-di-0-isopropylidene-/?-~-fructopyranose (58).59 The furanosyl ring in (57)has an unusual conformation with both C-3 and C-4 in the exo position in contrast to other furanosyl rings investigated to date presumably because of the effect of the bicyclic ring system. The ring is said to be in a distinct envelope conformation as is the anhydride ring. The pyranosyl ring in (58) has a chair-distorted half-chair conformation as a result of the fusion of the five- and six-membered rings and each 1,3-dioxolan ring has an envelope conformation.(55) HO' HOw A large number of biologically active molecules have been examined with a view to obtaining some insight into either structural requirements for activity or into the actual mechanism of action of these compounds. Several thyroid hormones have been analysed in an attempt to establish the structural require- ments for maximum hormonal activity. 3'-Isopropyl-3,5-di-iodo-~-thyronine (59),60the most potent known thyromimetic agent has a conformation such that the j3-ring is oriented with the isopropyl group proximal to the a-ring. This is a very similar situation to that observed in the parent compound tri-iodothyro- nine in which iodine replaces the isopropyl moiety and it is suggested that this conformation is the active one in physiological solution.A study of the tri- iodothyroacetic acid N-diethanolamine complex6 ' has however indicated that the distal conformation may be of importance. 57 H. Wright J. Clardy and J. P. Ferris J. Amer. Chem. Soc. 1973,95,6467. 58 W.Dreissig and P. Luger Acfa Crysr. 1973 B29 1409. '' S.Takagi R. Shiono and R. D. Rosenstein Acfa Crysf. 1973 B29 1177. 6o J. K.Fawcett N. Camerman and A. C. Camerman Biochem. Biophys. Res. Comm. 1973,52,407. 6' V. Cody and W. L. Duax Biochem. Biophys. Res. Comm. 1973,52,430. M.B. Hursthouse and S. Neidle Other pharmacologically interesting analyses include that of a novel ring- expansion product (60)62of penicillin V P-sulphoxide and that of tirandamycic acid (61),63 which has enabled the acyltetramic antibiotics tirandamycin and streptolydigin to have complete stereochemical assignments.Methadone (62),64a potent narcotic analgesic has a large degree of conformational stability to and the structure found is characterized by a folding of the carbon chain so as to bring the basic nitrogen into close contact with the carbonyl carbon atom and it is suggested that methadone is effectively transported across the blood- brain barrier because of the hydrophobic nature of the surface of the molecule as revealed in this study. Extensive studies have continued on nucleic acid and protein constituents and their various analogues. 6-Azauridine (63)65 has like the parent uridine an anti conformation about the glycosidic bond and a C-3’-endo sugar pucker but differs considerably in the detailed arrangement of substituent stereochemistry 62 R.Thomas and D. J. Williams J.C.S. Chem. Comm. 1973,226. 63 D. J. Duchamp A. R. Branfman A. C. Button and K. L. Rinehart jun. J. Amer. Chem. SOC.,1973,95,4077. 64 H. B. Burgi J. D. Dunitz and E. Shefter Nature New Biol. 1973 244 186. 65 C. H. Schwalbe and W. Saenger J. Mol. Biol. 1973,75 129. Physical Methods-Part (iii ) X-Ray Crystallography 61 in the sugar ring. The anti-parallel double-helical arrangement of base-pairs in nucleic acids has been observed for the first time in two dinucleoside phosphates adenosyL3’,5’-uridine phosphate66 and guanylyL3’,5’-cytidine ph~sphate.~~ HO’ OH (63) These structures provide detailed information about the precise geometry of both the ribose phosphate linkage and the complementary base-pairing in the genetic code.The C-terminal tripeptide L-Pro-L-Leu-Gly-NH,68 of the hormone oxytocin has been found to have a compact intramolecularly hydrogen-bonded structure in the solid state whose basic feature a ten-membered p-turn structure has previously been postulated as being present in solution on the basis of n.m.r. evidence. One of the peptide bonds is significantly non-planar with a torsion angle of 10”. “ J. M. Rosenberg N. C. Seeman J. J. P. Kim F. L. Suddath H. B. Nicholas and A. Rich Nature 1973 243 150. ‘’ R. 0.Day N. C. Seeman J. M. Rosenberg and A. Rich Proc. Nut.Acad. Sci. U.S.A. 1973 70 849. L. L. Reed and P. L. Johnson J. Amer. Chem. SOC.,1973,95 7523.

ISSN:0069-3030    

DOI:10.1039/OC9737000046

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (i) Aromatic Compounds By A. R. BUTLER Department of Chemistry University of St. Andrews St. Andrews 1 Electrophilic Aromatic Substitution Recent work on this subject has been reviewed by Taylor’ in an admirable manner. Predictions of the effect of substituents on aromatic reactivity by MO calculations are difficult to make but semi-empirical models have been proposed which give very accurate results.’ However there is an interesting report that lengthy and costly MIND0 calculations of certain indices of aromatic reactivity (electron densities localization energies) show no better correlation with suscepti- bility to electrophilic attack than the same quantities calculated by the simpler Hiickel method. It has been proposed that charge-transfer complexes play a part in the mechanism of electrophilic aromatic substitution (Scheme 1).The evidence is XH Scheme 1 that the order of reactivity of different positions in substituted benzenes follows the order of hyperfine coupling constants in the e.s.r. spectrum of the radical ~ation.~ It would be interesting to see this tested in a case where unexpected reaction products are obtained. The effect of the cyclopropyl substituent on aro-matic reactivity depends upon the nature of the transition state. When it is late (eg. bromination) reactivity depends upon whether or not a bisected conforma- tion can be adopted to give maximum stabilization of the Wheland intermediate. R. Taylor in ‘MTP International Review of Science Organic Chemistry Series One’ ed.H. Zollinger Butterworths London 1973 Vol. 3 p. 1 ; R. Taylor in ‘Aromatic and Heteroaromatic Chemistry’ ed. C. W. Bird and G. W. H. Cheeseman (Specialist Periodical Reports) The Chemical Society London 1973 Vol. 1 p. 176. D. A. Forsyth J. Amer. Chem. SOC.,1973,95 3594. J. N. Murrell W. Schmidt and R. Taylor J.C.S. Perkin If 1973 179. E. B. Pendersen T. E. Petersen K. Torsell and S.-0. Lawesson Tetrahedron 1973,29 579. 63 A. R.Butler Thus compound (1) reacts faster than (2)and attack is at thep-position. Nitration with an early transition state does not depend upon the conformation of the cyclopropyl group and (1) and (2) react at similar rates to give the o-substituted product.’ Sulphonation is a reaction one would imagine to be very susceptible to steric influences but Blackborow6 reports that with NN-dimethylanisidine sulphona- tion and hydrogen exchange show the same positional discrimination although the latter reaction is 100 times faster.On the other hand Olah7 has discussed varying substrate and positional selectivity in aromatic sulphonylation in terms of the position of the transition state along the reaction profile. A criticism of this analysis will be discussed later (p. 74). A simple study of the relative rates of nitration of benzene and toluene by nitronium tetrafluoroborate has established that substrate selectivity depends markedly upon the solvent and emphasizes the vital role of solvation in fixing the reaction rate. The low value originally reported by Olah was found for solvent like n-hexane but with more polar solvents higher values are obtained.8 Nitration may be effected by metal nitrates in acetic anhydride and the rate of reaction depends upon the metal ion ;other results show that titanium nitrate is an electrophilic nitrating agent.It is unlikely that free NO2+ is formed and the mechanism is thought to be attack of benzene on the nitrogen of the nitrate group (Scheme 2).’ The use of NaN0,-KNO in a pyrosulphate-sulphate melt at 250°C as a nitrating agent has been investigated in some detail. A kinetic study using benzenesulphonate as substrate indicates a mechanism involving an intermediate formed from NO and the benzenesulphonate ion which + Scheme 2 W. Kurtz P.Fischer and F. Effenberger Chem. Ber. 1973 106 525; P. Fischer W. Kurtz and F. Effenberger ibid. p. 549. J. R. Blackborow J.C.S. Perkin II 1973 2387. ’ G. A. Olah S. Kobayashi and J. Nishimura J. Amer. Chem. SOC.,1973 95 564. * S. Sekiguchi A. Hirose S. Kato and K. Matsui Bull. Chem. SOC. Japan 1973,46,646. K. Fukunaga and M. Kimura Nippon Kagaku Kaishi 1973 1306; D. W. Amos D. A. Baines and G. W. Flewett Tetrahedron Letters 1973 3191. Reaction Mechanisms-Part (i) Aromatic Compounds decomposes to give nitrobenzene and SO,. lo Dinitrogen tetroxide is an effective if inconvenient nitrating agent. Measurement of relative reactivities did not permit the effective species to be identified with certainty but it is clear that nitrosation plays a significant role with highly activated substrates.Nitric acid in acetic anhydride is an effective nitrating agent but exhibits com- plex kinetics and gives unusual products. This in part is due to the tendency for addition products to form and more of these have been reported during 1973. At room temperature reaction with 1,4-dimethylnaphthalene results in side- chain attack to give (3),but at -40 "Cthe adduct (4)is obtained. '' With toluene cis- and trans-forms of (5)are obtained and decompose to give p-tolyl acetate. ' (3) (4) Fischer has also isolated (6)and (7) from 2,3-and 3,4-dimethylbenz0nitrile'~ and (8) from 3,4-dimethylanisole. l5 The nitro-group in such adducts is mobile as has been shown by a study of the products of the action of acetic acid on (9).16 Me NO Me NO Me NO, 0 0:'.0'. AcO HQ:i2 H OAc H OAc Me0 OAc Another example of the action of acetyl nitrate giving unexpected products is its reaction with cyclotriveratrylene (lo) which results in a mixture of (1 1) and (12). lo J. M. Schlegel and J. J. Robinson J. Amer. Chem. SOC.,1973,95 665. ' G. R. Underwood R. S. Silverman and A. Vanderwalde J.C.S. Perkin II 1973 1 i 77. l2 A. Fischer and A. L. Wilkinson Canad. J. Chem. 1972 50 3988. l3 A. Fischer and J. N. Ramsay J.C.S. Perkin II 1973 237. l4 A. Fischer and C. C. Greig J.C.S. Chern. Comrn. 1973 396. Is A. Fischer and D. R. A. Leonard J.C.S. Chem. Comm. 1973 300. l6 R. C. Hahn and M. B. Groen J. Amer. Chem. SOC.,1973,95,6128. A. R. Butler The unsubstituted compound 10,15-dihydro-5H-tribenzo[u,d,g]cyclononene does not undergo cleavage so that reaction of (10)must be due to the stabilization of the veratryl cation by the methoxy-groups.17 Me0 OMe Me0 OMe Me0 OMe CH,OAc CH,OAc Challis has continued his study of aromatic nitrosation.With p-substituted phenol the rate-determining step is loss of a proton from the dienone intermediate (13) and there is subsequent oxidation to give the 2-nitro-compound. For this 0 reaction there is a low p value which is characteristic of rate-determining proton loss. * At high pH dienone formation becomes the slow step. With resorcinol and its 0-methyl derivative the product is an oxime and either proton loss or reaction of undissociated substrate and H,NO,+ is rate-determining depending on the pH.For 1,3-dimethoxybenzene the slow step is decomposition of the dienone intermediate to give nitrosomethoxybenzene.20Nitrosation of various indoles in dilute acid is brought about by a variety of species depending on the conditions. The rate-determining step depends on the basicity of the substrate for less basic ones it is proton loss but with others it may be either formation of T. Sato T. Akima and K. Uno J.C.S. Perkin I 1973 891. B. C. Challis and R. J. Higgins J.C.S. Perkin If 1972 2365. l9 B. C. Challis and R. J. Higgins J.C.S. Perkin II 1973 1597. 2o J. Jahelka V. Sttrba and K. Valter Coll. Czech. Chem. Comm. 1973 38 877. Reaction Mechrmisrns-Part (i)Aromatic Compounds reagent or diffusion of reactants.* The transfer of a nitroso-group from N-nitro- sodiphenylamine to N-methylaniline and other nucleophiles is acid catalysed.In some cases nitrous acid is an intermediate but protonation is not the slow step.22 The reactivity of diazonium ions has been reviewed.23 In general bases react with benzenediazonium ions in the unprotonated form,24although at high pH pyrrole reacts as the conjugate base.25 Several studies of coupling with phenols have been reported.26 Attack of benzene on the benzenediazonium ion may result in displacement of the azo-group as molecular nitrogen and formation of di~henyl.~’ Reid has shown that Ga-thiathiophthen generally undergoes normal electrophilic substitution but in its reaction with benzenediazonium tetrafluoro- borate there is rearrangement and a hypervalent heterocyclic system results.28 For some time there has been doubt concerning the role of positive halogen in halogenation by acidified hypohalous acid.It is not formed in acidified hypo- bromous acid and the active electrophile is H20Br+. However this is not formed from hypobromous acid but by protonation of a substrate-HOBr complex formed in a pre-equilibrium step.29 A study of the variation of the kinetic hydro- gen isotope effect with bromide ion concentration in the bromination of naph-thalene by Ehrlich and Berliner3’ gives further proof of the two-step mechanism. Studies of brom~desilylation~~ have been reported. and brom~degermylation~~ There has been one further important study of the mechanism of aromatic iodination.At low iodide concentration in the acid-catalysed iodination of phenol the slow step is attack of molecular iodine on the substrate to give (14) but at higher concentrations compound (14) is formed in a reversible process 5.C. Challis and A. J. Lawson J.C.S. Perkin 11 1973 918. *’B. C. Challis and M. R. Osborne J.C.S. Perkin 11 1973 1526. 23 H. Zollinger Accounts Chem. Res. 1973 6 335. 24 M. RemeS J. DiviS V. Zvttina and M. Matrka Coll. Czech. Chem. Comm. 1973 38 1049. ’’ K. Mitsumura Y. Hashida S. Sekiguchi. and K. Matsui Bull. Chem. SOC.Japan. 1973 46 1770. 26 S. Kishirnoto 0. Manabe H. Hachiro and N. Hirao Nippon Kagaku Kaishi 1972. 2132 B. Demian Bull. SOC.chim. France 1973. 796; Z. V. Belitskaya M. V. Plakidina and T.L. Bagal Org. Reactivity (U.S.S.R.) 1971,8 1046. z’ P. Burri and H. Zollinger Helv. Chim. Acra 1973 56 2204. R. M. Christie A. S. Ingram D. H. Reid and R. G. Webster J.C.S. Chem. Comm.. 1973 92. 29 H. M. Gillon and J. H. Ridd J.C.S. Perkin 11 1973 1321. 30 A. Ehrlich and E. Berliner J. Org. Chem. 1972 37 4186. ’‘ J. Vklak and V. Chvalovsky Coll. Czech. Chem. Comm. 1973 38 1055. 32 J. VEelak and V. Chvalovsky Coil. Czech. Chem. Comm. 1972,37 3615. 68 A. R. Butler and the slow step is depr~tonation.~~ This is also true for iodination by iodine in concentrated sulphuric acid,34 where the electrophile is 13+. Inoue et al. have reported3' a method of electrochemical fluorination a general technique of increasing importance in synthetic organic chemistry.There .is a curious differ- ence between the reactions of cyanogen chloride and bromide with phenyltrim- ethylstannane. With the former benzonitrile results whereas the latter gives br~mobenzene.~~ There have been studies of electrochemical cyanation3' and thi~cyanation.~' It is common for aromatic metallation to occur ortho to a substituent containing oxygen or nitrogen. This is because co-ordination to the substituent occurs prior to attack of the aromatic ring3' Lead tetratrifluoroacetate will effect aromatic plumbylation which occurs para to a halogen ~ubstituent.~' Friedel-Crafts reactions continue to attract much attention but few of the studies reported in 1973 throw further light on the mechanism. For example partial orders were obtained in a kinetic study of acylation by acetic anhydride in concentrated sulphuric acid41 and another study indicates that a variety of factors control orientation in these reactiom4* Agranat and A~nir~~ have produced evidence to show that acylation reactions are reversible contrary to previously held beliefs.Utley and Yate~~~ have reported an electrochemical method of acylation using the anodic oxidation of 2,3,5,6-tetramethyloxyquinol diacetate which produces an acylium ion. Factors affecting the ease of cyclization under Friedel-Crafts conditions have been e~amined.~' The cyclization of cyclohept-4-ene- 1-carbonyl chloride to 2-endo-chlorobicyclo[ 3,2,1]octan-8-one is stereospecific suggesting formation of the non-classical ion (15) as an i~~termediate.~~ Cyclization of o-arylthiophenyl methanol occurs uia formation of a carbenium ion and there is a 1,2-sulphur shift following formation of the spiro-intermediate (16).33 E. Grovenstein N. S. Aprahamian C. J. Bryan N. S. Gnanapragasam D. C. Kilby J. M. McKelvey and R. J. Sullivan J. Amer. Chem. Soc. 1973 95 4261. 34 J. Arotsky A. C. Darby and J. B. A. Hamilton J.C.S. Perkin Il 1973 595. 35 Y. Inoue S. Nagase K. Kodaira H. Baba and T. Abe Bull. Chem. SOC.Japan 1973 46,2204. 36 E. H. Bartlett C. Eaborn and D. R. M. Walton J. Organometallic Chem. 1972 46 267. 37 K. Yoshida and T. Fueno J. Org. Chem. 1973,38 1045. 38 V. R. Kartashov E. V. Skorobogatova and I. V. Bodrikov Zhur. org. Khim. 1973,9 214. 39 D. W. Slocum and F. E.Stonemark J. Org. Chem. 1973,38 1677; D. W. Slocum and B. P. Koonsviteky ibid. p. 1675. 40 D. de Vos J. Wolters and A. van der Gen Rec. Trau. chim. 1973,92 701 ;D. de Vos J. Spierenburg and J. Wolters ibid. p. 701. '' A. Germain A. Commeyras and A. Casadevall Bull. SOC.chim. France 1973 2527 2537. '* J. P. Girault P. Scribe and G. Dana Tetrahedron 1973 29 413; L. J. Kricka and A. Ledwith J.C.S. Perkin I 1973 859. 43 I. Agranat and D. Avnir J.C.S. Chem. Comm. 1973 362. 44 J. H. P. Utley and G. B. Yates J.C.S. Chem. Comm. 1973 473. 45 A. A. Khalaf and R. M. Roberts J. Org. Chem. 1972,37 4227. 46 G. Capozzi G. Melloni and G. Modena J.C.S. Perkin I 1973 2250. Reaction Mechanisms-Part (i)Aromatic Compounds RH Jackson and his co-workers have reported further studies on indole com- pounds.Cyclization of(17)is known to occur via formation of the spiro-indolenine (18) and the tosylate has been found to react in the same way!' However although the main route in the cyclization of 4-(6-methoxyIndol-3-yl)butanol to 7-methoxy- tetrahydrocarbazole is the same there is a minor route involving direct attack at the 2-position owing to activation by the metho~y-group.~~ From a study of the rearrangement of isolated indolenines it is probable that this minor route is also operative in the simple alkylation of in dole^.^^ There is now considerable evidence that positional selectivity of ionic reactions in the gas phase depends upon the pressure." These reactions are characterized in general by low substrate selectivity but this does not apply to t-butylation since a much weaker electrophile is involved.' Taylor and Tewson' have shown that hydrogen exchange in superacids is 10" times faster than in trifluoroacetic acid. This enormous increase is due to enhanced reactivity of the electrophile and is not a medium effect. All available data for aromatic hydrogen exchange has been collected and standardized at 100 "Cand pH 0.53This permits an exact comparison to be made of the suscepti- bilities of many aromatic compounds to electrophilic attack. Using only substi- tuted benzenes there is an excellent correlation between the standardized rate constants and oP+values but if all the data are included the correlation is not as good.54 47 A.H. Jackson and B. Naidoo J.C.S. Perkin II 1973 548. 48 R. Iyer A. H. Jackson P. V. R. Shannon and B. Naidoo J.C.S. Perkin II 1973,872; R. Iyer A. H. Jackson and P. V. R. Shannon ibid. p. 878. 49 G. Casnati A. Dossena and A. Pochini Tetrahedron Letters 1972 5277. F. Cacace and E. Possagno J. Amer. Chem. SOC.,1973,95 3397. 51 F. Cacace and P. Giacomello J. Amer. Chem. SOC.,1973 95 5851. 52 R. Taylor and T. J. Tewson J.C.S. Chem. Comm. 1973 836. 53 A. El-Anani J. Banger G. Bianchi S. Clementi C. D. Johnson and A. R. Katritzky J.C.S. Perkin II 1973 1065. 54 S. Ciementi and A. R. Katritzky J.C.S. Perkin II 1973 1077. A. R.Butler 2 Nucleophilic Aromatic Substitution Crampton and Khan55 have shown that there is only a small energy difference between the 4- and 2-complexes formed from l-substituted 3,5-dinitrobenzenes and methoxide ion although the former is greatly increased by addition of bivalent metals ions.56 A spiro a-complex (19)has been reported.57 Aza-groups H2C -CH II 0 NMe (19) activate the ring towards nucleophilic attack as much as nitro-gr~ups.~' There have been several studies of the reaction of ketone anions with polynitrobenzenes to give a-complexes.With l-substituted 2,4-dinitrobenzene attack occurs at both the 3-and 5-positions to give (20) and (21).59 The hydrogen atoms of the X X Hoo2 MeCOCH NO NO CHJOMe methyl group of trinitrotoluene are sufficiently acidic to form an anion in alkaline solution and this will form a a-complex with trinitrobenzene.60 A transient a-complex has been detected in the reaction of the sodium salt of diethyl malonate with 2,4-dinitrofluorobenzene in DMSO to give diethyl 2,4-dinitrophenyl- malonate.6' Decomposition of the a-complex is the slow step in the reaction of substituted N-methylanilines with 2,4-dinitrochlorobenzene and 2,4-dinitro- fluorobenzene but no evidence for base catalysis was found.62 Reactions of 4-substituted 2-nitrochlorobenzenes with toluene-p-thiolate in DMF gives a 55 M.R. Crampton and H. A. Khan J.C.S. Perkin 11 1973 710. " M. R. Crampton and H. A. Khan J.C.S. Perkin ZZ 1973 1103. 57 S. Sekiguchi and T. Shiojima Bull. Chem. SOC. Japan 1973,46 693. J. Kavalek T. M. Chinh V. Mikan V. Sttrba and M. VeEeta COIL Czech. Chem. Comm. 1973,38 1935.59 N. Obi H. Kakizaki and M. Kimura Chem. and Pharm. Bull. (Jupan) 1973,21,235; N. Obi and M. Kimura ibid. 1972,20,2295; E. E. Gol'teuzen S. S. Gitis and A. Ya. Kaminskii Sin. Anal. Struckt. Org. Soedinenii 1971 121. " E. E. Gol'teuzen Yu. D. Grudtsyn S. S. Gitis and A. Ya. Kaminskii Zhur. org. Khim. 1972 8 1916; S. S. Gitis A. Ya. Kaminskii Yu. D. Grudtsyn and E. E. Gol'teuzen Doklady Akad. Nuuk S.S.S.R. 1972 205 102. 61 K. T. Leffek and P. H. Tremaine Canad. J. Chem. 1973,51 1659. '' J. Kavalek J. Kubias and V. Sterba Coll. Czech. Chem. Comm.. 1972 37 4041. Reaction Mechanisms-Part (i) Aromatic Compounds good Hammett plot (p = 6.65).63Taylor and vat^^^ report that the base- catalysed decomposition of (22) is greatly enhanced by addition of bovine serum albumin which acts as a macromolecular catalyst ;the product is (23).N The fascinating transformations brought about by reaction of the amide ion with heterocycles have been reviewed in a book by van der Plas6’ and new examples described e.g. chloropyrazine (24)is converted into 2-cyanoimidazole (27).The mechanism involves attack at C-3 and fisson of the C-3-N-4 bond to give (25) loss of HC1 and recyclization to (26);the final step is loss of hydrogen.66 Reaction of 4-bromo-2,6-diphenylpyrimidine with amide ion at -33 “C results in substitution by a benzyne mechanism but a minor route may involve an ANRORC me~hanism.~’ No 2,5-didehydropyrazine is formed in the analogous reaction of 2-chlor0-6-phenylpyrazine.~~ Lithium isopropylamide reacts with 6-bromo-4phenylpyrimidine by a complex ANRORC me~hanism.~’ In strongly basic media bromopyrazoles and bromothiophens undergo ‘halogen dances’ ;’O the reactions are intermolecular.’ * 63 P.Carniti P. Beltrame and S. Cabiddu J.C.S. Perkin ff 1973 1430. 64 R.P. Taylor and J. B.Vatz J. Amer. Chem. SOC.,1973,95 5819. ’’ H.C. van der Plas ‘Ring Transformations of Heterocycles’ Academic Press London 1973. 66 P. J. Lont and H. C. van der Plas Rec. Truv. chim. 1973,92,311. 67 J. de Valk and H. C. van der Plas Rec. Truv. chim. 1973,92 145. 68 P. J. Lont H. C. van der Plas and A. van Veldhuizen Rec. Trav. chim. 1973,92 708. 69 H. C. van der Plas and A. Koudijs Rec. Trau. chim. 1973,92 71 1. ’O J. F.Bunnett and C. E. Moyer J. Amer.Chem. SOC.,1971,93 1183. D. A. de Bie H.C. van der Plas G. Geurtsen and K. Nijdam Rec. Trav. chim.,1973 92 245. 72 A. R.Butler 3 Acidity Functions Gillespie and Peel7' have determined H values for a number of superacids :the highest value is 19.35 for HS0,F containing 7% SbF, 3s0,. Values for per- chloric acid in aqueous acetic acid have been reported.73 The problem of the proliferation of acidity scales has been discussed by Yates and co-w~rkers.~~ The search for a measure of the inherent acidity of an acid appears to be futile and it is now clear that Wyatt's75 observation that acidity is a unique function of the water activity applies to only H values and is probably fortuitous. The activity coeffi- cients of various indicators have been measured by independent means and from these hydronium ion activity can be calculated.The values obtained are remark- ably independent of the method used to obtain them. The utility of this approach is not to establish an intrinsic scale of acidity as in any reaction the important matter is the extent to which any particular substrate is protonated but it will permit calculation of the free energies of solvation of various cations. It was considered impossible to draw any conclusion from the linear relationship between H and log k for the hydrolysis of cellulose.76 All the problems associated with describing the acidity of a concentrated acid are parallelled in strongly basic media. For instance different H-scales are obtained particularly at high DMSO concentration using the ionization of nitrogen and oxygen weak The acidities of such media have been measured kinetically78 and a new scale (J-) based on the addition of hydroxide ions to substituted benzaldehydes has been proposed.79 In an interesting study hydrogen ion activities in strongly basic media have been measured using glass and dropping mercury electrodes.*' The new acidity function HGc has values higher than those for H-and H -." Similar values were obtained using a ferrocene-ferricinium ion couple as a reference electrode. 82 In alkaline ethylene glycol and DMSO the H-scale was found not to correlate well with logk for the solvolysis of chl~roform.~~ 4 Linear Freeenergy Relationships Various aspects of linear free-energy relationships have been reviewed by workers prominent in this field.84 It has been obvious for some time that the Hammett 72 R.J. Gillespie and T. E. Peel J. Amer. Chem. SOC.,1973 95 5173. 73 M. Godel A. Jussiaume and F. Coussemant Tetrahedron 1973 29 2889. 74 K. Yates H. Wai G. Welch and R. A. McClelland J. Amer. Chem. SOC.,1973 95 418. 75 P. A. H. Wyatt Discuss. Faraday SOC.,1957 No. 24 p. 162. 76 A. Mohn-Wehner H. K. Rouette and H. Zollinger Helv. Chim. Acta 1973 56 323. 71 A. Albagli A. Buckley A. M. Last and R. Stewart J. Amer. Chem. SOC.,1973 95 471 1. 78 M. F. Semmelhack R. J. DeFranco Z. Margolin and J. Stock J. Amer. Chem. SOC. 1973 95,426. 79 W. J. Bover and P. Zuman J. Amer. Chem. SOC.,1973,952531. 80 J. Janata and R.D. Holtby-Brown J. Electroanalyt. Chem. Interfacial Electrochem. 1973,44 137. 81 J. Janata and R. D. Holtby-Brown J.C.S. Perkin II 1973 991. 82 K. Yates and R. A. McClelland J. Amer. Chem. SOC.,1973,95 3055. 83 K. K. Kundu and L. Aiyar J.C.S. Perkin ?I 1973 143. 84 'Advances in Linear Free Energy Relations' ed. N. B. Chapman Plenum London 1972. Reaction Mechanisms-Part (i) Aromatic Compounds 73 equation is too simple to give an accurate measure of substituent effects and another two-parameter equation has been proposed which has better predictive powers.85 Wepstera6 has shown that the Yakawa-Tsuno equation is implicit in Hine's generalized equation.87 Transmission of substituent effects through the thiazole ring,88 pyridine ring,89 imidazole ring," furan and thiophen,' ' carbon-carbon double and triple bonds,92 and cyclopropane rings93 has been examined.From a study of the pK values ofa series ofcompounds ArXCH,CO,H (X = CH, CMe, NH 0,S or NHCH,) it was found that -M substituents in the p-position deviate from the Hammett equation.94 Because of such deviations insulated systems of this type are unsuitable for the determination of o" con-stant~.~~ The effect of substituents on the fluorine n.m.r. in compounds (28) (28) G = -CH2-or -HC=N-supports96 a two-parameter equation proposed elsewhere.97 A study of pK values of 4-substituted quinuclidines suggests that the substituent effect is trans- ferred along the o-bonds and is not a direct field effect.98 There is a linear rela- tionship with the Taft constant o*,provided the unsubstituted compound is excluded.The reason for this is not under~tood.~~ The nature of the Taft steric constant E has been considered"' and it is clear that this constant is successful only if the substituent does not adopt a preferred conformation."' It is important that further examples of this are found. A good correlation has been found between carbonyl stretching frequencies and o+ constants.lo2 This applies to phenyl esters but o' constants are used. This is also the appropriate constant for the reaction of various nucleophiles R. T. C. Brownlee and R. D. Topsom Terrahedron Letters 1972 5187. B. M. Wepster J. Amer. Chem. SOC., 1973,95 102. J. Hine J. Amer. Chem. SOC.,1959 81 1126; ibid. 1960 82 4877.D. S. Noyce and S. A. Fike J. Org. Chem. 1973,38,2433 3316 3318 3321. 89 D. S. Noyce J. A. Virgilio and B. Bartman J. Org. Chem. 1973,38,2657; D. S. Noyce and J. A. Virgilio ibid. p. 2660. 90 D. S. Noyce and G. T. Stowe J. Org. Chem. 1973 38 3762. 91 A. BeAo A. KrutoSikova L. FiSera and R. Frimm Coll. Czech. Chem. Comm. 1973 38 2734. 92 K. Izawa T. Okuyama and T. Fueno Bull. Chem. SOC.Japan 1973,46,2880. 93 G. Montando and C. G. Overberger J. Org. Chem. 1973,38 804. 94 A. J. Hoefnagel J. C. Monshouwer E. C. G. Snorn and B. M. Wepster J. Amer. Chem. SOC.,1973 95 5350. 95 A. J. Hoefnagel and B. M. Wepster J. Amer. Chem. SOC. 1973 95 5357. 96 S. K. Dayal S. Ehrenson and R. W. Taft J. Amer. Chem. Suc. 1972,94 91 13. 97 S. Ehrenson R.T. C. Brownlee and R. W. Taft Progr. Phys. Org. Chem. 1973,10 1. 98 J. Paleeek and J. Hlavaty CON. Czech. Chem. Comm. 1973 38 1985. 99 C. A. Grob W. Simon and D. Treffert Angew. Chem. Internat. Edn. 1973 12 319. loo T. Fujita C. Takayama and M. Nakajima J. Org. Chem. 1973 38 1623. A. Babadjamian M. Chanon R. Gallo and J. Metzger J. Amer. Chem. SOC.,1973,95 3807. A. Perjessy Tetrahedron 1973 29 2189 3207. A. R.Butler with esters indicating that during reaction there is uncoupling of resonance between the phenolic oxygen and the aromatic mystem. '03 In a very important paper Johnson and Schofield''" have analysed common interpretations of p as it reflects the nature (particularly charge distribution) of the transition state. They suggest that p should be the same whatever the substrate and that different values merely reflect different abilities to transmit substituent effects.A more rigorous approach would be to use the standard reactions (e.g. ionization of carboxylic acids) to define CT and CT' constants for each ring system (as Noyce is doing for a') and use these to obtain unique p values. In the present state of our knowledge of the transition state it might not be very profitable to compare p values obtained with different ring systems. Johnson and Schofield continue with an analysis of Olah's results where p values are used to designate early and late transition states. They contend that Olah's interpretation leads to a situation where reaction with a less reactive electrophile (high negative p) would be faster than reaction with a highly reactive electrophile (low negative p).Further analyses of the situation are awaited with interest. However this Reporter agrees with the closing remark 'linear free energy relationships (are) by definition incompatible with structure-reactivity correlations invoking variable transition states'. Jencks' O5 has reviewed the relation between mechanism and structure-reactivity relationships and there has been an analysis of the Marcus theory in terms of a model for a simple proton transfer. ' O6 There is now some confusion concerning the linearity of Brnrnsted plots. Kreevoy and Oh'" report that the plot for the hydrolysis of the diazoacetate ion catalysed by trialkylammonium ions is curved and account for this in terms of the Marcus theory.The kinetic isotope effect is also consistent with this. A very detailed and elegant analysis of the results permits the separation of the free-energy change into that part involved in the rate-determining step and that associated with preliminary steps. On the other hand Kemp and Casey"' found that the Brernsted plot for the base- catalysed reaction of benzisoxazoles to give salicyclonitrile over a very wide range of pK values is completely linear and conclude that curvature is always due to extraneous factors. The constancy of the /Ivalue reflects a transition state in proton-transfer reactions which has a uniform sensitivity to substituent effects over an appreciable range of transition-state energies.An attempt has been made to deal with the confusion surrounding the enthalpy-entropy or isokinetic relationship by using an extended Arrhenius equation. log lo' L. A. Cohen and S. Takahashi J. Amer. Chem. SOC.,1973,95,443. Io4 C. D. Johnson and K. Schofield J. Amer. Chem. SOC.,1973,95,270. W. P. Jencks Chem. Rev. 1972.12 705. lo' G. W. Koeppl and A. J. Kresge J.C.S. Chem. Comm. 1973 371. lo' M. Kreevoy and S. Oh J. Amer. Chem. SOC.,1973,95,4805. lo* D. S. Kemp and M. L. Casey J. Amer. Chem. SOC.,1973,95,6670. S. Wold and 0.Exner Chem. Scripta 1973 3 5.

ISSN:0069-3030    

DOI:10.1039/OC9737000063

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (ii) Orbital Symmetry Correlations and Pericyclic Reactions By R. GRIGG Department of Chemistry Queen's University Belfast B T9 5AG Northern lreland 1 General and Theoretical Aspects The now numerous theoretical treatments of pericyclic processes have provided a number of perspectives of concerted reactions. For the organic chemist some of these have been helpful and some incomprehensible but their conclusions have been overwhelmingly in accord with those of the original Woodward and Hoffmann treatment. In this context a recent series of papers by Epiotis' deserves mention for its attempt to encompass substituent effects the principle of least motion and non-stereoselectivity. In a series of papers which are a sequel to those mentioned last year,2 the concept of configuration interaction is applied to pericyclic reactions.This approach leads to the prediction that configuration interaction can reverse the stereoselectivity of a 4N pericyclic process by rendering the stereoselectivity of reactions towards the polar end of the spectrum opposite to the stereoselectivity of the non-polar reactions. In 4N pericyclic processes non-stereoselectivity is then the result of two competing concerted processes and should be found near the middle of the polarity spectrum. Polarity in this context refers to electron-donating and -attracting substituents on the substrate(s). In contrast 4N + 2 electron pericyclic processes are predicted to maintain their stereoselective preference throughout the entire range of substrate type.Looking at this from an aromaticity ~iewpoint,~ the conclusions can be restated in the form that an aromatic transition state is not influenced by substitution whereas an anti-aromatic transition state is responsive to substitution. The latter conclusion accords with the prediction4 that the orbital properties of cyclo- butadiene and its anti-aromaticity strongly depend on substitution and geometry. The original treatment of pericyclic processes by Woodward and Hoffmann leads to the prediction that the energy ordering of transition states for a reaction ' N. D. Epiotis J. Amer. Chem. Soc. 1973 95 1191 1200 1206 1214. R. Grigg Ann. Reporrs (B) 1972 69 120. M. J. S. Dewar Angew. Chem. Internat. Edn. 1971 10 761.R. Hoffmann. Chem. Comm. 1969 240. 75 76 R.Grigg should be ‘allowed’ < biradical or zwitterionic -= ‘forbidden’. Therefore the interaction between reactive sites in a biradical or zwitterionic case should be minimal since such interaction generates ‘forbidden’ character. This minimizing of interactions should in turn result in loss of stereospecificity. However a number of ‘forbidden’ processes occur with facility and stereospecificity and these are attracting more attention.2 Configuration interaction first applied to these problems by Schmidt,’ has been utilized in rationalizing a number of these cases6 Baldwin6 has criticized the use of ‘concerted’ and ‘allowed’ as inter- changeable synonyms and points out that orbital symmetry is conserved in some but not all concerted reactions and not conserved in some but not all non-concerted reactions.The sigmatropic sub-group has been discussed and the importance of subjacent orbital control as a significant electronic factor favouring stereospecific concerted ‘forbidden’ reactions has been proposed. Thus the transition state of a thermal suprafacial 1,3-sigmatropic process occurring with retention at the migrating carbon centre i.e. a forbidden .2 + 02 process is appreciably stabilized by interaction of the carbon p orbital of the migrating centre with a subjacent bonding ally1 orbital. This results in two of the four electrons involved being accommodated in a more stable orbital than would be the case in a non-interacting biradical transition state (Figure 1).Both 11/1 and t,h3 mix with p [see Figure l(a)] but the interactions approximately cancel each other. Subjacent orbital control of the transition state is not expected to become important until steric factors become unfavourable to the operation of Woodward-Hoffmann control. This revised ordering of transition state energies ‘allowed’ < ‘forbidden’ concerted < non-interacting biradical or zwitterion will itself be susceptible to variation and calculations on the degenerate methylenecyclo- propane rearrangement show the orthogonal biradical transition state is more stable than the ‘forbidden’ concerted ,2 + .2 pathway.8 The first paper applying trajectory techniques on quantum-mechanical potential surfaces to the dynamics of organic reactions’ is concerned with the insertion of singlet methylene into a hydrogen molecule.A number of reviews on pericyclic processes have appeared lo some of which are devoted exclusively or in part to applications in inorganic chemistry.” The proposed new class of orbital symmetry controlled reactions dyotropic rearrangements,12 which W. Schmidt Tetrahedron Letters 1972 58 1 ; Helv. Chim. Acra 197 1 54 862. J. E. Baldwin A. H. Andrist and R. K. Pinschmidt Accounts Chem. Res. 1972,5,402. J. A. Berson Accounts Chem. Res. 1972 5 406; J. A. Berson and L. Salem J. Amer. Chem. SOC. 1972,94 8917. W. T. Borden and L. Salem J. Amer. Chem. SOC. 1973,95,932. I. S. Y. Wang and M. Karplus J. Amer. Chem. SOC. 1973,95 8160. lo R. F. Hudson Angew.Chem. Internat. Edn. 1973,12 36; K.-W. Shen J. Chem. Educ. 1973 50 238; J. Mathieu Bull. SOC. chim. France 1973 807. ‘ ‘ K. Fukui and H. Fujimoto Kyoto Daigaku Nippon Kagakuseui Kenkyusho Koeushu 1972 29 27 (Chem. Abs. 1973 78 146 899); H. Fujimoto S. Kato S. Yamabe and K. Fukui Bull. Chem. SOC. Japan 1973 46 1071; R. G. Pearson Fortschr. Chem. Forsch. 1973 41 75. R. Grigg Ann. Reports (B) 1972 69 121. Reaction Mechanisms -Part (ii) Orbital Symmetry I E =4f10 E =2f10 I I I- I \ \ I +3-s" \ \ I $3-\ \ E \ I \ \ I 0 ++A $-f\:sfpI~2+ -4-+ -fP I I I I I I 3t "1#-2PO I I I I Figure 1 MO energy ordering for (a)a tforbidden' concerted *2 +,2 process and (b) a non-interacting biradical process involves the simultaneous migration of two a-bonds has been further studied.' MIND0/2 calculations and orbital symmetry considerations are utilized to analyse the stereochemical fate of migrating groups in thermal and photochemical dyotropic processes.An explanation of the a-effect the enhanced reactivity of nucleophiles possess- ing an unshared electron pair adjacent to a nucleophilic centre has been given in terms of Mobius-Hiickel theory.14 The a-effect has only been definitely observed for attack of nucleophiles on substrates with n-bonding. This is now rationalized in terms of a six-electron aromatic transition state to which the unshared electron pair adjacent to the nucleophilic centre contributes e.g. the addition of hydrazine to a carbonyl compound (1).An interesting application l3 M. T. Reetz Tetrahedron 1973 29 2189. l4 J. F. Liebman and R. M. Pollack J. Org. Chem. 1973 38 3445. 78 R. Grigg of frontier orbital theory to the direction of attack of nucleophiles and electro- philes on cyclohexanones has appeared. ’ One of the current problems which restricts the full practical exploitation of pericyclic processes is that it is not yet possible to predict when applicable which of several symmetry-allowed possibilities will be preferred. A contribution to this problem comes from the study of the thermal rearrangement of homo- bullvalenone (2) to (3).l6 Deuterium-labelling studies provide evidence for a vinylketone intermediate and are rationalized in terms of two ‘allowed’ eight- electron steps when a single six-electron process could have achieved the same result.2 Electrocyclic Reactions A book on valence isomerizations has appeared.” A bond order rule for electro- cyclic reactions has been developed.’8 Disrotatory closure is preferred if the bond order between the reacting centres is positive and conrotatory closure preferred if the bond order is negative. This rule applies to both symmetrical and non-symmetrical molecules and highlights a class of electrocyclic reactions where the bond order between reacting centres is zero or very small. This will result in non-stereospecific closure but the product ratio can be altered by introducing substituents. Ab initio calculations have been carried out on various cyclopropyl species.” MO calculations predict that C-C bond opening of thi-irans should be conrotatory but the corresponding sulphoxide should open in a disrotatory manner.” The anion (4) undergoes electrocyclic opening ca.lo4 times faster than anion (5).2’ Anion (4) can undergo conrotatory opening whereas (5) cannot and it is concluded that conrotatory opening is the favoured path by at least 23.8 kJ mol- The key step in the thermal rearrangements of aziridinyl ketones to pyrroles 15 J. Klein Tetrahedron Letters 1973 4307. 16 M. J. Goldstein and S.-H. Dai J. Amer. Chem. SOC.,1973 95 933. 17 G. Maier ‘Valence Isomerizations’ Chemical Pocket Books Verlag Chemie Wein- heim 1973 Vol. 17. 18 E. E. Weltin J. Amer. Chem. SOC.,1973 95 7650. 19 A.Liberles A. Greenberg and A. Lesk J. Amer. Chem. SOC.,1972,94,8685; L. Farnell and W. G. Richards J.C.S. Chem. Comm. 1973 334; L. Radom P. C. Hariharan J. A. Pople and P. v. R. Schleyer J. Amer. Chem. SOC.,1973 95 6531. 20 R. Hoffmann H. Fujimoto J. R. Swenson and C.-C. Wan J. Amer. Chem. SOC.,1973 95 7644. 21 M. Newcomb and W. T. Ford J. Amer. Chem. SOC.,1973,95 7186. Reaction Mechanisms -Part (ii) Orbital Symmetry [e.g.(6)+(7)]22and trans-divinyloxiran to a dihydrofuran [(8)-+(9)]23is the initial conrotatory opening of the heterocycle to a dipolar intermediate i.e. (10) and (1 l),respectively.A related ring-opening occurs in the thermal rearrangement of (u).~~Rearrangement is preceded by an endo-ex0 isomerization [(12)-B (1411 which it is suggested involves (13)formed by a disrotatory electrocyclic process.The intermediate can undergo a 1,4-hydrogen shift to give (15) while (12) and (14) rearrange to dienals by a concerted mechanism involving fission of an external cyclopropyl bond. Stereomutation of allyl cations usually proceeds via perpendicular (i.e. non- delocalized) allyl cations. However ub initio calculations show that variation of X in (16) should when X = Me or F lead to stereomutation [(16)+ (IS)] via cyclopropyl cation (17).25 When X = OH or NH the cyclopropyl cations (17) are more stable than the corresponding allyl cations. The two isomeric pentadienyl cations (19a) and (19b) have been observed in FS03H-S02C1F at -125 "C.They undergo thermal conrotatory cyclization to cyclopemtenyl cations.26 The bicyclo[5,1,O]octadienyl anion (20) undergoes disrotatory photo- equilibration with the monocyclic isomer (21).27 The diazo-group participates in a number of electrocyclic reactions which lead to diazepines e.g.(22)-+ (23).28 22 A.Padwa D. Dean A. Mazzu and E. Vega J. Amer. Chem. SOC.,1973,95 7168. 23 R. J. Crawford V. Vukov and M. Tokunaga Canad. J. Chem. 1973,51 3718. 24 J. Wolfhugel A. Maujean and J. Chuche Tetrahedron Letters 1973 1635. '' L. Radom J. A. Pople and P. v. R. Schleyer. J. Amer. Chem. SOC.,1973,95 8193. 26 N. W. K. Chin and T. S. Sorensen Canad. J. Chem. 1973,51 2776. 27 S. W. Staley and N. J. Pearl J. Amer. Chem. SOC.,1973,95 2731. A. A. Reid J. T. Sharp H. R. Soad and P. B. Thorogood J.C.S. Perkin I 1973,2543.80 R.Grigg Me Me (19) a; R' = RZ = Me R3 = H Me b; R' = R3 = Me R2 = H (20) (21) Formation of the iron tricarbonyl complex of cis4-cyclononatetraene (24) stabilizes the ligand and retards the electrocyclic closure to a dihydroindene (25)29 whereas attachment of acetylenic groups to cyclo-octatriene (26) facili-tates ring opening to (27).30 Kinetic studies on the thermal disrotatory cycliza- tion of a series of I-and 3-alkyl-l,3,5-hexatrienesyielded relative rates in the order 3Bu' > 3-Et 3-Me > 1-Et > 1-Me H.31 The activation enthalpies of the 3-alkyl series were in general 12.5 kJ mol-' less than either the 1-alkyl counterparts or the parent hydrocarbon. Six-electron anionic electrocyclic processes have been observed in dihydrobenzthiophenes [(28) -+ (29)13*and enolate anions of eucarvone [(30) -+(31)]; the related enolate (32) undergoes equilibration via an anionic Cope rearrangement at 150 "C[(32) -+ (33),4 5)].33 FCZCR -+ 29 E.J. Reardon and M.Brookhart J. Amer. Chem. SOC.,1973 95,431 1. 30 H. Straub J. M. Rao and E. Muller Annafen 1973 1339 1352. 31 C. W. Spangler T. P. Jondahl and B. Spangler J. Org. Chem. 1973 38 2478. 32 H. Kloosterziel and J. A. A. van Drunen Tetrahedron Letters 1973 1023. 33 A. J. Bellamy and W. Crilly Tetrahedron Letters 1973 1893. Reaction Mechanisms -Part (ii) Orbital Symmetry Me Me ca. I 2 B” 0- Me Me Me Me Irradiation of a-pyrones in a dilute argon matrix at low temperatures allows the i.r. spectra of the intermediate ketens to be observed (34).34 The complexity of the keten bands indicates several rotamers are formed and this is rationalized in terms of electrocyclic opening of electronically excited a-pyrone and formation of a mixture of rotamers in the process of demotion to the ground state.N-Benzoyl- enamines undergo photocyclization followed by 1,5-H shift to give trans-fused ring systems e.g. (35)+(36).35 I .5-H shift (35) 3 Cycloaddition Reactions Perturbation theory has been used to predict the preferred orientation (regio- selectivity) of concerted cycl~additions.~~ In many but not all cases 2 + 2 thermal cyclodimerizations are expected to occur in a head-to-tail manner and 2 + 2 photodimerizations in a head-to-head fashion if the reactions are concerted.34 0.L. Chapman C. L. Mclntosh and J. Pacansky J. Amer. Chem. SOC.,1973,95,244; R. G. S. Pong and J. S. Shirk ibid. p. 249. 35 I. Ninomiya T. Naito and T. Mori J.C.S. Perkin I 1973 505; 1. Ninomiya T. Naito T. Kiguchi and T. Mori ibid. p. 1696; I. Ninomiya T. Naito and T. Kiguchi ibid. pp. 2257 2261 ;G. R. Lenz Tetrahedron Letters 1973 1963. 36 N. D. Epiotis J. Amer. Chem. Soc. 1973 95 5624. 82 R.Grigg A similar treatment of 4 + 2 cycloadditions is also presented. However since the forces governing regioselection are weak the stabilization-energy difference between two distinct arrangements of the reactants in the transition state is comparatively small and steric and dipolar effects may be crucial. PMOtheory also predicts quite accurately the perispecificity of cycloadditions involving some cross-conjugated systems3' Polar cycloaddition~~~ have and cycloaddition reactions of cyclopr~penes~~ been reviewed and Kaupp has continued to demolish cherished examples of concerted photocycloadditi~ns.~~ New methods4' and techniques for generating singlet oxygen have appeared including polymer-based dye sen~itisers.~~ A detailed study of the reaction of singlet oxygen with 2,5-dimethylhexa-2,4dieneshows that both the rate of the reaction and the product distribution are solvent deper1dent.4~ Photo-oxidation of the diene in methanol at -78 "C allowed a 1,Zdioxetan (37) to be isolated.This and some solvent-incorporated products suggest that a perepoxide (38) is the precursor of (37).Related studies with adamant~lideneadarnantane~~ also favour a perepoxide intermediate. F~kui~~ has made the interesting suggestion that 2 + 2 cycloadditions of benzyne and of singlet oxygen to ethylene derivatives have a common feature. He proposes a novel approach geometry in which only one lobe of the addend ('02or benzyne) overlaps with the ethylene Ir-bond [e.g. (39) for benzyne]. This novel reaction path is clearly different from the 2 + 2 'allowed' mode and is supported by extended Huckel calculations. A detailed calculation of the keten 2 + 2 cycloaddition reaches similar con- clusion~.~~ This suggestion for benzyne additions should be contrasted with the configuration interaction treatment which suggests the 2 + 2 process may occur.' The thermal generation of electronically excited carbonyl compounds from dioxetans has been further studied and the results rationalized in terms of a concerted mechanism?' Studies on the thermal decomposition of tetramethyl- 1,Zdioxetan in degassed benzene show the reaction is autocatalytic and suggest a chain decomposition of the dioxetan molecule occurs as the direct result of interaction with its electronically excited cleavage product.48 The overwhelming majority of photochemical processes go from an initial reactant electronically excited state to a ground-state product.49 Conversion of an excited state of a 37 M.N. Paddon-Row P. L. Watson and R. N. Warrener Tetrahedron Letters 1973 1033. 38 R. R. Schmidt Angew. Chem. Internat.Edn. 1973 12 212. 39 M. L. Deem Synthesis 1972 675. O0 G. Kaupp Annalen 1973 844; Angew. Chem. Internat. Edn. 1973,12 765. K. Gollnick and G. Schade Tetrahedron Letters 1973,857. 42 D. C. Neckers A. L. Thayer and A. P. Schaap J. Amer. Chem. SOC.,1973,95 5820; J. R. Williams G. Orton and L. R. Unger Tetrahedron Letters 1973 4603. O3 N. M. Hasty and D. R. Kearns J. Amer. Chem. SOC.,1973.95 3380. O4 A. P. Schaap and G. R. Faler J. Amer. Chem. SOC.,1973,95 3381. O5 S. Inagaki and K. Fukui Bull. Chem. SOC.Japan 1973,46,2240. O6 R. Sustmann A. Ausmann and F. Vahrenholt J. Amer. Chem. SOC.,1972,944 8099. 41 N. J. Turro and P. Lechtken J. Amer. Chem. SOC.,1973,95 264. 48 P. Lechtken A. Yekta and N. J. Turro J. Amer. Chem. SOC.,1973,95 3027. 49 R.Grigg Ann. Reports (B) 1972,69 121. Reaction Mechanisms -Part (ii) Orbital Symmetry reactant into an electronically excited product molecule is exceedingly rare for molecules possessing a high number of vibrational modes. Two such processes the photochemical cleavage of tetramethyldioxetan to acetone (43 % triplet) and of naphthvalene (40)to naphthalene have now been uncovered.so Some triplet- state benzene is produced during the thermal rearrangement of certain Dewar benzene^.^ ’ Further studies have been reported on the thermal gas-phase rearrangement of bicyclo[2,l,O]pent-2-enes (41; R’ = H R2 = Me; R’ = Me RZ = H) into methylcyclopentadienes. None of the evidence requires or suppports a concerted #2 + #2 isomeri~rn.~~ In contrast the results of a kinetic study on the thermal rearrangement of hexamethylbicyclo[2,2,0]hexanes e.g.(42) -.) (43) + (a), are felt to support a concerted mechani~m.’~ The products and relative rates of cycloaddition of a series of olefins and acetylenes to dimethylketen have been reported. Steric and electronic factors accord with a concerted reaction in which the keten adds antarafacially with differing degrees of bond formation at the reaction termini in the transition state.54 The ketens (45; R = Me or Ph) undergo regiospecific intramolecular 50 N. Turro P. Lechtken A. Lyons R. R. Hantala E. Carnahan andT. J. Katz J. Amer. Chem. SOC.,1973,95,2035. 51 P. Lechtken R. Breslow A. H. Schmidt and N. J. Turro J. Amer. Chem. SOC.,1973 95 3025. 52 J.I. Brauman W. E. Farneth and M. B. D’Amore J. Amer. Chem. SOC.,1973,95,5043. 53 A. Sinnema F. van Rautwijk A. J. De Koning A. M. van Wijk and H. van Bakkum J.C.S. Chem. Comm. 1973 36.2.. 54 N. S. Isaacs and P. Stanbury J.C.S. Perkin 11 1973 166. 84 R.Grigg cycloaddition to (46) in high yield; none of the alternative product (47) could be detected.5s Studies of keten-allene cycl~additions~~ accord with a two-step non-concerted mechanism in contrast to those reported last year." Chloro-sulphonyl isocyanate adds to a-pinene to give an adduct (48)with an unrearranged carbon skeleton which supports a concerted me~hanism.'~ Photocycloaddition of powdered single mixed crystals containing 15% of (49) in (50) consistently gave a slightly optically active mixed dimer (51).5g This simple production of stable optically active samples from inactive starting materials is relevant to current hypotheses on the pre-biological origin of optical activity on the earth.A study of the photochemistry of the allenes (52; R' = H R2 = Ph; R' = Ph R2 = H) shows that the singlet state gives the .2 + .2 cycloadduct (53) as the major product and the di-lr-methane rearranged com- pounds (54; R' = H R2 = Ph; R' = Ph R2 = H) as minor products.60 S02CI I CI Ar= 0 Th Ar -c1 (49) 55 S. W. Baldwin and E. H. Page J.C.S. Chem. Comm. 1972 1337. " P. E. Brook,J. M. Harrison and K. Hunt J.C.S. Chem. Comm. 1973 733; W. G. Duncan W. Weyler and H. W. Moore Tetrahedron Letters 1973 4391. 57 R. Grigg Ann.Reports (B) 1972 69 128. 58 G.T. Furst M. A. Wachsman J. Pieroni J. G. White and E. J. Moriconi Tetrahedron 1973,29 1675. 59 A. Elgavi B. S. Green and G. M. J. Schmidt J. Amer. Chem. SOC.,1973,95 2058. 6o D. C. Lankin D. M. Chihal G. W. Griffin and N. S. Bhacca Tetrahedron Letters 1973 4009. Reaction Mechanisms -Part (ii) Orbital Symmetry 85 A general reaction of cyclopropyl-substituted allylic cations is rearrangement to cyclohexenyl and dienylic cations. Labelling of the a-cyclopropyl position with a methyl group shows a very specific skeletal change accompanies the rearrangement (55)-+(56). The reaction is best described as a concerted .2 + ,2 or .2 + ,2 cycloaddition.6' Stereospecific cycloaddition of the oxyallyl-Fe" complex (57) generated from ad-dibromoketones and Fe,(CO) to aryl-substituted olefins [(57) -+ (B)] has been observed but is thought to involve a two-step mechanism.62 (55) Ar D Fel'L H/-\H Me Me (57) Several reviews of 1,3-dipolar cycloadditions have appeared63 and further refinements of the molecular orbital model for 1,3-dipolar cycloadditions have been reported.64 Frontier orbitals are found to be of general utility in the ration- alization of relative rates and regioselectivity of 1,3-dipolar cycloadditions.Of the two regioisomeric adducts the favoured isomer will be that one in which the largest coefficients of the highest occupied and lowest unoccupied orbitals of the two addends are united. The primary I4C kinetic isotope effects in the 1,3-dipolar cycloaddition of N,a-diphenylnitrone and styrene to yield 2,3,5- triphenylisoxazolidine are consistent with a concerted mechanism65 and inconsistent with Firestone's biradical mechanism.66 The unidirectional addition of many 1,3-dipoles to both electron-rich and electron-deficient monosubstituted dipolarophiles is no longer observed when the dipolarophile is highly electron deficient in accord with prediction based on an MO treatment.67 Studies of 61 K.Rajeswari and T. S. Sorensen J. Amer. Chem. SOC. 1973 95 1239. 62 R. Noyori K. Yokoyama and Y. Hayakawa J. Amer. Chem. SOC. 1973,95 2722. 63 P. K. Kadaba Synthesis 1973 71; C. G. Stuckwisch ibid. p. 469; J. Bastide J. Hame-lin F. Texier and Y. Vo Quang Bull. SOC.chim. France 1973 2555 2871. 64 K.N. Houk J. Amer. Chem. SOC.,1972 94 8953; R. E. Duke R. W. Strozier and J. K. George ibid. 1973,95,7287; K. N. Houk,J. Sims C. R. Watts and L. J. Luskus ibid. p. 7301. 65 B. M. Benjamin and C. J. Collins J. Amer. Chem. SOC. 1973 95 6145. 66 R. A. Firestone J. Org. Chem. 1972 37 2181. 6' J. Sims and K. N. Houk J. Amer. Chem. SOC. 1973,95 5799. 86 R. Grigg the stereochemistry and regioselectivity of 1,3dipolar cycloadditions have provided information on steric and electronic factors in these processes.68 When treated with hydroxylamine or N-methylhydroxylamine in the presence of a protondonor catalyst fruns-A'("hecosteroids (59) are converted stereo- specifically and in good yield into the corresponding isoxazolidine derivatives (61) by a transannular 1,3-dipolar cycloaddition of the intermediate nitrone e.g.(60).69The naphthotriazine derivative (62) undergoes a remarkable 1,ll- dipolar cycloaddition to acetylenic esters to give acenaphthotriazines e.g. (63) after spontaneous dehydrogenation. 70 AcO N-0 Me Me I I N4Y.N-McO,C=CCO Me (I5 A+ /\ ,-MeOzC C0,Me Me Oxazaphospholes (64) react with isocyanides by a [3 + 11-cycloaddition via formation of a nitrile ylide (65) to give (66).71 Kinetic studies of the thermal R. Gree F. Tonnard and R. Carrie Tetrahedron Letters 1973 453; M. Joucla R. Gree and J. Hamelin Tetrahedron 1973 29 2315; G. Bianchi C. De Micheli R. Gandolfi P. Grunanger P. V. Finzi and 0.V. de Pava J.C.S. Perkin I 1973 1148. '' M. Lj. Mihailovic Lj.Lorenc Z. Maksimovic and J. Kalvoda Terrahedron 1973 29 2683. 70 C. W. Rees R. W. Stephenson and R. C. Storr J.C.S. Chem. Comm. 1972 1281. " K. Burger. J. Fehn and E. Muller Chem. Ber.. 1973,106 I ;K. Burger W. Thenn and E. Muller Angew. Chem. Internat. Edn. 1973 12 154. Reaction Mechanisms -Part (ii) Orbital Symmetry cycloaddition of N-phenylmaleamide to (67) suggest the dipolar intermediate (68) is involved.72 Oxycarbene intermediates (69) generated by thermolyses of lactone tosylhydrazone salts decompose by several pathways. One of these is a highly stereospecific fragmentation to olefin which is suggested to be a [4 + 23-cycloreversion [(69)+(70)].73 Conflicting views74 are still held about the perepoxide or concerted ene mechanism for formation of allylic hydroperoxides from olefins and singlet oxygen.75 The proposed ene mechanism for the selenium dioxide oxidation of olefins (71) has been supported by the trapping of the intermediate seleninic acid.76 Further studies have been reported of intramolecular ene reac-tion~’~,~* leading from acyclic precursors to 5-9 membered rings e.g.(72) -+(73; X = NMe). In cases where enolization is favourable e.g. (72; X = CH,) the ene reaction is thought to involve the enol (74) whereas when enolization is not facile a direct H-shift is more probable.77 72 S. R. Tanny and F. W. Fowler J. Amer. Chem. SOC.,1973,95 7320. 73 A. M. Foster and W. C. Agosta J. Amer. Chem. SOC.,1973,95 608. 74 A. Nickon J. B. DiGiorgio and P. J. L. Daniels J. Org.Chem. 1973 38 533; L. M. Stephenson D. E. McClure and P. K. Sysak J. Amer. Chem. SOC.,1973,95 7888. 75 R. Grigg Ann. Reporrs (B) 1972 69 133. ’‘ K. B. Sharpless and R. F. Lauer J. Amer. Chem. SOC.,1972,94 7154; D. Arigoni A. Vasella K. B. Sharpless and H. P. Jensen ibid. 1973 95 7917. 77 M. Bortolussi R. Block and J. M. Conia Tetrahedron Letters 1973 2499 4171. J. B. Lambert and J. J. Napoli J. Amer. Chem. SOC., 1973 95 294. 88 R.Grigg A number of papers dealing with competition between the ene reaction [2 + 21-cycloadditions and [4 + 21-cycloadditions have appeared." The reaction of vinyloxyboranes with carbonyl compounds appears to involve an ene mechanism [(75) -+(76)]?' The retro-ene reaction of organo-selenium compounds (77) proceeds under mild conditions and is finding numerous synthetic uses." The nitrones (78) undergo a retro-ene reactiong2 at 80-210 "C and the sulphones (79) fragment to sulphur dioxide and olefin (80) with the transfer of a carbon substit~ent.~~ RS (77) R' (79) The cycloaddition of ally1 cations to conjugated dienes has been reviewedg4 and the stereochemistry of the cycloaddition of oxyallyl to conjugated dienes has been further studied.85 Approximate frontier orbital energies and coefficients 79 P.Crews and J. Beard J. Org. Chem. 1973,38,522; V. Usieli and S. Sarel ibid. p. 1703; S. Sarel A. Felzenstein and J. Yovell J.C.S. Chem. Comm. 1973 859. T. Mukaiyama K. Inomata and M. Muraki J. Amer. Chem. SOC.,1973,95 967. " K. B. Sharpless and R.F. Lauer J. Amer. Chem. SOC.,1973 95 2697; H. J. Reich I. L. Reich and J. M. Renga ibid. p. 5813; K. B. Sharpless R. F. Lauer and A. Y. Teranishi ibid.,p. 61 37. 82 D. R. Boyd Tetrahedron Letters 1973 3467. 83 J. B. Hendrickson and R. Bergeron Tetrahedron Letters 1973 3609. 84 H. M. R. Hoffmann Angew. Chem. Internat. Edn. 1973 12 819. 85 S. Ito H. Ohtani and S. Amiya Tetrahedron Letters 1973 1737; R. Noyori Y. Baba S. Makino and H. Takaya ibid. p. 1741; C. E. Hudson and N. L. Bauld J. Amer. Chem. SOC.,1973,95 3822. Reaction Mechanisms -Part (ii) Orbital Symmetry for the HO (highest occupied) and LU (lowest unoccupied) orbitals of Diels- Alder participants allow prediction of the preferred Diels-Alder regioisomer. The larger terminal coefficient of each addend will become bonded preferentially in the transition state.For ‘normal’ Diels-Alder reactions involving n-rich diene and n-poor dienophile the ‘ortho’ regioisomer is favoured for l-substituted butadienes and the ‘para’ regioisomer with 2-substituted diene~.~~** A similar treatment of Lewis acid catalysed Diels-Alder reactions provides an MO explanation for the large rate acceleration and greatly increased regioselectivity.88 Studies of the endo-exo selectivity of various Diels-Alder reactions have appeared8’ and evidence obtained for attractive interactions between diene and halogen atoms in halogeno-dienophiles.” Cycloaddition to (81) occurs stereo- specifically in a manner such that repulsive interactions in the transition state are minimized.’* Thus the non-synchronous but concerted cycloaddition of cyclopentadiene could give rise to two transition states (82) and (83).The sole product is (84) arising from the more stable transition state (83). The Diels-Alder addition of singlet oxygen to acyclic 1,3-dienes is a major process even in the presence of allylic hydrogen^.'^ The dithenium fluoroborate (85) is the synthetic equivalent of carbon monoxide in that cycloaddition of dienes gives (86)’ which can be converted to (87) in three steps.93 A one-step 86 K. N. Houk J. Amer. Chem. SOC. 1973,95,4092. ’’ 0.Eisenstein and N. T. Anh Bull. SOC. chim. France 1973 2721 2723. 88 N. T. Anh and J. Seyden-Penne Tetrahedron 1973 29 3259; K. N. Houk and R. W. Strozier J. Amer. Chem. SOC.1973 95 4094. 89 D. W. Jones and G. Kneen J.C.S. Chem. Comm. 1973 420; D. W. Jones and R. L. Wife ibid. p. 421; D. Bellus K.v. Bredow H. Sauter and C. D. Weis Helv. Chim. Acta 1973 56 3004; G. Desimoni G. Colombo P. P. Righetti and G. Tacconi Tetrahedron 1973 29 2635; K. Imagawa K. Sisido and M. Kawanisi Bull. Chem. SOC.Japan 1973,46 2922. ’O K. Seguchi A. Sera and K. Maruyama Tetrahedron Letters 1973 1585; E. T. McBee M. J. Keogh R. P. Levek and E. P. Wesseler J. Org. Chem. 1973 38 632. ’’ C. Kt Bradsher F. H. Day A. T. McPhail and P.4. Wong J.C.S. Chem. Comm. 1973 156. 92 K. Kondo and M. Matsumoto J.C.S. Chem. Comm. 1972 1332. ’’ E. J. Corey and S. W. Walinsky J. Amer. Chem. SOC.,1972 94 8932. 90 R.Grigg condensation of thioamide aldehyde and olefin gives dihydr0-1,3-thiazines.~~ The reaction is thought to involve the thioamidoalkyl ion (88) and addition to the olefin is regiospecific and stereospecific [(88) +(89)].R2 SWS BF,-R' v R' (88) (89) The suggestion has been made9' that the photochemical formation of bicyclo-[3,1,O]hex-2-enes from hexatrienes [e.g. (90) -+(91)] formally a ,4 + .2 or .4 + .2 process proceeds from an excited state in which the centre double bond has twisted to give a bisallyl system. Closure to the cyclopropane ring then occurs to give (92) and is followed by closure to (91). The syn-benzene dioxide (93) undergoes valence tautomerism to (94) at 50 "C whereas anti-benzene dioxide is stable up to 150°C. The tris-homobenzene dioxides also exhibit considerably different thermal ~tabilities,~~ and activation parameters have been reported for systems of this type.97 Homofulvenes react with dieno- philes via a 6 + 2 cycloaddition [(95) 3(96)],'* whilst cycloheptatrienethione undergoes a rare .8 + ,2 cycloaddition with maleic anhydride.99 Paracyclo- phadiynes undergo a remarkable multicycloaddition reaction [(97) +(98)].loo 94 L.Abis and C. Giordano J.C.S. Perkin I 1973 771. " W. Dauben and M. S. Kellog J. Amer. Chem. SOC.,1972,94 8951. 96 E. Vogel H.-J. Altenbach and E. Schmidbauer Angew. Chem. Internar. Edn. 1973 12 838. " A. de Meijere D. Kaufmann and 0. Scheller Tetrahedron Letters 1973 553; H. Prinzbach and D. Stusche Helv. Chim. Acta 1971 54 755. " R. Askani and J. P. Chesick Chem.Ber. 1973 106 8. '9 T. Machiguchi M. Hoshino S. Ebine and Y. Kitahara J.C.S. Chem. Comm. 1973 196. loo T. Kaneda T. Ogawa and S. Misumi Tetrahedron Letters 1973 3373. Reaction Mechanisms -Part (ii) Orbital Symmetry NC. CN 4 Sigmatropic Reactions A study of [1,2]-shifts in carbonium ions in which either a methyl group-or the electronegative diphenylphosphinyl group (Ph,PO) can migrate shows that Ph,PO migration slightly predominates. It is suggested that it is the ability of the group that remains behind to support the positive charge rather than 'migra- tory aptitude' which is important in these reactions.'" The bicyclo[4,2,0]octenes (99; X = OAc or OSiMe,) were chosen as ideal substrates to investigate subjacent orbital control' in a thermal [1,3]- sigmatropic rearrangement [(99)+(loo)].The endo-methyl groups produced a sufficient steric blockade to the allowed .2 + .2 process (Si) to allow the 'forbidden' .2 + ,2 process (S,) to predominate. Rate ratios (S,/Si)of 12 (X= OAc) and 15 (X = OSiMe,) were observed and interpreted in terms of subjacent orbital control.' O2 Careful study of the thermal methylenecyclopropane rearrangement using the four racemic diastereoisomeric 2-cyano-3-methylethylidenecyclo-propanes allows both a Mobius transition state and subjacent orbital control to be ruled out in this case.' O3 However optically active (101 ;R = H) is thermally racemized more slowly than (101; R = D) equilibrates with (102). Using a trideuterio-derivative of (101 ; R = D) the 1'3-shift was shown to be 65 % antara-facial with respect to the allylic component.' O4 Photochemical and thermal 1'3-boron shifts have been observed (103; R = Me or Ph).'" Photochemical rearrangement of some diphenylbicyclo[3,1,O]hexenes [e.g.(104)-+ (1091 in the excited singlet state showed a preference for involvement of the internal cyclo- propyl bond.A concerted 1,3-suprafacial process was primarily utilized although lo' D. Howells and S. Warren J.C.S. Perkin 11 1973 1645. lo* J. A. Berson and R. W. Holder J. Amer. Chem. SOC.,1973,95 2037. lo' W. von E. Doering and L. Birladeanu Terrahedron 1973,29 499. lo* J. E. Baldwin and R. H. Fleming J. Amer. Chem. SOC.,1973,95 5256 5261. Io5 K. G. Hancock and J. D. Kramer J. Amer. Chem. SOC.,1973,95. 3425. 6463.92 R.Grigg a possible 1,3-antarafacial shift with inversion at the migrating centre was also observed. The cyclopropyl inversion process was designated a 1,l -sigma- tropic shift.'06 H R R\ B-NMe Me Ph Ph It is suggested that any electromeric substituent at C-3 in cis-penta-1,3-dienes should tend to favour the anti-aromatic antarafacial 1,5-H shift but the effect should be most pronounced with -E substituents particularly those with HOMOSof very high energy e.g.(106; X = NMe or 0-).Similar symmetrically placed substituents at C-2 and C-4 should have the same effect.lo7 The thermal scrambling of substituents [(107) +(108)] may occur via a 1,5-shift in the bicyclic valence tautomer. O8 X Me The thermal rearrangement of the ortho-oxyanilium ylide (109) gives (1 10) by a [1,4]-shift and (1 11) by successive [2,3]- to give (1 12) and [3,3]-~hifts."~ Reactions with deuteriated substrates allied with CIDNP studies show the rearrangement involves competing but distinct concerted and radical pair lo6 H.E. Zimmerman and G. A. Epling J. Amer. Chem. SOC.,1972 94 8749. lo' R. C. Bingham and M. J. S. Dewar J. Amer. Chem. SOC. 1972,94,9107. lo* L. A. Paquette R. H. Meisinger and R. E. Wingard J. Amer. Chem. SOC.,1972 94 9224. Io9 W. D. Ollis I. 0.Sutherland and Y.Thebtaranonth J.C.S. Chem. Comm. 1973 653 654; S. Mageswaran W. D. Ollis I. 0.Sutherland and Y. Thebtaranonth ibid. p. 651. Reaction Mechanisms -Part (ii) Orbital Symmetry processes with a contribution of 15-22% from the radical pair mechanism at 60°C.Thus the observation of a CNDIP effect does not rule out the existence of a concerted mechanism which might even be the predominant pathway. These results clearly reopen the question of the mechanistic detail of [1,2]-anionic rearrangements for which CNDIP evidence forms the basis of assignment of an exclusive radical pair mechanism. The vinylogous compounds (1 13) rearrange at 0 "C by competing [1,4]- and [4,5]-shifts.' lo Related [4,5]-shifts occur even in the more flexible (1 14) and allow some conclusions to be drawn on the geometry of the transition state.' l1 The relative rates of the [2,3]-sigma- tropic processes (1 15) +(1 16; X = NMe or S) compared with their acyclic counterparts are cited as positive evidence for bonding in the transition state consistent with a concerted mechanism.' R' R2 Comparison of substituent effects on the relative rates of Cope rearrangement of a number of 1,Sdienes suggests that hexa-1,5-diene is more or less poised between a biradical and concerted mechanism and that appropriate substitution 'lo W.D. Ollis R. Somanathan and I. 0.Sutherland J.C.S. Chem. Comm. 1973 661. ' I I T. Laird and W. D. Ollis J.C.S. Chem. Comm. 1973 658. 'I2 S. Mageswaran W. D. Ollis and I. 0. Sutherland J.C.S. Chem. Comm. 1973 656; W. D. Ollis I. 0.Sutherland and Y. Thebtaranonth ibid. p. 657. 94 R. Grigg at C-2 and C-5 by electromeric substituents should stabilize a cyclohex-1,4-ylene intermediate (1 17) and hence favour the biradical me~hanism."~ cis-Divinyl- cyclo-propane has been synthesized and shown to rearrange to cyclohepta-1,4- diene below room temperature (AG* = 84 kJmol-').' l4 Cope rearrangements in bicyclic systems have continued to attract attention especially bicyclo[6,1,0]- nonadiene systems (118; X = CH, CHMe 0 or N-C0,Et).''5 For the process (1 18) -+ (1 19) the rates decrease in the order N-C0,Et > CH > 0.0 Regiospecificity of Claisen rearrangements in polysubstituted aromatic com- pounds is affected by the presence of intramolecular hydrogen-bonding which results in energetic preference for one of two possible transition states.' l6 Thus in (120) rearrangement occurs exclusively to C-3 whereas the corresponding acetate gives products arising from rearrangement to both C-3 and C-5.The site specificity of the [3,3]-sigmatropic rearrangements in 3-allylindolenines has been studied and a prior imine-enamine tautomerism uncovered.' '' Ally1 ethers (121) thermally rearrange to (122; R2= C,H, R3= Ac) and (122; R2 = Ac R3= C,H,); the latter arises via initial Claisen rearrangement to the o-acetyl site followed by a [ 1,5]-acetyl shift in the intermediate dienone.' ' Reaction of a-bromoesters of allylic or acetylenic alcohols with zinc dust provides a useful synthesis of y,d-unsaturated acids via a [3,3]-sigmatropic rearrangement of the intermediate zinc enolate [(123) -+ (124)I.ll9 An extensive series of papers by Schmid and his co-workers'20 reports on charge-induced and charge-controlled [3,3]-sigmatropic processes.Lewis acids such as zinc chloride boron trifluoride silver salts and Brsnsted acids are shown to appreci- ably accelerate a wide range of [3,3]-sigmatropic processes. 'I' M. J. S. Dewar and L. E. Wade J. Amer. Chem. SOC. 1973,95 290. 'I4 J. M. Brown B. T.Goulding and J. J. Stofko J.C.S. Chem. Comm. 1973 319. 'I5 W. Grimme and K. Seel Angew. Chem. Internat. Edn. 1973 12 507; W. Grimme J. Amer. Chem. SOC. 1973 95 2381. 'I6 S. Marcinkiewicz Bull. Acad. polon. Sci. St+. Sci. chim. 1972 20 861; D. G. Clark L. Crombie and D. A. Whiting J.C.S. Chem. Comm. 1973 580; F. Vogtle and E. Goldschmitt Angew. Chem. Internat. Edn. 1973,12,767. 'I7 R. K. Bramley J. Caldwell and R. Grigg J.C.S. Perkin I 1973 1913; Tetrahedron Letters 1973 3207. ' C.P.Falshaw S. A. Lane and W. D. Ollis Chem. Comm. 1973,491. J. E. Baldwin and J. A. Walker J.C.S. Chem. Comm. 1973 117. lZo R. Borgulya R.Madeja P. Farhrni H.-J. Hansen H. Schmid and R. Barner Helu. Chim. Acta 1973,56 14; A. Wunderli J. Zsindely H.-J. Hansen and H. Schmid ibid. p. 989; U. Widmer J. Zsindely H.-J. Hansen and H. Schmid ibid. p. 75; M. Schmid H.-J. Hansen and H. Schmid ibid. p. 105; H.Schlossarczyk W. Sieber M. Hesse H.-J. Hansen and H. Schmid ibid. p. 875; U. Kock-Pomeranz H.-J. Hansen and H. Schmid ibid. p. 2981. Reaction Mechanisms -Part (ii) Orbital Symmetry 0 OZnBr A A. R~R~C 0 R~R~C'-o 11-Br CHR4 R3CH)$CHR4 R3CH=/ Deuterium labelling uncovered a degenerate butadienylcyclopropane re-arrangement 12' which occurs in (125; arrows) above 1 10 "C.The [ 1,3]-sulphur migration (126)* (127) occurs such that the new C-S bond is formed with retention of configuration by what appears to be a concerted mechanism.'22 The inspired coupling of a photochemical [1,16]-H shift with a 16-electron electrocyclic process used in the elegant construction of the corrin ring'23 has now been applied [(128)-+ (129)] to the synthesis of a l-hydro~ycorin.'~~ W. Grimme and W. von E. Doering Chem. Ber. 1973 106 1765. lz2 J. Kitchin and R. J. Stoodley J.C.S. Perkin I 1973 2460. lZ3 A. Eschenmoser Quart. Rev. 1970,24 366. lZ4 E. Gotschi and A. Eschenmoser Angew. Chem. Internat. Edn. 1973 12 912. 96 R.Crigg 5 Cheletropic Reactions Non-empirical MO studies of several carbonyl-nitrenes have been reported' 25 and by use of orbital correlation diagrams the direct insertion of the lowest singlet state nitrene into a-bonds is shown to be a 'forbidden' process.However an energetically favourable insertion pathway occurs when the nitrene approaches the o-bond in an orientation which aligns its lowest unoccupied orbital with one end of the bond thus avoiding the symmetry restrictions. A large amount of singlet biradical character can develop in the transition state. The photochemical cheletropic loss of sulphur dioxide from (1 30; X = SO, R' = R2 = alkyl R3 = C0,Me) is non-stereospecific and episulphone inter- mediates may be involved.'26 Contrary to a previous report,'27 the thermal loss of sulphur monoxide from (130; X = SO R' = R2 = alkyl R3 = C0,Me) is reasonably stereoselective and proceeds in high yield.However this discrepancy could well be due to the presence of methoxycarbonyl groups in one case (130; X = SO R3 = C0,Me)'26 but not in the other.'27 The less than 100% stereo-selectivity is circumstantial evidence for a biradical intermediate. '26*1,' Studies on the cheletropic loss of phosphorus derivatives e.g. [130; X = P(OEt),Me R' = Me R2 = R3 = provide support for the suggestion that the cheletropic process will involve axial-axial or equatorial-equatorial bond breaking at trigonal-bipyramidal phosphorus.' 29 Formation of high-energy silicon atoms by the nuclear recoil technique in the presence of butadiene gives rise to silylene (SIH,) consisting of 80% triplet and 20 % singlet both configura- tions add to butadiene to give (130; X = SiH, R' = R2 = R3 = H).130 The question of linear uersus non-linear cheletropic processes has been studied with (131tj133).'3' Bridge extrusion under the influence of basic hydrosulphite is rapid in (131) and (133) where a linear cheletropic process (4n + 2 case) is possible.In contrast (132) for which a non-linear cheletropic process (4n case) is predicted evolves very little gas (ca. 10%) and fails to generate a hydrocarbon fragment. Thermolysis of cyclopropyl azides generates olefins stereo-specifically.'32 NNO NNO NNO R' P. E. Alewood P. M. Kazmaier and A. Rank J. Amer. Chem. Soc. 1973 95 5466. 12' W. L. Prins and R. M. Kellog. Tetrahedron Lerrers 1973 2833. ''' D.M. Lemal and P. Chao J. Amer. Chem. SOC.,1973 95 920 922. C. D. Hall J. D. Bramblett and F. F. S. Liu J. Amer. Chem. SOC.,1972 94 9264. R. Hoffmann J. M. Howell and E. L. Mutterties J. Amer. Chem. SOC.,1972,94 3047. I3O G. P. Gennaro. Y.-Y. Su 0. F. Zeck S. H. Daniel and Y.-N. Tang J.C.S. Chem. Comm. 1973,637. I3l A. G. Anastassiou and H. Yamamoto J.C.S. Chem. Comm. 1973 840. 132 G. Szcimies and J. Harnisch J.C.S. Chem. Comm. 1973 739. Reaction Mechanisms -Part (ii) Orbital Symmetry 6 Metal Catalysis A further model for the catalysis of 'forbidden' processes has been suggested.' 33 Dramatically lower temperatures suffice for the Cope rearrangements of cis-divinylcyclobutanes to cyclo-octa-1,5-dienes and of cis,rrans-cyclodecadienes (1 34) -+ (135) in the presence of Pd".'34 Rh'-catalysed cheletropic processes have been observed [( 136)-+ (1 37)]' and Cu' catalysis of an electrocyclic process has been discovered [(138)-+ (139)].'36 (136) (1 37) Me Ph J==*=( CuCl Ph conrot' Me)=*-Ph 6Me Me Ph 13' F.D. Mango Tetrahedron Letters 1973 1509. '34 P. Heimbach and M. Molin J. Organometallic Chem. 1973 49 477 483. '35 H. C. Volger H. Hogeveen and C. F. Roobeek Rec. Trav. chim. 1973,92 1223. '36 K. Kleveland and L. Skattebol J.C.S. Chem. Comm. 1973 432.

ISSN:0069-3030    

DOI:10.1039/OC9737000075

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (iii) Enzyme Mechanisms By M. AKHTAR and D. C. WILTON Dept. of Physiology and Biochemistry University of Southampton SO9 5NH 1 Introduction We have continued our practice of reviewing only those developments in Enzyme Mechanisms which fall within well-defined areas. In this chapter the previous reviews on ‘P,yridine Nucleotide Linked Reactions’ and ‘Active Site Directed Inhibitors’2 have been up-dated. In addition. we have introduced for the first time a section on mechanistic aspects of ‘Flavin-linked Enzymic Reactions’. Because enzyme mechanisms cover large areas of organic chemistry biochemistry and physiology it has not been possible for us to do justice to all the important developments in this field. We are particularly conscious of not having covered literature on the use of e.s.r.n.m.r. and fast reaction techniques as extensively as some may regard as necessary. We hope that this omission will be put right by the next reporter. 2 Flavin-linked Enzymic Reactions D-Amino-acid 0xidase.-Riboflavin (1) after being enzymically converted into either flavin mononucleotide (la) or flavin adenine dinucleotide (1 b) takes part in several biological redox reactions. The precise mechanism through which the flavin coenzymes participate in these reactions has been extensively investigated3 during 40 years since the first flavoprotein old yellow enzyme was dis~overed.~ The most popular view3 until 1970had been that flavin-linked biological reactions occur through the direct transfer of hydrogen atom(sj between the substrate and the coenzyme oxidized flavin + RH reduced flavin + R Then Hamilton made the interesting suggestion’ that the overall oxidation- reduction observed in flavin-linked enzymic reactions may not be due to direct ’ M.Akhtar and D. C. Wilton Ann. Reports (B) 1970 67 557. M. Akhtar and D. C. Wilton Ann. Reports (B) 1971 68 167. For review see (a) D. Wellner Ann. Rev. Biochem. 1967 36 669; (b) P. Strittmatter Ann. Rev. Biochem. 1966 35 125; (c) K. Yagi Ado. Enzymol. 1971 34 41 ;(4A. H. Neims and L. Hellerman Ann. Rev. Biochem. 1970,39,867. 0. Warburg and W. Christian Biochem. Z. 1932,254 438. L. E. Brown and G. A. Hamilton J. Amer. Chem. SOC. 1970,92,7225. 98 Reaction Mechanisms -Part (iii) Enzyme Mechanisms CH,-(CHOH)3-CH2-O-X I 0 (1) X = H; oxidized flavin 0 II (la) X = -P-O-;oxidized flavin mononucleotide I 0- 00 I1 II (lb) X = -P-0-P-0-CH adenine;oxidized flavin adenine dinucleotide t--f OH OH hydrogen transfer but the indirect consequence of a multi-step reaction sequence.The hypothesis is illustrated in Scheme 1 with reference to the enzyme D-amino-acid oxidase which catalyses the reaction RCH(NH2)COZH + 02 + RC(O)CO,H + NH + H202 (1) The first step in the mechanism postulated by Hamilton is the formation of a covalent adduct (4) between the substrate and flavin which then decomposes to give the reduced coenzyme (5) and the imino-compound (6). The latter (6) on subsequent hydrolysis gives the keto-acid.The intermediary role of an imino-acid in the D-amino-acid oxidase reaction was established by conducting the enzymic reaction in the presence of tritiated NaBH, when labelled alanine accumulated.6 During the past two years results obtained with substrate analogues have given further insight into the structure of the substrate-flavin adduct and the mechanistic sequence involved in transformations catalysed by D-amino-acid oxidase and lactic oxidase. It has been shown that D-amino-acid oxidase which catalyses the physiological reaction of equation (l) can also utilize b-chloroalanine (8)and the carbanion of nitroethane (10)as substrates. With B-chloroalanine u-amino-acid oxidase gives two types of product. In the presence of molecular oxygen the reaction is similar to that with the physiological substrate.and p-chloropyruvate is formed (8)-+(9). In the absence of oxygen however a novel reaction occurs7 which results in the elimination of HCl and the formation of pyruvate (8)-+(7). in an oxygendependent reaction the carbanion of nitroethane is converted into acetaldehyde and NO,-(10)+(1 1) by D-amino-acid oxidase.' Nitroethane itself is not a substrate for the enzyme. ' E. W. Hafner and D. Wellner. Proc. Nut. Acad. Sci. U.S.A. 1971 68 987. C. T. Walsh A. Schonbrunn and R. H. Abeles J. Biol.Chem. 1971 246 6855. * (a) D. J. T. Porter J. G. Voet. and H. J. Bright J. Biol. Chem. 1973 248 4400;see also (6) D. J. T. Porter J. G. Voet and H. J. Bright J. Bid. Chem. 1972 247 1951. M.Akhtar and D. C. Wilton Me CO,H \/ c -+ /\ H NH (3) (2) Throughout ;formula (2) represents 'C0,H oxidized flavin coenzyme bound Me (4) to the appropriate enzyme. Me Me \ (2) + H,O 0 + //C-CO,H -!% \C=O + NH, / HN HO,C (6) (7) (5) Scheme I 0 II NH + HCI + Me-C-CO,H I HI /aerobic (7) CH -C-C0,H AH \? 0 II (8) NH + H,O + H0,C-C-CH,CI 0 Na+[Me-CH-NO,] -% Me-Cc + NO,-+ Na' + H,O Several mechanisms for the action of D-amino-acid oxidase which may also permit rationalization of reaction pathways followed by the artificial substrates (8) and (10) have been ~onsidered.~ In the Reporters' view however the suggestion' of Porter et al.,which assumes that in the metabolism of the carbanion of nitroethane the adduct (12)is formed merits special attention.The outstanding feature of this mechanism (Scheme 2) is the proposal that an early step in the enzymic reaction is nucleophilic attack by the carbanion of nitroethane at N-5of the flavin moiety to give the adduct (12). The further conversion of the latter '1 Reaction Mechanisms -Part (iii) Enzyme Mechaiiisms adduct (12) into products then occurs by unorthodox reaction steps shown in Scheme 2. The extension of this mechanism to the physiological reaction using H’ -Me ‘-1 J i-(2) 0,(11) + (5) Me-C-H I CN (14) Scheme 2 D-alanine will involve the participation of an additional a-C-H bond cleavage step prior to the formation of the adduct (15)(Scheme 3). The further decompo- sition of the latter adduct (15)then furnishes the reduced flavin (5)and the imino- acid (6).The keto-acid is produced from the latter by hydrolysis and the original structure of the flavin moiety is regenerated through the involvement of 0,. When the mechanism is applied to the rationalization of the results obtained with P-chloroalanine the introduction of a modification is necessary. The Reporters’ opinion is that in the physiological-type reaction (Scheme 3) oxygen is not involved in the final step but participates more directly in the decomposition of the adduct (15) as shown in Scheme 4. With this modification the initial adduct (16) formed from P-chloroalanine decomposes with the involvement of O=O to give products as shown in the oxidative pathway of Scheme 5.It is now apparent why in the absence of oxygen the same adduct (16)may decompose by an alter- native pathway (anaerobic pathway Scheme 5)to give pyruvate HCl and NH,. It is interesting to note that in the anaerobic metabolism of P-chloroalanine labelled with tritium in the a-position the product pyruvate contains a substantial amount of tritium at the P-p~sition.~ This experiment suggests that the hydrogen atom removed in the first step of the conversion is transferred to the P-position of the product without exchange with the protons of the medium. a-Amino-P- chlorobutyrate is also accepted as a substrate by the D-amino-acid oxidase but M. Akhtar and D. C. Wilton + ’(5; + N NHi ‘Me (2) + H,02 * + H02C NH %(7) + NH, Me> (5) Scheme 3 + (6)+ (7) + H (15) Scheme 4 in this case the reaction follows predominantly an anaerobic pathway leading only to the formation of a-ketobutyrate.’ The support for the existence of a covalent complex involving the a-carbon atom of the substrate and N-5 of the coenzyme comes from two types of experi- ments.It has been shown that when the reaction of D-amino-acid oxidase with the carbanion of nitroethane (10)is performed in the presence ofCN- the enzyme is inactivated and 1 mole of CN-per mole of flavin is incorporated into the enzyme.8” The inactivation has been explained 8u by assuming that CN-reacts with the Schiff-base intermediate (13) to give a ‘dead-end’ complex (14). Using ’ C.T. Walsh E. Krodel V.Massey and R. H. Abeles J. Biol. Chem. 1973 246 1946. Reaction Mechanisms -Part (iii) Enzyme Mechanisms I z-u, + h X t? + h + c + a t X 0 u em E I ps'l M. Akhtar and D. C. Wilton spectroscopic techniques several laboratories have reported that the interaction of D-amino-acid oxidase with D-alanine results in the formation of a species having absorption properties characteristic of a 'dihydroflavin type' of chromo-phore.3c Qualitatively similar species are formed through the interaction of D-amino-acid oxidase with either P-chl~roalanine'~ or cr-amino-P-chlorob~tyrate.~ When substrates labelled with deuterium at the a-position are used the formation of the spectral species is attended by a three-fold kinetic isotope effe~t.~~.~-' The isotope effect data are consistent with the formulation of the initial complex as shown in structure (15),rather than with structures of the type (4)or (17) since the formation of the former complex requires the cleavage of the a-C-H in the crucial stage of the reaction.No C-H bond is labilized in the formation of either (4)or (17). It should be noted however that the isotope effect data are in accord with another formulationg for the substrate-flavin complex (18) therefore the mechanistic discussion should be considered prelimi- nary pending the reliable elucidation of the structure of the substrate-flavin adduct. Me-C-CO,H I H (17) An unpalatable aspect of the mechanism proposed in Scheme 3 is the cleavage of the relatively non-activated C-H bond of alanine in the initial stage of the reaction.A careful examination of the biological literature however reveals other precedents for the removal of a proton from the a-position of carboxylic acids. One may argue that such a deprotonation may be aided by enhancing the electron-withdrawing property of the carboxylic group by complexing the substrate with enzyme active-site groups which decrease the ionization of the 0-H bond and also co-ordinate with the carbonyl group as in Scheme 6. H 0-I/ -c-c I No Scheme 6 lo V. G. Voet D. J. T. Porter and H. J. Bright Z. Nuturforsch 1972,27b 1054 as quoted in ref. 8a. K. Yagi M. Nishikimi N. Ohishi and A. Takai F.E.B.S.Letters 1970,6 22. Reaction Mechanisms -Part (iii) Enzyme Mechanisms Flavoenzyme L-Lactate 0xidase.-Another flavin-linked enzyme L-lactate oxidase catalyses the oxygen-dependent conversion of L-lactic acid into acetic acid and CO MeCH(OH)CO,H + 0 + MeC0,H + CO + H,O (2) Unlike the D-amino-acid oxidase reaction shown in equation (l) this process does not form hydrogen peroxide. The type of mechanistic approach detailed above for the amino-acid oxidase reactions has been extended to the study of L-lactate 0~idase.l~ It has been shown that Q-chlorolactate is a substrate for L-lactate oxidase and may be converted into two different types of products. In an oxygen-dependent decarboxylation chloroacetate and CO are generated while molecular oxygen is reduced to the level of H,O (19)-+ (20);alternatively Q-chlorolactate can be converted in a reaction independent of oxygen into pyruvate and chloride ion (19) -+(7).In the latter conversion the a-proton of the substrate is transferred to the Q-position of the product without exchange with the protons of the medium. The conversion of the physiological substrate OH 0 P aI CO + H,O + CI-CH,-CO,H 2CH,-C-H -6H,-&-CO,H + HCI I1 I II C1 C0,H H O L-lactate labelled with deuterium at the a-position is attended by an isotope effect kH kD = 1.8 thus suggesting that an early step in the substrate oxidation by L-lactate oxidase is the abstraction of the a-hydrogen atom. The above reactions of Q-chlorolactate with the lactate oxidase are strikingly similar to the reaction of Q-chloroalanine with both D-and L-amino-acid oxidases.In the light of this fact a mechanism similar to that suggested for amino-acid oxidases is outlined for lactate oxidase reaction Scheme 7 except that in this case the for- mation of the decarboxylated product necessitates the assumptions that both H,O and pyruvate remain bound to lactate oxidase and that the enzyme contains lactate + -+ 01 -+ (2) + MeC0,H (2) BH Me-C-CO,H + H,O + H,O + CO (22) Scheme 7 W. B. Sutton J. Biol. Chem. 1957 226 395 and references therein. l3 C. Walsh 0. Lockridge V. Massey and R. H. Abeles J. Biol. Chem. 1973 248 7049. M. Akhtar and D. C. Wilton the additional activity for catalysing their conversion into acetate and CO,.This deduction is consistent with the earlier finding that one of the oxygen atoms of acetate orginates from molecular oxygen. l4 N-Methylglutamate Synthetase.-The involvement of an oxidized flavin moiety has recently been established for another enzyme catalysing the interconversion of glutamate (23) and N-methylglutamate (27). When viewed casually the reaction of equation (3)appears to involve a direct displacement of -NH by MeNH- ; however the knowledge of the compulsory requirement of oxidized flavin for the conversion necessitates the consideration of a more complex reaction pathway. L-glutamate +methylamine S N-methylglutamate+ammonia (3) The ability of the flavin moiety to form covalent intermediates in lactate and amino-acid oxidase reactions may explain this interconversion as shown in Scheme 8.The first step is the formation of a substrateflavin complex (24) which undergoes elimination to give NH and the Schiff base (25). The reversal of the B:) C R’ QHz {=-\+ N H I MeNH, -*(2) +R-C-CO,H -I B-H ‘C-CO,H NHMe / NHMe (27) R =HOzC(CHz)z-R Scheme 8 I4 0.Hayaishi and W. B. Sutton J. Amer. Chem. SOC.,1957 79 4809. Is R. J. Pollock and L. B. Hersh. J. Biol. Chem. 1973 248,6724. Reaction Mechanisms -Part (iii) Enzyme Mechanisms overall sequence but using MeNH instead of NH 3 provides a simple mechanistic basis for the interconversion involving the oxidized flavin moiety in a major catalytic role. In the enzymic reaction when glutamate labelled with tritium at the a-position is used all the radioactivity is retained in the product thus suggesting that the hydrogen atom removed in the conversion (23)+(24) is transferred to N-methylglutamate without exchange with the protons of the medium.3 Pyridine Nucleotide-linked Dehydrogenases The dehydrogenases were last reviewed in this series' at a tantalizing stage when the amino-acid sequences coupled with the high-resolution X-ray structures of a number of enzymes were nearing completion. However very few conclusions could then be drawn regarding the individual amino-acid residues at the active site that were involved in binding and catalysis. This situation is now resolved in the case of lactic dehydrogenase. Lactic Dehydrogenase (LDH).-This enzyme catalyses the reversible reaction MeCHOHC0,H + NAD+ MeCOC0,H + NADH + H+ and at neutral pH has an obligatory binding order of coenzyme followed by substrate.The 2.0 A resolution X-ray structure and the primary sequence have now been worked out for the dogfish muscle M enzyme.16 The enzyme consists of four identical sub-units with a cleft present in each sub-unit in which coenzyme and substrate bind. A peptide loop residues 98-114 folds down over this active centre pocket in the ternary complex. The major events occurring during binding and catalysis are summarized below (see Scheme 9). (a) The adenine part of the coenzyme binds first to a hydrophobic pocket with its NN group pointing outwards to the enzyme surface. NAD' linked to Sepharose through this residue will still bind to LDH.l7 (b) The pyrophosphate group of the coenzyme is positioned by binding to residues in the cleft and is finally locked in place by a salt bridge with Arg-101. This residue moves through 13 A to achieve this interaction in the ternary complex. The two ribose residues are hydrogen-bonded to various groups in the cleft as shown in Scheme 9. (c) In order to facilitate the binding of NAD' it is suggested that the side-chain carboxyl of Glu-140 is available to balance the positive charge of the quaternary nitrogen in the nicotinamide ring. This carboxyl approaches the A face of the pyridine ring while the B face resides in a hydrophobic environment. It is the A face of the coenzyme which is positioned towards the substrate.*'M. J. Adams M. Buehner K. Chandrasekhar G. C. Ford M. L. Hackert A. Liljas, M. G. Rossman I.E. Smiley W. S. Allison J. Everse N. 0.Kaplan. and S. S. Taylor Proc. Nat. Acad. Sci. U.S.A. 1973. 70 1968. " K. Mosbach H. Guilford R. Ohlsson and M. Scott Biochern. J.. 1972 127 625. 108 M. Akhtar and D. C. Wilton Hydrophobic His OH OH coo-Asp 53 I * NYN NH Arg 109 NH I Arg 171 Scheme 9 A diagram of the active site of lactic dehydrogenase (d) The substrate is bound by its carboxyl through a salt bridge to Arg-171 while the methyl group is orientated so that at least one of the hydrogens extends towards the surface of the protein. It is noteworthy that phenyl pyruvate is a substrate analogue with the same V,, as pyruvate.I6 (e) His-195 in the ternary complex is correctly positioned to act as either a proton donor for pyruvate reduction or a proton acceptor for lactate oxidation.(f) The essential thiol group Cys-165 of lactate dehydrogenase,' which is situated at the bottom of the active site cleft is not concerned with the binding of substrate or the coenzyme. (g) There is no tryptophan residue' situated near the active site. The precise mechanism by which the chemical transformation is brought about may now be looked at in more detail. The first point that must be clarified is that whereas a negatively charged carboxy-group from Glu- 140 would facilitate the binding of NAD the presence of such a charge would tend to reduce the electron- accepting ability of the pyridine ring and hence deactivate the coenzyme.Arg- 109 is a loop residue which has moved through 23 A in the ternary complex. The Reporters therefore would suggest that a possible role for this residue is to attract the negative charge of the glutamate in the ternary complex so that the positive charge on the pyridine nitrogen of NAD' may be neutralized by hydride transfer from the lactate. However in the oxidation of NADH the movement of this glutamate residue towards the pyridine ring would facilitate the formation of the positively charged nitrogen. There is much interest regarding the stage at which the 'essential' His-195 is protonated or deprotonated during the reaction. Using o-nitrophenyl pyruvate as a substrate the reaction has been studied Reaction Mechanisms -Part (iii) Enzyme Mechanisms by monitoring the proton concentration of the medium." It was observed that in the reduction of the pyruvate analogue protonation of the histidine occurs after the binding of the NADH and is intimately linked with the binding of the substrate.Moreover it has been established that during the conversion of lactate into pyruvate the proton is conserved in the ternary complex and is only lost after the release of the pyruvate. l9 These studies also indicate that a group of pK 6.8 the 'essential' histidine is the group involved in proton uptake and release. The central role of this essential histidine at the active site of the enzyme coupled with a compulsory requirement for protonation at the time of pyruvate binding prior to the actual chemical transformation highlights the importance of the proton transfer step in the overall chemical reaction.On the basis of work carried out on the pyridine nucleotide-linked reduction of carbon-carbon double bonds it was shown that the first step in the chemical transformation is the activation of the substrate by an enzyme mediated protonation giving an electron deficient carbon centre which is subsequently neutralized by hydride transfer from the pyridine nucleotide.20 It would appear that a similar sequence (Scheme 10) of bond-forming events may operate in the reduction of carbonyl compounds as was suggested previously.'*21 Scheme 10 Liver Alcohol Dehydrogenase.-Although the primary sequence of this enzyme has been known for some time22 the X-ray structure at high resolution has only recently been el~cidated.~~ The enzyme is a dimer of two identical sub-units each of which is made up of two lobes of unequal size separated by a wide deep cleft that contains the active site.The coenzyme binding site is very similar to that observed with LDH. The smaller lobe of the sub-unit binds the adenine in a hydrophobic pocket while the rest of the coenzyme in the wide open conformation points down into the cleft. It is estimated that the nicotinamide ring is located in close in J. J. Holbrook Biochem. J. 1973 133 847. 19 J. J. Holbrook and H. Gutfreund F.E.B.S. Letters 1973 31 157. 20 D. C. Wilton K. A. Munday S. J. M. Skinner and M. Akhtar Biochem.J. 1968 106 803; I. A. Watkinson D. C. Wilton K. A. Munday and M. Akhtar Biochem. J. 1971 121 131; I. A. Watkinson D. C. Wilton A. D. Rahimtula and M. Akhtar European J. Biochem. 1971 23 1. 21 M. Akhtar D. C. Wilton I. A. Watkinson and A. D. Rahimtula Proc. Roy. SOC.,1972 B180,167. 22 H. Jornvall European J. Biochem. 1970 16,25. 23 C. 1. Branden H. Eklund B. Nordstrom T. Boiwe G. Soderlund E. Zeppezauer I. Ohlsson and A. Akeson Proc. Nat. Acad. Sci. U.S.A. 1973 70 2439. I10 M. Akhtar and D. C. Wifton proximity to one of the two zinc atoms which is located at the bottom of the active site cleft. It is to this zinc atom that the chelating agent 1,lO-phenanthroline a competitive inhibitor binds. The substrate binding site is thought to be located at the bottom of the active-site cleft.The other zinc atom is found near the surface of the sub-unit far removed from the active-site cleft and is completely surrounded by protein. Its function is unknown but it may be to maintain the proper conformation of the sub-unit. Cytoplasmic Malate Dehydrogenase.-The X-ray structure at 2.9 A resolution has now been determined24 and a preliminary examination of the picture suggests a striking homology with LDH which includes a similar coenzyme binding area. Glyceraldehyde-%phosphate Dehydroge-e.-The 3.0 A electron-density map of the lobster enzyme has now been determined and preliminary observations have been made concerning its structure.25 Perhaps the most exciting observation concerning this enzyme is the fact that Lys-183 of one sub-unit binds to the pyrophosphate of the coenzyme in the active site of the adjacent sub-unit thus creating the unique situation in which the catalytic centre contains residues from two different sub-units.It should be remembered that a feature of the binding of ligands to this enzyme is that although a tetramer it shows two-fold symmetry and behaves as a pair of dimers as far as its reaction with coenzyme and substrate is concerned.26 Of particular relevance is the fact that the coenzyme binding site is very similar to that found in LDH. The Role of Pyridine Nucleotides in Carbohydrate Transformations.-In the 1971 Annual Report’ attention was drawn to the involvement of enzyme-bound pyridine nucleotides in several interesting transformations of carbohydrates.It was reported that the enzyme uridine diphosphate galactose Cepimerase which catalyses the reaction UDP-glucose (28) TUDP-galactose (30) contains tightly bound NAD and that the conversion may involve an oxidation-reduction sequence occurring through the intermediacy of the 4-keto-compound (29). Subsequently a different mechanistic sequence involving C-3 was considered for the conversion (28) (30).2’ The latest evidence however supports the original mechanistic proposal of Scheme 11. It has been shown28 that when UDP- galactose is incubated with substrate amounts of UDP-galactose 4-epimerase the intermediate keto-compound can be trapped by the addition of NaB3H4. The chemical degradation of the reduced hexoses showed that all the tritium was associated with C-4 thus providing evidence for the involvement of a 4-keto- compound in the enzyme reaction.28 Alternatively two groups have shown that when physiological and ‘artificial’ sugar substrates containing tritium at C-4 were 24 E.Hill D. Tsernoglou L. Webb and L. Banaszak J. Mol. Biol. 1972 72 577. 25 M. Buehner G. C. Ford D. Moras K. W. Olsen and M. G. Rossmann Proc. Nar. Acad. Sci. U.S.A. 1973 70 3052. 2b 0. P. Malhotra and S. A. Bernhard Proc. Nut. Akad. Sci. U.S.A. 1973 70 2077 and references therein. 27 L. Davis and L. Glaser Biochem. Biophys. Res. Comm. 1971,43 1429. U. S. Maitra and H. Ankel J. Biol. Chem. 1973 248 1477. Reaction Mechanisms -Part (iii) Enzyme Mechanisms incubated with UDP-galactose 4-epimerase the tritium was transferred to enzyme-bound NAD.leading to the formation of a complex consisting of enzyme- [3H]-NADH-4-ketohexose from which free E3H]-NADH was isolated and characterized by conventional method^.^'*^' Radioactive label was not trans- ferred to NADH when the corresponding sugars containing tritium at C-3 were used. CH,OH - NAD Scheme 11 Another example of the involvement of pyridine nucleotides in carbohydrate transformations is the conversion of CDP-D-glucose (3 1) into CDP4keto-3,6- dideoxy-D-glucose (37) shown in Scheme 12. The overall conversion occurs through stepwise removal of OH-6 and OH-3.31 The former is achieved by the sequence (31) +(32)--* (33)+(34) involving oxidation at C-4 and concomitant formation of enzyme-bound NADH ;j?-elimination then gives the unsaturated derivative (33) which upon reduction by NADH is converted into CDP-4-keto- 6-deoxy-~-glucose (34).In this process the hydrogen at C-4 of the substrate is transferred to C-6 of CDP4-keto-6-deoxy-~-glucose (34) via the coenzyme. The reduction of the latter compound (34) to the 3,6-dideoxy-derivative (37) requires the participation of NADH or NADPH. The reaction may therefore be con-sidered to involve a rather difficult displacement of the 3-hydroxy-group by an H-ion from the coenzyme. The recent demonstration however that 29 W. L. Adair. 0.Gabriel D. Ullrey and H. M.Kalckar J. Biol. Chem. 1973,248,4635; see also W. L. Adair 0. Gabriel D. Stathakos and H. M. Kalckar J.Biol. Chem. 1973,248,4640. 30 J. N. Ketley and K. A. Schellenberg Biochemistry 1973 12 315. 31 V. P. Gonzalez-Porque and J. L. Strominger Proc. Nut. Acad. Sci. U.S.A. 1972 69 1625. M. Akhtar and D. C. Wilton pyridoxamine-5'-phosphateis required as a cofactor for the conversion permits the consideration of an indirect reaction sequence. The first step in the conversion is the formation of the Schiff base intermediate (35). The presence of the pyridinium ion in the species (35) facilitates deprotonation at C* and elimination forming (36). The reduction of the conjugated double bond by NAD(P)H in (36) then occurs through a mechanism for which there are several precedents. OH OH (35) (34) (36) (37) + pyridoxamine-5-phosphate Scheme 12 Th central role of the coenzyme in bringing bout the movement of the loop residues in LDH (see above) highlights the importance of this ligand in the overall active-site conformation of pyridine nucleotide-linked enzymes.This point is illustrated by recent observations concerning the enzyme 6-phosphogluconate dehydrogena~e.~~ This enzyme catalyses the reaction (38) +(42) shown in 32 M. Rippa M. Signorini and F. Dallocchio J. Bioi. Chem. 1973 248 4920. 113 Reaction Mechanisms -Part (iii) Enzyme Mechanisms Scheme 13. Using a modified substrate (39)it was possible to isolate the predicted intermediate (41). The decarboxylation of (41)by the enzyme to give (43) required the presence of NADPH even though this coenzyme is not directly involved in the decarboxylation step.(38) R = OH (40) R = OH (42) R = OH (39) R = H (41) R = H (43) R = H Scheme 13 4 Active-site Directed Inhibitors The use of active-site directed alkylating inhibitors continues to be a major tool for studying enzyme mechanisms and identifying amino-acid residues at the active site. The purpose of this section is not to give a comprehensive list of compounds that have been used since this subject was last dealt with in these Reports2 but to highlight novel compounds and new methods of approach. The use of epoxides as alkylating agents has been further developed by Rose’s group as a means of investigating the mechanism of isomerases. Triose phosphate isomerase was inactivated by both the D-and L-isomers of glycidol phosphate (44);33 however inactivation by the D-isomer was ten times faster.Similarly the H2Y\ HC-0 I R (44) R = -CH,08 (45) R = -(CHOH)3CH20@ enzyme phosphexoisomerase was inactivated by 1,2-anhydro-~-mannitoI-6-phos-phate the R-isomer of the epoxide (45).34With both enzymes nucleophilic attack is by a glutamate residue at C-1 of the inhibitor. In the case of the triose phosphate isomerase the peptide sequence suggests that it is the same glutamate residue that is modified by both isomers of the epoxide. These results are consistent with a single base mechanism of proton transfer for both these enzymes (Scheme 14). Thus the carboxylate anion of the glutamate side-chain first removes a proton from the hydroxyl carbon to produce a cis-enediol intermediate.The reaction may 33 K. J. Schray E. L. O’Conneli and I. A. Rose J. Biol. Chem. 1973,248,2214. 34 E. L. O’Connell and I. A. Rose J. Biof. Chem. 1973 248 2225. 114 M. Akhtar and D. C. Wilton be completed by the carboxyl protonating the carbon atom originally present as the carbonyl. It is proposed that an electrophilic group which normally polarizes the carbonyl to allow proton transfer also acts as an acidic group to facilitate nucleophilic substitution at the epoxide (see Scheme 14). Another active-site H H I \ C-0-H C=& H-?-Em Enz -COO- _C I -+ Enz-COOH -110-fX-Enz W C-0-H I /c O R R CH,OH Enz-COO-I H -X -Em c=o I Scheme 14 directed epoxide that has been used successfully to alkylate a carboxy-group is the 2’,3‘-epoxypropyl P-glycoside of di-(N-acetyl-D-glucosamine) (46).This compound is an effective irreversible inhibitor of lysozyme and has been shown to modify the P-carboxy-group of A~p-52.~’ (N-acetyl glucosamine) -0 -CH -CH -CH, ‘d The use of a bifunctional and hence potentially cross-linking alkylating agent has always had the added attraction that it allows certain conclusions to be drawn concerning the spatial relationship of two amino-acid residues in the native protein. The covalent intermediate that is observed during the course of many enzymic reactions can often provide one of these points of attachment to the protein. A suitable electrophilic group on this intermediate may then react with amino-acid residues at the active site.The active-site serine of a-chymotrypin was acylated by the inhibitor 3,4-dihydro-3,4-dibromo-6-bromomethyl coumarin (47).36 The acetyl-enzyme (48) then readily underwent nucleophilic substitution at the bromomethyl group probably via a quinonemethide intermediate (48a). It would appear that His-57 of a-chymotrypsin was alkylated by this reagent. Another example of the use of a bifunctional alkylating agent is the inactivation of the enzyme 2-keto-3deoxy-6-phosphogluconicaldolase by brom~pyruvate.~’ 35 Y. Eshdat J. F. McKelvy and N. Sharon,J. Biol. Chem. 1973 248 5892. 36 J. J. Bechet A. Dupaix J. Yon,M. Wakselman J. C. Robert and M. Vilkas European J. Biochem. 1973 35 527. 37 H. P. Meloche J. Biol.Chem. 1973 248 6945. Reaction Mechanisms -Part (iii) Enzyme Mechanisms I15 Enz-X \ Br Br I c=o cH&Br 0 I 0 I (47) This inhibitor reacts with a carboxylate residue as well as with the &-amino-group of lysine which on subsequent treatment with borohydride gives a secondary amine. Thus the carboxylate and the lysine must be in close proximity at the active site of the enzyme as shown in Scheme 15. Br H I I I CH,-C-C0,-Br-YHz-t-coz-YHz-Y-CoZ-II 0 'NH BHd-0 0 I I &=o i" A Scheme 15 Isocyanates are now starting to be used as alkylating groups for affinity labelling of enzyme active sites. The mechanism of their reactivity is shown in Scheme 16. Butyl isocyanate (49) has been shown to alkylate specifically a cysteine residue at the active site of yeast alcohol dehydr~genase.~' Interestingly this is not the same 'reactive' cysteine that is alkylated by iodoacetamide.H+ Me(CH,),-N-C=O "1 -P Me(CH,),-NH-C //O Y \ (49) s S I I Enz Enz Scheme 16 Acetylenic compounds are now finding considerable use as alkylating agents and they have proved to be powerful inactivators of decanoyl dehydra~e,~~?~' thio1ase:l y-cystathionase,42 and plasma amine ~xidase.~~ In all cases it is J. Twu and F. Wold Biochemistry 1973 12 381. 39 G. M. Helmkamp R. R. Rando D. J. H. Brock and K. Bloch J. Biol. Chem. 1968 243 3229. 40 M. Morisaki and K. Bloch Biochemistry 1972 11 309. *I P. C. Holland M. G. Clark and D. P. Bloxham Biochemistry 1973 12 3309.42 R. H. Abeles and C. T. Walsh J. Amer. Chem. SOC. 1973.95 6124. 43 R. C. Hevey J. Babson A. L. Maycock and R. H. Abeles J. Amer. Chem. SOC., 1973 95 6125. M. Akhtar and D. C. Wilton proposed that the enzyme first isomerizes the acetylene to an allene which is subject to nucleophilic attack by a suitable group at the active site. This nucleo- phile has been identified as a histidine in the case ofdecanoyl dehydra~e,~’ while a cysteine residue is proposed for thi~lase.~~ Scheme 17 proposed for thiolase Scheme 17 illustrates the mechanism of inactivation of enzymes by acetylenic compounds. Enzyme-generated allene intermediates have also been implicated in the inactiva- tion of plasma amine oxidase by 2-chloroallylamine43 (50),as shown in Scheme 18.- C1 H I ICH,=C-CHI IX IX ICCl b H I c‘ -+ CH,=C-CH -+ CH,=C=CHI 1 NH +NH +NH II II (50) C C /\ /\ pyridoxal enzyme? Scheme 18 In the 1971 report2 evidence was reported which suggested that catalytic activity of several proteolytic enzymes is greatly enhanced by interaction between the enzyme active site and groups of the substrates remote from the amide bond to be cleaved. Studies of this nature have now been extended to ela~tase.~~ which is a serine proteinase elaborated by the pancreas and is involved in the hydrolysis of elastin the insoluble protein of connective tissue.45 A systematic study of the types of product formed when several synthetic peptides of varying sizes are hydrolysed by elastase has led to the deduction44 that the enzyme active site possesses at least six sub-sites for the binding of substrates.At least four of these 44 D. Atlas and A. Berger Biochemistry 1973 12 2573; D. Atlas S. Levit I. Schechter and A. Berger F.E.B.S. Letters 1970 11 281; R. C. Thompson and E. R. Blout Biochemistry 1973 12 51 57 66 and references therein. 45 For a review see B. S. Hartley and D. M. Shotton in ‘The Enzymes’ ed. P. D. Boyer Academic Press 1971 Vol. 3 p. 323. Reaction Mechanisms -Part (iii) Enzyme Mechanisms 117 sub-sites are occupied by the N-terminal and the remaining two by the C-terminal residues of the substrate and hydrolysis occurs at the amide bond residing between sub-sites S and S; as shown in Scheme 19. The knowledge that the occupancy Ala-Ala-Ala-AlaFLys-Phe s s s s S,’ S,‘ Scheme 19 of sub-sites S,,S ,S3,and preferably S4 is mandatory for the ‘perfect’ interaction of the substrate with the active-site region has led to the synthesis of effective active-site directed inhibitors.Thus single amino-acid derivatives containing electrophilic centres such as (51)do not interfere with the activity of the enzyme;46 however chloromethyl ketone derivatives of tri- and tetra-peptides are potent inhibitors of enzyme action.47 The tetrapeptide analogue (53)is ca. 12 times better as an alkylator of elastase than is the tripeptide derivative (52). This order of 0 0 II II Tosyl -NH -CH(R)-C -CH -C1 Ac -(Ala),-Ala -C -CH $1 (51) (52) n = 2 (53) n = 3 reactivity of the inhibitors is similar to the rates of hydrolysis of the corresponding peptide substrates by elastase.Preliminary evidence suggests that the inhibitors (52) and (53) act by modifying a single histidine residue of the enzyme. Another type of inhibitor48 which does not inactivate the enzyme but binds tightly to elastase is the aldehyde derivative (54). The tight binding of the inhibitor to the enzyme has been attributed48 to the reversible formation of a tetrahedral inter- mediate (53,which closely corresponds to an intermediary stage in the hydrolysis of amide substrates. 0 /-Ac-Pro -Ala-Pro-NH -CHMe-C \ H (54) Enz-CH -OH H I R-C-OH I Enz-CH,-0 (55) 46 H. Kaplan V. B. Symonds V. B. Dugas and D. R. Whitkar Canad. J. Biochem.1970,48 649; L. Visser D. S. Sigman and E. R. Blout Biochemistry 1971 10 735. 47 (a)R. C. Thompson and E. R. Blout Biochemistry 1973 12 44; (b) J. C. Powers and P. M. Tuhy ibid. p. 4767. 48 R. C. Thompson Biochemistry 1973 12 47. M. Akhtar and D. C. Wilton Somewhat similar results had previously been obtained with leucine amino- peptidase. This enzyme cleaves N-terminal amide bonds in peptides and proteins and also hydrolyses synthetic substrates such as L-leucine-p-nitroanilide and ~-1eucinamide.~~ The chloromethyl ketone derivative of leucine (56) does not inactivate the enzyme but is a potent reversible inhibitor of the enzyme action.” The strong binding ofthe inhibitor to the enzyme may be rationalized by assuming that the carbonyl group of the inhibitor activated by the a-chloro-substituent reversibly forms tetrahedral intermediateas shown in theconversion (57a) -+(58a).For comparison the first step of the mechanism postu1ated5l for the hydrolysis of amide bonds by leucine aminopeptidase is also shown (57b) -+ (58b). Me 0 \ II CH-CH2-CH(NH,)-C-CH -CI / Me (56) NH2 \ /“ H CH \ M2cs-E I1 2,- X (57) a; X = CH,CI (58) a; X = CH,CI b;X = NH b;X = NH *9 For a review see R. J. Delange and E. L. Smith in ‘The Enzymes’ ed. P. D. Boyer Academic Press 1971 Vol. 3 p. 81. P. L. Birch H. A. El-Obeid and M. Akhtar Arch. Biochem. Biophys. 1972 148,447. ’ G. F. Bryce and B. R. Rabin Biochem. J. 1964,90 513.

ISSN:0069-3030    

DOI:10.1039/OC9737000098

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (iv) Polar Reactions By N. S. ISAACS Dept. of Chemistry The University Whiteknights Park Reading RG6 2AD 1 Aliphatic Nucleophilic Substitution The exact formulation of the S,2 transition state still occupies a considerable amount of attention. Theoretical studies continue to be made with greater refinement and the normally expected inversion geometry is preferred to 'front- face' attack of the nucleophile.' The system CN-+ CH,-F-+ NC-CH + F-has been studied by partitioning energy changes into contributions from spatially defined fragments.2 Bond-making and -breaking contributions (-141 and 163 kcal mol-' respectively) lead to a predicted activation energy of 22kcal mol-'. Such studies referring to the gas phase aid understanding rather than afford experimentally verifiable values.The idea of pentaco-ordinate carbon as an intermediate rather than a transition state in the S,2 reaction is not new,3 but an attempt has now been made to stabilize such a species using the rigid anthracene frarnew~rk.~ Although (1) undergoes the 'bell-clapper' rearrangement (1) (3)as shown by n.m.r. line broadening no definite evidence for the discrete existence of (2)could be adduced. N.m.r. shifts have also been claimed to show complex formation between chloride ion and benzyl or aryl- thiomethyl halides depicted as (4); K values fall in the ranges 0.001-0.1 and p "e. I +/ Ph \ Me '> / Ph Ph \ IW / s+-c s (1) (2) (3) ' (a)A. Dedieu and A. Veillard J. Amer. Chem. SOC.,1972,94,6730; (b) W.T. A. M. Van der Lugt and P. Ros,Chem.Phys. Letrers 1969,4 389; (c) A. J. Duke and R. F. Bade Chem. Phys. Letters 1970 5 328. R. F. Bader A. J. Duke and R. R. Messer J. Amer. Chem. SOC.,1973,95 7715. W. von E. Doering and H. H. Zeiss J. Amer. Chem. SOC.,1953,75,4733. (a)J . C. Martin and R. J Badelay J. Amer. Chem. SOC.,1973,95,2572; (6)A. J. Parker S. G. Smith I. D. R.Stevens and S. Winstein J. Amer. Chem. SOC.,1970 92 115. 119 120 N. S. Isaacs 0.24.5 re~pectively.~ However it is not clear whether these contact complexes are in any way relevant to sN2 reactions. Still another approach to this question has been attempted by an examination of the Brcansted coefficients (from plots of log k against log K,) for the variation of the nucleophile (BN)and the leaving group (PL)in a displacement reaction.6 It may be reasoned by perturbation theory' that these values reflect the extent of bond formation and bond breaking respectively.Such studies have been reported in displacements at sulphur e.g. in (5) and (6) 0 0 R R OH-II IrS I Ph,C-S I' + Ph,C-S + OAr-X-eS-Y + X-S + Y-\ \ II OAr OH 0 /jN = 0.25 PL= -0.97 (bond making lags far behind bond breaking) and BN = 0.75 -0;PL= -0.71. The indication at least for moderate nucleophiles is of a fairly symmetrical transition state but the abrupt curve in the Brransted plot towards the strong-base end reveals complexities which call into question the whole concept of the use of Brransted coefficients to map sN2 pathways.In recent years a new view ofaliphatic substitution reactions has been proposed by Sneen8- l4 and co-workers which may be summarized by the sequence shown in Scheme 1. In many ways this resembles the Winstein' 'merged mechanism' olefin SOH/ 3-SOH/ AN-\El 1 SOR NR ROS RN olefin products Scheme 1 J.-I. Hayami N. Tanaka N. Hihara and A. Kaji Tetrahedron Letters 1973 385. ' L. Senatore E. Ciufferini A. Fava and G. Levita J. Amer. Chem. SOC.,1973,95 2918. R. F. Hudson Chemie 1963 16 173. R. A. Sneen Accounts Chem. Res. 1973,6,46. H. Weiner and R. A Sneen J. Amer. Chem. SOC.,1965,87 287 292. lo R. A. Sneen and J. W. Larsen J. Amer. Chem. SOC.,1966,88 2593. I ' R. A. Sneen and J. W. Larsen J. Amer. Chem. Soc. 1969 91 362. l2 R. A. Sneen and H.M. Robbins. J. Amer. Chem. SOC.,1969,91 3100. R. A. Sneen and J. W. Larsen J. Amer. Chem. SOC.,1969,91 6031. l4 R. A. Sneen and H. M. Robbins J. Amer. Chem. SOC.,1973,95 7868. IS S. Winstein D. Darwish and N. J. Holness J. Amer. Chem. SOC.,1956 78 2915. Reaction Mechanisms -Part (iu) Polar Reactions or the Doering and Zeiss3 two-step process but the reactive intermediate pro- posed for a great many if not all nucleophilic displacement reactions is the ion-pair I1 ; this may react directly to give products or may proceed first to the solvent-separated ion-pair 111 but it is considered unlikely to lead to the solvated carbonium ion IV. It is proposed that this mechanism is shared by systems pre- viously classified as SN1,SN2 SN2' and El and E2 and may also incorporate neighbouring-group participation and rearrangements.By kinetic analysis of the competitive reactions of solvent and nucleophile with a substrate the product ratio is given (as for conventional SN2 reactions) by and the rate ratio by where ksolvis the rate for pure solvolysis and x = k- Jks. Clearly if this scheme operates equation (2) becomes identical with traditional SN2 and SN1behaviour of the limits of x thus lim (X + ~)keXpt,/ko= 1 + m"] (SN~, k-1 >> ks) lim (x -+ O)k,x,tl/ko = 1 (SNl,k-<< ks) The second case is not radically different from a traditional SN1scheme but the first requires a rate-determining destruction of the ion-pair 11. The substrate is supposed to be in rapid equilibrium with 11 which is only infrequently in- volved in irreversible reaction with solvent or added nucleophile.This perhaps is the point which departs most from older views that the activation step in an SN2 reaction is initiated by attack of the nucleophile. Testing this hypothesis is not easy and is most likely to succeed in the 'border- line' region where the predictions from equations (1)and (2)may be contrasted with those of other mechanisms. Seven secondary and benzylic systems have been analysed in this way and the results shown to be in accordance with the predictions of the unified mechanism and in some instances have been shown to depart from other models. For instance the competitive reaction of a-phenylethyl bromide with azide ion in ethanol gives rate ratios kexpt,/kO as a function of azide ion concentration which deviate widely from the line predicted for two S,2 reactions and fit a curve appropriate to x = 8.50 in equation (2).It is not clear whether the experimental results would be explained by other models such as a mixture of SN1 and S,2 processes ;this system is one in which ionization would be highly probable. The relatively small selectivities in competitive reactions ob-served between reactions of SN2 character and those of SN1 are claimed to be better explained in terms of the unified mechanism. Stereochemical consequences of displacement reactions can be accommodated and criticisms'6*' concerning '' B. J. Gregory G. Kohnstam M. Paddon-Row and A. Queen Chem. Comm. 1970 1932. " D. J.Raber J. M. Hems R. E. Hall and P. von R. Schleyer J. Amer. Chem. Soc. 1971 93,4821. I22 N. S. Isaacs salt effects have been answered.12 The mechanism envisaged by Sneen may turn out to have wide validity but much more extensive and critical testing is required particularly if the author is to achieve his aim of bringing primary and methyl systems within the scope of a unified displacement mechanism. Careful measurements of the chlorine kinetic isotope effect and its temperature dependence have been made on prototype SN1and SN2 reactions (methanolysis of t-butyl chloride and the reaction of n-butyl chloride with thiophenoxide ion in methanol respectively18 and the values obtained are in accordance with the predictions of Bigeleisen' using conventional S,1 and SN2 model geometries ofthe respective transition states.The former in accordance with the expectedly higher degree of bond breaking shows the greater effect (k3,/k35 = 1.0106 as against 1.0089 for the bimolecular reaction). These values at least seem to argue against a unified type of transition state; one would not expect to observe a primary isotope effect in a rate-determining attack upon an ion-pair. Displacements at carbon attached to the ferrocene nucleus [e.g.as in (7)] seem to be anomalous in that highly nucleophilic leaving groups may be displaced and Me Fe retentionofconfigurationoccurs." It issupposed that acarbonium ion mechanism is occurring here. Halide exchange at bridgehead positions can be readily achieved using AIBr formed in situ21 (though the preformed compound is almost inactive) and a halogenated solvent ;thus(8)gives(9).The mechanism is uncertain but competitive C. R. Turnquist J. W. Taylor E. P. Grimsrud and R. C. Williams J. Amer. Chem. SOC. 1973,95,4133. l9 J. Bigeleisen and M. Wolfsberg Adv. Chem. Phys. 1958 1 15. 2o G. Marr B. W. Rockett and A. Rushworth Tetrahedron Letters 1970 1317. G. W. Gokel D. Marquarding and I. K. Ugi J. Org. Chem. 1972 37 3052; J. F. McKinley R. E. Pincock and W. B. Scott J. Amer. Chem. SOC.,1973,95 2030. Reaction Mechanisms -Part (iu)Polar Reactions 123 elimination is not favourable in these systems. Displacement using organo-copper reagents is of considerable synthetic potential.22 2 Solvolytic Reactions The importance of steric factors in solvolysis is one that is difficult to assess and quantify but in certain instances may be paramount.Rates of ethanolysis of 1-and 2-adamantyl arenesulphonates ( 1Oa.b) (S,1 or k,) show an almost identical (10) a; R' = H R2 = OSO2T0l b; R' = OS02Tol R2 = H response to the effects of leaving groups (p = 1.76 and 1.86 re~pectively).~~ This argues that electronic influences are small and constant leaving steric effects upon ionization to account for the rate differences. Relief of steric strain has been put forward to account for rate differences in methanolysis of methylated adamantyl systems (1 la,b) although the same explanation does not hold in the norbornyl series (12a,b) in which the methylated derivatives react more slowly than the &:' >li R&R (lla) R' = Me R2 = OS02Tol R' = OS0,Tol R2 = Me (1 fb) (12) parent In these systems there is likely to be a fine balance between enthalpy and entropy effects which would be difficult to disentangle.Steric strain relief is most likely the explanation for the decreasing p-factors with increasing bulk ofsubstituents in the series(l3)+15)(PNB = p-nitrobenz~ate).~' Ar(neopentyl),C-PNB ArBu'(neopenty1)C-PNB ArBu:C-PNB (13) (14) (15) P -2.91 -2.64 -1.30 22 C. R. Johnson and G. A. Dutra J. Amer. Chem. SOC.,1973 95 7777 7783; G. H. Posner C. E. Whitten and J. J. Sterling ibid. p. 7788; K. Oshima H. Yamamoto and H. Nozaki ibid. p. 7926. '' D. N. Kevill K. C. Kalwyck D. M. Shold and C. B. Kim J.Amer. Chem. SOC.,1973 95 6022. 24 D. Faulkner M. A. McKervey D. Lenoir C. A. Senkler and P. von R. Schleyer Tetrahedron Letters 1973 705. 25 H. Tanida and H. Matsumura J. Amer. Chern. SOC.,1973 95 1586. 124 N. S. Isaacs The highly compressed di-t-butylaryl compounds derive so much of the driving force to ionization from strain relief that electronic demands upon the aryl sub- stituent are considerably reduced. Rates of unimolecular solvolysis have long been held to give a measure of carbonium ion stability.26 More recently this information has also become avail- able from 13Cn.m.r. spectroscopy since the chemical shift of the positive carbon of the free cation in superacid solution reveals how much charge is delocalized onto substituent groups.” There should therefore be a relationship between 13Cn.m.r.shifts and solvolytic rate data. Unfortunately this seems not to be the case at least in the series (16a-~).*~ The phenyl group appears more electron- releasing thancyclopropyl by then.m.r. probe but less soby thesolvolyticcriterion. R (16) a; R =Me b; R=Bd C; R =Ph It is not clear where the discrepancy lies; probably the use of enthalpies of acti- vation rather than rates at one temperature might resolve the problem but clearly caution must be exercised in interpreting reaction data in terms of carbonium ion stability. Model systems e.g. 2-adamantyl( 10a)29 and pinacolyl(1 7)30esters and halides which solvolyse only by the ionization route (k,) and which by virtue of their Me Me \/ .c -c.Me‘] L*H Me OS0,Ar structure ought not to experience solvent assistance (k,) or neighbouring-group assistance (k,) have been devised in order to estimate the extents of unassisted rates in other systems. If both model systems behave as predicted it might be supposed that they should show a similar solvent dependence. In fact the rate ratio k(l,,a,/k(17)varies quite widely (from 72 to 20 between aqueous ethanol and formic acid) suggesting that the mechanism of at least one model is not ‘pure’ in all 26 C. K. Ingold ‘Structure and Mechanism in Organic Chemistry’ Bell London 1969. 27 G. A. Olah and A. M. White J. Amer. Chem. SOC.,1969,91 5801. 28 H. C. Brown and E. N. Peters J. Amer. Chem. SOC.,1973.95 2400. 29 J. F. Fry C.J. Lancelot L. K. M. Lam J. M. Harris R. C. Bingham D. J. Raber R. E. Hall and P. von R. Schleyer J. Amer. Chem. SOC.,1970,92 2338. 30 V. J. Shiner R. D. Fisher and W. Dowd J. Amer. Chem. SOC.,1969,91 7748. Reaction Mechanisms -Part (iv) Polar Reactions 125 solvents e~amined.~' One possibility is that the pinacolyl esters derive some assistance to ionization (kb)from the migrating /I-methyl group. Vinyl halides and esters are well established as able to undergo unimolecular solvolysis especially if an a-aryl group is present ;1,Zshifts of /I-anisyl group can occur [(18)+ (19)].32 An a-cyclopropyl group is greatly rate-enhancing but ArHph[ArH1:] AcOH + AcOq ArHAr + Ar Br Ar Ph AcO Ph (18) Ar = p-MeOC,H (19) rather like /I-phenyl a /I-cyclopropyl group is less effective than methyl :33 both groups are more effective when trans to the leaving group than when cis.Also the deuterium secondary isotope effect is somewhat greater from the trans$- position than from cis-B (kH/kDct,,,, = 1.57; kH/kD(eis)= l.10).34 Isotope effects in halogenoallene solvolysis have been measured ;35 the a-effect (kH/kD = 1.22) is comparable with effects in vinyl systems. y-Methyl isotope effects are also quite considerable (k,,CH3/ky-CD3= 1.25). The allene (20) solvolyses 6500 times faster than the structurally similar (21).36 The mechanisms are S,1 (m,= 0.73 AH = 20 kcal mol-' AS = -11cal K-') but the origin of this effect is obscure probably steric. Me Me The long-controversial question of solvolysis of 2-norbornyl derivatives has been reviewed by BrownJ7 and cogent arguments have been presented for the classical formulation of the 2-norbornyl cation.Further evidence supporting the classical nature of 6-arylnorborn-2-enyl cations (22) has been presented in the form of a comparison of Hammett p-values of -4.17 and -4.21 respectively for ionization rates of exo- (22a) and endo-compounds (22b).38 If significant n-participation were occurring (in the exo-case only) the electronic demand from 31 J. E. Nordlander R. R. Gruentzmacher and F. Miller Tetrahedron Letters 1973,927. 32 Z. Rappoport A. Gal and Y.Harminer Tetrahedron Letters 1973 641. 33 D. R. Kelsey and R. G. Bergman J.C.S. Chem. Comm. 1973 589. 34 D. D. Maness and L. D. Turrentini Tetrahedron Letters 1973 755.35 M. D. Schiavelli and D. E. Ellis J. Amer. Chem. Soc. 1973 95 7916. 36 M. D. Schiavelli P. L. Timpanaro and R. Brewer J. Org. Chem. 1973 38 3054. " H. C. Brown Accounts Chem. Res. 1973 6 377. 38 E. N. Peters and H. C. Brown J. Amer. Chem. Soc. 1973,95 2398 7920. 126 N. S. Isaacs (22) a; R' = OPNB R2= Ar b; R'= Ar R2= OPNB the aryl group should be lower than for endo-solvolysis. Rate enhancement is at any rate comparable with values for cyclopentenyl esters (23)-(25).38 Secondary deuterium isotope effects have been shown to be a function of the leaving group the upper limit increasing in the order I- (1.09) C1- (1.15) RS02-(1.22).36,29*40 One interpretation is that the transition from tight to solvent- separated ion-pair is kinetically significant even rate-determining.Interpretation of the magnitudes of secondary isotope effects is a highly developed art; for example a value of 1.15 for the a-effect in the ethanolysis of cyclopentyl brosylate is taken41 to indicate the rate-determining step as being solvent separation of the ion-pair rather than attack by solvent k (expected isotope effect for an SN2 reaction is 1.22). In solvents of higher polarity (ethanol-water trifluoroethanol- water) the isotope-effect values rise (1.18 and 1.25) which is interpreted as solvent attack becoming kinetically important despite the lower nucleophilicity of these solvents. Solvolysis of deuteriated cyclobutyl mesylates gives a p and y secondary isotope-effect ratios of 1.102 0.934 and 1.055 respectively ;the normal y-effect is taken to indicate a 1,3-interaction in the transition state.42 By deuterium labelling rates of solvolysis of cyclohexyl tosylate have been partitioned into rates of formation of both substitution and elimination products both that from a direct reaction and after a 1,2 hydride shift.The ratios of these four types of product vary somewhat with solvent (an ion-pair mechanism is supported) but 20 % of the substitution product and 5-50 % of the cyclohexene has suffered rearrangement.43 39 V. J. Shiner and W. Dowd,J. Amer. Chem. SOC.,1971,93 1029. 40 V. J. Shiner M. W. Rapp E. A. Halevi and M. Wolfsberg J. Amer. Chem. SOC.,1968 90 7171. 41 K. Humski V. Sendijarivic and V. J. Shiner J. Amer. Chem. SOC.,1973 95 7722.42 B. Goricnic Z. Majerski S. Borcic and D. E. Sunko J. Org. Chem. 1973 38 1881. 43 J. B. Lambert and G. J. Putz J. Amer. Chem. SOC.,1973.95 6316. 127 Reaction Mechanisms -Part (iv) Polar Reactions 3 Neighbouring Group Participation The effect of an a-methyl group in solvolyses of 7-sulphonates in the norbornane series (23H25)decreases dramatically as the electronic demands of the reaction become satisfied by n-parti~ipation.~~ Participation may also be important in the solvolysis of (26),but in any event rearranged products are found.45 .OAc OTos It is known that the reactivity ratio B-phenylethyllethyl (solvolysis of tosylates) increases rapidly as the ionizing power of the solvent is increased (e.g. by 7500-fold between ethanol and trifluoroacetic acid).This is undoubtedly due to an increase in the phenyl-assisted component k of the phenylethyl reaction relative to k or k for both reactions. This increase in k might in turn be due to a dissimilar response of the two processes to solvent polarity (m,>m,)or an increase in the extent of aryl bridging brought about by solvent change. It is found that the solvent response is similar to that of neophyl systems (27) in which bridging (k,) is the only term of significance;consequently the latter term is ~nimportant.~~ Ph \7 Ph \+ Ph-C-CH + /C-cHzPh Ph’ Ph d& The presence of aryl assistance in fi-phenylethyl ester solvolysis has been de- monstrated in (28) by the presence of a 14C-secondary kinetic isotope effect (I4Clocated at position 1 of the aromatic ring); a maximum isotope effect would depend upon there being no internal return a condition obtaining in neophyl Me OBros 44 P.G. Gassman and J. M. Pascoe J. Amer. Chem. SOC.,1973,95 7801. 45 R.M. Coates and K.Yano J. Amer. Chem. SOC.,1973,95 2203. 46 F. L. Schadt and P. von R. Schleyer J. Amer. Chem. SOC.,1973 95 7860. 128 N. S. Isaacs systems. It is reported that the isotope effect in neophyl solvolysis is very close to that in 2-(panisyl)ethyl systems both being greater than in P-~henylethyl.~’ On the basis of rate data it is concluded that P-aryl participation occurs in the solvolysis of /I-azulenylethyl sulphonates (29) whether the azulene system is bonded at 2- 4- 5- or 6-p0sitions.~*,~’ Entropies of activation are typically highly negative (4-azulenyl -25 ;6-azulenyl -20 cal K-I) and similar to the values for p-phenylethyl.Rates however are 68000 times greater than for fi-phenylethyl.50 Other effective participating groups (rates relative to p-phenylethyl) are 3-indolyl(7200) ferrocenyl(1400) and thiophenyl(21). Cyclo-octatetraene on the other hand shows no tendency to act as a nucleophilic neighbouring group by kinetic criteria though rearrangements of P-(cyclo-octatetraeny1)ethyl sulphonates (30) to (3 1)and (32) occur on solvolysis suggesting .c-c-H -1 H __ OAc H-l‘OTos H that some contribution from k or k is important.” Trifluoroacetolysis of the deuteriated 2-butyl tosylate (33) reveals the products to be (34) and (39 with no detectable amounts of (36) or (37).52 This is the expected result if hydrogen participation occurs with the formation of the transition state rather than a rapidly equilibrating 2-butyl cation.Solvolysis with concomitant hydrogen migration is also proposed in the bicyclo[3,3,1]nonane series (38) on the basis of 47 Y. Yukawa S. G. Kum and H. Yamataka Tetrahedron Letters 1973 373. 48 R. N. McDonald N. L. Wolfe and H. E. Petty J. Org. Chem. 1973 38 1106. 49 R. N. McDonald N. L. Wolfe H. E. Petty R. G. Cooks and P. T. Cranor J. Org. Chem. 1973,38 1 114. 50 D. S. Noyce and R. L. Castenson J. Amer. Chem. SOC., 1973 95 1247. 51 L. A. Paquette and K. A. Henzel J. Amer. Chem. SOC.,1973,95,2724,2726. 52 J. J. Dannenberg D. H. Weinwurzel K.Dill and B. J. Goldberg Tetrahedron Letters 1972 1241. Reaction Mechanisms -Part (iv) Polar Reactions 129 CF CO H CH,CH,-CDCD CH,CH,CDCD + CH,CHCDHCD, I I I OTos OCOCF OCOCF (33) (34) (35) CH,CHDCHCD CH,CDCH,CD, I I OCOCF OCOCF (36) (37) a non-linear Hammett plot (substitution in Ar) indicating a change in mechanism as electron-releasing substituents are placed in the aromatic nucleu~.~~*~~ A similar consideration may also apply in hydrolysis of longifoline derivatives (39). U (39) Participation by cyclopropane rings depends acutely on the orientation with respect to the reaction centre e.g. little or no participation occurs in solvolysis of (40) although rearrangement of the cations so formed does OCCU~.~~,~~ The D (40) OPNB series of solvolytic rates for (41H44)indicates that participation is a continuous function of the dihedral angle between cyclopropane ring and leaving group ;' a 60" angle seems particularly unfavourable.Large effects of the cyclopropane ring on solvolysis of endo-compounds (45)-(47) are recorded but there is no evidence of any contribution from (48) a bishomo-antiaromatic structure which should destabilize the cati~n.~~?~~ Participation by the cyclopropane ring is likely to be of importance in the system (49).60 53 L. Stehelin L. Kannellias and G. Ourisson J. Org. Chem. 1973 38 847. 54 L. Stehelin L. Kannellias and G. Ourisson J. Org. Chem. 1973 38 851. 55 E. C. Friedrich M. A. Solch and S. Winstein J. Org. Chem. 1973 860.56 E. C. Friedrich and M. A. Solch J. Amer. Chem. SOC.,1973 95 2617. 57 Y. E. Rhodes and V. G. diFate J. Amer. Chem. SOC.,1972,94 7582. 58 P. G. Gassmann and X. Creary J. Amer. Chem. SOC.,1973 95 6852. 59 P. G. Gassmann and X. Creary J. Amer. Chem. SOC.,1973 95 2729. 6o J. B. Lambert A. P. Jovanivich J. W. Hamersma F. R. Koenig and S. S. Oliver J. Amer. Chem. SOC.,1973 95 1570. 130 N. S. Isaacs (42b) kJk 4 x 2.5 x TosO (43b) 4 x 103 The carbonyl group is not one to manifest neighbouring-group participation most strongly yet it is claimed to do so in the following examples. Enhanced endolexo solvolytic ratios in (50a) and (Sob) are taken as evidence forparticipation of the 7-keto-gro~p.~' [The value of this ratio for the parent system (5 1) is 0.17 R;,R' 8OTos / A1 R2 (50) a; R'R2 = =O (51) a; R' = H R2 = OTOS b; R' = OTOS,R2 = H b; R' = OTOS R2= H 61 R.Baker and J.C. Salter J.C.S. Perkin 11 1973 150. Reaction Mechanisms -Part (iu) Polar Reactions compared to for the norbornyl tosylates.] The analogous ketals appear also to derive some driving force from Me0-4 participation (known to be negligible in acyclic systems62) though this is claimed for (53)on the basis of an enhanced endolexo ratio and more negative entropy of a~tivation.~~ The bridgehead oxygen in (54) apparently does not assist endo-solvolysis ;both endo- and exo-isomers suffer from inductive deceleration of solvolytic rates.64 Amide carbonyl participation evidently occurs in the hydrolysis of (55);65 the intermediate cation (56) is isolable as the tetrafluoroborate.Also the rapid hydrolysis of the ester (57) produces the isolable intermediate (58).66 R-C. I R-CO (55) (56) HR The carboxylic acid group may act as either a nucleophilic or an electro- philic participating group. As the former the hydrolysis of 0-and p-carboxy- benzal chlorides6' (59) and (60) may be cited and as the latter the hydrolysis of 62 P. G. Gassmann and J. L. Marshall J. Amer. Chem. SOC.,1966 88 2822. 63 P. G. Gassmann J. L. Marshall and J. G. McMillan J. Amer. Chem. SOC.,1973 95 63 19. b4 L. A. Paquette and I. R. Dunkin J. Amer. Chem. SOC.,1973 95 3067. 6s D. A. Tomalia and J. N. Paige J. Org. Chem. 1973 38 422. 66 K. Bowden and A.M. Last J.C.S. Perkin II 1973 3S1. " V. P. Vitullo and N. R. Grossman J. Org. Chem. 1973 38 179. 132 N. S. Isaacs disalicylacetals (61);68 these fast hydrolyses are independent of hydronium ion catalysis. 0Q Phenolic hydroxy-group participation swings carbamate hydrolysis from the normal addition4imination mechanism via an isocyanate iri favour of an internal nucleophilic displacement (62a)69 and similarly for the corresponding o-hydroxy- methyl compound (62b).70 (-CH,OH) I:B (62) a; Z = OH b;Z = CH,OH Ring-opening of the epoxide (63)is strongly assisted by the 7 a-hydroxy-group acting in an electrophilic ~apacity.~' N3-''0 0 @ \H' (63) 68 E. Anderson and T. H. Fife J. Amer. Chem. SOC.,1973,95 6437. 69 J. E.C. Hutchins and T. H. Fife J. Amer. Chem. SOC.,1973 95 2282. 'O J. E. C. Hutchins and T. H. Fife J. Amer. Chem. SOC.,1973 95 3786. '' D. H. R. Barton and Y. Hauminer J.C.S. Chem. Comm. 1973 839. Reaction Mechanisms -Part (iv) Polar Reactions 4 CarboniumIons A survey of carbocation chemistry in superacid media has been published72 and also information concerning Hannett acidity functions in these highly protonating media.73 Values as high as H = 19 are recorded for the system HS03F-SbF5. New carbonium ion species which have been observed include the bkration (64),’* protonated naphthalene (65),75 acenaphthene (66),76 and the nortricyclyl cation (67).7 The tricycloundecyl cation (68) undergoes a five-fold degenerate R rearrangement with respect to both ally1 moieties [i.e.behaves as (69)].78 Other degenerate rearrangements observed include those of the bicyclo[2,l,l]hexyl cation (70),” bicyclo[3,2,l]octadienyl (71),*’ and deltacyclyl (72).8 Several rearrangements of cyclopropylallyl systems8* e.g.(73)4(74) and cycloallyl 72 G. A. Olah Angew. Chem. Internat. Edn. 1973 12 173. 73 R. J. Gillespie and T. E. Peel J. Amer. Chem. SOC.,1973 95 5 173. 74 G. A. Olah G. Liang P. von R. Schleyer E. M. Engler M. J. S. Dewar and R. C. Bingham J. Amer. Chem. SOC.,1973,95 6829. 75 G. A. Olah G. D. Mateescu and Y. K. Mo J. Amer. Chem. SOC.,1973 95 1865. 76 G. A. Olah G. Liang and P. Westerman J. Amer. Chem. SOC.,1973,95 3698. 77 G. A. Olah and G. Liang J. Amer. Chem. SOC.,1973,95 3792. ’’ M. J. Goldstein and S.A. Kline J. Amer. Chem. SOC.,1973 95 935. 79 G. Seybold P. Vogel M. Saunders and K. B. Wiberg J. Amer. Chem. SOC.,1973,95 2045. ‘O H. Hart and M. Kazuya J. Amer. Chem. SOC.,1973,95,4096. P. K. Freeman and B. K. Stevenson J. Amer. Chem. SOC., 1973.95 2890. 82 K. Rajaswari and T. S. Sorensen J. Amer. Chem. SOC.,1973,95 1239. 134 N. S. Isaacs (to bicycloalkyl) e.g. (75)+(76),have been studied.83 Strained cyclobutyl cations such as (77) rearrange stereospecifically (77) +(78).84 Me3cQ Me &Me Me Me 'Me (75) (76) 83 L. Huang K. Ranganayakulu and T. S. Sorensen J. Amer. Chem. SOC.,1973.95 1936. P. G. Gassman and E. A. Armour J. Amer. Chem. SOC.,1973,95 6129. Reaction Mechanisms -Part (iv) Polar Reactions CH,OTos (77W Protonated hydrazobenzene (80)and azoxybenzene (79) have been identified presumably species identical with intermediates in the benzidine and Wallach rearrangement^.^' Bridgehead carbonium ions are notably difficult to form.Two compounds which ionize considerably faster than t-butyl esters are (81) and (82);86the related biscation (83)has now been observed as a long-lived species at 0 0C.87 & eb B~'C~ 3.757H-fB (81) (82) H 3.417 H 2.557 krcl 10' 104 1 (83) Dealkylation of t-butylbenzene (84) a reverse Friedel-Crafts reaction can occur in superacid solution,88 and protolysis of C-C and C-H bonds can also occur e.g. (85)-P (86).89 BU' Bu' H (84) " G. A. Olah K. Dunne D. R. Kelly and Y. K. Mo,J. Amer. Chem. SOC.,1972,94,7438.86 A. de Meijere and 0.Schallner Angew. Chem. Internat. Edn. 1973 12 399. A. de Meijere 0.Schallner and C. Weitmeyer Angew. Chem. Internat. Edn. 1971,10 404. G. A. Olah and Y.K. Mo,J. Org. Chem. 1973.38 3221. 89 G. A. Olah and Y. K. Mo J. Amer. Chem. SOC..1973,95,6827. 136 N. S. Isaacs ,Bu' Bu' + 2Me3C+ Proton migration in benzenonium ions is well recognized. Protonated fluoro- benzene a mixture of the three isomers at 33 "C,becomes only the 3-and 4-fluoro- compounds at -10 "C and only the 4-fluoro-compound the most stable isomer at -84 OC90 Evidence of the mobility of nitro-groups in aromatic substitution reactions comes from the acid-catalysed rearrangement of (87).91 OAc Many carbonium ion rearrangements can be explained by postulating the intermediacy of protonated cyclopropanes this concept has been re~iewed.~' A reaction difficult to reconcile with other mechanisms is the carbon and hydrogen scrambling of the 2-propyl cation (88) which occurs in superacid solution.93 'CH $ CH CH /\ /+\ 'LA CH3 CH3 H3C-CH2 / Careful kinetic and product studies accord with this mechanism but not with others in which the 1-propyl cation is required to be an intermediate.Hydrogen-exchange and alkylations of alkanes in superacid are presumed to occur uia 'five-co-ordinate' carbon species ; the scope of these reactions [for example (89)-+ (go)] has been further extended.9L97 Similar intermediates 90 G. A. Olah and Y. K. Mo J. Qrg. Chem. 1973,38 3212. 91 P. C. Myhre J.Amer. Chem. SOC.,1973,95 7921. 92 M. Saunders P. Vogel E. L. Hagen and J. Rosenfeld Accounts Chem. Res. 1973 6 53. 93 C. C. Lee A. J. Cessna E. C. F. KO and S. Vassie J. Amer. Chem. SOC.,1973 95 5688. 94 G. A. Olah J. R. deMember and J. Shen J. Amer. Chem. SOC.,1973,95,4952. 95 G. A. Olah J. Shen and R. H. Schlosberg J. Amer. Chem. Soc. 1973,95,4957. 96 G. A. Olah Y. K. Mo and J. A. Olah J. Amer. Chem. SOC.,1973 95 4939. 97 G. A. Olah Y. Halpern J. Shen and Y. K. Mo J. Amer. Chem. SOC.,1973,95,4960. Reaction Mechanisms -Part (iu) Polar Reactions are postulated for hydride abstractions by carbonium ions and evidence in favour of this scheme is provided by the exchange of deuterium with the transferring hydrogen in reactions of perdeuteriotrityl cation (91) with complex hydrides or tr~pylidene.~~ Recent structural investigations of carbonium ions include the I9F n.m.r.spectra of p-fluorobenzyl cations ;98 the higher-field chemical shifts in the order acyclic monocyclic bicyclic may indicate steric restriction on sol-vation. Similar considerations may be important in the physical processes responsible for solvent shifts of fluorophenyl compounds used as a solvation parameter.99 '3C n.m.r. spectra of protonated carboxylate esters (92)"" ''' OH p.p.m. 177 169 164 158 17.5,( CH,-CH2-CH2-CH2-C I+ \ 66+ 6+ OMe indicate a smooth diminution of charge density along the carbon chain. This contrasts with the charge densities alternating along the chain from the perturbing substituent"' as predicted by CNDO calculations.The same technique shows that cyclic allyl cations bear almost all the charge at the allyl termini (93),'03 and benzoyl cations have considerable charge delocalization into the aromatic ring owing to contributions from structures such as (94).' O4 Experimental charge densities in polyenylic cations have been compared with predictions from several types of MO calculation.'05 That which appears best to reproduce experimental 98 G. A. Olah and J. J. Svoboda J. Amer. Chem. SOC.,1973,95 3794. 99 R. W. Taft and L. D. McKeever J. Amer. Chem. SOC.,1965,87 2488; D. G. Farnum and D. S. Patton J. Amer. Chem. SOC.,1973 95 7728. loo G. A. OlahandY. K. Mo J. Org. Chem. 1973,38 353. lo' G. A. Olah and P. W. Westerman J. Org.Chem. 1973 38 1986. lo* J. A. Pople and M. Gordon J. Amer. Chem. SOC.,1967 89,4253. Io3 G. A. Olah and G. Liang J. Amer. Chem. SOC.,1972,94,6434. '04 G. A. Olah and P. W. Westerman J. Amer. Chem. SOC.,1973 95 3706. lo5 H. V. Navangal and P. E. Blatz J. Amer. Chem. SOC.,1973,95 1508. 138 N.S.Isaacs 0 -41 0 -41 p.p.m. +48 + (93) (94) results is the semi-empirical o-technique though correct trends are apparent even using simple Huckel theory. Protonation of phenols and anisoles has been studied ;Io6 methylation of anisole by CH,F-SbF gives the oxonium ion (95) which is stable at -70°Cbut is Me ?+ ,Me ?Me OMe (95) converted into methylated anisoles at higher temperatures by an intermolecular rearrangement.'" Heats of formation of t-butyl and t-pentyl cations (169 and 161 kcal mol-' respectively) have been determined in the gas phase by the equilibrium (96) S (97) ;(AAG" = -2.9 kcal mol- ',AAH" = -3.6 kcal mol-H + + I Me,CH + Me,CEt S Me,C + Me,CEt (96) (97) AAS' = 2.3 cal K-').'O* Further examples of cycloadditions of allylic cations to olefins and dienes have a~peared,"~ as has a review of this topic.'" The 2-methoxyallyl cation (98) is especially readily formed and reactive in Diels-Alder reactions.Potential-surface calculations have been carried out on ally1 cations 0 '06 G. A. Olah and Y. K. Mo J. Org. Chem. 1973.38 2212 353. lo' G. A. Olah and E. G. Melby J. Amer. Chem. SOC.,1973,95,4971. IonJ. J. Solomon and F. H. Field J. Amer. Chem. SOC.,1973.95.4483.'09 A. E. Hill G. Greenwood,and H. M.R. Hoffmann J. Amer. Chem. SOC.,1973 95 1338. 'lo H. M. R. Hoffmann Angew. Chem. Inrernar. Edn. 1973 12. 819. Reaction Mechanisms -Part (iu) Polar Reactions 139 and predictions made concerning the mechanisms of geometrical isomeriza- tion0f(99).'"*"~ Two mechanisms may be considered ;simple bond twisting (a) and intermediate isomerization to a cyclopropyl cation (b). It is predicted that X %kr (99) 2-fluoro and 2-methylallyl cations undergo isomerization by path (b) but 2-hydroxy- and 2-aminoallyl cations must use path (a)since the corresponding cyclopropyl cations are more stable than the ally1 isomers. The cyclopentadienyl cation (100) is known to be a very difficult species to form solvolytically,' '' and MO calculations of varying sophistication have been used on this species.' ''-'16 The ion has been formed at low temperature in superacid solution and shown by itse.s.r.spectrum to be a triplet in theground state as predicted by simple theory.' '' A convenient alcohol -+amine conversion (101) +(102) evidently proceeds via a carbonium ion intermediate or ion-pair (lola). Yields can be high when a reasonably stable carbonium ion is formed.' The subject of carbonium ions n-bonded to metals has now an enormous literature. A brief review of this topic serves to introduce the reader to this subject of increasing significance.' ' 'I1 L. Radom J. A. Pople and P. von R. Schleyer J. Amer. Chem. SOC.,1973,958193. 'I2 L. Radom P. C. Hariharan J.A. Pople and P. von R. Schleyer J. Amer. Chem. SOC. 1973,95 6531. 'I3 R.Breslow and J. M. Hoffmann J. Amer. Chem. SOC.,1972,94,2110. 'I4 M. J. S.Dewar and R. C. Haddon J. Amer. Chem. SOC. 1973,95 5836. ''' H. Kollmer H. 0.Smith and P. von R. Schleyer J. Amer. Chem. SOC.,1973,95 5834. ' l6 W. J. Hehre and P. von R. Schleyer J. Amer. Chem. SOC.,1973,95 5837. ''' M. Saunders R. Berger A. Joffe J. M. McBride J. ONeill. R.Breslow J. M.Hoff-mann C. Pevchonock E.Wasserman R. S.Hutton and V.J. Kuck J. Amer. Chem. SOC.,1973,95 3017. 'IBJ. B. Hendrickson and I. Joffee J. Amer. Chem. SOC.,1973,95,4083. 'I9 M. H. Chisholm and H. C. Clark Accounts Chem. Res. 1973,6,202; T. H. Whitesides R. W. Arhat and R. W.Slaven J. Amer. Chem. SOC.,1973,95 5792. 1 40 N.S. Isaacs - ROH + R-0 i=R+O -P R+NH -+ R-NH \ \ I I c=o S0,CI S0,Cl / HN HN +co pzo I I S0,CI S0,CI (101) (101a) 5 Addition Reactions Applications of linear free energy relationships (LFER) to polar additions have been made; Charton and Charton have correlated some 28 systems using the extended Hammett relationship,' *' logk,, = an + PoR + const where uIand uRare 'inductive' (localized) and 'resonance' (delocalized) substituent constants. Systems for which a >> /3 are deduced to react via bridged intermediates e.g. (103) while those for which a << B are supposed to form open carbonium-ion intermediates such as (104). Values of p span the range -12 to -35 for electro- philic additions and + 14 to +35 for nucleophilic additions e.g.to give (105). ---* R-f' R\\ + Br2 -RT/Br+Br- a = -13 P = -3.56 (103) Br R R - R CH,< + H,O+ + CH,ACH CH,\-cH,; a = -4.3 P= -32.9 OH LFER analysis of the addition of bromine to stilbenes has been made in terms of a combination of substituent effects from the two rings the reaction constants p and pa being -5.07 and -1.40 respectively. The fact that the reaction responds differently to substituents in each ring indicates the transition state to be non- symmetrical (106) even if a bridged intermediate (107) is duly formed.I2' IZo M.Charton and B. I. Charton J. Org. Chem. 1973 38 1631. J. E. Dubois and M.-F.Ruasse J. Org. Chem. 1973 38 493. 141 Reaction Mechanisms -Part (iv) Polar Reactions (106) Dipolar aprotic solvents are capable of being captured during addition reactions and stable adducts such as (108) are isolable.'22 Hypohalous acid additions to dienes123 and to cinnamic acid derivativeslZ4 have been studied and the stereo- chemistries of the products established with precision.The trans-cinnamate esters give a mixture of erythro-and threo-a-halogeno-fi-hydroxyphenyl-propionic acids. Steric effects of 7,7-dimethyl substitution upon products of addition of nor- bornene are quite severe. The methyl groups force addition in most cases from essentially exo to largely or completely endo [e.g. (109-(l10)].'25 Addition of fluorine to olefins (111) (or at least to diphenylethylenes) may be achieved by xenon difluoride in the presence of acid.'26 (110a) (1 lob) R=H 99.5 0.5 R = Me 5 95 "' C.Anselmi G. Certi B. Macchia F. Macchia. and L. Monti Tetrahedron Letters 1972 1209. D. R. Dalton and R. M. Davies Terruhedron Letters 1972 1057. L24 P. B. D. de la Mare and M. A. Wilson J.C.S. Perkin II 1973 653. H. C. Brown J. H. Kuwakami and K. T. Lin J. Amer. Chem. SOC.,1973,95 2209. 126 M. Zupan and A. Pollak J.C.S. Chem. Comm. 1973 845. 142 N. S. Isaacs The kinetic form of the substitution by secondary amines in (1 12) is consistent with an addition-elimination mechanism in which deprotonation (k,) of the XeF, > >=( HF FF Ar CN Ar CN ";kc" R,NH+ x..)-<.-x; )=( X CN CN CN +NH2 YH I (X = CN F OR) RI R (1 12) (1 13) intermediate (113) is kinetically ~ignificant.'~' It is found that k,(obs) = k' + k"[R,NH].An analogous mechanism is proposed for acetylenic halide substitu- tion by thiophenoxide ion (1 14)+(1 1S).' 28 Large positive p-values (p = 3.4 for ArS;AkSAr __+ ArCEC-hal -hal-ArC=C-SAr ha1 (1 14) (115) chloride displacement and 3.9 for bromide) are consistent with rate-determining attachment of nucleophile to the acetylenic carbon. Also chloride is more readily displaced than bromide (kC,/kBr = 2.54.2) typical of a reaction in which C-halogen bond fission is not rate-determining. Addition of arylsulphenyl chloride to the allene (116) is proposed to occur via the bridged intermediate since there is a considerable inverse secondary deuterium isotope effect for the 3-deuterio-compound but a very small effect for the l-deuterio.I2' It would appear that the transition state involves the terminal carbon becoming more nearly sp3 hybridized but there being little change in hybridization at C-1.Additions of alcohols carboxylic acids etc. to the C=N bond in (117) have been reported.' 30 12' Z. Rappoport and P. Peles. J.C.S. Perkin II 1973. 616. 128 P. Beltrame P. L. Beltrame. M. G. Cattania. and M. Simonetta. J.C.S. PerkinII 1973 63. K. Izawa T. Okuyama and T. Fueno J. Amer. Chem. SOC.,1973,95,4090. J. L. Zollinger. C. D. Wright J. J. McBrady D. H. Dybvig F. A. Fleming G. A. Kurhajec. R. A. Mitsch and E. W. Neuvar J. Org. Chem. 1973 38 1065. Reaction Mechanisms -Part (iv)Polar Reactions (F,N),C=NF +ROH -+ (F,N),C-NHF I (117) OR 6 Elimination Reactions Bredt's rule excluding the formation of bridgehead bicyclic olefins on grounds of steric strain has proved a challenge to synthetic chemists and it seems now estab- lished that bicyclo[x,v,z]alk-1-enes with (x +y +z) =S 3 7 are stable com- pounds which can be prepared e.g.(118)-(119). Compounds for which S <7 are unstable but some have been prepared transiently. Thus bicyclo[2,2,l]hept-l- ene may be generated by the route (120) -P (121) and trapped by its Diels-Alder reaction with furan. The same ratio of the two stereoisomeric adducts (122) and (123) results with considerable variation of conditions and starting materials supporting a reaction with a common intermediate. The subject of Bredt's rule has been reviewed.I3' Eliminations of sulphonates adjacent to heteroatoms should be facile on account of the resonance stabilization of an intermediate carbonium ion (124).However in compounds such as (125) the bridgehead nitrogen compounds react a. +/ + x-c 4-b x=c / /\/\ 10-20 times slower than the corresponding carbon analogues.' 32 This could be due to the unfavourable strain introduced by the bridgehead double bond. G. Kobisch Angew. Chem. Internal. Edn. 1973 12 464. 132 P. G. Gassman R. L. Cryberg and K. Shudo J. Amer. Chem. SOC.,1974 in press. 144 N. S. Isaacs The reaction of the bromosulphone (126) with t-butoxide ion leads to substitution by an elimination-addition mechanism.' 33 The subject of mechanism in base-induced /3-eliminations has become anything but clear in the past few years with the introduction of the E2C-E2H and syn-anti mechanistic dichotomies.' 34 Ethoxide-induced elimination of (127) shows both \+ NMe3 Q-(secondary) and p-(primary) isotope effects which vary in magnitude smoothly with electronic effects of aryl substituents (p =0.95) the values of kdk being of the order respectively 1.04 and 4.5.' 35 Eliminations of P-bromoethylbenzenes (p =2.85) show primary isotope effects k& =7-9.5 which also depend on aryl sub~titution.'~~ These systems can be interpreted in terms of an El42 continuum and tunnelling is probably important in the latter case.Conversion of cyclohexyl tosylate into the dimethyl analogue (128) a 'neopentyl' system retards the rate of elimination (by C1-) by only a factor of 12 which the authors deem to be insufficient to support any degree of E2C ~haracter.'~' The Brnrnsted coefficient for thiolate- induced eliminations of 2-halogeno-2-methylbutanes (129) p =0.134.16 is ,OTos c1 / CH,CH,CCH, \ CH3 interpreted as indicative of very weak bonding between nucleophile and p-proton in the transition state despite the fact that this system would be expected to be of the E2H type.' 38 Products of elimination and consequently the pathways used are sensitive to the nature of the base ;the introduction of cation-complexing crown ethers affects the ratio of syn-to anti-elimination products in reactions of C.B. Quinn J. R. Wiseman and J. C. Calabrese J.Amer. Chem. SOC.,1973,95 6121. 134 N. S. Isaacs Annual Reports (B) 1972,69 180. '35 P. J. Smith and S. K. Tsui Tetrahedron Letters 1972 917. 136 L. F. Blackwell P. D. Buckley J. W. Jolley and A. K. H. McGibbon J.C.S. Perkin ZI 1973 169. 13' J. F. Bunnett and D. L. Eck J. Amer. Chem. Soc. 1973,95 1897 1900. 138 D. S. Baily and W. H. Saunders J. Org. Chem. 1973 38 3363. Reaction Mechanisms -Part (iv) Polar Reactions 145 cyclodecane derivative^'^^ and also the cisltrans and orientation ratios in elimi- nations of 2-bromobutane and the acenaphthene derivative (130).140,'41 This test is usually considered to differentiate reactivity due to a solvated ionic base and to an ion-pair. Dehydration of di-t-butylcarbinol (1 3 1) by hexamethylphosphoric triamide (HMPT) yields the rearranged olefin (132) which is explained in terms of a carbonium ion intermediate not a species usually associated with reactions in this ~olvent.'~' Sulphuranes (133) will also cause efficient dehydration of an Me (131) (1 32) Ar,S-OBu' -/C-CH, Ar,SR + Me,COH-a Ar,SR -a+ CH\ -Ar,SO I (133) OBu' CH3 alcohol even at low temperatures (p = -1.68).'43 Oxalate proves to be especially favourable towards elimination of isopropyl tosylate compared with other carboxylate ions which lead principally to substitution.' 44 Mesylation followed by pyridine-induced elimination can generate olefins in high yield'45 from iodo- hydrins (134).MeS0,CI py. -20°C O'fYR I OH ( 134) 139 M. Svoboda J. Halpala and J.Zavada Tetrahedron Letters 1972 265. I4O D. H. Hunter Y. Lin A. L. Mclntyre D. J. Shearing and M. Zvagulis J. Amer. Chem. SOC. 1973 95 8327; D. H. Hunter and D. J. Shearing J. Amer. Chem. SOC. 1973,95 8333. 141 R. A. Bartsch G. M. Pruss D. M. Cook R. L. Buswell and K.-E. Wiegers J. Amer. Chem. SOC.,1973,95,6745. 14* J. S. Lomas D. S. Sagatys and J. E. Dubois Tetrahedron Letters 1972 165. 143 L. J. Kaplan and J. C. Martin J. Amer. Chem. SOC.,1973 95 793. 144 E. J. Corey and S. Terashima Tetrahedron Letters 1972 111. 14' E. J. Corey and P. A. Grieco Tetrahedron Letters 1972 107. 146 N.S. Isaacs 7 Carbanions The predicted conrotatory ring-opening of a cyclopropane anion (1 35) has been shown to take place.146 A (very small) diatropic character has been found in the anion (136) but not in the related species (137) and (138).It is concluded that there is some homoaromatic character and delocalization of charge into the cyclo- propane ring.' 47-149 The relative rates of proton exchange of (139) and (140) indicate that the homoaromatic anion (141) is more stable than (142) and no additional stabilization from bicycloaromaticity need be considered.' The mono- and di-anions of (143)have been prepared ;the n.m.r. spectrum of the latter A-H (139) (140) H (144) shows that the charge is delocalized over the carbonyl group and the C-6-C-7 double bond making this a bishomo-analogue of the cyclopentanone 146 M. Newcombe and W. T. Ford J. Amer. Cliem. SOC.,1973,95 7186. 147 S.W. Staley and W. G. Kingsley J. Amer. Chem. SOC.,1973 95 5804. 14' S. W. Staley and G. M. Cramer. J. Amer. Chem. SOC.,1973 95 5051. 149 S. W. Staley. G. M. Cramer and W. G. Kingsley J. Amer. Chem. SOC.,1973,95 5052. Is' M. V. Moncur and J. B. Grutzner. J. Amer. Chem. SOC.,1973 95 6449. Reaction Mechanisms -Part (io) Polar Reactions dianion (145).15' Proton-exchange rates in the bicyclic ketone series'52 (146) and in 7-cyanonorbornenes' 53 indicate that ring-strain can accommodate the data without invoking exotic homoaromatic concepts. The I3C n.m.r. spectra 0- of a number of delocalized carbanions e.g. (147) have been recorded and the chemical shifts shown to correspond with a high charge density at the odd carbon positions as predicted.' 54 Rates of reaction with electrophiles (indicated by product structures) are not entirely according to the charge densities but attack at internal positions is somewhat preferred.+142 p.p.m. Acidity measurements by the equilibration method using cyclohexylamide have been made on thiophene (a-H pK = 38.42) benzothiophen (a-H pK = 37.05),benzofuran (a-H pK = 36.84) isothiazole (2-H pK = 29.50) and benz[d J-isothiazole (2-H pK = 28.08). Referred to 9-phenylfluorene (pK = 18.49) the internal precision of these measurements is extremely high.'55 Acidities (by the kinetic method) of phenylmethanes and related compounds have been determined. A satisfactory Br~rnsted relationship between pK for this reaction and pK for known thermodynamic acidities has permitted a value for the pK of toluene (40.9) to be obtained by extrap~lation.'~~*'~~ An other potentially very useful relation- ship has been found between heats of deprotonation of weak Br~rnsted acids (by DMSO-) and thermodynamic acidities over a range of 50 pK units and in- cluding carboxylic acids alcohols and weak carbon acids.' 58 G.B. Trimitsis E. W. Crowe G. Slomp and T. L. Hills J. Amer. Chem. SOC.,1973 95 4333. G. A. Abad S. P. Jindal and T. J. Tidwell J. Amer. Chem. SOC.,1973 95 6326. Is' D. D. Davies and W. B. Bigelow Tetruhedron Letters 1973 149. R. B. Bates S. Brenner C. M. Cole E. W. Davidson G.D. Forsythe D. A. McCombs and A. S. Roth J. Amer. Chem. SOC.,1973 95 926. A. Streitweiser and P. J. Scannon J. Amer. Chem. SOC.,1973,95 6273.Is' A. Streitweiser P. H. Owens G. Sonnichsen W. K. Smith G. R. Ziegler H. M. Niemayer and T. L. Kruger J. Amer. Chem. SOC.,1973.95 4254. Is' A. Streitweiser M. R. Granger F. Mores and R. A. Wolf J. Amer. Chem. SOC.,1973 95. 4257. E. M. Arnett T. C. Moriarty L. E. Small J. P. Rudolph and R. P. Quirk J. Amer. Chem. SOC.,1973.95 1492. 148 N. S. Isaacs Cyclo-octatetraene and some derivatives equilibrate with their dianions to form anion-radicals. Thermodynamic parameters for some of these equilibria have been obtained and indicate the entropy term to account largely for differences in K.ls9 Carbanions undergo arylation by a chain mechanism involving inter- mediate anion-radicals (SRNl mechanism) ( 148).160 PhBr + In' -+ PhBr; + In PhBr; + Ph' + Br-Ph' + -* ...-:*.-Ph A carbanionic elimination (Elcb) is proposed for dehydrohalogenations of (149) in which there is a negligible primary isotope effect a positive reaction constant (p = 3.94) and P-hydrogen exchange prior to reaction.16' The base- catalysed halogenation of acetylenes shows third-order kinetics rate = k[RC-CH] [OH-] [OCl-1 a very small solvent isotope effect and a moderate PhCHClCF,X (149) positive p-value (0.8).162It is proposed that the fast reversible ionization of the acetylene is followed by co-ordination of hypohalite ion to form a (structurally unspecified) dianion R-C-COC12- which then reacts with water etc.to give the halogenoacetylene. Base-catalysed dehydration of P-ketols such as 9-hydroxy-1O-methyl-2-decalone has been studied ; the mechanism proposed involves a general-base- catalysed a-proton removal and expulsion from the enolate ion which may be rate-determining at high catalyst concentration.The kinetics are complex as there are probably several steps of comparable rate.'63 8 Carbonyl Reactions Relaxation techniques have been used to measure rates of the fast amine addition reactions to pyridine-4-carboxaldehyde ; the value for piperazine is more than lo51mol-' s-' 164 Attention has been drawn to a number of carbonyl reactions G. R.Stevenson and J. G. Concepcion J. Amer. Chem. SOC.,1973 95 5692. I6O R.A. Rossi and J. F. Bunnett J. Org. Chem. 1973 38 3020. 16' H. F. Koch D. B. Dahlberg P. G. Toczko and R.L. Salsky J. Amer. Chem. SOC.1973,95 2029. R.-R.Liu and S. I. Miller J. Amer. Chem. Suc. 1973 95 1602. D. J. Hupe M. C. R. Kendall G. T. Sinner and T. A. Spenser J. Amer. Chem. SOC. 1973.95 2260 2271. 164 H. Diebler and R. N. F. Thorneley J. Amer. Chem. Suc. 1973.95 896. Reaction Mechanisms -Part (iv) Polar Reactions 149 in which the rate-determining steps are encounter-limited,16’ usually proton transfers. For example the thiolester (150) hydrolyses by the mechanism shown 4-0 CF3Cq; + RSH 0 for which estimated rate constants are k-x lo9 k x 4 x lo91mol-’ s-’. The nucleophilic fission of the a-disulphone (151) by 20 nucleophiles shows a rate dependence parallel to their reactivity towards the carbonyl group. Rates 0 II Ph-S02-SOz-Ph Ar0-S -C1 II (151) 0 are fast necessitating stopped-flow measurements.’ 66 A normal reactivity scale of nucleophiles towards the arylchlorosulphates (152) is found and the favoured mechanism is of a displacement at chlorine.’ 67 Hydrolysis of imidate esters (153) shows differences in behaviour depending upon the basicity of the OR2 R’-C / ORz R’+Nh R3 ORz R‘+-NHR >NHR3 OH OH OR2 11 + 11 -+ 11 -+ Rf+NHR3 ORZ ORZ 0- R’-C / ‘NR3 (153) \ RtTNHR3 R’.+YH /O- NH R/ R3NH2+ R1COzR2 or R1CONHR3+ RzOH Scheme 2 165 R.E. Barnett Accounts Chem. Res. 1973 6,41. J. L. Kice and E. Legan J. Amer. Chem. SOC.,1973,95 3912. 16’ E. Buncel A. Raoult and L. A. Lancaster J. Amer. Chem. SOC.,1973 95 5964. 150 N.S. Isuacs amine moiety. Esters derived from strongly basic amines show a decreasing amount of the amine product with pH whereas the opposite is true for those derived from weakly basic amines.16* The reasons no doubt lie in the complex reaction scheme (Scheme 2) in which a series of intermediates differing in their position and state of protonation can each give rise to amine or amide products.A sulphurane (154)has been shown to cleave amides efficiently a hydrogenation step is needed to complete the rea~ti0n.l~~ N.m.r. spectra ofa series of protonated 0 / PhC \ H -Pd Ph,S i:" OC-CF3 Ph,S=NPh *Ph,S + PhNH CF 2 carboxylic acid anhydrides which are stable species in superacid solution have been reported maleic anhydride for example protonates at the carbonyl group to give (155).l7' +OH ''* T.Okuyama T. C. Pletcher D. J. Sahn and G. S. Schmir J. Amer. Chem. Soc. 1973 95 1253. J. A. Franz and J. C. Moitu J. Amer. Chem. SOC.,1973,85 2017. "O G. A. Olah Y. K. Mo,and J. L. Grant J. Org. Chem. 1973,38 3207.

ISSN:0069-3030    

DOI:10.1039/OC9737000119

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

4 Electron Spin Resonance Spectroscopy and Free Radical Reactions By W. T. DIXON Dept. of Chemistry Bedford College. Regent’s Park Inner Circle 1ondon NW7 4NS 1 Jntroduction Once again this year has been one of further consolidation rather than of innovation in the field of free radical chemistry. Leaving aside the explosion of interest in CIDNP and related topics which give information about what happens immediately before there is a change of spin multiplicity and more particularly about the species involved in such a step most studies of free radicals and their reactions have utilized electron spin resonance. Classical ‘kinetic’ studies of the type long-used in electrophilic aromatic substitution in which different molecules or sites compete for some active radical such as hydroxyl aryl alkyl or even hydrogen seem to be dwindling in the absence of any clearly defined aims or interpretation.This might be ex-pected since the emphasis tends to be on substituent effects in the molecules ‘attacked’ and not so much on the free radicals themselves. Any branch of chemistry which pertains to a class of compounds will consist mainly of their synthesis analysis and their chemical and physical properties. E.s.r. is an analytical technique par excellence for free radicals and is also useful in following their reactions i.e. by means of their rates of disappearance appearance of new radicals etc. Not only do e.s.r. spectra provide useful finger- prints for radicals the exact values of the coupling constants (and also the g-factors) depend rather critically on the geometry of the radical in question and this aspect is one that is being very actively pursued.The ‘synthesis’ of free radicals is achieved by relatively few methods. One usually starts with organic molecules in which all the spins are paired. Unpaired spins can only be introduced either by photons inorganic radicals or by thermal or mechanical (the same thing really) fission of bonds. A survey of the literature shows relatively few main groups of active workers each of which has developed expertise in a particular technique of getting free radicals. One might regard these techniques as ways of initiating the synthesis of radicals and they consist in the main of radiolysis (i.e. irradiation with prays) irradiation or reduction of peroxides nitro-compounds ketones etc.auto-oxidation and oxidation by metal ions such as Ce”’. Usually the radicals of interest arise from some secondary 151 I52 W. T. Dixon or tertiary process. For example hydroxyl radicals formed from the reduction of N20 by solvated electrons which are in turn formed in the y-radiolysis of water attack aromatic substrates to give in general adduct radicals. Apart from the predictable investigations of stable radical anions or nitroxides of more and more intriguing shapes and the filling in of 'gaps' in the array of simple radicals which have been studied the most interesting developments have been in stereochemistry. The conformations and configurations of radicals have been very much emphasized and some stereospecific radical reactions have been thoroughly investigated.As was the case last year it seems that the best way of classifying the material is in terms of the types of radicals. 2 Simple Alkyl and Aryl Radicals Remarkably strong steric interactions of fluorine atoms exist in fluorinated alkyl radicals so much so that fluorinated ethyl radicals invariably give e.s.r. spectra which are temperature dependent implying hindered rotation. For example CF2CH has an internal rotation barrier of about 2 kcal mol-' and exists in an equilibrium between the three equivalent forms (1)+3).' It is unusual 'a ,Hb Hc ,Ha \I \I \\I L C -C //\ /;\ F:F F:F Hc Hb ,Hc '\ /' to be able actually to observe directly restricted rotation of a methyl group and the effect here may be enhanced by the fact that the geometry at the a-carbon atom is pyramidal and not planar as in ethyl itself since the arrangement about the a-carbon deviates more and more from planarity as hydrogen alkyl or even CF groups2 are replaced by fluorine atoms.This trend is deduced from the changes in 13C or 19F coupling constants; for example a(a-F) increases with the number of fluorine atoms attached directly to the a-carbon atom. Rather unexpectedly perhaps symmetrical conformations are the most stable for P-fluoroethyl radicals whether there be one two or even three p-fluorine atois. This has been deduced from the size of the P-proton coupling constants in (4) and (5) though the e.s.r.spectra* of these radicals are temperature depen- dent showing hindered rotation ' 'K. Schen and J. K. Kochi Chem. Phys. Letters. 1973 23 233. R. V. Lloyd and M. T. Rogers J. Amer. Chem. SOC.,1973 95 1512. I. Biddles J. Cooper A. Hudson R. A. Jackson and J. T. Wiffen Mof. Phys. 1973 25 225. *When not specifically stated splittings are given in units of G (=lo-* T). Electron Spin Resonance Spectroscopy and Free Radical Reactions The e.s.r. spectra of chloro- and bromo-alkyls also generally show some tem- perature dependence as one might expect and there is a certain amount of rather flimsy theoretical and empirical evidence that there are unsymmetrical halogen bridges in molecules such as CH,CH,Cl and CH,CH,Br. This idea of halogen bridging is deduced from low values of P-proton splitting~,~.' trans addition reactions,6 and also from CIDNP observed in the n.m.r.spectra of the products of addition reactions.' Perfluoroalkyl radicals formed by the U.V. irradiation of perfluorinated fatty-acid salts of Pb'" abstract protons but not fluorine atoms from -CHF or -CH,F groups,8 and methyl radicals abstract hydrogen from the a-positions of side-chains of alkylbenzenes in preference to adding to the aromatic ~keleton.~ This contrasts somewhat with the behaviour of phenyl," thiazolyl,' or even hydrogen atoms,' which tend to add to aromatic rings in a rather unselective way. In such studies the isomer distribution of the products may not be simply related to the relative reactivities of the original positions.lo A dramatic decrease in attack ortho to a t-butyl group'.' shows the importance of steric factors in such reactions. Phenyl radicals will not only abstract aliphatic hydrogen atoms but also iodine and since the rate of this process with (6)is the same as that with (7),there can be no 'anchimeric assistance' from sulphur in the latter case.13 This may be attributed to a large dihedral angle making such assistance via S-bridging unfavourable. 3 Benzyl-type Radicals The technique of y-irradiation of aqueous solutions containing nitrous oxide has proved to be an efficient way of generating organic radicals uia the hydroxyl I. H. Elson K. S. Chen and J. K. Kochi Chem. Phys. Letters 1973 21 72. K. S. Chen I. H. Elson and J. K. Kochi J.Amer. Chem. SOC.,1973 95 5341. P. S. Skell R. P. Pavlis D. C. Lewis and K. J. Shea J. Amer. Chem. SOC.,1973,95,6735. ' J. H. Hargis and P. B. Sherkin J.C.S. Chem. Comm. 1973 179. P. B. Ayscough J. Machora and K. Mach J.C.S. Faraday II 1973,69 750. S. J. Hammond and G. H. Williams J.C.S. Perkin II 1973 484. lo J. T. Hepinstall jun. and J. A. Kempmeier J. Amer. Chem. SOC.,1973 95 1904. ' I G. Vernin H. J. M. Dou and J. Metzer J.C.S. Perkin II 1973 1093. W. A. Pryor T. H. Liu J. P. Stanley and R. W. Henderson J. Amer. Chem. Soc. 1973 95 6993. l3 W. C. Danen D. G. Saunders and K. A. Rose J. Amer. Chem. Soc. 1973 95 1612. 154 W. T. Dixon radical or its anion (Scheme 1). The 0' ion abstracts hydrogen readily from alkyl groups and so generates for example benzyl radicals from alkylbenzenes.The electronic spectra of these radicals have been observed in pulse radiolysis y-rays e Scheme 1 experiment^'^ and it has been shown that the mechanism in strongly alkaline solution is direct hydrogen abstraction whereas in more acidic solutions (below pH -10)a more complex process occurs (Scheme 2). In both extreme cases the C6H,CH3 + -OH -.+ [C,H,CH,(OH)] % C,H,CH2-etc. observed Scheme 2 main product is bibenzyl. The reaction in alkaline solution has been utilized to generate many substituted benzyl radicals,' which are remarkable in that the coupling constants depend only very slightly on the nature of the substituents e.g. (8) and (9). s0,-0-( 8) (9) The signs of the fluorine coupling constants in 0-,m-,and p-fluorobenzyl have been determined using CIDNP,l6 since the polarizations induced depend on the signs of the coupling constants.The reaction used was the photolysis of the appropriate benzylphenone in carbon tetrachloride (Scheme 3). The 0-and l4 H. C. Christensen K. Sehested and E. J. Hart J. Phys. Chem. 1973,77 983. '' P.Neta and R. H. Schuler J. Phys. Chem. 1973 77 1368. I6 (a) J. Bargon and K. G. Seigert J. Phys. Chem. 1973 77 2877; (b) D. Bethell M. R. Brinkman and J. Hayes J.C.S. Chem. Comm. 1972 1324. Electron Spin Resonance Spectroscopy and Free Radical Reactions ArCH,COPh ‘2‘ ArCH,. + SCOPh * CCI , 1 [ArCH,. *CCI,] I pola;:;tion ArCH,-CCI (polarized n.m.r. spectrum) Scheme 3 p-fluorine coupling constants were positive but the m-F was negative as expected.Similar empirical conclusions have been deduced from studies of aryl semi- quinones.” The conformation of adifluorobenzyl radicals is a planar one in the absence of ortho substituents.’* This has been deduced from the fluorine splittings which are about 50 G compared with 56 G in CFHCONH, known to be planar and with 72 G in CF,CONH, which is pyramidal. 4 Cyclic Adduct Radicals The y-radiolysis of water gives solvated electrons which can be effectively re- garded as hydrogen atoms these may add on to suitably active species such as furan to give adducts analogous to cyclohexadienyl. As we have already said the presence of N,O leads to hydroxyl radicals which can add on similarly or abstract active hydrogen atoms.Thus the parent radicals of the furan series” can be obtained in concentrations sufficiently large for detection by e.s.r. (Scheme 4). H Scheme 4 P. Ashworth and W. T. Dixon J.C.S. Perkin II 1973 1533. L. D. Kispert. H. Liu. and C. U. Pittman jun. J. Amer. Chem. Suc. 1973 95 1657. l9 R. H. Schuler G. P. Laroff and R. W. Fessendem J. Phys. Chem. 1973,77,456. 156 W. T. Dixon In base when the active species in the presence of N20is O' 2,5-dimethylfuran yields an analogue of benzyl (Scheme 5). 2-Nitrofurans lose the nitro-group 13.2 Scheme 5 when subject to attack by *OHin a similar way,20 but in the case of l-bromo- furanoic acid the ring opens (Scheme 6). Similar types of adducts are formed * 02C0Br 0 -HO Br 02'no] Scheme 6 with pyrole derivatives,21 although the parent molecule itself reacts furtner to eliminate water (Scheme 7).02cQI .OH) 02cUH3.4 \ OH IH H0.28 Scheme 7 C. C. Greenstock I. Dunlop and P. Neta J. Phys. Chem. 1973,77 1187. 21 A. Samuri and P. Neta J. Phys. Chem. 1973,77 1629. Electron Spin Resonance Spectroscopy and Free Radical Reactions The tendency of OH to add to unsaturated systems wherever that is possible is again illustrated by the radiolysis of aqueous ally1 alcohol22 in the presence of N,O (Scheme 8). CH,=CHCHOH Y Scheme 8 Renewed interest in Fenton's reagent has led to further exhaustive studies of the isomer distributions of products from the hydroxylation of nitrobenzene chlorobenzene toluene etc.,' and a large number of hydroxycyclohexadienyl- type radicals have been identified by means of e.s.r.spectroscopy in the oxidation of benzene- and pyridine-carboxylic acids23 by Fenton's reagent (Scheme 9). Fe" + H,O -+ Fe"' + -OH + -OH Scheme 9 5 Further Radicals from Peroxides Fenton's reagent has also been used to oxidize unsaturated aliphatic com- pound~~~,~~ and some interesting reactions have developed. From alkynes a number of possibilities can occur depending on whether substrate-reducing or -oxidizing agents are present in excess (Scheme 10). Similar types of situation can occur with Ti"'-H,02 and e.s.r. kinetic studies indicate that the acetonyl radical is reduced by Ti"' quite effectively in neutral solution.26 Limitations in the kinetic approach not only to the Ti1"-H,02 system but also to steady-state situations in general have been pointed out again.,' During the photolysis of maleoyl phenyl peroxide,28 fission of the peroxy bond leads to the formation of two carboxyl radicals in the same molecule and CO is lost stepwise so that there is appreciable probability of again forming 22 M.K. Eberhart and M. Yoshida J. Phys. Chem. 1973 77 589; M. Simic P. Neta and E. Hayon ihid. p. 2662. *' T. Shiga T. Kishimoto and E. Tomita J. Phys. Chem. 1973,77 330. 24 C. Walling and G. M. El Taliawi J. Amer. Chem. Soc. 1973,95 844. 25 C. Walling and G. M. El Taliawi J. Amer. Chem. SOC.,1973 95 848. 26 B. C. Gilbert R. 0.C. Norman and R. C. Sealy J.C.S.Perkin If 1973 21 74. 27 D. Meisel G. Czapski and A. Samuni J.C.S. Perkin fI 1973 1702. 28 M. M. Martin and J. M. King J. Org. Chem.. 1973. 38. 1588. 158 W. T. Dixon CH,CHO HO CH-CH .OH ~ (Fell-H 20z) \ / C=kH H HOCH,CHO Me \ MeCGCMe 'OH b C=eMe Ho\ /c,'c/ Me Me \ Me CMe .4 MeC Scheme 10 a bond between the two radical fragments (Scheme 11). In contrast to alkyl- carboxyl radicals alkoxy-adducts with CO are comparatively long-lived and 0 It PhC -C I1 \ 0 HC. p.0' phgo Ph PhCZCH Polymers 0 PhC. 0. tI / HC-C \ phq 0 0 Scheme 11 add on to double bonds2' to form carbonates (Scheme 12). However in the absence of alkenes the e.s.r. spectra of the alkoxyl radicals only are observed.6 Radical Reactions of Cyclopropyl Derivatives It is not difficult it seems to form cyclopropane by a free radical path. For example 1,3-di-i0dopropane reacts with benzoyl peroxide in carbon tetra- 29 D. J. Edge and J. K. Kochi J. Amer. Chem. Soc. 1973,95 2635. Electron Spin Resonance Spectroscopy and Free Radical Reactions 0 / RO-C 0 \ / 0 RO-C l-\ 7 #>i< 0 hv 0-/ 0 RO-C I C \\ + 0 (RO. + CO2) RO’ ‘\o Scheme 12 chloride to form amongst other things cyclopropane (Scheme 13).30 However the three-membered ring is easily opened by radical attack and some interesting Bz202+2Bz0.~2Ph. + 2C02 ICH,CH,CH,CI ICH2CH2CH21~ICH2CH2CH2 -A Scheme 13 stereochemistry results. The radical bromination of cis,cis-trimethylcyclo-propane31 gives only three of the possible products which may be formed by the sequence shown in Scheme 14.The observed products show that the initial bromine attack was from an equatorial direction and this has been confirmed in a number of other cases.32 Generally speaking cyclopropyl itself can only be observed at low temperatures since it tends to open to form an allyl-type radical (Scheme 15).33 Thus ring- opening occurs by fission of the bond opposite to the site of the odd electron. Facile ring-expansion can occur if there is an odd electron on a side chain34 attached to the cyclopropyl ring (Scheme 16) and this is really the same type of reaction as the ring-opening by a bromine atom. A similar type of reaction takes place in cyclopropoxyl radicals but there the formation of a ketonic group is preferred to the formation of a four-membered ring (Scheme 17).35 ’O A.F. Drury and L. Kaplan J. Amer. Chem. SOC.,1973,95 2217. ” G. G. Maynes and D. E. Appleguist J. Amer. Chem. SOC.,1973,95 856. ’‘ K. J. Shea and P.S. Skell J. Amer. Chem. SOC.,1973 95 6728. ’’ K. S. Chen D. J. Edge and J. K. Kochi J. Amer. Chem. SOC.,1973,95 7036. )‘M. P.Doyle R. W. Raynolds R. A. Barents T. R.Bade W. C. Danen and C. T. West J. Amer. Chem. SOC.,1973 95 5988. ” C. H. De Puy H. L. Jones and W. M. Moore J. Amer. Chem. Sor. 1973 95 477. 160 W. T. Dixon Me M&e -+ Br< (equatorial approach) Br (threo) \ TBrMe dl (500/,) Scheme 14 (seen at low temperatures) Scheme 15 Scheme 16 Scheme 17 161 Electron Spin Resonance Spectroscopy and Free Radical Reactions 7 Further Aliphatic Radical Reactions Alcohols may undergo hydrogen abstraction from the hydroxy-group during the decomposition of persulphate ion3' catalysed by photons or reducing metal ions such as Ag'.The reaction is supposed to proceed by simple electron transfer R'R'CHOH '0,;[RIR'CHOH]~-~ R'R'CHO-The alkoxyl radical may be trapped by the N-oxide PhCH=N which \ Bu' adds on alkyl and alkoxyl radicals to give nitroxides; the latter may be identified from their e.s.r. spectra. In a particular case the reaction proceeds as shown in Scheme 18. The mechanism has been elucidated by means of the ingenious PhCH,CH,OH so -* PhCH2CH20* -+ PhCH,.+ CH,O PhCH OH PhCHZCH2 Ph PhCH =NOBu' 1' PhCHO 0 But / \ PhCH -N N-0 I\ / PhCH,CH,O But PhCH Scheme 18 device of conducting it first in the presence of the above radical trap which evidently stops the reaction before the break-up of the alkoxyl radical and then separately in the presence of t-butyl pitrone which traps alkyl radicals but not alkoxyl radicals. The adduct of PhCHCH,OH is a very minor constituent of the nitroxide product of which the mqjor component is benzyl t-butyl nitroxide. An interesting radical rearrangement occurs3' when the halogen atom is abstracted from a b-bromoalkyl ester by trialkyltin hydride plus t-butoxyl radicals (Scheme 19). The most plausible mechanism seems to be that the ester group 'walks' to its new position (Scheme 20).It is interesting that in the case when R2 = phenyl it migrates perhaps via formation of a cyclohexadienyl-type of intermediate (Scheme 21). Intramolecular radical cyclization also takes place in the addition of perfluoroalkyl iodides to hepta-1,6-diene in preference to simple addition to one of the double bonds (Scheme 22).38 36 A. Ledwith P. J. Russell and L. H. Sutcliffe J.C.S. Perkin /I 1973 630. 37 A. L. J. Beckwith and C. B. Thomas J.C.S. Perkin I/ 1973 861. 3* N. 0.Brace J. Org. Chem.. 1973. 38 3167. 162 W. T. Dixon R’ R’ / I 0-c=o PC=O / Me-C-CH,Br Bu3Sn; MeC I I\ R’ R’ CH,. Bu,SnH 1 MeCHRZCH,OCOR1 Scheme 19 1 Product Scheme 20 -$ Me MeC-kH Met-CH, I OAc I OAc OAc Scheme 21 Scheme 22 The radical addition of t-butyl hypochlorite to ~inylacetylene~~ starts with addition of t-butoxyl to one end of the molecule and thereafter chlorine goes on at one of the others (Scheme 23).’’ M. L. Poutsma and P. A. Ibarbia. J. Amer. Chem. SOC.,1973. 95 6000. Electron Spin Resonance Spectroscopy and Free Radical Reactions BuOCl \ CH,=CH~=CHOBU BuOCH2CHC1CECH BuOCH,CH=C=CHCl CH,=CHCCl=CHOBu 1 (CH,CICH=CClCHO) Scheme 23 8 RadicaIIons A particularly interesting anion which has been generated with great difficulty is that of hexaflu~robenzene,~' i.e. C6F6- which although it would seem super- ficially to resemble C6H6-is evidently completely different since the six fluorine nuclei have spIittings of 137G.The reason for this enormous coupling constant is that the odd electron is in a Q rather than a n molecular orbital. This is itself a result of the large number of electrons in the n molecular orbitals owing to the fact that each fluorine atom contributes two n-electrons. Because of this the odd electron goes into the first empty Q anti-bonding orbital instead of the first n* orbital as is the case with the benzene negative ion. Dinegative ions of benzen-oid carboxylic acids have been produced in basic media by reduction with solvated electrons4' and the carboxylate group has a similar effect to oxygen in phenoxyl or semiquinone ions so that the coupling constants rather resemble those in those radicals. These splitting patterns can be understood in terms of the symmetry of the benzene MOs as shown in Scheme 24 the substituents co; i0 c02-.coz-0 0 0.05 0.75 Scheme 24 having the effect of putting the odd electron into the orbital with the greatest value at the adjacent carbon atoms. *O L. F. Williams M. B. Yin and D. E. Wood J. Arner. Chem. Soc. 1973 95 6475. ** P. Neta and R. W. Fessenden J. Phys. Chem. 1973,77,620. 164 W. T. Dixon The heptafulvalene trinegative ion4 has been prepared and there is coupling only with the protons of one ring. Since this is large and in view of the strong repulsions between the two ring systems arising from three negative charges it seems that the two rings could be perpendicular to each other as shown in (10).Some naphthalene negative ions have been generated usually electrolytically and it is found that t-butyl or trimethylsilyl groups attached to the naphthalene skeleton do not have very much effect on the spin distrib~tion.~~ However bridges across the peri-positions can have much greater as well as providing rigid frameworks through which spin density can be transmitted relatively efficiently e.g. (1 1) and (12).45 HH I19 014 1.1 (12) The negative ions of halogenoquinolines have been studied p~larographically~~ and from the half-wave potential loss of chloride ions could be deduced. Thus both quinoline itself and 6-fluoroquinoline gave simple half-wave potentials corresponding to the formation of their negative ions. 6-Chloroquinoline on the other hand gave two half-wave potentials one corresponding to that of quinoline.This is attributed to the sequence shown in Scheme 25. It is doubtful however that the sigma 6-quinolinyl radical' would ever actually have a discrete existence. A disproportionation step in the presence of protons seems more likely. Steric strain is apparent from the e.s.r. spectra of 4,4'-polymethylene- biphenyl radical anions (13),47 but when the methylene chain is longer than 15 CH units the coupling constants indicate that strain is virtually absent. 42 N. L. Bauld C. S. Chang and J. H. Eilert Tetrahedron Letters 1973 153. " A. G. Evans B. Jerome and N. H. Rees J.C.S. Perkin II 1973 2091. 44 S. F. Nelsen and J. P. Gillespie. J. Amer. Chem. Soc..1973 95 1874. 45 S. F. Nelsen and J. P. Gillespie J. Amer. Chem. SOC.,1973 95 2940. 46 K. Alwain and J. Grimshaw J.C.S. Perkin II 1973 1811. 47 K. Ishizu F. Nimoto H. Hasegawa K. Yamunoto and N. Nakazaki Bull. Chem. Soc. Japan 1973 46 140. 165 Electron Spin Resonance Spectroscopy and Free Radical Reactions . ,..-. % ,.__. first A,+ N le- Scheme 25 Incidentally aromatic radical anions can be produced advantageously by using trimethylsilyl~odium~~ rather than sodium metal dispersed in a suitable solvent. Further e.s.r. work has been done on the auto-oxidation of hydroquinones and quin~nes’’~~~~~~ and dimeric intermediates e.g. (14) and (13,positively -? 0 identified.49b It is interesting that whereas spin density is transmitted around the ring of an aryl substituent attached to semiquinone the carbonyl groups of a quinonoid substituent seem to present a barrier to the odd electron.The e.s.r. spectra of some of these dimeric species were originally attributed to radicals of different and this illustrates the dangers of trying to identify radicals only on the basis of the number and type of coupling constants in an e.s.r. spectrum. A remarkable feature about some ‘heterocyclic’ ~emiquinones~’ is that the second rings containing nitrogen atoms e.g. (16) and (17) seem to have but little effect on the spin density which remains mainly on the semi- quinone part. 40 H. Sakumi. A. Okada H. Umino and M. Kira J. Amer. Chem. SOC.,1973,95,955. 49 (a)J. A. Pedersen J.C.S. Perkin II 1973,424; (6) P.Ashworth and W. T. Dixon J.C.S. Perkin II 1973 2128. M. K. V. Nair K. S. V. Santhanaan and B. Venkataraman J. Magn. Resonance 1973 9 229. 166 W. T. Dixon 0' 0' A number of naphthoxyl radicals e.g. (18) and (19) have been identified by e.~.r.~l and it seems that substituents have little effect on the spin distribution which is slightly different in the case of fl-naphthoxyl(l9) from that expected by comparison with phenoxyl and naive MO theory. 2.5 10.75 1.45 0.0 A ring-closure reaction has been observed when suitably hydroxylated benzo- phenones are oxidized by alkaline ferricyanide to xanthones (Scheme 26).52 It would be interesting to see whether it is the dihydroxylated ring which under- 0-major product minor product Scheme 26 goes the initial attack because although the radical cyclization uia the oxygen shown in Scheme 26 looks feasible the spin density on the oxygen atom must be small whereas in the para-position of phenoxyl it is large.'' W. T. Dixon W. E. J. Foster and D. Murphy J.C.S. Perkin 11 1973 2124. 52 P. D. McDonald and G. A. Hamilton J. Amer. Chem. SOC.,1973.95 7752. Electron Spin Resonance Spectroscopy and Free Radical Reactions 9 Radicals containing Group IV Elements Several more examples of sH2 reactions of tin and lead compounds have been reported and these can be grouped into those which occur at a halogen atom :53*54 RCI + SnMe -P R-+ ClSnMe which are of course already well-known and which are used extensively in the case of alkylsilyl radicals for the production of alkyl radicals and those which take place at the Group IV atom:” BuO.+ R,SnX,- + BuOSnR,-,X,- + R-(X = halogen) This last type of reaction is to be contrasted with the reaction with tin tetra-alkyl-tin where hydrogen abstraction takes place in preference to substitution :” R’CH2SnR2 + BuO. -P BuOH + R’t?HSnR2 The rates of addition of Group IV radicals to carbonyl compoundss6 are in the order R,Si-> R,Ge. -R,Sn. > R,Pb. and the rate of this reaction with a given radical R3M* is in the order diketone > oxalate > ketone > trifluoroacetate > acetate The reactions of the silicon analogue of the t-butoxyl radical have been studied via photolysis of the peroxide:” Me,SiOOBu‘ !% Me,SiO* + Bu’O* This radical reacts with the starting material to give a silicone ether by an sH2 mechanism Me,SiO.+ Me,SiO,Bu + Me,SiOSiMe + *02Bu In the presence of alkenes both primary radicals may add Me,SiO* + CH,=CH2 -P Me,SiOCH,CH,. and with buta-1,3-diene there are several possibilities such as straightforward addition or more complex reactions e.g. Scheme 27. In the case of organosilyl ” J. Cooper A. Hudson and R. A. Jackson J.C.S. Perkin II 1973 1056. ’* D. A. Coates and J. M. Tedder J.C.S. Perkin II 1973 1570. 55 A. G. Davies and J. C. Scaiano J.C.S. Perkin 11 1973 1777. 56 J. Cooper A. Hudson and R. A. Jackson J.C.S. Perkin If 1973 1933. 57 D. J. Edge and J. K. Kochi J.C.S. Perkin 11 1973 182. 168 W. T.Dixon Me,SiO,Bu I SiMe SiMe3 SiMe (cis-trimethylsilylallyl) Scheme 27 derivatives of hydroxylamine rearrangement to the nitroxide can occur :'* Bu,O 2Bu0. R,SiNHOSiR3 BU0.r R,SiNa-SiR 1 (R,Si),N'O 10 Radicals containing Nitrogen Nitroxides are still probably the most widely studied radicals because of their ease of formation use of nitroso-compounds as radical traps and their stability. They are so stable that large enough concentrations can be achieved to enable one to obtain their n.m.r. spectra in some cases. From the n.m.r. spectrum one can obtain the signs of the coupling constants since they determine the direction of the 'contact' chemical shift. This exercise has been completed for a-and for P-naphthyl t-butyl nitroxides (20) and (2l)." The spin distributions bear 0' I 13.5 NBu -0.218 NBu -0.064 -0.101 -0.43 0.39 0.865 almost no relationship to those in a- and P-naphthoxyi and in the case of the a-naphthyl derivative the coupling constants suggest that there is some degree of twisting about the carbon-nitrogen bond.A variety of cyclic nitroxides have 58 R. West and P. Boudjouk,J. Amer. Chem. SOC.,1973,95 3983. 59 J. L. Duncan A. R. Forrester G. McConnachie and P. D. Mallinson J.C.S. Perkin If 1973. 718. Electron Spin Resonance Spectroscopy and Free Radical Reactions 169 been prepared and the spin label allows investigation of the flapping of rings6' as well as their conformations6' to be determined from the e.s.r. parameters. An interesting class of nitroxide radicals has been studied using the spin trap (22).Addition occurs at the carbon atom and the radical formed may be strongly Bu' / R.=C=N -RCH,NB~~ -\ I Scheme 28 asymmetric i.e. Scheme 28.62 Looking along the methylene-carbon-nitrogen bond there will be two stable conformations (23) and (24). If R is an asymmetric HA \\ \ -0-N -But I group such as CH,CHOH then even when there is fast interconversion between these two conformations the two protons will have different average splittings. The disparity increases with the size of R.. If there is sufficient steric hindrance alkyl groups may be forced to add to the oxygen of a nitroso group rather than to the nitrogen atom (Scheme 29).63a From the coupling constant of the nitrogen atom (ca.10G)the N-alkoxyanilino- radical is probably a n-type and so are the aliphatic analogues e.g. Scheme 30.63b On the other hand iminoxyl radicals are of a-t~pe,~~ as are iminyl radicals (Scheme 31). An interesting rearrangement takes place after radical attack on aryl hydra- zonates (Scheme 32).65 To finish this section on nitrogen radicals it seems appropriate to mention the reduction of nitroxides to the corresponding secondary amines with iron carbonyls (Scheme 33).66 'O R. E. Rolfe K. D. Sales and J. H. P. Utley J.C.S. Perkin 11 1973 1171. " V. Malatesta and K. U. Ingold J. Amer. Chem. SOC.,1973 95 6390 6395; J.C.S. Perkin 11 1973 2134; S. F. Nelsen and R. T. Landis jun. J. Amer. Chem. SOC.,1973 95 6454. 62 B. C. Gilbert and M.Trenwith J.C.S. Perkin 11 1973 1834. 63 (a)S. Terabe and R. Konaka J.C.S. Perkin 11 1973 369; (b)W. C. Danen C. T. West and T. T. Kensler J. Amer. Chem. SOC.,1973,95 5716. "G. D. Mendenhall and K. U. Ingold J. Amer. Chem. SOC.,1973,95,2963 3422 65 A. F. Hegarty J. A. Kearney and F. L. Scott J.C.S. Perkin 11 1973 1422. 66 H. Alper J. Org. Chem. 1973 38 1417. 170 W.T. Dixon (nitroxide) M = C Si or Sn (N-alkoxyanilino-radical) scheme 29 0 4 RNHC hv RNH (amino-radical) \ OOBu' (proxy-carbamate) *"". I RNOBU' RNHOBu' Scheme 30 Bu,C=NH Bu'o. Bu,C=N* -% BuC=N-o* 2.8 28.4 (sigma radical) \ INo Bu,C=NNO Scheme 31 11 Radicals containingGroup V Elements The work on phosphoranyl radical^^',^^ and the corresponding arsenic com- pounds has continued along the same lines as last year.The structure of these radicals is one of a trigonal bipyramid with alkoxyl or halogen ligands filling 6' D.Griller and B. P. Roberts J.C.S. Perkin 11 1973 1339. 68 D. Griller and B. P. Roberts J.C.S. Perkin 11 1973 1416. Electron Spin Resonance Spectroscopy and Free Radical Reactions 0 I Ph1’ PhC=N-NHPh =N-NPh X 9‘ 0-Ph&=N-NPh 3 0 Ph‘ II Ph’ PhC-N-L-Ph ;;-; PhCONHN’ \ Ph Scbeme 32 Fe,(CO) I Q-Q I I 0 H Scheme 33 the axial positions preferentially e.g. (25) and (26). The phosphorus and arsenic compounds undergo similar types of reaction (Scheme 34). Some chelating ligands have been attached to phosphorus yielding ‘spiro- phosphoranyl’ radicals,68 and exchange of halogen between equatorial and axial positions has been observed by e.s.r.(Scheme 35). 12 Radicals containingGroup VI Elements The pulse radiolysis of thiols or ‘sulphydryl’ compounds leads to sulphur radicals which readily form links with further sulphur to give a negative ion in which 172 W. T. Dixon BuOPX +X. 7 PX,WBuOPX L Bus +OPX BuOAsPh +Ph-2 Ph,As%BuOAsPh L Bu. +OAsPh Scheme 34 CI OR 1 ,OR I,c1 CCP EP I\OR I \OR OR OR Scheme 35 there are two sulphur atoms (Scheme 36).70371This well-known oxidative coupling of sulphur is so strong a tendency that it appears that it can even happen with dialkyl sulphides (Scheme 37).72 A great variety of radicals may be generated from such aliphatic sulphur cation radicals for example when there is aa-hydroxy- group (Scheme 38).73 te-RSSR H *idisproportionat ion /SH s R +R’I \ \I SH S Scheme 36 Some interesting thiophen derivatives (27H29) have been prepared in which different isomers can be distinguished in the e.s.r.spe~tra.’~ 69 E. Furirnsky J. A. Howard and J. R.Morton J. Amer. Chem. SOC.,1973 95 6574. ’’M. Z. Hoffman and E. Hayon J. Phys. Chem. 1973,77,990. P. C. Chan and B. H. J. Bielski J. Amer. Chem. Sor.. 1973 95 5504. ’’B. C. Gilbert D. K.C. Hodgeman and R.0.C. Norman J.C.S. Perkin 11 1973 1748. 73 B. C. Gilbert J. P.Larkin and R.0.C. Norman J.C.S. Perkin If 1973 272. 74 C. M. Camaggi L. Lunazzi and G. Placucci J.C.S.Perkin 11 1973 1491. Electron Spin Resonance Spectroscopy and Free Radical Reactions +. +. Me,S .OH Me,S b Me,SSMe, (Ti"l-H,O, 10H 6.8 (12 protons) CH,SMe 16-5 3.6 Scheme 37 +. RCHOHCH,SR -+RCHO +CH,SR + H+ L R \ .+ C=O + H+ + SR / H3C (trapped but not observed directly) Scheme 38 R\S Qs--0 s .- s I I I I R I R R (27) &cis (28) cis,trans (29) trans,trans Sulphonyl radicals (30)and (31) have been prepared by abstraction of chlorine from sulphonyl chlorides 75 with the triethylsilyl radical. The assignments were made on the assumption of twisting of the -SO,. and that the configuration CH,CH,CH,SO,CI b CH ,CH2CH,SO5 0.7 2.1 7 (30) at the sulphur is pyramidal the preferred conformation leading to asymmetry.This is rather different from the case of the primary alkyl sulphonyls (32)-(34) where rotation is relatively unrestricted it seems. 13 Spin Delocalization through a-Bonds The existence of substantial P-proton coupling constants in alkyl radicals and in alkyl-substituted aromatic radicals proves in itself that spin density 7s A. G. Davies B. P. Roberts and B. R.Sanderson J.C.S. Perkin If 1973,626. 174 W. T. Dixon can be transmitted through o-bonds. This process which arises from the inter- action of a n-type atomic orbital and the orbitals of a neighbouring a-bond is called hyperconjugation and the idea can be extended to account for some very long-range coupling constants e.g. those in (35)and (36).'6 10.8 = 1.5 In the bridged naphthalene anion already mentioned there is even an observable S-coupling constant.These long-range splittings generally are observed in systems in which a rigid conformation exists which is favourable for each hyper- conjugative interaction. There are some empirical rules which have some foundation in simple MO theory which amount to saying that transmission through a a-system only occurs when the bands are lined up with each other. More sophisticated the~ries'~ are able to account for negative spin densities on y-protons as well as positive densities on p-and &protons when the conforma- tion is favourable (see the Figure). Particular cases of o-delocalization occur when the steric forces cause twisting in aromatic systems.' 7g78*79 The coupling constants of protons attached to aryl substituents generally arise from a mixture of two components one from transmissions of spin density through the n-system and the other through the a-system.Twisting becomes apparent when the ortho and para proton splittings decrease in relation to the meta proton coupling constants. When the twisting becomes much more pronounced a situation is found in which the meta splitting is much larger than the others e.g. in the rubrene positive or negative radical ions (37).79 A particularly clear example of this effect appears in the series of aryl semiquinones (38)--(40).'7 The large meta coupling which is apparent when the aryl ring is approximately perpendicular to the nodal plane of the odd ele~tron,'~ is simply a case of S-coupling described before.76 J. K. Kochi P. Bakuzis and P. J. Krusic J. Amer. Chem. Soc. 1973 95 1516. 7' Y. Ellinger A. Rassat R. Subra and G. Berthier J. Amer. Chem. SOC.,1973,% 2372. H. G. Aurich H. Forster A. Lotz and W. Weiss Chem. Ber. 1973 103 2832. l9 R. Biehl K. P. Dinse K. Mobius M. Plato and H. Kurreck Tetrahedron 1973,29,363. Electron Spin Resonance Spectroscopy and Free Radical Reactions ab > 0 Figure Diagram showing interactions responsible for transmission of spin density through a-bonds. Orbitals in which there is relatively high positive spin density are shaded. Ph Ph Ph Ph (37) O @27 P (0.05).13 e0.0 \ 0.16 / 0.13 / / 0.15 0.27 0. I 3 \ / Me \ (0.05) 0-0-0-(38) (39) (40) increasing dihedral angle + 14 Some Miscellanies There has been some interest in the structure of methyl-lithium which is a tetramer consisting of a tetrahedron of lithium atoms with a methyl group by 176 W.T. Dixon the centre of each face. The e.s.r. spectrum of the corresponding alkyl radical,80 in which one hydrogen atom has been removed has been obtained and shows as expected hyperfine coupling with three equivalent 7Li nuclei [1(7Li) = $1. This is consistent with the structure (41). There must be rapid rotation of the methylene group to account for the equivalence of the three lithium nuclei. Further examples of emission lines in e.s.r. spectra have been observed8' which can give information in particular about the situation when a radical is actually being formed or possibly destroyed.A report of a reaction which has a measurable dependence on magnetic field82 strength might well be related to this for though magnetic energies are much too small under usual conditions to have any visible effect on radical reactions when the singlet-triplet transition probability depends on the field the latter could have pronounced effects on that step of a reaction. If this result is confirmed it could have important theoreti- cal and practical implications. Finally it should be noted that the following texts have appeared a simple introduction to free radical chemistry83 and a comprehensive monograph.84 K. S. Chen F. Bertini and J. K. Kochi J. Amer. Chem.Sor. 1973,95 1340. P. W. Atkins A. J. Dobbs and K. A. McLauchlan Chem. Phys. Letters 1973,23,204. R. Z. Sagdeev K. V. Salikhov T. V. Leshina M. A. Kamkha S. M. Skein and Yu. N. Molin Pis'zma Zhur. eksp. teor. Fiz. 1972 16 599. 83 J. I. G. Cadogan 'Principles of Free Radical Chemistry,' Monographs for Teachers The Chemical Society. London. 1973 No. 24. 84 J. K. Kochi 'Free Radicals Vol. I Dynamics of Elementary Processes' Wiley New York. 1973.

ISSN:0069-3030    

DOI:10.1039/OC9737000151

出版商:RSC    

年代:1973

数据来源: RSC