ISSN:0069-3030    

DOI:10.1039/OC97269FX001

出版商:RSC    

年代:1972

数据来源: RSC

ISSN:0069-3030    

DOI:10.1039/OC97269BX003

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

2 Physical Methods Part (i) Organic Mass Spectrometry By R. A. W. JOHNSTONE The Robert Robinson Laboratories University of Liverpool P.O. Box 147 Liverpool L69 3BX and F. A. MELLON Agricultural Research Council Unit of Invertebrate Chemistry and Physiology The Chemical Laboratory The University of Sussex Brighton Sussex BNI 9QJ In this Report we continue the practice established in the last Report of covering selected areas of organic mass spectrometry. The coverage is far from exhaustive and many references have been omitted for brevity. However the references given are leading ones and for greater coverage the reader is advised to consult the Specialist Periodical Reports or the incredibly condensed yet wide-ranging survey-cum-catalogue of mass spectrometry which has appeared with over 1700 references to current or recent work.2 As a guide to trends in mass spectrometry the reader would find value in consulting the abstracts of the 20th Annual Con- ference of the American Society for Mass Spe~trometry.~ A very useful book on the uses of mass spectrometry in biochemistry has a~peared,~ along with another introductory text on general mass spectrometry,’ and a review.6 1 Theoretical Aspects Most of the recent theoretical investigations on rate processes still use the grossly over-simple quasi-equilibrium equation k = v( 1 -E,/E)N-’.This equation has sufficient parameters to allow it to be ‘fitted’ to many experimental observations without difficulty. Although the equation is very useful for teaching or illustra- tive purposes there are many dangers inherent in its indiscriminate application ‘Mass Spectrometry’ ed.D. H. Williams (Specialist Periodical Reports) The Chemical Society London 1971 Vol. 1; 1973 Vol. 2. A. L. Burlingame and G. A. Johnson Anafyt. Chem. 1972 44 33713. Abstracts of the 20th Annual Conference on Mass Spectrometry and Allied Topics arranged by the American Society for Mass Spectrometry in co-operation with ASTM Committee E-14 Dallas June 1972. ‘Biochemical Applications of Mass Spectrometry’ ed. G. R. Waller J. Wiley Chichester 1972. ‘Principles of Organic Mass Spectrometry’ D. H. Williams and I. Howe McGraw-Hill London 1972. ‘Mass Spectrometry’ ed. A. Maccoll M .T.P. International Review of Science Physical Chemistry Series 1 Vol.5 Butterworth Baltimore 1972. 7 8 R. A. W.Johnstone and F. A. MelIon to experimental data. For example calculation of the pre-exponential factors of the above equation from mass spectrometric data was adduced as evidence for hydrogen bonding in the transition state for loss of C2H,0 from the molecular ions of ortho-substituted acetanilides.’ Further experiment has led to a retrac- tion of this hypothesis.* As in our previous Report,’ we strongly recommend that if quasi-equilibrium calculations are to be carried out at all the full equation be used especially in view of the ready access of most scientific investigators to computers. We have criticized the use of photoelectron spectra as energy distributions in QET calculations on electron-impact-induced decompositions citing our own unpublished workg Further experimental evidence that photoelectron spectros- copy provides too crude an approximation to electron-impact-induced internal energy distributions in ions has now appeared.lo An interesting investigation into the relative accuracies of expressions for determining rate constants in ion-molecule reactions was undertaken with the aid of ion-cyclotron mass spectrometry.’ 2 Ionization and Appearance Potentials The question of the accuracy of ionization and appearance potentials obtained from electron-impact ionization-efficiency curves appears to be reaching a stage where a definitive answer can be given in the near future. There seems little doubt that ionization and particularly appearance potentials determined by semi- empirical methods such as the semi-log plot vanishing current and Warren techniques or variations on these are somewhat ambiguous.Although the reproducibility of these may be very good their accuracy is questionable especially when there is considerable curvature at the foot of the ionization-efficiency curve. Mathematical analysis of ionization-efficiency curves promises to overcome the drawbacks in the semi-empirical methods and there is currently a lot of activity in this area. The various methods of determining appearance potentials have been evaluated with reference to the critical-slope approach. l2 Of the more interest- ing results of this investigation the following are highly relevant (i) differences between the appearance potentials of normal and metastable fragment ions were on average 0.45 eV when determined by the popular semi-log plot method but were only 0.04 eV when determined by the critical-slope method -investigators of kinetic shifts beware! This problem was highlighted in a recent review.130 (ii) The differences between the appearance potentials of fragment ions deter- mined by the semi-log plot and critical-slope methods were on average 0.45 & 0.17 eV. (iii) Four high-energy competitive fragmentations gave appearance ’ S. A. Benezra and M. M. Bursey J. Chem. SOC.(B) 1971 1515. S. A. Benezra and M. M. Bursey J.C.S. Perkin II 1972 1537. Annual Reports (B) 1971 68 6. 10 G. Innorta S. Torroni and S. Pignataro Org.Mass. Spectrometry 1972 6 43. I‘ T. McAllister Internat. J. Mass Spectrometry Ion Phys. 1972 8 162. J. L. Occolowitz and B. J. Cerimele ref. 3 p. 95. l3 T. W. Bentley and R. A. W. Johnstone Adv. Phys. Org. Chem. 1970 8 (a) p. 185; (6)p. 164. Physical Methods-Part (i) Organic Mass Spectrometry 9 potentials by the semi-log plot method greater by 0.9-1.0 eV than those obtained by the critical-slope method. Further evidence for the potential of electron-impact data obtained from conventional ion sources has been pr~vided'~ by a fairly comprehensive investi- gation into the use of the electron-energy-distribution-difference te~hnique'~ allied to computer acquisition of ionization data. The accuracy of measuring ionization potentials was comparable with photoionization and photoelectron methods and for appearance potentials it was shown that some cases of reported kinetic shifts were due to the inaccurate methods previously used to measure appearance potentials.It is interesting to note in view of the results obtained with the critical-slope method that the energy-distribution-difference approach is not a proper mathematical folding but it can be shown that it is also a critical- slope method. '' A third-derivative technique17 has been used in attempts to overcome the resolution problems in the second-derivative method. '* Good agreement with photoionization and monoenergetic electron-impact data was found although the method suffered from problems due to random noise the effects of which are multiplied greatly when second or third derivatives are taken from ionization- efficiency curves.To overcome the noise problem ionization-efficiency curves have been scanned many times and the data averaged to give excellent results." However appearance potentials determined by the second-derivative method may be subject to large errors in some cases.2o A simple new technique for measuring ionization and appearance potentials2 ' will undoubtedly suffer from the drawbacks inherent in the other empirical methods. 3 Ionization Methods The use of electron impact to produce mass spectra continues to be the most widely used of all the methods of ionization. Its attraction is partly due to its earlier evolution but is also due to the relative robustness and ease of operation of ion sources constructed on this principle.However two other methods chemical and field ionization are rapidly gaining ground and offer attractive features unavailable by electron impact. Field ionization (FI) and field desorp- tion (FD) mass spectrometry continue to be areas in which there are few but active groups of workers. Both FI and FD methods give abundant molecular ions but relatively little fragmentation and they prove ideal therefore for examining 14 R. A. W. Johnstone and F. A. Mellon J.C.S. Faraday 11 1972 68 1209. 15 R. E. Winters J. H. Collins and W. L. Courchene J. Chem. Phys. 1966 45 1931. 16 R. A. W. Johnstone and B. N. McMaster to be published. 17 C. D. Finney and A. G. Harrison Internat.J. Mass Spectrometry Ion Phys. 1972 9 221. I8 J. D. Morrison J. Chem. Phys. 1953 21 1767. 19 R. G. Dromey J. D. Morrison and J. C. Traeger Internat. J. Mass Spectrometry Ion Phys. 1971 6 57. 20 G. G. Meisels and B. G. Giessner Internat. J. Mass spectrometry Ion Phys. 1971 7 489. 21 G. D. Flesch and H. J. Svec Internat. J. Mass Spectrometry Ion Phys. 1972 9 106. 10 R.A. W. Johnstone and F. A. Mellon mixtures since the mass spectrum of a mixture is composed almost entirely of molecular ions.22 High-resolution FI mass spectrometry gives the molecular formulae of the components of a mixture.23 Although FI and FD methods give some fragmentation the reproducibility of the mass spectral fragmentation pat- terns is apparently not good and spectra are frequently accumulated on photo- plates rather than by a more convenient electrical recording device.The FD method gives particularly good results with labile or difficultly volatile materials that are available only in small quantities because the mass spectra are obtained at room temperature. For example the mass spectra of 0.1-1.0nmole of amino-acids (including arginine and cystine) can be obtained without the prepara- tion of derivatives and the mass spectrum of a pentapeptide containing arginine has been obtained similarly.24 The low temperatures employed in FD work constitute probably the biggest advantage of this method over chemical ioniza- tion. There are now many groups of workers with chemical ionization (CI)sources and several important advances have been made in practical techniques.CI mass spectroscopy suffers like FI work in producing relatively little fragmenta- tion although molecular ions are abundant. The absence of fragmentation patterns is a serious drawback because a great deal of structural information is then not available. To combine the advantages of abundant molecular ions with extensive fragmentation CI mass spectroscopy has been carried out with mix- tures of water and argon as reagent gases.25 In the technique described argon is used as the carrier gas in gas chromatography and water is injected into the effluent before it passes into the ion source where two sorts of reaction (1) and (2) occur. Reaction (1) is protonation of a molecule (M) by H30+ to produce M + H30+ -+ MH+ + H,O M + Ar" -+ M+' + Ar a quasi-molecular ion (MH) having little excess of internal energy and therefore there is little fragmentation of the MH ion i.e.it is abundant in the mass spectrum. Reaction (2) is a charge-exchange reaction to produce a molecular ion with a considerable excess of internal energy so that fragmentation is rapid and exten- sive i.e.abundant fragment ions are produced. Thus reactions (1)and (2) together produce a mass spectrum with abundant molecular ions and fragment ions. This method also illustrates another advantage of CI with g.c.-m.s. namely that no molecular separator is needed between the end of the g.c. column and the ion source.26 22 H. D. Beckey H. Knoppel G. Metzinger and P. Schultze 'Advances in Mass Spectro- metry' Vol.3 ed. W. H. Mead institute of Petroleum London 1966 p. 35; H. D. R. Schuddemage and D. 0. Hummel ibid. Vol. 4 ed. E. Kendrick 1968 p. 857. 23 J. B. Forehand and W. F. Khun Analyf. Chem. 1970,42 1839; H. R. Schulten H. D. Beckey H. L. C. Menzelaar and A. J. H. Boerboom Analyr. Chem. 1973 45 191. 24 H. W. Winkler and H. D. Beckey Org. Mass Spectrometry 1972 6 655. 25 D. F. Hunt and J. F. Ryan Analyr. Chem. 1972 44 1306. 26 G. P. Arsenault J. J. Dolhun and K. Biemann Chem. Comm. 1970 1542. Physical Methods-Part (i) Organic Mass Spectrometry 11 Other reagent gases have been used in CI sources. Ammonia has been pro- posed as a selective reagent for certain functional groups in molecules e.g. conjugated ketones,27a and nitric oxide has been used to ‘identify’ functional groups by the nature of the quasi-molecular ion pr~duced.~” These investiga- tions promise significant advances in structure elucidation by mass spectrometry of very small quantities of material.Other uses of CI are included in Section 6. An intriguing development is the production of CI spectra at low ion-source pressures. Normally in C1 work the source is operated at a relatively high gas pressure and this can cause difficulties through high-voltage arcing. By the use of ion-storage ion-molecule reactions can be obtained at much lower pressures than in the normal CI source. The device is a three-dimensional quadrupole ion storage trap and hence its name quistor.28 4 Chromatographic-Mass Spectrometric Methods The most widely used combination of two analytical methods is that employing gas chromatography and mass spectrometry (g.c.-m.s.).Gas chromatography has gone through a long development period and has now reached a stage where separation of complex mixtures is routine. Similarly mass spectrometry has been developed as a powerful analytical tool which by the use of empirical rules gives a great deal of information on the structures of molecules. The two methods in tandem yield an analytical instrument far more powerful than either of the individual methods alone. There has been one major difficulty in operating gas chromatographs in tandem with mass spectrometers and this is caused by the need to have relatively high gas flows and pressures in the former instrument but relatively very low gas pressures in the latter.The following section describes the efforts made to circumvent the difficulty. Commonly open tubular (capillary) gas-chromatographic columns use gas flows of less than about 2mlmin-’ and these gas flows can be accepted by modestly sized pumps in the mass spectrometer. It is possible therefore to couple a capillary gas-chromatographic column directly into the ion source of the mass spectrometer so that all the g.c. efffuent is available for a mass spectrum. If the gas flow through the capillary is a little too high a splitter can be used to vent a proportion of the effluent to the atmosphere although of course that proportion is then lost and is not available for mass spectrometric analysis.Recently the use of very high-capacity pumps has been described so that one can allow the total effluent of a g.c. column (up to 20 ml min- ’) to flow directly into the mass ~pectrometer.~’ Under these circumstances even packed g.c. columns can be used. As mentioned briefly earlier CI sources work at relatively high pressures and use high-capacity pumps so that g.c. effluents can be passed directly into the 27 (a) I. Dzidic and J. A. McCloskey Org. Mass Spectrometry 1972 6 939; (b) D. F. Hunt and J. F. Ryan J.C.S. Chem. Comm. 1972 620; see also F. H. Field Accounts Chem. Res. 1968 1 42 and M. S. Wilson I. Dzidic and J. A. McCloskey Biochem. Biophys. Acta 1971 240 623. J. F. J. Todd and G. Lawson Chem. in Brit. 1972 8 373. 29 R.F. Bonner G. Lawson and J. F. J. Todd J.C.S. Chem. Comm. 1972 1179. 30 W. Henderson and G. Steel Analyt. Chem. 1972 44 2302. 12 R.A. W. Johnstone and F. A. Mellon ion source and the g.c. carrier gas becomes the reactant gas of the CI process. Thus with these sources methane or argon is frequently used as the g.c. carrier gas. When electron-impact sources are used with g.c. apparatus it is not only essen- tial to maintain a low pressure in the ion source but the residual carrier gas passed into the source must have an ionization potential high enough for it not to be ionized along with the organic material under investigation. For this reason helium is the carrier gas of choice when electron-impact sources are coupled to g.c. instruments and the electron energy is maintained below 20 V.Therefore although the carrier gas does not pose much of a problem the need for low gas pressures in the ion source does. A device is needed to separate as much carrier gas as possible from the organic material eluted from the g.c. column (enrichment) and to pass as much organic material as possible to the mass spectrometer (transfer efficiency). The ideal device (molecular separator) would provide infinite enrichment with 100% transfer but most practical models are far from this standard and much of the organic material eluted from the g.c. column is lost resulting in a reduction in effective sensitivity of the combined g.c.-m.s. technique compared with either technique alone. The simplest device for passing organic effluent from a g.c.column into a mass spectrometer is simply a short length of cooled capillary tube at the end of the g.c. column in which the organic material is condensed. The capillary tube and its contents are then carried to the mass spectrometer and a mass spectrum is obtained in the usual way. This method is somewhat clumsy and inefficient and not recommended for regular use but where say only one or two components eluted from a g.c. column need to be looked at occasionally it provides a simple cheap method. Generally molecular separators are on-line devices that are used continuously. A brief list of the currently used molecular separators is given here for the benefit of the reader but for a more detailed description a number of recent reviews should be c~nsulted.~~ The Ryhage (Jet) separator32 depends on the relatively much greater rate of diffusion of helium compared with organic com- pounds of higher molecular weight from a stream of them passing through a low- pressure area.This low-pressure area is simply a small evacuated gap between a narrow jet and a slightly larger orifice. Despite its all-metal construction thermal decomposition is usually low because the sample traverses the separator at speeds in excess of the velocity of sound. Nevertheless some compounds particularly polar ones are lost in the separator especially when present in low concentrations and there is a need for an all-glass separator. The transfer effi- ciency is variable but in favourable cases can exceed 50 %.The Llewellyn (mem- brane) separator33 allows organic material to dissolve in and diffuse through a very thin non-porous membrane into the mass spectrometer but carrier gas ” A. N. Freedman Analyt. Chim. Acta 1972 59 19; R. Ryhage and S. Wikstrom in ‘Mass Spectrometry. Techniques and Applications’ ed. G. W. A. Milne Wiley London 1971; G. A. Junk Internat. J. Mass Spectromelry Ion Phys. 1972 8 1. 32 R. Ryhage Analyt. Chem. 1964,36 759; Arkiv. Kemi 1967 26 26. 33 P. Llewellyn and D. Littlejohn 16th Annual Conference on Mass Spectrometry and Allied Tapics ASTM Committee E14 Pittsburgh 1968. Physical Methods-Part (i) Organic Mass Spectrometry 13 being less soluble does not dissolve in the membrane material and is vented straight to atmosphere.The membrane is usually made of silicone rubber but because the solution-diffusion process can take a relatively long time (0.1 s) some loss of the g.c. resolution may be noticeable particularly with capillary columns through mixing of components in the membrane. Although it is a good separator with high transfer and enrichment factors it cannot be used for extended periods at temperatures much above 200 “C. An all-glass membrane separator is now marketed. In the Watson-Biemann separator,34 enrichment is obtained by the different rates of diffusion of carrier gas and organic material on passage through a short length of tubular glass frit. The efficiency varies between 10 and 50% and being of all-glass construction this type is relatively trouble- free although the large surface area leads to some thermal decomposition prob- lems.The above three separators are the ones most commonly used and all are available commercially either as separate items or built into g.c.-m.s. units. Other separators which have been described include the silver membrane,35 the variable,36 and the reaction types,37 each of which has advantages and dis- advantages but has not been widely used. G.c.-m.s. methods are utilized extensively in chemical biochemical and bio- medical research and are mentioned again later. Other couplings of analytical techniques with mass spectrometry include protein ~equenator,~~ centrichr~matography,~~ and liquid-liquid chromatog-raph~.~~ 5 Computers The use of computers for acquisition of data from mass spectrometers is well established and the main area of interest has shifted to their use as aids to the interpretation of data.Storage of mass spectra on ‘files’ or in a ‘library’ which can be searched by computer has attracted considerable attention. To reduce the amount of information about each mass spectrum that needs to be stored abbreviated spectrum files are used in which only the more important charac- teristics of a mass spectrum are retained.40 For example it has been shown recently4* that by noting only two peaks in every 14 mass units along with some information on abundances a library of spectra can be set up and searched by computer in a matter of seconds. With the mass spectrum of a compound of unknown structure the library user can request the computer to search its files.34 J. T. Watson and K. Biemann Analyt. Chem. 1964 36 1135; ibid. 1965 37 844. R. Cree Conference on Analytical Chemistry and Applied Spectroscopy Pittsburgh March 1967. 36 C. Brunee H. J. Buttemann and G. Kappus Abstracts of the 17th Annual Conference on Mass Spectrometry and Allied Topics ASTM Committee E14 Dallas 1969 p. 121. ” P. Simmonds G. R. Shoemaker and J. E. Lovelock Analyt. Chem. 1970 42 881. 38 F. W. Karesch and P. W. Rasmussen Analyt. Chem. 1972 44 1488. 39 R. E. Lovins J. Craig and T. Fairwell ref. 3 p. 163; R. E. Lovins J. Craig F. Thomas and C. McKinney Analyt. Biochem. 1972 47 539. 40 H. S. Hertz R. A. Hites and K. Biemann Analyt. Chem. 1971 43 681. 4‘ S.L. Grotch Analyr. Chem. 1973 45 2. 14 R.A. W.Johnstone and F. A. Mellon If the computer has any spectra to match the unknown they are printed out. This sort of retrieval system has been developed to a considerable level of sophistication by incorporating a ‘conversational’ mode of operation between the user and the computer.42 In the conversational mode the user can ask a series of previously specified questions which the computer answers by search- ing the stored information from about 9O00 spectra. In this way the user can obtain a short list of possible identifications of an unknown very rapidly by feeding a minimum of information to the computer. Other workers have described a similar interrogation system.43 After examining the short list the user can add more information if that is necessary to obtain a closer identifica- tion.In a similar system library search facilities have been extended to include data from nuclear magnetic resonance and i.r. as well as from mass spectro- metr~.~~ Computer-aided classification and interpretation of mass spectra has been reviewed4’ as has the use of computers with g.c.-m.s. Another active area of research has been the application of computers as ‘learning’ or ‘artificial intelligence’ machines and an important advance has been the introduction of a pattern classifier of mass spectral information from non-linear chemical system^.^' In a more specific application of artificial intel- ligence a computer has been used to identify oestrogenic steroids through interpretation of high-resolution mass spectral data.48 6 Chemical Biochemical and Biomedical Uses of Mass Spectrometry The high sensitivity of mass spectrometry is being exploited increasingly for investigations of small samples of tissue or blood plasma in forensic science drug detection and metabolic studies.By the use of specialized techniques pico- gram quantities of known compounds can be identified and measured accurately. With such sensitivity only tiny amounts of tissue or plasma are needed. The specialized techniques needed for these studies are straightforward with the right equipment and several manufacturers supply suitable instruments. To identify small amounts of known compounds the whole range of the mass spectrometer is not scanned but 14 of the most abundant or characteristic peaks in the mass spectrum are scanned rapidly in succession.This method is termed mass fragmentography and has been reviewed with emphasis on its use for detecting biogenic amines psycho-active compounds pesticides pollutants 42 S. R. Heller H. M. Fales and G. W. A. Milne Org. Mass Spectrometry 1973 7 107; S. R. Heller Analyt. Chem. 1972 44 1951. 43 D. H. Smith and G. Eglinton Nature 1972 235 325. 44 T. Emi and J. T. Clerc Helc. Chim. Acta 1972 55 489. 45 D. H. Smith Analyt. Chem. 1972 44 536. 46 F. W. Karasek Analyt. Chem. 1972 44 32A. 47 J. B. Justice D. N. Anderson T. L. Isenhour and J. C. Marshall Analyt. Chem. 1972 44 2087. 48 D. H. Smith B. G. Buchanan R. S. Engelmore A. M. Duffield A.Yeo E. A. Feigen-baum J. Lederberg and C. Djerassi J. Amer. Chem. SOC. 1972 94 5962. Physical Methods-Part (i) Organic Mass Spectrometry 15 steroids purines prostaglandins and glucose.49 If we suppose a known com- pound has two characteristic peaks in its mass spectrum at say m/e 100 and 200 then in mass fragmentography the tissue sample or extract to be examined is heated in the ion source whilst the mass spectrometer ‘looks’ only for peaks at m/e 100 and 200 alternately. If the peaks are present then the compound can be assumed to be present and its amount estimated. As an example the minimum quantity of the drug imipramine which could be ‘identified’ in this way was 50 pg.” The accurate estimation of the amount of a substance present in these small quantities requires the integration of the intensity of mass fragmentographic peaks with time.Thus in the hypothetical example given above the intensities of the peaks at m/e 100 and 200 would be recbrded at definite time intervals from when they first appeared until they last disappeared. Intensity of peak plotted against time then gives a curve under which the area represents a measure of the amount of compound present. To obtain the most accurate measure- ments the intensity of a peak in the mass spectrum of a standard compound vaporized into the ion source must be measured simultaneously. This method as first introduced,’ has been adversely criticized because considerable fluctua- tions in sensitivity and scattering of quantitative data were found because it was not possible to maintain constant or reproducible conditions in the ion source.” However a small modification was made so that the standard and the compound being investigated were flash-evaporated together into the ion source.The modification led to a great improvement in quantitative estimations as exempli- fied with dansyl derivatives of amines.’2 Integrated mass fragmentography has been used for example in estimations of barbiturates and metabolites in plasma samples of new-born children,’ lidocaine and its metabolite^,^^ heroin,’ ’ prostaglandin^,^^ and biogenic amine~.~ Apart from these advances in the estimation of small quantities of known compounds mass spectrometry has been widely used often with gas chromatog- raphy to identify substances of biogenic interest.Thus sulphonamides which usually decompose in g.c.-m.s. systems5 were successfully studied after N-methylati~n.~’Riboflavin and flavoprotein-derived compounds were identified ” A. E. Gordon and A. Frigero J. Chromatog. 1972 73 401. 5o A. Frigero G. Belvedere F. De Nadai R. Fanelli C. Pantarotto E. Riva and P. L. Morselli J. Chromatog. 1973 74 201. 51 J. R. Majer and R. Perry J. Chem. SOC. (A) 1970 822. 52 N. Seiler and B. Knodgen Org. Mass. Spectrometry 1973 7 97; see also 0. Borga L. Palmer A. Linnarsson and B. Holmstedt Analyf. Letrers 1971,4,837; L. Bertilsson A. J. Atkinson J. R. Althaus A. Harfast J. E. Lindgren and B. Holmstedt Analyt. Chem. 1972,44 1434. 53 G. H. Draffan R. A. Clare and F.M. Williams J. Chromatog. 1973 75 45. 54 J. M. Strong and A. J. Atkinson Analyt. Chem.. 1972 44 2287. 55 G. -R. Nakamura T. T. Noguchi D. Jackson and D. Banks Analyt. Chem..,1972,44 408. 56 J. T. Watson D. Pelster B. J. Sweetman and J. C. Frohlich ref. 3 p. 85. 57 A. A. Boulton D. A. Durden and S. Philips ref. 3 p. 102. 58 D. R. Dill and R. L. McKinley J. Gas Chromatog. 1968 6 68; L. Fishbein J. Chromatag. 1967 30 596. 59 B. Blessington Org. Mass Spectrometry 1972 6 347. 16 R. A. W. Johnstone and F. A. Mellon at the 100nmole and an anthelmintic and its metabolites were studied.'l CI methods are increasingly used in this sort of research as the following range of compound types illustrates macrolide antibiotics,62 sugars63 (where ammonia is recommended as the reagent gas) ceramides and gangli~sides,~~ and insecti- cide~.~~ Carbohydrates have been investigated by electron-impact mass spectrometry either after conversion into derivatives (permethylated peracetylated pertri- methylsilylated) or directly by FI and FD methods.From their mass spectra alone it appears possible to identify fructoses,66 to distinguish between cyclic and acyclic forms,' between furanoses and pyranoses,68 and between aldoses and ketde~,~' and to gather information on the nature of glycosidic linkages7' In the last Annual Report we stressed the possible utility of mass spectrometry in research on peptides obtainable in only very small quantities. Very elegant examples of the use of this method have now appeared with the publication of the structures of several releasing hormones from the hypothalamus.Hormones which inhibit the release of melanocyte-stimulating hormone have been identi- fied as Pro-Leu-Gly-NH and Pro-His-Phe-Arg-GlyeNH ,72 and those which release luteinizing (and follicle-stimulating) growth and thyrotropin-stimulating hormones as respectively (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH ,7 Val-His-Leu-Ser-Ala-Glu-Glu-Lys-Glu-Ala~OH,74 and (pyro)Glu-His- ProaNH .75 The structure of a mutant peptide from an abnormal haemoglobin has been ~onfirrned.~~ G.c.-m.s. has been used to elucidate the structure of a peptide antibi~tic.~~ Pyrolysis of peptides to form diketopiperazines which are identified by g.c. has been proposed as a method of sequencing peptides7* Initial results on a " P.Brown C. L. Hornbeck and J. R. Cronin Org. Mass Spectrometry 1972 6 1383. 61 W. J. A. VandenHeuvel R. P. Buhs J. R. Carlin T. A. Jacob F. R. Koninszy J. L. Smith N. R. Trenner R. W. Walker D. E. Wolf and F. J. Wolf Analyt. Chem. 1972 44 14. 62 R. L. Foltz ref. 3 p. 258. 63 A. M. Hogg and T. L. Nagebhushan ref. 3 p. 31 1. 64 S. P. Markey R. C. Murphy and D. A. Wenger ref. 3 p. 318. 65 F. J. Biros R. C. Dougherty and J. Dalton Org. Mass Spectrometry 1972 6 1161. 66 K. D. Das and B. Thaynmanavan Org. Mass Spectrometry 1972 6 1063. 67 N. K. Kochetov and 0. S. Chizhov Adv. Carbohydrate Chem. 1966 21 39. H. Ch. Curtins M. Miiller and J. A. Vollman J. Chromatog. 1968 37 216. 69 S. Karady and S.H. Pines Tetrahedron 1970 26,4527. '' J. Karkkainen Carbohydrate Res. 1971 17 1; J. P. Kamerling J. F. G. Vliegenthart J. Vink and J. J. De Ridder Tetrahedron 1971 27 4275. " R. M. G. Nair A. J. Kastin and A. V. Schally Biochem. Biophys. Res. Comm. 1971 43 1376. 'Iz R. M. G. Nair A. J. Kastin and A. V. Schally Biochem. Biophys. Res. Comm. 1972 47 1420. '' A. V. Schally R. M. G. Nair T. W. Redding and A. Arimura J. Biol. Chem. 1971 246,7230. '4 A. V. Schally Y. Baba R. M. G. Nair and C. D. Bennet J. Biol. Chem. 1971,276,6647. '' K. Folkers F. Enzmann J. Boler A. V. Schally and C. Y. Bowers J. Medicin. Chem. 1971 14 469; C. Bogentoft J. Chang H. Sievertsson B. Currie and K. Folkers Org. Mass Spectrometry 1972 6 735. 76 H. R.Morris and D. H. Williams J.C.S.Chem. Comm. 1972 141. " W. A. Konig H. Hagenmaier and E. Bayer 2.analyt. Chem. 1972 259 21 1. 78 A. B. Mauger Chem. Comm. 1971 39. Physical Methods-Part (i) Organic Mass Spectrometry 17 similar approach using g.c.-m.s. for identification of the diketopiperazines have been described.79 7 Metastable-ion Studies Investigations of metastable ions as probes into the nature of transition states for slow decomposition reactions in the mass spectrometer continue. The elimination of keten from p-chloroacetanilide was found to give deuterium isotope effects on competing metastable transitions from which it was concluded that elimination occurred uia a four-membered transition state involving transfer of hydrogen to nitrogen rather than via a six-membered transition state with transfer of hydrogen to the aromatic ring.80 However a cautionary note" has been sounded regarding the characterization of ion structures" by using relative abundances of metastable ions due to two or more competing reactions.Follow- ing experiments on benzylic fluoro-compounds it was pointed out" that ions of identical structure will give a range of intensity ratios because a broad range of internal energies can give rise to metastable decompositions. These workers suggested that changes in the ratio of two or three times could not be considered structurally significant and that much larger changes should be sought before drawing structural inferences. It seems to us that a corollary of this is that two or more different structures could give similar intensity ratios for metastable decompositions especially when the structures are not too dissimilar.Ion structures which are similar could well decompose through a common transi- tion state. In any case there seems no overwhelming reason to suppose that the metastable decompositions bear much resemblance to the faster higher-energy processes occurring in the ion source. 36 A metastable decomposition may occur with release of an excess of internal energy into the reaction co-ordinate. This release of energy causes the peak to broaden. A study of the ratios of this energy release measured by metastable peak widths for loss of hydrogen or deuterium from a number of molecular ions was undertaken and cases in which the activation energy for the reverse reaction was important were identified.83 Ion kinetic energy spectroscopy has been applied to investigations of charge- localization in doubly charged ions of pyrazine pyrimidine and pyrida~ine.~~ The results suggested that the doubly charged ions were linear structures with the charges localized at nitrogen.'' R. A. W. Johnstone and T.J. Povall Meeting of the Protein Group of The Chemical Society Manchester January 1973. N. Uccella 1. Howe and D. H. Williams Org. Mass Spectrometry 1972 6 229. *' K. R. Jennings and A. Whiting Org. Mass Spectrometry 1972 6 921. *' Examples cited in ref. 81 include T. W. Shannon and F. W. McLafferty J. Amer. Chem. SOC.,1966 88 5021; N. A. Uccella I. Howe and D. H. Williams J. Chem.SOC.(B), 1971 1933. 83 M. Bertrand J. €4. Beynon and R. G. Cooks Internat. J. Mass Spectrometry Ion Phys. 1972 9 346. 84 J. H. Beynon R. M. Caprioli and T. Ast Org. Mass Spectrometry 1972 6 273. R. A. W.Johnstone and I;. A. Mellon 8 Conclusion Mass spectrometry in organic chemistry appears to be following the almost classical case-histories of other spectroscopic methods. After years of little interest except to a few physical and petroleum chemists the technique was used by one or two eminent chemists who realized the potential help it could give in structure elucidation. There then followed feverish activity by an increasingly large number of researchers whilst thousands of known compounds were examined to provide empirical guide-lines for understanding mass spectrometric decomposition processes.Lagging slightly behind came increasing improvement and sophistication in instruments and practice. The heyday of the empirical searcher for truth seems to have reached or passed its maximum (if only because there are no more readily available compounds to examine!) leaving mostly the dedicated to worry over mechanisms and theory. However mass spectrometry has been and continues to be taken up enthusiastically as a working tool not only by the organic chemist but also by biochemists and their ilk. Perhaps in a few short years mass spectrometry will be as commonplace and routine as i.r. spectroscopy is to us now but it will not have been without its moments of glory.

ISSN:0069-3030    

DOI:10.1039/OC9726900007

出版商:RSC    

年代:1972

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 It is of course impossible in a Report of this size to cover comprehensively all aspects of n.m.r. spectroscopy. This Report concentrates primarily therefore on two areas which are expanding rapidly namely chemically induced dynamic nuclear polarization and Fourier-transform spectroscopy. Some other aspects are treated briefly under Miscellaneous Studies. Papers concerned solely with the compilation of chemical shifts and coupling constants on series of related compounds with the routine use of n.m.r. for identification or structural work or with well-established procedures for studying exchange processes or conforma- tional problems have been largely excluded.This year marked the appearance of the first volume of the Specialist Periodical Reports in Nuclear Magnetic Resonance edited by R. K. Harris which is orientated towards a discussion of the phenomenon itself rather than towards a summary of the applications of n.m.r. in the various areas of chemistry. 1 Chemically Induced Dynamic Nuclear Polarization High-field Studies.-Two reviews have appeared which separately present the qualitative aspects' of CIDNP along with a simple classical explanation of the radical-pair theory and the quantitative applications' and extensions of the theory. A concise elementary review3 and a general review4 have also appeared. Kaptein' has critically re-examined the radical-pair theory for CIDNP in high magnetic fields and has presented an extended model which takes into account random-walk diffusion of the radicals within a pair.Such a modifica- tion is necessary since the lifetime of an initially formed radical pair is too short (< 10-s) for the nuclear-spin-dependent singlet-triplet (S-T,) mixing (and hence nuclear spin selection) to occur and therefore polarization is due to spin selection in subsequent encounters of the original pair. In many respects the model is similar to that proposed by Adrian.6 Differences arise in the treatment ' ' H. R. Ward. Accounts Chem. Res. 1972 5 18. R. G. Lawler Accounts Chem. Res. 1972 5 25. S. H. Pine J. Chem. Educ. 1972 49 664. A. L. Buchachenko and F. M. Zhidomirov Russ.Chem. Rev. 1971 40,801. R. Kaptein J. Amer. Chem. SOC.,1972 94 6251. ' F. J. Adrian J. Chem. Phys. 1970 53 3374; 1971 54 3912. 19 I.H. Sadler of pairs formed by radicals with uncorrelated spins and in the use of a finite rather than zero value for the electron-exchange integral (J). (However see Low-field Spectra.) An important feature of the revised model is the prediction that rela- tively long-lived radical pairs will contribute to the polarization. The diffusion model gives a description of the relative line intensities that is as good as or better than that provided by the previous radical-pair model. The diffusion model has been extended7 to cover situations where the conversion of a radical pair into a new pair by rearrangement fragmentation or transfer becomes competitive with product formation from the original pair.Such processes are often sufficiently rapid (ca. s) for the spin correlation of the original pair to be maintained in the new pair and thus polarization may be observed in the products of the new pair and of pairs formed by subsequent reactions. Calculations which show that secondary pairs formed after relatively long times (up to s) could still give rise to observable CIDNP effects have been supported by experiment.8 The revised quantitative treatment in no way affects the qualitative predictions that are possible using Kapteins rules.' A set of rules has also been developed" for the semiquantitative analysis of first-order multiplet spectra by a graphical met hod.Several detailed studies of the decomposition of diacyl peroxides have appeared. The polarizations of the proton resonances observed' ' during the thermal decomposition of acetyl peroxide in hexachloroacetone are consistent with Scheme 1 (R' = CH,). The decarboxylation process is slow enough for polariza- tion to occur in the acetoxyl-methyl radical pairs and be observed in the geminate -co -co -(R'CO,) + 2R'CO,. R'. R'CO,. --P 2R'. /R' C0,R' lR2X R'X + R2* Ri R'X+ R2* R' =Me E A E - R' = Et none - EfA AIE (E emission A absorption) Scheme 1 recombination product methylacetate. The unusual net polarization of the ethane resonance which cannot be due to S-To mixing in the methyl radical pair since net effects cannot arise from pairs of equivalent radicals arises from S-To mixing in the preceding pair.The polarization is retained in the methyl radical pair and R. Kaptein J. Amer. Chem. SOC.,1972 94 6262. ' R. A. Cooper R. G. Lawler and H. R. Ward J. Amer. Chem. SOC.,1972 94 552. R. Kaptein Chem. Comm. 1971 732. lo K. Muller J.C.S. Chem. Comm. 1972 45. '' R. Kaptein J. Brokken-Zijp and F. J. J. de Kanter J. Amer. Chem. SOC.,1972 94 6280. Physical Methods-Part (ii) Nuclear Magnetic Resonance appears in the final product. This phenomenon has been termed a memory eflect. CIDNP spectra obtainedI2 during the decomposition of higher acyl peroxides (R' = ethyl or lauryl) in solutions containing alkyl iodides,R2 = Et or Pr' show only multiplet effects arising from spin selection in the 2R'.alkyl radical pair. No polarization is observed in the ester R'C0,R' and the results are in accord with the rapid decarboxylation of the acyloxyl radicals. Multiplet polarization (E/A)is also observed in the reagent alkyl iodide and this results from spin selection in diffusive encounters of two R2 * radicals. During the decomposition' of phenyl acetyl peroxide in carbon tetrachloride- bromotrichloromethane mixtures decarboxylation is again sufficiently rapid that nuclear spin selection does not occur in pairs containing benzoyloxyl radicals. Polarization is only observed in the spectra of the non-cage products benzyl bromide (E) and l,l,l-trichloro-2-phenylethane(A)and again results from spin selection in benzyl-trichloromethyl radical pairs formed by diffusive encounters.A quantitative model is proposed to explain the variation in intensity of the benzyl bromide polarization with bromotrichloromethane concentration. CIDNP spectra of alkyl benzoates obtained* during the thermolysis of benzoyl peroxide in solutions containing alkyl iodides are interpreted in terms of rapid reaction of the alkyl iodide with a benzoyloxyl-phenyl radical pair to give iodo- benzene and a new benzoyloxyl-alkyl radical pair. Such a process which proceeds PhCO,. Ph- + RI + PhI + PhCO,. R. -+ PhC0,R with conservation of spin multiplicity is termed pair substitution. Spectra analo- gous to those arising from pair substitution were obtained by the thermolysis of the appropriate acyl benzoyl peroxide.The polarization observed for the proton resonances of the alkylbenzenes formed in these reactions arises from spin selection in a phenyl-alkyl radical geminate pair and from the rate of decarboxy- lation of the benzoyloxyl radical it is shown that the geminate pair must exist for up to 10-6-10-7 s. The intermediacy of arylcyclohexadienyl radicals in the homolytic arylation ofaromatic compounds has been dem~nstrated'~ using CIDNP techniques. The net effects observed for the products (1)and (2) obtained during the decomposi- tion of perdeuteriobenzoyl peroxide in hexachloroacetone-l,3,5-trichlorobenzene mixtures are in accordance with Scheme 2. Evidence that polarization of (2) does not occur where a hydrogen atom is abstrated by a single radical from a neutral molecule is provided by the use of hexamethylbenzene in place of trichlorobenzene.In this instance only unpolarized resonances are obtained for (2). CIDNP effects ~bserved'~ during the room-temperature photolysis of the trans-azo-compound (4)and the thermolysis of cis-isomer (3) in benzene (Scheme l2 R. A. Cooper R. G. Lawler and H. R. Ward J. Amer. Chem. SOC.,1972,94 545. l3 C. Walling and A. R. Lepley J. Amer. Chem. SOC.,1972 94 2007. l4 S. R. Fahrenholtz and A. M. Trozzolo J. Amer. Chem. SOC.,1972,94 282. Is N. A. Porter L. J. Marnett C. H. Lochmiiller G. L. Gloss and M. Shobataki J. Amer. Chem. Sac. 1972 94 3664. I. H. Sadler D,C,Cl + Cl,C.CO.CCI D5C6bC, J \r/ HCI radical pair 1 C6D,.C,H,C13 (A)+ C13C-CO-CHC12 (E) (1) (2) Scheme 2 3) show clearly that (a)photolysis of (4)only causes isomerization to the cis-compound (3) which decomposes thermally at room temperature; (b) loss of nitrogen does not occur via concerted cleavage of both C-N bonds but by a step- wise process involving the radical pair (5); and (c)the cis-compound undergoes thermal isomerization to the trans-isomer via the pair (5).The observation" of N=N / Ph (3) \CMe,Ph \ PhN,. *CMe,Ph -+ Ph. eMe,Ph + N, 11 J (5) \ / Ph \ free radicals N=N \ CMe,Ph (4) Scheme 3 multiplet effects (E/A) for the protons and to the carbon-magnesium bond obtained during the formation of Grignard reagents from ethyl and isobutyl iodides provides strong evidence that Grignard reagents are formed largely if not exclusively by radical routes.An unusual CIDNP spectrum has been obtained" during the photolysis of 2-phenylisobutyraldehyde in benzene. Cumene formed from a cumyl-formyl radical pair exhibits multiplet polarization (A/E)for the methyl triplet but pure l6 H. W. H. J. Bodewitz C. Blomberg and F. Bickelhaupt Tetrahedron Letters 1972,281. K. Schaffner H. Wolf S. M. Rosenfeld R. G. Lawler and H. R. Ward J. Amer. Chem. SOC.,1972 94 6554. Physical Methods-Part (ii) Nuclear Magnetic Resonance emission for the methine proton resonance. This is however consistent with a triplet multiplicity of the precursor and the extremely large hyperfine splitting in the formyl radical. Discrepancies between the simulated and observed multiplet patterns for the methine proton are explained by the difference in spin- lattice relaxation times (TI) of the methine and methyl protons.Under such conditions an anomalously large net enhancement is to be expected.’* Evidence is presented however which shows that in this system the CIDNP effects arise from a minor pathway involving triplet-born radical pairs and that the principal pathway to the products is a concerted process. Roth has examined” the triplet-sensitized and non-sensitized photodecomposition of diazornethane in toluene. In the former case a multiplet effect (A/E) was observed for triplet ethylbenzene consistent with formation oia a benzyl-methyl radical pair generated via a triplet precursor. In contrast no polarized signals were observed during the non-sensitized reaction although ethylbenzene was formed in high yield.This indicates that radical pairs are not involved in the latter case and that ethylbenzene formation from singlet methylene occurs via a one-step inser- tion process. The photolysis of the diazocyclohexadienones (6) and (7) in cyclo- hexane and carbon tetrachloride yields CIDNP spectra which indicate that the carbene (8) reacts in the singlet state whereas its di-t-butyl derivative (9) behaves as a triplet.20 A detailed analysis has been given2’ of the CIDNP spectra obtained during the photolysis of di-t-butyl ketone. N (6) R = H (8) R = H (7) R = CMe (9) R = CMe Remarkably few studies of carbon-13 CIDNP have been reported One obvious advantage over proton CIDNP is the possibility of observing tertiary radical sites.The initial work by Lippmaa and co-workers demonstrated” that the magnitude of polarization for I3C nuclei could be at least an order of magni- tude larger than for protons. Polarized 13Csignals for benzene (E) carbon di- oxide (E),biphenyl (A),and phenyl benzoate (A),formed during the thermolysis of a 25% solution of benzoyl peroxide in cyclohexanone were readily visible during a single scan at natural abundance levels under conditions where signals from unpolarized 3Cnuclei in the peroxide and reaction products did not exceed K. Muller and G. L. Closs. J. Amer. Chem. Soc. 1972 94 1002. l9 H. D. Roth J. Amer. Chem. Soc. 1971,94 1761. *’ M. L. Kaplan and H. D. Roth J.C.S. Chem.Comm. 1972 970. *’ M. Tomkiewicz A. Groem and M. Cocivera J. Chem. Phys. 1972 56 5850. 22 E. Lippmaa T. Pehk A. L. Buchachenko and S. V. Rykov Chem. Phys. Letters 1970 5 521. 24 I. H. Sadler the noise level. Such high concentrations of reagents are not always practicable and it is often necessary to time-average over 15-30 scans and employ proton noise decoupling to obtain satisfactory CIDNP spectra. Decoupling of the hydrogen nuclei has no measurable effect on the total intensity of a polarized I3C resonance. Normally only the 13C nuclei comprising or adjacent to the radical site show polarization. Multiplet effects only observable in the absence of proton noise decoupling are in general very weak in comparison with net effects.A more recent studyz3 of the decomposition of benzoyl peroxide in tetrachloroethylene confirms the earlier results.2 Most polarization results from spin selection in benzoyloxyl-phenyl radical pairs. The polarization of the major product trichlorostyrene (E) arises from the addition of a polarized phenyl radical to the solvent followed by rapid loss of chlorine. The signs of the product polarizations are in accordance with Kaptein's rule' for net effects. In some instances polarized signals were observed for as long as two hours after the start of the reaction. The above studies employed conventional continuous- wave techniques which necessarily restrict spectrum accumulation to within a small frequency range for very fast reactions. The use of pulsed Fourier- transform techniques enables the observation of the whole '3C chemical-shift range within seconds.It should then be possible to follow the time dependence of polarization at relatively close intervals providing it is possible to store separately the accumulated free induction decays from each batch of pulses. Such a technique has been employed to study the alkali-metal reduction24 of p-methoxybenzenediazonium fluoroborate. The observed polarized signals can be interpreted in terms of the intermediacy of a free-radical encounter between CH30C,H4. and CH30C,H4-N2-O* radicals ;however a detailed discussion is not given. The first report25 of nitrogen-15 CIDNP indicates the intermediacy of a radical pair in the azo-coupling reaction of benzenediazonium fluoro borate with alkaline solutions of phenol a reaction generally considered as electrophilic substitution.Strong polarization of the "N signals of both the product and the diazonium salt is consistent with a mechanism involving a reversible electron transfer as the first step (Scheme 4). ArA2 + 00-[ark -00]+ ArN=N Scheme 4 Several examples of fluorine-19 CIDNP have appeared. Some unusual emission-absorption patterns have been observed26 for the '9F resonance of 23 E. M. Schulman R. D. Bertrand D. M. Grant A. R. Lepley and C. Walling J. Amer. Chem. SOC.,1972,94 5972. 24 S. Berger S. Hauff P. Niederer and A. Rieker Tetrahedron Letters 1972 2581. zs N. N. Bubnov K. A. Bilevitch L. A. Poljakova and 0.Y. Okhlobystin J.C.S. Chem. Comm. 1972 1058.26 D. Bethell M. R. Brinkman and J. Hayes J.C.S. Chem. Comm. 1972 475 1323. Physical Methods-Part (ii) Nuciear Magnetic Resonance 25 2,2-diaryl-l-phenylethylfluorides obtained by the insertion of diarylmethylene into the benzylic C-H bond of benzyl fluoride. The use of diphenylmethylene leads to a fluorine quartet that is polarized AAEA at 56 MHz. At 94 MHz the emission intensity is greatly reduced and the third and fourth lines are split into doublets. This unusual behaviour is thought to result from the coupling of the polarized I9F nucleus with a polarized vicinal proton which is undergoing more rapid nuclear spin relaxation. The changes in '9Fpolarization patterns obtained using substituted diarylmethylenes are attributed to different g-values of the radicals within the pairs.Differences between the polarized and corresponding product 9Fresonances obtained27 during the decomposition of benzoyl peroxide in benzyl fluoride are interpreted in terms of the formation of a methylenecyclohexadiene intermediate which undergoes rearrangement to the isolable a,&-difluorobibenzyl (Scheme 5). 2PhkHF -P --* Ph-CHFCHF-Ph CHFPh Scheme 5 Low-field Studies.-Although polarizations resulting from reactions carried out at zero or low magnetic field (< 100G) have received comparatively little atten- tion two similar have appeared to account for the observed effects. Both are extensions of the radical-pair theory for high fields and differ only in the method of averaging the spin character of the radicals over the time during which they are eligible to react.In such experiments it is necessary to consider the mixing of the electronic singlet state (S) with all three triplet states (T+ To,T-). For reactions carried out in zero fields the resulting n.m.r. spectra show unusual characteristics. For two coupled groups of equivalent nuclei the low-field line of the upfield multiplet and the high-field line of the downfield multiplet are absent. Such an effect is observed during the photolysis of pro- pionyl peroxide in carbon tetrachloride-bromotrichloromethane mixtures where the low-field multiplet (CH,) of ethyl bromide shows three lines (A) and the high-field multiplet (CH,) two lines (E). In high-field reactions both resonances exhibit multiplet effects (AIE).Kaptein's rule for multiplet effects may be used for zero-field spectra providing that E/A is interpreted now as E for all resonances of nuclei appearing downfield in the spectrum and A for the upfield group. For reactions run in low and intermediate fields zero-field effects are modified by the relative contributions of S-T and S-To mixing. Unlike S-To transitions S-T transitions involve changes in nuclear spin. For a single group of nuclei polariza- tion resulting from S-T mixing is opposite for singlet and triplet precursors as 27 D. Bethell M. R. Brinkman and J. Hayes J.C.S. Chem. Comm. 1972 1324. 28 R. Kaptein and J. A. den Hollander J. Amer. Chem. SOC.,1972 94 6269. 29 J. I. Morris R. C. Morrison D. W. Smith and J. F. Garst J.Amer. Clrem. SOC.,1972 94 2406. 26 I. H. Sadler for S-To mixing but unlike the high-field case is the same for geminate recombina- tion products and for transfer products. In the case of a one-proton radical pair in a low magnetic field polarization results from S-T mixing only and can be shown to vary both in magnitude and sign with the field strength. The particular variation pattern that is observed depends upon the hyperfine coupling constant and electron-exchange integral. In some cases a double change in sign is predicted and this has been observed2’ for the proton resonance of chloroform formed during the photolysis of di-isopropyl ketone in carbon tetrachloride. Later work3’ has shown that the observed oscillation for the field dependence of the chloroform polarization may be reproduced using a zero exchange integral (J = 0) provided that all the protons and all the chlorine nuclei in the radical pair are included in the calculation.Similarly good agreement with experiment is obtained for high-field studies using J = 0 when all the nuclei coupled to the free electrons of the radicals even those which do not normally affect the n.m.r. spectrum are included. Since this parameter was previously assumed to have a value comparable with the hyperfine couplings and was chosen to give the best agreement with experiment its elimination is welcomed. It appears that the field dependence of low-field polarization will provide a good method for testing theoretical models of the radical-pair theory and the parameters involved.2 Fourier-transform Spectroscopy Carbon-13 Techniques and Results.-An excellent book3’ on 13C magnetic resonance aimed at the organic chemist and a collection32 of 500 assigned I3C n.m.r. spectra have appeared. It is now generally accepted that carbon-13 chemical shifts should be referenced to tetramethylsilane and a useful list33 of chemical shifts for common n.m.r. standards and solvents has been compiled. Natural-abundance carbon-13 spectra are largely obtained by Fourier-transform (FT) technique^.^^ While raising ’3C spectroscopy from the province of the specialist to the position of a routine operation FT spectroscopy has a number of deficiencies. Since the various 13Cnuclei in a molecule have different relaxation times (TI)and when proton noise decoupling is employed have dif- ferent nuclear Overhauser enhancements (NOE) large variations in line intensi- ties are observed often making integration pointless.This problem may be overcome by the addition of paramagnetic metal ions to reduce the Tl relaxa-tion times of the nuclei and thus eliminate the Overhauser effect. Such reagents however must be stable inert and soluble in organic reagents cause no contact or pseudocontact shifts and not seriously affect the T2 relaxation times so that 30 Ref. 28 footnote 24. ’’ G. C. Levy and G. L. Nelson ‘Carbon-13 Nuclear Magnetic Resonance for Organic Chemists’ Wiley New York 1972. ’’ L. F. Johnson and W. C. Jankowski ‘Carbon-13 NMR Spectra’ Wiley New York 1972.” G. C. Levy and J. D. Cargioli J. Mugn. Resonance 1972 6 143. 34 T. C. Farrar and E. D. Becker ‘Pulse and Fourier Transform NM R’ Academic Press New York 1971 ;R. Bell ‘Introduction to Fourier Transform Spectroscopy’ Academic Press New York 1972. Physical Methods-Part (ii) Nuclear Magnetic Resonance 27 undue broadening of resonances does not occur. Tris(acety1acetonato)-chromium(r1r) has been used effe~tively,~ in particular for organometallic car- bony1 compounds. At concentrations of relaxation reagent below 0.05 moll-’ negligible line broadening occurs and good intensity ratios are obtained. Similar results have been obtained36 for organic compounds using the corresponding iron(rI1) complex. Such relaxation reagents enable the pulse repetition rate to be increased thus allowing a shorter total time for a given quantity of material.The presence of paramagnetic species however would be inadvisable where line 13C-intensities from CIDNP reactions were required. The use of a gated proton- decoupling te~hnique,~’ however can suppress and virtually eliminate the NOE without affecting relaxation. In such an experiment the proton irradiation is switched on just (ca.0.1 s) before the I3Cexcitation pulse and switched off imme-diately after the acquisition (ca. 1 s) of the free induction decay (f.i.d.). Since the decoupling effect is almost instantaneous but the Overhauser intensity increase requires a time of the order of the T1 values for I3C then for many small and medium-sized molecules no signal enhancement is observed.A short delay (ca. 1 s) is required between the end of the acquisition of the f.i.d. and the next pulse. By varying the pre-irradiation time (t) of the proton resonances it is possible to measure both TI and the nuclear Overhauser enhancement,* since the signal intensity (S,)is given by S -S = (S -So) exp (-t/T,) where S is the signal observed with continuous decoupling. The reverse switch- ing of the decoupler so that it remains on at all times except during pulsing and acquisition of the f.i.d. yields un-decoupled spectra with Overhauser enhance- ments. In this operational mode a pulse delay of the order of TI is required which in some instances may result in no greater signal-to-noise ratio in a given period than would be obtained by continuous pulsing with no decoupling field.A technique referred to as selective-saturation Fourier transform (SSFT) has been described3* for the selective removal of any line in the transformed spectrum. A relatively long (1-2 s) burst of a single 13C radiofrequency is applied during the delay period between the end of the accumulation of one f.i.d. and the next pulse. This is of particular value for the removal of strong solvent ’3C resonances or for selectively saturating the major signal in studies of 13C-13Cinteractions in highly enriched samples. In a related technique,39 the decoupling power is swept rapidly (40 kHz s-’) over a selected region of the 13C spectrum during the delay period. This has been used to irradiate regions of 13C satellite resonances 35 0.A.Gansow. A. R. Burke and G. N. La-Mar J.C.S. Chem. Comm. 1972 456. 36 S. Barcza and N. Engstrom J. Amer. Chem. SOC., 1972.94. 1763. 37 R. Freeman H. D. W. Hill and R. Kaptein 1. Magn. Resonance 1972 7. 327. 3* J. Schaefer J. Mugn. Resonance 1972 6 670. 39 H.C. Darn and G. E. Maciel J. Phys. Chem. 1972 76 2972. * Unfortunately two definitions prevail at present and are not always clearly differen- tiated if a peak intensity in the absence of NOE is taken as unity then q is the relative increase in intensity. Sometimes however the roral relative intensity of the peak i.e. (I + q) is taken as the NOE. 28 I. H. Sadler in proton-noise-decoupled '3C spectra to assign '3C resonances where conven- tional off-resonance proton decoupling is not conclusive.A graphical method has been presented4' for the unambiguous assignment of 13C resonances using selective off-resonance decoupling. In such experiments the residual splitting (J,) and the coupling constant (JCH)are given by the expres- sion; yH2/271 = J, Av/J, providing that the decoupling power (?jH,/271) is considerably greater than the separation (Av) of the proton irradiation frequency and the resonant frequency of the proton causing the splitting. Under these circumstances J varies linearly with Av and by plotting the peak frequencies in the 3C spectrum against the proton irradiation frequencies straight lines are obtained which intersect at the chemical shifts of the directly bonded 13C and 'H nuclei.Where proton assignments are known it is possible to assign I3C nuclei unambiguously and oice versa. It is particularly applicable to closely spaced resonances where overlap may render the measurement of residual couplings difficult. In this manner it has been possible to assign4' the 13C resonances in NAD' and to correct41 misassignments in the proton spectrum of NADH. Non-linear plots are obtained however if the range of proton irradiation fre- quencies is too wide and/or where only a low decoupling power is employed since under such circumstances the above equation is not valid.42 Numerous papers have been concerned with the measurement and additivity relationships of 13C chemical shifts and 13CH coupling constants. The effect of deuterium substitution on the chemical shifts of benzene and a number of mono- substituted derivatives has been examined.43 The deuterium-bearing carbon atoms are shifted upfield by ca.0.3p.p.m. and the adjacent carbon atom by ca. 0.1 p.p.m. Deuterium shifts caused by deuterium labelling have been used for the assignment of I3C resonances in dim ethyl nor born an one^^^ and to assist in mechanistic studies of hom~enolization.~~ A of monohalogenobenzenes emphasizes the electronegativity dependence of the l3C-H coupling constant and shows that the three-bond couplings are larger in magnitude than the two-bond couplings. Substituent contributions to the 13C chemical shifts and 13C-H coupling constants for the monohalogenobenzenes calculated relative to benzene also account on an addi- tivity basis for observed couplings in a large number of symmetrical ortho-and meta-dihalogenobenzenes.Evidence for a Karplus-type relationship for vicinal three-bond '%-H couplings comes from a study4' of the rigid C(2)-enriched anhydrouridine derivatives (10)and (11).Dihedral angles were estimated from molecular models and the corresponding couplings in uridine suggest that it 40 B. Birdsall N. J. M. Birdsall and J. Feeney J.C.S. Chem. Comm. 1972 316. 41 B. Birdsall and J. Feeney J.C.S. Perkin ZI 1972 1643. 42 K. G. R. Pachler J. Magn. Resonance 1972,7,442. 43 R. A. Bell C. L. Chan and B. G. Sayer J.C.S. Chem. Comm. 1972 67. 44 J. B. Stothers C. T. Tan A. Nickon F. Huang R. Sridhar and R. Weglein J. Amei-. Chem. SOC.,1972,94,8581.4s D. H. Hunter A. L. Johnson J. B. Stothers A. Nickon J. L. Lambert and D. F. Covey J. Amer. Chem. SOC.,1972,94,8582. 46 A. R. Tarpley and J. H. Goldstein J. Phys. Chem. 1972 76 515. 47 R. U. Lemieux T. L. Nagabhusan and B. Paul Canad. J. Chem. 1972,50 773. Physical Methods-Part (ii) Nuclear Magnetic Resonance 0 H HO H (10) adopts the anti-conformation in solution. Recent INDO-MO calculation^^^ show that the conformation dependence of the three-bond 13C-H coupling (,JCH) in propane follows the relation 35,-H= 4.26 -1.00 cos4 + 3.56 cos24 where +is the dihedral angle. The values for the uridine derivatives lie approxi- mately 0.5-1.0 Hz below the curve for propane. Unfortunately very few data are available at present for testing the generality of the relation.A few papers are devoted to the measurement and correlation of 13C-13C coupling constants. These have been obtained by continuous-wave methods49 on singly and doubly labelled compounds or at natural abundance by examina-tion of 13C satellites of 3C resonances by Fourier-transform techniques with proton noise decoupling. Low values (10-15 Hz) in cyclopropane derivatives4' confirm the low s-character of the ring bonds. Couplings in Hi3C-I3C systems to are pr~portional~~ l3C-H couplings (Jcc = 0.27JCH)in similar bonding situations as predicted and observed earlier" for the correlation of carbon-proton and proton-proton couplings (JCH= 0.3 JHH). This close agreement suggests that the coupling mechanisms are similar.In ethyl isopropyl and t-butyl derivatives H3'3C-'3C coupling increases with the number of methyl groups.51 Coupling constants between the a and ring carbons in a series of benzyl compounds PhCH2X where X = CH, CH,OH CH,Cl C02H COCI or CN have been determined.52 Coupling to the rneta-carbon atom is greater than to the ortho-carbon atom (3J3,> 2J2a),and the one-bond coupling 'Jla increases with the degree of s-character of the a-carbon atom and the electronegativity of the substituent. Other uses of I3C n.m.r. spectroscopy include (a) the determinations3 of keto-enol ratios in acetylacetone ethyl acetoacetate isopropylidene malonate 48 R.Wasylishen and J. Schaefer Canad. J. Chem. 1972,50,2710. 49 F. J. Weigert and J. D. Roberts J. Amer.Chem. SOC.,1972,92,6021. G. J. Karabatsos J. D. Graham and F. M. Vane J. Amer. Chem. SOC..1962,84 37. K. D. Summerhays and G. E. Maciel J. Amer. Chem. SOC.,1972,94,8348. 52 A. M. Ihrig and J. L. Marshall J. Amer. Chem. SOC.,1972,94 1756. 5J J. H. Billmann S. A. Sojka,and P. R. Taylor J.C.S. Perkin II 1972 2034. 30 I. H. Sadler and ascorbic acid in which good agreement was obtained with ratios found by other analytical methods ; (b) the ob~ervation~~ of helix-coil transitions in polypeptides ;(c) the conformational analysis of methylcyclohexanes5 ’and of methylcycloheptane derivatives ;56(6)the demonstration” that small branches in low-density polyethylene are n-butyl groups thus supporting a previous sug- tion of an intramolecular hydrogen-abstraction process taking place during polymer formation ; and (e) the study58 of transannular interactions in eight-membered-ring carbonyl compounds.A method has been described59 to obtain high-resolution n.m.r. spectra of rare (e.g. 13C. ”N 2H) or chemically dilute magnetic nuclei in solids. However the practical aspects render it unusable at present for the majority of chemists. Carbon-13 Relaxation Studies.-Spin-lattice relaxation times (Tl) for I3Cnuclei are largely measured with complete proton decoupling by inversion-recovery,” saturation-recovery,6 or progressive-saturation62 Fourier-transform tech-niques. These methods are successful but can be very time-consuming particu- larly where TI is long. A method has been proposed63 for reducing the time required in these experiments.Measurements of line intensities S, S are obtained at two different pulse intervals t = a and t = b. The ratio of the two intensities of a given resonance is given by the expression S -1 -Kexp(-a/T,) I -S 1 -K exp (-b/T,) K = 2 for inversion-recovery method ; K = I for saturation methods. This intensity-ratio method applied to progressive saturation has been made the basis of a programme which automatically selects the pulse intervals to optimize the determination of TI. This method when applied to the I3C spectrum of cortisone acetate gives results in good agreement with those obtained by the conventional inversion-recovery technique. A theoretical treatment has appeared64 which indicates that in the absence of proton irradiation the apparent TI can differ significantly from the proton- decoupled value and tends to be longer when measured by pulse methods and shorter when measured by adiabatic rapid-passage (a.r.p.) techniques.Experi- mental results for benzene are in agreement with the proposals. Under proton- 54 L. Paolillo T. Tancredi P. A. Temussi E. Trivellone E. M. Bradbury and C. Crane- Robinson J.C.S. Chem. Comm. 1972 335; C. Boccalon A. s. Verdini and G. Giacometti J. Amer. Chem. SOC. 1972 94 3639. 55 D. K. Dalling and D. M. Grant J. Amer. Chern. SOC.,1972,94 5318. 56 J. D. Roberts and M. Christl J. Org. Chem. 1972 37 3443. 57 D. E. Dorman E. P. Otocka and F. A. Bovey Macromolecules 1972 5 574. 58 T. T. Nakashima and G. E. Macial Org.Magn. Resonance 1972 4 321. 59 A. Pines M. G. Gibby and J. S. Waugh J. Chem. Phys. 1972,56 1776. 6o R. Freeman and M. D. W. Hill J. Chem. Phys. 1970,53 4103. J. L. Markby W. J. Horsiey and M. P. Klein J. Chem. Phys. 1971 55 3604. 62 R. Freeman and H. D. W. Hill J. Chem. Phys. 1971,54 3367. 63 R. Freeman H. D. W. Hill and R. Kaptein J. Magn. Resonance 1972,7 82. 64 T. D. Alger R. Freeman and D. M. Grant J. Chem. Phys. 1972 57 2168. Physical Methods-Part (ii) Nuclear Magnetic Resonance 31 decoupled conditions the same value for Tl is obtained by both methods and can be regarded as valid. The measurement of nuclear Overhauser enhancements (q) together with Tl relaxation times can provide information concerning the relaxation mechanisms.Since the Overhauser effects arise only from I3C-' H dipole-dipole (d.d.) inter- actions the contribution TIdd due to this mechanism can for most small or average organic molecules be obtained65 from Tl according to the equation Tlddy,T1/2y,qcH and separated from contributions TIo,from other relaxa- = tion mechanisms viz. 11 1 -=----Tl 7-,dd T," + Other relaxation mechanisms include spin rotation (s.r.) chemical shift anisotropy (c.s.a.) scalar coupling (s.c.) and intermolecular processes caused for example by the presence of paramagnetic species such as dissolved oxygen. Since the dipolar contribution is related to the effective correlation time T~, in some cases it is possible to estimate barriers to rotation which are outside the range normally covered by variable-temperature n.m.r.studies. In the absence of relaxation processes other than d.d. takes the maximum value of 1.988 providing that molecular reorientation is sufficiently rapid (>10" rad s-I). This is not the case for large macromolecules where the NOE is reduced since the dipolar relaxation is affected by relatively slow segmental motion of the molecule. Theoretical treatments of the behaviour of the NOE and of relaxation times in such cases have been given.66 13C Spin-lattice relaxation in benzene67 is essentially by a d.d. mechanism (q = 1.6) with significant contributions from either s.r. or c.s.a. processes. In monosubstituted benzenes containing carbon oxygen or nitrogen as substi- tuents the d.d. mechanism again dominates.The carbon atom para to the substi- tuent shows faster relaxation than do the ortho-and rneta-carbon atoms indicating preferred rotation of the molecule about the axis bisecting the substi- tuent and the ring. Relaxation of the methyl carbon in toluene is dominated by spin rotation. The variation of TI with magnetic field strength together with NOE measurements on 1,4-diphenylbutadiyne (12) (Tl values in seconds) show6* that 60% of the relaxation of the P-carbon arises from a c.s.a. mechanism at 23 kG the remaining 40% being largely d.d. In the only previous example 65 K. F. Kuhlman D. M. Grant and R. K. Harris J. Chem. Phys. 1970 52 3439. 66 J. Schaefer and D. F. S. Natusch Macromolecules 1972 5 416; D. Doddrell V. Glushko and A. Allerhand J.Chem. Phys. 1972 56 3683. " G. C. Levy J.C.S. Chem. Comm. 1972,47. 68 G. C. Levy D. M. White and F. A. L. Anet J. Magn. Resonance 1972,6,453. 32 I. H. Sadler (carbon disulphide) where c.s.a. has been established this mechanism only contributes at very low temperatures and high field strength^.^^ In bromo- benzene,70 the relaxation of 13C nuclei bonded to bromine is dominated by scalar relaxation with 79Br and by scalar and/or d.d. relaxation with *'Br. A zero value for q indicates the absence of 13C-lH d.d. relaxation. Since the gyromagnetic ratios of 13C 79Br and 81Br are very nearly the same interactions are not un- expected. TI Measurements on substituted ferrocenes indicate7' that the rings are able to spin with respect to each other within the molecule independent of the overall tumbling of the molecule.A dynamic method for the measurement of Tl and NOES has been used72 to show that the 13Crelaxation of the 1- and 3-methyl groups in 1,2,3-trimethyl- benzene and 1,2,3,5-tetramethyIbenzeneis dominated by a d.d. mechanism but that a substantial s.r. contribution is present for the 2-methyl group and the 5-methyl group (where applicable). Comparison of T:* values for these carbon atoms and the unsubstituted ring carbon atoms confirms that the 2-methyl group is essentially a free rotor. The rotational barrier for the other methyl groups is estimated at ca. 1.5 kcal mol- *,in good agreement with values expected from other estimates. Analogous situations were previously dern~nstrated~~ in mesitylene and o-xylene.The slight variation of q Tl ,and T:d with magnetic field strength suggested the minor participation of a c.s.a. relaxation process. A number of smaller molecules have also been studied. Increased rotational free- dom at the free ends of the butyl groups in di-n-butylamide has been observed.74 A study7' of acetone l,l,l-trichloroethane dimethyl sulphoxide t-butyl chloride and methyl acetate shows the relative contributions of d.d. and s.r. mechanisms in each case and gives rotational barriers for the methyl group that are in good agreement with literature values. Relaxation in chloroform methanol and the methyl carbon in acetic acid is mainly uia a d.d. process with s.r. becoming impor- tant at higher temperatures for methanol.76 Methyl iodide and carbon di- sulphide (except as noted above) are dominated by s.r.; for bromoform scalar relaxation is probably the major process.76 For small medium and symmetric molecules the following observations can be made. (i) Relaxation for 13Cnuclei bonded to one or more protons is mainly dipolar and relatively unaffected by the presence of small amounts of dissolved oxygen. (ii) For non-protonated nuclei degassing is essential since relaxation by oxygen can become very significant. (iii) Spin rotation becomes significant for freely rotating methyl groups. (iv) Chemical shift anisotropy is not generally significant. (v) Scalar relaxation only contributes when a quadrupolar nucleus such as Br is directly bonded to the 3C 69 H.W. Spiess D. Schweitzer U. Haeverten and K. H. Hausser J. Mugn. Resonance 1971 5 101. '' G. C. Levy J.C.S. Chem. Comm. 1972 352. 71 G. C. Levy Tetrahedron Letters 1972 3709. 72 T. D. Alger D. M. Grant and R. K. Harris J. Phys. Chem. 1972,76,281. 73 K. F. Kuhlmann and D. M. Grant J. Chem. Phys. 1971,55,2998. 74 G. L. Levy and G. L. Nelson J. Amer. Chem. SOC. 1972,94 4897. '' J. R. Lyerla and D. M. Grant J. Phys. Chem. 1972 76 3213. 76 T. C. Farrar S. J. Druck R. R. Shoup and E. D. Becker J. Amer. Chem. SOC.,1972 94. 699. Physical Methods-Part (ii) Nuclear Magnetic Resonance 33 nucleus. (vi) Intermolecular effects although not usually important for '3C nuclei can be reduced or eliminated by working in dilute solution in a mag- netically inert solvent.Measurements of spin-spin relaxation times (T2)are comparatively rare. The most promising approach appears to be by the measurement of TIP,which is essentially equal to T in The spin-echo method (SEFT)has been used78 to measure T for 13C nuclei (and also 2H,'H and "F) in benzene methyl iodide toluene carbon disulphide and other small molecules. The authors suggest that a good approximation to T which is of general validity for organic molecules is given by 1 1 1 T2(13C)-T,(13C)+-2T,('H) Clearly the acceptance of this will depend upon the availability of data. The value of SEFT as a generally applicable method for the measurement of T2 is however q~estionable.~~ Other Nuclei.-The use of Fourier-transform methods in 'H n.m.r.spectroscopy while not necessary for the majority of studies allows the observation of molecules in very high dilution. The spectra of aziridine and N-deuterioaziridine have been obtainedSo in the gas phase to minimize intermolecular effects and barriers to inversion of 17.3 kcal mol- ' (68 "C) and 17.9 kcal mol- (79 "C) have been estimated. The same sort of spectral simplification obtained in a proton-noise- decoupled xiatural-abundance '3Cn.m.r. spectrum may be obtained by examin- ing 'fully' tleuteriated molecules containing randomly distributed H nuclei under conditions employing 2H decoupling. The spectra obtained are then first- order.81 All the proton resonances are visible as single lines for example using commercial perdeuteriomethylcyclohexane (1.1 % H).Since methods are avail- able for the synthesis of deuterio-compounds containing small amounts of randomly distributed 'H this procedure should be useful for simplifying complex 'H n.m.r. spectra although it should be remembered that small but not neces- sarily negligible isotopic shifts in resonance positions may occur. Fourier-transform spectroscopy is particularly suited to the study of the behaviour of biological mcllecules at very low concentrations (10-4-10-moll-l) in aqueous solutions. Even using deuterium oxide instead of water the intensity of the residual HDO resonance may exceed the resonances of interest by 2-3 orders of magnitude. Apart from obscuring the region of interest and possibly intro- ducing beat frequencies in the remainder of the spectrum this may result in the dynamic range of the computer being exceeded before sufficient desirable signal 77 R.Freeman and H. D. W. Hill J. Chem. Phys. 1971,55 1985. 78 U. Haeberlen H. W. Spies and D. Schweitzer J. Magn. Resonance 1972,6 39. '' T. C. Farrar A. A. Maryott and M.S. Holmberg Ann. Rev. Phys. Chem. 1972 23 193. Bo R. E. Carter and T. Drakenberg J.C.S. Chem. Comm. 1972 582. J. J. Katz G. N. McDonald and A. L. Harkness J.C.S. Chem. Comm. 1972 542. 34 I. H. Sadler is obtained. This may be overcome in principle by block-averaging the trans- forms. In practice this requires accurate phase setting for the first block which may prove difficult on the weak signals. A number of methods for the reduction or elimination of the residual HDO resonance have been reported.Water-eliminated Fourier-transform spectroscopy82 (WEFT) makes use of the large difference in TI between the resonances of large molecules (< 1 s) and HDO in D20 solution (5-15 s). Use of the 'inversion-recovery' pulse sequence (T-180"-t-90"), where Tis a relatively long waiting period [35Tl(HDO)] and t the time required for the HDO resonance to acquire zero magnetization eliminates HDO from the spectrum. Shorter values of Tand t may be used providing that t 3 5T,-(sample). An alternative sequence (180"-HSP-t-90"-T) where HSP is a homogeneity-spoiling pulse which destroys any residual transverse magnetiza- tion has also been proposed.83 The useg3 of a steady-state sequence of pulses (90"-T) with pulse interval T < T,(HDO) considerably reduces the intensity of the HDO resonance in comparison with signals of shorter relaxation times but does not eliminate it.The method is useful if the signals of interest are not in the regior of the HDO resonance. The possibility of obtaining nitrogen- 15 n.m.r. spectra at natural-abundance levels has recently been dem~nstrated.~~ Two major problems arise. First TI tends to be long particularly where the 15Natom possesses no directly bonded protons thus necessitating long pulse delays. Secondly considerably reduced or zero signals may result when proton noise decoupling is employed since the full negative nuclear Overhauser effect resulting in an inverted signal may be in part offset by non-dipolar relaxation processes which would not affect the normal positive signal.The addition of small amounts of bis(acety1acetonato)- chromium(rr1) to the sample overcomes these problems to some extent.85 At concentrations above ca. 0.1 moll-',line-broadening becomes apparent. Spectra have been obtained for quinoline," benzamides and ben~onitriles,~ 'methyl- and phenyl-hydroazines,88 and various amine~.*~ In the last-named compounds the 'sN shifts correlate linearly with the 13Cshifts of alkanes derived by replacing the nitrogen atom by an appropriately substituted carbon atom. Only three studies of silicon-29 resonances all continuous-wave have appeared prior to this year. The sensitivity of silicon-29 in natural abundance is only twice that of carbon-13 and the nucleus has a negative nuclear Overhauser effect.A recent Fourier-transform study" of the "Si resonances of tetramethylsilane diphenylsilane and octamethylcyclotetrasiloxane has been reported. It appears that tetramethylsilane would make a good standard above 0 "Csince the NOE S. L. Patt and B. D. Sykes J. Chem. Phys. 1972 56 3182. 83 F. W. Benz J. Feeney and G. C. K. Roberts J. Magn. Resonance 1972,8 114. " R. L. Lichter and J. D. Roberts J. Amer. Chem. Soc. 1971 93 3200; J. M. Briggs L. F. Farnell and E. W. Randall Chem. Cornm. 1971 680. 85 L. F. Farnell E. W. Randall and A. I. White J.C.S. Chem. Comm. 1972 1159. 86 P. S. Pregosin E. W. Randall and A. I. White J.C.S. Perkin II 1972 1. 8i P. S. Pregosin E. W. Randall and A. I. White J.C.S. Perkin II 1972 513.R. L. Lichter and J. D. Roberts J. Amer. Chem. SOC.,1972 94 4904. 89 R. L. Lichter and J. D. Roberts J. Amer. Chem. SOC.,1972,94 2495. '' G. C. Levy J. Amer. Chem. Soc. 1972 94,4793. Physical Methods-Part (ii) Nuclear Magnetic Resonance 35 is very low at room temperature and the spin-lattice relaxation time (TI = 20 s) is relatively short for silicon nuclei. Tl Values for hydrogen-bearing silicon atoms are expected to be about nine times as long as the analogous I3Cvalues. Nuclear Overhauser effects could be removed using gated decoupling method^.^' A large number of 29Si resonances have been obtained” by continuous-wave methods. The shift range is smaller than that for I3Cresonances. 3 Miscellaneous Studies A short reviewg2 and two more comprehensive reviewsg3 have appeared con- cerning the applications of shift reagents.A new readily prepared reagent tris(decafluoroheptanedionato)europium Eu(fhd) (13) has been reported.94 This complex is superior to the generally used reagents Eu(dpm) (14) and Eu(fod) (1 5)in that it is readily soluble in carbon tetrachloride (ca.300 mg rnl- ’) has no proton resonances which could obscure regions of the spectrum and shows somewhat larger shifts for protons remote from the substrate-complexing site. Replacement of europium by other lanthanides results in broadened resonances. A shift reagent of a different kind which combines specifically with amines is CH ,CH ,CH ,CH c=o’ N (13) R’ = Rz = C2F5 (14) R’ = R2 = CMe (15) R’ = CMe,; R’ = C,F H,CCH2CH2CH2 (16) provided95 by iron(n) phthalocyanine.This makes use of the large magnetic anisotropy of the ring system. The resulting complex (16) is diamagnetic and thus no line-broadening occurs. The alkyl resonances appear as clear multiplets over the region 1G14.r and the amine resonance at 175. The specificity of the new reagent should be of value when studying polyfunctional compounds. Y’ R. L. Scholl G. E. Maciel and W. K. Musker J. Amer. Chem. SOC.,1972 94 6376. ” M. R. Peterson and G. H. Wahl J. Chem. Educ. 1972 49 790. ’’ R. von Ammon and R. D. Fischer Angew. Chem. Internat. Edn. 1972 11 675; J. Grandjean Ind. chim. belge 1972 37 220. y4 G. A. Burgett and P. Warner J. Magn. Resonance 1972 8 87. 95 J.E. Maskasky J. R. Mooney and M. E. Kenney J. Amer. Chem. Sac. 1972 94 2132. 36 I. H. Sadler Shifts caused by the lanthanide reagents appear to be essentially of the pseudo- contact type ;96 however in some cases particularly where 7c-systems are in- ~olved,~' a contact interaction is also present and appears to be considerably more pronounced for I3Cnuclei than for protons.98 Increasing contact contribu- tions have been observed along the series Pr(fod) ,Yb(fod) ,Eu(dpm) ,Eu(fod) where substituted pyridine N-oxides and anilines are used as substrates. A method has been given99 for separating the contact and pseudocontact contribu- tions to shifts caused by europium nitrate. The conditions have been clarified"' under which the pseudocontact contribution is given by an expression of the type K(3COS'~ -1)-3 and a simple graphical method for the analysis of induced shifts has appeared.' O1 A new theoretical treatment of lanthanide- induced shifts has been proposed.lo2 Various workers99* 103-10s have studied the variations of the induced shift with concentration of shift reagent (L) and/or substrate (S),in an attempt to elucidate the equilibria involved. However there is disagreement over whether just the firstlo4 or bothIo5 of the equilibria L + SSLS,LS + S LS are necessary to obtain the best description of the systems. Spectra obtained at -80 "C from dideuteriomethylene chloride solutions of Eu(['H9]fod) with excess of dimethyl sulphoxide show resonances due to both the free and complexed substrate and under these conditions each molecule of shift reagent co-ordinates two molecules of substrate.Methods have been devised for the eliminati~n'~' of errors which may arise in plots of induced shift versus L:Sratio and from inaccurate estimates of concentrations and for the automatic sorting of signals in complex shift-reagent spectra. lo' The use of shift reagents for resonance and configuration assignments has been widespread. Chiral shift reagents have been sh~wn''~ to be capable of differentiating between enantiotropic protons at prochiral centres. Tris-[3-hepta- y6 W. D. Horrocks and J. P. Sipe J. Amer. Chem. SOC.,1971 93 6800; J. Reuben and J. S. Leigh J. Amer. Chem. SOC. 1972,94,2789; I. Armitage J. R. Campbell and L. D. Hall Canad.J. Chem. 1972 50 2139. 97 B. F. G. Johnson J. Lewis P. McArdle and J. R. Norton J.C.S. Chem. Comm. 1972 585. y8 A. A. Chalmers and K. G. R. Pachler Terrahedron Letters 1972 4033; R. J. Cushley D. R. Anderson and S. R. Lipsky J.C.S. Chem. Comm. 1972 636; M. Herayama E. Edagawa and Y. Hanyu J.C.S. Chem. Comm. 1972 1343. 99 J. R. M. Saunders S. W. Hanson and D. H. Williams J. Amer. Chem. SOC.,1972,94 5325. loo J. M. Briggs G. P. Moss E. W. Randall and K. D. Sales J.C.S. Chem. Comm. 1972 1180. lo' R. M. Wing T. A. Early and J. J. Uebel Tetrahedron Letters 1972 4153. lo2 B. Bleaney J. Magn. Resonance 1972,8,91; B. Bleaney C. M. Dobson B. A. Levine R. B. Martin R. J. P. Williams and A. V. Xavier J.C.S. Chem. Comm. 1972 791. lo3 D. R. Kelsey J.Amer. Chem. SOC. 1972,94 1764; R. K. Mackie and T. M. Shepherd Org. Magn. Resonance 1972 4 557. Io4 J. A. Wittstruck J. Amer. Chem. SOC.,1972 94 5130; I. Armitage G. Dunsmore L. D. Hall and A. G. Marshal Canad. J. Chem. 1972 50 21 19. lo5 B. L. Shaprio and M. D. Johnston J. Amer. Chem. SOC. 1972,94 8185. lo6 D. F. Evans and M. Wyatt J.C.S. Chem. Comm. 1972 312. '07 J. W. ApSimon and H. Beierbeck J.C.S. Chem. Comm. 1972 172; J. W. ApSimon H. Beierbeck and A. Fruchier Canad. J. Chem. 1972,50 2725. lo' J. W. ApSimon H. Beierbeck and A. Fruchier Canad. J. Chem.. 1972,50 2905. R. R. Fraser M. A. Petit and M. Miskow J. Amer. Chem. SOC. 1972 94 3253. Physical Methods-Part (ii) Nuclear Magnetic Resonance fluoropropylhydroxymethylene-(+)-camphorato]praseodymium(r~~)causes a chemical shift difference of up to 0.8p.p.m.for the benzylic protons in benzyl alcohol and its derivatives. Since the resonances now take the form of an AB quartet a value for the geminal coupling constant JHHmay be obtained. Care must be exercised in obtaining coupling constants from shift-reagent spectra since small changes in J with reagent :substrate ratio are sometimes observed. ' ' Chiral reagents have also been used to distinguish"' between rneso-and racemic diastereomers e.g. 2,3-epoxybutane. The non-chiral reagents Eu(dpm) and Eu(fod) will also induce differential shifting of diastereotopic protons e.g. the IT-methylene protons in 3-phenylpropan-1-01' l2 and the protons of the gern-dimethyl group in the ethylenehemithio-acetal ofmethyl isopropyl ketone.l3 In suitable cases shift reagents have provided a convenient means of varying the coalescence temperature of protons undergoing exchange where the separate resonances are shifted by different amounts. Such variations have been obtained for 4,4,7,7-tetramethy1cyc1ononanone' l4 in carbon disulphide in the presence of Eu(dpm) and for NN-dimethyl derivatives of formamide acetamide and propionamide' '' in tetracyanoethylene in the presence of Eu(fod) . A lanthanide shift reagent substrate ratio (L :S) of 0.5 raises the coalescence temperature of dimethylformamide to 164 "Cfrom 114 "C in the absence of shift reagent. Lower L :S ratios (0.3)are recommended. In this study a steady increase in AG* was obtained suggesting that the method may be helpful in obtaining accurate values of AS*.The method is however restricted to temperatures higher than 10 "C since below this level line-broadening effects and solubility problems arise. The use of total lineshape methods for the determination of exchange rates has been critically examined. 'l6 Serious systematic errors are liable to arise from improper temperature calibration neglect of linewidth changes over the tempera- ture range and ignorance of the temperature dependence of the chemical shifts between the exchanging sites. For these reasons total lineshape analyses should not be extended much above the coalescence temperature. Molecular geometries have been obtained from studies in nematic liquid crystals' l7 for a variety of molecules including cyclohepatrienone,' l8 which shows only slight bond alternation norbornadiene,' l9 1,4-naphthoquinone,' 2o 'lo B.L. Shapiro M. D. Johnston and R. L. R. Towns J. Arner. Chern. SOC.,1972 94 4381. M. Kainosho K. Ajisaka W. H. Pirkle and S. D. Beare J. Amer. Chem. SOC.,1972 94 5924. 'I2 P. S. Mariano and R. McElroy Tetrahedron Letters 1972 5305. 'I' P. Joseph-Nathan J. E. Herz and V. M. Rodriguez Canad. J. Chem. 1972 50 2788. G. Borgen Acta Chern. Scand. 1972 26 1740. H. N. Cheng and H. S. Gutowsky J. Amer. Chem. Soc.. 1972.94. 5505. ' I' R. R. Shoup E. D. Becker and M. I. McNeel J. Phys. Chem. 1972,76 71. 'I' P. Diehl and C. L. Khetrapal 'NMR Basic Principles and Progress' Springer-Verlag Berlin 1969 Vol. I p. 1 ;S.Meiboom and L. C. Snyder Accounts Chem. Res. 1971 4 81. C. A. Veracini and F. Pietra J.C.S. Chern. Comrn. 1972 1262. 'I9 E. E. Burnell and P. Diehl Canad. J. Chem. 1972 50 3566. J. M. Dereppe J. Degelaen and M. van Meerssche Org. Magn. Resonance 1972 4 551. 38 I. H. Sadler and benzonitrile.'21 To assist in such work a computer program SHAPE has been developed,' 22 which starts from trial orientation parameters and nuclear co- ordinates and the experimentally determined direct coupling constants and then determines iteratively the final degree of orientation and shape of the nuclear skeleton by a least-squares procedure. Two papers have been concerned with estimating the shielding effects of the cyclopropane ring. A ring-current model has been used'23 to construct a map from which shielding contributions to chemical shifts may be obtained with only the aid of molecular models good agreement with experimental values being obtained for over 40 compounds of known geometry.A compari~on'~~ of two other approaches the group-anisotropy and bond-anisotropy models indicates that the former is superior in predicting chemical shifts. A new set of tables for the estimation of the shielding effects on protons in the vicinity of a benzene ring has been derived'25 on a quantum-mechanical basis. It is shown that the presently used Johnson-Bovey tables' 26 over-estimate the deshielding effects in planar condensed hydrocarbons but that the new set under-estimates shielding at positions above the rings somewhat more so than the Johnson-Bovey set.Procedures have been described' 27for obtaining relative internuclear distances particularly in three-spin systems from nuclear Overhauser measurements. A number of conclusions have been drawn which are of particular value if the enhancements are to be used in a qualitative manner (a)a zero NOE does not necessarily imply that the two spins are distant since it may result from a cancel- lation of a direct and an indirect effect ;(b)in the absence of chemical exchange a negative NOE between two spins indicates that a third spin lies between them; (c)indirect effects through rapidly relaxing spins or groups of spins e.g. methyl protons are small; (d)the relative values of the enhancements of spin A when other spins are saturated is a better indication of the position of A with respect to those other spins than are their relative enhancements when A is saturated; (e)if qx and qy are the only large enhancements of spin A obtained on saturating spins X and Y then rAX/rAy = (qY/qx)%where TAX is the AX internuclear distance and similarly for rAy.It has been shown'28 experimentally and theoretically that the aromatic solvent-induced shift (ASIS) of a solute depends strongly in magnitude and sign on the internal reference used. It appears to bear virtually no relation to presumed specific interactions between the solute and solvent. Various procedures are described to eliminate the effects of the internal reference. ' C. A. Veracini P. Bucci and P. L. Barili Mol.Phys. 1972 23 59. Iz2 P. Diehl P. M. Henrichs and W. Niederberger Mol. Phys. 1971,20 139. 123 C. D. Poulter R. S. Boikess J. I. Braumann and S. Winstein J. Amer. Chem. SOC. 1972,94,2291. L24 R. C. Hahn and P. H. Howard J. Amer. Chem. SOC.,1972 94 3143. C. W. Haigh and R. B. Mallion Org. Magn. Resonance 1972,4 203. lZbC. E. Johnson and F. A. Bovey J. Chem. Phys. 1958 29 1012. '" R. E. Schirmer and J. H. Noggle J. Amer. Chem. Soc. 1972 94 2947. Iz8 F. H. A. Rummens and R. H. Krystynak J. Amer. Chem. Sor. 1972,94 6914. Physical Methods-Part (ii) Nuclear Magnetic Resonance Heteronuclear 1H-(2Dj INDOR spectroscopy has been used for the first time to measure' 29 deuterium chemical shifts notably in [2H,]acetone [2H,]benzene ['H ,]dimethyl sulphoxide and 1,2,5,6-di-O-isopropylidene-a-~-[3-Hlallofura-nose.It is emphasized that the values for the first three compounds will differ slightly from those of the related perdeuterio-derivatives. The following aspects and applications of n.m.r. have been reviewed :organo-phosphorus compounds ;I3' the assignment of stereochemistry about double bonds ;l 'conformational studies of cyclic polypeptides ;'32 the analysis and classification of AA'XX'and AA'BB' systems in 'H n.m.r. the effect of solvents on coupling constants high-field studies ;l 35 the orientation of molecules in electric fields recent developments,'37 and general aspects.l3' 129 J. R. Campbell L. D. Hall and P. R. Steiner Canad. J. Chem. 1972 50 504. 130 B. I. Ionin and T. N. Timofeeva Russ.Chem. Reu. 1972 41 390. 131 G. J. Martin and M. L. Martin Progr. N.M.R. Spectroscopy 1972 8 163. 132 F. A. Bovey A. 1. Brewster D. J. Patel A. E. Tonelli and D. A. Torchia Accounts Chem. Res. 1972 5 193. 133 H. Gunter Angew. Chem. Internat. Edn. 1972 11 861. S. L. Smith Fortschr. Chem. Forsch. 1972 27 117. 135 A. A. Grey Canad. J. Spectroscopy 1972 17 82. 136 C. W. Hilbers and C. MacLean in 'NMR Basic Principles and Progress' Springer- Verlag Berlin 1972 Vol. 7 p. 1. 13' E. D. Becker Appl. Spectroscopy 1972 26 421. 13' P. L. Corio S. L. Smith and J. R. Wasson Anulyt. Chem. 1972 44 407R.

ISSN:0069-3030    

DOI:10.1039/OC9726900019

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

2 Physical Methods Part (iii) Theoretical Organic Chemistry and ESCA ~~~~~ -By D. T. CLARK Department of Chemistry University of Durham 1 Introduction In such rapidly expanding fields it is inevitable and indeed desirable that in a report of this size there has to be a certain amount of selection. As far as theoreti- cal organic chemistry is concerned reasonably complete coverage of develop- ments in applications of non-empirical treatments has been made together with particularly important semi-empirical treatments. The trend clearly evident in last year’s report of detailed studies of systems of real chemical importance rather than yet another calculation of the barrier to rotation in ethane has been main- tained. This is typified for example in studies of the protonation of benzene and the investigation of bridged us.classical ions in the ethylenebenzenium-phenyl-ethyl cation system. A fairly complete coverage is also given of theoretical and experimental aspects of ESCA applied to organic chemistry. This exciting field is continuing to develop rapidly and applications reported range from the study of non-classical ions to structural isomerisms in co-polymers. 2 Theoretical Organic Chemistry Barriers to Rotation.-Neutral Molecules. The successful interpretation of barriers to internal rotation about carbon-carbon single bonds within the Hartree-Fock formalism suggests strongly that correlation energy effects are small. It is nice to have this confirmed and Clementi and Popkie2 have investi- gated this in some detail for ethane.Using a very large basis set GTO (C 12s 7p Id; H 6s 2p) CGTO (C 6s 3p Id; H 3s 2p) approaching the Hartree-Fock limit the computed barrier to rotation is in good agreement with experiment. Electron correlation taken into account by making use of Wigner’s formula relating the electron density distribution to the correlation energy is closely similar for the eclipsid and staggered conformers and hence makes little contribution to the barrier. ’ Cf.Ann. Reports (B) 1971 68 43. E. Clementi and H. Popkie J. Chem. Phys. 1972,57,4870. 40 Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA The barrier to rotation about the central bond in buta-1,3-diene has been investigated3 in order to study the importance of electron correlation in rota- tion about bonds with some double-bond character.The basis set consisted of GTO (7s 3p for C 3s for H) CGTO (2s lp for C 1s for H) and part of the correla- tion energy may be taken into account by a second-order perturbation treatment. Rigid rotation was assumed and the results are shown in Figure 1. O 0O 45 90O 135" I goo Torsional nngle Figure 1 Potential energy for the internal rotation about the central C-C bond of buta-1,3-diene. Curve a corresponds to the SCF calculations curve b to the SCF plus correlation results. The zero reference values are -154.4643 and -154.7309 a.u.for curves a and b respectively (s-trans conformation) (Reproduced by permission from Chem. Phys. Letters 1972 13 249) It is clear that correlation effects modify the potential energy curve to quite a small extent except in the vicinity of the second minimum corresponding to torsion angles of 145"and 157" in the SCF and perturbation treatments respec- tively being 2.60 and 1.68 kcal mol-' above the trans energy respectively U.Pincelli B. Cadioli and B. Levy Chem. Phys. Letters 1972 13,249. D.T. Clark (observed 2.3 kcal mol- I). This all suggests that rotation about essential single bonds is quite adequately dealt with within the Hartree-Fock formalism. In an extensive series of studies4 Pople and co-workers have examined internal rotation in a large number of systems of considerable importance to organic chemists uiz. C-C C-N C-0 N-N N-0 and 0-0 bonds.The molecules studied were ethane methylamine methanol hydrazine hydroxyl- amine and hydrogen peroxide and -each of the monomethyl and monofluoro derivatives. Calculated energies were then analysed in terms of a Fourier-type expansion of the potential function uiz. for rotation in ethane methylamine and methanol internal rotation is described by a simple three-fold potential V(cp) = +v3(1-cos 3cp) where V is a three-fold barrier and cp a dihedral angle. For hydrazine hydroxyl- amine and hydrogen peroxide the potential functions are more complicated and to a reasonable approximation may be written as V(cp)= $V,(l -cos cp) + $V2(1 -cos 2cp) + +V3(1 -cos 3cp) and finally for asymmetric molecules such as substituted hydrazines etc. addi-tional terms are needed to reflect the lack of symmetry about cp = 180°,i.e.~(cp)= $~,(l-cos cp) + +V2(1 -cos 2q) + +V3(I -cos 3cp) + V sin cp + V sin 2cp The analysis of barriers in terms of one-fold (Vl)? two-fold (V2),and three-fold (V,) components facilitates the interpretation of the results. Standard geometries were assumed and calculations were carried out at the STO 4.31 G level. The great value of such systematic investigation is the quantitative interpretation of data and the recognition of fundamental factors influencing conformational preferences. The following generalizations are apparent from this study. Three principal effects are discernible. The first effect is some form of bond-bond repulsion which is sufficiently peaked to lead to a negative V component in the Fourier expansion.The magni- tudes of V for the parent molecules is given in Table 1. The decrease in V3 for Table 1 Magnitudes of V3/kcal mol- for molecules X-Y" X Y CH3 NH2 OH CH 3.26(9) 2.13(6) 1.12(3) NH2 2.13(6) 1.27(4) 0.84(2) OH 1.12(3) 0.84(2) 0.22(1) Numbers in parentheses are bond-bond interacticns the sequence CH3-CH, CH3-NH, CH,-OH in the approximate ratio 3 :2 1 is well known. The results in the table show that this is a general effect i.e. there is a decrease in V3 for all the sequences X-CH, X-NH2 X-OH L. Radom W. J. Hehre and J. A. Pople J. Amer. Chem. SOC., 1972 94 2371. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA (X = CH, NH, or OH) and the values are seen to be approximately propor- tional to the number of bond-bond interactions.This suggests it is not neces- sary to invoke any V components involving lone-pair interactions to explain the data. A consequence of this bond-bond interaction is a preference for staggered conformations in molecules with a methyl group at one end. The second effect is the stabilizing influence of back-donation from lone-pair orbitals at one end of the molecule into antibonding a-orbitals at the other. Such an effect is greatest if the effective axis of the lone-pair orbital is coplanar with the bond into which electrons are being transferred. It is also strongly accentuated if this bond is polar and electron-withdrawing. The lone-pair back-donation effect leads to large V terms in the total potential with important stereochemical consequences.This is particularly the case for fluorine-substi- tuted molecules (such as FCH,-OH). If there are lone-pair orbitals at both ends of the molecule (as in NH,-NH, NH,OH and HOOH) their axes tend to be perpendicular to each other so that such back-donation can occur more effectively. The third effect is the interaction of local dipoles at the two ends of the mole- cule. This leads to lower energies for conformations in which the dipole compo- nents perpendicular to the bond are anti-parallel to each other and is reflected in ' a V term which may also be an important factor determining the equilibrium conformation. The V term may also be influenced by steric interactions. In a further paper5 internal rotation in some twenty organic molecules of the type X-Y X-CH,-Y X-NH-Y X-0-Y and X-CO-Y (X and Y are CH, NH, OH or CHO) have been investigated again with STO 4.31 G basis sets.Where experimental data are available the mean absolute deviation for rota- tional barriers is an impressive 1.2 kcal mol-'. For most of the molecules considered the conformation with lowest energy is predicted to be one with single bonds in the trans arrangement where possible in good agreement with experi- mental data. In molecules where an appropriate choice is available lower energies are achieved if methyl groups are arranged cis to neighbouring carbonyl groups. This effect has been recognized in experimental structures and is well accounted for by the theory. It may be interpreted as a consequence of the dipole-induced-dipole interaction between the highly polar carbonyl group and the polarizable methyl group.Pople and co-workers have also investigated6 barriers to rotation in an exten- sive series of monosubstituted benzenes Ph-X (STO 3G basis set). Where available the results are in good agreement with experiment. Of particular interest are the results for the series X = CH, CH,CH, CH,F CHF, and CH=CH . The corresponding barriers are (partially flexible rotation) 0.0 2.2 0.25 0.18 and 4.42 kcal mol- '. For ethylbenzene the most stable conformer is predicted to be orthogonal suggesting a preference due to C-C hyperconjuga-tion (rather than C-H). The calculated barriers for benzyl and benzal fluorides L. Radom W.A. Lathan W. J. Hehre and J. A. Pople Austral. J. Chem. 1972 25 1601. ' W. J. Hehre L. Radom and J. A. Pople J. Amer. Chem. SOC.,1972 94 1496. D. T. Clark are similar and very small the preferred conformers having the C-F and C-H bonds in the plane of the ring respectively. For styrene the barrier is somewhat larger than that calculated for rotation about the 2-3 bond in buta-1,3-diene. An investigation has been made’ of component energy terms for barriers to rotation in the series ethane propane propene and acetaldehyde. Two interest- ing conclusions may be drawn from this work computed barriers to rotation are fairly insensitive within wide limits to the basis set (c$ ref. 1); on the other hand the signs and magnitudes of component terms are very sensitive to basis set and hence caution is necessary in their interpretation.The calculations reveal evi- dence for hyperconjugative contributions to the attractively dominated barriers in propene and acetaldehyde. The particular merit of carefully parametrized semi-empirical calculations foremost amongst which are Dewar’s MIND0 schemes is that some sort of allowance can be made for electron correlation effects. Such effects are likely to be important in for example rotation about a double bond and for this reason non-empirical calculations tend to overestimate such barriers. This fact in itself is useful since information can be obtained on the importance of electron correlation in such processes. On the other hand a parametrized treatment may well give very accurate values for barriers to rotation about double bonds and allow trends to be rationalized and predictions to be made but without giving any real insight into the relative importance of the many contributing factors.As an example of the value of careful semi-empirical investigations however we may cite the work of Dewar and Kohn’ on barriers to rotation in cumulenes and ethylene derivatives and a representative series of results is given in Table 2. Particularly worthy of note are the calculated reductions of barrier heights in the series ethylene methylenecyclopropane and cyclopropylidenecyclopropane amounting to -5 kcal mol- per cyclopropane ring. Introduction of a cyclo- propene residue has a much more dramatic effect lowering the barrier by 23 kcal mol- ’.The calculated barrier for calicene is 26.8 kcal mol-’ the low value being explicable in terms of a low-energy zwitterionic structure (as revealed by charge distribution). On this basis substituents capable of stabilizing positive and negative charges in the three-membered and five-membered ring respec- tively might be expected to lower the barrier (cf:l-formyl-5,6-di-n-propylcalicene 18-19.4 kcal mol-I). This rosy picture of the interpretation of barriers to rotation by MIND0/2 calculations must be tempered however. Often results of incomplete investiga- tions have been reported. Thus for buta-1,3-diene the calculated barrierg to rotation about the 2-3 bond obtained from calculations on the cis and trans conformers is 2.2 kcal mol- l in excellent agreement with the experimental results.Unfortunately both cis-and trans-butadiene are calculated (MIND0/2) to be less stable than a conformer of C2symmetry with the double bonds ’ A. Liberles B. O’Leary J. E. Eilers and D. R. Whitman J. Amer. Chem. SOC.,1972 94 6894. M. J. S. Dewar and M. C. Kohn J. Amer. Chem. SOC.,1972,94,2699. J. W. McIkr jun. and A. Komornicki J. Amer. Chem. SOC.,1972 94 2625. -/ Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA Table 2 Molecule Rotational barrier kcal mol-' calcd (obsd) Ethylene 53.46 (65.0) Allene 36.73 Butatriene 31.60 (30.0) Pentatetraene 24.84 Hexapentaene 22.05 (20.0) Propene 53.5 cis-But-2-ene 50.1 52.5 (62.8) lsobutene 51.2 47.5 (43.4) -v 46.1 51.1 D= 48.1 w 43.4 D-30.6 35.4 45.6 26.8 approximately at right angles.Barriers to rotation in amides are grossly under- estimated' by MINDO/2. It is strange that these and other deficiencies of MIND0/2 (H,O linear NH planar) have not received better publicity to avoid the possibility of completely erroneous theoretical studies for which the method is not well suited. One of the more novel conformational processes investigated" is that involv- ing linearly hydrogen-bonded peptides when the plane of one peptide unit is rotated around the hydrogen bond from 0 to 90 degrees. The system studied consisting of the formamide dimer is a prototype for a process of fundamental importance with regard to the interpretation of the role attributed to hydrogen lo H.Berthod and A. Pullman Chem. Phys. Letters 1972 14 217. D. T. Clark bonding in the stabilization of protein conformations. The interesting result emerges that there is virtually no energy change involved in this rotation. Carbonium ions. The electronic structures of carbonium ions (or more correctly carbocations' ') still continue to excite considerable interestI2 theoretically at the non-empirical level. Conformations and stabilities of substituted ethyl propyl and butyl cations have been investigated at the STO 3G level. A separation of substituent effects into hyperconjugative and inductive effects is possible assum- ing that the latter are conformationally independent. Representative data are given in Table 3.The results suggest that whereas for X = H the two conformers Table 3 Rotational barriers (kcal mol- ')forprimary carbonium ions R+ Barrier X Y (B-A) 2.52 XH X H CH3 CCH 0.45 H 0 CN -1.95 OH -7.67 F -9.31 H CH3 -2.68 CH3 0.01 F 4.63 F -0.01 F 7.82 CH3 -11.10 3.73 2.52 2.42 F 2.11 OH 0.91 BH CN 0.87 4.30 3.97 3.73 3.61 3.38 2.92 A B A and B have approximately the same energy P-substitution is accompanied by a definite conformational preference. This can be associated with the number of electrons in the formally vacant 2p orbital at the positive carbon in A and is largely a measure of the relative hyperconjugative abilities of CH and other C-X " G.A. Olah J. Amer. Chem. SOC., i972 94 808. l2 L. Radom J. A. Pople and P. von R. Schleyer J. Amer. Chem. SOC.,1972,94 5935. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA bonds.' In particular C-C is more effective than C-H hyperconjugation. Both conformations are stabilized or destabilized relative to the unsubstituted ethyl cation by an inductive type of effect. Substituents in 7 and 6 positions modify the hyperconjugative interaction with the positive carbon and also have appreciable inductive stabilizing and destabilizing components (falling off by -5 for each interposed CH group). Carbanions. Barriers to rotation (and inversion) in simple carbanions have received little attention compared with studies of carbonium ions.An interest- ing comparison has now been drawnI3 for P-substituted ethyl cations and anions. At both a qualitative and a quantitative level the role of hyperconjugative inter- actions is substantial and leads to an important generalization for anions which should be compared with that discussed in the previous paragraph for cations if X (Table 3) is more electronegative than H then the anion favours conformer A and if X is less electronegative than H then the anion favours conformer B. As simple examples Table 4gives the calculated barriers (STO 3G) for the Table 4 Calculated barriers [E(B) -E(A)J/kcal mol- for two XCH,-CH species Cation Radical Anion (BH2)CH2-CH2 FCH2-CH2 + 10.4 -8.4 +0.3 0.0 -6.2 +9.2 extremes represented by X = BH and F.The striking reversal in conformational preferences in going from cation to anion is clearly evident as is the small con- formational preference suggested for the radicals. For the anions there will undoubtedly be distortion from a planar to a pyra- midal arrangement at the charge centre and although this will modify the quantitative results discussed above the conclusion should not be invalidated by this factor. These factors have been taken into account in a study of the system X-CH; (X = H CH, and CH;) by Wolfe and Csizmadia and co-~orkers'~ as part of a general study of the stereochemical consequences of adjacent lone pairs. The results for rotation inversion are displayed in Figures 2 and 3. The principal features of note are that the inversion barriers are in the order X = CH > H > CH, whereas the rotation barriers are in the order X = CH < CH; the barrier to rotation in ethyl anion being comparable with that in ethane.The barrier to double inversion in the ethylene dianion is almost twice that of a single inversion and the energy maximum corresponds to a structure having two planar CH groups at right angles to each other. Analysis of the total and component energy curves suggests that lone-pair-lone-pair interactions behave as l3 R. Hoffman L. Radom J. A. Pople P. von R. Schleyer W. J. Hehre and L. Salem J. Amer. Chem. SOC.,1972 94 6223. l4 S. Wolfe L. M. Tel J. H. Liang and I. G. Csizmadia J. Amer. Chem. SOC.,1972 94 1361 D.T. Clark ROTATION ALONG THE C-C BOND (0) y= 0' 124 24r (r 1W 240 360.1'1'1. I ' 1 I ' 17845 -77.44 --77.46 -CI w -77.48-a Figure 2 Lejt-hand side the total energies of ethane (l),ethyl carbanion (3),and ethylene dicarbanion (4) as a function of rotation about the C-C bond (8). In the direction of decreasing energy the curves are as follows (4) at the ethylenic C-C bond length and pyramidal angles 105 and 110" (top two curves); (4) at the optimized C-C bond length (1.60A) and pyramidal angles 105 and 110"; (3);(1). Right-hand side the total energy of (4) and irs components as a function of rotation about the C-C bond at the optimized C-C bond length (1.60A) and pyramidal angles (105"). The scale of the curve for total energy has been expanded fourfold with respect to those of the components (Reproduced by permission from J.Amer. Chem. SOC. 1972,94 1361) though they are invariant with dihedral angle. This contrasts with many previous discussions. The relative importance of gauche effects associated with polar bonds and lone pairs is inferred to be polar-bond-polar-bond > polar-bond-lone-pair > lone-pair-lone-pair. Electronic Structure of Molecules Radicals and Ions.-Substituent Efects. A distinct advantage of a non-empirical as opposed to semi-empirical study of substituent effects is that the approximations and limitations of basis set etc. may be closely controlled for the former and hence trends within series and dif- ferences between members may be interpreted with a considerable degree of confidence.The effect of substituents on the benzene ring is of prime interest Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA PYRAMIDAL ANGLE (9) BOND ANGLE (0) Figure 3 Inversion curves of methyl carbanion (2)(upper curve) ethyl carbanion (3)(lower curve) and the curves for single inversion and double inversion of (4) ; the latter two cross-sections were taken near the absolute minimum of the hypersurface of (4) (Reproduced by permission from J. Amer. Chem. Soc. 1972,94 1361) and in a detailed and fascinating study Pople and co-workers have studied6 35 monosubstituted benzenes with a minimal STO 3G basis set. Although the results are too numerous to study individually a few representative examples illustrate the utility of such detailed studies (phenol nitrosobenzene and trifuoromethyl- benzene).Phenol is predicted to be planar with a barrier to rotation (C-0 bond) of 5.2 kcal mol- comparable with that calculated for nitrosobenzene. The calculated n-electron distributions are given in Figure 4 together with the total oand 7t charges donated by the substituent to the ring (for comparison for H substituent q = -0.063; qn = 0). OH is thus seen to be cr withdrawing and n donating whereas CF is both cr and 7t withdrawing. The order of cr withdrawal is OH > NO > CF,. D.T. Clark H 0 0’ N4 10.975 1.039 0.984 40 +0.185 +0.110 +0.021 4 -0.102 +0.037 +0.011 Figure 4 For NO and CF (nwithdrawing) the n distribution follows the traditionally expected order rn > o,p whereas for OH (a good donor) the reverse applies.Overall the results are gratifyingly in agreement with most organic chemists’ expectations. Neutral Molecules. Considerable emphasis has been put on the fact that one of the most readily calculable properties of a molecule is its geometry. This applies equally to non-empirical and specifically parametrized semi-empirical (e.g. MINDO) treatments although from the literature the uninitiated might get the erroneous impression that empirical calculations of the Extended Huckel Theory (EHT) variety are adequate for this task. The author can do no better to correct this viewpoint than suggest a perusal of the paper by Bloemer and Bruner.15 The clear prediction evident from this work is that as far as EHT is concerned benzene does not exist ! (three acetylenes are much more stable).This should be sufficient to induce a healthy scepticism of ‘detailed’ potential energy surfaces calculated with EHT. The computational simplicity of calculations employing the FSGO model has previously been remarked upon.’ With very small basis sets giving in absolute terms very poor energies (typically -85 %) of the Hartree-Fock limit a detailed study by Frost and Nelson16 has shown that none the less calculated geometries for three- and four-carbon hydrocarbons are in excellent agreement with experi- ment and the claim is made that the simple FSGO method appears to be the most practical ab initio model at the present time for doing extensive geometry minimizations.In continuation of the extensive work on simple molecules using the FSGO approach Christoffersen and co-workers have investigated methylamine dimethylamine hydrazine methylimine di-imide pyridine pyrazine and pyrrole. In general a good qualitative account is given of molecular geometries barriers to rotation and ordering of both core and valence energy levels by comparison with more sophisticated calculations. In a further paper18 a series of simple oxygenated organic systems have been studied. Two of the more unusual systems which have been investigated non-empirically and which are of special interest are CH,PH as the simplest hypothetical example Is W. L. Bloemer and B. L. Bruner Chem. Phys. LeKterS 1972 17 452. l6 J. L. Nelson and A.A. Frost J. Amer. Chem. SOC.,1972,94 3727. ” D. W. Gensin and R. E. Christoffersen J. Amer. Chem. Sac. 1972 94. 6904. B. V. Cheney and R. E. Christoffersen J. Chem. Phys. 1972 56 3503. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 5 1 of a phosphorus ylidelg and glycylglycine20 as the simplest example of a system containing a peptide bond. Extensive studies have been reported of aspects of the electronic structure of strained hydrocarbons ; namely bicycle[ 1,1,0]-butane (1),21,22 bicyclo[l,l,l]pentane (2),21-23 and tri~yclo[l,l,l,O~*~]pentane (3).22 H&H HwH (1) (2) (3) Notable features for (1H3) which one might hopefully shed some light on in a detailed calculation are (i) for (1) the central bond exhibits both olefinic and non-olefinic properties the bridgehead protons are acidic with a large 3C-H coupling constant ;(ii) (2)has the shortest non-bonded carbon-carbon distance on record and a surprisingly large long-range spin-coupling constant between bridgehead protons (18 Hz) ;(iii)(3) represents the first member of the propellanes.[1,1,1]Propellane and its electronic structure is obviously of considerable interest more particularly since one might expect the molecule to have an inordinately large strain energy. (Hoffman and St~hrer~~ have outlined qualitatively aspects of the structure of propellanes in general.) For bicyclobutane the three sets of calculations are in broad general In the more extensive study of Newton and Schulmanz2 considerable insight into the electronic structures of all three strained systems is obtained by transforming the usual (delocalized) MO's to a set of maximally localized ones according to the Edmiston and R~edenberg~~ procedure (which minimizes the total exchange energy).Such a model provides a conceptually easier way of looking at the bonding as far as organic chemists are concerned. Straight analysis of the delocalized MO's does not provide a simple picture of the nature of the central C-C bond since there is significant mixing of CC and CH symmetry orbitals. Employing the localized orbital description however the picture becomes clearer. The hybridizations involved in each 'localized' bond are given in Table 5 together for comparison with data for ethane and cyclopropane with equivalent basis sets.Essentially the same pattern emerges from INDO calculations. The striking feature evident from these data is the negligible s character in the hybrids comprising the central bond ( -96 % p in character) and the orientation of these hybrids is such as to give a bond bent by 30.8" (i.e.only 4"more bent than for cyclopropane in this basis set). This is shown more clearly by a density contour map (Figure 5). The bicyclobutane 'side' bonds are formed from carbon bridge- ~ head and methylene orbitals which are hybridized s~ and s~~.' ~. respectively '' I. Absar and J. R. Van Wazer J. Amer. Chem. SOC.,1972 94,2382. 2o J. A. Ryan and J. L. Whitten J. Amer. Chem. SOC.,1972 94 2396. 2' D. R. Whitman and J. F. Chiang J.Amer. Chem. SOC.,1972,94 1126. '' M. D. Newton and J. M. Schulman J. Amer.*Chern.SOC.,1972 94 767. 773. '' J. M. Lehn Chem. Phys. Letters 1972 15 450. 24 W. D. Stohrer and R. Hoffman J. Amer. Chem. SOC.,1972 94 779. 25 C. Edmuston and K. Riedenberg J. Chem. Phys. 1965 43 597. D. T.Clark Table 5 Hybridization Molecule Bond (minimal basis set GTO) Ethane cc SP4.01 SP3.O2 Cyclopropane CC sP5.69 CH sP2.27 Bicyclobutane C,-C3 sP2.43 sp2 .9 7-sp 5.10 c,-c* C1-Hbrhd sP1.58 C H endo sP2.23 C2H exo sP2.26 the latter being close to the cyclopropane value sp5.7. The side bonds are also bent outward by 33" from their C-C bond vectors and are rotated downward into the region between the two cyclopropane planes. The out-of-plane distor- tion of the side bond arises mainly from the bridgehead hybrids (-10% out of plane) while the methylene hybrids are within 2" of planarity.The bridgehead Figure 5 Total electron density (a.u.) of bicyclobutane (Reproduced by permission from J. Amer. Chem. SOC.,1972,94,767) CH bonds are constructed from SP'.~hybrids (high % s character) in contrast to the methylene hybrids sp2.* and sp2.3 for endo and exo protons respectively (cf:cyclopropane s~~.~). This is consistent with the acidic nature of the bridge- head protons. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 53 With the extended basis set (STO 4.31G) some aspects of the energetics of the ring system have been studied. By setting up a series of isodesmic reactions e.g.for cyclopropane for bicyclobutane C4H + C2H6 + 2C3H6 and knowing the calculated enthalpies of reaction the zero point energy for each species and the experimental enthalpies of formation for methane and ethane strain energies for bicyclobutane and cyclopropane may be calculated. The values are 70 and 32 kcal mol- l respectively which compare well with the corresponding experimental values (63 and 25 kcal mol- I). These results are based on experimental geometries and it is of some interest to investigate the geometry theoretically. The molecule is too large for complete optimization. With the minimal basis CGTO basis set trends in C-C bond lengths in the series ethane cyclopropane bicyclobutane are reproduced (but in absolute terms are a little too large).Steric crowding in 1,3-disubstituted bicyclobutanes might be expected to distort the H-C-1-C-3 angles. The calculations show that this angle is soft and changes of as much as 15" require only 5 kcal mol-',an amount which could be partially recovered by conjugative interaction in the case of unsaturated 1,3-derivatives. Distortion of the dihedral angle is somewhat more costly but the angle is still also quite soft changes of lo" requiring only -5 kcal mol- *. By contrast stretching the C-1-C-2 and C-3-C-4 bonds by 0.2A whilst maintaining equilibrium values for the other C-C bonds and dihedral angle as might represent the early stages of the thermal conversion into butadiene is calculated to be relatively expensive costing 27 kcal mol- I.The energetics of breaking the side and central bonds to obtain 1,2- and 1,3-diradicals respectively have also been investigated. The interesting results that emerge are that for 1,3-diradical with square-planar geometry with the same C-C side-bond lengths a lower limit of 19 kcal mol- ' in energy above the ground state is calculated whereas for a l12-diradical obtained by expanding the C-1 -C-2 bond until the C-1-C-3-C-2 bond angle reaches 110" (keeping the dihedral angle and other C-C bond Iengths fixed and allowing the CCH moiety to become planar) is much higher in energy -34 kcal mol- Thus the l12-diradical appears to be less stable than the 1,3. In the case of [l,l,l]propellane (D3hsymmetry) partial geometry optimization [STD 4.31G basis set] gives normal side-bond lengths of 1.53 A and a distance between the bridgehead carbons of 1.60 A.The analogous bridgehead distance in bicyclopentane is calculated to be 1.885 A,in very good agreement with experi- mental estimates. Transformation to localized orbitals reveals negative overlap in the region between the bridgehead carbon for both molecules i.e. there is no evidence for a central bond in these molecules (cf Figure 6 and Figure 5 for bi- cyclobutane). The hybridizations for the relevant localized orbitals (for the minimal CGTO basis sets) are given in Table 6. D. T. Clark Figure 6 Total electron densities (a.u.) of [l,l,l]propellane(above) and bicycle[ 1,1,1]-pentane (below) (Reproduced by permission from J.Amer. Chem. Soc. 1972,94,773) Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA Table 6 Molecule Bond Hybridization [1,1,1]Propellane C-1-C-2 side sP1.33 sP4.31 C-1-C-3 central SP4. Bicycle[l,l,l]pentane C-1-C-2 C-2-H-1 3P3.46 sP3.64sP2.66 C-1 -H sP2.22 C-2-H sP2.62 If the numbers in Tables 5 and 6 look a little strange in terms of the concept of localized hybrid orbitals familiar to organic chemists it should be emphasized that the localization transformation employed leads to hybrid orbitals which are not constrained to be orthonormal. Comparisons with the data in Table 5 are instructive. An interesting feature of the electronic structure of bicyclopentane is the unusually large long-range coupling constant between the two bridgehead protons (18 Hz).This is successfully reproduced from an INDO finite perturba- tion method. Strain energies can again be calculated from thermodynamic data and appro- priate isodesmic reactions and are 6M4 kcal mol- ' for bicycle[ l,l,l]pentane and 105-110 kcal mol- ' for [l,l,l]propellane depending on the isodesmic processes chosen. In terms of strain energy per framework bond cyclopropane (3 bonds) bicyclobutane (5) bicyclopentane (6) and [ l,l,l]propellane (7) the calculated values range from 11 kcal mol- per bond for the former through 14 11 to 15 kcal mol-' per bond. Viewed in this way the strain energy for [l,l,l]propellane which is larger than the bond energy for a typical C-C bond looks more reasonable. The inclusion of d functions to an STO 6.31G basis set for carbon has been shown to improve the agreement between theory and experiment for the relative energies of cyclic uersus open-chain hydrocarbons.26 With this basis set strained cyclic molecules such as cyclopropene and cyclopropane are preferentially stabilized with respect to their open-chain analogues by the addition of d func-tions.It should be emphasized however that these serve merely to polarize the valence s,p basis set and as shown above the gross features of the electronic structures of strained species are well accounted for within a framework of valence s-and p-orbitals. Dewar and by revised parametrization have extended MIND0/2 to include organofluorine compounds. Calculated heats of formation molecular geometries and dipole moments for a wide variety of saturated and unsaturated compounds are overall in impressive agreement with experiment.Within the limitations of the method this extension should prove particularly valuable for predicting the properties of organofluorine systems. Non-empirical investigations have almost exclusively been directed to investi- gations of ground-state properties although increasing attention is being paid P. C. Hariharan and J. A. Pople Chem. Phys. Letters 1972 16 217. '' M. J. S. Dewar and D. H. Lo J. Amer. Chem. SOC.,1972,94 5296. 56 D.T. Clark to the discussion of excited states. A topic of considerable fundamental interest is the nature of the lowest excited (m*) singlet state of ethylene.Surprisingly at the ub initio level the picture is confused. Early work has suggested that in the planar geometry the TIT* state is a diffuse Rydberg-like state.28 The experi- mental evidence however militates against such a diffuse picture for the state and the suggestion has been made that this apparent discrepancy may be due to neglect of electron correlation effects.29 Three sets of workers have now investi- gated this problem but with no great measure of agreement between them.29-31 Excited states of ap unsaturated ketones32 and of keten33 have been investi- gated and a comprehensive study of substituent effects on n -,TC*transitions in simple molecules has been reported. 34 Pople and co-~orkers~~ have now extended their studies at the STO 4G and 4.31G level to the calculation of excitation energies and accompanying geometry changes for m*transitions in simple molecules.The theoretical results are in good agreement with experiment. Radicals. A valuable survey of the electronic properties of diradicals has been given by Salem and Rowlands. 36 Considerable computational effort has been expended in trying to resolve one of the principal physical problems underlying carbene chemistry namely the magnitude of the singlet-triplet separation in methylene.37-39 Although the electronic structures of the 'A and 3B1states of CH have been investigated extensively within the Hartree-Fock formalism over the past few years with some considerable success (e.g.that the 3B state should be bent rather than linear as had originally been inferred from spectroscopic investigations) the question of the exact singlet-triplet separation has not been settled either theoretically or experimentally.(We might expect that calculations within the HF formalism i.e.neglecting electron correlation would overestimate the splitting.) The best theoretical estimate including the effect of electron correla- tion now is 11.0 2 kcal mol- for the singlet-triplet energy differen~e.~~ The effect of inclusion of d polarization functions is quite substantial as far as this energy gap is concerned and a discussion has been given of this effect on addition and insertion reactions and a rationalization put forward for the unreactivity towards insertion into carbon-carbon single bonds3* 28 T.H. Dunning W. J. Hunt and W. A. Goddard Chem. Phys. Letters 1969 4 147. 29 H. Bash Mol. Phys. 1972 23 683. 30 B. Levy and J. Ridard Chem. Phys. Letters 1972 15 49. 31 C. F. Bender T. H. Dunning H. F. Schaeffer W. A. Goddard and W. J. Hunt Chem. Phys. Letters 1972 15 171. 32 A. Devaquet J. Amer. Chem. SOC.,1972 94 5160. 33 J. E. Del Bene J. Amer. Chem. SOC.,1972 94 3717. 34 R. Ditchfield J. Del Bene and J. A. Pople J. Amer. Chem. SOC.,1972 94 703. 35 R. Ditchfield J. Del Bene and J. A. Pople J. Amer. Chem. SOC.,1972 94 4806. 3h L. Salem and C. Rowland Angew. Chem. Internat. Edn. 1972 11 92. 37 P. J. Hay W. J. Hunt and W. A. Goddard Chem. Phys. Letters 1972 13 30. 38 C. F. Bender H. F. Schaeffer D. R. Franceschetti and L. C. Allen J. Amer.Chem. SOC.,1972 94 6888. 3y S. Y. Chu A. K. Q. Siu and E. F. Hayes J. Amer. Chem. SOC.,1972 94 2969. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA Carbonium Ions. In discussing computations of rotational barriers for substi- tuted ethyl propyl and butyl cations mention was made of Pople's extensive ~tudies.'~.'~ In general these calculations also give a good account of the relative stabilities of simple alkyl carbonium ions and in this connection it is of interest to compare the results with Dewar's reparametrized MIND0/2 studies.40 In the latter heats of formation have been computed directly which are in good agreement with available experimental results. Some representative results for isomeric species are given in Table 7.Detailed studies of geometries and relative Table 7 Re/. energieslkcal mol-Ab initio12 Species STO 3G MIND0/240 CH3CH2CH2CH2+ 0 0 CH3CH2CH+CH -20 -26 CH3CH2CH,+(CH313Cf 0 -37 0 -38 (CH312CH+ -20 -25 energies for isomeric C3H7+species have been carried out by both Pople41 and Dewar4' and their co-workers and form an interesting comparison between non- and semi-empirical calculations. In an extensive series of geometry optimizations at the STO 3G level followed by further calculations with the more flexible STO 4.31G basis set Pople and co-workers studied C,H,+ cations the two conformers of methyl-staggered 1-propyl cation (4)and (5) the eclipsed conformer of 1-propyl cation (6),corner- face- and edge-protonated cyclopropane (7t-(10) H-bridged propyl cation (1 l) and the 2-propyl cation (12).The results are given in Table 8. By comparison \ Methyl-staggered I-propyl cation (4). Methyl-staggered 1-propyl cation (5). 40 N. Bodar M. J. S. Dewar and D. H. Lo J. Amer. Chem. SOC.,1972,94 5303. 41 L. Radom J. A. Pople V. Buss and P. von R. Schleyer J. Amer. Chem. SOC.,1972 94 311. D.T. Clark /c2\ Corner-protonated cyclopropane (8) Edge-protonated cyclopropane (9). Hl H3 2-Propyl cation (1 2). Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA Table 8 Rel. energieslkcal mol- Non-empirical STO 4.31G41 MIND0/240 2-Propyl(12) 0 0 Methyl-eclipsed (6) 16.9 24.5 Corner-protonated(7) 17.3 Methyl-staggered (4) 17.4 Corner-protonated(8) 17.4 3.5 H-bridged (11) 18.2 Methyl-staggered (5) 19.4 Edge-prot ona ted (9) 27.1 -3.7 Face-protonated(10) 139.6 56 Dewar and co-workers investigated 1- and 2-propyl cations and corner- face- and edge-protonated cyclopropane; their results are also given in Table 8.The more complete studies of Pople and co-workers reveal an interesting feature of the electronic structure of the 'classical' 1-propyl cation which in conformers (4H6) shows strong distortion towards a partially bridged species looking somewhat like a distorted corner-protonated cyclopropane. The two sets of results are in striking disagreement! The MINDO calcula- tions predict edge-protonated cyclopropane as the most stable species whereas for the non-empirical calculations the chemically more reasonable result that the isopropyl cation is the lowest energy species is obtained.Both calculations agree however on the high-energy status accorded to face-protonated cyclo- propane. Cross-sections through potential energy surfaces show in the case of the MINDO investigation that the only potential minima are edge-protonated cyclopropane and the 2-propyl cation whereas in the non-empirical investiga- tion the two potential minima correspond to the 2-propyl cation and the methyl-eclipsed 1-propyl cation (6),which is so distorted as to be best considered as distorted corner-protonated cyclopropane. Unfortunately the potential energy surface is relatively flat [only 0.5 kcal mol-* separates (6) from (7) (8) and (4)] and solvent effects may have significant effects.In terms of detailed interpretation of the experimental results therefore neither study can be regarded as definitive. The semi-empirical calculations however undoubtedly consider- ably overestimate the stability of species of high degree of connectivity (bridged us. open ions) and this is characteristic of such calculations not only for ions. For example MIND0/2 incorrectly predicts4' that C is an equilateral triangle whereas even a relatively crude ab initio calculation correctly predicts it to be linear. Pople and co-workers have reported44 detailed calculations including polarization functions (d functions on carbon p functions on hydrogen) in the basis sets of the structures of the cations CH3+ CH5+ CZH3+ and C2H5+.A 42 M.J. S. Dewar Topics Curreni Chem. 1971 23 I. 43 D. H. Liskow C. F. Bender and H. F. Schaeffer J. Chem. Phys. 1972,57,4509. 44 P. C. Hariharan W. A. Lathan and J. A. Pople Chern. Phys. Lerrers 1972 14 385. D. T. Clark systematic procedure for improving basis sets and refining equilibrium geometries has been developed. It is found that the addition of polarization functions has a greater stabilizing effect on non-classical forms of C2H,+ and C2H,+. In the case of C,H,+ the energy for bridge-protonated ethylene is now computed to be slightly lower (0.9 kcal mol-’) than for the classical ethyl cation. Potential Energy Surfaces for Organic Reactions.--~nntroduction. The detailed understanding of the dynamics and stereochemistry of organic reactions requires a knowledge of many-dimensional potential energy (PE) surfaces.Leaving aside theoretical difficulties (e.g. the inability of the HF model to describe bond break- ing) the sheer scale of computations on all but the very simplest systems dictates that some form of compromise be made. These may be put into two categories. In the first type the dimension of the surface is reduced by eliminating certain degrees of freedom which can reasonably be assumed to remain constant throughout the course of the reaction. The second type involves consideration of most if not all of the degrees of freedom of the system but seeks only to locate certain chemically interesting points on the PE surface perhaps followed by limited investigations of interconnections between such points.Both approaches have their merits and representatives of each type are given below. The location of a transition state on a PE surface can in principle be accomp- lished by brute force (suitably tempered by chemical and theoretical intuition). In an elegant series of investigations however M~Iver~,~’ has presented a logical sequence for locating and identifying transition states for systems of many degrees of freedom by focusing attention on the gradient of the PE function. The tech- nique has then been applied with some success to the electrocyclic transformation of cyclobutene to butadiene studied by means of MIND0/2 calculation^.^ The question of symmetric transition states for cycloaddition reactions has also been in~estigated.~’ Thus considering (e.g.2 + 2 2 + 4 2 + 6 4 + 6) cycloadditions (represented by A + B) the question often arises is the transition state symmetric? By considering the form of the force constant matrix at the transition state the interesting prediction may be made that the likelihood of the transition state being non-symmetric (i.e. corresponding to different extents of bond-making of the two new 0 bonds) should increase as n and m increase. MIND0/2 calcula- tions on representative systems4’ indicate that the likelihood at this level of approximation is translated into a high probability and suggest that in general transition states for cycloaddition reactions are very likely to be non-symmetric. 45 J. W. McIver J.Amer. Chem. SOC.,1972 94 4782. Physical Methods-Part (iii) Theoreticul Organic Chemistry und ESCA 61 General Reviews. A general review has been presented of the formulation of the Woodward-Hoffman rules in terms of an extended valence bond The general formalism for the analysis of electrocyclic reactions using localized orbitals has also been discus~ed.~' In an important and lengthy paper G~ddard~~ has examined the results of recent ab initio calculations (by the generalized valence bond method) of reaction co-ordinates and has noted that for a reaction to have a low activation energy certain phase relationships must occur between the orbitals of the reactants and the orbitals of the products. This is developed into a generalized scheme denoted as the orbital phase continuity principle (OPCP),which has the distinct advantage compared with simple orbital symmetry arguments that it does not depend on molecular symmetry and can therefore be applied easily to reactions involving no symmetry.A further advantage accrues from the fact that OPCP is based on generalized valence bond (GVB) SCF theory and hence overcomes the principal deficiency of the Hartree-Fock model of not properly describing bond breaking. A general discussion reveals a pattern of results fully compatible with predic- tions based on simple orbital symmetry considerations for electrocyclic sigma- tropic group-transfer and elimination reactions. Some interesting exceptions are predicted however for addition reactions involving open-shell molecules [e.g.NH('A) and O,('A,)] which for reaction with ethylene e.g. 0-0 -* II 02(lA,) + >=( HzC-CH are favourable according to OPCP but forbidden in the WH approach (for C, geometry). This original approach clearly has great potential and is worthy of very close investigation by organic chemists. Concerted Cycloadditions. The qualitative predictions based on simple orbital symmetry arguments continue to be the subject of quantitative treatments. The formally symmetry-forbidden ,2 + ,2 decomposition of cyclobutane into two ethylenes has been investigated in some detail by Salem and Wright.49 A minimal basis set of Slater orbitals was employed and limited configuration interaction included to accommodate some of the change in correlation energy.Some 50 points were investigated in which the variables were R R, and B:A section 46 W. J. van der Hart J. J. C. Mulder and L. J. Oosterhoff J. Amer. Chem. SOC.,1972 94 5724. 47 J. Langlet and J. P. Malrieu J. Amer. Chem. SOC.,1972 94 7254. 48 W. A. Goddard J. Amer. Chem. SOC.,1972 94,973. J. S. Wright and L. Salem J. Amer. Chem. SOC., 1972 94 322. 62 D. T. Clark 2.55 2.35 2.15 ul 1.95 1.75 1.55 83 1 1.55 1SO 1.45 1.40 1.35 Rl/A Figure 7 Ab initio potentiul surface for the rectangulur decomposition of C,H (Reproduced by permission from J. Amer. Chem. SOC.,1972,94 322) of the PE surface is given in Figure 7. Cyclobutane (p = 45") is in the bottom left-hand corner (energy reference -155.839 a.u.) whilst the region in the top right-hand corner represents two ethylene units (0 = 0).The configuration and state correlations for the proposed reaction co-ordinate are shown in Figure 8. For the reaction C,H +2C,H along this rectangular decomposition path the calculated activation barrier is 156 kcal mol- ' thus giving a quantitative estimate of the forbidden nature of such a transformation. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 63 -154.50 C,H,** -154.70 -154.90 -155.10 -155.30 -155.50 -155.70 -155.90 Reaction co-ordinate T.S. Figure 8 Conjguration and state correlation diagram from the ab initio calculation (Reproduced by permission from J. Amer. Chem. Soc. 1972,94,322) Electrocyclic Reactions.Following the investigation of the cyclobutene-buta- diene system reported last year5' a more extensive study has now been published5 in which the effects ofring torsion upon the reaction mechanism for the thermally induced transformation have been studied. The main conclusions of previous work require very little modification and the main effect of ring torsion upon the mechanism is to decrease the C-C distance R at which CH rotation becomes favoured relative to the corresponding value for a constrained reaction path in which torsion is not allowed. The calculations also clearly show that formation of trans-butadiene the ultimate product of the reaction involves the cis-isomer as intermediate rather than direct conversion as a result of simultaneous CH rotation and ring torsion.Zsornerizations. Further details have appeared of Salem's on the geometrical isomerism of cyclopropane reported last year. 50 K. Hsu R. J. Buenker and S. D. Peyerimhoff J. Amer. Chem. SOC.,1971 93 21 17. 51 K. Hsu R. J. Buenker and S. D. Peyerimhoff J. Amer. Chem. Soc. 1972,94 5639. 52 J. A. Horsley Y. Jean C. Moser L. Salem R. M. Stevens and J. S. Wright J. Amer. Chem. SOC.,1972 94 279. 64 D.T. Clark The isomerization of methyl cyanide to the isocyanide has been the subject of investigation at both the non-empirical level (with an extended basis set)53 and by the MIND0/2 method.54 Interestingly enough the latter predicts that the reaction should proceed via a stable intermediate resembling a 7t complex H \\ C-H H' I NrC Dewar and Kohn5 rightly point out that such an intermediate would be unique since no case has yet been reported of a stable neutral metal-free organic 7c complex.Unfortunately the more detailed non-empirical study5 33 does not show this behaviour and casts doubt again on the behaviour of the MINDO/2 schemes as far as bridged species are concerned. Radical Reactions. The PE surfaces for hydrogen abstraction and exchange in the H + CH and for addition of the NH; radical to ethylene,58 have been investigated. Extensive studies have also been presented of the electronic structure of the ground and lower excited states of formaldehyde and their dissociation into both radical and molecular produ~ts.~~,~' Nucleophilic Substitution.Further details of Dedieu and Veillard's work on prototype potential energy surfaces for S,2 reactions have been published.6 ' Carbonium Ion Rearrangements. In investigating aspects of potential energy surfaces of carbonium ions the most logical approach is to investigate chemically interesting points in some detail and then consider interconversion between species. For example for the surface of the C4H7+ system obvious points of interest are represented by cyclobutyl cyclopropylcarbinyl and homoallyl cations. For the latter two species Hehre and Hiberty have now investigated62 geometries (at the STO 3G level) and relative energies (at the STO 4.31G level). For each of the four possible homoallyl cations (1 3)+ 16) possessing planes of (13) (14) (15) (16) (17) 53 D.H. Liskow C. F. Bender and H. F. Schaeffer J. Amer. Chem. SOC., 1972,94 5 178. 54 M. J. S. Dewar and M. C. Kohn J. Amer. Chem. SOC.,1972,94 2704. 55 D. H. Liskow C. F. Bender and H. F. Schaeffer J. Chem. Phys. 1972,57,4509. 56 S. Ehrenson and M. D. Newton Chem. Phys. Letters 1972 13 24. 57 K. Morokuma and R. E. Davis J. Amer. Chem. SOC.,1972 94 1060. '* S. Shih R. J. Buenker S. D. Peyerimhoff and C. J. Michejda J. Amer. Chem. Soc. 1972 94 7620. 59 D. M. Hayes and K. Morokuma Chem. Phys. Letters 1972 12 539. 6o W. H. Fink J. Amer. Chem. Soc. 1972 94 1073 1078. 61 A. Dedieu and A. Veillard J. Amer. Chem. SOC.,1972,94 6730. 62 W. J. Hehre and P. C. Hiberty J. Amer. Chem. SOC.,1972 94 5917.Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 65 symmetry the transformation to the bisected cyclopropylcarbinyl(17) was found to be a downhill process (Table 9). This suggests that the observation of solvolysis products derived from homoallyl cation arises from a modification of this PE surface owing to solvent effects. Table 9 Energy data (kcal mol- ')formolecules (I 3)-( 17) Molmdr~ 4.31G STO 3G Bisected cyclopropylcarbinyl (17) 0 0 trans staggered homoallyl(l5) 20.0 33.4 cis staggered homoallyl (13) 21.4 35.0 trans perpendicular homoallyl (16) 22.3 32.7 cis perpendicular homoallyl(l4) 23.2 34.4 Illustrative of the sort of problems now amenable to detailed theoretical study are investigations of the ethylenebenzenium cation and of protonated ben~ene.~ The long-standing problem of the representation in terms of rapidly equilibrat- ing classical /?-phenylethyl cation or non-classical bridged ion has largely been settled by the work of Olah.64 However it is nice to confirm the much greater stability of the bridged ion by direct calculation.Four conformers of the classical ion have been investigated and the results are shown in Table 10 together with the computed (partially optimized) geometry for ethylenebenzenium ion. Table 10 Energy &tcr (kcal mol- ')for molecules (18F(22) and the computed geometry ofthe ethylenebenzenium ion Molecule STO 3G Bridged ethylenebenzenium (18) 0 Orthogonal perpendicular ethylenebenzenium (20) 35.4 Orthogonal staggered ethylenebenzenium (19) 42.3 Planar perpendicular ethylenebenzenium (22) 46.5 Planar staggered ethylenebenzenium (2 1) 48.8 r(C,C2) = 1.598 A r(C,C,) = 1.431 A H2 H2 r(C2C2')= 1.460A HI,'c ',HI r(C,C4) = (1.400 A) r(C4C5)= (1.400 A) <-,c2 r(C2H,) = (1.080A) r(C3H3)= (1.080 A) H3 ,Cl /H3 r(C4H4)= (1.080A) r(C5Hs)= (1.080A) c3 c3 LC,C,C,' = 54.4" LC3C1C3'= 115.8" I I LC,C,C4 = 122.1" LC3C4C5= (120.0") /c4.34 LC4C,C4' = (120.0") H4 C H LH12C2C2"Z= 158.2" LH,C,H2 = 115.7" I LH,C,C = 118.3" LH4C4C = (120.0") H5 LHsCsC4 = (120.0") b3 W. J. Hehre J. Amer. Chem. SOC. 1972 94 5919. 64 G. A. Olah and R. D. Porter J. Amer. Chem. SOC.,1972,94 6877. D.T. Clark The theoretical of the protonation of benzene provides striking con- firmation for the model of electrophilic substitution built up by painstaking experimental investigations.The lowest energy structure corresponds to the proton bonded to a ring carbon which assumes approximately tetrahedral geometry. This is found to be -20 kcal lower in energy than a proton-bridging carbon-carbon bond whilst edge- and face-protonated structures are very much higher in energy. Preliminary calculations indicate that the bridged protonated species is a saddle point for proton migration. 3 ESCA Introduction.-The growing importance of ESCA as a spectroscopic technique is evidenced by meetings devoted exclusively to this and by the introduction of a new Useful reviews of the literature in addition to that reported last year are given in ref.69. An interesting comparative review of applications of n.q.r. n.m.r. and ESCA to organonitrogen systems has been given.70 A useful introduction to ESCA has been given by N~rdling.~’ An introduction to electron spectroscopy has also appeared in Chemical Society Reviews.72 65 W. J. Hehre and J. A. Pople J. Amer. Chem. SOC. 1972 94 6901. 66 ‘Electron Spectroscopy’ Proceedings of International Conference Asilomar Sept. 1971 ed. D. A. Shirley North-Holland Amsterdam 1972. 67 Chem. SOC. Faraday Division Discussion Meeting Brighton September 1972. 68 Journal uJ Electron Spectroscopy and Related Phenomena Elsevier Oct. 1972 Vol. 1. :9 D. M. Hercules Analyt. Chem. 1972 44 106R. ’H. G. Fitzky D. Wendisch and R. Holm Angew. Chern. Internat. Edn. 1972 11 979.” C. Nordling Angew. Chem. Internat. Edn. 1972 11 83. ’’ C. R. Brundle A. D. Baker and M. Thompson Chem. SOC. Reu. 1972 1 355. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 67 Instrumentation.-With the majority of commercial instruments employing an unmonochromatized X-ray source (either MgKor ,,or AlKor ,,,) the best attain- able resolution is more often than not limited by the inherent width of the exciting radiation (-0.8 eV for MgKor,,, -1.0eV for AlKcr,,,). Chemical shifts are frequently of the same order of magnitude and although under carefully controlled conditions lineshapes and peak widths may be sufficiently accurately defined to allow deconvolution of unresolved peaks an improvement in resolu- tion would clearly extend the scope of the technique.The development of X-ray monochromators has drastically improved the situation and there are indications that the inherent widths of many core levels of interest to organic chemists may be sufficiently small to allow subtle variations in electronic environment which are unobservable with present instrumentation to be detected by ESCA. (The inherent width of the Cls level in some molecules may be <0.1 eV which is less than +5 of the width normally observed with most commercial instruments). Most of the design innovations in ESCA spectrometers are attributable to the father of the technique Kai Siegbahn who has now publi~hed’~,’~ design details for new instruments incorporating monochromators and employing either disper- sion compensation or slit filtering.The importance of such developments cannot be overstressed since they will provide the same sort of impetus to ESCA that development of n.m.r. spectrometers operating at higher field strength had to the development of n.m.r. in its infancy. Theory.-The most fundamental measurements made in ESCA are shifts in core levels. The interpretation of such data provides a fertile area of research for the theoretician and considerable computational effort has been expended in under- standing ‘chemical’ shifts. In theory the binding energy of an electron in a core level of an atom in a molecule may be calculated as the energy difference between the neutral molecule and the hole state. In practice such calculations are normally carried out within the Hartree-Fock model which neglects both relativistic and correlation-energy changes.Although for core levels changes in the latter two terms are known to be small the question of how small is small has remained open in the case of molecules. In a detailed study of the ionized states of the CH molecule with a basis set approaching the Hartree-Fock limit Clementi and Popkie have demon~trated’~ that for the 1s hole state the correlation energy is exactly the same as for the neutral molecule. Correlation energy therefore makes no contribution to the binding energy of the 1s electron which is given within experimental error as the energy difference at the Hartree-Fock limit. The diffi- culty and expense of carrying out such calculations has provided the impetus for searching for computationally simpler models.For limited series of closely related molecules Koopmans’ Theorem gives an adequate interpretation of chemical shifts of core levels. However this depends upon the fact that for 73 K. Siegbahn D. Hammon H. Fellner-Feldegg and E. F. Barnett Science 1972 176 245. 74 K. Siegbahn Proceedings Third International Conference on Atomic Physics Boulder Colorado Aug. 1972. 75 E. Clementi and H. Popkie J. Amer. Chem. Soc. 1972,94 4057. 68 D.T. Clark related molecules with similar valence electron distributions relaxation energies (ignored in Koopmans’ Theorem) tend to be closely similar. If this is not the case then Koopmans’ Theorem cannot be expected to apply.In the case of sydnones for+ example the unusual valence electron distribution results in different relaxa- tion energies for different atoms and hence Koopmans’ Theorem does not give a quantitative description of shifts for such a system.76 The incorporation of relaxation into chemical shift calculations is most readily accomplished with the Equivalent Core Thermodynamic model of Jolly and Hendri~kson.~~ More often than not the necessary thermodynamic data are not available although the heats of reaction necessary for computing shifts corre- spond to simple isodesmic reactions for which theoretical heats of formation may be calculated quite accurately with relatively modest basis sets. Clark and Adams have inve~tigated~~ this approach in some detail and Cls binding energies for a variety of organic molecules encompassing wide variations in valence electron reorganization or relaxation accompanying photoionization of core levels with conspicuous success.Calculations employing MIND0/2 are also qualitatively successf~l.~ Non-empirical calculations are feasible on only a minute propor- tion of molecules of interest to the organic chemist and hence considerable effort has been devoted to the development of reliable computationally inexpensive models in which only the valence electrons are considered. Two distinct but related approaches have been developed. The charge potential model in which binding energies are related to the charge distribution in a molecule as was originally developed by Siegbahn and co-workers” and may be related to Koopmans’ Theorem (i.e.in a zero differential overlap treatment by expanding the expression for the Fock eigenvalues and grouping together terms independent of the local electronic environment).This model has great conceptual appeal to the average chemist relating as it does charge distribution and binding energies. Charge distributions defined in terms of electron populations on atoms are however somewhat arbitrary since the electron distribution in a molecule is a continuous function. As an alternative (and more correct approach) therefore Schwartz” has developed the potential at an atom model the main drawback of which is lack of conceptual simplicity as far as the average chemist is concerned.Most discussions of chemical shifts of binding energies for larger molecules have 76 M. Barber S. J. Broadbent J. A. Connor M. F. Guest I. H. Hillier and H. J. Puxley J.C.S. Perkin II 1972 1517. ” W. L. Jolly and D. N. Hendrickson J. Amer. Chem. Soc. 1970,92 1863. 78 D. T. Clark and D. B. Adams J.C.S. Furuduy II 1972,68 1819. 79 D. C. Frost F. G. Herring C. A. McDowell and I. S. Woolsey Chem. Phys. Letters 1972 13 391. K. Siegbahn C. Nordling G. Johansson J. Hedman P. F. Heden K. Hamrin U. Gelius T. Bergmark L. 0.Werme R. Manne and Y. Baer ‘ESCA Applied to Free Molecules’ North-Holland Amsterdam 1969. 81 M. E. Schwartz Chem. Phys. Letlers 1970 6 631; 7 78. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 69 centred around these two models or variants of them.82-87 In two important papers Shirley and co-workers have shown how within valence electron only treatments the effect of relaxation energies may be incorporated into the charge potential model," and they have demonstrated the common features in the potential at an atom and equivalent core models.89 The majority of ESCA investigations on organic molecules refer to measure- ments on the condensed phase.If the sample is in electrical contact with the spectrometer then the Fermi level is a convenient energy reference. On the other hand theoretical calculations refer to isolated molecules with the vacuum level as energy reference. (Measurements on solids and theoretical calculations can be related by means of an appropriate Born cycle.) The relaxation or reorganization energy the neglect of which is implicit in Koopman's Theorem as discussed above relates to isolated molecules and the question then arises will the relaxation of valence electrons accompanying photoionization of a core level be different if the molecule is studied in the condensed phase? An interesting discussion of this consideration which has largely been neglected up to now has been given by Shirley."' Chemical shift data and their relationship to electronic structure form a large part of the information derived from ESCA experiments on molecules radicals and ions.For paramagnetic species in addition the phenomenon of multiplet splitting can give direct information (complementary in many ways to that obtainable from e.s.r.) on the spin distribution of unpaired electron~.~~ As an example of this type of information derived from ESCA measurements Table 11 gives data pertaining to the Ols,Nls and Cls core levels of di-t-butyl nitroxide radicalg2 and for comparison data for NO.If there are k unpaired electrons (coupled to spin S) in the valence shell of a paramagnetic species then for an s hole state (e.g. 1s in Ols Nls) the multiplet splitting is given by where.&= fraction of unpaired valence electrons on atom i and 82 F. 0.Ellison and L. L. Larcon Chem. Phys. Lerters 1972 13 399. 83 K. Ishida H. Kato H. Nakatsuyi and T. Yonezawa Bull. Chem. SOC.Japan 1972 45 1574. 84 R. Rein A. Hartrnan and S. Nir IsraelJ. Chem. 1972 10 93.85 A. Imamarnura H. Fiyita and C. Nagata J. Amer. Chem. SOC.,1972 94 6287. 86 M. E. Schwartz and J. D. Switalski J. Amer. Chem. SOC.,1972 94 6298. M. E. Schwartz J. Amer. Chem. Sac. 1972 94 6899. D. W. Davis and D. A. Shirley Chem. Phys. Letters 1972 15 185. 89 D. A. Shirley Chem. Phys. Letters 1972 15 325. 'O D. A. Shirley Chem. Phys. Letters 1972 16 220. " Cf. ref 80. 92 D. W. Davis and D. A. Shirley J. Chem. Phys. 1972 56 669. 70 D. T. Clark Table 11 Binding energies and splittings of Is core levels (eV)92 Binding Linewidth Measured Case" energy (FWHM) splitting AE -NO(' n) 41 1.5(5)* 1.412( 16) -NOP n) 410.1(5) 0.93(2) No(lnj 543.6(5j 543.1(5) 0.9 l(2) 0.53q21) NG( n) dtb NO('n) 406.9(5) 1.1 3(4) 0.539(42) dtb NO(jIl) 406.4(5) dtb NO(' n) 536.7(5) 0.88(3) 0.448(26) dtb N?k3ITl-536.2(5) MethTC ' 290.3i5j 1.16(5) Tertiary C 29 1.4( 5) "The atom losing a Is electron is underlined.Assumed final-state symmetry is denoted parenthetically and 'dtb' means 'di-t-butyl'. I Standard deviation in the last digit is given parenthetically. Abso-lute values of binding energies are accurate to only 0.5 eV. i.e. a one-centre exchange integral between the core and valence orbitals on atom i. Hartree-Fock calculation^^^ on the four final states that can be formed by removing a single Is electron from NO(2x,) are in excellent agreement with the experimental measurements and indicate that there is a much larger unpaired spin density on nitrogen. By comparison the splittings for the Nls and 01s core levels of di-t-butyl nitroxide radical indicate that the unpaired spin density on oxygen is similar to that in NO but the nitrogen atom loses spin density (to the alkyl groups).As an added bonus the observation that the absolute binding energies for both the Nls and 01score levels are reduced on going from NO to the organic radical is indicative of increased electron density about these atoms. Clearly with improvements in resolution the investigation of multiplet effects in organic free radicals will be valuable. Chemical shift data and multiplet splittings give information regarding the distribution of valence electrons in molecules etc. Further detailed information can also sometimes be obtained from the observation of satellite peaks to the low kinetic energy side of the primary photoionization peaks associated with double ionization (shake-off) and excitation (shake-up) processes accompanying photoionization.The sudden perturbation of the atomic potential at the moment of departure of a core electron in the initial photoionization process can bring about the emission or excitation of a valence electron and in the sudden approxi- mation the probability of exciting an electron from the orbital nlj of the neutral atom to the n'lj orbital of the ion is given by pn,lj+nlj =NiJ'+~~j+~,~jd~ l2 Since this probability involves the overlap of the two orbitals the selection rules governing the shake-up excitation are of the monopole type i.e. AJ =AL = AS =AMJ =AML =AMS =O 93 P.S. Bagus and H. F. Schaeffer J. Chem. Phys. 1971 55 1174. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA The first observation and interpretation of such phenomena was for the inert gases but several organic molecules have now been investigated which demons- trate the interesting information contained therein. In an important paper,94 Hillier and co-workers have shown how the positions and intensities of satellites in simple molecules may be calculated using relatively crude (INDO) wave-functions. A discussion of shake-up satellites for CO COz,and C,Oz has been given together with a valuable general discussion rationalizing the failure to observe shake-up satellites in many simple molecules (e.g. benzene thiophen pyrrole and furan).An interesting example provided by 3-methyl~ydnone,’~ is shown in Figure 9. A satellite is clearly evident close to the Nls peaks (incom- pletely) resolved corresponding to N-1 and N-2 respectively in order of decreas- ing binding energy. Detailed calculations show that the satellite arises from shake-up of an electron from the highest occupied n orbital with large amplitude at N-2 to the lowest x* orbital also with large amplitude at N-2. 3-Met hylsydnone I I 1 I 1 407 405 403 401 399 Figure 9 Nls spectrum of 3-methylsydnone showing the presence of a satellite (binding energy 405.8 eV) Substituent Eflects. Systematic studies ofsubstituent effects in benzene pyridine pyrazine pyrimidine and pyradazine and their perchloro- and perfluoro- derivatives have been reported by Clark and co-worker~.~~ The results may be y4 L.J. Aarons M. F. Guest and I. H. Hillier J.C.S. Furuduy ff 1972 68,1866. D. T. Clark R. D. Chambers D. Kilcast and W. K. R. Musgrave J.C.S. Furuduy ZZ 1972 68 309. 72 D.T. Clark discussed quantitatively in terms of the charge potential model and all-valence- electron SCFMO calculations. The close analogy between organic chemists' intuitive ideas concerning charge distribution and chemical shifts is nicely demonstrated by the data. A detailed study has been made by Shirley and co- workers of fluorinated benzenes." The results may be discussed quantitatively employing the potential at an atom model using CND0/2 wavefunctions. Fluorobenzene has been the subject9' of a detailed non-empirical LCAO MOSCF treatment which confirms that in order of decreasing binding energy the assignment of Cls levels previously made98 is Substituent effects in alkyl iodides have been studied99 and by comparison with data corresponding to the 5p ionization potentials obtained from U.V.photo- electron spectroscopy it can be established that chemical shifts are due to varia- tions in electron distribution along the carbon-iodine bond. Nitrogen Is core binding energies have been reported'00 for salts (primarily hydroiodides) of pyridine monoprotonated pyrazine 1,2- 1,4- and 1,Sdiaza- naphthalenes 1,2- and l75-diarninonaphthalenes,1,lO-phenanthroline and 2,2'-bipyridyl. The binding energy differences between the protonated and unprotonated nitrogens are indicative of substantial electron withdrawal from the aromatic rings.Charge Distributions Direct from ESCA Measurements.-The direct determina- tion of charge distributions for complex molecules from molecular core binding energies presents an interesting challenge. The most obvious way of accomplish-ing this would be by inversion of the charge potential model i.e. knowing the constants Eo and kj [equation (l)] for each core level of the constituent atoms of the molecule and its geometry having measured the binding energies (EJ,set up a series of simultaneous equations and solve for the charges qi. The feasibility of this approach has been spectacularly demonstrated by several groups of workers.96,101-103 The most detailed investigation has included the computa- tion of charge distributions in bicyclic aromatic hydrocarbons and their perfluoro- analogues.'o1 The parameters kiand EP for Cls and Fls can be established by studying series of closely related molecules for which theoretically calculated charge distributions (usually CND0/2) are available.In the particular case of 96 D. W. Davis D. A. Shirley and T. D. Thomas J. Amer. Chem. SOC.,1972 94 6565; J. Chem. Phys. 1972,56 671. 97 D. T. Clark D. Kilcast D. B. Adams and I. Scanlan J. Electron Spectroscopy 1972 1 153. 98 D. T. Clark D. Kilcast and W. K. R.Musgrave Chem. Comm. 1971 576. 99 J. A. Hashmall B. E. Mills D. A. Shirley and A. Streitweiser J. Amer. Chem. Soc. 1972 94,4445. loo L. E.Cox J. J. Jack and D. M. Hercules J. Amer. Chem. Soc. 1972 94 6575. '0' D. T. Clark D. B. Adams and D. Kilcast Chem. Phys. Letters 1972 13 439. lo* D. T. Clark W. J. Feast D. Kilcast D. B. Adams and W. E. Preston J. Fluorine Chem. 1972,2 199. lo3 G. D. Stucky D. A. Mathews J. Hedman M. Klasson and C. Nordling J. Amer. Chem. Soc. 1972 94 8009. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA molecules containing hydrogen a problem arises since there are no energy levels characteristic of the hydrogen 1s orbitals. This can be overcome by defining pseudo Ei-EP and ki values for hydrogen which reproduce the computed charge distributions in reference molecules such as methane and benzene. The experimental charge distributions obtained in this way are in excellent agree- ment with direct theoretical calculations for C F and H atoms.In a study of experimental charge distributions in fluorobenzenes Shirley and Davis96 circumvented this particular problem by requiring that the charge distribution on each hydrogen be the same and then made use of the extra equation express- ing the overall neutrality of the molecules. Clark and co-workers have shown how for measurements on solid samples this extra equation can be used to investigate sample charging."' As a representative example of the state of the art,"' Figures 10 and 11 show the measured Cls levels of tetradecafluoro- tricyclo[6,2,2,0'*7]dodeca-2,6,9-triene (23) which together with the Fls levels allows the direct determination of the experimental charge distribution as shown.The very close agreement with theoretically calculated (in this case CND0/2 since the parameters ki and EP have been established for such charge -0.14) (-0.15) '(-0.18) -0.16 -0.19 Figure I0 Experimental and CND0/2 charge distributions in compound (23). CND0/2 SCF-MO charges in parentheses (Reproduced by permission from J. Fluorine Chem. 1972,2 199) D. T. Clark Binding energy feV Figure 11 The Cls spectrum and its deconuolution for compound (23) (Reproduced by permission from J. Fluorine Chem. 1972,2 199) distributions) charge distributions is quite striking. For this size of molecule it is probably true to say that it is easier to obtain charge distributions by experi- ment than by direct calculation.Nordling and co-workers have in~estigated"~ charge distributions for tetra- cyanoethylene tetracyanoethylene oxide tetracyanopropane cyclopropane and ethylene oxide. A qualitative discussion of charge delocalization in 1,3,5-trithian oxides has also been given.lo4 Although not of direct interest to the material presented in this report mention might also be made of an interesting investigation of the valency of iron in ferredoxins.lo5 Structural Studies.-Halogenocarbun Chemistry. The large shifts induced in core levels on replacing hydrogen by fluorine or chlorine make ESCA studies of halo- genocarbons particularly attractive with currently available instrumentation. The interesting structural features in this field also pose problems for many conventional spectroscopic techniques.With detailed investigations of simple systems and development of quantitative models application of ESCA to struc- tural problems in this field is beginning to have a considerable impact. Thus the structure of allylpentachlorocyclopentadiene obtained by reaction of a solution of hexachlorocyclopentadiene in diethyl ether which has been successively treated at -20 "Cwith two molecular proportions of LiAlH and allyl bromide could be d e orfas shown in Figure 12. Previous attempts at unambiguously determining the structure of the product by conventional techniques had not allowed an unambiguous assignment between d and e. The Cls spectra of the precursor and allyl pentachlorocyclopentadiene' O6 shown in Figure 13 allow a ready distinction to be made between d and e,fon the basis of the presence or absence of high binding energy peak due to a CCI group.The structure may '04 H. Iwamura M. Fukunaga and K. Kushida J.C.S. Chem. Comm. 1972 450. D. Leibfritz Angew. Chem. Internal. Edn. 1972 11 232. lo6 D. T. Clark W. J. Feast M. Foster and D. Kilcast Nature 1972 236 107. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA a b C d e f Figure 12 Reaction pathway and possible chemical structures (Reproduced by permission from Nature 1972,236 107) 289 J i 241 249 287 2k5 ' 2k7 2k5 2b Binding energyjeV Figure 13 Cls spectra of hexachlorocyclopentadieneand allylpentachlorocyclopentadiene (Reproduced by permission from Nature 1972,236 107) D.T.Clark thus be unambiguously determined on the basis of measurements requiring -20 min of instrument time and -0.1 pl of sample. By comparison the structure can also be settled by n.m.r. (3sCl 37Cl) measurements but the sample size is now -1 ml and the time taken -5 h. The advantage of ESCA is clearly demonstrated. A more complex example is provided by the determinationlo7 of the site of nucleophilic substitution'in perfluoroindene. Reaction of perfluoroindene with sodium borohydride in diglyme gave a mixture ofdihydro products in a 4 1ratio. 'H and 19F n.m.r. measurements together with i.r. studies established that the product was a mixture of 1,1,3,4,5,6,7- and 1,1,2,4,5,6,7-heptafluoroindenes(24) and (25).However it was not possible by conventional spectroscopic techniques to identify the major isomer. The isomers were not separable on available g.1.c. packings and the quantity of sample available was -0.1 gm. From theoretical 293.0 291.0 284.0 283.0 28t.O 293.0 291.0 284.0 287.0 283.0 Figure 14 Compirter-simulated theoretical Cls spectra for the individual components and mixtures of(24) and (25). (a) (24);(b) (25);(c)(24):(25),4 :1 ;(d) (25):(24) 4 :1 (Reproduced by permission from Nature 1972 239 47) lo' D. B. Adams D. T. Clark W. J. Feast D. Kilcast W. K. R. Musgrave and W. E. Preston Nature J 972 239 47. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA (CND0/2) SCFMO calculations of charge distributions spectra for the Cls levels for 4 1 mixtures of (24):(25)and (25):(24)may be computed as shown in Figure 14.Comparison in terms of peak intensities and absolute binding energies with the measured Cls levels for the mixture Figure 15 allows un- ambiguous assignment of major component as (25). I 29j.O 29 1 .o 26.0 28i.o 28i.O Figure 15 Experimental Cls spectrum of the mixture of (24) and (25) hydrohepta-fluoroindene. (Binding energies in eV) (Reproduced by permission from Nature 1972,239,47) Organonitrogen Compounds. In addition to the papers previously mentioned on six-membered ring nitrogen heterocycle^,^^ protonated nitrogen bases,’” and ~ydnones,’~ interesting applications of ESCA have been made to the electronic structure of ‘hexanitrosobenzene’108 and the nature of protonated 1,8-bis- (dimethy1amino)naphthalene (‘proton sp~nge’).’’~ The Cls Nls and 01s ‘On J.Bus Rec. Trav. chim. 1972 91 552. ‘09 E. Haselbach A. Henriksson F. Jachimowicz and J. Wirz Helv. Chim. Acta 1972 55. 1757. D. T. Clark N& ,k-O O4 I> Cls Nls 01s 405.0 533.4 287.5 285.6 I I I I 290 285 405 400 535 530 -Electron binding energy/eV Figure 16 Electron spectrum of benzotri~[c]-2-0~yfurazan, excited with MgKcr-radiation (Reproduced by permission from Rec. Trau. chim. 1972,91 552) spectra measured for ‘hexanitrosobenzene’ Figure 16,show that the hexanitroso structure is ruled out and support the formulation as benzotris[c]-2-oxyfurazan which had previously been suggested on the basis of X-ray diffraction and i.r.investigations. The doublet nature of the Nls region of protonated 1,8-bis- (dimethylamino)naphthalene,Figure 17 indicates that the system possesses an unsymmetrical N-H. .N hydrogen bridge. Carbonium Ions. More details have appeared of ESCA investigations of nor- bornyl cation and related systems by Olah and co-workers.”’ The difficulty in generating and maintaining uncontaminated surface layers containing reactive species is evidenced by the poorly resolved spectra which are none the less sufficiently resolved to demonstrate the distinction between classical and non- classical ions. The time scale involved as far as ESCA measurements are con- cerned is extremely short (the lifetimes of hole states are typically in the range ‘‘O G.A. Olah G. D. Mateescu and J. L. Riemenschneider J. Amer. Chem. SOC.,1972 94. 2529. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA I I 4 1 eV 403 40 1 399 Figure 17 (Reproduced by permission from Helv. Chirn. Acta 1972,55 1757) 10-14-10-s). ESCA is thus in principle capable of distinguishing between non-classical and rapidly equilibrating classical ion formulation of norbornyl cation (26),(27a and b). Olah and co-workers have investigated norbornyl cation and related model ions (28H30) with varying degrees of charge localization. D. T. Clark The Cls spectra show two distinct peaks for (28H30) with the peak at higher binding energy in each case being attributed to the carbon atom bearing substan- tial positive charge (cJ Table 12 and comparison with t-butyl cation) Figure 18.Table 12 Binding energy digerences of curbonium ion centres from neighbouring carbon atoms Ion AEb(Ct-C) Approximate rel. C+/C intensity (CH3)$+ (29) (30) (28) 3.9 +_ 0.2 4.2 f0.2 3.7 * 0.2 4.3 & 0.5 113 115 117 114 (26) 1.7 f0.2 215 Cls spectra for 2-methylnorbornyl cation (30) show a smaller separation indicative of some CT delocalization in the bicyclo[2,2,l]heptyl system. In striking contrast the Cls spectrum of norbornyl cation shows a single broad line with a pronounced shoulder on the higher binding energy side (corresponding to C-2 and C-6). The separation of 1.7eV clearly shows the extensive charge delocaliza- tion and thus confirms the I3C n.m.r.and Raman spectroscopy data that the norbornyl cation is best formulated as a methylene-bridged five-co-ordinated 'non-classical' ion. Charge delocalization in acyl cations has also been investigated" for the hexafluoroantimonates. Spectra for CH,CO+ and C,H,CO+ are shown in Figure 19. The shifts in Cls binding energies between CO and CH (or C6H5) are substantial 6.0 eV (5.1 eV) (c$ 2.6 eV for CH,CHO). The larger shift and higher absolute binding energy for the CO carbon 1s level in CH,CO+ compared with C,H,CO provides strong evidence for the much greater charge delocaliza- + tion in the latter. Polymers. The application of ESCA to problems of structure and bonding in polymers is a rapidly expanding field. The great advantages of the technique in being able to study in principle the core and valence levels of any element regard- less of nuclear properties such as magnetic or electric quadrupole moments coupled with the low sample requirements and the ability to study involatile insoluble solids is nowhere more apposite than in the study of polymers.As part of a systematic study the general philosophy of applying ESCA to polymer chemistry has been outlined.l12 A detailed study has been made of nitroso rubbers. * Theoretical calculations employing CND0/2 charge distributions and the charge potential model show l1 that for saturated systems the factors determining shifts are sufficiently short range for quantitative *I1 G. D. Mat-escu J. L. Riemenschneider J. J. Svoboda and G. A. Olah J. Amer.Chem. SOC.,1972 94 7 19 1. 'Iz D. T. Clark D. Kilcast W. J. Feast and W. K. R. Musgrave J. Polymer Sci. Purr A-I Polymer Chem. 1972 10 1637. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 8 1 CIS 202 I\ +CH ’\ 0 206.4 c I 1 I 290 285 280 e Binding energy Figure 18 Carbon Is electron spectrum of norbornyl cation (lower truce) and 2-methyl- norbornyl cation (upper trace) (Reproduced by permission from J. Amer. Chem. SOC. 1972,94,2529) treatments of ESCA data for polymers to be feasible. For the nitroso rubbers investigated (copolymers of CF,NO and CF,=CFX X = F H or C1) individual core levels have linewidths little different than that for comparable monomers. The ESCA data together with theoretical calculations on model systems incor- porating all short-range effects give a wealth of data which in increasing level of complexity may be listed as :element maps demonstration of alternating 1,l-copolymer nature of the polymers and in the case of X = H and C1 information D.T.Clark CIS 698 1872 0 290 285 280 eV Binding energy Figure 19 Carbon 1s electron spectra of methyloxocarbenium and phenyloxocarbenium hexa$uoroantimonate (Reproduced by permission from J. Amer. Chem. Soc. 1972,94 7191) l3 C. R. Ginnard and W. M. Riggs Analyr. Chem. 1972,44 1310. J. M. Andre and J. Delhalle Chem. Phys. Letters 1972 17 145. '15 M. H. Wood M. Barber I. H. Hillier and J. M. Thomas J. Chem. Phys. 1972 56 1788. ' l6 M. M. Millard Analyt.Chem. 1972,44 828. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA on structural isomerism. The effect of fluorine substitution on molecular core binding energies has been investigated for homopolymers of vinyl fluoride vinylidene fluoride and trifluoro- and tetrafluoro-ethylenes.' l3 The results have been discussed in terms of CND0/2 and EHT charge distributions' l4 and Pauling electronegativities.' An experimental and theoretical study has been reported of the valence bond structure of polyethylene' ' which complements the study reported last year for PTFE. As an interesting example of the scope of ESCA as a technique an investiga- tion has been reported of surface oxidized wool fibre.'

ISSN:0069-3030    

DOI:10.1039/OC9726900040

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

2 Physical Methods Part (iv) Optical Rotatory Dispersion and Circular Dichroism By P. M. SCOPES Westfield College Hampstead London NW3 7ST 1 Developments in Technique During 1972 there have been several developments in the technique of optical rotatory dispersion (0.r.d.) and circular dichroism (c.d.) measurements particu- larly in extending the accessible wavelength range. For example 0.r.d. and c.d. have not been used extensively for the study of carbohydrates despite the importance which these compounds assumed in earlier work with monochromatic rotations. This situation which arises from the absence in carbohydrates of a chromophore absorbing in the easily accessible region of the spectrum has been changed by the development of vacuum-u.v. c.d.equipment measuring down to about 164 nm.’ This year a study has been made2 of the c.d. of three unsubstituted monosaccharides (D-glucose D-galactose and D-xylose) in anomeric equilibrium in aqueous solution. All three compounds have been shown to exhibit Cotton effects with a definite maximum near 170 nm but the origin of the corresponding electronic transition is not known. At much longer wavelengths vibrational c.d. has been detected for the first time in the i.r. spectrum of a cholesteric me~ophase;~ corresponding i.r. 0.r.d. has also been ob~erved.~ The measurement of c.d. in oriented optically active solids can give erratic results due to birefringence and an attempt has been made5 to assess the reliability of the results obtained by this technique.Most of the work reported this year has been concerned with a much more precise definition of the relationship between chirality and the sign of the Cotton effect with the ‘failures’ of accepted semi-empirical rules and with the apparent anomalies. This will be considered according to the chromophore concerned. 2 Carbonyl Compounds For more than a decade the octant rule6 has provided the general framework for consideration of carbonyl n+ n* Cotton effects but there has always been ‘ W. C. Johnson Reu. Sci. Instr. 1971 42 1283. R.G. Nelson and W. C. Johnson J. Amer. Chem. SOC. 1972 94 3343. R. J. Dudley S. F. Mason and R.D. Peacock J.C.S. Chem. Comm. 1972 1084. B. Schrader and E. H. Korte Angew. Chem. Internat. Edn. 1972 11 226. ’ B.Norden Acta Chem. Scand. 1972 26 1763. W. Moffitt R. B. Woodward A. Moscowitz W. Klyne and C. Djerassi J. Amer. Chem. SOC..1961. 83.4013. 84 85 Physical Methods-Part (iu)O.R.D. and C.D. some ambiguity about the position of the nodal surface separating 'front' and 'back' octants and about the predicted reversal of sign in front octants. Compari- son of c.d. data for 7-keto-5a-steroids a 7-keto-~-homo-5a-steroid(1) and the de-D-analogue (2) now shows quite unambiguously the anticipated reversal of sign for alkyl substituents in front octants (here the D-ring) and permits assign- ment of a numerical value for the contribution to the carbonyl Cotton effe~t.~ A detailed analysis of cyclopropyl ketones that are perturbed in front octants has also appeared ;* for these compounds the author suggests that the third nodal surface is curved and passes approximately through the middle of the C=O bond with the convex face towards oxygen.Attention has been drawn to the apparent failure of the octant rule in the twistane ~eries,~ for which the absolute configuration originally allotted to (+)-twistane by 0.r.d. has been reversed by a chemical correlation" and by c.d. measurements on various derivatives of twistane-cis-4,5-dioI to (3). The original assignment was based on the application of the octant rule to the ketone (-)-(4). The present authors' emphasize that in this compound the side chain (3) (4) HO,CCH, which determines the sign of the Cotton effect is a p-axial substi- tuent ;since this is believed to be anti-octant in its contribution there is no dis- agreement between results obtained by different methods.In related work,' the c.d. of several steroids incorporating the bicyclononane structure supports the suggestion that the increments found for P-substituents in adamantanones are generally valid. Carbonyl Cotton effects have also been studied for an extensive series of 3-keto-steroids with varying configurations of the hydrocarbon skeleton.' * D. N. Kirk W. Klyne and W. P. Mose Tetrahedron Letters 1972 1315. ' J. F. Tocanne Tetrahedron 1972 28 389. G. Snatzke and F. W. Zamojska Tetrahedron Letters 1972 4275. lo '' M. Tichq Tetrahedron Letters 1972 2001. G. Snatzke and K. Kinsky Tetrahedron 1972 28 289. l2 H.J. C. Jacobs and E. Havinga Tetrahedron 1972 28 135. P.M. Scopes Cotton effects have been reported' for the n * o* transition of the carbonyl group between 185and 195 nm ; the results for a series of steroid ketones show that decalones lacking a-and /3-axial substituents give small or negligible Cotton effects but when axial groups are present they make strong contributions to the n+ o* maximum following the same signs as back octants in the normal octant rule for the n jn* transition (5). (There is no evidence for front octant effects for the n+ o* transition ref. 7.) I I I I (small) + ( sinaI I ) I 1 I Vicinal effects in diketones have been discussed by several groups of workers'&'' and a further contribution'* has been made to the study of chirality in skewed a-diketones.3 Olehs and Related Compounds Our understanding of the relationship between chirality and the sign of the observed Cotton effect for many unsaturated chromophores is still very incom- plete ;apparent anomalies in the behaviour of heteroannular cisoid dienes' and of isolated double bonds" have been discussed. Levin and Hoffman2' suggest that two effects are important in determining the sign of the observed c.d. in olefins ;the dominant effect is the torsion in the olefin chromphore and the second contribution is due to perturbation of the chromophore by substituents. Bee~ham~~.~ has reported an extensive survey of the relationship between chirality and c.d. of a@-unsaturated lactones based on evidence of precise l3 D.N. Kirk W. Klyne W. P. Mose and E. Otto J.C.S. Chem. Comm. 1972 35. l4 D. A. Lightner G. D. Christiansen and J. L. Melquist Tetrahedron Letters 1972,2045. * G. Snatzke and K. Kinsky Tetrahedron 1972 28 295. G. Cleve and G. A. Hoyer Tetrahedron 1972 28 2637. G. Snatzke and H. Klein Chem. Ber. 1972 105 244. W. Hug and G. Wagniere Helv. Chim. Acra 1972 55 634. E. Charney J. M. Edwards U. Weiss and H. Ziffer Tetrahedron 1972 28 973. 2o A. Yogev J. Sagiv and Y. Mazur J.C.S. Chem. Comm. 1972,411. 21 C. C. Levin and R. Hoffman J. Amer. Chem. SOC.,1972,94. 3446. A. F. Beecham Tetrahedron 1972 28 5543. 23 A. F. Beecham Tetrahedron Letters 1972 1669. Physical Methods-Part (it.) O.R.D.and C.D. molecular geometry from X-ray analyses. The author concludes that the sign- chirality relationship previously proposedz4 for pentenolides is correct and that the same relationship holds for butenolides (contrary to the existing rulez5). 4 Aromatic Chromophores The optical activity of a wide range of chromophores of C,symmetry has been discussed in detail by Hug and Wagniere,26 and the particular case of the di- benzoate chirality rule (referred to as the 'exciton chirality method' by the authors) has been re~iewed.~' The observed c.d. of a series of chiral derivatives of 9,10-ethano-9,10-dihydroanthracene(symmetry C,) has been shown28 to correspond to rotational strengths calculated by the dipole-velocity method rather than by the point-dipole exciton treatment and the reasons for this inconsistency have been considered.Interaction between aromatic chromo- phores has also been reported for a triptycene deri~ative,~ and for (S)-trans-1,2-di-(4-pyridyl)oxiran. Problems of interpretation also arise for compounds containing isolated aromatic chromophores from overlap of Cotton effects due to the 'Loaromatic transition (ca. 220 nm) with those from other chromophores. Verbit and Price3' have studied the c.d. of substituted phenylcyclohexanes and observe that the 'La transition is characterized by a width at half-height of 10-20 nm. They suggest that Cotton effects in this range and at the appropriate wavelength should be attributed essentially to the 'L transition. The influence of the substitution pattern of an aryl nucleus on the observed 'L Cotton effect has also been studied.The absolute configuration of several natural products has been allotted from studies of their chiroptical properties. Previous conflicting results on the Zbogu and Voacanga groups of alkaloids have been resolved by a c.d. on coronaridine (6) catharanthine (7) and their respective derivatives which 24 G. Snatzke Angew. Chem. Internat. Edn. 1968 7 14. 25 G. Snatzke H. Schwang and P. Welzel 'Some Newer Physical Methods in Structural Chemistry ed. R. Bonnett and J. G. Davis United Trade Press London 1967 p. 159. 26 W. Hug and G. Wagniere Tetrahedron 1972 28 1241. '' N. Harada and K. Nakanishi Accounts Chem. Res. 1972,5 257. 28 S. Hagishita and K. Kuriyama Tetrahedron 1972 28 1435.29 J. de Wit and H. Wynberg Tetrahedron 1972 28 4617. 3" G. Gottarelli and B. Samori J.C.S. Perkin 11 1972 1998. 31 L. Verbit and H. C. Price J. Amer. Chem. SOC.,1972 94 5143. 32 G. Snatzke M. Kajtar and F. W. Zamojska Terruhedron 1972 28 281. '' K. Blaha Z. Koblicova and J. Trojanek Tetrahedron Letters 1972 2763. P.M. Scopes are shown to belong to two groups of enantiomeric type; lysergic acid deriva- tive~,~~ spirobenzylisoquinoline alkaloids,35 and pyrrolizidine alkaloids36 have also been studied. For 1-indanones and 1-tetralones there is a clash between configurational assignments based on c.d. and on Horeau's method which has been discussed by Snatzkea3' C.d. measurements have been suggested as a pos- sible method for distinguishing between C-glycosylflavones (8) substituted at C-6 and C-8.38 5 Carboxylic Acids and Related Compounds C.d.curves offer a possible basis for the analysis and identification of protected amino-acids as well as a tool for the study of their conformation. This year reports have appeared concerning 3-nitr0-2-pyridyl-,~~ 3-hydroxypyridi- ni~rn,~',~' and cyclic ~ultam~~ dimed~nyl,~~ derivatives of amino-acids ;in each case the authors have considered both the absolute configuration of the amino- acid and the conformational possibilities of the protected derivative. Gafield and his colleagues44 have studied the chiroptical behaviour of N-nitrosamino- acids and model N-nitrosamines and have concluded that the signs of contribu-tions in the regional rule that was originally proposed for this chr~mophore~~ should be reversed.The relationship between the conformation of L-cystine and its chiroptical behaviour has also been discussed ;46 the authors conclude that the relatively large magnitude of the observed c.d. is due to unequal proportions of the various rotamers present and not to endocyclic interactions or to a biased screw sense. j4 K. Blaha Coll. Czech. Chem. Comm. 1972 37 2473. j5 M. Shamma J. L. Moniot R. H. F. Manske W. K. Chan and K. Nakanishi J.C.S. Chem. Comm. 1972 310. j6 J. Hrbek L. Hruban A. Klasek N. K. Kochetkov A. M. Likhosherstov F. Santavy and G. Snatzke Coll. Czech. Chem. Comm. 1972 37 3918. 37 M. J. Luche A. Marquet and G. Snatzke Tetrahedron 1972 28 1677.38 W. Gaffield and R. M. Horowitz J.C.S. Chem. Comm. 1972 648. 39 C. Toniolo D. Nisato L. Biondi and A. Signor J.C.S. Perkin I 1972 1179 1182. 40 T. Grmneberg and K. Undheim Acra Chem. Scand. 1972 26 2267. dl M. Gacek and K. Undheim Acta Chem. Scand. 1972,26 2655. 42 V. Tortorella G. Bettoni B. Halpern and P. Crabbe Tetrahedron 1972 28 2991. 43 G. Snatzke and S. H. Doss Tetrahedron 1972 28 2539. 44 W. Gaffield L. Keefer and W. Lijinsky Tetrahedron Letters 1972 779. 45 G. Snatzke H. Ripperger Chr. Horstmann and K. Schreiber Tetrahedron 1966 22 3103. 46 J. P. Casey and R. B. Martin J. Amer. Chem. SOC. 1972 94 6141. Physical Methods-Part (iv) O.R.D. and C.D. Derivatives of alkylphosphonothioic acids [RP(:S)(OH),] have also been st~died.~ ’ 6New Chromophores New chromophores include both less-common functional groups which absorb in an easily-accessible region of the spectrum and common functional groups which absorb in a region of the spectrum accessible only with the most recent equipment.Examples of the former include t)enzthiazole and benzthiazolidine derivatives4* and 4-methylphenylthio-derivatives of carbohydrates,4’ nitrate esters,’’ and nitroxide radicals.51 For nitrate esters a planar symmetry rule is proposed ;” the nitroxide group studied in optically active decahydroquinoline nitroxide radical^,^' shows a c.d. band at 420-450 nm the sign of which follows an octant rule analogous to the ketone octani. rule. The hydroxy-group is one of the most common functional groups and has hitherto been regarded as transparent for chiroptical purposes.Significant Cotton effects have now been measured for the hydroxyl chromophore near 190 nm$’ also for the gem-dimethylcyclopropyl group in the same wavelength regi~n.~ ” M. Mikolajczyk M. Para J. Omelanczuk M. Kajtar and G. Snatzke Tetrahedron 1972,28,4357. 48 G Snatzke F W. Zamojska L. Szilagyi R. Bognar and I. Farkas Tetrahedron 1972 28 4197. 49 K. Blaha V. Heimankova J. Jary and A. ZobaEova Coll. Czech. Chem. Comm. 1972,37,4050. R. E. Barton and L. D. Hayward Canad. J. C‘hem. 1972,50 1719. ” J. S. Roberts and C. Thomson J.C.S. Perkin .[I 1972 2129. 52 D. N. Kirk W. P. Mose and P. M. Scopes J.C.S. Chem. Comm. 1972 81. 53 F. Fringuelli A. Taticchi F. Fernandez D. M.Kirk and P. M. Scopes J.C.S. Chem. Comm. 1972 191.

ISSN:0069-3030    

DOI:10.1039/OC9726900084

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

2 Physical Methods Part (v) X-Ray Crystallography By A. F. CAMERON Chemistry Department University of Glasgow Glasgow G 12 8QQ 1 Introduction The current twelve-month period covered by this report has seen the continued publication of a large number of crystallographic examinations of organic com- pounds. Within this body of published work however it is possible to identify certain trends. Thus groups of workers may study series of compounds which are sufficiently large to indicate significant structural trends but more impor- tantly they are able to achieve this object in a relatively short space of time. More- over apart from studies of natural products it is now fairly unusual to encounter the heavy-atom method the use of direct methods for light-atom structures being commonplace.It would seem that the accuracy which may be achieved by use of diffractometer techniques of data collection for light-atom structures has resulted in a renewed interest in the detailed bonding effects which may be detected and studied by X-ray crystallography. In this context we observe an increasing number of publications in which genuinely ‘long’ C(sp3)-C(sp3) bonds are reported. As in previous years the large volume of published work necessitates that this article can describe no more than a small number (ca. 10%) of the organic studies which have been reported. Those analyses which are included for discussion have therefore been chosen in an attempt to present a spectrum of the crystallographic studies of organic molecules which are currently being reported and to give some impression of the relevance of the results to modern chemistry.2 Conformation and Bonding Several analyses have been undertaken to study the bonding and conformations of ylides. Compounds of this type which have been examined include the ammonium ylides (1) and (2)’’ and the sulphonium ylide (3),2 all of which are (1) (2) N. A. Bailey S. E. Hull G. F. Kersting and J. Morrison Chem. Comm. 1971 1429. J. P. Schaefer and L. L. Reed J. Amer. Chem. SOC.,1972 94 908. 90 Physical Methods-Part (v) X-Ray Crystallography I I Me Me (34 (3b) stabilized by the carbonyl function. The delocalization of the negative charge into the carbonyl groups of all three molecules is evidenced both by the lengths of the C-CO bonds [1.36 A in (1); 1.34 8,in (2); 1.400(6) 8,in (3)] and also by the lengths of the carbonyl bonds themselves [respectively 1.27 1.30 and 1.248(5)A].In the case of (3) it is suggested that the canonical form (3b) contri- butes 85 % to the structure. (+)-3-Diazocamphor (4)3 is also an ylide but in contrast to the geometries of the previous molecules the dimensions [C-CO 1.448(9);C=O 1.215(8) 8,]suggest that the additional stability of diazoketones over the corresponding diazoalkanes results from only minor contributions from the enolate forms of the ketonic derivatives. An allene-type geometry has been observed for di-p-tolylcarbodi-imide (5),4 in which the two C-N=C planes are approximately normal (38') to each other and in which the central N=C=N valence angle has a value of 170.4(4)".An interesting feature of this molecule is that the two C=N bonds have significantly different lengths [1.204(4) and 1.223(5) A] which are thought to result from dif- ferent values of the torsion angle (7.8" and 19.8") about the N-C(pheny1) bonds the longer bond being associated with the larger angle. Diphenylmethylene- aminodimesitylborane (6)' also proves to have an allene-type geometry the C-B-C and Ph-C-Ph planes being inclined at 87". The length of the B=N bond is 1.408,. Small-ring compounds which have been studied include diphenylcyclopro- penethione (7a),6 which is planar with the exception of the phenyl rings which are twisted out-of-plane by 4". The S=C bond has a length of 1.630(2)& and the non-equivalence of the C-C bonds within the cyclopropene ring [C=C A.F. Cameron N. J. Hair and D. G. Morris J.C.S. Perkin II 1972 1331. A. T. Vincent and P. J. Wheatley J.C.S. Perkin II 1972 687. G. J. Bullen and K. Wade Chem. Comm. 1971 1122. L. L. Reed and J. P. Schaefer J.C.S. Chem. Comm. 1972 528. A. F. Cameron (mesityl) C Ph \ / B=N=C / (mesityl) C \Ph Ph Ph Ph Ph (6) (74 (7b) 1.338(2);C-C 1.403(2)A]indicates that the structure is not well defined in terms of the zwitterionic form (7b) which would probably exhibit the equivalent bond lengths previously demonstrated for the cyclopropenium ion. Cyclobutane derivatives which have been examined include the head-to-head allene dimers (8) and (9),7 and the photo-cycloaddition product The analyses of (8) and (9) are the first to be reported for compounds containing the 1,2-dimethylenecyclo- butane group.In both molecules the chlorine atoms are trans and neither the cyclobutane rings nor the butadiene moieties are planar. The configuration of (10) is consistent with the suggestion that the photo-addition starts at C-3 and that rotational equilibration of the diradical intermediates is completed before ring-closure. In this case also the cyclobutane ring is non-planar with a dihedral angle of 149.3'. Me Me phYph CI C1 c1-c1 or (53 + C! The analyses of the oxazepines (11)9 and (12)" are representative of the con- formational studies of seven-membered heterocyclic compounds. Both molecules adopt boat conformations and the bond lengths are consistent with their being ' S.R. Byrn E. Maverick 0. J. Muscio K. N. Trueblood and T. L. Jacobs J. Amrr. Chem. SOC.,I97 1,93 6680. F. P. Boer and P. P. North J.C.S. Perkin 11 1972 416. B. Jensen Acta Cryst. 1972 B28 774. lo B. Jensen Acta Cryst. 1972 B28 771. Physical Methods-Part (u) X-Ray Crystallography conjugated trienes. Another seven-membered ring derivative 4,5-dihydrothiepin 1,l-dioxide (13),11 exhibits unusually short C=C bonds (1.31 1 A). It is suggested that this effect may arise from the electronegativity of the >SO group. The Ph C,H,-p-Br (11) (12) eight-membered ring of (14)12 is constructed from the three planar groups N-C-C-CH N-C-C-CH, and N-P-N.The phosphorus atom is tetrahedral and the mean P-N bond length is 1.644 A. The bonding environ- ments of the nitrogen atoms are planar and it is suggested that they are sp2 hybridized. Cyclohexasulphur-1,3-di-imide(15) proves to have a crown con- f~rmation,'~ but does not possess the expected mirror symmetry. The average S-S and N-S bond lengths are respectively 2.055(2) and 1.672(4) A. 0 .C' Both 1,2,3,4-tetrathiadecalin( 16)' and cis-1,4,5,8-tetraoxadecalin ( 17)' adopt chair-chair conformations. The geometry of (16) is noteworthy for the small values of the dihedral angles at the three S-S bonds (68.3,66.1 and 69.1") and (17) is said to be a unique example of two adjacent anomeric moieties incor- porated in a bicyclic system with C symmetry.Several bicyclo[3,3,l]nonane compounds which are unsubstituted at positions 3 and 7 have also been shown to adopt chair-chair conformations although the cyclohexane rings are distinctly flattened. However in cases where there are bulky endo substituents either at position 3 or at position 7 it has been predicted that a boat-chair conformation would be more favourable. Thus for (18) and its 2-hydroxy-analogue it has been argued that boat-chair geometry would relieve the Br -H-C-7 interaction which would otherwise occur in the chair-chair form. An analysis of (18)16 I' H. L. Ammon M. R. Smith and E. Kelso Acra Cryst. 1972 B28 246. ' * T. S. Cameron J.C.S. Perkin II 1972 591. l3 H. J. Postma F. van Bolhuis and A. Vos Acta Cryst. 1971 B27 2480. l4 F. Feher A.Klaeren and K.-H. Linke Acta Cryst. 1972 B28 534. l5 B. Fuchs I. Goldberg and U. Shmueli J.C.S. Perkin II 1972 357. I' P. D. Cradwick and G. A. Sim J. Chem. Sac. (B) 1971 2218. A. F. Cameron confirms the boat-chair conformation in this instance and reveals additionally that this conformation is adopted despite the almost eclipsed positions of the bromine and carbonyl moieties [Br -0 3.05 A]. Heterocyclic molecules which exhibit extensive delocalization have been studied in some depth. 1,8-Naphthyridine (19)17 proves to be non-planar with the two rings twisted in opposite directions about the bridgehead C-C bond. The twisting is attributed to repulsion between the nitrogen lone-pair electrons since the molecule is planar when co-ordinated to a metal atom via the nitrogen atoms.2-Oxazolidinone (20a)' was examined to investigate the molecular geometry in the light of the unusual ability of the molecule to complex with a wide variety of compounds such as phenols aspirin saccharin iodine etc. The molecule is planar and the dimensions indicate that (20b) and (20c) are major resonance components thus resulting in a high degree of polarization which may well be responsible for the unusual complexing properties. Both (21a) and (2lb)" are pyrazolinone azomethine dyes. Neither molecule is planar but (21a) deviates more from planarity than does (21b) the dihedral angles between rings A and B having values of 56.6 and 13.9" respectively. The dimen- sions of the azomethine linkages in the two molecules also differ significantly [N-C 1.399(3) N=C 1.297(3)8 in (21a); N-C 1.399(3) N=C 1.292(3)8 in (21b)j and it is concluded that for these two molecules at least the azomethine linkage is not an isoenergetic system.The influence of the heteroatom on the delocalization properties of certain molecules is exemplified by the analyses of (22a) and (22b).20 Chemically the two molecules are quite different the 7-amino-group of (22a) undergoing ex- tremely facile nucleophilic substitution whereas that of (22b) reacts much less li A. Clearfield M. J. Sims and P. Singh Acra Cryst. 1972 B28 350. J. W. Turley Acta Cryst. 1972 B28 140. l9 D. L. Smith and E. K. Barrett Acta Cryst. 1971 B27 2043. *' E. Shefter B. E. Evans and E. C. Taylor J. Amer. Chem.SOC.,1971 93 7281. Physical Methods-Part (v) X-Ray Crystallography N 6NY Ry-yR d -”X (22) a;X = 0 b;X = S NEt (21) a; R = H b;R=Me readily. There is also ready photo-addition to the 6,7-bond of (22a) a property which is not found in (22b) and its analogues. The analyses reveal that whereas (22b) is extensively delocalized throughout the whole molecule (22a) is de- localized only in the pyrimidine ring and may be thought of as a pyrimidine ring with a pair of strongly electronegative substituents (oximes). The suscepti- bility of (22a) to nucleophilic attack at C-7 may therefore be attributed to an elec- tron deficiency at that atom while the facile photo-reduction may be ascribed tentatively to a high formal oxidation state.It is also worthy of comment that the 6,7-bond has a length of 1.330 8 in (22a) and 1.355 8 in (22b) this being the largest difference between the pyrimidine rings of the two molecules. A similar conclusion results from the examination of 5-chloro-2,1-benzisothiazole(23),2 the dimensions of which suggest that it is almost completely delocalized. This is in contrast to the incomplete delocalization of the benzisoxazole analogues and there is again a difference in the chemical reactivities of the sulphur and oxygen compounds. Both chemical and n.m.r. evidence indicate that whereas 11,1l-difluoro-1,6- methano[lO]annulene shouId possess the annulene structure (24) the corre- sponding 11,ll-dimethyl derivative should possess the bisnorcaradiene struc- ture (25).A previous analysis22 had confirmed this prediction in the case of the difluoro-compound and a more recent study of the dimethyl -analogue2 indi- cates that it is structurally quite different from (24),the structure (25) being more appropriate. It must be stated however that the validity of this latter conclusion necessitates regarding the C-1 -C-6 distance of 1.80 8 as an extremely long and weak bond. (23) (24) (25) 21 M. Davis M. F. Mackay and W. A. Denne J.C.S. Perkin II 1972 565. 22 C. M. Gramaccioli and M. Simonetta Tetrahedron Letters 1971 173. 23 R. Bianchi A. Mugnoli and M. Simonetta J.C.S. Chem. Comm. 1972,1073. 96 A. F. Cameron 'Long' C(sp3)-C(sp3) bonds are also a feature of several cage molecules such as the ethano-bridged diadamantane (26),24 and the heterocyclic derivatives (27)25 and (28),2" although in none of these cases do any of the bonds approach the values observed in (25).In such molecules the long bonds are usually those bonds about which the substituents are fully eclipsed. Thus in (26) the ethano- bridging bond has a length of 1.552(2)A and the bond forming the junction of the fused piperazine rings in (27) has a length of 1.574(3)A. In the case of (28) which is the photodimer of 5,6,7,8-tetrahydro-2-quinolone, the long bonds [1.623(3)A] are those which affect the dimerization and their length is associated with the facile reversal of the dimer of the monomeric state. @ o)g$o N Investigations of long bonds involving sulphur atoms continue apace.Of particular relevance to such structural studies are the recently published CND0/2 calculation^^^ for asymmetrically substituted thiathiophthens. These calcula- tions predict that 2-methyl and 2-phenyl substituents cause lengthening of the S-S bond in the substituted ring and that in the phenyl-substituted case the lengthening depends on the angle of twist of the phenyl group relative to the thiathiophthen. 3-Methyl and 3-phenyl substituents are predicted to cause a shortening of the relevant S-S bond although the effect is very small for the phenyl-substituted molecule. These results are not only confirmed by previous analyses of the thiathiophthens but also gain further support from the subse- quent analyses of the diaza-analogues (29)28 and (30).29 In the case of (29) there is little difference between the inclinations (2.9 and 7.0") of the two phenyl rings relative to the heterocyclic system and the S-S bonds [2.319 2.328 A] are very similar.However in the 2,5-dianilino derivative (30) one aniline group is in- clined at 51" to the heterocyclic system and is associated with a short s-S bond [2.225(3)A] whereas the angle of inclination of the other aniline substituent (1 1") is reflected in an S-S bond length of 2.475(3)A. (29) (30) 24 S. T. Rao and M. Sundaralingam Acta Cryst. 1972 B28,694. 25 R. D. Gilardi Acta Cryst.,1972 B28 742. 26 J. N. Brown R. L. R. Towns and L. M. Trefonas J. Amer. Chem. Soc. 1971,93 7012. 2' L. K. Hansen A. Hordvik and L. J. Saethre J.C.S. Chem. Comm. 1972 222.28 A. Hordvik and L. Milje J.C.S. Chem. Comm. 1972 182. 29 A. Hordvik and P. Oftedal J.C.S. Chem. Comm. 1972 543. Physical Methods-Part (11) X-Ray Crystallography In molecules where there are approximately linear arrangements of four sulphur atoms a much wider variation of S-S distances is observed. Thus in (31)30the S-1-S-2 [2.482(1)A] S-2-S-3 [2.209(1)A] and S-3..-S-4 [2.965(1) A] distances indicate that the S-1-S-2-S-3 sequence constitutes a formal thia- thiophthen resonance system which is relatively unperturbed by the presence of S-4. However this structure may be contrasted with the structures of (32)3’ [S-l-S-2 and S-3-S-4 2.062 A; S-2**.S-3 2.863 A] and (33)32 [S-l..-S-2and S-3.-*S-4 2.8 A ; S-2-S-3 2.2 A] in which no thiathiophthen structures are apparently established although the relatively long S..-Scontacts of ca.2.8 A must represent some degree of interaction however weak. R (33) R = Me or Ph Bonding situations comparable to those of the thiathiophthens may also be identified in molecules containing oxygen or nitrogen replacing one or more of the sulphur atoms. In (34)33 the N-S distances are considerably longer [1.901(5) 1.948(5) A] than an N-S single bond whereas (35)34 contains a short S..-O[2.255(8)A] interaction. In the case of(35),the length of the carbonyl bond (35) (34) is 1.269(14)A and the authors suggest that there is now evidence of correlation between Av values for ketones and the strengths of the S..*Ointeractions in which they are involved. 30 J.Sletten Acta Chem. Scand. 1971 25 3577. 31 J. Sletten Acra Chem. Scand. 1972 26 873. ’* J. E. Oliver J. L. Flippen and J. Karle J.C.S. Chem. Comm. 1972 1153. 33 A. Hordvik and K. Julshamn Acra Chem. Scand. 1972 26 343. 34 R. Pinel Y. Mollier E. C. Llaguno and I. C. Paul Chem. Comm. 1971 1352. A. F. Cameron 3 Solid-state Rearrangements and Intermolecular Interactions Several analyses have been devoted to studying the courses of solid-state reactions and rearrangements. For example the benzophenone oxime-0-picryl ethers (36a-c) not only undergo Beckmann rearrangements in solution to form [cia the intermediates (37a-c)] the respective picryl anilides (38a-c) but on heat- ing have also been observed to undergo the same reaction in the crystalline state to produce identical products.This observation prompted a crystallographic in~estigation~~ (Table) of (36a-c) and (38a-c) which also included full analyses Table Crystallographic data for the derivatives (36a4) and (38a-c) Volume per molecule Compound Space group A3 Packing fraction" 0.95 0.96 0.99 " The packing fraction is defined as 1 -A/T where A is the difference in molecu-lar volumes and T is the volume of the larger molecule. of (36b) and (36c). This study reveals that the conversions (36aj 38a) and (36b +38b) give rise to a contraction of only about 5% in cell volume and that the conversion (36c -+ 38c) produces no measurable contraction. In those re- arrangements where the molecular shapes and interplanar spacings of the start- ing materials suggest minimal disruption of the crystal the products in fact p-X-C6 H4\ /O-Pic pic -0 \ -+ /C=N p-Y-C,H4 P-X-C,H /C=N \C,H,-p-Y (36) (37) a;X = Y = H b;X = Br Y = H c; X = H,Y = Br C6H4-p-Y (38) separate as micro-crystallites which have no net orientation with respect to the parent crystal.However it is possible to construct models of the products which have space-filling characteristics similar to those of the reactants and this may 35 J. D. McCullough I. C. Paul and D. Y. Curtin J. Amer. Chem. Sac. 1972 94 883. Physical Methods-Part (v) X-Ray Crystallography 99 well account for the tendency of the products to remain in the matrix of the starting material. In another case the pho to-dimer izat ion of 2-benzy l-5-p-br omobenzylidene-cyclopentanone (39),36it proved possible to complete an analysis of the dimer but crystal decomposition prevented more than an initial investigation of the monomer.However both monomer and dimer crystallize in the same space group Pbca with unit cells of similar volume (< 3.5 % difference) and it would seem that the small changes in cell dimensions are sufficient to allow the dimeriza- tion to take place without drastic reorganization of the molecular arrangement. C,H,-p-Br flBr / hv Ph *H-Ph Ph 0 H 0 (39) C,H ,-p-Br In both previous examples the overall reaction has comprised two elements. Firstly there is the reorganization in the solid-state arrangement of the molecules and secondly there is the formation of new chemical bonds to establish the products the exact sequence of events probably depending on an intimate inter- dependence of the two processes.However it is possible to have a solid-state transformation which involves only a spatial rearrangement of the molecules without the attendant chemical changes of the previous two cases. Thus di- methyl 3,6-dichloro-2,5-dihydroxyterephthalate(40)37occurs in yellow and OH OH (40) white crystalline forms and it is possible to convert the yellow into the white form. Analyses of both crystalline modifications reveal that both forms crystal- lize in space group Pi (yellow form one molecule per cell a = 9.595 b = 4.301 c = 7.970 A cc = 114" 19' /l = 94" 58' y = 106" 9' ;white form two molecules per cell a = 9.842 b = 7.841 c = 10.576& ct = 116" 23' /l = 124" lo' 7 = 88" 59').The planar centrosymmetric molecules of the yellow phase are stacked along b and are characterized by an internal hydrogen bond. In the structure of the white phase the molecules are non-planar the methoxycarbonyl groups being 36 D. A. Whiting J. Chem. SOC.(C) 1971 3397. 37 S. R. Byrn D. Y.Curtin and I. C. Paul J.Amer. Chem. SOC.,1972 94 890. A. F. Cameron rotated out of the benzene plane by 86" 28' and 72" 38' and although the mole- cules are again stacked along b they are in this case linked by intermolecular hydrogen bonding. Comparison of the two crystal structures reveals that the yellow --+ white transformation involves a change from intra- to inter-molecular hydrogen bonding a change in conformation from planar to non-planar and also a flipping of every aromatic ring through 180°C.Rather less dramatic but nevertheless significant differences are observed on comparison of the room-temperature and liquid-nitrogen-temperature phases of Wurster's Blue perchlorate [(TMPD)ClO,] (41).38 In both cases the TMPD+ (41) ions are stacked along a the ions being equidistant in the room-temperature phase but with alternating aromatic . aromatic interplanar separations in the low-temperature phase. However despite the alternating distances in the latter form a close examination reveals that equidistance is maintained in the N N interionic separations as a result of side-stepping and flexing of the molecules.-N distances in both forms are very similar. Moreover the N Other investigations of interactions between molecules and ions in the solid state have included analyses of several charge-transfer complexes such as NN'-dibenzyl-4,4'-bipyridylium di-i~dide~~ and (morpholiniumf),(7,7,8,8-tetracyano-quin~dimethane);-.~' In addition two studies of hydrogen bonding41p4* have revealed the existence of a dihydrated oxonium ion H,O:. 4 Natural Products Related and Biologically Active Molecules 11-&-Retinal (42)43acts as a photochemical sensor in visual systems and in the dark is covalently linked to proteins (opsins) in the retina. The primary event in the visual excitation process is the conversion of the 1 1-cis-isomer into all-trans- retinal.In an effort to provide information which will contribute towards a Me Me Me OA H 38 J. L. de Boer and A. Vos Acta Crysl. 1972 B28 835. 39 J. H. Russell and S. C. Wallwork Acta Cryst. 1971 B27 2473. 40 T. Sundaresan and S. C. Wallwork Acta Cryst. 1972 B28 491. 41 J.-0. Lundgren Acta Cryst. 1972 B28 475. 42 J.-0. Lundgren and P. Lundin Acta Cryst. 1972 B28 486. 43 R. D. Gilardi I. L. Karle and J. Karle Acta Cryst. 1972 B28 2605. Physical Methods-Part (u) X-Ray Crystallography 101 detailed understanding of the visual process analyses of both isomers have been undertaken. The chain of all-tr~ns-retinal~~ proves to be extended although it is both markedly curved within its general plane and is also slightly bent normal to the plane.The main feature of the side-chain of 11-cis-retinal is the signifi- cantly non-zero torsion angle about the C-12-C-13 single bond such that the conversion of the 11-cis into the all-trans isomer involves both a rotation of 180" about the C-11-C-12 double bond. and also a rotation of ca. 141" about the C-12-C-13 bond. Although chemically different both diphenylhydantoin (43)45 and diazepam (44)4hshow similar anticonvulsant drug activities. An examination of both compounds reveals that despite the chemical differences the space-filling charac- teristics are very similar. In particular the relative orientations of the phenyl rings and the carbonyl groups in the two molecules are directly comparable. Me H (43) (44) This observation leads to a tentative and preliminary suggestion that the latter feature may be pertinent to anticonvulsant activity.It has also been suggested that many local anaesthetics owe their activity at least in part to an ability to complex with phospholipids in neural membrane the resulting complex being instrumental in blocking nerve conduction. Previous studies of phosphate complexes of the local anaesthetics procaine and phenacaine have led to the additional suggestion that it is the hydrogen-bond donor capabilities of such molecules which are of significance in the biological complex formation. These studies have now been extended by analyses of the bis-p-nitrophenyl phosphate complex of benzocaine (ethyl-4-aminoben~oate)~'and of lidocaine hexafluoro- arsenate (45).48 In the case of the benzocaine complex all the hydrogen atoms of Me Me (45) 44 T.Hamanaka T. Mitsui T. Ashida and M. Kakudo Acta Cryst. 1972 B28 214. 4s A. Camerman and N. Camerman Am Crysr. 1971 B27 2205. 46 A. Camerman and N. Camerman J. Amer. Chem. SOC.,1972,94 268. 47 J. Pletcher M. Sax and C. S. Yoo Acta Crysr. 1972 B28 378. 48 A. W. Hanson Acta Cryst. 1972 B28 672. A. F Cameron the protonated amino-group participate in Nf -H -0 hydrogen bonding with the phosphate group. The amino-group of lidocaine is also protonated and is sttrongly hydrogen bonded to the carbonyl-oxygen atom of a neighbouring molecule while the amido-group is weakly hydrogen-bonded [N-H. * -F 3.040(5)A] to the hexafluoroarsenate moiety.Terpenoid structures which have been examined include the sesquiterpenoid germacradienolide lactones eupacunin (46),49 liatrin (4’3,’’and melampodin (48).’ Both eupacunin and liatrin show significant anti-leukaemic and tumour- inhibitory properties and are in addition the first recognized germacranolide Me ‘rl ,Me Me%cHz (46) R = angeloyl ‘0 (47) MeO.+O cis-cis dienes. In contrast melampodin possesses a cis-trans geometry which results in severe distortions of the molecular geometry evidenced by torsion angles of 24 and 8” about the rrans and cis double bonds respectively. The structures of the diterpenes (-)-kaur-15-en-19-a1 (49)52 and 12-hydroxydaphne- toxin tribromoacetate (50)’ have also been determined. Although the former superficially resembles a steroid it proves to have an absolute stereochemistry exactly opposite to that normally observed for steroids.12-Hydroxydaphne-toxin has a molecular structure very similar to the structures of phorbol and 49 S. M. Kupchan M. Maruyama R. J. Hemingway J. C. Hemingway S. Shibuya T. Fujita P. D. Cradwick A. D. U. Hardy and G.A. Sim J. Amer. Chem. Soc. 1971 93 49 14. S. M. Kupchan V. H. Davies T. Fujita M. R. Cox and R. F. Bryan J. Amer. Chem. Soc. 1971 93 4916. S. Neidle and D. Rogers J.C.S. Chem. Comm. 1972 140. 52 I. L. Karle Acra Crysr. 1972 B28 585. 53 J. Coetzer and M. J. Pieterse Acta Cryst. 1972 B28 620. Physical Methods-Part (v) X-Ray Crystallography 103 neophorbol. There have also been several analyses of unusual steroids.9-0x0-9,l l-secogorgost-5-ene-3~,ll-diol 11-acetate (51)’’ and 23-demethylgorgosterol (52)54are cyclopropane-containing marine steroids while 4,4-dichloro-2a-aza-~-homocoprostan-3-one(53)’ contains an elactam ring. The analyses of two Me H-0 Me (49) OCOCH,Br (50) HO .. Me Me MeMe HO ” ci ‘CI (52) (53) crystalline modifications of 2,4-dibrom~estradiol~reveal that the same steroid molecule in three different crystalline environments (one modification contains two independent molecules per asymmetric unit) may well show significant variations in conformation. It is concluded that steroid conformations are s4 E. L. Enwall D. van der Helm I. N. Hsu T. Pattabhiraman F. J. Schmitz R. L. Spraggins and A. J. Weinheimer J.C.S.Chem. Comm. 1972 215. 55 H. Altenburg D. Mootz and B. Berking Acta Crysr. 1972 Bt8 567. s6 V. Cody F. DeJarnette W. Duax and D. A. Norton Acta Cryst. 1971 B27 2458. 104 A. F. Cameron influenced both by non-bonded intermolecular contacts and also by inter- molecular hydrogen bonding and that in the absence of other evidence care must be exercised when extrapolating from the results of a crystallographic determination. Other natural products and related derivatives which have been extensively examined include alkaloids sugars amino-acids and other constituents of proteins etc. Novel alkaloid structures are represented by the pyridine alkaloids maytoline (54)57and sceletium alkaloid A (55),'* and by the tetrahydroimi- dazo[ 1,2-a]pyrimidine alkaloid alchorneine (56).59 Sugars which have been studied include the septanose 3-0-acetyl-1,2 :4,5-di-O-isopropylidene-or-~-gluco-septanose (57h6' the seven-membered ring of which has a distorted chair OMe 0 AcO ._ H Ac (54) (55) Me OMe Me ' I CH Me-py>.-< Me Br-" H H Me (57) """;YY 0IOH HCH20H CH,OH OH OH H OH OH H (59) 5' R.F. Bryan and R. hl. Smith J. Chem. SOC.(B) 1971 2159. 58 P. W. Jeffs P. A. Luhan A. T. McPhail and N. H. Martin Chem. Comm. 1971 1466. 59 M. Caserio and J. Guilhem Acta Cryst. 1972 B28,151. 6o E. T. Pallister N. C. Stephenson and J. D. Stevens J.C.S. Chem. Comm. 1972 98. Physical Methods-Part (u) X-Ray Crystallography CH,OH CH,OH (60) conformation and the disaccharide 3,6-anhydro-~~-~-glucosyl-1,4 :3,6-dian-hydro-P-D-fructoside (58),6 which contains a highly strained tricyclic furanose moiety.The structures of the trisaccharides 1-kestose (S9)62 and planteose dihydrate (60)63have also been determined the latter proving to have an overall circular conformation in which the glucose and galactose units are hydrogen- bonded to the same hydroxy-group of a neighbouring molecule. " N. W. Isaacs and C. H. L. Kennard J.C.S. Perkin 11 1972 582. " G. A. Jeffrey and Y. J. Park Acta Cryst. 1972 BZS,257. 63 D. C. Rohrer Acta Cryst. 1972 B28 425.

ISSN:0069-3030    

DOI:10.1039/OC9726900090

出版商:RSC    

年代:1972

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 Three important reviews of this subject appeared in 1972. Taylor’s contribution’ to Volume 13 of ‘Comprehensive Chemical Kinetics’ comprises an enormous collection of kinetic data and a perceptive analysis of the results. This review will be invaluable to all workers in this field. Ridd’ has provided a valuable study of substitution in four- and five-membered heterocyclics and includes a section on linear free-energy relationships. Intermediates in electrophilic aromatic substitu- tion are the subject of the third review. There are comments on the controversial subject of the intermediacy of 7c-complexes7 on diffusion-controlled reactions and on the symmetry of o-c~mplexes.~ One controversial topic reported last year was the correct explanation for the variable amount of disubstitution obtained in the nitration of bibenzyl by nitro- nium tetrafluoroborate.This was explained by Ridd in terms of the rate of mixing affecting a diffusion-controlled reaction but Olah,4 in defence of his well- known views on the role of 7c-complexes in such reactions suggested that NO; complexes with the ring already substituted the second substitution being the result of an intramolecular migration. However in a further study of this reaction Gastaminza and Ridd’ were unable to find any evidence for complexing and the rate of mixing is the most important factor.There is substantial evidence that the deactivating effect of positive poles in aromatic nitration is transmitted not along a-bonds but directly through space (a field effect). Further evidence in support of this view has appeared. Nitration at the rn-position of (1) is slower than in (2) although the positive pole is separated from the ring by the same number of a-bonds. However the presence of the cyclohexyl ring in (1) holds the pole much closer to the ring and deactivation occurs because of a direct field effect.6 The same phenomenon is illustrated more ‘ R. Taylor in ‘Comprehensive Chemical Kinetics’ ed. C. H. Bamford and C. F. H. Tipper Elsevier Amsterdam 1972 Vol. 13 p. 1. J. H. Ridd in ‘Physical Methods in Heterocyclic Chemistry’ ed.A. R. Katritzky VOl. 4,p. 55. P. Rys P. Skrabal and H. Zollinger Angew. Chem. Internat. Edn. 1972 11 874. G. A. Olah Accounts Chem. Res. 1971 4 244. A. Gastaminza and J. H. Ridd J.C.S. Perkin II 1972 813. A. Ricci and J. H. Ridd J.C.S. Perkin II 1972 1544. 107 108 A. R.Butler (1) dramatically by comparing the rates of nitration of (3) and (4) where n = 2 and m = 4. The presence of the bridge which holds the positive poles close to the ring deactivates (4)by a factor of 100compared with (3). Unfortunately for this simple explanation it was found that the bridged compound with n = 1 where (4) the pole is not brought any closer to the ring by bridging is also deactivated. Undoubtedly factors other than the direct field-effect are operative but accord- ing to the evidence at hand it seems that this is the predominant one.' Steric factors do not appear to be important as the same effects are observed in hydrogen exchange.8 As well as deactivating the system protonation may also change the site of reaction.In acidic solution nitration of 1-methyl-4-phenylpyrazole(5) occurs in the phenyl ring but in acetic anhydride as solvent it is on the pyrazole ring.9 6 N-NMe There have been further studies of ionic reactions in the gas phase including acetylation and nitration. For the former reaction the effect of substituents is the same as that for reactions in solution but for nitration (where the nitrating species is generated from ethyl nitrate) a nitro-group activates the aromatic ring towards attack.It is suggested that the nitrating species is CH,ONOl rather than NO and the first step is electrostatic interaction between the aromatic ring and the nucleophilic oxygen of CH20NO;." Last year it was reported that gas- phase hydrogen exchange may be effected by the use of the helium tritide ion (HeTf).'' Now a study of the reactions of the D2T+ion has been reported. Reaction with arenes results in hydrogen exchange and the pattern of reactivity ' A. Ricci R. Danieli and J. H. Ridd. J.C.S. Perkin IZ 1972 1547. A. Danieli A. Ricci and J. H. Ridd J.C.S. Perkin II 1972 2107. I. J. Ferguson M. R. Grimmett and K. Schofield Tetrahedron Letters 1972 2771. lo R. C. Dunbar J. Shen and G. A. Olah J. Amer. Chem. SOC.,1972,94,6862.'I F. Cacade and G. Perez J. Chem. SOC.(B) 1971 2086; F. Cacace R. Cipollini and G. Ciranni ibid. p. 2089; F. Cacace 'Advances in Physica1,Organic Chemistry' ed. V. Gold Academic Press London 1970. Reaction Mechanisms-Part (i) Aromatic Compounds is the same as that observed with HeT+ i.e.low substrate selectivity (a ratio for reaction with toluene and benzene of only 1.3) but high positional selectivity. These effects are explained by postulating that the attractive electrostatic forces between attacking ion and substrate lead to a long-lived intermediate. Further reaction giving rise to high positional selectivity occurs within the interme- diate.' Such a view is reminiscent of Olah's postulated .It-intermediates. Exactly the same behaviour pattern is found for the reaction of HeT+ with liquid arenes.' Gas-phase electrophilic bromination shows the same lack of substrate selectivity an effect which is not generally observed for bromination in the liquid phase.14 These gas-phase reactions make it possible to compare reactivities under condi- tions where there are no complications due to solvation effects with theoretical predictions.For example MO calculations have shown that the most stable form of protonated benzene has the proton attached directly to a carbon atom but as the authors ppint out,' this assumes no solvation effects and must be com- pared with gas-phase protonation. It is very difficult to measure the reactivity of neutral N-heterocyclics towards electrophiles as they generally react in the protonated form.However the technique of gas-phase pyrolysis of the appropriately substituted ethyl acetate developed so successfully by Taylor does permit this. All the positions in free quinoline have been examined and are less reactive than the corresponding posi- tions in naphthalene but more reactive than those in pyridine." A number of stable a-complexes formed by the halogenation of triaminobenzenes have been isolated and characterized.' ' Nitration of activated substrates in sulphuric acid is thought to be encounter- controlled and should therefore have a low energy of activation (ca.25 kJ mol- '). The observed value of 72 4kJ mol-'in 68.3 % sulphuric acid is due to the large enthalpy change occurring in the step preceding nitration (i.e.HN03-+NO + OH-).Dissociation is complete in 92% acid." The mechanism of nitration in acetic anhydride is still under investigation. Hartshorn Moodie and Schofield" have compared the relative rates of nitra- tion of a number of anilides and aromatic ethers in acetic anhydride and sulphuric acid. The patterns of reactivity are so different that it is clear that dif- ferent mechanisms are operative. One important factor is interaction between substrate and solvent which in an extreme form amounts to protonation. Kinetic studies using acetic anhydride as solvent show that the reaction is of zero or first order in substrate. It is suggested that NO; (the nitrating agent) is formed in the following equilibrium N,O + AcOH * NO + NO;(AcOH) *'F.Cacace R. Cipoilini and G. Occhiucci J.C.S. Perkin II 1972 84. l3 F. Cacace and S. Caronna J.C.S. Perkin II 1972 1604. l4 F. Cacace and G. Stocklin J. Amer. Chem. SOC.,1972 94 2518. Is W. J. Hehre and J. A. Pople J. Amer. Chem. SOC. 1972 94 6901. l6 R. Taylor J. Chem. SOC.(B) 1971 2382. ' P. Menzel and F. Effenberger Angew. Chem. Innternat. Edn. 1972 I I 922. S. R. Hartshorn R. B. Moodie and K. Stead J.C.S. Perkin II 1972 127. l9 S. R. Hartshorn R. B. Moodie and K. Schofield J. Chem. SOC.(B) 1971 2454. 110 A. R.Butler and that with activated substrates the reaction is encounter-controlled and therefore of zero order in substrate. With less reactive substrates NO has time to undergo solvation to give NO:(HNO,) a weaker electrophile and the reaction becomes first order.20 Isomer ratios in the nitration of o-xylene vary with the acidity2’ and this may be due to nitro-group migration in the Wheland intermediate in an acid-catalysed reaction (Scheme 1).22 Nitration of the highly deactivated substrate Scheme 1 2,3-dinitroaniline involves N-nitration to give a nitrosamine with subsequent rearrangement to give ring nitration rather than direct nitration of the proto- nated c~rnpound.’~ Addition may accompany nitration.Nitration of 1,2,3,5-tetramethoxy-benzene gives a mixture of (6) and (7),24 whereas ethylmesitylene and fuming nitric acid give (Q2’ A small amount of (9) is obtained on the nitration of 2,6-dimethylneopentylbenzene.26 There have been no detailed mechanistic studies of these reactions.Electrophilic substitution generally involves replacement of hydrogen but other leaving groups are possible. Nitration of 4-iodoanisole results in the forma- tion of equimolar amounts of 4-nitroanisole and 2,4-di-iodoanisole clearly nitrodeiodination occurs and this is accompanied by iodination of unreacted 4-iodoanisole. The second stage of this reaction is nitrodeiodination of 2,4-di- iodoanisole to give 2-iodo-4-nitroanisole and iodine. Now a mixture of iodine and nitric acid is an iodinating agent and will iodinate 4-nitroanisole formed in the first step at the 2-position to give the same final product (Scheme 2). A 2o S. R. Hartshorn J. C. Hoggett R. B. Moodie K. Schofield and M. J. Thompson J. Chem. SOC.(B) 1971,2461. 21 R.G. Coombes and L. W. Russell J. Chem. SOC.(B) 1971 2443. 22 P. C. Myhre J. Amer. Chem. SOC.,1972 94 7921. 23 J. H. Ridd and E. F. V. Scriven J.C.S. Chem. Comm. 1972 641. 24 B. A. Collins K. E. Richards and G. J. Wright J.C.S. Chem. Comm. 1972 1216. 25 H. Suzuki M. Sawaki and R. Sakimoto Chem. Comm. 1971 1509. 26 A. J. M. Reuvers F. F. van Leeuwen and A. Sinnema J.C.S. Chem. Comm. 1972,828. Reaction Mechanisms-Part (i) Aromatic Compounds 111 ~ - ~ I I NO2 Scheme 2 detailed study of this reaction by Butler and Sander~on~~ has shown that the effective deiodinating species is not nitric but nitrous acid always present as an impurity and there is subsequent oxidation to the nitro-compound. Nitration of Ldiodoanisole with nitronium tetrafluoroborate does not result in deiodina- tion at all but nitration at the 2-position.Thus the situation is that the weak electrophile NO' can displace iodine whereas the strong electrophile NO does not. A similar situation applies to p-tolyltrimethylsilane (10). Nitration occurs at the 2-position but nitrosation results in displacement of the SiMe group and the final product is p-nitrotoluene.28 Azodehalogenation has also been ~tudied.~' Studies of aromatic nitrosation indicate that as an electrophile NO' is lo'* times weaker than NO; .30 There is no evidence for C1+ in electrophilic chlorina- ti~n.~l The active species in Friedel-Crafts reactions has been investigated. Various cornplexe~,~ acetylium ions,3 diacetylium ions,34 oxonium ions,35and alkyl 27 A.R. Butler and A. P. Sanderson J.C.S. Perkin II 1972 989. 28 C. Eaborn Z. S. Salih and D. R. M. Walton J.C.S. Perkin ZI 1972 172. 29 P. B. Fischer and H. Zollinger Helu. Chim. Am 1972 55 2139. 30 B. C. Challis R. J. Higgins and A. J. Lawson J.C.S. Perkin II 1972 1831. 31 C. G. Swain and D. R. Crist J. Amer. Chem. SOC. 1972 94 3195. 32 I. Hashimoto A. Kawasaki and Y. Ogata Tetrahedron 1972 28 217; R. Corriu M. Dore and R. Thomassin Bull. SOC. chim. France 1972 2829. 33 R. Corriu M. Dore and R. Thomassin Tetrahedron 1971 27 5819. j4 A. Germain A. Commeyras and A. Casadevall Bull. Sac. chim. France 1972 3177. 35 L. R. Pettiford J.C.S. Perkin II 1972 52. 112 A. R. Butler cations36 have all been implicated. The benzylation of benzene and toluene with a variety of catalysts has been examined in great detail.The isomer distribution is fairly insensitive to conditions but this is not true of the substrate selectivity. With AlCl and a series of substituted benzyl chlorides it is possible to see how the ortho :para ratio of the products varies with substrate selectivity. In general the p-isomer predominates with greater reactivity. This suggests that the transi- tion state of highest energy (which fixes the isomer distribution) depends on the reactivity. The transition state may be ‘early’ and resemble the reactants (n- complex) or be ‘late’ and resemble the Wheland intermediate (o-complex). So in this rather changed manner n-complexes still have a role as intermediates in electrophilic aromatic sub~titution.~’ 1-Methyltetrazole (11) undergoes hydrogen exchange at the 5-position by a carbanion mechanism and complexing with a transition-metal cation (Cu2 or +-M ~ N ~ N \ N” I (1 1) Zn2+) produces a very substantial increase in rate.This result is significant in understanding the production of carbanions in biological systems where metal ions are known to be required. It may also have important synthetic conse- quences. * 2 Nucleophilic Aromatic Substitution Recent mechanistic studies have been reviewed in concise and perceptive manner by Ross39 in Volume 13 of ‘Comprehensive Chemical Kinetics’. The role of intermediates in such reactions have been di~cussed,~ and Ridd2 has provided a review of the reactivity of heterocyclics towards nucleophiles.The problem of the a-effect (the enhanced reactivity of nucleophiles with a lone pair of electrons alpha to the site of nucleophilicity) has been examined for reactions involving displacement from aromatic compounds. For amines4’ the a-effect is associated with reactions having a fairly large Brransted value i.e. reactions in which considerable bond formation has occurred in the transition state. However this generalization does not apply to nucleophiles other than amines and it seems certain that the phenomenon of the a-effect is due to a variety of causes.41 The reactions of 2,4-dinitrochlorobenzene with butylamine and benzamidine are both first order in amine and the latter is less reactive. However with 4,7-dinitrofluoronaphthalene the reaction is second order in butylamine indicating base-catalysis in the slow removal of the fluoride ion.However the 36 G. A. Olah J. M. DeMember and R. Weiss J. Amer. Chem. SOC.,1972,94 5718. 37 G. A. Olah and S. Kobayashi J. Amer. Chem. SOC.,1971 93 6964; G. A. Olah S. Kobayashi and M. Tashiro ibid. 1972,94 7448. 38 H. Kohn S. J. Benkovic and R. A. Olofson J. Amer. Chem. SOC. 1972 94 5759. 39 S. D. Ross ref. 1 p. 407. 40 J. E. Dixon and T. C. Bruice J. Amer. Chem. SOC.,1972,94,2052. 41 J. E. Dixon and T. C. Bruice J. Amer. Chem. SOC.,1971 93 6592. Reaction Mechanisms-Part (i) Aromatic Compounds reaction is first order in benzamidine and it seems probable that benzamidine is acting as a bifunctional catalyst with a cyclic transition state (12).42 A similar result was obtained on comparing the reactions of imidazole and pyrazole with 2,4dinitrofluorobenzene although with pyrazole the reaction is of mixed order both first and second in pyrazole.However bifunctional catalytic activity of pyrazole is indicated.43 Normally one thinks of the nitro-group activating an aromatic ring towards nucleophilic attack but in certain circumstances this group may be replaced by a nucleophile to give a nitrite ion. This occurs in the reaction of 1,2,4-trinitro- benzene and o-dinitrobenzene with piperidine in benzene,44 and also the reaction of hydroxide ion with 2,4-dinitrobenzenediazonium ions. In the analogous reaction with the 2,6-dichloro-4-nitrobenzenediazoniumion chloride and nitrite are displaced at comparable rates.4s Displacement also occurs on 5-halogeno- 1-methyl-3-nitro-l,2,4-tria~ole.~~ Reaction of phenols in the presence of pyridine with the benzoate (13) gives the expect aryl ether.However with sterically hindered phenols the products are aryl 3,5-dinitrosalicylates and the reaction is thought to involve intermediate formation of the lactone (14).47 In the alkaline hydrolysis of 2,4-dinitrophenyl esters of benzoic acid nucleophilic attack is on the aromatic ring rather than at the carbo~y-group.~~ 42 G. Biggi F. Del Cima and F. Pietra J.C.S. Perkin 11 1972 188. 43 F. Pietra and F. Del Cima J.C.S. Perkin IZ 1972 1420. 44 F. Pietra and D. Vitali J.C.S. Perkin 11 1972 384. 0. MachaEkova V. StErba and K.Valter Coil. Czech. Chem. Comm. 1972,37,2197. 46 M. S. Pevzner V. Y. Samarenko and L. I. Bagal Khim. geterotsikl. Soedinenii 1972 848. 47 R. Muthukrishnan R. Kannan and S. Swaminathan J.C.S. Chem. Comm. 1972,358. 48 L. S. Prangova L. S. Efros and I. Y. Kvitko Organic Reactiuiry (Turtu) 1971,8 381. 114 A. R.Butler Fendler and Fendler4’ have reported a very complete study of the kinetics of Meisenheimer complex (a-complex) formation between methoxide ion and 2,4,7- trinitromethoxynaphthalene. Crampton and Khanso have shown that the equili- brium constant for 0-complex formation with a number of substituted anisoles depends upon the methoxide concentration. This variation is caused by changes in the rate of complex dissociation and may be due to stabilization of the complex by ion association.A very stable 1,3-complex (15) is formed from 2,6-dinitro-4- trifluoromethylsulphonylanisole,but it reverts to the more stable 1,l-complex.’ O2N(-JpeOMe H SOZCF (15) Bernasconi” has used temperature-jump stopped-flow to study the kinetics of formation of both the 1,3- and 1,l-complexes of 2,4,6-trinitroanisole and methoxide ion. For the former formation is very fast but there is a low equili- brium constant for the 1,l-complex this situation is reversed. It appears that the weak nucleophile aniline can displace rnethoxide ion from the a-complex with trinitrobenzene to give (16).53 H NHPh (16) Hydrogen bonding in Meisenhiemer complexes has been detected in a most elegant manner by Berna~coni.’~ Deprotonation of (17) is effected by hydroxide ion.A study using a temperature-jump technique has shown that the rate of deprotonation is 2 x lo81 mol-s-for the three secondary amines studied which is 100 times less than the diffusion-controlled transfer of a proton from an (17) 49 E. J. Fendler and J. H. Fendler J.C.S. Perkin II 1972 1403. M. R. Crampton and H. A. Khan J.C.S. Perkin IZ 1972 1173. 51 F. Millot J. Morel and F. Terrier Compt. rend. 1972 274 C 23. s2 C. F. Bernasconi J. Amer. Chem. SOC.,1971,93 6975. 53 E. Buncel and J. G. K. Webb Cunud.J. Chem. 1972,50 129. s4 C. F. Bernasconi J. Phys. Chem. 1972 75 3636. Reaction Mechanisms-Part (i) Aromatic Compounds I15 ammonium ion to hydroxide ion. This reduction is thought to be due to hydrogen bonding between the nitrogen of the amine group and the nitro-group in the o-position.Displacement on picryl chloride was thought to be an S,2 reaction but a recent study using DMSO as solvent has shown that the first step is formation of a 1,3-~omplex.~~ The first a-complex (18) of selenophen has been rep~rted.’~ Popp’ has reported an interesting example of an unexpected reaction occurr- ing in a sterically crowded molecule. Electrochemical reduction of (19) results in cyclization to give (21). The mechanism involves two-electron oxidation and formation of the intermediate (20) by intramolecular nucleophilic attack. In the final step the t-butyl group is lost as Me,C=CH,. (19) 3 Acidity Functions Little work appeared in 1972 to remove the confusion surrounding the exact significance of the acidity of a concentrated acid.However Yates and ShapiroS8 showed that the H scale generated by indicators not possessing nitro-groups is the same as that from nitroanilines. This gives confidence in the H scale as a measure of the ability of a concentrated acid to protonate a primary amine. Also activity coefficient measurements have shown thatf, +/’ is a constant for primary aniline indicators as suggested by Hammett.” Postle and Wyatt6’ report that added salts have a very large effect on HR because the forward (k,) and back (kb) reactions are affected in opposite ways causing a large shift in the equilibrium. The value of k,is a linear function of H, so that differences between H,and H are due in part to the effect of anions on k,.55 M R. Crampton M. E. El Ghariani and H. A. Khan Tetrahedron 1972 28 3299. 56 F. Terrier A.-P. Chatrousse R.Schaal C. Paulmier and P. Pastour Tetrahedron Letters 1972 1961. 57 G. Popp J. Org. Chem. 1972 37 3058. 58 K. Yates and S. A. Shapiro Canad. J. Chem. 1972,50 581. 59 T. R. Essig and J. A. Marinsky Canad. J. Chem. 1972,50,2254. 6o M. J. Postle and P. A. H. Wyatt J.C.S. Perkin II 1972 474. 116 A. R. Butler As a criterion for reaction mechanism the acidity dependence of a reaction is often difficult to interpret. There is a curved relationship between HR and H for hydrochloric acid and yet for related reactions log k may be a linear function of H in one case and HRin another.It is argued that this may reflect the nature of the transition state.61 The ionization of 1,3-diphenylindene has been used to generate an acidity scale for sodium methoxide in methanol and the resultant values of H-correlate well with the base-catalysed hydrogen exchange of fluorene.62 However in a detailed analysis More O'Ferra1162" has shown that correlation with H-is a poor guide to reaction mechanism. Plots may be non-linear and reactions with different mechanisms may show the same type of correlation. Linear plots are more fre- quently obtained using the complex term H-pKMeOH -log(^^^^-/^^^^) and the slope of this line may reflect the structure of the transition state. Follow- ing a study of the isomerization of allylbenzenes in aqueous DMSO Bowden and argue cautiously that the slope of the plot of log k us.H-reflects the degree of proton transfer in the transition state and this conclusion is consistent with the hydrogen-isotope effect. 4 Linear Free-energy Relationships There are several possible approaches to the Hammett and related equations. The first and most successful is to treat them as approximate empirical correla- tions of predictive value. What is so astonishing is the variety of phenomena which fit the simple Hammett equation. It applies to peaks in the n.m.r. spectra of pyra~ines,~~ CN stretching frequencie~,~' I3C n.m.r. shifts in benzyl cations,66 chemical shifts of non-aromatic protons,67 barriers to rotation,68 spin-spin coupling constant^,^^ charge-transfer energy,70 and the reactions of p~rphins.~ No extension of the Hammett equation is required for free-radical reactions.72 Once a more precise correlation is sought it is necessary to modify the Hammett equation either generally by the introduction of an extra parameter,73 or for a particular system (e.g.cyclohexyl or silicon substituents7 '). The " A. J. Kresge H. J. Chen and Y. Chiang J.C.S. Chem. Comm. 1972 696; M. Godel A. Jussiaume and F. Coussemant Tetrahedron Letters 1972 23 17. 62 A. Streitwieser C. J. Chang and A. T. Young J. Amer. Chem. SOC.,1972 94 4888. 62aR. A. More O'Ferrall J.C.S. Perkin II 1972 976. 63 K. Bowden and R. S. Cook J.C.S. Perkin lI 1972 1407. 64 G. S. Marx and P. E. Spoerri J. Org. Chem. 1972 37 11 1. 65 T. Funabiki and K.Tarama Bull. Chem. SOC.Japan. 1972,45,2945. 66 G. A. Olah R. D. Porter C. L. Jeuell and A. M. White J. Amer. Chem. SOC.,1972 94 2044. 67 B. Kamienski and T. M. Krygowski Tetrahedron Letters 1972,681. 68 L.-0. Carlsson Acta Chem. Scand. 1972,26,21; T. B. Grindley A. R. Katritzky and R. D. Topsom Tetrahedron Letters 1972 2643. 69 S. Rodmar S. Gronowitz and U. Rosen Acta Chem. Scand. 1971 25 3841. 70 K. Sekigawa Tetrahedron 1972 28 505 515. 71 M. Meot-Ner and A. D. Adler J. Amer. Chem. SOC.,1972,94 4763. l2 A. P. G. Kieboom Tetrahedron 1972 28 1325. 73 Y. Yukawa Y.Tsuno and M. Sawada Bull. Chem. SOC.Japan 1972 45 1210; Y. Tsuno M. Fujio Y.Takai and Y. Yakawa Bull. Chem. SOC.Japan 1972,45 1519. 74 J. L. Mateos H. Flores and H. Kwart J. Org. Chem. 1972 37 2826.75 J. Lipowitz J. Amer. Chem. SOC.,1972 94 1582. Reaction Mechanisms-Part (i) Aromatic Compounds danger with parametrization is that it is not always possible to distinguish between parameters which have a physical significance and those which are mathematical devices. Another approach when the simple Hammett equation breaks down is to 0'values are required. It is known that cassume that new values for the 2-thienyl and the 1-position of bi~henylene~~ vary with the reaction studied. This may be interpreted in terms of the resonance demands of the reaction. For the reactions of aromatic systems other than benzene it can be assumed that 6'constants will apply and c+orcdifferent values for thi~phen~~ and novalues for polycyclic systems have been determined.79 An entirely new set of c+values based on the rates of protodetritiation of aromatic compounds in TFA have been prepared by Baker Eaborn and Taylor.80 They are fairly successful when applied to electrophilic aromatic substitution.The final approach to the Hammett equation is to use it as a basis for a theoretical analysis of the transmission of substituent effects. Godfrey8 rejects the division into field and inductive effects and has discussed non-linear free- energy plots in terms of his recently proposed field and charge transfer (FCT) treatment. The relative importance of these effects depends upon the reaction considered and a good correlation will be obtained only if the effects are the same as in the reaction used to define 0.The FCT theory has been applied to o-substi- tuents.82 Some work on substituent chemical shifts in p-substituted fluoro- benzenes indicates* that cpis a better measure of resonance interaction between substituent and the aromatic ring than cR.This analysis throws some doubt upon the validity of previous attempts to separate substituent effects into inductive and resonance components. Values of p for the trifluoroacetylation of thiophens furans and pyrroles have been determined by Clementi and mar in^^^ and have been interpreted in terms of varying transition-state structure(a- or n-complex). However Forsyth and NoycegS propose that it is due to varying charge distribution in the transition state. The temperature dependence of the Hammett equation has been consideredg6 and Wold and Sjostrom have performed a major statistical analysis of available data to find the best values of c(i.e.those values which give a linear correlation for most reaction^).^^ This updates Jaffk's classic review of the subject.76 F. Fringuelli G. Marino and A. Taticchi J.C.S. Perkin IZ 1972 158. 77 R. Taylor M. P. David and J. F. W. McOmie J.C.S. Perkin IZ 1972 162; R. Taylor ibid. p. 165. D. S. Noyce C. A. Lapinski and R. W. Nichols J. Org. Chem. 1972,37 2615; D. S. Noyce and H. J. Pavez ibid. pp. 2620 2623. 79 M. Sawada Y. Tsuno and Y. Yukawa Bull Chem. SOC. Japan 1972,45 1206. R. Baker C. Eaborn and R. Taylor J.C.S. Perkin 11 1972 97. M. Godfrey Tetrahedron Letters 1972 753. 82 M. Godfrey Tetrahedron Letters 1972 3203.83 1. R. Ager and L. Phillips J.C.S. Perkin ZI 1972 1975; I. R. Ager L. Phillips T. J. Tewson and V. Wray ibid. p. 1979. 84 S. Clementi and G. Marino J.C.S. Perkin 11 1972 71. D. A. Forsyth and D. A. Noyce Tetrahedron Letters 1972 3893. 86 L. D. Hansen and L. G. Hepler Canad. J. Chem. 1972,50 1030. 87 S. Wold and M. Sjostrom Chem. Scripta 1972 2 49. 118 A. R. Butler Substituent effects display an angular dependence in the dissociation of the acids (22) (23) and (24)88 and in the H-F coupling in substituted fluorocyclo- pro pane^.^' These observations support transmission of substituent effects by a direct field effect and not along a-bonds. (22) (23) (24) pK 6.261 6.4 16 6.470 There has been a further test of the Westheimer postulate that the k& ratio will be a maximum when the proton is half transferred in the transition state.For hydrogen exchange in indoles with a variety of catalysts the isotope effect was found to be essentially constant over a range of differences in pK and this gives no support to the postulate. The authors conclude with an excellent discus- sion of the problem.’* The significance of the terms tl and /? in the Brsnsted equation has again been the subject of several reports. Murdoch9* has shown by a theoretical treatment based on the Hammond postulate that o! cannot in any precise sense reflect transition-state structure and this has been further confirmed by Bordwell and B~yle~~ in a study of the rate of deprotonation of a number of nitroalkanes and ketones by a variety of amine catalysts.Brernsted CI values have also been examined in terms of the Marcus theory93 for a number of aliphatic diazo- compounds. The value of a-changes as the catalyst is changed but is independent of the diazo-compound. Values of o! outside the theoretical range ((3-1) are explained by destruction of the n-system where a carbon base is protonated. This does not occur when oxygen or nitrogen bases are ~rotonated.’~ A much simpler deduction of transition-state structure from a Brsnsted plot has been made by Rogne9’ in a study of the reaction of aromatic sulphonyl chlorides with anilines. It seems reasonable to suppose that bond formation is less advanced in the transition state when there is an electron-donating substi- tuent at the p-position in the sulphonyl chloride.Now 2-and 2,6-substituted anilines show negative deviations from the Brcansted plot of this reaction for steric reasons but this effect is less pronounced with an electron-donating C. L. Liotta W. F. Fischer E. L. Slightom and C. L. Harris J. Amer. Chem. Soc. 1972,94,2129. B9 K.L.Williamson S. Masser and D. E. Stedman J. Amer. Chem. SOC..1971,93 7208. 90 B. C. Challis and E. M. Millar J.C.S. Perkin I[ 1972 11 16 1618 1625. 9‘ J. R. Murdoch J. Arner. Chem. SOC.,1972 94,4410. 92 F. G. Bordwell and W. J. Boyle J. Amer. Chem. SOC., 1972,94,3907. 93 R. A. Marcus J. Phys. Chem. 1968 72 891. 94 W. J. Albery A. N. Campbell-Crawford and J. S. Curran J.C.S. Perkin 11 1972,2206.95 0. Rogne J.C.S. Perkin /I 1972 472. Reaction Mechanisms-Part (i) Aromatic Compounds substituent at the p-position. This is consistent with the reduced amount of bond formation. The c1 effect has been the subject of a theoretical study using a polyelectron perturbation method,96 and it has been detected among N- heterocyclic^.^' Hibbert and Long98 report that the hydroxide ion is anomalously unreactive as a base catalyst for proton transfer from a carbon acid. Base-catalysed hydrogen exchange in indoles involves formation of an anion and the rate-determining step may be looked upon as attack of an indole anion on water. However a Brsnsted plot based on this (using pK values of substituted indoles) has a slope outside the theoretical range.The reasons for this have been discussed in detail.99 Until now there has not been an entirely satisfactory scale of nucleophilicity. However Ritchie and co-workerstoO have shown that the reaction of a very large number of nucleophiles with various cations (e.g. aryidiazonium ions Crystal Violet Malachite Green) may be correlated by the simple expression logk = logkHz + N where k is the rate of reaction of cation with the nucleophile kH20is the rate of its reaction with water and N is characteristic of the nucleophile and the solvent. Thus N is a quantitative measure of nucleo-philicity with wide-ranging applicability. 96 F. Filippini and R. F. Hudson J.C.S. Chem. Comm. 1972 522. 97 J. A. Zoltewicz and H. L. Jacobson Tetrahedron Letters 1972 189; J.A. Zoltewicz and L. W. Deady J. Amer. Chem. SOC.,1972,94,2765. 98 F. Hibbert and F. A. Long J. Amer. Chem. SOC.,1972,94 2647. 99 B. C. Challis and E. M. Millar J.C.S. Perkin 11 1972 111 1. loo C. D. Ritchie and H. Fleischhauer J. Amer. Chem. SOC.,1972,94 3481; C. D. Ritchie and P. 0.I. Virtanen ibid. pp. 4963 4966.

ISSN:0069-3030    

DOI:10.1039/OC9726900107

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (ii) Orbital Symmetry Correlations and Pericyclic Reactions By R. GRlGG Department of Chemistry University of Nottingham Nottingham NG7 2RD 1 Theoretical Aspects Alternative theoretical treatments of pericyclic processes continue to appear and a number of pericyclic processes have been discussed in terms of the principle of least motion.2 A number of new concepts of importance in pericyclic processes such as the relationship between symmetry topology and ar~maticity,~ and bond stretch isomerism and polytopal rearrangement^,^ have also been dis- cussed. The problem of those ‘forbidden’ processes which occur comparatively easily has been discussed’ and it is concluded that a majority of the observed ‘forbidden’ processes are concerted if they require the opening of only one C-C bond.It is suggested that substituents which introduce low-lying excited singlet states can dramatically enhance the rates of forbidden reactions by increasing the anharmonicities of the potential curves. A series of stimulating papers formulat- ing a new theoretical approach to thermal and photochemical cycloaddition reactions has appeared6 in which the manifold problems of predicting rates stereo- chemistry and solvent effects are tackled. A very important difference between this approach and previous theoretical treatments is the implication that non- stereospecificity(e.g.in thermal 2 + 2 reactions) might be the outcome of several well-defined and competing concerted processes rather than an indication of the intervention of a partially or totally non-discriminating intermediate such as a biradical.The energy separation of the interacting MO’s of the cycloaddends is noted as the key factor which determines the extent by which a concerted reaction will be favoured over a non-concerted reaction. Thus thermal cycloadditions are classified according to a donor-acceptor scheme giving a spectrum varying from cycloaddends with similar electron-donor and -acceptor abilities undergoing non-polar addition through systems with diverging electronic character to the W. J. van der Hart J. J. C. Mulder and L. J. Oosterhoff J. Amer. Chem. SOC.,1972 94 5724; W. A. Goddard ibid. p. 793; R. J. Buenker S. D. Peyerimhoff and K. Hsu ibid. 1971 93 5005; R. G. Pearson ibid.1972,94 8287. 0. S. Tee and K. Yates J. Amer. Chem. SOC.,1972 94 3074. M. J. Goldstein and R. Hoffmann J. Amer. Chem. SOC.,1971 93 6193. W.-D. Stohrer and R. Hoffmann J. Amer. Chem. SOC.,1972,94 779 1661. W Schmidt Tetrahedron Letters 1972 581 ; Heh. Chim. Acta 1971 54 862. N. D. Epiotis J. Amer. Chem. SOC. 1972 94 1924 1935 1941 1946. 120 Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations extreme near-ionic cycloaddition. It is suggested that when the MO interactions (HOMO/LUMO) between cycloaddends are strong a concerted reaction will be favoured whereas a weak interaction will favour the two-step mechanism. Since HOMO/LUMO interactions are weakest towards the extreme non-polar end of the spectrum for both 2 + 2 and 4 + 2 cycloadditions it is in this region that two-step cycloadditions are expected.A similar reactivity spectrum is discussed for photochemical reactions. Perturbation theory has been applied to the lowest triplet state of conjugated hydrocarbons7 and the rules for ground-state aromaticity are found to be reversed in the lowest triplet state such that 4n rings display 'aromatic' character whereas 4n + 2 systems display 'antiaromaticity'. A major contribution to rationalizing the anomalies in the mechanics of photochemical processes has appeared.8 Following a previous pioneering paperg concerned only with electro- cyclic processes Dougherty employs PMO theory and classifies photochemical reactions into three general types (i) X-type reactions which occur entirely on an excited-state surface and result in luminescent products ; (ii) N-type reactions which start from an excited state and proceed to a non-bonding (intermediate) ground state; (iii) G-type reactions which start on an excited surface and proceed directly to a bonding ground-state configuration.Photochemical pericyclic reactions are G-type processes and result in ground-state products because of a breakdown of the Born-Oppenheimer approximation.' A suggestion for a new class of pericyclic reactions dyotropic processes (Gk. dyo; two) has been made." Dyotropic processes are defined as processes in which two a-bonds simultaneously migrate intramolecularly. This can lead to an interchange of bonds [e.g. (1)-P (2)] as observed in many vicinal trans-dibromosteroids.' ' However no direct positional interchange need occur since the photoracemization (3) + (4)12is also classified as a dyotropic process.X Bi (3) (4) N. C. Baird J. Amer. Chem. SOC.,1972 94,4941. R. C. Dougherty J. Amer. Chem. SOC.,1971,93 7187. ' W. Th. Am. van der Lugt and L. J. Oosterhoff J. Amer. Chem. Soc. 1969,91 6042. lo M. T. Reetz Angew. Chem. Infernat. Edn. 1972 11 129 130. P. L. Barili G. Bellucci G. Berti F. Marioni A. Marsili and I. Morelli J.C.S. Perkin IZ 1972 59. D. G. Farnum and G. R. Carlson J. Amer. Chem. SOC.,1970,92 6700. 122 R.Grigg A number of reviews covering both arornaticl3 and related heterocyclic systems14 and their valence isomers have appeared. The theory of cycloaddition reactions has also been reviewed15 and two new books on pericyclic processes have appeared." A curly arrow symbolism employing three types of arrow has been proposed which allows both electron shifts and stereospecificities of peri-cyclic processes to be depicted and provides a simple predictive approach at the same time.' 2 Electrocyclic Reactions Both CND0/2 and MIND0/2 studies18 concur with Dewar's view [see Ann.Reports (B),1971,68 1441 that cyclopropyl radicals should undergo disrotatory opening to the allyl radical and in a pyramidal radical one disrotatory mode is favoured over the other [i.e.(5)]. A further example of steric control in the con- rotatory opening of a cyclopropyl carbene to an allene has been provided [(6)-D (7)I.l' Both thermal and solvolytic" opening of cyclopropyl derivatives have attracted much attention.Thermal ring-opening of cyclopropyl chlorides leads to stereospecific recapture of the chloride ion by the allyl cation on the same face of the molecule [e.g. (8)-(9)].2' The concerted solvolysis of exo-substituted bicyclo[2,l,O]pentanes (10) to cyclopentenes is clearly sterically impossible. Studies show that exo (10) into endo (11) conversion occurs first l3 (a) E. E. van Tamelen Accounts Chem. Res. 1972 5 186; (6) S. Masamune and N. Darby ibid. p. 272; (c)L. T. Scott and M. Jones Chem. Rev. 1972,72 181. l4 A. G. Anastassiou Accounts Chem. Res. 1972 5 281. Is W. C. Herndon Chem. Rev. 1972 72 157. l6 T. L. Gilchrist and R. C. Storr 'Organic Reactions and Orbital Symmetry' Cambridge Univ.Press 1972; R. E. Lehr and A. P. Marchand 'Orbital Symmetry. A Problem Solving Approach' Academic Press 1972. C. Kaneko Tetrahedron 1972 28 4915. G. Boche and G. Szeirnies Angew. Chem. Internat. Edn. 1971 10 91 1,912. l9 W. R. Moore and R. D. Bach J. Amer. Chem. Soc. 1972,94 3148. 2o P. von R. Schleyer W. F. Sliwinski G. W. Van Dine U. Schollkopf J. Paust and K. Fellenberger J. Amer. Chem. SOC.,1972 94 125; W. F. Sliwinski T. M. Su and P. von R. Schleyer ibid. p. 133. *l I. Fleming and E. J. Thomas Tetrahedron 1972 28,4989. Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations 123 thus removing the steric constraints and is followed by a rapid solvolysis to ( 12).22 The exo-endo isomerization could conceivably involve either 1,4 or 1,5 ( =4,5)bond fission generating a biradical intermediate.Studies on deuteri- ated derivatives demonstrate that 1,6bond cleavage is occurring.23 Recent calculation^^^ indicate that the bicyclopentanes (13 ;R = F or OR’)can undergo thermal ring-flip by an ‘allowed’ path. Electrocyclic opening of cyclopropyl anions to allyl anions has been achieved but the mode ofopening was not determined 25*26 except in one case [( 14)-+(IS)] where the molecule is constrained to the unfavourable disrotatory mode.” It proved possible in some cases to trap the allyl anions by cycloaddition to aromatic olefins (16)-+ (17)26and a related cycloreversion has also been achieved ( 18) -+( 19).2 H Ph PhCH=CH ---A CN H-H Ph H Ph C0,Me C0,Me Phfico2Me + PhAMe Ph Nx=N Me Ph C0,Me (18) (19) ” K.Fellenberg U. Schollkopf C. A. Bahn and P. von R. Schleyer Tetrahedron Letters 1972 359; J. J. Tufariello A. C. Bayer and J. J. Spadero ibid. p. 363. 23 J. J. Tufariello and A. C. Bayer Tetrahedron Letters 1972 3551 24 D. B. Chesnut S. Ferguson L. D. Smith and N. A. Porter Tetrahedron Letters 1972 3713. 25 R. Huisgen and P. Eberhard J. Amer. Chem. Soc. 1972,94 1346. ‘* G. Boche and D. Martens Angew. Chem. Infernat. Edn. 1972 11 724. l7 M. E. Londrigan and J. E. Mulvaney J. Org. Chem. 1972,37,2823. 28 P. Eberhard and R. Huisgen J. Amer. Chem. Soc. 1972,94 1345. 124 R.Grigg Pyrolysis at 280 “C of cis-3,4-dimethylcyclobutenegives ca. 0.005 % of trans,-trans-2,4-hexadiene the product of a ‘forbidden’ disrotatory opening.From this and a consideration of steric effects it is concluded that the conrotatory transition state is 15 kcal mol-I lower in energy than the disrotatory Studies on electrocyclic reactions in the vitamin D series and of benzene valence isomers which are sterically constrained to occur by ‘forbidden’ paths have provided useful kinetic data.30.3 Thus the antiaromatic transition state for the re-arrangement (20) +(21) is markedly stabilized by unsymmetrical substitution on the two central carbons.31 2-Pyridones’ generally thought to only undergo 4 + 4 photocycloadditions have now been found to undergo disrotatory photocycliza- tions to the bicyclic isomers (22) +(23).32 Photocyclization ofazine monoxides (24)-+ (25) occurs from the excited singlet state.33 The radical-anions prepared from the benzocyclobutenes (26 ;R’= H R2 = Ph or R’= Ph R2= H) undergo stereospecific conrotatory opening to the xylylene radical-anions (27) and the corresponding dianions formed by further reduction can be trapped with dimethyldichl~rosilane.~~ .I X A I R’ R‘ R2 I K’ (24) (25) 29 J.I. Brauman and W. C. Archie J. Amer. Chem. Soc. 1972 94 4262. 30 A. M. Bloothoofd-Kruisbeek and J. Lugtenburg Rec. Trav. chim. 1972,91 1364. 31 R. Breslow J. Napierski and A. H. Schmidt J. Amer. Chern. SOC.,1972 94 5906; D. M. Lemal and L. H. Dunlap ibid. p. 6562. 32 H. Furrer Chem. Ber. 1972 105 2780; R. C. De Selms and W. R. Schleigh Tetra-hedron Letters 1972 3563. 33 W.M. Williams and W. R. Dolbier J. Amer. Chem. SOC.,1972 94 3955. 34 N. L. Bauld C.-S. Chang and F. R. Farr J. Amer. Chem. Soc. 1972,94 7164. 125 Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations Ph Photoequilibration of cyclohexa-1,3-dienes with hexa-1,3,5-trienes has been studied,35 and the effects of ground-state conformational control on the direc- tion of conrotatory opening have been disc~ssed.~~ Structural and charge effects on the cycloheptatriene-norcaradiene3' and cyclo-octatriene-bicyclo[4,2,0]-he~adiene~~ equilibria have been reported Calculations on the related hetero- cyclic equilibria (28) (29) (X = 0,NR or S) predict that protonation on the heteroatom will displace the equilibrium towards the bicyclic form (29).39a N.m.r.studies show that the azepines (30) exist predominately in the monocyclic form whereas the diazepines prefer the bicyclic structure (31).39b R,2 R5 R4 A further facet of the mechanisms of rearrangement of bicyclo[6,1 ,O]nonatrienes [see Ann. Reports (B),1971,68 1491 has been uncovered by studies on the esters (32a and b) which are thermally converted into an 86 14 mixture of(33) and (34).40 At 100 "C epimerization (32a) +(32b) without rearrangement occurred and an analogous epimerization of (32; R' = Me R2 = C0,Me) to (32; R' = CO,Me R2 = Me) was observed at 160 "C. A biradical mechanism involving breaking of the 1,9-bond is favoured for this reaction. It has also proved possible to prepare (35) and study its Cope rearrangement to (36)41 at temperatures below 0°C.The reverse process (36) +(35)has been suggested to intervene in the conversion of some bicyclo[6,l,0]nonatrienes into the corresponding dihydr~indenes.~~ 35 W. G. Dauben J. Rabinowitz N. D. Vietmeyer and P. H. Wendschuk J. Amer. Chem. SOC.,1972,94 4285. 36 C. W. Spangler and R. P. Hennis J.C.S. Chem. Comm. 1972 24. 37 J. Daub and W. Betz Tetrahedron Letters 1972 3451; E. Vogel W. Wiedemann H. D. Roth J. Eimer and H. Gunther Annafen 1972,759 1. 38 F. A. Cotton and G. Daganello J. Amer. Chem. SOC.,1972 94 2142. 39 (a) W.-D. Stohrer and R. Hoffmann Angew. Chem. Internat. Edn. 1972 11 825; (b) A. Steigel J. Sauer D. A. Kleier and G. Binsch J. Amer. Chem. Soc. 1972 94 2770. 40 M. B. Sohn M. Jones and B. Fairless J.Amer. Chem. SOC.,1972 94 4774. 41 L. A. Paquette and M. J. Epstein J. Amer. Chem. SOC.,1972 94 5936. 42 P. Radlick and W. Fenical J. Amer. Chem. SOC.,1969 91 1560; A. G. Anastassiou and R. C. Griffith ibid. 1971,93 3083. I26 R. Grigg The related aza-system has been studied and was found to give the trans-dihydro- ind01e~~ in accord with prediction and not the cis-product as previously reported. H Et0,C (32) a; R’ = D R2 = C0,Et (33) (34) b;R’ = CO,Et R2 = D Ph Ph Ph (35) (36) A number of thermal44 and phot~chernical~~~~~ electrocyclic reactions in both ani~nic~~.~’ species have been reported. An intriguing example and ~ationic~~ [(37)-+(38)] is thought to arise via photochemical conrotatory opening of the protonated species to a heptatrienyl cation (39) followed by a thermal conrota- tory closure utilizing a pentadienyl cation moiety.46 Electrocyclic reactions followed by elimination reactions [e.g.(40 +(41)-+(42)] have synthetic poten- tial in aromatic and heterocyclic chemistry.47 bFSY;H,,9-R (I R (38) R (37) R = H or Me (39) $ =y$ +)$ /N-OH \ N-OH \N (40) (41) (42) 43 A. G. Anastassiou R. L. Elliot and A. Lichtenfield Tetrahedron Letters 1972 4569. 44 R. B. Bates S. Brenner and C. M. Cole J. Amer. Chem. SOC.,1972 94 2130; R. B. Bates S. Brenner and B. I. Mayall ibid. p. 4765. 45 H. Kloosterziel and G. M. Gorter-La Roy J.C.S. Chem. Comm. 1972 352. 46 R. Noyori Y. Ohnishi and M. Kato J. Amer. Chem. SOC.,1972 94 5105. 47 P. Scheiss H.L. Chia and P. Ringele Tetrahedron Letters 1972 313; C. Jutz and R. M. Wagner Angew. Chem. Internat. Edn. 1972,11 315. Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations 127 3 Cycloaddition Reactions The plenary lectures of a symposium on cycloadditions have been published?’ MIND0/2 calculations and considerations of transition-state geometry suggest that in general transition states of cycloaddition reactions are likely to be non- symmetric. For N + M cycloadditions the likelihood of a non-symmetric transition state will increase as N and M in~rease.~’ This asymmetry in the transi- tion state can be turned to a predictive advantage since the preferred reaction paths can be predicted by considering formation of the most stable (hypothetical) biradical intermediate” as is well known for the Diels-Alder reaction.A new criterion the rate ratio for em-addition to norbornene (k,) and 7,7-dimethyl- norbornene (k2),for distinguishing between cyclic and non-cyclic addition processes has been proposed. Processes with cyclic transition states have k,/k2= 480-1820 whereas for non-cyclic processes k,/k < 58.51 The lifetime of singlet oxygen (‘Ag) contrary to popular belief is solvent dependents2 and a new source of singlet oxygen potassium perchromate has been rep~rted.’~ The pyrolysis of the cyclobutane (43) is non-stereospecific and leads to cis-and trans-2-butene and cis-and trans-dideuteri~ethylene.’~ In contrast the thermal cleavage of the bicyclo[2,2,0]hexane (44) to the corresponding hexa-1,5-diene is stereospecific and apparently a concerted ,2 + ,2 pro~ess.’~ The gas-phase isomerization of the methyl bicyclo[2,1 ,O]pentenes (45a and b) gives mixtures of the corresponding cyclopentadienes (46a and b) uia ,2 + ,2 proce~ses.’~ How-ever the previous liquid-phase work which reported (45a) as giving (46b)” has been repeated and the product shown to be (46a).58 Clearly double-labelling experiments are required in.this series. Thermal decomposition of the dioxetan (47)efficiently and selectively yields triplet-state acetone which is not generated from acetone singlet precursor^.^^ Me Mb**D R’ :xGD qR2Rd2 ‘D (44) (45) a; R’ = Me R2 = H (46) (43) b; R’ = H RZ = Me 48 ‘Cycloaddition Reactions’ ed. R. Gompper Butterworths London 1972.49 J. W. Mclver J. Amer. Chem. SOC.,1972 94 4782. G. L. Goe J. Org. Chem. 1972 37 2434. 51 H. C. Brown and K.-T. Liu J. Amer. Chem. SOC.,1971 93 7335. 52 P. B. Merkel and D. R. Kearns J. Amer. Chem. SOC.,1972 94 1030; P. B. Merkel R. Nilsson and D. R. Kearns ibid. p. 1030; C. S.Foote E. R. Peterson and K.-W. Lee ibid. p. 1032. ” J. W. Peters J. N. Pitts I. Rosenthal and H. Fuhr J. Amer. Chem. SOC.,1972,94,4348. ’4 R. Srinivasan and J. N. C. Hsu. J.C.S. Chem. Comm. 1972 1213. 55 M. J. Goldstein and M. S. Benzon J. Amer. Chem. SOC.,1972 94 51 19. ’’ J. E. Baldwin and G. D. Andrews J. Amer. Chem. SOC.,1972,94 1775. ” J. E. Baldwin and A. H. Andrist Chem. Comm. 1970 1561. ” S. McLean D. M. Findlay and G. I. Dmitrienko J.Amer. Chem. SOC.,1972,94 1380. 59 N. J. Turro and P. Lechtken J. Amer. Chem. SOC.,1972 94 2886. 128 R.Grigg MeuMe -% [CH3COCH3]3+ [CH3COCH,]' Me Me -50% -1% (47) Keten cycloadditions and cycloreversions of cyclobutanones" continue to attract attention. MO treatments indicate that stabilization through the inter- action of the ketenophile n-system with the carbonyl n-bond plays a dominant role in the orthogonal .2 + ,2 approach of the two reactants and is also respon- sible for directing addition to the C=C as opposed to the carbonyl group of the keten.61 8-Oxoheptafulvene (48) behaves as a typical keten in cycloadditions and with cyclopentadiene gives (49).62 The keteneimmonium cation (50) generated at -60 "C reacts with olefins and dienes by what is thought to be a concerted ,2 + ,2 cycloaddition giving on work-up the corresponding cyclo- butanones (51) in high yield.6 Studies on keten-allene cycl~additions~~~~~ using optically active allenes suggest that the reaction is a concerted .2 + ,2 process in which either allene or keten may be utilized ~uprafacially.~~ A study of secondary deuterium isotope effects in allene-olefin cycloadditions leads to the conclusion that the thermal ,2 + .2 processes proceed stepwise whereas the ,2 + .4 cycloadditions are concerted.66 Photocycloaddition of certain olefins to the nitrile group of benzonitrile is followed by electrocyclic opening of the intermediate 1-azetine (52)+ (53).67 Photoelectron spectroscopy provides an explanation for the failure of hypo- strophene (54) to photocyclize to (55).The reaction is rendered symmetry 'for-bidden' by effective through-bond coupling of an exceptionally high-lying a-level with the two 7c-orbitals.68 The kinetics of the hydroboration of alkenes have been studied and deuterium isotope effects are consistent with a concerted four- centred addition of B-H to the double bond.69 However it is suggested that oczo-% / (48) (49) 6o K. W. Egger and A. T. Cocks J.C.S. Perkin ZZ 1972,2 11 ;J. Metcalfe H. A. J. Carless and E. K. C. Lee J. Amer. Chem. SOC.,1972,94 7235. 61 R. Sustmann A. Ansmann and F. Vahrenholt J. Amer. Chem. SOC.,1972,94 8099. 62 T. Asao N. Morita and Y. Kitahara J. Amer. Chem. SOC.,1972.94 3655. 63 J. Marchand-Brynaert and L.Ghosez J. Amer. Chem. SOC.,1972,94 2870. 64 W. Weyler L. R. Byrd M. C. Caserio and W. H. Moore J. Amer. Chem. SOC.,1972 94 1027. 65 M. Bertrand J.-L. Gras and J. Gore Tetrahedron Letters 1972 1189 2499. 66 S.-H. Dai and W. R. Dolbier J. Amer. Chem. SOC.,1972 94 3946. 6' T. S. Cantrell J. Amer. Chem. SOC.,1972 94 5929. 68 W. Schmidt and B. T. Wilkins Tetrahedron 1972 28 5649. 69 D. J. Pasto B. Lepeska and T.-C. Cheng J. Amer. Chem. SOC.,1972,94 6083; D. J. Pasto B. Lepeska and V. Balasubramaniyan ibid. p. 6090. Reaction Mechanisms-Part (ii) Orbital symmetry Correlations 1 29 (CH,),C=C=&Me BF,-H,O (50) Me Me (51) (52) (53) R = Me or OMe the energy barrier to this ,2 + @2cycloaddition is overcome by prior formation of a n-c~mplex.~~ Frontier orbital effects on the Diels-Alder reaction [see Ann.Reports (B),1971 68,1551 have been placed on a semiquantitative basis.71 The case for the import- ance of van der Waals forces in determining the preferred endo orientation of the methyl group in the Diels-Alder adducts of the methyl-substituted dienophiles (56; X = CN CHO or C0,Me) has been re-argued with supplementary results for 2 + 2 + 2 cycloadditions to norbornadiene which also show the same orienta- tional ~electivity.~~ Synthesis and kinetic study of the thermal reactions of the optically active butadiene dimer 4-vinylcyclohexene (57) revealed that racemiza- tion and deuterium exchange was occurring implicating fission to a biradical and demonstrating that a concerted Cope rearrangement was not involved.The data obtained suggest that Diels-Alder dimerization of butadiene is concerted per- haps two-stage but not The thermal intramolecular cycloaddition of (58) gives (59a) the product of a 4 + 2 cycloaddition rather than (59b) the 2 + 2 product.74 This study shows that the 4+ 2 process is kinetically favoured by at least 4kcal mol-'. Electron-donor solvents (dioxan o-xylene) stabilize the reactants in a Diels-Alder reaction whereas more electronegative solvents lo P. R. Jones J. Org. Chem. 1972 37 1886. R. Sustmann and R. Schubert Angew. Chem. Internat. Edn. 1972,11 839. 72 Y. Kobuke T. Sugimoto J. Furukawa and T. Fueno J. Amer. Chem. SOC.,1972,94 3633. 73 W. von E. Doering M. Franck-Neumann D. Hasselmann and R.L. Kaye J. Amer. Chem. SOC.,1972,94 3833. l4 A. Krantz J. Amer. Chem. SOC.,1972,94,4020. 130 R.Grigg (CHCl, C,H,Cl) stabilize the transition state. The solvent effect on the enthalpy of activation is a consequence of these two A dramatic solvent effect in Diels-Alder additions to the cyclobutene double bond in (60)is ascribed to inter- action of the hydroxy-group with the double bond. The rate in DMSO is 470 times that in chloroform. Intramolecular hydrogen-bonding of the hydroxy-group to the double bond in chloroform solvent results in decreased electron density in the double bond and hence discourages addition of electron-deficient diene~.~~ Systems related to (60)may provide a probe for separating the effects of steric and electronic influences on Diels-Alder reaction^.'^ Most current =4participants in K4+ .2 cycloadditions require activated olefins as partners.A series of papers77 introduces and exploits a new class of dienophiles which react easily with un- activated olefins. a-Chloronitrones (61) are the precursors and they undergo a facile silver-ion-induced addition to unactivated olefins to give products (63) considered to arise from addition of N-alkyl-N-vinylnitrosonium ions (62). New sulphur dienophiles include disulphur monoxide,78 ~ulphines,~ and N-sulphonylamines.8o Acetylenic dienophiles react with thiophens to give benzene derivatives via non-isolable intermediates8 However in the presence of AlCl a reaction (59) a; R’ = D R2 = H (60) b;R1 = H,R2 = D ’’ P. Haberfield and A.K. Ray .I. Org. Chem. 1972 37 3093. ’‘ I. W. McCay M. N. Paddon-Row and R. N. Warrener Tetrahedron Letters 1972 1401 ; M. N. Paddon-Row and R. N. Warrener ibid. p. 1405; M. N. Paddon-Row ibid. p. 1409. ’’ U. M. Kempe. T. K. Das Gupta K. Blatt P. Gygax D. Felix and A. Eschenmoser Helv. Chim. Acta 1972 55 2187; T. K. Das Gupta D. Felix U. M. Kempe and A. Eschenmoser ibid. p. 2198; P. Gygax T. K. Das Gupta and A. Eschenmoser ibid. p. 2205. 78 R. M. Dodson V. Srinivasan K. S. Sharma and R. F. Sauers J. Org. Chem. 1972 37 2367. ’’ B. Zwanenburg L. Thijs J. B. Broens and J. Strating Rec. Trav. chim. 1972,91,443. E. M. Burgess and W. M. Williams J. Amer. Chem. Soc. 1972 94 4386. R. Helder and H. Wynberg Tetrahedron Letters 1972 605; H. J.Kuhn and K. Gollnick ibid. p. 1909. Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations 131 DcH2vcH2D Me Me occurs at room temperature (64) +(65),82 suggesting that the other cycloaddi- tions may be more complicated than at first thought. Good evidence for the intermediacy of oxyallyl cations (66) in the ironcarbonyl- initiated cycloadditions (67) -+ (68) has been provided.83 Similar ions can be generated from 2-dimethylamino-4-methylene-l,3-dioxolans.84Tetrahydro-furan and its alkyl derivatives are deprotonated by n-butyl-lithium in hexane and undergo a .4 + .2 cycloreversion (69) +(70).85 The related radical cleavage (71) -+ (72)is non-concerted.86 Further stereospecific examples of the addition of aza-ally1 anions to olefins have been reported [e.g.(73)+(74)].8’ 0-R-R (70) (71) (72) Ph H %ph -PhlJ; J,:,A H Ph N Ph Ph H (73) (74) H.Wynberg and R.Helder Tetrahedron Letters 1972 3647. 83 R. Noyori Y. Hayakawa M. Funakura H. Takaya S. Murai R.4. Kobayashi and S. Tsutsumi J. Amer. Chem. SOC.,1972 94 7202. H. M. R. Hoffmann K. E. Clemens and R. H. Smithers J. Amer. Chem. SOC.,1972 94 3940. 85 R. B. Bates L. M. Kroposki and D. E. Potter J. Org. Chem. 1972 37 560. 86 W. R. Dolbier I. Nishiguchi and J. M. Riemann J. Amer. Chem. SOC.,1972,94 3642. 87 T. Kauffmann and E. Koppelmann Angew. Chem. Internat. Edn. 1972 11 290; T. Kauffmann K. Habersaat and E. Koppelmann ibid. p. 291. 132 R.Grigg MO calculations provide an explanation for the unexpected resistance of (75)88 and (76)89to the retro-Diels-Alder elimination of C202and N20,respectively.The thermal decomposition of (77) gives (78) and not (79) as the primary product and is therefore not a retrohomo-Diels-Alder rea~tion.~' The photochemical Diels-Alder reaction (e.g. 80-8 l),if concerted could involve a ,4 + ,2 or ,4 + .2 cycloaddition. Results in this area indicate that the selectivity of the process is controlled by substrate structure and that it would be unwise to depend on orbital symmetry control in exploiting this reacti~n.~ (80) (81) Further theoretical and experimental studies on 1,3-dipolar cycloadditions have been reported but again steric effects are not satisfactorily encompas~ed.~~ The question of regioselectivity in 1,3-dipolar cycloadditions has been discussed and the case for a biradical mechanism argued at length.93 The synthetic poten- tial of 1,3-dipolar species generated in situ and trapped intramolecularly [e.g.(82)+(83) or (84)] has been well ill~strated.~~ 1,3-Dipolar cycloreversions are implicated in the thermal decomposition of pyrazolinesg5 and triaz~les.~~ 88 R. C. Haddon Tetrahedron Letters 1972 3897. 89 J. P. Snyder L. Lee V. T. Bandurco C. Y. Yu and R. J. Boyd J. Amer. Chem. SOC. 1972,94 3260. 90 E. L. Ellred and J. C. Hinshaw Tetrahedron Letters 1972 387. 91 D. A. Seeley J. Amer. Chem. SOC.,1972,94,4378; A. Padwa L. Brodsky and S. Clough ibid. p. 6767; C. W. Alexander and J. Grimshaw J.C.S. Perkin I 1972 1374. 92 R. Sustmann and H.Trill Angew. Chem. Internat. Edn. 1972 11 838; J. Bastide N. El Ghandour and 0.Henri-Rousseau Tetrahedron Letters 1972 4225. 93 R. A. Firestone J. Org. Chem. 1972 37 2181. 94 W. Oppolzer Tetrahedron Letters 1972 1707. 95 D. H. White P. B. Condit and R. G. Bergman J. Amer. Chem. SOC.,1972 94 1348; R. A. Keppel and R. G. Bergman ibid. p. 1350; D. E. Eaton R. G. Bergman and G. S. Hammond ibid. p. 1351. 96 L. H. Zalkow and R. H. Hill Tetrahedron Letters 1972 2819. Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations The question of whether singlet oxygen reacts with olefins by a concerted ene mechanism (85)*(86)or by a perepoxide route (85)-+(87) continues to cause controversy. The azide-trapping experiments which favoured the perepoxide route involved a misinterpretation of the results.It appears that azide radicals were responsible for the products and that azide ions strongly quench singlet oxygen.97 The concerted ene mechanism continues to attract most support.98 Asymmetric induction in the ene reaction of (-)-methyl glyoxylate with pent-l- ene has been studied.99 Optical yields were found to depend on temperature solvent and catalyst. The allylic Grignard reagent (88) undergoes an intra- molecular ene-type reaction giving predominantly the cis-product (89).loo 0 0 II r4o 0 97 C. S. Foote T. T. Fujimoto and Y. C. Chang Tetrahedron Letters 1972 45; K. Gollnick D. Haisch and G. Schade J. Amer. Chem. SOC.,1972 94 1747; N. Hasty P. B. Merkel P. Radlick and D. R. Kearns Tetrahedron Letters 1972 49.98 C. S. Foote and R. W. Denny J. Amer. Chem. SOC.,1971,93 5162 5168; A. Nickon V. T. Chuang P. J. L. Daniels R. W. Denny J. B. Di Giorgio J. Tsunetsugu H. G. Vilhuber and E. Werstiuk ibid. 1972 94 5517. 99 0.Achmatowicz and B. Szechner J. Org. Chem. 1972 37 964. loo H. Felkin J. D. Umpleby E. Hagaman and E. Wenkert Tetrahedron Letters 1972 2285. 134 R.Grigg Thermal elimination (retro-ene) reactions of esters,"' carbonates,"' thiol-acetate~,"~and NN-dialkyl carbonate^"^ (90)+(91) have been studied and all appear to be concerted processes although bond-breaking and bond-making may well be non-synchronous. Pyrolysis of adamantane sulphonate esters (92)gives (93)and (94). The latter product is thought to be an example of a general reaction envolving a seven-membered transition state (95).'05 Y (90) X =2=0,Y=R X =Z =0,Y =OR X = S,Y =R,Z =0 X=Z=O,Y=NR 0 0 (92) (93) 2 3 (94) The 4 +4 photodimerization of anthracene is a two-step singlet process involving a biradical intermediate.'06 4 Sigmatropic Reactions Optically active (96)was subjected to thermal rearrangement and the deuterium- scrambled product (96;D at *positions) separated from the skeletally rearranged products. From a study of the rate constants for racemization and for deuterium scrambling it was concluded that a major amount and possibly all of the degener- ate rearrangement proceeds with antarafacial participation of the allylic unit. lo' The bicyclohexenes(97) rearrange at 30-50 "Cto (98),apparently by concerted suprafacial 1,3-shifts with inversion at the migrating centre.lo* lo' A. Tinkelenberg E. C. Kooyman and R. Louw Rec. Trav. chim. 1972 91 3; R. Taylor J.C.S. Perkin 11 1972 165; H. Kwart and J. Slutsky J.C.S. Chem. Comm. 1972 1182. Io2 D. B. Bigley and C. M. Wren J.C.S. Perkin 11 1972 926 1744. P. C. Oele A. Tinkelenberg and R. Louw Tetrahedron Letters 1972 2375. H. Kwart and J. Slutsky J.C.S. Chem. Comm. 1972,552; N. J. Daly and F. Ziolkowski ibid. p. 911. J. Boyd and K. H. Overton J.C.S. Perkin I 1972 2533. '06 G. Kaupp Angew. Chem. Internal. Edn. 1972 11 313 718. lo' J. E. Baldwin and R. H. Fleming J. Amer. Chem. Soc. 1972,94 2140. Io8 F. Scheidt and W. Kirmse J.C.S. Chem. Comm. 1972 716. Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations Examples of 1,3-migration of silicon have been reported.log A number of examples of thermal 1,7-antarafaciaI H shifts involving olefinic side-chains of substituted benzenes have been uncovered,' lo and a thermal 1,7-migration with inversion at the migrating centre occurs in the bicyclononatrienes (99)3(100).l1 Thermal rearrangement of (101) gives a mixture of (102 ; 91 %) and (103 ; 9 %).These arise by competitive homo-1,7-H shift (i.e.64s + n2s+ %2J and homo-1,5-H shift with the former being favoured kinetically [and leading to (102)].112 Me (97) R = OMe or N (98) (99) X = Me Y = CN X = CN.Y = Me Studies on the photochemistry of by-unsaturated ketones have shown that 1,3-acyl shifts result from the singlet state whereas the triplet-state ketones undergo oxa-di-n-methane rearrangements.Several attempts have been made to rationalize this divergent behaviour,' and steric conjugative and conforma- tional effects on l,3-acyl migrations have also been discussed. l l4 A second higher-energy degenerate rearrangement of hexa- 1,5-diene has been uncovered using tetradeuteriated material and is tentatively assigned the 'boat' Io9 H. Kwart and J. Slutsky J. Amer. Chem. SOC.,1972,94 2515. 'lo H. Heimgartner H.-J. Hansen and H. Schmidt Helv. Chim. Acta 1972 55 1385; R. Hug,H.-J. Hansen and H. Schmidt ibid. p. 1828. ''I F. G. Klarner Angew. Chem. Internat. Edn. 1972 11 832. "* J. C. Gilbert K. R. Smith G. W. Klumpp and M. Schakel Tetrahedron Lerters 1972 125.D. I. Schuster G. R. Underwood and T. P. Knudsen J. Amer. Chem. SOC.,1971 93 4305; K. N. Houk D. J. Northington and R. E. Duke ibid. 1972 94 6233. H. Sato N. Furutachi and K. Nakanishi J. Amer. Chem. SOC.,1972,94,2150. 136 R. Grigg transition state. A mathematical analysis of possible 1,3-and 3,3-sigmatropic rearrangements in hexa- 1,5-diene is also given and a variety of transition-state geometries considered for each case. The analysis emphasizes that appropriate experiments can make as yet unrealized mechanistic distinctions with complete rigour. ' ' CND0/2 and extended Hiickel calculations indicate that of the possible C,Hi systems the 9-barbararyl cation (104) enjoys unusual stabilization. This is due to strong conjugative interaction of the central p-orbitals with the cyclo- propane rings as depicted in (105)' l6 The unexpected retention of configuration in the solvolysis (106)j (107) revealed on further study that Cope rearrange- ment of the bridgehead carbonium ion (108) was intervening.'" A study of the Cope rearrangement (109)+(110)has provided evidence that a conformational change (111) +(1 12) precedes and follows the Cope rearrangement.'* A number of studies on steric effects in Cope rearrangements have been reported. l9 EtCO H v 4 4 I OCOEt D. D nD L \ r " / D n n (109) (110) l1 M. J. Goldstein and M. S. Benzon J. Amer. Chem. SOC.,1972 94 7147 7149. S. Yoneda S. Winstein and Z.-i. Yoshida Bull. Chem. Sot Japan 1972 45 2510; R.Hoffmann W.-D. Stohrer and M. J. Goldstein ibid. p. 2513. R. Breslow and J. M. Hoffman J. Amer. Chem. SOC.,1972 94 21 11. 118 H. Gunther J. B. Pawliczek J. Ulmen and W. Grimme Angew Chem. Internat. Edn. 1972 11 517. 'I9 C. J. Dixie and I. 0.Sutherland J.C.S. Chem. Comm. 1972,646; T. Sasaki S. Eguchi, and M. Ohno J. Org. Chem. 1972,37,466; C. Ullenius P. W. Ford and J. E. Baldwin J. Amer. Chem. SOC.,1972 94 5910. Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations R' (113) a R' = R2 = H b; R' = H R2 = Me In particular the reIative rates of Cope rearrangement via a boat transition state to the corresponding cyclo-octa-1,5-diene of (113a) and (113b) are 181 OOO 1.'" Rearrangements in diallyl or ally1 propargyl ammonium ylides occur pre- dominantly by a concerted 2,3-sigmatropic shift but minor amounts of 1,Zshift products are sometimes obtained presumably involving a radical-pair mechan- ism.' 21 Ylides generated by intra- and inter-molecular reactions of heteroatoms with carbenes undergo 2,3-sigmatropic shifts [e.g.(114)+ (115)].'22 Deprotona- tion of dihydropyrans (116)generates the anions (117) which undergo rearrange- ment possibly via a 1,6sigmatropic shift to (1 18).123 C0,Me Ix.] X '''cozMe'z+ -3 qC0,Me (114) X = SR OR NR2 C1 or Br C(CO Me) (1 15) 5 Cheletropic Reactions MO calculations on cheletropic reactions of diazirine and vinylene carbonates have appeared.124 A theoretical treatment of five-co-ordinate phosphorus '" J. A. Berson and P. B. Dervan J.Amer. Chem. Soc. 1972,94 7597; J. A. Berson P. B. Dervan and J. A. Jenkins ibid. p. 7599. 12' R. W. Jemison T. Laird and W. D. Ollis J.C.S. Chem. Comm. 1972 556; T. Laird and W. D. Ollis ibid. p. 557; V. Rautenstrauch Helv. Chim. Acta 1972 55 2233; S. Julia C. Huynk and D. Michelot Tetrahedron Letters 1972 3587. W. Ando S. Kondo K. Nakayama K. Ichibori H. Kohoda H. Yamato I. Imai S. Nakaido and T. Migita J. Amer. Chem. SOC.,1972 94 3870; J. E. Baldwin and J. A. Walker J.C.S. Chem. Comm. 1972 354; K. Kondo and I. Ojima ibid. p. 860; M. Yoshimoto S. Ishihara E. Nakayama E. Shoji H. Kuwano and N. Soma Tetrahedon Lerters 1972 4387. V. Rautenstrauch Helv. Chim. Acta 1972 55 594. 24 J. Fleischhauer and H. D. Scharf Tetrahedron Letters 1972 11 19; J. P. Snyder R.J. Boyd and M. A. Whitehead ibid. p. 4347. 138 .R.Grigg suggests that the cheletropic process (119) will involve axial-axial or equatorial- equatorial departure of the R substituents from the trigonal-bypyramidal phosphorus.’ 25 Cycloheptatrienylcarbene(120) undergoes cheletropic loss of acetylene from its norcaradiene valence tautomer to give benzene.’ 26 Numerous examples of a preparatively useful fragmentation-cheletropic sequence involving N-aminoaziridine monohydrazones have been reported e.g. (121)+(122).127 A combined disrotatory cyclizationsheletropic process has been devised for the synthesis of polypyrrole macrocycles related to corrins [e.g.(123)+(124)].128 N R’ Ill N I R2 Me kS (124) 125 R. Hoffmann J.M. Howell and E. L. Muetterties J. Amer. Chem. SOC.,1972,94,3047. lZ6 H. E. Zimmerman and L. R. Sousa J. Amer. Chem. SOC.,1972,94 834. ”’ D. Felix R. K. Muller U. Horn R. Joos J. Schreiber and A. Eschenmoser Hefv. Chim. Acra 1972 55 1276. lZ8 M. J. Broadhurst R. Grigg and A. W. Johnson J.C.S. Perkin I 1972. 1124 21 11. Reaction Mechanisms-Part (ii) Orbital Symmetry Correlations A number of examples are given and rate enhancements resulting from incorpora- tion of metal ions are discussed. A study of the rates of quinone dehydrogenations of cyclohexa-l&dienes has led to the suggestion that these may be concerted hydrogen-transfer processes. 12’ lz9 F. Stoos and J. Rocek J. Amer. Chem. SOC.,1972,94,2719.

ISSN:0069-3030    

DOI:10.1039/OC9726900120

出版商:RSC    

年代:1972

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 In order to cover adequately large areas included in enzyme mechanism new topics have been surveyed in each of the last two Reports. This approach is continued this year except that literature on coenzyme-B ,-dependent biological reactions originally reviewed' in 1970 has now been brought up to date. Section 2 'Conformations of Substrates and Conformational Changes at the Active Sites' complements last year's Report,2 which was exclusively devoted to the identification and regulation of groups involved in enzyme catalysis. A section on the stereochemistry of enzymic reactions and another on non-RNA-dependent synthesis of peptides have also been included.1 Coenzyme-B A common feature of most coenzyme-B (1) dependent biological reactions involves the counter transfer of a hydrogen atom and a leaving group between two adjacent carbon atoms I IH-CB-'C-X I 1+ X-CB-"C-H I I I I {-NAN 5' 5' CO"'j-CH,-R E (CO"' +CH,-R fi (1) Partial structure of coenzyme-B -* Me Me 5' N A Of Co"'+CH -R ' M. Akhtar and D. C. Wilton Ann. Reports (B) 1970 67 557. * M. Akhtar and D. C. Wilton Ann. Reports (B),1971 68 167. 140 Reaction Mechanisms-Part (iii) Enzyme Mechanisms OH OH R= in all coenzyme structures 0 Adenine The most extensively studied examples from a mechanistic viewpoint are the dioldehydrase- and ethanolamine deaminase-catalysed transformations (Scheme l).l H HO > <O; Dtoldehydrase R H R OH R H (2) R = Me or H (3) (4) Scheme 1 The experimental evidence available at the time of writing the 1970 Report permitted the deduction,' which has received strong support from recent work,3 that the crucial event in the coenzyme-B ,-linked transformations may involve the transfer of the migrating hydrogen atom of the substrate to the C-5' of the coenzyme to give rise to an enzyme-bound 5'-deoxyadenosine [see structure (13)] as a transitory intermediate.One of the hydrogen atoms of the methyl group of 5'-deoxyadenosine is subsequently transferred to form the product and regenerate the coenzyme. The cleavage of the carbon-cobalt bond during catalysis could occur through one of three possible dissociation mechanisms involving car- banion @) radical (9) or carbonium ion (10)species.(C~III)CH,-R (C+)CH,-R (cot)~H,-R (8) (9) (10) Recently attention has been focused mainly on the identification of the primary species formed upon the cleavage of the C-Co bond. It was shown that the enzyme glyceroldehydrase which normally converts glycerol into P-hydroxy- propionaldehyde but can also catalyse the analogous conversion (2)-B (4; R = Me) when mixed with propane-1,2-diol and coenzyme-B, gave rise to the appear- ance of absorption bands at 61 1 and 655 nm attributed to the formation of CO" cobalamin specie^.^ The concentration of the latter species increased to a steady- state concentration of 80 % of the enzyme-bound coenzyme present initially.T. H. Finlay J. Valinsky K. Sato and R. H. Abeles J. Biol. Chern. 1972 247 4197. S. A. Cockle H. A. 0.Hill R. J. P. Williams S. P. Davies and M. A. Foster J. Amer. Chem. SOC.,1972,94 27.5. M. Akhtar and D. C. Wilton When the substrate had been consumed the concentration of Co" cobalamin decreased and the coenzyme was reformed. In another experiment the e.s.r. spectrum of the enzymic reaction mixture was also measured and showed the appearance of two signals with g values of 1.944and 2.035 which were assigned4 by the authors to the biradical species (9). Although e.s.r. signals during co- enzyme-B ,-dependent enzymic reactions have been observed in several other lab~ratories,~ the concentrations of the unpaired electrons in these studies were low and the possibility that the radical species may be formed in a side reaction could not be excluded.In recent reports the demonstration of the presence of high concentrations of the radical species4 (accounting for about 25 % of the coenzyme) coupled with the spectral evidence3v4 for the existence of the Co" cobalamin intermediate lends support to the view that the initial dissociation of the carbon- cobalt linkage may occur through a homolytic mechanism as was originally suggested by Eggerer et aL6 Another approach for identifying the species formed on the dissociation of the C-Co bond was designed by Law et aL7 These workers took advantage of the fact that the 5,6-dimethylbenzimidazolylmoiety of coenzyme-B, may be substi-tuted by 4-hydroxy-2,2,6,6-tetramethylpiperidine N-oxyl to give the spin-label coenzyme-B, analogue (la) which can replace the natural coenzyme in the ethanolamine deaminase reaction (5)-+(7).The rationale behind this approach is that if radical intermediates are involved during the enzymic reaction addi- tion of the substrate to the spin-label coenzyme-B ,,-enzyme complex will result in the disappearance of the nitroxide e.s.r. radical owing to its presence in the vicinity of another radical species (1 l) during catalysis. The signal will however Co"'+CH2-R + HO Co".)CH2-R reappear when the substrate has been utilized. Experimentally this was found to be the case.7 For the remaining two possibilities the authors argued as follows.If heterolytic cleavage occurs to give a carbanion and a Co"' cobalamin the nitroxide e.s.r. signal will remain unchanged. In the case of heterolytic cleavage to a carbonium ion and a Co' cobalamin species the nitroxide will be expected to be displayed' as a ligand for the cobalt and its radical character irreversibly (a) J. A. Hamilton and R. L. Blakley Biochim Biophys. Acta 1969 184 224; (6) B. Babior and D. C. Gould Biochem. Biophys. Res. Comm. 1969 34 441; (c) J. A. Hamilton R. L. Blakley F. D. Looney and M. E. Winfield Biochim. Biophys. Acta 1969 177 374; (d) J. A. Hamilton R. Yamada R. L. Blakley H. P. C. Hogenkamp, F. D. Looney and M. E. Winfield Biochemistry 1971 10 347; (e) R. Yamada Y. Tamao and R. L. Blakley ibid. p. 3959. H. Eggerer F.Overath F. Lynen and E. R. Stadtman J. Amer. Chem. SOC.,1960 82 2643. P. Y. Law D. G. Brown E. L. Lien B. M. Babior and J. M. Wood Biochemistry 1971 10 3428. J. Brodie and M. Poe Biochemistry 1971 10 914. Reaction Mechanisms-Part (iii) Enzyme Mechanisms lost owing to reduction by the Co' species. The validity of this last assumption however must be questioned in view of a recent report in which it was shown that nitroxide radicals may not be reduced' by such strong reducing agents as Li(OR),AlH or LiAlH,. A different approach was used by the Brandeis group3 who argued that if a heterolytic cleavage resulting in the formation of a carbonium ion and a Co' species operates during enzyme catalysis the latter species owing to its nucleo- philic character may react with a suitable electrophilic reagent.Dioldehydrase which is involved in the reaction (2)-+(4:R = H) also catalyses an exchange of the C-5' hydrogen atoms of the coenzyme with C-2 hydrogen atoms of the product acetaldehyde. Chloroacetaldehyde can replace acetaldehyde in the hydrogen-exchange reaction ; since during the course of the reaction involving chloroacetaldehyde the displacement of the type ]p3 //O (CO.) CH -C -H was not observed the author concluded that a Co' species is not involved in coenzyme-B ,-linked reactions. The conclusion may be correct ;the rationale is however questionable in view of a recent report highlighting the fact that the presence of an alkylating agent in the vicinity of a nucleophilic centre at the enzyme active site does not necessarily lead to alkylation in preference to other modes of reaction." In spite of some reservations the evidence presented points to (but does not prove) a homolytic cleavage of the C-Co bond of the coenzyme as an early step in catalysis.In the light of this information the mechanistic sequence of Scheme 2 H (Co"'+CH,-R H H H Htf".H + 11 a HO H-OH + [(colI-);+] HO H (coii.)CH -R (2) .Ib (13) (1) = (9) :HHOH c H+---((H H H (coq OH H H \ \ H-C-R (15) (14) (co*~~)H-c-R / / H' 1Id H' "49 ' O€ (CO~~-)H-C-R / H' Scheme 2 D. J. Kosman and L. H. Piette Chem. Comm. 1969 926. lo H. P. Meloche M. A. Luczak and J. M. Wurster J. Biol. Chem. 1972 247 4186. M. Akhtar and D.C.Wilton may be considered3v4 for the reaction catalysed by dioldehydrase. Reaction a of Scheme 2 resulting in the abstraction of a hydrogen atom from the substrate by the coenzyme requires a special mention. In several other coenzyme-B,,- dependent reactions the equivalent stage requires the transfer of a hydrogen atom from a non-activated C-H bond of the substrate to the C-5’ of the coenzyme. A carbon with radical character as in (9) is no doubt better suited for this role than an equivalent ionic species. However in order to furnish the product the intermediate (14) must rearrange to (15) with the migration of a OH group which requires unorthodox behaviour from a radical species. If this mechanistic principle is extended to ribonucleotide reductasel even greater difficulty arises since in this case the equivalent stage requires the expulsion of OH as a hydroxyl radical.One must therefore invoke an ionic rearrangement preferably involving a C’ for reaction c of Scheme 2. Thus the current mechanistic view on B ,-dependent enzymes involves attribut- ing a dual role to the C-Co bond a homolytic bond fission involved in the hydro- gen-transfer step and a heterolytic cleavage permitting rearrangement displace- ment and elimination reactions during catalysis. A detailed discourse on the mechanism of action of B ,,-dependent enzymes with particular emphasis on /I-methylaspartate-glutamate mutase is available.’ Although in general the mechanistic features of coenzyme-B,,-dependent mutases of type Pa P R-CH,-CH,-NH R-CH(NH,)-be are similar”12 to those of the enzymes discussed above there appears to be one difference.In these cases the migration of the amino-group may occur via Schiff-base formation with carbonyl compounds such as pyridoxal phosphate. Several other corrinoid-linked biological reactions such as the formation of acetate from methyltetrahydrofolate occur through the participation of methyl- B (19).l4 Although the precise mechanism of action for this reaction is not yet known the conversion occurs through the retention of all three hydrogen atoms of the methyl group of (18) or (19) in acetic acid.” Enzf Co) + Me-Tetrahydrofolate + Enzf Co+Me NADPH (17) + MeC0,H co + (17) (18) (19) R. G. Eager B. G. Baltimore M. M. Herbst H.A. Barker and J. H. Richards Bio-chemistry 1972 11 253. C. G. D. Morley and T. C. Stadtman Biochemistry 1971 10 2325. l3 C. G. D. Morley and T. C. Stadtman Biochemistry 1972 11 600 and references cited therein. l4 For a review on coenzyme-B,,-linked reactions see H. A. Barker Ann. Rev. Biochem. 1972 41 55; H. Wcissbach and R. T. Taylor Vitamins and Hormones 1970 28 415. l5 D. J. Parker H. G. Wood R. K. Ghambeer and L. G. Ljungdahl Biochemistry 1972 11. 3074. 145 Reaction Mechanisms-Part (iii) Enzyme Mechanisms 2 Conformations of Substrates and Conformational Changes at the Active Sites of Enzymes A great deal of emphasis has recently been laid on the determination of con- formations which substrates attain at the active sites of enzymes and also on monitoring the subtle conformational changes in protein structure occurring when allosteric effectors and substrates progressively bind to enzymes to give catalytically active complexes.Conformational and Mechanistic Studies with Glutamine Synthetase.-Sheep brain glutamine synthetase catalyses the formation of glutamine from glutamate NH, and ATP and has been extensively studied by Meister and co-workers. The overall reaction is believed to occur in two stages involving the intermediacy of enzyme-bound glutamyl phosphate (211 followed by its decomposition by NH .16-18 The precise configuration which an open-chain flexible molecule such as glutamate (20) may attain at the enzyme active site is usually difficult to 2-H02C-(CH2)2-CH(NH2)C02H 03-P-O-CO-(CH2)2-delineate.In the case of glutamine synthetase however Meister and co-workers took advantage of the relatively broad substrate specificity" of the enzyme and showed that cis-l-amino-1,3-dicarboxycyclohexane (23) was a good substrate for the enzyme and was converted into the corresponding 5-amido-deri~ative.'~ The alignment of the glutamyl moiety of(23) at the active site is thus limited to two arrangements allowed by the two favourable conformations of the cyclohexane ring as shown in (23a) and (23b). The subsequent demonstration that cis-l-amino-1,3-dicarboxycyclopentane(24)is also a good substrate2' for the enzyme suggests that the geometry of the atom of the glutamyl skeleton as present in (23a) is the most likely one since the great rigidity of the cyclopentane ring will permit only this arrangement at the enzyme active site.B3NH2 q c 0 2 H +02H qHCo2" 'COzH HOzC H02C 0 (234 (23b) (24) (25) l6 For a review see A. Meister Adt.. Enzymol. 1968 31 183; subsequent developments in the field are summarized in refs. 17 and 18. " J. D. Gass and A. Meister Biochemistry 1970 9 1380. S. S. Tate Fang-Yun Lew and A. Meister J. Biol. Chem. 1972 241 5312. l9 J. D. Gass and A. Meister Biochemistry 1970 9 842. *' R. A. Stephani W. B. Rowe J. D. Gass and A. Meister Biochemisrry 1972 11 4094. 146 M. Akhtar and D. C. Wilton An aspect of the glutamine synthetase reaction which has aroused much controversy is whether y-glutamyl phosphate (21) is a ‘true’ intermediate in the reaction.Using glutamate as the substrate attempts to isolate the intermediate (21) were unsuccessful and resulted in the isolation of pyrrolidonecarboxylic acid (25) presumably formed by a cyclization reaction. The use of the rigid derivative (23) for this purpose offered a distinct advantage since in this case the cyclization is unfavourable and the phosphate derivative was isolated from an enzymic incubation.21 In contrast to the involvement of a phosphoryl interme- diate with the sheep enzyme Boyer and co-workers on the basis of kinetic evidence and isotope-exchange studies have concluded that glutamine synthetase from E. coli catalyses the reaction via a concerted mechanism without the partici- pation of a phosphoryl intermediate.22 Mechanistic and Allosteric Studies with Cytidine Triphosphate Syntheta~e.~ ,-This is an allosteric enzyme ;it consists of four identical sub-units and is activated by the effector guanosine triphosphate (GTP) to catalyse the following reaction :24 UTP + Glu-NH + ATP Glu-OH + ADP + Pi + CTP (1) (32) (22) (20) (35) The information available to date allows the overall conversion in reaction (1) to be separated into two broad stages involving the liberation of enzyme-bound NH, reaction (2) followed by its utilization in CTP formation reaction (3).Glu-NH + H,O + Glu-OH + ‘NH,’ (2) UTP + ‘NH,’ + ATP -+CTP + ADP + Pi (3) The evidence for the operation of reaction (2) includes the demonstration that in the absence of the acceptor UTP the enzyme shows glutaminase activity and also the fact that added NH can replace glutamine in reaction (3).It has now been shown25 that the activator GTP acts almost exclusively on the glutaminase activity [reaction (2)]. The NH,-dependent CTP-forming activity of the enzyme is not altered by the allosteric effector. The reaction (2) resulting in ‘NH,’ formation has been shown to occur through the sequence (26) +(27)-+ (28)-+(Glu-OH) involving the participation of a covalent intermediate26 in which the glutamyl residue is linked to a SH group on the enzyme. The same SH group reacts27 with the diazoketone analogue [see (29)] through the reaction (29)- (31). This latter reaction is enhanced2* about eightfold by the effector GTP and requires only part of the catalytic 21 Y.Tsuda R. A. Stephani and A. Meister Biochemistry 1971 10 3186. 22 F. C. Wedler and P. D. Boyer J. Biol. Chem. 1972 247 984. 23 I. Liebrrman J. Biol. Chem. 1956 222 765. 24 K. P. Chakraborty and R. B. Hurlbert Biochim. Biophys. Acta 1961 47 607; C. W. Long and A. B. Pardee J. Biol. Chem. 1967 242 4715. 25 A. Levtizki and D. E. Koshland Biochemistry 1972 11 241 247. z6 A. Levitzki and D. E. Koshland Biochemistry 1971 10 3365. 27 C. W. Long A. Levitzki and D. E. Koshland J. Biol. Chem. 1970 245 80. 28 A. Levitzki W. B. Stallcup and D. E. Koshland Biochemistry 1971 10 3371. Reaction Mechanisms-Part (iii) Enzyme Mechanisms 0 e h 00t? P rn h3 " w w c:,"' h I-t? N w v,kNs 0 M.Akhtar and D.C. Wilton machinery needed for NH formation namely the glutamylation step.This particular feature permits the precise deductionz5 to be made that the binding of allosteric effector GTP to the enzyme enhances the activity of the groups partici- pating in glutamylation as represented by the conversion (26)+ (28). The mechanism of the second stage of the reaction (3) has also been studiedz6 and is elaborated in the sequence (32)- (35). Particular attention is drawn to the step (33) +(34) which requires ATP to shift the equilibrium towards product formation. 3 Subunit Interactions in Dimeric Enzymes A large number of oligomeric enzymes consist of two or four apparently identical subunits.29 Recently efforts have been directed towards the delineation of the mutual catalytic relationship between the two identical subunits of dimeric enzymes.In this connection three broad possibilities may be considered (a)only one of the subunits of the dimer contains a catalytically functional active site (b)both of the subunits contain active sites which are functional simultaneously or (c) both of the subunits contain active sites but these function sequentially. Recent studies suggest that the last mechanism may operate for several dimeric enzymes. One such study has been carried out with alkaline phosphatase (E.coli) which is a dimer3' of molecular weight 86 OOO and consists of two identical sub- unit~.~ ' At pH > 7.0 the alkaline phosphatase catalyses the hydrolysis of mono- phosphate esters R-0-PO -(in most studies p-nitrophenyl phosphate is used as a convenient substrate) via a phosphoryl+nzyme intermediate involving an OH groupofa serinere~idue.~',~~ Incubation oftheenzyme with an organic [3zP]- phosphate at pH 4-5 resulted in no net hydrolysis but in the formation of a monophosphated enzyme which was separated from the substrate by Sephadex chr~matography.~~ The liberation of 3zP from the purified monophosphorylated enzyme was greatly enhanced in the presence of a substrate analogue p-chloro- anilidophosphonate.The experiments were interpreted in terms of a 'Flip-Flop' mechanism34 in which binding of substrate on the site A stimulates dephosphory- lation on the site B(reaction d Scheme 3). In the next cycle site A is phosphorylated 29 For a review see I. M. Klotz N. R.Langerman and D. W. Darnall Ann. Rev. Biochem. 1970 39 25. 30 M. J. Schlesinger Brookhaven Symp. Biol. 1964,17 66. 3t F. Rothman and R. Byrne J. Mol. Biol.,1963 6,330. 32 J. H. Schwartz Proc. Nar. Acad. Sci. U.S.A. 1963 49 871. 33 L. Engstrom Arkiu Kemi 1962 19 129. 34 M. Lazdunski C. Petitclerc D. Chappelet and C. Lazdunski European J. Biochem. 1971 20 124. Reaction Mechanisms-Part (iii) Enzyme Mechanisms B Enz-OH hz-OH(R-O-PO:-) RoH R-0 -PO -1. a (A ' (A Enz-OH Enz-OH Enz-O-PO -Enz-o-PO -p. R-0-PO -"(A Enz-OH Enz-OH(R-O-PO;-) Scheme 3 and its dephosphorylation is stimulated by the binding of the substrate to B (Scheme 3). A related phenomenon was observed with horse liver alcohol dehydrogenase which catalyses the reaction RCHO + NADH + H+ S R-CH,OH + NAD The amino-acid sequence of the ethanol-active isozyme indicates that the two polypeptide chains making the dimer are identical.35 The mechanism of the enzyme has been studied by the stop-flow technique under conditions such that product formation may be studied during a single turnover of the enzyme catalysis.Such experiments using a variety of aromatic aldehydes gave biphasic kinetics in which half the product corresponding to one active site per mole of the enzyme was released at a considerably greater rate than the other half.36-3 * Two broad conclusions may be drawn from such studies :36-39 first that both subunits contain catalytically functional active sites but that the sites are kinetically non-equivalent and secondly that the state of liganding at one subunit in the dimer regulates the activity of the other.4 N.M.R. and E.S.R. Currently n.m.r. and e.s.r. techniques are being increasingly applied to the eluci- dation of conformational interactions and the determination of distances between 35 H. Jornvall European J. Biochem. 1970,16,25,41. 36 S. A. Bernhard M. F. Dunn P. L. Luisi and P. Shack Biochemistry 1970,9 185. 37 J. T. Mcfarland and S. A. Bernhard Biochemistry 1972,11 1486. 38 P. L. Luisi and R. Favilla Biochemistry 1972 11 2303. 39 For similar studies on malic dehydrogenase see K. Harada and R. G. Wolfe J. Biof. Chem. 1968 243,4123 4131. M. AkhtarandD. C. Wilton a paramagnetic centre and sensitive nuclei at the active site.40 Examples of this approach include work on the enzyme creatine kina~e,~'.~' which in the presence of Mn" catalyses the reaction Me ATP + \ YNH -+ ADP + Me \ YNH /N-c\ /N-c\ HOzCCHz NHZ HOzC*CHz HN-PO;-Using Mn" as a paramagnetic probe it was shown that the relaxation rate of water protons (PRR) expressed by an empirical enhancement factor E was increased (E = 8.1) only when ADP Mn" and enzyme were present together.Since the PRR of water for Enz-Mn-ADP was the same as for Mn-ADP it was concluded that in the ternary complex (Enz-Mn-ADP) Mn" was bound only to ADP and not to the enzyme.42 The addition of creatine to the ternary 42343 complex caused a decrease in the enhancement value (E~,for the ternary complex Enz-Mn-ADO = 8.1 and E~, for the quaternary complex Enz-Mn-ADP- creatine = 5.3).That the decrease accompanying the conversion ternary + quaternary was not due to the binding of creatine to Mn resulting in the displace- ment of water ligand from the enzyme-bound Mn was shown by determining E and cq at different temperatures. The decrease was therefore attributed to the creatine-induced structural rearrangement at the enzyme active site. The addi- tion of NO; to the quaternary complex resulted in a further decrease in PRR (E for Enz-Mn-ADP*reatine-NO = 2). These results coupled with parallel using e.s.r. indicated a further modification of the structure at the active site as had been previously suggested from SH reactivity and kinetic A schematic arrangement of Mn ADP NO; and creatine on the active site is shown in (36) and is based on distances derived from relaxation rates of the ADP creatine ~//////////,,////,/// // / /,,,,,,,/,-,,,/,,,/,//, (36) Nitrate occupies the site of the y-phosphate of ATP substrate nuclei.42 Another example is the study of relaxation rates of various protons of toluene-p-sulphonamide when bound to Mn-carbonic anhydrase 40 For reviews and comments see (a)A.S. Mildvan and M. Cohn Adc.. Enzymol. 1970 33 1 (6) 0.Jardetzky and N. G. Wade-Jardetzky Ann. Rev. Biochem. 1971,40 605; (c)P. Knowles 'Essays in Biochemistry' ed. P. N. Campbell and F. Dickens Academic Press London and New York 1972 Vol. 8 p. 79. 41 G. H. Reed H. Diefenbach and M. Cohn J. Biof. Chem. 1972 247 3066. 42 G. H. Reed and M.Cohn J. Biol. Chem. 1972.247 3073. 43 Similar studies have been carried out using analogues of creatine ;see A. C. McLaughlin M. Cohn and G. L. Kenyon J. Biol. Chem. 1972,247,4382. 44 E. J. Milner-White and D. C. Watts Biochem. J. 1971 122 727. Reaction Mechanisms-Part (iii) Enzyme Mechanisms 151 which permitted the determination of the distances between Mn" and various protons as shown in (37).45 In another related approach a paramagnetic nitrox- ide radical was covalently attached to histidine-1 5 of lys~zyme.~~ The resulting spin-labelled enzyme (38) broadened the nuclear resonance spectra of N-acetyl- -a-D-glucosamine bound at the active site and these broadenings were used to estimate the distance from histidine-15 to the acetamido-group of the sugar.The paper describes several other related observation^.^^ 3 0-N H q NH-CO-CH,-His-15 (37) 5 The Stereochemistry of Enzyme Reactions The synthesis of stereospecifically labelled substrates especially those which undergo extensive further metabolism has allowed many diverse enzymic reactions to be studied and important stereochemical information to be obtained concerning the mechanisms of individual reactions. Perhaps the most notable example of this approach was the synthesis of the various stereoisomers of mevalonic acid in which hydrogens at the pro-chiral centres C-2 C-4 and C-5 were stereospecifically deuteriated or tritiated.47 More recently considerable attention has been focused on the synthesis of acetate in which the hydrogens of the methyl group were chirally labelled with protium deuterium and tritium.48 The synthesis of these chiral acetates and their use to establish the stereochemistry of the malate synthase system has been reported previ~usly.~~ These acetates have now been used to investigate other biochemical problems involving the intraconversion of methyl and methylene groups.The conversion of acetyl CoA into citrate is catalysed by two enzymes the better known si-citrate synthase which is found as part of the tricarboxylic acid cycle and the other re-citrate synthase found in certain bacteria (the terms re and si refer to the side of a trigonal carbon atom or double bond as determined by the convention proposed by Hanson5*). The cleavage of citrate may be achieved by citrate lyase or ATP-citrate lyase.In order to study the stereo- chemical course of the citrate lyase reaction it is necessary to label the methylene 45 A. Lanir and G. Navon Biochemistry 1972 11 3536. 4h R. H. Wein J. D. Morrisett and H. M. McConnell Biochemistry 1972 11 3707. " J. W. Cornforth R. W. Cornforth C. Donniqger G. Popjak G. Ryback and G. J. Schroepfer Proc. Roy. Soc. 1966 B163 436. '* J. W. Cornforth J. W. Redmond H. Eggerer W. Buckel and C. Gutschow Nature 1969 221 1212; J. Luthy J. Retey and D. Arigoni Nature 1969 221 1213. 49 J. Staunton Ann. Reports (B) 1969 66 555. '' K. R. Hanson .I.Amer. Chem. Soc. 1966,88 2731. 152 M. Akhtar and D. C. Wilton group of citrate that will give rise to the methyl group of acetate.This was achieved enzymically by Cornforth and his associates using stereospecifically tritiated oxaloacetate unlabelled acetyl CoA and re-citrate synthase” (Scheme 4). The Acetyl CoA + HO,C\ T H1 ,;‘c-c* ~ \ CO,H re-Cit rate synthase ’ Citrate lyase (D,O) ’ H D ‘*. /C* T‘ ‘C02H ( 3R)-[3-3 H Oxaloacetate S-Citra te Oxaloacetate TD f H HO,C.CH D**. / H si-Citrate %* *,, Citrate lyase D.**c*/ 0 \2 ,c; ’ C synthase ,; j H02d OH T‘ \!-SSCoA S-Acetyl CoA CO,H T’ \CO,H S-Citrate S-Acetate Scheme 4 citrate has the labelled methylene in the acetate-producing part of the molecule so that subsequent cleavage with citrate lyase in the presence of deuterium oxide gave chiral acetate.The chirality of this acetate was determined using the malate synthase system (Scheme 5) in which owing to kinetic isotope effects the protium D H02C D 7 HO,C H-.. / Malqte /T T‘%* \ c-c*1 ,; >c=c* syn thase’ \ \CO,H HO H \CO,H D,O H CO,H R-Acetate H. ‘-. / T H0,C \ T \ D Fumy HO,C \/c=c*/D Malate synthase’ D‘ ‘CO,H C* HO..‘ c-c* H \CO,H T20 H \C02H S-Acetate Scheme 5 #,, H. Eggerer W. Buckel H. Lenz P. Wunderwald G. Gottschalk J. W. Cornforth C. Donninger R. Mallaby and J. W. Redmond Nature 1970 226 517; W. Buckel H. Lenz P. Wunderwald V. Buschmeier H. Eggerer and G. Gottschalk European J. Biochem. 1971 24 201; H. Lenz W. Buckel P. Wunderwald G. Biedermann V. Buschmeier H. Eggerer J. W. Cornforth J. W. Redmond and R.Mallaby ibid. p. 207; P. Wunderwald W. Buckel H. Lenz V. Buschmeier H. Eggerer G. Gottschalk J. W. Cornforth J. W. Redmond and R. Mallaby ibid. p. 216. Reaction Mechanisms-Part (iii)Enzyme Mechanisms 153 is preferentially removed. The percentage loss of tritium obtained when the malate is dehydrated using fumarase is a measure of the chirality of the methylene in the malate. The results established that citrate lyase catalysed an inversion of configuration between citrate and acetate as shown in Scheme 4. The above results were then used to study the stereochemistry of the si-citrate synthase.’ Conversion of (R)-or (S)-acetate into citrate followed by reconver-sion back into acetate using citrate lyase resulted in an overall retention of con-figuration in the actate and since it has already been shown that the lyase reaction proceeded with inversion the citrate synthase reaction must also have occurred with inversion as shown in Scheme 4.The reactions catalysed by ATP-citrate lyase and re-citrate synthase also showed inversion of configuration.’ In an alternative approach5 Arigoni’s group studied the stereochemistry of the si-citrate synthase system using (R)-and (S)-chiral acetates and analysed the resulting citrate by conversion through isocitrate to succinate. The absolute configuration of the methylene of the succinate was determined using succinic dehydrogenase. Rose’s group has confirmed the results on the si-citrate synthase and the lyases by making use of the enzyme aconitate isomerase which was shown to catalyse the labilization of the 4-pro-S-hydrogen of both cis-and trans-aconitate5 (Scheme 6).This observation allowed [4S-’H]citrate to be prepared from trans-aconitate in which the labelled methylene was in the acetate-producing part of HO,C H HO,C \ ,,‘,‘ \ H \ /H H H+ ,,c 7 H-.\-Y5Hi \&c/ H / c-c /\ \ HO,C C0,H HO,C CO H trans-Aconitate cis-Aconitate Scheme 6 the citrate molecule and hence cleavage of this citrate in deuterium oxide gives a species of chiral acetate. The chiral acetates required for this study of the si-citrate synthase’ were prepared biosynthetically from phosphoenol pyruvate (see below). The enzyme isopentenyl pyrophosphate isomerase catalyses the reaction shown in Scheme 7T.The methylene at C-4 may be specifically Iabelled with tritium by using [2R-or 2S-3H]mevalonate and the chiral methyl group that should result from isomerization in deuterium oxide was analysed by conversion 52 J. Retey J. Luthy and D. Arigoni Nature 1970 226 519. ’’ J. P. Klinman and I. A. Rose Biochemistry 1971 10 2259. 54 J. P. Klinman and I. A. Rose Biochemistry 1971 10 2267. t The numbers a b and c refer to decreasing order of priority and make a clockwise (R) rearrangement. This makes the side of C-3 viewed by the reader re. In designating C-4 of isopentenyl pyrophosphate where identical ligands normally prevent the application of this rule the sides at C-4 are named according to those of the adjoining trigonal carbon C-3 in this case.M. Akhtar and D.C. Wilton Enz-X I D Me H DT H Dimethylallyl pyrophosphate Enz-X-Isopentenyl pyrophosphate Scheme 7 of the dimethylallyl pyrophosphate into farnesol followed by ozonolysis and oxidation to give acetate. Analysis of the acetate (Scheme 5)showed that protona- tion during the isomerization had occurred to the re side of the double bond and a concerted addition-abstraction process has been proposed5 (Scheme 7). Apart from the stereospecifically labelled mevalonates and chirally labelled acetates a third specifically labelled compound that has found considerable use in solving a number of stereochemical problems is phosphoenol pyruvate (PEP) in which the two vinyl hydrogens are labelled specifically with either deuterium or tritium (or both).The method used for the specific labelling of the vinyl hydrogens of PEP with deuterium involved biosynthesis from (1R)-[1-2H,]-fructose 6-phosphate. Assignment of the absolute configuration of the product was achieved by n.m.r.56 That this assignment could be made meant that the enolase reaction was stereospecific and that removal of the OH group occurred anti to the C-2 proton whereas in the reverse direction the OH is added to the re side of the double bonds6 as shown in Scheme 8. The synthesis of PEP labelled with both deuterium and tritium of known absolute configuration allowed an investigation of the stereochemical course of the conversion of PEP into pyruvate catalysed by pyruvate kina~e.'~ This conver- sion should result in the methyl group of the pyruvate attaining chirality and this chirality may be determined by conversion of the pyruvate into acetyl CoA and analysis of the methyl group by the malate synthase system (Scheme 5).The approach established that the proton donated by the pyruvate kinase adds to the si side of the PEP. The chirally labelled pyruvate was used to establish the stereochemical course of the biotin-dependent carboxylation to give o~aloacetate.~~ This was made possible because only 8 % of the tritium was lost during the carboxylation instead 55 K. Clifford J. W. Cornforth R. Mallaby and G. T. Phillips Chem. Comm. 1971 1599; J. W. Cornforth K. Clifford R. Mallaby and G. T. Phillips Proc. Roy. Soc. 1972 B182 277.56 M. Cohn J. E. Pearson E. L. O'Connell and I. A. Rose J. Amer. Chem. Soc. 1970 92 4095. 57 I. A. Rose J. Biol. Chem. 1970 245 6052. Reaction Mechanisms-Part (iii) Enzyme Mechanisms CO2H T-C-D I Oxaloacetate c=o P TD t! \/ Tcc-oH Enolase C Pyruvate) T-C-D I ___* II kinase I H-C--08 C c=o /\ I AO,H C0,H 08 C0,H 2-Phosphoglyceric Phosphoenol Pyruvate acid pyruvate T-C-D Malate I HO-C-H ~ I CO,H Scheme 8 of a theoretical 33 % and it therefore follows that there is a considerable isotope discrimination in favour of the removal of the protium. The determination of the absolute configuration at C-3 of the resulting oxaloacetate by conversion through malate into fumarate established that addition of the carbon dioxide to the C-3 of pyruvate occurred with retention of configuration as outlined in Scheme 8.Similarly the conversion of the deuteriated and tritiated malate back into pyruvate using malate enzyme was also shown to occur by retention of configuration5 (Scheme 8) a result confirmed by Cornforth's group using an alternative approach.58 There are three enzymes which catalyse the carboxylation of PEP namely PEP carboxylase PEP carboxytransphosphorylase and PEP carboxykinase. Incubation of specifically tritiated PEP with these enzymes and .analysis of the resulting oxaloacetate established that in all three cases addition of CO occurred to the si side of the double The condensation of PEP and erythrose 4-phosphate to give 3-deoxy-~- aribinoheptulosonate 7-phosphate (DAHP)provided another system for utilizing the specifically labelled PEP.The reaction which is outlined in Scheme 9 was shown to proceed through si attack on C-3 of PEP.60 It is significant that a K. H. Clifford J. W. Cornforth C. Donninger and R. Mallaby European J. Biochem. 1972 26 40 1. 59 I. A. Rose E. L. O'Connell P. Noce M. F. Utter H. G. Wood J. M. Willard T. G. Cooper and M. Benziman J. Biol. Chem. 1969 244 61 30. '' H. G. Floss D. K. Onderka and M. Carroll J. Biol. Chem. 1972 247 736; D. K. Onderka and H. G. Floss J. Amer. Chem. SOC.,1969,91 5894. M. Akhtur and D.C. Wilton CO,H I O=C T CHZO 8 Lf I ,C-OH H\ + ,C-CHO HI T OH Phosphoenol pyruvate Erythrose 4-phosphate H OH 3-Deoxy-~-Aribinoheptulo-sonate 7-phosphate Scheme 9 combined chemical and enzymic degradation showed at least an 80 % stereo-specificity at C* in the overall reaction because it had previously been proposed that the mechanism for DAHP synthetase proceeded uia the intermediacy of a free methyl group at C-3 of PEP.61 Such a proposal is not consistent with the above retention of stereospecificity unless this methyl group is sufficiently hindered to prevent rotation before the subsequent deprotonation step occurs.On the other hand DAHP synthetase does catalyse an exchange of protons of PEP with the medium and this could be explained by a side reaction in which PEP forms a carbanion in the presence of erythrose 4-phosphate that is protonated and de-protonated during the course of the reaction thus resulting in a certain amount of scrambling at C-3.60 The chiral centre produced at C* of DAHP was utilized to establish the stereo- chemistry of the 1,4-conjugated elimination of phosphoric acid occurring in the synthesis of chorismic acid uia shikimic acid.The conversion of doubly labelled [7-I4C,6R or 6S3H]shikimic acid to chorismic acid and measurement of the resulting tritium :carbon ratio established that the 6-pro-R-hydrogen is lost and hence that the elimination was anti.60 In an alternative pathway the dehydra- tion of dehydroshikimate to give protocatechuate also lost the 6-pro-R-hydrogen in a syn elimination of water.62 Apart from the information obtained by using chirally labelled acetate and specifically labelled PEP stereochemical aspects of a number of other enzyme systems have been investigated.It has been established that in the NAD-linked reaction catalysed by the flavoprotein enzyme dihydro-orotic acid dehydro- genase there is an anti elimination of the C-4-and C-SS-hydr~gens.~~ In the presence of catalytic amounts of NAD both hydrogens exchange with the medium; however the 5s-hydrogen exchanges twice as fast as that at C-4 (Scheme 10). The mechanism for the conversion of urocanate (39) into 3-(imidazol-4’-on- 5’-y1)propionate(40) which is catalysed by the enzyme urocanase has been described in a previous Report.’ The stereochemistry of proton addition from A. B. DeLeo and D. B. Sprinson Biochem. Biophys. Res. Comm. 1968 32,873. 62 K.H. Scharf M. H. Zenk D. K. Onderka M. Carroll and H. G. Floss Chem. Comm. 197 1,765. 63 P. Blattmann and J. Retey European J. Biochem. 1972 30 130. 157 Reaction Mechanisms-Part (iii) Enzyme Mechanisms Dihydro-orota te _____+ dehydrogenase H I H Dihydro-orotic acid Orotic acid Scheme 10 the medium has now been investigated by carrying out the reaction in deuterium oxide. Chemical degradation of the product established that both the protons in the side-chain were added to the re side of the double bond64 (Scheme 11). CO,H / Urocanase D*O ' Scheme 11 An interesting example of an inhibitor which is also a partial substrate is found in the case of bromopyruvate and the enzyme 2-keto-3-deoxy-6-phospho-gluconate aldolase.The 3R-hydrogen of the bromopyruvate is exchanged at about 50 times the rate at which the inhibitor alkylates the enzyme. Using [3S-3H]bromopyruvate it was established that alkylation of the enzyme involved inversion of configuration at C-3 of the pyruvate. lo One reason for establishing the stereochemistry of enzymic reactions is to see if there are correlations between reactions which might suggest either similar mechanisms or common evolutionary origins for the enzymes. A particularly striking example of the latter possibility is found for mammalian NADPH-linked steroid reductases and dehydrogenases where all known examples that transfer the hydride ion to the a side of the steroid use the 4B-hydrogen of the cofactor. On the other hand hydride transfer to the p face of steroids originates from the 4A position of the c~factor.~~ 6 The Biosynthesis of Peptides by Non-ribosomal Multi-enzyme Complexes The biosynthesis of the cyclic polypeptides Gramacidin S (41) and Tyrocidine (42) has received considerable attention over the past few years.66 It is now well 64 F.Kaeppeli and J. Retey European J. Biochem. 1971 23 198. 65 M. Akhtar D. C. Wilton I. A. Watkinson and A. D Rahimtula Proc. Roy. SOC. 1972 B180 167. 66 Y. Saito S. Otani and S. Otani Adu. Em.vtnoI. 1970 33 337; F. Lipmann Science 197 1 173 875 ;S. G. Laland 0. Froyshov C. Gilhuus-Moe and T. L. Zimmer Nature New Biol. 1972 239 43. 158 M. Akhtar and D.C. Wilton established that these compounds are synthesized on a multi-enzyme complex which itself codes for the sequence of amino-acids in the peptide by having multiple binding sites one for each amino-acid residue.Activation is achieved by linking amino-acids to their respective sites as thioesters after which the growing peptide chain is transferred from one site to the next as each amino- acid is incorporated into the sequence. In the case of the biosynthesis of Gramacidin S the synthetase consists of two units. The smaller unit (Enzyme 11) is responsible for the racemization as well as activation of phenylalanine. The larger unit (Enzyme I) first primes itself with the four remaining amino-acids in sequence as thioesters on four separate sites while the fifth site binds the completed pentapeptide until the second penta- peptide is synthesized when the two are linked in head-to-tail condensations.It is suggested that the transfer of the growing peptide chain from one amino-acid residue to the next is achieved by an arm consisting of a pantetheine residue in a manner analogous to that in fatty-acid synthesis. The sequence of events for synthesis is shown in Scheme 12. /NHz SH SH SH Phe SH I Phe ‘,A I Pantetheine arm 5 NH D-Phe-+Pro-+Val-Om-’Leu Leu+-Orn+Val+ Pro+ D-Phe t I - SH HS‘.G . (41) D-Phe-+Pro+PheQ-Phe+AspNH2t Leu+Orn+-Val+Tyr+GluNH (42) Scheme 12 There are also three linear Gramacidins A B and C which are pentadeca- peptides and these are also biosynthesized by a non-rib~somal~’ system which ’’ 0.Froyshov T. L. Zimmer and S.G. Laland F.E.B.S. Letters 1972 20 249. Reaction Mechanisms-Part (iii)Enzyme Mechanisms has been purified.68 It is interesting to note that the biosynthesis of the cyclic trimer 2,3-dihydroxy-N-benzoyl-~-serine also involves enzyme-bound thioester intermediate^.^' '' K. Bauer R. Roskoski jun. H. Kleinkauf and F. Lipmann Biochemistry 1972 11 3266. 69 G. F. Bryce and N. Brot Biochemistry 1972 11 1708.

ISSN:0069-3030    

DOI:10.1039/OC9726900140

出版商:RSC    

年代:1972

数据来源: RSC