ISSN:0069-3030    

DOI:10.1039/OC97168FX001

出版商:RSC    

年代:1971

数据来源: RSC

ISSN:0069-3030    

DOI:10.1039/OC97168BX003

出版商:RSC    

年代:1971

数据来源: RSC

摘要:

2 Physical Methods Part (i) Organic Mass Spectrometry ~~~~~ By R. A. W. JOHNSTONE and F.A. MELLON Dept. of Organic Chemistry University of Liverpool Liverpool L69 3BX Many areas of mass spectrometry have received comprehensive coverage in a recent Specialist Periodical Report ;l this publication is an extensive catalogue of recent work2 and some of the sections such as the one on computer methods give a clear factual account of the current position and trends. To avoid serious overlap with the Specialist Periodical Report this section attempts to assess the influence on organic chemistry of new knowledge and techniques in mass spectrometry. For these reasons the coverage here is selective and certainly not exhaustive in references for which the Specialist Periodical Report should be used.A new introductory book on mass spectrometry has appeared which includes most of the more recent advance^,^" and also one on techniques and applications.3b 1 Theoretical Aspects The empirical application of mass spectrometry to the solution of analytical problems is widespread in organic chemistry. Used empirically the technique is very valuable but a clearer understanding of the theory of mass spectrometry could help its empirical application. Attention to the theory has concentrated in the past mostly on qualitative attempts to explain the fragmentation of mole- cules of known structure in terms of the bond cleavage electron shift and func- tional group approaches long familiar to organic chemists. Knowledge or rationalizations accumulated in this way can then be used to guide the inter- pretation of the mass spectra of unknown compounds (see also Section 5 on the use of computers).The two most widely used of these qualitative theories are based on product-stability arguments4 and charge-localization concept^.^ ‘Mass Spectrometry,’ ed. D. H. Williams (Specialist Periodical Reports) The Chemical Society London 197 1 Vol. 1. R. I. Reed Narure 1971 234 112. (a) R. A. W. Johnstone ‘Mass Spectrometry for Organic Chemists,’ Cambridge University Press 1972; (b) G. W. A. Milne ‘Mass Spectrometry Techniques and Applications,’ Wiley New York 1972. K. Biemann ‘Mass Spectrometry Organic Chemical Applications,’ McGraw-Hill New York 1962 p. 76. H. Budzikiewicz C.Djerassi and D. H. Williams ‘Mass Spectrometry of Organic Compounds,’ Holden-Day San Francisco 1967 p. 9 -27. 5 R. A. W.Johnstone and F. A. Mellon Both theories have their adherents but one tends to be more fashionable6 mostly because 'arrows' or 'fish-hooks' can be drawn to represent the movement of electrons sometimes in an apparently logical manner. A recent article has attempted an unbiased critical review of these theories and their ba~kground.~ The mass spectrum of selenomethionine has been interpreted as a success for charge-localization theory over product-stability arguments,8 and has been cited widely' as a significant success. Extensive energy measurements and more careful investigation of the mass spectra of selenomethionine and of methionine strongly suggest that for these compounds at least charge-localization theory is incorrect although it may be useful for post fact0 rationalization of a mass spectrum.In a more quantitative way the use of quasi-equilibrium theory (QET) to interpret mass spectrometric fragmentation has been tried on two levels one extremely simple the other complex. The full QET" is based on several major assumptions and for its use requires some information which is not easy to obtain. For example the energy distributions in ions the correct vibrational frequencies to use and the possibility of decomposition from excited electronic states are typical parameters which are difficult to assess. Because of these factors the use of QET in polyatomic systems has developed relatively slowly.After some early successes in predicting the mass spectra of alkanes," QET has been used only sporadically. Very recently attempts have been made to 'predict' the observed fragmentation behaviour of some aromatic compounds. ' In view of the known' differences between photon-impact and electron-impact mass spectra the reasons for which have been discussed,' it is unfortunate that these attempts to calculate electron-impact mass spectra' * were based on energy distributions for the ions derived from photoelectron spectroscopy. Electron- impact and photon-impact energy distributions are generally not similar.' At a much less sophisticated level QET can be reduced to the very simple equation (1)14 by which the rates of fragmentation (k)of ions are described in terms of the number of oscillators (N)in the ion the excess of energy (E)over and above the energy required for fragmentation (EJ and a frequency factor (v).k = v[l -E,/EIN-' (1) See any issue of e.g. Org. Mass Spectrometry. ' T. W. Bentley and R. A. W. Johnstone in 'Advances in Physical Organic Chemistry,' ed. V. Gold Academic Press 1970 Vol. 8 pp. 151-269. H. J. Svec and G. A. Junk J. Amer. Chem. Soc. 1967 89 790. T. W. Bentley R. A. W. Johnstone and F. A. Mellon J. Chem. SOC.(B) 1971 1800. lo See M. Vestal in 'Fundamental Processes in Radiation Chemistry,' ed. P. Ausloos Interscience 1968 pp. 59-1 18 for a comprehensive review of current QET applications. l1 H. M. Rosenstock M. B. Wallenstein A. L. Wahrhaftig and H.Eyring Proc. Nur. Acad. Sci. U.S.A. 1952 38 667. l2 F. W. McLafferty T. Wachs C. Lifshitz G. Innorta and P. Irvine J. Amer. Chem. SOC.,1970 92 6867. R. A. W. Johnstone and F. A. Mellon unpublished data. The multiplicity of processes found in 'mono-energetic' electron impact IE curves also support this contention. l4 H. M. Rosenstock A. L. Wahrhaftig and H. Eyring 'The Mass Spectra of Large Molecules Part 11 The Application of Absolute Rate Theory,' Technical Report No. 2 Institute for the Study of Rate Processes University of Utah 25 June 1952. Physical Methods-Part (i) Organic Mass Spectrometry To use this equation to predict mass spectrometric ion abundances [A] the rates of decomposition (k)must be folded with the energy distribution P(E) in the ions [equation (2);assuming no subsequent decomposition of the fragment [A1 = n,(E) * P(E) (2) ion; nA = number of ions A at an energy El.Equation (1)is so oversimplified that it should not be surprising to find that calculations based upon it have needed to adjust often questionably one or more parameters to obtain even modest correlations with observed fragmentations of organic compounds. It is doubtful whether this simple equation will ever be satisfactory for explaining mass spectra except in a quali-quantitative fashion. Attempts to calculate mass spectra with equations (1) and (2) have used ‘adjusted’ v N E P(E) and combinations of these parameter^.'^ The time is ripe to relegate equation (1) to the place it deserves in history except where it can be used in a semi-quantitative descriptive sense.Some of the quali-quantitative predictions based on equation (1) have been predicted qualitatively without its help. l6 2 Ionization and Appearance Potentials Ionization and appearance potentials are important thermochemical quantities. Experimentally the determination of ionization and appearance potentials using a mass spectrometer leaves much to be desired and there is little doubt that many literature values for these quantities are seriously in error. The appearance potential of an ion measured by mass spectrometry may be inaccurate for a number of reasons but probably the most important of these are the ‘kinetic shift’ and the inadequacy of past experimental methods for dealing with curvature at the foot of an ionization efficiency curve.The kinetic shift caused by the fact that an ion must have some energy in excess of the thermochemical appearance potential for fragmentation to be observed in the mass spectro- meter is likely to be important when a fragmentation requires a large activation energy (excess of energy in the ion must be concentrated along the breaking bond) or when the decomposing ion has a large number of degrees of freedom amongst which its excess of energy can be dissipated. It has been suggested that kinetic shift can be estimatedI7 by comparing the appearance potentials of metastable and normal ions. Theoretically this concept seems sound but as applied experimentally,’ the results can be very misleading7 because of inadequacies in the experimental methods used.It has been found that insensitivity in the mass spectrometric detecting system may be a major cause of many observed ‘kinetic shifts’.l9 Is See for example A. N. H. Yeo and D. H. Williams Org. Mass Spectrometry 1971 5 135 and references therein. l6 F. H. Field and J. L. Franklin ‘Electron Impact Phenomena and the Properties of Gaseous Ions,’ Academic Press New York 1957 pp. 78 79. I. Hertel and Ch. Ottinger 2. Naturforsch. 1967 22a 40. ’*J. H. Beynon J. A. Hopkinson and G. R. Lester Internat. J. Mass Spectrometry Ion Phys. 1969 2 291. l9 R. A. W. Johnstone and F. A. Mellon unpublished data. 8 R. A. W.Johnstone and F. A. Mellon Mathematical analytical methods are available” for dealing with curvature at the foot of an ionization efficiency curve.This curvature is made up from an approximately Maxwellian spread of energies in the electrons from a heated filament together with ‘true’ curvature caused by closely separated or overlapping electronic and vibronic states. The mathematical methods of analysing experi- mental ionization efficiency curves remove most of the effects of the spread in electron energies and leave the ‘true’ curvature; in ideal situations this ‘true’ curvature is found to be compounded of many short straight lengths. Care is still necessary with some of these mathematical methods one in particular (Morrison’s second-derivative technique) has been shown theoretically to give positive errors of up to 0.35 eV in some cases.21 In experiments utilizing a computer to gather and interpret data appearance and ionization potentials seem much more accurately measurable22 than by older methods.An added advantage of this computer-aided method is the tremendous reduction in time needed for the measurements. Using these computer-analytical methods accurate heats of formation and evidence for the existence or otherwise of kinetic shifts can be obtained.’ Other workers have reported similar computer- aided methods for the acquisition of ionization efficiency curves,’ and one 3924 has used appearance potentials found by such a method as a distinguish- ing factor between structural isomers. 3 Ionization Methods The appearance of the mass spectrum of any compound depends on the excess of energy (electronic and vibronic) left in the molecular ion after the ionization step because the excess of energy eventually gives rise to the observed frag- mentation.Thus different methods of ionization can have large effects on the mass spectrum. So far this discussion has centred on electron-impact induced fragmentations of ions as this is still the most widespread method of ionization used in the mass spectrometry of organic compounds. However there have been significant advances in other methods of ionization and these hold con- siderable promise for future general use in organic mass spectrometry. Photo-ionization has been used for a long time and a recent review has discussed its applications.2s A disadvantage of photo-ionization which has held up its general application is the low ion yield due to the relatively low intensity of light which can be directed into the ion-source.The molecular ion in a photo- ionization mass spectrum is usually abundant and the number of fragment ions much reduced compared with electron-impact mass spectra. Mass spectra 2o J. D. Morrison J. Chem. Phys. 1953 21 1767; 1963 39 200; R. E. Winters J. H. Collins and W. L. Courchene ibid. 1966 45 1931. 21 G. G. Meisels and B. G. Giessner Internat. J. Mass Spectrometry Ion Phys. 1971 7,489. 22 R. A. W. Johnstone F. A. Mellon and S. D. Ward Internat. J. Mass Spectrometry Ion Phys. 1970 5 24 1. 23 M. L. Gross and C. L. Wilkins Anafyt. Chem. 1971 43 1624. 24 R. G. Dromey J. D. Morrison and J.C. Traeger Internat. J. Mass Spectrometry Ion Phys. 1971 6 57. 25 N. W. Reid Internat. J. Mass Spectrometry Ion Phys. 1971 6 1. Physical Methods-Part (i) Organic Mass Spectrometry 9 produced by photon-impact may be much simpler to interpret and could be obtained more widely if suitable light sources were available. Field ionization in which a steep electrical potential gradient enables quantum tunnelling of an electron from a molecule to an electrode to occur continues to make steady progress,26 and ion sources based on this technique are available commercially. The excess of energy imparted to a molecular ion during field ionization is very low so that fragmentation is greatly reduced compared with electron-impact ionization at 70 eV and abundant molecular ions are obtained.Sometimes the abundance of fragment ions is embarrassingly small for structural analysis and the commercial ion sources are designed to operate either in the field or electron-impact ionization mode. The spectra of a compound ionized under both conditions can then be compared. Another way in which fragmen- tation of molecular ions produced by field ionization could be induced is by ion-molecule collisions.27 Here the molecular ions are passed through a region of gas at sufficiently high pressure for ion-molecule collisions to occur and the collisional energy appears as vibrational energy leading to fragmentati~n.~~ A disadvantage of field-ionization compared with electron-impact methods has been the low usable ion yield but it is now reported that with ‘super-emitting’ electrodes the ion yields of the two methods are comparable.** A second disadvantage of field ionization applies also to electron-impact sources viz.the sample must be introduced into the source as vapour and therefore thermal energy must be supplied before ionization. Especially for labile aliphatic com- pounds or compounds which are difficult to volatilize this extra thermal energy can lead to excessive fragmentation to such an extent that no molecular ions are observed and usable information from fragment ions is nil. The problem has been overcome in field-ionization sources by the field-desorption tech- nique.” The substance to be investigated is applied as a very thin coating to the field-ionizing electrode.No heat is required to vaporize the sample and ions formed in the condensed phase at the electrode are shot out into the mass spectro- meter. Results obtained in this way with compounds which are difficult to deal with by electron-impact mass spectrometry are impressive. 30 For example the electron-impact mass spectrum of glucose has no molecular ion and few fragment ions of diagnostic value ; field-ionization yields a molecular ion and many fragment ions ; field-desorption yields an abundant molecular ion with a few fragment ions in low abundance.29 Further developments of this technique are awaited with interest particularly by those research workers who need to analyse such mass spectrometically difficult compounds as sugars carbohydrates glycosides peptides and nucleotides.26 See H. D. Beckley Angew. Chem. Internat. Edn. 1969 8 623 for a comprehensive review. K. R. Jennings Internat. J. Mass Spectrometry Ion Phys. 1968 1 227. 28 H. D. Beckley H. Hilt A. Maas M. D. Mighaed and E. Ochterbeck Innternat. J. Mass Spectrometry Ion Phys. 1969,3 161 ;M. D. Mighaed and H. D. Beckley ibid 1971,7 1. 29 H. D. Beckey Innternat. J. Mass Spectrometry Ion Phys. 1969 2 500. ’”H. Krone and H. D. Beckey Org. Mass Spectrometry 1971 5 983. 10 R. A. W.Johnstone and F. A. Mellon Another method of ionization making rapid progress and which promises to be of great value for labile compounds is chemical i~nization.~' In this technique a reactant gas ion (commonly CH,+ from methane) ionizes a molecule (M) by proton exchange to yield a 'quasi-molecular' ion (MH') as shown in equation (3).Various other reactant gas ions have been used e.g. argon ethane CH5' + M -+ CH + MH' (3) propane and i~obutane.~~ Reactant gas ions like CHsf are thought to be essentially thermally equilibrated by collision with CH molecules before they collide with and ionize the molecule (M) under investigation. Fairly closely defined amounts of energy are transferred from the reactant gas ion to the quasi-molecular ion during its formation. The quasi-molecular ions are even- electron species containing little excess of vibrational energy and fragmentation of these MH' ions is greatly reduced compared with the Mt ions formed by electron impact. Generally there is enough excess of energy in the quasi- molecular ions to give moderately abundant fragment ions for structural analysis ; these chemical-ionization mass spectra are notable for their abundant quasi- molecular ions.Again the sample must be vaporized into the ion-source for chemical ionization which can be detrimental to labile compounds. Nevertheless very encouraging results are being obtained as illustrated by the reported mass spectra of oligopeptide~.~~ When the reactant gas ion is monatomic (e.g.argon) a precisely defined amount of energy is transferred during ionization [equation (4)]. The molecular ion produced in this case is an odd-electron species not a quasi-molecular ion and Af+M-+Mf+A (4) the excess of energy it contains is the difference between the ionization potentials of argon and the molecule (M).Commercial chemical-ionization sources are available. Ion-molecule reactions utilizing hydrated species (H904' and D904') have been used recently as an alternative ionizing technique to obtain the amino-acid sequence of a ~eptide.~~ The method was observed to give a large protonated 'molecular ion' and intense sequence ions (compare remarks on increasing fragmentation through ion-molecule reactions in the section of field ionization above). F. H. Field Accounts Chem. Res. 1968 1 42. 32 F. H. Field P. Hamlett and W. F. Libby J. Amer. Chem. SOC.,1967 89 6035; J. Michnowicz and B. Munson Org. Mass Spectrometry 1970 4 1481; F. H. Field J. Amer. Chem. Soc. 1969 91 2827. 33 A.A. Kiryushkin H. M. Fales T. Axenrod E. J. Gilbert and G. W. A. Milne Org. Mass Spectrometry 1971 5 19. 34 R. J. Beuhler L. J. Green and L. Friedman J. Amer. Chem. SOC.,1971 93 4307. Physical Methods-Part (i) Organic Mass Spectrometry 4 Gas Chromatographic-Mass Spectrometric (GC-M.S.) Methods Gas chromatography coupled with mass spectrometry is a valuable analytical technique for dealing with small quantities of mixtures. Usually the mixture is separated completely or partially by standard gas-chromatographic techniques and the separated components are identified from their mass spectra and retention times. The separated components can be condensed out of the gas-chromato- graphic column effluent and introduced into the mass spectrometer by the usual inlet systems.A more efficient use of g.c.-m.s. methods is obtained by passing the already volatilized separated components directly from the g.c. column into the mass spectrometer. By using a chemical-ionization source and methane as the carrier gas in the g.c. apparatus the carrier gas becomes the reactant gas in the ion source.35 Chemical-ionization sources are designed to operate at higher pressures than electron-impact sources and for the latter it is necessary to remove as much g.c. carrier gas as possible before it reaches the source. The carrier gas may be separated from entrained organic components by using a molecular separator of which there are now several types known and some of them commercially available. A recent article has reviewed the desirable and undesirable features of these separat01-s.~~ A major advance which occurred recently has been the successful coupling of a gas chromatographic apparatus to a field-ionization source.37 The combined g.c.-m.s.method is finding ever wider use as the evidence of a rapidly increasing number of research publications shows.38 Articles and reviews of the subject have appeared3’ and there is no call to cover the same ground here. It is pertinent to note that complex mixtures analysed in this way would take many times longer if tackled by other methods. Particularly attractive are the advances which can now be made in investigations of drug metabolism on a micro-~cale.~~ An instrumental advance of importance for g.c.-m.s. appli- cations has been the development of a ‘multiple ion detector’ system capable of recording three different masses simultaneously.This has also been converted into a peak-matching device capable of a ‘dynamic resolution’ of 70000 for a static resolution of 5-00 in a single-mass spe~trometer.~~ 5 Computers The use of computers to acquire accurate mass data is now well established so that with one sweep of the mass spectrum it is possible to obtain not only the molecular formula of a compound (elemental composition of molecular ion) 35 G. P. Arsenault J. J. Dolhun and K. Biemann Chem. Comm. 1970 1542. 36 G. A. Junk Internat. J. Mass Spectrometry Ion Phys. 1972 8 1. 37 P. G. Burkhalter Analyt. Chem. 1971 43 17. 38 See for example numerous publications in J.Chromatography and J. Sci.Instr. 39 C. J. W. Brooks pp. 288-307 in ref. 1 ; see also ref. 36. 40 C. J. W. Brooks A. R. Thawley P. Rocher B. S. Middleditch G. M. Anthony and W. G. Stilwell in ‘Advances in Chromatography,’ ed. A. Zlatkis Chromatography Symposium University of Houston Houston 1970 p. 262. 41 C.-G. Hammar and R. Hessling Analyr. Chem. 1971 45 298 307. 12 R. A. W.Johnstone and I;. A. Mellon but also the elemental compositions of all fragment ions. This kind of information is of considerable value in elucidating the fragmentation of complex molecules. The mass spectrum of a compound with even a modest molecular weight may contain many fragmented ions for each of which the computer data-acquisition system produces one or more elemental compositions.Such a list of elemental compositions is not easy to sift for information of use in structural analysis. For this reason it was proposed that element maps should be con~tructed.~~ These element maps contain the elemental compositions arranged in columns of increasing complexity and simplify the task of information searching. Little use has been made of element maps and it is difficult to evaluate their general usefulness. Now that mass spectrometric data-acquisition systems are more widely distributed (several universities in the U.K. possess them) more people may make use of element maps and make a proper evaluation possible. In a slightly less sophisticated manner routine mass spectra may be stored by a com- puter and compared with spectra already held in the computer memory bank.With a large number of stored spectra it is then possible to identify a compound from its mass spectrum if the mass spectrum has been obtained previously and stored.43 A recent theoretical investigation using the principles of information theory has implied that a mass spectrum can be encoded in 48 bits of information or two words of core store in a computer with a word length of 24 bits.44 This means that a relatively small computer could be used to conduct library searches. At a more advanced level computers are being made not simply to compare spectra but to recognize patterns. The computer is programmed to abstract patterns when presented with the low-resolution mass spectra of a group of similar known compounds.Information acquired by this technique is then applied to unknown compounds which the computer will hopefully classify according to patterns ‘learnt’ during the ‘training’ procedure. This is the learning machine approach so-called because information can be continuously updated and the probability of correct assignments correspondingly increased the larger the number of compounds examined.45 A recent improvement in the classifica- tion of low-resolution mass spectral data has resulted in a predictive ability of up to 98%.46 As a further example the fragmentation behaviour of ketones can be rationalized in terms of the functional keto-group and other attached groups and the information stored in the computer. Examination of the mass spectrum of an unknown ketone by the computer and comparison with the stored information from known ketones enables it to make deductions of likely structure.In a similar fashion the computer can be programmed to distinguish between for example ketones ethers and amines. Initial results seem 42 K. Biemann P. Bommer and D. M. Desiderio Tetrahedron Letters 1964 1725. 43 S. A. Abrahamson Sci. Tools 1967 1429; H. S. Hertz R. A. Hites and K. Biemann Analyt. Chem. 1971 43 681. 44 L. E. Wangen W. S. Woodward and T. L. Isenhour Analyt. Chem. 1971,43 1605. 45 T. L. Isenhour and P. C. Jurs Analyt. Chem. 1971 43 20A reviews many aspects of learning machines applied to chemistry (including mass spectrometry). 46 P. C. Jurs Analyt. Chem. 1971,43 22. PhysicaI Methods-Part (i) Organic Mass Spectrometry 13 promising47 but there is still a very long way to go before automatic positive structural analysis is possible by artificial intelligence.Another area in which full use can be made of the exceptional data storage ability of computers lies in g.c.-m.s. work which generates a great deal of infor- mation. After a substance has emerged from a g.c. column its mass spectrum is obtained and then stored on a magnetic disc or tape ;the spectrum may then be recalled from the store at will. In this way a complete gas-chromatographic analysis can be completed and all the mass spectra stored for printing out or display later at leisure.48 It is also possible to programme the computer to search for the mass spectrum of a specified compound amongst all those held in its store without having all the mass spectra printed out.The use of computers for data acquisition in connection with ionization and appearance potential measurements has already been discussed above. Also it should be mentioned that the mathematical analysis techniques described earlier can be used to abstract high-resolution data from low-resolution ~pectra.~’ 6 Metastable Ions In any fragmentation process m -+ rn; the parent ion (rn,f) can decompose to the daughter ion (m:) anywhere in the mass spectrometer. With conventional mass spectrometers of the type generally used by organic chemists this frag- mentation is almost complete for many m ions before they leave the ion source and only rn; ions are observed.Some m ions have insufficient excess of energy to decompose and appear as m,f ions. These m mi ions can be termed ‘normal’ ions. However some m,f ions have just sufficient excess of energy to decompose to mi between the ion source and collector. Because the momentum of m is shared between its fragmentation products these mi have less translational energy than ‘normal’ m; ions and appear in a different place in the mass spectrum. The my ions with less than the full translational energy are the inaptly named metastable ions and they may be observed as broad peaks of low abundance. In a routine mass spectrum the apparent mass of a metastable ion (m*)is given by the expression m* = mz2/rn1 where m, m2 are the masses of the ions m rnz.These metastable ions are very useful for deciphering fragmentation pathways. Metastable abundance ratios for production of C3H8N+ ions together with 13C and deuterium labelling have been used to classify ion structures from fifteen different isomers.50 It was claimed to be possible to distinguish five structurally distinct ions. Metastable ions have also been used to observed deuterium isotope effects in mass spectra. 51 Many more metastable transitions can be observed in double-focusing mass spectrometers by the technique of 47 A. M. Duffield A. V. Robertson C. Djerassi B. G. Buchanan G. L. Sutherland E. A. Feigenbaum and T. Lederberg J. Amer. Chem. SOC.,1969 91 2977. ‘* R. Binks R. L. Cleaver J. S. Littler and J. Macmillan Chem. in Britain 1971 7 8 reviews this and other aspects of low-resolution mass spectra data acquisition.49 R. G. Dromey and J. D. Morrison Internat. J. Mass Spectrometry Zon Phys. 1971,6,253. N. Uccella I. Howe and D. H. Williams J. Chem. SOC.(B),1971 1933. ” I. Howe and D. H. Williams Chem. Comm. 1971 1195. 14 R. A. W.Johnstone and F. A. MeIlon ‘defocusing’ the normal ion beam.52 In defocusing metastable ions (m;)formed after rn; leaves the ion source but before it enters the field of the electric sector can be detected by altering the accelerating potential at the ion source but keeping the potential across the sector plates constant. Normal ions are then no longer focused by the electric sector but metastable ions are. In a variation on this technique the accelerating voltage at the ion source is held constant and the electric sector voltage is varied.By putting a second electron multiplier in the path of the ion beam the metastable ions can be detected ; this method has been termed ion kinetic energy (i.k.e.) spectro~copy.’~ It is beyond the scope of this article to discuss i.k.e. spectroscopy at length but many metastable ions can be observed by its use and of particular interest to the organic chemist it appears that small structural differences between isomers are dete~table,’~ which is often not the case from an examination of routine mass spectra. Mention may be made of a new device for enhancing metastable ions which makes use of the different translational energies of these and normal ions.” 7Mass Spectra of Organic Compounds Data continue to accumulate on the mass spectra of a wide variety of compounds’ and wider-ranging attempts are being made to rationalize and correlate frag- mentation behaviour.56 Some classes of compounds are receiving particularly marked attention because of their biological importance. Thus the identification of prostaglandins can be made by g.c.-m.s. method^,'^ and mass spectra of nucleotides have been ~btained.’~ There is heavy emphasis on the mass spectro- metry of peptides because it is possible to obtain the sequence of amino-acids in a peptide from its mass spectrum. This specialized topic was of sufficient importance for a European summer school to be ~rganized.’~ The ability to extract an amino-acid sequence from one mass spectrum is attractive but there have been and still are difficulties preventing the completely successful application of mass spectrometry to this problem.Not least of these difficulties is one of scale. Peptide chemists and biochemists are accustomed to handle nanomole amounts of peptides and are unlikely to be much impressed with results obtained with millimole quantities. For example 10 millimoles of a peptide of molecular weight 1000 is 10mg which is ‘bucket-scale’ in peptide work and very routine even for mass spectrometry. 52 M. Barber and R. M. Elliot ASTM Committee E14 Conference on Mass Spectrometry Montreal June 1964; K. R. Jennings J. Chem. Phys. 1965 43 4176. 53 J. H. Beynon J. W. Amy and W. E. Baitinger Chem. Comm.1969 723. 54 E. M. Chait and W. B. Askew Org. Muss Spectrometry 1971 5 147. s5 A. McCormick N. R. Daly R. E. Powell and R. Hayes 5th Mass Spectroscopy Group Meeting University of Bristol July 197 1. 56 T. W. Bentley and R. A. W. Johnstone J. Chem. Sac. (B),1971 1804. ’’ E. Granstrom and B. Samuelsson J. Amer. Chem. SOC. 1969 91 3398. 58 A. M. Lawson R. N. Stillwell M. M. Tacker K. Tsuboyama and J. A. McCloskey J. Amer. Chem. SOC.,1971 93 1015. 59 European Molecular Biology Organisation Meeting Paris September 1971 ; (a) reported by R. A. W. Johnstone. Physical Methods-Part (i) Organic Mass Spectrometry 15 Another difficulty in the mass spectrometry of peptides is that of volatilizing them into the ion-source and from this point of view field-desorption experiments may prove particularly valuable.Generally peptides with approximately 8-12 amino-acid residues will give good mass spectra provided the peptide has been suitably modified. The zwitterionic character of a peptide is removed by acylation (acety16' or ethoxycarbony16 I) of the N-terminal and methylation of the C-terminal. It is then often necessary to N-methylate the amide bonds to reduce intermolecular hydrogen bonding and increase volatility.6 Several methods of N-methylation have been described and one recommended for general use for all but arginine residues.63 Despite all these researches only one peptide structure has genuinely been deduced from just the mass spectrum.64 A second example is of a somewhat dubious nature because extensive pyrolysis of the peptide occurred on its introduction into the mass spe~trometer.~~ Cyclic peptides frequently are much more volatile than linear ones and can be volatilized without the preparation of derivatives.However because they are cyclic and may open indiscriminately on fragmentation it is often difficult to decipher the amino-acid sequence. Another method for sequencing long peptides is to break them down chemi- cally or enzymically into shorter peptides. These shorter usually di- or tri- peptides are separated and identified by g.c.-ms. analysis of their trifluoroacetyl derivatives.66 From the total information obtained it is possible to build up the structure of the original peptide as was done with fungal antitoxin^.^^ Other experiments along these lines but using acetylated derivatives have been des- cri bed.9a 8 Miscellaneous Some recent mechanistic studies of note have included attempts to evaluate factors influencing rates of fragmentation in ortho-disubstituted benzenes using qualitative QET arguments.68 Steric effects were documented in the same fashion as the difference between appearance and ionization potentials has been used to describe electronic effects. Steric effects have also been included in a system of 'interaction values' used to explain the observed variations of ion intensities in the mass spectra of tri- methylsilylated pyran~ses.~~ 'O A. Prox and K. K. Sun Z. Naturforsch. 1966 tlb 1028. 61 J. D. Kamerling W. Heerma and J. F. G. Vliegenhart Org.Mass Spectrometry 1968 1 351. 62 B. C. Das S. D. Gero and E. Lederer Biochem. Biophys. Res. Comm. 1967 29 211. 63 G. Marino L. Valente R. A. W. Johnstone F. Mohammedi-Tabrizi and G. C. Sodini Chem. Comm. 1971 64 K. L. Agarwal G. W. Kenner and R. C. Sheppard J. Amer. Chem. SOC. 1969,91,3096. " D. M. Desiderio G. Ungar and P. A. White Chem. Comm. 1971 432. '' F. Weygand A. Prox E. C. Jorgensen R. Axen and P. Kirchner Z. Naturforsch. 1963 18b 93. 67 A. Prox J. Schmid and H. Ottenheym Annalen 1969,722 179. " S. A. Berezra and M. M. Bursey J. Chem. SOC.(B) 1971 1515. 69 S. C. Havlicek M. R. Brennan and P. J. Scheur Org. Mass Spectrometry 1971,5 1273. R. A. W.Johnstone and F. A. Mellon An overwhelming majority of publications in organic mass spectrometry is concerned with the mass spectrometric fragmentation of positive ions and little work has appeared concerning negative-ion spectroscopy.Early experiments in negative-ion mass spectrometry were unpromising because negative ions are usually not easy to produce by electron impact. Even when negative ions can be produced there is less fragmentation and what elimination reactions there are tend to be more complex than those of positive ions. More recent work has not changed this impression which is exemplified by the elimination of HNO and HF from p -ni trophen y1trifluoroace tamides. Ion cyclotron resonance (i.c.r.) spectroscopy in which the ions have much longer lifetimes than those produced in conventional mass spectrometers has been re~iewed.~’ The longer ion lifetimes mean there are greater chances of ion-molecule collisions occurring and i.c.r.is proving of considerable value for studying ion-molecule reactions. Mechanistic studies into ion structures have been pursued by utilizing these ion-molecule reactions and particular emphasis has been placed on studies of the structures of ions resulting from the six-centre rearrangement of ketones. These particular rearrangement ions at m/e 58 [equation (5)]could possibly have a number of structures but the enol and enol mje 58 keto keto forms are most favoured” and of the two the available evidence of i.c.r. spectroscopy supports the enol structure. The evidence is based on the ion- molecule reactions undergone by the ion at m/e 58 compared with those of the molecular ion of acetone and with those of the fragment ion at m/e 58 from methylcyclobutanol [equation (6)].Similar experiments have been carried out with other compounds.73 m/e 58 Other i.c.r. investigations include the perennial problem of the mechanism of ‘tropylium ion’ formation in the mass spectrum of benzyl compounds. The reactivity of C7H,f ions in the mass spectrum of toluene was shown to differ 70 J. H. Bowie Austral. J. Chem. 1971 24 989. G. C. Goode R. M. O’Malley A. J. Ferrer-Correia and K. R. Jennings Chem. in Britain 1971 7 12. 72 J. Diekman J. K. MacLeod C. Djerassi and J. D. Baldschwieler J. Amer. Chem. Soc. 1969,91,2069. 73 G. Eadon J. Diekman and C. Djerassi J. Amer. Chem. SOC.,1969 91 3986. Physical Methods-Part (i) Organic Mass Spectrometry from that of norbornadiene or cycloheptatriene in its ability to abstract NO from alkyl nitrates.74 Toluene ions underwent the ion-molecule reaction C7H8++ RONO -+ C,H,NO2+ + RO-whereas the other isomers would not give this reaction.Similarly structural isomers of C,H ions from a variety of sources have been distinguished by their ability to react with amm~nia.’~ to carry Initial attempts have been rep~rted’~ out stereochemical analysis by examining the differing ion-molecule reactions of stereochemical isomers using i.c.r. It was possible to distinguish exo- and endo-borneol from the ion-molecule reactions between their molecular ions and biacetyl. Purely analytical applications of mass spectrometry have reached an advanced level in the work reported on the identification of constituents of human blood and tissues on a very small scale.77 Quantitative high-resolution mass spectro- metry was used to simultaneously determine the amounts (pg) of up to five constituents in about 5mg of desiccated tissue.This sort of work opens up research intro drug metabolism and suggests a possible extension to biosynthetic studies in plants where the simultaneous monitoring of several constituents needs to be carried out over a period of time. ” M. K. Hoffmann and M. M. Bursey Tetrahedron Letters 1971,27,2539;M. M. Bursey M. K. Hoffmann and S. A. Benezra Chem. Comm. 1971 1417. l5 F. W. McLafferty and M. L. Gross J. Amer. Chem. Sac. 1971,93 1267.l6 M. M. Bursey and M. K. Hoffmann Canad. J. Chem. 1971,49 3395. l7 W. Snedden and R. B. Parker Analyt. Chem. 1971,43 1651.

ISSN:0069-3030    

DOI:10.1039/OC9716800005

出版商:RSC    

年代:1971

数据来源: RSC

摘要:

2 Physical Methods Part (ii) Nuclear Magnetic Resonance By I. H. SADLER Department of Chemistry University ofEdinburgh West Mains Road Edinburgh EH9 3JJ The widespread use of n.m.r. spectroscopy in structure and stereochemical studies makes a complete survey of the field impracticable here. For such a survey the reader is referred to Volume 1 of the Chemical Society Specialist Periodical Report entitled 'Nuclear Magnetic Resonance,' which was published earlier this year. This Report deals primarily with three areas of increasing importance to organic chemists :the use of shift reagents chemically induced dynamic nuclear polarization and carbon-1 3 magnetic resonance. Other aspects of n.m.r. including conformation and kinetic studies have received somewhat short measure under miscellaneous studies where emphasis has been placed on methods rather than results.Some areas including theoretical work solvent effects and studies of nuclei other than hydrogen and carbon have had to be omitted. The previous survey of n.m.r. in Annual Reports appeared in 1968 and therefore where appropriate significant material from 1969 and 1970 has been included in this Report. 1 Chemical Shift Reagents A principal shortcoming of proton magnetic resonance lies in its inability to distinguish clearly between similar but not equivalent protons and the resulting region of the spectrum is often complex and difficult to analyse. The addition of transition-metal ions to induce differential shifts among similar protons usually also results in considerable line broadening and a consequent loss of information owing to the reduction by the paramagnetic species of the proton spin-lattice relaxation times (Tl).Most of the lanthanides however are considerably less efficient in reducing Tl than the more common transition-metal ions,' and euro- pium(II1) particularly so. The tris-P-diketone complexes of these metals behave as weak Lewis acids and readily increase their co-ordination number using ligands possessing lone electron pairs. Initially Hinckley reported2 that the presence of the dipyridine adduct of bis(dipivalomethanato)europium(m) Eu(dpm) ,2py (I) results in substantial ' R. L. Conger and P. W. Selwood J. Chem. Phys. 1952 20 383. C. C. Hinckley J. Amer. Chem. SOC.,1969 91 5160.18 Physical Methods-Part (ii) Nuclear Magnetic Resonance 19 downfield shifts of the proton resonances of cholesterol with very little line broadening. Larger downfield shifts are observed when the pyridine-free com- plex Eu(dpm) (2) is used ;,the resonances from different protons are shifted by different amounts and the spectrum assumes a more first-order appearance. The addition of 0.5 molar equivalents of (2) to a solution of 4-t-butylcyclo- hexanone causes the proton resonances to be separated over the range of 10p.p.m. clearly revealing the proton couplings. Asimilar separation of the spectrum is obtained for quinoline. The tris(dibenzoylmethanat0)-complex,Eu(dbm) (3) (1) R = CMe,; + 2py Eu (2) R = CMe (3) R = Ph 0-c \ is too insoluble for general use.The praseodymium complex Pr(dpm) causes upfield shifts approximately three times as large as the downfield shifts of Eu(dpm) but the signals are slightly less well defined.4 Shifts of proton reso- nances have been observed for a variety of molecules including alcoholsY2-' ester~,~*~,' amines,3,6.12,13 epoxide~,'~ 5,16 ethers, ketone^,^.^.'^,'^ oximes,' sulph~xides,'~ polymers,20 carbohydrates,21 steroid^,^,^,',^^ and terpene~.~~ J. K. M. Saunders and D. H. Williams Chem. Comm. 1970,422; J. Amer. Chem. Soc. 1971 93 641. J. Briggs G. H. Frost F. A. Hart G. P. Moss and M. L. Staniforth Chem. Comm. 1970 749. P. V. Demarco T. K. Elzey R. B. Lewis and E. Wenkert J. Amer. Chem. Soc. 1970 92 5734 5737. D.R. Crump J. K. M. Saunders and D. H. Williams Tetrahedron Letters 1970 4419,4949. ' C. C. Hinckley J. Org. Chem. 1970 35 2834. G. V. Smith W. A. Boyd and C. C. Hinckley J. Amer. Chem. Soc. 1971,93 6319. D. E. Sunco L. Tomic Z. Majerski and M. Tomic Chem. Comm. 1971 719. lo G. H. Waal and M. R. Peterson Chem. Comm. 1970 1167. l1 A. F. Cockerill and D. M. Rackham Tetrahedron Letters 1970 5149. l2 D. C. Remy and W. A. Van Sam Tetrahedron Letters 1971,2463; H. Van Brederode and W. G. B. Huysmans Tetrahedron Letters 1971 1695. l3 E. Ludger Chem.-Ztg. 1971 95 325. l4 M. R. Willcott J. F. M. Oth J. Thio G. Plinkie and G. Schroder Tetrahedron Letters 1971 1579. F. I. Carroll and J. T. Blackwell Tetrahedron Letters 1970 4173. l6 M. Yoshimoto T. Hiraoker H.Kuwano and Y. Kishida Chem. and Pharm. Bull. (Japan) 1971 19 849. P. Belanger G. Freppel D. Tizane and J. C. Richer Chem. Comm. 1971 266. Z. W. Wolkowski Tetrahedron Letters 1971 825. l9 R. R. Fraser and Y. Y. Wigfield Chem. Comm. 1970 1471. 2o A. R. Katritsky and A. Smith Tetrahedron Letters 1971 1765; F. F. L. Ho J. Polymer Sci.,Part B Polvmer Letters 1971 9 491. 21 I. Armitage and L. D. Hall Canad. J. Chem. 1971,49 2770. 22 J. E. Hertz V. M. Rodriguez and P. Joseph-Nathan Tetrahedron Letters 1971 2947. 23 D. G. Buckley G. H. Green E. Ritchie and W. C. Taylor Chem. and Ind. 1971 298; 0. Achmatowicz A. Ejchart J. Jarczak L. Kozerski and J. St. Pyrek Chem. Comm. 1971 98. 20 I. H. Sadler Nitro-compounds show only very small shifts and compounds containing only halogens or carbon-carbon double bonds remain ~naffected.~ The presence of acidic or phenolic groups causes decomposition of the shift reagents.The use of dry pure materials and solvents is necessary during the preparation and use of the reagents since they preferentially complex with water and their effec- tiveness is greatly reduced if not entirely eradicated. For similar reasons polar solvents are to be avoided. The magnitude of the shift normally varies linearly over a shift-reagent-to-substrate molar ratio range of 0.14.5. This is to be expected for a rapid equilibrium between a reagent-substrate complex and substrate molecules." At molar ratios >0.5 the shift magnitude tends to a limiting value. Shifts are reported either as values extrapolated linearly to a molar ratio of 1.0 or preferably as the gradient (p.p.m./mol.M(dpm),/mol. substrate) of the linear portion of the shift us. molar ratio graph. These gradients depend upon the substrate functional group and its environment. In the absence of steric factors the shift gradients of the methylene group in RCH,X decrease3 along the sequence X = NH > OH > C0.C > OR > C0,R > CN. Shift magnitudes can be increased by lowering the temperature9* but this normally results in broader signals. The shifts are to a pseudocontact interaction between the metal atom and a substrate atom possessing one or more lone electron pairs. Since this is a through-space magnetic dipolar interaction which alters the local mag- netic field but does not affect the bonding electron densities coupling constants should not be altered.Providing therefore that the resonances are not too ill defined it is valid to obtain coupling constants directly from the spectrum if first-order conditions hold. Thus it has been possible24 to obtain long-range coupling constants for the interaction of the ring protons with the methyl protons in 2-methylpyrazine and its monomethoxy-derivatives. The magnitude (Ad) of this type of shift is expressed by the equation:25 A6 = K(3 COS~ $ -1)r-where K is a constant for a particular complex at a given temperature 4 is the proton-metal-co-ordination site internuclear angle and r is the proton-metal distance. Thus in a particular example the relative shifts depend only on the associated angles and distances.Several worker^^.^.^,'^*' have found that such shifts often seem to a fair approximation to show only a dependence on r-3. In these cases the metal atom must be so located that the variation in 4 is suffi-ciently small enough to be ignored. Reports5*' ',I3 of correlation with other orders of r can probably be attributed to an incorrect assumption of the location of the metal atom or neglect of the angular dependence or both. The importance of the angular variation is illustrated26 by the Eu(dpm) induced upjeld shifts of the methoxy-proton resonances in (4). All other proton resonances are dis- placed downfield. This behaviour is expected when (3 cos 4 -1) < 0 i.e. 24 A. F. Bramwell G. Riezebos and R.D. Wells Tetrahedron Letters 1971 2489. 25 H. M. McConnell and R. E. Robertson J. Chem. Phys. 1958,29 1361. 26 P. H. Mazzocchi H. J. Tamburin and G. R. Miller Tetrahedron Letters 1971 1819. Physical Methods-Part (ii) Nuclear Magnetic Resonance 55" < 4 < 125". The opposite effect is observed using Pr(dpm),. With both reagents a sufficiently first-order spectrum was obtained to allow the coupling constants for all protons to be measured. In the presence of Eu(dpm) no shifts are observed27 for the meta- and para-proton resonances in cis-4-t-butyl-l- phenylcyclohexanol(5). This is consistent with europium-oxygen co-ordination. The proton resonance shifts observed for pyridine the picolines pyridazine pyrimidine pyrazine quinoline and isoquinoline cannot be correlated with a realistic value for the europium-nitrogen distance unless the angular dependence is included.28 Confirmatory evidence for the pseudocontact origin of the shift has been obtained from a of the Pr(dpm) induced shifts in horneol (6).The rigid stereochemistry of this molecule provided a model in which geo- metrical factors could be accurately calculated. A set of values for the geometric factor (3cos2 4 -l)r-, was calculated for all protons using a position for the metal atom estimated from inspection of Dreiding models and a consideration of other factors. These values were refined by a reiterative procedure to make deviations from proportionality with observed shifts as small as possible a value for K being selected to allow direct comparison with observed shifts.A complete assignment of the resonances and evaluation of the coupling constants was also possible. The praseodymium atom co-ordinates derived in this study have been used to calculate30 the induced shifts expected in the carbon-I3 magnetic resonance spectrum of borneol. These agreed well with the experi- mental values and allowed for the first time the complete assignment of the carbon-13 resonances. Analogous results were also obtained using the europium complex. It is noteworthy that the proportionality constant K for the best Me Me v (6) (7) 27 N. S. Bhacca and J. D. Wander Chem. Comm. 1971 1505. W. L. F. Armarego T. J. Batterhan and J. R. Kershaw Org. Magn. Resonance 1971 3 575.29 J. Briggs F. A. Hart and G. P. Moss Chem. Comm. 1970 1506. 2o J. Briggs F. A. Hart G. P. Moss and E. W. Randall Chem. Comm. 1971 364. 22 I. H. Sadler fit of the carbon-13 data is 1.16 KH where KH is the corresponding constant for the proton data. Since the pseudocontact shift A6 is independent of the nuclear magnetic moment these constants should be identical. These results show that the shifts originate predominantly if not exclusively from a pseudocontact mechanism and providing that the metal atom is correctly located there is no need to involve a major contact contribution. The use of a computer program has been reported31 to determine the position of the lanthanide ion by maxi- mizing the correlation bet ween the experimentally measured induced shift and the geometric factor.Its application to adaman tan-2-01 trans-4-t- bu tylcyclo- hexanol and the hydroxyoxetan (7) is described. The results for (7) indicate that the europium atom co-ordinates to the ether oxygen atom. The presence of a small contact contribution cannot always be excluded especially in the presence of aromatic molecules where unpaired electron spin density can be transferred through a n-electron system e.g. in quinoline the J2.3 coupling appears to decrease3 at relatively high reagent-to-substrate molar ratios. A contact contribution has been also demon~trated~~ for 31Pshifts in phosphates and phosphonates induced by Eu(NO,) ,6D,O. In molecules possessing more than one functional group the preferred order of co-ordination of Eu(dpm) to saturated molecules has been found33 to be alcohols > amines > ethers > ketones -esters.This sequence may be altered by steric factors. Unsaturation increases co-ordination to ketones. Where an ether oxygen atom is part of an aromatic system as in furan the co-ordination is very weak. In the polyethers MeO(CH,CH,O),Me symmetrical co-ordination of Eu(dpm) or Pr(dpm) to the two extreme oxygen atoms for n = 4-8 yields relatively simple spectra.34 A graphical method has been described3' for separat- ing the relative contributions to induced shifts resulting from the metal atom co-ordinating at two sites in a molecule and has been applied to testosterone and its 17wmethyl derivative. It should be emphasized that this method is based on the assumption that the angular dependence in the above equation may be ignored and should therefore be used with caution.Although less extensively st~died,~~-~~ the ytterbium complex Yb(dpm) is of value and causes shifts approximately twice those of Eu(dpm) in the same direction. A comprehensive of amines indicates that steric factors related to the accessibility and inversion of the lone electron pair are particularly impor- tant and complexing ability increases along the sequence triethylamine < pyridine < diethylamine < quinuclidine < ethylamine. The data correlate well with r-3 assuming a Yb-N distance of 3A. Ketone and aldehyde studies37 31 S. Farid A. Ateya and M. Maggio Chem. Comm. 1971 1285. 32 J. K. M. Saunders and D.H. Williams Tetrahedron Letters 1971 2813. 33 H. Hart and G. M. Love Tetrahedron Letters 1971 625. 34 A. M. Groters T. Smid and E. de Boer Tetrahedron Letters 1971 4863. 3s C. C. Hinckley M. R. Klotz and F. Patil J. Amer. Chem. SOC.,1971 93 2412. 36 C. Beaute Z. W. Wolkowski and N. Thoai Tetrahedron Letters 1971 817. 37 Z. W. Wolkowski Tetrahedron Letters 1971 821. 38 Z. W. Wolkowski C. Beaute and N. Thoai Chem. Comm. 1971 700. 39 C. Beaute Z. W. Wolkowski J. P. Merda and D. Lelandais Tetrahedron Letters 1971 2473. Physical Methods-Part (ii) Nuclear Magnetic Resonance 23 reveal stereochemical information e.g. phorone and mesityl oxide retain pre- dominantly a sym-cis conformation. In fluorenone the ytterbium atom is collinear with the carbonyl group but in indan-1-one it is displaced on a line 60" from this axis and anti to the aromatic ring.O~imes~~ appear to co-ordinate at the oxygen atom and imines azo- and nitro-compounds remain virtually ~naffected.~~ Amides show shifts comparable with those of ketones co-ordination being via the carbonyl group3* The reagent has been used to assign39 structures to several chloro- and bromo-vinylaldehydes. A systematic quantiative study of the effect of dpm complexes of all the lan- thanides except La ce and Lu on the 'H n.m.r. spectra of 4-vinylpyridine 4-picoline N-oxide and n-hexyl alcohol has been rep~rted.~' In addition to the forementioned upfield shifts are reported for Nd Sm Tb Dy and Ho while downfield shifts are observed for Er and Tm.The study confirms the geo- metric dependence of the shift ratios and the signs of the shifts correlate quali- tatively with available magnetic anisotropy data confirming their pseudocontact nature. Spectra of Gd(dpm) systems were severely broadened suggesting a contact shift which if present in any lanthanide complex could be expected to show up here. A study of relative broadening abilities of these lanthanides shows that although Tb Dy Ho and Tm cause shifts greater in magnitude than those of Pr Eu and Yb they also give broader lines. Chemical shift reagents provide a powerful tool for solving stereochemical and conformational studies. Typical applications include the assignment4' of configurations to the phosphetans (8) by examination of the resonance of the Me Me Me Me (8) R = Ph Me OEt SEt CH,Ph or NHCH,Ph C-3 proton ;the estimation42 of syn-anti ratios in oxime mixtures obtained from alkyl methyl ketones ; the determination of the stereochemistry of cis- and tr~ns-4-t-butyl-l,2,2-trimethylcyclohexanols,~~ 3-(l-naphthyl)-l,3,5,5-tetrame- thylcyclohexanols,44 and the perhydrophenalols (9) and ( of 3-endo-substituted bicyclo[3,3,l]~onanes indicate that these adopt boat-chair conformations.Possible conformational changes induced by complexing to the europium atom were shown to be only very slight. Bicyclo[3,3,1]nonan-3-one 40 W. D. Horrocks and J. P. Sipe J. Amer. Chem. SOC.,1971 93 6800. 41 S. Trippett and J. R. Corfield Chem. Comm. 1971 721. 42 K. 0. Berlin and S. Rengaraja J.Org. Chem. 1971 36 2912. 43 P. Belander C. Freppel D. Tizane and J. C. Richer Canad. J. Chem. 1971,49 1988. 44 B. L. Shapiro J. R. Hlubucek G. R. Sullivan and L. F. Johnson J. Amer. Chem. Suc. 1971,93 3281. 45 F. A. Carey J. Org. Chem. 1971 36 2199. 46 I. Fleming S. W. Hanson and J. K. M. Saunders Tetrahedron Letters 1971 3733. I. H.SadIer appears to exist as a 1 1 mixture of chair-chair and chair-boat conformation^.^^ A preferred conformation has been assigned48 to griseofulvin. Structures have been assigned49 to the diastereomeric forms of bis(phenylsulphiny1)methane (Ph-SOCH,.SO-Ph) on the basis of the resonances of the methylene protons which in the absence of shift reagent appear as singlets. In the presence of Eu(dpm) those from the meso-form being non-equivalent appear as a quartet whereas those from the racemic form being equivalent remain as a singlet.The introduction of chiral shift reagents has made possible the determination of optical purity by n.m.r. In the presence of tris-[3-(trifluoromethylhydroxy-methy1ene)-(+)-camphorato]europium (1l) the singlet resonances from the C-l protons of 2-phenylbutan-2-01 may be separated” by 0.3 p.p.m. Tris-[3-pivaloyl-(+)-camphorato]europium (12) is particularly effective for amines. (11) R = CF (12) R = But Slight disadvantages of the dpm reagents lie in their low solubility in non- alcoholic solutions and their markedly reduced effectiveness when used with weak Lewis bases e.g.ethers and esters. These problems are largely overcome52 by the use of tris-(1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctadionato)europium Eu(fod) (13) and the corresponding praseodymium complex Pr(fod) .The presence of the electronegative fluorine atoms increases the acceptor properties of the reagent. Relatively high concentrations (> 1.0 molar ratio shift reagent substrate) may be used and virtually no peak-broadening is observed. The proton resonances of di-n-butyl ether which are not significantly affected by Eu(dpm), are displaced substantially by Eu(fod),. This reagent has been of 47 M. R. Vegar and R. J. Wells Tetrahedron Letters 1971 2847. 48 S. G. Levine and R. E. Hicks Tetrahedron Letters 1971 31 1. 49 J. L. Greene and P. B. Shevlin Chem. Comm. 1971 1092. H. L. Goering J. M. Eikenberry and G.S. Koermer J. Amer. Chem. Soc. 1971 93 591 3. 51 G. M. Whiteside and D. W. Lewis J. Amer. Chem. Soc. 1970,92 6979; 1971,93,5914. 52 R. E. Rondeau and R. E. Sivers J. Amer. Chem. Soc. 1971,93 1522. Physical Methods-Part (ii) Nuclear Magnetic Resonance particular value in assigning alkyl resonances of tertiary alkylamides5 and the stereo~hemistry~~ of the tricyclic benzodioxans (14). A different type of shift reagent has been reported,55 in which the compound to be studied is held in the ring-current-induced asymmetric magnetic field of a porphyrin ring system by covalent bonding to a germanium atom located at the centre. The bonds are formed by the reactions of compounds (15) and (16) with functional groups on the compound being studied.Suitable groups are weakly and strongly acidic hydroxy-groups and metallic ligands in Grignard reagents and organolithiums. In view of the inapplicability of the lanthanide shift reagents to halides carboxylic acids and phenols the new reagents are particularly useful. The proton resonances of the methyl group in dimethyl- germaniumporphin (17) obtained from (15) and methylmagnesium iodide (15) R = H; X = C1 R (16) R= Ph; X = OH (17) R= H; X = Me (18) R = H; X = n-C,H X occur as a sharp singlet at 18 z and those from the corresponding di-n-octyl derivative (18) are spread over 9-187. Since these reagents are diamagnetic they have the advantage that they cannot show line-broadening effects which sometimes becomes significant with lanthanide shift reagents.2 Chemically Induced Dynamic Nuclear Polarization The ob~ervation~~,~’ of enhanced absorption (A) or emission (E) signals in n.m.r. spectra of reacting systems is evidence for the participation of free radicals 53 L. R. Isbrandt and M. T. Rogers Chem. Comm. 1971 1378. 54 J. F. Caputo and A. R. Martin Tetrahedron Letters 1971 4547. 55 J. E. Maskasky and M. E. Kenney J. Amer. Chem. SOC.,1971,93 2060. 56 H. Fischer and J. Bargon Z. Naturforsch. 1967 22a 1551 1556; 1968 23a 2109; H. R. Ward J. Amer. Chem. SOC.,1967 89 5517. 57 H. Fischer and J. Bargon Accounrs Chem. Res. 1969 2 110; R. G. Lawler J. Amer. Chem. SOC.,1967 89 5519. 26 I. H. Sadler in the reaction and is generally referred to as chemically induced dynamic nuclear polarization (CIDNP).The effect was originally explained57 by cross- relaxation of electron and nuclear spins resulting in a non-Boltzman distribution in the nuclear spin levels of the radical which was transferred to the products upon reaction. More evidence of the phenomenon showed this theory to be untenable. In particular it is unable to explain multiplet effect^^^,^^ (the presence of both A and E within a multiplet) and places a theoretical limit on the magnitude of the polarization which is often exceeded in practice.59 The experimental observations for combination and disproportionation reactions carried out within the spectrometer are explained rather better by the radical pair theory first developed independently by CIOSS~~~~ and by Kaptein and Oosterhoff.62 Similar treatments differing slightly in quantitative formulation have been offered63 by Fischer and Adrian.The reaction of a precursor molecule (M) yields a radical pair (RP) which may either yield cage products by combination or disproportion of the components within the cage or separate into two free radicals. The separate radicals may then undergo transfer reactions or form new radical pairs by diffusion M -+ R-P-+ R-P 1 sx diR. RX,PX + R-+ Pa -+ R-R,P-P Initially the electronic state of the radical pair is that of the precursor M. Inter-actions between the unpaired electrons and neighbouring nuclei in a particular radical pair cause mixing of the electronic singlet (S) state and the M = 0 component of the triplet (To)state to an extent that is governed by the nuclear spin states.Mixing of the singlet state with the M = +1 components of the triplet (T+)state are not significant in fields greater than a few thousand gauss. Since the rate of cage-product formation depends upon the singlet character of the mixed electronic state those nuclear spin states which give rise to a state predominantly triplet in character will be depleted in the cage product and those conferring a predominantly singlet nature on the mixed state will be enhanced in the cage product. In certain cases this leads to observable polarizations. It is possible to obtain the magnitude and sign of the polarization from the hyperfine splitting constants and g-values of the component radicals and the multiplicity of the precursor.Free-radical displacement and trapping reactions 58 H. R. Ward and R. G. Lawler J. Amer. Chem. Soc. 1967 89 5518. 59 G. L. Closs and L. E. Closs J. Amer. Chem. Soc. 1969 91 4549 4550. 6o G. L. Closs J. Amer. Chem. Soc. 1969 91 4552; G. L. Closs and A. D. Trifunac J. Amer. Chem. Soc. 1969 91 4554; 1970 92 2183; G. L. Closs C. E. Doubleday and D. R. Paulson ibid. p. 2185. 61 G. L. Closs and A. D. Trifunac J. Amer. Chem. Soc. 1970 92 2186. 62 R. Kaptein and L. J. Oosterhoff Chem. Phys. Letters 1965 4 195 214. 63 H. Fischer Chem. Phys. Letters 1970 4 611; 2. Naturforsch. 1970 25a 1957; F. J. Adrian J. Chem. Phys. 1970 53 3374; 1971 54 3912. Physical Methods-Part (ii) Nuclear Magnetic Resonance 27 can be treated by the same model when nuclear relaxation processes are in- cl~ded.~~ Both multiplet and net emission and absorption effects are explained and no limit is placed on the magnitude of the polarization.Combination of identical radicals can only give rise to multiplet effects (not observable for single resonances). Cage products are expected to show opposite polarization to products resulting from radicals escaping from the pair (e.g. transfer products) and this is observed in practice.65 Polarizations resulting from a singlet precursor are opposite in sign to those from a triplet precursor. Recombination of radical pairs formed by diffusive encounters gives polarization of the same sign as a triplet precursor but with reduced intensity.66 The model provides a satisfactory explanation for a large number of observed polarizations including those of products from the singlet and triplet decompositions of benzoyl peroxides in a variety of solvent^,^' and those of 1,1,2-triarylethanes obtained6' by (a) the photochemical decomposition of diphenyldiazomethane in toluenes (b) the thermolyses of the appropriate azo-compounds and (c) the decomposition of peroxides in mixtures of toluenes and diphenylmethanes.Tomkiewicz and Cocivera have extended6* the theory to account for the different intensity distributions (as well as the difference in sign) observed for products resulting from singlet and triplet precursors of a radical pair. Kaptein has presented69 two qualitative rules from which the sign of polariza- tion observed for a product may be predicted.The CIDNP spectrum of a nucleus i originally belonging to radical a of a pair ab and possibly coupled to a nucleusj in the product is described by the sign of r for net effects (A or E) and rmfor multiplet effects (E/A low-field part of a multiplet E high-field part A ;A/E reverse of E/A) r =~EA~A~ +ve for A -ve for E r =pcA,A,o,,Ji +ve for E/A -ve for A/E where the parameters take the following signs -for ab formed from a singlet precursor +for ab formed from a triplet precursor 4+ for ab formed by diffusive encounter of two radicals +for cage recombination (or disproportionation) products &{ -for products of escaped radicals (e.g. transfer products) +for nuclei i and j belonging to the same radical gij{ -for nuclei i and j belonging to different radicals +for g-factor of a greater than g-factor of b -for g-factor of a less than g-factor of b 64 G.L. Closs and A. D. Trifunac J. Amer. Chem. SOC. 1970,92 7227; G. L. Closs and D. R. Paulson J. Amer. Chem. Soc. 1970 92 7229. 65 B. Blank and H. Fischer Helv. Chim. Acta 1971 89 905. 66 M. Lehnig and H. Fischer Z. Naturforsch. 1970 25a 1963; J. Phys. Chem. 1971 75 3410. 67 R. Kaptein J. A. den Hollander D. Antheunis and L. J. Oosterhoff Chem. Comm. 1970 1687; S. R. Farenholtz and A. M. Trozzolo J. Amer. Chem. SOC.,1971,93 253. 68 M. Tomkiewicz and M. Cocivera Chem. Phys. Letters 1971 8 595. 69 R. Kaptein Chem. Comm. 1971 732. I.H. Sadler Ai Aj,and Jijtake the signs of the appropriate hyperfine splitting and nuclear spin coupling constants. The correct polarization is obtained in straightforward cases where the signal exhibits either a net effect or a multiplet effect. Where both multiplet and net effects are observed the spectrum is usually described by the combination of both rules; however under conditions where AgPHOis very large compared with Ai or where the spectra are very strongly coupled the multi- plet effect may be reversed. The rules imply that the strong emission signal observed for p-dichlorobenzene obtained during the decomposition of di-(p-chlorobenzoyl) peroxide in hexa- chloroacetone originates from p-chlorophenyl radicals that have escaped from an aroyloxy-aryl radical pair.This conclusion was also reached from chemical arguments65 concerning the effect of trapping agents upon the CIDNP patterns and product distributions. These rules will be of obvious value in mechanistic studies with regard to precursor multiplicity and radical pair composition. Emission signals have also been observed for benzene formed via the de- compo~ition~~ of N-nitrosoacetanilide phenylazotriphenylmethane and dia- zoaminobenzene in cyclohexane toluene cumene and acetic anhydride and for methane formed by the thermal decomposition7’ of 00f-diacetyl-4-hydroxy- aminoquinoline 1-oxide (19) in dioxan. On the basis of CIDNP effects observed during the acetylation of y-picoline N-oxide with acetic anhydride the inter- mediacy of the radical pair (20) is proposed.72 The ob~ervation’~ of an E/A OAc (19) multiplet for the methine proton Ha,in the aniline derivative (23) obtained from the reaction of benzyne with NN-dimethylbenzylamine has been used as con- firmatory evidence for the formation of radical pair (22) via the steps shown from an ortho-betaine (21).The sign of the multiplet is in accordance with Kaptein’s Rules. A similar polarization effect is reported74 for an analogous reaction between benzyne and dibenzyl sulphide. Strong emission by the methine proton in the oxime ether (25) obtained75 by thermolysis of fluorenone ’O L. F. Kasukhin M. P. Ponomarchuck and V. N. Kalinin Zhur. org. Khim. 1970 6 2531. Y. Kawdzoe and M. Araki Chem. and Pharm. Bull. (Japan) 1971 19 1278.72 H. Iwamura M. Iwamura T. Nishida and S. Sato J. Amer. Chem. Soc. 1970,92,7474. 73 A. R. Lepley R. H. Becker and A. G. Giumanini J. Org. Chem. 1971 36 1222. 74 H. Iwamura M. Iwamura T. Nishida M. Yoshida and J. Nakayana Tetrahedron Letters 1971 63. ’5 D. G. Morris Chem. Comm. 1971 221. Physical Methods-Part (ii) Nuclear Magnetic Resonance 29 Me Me Me Me t) I I p$:Me Ph-A+-Me + [Ph-N?1 .Me "-;'-M] I --+ Ph-y: I + I -H-C-Ph Ph-C-Ph-C-Ph -C* Ph-C-Me I I I H H Ha N-benzhydrylnitrone (24) provides further evidence for the homolytic nature of the Martynoff rearrangement. CIDNP during the photolysis of di-isopropyl ketone has been described.76 In most solvents polarization is in accord with radical pair formation via a Norrish Type I split from a triplet state ketone.In carbon tetrachloride the reaction probably involves complex formation of the solvent with the excited singlet state of the ketone. 0-+/ X=N -P X=N-O-CHPh, \ CHPh (24) X = 9-Fluorenylidene (25) A of the decomposition of 0.2 moll -' isobutyryl peroxide in hexa- chlorobutadiene containing varying initial concentrations of bromotrichloro- methane shows a variation and sign reversal for the polarization of the chloroform signal implying formation by two competing routes (see Scheme). At concentra-tions of bromotrichloromethane greater than 0.11 mol I-' an enhanced absorp- tion signal is obtained indicative of chloroform formation mainly by dispropor- tionation of a singlet [.CCl, CHMe,] radical pair (S); this being formed by S ~ (RCO,) + 2C0 + 2R.--+ RR RH R(-H) S RBr + R. CCI --+ RCCI, CHCI, R(-H) lBrCCII (A) RBr + 2433 R. + .CCl R. CCI + RCCI, CHCI, R( -H) (E) Scheme l6 J. A. den Hollander R. Kaptein and T. A. T. M. Brand Chem. Phys. Letters 1971 10 430. l7 R. Kaptein F. W. Verheus and L. J. Oosterhoff Chem. Comm. 1971 877. I. H. Sadler reaction of the initial singlet [2*CHMe,] radical pair with bromotrichloromethane. At concentrations of bromotrichloromethane less than 0.11mol I-' an emission signal results indicating the major route is from a radical pair (F) formed by diffusive encounters of CC1 and CHMe radicals. Consideration of the likely reaction rates suggests that spin correlation effects of radical pairs in solution may be of relatively long duration (microseconds).A variation of product polarization with concentration of peroxide and transfer reagent has also been observed78 in the decomposition of phenyl acetyl peroxide in carbon tetra- chloride-bromotrichloromethane mixtures. CIDNP studies79 of the decomposition of bis(pentafluorobenzoy1) peroxide in hexachlorobutadiene containing a variety of aromatic compounds suggest that the pentafluorobenzoyloxyl radical shows marked electrophilic properties. The photolysis of diazomethane in carbon tetrachloride to yield pentaerythrityl tetrachloride is thought to proceed via a multistep chain reaction initiated by reaction of methylene with carbon tetrachloride. Roth has obtained" an emission signal from a minor side-product 1,1,1,2-tetrachloroethane,formed by cage recombination of the radical pair produced in the initiation step indicating that methylene is formed predominantly if not exclusively as a singlet species.Tri- chloromethyl radicals escaping the pair are involved in propagation of the chain process. CIDNP spectra obtained" during the singlet and triplet photo- sensitized photolysis of diazirine in deuteriotrichloromethane indicate singlet methylene preferentially abstracts chlorine atoms whereas triplet methylene abstracts hydrogen atoms ;the presence of one-step C-H insertion by methylene is not excluded by these results. Strong emission signals have been obtained8' for all dimerization products of the diradical (27) formed by thermolysis of the bicyclic azo-compound (26).Closs has rationalized8 this using an extension of the radical pair theory. A one-step reaction between two triplet trimethylene diradicals may give either multiplet or emission spectra ;if the reaction occurs in two steps by an initial singlet-triplet combination to give a triplet diradical pure emission only may be observed resulting from singlet-triplet transitions. No polarization is observable for a one-step reaction between two singlet trimethylene Me (26) 78 C. Walling and A. R. Lepley J. Amer. Chem. Soc. 1971 93 546. 79 J. Bargon J. Amer. Chem. SOC.,1971 93 4630. H. D. Roth J. Amer. Chem. Soc. 1971 93 1527. H. D. Roth J. Amer. Chem. SOC.,1971,93,4935. *' J. A. Berson R. J. Bushby J. M. McBride and M.Tremelling J. Amer. Chem. SOC. 1971,93 1545. 83 G. L. Closs J. Amer. Chem. Soc. 1971 93 1546. Physical Methods-Part (ii) Nuclear Magnetic Resonance 31 diradicals. Unexpected6' observation'" of CIDNP effects in the spectrum of dec- 1 -ene obtainable from a decamethylene diradical formed during the thermol- ysis of cyclohexane diperoxide (28),is attributed to the availability of multiplicity independent competing reaction paths for the diradical. Relatively few studies have been carried out using low-strength magnetic fields. In such cases e.g. the rea~tion'~ of act-dichlorotoluene with ethyl-lithium polarization is detected by transferring the sample to the spectrometer after the reaction is complete. Under these conditions mixing of the singlet state with all three triplet states becomes irnp~rtant'~ and Kaptein's rules require m~dification.~' A simple method has been developed" for the calculation of nuclear polarizations in products of radical coupling reactions carried out at zero magnetic field and explains the polarization of 4-bromo-2,3-dideuterio- chlorobenzene obtained by the decomposition of the parent diacyl peroxide in bromotrichloromethane-hexachlorobutadieneoutside the spectrometer.The high-field spectrum is correlated with the zero-field energy levels. Low-field polarizations have also been observed*' for reaction of the naphthalene anion- radical with isopropyl chloride. No polarization is observed or expected at high fields. CIDNP is obviously of immense value in mechanistic organic chemistry ; however it cannot be stressed too strongly that the observation of such effects imply neither that the product is necessarily the major product nor that the ob- served pathway is a major one ; neither can pathways be excluded solely on the basis of no observed effect.3 Carbon-13 Resonance The low natural abundance (1.1 %) and inherent insensitivity to detection (1.6% of that for the proton for a given field strength) of the nucleus has hindered carbon-13 magnetic resonance studies by conventional continuous-wave tech- niques. Improvements over the past few years in instrument design have led to increased basic sensitivity and stability the latter allowing the effective use of spectrum accumulation. Proton noise decoupling the broad-band irradiation of the entire proton resonance frequency range while recording the 13C n.m.r.spectrum increases sensitivity by a factor of about seven by combining the com- ponents of a multiplet within a single peak and also by virtue of a positive inter- nuclear Overhauser effect. Although it gives a simpler spectrum this procedure eliminates structural information about the number of protons bonded to each carbon nucleus. This can be remedied by off-resonance deco~pling,~' where irradiation is applied some two or three hundred cycles away from the proton 84 R. Kaptein M. Frater-Schroder and L. J. Oosterhoff Chem. Phys. Letters 1971,12 16. 85 H. R. Ward R. G. Lawler H. Y. Loken and R. A. Cooper J. Amer. Chem. SOC. 1969,91,4928.86 F. J. Adrian Chem. Phys. Letters 1971 10 70. 87 J. L. Charlton and J. Bargon Chem. Phys. Letters 1971 8 442. J. F. Garst F. E. Barton and J. I. Morris J. Amer. Chem. SOC.,1971 93 4310. 89 E. Wenkert A. 0. Clause D. W. Cochrane and D. Doddrell J. Amer. Chem. SOC. 1969,91 6878. 32 I.H. Sadler resonances. This results in a partially decoupled spectrum in which the carbon resonances show relatively small splittings (10-50 Hz) from the directly bonded protons only while the Overhauser enhancement remains virtually unaffected. A major development has been the commercial availability of instruments for routine Fourier transform nuclear magnetic resonance spectrosc~py~~~~~ (FT-n.m.r.). This technique involves the irradiation of the sample with a radio frequency pulse short enough to simultaneously excite the resonances of all nuclei of a given isotope in the molecule.The resulting decay of magnetization of the sample the free induction decay is recorded as a function of time and converted by Fourier transformation into a conventional frequency spectrum. The pulse duration is a few microseconds and the free induction decay is recorded over ca. one second. A complete spectrum may therefore be obtained in a time considerably less than the spin-lattice relaxation times of the nuclei. Time averaging of many runs leads to about a ten-fold improvement in sensitivity over normal methods for the same total observation time. Measurement of spin-lattice relaxation times (TI)for individual carbon-13 nuclei is fast becoming a routine procedure in noise-decoupled FT-n.m.r.Normally an inversion-recovery technique is empl~yed,~~,~~ in which a 180" pulse is applied to invert the spin-level populations followed after a delay time T,by a 90" pulse for initiation of the free induction decay. The pulse sequence (180-7-90) may be repeated when thermal equilibrium of the spin system has been re-established usually at least three times the longest value. This method has also been termed 'partially relaxed Fourier transform n.m.r.' (PRFT).93 The peak intensities (A,) in a PRFT spectrum are giveng4 by A = A,[1 -2exp(-z/T1)] where A is the corresponding intensity for the spin system at equilibrium. Resonances appear as emission or absorption lines according to whether 7 is smaller or greater than 7''In 2.This display of the spectrum often resolves overlapping resonances arising from carbon atoms with very different relaxation times. Normally a series of PRFT spectra are obtained as a function of z. Application of this technique to different organic molecules has shown that TI values for carbon-13 nuclei are not always as great as has been formerly supposed. For small and highly symmetrical molecules Tl values are often greater than ten seconds and sometimes as long as a minute for example 3,5-dimethylcyclohex-2- enone (29)95 and 2-ethylpyridine (30),92(Tl values in seconds). For relatively large and asymmetric molecules however Tl values are often less than five seconds for example adenosine monophosphate (3 1).94 Allerhand and Doddrell and co-workers have determined carbon-13 7'' values for several widely differing types of natural product including protein ribonu~lease,~~ cholesteryl chloride 90 W.Bremser H. D. W. Hill and R. Freeman Messtechnik 1971 79 14; T. C. Farrar and E. D. Becker 'Pulse and Fourier Transform NMR,' Academic Press New York 1971. y1 E. Breitmaier G. Jung and W. Voelter Angew. Chem. Internat. Edn. 1971 10 673. 92 R. Freeman and H. D. W. Hill J. Chem. Phys. 1970,53 4103. 93 A. Allerhand D. Doddrell V. Glusko D. W. Cochran E. Wenkert P. J. Lawson and F. R. N. Gurd J. Amer. Chem. Sor. 1971,93 544. 94 A. Allerhand and D. Doddrell J. Chem. Phys. 1971 55 189. 95 R. Freeman and H. D. W. Hill J. Amer. Chem. Soc. 1971,54 3367.Physical Methods-Part (ii)Nuclear Magnetic Resonance 0 o\\P,o-6H2Q!H 0.19 HO/\OH OH and sucrose,94 stachyose and raffino~e,’~ and vitamin B, co-enzyme B1, and other corrinoids.” These workers have shown how Tl values are of immense value in assigning the carbon-13 resonances and in the study of internal molecular reorientation.” They propose three principle^'^ which should be considered when using PRFT spectra for resonance assignments in large and asymmetric molecules (a) Spin-lattice relaxation of protonated carbon atoms results almost exclusively from dipolar interactions with attached protons with Tl given by 1/T = NFt2yc2y,2rc,-6~f where N is the number of directly attached protons yc and yH are appropriate gyromagnetic ratios rCHis the C-H distance and T~ is the effective correlation time for rotational orientation ; (b) non-protonated carbon atoms invariably have greater Tl values than protonated carbon atoms ;(c) different carbon atoms within a molecule may not all have the same T,.differences arising from aniso- tropic effects or internal molecular orientation. An alternative method of measur-ing T values by a pulse method based on the progressive saturation technique has also been described” and the values obtained for 3,5-dimethylcyclohex-2-enone are in good agreement with the PRFT values. A recent review” of FT-n.m.r. is somewhat confusing when discussing multipulse techniques. A new method for measuring spin-spin relaxation times (T,) has been reported99 in which a selective 90” pulse is applied along the x-axis of the rotating frame followed by a continuous r.f.field applied along the y-axis for a period of seconds (t). During this period the magnetization is aligned along y and decays at a rate determined by the spin-lattice relaxation time (T,J in the rotating frame essen ially equal 96 A. Allerhand and D. Doddrell J. Amer. Chem. Soc. 1971 93 2777. ’’ D. Doddrell and A. Allerhand Proc. Nut. Acad. Sci. U.S.A. 1971 68 083; Chem. Comm. 1971 728. 98 D. Doddrell and A. Allerhand J. Amer. Chem. Soc. 1971 93 1558. 99 R. Freemann and H. D. W. Hill J. Chem. Phys. 1971 55 1985. I. H. Sadler to T2. Fourier transformation of the signal yields a conventional spectrum in which the line intensities A are given by 4= A exp(-t/T,,) where A is the initial intensity of the line.Integrated carbon-13 resonance spectra are rarely reported probably because of the uncertainty in the extent of the relative Overhauser enhancements. accurate integrals are possible for FT-n.m.r. carbon-13 spectra and it appearsg4 that for complex molecules e.g. cholesteryl chloride the Overhauser enhance- ments and therefore the integrated intensities are the same for nearly all carbon atoms. This is not necessarily so for small molecules. An intensity ratio of 3.5 :1 instead of 2 1 is obtained from the 13C n.m.r. spectrum"' of acetone and the relative intensities of vinyl acetate (32) are as shown. The Overhauser enhancement may be removed by adding very small quantities of a paramagnetic species (<0.05 moll-').Di-t-butyl nitroxide and the perchlorates"' of chro- mium(III) manganese(II) and iron(rr1) have been used effectively. At such low concentrations line-broadening effects are barely visible. The intensity loss is fully recovered by readjusting pulse intervals to take advantage of the faster relaxation. Following an earlier suggestion,lo2 it has been shown'03 that alternately pulsing broad-band proton decoupling power (1s) and carbon-13 power (30 p) to initiate free induction decay with a short delay time (0.5 s) leads to a signal improvement over the undecoupled spectrum by a factor of ca. three in the Fourier transform spectrum and true 3C-H coupling constants are obtained. In this respect the alternate-pulsed n.m.r.technique is superior to off-resonance or single-resonance decoupling methods which frequently distort lineshapes and coupling constants. Using this technique resonance assignments have been made and coupling constants determined for butan-1-01 and for dimethyl sul- phoxide. The value of noise-decoupled 13C n.m.r. for the study of conformational problems has been e~tablished,"~ carbon-13 shifts being extremely sensitive to the conformational environments of the nuclei. Problems common in 'H n.m.r. in determining linewidths and coalescence temperatures of the complex patterns arising from homonuclear spin-spin coupling are absent in 13Cn.m.r. ; loo G. N. La Mar J. Amer. Chem. SOC.,1971 93 1040. Iol R. Freeman K. G. R. Pachler and G. N.La Mar J. Chem. Phys. 1971 55 4586; G. N. La Mar Chem. Phys. Letters 1971 10 230. Io2 J. Feeney D. Shaw and D. J. S. Pauwells Chem. Comm. 1970 554. lo3 0.A. Gansow and W. Schittenhelm J. Amer. Chem. SOC.,1971 93 4294. D. K. Dalling and D. Grant J. Amer. Chem. SOC.,1967 89 6612; G. W. Buchanan and J. B. Stothers Canad. J. Chem. 1969,47 3605. Physical Methods-Part (ii) Nuclear Magnetic Resonance the chemical shifts between the alternative sites for a carbon atom in inter- converting conformations are generally much larger than those exhibited by protons and generally provide a wider range for temperature study in addition to raising the coalescence temperatures compared with those for proton reso- nances. There is often more than one equilibrating carbon atom in a molecule which can provide corroborative evidence and there are usually also non- equilibrating carbon atoms present which may be used to determine reference linewidths.A disadvantage of 13C n.m.r. compared with 'H n.m.r. is that many compounds e.g. cyclohexane because of symmetry possess no carbon atoms which equilibrate between two different environments. The '3C n.m.r. spectrum'05 of cis-decalin shows a sharp resonance owing to the carbon atoms at the ring junction which are in an identical environment in both forms. The remaining eight carbon atoms give rise to four lines at low temperatures which collapse to two lines under rapid kinetic averaging at high temperatures. Neither the low nor the high temperature methylene signals are as sharp as the ring junction resonances owing to residual kinetic effects.Activation parameters for this molecule 9-methyl-cis-decalin and 1,l- cis-1,2- trans-1,3- and cis-1,4- dimethylcyclohexane have been determined,' ' and are in good agreement with literature values determined from 'H n.m.r. studies where available. Resonances of the axial conformer of methylcyclohexane have been observed '06 for the first time by working at -110 "Cin a 59 kG magnetic field. An A value of 1.6kcal mo1-l obtained for the methyl group is in good agreement with the accepted value (1.7 kcal mol- '). A variable-temperature studylo7 of cyclo- nonane strongly supports a twist-boat-chair conformation (33) rather than the alternative twist-chair-boat form (34). The 250 MHz 'H n.m.r.spectra also support these results. The spectra of a large number of 1,3-dioxans have been rep~rted'~~*''~ and the chemical shifts of the ring and substituent carbon atoms correlate with the corresponding cyclohexane analogues if the deshielding effect of the ring oxygen atoms is taken into account for 5-axial substituents. In some cases O9 non-chair conformations are significant. Conformational and con- figurational assignments to twenty methyl and aryl glycosides have been made"' D. K. Dalling D. M. Grant and L. F. Johnson J. Amer. Chem. SOC.,1971 93 3678. F. A. L. Anet C. H. Bradley and G. W. Buchanan J. Amer. Chem. SOC.,1971,93,258. lo' F. A. L. Anet and J. J. Wagner J. Amer. Chem. SOC.,1971 93 5266. lo' A. J. Jones E. L. Eliel D.M. Grant M. C. Knoeber and W. F. Bailey J. Amer. Chem. SOC.,1971,93,4772. G. M. Kellie and F. G. Riddell Chem. Comm. 1971 1031. lo E. Breitmaier W. Voelter G. Jung and C. Tanzer Chem. Ber. 1971 104 1147. 36 I. H. Sadler on the basis of chemical shift data anomeric glycosides being readily distin- guished. The anomeric equilibria of ketoses in water have also been studied' '' by continuous wave and Fourier-transform methods demonstrating in this instance the superiority of the latter. Applications to the determination of stereoregularity in polymers have also been described. '* The feasibility of 13C n.m.r. for the study of carbonium structure has been ~urveyed"~ by Olah and his co-workers. Unlike 'H n.m.r. it is particularly suited to distinguishing between two rapidly equilibrating classical ions and the alternative non-classical ion by virtue of the marked sensitivity of carbon-13 chemical shifts to charge densities.Of general interest is the a~signment"~ of a symmetrical o-delocalized non-classical structure to the norbornyl cation (35). The 2-methyl and 2-ethyl derivatives show' l4 partial delocalization whereas the 2-benzyl derivative is virtually classical.' l4 The 1,2-dimethylnorbornyl cation (36) appears' to be a partially a-delocalized carbonium ion which undergoes a rapid 1,2-Wagner-Meerwein shift. Symmetrically bridged non-classical structures have been demonstrated' l6 for the bromonium ion (37) and phenonium ion (38). Ally1 cations appear' l7 to show very little direct 1,3-interaction.The chemical shifts of the atom bearing the charge in triaryl carbonium ions and aryl methyl carbonium ions correlate' '* well with c' substituent constants. Br 1+\ Q Me2C-CMe2 (37) H2C-CH2 (38) 111 D. Doddrell and A. Allerhand J. Amer. Chem. Soc. 1971 93 2779. 112 J. Schaefer Macromolecules 1971 4 98 105 107 110; A. Zambelli G. Gatti G. Sacchi W. 0.Crain and J. D. Roberts Macromokcules 1971 4 475. 113 G. A. Olah and A. M. White J. Amer. Chem. Soc. 1969 91 5801. 114 G. A. Olah A. M. White J. R. De Member A. Commeyras and C. Y. Lui J. Amer. Chem. Soc. 1970,.92 4627. 115 G. A. Olah J. R. De Member C. Y. Lui and R. D. Pugmire J. Amer. Chem. Soc. 1971,93 1442. 116 G. A. Olah and R. D. Porter J. Amer. Chem. SOC.,1971,93 6877.117 G. A. Olah P. R. Clifford Y. Halpern and R. G. Johanson J. Amer. Chem. Soc. 1971,93,4219. 118 G. A. Olah R. D. Porter and D. P. Kelley J. Amer. Chem. Soc. 1971 93 464; G. J. Ray R. J. Kurland and A. K. Colter Tetrahedron 1971 27 735. Physical Methods-Part (ii) Nuclear Magnetic Resonance 37 The carbon-13 methyl chemical shifts of acetate and methoxy substituents of several pyranoses have been measured' using the 1H-['3C] INDOR tech-nique i.e. observation of the intensity charge of a 13C-satellite peak in the 'H n.m.r. spectrum while sweeping the irradiation frequency through the range of the I3C n.m.r. spectrum. Correlations between carbon-1 3 chemical shifts and charge densities have been pointed out for aliphatic compounds,' 2o aza-indenes,12 benzene deriva- tives,' 22 benzimidazoles and purines,12j and thymines and ~racils.'~~ An em- pirical method for predicting carbon-13 chemical shifts has been presented by Mason125 who has shown that when corrected by subtraction ofa diamagnetic shielding contribution CT~, shifts may be obtained from a series of additive parameters.The value of odfor a particular carbon atom depends only on those atoms directly bonded to it. Corrected shifts for linear and branched acyclic alkanes and simple cycloalkanes (except cyclopropane) can be calculated by counting -25.4 p.p.m. for each a-carbon -8.4 for each P-carbon +1.5 for each y-carbon and -1.4 for each &carbon with -1.4 as a constant term for shifts measured from methane.The methylcyclohexane parameters vary with conformation. Additivity is also observed for polysubstitution by halogen alkoxy and aryl groups and in linked or fused aromatic molecules and simple olefins acetylenes and carbonium ions. Where conjugative interaction with multiple bonded substituents can occur the corrected shift may be reduced. A comprehensive study'26 of carbon-13 spectra of 50 norbornane and nor- bornene derivatives has appeared. The chemical shifts are approximately additive for similar compounds and can be used for structural assignments. The difference in resonance of em-and endo-methyl groups is attributed to different 1,4-non-bonded interactions between the carbon atoms and not to magnetic anisotropic effects. Carbon-1 3 and proton shift data for numerous acetylenes have been presented'" and analysed.It appears that in phenylacetylene ethyl ethynyl sulphide and triethynylphosphine and its oxide a charge shift occurs from the triple bond to the substituent whereas in alkynyl ethers and amines the direction is reversed. A relatively high shielding of carbon and phosphorus attached to the triple bond is attributed to a reinforcement of diamagnetic aniso- tropy caused by overlap of the z-systems of the triple bond and the substituent. ExaminationI2 of several N-nitrosoanilines and N-nitrosoamines shows that 'I9 R. Burton L. D. Hall and P. R. Steiner Canad. J. Chem. 1971 49 588. ''O P. Lazzeretti and F. Taddei Org. Magn. Resonance 1971 3 113. R. J. Pugmire M. J. Robins D. M. Grant and R.K. Robins J. Amer. Chem. SOC. 1971 93. 1887. P. Lazzeretti and F. Taddei Org. Magn. Resonance 1971 3 283; G. C. Levy G. L. Nelson and J. D. Cargioli Chem. Comm. 1972 506. R. J. Pugmire and D. M. Grant J. Amer. Chem. Soc. 1971 93 1880. lZ4 A. R. Tarpley and J. H. Goldstein J. Amer. Chem. Soc. 1971 93 3573. J. Mason J. Chem. SOC.(A),1971 1038. 126 E. Lippmaa T. Pehk J. Paasivivta N. Belikova and A. Plate Org. Magn. Resonance 1970 2 58 1. 12' D. Rosenberg and W. Drenth Tetrahedron 1971 27 3893. P. S. Pregosin and E. W. Randall Chem. Comm. 1971 399. 38 I.H. Sadler the carbon shifts depend upon the orientation of the nitroso oxygen atom; evidence is presented for the coplanarity of the two n-systems in N-methyl-N- nitrosoaniline. Several substituted allenes have been examined.129 These compounds are particularly suitable for I3C n.m.r. spectroscopy although not previously studied. For a given alkyl substituent a linear relationship holds between the shift of the central (/?)allene carbon atom and the number of these substituents. Ethyl methyl and s-alkyl substituents each contribute +4.8 +3.3 and +7(+2) p.p.m. respectively above the shift of the P-carbon atom. An approximately linear relationship holds between the shifts of the /?-carbon atom in monosubstituted allenes and the a-carbon atom in the corresponding p-substituted ethylenes. Other compounds examined include mono- di- and tri-substituted benzenes,' 30 polycyclic aromatic hydrocarbons and helicenes,' ' adamantane derivatives,' 32 bicycl0[2,2,2]0ctanes,'~~ cyclopentanes,' 34 cyclo-hexanes,' 3s and organophosphonates.'36 A concise review of carbon- 13 magnetic resonance has appeared. 4 Miscellaneous Studies The theory of nuclear spin-spin coupling and the calculation of coupling constants by molecular orbital methods have been discussed. '38 Systematic analyses have been pre~ented'~' for the AA'BB' and AA'BB'MX spin systems for I = 3 nuclei and expressions obtained for the transition frequencies and intensities which have maximum accuracy consistent with practicable use. Inconsistencies in earlier treatments of the AA'BB' system have been clarified. The 'H n.m.r. spectrum of naphthalene has been completely analysed 140 as an 8-spin system ; long-range couplings exist between all inter-ring pairs of protons.Analysis of the INDOR spectra of the AMX ABX A,X and related spin systems have been given,I4' together with the illustrations of the value of the INDOR technique in structure elucidation and the detection of hidden lines in complex 'H n.m.r. spectra. A method termed the 'Dihedral Angle Estimation by the Ratio Method' has been presented'42 for assigning dihedral angles to hydrogen atoms adjacent to a 129 R. Steur J. P. C. M. Van Dongen M. J. A. De Bie W. Drenth J. W. De Haan and L. J. M. Van de Ven Tetrahedron Letters 1971 3307. I3O M. Goh Y. Sasaki and M. Suzuki Chem. and Pharm. Bull. (Japan) 1971 19 2301. I3I R. H. Martin N. Defay and D. Zimmerman Tetrahedron Letters 1971 1871. T. Pehk E. Lippmaa V. V. Sevostjanova M.M. Krayuschkin and A. J. Tarasova Org. Magn. Resonance 1971 3 783. 133 G. E. Maciel and H. C. Dorn J. Amer. Chem. Soc. 1971,93 1268. *34 J. D. Roberts M. Christl and H. J. Reich J. Arner. Chem. Soc. 1971 93 3468. 135 T. Pehk and E. Lippmaa Org. Magn. Resonance 1971 3 783. 136 G. A. Gray J. Amer. Chem. Soc. 1971 93 2132. 13' E. W. Randall Chem. in Britain 1971 7 371. 13' J. N. Murrell Progr. N. M. R. Spectroscopy 1971 6 1. 13' J. J. Batterham and R. Bramley Org. Mugn. Resonunce 1971 3 83. I4O R. W. Crecely and J. H. Goldstein Org. Magn. Resonance 1970 2 613. I4I F. W. van Deursen Org. Magn. Resonance 1971 3 221. 142 K. N. Slessor and A. S. Tracey Canad. J. Chem. 1971,49 2874. Physical Met hods-Part (ii) Nuclear Magnetic Resonance methylene group by using accurate vicinal coupling constants (J,,J2) in a modified Karplus equation J + c -k cos’$ -J2 + c k2 COS’(O -$1) where k ,k are the Karplus constants 4 ,othe angles shown in the projection (39) and c another constant.The method is based on the assumption that although the Karplus constants vary their ratio k :k remains fixed equal to 1.0 (41,$2 < 42) or 0.9 < n/2 c $2). Using the theoretical value of 0.28 H (39) for c a complete solution for 4 and $2 is possible without knowledge of k,. Application of available data from the low-temperature spectrum of octadeuterio- cyclohexane143 without prior assumption of proton identities predicted a slightly flattened chair conformation with proton assignments identical with those originally proposed and also allowed calculation of the Karplus constants.Dihedral angles computed this way appear not to be influenced by the effects of ring strain and substituent electronegativity. The conformational preferences of several four- to six-membered ring systems were investigated. Lambe~t’~~ has examined the use of the R value as a measure of distortion in six-membered rings of the types (40H43) compared with cyclohexane. The n.m.r. spectrum of a -X-CH,-CH,-Y- fragment yields two coupling constants 3Jt,,,s,defined equal to 3Ja + Jee)and 3Jcis,equal to Jae. The ratio J,,,, Jcis,known as the R value is independent of the electronegativities of the attached atoms X and Y. R Values for flattened fragments are normally less than 1.9 and for puckered fragments greater than 2.2.Appli~ation’~~ of the Karplus equation relates the R value to the internal dihedral angle $ 143 E. W. Garbisch and M. G. Griffith J. Amer. Chem. SOC.,1968 90 6543. 144 J. Lambert Accounts Chem. Res. 1971 4 87. 145 J. B. Lambert and F. R. Koeng Org. Magn. Resonance 1971 3 389. 40 I. H. Sadler A quantitative assessment has been made'46 of the severe degree of flattening in various benzo-substituted five- and six-membered ring compounds. A study 147 of some specifically deuteriated t-butylcyclohexanes shows that an equatorial t-butyl group distorts the chair conformation of the ring and the chemical shifts of the ring protons differ from those in cyclohexane. In consequence the use of a t-butyl group as a holding group in conformational analysis is not always justified and previous doubts on the validity of much published work on con- formational preferences are well founded.The validity of the approximate equations (a) k = (n/$)Av and (b) k = (n/fi)d-) for calculation of rates of exchange in dynamic n.m.r. has been examined'48 by comparison of rates with those obtained by complete lineshape analysis. Although previously criticized 149 as unreliable equation (u) normally yields reliable estimates of rates at coalescence when nuclei are not spin-coupled. Equation (b) may be used for spin-coupled nuclei (AB system) but only if the chemical shift difference (Av) exceeds the coupling constant (J). It is important however to realize that errors of 10,25 and 100 in rate constants at 300 K produce errors in AG* of only 0.06,0.1,and 0.4 kcal mol-' respectively.A linewidth method has been reported' 50 for determining chemical exchange rates between two equally populated sites. The Gutowsky-Holm equation simplified by the assumption of a large spin-spin relaxation time was used to produce a family of curves for various Av values relating the rate of exchange to the linewidth at one-half the peak height corrected for both field inhomogeneity effects and couplings. For NN-dimethylacetamide and NN-dimethylcarbamoyl chloride this method yielded activation parameters in excellent agreement with those from total lineshape analyses. Examination of structurally related amides and thioamides indicated that their rotational barriers were not greatly different.Among the vast number of kinetic studies reported are the following confor- mational mobility in 18-annulene,' 4H-1,2-diazepines,'52 and cyclodecapen- taenes ; 53 nitrogen inversion in dibenzylmethylamine' 54 and N-chlorodibenzyl- amine ;'55 a degenerate valency isomerism' 56 in 7-acetyl-3-methylanthranil involving a 1,9-shift (44); tautomeric equilibria of 1-methyl-5-methylamino- tetrazoles'57 which exist predominantly in the amino-form (45); and the hin- dered rotation of t-butyl groups in 2-benzyl-2-chloro-3,3-dimethylbutane and 146 H. R. Buys Rec. Trav. chim. 1969 88 1003. 147 J. D. Menijnse H. Van Bekkum and B. M. Wepster Rec. Trav. chim. 1971 90 779. 148 D. Kost E. H. Carlson and M.Raban Chem. Comm. 1971 657. 14') G. Binsch Topics Stereochem. 1968 3 97. I5O K. C. Ramey D. J. Louick P. W. Whitehurst W. B. Wise R. Mukherjee and R. M. Moriaty Org. Magn. Resonance 1971 3 201. 151 J. M. Gilles J. F. M. Oth F. Sondheimer and E. P. Woo J. Chern. Soc. (B),1971,2177. U. Svanholm Acta Chem. Scand. 1971 25 640. S. Masamune K. Hojo K. Hojo G. Bigam and D. L. Rabenstein J. Amer. Chenr. Soc. 197 I 93 4966. '54 M. J. S. Dewar and W. B. Jennings J. Amer. Chem. Soc. 1971 93,401. W. B. Jennings and R. Spratt Chem. Cornrn. 1971 54. 156 K. Parry and C. W. Rees Chem. Comm. 1971 833. 15' G. Bianchi A. J. Boulton I. J. Fletcher and A. R. Katritzky J. Chem. Soc. (B) 1971. 2355. Physical Methods-Part (ii) Nuclear Magnetic Resonance 2-chloro-2,3,3-trimethylbutane,' 58 and t-butyldimethylamine.' 59 Many papers have been concerned with rotation about single bonds in halogenated alkanes and conformational equilibria in dioxans and saturated nitrogen heterocycles.The 'H n.m.r. spectra of carbonium ions continue to be studied widely. Observation of the spectrum of the deuteriated bicyclo[3,l,0]hex-3-en-2-yl cation (46) reveals16' a slow sigmatropic rearrangement not observable in the Me Me I L 7 To 'd Me Me Me 40 N-N il' /r( )" '+ HN N II Me Me D (45) (46) unlabelled species. Olah and Halpern have found lei' conditions for protonation of olefins in super-acids to give carbonium ions without simultaneous polymeri- zations. Unfortunately there appears to be no single general procedure applicable to all olefins ;various procedures are described.A method has been developed' 62 for the quantitative determination of the relative stabilities of aryl carbonium ions in which the equilibrium between two carbonium ions and their covalent precursors is observed directly by 'H n.m.r. Good agreement with e.m.f. methods was obtained for rneta- and para-substituted tritylcarbonium ions. Systematic differences obtained for 9-arylxanthyl derivatives where the leaving group is varied are attributed to steric interactions in the covalent precursors. Several groups of workers '63,164 have examined Meisenheimer complexes formed by the attack of alkoxide or hydroxide ion on aromatic molecules heavily substituted with electron-wit hdra wing groups.2,4,6-Trisu bsti tu ted anisoles (47)-(49) appear'63 to give short-lived 1,3- and 1,5-complexes which rearrange to the thermodynamically more stable 1,l-complexes. The n.m.r. spectra of cumyl benzyl and a-methylbenzyl anions' 65 and of the dianions of tetraphenyl-158 J. E. Anderson and H. Pearson. J. Clwm. SOC.(B),1971 1209. 159 C. H. Bushwaller J. W. O'Neil and H. S. Bilofsky Tetrahedron 1971 27 5761. I60 P. Vogel M. Saunders N. M. Hasty and J. A. Berson J. Amer. Chem. SOC.,1971 93 1551. 161 G. A. Olah and Y. Halpern J. Org. Chem. 1971 36 2354. 162 J. V. McKinley J. W. Rakshys A. E. Young and H. H. Freedman J. Amer. Chern. SOL.. 1971 93 4715. lh3 M. R. Crampton. M. A. F1 Gharian and H. A. Khan Chem. Comm. 1971 834; F.Terrier J. C. Hallc M. P. Sirnounin and M. J. Lecourt Org. Magrz. Resonunce 1971 3. 361. I.H. Sadler OMe Me0 OMe L. "rxr"", XQm2 MeO-) x@02 OMe '..* .J \ * H Y Y Y (47) X = Y = NO (48) X = C1 CF or CN; Y = NO (49) X = NO,; Y = C1 or CO,Me ethylene'66and [12]annulene' 67 have been observed with alkali-metal counter- ions in THF. A useful modification has been described'68 for an HAlOO spectrometer to allow wide sweep ranges (up to 20 khz) to be used and homonuclear INDOR experiments to be carried out in the field-frequency locked mode. A method of correcting base-line distortion and a phase shift network are given. Modifica- tions for heteronuclear spin decoupling' 69 and homonuclear 'H-[' HI and hetero- nuclear 'H-['3C] INDOR experiments have also been described.' 70 5 Reviews and Books The following aspects of n.m.r.have been reviewed nuclear magnetic double resonance including INDOR ;' ' use of the intramolecular nuclear Overhauser effect in the assignment of organic structures studies in liquid crystals ;173 nitrogen magnetic resonance,' 74 the study of hindered rotation and inversion in and molecular relaxation mechanisms in polymers ;'76 and application to the study of polymer config~rations.'~~ Reviews have also ap- peared concerning n.m.r. studies of amides' 78 and paramagnetic complexes.' 79 Two books devoted to spectral analysis,18' and single volumes on fluorine chemical shifts' 81 and n.m.r. studies of polymers' 82 have appeared.lh4 E. J. Fendler W. Ernsberger and J. H. Fendler J. Org. Chem. 1971 36 2533. Ib5 K. Takakashi M. Takaki and R. Asami Org. Magn. Resonance 1971 3 539. K. Takakashi Y. Inoue and R. Asami Org. Magn. Resonance 1971 3 349. 16' J. F. M. 0th and G. Schroeder J. Chem. Soc. (B) 1971,904. 168 P. N. Jenkins and L. Phillips J. Phys. (E) 1971 4 530. R. Burton and L. D. Hall Canad. J. Chem. 1970,48 59. R. Burton L. D. Hall and P. R. Steiner Canad. J. Chem. 1970 48 2679. 171 W. von Philipsborn Angew. Chem. Internat. Edn. 1971 10 472. 17* G. E. Bachers and T. Schaefer Chem. Rev. 1971 71 617. 173 S. Meiboom and L. C. Snyder Accounts Chem. Res. 1971 4 81. 174 E. W. Randall and D. G. Gilles Progr. N. M. R. Spectroscopy 1971 6 119. 175 H. Kessler Angew.Chem. Internat. Edn. 1970 9 219. L76 D. M. McCall Accounts Chem. Res. 1971 4 223. 17' H. Cheradame Bull. Soc. chim. France 1971 2023. 78 W. E. Stewart and T. H. Siddall Chem. Rev. 1970 70 5 17. 179 K. Schwarzhaus Angew. Chem. Internat. Edn. 1970 9 946. R. A. Hoffman S. Forsen and B. Gestbloom 'NMR Basic Principles and Progress,' Springer-Verlag Berlin 1971 vol. 5; A. J. Abraham 'Analysis of High Resolution NMR,' Elsevier Amsterdam 1971. J. W. Emsley and L. Phillips 'Progress in N.M.R. Spectroscopy,' Pergarnon Oxford 1971 vol. 7. P. Diehl E. Fluck and R. Kosfeld 'NMR Basic Principles and Progress,' Springer- Verlag Berlin 1971 vol. 4.

ISSN:0069-3030    

DOI:10.1039/OC9716800018

出版商:RSC    

年代:1971

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 Over the past few years there has been a spectacular increase in the level of sophistication of theoretical treatments of molecules of interest to organic chemists. Unfortunately the single-quantum jump with small but finite proba- bility which was required to excite organic chemists over the inertial barrier for understanding the theoretical background to say extended Hiickel calculations has now been supplanted by a double-quantum process with an apparently vanishingly small probability when it comes to a consideration of ‘ab initio’ quantum-chemical calculations. This is clearly evidenced by considering the contents of the previous section in Annual Reports that was devoted solely to Theoretical Organic Chemistry in 1964.At that stage of development organic chemists were encouraged to study texts by Roberts’ and Streitweiser.2 Things have reached such a stage now where this Reporter would recommend every organic chemist to study the text by Richards and Hor~ley.~ The 1960’s may fairly be classified as a qualitative era in that the application of semi-empirical (EHT CNDO INDO MINDO etc.) quantum-mechanical treatments has led to a qualitative understanding of the structures bonding and reactivities of a wide variety of organic molecules. The most outstandingly successful example of this is the development of the ideas embodied in Woodward and Hoffman’s ‘principles of conservation of orbital ~ymrnetry’.~ To paraphrase (and misquote) Salem,5 ‘The start of the new decade may well mark the beginning of a new era in which the very concept of organic reactions will undergo a pro- found change.There are indications that the beautiful mechanistic schemes used by organic chemists to interpret organic reactions will shortly be supple- ’ J. D. Roberts ‘Notes on Molecular Orbital Calculations,’ W. A. Benjamin New York 1961. A. Streitweiser ‘Molecular Orbital Theory for Organic Chemistry,’ J. Wiley New York and London 196 1. W. G. Richards and J. A. Horsley ‘Ab Initio Molecular Orbital Calculations for Chemists,’ Clarendon Press Oxford 1970. R. B. Woodward and R. Hoffman ‘The Conservation of Orbital Symmetry,’ Academic Press New York 1970.L. Salem Accounts Chem. Res. 1971 4 322. 43 D.T. Clark mented and may eventually be replaced by a detailed picture of the dynamic behaviour of the reacting species on a complex potential-energy surface. Ex- tremely small but often highly instructive fragments of potential-energy surfaces for some elementary organic reactions have already been calculated by ‘ab initio’ methods. In the coming years one can confidently predict the total resolu- tion of several organic transition states and of the potential-energy surfaces surrounding them as well as preliminary calculations of the dynamical pathways on these surfaces’. The major portion of this Report details some of the important advances made in the past year or so in the application of non-empirical quantum-chemical methods to organic systems.Valuable review articles of a more qualitative nature are listed in reference 6. The remaining part of the Report considers application of the important new technique of ESCA (Electron Spectroscopy for Chemical Analysis) to structure and bonding in organic systems. (Rather more space will be devoted to ESCA in next year’s Report). 2 Theoretical Organic Chemistry Introduction.-Before discussing the developments which have taken place in 1970-71 it is perhaps worthwhile sounding a note of caution. With the ready availability of standard computer packages the application of semi-empirical MO treatments to organic systems has proliferated at an alarming rate over the past five years.It is inevitable that a certain percentage of the published work has little scientific value and this raises serious questions if this situation is maintained with respect to non-empirical program packages and large amounts of valuable computer time are thereby wasted. There is perhaps an inbuilt safety barrier in the indiscriminate application of non-empirical treatments to organic molecules in that compared with say a corresponding calculation at the CND0/2 level the computing power required is 2-3 orders of magnitude greater and therefore more difficult to come by. However it will be a pity if indiscriminate and unscientific applications sow the seeds of doubt as to the usefulness of applying the more rigorous theoretical treatments to organic systems.Since there is a real danger of lack of communication between theoreticians on the one hand and practising organic chemists on the other (which if allowed to develop would be unfortunate) it is felt to be worthwhile spending a little time outlining the background and some of the terminology involved in non-empirical quantum-chemical treatments. With very few exceptions electronic wavefunctions of molecules have been approached by the Hartree-Fock method in which the wavefunction is taken as an anti-symmetrized product (determinant) of spatial and spin functions i.e. for a closed shell the total wavefunction V is defined as in equation (1). The = A [$,(I )a(1)$,(2)8(2)‘ ’ ’ $,(2n)P(2n)l (1) molecular orbitals $i are expanded as linear combinations of a set of basis func- (a) R.Hoffmann Accounts Chem. Rrs. 1971 4 1; (b)K. Fukui ibid.,p. 57; (c) R. G. Pearson ibid. p. 152; (d)H. E. Zimmerman ibid.p. 272; (E) M. J. S. Dewar Angew. Chem. Internat. Edn. 1971 10 761. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA tions 'p as shown in equation (2). The q,,are normally centred on the atoms so the expansion of equation (2) is often described as the linear combination of atomic orbitals (LCAO) approximation. The LCAO coefficients CPi are deter- mined by the variational principle so as to minimize the total energy [equation (3)] where 2 is the many-electron Hamiltonian. Within the LCAO approxima-tions the MO's (@J can be more accurately represented the larger the basis set (q,) since this allows greater flexibility in representation.However the amount of computation that is necessary increases rapidly (by a factor of -n4) with the number of basis functions (n) so that a compromise must generally be struck between accuracy and the sheer physical possibility (in terms of computer power time and money available) of carrying out the calculation with a very large basis set. Molecular orbital theory is simplest to apply and interpret if the basis set is minimal that is it consists of the least number of atomic orbitals (of appropriate symmetry) for the atomic ground-state. Thus for typical organic molecules a minimal basis set consists of a 1s orbital for hydrogen Is 2s 2px 2p, 2p for carbon nitrogen etc.and Is 2s 2px 2py 2p, 3s 3px 3py 3p for phosphorus sulphur etc. If a larger number of basis functions than the minimal is used the basis set is usually described as extended. Once the LCAO MO's are determined the charge density can be analysed in terms of the basis functions 'p,. If there are two electrons per molecular orbital the total charge density is p as defined in equation (4),where P,, is the occ density matrix defined by P," = 2 1CPiCvi.This matrix contains detailed 1 information about the electronic charge distribution. The diagonal element P, is the coefficient of the distribution q,' and measures the electron population for this orbital. The off-diagonal elements PPyare overlap populations related to the charge density associated with the overlap q,q,.Since organic chemists like to be able to talk in terms of a charge distribution in a molecule (i.e. to assign a specific charge to each atom in a molecule) use is often made of a Mulliken population analysis. The gross population for an orbital q is then defined as qr(,as shown in equation (5),where S, is an overlap integral and the net charge A charge = ZA-cqp P assigned to atom A is given by equation (5a) where Z is the atomic number and the sum is over atomic orbitals on atom A. It should be emphasized however D.T. Clark that ascribing the electron population to a given atom just because an orbital is centred on that atom is a simplification especially if the orbital concerned is diffuse and there is also the rather arbitrary way in which the overlap populations are divided between atoms.A Mulliken population analysis should therefore only be regarded as giving a crude idea of the electron distribution in a molecule and the absolute values of 'charges' at atoms that may be calculated in this way depend quite markedly on the basis set used. However despite its limitations a population analysis is conceptually close to qualitative organic ideas about charge distribution in molecules. A much clearer picture of the overall electron distribution in a molecule is obtained from plotting density contour maps. The total electron density p(F),at a point r" is given by equation (6) where Cijis the molecular orbital coefficient (normalized to the proper electron occupancy) ij for the i'th molecular orbital and the j'th normalized orbital qj.Contour maps linking points of equal densities may then be plotted and are not so critically dependent on minor changes in the basis set. Of particular value in illuminating features of chemical bonding is the 6 function 6(F) = p&) -pA(F) which represents the difference between the total molecular electron density p&) and the sum of the juxtaposed atomic densities at r" pA(7). The general problem of finding LCAO coefficients Cpi by the variational method was solved by Roothaan who derived equation (7) where the E~ are one-electron energies and Fp is the Fock matrix defined in equation (8). Here H, is the matrix of the one-electron Hamiltonian for motion in the field of bare nuclei and (pvIAo)is the two-electron integral [see equation (9)J Since the density matrix P, depends on the MO coefficients Cpi,the family of equations (7) are not linear and have to be solved by an iterative procedure ; they are therefore described as self-consistent-field (LCAO MO SCF)equations.The most difficult part of LCAO MO SCF theory is the evaluation of the large number of two-electron integrals. To take a simple example in a minimal- basis-set calculation on benzene there are 222 l l l two-electron integrals to be computed. The simplest type of atomic orbital to use in a minimal basis set involves Slater-type orbitals (STO) of the form shown in the expression (lo) %l(& CPY -exp ( -ir) (10) where Y,,JB q) is a spherical harmonic describing the angular dependence and in the radial portion n is the principal quantum number and ( is a scale factor Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA which determines the size of the orbital.(An extended basis set in which each atomic orbital is represented by two STO’s is called a double-zeta basis-set). However for polyatomic molecules the evaluation of the three- and four-centre two-electron repulsion integrals (pvJh)is exceptionally difficult and time-consuming and hence comparatively few systems of interest to organic chemists have been investigated using a basis set of STO’s. The spectacular growth of non-empirical treatments of organic molecules stems from the use7 of gaussian- type functions [exp ( -crr2)]to represent the radial part of a given basis function rather than a simple exponential as for a STO.The attractive aspect of employing gaussian-type orbitals (GTO) is that the product of two GTO’s is another GTO and hence the three- and four-centre integrals can be readily computed. The computational simplicity accruing from using a gaussian basis set is offset to a certain degree by the fact that for a Is orbital for example a single GTO has an incorrect radial dependence in the vicinity of the nucleus as compared with a single STO. A linear combination of several GTO’s having different values of the exponent (a) is therefore required to compensate for this and hence for calculations of comparable quality many more integrals need to be computed for a GTO basis set than for a STO basis set.Nonetheless at the present time the much faster evaluation of integrals more than offsets this so that nearly all calculations on molecules of interest to organic chemists have been carried out with GTO basis sets. The assessment of the proper angular dependence for these gaussians has proceeded along two lines. The first involves multiplication of the radial term by the appropriate spherical harmonic XJO cp) in direct analogy to the construction of STO’s and these are called Cartesian gaussian basis sets. Secondly Preusss has proposed that the desired angular characteristics can also be obtained by taking a linear combination of simple gaussians rather than multiplying by the spherical harmonics. These sums of gaussians are referred to as lobe functions.For example a p-type gaussian lobe function can be ex-pressed as in equation (I l) where 7 is a unit vector and R is a constant defining gLp(jj) = Nt,{exp [-a(r -R0J)’] -exp [ -a(r + R07)’]) (1 1) the distance from the origin (usually but not necessarily a nuclear co-ordinate) of the centre for the two simple gaussians. The apparent disadvantage of using gaussian lobe functions is the extra constants (R,); however it can be shown that if R is set equal to Ca-* where a is the gaussian exponent and C is a constant (C -0.03) then for a given set of gaussian functions using the same exponents the results are closely similar whether Cartesian or lobe basis sets are employed.’ Mention should also be made of a further type of gaussian basis set which is giving very promising results for quite large molecules using Floating Spherical Gaussian Orbitals (FSGO).With few exceptions calculations involving car- tesian- and lobe-type GTO’s as basis sets have centred these functions on the ’ S. F. Boys Proc. Roy. Sac. 1950 A200 542. H. Preuss 2.Naturforsch. 1956 lla 823; Internat. J. Quantum Chem. 1968 2 651. S. Shih R. J. Buenker S. D. Peyerimhoff and B. Wirsam Theor. Chirn. Acta 1970 18 277. D.T. Clark atoms in a molecule and the results are therefore readily interpreted in terms with which organic chemists are already familiar. This does not apply with FSGO's defined in equation (12) where pi is the radius of orbital i and Riis its position.cp = N exp [-(I. -R,)Z/p,Zl (12) For a given basis set the energy of a molecule is then minimized with respect to the positions of the gaussian orbitals and their radii. The great virtue of the FSGO approach is its computational simplicity but the results are not directly related to an organic chemist's qualitative ideas concerning bonding. The number of integrals which have to be stored particularly when using a basis set of GTO's (in which all coefficients are settled variationally) ensures that for large molecules the storage problems rapidly become insuperable The number of stored integrals can be considerably reduced by taking appropriate linear combinations of GTO's (with coefficients fixed) and such a basis set is then referred to as a contracted gaussian basis set (CGTO)." A particular variant of this treatment is to expand a basis set of STO's in terms of linear combinations of nGTO's the coefficients and exponents being determined by some least-squares fit criterion.Such a basis is known as an STOnG set.' The objectives of non-empirical quantum-chemical investigation of organic systems can be classified roughly as follows (i) For known species to give fundamental insights into their electronic struc- ture and to allow fuller interpretation of relevant experimental data. (ii) Prediction of electronic properties and hence of the chemistry of species which are at present unknown or have not been isolated. (iii) Elucidation of the details of the processes occurring during chemical reac- tions by computing potential-energy surfaces.In this ambition theoretical chemists have a distinct advantage over their experimental brethren in that they can choose the nuclear configuration and reaction paths and can examine in detail the changes in bonding for each likely course of a reaction. For the experimentalist a direct observation of a transition state in a reaction is in principle impossible since by definition this represents the point of highest energy on the lowest free-energy path from reactants to product. A theoretical limitation is that as previously pointed out nearly all non- empirical calculations on organic systems have been made within the Hartree- Fock (HF) one-electron model which neglects correlation and relativistic effects (for most molecules of interest to organic chemists relativistic effects are unimportant).Although the Hartree-Fock method takes adequate account of the average interaction between an electron and all the other electrons in a molecule it does not take account of the instantaneous correlation of electronic motions. For a two-electron atom for example (both electrons described by the same spatial wavefunction with different spin parts) the HF method would I" E. Clementi Spec. IBM Tech. Report IBM Research Lab. San Jose California 1965. W. J. Hehre K. F. Stewart and J. A. Pople J. Chern. Ph?js. 1969 51 2657. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA not accommodate the fact that at any instant ifone electron had a high probability of being on one side of the nucleus then the other electron would have a high probability of being on the opposite side; and if one was close in to the nucleus the other would be further away.As a result the main deficiency of the HF method is its inability to properly describe the processes of stretching and break- ing a bond. It is important to grasp this point since this is the single most important error that is likely to arise from the indiscriminate use of program packages without understanding the underlying theory. This failure of HF theory is best illustrated by a simple example the H2 molecule. Expansion of the h v, w w -.go a -1.20 t 1 1 I 1 I I 1 0.0 1.0 2.0 3.0 4.0 5.0 R (a.u.) Figure 1 The energy of H as obtained from Hartree-Fock calculations compared with the exact non-relativistic energies single-determinantal wavefunction corresponding to the ground state for H2 shows that at large internuclear distances instead of arriving at a dissociation limit 2H' the HF wavefunction behaves incorrectly.This arises from spurious ionic terms. By definition the correlation energy is given as the difference between the Hartree-Fock energy and the exact non-relativistic energy. From Figure 1 it is clear that since the HF energy curve and the exact energy curve are parallel to one another up to -2.5 a.u. a distance corresponding to ca. twice the H-H bond length the correlation energy remains fairly constant in this region. At large internuclear distances the correlation energy increases rather rapidly and it is in this region that the HF method goes seriously astray.The lesson to be learnt from this is that bond stretching up to a certain point will be adequately treated by HF theory i.e. we will be some way from the exact solution but parallel to it.* In the extreme case of atomization of a molecule the correlation errors * It should be emphasized however that in general one of the most readily calculable properties of a molecule even with a poor basis set is its geometry (cf ref. 12). l2 L. Radom W. A. Lathan W. J. Hehre and J. A. Pople J. Arner. Chem. SOC. 1971,93 5339. D. T. Clark will mount up and hence heats of atomization are poorly described by HF calculations ;however this is not quite so serious a deficiency as it sounds.To sum up calculations within the Hartree-Fock one-electron model are likely to be adequate for attaining objectives (i) and (ii) at least for closed-shell species and in certain cases also objective (iii). However in a large number of situations arising in studying potential-energy surfaces the HF model will be inadequate and the more complicated (and computationally more expensive) multi-configuration SCF (MC SCF) theory will be required. One outstanding application has already been published and is discussed below. The published work discussed in this Report can be classified roughly into the three categories set out as the objective of non-empirical quantum-chemical treatments although inevitably there is a certain amount of overlap between these broad classifications.Barriers to Rotation.-Neutral Molecules. An important application in which theory can provide insight not readily available experimentally is in studying barriers to rotation. Internal rotation in ethane has been extensively studiedI3 and the following points of interest emerge. A minimum-basis-set STO calcula- tion in which electron correlation has been partly taken into account by a second-order perturbation treatment has shown that the barrier to rotation is decreased by only 0.13 kcal mol- by correlation effects.14 This important result confirms that barriers to rotation in simple molecules can be understood within the Hartree-Fock method and that correlation effects are unimportant. (It is worth noting that an extended STO basis-set calculation on the barrier to inversion in NH3 has also shown that correlation effects are negligible for this type of process).’ It is interesting to note that the experimental barrier to rotation in ethane (2.93kcal mol- ’) is satisfactorily reproduced even by calculations using a limited basis set (cf.Table l) the exception being the FSGO basis-set calculations which might more properly be described as ‘sub’-minimal. It is salutary to recognize the fact that the calculated barriers to rotation are minute fractions of the total energies (-1/20 000th) and their measurement can be compared to the feat of weighing a captain by noting the displacement of his ship when he is or is not on board. A slight increase in C-C bond length is predicted in going from the staggered to the eclipsed conformation.Interesting insights into the factors determining the barrier height may be obtained from detailed analysis of the wavefunction in terms of attractive and repulsive energy components. To provide a physical and mathematical basis for understanding the barrier origin Allen” has proposed that the total energy and Vrepulsive, be divided into two components Vattractive where V, = V, (potential energy due to nuclear electron attraction) and Vrep= V, + V, + T (V, is the potential energy due to electron-electron repulsion V, is the potential energy due to nuclear-nuclear repulsion and T is the electronic kinetic energy). Table 2 l3 E. Clementi and W. von Niessen J. Chem.Phys. 1971 54 521 and references therein l4 B. Levy and M. C. Morreau J. Chem. Phys. 1971 54 3316. ’‘ R. M. Stevens J. Chem. Phys. 1971 55 1725. L. C. Allen Chem. Phys. Letters 1968 2 597. Table 1 Non-empirical barriers to rotation Neutral Species Calculated barrier Total energy1a.u. Comments Basis set Ref kcal mol- ' for staggered conformer Ethane 3.32 rigid rotation assumed 16 STo 4G 3.33 -78.862315 potential constants evaluated STO 3G* } 2.90 -78.30618 staggered D,,;rc-c I ,538A STO3G ' n rC-H 1.086 A HCH 108.2" [Experimental values rc-c 1.531 A rC-H 1.096 A n HCH 107.8"] > 17 Eclipsed D, ;rc-c I .548 A n rC-H 1.086A HCH 107.8" 2.80 -79.1 1582 Staggered D,,% 1.529 A STO 431G rCVH1.083A HCH 107.7' 1 0 Eclipsed ;as for STO 3G G 2.58 -78.9781 10 Rigid rotation.Analyses C 10s 6p H 4s GTO 3 barrier in terms of attractive C GTO**(2s 2p 2s) 18 R' and repulsive terms. Comparison with ethyl fluoride i 5.17 -67.347295 Rigid rotation. Expt. geometry Minimal FSGO } 19 also calc. rc-c 1.397 A 3.14 -79.203142 Rigid rotation. Experimental C 9s 5p H 4s GTO } 13 geom. 3.65 -79.23770 Staggered D3d; rc-c 1.551A C 11s 7p H 6s GTO EH 107.3' S 3p 3s C GTO 20 Eclipsed D, ;rc-c I .570 A augmented by 3d, ,3d,, and eH 107.0" 2p polarization function CH3CHO ul c Exptl. 1.16 kcal; most 1.09kcal -152.85495 using exptl. geom. rigid 50s 45p GTO 24 stable conformer H rotation C GTO (4s 6p,2s) eclipsing oxygen Neutral Species Calculated barrier Total energy1a.u.Comments kcal mol- for staggered conformer Me H \/ H'/c=c\ H Exptl. 1.98 kcal; most 1.25 kcal -116.92656 using exptl. geom. rigid stable conformer H rotation eclipsing C=C 1.418 -115.656681standard model geom. rigid rotation 1.547 -115.657787 partially flexible 1.491 -116.488399) CCC optimized Me F \I c=c H / \ H cis-fluoropropene Exptl. 1.07 kcal mol-' ; 1.07 -215.71120 Exptl. geometry most stable conformer H eclipsing C=C Me H \/ H /c=c\ F trans-fluoropropene Exptl. 2.20 kcal mol- ; 1.34 -21 5.70738 Exptl. geometry most stable conformer H eclipsing C=C Basis set Ref g C 10s 5p H 5s GTO C }26 C GTO (3,1,l) STO 3G STO 3G 16 STO 3G C F 10s 5p H 5s GTO C F C GTO (3,1,1) ? Y C F 10s 5p H 5s GTO C F } 26 2 C GTO (3,1,1) s.Me-CEC-Me -153.036672 Exptl. geometry STO 3G Exptl. 30 cal mol- ' -154.140064 rigid rotation STO 4c) Exptl. geometry CH rCH2 -rigid rotation Exptl. cis-trans energy cis-trans energy diff. STO 3G diff. 2.3 kcal mol-'; 2.92 kcal mol -'; trans-cis barrier trans-cis barrier 5.0 kcal mol -' 6.61 kcal mol- '; partially flexible rotation cis-trans energy diff. -. h -. 2.05 &a1 mol -'; C. W trans-cis barrier 6.73 kcal mol- ' Ethylene 138.6 -77.07121 Exptl. geometry rigid rotation STO 3G Exptl. 65 kcal mol-' Allene 91.9 -114.41941 Exptl. geometry rigid rotation STO 3G 16 0 Butatriene 73.9 -151.77131 Exptl. geometry rigid rotation STO 3G 16 42 -.l6 L. Radom and J. A. Pople J. Amer. Chem. Soc. 1970,92 4786. W. A. Latham W. J. Hehre and J. A. Pople J. Amer. Chem. Soc. 1971 93 808. L. C. Allen and H. Basch J. Amer. Chem. Soc. 1971 93 6373. l9 R. E. Christoffersen D. W. Genson and G. M. Maggiova J. Chem. Phys. 1971,54 239. '' A. Veillard Theor-. C'him. Acta 1970 18 21. * STO nG least-squares expansion of STO basis set in terms of nGTO per STO. CJ ref. 11. ** C GTO (2s 2p 2s) contracted gaussian basis set consisting of 2s,2p functions for C 2s for H. ul P Table 2 Energy c0mponentsla.u. .for ethane and ethylfluoride ET Vne = Vat Ke V"n T GJ-staggered -177.94095 -579.27127 144.1 5666 78.86430 178.30936 40 1.33037 C2H5F {eclipsed -177.93682 -579.36739 144.20185 78.89841 178.33030 40 1.43057 staggered -79.14755 -267.25143 67.19480 41.93098 78.97811 188.10388 C2H6 {eclipsed -79.14344 -267.28342 67.20999 41.93845 78.99155 188.13999 Energy component difSerences AET A Vrep A Vatt C,H,F 0.0041275 0.1002455 0.0961151 DifSerenceJkcalmol 2.59 C2H6 0.0041 113 0.036 1037 0.0319939 DifSerencelkcal mol -' 2.58 Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA shows the energy components obtained for ethane and for comparison those for ethyl fluoride obtained with a comparable basis set.' The energy component dif-ferences (eclipsed-staggered) are also shown in Table 2.Figure 2 shows the opposing phase relationships between the attractive and repulsive components and this is a characteristic feature of every barrier (rotation inversion etc.) in every molecule.For both molecules AV,, >AVatt,and the barriers are therefore denoted as repulsive-dominated. From Table 2 and Figure 2 it is clear that the absolute magnitudes of the energy component differences are larger for ethyl fluoride than for ethane although the calculated barriers are almost identical. It is almost as if an extra potential-energy term is being added (approximately equally) to Val and Vrep in going from ethane to ethyl fluoride. This can be attributed to the difference in effective potential between the fluorine and hydrogen atoms. Since the radius of the fluorine atom is close to that of hydrogen we are simply seeing the effect of lowering the potential well around one of the rotating atoms due to the high charge density of fluorine....... C,H,F --C,H .lo.\ .oa !?' .06-.. ;: ?#i " !i ..... 0" 60" (eclipsed) (staggered) Figure 2 V,, and Vrep energy components for ethyf JIuoride ( ...) and ethane (-) (Reproducedby permission from J. Amer. Chem. Soc. 1971 93 6373) In an attempt to shed insight of a kind closer to the traditional viewpoint of organic chemists Clementi and Von Niessen13 have decomposed the ethane total energy as a function of rotational angle into one- two- three- and four-centre contributions. The three-centre term undergoes the greatest change of magnitude but the direction of its change is opposite to that of the barrier 56 D. T. Clark itself and it therefore appears that the bond-energy analysis scheme22 provides no simple physical or chemical concept for understanding the barrier.As an example of a different type of barrier Allen and co-w~rkers~~ have shown that in acetaldehyde the barrier is attractive-dominated (Figure 3) and therefore provides a useful counterpart to the repulsive-dominated ethane barrier. 498.27000 1 345.43000 498.27500 345.42500 498.28000 345.4200 -J 3 a W 498.28500 a H ECLIPSItIG 0 H ECLIPSING H Figure 3 Energy and energy components vs. torsional angle for acetaldehyde (Reproduced by permission from J. Chem. Phys. 1971,54 2828) With this in mind Allen and J~rgensen~~ have carried out a charge-density analysis of the rotational barriers for both molecules.This analysis provides an enlightening physical understanding of the origin of the two types of barrier. Considering ethane it is clear even from the results of a Mulliken population analysis that the origin of the repulsive-dominated barrier is likely to be under- standable in terms of the change in electron distribution as a function of rotation. It is convenient to define a 6 function 6(F) that is applicable to rotational barriers. Such a function [equation (13)]yields the difference between the electron density for the less-stable conformer pLs(F) and that for the equilibrium conformer pE(F)at r in terms of the rotational barrier. By convention in plotting such a function a solid contour indicates an increase in electron density and a dashed contour indicates a decrease in electron density.Solid letters correspond to the location of atomic nuclei and dashed letters represent projections of nuclei onto the plane of the plot. (1 a.u. of density = le u0-3= 6.74873 A-3). Analyses of charge-density difference maps for barriers to rotation are com- plicated by the fact that there are two sources contributing to the difference. First there are substantial changes due to the different location of atomic orbitals in the two conformers. This is not of particular relevance and it is the second source due to the difference in actual molecular orbital coefficients which is 22 CJ B. Nelander J. Chem. Phys. 1971 54 2949. 23 R. B. Davidson and L. C. Allen J. Chem. Phys. 1971 54 2828.24 W. L. Jorgensen and L. C. Allen J. Amer. Chem. SOC.,1971 93 567. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA responsible for the more subtle distortions associated with the nature of the barrier. This is a point which had not been fully appreciated by previous workers. It is possible to circumvent this by selecting planes perpendicular to the C-C axis that are far enough from the rotated atoms that the change in the location of their atomic orbitals does not obscure the charge distortions caused by the difference in the MO coefficients. For example Figure 4 shows the difference Figure 4 Difference plot of the eclipsed ethane electron density minus the staggered ethane electron density 0.5 a.u. behind the plane of the stationary methyl hydrogens.Contour 1 is at +0.00002 a.u. and the contour interval is +0.00002 a.u. (Reproduced by permission from J. Amer. Chem. Soc. 1971 93 567.) plot for eclipsed minus staggered ethane in the plane positioned 0.5 a.u. behind the hydrogen in the stationary methyl group (the xy plane at z = -1.2). This clearly shows that there is more charge behind the stationary hydrogen atoms in eclipsed ethane than in staggered. This results from the increase in repulsion between the eclipsing hydrogen atoms an increase which forces charge behind them. The increased repulsion is confirmed by the H(l)-H(4) overlap population (Table 3). A decrease in electron density behind the carbon atom in the stationary methyl group is also observed. This decrease is consistent with the fact that the C-C bond in the eclipsed ethane is slightly weaker than that in staggered ethane [C-C bond length slightly greater C(1)-C(2) bond overlap population slightly smaller].The interaction between the methyl groups in rotating from their position in staggered to that in eclipsed ethane follows the same pattern of charge decrease between the centres of repulsion and charge increase behind them as is observed in the interaction between two helium atoms (Figure 5). D. T. CIark Table 3 Mulliken overlap populations for ethane Staggered ethane Eclipsed ethane Atom 1 Atom 2 P12 (staggered) p1 (eclipsed) C1 c2 0.49281 0.48096 c Hl 0.76877 0.76998 Cl H -0.04931 -0.04940 Hl H4 -0.00174 -0.00587 HI H6 0.00105 0.00085 Hl H2 -0.01364 -0.01355 Atomic charges from population analysis for ethane Atom Staggered Eclipsed C 6.81657 6.817 19 H 0.72784 0.72761 For acetaldehyde since the barrier is attractive-dominated the electron-density distributions should reflect a loss of attraction in rotating from the H-eclipsing0 to the less stable configuration.This is nicely illustrated by a consideration of the difference of the H-eclipsing-H minus the H-eclipsing-0 electron density in the plane of the C-C-0 fragment (Figure 6). It is clear that virtually no change in the electron density near the aldehyde hydrogen is caused by the rotation (i.e. interactions between methyl group and aldehyde hydrogen do not significantly contribute to the barrier).The plot reveals a large charge build-up in the region around the oxygen atom and between the C=O double bond and its eclipsing methyl C-H bond in the more stable H-eclipsing-0 conformer. In the ethane case the opposite effect was observed i.e. there was a charge loss between the C-H bonds when they became eclipsed. The charge increases between the eclipsing bonds and around the oxygen are therefore the charge distortions responsible for the attractive- dominant nature of the rotational barrier. It is the loss of this highly favourable interaction between the methyl group and the oxygen in the H-eclipsing-0 conformer that causes the increase in V, which occurs when the methyl group is rotated to the higher-energy configuration. The large charge build-up around oxygen results from its high electronegativity which draws electron density from the methyl hydrogens.This is supported by the population analysis in Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 5 Figure 5 Diflerence plot of the helium dimer electron density minus the sum of the electron I densities of two helium atoms at an internuclear separation of 2.0 a.u. Contour 1 is at f0.002 a.u. and the contour interval is 0.004 a.u. (Reproduced by permission from J. Amer. Chem. SOC.,1971 93 567) H Figure 6 Diflerence plot of the H-eclipsing-H acetaldehyde minus the H-eclipsing-0 acetaldehyde electron density in the plane of the CCC fragment the yz plane being at x = 0. Contours are 1 = kO.001 2 = k0.004,3 = k0.007 4 = kO.01 5 = k0.05 6 = f0.15 7 = f0.25 a.u.(Reproduced by permission from J. Amer. Chem. SOC. 1971 93 567) 60 D. T. Clark which there are positive overlap populations between the oxygen and all of the methyl hydrogens for the more stable conformer whereas in the H-eclipsing-H conformer the oxygen has a positive bond overlap population only with the most distant methyl hydrogen (Table 4). A part of the charge increase between the C-0 bond and its eclipsing C-H bond is due to the change in location of the methyl hydrogen orbitals but even allowing for this the conclusions remain the same. It is evident in studying the calculated barriers to rotation in ethane that with the exception of the FSGO basis set the results are not particularly sensitive Table 4 Mulliken overlap populations for acetaldehyde H-eclipsing-0 xk H-eclipsing-H p,,(H-eclipsing-0) 0.46322 -0.15938 0.75861 0.74345 0.74345 -0.15743 1.12466 -0.07350 -0.05209 -0.05209 0.78107 0.00783 0.00155 0.00155 -0.13351 -0.03576 0.03576 0.00382 -0.04067 0.00228 0.00228 Atomic charges from population analysis for acetaldehyde Atom H-eclipsing-0 Cl 6.58751 c2 5.78991 0 8.35078 HI 0.78728 H2 0.80796 H3 0.80796 H4 0.86860 p12 (H-eclipsing-H) 0.41908 -0.13911 0.76302 0.73026 0.76302 -0.16309 1.09329 -0.060 19 -0.04986 -0.06019 0.81203 -0.00164 -0.00164 0.00408 -0.12952 -0.04148 -0.026 17 0.00298 -0.04 148 0.0041 8 0.00298 H -eclipsing-H 6.58941 5.80340 8.35049 0.78758 0.81937 0.78758 0.86217 Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 61 to the basis set employed.Thus the computed barrier with Pople's limited STO 3G basis set is comparable with that from Veillards' extended-basis-set calcula- tion which approaches the Hartree-Fock limit. This is an important result because the STO 3G basis set is sufficiently small to allow much larger organic systems to be studied. In an extensive series of papers Pople and co-~orkers~~ have studied a wide variety of molecules and ions of interest to organic chemists and this work overall represents the single most important contribution to theoretical organic chemistry.The great wealth of information derived from non-empirical calculations may be illustrated by selection of a few examples. For propene the calculated barriers to rotation are in good agreement with experiment. Allen and Scarzafava26 have also investigated the effect of replacing H by F in the double bond and they have successfully reproduced the anoma- lously low barrier to rotation in cis-fluoropropene. This represents one example of a phenomenon which is becoming clearer with the advent of more rigorous theoretical treatments of the quite drastic effects on barriers to rotation of relatively remote substituents ((5section on carbonium ions p. 62). Component energy analysis reveals that the barrier for cis-fluoropropene is attractive- dominated whereas those for propene and trans-fluoropropene are repulsive- dominated.In but-2-yne the two methyl groups are separated by an acetylenic linkage and the interaction between them is extremely small (calculated barrier 5-4 cal mol-I); even so the staggered conformation is predicted to be the most stable." A detailed study of rotation about the central C-C bond in buta-1,3- diene shows the importance of geometry optimization where steric interactions are large. Both the cis-trans energy difference and the barrier to rotation are well accounted for on the basis of a flexible- as opposed to a rigid-rotor model.I6 Barriers to rotation about double bonds have been investigated for ethylene allene and butatriene.I6 The accurate representation of barriers to rotation in these cases is not possible within the Hartree-Fock method since correlation effects are important.(This can be thought of nai'vely as a special case of breaking a bond and the single-determinantal wavefunction again contains spurious ionic terms). The calculated barriers are therefore too large; however the trends should be correctly predicted i.e. the barriers decrease along the cumulene series. For small angles of twist the single-determinantal wavefunction provides an adequate description and this can be seen from the calculated force-constants and hence twisting wavenumbers. The values of 1237cm-' and 1022cm-' obtained for ethylene and allene can be compared with the experimental values of 1027 cm-' and 812 cm- respectively so that both are rather too high but in the correct order.The discussion so far has centred on barriers to rotation which can be com- pared directly with those determined by experiment. In the case of reactive intermediates such as free radicals or carbonium ions experimental data are 25 W. A. Latham W. J. Hehre R. F. Curtiss and J. A. Pople J. Amer. Chem. SOC.,1971 93 6377 and references therein. 26 E. Scarzafava and L. C. Allen J. Amer. Chem. SOC.,1971 93 3 11. 62 D.T. Clark more often than not lacking so that theoretical studies can provide especially valuable insight in these situations. Free Radicals. It is interesting to compare the calculated barriers to rotation for ethyl and acetyl radicals with those for ethane and acetaldehyde respectively.Ethyl radical is predi~ted'~ to have a staggered configuration with a barrier to rotation of 0.46 kcal mol-' (STO 3G) or 0.62 kcal mol-' (STO 4.31G) which as expected is much smaller than that for ethane. Correspondingly since the attractive barrier in acetaldehyde is dominated by the favourable interaction between oxygen and the eclipsing hydrogen atom removal of the aldehydic hydrogen only lowers the barriers slightly (calculated 0.38 kcal mol- ') and the most stable conformer is the eclipsed.27 (Unrestricted Hartree-Fock calculations on acetyl radicals also give a good account of the hyperfine splitting constant^).^' Carboniurn Ions. Barriers to rotation in a number of carbonium ions have been investigated with interesting results (Table 5).Clearly the traditional viewpoint of organic chemists that in simple alkyl carbonium ions there is essentially free rotation is not entirely correct. Without discussing all of these results in detail a few features are worth commenting on. The fluoroethyl cation is isoelectronic with acetaldehyde and in fact the barriers to rotation are very similar. Both t-and 2-fluoroethyl cations have been shown to possess attractive-dominated barriers whereas 2-chloroethyl cation has a repulsive-dominated barrier. A re-markable feature is the long-range effects of substituents in the substituted propyl cations. These results can be rationalized in terms of preferential stabiliza- tion of the perpendicular staggered conformations through interaction of the CH2X group with the 2p(C+)orbital leading to its increased p~pulation.~' Barriers to Inversion.-Barriers to inversion have been calculated for several species of interest to organic chemist^,^ 1-33 and provide data which are difficult to obtain experimentally (Table 6).Comparison of the corresponding iso- electronic nitrogen and carbanionic species shows that in general barriers to inversion increase in going from the former to the latter when the inversion centre is part of a ring.* A notable exception included for comparison arises for cyclo- propenyl anion and the elusive 2H-azirine both of which are formally classified as being anti-aromatic. The calculated barrier to inversion for vinyl radical is quite small compared with that for vinyl anion which can therefore be regarded as being stereochemically rigid.The high barrier to inversion in vinyl anion raises the possibility that rotation about the double bond might be a competitive process as shown in Scheme 1. In an elegant study Lehn and co-workers have investigated these possibilities for the isoelectronic sequence X = Ot N and C-(R' = R2 = R3 = H). The '' A. Veillard and B. Rees Chem. Phys. Letters 1971. 8. 267. 31 D. T. Clark 2nd International Jerusalem Symposium on Quantum Chemistry and Biochemistry Israel Academy of Sciences and Humanities 1970 p. 238. 32 J. M. Lehn B. Munsch and Ph. Millie Theor. Chim. Acta 1970 16 351. " A. Veillard and B. Reed Theor. Chim. Acta 1971 8 267. * In this respect a double bond behaves as a two-membered ring.Table 5 Barriers to rotation in substituted ethyl cations s s X Calculated Most stable Comments Basis set Ref. $-barrierslkcal mol-conformer I 'a XCH,CH,+ H 0.0 -Rigid rotation C 7s 3p H 3s GTO 28 P h 0.0 -Rigid rotation STO 3G 17 e 0.22 -Flexible rotation STO 3G -. W F 10.53 Eclipsed Rigid rotation C 7s 3p H 3s GTO 29 C GTO (3 1 1) } 3 c1 1.40 Staggered Rigid rotation STO 3G 28 8 CH3 2.52 Staggered Rigid rotation STO 3G s. CH2CH3 3.73 Staggered Rigid rotation STO 3G 5 CH,F 2.1 1 Staggered Rigid rotation STO 3G 0 CH20H 0.91 Staggered Rigid rotation STO 3G 30 6;; CH2CN 0.87 Staggered Rigid rotation STO 3G 3 17.54 Staggered Rigid rotation STO 3G 5' (bisected) CH3-CHF+ 0.62 Eclipsed C 7s 3p H 3s GTO C GTO (3 1 1) 28 D.T. Clark XXIIIrd International Congress of Pure and Applied Chemistry Butterworths London 1971 vol. 1 p. 31. 29 D. T. Clark and D. M. J. Lilley Ch5m. Comm. 1970 603. 30 L. Radom J. A. Pople V. Buss and P. von R. Schleyer J. Amer. Chem. SOC.,1970 92 6987. 64 D. T.Clark Table 6 Calculated barriers to inversion Calculated Barriers to Basis set Ref Molecule barrier/ rotation1 kcal mol-' kcal mol -' 'r 20.85 -C 5s 2p H 2s GTO C 5s 2p H 2s GTO > 31 52.0 __ C 5s 2p H 2s GTO 35.14 -C 5s 2p H 2s GTO 2 H 17.2 31.4 C 0 10s 6p H 5s GTO \ /H CGTO (5 3,3) /=O+ H H 27.9 57.5 C 0 10s 6p H 5s GTO 32 \ /H CGTO(5,3,3) /c=N3 H C 0 10s6p H 5s GTO CGTO(5,3,3) C 0 10s 6p H 5s GTO 33 CGTO(5,5,3) CH3\ 29.0 C 0 10s 6p H 5s GTO 33 CGTO(4s,2p,2) oC=O Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA R’ R3 \/ c-x 4 R2 R3 =H Rotation Scheme 1 barriers to both the inversion and rotation increase in the same order and the sequence of inversion barriers may be rationalized in terms of a balance of attractive and repulsive terms.The calculations clearly demonstrate that in- version in these species is energetically much more favourable than rotation. Electronic Structures of Molecules Radicals and Ions.-A considerable amount of literature already exists concerning non-empirical wavefunctions for molecules of interest to organic chemists and it has been comprehensively covered by Richards et al.in 1970.34 In an extensive series of investigations Pople and co-workers have studied a large number of molecules and acquired some interest- ing data.25 A few of the more important papers are discussed in detail below. Substituent EfSects. The physical organic chemist’s views concerning the elec- tronic effects of substituents attached to both saturated and unsaturated centres derive largely from measurements of acidities basicities and substitution rates (electrophilic nucleophilic and free-radical). The feature common to all of these measurements is that they invariably refer to the liquid phase and yet in deriving magnitudes and signs of substituent effects scant attention has been paid to the role of the solvent. With an ‘ab initio’ treatment one might reasonably expect to predict what would happen in the gas phase to isolated molecules and knowing this it should then be possible to say what can and cannot be ascribed to solvent effects in such systems.Detailed non-empirical calculations are therefore likely to provide by default important information on the role of the solvent. It is becoming increasingly evident that the traditional (simplistic) view of substituent effects currently held by a majority of organic chemists will have to be drastically 34 W. G. Richards T. E. H. Walker and R. K. Hinkley ‘Bibliography of Ab lnitio Molec-ular Wave Functions,’ Clarendon Press Oxford 1970. 66 D.T. Clark modified in the next few years. We mention here one particularly striking example concerning the electronic properties of the methyl group.The tradi- tional views concerning (a)the acidities of simple alcohols MeOH > EtOH > Pr'OH > Bu'OH and (b)the basicities of simple amines Me,N > MeNH > NH ,has led to the postulate that methyl is electron-releasing (relative to hydro- gen). Fortunately the development of ion cyclotron resonance spectroscopy now allows the evaluation of gas-phase acidities3' and ba~icities,,~ and the interesting result emerges that the order (a)for the solution phase is completely reversed for the gaseous phase. In an important theoretical study Pople and Hehre have shown37 that in alcohols and amines a methyl group is overall electron-attracting with respect to hydrogen. However if the total energies of the neutral and protonated or deprotonated systems are calculated then the experimental ordering of gas-phase proton affinities is reproduced.The relevant results are shown in Table 7. This emphasizes the fact that energies of proton- transfer reactions do not necessarily correlate with charge densities on the atom Table 7 Energies and atomic p~pulations~~ Molecule E1a.u. E (Proton E (Proton 4xa ha addition)/ removal)/ kcal mol-' kcal mol-' NH3 -55.45254 -258.3 555.3 -0.481 0.160 MeNH -94.03005 -266.0 539.0 -0.405 0.157 Me,NH -132.60922 -271.2 523.8 -0.332 0.156 Me3N -171.18930 -274.7 -0.263 -H*O -74.96072 -228.6 568.0 -0.372 0.186 MeOH -113.54550 -235.8 535.4 -0.308 0.189 Me,O -152.13214 -239.7 -0.244 -qX,qH are Mulliken populations on the neutral molecules.qx is the charge on the atom from which the proton is to be removed and 4 is the charge on the hydrogen to be removed. to which the proton is attached and a more reasonable qualitative explanation of the results is that a methyl group provides an extended structure which can be polarized more effectively (than hydrogen) by both cationic and anionic centres. Pople and co-workers3' have made an extensive study of charge distributions in alkanes alkenes and alkynes and fluorinated analogues and have demon- strated the widespread alternation in charge in both the fluorine-substituted unsaturated and saturated hydrocarbons. This confirms an earlier result from the computationally simpler semi-empirical CND0/2 SCF MO treatment.Typical results for ethane ethylene and acetylene and their monofluoro- derivatives are given in Table 8. The energy of each molecule has been minimized 35 J. I. Braumann L. K. Blair E. L. Rufford and L. B. Young J. Amer. Chem. SOC. 1971,93. 4609. 36 J. I. Braumann and L. K. Blair J. Amer. Chem. Soc. 1971 93 391 1. 37 W. J. Hehre and J. A. Pople Tetrahedron Letters 1970 1959. 38 W. H. Hehre and J. A. Pople J. Amer. Chem. SOC.,1970 92 2191. Physical Methods-Part (iii)Theoretical Organic Chemistry and ESCA Table 8 Charge distributions and orbital exponentsfor some simple organic moIecules3 Molecule Charge distribution Basis set Optimum exponentsfor valence electron) orbitals (2s 2p for C and F 1sfor H) H H Hf9 \I -26/ 1.76 CH3CH3 c-c STO 3G / I \ 1.18 H HH CH3CH2F +llH H H-'; \I -58C-C I/ +zag STO 3G 1.79 1.76 2.56 /\ +13H F-165 1.19 1.18 H ~+78 CH,=CH2 \ -156 H / H STO 3G 1.70 1.23 1.76 1.68 CH2=CHF STO 3G 2.57 1.21 1.23 1.68 HCECH STO 3G 1.31 HCrCF STO 3G 1.74 1.64 2.59 1.33 with respect to the exponents (5)of the basis functions (minimal basis set STO expressed as least-squares fit to 3GTO) and the exponents provide interesting extra insight into the changes in electron distribution brought about by fluorine substitution.For example for fluoroethylene the higher exponents for valence 2s and 2p orbitals on C(l) attached to fluorine show that these orbitals are more compact than those on C(2). The hydrogen 1s orbital in fluoroacetylene is also more compact (5 =1.33)than in ethane say (<=1.18) and this arises from the much larger positive charge on the atom.Charge distributions in the series CH, CHF CF have been discussed and used to interpret the degree of electro-philicity of these carbene~.~~ The concept of CT-nseparation in MO calculations was originally based on an assumption of the independence of the n-electrons above and below the plane J9 J. F. Harrison J. Amer. Chem. SOC.,1971 93 4112. D.T.Clark of the molecule and the a-electrons localized near the molecule plane. The fact that there is strong interpenetration of the a-and n-electron densities is nicely demonstrated by a minimal-basis-set STO treatment,40 in which density contours have been plotted for individual CT and 7r MO’s.Figure 7 for example shows a superposition of the 3e, (a)and lei,(71) molecular orbitals for benzene and indicates significant interaction between the a-and n-electrons. Figure 7 Superposition of the 3e, (0)and le, (n)molecular orbitals in benzene. Plane perpendicular to the molecular plane of benzene and bisecting opposite C-C bonds. Contours start at 0.004 contour interval 0.004 a.u. (Reproduced by permission from J. Amer. Chem. Soc. 1971,93 2603) Geometries. One of the most readily calculable properties of a molecule is its equilibrium geometry and even with a relatively poor basis set bond angles and bond lengths can normally be computed to within a few percent. (a) Neutral molecules. Reference has already been made to geometry optimiza- tions in discussing barriers to rotation in simple molecules in the previous section.Calculations have mainly been oriented towards studying systems for which accurate experimental data are available as functions of the basis set. This is a necessary preliminary step if one hopes to use non-empirical calculations to predict geometries for species which have either not been isolated or for which structural data are not yet available (see the following section on carbonium ions). The agreement between theory and experiment is impressive (Table 9). (b) Carbenes. Table 10 displays the result^'^,^^ for some carbenes which have been studied experimentally. For methylene itself there are two points of major ‘O R.M. Stevens E. Switkes E. A. Laws and W. N. Lipscomb J. Amer. Chem. Soc. 1971,93,2603. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 69 Table 9 Calculated geometries for neutral species' Molecule Experimental CH4 rc-n 1.0858 C2H2 rc-H 1.061 A rc-c 1.203A 1.541A' 1.086A 1.086 A 1.089 A n H,C,C 111.2" 10.7" STO 3G A > H,C,C2 111.2" 10.7" n H,ClH3 107.7" 08.2" -C,C,C 112.4" 12.4" n-I H,C,H 106.1' 107.2" interest. First there is the geometry of the ground (triplet) state for which earlier spectroscopic evidence indicated a linear structure and secondly the triplet-singlet energy gap. All non-empirical studies so far reported have indicated a bent structure for 3B methylene in apparent conflict with the existing experimental data.However Herzberg has re-interpreted the data to give a bond angle of 136",a value that is in good agreement with the theoretical estimates. The calculated triplet-singlet separations range from 22-40 kcal mol- '. (c) Radicals. Pople and co-workers have studiedI4 several radicals of funda- mental importance to organic chemists and the results are summarized in Table 11. Methyl radical is predicted to be planar however as a prototype for studying the effect of angle deformation. Allen Von Schleyer and Buss4' have considered distorted methyl radical in which for equal C-H bond lengths the carbon and two hydrogen atoms are in a plane with an HCH angle of 90". The distorted radical is then predicted to be non-planar with a barrier to inversion of 1.2 kcal mo1-'.The e.s.r. data on cyclopropyl and 7-norbornyl radicals support the conclusion that angle-strained radicals are non-planar. For free ethyl radical a bridged structure is found to be very unfavourable and the ground-state structure is well represented by the classical formulation. (d) Carbonium ions. A representative series of carbonium ions which have been studied is given in Table 12. C2H3' and C2H5+ are prototypes for addition of a proton to an alkyne and alkene respectively whereas CHSf and C2H,+ are prototypes for protonated alkanes. Whereas methyl and vinyl cations are predicted to be planar about the electron-deficient centre in ethyl cation the carbonium centre C( 1) is slightly non-planar the distortion being toward a staggered configuration about the C-C bond.14 For the methyl 0x0-carbonium ion of interest from the standpoint of the Friedel-Crafts reaction the calculated 41 V.Buss P. von R. Schleyer and L. C. Allen A.C.S. Meeting University of Delaware 1970. Table 10 Calculated geometries of some carbenes Carbene Electronic state Calculated Exptl. Comments Basis set Ref. structure structure CH2 3B rCUH1.082A rC-H 1.029 A originally assigned linear A STO 3G HCH 125O.5 HCH 136" structure from exptl. data rC-H 1.069A STO4.31G n HCH 132.0' n HCH 132.5" Using exptl. rCpH C 10s lop gaussian lobe contracted 4s 2p. H 5s lA1 contracted 2s 14 -rC-H 1.123 A rC-H 1.1 I A Calculated energy difference ---.-/----HCH 100.5' HCH 102.4" (3B -'A,) -40 kcal mol -STO 3G rC-H 1.100 A -37 kcal mol- n STO4.31G HCH 105.4' n HCH 105.0' Using exptl.C 10s lop gaussian lobe rC-H = -22 kcal mol-' contracted 4s 2p. H 5s ---.---.. contracted 2s CHF A' HCF 104" HCF 101.8' Using exptl. rC-H and rC-F C F 10s lop gaussian lobe rC-H 1.12 A contracted 4s 2p. H 5s rCAF1.31 contracted 2s -3Aff HCF 122' -Using rC-H and TC-F as for A' Calculated singlet-triplet ' 39 ---. n separation 0.0 kcal mol-' lA1 FCF 105.0" FCF 104" Using exptl. rC-F C,F 10s lop gaussian lobe rC-H 1.30 a contracted 4s 2p. H 5s contracted 2s 3B1 FCF 120" Using exptl. rC+ singlet-C,F 10s lop gaussian lobe triplet separation contracted 4s 2p. H 5s 39 kcal mol-' contracted 2s Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA II 009 4 L m c e- 21 wL c 2 L V Table 12 Calculated geometries for some carbonium ions h) Ion Calculated structure Experimental Comments Basis set Re& CH 3+ planar STO 3G YC-" 1.120 A rC-" 1.076 A STO 4.31H 2 C2H3' H rl 1.281 r\ r2 = r3 = 1.106 A STO 3G rKy)<", C7-C-Hl rd = 1.106A I H-14 With same basis set bridged structure 5 6.76 kcal mol-' higher in energy STO 3G H4C2H = HlClH2= a r; 1.091 A ri 1.115 A r 1.403 A r2 1.348 A a = 102.2' p = 177.1" r3 1.099& 8 = 2.5' e = 46.60 5 = 113.6",vl = 116.7'.CI = 118.8" tY CH3CO+ rc-c 1.457 A 1.452 A in rc-o 1.11 A C,O 7s 3p H 3s GTO Y [CH3CO+SbC16-] rC-H (4,2,2) 1.09 A)assumed lCG.0 rc-c 1.452 A 1.452 A in rc-o 1.11 A C,O 9s 5p H 4s GTO 42 g [CH3CO+SbC16-] rC-H 1.09 A}assumed CGTO (5,3,3) % Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA m* d b m 0 2 2 0 2 0 5; L4 5; cn h I .-v) h ....4-33 -mmnc LLLL ern LL 74 D.T.Clark bond length is in good agreement with experiment and a population analysis reveals that the positive charge is essentially localized on the carbonyl carbon.42 The electronic structures of protonated methane and ethane have been extensively investigated. It is of interest to compare the results of Pople’s minimal-basis-set (STO 3G)14 calculations with those of Ray,43 using a very small basis set of FSGO’s.Both calculations indicate a structure of C symmetry looking roughly like a methyl cation plus a hydrogen molecule. From the location of the FSGO’s it is clear that CH5+ might be regarded as having three two-centre two-electron bonds and one two-electron three-centre bond. Interestingly enough the two approaches predict different results for C2H +. Pople’s STO 3G calculations predict a symmetrical bridged structure a noteworthy feature being the very long C-C bond length suggesting ready bond cleavage on protonation of alkanes. The FSGO basis-set calculation predicts a structure analogous to that for CH5+ i.e. a loose C2H5+-H2 complex. However Pople specifically con- sidered this type of structure and obtained an energy 11 kcal higher than for bridge-protonated ethane.It would therefore appear that limited-basis-set FSGO calculations are not entirely adequate for discussing the geometries of molecules. Thermochemical Data.-Relative Energies of Isomeric Species. It has already been noted in the Introduction to Section 2 that calculations within the Hartree- Fock formalism are incapable of reproducing heats of atomization of molecules as a result of the neglect of correlation energies. This deficiency is not necessarily as serious as it sounds because a large part of chemistry deals with the transforma- tions of one molecule into another or into smaller molecules. Where such trans- formations involve no change in the number of electron pairs correlation energy changes are quite small and hence calculations within the Hartree-Fock limit can often provide valuable thermochemical data.Some workers have expended considerable effort in parametrizing semi-empirical SCF MO treatments to accurately produce heats of atomization the most successful being Dewar’s MIND0 schemes.44 By incorporating experimental data into the theoretical schemes correlation energy changes on atomization can be accommodated. Unfortunately it would appear that the parametrization is highly specific with regard to the classes of compounds for which reliable results are produced and for charged species in particular the stabilities of species with a high degree of connectivity (e.g.bridged ions) are seriously ~verestimated.~~ This is an important point to appreciate for the average organic chemist who is not too much interested in the theory but more in the numbers that come out of the end of a program package.42 B. Rees A. Veillard and R. Weiss Theor. Chim. Acra 1971 23 266. 43 N. K. Ray Theor. Chim. Acta 1971 23 11 1. 44 C’ N. Bodor M. J. S. Dewar A. Hargret and E. Haselbach J. Arner. Chem. SOC. 1970 92 3854 and references therein. 45 C’ R. Sustmann J. E. Williams M. J. S. Dewar L. C. Allen and P. von R. Schleyer J. Amer. Chem. SOC.,1969,91,5350; N. Bodor and M. J. S. Dewar J. Amer. Chem. SOC. 1971,93 6685. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 75 In an elegant series of investigations Pople and co-worker~~~-~~ have shown how the limitations of the Hartree-Fock method for calculating heats of forma- tion may be circumvented by studying bond-separation reactions.The aim of this procedure is to estimate the energy of an organic molecule containing at least three heavy (non-hydrogen) atoms relative to the energies of simpler mole- cules containing only two heavy atoms but with the same types of bond. As an example consider a formal reaction in which a large molcule is one of the reactants and the products are the simplest molecules containing similar bonds between heavy atoms. Propene for example has one C-C bond and one C=C bond so that the products would be ethane and ethylene and hence to maintain the stoicheiometry a methane molecule must be added to the reactants uiz. CH,-CH=CH + CH -+ CH3-CH3 + CH2=CH2 A unique reaction of this type can be set down for any large molecule which can be represented by a classical valence structure without unpaired electrons or formal charges.Changes in correlation energy in such a reaction are very small and therefore with an adequate basis set the bond-separation energies may be accur- ately calculated. A few examples are given in Table 13. Having demonstrated the validity of this calculation the next step forward is to take the experimentally determined heats of formation for the small molecules together with the bond- separation energy in order to calculate the heat of formation of the original molecule (Table 13). In an extensive series of investigation^,^^.^' Pople and co-workers have provided valuable information on (a) isomerization in saturated systems (b) prototropic rearrangements and (c) isomerization of single- plus triple-bond systems to cumulated double bonds.The information thus provided (see Table 13) is invaluable since in many cases the relative energies of species can only be inferred from experimental data. It is evident from the few values given in Table 13 that even the minimal-basis- set STO 3G can give surprisingly good values for heats of formation in this way. It is interesting to compare the isomerization energies that have been obtained directly as calculated energy differences and those that have been derived from bond-energy analysis ; these are shown together for a representative series of systems in Table 13.Of particular note are the calculated energetic preferences of acetaldehyde over vinyl alcohol formaldoxime over nitrosomethane and keten over hydroxyacetylene. Heats of hydrogenation may also be successfully discussed. The application of even the minimal STO 3G basis set to larger organic molecules is computationally expensive and an interesting approach to looking -26 R. Ditchfield W. J. Hehre J. A. Pople and L. Radom Chem. Phys. Letters 1970 5 13. 47 W. J. Hehre R. Ditchfield L. Radom and J. A. Pople J. Amer. Chem. Soc. 1970 92 4796. 4H L. Radom W. J. Hehre and J. A. Pople J. Amer. Chem. Soc. 1971 93 289. L. Radom W. J. Hehre and J. A. Pople J. Chem. SOC.(A) 1971 2299. Table 13 Thermochemical information derived from non-empirical LCAO MO SCF calculations (1) Bond separation energieslkcal mol -Reaction Theory Exptl.Basis set CH3CHzCH2 + CH + C2H6 + C2H4 4.1 5.0 STO 4.31G CH2=C=CH2 +CH4 -+ 2C2H -4.6 -4.0 STO 4.31G NH2CH0 +CH4 -+ CH3NH2 +CH20 32.4 29.8 STO 4.31G (2) Heats offormationlkcal mol- ' CH3CH2CH3 -23.1 -24.82 STO 3G -23.8 STO 4.31G CH3CH2NH2 -10.0 -11.27 STO 3G -11.4 STO 4.31G CH3CH20H -53.6 -56.19 STO 3G -55.7 STO 4.31G CH3CH2F -61.8 -62.5 STO 3G -64.5 STO 4.31G (3) Isomerization energieslkcal mol- in saturated systems Process F-3 CH3CH2NH2 + CH3NHCH3 8.5 9.0 6.8 STO 4.31G -CH3CH2OH -+ CHjOCH 11.6 15.2 12.2 -OHCH20H + OHOCH 63.4 64.5 62.6 (4) Isomerization energieslkcal mol for prototropic rearrangements Process CH3CH=0 -+ CH2=CH-OH 12.9 14.6 CH3-N=NH -+ CH2=N-NH2 2.0 5.3 -STO 4.31G CH3-N=0 -+ CH2=N-OH -12.6 -3.1 NH2-CH=0 -+ NH=CH-OH 23.0 25.6 PhysicaI Methods-Part (iii) Theoretical Organic Chemistry and ESCA \D2 u? -1 I I l l ! l I l l I hs u?3- SO In I -cn m 4 -z 0-c h v s .- 0 ,p.0 c 2 9 - QJ M .- u,6 78 D. T.Clark at larger molecules has been developed by Christ~ffersen.’~ Basically the ap- proach is to use the computationally inexpensive FSGO basis set the non- linear parameters for each basis function (orbital radii location of FSGO’s) being determined by investigating suitable small fragments. (For hydrocarbons for example CH and CH,. have been used). Using the molecular fragment data ‘ab initio’ SCF calculations can be carried out relatively inexpensively on quite large molecules.The basis sets are very limited and typically produce values that are ca. 86 % of the Hartree-Fock energy whereas a minimal-basis-set STO-type calculation would typically give >96 % of the total energy. Nonethe- less for relative energies the method can give useful results. Calculations have been carried out on benzene and isomeric species fulvene 2,3-dimethylenecyclo- butene trimethylenecyclopropane and Dewarbenzene. Naphthalene azulene and fulvalene have also been investigated. The results are given in Table 13. It is clear that absolute energy differences are considerably overestimated (e.g. Dewarbenzene is probably -60 kcal less stable than benzene).It is interesting to note that the MIND0 procedure predicts51 the ordering benzene > fulvene > 2,3-dimethylenecyclobutene > Dewarbenzene > trimethylenecyclopropane. The electronic structures and relative energies of ortho- rneta- and para- benzynes have been evaluated ’ in an SCF treatment followed by configuration interaction (CI) to accommodate correlation-energy differences particularly between different electronic states. The results are given in Table 13. The salient features are as follows. At the geometry considered (corresponding to benzene with two hydrogens removed) ortho-benzyne is predicted to have a singlet ground-state. A single-determinantal SCF calculation predicts a triplet ground- state but the many-determinant CI wavefunction corrects for the large correlation- energy difference between singlet and triplet states.The Pauli exclusion principle ensures that correlation effects are built into the triplet wavefunction so that the effect of CI is to lower the energy of the singlet more than the triplet. A single-determinantal wavefunction does not adequately describe the weak interaction between the lone-pair-like a-orbitals owing to the undue weighting given to ionic terms (cf earlier sections). Both rneta-and para-benzyne are predicted to have triplet ground-states but with energetically relatively accessible singlet states. In absolute energies the predicted orders of stability are singlet states ortho > meta > para; triplet states para > meta > ortho and this order applies even for the single-determinantal treatments.Hydrogen-bonds. Deserving of special mention because of several notable aspects is a study ofthe interaction between molecules in the particularly import- ant case of the hydrogen-bonded guanine<ytosine base pair.53 For the Guinness Book of Records this enormous computational problem required 8 days of cpu time on the largest commerical computer available and involved the computa- tion sorting retrieving and processing of some 70 000 000 000 integrals over 50 R. E. Christoffersen J. Amer. Chein. Soc. 1971 93 4104. 51 N. C. Baird and M. J. S. Dewar J. Amer. Chem. Soc. 1969 91 352. 52 D. L. Wilhite and J. L. Whitten J. Amer. Chem. Soc. 1971 93 2859. 53 E. Clementi J. Mehl and W. von Niessen J.Chem. Phys. 1971 54 508. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 4 h-b-3 n22 GUANINE CYTOSINE h '2 ? * 1 I I I v 9 It 13 '1 15 ' 2 -I h-b-3 -2 --3 I I 1 I I I 1 Figure 8 Positions of the H atom along the three hydrogen-bonds in the guanine-cytosine base pair (Reproduced by permission from J. Chem. Phys. 1971,54 508) 80 D.T.Clark gaussian functions. It is a tribute to both computer manufacturers and more importantly to the large number of man years devoted to writing efficient pro- grams that calculations on this scale would not have been envisaged even 10 years ago. Nevertheless it would seem unlikely that computations of this order of magnitude will be undertaken in university environments in the foreseeable future.The calculations clearly illustrate the importance of the contraction technique since for the uncontracted basis set of 334GTO's -2.41 x lo9 integrals would have to be processed in the SCF calculation for each point on the potential-energy surface. The storage space required would occupy a few hundred magnetic tapes and would be physically impracticable. With a contracted basis set of 105 functions however the integrals can be stored on two magnetic tapes. For the base pair as shown in Figure 8 calculations were performed corres- ponding to independent movement of the hydrogens in each of the three hydrogen- bonds the geometries of and separation between the bases being fixed. The potential-energy curves are shown in Figure 9 and it is clear that only a single minimum is calculated for each hydrogen-bond.This contrasts with earlier semi- empirical work which predicted double minima. It should be pointed out however that despite the huge computational effort involved in producing Figure 9 the treatment cannot be regarded as providing an adequate overall picture for hydrogen-bonding in this system. Each hydrogen-bond was studied independently of the other two (the other two have the hydrogens fixed at the equilibrium position). Co-operative effects may well be important and this would require a much larger computational program to be carried out with the geo- metry searches over a three-dimensional grid. It is also undoubtedly true that there will be small changes in geometry (particularly about the carbonyl and amino-groups involved in hydrogen-bonding) as a function of the positions of the hydrogens although in a co-operative motion this effect would tend to cancel.Potential-energy Surfaces for Organic Reactions.-The most exciting deveiop- ment in the past three years in theoretical organic chemistry has been the applica- tion of rigorous quantum-chemical techniques to the study of organic reaction mechanisms. Since the p~blication~~ in 1969 of the first non-empirical cross- sections through a potential-energy surface for an organic reaction (the cyclo- propyl-ally1 cation transformation) progress has been made with regard to several reactions of fundamental importance. The single most detailed study due to Salem and co-worker~,~~ has defined a transition state for the geometrical isomerization of cyclopropane.The electrocyclic transformation of cyclobutene to butadiene has been st~died,~~,~~ and also cross-sections through the potential- energy surfaces for prototype bimolecular nucleophilic displa~ernents~~-~~ and 54 D. T. Clark and D. R. Armstrong Theor. Chim. Acra 1969 13 365. L. Salem XXIIIrd International Congress of Pure and Applied Chemistry Butterworths London 1971 vol. I p. 197. 56 K. Hsu R. J. Buenker and S. D. Peyerimhoff J. Amer. Chem. SOC.,1971,93,2117. 57 R. J. Buenker S. D. Peyerimhoff and K. Hsu J. Amer. Chem. SOC.,1971 93 5005. 5h A. Dedieu and A. Veillard Chem. Phys. Letters 1970 5 328. sy A. Dedieu and A.Veillard 21'"' Reunion Annuelle de la Societe de Chimie physique Paris Sept. 1970. '' A. J. Duke and R. F. W. Bader Chem. Phys. Letters 1971 10 631. t -92802 C -92804 --92806-3 0 -$ -92808 -z -92810 -i I -92812 1 1 -928 14 L 1--92815 DISTANCES (0 u 1 Figure 9 Potential energy curves for h-b-1 h-b-2 and h-b-3 for guanine-cystosine base pairs (Reproduced by permission from J. Chem. Phys. 1971,54 508) 82 D.T. Clark electrophilic additions to olefins.28 In probably the most significant paper theoretically Basch61 has calculated a reaction path for the dimerization of methylene including a large part of the correlation change in a multi-configura- tion SCF treatment. The Geometrical Zsomerization of Cycl~propane.~~ In a Report of this size it is not possible to do justice to this major contribution to the chemical literature.Any chemist who wants to get a feel for the difficulties inherent in constructing a multi-dimensional potential-energy surface for even a simple organic reaction can do no better than read Salem's paper.55 This meticulous and painstaking attempt at the total resolution ofa transition state for an organic reaction extended over 2 years required 350 hours of IBM 360/75cpu time and involved the computation of -700 points on the 21-dimensional surface. The calculations employed a minimal STO basis set and in the region of trimethylene diradical (see later) a 3 by 3 configuration interaction calculation was performed between the ground (tj') doubly excited [(tj')2],and singly excited (4~') configurations.This accounts for a considerable portion of the correlation energy of one electron pair. The steps in the construction of the potential-energy surface then proceeded along the following lines. The geometry of cyclopropane itself was first optimized together with thsO exponents. The calculated geometry Rc-c = 1.479 A RC+ = 1.082A HCH = 112.8" is in good agreement with experiment (Rc-.c = 1.510 +_ 0.002& RC+ = 1.089 +_ 0.003 A and-= 115.1" & lo). Possible reaction mid-points having reflection symmetry were then investigated followed by a study of 'Type I' reaction pathways constrained to proceed uia such mid-points. This initial search relies on the fact that reactant and product (cyclopropane) are mirror images with respect to the plane of the carbon atoms so that the reaction can proceed via a mid-point which has the mirror plane as a symmetry element and this corresponds to a synchronous narcissistic process (see ref.5). Having studied such a reaction path the constraint of passing through a symmetrical mid-point was lifted and 'Type 11' pathways which avoid a symmetrical mid-point were investigated. The final structure of the transition state is shown in Figure 10. Although the minimum-energy pathway to the transition state has not yet been finally elaborated Figure 11 shows a typical calculated pathway which could be followed by the molecule during geometrical isomerization. The C-C bond first lengthens until at a CCC angle of 113" the face to face [FF] configuration of trimethylene diradical is reached.(The CI treatment ensures that the extensive bond-lengthening is relatively well described). At this point 48.4kcal mol- have been expended. The isomerization process now occurs in an enlarged ring with very little energy change the calculated activation energy being 52.6 kcal mol- '. From face-centred trimethylene diradical the terminal CH groups undergo an initial conrotatory motion; however between 60 and 90" in angle of rotation of the principal group the other terminal group reverses into a disrotatory motion. At 90" the edge-to-face 61 H. Basch J. Chem. Phys. 1971 55 1700. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 00 -.-.1 z 0 t- -L 0 60" 80' 90" 95" (.(I 112.5 *& aH~ (EFI' TS HB'P q%HB 180" ' HA ~e-3 100' 120" 140' 160" "HA (FF)' 'HA Figure I1 "on-minimum' energy pathway via the transition state in the geometrical isomerization of cyclopropane.The methylene rotation angle 4 is shown in the lower centre (Reproduced by permission from XXIIIrd International Congress of Pure and Applied Chemistry Butterworths London 1971 vol. 1 p. 197) 7 0 ij-% Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA configuration of trimethylene diradical is reached in which both methylene groups are pyramidalized on the same side of the plane. Proceeding via the transition state the forward rotation of the principal group is assisted by a forward-backward-forward rotation of the other group until at 180" the face-to- face configuration of trimethylene with pyramidalization at the principal group is reached.Depyramidalization is then followed by ring closure to complete the geometrical isomerization. The pathway is chiral without any symmetric mid- point (Type 11). The non-synchroneity of such a pathway is apparent from the delayed crossing of the carbon-carbon plane by the external hydrogen atom A relative to the internal hydrogen B. The transformation can thus be seen as a stretching motion involving a steep energy surface followed by rotational motions on a fairly flat surface. S,2 Reactions. Cross-sections through the potential-energy surfaces for the following SN2reactions have been c~mputed.~~-~' (a) H-+ CH4 + (CH5)--+ CH4 + H- (b) H-+ CH3F + (CFH4)-+ CH,F + H- (c) F-+CH3F + (FCH,F)-* CH3F +F- (d) CN-+CH3F -* (CNCH,F)-+ CH,CN +F-' It is important to realize that a sufficiently large and flexible basis set must be used in studying such systems to accommodate the considerable changes in electron distribution in proceeding from reactants to products.To describe adequately the diffuse charge distribution in the non-bonding regions in CN- for example a large basis set including polarization functions is required.60 (From this point of view it is probably true that results for anionic species are more critically dependent on basis set than those for cationic species).These represent important prototype systems for assessing the importance of solvation terms in S,2 reactions since the calculations refer to isolated mole- cules in the gas phase. The salient features are given in Table 14. For the hypo- thetical reaction involving CH and H-the transition state is calculated to have D3h symmetry and the calculated activation energy is 60.2 kcal mol-'. The calculations show that there is a decrease in the C-H bond length compared with CH for the hydrogens in the plane. This is also apparent in the reaction CH,F + H-+CH,F + H-. There are two interesting features evident in comparing the calculations. First replacement of H by F at the reaction centre lowers the activation energy to 55.3 kcal mol-' and secondly all the C-H bonds are significantly shortened.The reaction F-+ CH,F -+CH,F + F-has been studied by Veillard and Dedie~~~,~~ and also by Bader and Duke,60 and the two sets of results are in good agreement. It is interesting to note that although Veillard and Dedie~~*?~~ used a larger basis set of primitive functions by choosing a better grouping in the contracted functions Bader and Duke6' obtained lower total energies. The calculated activation energies are in good agreement and again the C-H bonds are somewhat shorter than in the reactant. The extensive delocalization of the negative charge is evident from the density contour map,60 00 Table 14 Non-empirical calculations on S,2 reactions m Reaction Heat of reaction Activution Geometry of T.S.Basis set /kcal mol -burrier /kcal mol- \ H-+CH + CH,+ H-0 60.2 H,/' C 1 Is 7p,Id GTO contracted 1.063 A 5s 3p Id H 6s lp GTO i 4\11709A contracted 3s lp H-C-H Hq-H 2 > 59 H-+CH3F -+ CH3F +H- 0 55.3 9 5 4 GTO 5 3 3 C GTO C-F distance kept at 1.42 A since optimization leads to departure of F-J F-+CH3F + CH3F +F- 0 7.9 Geometry optimized with basis set as for H-+ CH3F. Activation barrier calculated with basis set for H-+ CH F-+CH3F -+ CH3F +F- 0 7.14 9 5 4GT0 5 3 3 C GTO for geometry searches F-+ CH3CN -+ CH3F + CN-5.24 17.33 Energy differences from final geometries C F N 10,6 60 7 6 GTO 5 3 3 CGTO augmented by polarization functions for CN s and p c polarization x. functions add.Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 87 and by spatial partitioning of the molecular charge distribution the approximate charges are -0.86e on each fluorine and +0.73e on the CH fragment. This is in line with the experimental observation that electron-releasing substituents are activating. This also suggests that the solvation of the transition state will be considerably smaller than that for the reactants and thus solvation energy terms are expected to contribute a substantial portion to the observed activation energies for S,2 reactions. For the F- + CH3CN reaction a heat of reaction of -5.24 kcal mol- is computed. An approximate geometry optimization for the (FCH,CH)- species shows it to be 17.33kcal mol- ’ higher in energy than the reactants.It is note- worthy that the C-F bond is calculated to be rather long so that the transition state looks rather more like the reactants. This provides a striking theoretical verification of the oft-used Hammond-Polanyi6’ postulate. Dinzerization of Methylenes. The dimerization of methylenes to produce ethylene might be considered as the simplest concerted cycloaddition (a double bond being considered as a two-membered ring) and hence provides a simple case where the results of a rigorous theoretical treatment can be compared with qualitative ideas based on conservation of orbital symmetry. The least-motion coplanar approach of two singlet methylenes to form ground-state ethylene is readily shown to be symmetry-forbidden due to a level crossing.This crossing in the orbital correlation diagram should lead to an avoided crossing in the state-level diagram. This could arise from the situation that the lowest-energy electronic configuration of ethylene is not the lowest-energy configuration of two singlet coplanar methylenes at large distances from each other. The single-determinantal Hartree-Fock theory is unable to describe such a situation correctly. A multi-configuration approach (see ref. 63) improves on the Hartree-Fock result by including the important parts of the correlation energy error implicit in going to the wrong dissociation limits and in the over-estimation of ionic term contribu- tions to the single-configuration-wavefunction formalism. The implementation of MC SCF theory has proved computationally difficult for other than diatomic molecules but an important step forward has now been taken by Basch6’ in studying the reaction path for the dimerization of methylenes.The ground state of ethylene is given by 11) = (core)”(02)(n2) whereas the electronic configuration of two appropriately oriented singlet methylenes is 111) = (core)”(o)’(o*)’ differing from that for ethylene by the pair excitation (x’ -+ a*’). Other configurations which might be considered which involve the o,n,o*,and n*-orbitals are 1111) = (core)’2(o)2(n*)2 (IV) = (core)’2(n)2(n*)2 IV) = (core)’2(n)2(o*)2 IVI) = (core)’2(n*)2(o*)2 62 G. S. Hammond J. Atnrr. Chem. SOC.,1955 77,334. 63 E. Clementi Chem. Rev. 1968 68 341.88 D.T. Clark and these form a complete set of functions with regard to distributing two (spin- paired) electrons over four orbitals. The multi-configuration wavefunction may then be written as $ = C,II) + CI,lII) + CIlIIIII)+ C,,IIV) + CvIV) + CvllVI). The total energy is then minimized by applying the variational principle to both the orbitals and the configuration expansion coefficients and by constraining the orbitals to be normalized. Calculations were carried out at nine carbon-carbon internuclear distances and the results are shown in Figure 12 for the two lowest- energy solutions. -77.10 -.60-5-.80--78.00 -I I 0 2 4 6 8 AR Figure 12 The lowest-energy MC SCF solutionsfor the dimerization of methylene (Reproduced by permission from J.Chem. Phys. 1971,55 1700) Before considering these results it is interesting to recall the results obtained by Hoffmann et a/. using extended Huckel theory.64 They found that the lowest- energy singlet configuration of the methylene dimer changes at a C-C distance of -3 I$ with 11) being the lowest-energy configuration at the normal ethylene geometry and 111) the lowest-energy configuration at large internuclear separa- tions. This analysis then purports to show that there will be an avoided crossing and therefore a barrier to be overcome during the reaction. The MC non- empirical study shows this not to be the case. Analysis of the two wavefunctions as R + ashows that the dissociation limit for the lower energy pathway corres- ponds to two triplet-state methylenes (two triplets can be coupled to give the proper spin and space symmetry to interact with the closed-shell ethylenic electronic configuration).The coplanar interaction of two triplet methylenes (the triplet state is in fact the ground state of methylene cf Section on molecular geometries p. 68) is therefore predicted to occur without activation barrier 64 R.Hoffmann R. Gleiter and F. B. Mallory J. Amer. Chem. Soc. 1970 92 1460. Physical Methods-Part (iii)Theoretical Organic Chemistry and ESCA to produce ground-state ethylene. Analysis of the higher-energy repulsive path- way shows that the dissociation limit does in fact correspond to two singlet methylenes which are therefore predicted not to dimerize since the reaction path is completely repulsive.This detailed MC treatment shows the deficiencies of not only simple MO treatments of bond making and breaking but also at the non-empirical level of the Hartree-Fock method. The Electrocyclic Transformation of Cyclobutene to cis-Butadiene. One of the early successes of conservation of orbital symmetry arguments was the rational- ization of the stereospecific thermal conrotatory ring-opening of cyclobutene derivative^.^ Clearly however more information besides the symmetry rule is needed before one can state that the reaction mechanism is understood. For example does the rotation in a conrotatory (or disrotatory) fashion occur before after or during the bond-breaking process? More generally it is desirable to determine the true reaction path since only then is it possible to calculate the activation energy.Buenker Peyerimhoff and Hsu~~ have now analysed in detail several cross-sections through the potential-energy surface for this trans- formation. In the process of deducing the minimum energy path in the trans- formation it is necessary to take account of 24 degrees of freedom so that some simplifying assumptions need to be made. It seems reasonable to assume that in a \ Figure 13 Dejinition of geometrical parameters for the C,H system (Reproduced by permission from J. Amer. Chem. SOC. 1971 93 2 1 17) concerted process a certain degree of symmetry is maintained throughout the course of reaction and this reduces the number of independent geometrical parameters.Figure 13 shows the C,H system in such a symmetrical con- figuration. Knowing the experimental geometries of both cyclobutene and buta- diene an intelligent guess can then be made as to which parameters remain essentially unchanged throughout the transformations (the C-H bond lengths D.T. Clark for example). Clearly the parameters which exhibit the largest changes as the reaction proceeds are the out-of-plane angle of rotation of the methylene groups and the C(lFC(4) bond distance R. Parameters which exhibit significant but not exceptionally large changes during the isomerization are the other C-C bond distances RB(central bond) and RD(lateral bond) and the angles CI and B. The distances R and RDcan conveniently be defined in terms of an auxiliary para- meter varying continuously from 0-1.The general procedure utilized therefore is to treat the C( 1)-C(4) distance R and the methylene rotation angle as principal independent variables and the other less critical parameters may then also be varied but not optimized as thoroughly. The interesting features which emerge from the study are as follows. The energetically favoured mode of rotation of the methylene groups in the ring opening of cyclobutene is critically dependent on the distance R. For R = 2.9 a.u. (approx. the distance in cyclobutene itself) rotation of the methylenes into the plane is energetically very expensive (-400 kcal mol- ') and in fact the favoured mode is then the disrotatory. The energy required to effect this transformation is calculated to drop quite rapidly as R increases and the favoured mode then becomes the conrotatory.For every distance R the lowest-energy conformation is calculated to have 8 either equal to 0 or 90" and this raises the question as to how the rotation takes place for either the forward or the reverse reaction. The only reasonable answer seems to be that the methylene rotation takes place entirely at the distance R (or at least a very narrow range of R) for which the 0 and 90" conformations have approximately equal energy. This implies that as in the geometrical isomerization of cy~lopropane,~~ rather then being a smooth continuous transformation there is first of all a bond-stretching process which is then followed by rotation of the methylenes with very little change in ring geo- metry before there is a final relaxation into the cis-butadiene structure.The crossing point at which the energies of 8 = 0 and 8 = 90 conformations are equal is calculated to occur at R = 4.32a.u. SCF calculations corresponding to 15" intervals in rotation at this distance were investigated and the result- ing potential curves are shown in Figure 14. The conrotatory mode is clearly favoured the potential-energy curve being fairly symmetrical with a maximum barrier height (0 = 51") of 20 kcal mol-'. Since there is a change in ground-state electronic configuration for the disrotatory mode a configuration interaction cal- culation is required in order to adequately describe this mode of transformation.The results of CI calculations are also shown in Figure 14,and the conrotatory mode is calculated to be approximately 13.6 kcal mo1-l lower in energy than the disrotatory one. The distance R at which the 8 = 0 and 90" conformations have the same energy is computed to be slightly longer (4.49a.u.) when CI is taken into account. The energy required to stretch the C-C bond to this distance starting from cyclobutene is calculated to be -27 kcal mol- ',and for the pure conrotatory motion at this bond length a further -20 kcal mole-' is required. The overall activation energy is therefore calculated to be -47 kcal mol -' in reasonable agreement with experiment (dimethylcyclobutene 35 kcal mol -I). Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 91 1 -90-\ \ -110 \ \ '3Ot THETA POTENTIAL CURVES AT R ?I7Pk -19 67, I Figure 14 Total energy for the con- and dis-rotatory C,H structures as a .function of the rotation angle 0.The lower curves refer to the CI calculctions and the energies for cyclobutene and cis-butadiene are also given (Reproduced by permission from J. Amer. Chem. SOC. 1971,93 21 17) The striking feature evident in this study and in the geometrical isomerization of cyclopropane is the demonstration that these simple concerted organic reactions proceed in distinct stages of bond stretching followed by rotation rather than proceeding in a continuous manner. The fact that rotation takes place over a very narrow range of R indicates that it is at this distance that one should calculate orbital and state correlation diagrams for comparison with the qualitative Woodward and Hoffman diagrams.In a further paper Buenker Peyerimhoff and Hsu' have in fact analysed qualitative theories of electrocyclic transformation in terms of the results of 'ah initio' SCF and CI calculations. 3 Electron Spectroscopy for Chemical Analysis (ESCA) Introduction.-In the previous section of the Report the results of non-empirical calculations on a wide variety of organic systems were discussed in some detail. Such calculations explicitly consider all the electrons both core and valence 92 D. T. Clark and hence give (via Koopmans’ theorem) the energy levels in a molec~le.~~~~~ Electron Spectroscopy for Chemical Analysis* (ESCA) developed by Professor Kai Siegbahn at Uppsala University gives an experimental technique for the direct observation and measurement of both core and valence energy levels of molecule^.^^*^^ Although the technique has been developed over the past 20 years or so it is only in the past few years that applications in organic chemistry have revealed the great potential of the technique for studies of structure and bonding.The range of application is already very great ranging from systematic studies of substituted effects in simple organic molecules69 to quantitative evaluation of cereal grain nutritional value.” Clearly the next few years will witness a dramatic growth in applications of ESCA to organic chemistry across a broad front.The principal advantages of the technique are as follows (1) The sample may be a solid liquid or gas (it is as easy to study a high- molecular-weight polymer as it is to study a gaseous sample). (ii) The sample requirement is modest. In favourable cases 1 mg of solid 0.1 ,d of liquid or 0.5 cm3 of gas (at STP) will suffice. (iii) The technique has high sensitivity is independent of the spin properties of any nucleus and is applicable in principle to any element of the Periodic Table. (iv) The information it gives is directly related to the electronic structure of a molecule and the theoretical interpretation is relatively straightforward. (v) Information can be obtained on both the core and valence energy levels of a molecule. In terms of the sheer amount of useful data produced per sample ESCA is probably the most powerful spectroscopic tool available to chemists.The actual experiment performed is extremely simple and involves the measurement of binding energies of electrons in molecules by determining the energies of electrons ejected by the interaction of a molecule with a mono-energetic beam of X-rays. In principle all electrons from the core to the valence levels can be studied and in this respect the technique differs from U.V. photoelectron spectros- copy in which only the lower-energy valence levels can be studied. For a variety of reasons the most commonly useful X-ray sources are AlKcr,, and MgKcc,,, 65 W. G. Richards internat. J. Mass Spectrometry ion Phys. 1969 2 419.66 D. T. Clark and M. Barber Chem. Comm. 1970 22. 67 K. Siegbahn C. Nordling A. Fahlman R. Nordberg K. Hamrin J. Hedman G. Johansson T. Bergmark S.-E. Karlsson I. Lindgren and B. J. Lindberg ESCA- Atomic Molecular and Solid State Structure Studied by Means of Electron Spec- troscopy’ Nova Acta Regiae Soc. Sci. Upsaliensis Ser. IV Vol. 20 1967. Revised edition in preparation by North-Holland Publishing Co. Amsterdam. 68 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 Publishing Co. Amsterdam 1969. 69 D. T. Clark and D. Kilcast J. Chem. Soc. (A) 1971 3286. 70 M. P. Klein and L. N. Kramer Improving Plant Protein Nucl. Tech. Proc. Symposium Lawrence Radiation Lab.Tech. Report 243-52 1970; (Chern. Ah. 1971,75 105 912a). * Also variously called X-ray Photoelectron Spectroscopy (XPS) Induced Electron Emission Spectroscopy (IEES) and High-Energy Photoelectron Spectroscopy (HEPS). Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 93 with photon energies of 1486.6and 1253.7 eV respectively. Relevant background material is given in references 67 and 68. Major fields of application of ESCA in organic chemistry in the past year are detailed below and rather more space will be devoted to the topic in subsequent Reports. Analysis.-Since the binding energies of core levels are characteristic of an element one obvious area of application is in chemical analysis.The constituent elements of a molecule are readily identifiable (Figure 15 shows a trivial example)69 and with calibration of relative cross-sections the empirical formula may also be determined. A novel application due to Klein and Krame~-,~' employed ESCA to analyse the quantity and quality of grain protein. The sample requirement of a few milligrams and the non-destructive nature of the technique are of particular relevance in this connection since it is feasible to excise a small section of a seed for analysis whilst retaining the remainder for planting. With modern instrumentation an analysis can be performed in -10 minutes. The quantity of protein may be determined by integration of the total photoelectron peak associated with the N, levels. Two measurements of the quality of protein were employed.The basic amino-acids lysine arginine and histidine can be estimated from a deconvolution of the N, levels into amino and amide types. The sulphur-containing amino-acids cystine cysteine and methionine can be estimated from the Szpcore levels. Typical data for Rapida Oats and Light Red Kidney Bean are included in Table 15. Table 15 Comparison of results for analysis of grain protein using ESCA and conventional analysis Seeti Elemental analysis "/,N (ESCA) "N (wet %S (ESCA) %S (wet analysis) analysis) Rapida Oats 2.2 f0.2 1.9 0.2 0.1 f0.3 0.02 0.02 Light Red Kidney Bean 3.2 f0.3 4.1 & 0.3 0.08 f0.04 0.13 f0.06 Light'x basic Red Kidney Bean A.A. 17.5 f5 17.4 It should perhaps be emphasized that in studying solids ESCA is essentially a surface technique and depending on the core level studies and using the usual photon sources the escape depth of photoelectrons is in the range CrlOOA.Thus ESCA provides a powerful tool for surface analysis and applications in biological chemistry (e.g. cell walls) will undoubtedly be of considerable import- ance in the future. Preliminary studies on nucleic acid bases" and t-RNA72 have already appeared. 7' M. Barber and D. T. Clark Chrtn. Cnmm. 1970 22 23 24. 72 L. D. Hulett and T. A. Carlson Clinical Chem. 1970 16 677. f1s A x10 U 'lt1' --t.f't ' 25.fi.l. 695 I 690 610 630 650 292 288 284 278 270 206 198 28 50 32. 16 8 Binding energylev Kinetic cnergyleV Binding energy / eV Figure 15 High-resolution photoelectron spectrum of CF,CHCI excited by MgKa,, Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA Theoretical Chemistry.-Having measured a spectrum one is posed with the problem of interpreting it qualitatively and quantitatively in terms of the elec- tronic structure of the molecule.In general however it is not the absolute binding energy of a given core level which is of interest but the ‘shifts’ with respect to some reference. It has been shown73 from extended-basis-set calculations on small molecules that ‘shifts’ in core binding energies may be quantitatively described by considering the orbital energies of the neutral molecules. It is of considerable interest therefore to see if minimal-basis-set ‘ab initio’ calculations on larger molecules can also adequately describe shifts in core binding energies.In an extensive series of studies Clark and co-w~rkers~~~~ have now investigated this point for a considerable number of important organic molecules for which non-empirical calculations are available. Of particular interest are the results for the five-membered ring heterocycles pyrrole furan and thiophen 74 the and six-membered ring heterocycles pyridine and pyra~ine,~~ the bicyclic hydrocarbon naphthalene.’ The five-membered ring heterocycles have also been investigated by Siegbahn and co-~orkers~~ and the results are compared in Table 16. The results are in good overall agreement notable features being Table 16 Calculated and observed C, shifts Molecule ShiftIeV Experimental Re$ calculatedfrom shiftlev orbital energies Py rr ole ~(2~3) 1.25 0.90 74 0.98 77 1.10 74 1.20 77 Thiophen C(2)-C(3) 0.0 0.0 74 0.3 0.3 77 Pyridine C(2tC(3) C(2)-C(4) -0.8 -0.6 -0.4 76 Pyrazine Naphthalene C-C(2) (pyridine) C( 2)-C( 9) 0.5 1.o 0.6 0.8 76 75 the observed and calculated trends of shifts in the order thiophen < pyrrole < furan for the five-membered rings and the alternation in binding energies in the pyridine ring.For naphthalene the higher binding energies of the bridgehead carbons are confirmed. Non-empirical calculations are not feasible on the vast majority of compounds of interest to the organic chemist and a considerable effort has therefore been 73 Cf.D. W. Davis J. M. Hollander D. A. Shirley and T. D. Thomas J. Chrm. Phys. 1970,52 3295. 74 D. T. Clark and D. M. J. Lilley Chem. Phys. Letters 1971 9 234. 75 D. T. Clark and D. Kilcast J. Chem. SOC.(B) 1971 2243. ’‘ D. T. Clark R. D. Chambers D. Kilcast and W. K. R. Musgrave J. C. S. Faruduy II 1972 68 309. ’’ U. Gelius C. J. Allan G. Johansson H. Siegbahn D. A. Allison and K. Siegbahn UUIP 746 Institute of Physics Uppsala 1971. D.T.Clark expended to develop reliable theoretical models which can be used to quantify results for larger molecules. By expanding the expression for the Fock orbital energies it is possible to show that the binding energy of a core level is related to the charge distribution in a molecule.68 The relationship [equation (14)]has been extensively discussed in the literature and shifts in C, levels for substituted aliphatic,6y aroma ti^,'^ and heterocyclic molecule^^^"^ can be quantitatively described by the charge potential model in terms of CND0/2 SCF MO charge distributions.(Figure 16 shows one such correlation for aromatic hydrocarbons and their perfluoro- analogue^).^^ The model can also be used to assign core levels when there is ambiguity. For thiazole for example the CISspectrum appears as three distinct peaks and the assignment Figure 16 Plot of binding energieslev corrected ,for the Madelung potential against the charge as calculated by the CNDOI2 method for the C, levels for aromatic hydro- carbons and perjluoro-analogues may be made74 on the basis of CND0/2 calculations.The results are shown in Table 17. From equation (14) it is evident that molecular core binding energies reflect the overall potential at each atom provided by the valence electron distribution and therefore they tend to parallel what might be termed the organic chemists’ Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 97 Table 17 Calculated and experimental electron binding energies of thiazole Atom Calculated rel. E~perimental’~ binding energylev binding energylev urom equation ( 1411 C(4) +0.7 +0.4 (32) (0.0) (0.0) (25) -1.2 -0.7 ‘intuitive’ charge distributions derived from considering the chemistry of the This most valuable feature of ESCA that the shifts in binding energies can be quantitatively described by calculations on the ground-state molecule will be discussed in more detail below.Relationship to Other Data.-Thermodynamic Data. In a brilliantly original approach Jolly and Hendrick~on~**~~ have shown that it is possible to estimate thermodynamic data from measured core binding energies and vice versa. Particularly valuable information which may be obtained in this way includes the gas-phase proton affinities for organic molecules. Table 18shows some represen- tative data.77 Table 18 Proton afinitie~,~* estimated using ESCA Compound Proton afinitylkcal mole-Pyrrole 247 CH,NH 247 CH,CONH 239 n-C,H,OH 202 C,H50H 192 Clark and Adamsso have utilized the equivalent-core thermodynamic approach in a study of shifts of core binding energy in halogenated methanes.Theoretically calculated heats of reaction give a good overall account of shifts in C, levels within the limited series of fluorinated and chlorinated methanes. This provides an alternative to the use of the charge-potential model for assigning and quantita- tively discussing shifts in core binding energies. N.M.R. Chemical Shifts. The shift in core binding energies on a given nucleus can be related theoretically to the diamagnetic contribution to the (n.m.r.) chemical shift for that nucleus.*’ It seems likely therefore that ESCA studies will provide valuable information complementary to that obtained in many cases by n.m.r. For a closely related series of compounds it can be shown that the 78 W.L. Jolly and D. N. Hendrickson J. Amer. Chetn. Soc. 1970 92 1865. 79 Cj J. M. Hollander and W. L. Jolly Accounts Chem. Res. 1970 3 193. 8o D. T. Clark and D. B. Adams Nature Physical Science 1971 234 95. ’’ H. Basch Chem. Phys. Letters 1970 5 337. 98 D.T.Clark factors dominating the screening constant for a given nucleus are similar to the factors contributing to the shift in molecule core binding energy.69 This has been nicely dem~nstrated~~ for the series CH, CH,Cl, CHCI, CCl, and a linear relationship between 13C chemical shift and C1 binding energy exists. These data69 also illustrate the limitations of ESCA in terms of resolution compared with high-resolution n.m.r. spectroscopy. In going from CH to CCl for example the C, shifts span a range of 7.1 eV with typical line- widths of 1.2 eV using MgKa,.photon source. The corresponding figures for 13C n.m.r. are 100 p.p.m. and -0.1 p.p.m. By far the largest contribution to the C,,linewidths comes from the photon source (-0.8 eV) and the advent of X-ray monochromators with the concomitant decrease in photon linewidth will considerably improve the attainable resolution in ESCA. It should be empha- sized however that the natural linewidths of core levels of interest to organic chemists are not inconsiderable e.g. for C, 5 0.2eV so that even with mono- chromatization the ratio of total shift to natural linewidth will still be considerably larger fdr 13C n.m.r. ESCA does of course have many areas of application in organic chemistry where n.m.r.spectroscopy cannot compete (e.g. the study of certain polymers study of surfaces etc.); however in many fields of application the two techniques give complementary data and hence too much stress should not be Fut on competition between the two as structural tools. One point which may not yet be appreciated is the fact that ESCA gives the chemist one of the fastest timescale measurements typically -10-l5 s and can therefore provide information for some systems not available to the relatively long timescale encountered in n.m.r. spectroscopy. Application to Organic Systems.-Systematic Investigations of Substituent Eflects. The results of systematic investigations have been published for a wide variety of organic molecules ranging from organosulphur compounds8 to halogenated aliphati~,~~?~ aroma ti^,^^^^^ and heterocyclic corn pound^.^^.^^ The factors determining substituent effects are now well understood and the results may be quantified in terms of either non-empirically calculated orbital energies or the charge-potential model.A few representative examples illustrate the immediacy of results. The shifts in C1 binding energies as a function of substituent X in the series CC1,X and CC1,HX have been investigated and the results are shown in Figure 17. Overall electron-attracting groups (with respect to H) increase the binding energy e.g C1 CF, Br CCl, whereas electron- releasing substituents such as Ph decrease the binding energy. The shifts in core binding energy therefore reflect fairly directly the organic chemists’ qualita- tive ideas concerning the charge distribution about the carbon atom.This is also shown by the results for monosubstituted benzenes.84 In fluorobenzene for example the order of decreasing C, binding energy is C(l) > C(3)C(5) 82 U. Gelius P. E. Heden J. Hedman B. J. Lindberg R. Manne R. Nordberg C. Nord-ling and K. Siegbahn Phys. Scriptu 1970 2 70. 83 B. J. Lindberg J. Bernt K. Hamrin G. Johansson U. Gelius A. Fahlman C. Nordling and K. Siegbahn Phys. Scriptu 1970 1 286. 84 D. T. Clark D. Kilcast and W. K. R. Musgrave Chem. Comm. 1971 516. Physical Methods-Part (iii)Theoretical Organic Chemistry and ESCA Figure 17 Correlation between C, levels for the series CC1,X and CHC1,X (meta) > C(2)C(6)(ortho)> C(4)(para) and this again parallels the organic chemists’ ‘intuitive’ charge distributions.The effect of halogen substitution on molecular core binding energies has been extensively investigated for polycyclic aromatic hydrocarbons’ and six-membered-ring heterocycle^.^ With the information derived from fundamental series such as these the way is now open to development of the technique as a major structural tool. Structural Applications. (a)Carbonium ions. Preliminary accounts of two exciting applications of ESCA to carbonium ion chemistry have been reported. Olah and co-~orkers~~ have measured the C, levels of t-butyl trityl and tropylium cations. The measured C, levels for t-butyl cation reveal the high positive charge at C(1) and the shift between C( 1) and the methyl carbons of 3.4 eV may be compared with the results obtained from an ‘ab initio’ calculation of orbital energy differences of 4.45eV.(There are sound theoretical reasons why the two should not be identical since the calculation neglects lattice contributions to the shift which are of some importance for charged species.) By contrast both trityl and tropylium cations studied as their hexafluoroantimonates show only a single C, line behaviour that is consistent with extensive charge de- localization. A preliminary account has also been presented of studies on 1- adamantyl and norbornyl cations.86 By comparing the two it would appear that the formal charge in norbornyl cation is extensively delocalized which strongly suggests a non-classical structure for the ion.(b) Structure ofthiathiophthens. The electronic structure of 6a-thiathiophthens has intrigued chemists for some considerable time and the question of a sym- *’ G. A. Olah G. D. Mateescu L. A. Wilson and M. H. Gross J. Atner. Chem. Soc. 1970 92 7232. 86 G. D. Mateescu and J. L. Reimen-Schneider Asilomar International Conference on Electron Spectroscopy 1971 to be published by North-Holland Publishing Co. Amsterdam. 100 D.T. Clark metrical (1) or unsymmetrical (2) structure has now been investigated by ESCA.S~-S~ m s-s s By measuring the sulphur molecular core binding energies in principle a fundamental distinction may be made between the two possible structures. CNDO SCF MO calculations for example on symmetrical and unsymmetrical structures used in conjunction with the charge potential model predict that in the symmetrical structure the core levels of the central sulphur atom should be much more tightly bound than those for the two outer sulph~rs.~~*~~ For an unsymmetrical structure however the three sulphurs are predicted to have different core binding energies in the order S(6) < S(l) 4S(6a).For the un- symmetrically substituted 2-methylthiathiophthen and for the sterically crowded 3,4-diphenylthiathiophthen the results are clear-cut and the observation of three distinct sulphur core binding energies for each molecule demonstrates that these molecules have unsymmetrical ring geometriess8 (i.e. one short and one long S-S bond).For the 3,4-diphenyl derivative this result confirms the X-ray crystallographic data. For the symmetrically substituted 2J-dimethyl derivative an interesting situation has developed since Clark et a/.* have interpreted these results in terms of a symmetrical ring structure whereas Lindberg et al. prefer an unsymmetrical ring str~cture.'~ The difference in interpretation may arise from different linewidths for the central and terminal sulphurs. If Lindberg's datas9 are re-interpreted in terms of a symmetrical structure the two sets of data in regard to absolute binding energies and shifts between terminal and central sulphurs are in complete agreement. Clearly further work is indicated to be necessary in this system. (c) Polymers. An interesting feature of ESCA as a spectroscopic tool is the relatively small increase in linewidth (in the absence of specific interactions such as hydrogen-bonding) in going from the gaseous to the solid phase.Since the factors which determine the shifts of core levels are of relatively short range [see equation (14)] it seems likely that linewidths for polymers might be little different from those for monomers. This has now been confirmed. Clark and Kilcast" have made a detailed study of both the core and valence energy levels of polytetrafluoroethylene. The spectrum (Figure 18) shows that line-widths for the core levels of the homopolymer are only some 20 % larger than those for the monomer. This points to the likely utility of ESCA for structural studies in 87 D.T. Clark D. Kilcast and D. H. Reid Chem. Cornm. 1971 638. " D. T. Clark and D. Kilcast Terrahedron 1971 27 4367. 89 R. Gleiter V. Hamrig B. Lindberg S. Hogberg and N. Lozach Chem. Phys. Letters 1971 11 401. 90 D. T. Clark and D. Kilcast Nature Phys. Sci.,1971 233 77. Physical Methods-Part (iii) Theoretical Organic Chemistry and ESCA 101 organic polymers since the resolution will be little different from that obtainable on monomeric systems. The sharp well-defined valence energy levels have been assigned on the basis of SCF MO calculations on model systems and in order of decreasing binding energy the peaks may be assigned to core-like F2sorbitals C-C bonding orbitals C-F bonding orbitals and Fzplone-pair orbitals. Carbon 1s Valence band 5xld c.ps.B CD x3 Fluorine Is A \ 694 692 690 688 20 Figure 18 Fluorine 1s and carbon 1s core levels and the valence levels of a pressedjilm of PTFE on a gold backing obtained with MgKa,,2 radiation (Reproduction by permission from Nature Phys. Sci. 1971 233 77)

ISSN:0069-3030    

DOI:10.1039/OC9716800043

出版商:RSC    

年代:1971

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 N.W.3 FORsome time there has been a change in emphasis in optical rotatory dispersion (0.r.d.) and circular dichroism (c.d.) studies. Originally the main interest of the technique lay in its application to configurational assignments (both relative and absolute configurations) and also to problems of conformation. Subsequently beginning with the ketone octant rule,’ there was great interest in the semi- empirical regional rules which relate the sign of a Cotton effect to the molecular geometry around the chromophore and also in the exploration of new chromo- ph~res.~,~ More recently the centre of interest has become the nature of the electronic interactions between chromophores and the identity of the transitions responsible for the observed Cotton effects.This change in emphasis has accom- panied the growth of other techniques which can be employed to study molecular configuration and conformation (particularly n.m.r. and X-ray crystallography). It is significant that between 60 and 70 % of all o.r.d./c.d. papers published during 1971 were concerned chiefly with the interactions between two adjacent groups (either two chromophores or one chromophore and a substituent) or with the electronic basis for previously formulated semi-empirical regional rules. Com- paratively few papers in this period were concerned primarily with assignment of configuration or conformation.A monograph on the theory of optical activity has appeared during the year5 and also a short introduction to the chiroptical technique^,^ designed to give adequate background information to those wishing to apply the technique to stereochemical problems. For early work see C. Djerassi ‘Optical Rotatory Dispersion,’ McGraw-Hill New York and London 1960. W. Moffitt R. B. Woodward A. Moscowitz W. Klyne and C. Djerassi J. Amer. Chern. Soc. 1961 83 4013. For summary see P. Crabbe ‘Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry,’ Holden-Day San Francisco 1965 and French edition Gauthier- Villars Paris 1968. P. Crabbe ‘An Introduction to the Chiroptical Methods in Chemistry,’ available through Syntex S.A. Apartado 10-820 Mexico.D. J. Caldwell and H. Eyring ‘The Theory of Optical Activity,’ Wiley-Interscience New York and London 1971. 102 Physica! Methods-Part (iu)O.R.D.and C.D. 1 Compounds containing Carbonyl Groups Olefinic Bonds and Related Chromophores The most significant developments this year have been the study of interactions between substituent and the carbonyl chromophore,6-10 and the concept of allylic and homoallylic axial bond chirality. Hudec and his colleagues6 have extended their previous work” to cr-amino- ketones derived from camphor (1; R = NH ,NHMe or NHEt) and have shown that coupling of the n,n* and O,G* energy levels is enhanced where the nitrogen can adopt a W arrangement with respect to one of the lobes of the carbonyl group and that there is a red shift of the c.d.maximum compared with the parent ketone. For ketones with y-substituents7 and &substituents,* c.d. spectra indicate that interaction takes place between the substituent and the chromophore uia o-bonds when a W path exists between the two groups e.g. a 3P-substituent (but not a 3a) in a 5a-steroid 7-ketone (2). It is significant that this interaction can XdXo H be detected by c.d. but not by U.V. measurements an example of the greater sensitivity of c.d. as a spectral probe. Lightner and Beaversg have studied the n -+n* carbonyl transition in some interesting By-cyclopropyl ketones and their results have emphasized that it is the exact geometry of the molecule which determines whether two groups are A.H. Beckett A. Q. Khokhar G. P. Powell and J. Hudec Chem. Comm. 1971 326. M. T. Hughes and J. Hudec Chem. Comm. 1971 805. G. P. Powell and J. Hudec Chem. Comm. 1971 806. D. A. Lightner and W. A. Beavers J. Amer. Chem. Soc. 1971 93 2677. lo C. Coulombeau and A. Rassat Bull. Soc. chim. France 1971. 516. I’ A. W. Burgstahler and R. C. Barkhurst J. Amer. Chem. SOC.,1970,92 7601; cf. J. K. Gawronski and M. A. Kieczewski Tetrahedron Letters 1971 2493. R. N. Totty and J. Hudec Chern. Comm. 1971 785. l3 A. F. Beecham A. McL. Mathieson S. R. Johns J. A. Lamberton A. A. Sioumis T. J. Batterham and J. G. Young Tetrahedron 1971 27 3725. l4 A. F. Beecham Tetrahedron 1971 27 5207. J. Hudec Chem. Comm. 1970 829. 104 P.M. Scopes weakly or strongly interacting.The literature data for cyclohexanones in rigid arrays of cyclohexane rings have also been surveyed" in order to study the contributions made to the carbonyl Cotton effect by alkyl groups in various positions. Several groups of workers have been studying the strong n-+7c* Cotton effects of conjugated dienes and enones whose signs have previously been ration- alized according to the helicity of the conjugated system. Burgstahler' ' has now suggested that the primary factor controlling the sign of the Cotton effect is asymmetric perturbation of the chromophore through excited state interactions with allylic axial (or pseudo-axial) bonds. The same conclusion has been reached by a study of A4-3-keto-steroids.'2 In particular the significance of an allylic oxygen substituent has been studied by Bee~ham'~~'~ who has shown that for conjugated dienes with an allylic oxygen substituent that part of the helical system which contains one double bond and the allylic oxygen predominates over that part of the helix which contains two double bonds in determining the sign of the observed Cotton effect (3).The influence of allylic oxygen on isolated cisoid; +ve cisoid; -ve transoid ; +ve transoid ; -ve (3) X-Y is C=C or C-0 double bonds has been studied in detail by Scott and Wrixon,16 and Beecham14 has pointed out that the concept of interaction between substituent and chromo- phore (e.g.allylic oxygen and a double bond) has blurred the previous distinction between an inherently dissymmetric chromophore and a symmetrical chromo- phore that is dissymmetrically perturbed.Other important work on isolated double bonds includes further analysis of methylene steroids by the olefin octant rule" and a development of work with platinum(rI)+lefin complexes.' * l6 A. I. Scott and A. D. Wrixon Tetrahedron 1971 27 4787. M. Fetizon I. Hanna A. I. Scott A. D. Wrixon and T. K. Devon Chem. Comm. 1971 545. I' A. I. Scott and A. D. Wrixon Tefrahedron 1971 27 2339. Physical Methods-Part (iu)O.R.D. and C.D. Two opposing views of the probable conformations of a-diketones have been put Hug and Wagnikre" have calculated the ground states and excited states of butadiene acrolein and glyoxal and have used their results as models to predict the optical activity of dienes enones and diones.They propose that the sign of the Cotton effect in a-diketones is governed by the helicity of the ground and excited states. Burgstahler2' suggests that particularly in view of the evidence from dienes and enones axial bond chirality contributions will be very important; this leads to opposite conclusions about the chiralities of par- ticular diketones and X-ray studies may be necessary to resolve the difference. A very detailed study has been made of the a-diketone camphorquinone,2' and of a number of related z-oximino-ketones.22 2 Compounds containing Carboxyl and Related Chromophores Recent c.d. work with compounds containing carboxyl chromophores has shown the same preoccupation with the interactions of neighbouring groups as have ketone and olefin studies particularly with respect to &-substituted Gaffield and Galett~~~ have made a very detailed study of x-chloro- and a-bromo-alkylcarboxylic acids which show two c.d.bands in the n +n* region. The authors suggest that these bands arise from two different conformations in which the carbonyl oxygen eclipses the (C-a)-halogen (4a) and the (C-a)-alkyl bond (4b) respectively. The signs of the observed Cotton effects are then ration- alized by a rule analogous to the ketone octant rule.2 a-Alkyl-a-mercapto-carboxylic acids24 also show more than one c.d. band in the n-+n* region. The long wavelength lowest energy band at 271 nm may be attributed to a less stable conformer in which coupling occurs between the carboxyl chromophore and a non-bonded orbital of the hetero-atom (cf previous work on amino- acids).28 The c.d.spectra of z-arylcarboxylic acids are difficult to interpret because transitions of the isolated chromophores (carboxyl n -+n* and aromatic 'La IY W. Hug and G. Wagniere Helc. Chirn. Acta 1971 54 633. 20 A. W. Burgstahler and N. C. Naik Hek. Chirn. Acta 1971 54. 2920. 21 E. Charney and L. Tsai J. Amer. Chern. Soc. 1971 93 7123. 22 H. E. Smith and A. A. Hicks J. Org. Chem. 1971 36 3659. 23 W. Gaffield and W. G. Galetto Tetruhedroiz 1971. 27. 915. 24 P. M. Scopes R. N. Thomas and M. B. Rahman. J. Chc>tir.Soc. (0, 1971 1671. 25 J. C. Craig W. E. Pereira B. Halpern and J. W. Westley Tetrahedron 197 1 27 1 173. 26 0. Korver Tetrahedron 1970 26 5507.27 W. Klyne P. M. Scopes R. N. Thomas and H. Dahn Helo. Chirn. Acta 1971 54 2420. 28 J. C. Craig and W. E. Pereira Tetrahedron Letters 1970 1563; Tetrahedron 1970 26 3457. 106 P.M. Scopes band) occur in the same region of the spectrum and the extent of interaction between the chromophores is unknown. Three groups of workers have studied 7929 this problem2 5-2 and have reached different conclusions. Craig and his colleagues25 consider that the two transitions they observe between 210 and 230nm are attributable respectively to the 'La aromatic transition and to a mixed transition involving overlap of n-orbitals from both chromophores. Con- versely Djerassi2' has suggested that in a-substituted phenylacetic acids the Cotton effects at short wavelength are primarily due to the carboxyl n +n* transition.Recent work with cr-aryl-a-amir~o-acids~~ has shown that the strong Cotton effects occurring between 210 and 230nm arise from the superposition of at least two separate bands. The experimental c.d. curves can be analysed by means of a curve resolver into two sets of Gaussian components near 218 nm and 200nm respectively and it is suggested that these correspond to carboxyl n -+ n* and aryl 'La transitions. However more than one curve analysis of the experimental results is possible and more work is still needed. Closely related to work on a-aryl acids is an important detailed paper on substituted ben~amides.~' A careful comparison is made between the U.V. and c.d.spectra and the authors conclude that the observed c.d. can be interpreted best by assuming that the n+n* transition of the benzamido-chromophore is responsible for the Cotton effect observed at -24&250 nm between the 'L and 'La aromatic bands. Amides of aldonic acids have also been in~estigated.~~ The c.d. spectra of some cyclic hexapeptides containing S-benzylcysteinyl residues have been used to investigate the orientation of the aromatic chromo- phores relative to the main peptide ring.32 Cyclic peptides of ala~~ine~~ and of glutamic acid34 have also been investigated. 3 The Aromatic Ring and Related Chromophores Various regional rules for aromatic chromophores have been published over the past few years and an attempt has now been made to interrelate these3' in terms of the contributions of second third and fourth chiral spheres.As for other chromophores there has been interest in the interactions of two separate aro- matic groups e.g. in a series of phenyl- and diphenyl-alkylamine hydrochlorides studied by Smith and Willi~.~~ Their work demonstrates that when two phenyl groups are connected by three or more a-bonds no vicinal interaction occurs 29 G. Barth W. Voelter H. S. Mosher E. Bunnenberg and C. Djerassi J. Amer. Chem. Soc. 1970 92 875. 30 W. C. Krueger R. A. Johnson and L. M. Pschigoda J. Amer. Chem. Soc. 1971 93 4865. 31 K. Kefurt Z. Kefurtova J. Nemec J. Jary I. Frit and K. Blaha Cull. Czech. Chem. Comm. 1971 36 124. 32 K. Blaha I. Frit Z. Bezpalova and 0. Kaurov Coll.Czech. Chem. Comm. 1970 35 3557; cf. T. M. Hooker and J. A. Schellman Biopolymers 1970 9 1319. 33 V. T. Ivanov V. V. Shilin G. A. Kogan E. N. Meshcheryakova L. B. Senyavina E. S. Efremov and Yu. A. Ovchinnlkov Tetrahedron Letters 1971 2841. 34 M. Kajtar M. Hollosi and G. Snatzke Tetrahedron 1971 27 5659. 35 G. Snatzke and P. C. Ho Tetrahedron 1971 27 3645. 36 H. E. Smith and T. C. Willis J. Amer. Chem. Soc. 1971 93 2282. Physical Methods-Part (iu)O.R.D.and C.D. 107 but when the groups are separated by only one or two a-bonds homo- conjugation occurs and there is a large enhancement of the observed aromatic transition. The rotational strengths of a number of complex molecules have been cal- culated by Mason and his co-workers using a n-SCF approximation.The compounds studied include the alkaloid ~alycanthine,~ [5]helicene and the related dibenzo[e,g]phenanthrene-9,1O-carboxylicacid,38 and [6]helicene and [7]heli~ene.~~ The results show that the dextrorotatory isomers of [4]-,[5]- [6]- and [7]-helicene all have the (P)-configuration (right-hand helix) as suggested by simpler polarizability and free electron models. A detailed account of the chiroptical properties of the vespirenes (9,9'-spiro- bifluorene derivatives) has been p~blished,~' and also further work on the optical activity of allene~~'.~~ and the physical basis of the Lowe-Brewster rule. 4 Work on Configuration and Conformation Despite the current emphasis on the nature of the electronic transitions respons- ible for observed Cotton effects there has also been notable work on configura- tional assignments in a wide range of compounds including lythraceae alkaloids,43 binaphthyl~,~~ In the two latter cases the absolute con- and l-aryltetralin~.~~ figurations assigned by c.d.measurements have been confirmed by X-ray crystal analysis. A combination of chemical and chiroptical methods have been used to establish the absolute configuration of ( [by comparison with (+)-a-carotene] and of (+)-ci~-y-irone~~ [by comparison with (-)-camphor and (+)-cis-a-irone]. The c.d. of less-common amino-a~ids~~ and of methylisothio- cyanate amino-acid add~cts~~ has also been reported. Some important alkyl tetralones have been investigated by Snatzke and his co-~orkers.~'The absolute configurations of the molecules are known and c.d.measurements were used to study the probable conformation. '' W. S. Brickell S. F. Mason and D. R. Roberts J. Chern. Soc. (B) 1971 691. 3* A. Brown C. M. Kemp and S. F. Mason J. Chem. SOC.(A) 1971 751. 3q W. S. Brickell A. Brown C. M. Kemp and S. F. Mason J. Chem. Soc. (A) 1971 756. 4o G. Haas P. B. Hulbert W. Klyne V. Prelog and G. Snatzke Helc. Chim. Actu 1971 54 49 1. 41 P. Crabbe E. Velarde H. W. Anderson S. D. Clark W. R. Moore A. F. Drake and S. F. Mason Chem. Comm. 1971 1261. 42 H. Wynberg and J. P. M. Houbiers J. Org. Chem. 1971 36 834. 43 J. P. Ferris C. B. Boyce R. C. Briner U. Weiss I. H. Qureshi and N. E. Sharpless J. Amer. Chern. SOL-.,1971 93. 2963. 44 P. A. Browne M.M. Harris R. Z. Mazengo and S. Singh J. Chem. Sor. (C),1971 3990. 4s W. L. Bencze B. Kisis R. T. Puckett and N. Finch Tetrahedron 1970 26 5407. 46 R. Buchecker and C. H. Eugster Heh. Chim. Acta 1971 54 327. 47 V. Rautenstrauch and G. Ohloff Heh. Chim. Acfa 1971 54 1776. 48 L. Fowden P. M. Scopes and R. N. Thomas J. Chem. Soc. (C) 1971 833. 49 C. Toniola Tetrahedron 1970 26 5479. J. Barry H. B. Kagan and G. Snatzke Tetrahedron 1971 27 4737. 108 P.M. Scopes 5 New Chromophores The n+n* transition of cyclic thionocarbonates has been studied in detail; the signs of the Cotton effects are related to the chirality of the five-membered thionocarbonate ring. The 3-cephem chromophore (5) has been studied in a series of cephalosporin antibiotic^.^^ The authors show clearly that the c.d.spectra (which show two bands of opposite sign) are a more sensitive spectral tool than U.V. measure-ments (which show one maximum only) for these compounds. The longer wave- length band at -260 nm has previously been attributed to the interaction of the n-electrons of the double bond with lone-pair electrons on the nitrogen atom ; the present work attributes the 230 nm band to overlap of the n-orbitals of the p-lactam and double bond. y2 CH(CH,),CONH I CO2H 0 co,H ” A. H. Haines and C. S. P. Jenkins J. Chrnz. Soc. (C) 1971 1438. ’’ R. Nagarajan and D. 0.Spry J. Amer. Chem. Soc. 1971 93 2310.

ISSN:0069-3030    

DOI:10.1039/OC9716800102

出版商:RSC    

年代:1971

数据来源: RSC

摘要:

2 Physical Methods Part (v) X-Ray Crystallography By A. FORBES CAMERON Chemistry Department The University of Glasgow G12 8QQ 1 Introduction OFthe more general crystallographic publications which have become available in recent months one in particular merits special comment. This two-volume reference work contains 4473 references to 4098 distinct carbon-containing compounds the structures of which had been reported up to 1969. Both for crystallographers and for those who wish to use crystallographic results these books will greatly simplify the identification and location of structures which have already been studied. It is to be hoped that this effort will be extended to include purely inorganic compounds and that the data will be regularly updated.In previous reports structure analyses have been selected for discussion according to the types of compounds which have been studied. This approach has been abandoned in the preparation of this article which has been written in an attempt to convey an impression of the results and conclusions which are currently being derived from crystal-structure analyses. The criteria for selecting analyses for inclusion have therefore been either the reasons which provoked a particular analysis or the information which resulted from it. The discussion is under four main headings which it is hoped broadly summarize the main fields of crystallographic interest in organic compounds. By this technique the author hopes to have produced a critique which will help to demonstrate the relevance of X-ray studies during the past year.2 ConformationalStudies One interesting aspect of conformational studies has been the report of the crystallographic investigation of the orientation and conformation of a guest molecule in a clathrate inclusion-compound.2 The thiochroman (1) forms clath- rates in which the guest molecule in this case the acetylenic compound (2) is accommodated in a cavity approximating to an hour-glass in shape (3). The guest molecule is held in the clathrate with the acetylenic bond contained by the ‘waist’ of the cavity and with the bulkier tetrahedral units projecting into the ‘Molecular Structures and Dimensions,’ ed. 0.Kennard and D. G.Watson Cambridge Crystallographic Data Centre and I.U.Cr. vols. 1 and 2 1970.’ D. D. MacNicol and F. B. Wilson Chem. Comm. 1971 786. 109 A. Forbes Cameron upper and lower halves of the cavity. All the guest molecules are found to adopt a staggered conformation with statistical disorder of the hydroxy- and methyl- groups to conform with the imposed 3 crystallographic symmetry of the cavity. C Ill ;=r-6 c Me+Me I \ OH There have been several analyses of corrinoid and phthalocyanine derivatives for the most part carried out to investigate distortions of the macrocyclic ring systems whether inherent in the unsubstituted molecule or induced by the presence of oversized metal atoms. For example the corrole derivative 8,12-diethyl-2,3,7,13,17,18-hexamethylcorrole(4),3 is not strictly planar the non-planarity probably being a property of the ring system itself and attributable Me Me I Me Me both to short N-e-Nnon-bonded contacts and also to the direct C(l)-C(19) link.In this case there is in addition crystallographic evidence that the three inner hydrogen atoms are statistically distributed between the four nitrogens. A non-planar conformation is also deduced from the analysis the first in a particularly elegant series by Dunitz and co-workers of the synthetic corrinoid H. R. Harrison 0.J. R. Hodder and D. C. Hodgkin J. Chem. SOC.(B). 1971 640. Physical Methods-Part (v) X -Ray Crystallography derivative Ni"-1,8,8,13,13-pentamethyl-5-cyano-tra~~s-corrinchloride (5),4 in which the tendency of the nickel atom towards tetrahedral co-ordination is reflected in distortions throughout the entire corrin ligand-system.The synthetic precursor of (5) the c/D-seco-corrinoid Nil' complex (6),' has also been studied to investigate the role of the complexed nickel atom in holding the molecular conformation such that the cyclization reaction may easily take place. The analysis reveals that the almost tetrahedral nickel co-ordination results in the condensation centres lying close together in such a way that the reaction can CN CN take place with a minimum of molecular reorganization. In a similar investiga- tioq6 the structure of the A/D-seco-corrinoid complexes of Ni" Pd" and Pt" have been determined differences between the structures being of relevance to the case of the photochemical cyclization (7)+ (8) which has the order Pd" > Pt" with the Ni" complex completely resisting both photochemical and thermal cyclization.The analyses show that there is virtually no conformational Me Me Me Me Me> Me Me h1' ___) CN CN (7) (8) difference between the Pd" and Pt" compounds which tend to be planar and lead to the conclusion that electronic factors probably play an additional role in determining the relative reactivities of these two compounds. On the other hand the conformation of the Ni" complex is quite different showing a tendency ' J. D. Dunitz and E. F. Meyer jun. Helr. Chim. Acra 1971 54 77. ' M. Dobler and J. D. Dunitz Hrlc. Chim. Acfa 1971 54 90. M. Currie and J. D. Dunitz Hell). Chem. Acra 1971 54 98.A. Forbes Cameron towards tetrahedral co-ordination which indicates that the grossly different reactivity of this complex probably results from steric factors. Whereas dichloro- octaethylporphinatotin(~v)’is essentially planar non-planar conformations have been found both for dichlorophthalocyaninatotin(1v)’ and also for a mono- hydrated dipyridinated magnesium-phthalocyznin complex.’ These last three analyses demonstrate that for those macrocyclic ring systems which are not in-herently grossly non-planar the degree of ‘ruffling’ or ‘crumpling’ may be attributed to the size of the central metal atom in relation to the size of the available ‘hole’. Not only is the fifteen-membered cyclic diamide 5,9-dioxo-1,7,13-trioxa-4,10-diazacyclopentadecane nearly planar but the molecule almost possesses C symmetry and there is the additional possibility of multiple N-H..-0hydrogen bonding within the ring. In contrast the eight-membered ring of 3,7-dimethyl-1,5- dioxa-3,7-diazocyclo-octane-2,4,6,8-tetraspirocyclopropane (9),’’ has a crown- like conformation with the cyclopropane groups in two planes perpendicular to the general plane of the ring. Another spiro-compound which has been examined is (S)-(-)-spiro[4,4]nonane-1,6-dione(lo),‘* the crystallographically related rings adopting a conformation intermediate between envelope and half-chair forms but closer to the latter. The results of this analysis have been compared with theoretical valence-force calculations agreement within experimental limits for the most part being obtained.(10) (9) Studies of the geometries and conformations of polycyclic compounds have been nearly all directed towards seeking geometrical evidence for molecular strain which may be related to chemical or spectroscopic properties. Thus the p-chloroanilide derivative of bicyclo[5,3,l]undec-7-en-1 1 -one- 1-carboxylic acid (11)13 represents a case close to the limit for the possible existence of a bridgehead double bond. As a result the molecule exhibits unusual properties behaving in some instances as a conjugated enone and in others as though the n-bond systems were isolated. The analysis reveals a very large degree of twisting in the 7 D. L. Cullen and E. F. Meyer jun. Chem. Comm. 1971 616. n D. Rogers and R.S. Osborn Chem. Comm. 1971 840. 9 M. S. Fischer D. H. Templeton A. Zalkin and M. Calvin J. Arner. Chetn. Soc. 1971 93 2622. LO G. Samuel and R. Weiss Chetn. Conitn. 1970 1654. 11 H. Schenk Acta Cryst. 1971 B27 185. 12 C. Altona R. A. G. de Graaff C. H. Leeuwestein and C. Romers. Chem. Comm. 1971 1305. 13 A. F. Cameron and G. Jamieson J. Chetn. Soc. (B) 1971 1581. 113 Physical Methods-Part (v)X-Ray Crystallography molecule which has the effect of inhibiting complete overlap of the n-bond electrons. Similarly adamantylidene-adamantane (l2)I4 was studied because of chemical interest in addition reactions of the double bond. However the geometry of this molecule shows no abnormal features nor distortions and the molecule possesses approximate mmm symmetry.On the other hand the rather similar and unusual caged hydrocarbon decahydro[ 1,2,4 :5,6,8]dimetheno-sym-indacenedione (13)' which is the dione derivative of Binor-S does show evidence of considerable strain in the nortricyclanone subunits. Molecular strain is also inferred in both 8-carboxy-l-hydroxy-2-oxobicyclo[3,2,2]non-6-ene-9,4-carbo-lactoneI6 and tricyclo[4,3,1,1 3*8]undecane-4,5-dione,''the dihedral angle in the dicarbonyl chromophore of the latter compound being 11.9'. There is also evidence of molecular strain resulting in non-planar conformations of the substituted aromatic rings in cyclophanes. Thus in 8,16-imino-cis-[2,2]- metacyclophane (14),'*the dihedral angle between the aromatic rings is 93' and each aromatic ring is slightly distorted into a boat-like conformation while in [2,2]metaparacyclophane-1,9-diene(15),' both aromatic rings show a significant boat distortion which although only moderate for the meta-bridged ring is severe for the para-bridged ring.In this latter case the aromatic rings are inclined at 41" to each other. l4 S. C. Swen-Walstra and G. J. Visser Chem. Corntn. 1971 82. lS F. P. Boer M. A. Neuman R. J. Roth T. J. Katz J. Amer. Chetn. Soc. 1971 93 4436. l6 D. J. Pointer J. B. Wilford and K. M. Chui J. Chem. SOC.(B) 1971 895. l7 P. B. Braun J. Hornstra and J. I. Leenhouts Acta Cryst. 1970 B26 1802. A. W. Hanson and K. Huml Acta Cryst. 1971 B27 459. l9 A. W. Hanson Acra Crysr. 1971 B27 197. A. Forbes Cameron Analyses of the a-isomers (thermodynamically stable) of several S-alkylthio- hydroximates of which sinigrin and other mustard-oil glycosides are naturally occurring examples reveal that these stable forms possess the syn-(alkylthio) configuration.The particular compounds which have been studied are S-methyl- 0-(N-methylcarbamoy1)aceto t hiohydroxima te (1 6a)2 and the corresponding S-cyanoethyl derivative (16b),20 and S-(cyanoethy1)acetothiohydroximate (17).2 It is worthy of note that the mean N-0 bond length of 1.446 A in (16a) and (16b) which are substituted oximes is considerably longer than the value of 1.41 A in (17) and the value of 1.40 8 found in other free oximes. 0 / R-S \ /o-c N rCCH,CH S OH \/ 'NHMe /C=N /C=N Me H3C (a) R = Me (b) R = CH2CH2CN 3 Bonding Studies There have been several studies of molecular geometries in relation to the bonding in annulenes and related compounds.The cis,trans,cis stereochemistry of cyclodeca-2,4,8-triene-1,6-dione(18),22 which is the diketo-tautomer of 1,6-dihydroxyr lolannulene has been confirmed. The molecule is non-planar and the observed torsion angle of 160" at the traits double bond is consistent with chemical evidence that traits double bonds in medium-ring olefins are subject to considerable strain. 4,9-Methano[l llannulenone (19),23 an analogue of tropone was examined to obtain molecular dimensions for comparison with those of tropones bridged[ lo]- and bridged[ 141-annulenes. The analysis reveals alternation of bond lengths with the valency angles being considerably distorted from 120° and the carbonyl function is found to be syiz with respect to the 2o M.G. Waiteand G. A. Sim J. Chem. Soc. (B),1971 752. 21 M. G. Waite and G. A. Sim J. Chem. SOC.(B),1971 1102. 22 0.Kennard D. L. Wampler J. C. Coppola W. D. S. Motherwell D. G. Watson and A. C. Larson Acta Cryst. 1971 B27 1116. 23 D. W. Hudson and 0.S. Mills Chem. Comm. 1971 153. Physical Methods-Part (v) X -Ray Crystallography bridging methano-group. Another bridged annulene 7-methoxycarbonyl-anti- 1,6:8,13-bismethano[ 14lannulene (20)24also shows striking alternation of bond lengths confirming the polyenic nature of this anti bis-bridged compound in contrast to the aromaticity of the corresponding syiz derivatives.An example of the latter is provided by 1,6:8,13-butanediylidene[14]annulene(21),25 which shows only very slight alternation of bond lengths. 11,l l-Difluoro-1,6-methano-[lolannulene (22)26was studied to investigate the influence of bridge substituents on the hypothetical equilibrium between 1,6-rnethano[lO]annulene and bis- norcaradiene n.m.r. and chemical evidence having indicated that the difluoro- derivative should be an annulene and the dimethyl derivative a bis-norcaradiene. The analysis of the difluoro-derivative confirms that it is an annulene with a non-planar ring and some alternation of bond lengths. Considerable eflort has been devoted to studies of the bonding and conforma- tions of ylides and similar compounds with particular reference to the possibilities of extended conjugation involving d,-p overlap.The two N-ammonio-amidates (23) and (24)27are first-row ylides in which there is no possibility of d,-p overlap between the quaternary ammonium group and the vicinal electronegative atom Me Me \+ Me-.N-N-NO, \+ ~e-N-N Me/ Me/ (23) the only interactions being electrostatic in nature. The two molecules adopt almost identical conformations in which there is possible bifurcated hydrogen. -* oxygen bonding involving in each case two hydrogen atoms one from each of two N-methyl groups. On the other hand in second-row ylides as exemplified by certain sulphurane and phosphorane compounds there exists the possibility of d,-p overlap involving d-orbitals of the sulphur and phosphorus atoms 24 C.M. Gramaccioli A. Mimun A. Mugnoli and M. Simonetta Chem. Comm. 1971 796. 25 C. M. Gramaccioli A. Mugnoli T. Pilati M. Raimondi and M. Simonetta Chem. Comm. 1971 973. 26 C. M. Gramaccioli and M. Simonetta Tetrahedron Letters 1971 173. 27 A. F. Cameron N. J. Hair D. G. Morris and D. M. Hawley Chem. Comm. 1971 725. A. Forbes Cameron respectively. Amongst the sulphurane compounds studied are the two sulphonyl- stabilized ylides (25)28 and (26),” 2-dimethylsulphuranylidene-1,3-indanedione (27),30 trans-4-t-butyl-l-(l\r-ethyl-~-p-toluenesulphonylamino)-I-thionacyclohex-ane fluoroborate (28),3’ and 2,2’-bis-1,3-dithiole (29).32 The dimensions of all five compounds indicate significant levels of d-orbital participation in the bonding and in the case of the dithiole derivative (29) further evidence is provided by CNDO calculations.Similar conclusions are derived from examinations of the phosphorane derivatives (30),28(31)33 and (32).34 The analysis of hexaphenyl- carbodiphosphorane (33)3 raises several interesting if unexplained points having (p-Me . C6H&Pf Ph,P=C=PPh3 (32) (33) 28 A. F. Cameron N. J. Hair and D. G. Morris Chem. Comm. 1971 918. 29 A. Kalman B. Duffin and A. Kucsman Acta Cryst. 1971 B27 586. 30 A. T. Christensen and E. Thom Acta Cryst. 1971 B27 581. ’’ R. E. Cook M. D. Glick J. J. Rigau and C. R. Johnson .I.Amer. Chern. Soc. 1971 93 924. 32 W. F. Cooper N. C. Kenny J. W. Edmonds A. Nagel F. Wudl and P. Coppens Chem.Cnmm. 1971 889. 33 M. J. E. Hewlins J. Chem. SOC.(B) 1971 942. 34 0. Kennard W. D. S. Motherwell and J. C. Coppola J. Chem. SOC.(0, 1971 2461. 35 A. T. Vincent and P. J. Wheatley Chem. Comm. 1971 582. Physical Methods-Part (0) X -Ray Crystallography 117 been undertaken to investigate the geometry of the P=C=P system in the light of evidence that the X=C=C system is not linear when 5 has a vacant d-orbital and in the light also of the 140" angle found in the P=N=P system. However the compound crystallizes with two crystallographically independent molecules in the unit cell one of which has a P-C-P angle of 145" whereas the other has an angle of 131" there being no obvious reason for the difference. Moreover the difficulties of explaining bonding and electron delocalization solely on the basis of bond lengths are exemplified by the analyses of three sulphur-containing heterocyclic compounds.Thus S-C bond lengths of 1.719(3)8 and 1.721( 3) 8 in 4,4'-diacetoxy-5,5'-dimethyl-2,2'-bithiazolyl (34)36 are interpreted as indicating considerable double-bond character while similar lengths of 1.739(3) 8 and 1.763(3) 8 in 2-methylaminobenzothiazole (35)37 are said to be consistent with single bonds. Alternatively the exocyclic S-C bond of length 1.681(5) 8,in 4-amino-3-hydrazino-5-rnercapto-1,2,4-tria~0le~~ is taken to be consistent with contributions from the canonical forms (36) t-)(37). (35) MeOCOk=-( Me y2 N-N "-N H H A greater understanding of compounds which contain short S.-.O intra-molecular interactions has resulted from the studies of the three compounds (38) (39),39and (40),"O the shortest S. *Odistance [2.034(5) A] being found in (38) and the longest [2.373(7)A] in (40). These analyses lead to the conclusion that S...O bonding in nitro-compounds is rather similar to that in corresponding carbonyl compounds whereas stronger interactions are found in nitroso- derivatives as substantiated by the S-preference for nitroso- over either nitro- or 36 K. J. Palmer R. Y.Wong and K. S. Lee Actu Cryst. 1971 B27 1817. 37 M. Fehlmann Actu Cryst. 1970 B26 1736. 38 N. W. Isaacs and C. H. L. Kennard J. Chem. SOC.(B) 1971 1270. 39 P. L. Johnson K. I. G. Reid and I. C. Paul J. Chem. SOC.(B),1971 946. 40 K. I. G. Reid and I.C. Paul J. Chem. Sor. (B),1971 952. A. Forbes Cameron OA Ph NO2 Br (38) (39) (40) carbonyl groups. It is suggested that this may result from the importance of the ten n-electronic thiathiophen structures in the corresponding nitroso-compounds. The rather longer S. * -0interactions found in carbonyl derivatives are exemplified by 3-phenyl-l-propene-1,3-dione-l-(dimethyl mercaptole) (41),41 3,5-bis(pival- oylmethylene)-l,2,4-trithiolan(42),42 and the desaurin from acetophenone (43),43 the shortest interaction [2.509(5)A] occurring in (42),and the longest [2.727(10) A] in (43). There is also the possibility of a long-range S. * -0interaction in 5-methoxy- carbonylmethylene-2-piperidino-A2-thiazolin-4-one.44 The compound (44),45 an oxygen analogue of thiathiophthen is nearly planar and has an almost linear 0-S-0 [176.1(1)"] arrangement.The extremely long S-0 bonds [1.879(2) A] could alternatively be interpreted as representing extremely short S. -0contacts of the above type. 4 Biological Studies In addition to the effects of conformation the particular functions of biologically active molecules are in many cases determined by the possible intermolecular and intramolecular associations which they can form. X-Ray crystallographic studies can often provide information of direct relevance to such structure- activity relationships and are being increasingly applied in this field to the I. P. Mellor and S. C. Nyburg Acta Cryst. 1971 B27,1954. 42 I. P. Mellor and S. C. Nyburg Acra Cryst.1971 B27 1959. 43 I. R.Lynch I. P. Mellor and S. C. Nyburg Acfa Crysr. 1971 B27 1948. J4 A.F. Cameron and N. J. Hair J. Chem. SOC.(B) 1971,1733. 45 R. D. Gilardi and I. L. Karle Acta Cryst. 1971 B27 1073. Physical Methods-Part (v)X -Ray Crystallography 119 extent that the analyses described in this section represent only a very small fraction of the total number of biologically and pharmacologically important molecules which are being studied. Both the relative potencies of the free-acid and anionic forms of barbiturates and also the possible interference by barbiturates in the binding of calcium to phospholipids are subject to considerable controversy. As a result various derivatives and salts of barbituric acid have been extensively investigated.The analysis of calcium 5,Sdiethylbarbiturate (45)46 reveals that the deprotonated nitrogen atoms are co-ordinated to the calcium ions while the remaining pro- tonated nitrogen atoms function as hydrogen-bond donors in the formation of isolated barbital (5,Sdiethylbarbituric acid) dimers. However although the formation of sodium 5,5-diethylbarbiturate4’must also involve loss of a proton from an imine group in this case the formal negative charge is apparently dis- tributed over the oxygen atoms and the molecules are hydrogen-bonded to form ribbons with the sodium ions tetrahedrally co-ordinated by oxygen atoms. The molecular conformation of the barbital anion in the sodium salt is similar to that of barbital48 itself. Barbital also forms several polymorphs in which the individual molecules possess similar dimensions and conformations but differ in the N-Ha * -0 hydrogen-bonded frameworks extending throughout the crystals.For comparison with the above structures 5-ethylbarbituric acid (46a) and 5-hydroxy-Sethylbarbituric acid (46b)49 have been examined the rings in both compounds having a ‘flap’ conformation with C(5) displaced from other- wise nearly planar rings. In contrast with these two compounds 5-ethyl-5-(3’,3’- dimethylbuty1)barbituric acid (46~)~’ has a ring which is virtually planar with r 01 0 (45) (a) R = H (b) R = OH (c) R = CH,CH2CMe (46) the ethyl and dimethylbutyl C(5)-substituents forming a hydrocarbon chain which extends in a direction nearly perpendicular to the ring.This compound differs also in the mode of hydrogen bonding between molecules in the crystal. The activities of many chemotherapeutic and biologically active molecules may be related to the types of complexes which they form in biological environ- ments and structure analyses are now being used to investigate not only the 46 B. Berking Chem. Comm. 1971 674. 47 B. Berking and B. M. Craven Actu Cryst. 1971 B27 1107. 48 B. M. Craven and E. A. Vizzini Actu Cryst. 1971 B27 1917. 4y B. M. Gatehouse and B. M. Craven Actu Cryst. 1971 B27 1337. G. L. Gartland and B. M. Craven Actu Cryst. 1971 B27 1909. A. Forbes Cameron structures of such complexes but also the interactions which are important in their formation.An example of such studies is provided by the examination of the complex formed between the local anaesthetic phenacaine NN’-bis-(4- ethoxypheny1)acetamidium (47a)’ and bis-(p-nitrophenyl) phosphate (47b). This complex is representative of the class of complexes formed between local [p-EtO-C,jH,-NH-C-NH-C,H,-OEt-p] ’ I Me (474 anaesthetics and phosphodiesters and it has been suggested that complex forma- tion of this type may be involved in the bindings of a local anaesthetic molecule to phospholipids in the neural membranes the adduct being instrumental in blocking nerve conduction. The analysis was undertaken to compare the geometry of the complex with the similar complex formed by the local anaesthetic procaine. The analysis of the phosphate complex L-arginine phosphate mono- hydrate52 is similar to the study mentioned above in that the functions of arginine molecules and residues in living matter are characterized by the strong basicity of the guanidyl group and its ability to bind to phosphate groupings.In this complex the arginine molecule is a zwitterion possessing an unusual folded conformation and is bound to the phosphate moieties by hydrogen-bonds. Although pyridoxamine 5’-phosphate hydrochloride5 is not itself a complex of the type described above its study is nevertheless of relevance to complex forma- tion since it is generally accepted that the biological activity of Vitamin B is due in great part to the participation of a phosphorylated derivative pyridoxal 5’-phosphate as a co-enzyme in many enzymatic reactions of a-amino-acids.This analysis again shows the importance of hydrogen bonding in intermolecular associations involving phosphate derivatives. The important ability of many antibiotics to form complexes with metal ions has prompted several extremely interesting investigations of this property. Monensin (48)54 has been examined both as the free acid and as the silver salt. In the metal complex the monensin anion forms a macrocycle secured by a pair of hydrogen-bonds between the two hydroxy-groups and the carboxylate group at opposite ends of the molecule with the Ag’ ion co-ordinated to six oxygen atoms in the resulting cavity. However contrary to previous suggestions the 51 M. Sax J. Pletcher C. S. Yoo and J.M. Stewart Acta Cryst. 1971 B27 1635. ’* K. Aoki K. Nagano and Y. litaka Acfa Crysf.,1971 B27 11. F. Giordano and L. Mazzarella Acta Cryst. 197 1 B27 128. 54 W. K. Lutz F. W. Winkler and J. D. Dunitz Hela. Chim. Acra 1971 54. 1103. Physical Methods-Part (u) X-Ray Crystallography 121 OH Me CH,OH Me )-C0,H Me (48) free acid is also cyclic but differs in the number and arrangement of hydrogen bonds and hence in the relative positions of the oxygen atoms which form the complex with the metal ion. Moreover a possible mechanism for the complex formation is suggested by the mono-hydration of free monensin this additional hydrogen-bonded water molecule being oriented in such a way that it could also function in the hydration sphere of a metal ion and be subsequently displaced as H30+ when the metal ion is assimilated into the monensin molecule.Boromy- in,^ a novel antibiotic and the first well-defined boron-containing organic compound to have been found in nature has been shown to have an almost spherical molecule with a lipophilic surface and possessing a cleft lined with oxygen atoms which will accommodate metal ions with which the compound is complexing. The antibiotic X-537A (49),56 active against coccidial infec- tions in chickens forms cylinder-like dimers in its silver salt the cylinders having a hydrophobic exterior and containing the two Ag+ ions each of Me HEt O OOH Et 0 OH 'Me Me (49) which is complexed by five oxygen atoms and one phenyl ring. This arrangement for the silver salt contrasts with that found in the barium salt which consists of two antibiotic molecules forming a circular complex with a Ba2+ ion at the centre but again possessing a hydrophobic exterior.The latter authors in parti- cular suggest that it is the ability of antibiotics like X-537A to form such varied complexes which allows them to transport metal ions through membranes and hence forms the basis of their biological activities. Thus the antibiotic X-206 the largest polyether antibiotic for which a molecular structure has been established wraps itself around silver ions in such a way that the backbone of the molecule describes a path similar to the seam on a tennis ball completed by an 55 J. D. Dunitz D. M. Hawley D. MikloS D.N. J. White Yu. Berlin R. Marusic and V. Prelog Helv. Chim. Acta 1971 54 1709. 56 C. A. Maier and I. C. Paul Chem. Comm. 1971 181. 57 J. F. Blount and J. W. Westley Chem. Comm. 1971 927. A. Forbes Cameron internal hydrogen bond from O(7) to O(13). In this case the silver ion is co- ordinated unsymmetrically by six oxygen atoms. It has also been suggested that there is a possible relationship between metal ions and cancer and that a common property of some antitumour agents is the ability to function as chelating agents. Subsequent to this suggestion a large number of thiosemicarbazones were prepared and it was found that all the compounds of this class which were active as tumour inhibitors were also capable of acting as terdentate N-N-S ligands.However 2-formylthiophen thiosemicarbazone (51)'8 was anomalous in showing no antitumour activity although it could apparently act as an N-N-S chelate. The analysis reveals that the S atom is trans to N(l) whereas a cis relationship is required for chelate action. Moreover a large degree of double-bond character in the C(6)-N(2) bond acts as a barrier to the rotation necessary to produce a possibly active isomer. 1,3-Bis-(8-theophylline)propane (52 n = 3)59 is another interesting antitumour compound since theophylline itself possesses no activity and of the series of compounds (52 n = 2-8) it is the only one to show activity. This indi- cates the importance of the separation and relative orientations of the two theophylline moieties and since the analysis reveals that the molecule possesses a folded conformation there is also the suggestion of complex formation in the Me Me (52) biological activity.The analysis of the antitumour compound 9,10-bis(chloro- methyl)anthracene6' was carried out to provide structural details for comparison with other active molecules. In this case there is a slight tendency towards a boat- chair-boat conformation as a result of steric hindrance by adjacent groups on the anthracene nucleus. 58 M. Mathew and G. J. Palenik Acra Crysr. 1971 B27 59. 59 L. S. Rosen and A. Hybl Acta Crysr. 1971 B27 952. 6o E. J. Gabe and J. P. Glusker Acta Crysr. 1971 B27 1925. Physical Methods-Part (v) X-Ray Crystallography That the detailed conformations of pharmacologically active molecules are of importance has been demonstrated by several analyses.For example the prome- dols are widely used as analgesics the most active being ( +)-/?-promedo1 (53a) whereas the least active is (+ )-y-promedol (53b).61 Analyses of both isomers have not only allowed unambiguous determinations of both stereochemistries but reveal in addition that in the active 8-isomer the phenyl ring adopts an axial conformation similar to the conformations which are found in both morphine and codeine. Isoproterenol sulphate dihydrate (54)62 is used in cases of heart-block and in the treatment of asthma possessing a bronchodilatory action (a) R' = Ph;R2 = OH (54) (b) R' = OH;R2 = Ph (53) similar to that of adrenalin and noradrenalin.A feature of all three compounds is the cis relationship of the ammonium and hydroxy-groups which are close enough for possible hydrogen-bonding between them and it is suggested that interactions of this type may play an important part in the biological activities of such compounds. Similar suggestions have been made as the result of the analysis of the methylene chloride solvate of Pancuronium bromide (55),63used clinically as a neuromuscular blocking agent. The piperidino-groups at both ends of the steroid nucleus are each involved in hydrogen-bonded interactions with the adjacent acetoxy-functions resulting in a rigid conformation both in the crystalline state and in solution. The authors suggest that the cage-like hydrogen- bonded structures may be intimately involved in the biological activity of this compound.0 '' W. H. De Camp and F. R. Ahmed Chem. Comm. 1971 1102. b2 M. Mathew and G. J. Palenik J. Amer. Chem. SOC.,1971 93 497. 63 D. S. Savage A. F. Cameron G. Ferguson C. Hannaway and I. R. Mackay J. Chem. SOC.(B) 1971,410. A. Forbes Cameron Structure-activity relationships of other steroid derivatives have also been extensively For example although the introduction of a 6a,7a-difluoromethylene group generally potentiates the anti-inflammatory activities of various corticoids the 6a,7~-difluoromethylene-16a,l7a-isopropyli-denedioxy-corticoids are an exception showing decreased activities. It has been postulated that this results from impaired interaction with receptor sites owing to the two large a-face substituents causing conformational distortions of rings c and D.To test this hypothesis the steroid derivative (56)” has been examined Br I ‘fF Ph F as part of a more general investigation. The analysis reveals that there is the possibility of hydrogen-bonding between hydrogen atoms on C(17) and C(18) and the hydroxy-oxygen O(11). Similarly the fluoro-steroid (57)73has been studied because the progestational activities of steroids contaning a dioxolan 64 W. L. Duax A. Cooper and D. A. Norton Acra Cryst. 1971 B27 1. 65 C.M. Weeks A. Cooper D. A. Norton H. Hauptman and J. Fisher Acta Cryst. 1971 B27,1562. 66 W. L. Duax Y.Osawa A. Cooper and D. A. Norton Tetrahedron 1971 27,331. b7 W. L.Duax H. Hauptman C. M. Weeks and D. A. Norton Chem. Cumm. 1971 1055. 68 P. Coggon A. T. McPhail S. G. Levine and R. Misra Chem. Comm. 1971 1133. 69 D. R. Pollard and F. R. Ahmed Acta Cryst. 1971 B27,1976. 70 J. C. Portheine and C. Romers Acta Cryst. 1970 B26,1791. 71 E. Thom and A. T. Christensen Acta Cryst. 1971 B27,794. 72 E.Thom and A. T. Christensen Acta Cryst. 1971 B27,573. 73 G.W. Krakower B. T. Keeler and J. Z. Gougoutas Tetrahedron Letters 1971 291. 125 Physical Methods-Part (v) X-Ray Crystallography ring fused to the 16aJ 7a-positions of progesterone and also unsymmetrically substituted at the 2'-position have been shown to be dependent on the stereo- chemistry of the 2'-substituents. Thus the fi-methyl-a-phenylmethylenedioxy-compound (57) is more active than progesterone whereas the a-methyl-P- phenylmethylenedioxy-isomer although thermodynamically the more stable is essentially inactive.The analysis of (57) reveals that the conformation of ring D is very similar to that in 4-bromoestradiol approximating to a p-C(l3)- envelope and also that the dioxolan ring is not markedly puckered having a maximum torsion angle of only 32". However the phenyl ring is tucked well under the a-face of the steroid nucleus extending as far as ring B and is only 3.70 A distant from the fluorine atom. Such a conformation is not possible with the other isomer. Syntheses of aza-derivatives of steroids have been undertaken with the object either of enhancing activity or of reducing side-effects.Analysis of 12-keto-17-deoxo-8-azaestrone methyl ether hydrobromide (58)74 was carried out to study the geometries of such derivatives and led to the conclusion that the molecular parameters of the estrogen ring-system remain relatively constant regardless either of the insertion of nitrogen at the 8-position or of whether any of the rings possess hydroxy- carbonyl or methoxy-substituents. 5 General Structural Studies Most of the analyses described in the previous three sections have been of com- pounds of known molecular structure and were undertaken specifically to provide details of molecular geometries conformations or biological activities. Compounds of unknown molecular structure mostly natural-product deriva- tives are still widely studied by X-ray techniques.Thus there have been several studies of terpenoid derivatives. Ipecoside the first substance shown to be a nitrogenous secocyclopentane monoterpene glucoside has been examined as the dimethyl derivative 00-dimethylipecoside (59).7 Similarly the structures of jatrophone dihydrobromide (60)76 and gutierolide (61),77 both diterpenoid J. N. Brown R. L. R. Towns and L. M. Trefonas J. Heterocyclic Chem. 1971,8 273. '' 0. Kennard P. J. Roberts N. W. Isaacs F. H. Allen W. D. S. Mortherwell K. H. Gibson and A. R. Battersby Chem. Comm. 1971 899. 76 R. C. Haltiwanger and R. F. Bryan J. Chem. SOC.(B) 1971 1598. 77 W. B. T. Cruse M. N. G. James A. A. Al-Shamma J. K. Beal and R. W. Doskotch Chem. Comm. 1971 1278. A. Forbes Cameron Me0 Meo%:WOH CH,OH H' Me0,C ' H derivatives have been determined while the triterpenoid structures which have been studied include 24,25-dibromokulactone (62)78and a spirotriterpane (63)79 isolated from crude petroleum.Mi Me K. W. Ma F. C. Chang and J. C. Clardy Chem. Comm. 197 1,424. '' G. W. Smith Acta Crysf.,1970 B26,1746. Physical Methods-Part (u) X -Ray Crystallography 127 Alkaloid structures which have been resolved include bellendine (64)," narcissidine methiodide (65)," buxenine-G (66),s2 and laurepukin (67).83 Of these bellendine is the first alkaloid isolated from a proteaceous plant which has been shown to have a y-pyronotropane structure and the analysis of narcissidine methiodide proves that the previously postulated structure was incorrect.0 QyJMe OMe Meom Me0 I-Me MeHN Other natural products which have been studied include a derivative of dothi- stromin (68),'" which is a fungal toxin implicated in pine-needle blight (&)-dehydroaltenusin (69)' and the p-bromosulphonyl derivative of ophiobolin D (70).86 Several sugars and sugar derivatives have also been studied including methyl-a-~-altropyranoside,'' a-lactose m~nohydrate'~~~~1,6:2,3-dian-and hydro-P-~-gulopyranose.~~ 'O W. D. S. Motherwell N. W. Isaacs 0. Kennard I. R. C. Bick J. B. Bremner and J. Gillard Chem. Comm. 1971 133. A. Irnrnirzi and C. Fuganti J. Chem. SOC.(B) 1971 1218. R. T. Puckett G. A. Sim and M. G. Waite J. Chem. SOC.(B) 1971 935. 83 W. E. Oberhansli Helv. Chim.Acta 1971 54 1389. 84 C. A. Bear J. M. Waters T. N. Waters R. T. Gallagher and R. Hodges Chem. Comm. 1970 1705. 85 D. Rogers D. J. Williams and R. Thomas Chem. Comm. 1971 393. 86 S. Nozoe A. Itai and Y. Iitaka Chem. Comm. 1971 872. B. M. Gatehouse and B. J. Poppleton Acta Cryst. 1971 B27 871. " D. C. Fries S. T. Rao and M. Sundaralingam Acta Cryst. 1971 B27 994. 89 C. A. Beevers and H. N. Hansen Acta Cryst. 1971 B27 1323. 90 B. Berking and N. C. Seeman Acta Cryst. 1971 B27 1752. A. Forbes Cameron ~0% H 0 OMe

ISSN:0069-3030    

DOI:10.1039/OC9716800109

出版商:RSC    

年代:1971

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3 Reaction Mechanisms Part (i) Aromatic Compounds By A. R. BUTLER Department of Chemistry University of St. Andrews St. Andrews 1 Electrophilic Aromatic Substitution During 1971 there have been two excellent reviews of this subject covering the main areas of controversy.’?’ Nitration by nitronium salts has been shown by Olah and his co-workers to have low relative reactivity between arenes but high positional selectivity and this has been explained by initial formation of a 7c-complex followed by rate-determining conversion to a o-c~mplex.~ In his review Olah’ defends this interpretation against the view that the results are better explained in terms of inadequate mixing of the reactants. He also suggests that in electrophilic substitution the transition state may be early and resemble the reactants (n-complex) or late and resemble the products (a-complex).In contrast Ridd’ reviews the evidence in favour of regarding Olah’s results as due to inadequate mixing and gives a summary of investigations into the mechan- ism of aromatic nitration. Further support for inadequate mixing comes from a study of the nitration of some polymethylbenzenes by Zollinger et aL4 In spite of wide synthetic use nitration by nitric acid in acetic anhydride is still a mechanistic puzzle. Hartshorn Moodie and Schofield’ report that a different value is obtained for the relative reactivity of benzene and toluene from that obtained with nitrating agents known to contain NOz+ as the active species indicating a unique mechanism for nitration by this reagent.Relative reactivity and isomer ratios may be influenced by solvation effects but two systems have been described which avoid this complication an intermediate similar to a a-complex has been detected in the gas phase by ion cyclotron resonance,6 and the helium tritide ion (HeT’) is a powerful electrophile effecting hydrogen exchange on halogenobenzenes in the gas phase.7 * G. A. Olah Accounts Chem. Res. 1971 4 240. J. H. Ridd Accounts Chem. Res. 1971 4 248. S. J. Kuhn and G. A. Olah J. Amer. Chem. SOC. 1961,83,4564. E. Hunziker J. R. Penton and H. Zollinger Helv. Chim. Acta 1971 54 2043. S. R. Hartshorn R. B. Moodie and K. Schofield J. Chem. SOC.(B) 1971 1256. S. A. Benezra M. K. Hoffman and M. M. Bursey J. Amer. Chem.SOC.,1970 92 7501. ’ F. Cacace and G. Perez J. Chem. SOC.(B) 1971 2086; F. Cacace R. Cipollini and G. Ciranni ibid. 1971 2089. 129 130 A. R.Butler In an interesting study Perrin* has assessed the leaving ability of some electro- philes by a study of the reactions of model compounds. For example reaction of (1) with HCl results in migration or loss of NOz+ rather than Cl'. However with the bromo-analogue it is Br' which is lost. As well as being an intrinsic C1 NO characteristic of the electrophile leaving ability depends on whether the electro- phile is lost from the a-complex in a unimolecular process or removed by a nucleophile. In the former case the order is NO2+ < i-Pr+ -SO < t-Bu+ -ArN,' < ArCHOH' < NO+ < CO < B(OH), and in the latter case Me' < CI+ < Br+ < D' < RCO' < H+< I' < Hg2+ < Me,Si+.Data from a variety of other sources are used to establish these orders. In some related work Perrin and Skinner' have measured ips0 partial rate factors i.e. the activating or deactivating effect of a substituent on electrophilic attack at the carbon atom bearing the substituent. The reaction used was nitration of phalogenoanisoles which results in partial replacement of the halogen. For H I Br and C1 the values are 1,0.119,0.077,and 0.069 respectively values which show surprisingly little variation. The situation is somewhat complicated by the occurrence of demethylation particularly with the chloro-compound. The importance of the direct field effect in the deactivating properties of positive poles has been demonstrated by comparing the rates of nitration of (2) and (3).The inductive effects along the a-bonds are the same in both cases but (3) nitrates 200 times slower than (2) owing to the different positions of the positive poles." If the positive pole is attached directly to the ring then the inductive effect is relatively more important although the field effect is still operative.' There is evidence of d,-p interaction between the aromatic ring and positive poles con- s C. L. Perrin J. Org. Chem. 1971 36 420. C. L. Perrin and G. A. Skinner J. Amer. Chem. SOC.,1971 93 3389. lo ' G. Mossa A. Ricci and J. H. Ridd J. Chem. SOC.(B),1971 714. F. De Sarlo G. Grynkiewicz A. Ricci and J. H.Ridd J. Chem. SOC.(B) 1971 714. Reaction Mechanisms-Part (i) Aromatic Compounds + + taining -Me and -SeMe, as there is with positive poles of P As and Sb but not pn-pn overlap.12 Creation of a positive pole may change completely the position of nitration ModroI3 reports that in a non-acidic medium nitration of N-benzylaniline occurs on the aniline moiety but protonation of the nitrogen diverts attack to the benzyl ring. Aromatic nitrosation is an important reaction which has received very little attention. Challis and Lawson14 report full details of a study of the nitrosation of phenol and anisole in perchloric acid. For phenol the rate is constant below 1M-acid and then increases to reach a maximum in 7.5M-acid. For anisole there is no acid-independent region but with both loss of a proton is the slow step.For this reason acidity dependence studies are not diagnostic of the mechanism. Phenol reacts via a dienone intermediate not available to anisole and although demethylation occurs with the latter this follows nitrosation. Identification of the nitrosating species is difficult but above SM-acid it is probably NO'. Nitration via nitrosation and oxidation has been recognized as an important pathway and it appears that this is what occurs in the attempted nitration of thiophen. The high susceptibility of heterocycles towards nitrosation and the production of nitrous acid in an autocatalytic process results in the reaction being very vi01ent.l~ Nitrosation is thought to occur to some extent even in nitration by nitronium salts.4 There have been numerous studies of aromatic halogenation and one of the most interesting is an account by Taylor and McKillop16 of the use of thallic trifluoroacetate in effecting iodination.There is immediate reaction with the aromatic compound to give an organothallium intermediate (4) which may be isolated. Reaction of this with aqueous potassium iodide results in anion ex- change to give the intermediate (5) which loses thallous iodide and iodine enters the ring at the site of thallation. The method is simple yields are good and it has wide applicability including heterocycles. With o/p directing sub- stituents attack is normally at the p-position but if the reaction mixture is heated before addition of KI the rn-iodo-compound is obtained owing to a change from kinetic to thermodynamic control of the product.If there is a basic H. M. Gilow M. De Shazo and W. C. Van Cleve J. Org. Chem. 1971,36 1745. l3 T. A. Modro Roczniki Chem. 1971 45 825. l4 B. C. Challis and A. J. Lawson J. Chem. SOC.(B) 1971 770. A. R. Butler and J. B. Hendry J. Chem. SOC.(B) 1971 102. A. McKillop J. D. Hunt M. J. Zelesko J. S. Fowler E. C. Taylor G. McGillivray and F. Kienzle J. Amer. Chem. Soc. 1971 93 4841. 132 A. R.Butler site in the substituent the thallium salt complexes with this first and thallation occurs at the o-p~sition.’~ A mixture of iodine and nitric acid is a common iodinating agent. It is generally supposed that there is direct iodination in an equilibrium step and that nitric acid acts by removing the HI formed and the equilibrium position shifts in favour of the iodo-compound.This has been shown to be incorrect and some other mechanism must be found.I8 A detailed kinetic study by Butler and Sander- son,” using acetic acid as solvent has shown that the reaction is catalysed by nitrous acid and hydrogen ions and that the iodinating species is probably protonated NO,I which reacts with the aromatic substrate in a slow step. The rate-determining step in acid-catalysed decarboxylation depends upon the acidity. The reaction of pyrrole-2-carboxylic acid follows the same pattern as that reported by Long for the decarboxylation of azulene- 1-carboxylic acid i.e. rate-determining protonation of the anion to give (6) at low acidity and rate- determining decarboxylation of (6) at high acidity.20 Because of the ease with which it may be followed and the absence of com- plicating steric effects hydrogen-exchange reactions in acidic solution continue to be used for comparing the reactivities of different positions on aromatic rings.The effect of substituents on hydrogen exchange at the 2- 3- and 8-positions of fluoranthene (7) has been analysed in terms of atom-atom polarizabilities a-inductive effects and the direct field effect.’l Only the 6-position of the 2,3- dihydro-5,7-dimethyl- 1P-diazepinium ion (8) undergoes detectable hydrogen H H H 4 3 (7) exchange in strong acid as the positive charge in the intermediate may be located on the two nitrogen atoms., The relative reactivities of the 2- and 3-positions of pyrrole invert as the acidity is changed and it is suggested that this is due to an earlier transition state in a more acidic rnedi~rn.’~ Comparison of the relative reactivities of different positions in an aromatic system with the predictions of l7 E.C. Taylor F. Kienzle R. L. Robey A. McKillop and J. D. Hunt J. Amer. Chem. SOC.,1971 93 4845. la A. R. Butler J. Chem. Educ. 1971 48 508. l9 A. R. Butler and A. P. Sanderson J. Chem. SOC. (B) 1971 2265. G. E. Dunn and G. K. J. Lee Cunad. J. Chem. 1971,49 1032. K. C. C. Bancroft and G. R. Howe J. Chem. SOC. (B) 1971 400. 22 A. R. Butler D. Lloyd and D. R. Marshall J. Chem. SOC.(B) 1971 795. ’’ G. P. Bean Chem. Comm. 1971,421.Reaction Mechanisms-Part (i) Aromatic Compounds 133 MO calculations meets with some success but the same type of calculation does not always give the best prediction. For the non-equivalent positions of indoli- zine (9),n-electron densities give a better correlation than localization energies.24 In view of their inherent approximations and the neglect of solvation effects such simple calculations appear to be of little value in elucidating the exact mechanism of hydrogen exchange. In recent years there has been interest in the mechanism of electrophilic attack on aromatic side-chains and Eaborn and Wright2’ report a study of hydrogen exchange in trifluoroacetic acid of the methyl group of 2-methylbenzo[b]thiophen (10). The reaction appears to involve ring protonation and slow proton loss to give the olefinic compound (11) (Scheme 1).Scheme 1 Among unusual pathways in electrophilic aromatic substitution the formation of dienones is important. They are for example formed in the chlorination of 3,4dimethylphenol and related compounds.26 During work-up of the reaction mixture a dienone intermediate may be destroyed and the normal reaction pro- duct obtained. A study of such a conversion the acid-catalysed rearrangement of (12) to (13) has been reported. The rate of reaction is directly proportional to Ho and substitution of protium by deuterium at the 4-position depresses the rate by a factor of Nitration of 5-bromohemimellitene gave 2-nitro-3,4,5- trimethylphenol in 60% yield owing to decomposition of the dienone inter- mediate (14) formed during the reaction.28 A very full study has shown that formation of 2,4-dinitro-3,5-di-t-butyltoluene and 2,6-dinitro-3,5-di-t-butyl-24 W.Engewald M. Muhlstadt and C. Weiss Tetrahedron 1971 27 851 4171. 25 C. Eaborn and G. J. Wright J. Chem. SOC.(B) 1971 2262. 26 P. B. D. de la Mare and B. N. B. Hannan Chem. Comm. 1971 1324. ” P. B. D. de la Mare A. Singh J. G. Tillett and M. Zeltner J. Chem. SOC.(B) 1971 1122. 28 D. J. Blackstock M. B. Hartshorn A. J. Lewis K. E. Richards and J. Vaughan J. Gem. SOC.(B) 1971 1212. 134 A. R.Butler toluene from the nitration of 2,4,6-tri-t-butylbenzeneis due to rearrangement of the intermediate cyclohexadienyl carbonium ion (15)and alkyl fragmentation of the 4-t-butyl 2 Nucleophilic Aromatic Substitution There is now convincing evidence that nucleophilic aromatic substitution occurs by a two step mechanism (S,Ar) involving formation of an intermediate (16) similar to a Meisenheimer complex (Scheme 2).Bowden and Cook3' report that in the alkaline hydrolysis of a number of substituted nitrobenzenes and 2,4- dinitrobenzenes in aqueous DMSO the rate-determining step depends upon the Scheme 2 composition of the medium. In cases where addition of hydroxide ion is slow the ratio k(H,O)/k(D,O) is ca. unity for those reactions with a transition state resembling the reactants but smaller for more advanced transition state^.^ Solvent effects in such reactions are complex and appear to be very specific.For example addition of methanol lowers the rate of reaction between thiocyan- ate ion and 2,4-dinitroiodobenzene owing to strong solvation of the thiocyanate ion by methanol.32 It is the presence of the nitro-groups which renders the aromatic ring susceptible to nucleophilic attack and picryl chloride reacts with as weak a base as imidazole to give 2,4,6-trinitrophenylimida~ole.~~ With only one nitro-group the reaction 2q P. C. Myhre M. Beug K. S. Brown and B. Ostman J. Amer. Chem. SOC.,1971 93 3452. 30 K. Bowden and R. S. Cook J. Chem. SOC.(B) 1971 1765 1771. 31 K. Bowden R. S. Cook and M. J. Price J. Chern. SOC.(B),1971 1778. 32 Y.Kondo K. Uosaki and N. Tokura Bull. Chetn. SOC. Japan 1971,44 2548. 33 R. Minetti and A. Bruylants Bull.Classe Sci. Acad. Roy. Belg. 1971 56 1047. Reaction Mechanisms-Part (i) Aromatic Compounds is much more difficult but the anions derived from various phenylalkylaceto- nitriles will displace chlorine from a number of chloronitr~benzenes.~~ Fluorine para to a nitro-group is replaced by methoxide ion in methanol faster than at the o-position but with 2,4-difluoronitrobenzene it is fluorine at the 2-position which is replaced first indicating that the effect of a second fluorine on a para activated system is different from that on an ortho activated system.35 Nucleophiles with a lone pair c1 to the site of nucleophilicity exhibit an enhanced reactivity and this shows up as a positive deviation in a Bransted plot. Bibbi and Pietra36 have looked for this a-effect in aromatic substitution but without success.In reaction with 2,4-dinitrochlorobenzene four primary amines give a linear Brernsted plot with a high p-value but the exalted positions of hydrazine and methoxylamine are not greater than those of other nucleophiles which have no lone pair c1 to the site of nucleophilicity (e.g.aniline and morpholine). As mentioned previously when discussing the direct field effect of positive poles in electrophilic aromatic substitution the importance of interactions through space is being increasingly recognized. Similar considerations apply in the reaction of hydrogen peroxide and the hydroperoxide ion with 3'-sub- stituted 3,4-benzotropolone- 1',2'-quinone monoanion (17) and the dianion of (17) purpurgalloquinone.Collier3' has concluded that charge repulsion decides which species is the more reactive. Comparison of the activating effects of nitro- and aza-groups in nucleophilic substitution has received considerable attention. A study of the reactions of hydroxide ion with various alkoxynitropyridines indicates the absence of steric factors with the a~a-group.~' Aza-activation is much smaller in five-membered rings than in six and in thiazoles all positions (2-,4- and 5-)are equally activated contrary to previously held views. There is no addition-elimination mechanism in the reactions of these compounds with methoxide ion.39 In the reactions of 2-chlorothiazole with benzenethiolate ion the 4- and 5-positions act as rn-and p-positions in benzene with respect to a Hammett plot and the high p value (+ 5.3) indicates how very sensitive thiazoles are to substituent effects4' 34 M.Makoszu J. M. Jaguoztyn-Grochowska and M. Jaurdosiuk Roczniki Chem. 1971 45 858. 35 T. L. Bamkole and J. Hirst Chem. Comm. 1971 69. 36 G. Bibbi and F. Pietra J. Chem. Soc. (B),1971 44. 31 P. D. Collier J. Chem. SOC.(B),1971 637. 38 J. Murto L. Nummela M. L. Hyvonen and I. Wartiovaara Suomen Kem. (B),1970 43 517. 39 M. Bosco L. Forlani P. E. Todesco and L. Troisi Chem. Comm. 1971 1093. 40 M. Bosco L. Forlani V. Liturri P. Riccio and P. E. Todesco J. Chem. SOC.(B),1971 1373. 136 A. R.Butler As might be expected triazines are very susceptible to nucleophilic attack. The replacement of one chlorine on 2,4-dichloro-6-phenylamino-sym-triazine is catalysed by a tertiary amine and involves formation of (18) as the slow Zollinger et have reported a very interesting study of the kinetics of the alka- line hydrolysis of various chloro-sym-triazines.The initial reaction is attack by hydroxide ion and protonation to give the intermediate (19) formed in a non-steady equilibrium state which undergoes deprotonation and release of chloride ion. The kinetics were analysed by the use of an analog computer. The similarity between the intermediate formed in nucleophilic aromatic substitution and Meisenheimer complexes has led to a large number of studies of these complexes in recent years. This has been aided by the development of techniques for following very fast reactions such as stopped flow and temperature jump.These have been applied by Fendler et to the reaction between hydroxide ion and 1,3,5,8-tetranitronaphthalene.The equilibrium constant is reduced by a factor of 0.3 with deuteroxide in D,O. Although cyanide groups do activate the aromatic ring towards complex formation they are much less effective than nitro-gr~ups.~~ The first step in the reaction of methoxide ion and various nitro- and cyano-anisoles is formation of a 1,3-complex (20)and there is slow conversion to the thermodynamically more stable 1,l-complex (21).45 Also the initial reaction between 4-substituted 2,6-dinitrochlorobenzene and methoxide ion is formation of a 1,3-complex although there is eventual OMe CN CN 41 G.Ostrogovich E. Fliegl and R. Bacaloglu Tetrahedron 1971 27 2885. 42 P. Rys A. Schmitz and H. Zollinger Helv. Chim. Acta 1971 35 163. 43 J. M. Fendler E. J. Fendler and L. M. Casilo J. Org. Chem. 1971 36 1749. 44 E. J. Fendler W. Ernsberger and J. H. Fendler J. Org. Chem. 1971 36 2333. 45 C. Deaving F. Terrier and R.Schaal Compt. rend. 1970 271 C 349; F. Terrier J. C. Halle M. P. Simonnin and M. J. Lecourt Org. Mugn. Resonance 1971 3 361; F. Terrier and M. P. Simonnin Bull. Soc. chim. France 1971 677. Reaction Mechanisms-Part (i) Aromatic Compounds 137 replacement of the chlorine.46 In certain cases (e.g. N-t-butyl-2,4,6-trinitro-benzamide) Meisenheimer complex formation is followed by replacement of a nitro-gr~up.~ Bernasconi4* reports that the initial reaction between trinitrotoluene and methoxide ion is formation of the anion (22) and this then reacts with more trinitrotoluene to give a Meisenheimer complex of probable structure (23).02NooMe .-NHCHMeCONHMe NO2 (24) Anion formation does not occur however with 3,5,6,%tetranitroacenaphthene and the sodium salt of the complex may be isolated.49 The kinetics of the forma- tion of (24) from 2,4,6-trinitroanilino-N-methylpropionamide and methoxide ion have been studied. Acidification of an alcoholic solution of this complex gives the conjugated acid.50 There is hydrogen bonding between the amino- group and the ortho nitro-group which is maximized in the conformation adopted by the Meisenheimer complex but if the amido-group is alkylated and hydrogen bonding is not possible the anilino-group ionizes and no complex is formed.If the anilino-group is alkylated no 1,l-complex can form for steric reasons and instead a 1,3-complex results.51 Full details have been given of the formation of a Meisenheimer complex of thiophen (25) resulting from the interaction of 2-methoxy-3,5-dinitrothiophen and methoxide ion. This complex forms more readily than that from trinitro- anisole and related intermediates are formed during nucleophilic attack on " M. R. Crarnpton M. A. El Ghariani and H. A. Khan Chem. Comm. 1971 834. *' E. J. Fendler D. M. Camioni and J. H. Fendler J. Org. Chern. 1971 36 1544. '' C. F. Bernasconi J. Org. Chem. 1971 36 1671. '' C. H. J. Wells and J. A.Wilson Tetrahedron Letters 1971 4521. 50 J. J. K. Boulton and N. R. McFarlane J. Chem. Soc. (B),1971 925. 51 J. J. K. Boulton P. J. Jewess and N. R. McFarlane J. Chem. SOC.(B),1971 928. 138 A. R.Butler thiophen compounds but reactions other than displacement may occur subse- quently (e.g.ring opening).’* Reaction of octahydrotriborate and 2,4,6-trinitrochlorobenzeneresults in hydride transfer to give (26),the parent Meisenheimer complex. Hydride ion will also displace chlorine from this compound but no evidence could be obtained for formation of the l,l-~ornplex.~~ CI EtO C1 NO* PerkinsS4 has described a case where nucleophilic substitution occurs on a ring system not activated by an electron-withdrawing group. Ethoxide ion will displace chlorine from 5-chloroacenaphthylene and the addition intermediate may be stabilized by formation of a cyclopentadienide ion (27).There have been further studies on the effect of surfactants and electrolytes on the rate of formation and decomposition of Meisenheimer complexes. A complex pattern emerges which cannot be explained in terms of simple electrolyte the~ry.~’ The displacement of fluorine by nucleophiles displays a number of special features. A variety of products results from attack of polyfluoroalkyl anions on pentafluoropyridine and tetrafluoropyridazine. With CF,CF there is kinetic control of the products but with increasing bulk there is a gradual change to thermodynamic control and this is complete with (CF,),C-.56 3 Acidity Functions Work over the past few years has shown that the value of an acidity function depends very much on the indicator used to measure it.Now one can only talk about the acidity of a concentrated acid relative to a particular base. All this has lessened the value of acidity function dependence as a criterion of reaction mechanism. The whole matter is admirably discussed in Rochester’s’ mono-graph on the subject and during 1971 little has been reported to modify the 52 G. Doddi G.Illuminati and F. Stegel J. Org. Chem. 1971 36 1918. 53 L. A. Kaplan and A. R. Siedle J. Org. Chem. 1971 36 937. 54 M. J. Perkins Chern. Comrn. 1971 231. 55 J. H. Fendler E. J. Fendler and M. V. Merritt J. Org. Chem. 1971 36 2172; L. M. Casilio E. J. Fendler and J. H.Fendler J. Chem. SOC.(B) 1971 1337. 56 R. D. Chambers R. P. Corbally M. Y.Gribble and W. K. R. Musgrave Chem. Cornrn. 1971 1345. 57 C. H. Rochester ‘Acidity Functions,’ Academic Press London 1970; Progr. Reaction Kinetics 197 1 6 143. Reaction Mechanisms-Part (i) Aromatic Compounds 139 position. However Kresge et a1.58 have reported a very full and important study of the acidity dependence of hydrogen exchange. In concentrated acid 1,3,5-trihydroxybenzene its methyl and ethyl ethers and a number of related com- pounds are protonated giving benzenonium ions which may be considered the same as the a-complexes occurring in electrophilic aromatic substitution. With the ethers protonation occurs para to the hydroxy-group rather than para to the alkoxy-group.Even anisole is C-protonated in perchloric acid more concentrated than 70%. When studied as a function of acid concentration the concentration of the conjugate acid depends linearly upon the acidity function H (based on the protonation of carbon59) and not H, but the slopes of the plots vary and are not unity. The superiority of H over Ho is not surprising as the latter is based on the protonation of nitrogen. Extrapolation to dilute acid gives a set of pK values and assuming that substituent effects are additive the pK of the conjugate acid of benzene is estimated to be -23. Studies of the behaviour of these compounds in concentrated acid have been extended to include the rates of hydrogen exchange. The rates give a linear correlation with both Ho and H and with both the slopes vary from compound to compound.The authors argue from this that there is no unique relationship between kinetic acidity dependence and reaction mechanism. By comparing the acidity de- pendence of equilibrium protonation and hydrogen exchange it is possible to estimate the degree of proton transfer in the transition state of the latter reaction. The results agree well with similar estimates made from the size of the exponent in the Brransted relation. Differences in substrate structure and in the degree of proton transfer in the transition state will explain the variation of kinetic acidity dependence for different compounds. A book by Liler6' contains a detailed account of the acidity functions of sulphuric acid and also discusses activity coefficients and the hydration treatment of acidity functions.Values of Ho are very sensitive to changes in the ionic strength.6 Values of H-for various alkali-metal glycoxides in ethylene and propylene glycols have been reported62 and the H-function in aqueous DMF has been measured.63 4 Linear Free Energy Relationships The various forms of the simple Hammett equation are difficult to substantiate on theoretical grounds but from a practical point of view they are able to 58 A. J. Kresge Y. Chiang and L. E. Hakka J. Amer. Chem. SOC.,1971 93 6167; A. J. Kresge H. J. Chen L. E. Hakka and J. E. Kouba ibid. 1971 93 6174; A. J. Kresge S. G. Mylonakis Y. Sato and V. P. Vitullo ibid. 1971 93 6181; A. J. Kresge Y. Chiang and S.A. Shapiro Canad. J. Chem. 1971 49 2777. 59 M. Reagan J. Amer. Chem. SOC.,1969 91 5506. 'O M. Liler 'Reaction Mechanisms in Sulphur Acid,' Academic Press London 1971. '' P. J. Staples and E. Hogfeldt J. Chem. SOC.(A) 1971 2074. 62 N. Chattanathan and C. Kalidas Austral. J. Chem. 1971 24 83; N. Chattanathan and C. Kalidas Bull. Chem. SOC.Japan 1971 44 1004; K. K. Kundu and L. Aiyar J. Chem. SOC.(B) 1971 40. 63 E. Buncel E. A. Symons D. Dolman and R. Stewart Canad. J. Chem. 1970 48 3354. 140 A. R.Butler correlate a wide variety of phenomena the basicity of pyridine~,~~ the deoxy- genation reaction of nitrobenzenes and triethyl ph~sphite,~~ the dissociation constants of 5-~tyryltropolones,~~ the syn-anti topomerization of N-arylimino-carb0nateq.6~ the Hofmann rearrangement,68 13C I4N and 'H shifts in n.m.r.spectro~copy,~~ the rate of interaction of the fluorenone triplet and substituted aniline~,~' and the pyrimidal inversion of nitrogen71 are a selection from papers appearing in 1971. The main theoretical interest comes in analysing the various modes of transmission of substituent effects to different sites in the molecule. The prominence given recently to field effects (as in the Dewar-Grisdale treat- ment72) has been questioned by Eaborn Eastmond and Walt~n~~ from a study of the alkaline cleavage Of XC,&C-C-c-CSiEt3 where the substituent X was found to have a considerable effect on the rate in spite of its distance from the reactive site. However the Dewar-Grisdale treatment which was sur-prisingly successful in spite of its simplicity has been extended to include the mesomeric field effect (e.g.in aniline mesomeric interaction between -NH2 and the ring leads to charge transfer from nitrogen to the 0-and p-positions and the resulting negative charge can then influence a reaction centre by a field effect) and to consider neutral substituents as finite dipoles rather than point charges. This treatment has been applied successfully to the reactions of a number of ring systems but not to "F chemical shifts.74 G~dfrey~~ has given an extensive analysis of substituent effects and has applied MO theory to field effects. This treatment has been applied successfully to the ionization poten- tials and some reactions of benzene compounds.It predicts the observed non- additivity of substituent effects in electrophilic aromatic substitution. The formation of complexes between Ag' and exo- and endo-substituted norbornenes has been analysed on the basis of the Kirkwood-Westheimer-Tanford The pyrolysis of substituted 1-phenylethyl acetates by Taylor7 has again proved to be a very powerful method of examining substituent effects and a new value of CT' for the rn-CF group has been proposed (+0.565).78 An angular dependence of a substituent effect has been observed reversing the positions of 64 C. D. Johnson and G. B. Ellam J. Org. Chem. 1971,36,2284. 65 R. J. Sundberg and C.-C. Lang J. Org. Chem. 1971 36 300. 66 K. Hamada S. Nakama K. Imafuku K. Kurosawa and H. Matsumura Tetrahedron 1971 27 337.67 H. Kessler P. F. Bley and D. Leibfritz Tetrahedron 1971 27 1687. 68 T. Imamoto Y. Tsuno and Y. Yukawa Bull. Chem. SOC.Japan 1971,44 1632 1639. 69 F. W. Wehrli W. Giger and S. Wilhelm Helu. Chim. Acta 1971 54 229; A. Mathias P. Hampson and R. Westhead J. Chem. SOC.(B),1971 397; R. R. Fraser and R. N. Renaud Canad. J. Chem. 1971,49 755 800. 70 S. G. Cohen and G. Parsons J. Amer. Chem. SOC.,1970,92 7603. " J. Stackhouse R. D. Baechler and K. Mislow Terrahedron Lerters 1971 3441. 72 M. J. S. Dewar and P. Grisdale J. Amer. Chem. SOC.,1962 84 3548. 73 C. Eaborn R. Eastmond and D. R. M. Walton J. Chem. SOC.(B) 1971 127. 74 M. J. S. Dewar R.Golden and J. M. Harris J. Amer. Chem. SOC.,1971 93 4187. '' M. Godfrey J.Chem. SOC.(B) 1971 1534 1537 1540 1545. 76 C. F. Wilcox and W. Gaal J. Amer. Chern. SOC.,1971 93 2453. 77 R. Taylor J. Chem. SOC.(B) 1971 255 1450. '* R. Taylor J. Chem. SOC.(B) 1971 622. Reaction Mechanisms-Part (i)Aromatic Compounds the hydrogen and chlorine in the acid (28) has an effect on the pK value.79 Bentley and Johnstone" have proposed a new set of 0 values based on ionization potentials determined by mass spectrometry. Non-linear Hammett plots have been discussed8 and Ostrogovich Csunderlik and Bacaloglu82 provide a good example of this phenomenon in the reaction of substituted anilines with ethyl chloroformate. The value of p for a reaction varies with the temperature according to the equation p = p,(l -PJT)where pi is the isokinetic temperature providing that 6AH" and 6AS" are temperature inde~endent.~~ Matsui and Tokura have considered the effect of changing solvent on p.84 The significance which may be attached to the coefficients in the Brransted equation is now a matter of contention.Linearity applies only within a family of catalysts and the value of aor P may vary from family to family. For the reaction of p-nitrophenyl triphenylmethanesulphenatewith a number of amines P has the following values 1.5 (anilines) 0.84 (pyridine) 0.75 (heterocyclic amines) and 0.58 (primary aliphatic amine~).~' The size of p was thought to represent the degree of proton transfer in the transition state and this view is maintained by Hibbert Long and Waters86 in a study of hydrogen exchange on malonitrile and t-butylmalononitrile.However this view is doubted by Bordwell and Boyles7 who found no trend relating the size of for the ionization of phenylnitromethanes and the relative basicity of the catalyst and the reactive site which should decide the position of the proton in the transition state. These authors give the following assessment of the situation 'the hope which at one time seemed bright for a simple general correlation of Brransted coefficients kinetic isotope effects and solvent isotope effects with the extent of proton transfer in the transition state has proven vain'. A similar position on this matter is adopted by Kresge et d8' who from a study of the hydrolysis of vinyl ethers conclude that the size of the '9 E. J.Grubbs R. Fitzgerald R. E. Phillips and R. Petty Tetrahedron 1971 27 935. T. W. Bentley and R. A. W. Johnstone J. Chem. SOC.(B) 1971 263. " J. 0. Schreck J. Chem. Educ. 1971 48 102. " G. Ostrogovich C. Csunderlik and R. Bacaloglu J. Chern. SOC.(B) 1971 18. 83 L. G. Hepler Canad. J. Chem. 1971 49 2803. 84 T. Matsui and N. Tokura Bull. Chem. Soc. Japan 1971 44 756. 85 E. Ciuffarin L. Senatore and M. Isola J. Chem. SOC.(B) 1971 2187. 86 F. Hibbert F. A. Long and E. A. Waters J. Amer. Chern. SOC.,1971 93 2829. " F. G. Bordwell and W. J. Boyle J. Amer. Chern. SOC.,1971 93 512 514. *' A. J. Kresge H. L. Chen Y. Chiang E. Murrill M. A. Payne and D. S. Sagatys J. Amer. Chem. Soc. 1971 93 413. 142 A. R.Butler Brsnsted exponent may be affected by intermolecular effects such as interactions between substrate and catalyst in the transition state.Dixon and BruiceE9 report that the enhanced nucleophilicity of nucleophiles with a lone pair o! to the site of attack is not explained by the high stability of the products and large amount of bond formation in the transition state. 89 J. E. Dixon and T. C. Bruice J. Amer. Chem. Sac. 1971 93 3248.

ISSN:0069-3030    

DOI:10.1039/OC9716800129

出版商:RSC    

年代:1971

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (ii) Orbital Symmetry Correlations and Pericyclic Reactions By R. GRIGG Department of Chemistry University of Nottingham Nottingham NG7 2RD 1 Orbital Symmetry Correlations The major proponents of alternative treatments of pericyclic processes to that proposed by Woodward and Hoffmann,' have reviewed their theories. Basically these approaches fall into two main categories. Fukui' limits his consideration to the frontier orbitals (the highest occupied molecular orbital and the lowest unoccupied molecular orbital) since these are energetically the most accessible and considers favourable overlap of the frontier orbitals must occur in the region of bond formation for a concerted process to be favoured. This requires a know- ledge of the symmetries of the frontier orbitals but has great utility in interpreting complicated reactions involving extensive bond relocation.The other approach requires no knowledge of MO theory since it utilizes the 'basis set orbitals' i.e. the assortment of orbitals present prior to a MO calculation. This approach has been used both by Dewar3 and by Zimmerman4 and will prove attractive to chemists with no knowledge of MO theory. Their treatment leads to the con- clusion that thermal pericyclic processes proceed preferentially uia aromatic transition states whereas photochemical pericyclic reactions involve anti- aromatic transition states. The idea of an aromatic transition state was first suggested for the Diels-Alder reaction5 some years ago. A number of other reviews have appeared dealing with the interaction of orbitals through space,' orbital symmetry and inorganic chemistry,' and orbital symmetry in thermal and photochemical reactions.* The energetics of photochemical pericyclic processes call for some rethinking of the original Woodward and Hoffmann approach.Although the predictions for photochemical processes have in the main been well substantiated the ' R. B. Woodward and R. Hoffmann Angew. Chem. Internut. Edn. 1969 8 781. K. Fukui Accounts Chem. Res. 1971 4 57. ' M. J. S. Dewar Angew. Chem. Internut. Edn. 1971 10 761. H. E. Zimmerman Accounts Chem. Res. 1971,4 272. ' M. G. Evans Trans. Faraday Soc. 1939 35 824. R. Hoffmann Accounts Chem. Res. 1971 4 1. R. G. Pearson Accounts Chem.Res. 1971 4 152; Pure Appl. Chem. 1971 27 145. H. Katz J. Chern. Educ. 1971 48 84; M. C. Caserio J. Chem. Educ. 1971 48 782. 143 144 R. Grigg mechanics of some of the processes are obscure. Thus the photocyclization of butadiene does not produce the first excited singlet state of cyclobutene which is energetically inaccessible from the first excited singlet state of butadiene instead ground-state cyclobutene is produced. The excited state responsible for the cyclization therefore may not be the first excited singlet state.' A related problem exists in (l),which is unreactive in the first excited singlet state and requires further energy input before opening to (2)." 2 Electrocyclic Reactions Although construction of a correlation diagram for electrocyclic reactions of radical species does not demonstrate any preference for a conrotatory or a disrotatory process extended Huckel calculations led to the prediction that radical reactions should proceed with the same stereochemistry as the corres- ponding anionic species e.g.cyclopropyl radicals should resemble cyclopropyl anions and open in a conrotatory fashion.' However MIND0/2 calculations lead to the prediction' 'that radicals should resemble the corresponding cations e.g. cyclopropyl radicals should undergo disrotatory opening. It is to be hoped that despite the difficulties associated with radical reactions a test of these opposing predictions will be forthcoming. MIND0/2 studies have also been reported for disfavoured ('forbidden') electrocyclic processes.The thermal opening of the oxaziridines (3) produces the nitrones (4) and occurs by both conrotatory modes giving a cis/trans mixture. Low-temperature irradiation reforms the oxaziridine by disrotatory clo~ure.~ The aziridine (5) is sterically unable to undergo conrotatory opening to the dipolar species (6) and the disrotatory process14 occurs at 135 "C as found for the related oxirane (7) which gives @).I5 The solvolysis rates of substituted N-chloroaziridines are as expected for a concerted ionization-ring cleavage process. l6 Thus relative solvolyses rates of (9; R = H) (9; R = Me) and (10) are 1 1490 155 000; W. Th. A. M. van der Lugt and L. J. Oosterhoff J. Amer. Chem. SOC. 1969 91 6042. lo J. Meinwald G. E. Samuelson and M.Ikeda J. Amer. Chem. SOC.,1970 92 7604; J. Michl J. Amer. Chem. SOC.,1971 93 523. 'I M. J. S. Dewar and S. Kirschner J. Amer. Chem. SOC.,1971 93 4290. l2 M. J. S. Dewar and S. Kirschner J. Amer. Chem. SOC. 1971 93 4291 4292. l3 J. S. Splitter T.-M. Su H. Ono and M. Calvin J. Amer. Chem. Soc. 1971 93 4075. l4 J. W. Lown and K. Matsumoto J. Org. Chem. 1971 36 1405. E. F. Ullman and J. E. Milks J. Amer. Chem. SOC.,1962 84 1315; E. F. Ullman and W. A. Henderson J. Amer. Chem. SOC. 1966 88 4942. l6 P. G. Gassman Accounts Chem. Res. 1970 3 26. Reaction Mechanisms-Part (ii) CND0/2 calculations for this process predict the disrotatory opening. l7 Further examples of electrocyclic reactions of 3-membered heterocycles are included in the cycloaddition section.0 0 +/ /\ + ArCH=N Ar CH- NR \ R (3)(3) (4)(4) Ph Ph 1 0 (7) R H R (9) A weight of experimental evidence *suggests the thermal vinylcyclopropane-cyclopentene rearrangement is non-concerted and occurs via a diradical inter-mediate. However vinyl epoxides have an alternative symmetry-allowed pathway. Thermolysis in the gas phase of the cis-epoxide (11) furnishes the 6-electron ylide (12) which partially equilibrates with the isomeric ylide (13) but predominately cyclizes to the dihydrofuran (14).19 The degenerate rearrange-ment of the vinylcyclopropane thujene (15) has been studied using an optically active trideuterio-derivative and shown to be non-concerted.20 " R. G. Weiss Tetrahedron 1971 27 271.M. R. Wilcott and V. H. Cargle J. Amer. Chem. Soc. 1969 91 431 1; A. D. Ketley A. J. Berlin and L. P. Fisher J. Org. Chem. 1966,31 2648; M. J. S. Dewar Tetrahed-ron 1966 suppl. no. 8 p. 75. I9 J. C. Paladini and J. Chuche Tetrahedron Letters 1971 4383. W. von E. Doering and E. K. G. Schmidt Tetrahedron 1971 27 2005. 146 R. Grigg Me Ph 'H f A A 7 q-3 t MewMe (14) Thermal rearrangement of the tricycloheptane (16) occurs by two competing pathways21 to give (17) and (18). The observed energies of activation are difficult to rationalize by a diradical mechanism and in contrast to the thermal rearrange- ment of (19),22a concerted process may be operative. The cyclobutyl-cyclopropylcarbinyl rearrangement occurs with preferential inversion at the reaction site [(20)+ (21)].23 The process may be viewed as a two-electron electrocyclic process analogous to that occurring in the solvolysis of cyclopropyl derivatives.The reaction is sensitive to steric effects and as expected the cis-isomer (20; R = alkyl) solvolyses slower than the trans-isomer (22; R = alk~l).~~ 21 H. M. Frey R. G. Hopkins and L. Skattebol J. Chem. SOC. (B) 1971 539. 22 M. C. Flowers and A. R. Gibbons J. Chem. SOC. (B) 1971 612. 23 I. Lillien G. F. Reynolds and L. Handloser Terrahedron Letters 1968 3475; I. Lillien and L. Handloser ibid. 1969 1035; Z. Majerski and P. von R. Schleyer J. Amer. Chem. SOC. 1971 93 665. 24 I. Lillien and L. Handloser J. Amer. Chem. SOC.,1971 93 1682.Reaction Mechanisms-Part (ii) X -%’ ‘H Thermolysis of the deuteriated cyclobutene (23) leads to conrotatory opening in both directions with a slight predominance of one isomer (24 25 ;52.3 47.7). This is interpreted as a slight preference for a transition state involving D-D H OSiMe Me,SiO D Me,SiO H Me$ D OSiMe interaction [i.e. (26)] as a consequence of the smaller effective size of carbon-bound deuterium compared to hydr~gen.~’ However the isomeric stability of the pure dienes under the reaction conditions was not reported. The thermal opening of benzocyclobutanes to 0-quinodimethanes followed by an intra- molecular Diels-Alder reaction has been utilized in elegant syntheses of fused-ring systems e.g. (27)-(28). The scheme has been applied to the synthesis of ( f)-chelidonine(29).26 25 R.E. K. Winter and M. L. Honig J. Amer. Chem. SOC.,1971 93 4616. 26 W. Oppolzer J. Amer. Chern. SOC.,1971 93 3833 3834; W. Oppolzer and K. Keller ibid. p. 3836. 148 R. Grigg 07 The position of the disrotatory cycloheptatriene-norcaradiene equilibrium [(30)= (31)] is markedly influenced by the C-7 substituents R1 and R2. Substi-tuents containing n-systems more particularly electron-withdrawing substituents appear to be essential for the stabilization of the norcaradiene valence isomer ;a simple theoretical explanation for this has been pr~vided.~' A number of new examples have been reported2* and some studied by l3Cn.m.r. Ability of C-7 substituents to stabilize the norcaradiene valence tautomer is in the order C(CN) > C(Ph)CO,R z C(Ph)PO(OMe) > C(CO,R) .Valence isomerism Thus the in the azocine series is also markedly affected by sub~tituents.~~ equilibrium (32) S(33) lies wholly on the side of (33) for n = 3 or 4. When n = 5 the equilibrium (32) $(33) is established at 100 "C whereas when n = 6 only (32) is present. Some interesting dienophile specificities in intercepting valence H 27 R. Hoffmann Tetrahedron Letters 1970 2907. 28 E. Ciganek J. Amer. Chem. SOC.,1971 93 2207; G. E. Hall and J. D. Roberts J. Amer. Chem. SOC.,1971 93 2203; H. Durr and H. Kober Angew. Chem. Internat. Edn. 1971 10 342; H. Gunther €3. D. Tunggal M. Regitz H. Scherer and T. Keller Angew. Chem. Internat. Edn. 1971 10 563.29 L. A. Paquette J. F. Hansen and J. C. Philips J. Amer. Chem. SOC.,1971 93 152; L. A. Paquette T. Kakihana and J. F. Kelly J. Org. Chem. 1971 36 435; L. A. Paquette Angew. Chem. Internat. Edn. 1971 10 11. Reaction Mechanisms-Part (ii) tautomers have been reported for fluorocyclo-octatetraene.30 Thus tetracyano- ethylene intercepts the valence tautomer (34) whereas the azodienophiles (35 ; R = Me or Ph) intercept (36) exclusively. N The thermal rearrangement cis-bicyclo[6,1,O]nona-2,4,6-trienes continues to attract attention. The problem is that the thermal rearrangement of 9-substituted derivatives (37; R' = R2 = H; R' = H R2 = alkyl) should on simple electro- cyclic ring opening give the cis,cis,cis,trans-cyclononatetraene (38) which on disrotatory closure involving a six-n-electron portion of (38) should furnish a trans-8,9-dihydroindene (39).The products from the parent system (37; R' = R2 = H) and the monoalkyl derivatives are however predominantly the cis-8,9-di h ydroindenes. It seems generally agreed that the all-cis cyclononatetraene (40)is the immediate precursor of the cis-8,9-dihydroindene and indeed (40) has been prepared and shown to undergo the expected cyclization to (41 ;R' = R2 = H).32 A number of 30 G. Schroder G. Kirsch J. F. M. Oth R. Huisgen W. E. Konz and U. Schnegg Chem. Ber. 1971 104 2405. 31 E. Vogel W. Grimme and E. Dinne Tetrahedron Letters 1965 391 ; P. Radlick and W. Fenical J. Amer. Chem. SOC.,1969 91 1560. 32 G. Boche H. Bohme and D. Martens Angew.Chem. Internat. Edn. 1969 8 594; P. Radlick and G. Alford J. Amer. Chem. SOC.,1969 91 6529. 150 R. Grigg valence tautomers of the bicyclo[6,l,O]nonatriene have been suggested as possible intermediates. However some possible rearrangement pathways have been ruled out by the observation that the hexadeuterio-derivative (42) rearranges to (43).33 The importance of the conformation of the bicyclo[6,1,O]nonatriene was first suggested by Staley and Henry,34 who reported that the 9,9-dimethyl derivative (37; R' = R2 = Me) rearranges to the trans-dihydroindene (39; R' = R2 = Me) in contrast to the parent system and the 9-monoalkyl derivatives. Thus the favoured conformation for thermal rearrangement was considered to be (44) leading to cis-dihydroindenes whereas the severe steric interactions in the 9,9-dimethyl derivative would cause it to adopt conformation (45).This view is H R (44) (45) (43) supported by kinetic data showing a higher-energy transition state for (49 and a reinvestigation of the rearrangement of (37; R' = H R2 = Me; R' = Me R2 = H) is in accord with this view.35 Thus the rearrangement of (37; R' = H R2 = Me; AG* = 31 kcal mol-') kinetically resembles that of (45 ;AG* = 32 kcal mol- ') whereas the rearrange- ment of (37; R' = Me R2 = H; AG* = 27.4kcalmol-') with conformation (44; R = Me) favoured was similar to the parent compound (37; R' = R2 = H ; AG* = 28 kcal mol- '). Careful investigation of the reaction mixture from (37; R' = H R2 = Me) indicated some trans-dihydroindene was possibly formed.An in~estigation~~ of the 9-chloro-derivatives (37; R' = D R2 = C1; R' = C1 R2 = D) has shown that (37; R' = C1 R2 = D) in which the folded conformation (44) is readily attained rearranges to the cis-dihydroindene (41 ; R' = D R2 = C1) presumably uia the all-cis cyclononatetraene. However (37; R' = D R2 = C1) in which the extended conformation should be favoured '' J. E. Baldwin and A. H. Andrist J. Amer. Chem. SOC.,1971 93 4055. S. W. Staley and T. J. Henry J. Amer. Chem. Sac. 1969 91 1239. 35 A. G. Anastassiou and R. C. Griffith Chem. Comm. 1971 1301 3b J. C. Barborak T.-M. Su P. v. R. Schleyer G. Boche and G. Schneider J. Amer. Chem. SOC.,1971 93 279; see also A. G. Anastassiou and E. Yokali J. Amer. Chem.Sac. 1971 93 3803. Reaction Mechanisms-Part (ii) undergoes migration of chlorine uia the valence tautomer (46)followed it is suggested by fast disrotatory opening of the cyclopropane ring consequent upon ionization of the chloride giving the allylic ion (47) which recaptures the chloride ion on the same face giving (48). HH c1-C1 (47) (48) In contrast to (37; R' = R2 = H) the cis-bicyclo[6,2,0]deca-2,4,6-triene(49) rearranges initially to a single product (50),as expected from orbital symmetry consideration^.^ Presumably the two-carbon bridge in (49)again favours an extended conformation analogous to (45). Irradiation of undeuteriated (49) gives a rapidly equilibrating mixture of the valence isomers (51) and (52). (51) (52) An interesting steric effect is noted38 in the photochemistry of the substituted cyclohexadienes (53; R' = H R2 = Ph; R' = Ph R2 = H) which open in the conrotatory mode that avoids a cis relationship between the (initial) C-1 and C-6 37 S.W. Staley and T. J. Henry J. Amer. Chem. SOC.,1971 93 1293; 1970,92 7612. 38 A. Padwa L. Brodsky and S. C. Clough Chem. Comm. 1971 417. 152 R. Grigg phenyl substituents giving (54; R' = H R2 = Ph; R' = Ph R2 = H) as intermediates followed by ,4 + ,2 cycloadditions to give (55). A general electrocyclic ylide reaction [(56)-+ (57)] has been proposed and examples utilizing pyridinium ylides reported.39 The conrotatory 16-n-electron electrocyclic closure of the cation (58) occurs at room temperature4' to give the trans-macrocyclic compound (59).Me Me Me Me Et Me Me -N N -+ El Me Me Me Me 3 Cycloaddition Reactions Reviews have appeared on singlet oxygen4' and ketenimine~.~' The main lectures presented at a symposium on cycloaddition reactions have been pub- li~hed.~~ The .2 + 02a cycloreversion of a cyclobutane to two ethylenes would impose severe distortions on the transition state since two of the methylene carbons are required to rotate through ca. 180". Convincing examples of this reaction are rare.44 Conversely thermal electrocyclic opening of a cyclobutene to a butadiene may also be viewed as a 2 + 2 cycloreversion which requires the methylene carbons to rotate through ca. 90". The latter process is comparatively easy and stereospecific.These considerations prompted a of the thermal opening of 2,3-dimethylbicyclo[2,l,0]pentanes,to 2,5-heptadienes in which the cyclo- propane orbital axes [(60) dashed lines] are already canted with respect to the breaking C-2-C-3 bond and thus an angular rotation intermediate between the cyclobutane and cyclobutene cases is required. The experimental results indicate a conrotatory/disrotatory preference of ca. 10,which is 10-30 times greater than 39 Y.Tamura N. Tsunjimoto and M. Ikeda Chem. Comm. 1971 310. 40 R. Grigg A. P. Johnson A. W. Johnson and M. J. Smith J. Chem. Soc. (0,1971 2457. 41 D. R. Kearns Chem. Rev. 1971 71 395. 42 G. R. Krow Angew. Chem. Internat. Edn. 1971 10 435. 43 Papers in Pure Appl. Chem. 1971 27 597-679. 44 A.T. Cocks H. M. Frey and I. D. R. Stevens Chem. Comm. 1969,458; J. E. Baldwin and P. W. Ford J. Amer. Chem. Soc. 1969 91 7192. IsJ. A. Berson W. Bauer and M. M. Campbell J. Amer. Chem. SOC.,1970,92 7515. Reaction Mechanisms-Part (ii) 5 the corresponding (2 + 2,)/(2 + 2,) rates in cycl~butanes,~~ but at least five orders of magnitude less than that of a cyclobutene opening.46 A concerted mechanism is favoured for this process in contrast to the analogous thermal opening of bicyclo[2,2,0]hexanes which involves a diradical intermediate.47 Extended Hiickel calculations on the potential surface for nonconcerted opening of cyclobutane to a tetramethylene diradical does not show an energy minimum corresponding to the diradical but rather a large energetically flat region of the potential surface termed a ‘twixtyl’ corresponding in modern collision theory to the intermediate.48 An earlier proposed example of a ,2 + ,2 cycloaddition [(61)+(62)]49 must be reconsidered in the light of studies on (63) which di- merizes to three cyclodimers in which the formal ,2 + ,2 product (64) pre- dominate~.~~ It is concluded that a diradical intermediate (65) is probably involved and that the energy barrier for disrotatory closure of (65) is slightly less than that for conrotatory closure since it enables the coplanarity of the ally1 systems to be maintained.However such an argument clearly cannot apply to (61)-+(62) although the proximate cyclohexadiene n-system might have a related effect. Observations bearing on these problems have been reported by 46 G.A. Doorakian and H. H. Freedman J. Amer. Chem. SOC.,1968,90 5310 6896. 47 E. N. Cain Tetrahedron Letters 1971 1865; L. A. Paquette and J. A. Schwartz J. Amer. Chem. SOC.,1970 92 321 5. 48 R. Hoffmann S. Swaminathan B. G. Odell and R. Gleiter J. Amer. Chem. Soc. 1970 92 709 I. 49 K. Kraft and G. Koltzenberg Tetrahedron Letters 1967 4357 4723. A. Padwa W. Koen J. Masaracchia C. L. Osborn and D. J. Trecker J. Amer. Chem. SOC.,1971 93 3633. 154 R. Grigg -Na-NH Hey,’ who observed surprisingly high stereospecificity in the reductive ring cleavage of cis-1,2-divinylcyclobutanes[e.g. (66)]. Reduction leads mainly to the &,trans-octadienes (67 ; R = H 69 %; R = Me 72 %). This is interpreted as a conrotatory opening of the intermediate (di?)radical-anion to give the allylic anions which are then protonated to yield the thermodynamically more stable disubstituted double bonds.A correlation diagram for this process is provided. The oft-quoted example of a .2 + .2 photochemical reaction the conversion of bicycloheptadienes (68) to quadricyclanes (69) appears to be a non-concerted proce~s.’~ Using a recently developed kinetic model it has proved possible to demonstrate that a two-step singlet photoaddition occurs for (68; X = CH or 0,R’ = Ar R2 = H or Me). Dewar-benzene is not formed from the first excited singlet or triplet states of benzene but from the second excited singlet state in a symmetry allowed pro~ess.’~ Stereospecific 1,2- and 1,4-photocycloaddition of olefins to benzene have been reported :54 cis-but-2-ene gives (70) and (71).However from preliminary observations it appears the first excited singlet state (‘B2J of benzene is involved in an apparently energetically unfavourable” concerted process i.e. concerted 1,3-cycloadditions are favoured from the ‘BZustate whereas the 1,2- and 1,4- processes are not. Although 1,3-photocycloadditions to benzene are known to be H Me ‘ H H (70) (71) H. Hey Angew. Chem. Internat. Edn. 1971 10 132. 52 G. Kaupp Angew. Chem. Internat. Edn. 1971 10 340. 53 D. Bryce-Smith A. Gilbert and D. A. Robinson Angew. Chem. Internat. Edn. 1971 10 745. 54 K. E. Wilzbach and L. Kaplan J. Amer. Chem. SOC.,1971 93 2073. 55 D. Bryce-Smith Chem.Comm. 1969 806. Reaction Mechanisms-Part (ii) stereospecific the question of endo or exo preference of substituents has remained unresolved. An ingenious application of [1,5]-sigmatropic shifts has enabled this problem to be resolved.56 The major isomer from the 1,3-cycloaddition of cis-but-2-ene to benzene is unchanged on heating at 300 "C for 20 min and is assigned the endo-configuration (72; R' = Me R2 = H). In contrast the minor isomer undergoes quantitative isomerization to (73) under these conditions and has the exo-configuration (72; R1= H R2 = Me). Similar studies were carried out on the trans-but-2-ene adducts and on the 1,3-cycloaddition products from benzene toluene and xylenes with cy~lobutene.~ The cyclobutene adducts all had the endo-configuration (e.g.72 R' = cyclobutyl) and rearranged on heating to derivatives of the tricyclodecadiene (74). Toluene and xylene cycloaddition ,-j";.. l"i H (74) (73) products with cyclobutene show preferential locating of a methyl group at the C-1 position [cf (72)]. The perturbational MO method has been applied5' to the Paterno-Buchi reaction (olefin + ketone or aldehyde +oxetan) and predicts a concerted path will be favoured by electron-withdrawing substituents on the olefin and electron-donating substituents on the carbonyl compound. Reversal of this substituent type is predicted to favour a diradical mechanism. Perturbational MO treatments support the roles of the frontier orbitals in determining the stereochemistry of the Diels-Alder reaction and correctly predict the effect of substituents on the rate of the reaction.59 In a 'normal' Diels-Alder reaction involving an electron-rich diene and an electron-poor dienophile the diene LUMO (lowest unoccupied MO) and dienophile HOMO (highest occupied MO) are closest in energy and result in the dominant stabilizing interaction [Figure l(a)].In the reverse electron demand Diels-Alder reaction the diene-HOMO-dienophile-LUMO interaction is the predominant one [Figure l(b)]. The effect of electron-donating substituents on the diene is to raise both the HOMO and LUMO in energy but the HOMO suffers a greater increase than the LUMO. Conversely electron-attracting substituents on the dienophile lower the energy of the HOMO and LUMO but the LUMO experiences a greater fall in energy.Thus both substitution patterns conspire to produce a more effective 56 R. Srinivasan Tetrahedron Letters 197 1 455 1. 57 R. Srinivasan J. Amer. Chem. Soc. 1971 93 3555. W. C. Herndon Tetrahedron Letters 1971 125; W. C. Herndon and W. B. Giles Mol. Photochem. 1970 2 277. 59 R. Sustmann Tetrahedron Letters 1971 2721; 0. Eisenstein and N. Trong Anh ibid. p. 1191. 156 R. Grigg -LUMO I LUMO-I I I -LUMO I I ----+---------I %HOMO HOMO% I E HOMO# #HOMO I Diene Dienophile. I Diene Dienophile (a) (b) Figure 1 HOMO-LUMO energy ordering for (a) normal Diels-Alder reaction and (b) inverse electron demand Diels-Alder reaction HOMO-diene-LUMO-dienophile interaction and hence facilitate the cyclo- addition.Substitution at the terminal positions of the diene is electronically more effective than substitution at C-2 or C-3. The effect of Lewis acid catalysts on the Diels-Alder reaction involves complexation of the dienophile with consequent lowering of the energy of the dienophile LUMO and acceleration of the reaction. Lewis acid catalysts also affect the isomer distribution6' and it has been suggested that the Diels-Alder reaction involves initial linking of the 'softest' centres.6 ' The suggestion62 that attractive van der Waals (dispersion) forces between methyl groups in the dienophile and unsaturated diene centres may play a role in stabilizing Diels-Alder transition states has been refuted.63 The important interactions are electronic (HOMO-LUMO) and steric (van der Waals re- pulsion between saturated centres) except in reactions of chlorinated dienes [e.g.(75)-(76) + (77) ca. 9 :1I6O in which positive attractive interaction be- tween the C-7 chlorine and the dienophile outweighs the steric factors which would favour (77). c1 c1 + #i cl?i c1 o$ 0 c1 oq0 c1 c1 cl%' (75) 6o K. L. Williamson and Y. L. Hsu J. Amer. Chem. SOC.,1970 92 7385. 61 0. Eisenstein J.-M. Lefour and N. Trong Anh Chem. Comm. 1971 969. 62 Y.Kobuke T. Fueno and J. Furukawa J. Amer. Chem. SOC.,1970 92 6548. 63 K. N. Houk and L. J. Luskus J. Amer. Chem. Sor. 1971,93 4606. Reaction Mechanisms-Part (ii) Rate comparisons for the loss of nitrogen from (78) and (79; n = 1-3) in a retro-homo-Diels-Alder reaction indicate concerted processes are operative for (78)and (79 ;n = 2 or 3) where (79 ;n = 1)decomposes by a diradical mechanism.A concerted mechanism in this case would impose severe strain in the transition state as C-1 C-2 C-3 and C-7 rehybridize to the diene.64 A related double- nitrogen elimination from an intermediate (80) gives the cis-dihydronaphthalene (81).65 An example of the rarely observed homo-Diels-Alder has been reported [(82)+(83)].66 The high ground-state energy and favourable geometry of (82) H a H N CN (83) overcome the normally prohibitively high energy demands of the n2s + 02 + n2 process. A Diels-Alder reaction of ci~-bicyclo[6,l,O]nonatriene provides evidence for the intermediacy of cis,cis,trans,cis-l,3,5,7-cyclononatetraene,since two trans-adducts are obtained [e.g.(84)*(85)p (see electrocyclic section).0 (84) E. L. Allred and A. L. Johnson J. Amer. Chem. SOC.,1971 93 1300. 65 K.-W. Shen Chem. Comm. 1971 391; J. Amer. Chem. SOC.,1971,93 3064. 66 J. E. Baldwin and R. K. Pinschmidt Tetrahedron Letters 1971 935. 67 A. G. Anastassiou and R. C. Griffith J. Amer. Chem. SOC.,1971 93 3083. 158 R.Grigg H H L (86) (87) Cases of borderline6* or non-~oncerted~’ 4 + 2 cycloadditions have been reported. Benzyne adds to cycloheptatriene to give the 2 + 2 adduct (86) presumably by a non-concerted mechanism,70 and not the 6 + 2 adduct as previously th~ught.~’ Photogenerated benzyne is identical in symmetry pro- perties with that prepared by conventional thermal routes and undergoes the same cycl~additions.~~ Chromium pentoxide etherate (87) is not a source of singlet oxygen as previously supposed the observed reactions being caused by traces of chromic acid.73 A study of the ene reaction using I3C-labelled ene components and diazoester enophile~~~ provides evidence for an alternative pathway to the concerted process. Thus (88 ;X = CH) gives (89),indicating a possible free-radical contribu- tion of 30 % (max). The related ene reaction of (88 ;X = N) had a much greater contribution from a non-concerted path (80% max; 40% min). Ene reactions between tetramethylallene and electron-deficient acetylenes are possibly two-step proce~ses.~ The reaction of allylboranes with olefins gives 1,3-dienes probably by an ene reaction [(90)+ (91)].76 * Et0,C-N=N -CO,Et 15*” 85*% PhCH=X-CH2Ph Ph-CH=CH-CH-Ph I (88) N-C02Et HNC0,Et (89) (90) 68 G.Kresze and W. Kosbahn Tetrahedron 1971,27 1931 ;G. Kresze H. Saitner J. Fir1 and W. Kosbahn ibid. p. 1941. 69 I. J. Westerman and C. K. Bradsher J. Org. Chem. 1971 36 969. 70 L. Lombard0 and D. Wege Tetrahedron Letters 1971 3981 ; P. Crews M. Loffgren and D. J. Bertelli ibid. p. 4697. H. Yamada Z. Yoshida and H. Kuroda Tetrahedron Letters 1971 1093. 72 M. Jones and M. R. Decamp J. Org. Chem. 1971,36 1536. 73 J. E. Baldwin J. C. Swallow and H. W.-S. Chan Chem. Comm. 1971 1407. 74 M. M. Shemyakin L. A. Neiman S. V. Zhukova Y. S. Nekrasov T.J. Pehk and E. T. Lippmaa Tetrahedron 1971 27 28 11. 75 H. A. Chia B. E. Kirk and D. R. Taylor Chem. Comm. 1971 1144. l6 B. M. Mikhailov and Y. N. Bubnov Tetrahedron Letters 1971 2127 2153. Reaction Mechanisms-Part (ii) The steric course and regioselectivity in 1,3-dipolar cycloadditions of diazo- acetic esters to cQ-unsaturated esters has been ~tudied.~ Interaction between substituents on the lY3-dipole and the dipolarophile can be attractive (7t-overlap dipole-dipole interaction) or repulsive (van der Waals strain) and interplay of these factors determines the preferred transition state. A perturbational MO treatment of substituent effects on rates of 1,3-dipolar cycl~additions~~ provides a rationale for the observed trends in terms of HOMO-LUMO interactions similar to those described for the Diels-Alder reaction (Figure 1).Numerous reports of the thermal and photochemical generation and trapping of lY3-dipolar species from 3-membered heterocycles have a~peared.'~ Calculations of the tendency to diradical character in open forms of 3-membered rings [(92) -+ (93) or (94)] indicate a maximum tendency for cyclopropane (80%)and a minimum for cyclopropyl anion (8%) with oxiran (38 %) and aziridine (30 %) intermediate in value.80 A + (96) 2-Am-allyl-lithium compounds (95) undergo anionic .4 + .2 1,3-cycloadditions to >C=C< >C=N- -N=N- and -C=C-in preparatively useful yields [e.g.(95)+(96)].*' 4 Sigmatropic Reactions The remarkable methylenecyclopropane rearrangement [e.g.(97)+(98) + (99)] has been investigated82 using optically active (97; R = Me). cis-trans Isomerism 77 P. Eberhard and R. Huisgen Tetrahedron Letters 1971 4337 4343. 78 R. Sustmann Tetrahedron Letters 197 1 27 1 7. 79 R. Huisgen and H. Mader J. Amer. Chem. SOC.,1971 93 1777; H. Hermann R. Huisgen and H. Mader ibid. p. 1779; E. Brunn and R. Huisgen Tetrahedron Letters 1971,473; R. Huisgen and W. Scheer ibid.,p. 481 ; R. Huisgen V. Martin-Rarnos and W. Scheer ibid. p. 477; J. H. Hall and R. Huisgen Chem. Comm. 1971 1187; J. H. Hall R. Huisgen C. H. Ross and W. Scheer ibid. p. 1188; K. Burger and J. Fehn Angew. Chem. Internat. Edn. 1971 10 728 729; J. J. Pommeret and A. Robert Tetrahedron 1971 27 2977; H. Harnberger and R. Huisgen Chem. Comm. 1971 1190; A.Dahrnen H. Hamberger R. Huisgen and V. Markowski ibid. p. 1192; A. Padwa and J. Smolanoff J. Amer. Chem. Soc. 1971 93 548; H. Gotthardt Tetra-hedron Letters 1971 1277; H. Gotthardt and F. Reiter ibid. p. 2749; M. Marky H.-J. Hansen and H. Schmid Helu. Chim. Acta 1971 54 1275; C. S. Angadujavar and M. V. George J. Org. Chem. 197 1 36 1589. E. F. Hayes and A. K. Q. Siu J. Amer. Chem. SOC., 1971,93,2090. T. Kauffmann and R. Eidenschink Angew. Chem. Internat. Edn. 1971 10 739. 82 J. J. Gajewski J. Amer. Chem. Soc. 1971 93 4450. 160 R. Grigg (97) competes with the rearrangement and suggests the reaction proceeds by way of an orthogonal diradical (loo),as first discussed by von Doering and Roth for the rearrangement of optically active Feist's ester (97; R = C0,Me).83 The pro- posed sigmatropic z2s + ,2 process' cannot be ruled out as a parallel pathway resulting in some product.MIND0/2 calculation^^^ predict the most stable singlet structure is the orthogonal diradical. The orthogonal diradical path also receives support from studies on related hydrocarbon^^^ such as (101) and (102). The photochemically allowed methylenecyclopropane rearrangement (1,3-suprafacial sigmatropic shift) is accompanied by fragmentation to alkylidene- carbenes.86 Me Me Me Me Me TAMe R Ar H H The full paper on the proposed antara-antara Cope rearrangement [e.g. (103)+(104)]has appeared.87 Baldwin and Kaplan" present a well reasoned case for interpreting such rearrangements as involving an initial conrotatory opening of the cyclobutene moiety followed by conrotatory closure involving the other double bond and provide an example [(105)-+ (106)] not containing 83 W.von E. Doering and H. D. Roth Tetrahedron 1970 26 2825. 84 M. J. S. Dewar and J. S. Wasson J. Amer. Chem. Soc. 1971 93 3081. 85 M. E. Hendrick J. A. Hardie and M. Jones J. Org. Chem. 1971 36 3061 ; T. B. Patrick E. C. Haynie and W. J. Probst Tetrahedron Letters 1971,423; W. R. Dolbier A. Akiba J. M. Riemann C. A. Harmon M. Bertrand A. Bezagnet and M. Santelli J. Amer. Chem. Soc. 1971,93 3933; M. C. Flowers and A. R. Gibbons J. Chem. Soc. (B) 1971 362; W. R. Roth and Th. Schmidt Tetrahedron Letters 1971 3639. 86 A. S. Kende Z. Goldschmidt and R. F. Smith J. Amer. Chem. Soc.1970 92 7606; J. C. Gilbert and J. R. Butler ibid. p. 7493. T. Miyashi M. Nitta and T. Mukai J. Amer. Chem. Soc. 1971 93 3441. J. E. Baldwin and M. S. Kaplan J. Amer. Chem. Soc. 1971 93 3969. Reaction Mechanisms-Part (ii) [b] D the magical C-1 methoxy-substituent so important in (103). Cope rearrangement of meso-3,4-diphenylhexa- 1,Sdiene gives 37 % of transpans- 1,6-diphenylhexa- 1,5-diene on rearrangement via a boat transition state,89 indicating the conse- quence of steric perturbations on the chair transition state. An example of the sulpho-Cope rearrangement using (107) has been reported,” and a variety of fascinating [3,3]-sigmatropic rearrangements in fused-ring systems continue to be disc~vered.’~ Thus the hydrocarbon hypostrophene (108) undergoes a degenerate Cope rearrangement at 35 “C although at higher temperatures an irreversible diradical rearrangement supervene^.^^ A new general ylide sigmatropic hydrogen shift [(109) -+ (1 101 has been proposed93 and examples provided for (109 ; X = S,Y = 0)94 and (109 ;X = N Y = O).93 These processes occur at room temperature and below.An alternative and probably diradical path giving olefin and X=Y competes when the mole- cular geometry is not favourable for the hydrogen-transfer reaction. A study of the [2,3]-sigmatropic shift occurring when optically active (1 11) is treated with butyl-lithium has established that a supra-supra shift occurs.9s Initial results on the effect of transition state geometry on [2,3]-sigmatropic shifts have been rep~rted.’~Thus the quaternary salts (112; R = CH,CH=CHPh or CH2Ph) form stable ylides (113) owing to the forced orthogonal relationship between 89 R.P. Lutz S. Bernal R. J. Boggio R. 0. Harris and M. W. McNicholas J. Amer. Chem. SOC.,1971,93 3985. 90 J. F. King and D. R. K. Harding Chern. Cornm. 1971 959. 91 E. Vedejs Chem. Cornm. 1971 536; J. W. Hanifin and E. Cohen J. Org. Chem. 1971 36 910; J. P. Synder L. Lee and D. G. Farnum J. Amer. Chem. SOC.,1971,93 3816. 92 J. S. McKennis L. Brener J. S. Ward and R. Pettit J. Amer. Chem. SOC.,1971 93 4957. 93 J. E. Baldwin A. K. Bhatnagar S. C. Choi and T. J. Shortridge J. Amer. Chem. SOC. 1971,93,4082. 94 A. Kondo and A. Negishi Tetrahedron 1971 27 4821; J. E. Baldwin G. Hofle and S.C. Choi J. Arner. Chern. SOC.,1971 93 2810. 95 J. E. Baldwin and J. E. Patrick J. Amer. Chem. SOC.,1971 93 3557. 96 S. Mageswaran W. D. Ollis I. 0. Sutherland and Y. Thebtaranonth Chem. Comm. 1971 1494. 162 R. Grigg (1 11) (1 12) (1 13) the N-R bond and the enolate mystem. In contrast the more-flexible azabi- cyclo[3,3,l]nonane system (114; R = CH,CH=CHPh) in which the N-R bond and the enolate mystem are at an angle of ca. 30° does undergo a [2,3]- shift giving (115). However the Stevens rearrangement (radical pair mechanism) of (114; R = CH,Ph) does not occur. An anionic version [(116) *(117)] of a (1 16) (117) [2,3]-sigmatropic shift has been reported and occurs at low temperature in good yield. ' The rearrangement (118) -+ (119) has been studied by deuterium labelling and occurs by intramolecular Diels-Alder reaction giving (120) followed by a U" (119) &+HH&+ (120) (121) 97 J.F. Biellmann and J. B. Ducep Tetrahedron Letters 1971 33; V. Rautenstrauch Helv. Chim. Acta 1971 54 739. Reaction Mechanisms-Part (ii) Me hv 7 Me*Ph double [1,5]-hydrogen shift [(120) -+(121) -+ (1 19)].98 Photochemical [1,3]- suprafacial shifts with retention of configuration at the migrating centre have been reported for several systems [e.g. (122)-+ (123)].99 Surprisingly the thermal reversal (123) *(122) occurs with 90 % retention of configuration at the migrating centre. This apparent violation of orbital symmetry is attributed to the very unsymmetrical nature of the dicyanoallyl framework across which the a-phenyl- ethyl group migrates.The node in the HOMO of the x framework no longer passes through C-2. This observation invoked a cation against the uncritical application of orbital symmetry rules to highly perturbed systems. 5 Cheletropic Reactions In contrast to the ready decarbonylation of benzonorbornadienones the hydra- zone (124) is remarkably thermally stable.'00 Failure to achieve cheletropic elimination of the isocyanide is thought to be due to the steric effect of the N-benzoxazoline substituent retarding the attainment of a linear geometry by N-R (124) R = I the bridging C-N-N- array of atoms. In contrast what appears to be a cheletropic isocyanide addition involving a 1,3-dipolar species [(125) -+ (126)] has been reported."' On treating dihydrothiophenium salts [e.g.(127)] with 98 J. A. Berson R. R. Boettcher and J. J. Vollmer J. Amer. Chem. Soc. 1971 93 1540. " R. C. Cookson and J. E. Kemp Chem. Comm. 1971 385; R. C. Cookson J. Hudec and M. Sharma ibid. pp. 107 108. loo R. S. Atkinson A. J. Clark and R. E. Overill Chem. Comm. 1971 535. lo' J. A. Deyrup Tetrahedron Letters 1971 2191. 164 R. Grigg butyl-lithium proton abstraction competes with S-alkylation. The S-alkylated products [e.g. (128)] undergo a cheletropic reaction furnishing methyl butyl sulphide and the hexadienes (129). Cheletropic elimination of SO from the corresponding dihydrothiophen sulphones generates only the trans,trans-2,4- hexadiene. The large amount of cis&-diene (33.5%) generated from (128) arises from steric interactions of the ring methyl groups with the S-alkyl groups in the transition state which adversely affect the disrotatory mode leading to the trans,trans-diene (58.5% produced).lo2 6 Homogeneous Catalysis and Pericyclic Processes A number of possible functions of metal ions in catalysing pericyclic processes merit consideration (a) the metal ion could convert symmetry-'forbidden' processes into symmetry-allowed concerted processes by interaction of the MO systems of substrate(s) and metal ion (b) the symmetry-'forbidden' process could occur stepwise via labile o-bonded organometallic intermediates or (c) both allowed or 'forbidden' [operating by either (a) or (b)]reactions (especially multicomponent processes) could be facilitated by prior co-ordination to a metal ion reducing unfavourable entropy factors.Numerous theoretical treatments of (a)have appeared. '03-lo6 More particu- larly the major focus of attention has been the metal-catalysed disproportiona- tion of olefins [(130) (131)]. The results of the theoretical treatments while R'CH CHR~ R'CH=CHR~ I1 II s R'CH CHR~ R~CH=CHR~ agreeing that 'forbidden'-to-allowed catalysis can occur differ in the way in which this is visualized to occur. These differences are still the subject of conten- tionlo4 and result from different choices of theoretical models. One scheme"' considers the reaction to occur via a cyclobutane and utilizes a pair of orthogonal d-orbitals one filled and one empty to transfer a pair of electrons from a substrate orbital which is antibonding at the site of reaction to one which is bonding in the region of reaction.An alternative treatment'06 suggests simultaneous rupture of B. M. Trost and S. D. Ziman J. Amer. Chem. SOC.,1971 93 3826. lo3 F. D. Mango Adv. Catalysis 1969 20 291; G. L. Caldow and R. A. MacGregor J. Chem. SOC.(A) 1971 1654. lo4 W. Th. A. M. van der Lugt Tetrahedron Letters 1970 2281. lo5 F. D. Mango Tetrahedron Letters 1971 505. lo6 W. B. Hughes J. Amer. Chem. SOC.,1970 92 532; G. S. Lewandos and R. Pettit Tetrahedron Letters 1971 789. Reaction Mechanisms-Part (ii) 7~-and o-bonds occurs and considers that an intermediate cyclobutane is not involved. Evidence supporting this contention is presented for a heterogeneous catalytic system which shows little tendency to convert cyclobutane to ethylene.One area attracting much experimental attention is the metal-catalysed re- organization of strained-ring systems by formally 'forbidden' reactions such as the Ag'-catalysed rearrangements of cubane and related derivatives [( 132) and (133)]lo7 to systems containing cyclopropane rings e.g. (133) +(134).'08 I C0,Me C@,Me R' Metal catalysis [Ag' Rh' Ir' Pd" or Ru"] of theformal u2a+ u2aconversion of bicyclo[l,l,O]butanes to butadienes [e.g. (135)+ (136)]'09 has been the subject of numerous studies. 'lo Related Rh'-catalysed rearrangements of olefinic epoxides and bicyclo[6,1,O]nonatrienes [e.g. (137) -+ (138)] have also been reported.'" The initial theories suggested to account for these extensive bond relocations reflect the ingenuity of the chemists involved but Katz and Cerefice' l2 provided (137) lo' W.G. Dauben C. H. Schallhorn and D. L. Whalen J. Amer. Chem. SOC.,1971,93 1446; L. A. Paquette R. S. Beckley and T. McCreadie Tetrahedron Letters 1971 775; L. A. Paquette and J. C. Stowell J. Amer. Chem. SOC.,1971 93 2459. H. H. Westberg and H. Ona Chem. Comm. 1971,248. M. Sakai H. Yamaguchi H. H. Westberg and S. Masamune J. Amer. Chem. SOC. 1971 93 1043; L. A. Paquette S. E. Wilson and R. P. Henzel ibid. p. 1288. lo P. G. Gassman and F. J. Williams J. Amer. Chem. Soc. 1970,92,7631 ; P. G. Gassman T. J. Atkins and F. J. Williams ibid. 197 1,93 18 12 ; P. G. Gassman and F.J. Williams Tetrahedron Letters 1971 1409; P. G. Gassman and T. J. Atkins J. Amer. Chem. SOC. 1971 93 1042; L. A. Paquette R. P. Henzel and S. E. Wilson ibid. p. 2335; L. A. Paquette Accounts Chem. Res. 1971 4 280. R. Grigg and G. Shelton Chem. Comm. 1971 1247; R. Grigg R. Hayes and A. Sweeney ibid. p. 1248. 'I2 T. J. Katz and S. A. Cerefice J. Amer. Chem. SOC. 1971 93 1049. 166 R. Grigg kinetic evidence for a stepwise process and some organorhodium complexes have been isolated in the isomerization of quadricyclane to norbornadiene. Maitlis Childs and Kaiser' l4 suggested these catalysts were functioning as weak Lewis acids and provided many examples of such catalysts which effected transformations of tri-t-butylprismane (139).Even trinitrobenzene was effective in this case! Other workers'" subsequently concurred with the Lewis acid interpretation although the variqtion of product distribution with metal catalyst still calls for further study and the role of oxidative-addition processes in these rearrangements remains to be clarified. 'l6 'I3 L. Cassar and J. Halpern Chem. Comm. 1970 1082. K. L. Kaiser R. F. Childs and P. M. Maitlis J. Amer. Chem. SOC.,1971 93 1270. P. G. Gassman and T. J. Atkins J. Amer. Chem. Soc. 1971 93 4597; M. Sakai and S. Masamune ibid. p. 4610; M. Sakai H. H. Westberg H. Yamaguchi and S. Masamune ibid. p. 4613. 'I6 J. E. Byrd L. Cassar P. E. Eaton and J. Halpern Chem. Comm. 1971 40.

ISSN:0069-3030    

DOI:10.1039/OC9716800143

出版商:RSC    

年代:1971

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 The University of Southampton SO9 5NH From a mechanistic viewpoint an enzymic reaction may be separated into two broad stages. The first stage is concerned with the formation of the Michaelis Complex in which the substrate is attached to the enzyme surface in an arrange- ment that is appropriate for the second stage the catalysis to occur. Understand- ing the formation of the Michaelis Complex requires knowledge of the physico- chemical forces which direct the approach of the substrate to the active site the molecular interactions between substrate(s) and the binding groups which hold the complex together and the features which regulate the effectiveness of the enzyme binding-site groups.The investigations pertinent to the catalytic stage include the identification of the catalytic groups determination of the chemical nature of the intermediates involved in the overall process the elucidation of the ideal special arrangement of the substrates with respect to the catalytic groups and determination of any factors which may influence the reactivity of the catalytic groups. This report summarizes some of the major approaches currently being used which shed light on the nature of the active sites of enzymes and proteins. Par- ticular emphasis is laid on the identification function and regulation of groups involved in enzyme catalysis. 1 The Binding of Substratesto the Active Sites of Proteolytic Enzymes and the Influence of Secondary Interactions on Catalysis It has been recognized for a long time that low molecular weight synthetic substrates may be hydrolysed by proteolytic enzymes such as pepsin through a mechanism and at a site normally used for the hydrolysis of protein substrates ; however the rates of hydrolysis for the latter are usually several orders of magni- tude faster than those for the best synthetic substrates.These observations led to the view that substrate groups remote from the bond to be cleaved may play an important role in modulating the activity of the catalytic groups of enzymes. A more quantitative examination of this view has now been made possible by rate specificity and X-ray crystallographic studies carried out using systematically modified peptide substrates.167 M. Akhtar and D.C. Wilton Papain can accommodate at least seven amino-acid residues at the active site’ (Scheme 1). The regions involved in the binding are termed ‘subsites’ and are designated as S,-S and S;-S; the hydrolysis occurring between S and S; . The nature of the products formed from the hydrolysis of the substrates (lH4) by papain has permitted the deduction that the substrates align at the active site as shown in Scheme 1. An aromatic amino-acid residue when present always occupies the subsite S2 and the hydrolytic cleavage occurs not at the peptide bond linking this aromatic residue but at the peptide bond adjacent to it.’ This method of mapping the active site has been extended2 to carboxypeptidase A.1 H-Ala-Ala-Phe-Lys-Ala.NH (4) H.Ala-Phe-Ala-Ala.OH (3) HePhe-Ala-Ala-Ala-OH (2) H-Phe-Ala-LysOH (1) t 4 I s I s I s 1 s; I ///////1//// 11111 Enzyme Scheme 1 The studies carried out using compounds in which the peptide bond under- going cleavage is replaced by ester or amide linkages (5)have shown that papain- catalysed hydrolysis occurs via the mechanism of Scheme 2 (for details see ref. 3). The first step is the formation of the Michaelis Complex (5)(6),which then rearranges to give the acyl enzyme intermediate (7) and finally hydrolysis yields the product (8). 0 //R-C-X + Enz-S-H (5)(6) 0 //R-C-S-Enz + HX (5) (6) (7) 1lH20 0 R-C-OH// + (6) (8) X = leaving group; R = peptide chain Scheme 2 We will now consider the experimental approach for assessing the contribution to the overall catalysis which each part of the substrate molecule may make by binding to the enzyme.The ratio k,,,/K has been suggested4 to be a suitable parameter for determining the catalytic specificity of proteolytic enzymes ; as A. Berger and I. Schechter Phil. Trans. Roy. Sue. 1970 B257,249. ’ I. Schechter European J. Biochem. 1970 14 5 16. M. R. Hollaway Ann. Reports (B) 1968 65 601. M. L. Bender and F. J. Kezdy Ann. Rev. Biochem. 1965 34 49. Reaction Mechanisms -Part (iii) Enzyme Mechanisms an approximation a higher k,,,/K value indicates a better substrate. In the case of papain hydrolysis an impressive influence on productive binding is noted when structural modifications are introduced at groups remote from the bond to be cleaved.’ The k,,,/K data in Scheme 3 show the adverse effect of the progressive replacement of the amide group adjacent to the bond to be cleaved by methylene groups [(10)--(12)].Also to be noted is the improvement in the k,,,/K value when the N-terminal residue in (lo) PhCO- is replaced by PhCH2CH(NHAc)-CO-as in (9). (9) AcNH 0 0I II II 1Ph-CH,-CH-C-NH-CH2-C-O-C6H4N02 kcaJKm 1.7 x lo7 (10) 0 0 II II Ph-C-NH-CH2-C-O-C6H4N02 2.2 x lo5 (1 1) 0 0 II IIPh-C-CH2-CH2-C-0-C6H4N02 4.5 x lo3 0 Scheme 3 The available kinetic data,5 together with the knowledge of the X-ray structure of papain,6 have been married into a pictorial view of the enzyme mechanism (Scheme 4).5,7 The model building used L-phenylalanylalanine amide (13) as the ~ubstrate.~ It is suggested5 that the aromatic residue of (13)is accommodated in the hydrophobic part of the cleft comprising the side-chains of the amino-acid residues tyrosine-67 tryptophan-69 phenylalanine-207 alanine-160 valine-133 and valine-157.The -NH group (marked as NA)of the substrate (13) is then within hydrogen-bonding distance of the side-chain carboxy-group of aspartic acid-158. The interaction of the aromatic ring with the hydrophobic groups allows the -NH-and -CO-groups of the amide linkage of the substrate to hydrogen-bond more effectively with C=O of aspartic acid-158 and -NH-of glycine-66 respectively. The fixing of the amide bond in this fashion results in severe non-bonded interaction between the bond about to be cleaved and the a-CH group of histidine-159.From the model of the enzyme-substrate complex it would appear that non-bonded interaction could be relieved by forcing the carbon atom of the amide or ester bond about to be cleaved towards sp3 hybri-dized configuration through attack by the thiol group of cysteine-25. Thus a crucial step in the overall reaction has been performed. G. LoweandY. Yuthavong Biochem. J. 1971 124 107. J. Drenth J. N. Jansonius R. Koekoek H. M. Swen and B. G. Wolthers Narure 1968 218 929; J. Drenth J. N. Jansonius R. Koekoek L. A. A. Sluyterman and B. G. Wolthers Phil. Trans. Roy. Soc. 1970 B257 231. B. G. Wolthers J. Drenth J. N. Jansonius R. Koekoek and H. M.Swen Proceedings of the International Symposium on Structure-Function Relationships of Proteolytic Enzymes Munksgaard Copenhagen 1970 p. 272; J. Drenth J. N. Jansonius R. Koekoek and B. G. Wolthers Adv. Protein Chem. 1971 25 79. M.Akhtar and D. C. Wilton Scheme 4 The model could rationalize5 why papain shows stereospecificity for L-amino- acids in both positions of the substrate (13). With L-configuration the a-CH bond (*H)points into the body of the enzyme; amino-acids with D-configuration will not be tolerated since this would require interchanging the position of the a-hydrogen atom (*H)with the amino-acid side-chain thus giving rise to sterically unfavourable interactions. Similar reasons can be envisaged for the requirement of L-configuration for the aromatic amino-acid.Attention is drawn to a related X-ray crystallographic study' with chymotryp- sin A. The chloromethyl ketones of the structure (14a) irreversibly inactivate chymotrypsin through alkylation at histidine-57. The crystallographic structure of the enzyme-inhibitor complex (14b) has highlighted the importance of the secondary interactions existing between the active site and the amide bonds a p and y of the substrate (14) away from the bond to be cleaved. 0 Me 0 Me 0 Ph 0 I1 1 I1 I I1 I I1 Me.C-NHCHC-NHCH.C-NH.CH.C-CHC-CH2-X Y B o! (14a) X = C1 (14b) X = protein D. M. Segal J. C. Powers G. H. Cohen D. R. Davies and P. E. Wilcox Biochemistry 1971 10 3728. Reaction Mechanisms -Part (iii)Enzyme Mechanisms The specificity and the mechanism of action of another proteolytic enzyme pepsin has also been extensively inve~tigated,~ though studies on its structure are at present at a rather less advanced stage.Pepsin consists of a single poly- peptide chain and has a molecular weight of about 35 000. Unlike the cysteine and serine proteases which catalyse the hydrolysis of an amide linkage through the formation of an acyl enzyme intermediate pepsin catalysis appears to involve the formation of an amino-enzyme intermediate. An abbreviated pathway for the overall reaction using benzyloxycarbonyl-L-tyrosyl-L-tyrosine(15) as substrate is shown in Scheme 5. The mechanism has received support from trans- peptidation experiments" and from the fact that incubation of unlabelled (15) with labelled (17) or (18) results in the incorporation of radioactivity in the recovered starting material only from (17) and not from (18)." Detailed discus- sions on the mechanism of action of pepsin are available.' ',12 RO R I II I ZNHCHC-NHCH-COOH + Enz -XH (15) R R I I CEnz -NHCH-COOH + ZNH-CHCOOH (16) (17) R 1 I Enz -XH + NH,.CHCOOH (18) R = tyrosine residue ;Z = benzyloxycarbonyl Scheme 5 With small synthetic substrates of structure A-X-Y-B where the X-Y bond is cleaved pepsin exhibits a preference for Phe in the X-position and for Trp Phe and Tyr in the Y-position.Scheme 6 shows some of the available on the peptic cleavage of the Phe-Phe bond in substrates (19H22). The replacement of the N-terminal group from benzyloxycarbonyl (Z) to Z-Gly- to Z-Gly-Gly- has progressive favourable effect on the k,,,/K values.It should be noted that there is a decrease in the kinetic parameter when the benzyloxycarbonyl group in (21) is replaced by a hydrogen atom as in (22). Thus it would appear that the presence of a hydrophobic benzyl group two amino-acid residues away from the amino terminus of Phe-Phe has a marked J. S. Fruton Adv. Enzymol. 1970 33 401. lo H. Neumann Y. Levin A. Berger and E. Katchalski Biochem. J. 1959 73 33. " J. S. Fruton S. Fujii and M. H. Knappenberger Proc. Nat. Acad. Sci. U.S.A. 1961 47 759. l2 J. R. Knowles Phil. Trans. Roy. SOC. 1970 B257,135. G. P. Sachdev and J. S. Fruton Biochemistry 1969 8 423 1. M.Akhtar and D. C. Wilton kcatlLl Z-Phe-Phe-OX (19) 3.7 Z-Gly-Phe-Phe-OX (20) 7.8 Z-Gly-Gly-Phe-Phe-OX (21) 180 H-Gly-Gly-Phe-Phe-OX (22) 3.0 Z = benzyloxycarbonyl ;OX = leaving group Scheme 6 effect on the catalytic efficiency. These and related results on pepsin14 coupled with those from similar studies on carboxypeptidase A,2 thermolysine,l5 throm-bin,16 rennin,14 and bacterial proteina~es'~ have highlighted the role of group(s) remote from the bond to be cleaved in modulating the activity of the catalytic groups of enzymes. The most dramatic illustration of the effect of substrate binding on the con- formation of active-site groups remains the example of carboxypeptidase A in which it was noted that the binding of the substrate glycyl L-tyrosine to the enzyme promotes the displacement of the hydroxy-group of Tyr-248 through a distance of 12A so that it may participate in catalysis.l7 Comprehensive treatment of the structure and function of proteolytic enzymes is available in reviews," reports of symposia," and books.20 2 Bisubstrate Reactions The Effect of the Binding of One of the Substrates on the Activity of the Catalytic Group(s) We have seen above how the substrate groups away from the sensitive bond in- fluence the catalytic activity of the hydrolytic enzymes. A related phenomenon is noted with enzymes which participate in reactions involving two substrates. Isocitrate dehydrogenase catalyses the oxidative decarboxylation of isocitrate (23) into a-oxoglutarate (28) ;the overall conversion occurs through the sequence of Scheme 7.This involves the NADP-dependent oxidation of (23) to give the hypothetical intermediate (26) which decarboxylates to the enol (27) ; the latter after rearrangement then furnishes the product (28). In the formal reversal of the reaction one of the P-hydrogen atoms of (28) would be expected to exchange l4 I. M. Voynick and J. S. Fruton Proc. Nat. Acad. Sci. U.S.A. 1971 68 257. l5 K. Morihara and H. Tsuzuki European J. Biochem. 1970 15 374. l6 R. K. H. Liem R. H. Andreatta and H. A. Scheraga Arch. Biochem. Biophys. 1971 147 201. l7 W.N. Lipscomb G. N. Reeke J. A. Hartsuck F. A. Quiocho and P. H. Bethge Phil. Trans. Roy. Soc. 1970 B257 177. I' D.M. Blow and T. A. Steitz Ann. Rev. Biochem. 1970 39 63; also see G.P. Hess and J. A. Rupley Ann. Rev. Biochem. 1971 40 1031. l9 A Discussion on the Structure and Function of Proteolytic Enzymes organized by D. C. Phillips D. M. Blow B. S. Hartley and G. Lowe Phil. Trans. Roy. SOC.,1970 B257 65-265 ;see also ref. 7. 'O 'The Enzymes,' ed. P. D. Boyer Academic Press New York and London 1971 vol. 4; C. J. Gray 'Enzyme-Catalysed Reactions,' Van Nostrand Reinhold London 1971. Reaction Mechanisms -Part (iii) Enzyme Mechanisms 173 with the protons of the medium. Such a reaction however is observed2’ only when a-oxoglutarate (28) and the enzyme are incubated in the presence of NADPH. The experiment highlights the fact that the catalytic group(s) par- ticipating in equilibrium c (Scheme 7) become available only after the coenzyme site is occupied by NADPH.HO-CH-COOH +?=C-COOH 1 I //O H-C-C + NADP NADPH + \ I 0-H (24) (25) CH2-COOH CH,-COOH] (23) 0 COOH HO CH2-COOH CH2-COOH (28) (27) Scheme 7 The pyridoxal phosphate dependent serine transhydroxymethylase (SHM) catalyses the transfer of a C ,-unit from methylenetetrahydrofolate (30) to glycine to give tetrahydrofolate (29) and serine. It has been suggested22 that the conver- sion occurs through the sequence a-d (Scheme 8). The first event in the con- version is the reaction of glycine with the enzyme-pyridoxal complex (32) to give the Schiff-base intermediate (33) which undergoes deprotonation to give a resonance-stabilized carbanion or its equivalent species (34).The carbanion then reacts with ‘formaldehyde’ released at the active site from (30) to give the pyridoxal derivative of serine (35). There is a four-fold increase23 in the rate of reaction of glycine with the pyridoxal-enzyme complex (equilibrium a) when the second- substrate site is occupied by tetrahydrofolate. An even more dramatic influence of the binding of tetrahydrofolate to (32) is reflected on an exchange rea~tion~~.~~ occurring through the combination of equilibria a and b. No detectable cleavage of the C-H bond of glycine is observed when glycine is incubated with SHM ; however the addition of tetrahydrofolate results in a rapid exchange of the S-hydrogen atom of glycine with the protons of the medium.22 The experiments show that the activity of the catalytic groups participating in equilibria a and b is greatly enhanced by the binding of tetrahydrofolate to the enzyme.Related ” G. E. Lienhard and I. A. Rose Biochemistry 1964 3 185; Z. B. Rose J. Biol. Chem. 1960,235 928. 22 P. M. Jordan and M. Akhtar Biochem. J. 1970 116 277. 23 L. Schirch and M. Ropp Biochemistry 1967 6 253. 24 L. Schirch and W. T. Jenkins J. Biol. Chem. 1964 239 3801. 174 M. Akhtar and D. C. Wilton H Rl&R2 I HsTH&)OH + CH,-NHR NH2 N R3 I H ENZ (31) (29) N-X = N-H + (30) N-X = N=CH H HYHCOOH . -yCOOH oH-~Hy~oOH Serine 2 7-t 7 7 ‘HCHO’ generated (32) from (30) f” (29) and (30) R = Ph-C-(gIutamyl),; (32) R’ = CH,.043 R2 = OH R3 = Me I1 0 Scheme 8 phenomena showing the effect of cosubstrates on hydrogen atom exchange reactions have been noted with several enzymes including deoxycytidylate hydr~xymethylase,~~ malate synthetase,26 and citrate ~ynthetase.~~ 3 The Effect of Changes in Enzyme Structure on Catalytic Activity We have so far dealt with the effect of substrate structures on the activity of the catalytic groups of enzymes.The availability of rapid methods for the synthesis of peptides and proteins has permitted the study of another aspect. The staphylo- coccal nuclease catalyses the hydrolysis of 3‘,5’-phosphodiester linkages in both DNA and RNA to give the corresponding 3’-phosphomononucleotides. A limited tryptic hydrolysis of the nuclease yields two large fragments nuclease- T-(6-48) and nuclease- T-(49- 149).These two fragments bind non-covalently to form nuclease-T’ a complex structurally similar to the nuclease but only 8-10% as active. The reported three-dimensional structure of the nuclease suggests that the amino-acid residues Asp-21 Arg-35 Asp-40 and Glu-43 are functionally important.28 Peptide analogues corresponding to the nuclease region 6-47 have been prepared with single site substitutions at the four positions (residues 21 35,40 and 43). These peptides were tested for their ability to form complexes with nuclease-T-(49-149) and for catalytic activity when the complex formation o~curred.’~Only the substitution that did not alter the net charge allowed the complex formation i.e. the replacement of Asp-21 with glutamic acid allowed the 25 Yun-Chi Yeh and G.R. Greenberg J. Biol. Chem. 1967 242 1307. 26 H. Eggerer and A. Klette European J. Biochem. 1967 1 447. 27 H. Eggerer Biochem. Z. 1965,343 11 1. 28 A. Arnone C. J. Bier F. A. Cotton V. W. Day E. E. Hazen D. C. Richardson J. S. Richardson and A. Yonath J. Biol. Chem. 1971 246 2302. 175 Reaction Mechanisms -Part (iii) Enzyme Mechanisms complex formation but not when it was replaced with asparagine. The study29 also showed that the formation of the catalytically active complex required essentially the entire amino-acid sequence of nuclease- T(6-48). In another study3’ by the same group it has been shown that a catalytically active complex is formed when nuclease- 7349-149) binds to nuclease- T-(1-126). The redun- dant portion (residues 49-126) of nuclease-T-(1-126) hangs away from the molecule as shown in the Figure and does not interfere with the ordered structure of the complex.I26 and nuclease-T-( 1-126) (I). Figure Interaction of nuclease-T-(49-149) (0) The ordered structure is surrounded by the circle. (Simpl$ed adaptation of aJigure from ref 30) Studies31 on leucyl-tRNA synthetase also indicate that the enzyme may be broken into two fragments by proteolysis and then rejoined non-covalently to give full activity. The larger of the two fragments is able to catalyse the ATP/PP exchange but has no synthetase activity. 4 The Identification of Catalytic Groups Active-site-directed Inhibitors.-Since the early days of enzymology a major approach to the study of enzyme mechanisms has been the use of inhibitors that are able to chemically modify reactive groups on the protein.This line of research which has been extensively reviewed in the past has evolved the concept of the active-site-directed irreversible inhibit~r.~~,~~ These reagents are designed such that they have a very close similarity to the normal substrate and therefore will form a Michaelis Complex with the enzyme. However the presence of a suitably reactive group on the inhibitor should allow it to react chemically with residues at the active site that are involved in the catalytic process. Such inhibitors are 29 I. M. Chaiken and C. B. Anfinsen J. Biol. Chem. 1971,246 2285. 30 H. Taniuchi and C. B. Anfinsen J. Biol. Chem. 1971 246 2291 ; I.Parikh L. Corley and C. B. Anfinsen J. Biol. Chem. 1971 246 7392. 31 P. Rouget and F. Chapeville European J. Biochem. 1971 23 459. 32 L. Wofsy H. Metzger and S. J. Singer Biochemistry 1962 1 1031. B. R. Baker ‘Design of Active-Site-Directed Irreversible Enzyme Inhibitors,’ Wiley New York 1967. 176 M. Akhtar and D. C. Wilton eagerly sought by both mechanistic enzymologists and chemical pharmacologists since by their very nature they have tremendous potential both as tools for investigating enzymes and for therapeutic purposes. The object of this part of the review is to highlight recent developments in the field of active-site-directed irreversible inhibitors. The literature up to 1969 is available in reviews.34 For convenience we have discussed in separate sections the reactions of inhibitors on each class of enzyme.Oxidoreductases. There has been much interest in the development of alkylating inhibitors structurally related to NADf. The pyridine analogue (36) has been successfully used to alkylate both a histidine and a cysteine at the active site of lactic dehydr~genase.~ More recently the NAD analogue 5-bromoacetyl-4- methylimidazole dinucleotide (37) in which the alkylating bromoketone is in the adenine part of the cofactor has been incorporated into liver alcohol de- hydrogenase. Diazo-compounds are finding increasing use in the labelling of amino-acids at the active site of enzymes. Their special advantage lies in the fact that once the inhibitor is bound at the active site then photolysis of the diazo-group will generate a highly reactive carbene RR'C=N 5 RRT This carbene has the potential to react with any amino-acid residue and in particular it is able to insert into the C-N bond of aliphatic amino-acids and phenylalanine.These amino-acids are immune to modification by any normal reagent. 0 0 I1 II uC-CH2Br ("d' N C-CH,Br 0-0-i (36) I I Ribose-0-P-0-P-0-Ribose I1 11 00 (37) + Me,N-CH,-CH-CH,-COO-0 I II 0 \ C-CH,Br II 0 (38) (39) 34 E. Shaw Physiological Rev. 1970 50 244; B. E. Vallee and J. F. Riordan Ann. Rev. Biochem. 1969 38 733. 35 C. Woenckhaus J. Berhauser and G. Pfleiderer Z. physiol. Chem. 1969 350 473. 36 C. Woenckhaus and R. Jeck Z.physiol. Chem. 1971 352 1417. Reaction Mechanisms -Part (iii) Enzyme Mechanisms 177 The [''C]diazoacetate ester of 3-hydroxymethylpyridine (38) has been enzymi- cally exchanged with NAD to give the 3-diazoacetoxymethyl analogue of NAD. This conversion was achieved by the enzyme diphosphopyridine nucleosidase which normally hydrolyses NAD to give adenosine diphosphoribose (ADPPR) and nicotinamide but will also catalyse an exchange whereby the diazo-derivative of nicotinamide (38) may be incorporated into the ADPPR moiety Nicotinamide Adenine (38) Adenine \ I + (38) --* I I Ribose-P-P-Ribose Ribose-P-P-Ribose +Nicotinamide The diazo-analogue of NAD was allowed to react with yeast alcohol dehydrogen- ase and then photolysed ;subsequent hydrolysis of the enzyme gave a number of radioactive products.37 This lack of specificity in the reaction of the carbene with groups on the enzyme is disappointing.It is hoped that more conclusive results will be obtained by synthesizing suitable diazo-analogues that are more rigidly held to the coenzyme binding site of the enzyme. Transferases. Identification of a histidine residue at the active site of the enzyme carnitine acetyl transferase has been achieved by the inhibitor bromo- acetylcarnitine (39) ; to date however no catalytic function has been ascribed to this residue.38 Hydrolysases. The hydrolysases and in particular the proteolytic enzymes and cholinesterase have long been a major focus of attack for the classical alkylating inhibitors.More recently particular use has been made of the potentially long- lived acyl intermediate formed during hydrolysis. Reactive groups are attached to the acyl moiety in order that they might react with other residues at the active site of the enzyme. Westheimer's group has formed acyl intermediates of both chymotryp~in~~ and trypsin4' where a diazo-group is attached to the acyl moiety. In the case of trypsin photolysis resulted in the radioactive inhibitor (40) being inserted into an alanine residue since subsequent hydrolysis of the enzyme gave radioactive glutamic acid. The overall reaction is shown in Scheme 9. This is the first time a non-polar amino-acid has been identified at the active site of an enzyme by a purely chemical approach. A major achievement in the chemical modification of proteins is to introduce bifunctional alkylating inhibitors.Notable successes have been achieved with this approach in the case of papain ficin and bromelain using dibrom~acetone.~ Although available evidence suggests that there are two catalytically important carboxy-groups in pepsin only one of these has been identified using 14C-labelled dia~oacetylphenylalanine.~~ Fruton and his co-workers have now reported the 37 D. T. Browne S. S. Hixson and F. H. Westheimer J. Biol. Chem. 1971 246 4477. '* J. F. A. Chase and P. K. Tubbs Biochem. J. 1970 116 713. 39 J. Shafer P. Baronowsky R. Laursen F. Finn and F. H. Westheimer J. Biol. Chrm. 1966 241 42 1. 40 R. J. Vaughan and F. H. Westheimer J. Amer. Chem. SOC.,1969,91 217.41 S. S. Husain and G. Lowe Biochem. J. 1968 108 855; 1970 117 333 341. J2 R. S. Bayliss J. R. Knowles and E. Wybrandt Biochern. J. 1969 113 377. 178 M. Akhtar and D.C. Wilton Trypsin + + 0 C0,Et \c* CH,I CH N CH \ /H0-c-c 1 YH2 (I I C=O/\ NH HN/'C=O 0 C0,Et\ I0-c-c:I CH CH CH2 * -1 Iy 2 I\ C=O NH Hi \C=O COOH I I *CH2 YHZ + I NH,-C-H I COOH (38) Scheme 9 use of a bifunctional inhibitor l,l-bis-(diazoacetyl)-2-phenylethane(41) to inactivate pepsin.43 The precise site of cross-linking has yet to be identified. A lysine has been implicated at the active site of adenosine deaminase by using the inhibitor 9-(p-bromoacetamidobenzyl)adenine (42).44 C0,Et 0 0 I II II C=N NZCH-C C-CHN, I \/ c=o CH I I 0 CH NO (40) Me I p N%N> c=o 'N I 0 0 NH-C-CH,Br II (42) 43 S.S. Husain J. B. Ferguson and J. S. Fruton Proc. Nat. Acad. Sci. U.S.A. 1971 68 2765. 44 G. Ronca M. F. Saettone and A. Lucacchini Biochim. Biophys. Acra 1970 206 414. Reaction Mechanisms -Part (iii) Enzyme Mechanisms Lyases. The irreversible inhibition of acetoacetate decarboxylase by 2,4-dini- trophenyl propionate (43) has been successfully used to investigate the pK of the active-centre lysine re~idue.~’ The pH dependence of acylation of this group by (43) indicated that it had a pK of 5.9 about 4 pH units lower than that of a normal lysine. The anomalous pK allows this lysine to be in the non-protonated form at pH 6 the enzyme pH which is normally required for Schiff-base formation between enzyme and substrate.Isornerases. Studies on triose phosphate isomerase have included the use of two types of active-site-directed inhibitors 3-halogenoacetol phosphate (44)46947 and glycidol phosphate (45).48 In both cases the site of esterification is a glutamic acid residue and sequencing of the amino-acids around this residue has estab- lished that it is in fact the same glutamic acid residue that is modified with each inhibitor. This glutamate residue has been ascribed a basic function in the reaction mechanism. I PX Ll H 0 (‘6 It /\ Enz -C-O-CH2-CHZ-CH2O@ +chemical reduction 0 II Enz -C-O-CHZcX I c=o I CH208 (44) AIlosteric-site-directed Inhibitors. There is now considerable interest in the design of allosteric-site-directedinhibitors of key regulatory enzymes.Work on glutamic dehydrogenase (GDH) has already established the importance of a tyrosine residue at the binding site of the allosteric effector GTP.49 Now the covalent attachment of the oestrogen analogue diethylstilboestrol to the allosteric site of this enzyme has been reported,” Tritium-labelled bromoacetyldiethyl-45 D. E. Schmidt and F. H. Westheimer Biochemistry 1971 10 1249. 46 F. C. Hartmann Biochemistry 1971 10 146. 47 A. F. W. Coulson J. R. Knowles J. D. Priddle and R. E. Offord Nature 1970 227 180; A. F. W. Coulson J. R. Knowles and R. E. Offord Chem. Comm. 1970 7. 48 J. C. Miller and S. G. Waley Biochem. J. 1971 123 163; S. G. Waley J.C. Miller 1. A. Rose and E. L. O’Connell Nature 1970 227 181. j9 N. C. Price and G. K. Radda Biochem. J. 1969 114 419. J. Kallos and K. P. Shaw Proc. Nut. Acad. Sci. U.S.A.. 1971.68. 916. M. Akhtar and D.C. Wilton stilboestrol (46) was prepared and successfully incorporated into the enzyme to the level of one mole of steroid per mole of enzyme sub-unit. The radioactivity was removed by treatment with alkali or hydroxylamine indicating that the steroid was covalently bound through an ester linkage. The alkylation had ‘fixed’ the enzyme in its Y conformation where it has little glutamate dehydro- genase activity but enhanced dehydrogenase activity towards alanine GTP oestrogen GDHW)4 ADP GDH(Y) glutamate activity alanine activity The synthesis of diazomalonyl derivatives of cyclic-AMP has led to the successful labelling of the cyclic-AMP binding site of the enzyme phosphofructokinase.Tritiated 02’-(ethyl-2-diazomalonyl)cyclic-AMP (47) was photolysed in the presence of the enzyme to generate a reactive carbene and resulted in covalent binding. Prior to photolysis (47) was able to mimic the effect of cyclic-AMP and a direct competition between (47) and cyclic-AMP for the allosteric site was also observed. The authors did not measure the enzyme activity of the covalently modified phosphofructokinase. The Active Sites of Antibodies. The major problem in synthesizing active-site- directed irreversible inhibitors capable of chemical modification of the enzyme is the chemical limitation imposed by the nature of the natural substrate.A unique alternative offers itself in the field of immunology where the substrate may be first decided upon and then the antibody is produced to that substrate. In practice the substrate (hapten) is linked to a protein in order to elicit an immune response. The dinitrophenol hapten has been extensively used to produce the necessary antibody and then suitably activated DNP derivatives have been prepared to investigate the active site of the antibody. Compounds of the type (48) have allowed the identification of a tyrosine residue present in the light chain of the immunoglobulin.52 Bromoacetyl derivatives of the DNP hapten have now been used53 in which the bromoacetyl moiety is placed at varying distances from the 51 D.J. Brunswick and B. S. Cooperman Proc. Nut. Acud. Sci. U.S.A. 1971,68 1801. 52 E. J. Goetzl and H. Metzger Biochemistry 1970 9 3862. 53 D. Givol P. H. Strausbach E. Hurwitz M. Wilchek J. Haimovich and H. N. Eisen Biachemistr.y 1971 10 346 1. Reaction Mechanisms -Part (iii) Enzyme Mechanisms DNP grouping (49a4) (see Table). With this series of active-site-directed reagents both a tyrosine in the light chain and a lysine in the heavy chain were alkylated. However the proportion of each amino-acid that is alkylated depends on the distance between the DNP grouping and the bromoacetyl grouping as shown in the Table. Diazonium fluoroborate NO (48) Table of the radioactivity in TYr LYS Compound (light (heavy chain) chain) DNP.NH-CH2CH,-NH.C0.CH,Br (49a) 96 4 DNP-NHCH,-CH,CH.NH.COCW,Br (49b) 87 13 COOH DNP.NH.CH ,-CH ,CH ,-CH-NHCO-CH ,Br (49c) 66 34 COOH DNP-NHCH ,.CH 2.CH2.CH ,.CHON HCO-CH2Br (49d) 5 95 COOH 0 I1 -CH-C-(NH),I 0 II -C-CH,Br Lysine I ENH A further extension of this work was to make a bifunctional alkylating in- hibitor (50) in which the two bromoacetyl groups were at the critical distances as determined from the above results (see Table).With this reagent the authors were able to cross-link light and heavy chains through their respective tyrosine and lysine residues. Thus it would appear that these two residues located in two different chains at the active site of the immunoglobulin are about 5 A apart. Another approach to the structural determination of the active site of anti-bodies is the use of nitrophenyl derivatives (51) capable of generating nitrenes on photolysis.Nitrophenyl azides (51) have been successfully incorporated into antibodie~.~~ s4 G. W. J. Fleet R. R. Porter and J. R. Knowles Nature 1969 224 51 I 182 M. Akhtar and D. C. Wilton The Trapping of Covalent Intermediates.-There are at least three bio-organic approaches through which an intermediary stage in an enzymic reaction may be frozen to identify the group(s) involved in catalysis. In a hydrolytic reaction of the type Enz-XH + A-B Enz-X-A + BH HO Enz-XH + A-OH the group -XH may be identified if the reaction is performed under conditions (temperature or pH) which favour the formation of the complex Enz-X-A but are unsuitable for its further decomposition by the reaction of equilibrium b.This approach has been used to identify the serine residue on the active site of alkaline phosphatase.” Alternatively in some cases the use of a substrate analogue A-B has permitted the isolation of the complex Enz-X-A’ because its formation by the reaction of equilibrium a is faster than its hydrolytic decom- position (Eq. b). This approach has been successfully employed in the case of some protolytic enzymes and the appropriate examples are discussed in ref. 3. A second approach may be envisaged for identifying catalytic groups of enzymes which participate in group transfer reactions occurring through the sequence A-B + Enz-X-H Enz-X-A + BH Enz-X-H + A-Y In these cases the intermediate Enz-X- A may accumulate when the incuba- tion is conducted in the absence of the acceptor Y-H.An example of this principle is found in the case of phosphoglycerate kinase which catalyses the conversion of 3-phosphoglycerate into 1,3-diphosphoglycerate through a sequence of two reactions a Enz + ATP 2 Enz-8 + ADP EnzB + 3-phosphoglycerate 6 Enz + 1,3-diphosphoglycerate When in the above reaction the enzyme was incubated in the absence of the substrate but with ATP and the ADP formed by equilibrium a was removed by a coupled enzyme system the accumulation of the phosphorylated enzyme intermediate (Enz-P) o~curred.’~ In the intermediate the phosphoryl moiety was shown to be linked to a carboxy-group of the enzyme.Other examples of this type are the cases of acetate kina~e,~’ and succinyl coenzyme A ~ynthetase,’~ ATP-citrate lya~e.’~ SchifS Base Intermediates. When an intermediate enzyme-substrate complex contains a reactive covalent linkage which may be stabilized by a chemical modification this then permits the identification after a suitable degradation ’’ J. H. Schwartz Proc. Nut. Acad. Sci. U.S.A. 1963,49 871 ;L. Engstrom Arkiu Kemi. 1962 19 129. 56 C. T. Walsh and L. B. Spector J. Biol. Chem. 1971 246 1255. 57 R. S. Anthony and L. B. Spector J. Biol. Chem. 1970 245 6739. 58 R. F. Ramaley W. A. Bridger R. W. Moyer and P. D. Boyer J. Biol. Chem. 1967 242 4287. 59 C. T. Walsh and L. B. Spector J. Biol. Chem. 1969,244,4366. Reaction Mechanisms -Part (iii) Enzyme Mechanisms of the catalytic group.The approach has proved useful in identifying the active- site groups of enzymes where catalysis occurs through the formation of Schiff base intermediates. The earliest example of this is the enzyme fructose-1,6- diphosphate aldolase which catalyses the reversible reaction between dihydroxy- acetone-1-phosphate (52)and glyceraldehyde-3-phosphate The reaction (53).60761 may be considered to involve the cleavage of the a-C-H bond of the ketone (52) to give a carbanion intermediate which condenses with the aldehyde (53)to furnish 0 H-C / I (53) R /H-C I R 0 H-C I R 11 - Fructose + Enzyme S C=NH- I HCOH CH,-OP0,2 -R= I HO-LH HX-EI I (56) R H-C-OH Scheme 10 the product.Mechanistic studies have however highlighted the elegant process evolved by biological systems to improve the electron-withdrawing property of a carbonyl group through its conversion into a protonated Schiff base (54) which facilitates the cleavage of a C-H bond to yield the species (55). The overall reaction thus occurs through the sequence of Scheme 10. The intermediacy of the species (54) was demonstrated when the addition of NaBH to a solution of the enzyme and the ketone (52) resulted in inactivation of the enzyme activity and the stable linking of the substrate to enzyme. Suitable degradative experiments established that the N-atom of (54)belonged to an E-amino-group of lysine.60 Schiff base intermediates have also been established for transaldolase aceto- acetic decarboxylase 2-keto-6-deoxy-6-phosphogluconate aldolase 2-deoxy-~- ribose-5-phosphate aldolase and 2-keto-4-hydroxyglutarate aldolase.The literature on these enzymes has been reviewed up to 1968.61Recently the in- volvement of a Schiff base has also been established for N-acetylneuraminic 6o J. C. Speck P. T. Rowley and B. L. Horecker J. Amer. Chem. SOC.,1963 85 1012. 61 D. E. Morse and B. L. Horecker Ado. Enzymol. 1968 31 125. 184 M. Akhtar and D. C. Wilton acid aldola~e.~~?~~ The nature of the group X in intermediates of the type (54) has been investigated and preliminary experiments suggest that the group is a histidine residue in the case of fructose-l,6-diphosphatealdola~e,~~ a cysteine in N-acetylneuraminic acid aldolase,62 and a carboxylic acid group in 2-keto-6-deoxy-6-phosphogluconate ald~lase.~ Attention is drawn to another type of aidolases (class I1 ;Schiff-base aldolases are class 1) in which the electron-withdrawing property of the ketone group is enhanced not through a Schiff-base formation but through complexing with a metal ion.This sub.ject has been reviewed.61 A Schiff base intermediate is also involved in b-amino-levulinic acid dehydra- tase which catalyses the condensation of two molecules of b-amino-levulinic acid (57) to give porphobilinogen (59). This was shown66 by the incubation of the enzyme with the substrate (57) followed by treatment with sodium borohydride which led to the inactivation of the enzyme. The sequence of Scheme 11 for the conversion has been proposed to account for this and related observations.66 COOH COOH I I y2 YHz A v 7H2 Enz-NH2 + FH2 Enz -N=C P=* I H2N-CH2 y2 NH (57) (58) p57 COOH COOH I I HOOC CH HOOC CH, II II CH CH CH CH + Enz Enz -NH AH2 H,N-CH G O N H -H,N-CH 10 H (59) Scheme 11 We have discussed above the chemistry of the active site of those proteins whose sole function is to catalyse chemical transformations.Another type of protein molecule of biological interest is that in which a chemical conversion is intimately 62 J. E. G. Barnett D. L. Corina and G. Rasool Biochem. J. 1971 125 275. 63 R. Schauer 2.physiol. Chem. 1971,352 1517. 64 P. Hoffee C. Y. Lai E. L. Pugh and B. L. Horecker Proc.Nut. Acud. Sci. U.S.A. 1967 57 107. 65 H. P. Meloche Biochemistry 1970 9 5050. 66 D. L. Nandi and D. Shemin J. Biol. Chem. 1968,243 1231 1236. Reaction Mechanisms -Part (iii) Enzyme Mechanisms coupled to the transmission of a physiological impulse. These proteins are termed receptor molecules. The work on the visual receptor of bovine retina rhodopsin has highlighted the existence of two broad biochemical processes (Scheme 12).67 The first (equation a) involves the combination in a dark reaction of 11-cis-retinal with the protein opsin to give rhodopsin E,,, 498 nm (the absorption maximum is species-dependent and is in the range 440-560 nm). (60) hv H,O + 7-+ all-trans-retinal + NH,-opsin Scheme 12 The bathochromic shift accompanying this reaction permits the complex (60) to absorb the wavelength abundantly available in the sunlight when rhodopsin (60) participates in the transmission of the impulse responsible for visual sensation and is converted into opsin and all-trans-retinal (equation b).Two features of equation a (Scheme 12) of particular interest in the present context are the nature of the retinal-opsin linkage in (60) and the factor contributing to the batho- chromic shift of 6&180 nm accompanying the formation of rhodopsin. The first of these was investigated when it was shown that rhodopsin upon exposure to light in the presence of sodium borohydride gave a reduced derivative for- mulated as dihydrometarhodopsin 11. In this derivative the retinyl moiety was shown to be linked to an E-amino-group of ly~ine.~~.~~ This and related experiments7' showing the existence of a Schiff-base linkage [as in (60)] at the active site of rhodopsin could partly rationalize the bathochromic shift accompanying equation a since it is known that Schiff bases formed from retinal and primary amines upon protonation have A,, 430 nm.The elucidation of the factor(s) which may make further contribution to the red shift in visual proteins has stimulated a great deal of work on model systems. It has recently been shown that retinylideniminium ions show solvent-dependent bathochromic shift^^',^' which may be related to the refractive index of the solvent.71 Further- more protonated Schiff bases of retinal (&,, 430nm) undergo dramatic red shifts (up to 530 nm) in non-polar environments in a frozen ~tate.~'?~~ The model '-For a review see G.Wald Nature 1968 219 800. 68 (a) M. Akhtar P. T. Blosse and P. B. Dewhurst Chenz. Corrrm. 1967 631 ; (b)Biochem. J. 1968 110 693. 69 D. Bownds Nature 1967 216 1178. 7o M. D. Hirtenstein and M. Akhtar Biochem. J. 1970 119 359. " C. S. Irving G. W. Byers and P. A. Leermakers Biochemistry 1970 9 858. l2 M. D. Hirtenstein and M. Akhtar Nature New Bid. 1971 233 94. 73 W. Waddell and R. S. Becker J. Amer. Chem. SOC.,1971,93 3788. 186 M. Akhtar and D. C. WiIton experiments although not providing a precise physical explanation for the absorption spectra of visual pigments do however suggest that the presence of a protonated retinylidene chromophore in a specialized non-polar environment at the active site may make a significant contribution to the red shift.Thus in visual proteins the profound modification of the absorption properties of the chromophoric prosthetic group has allowed speculations on the nature of the environment at the active site. An analogous experimental approach of broad application involves the introduction of an ion or a small molecule called ‘probe’ into a special site of an enzyme or a protein. The measurement of a suitable spectroscopic property of the probe may then give useful information about its environment and about relatively minor changes around the probe- binding site. The literature on the use of emis~ion,~~’.~ e.~.r.,’~‘ ab~orption,~~‘,~ and n.m.r.74u,d probes has been reviewed and is not discussed here.5 Surface Structure of Proteins and Enzymes Work on rhodopsin has drawn attention to another facet of the chemistry of proteins. Most extensively studied from a crystallographic viewpoint have been the water-soluble proteins which catalyse the reaction of or participate in the transport of polar substrates. The examination of the tertiary structures of these proteins has allowed the general conclusion to be drawn that they contain non- polar (hydrophobic) residues in the core of the molecule and the polar side- chains (charged groups) are located on the surface. l8 This structural arrangement accounts for the water solubility of these proteins. Rhodopsin on the other hand is a membrane protein which resides in the rod outer segments where it is held by lipid molecules and participates in the reaction of a highly non-polar substrate.In view of these features it is noteworthy that rhodopsin is completely insoluble in water and dissolves only in detergent solutions. Similar features are also noted for other membrane-bound proteins which are involved in the reactions of non-polar substrates. Particular mention may be made of a bacterial mem- brane enzyme C ,-isoprenoid alcohol phosphokinase. The enzyme which catalyses the ATP-dependent phosphorylation of C ,-isoprenoid alcohols is soluble in butanol and has a high content (58%) of non-polar amino-acid~.’~ These examples suggest that these membrane-bound proteins acting on non-polar substrates may in fact contain more non-polar amino-acid residues on the surface.In closing this chapter we draw attention to how current knowledge of enzyme mechanisms has led to the chemical synthesis of a polymer with enzymic activity. A derivative of polyethyleneimine containing dodecyl groups to bind small molecules and methyleneimidazole side-chains to provide nucleophilic catalytic groups has been shown to hydrolyse p-nitrophenyl acetate at a rate appr~aching~~ that of the enzyme chymotrypsin. ’‘ (a) G. K. Radda Biochem. J. 1971 122 385; (6) R. B. Freedman Quart. Rev. 1971 25 431 (c) H. M. McConnell and B. G. McFarland Quart. Reu. Biophys. 1970 3 91 ; (6) A. S. Mildvan and M. Cohn Adc. Enzymol. 1970 33 1. ’’ H. Sandermann and J. L. Strominger Proc.Nat. Acad. Sci. U.S.A. 1971 68 2441. 76 I. M. Klotz G. P. Royer and I. S. Scarpa Proc. Nut. Acad. Sci. U.S.A. 1971 68 263.

ISSN:0069-3030    

DOI:10.1039/OC9716800167

出版商:RSC    

年代:1971

数据来源: RSC