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.