2 Physical Methods and Techniques Part (iii) Circular Dichroism By P. M. SCOPES Department of Chemistry Westfietd Coltege London NW3 7ST 1 Introduction In the two years since this subject was last discussed in Annual Reports circular dichroism (c.d.) has essentially replaced optical rotatory dispersion (0.r.d.) as the main chiroptical technique for the study of dissymmetric molecules in the visible and U.V. regions of the spectrum. During the same period several related but specialized topics have been developed which augment ‘normal’ c.d. These topics include important work on circularly polarized Raman spectra by Barron and Buckingham’ and on i.r. c.d. by Holzwarth and his colleagues.2 Studies of induced c.d. in achiral aromatic compounds have been made by two independent groups of worker^,^*^ and several more papers on magnetic c.d.have also ap- peared.’ The proceedings of the NATO advanced study institute on 0.r.d. and c.d. held at Pisa in September 1971 were published during 19736 and a special collection of papers has appeared’” which commemorates the centenary of van’t Hoff and Le Bel’s stereochemical work of 1874 An article surveying developments in stereochemistry since 1874and giving many key references has also appeared.7b This particular Report is concerned chiefly with the c.d. of discrete organic molecules and is arranged according to the dominant chromophore. It does not include a discussion of work on macromolecules which has been reviewed separately ;see ref. 8 for a monograph on the optical activity of proteins.’ L. D. Barron and A. D. Buckingham J.C.S. Chem. Comm. 1973 152; L. D. Barron M. P. Bogaard and A. D. Buckingham J. Amer. Chem. SOC.,1973 95 603; L. D. Barron and A. D. Buckingham J.C.S. Chem. Comm. 1974 1028. G. Holzwarth E. C. Hsu H. S.Mosher T. R. Faulkner and A. Moscowitz J. Amer. Chem. SOC. 1974 96 25 1 ;T. R. Faulkner A. Moscowitz G. Hoizwarth E. C. Hsu and H. S. Mosher ibid. p. 252. ’ S. Takenaka N. Matsuura and N. Tokura Terruhedron Letters 1974,2325; N. Tokura T. Nagai S. Takenaka and T. Oshima J.C.S. Perkin II 1974 337; S.Takenaka K. Kondo and N. Tokura ibid. p. 1749. F. D. Saeva P. E. Sharpe and G. R. Olin J. Amer. Chem. SOC. 1973,95,7656 7660; F. D. Saeva and G. R. Olin ibid. p. 7882. A. J.McCafTery and M. D. Rowe J.C.S. Faruday II 1973 1779 and preceding papers; R. E. Linder G. Barth E. Bunnenberg C. Djerassi L. Seamans and A. Moscowitz J.C.S. Perkin II 1974 1712 and preceding papers. ‘‘Fundamental Aspects and Recent Developments in Optical Rotatory Dispersion and Circular Dichroism’ ed. F. Ciardelli and P.Salvadori Heyden London 1973. ’ (a) Tetrahedron 1974. 30,1477-2007; (b)E. L. Eliel Chemrech. 1974 758. * B. Jirgensons ‘Optical Activity of Proteins and Other Macromolecules’ Springer New York 1973 Second Edn. 35 P.M. Scopes 2 The Carbonyl Chromophore Ketones For many years the octant rule' has provided the framework for the semi- quantitative interpretation of saturated carbonyl Cotton effects. The rule relates the sign and to some extent the magnitude of the Cotton effect to the geometry of the molecule around the carbonyl group but precise quantitative interpretation has never been possible and several anomalies have been noted.A new survey of carbonyl n -+ n* Cotton effects in decalones and related compounds has now been published. lo This paper based on c.d. measurements describes an empirical analysis for ketones of the 'extended decalone' type which leads to numerical contributions for ring systems and alkyl substituents (~AE values). One strength of the analysis is the very wide range of ketones examined more than 120 indi-vidual compounds including trans-fused cis-fused and 'middle-ring' types. A number of new key compounds were synthesized for the work and although most of the data refer to methanol and hexane solutions many representative compounds were also examined in dioxan and acetonitrile.From this extensive data collection the empirical analysis gives 6Ae values which may be summed to provide calculated A& values usually within kO.2 units of the experimental value i.e. close to the limits of experimental error common for c.d. measurements. Two main hypotheses arise from the analysis. The first follows recent work by Hudec' which showed that heteroatoms can exert significant long-range effects on the carbonyl n-+ 1~* Cotton effect if the conformation is such that a planar 'zig-zag' of bonds connects the heteroatom and the carbonyl oxygen. The present analysis" develops the idea for extended decalones and leads to the suggestion that the length of a 'primary zig-zag' of C-C bonds (see octant projection Figure 1) is the major factor in determining the magnitude of the Cotton effect ! 1 pic.cfc. I Figure 1 W. Moffitt R.B. Woodward A. Moscowitz W. Klyne and C. Djerassi J. Amer Chem. Soc. 1961 83 4013. lo D. N. Kirk and W. Klyne J.C.S. Perkin I 1974 1076. " J. Hudec Chem. Comm. 1970 829; M. T. Hughes and J. Hudec ibid. 197 805; G. P. Powell and J. Hudec ibid.,1971 806. Physical Methods and Techniques-Part (iii) Circular Dichroism in any given compound. The second hypothesis concerns the effect of a p-axial methyl group which appears to be consignate12 when the group is a substituent on a primary zig-zag of more than two C-C bonds but dissignate if the primary zig-zag has only one or two bonds.Although the latter finding is entirely empirical the two ideas provide a rationalization of all available data and in particular provide for the first time an interpretation of data for the cis-and the truns-decalones within one scheme. Anomalies concerning the octant rule have been investigated by Lightner and his colleague^'^ who have synthesized specific compounds to test potentially anomalous situations. The norbornane derivative (1)’3a and the adamantane derivative (2)13‘ each have perturbing substituents in front octants only and show Cotton effects of the sign predicted by the octant rule (positive and negative respectively). The same authors have studied the anti-octant behaviour of a methyl group in certain geometrical situations in the rigid bicyclo[2,2,l]heptan- 7-ones (3a and b).’ 3b (3) a; R1= Me RZ= H b; R’= €3 R2= Me The effect of ring heteroatoms (N 0,and S) on the Cotton effect of cyclo-hexanones has been described by Djerassi;14 0 and N are weakly ‘anti-octant’ and S ‘octant’ in behaviour as compared with the methylene group.The rigid cyclopentanone (4) which contains two fused norbornyl systems has an excep- tionally high rotatory power for a saturated ketone (A&z 20). This has been attributed15 to the non-polarity of the five-membered ring enhanced by a large number of perturbing atoms all falling within octants of the same sign. W. Klyne and D. N. Kirk Tetrahedron Letters 1973 1483.l3 (u)D. A. Lightner and D. E. Jackman J.C.S. Chem. Comm. 1974,344; (6)D. Lightner and D. E. Jackman J. Amer. Chem. SOC. 1974 96 1938; (c) D. A. Lightner and T. C. Chang ibid. p. 3015. l4 M. M. Cook and C. Djerassi J. Amer. Chem. Soc. 1973,95 3678. E. Weissberger J. Amer. Chem. SOC., 1974,96 7219. 38 P.M. Scopes 3 ’Ihe Aromatic Chromophore Biaryls and Alkaloids Recent papers on aromatic compounds fall into three main groups. One group of papers is concerned with the c.d. spectra of more complex aromatic compounds including twisted biaryls and cyclophanes another is concerned with the absolute configuration of natural products chiefly alkaloids and the third is based on compounds in which the aromatic group is introduced as a substituent to produce a chromophoric derivative suitable for chiroptical investigation.A wide range of chiral biaryls including biphenyls binaphthyls and certain 9,9’-bianthryls has been studied by Mason and his colleagues.16 They have investigated the relationship between the c.d. spectra and the stereochemical configuration of the compounds as a function of the dihedral angle between the planes of the aromatic rings. The c.d. of 2,2’-dimethyl-l,l’-bianthryland its anion radical and dianion have also been re~0rted.I~ C.d. data have been recorded for a series of 9,10-ethano-9,1O-dihydroanthracene derivatives.” The results confirm previous observation^'^ that for 1,5-disubstituted compounds it is the chirality of the dihydroethanoanthracene skeleton that determines the sign of the Cotton effect and not the nature of the substituents at C-11 which have negligible in- fluence.For derivatives lacking substituents at C-5 only relatively weak Cotton effects are observed which are.less easy to interpret. Several types of chiral cyclophane have also been studied,” and their c.d. rationalized in terms of a sector rule. Apparent discrepancies” between the results of the Bijvoet X-ray method and the exciton chirality method which greatly perturbed stereochemical thinking in early 1973 were soon resolved ;22923 c$ also the discussion in the X-ray section of last year’s Annual Reports (B) pp. 54-55. The absolute configurations of several groups of Iboga and Voacanga alkaloids have been allotted by X-ray crystallographic studies on (+)-coronaridineZ4 as well as by chemical studies relating (+ hdihydrocatharanthine to ~leavamine.’~ Preliminary c.d.work on (-)-coronaridineZ6 has now been extended and detailed studies of the chiroptical properties of this group of alkaloidsz7” and of the 5,16- cyclo-3,4-secocorynane have appeared. In addition the chiroptical properties of the pentacyclic 5,16-cyclocorynane group have been correlated l6 S.F. Mason R. H. Seal and D. R. Roberts Tetrahedron 1974,30 1671. l7 0.Ito and M. Hatano J. Amer. Chem. SOC. 1974,96,4375. M. J. Brienne and J. Jacques Bull. SOC. chim. France 1974 2647. l9 S. Hagishita and K. Kuriyama Tetrahedron 1972 28 1435. *O E. Langer H. Lehner and K. Schlogl Tetrahedron 1973 29 2473. 21 J. Tanaka C.Katayama F. Ogura H. Tatemitsu and M. Nakagawa J.C.S. Chem. Comm. 1973,21. 22 S. F. Mason J.C.S. Chem. Comm. 1973 239. 23 A. M. F. Hezemans and M. P. Groenewege Tetrahedron 1973,29 1223. 24 J. P. Kutney K. Fuji A. M. Treasurywala J. Fayos J. Clardy A. I. Scott and C. C. Wei J. Amer. Chem. SOC. 1973,95 5407. 25 N. Camerman and J. Trotter Actu Cryst. 1964 17 384. 26 K. Biiiha Z.Koblicova and J. Trojiinek Tetrahedron Letters 1972 2763. 27 (a)K. Blaha Z. Koblicova and J. Trojanek CON. Czech. Chem. Comm. 1974,39,2258; (6) K. B1aha and J. Trojiinek ibid. 1973 38 929; (c) K. Bliiha Z. Koblicova and J. Trojanek ibid. 1974 39 3168. Physical Methods and Techniques-Part (iii) Circular Dichroism 39 with those of related indole alkaloids particularly the yohimbane and eburnane types.27c In other series the absolute configurations of cryptostyline-I -11 and -111 (1-phenyltetrahydroisoquinolinetype) have.been allotted by X-ray analysis and by c.d. measurements;28 details of earlier work on rhoeadine and iso- rhoeadine derivatives have been published29 and the c.d. of a series of sparteine alkaloids has been de~cribed.~' Seven theaflavins pigments isolated from black tea have been studied by a wide range of physical techniques including c.d. ;31 among oxygenated heterocyclic products the chiroptical properties of 4-substituted flavan~~~ and of the related compound siccanin have been discussed.33 For compounds in which the aromatic ring has greater conformational mobility solvent studies and low-temperature measurements have been used to provide additional information about the conformation of the molecule or about the electronic transitions involved.Conformational transmission has been studied in nitrobenzoic esters of chiral alcohols such as menthol,34 and c.d. data for dansyl amino-acids have been rationalized in terms of the twisting of the sulphonamide group in these derivative^.^^ Some a-halogenopropion- anilides have been studied in a range of solvents and the data explained in terms of the preferred conformation^.^^ The c.d. of isomeric 1-pyridylethanols at low temperature provides some additional evidence3' for the existence of a second n+ R.* electronic transition of the pyridine chromophore at ca. 240 nm. 4 Sulphur-cmtainingCompounds The optical activity of chiral disulphides has been studied both the~retically~~.~~ and empirically40341 in order to try and correlate the observed chiroptical behaviour with the CSSC dihedral angle.Previous work on model dithiadecalins has been extended4* and the effects of methyl and phenyl substituents on 2,3-dithiadecalins and 2-thiahexahydroindanes have been disc~ssed.~' New c.d. data have also been reported for gliotoxin and related compounds.42 In further work on steroidal ally1 sulphoxides the relative orientation of the olefinic double bond and the sulphoxide group has been shown to have significant influence on J. F. Blount V. Toome S. Teitel and A. Brossi Tetrahedron 1973 29 31. 29 J. Hrbek L. Hruban V. Simhnek F. Santavy and G.Snatzke CON. Czech. Chem. Comm. 1973,30,2799. 30 W. Klyne P. M. Scopes R. N. Thomas J. Skolik J. Gawronski and M. Wiewiorowski J.C.S. Perkin I 1974 2565. 31 P. D. Collier T. Bryce R. Mallows P. E. Thomas D. J. Frost 0.Korver and C. K. Wilkins Tetrahedron 1973 29 125. 32 G. Snatzke F. Snatzke A. L. Tokes M. Rakosi and R. Bognar Terrahedron 1973 29 909. 33 S.Nozoe K. Hirai F. Snatzke and G. Snatzke Tetrahedron 1974 30,2773. 34 U. Nagai E Abe. and R. Sano Tetrahedron 1974,30,25. 35 T. Polonski A. Chimiak and M. Kochman Tetrahedron 1974 30,641. 36 G. Snatzke M. M. El-Abadelah and M. 2. Nazer Tetrahedron 1973 29 487. 37 G. Gottarelli and B. Samori J.C.S. Perkin ZZ 1974 1462. 38 J. Webb R. W. Strickland and F. S. Richardson J. Amer. Chem. SOC.,1973,95,4775.39 R. W. Woody Tetrahedron 1973,29 1273. 40 L. A. Neubert and M. Carmack J. Amer. Chem. SOC. 1974,96,943. *' S. Hagishita and K. Kuriyama J.C.S. Perkin II 1974 686. 42 R. Nagarajan and R. W. Woody J. Amer. Chem. SOC. 1973,95 7212. 40 P.M.Scopes the c.d. whereas the chirality at sulphur does not necessarily play a dominant roie.43 5 Olefins Mason and his colleagues have reported the existence of a Cotton effect associated with the olefin Rydberg transition and have measured it for a-pinene in the gas phase.44 Solvent effects associated with this and other olefin transitions have been discussed by Andersen and his who have also published an extensive discussion of allylic bond polarization in olefins and related homo- conjugated systems.46 The c.d.of a series of olefins derived from cedrane has also been rep~rted.~” 6 The Carboxyl Chromophore Acids Esters Lactones and Related Compounds The exciton chirality method was originally applied to steroid dibenzoates and related compounds48 but has been extended over the years.49 A recent paper5’ describes the existence of long-range effects as detected in the c.d. spectra of bis- (p-dimethylaminobenzoate) esters of steroid glycols. In these compounds the two ester groups are widely separated e.g. diesters of 3p,1 la- 38,l lp- and 3j,15p-dihydroxy-5a,lk-steroids. Despite the distance separating the two aryl ester chromophores the A&values are still much greater (up to 10 times) than those for the isolated groups ;calculations yield predicted A&values in reasonable agree- ment with observed values.Two groups of workers have studied the absolute configuration of abscisic acid and related compounds using c.d. measurement^.^'^^^ The c.d. spectra show strong exciton coupling arising from interactions between the chromophores in the ring and in the side-chain and the absolute configuration deduced is in agree- ment with that determined by chemical methodss3 The extension of the exciton chirality method to other chromophores has been discussed for conjugated 43 D. N. Jones J. Blenkinsopp A. C. F. Edmonds E. Helmy and R. J. K. Taylor J.C.S. Perkin I 1974 937. 44 A. F. Drake and S. F. Mason J.C.S. Chem. Comm. 1973 253. ” N. H. Andersen and Y. Ohta J.C.S. Chem. Comm. 1974 730.46 N. H. Andersen C. R. Costin D. D. Syrdal and D. P. Svedberg J. Amer. Chem. Soc. 1973,95 2049; N. H. Andersen C. R. Costin and J. R. Shaw ibid. 1974,96 3692. 47 M. Fetizon Y. Le Bigot and J. Rens Tetrahedron 1973 29 2815. 48 N. Harada M. Ohashi and K. Nakanishi J. Amer. Chem. SOC. 1968 90 7349; N. Harada and K. Nakanishi ibid. p. 735; 1969 91 3989; N. Harada K. Nakanishi and S. Tatsuoka ibid. p. 5896. 49 N. Harada and K. Nakanishi Accounts Chem. Res. 1972,5 257. 50 Sow-mei Lai Chen N. Harada and K. Nakanishi J. Amer. Chem. SOC.,1974,96,7352. ’’ G. OhlofF E. Otto V. Rautenstrauch and G. Snatzke Helv. Chim. Acta 1973 56 1874. 52 M. Koreeda G. Weiss and K. Nakanishi J. Amer. Chem. Soc. 1973,95,239; N. Harada ibid. p. 240. 53 G. Ryback J.C.S.Chem. Comm. 1972 1190. Physical Methods and Techniques-Part (iii) Circular Dichroism 41 enones and related corn pound^'^ and for N-salicylidenimino derivatives.’ ’ An apparent exception to the dibenzoate rule has been discovered in connection with the absolute configuration of ~aryoptin.’~ Among simple acids and esters there Is continuing emphasis on the c.d. of amino-acids because of their relevance to work with proteins. In a detailed study of L-alanine and its conformational isomer^,^' the rotatory strengths calculated from LCAO-MO-SCF-Cl wavefunctions have been compared with experi- mental c.d. spectra and with predictions based on various sector rules for a-amino-acids. The far-u.v. c.d. of L-tryptophan has also been discussed in detail.58 The chiroptical properties of 2-methyl-substituted acids and esters have been studied together with n.m.r.data obtained with optically active shift reagent^.'^ With certain assumptions about the rotamer population the results are inter- preted in terms-of an empirical rule relating the sign of the n +n* Cotton effect with the geometry of the molecule round the chromophore. The c.d. of cx-tri-methylammonium carboxylic acids has been studied and compared with that of a-amino-acids.60 An empirical analysis for the c.d. data has been made for about 70 secondary acetates and acetamides in which the acetoxy- or acetamido- group is a substituent on a cyclohexane ring.61 Two assumptions are made firstly that acetates and acetamides adopt a strongly preferred conformation in solution (as in the crystal) and secondly that the contributions 6Ae of individual C-C bonds in the molecule to the total AEvalue are additive.The results appear to confirm these assumptions and to suggest the position of one of the nodal surfaces of the carboxy chromophores. The chiroptical properties of some simple five- and six-membered lactones62 and of some adamantane lac tone^^^ have been studied and interpreted in terms of their second- and third-sphere contributions to the n-+ T* transition. C.d. data have also been reported for a series of five-membered lactones derived from the aldopentonic acids.64 The absoIute configuration of (+)-canthark acid (5) (5) 54 M. Koreeda N. Harada and K. Nakanishi J. Amer. Chem. SOC.,1974,96 266.55 H. E. Smith J. R. Neergaard E. P. Burrows and Fu-Ming Chen J. Amer. Chem. Sac. 1974,96 2908. 5h S. Hosozawa N. Kato and K. Munakata Tetrahedron Letters 1974 3753. 57 J. Webb R. W. Strickland and F. S. Richardson Tetrahedron 1973 29 2499. 58 H. E. Auer J. Amer. Chem. Soc. 1973,95 3003. 59 0. Korver and M. van Gorkom Tetrahedron 1974,30,4041. 6o M. Gacek and K. Undheim Tetrahedron 1973 29 863. ” L. Bartlett D. N. Kirk and P. M. Scopes J.C.S. Perkin I 1974 2219. 62 0. Cervinka L. Hub F. Snatzke and G. Snatzke CON. Czech. Chem. Comm. 1973 38 897. 63 M. Keller and G. Snatzke Tetrahedron 1973 29 4013. 64 J. J. K. Novak Coll. Czech. Chem. Comm. 1974 39 869. P.M.Scopes has been determined on the basis of c.d. measurement^^^ and by application of the Horeau method.7 Miscellaneous Chromophores The c.d. curves of many natural products are so complex that assignment of individual bands to particular electronic transitions is difficult and correlations between the stereochemistry of a molecule and the sign of the observed dichroism can only be made on an empirical basis. This is true for example of caro- tenoids ;66-68 a recent paper66 uses c.d. curves to show that a-zeacarotene (6) (6R)-7’,8’-dihydro-~rl/-carotene, has the same absolute configuration at C-6 as natural ( +)or-carotene (6‘R)-P&-carotene. Cotton effects have also been reported for the visible region of the spectrum for six compounds and on this basis it is suggested that all carotenoids with C-6I(R)-chirality show a positive Cotton effect at their longest wavelength absorption band (450-500 nm).The first assignment of absolute stereochemistry to a C,,-carotenoid follows from c.d. correlation with natural (2R,2’R)-PP-~arotene2,2’-diol.~~ The c,d. spectra of corrinoids are also very complicated but the solvent- and temperature-dependence of the spectra have been studied for vitamin B12 and many related corn pound^.^^ The c.d. of the polycyclic polyether antibiotic X-537Ahas been studied in a variety of solvents and in the presence of amines and of univalent and bivalent metals for which it acts as a cation carrier.7o Other groups of compounds investigated include steroidal nitroxides7 and carbohydrate azide~.~~ 8 Hydrocarbons In the past two years several groups of workers have reported c.d.curves at short wavelengths for saturated hydrocarbons and closely related compounds. These include steroids (studied in ~olution),~ (3S,5S)-2,2,3,5tetramethylheptane 65 M. G. Peter G. Snatzke F. Snatzke K. N. Nagarajan and H. Schmid Helv. Chim. Acta 1974,57 32. 66 R. Buchecker and C. H. Eugster Helv. Chim. Acta 1973 56 1124. 67 R. Buchecker P. Hamm and C. H. Eugster Helv. Chim. Acra 1974,57 631. A. G. Andrewes S. Liaaen-Jensen and G. Borch Acta Chem. Scand. 1974 28,737. 69 R. Bonnett J. M. Godfrey V. B. Math P. M. Scopes and R. N. Thomas J.C.S. Perkin I 1973 252. ’O S. R. Alpha and A. H. Brady J. Amer. Chem. SOC.,1973,95 7043. ’* R. Ramasseul A. Rassat and P. Rey Tetrahedron 1974 30,265. ’’ D.R. Dunstan W. P. Mose and P. M. Scopes J.C.S. Perkin I 1973 2749. 73 D. N. Kirk P. M. Scopes and B. M. Tracey Tetrahedron Letters 1973 1355. Physical Methods and Techniques-Part (iii)Circular Dichroisrn 43 studied in the vapour phase,74 and the (1S,2R)-dimethyl-(2-methylcyclopropyl)-carbenium ion the first experimental observation of a Cotton effect in a carbenium Full details have also been published of the chiroptical behaviour of twistane and the related unsaturated hydrocarbon twi~tene.~~ Compounds in which the chirality is due solely to the replacement of one hydrogen atom by deuterium include [l-2H]neopentyftosylate,77(-)(S)-[4-’H]-2,2-para~yclophane,~* and 1R-[ l-2H]-ol-fenchocamphorquinone.79This latter paper also contains the first report of the c.d.of a compound in which chirality arises from the replacement of one oxygen atom by the isotope ‘*O. 74 S. D. Allen and 0.Schnepp J.C.S. Chem. Comm. 1974,904. ’’ R. G. Ghirardelli,J. Amer. Chem. SOC.,1973,95 4987. I’ M. Tichg CON. Czech. Chem. Comm.. 1974,39,2673. l7 P. H. Anderson B. Stephenson and H. S. Mosher J. Amer. Chem. Sac. 1974,96 3171. ’* P. H. Hoffman E. C. Ong 0. E. Weigang and M. J. Nugent J. Amer. Chem. Soc. 1974,% 2620. 79 W. C. M. C. Kokke and L. J. Oosterhoff J. Amer. Chem. SOC.,1973,95,7159.