2 Part (iii) OPTICAL ROTATORY DISPERSION AND CIRCULAR DICHROISM by P. M. Scopes ( Westfield College Hampstead London N.W.3.) THEchiroptical techniques,’ optical rotatory dispersion (0.r.d.) and circular dichroism (c.d.) are increasingly finding a place as routine tools in organic chemistry particularly for natural products from the smallest molecule to biopolymers. Applications of 0.r.d. and c.d. to stereochemical problems increased by more than 50% this year by comparison with 1967 and there was also a large increase in published work concerned primarily with the development of the two techniques ; three have been published and also a French edition of CrabbC’s valuable book? At present virtually all measurements of 0.r.d. and c.d. are made on liquid samples but advances have been made this year towards work in the gaseous and solid phases.The c.d. of ( +)-3-methylcyclopentanone vapour has been examined6 in the vacuum U.V. region down to 167 nm; three optically active absorption bands were noted below 200 nm as well as the usual carbonyl n -,x* transition at ca. 300 nm. In order to measure the c.d. of a crystalline solid the sample must be suspended in a disc of chemically inert optically transparent and non-iso- tropic medium. Kahn and Beychok’ have used a mull of a silicon polyether with hexagonal crystals of L-cystine to investigate the relationship between the solid phase c.d. and the chirality of the disulphide bond Ollis Mason and V. Paelog K. Ned. Akad. Von Wetenschappen 1968 B71 108 c$ also U.Wheis Experientia 1968 24 1088. G. Snatzke Angew. Chem. 1968,80 15. S. Beychok Ann. Rev. Biochem. 1968,37,437. J. A. Schellman Accounts Chem. Res. 1968 1 144. P. Crabbe ‘Applications de la Dispersion Rotatoire Optique et du Dichroisme Circulaire Optique en Chimie Organique,’ Gauthier-Villair Paris 1968. S. Feinleib and F. A. Bovey Chem. Comm. 1968,978. ’ P. C. Kahn and S. Beychok J. Amer. Chem. SOC.,1968,90,4168. P.M. Scopes their collaborators* have used a similar technique with KCl discs to establish the chirality (M)for the propeller conformation adopted by ( +)-tri-o-thymotide in the solid state (I).The molecule was shown to adopt the same conformation in ethereal solution at -78". in general the development of low temperature c.d.has been disappointingly slow hampered by the lack of suitable commercially-available jacketed cells. The potential use of this method for conformational studies is very great as illustrated this year by work on acyclic ketones (acylated steroid^)^ and on unsaturated steroid ketones." Practical methods and instrumentation have been reviewed by Gervais.' ' Symmetry Rules.-Curbonyl chrornophore. There has been considerable controversy in the past over theoretical treatments of the origin of Cotton effects and over the symmetry rules which relate the sign and magnitude of a Cotton effect to the geometry of the dissymmetric surroundings of a symmetrical chromophore (cf previous Ann. Reports). The present theoretical situation has been well reviewed by S~hellman,~ who stated that the three mechanisms which have been proposed to explain the origin of optical activity i.e.the one- electron mechanism the coupling of two electric transition moments and the coupling of one electric and one magnetic moment should be regarded as complementary and not as alternatives. In particular Schellman discusses the symmetry rules for the peptide and carbonyl groups and cites further evidenceI2 which supports an octant (as opposed to quadrant) rule for ketones. c$ also the important paper by Hohn and Weigang on electron correlation models which deals in great detail with the carbonyl group.I3 The octant rule has been further explored by Djera~si'~" and by Snatzke14' who have synthesised a series of conformationally rigid adamantanones with substituents in specific selected positions.Equatorial substituents a-to a carbonyl group in a cyclohexanone ring have been shown to make small but measurable contributions to the carbonyl Cotton effect.' P-Substituted adamantanones have been investigated in detailI4 and some substituents e.g. CO,H have been shown to be anti-octant in their behaviour when substituted axially but to follow the normal rule when substituted equatorially. Previous workers have reported a 'reverse octant rule' for the n -+ x* Cotton effect of a-cyclopropyl- and a-epoxy-ketones. A thorough c.d. investiga- tion of about twenty such ketonesf5 has shown that the sign of the n + 7c* * A. P. Downing W. D. Ollis 1. 0.Sutherland J. Mason and S.F. Mason Chem. Comm. 1968 329. G. Snatzke D. M. Piatak and E. Caspi Tetrahedron 1968,24,2899. lo G. Snatzke and K. Schaffner Helu. Chim. Acta 1968,51 986. H. P. Gervais Compt. rend. 1967,264 B 1192. l2 T. D. Bouman and A. Moscowitz J. Chem. Phys. 1968,48,3115 Cf also R. M. Lynden-Bell and V. R. Saunders J. Chem. SCC.(A),1967,2061. l3 E. G. Hohn and 0.E. Weigang J. Chem. Phys. 1968,48 1127. I4O W. S. Briggs M. Suchy and C. Djerassi Tetrahedron Letters 1968 1097. 14* G. Snatzke and G. Eckhardt Tetrahedon 1968,24 4543. l5 K. Kuriyama H. Tada Y. K. Sawa S. It8 and I. Itoh Tetrahedron Letters 1968 2539; cf W. Reusch and P. Mattison Tetrahedron 1968,24 4933; F. K. Butcher R. A. Coombs and M. T. Davies Tetrahedron 1968.24 4041. Optical Rotatory Dispersion and Circular Dichroism 37 Cotton effect is determined by the octant in which the -CH2-group (cyclo- propylketones) or -0-group (epoxyketones) lies; the sign follows the normal and reversed octant rules respectively; An important study of a$-unsaturated ketones has appeared16 and also detailed reports on the 0.r.dJc.d.of the limonoids’ and on steroid-3-ethylene-dithio-4-ketones;’ the absolute configuration of twistane has been assigned from an 0.r.d. study of related ket0nes.l’ Aromatic chromophores. An account has appeared2’ of the allotment of absolute configuration to twenty representative members of the tetracyclin group. N.m.r. was used to establish the relative configuration of the chiral centres within each compound and the absolute configuration was established by empirical comparison of the c.d.curves with those of daunomycin of known absolute stereochemistry.2 ’ The conformation of the tetracyclins in solution has also been studied by c.d.22 Much interest has been shown in fla~ans,~~.~~ isoflavans2’*26 and related compo~nds.~ Many detailed investigations among alkaloids include those in the yohim- bane28 and eburnane2’ series and of the keto-indo1e3O pr~toberberine~’ and ly~orine~~ types. Other work includes that on small conformationally-labile aromatic mole- cules and on large inherently dissymmetric helical compounds. 34 Sulphur and phosphorus chromophores. There has been a remarkable surge of interest in sulphur chromophores during the past year. The inherent chirality of the disulphide bond in L-cystine has been discussed l6 H.Ziffer and C. H. Robinson Tetrahedron 1968,24,5803. l7 D. L. Dreyer Tetrahedron 1968,24,3273. C. H. Robinson L. Milewich G. Snatzke W. Klyne and S.R. Wallis J. Chem SOC. (C) 1968 1245. l9 K. Adachi K. Naemura and M. Nakazaki Tetrahedron Letters 1968 5467. 2o H. Brockmann H. Brockmann Jun. and J. Niemeyer Tetrahedron Lezters 1968 4719 preliminary work H. Brockmann Jun. and M. Legrand Tetrahedron 1963 19 395. 21 F. Arcamone G. Cassinelli G. Franceschi P. Orezzi and R. Mondelli Tetrahedron Letters 1968 3353. 22 L. A. Mitscher A. C. Bonacci and T. D. Sokoloski Tetrahedron Letters 1968,5361. 23 W. Gafield and A. C. Waiss Chem. Comm. 1968,29. 24 K. R. Markham and T. J. Mabry Tetrahedron 1968,24 823.25 L. Verbit and J. W. Clark-Lewis Tetrahedron 1968 24 5519. K. Kurosawa W. D. Ollis B. T. Redman I. 0. Sutherland 0.R. Gottlieb and H. Magalhaes Alves Chem. Comm. 1968 1265. ” W. D. Ollis C. A. Rhodes and I. 0.Sutherland Tetrahedron 1967,23,4741. *’ J. Trojanek Z. Koblikova and K. Blaha Coll. Czech. Chem. Comm. 1968,33,2950. 29 K. Blaha K. Kakova Z. Koblikova and J. Trojanek Coll. Czech. Chem. Comm. 1968,33 3833. 30 W. Klyne R. J. Swan A. A. Gorman A. Guggisberg and H. Schmid Helv. Chim. Act4 1968 51. 1168. 31 T. Kametani and M. Ihara .I.Chm. SOC.(C) 1968 1305. K. Kotera Y. Hamada and R. Mitsui Tetrahedron 1968,24,2463. 33 H. E. Smith M. E. Warren and L. I. Katzin Tetrahedron 1968 24 1327; L. Verbit and P. J. Heffron Tetrahedron 1968,24 123 1 ; L.Verbit A. S. Rao and J. W. Clark-Lewis Tetrahedron 1968 24,5839. 34 R. H. Martin M. F. Barbieux J. P. Cosyn and M. Gelbcke Tetrahedron Letters 1968 3507; H. Wynberg and M. B. Groen J. Amer. Chem. SOC. 1968 90. 5339; H. Musso and W. Steckelberg Ber. 1968 1510. 38 P.M. scopes in an important paper by Coleman and Blo~t.~~ Computer analysis resolved the observed c.d. curve into three separate maxima including a very strong negative maximum at 187 nm. This band is attributed to the dissymmetry of the disulphide group and corresponds to the anomolously large rotations which have been observed previously at cu. 200 nm for cystine and proteins containing cystine (cf other work on di~ulphides~~). Papers have appeared on several types of compound where the asymmetry arises from different configurations at a hetero-atom.The empirical rule which relates the sign of the Cotton effect at cu. 200 nm to the absolute configuration at the sulphur atom in methy1a1ky1su1phoxides3’has been clarified by Mislow and his colleagues ;38 steroidal sulphoxides have also been explored in detail.39 An intriguing correlation the ‘inter-system matching of Cotton effects’ has been noted by Mislow4’ for the c.d. curves of three aryl sulphoxides and three closely related phosphine oxides. Each pair of compounds was known from external evidence to have the same absolute configuration and to differ I I only in the replacement of O=S by O=P-Me and by one methyl group at I I a remote position in one aromatic ring (11) and (111).The c.d. curves of the sulphoxides corresponded very closely in sign and shape to those of the phosphine oxides. This sort of agreement would normally be regarded as fortuitous but in this case seems to provide a dramatic confirmation of the independently-assigned absolute configurations. For other work on asym- metric phosphorus derivatives see ref. 41. A major difficulty of the chiroptical techniques is made evident in a study by Djerassi et of steroid thiocyanates having an optically active weak absorption band at ca. 250 nm. On the assumption that this transition for 35 D. L. Coleman and E. R. Blout J. Amer. Chem. SOC.,1968,90,2405. 36 M. Carmack and L. A Neubert J. Amer. Chem SOC.,1967,89,7134;A. F. Beecham J.W. Loder and G. B. Russell. Tetrahedron Letters 1968. 1785. 37 K. Mislow M. M. Green P. Law. J. T. Melillo. T. Simmons. and A. L. Ternay. J. Anier. Chem. SOC.,1965,87 1958. 38 M. Axelrod P. Bickart M. L. Goldstein M. M. Green A. Kjaer and K. Mislow Tetrahedron Letters 1968 3249. 39 D. N. Jones M. J. Green and R. D. Whitehouse Chem. Comm. 1968 1634; D. N. Jones D. Mundy and R. D. Whitehouse ibid. 1636; D. N. Jones. M. J. Green M. A. Saeed and R. D. White- house J. Chem. SOC.(C) 1968 1362. 40 F. D. Saeva D. R. Rayner and K. Mislow J. Amer. Chem. SOC.,1968,90,4176. 41 W. D. Balzer Tetrahedron Letters 1968 1189; C. Donninger and D. H. Hutson Tetrahedron Letters 1968,4871. 42 C. Djerassi D. A. Lightner D. A. Schooley K. Takeda T. Komeno and K.Kuriyama Tetra-hedron 1968,24,6913. Optical Rotatory Dispersion and Circular Dichroism 39 thiocyanates is qualitatively analogous to the n -+ n* transition of a~ides,~~ the authors suggest that an octant rule should be obeyed. In the absence of rigid -SCN derivatives this cannot be rigorously tested ;instead the observed c.d. and the proposed rule are used to suggest the preferred conformations of the thiocyanate group with respect to the steroid mucleus. This work serves to emphasise the need for detailed studies wherever possible on compounds of rigid geometry and also the fact that in our present state of knowledge the chiroptical techniques answer only one question at a time. Chromophoric derivatives. The azide octant has been used to study the preferred conformation around the C-N bond in azidosugars ;44 further work has also appeared on benzimidazole and quinoxaline derivatives of carbohydrate^.^^ Dimedone derivatives of amines have been investigated in and it has been shown that derivatives of aliphatic amines have the R or S configuration give positive or negative Cotton effects respectively at ca.280 nm. The solvent dependence of the c.d. for some N-thiobenzoylamino- acids and peptides has been examined.47 Carboxyl chromoyhores. There has been much interest in attempts to define a symmetry rule for the carboxyl chromophore (cJ:previous Ann. Reports); an apparent anomaly in the early treatment of the lactone Sector rule has now been discussed fully.48 Beecham has suggested that the fundamental factor determining the sign of a lactone Cotton effect is the chirality of the lactone ring itself and that more remote parts of the molecule make only negligible contributions to the r~tation.~’ The Cotton effects observed in some 7-ace- toxyrosenono lactone derivatives are so strong as to suggest interaction between the lactone and acetate chromoph~res.~~ Detailed studies have been made on several quite distinct groups of carboxylic acids and esters including diterpene acids,51 and an homologous series of steroid-17~-carboxylicesters.52 A comparative study of the u.v./o.r.d./c.d.behaviour of many common hydroxy- and amino-acids has been made by Katzin and GulyasS3 over a wide pH range ; three studies of arylamino-acids have been made.54 The interest in amino-acids is typical of the general attention being given to those small molecules which are the building blocks for biologically im- portant macromolecules.It is outside the scope of this review to discuss in 43 C Djerassi. A. Moscowitz. K. Ponsold and G. Steiner. J. Anier. Cheni. Sac.. 1967. 89. 347. 44 H. Paulson. Chrni. &r. 1Y6X. 101. 1571. 45 W.S. Chilton and R. C. Krahn J. Aniei-. Chetn. Soc. 1968 90,1318. ’’ P. Crabbe B. Halpern and E. Santos Tetrahedron 1968 24 4299. 4315. 47 G. C. Barrett Chem. Comm. 1968 40. 48 W. Klyne. P. M. Scopes. R. C. Sheppard. and S. Turner. J. Chem. SOC.(C) 1968 1954. 4’) A. F. Beecham. Trtrtrlirdr-or1 Lcrtrr-.j. 196X. 2355. 35Y 1. 5o C. W. Holzapfel and P. S. Steyn. Tetrrrhrrlron.196X. 24,3321. J. D. Renwick and P. M. Scopes J. Chem SOC.(C) 1968,1949. 52 J. D. Renwick and P. M. Scopes J. Chem. SOC.(C) 1968,2574. 53 L.I. Katzin and E. Gulyas J. Amer. Chem. SOC.,1968,90 241. 54 1. Frif. V. Spiro and K. Blaha. Coll. Czech. Chem. Comm.. 1968,33. 4008 cf also H. Wyler and J. Chiovini. Hek. Chini. Acru. 1Y68. 51 1476 and Y. P. Myer and L. H. MacDonald. J. .Amer. Cheni. Soc... 1967 89 7142. P.M. Scopes detail the 0.r.dJc.d. of macromolecules but significant work has appeared on monosaccharide^,^^ small pep tide^,'^ and mononucleosides.57 A fascinating paper by Gabbay” describes the c.d. induced in an optically inactive aromatic amine added to RNA or to DNA. The ‘reporter’ molecule exhibits a positive maximum near 360 nm when added to RNA and a negative maximum when added to DNA.These results may be compared with the 0.r.d. and c.d. associated with charge-transfer bands and observed for intra- and inter-molecular electron-donor-acceptor complexes of amino-acids and peptides,” and suggest a potential method for studying helix topography. Magnetic Optical Rotatory Dispersion and Magnetic Circular Dichroism (m.0.r.d. and m.c.d.).-Recently a number of important papers have appeared on m.0.r.dJm.c.d. (chiefly the latter) and it is hoped that this subject may be reviewed in Ann. Reports in the near future. These techniques are not dependent on the presence of a chiral structure and their applications in structural chemistry are mainly concerned with studying the nature of the electronic transitions corresponding to a particular absorption.As spectroscopic tech- niques m.0.r.dJm.c.d. are particularly sensitive but almost inevitably equipment will be of great expense. A review of this work has appeared,60 and the variety of compounds which may be studied by the technique is illustrated by papers on chlorins,6 lU annulenes,61b and nucleosides,61C on aliphatiP2 and on aromatic hydrocarbon^.^^ 55 I. Listowsky G. Avigad and S. Englard Carbohydrate Rex 1968 8 205; I. Listowsky and S. Englard Biochem. Biophys. Res. Corn. 1968,30 329. ” D. R. Dunstan and P. M. Scopes J. Chem SOC. (C) 1968 1585. ’’ D. W. Miles S. J. Hahn R. K. Robins M. J. Robins and H. Eyring J. Phvs. Chem.. 1968 72 1483 and preceding papers. 58 E. J.Gabbay J. Amer. Chem SOC. 1968,90 6574. 59 P. Moser Helu. Chim. Act4 1968,51 1831. ‘O B. Briat and C. Djerassi Nature 1968,217 918. 61 B. Briat D. A. Schooley R. Records E. Bunnenberg and C. Djerassi J. Amer. Chem. SOC. 1967 89 (a) 6170; (b) 7062; (c) W. Voelter R. Records E. Bunnenberg and C. Djerassi ibid. 1968 90 6163. 62 H. K. Wipf J. T. Clerc and W. Simon Helu. Chim. Acta 1968,51 1051 1162. 63 P. J. Stephens P. N. Schatz A. B. Ritchie and A. J. McCaffery J. Chem. Phys. 1968,48 132.