2. Part (iii). OPTICAL ROTATORY DISPERSION AND CIRCULAR DICHROISM By P.M. Scopes (Westfield College London N. W.3) DURING 1967 there has been a big increase (more than 40%) in the number of papers on the optical rotatory dispersion (0.r.d.) and circular dichroism (cad.) of organic molecules (excluding macromolecules) and even more dramatic increases in the number of publications discussing c.d. of inorganic complex ions and magnetic optical rotatory dispersion (m.0.r.d.). Reviews have been published on aromatic compounds,’ and on the general relationship between optical activity and the structure of organic compounds.2 -’ This report deals primarily with the o.r.d./c.d. of the smaller organic mole- cules but in addition these techniques are widely applied to the study of natural macromolecules particularly proteins and nucleic acids.The pro- ceedings of the International Conference on the Conformation of Biopolymers held at Madras in January 1967 have been published and include a wealth of material on o.r.d./c.d.6 An important paper has appeared describing a simple spectropolarimeter attachment for recording fully compensated m.0.r.d. ~pectra,~ and in another instrumental advance flash photolysis and 0.r.d. have been combined’ in order to investigate possible structural changes occuring on electron-excitation and also the absolute configuration of excited states. During 1967 several leading workers have emphasised that our present knowledge of the relationship between the structure of organic molecules and their o.r.d./c.d.usually permits us to determine only one unknown factor at a time from an experimental measurement. Thus an 0.r.dJc.d. curve may be used either to determine the configuration of a molecule (directly or by empirical comparison with other chemically and conformationally analogous molecules of known configuration) or to study the conformation of molecules whose configuration is already known. It is rarely possible to determine both configuration and conformation at the same time.when both are unknown. Mason has exposed the problem clearly in work on the c.d. and absolute P. Crab& and W. Klyne Tetrahedron 1967,23,3449. P. Crabbt in ‘Topics in Stereochemistry’ ed. E. L. Eliel and N. L. Allinger Interscience New York 1967 vol.1 p. 93. ’ A. D. Liehr Transition Metal Chem. 1966,2 165. K. Kuriyama Japan Analyst. 1966 Ann. Rev. 27R ’ M. Suzuki J. Synthetic Org. Chem. Japan 1966,24,885. ‘Conformation of Biopolymers,’ vols. I and 11 ed. G. N. Ramachandran Academic Press London 1967. ’J. T. Clerc H. K. Wipf and W. Simon Helv. Chim. Acta 1967,50 1794. * P. A. Carapellucci H. H. Richtol and R. L. Strong J. Amer. Chem. Soc. 1967,89 1742. P.M.Scopes configuration of Troger's base (l).9 The molecule is conformationally labile and each enantiomer (1R,3R)or (1S,3S) can adopt either a 'folded' conforma- tion (central rings twist) or an 'open' conformation (central rings half-boat). Calculations showed that c.d. maxima of the same sign would be expected either for the (1R,3R) configuration in the folded conformation or for the (1S,3S) configuration in the open conformation and therefore it was im- possible to deduce the absolute configuration of Troger's base from c.d.measurements alone. In fact other conformational studies suggest that the molecule exists predominantly (>90%) as the folded conformer at room temperature and from c.d. measurements ( +)-Troger's base has been allotted the (1R,3R) configuration (2). Me0--N Me&> ' (2) Snatzke has commented on similar problems in connection with the c.d. of a-ketols in the curcurbitacin series;" the known configurations of some steroid 17-carboxylic acids have been used'' to discuss their preferred con- formations. Another source of difficulty arises from unsuspected solvent interactions and Djerassi Kjaer and their colleagues'2 have drawn attention to the need for caution in assigning configuration to chiral molecules solely on the basis of the sign of the Cotton effect in systems where the solute-solvent interaction is unknown.Even in a given solvent cases are recorded of homologous com- pounds of identical chirality exhibiting Cotton effects of opposite sign. Carboy1 Chromophore.-The 0.r.d.lc.d. of the carbonyl group has been more extensively studied than that of any other chromophore and this is reflected in the number of papers which apply 0.r.d. as a routine tool in stereo- chemical problems. Of these applications more than 60 "/ are to ketones and many make use of the Octant Rule,13 which has recently been applied14 to S.F. Mason G. W. Vane K. Schofield R. J. Wells and J. S. Whitehurst J. Chem. SOC.(B) 1967,553. lo G. Snatzke P. R. Enslin C. W. Holzapfel and K. B. Norton J. Chem. Soc.(C),1967,972. G. Gottarelli W. Klyne and P. M. Scopes J. Chem. Soc.(C) 1967 1366. l2 E. Bach A. Kjaer R. Dahlbom T. Walle B. Sjoberg E. Bunnenberg C. Djerassi and R.Records Acta Chem. Scand. 1966,20,2781. l3 W. Mofitt R. B. Woodward A. Moscowitz W. Klyne and C. Djerassi J. Amer. Chem. SOC. 1961,83,4013. l4 J. Go& C. Djerassi and J. M.Conia Bull. SOC.chim. France 1967,950. Part (iii) Optical Rotary Dispersion and Circular Dichroism 49 cyclo butanones. Studies of these compounds indicated an increase in con- formational rigidity at -192” (cf.Velluz and Legrand14”). For much o.r.d./c.d. work it is useful to eliminate the complications of flexible conformationally labile compounds and to work with rigid molecules. Such monoterpene ketones of the camphor type have been used by Coulombeau and Rassat15 to study solvent effects. The authors showed that bicyclo[2,2,1]- heptanones have a c.d. band at 300 mp which is always greater in magnitude for a polar than for a non-polar solvent. There is no possibility of confor- mational change in these ketones and the authors were able to exclude the possibility of compound formation ; they therefore attribute the observed difference to solvation of the ketones in the polar hydroxylic solvents and suggest a model for the ketone-solvent complex. Cookson and his co-workers have used py-unsaturated ketones and their aryl derivatives in the dehydrocamphor and dehydroepicamphor series to study the degree of mixing of the n -,7t* and 7c -+ IC*transitions of the chromo- phore.I6 As expected the transitions show A& of opposite sign and the effects of mixing are greatest in the aryl derivatives.0.r.d. or c.d. curves have also been used to study the conformation of diastereoisomeric 4-hydroxymenth- ones’ and of diastereoisomeric keto-acids derived from menthofuran photo- peroxide. In many cases the 0.r.d. of ketones has been used to determine the stereo- chemistry of natural products. The Cotton effect of a complex keto-lactone was used to assign the absolute stereochemistry to ginkg~lide’~ (independently cross-checked by Bijvoet X-ray2’) and the c.d.of py-unsaturated ketones has been used to establish’’ stereochemistry in the pelenolides (a new group of macrocyclic sesquiterpene lactones). The 0.r.d. of the alkaloid ( -)-pelletierine confirms22 the configuration R previously allotted to the single asymmetric centre by chemical transformations. Ketones derived from the tricothecane skeleton23 and from ~edrane~~ have been studied by c.d. and cyclopropyl and epoxy-ketones related to umbellulone by 0.r.d.” 0.r.d. curves have been used by Djerassi26 to investigate the base-catalysed equilibration at C-14 of 15-0x0-steroids. The proportions of different con- 14’ L. Veiluz and M. Legrand Compt. rend. 1967 C 265 663. Is C. Coulombeau and A. Rassat Bull.SOC. chim. France 1966 3752. l6 D. E. Bays R. C. Cookson and S. MacKenzie,J. Chem. Soc.(B) 1967,215; D. E. Bays and R. C. Cookson ibid. p. 226. ‘I T. Suga T. Shishibori and T. Matsuura J. Org. Chem. 1967,32,965. C S. Foote M.T. Wuesthoff and I. G. Burstain Tetrahedron 1967,23 2601. l9 M. Maruyama A. Terahara Y. Nakadaira M. C. Woods Y. Takagi and K. Nakanishi Tetra-hedron Letters 1967 315. 2o N Sakabe S. Takada and K. Okabe Chem. Comm. 1967,259. ‘’ M. Suchy,Z. Samek V. Herout R. B. Bates G. Snatzke and F. Sorm,Coll. Czech. Chem. Comm. 1967,32 391 7. 22 H. C. Beyerman L. Maat and J. P. Visser Rec. Trau. chim. 1967,86,80. 23 G:Snatzke and Ch. Tamm Helv. Chim. Acta 1967 50 1618. 24 W Wojnarowski and G. Ourisson Bull SOC. chim. France 1967 219.25 R. T. Gray and H. E. Smith Tetrahedron 1967,23,4229. 26 A R Van Horn and C. Djerassi J. Amer. Chern. SOC.,1967,89,651. P. M.Scopes formers present in (+)-6/3-bromo-3,8dimethyldecahydroazulen-5-one in various solvents have been studied by ~.d.~' Two groups of workers28* 29 have independently synthesised a number of interesting heterocyclic ketones e.g. S( + )-1-oxoquinolizidine (3). The results of Yamada and Kunieda2* appear to show that tertiary nitrogen has an 'anti-Octant' effect (i.e.,makes an Octant contribution of sign opposite to that of an alkyl group) although the results are subject to some slight con- formational uncertainty. The Cotton effects of many halogen-substituted @-unsaturated ketones have been re~orded,~' but the substituent effect could not be correlated with an octant rule.Interesting carbohydrate ketones have been investigated by Paulsen and his colleagues3' (cf. other carbohydrate work32). OMe OMe (4) OMe Aromatic Chromopbores.-An extensive general survey of the 0.r.d. and c.d. of aromatic compounds has been published.' Much of the work discussed in this review is only partly complete and theoretical interpretation is possible only in a few limited cases; its value lies in the breadth of the field covered and in the suggested areas for future research. The absolute configurations of ( -)argemonine (4)33 and (+)-Troger's base (1)9 have been determined by Mason by the coupled oscillator method as (1S,5S) and (1R,3R) respectively. These results are in accord with those obtained for ( -)-argemonine by rigorous chemical degradation (Battersby and his co-~orkers~~).Empirical comparisons of 0.r.d. curves with those of reference compounds of known configuration have been used to determine '' K. Kuriyama T. Iwata M. Moriyama M. Ishikawa H. Minato and K. Takeda,J. Chem. Soc.(C) 1967,420. S. Yamada and T. Kunieda Chem. and Pharrn. Bull. (Japan) 1967,15,490. 29 S. F. Mason K. Schofield and R. J. Wells J. Chem. Soc.(C) 1967 626. 'O J. C. Bloch and S. R. Wallis J. Chem. Soc.(B),1966 1177. K. Heyns J. Weyer and H. Paulsen Chem. Ber. 1967 100,2317 32 H. Paulsen Chem. Ber. 1967,100 515 806. 33 S. F. Mason K. Schofield R. J. Wells J. S. Whitehurst and G. W. Vane Tetrahedron Letters 1967 137; S.F. Mason G. W. Vane and J. S. Whitehurst Tetrahedron 1967,23,4087. 34 A. C. Barker and A. R. Battersby Tetrahedron Letters 1967 135; J. Chem. Soc.(C) 1967 1317. Part (iii) Optical Rotatory Dispersion and Circular Dichroism 51 the absolute configurations of plicatic acid3’ (by reference to other lignans) and of latif~lin~~ (by reference to quinol diacetates). Aromatic amines aromatic alcohols and their derivatives have been studied by four groups. The 0.r.d. of phenyl- and diphenyl-propylamines and related imides has been compared with that of corresponding compounds in the cyclohexylpropylamine series.37 The o.r.d./c.d. of other a-and P-aryl- amine~~~ and the 0.r.d. of some aromatic alcohols have also been rep~rted.~’ Papers have also appeared on P-arylcarboxylic acids4’ and on compounds containing the thiophen or furan chrom~phores.~’ Indole alkaloids of the yohimban and corynanthean groups have been extensively studied,42 as have some oxindole alkaloids.43 From detailed work on lycorine and.related compounds Takeda and his co-workers have proposed an ‘octant rule’ for the Cotton effect associated with the 280-290 mp aromatic transition44 in this group. Other work has appeared on cinchona alkaloids,45 lupin alkaloids,46 and compounds of the rhoeadine groups.47 Nitrogen Chromophores.-Multiply- bonded nitrogen chromophores have been studied by several gro~ps.~~-’’ Snatzke and Himmelrei~h~~ have reported c.d. data for many 20-0x0-steroids with heterocyclic rings (pyrazoline oxazoline and isoxazoline) fused at positions 16 and 17.The observed c.d. maxima can be correlated with the stereochemistry of the steroid side-chain. A paper by Chilton and Krahn4’ describes a survey of arabinose derivatives with a heterocyclic ring (benzimidazole quinoxaline or phenyltriazole) at C-2 (sugar numbering). Preliminary results suggest that the benzimidazole and quinoxaline derivatives with S-configuration at C-2 have positive Cotton effects at 245 and 315 mp respectively. 35 R. J. Swan W. Klyne and H. MacLean Canad. J. Chem. 1967,45 319. 36 D. M. X. Donnelly B. J. Nangle P. B. Hulbert W. Klyne and R. J. Swan J. Chem. Soc.(C) 1967,2450. 3’ A. La Manna V. Ghislandi P. B. Hulbert and P. M. Scopes 11. Farmaco(Ed. Sci.) 1967 22 1037. 38 L.Verbit J. Amer. Chem. SOC.,1966,88,5340; J. C. Craig R. P. K. Chan and S. K. Roy Tetra-hedron 1967,23 3573. “ 0.Cervinka and 0.Btlovsk9 Coll. Czech. Chem. Comm. 1967,32 4149. 40 L. Verbit and Y. Inouye J. Amer. Chem. SOC. 1967 89 5717; L. Verbit and P. J. Heffron Tetrahedron 1967,23 3865. 41 L. Verbit E. Pfeil and W. Becker Tetrahedron Letters 1967 2169. 4’ W. Klyne R. J. Swan N. J. Dastoor A. A. Gorman and H. Schmid Helv. Chim. Act& 1967 50,115; C. M. Lee W. F. Trager and A. H. Beckett Tetrahedron 1967,23,375; W. F. Trager C. M. Lee J. D. Phillipson and A. H. Beckett Tetrahedron 1967,23,1043;M. Von Strandtmann R.Eilertson and J. Shave] J. Org. Chem. 1966,31,4202. 43 J. L. Pousset J. Poisson R. J. Shine and M. Shamma Bull. SOC.chim. France 1967 2766; A.F. Beecham N. K. Hart S. R. Johns and J. A. Lamberton Tetrahedron Letters 1967,991. 44 K. Kuriyama T. Iwata M. Moriyama K.Kotera Y. Hamada R. Mitsui and K. Takeda J. Chem. Soc.(B) 1967 46. 45 G. G. Lyle and W. Gaffield Tetrahedron 1967,23 51. 46 S. I. Goldberg and R. F. Moates J. Org. Chem. 1967,32 1832. 47 F. Santavy J. Hrbek,and K. Blaha Coll. Czech. Chem. Comm. 1967,32,4452. 48 G. Snatzke and J. Himmelreich Tetrahedron 1967,23,4337. 49 W. S. Chilton and R. C. Krahn J. Amer. Chem. SOC.,1967,89,4129. 52 P. M. Scopes The linear azide chromophore has also been studied in a series of steroidal azides. Sulphur Chromophores.-The 0.r.d. of the sulphoxide chromophore has been discussed for compounds in which the sulphur atom is part of an acyclic chain,” and for oxides of cyclic sulphur compounds.52 In either case diastereo- isomeric sulphoxides differing only in the configuration at sulphur give Cotton effects of opposite sign.0.r.d. data have also been reported for some rigid cyclic ~ulphides,’~ and c.d. data for a series of substituted dithiolans (dithi~acetals).’~ RippergerS5 has studied the c.d. of a number of dithiourethanes containing the chromophore R S C(:S) N. The experimental results can be interpreted in terms of a quadrant rule in which the regional sign distribution is the same as that previously founds6 for carboxy- and related chromophores. Phosphorus Chromopbore.-Mislow and his co-workers have reporteds7 0.r.d. data for a pair of diastereoisomeric menthylmethylphenylphosphinates (5).The chirality of the arylphosphoryl chromophore dominates the o.r.d. and positive and negative Cotton effects were observed for the diastereoisomers having R-and S-configuration respectively at the phosphorus atom. Ph 3 H,C*NYP=O I &(5) Chromophoric Derivatives.-The 0.r.d. and c.d. of N-thiobenzoyl and N-phenylthioacetyl derivatives of or-amino-acids have been studied in different s0lvents.’~958 Cotton effects have also been reported for N-(2-pyridyl-N- oxide)amin~-acids,~~ for thioamides of cycloalkanedicarboxylic acids,60 and for selenophenyl and selenonaphthyl esters of amino-acids.6 ’ Mono-and Di-enes.-The c.d. of dethiogliotoxin6’ shows a negative band at 265 mp as would be expected from the known chirality of the diene system.This may help to explain the apparent anomaly between the 0.r.d. of gliotoxin C. Djerassi A. Moscowitz K. Ponsold and G. Steiner J. Amer. Chem. SOC., 1967,89 347. ” D. N. Jones and M. J. Green J. Chem. Soc.(C) 1967,532; D. N. Jones M. J. Green M. A. Saaed and R. D. Whitehurst Chem. Comm. 1967 1003. ’’ R. Nagarajan B. H. Chollar and R. M. Dodson Chem. Comm. 1967 550; P. B. Sollman R. Nagarajan and R. M. Dodson ibid. p. 552. 53 P. Laur H. Hauser J. E. Gurst and K. Mislow J. Org. Chem. 1967 32 498. 54 R. C. Cookson G. H. Cooper and J. Hudec J. Chem. Soc(B) 1967,1004. 55 H. Ripperger Angew. Chem. Internat. Edn. 1967,6,704. ’tj J. P. Jennings W. Klyne and P. M. Scopes J. Chem. SOC.,1965 7211 7229. ’’ R. A. Lewis 0.Korpium and K.Mislow J. Amer. Chem. SOC.,1967,89,4786. ’’ G. C. Barrett J. Chem. Soc.(C) 1967 1. ’’ V. Tortorella and G. Bettoni Chem. Comm. 1967 321. 6o Y. Inouye S. Sawada M. Ohno and H. M. Walborsky Tetrahedron 1967,23 3237. “ K. Blaha I. Fric and H. D. Jakubke Coll. Czech. Chem. Comm. 1967,32 558. 62 H. Ziffer U. Weiss and E. Charney Tetrahedron 1967,23 3881. Part (iii) Optical Rotatory Dispersion and Circular Dichroism 53 f I C,H,wCdO,C.CH I ;I (6) itself and its absolute configuration established by Bijvoet X-ray measure- ments (cf. last year's Ann. Reports). The chirality of isolated double bonds has been studied further.63 Carboxy-chromophores.-A detailed survey64 has been made of the 0.r.d. of alp-unsaturated lactones in the steroid cardenolides which show the first extremum of a Cotton effect at 260 mp; the sign can be correlated with the configuration at C-17 and C-14.Some confusion exists in the literature over the three quite separate attempts which have been made56*65*66 to correlate the o.r.d./c.d. of lactones with their molecular geometry. Legrand and Bu~ourt~~ have now considered the sign of lactone Cotton effects in terms of the conformation of the lactone ring. The carboxy-group Sector Rule (originally developed for lactones' 6 has now been used to study the 0.r.d. of the -CO*O- chromophore in esters (steroid acetates)68 and in steroid 17P-carboxylic acids' ' and dinorcholanic acids,69 all of known configuration. The signs of the carboxy-group Cotton effects for these acids and esters can all be rationalised in terms of the Sector Rule and the preferred conformations suggested in the literature for these compounds.0.r.d. has also been used to investigate the absolute configuration of some long-chain hydro~y-acids,~' and to study the effect of alkali on the rotation of a-hydroxy-carboxylic acids.7 A positive Cotton effect has been observed7' for R( +)-[1-2Hl]butyl acetate (6) an ester whose optical activity arises solely from isotopic sub- stitution. The c.d. of malimide and tartarimide has been reported.73 The 0.r.d. of small peptides is receiving growing attention. Detailed papers have appeared74 on glycine peptides having one leucine residue in different positions in the glycine chain on protected peptides of alanine and ~erine,~~ A.Yogev D. Amar and Y. Mazur Chem. Comm. 1967 339. 64 F. Burkhardt W. Meier A. Fiirst and T. Reichstein Helu. Chim. Acta 1967,50,607. 65 G. Snatzke H. Ripperger Chr. Horstmann and K. Schreiber Tetrahedron 1966 22 3103. 66 H. Wolf Tetrahedron Letters 1966 5151. " M. Legrand and R. Bucourt Bull. SOC.chim. France 1967,2241. '' J. P. Jennings W. P. Mose and P. M. Scopes,J. Chem. Soc.(C),1967 1102. 69 G. Gottarelli and P. M. Scopes J. Chem. Soc.(C),1967 1370. 'O T. H. Applewhite R. G. Binder and W. Gafield J. Org.Chem. 1967,32 1173. 7? K. Droll and V. Klingmiiller Tetrahedron Letters 1967 2795. 72 L. Verbit J. Amer. Chem. SOC. 1967,89 167. 73 H. R. Dave and M. K. Hargreaves Chem. Comm. 1967 743. 7* A. F. Beecham Tetrahedron Letters 1967 21 1 Tetrahedron 1967 23 4481 ; Austral.J. Chem. 1967,20 1983. 75 P. M. Scopes D. R. Sparrow J. Beacham and V. T. Ivanov J. Chem. Soc.(C) 1967 221. P. M.Scopes and on some di- and tri-peptides containing aromatic amino-acid residue^.'^ 0.r.d. curves have been interpreted by Shields and M~Dowell’~ as evidence of secondary structure in a protected tetrapeptide. MagneticCircularDichroism.-Important papers on7 m.c.d. which appeared at the end of 1967 will be considered fully in next year’s report. ’tj E. W.Gill Biochim. Biophys. Acta 1967 133,381. ’’ J. E. Shields and S. T. McDowell J. Amer. Chem. SOC.,1967,89 2499. B. Briat D. A. Schooley R. Records E. Bunnenberg,and C. Djerassi J. Amer. Chem. SOC.1967 89,6170,7062 cf. also D. A. Schooley E. Bunnenberg and C. Djerassi Proc. Nut. Acad. Sci. U.S.A. 1966,61377.