2 Physical Methods-Part (iii) Optical Rotatory Dispersion and Circular Dichroism By P. M. SCOPES Westfield College Hampstead London N.W.3 OVERthe past ten years the chiroptical techniques optical rotatory dispersion (0.r.d.) and circular dichroism (c.d.) have increasingly become routine tools for the study of dissymmetric molecules. An important review of c.d. for 196@-70 has recently been published.' The first correlations between stereochemistry and the sign of Cotton effect were based entirely on empirical generalizations. Subsequently semi-empirical regional rules which relate the geometry of a molecule to the sign of its Cotton effect were developed for some chromophores and in only a few cases has it been possible to determine the absolute configura- tion of a molecule directly by calculation of the expected sign of the Cotton effect for a particular configuration.This select list has now been extended by two more examples. The (-)-tris-2,2'- biphenylylenephosphorus(v) ion has been shown2 to have the form of a left- handed screw when viewed along the three-fold rotation axis (1) [i.e. the (M)-configuration in the Cahn-Ingold-Prelog nomenclature3] by analysis of its c.d. and absorption spectra in terms of an exciton model. (+)-trans-Stilbene oxide in which the dichroism derives principally from coupling between the excitation moments of the two aryl chromophores has been shown4 to have the (R)-configuration at both asymmetric carbon atoms. This result agrees with that obtained by chemical degradation and acts as a check on the validity of non-empirical calculation of absolute configuration.' L. Velluz and M. Legrand Bull. SOC.chim. France 1970 1785. D. Hellwinkel and S. F. Mason J. Chem. SOC.(B) 1970,640. R. S. Cahn C. K. Ingold and V. Prelog Angew. Chem. 1966,78,413. G. Gottarelli S. F. Mason and G. Torre J. Chem. SOC.(B) 1970 1349. Part (iii) Optical Rotatory Dispersion and Circular Dichroism Eyring and his colleagues' have used bond-bond coupling theory to calculate rotational strengths for a number of nucleosides and the agreement with experimental observation suggests that coupled oscillator theory accounts for most of the observed optical activity in pyrimidine nucleosides. Another general approach by Hoffmand based on electric transition moments yields calculated rotatory strengths of the correct order of magnitude for a twisted diene but the results are not in quantitative agreement with experiment.Wagniere and Hug have suggested a very simple relationship between the chirality of molecules of C,-symmetry [e.g.helicenes dienes diones and -enone (pseudo C2)],the direction of polarisation of the transition with reference to the C2 axis and the sign of their long-wavelength Cotton effect7 For com- pounds of right-handed chirality transitions in which the electric and magnetic dipoles are parallel (or anti-parallel) to the two-fold axis give rise to negative Cotton effects ;transitions in which the dipoles are perpendicular to the two-fold axis give positive Cotton effects.If the direction of polarisation is known the sign of Cotton effect can be predicted for a given absolute configuration or conversely if the absolute configuration is known the polarisation of the transi- tions can be determined by studying experimentally the sign of the Cotton effect. 1 Regional Rules for Symmetrical Chromophores In its original form,8 the Octant Rule for saturated ketones established a relation- ship between the geometry of the molecule around the carbonyl group and the sign and magnitude of the contribution made to the Cotton effect by alkyl groups or carbon-carbon bonds. More recently the influence of other functional groups close to the chromophore has been investigated by two independent groups of workers who have established that a-hydroxy- and a-acetoxy-ketones in steroidsg and in camphor derivatives" show anti-octant behaviour (i.e.make a contribution opposite in sign to that shown by an alkyl group at the same position).Snatzke and Eckhardt" in a detailed study of 8-substituted adaman- tanones (2) have found that OAc ON02 and SCN groups in an equatorial (ax) (2) W. H. Inskeep D. W. Miles and H. Eyring J. Amer. Chem. SOC.,1970 92 3866; D. W. Miles W. H. Inskeep M. J. Robins M. W. Winkley R. K. Robins and H. Eyring J. Amer. Chem. SOC.,1970 92 3874. R. R. Gould and R. Hoffmann J. Amer. Chem. SOC.,1970,92 1813. ' G. Wagniere and W. Hug Tetrahedron Letters 1970 4765. * W. Moffitt R. B. Woodward A. Moscowitz W. Klyne and C. Djerassi J. Amer. Chem. SOC.,1961 83,4013.J. R.Bull and P. R. Enslin Tetrahedron 1970 26 1525. lo L. Bartlett D. N. Kirk W. Klyne S. R. Wallis H. Erdtman and S. Thoren J. Chem. SOC.(C) 1970,2678. " G. Snatzke and G. Eckhardt Tetrahedron 1970,26 1143. P.M. Scopes configuration obey the octant rule but are anti-octant in an axial configuration. The hydroxy-group is anomalous and obeys the Octant Rule in both the p-equatorial and axial configurations. Other authors have shown that a methyl group in the p-axial position is also anti-octant12 and they relate this to the prediction of Pao and Santry13 that the sign of rotation for a B-axial substituent should be opposite to that predicted by the Octant Rule. In a short but important general survey HudecI4 has suggested that there are two ways in which one of the lobes of the carbonyl 7c* orbital may interact through cbonds with a lone pair on a nitrogen atom.If the chain of G bonds is formed entirely of anti-peri-planar links (W arrangement) the nitrogen substituent has an octant effect (3); I '€4 H (3) if the chain includes one (or more) syn-clinal links the nitrogen has an anti-octant effect (4). Further details of this important work are still to be published. In related work with 3-aryl norbornan-2-ones Thomas and Mis10w'~ have shown that the 3-substituent makes an anti-octant contribution to the ketone Cotton effect attributed to transition moment coupling between the carbonyl and aryl chromophores. Full details have now been publishedI6 of the symmetry rule for chiral olefins which relates the absolute configuration to the sign of the n-n* Cotton effect near 200nm.The rule has been tested on about seventy olefins and appliedI7 in the assignment of absolute configuration to some derivatives of taxane. How- ever a report has also been publishedI8 of the c.d. of eighteen exocyclic methylene steroids which do not obey the Scott-Wrixon rule. The French authors and also Scott in another paperIg note that the situation is made complex by the l2 M. E. Herr R. A. Johnson W. C. Krueger H. C. Murray and L. M. Pschigoda J. Org. Chem. 1970,35 3607. l3 Y.H. Pao and D. P. Santry J. Amer. Chem. Soc. 1966,88,4157. l4 J. Hudec Chem. Comm. 1970,829. Is H. T. Thomas and K. Mislow J. Amer. Chem. Soc. 1970 92 6292. Ih A. I. Scott and A.D. Wrixon Tetrahedron 1970 26 3695. D. P. D. C. de Marcano T. G. Halsall A. I. Scott and A. D. Wrixon Chem. Comm. 1970 582. Is M. Fetizon and I. Hanna Chem. Comm. 1970,462. Iq A. I. Scott and A. D. Wrixon Chem. Comm. 1970,43. Part (iii) Optical Rotatory Dispersion and Circular Dichroism 39 presence of at least three transitions occurring near 200 nm which may overlap and may be of opposite sign. At present there is no explanation for this difference between cyclic and exocyclic double bonds. Snatzke and his colleagues have made detailed studies of two series of com- pounds containing aryl chromophores (2-aminotetralols and 2-aminoindanol~),~~ and the alkaloids of the tetrahydroberberine group.21 The authors suggest that if the second sphere (i.e.the non-aryl ring fused to the aryl chromophore) is chiral this determines the sign of the ‘L Cotton effect but that a sector rule with six regions above and below the aromatic plane determines the third or fourth sphere effects. An extension of this treatment to the ‘Laband is proposed and the absolute configurations of several alkaloids are allotted on this basis. In cases where regional rules cannot yet be formulated empirical correlations can often be made by comparison with 0.r.d. or c.d. data for closely analogous compounds. For example a detailed survey22 of flavanones and their glycosides has shown that flavanones having the (2s)-configuration and an equatorial 2-aryl substituent have a positive Cotton effect at -330 nm (n-+ .n* transition) and a negative Cotton effect at 280-290nm (n-+ TC*transition).Optically active [2,2]paracyclophane derivatives have also been surveyed.23 Among new chromophores the first resolution of a selenoxide has been achieved24 and the Se(R)-and Se(S)-phenylselenoxides of cholestane (from 5a-cholestane-6-selenols)have been shown to give positive and negative Cotton effects respectively. Aliphatic C-nitroso-compounds have also been investi- gated2’ but the c.d. curves although qualitatively reproducible could not be used for quantitative measurements. A correlation has also been achieved between the sign of Cotton effect and the absolute configuration of a series of (2R)-halogenoalkane~.~~ For iodo- bromo- and chloro-alkanes the c.d. maxi- mum occurs at -253 nm -204 nm and <200 nm respectively.Compounds containing the carboxyl chromophore are particularly significant because of their relationship to natural biopolymers including polyesters and proteins. Goodman and his colleagues27 have made a detailed study of three rigid compounds containing a -COO-chromophore (lactide diphenyl- glycolide and a-campholide) and have compared them with the acyclic analogues. It is significant that the relationship between the c.d. of acyclic methyl O-acetyl- @)-lactate and (S,S)-lactide is not the same as that between N-acetyl-(Qalanine amide and (S,S)-alanine diket~piperazine.~ The importance of using carefully ’O E. Dornhege and G. Snatzke Tetrahedron 1970 26 3059. ” G. Snatzke J. Hrbek L. Hruban A. Horeau and F.SantavJ; Tetrahedron 1970 26 5013. 22 W. Gaffield Tetrahedron 1970 26 4093. H. Falk P. Reich-Rohrwig and K. Schlogl Tetrahedron 1970 26 5 1 1. 24 D. N. Jones D. Mundy and R. D. Whitehouse Chem. Comm. 1970 86. 25 N. D. Vietmeyer and C. Djerassi J. Org. Chem. 1970,35 3591. 26 B. A. Chaudri D. G.Goodwin H. R. Hudson L. Bartlett and P. M. Scopes J. Chem. SOC.(C) 1970 1329. 27 C. Toniolo V. Perciaccante J. FaIcetta R. Rupp and M. Goodman J. Org. Chem. 1970 35 6. 40 P. M. Scopes chosen analogies is emphasised in other work on cc-campholide.28 Greenfield and Fasman2’ have studied the n -+ n* transition of the isolated amide bond in (R)-(+ )-3-methylpyrrolidin-2-one and Blaha and FriE3’ have surveyed the 0.r.d. of a large number of diketopiperazines as models for the peptide bond in macromolecules.Other work has been published on the 0.r.d. and c.d. of a-amino- and a-hydroxy-acids3 and on sesquiterpene lac tone^.^^ 2 Configurational Assignments Allotments of absolute configuration by 0.r.d. or c.d. may be made either by application of firmly based regional rules or by direct comparison of the un- known with a closely analogous compound of known stereochemistry. For example the absolute configuration of a rigid ketone related to perhydrotri- phenylene has been assigned33 by application of the Octant Rule. In contrast empirical correlations have been used to allot configurations to C-6 in l~tein~~ and to C-6 in semi-a-~arotenone.~~ The aromatic chirality rule36 has been applied to determine the absolute configuration of the antibiotic cervicarcin3 and by comparison of closely related series of compounds configurations have been allotted to alkaloids of the seredamine group (indole chrornoph~re)~ and the roemeramine-mecambrine group (tetrahydroisoquinoline nucleu~).~’ The structure and configuration of panepoxydone and related compounds have been established4’ by a combination of chemical transformations and physical measurements.A number of workers have noted the hazards of configurational assignments based on c.d. measurements. For example daphnetoxin (5) and phorbol (6) of known absolute configuration give c.d. curves of opposite sign4’ X-Ray measurements on derivatives of daphnetoxin and phorbol show that the a/3-unsaturated carbonyl chromophores have opposite chirality in the two molecules despite their configurational identity.In another ‘configuration’ us. ‘conforma-tion’ problem the absolute configuration of a flexible diene for which the skew sense is not known has been allotted by empirical comparison with a closely analogous compound (1,2-dihydroarene-l,2_diol~).~~ 28 A. F. Beecham and R. R. Sauers Tetrahedron Letters 1970 4763. 29 N. J. Greenfield and G. D. Fasman J. Amer. Chem. Soc. 1970,92 177. 30 K. Blaha and I. Frit Coll. Czech. Chem. Comm. 1970 35 619. 31 J. C. Craig and W. E. Pereira Tetrahedron Letters 1970 1563; Tetrahedron 1970 26 3457. 32 W. Stocklin T. G. Waddell and T. A. Geissman Tetrahedron 1970 26 2397. 33 M. Farina and G. Audisio Tetrahedron 1970 26 1839.34 D. Goodfellow G. P. Moss and B. C. L. Weedon Chem. Comm. 1970 1578. 35 R. Buchecker H. Yokoyama and C. H. Eugster Helu. Chim. Actu 1970,53 1210. 36 N. Harada H. Sato and K. Nakanishi Chem. Comm. 1970 1691. 37 S. Marumo N. Harada K. Nakanishi and T. Nishida Chem. Comm. 1970 1693. 38 M. Hanacka M. Hesse and H. Schmid Helu. Chim. Acta 1970,53 1723. 39 J. Slavik P. Sedmera and K. Blaha CON. Czech. Chem. Comm. 1970,35 1558. 40 Z. Kis A. Closse H. P. Sigg L. Hruban and G. Snatzke Helv. Chim. Acta 1970 53 1577. 41 G. H. Stout W. G. Balkenhol M. Poling and G. L. Hickernell J. Amer. Chem. SOC. 1970 92 1070. 42 D. M. Jerina H. Ziffer and J. W. Daly J. Amer. Chem. SOC. 1970,92,1056. Part (iii) Optical Rotatory Dispersion and Circular Dichroism 41 The relationship between the sign of Cotton effect and absolute configuration may be completely reversed if a new substituent is introduced.This has been HOCH~ emphasised by Fischer and Dreiding in a study of cyclodopa derivative^^^ and also in connection with phenyl-substituted tetrahydro-isoq~inolines.~~ The situation is particularly complex when a molecule contains two chromo- phores absorbing at (or near) the same wavelength ;e.g. the acid-lactone trans-n-camphanic acid (7).45 Me 0 3 Conformational Studies; Solvent and Temperature Dependence For compounds of known configuration the chiroptical techniques are a powerful tool for the study of conformation. This year c.d. has been used to study the conformation of the five-membered ring in hexahydroindanone~~~ and of the five- and seven-membered rings in some ~-nor-~-homo-steroids.~~ The conformation of the carboxy-group in acids and esters has been studied by three groups of ~orkers.~~-~~ have studied Djerassi and his co-worker~~~ the solvent and temperature dependence of the c.d.spectra of a series of a-43 N. Fischer and A. s.Dreiding Helv. Chim. Acta 1970,53 1937. O4 V. Toome J. F. Blount G. Grethe and M. UskokoviC Tetrahedron Letters 1970,49. O5 M. J. Brienne and J. Jacques Tetrahedron 1970 26 5087. O6 M. J. Brienne A. Heymes J. Jacques G. Sn'atzke W. Klyne and S. R. Wallis J. Chem. SOC.(0,1970,423. " M. Lj. Mihailovic Lj. Lorenc J. ForSek H. NeSovic G. Snatzke and P. TrSka Tetrahedron 1970 26 557.O8 G. Barth W. Voelter H. S. Mosher E. Bunnenberg and C. Djerassi J. Amer. Chem. SOC.,1970 92 875. O9 1. Listowsky G. Avigad and S.Englard J. Org. Chem. 1970 35 1080. 50 W. P. Mose and P. M. Scopes J. Chem. SOC.(0,1970,2417. 42 P. M. Scopes substituted phenylacetic acids which they have regarded as conformationally mobile homo-conjugated systems. Listowsky and his colleagues49 have com- pared the c.d. spectra of a-hydroxy- and a-alkyl-carboxylic acids. For the a-hydroxy-acids they suggest a conformation in which the hydroxy and carbonyl groups are eclipsed and for the a-alkyl-substituted acids coplanarity of car- boxy-group and the a-substituent. The influence of solvent on carbonyl Cotton effects has been studied for rigid steroid ketones5' and for the more flexible pulegone oxide.52 Solvent effects for the 0.r.d.x.d.of a-chlorosulphoxides have also been reported.53 The 0.r.d. curves of several a-silyl ketones (8) have been studied in a series of twenty sol- vent~~~ and a correlation has been drawn between the basicity of the solvent 0 Br (8) and the Cotton effect. The authors suggest that this is due to co-ordination of the solvent molecule with the available 3d orbitals of the silicon atom. 4 Miscellaneous Although the first extensive group of papers on magnetic 0.r.d. and c.d. were published three years ago the cost of the equipment is prohibitive and only a few papers have appeared this year e.g. an important paper55 which compares c.d. and m.c.d. for chlorophyll and related pigments.The proceedings of a major symposium on magneto-optical effects (held in December 1969) have now been p~blished.~~ The development of 0.r.d. and c.d. has been closely linked to the instrumenta- tion available and it is interesting to note that the c.d. of (+)-3-methylcyclo- pentanone has been measured'' down to 165 nm in the gas phase using a newly developed instrument. Electric-field-induced dichroism has been explored58 in a number of polyamino-acids. Finally the first resolution of a chiral borane has been reported.59 Iso-docosahydro-octadecaborane (B 8H22) has been resolved by the formation of diastereoisomeric compounds with (+)-camphidine hydrochloride and shows 0.r.d. curves with several Cotton effects between 500 and 200nm.51 D. N. Kirk W. Klyne and S. R. Wallis J. Chem. Sac. (C) 1970 350. 52 T. M. Feeley and M. K. Hargreaves J. Chem. SOC.(0,1970 1745. 53 M. Cinquini S. Colonna I. Moretti and G. Torre Tetrahedron Letters 1970 2773. 54 R. Corriu and J. Masse Tetrahedron 1970 26 5123. 55 C. Houssier and K. Sauer J. Amer. Chem. SOC.,1970 92 779. 56 Symposia of the Faraday Society 1969 No. 3. 57 0.Schnepp E. F. Pearson and E. Sharman Chem. Cornrn. 1970 545. *' E. Charney J. B. Milstien and K. Yamaoka J. Amer. Chem. SOC.,1970,92 2657. 59 S. Heimanek and J. PleSek CON. Czech. Chem. Comm. 1970 35 2488.