摘要:

QUARTERLY REVIEWS THE CHEMICAL SOCIETY PATRON HER MAJESTY THE QUEEN President E. L. HIRST M.A. D.Sc. LL.D. F.R.S. Vice-presidents who have filled the office of President SIR IAN HEILBRON D.S.O. D.Sc. W. H. MILLS M.A. Sc.D. F.R.S. SIR CYRIL HINSHELWOOD M.A. D.Sc. F.R.S. C. K. INGOLD D.Sc. F.R.I. F.R.S. F.R.I.C. LL.D. F.R.S. SIR ERIC RIDEAL M.B.E. M.A. Sc.D. F.R.S. W. WARDLAW C.B.E. D.Sc. Vice-presidents E. D. HUGHES D.Sc. F.R.I.C. 13. W. MELVILLE D.Sc. F.R.I.C. E.R.H.JoNEs,D.SC.,F.R.I.C.,F.R.S. R. P. LINSTEAD C.R.E. M.A. D.Sc. F.R.S. F.R.S. M. STACEY Ph.D. D.Sc. F.R.S. SIR ALEXANDER TODD M.A. D.Sc. F.R.S. F.R.S. Honorary Treasurer M. W. PERRIN C.B.E. M.A. F.R.I.C. Honorary Secretaries L. E. SUTTON M.A. D.Phil. F.R.S. F. BERGEL D.Phil.Nat,. D.Sc. J. CHATT M.A. Sc.D. F.R.I.C.F.R.I.C. Ordinary members of Council D. W. ADAMSON M.Sc. D.Phil. H. M. N. H. IRVING M.A. D.Phil. C. C. ADDISON D.Sc. Ph.D. F.R.I.C. G. W. KENNER ALSc. P1i.D. G. R. BARKER B.Sc. Ph.D. 33. LYTHGOE M.A. Ph.D. F.R.I.C. R. M. BARRER D.Sc. Sc.D. F.R.S. A- MACCOLL M.Sc-9 Ph-D. V. C. BARRY D.Sc. M.R.I.A. F* B.Sc. Ph*D. J. M. ROBERTSON M.A.,D.Sc. F.R.S. F. BELL D.Sc. F.R.I.C. F.R.S.E. H. N* RYDoN D*Sc' D'Phi"' A. G. EVANS Ph-D.9 D-Sc.9 F.R-1-C. H. D. SPRINGALL M.A. ~ . p h i l . W. GERRARD D.Sc. Ph.D. F.R.I.C. A. HICKLINU D.Sc. Ph.D. F.R.I.C. L. HUNTER Ph.D. D.Sc. F.R.I.C. A.R.I.C. F.R.I.C. F.I.C.I. F.R.I.C. F.R.I.C. F.R.I.C. L. A. I<. STAVELEY M.,4. M7. WILD B.Sc. Ph.D. A.R.I.C. G. T. Young Ph.D. M.A. A.R.I.C. General Secretary J. R. RUCK KEENE M.B.E. T.D. M.A. Librarian Deputy Librarian R..G. GRIFFIN F.L.A. J. BIRD Telephone Numbers Regent 0675-6. Printed in Great Britain by Butler & Tanner Ltd. Frome and London QUARTERLY REVIEWS VOL. X 1956 Publication Committee Chairrnun; C. K. INGOLD D.Sc. F.R.I.C. F.R.S. C. C. ADDISON D.Sc. Ph.D. F.R.I.C. G. BADDELEY Ph.D. D.Sc. F.R.I.C. D. H. R. BARTON D.Sc. F.R.T.C. F. BEROEL D.Phil.Nat. D.Sc. E. BOYLAND D.Sc. Ph.D. J. CHATT M.A. Ph.D. F.R.I.C. P. B. D. DE LA MARE D.Sc. Ph.D. H. J. EMELEUS D.Sc. A.R.C.S. D. H. EVERETT M.B.E. M.A. G. GEE Sc.D. A.R.I.C. F.R.S. B. A. HEMS D.Sc. F.R.I.C. E. L. HIRST MA. D.Sc. LL.D. H. R. ING M.A. D.Phil. F.R.S. H. A t . N. H. IRVING M.A. D.Phil. D. J. G. IVES D.Sc. A.R.C.S. F.R.S. F.R.I.C. F.R.S. D.PhiI. F.R.S.E. F.R.S. F.R.I.C. F.R.I.C. E. R. H. JONES D.Sc. F.R.I.C. G. W. KENNER M.Sc.Ph.D. H. 6. LONGUET-HIGGINS M.A. B. LYTHGOE M.A. Ph.D. F.R.I.C. R. A. MORTON D.Sc. Ph.D. F.R.S. A. NEURERQER Ph.D. M.D. F.R.S. R. G. W. NORRISH Sc.D. F.R.I.C. M. W. PERRIN C.B.E. M.A. V. PETROW Ph.D. D.Sc. F.R.I.C. H. M. POWELL M.A. B.Sc. F.R.S. P. L. ROBINSON D.Sc. F.R.I.C. K. SCHOFIELD Ph.D. D.Sc. F.R.I.C. N. SHEPPARD M.A. Ph.D. M. STACEY Ph.D. D.Sc. F.R.S. L. E. SUTTON M.A. D.Phil. F.R.S. H. W. THOMPSON M.A. D.Sc. F.R.S. E. E. TURNER M.A. D.Sc. F.R.S. A. R. J. P. UBBELOHDE M.A. D.Sc. F.R.S. D.Phi1. F.R.S. F.R.I.C. F.R.S. Editor R. S. CAHN M.A. D,Phil.Net. F.R.I.C. Assistant Editors A. E. SOIKERFIELD Ph.D. A. D. MITCHELL D.Sc. F.R.I.C. L. C. CROSS Ph.D. A.R.C.S. F.R.I.C. LONDON T H E C H E M I C A L S O C I E T Y CONTENTS PAGE THE PROPERTIES AND NATURE OF ADSORBENT CARBONS.By J. J. Kipling . . 1 PHENOL TAUTOMERISM. By R. H. Thomson. . 27 Barton and R. C. Cookson . . 44 83 THE PRINCIPLES OF CONFORMATIONAL ANALYSIS. By D. H. R. RADIOACTIVATION ANALYSIS. By E. N. Jenkins and A. A. Smales THE INDOLE ALKALOIDS EXCLUDING HARMINE AND STRYCHNINE. FLASH PROTOLYSIS AND KINETIC SPECTROSCOPY. By R. G. W. Norrish and B. A. Thrush . . 149 NUCLEAR METHYLATION OF FLAVONES AND RELATED COM- POUNDS. By A. C. Jain and T. R. Seshadri . . 169 RAMAN SPECTRA OF INORGANIC COMPOUNDS. By L. A. Wood- ward . . 185 SILYL COMPOUNDS. By Alan G. MacDiarmid . . 208 PEPTIDES METHODS OF SYNTHESIS AND TERMINAL-RESIDUE STUDIES. By H. D. Springall and H. D. Law . . 230 FOREWORD TO ISSUE No. 3 . 259 OXIDATIVE-HYDROLYTIC SPLITTING OF CARBON-CARBON BONDS By M. M. Shemyakin and L.A. By J. E. Saxton . . 108 OF ORGANIC MOLECULES. Shchukina . . 261 LATTICENERGY OF IONIC CRYSTALS. By A. F. Kapustinskii . 283 DIRECT MEASUREMENT OF MOLECULAR ATTRACTION BETWEEN SOLIDS SEPARATED BY A NARROW GAP. By B. V. Derjaguin I. I. Abrikosova and E. M. Lifshitz . . 295 TETRA- AND TRI-CHLOROALKANES AND RELATED COMPOUNDS. By A. N. Nesmeyanov R. Kh. Freidlina and L. I. Zakharkin 330 ACETYLENIC COMPOUNDS AS NATURAL PRODUCTS. By J. D. Bu’Lock . . 371 THE CHEMISTRY OF THE AROMATIC HETEROCYCLIC N-OXIDES. THE STEREOCHEMISTRY OF SUB-GROUP VIB OF THE PERIODIC TABLE. By S. C. Abrahams . . 407 SULPHUR NITRIDE AND ITS DERIVATIVES. By Margot Goehring 437 REACTIONS IN SOME NON-AQUEOUS IONISING SOLVENTS. By V. Gutmann . . 451 HOMOGENEOUS REACTIONS OF MOLECULAR HYDROGEN IN SOLU- TION. By J. Halpern . . 463 THE LOCATION OF HYDROGEN ATOMS IN CRYSTALS. By R. E. Richards . . 480 By A. R. Katritzky . . 395 CUMULATIVE INDEXES Vols. 1-X . . 499

ISSN:0009-2681    

DOI:10.1039/QR95610FP001

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

PHENOL TAUTOMERISM By R. H. THOMSON B.Sc. PH.I). F.R.I.C. (UNIVERSITY OF ABERDEEN) CARBONYL compounds exist almost exclusively in the keto-form unless structural features are present (e.g. hydrogen bonding or steric hindrance) which stabilise the enol form as in the P-diketone (I) or the complex enol (11). On the other hand simple aromatic enols i.e. phenols exist ex- clusively in the enolic form but ketonic properties become more pronounced in polyhydric phenols and especially in the hydroxyl derivatives of polycyclic aromatic hydrocarbons. This Review deals with the tautomeric behaviour of aromatic enols particularly those which can be isolated in the ketonic form. The hydroxyl derivatives of thiophen and furan are included but not heterocyclic compounds which show lactam-lactim tautomerism.Hydr0xybenzenes.-Summation of the bond energies for the system )CH-C=O and )C-C-OH shows that the keto-structure is more stable than the enol by ca. 18 kca,l./mole. In phenol (111) however the energy gained by rearrangement to the hypothetical keto-structures (IV) is offset by the simultaneous large decrease in resonance energy (ca. 35 kcal./mole). These figures although only approximate indicate that phenol must be 1 1 OH 0 0 (111) (IV 1 predoniinantly enolic. [Conant and Kistiakowsky calculated the free energy of enolisation of (IV) to be - 18.6 kcal./mole.] There is in fact no evidence for the existence of the keto-forms although the presence of a minute proportion of them in equilibrium with the " enol " (111) is not ruled out (cf. a ~ e t o n e ~ at the other extreme where the enol content is only 2.5 x Fuson Gorse and McKeever J .Anzer. Chem. SOC. 1940 62 3250. Branch and Calvin " The Theory of Organic Chemistry " Prentice-Hall Inc. Conant and Kistialiowsky Chem. Rev. 1937 20 181. Schwarzenbach and Wittwer Helv. Chim. Acta 1947 30 669 New York 1946. 27 28 QUARTERLY REVIEWS The iiitroductioii of additional enolic centres should assist the develop- iiient of ketonic character since the energy which accrues in the formation of multiple keto-groups would compensate for the loss of resonance stabilisa- tion. However a survey of the literature reveals no clear evidence that ketonic forms are present in solution even in the most favourable case of phloroglucinol. (The infrared spectra 5 establish that the solids are entirely enolic.) Hayashi 6 claimed that carbonyl bands in the Raman spectrum of resorcinol (in methanol solution) confirm the existence of the ketonic form but as the measurements were obtained by irradiating the resorcinol solution for periods of 17 hours upwards during which it became pale red this claim is open to doubt.The ultraviolet spectrum of resorcinol is that of a normal phenol.' Sonn and Winter 8 concluded from bromina- tion experiments that phloroglucinol existed in alcoholic solution in a tautomeric monoketo-form but evidence based solely on chemical reactions is inconclusive and supporting physical evidence is lacking. As judged by the infrared spectrum phloroglucinol is entirely enolic in dioxan sol~tion.~ The classical evidence for the tautomeric nature of phloroglucinol is the formation of a trioxinie,10 the structure of which has recently been con- firmed,g and if hydroxylamine is replaced by ammonia reaction under similar conditioiis (long storage in a closed vessel at room temperature) yields 3 5-dihydroxyaniline and 3 5-diaminophenol.ll As these experi- ments with phloroglucinol were done in a basic medium the presence of the mesomeric anion (V) may be inferred but the free existence of cyci'o- hexanetrione molecules is doubtful.The only true ketones obtained from phloroglucinol are polysubstituted derivatives in which one or more of the 5 Barnes Gore Liddel and Williams " Infrared Spectroscopy " Reinhold New York 1944 ; Randall Fowler Fuson and Dangl " Infrared Determination of Organic St,ructures " Van Nostrand New York 1949. 6 Hayashi Sci. Papers Inst. Phys.Chenz. Res. (Tokyo) 1933 21 69. 7 Friedel and Orchin " Ultraviolet Spectra of Aromatic Compounds " Wiley New * Sonii a i d Winter Ber. 2928 61 2303. 8 Farmer arid Thonison Chem. c u i d Irtd. 1956 86. lo Baeyer Ber. 1886 19 159. 11 Pollak Moncitah. 1893 14 419. York 1951. labile hydrogen atoms has been replaced. Thus methylation with methyl iodide and aqueous potassium hydroxide gives a mixture of O-Me and C-Me compounds leading ultimately to the hexamethyl ketone (VI). l2 Chlorina- tion of phloroglucinol also gives a hexachlorinated end-product (VI ; C1 in place of Me).13 .Similar gem-substitution occurs in resorcinol but in phenols which lack a vicinal carbon atom activated by two enolic centres alkylation is restricted to simple C-substitution by the Claisen procedure using reactive ally1 or benzyl halides.14 The mesomeric anion (VII) of resorcinol contains an q?-unsaturated carbonyl system the existence of which is neatly demonstrated by reduction with sodium amalgam to cycZo- hexane-1 3-dione (dihydroresorcinol).l5 Hydrogenation over nickel in alkaline solution is more efficient. l 6 In a search for further evidence on the tautomeric nature of polyhydric phenols Fuchs 17 studied the addition of sodium hydrogen sulphite to quinol resorcinol and phloroglucinol. After prolonged reaction adducts were obtained from quinol and resorcinol to which he assigned the struc- tures (VIII) and (IX) respectively.* (An adduct C6H60,,3NaHS0 from phloroglucinol was not obtained pure.) These structures imply that \/ HO/\SO,Na (VIII) (1x1 addition has occurred at the ethylenic double bond as well as a t the tauto- meric carbonyl groups which is plausible in the case of resorcinol but the structure (VIII) is doubtful.Apart from this work there are no other indications that quinol can react in a tautomeric form -f and the product obtained by Fuchs gave a transient blue ferric chloride colour suggesting the presence of a quinolsulplionic acid. Similar bisulphite compounds are of course intermediates in the Bucherer reaction which is of great technical importance in the naphthalene series.ls Prom a study of the reaction kinetics Cowdrey and Hinshelwood l9 suggest that bisulphite adds to il C=C and not to a C=O linkage. This seems to be a necessary postulate l2 Herzig and Erthal Monatsh. 1910 31 827. l3 Zincke and Kegel Ber. 1889 22 1467. l5 Merling ibid.1894 278 28. Claisen Annalen 1925 442 210. Fuchs and Elsner Ber. 1919 52 2281 ; 1920 53 886 ; Fuchs B e y . 1921 54 Reviewed by Drake '' Organic Reactions " Wiley New York 1942 Vol. I l6 Org. Xynth. Coll. Vol. 111 p. 278. 245. Chapt. 6. l8 Cowdrey and Hinshelwood J. 1946 1036 ; Cowdrey J. 1946 1041 1044. * The compounds were originally written with sulphite ester groups t A number of substituted quinols can be obtained in both onol and keto-form Tsutomerism is restricted to keto -+ enol conversion. > C(OH)*O*SO,Na. by independent methods. See p. 37. 30 QIJARTERLY REVIEWS in Bucherer reactions involving secondary amines and may well be true in other cases hut until we know more about the reaction of bisulphite with aromatic compounds in general addition products such as those of Fuchs are of limited value in the study of tautomerism.Bucherer and Schenkel 20 showed long ago that even pyridine forms an adduct with bisulphite of formula C5H5N,3NaHS0,,2H20 ; the nature of this com- pound is obscure but the pyridine molecule was profoundly modified as the adduct readily liberated ammonia on treatment with alkali. Many reactions of monohydric phenols involve the tautomeric form which becomes obvious if the labile hydrogen is replaced by an entering substituent thus Tautomerism is by no means confined t o the polyhydric phenols. enabling a ketonic product to be isolated. A well-known example is the Reimer-Tiemann reaction tjhe first step of which can be considered a special case of C-alkylation. The reaction is not impeded by small alkyl groups in the o- and p-positions so that e.g.o-cresol yields 21 the ketone (X) as well as the hydroxy-aldehyde (XI). The formation of a " blocked tautomer " in this way has been used by Woodward 22 as a method for the introduction of angular methyl groups. Thus the hydroxy-aldehyde formed in the reaction of 6-hydroxytetralin with chloroform in alkaline solution is accompanied by the dienone (XII) which may then be hydro- genated to it methyldecalol. Ar c N.0' Another old reaction in this category is the formation of indophenols by condensation of arylnitIroso-compoui-ids with pheiiols under basic con- dit,ions. This reaction is of practical importance in the preparat'ion of Zo Bucherer and Schenkel Ber. 1908 41 1346. 21 Auwers and Keil Ber. 1902 35 4201. 22 Woodward d . Awer. Chenz. SOC. 3940 62 1208.THOMSON PHENOL TA'ZJTOMERISM 31 oxazine dyes from p-nitroso-dialkylanilines ; with the latter basic condi- tions are obviously unsuitable and usually the phenol is condensed with the hydrochloride of the nitrosoamine in acetic acid. 23 More recently it has been shown that ketones may be formed by oxida- tion of monohydric phenols with lead tetra-acetate. 2 4 Here the essential intermediate is a mesomeric radical produced by dehydrogenation of a suitably substituted phenol e.g. (XIII). The final products depend upon the structure of the phenol and also on the solvent; dimerisation occurs in benzene solution but in acetic acid which assists the propagation of acetate radicals acetoxylation predominates. Phenol itself affords only a M e M e Me' h Me dimeric product (4 4'-dihydroxydiphenyl) but with increasing o p - substitution this reaction diminishes and with mesitol only acetoxylation occurs irrespective of solvent.Attack by acetate radicals a t substituted 0- and p-positions stabilises the dienone system 2 4-dimethylphenol yield- ing the ketones (XIV) and (XV). Similar products are obtained by oxidis- ing phenols with organic peroxides. 25 A related reaction is Bamberger's oxidation 26 of p-alkylated phenols to y-qixinols [e.g. (XVI) from mesitol] by using Caro's acid in the presence of magnesium carbonate where the substitution is presumably effected by *O*SO,- radical ions. Hydroxynaphthalenes (excluding 1 4-naphthaquinols) .-The tautomeric properties of the hydroxynaphthalenes are one of the many indications that naphthalene is less aromatic than benzene.The naphthols are in general much more reactive than phenol and share many reactions in common with resorcinol which is to be expected in view of the large resonance stabiliaation of the ketonic structures (XVII) as compared with (IV). There are however a few limitations due to bond fixat,ion as seen 2 3 Koechlin and Witt G. P. 15,915 ; Mohlau Ber. 1883 16 2843 ; 1892 25 1056. 2 4 Wessely et al. Monatd~ 1954 85 69 and previous papers ; Cavill Cole Gilham 25 Cosgrove and Waters J. 1951 388 ; Campbell and Coppinger J . Avzer. C'hem. 26 Bamberger Ber. 1903 36 2028. and McHugh J. 1954 2785. Soc. 1952 74 1469 ; Wessely and Schinzel Monatsh. 1953 $4 425 969. 32 QTTARTERLY REVTEWS in the failure of the naphthol (XVIII) to condense wit'h p-nitlrosodiniethyl- aniline.27 QJ-J* ~ &OH Me Numerous gem-substituted derivatives are known especially of /?- naphthol. A feature of these ketones stitnents arc eliminated to restore the is the ease with which blocking sub- more stable fully aromatic st,riicture. This tendency is demonstrated by the formation of 1 -nitro-2-naphthol by reaction of the ketone (XIX) in acetone with aqueous sodium hydroxide.25 In an extensive investigation of the halogenonaphthols Fries 29 and his associates showed that bromination of @-naphthol in acetic acid was a reversible reaction and for the gem-dibromo-ketone (XX) this results in rearrangement to 1 6-dibromo-2-naphthol when the ketone is treated with hydrogen bromide in acetic acid. Further debromination of the dibromo- naphthol (to 6-bromo-2-naphthol) is then possible.The selective removal of o-halogen substituents by acid reducing agents (commonly acid stannous chloride) is a useful reaction in the naphthol series. Nicolet 3O showed the reaction to be independent of the stannous chloride concentration and the first step is clearly the acid dehalogenation shown above. 27 Wedekind Ber. 1898 31 1675. 28 Fries Annalen 1912 389 316. 29 Fries and Schimmelschmidt ibid. 1930 484 245. 3u Nicolet J . Amer. Chem. SOC. 1927 49 1810. THOMSON PHENOL TAUTOMERISM 33 Ketones can frequently be obtained by reduction of naphthols under basic conditions the nearest parallel t o the sodium amalgam reduction of resorcinol being the formation of the diketone (XXI) by reduction of naphtharesorcinol with Raney nickel alloy and aqueous has not been adequately characterised.Reduction of 1 5- and 1 6-dihydroxynaphthalenes by the same method gives 5- and 6-hydroxytetralones respectively but a- and @-naphthol are unaffected. However reduction of /3-naphthol with (XXI) sodium and liquid ammonia in the presence of pentyl alcohol gives P-tetral~ne,~~ and the latter can also be obtained by hydrogenation of ,&naphthol over palladium-charcoal in the presence of a base.33 Hydroxythi0phens.-Since tautomerisation in phenol is restricted by resonance stabilisation it would be expected that enols which form part of less aromatic systems might in some cases exist in the ketonic form. This is not found in the naphthol series but is exemplified by the hydroxy- thiophens. 2-Hydroxythiophen 34 (XXII) is a weak acid it gives a red ferric chloride colour couples in alkaline solution with diazo-compounds FJOH CIA Or lT)=o )CH2-CH,*C0,H sodium hydroxide 31 although unfortunately the compound 0 o$.o HO--OH S S S S /-O (XXII) (XXIII) (XXIV) and forms an acetate benzoate and methyl ether; on the other hand in the tautomeric keto-form (XXIII) it yields a benzylidene derivative and readily undergoes hydrolytic fission (the keto-form is of course a thio- lactone).Its ultraviolet absorption (in aqueous solution) is in accord with the ketonic structure whilst the infrared spectrum of the liquid itself shows carbonyl and hydroxyl absorption and peaks corresponding to both ali- phatic and aromatic C-H bonds. These properties amply demonstrate the existence of a tautomeric equilibrium in marked contrast to phenol. It is interesting too that the enol derivatives (e.g.the acetate and the methyl ether) of 2-hydroxythiophen and of phenol show a close physical resemblance (b.p. odour) typical of thiophen and benzene analogues but the parent hydroxy-compounds themselves are physically dissimilar. 3-Hydroxy- dhiophen 34 is less stabie and has not been isolated in a pure state. 3 4- Dihydroxythiophen is known only as its dibenz0ate,~5 but the compound (XXIV) has been obtained and is as expected entirely en01ic.~~ Normally one carbonyl group of a cyclic o-diketone is enolised as in this form the repulsion of the cis-carbon-oxygen bonds is reduced 37 and in a thiophan 31 Papa Schwenk and Breiger J. Org. Chem. 1949 14 366. 32 Birch J. 1944 430. 33 Stork and Foreman J. Arner. Chem. Soc. 1946 68 2172. 3 4 Hurd and Kreutz ibid.1950 72 6543. 35Fager ibid. 1945 67 2217. 36 Karrer and Kehrer Helu. Chim. Acta 1944 27 142. 37 Dewar " The Electronic Theory of Organic Chemistry " Oxford 1949 p. 102. c 34 QUARTERLY REVIEWS ring greater stability is achieved by complete eiiolisation giving a fully conjugated system. Hydroxy€urans.-Much less is known about the hydroxyl compounds in this series. They appear to be predominantly ketonic in no way re- sembling phenols and with the exception of the 2-hydroxyfurans (XXV) [which exist as but-B-enolides e.g. (XXVI)] and the 2 5-dihydroxyfurans (i.e. succinic anhydrides) the majority are unstable. This agrees with the low resonance stabilisation of the furan ring. It is doubtful if the mono- hydroxyfurans theinselves have ever been obtained as such although both have been claimed.38 The substances were described as crystalline solids .~ ( )"O 0 (XXV) (XXVI) (XXVII) which darken and resinify spontaneously form dark solutions in aqueous alkali and do not reduce Tollens' reagent ; yet in spite of their instability both can be nitrated and then reduced to give seemingly stable amino- hydroxy-comp~unds.~~ 3-Hydroxyfuran forms an adduct with maleic anhydride but khere is no real evidence for the structure of the isomeric compound (prepared by fusion of 5-sulphofuran-2-carboxylic acid with sodium hydroxide in the presence of potassium chlorate) which appears t o be unlike its homologues. Cleavage of the acetate of 2-hydroxyfuran (XXV) (obtained by pyrolysis of 2 5-diacetoxy-2 5-dihydrofuran) yields crotono- lactone [double-bond isomer of (XXVI)].This occurs to some extent during the preparation 40 of 2-acetoxyfuran and again on its treatment with chlorine or bromine (at - 5" to - lo") halogenocrotonolactones result.41 The free existence of the enol (XXV) therefore seems very unlikely. Most known 3-hydroxyfurans are highly substituted and appear t o have the properties of aliphatic keto-enol systems but physical data are lacking. 3 4-Dihydroxyfuran has not been prepared but the compound (XXVII) is known 42 and exists essentially in the enol form. In addition to the normal enolisation of cyclic o-diketones this compound which can be regarded as two linked p-keto-ester systems is stabilised by chelation. Hydroxythionaphthens and Hydroxybenzo€urans.-As we have seen fusion of a second benzene ring on to phenol leads to increased ketonic character and the effect on the hydroxythiophens and hydroxyfurans is the same the benzo-analogues being best described as thionaphthenones and benzofuranones (coumaranones and isocoumaranones) .Both groups show the characteristic chemical properties of keto- and enol forms with the exception of the isocoumaranones which behave as lac tone^.^^^ 44 They 38 Hodgson and Davies J . 1939 806. 39 Idem J . 1939 1013. 40 Clauson-Kaas and Elming Acta Chem. Scand. 1952 8 560. 41 Elmicg and C lauson-Kaas ibid. p. 565. 4 2 Hoehn Iowa State Coll. J . Xci. 1936 11 66. 43 Hartough and Meisel " Compounds with Condensed Thiophen Rings " Inter- 4 4 Elderfield " Heterocyclic Compounds " Wiley New York 1951 Vol. 11. science New York 1954. THOMSON PHENOL TAUTOMERISM 35 probably all exist in the keto-form in the solid state ; the benzofuranones remain in the keto-form in solution but there is no reliable information concerning the thionaphthenones which may like the hydroxythiophens form an equilibrium in solution.Bromine estimations showed coumar- anone 45 to be almost entirely ketonic and thionaphthen-3-one 46 to contain 5% of the enol form in solution but again this is chemical evidence only. Marschalk *' apparently obtained thionaphthen-2-one in two modifications. Distillation of a sample of m.p. 44-45' gave a product of m.p. 33-34' and in one experiment he was able to convert this back into the higher- melting form by dissolution in aqueous sodium hydroxide and acidification. This suggesta that the compound m.p. 44-45" is the enol and the com- pound m.p.33-34' is the keto-form but apparently it is only the latter which gives a ferric chloride colour (blue). There is evidently some con- fusion here but it is just possible that Marschalk did isolate two tautomeric forms although he did not make this claim himself. If so this is the simplest aromatic enol known in both forms. isocoumaranone is known in two crystal modifications but these are not tautomeric forms.48 1 rl-Naphthaquinols.-In the naphthalene series when two hydroxyl groups are present in the same ring it becomes possible to isolate the tauto- meric diketo-form provided that both carbonyl groups are conjugated with the second benzene ring as in (XXIX). [The gain in bond energy as a result of ketonisation (m. 2 x 18 kcal./mole) is approximately equal to the loss of resonance energy of one benzene ring.] Both the dienol (XXVIII) and the diketone (XXIX) are stable compounds under normal 6 OH 0 03 0 (XXVIII) (XXIX) conditions and can be crystallised unchanged.A spectroscopic examina- tion 49 has shown that the diketone exists as such both in the solid state and in solution and there is no indication of the existence of an equilibrium a t ordinary temperatures. However in the estimation of naphthaquinol by ceric sulphate titration Braude et aL50 found that the titre gradually decreased to about 75% of its original value when the quinol was heated in phenetole at 131' tautomerisation would account for this but other factors may be concerned as the proportion of the keto-form seems rather high. The diketone * (XXIX) was first obtained by Madinaveitia and 45 Auwers and Auffenberg Ber.1919 52 92. 46 Auwers and Theis Ber. 1920 53 2285. 47 Marschalk J. prakt. Chem. 1913 88 227. 48 Stoermer Annalen 1900 313 79. 49Thomson J. 1950 1737. 5OBraude Jackman and Linstead J. 1954 3548. * Formulated as a monoketone by Olay Rev. Acad. Cienc. Madrid 1935 82 384. 36 QUARTERLY REVIEWS Olay 51 by fusion of the dienol (XXVIII) at ca. 210" in a vacuum followed by rapid cooling to " freeze the equilibrium " ; the diketone (2 3-dihydro- naphthaquinone) was then separated by chloroform extraction. In this way about 10% of the dienol can be isolated in the tautomeric form.49 All the simple 2 3-dihydronaphthaquinones have been obtained by Olay's procedure but the method is limited as some quinols decompose on being heated. A possible alternative is the catalytic method employed by Grob et u Z .~ ~ in the isomerisation of the enol (XXX) to the ketone (XXXI). OH 0 HN-CH In this case direct heating (at temperatures below the decomposition point) effected no rearrangement but by heating the phenol with palladium- charcoal in xylene-tetralin the ketone was obtained in 80% yield. Although keto-enol changes (e.g. carvone + carvacrol 53) and dienone -+ phenol rearrangements 54 have been brought about by heating with palladium- charcoal this enol + keto conversion appears to be unique. Rearrange- ment of the naphthalene system (in XXX) to the dihydroindole system (in XXXI) (AH ca. 4.5 kcal./mole) is possibly more favourable energetically than the conversion of the naphthalene system (in XXVIII) into the benzene system (in XXIX) but nevertheless this technique merits investigation.The reverse keto -+ enol change (XXIX -+ XXVIII) is readily effected by dissolution of the diketone in cold alkali and in practice enolisation occurs frequently under reaction conditions. Certain reactions of naphthaquinols proceed via the diketo-forms although this does not establish the existence of a tautomeric equilibrium. A number of substituents including halogen NHPh SR S02R SO,H and (in some cases) OH can be removed from positions 2 and 3 of 1 4-naphthaquinones by reduction with acid stannous chloride the first step being a rapid reduc- tion of the quinone to the quinol (XXXIII).55 A few o-substituents can also be removed from naphthols of the type (XXXII ; R = halogen SO,H and probably SR *) under the same conditions but the others are stable unless a second hydroxyl group is present as in (XXXIII).It is likely therefore that the reaction proceeds by tautomerisation to the 51 Madinaveitia and Olay Anal. Pis. Quim. 1933 31 134. 5 2 Grob and Voltz Helv. Chim. Acta 1950 33 1796 ; Grob and Hofer ibid. 1952 53 Linstead Michaelis and Thomas J. 1940 1139. 5 4 Homing J. Org. Chem. 1945,10 263 ; Leonard and Berry J . Amer. Chem. SOC. 5 5 Bruce and Thomson J. 1954 1428. * l-p-Tolylthio-2-naphthol can be reduced to j5-naphthol with stannous chloride. 35 2095. 1953 75 4989. THOMSON PHENOL TAUTOMERISM 37 diketone (XXXIV ; R = OH NHPh or S0,R) followed by acid-catalysed elimination of the substituent R as shown. .1 (XXXII) (XXXIII) (XXXIV) (XXVIII) Another reaction which involves the ketonic forms of naphthaquinols is the formation.of tetralins by Clemmensen reduction. Tetralin can also be obtained less readily by Clemmensen reduction of cc- and ,&naphthol and Madinaveitia 56 considered the rate of reduction to be proportional to the ease of tautomerisation. The diketone (XXIX) forms a bis-p-nitro- phenylhydrazone attempts to obtain this by reaction of the dienol (XXVIII) with p-nitrophenylhydrazine produce only 4-p-nitrophenylazo- l-naphthol the initial hydrazone formed by condensation at one enolic centre being oxidised in the tautomeric hydrazo-form. A number of naphthaquinols are known in both keto- and enol forms which are not interconvertible 2 3-dichloronaphthaquinol (XXXV) and 1 4-naphthaquinone dichloride (XXXVI) are typical. Enol -+ keto con- version cannot be brought about by fusion as the dienol decomposes a t high temperatures and the reverse change is restricted by the tendency of the diketone to form a quinone by elimination of hydrochloric acid.This is facilitated by both acids and bases so that in ketones of type (XXXV) (XXXVI) (XXXVII) (XXXVIII) (XXXIX) (XXXVI) enolisation and elimination reactions which proceed via similar ionic intermediates are in competition and the result depends upon the structure of the diketone and sometimes on the catalyst. I n naphthalene compounds elimination predominates but concurrent enolisation and elimination has been observed in a few instances whereas the corresponding benzenoid compounds show a greater tendency to rearrange to aromatic structures as shown by the natural product gliorosein (XXXVIII or XXXIX) which rapidly enolises in a basic medium.57 Benzoquinone dichloride slowly forms the corresponding dienol diacetate when warmed with acetic anhydride in the presence of sulphuric acid but if the catalyst is changed to toluene-p-sulphonic acid the elimination proceeds more 66 Madinaveitia Anal. PLs. Quim. 1934 32 1100. 57 Vischer J. 1953 815. 38 QUARTERLY REVIEWS rapidly and the product (after re-addition of the hydrochloric acid) is 2 5-dichloroquinol diacetate. Under the same conditions the dichloride (XXXVI) gives only 2-chloro-1 4-naphthaquinone. Again when benzo- quinone dichloride is suspended in acid stannous chloride at 0" both elimination and enolisation occur and a mixture of 2-chloro- and 2 3- dichloro-quinol is obtained. 58 Amongst related naphthalene compounds Russian workers 59 have shown that 2 3-epoxynaphthaquinone in hot aqueous solution gives via the glycol (XXXVII) a mixture of 2-hydroxy- 1 4-naphthaquinone (by elimination) and 2 3-dihydroxy-1 4-naphtha- quinone (by enolisation and aerial oxidation) and the latter is also obtained by aeration of the diacetate of (XXXVII) in alcoholic potassium hydroxide.6O Blocked tautomers are also found in this group but whereas they are obtained from monohydric phenols by substitution reactions here they are usually formed by quinone addition reactions e.g. addition of sodium hydrogen sulphite to 2-methyl-1 4-naphthaquinone gives both the quinol (XL) and the diketone (XLI).61 The compound (XLII) obtained by addition of hypochlorous acid to 3-hydroxy-2-methyl- 1 4-naphthaquinone (XL) (XW (XLII) (XLIII) is remarkable e 2 in that it does not revert to a quinone when heated in vacuo but loses water to form the triketone (XLIII).I n one instance a non- enolisable ketone has been obtained in the diphenyl series by a quinone addition reaction addition of hydrochloric acid to the diquinone (XLIV) 0 0 0 0 (XLIV) (XLV) gives the adduct (XLV) (and not the isomeric diquinol) which in spite of the extended conjugated system in the compound is very unstable and on attempted crystallisation dissociates into the original components.63 The introduction of hydroxyl groups at the peri-positions of 2 &&hydro- 58 Dimroth Eber and Wehr Annalen 1925 446 132. 59 Shchukina Khokhlov and Shemyaliin J . Gen. Chern. (U.S.S.R.) 1951 21 908. 6o Shchukina Vinogradova and Shemyakin ibid.p. 1661. Cormack Moore and Balis J. Arne?. Chem. SOC. 1950 72 844 ; Moore and Washbum ibid. 1955 7'7 6384. 6 2 Shvetsov and Shemyakin J . Cew. Chem. (U.S.R.R.) 1949 19 480. 63 Lindberg A d a Chem. Scand. 1951 5 885 ; Erdtrnan Proc. Roy. SOC. 1933 A 143 191. THOMSON PHENOL TAUTOMERISM 39 naphthaquinone as in F-hydrojuglone (XLVII ; R = H) and p-hydro- naphthazarin (XLVII ; R = OH) stabilises the diketo-system,* in part R OH HO OH 0 ry) )I Ho 0 (XLVI) (XLVII) by strong hydrogen bonding and lowers the activation energy for the enol-+ keto change so that these ketones can be obtained under much less vigorous conditions. Thus when a solution of a-hydrojuglone (XLVI ; R = H) in dilute hydrochloric acid (containing a little stannous chloride to prevent oxidation) is warmed it becomes yellow and the keto-form can be isolated by chloroform extraction.If the colourless solution is then set aside it slowly becomes yellow again as the equilibrium is restored.? The tetrahydroxynaphthalene (XLVI ; R = OH) behaves in the same way but as this compound is very susceptible to oxidation p-hydronaphthazarin is normally made by reduction of naphthazarin (5 8-dihydroxy-1 4- naphthaquinone) in hot acid stannous chloride solution from which it crystallises on cooling (90% yield 64). Elimination of substituents from naphthaquinols proceeds much more readily when a peri-hydroxyl group is present and a new feature arises in the case of substituted a-hydronaphth- azarins.65 66 The compound (XLIX) can tautomerise in two ways the reaction being controlled by the substituent.It can be seen that tauto- merisation at one enolic centre will be opposed by the + T effect of the group R and consequently rearrangement will occur preferentially in the other ring. Hence in the reduction of naphthazarins where R = OH or NHPh ketones of type (XLVIII) are formed but where R = SO,R the alternative (L) is produced and the substituent is then eliminated to give 6 4 Wheeler and Edwards J . Amer. Chem. SOC. 1916 38 387. 6 5 Bruce and Thomson J. 1952 2759. 66 Idem J. 1955 1089. * The 7-methyl derivative of (XLVII ; R = H) occurs in Nature (Cooke Dowd and Webb Nature 1952 169 974; Cooke and Dowd Austral. J . Sci. Res. 1952 5 A 760 ; Austral. J . Chem. 1953 6 53). -f Olay (Rev. Acad. Cienc. Madrid 1935 32 384) found (by Meyer estimation) that 2-methyl-p-hydrojuglone was 43 yo ketonic a t equilibrium and 1 4-naphthaquinol 10% ketonic.Both figures are probably too high but they illustrate the difference between the two compounds. 40 QUARTERLY REVIEWS @-hydronaphthazarin as the final product. Weaker + 111 groups (SR and halogen) are also eliminated but this of course occurs in simple naphthols. Hydroxyanthracenes.-In the anthracene series the general pattern is very similar to that seen in the naphthalene compounds the hydroxyl derivatives showing a greater tendency to exist in the tautomeric keto- form. Of the monohydroxy-compounds a- and P-anthranol are very like a- and @-naphthol but in 9-anthranol (LI ; R = H) we have the simplest monohydroxy-aromatic compound (excluding 2-hydroxythionaphthen) which is stable in both tautomeric forms.The keto-form (LII) (cf. benzophenone) is the more stable which implies that the resonance energy associated with the central " benzene " ring is < 18 kcal./mole in accord with the absence & R OH QpJJ R 0 Ph 0-OH of aromatic properties. I n his classical work Meyer 67 showed that both forms tautomerise slowly in solution (in the absence of catalysts) the equilibrium attained being always predominantly ketonic. On slow cool- ing a melt crystallises as anthrone but after rapid cooling some anthranol is also present. The chemical properties of the two forms are quite distinct a t ordinary temperatures the keto-form being comparatively unreactive in the absence of enolising catalysts. It was observed by Julian et u Z . ~ ~ that 10-alkyl(and -aryl)-anthranols (LI) readily took up atmospheric oxygen to form peroxides considered to have the transannular structure (LIII) as they could be reduced catalytically to the corresponding 10-alkyl- & Ph 0 oxanthranols and on pyrolysis they yielded anthraquinone and the corre- sponding alcohol.The transannular structure was disputed by Dufraisse et and by a detailed study of the oxidation product of 9-phenylanthranol 68 Julian and Cole J . Amer. Chem. SOC. 1935 57 1607 ; Julian Cole and Diemer 69 Dufraisse Etienne and Rigaudy Bull. Soc. chim. (France) 1948 804. Meyer Annalen 1911 379 37. ibid. 1945 67 1721. THOMSON PHENOL TAUTOMERISM 41 they established the keto-hydroperoxide structure (LIV). These anthranols therefore fall into line with a number of other aryl-substituted enols which form hydro peroxide^.^^ Of particular interest is the formation of the keto- hydroperoxide (LIV) by aeration of an alkaline solution of the anthranol which involves oxidation of the mesomeric anion (LV) as shown.1 4-Dihydroxy- anthracene is converted into the diketo-form (LVI; R = H) by fusion (50% yield),65 and the diphenyl derivative (LVI ; R = Ph) is formed merely by treating a solution of 1 4-dihydroxy-9 10-diphenylanthracene with hydrochloric acid.71 As in the naphthalene series very stable diketones are formed when peri-hydroxyl groups are present. ZeucoQuinizarin (LVI ; R = OH) is easily obtained by reduction of quinizarin in hot acid solution 7 2 it enolises in alkaline solution but the tetrahydroxyanthracene obtained on acidification rearranges to the more stable diketone during crystallisation.The structure of the compound (LVI; R = OH) is established by its synthesis from naphthaquinol and succinic anhydride 73 and by its infrared specfrum,7* but the structures of the diacetate and dimethyl ether are uncertain. By treatment of Zeucoquinizarin with acetyl chloride in cold pyridine the diacetate can be formed without enolisation of the carbonyl Relatively little is known of the dihydroxyanthracenes. ( L W (LVII) groups (this is verified by acetylation of /I-hydronaphthazarin and /I-hydro- juglone in the same way). The identical diacetate can also be obtained by reduction of quinizarin diacetate in the cold with zinc and acetic acid followed by warming of the solution of 1 4-diacetoxyanthraquinol in an inert atmosphere. Zahn and Ochwat 73 proposed structure (LVII ; R = Ac) for this compound which implies that Zeucoquinizarin reacts in the tautomeric form (LVII ; R = H) in the first method of preparation and a rather improbable tautomerisation occurs in the second.The alterna- tive structure (LVI ; If this is correct migration of the acetyl groups to peri-positions must have occurred in the course of the synthesis from quinizarin diacetate; there are several pre- cedents for this similar migration of acyl groups has been observed under various conditions in glyceride^,'^ o-dihydroxyanthraq~inones~76 and 'O Criegee in Houben-Weyl " Methoden der Organischen Chemie " Georg Thiem Verlag Stuttgart 4th Edn. 1952 Vol. 8 p. 25. 71 Bichet Ann. Chim. (France) 1952 7 235. 7 2 Meyer and Sander Annulen 1920 420 113. 73 Zahn and Ochwat ibid.1928 462 72. 7 4 Flett J. 1948 1441. 75 Daubert and King J. Amer. Chem. Soc. 1938 60 3003. '13 Kubota and Perkin J. 1925,127,1889 ; Perkin and Storey J. 1928,229 ; Perkin R = OAc) is more plausible. and Storey J. 1929 1399. 42 QUARTERLY REVIEWS in one instance in a peri-dihydr~xynaphthalene.~~ ZeucoQuinizarin dimethyl ether presents a similar problem it is formulated.73 as (LVII ; R = Me) but it is not clear how this arises by reduction of quinizarin dimethyl ether. In general #I-substituents (C1 OH S03H NHPh) 7 2 7 78 are very readily eliminated on reduction of quinizarins. There is however one case (purpurin) in which reduction (in the absence of strong acids) leads to retention of a P-substituent the product (LVIII) on subsequent treat- ment with strong acid or alkali is smoothly converted into quinizarin and no doubt analogues of (LVIII) could be obtained by reduction in the same way.0 HO II NH HO 11 (LVIII) (LIW It is relevant here that certain aminoanthracenes have tautomeric properties not shown by the aminobenzenes and aminonaphthalenes. 9-Anthramine 79 is not unlike anthranol although it is known only in the amino-form,80 but imino-forms can be isolated if peri-hydroxyl groups are also present. The simplest example is Zeuco- 1 4-dianiinoanthraquinone (LIX). This can be obtained by hydrogenation of the diaminoquinone in the cold and then heating in an inert atm~sphere.~~ It is normally made on the large scale by heating Zeucoquinizarin with ammonia and the ready introduction of basic groups by direct condensation of primary amines with Zeucoquinizarin makes the latter a key intermediate in the manufacture (LX) (LX) of many aniinoanthraquinones.As the imino-groups are rather easily hydrolysed conversion of the Zeuco-compounds into the quinones by aeration of their alkaline solutions must be avoided and the usual procedure is to heat the Zeuco-compound in nitrobenzene preferably with an enolising catalyst. Again elimination of P-substituents can occur during the forma- tion of the Zeuco-amino-compounds and this extends also to heterocyclic derivatives. Reduction of the bromoanthrapyrimidine (LX) with acid 77 Hayes and Thomson J. 1955 904. 78 Marschalk Bull. SOC. chim. (France) 1927 41 943 ; G.P. 95,271. 79 Kauffler and Suchannek Ber. 1907 40 518 ; Meyer and Schlosser Ber. 1013 46 29. Craig and Short J. 1945 419. THOMSON PHENOL TAUTOMERISM 43 stannous chloride or sodium dithionite gives a bromine-free Zeuco-compound,*l presumably (LXI) and halogen is similarly lost in the reduction 82 of the phthaloylacridone (LXII) .In this case the stable Zeuco-compound formed must be (LXIII) or (LXIV). Hydro-1 Derivatives of More Complex Hydrocarbons.-In the higher polycyclic compounds keto-forms become increasingly stable. Compounds with hydroxyl groups located in a terminal ring are similar to cc- and p-anthranol but when an enolic centre occurs a t a meso-position in a linear hydrocarbon usually only the keto-form is known although tautomerism similar to the anthrone-anthranol system may occur in angular hydro- carbons. This distinction arises because the linear enol structures include more quinonoid rings and hence are less stable than the angular enol structures.* The simplest angular enol is 9-phenanthrol the keto-form of which is unknown (contrast anthranol) whereas the ketones (LXV) and (LXVI) are insoluble in boiling aqueous sodium hydroxide and their enols have not been isolated.On the other hand both tautomeric forms of the benzanthrone (LXVII) exist and can be crystallised unchanged from benzene although the enol isomerises fairly rapidly in acetone.83 0 (LXVII) Reports on Dyestuffs Intermediates etc. Microfilm P.B. 70,332 Reel lc Frames B.P. 587,006. 2 16-220. 83 Fieser and Hershberg J . Amer. Ghem. SOC. 1937 59 1028. * The para-localisation energies of a number of polycyclic hydrocarbons have been calculated by Brown ( J . 1950 691) and are in accord with the stability of the keto- forms.

ISSN:0009-2681    

DOI:10.1039/QR9561000027

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

By D. H. R. BARTON D.Sc. F.R.S. (THE UNIVERSITY GLASGOW) and R. C. COOKSON M.A. PH.D. (BIRRBECK COLLEGE LONDON W.C.1) Introduction.-The word “ conformation ” first used by W. N. Haworth,l can be defined in several ways. One of the most general definitions is as follows the conformations of a molecule are those arrangements in space of the atoms of the molecule which are not superposable upon each other. Such a definition includes arrangements of atoms in which angle strain has been introduced though this is not normally of great importance. Thus a’lmost all molecules will have theoretically an infinite number of con- formations. It is fortunate that the complexities which might arise from such considerations are minimised by the fact that in general only a few of the possible conformations are energetically preferred.I n the German language the word “ constellation ” of more recent origin,2 is used in the same sense,3 and in the literature of chemical physics the term “rotational isomer ”. For the vast majority of molecules the energy barriers between different conformations are too low to allow the separation of pure conformational isomers a t normal temperatures in the liquid or vapour phase but sufficient intramolecular congestion can raise the barrier enough to make such a separation possible experimentally. Familiar examples are provided by resolvable diphenyl derivative^.^ Tri-o-thymotide has recently been shown to undergo spontaneous resolution into conformational enantiomorphs of low optical ~tability.~ The Preferred Conformations of Some Simple Hydrocarbons In the last two decades many of the powerhl methods of modern chemical physics including electron and X-ray diffraction infrared Raman and microwave spectroscopy and statistical mechanics have been used to demonstrate the existence and nature of preferred conformations in simple W.N. Haworth “ The Constitution of Sugars ” E. Arnold and Co. London 1929 p. 90. Ebel “ Stereochemie ” Ed. Freudenberg Deuticke 1932 p. 825. Prelog J . 1950 420. Turner and Harris “ Organic Chemistry ” Longmans Green and Co. pp. 605 et seq. ; Shriner Adams and Marvel “ Organic Chemistry ” ed. Gilman 2nd edn. Wiley 1943 Vol. I pp. 343 et seq. 5 Baker Gilbert and Ollis J. 1952 1443 ; Powell Nature 1952,170,155 ; Newman and Powell J . 1952 3747. For examples of stable conformational isomers in other ring systems see inter al.Bentley and Robinson J . 1952 947 ; Bell ibid. p. 1527 ; Wittig and Zimmermann Chem. Ber. 1953 86 629 ; Hall and Turner J . 1955 1242 and references given there. 44 BARTON AND COOKSON CONFORMATIONAL ANALYSIS 45 molecules. For more detailed summaries of this background the reader is referred to the reviews by McCoubrey and Ubbelohde and by Mizushima.' Ethane.-Fig. 1 illustrates the energy of a molecule of ethane as a function of conformation in this case depending only on the relative orienta- tion of the two methyl groups. The molecule has the maximum energy FIGS. 1 and 2 I H..'- HyH "'" H (HI (1) 0" ( 2 ) 60" Views down the C-C bond of ethane when the set of three hydrogen atoms attached to the near carbon atom eclipse those attached to the far carbon atom when viewed down the C-C bond (1).The energy is at a minimum when each C-H bond bisects the angle formed by two C-H bonds of the other carbon atom (2). The barrier to rotation is estimated n-Butane.-The conformation of n-butane with lowest energy is the fully transoid staggered conformation (3). The two other minima in the potential as about 2.8 kcal. per mole. r! M C M C Fully eclipsed Skew or gauche energy curve (Pig. 2) correspond gauche conformations (4). It has (Me) (5) (4) Me to the Me Me (H) Eclipsed Staggered two enantiomorphous skew or (6) (3) been calculatedg that the energies of McCoubrey and Ubbelohde Quart. Rev. 1951 5 364. 7 Mizushima " The Structure of Molecules and Internal Rotation ' I Academic * Inter al. Kistiakowsky Lacher and Stitt J. Chem. Phys. 1939 7 289 ; Pitzer Pitzer Discuss.Furuday SOC. 1951 10 66 and references there cited. Press 1954. Chenz. Rev. 1940 27 39 ; McCoubrey and Ubbelohde ref. 6. 46 QUARTERLY REVIEWS the fully eclipsed (5) eclipsed (6) and skew (4) conformations are about 3.6 2.9 and 0.8 kcal. per mole respectively greater than that of the staggered conformation (3). The last value is in excellent agreement with the tempera- ture-dependence of the appropriate Raman lines. lo I n aliphatic compounds the most stable conformation is usually that in which the substituents on adjacent tetrahedral carbon atoms adopt the fully staggered conformation [as (3)j the two largest groups (or in qualification the two most strongly repelling dipoles) taking up the 180" arrangement. Eclipsed conformations are always avoided wherever possible.cyc1oHexane.-The conclusion by Sachse 11 and by Mohr 12 that cyclo- hexane can exist in only two conformations free from angle-strain has long been accepted by chemists. That the chair conformation (7) is more stable than the boat (8) is attested by much physical evidence including infrared l3 and Raman l4 spectroscopy and electron diffraction,15 and by thermo- dynamic considerations.16 17 Derivatives of cyclohexane always tend to take up the chair conformation whenever this is stereochemically possible (see detailed discussion later). The Decalins.-If boat conformations are accepted as less stable than chair conformations then both cis- and trans-decalin have unique preferred eonformations illustrated in (9) and (10) respectively. Hassel and his collaborators 1 5 l 8 9 l9 have shown by electron diffraction that in the vapour phase molecules of cis-decalin do indeed exist in the two-chair conformation (9) rather than in the long unchallenged two-boat conforma- lo Szasz Sheppard and Rank J .Chem. Phys. 1948 16 704. 11Sachse Ber. 1890 23 1363; 2. phys. Chem. 1892 10 203. 12 Mohr J. prakt. Chem. 1918 98 315. 13 Rasmussen J. Chem. Phys. 1943 11 249 and papers there cited. 1 4 Kohlrausch and Wittek 2. phys. Chem. 1941 48 B 177 ; Gerding Smit and l5 Hassel and Viervoll Acta Chena. Xcand. 1947 1 149 and papers there cited. Is Aston Schumann Fink and Doty J . Anzer. Chem. SOC. 1941 63 2029. 1 7 Beckett Pitzer and Spitzer ibid. 1947 69 2488. 18 Hassel Tidsskr. Kjenzi Bergvesen Met. 1943 3 91. 19 Bastiansen and Hassel ibid. 1946 6 70 ; Nature 1946 157 765.W'estrik Rec. Trav. chirn. 1942 61 561. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 47 tion (11).12 the conformation (9) for subst,ituted cis-decalins.20 2 1 y 22 23 Much chemical evidence has also been adduced in favour of Reasons for the Existence of Preferred Conformations The interaction energy between two non-bonded atoms is weakly attrac- tive up to distances of approximat,ely the sum of the van der Waals radii of the atoms concerned. At distances less than this the interaction energy soon becomes repulsive and a high exponential function of interatomic distance. 24 In the fuily staggered conformation of a straight-chain aliphatic compound the distances between non-bonded atoms approximate quite closely to the sum of the van der Waals radii. Any rotation about a C-C bond (see above) brings the atoms attached to the main chain closer together and calls into play destabilising (repulsive) forces.In general it can be said that the energy of a particular conformation of a molecule depends on the presence or in specially formed cases (see above) the absence ofrepulsive interactions between non-bonded atoms. To a certain extent these repulsive interactions can be modified by bond-angle deformation. Modification by bond extension is not important because of the relatively large energy requirements for such a process. In the absence of direct physical evidence the most stable conformation of a molecule may then be selected by the principle of minimisation of (repulsive) non-bonded interactions. We would emphasise however that simple considerations of this kind are subject to qualification when other intramolecular forces due to hydrogen bonding or electrostatic effects (dipole or integral change interactions) come into play (see p.81). Consequences of the Existence of Preferred Conformations In the last five years the importance of the existence of preferred con- formations in organic molecules has become widely recognissd under the title of " conformational analysis ',. The present Review sets out to sum- marise with the aid of the appropriate background the more important aspects of the subject from the point of view of the organic chemist.25 The fundamental tenet of conformational analysis is that the physical and chemical properties of a molecule can be related to its preferred con- formation. The more important applications of this concept may be classified as follows (i) Phenomena that are a direct consequence of a preferred conforma- tion (a) Physical properties such as specific absorption bands in the 2o Barton and Miller J .Amer. Chem. SOC. 1950 72 1066. 21 Barton Experientia 1950 6 316 ; J. 1953 1027. 2 2 Beyler and Sarett J . Anzer. Chem. SOC. 1952 74 1406. 23 W. G. Dauben Tweit and Mannerskantz ibid. 1954 76 4420. 2 4 See for example C. K. Ingold " Structure and Mechanism in Organic Chemistry " Cornell Univ. Press Ithaca New York 1953 Chapter I1 ; Hughes Quart. Rev. 1948 2 107. 2 5 For more fully documented accaunts of certain phases of the problems see Orloff Chem. Reu. 1954 54 347 and Klyne in " Progress in Stereochemistry " Butterworths London 1954 Vol. I Chapter 11. 48 QUARTERLY REVIEWS ultraviolet or infrared region.( b ) Chemical effects dominated by steric com- pression such as ester hydrolysis (reaction rates) and relative stabilities of epimers (equilibria). (ii) Phenomena due to the interplay of conformational preferences and the geometrical requirements of the transition states of reactions (usually colline- arity or coplanarity of participating centres). Some Illustrations from Aliphatic Chemistry The Relative Stabilities of erythro- and threo-Isomers.-Let us consider the non-bonded interactions in an erythro-compound (12) as compared with those in its threo-diastereoisomer (13). In these and later formulz S M and L denote substituents attached to the same carbon atom which are \ c I I S-t-M I S-F-M I S-C-M i M-C-S I I i SYM I My k M y 5 ys y ... . I . .- .- -. ,. .. * -. .. - . ' S M**"*' "= "S s. "L L,'" ''.'M M/-*' *.. L L L L (14) (15) (16) (17) respectively smallest medium and largest in effective size. Each substituent will repel the two adjacent substituents on the next carbon atom; the sum of these repulsive energies for the stable staggered conformation (14) of the erythro-compound and for the three more stable conformations (15) (16) and (17) of the threo-isomer may be represented as follows (14) 2(L S) + 2(L M) + 2(M S) (15) 2(L M) + 2(L S) + S S + M M (16) 2(L:M) + 2(M:S) + L L + S S (17) 2(L S) + 2(M S) + L L + M M The differences in compression energy between the stable conformation of the erythro-compound and the three more stable conformations of the threo-compound are then (14) - (15) = 2(M S) - (M M + S S) (14) - (16) = 2(L (14) - (17) = 2(L M) - ( L L + M M) S) - ( L L + S S ) Since repulsion is a high exponential function of interatomic distance (M M) > (M S) (L L) > (L S) and (L L) > (L M) so that in each case (14) - (15) (14) - (16) and (14) - (17) should be a negative quantity.BARTON AND COOKSON CONFORMATIONAL ANALYSIS 49 In general then for diastereoisomeric pairs of non-polar compounds in which differences in free energy are mainly due to differences in compression energy the erythro-isomer should be more stable than the threo-isomer. The relative stabilities have been established of many pairs of meso- and racemic and of erythro- and threo-isomers either by direct equilibration or by introduction of the second asymmetric carbon centre in a reaction that is known to result (from its mechanism) in a mixture approximating to the equilibrium mixture.In many cases the expected stability order is found experimentally. For example equilibration 26 of the racemic succinic acids (18 ; R = R’ = alkyl aryl halogen or OH) gives the more stable meso-acids (19 ; R = R’). Similarly the threo-acids (18 ; R + R’ = alkyl aryl halogen or OH) isomerise to the erythro-acids (19 ; R + R’). Racemic stilbene dichloride 27 and dibromide 28 isomerise to equilibrium mixtures composed chiefly of the meso-dihalides. In many examples of this kind however the situation is complicated by dipole interactions which also favour the isomers which should be more stable from the conformational point of view. 502H 702H I I Cram and Abd Elhafez 29 have tabulated the products of reduction of ketones (20 ; R = aryl R’ = OH or NH,) and of oximes (21 ; R = aryl R’ = OH or NH,) with sodium and alcohol or with sodium amalgam reagents that are accepted as producing the more stable e~imer.~O The erythro(or meso)-isomer (22 and 23) is always formed in greater amount.p R R p I I I I I I I I R’-C-H R’-C-H R’-~-H R’-~-H l - I I C z N O H H2N-$-H I - I C-0 HO-C-H R I ! R k R (20) (22) (21) (23) 26 Fourteen examples are tabulated by Wagner-Jauregg (quoting Wolf) in “ Stereo- chemie ” ed. Freudenberg Deuticke 1932 p. 873 ; see also Linstead and Whalley J. 1954 3722. 27 Zincke Annalen 1879; 198 135. 28 Wislicenus and Seeler Ber. 1895 28 2693 ; Buckles Steinmetz and Wheeler J. Arner. Chem. SOC. 1950 72 2496 ; Abd Elhafez and Cram ibid.1953 75 339. 20 Idem ibid. 1952 74 5828. 30 Barton and Robinson J. 1954 3045. D 50 QUARTERLY REVIEWS Rates of Elimination from erythro- and threo-Compounds.-In the debromination of 1 2-dibromides by iodide ion symbolised below,31 the meso-dibromide (24) always 32 reacts more rapidly than the DL-isomer (25). Since the transition state of an E2 reaction such as this requires that the four centres concerned in the reaction should be coplanarY2OJ 3 3 ~ 34 with the two C-Br bonds antiparallel the conformation required for the meso- dibromide is (24) that for the m-dibromide (25). In the transition state M i truns-But - 2 -ene M cis- But - 2 -ene arising from (24) each methyl group is becoming eclipsed by a hydrogen atom whereas in that arising from (25) the two methyl groups are becoming eclipsed.The transition state is therefore of higher energy with respect to the ground state for (25) than it is for (24). Correspondingly meso-stilbene dibromide is debrominated by iodide ion about one hundred times as fast as the racemic isomer.32~ 35 Cram's Rule of Asymmetric Induction.-From consideration of the pro- ducts of proved configuration resulting from reactions involving addition to a carbonyl group adjacent to an asymmetric carbon atom Cram and ' Abd Elhafez 29 were able to propose the following rule " In reactions of the type (26) + (27) that diastereoisomer will predominate which would be 0 0 2 formed by the approach of the entering group [R'] from the less hindered side of the double bond [of the carbonyl group] when the rotational con- formation of the C-C bond is such that the double bond is flanked by the 31 Winstein Pressman and Young J .Amer. Chern. Xoc. 1939 61 1645. 32 Young Pressman and Coryell ibid. p. 1640. 3 3 Young Abs. Papers 8th Nat. Org. Chem. Symposium Amer. Chem. Soc. St. 34 Dhar Hughes Ingold Mandour Maw and Woolf J. 1948 2711. 35 For a pertinent case involving dehydrochlorination see Cram and Abd Elhafez Louis Dec. 1939 p. 92. J . Amer. Chem. SOC. 1952 74 5851. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 51 two least bulky groups [S and MI attached to the adjacent asymmetric centre.’’ Thus in the addition of Grignard reagents or reduction by lithium aluminium hydride the carbonyl-oxygen atom being co-ordinated to the metal atom (MgX or AlH,) becomes effectively the largest group and thus orients itself between S and M.The approach of the R’ group is then directed as would be expected from that side of the molecule to which S is attached rather than M. Prelog’s Approach to Asymmetric ,Synthesis.-Prelog and his collabora- tors 36 have submitted to conformational analysis the extensive experimental results of McKenzie and his school on the configurational course of the addit’ion of Grignard reagents to phenylglyoxylic esters of asymmetric alcohols and have been able to relate the sign of rotation of the atrolactic acid produced on hydrolysis with the configuration of the original asymmetric alcohol. The most stable conformation of the phenylglyoxylic ester was considered to be (28) in which the two carbonyl groups are planar and anti to each other with the two larger groups of the asymmetric alcohol (29) skew to the ester-carbonyl oxygen.Addition of methylmagnesium halide will be more HO I I HO-5-S I c (29) 502H I Me-$ -OH Ph I I rapid from the less hindered side of the carbonyl group leading to a pre- ponderance of (30) over its diastereoisomer. Thus the formation of a partially racemic but lzvorotatory atrolactic acid showing an excess of the enantiomorph (31) indicates that the alcohol has the absolute configuration represented by (29). Conversely a dextrorotatory atrolactic acid indicates that the parent alcohol has the opposite configuration to (29). This method has been applied 36 to the determination of the absolute configuration of several groups of natural products. Relative Rates of Cyc1isation.-The rate of any reaction proceeding 36 Prelog Helv.Chirn. Acta 1953 36 308 ; Prelog and Meier ibid. p. 320 ; W. G. Dauben Dickel Jeger and Prelog ibid. p. 325 ; and later years. 52 QUARTERLY REVIEWS through an approximately planar transition state or intermediate whatever the ring size and whether or not the final product is cyclic will in general be smaller for the diastereoisomer reacting through the transition state or intermediate where large groups are eclipsed than for the isomer where smaller groups are eclipsed. ( a ) 1 2-cis-Cyclisations. Thus the reaction of form (32) via (33) will be slower than the reaction of form (34) via (35).37 Well-authenticated examples of this effect in a five-membered transition state are the rates of (32) (33) X L' s' (34) (35) acyl migration in 1 2-a~mino-alcohols such as erythro- (36) (slow) and threo- (37) (Fa&) ephedrine 389 39 and the slower rate of condensation with acetone of 9h I HO-C-H MeNH-q -H I I 1 de (36) meso- (38) than of racemic (39) dihydroben~oin.~~ The readier 9h 9 h Ph I I I HO-C-1 I HO-C-H HO-C-H H-7- I HO-$-H d e i h 6h I H-$ -NHMe I I I I I I I (37) (38) ? 9h I HO-C-H I HO-C-H Me-(:-H I H-G-Me I I 6 h I Gh (39) 37 Some of the links in the ring may be partial bonds.Z may represent one or more ring atoms (or conceivably none) X and Y are atoms or groups of the type referred to in the cursive text. 38 Welsh J . Arner. Chem. SOC. 1947 69 128 ; 1949 '71 3500. 39 Fodor Bruckner Kiss and Ohegyi J . Org. Chern. 1949 14 337 ; see also Close 40Hermans 2. phys. Chem. 1924 113 337. J . Orq. Chem. 1950 15 1131. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 53 pyrolysis 29 of the xanthate of threo- (40) than of erythro-1 2-diphenyl- propan-1-01 (41) illustrates the operation of the effect in an approximately planar six-membered transition state.The relative rates of cyclisation of erythro- and threo-isomers may be reversed when the transition state is non-planar. Wendler 41 has suggested that the diastereoisomer of 3-acetamido-1 3- diphenylpropan-1-01 which undergoes N + 0 acetyl migration in acid solution has the configuration (42) on the grounds that the intermediate (43) in the migration suffers from no serious non-bonded interactions. On the other hand the other diastereoisomer (44) does not undergo migration 42 because this would involve an intermediate (45) with a strong non-bonded repulsion between phenyl and hydroxyl (or methyl) groups.43 (b) 1 3-cis-Cyclisations.H H (44) (45) In a trans-cyclisation with displacement of an adjacent substituent through a planar cyclic transition state symbolised in (34) + (46) as a general formulation of neighbouring-group partici- pation,44 the diastereoisomer (34) which reacted more rapidly in the cis- (c) 1 2-trans-Cyclisations. eyclisation now passes into a product (46) where the large groups are eclipsed. It reacts therefore more slowly than its isomer (32) where the product has only eclipsing of the large and the small groups. The reality of this effect for a three-membered transition state or inter- 4l Wendler Experientia 1953 9 416. 42 Stiihmer and Frey Arch. Phurm. 1953 286 8. 43 The hydroxyl group and one of the phenyl groups of the oxazine (45) are both 44 Winstein Morse Grunwald Schreiber and Come J .Arner. Chern. SOC. 1952 axial (see p. 55). 74 1113. 54 QUARTERLY REVIEWS mediate has been demonstrated in relative rates of phenyl-group migration (through phenonium-ion intermediates) for appropriate pairs of diastereo- isomers.44 45 Curtin in particular has emphasised the role of such a " cis- effect " in controlling the relative rates of competing pinacolic aryl migrations of 1 2-diary1 systems.46 To emphasise the contrast between cis- and trans-1 2-cyclisations let; us consider the reactions of the two diastereoisomeric 2-amino-1 2-diphenyl- ethanols. Thionyl chloride cyclises the N-formate of the erythro-isomer (47 ; R = H) via the chlorosulphite and with inversion to the oxazoline salt (48 ; R = H) under conditions that do not affect the formate (49) of H Ph .py-i Ph H 0 soc12 * H Ph pheNH+ " 0 4 (49) (50) the threo-isomer.*' On the other hand the threo-N-acetate (49 ; R = Me) undergoes N +- 0 acetyl migration through cis-cyclisation to the oxazolidine (50) on treatment with alcoholic hydrogen chloride conditions which leave the N-acetate (47 ; R = Me) of the erythro-isomer unchanged.39 Some Illustrations from Alicyclic Chemistry Examination of a model of the chair conformation of cyclohexane shows Six of the that the C-H bonds are of two geometrically different types.axis 4 5 Cram ibid. p. 2152. 46 Curtin and Crew ibid. 1955 77 354 and earlier papers ; for a review see Curtin 47 Weijlard Pfister Swanezy Robinson and Tishler J . Arner. Chem. SOC. 1951 For related transformations see inter &a Elliott J.1949 589 ; 1950 62 ; Rec. Chem. Progr. 1954 15 111. 73 1216. Ann. Reports 1953 50 277. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 55 bonds lie parallel to the threefold symmetry axis of the ring as in (51) and have been designated “ axial ”.48 The other six bonds radiate out from the ring as in (52) and have been named “ equatorial ”.48 In the chair conformation of cyclohexane each equatorial hydrogen atom is skew to the four hydrogen atoms on the two adjacent carbon atoms and about 2-5 A distant from each of them [l 2-H H interactions ; see (53)J Each axial hydrogen atom is flanked by two equatorial hydrogen atoms attached to the adjacent carbon atoms in the same geometrical relation [l 2-H H interactions ; see (54)l. Each axial hydrogen atom is also about 2-5 ,& away from the other two axial hydrogen atoms on the same side of the ring [l 3-H H interactions ; see (54)l.All other H H or C H interactions are relatively unimportant. H.. (53) (54) Preferred Conformations of Simple cycloHexane Derivatives.-A study of accurate scale models shows that any substituent larger than hydrogen in an axial conformation is closer to the two axial hydrogen atoms (1 3-inter- actions) on the same side of the ring than the same substituent in an equa- torial conformation is to the adjacent equatorial and axial hydrogen atoms (1 %interactions). In consequence the stronger (repulsive) 1 3-interactions R (59) (60) (61) (62) dominate the energy relations and a substituent in general prefers to adopt an equatorial rather than an axial conformation.The extensive investigations of Hassel and his collaborators 49 on the 48 Barton Hassel Pitzer and Prelog Nature 1953 172 1096. “ Equatorial ” and “axial ” replace the earlier synonyms K and E (Hassel Tidsskr. Kjemi Bergvesen Met. 1943 3 32) and “equatorial ” and “polar ” (Beckett Pitzer and Spitzer J . Amer. Chem. SOC. 1947 69 2488). 49 Reviews Hassel and Ottar Acta Chem. Scand. 1947 1 929 ; Hassel Research 1950 3 504; Quart. Rev. 1953 7 221. 56 QUARTERLY REVIEWS electron diffraction of cyclohexane derivatives in the vapour phase-con- ditions where intermolecular interactions are a t a minimum-have revealed that a cyclohexane derivative normally exists predominantly in the chair conformation which has the maximum number of substituents equatorial. Thus monosubstituted cyclohexanes are to be represented 50 as (55) rather than (56) truns-1 2-disubstituted cyclohexanes as (57) rather than (58) cis-1 3-disubstituted derivates as (59) rather than (60) and trans-1 4- compounds as (61) rather than (62).Such alternative chair conformations can be interconverted by merely passing the cyclohexane ring through a planar or equivalent conformation. The interconversion of the two chair conformations through such an inter- mediate having angle-strain and higher non-bonded interactions generates an energy barrier between the two of only a few kcal./mole too small to allow their separation in the liquid or vapour state by the classical methods of organic chemistry. Since rates of thermal equilibration of conformational isomers are therefore generally much greater than rates of chemical reactions a reaction proceeding by a mechanism involving a transition state having geometrical requirements better satisfied by a less stable conformation may well follow a path mainly through that less stable c~nformation.~~ Mono- cyclic cyclohexane derivatives 52 are therefore from the point of view of reaction mechanism always subject to conformational ambiguities.Con- densed cyclohexane systems discussed below in which ring conversions are more difficult or geometrically impossible do not suffer from the same objections. Winstein and Holness 6 3 have recently ensured conformational homogeneity in an ingenious manner by using cis- (63) and trans-tert.- butylcyclohexanol (64). The very bulky tert. -butyl grouping guarantees the absence of any significant proportion of conformations with this group axial.Condensed cyclo Hexane Ring Systems.-The most stable conformation of a cyclohexane ring system is that with the greatest number of chair rings (see above). In most cases this principle enables an unambiguous con- formation to be deduced for such systems. Thus trans-anti-trans-per- hydrophenanthrene is to be represented as (65) the trans-a/B steroids (66) as (67),209 21* 5 4 and oleanane (68) the most important parent hydrocarbon 60 These and similar formulae in the present article are stylised representations of the true conformations. They are not intended to be accurate perspective or orthogonal projections. 5l Eliel Experientia 1953 9 91. 5 2 For an excellent review of monocyclic cyAohexane derivatives see Orloff Chem.5 3 Winstein and Holness J . Amer. Chem. SOC. 1955,77 5562. We are most grateful 6 4 Barton and Rosenfelder J . 1961 1048. Rev. 1954 54 347. to Professor Saul Winstein for informing us of his results before their publication. 57 of the pentacyclic triterpenoids as ( 69).55 All these conformational assign- ments are quite unambiguoixs and are supported by a wealth of chemical evidence. 56 BARTON AND COOKSON CONFORMATIONAL ANALYSIS R H A H H I g d d H I A ti An interesting demonstration 57 58 of the destabilising effect of boat conformations is provided by the fact that trans-syn-cis-perhydroplien- anthrene (70) where all rings can adopt chair conformations is more stable than the trans-syn-trans-isomer (71) where one ring is forced to assume a boat conformation. 55 Barton and Holness J .1952 78 ; Barton J. 1953 1027. 66 Conformations deduced from minimisation of non-bonded interactions refer ideally only to isolated molecules the conformations of which are entirely controlled by intra- molecular forces. In the crystal lattice it is conceivable that intermolecular forces could become dominant and that different conformations might be favoured. Fortu- nately in most cases it appears that the ideal conformation of the isolatedmolecule is also preserved in the crystal. For impressive examples see Carlisle and Crowfoot Proc. Roy. Sac. 1945 A 184 64 (cholesteryl iodide) ; Fridricksons and Mathieson J. 1953 2159 (lanostenyl iodoacetate) ; Carlisle and Abd El Rehim Chem. and Ind. 1954 579 (methyl oleanolate iodoacetate). 67 Linstead and Whetstone J. 1950 1428.6* Johnson Experientia 1951 7 315. 58 QUARTERLY REVIEWS Calculation of Energy Differences between Geometrical Isomers.-The calculation of energy differences by semiempirical procedures 59 can be extended to provide the relative stabilities of conformational isomers.60 The calculations led to the observed stability orders of chair- > boat-cyclo- hexane 2-chair trans-decalin > %chair cis-decalin 2-chair cis-decalin > %boat cis-decalin. A more convenient method has been developed,61 based upon Pitzer's treatment 62 of the methylcyclohexanes. This simple empirical approach assigns an interaction energy of 0.8 kcal./mole to each skew interaction as in n-butane (4). cis-Decalin for example has three skew interactions that do not occur in trans-decalin and is therefore ca.2-4 kcal./mole less stable in excellent agreement with experiment .63 The calculations have been extended 61 to include perhydro-phenanthrenes and -anthracenes and the calculated relative stabilities of some of the isomers have been confirmed experimentalIy.6lS G4 Reaction Rates and Equilibria controlled by Steric Compression.-(a) Relative stabilities of epimers. At a given secondary carbon atom in a cyclo- hexane ring system a substituent being necessarily larger than a hydro- gen atom is more stable in an equatorial than in the corresponding axial conformation. In a rigid fused ring system in which conformational inter- conversion is impossible the axial or equatorial conformation of a substituent depends directly on its configuration. 21 The most thoroughly explored ring system which tests this generalisation is the trans-A/B steroid nucleus (66) (67).In formula (72) the experimentally determined configuration (a or p) and the conformation (e or a) 65 of the more stable epimeric secondary alcohol is indicated ab every relevant position of the nucleus ; in every case the equatorial alcohol is more stable than its axial epimer.21 66 SimiIarly 69 Dostrovsky Hughes and Ingold J. 1946,173 ; Westheimer and Mayer J. Chem. Phys. 1946 14 733 and references there cited ; Hill ibid. 1948,16 938 and references there cited. 6o Barton J. 1948 340. 6 1 Turner J . Amer. Chern. SOC. 1952 74 2118 ; Johnson ibid. 1953 75 1498. 6 2 Beckett Pitzer and Spitzer ibid. 1947 69 2488. 63 The experimental value is 2-12 kcal./mole for the liquid phase at 25' (Davies An approximate correction 6 1 64Robins and Walker J.1954 3960; 1955 1789; Chem. and Ind. 1955 772. 6 5 e* represents an equatorial conformation with respect to ring c. 66 See also Barton in LettrB Inhoffen and Tschesche " Ober Sterine Gallensauren and Gilbert J . Amer. Chem. SOC. 1941 63 1585). to convert the calculated value to the same state yields a figure of 2.07 kcal. und verwandte Naturstoffe " Enke Stuttgart 1956. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 69 compounds with enolisable substituents such as alkoxycarbonyl 67 on equilibration with base yield mainly the equatorial epimers. Br I H H (73) (74) The relative stabilities of several steroidal 1 2-dihalides have been determined.G8 The diaxial cholestene 2/3 3cc-dibromide (73) for example rearranges to the diequatorial dibromide (74).This is a case where the forces of steric compression are opposed by those of dipole repulsion. No doubt form (73) is destabilised particularly by the large 2P-axial bromine ratio to axial 10-methyl interaction for cydohexene trans-dibromide is rather more stable in the diaxial than in the diequatorial conforn~ation.~~ It is interesting that the all-equatorial chloride bromide (76) rearranges presum- ably by interchange of the bromine atoms and con formational inversion to (76) the chlorine atoms taking up axial positions in preference to the larger bromine atoms.70 A (75) Cl (76) Reduction of ketones or oximes with sodium and alcohol has long been known to give mixtures of epimeric alcohols or ainines of approximately the same composition as direct equilibration.More recently it has been sug- gested that all reductions by alkali metals and proton donors proceeding through carbanions give predominantly the most stable product Included are reductions of conjugated dienes q9-unsaturated ketones aromatic 67 Klyne " Progress in Stereochemistry " Butterworths London 1954 Vol. I p. 37 et sep. 68 Alt and Barton J. 1954 4284. 69 Bastiansen and Hassel Tidsskr. Kjemi Bergveseiz Met. 1946 6 96 ; Larnaudie Compt. rend. 1953 236 909 ; Kwestroo Meijer and Havinga Rec. Trnv. ch,im. 1954 73 717 ; Kozima Sakashita and Maeda J . Arner. Chem. Xoc. 1954 76,1965 ; Bender Flowers a8nd Goering ibid. 1955 77 3463. 'O Andersen Hassel and Lunde Acta Chem. Scand. 1952 6 966. 71 Barton and Robinson J. 1954 3045 ; in view of the interesting results recently reported by Cram Allinger and Langemann (Chem.and Ind. 1955 919) the reservation must be made that the carbanions must be sufficiently long lived to exercise their stereochemical preference. See also Johnson Bannister Bloom Kemp Pappo Rogier and Szmuszkovicz J . Amer. Chem. Xoc. 1953 75 2275 ; Arth Poos Lukes Robinson Johns Fleurer and Sarett ibid. 1954 76 1715. 60 QUARTERLY REVIEWS systems and halides. For exarnple,'l 5cc-chlorocholestane (77) and 5/3 6a- dibromocholestane (78) both afford cholestane (79) with the more stable trans-a/B fusion on reduction with lithium and liquid ammonia. Ci (77) &'- H (79) Br Ejr The uniform production of products of more stable configuration is most simply explained by assigning to the carbanion a definite but easily inverted tetrahedral configuration and by assigning to the electron pair steric require- ments somewhat larger than hydrogen but smaller than other substituents.Since at a given secondary carbon atom in a cyclohexane system the steric compression of an equatorial is less than that of an axial hydroxyl group one would expect equatorial hydroxyl groups to be more easily esterified than their axial epimers and the same relation to hold for the hydrolysis of t,heir esters. For the same reason an ester of an equatorial carboxylic acid should be hydro- lysed more rapidly than its axial epimer. Using the kM'LS-A/B steroid nucleus for illustration formula (80) shows which epimeric ester is more rapidly hydrolysed.21s e6 Agreement with expectation is complete. A closer correlation of hydrolysis rates with the relative magnitudes of non-bonded interactions can be secured without ( b ) Relative rates of esteriJication and hydrolysis.66 (c) Relative rates of solvolysis. It is difficult to compare the rates of pure X,1 replacement reactions of cyclohexyl compounds owing to the ease with which competing reactions take place. It would be expected that the extra steric compression to which axial substituents are subjected would be a t BARTON AND COOKSON CONFORMATIONAL ANALYSIS 61 least one factor leading to faster solvolysis rates relative to those of the corresponding equatorial substituents. This is probably the case for the XN1 solvolysis 7 2 of neomenthyl chloride (81) relative to menthyl chloride (82). For SN2 replacement processes axially oriented substituents should be replaced more rapidly than equatorially oriented substituents.This is because the approach to the back of an equatorial substituent is hindered by the axial groups [see formula (83)]. For the epimer approach of the reagent is hindered only by 2-substituents [see (84)l. Gallagher and Long 73 H (85) described an example of the expected difference when they showed that the axial llj3-bromine atom of methyl 3a-acetoxy- 1 lj3-bromo- 12-oxocholanate (85) was replaced with inversion by OH- more rapidly than was the equatorial 1 la- bromine of its epimer. ( d ) Rates of oxidation of secondary alcohols. The relative rates of oxidation of epimeric pairs of secondary alcohols to the ketone by chromic acid or by hypobromous acid are just the reverse of the relative rates of hydrolysis of their carboxylic esters.The equatorial cholestan-3/3-01 for example is oxidised to cholestanone more slowly than is the axial cholestan- 3a-01.'~ This is understandable if the rate-controlling step is not the forma- tion of the corresponding chromate or hypobromite but attack of some nucleophilic species on the hydrogen atom 21 after the ester has been formed. Westheimer et ~ 1 . ~ ~ have shown that this is indeed the case for certain chromic acid oxidations. Chromic acid oxidation has recently been shown to be subject to steric acceleration ; 76 that is the more hindered the alcohol the greater is the 7 2 Hughes Ingold and Rose J . 1953 3839 ; see also unpublished results cited in ref. 53. 79 Gallagher and Long J . Bid. Chem. 1946 162 521. 7 4 Vavon and Jacubowicz Bull. SOC. chim. France 1933 53 581.7 6 Westheimer et al. J . Amer. Chem. SOC. 1949 71 25 ; 1951 73 65 ; 1952 '74 76 Schreiber and Eschenmoser Angew. Chem. 1955 67 278 ; Helv. Chim. Acta 4383 4387. 1955 38 1529. 62 QUARTERLY REVIEWS release of compression energy in the transition state and the faster the reaction. Steric acceleration of solvolysis is a well-known phenomenon 77 and one can envisage in similar terms the acceleration of carbonium-ion rearrangements through the release of com- pression energy accompanying the rearrangement. For example the con- version of a high-energy boat conformation into a lower-energy chair con- formation through some carbonium-ion rearrangement might be regarded (e) Conformational driving forces. HO & @ I HO (86) (87) as a reaction assisted by a conformational driving force.An interesting example 78 is possibly provided by the acid-catalysed rearrangement of euphenol(86) to isoeuphenol (87). Analogous conformational driving forces no doubt play a part in the anomalous trans-annular reactions of medium- sized rings.79 (f) Dissociation constants. fGane and Ingold 8O developed measure- ment of dissociation constants into a powerful method of investigating the conformations of symmetrical acyclic dicarboxylic acids in solution. In the cyclohexane series 81 82 the cis- and trans-1 2-dicarboxylic acids show a large difference in ApK, the difference in the pK,'s of the first and the second dissociation constants. The smaller ApK,value for the trans-1 2-acid is due to the greater separation between the integral charges in the dianion APE cis trans cycZoHexane-1 2-dicarboxylic acid .. 1.80 1.15 cycZoHexane- 1 3-dicarboxylic acid . . 0.76 0.82 whichtadopts because of electrostatic repulsion the diaxial(88) rather than the diequatorial conformation (89). In the dianion from the cis-acid for which only one chair conformation is possible (go) the charges are closer together 77 Hughes Quart. Rcw. 1951 5 245 ; F. Brown Davies .Dostrovsky Evans and Hughes Nature 1951 167 987 ; H. C. Brown and Fletcher J . Amer. Chem. SOC. 1949 71 1845 ; Bartlett et al. ibid. 1955 77 2801 2804 2806. 78 Barton McGhie Pradhan and Knight Chem. and Ind. 1954 1325 ; J . 1955 876 ; see also Arigoni Viterbo Dunnenberger Jeger and Ruzicka Helv. Chim. Acta 1954 37 2306. 79 Prelog J . 1950 420 ; Cope Fenton and Spencer J . Amer. Chem. SOC. 1952 74 5884 ; Prelog and Schenker HeZw.Chim. Acta 1952 35 2044 ; Prelog Schenker and Kiing ibid. 1953 36 471. 80 Gane and Ingold J. 1931 2153 ; Ingold ibid. p. 2179. 81 Speakman J. 1941 490 and references there cited. 82 Barton and Schmeidler J . 1948 1197. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 63 in fact the same distance apart as in (89). I n the 1 3-diacids the difference co; COi H co; H (88) (89) (90) in ApK is smaller and for similar reasons the trans-acid has the larger value. This would be expected from the conformations (91) and (92) the negative charges being closer in the trans- than in the cis-acid. Analysis H (91) (92) (93) of dissociation-constant data 8 2 for the tricarboxylic acid (93) shows that here the balance of electrostatic factors makes (94) the preferred conforma- tion for the trianion rather than the alternative (95).Similarly for epimeric amino-acids )NH+ C02- ApK is greater for the epimer in which the two poles are closer together in the preferred con- format ion .s3 To the extent that ionisation of acids and bases is determined by the degree of solvation of the ions in otherwise non-polar molecules axial acids and amines would be expected to be weaker than their equatorialepimers owing to greater hindrance to solvation in the axial ions. Amongst epimeric pairs of cyclohexanecarboxylic acids the stronger are those that can take up an equatorial c~nformation.~~ Even a t position 3 of cholestane the least hindered in the entire steroid nucleus the equatorial S/I-dimethylamino- derivative is 0.20 pK unit stronger than the axial 3a-epimer in 50% aqueous tert.-butyl alcohoLS5 I- - - - - -1 83 See p. 80. 84Dippy S. R. C. Hughes and Laxton J . 1954 4102. 8 5 Bird and CookEon Chem. and Ind. 1955 1479. 64 QUARTERLY REVIEWS Physical Properties.-(a) Infrared spectra. The most far-reaching and valuable correlations between the conformations of molecules and their physical properties relate to light absorption.86 The frequency of the C-0 stretching vibration of secondary alcohols is always higher for the equatorial than for the axial epimer. show this band at about 1040 cm.-l and axial ones at about 1000 cm.-l. Page 88 has recently found that for epimeric pairs of acetoxy- and methoxy-steroids the steroid C-0 stretching frequency in the 1150-1000 cm.-l region is higher for the equatorial than for the axial epimer. The higher frequency of equatorial C-X stretching vibrations is probably quite general.These regularities are obviously of use for the assignment of configuration to alcohols derived from conformationally rigid system .89 Even the C-D stretching frequency of appropriate deutero-compounds depends on whether the deuterium is axial or e q u a t ~ r i a l . ~ ~ R. N. Jones and his collaborators 91 have shown that introduction of an equatorial a-halogen atom into a cyclohexanone increases the carbonyl stretching frequency by about 20 cm.-l whereas an axial a-halogen atom scarcely affects the frequency. Equatorial and axial a-halogeno-cyclohexanones also differ characteristically in their ultraviolet absorption spectra. The effects are just the reverse of those in the infrared region. Thus an equatorial a-bromine atom shifts the weak absorption band that occurs in all saturated ketones a t about 280 mp to slightly shorter wavelengths but an axial a-bromine atom produces a marked shift to longer wavelengths with a three- or four-fold increase in intensity.92 Rather similar behaviour is shown by a-hydroxy- and a-acetoxy-ket~nes.~~ The approximate shift (AA) in wave- length of the weak band caused by a-substitution may be summarised as in the annexed Table.Equatorial alcohols usually ( b ) Ultraviolet spectra. AR(mp) a-Substituent c1 . . - 7 + 22 Br . . - 5 3- 28 . - 1 2 + 17 + 10 OH . OAc . . - 6 It should be noted that acetylation of an equatorial a-ketolShifts the maxi- s~ For a more detailed review see Braude and Waight " Progress in Stereo- chemistry " ed. Klyne Butterworths 1954 p.126 ; for the relation between con- formation and ultraviolet absorption of cyclic conjugated dienes see Braude Chem. and Ind. 1954 1557. Jones Humphries Herling and Dobriner J . Amer. Chem. SOC. 1951 73 3215 ; Cole Jones and Dobriner ibid. 1952 74 5571 ; Fiirst Kuhn Scotoni and Giinthard Helw. Chim. Acta 1952 3!5 951. s8 Page J. 1955 2017. For example see Cole J. 1952 4969 ; Aebi Barton Burgstahler and Lindsey J. 1954 4659. For correlation of infrared spectra and conformation of carbohydrates see Barker Bourne Stacey and Whiffen ibid. p. 171 ; Barker Bourne Stephens and Whiffen ibid. pp. 3468 4211. Corey Sneen Danaher Young and Rutledge Chem. and Ind. 1954 1294. R. N. Jones Ramsay Herling and Dobriner J . Amer. Chem. SOC. 1952,74 2828. B 2 Cookson J. 1954 282.93 Cookson and Dandegaonker J . 1955 352. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 65 mum to longer wavelengths whereas acetylation of the axial epimer shifts it to shorter wavelength^.^^ 94 (c) Adsorption and partition. As one would expect from simple mechani- cal considerations a compound with an equatorial polar group is in general more strongly adsorbed on a chromatographic column than its epimer with an axial substituent. 21 Examples where this order of elution from alumina is followed are the various 2 3-dihalogenocholestanes 95 and the dihydro- lysergic acids.96 However exceptions have been noted,97 perhaps because surface forces may compel adsorbed molecules to adopt conformations that are not preferred in solution. Least deviation from the rule would therefore be expected in partition chromatography and indeed Savard 98 observed that axial steroidal alcohols travel faster on paper than their equatorial epimers .The von Auwers-Skita rules,9g accord- ing to which the cis-compound (of a pair of cis-trans-isomers) has the higher refractive index and density break down when applied to 1 3- disubstituted cyclohexanes where the reverse order holds. loo The rules are also frequently ambiguous when applied to polycyclic systems such as steroids. A modified rule is valid according to which for substituted cyclo- hexanes the stereoisomer with the more axial substituents has a higher refractive index and density.lo1 Kelly lo2 has proposed a generalised version of the rule stating that for isomeric cyclohexane and tetrahydropyran derivatives which are similarly substituted on corresponding ring carbon atoms the refractive indices and densities are inversely related to con- formational stability.InJEuence of Conformation on Reactions with Particular Xtereoelectronic Requirements.-(a) Diaxial bimolecular elimination. The transition state of lowest energy for an ionic E2 reaction (elimination of X and Y) requires 21 669 lo3 the four centres concerned to be in one plane as in (96). In conformationally rigid ring systems based on cyclohexane this geometrical (d) Refractive index and density. 9 4 Baumgartner and Tamm Helv. Chim. Acta 1955 38 441. 96Alt and Barton J. 1954 4284. g6 Stoll Petrzilka Rutschmann Hofmann and Giinthard Helv. Chim. Actu 1954 97 Brooks Klyne and Miller Biochem. J. 1953 54 212. 98 Savard J. Biol. Chem. 1953 202 457.99 Von Auwers Annalen 1920 420 89 ; Skita Ber. 1920 53 1792. 100 Mousseron and Granger Bull. SOC. chim. Prance 1938 5 1618 ; 1946 218 ; 13eckett Pitzer and Xpitzer J . Amer. Chem. SOC. 1947 69 2488 ; Goering and Serres ibid. 1952 74 5908 ; Noyce and Denney ibid. p. 5912 ; Haggis and Owen J. 1953 ~$08 ; Darling Macbeth and Mills ibid. p. 1364. 37 2039. 101 See Allinger Experientia 1954 10 328. 102 Kelly personal communication. 1°3 Young Pressman and Coryell J . Amer. Chem. SOC. 1939 61 1640 ; Winstein Pressman and Young ibid. p. 1645 ; Dhar Hughes Ingold Mandour Maw and Woolf J. 1948 2117 ; Barton and Miller J . Amer. Chem. SOC. 2950 72 1066 ; Barton and Rosenfelder J. 1951 1048; for an interesting application in Wolff-Kishner reduc- tions of a-ketols see Turner Anliker Helbling Meier and Heusser Helv.Chim. Acta 1955 38 41 1. E 66 QUARTERLY REVIEWS requirement is satisfied by 1 2-trans-diaxial substituents but not by 1 2-trans-diequatorial or of course by 1 2-cis-substituents. This rule which replaces the less demanding rule of " trans-elimination " has been demonstrated especially in the debromination of 1 2-dibromides by iodide ion 1°4 as in (97). I X Br t 1- An example where the course of a reaction is controlled by preference for diaxial elimination concerns yohimbic acid (98) and its 16-epimer corynanthic acid.105 Base induces the elimination of sulphuric acid from the sulphuric acid ester of yohimbic acid [see (99)] but of carbon dioxide and sulphuric acid from the corresponding ester of corynanthic acid [see (loo)]. I n each case the reaction follows the course of diaxial elimination.aT%H H/' I6 HOZC**'* OH (98) QH k,c&o H &&\) -S%-b H-jf,) - q - 6 (99) (100) Many more examples of preferred diaxial elimination could be quoted. However Bordwell and his colleagues lo6 have recently shown that elimina- tion of a cis-hydrogen atom rather than of an alternative trans-one may 104 In simple aliphatic compounds alternative mechanisms are possible Hine and 106 Cookson Chem. and I n d . 1953 337 ; Janot Goutarel le Hir Amin and Prelog 106 Weinstock Peerson and Bordwell J . Amer. Chem. SOC. 1954 76 4748 ; Bord- Brader J . dmer. Chem. SOC. 1955 77 361. Bull. SOC. chim. France 1952 1085. well and Kern ibid. 1955 7'7 1141 ; Bordwell and Peterson ibid. p. 1145. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 67 take place when the former is made sufficiently acidic by a strongly electron- attracting group.Thus trans-2-toluene-p-sulphonylcyclohexyl toluene-p- sulphonate (101) undergoes second-order base-induced elimination of toluene-p-sulphonate ion to give the cyclohexene (102) rather than (103). The cis-isomer nevertheless still reacts more rapidly (by trans-elimination and presumably through the diaxial conformation) than the trans-isomer to give the same product. The converse of the well-established rule (see above) of preferred diaxial elimination in ionic-type reactions would be preferred diaxial addition. It has recently been demonstrated 95 that electrophilic addition of halogen proceeds in this manner in systems where conformations are unambiguous. For example bromine adds to cholest- 2-ene (104) to give mainly the diaxial 2a 3a-dibromocholestane (105) pre- sumably through the 2cc 3a-bromonium ion (106).Similarly addition of hypobromous acid to cholest-2-ene affords mainly the diaxial 3a-bromo- SP-hydroxycholestane (107). (c) Diaxial ring opening and closing in cyclohexene oxides. Either electrophilic or nucleophilic opening of epoxides affords mainly the diaxial product.108 This is exemplified g5 for ring A of the steroids by the reaction (b) Diaxial electrophilic addition. H H H 1 Br (105) ' J 107 Banerji Barton and Cookson unpublished work ; preferred diaxial addition l08 Fiirst and Plattner Abs. Papers 12th Int. Congr. Pure Appl. Chem. New York of hypohalous acid is a general rule. 1951 p. 405 ; see also Barton J . 1953 1027. 68 QUARTERLY REVIEWS of cholest-2-ene a-epoxide (108) with hydrogen bromide to give the diaxial 2/3 3a-bromohydrin (109) rather than the alternative trans- but diequatorial 3p 2a-bromohydrin and of the 2p 3P-epoxide (110) to give the 3a 2p- bromohydrin (107).The expected faster ring closure of diaxial than of diequatorial halogeno- hydrins has also been observed.lo7 Thus under standard conditions the times required for 90% reaction in the base-induced epoxide formation from the diaxial bromohydrins 3a-bromocholestan-2~-ol (107) and 2P-bromo- cholestan-3a-01 (109) are respectively 1.5 and 3-5 minutes. In contrast 40 hours are required before the reaction of the diequatorial Ba-bromo- cholestan-3p-01 (11 1) has reached 90% of completion. By analogy with preferred diaxial ring closure to ethylene oxides (see above) neighbouring-group participation of the kind extensively studied in simpler systems by Winstein and his school log should proceed more readily when the trans-1 2-sub- stituents concerned are both axial than when they are both equatorial.The replacement reactions of the various 2 3-halogenohydrins of cholestane vindicate this view.95 For example treatment of the 2g 3a-hromohydrin (109) with thionyl chloride gave via the bromonium ion (112) mainly the diaxial 2/3 3a-bromochloride (113) whilst the 3a 2p-bromohydrin (107) afforded via (106) mainly the diaxial 3a 2/3-chlorobromide (1 14). Under the same conditions the diequatorial bromohydrin (1 11) was recovered (a) Diaxial neighbouring-group participation. CI (114) unchanged. The diaxial chlorohydrins in which the less nucleophilic chlorine atom is known to provide a smaller driving force,l1° showed partici- pation of chlorine in replacement of hydroxyl only in reaction with the strongest electrophilic reagent phosphorus pentachloride.The phenomena referred to in this section and also the relative ease of 109 Winstein and his collaborators J . Amer. Chem. SOC. many papers under the 110 Winstein and Grunwald J. Amer. Chem. SOC. 1948 70 828. title " The Role of Neighbouring Groups in Replacement Reactions " 1942 et seq. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 69 epoxide formation (see above) demonstrate again the important geometrical preference for four coplanar reaction centres. l1 I n cyclohexane compounds rearrangements in which the ring size is unchanged take place most readily when the centres involved are coplanar [as in (1 15)] that is when the group eliminated and the migrating carbon atom are both axial.21 c6 The epimeric 17P-amin0-17a-hydroxy- 17a-methyl-~-homo-steroids provide (e) DiaxiaE rearrangements.reaction an interesting with and nitrous illustrative acid.l12 contrast The 17a-~-hydroxy-group in their modes of y/Jm '$ displaces nitrogen from the intermediate diazonium ion (1 16) to give the oxide (117) as expected from the discussion above. But the diazonium ion (118) from the 17aa-hydroxy-com- pound in which the antiparallel axial groups are N,+ and Me undergoes methyl migration and ketonisation to give the oxide (119). (115) (f) Ring contraction. Under the compulsion of the same stereo-electronic force which is the theme of much of this Review rearrangements of cyclohexane compounds involving ring contraction proceed most easily when the eliminated group is equatorial for only then are the requisite 1 2-bonds coplanar and antiparallel.is the dehydration of the epimeric triterpenoid 3a- and 3a-alcohols. The axial 3a-alcohols (120) are dehydrated simply to the A2-compounds ( l z l ) whilst the equatorial 3~-alcohols ( 122) undergo on treatment with phosphorus pentachloride dehydration with ring contraction to give rearranged olefins 1,123). Use of infrared spectroscopy to determine An instructive example 21 (9) Halogenation of ketones. ll1 This can also be discussed in terms of " orbital overlap " ; see Brutcher and Roberts Abs. Papers 126th h e r . Chem. SOC. Meeting New York 1954 p. 52-0. Change in ring size introduces a further factor ; see idem Abs.Papers 127th Amer. (:hem. SOC. Meeting Cincinnati 1955 p. 39-K. 112 Klyne and Shoppee Chem. and Ind. 1952 470 ; Cremlyn Garmaise and Hhoppee J. 1953 1847 ; see also Ramirez and Stafiej J . Amer. Chem. SOC. 1955 77 134. 70 QUARTERLY REVIEWS configuration (see above) has established 113 that in the bromination of cyclohexanones the axial cc- bromo-ketone is always formed more rapidly than the equatorial epimer. This is attributed 113 to the favourable geo- metrical arrangement of the morbitals of the enol for overlap with the enter- HO H __I___) ing-bromine vacant orbital in the transition state for axial addition compared with equatorial addition [see (124)l. An alternative explanation based on preferred diaxial electrophilic addition (see above) to the enolic ethylenic linkage followed by elimination of hydrogen bromide [see (125)] cannot yet be wholly excluded.?r+ I Br 113 Corey Experientia 1953 9 329 ; J . Amer. Chem. Xoc. 1954 76 175. BkRTON AND COOKSON CONFORMATIONAL ANALYSIS 71 (h) Reaction of amines with nitrous acid. Another useful generalisa- tion 114 115 is that equatorial amines are converted by nitrous acid into alcohols of the same configuration but axial amines yield mostly olefin with some inverted alcohol. The course of the reaction differs somewhat then from that typical of acyclic amines where the intermediate diazonium ion decomposes by the 8,l mechanism to form olefin and alcohol mostly of ~~ ~~ -~ 1 1 4 Mills J. 1953 260 ; Bose Experientia 1953 9 256 ; cf. Barton and Rosen- felder J.1951 1048. 115 W. G. Dauben Tweit and Mannerskantz J. Amer. Chem. SOC. 1954 76 4420 ; w. G. Dauben and Jiu ibid. p. 4426 ; W. G. Dauben Tweit and MacLean ibid. 1955 77 48 and references there cited. 72 QUARTERLY REVIEWS inverted configuration.116 Thus the products of deamination of the four trans-decalyl-amines are set out in the annexed chart. The two equatorial amines (126) and (127) give equatorial alcohols only (128) and (129) respectively. The two axial amines (130) and (131) afford mostly olefin accompanied by equatorial alcohol 115 as indicated. Nitrous acid converts trans-2-amino-1 -phenylcyclohexanol (132) into pro- ducts derived from 1 -phenylcycZohexene oxide (133). The cis-isomer (134) which by analogy with acyclic compounds would have been expected to undergo mainly phenyl migration to yield 2 -phenylcycZohexanone gives (134) instead 99% of the ring-contracted cyclopentyl phenyl ketone.The differ- ence in behaviour may be attributed 117 to the fact that the conformation required for migration of the phenyl group is one of high energy relative to (134). Some Illustrations from Heterocyclic Chemistry Fortunately the substitution of hetero-atoms such as nitrogen and oxygen for one or more of the carbon atoms of a cyclohexane ring causes as will be 1 Bond lengths (A) 1 Bond angles I I I- t 1 c-c 1.54 c-c-c 109" G N c-N-c I c-0 I clear from the data summarised in Table 1 only slight distortion of the ring. Consequently the generalisations that have emerged in the discussion of cyclohexane chemistry can be carried over (with slight modification where necessary) to the heterocyclic analogues.Since the p-orbitals of nitrogen 116 Ingold " Structure and Mechanism in Organic Chemistry " G . Bell London 1953 p. 397. 11' Curtin and Schumukler J. Arner. Chem. Soc. 1955 77 1105. 11* Maccoll in " Progress in Stereochemistry " ed. Klyne Butterworths 1964 p. 361. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 73 and oxygen appear to maintain an approximately tetrahedral distribution,ll9 the analogy becomes even more complete. Tetrahydropyran for example is represented loy (135) and piperidine by (136) and (137) in which by analogy with the stereochemistry of carbanions (see p. 78) the former may be expected to predominate.120 The four stereoisomeric dihydrolysergic acids ( 138) probably represent the piperidine compounds that have been most thoroughly investigated from the conformational point of view.121 Reduction of lysergic acid (139) with sodium and butanol gives Alkaloid Chemistry.-(a) The lysergic acids.(138) (139) mainly dihydrolysergic acid-I. This is therefore the most stable of the four stereoisomers of (138) and may be assigned the conformation and stereo- (140) (141) chemistry depicted in partial formula (14O) with all substituents on the piperidine ring equatorial. The expression (141) must then represent the 8-epiiner dihydroiso-lysergic acid-I for vigorous alkaline hydrolysis of derivatives of the latter acid affords the equatorial epimer (140). The methyl ester of the equatorial dihydrolysergic acid-I (140) is hydrolysed more rapidly than that of the axial acid (141). Nitrous acid deamination 119 C.A. Coulson " Valence " Oxford Univ. Press 1952 p. 209. 120 For illustrations of piperidine ring conformations see Leonard Thomas and Gash J . Amer. Chern. SOC. 1955 77 1552 and references there cited ; Przybylska and Barnes Acta Cryst. 1953 6 377 ; Lindsey and Barnes ibid. 1955 8 227 ; Visser Manassen and de Vries ibid. 1954 7 288. 121 Stoll Petrzilka Rutschmann Hofmann and Giinthard Helv. Chim. Acta 1964 37 2039 and references there cited ; see also Stenlake J. 1955 1626. 74 QUARTERLY REVIEWS -lysergic acid-I (e) (140) . . . . . -isolysergic acid-I (a) (141) . . . . -lysergic acid-I1 (a) (144) . . . . -isolysergic acid-I1 (e) (142) . . . . of the primary amine produced by Curtius degradation of the equatorial acid (140) proceeds to give the corresponding alcohol with retention of configura- tion.I n contrast the epimeric axial amine obtained in the same way from the axial acid (141) suffers elimination on deamination. The two remaining isomeric dihydrolysergic acids dihydro- and dihydro- iso-lysergic acid-11 must have rings c and D cis-fused. Of the two alterna- tive conformations possible for this ring system that having the large aromatic group equatorial [as in (142)] is preferred to that where it is axial [as in (143)l. Dihydroisolysergic acid-I1 is the more stable epimer and thus 3-00 4.80 4-61 3-41 k (142) (143) has the equatorial carboxyl group (142). In confirmation the methyl ester of this acid is more rapidly hydrolysed than is that of dihydrolysergic acid-I1 ( 144). Table 2 shows that the difference between the first and the second dis- sociation constants of the two pairs of amino-acids is less for the equa- torial epimers than for the axial epimers where the dissociable groups are closer together.TABLE 2 I Dihydro-acid ( b ) The tropune alkaloids. These alkaloids comprise another thoroughly investigated group,122 though the bridged piperidine ring system (145) intro- 122 For excellent and comprehensive reviews see Stoll and Jucker Angew. Chem. 1954 66 376 and especially Fodor Acta Chirn. Acad. Sci. Hung. 1955 5 380 ; Experi- entia 1955 11 129. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 75 Esters of tropine The duces some atypical features in conformational behaviour. (146) are hydrolysed more slowly 123 than those of y-tropine (147). Me (14s) (146) (147) axial hydroxyl group of tropine (146) can be isomerised to the equatorial configuration in y-tropine 124 (147) and the axial carboxyl group of ecgonine (148) to the equatorial one of y-ecgonine 125 (149).C02H Me I H n I (148) (149) ( .150) Carbohydrate Chemistry .-Much of the chemistry of the pyranose sugars has been placed on a rational basis by the admirable work of Reeves,12* who has investigated the conformations of sugars by examining their capacity for complex formation with " cuprammonium " solutions and their rates of reaction with lead tetra-acetate. I n all cases where it is geometrically possible the pyranose ring adopts the chair conformation (lSO) which is also preferred in the crystal lattice.127 The complexes formed by 1 2-glycols in cuprammonium solution contain the copper atom linked to the two oxygen atoms in a five-membered ring.The geometrical requirements are therefore similar to those of the cleavage of 1 2-glycols with lead tetra-acetate in which a cyclic complex of PbIV is an intermediate at least for glycols that react relatively rapidly.128 Although the data for lead tetra-acetate concern relative rates and those l23 Sixma Siegmann and Beyerman Proc. k. ned. Akad. Wetenschap. 1951 54 B 452; Siegmann and Wibaut Rec. Trav. chim. 1954 73 203; Hromatka Csoklich and Hofbauer Monatsh. 1952,83 1323. For a discussion see Fodor ref. 122 ; Nickon and Fieser J . Amer. Chem. Soc. 1952 '94 5566. For a discussion of the occurrence of the boat piperidine conformation in tropanes see inter aE. Zenitz Martini Priznar and Nachod ibid. p. 5564 ; Sparke Chem. and Ind. 1953 749 ; Archer and Lewis ibid.1954 853. 124 WillstBtter Ber. 1896 29 936. 125 Findlay J. Amer. Ch,ern. SOC. 1953 '75 4624 ; 126 Reeves ibid. 1949 71,215 2116 ; 1950 72 1499 ; 19574 6 4595 ; Adv. Carbo- hydrate Chem. 1951 6 107. 12' Inter aE. Cox Goodwin and Wagstaff J. 1935 1495 ; Cox and Jeffrey Nature 1939 143 894; Astbury and Dsvies ibid. 1944 154 84; Beevers and Cochran Proc. Roy. SOC. 1947 A 190 257 ; McDonald and Beevers Acta Cryst. 1950 3 394. 1954 76 2855. 12* Criegee and Buchner Ber. 1940 73 563. 76 QUARTERLY REVIEWS for cuprammonium complexing concern equilibria the close parallel between the two reactions summarised in Table 3 is thus not unexpected. For both reactions the most favourable arrangement of the glycol is when the two alcohol groups are in one plane. This is satisfied by a cis-1 2-glycol on a five-membered ring or on the " sides " of a boat six-membered ring.129 For both reactions a cis(e,a)-glycol is more favourable than a trans(e,e)- glycol because it allows a closer approach to coplanarity (see below).I n almost every case the conformation indicated by the behaviour of the pyranoses and their derivatives with cuprammonium agreed with that re- quired for a minimisation of non-bonded interactions (niaximum number of equatorial substituents). Ring form Furanose P yranose (chair) Pyranose (boat) TABLE 3 CiS trans cis (e,a) trans (e,e) trans (a,a) cis (side of boat) Rate of reaction with lead tetra-acetate Instantaneous Slow Rapid Slow Very slow Instantaneous Extent of reaction with ciiprammonium solution Large None Medium Small None Large _____ The formation of acetals by carbohydrate molecules and related poly- hydric alcohols can also be rationalised in a satisfactory manner by con- formational considerations.130 The chemistry of the inositols also lends itself to conformation& analysis.131 Other Six-membered Heterocyclic Rings.-Several other heterocyclic analogues of cyclohexane have been shown by physical methods to exist in H lz9 The point could also be illustrated by the complex-formation of glycols with boric acid so extensively studied by Boescken and his colleagues (Boeseken Adv. Carbo- hydrate Chem. 1949 4 189). 130 Barker and Bourne J. 1952 905 ; Barker Bourne and Whiffen ibid. p. 3865 ; Mills Chem. and Ind. 1954 633. 131 Chargaff and Magasanik J . Biol. Chem. 1948 175 939 and references there cited ; Magasanik Franzl and Chargaff J .Amer. Chem. Soc. 1952 '74 2618 ; Angyal and MacDonald J. 1952 686 ; Posternak and Reymond Helv. CJzim. Acta 1953 36 260. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 77 the chair conformation. Thus the preferred conformations of 1 4-dichloro- piperazine 132 and of 2 4 6-trimethyl-1 3 5-triazacydohexane (“ alde- hyde ammonia ”) 133 are (151) and (152) respectively. As in the cyclohexane series cis-1 4-dioxan-2 5-dicarboxylic acid (153) is less stable than the trans-acid (154) and the cis-2 6-diacid (155) is more stable than the trans- analogue 134 (156). a-Tristhioacetaldehyde (157) is as expected less stable than the /3-isomer lZ5 (158). Conformations of Six-membered Rings containing Trigonal Atoms.-The successive substitution of trigonal for tetrahedral carbon atoms in a six- membered ring results in general in an increasing approach of the ring to planarity.All possible combinations of tetrahedral and trigonal ring atoms cannot be considered here ; each system requires separate evaluation and generalisations about the properties of equatorial and axial bonds in saturated rings can be applied only with reserve. In cycZohexanone (159) the single trigonal carbon atom introduces only slight distortion relative to cyclohexane itself though it obviously modifies some of the non-bonded interactions for example an cc-equatorial substituent is almost eclipsed by the carbonyl group. In cyczohexane-1 4-dione (160) the interactions are still further modified and tlhe dipole moment is compatible with the presence of about 10% of the boat conformation.136 The two conformations of cyczohexene not involving (a) cycloHexanones. ( b ) cycloHexenes. 132 Andersen and Hassel Acta Chem. Scand. 1949 3 1180. 133 Lund ibid. 1951 5 678. 134 Summerbell and Stephens J . Amer. Chem. Soc. 19454 76 731 6401. 135 Baumann and Fromm Ber. 1891 24 1428 ; Chattaway and Kellett J. 1930 1352 ; Hassel and Viervoll Acta Chem. Scand. 1947 1 149. 136 Le FBvre and Lo FBvre J. 1935 1696. For an investigation of the importance of boat conformations in androstane- and actiocholane-3 l7-dioneY as determined by (lipole-moment measurements see Nace and Turner J . Arner. Chem. Soc. 1953 75 4063. 78 QUARTERLY REVIEWS appreciable angle strain are shown schematically in (161) and ( 162).13' The conclusion by Beckett Freeman and Pitzer 138 from thermodynamic data that the " half-chair " conformation (161) is more stable than the " half-boat " (162) by 2.7 kcal.per mole is supported 139 (with the usual -o k7A0 e!+T+-e a' Q (159) (160) (161) reservations see above) by the X-ray analysis of several crystalline sub- stances all of which have the half-chair conformation (161). I n this con- formation the ethylenic linkage keeps the two trigonal and allylic carbon atoms approximately in one plane. The two non-allylic methylene groups are completely staggered with respect to each other so that their C-H bonds resemble normal axial and equatorial bonds in cydohexane. The bonds attached to the two allylic carbon atoms approximate only to axial and equatorial bonds and may be described as quasi-axial (a') and quasi- equatorial (e') [see (161)l.The few examples available 137 suggest that substituents are usually more stable in equatorial and quasi-equatorial than in axial and quasi-axial conformations. 140 (c) cycloHexene oxides. Electron diffraction 141 shows that the six- A i7 membered ring of cyclohexene oxide adopts a conformation (163) similar to the half-chair conformation of cyclohexene itself. (d) cycloHexenone and cyclohexenyl cations anions and radicals. In cyclohex-2-enone the introdubtion of a third trigonal carbon atom destroys See also Raphael and Stenlake ibid. 1953 1286 ; Orloff Chern. Rev. 1954 54 409 ; Corey and Sneen J . Amer. Chem. SOC. 1955 77 2505. 137 Barton Cookson Klyne and Shoppee Chern. and Ind. 1954 21. 138 Beckett Freeman and Pitzer ibid. 1948 70 4227. 139 Inter al.Carlisle and Crowfoot Proc. Roy. SOC. 1945 A 184 64 ; Pastern& Acta Cryst. 1951 4 316 ; Lasheen ibid. 1952 5 593 ; Bastiansen and Markali Acts Chem. Scand. 1952 6 442 687 ; cf. Lindsey and Barnes Acta Cryst. 1955 8 227. This conformation seems to have been first suggested for tetralin by Mills and Nixon (J. 1930 2510) and for cyclohexene by Boeseken and Stuurman (Proc. k. ned. &ad. Wetenschap. 1936 39 2). 140 But see Goering Blanchard and Silversmith J . Amer. Chem. Xoc. 1954 76 5409. 141 Ottar Acta Chem. Scand. 1947 1 283. For a discussion of the reactions of cyclohexene oxides and anhydro-sugars in terms of this conformation see inter al. Cookson Chern. and I n d . 1954 223 1512; Angyal ibid. p. 1230. BARTON AND COOKSON CONFORMATIONAL ANALYSIS 79 any resemblance to boat or chair conformations.If all the ring carbon atoms except are approximately coplanar the ring can adopt only one conformation (164) which is free from angle strain. cycZoHexeny1 cations anions and radicals may be expected to have similar conformations. Owing to the greater overlap possible between (say) the p-orbital of a nucleophilic species and the partially vacant orbital of a cyclohexenyl cation in the transition state for quasi-axial addition than for quasi-equatorial addition one might expect that addition to a cyclohexenyl cation would give usually as the kinetically controlled product the quasi-axial isomer. Thus in the geometrically equivalent tetralin series X,1 hydrolysis of the bromide from podophyllotoxin 1429 143 (165) gives the quasi-axial epi-podophyllo- toxin 144 (166) although it is the less stable epimer.OH H &LH / oco OH OMe H (165) (166) Conformational Anomalies.-Whilst the principles of conformational analysis as outlined in this Review serve to correlate a great many experi- mental facts in a satisfactory manner there are certain cases where anomalies of behaviour have been observed. In the sequel some of the more important of these are discussed. (a) Polysubstituted cyclohexanes. Attention has been directed 145 to certain 2 2 6 6-tetrasubstituted cyczohexyl compounds in which the usual stability order of epimers is reversed. A simple consideration of non-bonded interactions shows that if a 2 2 6 6-tetrasubstituted cycbhexyl compound R R X (167) (168) (169) is more stable in the axial (167) than in the equatorial form then the same reversed stability order must on the assumption of fixed conformations 142 Hartwell and Schreclier J .Amer. Chem. SOC. 1951 73 2909. 143 Schrecker and Hartwell ibid. 1952 74 5676. 144 Idem ibid. 1953 75 5916. 1 4 5 Barton Chem. and Irzd. 1953 664. 80 QUARTERLY REVIEWS hold for (168) and (169). All other R-substituted cychhexyl compounds should however follow the usual stability order. An interesting example in compounds of the class (169) has been discussed Me by Fodor and his collaborators,122 whose evidence suggests 146 that in tropane derivatives the methyl group is axial as in (170). All the discussion in this Review on the relative stabilities of epimers and of alternative conformations refers strictly only to non-polar molecules in which the forces between atoms close together but not directly linked are repulsive and inversely proportional to a high power of interatomic distance.I n addition to such repulsive forces induced by the approach of the outer electronic orbitals of different atoms account must be taken of normal (attractive or repulsive) electrostatic forces between integral charges or dipoles which vary inversely with a much lower power of distance.147 An example where conformation appears to be deter- mined more by integral charge interaction than by non-bonded repulsions has already been cited on p. 63 [see (SS)]. Physical evidence shows that the trans- 1 2-dihalogeno-cyclohexanes consist of comparable coiicentrations of the diequatorial and diaxial con- f o r m a t i o n ~ ~ ~ ~ an anomaly usually attributed to dipole repulsion in the diequatorial conformations.The Raman spectra of the trans- 1 4-dihalo- genocyclohexanes have been interpreted 149 as showing the presence in solvents such as ether of a preponderating concentration of the diaxial conformation although only the expected diequatorial conformation exists in the crystal. Conformational equilibria are of course a function of temperature and especially for polar substances of the polarity of the medium. In spite of reservations with regard to 1 2-dihalogenocycb- hexanes the preferred conformations of most polyhalogenocycZohexanes of the benzene hexachloride type appear to be those with the maximum number of equatorial substituents.l5O 151 146 This argument accepts of course that the bulk of a methyl group should be greater than that of an electron pair.One must note however that X-ray diffraction (Visser Manassen and de Vries Acta Cryst. 1954 7 288) of tropine hydrobromide reveals that the methyl group is equatorial not the hydrogen atom. As always in the crystalline state the conformation may be influenced by intermolecular forces. 147 Ingold " Structure and Mechan&n in Organic Chemistry " G. Bell London 1953 Chap. 111. 148 Inter al. Bastiansen and Hassel Tidsskr. Kjemi Bergvesen Met. 1946 6 96 ; Larnaudie Compt. rend. 1953 236 909 ; Tulinskie Di Giacomo and Smyth J . Amer. Chem. Soc. 1953 75 3552 ; Kozima Sakashita and Maeda ibid. 1954 76 1965 ; Bender Flowers and Goering ibid. 1955 77 3463 ; Kwestroo Meijer and Havinga Rec. Truv. chim. 1954 73 717. ( b ) Dipoles and integral charges. (170) +iP 149 Kozima and Yoshino J .Amer. Chem. SOC. 1953 '95 166. 150 Bastiansen Ellefsen and Hassel Acta Chem. Scund. 1949 3 918 ; Norman ibid. 1950 4 251 ; van Vloten Kruissink Strijk and Bijvoet Acta Cryst. 1950 3 139. 151 The reactions of these substances illustrate well the stereospecificity of addition and elimination. See inter al. Cristol Hause and Meek J . Amer. Chem. Xoc. 1951 73 674 ; Hughes Ingold and Pasternak J. 1953 3832 ; Kolka Orloff and Griffing, BARTON AND COOKSON CONFORMATIONAL ANALYSIS 81 The delicate balance between dipolar and steric repulsions is nicely illustrated by the following example. 152 2-Bromocyclohexanone exists in solution in the axial (171 ; R H) rather than in the equatorial conforma- tion (172 ; R = H) in which repulsion between the C=O and CeBr dipoles would be greater.The 4 4-dimethyl derivative however exists in + (171) (172) (173) the conformation with the bromine equatorial (172 ; R = Me) since the methyl group introduces a large repulsive 1 3-interaction into the axial conformation (171). It is possible for intramolecular hydrogen bonds to introduce sufficiently powerful attractive forces to modify or reverse normal conformational preferences. Thus in the 0-H stretching region of the infrared spectrum cis-cyclohexane-1 3-diol in dilute solution in carbon tetrachloride shows evidence 153 of strong internal hydrogen bonding due to the diaxial conformation (173). cis-Substituents on a cyclohexane ring one of which must be equatorial and one axial are separated by the same distance as trans-substituents when both of these are equatorial.So a t first sight cyclisation reactions involving either cis- or diequatorial trans-substituents might be expected to take place equally easily. However for all reactions requiring an approximately coplanar transition state and not involving replacement of the cyclohexane sub- stituents cis(e,a)-compounds react more rapidly than trans- (e,e)-compounds. Familiar examples are the reactions of 1 2-diols with lead tetra-acetate 154 and with periodic acid,155 and of 1 2-amino-alcohols with lead tetra- acetate,156 and acyl migration in 1 2-amin0-alcohols.~~~ Hassel and Ottar,158 in a slightly different context first drew attention to the different response of a chair ring to the two different types of distortion imposed on it by bringing cis(e,a)- or trans(e,e)-substituents into more nearly coplanar positions.The distortion induced by forcing adjacent equatorial J . Amer. Chem. Xoc. 1954 76 3940 ; Riemschneider Monatsh. 1955 86 101 ; Cornu- bert and Rio Bull. SOC. chim. France 1955 60 and previous papers by the several authors. (c) Hydrogen bonds. (d) Differential reactivity of cyclohexane- 1 2-diols. 152 Corey J . Amer. Chem. SOC. 1953 75 2301 3297 ; 1954 76 175. 153 Kuhn ibid. 1952 74 2492 ; 154 Criegee Kraft and Rank Annalen 1933 507 184 ; 155 Price and Knell J . Amer. Chem. SOC. 1942 64 552. 156 McCasland and Smith ibid. 1951 73 ,5164 ; Posternak Helv. Chim. Acta 15' Fodor and Kiss Nature 1949 164 917 ; J . Arner. Chern. SOC. 1950 72 3495. 15* Hassel and Ottar Acta Chem. Scand. 1947 1 929. 1954 76 4323. Prelog Schenker and Giinthard Helv.Chim. Acta 1952 35 1598. 1950 33 1597. F 82 QUARTERLY REVIEWS and axial substituents more nearly into the same plane (174) leads to a flattening of the ring and an increase in endocyclic valency angles the axial atoms or groups move further away from one another. The whole movement resembles an incipient conformational inversion and requires W H A (174) H A (175) little energy. On the other hand forcing two equatorial bonds more nearly into the same plane (175) entails a reduction in the separation of the axial atoms or groups and therefore much more energy is required. In agreement with this approach normally only cis(e,a)-cycbhexane- 1 2- diols condense with acetone to form isopropylidene derivatives. 159 lS0 For an interesting exception see Angyal and Macdonald J .1952 686.

ISSN:0009-2681    

DOI:10.1039/QR9561000044

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

RADIOACTIVATION ANALYSIS By E. N. JENKINS M.Sc. A.R.I.C. and A. A. SMALES B.Sc. F.R.I.C. (ATOMIC ENERGY RESEARCH ESTABLISHMENT HARWELL NR. DIDCOT BERKS.) Introduction IN radioactivation analysis the weight of the required element in a sample is determined by measuring the intensity of induced radioactivity rather than by measuring say the optical density of a coloured solution the weight of a precipitate or the volume of reagent consumed during a titration. The intensity of induced radiation is directly proportional other things being equal to the weight of the required element and is of course independent of the state of chemical combination of the element. The assay of certain ores for uranium and of fertilisers for potassium are common industrial examples of quantitative chemical analysis by measurement of radio- activity.The a- p- and y-radiation from 238U and its decay products and the p- and y-radiation from 40K (of 0.012~0 abundance in natural potassium) are examples of natural or spontaneous radioactivity only twelve elements of atomic number 92 or less show any such appreciable spontaneous radioactivity in the naturally occurriog mixture of isotopes. Most of the remaining elements can however be converted into artificially radioactive isotopes by appropriate nuclear bombardment or " activation ". The process of nuclear bombardment of a weighed sample normally together with a standard followed by measurement of the intensity of the induced radiation constitutes radioactivation analysis. Normally the method in- cludes the isolation and purification of the required artificially radioactive isotope or mixture of isotopes by specific chemical operations often per- formed in the presence of milligram amounts of an inactive isotopic carrier added after the activation in favourable cases this isolation is not required and the final measurement is made on the intact sample.In either case the mass of the required constituent Y in the sample is finally calculated by the simple equation Mass of Y in sample = Radiation intensity from Y in sample Radiation intensity from Y in standard Mass of Y in standard x Radioactivation analysis is applicable in principle to almost all the elements though a few of them present great difficulty. In general the distinctive features of the method are its extreme sensitivity its freedom from contamination by reagents the ease with which both the sample and the standard may be activated at the same time and the possibility in certain cases of preserving the samples intact through the analysis.83 84 QUARTERLY REVIEWS Experimental methods The methods and techniques involved in radioactivation analysis will be discussed with particular reference to a specific and important example the determination of small quantities of arsenic in biological material.1 Sampling and Activation.-A feature of radioactivation is the minimum pretreatment received by the sample before activation. Chemical treat- ment say for concentration of the arsenic or for the removal of interfer- ing elements or for the oxidation of organic matter is rarely necessary a t this stage. The physical preparation of the sample consists only of weighing it into a suitable irradiation container such as a quartz or Polythene ampoule which is then sealed.Refractory minerals may require preliminary crushing and grinding to aid their eventual dissolution Just as in any other sensitive analytical method extreme care must be taken to avoid contamination of the sample at this stage. I n particular the laboratory and balance used when weighing out samples must be segregated from the main chemical laboratory where radiochemical operations will be carried out involving macroquantities e.g. of arsenic as carriers. The most widely used method of activating the sample and standard is to place them side by side within the high flux of thermal and fast neutrons and y-rays provided by a nuclear reactor. This process is usually called a " pile irradiation ".Most of the nuclear reactions useful in radioactivation analyses can be induced by the thermal neutrons occasional use can be made of the fast-neutron component of the pile flux. Alternative methods of providing an intense neutron flux or bombardment with deuterons or other charged particles will be mentioned later. In the example we have chosen the activation of arsenic by pile irradiation the appropriate nuclear reaction is 75As(n,y)76As (t4 = 26.8 hr. p- and y-active) and it proceeds with a cross-section (for thermal neutrons) of 4.1 barns. An important feature of nuclear reactors particularly those of the graphite moderated type (e.g. B.E.P.O. Harwell) is their capacity for the simul- taneous irradiation of several hundreds of small samples (including standards if required).The practical details of tlhe irradiation of samples in B.E.P.O. have been discussed fully in a review by Smales.2 The irradiation facilities are available to outside workers and information can be obtained fkom the Isotope Division A.E.R.E. H a r ~ e l l . ~ Given adequate facilities for the irradiation of analytical samples the analyst will next be interested in the quantitative laws governing the growth of induced activity in the sample and the standard and its decay on removal from the irradiation device. Generally speaking it seems fair to remark that activation of a minor constituent by thermal neutrons is influenced far less by the nature of the solid or liquid matrix than is the case with Smales and Pate Analyst 1952 '77 196. Smales Atomics 1953 4 No.3 55. " Radioactive Materials and Stable Isotopes " Catalogue No. 3 Isotope Division Atomic Energy Research Establishment Harwell near Didcot Berks. 1954. JENKINS AND SMALES RADIOACTIVATION ANALYSIS 85 spectrometric arc or spark excitation. This implies that radioactivation analysis stands in much less need of specially prepared standards than direct emission or mass spectrometry. Normally the sample may be irradiated side by side with a primary chemical standard say a pure metal or oxide or a small volume of a standard solution. However it is not always per- missible to assume that the effective neutron flux is uniform throughout the combination of sample and standard. Apart from possible local variations in pile flux (which could be tested for by irradiating a number of specimens simultaneously) a variation in flux may be introduced through neutron absorption (self-shielding) by the required constituent or by others.For- tunately many common matrix materials (Si 0 C H Al) have low total absorption cross-sections for neutrons of thermal or of intermediate energy. The absorption by a minor const'ituent would not normally be excessive and the standard could be appropriately diluted to an equally low concentra- tion of absorbing centres. Where tlhe matrix material or a major constituent of it is opaque to thermal neutrons then the sample weight must be restricted to the minimum. The complete calculation of the self-shielding faqtor for a given matrix in a given shape integrated over the whole spectrum of pile neutrons would be a formidable task and only approximate solutions have been put f ~ r w a r d .~ A useful preliminary assessment can be made using the simple exponential equation f = foewNuT where fo f are the incident and attenuated fluxes N the number of absorbing centres per cm.3 r the radius of a spherical sample and cr the total atomic neutron absorption cross-section for the complete spectrum of pile neutrons a t the point of irradiation (not merely the cross-section for thermal neutrons). Attention has recently been drawn again by Plumb and Lewis to the effect of neutrons of ( ( resonance " energies. Any contribution by neutrons of intermediate energy to the tot'al self-shielding effect will be reduced if the irradiations are carried out (at considerable loss of sensitivity) in the thermal column of the reactor.I n all cases the practical effect of self-shielding in a given sample and/or standard could be judged by simultaneous irradiation of a number of samples of different weights or dilutions. The growth of induced activity during irradiation follows the law Io (dis. min.-l) where IoB = induced radioactivity due to product B t / t = ratio of irradia- tion time to half-life of B WA = mass of target element A 8 = fractional abundance of a specific isotope 6 = activation cross-section (in barns) for that specific isotope MA = atomic weight of the element A andf = activat- ing flux of neutrons per cm.2 per sec. The expression [l - exp (- 0.693t/tj)] is often called the (' growth = 60Wg.0.6.02.1023.0,.10-24.f[l - eXp (- 0*693t/'t:)]/nf~ Hughes and Harvey " Neutron Cross Sections " B.N.L.325 U.S. Govt. Printing 5 Keyes U.S. Atomic Energy Commission Unclassified Report No. A.E.C.D.-3@@0 6 Plumb and Lewis Nucleonics 1955 33 No. 8 42. Office Washington 25 D.C. 1955. 1950. 86 QUARTERLY REVIEWS factor ”. It has a value of 0-5 for an irradiation time equal to the half- life of the product ; for longer periods of irradiation it rises more slowly to a limiting value of 1.0. Practically an irradiation for 5 half-lives induces almost a saturation activity of magnitude controlled solely by the factors WA 8 oa MA andf. Under these conditions and with the values WA = 10-6 g. f = 1012 cm.-2 sec-1 (appropriate for irradiations in B.E.P.O.) the previous equation reduces to This equation is convenient in making a rapid preliminary assessment of activation possibilities.The decay of the induced activity starting as soon as the irradiation ceases follows the law I d = IoB exp (- 0.693d/t4) where Idg is the residual radioactivity of B after a time d. In the specific case of arsenic irradiation almost to saturation would require a t least 5 days ; a t the end of this period the induced activity due to 76As from lop6 g. of arsenic in the sample may be calculated as follows Io = 3.6 x lo7 x 4.1 x 1.00/75 = 1.96 x lo6 dis. min.-l pg.-I Twenty-four hours after the end of the irradiation the residual activity would still be about 1 x lo6 dis. min.-l. Radiochemical Purification.-Immediately after irradiation the sample is normally subjected to radiochemical purification in order to isolate the required product e.g. 76A~ free from extraneous radioactivity.For example the irradiation of lop6 g. of arsenic in 1 ml. of blood for 5 days would yield not only 2 x lo6 dis. min.-l of 76As but also 4 x lo7 dis. min.-l of 37-min. 38Cl and 2 x lo8 dis. min.-l of 14.8-hr. 24Na. Rather than undertake the labour of the quantitative separation and purification of 10-6 g. of arsenic with the attendant risks of losses such as those due to absorption on precipitates the analyst adds 50 mg. of inactive arsenic as a carrier for the radioactive 76As. Provided that the mixture can now be treated so as to bring all arsenic atoms normal and radioactive into the same chemical form-say as arsenate-the subsequent chemistry need not be quantitative. g. of arsenic (or it could well be loblo g. for radioactivation analysis has been applied a t this low level) is replaced by that of purifying 50 mg.of arsenic with quantitative determination of the chemical yield that is the percentage recovery of the added arsenic carrier. In the specific example of the deter- mination of arsenic in biological material the arsenic in the sample might be present as As02-l A s O ~ ~ - As3+ or as an organic compound The carrier was added as sodium arsenite followed by a wet oxidation of the sample and added carrier with hydrogen peroxide nitric acid sulphuric acid and perchloric acid. The radiochemical purification of the induced activity in the presence The problem of the quantitative recovery of JENKINS AND SMALES RADIOACTIVATION ANALYSIS $7 of the carrier involves normal chemical procedures such as precipitation distillation solvent extraction ion exchange and cknomatography.An operation frequently of use consists of " scavenging " traces of unwanfed elements from solution by forming in it a strongly adsorptive precipitate e.g. of ferric hydroxide antimony sulphide or barium sulphate. It is of course restricted to conditions such that the carrier element remains in solution. The purification need not be too time-consuming ; the operations may be carried out on a semimicro-scale and permit the use of a clinical centrifuge as a rapid alternative to filtration. Again small losses due to incomplete transference of solutions or to incomplete precipitation are adjusted by final measurement of the chemical yield. It has been found possible to purify the relatively short-lived isotope 233Th (half-life 22.1 min.) from very high initial extraneous ,&activities due to uranium zirconium yttrium and rare-earth elements within two hours of the irradiation and dissolution of the ample.^ The purification of arsenic in irradiated biological material or germanium oxide included several precipitations as the metal with ammonium hypophosphite distillation under oxidising conditions to remove germanium while the arsenic remains in the acid mixture and distillation of arsenic as arsenious chloride under reducing conditions.Useful accounts of the radiochemical purification of a variety of elements have been published by Meinke,* by Coryell and S~garman,~ and by Klein- berg. 10 During the radiochemical purification of the induced activity from the sample the standard will require similar but possibly less extensive treatment.At the very minimum the standard must be taken into solution together with carrier and then precipitated and weighed for determination of chemical yield in exactly the same chemical form as the end-product of the purification of the sample. In our example arsenic was finally precipitated from acid solution with ammonium hypophosphite washed with water and dried under a radiant heater. In the example followed above inactive 75As was converted by neutron capture into the p- and y-active 76A~ which was purified after admixture with arsenic carrier by chemical procedures specific for arsenic. It should be pointed out that cases arise where the product of pile irradiation is not identical chemically with the target element-cf. oxygen and uranium among others in the Table (p.94). In the determination of uranium utilising the fission of 235U it is convenient to add barium carrier to the irradiated sample and to carry out chemical procedures which are specific for barium not for uranium.ll Measurement of Source.-The mounting and counting of the carrier precipitates bearing radiochemically pure induced activity demand only 7 Jenkins Analyst 1955 80 301. 8 Meinke U.S. Atomic Energy Commission Unclassified Reports Nos. A.E.C.D.-2738 9 Coryell and Sugarman " The Fission Products Book 3 " National Nuclear Energy 10 Kleinberg U.S. Atomic Energy Commission Unclassified Reports No. LA-1566 11 Smales Analyst 1952 77 778 ; Seyfang and Smales ibid. 1953 78 394. 1949 and -3084 1951. Series Vol. IV-9 McGraw-Hill New York 1951. 1953 and LA-1721 1954. 88 QUARTERLY REVIEWS an elementary knowledge of radiochemistry.12 It is usually convenient to make the precipitates into a slurry on circular aluminium trays about an inch in diameter.Considerable attention must be paid to obtaining a uniform thickness over the tray ; in the most precise work the thickness should be so far as possible similar for the sample and the standard. With the counting equipment a t present commercially available in this country the ultimate sensitivity of radioactivation analysis is best attained by counting /?-particles rather than y-photons. Simple p-counting equip- ment comprising a lead-shielded end-window Geiger tube a power pack to give up to 1800 v a pre-amplifier and a scaling unit costs only a few hundred pounds and is becoming widely available. Doubtless y -counting will in future assume greater prominence with the improvement of tech- niques-possibly this may include a reduction in the present high background of scintillation crystals and the provision of inexpensive and stable multi- channel pulse-analysers.At the moment the chief interest in y-measure- ments lies in y-spectroscopy l3 usually with moderately intense sources to select individual y-energies and avoid much of the necessity for chemical separations. Examples of this approach will be given below. Measurement of the /3-activity of the sample and standard is best regarded as measurement of a ratio between two sources of similar composition and thickness at identical counting geometry. In this way many of the potential errors of absolute /?-counting (variations in self-absorption self-scattering back-scattering external absorption) are avoided./%Particles of maximum energy below 0.2 Mev require special mounting and counting techniques and in some cases a gas-flow proportional counter is used with the sample mounted internally with 272 geometry. Most of the elements listed in the Table with favourable sensitivity can be determined by making the final measurements with an end-window Geiger tube preferably of the mica- window EHM2 type. One fundamental aspect of measuring radioactivity must be stressed- the statistical nature of the radioactive process causes variations to appear between successive measurements on the same sample (even where decay loss is insignificant over the duration of the experiment). The standard deviation of a series of repeated measurements is an index of this variability and is numerically equal to the square root of the average number of particles or photons recorded during each measurement (not the square root of the count rate).The statistical fluctuations in measurements of radioactivity need not introduce large errors provided that the counting periods are prolonged so as to include 10,000 counts; the standard deviation is then 100 i.e. the coefficient of variation is 1%. The lower limits of reasonably precise measurement are governed by the efficiency of the counter and by the natural background of the equipment- owing to radioactive elements in the constructional materials and to cosmic l3 Cook and Duncan " Modern Radiochemical Practice " Oxford Unix-. Press l3 Owen Atorrzics 1953 4 No. 1 5 ; No.2 34 ; Connally and Lebmuf ,4naZ9t. Oxford 1952. Chent. 1953 25 1095; Peirson Natztre 1954 173 990. JENKINS AND SMALES RADIOACTIVATION ANALYSIS 89 radiation. Reasonable limits are 100 dis. min.-l for /3-emitters where the maximum /3-particle energy exceeds 0.2 MeV 1000 dis. min.-l for isotopes emitting softer ,&radiation and 1000 photons min.-l for y-emitters. The upper limit of precise measurement can be extended at will by taking only a small known fraction of the purified carrier for the actual measurement of radioactivity . In the above discussion we have assumed that the chemical treatment of the sample after addition of the carrier isolated the required activity com- pletely free from extraneous activities. Much of the reliability of radio- activation analysis arises from the ease with which this assumption can usually be checked.The radiochemical purity of the final precipitates isolated from sample and standard respectively may in the first instance be checked by a series of decay measurements. Aft,er appropriate corrections the count rates at various intervals are plotted on a logarithmic scale against time on a linear scale. Successive count rates obtained during the decay of a single radiochemically pure isotope will lie on a straight line of slope related to the half-life. Alternatively the penetrating power of the /3-radia- tion may be measured through a series of aluminium absorbers of increasing thickness with correction for any concomitant decay. The corrected count rates are again plotted on a logarithmic scale but against the absorber thickness on a linear scale.The shape of the absorption curve is char- acteristic of the p-spectrum of a particular isotope and may be closely compared with standard curves recorded with especially purified isotopes under the same conditions. The penetrating power of any y-radiation emitted by the isolated radioactive isotope may be measured through a series of lead absorbers a scintillation counter would normally be used as a detector. Finally the characteristic y-spectrum of the isotope can be recorded by means of a sodium iodide scintillation spectrometer l3 (see Figure) provided that the source is of reasonable intensity (with present equipment including a single-channel pulse analyser at least 1000 photons min.-l are required to obtain reasonable results). The record may be compared with standards.In certain cases the purified induced activity may be a mixture of radio- active isotopes e.g. the irradiation of cerium under the conditions defined in the footnotes to the Table would give 141Ce (33 days 0.58 Mev ,6,0.145 Mev y ) together with 14We (33 hr. 1-39 Mev @ 0.035 0.126 0.160 0.289 0.356 0.660 and 0-720 Mev y). The test of radiochemical purity remains that of comparing the sample and the standard under similar conditions. It is not expected that each of the three parameters half-life shape of p-absorption curve and shape of y-spectrometer record can in every case be precisely determined for example several activities listed in the Table decay only comparatively slowly. In general enough characteristic results may be gathered to establish the required degree of purity.The practical steps in a normal radioactivation analysis may now be summarised 1. Simultaneous activation of weighed quantities of sample and standard. 2. Dissolution of sample and standard each in the presence of carrier. 90 QUARTERLY REVIEWS 3. Treatment of sample and standard to bring the induced activity and 4. Chemical purification of carrier in the solution from the sample (and the carrier into the same chemical form in a homogeneous mixture. y-Spectrum of 7sAs. A Photoelectric y-capture peak at 1.21 Mev. B 9 9 9 , , 0.65 M ~ v . c D Compton continuum due to y of 0.55 MeV. E Back-scatter peak due to y of 0.55 Mev. 9 ¶ ¶ , , 0-55 M ~ v . possibly also from the standard) until the induced activity is radiochemically pure. 5. Determination of the chemical yields of carrier for the sample and standard severally.6. Comparison of the intensity of radioactivity of suitably mounted sources prepared from sample and standard under identical counting con- ditions with appropriate corrections for chemical yield decay dead-time losses in the counter etc. 7. Confirmation of the radiochemical purity of the isolated induced activities by measuring (a) the rate of decay ( b ) the shape of the p- and possibly the y-absorption curves and (c) in suitable cases the characteristic y-spectrometer record. JENKINS AND SMAI;ES RADIOACTIVATION ANALYSIS 91 Limitations caused by conflicting nuclear processes In the preceding discussion it was assumed that 76A~ the illustrative example could be formed in the sample as in the standard only by thermal neutron activation of the required element arsenic.However in certain rather special cases the required activity may be induced by neutron bombardment of some element other than arsenic. This hardly ever occurs except when the required element is accompanied in the sample by a large excess of an element differing from it by only one or two units of atomic number. Nuclear reactions of the (n,p) or (n,cc) type may then induce an activity in the foreign element identical with that of the product of the (n,y) reaction of the target element. A more subtle case arises when a foreign element of atomic number one unit less than that of the required element is actually transmuted into the latter by the succession of an (n,y) reaction and /3-decay. Examples of each of the above type of interference are given below.(a) During determination of traces of sodium in aluminium the fast neutron component of the pile flux induces the reaction 27Al(n,~t)2~Na [cf. 23Na(n,y)24Na]. Measurements made by Salmon 14 show that the spurious sodium activity introduced in this way is equivalent to 81 p.p.m. of sodium for irradiations near the centre of B.E.P.O. (1954). (b) Le Claire Gregory and Smales l5 attempted the estimation of traces of 40A in sylvite (KCI) minerals by neutron activation to 41A (this determina- tion would be significant in estimating the ages of such minerals). The estimation is subject to prohibitive interference from the reaction ( c ) Smales and Pate l6 have shown that the following sequence of reactions occurs during the activation of germanium 74Ge(n,y)75Ge(tg 1-37 hr.) ; 75Ge (/3 decay) 75As (stable) ; 75As(n,y)76As(tg 26.8 hr.) However insufficient arsenic is produced by transmutation from the germanium to introduce appreciable error into the determination of arsenic in germanium dioxide at the 0.05 p.p.m.level when the irradiations are made for 15 hours a t a flux of 10l2 neutrons sec.-l. It must be emphasised that the limitations described in this section become apparent only in rather special cases where one is trying t o deter- mine traces of an element in the presence of a very large excess of an element which adjoins it in the Periodic Table the cross-sections for (n,p) ( n ~ ) reactions or the yield of the combined (n,y ; #I) reaction being normally extremely low. The ( n g ) and the (n,a) reaction are normally due to the fast-neutron componept of the pile flux and can often be avoided if the irradiations are carried out in the thermal column.This irradiation facility provides a substantially lower flux than that near the centre of the pile and the analyses are correspondingly less sensitive. A.E.R.E. C/R 1324 1954. Each case relates to activation using pile neutrons. lK( n,p ) lA [ cf. 4OA( n y ) 41A]. 1 4 Salmon United Kingdom Atomic Energy Authority Unclassified Report No. 15 Le Claire Gregory and Smales personal communication. 16 Smales and Pate Analyt. Chem. 1952 24 717. 92 QUARTERLY REVIEWS The production of spurious 76As from germanium during the determina- tion of traces of arsenic in 1 g. samples of germanium dioxide depends on the time of irradiation and on the square of the neutron flux although the error is + 0.08 p.p.m.for 75 hours’ irradiation at 2 x 10l2 neutrons sec.-l it falls to + 0.0001 p.p.m. for 10 hours’ irradiation a t 2 x loll neutrons cm.-2 sec.-l. At this reduced flux and irradiation time the method retains adequate sensitivity for the analysis of 0.001 p.p.m. of arsenic. General discussion of radioactivation analysis for trace elements Irradiation of lowg g. of arsenic under standard conditions has been calculated (p. 84) to yield 2 x lo6 dis. min.-l. 100 dis. min.-l can be measured with reasonable precision when normal @-counting equipment is used. After allowance for minor losses due to decay incomplete chemical recovery etc. the lower limit of satisfactory analysis for arsenic may be set at 10-10 g. and Smales and Pate l6 have measured arsenic a t this level in distilled water.It is well known that the measurement of radioactivity permits the detection of extremely minute quantities of the natural radio- active series the analyst may now extend the scope of highly sensitive radioactivity measurements to include species which are themselves inactive but which acquire induced activity on neutron activation. By reason of this intrinsic sensitivity radioactivation analysis is particularly suited to the determination of trace elements i.e. elements present in a sample a t a concentration of 100 p.p.m. or less. The utility of an analytical method can be assessed by answering the questions (a) What property is measured ? ( b ) What elements can be determined and t o what lower limits ? (c) Is the element determined identified with certainty ? (d) Can several elements be determined simultaneously ? (e) How reliable are the quantitative results ? (a) What Property is measured ?-Radioactivation like emission or iiiztss spectrometry is a method of determining elements irrespective of their state of combination.Chemical bonds are frequently broken during neutron and y-ray bombardment. That is radioactivation does not disclose the chemical form in which an element occurs in a sample and it cannot be used for determination of specific compounds. It has just been stated that radioactivation is a method of determining elements but strictly it determines a specific isotope of the element that is radioactivation analysis for say dysprosium proceeds through a measure- ment of the induced activity due to the product of the reaction l64Dy(n,y)lg5Dy.Now the abundance of 164Dy in naturally occurring dysprosium is 28.47% the other important stable isotopes being those of mass 156 158 160 161 162 and 163. None of those isotopes is directly measured. Radioactivation has of course been used as a method of isotopic- abundance analysis e.g. by measuring the ratio 235U total uranium for enriched and for depleted uranium metal. l 1 These are favourable cases, JENKINS AND SMALES RADIOACTIVATION ANALYSIS 93 however and in general radioactivation is very much less versatile than inass spectrometry for isotopic analysis. (b) What Elements can be determined and to what Lower Limits?- On p. 92 the limit of sensitivity of radioactivation analysis for arsenic was discussed on the assumption that the sample was irradiated to satura- tion at a flux of 1OI2 neutrons cm.-2 {ec.-l and that 100 dis.min.-1 of induced activity due to 76As can be isolated and measured. It is in- structive to extend this discussion over the entire range of chemical elements. A practical definition of sensitivity might be taken as that weight of element which on irradiation a t a flux of 10l2 neutrons cm.-2 sec.-l to saturation or for one month (whichever is the shorter) followed by decay for 2 hours gives 100 dis. rnin.-l of residual induced activity. The Table sets out the absolute weights of various elements which one could expect to measure the corresponding concentrations depend on the sample weight-in general 1 g. would be a fair figure possibly rather more .for solids and rather less for liquids.The coefficient of variation of single analyses for a given element would be about 10% if the sample and the background could each be measured for an hour. sec.-l assumed in calculating the results given above is appropriate for irradiations carried out near the centre of a graphite-moderated natural-uranium reactor of the B.E.P.O. type. Higher fluxes (available over a smaller effective volume) are available in water-moderated reactors of similar or higher power rating e.g. figures of 7 x 1013 and 5 x 1014 have been quoted for the Canadian heavy-water reactor at Chalk River l7 and for the American light- water-moderated Materials Testing Reactor at 1daho.l' Heavy-water reactors now under construction at Harwell l8 should in time provide irradiation facilities which will extend the sensitivities quoted in the Table by a factor of nearly 100.In certain cases elements listed with poor sensitivities in the Table may be analysed more readily by other methods of activation or detection. The most important alternative to pile irradiation is the use of a cyclotron beam of protons or deuterons. The disadvantages compared with pile irradiation are the limited cross-sectional area of the beam and the limited degree of penetration of charged particles into solid samples. The radioactivation analyses of carbon in steel by von Ardenne and Bernhard and others,25 and in organic compounds by Sue 2r exemplify a cyclotron-induced reaction which could not have been brought about in the pile namely 12C(d,n)13N (9.9-min. 1-2 Mev positron emitter). Bade and others 27 used the 22 Mev betatron at the G.Roussy Institute Villejuif France for the radioactivation analysis of oxygen down to a 6 mg. level in organic compounds and down to 0.1% in aluminium metal by using the reaction 160(y,n)150(t$ 2.1 min. 1.7 Mev Pf). These workers indicated l7 " Catalogue of Nuclear Reactors " C.R.R.-590 Atomic Energy of Canada Ltd. 18 " First Annual Report of the United Kingdom Atomic Energy Authority 1954- The flux of 10l2 neutrons Chalk River Ontario 1955. 5 5 " H.M.S.O. London 1955. 94 QUARTERLY REVIEWS Estimated sensitivities of radioactivation analyses by irradiation in a natural uranium graphite-moderated reactor (for notes see pp. 96 97). a s Element Actinium * . Aluminium . Antimony. . Argon. . . Arsenic . . Astatine * . Barium . . Beryllium.. Bismuth . . Boron. . . Bromine . . Cadmium. . Czesium . . Calcium . . Carbon . . Cerium . Chlorine . . Chromium. . Cobalt. . . Copper. . . Dysprosium . Erbium . . Europium. . Fluorine . . Francium * . Gadolinium . Gallium . . Germanium . Gold . . . Hafnium . . Helium . . Holmium . . Hydrogen. . Indium . . Iodine . . . Iridium . . Iron . . . Krypton . . Activated form Parent zz7Ac '*A1 ."Sb with lZ4Sb L'A 7 6As Parent zloAt L 3 g B ~ l0Be L2B 30mBr + 80Br with szBr l15Cd with l17Cd and l1 5mCd 134cs 45Ca 14c 21OBi 41Ce with 143Ce 51Cr 60Co 64Cu 38c1 5Dy 171Er 152mE~ 20F Parent 3Fr 159Gd 2Ga 75Ge with 77Ge lg8Au lslHf 6He 3H 166H~ 3H l161n with 1281 with lg21r 59Fe 85Kr 11 4rn-ll 4mIn 1941r Half-life 22 y. 1% a 2-3 min. 2.8 d. 60 d. 1.8 hr. 26.8 hr. 3.3 hr. EC 0*20y0 a 35 min.2.7 x 106 y. 5.0 d. 0.03 sec. 4.6 hr. 35.9 hr. 54 hr. 2.9 hr. 43 d. 2.3 y. 152 d. 5580 y. 32 d. 33 hr. 37.3 min. 27 d. EC soft p 3% Y 58% p- + ps 5.2 y. 12.8 hr. EC 2-3 hr. 7.5' hr. 9.3 hr. p EC 12 see. 21 min. 18.0 hr. 14.1 hr. 82 min. 12 hr. 2.7 d. 45 d. (unknown) 12.4 y. 27.2 hr. 12.4 y. 54 min. 50 d. 25 min. 19 hr. 75 d. 45 d. 4.4 hr. soft /3 soft p Estimate sensitivit (g.1 5 x 10-13 Poor 1 x 10-10 5 x 10-10 5 x 10-11 1 x 10-16 1 x 10-9 Poor 5 x 10-8 Poor 1 x 10-10 1 x 10-9 5 x 10-10 Poor i x 10-7 1 x 10-9 5 x 10-9 1 x 10-7 5 x 10-10 1 x 10-10 1 x 10-12 1 x 10-10 1 x 10-12 Poor 1 x 10-18 5 x 10-10 1 x 10-10 5 x 10-12 5 x 10-10 5 x 10-6 5 x 10-12 Poor 1 x 10-11 5 x 10-9 i x 10-9 1 x 10-7 1 x 10-11 5 x 10-11 NCteil * K 0.8 * K 0.11 K < 0.4 K 10-4 To give 100 (p-+p+) min.-l K 0.05 * n,p on 3He K 1 x 10-5 JENKINS AND SMALES RADIOACTIVATION ANALYSIS 95 Element Lanthanum .Lead . . . Lithium . . 7 . . 7 9 . . Lutecium . . Magnesium . Manganese . Mercury . . Molybdenum . Neodymium . Neon . . . Nickel. . . Niobium . . Nitrogen . . Osmium . . Oxygen . . Palladium. . Phosphorus . Platinum . . Polonium * . Potassium. . Praseodymium Promethium * Protactinium * Radium" . . Radon* . . Rhenium . . Rhodium . . Rubidium. . Ruthenium . Samarium. . Scandium. . Selenium . . Silicon . . . Silver . . . Sodium . . Strontium. . Sulphur . . Tantalum . . Technetium * . 9 Tellurium . . Activated form ________ 140La zOgPb 8Li n,u 3H '8F 177Lu with 176Lu 7Mg zo3Hg 147Nd with 149Nd 3Ne s5Ni 9 4 m E b 5 6 ~ n 9 9 ~ 0 16N with lglOs or 18F l09Pd 32P 1 9 7 P t with lg9Pt Parent 210Po 42K Parent 7Pm Parent z31Pa Parent 226Ra Parent 2 2 2Rn ls8Re with lssRe 10 4mRh-10 4Rh 86Rb with 88Rb lo5Ru with lo3Ru 3Sm 46Sc with 8% 31Si llOmAg-110Ag 24Na 89Sr 3 5 s or 32P 18ZTa Parent g * T ~ 99mTc 'Te 1 9 3 0 s 1 9 0 2Pr 8lmSe-8lSe with lz9Te Tabk Half-life 40 hr.3.3 hr. 0.8 sec. 12.4 y. 112 min. fl+ 6.8 d. 3.7 hr. 9-6 min. 2.6 hr. 48 d. 67 hr. 11.6 d. 1.8 hr. 40 sec. 2.6 hr. 6.6 min. IT 7.3 sec. 31 hr. 16 d. soft /3 29 sec. 112 min. /3+ 13.4 hr. 14.3 d. 18 hr. 31 min. 138 d. cc 12.4 hr. 19.3 hr. soft fl l3 (0.1%) 2.6 y. 1620 y. u 3.8 d. u 17 hr. 91 hr. 4.3 min. 19 d. 18 min. 4.5 hr. 40 d. 46 hr. 85 d. 57 min. 17 min. 2.6 hr. 270 d. 15 hr. 54 d. 87 d. soft fl 14.3 d. 111 d. 6 h. IT y 9.3 hr. 70 min. 3.4 x 105 y. 61 > 107 y. Estimated sensitivity (g.1 5 x 10-11 5 x 10-6 Poor 5 x 10-10 Possibly < 5 x 10-12 5 x 10-5 1 x 10-9 1 x 10-11 1 x 10-8 5 x 10-10 Poor 1 x 10-8 5 x 10-2 Poor 1 x 10-9 Poor 1 x 10-10 5 x 10-10 5 x 10-7 1 x 10-9 1 x 10-10 5 x 10-11 1 x 10-11 5 x 10-18 1 x 10-11 1 x 10-9 5 x 10-14 5 x 10-13 5 x 10-3 1 x 10-9 5 x 10-10 1 x 10-11 5 x 10-1' 5 x 10-8 1 x 10-8 1 x 10-10 5 x 10-8 1 x 10-10 Poor Possibly 5 x 10-9 1 x 10-7 5 x 1 0 - 7 sensitive 5 x 10-9 :ontinued on next page.Notes K 0.4 d K 0.02 To give 100 fl min.-l K 2 x 10-8 K 2 x 10-8 d * * * * * 96 QUARTERLY REVIEWS Terbium . . Thallium . . Thorium . . Thulium . . Tin. . . . Titanium . . Tungsten . . Uranium . . Vanadium. . Xenon. . . Ytterbium . Yttrium . . Zinc . . . Zirconium. . Activated form 16oTb 233Th or 233Pa 17OTrn 121Sn with 12%n 61T i 187W or 2 3 9 N ~ or 140Ba 52V 133Xe with I35Xe 175Yb SOY 69Zn g7Zr with g5Zr 2 0 4 ~ 1 239U Half-life 73 d.2.7 y. 22 min. 27.4 d. 129 d. 27 hr. 40 min. 6 min. 24 hr. 23.5 min. 2.3 ci. 12-S d. 3.7 min. 5.3 d. 9.2 hr. 4.2 d. 61 hr. 52 min. 17 hr. 65 d. Estimated sensitivity (6.) 5 x 10-11 1 x 10-8 1 x 10-10 5 x 10-11 5 x 10-9 5 x 10-9 1 x 10-2 6 x 10-1’ 1 x 10-8 1 x 10-10 Poor 5 x 10-9 5 x 10-9 5 x 10-11 1 x 10-10 5 x 10-9 1 x 10-7 I i Notes I Fission of 235U K 9 Notes t o Table ( a ) The sensitivities given in the Table have been rounded to the nearest 5 times an integral power of 10. The irradiations are assumed to have been carried out a t a thermal neutron flux of 10l2 sec.-l for one month (or to saturation if this period is less) and to have been followed by a two-hours’ delay during which radiochemical purification is carried out with quantitative yield.In rare cases where the fast neutron component of the pile flux is used e.g. to induce the S(n,p) reaction the sensitivities given apply to the neutron distribution a t the centre of the B.E.P.O. reactor a t Harwell. The radiochemically pure sources are assumed to be counted under an end-window Geiger counter a t an efficiency of 10% for p-particles or positrons of maximum energy > 0.2 Mev and of 1% for ?-particles of lower energy (tabulated as “ soft p ” ) . These efficiencies are deemed to include self-absorption effects in the sources. In the rare cases where the only suitable activated form decays only through isomeric-transition (IT) or electron- capture (EC) processes it is assumed that the source is y-counted under a scintilla- tion counter a t 10% efficiency ; the sensitivity limit has then been set a t a weight sufficient t o give lo3 y-photons min.-l (rather than lo2 particles min.-l as in /I-counting) to allow for the higher background normally characteristic of the y-counter.It is impossible in one compact table to indicate all the possibilities of pile activation the data presented here relate particularly to the possibilities of conducting highly sensitive analyses within two hours of irradiation. I n some cases the analyses could be carried out (with some loss of sensitivity) by using longer-lived isotopes e.g. analysts not working near a pile might not wish to use the 52-min. 69Zn for zinc analysis a t 5 x g. but could still use a 14-hr. 6gmZn or a 250-day 65Z1~ a t a level of perhaps lo-’ g or more.These possibilities can only adequately be appreciated by consulting the tables of nuclear data. Elements marked * occur in Nature as radioactive isotopes of reasonable specific activity or else the only known forms are artificially prepared isotopes in which case the isotope of greatest half-life has been selected. Many of these elements are x-emitters because of the much lower background the sensitivity of cr-counting is about 100 times that of P-counting but a proportionately longer time must be spent on the counting periods to attain reasonable precision. The Table is based upon the General Electric Company’s Chart of the Nuclides,l9 and upon the “ Table of Isotopes ” by Seaborg and others.20 “ Chart of the Nuclides ” General Electric Company Schenectady New York 4th Edn.1952. 2o Hollander Perlman and Seaborg Rev. Mod. Phys. 1953 25 469. JENKINS AND SATALES RADIOACTIVATION ANALYSTS 97 ( b ) The abundance of 3He in norinal helium has been assumed to be 1.3 x %. The 3He(n,p) reaction could detect 5 x 10-l2 g. of enriched 3He. ( c ) The 2H(n,y)3H reaction would be moderately sensitive as a means of analysis of enriched deuterium with a sensitivity of 1 x 10-5 g. ( d ) The possibility of radioactivation analysis for lithium or oxygen by means of lSF arises from the sequence *Li(n,~x)~H lSO( 3H,n)18F. The sensitivity given by Osmond and Smales 21 for oxygen applies to the determination of oxygen in finely divided (< 50 p ) metallic beryllium intimately mixed with an excess of lithium fluoride. In principle the reactions could be applied also to the determina- tion of lithium.The flux of fast neutrons in pile irradiations may be increased by placing the sample inside a hollow uranium cylinder under these conditions the yield in this reaction in the B.E.P.O. pile increases 22 by a factor of seven-the sensitivity of the sulphur determination would then be about 1 x lo-* g. This fast neutron reaction is included in the Table to illustrate the possibilities of using peutron-induced reactions other than the ( n y ) reaction. A possible advantage of a method for sulphur based on 32P is the ease of measuring the 1.7 Mev b-radiation rather than the 0.17 Mev b-radiation from 35S. An obvious disadvantage is the parallel production of 32P by ( n y ) reaction on any phosphorus in the sample which necegsitates a separate analysis.The interference from phosphorus might be greatly reduced by the use of a cadmium screen to absorb the thermal neutrons. (f ) Herr 2 3 and Alperovitch and Miller 24 have obtained preliminary evidence for the presence of a long-lived 9 8 T ~ in mineral samples by activation to S9mTc. It is not yet possible to state the sensitivity of the method in terms of the mass of @Tc. ( 9 ) When sensitivity calculated according to the convention adopted is par- ticularly low the value of the function K = lOOOu,/M~ has been tabulated as well as the half-life. Certain elements show a high K value and the poor sensitivity is entirely due to the very short or very long half-life. the possibility of extending the method to carbon and nitrogen activated to 20-min. 11C and 10-niin. 13N respectively.The use of the pile or of the cyclotron or betatron discussed so far in this Review has been to produce an activated isotope which can be isolated chemically and measured e.g. by using a Geiger-Muller counter after the irradiation has ceased. This intention is soinetimes frustrated by the over- long or overshort half-life of the product. An alternative approach is to measure each activating collision actually during irradiation. This has been adopted by Gaudin and Pannell 28 in measuring beryllium down to 1-2 p.p.m. in minerals by counting the prompt neutrons emitted during the reaction 9Be(y,n)24He. In the specific case of 9Be the threshold for the photoneutron reaction is below 2 MeV and a portable y-source (60d-l24Sb max. y-energy 2-04 MeV) is adequate for the irradiation.The prompt neutrons are counted by means of a boron trifluoride pulse ionisation chamber. The principle of the instantaneous detection of activating collisions has been extended to pile-irradiations. A natural limitation is the requirement that the measuring device must be very sensitive to the required nuclear event 21 Osmond and Smales Analyt. China. Acta 1954 10 117. 22 Whitehouse anti Putman “ Radioactive Isotopes ” Oxford Univ. Press Oxford 23 Herr 2. Naturforsch. 1954 9a 907. 2 4 Alperovitch and Miller Nature 1955 176 299. 25 von Ardenne and Bernhard 2. Physik 1944 122 740. 26 Sue Conapt. rend. 1953 237 1696. 27 Basile Hur6 LBvhque and Schuhl ibid. 1954 239 422. 28 Gaudin and Pannell AizaZyt. Chem. 1951 23 1261. ( e ) The 32S(n,p)32P reaction requires a neutron energy of a t least 1 Mev.1953 p. 124. G 98 QUARTERLY REVIEWS and yet remain insensitive to the pile flux of slow and fast neutrons and y-photons. In principle a pulse ionisation chamber might be used to deter- mine traces of say boron lithium or uranium,2Sa all of which eject heavily ionising particles (a-particles tritons or fission fragments) when irradiated with neutrons. The sample would be contained within the counting chamber. Actual analyses for each of these elements have in fact been made by using a nuclear emulsion as detector. The sample is evaporated from a microdrop (commonly 0.001 nil.) on to a metallic support which is irradiated in close contact with a sensitive emulsion. The emulsion is then developed and fixed and the photographic record is examined under a microscope.It is possible to distinguish tracks due to a-partJicles tritons or fission fragments from the shorter tracks due for example to protons. The reactions involved are (i) 10B(n,a)7Li (used by Faraggi by Mayr and by Loveridge and Smales to determine boron down to 2 x lop9 g.).29 (ii) 6Li(n,~)~H (used by Picciotto and Van Styvendael to determine lithium down to (iii) 235U(n fission) (used by Curie and Faraggi t,o study the localisation of uranium on the surface of polished mineral specimen^).^^ Of the 82 elements which are not naturally radioactive with high specific activity all but hydrogen seem susceptible to radioactivation analysis in favourable circumstances. Beryllium boron carbon and oxygen although unsuited to neutron activation may be activated by other means. Aluminium fluorine neon niobium rhodium titanium and vanadium while susceptible to activation by thermal neutrons give relatively short- lived isotopes which would decay prohibitively during moderately prolonged radiochemical separations.(c) Is the Element determined identified with certainty ?-The specificity of radioactivation analysis is high. It relies on three and sometimes four characteristics viz. the specific radiochemical purification the half-life of the product the maximum P-energy as determined from aluminium absorption measurements and in favourable cases the y-spectrum. (d) Can several Elements be determined simultaneously ?-It is obviously possible to irradiate an unknown sample for say 1 month and then to take it into solution add carriers separate the groups and isolate specific coni- pounds.This technique would not normally be considered as valuable a means of qualitative analysis as the simultaneous recording of a wide range of elements by emission or mass spectrometry. In certain cases it is feasible to carry out analyses for a limited range of elements after a single irradiation of a sample and a mixed standard for instance Smales and others during their analyses of marine sediments and of rock samples separated 2.5-hr. 65Ni 12.9-hr. 64Cu and 5.2-y. 6oCo in that g.).30 28a Stewart and Bentley Xcience 1954 120 50. 2B Faraggi Kohn and Doumerc Cornpt. rend. 1952 235 714 ; Mayr Nucleonics 30 Picciotto and Van Styvendael Compt. rend. 1951 232 855. 31 Curie and Faraggi ibid. p. 959. 32 Smales Geneva Conference on Peaceful Uses of Atomic Energy August 1955 1954 12 No.5 58 ; Loveridge and Smales unpublished work at Harwell. Paper 770. JENKINS AND SMALES RADIOACTIVATION ANALYSIS 99 The simultaneous analysis for several trace elements by irradiation followed by direct estimation of individual disintegration rates without radiochemical separations is sometimes feasible provided that the activity clue to the main constituents is not excessive. The individual trace elements may be recognised by resolving the gross decay curve or with much greater certainty by a combination of decay studies and y-spectroscopy. For clxample Smales 32 irradiated a sodium-potassium alloy for a long time and tjhen allowed two weeks for decay ; subsequent y-spectroscopy without chemical separation revealed 134Cs (y-energies 0.59 0-80 Mev) lloAg (0.88 1.36 1.48 Mev) and 87Rb (1.09 Mev).In these cases identification was by ;)-energy only as the products were long-lived. The quantitative analyses revealed Ag 100 p.p.m. Rb 5 p.p.m. and Cs 0.1 p.p.m. the last figure being ;tctually obtained in a separate analysis which included a radiochemical purification. In a similar study Morrison anti Cosgrove 33 irradiated silicon for 3 days then measured 69Zn 7 6 A ~ lX7W 59Fe 24Nn 42K and 182Ta by ( lirect y mintillation spectrometry. (e) How reliable axe the Quantitative Results ?-The precision of results (an index of the reproducibility of repeated individual analyses) must be (listinguished from the absolute accuracy or closeness of the mean value to the truth. Radioactivation like the other general methods of trace analysis should give a coefficient of variation of no worse than 10% for single determinations < L t an adequate level of trace element i.e.at the levels for the various chlements quoted in the Table. By careful work at somewhat higher levels the coefficient of variation can be lowered to 1%. The possibilities of very precise radioactivation analysis have been demonstrated by Seyfang’s deter- mination 34 of the isotopic content of depleted and enriched uranium this analysis which involves measuring the fission product 14*Ba produced on pile-irradiation of the 235U constituent is similar in principle to a trace- element analysis and the method was originally used to determine traces of natural uranium. In Seyfang’s most recent work 7 portions of natural uranium as the oxide U30, were simultaneously irradiated then treated chemically and the final barium sulphate sources were P-counted each source recording about 50,000 counts in 4 minutes.The series of 7 c:orrected counts showed a coefficient of variation of only 0.5%. The statistical errors in the determination of the counting rates account for 0.4% i.e. for most of the observed variation. It may be estimated that tihe analysis of an unknown sample by simultaneous irradiation of one portion of sample and one portion of standard should be subject to a caoefficient of variation of 0.7 yo in these particular conditions. The precision attainable by a given trace-element method normally tlecreases as the amount of the required constituent present becomes smaller. ‘Che precision a t any given level depends not only on the intrinsic sensitivity of the method but also on a factor present in greater or smaller degree in all trace-element analytical methods namely the “ background ”.The Morrison and Cosgrove AnaZylt. Chem. 1955 27 810. 3 4 Seyfang Analyst 1955 80 74 ; cf. ref. 11. 100 QUARTERLY REVIEWS “ background ” may take the form of contamination collected froni reagents or the atmosphere as in absorptiometry and certain other methods or of the residual current in polarography or of the electronic noise level in recording spectrometry or of the extraneous radioactivity due to cosmic radiation etc. in radioactivation analysis Strictly i t is not the absolute level of the background but rather the fluctuation between one measurement and another which is the limiting factor. One of the most restrictive types of background is that set by coil- tamination from impurities in reagents.This often remains a problem even after reagents of the highest quality have been subjected to further elaborate purification. The radioactivation niethod avoids errors introduced by impure reagents and it remains to take adequate precautions against surface contamination by e.g. atmospheric dust during the physical preparation of the sample. This method like any other is still subject to a background which however is normally of a low level it is the intrinsic background of the shielded counting assembly normally of the order of 10 counts per minute for an end-window Geiger-Muller tube of 1 inch diameter ; its relative insignificance for many trace analyses is illustrated b y the facts that even the iniiiiite weights of various elements listed in the Table would normally give a count rate (due to sample plus background) of 20 counts per minute and that the coefficient of variation of the background (for an hour’s counting) would be as little as 4%.Next must be discussed the absolute accuracy of the method i.e. the degree to which the experiineiitally determined level of the trace constituent obtained as the mean of many analyses with high reproducibility approaches the truth. This is sometimes expressed as the bias (positive or negative) of the method. In many methods of analysis including radioactivation the sample is compared directly or indirectly with a standard. If then there is adequate precision the absolute accuracy of the method depends on the availability of a suitable standard i e .one whose composition is accurately known to an accuracy exceeding the maximum accuracy of the trace- element determination. This requirement is often met by weighing out elements or compounds of known composition or by dispensing solutions of such reference substances. Further the behaviour of the standard in colour development excitation activation etc. niust exactly parallel that of tlhe trace constituent in the sample. For example a sample of finely ground rock might be excited for say 40 seconds by a graphite arc for emission spectro- metry volatilisation of a trace constituent froin the rock matrix might then not be matched in a parallel excitation of say a solid dilution of the oxide of the element in graphite or silica. Radioactivation is independent within reasonable limits of the nature of the solid matrix of the sample provided that the weight and concentration of the sample and the standard are sufficiently low to avoid the self-shielding errors discussed on p.85. This arises because radioactivation is a nuclear process and does not involve considerations of the volatility of atomic species their adhesion to other species or the excitation behaviour of their JENKINS AND SMALES RADIOACTIVATION ANALYSIS 101 external electrons. Direct radioactivation followed by measurement of dis- integration rate all on the intact solid sample and accompanied by a parallel analysis of a standard should approach absolute accuracy. The standard eould be a pure element or compound or a liquid or solid dilution. In this hypothetical case it has been supposed that the disintegration rate of the activated product could be measured directly on the solid sample (and on the standard) without loss due to self-absorption or interference due to foreign activities.This ideal has been attained in cert'ain insta,nces such as the direct y-spectrometer nieasurements (pp. 99 103). More generally the sample must be dissolved after irradiation and a carrier added followed by radiochemical purification of the element concerned. The radioactivation method will retain high accuracy-if the activated species passes completely into true solution without loss by volatility adsorption or persist'ent tlraces of insoluble residues and if the dissolved species undergoes complete isotopic exchange with the added carrier. Summarising t>he radioactivation method should give a low bias in those I'avourable cases where it can be applied without radiochemical separation.In its more general applications its accuracy is as good as that of the mass- spectrometer isotope-dilution method and greater than that of direct einissioii or mass spectrometry. It is very valuable as a method for the standardisat)ion of samples e.,q. rock samples containing trace elements which can then be used as standards for emission or mass spectrometry (see below). Practical applications of radioactivation analysis to the determination of trace elements There are four major fields \$here analysis of trace elements is required namely geochemistry biology physics of the solid state and nuclear physics. Geochemistry.-Geochemistry requires reliable analysis of the distri- imtion of the elements often only in minute amounts throughout the earth's erust the oceans and meteorites.The analytica81 results provide essential data for the theorist a'nd are occasionally of immediate practical interest as in geochemical prospecting i.e. detection of trace elements in neighbouring soils vegetation and waters. Brown and Goldberg 35 used radioactivation in analyses of iron meteorites for gold gallium rhenium and palladium ; and Reed and Turkevitch 36 used i t for uranium. By its use Morris and Krewer 37 determined gallium in blende and Long 38 and later workers detlermiiied tant alum in minerals Smales 39 has reported the determination of nickel copper cobalt palladium gold and rubidium in samples of granite and diabase which have had world-wide circulation as standards in rock 3 5 Brown and GoltUx~g 8ciw7c0 1940 109 347; Goltlherg arid Brown Analyt.36 Reed ~ n t l 'I'urkevitc.h Nuturc 1955 176 7'34. 37 Morris aiitl Brewer G'eockim. C'ositiocJ~it)L. Acftr 1954 6 134. 38 Long Analyst 1951 76 644. 3D Smales Geochi,ri. C'osmochini. Acta 1956 8 300. Clteirz. 1950 22 3013. 102 QUARTERLY REVIEWS analysis. The same author l1 determined traces of uranium in monazite zircon and dunite and Jenkins 7 determined thorium in similar materials. Determination of traces of uranium and thorium in igneous rocks e.g. granite is important in attempts to estimate the age of the earth's crust (the radioactivation analyses would of course require to be supplemented by ?n alternative and more sensitive method of determination of lead- preferably by the mass-spectrometer isotope-dilution technique).In a different method of dating applicable to potassium minerals Moljk Drever and Curraii 40 determined 40A by radioactivation. Herr 23 and (independ- ently) Alperovitch and Miller 24 recently published preliminary evidence for the occurrence of a long-lived 9 * T ~ in Nature based on neutron activation and detection as 99mTc. Smales and Wiseman 41 have discussed the origin of the nickel found in deep-sea sediments which Pettersson and Rotschi 41a had ascribed to the deposition of meteoritic dust. Radioactivation analysis for nickel copper and cobalt in representative samples of globigerina ooze red clay and oceanic rocks from the At'lantic the Pacific and the Indian Ocean showed that the ratios nickel cobalt nickel copper and copper cobalt were not those accepted for meteorites (13-1 92 and 0.14 respectively) and were very close to the normal ratios for igneous rocks (3.5,1.1 and 3.0 respectively).Recent Harwell determinations by radioactivation of trace elements in sea-water include arsenic,42 rubidium cmium 43 and strontium.44 Biology.-Biological work often necessitates determining major con- stituents in minute samples e.g. sodium and potassium in single nerve fibres.45 Trace analysis is of great importance in studies of the metabolism of potentially toxic elements and of elements which appear to be essential to an organism. In certain cases determination of non-radioactive traces may be sounder than the alternative of following the distribution and excretion of an added radioactive tracer for sensitive systems may conceivably be modified by the radiation.This objection does not apply to activation of the samples after the required metabolic process has taken place. Harrison and Raymond 46 point out that administration of radioactive isotopes while giving valuable information on the relative retention and distribution of elements cannot give information on the absolute excretion rates of these elements. Radioactivation has been applied to problems of animal meta- bolism by Tobias and Dunn 47 who studied the distribution of gold through- out the tissues of a mouse 30 days after administration of 1 X g. 40 Moljk Drever' and Curran Nucleonics 1955 13 No. 3 44. 41 Smales and Wiseman Nature 1955 175 464. 414 Pettersson and Rotschi Geochim. Cosinochiin. Acta 1962 2 81.4 2 Smales and Pate ,4iaalyst 1052 77 188. 43 Smales and Salmon ibid. 1955 80 37. 4 4 Hummel and Smales Analyst in the press. 4 5 Keynes and Lewis Nature 1950 165 809. 46 Harrison and Raymond J. Nuclear Energy 1955 1 290. 47 Tobias and Dunn U.S. Atomic Energy Commission Unclassified Report No A.E .C.D. -2099B. JENKINS AND SMALES RADIOACTIVATION ANALYSIS 103 of inactive gold and by Harrison and Raymond 46 who studied the fzcal and urinary excretion of strontium and barium from a human subject on a normal diet. Smales and Pate illustrated the potentialities of radioactivation in the study of arsenic metabolism by carrying out analyses on the individual organs of a normal mouse.1 Few applications of radioactivation analysis appear to have been made to studies of the metabolism of trace elements during plant growth.The sensitivity of this method is adequate (at a flux of 10l2 neutrons (3111.12 sec.-l) to measure submicrogram amounts of P Ca K Cs Fe Mn Cu Zn Mo Co or C1 it is interesting that the method is not as sensitive as micro- biological assay for molybdenum. 48 Boron would require a specialised technique (see p. 98) and nitrogen and magnesium could be determined a t present only a t relatively high levels. I n certain cases the radioactivation method which determines the mass of the trace element may usefully supplement microbiological methods which determine the avaiZabiZity of the element. The determination of czsium and rubidium in seaweed by Smales and Salmon 43 showed that these elements are enriched with respect to sodium compared to the corresponding values for sea-water.Physics of the Solid State.-This includes problems as to the effect of trace impurities on electrical optical and mechanical properties of solids. For example the electrical properties of semiconductors such as germanium and silicon are profoundly changed by the presence of 1 part in loB of copper or nickel. The scope of the various methods of trace analysis in the semi- conductor field has recently been reviewed by one of us.49 Radioactivation has been used for the analysis of arsenic l6 down to 0-005 p.p.m. and for nickel 32 down to 0.1 p.p.m. in germanium by Smales and his co-workers ; for rare earths antimony molybdenum copper and zinc in germanium oxide and metal a t 0.1 p.p.m. by J a k o ~ l e v ~ ~ and for copper in germanium to 0.001 p.p.m.by S ~ e k e l y . ~ ~ Arsenic and copper have been determined by Smales 32 and by James and Richards 52 in silicon down to 0.0001 p.p.m. In some cases it is now possible to measure a range of elements simultaneously as discussed on p. 98 by y-spectrometry on the activated sample. This approach has been followed by Smales 32 * and by Morrison and C0sgrove.3~ Trace analyses by means of radioactivation have given important results in the study of phosphors and luminescent solids and of y-dosimeter glasses ".g. Delberg Glendenin and Yuster 53 measured thallium down to g. in potassium iodide crystals Grillot 5 4 measured g. of copper and 48 Nicholas Analyst 1952 77 629. 49 Smales J. Electronics 1955 1 327. 50 Jakovlev Geneva Conference on Peaceful Uses of Atomic Energy August 1055 61 Szekely Analyt.Chem. 1954 26 1500. 5 2 James and Richards Nature 1955 175 769. 5 3 Delbecq Glendenin and Yuster Analyt. Chem. 1953 25 350. 5 4 Grillot Compt. repzd. 1952 234 1775 ; cf. Bancie-Grillot and Grillot ibid. * Cf. also ref. 49. Paper 632. 1953 237 171. 1 (a4 QUARTERLY REVIEWS chlorine in zinc sulphide powders and Peirson 5 5 has identified and measured manganese as an impurity in metal phosphates of possible application to dosimeter preparation. In the metallurgical field traces of various impurities have been deter- mined by radioactivation in high-purity iron,56 32 aluminium 57 and mag- nesium 58 metal. Nuclear Physics.-The application of nuclear physics to the atomic- energy project has set high standards of purity for such basic materials as uranium thorium graphite light and heavy water beryllium zirconium and plutonium.For example traces of strong neutron-absorbers such as cadmium boron lithium or the rare earths cannot be tolerated in the uranium rods the aluminium cans or the graphite moderator of the B.E.P.O. reactor. Among other methods radioactivation analysis has been used at Harwell for the determination of the individual rare earths 59 and of vana- dium 60 in graphite of hafnium in zirconium,61 of oxygen in beryllium,21 and of magnesium chromium rubidium czsium silver antimony strontium and cobalt in a sodium-potassium alloy of possible interest as a reactor coolant .62 Practical applications of radioactivation analysis on intact samples The first distinctive feature of radioactivation analysis is its extreme sensitivity already discussed.The second important feature has only been touched on above that is the analysis of intact samples. This concept of non-destructive analysis has implications which extend even to industrial processing. There are at least four reasons for interest in an analytical method which might be applied non-destructively. (a) If it is very rapid and can be made automatic it could be applied to automatic process-control e.g. to sorting of mineral mixtures. Or it may be used in process control by providing a human controller with rapid information. This information need not always be of the highest precision provided it is prompt. ( b ) Certain samples are non-consumable by reason of their historical scientific or other interest or they may be highly toxic. ( c ) In certain cases any chemical treatment of t,he sample may be suspect owing to potential loss of the required constituent by e.g.volatilisation during acid digestion. (d) It is sometimes possible to derive inforination about the spatial or surface distribution of the required constituent in an intact sample. 55 Peirson unpublished work a t Harwell. 513 Albert Caron and Chaudron Gonzpt. rend. 1953 236 1030. 67 Idem ibid. 1951 233 1108. 58 Atchison and Beamer Annlyt. C'heiiz. 1052 24 1812 59 Cornish U.K. Atomic Energy Authority Report A.E.R.E. C/R 1224 1953. 130 Sinales anti Mapper '1J.K. Atomic Energy Authority Report A.E.R.E. C/R 131 Smales and Fullwood mipuhli~heti wolk. 6 2 Smales Geneva Conference on Peaceful Uses of Atomic Energy August 1955 607 1950. Paper 766. Cf. ref. 32. JENKINS AND SMALES RA DIOACTIVATION ANALYSIS 105 Radioactivation analysis offers advantages in each of these four fields.In most cases the induced activity is measured by its y-radiation which is normally able to penetrate the intact solid without prohibitive loss by self- absorption. The increasing use of y-scintillation spectrometers l3 facilitates the specific recognition of characteristic y-energies. It should be emphasised that this type of application accepts each sample very much on its own merits and the user must be aware of potential interference by extraneous induced activities-that is it is less universally applicable than the normal sequence of radioactivation analysis including radiochemical purification. Nevertheless in specific instances it is invaluable. The potentialities are illustrated by the following examples (i) Rapid routine analysis (automatic or otherwise) will normally measure a major constituent rather than a trace element and great interest will attach to short-lived induced activities (many of the data in the Table are irrelevant in this respect and the full compilations should be consulted).Gaudin and his co-workers 63 investigated the activit'ies induced in 150 specimens of 51 different mineral species by irradiation for 2-5 seconds in a pile at 1012-1013 neutrons sec.-l. The y-activities were measured 30 seconds after irradiation. Under these conditions even oxygen and fluorine give significant activities. The aut)hors concluded that it should be possible to separate felspars from iron minerals copper minerals from pyrites or galena from limestone but they stress that each ore-body would present a specific problem as the activities induced in a given mineral species varied considerably from one sample to the next owing to the varying content of impurities.Industrial application of this type of work would require a portable (or readily accessible) neutron source-Gaudin concludes that a flux of about 100 times that offered by curie-level radium-beryllium sources is desirable. It seems possible that this gap can be closed both by the use of more sensitive y-count!ers (a sodium iodide scintillation countm would give about 100 times the sensitivity of tJhe Geiger-Muller tube used by Gaudin) and by the development of neutron sources of higher flux. For example a large antimony-beryllium source might be prepared by pile irradiation of a massive compact or large sources of the Be(ct,n) type might become available by the use of cheaper ct-emitters than radium.Further particle accelerators might be designed specifically to offer moderate neutxon fluxes (by bombardment of an appropriate target) at a reasonable capital cost. (ii) Radioactivation analysis is being applied currently in the authors' laboratories 64 to the rapid determination of plutonium in metallic and other inorganic compounds by pile-irradiation for 5 seconds followed by quantita- tive measurement of a specific y-emitting fission product e.g. 1311 (0.36 MeV) or 140Ba-La (1.60 Mev) by means of a scintillation spectrometer. In certaiii cases the quantitative measurement can be carried out with moderate precision by use of an inexpensive ionisation chamber (radiation nioiiitor) without discrimination between individual y-emitting fission products.Chemical methods are of course available for the analysis of snch materials 63 Gaudin Senftle aiid Freyberger Eiig. Min. J . 1952 153 No. 11 95 174. 6 4 Atkins Phillips a i d Jenkins unpublished n ork. 106 QUARTERLY REVIEWS but radioactivation is quicker and avoids excessive handling of a toxic material. Again several workers have determined the arsenic content of human hair in medicolegal analyses. Griffon and Barbaud 65 measured the in- duced 76As activity without chemical separation at various points along intact hairs. This approach might be useful in demonstrating relatively high levels of arsenic content if backed up by y-spectrometry and decay studies to provide a specific identification.It would have the virtue of preserving the specimen intact as a legal exhibit. (iii) Examples of the application of radioactivation to the analysis of silicon semiconductors by direct y-spectrometry immediately after irradia- tion have been given on p. 99. This technique avoids possible loss e.g. of arsenic during chemical dissolution. (iv) Autoradiography of uranium and thorium inclusions in polished mineral specimens has been carried out by placing a sensitive emulsion against the surface and recording the tracks of the ionising ct-particles. Curie and Faraggi 31 extended this method by irradiating the specimen and emulsion in mutual contact in the Chatillon pile. The densely ionising recoil fragments from the fission of uranium atoms left heavy tracks and served to distinguish uranium from thorium segregations in polished granite samples.Further applications of activation analysis to autoradiography have either involved direct irradiation of the sample and the emulsion as above or have brought the sample and the emulsion into contact after irradiation. The method has been used in studying the segregation of uranium and of lithium in mineral~,~l 30 of arsenic,66 boron,67 and carbon 68 in steels of lithium 69 and possibly boron and iodine 70 in biological samples and of sulphur phosphorus and chlorine- and bromine-containing organic compounds on paper chromatograms.71 The autoradiography of an activated sample need not be confined to the use of contact emulsions or films. The y-emitting centres on the active surface could be made to form an image on a distant film by the use of a y-sensitive pin-hole camera it appears that a resolution of a t least inch can be achieved.72 Alternatively the surface may be scanned by a lead- shielded collimator and the activity a t any given spot recorded.Conclusions Radioactivation analysis is extremely sensitive for a large number of the elements and in this respect may be compared with emission and mass 6 5 Griffon and Barbaud Compt. rend. 1951 232 1455. 66 Kohn " Radioisotope Conference 1954 " Butterworths London 1954 Vol. 11 13' Faraggi Kohn and Doumerc Compt. rend. 1952 235 714. 68 Curie J . Phys. Radium 1952 13 497. 69 Ficq Compt. rend. 1951 233 1684. 7o Mayr Nucleonics 1954 12 No. 5 58. T 1 Winteringham Harrison and Bridges ibid. 1952 10 No. 3 52 ; Schmeiser and Jerchel A?zqezo.Chenz. 1953 65 366 490. 7 2 Mortimer Anger and Tobias U.S. Atomic Energy Commission Unclassified Report No. U.C.R.L.-2584 1954. p. 68. JENKINS AND SMALES RADIOACTIVATION ANALYSIS 107 spectrometry. The ubiquitous traces of contaminants in most chemical reagents do not normally cause difficulties in radioactivation this is perhaps its most distinctive feature. The ease with which both the sample and the standard may be activated at the same time and under closely similar conditions makes the method valuable in the calibration of reference samples later to be used as standards for other methods such as emission spectroscopy. Activation is best carried out in the high flux of thermal neutrons within a nuclear reactor. At least 50 reactors l7 of various types were known to be operating in 1955 including several comparatively inexpensive low-power reactors which are suitable for use as neutron sources by universities and industrial research organisations. The chief significance of radioactivation analysis will probably be its contribution to the measurement of trace elements a secondary interest may be that of rapid industrial control analyses on intact samples.

ISSN:0009-2681    

DOI:10.1039/QR9561000083

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

THE INDOLE ALKALOIDS EXCLUDING HARMINE AND STRYCHNINE By J. E. SAXTON B.Sc. M.A. DPHIL. (Oxox.) (RESEARCH FELLOW HARVARD UNIVERSITY CAMBRIDGE MASS. U.S.A.) ALKALOIDS containing the indole ring system occur widely in Nature and have so far been isolated from upwards of twenty genera of plants and trees. They include many important and widely used alkaloids such as the ergot bases valuable as oxytocic drugs in childbirth strychnine valuable as a general tonic and also employed as a vermin killer yohimbine used in veterinary medicine as an aphrodisiac and the extracts of RauwolJia serpentina Benth. used in India for several purposes chiefly as a sedative. In addition extracts of AZstonia barks have been used in the Far East in the treatment of malaria but pharmacological experiments have shown that this reputation is undeserved.The pharmacological properties of all these plant extracts have stimulated chemical investigation into the structures of the alkaloidal constituents and so far the structures of approximately fifty alkaloids have been completely elucidated. The object of the present Review is to sunimarise the present knowledge of these indole alkaloids. No attempt will be made to cover the field exhaustively particularly for those groups where work has almost ceased owing to the elucidation of tjhe structures of the alkaloids and their con- firination by synthesis. The alkaloids of Pegan rim harmala and those of the Xtrychnos species which will be reviewed elsewhere have been omitted entirely from the discussion; so have the alkaloids of the AmaryZZiducpx (e.g.lycorine) Erythrina (e.q. /3-erythroidine) and Cryptocarya bowiei (e.g. cryptowoline iodide) which although they niay be regarded as containing a hydroindole structure are not related biogenetically to the remaining indole alkaloids since they are probably formed in the plant froni dihy- droxyphenylalanine and not from tryptophan. Activity in certain fields for example the Yohim be a i d Rauz~~oZjla groups lias been intense during the last five years and substantial contributions have been made to our knowledge of the alkaloids occurring in the plants of the species and their structures. Hence emphasis will be given here to the recent developments in these series. Papers amilable up to July lst 1955 have been covered. A brief and authoritative account of the structural relations and probable course of the biosynthesis of these alkaloids has bcen given by Sir Robert Robinson in the recently puhlishecl Weizmnnn 1ectiires.l For a comprehen- Robinson ‘‘ The Structural 1Zc.lutions of Natural Products ” Oxford Univ.Press 1955. 108 sive accouiit of the earlier work on the iiidolc all~aloirls the reader is referred t o Volunie I1 of " The Alkaloids ".2 Simple Indole Derivatives.-Iiidole itself occurs in certain plants and has been obtained from the distilled oil of jasmine flowers and from the decaying wood of CeZtis reticulosa. However it is not a true alkaloid and probably arises by degra'dation of more complex indole derivatives e.g. tryptophan. Four comparatively simple inonosubstituted indole bases have beell isolated from natural sources. from the seeds of Abrus precatorius L.hypaphorine (11) from the seeds of various Erythrina species gramine (111) 5 from barley leaves and Arundo donax and donaxarine C13H1602N2,6 also from the leaves of A . donax. They are abrine (I) aTHzNMez (Ill) The relation of abrine and Gramine on the other hand was hypaphorine to tryptophan is evident. formerly regarded as arising by condensa- tion of indole with equivalents of dimethylainine and formaldehyde a re- action analogous to the usual laboratory preparation. Leete and Marion 7 have shown however that in common with the other indole alkaloids grarnine is produced from tryptophan. In their experiments tryptophan (IV) containing 14C in the 2- and the P-position was fed to sprouting barley. The grainine isolated after eleven days was shonm to possess activity in both labelled positions in the same ratio as in the original tryptophan.Thus it \li.ould seem that the /3-carbon bond in indole is not ruptured during the transformation. The structure of donaxariiie has not yet been elucidated and little is known about it beyond its formula. The Ergot Alkaloids.-The evidence leading to the structures of the ergot alkaloids and the attempts to syiithesise then? have been revieweds by 2 " The Alkaloicls " Vol. 2 cck. Manskc and Holmes Academic Press New York 1952. 3 Ghatak and KFLLL~ J . Itldicclz Cke??~. SOC. 1932 9 383 ; Hoshino AnTzalen 1935 520 31 ; Gordon and J&(*~soII d . Ukd. C ~ ~ e 9 ~ ~ . 1035 110 151 ; Miller and Robson J. 1938 1910. 4 References 11-21 in " The Alkaloids " Vol. 2 (see ref. 2) p. 481. 6 Euler and Hellstrom Z.pkpiol. Chenz. 1932 208 43 ; Orekhov Norkina and Maximova Ber. 1935 68 436 ; Wieland and Hsing A?znaEeiz 1936 526 188 ; Kuhn and Stein Ber. 1937 70 567. 6 Madinaveitia J . 1937 1927. 7 Leete and Marion Canad. J . Chem. 1953 31 1195. 8 Stoll " Progress in the Chemistry of Natural Products " Vol. IX Springer Verlag Vienna 1952 p. 114 ; Glenn Quart. Rev. 1954 8 192. 110 QUARTERLY REVIEWS CON H - I H Me C G . N H ~ H . C H ~ . OH @Me " (VI) BMe " (VII) Me t,Na BHqz$OC12,3,NaCN @- 4,Methanolysis s,Hydrol Ac H (+)- LyeerQic Acid SAXTON THE INDOLE ALKALOIDS 111 Stoll and by Glenn who sumnzarise the evidence available up to the end of 1953 by which time the general formulae for the alkaloids were firmly estab- lished as (V). Ergometrine the simplest alkaloid of the series.has structure Recent work in this field has been concentrated on lysergic acid (VII) the common structural unit of the alkaloids and has culminated in the elegant synthesis by Woodward and his collaborators of (&)-lysergic acid by the route shown below starting from N-benzoyl-3-2'-carboxyethyl- 2 3-dihydroindole (VIII).9 I n order to direct ring closure on to the 4- position of the indole nucleus a dihydroindole derivative was employed as starting material. The lysergic acid ring system was then synthesised by standard methods and the indole double bond introduced in the final stage by a catalytic dehydrogenation in neutral aqueous solution a t a deactivated Raney nickel catalyst Both the acid and the hydrazide were completely identified by comparison with naturally occurring samples.Since the hydrazide had already been resolved and converted into ergometrine lo this constitutes the first total synthesis of an ergot alkaloid. (VI). CO NH2 GNM~ CO NH2 O M e Cycl isn . co;! CO.NH2 H (Vll) Four schemes for the biosynthesis of lysergic acid have been proposed recently. The first proposed by van Tamelen,ll involves condensation of dihydronicotinic acid or its equivalent [e.g. dihydrotrigonelline or (X)] with a didehydro-5-hydroxytryptophan (IX) the doubly activated 5-position Kornfeld Fornefeld Kline Mann Jones and Woodward J. Amer. Chem. SOC. 1954 76 5256. 10 Stoll and Hofmann Helv. Chim. Acta 1943 26 922 944. l1 Van Tamelen Experientia 1953 9 457. 112 QUARTERLY REVIEWS of the former coupling with the 4-position of the latter. Subsequent stages include the removal of the oxygen from the indole ring transamination oxidation of the product to an indolylacetic acid derivative cyclisation and isomerisation to lysergic acid (see previous page).This scheme is evidently not rigid and many variants can be envisaged for example the use of 5-hydroxy-3-indolylacetic acid as starting material. Since trigonelline and nicotinic acid [and so presumably dihydrotrigonelline and (X)] can arise in biological systems from tryptophan and since both tryptophan and 5-hydroxytryptophan are possibly formed from tyrosine the whole biosynthesis can be achieved by starting from tyrosine ; so it is noteworthy that tyrosine has been found t o be associated with the ergot alkaloids. l2 Sir Robert Robinson l2 commenting on this biosynthesis pointed out that although all the stages are feasible no 5-hydroxy-indole analogues of lysergic acid have been found in Nature as would be expected if this scheme were correct.I n addition quinones of type (IX) are not known although this does not mean that they cannot be formed transiently in vivo. Harley- Mason’s suggestion l 3 suffers from these same disadvantages. Since lysergic acid contains a tryptamine residue it is reasonable to assume that the two nitrogen atoms of the tryptophan precursor are retained and are the two nitrogen atoms of lysergic acid. This is the fundamental postulate of the other proposed biosyntheses. Harley-Mason’s scheme consists of condeiisation of tetradehydro-5- hydroxytryptophan with acetonedicarboxylic acid and formaldehyde by the standard Mannich reaction l3 The starting material could presumably also be didehydro-5-hydroxytrypto- phan (IX).The third mechanism proposed by Wendler l4 starts from tryptophan itself which is presumed to undergo ring closure to a tricyclic amino-ketone. Addition of citric acid dehydration and further ring closure then give l2 Beadle Mitchell and Nye Proc. Nut. Acad. Sci. U.S.A. 1947 33 155 ; Mitchell and Nye ibid. 1948 34 1 ; Dalgliesh Quart. Rev. 1951 5 227 ; Robinson Chew. and I n d . 1952 358 ; Fraiikel and Rainer Biochem. Z. 1916 74 167. l3 Harley-Mason Chem. and I n d . 1954 251. l4 Wendler Experientia 1954 10 338. SAXTON THE INDOLE ALKALOIDS 113 lysergic acid. The first stage which assumes anionoid reactivity of the &position of the indole nucleus is supported by the results of nitration of 2-methylindole and dihydropentindole which are nitrated in the 4-position,15 NH2 HO,C-C/H 0 NHR H H H -r GR -+I) H and is also a feature of the most recent and most elegant scheme proposed by Robinson.1 The initial stage in this biosynthesis involves condensation of t,ryptophan and succinic acid to give the keto-acid intermediate (XI) which then gives the tricyclic intermediate (XII) by ring closure and dehydration.C02 H $02 H /CH2 /CH2 HBC NHMe "ZC\ / cw &O?H co - c,H NHMe COz H ,CH2 CHzo - GYM' - (VII) i X l l ! " I londensation with formaldehyde (or its equivalent) completes the synthesis. I'his ketonisation to give the hypothetical intermediate (XII) is analogous to i he proved formation of aminolzvulic acid from glycine and succinic acid :16 NH,*CH,CO,H + HO,CCH,*CH,*CO,H + NH,*CH,.CO*CH,*CH,*CO,H 15 Plant J.1929 2493 ; Mathur and Robinson J . 1934 1415. l6 Sherniri arid Russell J . Amer. Chew?,. SOC. 1953 75 4873. H 114 QUARTERLY RBVIERS These four biosyntheses postulate dissection of the lysergic acid molecule according t o the various modes annexed. While it is not possible a t present to appraise the relative merits of these theories they should stimulate investigations involving the application of tracer-element techniques. CO H COZ H COe H &->NMe 4 7 i i e &'=;Me dS 673 byf H H H Harley - Mason Wendler van Tamelen and Robinson Alkaloids of Evodia rut zcarpa and Crypt olepis spp.-Condensation of tryptamine with its biological degradation product anthranilic acid and formaldehyde or formic acid leads to the alkaloids evodiamine (XIII) and rutacarpine (XIV) which occur in the Chinese drug wu chu yu the dried fruit of Evodia rutmarpa.These formula? were proposed by Asahina and have been amply confirmed by synthesis.17 -+ / J MeN (XIII) 1 Cryptolepine Cl6HI2N2 was originally isolated by Clinquart from Cryptolepis trianguzaris N. E. Br. and differs from all known alkaloids in that it is dark violet giving rise to yellow salts. The constitution was elucidated by Gellert Raymond-Hamet and Schlittler,lgb who obtained it from C. sanguinoZenta. Dehydrogenation by selenium gave a colourless Asahina and Kashiwaki J . Pharm. SOC. Japan 1915 405 1293 ; Asahina &id. 1924 503 1 ; Asahina Irie a i d Ohta ibid. 1927 543 51 ; Asahina Manske and Robinson J. 1927 1708 ; Asahina and Ohta J . Pharm. Soc. Japan 1928 48 313 ; Ber.1928 61 319 ; Ohta J. Pharrn. Soc. Pormosa 1938 51 2 ; J . Pharnz. Xoc. Japan 1940 60 311 ; Schopf and Steuer Annulen 1947 558 124. (u) Clinquart B u l l . Acad. m e d . belges 1929 9 627 ; (b) Gellert Raymond-Hamet and Schlittler Helv. Chirn. Acta 1951 34 642. SAXTON THE TNDOLE ALKAT,OIT)S 115 base C 15H10N2 which was converted into cryptolepine hydriodide by reaction with methyl iodide showing that the degradntion simply involved removal of a methyl group froin a nitrogen atom. The parent ring system was identified as quindoline (XV) which was already known. Hence cryptolepine hydriodide is quindoline methiodide and cryptolepine is (XVI) . \ Me I - It is tempting to explain the origin of this alkaloid in the plant by con- densation of tryptophan with anthranilic acid or o-aminobenzaldehyde followed by loss of the ethanamine side chain but there is little or no evidence a t present to indicate that such a course of reaction is possible.There is no doubt that the mechanism of formation is much more complex and it may involve preliminary condensation of the aldehyde a t the 3-position of the indole nucleus followed by rearrangement and cyclisation with elimina- tion of the ethanamine side chain aJE:~;;o+.c H~.CH(NH$CGH C&CH( NH~CGH MeH H H OH Alkaloids of Australian Rufacez.-The Aust<ralian rain-forest tree Penfaceras australis Hook has yielded three alkaloids containing a ring system not hitherto found in Nature.lg The alkaloids have been shown by Price and his co-workers to be 6-oxocanthine (XVII) and its 5-methoxy- (XVIII) and 4-methylthio-derivative (XIX).The first two alkaloids occur in the leaves of the plant whereas the first and the last are present in the wood. l9 Haynes Nelson and Price Austrulian J . Sci. Res. 1952 5 A 387 ; Nelson and Price ibid. pp. 563 768. 116 QUARTERLY REVIEWS Oxidation of 6-oxocanthine gave P-carboline-1-carboxylic acid (XX) which was readily identified and hydrolysis gave the acrylic acid derivative QTP 0 6 5 a3 SMe Me jxvrr) (XVIII) (XIXI (XXI) which was obtained in both cis- and trans-forms. As expected only the former of these was reconvertible into the alkaloid. The second alkaloid 5-methoxy-6-oxocanthine also gave p-carboline-1- carboxylic acid on oxidation and a P-carbolinylacrylic acid derivative fJJENK_Mno- (XVII) EtOH aTQ H CH // H02C.CH H C02H (xx) (XXO (XXII) on hydrolysis which was easily reconverted into the alkaloid.Hence the methoxyl group must be at position 4 or 5. Hydrogen bromide demethyl- ated the alkaloid to anenol (XXIII) which readily condensed with o-phenyl- enediamine to give the quinoxaline (XXIV) showing that the methoxyl group is a t position 5. CH // HO2C.C.OMe (xx I I) 03 0 (XXIV) The third alkaloid isolated from this plant is unique in that it contains sulphur. It is slowly attacked by alcoholic alkali to give an acidic substance (XXV) and methanethiol. The acidic substance which gave p-carboline-l- carboxylic acid on oxidation did not condense with o-phenylenediamine and hence the second oxygen atom and the methylthio-group in the alkaloid must be at position 4. This was proved by synthesis of the derivative SAXTON THE INDOLE ALKALOIDS 117 W N // CVvle SMe HOZC'CH I NaOH-)( EtOH (xx) -*-- (E t 0 C) t H (XXV) and the alkaloid itself from p-carboline-1-carboxylic acid by the annexed react ions.Biogenetically these alkaloids could arise by condensation of tryptamine with glutamic or hydroxyglutamic acid. The former condensation leads to 118 QUARTERLY REVIEWS hexaliydro-6-oxocanthine which is then oxidised to 6-oxocanthine or to 5-methoxy-6-oxocanthine (via XXVI) which on methylation gives the alkaloid 5 -methoxy - 6 - oxocant hine. The second condensation leads directly to 4-hydroxy-6-oxocanthine (XXVII) which can be converted by oxidation and substitution of a methylthio-group for a hydroxyl group into the third alkaloid 4-methylthio-6-oxocanthine. Alternatively a tlhio-analogue of hydroxyglutamic acid may be used as starting material.Sir Robert Robinson1 prefers condensation of tryptamine or tryptophan and aspartic acid to give 6-oxocanthine directly. 5-Hydroxy-6-oxocanthine is then derived as above and the third alkaloid via the hydroxy-ketone (XXVII) the product of hydration of 6-oxocanthine. Alkaloids of Calycant hacez-The alkaloid calycanthine has been isolated from various species of Calycanthacez e.g. C. glaucus Willd. C. floridus L. C. occidentalis Hook and Am. and Meratia przcox Rehder and Wilson. 2o A second alkaloid calycanthidine has been isolated from C. ghucus Willd. Recently a third alkaloid folicanthine has been isolated by Eiter and Svierak from C. j?oridus.20 Calycanthine C,,H2,N4 is a diacidic base which contains two methylimino-groups.Its ultraviolet spectrum shows that it is a true dihydroindole and the infrared spectrum shows the presence of an NH group. Quantitative coupling indicates that the molecule contains two reactive para-positions and oxidation with potassium nitro- sodisulphonate shows that there are two NH groups attached to benzene rings.21 Benzoylation and oxidation of calycant'hine afford N-benzoyl-N- methyltryptamine (XXVIII) which was identified by synthesis.22 When heated with phthalic anhydride calycanthine yields a substance identical Calycanthine and calycanthidine. H (XXVIII) with that obtained from tryptamine and phthalic anhydride which has been formulated as (XXIX) .23 Benzoylcalycanthine when treated with soda lime affords 2-phenylindole and quinoline but on the other hand calycan- thine itself gives N-methyltryptamine and a base which is probably a methyl-/3-carboline.24 Degradation with lead copper oxide sulphur or selenium produces calycanine C,GH,ON,. Selenium also produces @-carbo- 2o Eccles Proc. Amer. Pharm. ASSOC. 1888 84 382 ; Manske J . Amer Chem. SOC, 1929,51,1836 ; Manske and Marion Canad. J . Res. 1939,17 B 293 ; Barger Jacobs and Madinaveitia Rec. Trav. chim. 1938 57 548 ; Eiter and Svierak Monatsh. 1951 82 186; 1952 83 1453. 2 1 Robinson and Teuber Cl~em. and Ind. 1954 783. 2 2 Manske Canad. J . Res. 1931 4 275. 28 Marion and Maimke ibid. 1938 16 B 432. 2 4 Barger Madinaveitia and Streuli J . 1939 810. 119 line skatole 3-ethylindole and lepidine. These confusing results were explained in various ways by different investigators but none of the earlier formuh was completely satisfactory.Robinson has proposed a sym- metrical oxidatively coupled N-methyltryptamine dimer structure (XXX) for calycanthine. 21 There are other possible formulz involving aa- or PP-coupling of the two indole nuclei but this one is preferred. The degrada- SAXT'ON THE INDOLE ALKALOIDS tion product calycanine can be explained as arising from fission of the MeN-C-N system followed by rearrangement of the bisindolenine inter- mediate (XXXI) loss of the two ethanamine chains and aromatisation. Calycanine (XXXII) is thus formulated as quinolino(4' 3'-3 4)quinoline ; this has now been confirmed by ~ynthesis.~4~ Oxidation of calycanthine with silver acetate produces a pyrrolo- quinoline identified by synthesis as 1'-methylpyrrolo(2' 3'-3 4)quinoline (XXXIV).25 This could arise from a hexahydro-@-carboline by oxidation and ring closure a reaction reminiscent of Witkop and Goodwin's ozonolysis experiments in the yohimbine series,26 but its formation can also be explained on the basis of formula (XXX) for calycanthine. Loss of an ethanamine chain from the intermediate (XXXI) followed by oxidative coupling of the other ethanamine chain t o the /3-position of the indole nucleus would give the hypothetical intermediate (XXXIII). Rearrangement to give a quinoline ring system analogous to the above rearrangement of (XXXI) followed by loss of aniline and aromatisat'ion would give the required pyrroloquinoline. Hence the formation of the substance (XXXIV) does not necessarily imply the presence of a P-carboline or pyrroloquinoline ring system in calycanthine.24a Clark and Woodward personal communication. 25 SpBth Stroh Lederer and Eiter Monatsk. 1948 79 11 17 ; Eiter and Nagy 26 Witkop and Goodwin J . Amer. Chem. SOC. 1953 75 3371. ibid. 1949 80 607. 120 QUARTERLY REVIEWS Calycanthidine C,,H,,N, the second alkaloid obtained from C. glaucus Willd. is a dihydroindole containing a NH group linked directly to a benzene ring It affords a quinone on oxidation and couples with diazonium salts.21 Zinc dust distillation gave norharman and since the alkaloid contains no C-methyl group and no double bond it must be represented by a bridged-ring formula e.g. (XXXV). The position of the bridge and the indole structure require confirmation. H (xxxv) Me (XXXVI) (XXXVII) (xxxv II I ) FoEicanthine. The constitution (XXXVI) has been suggested for foli- canthine C18H2,N3 by Eiter and Svierak from the following evidence.,O It was degraded by hydrogen chloride to a base C,,H,,N, which was formulated as 2-3'-aminopropyl- 1 -methylindole (XXXVII) although it was not unequivocally identified.This indole base was also obtained by acetylation of the alkaloid followed by hydrolysis. I n contrast to this folicanthine itself was unaffected by alkalis. Hofmann degradation of folicanthine methiodide gave a base C,,H,,N, identical with that obtained by methylation of the base (XXXVII) and oxidation of the alkaloid by silver acetate gave dehydrofolicanthine formulated as (XXXVIII). Eiter and Svierak's formula requires this alkaloid to be an indole derivative con- taining one N-methyl group but the evidence recorded by these authors would seem to indicate a dihydroindole structure (ultraviolet spectrum) containing two N-methyl groups.The Yohimbine Group of Alkaloids.-By far the majority of the indole alkaloids can be regarded as originating in the plant from tryptophan dihydroxyphenylalanine and formaldehyde or their biochemical equivalents. SAXTON THE INDOLE ALKALOIDS 121 U Sempervirine Cinchonine OH Yohimbine,etc. OH I i / S-Yoh imbi ne etc Alstonine J. serpentine) (s) +Deserpidine reserpine and rescinnamine in methoxylated series) 0 Meltnonine - A ( 122 QUARTERLY REVIEWS The primary product of this condensation could be either of the dihydric phenols (XXXIX) or (XL) depending on whether reaction occurs at the 2- or the 3-position of the indole nucleus. The former possibility leads to the yohimbine series of alkaloids (called by Robinson the a-series) and may even lead to such apparently unrelated alkaloids as cinchonine in which the indole moiety has been converted into a quinoline derivative.The principal transformations of the primary condensation product (XXXIX) are given in the accompanying scheme. Occasionally mono- or di-meth- oxylated derivatives occur in Nature alongside the unsubstituted alkaloids but their biogenesis offers no difficulty since we can equally well start with a mono- or a di-methoxytryptamine. It is frequently possible to explain the formation of an alkaloid by alternative routes and these have in some cases been indicated. One point of unusual interest is the origin of the methoxycarbonyl group in yohimbine and its congeners.It could arise by simple condensation of the intermediate (XXXIX) with formal- dehyde followed by oxidation and methylation. An alternative suggestion by Robinson postulates conversion of the intermediate (XXXIX) into a tropolone by introduction of a single carbon atom. Reduction and a benzilic acid type of rearrangement then lead to yohimbine. It should be noted that in contrast to many natural processes this series of transformations appears not to be stereospecific. Thus for example nine stereoisomers of yohimbine are known and these differ not simply in the orientation of ring substituents but also in the stereochemistry of the C-D and D-E ring junctions. The formation of structure (XL) by the alternative condensation of dihydroxyphenylalanine with tryptophan and formaldehyde was postulated by Woodward to account for the biogenesis of the Xtrychnos alkaloid^.^' (4 Fission of the aromatic ring between the hydroxyl groups gives an inter- mediate which on condensation with an acetic acid equivalent leads to strychnine directly.The probability that this convincing and revolutionary theory was essentially correct was increased when it was applied by Robinson with marked success to derive the structure of emetir~e.~' It was still further increased when laboratory analogies for the formation of the com- pound (XL) were realised. 28 These two reactions namely the /I-condensation and the fission of the aromatic ring are probably the key stages in the formation of the other 27 Woodward Nature 1948 162 155 ; Robinson ibid. p. 524. 2* Robinson and Saxton J .1953,2596 ; Woodward Cava Ollis Hunger Daeniker and Schenker J . Amer. Chem. SOC. 1954 76 4749. SAXTON THE INDOLE ALKALOIDS 123 dihydroindole alkaloids. Unfortunately the structures of many of them e.g. gelsemine akuammine and aspidospermine are still unknown. In these examples Woodward’s theory is used as an invaluable aid in deriving the structures of the alkaloids to act as a basis for discussion and investiga- tion until further evidence becomes available. The features of both types of alkaloids may be combined in ajmaline (see below) which results from an internal #?-condensation in an intermediate (XLI) of the %-series. It is necessary to emphasise here that although biogenetic schemes are frequently written with definite chemical substances as intermediates it is not intended to convey the impression that these specific entities are involved to the exclusion of all others.For example the useof dihydroxyphenyl- alanine in the early stages implies the participation of this or of any biochemical equivalent e.g. dihydroxyphenylacetaldehyde. Similarly the use of formaldehyde implies the intervention of formaldehyde or any possible equivalent or progenitor e.g. glycine. The theories are justified by the structural relations observed between the alkaloids and by the (at present) limited evidence from experiments in vivo (e.g. the conversion of tryptophan into gramine in barley). The results of laboratory analogies in this respect (e.g. Robinson’s synthesis of tropinone 28a) are frequently encouraging although the greatest caution must be exercised in their interpretation and application to reactions in vivo.Further these speculations do not even presume an exact order in which the various stages occur particularly the simpler ones of methylation or acetylation which can be expected to proceed a t any convenient stage in the biosynthesis. Thus as Robinson points out,28b all the alkaloids in this series contain the “ berberine bridge ” carbon atom provided by the formaldehyde equivalent. This may mean the initial condensation of dihydroxyphenylalanine with formaldehyde to give an intermediate of type (XLB) which subsequently condenses with tryptophan to yield (XXXIX). The Alkaloids of Yohimbehe Bark.-Yohimbehe bark is themain source of yohimbine and its congeners and is obtained from a tree (Pausinystalia yohimba Pierre; syn.corynanthe yohimbe K. Schum.) found in the Came- roons and the French Congo. Included among the yohimbehe alkaloids are those obtained from Pseudocinchona africuna A. Chev. Of the thirteen alkaloids isolated from these sources nine are stereoisomers of yohimbine and by 1950 their structure was firmly established as (XLII). The final link in the chain of evidence leading to this structure namely the proof of the position of the hydroxyl group was provided by Swan who achieved the total synthesis of yohimbone (XLIII).29 The nuclear structures of the alkaloids having been established attention was directed towards the configurations of the asymmetric centres. Witkop was the first to adopt this approach and obtained evidence relating to the stereochemistry of the D-E ring junction by degrading yohimbic acid to an optically active trans-decahydro-N-methylisoquinoline (XLIV) and 3-vinyl- 286 Ref.1 p. 124. 20 Swan J. 1950 1534. 2*a Ref. 1 p. 63. 124 QUARTERLY REVIEWS indole (not isolated). Hence in yohimbine the rings D and E must be truns-fused provided that no change in stereochemistry has occurred during the degradation.30 Utilising this result and the methods of conformational analysis Janot and Goutarel and their co-workers have derived the stereochemistry of yohimbine and several of its isomers.31 Thus since yohimbine and y-yohim- bine give the same tetradehydroyohimbine (XLV) with lead tetra-acetate these two bases differ only in the configuration a t position 3. Catalytic reduction of this tetradehydroyohimbine regenerated yohimbine which is presumably the more stable isomer and therefore contains the greater number of equatorial carbon-carbon bonds as shown in (XLVI).The configurations of the hydroxyl and methoxycarbonyl groups remain to be determined. Since corynanthine can be converted into yohimbine by alkaline hydrolysis and re-esterification these two substances are identical with the exception of the configuration at position 16. The hydroxyl and the methoxycarbonyl group are therefore cis in one isomer and trans in the other. The different behaviour of the hydrogen sulphates of yohimbine and corynanthine towards dilute alkali allows the conformations to be deter- mined yohimbine hydrogen sulphate (XLVII ; R = S03H) gives an unsaturated acid whereas corynanthine hydrogen sulphate (XLVIII ; R = S03H) gives an unsaturated hydrocarbon by simultaneous decarboxy- lation.Since this reaction proceeds by elimination of axial groups it may be deduced that the hydroxyl group and the 16-hydrogen atom are in the axial positions in yohimbine and that the hydroxyl and the methoxycarbonyl group are in the axial positions in corynanthine. This conclusion is con- firmed by the readier hydrolysis of the equatorial ester group i.e. yohimbine 30 Witkop J. Amer. Chem. SOC. 1949 71 2559. 31 Janot Goutarel Le Hir Amin and Prelog Bull. SOC. chim. France 1952 1085 ; Le Hir Janot and Goutarel ibid. 1953 1027 ; Le Hir and Goutarel ibid. p. 1023 ; Bader Dickel Huebner Lucas and Schlittler J. Amer. Chem. Soc. 1955 77 3547. SAXTON THE INDOLE ALKALOIDS 125 should be more easily hydrolysed than corynanthine as found by experi- ment.Hence yohimbine is (XLVII ; R = H) and corynanthine is (XLVIII ; R = H). Cookson and Klyne have arrived at the same relative configurations and the latter has also presented evidence that (XLVII) represents the absolute configuration of yohimbine. 32 Similar reasoning allows the conformations of p-yohimbine (XLIX) y -yohimbine (L) alloyohimbine (LI) a-yohimbine (corynanthidine) (LI) and 3-epi-a-yohimbine [C,, epimer of (LI)] to be established with the exception of the methoxycarbonyl group in the three last-named alkal0ids.~1 Thus derivatives of all four possible yohimbanes have been found in Nature. OR (XLVl I I) c ":p H02C Two alkaloids of RauwolJa serpentina Benth.-isorauhimbine 33 and aerpine 34-have also been formulated as stereoisomers of yohinzbine. It has been suggested that the latter differs from v-yohimbine only in the configuration of the methoxycarbonyl group.The elucidation of the stereochemistry of these alkaloids stimulated attempts at stereospecific syntheses and a certain amount of success has c 32 Cookson Chem. and Ind. 1953 337 ; Klyne ibid. p. 1032. 33 Hofmann Helv. Chim. Acta 1954 37 314. 34 Chatterjee and Bose Experientia 1964 10 246. 126 QUARTERLY REVIEWS already been achieved. Att'ention was naturally paid initially to the syn- t'hesis of the four yohimbanes. aZEoYohiiiibnne (LIII) the first isomer to be synthesised had already been obtained by direct hydrogenation of semper- virine (LII),35 and it was prepared later together with its stereoisomer 3-epialloyohimbane (LIIIA) by synthesis from cis-perhydroindan-2-one (LIV).36 An analogous synthesis starting from trans-perhydroindan-2-0ne~ led to (-+)-yohimbane [epimeric with (LIII) at C,,? Comparison of synthetic aZZoyohimbane and yohimbane with material obtained from the related alkaloids demonstrated that the derived stereochemistry of the C-D and D-E ring junctions in these alkaloids was correct.* (LIV) Corynantheine b-yohimbine and their derivatives. Introduction of a carbon atom into the aromatic ring E of the intermediate (XXXIX) followed by conversion into an ester and Woodward-type fission between the hydroxyl groups leads to a hypothetical intermediate written formally as (LV) which may be the precursor of corynantheine (LVI) and many alkaloids in which ring E is heterocyclic. Corynantheine the only tetracyclic alkaloid of this series may thus be regarded as the biogenetic lirlk between the yohimbine isomers on the one hand and the d-yohimbine type with a heterocyclic ring E and the cinchonine type in which further complex transformations have occurred on the other.Corynantheine C22H'&O,"& obtained from Pseudocinchona africana is a tertiary indole base which gives alstyrine (LVII) on dehydrogenation by selenium. A whole series of transformations proved conclusively the 35 Le Hir Janot and Goutarel Bull. SOC. chim. (Prance) 1952 1091. 36 Stork and Hill J . Amer. Chern. Soc. 1954 76 949 ; van Tamelen and Shamma ibid. p. 950 ; Janot Goutarel Le Hir Tsatsas and Prelog Helu. Chim. Acta 1955 38 1073. * The assumption that hydrogenation of sempervirine gives a syn-cis-product and hence the accepted stereochemistry a t C(3j in alloyohimbine a-yohimbine 3-epi-u- yohimbine reserpine deserpidine and rescinnamine have been challenged by Janot Goutarel Le Hir Tsatsas and Prelog who deduced from a study of the molecular rotation changes observed during dehydrogenation of yohimbane and aZZoyohimbene that these two substances possess the same configuration at C(3).36 Hence these authors believe that all the above-mentioned alkaloids are epimers at C(3) of the generally accepted formulations. I n the absence of further evidence t8he earlier structures are used here. . SAXTON THE INDOLE ALKALOTDS 127 presence of the grouping Me0,C.C CH*OMe and when the base was finally obtlained analytically pure the presence of a vinyl group was also demon- strated. Many early specimens of the alkaloid were contaminated with dihydrocorynantheine which accompanies it in the plant.The mixture therefore yielded formaldehyde on ozonolysis and acetic acid in the Kuhn- Roth determination. The constitution (LVI) for corynantheine based on these results by Janot Goutarel and P r e l ~ g ~ ' was confirmed by degrada- tion of t,he alkaloid to 3-ethyl-4-isopropylpyridine and de-ethylalstyrine (LVIII) which were identified by synthesis. 37 Et (LVII) (LVIII) d-Yohimbine C21H2403N2 was first isolated from the mother-liquors of yohimbine preparations and has more recently been obtained from RauwoZ$a serpentina and named ajmalicine and raubasine. 38 Its ultraviolet spectrum is typical of an indole containing the system Me0,C.C C-OR with maxima a t 230 and 290 mp and an inflexion near 250 mp.The infrared spectrum L'x) Me0,C U' 37 Prelog Karrer and Enslin Helv. Chint. Acta 1949 32 1390 ; Chattcrjee arid Karrer ibid. 1950 33 802 ; Janot and Goutarel Bull. SOC. chinh. (France) 1961 588 ; Janot Goutarel and Prelog Helv. Chim. Acta 1951 34 1207 ; Karrer and St. Mainoni ibid. 1953 36 127 ; Prelog Janot Goutarel and Mirza ibid. p. 337 ; Karrer Schwyzer and Flam ibid. 1952 35 851 ; Janot and Goutarel Compt. rend. 1944 218 852 ; Karrer Blumenthal and Eugster Helv. Ghiwz. Acta 1964 37 787 ; Janot Goutarel and Chabasse-Massoiineau Bull. SOC. chim (France) 1953 1033 ; Anderson Clemo and Swan J. 1954 2962. 38 Siddiqui and Siddiqui J . Indian Chent,. Soc. 1931 8 (67 ; Heinemann Ber. 1934 67 15 ; Raymond-Hamet and Goutarel Conapt. rend. 1931 233 431 ; Goutarel and Le Hir Bull. SOC.chim. (France) 1951 909 ; Klohs Drap?r Keller Malesh and Petracek J. Amer. Chem. SOC. 1954 76 1332 ; Popelak Spingler anti Kaiser Natctr- wiss. 1953 40 625. 128 QUARTERLY REVIEWS confirms the presence of this grouping with characteristic twin peaks a t 5-89 and 6-21 ,LL. Selenium dehydrogenation gave alstyrine (LVII). Since the alkaloid contains C-Me but no isolated double bonds it must be penta- cyclic and was formulated by Goutarel and Le Hir as (LIX).38 The pro- duction of alstyrine on degradation is characteristic of all the alkaloids in this series in which ring E is opened or heterocyclic and is in striking contrast to the behaviour of yohimbine and its isomers which on similar treatment yield a mixture of yobyrine (LX) tetrahydroyobyrine (LXI) and keto- yobyrine (LXII).The alkaloids mayumbine from Pseudocinchona mayumbensis and akuammigine from Picralima nitida are formulated as stereoisoniers of d- yohimbine . 39 Alkaloids of Rauwolfia Species.-These alkaloids are obtained from the various species of RauwoZJia and in particular from R. serpentina Benth. indigenous t o the Dehra Dun valley or the Bihar district of India and from R. canascens Linn. Extracts of R. serpentina have been used medicinally for centuries in India. The drug has been prescribed for various disorders e.g. as a febrifuge as a cure for dysentery and as a hypnotic and sedative. It is also recommended for insomnia hypochondria and some forms of insanity but its most important action consists in its ability to reduce the blood pressure. The plant extracts vary somewhat in pharmacological activity depending on their origin those collected from the Dehra Dun valley being more active as a sedative and less active in the treatment of insanity than those obtained from the state of Bihar.This indicated the presence of several active principles in varying proportions in the different specimens and stimulated the chemical and pharmacological investigations which have been intense during the last few years. No less than 24 alkaloids have been isolated from this species alone although as yet some of them are not well known or characterised. The Table opposite gives a list of alkaloids isolated from RauwoZJia species complete up to October lst 1965. This group of alkaloids has recently been reviewed by Schlitt'ler Schneider and Pluninzer and by ChatterjeegO The versatility of the Rauwolufia species in respect of their pharmacological properties is paralleled by their ability as biosynthetical agents.In contrast to yohiinbehe bark which contains only alkaloids of the a-series extracts of RauwoZJia yield alkaloids of both the a- and the @-series together with mono- and di-methoxylated derivatives of the parent alkaloids. The presence of the unrelated alkaloids thebaine and papaverine has even been reported but this may prove to be due to contamination of the samples by opium Hofmann and Chatterjee and Talapatra report t,hat these two alkaloids were not present in their plant extracts.41 39 Raymond-Hamet Conapt. rend. 1951 232 2354 ; Janot Goutarel and Masson- neau ibid. 1952 234 860 ; Robinson and Thomas J . 1954 3479. 40 Schlittler Schneider and Plummer Angew.Chem. 1954 66 386 ; Chatterjee " Progress in the Chemistry of Natural Products " Vol. X Springer Verlag Vienna 1953 p. 390. 41 Hofmann Helv. Chirn. Acta 1954 37 849 ; Chatterjee and Talapatra Nuturwiss. 1955 42 182. SAXTON THE INDOLE ALKALOIDS Alkaloids of Rauwolfia species 129 Ajmalicine (6-yohimbine raubasine) . . . . Ajmaline . . . . . isoAjmaline . . . . neoAjinaline . . . . Ajmalinine. . . . . Alstonine . . . . . Aricine . . . . . . Corynanthine (rauhimbine) Deserpidine (canescine) . Methyl reserpate . . . Papeverine . . . . Perakenine. . . . . isoRauhimbine . . . Raumitorine . . . . Rauwolfinine . . . . Rauwolscine (a-yohimbine) Rescinnamine . . . . Reserpiline. . . . . isoReserpiline . . . . Reserpine . . . . . Reserpinine (raubasinine) isoReserpinine.. . . Sarpagine (raupine) . . Semperflorine . . . . Seredine . . . . . Serpentine . . . . . Serpentinine . . . . Serpine. . . . . . Serpinine . . . . t Tetraphyllicine ** Tetraphylline . . Thebaine . . . Yohimbine. . . alloYohimbine . . 3 -epi - ct -Y ohimbine p-Yohimbine . . y-Yohimbine . . $-Yohimbine . . Unnamed . . . . . . . . . . . . . . . . . . . . . . . Formula 21H 2 4 O 3N2 C20H 2 6 O ZN2 C20H2602N2 ,OH 2 6 O ZN2 C20H2603N2 21H 20' BN 2 2ZH 26' 4N 2 C21H 2 6 O 3N 2 c3 ZH 2 2sH3Oo 5N 2 C211H2104N C21H2603N2 2 2H 2 6 O aPIT 2 C1ilH260 ZN2 21H260 3N2 35H4209N 2 C23H 2 1 3 ~ 5 ~ 2 2sHm0 gN2 C33K4009N2 (= 2ZH260 4N2 2 ZH 26O 4N 2 21H 2 6 0 N 2 23H SO0 gN 2 21H 20° 3N2 C21H 22' 3N2 C21H2603N2 (=ZOH24ON2 C 1 9 H 2 2 O 2 N 2 DT C2,H,,ON c 2 0 H 2 4 0 N 2 (= 22H 2 6 O bN 2 C19H2103N 21H 26°3N2 C21H2603N2 21H2603N2 ,1H2603NB ,IH 2 1 3 ~ 3 ~ 2 C21H 26°3N2 B1.p 250-252" * 158-160 264-266 * 205-207 180-181 254 * 188 * 218-225 228-232 * 244-245 147 236 * 225-228 138 235-236 * 231-232 * 2 24-2 2 6 Amorphous 211-212 * 263 238-239 225-226 * 325 * 295 * 291 158 213 315 * 263-265 3 20-322 220-223 * 2 35-2 3 7 135-136 181-1 83 246-249 2 5 8-2 5 9 265-278 195 323 Rotation t - 58.1" (C) + '72.8 (E) + 128 (C) - 97 (C) - 58.3 (E) - 82 (P) - 137 (C) - 106 (P) 0 - 104 (P) - 34.7 (E) - 40 (E) - 38 (E) - 82 (P) - 117 (C) + 60 (C) - 98 (C) + 21 (PI - 73 (C) + 105 (P) - 90 (P) + 27 (PI - 279 (P) - 72.7 (P) - 48 (P) - 28.3 (P) Source 2 * With decomp.t Solvents A aqueous acetic acid ; C = chloroform ; E = ethanol ; M = meth- anol ; P = pyridine 2 c = R. canescens. ht = R.hirsuta. s = R. serpentina. cf = R. caffra. m = R. micrantha. d = R. densijlora. o = R. obscura. t = R. tetraphylla. se = R. semperylorens. h = R. heterophylla. p = €2. perakensis. v = R. vomit~ia;. ** This is now known to be didehydrodeoxyajmaline ; reuvomitine a recently isolated alkaloid is probably its tri-0-methylgalloyl derivative (Djerassi Gorman Pakrashi and Woodward personal communication). Several of tb. 2 Sllkaloids e.g. yohimbine alloyohimbine and Q-yohim- bine have already been discussed and hence need no further comment. The monomethoxy-derivatives of 6- yohimbine are represented by reserpinine I 130 QUARTERLY REVIEWS (from R. serpentina) and isoreserpinine (from R. canascens) which are formulated as stereoisomers of 11 -met.hoxy- 6-yohimbine (LXIII ; R = H R’ = OMe).38 41 42 It is noteworthy that reserpinine has also been “-Q R :lQ-$ N CH ct %; 0 O-CHE ~LXIV):R- R ~ = H (LXIVB):RIH,R=OM~ ( LX IVA) R-H R L O M ~ ( LX IVC) R- R’ = o M= (LXIII) Meo2C obtained from Vinca major L.collected in Normandy by Janot and Le Men 43 ; this is the first reported occurrence of an alkaloid of the yohimbine series in a plant indigenous to Europe. Aricine (10-methoxy-6-yohimbine) (LXIII R = OMe R’ = H) occurs in R. canascens and Cinchona pelletierana Wedd.,42 44 and its stereoisomer raumitorine in R. ~ o r n i t o r i a . ~ ~ The series is completed by the extraction of reserpiline (from R. serpentina) and isoreserpiline (from R. canascens) which are stereoisomers of 10 ll-dime- thoxy-6-yohimbine (LXIII R = R’ = OMe).429 46 Thus we find a quartet of alkaloids in the RauwoZJia species completely analogous to the Xtrychnos alkaloids strychnine (LSIV) a- and P-colubrine (LXIVA and B respectively) and brucine (LXIVC).As with the yohimbines the stereoisomerisni within the series illustrates the fact that the biogenetic pathway is not stereospecific. The Xtrychnos alkaloids on the other hand in common with most alkaloids of the #I-series must be produced by a much more selective mechanism since such stereoisomerism is not encountered. Taking cognisance of the fact that dehydrogenation reactions frequently participate in natural processes (cf. the biosynthesis of nicotine and papa- verine) it would be surprising if none of the alkaloids of this group existed in a more highly oxidised state than that represented by yohimbine or d-yohimbine.Several such alkaloids are known which are coloured and belong to the class of anhydronium bases. Their true constitution is inter- mediate between the zwitterion structure and the alternative quinonoid form. Sempervirine (LII) is the simplest of these alkaloids and occurs in Gelsemiurn sernpervirens and Mostuea buchh0lxii.4~ In view of the compre- 4 2 Weisenborn Moore and Diassi Chem. and Ind. 1954 375 ; Schlittler Saner and Muller Experientia 1954 10 133 ; Stoll Hofmann and Brunner Helv. Chiin. Acta 1955 38 270. 4 3 Janot and Le Men Compt. rend. 1954 238 2550 ; 1955 240 909. 44 Pelletier and Corriol J . Pharm. 1829,15 565 ; Goutarel Janot Le Hir Corrodi and Prelog Helv. Chirn. Acta 1954 37 1805 ; Raymond-Hamet Compt. rend. 1945 221 307. 45 autarel Le Hir Poisson and Janot Bull.SOC. chim. (France) 1954 1481. 46 Klohs Draper Keller and Malesh Chem. and Ind. 1954 1264. 47 Forsyth Marrian and Stevens J . 1945 579 ; Goutarel Janot and Prelog Experientia 1948,4,24 ; Prelog Helv. Chirn. Acta 1948,31,588 ; Bentley and Stevens Nature 1949 164 141 ; Woodward and Witkop J . Arner. Chem. SOC. 1949 ’71 379 ; Woodward and MacLamore ibid. p. 379 ; Gellgrt and Schwarz Helv. Chim. Acta 1951 34 779. SAXTON THE INDOLE ALKALOIDS 131 hensive range of alkaloids isolated from Rauwolfia species it is perhaps surprising that this comparatively simple one does not occur there. Its structure was derived from a study of its dehydrogenation products (LX- LXII) which are typical of the pentacyclic yohimbane system and its spectra and was confirmed by Woodward’s synthesis of sempervirine methochloride and sempervirine itself.(LXV) ( LXV A ) Serpentine serpentinine and alstonine. The coloured anhydronium base alkaloids are represented in the RauwolJia series by serpentine serpentinine and alstonine. The last -named was originally found in Alstonia constricta F. Muell. in which it is the principal alkaloid. It is of interest that alstonine has not been found in any of the remaining ten Alstonia species which have been investigated. The structure of serpentinine is at present obscure although it is evidently closely related to serpentine and alstonine (LXV) which are stereo- is0mers.~8 48 The constitutions of these two alkaloids were derived in- dependently and indeed it was only very recently realised that they are isomeric since serpentine was initially believed to contain two hydrogen atoms more than alstonine.The isolation of alstyrine (LVII) on dehydrogenation of serpentine by selenium and the close similarity of the spectra of the alkaloid and tetra- dehydroyohimbine (XLV) indicated the presence of the partial structure (LXVA). Proof of the presence of an ester group an ether link C-Me and finally a double bond indicated the formula (LXV) which was proved by identification of py-tetrahydroserpentine with d-y~himbine.~*> 49 The reputation of Alstonia barks in the Far East as an antimalarial and febrifuge stimulated investigation of the alkaloidal constituents in the search for possible quinine substitutes. However reliable pharmacological experi- ments have failed to substantiate this claim and AZstonia extracts are no 48 Schlittler Huber Bader and Zahnd Helv.Chim. Acta 1954 37 1912. 49 Schlittler and Schwarz ibid. 1950 33 1463 ; Bader and Schwarz ibid. 1952 35 1594. I* 132 QUARTERLY REVIEWS longer included in the official British Pharmacopceia. These investigations resulted in the isolation of several minor alkaloids but of these only alstoniline has been studied in any detail. The presence of the partial structure (LXVA) in alstonine was readily proved but the constitution of ring E presented more difficulty until it was realised that the anomalous behaviour of tetrahydroalstonol (obtained by reduction to a tetrahydrocarboline and the change (C0,Me -+ CH,*OH) was due to the presence of the grouping *O*C C*CO,Me which on reduction gave a labile ally1 alcohol derivative which rearranged in acid solution and yielded ethers with comparative ease.Comparison of the spectra and reactions of tetrahydroalstonine with those of the model compounds (LXVI) and (LXVII) by Bader proved conclusively the position of the double bond and the structure of alstonine was firmly established as (LXV). 50 Me4 Me Me Oy%Oyb MeOzC (LXVI) (LXVII) ( LXVI I I) (LXIX) Reaction of tetrahydroalstonine with methyl chloride yields the quater- nary salt melinonine-A which occurs in the bark of South American Xtrychnos melinoniana Baillon. 51 The alkaloid alstoniline C,,H,,O 3Nz*OH is characterised by the brilliant red colour of its salts the hydrochloride being obtained directly from the bark without previous addition of acid. It thus appears that alstoniline exists in Nature as the chloride a very rare occurrence in the alkaloid series.In spite of the fact that in alstoniline chloride the ring system is in a very highly dehydrogenated state this compound does not contain the chromo- phore of alstonine since the spectra of the two alkaloids are quite different. On the other hand the spectra of alstoniline and tetrahydroalstoniline resemble those of ketoyobyrine (LXII) and 6-methoxyindole respectively. Surprisingly dehydrogenation by selenium gave no identifiable products but potash fusion gave 2-methylisophthalic acid. Elderfield and Wythe’s tenta- tive formula (LXVIII) for alstoniline chloride is supported by comparison of its spectrum with that of 3-(6-methoxy-3-methyl-2-indolyl)-2-methyl- isoquinolinium iodide (LXIX) .52 Hence in the formation of alstoniline chloride from an intermediate of type (XXXIX) ring c has remained hydro- aromatic and ring E aromatic (although this may involve reduction and 6o Sharp J.1934 287 ; Sharp J. 1938 1353 ; Leonard and Elderfield J. Org. Chem. 1942 ‘7 556 ; Elderfield and Gray ibid. 1951 16 506 ; Bader Helv. Cizim. Acta 1953 36 215. 61 Schlittler and Hohl Helv. Chirn. Acta 1952 35 29. 62 Hawkins and Elderfield J. Org. Chem. 1942 ‘7 573 ; Elderfield and Wythe ibid. 1954 19 683 693. SAXTON THE INDOLE ALKALOIDS 133 re-aromatisation stages) while ring D has suffered dehydrogenation. The fully aromatic system in which ring c is also aromatic has not so far been found in Nature. Reserpine rescinnumine and deserpidine. Retention of all three sub- stituents in ring E of (XXXIXA) followed by further obvious transforma- tions leads to the important drug deserpidine (canescine) (LXX) found in Rauwolfia canuscens.The methoxylated derivative reserpine (LXXI) ocours in R. serpentina and several other RauwoZjia species while an analogous derivative of trimethoxycinnamic acid rescinnamine (LXXII) is also present in R. serpentina and R. v0rnitoria.5~ All three alkaloids are extremely valuable hypotensive and sedative agents and the limited amounts available have led to the prohibition of their export from the Indian sub-continent. In this connection the isolation of reserpine from Australian Alstonia con- stricta is important since it may provide an alternative source of this alkaloid for medical use.54 Reserpine C33H4009N2 the first of these three alkaloids to be isolated was easily shown to be an ester alkaloid by hydrolysis to reserpic acid (LXXIII) and trimethoxybenzoic acid.Rescinnamine similarly gave reserpic acid and trimethoxycinnamic acid. Reserpic acid was shown to be a derivative of yohimbane by degradation to 4-methoxy-N-oxalyl- anthranilic acid 5-hydroxyisophthalic acid and yobyrine (LX) and by its colour reactions which were characteristic of a tetrahydro-p-carboline. The relative positions of the hydroxyl and the carbonyl group were indicated by formation of a y-lactone and by isolation of 5-hydroxyisophthalic acid. Gs Muller Schlittler and Bein Exper;entia 1952 8 338 ; Haack Popelak Spingler and Kaiser Natumiss. 1954 41 214 ; Klohs Draper and Keller J . Amer. Chem. SOC. 1954 76 2843 ; Schlittler Ulshafer Pandow Hunt and Dorfman Experientia 1955 11 64 ; Stoll and Hofmann J .Amer. Chem. SOC. 1955 7'7 820. 5 4 Report from C.S.I.R.O. Melbourne quoted in the London Times May 26th 1955. 134 QUARTERLY REVIEWS These results enabled Schlittler and his co-workers and Neuss Boaz and Forbes to propose formula (LXXI) for reserpine.55 The methoxyl group was placed at position 17 for purely biogenetic reasons but was supported by conversion of methyl 0-toluene-p-sulphonylreserpate (LXXIV) into a derivative (LXXV) containing the chromophore Me0,C.C C-OMe which by acid hydrolysis and decarboxylation yielded reserpone (LXXVI). The position of the carboxyl group and hence the positions of the other substituents was proved by degradation of reserpinol (LXXIII ; CH,*OH in place of C0,H) to 7-hydroxymethylyobyrine (LXXVII) which was identified by synthesis of its methyl ether.56 OW? OMe OMe ( LXXV) (LXXV I II 1 (LXXVII) 5 H" 20 l5 I9 R - tri - 0- methyl -galloyl By analogy with this deserpidine which exhibits very similar pharmaco- logical properties to reserpine was formulated as (LXX).55 The stereo- chemistry of the ring system was elucidated by conversion of deserpidine into a-yohimbine a derivative of uZbyohimbane (LIII).Since the alkaloid is known to have the less stable configuration at position 3 and since one of the stages in this series of transformations involves epimerisation at this centre deserpidine and hence reserpine can be formulated as derivatives of 3-epiaZbyohimbane. The configurations of the substituents in ring E remain to be determined. Since reserpic acid readily gives a lactone it can be assumed that the carboxyl and the hydroxyl group are in the cis-position relative to one another.These conclusions were supported by Diassi 5 5 Furlenmeier Lucas MacPhillamy Muller and Schlittler Experientia 1953 9 331 ; Dorfman Huebner MacPhillamy Schlittler and St. Andre ibid. p. 368 ; Dorf- man Furlenmeier Huebner Lucas MacPhillamy Muller Schlittler Schwyzer and St. And-6 Helu. Chim. Acta 1954 37 59 ; Neuss Boaz and Forbes J . Amer. Chem. SOC. 1954 76 2463 ; Schlittler MacPhillamy Dorfman Huebner and St. Andre ibid. 1955 77 1071. 66 Huebner MacPhillamy St. Andre and Schlittler J . Amer. Chem. SOC. 1955 77 472 ; Schlittler MacPhillamy Dorfman Huebner and St. Andre ibid. p. 1071 ; Diassi Weisenborn Dylion and Wintersteiner ibid. p. 2028. SAXTON THE MDOLE ALEALOIDS 135 Weisenborn Dylion and Wintersteiner who obtained the quaternary salt (LXXVIII) in addition to the unsaturated ester by removal of the toluene- p - sulp hony 1 group from met hy 1 0 -toluene -p - sulph on ylr eserpat e .Since quaternary salt formation was assumed to involve inversion a t C(ls) the 18- oxygen bond must be cis with respect to the 15- and 20-hydrogen atoms. Finally if trans-elimination occurs in formation of the unsaturated ester (LXXV) then the 17-methoxyl group must also be cis with respect to the hydroxyl and the carboxyl group. Reserpine was therefore completely represented by formula (LXXIA) .56 More recent studies however have shown that these deductions were not entirely correct. The stereochemistry of the D-E ring junction has been confirmed by Huebner's synthesis of (A)- reserpane [l l-methoxy-3-epiaZZoyohimbane (LXXVI) with CO -+ CH,],56° but the spontaneous quaternisation which occurred on treatment of reser- pinol (LXXVIIIA ) or 3-isoreserpinol with toluene-p-sulphonyl chloride to give the mixed salt (LXXVIIIB ; X- = C1- or OTs-) indicated that the C(16)-C(22) bond must be trans with respect to the 15- and 20-hydrogen atoms instead of cis as a t first Since reserpine can be hydrolysed and methyl reserpate can be treated with sodium methoxide in boiling methanol without inversion the methoxycarbonyl group must be equatorial.Application of Hudson's lactone rule to reserpic lactone indicates that the 18-hydroxyl group has the ,&configuration and therefore reserpic acid is correctly represented by (LXXVIIIC) with reservations with regard to the configuration of the methoxyl group.According to van Tamelen and Hance this methoxyl group is probably trans with 18-substituents and the formation of (LXXV) respect to the 16- and and (LXXVIII) from participation. Quater- (LXXIV) probably occurs by neighbouring-group L nisation therefore proceeds with double inversion and retention of 56aHuebner Chem. and Ind. 1955 1186. 66b Huebner and Wenkert J . Amer. Chem. SOC. 1955,77,4180 ; Diassi Weisenborn Dylion and Wintersteiner ibid. p. 4687 ; van Tamelen and Hance ibid. p. 4692. 136 QUUTERLY REVIEWS configuration at C(ls). The all-trans-arrangement also explains the ready isomerisation of reserpine and its analogues to alloyohimbane derivatives. 56c Dihydroindole Alkaloids of the RauwoZfla Species.-Ajmaline. The principal alkaloid 38 of RauwoZjia serpentina and one of the first to be isolated is ajmaline C2,H,,02N2.Its ultraviolet spectrum and colour reactions the production of id-N-methylharman on distillation with zinc dust and the oxidation of ajmaline with potassium permanganate in acetone to 3-acetonyl-2 3-dihydro-3-hydroxy-1 -methyl-2-oxoindole (LXXIX) in- dicate clearly that the alkaloid is a derivative of 2 S-dihydro-l-methyl- indole. 57 Robinson and his co-workers have provided abundant evidence that the second nitrogen atom of ajmaline is contained in a carbinolamine grouping. However it' does not behave as a normal carbinolamine e.g. y-strychnine (LXXX). Thus the alkaloid shows reducing properties and Me (LXXIX) (LXXXI) gives an oxime which on dehydration and reduction of the nitrile with lithium aluminium hydride regenerates ajmaline.It can also be reduced by the Huang-Minlon procedure and on treatment with Raney nickel at 130" loses carbon monoxide [N*CH(OH*& *&He H 6 + CO] the pro- ducts from both reactions being seconda;y bases. On the other hand the basic strength of ajmaline (pK 8-15) is much higher than expected (cf. y-strychnine pK 5-60) and it gives 0-acetyl derivatives without fission of the C-N bond and is not reduced by zinc and acid. These results are interpreted by assuming that in ajmaline the carbinolamine grouping is so situated in a bridged-ring system that participation of the ammonium form (-+NH :CH-) is imp0ssible.~7 Deoxydihydroajmaline gives ethyl methyl ketone on oxidation while similar treatment of decarbonoajmaline gives butyric acid (and traces of the lower homologues).These results can be accommodated in the following partial formdz I I Me*CO*Et + -NH Me-CHEt +- -N-CH(OH)-CHEt I I c 4 - c c-c-c Deoxydihydr oa j maline A j maline C3H,*C0,H I CH3*C0,H c-c-c C,H,.CO,H +- -" + CO + CH,Et I Decarbonoajmaline '13~ Wenkertc and Liu Experiefitia 1955,11 302 ; Huebner MacPhillamy Schlittler and St. Andr6 ibid. p. 303. SAXTON THE INDOLE ALKALOIDS 137 The second hydroxyl group in ajmaline was assumed to be tertiary since although it can be acetylated it is comparatively inert towards oxidation. The failure of dehydration and replacement reactions indicates that the hydroxyl group may be situated at the apex of a bridged-ring system as it is in apocamphan-1-01 (LXXXI) which behaves similarly. Dehydrogenation of deoxydihydroajnialine and deoxyajmaline with palladised charcoal at 326" yields bases of the alstyrine type but their structures have not yet been completely elucidated.So far it is the only dihydroindole alkaloid known which gives alstyrine-like degradation products. The above results require that this alkaloid possess the partial formula (LXXXII) . By postulating an internal condensation at position 3 of the indole nucleus with one of the fragments of the ruptured benzene ring Robinson has expanded this to the alternatives (LXXXIII) and (LXXXIV).57 The structure of ajmaline poses a fascinating problem. OH E t Me Me ( LXXX I II) 'C The constitution of ajmaline was finally established in an elegant series of degradations by Schenker and Woodward who conclusively proved that it possesses the structure (LXXXIVA).5* Oxidation of deoxyajmaline with lead tetra-acetate led to the rapid formation of an indole-aldehyde (LXXXIVB) which suggested that one of the carbon atoms attached to position 2 or 3 of the dihydroindole moiety contains the inert hydroxyl group which must moreover be secondary since the product is an aldehyde and not a ketone.This was confirmed by isolation of a dihydroindole- ketone by the prolonged oxidation of deoxyajmaline with benzophenone and potassium tert.-butoxide. Reduction of this ketone by sodium boro- hydride gave epideoxyajmaline which gave the same aldehyde (LXXXIVB) as deoxyajmaline with lead tetra-acetate. The infrared absorption of the dihydroindole-ketone (carbonyl band at 5.74,~) suggested that the carbonyl group was present in a five-membered ring.These facts together with biogenetic considerations led to the formula (LXXXIVA) for ajmaline 67 Mukherji Robinson and Schlittler Experientia 1949 5 215 ; Raymond-Hamet Compt. rend. 1949 229 1165 ; An& Robinson Chakravarti and Schlittler J. 1954 1242 ; Robinson (with Anet Finch and Hobson) Chem. and Ind. 1955 285 ; Finch Hobson Robinson and Schlittler ibid. p. 653. m Schenker and Woodward personal communication. 138 QUARTERLY REVIEWS which was soon confirmed by a study of the dehydrogenation of deoxydi- hydroajmaline (LXXXIVC) by palladised charcoal at 250". The four pro- ducts isolated included N(a,-methylharman ajarmine (LXXXIVD ; as racemate) ajmyrine (LXXXIVE) and a base C20H24N2 probably identical WEt (LXXXIV A) Et \yEt (LXXXIV B) with one of Robinson's dehydrogenation products which had a spectrum almost superimposable on that of AT(,,-methylalstyrine.Final confirmation of this structure was obtained by synthesis of ajarmine (LXXXIVD) from N(,,-methylharman. The isolation of ajarmine and ajmyrine whose struc- ture (LXXXIVE) has now been confirmed by synthesis 58a demonstrates conclusively that N(b) in deoxydihydroajmaline is common to two six- membered rings and that in ajmaline it must be common to three such rings. The formulation of this alkaloid as a product of both 01,- and ,&type biogenetic condensations is thus confirmed. Me (LXXXIV E> R. serpentina also contains isoajmaline and a consideration of the chemical properties which are identical with those of ajmaline shows that this compound is simply a stereoisomer of the latter.571 59 In accordance with this conception isoajmaline can be produced from ajmaline by the action of heat or alkali and since the two alkaloids give the same decarbono- ajmaline they differ only in the configuration of the carbon atom adjacent to the carbinolamine grouping (denoted by an asterisk in LXXXIV).se Woodward and Yang personal communication. sn Siddiqui and Siddiqui J . Indian Chem. SOC. 1935 12 37. SAXTON THE INDOLE ALKALOIDS 139 The existence of neoajmaline reported by Siddiqui is now regarded as doubtful. An examination of Siddiqui’s specimen by the Oxford workers suggests that it is very probably ajmaline.60 Little is known about the remaining dihydroindole alkaloids which have been isolated from 3. serpentina. Both rauwolfinine C19H2602N2 and serpinine C,oH,,ON or C,,H,,ON, show weak reducing properties which may indicate the presence of a potential aldehyde group.Rauwolfinine shows certain other superficial resemblances to ajmaline hence it may possess a similar constitution and it is significant that in some specimens of R. serpentina ajmaline is replaced by rauwolfinine and the latter is the major alkaloid of the plant growing in North-Western India. It is therefore surprising that it was not isolated earlier.61 The Quebracho Alkaloids.-The quebracho alkaloids are obtained from various species of Aspidosperma and VaZZesia which are hard-wood trees found in South America. Several alkaloids have been isolated from Chese sources the four principal ones being aspidospermine vallesine quebrachine (yohimbine) and quebrachamine.62 The remaining alkaloids are aspido- samine haslerine and quirandine which were extracted from Aspidosperma quirandy Hassler by F l ~ r i a n i ~ ~ and aspidospermicine aspidospermatine and hypoquebrachine obtained from Aspidosperma quebrachoblanco Schlecht.62 Very little is known about these alkaloids and indeed the status of two of them as true alkaloids is open to question.Ewins has suggested that aspidosamine and hypoquebrachine are simply decomposition products of aspidospermine.63 Aspidospermine C22H3002N2 is the principal alkaloid of the group and occurs along with quebrachine in A. quebracholdanco with vallesine in Vallesia glabra and in several related species. It is a monoacidic base containing methoxyl methylimino- and N-acetyl groups. Hydriodic acid removes the N-acetyl group and ruptures the ether link to give aspidosine C19H260N2 which behaves in all respects as an aminophenol.The position of the phenolic hydroxyl is shown by a study of the ultraviolet and infrared spectra of the demethylated alkaloid which show a marked resemblance to those of vomicine (LXXXV). I n particular there is no hydroxyl band in the infrared spectrum owing to hydrogen bonding with the acetyl group. The presence of a dihydroindole group is proved by isolation of a mixture of indoles on dehydrogenation with zinc dust or palladium. The first formula (LXXXVI) proposed for aspidospermine explained readily all these experimental results and was easy to justify biogenetically but could not account for the occurrence of 3 5-diethylpyridine among the products of zinc dust distillation or for the result of Kuhn-Roth determination which 6o Siddiqui J.Indian Chem. Soc. 1939 16 421. 61 Bose ibid. 1954 31 47 691 ; Naturwiss. 1955 42 71. 6 2 Fraude Ber. 1878 11 2189 ; 1879 12 1560 ; Schlittler and Rottenberg Helv. Chim. Acta 1948 31 446 ; Hesse Annalen 1882 211 249 ; Fourneau and Page Bull. Sci. p h r m . 1914 21 7. 6s Floriani Rev. centro Estud. farm. bioquim. 1935 25 373 423 (Chem. Abs. 1936 30 1415); Ewins J . 1914 105 2738. 140 QUARTERLY REVIEWS indicates only one C-Me for deacetylaspidospermine. Indeed the isolation of 3 5-diethylpyridine is unexpected since all the alkaloids discussed above whether they belong to the a- or the p-series are 3 4-disubstituted pyridine (LrnV) (LXXXVI) derivatives. Witkop's alternative formula (LXXXVII) for aspidospermine explains readily its known behaviour but its possible biogenesis is not so apparent.Openshaw's ingenious suggestion is that it is formed from a methoxy-aldehyde (LXXXVII) analogous to the Wieland-Gumlich aldehyde (XLA ) which represents an intermediate stage in Woodward's biogenesis of strychnine. Reduction of the aldehyde followed by oxidation in the /&position to the carbonyl group (i.e. position 1 of the dihydroxyphenyl- alanine precursor) yields an aldol which on fission recyclisation reduction and acetylation gives aspidospermine (LXXXVIII) .64 (LXXXVII) 1 (LXXXVIII) Vallesine the second alkaloid isolated from these sources is probably deacetyl-N-formylaspidospermine. Schlittler and Rottenberg 62 have shown that deformylvallesine and deacetylaspidospermine are identical in chemical and physical properties but in spite of this and the identity of Rontgen powder diagrams and infrared spectra these authors formulate deacetyl- aspidospermine as a homologue of deformylvallesine for reasons which are not clear.The only other alkaloid known which gives a 3 5-disubstituted pyridine on degradation is ibogaine C20H260N2 obtained from Tabernanthe iboga Baillon. Extracts of the root bark of the Witkop states that the last-named substances are i d e n t i ~ a l . ~ ~ AZkaloids of Tabernanthe iboga. 64 Raymond-Hamet Compt. Tend. 1948 226 2154 ; Witkop J . Amer. Chem. SOC. 1948 70 3712 ; Witkop and Patrick ibid. 1954 76 5604 ; Openshaw Smith and Chalmers 13th Internat. Congr. Pure Appl. Chem. 1953 Abs. p. 223. SAXTON THE INDOLE ALKALOIDS 141 shrub are used by West African natives to increase resistance to fatigue and so this species has attracted wide attention from pharmacologists.Its chemical study however is in a much more elementary stage and although four alkaloids have been isolated and characterised none of their structures is known.65 Ibogaine is a monoacid base containing methoxyl C-methyl and imino-groups. Its ultraviolet spectrum and colour reactions disclose the presence of an indole nucleus and this is confirmed by the production of 5-methoxy-N-oxalylanthranilic acid on oxidation. Alkali fusion gives 3-ethyl-5-hydroxy- 1 2-dimethylindole (LXXXIX) which was identified by synthesis and 3-ethyl-5-methylpyridine.66 Assuming from the isolation of the latter a relation to aspidospermine Robinson derives the constitution (XC) for a dihydroibogaine by fission of the bond between the carbon atoms marked with an asterisk.Ibogaine must then contain another ring since there is no evidence for the presence of a double bond. Alkaloids of Picralima nit ida.-The dihydroindole alkaloids discussed above show few structural analogies with those of the a-series with the possible exception. of ajmaline. Aspidospermine is presumed to be formed by fission of the aromatic ring of the dihydroxyphenylalanine precursor followed by various reactions involving rupture and formation of further rings. The comparatively simple recombination of the aromatic ring frag- ments to give a six-membered ring similar to ring E of 6-yohimbine might also be expected and this has been postulated by Robinson to account for the behaviour of two alkaloids akuammine and y-akuammigine isolated from Picralirna nitidu Stapf.extracts of which are used by West African natives in the treatment of malaria and as an antipyretic. This reputation led Henry and Sharp to investigate the alkaloidal constituents but the investigations were not pursued when it was shown that the extracts are inactive in avian malaria. More recently however Raymond-Hamet has demonstrated that the principal alkaloid akuammine has a local anaesthetic action almost equal to that of cocaine and the investigations have been resumed by Robinson and his co-workers.67 Of the eight alkaloids so far isolated only akuammigine has been studied in addition to akuammine 6 5 Dybowski and Landrin Compt. rend. 1901 133 748 ; Haller and Heckel ibid. p.850 ; Delourme-Houd6 Ann. pharm. frang. 1946 4 30 ; Burckhardt Goutarel Janot and Schlittler Helv. Chim. Acta 1952 35 642 ; Goutarel and Janot Ann pharm. frang. 1953 11 272. 66 Janot Goutarel and Sneeden Helv. Chim. Acta 1951 34 1205 ; Raymond- Hamet Compt. rend. 1949 229 1359 ; Goutarel Janot Mrtthys and Prelog ibid. 1953 237 1718 ; Schlittler Burckhardt and GellBrt HeZv. Chim. Acta 1953 36 1337. 67 Henry and Sharp J. 1927 1950 ; Goodson Henry and MacFie Biochem. J. 1930 24 874; Raymond-Hamet Arch. mp. Pathol. Phamakol. 1942 199 399; Janot Le Men Aghoramurthy and Robinson Experientia 1955 11 343. 142 QUARTERLY REVIEWS and y-akuammigine. Its constitution as a stereoisomeride of d-yohimbine has already been mentioned. Akuammine,* CB2HB6O4N2 is a ditertiary dihydroindole base containing hydroxyl C-methyl N-methyl and methoxyl groups which dissolves readily in methanolic alkali giving a solution from which it can be regenerated.Its colour reactions are strongly reminiscent of those of p-methylamino- phenol and the presence of a similar grouping (based on 2 3-dihydro-5- hydroxy- 1-methylindole) also explains the relative instability of the alkaloid which has been known to decompose during attempted recrystallisation. Zinc dust distillation of the product gave 3-ethylpyridine and probably skatole. Hydrogenation was inconclusive and requires further study but presence of a double bond is considered probable by Robinson and Thomas who have combined these results in the provisional formula (XCI; R = OH) for akuammine.68 The second alkaloid y-akuammigine is believed to be deoxyakuammine (XCI ; R = H).It contains similar functional groups (with the exception of the phenolic hydroxyl group) but its basic strength and colour reactions are anomalous. Thus its basic strength is closer to that of strychnine than to that of strychnidine. Further ferric chloride gives a colour only on warming and diazo- coupling occurs reluctantly and only in buffered acetic acid. However nitration and nitrosation proceed normally. On the other hand the lithium aluminium hydride reduction product y-akuammigol behaves like strychnidine in all respects. These peculiar properties are interpreted in formula (XCI ; R = H) by assuming that the proximity of the dihydroindole nitrogen atom and the ester group results in deactivation of the potentially basic group across space by the carbonyl group.This proximity apparent from a study of molecular models and the tertiary nature of the ester group also explain the difficulty of hydrolysis of y-akuam- migine which was unaffected by vigorous treatment with alcoholic alkali.68 Alkaloids of Gelsemium Species.-The North American plant Gelsemiurn sempervirens has been known since 1870 to contain alkaloids ; Wormley isolated an amorphous base later obtained crystalline by Gerrard,Ggb and named gelsemine. Although a number of bases has been isolated in addition to gelsemine only four of these namely sempervirine gelsemicine gelsedine Henry J. 1932 2759 ; Millson Robinson and Thomas Experientia 1953 9 89 ; Robinson and Thomas J. 1954 3522. 6s (a) Wormley Amer. J . Pharm. 1870 42 1 ; ( b ) Gerrard Pharm.J. 1883 13 641 ; Jahresber. 1883 1353 ; Chou Chinese J . Physiol. 1931 5 345 (Chem. Abs. 1932 26 806) ; Chou Wang and Cheng ibid. 1936 10 79 (Chem. Abs. 1936 30 4270). * This alkaloid also known as vincamajoridine has recently been isolated together with reserpinine from Virzca major L.67 SAXTON THE INDOLE ALKALOIDS 143 and gelseverine are well established. Chinese Gelsemiurn species also contain several alkaloids but with the exception of gelsemine obtained from G . elegans (Gardn.) Benth. they do not appear to have been related to those extracted from the North American varieties.69 Gelsemine C20H2202N2 is the principal alkaloid of this series and has been studied in recent years by several groups of workers. One of its nitrogen atoms is contained in a tertiary basic group while the other is inert.Reduction of gelsemine with lithium aluminium hydride results in elimination of one oxygen atom with the formation of a dihydroindole base. This behaviour is characteristic of 3 3-disubstituted oxindoles and the presence of this grouping was confirmed by comparison of the ultraviolet spectra of gelsemine and 3 3-dimethylindo1ey and the colour reactions of gelsemine and strychnine. The second inert oxygen atom is presumed to be present in an ether link and the alkaloid was readily proved to contain a terminal double bond. The formula (XCII) was deduced from these results by H ( xcv) (xcvr) (X=C.NorO; n = 0. I or 2) Gibson and Robinson but the alternative formulae (XCIII) and (XCIV) were preferred by Goutarel Janot Prelog Sneeden and Taylor who interpreted the results of a series of transformations on gelsemine as indicat- ing the presence of the grouping (XCV).For example reaction with bromine led to a cyclic derivative formulated as (XCVI) and the reverse process was achieved by reduction with zinc and acid.70 These conclusions of Goutarel et al. were challenged by Jones and Stevens,714 who doubted 7O Chu and Chou J. Arner. Chem. SOC. 1940 62 1955 ; Marion Canad. J. Res. 1943 21 B 247 ; Kates and Marion J. Amer. Chem. SOC. 1950 72 2308 ; Canad. J . Chem. 1951 29 37 ; Gibson and Robinson Chem. and Ind. 1951 93 ; Goutarel Janot Prelog Sneeden and Taylor Helv. Chim. Acta 1951 34 1139 ; Goutarel Janot Prelog and Sneeden ibid. p. 1962 ; Prelog Patrick and Witkop ibid. 1952 35 640 ; Habgood Marion and Schwarz ibid. p. 638. Jones and Stevens J .1953 2344. 144 QUARTERLY REVIEWS whether gelsemine is an allylamine since Hofmann degradation of dihydro- gelsemine did not proceed normally as expected for a substance possessing the partial structure (*NMe*CH*CHMe*). The first positive evidence against the formulz (XCII-XCIV) was provided by Habgood and Marion,71b who demonstrated that gelsemine contains a methylene group adjacent to the basic nitrogen atom. Reaction of dihydrogelsemine with diethylazodi- carboxylate gave a product which behaved as a carbinolamine. Oxidation of this gave an amide the infrared spectrum of which suggested that it probably contained a five-membered lactam ring. Habgood and Marion interpreted this evidence by the following partial formula? and proposed for gelsemine the from tryptamine constitution (XCVII) which can be derived biogenetically and tyrosine.(XCVII) O;p? H The minor alkaloids of G. sempervirens are probably also oxindole deriva- tives but little is known about them. Oxindole alkaloids also occur in other botanical species e.g. mitraphylline formosanine and rhynchophylline in Ourouparia formosanu Matsumura et Hayata.72 Although the formula of gelsemine is not known with certainty the presence of the 3 3-disubstituted oxindole chromophore is well established. This grouping presumably arises in vivo by oxidation and rearrangement of indole derivatives a process which is also feasible in vitro e.g. the conversion (XCVIII) of 9-acetylhexahydro-10 1 l-dihydroxycarbazole by means of acid into a spirocyclic oxindole derivative (XCVIII). The reverse process was attempted with gelsemine by Witkop and Patrick since the tetrahydro- carboline obtained should be easier to study than gelsemine but so far without SUCC~SS.~ 71b Habgood and Marion Canad.J. Chern. 1955 33 604. 73 Chou Chinese J. Physiol. 1931 5 131 (Chern. Ah. 1931 25 4085) ; Raymond- Hamet Cornpt. rend. 1950 230 1405 ; Janot Goutarel and Friedrich Ann. pharm. franp. 1951 9 305 ; Schwarz and Marion Canad. J. Chem. 1953 31 958 ; J . Amer. Chem. SOC. 1953 75 4372 ; Cook Gailey and Loudon Chem. and Ind. 1953 640. 73 Plant and Robinson Nature 1950 165 36 ; Witkop J . Amer. Chem. SOC. 1950 72 614 ; Perkin and Plant ; J. 1923 -123 676. SAXTON THE INDOLE ALKALOIDS 145 Alkaloids of Calabash Curare.-The highly toxic constituents of gourd or calabash curare from various sources in South America have been investi- gated by Wieland and his collaborators and more extensively in recent years by Karrer and his associates.More than thirty alkaloids have so far been isolated by precipitation and separation of the reineckates or by chromato- graphic techniq~es.~~ They are all quaternary salts and a study of their ultraviolet spectra has shown that they all contain the indole ring system either as such or in various reduced or oxidised-reduced forms.75 Except with fluorocurine and mavacurine also isolated from Venezuelan Strychnos toxifera very little progress has been made in the elucidation of the structures of these alkaloids. Chemical studies have been hampered by the difficulty of isolating the pure alkaloids in large quantity. No doubt the problem would be simplified if the samples of curare consisted of extracts from one botanical species instead of a mixture of several species.Another dis- advantage is that the composition of the curare varies according to its source. Included in this group are the alkaloids of Xtrychnos toxifera and 8. mitscher- Eichii which are possible constituents of some samples of curare. Fluorocurine C20H2602N2+ contains one methylimino- one C-methyl and one acetylatable hydroxyl group and there is a double bond in the molecule. The ultraviolet spectrum closely resembles that of a 1 2 2- trisubstituted indoxyl and it is probable that the alkaloid contains this grouping. Reduction of fluorocurine with lithium aluminium hydride yields hydrofluorocurine which is converted by sulphuric acid into the trisubstituted indole mavacurine C20H250N2+ by loss of water.The quaternary nitrogen atom is the one which bears the methyl group since thermal decomposition of fluorocurine chloride gives norfluorocurine which is reconverted into the alkaloid by methyl chloride. Similarly normava- curine yields mavacurine. The indoxyl-nitrogen atom is probably bound in another ring since there is no imino-group in the molecule and the position of the C-methyl group excludes the possibility of an N-ethyl group. Selenium dehydrogenation of mavacurine gave a base which was not completely identified but was very probably an N-substituted /3-carboline derivative. The position of the double bond in these alkaloids was demonstrated by ozonolysis and Kuhn-Roth oxidation which gave respectively acetaldehyde and acetic acid.Further chromic acid oxidation of dihydrofluorocurine gave a significant amount of propionic acid confirming the presence of an ethylidene group CH,*CH :. Catalytic reduction of hydrofluorocurine chloride (C20H2,02N2Cl) yielded a tertiary base C20Hso02N, which contained two C-methyl groups and probably arose by reduction of the double bond and simultaneous Emde reduction. This product gave a mixture of acetic 7 4 Karrer and Schmid Helw. Chirn. Acta 1946 29 1853 ; 1947 30 1162 2081 ; 1950 33 512 ; Schmid Kebrle and Karrer ibid. 1952 35 1864 ; Kebrle Schmid Waser and Karrer ibid. 1953 36 345 ; Asmis Bkhli Giesbrecht Kebrle Schmid and Karrer ibid. 1954 37 1968 ; Giesbrecht Meyer Biichli Schmid and Karrer ibid. p. 1974 ; Asmis Schmid and Karrer ibid. p. 1983 ; Wieland Bahr and Witkop Annalen 1941 54'7 173; Wieland and Merz Chem.Ber. 1952 85 731. 75 Kebrle Schmid Waser and Karrer Helw. Chim. Acta 1953 36 102. 146 QUARTERLY REVIEWS and a-methylbutyric acid on oxidation. can be accommodated in the annexed partial formuh Hence the abovet ransformations LiAl Hi- CHZ$:CHMe C QYJbMe Hydrofluorocurine + Fluorocurine Mavacurine Emde base Since the infrared spectrum suggests the presence of an ortho-disubstituted benzene derivative it is clear that the two remaining carbon atoms and the hydroxyl group must be situated in the alicyclic portion of the molecule and further since the indoxyl group and the double bond are the only centres of unsaturation the alkaloids must be pentacyclic. Mavacurine and melinonine-A occur together in Xtrychnos melinoniana and hence it is possible that they are related biogenetically.The formula for mavacurine can therefore be expanded to (XCIX) and it only remains to justify the position i Melinonine - A c- of the hydroxyl group. Mavacurine is not a carbinolamine and Karrer and his co-workers are of the opinion that the most likely position is a t C(15). If this formula represents mavacurine fluorocurine must be (C) and may be formed in vivo from the former by oxidation and rea~~angement.7~ This 76 Bickel Giesbrecht Kebrle Schmid and Karrer Helv. Chim. Acta 1954 37 553 ; Bickel Schmid and Karrer ibid. 1955 38 649 ; €or summaries see Karrer Nature 1955 176 277; Karrer and Schmid Angew. Chem. 1955 67 361. SAXTON THE INDOLE ALKALOIDS 147 parallels the known rearrangement of 9-acetylhexahydro- 10 11 -dihydroxy- carbazole in alkaline solution to a spirocyclic iiidoxyl (CI).73 The author thanks Professor Sir Robert Robinson O.M.F.R.S. for his interest and advice Professor R. B. Woodward for permission to include some unpublished results and Miss J. C. Clark B.A. for reading the manuscript.

ISSN:0009-2681    

DOI:10.1039/QR9561000108

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

ERRATA Page 326 22 23 51 1955 Vol. IX No. 4 line Formula?. The formula a t the extreme right of each row should carry a 5@ not a 5a- hydrogen atom. 1956 Vol. X No. 1 Ref. 1671 This should read Savage J . Appl. .Phys. 1948 19 1 ; Fullam and Savage ibid. p. 654. 9 For 50" read 750". 17 Formulae (28) and (30). For larger groups read smaller groups. These should read O M S II 'g \ ,c / \O/ \ L O M s Ii '\.%\ / - P h Me C \c/c\o/c\L Ph II kid 0 (28) (30) 1956 Vol. X No. 2 acid C,,H,,O,. OH at position 5. 173 7 For dracoic acid C,,HI4O read dracoic 177 Upper formuh scheme. I n formula LIII insert For (XLIV) and (XLV) read (LIV) and 178 Fo;mula I n formula LXIX transfer Me0 from 180 3 For (XVa) read (XV). 181 20 After farrerol insert a comma. 182 Formula LXXXIII. A d d e R = OAg. 230 Footnote. For J. 1952,3522 readJ. 1951,3522. (LV). position 6 to position 7.

ISSN:0009-2681    

DOI:10.1039/QR9561000498

出版商:RSC    

年代:1956

数据来源: RSC

摘要:

CUMULATIVE INDEXES VOLUMES I-X ( 1947-1 956) CUMULATIVE INDEXES VOLUMES I-X ( 1947-1 956) CUMULATIVE INDEX O F AUTHORS Abraliams S. C. 10 407 Ahrikoxova I. I. 10 295 -4ddision C. C. 9 115 Albert A. 6 197 Allen G. 7 255 Amphlett C. B. 8 219 Anderson J. S. 1 331 Amstein H. R. V. 4 172 Atherton F. R. 3 146 Rvison A. W. D. 5 171 Bacon R. G. R. 9 287 Baddeley G. 8 355 Badger G. M. 5 147 Raltazzi E. 9 150 Barker S. A. 7 58 Barnartt S. 7 84 Barrer R. &I. 3 293 Barton D. H. R. 3 36 ; Bassett H. 1 247 Bateinan L. 8 147 Raughan E. C. 7 103 Hayliss N. S. 6 319 Bell R. P. 1 113 ; 2 I32 Rentlcy R. 4 172 Bergel F. 2 349 Huvington J. C. 6 141 Birch A. J. 4 69 Birrurnshaw L. L. 6 137 Rockris J. O’M. 3 173 Bolland J. L. 3 1 Bond G. C. 8 279 Bourne E. J. 7 58 Howen E. J. 1 1 ; 4 236 Bradley R.S. 5 315 Hraude $1. A. 4 404 13rernner 6. G. M. 2 1 l<rowti B. H. 5 131 Hrown R. D. 6 63 Bu’Lock J. D. 10 371 Burkin A. R. 5 1 Buniett G. M. 4 292 Burton H. 6 302 Cadogan. J . I. C:. 8 308 (’aldin E. J?. 7 255 Challenger. F. 9 255 Coates G. E. 4 217 Collinson E. 9 311 Cook A. R. 2 20.3 Cook J. W. 5 99 Cookson K. C.? 10 44 Cottrell T. L. 2 260 Foulson C. A. 1 144 Cowdrey W. A. 6 358 Cox E. G. 7 335 Crawford V A. 3 226 C’rombic L. 6 101 10 44 Cruiclrshaiik D. W J.. 7 Curran S. C. 7 1 Dalgliesh C:. E. 5 227 navies A. G. 9 203 Davies D. S. 6 358 Davies M. 8 250 Dawton R. H. V. M. 9 1 De Heer J. 4 94 De la Mare P. B. D. 3 126 Derjaguin B. V. 10 395 Dubinin M. M. 9 101 Duncan J. F. 2 307 Dunning W. J. 9 6 3 lzley D. D. 3 181 13melbus H. J. 2 132 Evans M. G. 4 94 ; 6 186 Freidlina R .Nh. 10 330 335 Gascoigiie R. M. 9 328 Gaydon A. G.. 4 1 Gee G. 1 263 Gent W. 1,. G . 2 3%: Gibson D. T. 3 263 Gillespie R. J. 2,277 ; 8 -10 Glenn A. L. 8 192 Goehriiig M. 10 437 Gold V. 9 51 Gray P. 9 362 Greenwood N. N. 8 1 Gunstone F. D. 7 175 Gutmann V. 10 451 Halpern J. 10 463 Harner. E’. M. 4 337 Hardy D. V. N. 2 25 Harris M. M. 1 29!) Hartley G. S. 2 151 Hassel O . 7 221 Hawkins E. G . E. 4 251 Hawkins J. D. 5 171 Haynes L. J. 2 4(j Hey D. H. 8 308 Hickling A.. 3 95 Hughes E. D. 2 107 ; 5 245 ; 6 34 Hush X. S. 6 186 Ingold C. K. 6 34 Irving H. M. 5 200 Jacobs B. W. M. 6 238 Jain A. C. 10 16!1 Janz G. J. 9 229 .Teffrey G. A. 7 335 Jenkins E. N. 10 83 50 1 Jones D. G. 4 195 Kapustinslrii A. F. 10 383 Katritzky A. R. 10 395 Kenyon J. 9 203 Khorana H. G. 6 340 Kipling J.J. 5 60 ; 10 1 Lamberton A. H. 5 75 Law H. D. 10 230 Lea F. M. 3 82 Leech H. R. 3 29 Leisten 6. A 8 40 Levy N.. 1 358 Lifshitz E. M. 10 195 Iinnett 6. W. 1 73 Lister. H. A. J. 2 307 Lister M. W. 4 20 Long L. H.. 7 131 Loudon J. D. 5 99 Lythgoe B. 3 181 JJewis J. 9 115 Maccoll A. 1 I f MaCoubrey J . C’.. 5. 361 MacDiarmid A. G. 10 208 MaKenria J. 7 231 Matidock A. G. 5 270 Maitland P. 4 46 Nanners D. J. 9 73 Marsh J. K. 1 Idti Ifartin R. L. 8 1 Megson N. J. L. 2 93 Millen D. J . 2 277 Morgan K. J. 8 12.3 JIorrison A. L. 2 341) Nusgrave W. K. R. 8 3 3 1 Sesinoytiiiov A. N. 10 330 Narrish R . G. W. 10 149 Nyhobn 12. S. 3 321 ; 7 377 Orgel L. E. 8 422 OWRtOIl P. G. 5 341 f’nge J. E. 6 26% Paneth F. A. 2 93 Pauson P. L.. 9 391 Pepper D. C. 8 88 Percival E. G. V. 3 369 Phillips F. C. 1 91 Praill P.F. G. 6 302 Kichards R. E. 10 480 Riddiford A. C. 6 157 Riley H. L. 1 59 ; 3 160 Rose J. D. 1 :358 Rowlirison J. S. 8 168 502 Satchell D. P. N. 9 51 Saxton J. E. 10 108 Schofield K. 4 382 Seshadri T. R. 10 169 Sexton W. A. 4 272 Bharpe A. G. 4 115 Shchukina L. A. 10 261 Shemyakin M. M. 10 261 Sheppaxd N. 6 1 ; 7 I9 Simes J. J. H. 9 328 Simpson D. M. 6 1 ; 7 19 Smales A. A. 10 83 Smith J. A. S. 7 279 Smith M. L. 9 1 Springall H. D. 10 230 Stacey M. 1 179 213 Staveley L. A. K. 3 65 Stern E. S. 5 405 CUMULATIVE INDEX Stone F. G. A.. 9 174 Sutton L. E. 2 260 Swallow A. J. 9 311 Synge R. L. M. 3 245 Szwarc M.;5 22 Taylor A. W. C. 4 195 Thomcls S. I,. 7 407 Thomson R. H. 10 27 Thrush B. A. 10 149 Tomkins F. C. 6 238 Topley B. 3 345 Trapnell B. M. W. 8 404 Trotman-Dickenson A.F. Truter F,. V. 5 390 Turner E. E. 1 399 Turner H. S. 7 407 7 198 Ubbelohde A. R. 4 356 ; Uri N. 6 186 Welsh A. D. 2 73 Warburton W. K. 8 67 Warhurst E. 5 44 Weedon B. C. L. 6 380 Wells A . F. 2 185 8 380 Wells R. A. '7 307 Whjffen D. H. 4 131 Whytlaw-Gray R. 4 153 Wilson H. N. 2 1 Woodward L. A. 10 185 Yoffe A. D. 9 362 Zrtkharkiii L. I. 10 330 5 364 CUMULATIVE INDEX OF TITLES Acetylenes infrared and Rainan spectra Acetylenic compounds as natural pro- Acid use of the term 1 11 3 Acids carboxylic anodic syntheses with of 6 1 ducts 10 371 6 380 association of 7 255 tion 5 60 act,ivity '7 I Adsorption of non-electrolytes from solu - Age geological determination of by raclio- Aldehydes polymerisation of 6 141 Aliphatic nitro-compounds 1 358 Alkaloids ergot 8 192 nine 10 108 indole excluding harmiiie and strych- steroi'dal 7 231 Alkanes tetra- and tri- and related com- Analgesics synthetic 2 349 Analysis inorganic applications of solvent extraction to 5 200 Anionotropy 4 404 Anodic syntheses with carboxylic acids 6 380 Aqueous solutions mechanism of electrode processes in 3 95 Aromatic bond 5 147 pounds 10 330 nitration 2 277 rearrangements 6 34 Association of carboxylic acids 7 256 Attraction molecular direct measurement of between solids separated by a narrow gap 10 295 Base use of the term 1 113 Biological degradation of tryptophan 5 227 methylation 9 225 reactions role of phosphoric esters iu 5 171 Bond aromatic 5 147 dissociation energies 5 22 properties interpretation of 2 260 Boron hydrides and related compounds 2 132 chemistry of 9 174 trifluoride co-ordination compounds of 8 1 C'arbides nitrides and carbonitrides of Carbohydrate sulphates 3 369 Carbon amorphous and graphite 1 59 Carbon-carbon bonds oxidative-hydro - lytic splitting of in organic molecules 10 261 iron 3 160 Carboii-carbon double bonds geometrical Carbon-hydrogen bond polarity of 2 383 Carbonitrides carbides and nitrides of iron 3 160 Carbons active study of porous structure of by a variety of methods 9 101 adsorbent properties and nature of isomerism about 6 101 10 1 Carbonyls metal chemistry of 1 331 Catalysis by metals specificity in 8 404 Catalysis hydrogen mechanisms of 3 209 Catalysts redox initiation of polymer- isation processes by 9 287 Cations organic reactions of 6 302 Charcoals active study of porous struc- ture of by a variety of methods 9 101 Chromatography inorganic 7 307 Colloidal electrolytes state of solution of Colour and constitution 1 16 Complex compounds stabilities of 5 1 Conductance ionic in solid salts 6 238 Configuration of flexible organic moleculefi 5 364 Conformational analysis principles of 10 44 Conjugated compounds free -el ec t roil approximation for 6 319 Constitution and colour 1 16 Co-ordination compounds of boron tri- fluoride 8 1 Crystal structure and melting 4 356 Crystal structures of salt hydrates and Crystals ionic lattice energy of 10 283 location of hydrogen atoms in 10 480 Cyanine dyes 4 327 2 154 complex halides 8 380 Decarboxylation thermal mechanism of Densities limiting 4 153 Dielectric absorption 8 250 Disproportionation in inorganic com- pounds 2 1 Diterpenoids chemistry of 3 36 Dyes cyanine 4 327 5 131 effects of light on 4 236 organic and their constitution 1 16 Electrode processes in aqueous solutions Electrolytes colloidal state of solution of and electrolytic processes effects of mechanism of 3 95 2 154 ultrasonic waves on 7 84 503 504 CUMULATIVE INDEX Electromagnetic separation of stable Elements heavy radioactivity of 5 270 isotopes 9 1 of 3 321 the thermocheinistry of 7 103 126 of Group VIII recent stereochemistry of Groups IVn and IV comments on of t,he rare-earth series separation of 1 terrestrial distribution of 3 263 transuranic chemistry of 4 20 Emission spectra of flames 4 1 Enzymic degradation of polysaccharides 9 73 synthesis of polysaccharides 7 58 Ergot alkaloids structure of 8 192 Esters carboxylic and related com- pounds alkyl-oxygen heterolysis i n 9 303 Xxchange reactions of hydrogen isotopes in solution principles of 9 51 Fatty acids straight-chain recci) t developments in the preparation of natural and synthetic 7 175 Ferrocene and related compounds 9 39 I Flames emission spectra of 4 1 Flash photolysis and kinetic spectroscopy 10 149 Flavones and related compounds nuclear methylation of 10 169 i.soFlavones 8 67 E’luorescence and fluorescence quenching Fluorine and its coinpounds lctlwratoi y and technical product,ion of 3 22 compounds organic reactions of 3 331 Force constants 1 73 Free-electron approximation for conjn- Free-radical addition reactions of olofiriic Friedel-Crafts reaction modern aspects Puran and pyren clierriicjtry some aspevts 1 1 gated compounds 6 319 systems 8 305 of 8 365 of 4 105 Geological age determination of by radio- Gmphite and amorphous carbon 1 59 activity 7 1 Halides reactions of in solution 5 245 complex crystal structures of 8 380 Halogens kinetics of thermal addition of Heats of formation of simple inorganic Heterocyclic nitrogen wnipounds nitra- Heterogeneous reactions transport control Heterolysis alkyl-oxygen in carboxylic.cycloHexane stereochemistry of 7 221 to olefinic compounds 3 126 compounds 7 134 tion of 4 382 in 8 157 esters and related compounds 9 203 Hydrocarbon,.; infrared and Raman spectra of. Part I. Acetylenes and olefins 6 1. Part 11. Paraffins 7 29 Hydrogen molecular homogeneous re- actions of in solution 10 463 Hydrogen atoms location of in crystal\ 10 480 ceatalysis mechanisms of 3 209 isotope exchange reactions in solutioii principles of 9 51 peroxide its radicals and its ions energetics of reactions involving 6 186 Hydrogenation catalytic and related re- actions mechanism of 8 279 Hyperconjugation 3 226 Ice structure of 5 344 Immunocheniistry aspects of 1 179 513 Intlole alkaloids excluding harmine and strychnine 10 108 Iiduction asymmetric and asymmetric transformation 1 299 Infrared and Raman spectra of hydro- carbons.Part I. Acetylenes arid olefins 6 1. Part 11. Paraffins 7 19 Inorganic analysis applica tioris of solvent extraction to 5 200 rhemistry and magnetism 7 377 chromatography 7 307 compounds disproportionation in 2 Z Raman spectra of 10 185 simple heats of formation of 7 134 iodine compounds some reactions of 8 123 Ir 1 hcc tlcideh synthetic s tructuro nritl activity in 4 272 Interhalogen compounds and polyhalitics Intermolecular forces and some properties lodiiie compounds inorganic some re- Ion exchange 2 307 Ionic conductance in solid salts 8 238 holvation 3 173 Ionisation potentialh far ultra\ io1t.t spectra and their significance iri chemistry 2 73 Iron carbides nitrides and carbonitrides of 3 160 Isomerism geometrical about carboii- carbon double bonds 6 101 Isotopes stable electromagnetic sepam- Isotopic exchange between different oxida - tion states in aqueous solution 8 219 Isotopically labelled organic coiiipouiids 4,115 .of matter 3 168 actions of 3 123 tion of 9 1 tracer techniques 4 172 synthesis of 7 407 Lactones physiologically active u n s ~ t ~ r - Lanthanons separation of 1 126 Lattice energy of ionic crystals 10 583 ated 2 46 CtJMULATTVE INDEX 505 Light absorption and photocheniistry 4 Liquids and solids transitions in 3 65 Magnetic resonance absorption nuclwr Magnetism and inorganic chemistrg 7 Mass spectrometry application to chcnii- Melting and crystal structure 4 356 Metal carbonyls chemistry of 1 331 Metal-ammonia solutions reduction of Metals specificity in catalysis by 8 404 Methyl radicals reactions of 7 198 Methylation biological 9 255 236 7,279 377 cal problems 9 23 oxides structure of 2 185 organic compounds by 4 69 nuclear of flavones ancl related com- pounds 10 169 Molecular interpretation of tJi ermo - dynamic propertieh of high polymers 1 265 structure determination by X-ray crystal analysis modern methods and their accuracy 7 335 Rlolecular-sieve action of solids 3 293 Molecules simple representation by mole- Morphine synthetic approaches to struc - cular orbitals 1 144 ture of 5 405 as 10 371 Natural products acetylenic Compouri(ls Nitramines some aspects of tlhe chemistry Nitration aromatic 2 277 of 5 75 of heterocyclic nitrogen compounds 4 Nitrides carbides ancl carbonitrides of Nitro-compounds aliphatic 1 358 Nitrogen dioxide-dinitrogen t,etroxide system structure and reactivity of 9 362 382 iron 3 160 Nitrosyl group chemistry of 9 1 16 Non -electrolytes adsorption of from wlu- Nuclear magnetic resonance absorption Nucleation in phase changes 5 31 5 Oceanic salt deposits 1 91 Olefinic system8 free-radical addition reactions of 8 308 Olefins infrared and Raman spectra of t,ion 5 60 7,279 8 1 kinetics of oxidation of 3 1 kinetics of thermal addition of halogens oxidation of 8 147 to 3 126 6 63 1,144 ( Irhitals molecdar a n d organic re&ctions representation of simple molecules by Organic cations reactions of 6 302 chemistry of derivatives of phosphorus compounds action of ionising radiations oxyacids 3 146 on 9 311 hehaviour in sulphuric acid 8 40 estimation of thermodynamic proper- isotopically IabeIlctl syiithcsis of 7 polarography of 6 262 reduction of by metal-ammonia solu- fluorine compounds reactions of 8 331 molecules flexible configuration of 5 oxidative-hydrolytic splitting of car- ties for 9 229 407 tions 4 69 364 bon-carbon bonds in 10 261 peroxides and their reactions 4 251 reactions and molecular orbitals 6 34 Organoinetnllic compounds of the firfit 5-Oxazolones chemistry of 9 150 Osidatioii of olefiiis 8 147 kinetics of 3 1 Oxidaiion-reduction potential of quin- ones relation to chemical structure three periodic groups 4 217 4 94 istry of 10 395 7 19 Oxides metallic structures of 2 185 N-Oxides aromatic heterocyclic chem- Pamffins infrared and Ramail spectra of Penicillins.chemistry of 2 203 Peptides methods of synthesis and terminal-residue studies of 10 330 naturally occurring 3 245 and proteins structural investigation Peroxides organic and their reactions 4 Phase changes nucleation in 5 315 Phenols tautomerism of 10 27 Phosphates condensed 3 345 Phosphoric esters role i n biologic~~l re- actions 5 171 Phosphorus oxyacids some aspects oE the organic chemistry of derivatives of 3 146 Photochemistry ancl light absorption 4,236 Photography cyanine dyes in 4 327 Photopolyrnerisation 4 236 Polarity of the carbon-hydrogen bond Polarography of organic compounds 6 Polyhalides and interhalogen compoundr Pulymerisation inittiation of by redox of 6 340 25 1 2 383 262 4 115 catalysts 9 287 ionic 8 88 of aldehydes 6 I41 reactions radical rate constant FS in 4 292 506 CUMULATIVE INDEX Polymers high thermodynamic properties of and their molecular interpretation 1 265 silicon chemistry of 2 25 Polysaccharides enzymic degracla t,ion of 9 73 enzymic synthesis of 7 58 Portland cement constitution of 3 82 Properties of matter and intermolecular Proteins and peptides structural investi- Pteridines 6 197 Purine and pyrimidine chemistry some Pyran and furan chemistry some aspects Pyrimidine and purine chemistry sorne Pyrrole pigments biogenetic origin of 4 forces 8 168 gation of 6 340 aspects of 3 181 of 4 195 aspects of 3 181 45 Quenching of fluorescence 1 1 Quinones relation between the oxidation- reduction potential arid chemical structure of 4 94 Radiations ionising action of on organic Rsdioectivation analysis 10 83 Radioactive tracers preparation of 2 93 Radioactivity determination of geological age by 7 1 Raman and infrared spectra of hydro- carbons.Part I. Acetylenes and olefins 6 1. Part 11. Paraffins 7.19 compounds 9 311 of the heavy elements 5 270 Raman spectra of inorganic compounds 10. 185 Rare-earth elements separation of 1 126 Reactions chemical estimation of ther- modynamic properties for 9 229 Rearrangements aromatic 6 34 Rcdox catalysts initiation of polymcri - sation processes by 9 287 potentials of quinones relation to chemi - ' cal structure 4 94 Reduction of organic compounds by metal-ammonia Compounds 4 69 Rotation spectra 4 131 Salt deposits oceanic 1 91 hydrates crystal structures of 8 380 Salts basic structure of 1 247 solid ionic conductance in 6 238 Bandmeyer and related reactions G2 35s Silicon polymers chemistry of 2 95 Silyl compounds 10 208 Sodium '' flame " reactions 5 44 Solids molecular-sieve action of 3 293 and liquids transitions in 3 65 separated by a narrow gap direct measurement of molecular attraction between 10 295 Solvation ionic 3 173 Solvents ionising non-aqueous reactions Solvent extraction and its applications to Specificity in catalysis by metals 8 404 Spectra charge-transfer and some related in 10 461 inorganic analysis 5 200 phenomena 8 422 emission of flames 4 1 far ultraviolet ionisation potentials and their significance in chemistry 2) 73 Spectra infrared and Raman of hydro- carbons.Part I. Acetylenes and ole- fins 6 1. Part 11. Para,fEns 7 19 Raman of inorganic compounds 10 185 rotation 4 131 Spectroscopy kinetic and flash pho tolysis Stabilities of complex conipounds 5 1 Stcreocliemistry of cyc'ohexnne 7 221 of the Group WIT elements 3 321 of Sub-group VIB of the periodic table 10 149 10 407 Steric hindrance 2 107 Steroidal alkaloids '7 231 Sub-group VIB stereochemistry of 10 Sulphur nitride and its derivatives 10 Sulphuric acid behaviour of organic 40 7 437 compounds in 8 40 Tautomerism of phenols 10 27 Terrestrial distribution of the elements 3 263 Thcrmocheniistry of the elements of Groups IVB and IV comments on 7 103 Thermodynamic properties estimation of for organic compounds and chemi- cal reactions 9 229 of high polymers and their molecular interpretation 1 265 Tracers radioactive preparation of 2 93 Transformation asymmetric and asym- Transitions in solids and liquids 3 65 Transport control in heterogeneous re- Transuranic elements chemistry of 4 20 Triterpenes tetracyclic 9 328 Tropolones 5 99 Trypt,ophan biological degradation of 5 metric induction 1 299 actions 6 157 227 Ultrasonic waves effects on electrolytes and electrolytic processes 7 84 Wool wax constitution of 5 390 X-Ray crystal analysis modern methods of molecular structure determination by and thpir.accuracy 7 335

ISSN:0009-2681    

DOI:10.1039/QR9561000499

出版商:RSC    

年代:1956

数据来源: RSC