摘要:

QUARTERLY REVIEWS THE CHEMICAL SOCIETY PATRON HER MAJESTY THE QUEEN President 13. J. EMEL~US C.B.E. M.A. D.Sc. F.R.S. Vice-Presidents who have filled the office of President SIR IAN HEILBRON D.S.O. D.Sc. SIR CHRISTOPHER INGOLD D.Sc. LL.D. F.R.S. F.R.I.C. F.R.S. SIR CYRIL HINSHELWOOD M.A. SIR ERIC RIDEAI, M.B.E. M.A. Sc.D. F.R.S. D.Sc. F.R.S. E. L. HIRST C.B.E. D.Sc. LL.D. TiV. WARDLAW C.B.E. D.Sc. F.R.S. F.R.I.C. Vice-presidents WILSON BAKER M.A. D.Sc. F.R.S. R. P. BELL M.A. F.R.S. R.D. HAWORTH,D.SC.,P~.D.,F.R.S. E.D.HUGHES,D.SC.,F.R.I.C.,F.R.S. F. G. MANN Sc.D. D.Sc. F.R.S. h. E. SUTTON M.A. D.Phil. F.R.S. Honorary Treasurer M. W. PERRIN C.B.E. M.A. F.R.I.C. Honorary Secretaries A. W. JOHNSON Sc.D. Ph.D. A.R.C.S. J. CHATT M.A. Sc.D. F.R.I.C. M. J. S. DEWAR M.A. D.Phil. Ordinary Members of Council R.G. R. BACON Ph.D. A.R.C.S. B. LYTHGOE Ph.D. F.R.T.C. F.R.S. R. M. BARRER D.Sc. Sc.D. F.R.S. A. MACCOLL M.Sc. Ph.D. A. J. BIRCH M.Sc. D.Phil. F.R.S. R. S.NYHOLM,D.SC.,F.R.I.C.,F.R.S. R. C. COOKSON M.A. Ph.D. R. E. RICHARDS M.A. D.Phi1. A G. EVANS Ph.D. D.Sc. F.R.T.C. L. A. K. STAVELEY M.A. A.C.FARTHINC,M.A.,B.SC.,A.R.I.C. J. C. TATLOW Ph.D. D.Sc. F.R.I.C. R. H.HALL,P~.D.,A.R.C.S.,F.R.I.C. R. H. ~THOMSON D.Sc. Ph.D. 33. A. HEMS D.Sc. F.R.I.C. L. HUNTER Ph.D. D.Sc. F.R.I.C. A. I. VOGEL D.Sc. D.I.C. F.R.I.C. L. H. LONG Ph.D. A.R.C.S. D.I.C. W. B. WHALLEY D.Sc. Ph.D. J. D. LOUDON Ph.D. D.Sc. W. F. K. WYNN.E-JONES D.Sc. F.R.I.C. F .R.I.C. General Secretary J. R. RUCK KEENE M.B.E. T.D. M.A. Librarian R. G. GRIFFIN F.L.R. Deputy Librarian J. BIRD Printed in Great Britain by Butler Sz Tanner Ltd.Frome and London QUARTERLY REVIEWS VOL. XII 1958 Publication Committee Chairman .- SIR CHRISTOPHER INGOLD D.Sc. F.R.I.C. F.R.S. C. C. ADDISON D.Sc. Ph.D. F.R.I.C. WILSON BARER M.A. D.Sc. F.R.S. E. BOYLAND D.Sc. 'Ph.D. I. G. M. CAMPBELL B.Sc. Ph.D. N. CAMPBELL D.Sc. Ph.D. N. B. CHAPMAN M.A. Ph.D. J. CHATT M.A. Sc.D. F.R.I.C. P. B. D. DE LA MARE D.Sc. Ph.D. M. J. S. DEWAR M.A. D.Phil. D. D. ELEY Sc.D. Ph.D. * H. J. EMELEUS C.B.E. M.A. D.Se. D.H.EvERETT,M.B.E.,M.A.,D.P~~~. G. GEE Sc.D. A.R.I.C. F.R.S. T. G. HALSALL Ph.D. M.A. A.R.I.C. R. A. HEMS D.Sc. F.R.I.C. D. H. HEY D.Sc. F.R.I.C. F.R.S. D. J. G. IVES D.Sc. A.R.C.S. A. W. JOHNSON Sc.D. Ph.D. F.R.S. F.R.I.C. A.R.C.S. E. R. H. JONES D.Se. F.R.I.C. G. TV. KENNER M.Sc. Ph.D. H. C. LONGUET-HIGGINS M.A.B. LYTHGOE M.A. Ph.D. F.R.T.C. A. NEUBERGER Ph.D. M.D. F.R.S. R. G. W. NORRISH Sc.D. F.R.I.C. H. T. OPENSHAW M.A. D.Phi1. M. W. PERRIN C.B.E.,M.A. F.R.I.C. V. PETROW Ph.l). 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. J. C. SPEAKMAN M.Sc. Ph.D. DSc. 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. I).Sc. F.R.S. D.Phil. F.R.S. F.R.S. F.R.S. F.R.S. D. H. WHIFFEN M.A. D.Phil. Editor R. $3. CAHN M.A. D.Phil.Nat. F.R.I.C. Deputy Editor L. C. CROSS Ph.D. A.R.C.S. F.R.I.C. Assistant Editors A. D. MITCHELL D.Sc. F.R.I.C. A. E. SOMERFIELD Ph.D. LONDON T H E C H E M I C A L S O C I E T Y CONTENTS MECHANISM AND REACTIVITY IN AROMATIC NUCLEOPHILIC SUBSTITUTION REACTIONS.By J. I?. Bunnett . REDUCTION BY METAL-AMINE SOLUTIONS APPLICATIONS IN SYNTHESIS AND DETERMINATION OF STRUCTURE. By A. J. Birch and Herchel Smith VERATRUM ALKALOIDS. By K. J. Morgan and J. A. Barltrop SOME THERMODYNAMIC AND KINETIC ASPECTS OF ADDITION POLYMERISATION. By F. S. Dainton and K. J. Ivin . CHEMISTRY OF SOME NEWER ANTIBIOTICS. By N. G. Brink and R. E. Harman . ACTIVE NITROGEN. . QUANTITATIVE NUCLEAR CHEMISTRY. By D. L. Baulch and J. F. Duncan . RECENT DEVELOPMENTS IN THE BIOCHEMISTRY OF NUCLEOTIDE COENZYMES. By J. Baddiley and J. G. Buchanan . THE STRUCTURE OF CARBONIUM IONS. By D. Bethell and V. Gold . THE TRIPLET STATE. By C. Reid . MECHANISMS FOR CARBON-HYDROGEN BOND BREAKAGE. By E. S. Lewis and M. C. R. Symons . ELECTRON RESONANCE SPECTROSCOPY OF FREE RADICALS. By D. H. Whiffen. THE RELATIVE AFFINITIES OF LIGAND ATOMS FOR ACCEPTOR MOLECULES AND IONS. By Sten Ahrland J. Chatt and N. R. Davies . MECHANISMS OF OXIDATION BY COMPOUNDS OF CHROMIUM AND MANGANESE. By William A. Waters . CHEMISTRY OF ~XYLYLENE ITS ANALOGUES AND POLYMERS. By L. A. Errede and M. Szwarc . STRUCTURE AND PROPERTIES OF C-NITROSO-COMPOUNDS. By B. G. Gowenlock and W. Luttke . COMPOUNDS CONTAINING CARBON-PHOSPHORUS BONDS By P. C. Crofts . By K. R. Jennings and J. W. Linnett PAGE 1 17 34 61 93 116 133 152 173 205 230 250 265 277 30 1 32 1 341

ISSN:0009-2681    

DOI:10.1039/QR95812FP001

出版商:RSC    

年代:1958

数据来源: RSC

摘要:

REDUCTION BY METAL-AMINE SOLUTIONS APPLICATIONS IN SMTHESIS AND DETERMINATION OF STRUCTURE By A. J. BIRCH and HERCHEL Smmr (CHEMISTRY DEPARTMENT MANCHESTER UNIVERSITY) WORK since the last reviews of the subject 1 y has been concerned chiefly with the exploitation of metal-nmine solutions in synthesis and in the investigation of natural products. Theoretical developments have been mainly incidental and have added little to what was already 1mown.l We are here concerned with the practical aspects but an appreciation of the theoretical background is essential for use of the reagents to the best purpose since variations in technique are possible. So references to theoretical aspects are made below where necessary but overlapping with earlier reviews has been avoided as far as possible. 1.Reduction by metal-ammonia and metal-amine solutions (a) partial or coniplete saturation of a wide variety of unsaturated substlances including polycyclic aromatic compounds dienes and trienes which are conjugated or are rendered so under the alkaline conditions of the reaction and in some cases of simple olefins ; and ( b ) reductive fission of alkyl aryl or diary1 ethers and sulphides and the hydrogen01 ysis of various groups attached to nitrogen oxygen and sulphur. Which particular reagent is used depends on the nature of the substrate and on how far if is desired tha,t reduction shall proceed. Metal and an 66 Acid ’’ in Liquid Ammonia.-The reagents so far ex- amined consist of an alkali metal and an “acid ” such as methanol or ammonium chloride in liquid ammonia sometimes with co-solvents such as ether or tet,rahydrofuran.The reagents are powerful if the “ acid ” is an alcohol and are then capable of reducing a terminal double bond or an isolated benzene ring. In this they differ fi.0~11 ammonia reagent’s lacking the alcohol although solutions of lithium in ethylamine are also capable of reducing benzene rings and terminal double bonds (see below). The alcohol also has the effect of buffering the reaction mixture preventing accumulation of strongly basic NH,. This explains the comparative simplicity of the results since base-catalysed rearrangements of double bonds are usually avoided. Reduction of a benzene ring leads to the cx6-dihydro- derivative unlike the lithium-ethylamine reagent where the as-dihydro- derivative which is probably formed initially is rearranged to the conjugated c+?-dihydro-derivative which is then rapidly reduced further.As will be seen similar results to the latter are obtained with calcium hexammine and by reduction with sodium and ethanol in liquid ammonia followed by Two main types of reduction are observed Birch Quart. Rev. 1950 4 69. ?Watt Cherti. l i e u . 1950 46 317. B 17 18 QUARTERLY REVIEWS an excess of sodium in a r n m ~ n i a . ~ The xb-hydrogen atoms added by the metal-alcohol-ammonia reagent avoid carbon atoms carrying dimethyl- amino- alkoxy- or alkyl groups in that order and are attracted to positions carrying carboxyl groups. The latter effect outweighs the others ; carboxyl groups labilise 0- and p-methoxyl groups in terms of the following equilibria to hydrogenolysis. The requirement for an added source of protons is now interpreted ROH Ar + E + Ar-* + HOR + Ar*H + OR- -$ ArH- - ArH + OR- The anion-radical Ar*- formed initially must add a proton in order that reduction may be completed; it appears not to be sufficiently basic to abstract this proton from ammonia and requires a more acidic proton source.If the acidity of this source is high as with ammonium salts the predominant reaction is evolution of gaseous hydrogen unless the substance is very rapidly and readily reduced ; alcohols seem to have about the optimum pK for the reduction of benzene rings. The reduction with sodium and methanol or ethanol in liquid ammonia of o-xylene,B naphthalene,' tetralin,8 arid 1 4-dihydronaphthalene has been subjected to a rigorous re-examination. The results confirm the originally defined reducing properties of the reagent.Diphenyl has been reduced in both rings giving a product showing no selective ultraviolet absorption which is either compound (I) or more probably compound (II).9 (1 ) rn (u) An important modification in technique has been the use of lithium instead of sodium or potassium for the reduction of aromatic rings. The greater solubility of lithium in liquid ammonia enables larger proportions of co-solvents to be used without the formation of two-phase systems ; consequently difficulties arising from the low solubility of substrates in ammonia systems can be overcome. Higher yields of reduction products may be associa3ted with the high concentration of metal and also with the higher normal reduction potential of lithium in ammonia (-2.99 v) compared with that of potassium or sodium (-2.59 and -2.73 v respectively).1° An earlier device for increasing the solubility of phenyl ethers in ammonia systems viz.the formation of glyceryl or 2-hydroxyethyl ethers,llP l2 enables the cheaper sodium or potassium to be used. This technique has not yet been fully investigated but in reduction of 3-2'-hydroxyetIhoxyoestra- a Birch J . 1946 693. Ref. 1 p. 88. Birch J . Roy. Inst. Ghem. 1957 80 100. Huckel and Worffel Ghem,. Bey. 1955 88 338. Kuckel and Schlee ibicl. p. 346. Idem ibid. p. 2098. Huckel and Schwen ibid. 1936 89 150. lo Wilds and Nelson J. Arney. Chem,. SOC. 1953 75 5360. l 1 Birch and Mukherji J . 1949 2531. l2 Birch J. 1960 36'1. BlRCH AND SMITH REDUCTION BY METAL-AMINE SOLUTIONS 19 1 3 5-trien-17p-01 l3 the yield of 19-nortestosterone is of the same order as by the lithium method.14 I n cases where there are serious losses of alkoxyl groups by reductive fission the method may be superior in that it inhibits hydrogenolysis through alkoxide formation by the side-chain hydroxyl group.It is possible also that reduction is facilitated by cyclic donation of a proton to an anionic intermediate. Terminal double bonds may be reduced by the alcohol-containing reagent. This has been observed with various dialkylallylamines 15 and with hex- 1 -ene which has been converted into hexane in 41% yield by two atomic propor- tions of sodium and methanol in liquid ammonia.l6 I n the last case no reduction occurs in the absence of an alcohol or when ammonium bromide is used as proton donor. Of particular interest is the observation that 2-cyclopropylpent-1 -ene gives 2-cyclopropylpentane l6 and no ring-open products with the sodium-ammonia-methanol reagent whereas methyl cyclopropyl ketone affords a mixture of methyl propyl ketone and pentan-2-01 with sodium and ammonium sulphate in liquid amrn0nia.l' A further illustration of the control exerted by the acid strength of the proton donor over the reduction products is the ultimate formation of aldehydes rather than alcohols when ammonium acetate is substituted for ethanol as the proton source in the sodium-ammonia reduction of amides.18 Alcohol production is ascribed to the ethoxide-catalysed decomposition and further reduction of the intermediate 1 -amino-alcohol (aldehyde-ammonia).The buffering of the medium by use of the more acidic ammonium acetate as proton source avoids this decomposition and the amino-alcohol is converted into the aldehyde during the working up 0- H+ R.CO.NH -+ ReAH-NH -+ RCH(OH)*NH -+ RCHO Job;,- NH +- R*CHO -+ R*CH,*OH Aldehydes may also be ultimately obtained by the sodium-ammonia-alcohol reduction of amidines (even arylamidines) presumably via the 1 1- diamines.ls This result is due to the lower acidity of NH than of OH and also to absence of hydrogenolysis of the C-N bonds.I n contrast to the reductive fission of C-0 bonds which in general occurs readily in benzyl ethers and in aryl acetals 19 and ketals,20 C-N bonds conjugated with aromatic nuclei are not split because nitrogen is less electrophilic than oxygen. Pyridine compounds are reduced more readily than the hydrocarbons Birch and Bauer unpublished work.l4 Wilds and Nelson J . Amer. Cheni. SOC. 1953 75 5366. lGKing J. 1951 898. l 7 Volkenburgh Greenlee Derfer and Boord ibid. 1949 71 3595. lQ Birch Hextall and Sternhell ibid. 1954 7 256. 2o Pinder and Smith J . 1954 113. Greenfield Friedel and Orchin J . Arner. Chein. SOC. 1954 76 1258. Birch Cymerman-Craig and Slaytor Austral. J . Chem. 1955 8 512. 20 QUARTERLY REVIEWS of the same ring size because the heteroatom is better able than carbon to stabilise a negative charge. Pyridine and quinoline compounds for example readily give 1 4-dihydro-derivatives ; 22 di- tri- and tetra-meric dihydro- compounds are also produced. Reduction can be effected even in the absence of added proton sources but the products may then contain larger amounts of polymers.Thiophen with sodium and ethanol in liquid ammonia gives a complex mixture of 2 3- and 2 5-dihydrothiophen but-2-ene-l-thiol but-l- and -2-ene and hydrogen sulphide.22 Presumably reduction occurs to 2 3- and 2 5-dihydrothiophen which then undergo further reactions because of the known ready reductive fission of C-S bonds. Pyrrole and furan rings appear to be unaffected. Sodium Potassium or Lithium in Liquid Ammonia.-In a number of instances little difference would be expected from the " buffered " and protonated reagents mentioned above. For example (-)-a-phellandrene (mentha-1 5-diene) is reduced by sodium or by sodium and ethanol in liquid ammonia to the same mixture of (-)- (60%) and (+)-menth-l-ene (40y0),23 showing a large proportion of ccp-reduction.The reduction of other 1 3-dienes to the 1 4-dihydro-derivativesY e.g. 2-methyl- 2 3-dimethyl- and 1 1 3-trimethyl-butadiene to the but-2-enes in yields of 98-99 93-94 and 72% respecti~ely,~~ should not be altered by the presence of alcohols. In other cases if addition of protons to the intermediate anions is avoided by ensuring the absence of proton sources other tha,n ammonia the occurrence of further reduction is inhibited by the negative charges present. Proton-addition occurs during the working-up. Sodium-ammonia reduction of dipheiiyl has been shown to be analogous to that ofnaph- thalene,25 two atoms of sodium being added to give a deep red sodium salt decomposed by ammonium chloride t,o 1 4-dihydr0diphenyI.~ The phenyl group here exerts an effect similar to that of carb0xyl,~7 as is to be expected from its ability to stabilise an adjacent anionic charge.Similarly fluorene yields an unstable dihydrofluorene of undetermined constitution which readily disproportionates to fluorene and 1 4 11 12-tetrahydro- fluorene.28 In related work it was shown that cyclopentadiene and indene give cyclopentene and indane respectively .s The reduction of a/?-unsaturated ketones to the saturated ketones of which examples are given below also illustrates the protective effect of a negative charge in an intermediate in permitting eventual isolation of the saturated ketone. Similar reactions have been carried out with unsaturated esters and acids. The protection of ally1 alcohols against hydrogenolysis 21 lief. 2 1). 362 ; Birch iinpublislietl work. z 2 S. P. Birch and McAllnn Natiwe 1950 165 S99.23 Birch unpublished work. 2 4 Levinn Svarclienko Kostin Treschova and Okinievicli Sborkin obshchei Khinc. 25Ref. 1 p. 81. 2G Benkesei. Arnold Lainbert and Thomas J . Amer.. Chew&. Soc. 195.5 77 6042. ?' Ref. 1 p. 86 ; Birch Hextall and Stcrnhell Austral. .7. Chetn. 1954 7 2%;. 28 Huckel and Schwen Rer. 1956 89 481. Akad. Nauk X.S.S.R. 1'353 1 356; Chem. Abs. 195.5 49 829. BIRCH AND SMlTH REDUCTION BY METAL-AMINE SOLUTiONY 21 and of acetylenes against reduction ca,n be achieved by initial formation of the salts. Lithium in Alky1amines.-Solutions of lithium in amines of low molecular weight such as methylamine ethylamine and the propylamines constitute reducing agents of very great power if little selectivity. The amines are in general more powerful solvents for organic substances than ammonia and have higher boiling points (C2H,*NH, b.p.16.5" ; NH, b.p. -33"). Accordingly their use ma,y avoid a common and serious difficulty often encountered in liquid ammonia reductions namely the low solubility of the substrate in the solvent system. The higher working tempgrature also undoubtedly facilitates the initial steps in the reduction and favours the conjugation and therefore further reduction of the primary products. The annexed examples illustrate typical reductions by these reagents Simple O E t - O E t + OEt QCHiCHiOH -t 0 CH~CH o H~ (44 7o i (24%) 29 26 CH,€H2€ SC *CCH21;CH 3 0 -78"_ CH,CH,CHLCHfCH,kCH3 CH,CH,*CH~CH*[CH,]jCH -k CHi[CH&CH3 oiefins may be saturated tetrasubstituted double bonds being least readily reduced in accord with the view that the process involves initial electron addition.1 A similar reduction of double bonds which must however be terminally situated occurs with sodium and methanol in 1 iquid ammonia (see above).Inhibition of the reduction of di- and tri-substituted double bonds by working at low temperatures (e.g. -78") has been observed.26 3O Isolated benzene rings are reduced to the tetrahydro-state or partly to the hexahydro-state depending on the conditions. Acetophenone gives the allylic alcohol 1-1 '-hydroxyethylcyclohexene whereas its diethyl ketal gives 1 -ethylcycZohexene in agreement with the view that hydrogenolysis of the 2y Benkeser Robinson Sauve and Thomas J . Amer. C!lreni. Soc. 1955 77 323. so Benkeser Rchroll and Sauve ibid. p. 3378. 22 QUARTERLY REVIEWS hydroxyl group in the intermediate benzyl alcohol is inhibited by salt formation.Similarly reduction of phenol (more correctly lithium phen- oxide) is very largely stopped a t the cyclohexanone stage probably by pro- tection of the carbonyl group as the enol anion. I n contrast formation of the phenoxide anion or the acetophenone enol anion 20 is sufficient to inhibit reduction by metal-ammonia-alcohol reagents. Use of excess of lithium favours dealkylation of anisole since the product then consists of phenol and cyclohexanone; the theoretical amount of lithium leads to a mixture of 2 5-dihydroanisole (the initial product) and the conjugated 2 3-dihydro- isomer. Although allyl (and benzyl) alcohols may resist hydrogenolysis owing to salt-formation allyl ethers for which salt-formation is impossible are readily cleaved.The course of the reaction is simila,r to that with the alkali metal-ammonia reagent but alkylamine systems offer the practical advantage of greater solvent power and reactivity. The cleavage of cis-( +)- carvotanacetyl methyl ether with lithium and ethylamine yields ( &)-p menth-l-ene,S1 in agreement with the view that the reaction proceeds through a symmetrical intermediate probably the rnesomeric anion produced together with alkoxide ion by the addition of two electrons.32 It is known that compounds capable of producing very stable anions in a fission reaction are reduced readily,33 so it would be expected that allyl acetates and benzoates should be cleaved more easily t,han the free alcohols provided the first stage is not reduction of the ester-carbonyl group.This has been demonstrated in the steroid series where for example lithium in ethylamine converts 3P-acetoxycholest-4-ene (111) to cholest-4-ene and 4-/3-acetoxycholest-5-ene (IV) and 6-/3-acetoxycholest-4-ene (V) both give the same mixture of cholest-4- and -5-ene.31 There is no evidence of formation of a t)hermodynamically unstable isomer since 3-j3-acetoxycholest-l -ene gives cholest-2-ene and none of the less stable ~holest-l-ene.~l Work on the fission of steroid epoxides has confirmed that the direc- t)ion of reductive ring opening as with propylene oxide,3* is consistent with a potential-determining stage involving the addition of 2 electrons. The 31 Hallswortli Henbest and Wrigley J . 1957 1969. 33 Ref. 1 11. 71. 3 3 Dean and Berchet J .Amel.. Chem. SOC. 1930 52 2823. 3 4 Birch J . Proc. Roy. Soc. New South Wules 1949 83 245. BIRCH AND SMITH REDUCTION BY METAL-AMINE SOLUTIONS 23 plansr geometrical requirements for the transition state 35 in such cases ensure that axial alcohols are produced stereospecifically. Thus 5a 6a- epoxides (VI) are converted into 5a-alcohols and 2a 3a- 7a 8a- and 9a 1 la-epoxides similarly give 3a- 8a- and %-alcohols respectively.36 Lithium aluminium hydride may reduce steroid vic-epoxides similarly,37 but it has no effect on the sterically hindered 7a 8a- and 9cc lla-epoxides thereby illustrating the power and low steric hindrance associated with the metal-amine reagents. Calcium Hexammine.-The reducing capabilities of calcium hex- ammine have been but little investigated during the period since the last review.Reductions are usually carried out with a suspension of the reagent in an inert solvent (e.g. ether dioxan 1 Zdimethoxyethane tetrahydrofuran) so that solubility may usually be achieved by choosing a suitable solvent. Under sufficiently vigorous conditions the reagent saturates the double bond in simple olefins ( 2 5-dimethylhex-2-ene for example gives 2 5-dimethylhexane 38) and reduces isolated benzene rings to the dihydro- or tetrahydro-~tate.~~~ 40 Methoxyl groups may be cleaved from the ring by fission of intermediates e.g. methyl m-tolyl ether gives l-methyl- cycZohexene,3 and 2-methoxynaphthalene gives a mixture of hexahydro- naphthalenes having homoannular conjugated diene systems. 4O Conjuga- tion is probably due to the presence of calcium amide.The Protection of Functional Groups.-The protection of reducible groups in some cases can be accomplished by salt formation to give anions. This has already been illustrated for ally1 alcohols and carbonyl compounds. Ethynyl groups may be similarly protected; thus the sodium salt of undeca-1 7-diyne is converted into undec-7-en-l-yne by sodium in liquid ammonia.41 This method which is simple in operation is only useful when the alcohol enol or acetylene is considerably the strongest acid present. The presence of an acid of comparable strength (e.g. ethanol) permits reduction to occur.20 Conversion of a carbonyl into a non-reducible group can be achieved through formation of an acetal ketal or enol ether provided the alkoxyl groups are not in an allylic or a benzyl position and the enol- ether double bond is unconjugated.Accordingly there are difficulties when the carbonyl group is in the a- or @-position to an aromatic ring.lg *O The problem has been solved for benzaldehyde derivatives by converting them 35 See e.g. Barton and Cookson Quart. Rev. 1956 10 67. 36 Hallsworth and Jenbest J. 1957 4604. 37 E.g. Plattner Heusser and Kulkami Helv. Chirn. Acta 1949 32 265 ; Plattner Furst Koller and Kuhn ibid. 1954 37 258. 3* Kazanskii and Gostunskaya J . Gen. Chem. (U.S.S.R.) 1955 25 1659. 39 Kazanskii and Glushev ibid. 1938. 8 6 4 2 ; Bull. Acud. Sci. [J.R.S.S. 1938 4O Birch and Dunstan unpublished work. *lDobson and Raphael J. 1955 3558. 1062 1065 and earlier papers. 34 QUARTERLY JLEVIEWS into tetrahydroglyoxalines e.g. (VII) which resist hydrogenolysis whilst the aromatic nucleus is reduced.ls The aldehyde group can then be regenerated by acid treatment'.The presence of other reducible groups is undesirable e.g. tetrahydro-1 2 3-triphenylglyoxaline (VII ; R = Ph) undergoes fission l8 because the N-phenyl groups stabilise the negative charge on the intermediate nitrogen anion. Hence dialkyltetrahydro- glyoxalines are generally used. tJnfortunately the method is inapplicable to ketones which fail to react with NN'-dialkyethylenediamines. Stereochemical Aspects of Reduction.-A review 42 of the products formed by the reduction of various multiple bond systems by dissolving metal reagents which act through the forination of intermediate carbanions has indicated that where stereoisomeric products are possible the thermo- dynamically stable ones are usually formed.The rule holds in many cases inter alia the reduction of acetylenes to trans-ethylene~,~~? 43 ketones to secondary alcohols oximes to amines conjugated dienes and trienes to olefins and ctf?-unsaturated ketones esters and acids to the corresponding saturated derivatives although recent work has shown that it is not univer- sally applicable. The case of x/?-unsaturated ketones is of particular importance. The reduction has been interpreted 42 as following the reaction B I l l I l l I I ! " E - I1 +- -_ - C.:C-c=o -j -C-c- c-0 -.+ ('H C (2 0 (VIII) (IX) path delineated. The stability of the en01 anion (IX) in the absence of an excess of '' acid " of comparable strength permits the eventual isolation of the saturated ketone. I n a further discussion 44 of this type of reaction it has been pointed out that (VIIL) should add a proton at the very basic ,8-position by a process involving little activation energy in which case tlhe nature of the product is determined by the most stable conformation of the anion rather t'hm the least hindered approach of the proton donor.This accounts for the fact that when the P-position is capable of yielding stereo- isomers the most stable one is invariably formed. For the cc-position other considerations apply and the nature of' the final product may depend on whether Icetonisation of' the en01 anion is therniodynamically or kinetically controlled. Kinetic control a t this stage has been observed to give the thermodynamically unstable isomer in reduction of the ketone (X) which gives the cis-isomer 4 4 (XI) readily convertible into the trans-isomer.A closely related example is formation of tlhe cis-product (XIII) by lithium- ammonia reduction of the styrene (XIT).45 The mechanism of reduction of 4 2 Barton and Robinson .I. 1954 3045. 43 Ctiinpbell (!hem. Iter.. l!U2 31 57. 4 4 Birch Srnith siid Tlioimton J . 195'7 1330. 4 5 Johnson Arkernim I h s t l i t i i i ~ m c l Dewalt J . driio.. (,'/teiji. Soc. 1956 78 6303. BIRCH AND SMITH REDUCTION BY METAL-AMINE SOLUTIONS 25 such styrene compounds is not clear but if it iizvolves an 8 9-dianion (steroid numbering) the first proton should be added a t the more reactive %position. The formation of the less stable isomer in this case has been ascribed to the influence of the 5a-hydroxyl group which by alkoxide formation induces the negative charge a t C,, to adopt the /3-position.When the less stable isomer is formed there is apparently a requirement that an aromatic ring shall be attached to the ring system since reduction of Ag-octal- 1 -one gives only the trans-decalone. 46 A possible explanation for this is that the aromatic ring reduces the energy difference between the cis- and the trans-form of an anion such as (XIV) and thereby ensures an appreciable concentration of the former a t equilibrium. In a more complex case in the steroid series the aromatic ring may not be necessary provided that approach of the proton-donor required for tlhe formation of the more stable product is sufficiently hindered this may be so in the reduction of 3/3-acetoxyergosta-S 22-dien-7-one 46 (XV).It has recently been shown that the sodium-ammonia reduction of' dideuteroacetylene gives trans-dide~teroethylene,~' in line with the fact that this method of producing trans-olefins from acetlylenes is completely stereo- specifi~.~3 41 It is notewortlhy that equilibrium mixtures contain appreci- able amount's of ~is-ethylenes.~~ 2. Use of metal-amine reagents in synthesis 801u- tions of potassium or sodium in liquid ammonia have found widespread application in synthesis for the reductive removal of unsaturated groups used as protecting agents for amino- imino- hydroxyl and thiol groups. They are of particular importance in peptide synthesis having the obvious general advantage over hydrolytic or catalytic methods for compounds which are labile in mid or contain sulphur. Benzyl toluene-p-sulphonyl and benzyloxycarbonyl groups are all efficiently replaced by hydrogen and (a) Metal-Ammonia Solutions.-(i) Removal of protecting groups.46 Birch Smith and Wilson unpublished work. 37 Rabinowitz and Looney J . Amw. Cheni,. SOC. 1963 75 2662. 4B Kilpatrick Prosen Pitzer and Rossini J . Res. Nut. Bur. Stand. 1946 36 559. 26 QUARTERLY ltEVIEWS cystinyl-peptides are cleaved to cysteinyl derivatives. are summarised as follows These applications (i) RS*CH,Ph -+ K*SH $- PhMe (ii) R.NH.SO,*C,H,Me-p -+ R-NH 1- p-C,H,Me.SH (iii) R*NHCO,CH,Ph + R-NH -t CO I- PhMc (iv) RSaSR -+ %R*SH (v) P,O*CH:,Ph -+ ROH + YhMe The use of reactions (i)-(iv) in the synthesis of sulphur-containing peptides ranging from glutathione 49 to oxytocin 5O has been r e ~ i e w e d . ~ l Cleavage by sodium-ammonia has also been used to remove benzyl groups protecting the hydroxyl groups in serine- and tyrosine-containing peptides 52 and the cyclic amino-groups in histidinyl-peptides.53 Peptide groups are apparently unaffected probably because of salt forniation. After the observation that dibenzyl and diphenyl hydrogen phosphate are converted into inorganic phosphate by sodium in liquid ammonia,54 the reagent has proved of crucial importance for the removal of protecting groups including benzyl tosyl and benzyloxycarbonyl in the synthesis of' various phosphates and pyro- phosphates of biological interest."9 j5 Thus the last stage in the synthesis of the " Acetobacter stimulatory factor " (ASF) involved the sodiuni- aninionia fission of four benzyl groups ;)* (PhCH,O),P( O).O.CH,.CMe,*CII( OCH,Ph) *!CO*?JH.CH,CH,] ,-S*CH,Ph -+ (HO),P( O)-O*CH,*CMe,CH( OH).[CO*NH.CH,*CH,] ,.SH An interesting fission of an allryl aryl ether is the selective demethylntion of the readily available homoveratrylamine [2-(3 4-dimethoxypheny1)ethyl- amine] to 2- (3-hydroxy-4-metJhoxyphenyl)ethylamine which can serve as a starting material for the synthesis of naturally occurring isovanillyl derivatives.The fission is based on the earlier conversion 57 of 3 4-di- me thox yt oluene into 3 - hydroxy- 4- met hoxy toluene. The resis tame of the 4-methoxyl group to hydrogenolysis follows from the proposed mechanism for the fission since the negative charge which must develop on oxygen for demethylation to ensue is destabilised by the electron-releasing para-group. Selectivity is therefore different from that observed in acid-catalysed demethyla tion.A cleavage that has found use in partial synthesis of steroids is t'he 49 Loring and du Vigneaud J . Biol. GlLenb. 1935 111 385. 5O du Vigneaud I-tersler Swan Koberts and Katsoyannis J . A n i e r . Chewr . J ~ O C . 51 du Vignenud " Syinposiun~ on Puptide Chemistry " Cheni. SOC. Sper. I'ubl. No. 3 52 GrasBman Wunsch and Deufel and Grassman Wunsvh and Fries quoted by 53 du Vigneaud and Behrens J . Biol. Chem. 1936.117 2 i ; Katchalski and Patchor- 5 4 Baddiley and Thain J . 1953 1611. 56 Baddiley and Mathias J . 19.54 2801 ; Arris Bnddiley Ijuchtiiiitii and Thain. 5 6 Harnlin and Fischcr t J . A m e r . ('hem. Soc. 1953 75 5119. 5 7 Birch J . 1947 102. 1954. 76 3113. 19x5 p. 49. Grassman Fo~tschr. Chem. org.Natui-sloffe 1956 13 547. nik XIVth Int. Congr. Pure Appl. Choni. 1065. J . 19.56 4968. BIRCH AND SMITH REDUCTION BY METAL-AMINE SOLUTIONS 27 reductive removal of the 12-acetoxy-group in hecogenin to give 1 I-oxotigo- genin.5s The reagent of choice was calcium in ammonia ; the reaction A cC most probably proceeds as annexed The free ketol gave the diequatorial diol whereas the cc-ketol (XVI) and the vinylogous ketol 6P-hydroxytesto- sterone both suffer loss of hydroxyl to give (XVII) 59 and testosterone 60 respectively. - a HO j nu (XVI) - (XVII) wn (ii) Reduction of cca-unsaturated ketones. The reaction which quantita- tively a t least is the most important application of the metal-ammonia reagent is the stereospecific reduction of various steroid ap-unsaturated ketones capable of giving rise to one or two new centres of asymmetry.The conversion of a number of 8-en-ll-ones (XVIII) into the corresponding Sp 9cc-dihydro-derivatives in high yield has proved invaluable in routes for the partial synthesis of cortisone.61 In these cases as in the reduction of 3P-acetoxycholest-8( 14)-en-15-one 6 2 (XIX) proton addition to give the $I@- and the 14cc-compound may be kinetically as well as thermodynamically favoured because of the influence of the bulky p-methyl groups. 58Chapman Elks and Wyman Chern. and Ind. 1965 603; Chapman Xlks 69 Zurcher Heusser Jeger and Geistlich Helv. Chirn. Acta 1954 37 1562. 6o Amendolla Rosenkranz and Sondheimer J . Amer. Chem. SOC. 1954 76 1226. 61 E.g. Sondheimer Yashin Rosenkranz and Djerassi ibid. 1952 74 2696 ; Sondheimer Mancera Rosenkranz and Djerassi ibid.1953 75 1282 ; Schoenewaldt Turnbull Chamberlin Rheinhold Erikson Ruyle Chemerda and Tishlar ibid. 1962 '74 2696; Bladon Henbest Jones Lovell and Woods J. 1954 125. Philips and Wyman J. 1956 4344. 6 2 Barton and Laws J. 1954 62. 28 QUARTERLY REVIEWS (iii) Acyloin condensations. Solutions of sodium in liquid ammonia enable the acyloin condensation to be carried out in a homogeneous solution. The method offers obvious practical advantages over the conventional method using sodium dispersed in boiling toluene and conditions have been found which lead to high yields of ncyloin particularly in intramolecular condensations. Thus dimethyl marrianolate methyl ether (XX) gives the ketol (XXI),637 G 4 which is readily converted into estrone and the method becomes the one of choice for the comuletion of ring D in a steroid synthesis.I None of the ketol (XXI) was oht'ained by the older technique. Similarly OH ( X X I I > dimethyl I1 lhecocholanate (XXII) gave n high yield of the tetra- cyclic 11 12-acyloin.63 The reaction has also been employed to provide 1 6- 0x0 test 0s terone . (b) Metal-Ammonia and Alcohols.-These reagents were originally developed for use in steroid synthesis with the object of preparing cyclo- hexenones from anisole derivatives by the reaction path (i). Chiefly as a result of their tendency to give the thermodynamically most stable products where stereoisomerism is possible they were later used for reductions of types (ii) and (iii). Although reactions (ii) and (iii) do not require alcohols Cii) -C=CCOR - -CH-CH-COR (R = OH ,OAlk,or Alk) I I (iii).& - & better yields have been obtained in iiiaiiy cases in their presence (because there are then fewer side reactions). However fairly slow reactions of type (ii) in presence of large excesses of alcohol normally give the alcohol rather than the ketone. A process of type (i) was applied in 1949 to 3-2'-hydroxyethoxyoestra-l 3 5-trien-17@-01 which gave 19-nortesto- 63 Sheehan Codcrre Cohen arid O'Neill J . Amer. G'hem. Soc. 1952. 74 6155. 6 1 Sheehan Coderre and Cmikshank i6id. 1953 75 6231. liB Adanis Patel Petrow and Stuart-Webb J. 1956 297. BIRCH AND SMITH REDUCTION BY METAL-AMINE SOLUTIONS 6'3 sterone,12 a hormone which had 30% of the androgenic activity of testo- sterone and was the first active androgen to be made by total synthesis.Subsequently a wide range of 19-nor-hormones 66 was prepared by this process some more active than the analogues of the natural series. 19- Nortestosterone ,!I-phenylpropionate (" Durabolin ") 6 7 and 17a-ethyl-19- nortestosterone (" Nilevar ") 68 are recommended for use as anabolic agents. Similar applications of the process to 3 4-disubstituted anisoles have provided essential steps in the total synthesis of steroids terpenes and alkaloids. Thus the anisole derivative (XXIII) gave the ketone (XXIV) 69 which formed tlhe basis of rings B c and D in a total synthesis of ll-oxy- genated steroids ; the anisole (XXV) gave the ketone (XXVI),io used to complete a total synthesis of (j-)-totarol and the anisole (XXVII) gave the ketone (XXVIII) which was converted into yohimbone.M e 0 P O H / @OH doMe&' (XXIII) O (XXIV) H ( x x v ) (xxv I) (XXVII) (xxv I I I> OMe A process of type (ii) proved of primary importance in the Merck total synthesis of cortisone in ensuring the correct trans-configuration at) the C-D ring junction reduction of the acid (XXIX) with potassium and propm-2-01 in liquid ammonia gave the dihydro-derivative (XXX) stereo- ~pecifically.~~ It is of theoretical interest that with an llg-hydroxyl group (axial) a predominant amount of the unwanted product with a l4g-hydrogen atom was obtained. Two possible explanations for this result are that (a) G G E . y . Djerttssi Miraiiiontes and Hosrdmmz J. Amer. Chew. Soc. 1953 75 4440 ; Sandovul Miramontes Hosenkranz Djerassi arid Sondheimer ibicl. 1). 41 17 ; Djerassi Lippriian and Grousnian ibid.1956 78 3479 ; Ringold Rosenkrtinz and Sondheimer ibid. p. 3477. 13' Anon. A4?igeu$. Chem. 1957 69 69. 68 Anon. Che?n. Ettg. News 1956 34 813.1. 69 Stork Loewenthal and Mukharji J. Amer. Chcm. SOC. 1956 78 501. 7o Barltrop and Rogers Chem. and Ind. 1957 20. 7 9 Arth Poos Lukes Rohinson Johns Feurer and Sarett J. -4mer. Chew. *Voc. Swan I. 1950 1534. 193.1 76 171.5. 30 QUARTERLY REVIEWS repulsion between negative charges on oxygen causes the niethoxycarbonyl group to assume the trans-a- (axial)-configuration or ( b ) proton transfer through the solvent from the 1 l/%hydroxyl group results in proton addition to the P-side of the 14-carbani0n.~~ Unquestionably the most impressive application of metal-ammonia reagents in synthesis was afforded by the Wisconsin total synthesis of ~teroids.’~ Processes (i)-(iii) were carried out simultaneously on compound (XXXI) to give the ketones (XXXII) and (XXXIII) having respectively five and six new centres of asymmetry.Thirty-two racemates of ketone (XXXII) and sixty-four of ketone (XXXIII) were therefore possible but in fact the mixture of the two compounds was obtained in 25% yield. (x x x I I I) \ A A A l J (XXX I I> Extension of the synthesis to 11-oxygenated steroids exploited the benzyl alcohol fission in the conversion of the trio1 (XXXIV) into the diol (XXXV). The latter can be reduced in much higher yield than its deoxy- analogue. This difference has been attributed to inhibition of hydrogenolysis of the methoxyl group by formation of the 11-alk0xide.7~ It is however significant that the 11-hydroxy-group is in the axial conformation where it can facilitate proton transfer to the 13-position by a cyclic (probably six- membered ring) mechanism.The reduction of 5-methoxytetralin systems which was a feature of these syntheses had previously presented difficulties 7G due to the fact that 1 4-addition of hydrogen must involve at least one position occupied by a charge-destabilising group. Workable yields were only obtained by use of a technique originally developed for sodium 73Kenner Ann. Kepoyts 1954 51 177. 7 4 Johnson Rogier Szmuszkovicz Hadlei. Ackerman Bhattacharya Bloom Stizlmann Clement J<annister and Wynbei-g J . Amer. Chem. SOC. 1956 78 6289 ; Johnson Bannister Bloom Kamp Pappo Roger and Szmuszkovioz ibid. 1953 75 3275. 75 Johnson Pappo and Johns ibid.p. 6339. 7ti Bivc h MUI-I*~LJJ and Sirlitti J . 19.51 1945. BIRCH AND SMITH REDUCTION BY METAGAMINE SOLUTIONS 31 reductions in the Boots laboratories 7 7 employing a two-phase system made by the addition of 40% or more of ethanol to the liquid ammonia. The resistance of vicinal dialkyl derivatives of anisole to reduction has been exploited to afford a selective reduction of' the 3 4-disubstituted anisole ring in the ether (XXXVI). The product (XXXVII) was used to synthesise ( -J-)-l8 19-bisnor-~-homotestosterone. 78 3. Uses in determinations of structure These uses are based chiefly on fission reactions largely of ethers. The metal-ammonia reagent has proved to be a tool of exceptional power in elucidating the structure and stereochemistry of a1 kaloids containing diary1 ether linkages.These ethers are very resistant to hydrolysis but can be reductively split in high yields with solutions of potassium or sodium in liquid ammonia. The simplest example is that of cularin which gives a 5-hydroxybenzyl-3 4-dimethoxyisoquinoline. 79 The method has been widely employed to determine the structure of biscoclaurin bases which in general are cleaved into two benzylisoquir~oline fragments of known or casily determined structure. The opt'ical rotations of such products give also the relative orientations of the asymmetric centres. Alkaloids contain- ing free phenolic groups are more difficult to cleave because of phenoxide formation. In berbamine (XXXVIII) the free phenolic group protects the adjacent diphenyl ether linkage and the product 81 is a base of the dauricin type (XXXIX).This on methylation can be cleaved into two benzyl- isoquinoline fragments (XXXIXa). Further examples of the use of the reagent are in the cleavage of phaeanthine 00'-dimethylcurine and OO'-dimethylisoch~ndrodendrine.~~ The usual co-solvents for these reactions 7 7 Short unpublished work. 79 Manske J. Ameta. ChewA. SOC. 1950 72 65. 8" Tomita Fujita and Miirni .I. Phawn. Lsoc. J q x m 1951 226. a1 Idem ibid. p. 301. 8 2 Kicid and Walker J. 1934 GO!) ; C'hewi. aiitl fnd. 1953 243. 78 Birch and Smith J. 1956 4009. 3 2 QUARTERLY REVIEWS (largely determined by the solubilities of the alkaloids) are toluene and benzene ; in the presence of dioxan phaeanthine yields in addition to the ‘‘ normal ” benzylisoquinoline cleavage products a third benzylisoquinoline formed by an alternative mode of scission.This result is possibly due to the participation of the more polar solvent in the solvent-induced stabilisa- tion of intermediate anions. Cleavage of pilocereine methyl ether into four isoquinolines enables the skeletal structure to be unambiguously defined as in (XL).83 The directions of fission are all predictable on the basis of the rules already set out.1 Alkali metal-ammonia solutions can effect Emde-type fission of quater- nary ammonium salts 84 and may be the reagents of choice because they ininimise the accompanying Hofmann reaction but this property has not so far been appreciably used in alkaloid investigations. It has recently been shown that axial niethoxycarbonyl groups in steroid or terpenoid structures are converted into carboxylic acid groups by alkali metals in ammonia whereas the corresponding equatorial group undergoes Bouveault-Blanc-type reduction to the hydroxymethyl group.85 The same result is obtained in the presence of alcohols and the reaction which appears to be so specific as to be diagnostic is clearly a hydrogenolysis similar to the fission of aryl methyl ethers.Reductive fission of naturally occurring dlyl alcohols and allyl and henzyl ethers may often be of great assistance. Thus the structure of lanceol (XLI) was confirmed by its reduction,86 with sodium and alcohol in liquid ammonia to the known bisabolene (XLII). As a further illustra- tion the terpenoid side chain of the mould metabolite mycelinnamide was recognised 8 7 as being an allyl ether of the geranyl type hy cleavage to inethylgeraniolene and derivative of p-hydroxybenzoic acid.Information as t o the relative configurations of catechins and epicatechins can be procured by cleavage of the benzyl ether linkages in these compounds. (+)-Catechin itself and ( - )-epicatechin give ensntiomorphous alcohols showing that the 3-hydroxyl groups are in opposed configurations as in (XLIII) and (XLIV),88 i.e. that (+-)- or (-)-catechin and (+)- or (-)-epicatechin have the Same configuration of the 3- hydroxyl group. Sodium-ammonia solutions have heen used to cleave what me probably phenyl and benzyl ether links in various lignins and give notable yields of compounds of low molecular weight. 89 Evidence regarding the stereochemistry of the carbon skeleton of various tetrahydrofuranoid lignans with structures such as (XLV) has been obtained by sodium-ammonia cleavage of the benzyl ether links and 83 Djerassi Figdor Bobbit.t and Markley J .Amel.. Chem. SOC. 1956 78 3861. 81 Clayson J . 1949 2016 ; Haworth Lunts and MrKenna J . 1956 3749 ; see 8 5 Wenkert and Jackson J . Amer. Chem. SGC. 1958 80 2 1 i . 86Birch and Murray J. 1951 1888. 8 7 Birch Massy-Westropp and Rickards J . 1956 3717. 88 Birch Clark-Lewis and Robertson J. 1957 358. 89 Freudenbcrg Engler Flickinger Sobek and Klunk Ber. 1938 71 1810 ; Shory- gina Kefeli and Semechkina Dokludy Aknd. Nauk S.S.S.R. 1949 64 689 ; J . Gen. (%em. ((T.S.S.R.) 1949 19 1558 ; Shorygina and Kefeli ibid. 1950 20 1199 1213; Shorygina and Seiuechltina ibid. 1 %53 23 6 1’7. also ref. 34. BIRCH AND SMITH XEDUCTION B Y METAL-AMINE SOLUTIONS 33 examination of the reactions of' the resulting stereoisomeric alcohols (XLVI) including t'heir cyclisations to the aryltetrahydronaphthalene derivatives (XLVII) some of which are natural lignans.Probable configurations for galbulin galcatin and galbelgin from Himantundra barks can be worked OH M e q o H ow) M e 9 (XLI 1) (XLI I I) HO OH (x LI v) CH2 M r z O ~ ~ ~ ~ H M e Me0 \ CH,CHMe MeO/ MeO~c,J~-J;e 'CHMe MeO/ M e O T e (XLVII) OMe O O M e (XLVI) OMe O O M e (XLV) OMe Me0 \ CH CHiOH I I FH-FH .OH HOCH CH "'"0 '0""' OMe (XLV I I I> (XLIX) ' OMe out.so The structure of the lignaii gmelinol (XLVIII) was filially deter- mined 91 as the result of the ring-fission to the trio1 (XLIX) which on oxida- tion with lead tetra-acetate gave formaldehyde. It has recently been discovered that preliminary reduction with sodium and ethanol in liquid ammonia facilit,ates the hydrolysis of the sugar residue from pyrimidine nucleoside~.~~ It is probable that the reagent by destroying aromaticity converts the nucleoside into an acid-lahile enamine glycoside.It will be obvious from the above brief survey that despite the large volume of work made possible by the introduction of the metal-amine reagents much remains to be done especially in investigating the reactivities of various metal- amine-proton-source coiiibimtions and in explaining the observed reactions. It should also be clear that the variety of reagents available and their great power coupled with the specificity obtainable by an appropriate formulation are amongst the factors which will ensure their continued use in structural and synthetic problems. IVe thank Dr. H. B. Henhest for informing us of results before their tblication. 9'J Bimli Milligan (Mrs.) 14;. Siiiitli. and S~maZke unl'ublishecl work. !I1 Birch Hughes and Sinitli. d t t s t r t r l . J . Clhev). 1954 7 83. !' Uurke J. Org. Chojt. 1933 20 6.13. c

ISSN:0009-2681    

DOI:10.1039/QR9581200017

出版商:RSC    

年代:1958

数据来源: RSC

摘要:

VERATRUM ALKALOIDS By K. J. MORGAN MA. B.Sc. D.PHIL. (CHEMISTRY DEPARTMENT THE UNIVERSITY BIRMINGHAM) and J. A. BARLTROP M.A. B.Sc. D.PHIL. (BRASENOSE COLLEGE and DYSON PERRINS LABORATORY OXFORD UNIVERSITY) THE veratruiii alkaloids which form part of the steroid group of alkaloids are obtained from liliaceous plants belonging to the sub-order MelanthaceE. Those which have received most attention are V . album and V . wiride native t o Europe and North America respectively and V . sabadilla or Schanocuulon ofjicinaZe but many other species of Veratrum and of the closely related Zygadenus genus have been investigated. Since the first recorded investigations into this group some forty alkaloids have been isolated and fully characterised ; no fewer than twenty-five have been reported since 1951 (Table 1).Brief summaries of the earlier investigations into the structure of these compounds have been supplemented by more recent and more extensive reviews by Jeger and Prelog,3 McKerina,* and Stoll.5 No attempt is made here to discuss in detail evidence already presented in these previous reviews. Hydrolysis of the ester and glycosidic alkaloids gives the corresponding alkaminea but under the conditions normally employed for such hydrolyses several of the alkamines are unstable and suffer isomerisation. By using mild and controlled conditions the true alkamines can readily be obtained Partial deacylation of many of the ester alkaloids occurs readily with methanol catalysed by the basic centre in the molecule and it may be that some of the esters notably those of germine isolated from natural sources are actually artefacts ; this applies particularly to germerine protoveratri- dine germidine germanidine and possibly gerin budine.as D-glucose. It is attached to t'he SP-hydroxyl group in isorubijervosine ; a similar arrangement is inferred for pseudojervine and veratrosine. The acids (I-VII) present in the ester alkaloids bear a marked relation to each other. The two aromatic acids vanillic (VII) and veratric (VI) differ only Henry " The Plant Alkaloids " J. and A. Churchill London 1949 ; Fieser and Fieser " The Xatural Products related to Phenanthreno " Reinhold Publ. Corp. New York 1949. Jeger and Prelog " The Alkaloids" Vol. 111 ed. Manske and Holmes Academic Press Inc. New York 1053. McKerina Qzicrrt. Rei'. l!Ki3 7 2 3 1 . Stoll (Auzeltu 1054 84 1190.Jacobs arid Craig J . Bid. Chent. 11114 155 565 ; Klolis 1 ~ I x I J C 1 ' . Kt~ller .Mnlcsli The glycosidic fraction of all three glycoalkaloids has been identified lPelletier and Caventou Ann. Chim. Phys. 1819 14 69. aid Petracek J . Amer. C'hem. SOC. 1953 75 2133. 34 MORGAN AND HAELTROP VERATRUM ALKALOIDS 35 in their degree of methylation and the aliphatic acids with the exception of acetic acid all possess the isoprene skeleton. Extraction of the Alkaloids.-Alkaloids are probably present in all parts of V . album and V . ~ i r i d e ~ but the insecticidal action of dried sabadilla characteristic of cevadine and veratridine is found only in the seeds. The usual sources are the roots and rhizomes of V . album and V . viride and the seeds of V . sabadillw. The alkaloids can be extracted from the appropriate parts of the dried and powdered plants by aqueous or alcoholic acid or by organic solvents.Subsequent separation of the bases from the crude extract has been achieved by fractional crystallisation precipitation or extraction lo and by chromatographic separations on alumina 9 l2 on silica gel,13 on kieselguhr,s and on an ion-exchange resin.l4 Chromatography on paper 8 l5 has proved convenient for characterising the alkaloids. Perhaps the most significant advance in recent years in the separation of complex mixtures has been the application of liquid-liquid countercurrent extrac- tion.16 This has rendered possible the investigation of the amorphous alkaloidal residues that resisted other analytical techniques and has resulted1' in the isolation of nearly all the recently discovered alkaloids.Structural Investigations General.-The more general methods of alkaloid degradation notably Hofmann and Emde degradations have not been widely or successfully used with the veratrum alkaloids. Such general methods as have been used are those normally associated with steroid chemistry. The nature of the carbon skeleton of the alkaloids has been elucidated largely from examination of the products of selenium dehydro- genation. It is found that the main reaction is a fission of the molecule into a hydrocarbon fraction and a nitrogenous fraction composed of substi- tuted pyridines (Table 2 ) . The essential basic product is 2-ethyl-5-methyl- pyridine (VIII). This is also obtained from the potato alkaloid solanidine and on the basis of this and certain other evidence it was concluded that the alkaloids of Xolanum spp.and such alkaloids of Veratrum spp. as are tertiary bases contain a perhydropyrrocoline residue. The correctness of this 'Poethke Arch. Pharm. 1937 275 357. Hegi and Fluck Pharm. Acta Helv. 1956 31 428. Allen Dicke and Harris J. Econ. Entomol 1944 37 400. lo ( a ) See e.g. Wright and Luff J. 1878 338 ; 1870 403 421 ; (b) Jacobs and Craig J. Biol. Chem. 1943,148 41 ; 1945,160,555 ; ( c ) Auterhoff Arch. Pharm. 1953,286,69. Pelletier and Jacobs J. Amer. Chem. SOC. 1953 75 3248. l 2 Kupchan Lavie Deliwala and Andoh ibid. p. 5510. l 3 Hennig Higuchi and Parks J . Arrier. Phavm. As.soc. 1931 40 168 ; Svoboda and 14Edwards Cliem. and Ind. 1933 488. l 5 See e.g. "ash and Broolcer J. Amer. Chem. Soc. 1953 75 1942 ; Auterhoff Arch.Pharrn. 1954 287 380 ; Macek and Vejdelek Chew.. Listy 1955 49 339 ; Nature 1955 176 1173 ; Levine and Fischbach J. Amer. PIicrrm. ASSOC. 1955 44 513. 1 6 Craig and Craig '' Technique of Organic Chemistry " Vol. 111 (2nd edn.) Part I page 149 ed. Weissberger Interscience Publ. h e . New York 1956. 1 7 See e.g. Fried White and Wintersteirier J. .4mer. Chem. SOC. 1949 71 3260 ; 1950 72 4621 ; Klohs Arons Draper Keller Boster Maledi and Petracek ibid. 1952 74 5107 ; Myers Morozovitz Glen Barber Papineau-Couture and Grant ibid. 1955 77 3348 ; Stuart and Parks J. Amer. Pharm. ASSOC. 1956 45 252. Parks ibid. 1954 43 (584. 1 1111 I L l I A ILI Ih I1 I1 'I I1 'I I1 . W I I11 'I1 ,7 All 'I1 a 111 'I1 k)n 'I &I 'I1 'I I11 'I1 'I z\I 'I1 YZ)I AjI 'I1 'I I11 'I1 'I il 'I1 'k)I ,I1 'I1 'k)I 111 'I1 'k)I G e t 1 + 8 i- H013 P.9 + 9.EP + 6 - F.E9 - I T - 81 - Z+1- ZT - s- 9 I - 19 - 69 - TL - 9.6- !?I - 08 - LE - GS*OP- z.% - ".1,G - Lo'- t Z - 98 - IT + 0 o f 8.L f 0 $4- zr.- Lf S * € - os.01- *l3H3 6%-892 ILG-OL-2 LOZ-90Z 90z LSZ-!XZ 0s T-09 1 ELZ-ZLZ EZZ-TZ% IEZ-OEZ 9EZ-PFZ EOZ-OOZ z91-691 P9 T-O9 T 9Ll-SLT 622-822 61Z-915 082-6 2 2 €81-287 Z61-I61 9EZ-9EZ c)L -2- 89 Z G89Z-LgG' Glycosidic alkaloids pse udoJer vine Veratrosino isoR ubi jervosine Alhwmines Protoverine Germine \Teracevinc Cevine h Z ygadenine Rubijervine isoRubijervine Jervinc Gmhssi~ed cilkctloids Veralbidine VeratrobRsinc Geralbine Yeragermine 30-1 -305 242-243 2i9-280 195-200 2 18-22 1 18 1-1 83 195-200 201-204 240-243 236-238 243-244 205-20G 181-183 285-288 221-223 .262-264 - 1 3 j - 53 j - 33 - 45 -;- 5.4 0 HO*C? - 20 - 12 - 11.; - 126 0 - 11 +5 - 24 - 17.5 + 19 - 140 + 9.2 - 68 - 77 0 - 4.87 H \'a Va Va VY :+ Key to soiircc of alkaloids \-a 1'.album ; Vv I-. viride ; Vs T.'. sabadillci ; Yf 1'. jirnbriolunc Gray ; \-e. 1'. eec7~oltzii Gray ; Ti V . lobelicmuni ; Yg T'. grandiflorunt ; l-st T-. staminetrm ; Vn T'. niqrurn ; Zi 2. interniedius ; Zv 2. t-ene7tosii.s ; Zp. 2. paniculatlts ; Zc Z. eleguns. t The roman numerals refer to the stnicfural forrnuk a t the base of the Table ; the arabic numerals in parentheses to the number of such residues present. a Idontical with neoprotoveratrine and verutetrine. Also known as germhutrine. c Identical with gerinitetrine H. (l S o t C37H5,0,,K as is reported in the literature. f Identical with neogermidine.g Also called veratrine and amorphous veratrine by early workers. * Also called vereti.inc. crvsti\llised veratrine. and nure veratrine bv earl\- workers. 3 Solvent is ethanol-chloroform. k Does not occur in Nature. e These acids appear t o be the erythro- and threo-isomers. S o t vanilloylcevine as indicated in t h s literature. 38 QUARTERLY ItBVIEW8 TABLE 2 . Dehydrogenation products Alkaloid Cevirie C ern 1 ine Pro t,ovcra t rine Jcrvi rie I‘eratrainine Rubi j er vine isoK uhi jerv ine Solanidine Solasodine 6-Picoline 2 -Et,hyl- 5-me thy 1 pyridino 2- 2’- Hydroxye t hyl- 5 -me th y Ipy ricline “Oxyethylmethylpyridinc” C,H,ON C evanthridine CZ5H,:K C,,H1,N Veranthridine C,,H,,N CSH13N 4 5-Benzindane C,,H, (fluorene) C,,H, (fluorene) C1,H,o (fluorene) C,,H, (fluorene) Cevanthrol C,,H,,O %-Et,liyl-~,-ineth3.1~)~ri~ii~~~ i c,,H, (fluorme) Cevanthridinc Cevanthrol 2 5-I)irnethylpyr.idine 2 -Ethyl-5-inethylpyridine C ,H ,ON Cevanthridine Cevant hrol C,,H, (benzindanc) C,,H, (fluorene) C,,H, ( fluorene) C,,H, (fluorene) C,,H, (benzofluorene) C,,H, (benzofluorene) C2,Hz, (benzofluorene) C 8H, (phenanthrene) CI*H,,O C,,H, (phenanthrene) C,,H, (phenanthrene) C,,H, (phenanthrene) * Names in parentheses indicate the spectral class to which the hydrocarbon t Probably 4’ 5’-dihydro-5-methylfurano(3’ 3’ 2 .3)pyridine. belongs. conclusion for the solanurn alkaloids has been demonstrated by synthesis but subsequent results have made i t necessary to modify this view for the more highly hydroxylated veratruni bases. The essential unity shown both by the formulz of a11 the fully character- ised alkainines (all except verutrobasine and geralbine which may be related to the holarrhena alkaloids are C, compounds) and by the basic dehydro- genation products is not found among the non-nitrogenous dehydrogenation products.Three types of hydrocarbon (and oxygenated derivatives) are formed. From cevine gerinine and protoverine cyclopentenofluorenes arc obtained. Jervine like cevine gives 4 5-benzindane and cyclopenteno- fluorenes but together with veratramiiie also yields 1 2-benzofluorenes. Phenanthrenes are produced by ruhijervine and isorubijervine but neither gives the Diels hydrocarbon which is formed by the solanurn alkaloids. At least two distinct types of carbon skeleton are thus indicated. Subsequent MORGAN AND BARLTROP VEKATEUM ALKALOIDS 3!j work has confirmed this and shown that the true steroid skeleton is to be found only in rubijervine and isorubijervine ; in all the other alkaloids a modified steroid skeleton is found.Rubijenrine and isoRubijervine.-The ring structure of these two alkaloids is that of the tertiary solanum alkaloids and both have been identified as hydroxysolanidines. Optical rotatory dispersions and molecular rotations lg have confirmed the view that rubijervine is l2x-hydroxy- solanidine ; isorubijervine has been identified as 18- hydroxysolanidine. The recent statement l9 of the full stereochemistry of solanidine enables complete structures (IX X) to be written for these two veratrum alkaloids. Jervine C2,H3903N is a secondary base which contains a hydroxyl group an ether bridge and a sluggishly reactive carbonyl group.These functions and the presence of a second double bond require that jervine be hexacyclic. The structure (XI) proposed by Fried Wintersteiner et al. 2O provides a satisfactory basis for interpreting the experimental evidence and will be used in the following discussion. Jervine.-( a) General. 18Me "Me H (i) The presence of the familiar steroidal 3/3-hydroxy-A5:6+ystern which was originally inferred from the formation of 3-0xo-A~:~-derivatives on oxidation has been demonstrated by comparison of molecular-rotation differences with those of steroids and more recently by formation 21 of 3 5-cyclo-derivatives of certain degradation products of jervine. (ii) The salient features of the carbon-nitrogen framework follow froiii the formation on dehydrogenation of a 4 5-benzindane and of cyclopenteno- and benzo-fluorenes which indicate that ring c is five-membered and of 2-ethyl-5-methylpyridine which suggests the form assumed by the steroidal side chain in this alkaloid.The keto-group in jervine is inert and is thus presumably at position 11. Dhydrojervine (XVI) has an infrared absorp- tion band 22 a t 1730 cm.-l typical of a cyclopentanone and this confirms the nature of ring c. 18 Pelletier and Locke J . Amel.. Cheiti. SOC. 1967 79 4531. IQ Sato and Latham C'hem. and Ind. 1955 444 ; J . Amer. Gkenb. SOC. 1956 78 20 Fried Wintersteiner Moore Iselin arid Klingsberg ibid. 1951 73 3970. 21Herz and Fried ibid. 1954 76 5621. 2 2 Anliker Heusser and Jeger Helv. Chim. Acta 1952 35 838. 3146. 40 QUARTERLY KEVIE\VS (iii) The relationship denionstrated (see p.44) I)et ween veratn~iiiinc (XXXI) and jervine establishes that the latter has a six-membered ring D and a 13-methyl group. (iv) The double bond conjugated with the keto-group has three possible locations. The 8 !)-position is untenable 1)ecause oxidation of 3-acetoxy- 5 6-unsaturated steroids with chromic acid gives the corresponding 7-0x0- derivatives and ON-diacetyl-7-oxojervi1~ prepared z 3 I ) J ~ this inethocl did not have the ultraviolet spectrum expected for the extended conjugated system (XII). The 1 l-oxo-A1~~~4-structun.e has been ascribed to an isomer of jervine (see below) leaving the 12 13-position as the only possible location for the double bond in jervine. This assignment receives strong support (XI I I) from the fact that whereas in jervine and its derivatives possessing unsatura- tion in this position the ether bridge is readily cleaved removal of the double bond by hydrogenation or by isomerisation to other positions gives molecules with niuch more stable bridges.This is a consequence of the allylic nature of the ethereal oxygen atom in jervine. (v) The isolation of a base probably 2-ethyl-3-hydroxy-5-methyl- pyridine (XIII) from the selenium dehydrogenation products suggests the position of one end of the ether bridge. The other end has been assigned to C(lil to account for its ready elimination and for the products of the jervisine rearrangement (see below). The partial structure (XIV) also affords by analogy with the quinine-niquine transformation a plausible explanation 24 of the remarkable scission which takes place * O 2*5 when jervine is heated to 140" with acetic anhydride and e Me H Me Me Me Me zinc chloride Me ye + O W H (xv) This evidence establishes the structure (XI) of jervine ; the transfornia- tions of jervine discussed below are interpreted in terms of this structure.(b) Reduction. Jervine when hydrogenated over platinum under alkaline conditions gives dihydrojervine which since it possesses a saturated C*C*CO*C-C grouping must have the structure (XVI). Hydrogenation of jervine or of dihydrojervine under acidic conditions leads to tetrahydro- jervine which since i t is still ketonic and forms an ON-diacetate must be formulated its (XVII). The resistance shown by the carbonyl group to :1:33. 2 3 Wintelatciner Moore Fried and Iselin I-'r-oc. Nut.-4ctrrl. P c i . r7.S.A . 1951 37 2 4 h'riod arid Klirigsbcrg .I. Awtci*. C'lierr!,. Soc. 1933 '75 4!)3!). 2 5 Mosher Forker Williams and O d ~ ~ - o o d i6itZ. 1952 74 1 c i 2 i . MORGAN AND BARLTKOP VERATRUM ALKALOIDS 41 1 Reagents 1 H -1% -OH-. 2 H,-Pt-H+. 3 Na-BuOH. catalytic reduction is noteworthy ; however it can be reduced chemically. Dihydrojervine (XVI) treated with sodium and butanol,26 gives '' 18 "- dihydrojervinol (XIX) in which the 1 I-hydroxyl group is or-orientated. Reduction of jervine under the same conditions was thought to give the 21-epimer but it has now been shown 27 that the product " a "-dihydro- jervinol (XVIII) is a diene-trio1 in which the ether bridge has been broken. Further reduction of '' p "-dihydrojervinol by catalytic methods or of tetrahydrojervine by sodium in butanol gives the same product " "- tetrahydrojervinol (XX) which contains an unhindered 1 la-hydroxyl group.Lithium aluminium hydride reduces tetrahydrojervine t,o the hindered 1 l$-hydroxy-isomer. Di- and tetra-hydrojervine are much more stable than jervine to acidic reagents. (c) Acetolysis. Jervine when heated with zinc chloride and acetic anhydride experiences scission to the doubly unsaturated ketone (XV). Acetolysis of jervine diacetate performed 28 a t room temperature and catalysed by small amounts of sulphuric acid leads to a mixture of the " indanone " (XXI) and tertiary alcohol (XXll). The react'ion has recently been interpreted 29 in terms of a concerted anionoid-cationoid attack on the C,,,,-O bond leading to an intermediate sulphate ester (XXIII) which has also been isolated.Hydrolysis will give the alcohol (XXII) which has been shown 28 to be converted under the conditions prevailing in the acetolysis into the indnnone (XXI) presumably by dehydration to a diene followed by oxidation or dismutntion to the indanone. The triacetate (XXII) is transformed by alcoholic potassium hydroxide into jervisine monoacetate (XXIV ; R = H R' = Ac) the structure of 2 6 Jacobs and Craig J . Bid. Cihem. 1943 148 51 ; Jacwbs uiitl Huebner ibid. 2 Iselin Moorts a i d Wintersteiner J. A ) j i ~ r . (,'hem. SOC. l!LX 78 403. 28 Wintersteiner and Moore ibitl. 1!)33 75 4938. 2'J Idmi ibid. 1956 '78 6193. 1947 170 635. 42 QUARTERLY REVIEWS which follows from the facts that i t is a saturated ketone containing an 0-acetyl but no N-acetyl group and that it is a weak tertiary base giving a basic triacetate ; its weakly basic nature may be ascribed to steric shielding of the nitrogen atom.It is thought 28 that the rearrangement proceeds via an intermediate (XXV) to an isomeric acetate (XXVI) the free amino- group of which can add to the c$-unsaturated ketone. Ac 0 3 O*S03H ' (XXIII) c (X x I) (XXI I) 1 Acetolysis of jervine diacetate catalysed by perchloric acid gives yet another product,2g a dihydro-1 3-oxaziniuni perchlorate (XXVII ; R = Ac X = ClO,) which when treated with weak bases rearranges to jervisine triacetate (XXIV ; R = R' = Ac). The structure of the perchlorate rests on the following evidence. Analysis shows that i t is derived from ;t hypothetical jerviiie triacetate by addition of the elements u f perchloric acid.It is identified spectroscopically as an a/?-unsaturated ketone and although it is a salt the absence of an N-H band in the infrared spectrum indicates that the nitrogen atom must be quaternary. The crucial evidence comes from consideration of the related salt (XXVII ; R = H X = C1) which together with N-acetylisojervine and jervisine 17-acetate (XXIV ; R = H R' = Ac) is formed when N-acetyljervine is treated with methanolic hydrogen chloride. This salt the infrared spectrum of which indicates the absence of an 0-acetyl group does in fact contain such a group in a masked form since with sodium carbonate it forms jervisine 17-acetate. The dihydro-oxazinium salt structure which provides the only reasonable inter- MOSGAN AND BARLTROP VERATRUM ALKALOIDS 43 pretation of these results is confirmed by catalytic reduction of the salt to a dihydro-derivative (XXVIII) from which acetaldehyde can be obtained.The dihydro-oxazinium salts are probably derived by a mechanism analogous to that invoked for the formation of the sulphate ester (XXIII); in the absence of any other anionoid reagent the oxygen atom of the N-acetyl group takes the place of the bisulphate ion / The base-catalysed rearrangement of the dihydro-oxazinium salts to jervisine derivatives may bc formulated as follows (d) Jervine isomers. Jervine has been found 30 to isomerise under the i tifluence of hydrogenation catalysts to A12:14-jervine * (XXIX). The oxygen bridge being no longer allylic is much more resistant to acid- catalysed rearrangements. It withstands methanolic hydrogen chloride under conditions which transform jervine into is0 jervine and the substance can even be recovered partially unchanged from the perchloric acid-acetic mhydride acetolysis mixtures.However under alkaline conditions there is slow isomerisation into yet another compound (XXX). I5 (x x x) Acid hydrolysis of #- jervine the naturally occurring glucoside of jervine isoJervine may also be obtained by trea,ting jervine itself gives isojervine. * Iselin and Wintersteiner 3O designate this cornpound A'b3-jervine. Iselin and Wintersteiner J . Amer. Chem. Soc. 1955 77 5318. 44 Q UAl<T'ERLY REVIEWS with methanolic hydrogen chloride. Since isojervine forms a triacetate the ether bridge has presumably been broken but details of its structure remain to be established. Veratra,mine.-This secondary base closely related to jervine is unique among the veratrum alkaloids in possessing a benzene ring in its skeleton.In addition it contains a 5 6-unsaturated 3P-hydroxyl group and a second acylatable hydroxyl group. The isolation of 3-hydroxy-5-niethylpyridine from the dehydrogenation products indicates that the second oxygen atom is located a t C(23) in the nitrogenous ring. The similarity between the dehydrogenation products from jervine and veratramine led Tamm and Wintersteiner 31 to suggest that this evidence is best accommodated in the structure (XXXI). Confirmation is provided by oxidation of veratramine to benzene-1 2 3 4-tetracarboxylic acid and of OON-triacetyldihydro- veratramine to an " indanone '' (XXXII) identical with that obtained by reduction of the indanone (XXI) from jervine.Further examination of the oxidation of triacetyldihydroveratramine has revealed that the indanone (XXXII) is not the major product. A substance which has been assigned 32 the epoxy-ketone structure (XXXIII) is formed in 30% yield. This epoxy-ketone is readily transformed under both basic and acidic conditions into an a-naphthol (XXXIV) formed by attack of C(7) on the oxide ring a t C(9) followed by aromatisation. Reduction of the epoxy-ketone by borohydride yields a trisecondary trio1 (XXXV) which is 6 AcO HO HO J (XXX IV) ( X X X l l I ~ AcO HO OH AcO Ac (xx x v I ) stable to glycol-splitting reagents has only one acylatable hydroxyl group and is oxidised by chromic acid to the monoket'one (XXXVI). It has been suggested that these surprising results can be explained conforma- s1 Tariirii ttnd WiiitcrsCciricr d .drrrer.. ChetrL. Soc. 1952 74 3x43. 34 Hosansky and Wintersteiner ibicl. 1956 78 3126. MORGAN AND BARLTROP VERATRUM ALKALOIDS 45 tionally in terms of the steric factors operating within the nine-membered ring. The Cevan Group.-The more highly hydroxylated alkamiizes protover- ine veracevine germine and zygadenine are closely related structurally. Degradation of derivatives of the first three to identical compounds and transformation of an ester of germine into an ester of zygadeniiie have demonstrated this. Much of the structural investigation of these alkaloids has been conducted with cevinc the stable and inore readily accessible isomer of veracevine and it is from the determination of the structure of cevine that our knowledge of the structures of the other nlkatnines is derived.This first isolated by Wright and Luff,l0 is it tertiary base containing neither N-methyl nor O-methyl groups. Exhaustive chemical and spectral investig2tions showed that it contains neither carbonyl nor olefinic double bonds. The nature of the carbon-nitrogen skeleton has been established largely by dehydrogenation experiments. Selenium dehydrogenation gives a mixture of basic and non- basic substances (Table 2). The non-basic materials were identified spectro- scopically and chemically as cyclopentenofluorenes ; the simpler basic fractions are 2 5-dialkylpyridines. Closely related pyridine and piperidine bases are formed by distillation of cevine with soda-lime and zinc dust. It is the more complicated bases cevanthridine 33 C25H27N veranthridine 34 C26H25N7 and the substance 34 CzoHI9N which reveal the structure of the cevan nucleus.Cevanbhridine a tertiary base is catalytically reduced to a tetrahydro- derivative which is a secondary amine. This suggests the presence of a quinoline or isoquinoline unit. Since the ultraviolet spectrum 35 of tetra- hydrocevanthridine resembles closely those of the cyclopentenofluorenes it follows that the nitrogen atom cannot be directly attached to a benzene ring since this would cause considerable spectral changes and that therefore cevanthridine is in fact an isoquinoline derivative. Accordingly cevan- thridine can best be formulated 36 as a cyclopentenoindenoisoquinoline (XXXVII). The presence of a fluorene nucleus has been confirined 37 by CevirLe C27H,30,N.It is therefore heptacyclic. I' / \ ' \ ' \ / (XXXVI I> 33310unt J. 1935 122; 31 Craig and Jacobs ibitl. 35 ldem ibid. 1). 393. 3G Jacobs and Pellctier J . 3 7 Pelletier and Jacobs J . (x xxv I I I ) (XXXIX) Jacobs and Craig J . Riol. Clreni. 1939 129 79. 1911 139 263. UHJ. Cheoi. 1933 18 'itis. Amer. Chem. SOC. 1954 '76 2028; l!J5G 78 1914. 46 QUARTERLY REVIEWS the ready and reversible oxidation of cevanthridine to the red fluorenone ox yceva nt hridine. Veranthridine has been formulated 36 as the analogous benzofluorene (XXXVIII). It can be reduced to an octahydro-derivative with the spectrum of a fluorene and oxidised to the red oxyveranthridine. The last substance probably formed by autoxidation has been isolated directly from the dehydrogenation mixture The base C,,H,,N then becomes (XXXIX).On the basis of this evidence Jacobs and Pelletier 36 suggested that cevan the nucleus of cevine was a c-nor-D-homo-steroid with the structure (XL). The alkamines veracevine germine protoverine and zygadenine are oxygenated derivatives of this skeleton. The formation of cyclopenteno- fluorenes on dehydrogenation is not inconsistent with this formulation since jervine under similar conditions also gives a mixture of cyclopenteiiofluorenes and benzofluorenes. (x L) This modified steroid skeleton is further confirmed by oxidation of cevine and of its derivatives studies of which lead also to determination of the position and nature of the eight oxygen atoms in the molecule. With chromic acid cevine yields 38 a mixture of acids and lactams.From the acidic fraction in addition to acetic acid six acids have been isolated 39 as their methyl esters (a) methylsuccinic acid ( b ) aa-dimethylsuccinic acid (c) a dicarboxylic acid CllHl4O8 or CllH1608 which also contains a lactone grouping ( d ) a hexanetetracarboxylic acid C,,H1408 ( e ) a heptane- tetracarboxylic acid Cl1Hl6O8 and ( f ) a tricarboxylic acid C14H1808 containing a lactone grouping. The most important of these is the acid (f) which under the action of heat or alkali loses the elements of water (2 mols.) to give decevinic acid Cl4H1,O6. The properties and transformations of decevinic acid (scheme 1) have been extensively investigated by Craig and Jacobs.39 Subsequent work by Gautschi Jeger Prelog and Woodward 4o has extended the earlier results and led to the formulation of decevinic acid as an acylglutaconic anhydride (XLIII).A similar structure was proposed independently by Taylor Barltrop and Morgan 41 from an examination of' the data provided by Jacobs and Craig. Dehydrogenation of decevinic acid under such mild conditions that 38 Craig and Jacobs J . A u i e r . Cheni. SOC. 1959 61 8252. 40 Gautschi Jeger Prelog arid Woodward Helu. Chim. Ada 1931 37 2880. 4 1 Morgan Thesis Oxford University 1952. Idem ,J. Biol. ClLern. 1940 134 123 ; 1941 141 253. MORGAN AND BARLTROY VERATKUM ALKALOIDS 47 major structural changes can be discounted yields 2-hydroxynaphthalic anhydride (XLII). This a t once fixes the relative positions of twelve of the fourteen carbon atoms. Decevinic acid is a dibasic acid possessing a carboxyl group and a weaker acidic function associated with the acylglutaconic anhydride system.When the acid is heated with alkali the anhydride Qo (XLI I) ' go 'vle02C Ac02C Go P po~@o MeM%o SH2 (XLIX) A c O ~ H02C H3C SCHEME 1 Reagents 1 Se. 2 MeMgBr. 3 OH- then Hf tho11 CH,N,. 4 Heat. 5 OH-. ti CH,N,. 7 Ac,O. ring opens with the consumption of a further equivalent of alkali giving a #I-keto-acid which suffers decarboxylation. The resultant dicarboxylic acid (XLIV) is itself a vinylogue of a P-keto-acid a'nd on further heating is decarboxylated with simultaneous lactonisation giving the compound (XLV) ; the infrared spectrum confirms t,he ketonic ring as six-membered and the lactone ring as five-membered. Hydrolysis and methylation of this Iceto-lactone gives a keto-ester which can be reduced by the Clemmensen method to an acid identified synthetically a's (-t-)-9-methyl-cis-decalin-l- caarboxylic acid (XLVI).All these results are adequately accommodated in the structure (XLIII) proposed for decevinic acid. Strong confirmatory evidence is provided by comparison 42 of the ultraviolet and infrared spectra of decevinic acid and of a-acetyl-a'-ethyl-@-methylglutaconic anhydride ( XLIX). However it is not possible from these results alone to discriminate * Barltrop and Morgan unpublished results. 48 QUARTERLY REVIEWS between t'he structure (XLIII) and one which contairiv the carboxyl group in the other peri-position. The alternative formulation is excluded by consideration of the cevan skeleton and by the structure of the hexane- tetracarboxylic acid and of the precursor acid f.Direct evidence for the position of the carboxyl group has been provided 43 by conversion of the 1~ et o -lactone (XLV) into %methyl- 5-isopropylnaphthalene (L) . The precursor acid (f) of decevinic acid yields a triester aiid is the y-lactone of a monocyclic saturated hydroxy-tetracarboxylic acid. Its ready conversion into decevinic acid eliminates all but two positions (LI LII) for the site of the lactonised hydroxyl group ; the second formulation does not satisfy the structural requirements of the cevine molecule and may be discarded. From the nature of the substitution on the carbocyclic ring of the precursor acid it follows that this ring must have originated as ring B in cevine. Further degradation of the acid (XLVI) to (+)-9-methyl-cis-1- decalone (XLVII) and thence to the cis-cyclohexane acid (XLVIII) has been achieved 4 4 and consequently links the stereocheniistry of cevinc at C(lu) with that of the steroids and t e r p e n e ~ .~ ~ HO,C $:2H f-' Ho2c* H do (LIII) (LI 1) 0 (LO OC-0 The hexanetetracarboxylic ucid on being heated gives first a dicyclic anhydride in which one ring is five-membered and then a keto-anhydride in which the carbocyclic ring is fi~e-membered.~~' 46 This keto-anhydride (LIII) has been syiithesised 4 7 and shown to be derived from the expected hexane acid (LIV). The hoinologous heptane tetracarhoxylic acid may then be written as (LV). In the carbon sl~eleton adopted for cevine fission to the precursor acid suggests that there are oxygen atoms a t position 4 and possibly also a t position 3. There can be only oiie more oxygen atom in rings A and B and that from the structure of the precursor acid must be located a t position 9.The side chain CH,*CO,H in the precursor confirms the writing of ring c as five-membered a conventional steroid would almost certainly suffer fission between C(ll) and C(lz). Cevine consumes two mols. of lead tetra-acetate or of periodic acid and la Prelog unpublished results. Guutschi Jeger Prelog and \Vood\rard Helv. Chinz. Actci 1955 38 296. Woodward Sondheimcr Tnub Heusler and McLamore J . Anzer. ('henr . h'oc. l+2111ing Vogel tJeg:er ant1 Prclug NeZij. Chkn. ,1ctu 1923 36 2W2. I !).-)2 '74 4223. l7 Jcger Mirza Prelog T'ogel and Woodw~rd ibid. 19.54 37 2293. MORGAN AND BARLTKOP VERATKUM ALKALOIDS 40 hence possesses at least two a-glycol systems. It is weakly acidic giving salts with alkali-metal alkoxides ; it is methylatedlOc by methanolic hydrogen chloride ; it reduces Fehling's solution and silver oxide and can be reduced by sodium in ethanol.These reactions all suggest that one of the glycol groups is actually an cc-ketol or acyloin. Since cevine has been shown not to contain a free carbonyl group it was further suggested that the ketonic function was ma,sked in a hemiketal group 417 4 8 (cf. LVI) thus providing the seventh ring required by the analytical figures for cevine. Confirmntrion of such a structure was obtained by the periodate fission of one of the glycol systems to an aldehydo-y-lact~ne.~~ 3 This recalls the y-lactonic function of the precursor acid and suggests the forniulation (LVIL). The other a-glycol grouping is ditertinry because while cevine triacetate is stable to chromic acid it still consumes one niol.of lead tetra-acetate. Although 2-dialkylaminoethanols are inert to lead tetra-acetate cc-dialkyl- amino-ketones undergo oxidative fission. Since cevine triacetate consumes only one mol. of lead tetra-acetate neither of the hydroxyl groups of the ditertiary glycol can be situated with respect to the nitrogen atom for such a circumstance would lead to the formation of an ct-dialkylamino- ketone as an intermediate and hence to the consumption of more than one mol. of oxidising agent. Also the absence of carbinolamine properties in cevine requires that there be no hydroxyl group located ct with respect to the nitrogen atom. These considerations leave the C/D ring junction at C(12) and C(14) as the only available site for the second glycol system.Five oxygen atoms have now been accounted for the remaining three must be located in rings D E and F and they can be placed by a process of elimination. One of the lactams formed in the chromic acid oxidation of cevine is optically active and has been shown by synthesis 51 to be ~ ( - ) - 5 - methylpiperidone (LVIII) ; there can thus be no oxygen atom situated between C(23) and C(2,). C(13) and C(15) are excluded as sites bearing the hydroxyl groups because they are adjacent to the tertiary glycol ; C(ls) and C(22) by the absence of carbinol amine properties. This leaves available only the positions 16 17 and 20. Accordingly the structure (XLI) can be written 5 2 for ceviiie (the stereo- chemical aspects are considered below).It is noteworthy that this structure contains a 1 2 3-trio1 which must be inert to glycol-splitting reagents. Hydroxpl groups held rigidly in There are no primary CH,*OH groups. I* Barton and Easthani J . 1953 421. 49 Barton and Brooks Ghern. a.nd Ind. 1963 1366. 50Barton Brooks and Fawcett J. 1954 2137. 51 Jeger Prelog Sundt and Woodward Helu. Chim. Actu 1954 37 2308. 5 2 Barton Jeger Prelog and Woodward Experientia 1954 10 81. D 50 QUARTERLY %EVIEWS hindered positions are known 5 3 to show such inactivity. It may be noted that titration of cevine with glycol reagents shows a slow continuing uptake of the reagents after the initial fast reaction is complete ; epimerisation 54 or oxidation 5 5 of the 16-hydroxyl group makes attack on the C(16)-C(17)-C(20) system more rapid.A sophisticated confirmation of the nature of the C/D ring system has been provided by chromic acid oxidation 56 of the ester alkaloid cevadine (see below). The primary product is the 12 14-seco-A8:9-4 12 14 16- tetrone (LIX) which cyclises and aromatises under the experimental condi- tions to a compound in which a 7-hydroxyindan-l-one unit was identified spectrally and chemically (cf. LX). It follows that ring c must be five- membered that there i s a hydroxyl group a t can be no hydrogen atom a t position 17. position 16 and that there The extensive evidence which has accumulated through the preparation of a large number of esters fully supports the structure ascribed to cevine. The alkamine is readily diacylated (at positions 3 and 16) and in the pres- ence of pyridine is triacylated.Triacylation must give protection to both hydroxyl groups in ring A since cevine triacetate is inert to chromic acid. Although the remaining hydroxyl groups are all tertiary acetylation of cevine triacetate in the presence of perchloric acid results in the introduction of a fourth acetyl group and the concomitant loss of a molecule of water. The product anhydrocevine tetra-acetate exists in aqueous acetic acid in equilibrium with cevine tetra-acetate and it has been shown spectro- scopically 50 to be cevine triacetate orthoacetate. The presence of an ortho- acetate system has also been demonstrated chemically 12 5 7 by the existence in the analogous derivative of the ester alka'loid cevadine (see below) of an acetyl residue stable to alkali but readily hydrolysed by acid.Hydrogena- tion of cevine triacetate orthoacetate gives cevine triacetate " dihydro- orthoacetate " formulated as an acetal since hydrolysis yields acetaldehyde ; re-oxidation of the " dihydro-orthoacetate " with chromium trioxide regenerates 55 the orthoacetate. The unique formation of an orthoester in this way demands fhe presence of three suitably orientated tertiary hydroxyl groups. A t least one of the hydroxyl groups in the tertiary glycol is bound in the orthoester because although cevine triacetate is oxidised by periodic acid cevine triacetate orthoacetate is stable. This fixes the general location 5 3 Criegee Kmft and Rank L4nnaZen 1935,507 159 ; Criegee Biichner and Walther b * Kupchan and Johnson ibici. 1956 78 3864. 6 5 Barton Brooks and de Mayo J. 1954 3950. 5 6 Mijovic Sundt Kyburz Jeger and Prelog HeZij.CILim. Acta 1955 38 231. 6'i Stoll and Seebeck ibid. 1954 37 824. Brr. 1940 7'3 571 ; WinCersLeiner arid Moore J. Ante?. C ' h c v i . ~ O C . 1950. 72 1923. MORGAN AND BARLTROP VERATRUM ALKALOIDS 51 of the orthoacetate group and models indicate that the l% 14- and 17- hydroxyl groups are suitably placed (LXI ; R = Ac). This provides additional evidence for the existence of a hydroxyl group at position 17 ; the necessity for such substitution is further indicated by the spectra of the 16-ketones obtained by oxidising cevine 3 4-diacetate and cevine 3 4- diacetate orthoacetate the differences between which require 5 5 that there be a hydroxyl group adjacent to the ketone in the simple diacetnte. A SOH ... Me Cevine triacetute ort hoacetate can be reduced at the hemiketal grouping by lithium in liquid ammonia to give dihydrocevine orthoacetate (LXII ; R = H) readily convertible into the triacetate (LXII ; R = Ac).The last triacetate is stable to chromic acid and so the hydroxyl group (which is bound as an ether in the hemiketal and must be y with respect to the potential carbonyl group in ring A) is tertiary and therefore must be located 55 a t position 9 as had been suggested above. Hydrolysis of the ester alkaloid cevadine with 20% alcoholic potassium hydroxide gives cevine as its potassium salt. When milder conditions are used a ketonic isomer of cevine cevagenine is obtained. 58 It is apparent that cevagenine cannot be the true alkamine of cevadine since the latter contains no ketonic carbonyl group. Use of very dilute alkali and very mild conditions gives a second isomer l1 l2 59 of cevine.The new isomer veracevine is non-ketonic. Its status as the true alkamine of the cevan alkaloids is established by the synthesis 6o of the naturally occurring esters cevacine and veratridine from it. I n the presence of alkali veracevine is isomerised irreversibly first to cevagenine and then with more concen- trated alkali to cevine. Apart from its instability to alkali veracevine is chemically very similar to cevine entirely analogous esters and orthoesters have been prepared 59 and the oxidation of it and its derivatives parallels that of the corresponding cevine compounds.61 The isomerism of the triad veracevine (LXIII) cevagenine (LXIV) and cevine (LXV) is that of hemiketal hydroxy-ketone and epihemiketal.12 That ring A is the seat of these changes has been established by the oxidation of all three bases by bismuth oxide to the same product cevilinic lactone.61 This substance a hydroxy-d-lactone (LXVII) appears to be formed by a Veraceuine.58 Stoll and Seebeck HeEv. C1hiiw. Acta. 1962 35 1270. 6o Macek T‘anecek I’elcova and Vejdelek Cliem. L&y 1956 50 603. c 1 Kupehan and Lavie J. Amer.. Chern. Xoc. 1954 76 314. Idem ibid. 1953 36 189. 52 GJUARTERLY REV IEWY benzilic acid rearrangement of the initially forined a-diketone (LXVI). The st,ructiire of the lactone was confirmed by reduction with sodium horohyvdride tlo the glycol (LXVIIZ) which was oxidised by periodate after protection of the rest of the inolecuIe by orthoest,er formation to a cyclo- pentanone (LXIX).(LXVI 1) (LXIX) Thc cheiiiistry of cevagenine (LXIV) differs in some respects froni that of the two hemiket,als. It is readily diacetylated a t positions 3 and 16. The absence of any simple triacyl derivatives further supports the tertiary nature and hence 9-position of the hydroxyl group masked as an ether in the hemiketals. The presence of a free 9-hydroxyl group provides a second trio1 system which can give orthoesters and two distinct cevagenine ortho- acetates have been prepared. Hydrolysis of cevadine orthoacetate diacetate (LXX ; R = angeloyl) by alkali gives cevageniiie D-orthoacetate (LXXI) which in dilute acid rearranges 6 2 to the isomeric cevagenine c-orthoacetate (LXXII). These structures have been assigned by comparison of the 0 (LXXII) spectra and molecular rotations of these compounds with the orthoacetates derived from the heinilietal alkainines.The stability of the c-orthoacetatc t o 20 yo potassium hydroxide soliit ion which coiiverts the D-orthoacetate into cevine orthoacetate may be attributed to the non-availability of the 9- hydroxyl group. Jt is possiblc with our present knowledge to assign to iiiany of these centres their appropriate configuration. 53 The C(4,-O-C(9) bridge demands that the A/E ring junction be cis and that the bridge be a-orientated. The assignment of configuratlion a t C(3) is based on the concept that the driving There are present in verncevine fourteen asymmetric centres. 6 2 Kupchiin .I. Amer. Chem. SOC. 1955 77 GS6. MORGAN AND UAKLTROP VEItATRUM ALKALOIDS ,5 3 force for the veracevine-cevine transformation is the theriiiodynaniic instability of an axial hydroxyl group with respect to its equatorial counter- part ; i.e.in veracevine and cevine the 3-hydroxyl groups are orientated /3 and a respectively. Cevagenine must possess transfusion of the A and B rings to account for the lack of interaction between the 4-carbonyl and the 9- hydroxyl group which with an A,’B-& arrangement would lead immediately to the construction of a heniiketal system. Since cevagenine is prepared under enolising conditions the 3-hydroxyl group must lie in the equatorial i.e. 0-direction. The B/c-ring junction in norinal steroids is invariably trans and the configuration of bhe %hydrogen atom invariably @. The c-orthoacetate of cevagenine requires that the 12- and the 14-hydroxyl group have the s;me a-orientation as thatl at position 9 and the formation of the D-orthoacetates extends this requirement t o position 17.The inertness of the trio1 system to periodic acid suggests that the 17- and the 20-hydroxyl group are diaxid and therefore have the or- and @-configuration respectively and that the D,,”E-ring junction is tram. Since 16-epicevagenine c-orthoacetate is split more readily than its isomer by periodic acid (suggesting that here we have a cis-16 17-glycol) we may assign a 0-orientation to the 16-hydroxyl group in the alkaloids. The ready methanolysis of the 16-esters finds a simple interpretation 54 in terms of the neighbouring-group effect of the 20-hydroxyl if both groups are /I and axial. The synthesis of the lactam (LVIII) has shown that the 27-methyl group is P-orientated.Thus an almost complete structure may be written for veracevine it is 4a 9a- epoxycevan-30 40 l2a 14cc 16/3 17a 20p-heptaol. The configurations a t C,, and C(13) require to be confirmed and that a t C(22) to be determined. The four naturally occurring alkaloids cevadine veratridine cevacine and vanilloylveracevine are respectively the angelic veratric acetic and vanillic esters of veracevine with the acyloxy-group a t position 3. Of the alkaloids found in Veratrum and Zygadenus spp. the most common are esters of germine. First isolated by Poethke,’? 63 germine C2,H4,08N was shown to be linked structurally with its formal isomer cevine by dehydrogena’tion to ~evanthridine.~~ Although germine does not contain a carbonyl group 6 5 it is reduced by sodium and butanol.@ The similarity of this behaviour to that of cevine suggested 52 that germine might also contain a inasked or-ketol system.This has been confirmed by the isolation of the ketonic isomer isogermine 6 4 9 65 and the non-ketonic isomer pseud~gerrnine.~~ All three alkamines give isopropylidene deriva- tives on condensation with acetone under acidic conditions ; 64 6 7 3 68 periodate oxidation of these derivatives of germine and pseudogermine gives the same aldehydo-y-lactone and iiidicates the presence of a 3-hydroxyl 4-hemiketal Germine. 63 Poetlike d i * c I ~ . f’hwnz. 1937 2’75 571. G 1 Craig and Jacobs J . Rid. C‘Aewi. 1943 148 37. 6 5 Jaffe and Jacobs ibitl. 1951 193 325. 6 G Craig and Jacobs ibid. 1943 149 451. G 7 Kupckian Fieser Narayaiian Fieser and Fried J . Anzer.Chem. Xoc. 1954 76 6* Kupclian and Snrajmian C‘henz. cind IntZ. 1955 251. 1200. 54 QUARTERLY REVIEWS system similar to that found in ~evine.6~9 69 The order of stability 70 of the isomers isogermine < germine < pseudogermine differs from that of the cevine triad ; acylation 71 of germine to give germidine and monoacetyl- neogermitrine establishes that it is the true allramine of the naturally occurring esters. Acetylation of all three isomers readily gives tetra-acetates and germine under forcing conditions (acetic anhydride and sodium acetate) gives a penta- acetate. ' 0 This implies first the existence in germine of five non-tertiary hydroxyl groups and secondly that the bridge from C,,,-O must be to a tertiary carbon atom and therefore presumably to position 9. The occurrence of a 7-oxygenated group is suggested by isolation of t,he hexanetetra- carboxylic acid formed in the oxidation of cevine but not the precursor of decevinic acid when gerniine is oxidised by chromic acid.64 The remaining four oxygen atoms are to be accommodated in hydroxyl groups two of which are secondary and two tertiary.While germine consumes three mols. of periodate the consumption of only one mol. by isopropylidene- germine indicates that three of these hydroxyls form a 1 2 3-trio1 system.* The inertness of germine tetra-acetate to glycol fission suggests that the triol forms either a sec.-sec.-tert,- or a tert.-sec.-tert.-systom. The absence of carbinolamine properties and the uptake of no more than three mols. of periodate lead to the exclusion of sites both cc and /3 with respect to the nitrogen atom for the location of the triol.Since isogermine and dihydro- germine neither of which possesses the C(4)-O-C(8) ether bridge consume only three mols. of periodate (like germine) there can be no hydroxyl group adjacent to C(s) ; the formation of the hexanetetracarboxylic acid on oxida- tion excludes the possibility of additional oxygenated groups in rings A and B. Consequently only positions 12 14 15 16 and 17 remain available for the triol amongst these a tert.-sec.-tert.-trio1 cannot be accommodated. The triol grouping has been placed6* a t positions 14 15 and 16. Subsequent results support this arrangement rather than the alternative 15 16 17. The residual hydroxyl group has been placed 70 at position 20 leading to the representation (LXXIII) as the structure of germine (the stereochemistry is discussed below).The presence of a sec.-sec.-tert.-trio1 is confirmed by hydrolysis of 00-iso- propylidenegermine diacetate formulated as (LXXIV) to a diacetate which consumes one mol. of periodate with the formation of an unsaturated keto- aldehyde (Amax 238 mp). This was assigned 68 the structure (LXXV) at a time when it was believed that germine possessed a C(4)-O-C(7) oxide structure. The alternative formulation (LXXVI) may perhaps be prefer- Kupchan Fieser Narayanan Fieser and Pried J . Amer. Chem. SOC. 1955 77 6896. 70 Kupchan and Xasayanan Chern. mad Ind. 1956 1092. 71 Weisenborn and Bolger J . Amer. Chern. SOC. 1954 76 5543. * The possibility that geriiiinc contains a 1 2 3-dialkylarriino-diol system such as (A) is excluded because acetylation of 00-isopropylidene- germine followed by hydrolysis gives a germine diacetate which con- sumes only one inol.of periodate and not two as this forinulation CC would require. (Ring F shown.) (A) MORGAN AND BARLTROP VERATRUM ALKALOIDS 55 It is difficult to reconcile the ultraviolet spectrum of this product able. with the presence of a 15 16 17-trio1 system in germine. The stereocheniistry of the masked ketol systein incorporates the pattern established in the cevine triad. The different sequence of stabilities among the germine isomers may be attributed 70 to a stabilisation of the hemiketal structures by hydrogen-bonding between the 4-hydroxyl and the a-orientated 7-hydroxyl groups (cf. LXXVII where the dotted bonds have steroid ,Me %-significance).That' the 7-hydroxyl group is indeed a-orientated is sug- gested 70 (a) by borohydride reduction of 7-dehydro- 14 15-isopropylidene- gcrmine 3 16-diacetate to 14 15-isopropylidenegermine 3-acetate by attack from the relatively less hindered front face of t'he molecule and ( b ) by acctylation of gerrnine with acetic anhydride and pyridine to germine 3 7 15 1G-tet3ra-acet,zte. This reagent which acetylates the 4-hydroxyl group in veracevine fails to do so with geriniiie becausc prior 7-acetylation gives a 7-acetate which when cc-orientated stericnlly hinders attack a t the 4-position. The tentative assignment of configurations to the hydroxyl groups in ring D is based on the resistance of isopropylidenegermine to acetylntioii of thc 7-hydroxyl group. This suggests that the 14- and the 15-hydroxyl groups are both or-orientated the failure of the disecondary 15 16-glycol to form an isopropylidene derivative suggests that these groups are trans.These notions find support in the ready methanolysis of the 7 16-acyl 56 QWARTEELY REVIEWS groups which indicates s4 that they bear a cis-1 3-relation to the 14- and 20-hydroxyl groups. A tentative structure for germine may accordingly be written as 4a 9a-epoxycevan-3/3 4p 7a 14a 150 16/3 20p-heptaol Some preliminary results 70 have been reported of atteiiipts to establish the structure of the naturally occurring esters of germine. The three alkaloids germidine isogermidine and neogermitrine are all esterified in the same position by a-methylbutyric acid. 72 Germidine and isogermidiiie possess an additional acetyl group.Since germidine is stable to periodat'e it must have an acyl residue in ring A and another a t position 15. iso- Germidine consuming one mol. of periodate to give an aldehydo-y-lactone is therefore not acylated in ring A. It follows that the cc-methylbutyric (LXXIII). acid moiety in all three esters must be at position 15. neoGermitririe may be oxidised by chromic acid to a ketone neogermitrone which after hydrolysis gives cz diosphenol probably (LXXVIII). This suggests that' the two MCOR Germitrine + Gerrrierine MPOH Av2O i Triacetylprotoveratridine 4- Protoveratridinc (a-Methylbutyry1)germine t MeOH (SIOU) Germidine SiI~Oli + Germanidine / MrO H 31 1 o 1 I isoGerrnidiiie TieoGerini trine Gern-ti tetrino ScHmrE 8. I r J e i . e l u t i o i z s ~ ~ ~ ~ of certuin esters of gel miite.- . 7 2 Kupchan and lleliwnla J. Amer. Chem. SOC. 195-1 76 5545. MORGAN Ah'l) UARLTROP VERATRUM ALKALOIDS 57 acetoxyl groups in neogermitrine are at positions 3 und 7 . Molecular- rotation evidence 70 indicates that the acetyl group in isogerinidine is at' position 16. These results and the recorded correlations (Scheme 2) and rotations 71 of other naturally occurring esters of gerniine enable tentative structures to be assigned (Table 3). TABLE 3 Germiiie esters Synthetic monoesters Synthetic tetraesters Protoveratridine Gerinidine isoGermidinc Germerine Germitrine neoGermitrine Triacetylprot ovt'ix vicl inc Germbudine nxoGernibudine Germitetrine Gerinanitrinv Position of a c y l groupb 15 rL I n pyridine. b Roman nu~nerads refer to forinula nuinbers on p.37 ; symbol " x " is used when the acid radical is not specified. the Zygade&e C27H4307N was first isolated i 3 from X. intermedius in 1913 and first identified 7 4 its a typical veratruin base in 1949. Subsequently the isolation i 2 75 of germine esters from many Zygadenus spp. and of vera- troylzygadenine from several Veratrum spp. confirmed the close relation between these species first suggested by the similarity of their pharmaco- logical properties. 76 Zygadenine a tertiary base containing neither O-methyl nor N-methyl groups possesses a typical masked a-ketol ~ystern.~4 7 7 Alkaline isomerisation gives first the free a-ketol iso- zygadenine,j7 which can be oxidised to a diosphenol and isomerised to the hemiketal pseudozygadenine. 77 The stabilities of the three isomers lie in the order zygadenine < isozygadenine < pseudozygadenine analogous to t,he veracevine triad.Zygadenine yields a triacetate readily a tetra-acetate under forcing conditions and with acetone an isopropylidene derivative. 79 The presence of a 1 2 3-trio1 in addition to the masked x-ketol group is indicated by i 3 Heyl Hepner and Lo' J . Anzer. C'he,n. SOC. 1913 35 868. '.IHeyl and Herr. ibid. 1949 71 1551. i5 Kupchan and Deliwala ibid. 1952 74 3202. iG Hunt Arne?.. J . Physiol. 1902 6 19 ; Mitchell and Sniitli ibid. 1911 B 318. " Kupchan and Deliwala J . Arne,.. Ckern. SOC. 1953 75 1025. Auterhoff and Giinther Arch. Phurm. 1955 288 453. Kupchan Lavie and Zonis J . Amw. C'hern. Soc. 1955 77 GXY. 8o Kupchan ibid. 1956 78 3546. $8 QUARTERLY REVIEWS periodate titrations.The structure (LXXIX) for zygadenine and its correlation with germine is proved 80 by the reduction of 7-dehydrogermine 3 16-diacetate to zygadenine 3 16-diacetate condensat>ion of the keto- group with propane- 1 3-dithiol followed by desulphurisation with Raney nickel led to the elimination of the carbonyl group. Only inonoesters of zygadenine have been isolated from natural sources ; the acid residues (acetyl vanilloyl and veratroyl) are presumed to be at position 3. Protoverine C2,H4309N is the most highly hydroxylated veratrum base. Apart from the presence of the cevan skeleton 81 and the characteristic masked a-ketol system,78 little is known of its struct'ure. The isomers iso- protoverine 8 2 and pseudoprotoverine 78 have been isolated and shown to be the corresponding free ketol and the isomeric hemiketal respectively.Protoverine yields an isopropylidene derivative ; 82 this and the presence of two readily rriethanolysed acyl groups in its tetraesters suggest that i t may prove to be a hydroxygermine. It is of interest that the three cevan bases protoverine germine and zygndenine which occur together in many Veratrum spp. appear to show in their fine structure close similarities which are not shared with veracevine. Fritillaria Alkaloids.-The Chinese drug Pei-mu consists of extracts of the dried bulbs of the liliaceous plant Pritillaria roylei. In the East it enjoys a considerable reputation as a general medical panacea.83 A more precise evaluation 84 detected similarit'ies between its pharmacology and that of veratrine. Recent structural investigations of the alkaloidal constituents of Pei-mu and other Pritillaria extracts have shown close chemical links between the principal alkaloids and those of Veratrurn spp.Imperialine C27H430& was first isolated 85 from P. imperialis ; recently it has been shown 86 to be identical with sipeimine 87 obtained from the Chinese drug Si-pei-mu ( F . roylei). It is a saturated tertiary base containing a carbonyl group and two alcoholic hydroxyl groups one of which is secondary and acylatable the other tertiary; it contains neither N-methyl nor O-methyl groups.s7 88 The presence of the cevan skeleton has been estab- lished by deh~drogenation.8~ I n addition to typical benzofluorenes (one of which CI8Hl4 has been identified as S-methyl-1 2-benzofluorene) and 2 5-lutidine there have been isolated veranthridine (XXXVIII) and a compound C2sH3,N9 which appears to be hexahydroveranthridine.Infrared spectra indicate that the carbonyl group which readily yields an oxime is located in a six-membered ring.S6 Oxidation of the secondary alcoholic H1 Craig and Jacobs J . Biol. Ghern. 1042. 143 427. v 2 Idem ibid. 1943 149 271. 8 3 ( a ) Liu Chang and Chang Chinese Med. J. 1936 50 849 ; (6) Chi Kao and a4Narumi TohGku J. Exp Med. 1935 26 325. 85 Franger Rer. 1888 21 3284. 8 6 Boit and Paul Chern. Beis. 1957 90 723. 8 7 Chu and Loh Actn Chim. Sinicw 1956 21 241 ; Chetn. A h . 1957 51 445. a8 Boit Chem. Bey. 1954 87 472. 89 Chu Loh and Hwang Actn Chiin. Sinica 1955 21 401 ; Chern. Abs. 1957 51 Chang J. Amer. Chem. SOC. 1930 58 1306. 4 5 ; Chu and Loh Actcc Chiwi.&?iica 1956 22 210; Chem. Abs. 10.57 51 445. MORGAN AND BARLTROP VERATRUM ALKALOIDS 59 group to give imperialone (sipeimone) which is neither an a- nor a@-diketone introduces a keto-group into a second six-membered ring. Examination of the recorded rotations of these compounds the reduction products and the esters suggests that the secondary hydroxyl group and the carbonyl groups may tentatively be placed a t positions 3 and 7 respectively (cf. LXXX) ; this leavespositions 12,13,17 and 20 as possible sites for the tertiary hydroxyl group. Peimine C27H4503N which may be identical with verticine 83b 9 91 apo~erticine,~~ and peimunine 93 can be extracted from F. roylei or P. werticilhta and forms the major part of the active principle of the drug Pei-mu. It is a saturated tertiary base containing neither N - nor O-methyl groups.Two of the oxygen atoms are present as acylatable secondary alcoholic groups.94 On mild oxidation g4a peimine is converted into the monoketone peiminine C,,H,,O,N which accompanies it in Pei-mu (peiminine may be identical with ~erticilline,~~ ~eimiphine,~~ ~eirnitidine,~~ and fritillarine "). Reduction of peiminine with sodium in ethanol regenerates peimine. The suggestiong8 that peimine is related to the veratrum alkaloids is confirmed by dehydrogenation to 2 5-lutidine and 1 2-benzofluorenes identical with those from im~erialine.~~ It has been further suggested 97 that peimine is a cevan-11 x y-triol and peiminine the corresponding cevan-1 l-one but the reactivity of the carbonyl group which yields an oxime seems to preclude position 11 for it.Iladdeanine C,4H3902N isolated 98 from F . raddeana is a saturated tertiary base which contains no N-methyl group. Although the ultraviolet spectrum 99 suggests the presence of an unconjugated carbonyl group and Chu Loh and Hwang Acta Chim. Sinicu 1956 22 205 ; Chem. ,4bs. 1957 51 445. O1 Pukuda J . C'hem. SOC. Japan 1929. 50 74. 9 2 Idem ibid. 1948 69 167. D3 Li J . Chinese Phavm. ASSOC. 19-10 2 235. 9 4 (a) Chu and Chou J . Amel*. Chem. SOC. 1947 69 123i ; ( b ) Chu and Loh Actu Chim. Sinica 1955 21 227 ; Chem. Abs. 1957 51 444. O6 Chou J . Arne?.. Pharin. ASSOC. 1947 36 215. 96 Wu J . Arnev. Chem. SOC. 1944 66 1778. 9 7 Chu Hu-ang and Loh Acta Clhirn. Rinica 19Xi. 21 232 ; C'hein. Abs. 1957 913 Lazur'evskii and Sadykov J . Gen. Chem. U.S.S.R.1943 13 159 ; Aslanov and D* Idem ibid. 1). 1790. 51 444. Sadykov Zhu7.. obshchei Ilhim. 1956 26 679. (j0 QUARTERLY REVIEWS the action of phosphorus pentachloride gives a trichloricle acetyl or beiizoyl chloride in pyridine gives the diacyl derivative. Isolation loo of a base C,,HI7N and phenanthrene on dehydrogenation with selenium coupled with a positive pyrrole pine-splint test given by the vapour of raddeanine (though not by the base C,,H,,N) are expressed 98 in a carbon-nitrogen skeleton (LXXXI). Hydroxyl groups have been tentatively placed at positions 3 and 5 to account for a positive Iiebermann reaction characteristic of 3-hydroxy-A5-sterols and for t'he forination of a compound C,4H,70,NS formulated as a cyclic sulphite with thionyl chloride.99~ loo Mild oxidation of raddeunine gives raddeanone but under more vigorous conditions 99 a hexanetetracarboxylic acid i1i.p.153 -157" is obtained. On the basis of the melting point this has been identified with the hexunetetracarboxylic acid from cevine this characterisation alone cannot be regarded as adequate for a t least seven of the known hexanetetracarboxylic acids melt between 150" and 161" ; it is difficult to sec how the cevine acid could be formed froin the proposed structure. There have been inany reports of the isolation of other fiitillaria and veratrum alkaloids. Many of these refer to bases which have yet to be fully characterised and inany others to apparently impure speci- mens which may subsequently prove to be identical with other preparations. A profitable discussion of these products is not possible at present. Other alkaloids. loo AsIanov and Gadykov Zhw. obshchei Khim. 1956 26 1 T S i .

ISSN:0009-2681    

DOI:10.1039/QR9581200034

出版商:RSC    

年代:1958

数据来源: RSC

摘要:

SOME THERMODYNAMIC AND KINETIC ASPECTS OF ADDITION POLYMERISATION By F. S. DAIKTON F.R.S. and K. J. IVIN PH.D. (DEPARTMENT OF PHYSICAL CHEMISTRY UNIVEHS~TY OF LEEIX) Introduction THE question is sometimes asked ‘ * Why does polyinerisation occur ’! ” The answer is divisible into two parts first that under the prevailing experimental conditions the free energy decreases during polymerisation the extent of reaction being determined by the magnitude of the decrease ; and secondly that a mechanism is available which perinits the reaction to proceed a t detectable speed. Much research in the high-polymer field has hitherto been devoted to the elucidation of the kinetics and mechanism of polymerisa- tions ; relatively little effort has been made towards the determination of free energies of polymerisation or towards the understanding of the factors which influence their magnitudes.I n this Review we shall summarise the existing thermodynamic data on the formation of addition polymers. Many of these data are derived from systems in which an effective equilibrium can be set up between the growth process and its reverse and we shall begin after a brief summary of addition polymerisation mechanisms by considering the effect of such reversal on the normal kinetic expressions. Theoretical outline Main Features of Addition Polymerisations.-The overall reaction of addition polymerisation can be represented by equation ( l ) in which n molecules of monomer M give a polymer niolecule M with an accompanying change of n.Axx in the thermodynamic function % e.g. H 8 or G the states of M and M being denoted by the subscript x (see p.67). I n eqn. (1) M has been used to denote the exact formula (MI), but i t will be more convenient to define M as any linear polymer molecule conhining 32 monomer units plus (or minus) two end-groups which are not closely related to the monomer. Thus M denotes the exact formula R(M,),R‘ where R and R‘ are end-groups not derived from MI and also denotes R(Ml),-lMl’ where M,’ is a group derived from MI e.g. by loss of a hydrogen atom. A given polymer sample always contains molecules of differing degrees of polymerisation 11 and the mean value is denoted by mp. The monomer either contains an unsaturated group e.y. C=C C=O or -P=N- or is a cyclic compound e.g. a cyclic ether imine ester anhydride Uurnett “ Mechanism of Yolymer Reactions ” Intersciencc New Y ork 19M.nM = M ; nAx (1) (u) Flory “ Principles of Polpier Clieniistry ” Cornell Univ. Press 19.53 ; 61 ( 6 ) 62 QUARTERLY REVIEWS sulphide or siloxane. I n both cases the reaction is usually a kinetically unbranched chain reaction in which the first step is the opening of the double bond or ring. This initiation step involves the conversion of a monomer molecule into an active centre represented by M1* which is capable of joining on to a second monomer molecule and of simultaneously transferring to it the capacity for further addition of monomer by the same type of reaction. This repetitive process is known as propagation and is represented by Mi* + MI+ Mi+1*. Again it should be noted that Mi* denotes a centre containingj monomer units plus (or minus) an end-group not re- lated to M,.The capacity for growth can be transmitted to another mole- cule X by the transfer of an electrically charged or neutral atom (or radical) in a process represented by Mi* + X+ MJ + X* (followed by X* + M + XM,*). X is called a chain-transfer agent and may be the monomer. The chain centres M3* are usually destroyed in terminatio?~ reactions which may involve two centres (mutual or quadratic termination) or one centre (linear termination). I n certain rare cases there may be no termination process e.g. (i) polymerisation of some cyclic monomers by a molecular mechanism,2 or (ii) anionic polymerisation in media of high polarity. Termination reactions not only control the concentration of chain centres and hence the rate of the propagation process but also together with transfer reactions are responsible for restricting the DP of the polymer.If the entities X are less than 100% efficient in starting new chains the transfer process will also function partly or wholly as a termination process and is then known as a degradative tramfer process is reasonably large (> loo) Axx in eqn. (1) is essentially the change in therniodynamic function for the propaga- tion process Axp. This point is amplified on pp. 67-68 Classification of Mechanisms.-Whilst the argument developed below is not contingent on the detailed polymerisation mechanism it will be con- venient to bear in mind the classification of mechanisms in terms of the chemical nature of the chain carriers. These may be free radicals cations anions or molecules according to the nature of the initiation step.Pree-radical centres can be generated by the action of heat light or ionising radiation on the monomer or by addition to the monomer of the free-radical products of a subsidiary reaction such as the decomposition of a peroxy- or azo-compound or an oxidation-reduction reaction. Mutual termination frequently predominates in radical polymerisation. Examples of linear termination are found in thc polymerisation of ally1 comp~unds,~ where termination is by degradative transfer to monomer and in systems to which terminating agents Y such as compounds of transition element^,^ have been added. Catalysts for catioizic polymerisation 6 are effective because either alone Fief. In p. 33G. Szwarc Ncifrtre 1956 178 1168 ; Szwaw Levy and Milkovich J . Anlei'. Chew.~ S O C . l93G 78 2666. Collinson Daintoii and NcKaughton. Z ' I ~ U ~ N . Famdny SOC. 19.57 53 489. Pepper Quad. Rev. 1954 8 88. We note here that provided '* Ref. lct p. 173. DAINTON AND IVIN THERMODYNAMICS OF ADDITION POLYMERISATION 63 or in association with a cocatalyst they can donate a cation to the monomer. For example initiation of the polymerisation of vinyl ethers by iodine,' and of styrene in 1 2-dichloroethane by stannic chloride in the presence of water as cocata,lyst are believed to involve the following processes OR 212 + 1+13- It-1,- + R-O-CH-SH2 + l-CH,-CH+I,- (M1*) CH3 I SnC1,,2H20 -1- C,H,-CH-CH -+ C,H -CH+,SnCl,OH-,H,O (M,*) Catalysts for anionic polymerisation are either bases such as sodium hydroxide or sodamide containing an anion capable of adding to the monomer or are entities of low ionisation potential such as dissolved sodium atoms or naphthalene anion^,^ which readily surrender an electron to the monomer to form a radical-ion such as C,H,-CH-CH,-.I n the latter case growth may occur simultaneously a t both radical and anionic ends. The mechanisms of ionic polymerisation are complex and difficult to unravel particularly when they involve the presence of solid catalysts such as those recently found to cause the formation of crystalline polymers from propene and ~ t y r e n e . ~ We simply note here that mutual termination is unlikely to be important because of the repulsion between two centres carrying a like charge. For example it is possible that under certain condit)ions the propagation step in the polymerisation of ethylene oxide may be written as .Some cyclic monomers may polyinerise by a moleculas. chain mechanism. R*[O*CH,*CH,].,,*OH + (CH2),0 -+ R*[O*CK2*CH2IrL+1*OH Equations for the Rate and Degree of Polymerisation and the Effect of Depropagation.-Addition polymerisation mechanisms can be summarised Rate Initiation RIP -+ M,* Ri Propagation Mj* + Ml + Mj+i* kp[M *][MI I Transfer (non-degradative) kfx 114 *I [XI Mj* -I- X+ Mj + X* Termination Mutual{ Linear (including degradative Combination Mj* + Mi* -+ Mi+j - d[M*]/dt = 21ctc[M*I2 isproportionation Mj* -+ Mi* + Mi -t Mj - d[M*]/dt = 2ktd[M*I2 chain transfer) Mj* -+ Y + Mj + Y' ~ t y r ~ * ~ [ y ~ oc) by the annexed scheme. [M*] = Z [Mi*] is t,he total concentration of chain centres and the velocity constants are assumed to be independent of j .When the degree of polymerisation is large the fraction of monomer removed by steps other than the propagqtion step is negligible so that the rate of polymerisation R, is given by j -1 12 - J q M 1 1 I ~ ~ " J ( 2 ) Eley mid Richards T r a m . Farnday Soc. 1949 45 425. 8 Colclough and Dainton Trans. Pa~aday SOC. in the press. Eirich and Mark J . Colloid Sci. 1956 11 748. 64 Q UARTEltLY REVlEtl'S and DP is given by the rate of reiuoval of niononier divided by the rate of formation of pairs of dead polymer molecule ends i.e. DP = R,,! (f([M*l) ) = k,lMlILM*l/ (f([M*I)) (3) where (it being assumed that initiation results in one dead end for each centre formed as in the benzoyl peroxide-initiated polymerisation of vinyl inonomers). I t should he noted that t#ermination by combination results in a polvmer molecule whose two dead ends have already been counted.Equations (2) and (3) have tieen widely and successfully used in the inter- pretation of the kinetics of inany systems under both steady- and non- steady-state c0nditions.l Thus many examples are known of the limiting cases of mutual (R cc A, ; DP cx Ri-l) and linear. termination (RIP cc Ri ; DP independent of Ri) in steady-state systems. However there are certain systems for which the above scheme is inadequate and in which the observed expressions for IZ, and DP can only be accounted for hy postulating the significant participation of the reverse of the propagation process The term depropagation lo appears to have found general acceptance. Equations (2) and (3) are now modified to 2f([M*]) =1 Xi + LM*](2kfJX] + kty[Y] + 2ktd[M*]) Depropagation Mi* -+ Mi-,* + M Rate = k,[M*] 3,) = (k,)lM,l - k,"*I (4) The variations of k and k with temperature will be given by Arrhenius expressions k, = A exp (-E,,/RT) k = A exp (-E,/RT).E, - Ed = A H - A H if DP is large. -AH is the enthalpy change for the overall reaction and is generally a positive quantity (polymerisation exothermic) several times larger than E so that Ed is usually much larger t,han E,. Thus although k may be negligible compared with kp[Ml] a t room temperature it will increase the more rapidly with increasing tempera- ture and we may predict that a teniperature will be reached when kJM,] will be equal to k, regardless of the variations of [M*] and f([M*]) with temperature. At this temperature which is called the ceiZing temperature T, the extrapolated R,-T and a - T curves will cut the temperature axis.Fig. 1 shows the relative values of k,,[M,] and Ed for pure styrene,ll calculated from known data and anassumed Ad of I O l 3 see.-'. It is clear that even in 0.01~1 solution k is not likely to be important for styrene below 150". vary with temperature will depend on the magnitude of the activation energy for the initiation process Ei. In Fig. 2 are show1 the variations which may be expected for the particular cases of catulysed (Ei finite) and rudiation-induced ( E - 0) reactions with and without chain transfer. The ceiling temperature can also be defined as the temperature above p The way in which R and 10Dainton and Ivin PTOC. Roy. SOC. 1952 A 212 207. Idem Nature 1948 162 705. DAINTON AND IVIN THERMODYNAMICS O F ADDITION POLYMERISATION 65 4 I- Tempera t w e (" K) FIG.1 Plots of kp[PYI1] and kd against temperature for styrene. A, = 100 1. mole-l sec.-l ; Ad = 1013 sec.-l (assumed) ; E = 6-5 kcal. mole- 1 ; Ed = 6.5 + 16.1 = 22.6 kcal. mole-l ; [MI] = 8 moles 1.-' (assumed constant). Curve I 10-4kd ; 11 10-4Ep[M1] ; 111 10 -P(kp[M1] - kd). [Modified with permission from nainton and Ivin Nature 1948 162 705.1 FIG. 2 Expected shapes of rate-temperature (full lines) and 1)P-temperature (broke?? lines) gi*aphs without ti>ansfer (upper three) and with transfer (lower two) to monomer. I n n c trnd e E is finite and in b and d Ei - 0. which the formation of Eong-chin polymer from monomer a t concentration [MI] is impossible. The fact that such a temperature exists is a direct result of the fact that polymerisation is a chemical aggregation process.A similar and more familiar situation exists for physical aggregation pro- cesses thus a solid cannot be obtained from a liquid unless the temperature is below the freezing point of the liquid. Solid liquid and freezing point E 66 QUARTERLY REVIEWS are physica,l analogues of polymer monomer and ceiling temperature respectively. Closer inspection of eqns. (4) and (5) shows that they cannot be expected to predict the variations of R and DP with temperature right up to T, because when k approaches k,[M,] becomes small and con- sumption of monomer in the initiation process is no longer negligible and k and kd may show a dependence on j. Nevertheless the limiting slope of dR,/dT as T approaches T may be numerically so large that such effects are of very minor importance and operate only over the last fraction of a degree below T,.A simple expression for the limiting slope is obtained by differentiating eqn. (4) with respect to temperature dR,/dT = [M*](kp[Ml]E,/RT2 - k,E,/RT2) -1 (kl)[JM1] - k d ) . d[M'k]/dT and substituting k,[M,] = E when T = T lim (dR,/dT) = k,[M,][M,*](E - Ed)/RTC2 T+T = k,[Ml][M*]AH,/RTC2 (6) k,~M,][&I*] is the rate which would have been observed at; T in the absence of depropagation. The curves in Fig. 2 have been drawn as though the effects of short-chain polymer formation were completely absent. Experimental curves may be expected to show some signs of turning to approach the temperature axis asymptotically in the temperature region where DP is less than 100.Provided such " tailing " is slight T as defined a t the beginning of the previous paragraph can be found by a short extrapolation of the approxi- mately linear portions of the rate or DP curves above the " tail ". In all cases the formation of very short-chain polymer is to be expected a t and above T because of the variation of AG with n when 72 is small. Again we have a physical analogy in the effect of crystal size on melting point ; l2 this effect is only detectable when the surface free energy contributes appreciably to the molar free energy of the solid i.e. for extremely small crystals. The predicted variation of T with [M,] can be found by equating k,[Ml] to k and inserting the Arrhenius expressions whence ( 7 ) An alternative approach to the problem is based on the recognition of T as the temperature a t which the free energy of polymerisation (for long- chain polymers) passes from a negative to a positive value as the temperature is raised (8) where AH and AS are the heat and entropy changes under the prevailing experimental conditions.Equation (8) emphasises the independence of T on Ri provided always that the polymer formed lias the same structure Tc = AH,/R In (Ap[M11/4 .'. T = A H,/aXP 12 See Partington " An Advanced Treatise on Physical Chemistry " Longmans London 1952 Vol. 111 pp. 246 466. DAINTON AND IVIN THERMODYNAMICS OF ADDITION POLYMERISATION 67 and hence the same thermodynamic properties. (S) we may write As = R In (APIAd) + R ln [M,] = ASI,' + R In [M,] where ASPo is the entropy change for [&I1] = 1 mole litre-1 Comparing eqns.( 7 ) and .'. T = AH,/(AS,O + R In [M,]) It would be better to choose unit activity instead of unit concentration for the standard state since ABPo may vary from one solvent to another because of variations in the activity coefficient of the monomer ; but lack of the necessary data usually renders this procedure impracticable. Instead of saying that a monomer a t concentration [MI] has a ceiling temperature T it will frequently be convenient to reverse the viewpoint and say that a t temperature T the monomer concentration in equilibrium with long-chain polymer is [MJ, where T = T and [MJe = [M1] = exp (AGpo/RT). Thermodynamic Defhitions and the Effect of Chain Length.-The thermo- dynamic quantities defined by eqn. (1) will depend on the states of the monomer and polymer and it is convenient to indicate these by means of the following subscripts Subscript x Monomer State Polymer State gg Gas Gas (usually hypothetical) gc Gas Condensed (liquid or amorphous solid) ls Liquid Solution in monomer ss Solution Solution sc Solution Condensed (liquid or amorphous solid) lc Liquid 9 9 9 9 $ 9 9 These are the symbols suggested earlier by us l3 (the m has been dropped from Ism).When the polymer is partially or wholly crystalline this may be denoted by appending a prime to the c of the above subscripts thus gc'. A superscript circle will be appended when the standard state is specified in terms of pressure or concentration e.g. ALY,," (standard state 1 mole 1.-l of monomer). This superscript is not necessary when the sub- script is lc and the 1 refers to the pure monomer which is taken as the standard state but must be retained when 1 refers to a mixture of two monomers when the standard state may be taken as unit concentration of each monomer.We have shown how the various quantities can be related to each other a t least in prin~ip1e.l~ Bywater l4 and Small l5 have also derived additional relations which allow correction for non-ideal polymer solution behaviour. The formation of a polymer molecule represented by M (see p. 61) may involve an initiation (or transfer) step n or n - 1 propagation steps depending on the nature of the initiation step and a termination (or transfer) step. When n is large enough the contributions to Axx from the steps other than propagation will be negligible and experimental values of Axx may be equated to that of the propagation step Axp.13Dainton and Ivh Trans. Paraday SOC. 1950 48 331. 1 4 Bywater ibid. 1955 51 1267. Small ibid. 1953 49 441. 68 QUARTERLY REVIEWS In two cases where the polymer can be represented exactly by (MJn the actual variations are known for ethylene l6 AHg,,' (kcsl. mole-l) = -22.348 + 19*592/n for n 3 a t 25" ; for cc-methylstyrene 1 7 AH, (kcal. mole-1) = 8-424 - 18-58/n for n = 11 to 46 a t 25" ; and for n > 120 the second terms in the equations are less than 2yo of the first terms. There are two factors determining the magnitude and sign of the second term (i) there are only n-1 additions required to form a polymer whose formula is ; this makes a positive coiitribution ; (ii) thc heat change may be abnormal for the first few additions of monomer ; this will be particularly marked in polymers whose main skeleton is under strain and will make a negative contribution as in cc-methylstyrene where (ii) evidently outweighs (i) Veriflcation and extensions of the theory General Conhnation.-For the common monomcrs such as styrene at concentrations of 0.1 - OM the values of AHx and ASx are such that T lies far beyond the range of the water thermostat and sometimes at tempera- tures where side reactions interfere.For these reasons few examples of ceiling temperatures and related phenomena are to be found in the literature hefore 1938. Indications of such effects occur in the observations that (1) gaseous formaldehyde at 300 mm. will not yolymerise at 100" in the presence of formic acid (Norrish and C,zrrutliers,18 1036) ; (2) isobutene and ol-methyl- styrene only yield high polymers when polymerised below room tempera- ture ; (3) the kinetics of polymerisation of rnethyl methacrylate show deviations from the Arrhenius law above 125" (Schulz [ y .n ' 0 ] and Blaschke,19 1942) ; (4) trimethylene disulphide is -c-c-s- stable in 0.05~1 solution but polymerises a t higher concentrations (Whitney and Calvin,20 1955) ; (5) the formation of allreiie polysulphones of general formula (I) from liquid mixtures of the alkene with sulphur dioxide only occurs below a certain temperature (Snow and Frey,21 1938). Snow and Frey were the first to notice the existence of a sharp temperature above which polymerisation would not occur and coined thc term '' ceiling temperature ". They later 22 obtained rate-temperature curves of the type shown in Pig.2 ( b ) and showed that T was independent of the catalyst (nitrates peroxides or ultraviolet light) used to initiate the reaction but were unable to offer a satisfactory explanation for their results. While all the observations listed above are consistent with the theory previously outlined a quantitative test of eqn. (9) is required to put i t on (1) l0 Jessup J . Chem. Phys. 1948 16 661. 1'Roberts and Jessup J . Res. Nat. Bur. Stand. 1951 46 11. l9 Schulz and Blaschke 2. phys. Chenr. 1942 51 B 75. ?O Whitney and Calvin J . Chcm. PIL~s. 1955 23 1750. Snow arid Frey I n d . Eng. Chem. 1938 30 176. 2 2 Idem J . Amer. Chem. SOC. 1943 65 2417. Norrish and Carruthers Trans. Faraday Soc. 1936 32 195. DATNTON AND IVIN THERMODYNAMICS OF ADDITION POLYMERISATION 69 a sound footing.This was first done by Dainton and Ivin lo who made a detailed investigation of the formation of but- 1 -em polysulphone and showed that contrary to Snow and Frey's earlier conclusions T did vary with composition in the rnanner required by eqn. (10) T = AHx,'(A&o + R In [MI 4- R In [S]) . . (10) This is eqn. (9) modified to allow for the fact that the overall repetitive process is represented by (MS)j* + M -t S -+ + (JlS).j+l" where M denotes the alkene and S the sulphur dioxide. A H and AsXo of In [M][S] against with rather greater can be obtained from the slope and intercept of a plot I/Tc. Calorimetric values of AH can be determined 20 30 40 50 60 Temperature ("c) F I G . 3 Rate of formcrtion of but- 1 -ene polysulphone f r o m monomer mixture containing 9.1 moles ?& of but-l-ene.A and R photochemical initiation a t two different intensities ; G and H initiation by silver nitrate a t two different concentrations ; J initiation by bonzoyl peroxide. [ Keproduced with permission from Dninton and Ivin Discuss. Paradrry Soc. 1953 14 199.1 precision and always come within the limits of error of those obtained by the application of eyn. (10) (see Table 1). Fig. 3 shows the rate-temperature curves obtained with a mixture containing 9.1 moles yo of but-l-ene (cf. Fig. 2) and demonstrates the independence of T of the niethod and rate of initia- tion.23 Fig. 4 shows that the same T, again independent of initiation conditions is obtttiiieti when the specific viscosity of the polymer (a measure 23 Daiiitoii and Ivin Discuss.Favaday Soc. 1953 14 199. 70 QUARTERLY REVIEWS TABLE I. Heats of formation of alkene pol.2/sulphones from monomers 1s 1s 1s ss (in CHCI, le lc 1s 1s Alkene a a a a b N a a Rut- 1 -eno cis-But -2-one trans-But-2-ene Hexadec- I - m e isoButene Propeiie Hex- 1 -ene cycZoPentene - AHx (kcal. base-mole-’)(l base-mole = M + S ) ~~ ~ From eqn. (10) 20.7 f 1.4 20.8 :k 0.7 19-3 f 0.5 19.2 f 1.2 20.0 -& 0.5 ~- ~ Calorimetric 21-2 3 0.1 20.15 & 0.1 19.9 & 0.1 20.2 f 0.1 18.7 & 0.1 20.7 -& 0.1 21.65 & 0.1 ~ I a Dainton Diaper ‘Ivin and Xheard Trans. Paraday SOC. 1957 53 1269 ; Cook Dainton and Ivin unpublished results. of m) formed a t a given percentage conversion is plotted against its temperature of preparation 10 [cf. eqn. (5)]. The striking nature of the ceiling-temperature effect is illustrated in 0 100 0.075 G * l- I 9 0.050 & 0.025 0 0 20 40 60 Tc Temperature o f preparation (“c 1 FIG.4 tempemture of pepwation with conditions as in Fig. 3. SpeciJic viscosily of but- 1 -ene polysulphone in acetone (c = 8 9. I. -1) plotted against IRcnrndnord. with nrrmfssinn frnm naintnn 2nd Tvin Pmr Rnii Sor 1052 A 919 2117 1 DATNTON AND IVIN THERMODYNAMICS OF ADDITION POLYMERISATION 'i 1 Fig. 5 which shows for a number of alkene-sulphur dioxide mixtures the rate of photochemical polymerisation determined in the same reaction tube nt successively lower t e i n p e r a t u r e ~ . ~ ~ Only in one or two cases are there FIG. 6 Contrccction rate plotted against temperature for the photochemical forniation of alkene polysulplzones.L Pent-2-ene ; M cyclohexene ; N trans-but-2-ene ; 0 equimoleculnr mixture of cis- and trans-but-2-ene ; P cis-but-2-cne ; Q pent-l-ene ; R hexadec-l-ene ; S propene ; T cyclopentene. [Reproduced with permission from Cook Dainton and Ivin .I. Polymer Sci. 1957 26 351 where full details can be found.] signs of " tailing " as T is approached. The magnitude of the viscosities in Fig. 4 indicates that DP > 100 a t least to within a few degrees of T for but-1 -ene polysulphone. The highest limiting slope is observed with cis-but-2-ene polysulphone formation the rate falls from about 0.4y0 per minute to zero in the 1 degree below T when reaction is induced by the unfiltered light from a 250-w compact-source mercury lamp. It is worth noting that in principle A H can be obtained from the limiting slope [see eqn.(G)] since kI,[M1][M*] at Tc can be found by extrapolation [point A in Fig. 2 ( e ) ] . It is interesting that a ceiling-temperature effect is also found in the reaction between sulphur dioxide and polyisoprene z5 which can be written [ =CHCH,*CH,*CMe-] +- SO + [-CH~CH,*C€€,-CMe -1 Depropagation a,lso plays a part in the reaction of sulphur dioxide with styrene but here the effect is somewhat different since styrene itself is readily polyinerised. 26 Monomer-Polymer Equilibria.-We have already drawn atkntion to the r-SO2-l 2 4 Cooli DtLinton and Ivin J . Polyvter Sci. 1057 26 351. 25 Van Amerongen ihid. 1951 6 633. 26 Barb ibid. 1953 10 4 0 ; Walling ibid. 1955 16 315. 72 QUARTERLY REVIEWS analogy which exists between physical aggregation and chemical aggregation processes.But whereas physical equilibria are mobile and rapidly established met'astable states being achieved only by cautious experimentation polymer- isation equilibria are generally immobile and metastability of both monomer and polymer is very common. The practical utility of this fact is obvious. To establish a reasonably mobile equilibrium between monomer and polymer it is necessary that a certain concentration of active centres be continually present. For systems in which there is no termination process every polymer molecule is an active centre whether molecular free-radical or ionic in nature and it is in these systems that equilibrium can be established rapidly and reversibly e.g. for or-methylstyrene catalysed 27 by sodium naphthalene in tetrahydrofuran (anionic centres) and also for gaseous formaldehyde in equilibrium with polyoxymethylene (unknown but presumably molecular centres) though no reliable equilibrium pressures are available.28 Further- more in such systems only long-chain polymer is present a t equilibrium and there is no danger of side reactions.I n the more usual case of systems where there is as loss of active centres in termination processes it is necessary 0. TO 1 - 0.08 R 2 4 6 8 70 12 Time ( h . 1 Ll I I ' 1 ' " 1 1 OO FIG. 6 Change of methyl methacrylate concentration with time ut 132.2" c. photoseiasitised by the solvent o -dichlorobenzene. [Reproduced with permission froin Bywater Trans. Paraday SOC. 1955 51 1267.1 if equilibrium is to be approached to balance this loss by continually supplying fresh active centres through a reaction of either monomer or polymer.Even then the approach to equilibrium is rather slow (for example see Pig. 6 for Bywater's results l4 on methyl methacrylate in o-dichlorobenzene solution with use of photochemical generation of centres) and in order to find the value of [MI] a t equilibrium it is politic to use extra- 2 7 McCormick J . Polymer Sci. 1957 25 488; Bywater and Worsfold ibid. 1957 26 299. 28 ( a ) Nielseii and Ebers J . Chem. Phys. 1937 5 824 ; ( b ) Nordgren Acta Path. Microbiol. Scand. (Stippl.) 1939 40 21. DATNTON AND IVIN THERMODYNAMICS OF ADDITION POLYMERISATION 73 0.2 r FIG. 7 Rate of fall of presswe (- d p / d t ) on irradiation of a mixture of gaseous methyl meth- acrylate with its solid polymer at A 107.0" ; B 118.0" ; C 128.3" ; D 138.5".The jleld above the pressure axis corresponds to polymarisation that below to depolymerisation. [Reproduced with permission from Ivin Trans. Faraday Soc. 1955 51 1273.3 polation or interpolation procedures [for example see Fig. 7 for Ivin's results 29 on the photochemically-induced equilibrium between gaseous methyl methacrylate a.nd its polymer from which it can be seen that for 34 2.1 n b F $2.1 7. ! 7.l 2-3 2.4 2-5 2 -6 2-7 FIG. 8 Equilibrium pressure of methyl methacrylate ( pe) as a function of temperature. [Reproduced with permission from Ivin Truns. Faruduy Soc. 1955 51 1273. ] zBIvin Trans. Faraduy SOC. 1955 51 1273. 74 QUARTERLY REVIEWS each temperature increase in applied pressure of monomer causes a tmnsition from net depolymerisation (dp/dt positive) t o net polymerisation (dpldt negative)].Extrapolation procedures are to be preferred because of the danger of side reactions and low polymer formation when the system is close to equilibrium. Fig. 8 shows the equilibrium pressures of met,hyl methacrylate over its polymer a t different temperatures plotted in the form of a Clapeyron-Clausius equation and emphasising the analogy with the vapour pressure of a liquid. 29 I n Table 2 are summarised the heat data obtained by the application of eqn. (9) and again there is good agreement with the calorimetric heats. Small discrepancies are readily accountable as (i) variations of AH with TABLE 2. Heats of polperisation from equilibrium monomer concentrations Monomer Methyl methacrylate Ethyl methacryla.te Me thacrylonitrile a-Methylstyrene 6-Hexanolactam 6-Hexanolactam Formaldehyde Formaldehyde Tetramethylem formal - AHx (ltcal.mole-') 13.4 0.5 (100-155") 12.9 14.4 f 0.6 (lOi'-138") 15.3 5 1 (110-144") 8.15 ( - 40" t o 0") 3.56 (220-280") 5-0 (7)" (65-120") (14)* (10-58") -3.5 (100-140") ss ( ? ) Calorimetric 13-9 f 0.3 14-1 (25") 8-42 3-8 (75") 3.25 (2 10- ~ 77") 230") 13 & 1 (20") 7.5 1 4.7 * Not reliable. X ~ lc Ic lc lc gc gc 1C 1C ss SS Ref. 3qn. (9 a b d f 9 i k m a 0 33 Cal. C e 7L j 1 n n Q a Bywater Trans. Faraday SOC. 1955 51 1267 ; b Ivin ibid. p. 1273 ; c Ekegren Ohm Granath and Kinell Acta Chem. Scand. 1950 4 126 ; d Cook and Ivin I'rans. Faraday SOC. 1957 53 1132 ; e Iwai J . SOC. Chem. Ind. Japan 1946 49 185 ; 1 By- water Canad. J. Chem. 1957 35 552 ; Bywater and Worsfold J. Polymer Scz. 1957 26 299; h Roberts and Jessup J .Res. Nut. Bur. Stand. 1961 46 11 ; i Meggy J. 1953 796 ; j Skuratov Strepikheev and Kanarsknya Kolloid. Zhur. 1952 14 185 ; k Hermans et al. Rec. Trav. chirn. 1955 74 1376 ; 1 Strepikheev et aE. Doklady Akad. Nauk S.S.f.R. 1966 102 105 ; m Nielsen and Ebers J . Chem. Phys. 1937 5 824 ; n Walker Formaldehyde " Reinhold New York 1953 ; 0 Nordgren Acta Patlz. Microbiol. Scand. (Suppl.) 1939 40 21 ; 9 Calc. from data given by Strepik- heev and Volokhina Doklady Akad. Nauk S.S.S.R. 1954 99 407 ; Q Strepikheev and Volokhina unpublished results reported at the Symposium on Macromolecular Chemistry Prague Sept. 1957. temperature (AC is commonly of the order -0.01 kcal. mole-1 deg.-l for polymerisation) and (ii) slight inaccuracy of eqn. (9) through use of concen- trations instead of activities (mriation of activity coefficients with tempera- ture will cause a systematic error in A H ) .Equilibrium concentrations of various monomers at 25" can be obtained by either interpolation or extrapolation of experimental values or when these are not available rough estimates can sometimes be made from kinetic data by assuming that A = 1013 sec.-l (see Table 3). Measure- DAINTON AND IVIN THERMODYNAMICS OF ADDITION POLYMERISATION 75 ments on the kinetics of degradation of poly(methy1 methacrylate) 30 have shown that A is of this order although of course the conditions are rather different (high temperature high viscosity) from those used to determine k,. TABLE 3. Equilibrium monomer concentrations at 25 O Monomcr Vinyl acetate Methyl acrylate Styreno Methyl methacryla!,e Methyl methacrylat,~ Methacrylonitrile a-Methylstyrene Trimethylene disulphide cycZoPenteno + SO But-l-ene + SO isoButene + SO 1 0 - 9 10-9 10-3 1.6 x 10-4 10-6 1.0 x 1 0 - 3 2.6 > 0.05 0.015 0.5 310 (AC,,' = RI' In 1hf,],) Method Est.imat,od from known values of k, E, AHp and an assumed Ad =1 1013 see.-'; -AHI values (Itcal.mole-') on right - 100-1 50" equilibrium data a t Extrapolated from Reported t o be stable in 0 . 0 5 ~ solution SO in excess ; obtained by extra- Value for isobutene unattainable polation from known values experimentally a Tong and Kenyon J . Amer. Chem. SOC. 1947,69 2245 ; Burnett " Mechanisms of Polymer Rea.ctions " Interscience New York 1954 ; c Roberts Walton and Jessup J . Polymer Sci. 1947 2 420 ; d Ebegren Ohm Granath and Kinell Acta Chem.Scand. 1850 4 126 ; c Bywater Trans. Faraday SOC. 1955 51 1267 ; f idem Canad. J . Chem. 1957 35 552; Bywater and Worsfold J . Polymer Sci. 1957 26 299; h Whitney and Calvin J . Chem. Phys. 1955 23 1750 ; i Cook Dainton and Ivin J . Polymer Sci. 1957 26 351 ; ridem unpublished results. Entropies of Polymerisation from Equations (9) and (lo).-Entropy changes as well as heat changes can be derived by the application of eqns. (9) and (10) and it would be interesting to know how these compare with those obtained from specific-heat measurements on the monomer and polymer by the application of the third law of thermodynamics. Unfortunately a t present there are no cases where both sets of measurements have been made although there are five systems in which specific-heat data are available.A minor difficulty arises in the application of the third law to polymers namely that polymers seldom approach perfect crystallinity a t the absolute zero and the degree of crystallinity may vary with the previous history of the specimen. Nevertheless the entropy differences between polymers subjected to various treatments such as quenching annealing and moulding are relatively small and the residual entropies a t the absolute zero will probably seldom exceed 1 cal. deg.-* inole-l (e.q. the value found for 30 Cowley and Melville Proc. Roy. SOC. 1949 A 199 1 14 24 39. 76 QUARTERLY REVIEWS TABLE 4. Experimental epztropies of polymerisation in cal. deg. - l bnse-mole-1 BIonoiiier From eqn. (10) Propene 4- SO But-l-ene + SO Hex-l-ene + SO Hexadec- l-ene + SO cis-But-2-ene + SO trans-But-2-ene + SO isoButene -$- SO cycZoPentene f SO From eqn.(9) Methyl methacrylate Ethyl methacrylate Met hacrylonitrile a-Meth y lstyreno 6 - Hexanolactain - ASx' 62.2 69.5 69- 1 66.3 69.7 66.7 78-5 64-2 28.0 & 1.5 29.5 29.7 f 1.5 34 & 2 26.3 2-85 X Ic 1s 1s 1s 1s lc 1s ss Ic lc lc lc ss ss Ref. a a a a a b a U c d f C C B h Kotes 1 base-mole = M + S For all except isobutene the calorimetric AHx has been eom- bined with the T values t o obtain ASXo by assuming both A H x and AS," to be independent of temperature. Standard state throughout 1 mole 1. for both M and S For temperature ranges see Table 2 Standard state 1 mole 1.-' Standard state 1 mole I.-' Doubtful value see Hermans et aZ. Rec. Trav. chim. 1955 74 1376 I Entropy (cal. deg.-lrnole-') Temp.(" C) I Monomer 1 Polymer From specific-heat measurements S tyrene isoButene Buta-1 3-diene Isoprene Tetrafluoroethylene 21.57 24.93 27.65 25.5 21.2 24-2 26.76 47.13 Ic lc lc lc lc lc lc' gc' - 23.16" 25.00 126-84 25.00 25.00 25.00 - 75.7 - 75.7 Other values I I l l Sulphur (S,) Ethylene Vinyl acetate Styrene Methyl methacrylate - 7.4 37.0 41.1 26 28 24-29 1s r S S S 49.75 57.16 70.84 51.7 47.6 54.8 44.00 64.37 28.18 32-23 43.1 9 22-9 26.4 30.6 17-24 17-24 159" ; from viscosity-temperature relation Entropy of polymer by extra- polation ofhomologous series; 25" From A values by taking Ad = 1013 see.-' at 25" ; stan- dard state 1 mole 1.-l a Cook Dainton and Ivin J. Polymer Sci. 1957 26 351 ; a idem unpublished results ; c Bywater Trans. Faraday Soc. 1955 51 1267 ; d Ivin ibid.p. 1273 ; C Cook and Ivin ibid. 1957 53 1132 ; f Bywater Canad. J. Chem. 1957 35 552 ; 0 Bywater and Worsfold J. Polymer Sci. 1957 26 299 ; h Meggy J. 1953 796 ; Boundy and Boyer " Styrene " Reinhold New York 1952 p. 67 ; j Dainton Devlin and Small Trans. Furaday SOC. 1955 51 1710; k Furukawa and Reilly J . Res. N a t . Bur. Stand. 1956 56 285 ; 1 Scott Meyers Rands Brickwedde and Bekkedahl ibid. 1945,35 39 ; 119 Furukawa and McCoskey ibid. 1953,51,321 ; fl Bekkedahl and Wood ibid. 1937 19 551 ; 0 Bekkedahl and Matheson ibid. 1935 15 503 ; * Furukawa McCoskey and Reilly ibid. 1953 51 69 ; Q Furukawa McCoskey and King ibid. 1952 49 273; r Fairbrother Gee a.nd Merrall J. Polymer Sci. 1955 16 45'5; 8 Burnett. '' Mechanism of Polymer Reactions " Interscience New York 1951. DAINTON AND IVIN THERMODYNAMICS OF ADDITION POLYMERISATION 77 TABLE 5 .Semi-empirim1 heats and entropies of polymerisation at 25" Heats and free energies in Itcal. entropies in cal. deg.-l mole-1 gg Values Ethylene Propene But- l-ene isoButene cin-But-2-ene t ~ m s - But - 2 -eno 2-Methylbut- l-ene &-Pent -2-ene 1 mns- Pent - 2-en0 2 3-l>imethylbut- 1-en( Hept- 1 -ene Styrene Butn-1 3-diem (1 2 polymn.) Buta-1 3-dienc (1 4 polymn.) Isoprene Ethylene CH :CHX( unconjug.) CH :CXY (unconjug.) Styrene 32.35 80.7 (20.91 18-4 (19.2) 18.1 (18.4) (18.7) (19.2) (18.1) ( 1 8-41 20.7 (20.5) 19.1 (194] 30.6 (20.51 (1 /-a; (l!) (18.7; ( I 6.9 23.1 22.9 25.0 17.8 lc Values alkenes Propene But- l-en? isol3u tene c i s - 13 u t - 2 -ene trccizs - B u t - 2 - ene Hex- 1 -en0 20.1 20.0 17.1 17.9 17-0 19.8 lc Values cycZoa.lkixne! [CH,] ; x = 3 -1 5 6 7 8 x = 3 4 C)H,*CH([CH,],-1 ; 27.0 25.1 5.2 - 0 - 7 5.1 8.3 25.1 23.9 4.1 - 2.2 23.3 22.3 3.2 - 1.8 34.0 39.9 39.8 41.0 39.1 38.0 40.1 34.4 39.8 40.7 35.6 Jossup a Dainton Diaper Ivin i ~ n d 8henrd.b Roberts's valuesf' given in paren- theses.Differenco in values for isobutene due to use by Dainton et u1.O of more recent value for its heat of form a t ion ' Dainton and Ivin,d by Anderson Beyer and Watson's generizlised I group method 26.95 (26-4 26.9 26-65 (27.3 24.85 23.95 26-85 12.1 12.0 9-2 10.5 9.9 11.8 16.5 13.2 10.2 2.5 0.7 - 8.9 20.2 17.2 15.3 7.6 22.3 18.0 15.7 8.5 22.1 21.2 2.2 - 1-4 4.9 11.0 19.1 18.8 - 0-5 - 4.5 16.6 16. 1 - 1-5 - 4.3 Dainton Diaper Ivin and Sheard.b Values in parentheses obtained by Dainton Devlin and Smalle with slightly different assumptions I in the coinnutation Dainton Dcvlin and Smal1.e Note correc- tions as below Sign of A S corrected A H and AG values cor- * rected for error.3 in ccjmputa tion a Jessup J .Chein. Phys. 1948 16 661 ; Dainton Diaper Ivin and SheiLrd Trans. Fai*aday SOC. 1957 53 1269 ; c Roberts J . Res. Eat. Bur. Stan . 1950 44 221 ; d Dainton and Ivin Trans. Faruday SOC. 1950 46 331 ; c Dainton Devlin m c l Small ibid. 1955 51 1710. 78 QUARTERLY REVIEWS amorphous rubber 31 is 0.28 cal. deg.-l mole-1). All available experimental entropies of polymerisation are listed in Table 4. The values for styrene give some idea of the extent to which AS," depends on temperature. The Semi-empirical Calculation of AH and AS,.-When experimental values of AH and AS are not available it is sometimes possible to make fairly reliable estimates by means of a semi-empirical group method such as that of Andersen Beyer and Watson.Such methods were reviewed recently by Janz 32 and depend upon the experimental fact that thermodynamic properties are approximately additive introduction of a given group into different compounds having the same effect so long as the substitution is made a t a structurally similar point. In a molecule such as polyisobutene the methods make no allowance for interaction between substituents on alternate carbon atoms. Any considerable difference between calculated and observed values may therefore be attributed to incomplete allowance for steric strain. Semi-empirical methods of this nature were first applied to the calculation of AHgg' for various alkenes by F1ory.l" Roberts 33 revised these values on the basis of improved thermochemical data and Dainton and Ivin l 3 extended the calculations to include both AHgg' and ASgg' for vinyl and vinylidene monomers over a range of temperature.While AHg,' and ASgg' are useful for indicating the magnitudes of structural and temperature effects AH, and AS, are more practical quantities ; but lack of information about the heat and entropy of vaporisation of the polymer is the usual obstacle to the calculation of AH, and AS,,. With hydrocarbons this information can be derived by extrapolation of data on homologous series and Dainton Devlin and Small 34 have estimated AH1 and AS, for the polymerisation of various substituted and unsubstituted cycloalkanes.The method can also be applied to the polymerisation of alkenes. I n Table 5 are summarised the more recent values derived by these methods. Structural Effects on Po1ymerisability.-Structural effects on polymerisa- bility in the thermodynamic sense can be studied by comparing either (i) free energies of polymerisation a t a given temperature or (ii) temperatures at which the free energy of polymerisation is zero i.e. ceiling temperatures. In either case a standard concentrat,ion condition must be specified e.g. the pure state 1 mole 1.-l or some other convenient concentration. -AH, values vary over a much wider range than -AS, values. Thus observed heats in kcal. mole-l range from about 8-4 (or-methylstyrene l7) to 21.3 (vinyl acet<ate 35) or 39 if the rather unreliable value for tetrufluoroethylene 36 37 is included ; Polymerisation of ethylene derivatives.31 Bekkedahl and Matheson J. Res. Nat. Bur. Stand. 1935 15 503. 32 Jam Quart. Rev. 1955 9 229. 33 Roberts J. Res. Nat. Bur. Stand. 1950 44 221. 34 Dainton Devlin and Small Trans. Faraday SOC. 1955 51 1710. 35Tong and Kenyon J. Amer. Chem. SOC. 1947 69 2245. 36 DUUS Ind. Eng. Chem. 1955 47 1445 ; Kirkbride and Davidson Natuye 1954 174 79 ; von Wartenberg and Schiefer 2. anorg. Chem. 1955 218 326 ; Scott, Good and Waddington J. Amer. Chem. SOC. 1955 77 245. 37 Furukawa McCoskey and King J. Res. Nat. Bur. Stand. 1952 49 273. DAINTON AND IVIN TIIERMODYNAMICS OF ADDITION POLYMERISATION 79 calculated values also lie within these limits. On the other hand observed entropies range only from 25 to 30 cal.deg.-l mole-l. (These limits are extended to 24 to 34 if the calculated value for truns-but-2-ene and the ss value for methacrylonitrile are included.) Thus the entropy contribution to the free-energy change a t 25" will usually lie between 7.4 and 9.0 kcal. mole-l. The effect of structure on AG, is therefore mainly through the heat term. Variations in AH arise mainly through (1) steric strain in the polymer as a result of bond stretching bond-angle deformation or interaction between non-bonded atoms ; (2) differences in stabilisatioii energy in the monomer and polymer as a result of conjugation or hyperconjugation. The variation in the semi-empirical AH values for simple alkenes (Table 5) must be due to hyperconjugation effects since (1) is not allowed for in the calculations and conjugation is absent.The difference between the observed l3 and calculated values of -AHl for isobutene (12.6 and 17-1 kcal. mole-' respec- tively) is accountable as (1). Steric hindrance also causes low heats of polymerisation of other 1 1 -disubstituted ethylenes such as vinylidene dichloride 35 ( - A H = 14.4 kcal. mole-1) and the methacrylate esters 38 39 ( -ANlc = 12-3-13.9 kcal. mole-l). The heat of hydrogenation of methyl methacrylate is the same as that of isobutene 40 so that conjugation in the methacrylates contributes very little towards stabilisation of the monomer. Conjugation to the ethylenic bond makes an appreciable contribution to the stabilisation of such monomers as styrene and its ring-substituted deriva- tives 41 (-AH, = 16.0-16.5 kcal. mole-l).In a-methylstyrene (1) and (2) combine to give an exceptionally low heat of 8.4 kcal. mole-l. The abnormal thermochemical properties of fluorine compounds are well known 4 2 and have been attributed to the effect of the antibonding electrons on the fluorine atom. It is therefore not surprising that -AH1 for tetrafluoro- ethylene is exceptionally high (39 & 4 kcal. mole-l) but in view of the experimental difficulties associated with the thermochemistry of fluorine compounds and the poor agreement between different investigators 36 it would be premature to discuss this value further until the limits of error have been confirmed. Structural modification of a monomer CH,:CHX or CH,:CXY by the introduction of a substituent on the group X has very little effect on AH so long as the substitution is made on an atom not adjacent to the double bond e.g.the methacrylates and the ring-substituted styrenes. But if the substitution is a t an atom adjacent to the double bond it substantial effect may result ; thus methyl 2-tert.-butylacrylate gives only a saturated dimer 43 in the presence of sodium and liquid ammonia at -80" whereas methyl methacrylate polymerises readily. Presumably the ceiling temperature of t'he former substance is below -80". 38 Ekegren Ohm Granath and Kinell Acta Chem. Scund. 1950 4 126. 39 Tong and Kenyon J . Amer. Chem. Xoc. 1946 68 1355. 40 Wheland " The Theory of Resonance " Wiley New York 1947 p. 61. 41Tong and Kenyon J . Amer. Chem. SOC. 1947 69 1402. 4 2 Sharpe Quart. Rev. 1957 11 49. 43 Crawford J. 1953 2658. 80 QUARTERLY REVIEWS We may now consider the relative constancy of -Ah', values.The calculated values for alkenes a t 25" range from 23-95 to 26.95 cal. deg.-l mole-1 (Table 5) but only in the case of isobutene is it possible to compare calculated (26.65) with the experimental value (28.S cal. deg. -l mole-l). The experimental value is thus 7% larger than that calculated (cf. -AH, where the experimental value is 26% less than that calculated). Thus steric hindrance in the polymer which markedly affects AH,, has comparatively little effect on AS1,. For example -4SlC for methyl methacrylate a t 25" can be estimated as about 26 cal. deg.-1 mole-I (from the value a t 120') while the value for cc-methyl- styrene a t -20" (26) is only a little higher than that for styrene (22). If anything it appears that steric hindranee raises -ASlc slightly i.e.causes the polymer to have a reduced entropy. This is understandable since the loss of internal rotational entropy in the polymer as a result of steric hindrance is likely to outweigh the gain of internal vibrational entropy. It is worth noting that A&', - ASggo a t 25" is approximately constant (10.5-14 cal. deg.-l mole-l) whether observed or calculated values of AS, are used. This difference is equal to the standard entropy of vaporisa- tion of the monomer less the standard entropy of vaporisation per unit of liquid or amorphous polymer. An approximate value for the latter may therefore be derived from the known values of As, and 8," (monomer) and a calculated value of Thus for styrene 8," (monomer) = 25.7 whence &','(polymer unit) = 15-1 cal.deg.-l mole-'. This may be com- pared with Svo(C,H unit) = 3.1G cal. deg.-l mole-l which can be obtained 34 by extrapolation of data on the ndkanes. It is of interest to analyse ASg," in terms of the component entropy changes translational AS, external rotational A& vibrational AS, and internal rotational AS,, in order to try to understand why it is that entropy is an approximately additive property so leading to approximately constant values of ASg,'. St S, and 8 for the monomer can be calculated from standard formula? its molecular weight moments of inertia and vibrational frequencies being known. Sir is found by difference between (St + LYr + 8,) and the experimental (third-law) value for Sgo(monomer). For the polymer it is readily shown from the standard formuh that Sv + Sir > St + S regardless of the molecular shape so that Xt + Xr may be neglected.Xv + Sir is thus the standard entropy of the gaseous polymer which must be found semi-empirically. The numerical values 44 for ethylene isobutene and styrene are summarised in Table 6. These values show that on polymerisation the loss of external rotational entropy nearly balances the gain in vibrational and internal rotational entropy so that -ASgg' has a value quite close to the monomer's translational entropy and this is fairly insensitive to the molecular weight of the monomer. Polysulphone formtion. Polysulphones are formed by the 1 1 copolymer- This conclusion appears to be a general one. * 4 Herzberg " Infra-red and Rrtrnan Spectra " Van Nostrand New York 1915 ; '' Tables of Thermodynamic Data " Amer.Petroleum Inst. New York 19 ; Kil- patriclr and Pitzer J . Res. Nut. Bur. Stand. 1946 37 163 ; Pitzer Guttman and Westrum J . Amer. Chern. SOC. 1946 68 2209. DAINTON AND TVIN THERMODYNAMICS O F ADDITION POLYMERISATION 81 TABLE 6. Analysis of A&,,,' into the contributions from various motions Ethylene isoBu tene Styrene ill 28-02 56.10 104.14 isation of sulDhur Mononier .~ cal. deg.-* irinlc-l 15.9 0.G 0 23- 1 !t. I 27.9 10.1 4 . 7 l'olyincr unit 52.4 1 S.4 70.2 29-2 82.5 47.0 cal. deg.-* mole-' 34.0 4 1.0 355 dioxide with a wide variety of ethylene derivatives. J. Heat and entropy data have been obtained for eight systems (see Tables 1 and 4) but a rather wider range of compounds can be compared if we confine our attention to ceiling temperatures determined at or corrected to a standard monomer concentration product of [M][S] = 27 mole2 (binary systems mole fraction of alkene about 0.09).I n Table 7 are summarised the values obtained by Cook Dainton and I ~ i n ~ ~ who also found that the following compounds would not copolymerise with sulphur TABLE 7 . Ceiling temperatures for polysulphone formation at [M][S] = 27 mole2 Stmiglit-chiiili alk-l-cnps Alk-2-enes and cyclic nllrenes Ethylene" > 135' isol3utene* 4.5' tmns-But-2-ene 33"(38")7 But- l-ene 64 3-Methylbut- I -cne* 36 But-2-ene(50yo cis 34.5 Pent-l-ene 63 4 4-Dirrieth),lj)ent- 14 Pent-2-eno 8 Propene* 90 2-Methylpent- 1 -ene - 34 cis-But-2-ene 36 (.iG)t 1 -ene* (-50% czs) Hex- 1 -ene 60 Hept-2-eno - 39 Hexadec- 1 -eneQ G9 cycloPen tene 108.5 (-88% cis) cycloHcxene 24 'The values for 5 allyl compounds range frvm 76" (alcohol*) t o 45' (forniate* and acetate).* Polymer insoluble in reaction mixture. t I'alues in parentheses corrected for isomerisation effect (see p. 89). dioxide a t any temperature down to - 80" 2-ethylbut-l-ene S-ethylhex- l-ene 2 4 4-trimethylpent-l-ene7 2-methylbut-2-ene 2 3-dimethylbut-2- ene 4-methylpent-2-ene allyl chloride and allyl bromide. The general pattern of behaviour is similar to that observed in the simple polymerisation of ethylene derivatives. Progressive substitution at the double bond lowers the ceiling temperature Tc. Substitution remote from the double bond produces a smaller but still quite large effect in alk-l-enes so long as sub- stitution leads to a branched alkene and in alk-2-enes regardless of the point of substitution.The series cis-but-%ene cyclopentene cyclohexene is rather remarkable. The high T for cyclopentene results from an abnormally high 82 QUARTERLY REVIEWS heat of reaction though the reason for the abnormality is uncertain. It may result from a reduction in interactions between non-bonded atoms in the polymer for example between a-methylene groups and the oxygen atoms as a result of the presence of t8he five-membered ring. Such an effect should lea,d to a more flexible polymer molecule and possibly t o a lower entropy of polymerisation. -Ah',," for the cyclopentene reaction is in fact the lowest for the five systems giving soluble polysulphones (see Table 4). However the standard entropies in these systems must be interpreted with caution because of the use of concentrations instead of activities in defining the standard state a.nd also because minor variations paralleling those calcu- lated for the simple polymerisation of alkenes (see Table 5) are to be 2 3 4 5 6 7 8 X F I G .0 Semi-empiricul free energy of polymerisation of cyclodkanes as a function of the number of atoms in the ring x. n Unsubstituted ; b methyl substituted ; c 1 1-dimethyl substituted. expected. The high -AS,,' for formation of isobutene polysulphone may result from stiffness in the polymer chain. The semi-empirical AH, and AS, values for the polymerisation of cyclonlkanes (Table 5) show that AH, makes the main contribution to AG', for 3- and 4-membered rings but that for 5- 6- and 7-membered rings the heat and entropy contributions are both important. I n Fig.9 are plotted the semi-empirical AGl values at 25" as a function of ring size. Two points stand out first the thermo- dynamic impossibility of polymerising the cydohexanes methylcyclopentane or 1 1-dimethylcyclopentsne at 25" ; secondly -AG, for a 3- or a 4-membered ring is greater than that for the corresponding 2-membered Polymerisation of ring compounds. DAINTON AND IVIN THERMODYNAMICS O F ADDITION POLYMERISATION 83 ring (alkene) mainly as a result of the higher value of -AH,,. However thermodynamic feasibility is no guarantee of practical realisation and there is no known way of polymerising cyclopropane or cyclobutane to high polymers. The only simple alkyl derivative of the cycloalkanes which forms high polymers is 1 :' l-dirnethylcyclopropane,45 which does so in the presence of aluminium tribromide.Some polymer is also formed with the 1 2- dimethyl ethyl and 12-propyl derivatives of cyclopropane and with the methyl and ethyl derivatives of cyclobutane but the reaction is not so fast or clean. isoPropylcyclobutane gives no polymer a t all.45 Compounds of formula cyclopropy1.R where R = CN CO*CH, or C6H are quite immune to the attack of free radicals which would cause rapid polymerisation of the compounds vinyl-R in similar circum~tances.~6 It appears that the best chance of opening a 3-membered carbon ring is by attack of an ionic reagent. It may be seen from Fig. 9 that it is not yet possible to estimate the free-energy changes for rings containing more than 8 atoms. However for much larger rings the values must approach zero and it is probable that AG, passes through a flat minimum in the region of x =9 or 10.Beyond this point crowding within the ring which is responsible for the curves' crossing AG, = 0 for a second time becomes less marked. Small 47 has considered the effect of ring size on AG, for heterocyclic compounds. The general shape of the relation between AG1 and x is expected to be similar to that calculated for the cycloalkanes particularly if the hetero-atom does not differ too much from carbon in size and bond angles (for example in oxygen and nitrogen compounds but not in sulphur compounds). Apart from a few heats of polymerisation there are very few quantitative thermodynamic data for the polymerisation of cyclic compounds. There is however a considerable body of information as to their polymerisability or otherwise and this is summarised in Table 8 together with the available heat data.The variations of AH of' the cyclic ethers with ring size and with substitution follow the pattern predicted for the cycloalkanes [cf. also formaldehyde -AH, approximately 7 kcal. mole-l (Table 2)]. In general mechanisms exist for the polymerisation of hetero- cyclic compounds when they are thermodynamically possible ; a negative sign in Table 8 can therefore be taken as very probably indicating a positive free-energy change for the hypothetical polymerisation. Unsubstituted rings containing less than 5 or more than 6 atoms are invariably polymerisable (cycloalkanes excluded). The signs of the free-energy changes for 5- and 6-membered rings are sometimes the same as for the cycloalkanes e.g.the cyclic ethers formals and amides sometimes reversed e.g. the cyclic esters sometimes both positive e.g. the cyclic anhydrides and amines and some- times both negative e.g. the polymethylene disulphides. The order of AG values for the 5- to %membered ring formals 48 is the same as that calculated for the cycloalkanes (8 7 5 6). Substitution in a heterocyclic 45Pines Huntsman and Ipatieff J. Amer. Chem. SOC. 1953 75 2315. 46Hammond and Todd ibid. 1954 76 4081. 47 Small Trans. Paraday SOC. 1955 51 1717. 48 Strepikheev and Volokhina Doklady Akad. Nauk S.S.S.R. 1954 99 407. F* I Ring atonis Sign of AC, tlkanes a t Alkanes calc. fo',,-c Ethers and formals Amides (lactams) Esters (lactones Anhydride Amines Sulphides TABLE 8. Polymerisability (+ or -) of some cyclic compounds as found by experiment with -AH (kcal.mole-1) in pareritheses Unsubstituted - cycZoPropane (27.0 Ic) + Ethylene oxide (22.6 Ic' ") Do not exist -+ Ethyleneimine 4 Negative - cycloButane (-25.1 Ic) + Trimethylene oxide (19-3 ss c ; + Propionolactone + Trimethylene sulphide d 5 Xegative - cycZoPentane (5.2 lc) + Tetrahydro- + Dimethylene furan" (3.6 lcf formal (6-2 lc e ) f Pyrrolidone (1.1 lcf) - y-Butyrolactonc - Ethylene carbonate - Succinic anhydride - Pyrrolidine f Trimethylene disulphideg. h 6 Positive - cycloHexane (-0.7 Ic) - Tetrahydro- pymn - Dioxan - Trimethylene (- 1.3 lcf) formal (0.0 lc e ) - 8-Valerolactam (2.2 lcf) + S-Valerol,zctono + Ethylene oxalate etc.i - Glutaric anhydride - Piporidins -+- Tetramethylene disulphide 7 Negative - cycloHeptane + Tetramethylene formal (4.7 lc 8) ? Oxacycloheptane (5.1 Ic) + 6-Hexanolactam (3-8 lcf) -t 6-Rexanolactonc -+- Adipic anhydride + Pentamethylene disulphide h + 1-Oxa-4 5- dithiacyclo- heptane (1.9 lc j 8 and higher Ncgat ive - cycZoOctane (8.3 lc) + Pentamethylene formal (12.8 lc e ) + 1 3 6 9-Tetra- oxacydoundec- ane 111 ring] -t- 7-Heptanolac- tam (5.3 lc f) $- 13 15 16 17 j- 18 26 dimeric ring carbona,tes ring carbonates + 8-19 ring a,nh ydrides + 11 18 26 ring cyclic dimers + Sulphur [S,] above 159" ( - 3.18 IS") + [CH?,lnS ; n = 6 - 10h Substituted Alkanes Ethers dmides Esters and siloxanes Amines + 1 1-Dimethyl- cyclopropane propane + n-Propylcyclo- propane 1 + Propylene + Ethylcyclo- oxide m + N-Substituted ethylene - imines p + Methylcyclo- butane + Ethylcyclo- butane - isoPropylcycZo- butane 1 + 3 3-Dimethyl- l-oxacyclo- butane ( 1 6-1 ss") + 3 3-Di(chloro- methyl)-1-oxa- cyclobutane [(CH,),NR,]+Br- ; + R = Me Et(?) - R = Prn Bun p - 2-Methyl- 2-chloromethyl- and 3-methyl- tetrahydro - furans - 4-Methyl-1 3- dioxano ? u-n-Propyl-8- - Lactone of valerolactone f u-2-hydroxy- ethoxybutyric acid i - 2-Phenyl-1 3- dioxac y clo hep - tane 0 - N-Substituted 6-hesanolac tam + 8 ring octa- met hylcyclo- tetrasiloxane r * T seems to be just above room temperature.t Estimated from heat of combustion of monomer given by Skuratov Kozina Shtekhsr and Varushyenko Sci. Trans. M.G.U. 1953 164 73 ; see Thermochemicnl Bulletin No. 3 (Internat. Union Pure Appl. Chem.). King J. 1949 1318; CRose J. 1956 546; d Bost md Conn Ind Eng. Chem. 1933 25 526 ; e Strepikheev and Volokhina unpublished results reported a t Symposium on Macromolecular Chemistry Prague Sept.1957 ; f Strepikheev et al. Doklady Akad. Nauk S.S.S.R. 1955 102 105 ; g Whitney and Calvin J . Chem. Phys. 1955 23 1750 ; Carothers Dorough and Van Natta J . Amer. Chern. SOC. 1932,54,561 ; j Dainton Davies Manning and Zahir Trans. Faraday SOC. 1957 53 813 ; k Fairbrother Gee and Merrall J . Polymer Sci. 1955 16 459 ; 1 Pines Huntsman and Ipatieff J . Amer. Chem. SOC. 1953 75 2315 ; Price and Osgan ibid. 1956 78 4787 ; n Farthing J . 1956 3648 ; O Strepikheev and Volokhina Doklady Akad. Nauk S.S.S.R. 1954 99 407 ; p Barb J . 1955 2577 ; Q Gibbs and Marvel J . Amer. Chem. SOC.. 1935. 57. 1137 r Scott. ibid.. 1946. 68. 2294. Where no reference is given. see Small. Trans. Faraduu SOC.. 1955.51. 1717. See Roberts J . Res. Nut. Bur. Stand. 1950 44 221 ; Affleck and Dougherty J . Org. Chem. 1950,15,865 ; 86 QUARTERLY REVIEWS compound invariably decreases its polymerisa.bility again as predicted for the cycloalkanes. ' The variation of AG with temperature is given by (d AG/dT) = -AX. When AS is small it is quite possible that its sign may change as the tempera- ture is changed. The cases in which AG is positive a t room temperature are the very ones in which AH and Ah' are small and in any given case it is impossible to predict without precise knowledge of the variation of AH and AX with temperature whether AG will become negative on raising or lowering the temperature or whether it will fall only to a positive minimum 960 - 840 - 720 - n 2 600 - -2 s 3 480 - .L * \ ?i 3 360 - 240 - 120 - I I I 750 200 250 300 FIG.10 Viscosity of liquid sulphur u,s a function of tentperntrrre. [Reproduced with perniission from Bacoii and It'anelli J. h w r . ('hem. Soc. 1943 G ( i U ! . ] Temperature ( O C 1 and then rise again. Because of the different possibilities it is desirable to vary the temperature over it wide range when testing a 5- to 8-membered ring compound for polymerisability. At present there appears to be only one case of a substance for which the free energy of polymerisation passes from a positive to a negative value as the temperature is raised and for which a polymerisation mechanism is available. This is the well-known case of sulphur where the change in sign occurs a t 159". The onset of polymerisation of S above this temperature accounts for the dramatic increase in viscosity 49 shown in Fig.10 the quantitative interpretation of 49 Bacon and Fanelli J . Amer. Chem. SOC. 1943 65 639. DAINTON AND WIN THERMODYNAMICS OF ADDITION POLYMERISATION 87 which by Fairbrother Gee and Merrall 50 has led to AH, = 3.18,kcal. mole-' and At?, = 7-4 cal. deg.-l mole-l for the addition of an S molecule t o the linear polymer. Above 159 O equilibrium is rapidly established between monomer (S,) and polymer (S8,J and it has been demonstrated by the measure- ment of paramagnetic resonance absorption that the polymer is free-radical in nature and not macr~cyclic.~~ It is well known that the equilibrium can be quenched giving " plastic " sulphur though this reverts to crystalline monomer fairly rapidly a t room temperature. By analogy with the com- moner ceiling-temperature phenomenon sulphur may be said to exhibit a " floor temperature " as a result of the positive heat and entropy of polymerisation.Many of the 5 6- and 7-membered ring compounds listed in Table 8 are readily interconvertible with polymer but to our knowledge only in the case of 6-hexanolactam have the equilibrium concentrations of monomer been derived. Several difficulties may arise in the determination of equili- brium concentrations or ceiling temperatures for these systems (1) the mobility of the equilibrium may make it difficult to quench; (2) the very influences which make AG small also make very small the changes in physical properties such as density and spectra which accompany polymerisation ; (3) the rate-temperature curves will be apt to have a low limiting slope because of the low heat change.However there is no reason why special methods should not be developed to deal with these cases and a rich harvest of results awaits the pat'ient investigator. Geometrical Isomerisation as Evidence of Depropagation Stereoisomeric Polymers.-For many polymerisations the average time interval betweeii successive propagation steps is about During this time the active centre will undergo many internal rotations about the skeletal bonds particularly about the terminal bond. Also if we are dealing with the polymerisation of an ethylenic compound the atoms attached to the terminal active carbon atom are likely to be coplanar with it or if not to be so nearly coplanar as to undergo many inversions during see. Hence we can expect that if cis- and trans-isomers can be polymerised separately or copolynierised with a third monomer t o yield 1 1 copolymers then (1) t,he polymers will be indistinguishable ; (2) if depropagation occurs there will be geometrical isornerisation with a t least one of the monomers and mually with both ; (3) if polymerisation is attempted above the ceiling temperature only isomerisation will result and the same equilibrium mixture will be reached whichever isomer is taken initially.The relevant propaga- tion and depropagation reactions may be represented thus see. H U R H H H These three expectations are borne out in the case of the forma.tion of 50 Fairbrother Gee and Merrall J. Polymer Sci. 1955 16 459. 5 1 Gardner and Fraenkel J. Amer. Ghem. SOC. 1956 78 3279. 88 QUARTERLY REVIEWS but-2-ene polysulphone from sulphur dioxide and cis- and rans-but-2-ene respectively.52 53 The difference in heat content of the two isomers in liquid sulphur dioxide derived from equilibrium measurements [ (3) above] is 1.4 kcal.mole-l which is slightly different from that of the pure gaseous isomers (1.04 kcal. mole-I) and when combined with the two heats of copolymerisation (Table 1) leads to the conclusion that the two polysulphones have heat contents which are identical within experimental error. The polymers also have identical infrared spectra 24 and further evidence for their identity has recently been obtained by Ske11.54 The relative rates of poly- merisation and isomerisation for the Irans- hut-2-ene system are shown in 0 Temperature (OC> F I G . 11 Sulphur dioxide-trans- but-2-ene system.A Photochemical polymerisation ; B isomerisation catalysed by benzoyl peroxide ; C polymerisation catalysed by benzoyl peroxide. The scales for polymer formation and isomerisation are multiplied by 108 and lo4 respectively. [Reproduced with permission from Bristow and Dainton Proc. Roy. Soc. 1955 A,’-229 525.1 Fig. 11. The polymerisation was followed dilatometrically so that the rate of polymerisation is the net rate of removal of alkene (the very small volume difference between the isomers being neglected). The various propagation and depropagation processes are represented by where M, M, and S denote cis-but-2-ene trans-but-2-ene and sulphur 5 2 Dainton Diaper Ivin and Sheard Trans. Faraday SOC. 1957 53 1269. 5 3 Bristow and Dainton Proc.Roy. SOC. 1955 A 229 500 525. 54 Skell Woodworth and McNamara J. Arner. Chem. SOC. 1957 79 1253. DAINTON AND IVIN TIIERMODYNAMICS OF ADDITION POLYMERISATION 89 dioxide and P and Q denote the two types of radical ends. The rate of alkene consumption falls to zero in the cis system when ([S][M,])o = ka8( kd + kdt)/kpckp8. Combining this with the corresponding expression for the trans system a t the same temperature we have ([S][M,])o/([S][M,])o = kpt/kpc. Thus the more reactive isomer (higher kp) gives the lower apparent equilibrium concentration product ([S][M]) a t a given temperature or conversely gives the higher apparent T a t a given concentration product. The qualification " apparent " must be used since a true equilibrium does not exist when the net rate of alkene consumption is zero rather a stationary state is attained in which one forward reaction is balanced by two back reactions.As might be expected from its higher free energy cis-but-2-ene is the more reactive isomer kpc/kpt having a constant value of 1.35 between 19.9" and 31.5". Combining this ratio with measurements on the cis-trans equilibrium in sulphur dioxide we obtain values of kdt/kd ranging from 1.87 a t 31.5" to 2.07 a t 19.9". The energy of activation difference Ed - Ed = 1.4 & 0.4 kcal. mole-l indicates that the separation of the energy levels in the transition states P..-M for the two isomers is about the same as that in the products P + M. The energies of activation for the isomerisation rates though less reliable fit into the same picture. These energy levels are clearly shown in Fig.4 of ref. 52. I n examining the effect of alkene structure on T for polysulphone formation it is desirable in the case of cis- and trans-but-2-ene to correct for the effect of isomerisation so as to obtain the T which would have been observed in its absence. This can be done and at [M][S] = 27 mole2 1.-2 raises T for cis-but-2-ene by 10" and for trans-but-2-ene by 5" (see Table 7). This effect must also be allowed for in deriving AH and A S from measure- ments of Tc in these systems (Table 1). There are a number of cases of induced cis-trans isomerisations where a similar mechanism involving the transitory opening of the double-bond pre~ails.5~ The theoretical possibility that because of a preferred mode of opening of the ethylenic bond and the subsequent retention of configuration of the active centres two geometric isomers might form stereoisomeric polymers was mentioned by Huggins 56 in 1944.Such stereoisomers might differ in physical properties. The original measurements 53 on the heats of copoly- inerisation of sulphur dioxide with cis- and trans-but-2-ene indicated that the two copolymers had heat contents differing by 2-3 & 0.6 kcal. base- mole-1. More recent and more accurate determinations 52 have shown the original results to be in error for reasons unknown and as mentioned above indicate identical heat contents for the two copolymers. Tong and Kenyon 5 7 concluded from measurements of the heat of 1 1 copolymerisa- t)ion of vinyl acetate with diethyl fumarate and with diethyl maleate that the copolymers differed in heat content by 0.7 0.5 kcal.monomer-unit-l and might be stereoisomers. However the slight difference may be account- able in terms of different heats of mixing of the monomers in the two systems. 5 5 Steinmetz and Noyes J . Arne?. Chem. SOC. 1952 74 4141. 6 6 Huggins ibid. 1944 66 1991. 6 7 Tong and Kenyon ibid. 1949 71 1925. 90 QUARTERLY REVIEWS For the polymerisation of a monomer such as styrene each monomer unit may be incorporated into the polymer chain in two ways D and L because of the presence of an asymmetric carbon atom. For the polymer- isation of dienes there are considerably more possibilities. In the past few years catalyst systems have been discovered which with appropriate monomers direct the propagation process in such a way as to produce polymer chains containing either identical or regularly alternating structural units.It has been possible to synthesise crystalline polystyrene and poly- propene as well as natural rubber and gutta-percha. These catalyst systems have been summarised and discussed recently by Eirich and Mark ; in all cases the propagation step appears to occur at a solid-liquid interface. A number of attempts have been made to induce optical activity in the main chain of a vinyl polymer by starting with a monomer containing an optically active side group. Only one of these has been suc~essfiil,~8 and then only when the monomer ( - )-a-methylbenzyl methacrylate was copolymerised witlh nialeic anhydride (azoisobutyronitrile being used as photosensitiser). Effect of Depropagation on Copolymer @omposition.-The copolymerisa- tion of two nionomers M and M generally involves four propagation steps addition of one or other monomer to one or other type of centre represented by MI* and M,*.M,* + M -+ M,* k, MI* + M -+ M,* kl M,* + M -+ M,* k2 Y l = wb2 r2 = W k 2 1 M,* -k RI -+ M,* k21 The copolymer composition d[M,]/d[M,] is given by and this equation has been found satisfactory for a wide variety of monomer pairs.l It is clear however that it will fail if one of the reverse reactions becomes important compared with its forward reaction provided of course that the latter is already important itself. Joshi 59 has suggested that this state of affairs may exist in systems such as styrene-fumaronitrile where eqn. (11) is unsatisfactory.60 It must be mentioned however that his detailed kinetic treatment is invalid because he has assumed that all M,” can break down to give M,* + M, wherea,s in fact only those with the terminal structure M,Ml* can do so.Further work is needed to test these ideas particularly in systems for which r2 w 0 where the theory can be considerably simplified. Thermal and Radiation Stability of Polymers.-The activation energy of the depropagation reaction is given by Ed = E - AH and since E is usually about 5 kcal. mole-1 the value of Ed is largely determined by that of AH,. k will be higher the lower Ed i.e. the lower -AH,. In fact 58 Beredjick and Schuerch J . Amer. Chem. SOC. 1956 78 2646. 69 Joshi J . Sci. I n d . Res. I n d i a 1956 15 B 553. 60Fordyce and Ham J . Amer. Chem. Xoc. 1951 73 1186. DAINTON AND IVIN THERMODYNAMICS OF ADDITION POLYMERISATION 91 those polymers which give high monomer yields on thermal degradation are the ones with low -AH, e.g.poly-formaldehyde -(methyl methacrylate) -or-methylstyrene and -methacrylonitrile.61 In many cases it has been shown that radicals are involved but the depropagation reaction may have to compete with abstraction and other reactions e.g. in polyisobutene and poly(viny1idene chloride) so that the number of successive depropagation steps is not always very large. These competing processes usually pre- dominate in polymers for which -AH is on the high side e.g. poly-ethylene -propene -acrylonitrile -(methyl acrylate) -(vinyl acetate). This is partly on account of the low kd but also because these polymers contain tertiary C-H bonds which are readily broken. A similar division of polymers is observed in the effect on polymers of ionising radiation which causes either cross-linking or degradation 62 (without production of monomer).Cross-linking is favoured when tertiary C-H bonds are present. When such bonds are absent the radicals produced by breakage of the main chain will tend to remain trapped within a cage of molecules and will either recombine to give the original molecule or dis- proportionate to give two smaller molecules so resulting in degradation. The latter will be favoured when the polymer molecule is under strain as in polymers of vinylidene-type monomers but several other factors enter into the interpretation of the results in these systems. Concluding remarks I n much of the early work on polymer chemistry the statement is fre- quently found that a particular compound will not polymerise even when heated for many hours a t high temperature.We can now be wise after the event and see that the simple Arrhenius formula relating rate and temperature does not always apply to a complex process such as poly- merisation. A rise in temperature is nearly always thermodynamically unfavourable towards polymerisation and if I - AGp I eventually falls to zero the rate of formation of high polymer is also bound to fall to zero whatever form the relation between rate and temperature may take a t lower temperatures. 61 Grassie " High Polymer Degradation Processes " Buttcrworths London 1956. 62 Wall J. Polymer Sci. 1955 17 141. 92 QUARTERLY REVIEWS Appendix Lists of heats of polymerisation not given elsewhere i n this Review X Rot,es - A H x Iron1 mnlo-l Monomer Ethylene Propene Acrylic acid Methacrylic acid Acrylonitrile Chloroprene Vinyl chloride Anethole Butyl vinyl ether Bu tadiene Isoprene 2 5 4 25" 2 r 0 gc 24.2 .) allowing 1.3 for heat of fusion lc 16.5 Room temp.lc 15.8 9 9 ? 1C' 17.3 76.8" lc 16.2 76.8" Ekegren et al.a lc 16-17 Estimated lc(?) 13.8 11( ?) 14.4 lc 17.4 lc 17.9 gc' Sc -16.5 - 78" Copolymerisat ion Monomer A Styrene Vinyl acetate isoPropeny1 Vinyl acetate Vinyl acetate Acry lonitrile Acrylonitrile acetate Monomer E Butadiene Maleic anhydride Maleic anhydride Diethyl maleate Diethyl fumarate Vinylidene dichloride Methyl methacrylate Moles o of A in polymer 4-30 50 50 60 50 0 -100 s lc lc lc lc lc sc - AZIx (Ircal. mole-') 17.1-17.7 Nelson et aLb 20.2 17.8 20.0 18.6 Nagao et ci1.c 13.0 -1 8.3 Baxendale et n2.d I For discussion of heat of copolymerisation as function of coinposit ion see Alfrey and Lewis J .Polymer Sci. 1949 4 221. For references see Dainton and Ivin (Trans. Famday SOC. 1950 46 331) or Roberts ( J . Res. Nut. Bur. Stand. 1950 44 221) except where otherwise stated a Ekegren ohm Granath and Kinell Actw Claem. Scand. 1950 4 126 ; b Nelson Jessup and Roberts J . Res. Nut. Bur. Stand. 1952 48 275 ; c Nagao and Yamaguchi J . Chem. Soc. Japan I n d . Chena. Sect. 1956 59 1363 ; 13axendale and Madaras J . Polymer Sci. 1956 19 171.

ISSN:0009-2681    

DOI:10.1039/QR9581200061

出版商:RSC    

年代:1958

数据来源: RSC

摘要:

CUMULATIVE INDEXES VOLUMES I-XI1 (1947-1958) CUMULATIVE INDEX OF AUTHORS Abrahams S. C. 10 407 Abrikosova I. I. 10 295 Addison C. C. 9 115 Ahrland S. 12 265 Albert A. 6 197 Allen G. 7 255 Amphlett C. B. 8 219 Anderson J. S. 1 331 Angyal S. J. 11 212 Arnstein H. R. V. 4 172 Atherton F. R. 3 146 Avison A. W. D. 5 171 Bacon R. G. R. 9 287 Baddeley G. 8 355 Baddiley J. 12 152 Badger G. M. 5 147 Bagnall K. W. 11 30 Baker W. 11 15. Baltazzi E. 9 150 Barker S. A. 7 58 Barltrop J. A. 12 34 Barnartt S. 7 84 Barrer R. M. 3 293 Barton D. H. R. 3 36; 10 44 11 189 Bassett H. 1 247 Bateman L. 8 147 Baughan E. C. 7 103 Baulch D. L. 12 133 Bayliss N. S. 6 319 Bell R. P. 1 113 2 132 Bentley R. 4 172 Bergel F. 2 349 Bethell D. 12 173 Bevington J. C. 6 141 Birch A. J. 4 69; 12 17 Bircumshaw L. L.6 157 Bockrjs J. O’M. 3 173 Bolland J. L. 3 1 Bond G. C. 8 279 Bourne E. J. 7 58 Bowen E. J. 1 1 ; 4 236 Bradley R. S. 5 315 Rraude E. A. 4 404 Bremner J. G. M. 2 1 Brink N. G. 12 93 Brown B. R. 5 131 Brown R. D. 6 63 Buchanan J. G. 12 152 Bu’Lock J. D. 10 371 Bunnett J. F. 12 1 Burkin A. R. 5 1 Burnett G. M. 4 292 Burton H. 6 302 Cadogan J. I. G. 8 308 Caldin E. F. 7 255 Challenger F. 9 255 Chatt J. 12 265 Coates G. E. 4 217 Collinson E. 9 311 Cook A. H. 2 203 Cook J. W. 5 99 Cookson R. C. 10 44 Cottrell T. L. 2 260 Coulson C. A. 1 144 Cowclrey W. A. 6 358 Cox E. G. 7 335 Crawford V. A. 3 226 Crofts P. C. 12 341 Crombie L. 6 101 Cruickshank D. W. J. 7 Curran S. C. 7 1 Dainton F. S. 12 61 Dnlgliesli C. E. 5 227 Davies A. G. 9 203 Davies D. S. 6 358 Davies M. 8 250 Davies N. R. 12 265 Davies R.O. 11 134 Dawton R. H. V. M. 9 1 De Heer J. 4 94 de la Mare P. B. D. 3 126 de Mayo P. 11 189 Derjaguin B. V.. 10 295 Dickens P. G. 11 291 Dubinin M. M. 9 101 Duncan J. F. 2 307; 12 Dunning W. J. 9 23 Eley D. D. 3 181 Emeleus H. J. 2 132 Errede L. A. 12 301 Evans M. G. 4 94; 6 335 133 186 Fensham P. J. 11 227 Foster A. B. 11 61 Freidlina R. Kh. 10 330 Gascoigne R. M. 9 328 Gaydon A. G. 4 1 Gee G. 1 265 Gent W. 1,. G. 2 383 Gibson D. T. 3 263 Gillespie R. J. 2 277 ; 8 Glenn A. L. 8 192 Goehring M. 10 437 Gold V. 9 51; 12 173 Gowenlock B. G. 12 321 Gray P. 9 362 Greenwood N. N. 8 1 Grfith J. S. 11 381 40; 11 339 Gunstone F. D. 7 175 Gutmann V. 10 451 Halpern J. 10 463 Hamer F. M. 4 327 Hardy D. V. N. 2 25 Harman R. E. 12 93 Harris M. M. 1 299 Hartley G. S. 2 154 Hassel O.7 221 Hawkins E. G. E. 4 251 Hawkins J. D. 5 171 Haynes L. J. 2 46 Heaney H. 11 109 Hey D. H. 8 308 Hickling A. 3 95 Hughes E. D. 2 107; 5 245 ; 6 34 Hush N. S. 6 186 Ingold C. K. 6 34; 11 1 Irving H. M. 5 200 Ivin K. J. 12 61 Jacobs P. W. M. 6 238 Jain A. C. 10 169 Janz G. J . 9 229 Jeffrey G. A. 7 335 Jenkins E. N. 10 83 Jennings K. R. 12 116 Jones D. G. 4 195 Kapustinskii A. F. 10 283 Katritzky A. R. 10 395 Kenyon J. 9 203 Khorana H. G. 6 340 Kjpling J. J. 5 60 ; 10 1 Lamb J. 11 134 Lamberton A. H. 5 75 Law H. D. 10 230 Lea F. M. 3 82 Leech H. R. 3 22 Leisten J. A. 8 40 Levy N. 1 358 Lewis E. S. 12 230 Lewis J. 9 115 Lifshitz E. M. 10 295 Linnett J. W. 1 73; 11 Lister B. A. J. 2 307 Lister M. W. 4 20 Long L. H. 7 134 Longuet-Higgins H. C. 11 Loudon J. D. 5 99 Luttke W. 12 321 Lythgoe B.3 181 291 ; 12 116 121 Maccoll A. 1 16 McCoubrey J. C. 5 364; MacDiarmid A. G. 10 208 McGrath W. D. 11 87 McKenna J. 7 231 Maddock A. G. 5. 270 Maitland P. 4 45 Manners D. J. 9 73 Marsh J. K. 1 126 Martin R. L. 8 1 Megson N. J. L. 2 25 Millar I. T. 11 109 Millen D. J. 2 277 Morgan K. J. 8 123; 12 Morrison A. L. 2 349 Musgrave W. K. R. 8 331 Nesmeyanov A. N. 10,330 Norrish R. G. W. 10 149 Nyliolm R. S. 3 321 ; 7 Ollis W. D. 11 15 Orgel L. E. 8,422 ; 11,381 Orville-Thomas W. J. 11 Overend W. G. 11 61 Owston P. G. 5 344 11 87 34 377; 11 339 162 Page J. E. 6 262 Paneth F. A. 2 93 Pauson P. L. 9 391 Pepper D. C. 8 88 Percival E. G. V. 3 369 CUMULATIVE INDEX Phillips F. C. 1 91 Pople J. A. 11 273 Praill P. F. G. 6 302 Reid C. 12 205 Richards R. E. 10 480 Riddiford A. C. 6 157 Riley H.L. 1 59 ; 3 160 Rose J. D. 1 358 Rowlinson J . S. 8 168 Satchell D. P. N. 9 61 Saxton J. E. 10 108 Schofield K. 4 382 Seshadri T. R. 10 169 Sexton W. A. 4 272 Sharpe A. G. 4,115 ; 11,49 Shchukina L. A. 10 261 Shemyakin M. M. 10 261 Sheppard N. 6 1 ; 7 19 Simes J. J. H. 9 328 Simpson D. M. 6 1 ; 7 19 Smades A. A. 10 83 Smith H. 12 17 Smith J. A. S. 7 279 Smith 31. L. 9 1 Springall H. D. 10 230 Stacey M. 1 179 213 Staveley L. A. K. 3 65 Stern E. S. 5 405 Stone F. G. A. 9 174 Sutton L. E. 2 260 Swallow A. J. 9 31 1 Symons M. C. R. 12 230 Synge R. L. M. 3 245 Szwarc M. 5 22; 12 301 Taylor A. W. C. 4 195 Thomas S. L. 7 407 Thomson R. H. 10 27 Thrush B. A. 10 149 Tipper C. F. H. 11 313 Tomkins F. C. 6 238 Topley B. 3 345 Trapnell E. M. W. 8 404 Trotman-Diekenson A. F. Truter E.V. 5 390 Turner E. E. 1 299 Turner H. S. 7 407 7 198 Ubbelohde A. R. 4 356; Uri N. 6 186 5 364 ; 11 246 Walsh A. D. 2 73 Warburton W. K. 8 67 Warhurst E. 5 44 Waters W. A. 12 277 Weedon E. C. L. 6 380 Wells A. F. 2 185 ; 8 Wells R. A. 7 307 Whiffen D. H. 4 131; 12 Whytlaw-Gray R. 4 153 Wilson H. N. 2 1 Woodward L. A. 10 185 380 250 Yoffe A. D. 9 362 Zakharkin L. I. 10 330 CUMULATIVE INDEX 03 TITLES Acetylenes infrared and Raman spectra Acetylenic compounds as natural pro- Acid use of the term 1 113 Acids carboxylic anodic syntheses with of 6 1 ducts 10 371 6 380 association of 7 255 Adsorption of non-electrolytes from solu- tion 5 GO Affinities relative of ligand atoms for acceptor molecules and ions 12 265 Age geological determination of by radio- activity 7 1 Aldehycles polymerisation of 6 141 Aliphatic nitro-compounds 1 358 Alkaloids ergot 8 192 indole excluding harmine and strych- nine 10 108 steroidal 7 231 veratrum 12 34 Alkanes tetra- and trj-chloro- and related oompounds 10 330 Analgesics synthetic 2 349 Analysis inorganic applications of solvent extraction to 5 200 Anionotropy 4 404 Anodic syntheses with carboxylic acids 6 Antibiotics newer chemistry of 12 93 Aqueous solutions mechanism of electrode processes in 3 95 Aromatic bond 5 147 380 nitration 2 277 nucleophilic substitutions mechanism rearrangements 6 34 and reactivity in 12 1 Association of carboxylic acids 7 255 Attraction molecular direct measurement of between solids separated by a narrow gap 10 295 Rase use of the term 1 113 Biological degradation of tryptophan 5 methylation 9 225 reactions role of phosphoric esters in 227 5 171 Bond aromatic 5 147 dissociation energies 5 22 properties interpretation of 2 260 pole coupling 11 162 chemistry of 9 174 Bonding chemical and nuclear quadru- Boron hydrides and related compounds 2 132 trifluoride co-ordination compounds of 8 1 Carbides nitrides and carbonitrides of Carbohydrate phosphates 11 61 Carbon amorphous and graphite 1 59 Carbon-carbon bonds oxidative-hyclro- lytic splitting of in organic molecules 10 261 Carbon-carbon double bonds geometrical isomerism about 6 101 Carbon-hydrogen bond polarity of 2,383 Carbon-hydrogen bonds mechanisms of Carbon-phosphorus bonds compounds Carbonitrides carbides and nitrides of Carbonium ions structure of 12 173 Carbons active study of porous st'ructure of by a variety of methods 9 101 adsorbent properties and nature of 10,l iron 3 160 sulphates 3 369 breakage of 12 230 containing 12 341 iron 3 160 Carbonyls metal chemistry of 1 331 Catalysis by metals specificity in 8 404 Catalysis hydrogen mechanisms of 3,209 Catalysis and semiconductivity 11 227 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 Chromium mechanisms of oxidation by compounds of 12 277 Collisions in gases energy transfer in 11 87 Colloidal electrolytes state of solution of 2 154 Colour and constitution 1 16 Combustions slow in the gas phase ele- mentary reactions in 11 313 Complex compounds stabilities of 5 1 Conductance ionic in solid salts 6 238 Configuration of flexible organic molecules 5 364 Conformational analysis principles of 10 44 Conjugated compounds free-electron approximation for 6 319 Constitution and colour 1 16 Co-ordination compounds of boron tri- 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 fluoride 8 1 complex halides 8 380 CUMULATIVE INDEX Decarboxylation thermal mechanism of Densities limiting 4 153 Dielectric absorption 8 250 Dihalogen compounds Grignard and or- ganolithium compounds derived from Disproportionation in inorganic com- pounds 2 1 Diterpenoids chemistry of 3 36 Dyes cyanine 4 327 5 131 11 109 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 Electromagnetic separation of stable Electron correlation and chemical conse- Electrons structures of molecules deficient Elements heavy radioactivity of 5 270 mechanism of 3 95 2 154 ultrasonic waves on 7 84 isotopes 9 1 quences 11 291 in 11 121 of 3 321 the thermochemistry of 7 103 126 of Group VIII recent stereochemistry of Groups IVB and IVY comments on of the rare-earth series separation of 1 terrestrial distribution of 3 263 transuranic chemistry of 4 20 Emission spectra of flames 4 1 Energy transfer of in gaseous collisions Enzymic degradation of polysaccharides 11,.87 9 73 synthesis of polysaccharides 7 58 Equivalent-orbital approach to molecular Ergot alkaloids struct,ure of 8 192 Esters carboxylic and related com- pounds alkyl-oxygen heterolysis in 9 203 Exchange reactions of hydrogen isotopes in solution principles of 9 51 structure 11 273 Fatty acids straight-chain recent developments in the preparation of natural and synthetic 7 175 Ferrocene and related compounds 9 391 Flames emission spectra of 4 1 Flash photolysis and kinetic spectroscopy Flavones and related compounds nuclear isoFlavones 8 67 Fluorescence and fluorescence quenching Fluorine and its compounds laboratory and technical moduction of.3. 22 10 149 methylat,ion of 10 169 1 1 Fluorine compounds organic reactions of general aspects of the inorganic chem- 8,331 istry of 11 49 Force constants 1 73 Free-electron aspproximation for conju- Free-radical addition reactions of olekic Friedel-Crafts reaction modern aspects Furan and pyran chemistry some aspects Gases elementary reactions in slow com- energy transfer in collisions in 11 87 Geological age determination of by radio- Graphite and amorphous carbon 1 59 Grignard reagents derived from dihalogen gated compounds 6 319 systems 8 308 of 8 356 of 4 195 bustions in 11 313 activity 7 1 compounds 11 109 1 Ialides complex crystal structures of 8 3 80 reactions of in solution 5 245 Halogens kinetics of thermal addition of to olefinic compounds 3 126 Heats of formation of simple inorganic compounds 7 134 Heterocyclic nitrogen compounds nitrn- tion of 4 382 Heterogeneous reactions transport control in 6 157 Heterolysis alkyl-oxygen in carboxylic esters and related compounds 9 203 cycloHoxane stereochemistry of 7 221 Hydrocarbons infrared and Raman spectra of.Part I. Acetylenes and olefins 6 1. Part 11. Paraffins 7 19 Hydrogen molecular homogeneous re- actions of in solution 10 463 Hydrogen atoms location of in crystals 10 480 catalysis mechanisms of 3 209 isotope exchange reactions in EOlUtiOn principles of 9 51 peroxide its radicals and its ions energetics of reactions involving 6 186 Hydrogenation catalytic and related re- actions mechanism of 8 270 Hyperconjugation 3 226 Ice structure of 5 344 Immunochemistry aspects of 1 179 213 Indole alkaloids excluding harmine and strychnine 10 108 Induction asymmetric and asymmetric transformation 1 299 Infrared and Raman spectra of hydro- carbons. Part I. Acetylenes and olefins 6 1. Part 11. Paraffins 7 19 Inorganic analysis applications of solvent extraction to.5. 200 CUMULATIVE INDEX Inorganic chemistry and ma,gnetism 7,377 chromatography 7 307 compounds disproportionation in 2 1 Raman spectra of 10 185 simple heats of formation of 7 134 iodine compounds some reactions of. 8 123 stereochemistry 11 339 Inositols 11 212 Insecticides synthetic structure and Interhalogen compounds and polyhalides Intermolecular forces and some propcrties Iodine compounds inorganic some re- Ion exchange 2 307 Ionic conductance in solid salts 6 238 solvation 3 173 Ionisation potentials and far ultra- violet spectra their significance in chemistry 2 73 Iron carbides nitrides and carbonitrides of 3 160 Isomerism geometrical about carbon- carbon double bonds 6 101 Isotopes stable electromagnetic separa- tion of 9 1 Isotopic exchange between different oxida- tion states in aqueous solution 8 219 Isotopically labelled organic compounds activity in 4 272 4 115 of matter 8 168 actions of 8 123 tracer techniques 4 172 synthesis of 7 407 ated 2 46 Lactones physiologically active unsatur- Lanthanons separation of 1 126 Lattice energy of ionic crystals 10 283 Ligand atoms relative aflbities of for acceptor molecules and ions 12 265 Ligand-field theory 11 381 Light absorption and photochemistry 4 Liquids ultrasonic analysis of relaxation Liquids and solids transitions in 3 65 236 processes in 11 134 Magnetic resonance absorption nuclear Magnetism and inorganic chemistry 7,377 Manganese mechanisms of oxidation by Mass spectrometry application t,o chemi- Melting and crystal structure 4 356 Meso-ionic compounds 11 15 Metal carbonyls chemistry of 1 331 oxides structure of 2 185 Metal-amine solutions reduction by ; applications in synthesis and deter- mination of structure 12 17 Metal-ammonia solutions reduction of 7 279 compounds of 12 277 cal problems 9 23 Methyl radicals reactions of 7 198 Methylation biological 9 255 nuclear of flavones and related com- Molecular interpretation of thermodynamic pounds 10 169 properties-of high polymers 1; 265 structure determination bv X-ray crystal analysis modern" methods and their accuracy 7 335 molecular-orbital and equivalent-or- bital approach to 11 273 Molecular-orbital approach to molecular Molecular-sieve action of solids 3 293 Molecules electron-deficient structures of simple representation by molecular Morphine synthetic approaches to struc- structure 11 273 11,121 orbitals 1 144 ture oE 5 405 as 10 371 Natural products acetylenic compounds Nitramines some aspects of the chemistry Nitration aromatic 2 277 of 5 75 of heterocyclic nitrogen compounds 4 Nitrides carbides and carbonitrides of Nitro-compounds.aliphatic 1 358 Nitrogen active 12 116 Nitrogen dioxide-dinitrogen tetroxide system structure and reactivity of 9 362 C-Nitroso-compounds structure and pro- perties of 12 322 Nitrosyl group chemistry of 9 115 Non -electrolytes adsorption of from solu- Nuclear chemistry quantitative 12 133 Nuclear magnetic resonance absorption Nuclear quadrupole coupling and chemi- Nucleation in phase changes 5 315 Nucleotide coenzymes recent develop- ments in biochemistry of 12 152 382 iron 3 160 tion 5 60 7,279 cal bonding 11 162 Oceanic salt deposit,s 1 91 Olofinic systems free -radical addition reactions of 8 308 Olefins infrared and Raman spectra of 6 ] kinetics of oxidation of 3 1 kinetics of thermal addition of halogens oxidation of 8 147 to 3 126 6 63 1.144 Orbitals molecular and organic reactions representation of simple molecules by Organic 'cations reactions of 6 302 organic compounds by 4 69 chemistry of derivatives of phosphorus Metals specificity in catalysis by 8 404 oxyacids 3 146 CUMULATIVE INDEX Organic compounds action of ionising behaviour in sulphuric acid 8 40 estimation of thermodynamic proper- isotopically labelled synthesis of 7 polarography of 6 262 reduction of by metal-ammonia solu- fluorine compounds reactions of 8 331 molecules flexible configuration of 5 oxidetive-hydrolytic splitting of car- radiations on 9 311 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 Organolithium reagents derived from di- Organometallic compounds of the first 5-0xszolones chemistry of 9 150 Oxidation by compounds of chromiumand halogen compounds ll 109 three periodic groups 4 217 manganese mechanisms of 12 277 of olefins 8 147- kinetics of 3 1 Oxidation-reduction potential of quin- ones relation to chemical structure 4 94 istry of 10 395 Oxides metallic structures of 2 185 N-Oxides aromatic heterocyclic chem- Paraffins infrared and Raman spectra of Penicillins chemistry of 2 203 Peptides methods of synthesis and 7 19 terminal-residue studies of 10 230 naturally occurring 3 245 and proteins structural investigation of 6 340 Peroxides organic and their reactions 4 25 1 Phase changes nucleation in 5 315 Phenols tautomerism of 10 27 Phosphates condensed 3 345 Phosphates of carbohydrates 11 61 Phosphoric esters role in biological re- actions 5 171 Phosphorus oxyacids some aspects of the organic chemistry of derivatives of 3 146 Photochemistry and light absorption 4,236 Photography cyanine dyes in 4 327 Photopolymerisation 4 236 Polarity of the carbon-hydrogen bond I’olarography of organic compounds 6,262 Polonium chemistry of 11 30 I’olyhslides and interhalogen compounds I’olymerisation initiation of by redox addition some thermodynamic and 2,383 4 115 catalysts 9 287 kinetic aspects of 12 61 Polymerisation ionic 8 88 of aldehydes 6 141 reactions radical rate constants in 4 292 Polymers high thermodynamic properties of and their molecular interpretation 1 265 9 73 silicon chemistry of 2 25 Polysaccharides enzymic degradation of 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 some Pyrrole pigments biogenetic origin of 4,45 Quadrupole coupling nuclear and chemi- cal bonding 11 162 Quenching of fluorescence 1 1 Quinones relation between the oxidation- reduction potential and chemical structure of 4 94 forces 8 168 gation of 6 340 aspects of 3 181 of 4 195 aspects of 3 181 Radiations ionising action of on organic Radicals free electron resonance spec- Radioactivation analysis 10 83 Radioactive tracers preparation of 2 93 Radioactivity determination of geological compounds 9 3 11 troscopy of 12 250 age by 7 1 Raman and infrared spectra of hydro- carbons.Part I. Acetylenes and olefins 6 1. Part 11. Paraffins 7,19 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 Itedox catalysts initiation of polymeri- sation processes by 9 287 potentials of quinones relation to chemi- cal structure 4 94 Reduction by metal-amine solutions ; applications in synthesis and deter- mination of structure 12 17 of organic compounds by metal- ammonia solutions 4 69 Relaxation processes molecular in liquids ultrasonic analysis of 11 134 Rotation spectra 4 131 Salt deposits oceanic 1 91 of the heavy elements 5 270 hydrates crystal structures of 8 380 CUMULATIVE INDEX Salts basic structure of 1 247 solid ionic conductance in 6 238 Sandmeyer and related reactions 6 358 Semiconductivity and catalysis 11 227 Sesquiterpenoids recent advances in chemistry of 11 189 Silicon polymers chemistry of 2 25 Silyl compounds,, 10 208 Sodium " flame Solids molecular-sieve action of 3 293 reactions 5 44 and liquids transitions in 3 65 separated by a narrow gap direct measurement of molecular attraction between 10 295 thermal transformations in 11 246 Solvation ionic 3 173 Solvent extraction and its applications to Solvents ionising non-aqueous reactions Specificity in catalysis by metals 8 404 Spectra charge-transfer and some related inorganic analysis 5 200 in 10 451 phenomena 8 422 emission of flames 4 1 far ultraviolet ionisation potentials and their significance in chemistry 2 73 infrared and Raman of hydrocarbons.Part I. Acetylenes and olefins 6 1. Part 11. ParafEns 7 19 Raman of inorganic compounds 10 185 rotation 4 131 Spectroscopy electron resonance of free kinetic and flash photolysis 10 149 radicals 12 250 Stabilities of complex compounds 5 1 Stereochemistry inorganic 11 339 Stereochemistry of cyclohexane 7 221 of Sub-group VIB of the Periodic Table of the Group VIII elements 3 321 10 407 Steric hindrance 2 107 Steric hindrance quantitative study of Steroidal alkaloids 7 231 Sub-group VIB stereochemistry of 10 Substitutions aromatic nucleophilic 11 1 40 7 mechanism and reactivity in 12 1 Sulphur nitride and its derivatives 10 Sulphuric acid behaviour of organic Sydnones 11 15 43 7 compounds in 8 40 Tautomerism of phenols 10 27 Terrestrial distribution of the elements 3 263 Thermochemistry 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- metric induction 1 299 Transformations thermal in solids 11 246 Transitions in solids and liquids 3 65 Transport control in *heterogeneous re- Transuranic elements chemistry of 4 Triplet state 12 205 Triterpenes tetracyclic 9 328 Tropolones 5 99 Tryptophan biological degradation of 5 actions 6 157 20 227 Ultrasonic analysis of molecular relaua- tion processes in liquids 11 134 Ultrasonic waves effects on electrolytes and electrolytic processes 7 84 Veratrum alkaloids 12 34 Wool wax constitution of 5 390 X-Ray crystal analysis modern methods of molecular structure determination by and their accuracy 7 335 p-Xylylene chemistry of and of its analogues and polymers 12 301

ISSN:0009-2681    

DOI:10.1039/QR9581200367

出版商:RSC    

年代:1958

数据来源: RSC