摘要:

CHEMICAL SOCIETY REVIEWS VOLUME 16, 1987 0 Copyright 1988 LONDON THE ROYAL SOCIETY OF CHEMISTRY CONTENTS PAGE OF UNUSUAL SPECIES SUPERACIDSSTABILIZATION CATIONIC IN PROTONIC AND ACIDIC MELTS. By T. A. O’Donnell 1 ARSONIUMYLIDES (WITH SOME MENTION ALSO OF ARSINIMINES, ANDSTIBONIUM BISMUTHONIUMYLIDES). By Douglas Lloyd, Ian Gosney, and Raymond A. Ormiston 45 ORTHO ESTERS AND DIALKOXYCARBENIUM STABILITY,IONS: REACTIVITY, STRUCTURE, AKD NEW SYNTHETIC By Ulf Pindur, Johann Muller, Camran Flo, APPLICATIONS. and Helmut Witzel 75 PROTOTROPIC ROUTES TO THETO 1,3-AND l,S-DIPOLES, AND 1,2-YLIDES: APPLICATIONS SYVTHESIS COMPOUNDS.OF HETEROCYCLIC By R. Grigg 89 OF MULTINUCLEAK AND BIOSYNTHETICAPPLICATIONS NMR TO STRUCTURAL STUDIES OF POLYKETIDE METABOLITES.MICROBIAL By T.J. Simpson 123 TATE AND LYLE LECTURE. STRUCTURAL CHARACTERI-AND CONFORMATIONAL DIFFERENTIATIONZATION OF CARBOHYDRATE ANTIGENS. By Elizabeth F. Hounsell 161 ASPECTSOF THE INTRAMOLECULARSTEREOCHEMICAL DIELS ALDER REACTION. By Donald Craig 187 PART I-THE PHYSICALSONOCHEMISTRY: ASPECTS. By John P. Lorimer and Timothy J. Mason 239 SONOCHEMISTRY:PART SYNTHETIC APPLICATIONS.By James Lindley and Timothy J. Mason 275 STABILITY ORGANICPRODUCT IN KINETICALLY-CONTROLLED REACTIONS. By Sosale Chandrasekhar 313 DESCRIPTIONS AND REACTIVITYRESONANT OF BONDING OF GROUPVIII-IB METALSIN THE SOLID STATE. By Paul A. Sermon 339 CHEMICAL OF SODIUM RELEVANTRECENT STUDIES NITROPRUSSIDE TO ITS HYPOTENSWE ACTION. By Anthony R. Butler and Christopher Glidewell 361 FOR THE INTRODUCTION INTO ORGANICMODERNMETHODS OF FLUORINE MOLECULES: AN APPROACH TO COMPOUNDSWITH ALTERED CHEMICALAND BIOLOGICAL ACTIVITIES. By John Mann 38 1 THE MEDICINAL OF ANTI-LEPROSYCHEMISTRY DRUGS. By M. Hooper 437 ANGULARGEOMETRIES HYDROGEN-BONDEDOF DIMERS:A SIMPLE ELECTROSTATIC OF THE SUCCESS PAIR MODEL. By A. C. LegonIYTERPRETATION OF THE ELECTRON and D. J. Millen 467 1987 Indexes 499

ISSN:0306-0012    

DOI:10.1039/CS98716FP001

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

C'hem. SOC.Rev., 1987, 16,45-74 Arsonium Ylides (with some mention also of Arsinimines, Stibonium and Bismuthonium Ylides) By Douglas Lloyd DEPARTMENT OF CHEMISTRY, UNIVERSITY OF ST. ANDREWS, ST. ANDREWS, FIFE, KY 16 9ST Ian Gosney and Raymond A. Ormiston DEPARTMENT OF CHEMISTRY, UNIVERSITY OF EDINBURGH, EDINBURGH, EH9 355 I Introduction Whereas much information has been published about phosphonium ylides, relatively little attention has been paid to arsonium ylides. There may be a psychological barrier in that for centuries the word arsenic has been associated with poisoning. In the case of triarylarsonium ylides, which are those most commonly used, there are no problems of this sort in their normal handling, but it must be emphasized that great care must be taken in handling alkylarsines and in these cases efficient fume-chambers are a necessity.Arsonium ylides are relatively easy to prepare, and are of particular interest in that they are more reactive than analogous phosphonium or sulphonium ylides in the Wittig reaction, in which they may provide alkenes or epoxides, the type of product depending on the nature of the substituents on both the ylidic carbon atom and the arsenic atom, and also to some extent on the solvent used. 2 Structure of Arsonium Ylides Arsonium ylides may be represented as hybrids of pentacovalent arsenic (1) and dipolar (2) structures. For convenience, in this review ylides will commonly be represented by covalent structures such as (1) but the dipolar contribution to such structures must be taken as understood.If electron-withdrawing centres are conjugated with the ylidic carbon atom, further dipolar structures, such as (3) and (4)may make major contributions to the overall structure. Delocalization of the negative charge in this way frequently leads to the ylides being isolable. Such ylides are commonly described as stable ylides; in this context stable is, in effect, usually synonomous with isolable. Many ylides are not, however, isolable, because of their high reactivity, in particular their very ready Arsonium Ylides hydrolysis. In this article such ylides will be called reactive ylides. Some other ylides, notably benzylylides, have reactivity intermediate between those ylides which are obviously stable or obviously reactive.In this article they will be termed semi-stabilized. Experimental evidence suggests that arsonium ylides are more dipolar than their phosphonium and sulphonium analogues. This is shown, for example, by dipole moment measurements on a series of tetraphenylcyclopentadienylides. The moments for the diphenylsulphonium, triphenylphosphonium, and triphenylarsonium derivatives are, respectively, 6.69, 7.75, 8.32 D.' Similarly triphenylarsonium fluorenylide has been shown to be more polar than its triphenylphosphonium analogue.2 Infra-red spectra of a number of stable arsonium ylides indicate their polarity and show that the negative charge is sited appreciably in the stabilizing substituent The stretching frequencies associated with P-carbonyl(1505-1525 cm-') or @-cyan0 substituents (2105-21 70 cm-') are significantly lower than those observed for analogous phosphonium ylides, in keeping with the greater polarity of the arsonium ylides.Analysis of the H-n.m.r. spectra of a series of cyclopentadienylides similarly indicates that the triphenylarsonium ylide is more polar and has greater delocalization of negative charge in the five-membered ring than its phosphonium or sulphonium analogues.6 Comparative studies of '3C-n.m.r. spectra of phosphonium and arsonium ylides also suggest more covalent bonding in the When methyltriphenyl- or tetramethyl-arsonium halides were converted into, respectively, triphenyl- or trimethyl-arsonium methylides there was only a small change in the CH coupling constant at the carbon atom undergoing deprotonation, whereas in the corresponding phosphorus system JCHwas greatly increased on deprotonation.This was taken to show that in the case of arsenic the bonding of the relevant carbon atom remained virtually unchanged, indicating a pseudo-tetrahedral geometry (9,in contrast to the case of phosphorus, when deprotonation causes an effective sp3 to sp2 rehybridization of the ylidic carbon atom (6). Introduction of silyl groups at the ylidic carbon atom causes a flattening of that atom' to a more planar structure. In arsonium acylylides the structure of the ylidic carbon atom appears to be planar.' The '3C-n.m.r. spectra of a series of triphenylarsonium p-substituted aroylylides indicated a high electron density on the ylidic carbon atom." The chemical shifts ' H.Lumbroso, D. Lloyd, and G. S. Harris, C.R. Seunces Acud Sci.. 1974, C278, 219. A. W. Johnson and J. 0. Martin. Chem. Ind. (London), 1965, 1726. N. A. Nesmeyanov, V. V. Mikulshin, and 0.A. Reutov, J. Orgunomer. Chem.. 1968. 13, 263. A. J. Dale and P. Frsyen, Acta Chem. Scand., 1970, 24, 3772.'I. Gosney and D. Lloyd, Tetrcihedron, 1973, 29, 1697. E. E. Ernstbrunner and D. Lloyd, Chem. Ind. (London), 1971, 1332. 'Y. Yamomoto and H. Schmidbauer, J. Chem. SOC..Chem. Commun., 1975, 668; H. Schmidbauer, W. Richter, W. Wolf, and F. H. Kohler, Chem. Ber., 1975, 108, 2649.'H. Schmidbauer, W. Richter, W. Wolf, and F. H. Kohler, Chem.Bar., 1975. 108. 2649. G. Fronza, P. Bravo, and C. Ticozzi, J. Orgunornet. Chem., 1978, 157, 299. lo P. Frsyen and D. G. Morris, Acta Chem. Scand.. Ser. B, 1976, 30, 435. Lloyd, Gosney, and Ormiston for the ylidic carbon atoms, but not those for the carbonyl carbon atoms, showed a correlation with the electronic character of the p-substituent." The difference between arsonium and phosphonium ylides is commonly ascribed to less efficient pn-dn overlap between the C-sp2 orbitals and the larger and more diffuse 4d orbitals of arsenic, and to decreased electrostatic interaction across the ylide bond, but it is probable that these are not the only factors involved. The P.E. spectra of trimethylarsonium methylide and its phosphorus analogue have been recorded and CND0/2 calculations have been carried out.' ' Results are in accord with a raising of the HOMO levels for the arsenic ylide compared to the phosphorus analogue, thereby lowering the d-population and the ylide bond order, and increasing the charge on the ylidic carbon atom.A. Conformation.--There has been an amount of study of the conformational mobility of P-carbonyl ylides (7). When R was a methoxy group separate signals for 2 and E isomers (with respect to the AsC=CO bond) were observable; coalescence occurred at higher temperatures.I2 The Z configuration is strongly favoured, presumably because of coulombic interaction between As' and 0-,but less so than in the case of phosphorus ylides. It was suggested that phosphorus orbitals overlap with the oxygen 2p-orbitals more effectively than do the more diffuse arsenic orbitals, giving rise to a P-0 interaction that is more bonding than the As-0interaction.I2 In that case stronger contraction of the arsenic orbitals should lead to stronger bonding, and this is supported by the observation that the Z-E ratio is higher when R' = CN than when R' = H or Ph.12 Similar variation of spectra with temperature was observed when R = SEt.13 When R was an alkyl or aryl group no such temperature dependence was ob~erved.~This can be rationalized in terms of a higher negative charge on a keto oxygen compared to an ester oxygen, leading to stronger coulombic interaction in the keto case and a freezing of the ylide into a Z structure.Some broadening of the 'I H. Starzewski, W. Richter, and H. Schrnidbauer, Chem. Ber., 1976, 109, 473.'' A. J. Dale and P. Frcayen, Acta Chem. Scand., 1971, 25, 1452. l3 H. J. Bestmann and R. K. Bansal, Tetrahedron Lett., 1981, 3839. Arsonium YIides methine signal was observed in the spectrum of the benzoylylide (7; R = Ph, R' = H), but this was attributed to a protolytic exchange rea~tion.'~ +AsPh3 I (8) In the case of P,P'-dicarbonyl substituted ylides (7, R' = COR") the situation is more complex but in nearly all cases n.m.r. spectra suggest that the molecule exists as the 2,Z-isomer (8).5 Exceptions may arise if the acyl group is stabilized in an alternative configuration by intramolecular hydrogen b~nding.~ y3 CH3- AS =CH,, I CH3-As I -CH3e CH2=As I -CH3,CH3-As II -CH3 CH3 CH3 H3 HZ (91 The 'H-n.m.r.spectrum of trimethylarsonium methylide (9)is of some interest.' At room temperature the expected two singlets are observed, at chemical shifts which indicate a considerable dipolar contribution to the structure of the ylide. At higher temperatures there is considerable line broadening of both signals; a coalescence temperature could not be attained because of the onset of thermal decomposition. This broadening was attributed to fast proton exchange among the groups on arsenic as shown in (9). Significantly, addition of trace amounts of a protic acid caused coalescence at room temperature, by catalysis of the proton exchange. B. X-Ray Structure Determination.-Examination of a number of stable arsonium acylylides' 6-' * and cy~lopentadienylides'~-~~shows that the ylidic bond has a l4 A.W. Johnson and H. Schubert, J. Org. Clwm., 1970, 35.2678.'' H. Schmidbauer and W. Tronich, Inorg. Clietn., 1968, 7, 168. 16 Meicheng Shao, Xianglin Jin, Yougi Tang, Qichen Huang, and Yaozeng Huang. Terrdiedron Lxrr., 1982, 5343. " Fan Zhao-chang and Shen Yang-Chang, Acru Chin?.Siniui, 1984, 42, 759; Xia Zong-Xiang and Zhang Zhi-ming, Actci Chin?.Sinica (Engl. Tram.), 1983. 41, 148.'' G. Ferguson. I. Gosney, D. Lloyd, and B. L. Ruhl. J. Cliem. Res., 1987. submitted. l9 G. Ferguson. D. F. Rendle, D. Lloyd. and M. I. C. Singer. J. Cliem. Sor.. Chem. Commun., 1971. 1647. lo G. Ferguson and D. F.Rendle, J. Client. Soc.. Dolton Trcins., 1975, 1284. l1G. Ferguson and D. F. Rendle. J. Clien?. Soc.. Dnlron Trans., 1976, 171. 48 Lloyd, Gosney, and Ormiston length (-1.861.88 A) intermediate between the sums of the covalent radii of singly bonded and doubly bonded carbon and arsenic, indicating an appreciable amount of single-bond character and consequently of dipolar character. It is also evident that the negative charge is spread from the ylidic carbon atom into the substituent acyl or cyclopentadienyl groups. The configurations of the acylylides with the oxygen atoms directed towards the arsenic atoms is also confirmed. This is especially noticeable in the case of ylide (10) wherein there is evidently strong interaction between the oxygen and arsenic atoms and the latter atom is distorted from a tetrahedral-type geometry towards a trigonal bipyramid configuration with the oxygen atom at one of the vertice~.'~'~' That this interaction is also important in solution is evident from the lower dipole moment;' dipole moment measurements also confirm that other acylylides take up similar conformations.22 3 Preparation of Arsonium Ylides The first account of the preparation of an arsonium ylide (1 1) was given more than eighty years ago (Scheme 1),23 although the correct ylide structure for the product was not provided for nearly half a century.24 This is an example of the 'salt method' for the preparation of ylides. Ph3As + PhCOCH,Br +--+ Ph,AsCH,COPh NaoH) Ph,As=CHCOPh Br- (11) Scheme 1 A.Salt Method.-In the salt method an arsonium salt, usually obtained by reaction of a halogeno compound with an arsine, is treated with a suitable base to provide the ylide. Stable ylides are frequently made and isolated by using aqueous alkali. Reactive ylides need anhydrous conditions and the use of a suitable strong base, and are used in sitti. Thus triphenylarsonium methylide (12) has been prepared in it was isolated by using as base sodamide in tetrahydrofuran under an atmosphere of nitr~gen.~ Trimethylarsonium methylide (13) has been made indirectly, by desilylation of the trimethylsilylmethylide (14) with trimethylsilanol.' Ylide ( 14) was itself made by the salt method from chloromethyltrimethylsilane.29 Ph,As=CH, Me3As=C H2 Me3As=C HS iMe3 (12) (13) (14) I' H.Lumbroso, D. M. Bertin, and P. Freryen. Bull. Soc. Chim. Fr., 1974, 819. 23 A. Michaelis, Lirhigs Ann. Chem., 1902, 321. 174. 24 F. Krohnkc, Ciwrn. Ber.. 1950, 83, 291.''S. 0.Grim and D. Sryfcrth, Chem. Itid (LOndOn). 1959, 849. "M. C. Henry and G. Wittig, J. Am. Chrni. Soc., 1960, 82, 563. 27 D. Scyfcrth and H. M. Cohen, J. Inorg. Nuti. Chrrn., 1961, 20, 73.''S. Trippett and M. A. Walker. J. Ckeni. Sot,. C.. 1971. 11 14.'',N. E. Miller, Inorg. C'lirwi., 1965, 4, 1458. 49 Arsonium Ylides A variety of stable arsonium ylides (1 5) wherein COX represents a ketone, ester, or amide function, has been prepared by the salt method3*4,30-39 as have arsonium cyclopentadienylides (16)40 and fl~orenylides.~'-~~ Ph A phenyl group attached to the ylidic carbon atom has a smaller stabilizing effect and a number of examples of such semi-stabilized ylides have been prepared by the salt A p~blication~~discussing the uses of reactive arsonium ylides for the stereospecific preparation of epoxides draws attention to the fact that arsonium salts are less readily prepared than phosphonium salts because of the poorer nucleophilicity of arsenic compared to phosphorus, and suggests methods for obtaining them.Primary salts were made from alkyl triflates, while or-branched salts were prepared from alkyldiphenylarsines, obtained from iodo-compounds as, for example, in Scheme 2. Reaction of alkyl halides with arsines to form arsonium salts is also promoted by the presence of silver tetrafl~oroborate.~~ Variants of the salt method include the use of 1,3-dihalogeno compounds, which Ph2AsLi 1.But CL ,AICl3ICH2CHMe2 Ph2AsCH2CHMe2 6"' Ph2isCHMe28r-2. NaBF4 Scheme 2 30 G. Asknes and J. Songstad. Actrr Chem. Srancl., 1964, 18, 655. 31 N. A. Nesrneyanov, V. V. Pravdina, and 0.A. Reutov, Dokl. Akud. Nnuk SSSR, 1964,155, 1364; Proc. Acad Sci. USSR, 1964, 155, 424. 32 N. A. Nesrneyanov, V. V. Pravdina, and 0.A. Reutov, Ix. Akud. Nuuk SSSR, Ser. Khim., 1965, 1474; Bull. Acucl. Sci. USSR, Dio. Chem. Sci., 1965, 1434. 33 Y. T. Huang, W. Y. Ting, and H. S. Sheng, Acru Chin?. Sinicn, 1965, 31, 38. 34 K. Isslieb and R. Lindner, Liehigs Ann. Chrm., 1967, 707, 120. 35 A.W. Johnson and R. T. Arnel, Con. J. C'hem., 1968, 46. 461. 36 P. Frnyen. Acru Chem. Scand., 1971, 25, 2541. 37 R. S. Tewari and K. C. Gupta, Indiun J. Chem., Seci. B. 1979. 17, 637. 38 Y. T. Huang. Y. C. Shen. J. J. Ma, and Y. K. Xin, Aciu Chim. Sinica, 1980, 38, 185. 3y R. K. Bansal and G. Bhagchandani. J. Prczki. Chrni., 1981, 323, 49. 40 D. Lloyd and M. 1. C. Singer, J. Chem. SOC.C, 1971, 2941. 4' G. Wittig and H. Laib. Liehigs Ann. Chem.. 1953, 580. 57. 42 A. W. Johnson, J. Org. Chem., 1960, 25, 183. J3 R. S. Tewari and K. C. Gupta. liiclicin J. Chem., Seer. B. 1978, 16, 623. 44 P. S. Kendurkar and R. S. Tewari, J. Orgrinomer. C'hrnr., 1973. 60, 247: 1975. 85, 173; N. Kumari, P. S. Kendurkar, and R. S. Tewari, ihicl., 1975. 96. 237. 45 P.S. Kendurkar and R. S. Tewari. J. Organornet. Chem., 1976. 108, 175.''R. S. Tewari and S. C. Chaturvedi, Tetrcihedrnn Leri., 1977, 3843: Indian J. Chem..Seer. B, 1979, 18, 359. 4' W. C. Still and V. J. Novack. J. Am. Chem. Soc., 1981. 103, 1283. 48 I. Gosney. D. Lloyd. and W. A. MacDonald, unpublished work. 50 Lloyd, Gosney, and Ormiston undergo both substitution and elimination reactions to provide ylides. This method (Scheme 3) was used to prepare the cyclopentadienylide (4).49 ASP h, Scheme 3 B. Preparation from Arsine Diha1ides.-In the presence of triethylamine, triphenylarsine dichloride reacts with a variety of compounds having acidic methylene groups, to give arsonium ylides (Scheme 4).” This method is limited to -Et3N Ph,AsCI, + CH,XY Ph,As=CXY Scheme 4 compounds in which X,Yare electron-withdrawing groups, i.e.to the preparation of stable ylides. C. Preparation from Arsine Oxides.-Compounds having reactive methylene groups also react with triphenylarsine oxide, either in acetic anhydride, or in triethylamine with phosphorus pentoxide also present, to give arsonium ylides. First applied to cyclopentadienes bearing either phenyl or acyl substit~ents,~~~’ 1-53 its use was extended to prepare a variety of stable arsonium ylide~.’,’~ When the reaction is carried out in acetic anhydride acetylation may accompany the condensation reaction, e.g. Scheme 5.5*40*5 The mechanism involves initial formation of an acetylated or phosphorylated cation, which reacts with a carbanion to form a salt which is strongly acidic because of its substituent electron-withdrawing groups.This salt is hence readily converted into an ylide by loss of a proton, whose removal is assisted by the acetic anhydride or triethylamine, e.g. Scheme 6. As with method B the arsine oxide method is limited to the preparation of stable ylides, since its success depends on the acidity of the methylene compound. Almost all examples of this method have utilized triphenylarsine oxide; tri-n-butylarsine oxide has been used in triethylamine but gave only intractable products in acetic anhydride.’ In a modification of this method, an ylide has been prepared by reaction of acetoacetanilide with diacetoxytriphenylarsorane, the latter compound having 49 B.H. Freeman and D. Lloyd, J. Chem. SOC.C, 1971, 3164. L. Homer and H. Oediger, Chem. Ber., 1958, 91,437; Liehigs Ann. Chem.. 1959, 627, 142. 51 G. S. Harris, D. Lloyd, N. W. Preston, and M. I. C. Singer, Chem. Ind. (London), 1968, 1483. 52 D. Lloyd and N. W. Preston, J. Chem. SOC.C, 1969, 2464. 53 B. H. Freeman and D. Lloyd, Tetrahedron, 1974, 30, 2257. s4 G. S. Harris, D. Lloyd, W. A. MacDonald, and I. Gosney, Tetrahedron, 1983, 39, 297. 51 Arsonium Ylides '5 '2 Et3N AcZO Ph3As= CHN02 4 CH3N02 + Ph3As0 ___j Ph,As=CAcNO, AS Ph3 + Ph3As0 AsPh, Ac Scheme 5 Ph3As0 + Ac,O [Ph3AsOAcl+>[Ph3AsCHXYlf[OAcl-CH,XY + Ac,O --+ [CHXYI-JAcP Ph3As=CXY X,Y = Electron-withdrawing groups Scheme 6 been prepared from triphenylarsine and lead tetraa~etate.~~ D.Preparation from Diazo Compounds.-Another method for the preparation of stable arsonium ylides consists of heating a diazo compound in the presence of an arsine. Evidence has been provided that the diazo compound first decomposes to give a carbene which adds to the arsine (Scheme 7).56 As first introduced for the Ph Ph PheNi heat ,p h o AsPh, Ph 1 Ph 1 Ph Ph Ph Scheme 7 preparation of arsonium cyclopentadienylides the two reagents were simply heated together.57 Subsequent improvements include plunging a mixture of the reactants into a preheated bath53 and, above all, the use of copper or copper salts as ''J. I. G. Cadogan and I. Gosney, J. Chrm. Soc.. Prrh-iri Tr~ins.I, 1974, 466.B. H. Freeman, G. S. Harris, B. W. Kennedy, and D. Lloyd, Clrmi. Cornrnun., 1972. 912. 57 D. Lloyd and M. I. C. Singer, Chrni. Ind. (London). 1967, 510. 52 Lloyd, Gosney, und Ormiston catalyst^.^^^^ Not only may copper derivatives catalyse the reaction, they may also promote ylide formation which does not take place in the absence of cataly~t.~.~~ In particular the uses8 of catalysts such as copper acetylacetonate enables reactions to be carried out in solution, for example in boiling benzene, cyclohexane, or ethanol, at temperatures well below the normal decomposition temperature of the diazo compound in~olved.~ A particularly effective catalyst is copper hexafluoro- 3*5 a~etylacetonate;~~'~'arsonium ylides have been prepared even at room temperature in its presence.60-61 The function of the catalyst appears to be to bring the reactants into close proximity to each other by their co-ordination at the copper; a variety of other metals have proved to be ineffective as catalyst^.^^^^^ This catalytic method not only simplifies the manipulation but also increases the scope of the reactants which may be employed.A variety of stable arsonium ylides has been prepared in this way, although attempts to obtain ylides from monoacyldiazo compounds such as ethyl diazoacetate were unsu~cessful.~ Occasionally unexpected products arise. Thus diazo-2,5-diphenylcyclopenta-diene gave a 2,4-diphenylcyclopentadienylide,possibly due to rearrangement of the intermediate ~arbene,~~ and 9-diazofluorene gives fluorenone ketazine, resulting from rapid reaction of the first-formed ylide with unchanged diazo c~mpound.~.~~ E.Preparation from other Ylides.-Related to the conversion of diazo compounds into arsonium ylides is the formation of arsonium ylides by thermal decomposition of iodonium ylides, either when melted62 or heated in solution5* with triphenylarsine in the presence of a copper salt, e.g. Scheme 8. RCO >C=AsPh3 R'CO R't 0 Scheme 8 Preparations of arsonium ylides by reactions of other arsonium ylides with suitable substrates such as acid chlorides,63 acid anhydride^,^'^^ chlor~silanes,~~ acetylenes,2 sulphines,28 or N-acylaziridine~~~ will be discussed in a later section (6C) dealing with reactions of arsonium ylides.F. Preparations involving a Reverse-Wittig Reaction.-Triphenylarsine oxide reacts with a number of electrophilic acetylenes with electron-withdrawing substituents in what are, in effect, reverse-Wittig reactions, providing thereby stable arsonium ''J. N. C. Hood, D. Lloyd, W. A. MacDonald, and T. M. Shepherd, Tetrahedron, 1982, 38, 3355.'' D. Lloyd and S. Metcalfe, J. Clzem. Res. (S). 1983. 292. ''I C. Glidewell, D. Lloyd. and S. Metcalfe, Tetrahedron, 1986, 42, 3887. C. Glidewell. D. Lloyd. and S. Metcalfe. unpublished work. '2 K. Friedrich. W. Amann, and H. Fritz, Chern. Ber., 1979, 112, 1267. 63 R. S. Tewari and D. K. Nagpal. Z. Naturforsclr.. B, 1980, 35, 99. 64 Yanchang Shen. Zhengxiang Cu. Weiyn Ding, and Yaozeng Huang, Tetrahedron Lett., 1984, 4425 "H. W.Heine and G. D. Wachob, J. Org. Chem., 1972, 37, 1049. 53 Arsonium Ylides ylides (Scheme 9).66Reaction is presumably initiated by nucleophilic Michael-type Ph3As0 + R’C=CR*-Ph3As=CR’COR 2 Scheme 9 reaction of the oxide on the acetylene, r.g. Scheme 10. As would be expected from such a mechanism, use of an unsymmetric acetylene, as in the foregoing example, results in virtually regiospecific attack by the oxide to give the product shown. Scheme 10 G. Some Unusual Arsonium Ylides.-A squaric acid derivative which is also an arsonium ylide has been made (Scheme 1 l).67 0 !&heme 11 A cumulated arsonium ylide has been prepared by reaction of a methoxycarbonyl arsonium ylide with sodium bis(trimethylsily1)amide (Scheme 121.13 Ph,As=CHCOOMe + NaN[SiMe312-Ph3As=C =C =O Scheme 12 The bisylide (17) was made by the salt method; it is unstable as a solid and especially in solution (Scheme 13).6s 4 Stability of Arsonium Ylides Many of the stable arsonium ylides are crystalline solids which may be kept in air 66 E.Ciganek. J. Org. Chem.. 1970. 35. 1725.‘’A. H. Schmidt, R. Aimene, and M. Hoch, Synrhesis, 1984. 754. 68 H. Schmidbauer and P. Nusstein, Organomerallics, 1985, 4, 344. 54 Lloyd, Gosney, and Ormiston + + NaNH2 Ph,MeAs=C=AsMePh,Ph,MeAs -CH,-AsMePh2 X-(1 7) Scheme 13 without significant decomposition. More reactive arsonium ylides need to be made as required and used in situ. Their decomposition usually arises from hydrolytic attack; most arsonium ylides appear to be thermodynamically stable at room temperature.A. Thermal Decomposition.-Some arsonium ylides have been reported to decompose when heated in solution. For example, when triphenylarsonium benzylide was heated in a boiling benzene+ther mixture it decomposed to give triphenylarsine and a mixture of ~tilbenes.~~Trimethylarsonium methylide likewise undergoes thermal decomposition to give trimethylarsine and ethylene.' A likely mechanism for these reactions involves carbenic decomposition of the ylide followed by attack of the carbene on unchanged ylide with expulsion of an arsine fragment (Scheme 14). An alternative mechanism has, however, been proposed,69 CHR'R~A~=CHR' R3As-CHR'-R3As +I1R~AS=CHR'-R~AS+ R'HC: +-I CHR' fCHRl Scheme 14 which implicates the presence of some protonated ylide, either residual salt from the mode of preparation, or arising from protonation of the ylide by traces of moisture.This undergoes nucleophilic displacement of its arsine group by a molecule of ylide to give a salt of (18) which then provides the isolated alkene by means of an elimination reaction. Protonated ylide is regenerated so that only catalytic amounts of it need be present. Some support for this latter mechanism as at least a contributing mechanism derives from the observation that thermal decomposition is greatly retarded in the presence of a large amount of base.69 The more stable triphenylarsonium benzoylylide could be recovered unchanged from prolonged heating in boiling benzene but decomposed in boiling toluene to give triphenylarsine and trans-1,2,3-tribenzoylcyclopropane.l4 The latter product could arise from conjugate addition of unchanged ylide to alkene formed by thermal decomposition of part of the ylide (Scheme 15).In support of this mechanism it is known that arsonium ylides can react with conjugated unsaturated ketone^^^,^^ or ester^^',^' to give cyclopropane derivatives. The formation of 69 N. A. Nesmeyanov, V. V. Pravdina. and 0.A. Reutov. Zli. Org. Kliitn., 1967,3,598;J. Org. Chem. USSR (EngI. 7rans.),1967. 3, 574. 'O Huang Yao-tseng, Shen Yan-Chang, MaJing-ji, and Xin Yuan-kong, Acta Clzim. Sittica, 1980, 38, 185.'' Y. T. Huang, Y.C. Shen, Y. K. Xin. and J. J. Ma, Sri. Sinica, 1980.23, 1396; Chem.Abstr., 1981,957407h. Arsonium Ylides Ph,As=CHCOPh A PhCOCH=CHCOPh Ph3As =C HC0Ph1 PhC=CH -CHCOPh PhCOaCophCOPh -Tb LbHCOPh /I Scheme 15 cyclopropane derivatives from acyl ylides but not from a benzylide or methylide presumably reflects the fact that in the latter cases the alkenes which are formed first are not susceptible to nucleophilic attack. Keto-stabilized phosphonium ylides undergo thermal decomposition with extrusion of phosphine ~xides,'~ but no such reaction takes place with keto- stabilized arsonium ylides, presumably since the driving force to form an arsenic- oxygen bond is much less than that to form a phosphorus-oxygen bond. However an interesting rearrangement seems to be involved in the mass-spectrometric decomposition of triphenylarsonium nitromethylide (19), arising from arsenic- oxygen bond formation, most plausibly explained by a four-centre oxygen transfer reaction (Scheme 16).' The phosphonium ylide corresponding to (19) decomposes +-+.Ph$s=CH Ph3AS -CH Ph,As=CHNO, + + + I II O=N* 0 0-N-0 (19) HCNO1-[Ph,As 01'' As Ph/\OH Scheme 16 spontaneously at room temperature to triphenylphosphine oxide and fulminic This is a rare case of an arsonium ylide being more stable than its phosphonium analogue and is also attributed to the much greater energetic drive to produce a P-0 bond compared to an As-0 bond. B. Hydrolysis.-Many arsonium ylides are hydrolysed in the presence of moisture to give an arsine oxide and an organic residue.The first reported example described the rapid conversion of the semi-stabilized trimethylarsonium fluorenylide into trimethylarsine oxide and fl~orene.~~ More stable arsonium ylides may require heating under reflux with solutions of sodium hydroxide to bring about hydrolysis; ''A. W. Johnson. 'Ylid Chemistry', Academic Press, New York, 1966, p. 105 '3 S. Trippett and D. M. Walker, J. Cheni. Soc., 1959. 3874. Lloyd, Gosney, and Ormiston some diketo ylides can be recovered unchanged even under these drastic condition^.^ Ease of hydrolysis may depend strongly on the solubility of the ylide in the reaction solvent. Thus, whereas triphenylarsonium 2,3,4,5tetraphenylcyclo-pentadienylide was recovered essentially unchanged from ethanolic potassium hydroxide solution in which it is barely soluble,74 it and other triarylarsonium analogues decomposed to provide tetraphenylcyclopentadienewhen heated in methanol, in which they are soluble.48 It has been ~peculated’~ that, by analogy with the mechanism proposed for the extensively studied hydrolysis of phosphonium ylides, the steps involved in hydrolysis are protonation, followed by formation of a pentacovalent arsenic species and finally loss of a carbanion (Scheme 17).Presumably for arsonium C H,XY Scheme 17 ylides, as for phosphonium ylides, the group which leaves the arsenic atom in the last step will be the group which provides the most stable carbanion.Thus ethanolysis of triphenylarsonium benzylide provides toluene via the intermediacy of the benzyl anion.” If there is no group present able to provide a stable anion, reaction may not proceed to give an arsine oxide. For example, triphenylarsonium methylide reacts with water to give the arsonium hydroxide (lo)*’ and trimethylarsonium methylide reacts with methanol to provide a pentacoordinate arsorane (21>.’“ + Ph,AsMe HO-MeOA s Me4 (20) (21 1 5 Basicity of Ylides and Acidity of their Conjugated Acids Many arsonium ylides dissolve in acids to form salts, from which they can be reobtained by treatment with a base, as in the salt method for their preparation. The basicity of the ylides indicates the relative stabilities of the ylides and their salts and in so doing gives some guide to the stability of the ylides.Thus stable ylides are less readily protonated than are reactive ylides and require weaker bases for their preparation from salts. Stabilizing substituent groups are commonly those which can delocalize the negative charge on the ylidic carbon atom. Measurements on a series of 14 B. H. Freeman. D. Lloyd. and M. I. C. Singer, Tetrahedron. 1972, 28, 343. 75 Ref. 72, p. 292.’‘ H. Schmidbauer and W. Richter. Angew. CIIP~~.,1975.87.204: Angew. Clrem..Inr. Ed. Engl.. 1975,14, 183. 57 Arsonium Ylides triphenylarsonium p-substituted benzoylylides (22) showed that their basicity is lower the more electron-withdrawing the p-sub~tituent.~.~~,~~ Similarly for the ylides (23, X = H), the basicity decreases as the group COZ becomes more capable Ph,As =CHCOC,H, X(p) (p-XC,H,),As=CH COZ (22) (23) of delocalizing a negative charge; the basicity when Z = alkyl or aryl is much less than when Z = OR or NR2.36Increase in the electron-donating character of X in (23), e.g.from H to Me to OMe causes an increase in basicity,36 as does replacement of a triphenylarsonium group by a trimethylarsonium But, while tri-p-tolylarsonium tri- and tetra-phenylcyclopentadienylidesare more basic than their triphenylarsonium analogues the corresponding o-tolylarsonium ylides are less presumably steric factors are relevant in the latter case. In studies of ylides having different heteronium atoms, e.g. on methoxycarbonyl-benzoyl ylide~,~.~',~~ylide~,~~ fl~orenylides,?~tetraphenylcyclopentadien-ylides,' 4,78 and triphenylcycl~pentadienylides,~~the arsonium ylides were uniformly more basic than their phosphonium or sulphonium analogues.These results imply that arsenic plays a smaller part than do phosphorus and sulphur in the distribution of negative charge from the adjacent carbanion. This difference has commonly been attributed (inter ah3*' ) to the lower 2330,34,35,79-81 electronegativity of the arsenic atom, which leads to a lower electrostatic interaction between the arsenic and ylidic carbon atoms, and to a lower effectiveness of pn-dn orbital overlap between these atoms because of the greater size and diffuseness of the arsenic 4d-orbitals compared with the 3d-orbitals of phosphorus or sulphur.But it has been pointed out that other factors in addition to electronegativity and pn-dn orbital overlap must play a part in determining the relative acidity of the heteronium salts and the stability of the related ylide~.~~ The involvement of steric factors has been n~ted.~~.~~ 6 Reactions of Arsonium Ylides By far the most important reactions are those of the Wittig type, with carbonyl and nitroso compounds. Other carbanionic reactions are considered and a final section deals with the formation of cyclic compounds from arsonium ylides. Hydrolysis has been discussed in Section 4B. A. Reactions with Carbonyl Compounds.-The first example of a reaction between an arsonium ylide and a carbonyl compound was recorded in a thesis in 1937.** It ''A.W. Johnson and R. B. LaCount, Tetrahrrlron, 1960. 9. 130. 78 D. Lloyd and M. I. C. Singer, Cheni. lid. (London). 1968. 1277. ''D. Lloyd and M. I. C. Singer. Tetrdiriiron. 1972. 28, 353. Ref. 72, pp. 284 299. "I H. Starzewski, W. Richter, and H. Schmidbauer, Chern. Bet-., 1976, 109, 473. 82 W. Heffe, Dissertation, University of Berlin, 1937; quoted by G. Wittig, Purr Appl. Chern., 1964,9, 249 (W. Heffe was a student with F. Krohnke). 58 Lloyd, Gosney, and Ormiston was reported that triphenylarsonium benzoylylide reacted with benzaldehyde to give benzylideneacetophenone.82Two publications dealing with the reactions of arsonium ylides with carbonyl compounds appeared in 1960.One described the formation of alkenes in high yield, starting from a fl~orenylide,~~ and the other reported that from triphenylarsonium methylide and benzophenone both 1,l-diphenylethylene and phenylacetaldehyde were obtained, with the latter predominating (1 :3.5); it was suggested that the aldehyde arose from an initially formed epoxide during an acid work-up of the reaction.26 Similarly a reaction between triphenylarsonium ethylide and p-tolualdehyde gave a mixture of a small amount of alkene and, as principal product, p-tolylacetone, again formed by acid induced rearrangement of an initially formed ep~xide.~~ Thus at an early stage in the study of arsonium ylides it was shown that either alkenes or epoxides might be formed, in contrast to the behaviour of phosphonium ylides, which gave only alkenes, and sulphonium ylides, which gave only epoxides.80 It was also apparent that arsonium ylides were more reactive than their phosphonium analogues, for while triphenylarsonium fluorenylide reacted with p-dimethylaminobenzaldehyde to give an alkene in high yield, triphenylphosphonium fluorenylide did not react with this aldehyde.42 This arsonium ylide reacted in high yield with a number of substituted benzaldehydes and with acetaldehyde; it did not react with acetone or acetophenone but did with the more reactive ketone p-nitroa~etophenone.~~ The reaction of triphenylarsonium benzylide (24) with p-nitrobenzaldehyde (Scheme 18) provided an alkene and an epoxide in about equal amount, together with equimolar amounts of triphenylarsine and triphenylarsine oxide.2 Ph3As=CHPh + OHL (24) Ph3As + PhCH-CHC,H,NO, Scheme 18 By contrast, in another investigation of the reactions between arsonium ylides and aldehydes, it was found that either an alkene or an epoxide was formed, depending upon the identity of the ylide, but not both together.28 Both alkenes and epoxides were always trans.28 This appears usually to be the case.(i) Comparison of Stable, Reactive, and Semi-stabilized Ylides. The general pattern which emerged was that stable arsonium ylides provided alkenes whilst reactive arsonium ylides gave epo~ides.**'~*~~*~~ This was attributed to stabilization of the transition state leading to alkene formation being provided by those same electron- withdrawing groups which stabilized the ylides.2*28 83 A.Maccioni and M. Secci, Rend Seminario Fac. Sci. Unic. Cagliari, 1964, 34, 328. Arsonium Ylides Thus arsonium ylides stabilized by acyl group^,^*^^-^ 1,32*43~84-86alkoxycarbonyl gro~ps,~,~~,~~ all provided cyano group^,^^-^' and cyclopentadiene rings53*74*78,79 alkenes, predominantly rrans, as products from reactions with carbonyl compounds. Most ylides with two electronwithdrawing substituents did not, however, take part in Wittig reaction^;^ steric factors may also sometimes inhibit reaction.54 Reactive ylides give good yields of trans-ep~xides.~~ Stereospecificity may vary with conditions. For example use of an arsonium tetrafluoroborate as precursor of the ylide, and potassium bis(trimethylsily1)amide as base gave 100% trans-epoxide, whereas with iodide as counterion and butyl lithium as base, there was less stereo~pecificity.~’Reactive ylides generated from optically active arsonium salts reacted with arylaldehydes to give trans-epoxides which were optically active.88 Allylic arsonium ylides show a similar pattern of reactions. An ethoxycarbonyl- ally1 ylide, having the ester group conjugated with the ylidic carbon atom, gave dienes in reactions with aldehydes or ketones,” whereas other allylic ylides lacking such an electron-withdrawing substituent gave vinylic epoxides in high yield,90*91 e.g.Scheme 19. In the latter case it was found that the presence of Scheme 19 hexamethylphosphoramide resulted in the formation of a diene instead of the ep~xide.~’ Semi-stabilized ylides are intermediate in behaviour between stable and reactive ylides, and may provide alkenes and/or epo~ides.~.~~~~~*~~,~~ In these cases other factors such as the substituent groups on arsenic, and the nature of the solvent and base, may become important in determining the nature of the product; this will be considered in more detail later.Small changes in the structure of the ylidic moiety may also have a marked effect; for example, whereas triphenylarsonium p-naphthylmethylide reacts to give epoxide, the presence of a bromine atom at the adjacent x-position of the naphthalene ring results in the formation instead of alkene~.~~ 84 Yaozeng Huang, Yuanyao Xu, and Shong Li, Org.Prep. Proced. Int.. 1982. 14, 373. w5 P. Bravo, C. Ticozzi, and A. Cezza, Cuss. Chim. Itul., 1975,105,109;R. S. Tewari and K. C. Gupta, Indian J. Chem., Sect. B, 1976, 14, 419; 1979, 17, 637; R. S. Tewari and S. C. Chaturvedi, Synthesis, 1978, 616; Yaozeng Huang, Lilan Shi, and Jianhua Yang, Tetrahedron Lett., 1985, 26, 6447. 86 Y. Z. Huang, Y. D. Xing, L. L. Shih, F. L. Ling, and Y. Y. Xu, Acta Chim.Sinica, 1981, 39, 348. ” Huang Yao-zeng. Shi Li-Ian, Li Bin-quan, and Ling Fang-le, Acta Ciiim. Sinica, 1983, 41, 269. D. G. Allen, N. K. Roberts. and S. B. Wild. J. Cliem. Soc.. Chem. Commun.. 1978. 346. no Yaozeng Huang, Yanchang Shen, Jianhua Zheng, and Shixiang Zhang, Synthesis. 1985, 57. 90 J. B. Ousset. C.Mioskowski, and G. Solladie. Tetrahedron Let!.. 1983, 4419. 91 J. B. Ousset, C. Mioskowski, and G. Solladie, Syntii. Comrnun., 1983. 13, 1193. 92 R. S. Tewari and S. Gupta, J. Organomet. Ciiem., 1976, 112, 279. Lloj*d,Gosney, and Ormiston These results may be summarized as in Figure 1. \ Reactive ylides Semi-stabilizea ylideg Stable ylides 12 e.g. CR’R’ = CH2.CHMe e.g. CR R = CHC,H,X e.g. CR’ Rz = CHCOR3 7 Increasing reactivity of ylide Figure I (ii) Reactivities of Arsoniurzi Ylides compared to those of Phosphonium and Sulphonium Ylides. Comparative studies involving acyl ylide~,~,’~ fl~orenylides,~~ and cy~lopentadienylides,’~*~~*~~*~~show that arsonium ylides are markedly more reactive than their phosphonium and sulphonium analogues.In many cases reactions proceed only in the case of the arsonium ylides; this is especially true the more electron-withdrawing are the substituents on the ylide carbon atom, although some arsonium ylides with two electron-withdrawing substituents will not react even with aldehydes as reactive as 2,4-dinitrobenzaIdehyde,’ The reactions of a series of arsonium ylides with p-nitrobenzaldehyde have been shown to be first order for each reagent and there is a general tendency for the more basic ylides to be the more reactive.36 The correlation is not, however, complete, since factors other than basicity, e.g. steric, must also affect the reactivity,’~~~.~~ but as a generalization it is largely valid and also must be a significant factor in the greater reactivity of arsonium compared to phosphonium and sulphonium ylides.A fair correlation has also been noted between the chemical shift of the signal from the methine proton in a series of stabilized ylides and their rates of reaction with p- nitrobenzaldehyde.36 (iii) Effects of Dfferent Substituents on the Arsenic Atom. The first report of such effects was in a study of the reactions of a series of tris-(p-substituted phenyl) arsonium ylides with benzaldehyde, when all these ylides gave epoxides in high yields save for the tris(p-dimethylamino) compound which gave instead the trans-alkene.93 In further experiments replacement of a triphenylarsonium group by a tris-(p-methoxypheny1)arsoniumgroup was found to have little effect on the ratio of products,2s and inclusion of the arsenic atom in a strained ring also had no effect.94 A comprehensive investigation of a series of ylides (25) with benzaldehyde showed that as X,Y became more electron-donating, so the proportion of alkene to epoxide increased.” For example, the ratios epoxide:alkene changed from -11 : 1 93 S. G.Dwyer, Ph.D. Thesis, University of North Dakota, 1970. q4 D. W. Allen and G. Jackson. J. Organomet. Cfiem., 1976, 110, 315. ” I. Gosney, T. J. Lillie. and D. Lloyd. Angew. Ch~rn..1977,89, 502; Angew. Cfwrn.,In[. Ed. Engl., 1977,16, 487. 61 Arsonium Ylides (X = Y = H) to -6.5:l (X = Y = MeO), -6:l (X = H,Y = NMe,), -4:l (X = NMe,, Y = H), -1: 1 (X = Y = Me,N). Even more striking is the effect of replacing these aryl groups by alkyl groups, viz.ratios epoxide: alkene were Ph,As, -11 : 1; Et,PhAs -1 :5; Et,As, -1 :87.95 These results strongly suggest that remote control of the major pathway followed in reactions of semi-stabilized arsonium ylides with carbonyl compounds might be achieved by choice of the appropriate arsonium group. The reactivity of arsonium ylides is also affected by both electronic and steric effects on the arsenic atom.48 (iv) Solvent Eflects. Initial studies of solvent effects, on the reactions of triarylarsonium benzoylylides with p-nitrobenzaldehyde in N,N-dimethyl-formamide, dimethyl sulphoxide, or methanol indicated little solvent effect in these cases,36 but later studies of the more finely balanced reactions of semi-stabilized ylides have provided examples of strong influence due to the effect of different base and solvent when the ylide is generated in the presence of a carbonyl compound.’5v46*91 Th us, when benzyltriphenylarsonium bromide or p-chloro- benzyltriphenylarsonium bromide were treated with sodium hydride in benzene in the presence of a variety of p-substituted benzaldehydes, the isolated products were alkenes, but if the base was sodium ethoxide in ethanol the isolated products were epoxide~.~~ Again scope for the control of the reaction paths at least of semi- stabilized ylides is indicated.Reactions providing alkenes have been found to be faster in methanol than in benzene; this has been ascribed to hydrogen-bonding rather than to polarity.36 (v) Reactions Mith Conjugated Enones.Arsonium ylides may react with conjugated enones or esters to give dienes, or by conjugate addition to provide cyclopropane derivatives,64.70,71.84.9 1 r.g. Scheme 20.” Formation of cyclopropane derivatives is discussed further in Section 6D. RCOCH=CMeCH=CR’R’ (R’ = Ph’. R2 = H or Ph3As= CHCOR R’ = R2 = Me) (R = OMe or Ph) (R3= Me,Ph, COOMd COR Scheme 20 (vi) Reactions with other C=X Functions. Semi-stabilized arsonium ylides react with thioketones; for example with cyclic thioketones triphenylarsonium benzylides Lloyd, Gosney, and Ormiston gave only exocyclic alkenes and no thiiran~.~~ Benzothiopyrones (and, better, benzopyrones) also react to give exocyclic alkenes, in these cases arylidene- benzopyran~.~’ Reaction of triphenylarsonium benzylide with benzylideneaniline gave 1,2,3-triphenylaziridine.28 This reaction is thus analogous to that of reactive arsonium ylides with carbonyl compounds.(vii) Mechanism. Since the behaviour of arsonium ylides in Wittig reactions appeared to be intermediate between that of sulphonium and phosphonium ylides, it was inferred that mechanisms similar to those accepted for the respective reactions of the latter ylides were involved,2*80 uiz. Scheme 21. The energetic driving 8+ 8-R& -CR R,AS-CR; R3As0 RP I -II (a)) +s=CR -0-CR; 0-CRI 2C=CR’i-0-CR; -R’ t +11 + Scheme 21 force to generate an arsenic-oxygen bond is not as strong as that to form a phosphorus-oxygen bond, so that there is not the same compulsion to alkene formation in the case of arsonium ylides, allowing the alternative pathway (b) to compete.It was suggested that in the case of stable ylides, wherein R‘ is an electron- withdrawing group, the presence of the latter group, which becomes conjugated with the carbon-carbon double bond in the final alkene, also stabilizes the transition state leading to the formation of this alkene, thus promoting pathway (a) with respect to pathway (b).2,28 The rates of reaction of acylylides, Ph,As=CHCOX with ketones decreases as X is more electron-withdrawing, making the ylide less nucle~philic.~~This observation, together with the relation between the reactivity and basicity of the ~lide~~ all suggest that the first and the second-order character of the rea~tion,,~,~~ step, which is slow and reversible, is the rate-determining step.The lack of solvent effect in the reactions between benzoylylides and p-nitrobenzaldehyde led to the s~ggestion,~that in alkene formation reaction goes directly to a four-membered ring transition state without intermediate formation of a betaine. This was seen to be consistent with the large negative entropy of reaction and the very low activation energies observed. 36 96 R. S. Tewari, S. K. Suri, and K. C. Gupta. Z. IVururfiwsch., B. 1980. 35,95. 97 R. S. Tewari. S. K. Suri, and K. C. Gupta. S~nrh.Commun.. 1980, 10, 457. 98 N. A. Nesmeyanov, E. V. Binshtok, 0.A. Rebrova.and 0.A. Reutov. Ix.Aknd Nouk SSSR. Ser. Khini., 1972, 21 13; Bull. Acad Sci. USSR. Dic. Chem. Sci., 1972, 2056. Arsonium Ylides Formation of an epoxide must, however, involve an intermediate betaine which reacts further by intramolecular displacement of an arsine. When pathways (a) or (b) are followed the electrons in the arsenic-carbon bond are displaced in an opposite direction in the two mechanisms. In alkene formation displacement is away from the arsenic atom and in epoxide formation displacement of electrons is towards the arsenic atom. The change in pathway, depending on the nature of the substituents at arsenic, could be associated with this, for electron- donating substituents on arsenic should assist displacement of the electrons away from arsenic and favour alkene formation as ~bserved.'~ For similar reasons electron-withdrawing substituents on the ylidic carbon atom should favour alkene formation. The observed solvent effects on the type of product f~rmed~~.~~ could also be associated with the structure of the intermediate.Formation of alkenes or epoxides necessitates, respectively, cisoid and transoid arrangements of the arsenic and oxygen atoms, and a transoid structure is likely to be much more favoured in a polar protic solvent such as ethanol than in benzene. (viii) Coda. Reactions of arsonium ylides with carbonyl compounds take place much more readily than with phosphonium or sulphonium ylides. The nature of the products depends on the character of substituents on the ylide carbon atom, where electron-withdrawing substituents favour alkene formation, and of substituents on the arsenic atom, where electron-donating substituents favour alkene formation.This may be summarized by Figure 2. Type of Ylide (Push, pull refer, respectively, $As=C, / to electron-donating or electron-Push-Pull-Alkenes withdrawing effects of substituents4t on the arsenic or carbon atoms) Epoxides+PuII -Push Figure 2 However choice of base and solvent can, in the case of less stabilized ylides, have an effect both on the product distribution and on the stereospecificity of the product. More detailed analysis is still required but it seems likely that, at least in the case of semi-stabilized ylides and possibly for others also, control over the product can be achieved by suitable choice of the substituents on arsenic and of the solvent, thus making a valuable addition to the organic chemist's synthetic armoury.B. Reactions with Nitrosobenzene.-Ylides may react with nitrosobenzene in a similar manner to their reactions with carbonyl compounds (Scheme 22). Sulphonium ylides give nitrones,80 phosphonium ylides give anils," and, true to their intermediate character, arsonium ylides may give either anils or nitrones or both.2*54-74*78*79Similar considerations should apply to these reactions as to those with carbonyl compounds, and again the reactivity of arsonium ylides is much Lloyd, Cosney, and Ormiston + -Ph3As = CR, P h,As -C R, Ph,As-CR, Ph,As 0 A I--II7+ -0 -NPh -0-NPh + PhNO R,C= NPh + 11 Ph3As-C A, P h3As PhN-0--+ 0+I [ PhN=CR,PhN-0 ? Scheme 22 greater than that of corresponding phosphonium (or sulphonium) ylides.74*78,79 p-Electron-donating substituents in aryl groups attached to arsenic increase the proportion of anil to nitrone, in keeping with their effect on reactions with carbonyl compounds, see for example Scheme 23.54 Ph Ph Phpho=NphPh -.ph>AsA5- PhNo ph\ +- Ph I PheiphPh Ph Ph 0 Ar = Ph 48.10 Ar = p-MeCgHL 60°10 Ar = p-MeOC,H, 48 '10 Scheme 23 C.Reactions with other Electrophi1es.-Because of the partial negative charge on the ylidic carbon atom, arsonium ylides are also attacked by other electrophiles.The first reported examples of such reactions are shown in Scheme 24.27,31 Chlorination has been achieved using iodobenzene tri~hloride.~~ 4-Br-+ '2 Ph$sCH BrCOPh Br-P h3As =CHCOP h <ph$sCH<cop S 0,-Scheme 24 99 R. M. Moriarty, I. Prakash, and W. A. Freedman, J. Am. Ckem. Soc., 1984, 106, 6082. 65 Arsonium Ylides Alkylation of trimethylarsonium methylide with methyl iodide gave ethyltrimethylarsonium iodide,26 but reaction of triphenylarsonium benzoylylide with ethyl iodide gave an 0-ethylated product rather than a C-ethylated prod~ct.'~ Phosphonium ylides undergo 0-alkylation 'O0 while sulphonium ylides undergo C-alkylation. It is suggested that 0-alkylation and C-alkylation of arsonium ylides result, respectively, from kinetic and thermodynamic contr01.'~ Alkylation of triphenylarsonium benzylide with methyl chloroformate gave a substituted ylide, by C-alkylation (Scheme 25).12 Scheme 25 Arsonium ylides react with fluoroalkenes; the isolated products, after hydrolysis, are disubstituted arsonium ylide~,'~~*'~~ e.g.Scheme 26. In some, but not all cases, the prehydrolysis product has been isolated. Ph,As=CHCN + CF,=CFCF, -[ Ph,As=C(CN)CF=CFCF,] Ph3As = C (C N) COCHFCF, Scheme 26 Acylation has been used frequently to convert arsonium ylides into other more 04v1 O5 acidstabilized ylides, reagents being acid ~hlorides,'~~~~*~~*'anhy-drides,5.14.39.63 or esters.' These examples all involve C-acylation but com-plications can arise, as Scheme 27 shows.I4 Presumably the reaction with benzoyl Scheme 27 I00 F.Ramirez and S. Dershowitz. J. Org. Chem., 1957, 22. 41. In' A. W. Johnson and R. T. Amel. J. Org. Cliem.. 1969, 34, 1240. ln2 Y. T. Huang, W. Y. Ding, W. Cai, J. J. Ma. and Q. W. Wang. Sci. Sinica. 1981. 24, 189; Chem. Ahstr., 1981.95. 91923a. lo3 Ding Wei-yu, Cai Wen. Dai Jin-Shan. Huang Yao-zeng, and Zhen Jian-hua, .4cta Chim. Sinicu, 1983. 41, 67. I*' K. C. Gupta and R. S. Tewari. Indim J. Cliem.. 1975. 13. 834. 105 p S K endurkar and R. S. Tewari, J. Organomet.Cheni.. 1975, 102. l41.. . 66 Lloyd, Gosney, and Ormiston bromide gives a kinetically controlled product which is converted into the thermodynamically controlled product in the presence of acetate. l4 In this case delocalization of the negative charge leads to acylation at a site other than the ylidic carbon atom.Similarly with cyclopentadienylides, wherein the charge may be delocalized around the ring, acylation takes place at other positions in the ring than the ylidic carbon atom, but, since a carbon-carbon bond is formed, there is no tendency for the acyl group to migrate (Scheme 28).52,79 AC 3: 1 Scheme 28 Aryldiazonium salts also react with cyclopentadienylides to give 2-or 3-phenylazo derivative^.^^.^^ Other reagents which react with arsonium ylides are phenyl sulphine and phenyl sulphene (Scheme 29).28Ethyl cinnamate is also a product of the latter reaction, presumably formed by the route shown in Scheme 30. The ylidic carbon atom of a number of acylylides reacted with tropylium bromide to give tropylarsonium salts (26), which decomposed by elimination of triphenylarsine to give P-acylstyrenes Ph3As=CHCOC6H,Br (p) + PhCH=SO +Ph3As=C/COC6H,Br (p) \sow ,Ph Ph3As =CHCOOEt + PhCH =SO, -Ph3As=C ‘S02Cti ,Ph Scheme 29 + ,COOEt Ph$S=CHCOOEt + PhCH=SOz +Ph$SCH/ ‘SOzCHPh CHCOOEt -/ \PhCH=CHCOOEt + Ph$s 03-CHPh Scheme 30 Arsonium Ylides and P-acyl-P-tropylstyrenes. O6 Triphenylarsonium benzoylylide was also alkylated with 1-p-nitrobenzoylaziridinein boiling toluene to give (27).6' COR Ph,As =C (26) ( 2 71 A more complex reaction ensues between acylylides and dimethyl acetylene- dicarboxylate, the product presumably arising via a four-membered ring intermediate (Scheme 31).28 Ph, As = CHCOR Ph3As-CHCOR ,C00MeI1 Ph,As=C \C+ +MeOOCC = CCOOMe = c HCOR MeOOCCzCCOOMe 1 COOMe Scheme 31 D.Formation of Cyclic Compounds from Arsonium Y1ides.-Cyclopropane derivatives have been prepared from reactions of arsonium ylides with x,P-enones 14,2 8.64.84.107 and a$-unsaturated esters.38*70y84In itial Michael type reaction is followed by intramolecular elimination of triphenylarsine, e.g. Scheme 32.28 ArCOCH=CHPh + Phps=CH,r ArCOCH-CHPh ArCOCH -CHPh +I + \I C H 9-A s Ph3 CH,L, Scheme 32 A variety of heterocycles has been made from arsonium ylides. For example, as mentioned in Section 6A(vi), 1,2,3-triphenylaziridinewas obtained by reaction with benzalaniline.2 r-Pyrones result from reactions of acylylides with diphenylcyclopropenone, presumably via attack by the acyl oxygen atom of the ylide on the cyclopropene ring.' Indoles have been prepared from reactions of o-aminophenylketones with reactive"' or arsonium ylides.Keto-stabilized ylides reacted with a- chloro-oximes to give trans-5-a~yl-A~-isoxazolines,~and isoxazoles have been lo6 G. Covicchio, M. DAntiono, G.Gaudiano, V.Marchetti, and P. P. Ponti, Tetrahedron Letr., 1977,3493. lo' N. A. Nesmeyanov and V. V. Mikul'shina, Zh. Org. Khim., 1971, 7, 696. P. Bravo, G. Gaudiano, P. P. Ponti, and M. G. Zubiani, Tetrahedron Lett., 1970. 4535. R. K. Bansal and S. K. Sharma, Tetrahedron Lett., 1977, 1923. 'lo R. K. Bansal and S. K. Sharma, J. Orgunomet. Chem., 1978, 149, 309.''I R. K. Bansal and G. Bhagchandari, Bull. Ckem. SOC.Jupan, 1980, 53, 2423. 'Iz P. Bravo, G. Gaudiano, P. P. Ponti, and C. Ticozzi, Tetrahedron, 1972, 28, 3845. Lloyd, Gosney, and Ormiston obtained from reactive arsonium ylides and a-isonitrosoketones' and from triphenylarsonium methylide and nitrile oxides. 'l4 The latter ylide reacts similarly with nitrile imines to give pyrazoles.' l4 With triphenylarsonium benzylides and benzoylylides benzene diazonium salts give 1,3,4,6-substituted 1,4-dihydro- 1,2,4,5- tetrazines in a reaction in which initial coupling of the reagents is followed by a dimerization.' ' E. Reactions of a Cumulated Arsonium Y1ide.-A cumulated arsonium ylide has been found to undergo similar reactions to its phosphonium analogue. The examples shown in Scheme 33 were cited.I3 + rl [Ph$sCMe =C= 0 I -I\ Ph,As=C=C 10 \." .Me n EtSHPh,As=C=C=O ____) Ph,As=CHCOSEt QCOPh H Scheme 33 7 Arsinimines Arsinimines (28) are the nitrogen analogues of arsonium ylides. They appear to be more resistant to hydrolysis than the ylides for even the simple non-stabilized example (28, R = H) can be handled in air, although it is less stable than its phosphonium analogue. +-Ph,As=NR Phps-NR A. Preparation of Arsinimines-The methods used for the preparation of arsonium ylides, namely salt method, use of arsine dihalides, condensation reactions with arsine oxides, and trapping of carbenes by arsines, have all been applied to the preparation of arsinimines.In contrast to the common use of the salt method for making ylides, there is only one example of its use for preparing an arsinimine, to provide what is as yet 'I3 P. Bravo, G. Gaudiano, and C. Ticozzi, Gnx. Cliim. ltal., 1972, 102, 395. I14 G. Gaudiano, C. Ticozzi. A. Umani-Ronchi, and A. Selva, Chem. Ind. (Milan),1967, 49, 1343. R. K. Bansal and S. K. Sharma, J. Organomet. Chem., 1978, 155, 293. Arsonium Ylides the simplest reported example (Scheme 34).' ' Arsinimines have been prepared from arsine dihalides, using the reactions between dibromotriphenylarsine and amides."7" l8 + NaNH, Ph,As + CINH, -Ph,AsNH, CI-+ Ph,As=NH H3 Scheme 34 The first reported example of the preparation of an arsinimine, in 1937, utilized the reaction of the sodium salt of chloramine T with triphenylarsine (Scheme 35)' ' This reaction, which has been repeated by later workers,' 2o is not, however, straightforward, and earlier work had shown that chloramine T reacts with the arsine to convert it into an arsine oxide,I2' which then condenses with the tosylamide to provide the final product.Other arsinimines have been made by the same method but in the majority of cases were isolated as their water adducts.122 In a modification of this reaction, chloramine T itself, rather than a salt, underwent an exothermic reaction with triphenylarsine in dry benzene, and the resultant intermediate, which was not isolated, gave, on treatment with copper powder, an arsinimine (Scheme 36).'23 Ph,As + [p-MeC6H,S0,NCIl' Na'F Ph3As=NS02C6H4Me(p) Scheme 35 Ph3As CUp-MeC6H4SOzNC~z PhH * __j p-MeC,H,SO,N = AsPh, Scheme 36 Triphenylarsine oxide reacts with a variety of nitrogen compounds, namely aryl isocyanates,' 249125 acyl isocyanates,' ' N-sulphinylamines,' 24 and N-sulphinyl- amides,' 24,1 26 to provide arsinimines.Nitriles fully substituted on the a-carbon atom add triphenylarsine oxide to give N-acylarsinimines;' 27 other nitriles did not react or instead condensed with the arsine oxide at the a-carbon atom to give ylides. Closely related to the arsine oxide method is a ready way for preparing R. Appel and D. Wagner, Angen. Chem., 1960, 72. 209. 'I7 B. D. Cbernokal'skii, S. S. Nasybullina, R. R. Shagidullin, I. A. Lamanova, and G.Kamai, I:o. Vyssh. Uchebn. Zaved. Khim. Khim. Teklinol.. 1966, 9, 768; Chem. Abstr., 1967, 66, 761 12. 'InP. Froyen, Acta Chem. Scand., 1969, 23, 2935. F. G. Mann and E. J. Chaplin, J. Chem. Soc.. 1937, 527. IZ0 G. Wittig and D. Hellwinkel, Chem. Ber., 1964, 97, 769. F. G. Mann, J. Chem. Sac., 1932, 958. D. S. Tarbell and J. R. Vaughan, J. Am. Chem. Soc., 1945, 67, 41. A. Schonberg and E. Singer. Chem. Ber., 1969. 102, 2557. P. Freryen, Acta Chem. Scand., 1971. 25. 983. 125 P. Froyen, Acla Chem. Scand., 1973. 27, 141. IZ6 A. Senning, Actu Chem. Scand., 1965, 19, 1755. G. Gadeau. A. Fouchaud, and P. Merot. Synthesis, 1981. 73. Lloyd, Gosney, and Ormiston arsinimines by heating together triphenylarsine, an amide, and lead tetraacetate in a one-pot reacti~n.~~,'~~ The reaction sequence, which is as shown in Scheme 37, is analogous to that postulated for the formation of arsonium ylides from triphenylarsine oxide in acetic anh~dride.~ Crystalline bisacetoxytriphenylarsine (29) has been isolated and shown to react with amides to give ar~inimines.~~,'~~ Tosyl and mesyl amides and benzamide react with (29) at room temperature, but less nucleophilic amides required heating in boiling 1,2-dichIoroethane for reaction to take place.55 Ph3As + Pb(OAc1, -Ph3As(0Aclz RCONH Ph3As= NSO,R Ph3As = NCOR (29) Scheme 37 As carbenes react with arsines to give ylides, so nitrenes give arsinimines.'287'29 The nitrenes were generated in situ by copper-catalysed decomposition of either azides128.129 or 3-aryl-l,4,2-dioxazolidin-5-ones.29 N-Ethoxycarbonyl- and N-p- tolylsulphonyl-triphenylarsinimines have been prepared by nitrene capture reactions in which the nitrenes were generated by the action of base on, respectively, a sulphonyloxyurethane and a ~ulphonarnide,'~~ e.g.Scheme 38. Et3N +-Et OOCNHOS0,CGH4N0,(p) EtOOCN: + Et,NH OS02C,H4N0,(p) / Ph,As =NCOOEt Scheme 38 B. Properties of Arsinimines.-Many arsinimines are stable solids, handleable in air; as with arsonium ylides, the presence of electron-withdrawing substituents on the nitrogen atom increases their stability. Infra-red spectra show that in N- acylarsinimines the negative charge is delocalized onto the oxygen atom.' l8 N-Benzyltriphenylarsiniminedecomposes when heated to give triphenylarsine oxide and benzonitrile.' l8 Arsinimines are hydrolysed by aqueous base' 8,''' or acid,' providing triphenylarsine oxide and an amide.With hydrogen chloride they form arsonium halides. l6 Arsinimines have been alkylated using methyl iodide' 18*125 and acylated by acyl halides.'I6 In the case of an N-acylarsinimine, methylation took place at either the oxygen or the nitrogen atoms (Scheme 39).'18 12' J. I. G. Cadogan and I. Gosney, J. Cheni. Soc., Chem. Commun., 1973, 586. lZ9 J. I. G. Cadogan and I. Gosney. J. Chem. Soc.. Perkin Trans. I, 1974, 460. 71 Arsonium Ylides -4Me1 t Ph,As=NCOPh Ph,AsN=C(OMe)Ph I-+ PhJAsNMeCOPh I' Scheme 39 N-Phenyltriphenylarsiniminereacted rapidly with benzophenone and with p-nitrobenzaldehyde or quinones, in a reaction analogous to the Wittig reaction, to form imines (Scheme 40).' A similar reaction with nitrosobenzene provided azobenzenes.'30 -Ph,As=NPh + RR' CO RR'C=NPh + Ph3As0 Scheme 40 Other reactions with electrophiles include those with phenyl isothiocyanate or carbon disulphide to give a carbodiimide, and with sulphur dioxide to give an N-sulphinylaniline.125 Reactions of N-phenyltriphenylarsinimine with triphenyl- acetonitrile-N-oxide provided an arsaheterocycle, and with dimethyl acetylene- dicarboxylate gave a product which was probably an arsonium ylide (Scheme 41).12' A final reaction of some interest was that of N-tosyltriphenylarsiniminewith phenyllithium to give pentaphenylarsenane, Ph,As.2o Ph3As= NPh ph0N-ASP h, NPh II CC00Me (probably ) Ph,As =C 'COOMe Scheme 41 8 Stibonium Ylides and Imines The first stibonium ylide to be isolated was triphenylstibonium tetraphenyl- cyclopen tadien ylide, obtained by thermal decomposition of diazo te traphenylcyclo- pentadiene in the presence of tripheny1~tibine.l~'It was less stable than its arsonium or phosphonium analogues, decomposing when heated in ethanol or nitromethane or with alkali. It formed a crystalline perchlorate. Spectroscopic data indicated that the ylide C-Sb bond was more polar and had less double-bond character than in the corresponding arsonium or phosphonium ylides. This was attributed to the less efficient overlap between the 2p orbitals of the ylide C$om and the d-orbitals of Sb, because of the greater size and diffuseness of the d-orbitals in this The greater dipolarity of the stibonium ylide compared to its arsonium, phosphonium, and sulphonium analogues is also in accord with its 130 P.Freryen, Acta Chem. Scand, 1971, 25, 2781. 13' D. Lloyd and M. I. C. Singer, Ciiem. fnd. (London), 1967. 787. Lloyd, Gosney, and Ormiston greater basicity and its higher reactivity towards benzaldehydes or nitroso-As a stable ylide it gave alkenes en reaction with aldehydes but, in contrast, the product from nitrosobenzene was a nitrone. Use of copper hexafluoroacetylacetonate as a ~atalyst'~-~@ has enabled the preparation and isolation of other stibonium ylides, Ph,Sb=CX,, X = RCO or RSO,, from diazo-compounds in solution in benzene.6@ They too appear, from their spectra, to be more dipolar than their arsonium analogues but, like the latter, they do not take part in Wittig reactions, even with very reactive aldehydes.They are stable in a dry atmosphere and are basic. In protic solvents they are slowly cleaved to give triphenylantimony oxide and the corresponding methylene compounds CH,X2. The preparation in solution of triphenylstibonium methylide has been reported, by the action of phenyl lithium on methyltriphenylstibonium tetrafluoroborate.26 Treatment of this solution with benzophenone, followed by acid work-up gave high yields of triphenylstibine and diphenylacetaldehyde,26 and it has been suggesteds6 that the latter product arose by acid-induced rearrangement of initially formed 1,l-diphenylethylene oxide, the likely product from reaction of this reactive ylide with a carbonyl compound.A stibinimine has been prepared'32 by reaction of triphenylstibine with chloramine T under conditions analogous to those used to prepare its arsenic counterpart. This stibinimine was stable in air, but was hydrolysed by water. Like its arsenic analogue it reacted with phenyl lithium to give pentaphenylantimony. 9 Bismuthonium Ylides and Imines If pn-dn orbital overlap between an ylide carbon atom and the heteroatom contributes to the stability of an ylide, then bismuthonium ylides should be much less stable than the other ylides of Group V elements, since the 6d-orbitals of bismuth are likely to be much too large and diffuse to provide any effective overlap.This is borne out by the properties of the one example of a bismuthonium ylide which has been reported.' 33 Triphenylbismuthonium tetraphenylcyclopenta- dienylide was obtained by thermal decomposition of diazotetraphenylcyclo-pentadiene in the presence of triphenylbismuth. Although as a solid it was stable for some time, it decomposed rapidly in solution; it was also decomposed rapidly by acid or base. This bismuthonium ylide is intensely blue, unlike its phosphonium, arsonium, or stibonium analogues which are yellow. Its electronic spectrum closely resembled that of pyridinium tetraphenyl~yclopentadienylide,~~and, like the latter compound but unlike its P, As, and Sb analogues, it was solvatochromic, giving, for example, blue solutions in ether or benzene but red-purple solutions in alcohol^.'^^^ 33 In nitrogen ylides pn-dn orbital overlap is not possible; the spectroscopic similarity between the triphenylbismuthonium and pyridinium tetraphenylcyclopentadienylidesand the huge difference between their spectra and those of the related stibonium, arsonium, phosphonium, and sulphonium '32 C.Wittig and D. Hellwinkel, Cl7mi. Ber.. 1964. 97. 789. D. Lloyd and M. 1. C. Singer. Chmi. Coninizm., 1967, 1042. Arsonium Ylides analogues, lends substance to the concept of the influence of pn-dn orbital overlap on the properties of ylides. Again using copper hexafluoroacetylacetonate as catalyst, some other bismuthonium ylides, Ph,Bi=CX,, X = RCO or RSO,, have recently been prepared by the diazo method and isolated.61 They appeared to be less stable than stibonium or arsonium analogues and decompose slowly when kept as solids.There is one report of the preparation of a bismuthimine, by the reaction of chloramine T with triphenylbismuth.128 This product was not isolated or characterized and quickly decomposed, but it is probable that the bismuthimine was obtained as an unstable product, since it reacted with phenyl lithium to give pentaphenylbismuth.

ISSN:0306-0012    

DOI:10.1039/CS9871600045

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Chem. SOC.Rev., 1987, 16, 75-87 Ortho Esters and Dialkoxycarbenium Ions: Reactivity,Stability, Structure, and New Synthetic Applications By Ulf Pindur*, Johann Muller, Camran Flo, and Helmut Witzel DEPARTMENT OF PHARMACY, UNIVERSITY OF MAINZ, SAARSTRASSE 21, D-6500 MAINZ, FEDERAL REPUBLIC OF GERMANY 1 Introduction The high synthetic potential of ortho esters’T2 and dialkoxycarbenium ions3 is reflected in their use as versatile electrophiles in preparative chemistry for the synthesis of selectively protected diketones, acylated heterocycles, and heterocyclic ring systems.’-’ As numerous reactions of ortho esters (I) take place in the presence of proton or Lewis acids with in situ generation of dialkoxy- or trialkoxycarbenium ions, a knowledge of the reactivities and structural features of this class of compounds is of considerable interest for the interpretation of their modes of reaction.In the present review, therefore, the mechanism and kinetics of the heterolysis of ortho esters and, hence, the structures and reactivities of the di- or trialkoxycarbenium ions (11) generated from them will be summarized. In the last section, some new synthetic applications of these electrophiles will be discussed. 0R’ 0R’ (1) (11) R = ALkyl, aryl, OR R’= ALkyt 2 Mechanism of the Proton-catalysed Ortho Ester Heterolysis The ortho esters (I) can be considered as relatively soft As such, they react with Lewis acids such as BF,, SbCl,,’ or PF,,9 as well as with Bronsted acids R. H. DeWolfe, ‘Carboxylic Acid Derivatives’, Academic Press, New York, London, 1970.E. H. Cordes in ‘The Chemistry of Carboxylic Acids and Esters’, ed. S. Patai, Wiley-Interscience, London, 1969. H. Perst, ‘Oxonium Ions in Organic Chemistry’, Verlag Chemie, Weinheim, Academic Press, New York, 1971. E. Akgiin, U. Pindur, and J. Muller, J. Hererocyclic Cheni., 1983, 20, 1303;5. Miiller, Thesis, University of Wurzburg, 1986. U. Pindur and C. Flo, Monatsh. Chem., 1986, 117, 375. U. Pindur, C. Flo, E. Akgiin, and M. Tunali, Liebigs Ann. Chem., 1986, 1621. ’U. Pindur, L. Pfeuffer, and C. Flo, Chem.-Ztg.,1986, 101, 307. H. Meerwein, K. Bodenbenner, P. Borner, F. Kunert, and K. Wunderlich, Liebigs Ann. Chem., 1960,632, 38. G. A. Olah, J. A. Olah, and J. J. Svoboda, Synthesis, 1973, 490.Ortho Esters and Diulko.u?,carhertiut~iIons Figure 1 Stereoelectronic control of the ortho ester cleavage' (H,SO,-SO,, trifluoroacetic acid," or HBF,") in anhydrous media to form the corresponding di- or trialkoxycarbenium ions (II).' In general, the heterolytic ortho ester cleavage proceeds under stereoelectronic control,' ,*14 i.e. it only takes place relatively rapidly when, in a defined conformation, the free electron pairs on the remaining heteroatoms have antiperiplanar orientations with respect to the leaving group (Figure 1). In conformation (I), the overlapping of the free electron pairs with the antibonding o*orbital of the leaving group 'OR' reaches a maximum so that the starting orbitals can undergo transformation to the product orbitals in (11) with a minimal structural change.In this way, an optimal relative stabilization of the transition state in the route from (I) to (11) is reached. In a (hypothetical) fixed conformation (III), however, a stereoelectronic barrier to the heterolysis giving (TI) exists. With the aid of the 'antiperiplanar lone pair hypothe~is','~ the unusual reluctance of some conformationally relatively fixed ortho esters to undergo acid hydrolysis' 5*1 and the product distribution obtained on hydrolysis of mixed cyclic ortho esters' 'can, among others, be explained well. A stereoelectronic effect, which is only meaningful in comparison to other systems, on the rate of formation of cations from sterically unhindered, conformationally flexible, aliphatic and aromatic ortho esters is most certainly only of minor significance. In these cases the sterically optimal conformation can be achieved 'almost always' as a result of the rapid rotation about the C-0 bond.3 Stability and Structure of the Di-and Trialkoxycarbenium Ions The fact that di- and trialkoxycarbenium ions are also smoothly accessible by lo B. G. Ramsay and R. W. Taft, J. Ant. Cltrnt. Soc., 1966, 88, 3058. A. Gerlach, Thesis, University of Marburg, 1969. l2 H. Meerwein, Angebr*.Ciiem.. 1955. 67. 374. l3 S. Chandrasekhar, A. J. Kirby. and R. J. Martin. J. Client. Soc.. Perkin Trans. 2, 1983, 1619. l4 P. Deslongchamps, 'Stereoelectronic Effects in Organic Chemistry', Pergamon Press, Oxford, 1983; P.Deslongchamps, Tetrahedron, 1975, 31, 2463. l5 R. A. McClelland and P. W. K. Lam, Ccin. J. Chrm., 1984, 62, 1068. l6 0.Bouad, G. Lamaty, and C. Moreau, J. Chem. Soc., Chem. Commun.. 1978.678;0.Bouad, G. Lamaty, C. Moreau, 0.Pomares, P. Deslongchamps. and L. Ruest, Can. J. Chem.. 1980. 58. 567: P. W. K. Lam and R. A. McClelland, J. Client. Soc.. Client. Commun., 1980, 883. P. Deslongchamps, Tetraliedron, 1975, 31, 2463. Pindur, Miiller, Flo, and Witzel Table 1 Relative energies of stabilization (Soof alkoxycarbenium ions according to reJ l9 Table 2 Enthalpies offormation [AH,(R+)] of dialko.uycarbenium ions in the gas phuse derived from the determination of the appearance potentials (R + ) of the corresponding ortho es rers OMe OMe"<Te Me-(.MeO-=(+ \ OMe OMe OMe AH,(R+) kJ mol-' 469 548 285 (kcal mol-') (1 12) (131) (68) Table 3 Enthalpies of formation (AHR+)of 1,3-dioxolan-2-ylium ions in solution. n 97'1. HzS04 n Me0 ROYO R H Me Ph AHR+ kJ mol-I -91.7 -105.9 -122.6 (kcal mol-I) (-21.9) (-25.3) (-29.3) The enthalpies of formation are calculated from the difference between the enthalpy of formation measured in 97% H,SO, (AH,,H,SO,) and the enthalpy of formation measured in CCI, (AHs,CC14): AHR+ = AH,,H2SO, -AH,,CCl, This correction takes the heat of solution used up by the dissolution of the non-ionized substrate in H,SO, into account. alkoxide transfer with the acceptor trityl cation'* proves their high thermodynamic stability.Taft and co-workers' have determined the relative energies of stabilization [SE(kJ mol-')I of some carboxonium ions (the corresponding methoxy-substituted methanes were precursors) by measuring their appearance potentials in a mass spectrometer. As expected, the energy of stabilization increased with the increasing number of groups with donor characteristics on the charge- bearing carbon atom. Correspondingly, the enthalpies of formation [AH,(R ')] of dialkoxycarbenium ions, generated from structurally closely related precursors, should decrease on going from left to right (Table 2). This, at least in the gas phase, is not the case." Measurements in the condensed phase for the formation of the structurally related 1,3-dioxolan-2-ylium (1,3- H.Meerwein, V. Hederich, H. Morschel, and K. Wunderlich, Liebigs Ann. Chem., 1960, 635, 1 l9 R. H. Martin, F. W. Lampe, and R. W. Taft, J. Am. Chem. Soc., 1966, 88, 1353. Ortho Esters and Dialko.uycarbenium Ions Table 4 'H n.m.r. resonuncrs qf methosy groups in methoxycurbenium ions (solvent:H,S0,-S03, reference: TMS) uccording 10 refiy. 3 und 10 OMe OMe"<Te Me-(: Ho<:Me MeO4; OMe OMe OMe OMe 6 (PPm) 5.20 4.95 4.90 5.0-5.1 MeMe ;-'0 AF * R-CC: + k \\ R-C! + R = Me, 60kJ rnd-' /"\'. 0-Me R = H, >60kJ md-' Me €2 ZE Scheme 1 Rotationul isomerizurion of dimethos~~curbeniumions dioxolenium) ions show an increase in the thermodynamic stability with increasing donor characteristics of the substituents at the pro-acyl carbon atom.'O 'H n.m.r.chemical shift data suggest that this stability order in solution is also valid for the open-chain representatives. The H-resonances of the 0-methyl protons of methoxycarbenium ions appear at higher fields in correlation with the strength of the charge delocalization" (see Table 4). An increasing charge delocalization should, as a rule, be accompanied by an increasing thermodynamic stability. A satisfactory explanation for the deviating spectroscopic behaviour of the C,-symmetrical cation in this series has not been found to date.3 Consideration of the trimethoxycarbenium ion as a so-called 'Y-aromatic' 1,22 could possibly provide a key to the interpretation. Dialkoxycarbenium ions exist as rotational isomers.For example, in the 'H n.m.r. spectrum of methyldimethoxycarbenium tetrafluoroborate at less than 14 "C, two 0-methyl resonances are observed." The barrier to rotation about the partial C-0 double bond (AF'#)was determined to be 60 kJ mol-' (14.3 kcal mol-') at 14 "C by coalescence measurementsz3 (Scheme 1j. In the case of R = H, as expected, AF# is higher (double signal at room temperaturelo). The existence of a further rotational isomer (E/Ej, as postulated by Bor~h,~~ could not be observed by other author^^^*^^ under comparable '"R. H. Martin, C. A. Chambers. Y. Chiang, C. S. Hillock, A. J. Kresge, and J. W. Larsen, J. Org. Ch~rn., 1984, 49. 2622. 21 P. Gund. J. CIiem. Eriuc,., 1972, 49. 100.*' R. West and J. Nin in 'Nonbenzoid Aromatics', ed.J. P. Snyder, Academic Press, New York, 1969. 23 R. K. Lustgarten. M. Brookhart. and S. Winstein, Tetrahedron Lett., 1971. 141. 24 R. F. Borch. J. Am. Cliem. Soc.. 1968. 90, 5303. 25 Ch. H. von Dusseau, S. E. Schaafsma, H. Steinberg, and T. J. de Boer, Tctraheciron Let[., 1969, 467. 26 M. Sundaralingam and A. K. Chwang in 'Carbonium Ions', Vol. V, ed. G.A. Olah and P. v. R. Schleyer, Interscience. New York, 1976. 78 Pindur, Miiller, Flo, and Witzel Figure 2 Conformation of the trialkox-vcarbenium ions conditions. Only a single, sterically favourable conformation with C,,-symmetry can be formulated for the trialkoxycarbenium ions. Correspondingly, the 'H n.m.r. spectra only show one signal for all three alkoxy groups, even at -60 "C (Figure 2).'0 The '3C n.m.r.spectra of the alkoxycarbenium ions provide information on the relation of the n-electron density at the cationic centre. Thus, as expected, the following order is found for the resonance position of the central carbon atom in acyclic representatives (CD,NO , &-scale): 199.0 185.1 178.5 167.3 +H-C(O Et) Me-C(O E t) 2' Ph-C(O Me) (MeO)3C BF4 These shift data permit the assumption of an increase in the n-electron density at the carbenium centre on going from left to right. From a comparison of the C-.-.O valency vibrations in the i.r. spectra with those of the reference ions MeCOO- (n-bond order: 0.5) and COi- (n-bond order: 0.33), Taft and co-workers" postulated a n-bond proportion of 0.24.3 for dialkoxycarbenium ions.H \'. 29 Me c:t 1.27&OH 0-H HSob' Figure 3 Bond lengths (in A) for acetic acid and the dihydroxymethylcurbenium ion26 Reliable data on the internal bond coordinates are to be expected from X-ray diffraction studies. Unfortunately, these data are not yet available for acyclic di- and trialkoxycarbenium ions. The data determined for the dihydroxymethy- lcarbenium ion,26 however, should be transferable to the system of interest here without any major deviations (Figure 3). The C-0 bond lengths of this cation are practically equal, the C-C bond length of 1.480 A is noticeably shorter than that of acetic acid as a result of hyperconjugation between the methyl group and the sp2-hybridized carboxonium 27 L. Hevesi, S.Desauvage, B. Georges, G. Evrard, P. Blanpain, A. Michel, S. Harkema, and G. J. van Hummel, J. Am. Chem. Soc., 1984, 106, 3784. 79 '0 Ortho Esters and Dialkoxycarbenium Ions Table 5 Calculated bond lengths, x-bond orders, and barriers to rotation for various 2- substituted 1,3-dioxolan-2-ylium ionsz9 R C-2-0 x-bond barrier to rotation bond order about the C-2-R bond *I length kJ mol-' (kcal mol-')'yo H 1.313 0.650 --Me 1.328 0.587 0.54 (0.013) R OH 1.328 0.540 35.6 (8.5)NH, 1.336 0.485 128.1 (30.6) Figure 4 Molecular structure of the 2,4,4,5,5-pentamethyl-1,3-dioxolan-2-yliumion in the crystal state2' carbon atom. The molecule is planar and the OH groups are cis and trans to the methyl group. The same geometry was recently found for the heteroanalogues, the bis(methy1thio)- and bis(methylse1eno)carbenium ions.27 Even in the 2,4,4,5,5-pentamethyl- 1,3-dioxolan-2-ylium ion the dioxolan-2- ylium ring is, as demonstrated by an X-ray crystal structure analysis, completely planar (see Figure 4).28 This structural result clearly shows how the high mesomeric energy of the 71-system (-O--C*=O-) more than compensates for the + sterically extremely unfavourable interaction between two syn-periplanar orientated pairs of methyl groups.The bond lengths between C-2 and the two oxygen atoms (1.28 and 1.24 A) lie between the values for a C-0 single bond in 1,3-dioxolanes (1.41 A) and a double bond (1.22 A). Pittman and co-workers achieved similar, but not completely concordant, results from model calculations on 1,3-dioxolan-2-ylium ions.29 These SCF-MO calculations according to the INDO approximation process (see Table 5) gave a 71-'* H. Paulsen and R.Dammeyer, Chem. Ber., 1973, 106, 2324. 29 C. U. Pittman, Jr., T. B. Patterson, and L. D. Kispert, J. Org. Chem., 1973, 38, 471 80 Pindur, Miiller, Flo, and Witzel A Lc r a, 0-R' a, t 'OR' route 1 route 2 Figure 5 Energy profile for the reaction of a dialkoxycarbenium ion with a nucleophile, according to re$ 30 bond order of about 0.54.65 for the C-2-0 bond, depending on the nature of the C-2 substituent. Hevesi et aL2' obtained even higher values of 0.74.8 by graphical extrapolation of the relationship bond length/n-bond order for acyclic carboxonium ions. Thus, both MO calculations and X-ray crystal structure data clearly illustrate the significant contribution of the oxonium resonance structure to the ground states of dialkox ycarbenium and 1,3-dioxolan-2-ylium ions.4 Reaction Paths and Reactivity of Alkoxycarbenium Ions In principle, dialkoxycarbenium ions (A) can react with nucleophiles (Nu) in two ways depending on the reaction conditions: either in a kinetically controlled reaction to form saturated 1,l-dialkoxy compounds (B) or in a thermodynamically controlled reaction with alkylation of the nucleophile (D)to give carboxylic esters (C) (Figure 5).30 The preferred route and thus the product distribution depends mainly on the nature of the nucleophile, the stability of the ambident cation (A), the reaction temperature, the reaction time, and the solvent.The combination 'hard nucleophile+nergy-rich cation' (AFl is large) should lead preferentially to kinetically controlled products whereas the reaction of soft nucleophiles with energy-poor cations (AF, is small) should lead to thermodynamically controlled products. In fact, apart from a few exception^,^' S. Hiinig, Angew. Chern., 1964, 76,400; Angew. Cheni.. Int. Ed. Engl., 1964, 3, 548. C. U. Pittman, Jr., S. P. McManus, and J. W. Larsen, Chern. Reu.. 1972, 72, 357. Ortho Esters and Diulkoxycarbenium Ions (I) Formation of the carboxonium ion OR HAR-C-OR ___3 R-C:+ A-t ROHI Y\OR OR (11) Addition of the nucleophile H,O OR OH "20R-CI k+ I R-C-OR + H+\:.I OR OR (111) Decomposition of the hemiortho ester OH I 8R-C-OR ___j R-C + ROH I \OR OR Scheme 2 Mechanism of the ortho ester hydrol-ysis products from the kinetically controlled reaction (route 1) can only be isolated when strong nucleophiles such as EtO- or CN-are used. In the heteroaromatic series, for example, indoles, carbazoles, and pyrroles are also sufficiently nucleophilic to attack the carbenium ion ~entre.~.~ Increases in the temperature and/or longer reaction times favour the thermodynamically controlled route 2. Our studies on the a'-acylating reactivity of acyclic ortho esters and di- or trialkoxycarbenium ions towards 2-methylindole have given the following orders of reactivity: As expected, trimethyl orthocarbonate as well as trimethoxycarbenium tetrafluoroborate represent the most unreactive a '-electrophiles.5 Kinetics and Mechanism of the Ortho Ester Hydrolysis The influence of the structures of di- and trialkoxycarbenium ions on their re- activity towards nucleophiles has previously been studied exhaustively on the three component system ortho ester-H,O-proton acid. From more recent studies on the kinetics and mechanism of the ortho ester hydrolysis, it can be deduced that this system is not well suited for the qualitative derivation of an order of reactivity of these cations. Today, it is generally accepted that the hydrolysis of ortho esters-as postulated earlier32*33-has to be formulated as a three-step mechanism (Scheme 2).' 5*34 ''E.H. Cordes and H. G. Bull, Chem. Rev., 1974, 74, 581. 33 T. H. Fife. Aic. Chem. Rex, 1972, 5, 264. Pindur, Miiller, Flo, and Witzel The previously predominant opinion that step I, i.e. the cleavage of the C-0 bond, is the rate-determining step of the ortho ester hydrolysis has now been replaced by a much more differentiated c~nsideration.’~ .~Kresge et ~ 1 showed ~ that, for certain substrates and increasing pH values, step I11 dominates over step I as the rate-determining factor. Comparative, quantitative measurements of the hydrolysis kinetics of 2-alkoxy- 1,3-dioxolanes and acyclic ortho esters have shown that the transition of the rate-determining step from I to 111 is, in the first instance, not dependent on the donor characteristics of the substituent at the pro-acyl carbon but that rather a solvation effect,34 which stabilizes the intermediately formed hemiortho esters differently, is responsible.In the case of dioxolanes, entropy may also play a decisive role. For certain ortho esters, the attack of water on the dialkoxycarbenium ion (step 11) can also be rate-determining. This was demonstrated for the examples of trimethyl orthornesit~ate~’ and conformationally fixedI6 ortho esters. In these cases, steric and stereoelectronic factors are decisive. De Wolfe and Jensen3* have measured the rates of hydrolysis of orthoformic, orthoacetic, orthobenzoic, and orthocarbonic esters. For acyclic ortho esters R-C(OR’),, they found the following order (Table 6).Table 6 Relative rates of hydrolysis of ortho esters (R’= alkyl) according to reJ 38 R Me > Et > H > Ph > OEt Relative rate 38.5 24.3 1.00 0.62 0.17 of hydrolysis For 173-dioxolanes, Kresge, Larsen et ~1.’’ obtained the following order (Table 7). Table 7 Relative rates of hydrolysis of 1,3-dioxolanes according to re$ 20 l\R Me > Ph > H Oxo Relative rate 125.7 30.8 1 Me0 R ofhydrolysis These experimentally determined data clearly demonstrate that the thermo- dynamic and kinetic stabilities do not proceed in parallel. The fact that the rate of hydrolysis in the acyclic series was decreased by phenyl substitution was not understood for a long time. This is now explained in terms of the spatial structure of 34 Y.Chiang, A. J. Kresge, M. 0.Lahti, and D. P. Weeks, J. Am. Chem. SOC.,1983, 105,6852. ” M. Ahmad, R.G. Bergstrom, M. J. Cashen, A. J. Kresge, R. A. McClelland, and M. F. Powell, J. Am. Chem. SOC.,1977,99,4827; M. Ahmed, R. G. Bergstrom, M.J. Cashen, Y.Chiang, A. J. Kresge, R. A. McClelland, and M. F. Powell, J. Am. Chem. SOC.,1979,101,2669; M. Ahmed, R. G. Bergstrom, M. J. Cashen, Y. Chiang, A. J. Kresge, R. A. McClelland, and M. F. Powell, J.Am. Chem. Soc., 1982,104,1156; R. A. Burt, Y.Chiang, A. J. Kresge, and M. A. McKinney, J. Am. Chcm. SOC., 1982,104, 3685. 36 R. A. McClelland, S. Gedge, and J. Bohonek, J. Org. Chem., 1981, 46, 886. ”R. A. McClelland and M. Ahmed, J. Am. Chem. SOC.,1978, 100, 7027. ’* R. H. DeWolfe and J.L. Jensen, J. Am. Chem. SOC.,1974,85, 3264. 83 Ortho Esters and Dialko.rycurbeniirm Ions the cation. Based on comparative measurements of the hydrolysis kinetics of open- chain and cyclic orthobenzoic esters, Kresge and co-~orkers~~ deduced that in open-chain carboxonium ions, in contrast to the corresponding 1,3-dioxolan-2- ylium ions, the phenyl ring is twisted out of the carboxonium plane. This gives rise to a reduction of the (p-n)-conjugation and thus of the thermodynamic stability. Larsen and co-workers4' have strengthened this theory (experimentally-determined structural evidence has not yet been reported) by measurements of the enthalpy of formation of methyl- and phenyl-substituted carboxonium ions. During studies on ortho ester hydrolyses in the cyclic series, it was noticed that the in situ generation of phenyl-substituted 1,3-dioxolan-2-ylium ion, although it is thermodynamically more stable by 16.5kJ mol-' (4kcal mol-'), occurs about four- times more slowly than the formation of the corresponding methyl-substituted ion (see Table 7).As a possible explanation, it has been suggested2' that, in the transition state of step I, which is similar to the substrate, the cation destabilizing -I effect of the phenyl group exceeds the stabilizing + M effect. This could also offer a plausible explanation for the striking sluggishness of the reactions of orthocarbonic esters, as we have also observed in our studies. Perhaps, however, for this reason step I1 takes up increasing importance as rate-determining step owing to the formation of the highly resonance-stabilized trialkoxycarbenium ion.6 New Synthetic Applications of Ortho Esters and Dialkoxycarbenium Ions The synthetic potential of ortho esters and di- or trialkoxycarbenium ions as alkylating and acylating agents is so e~tensive'-~.~'that only a few of the more recent preparative results can be mentioned here. In addition to the well-known applications as masking agents in the chemistry of carbonyl compounds' and for the synthesis of further carboxylic acid and alkoxy derivative^,^' their use for the formation of carbon-carbon bonds is of major significance. These electrophiles also function as a'-C synthons* for the construction of various heterocyclic ring sys- tems' and serve as preparatively useful condensation reagents in reactions with * a' is the notation for an acceptor synthon of the C-X series.'' Y.Chiang. A. J. Kresge, P. Salomaa, and C. I. Young, J. Am. Chrtn. Soc., 1974, 96. 4494. 40 J. W. Larsen, P. A. Bouis, and C. A. Riddle, J. Org. Climi., 1980, 45. 4969. (a) W. Kantlehner, B. Funke, E. Haug, P. Speh, L. Kienitz, and T. Meier, Sjw1ir.m 1977, 73. (h) G. Simchen, in Houben-Weyl, 'Methoden der Organischen Chemie'. ed. J. Falbe. 4th Edn., Vol. E5, Georg Thieme Verlag, Stuttgart, New York,1985. Pindur, Miiller, Flo, and Witzel electron-rich olefins and CH-acid systems.42 In particular, trialkyl orthoacetates have been employed successfully in the regio- and stereocontrolled formation of functionalized alkenes via the Claisen rearrangement.43 Acyclic and cyclic ortho esters as well as di-and trialkoxycarbenium tetrafluoroborates can be used successfully for the regiospecific acylation and alkylation of electron-rich n-systems (alkyl enol ethers, silyl enol ethers, enamines, indoles, carbazoles).Thus, for example, triethyl orthoformate or 2-methoxy- 1,3-dioxolane reacts with the l-trimethylsiloxy-l,3-butadiene(1) with high y-selectivity to form the y-protected 1,5-dicarbonyl compounds (2a) or (2b).44 The synthetic flexibility of this acylation variant is reflected in its wide scope of application: many simple silyl enol ethers, silyl ketene acetals, and enamines react with a high P-preference at the n-system with various acyclic and cyclic ortho esters under TIC],, ZnCl,, or BF, catalysis.4549 See reference 41b for further new derivatization reactions with ortho esters.Indoles (3)react as heterocyclic enamines with various acyclic ortho esters under proton catalysis and in dependence on the reaction conditions to form the 42 0.Wolfbeis and H. Junek. Tetrahedron Lett., 1973, 4905; 0.Wolfbeis, Z. Nuturforsch., 1976, 31b, 95. 43 G. B. Benett, Synlhesis. 1977, 589. 44 E. Akgiin and U. Pindur, Synthesis, 1984, 227. 45 T. Mukaiyama, Angew. Chem., 1977,89,858;Angew. Chem.. Int. Ed. Engl., 1977,16,817; T. Mukaiyama and M. Hayashi, Ckem. Lett., 1974, 15. 46 E. Akgiin and U. Pindur, Liehigs. Ann. Chem., 1985, 2472, 47 E. Akgun and U. Pindur, Monatsh.Chem., 1984, 115, 587. 48 E. Akgiin, M. Tunali, and U. Pindur, Monatsh. Chem., in press. 49 E. Akgiin. M. Tunali, and U. Pindur, Chern.-Zlg., 1986, 110, 335. Ortho Esters and Dialko.uq)carbenium Ions H (31 R’ = Alkyl NH AC 1.;)/yNHAcCOOMe R2 = H, alkyl, Ph RL Q-@H R’ (3) R2= H N R’H preparatively useful, functionalized indole derivatives (4)-(8).4,50-53 Of these products the acylindoles (5) are of special interest as building blocks for alkaloid synthese~.~Cyclic ortho esters such as, for example, 2-alkoxy- 1,3-dioxolanes also react to form compounds of the type (5).54 Triethyl orthoacetate reacts as an a’-C, synthon with 3-unsubstituted indoles to produce 3-vinylindole equivalent^.^^.^^ 4-Methoxyindole is regiospecifically functionalized at the 3-position by triethyl orthoformate to yield a tris(indoly1)methane of the type (8).57Whereas the parent 5” J.Muller, L. Pfeuffer, and U. Pindur, Monutsh. Chem., 1985, 116, 365. 51 U. Pindur and J. Miiller. J. Heferocylic Chem., in press; U. Pindur and J. Miiller, J. Chem. Soc., Cheni. Conimun., submitted. 52 U. Pindur and J. Muller, Chiniin, 1985, 39, 141. s3 L. Pfeuffer, E. Sody, and U.Pindur, Clieni.-Zrg.,in press. 54 E. Akgiin, M. Tunali, and U. Pindur, Arch. Phurm. ( Weinheini. Ger.), in press. 55 U. Pindur and J. Mull.er, Cliem-Ztg., 1984, 108, 150. 56 J. Muller, L. Pfeuffer, and U. Pindur, Chem.-Ztg., 1985. 109, 15. 57 H. Witzel and U. Pindur, manuscript in preparation. 86 Pindur, Miiller, Flo, and Witzel carbazole is preferentially dialkoxy-alkylated at N-9 on reaction with an excess of triethyl orthoformate, the analogous reaction with 4-methoxycarbazole results in regiospecific formylation at C-1.In the latter reaction, depending on the reaction conditions, carbazole derivatives analogous to compounds (6), (7), and (8) are formed as the subsequent products.’’ In the course of this functionalization method for heterocycles, we also studied the acylation and alkylation reactivity of the per se employed di- and trialkoxycarbenium tetrafluoroborates. Thus, for example, 3-unsubstituted indoles are regioselectively acylated or methoxycarbony-lated at position 3 on reaction with R-C(OAlk)T BF; (R = H, Me, Ph, OMe).6 3- Mono- and 2,3-disubstituted indoles react preferentially at N-1 with these ambident cations to form N-acyl-and N-alkylindoles.6 In the reactions of R-C(OAlk)l BF, (R = H, Me, OMe) with carbazoles, in dependence of the structure of the carbazole, a wide spectrum of products are formed, among which, above all, the synthetically interesting, acylated and alkylated carbazoles are formed in good yields.58 In these cases, H-C(OEt)i BF, reacts as an a’-C, synthon (formylation) and the thermodynamically more stable cations Me-C(OEt)l BF, and (MeO),C+ BF, react as alkylating agents (N-alk ylation).V‘ H R2 Finally, a further, new variant for the preparation of functionalized ketones should be mentioned. The reactions of 2-alkyl- 1,3-dioxolan-2-ylium fluoro- sulphonates (9) with alkynyltrialkylborates take place at the P-position of the alkynylborates (1 0). On hydrolytic work-up, these reactions give rise to (Z)-X,~-unsaturated ketones (12) whereas oxidative work-up results in the formation of specifically mono-protected 1,3-diketones (1 3).” 58 U. Pindur and C. Flo, Liebigs Ann. Chem.. 1987, in press. 59 A. Pelter and M. E. Colclough. Tetrahedron Lett., 1986, 27. 1935.

ISSN:0306-0012    

DOI:10.1039/CS9871600075

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Chem. SOC.Rev., 1987, 16, 89-121 Prototropic Routes to 1,3- and 1,5-Dipoles, and 1,2-Ylides: Applications to the Synthesis of Heterocyclic Compounds By R. Grigg DEPARTMENT OF CHEMISTRY, QUEEN’S UNIVERSITY, BELFAST BT9 5AG, NORTHERN IRELAND 1Introduction Proton transfer processes are of fundamental importance in synthetic and mechanistic chemistry, and in biological systems based, as they are, on an aqueous (protic) environment. Formal intramolecular proton transfers can be divided into two broad classes. The first class comprises unassisted or concerted hydrogen migrations where the migrating hydrogen moves intramolecularly over a z-electron framework under thermal or photochemical activation, e.g. (1 2).2 The electronic requirements and stereochemical outcome of this type of migration (sigmatropic reactions) were delineated by Woodward and Hoffmann in their classic series of papers on orbital symmetry controlled reactions3 and have been confirmed by many subsequent ~tudies.~ The second class comprises proton transfers where the assistance of an acid, base, transition metal, or transition- R R*-[ Xk-,iL] e RI I-X*yHZ x\ygz Scheme 1 (31 (4) R.P. Bell, ‘The Proton in Chemistry’, Cornell University Press, New York, 2nd edn., 1973; R. Stewart, ‘The Proton: Applications to Organic Chemistry’. Academic Press, 1985. ’R. M. Duhaime and A. C. Weedon, J. Am. Chem. SOC.,1985, 107, 6723. R. B. Woodward and R. Hoffmann, ‘The Conservation of Orbital Symmetry’, Verlag Chemie, Weinheim, Germany, 1970.‘C. W. Spengler, Chem. Rev., 1976, 76,187. Prototropic Routes to I ,3-and 1,5-Dipoles, and 1,2-Ylides metal complex is required. In this type of reaction the intramolecularity of the proton transfer can vary from zero to 100%. h is this class that our research is concerned with. 2 Prototropy in the Four-atom X=Y-ZH System Tautomerism is a term applied to reversible isomeric changes involving heterolysis and subsequent recombination of the ions to give an isomer of the original compound (Scheme Thus R* in Scheme 1 could carry either a positive or negative charge with the X-Y-Z framework carrying the opposite charge. When R = Hf (Scheme 1) the tautomeric process is called pr~totropy.~ Prototropy in the four-atom X=Y-ZH system includes some of the most important processes in organic chemistry such as ketomol [(3) e(4)],6 imir~e-enamine,~hydrazo-azo,* oxime-nitroso,' and nitro-aci-nitro" equilibria, and alkene isomerization.' All these processes have attracted substantial mechanistic studies and all are im- portant in organic synthesis.Keto-enol equilibration is the most important of this group and is the basis ofthe aldol condensation, Claisen ester condensation, Michael addition reaction, Robinson ring annulation etc. These synthetic applications owe their existence to the dramatic difference in chemical reactivity of the two tautomeric forms (3) and (4).Thus the labile proton HAin (3) has a pk, of ca. 19, whilst HB in (4)has a pk, of ca. 10. The diagnostic chemical reactivity of (3) is nucleophilic attack at the carbonyl group, whilst that of (4)is electrophilic attack at the 13-carbon atom.In simple ketones the concentration of enol is extremely small [enol](e.g.for acetone the equilibrium constant K = [ketone] = 6.0 x 10-s)12and such ~ enols cannot be detected even by sensitive modern spectroscopic techniques. Detec- tion and quantitation is based on the specific chemistry of the enol allied to kinetic studies, e.g. Lapworth's early kinetic studies' providing the first clear evidence for the intervention of an enol in the bromination of methyl ketones. Of course stable enols are known in which special substituents are employed to impart enhanced stability to the enol form.I4 Recently unstable enols have been generated and detected spectroscopically under carefully controlled conditions (e.g.propio- naldehyde enols from enol ether precursors)15 or by flash vacuum pyroly~is.'~ C. K. Ingold, 'Structure and Mechanism in Organic Chemistry', G. Bell and Sons, London, 1953.'S. Forsen and M. Nilsson. in 'The Chemistry of the Carbonyl Group', Vol. 2, ed. J. Zabicky, Wiley, 1970, p. 157. 'C.-G. Shin, M. Masaki. and M. Ohta. Bull. Cliem. Soc. Jpn., 1971. 44. 1657. P. Griess, Bu., 1874, 7. 1618; Annalen. 1886. 137, 60.'W. A. Tilden and W. A. Shenstone, J. Cliern. Soc., 1877.31, 554; R. Pummerer and F. Graser, Annnlen, 1953, 583, 207. lo D. Turnbull and S. M. Maron. J. Am. Chem. Soc., 1943,65, 212. H. H. Niemeyer and P. Ahlberg, J.Chem. Soc.. Chem. Commun., 1974, 799; S.-Y. Yokoyama, K.-I. Tanaka, and H. Haneda, ihid.. 1982, 820. l2 J. P. Guthrie, Cun. J. Cliem., 1979. 57. 797. l3 A. Lapworth. J. Chem. Soc., 1904, 85. 40. l4 H. Hart. Ch??.RcL...1979, 79. 51 5. B. Capon and A. K. Siddhauta, J. Org. Cheni., 1984, 49, 255. J.-L. Ripoll and M.-C. Lasne. Tr/rdirrlron IA/., 1980. 463; M.-C. Lasne and J.-L. Ripoll, ibid.,1982, 1587;A. Hakiki and J.-L. Ripoll. T~Wulretiror?Let/..1984. 3459; S. Saito, Clzmi. Phys. Lefr.,1976,42. 399. Grigg No. of lone Examples pair atoms I X=Y-ZH 0 Alkenes I1 X=Y-ZH X=Y-ZH X=Y-ZH 1 Imines, ketones, nitroalkanes I11 IV X=Y-ZH X=Y-ZH X=Y-ZH 2 3 Hydrazones, oximes, amidines Triazenes Scheme 2 X=Y-ZH Systems can be divided into four classes (Scheme 2) depending on the number of constituent atoms that possess lone pairs of electrons (note that more than one pair may be located on each atom).Formal 1,3-H shifts from Z to X (Scheme 1, R = H) are normally achieved by the intervention of a suitable catalyst although isotope labellingstudies show these catalysed prototropic equilibria often involve a substantial intramolecular component. Thus in base-catalysed alkene isomerizations, a type I system (Scheme 2), greater than 90% intramolecularity has been ~bserved,".'~ whilst in imines, a type I1 system, up to ca. 50% intromolecularity has been reported.' * The stereoselectivity and intramolecularity of the latter type of isomerizations have attracted attenti~n'~ because of their relationship to the biochemical transformations of %-amino acids catalysed by pyridoxal enzymes. These enzymic isomerizations involve a suprafacial 1,3-proton transfer in pyridoxal-amino acid imines." The precise mode of association be- tween the protonated base and the allyl- or azaallyl-anion leading to intra- molecular 1,3-proton transfer is unclear.The X=Y-ZH system may act as its own catalyst for a formal 1,3-H shift. Thus triazene isomerizations (R 'N=N-NHR' R'NH-N=NR') are usually bimolecular although a radical mechanism may be dominant in some cases.'l Thermal concerted 1,3-H shifts in X=Y-ZH systems would, if observed, occur via an antarafaciul migration (4x-electron transition state)3 with w2 the dominant molecular orbital (Figure 1).The migrating hydrogen is required to transfer from the top face of the x-system to the bottom face during its 1,3-shift. The geometrical constraints imposed by the three-atom framework and the availability of only an s 17 J. Klein and S. Brenner, Chem. Commun., 1969, 1020; S. Bank, C. A. Rowe, and A. Schriesheim, J. Am. Chem. Soc., 1963, 85, 2 1 15. in R. D. Guthrie and J. L. Hedrick, J. Am. Cliem. Snc., 1973, 95. 1971. 19 D. A. Jaeger, M. D. Broadhurst, and D. J. Cram, J. Am. Chrm. Soc., 1979, 101. 717. 20 J. C. Vederas and H. G. Floss, Acc. Chem. Res., 1980, 13, 455. 21 K. Vaughan, J. Chem.Soc.. Perkin Trans. 2, 1977. 17; L. Lunazzi. G. Panciera. and M. Guerra, ihid.,1980, 52. 91 Prototropic Routes to 1,3-and 1 ,j-Dipoles, and 1,2-Ylides Figure 1 Molecular orbitals of the ally1 system (X, Y, and Z=C) H H /R1 I (8) (10) (11) orbital on the migrating H-atom conspire to make the thermal antarafacial process unrealizable.However, there is no orbital symmetry restraint on step-wise processes for achieving the 1,3-proton transfer. Our contributions to this area of chemistry began with the realization that when the central Y atom in an X=Y-ZH system possesses a lone pair of electrons (Scheme 2, types 11-IV) a formal 1,2-H shift [(5) e(6)]becomes possible. A concerted 1,2-H shift involving the electrons of XY double bond and a 1,3-charge separation involves unfavourable orbital interactions and prohibitively high energies,22 e.g.reference to Figure 1 shows a 22 P. D. Adeney, W. J. Bourna, L. Radour, and W. R. Rodwell, J. Am. Chem. Soc., 1980, 102,4069; see also Y. Yoshioka and H. F. Schaefer, ibid., 1981,103, 7366 for the effect of orbital population on 1.2-H shifts. Grigg node at Y in the dominant molecular orbital (~2)in such processes, although when Y = C there is a small coefficient at Y.23 The lone pair on Y in (5) is orthogonal to the XY n-systcm and thus concerted proton transfer from Z to this orthogonal lone pair is free of orbital symmetry restrictions. However, a stepwise proton transfer would intuitively seem more likely. These considerations led us to suggest that such a new and novel type of prototropy, 1,2-proton shifts [(5) (6)], should occur resulting in a general method for generating certain 1,3-dipolar species (6).Like the ketomol situation discussed earlier the 1,3-dipole (6) would be expected to exhibit markedly different chemical properties to (5) and to be present in very small concentrations.Thus detection of (6) would require kinetic studies and/or a chemical test specific for (6). Fortunately, in the case of 1,3-dipoles a simple and synthetically useful method of detection is available, the 1,3-dipolar cycloaddition reaction (6)-(7). This is the most versatile method available for the synthesis of 5-membered heterocycle^.^^ The generality and scope of this remarkable reaction were first recognized by H~isgen.~’To date we have evidence for dipole formation in three X=Y-ZH systems representing types I1 and 111 (Scheme 2).These are: imines (C=N-CH), oximes (C=NOH), and hydrazones (C=N-NH). We have developed a wide range of simple, synthetically useful reactions based on thermal generation of dipoles from these and other sytems. 1mines.-These are type I1 X=Y-ZH systems and the formal 1,2-H shift in imines [(8) e(9)] results in azomethine ylides with an NH group. Such species are rare and to date only two stable examples and (1 1)27 are known. Compound (1 1) is of interest since it is the protonated form of Ruhemann’s purple, the product of the ninhydrin test. We have shown27 that several types of azomethine ylide are involved in this useful test for x-amino acids, which incidentally, also forms the basis of the method for detecting latent fingerprints on paper and other suitable materials.The facility with which the azomethine ylide (9) is formed would be expected to be dependent on the basicity of the central nitrogen atom and on the pk, of the proton HAin (8). These properties will, in turn, be influenced by the nature of the substituents R, R’, and R2. The effect of imine basicity on rate of dipole generation is illustrated in Figure 2.28Note that dipole formation is rate determining when N-phenylmaleimide is the dipolarophile. The basicity of the central nitrogen atom falls from R = NMe2 (the most basic) to R = NO2 due to the mesomeric effects of these substituents (13) and (14), relayed through the benzene ring. Thus the variation in rate, although not large, is 23 K.N. Houk, J. Sims, R. E. Duke, R. W. Strozier, and J. K. George, J. Am. Chem. SOC.,1973,95, 7287. 24 R. Huisgen, J. Org. Chem., 1976, 41, 403; A. Padwa, Angew. Chem., Inr. Ed. Engt., 1976, 15, 123; W. Oppolzer, ibid., 1977, 16, 10. ” R. Huisgen, Angeit. Chem., Int. Ed. Engt., 1963, 2, 565 and 633.’’J.-P. Fleury, J.-P. Schoeni, D. Cleriu. and H. Fritz, Heh. Chim. Acta, 1975, 58, 2018. 27 R. Grigg, J. F. Malone, T. Mongkolaussavaratana, and S. Thianpatanagul, J. Chem. SOL‘.,Chem. Commun., 1986, 421. 2H R.Grigg, H. Q. N. Gunaratne, and J. Kemp, J. Chem. SOC.,Perkin Trans. I, 1984, 41. Prototropic Routes to 1,3-and 1,5-Dipoles, and 12-Ylides in the expected direction. The deuterium isotope effect (Figure 2) is comparatively small for a process involving rate-determining dipole formation and the reason for this is uncertain at present.105'C toluene1 Rate Constant (s ') Isotope Effkt NMe, 44.6 x lo-' 1.21 Me0 7.8 x 10 2.14 H 3.55 x 2.70 CN 0.72 10-5 2.75 NO2 0.80 x 10 2.17 Figure 2 The eflect of imine basicity on rate of dipole generation H Stabit izing DestabiLizin g The formation of 1,3-dipoles from neutral imines is catalysed by both Bronsted (Figure 3) and Lewis (Figure 4) acids.29 The catalysed cycloadditions are both stereo- and regio-specific and with Bronsted acid catalysts the rate increases with decreasing pk, of the catalyst. In both catalysed and uncatalysed cycloadditions, imines of optically active x-amino acid esters give racemic cycloadducts.It is apparent from Figures 24 that dipole formation is stereospecific in both the catalysed and uncatalysed reactions and that the cycloadditions involve an endo transition state (Figure 2 and 3). Thus some property inherent in the imine system 29 R. Grigg and H. Q. N. Gunaratne, J. Chetir. Soc.. Chmi. Conrmun., 1982, 384. 94 Crigg 105"C -PhMe ' Ph +h C0,Me Cutulj-sr(1 mole) pk, f+ (min) None -120 & 4 2-Pyridone 11.99 88 k 6 Meldrums acid a 5.5 5h MeC0,H 4.75 6b 2,4-Dinitrophenol 4.0 3b " 2,Z-Dimethyl- 1,3-dioxan-4,6-dione. Approximate values Figure 3 imparts a kinetic bias to one dipole. The simplest explanation of this observation is shown in Scheme 3, and involves an intermediate hydrogen-bonded enol (uncatalysed route) or a hydrogen-bonded protonated imine (acid-catalysed route). We have shown that the same dipole configuration is generated in the racemization of x-amino ucids in the presence of aldehyde^.^' Me02C /Ph HCEC C02MePhCH 80°C -PhMe ' 9APhC02Me COzMePh H Lebtx Acid if (h) Yield P,,) -38 94 MeC0,H 1.8 -Zn(OAc),.2H20 3 88 AgOAc 3.25 95 LiOAc.2H20 5.5 93 Figure 4 The formation of azomethine ylides by prototropy from imines tolerates a range of aromatic, heterocyclic, and aliphatic aldehydes as imine precursors although the opportunity for imine-enamine equilibration and subsequent side-reactions of the enamine tautomer frequently makes aliphatic aldehydes less attractive.Other groups can replace ester for the activation of the ZH proton provided they lower R.Grigg and H. Q. N. Gunaratne, Tc.fruiieilron Lett., 1983,24,4457;K. Amornraksa, R. Grigg, H. Q.N. Gunaratne, J. Kemp. and V. Sridharan. J. Ciiem. Soc.. Perkin Trans. 1. in press. Prototropic Routes to 1,3-and I ,5-Dipoles, and 1,2-Ylides R ArA H R E -isomer Ar Scheme 3 CHCOZR CHCN 0II CH-C-Ph 0 II CHP(0E t Iz Figure 5 Groups activating the ZH proton the pk, of the ZH proton sufficiently to permit prototropy and some of those studied are listed in Figure 5. We have developed all these activating groups3 apart from cyano which has been studied by others.32 The prototropically generated azomethine ylides undergo cycloadditions with a 31 R.Grigg. H. Q. N. Gunaratne. V. Sridharan, and S. Thianpatanagul, Tetrahedron Letf., 1983.24, 4363. and unpublished observations. 32 M. Joucla and J. Harnelin, Termhedrott Lerf., 1978, 2885: 0.Tsuge, K. Ueno, S. Kanernasa, and K. Yorozu, Bull. Chem. Soc. Jpn., 1986, 59, 1809. Grigg 140 OC xyiene ' H Ph H 79O/O0cCHPh H Regiospecif ic Stereo spec if ic Scheme 4 Scheme 5 wide range of dipolarophiles, invariably via endo transition states, providing many novel heterocyclic compounds from readily available starting materials. Some examples of these simple one-step processes are shown in Schemes 4 and 5. The reaction can also be applied to the synthesis of bridged ring compounds and two examples of this are shown in Scheme 6.33 Pyridoxal (Vitamin B6) phosphate-dependent enzymes occur widely and are responsible for the synthesis, racemization, degradation, and interconversion of a-amino acids in living systems.34 These processes are known to proceed via formation of the corresponding pyridoxal imines (15).The initial reactive intermediates (16) or (17) are generated by cleavage of either bond (a) or (b) in (15) together with protonation of the pyridine nitrogen atom. Stereoelectronic control '' R.Grigg, L. D. Basanagoudar, D. A. Kennedy, J. F. Malone, and S. Thianpatanagul, Tetrahedron Lett., 1982, 2803; R. Grigg and D. Vipond, unpublished observations. j4 K. Bloch in 'The Enzymes', ed. P. Boyer, Academic Press, 3rd edn., 1972, Vol. 5, p. 441;L.Davis and D. E. Metzler, ihid., p. 33. Prototropic Routes to I ,3-and 1,S-Dipoles, and I ,2-Ylides CO, Me MeOzC NH 0 HA I HB exo only JHAHB = 0 HZ 110 'C toluene CO7Me J exo only Scheme 6 requires that the breaking bond [bond (a) or bond (b) in (15)l is aligned with the pyridyl azomethine ~c-system.~~ Racemases and transaminases function by cleavage of bond (a) in (15) and led us to consider, in the light of our experience with imines of a-amino acid esters, that (16) might be more properly regarded as 1,3-dipole with a proton residing on the imine nitrogen atom.36 We therefore prepared a range of pyridoxal imines of a-amino acid esters and examined their suitability as 1,3-dipole precursors. We were rewarded with a series of smooth, stereospecific cycloadditions (Scheme 7) which, with one or two exceptions, occur in excellent yielda3' Other reactions relevant to pyridoxal enzymes involving cleavage of bond (b) in (1 5) are discussed later in this '' H.C. Dunathan, Proc,. IVufl. Acud. Sci. C.S.,4..1966. 55, 712: J. R. Fischer and E. H. Abbot, J. Am. Chern. Snc.. 1979, 101, 2781. 3h P. Arrnstrong, D. T. Elrnore, R. Grigg, and C. H. Williams, Bioclwn. SOL,.Truns.. 1986, 404.''R. Grigg and J. Kernp. Termlierlron Lett.. 1978, 2823; R. Grigg and S. Thianpatanagul, unpublished observations. Grigg H I" R -C, COz H I I N I PO4 PO4Y -4:F!H H N' (15) (17) article, but it is clear that the concept of pyridoxal imines functioning as 1,3-dipoles provides a new approach to the design of suicide substrates for pyridoxal enzymes.36 An interesting and synthetically useful reaction occurs between imines and azoesters leading to imines of dehydroamino acid esters in good yield (Scheme 8).Several mechanisms can be advanced for this reaction but we accumulated good evidence in favour of Scheme 9 which requires formation of a 1,3-dipole and cycloaddition to give an undetected tria~olidine.~~ The key feature of the proposed R \c /co* Me Me I y.y.0-"oc"2&oH 110 -14OOC Me Pyridoxal imines R= H,Me,CHMe2 ,CH20H, CHzPh etc. Scheme 7 3x R.Grigg and J. Kemp, J. Cktti. Soc.. Chem. Contntun., 1977. 125. Prototropic Routes to 1,3-and 1,5-Dipoles,and 1,2-Mides Et02CNH -NHC02Et + COzMe ArCH 7OzMe Et02CN=NC02Et 130-1 40°C ’ ArCH \N I R2 R’ R’ R2= Me R’ = Me,R2= Et €/Z R’ = Ph, R2= H R’ = CHMe2 ,R2= H Scheme 8 Et02CN=NCOzEt OEt COZ Me + Me -EtOzCNH-NHCO 2 Et Scheme 9 IOOOC lornin t H2N-R HOAc CHO 0 (18) (19) Grigg mechanism is that the intermediate triazolidine is rendered labile by the presence of H*.In accord with this analysis, imines lacking a suitably placed hydrogen atom afford triazolidines in good yield.38 In attempting to prepare monoimines of o-phthalaldehyde we discovered a new, rapid, simple one-step synthesis of N-substituted isoindolin-1-ones (18) A(19).39 A wide variety of amine components (aliphatic, aromatic, heteroaromatic) can be incorporated into (19) and yields are excellent.Two mechanisms were considered R I H-0 CH,CO, HQ2J H/-“yD e;change Scheme 10 for this process, which is illustrated for an a-amino acid as the amine component (Scheme 10). First, formation of the monoimine, followed by ring-closure to the carbinolimine (20). Then either a 1,3-hydride shift [Scheme 10, path (a)] in which the hydroxy group aids the 1,3-shift [(20) arrows] or a prototropic pathway [Scheme 10, path (b)]. When the reaction was carried out in deuterioacetic acid, clean incorporation of one deuterium atom into the isoindolin- 1-one methylene group was observed. No exchange of H, was observed, showing that an azomethine ylide was not being generated. Moreover, since the a-amino acid possesses a chiral centre the product from the deuteriation experiment is a mixture of diastereomers.39 R. Grigg, H. Q. N. Gunaratne, and V. Sridharan, J. Chem. Soc.. Chem. Commun., 1985,1183. Prototropic Routes to 1,3-and I ,5-Dipoles, und I .2-Ylides However, the ratio of the diastereomers was found to be dependent on the steric bulk of the R group in the ;c-amino acid (Table 1) suggesting the deuteron was delivered intramolecularly [Scheme 10,(21), arrows] to the face of the intermediate isoindole remote from the R group, i.e. diastereofacially selective protonation was o~curring.~'Both (3-and (R)-amino acids give identical or very similar ratios of diastereomers (Table 1) as expected for intramolecular deuteron transfer via (21).N-CHC02 Me IR IFi C62Me (231 a, R = Me (24)a; R = C02Me, R' = Me (25) b; R = Ph b; R = Me, R'= C02Me c; R = C02Me, R'= Ph d; R = Ph, R' =C02Me (26) Ar = 2 -naphthyl Table 1 Diastrrronwr rutios of moiiodeuterio-(22) R in (22) Ratio ,from Ratio ,from (S)-aminoacid (R)-ur??inowid Me 1 : 1.20 1: 1.18 Ph 1.22:1 1.22: 1 PhCH, 1.32:1 1.17: 1 CHMe, 1.63:1 2.05: 1 CH,CHMe, 2.30: 1 2.03: 1 Bu' 7.10:1 - Subsequent to our work some related reactions were reported4' involving 0-formylarylazomethylenetriphenylphosphoranes,but without precise mechanistic detail. Intramolecular 1,3-dipolar cycloadditions have proved both valuable and powerful in natural product synthesis.42 Our prototropic generation of azomethine 40 L.Dunhamel, P. Duhamel. J.-C. Launay. and J.-C. Plaquevent, Bull. Soc. Chirn. Fmnc.e, 1984. 421. 41 A. Alemagna. P. del Buttero. E. Licandro. S. Maiovana, and A. Papagni. Trtruheriron. 1985, 41. 3321. 42 A. Padwa. .4nge~t,.C'henz., rnl. Ed. Engl., 1976. 15. 123: W. Oppolzer. ibfli.. 1977, 16, 10. 102 Grigg ylides from imines provides a simple and effective route to such processes.43 In intramolecular cycloadditions of imines of a-amino acid esters the dipolarophile can be incorporated into either of the two imine precursors, the aldehyde or the amino-acid esters. Examples of both types have been studied and successful, high yield, cycloadditions achieved in both cases. In every case the major product has cis-stereochemistry at the newly created ring junction (X-ray crystallography or n.0.e.difference spectroscopy) with zero or < 10% of trans-isomer being formed. An example in which the dipolarophile is incorporated into the aldehyde precursor is shown in (23). Heating imine (23a) in xylene (140 "C,24 h) gives a quantitative yield of an 87:9:4 mixture of (24a), (25), and (24b).43 An example in which the dipolarophile is incorporated into the amino acid moiety is provided by (26) which cyclizes (xylene, 140 "C,24 h) in quantitative yield to a 92: 8 mixture of (27) and (28).43 Cycloadducts (24a), (23, (27), and (28) arise from the 1,3-dipole (30a) which is generated in a kinetically controlled process. The minor product (24b) from (23a) arises from a small amount of dipole (31a) generated by stereomutation of (30a).In contrast to (23a) the imine (23b) gives a ca. 50: 50 mixture of (24c) and (24d), i.e. substantial dipole stereomutation (30b) T(31 b) occurs (Scheme 11). Factors A-ffecting Dipole Stereomutation. The occurrence of dipole stereomutation (30) (31) is a function of both imine structure and dipolarophile reactivity. With unactivated dipolarophiles, (i.e. terminal alkenes with no electron-withdrawing substituents) the kinetic dipole (30a) undergoes minor stereomutation [<5"/; of (31a) formed]43 whilst with activated dipolarophiles (e.g. acrylate, maleate and fumarate esters, N-phenylmaleimide etc.) no stereomutation is H a, R= Me b, R = Ph (311 Scheme 11 J3 P.Arrnstrong. R. Grigg, M. W. Jordan, and J. F. Malone, Teirahedron, 1985,41,3547; P. Arrnstrong and R. Grigg, unpublished observations Prototropic Routes to 1,3-and 1,5-Dipoles, and 1,2-Ylides (33) imine k,_ kinetic dipole &stereomutated dipole k-, k-2! Ik3 k4 cycloadduct cycloadduct Scheme 12 1,5 -Electrocyclitat ion H-'lo OY Ar H COzMe Ar H COzMe DDQ -25 OC C0,Me 1I I Ratio A: 6 -2:l Scheme 13 observed.44 In contrast (30b) undergoes essentially complete equilibration with (31 b) when generated in the presence of unactivated dipolarophile~,~~ partial equilibration when generated in the presence of maleate and fumarate but does not equilibrate when generated in the presence of maleimide~.~~ Thus equilibration of (30) is promoted by the presence of two aryl groups at the termini of the azomethine ylide system (30b). These participate in charge delocalization and lower the C(l)-N(2)-C(3) bond order and hence lower the barrier to dipole stereomutation (Scheme 11).The stereochemical outcome of the cycloaddition thus depends on the relative rates of cycloaddition (k3, k4) and stereomutation (k2) (Scheme 12). With maleimides as dipolarophiles, dipole formation is rate-determining (cycloaddition 44 R. Grigg, J. Kemp, and W. J. Warnock, J. Chem. SOC..Perkin Truns. I, in press; R. Grigg and J. Kemp, Tetrahedron Lett., 1980, 2461. 45 K. Amornraksa, R. Grigg, H. Q. N. Gunaratne, J. Kemp, and V. Sridharan, J. Chem. Soc., Perkin Truns.1, in press. 104 Grigg is fast) and only the kinetic dipole (30) is trapped (Scheme 12, k3 9 kl).With less active or unactivated dipolarophiles cycloaddition becomes rate-determining (Scheme 12, kl > k3)and stereomutation (30) (31) may compete if the energy barrier to rotation is sufficiently low. Two terminal aryl substituents (30b) are sufficient for this purpose. Studies of the stereochemistry of cycloadducts derived from (29b) and maleate esters44 support configuration (3 1b) for the stereomutated dipole rather than (32) (Scheme 1l), i.e. regiospecific rotation about the C(1)-N(2) bond in (30b) occurs and N(2)-C(3) rotation is not observed. In terms of dipole stability (32) would be predicted to be the least stable of the three azomethine ylides [(30)-(32)] from steric considerations (Ar-R interaction). The relative order of the steric interactions between HA and R in (30) and HA and the ester group in (31) will depend on the steric bulk of R.Dipole stereomutation (30) c(31) involves loss of cu. 5-6 kcal of stabilization due to the intramolecular H-bond in (30). Thus imines lacking a terminal substituent capable of H-bonding might exhibit a lower barrier to dipole stereomutation. In accord with this suggestion the imines (33) are much more susceptible to stereomutation than (29).46 Based on the extensive studies47 of the stereomutation of aziridines and the addition of aziridines to dipolarophiles it would be expected that aziridines might feature in the iminedipole equilibria (Scheme 11).At present we have no evidence for this suggestion. Further extension of the concept of formal 1,2-H shifts to the generation of 1,n-dipoles is conceivable and we have provided an example of 1,5-dipole formation (Scheme 13).48 The competitive 1,5-electrocyclization leading to A, and double- bond shift leading to B, are solvent-sensitive and the ratio of A to B increases from 2: 1 (toluene) to 5.5: I in a~etonitrile.~~ Speckamp et a1.49have reported an application of this 1,5-electrocyclization to the synthesis of indolines. Our report of a related reaction5' was subsequently found to be in~orrect.~' 0ximes.-Our initial studies on oximes51 showed that oximes of aldehydes and ketones give cycloadducts containing two moles of the dipolarophile and that these arise uiu path B of Scheme 14.Oximes are type 111 X=Y-ZH systems and the presence of two adjacent atoms bearing lone pairs renders them prone to Michael- type additions. To persuade oximes to react by path A (Scheme 14) it is necessary to encourage the formal 1,2-H shift by making available a lower energy pathway. One way of achieving this is by constructing a system that favours an allowed 1,5-H shift and which subsequently permits the possibility of proton transfer by 4h M. Joucla and J. Hamelin, TetraAedron Let[., 1978, 2885; 0.Tsuge, K. Ueno, S. Kanemasa, and K. Yorozu, Bull. Chem. Soc. Jpn, 1986, 59, 1809. 47 J. W. Lown, Rec. Cheni. Prog., 1971, 32. 51; H. W. Heine, R. Peavy, and A. J. Durbetaki, J.Org. Chem., 1966.31,3924; R. Huisgen. W. Scheer, and H. Mader. Angew. Cheni..Int. Ed. Engl.. 1969,8,602 and 604; J. H. Hall and R. Huisgen, J. Chem. Soc.. Chem. Commun.,1971, 1187; J. H. Hall, R. Huisgen, C. H. Ross, and W. Scheer. ibid, 1971, 1188; P. B. Woller and N. H. Cromwell, J. Org. Chem., 1970, 35. 888. 4x R. Grigg and H. Q. N. Gunaratne. Terrrrhedron Lett., 1983. 1201. 49 J. Dijink, J. N. Zen-jee. B. S. de Jong, and W. N. Speckamp, Hererocyles, 1983, 20, 1255.''R. Grigg and H. Q. N. Gunaratne. J. Clien7. Sic.. Chenr. Commun.. 1984, 661; see corrigenda J. Chem. Soc., C/ieni. C'onimun., 1985, 1271. 51 R. Grigg. M. Jordan, A. Tangthongkurn. F. W. B. Einstein. and T. Jones. J. C/zem.Soc., Perkin Trims.1. 1984. 47. Prototropic Routes to 1.3-and 1.5-Dipole.r, and 1,2-Ylides Scheme 14 1,5 Shift-4""I 0-H Ph OyyO 8h,l10DC 0 N/* 55"lo Scheme 15 intramolecular hydrogen bonding. The successful realisation of this objective52is illustrated in Scheme 15. Our initial studies of oxime cy~loaddition~~showed that although the 2:l adducts were formed in good yield they gave rise to mixtures of all the possible regio-and stereo-isomeric oxazolidines.However, we were attracted by the s2 R. Grigg and S. Thianpatanagul, J. C'iwm. Soc.. Prrkrn Trmi.>.I. 1984. 653. Grigg Figure 6 Potential synthetic variants in oxime cycloadditions Michael Addition Cqdoaddition intermolecular intermolecular intermolecular intramolecular intramolecular intermolecular intramolecular intramolecular X fix6140°C, 24h 85 -100% (33) (34) X =CO,CH,Ph or S0,Ph H AXU 14OOC looo/o X = C02CH2Ph or SOzPh Scheme 16 simplicity of the process and its potential synthetic flexibility.Thus the process consists of two distinct steps (Scheme 14), (i) Michael addition, (ii) cycloaddition, and this provides four broad classes of synthetic methodology (Figure 6). Further study of oxime cycloadditions was therefore initiated and the process has now been developed into a powerful synthetic method53 for the construction of complex molecular frameworks. To date examples of the first three classes in Figure 6 have been realised and suitable substrates for the final class are under preparation. The first class, exemplified by (33) (34), occurs regiospecifically in excellent yield.Two typical examples of a large number we have carried out of the second class are shown in Scheme 16 and (35) -(36). Stereochemistry of the cycloadducts was established by n.0.e. difference spectroscopy. The stereochemistry of the oxime starting material (s~n,anti) is not normally important since under the reaction J3 P. Armstrong, R. Grigg, and W. J. Warnock, unpublished observations. 107 Prototropic Routes to 1.3-and 1 ,5-Dipoles, and 1.2-Ylides LN-O H looo/o (35) (36) ,C02Me Me toluene, llO°C, Zh ' (37) (38) 85"/o +6 (39) conditions syn-anti interconversion is faster than cycloaddition. Thus (35) is a 65:35 mixture of oxime isomers but gives a single cycloadduct (36). A typical example of the third class is shown in (37) (38) and the inherent flexibility of this new methodology is further illustrated by processes such as (39) --+ (40) + (41) in which oximes react with substrates in which Michael acceptor and dipolarophile are combined within one molecule.The synthetic manipulation of oxazolidines by reductive cleavage of the N-0 bond and their usefulness as precursors of natural products is well known54 and suggests our new methodology will find many applications in this area. 54 A. P. Kozikowski, Arc. Chrm. Rex. 1984, 17, 410; J. J. Tufariello in '1,3-Dipolar Cycloaddition Chemistry', ed. A. Padwa, Vol. 2, Wiley-Interscience, 1984. p. 83; A. Padwa, ;bid. p.277. Grigg PhCH NHPh Ph \pJ/ -150 OC phx'r > 80°/, + Argon "h H H I1 Air , Ph 'INTO 150OC Ph 'N/NPh Scheme 17 Hydrazones.-These, like oximes, are type I11 X=Y-ZH systems (Scheme 2) and show a tendency to undergo competing or exclusive Michael additions through carbon as well as 1,3-dipolar cycloadditions via a formal 1,2-H shift. Typical 1,3- dipole behaviour is illustrated by the reactions in Scheme 17,55 which emphasizes the sensitivity of pyrazolidine products to oxidation under the reaction conditions. Intramolecular reactions to non-activated terminal alkenes, [e.g. (42a) +(43), with accompanying oxidation] or alkynes can also be achieved but in low yield ( d20%). With activated terminal alkenes (42b) the reaction is diverted to a Michael addition-cyclization process (42b) -(44).Certain N-sulphonylhydrazones on heating with N-phenylmaleimide give cyclopropyl derivatives (Scheme 18) e.g. Ar = 2-methoxyphenyl, in ca. 40% yield56 and this process can be accommodated by a 1,3-dipolar cycloaddition followed by elimination of sulphinic acid and nitrogen (Scheme 18). Related reactions to Scheme 18 have been reported by others.57 Early work of He~se~~ involving cycloaddition of hydrazones in acid solution has recently been repeated59 and the 4x-species participating in the cycloaddition is believed to be (45). Type 111 X=Y-ZH systems have the potential to function as 4n- participants in cycloadditions uia the neutral (46), N-protonated (47) or 1,3-dipolar (6) forms.R. Grigg, M. Dowling, and V. Sridharan, unpublished observations 55 R. Grigg, J. Kemp. and N. Thompson. Tetrahedron Let[., 1978, 2827. 5' R. M. Wilson, J. W. Rekers, A. P. Packard, and R. C. Elder, J. Am. Chem. SOC.,1980, 102, 1633; A. G. Schultz, J. P. Dittarni, and K. K. Eng, Tetrahedron Lett., 1984, 25, 1255. 58 K. D. Hesse, Annakn, 1970, 743, 50. 59 G. Le Fevre, S. Sinbandhit, and J. Hamelin, Tetrahedron, 1979, 35, 1821. 109 Prototropic Routes to 1,3-mu’ 1.5-Dipoles, and 1,2-Ylidi>s 14OoCJ (43) 20°/0714ooc ‘NHPh “aNhl(L2) a, R =H b, R =C02Me Ph Ph Ph 1*yyO Hx:lxylene, 140°C, 4h Ph Ar H 1 Ph Ph -NZ -Ar Ar Scheme 18 .. X*;,ZH Hx\‘1 /ZH (45) (46) Grigg RCHCOlH RCHz I I PO J GABA Dopamine Serotonin Histamine Scheme 19 (48)a, X =N b, X=CH (49) 3 Decarboxylative Route to Azomethine Ylides In the earlier discussion of the biochemistry of pyridoxal imines it was mentioned (1 5) -(17)that decarboxylation of r-amino acids is effected cia imine formation.60 This is an important biological process leading to the formation of the so-called biogenic amines (Scheme 19)and, as such, has attracted numerous model studies to establish laboratory analogies for the process.61 Strecker was the fird2 to observe the decarboxylation of an a-amino acid cia imine formation (with alloxan) in 1862 and the ‘carbonyl assisted’ in uitro decarboxylation of a-amino acids is now known as the Strecker Degradation.Important contributions to the 6o M. H. O’Leary. H. Yamada, and C. J. Yapp, Biochemisfry. 1981, 20, 1476; M. H. O’Leary and G. J. Piazza. hid,p. 2743.‘*R. M. Herbst. in ‘Advances in Enzymology’, Vol. 4, Interscience, 1946, p. 75; E. K. Hervill and R. M. Herbst. J. Org. Chem., 1944, 9, 21. h2 A Strecker, Annnlen. 1862, 123. 363. Prototropic Routes to 1,3-and 1,5-Dipoles, and 1,2- Ylides (50) 11 Scheme 20 Ph 6 4o:o+ HYph HO*oH I H2N ,CHC02 H OH 13 70°/o Scheme 21 112 Grigg 4.5’1” n.0.e. ,y-\ + QC,” H H 73“lo /COzMe2-Scheme 22 Scheme 23 scope and mechanism of the Strecker Degradation have been made by Moubacher and S~honberg,~~ and Chatelu~.~~ Badda~-,~~ When we began our work very little synthetic use had been made of the Strecker Degradation and the accepted mechanism (48a) -(49a) was analogous to that established for P,y-unsaturated acids (48b) -(49b).66 This mechanism seemed unlikely to us.It appeared more probable that the imine would undergo decarboxylation cia the zwitterionic form (50) (Scheme 20) generating a 1,3-dipole. The final location of the proton in the neutral imine product would then depend on a kinetically controlled proton transfer to the site in the dipole [(51) a orb] with the greatest electron density. The published literature on the Strecker Degradation is readily interpretable in terms of this mechanism, including heretofore unexplained variations in the final site of the imine double bond.Furthermore, the new mechanism is immediately open to a rigorous test by cycloaddition experiments de- signed to trap the postulated azomethine ylide (51). Such trapping experiments were immediately, and gratifyingly, suc~essful~~.~~ and the new method has proved to have a wide synthetic scope. Some typical examples are shown in Schemes 21-23.67.68 6.7 A. Schonberg and R. Moubacher. Ciimi. Rev.. 1952. 50. 261. “F. G. Baddar and S. A. M. Sherif. J. Ciirm. Soc.. 1956. 4292 and earlier papers. 65 J. Chatelus. Bull. So(,.Chirii. Frmice. 1964, 2523 and earlier papers. ”C. A. Buehler and D. E. Pearson. ‘Survey of Organic Syntheses’. Vol. 2, Wiley, 1977, p. 405. ” R. Grigg and S. Thianpatanagul, J. Clirm.Soc.. Clirm. Comrnun., 1984, 180. ’’R. Grigg, M. F. Aly. V. Sridharan. and S. Thianpatanagul. J. Chrrn. Soc.. Chmm. Coniriiun., 1984, 182. 113 Prototropic Routes to 1,3-und 1,5-Dipoles,and I ,2-Ylides Subsequently we became aware that Rizzi had previously suggested a 1,3-dipolar intermediate for the aldehyde induced decarboxylation of N-alkylamino acids under forcing condition^.^^ Fortunately for us he had not appreciated the scope of the process, which will tolerate wide variations in the carbonyl and dipolarophile components and occurs with all types of x-amino acid (primary, secondary; X,X-disubstituted, cyclic, and acyclic). It is not necessary, or usually desirable, to form the imine in a separate step. Merely reacting the amine and carbonyl compound in the presence of a dipolarophile is sufficient.Reaction temperatures range from room temperature to 120 ’C. Pyridoxal reacts in hot methanol or in aqueous acetonitrile with phenylglycine and N-phenylmaleimide (Scheme 2 1) to give a single cycloadduct. Adduct stereochemistry in Schemes 21-23 is assigned on the basis of n.0.e. difference spectroscopy and signal enhancement values are indicated in Schemes 21 and 22. Our initial studies67*68 led us to comment that dipole production via (50)-(51) (Scheme 20) might be expected to occur with little stereoselectivity compared to dipole formation by the formal 1,2-Hshift route (Scheme 3) in which H-bonding is considered to play an important role. However subsequent more detailed studies indicated stereospecific or highly stereoselective dipole formation by the decarboxylative route” and requires a revision of our initial suggestion of direct decarboxylation of the zwitterion (50) -(5 1).We now believe this process A%G-O Hammick 70 base Breslow 76 Scheme 24 /=“r -R YLide Nucleophilic Carbene (53) (54) ’’)G. P. Rizzi. J. Org. C’kcni., 1970, 35, 2069. R. Gri-gg, S. Surendrakumar, S. Thianpatanagul, and D. Vipond, J. C‘hmi. So(,.,Chrwi. Cotiimun., 1987, 47. Grigg involves an initial stereospecific or highly stereoselective cyclization (50) (52) to an oxazolidin-5-one (Scheme 20) followed by a 1,3-cycloreversion [(52) 1,3-Cycloreversions are known to occur stereo~pecifically~~ar1-0~~1.~ and Huisgen’s extensive work on cycloadditions of mesoionic oxazolones (munch- nones)73 provides numerous examples where transient bicyclic oxazolidin-5-ones gives rise to azomethine ylides by loss of carbon dioxide.Es~henmoser’~ and Seebach7 have isolated oxazolidin-5-ones and the former author has demonstrated thermal loss of carbon dioxide with formation of a 1,3-dipole. Our work suggests that the possible involvement of oxazolidin-5-ones in the biochemical decarboxylation of x-amino acids by pyridoxal enzymes merits serious consideration. The ninhydrin test referred to earlier in this article involves Strecker Degradation of x-amino acids cia azomethine ylides as shown by appropriate trapping experiment^.^^ 4 Decarboxylative Route to 1,2-Ylides Non-oxidative enzyme-catalysed decarboxylation of a-keto acids to aldehydes involves adduct formation with thiamine pyrophosphate.It is generally considered that this step is essential because a-keto acids lack a suitable ‘electron sink’ mechanism to stabilize negative charge development during decarb~xylation.~~~~~ However, it is well known that pyridine-2-carboxylic acid undergoes thermal decarboxylation via the zwitterion to give a 1,2-ylide (Scheme 24) which can be trapped by electrophiles (Hammick reaction).78 Furthermore, the ready deprotonation of azolium cations at C(2) (Scheme 24) to give a 1,2-ylide is the basis of the biochemistry of thiamine pyr~phosphate’~and important synthetic methodology for C-C bond f~rmation.~’ Thus the moiety (53) possesses intrinsic stabilizing features when part of an aromatic ring system in which R is a heteroatom or an sp2-carbon centre.This enhanced stability is usually attributed to carbene resonance (53) -(54), but it is unclear what, if any. contribution the presence of the aromatic ring makes to this enhanced stability. Acyclic examples of (53) might be generated by decarboxylation of imines of x-keto acids and this encouraged us to study such processes. The imines (Scheme 25) are readily prepared at ambient temperature and smoothly -I R. Grigg, J. Idle. P. McMeekin, and D. Vipond, J. Chetn. Soc.. Chetn. Commun., 1987, 49. ’’G. Bianchi and R. Gandolfi, in ’1.3-Dipolar Cycloaddition Chemistry’, ed. A. Padwa. Vol. 2, Wiley-Interscience.1984. p. 45 1. R. Huisgen. ‘Aromaticity’, Chemical Society Special Publication No. 21, 1967. p. 51; R. Huisgen. H. Gotthardt. and H. 0.Baeyer, Clietn. Ber., 1970, 103, 2368; J. Am. Cliem. Soc., 1970, 92, 4340.’‘A. Eschenmoser, c‘iicm. Soc. Rei.., 1976. 5, 377.’’D. Seebach, M. Boes, R. Naef, and W. B. Schweizer. J. Am. Chem. Soc., 1983, 105. 5390.’‘R. Breslow, J. Am. Cliern. Soc.. 1958,80, 3719; J. Duclos and P. Heake. Biochemistrj,. 1974, 13, 5358; M. Begtrup, J. Clieni. So(,..Cjzeni. Co~nmin.,1975, 344. l7 J. Crosby. R. Sine, and G. Lienhard, J. Am. Chei. Soc., 1970, 92, 2891; T. Lowe and L. Ingram, ’An Introduction to Biochemical Reaction Mechanisms’, Prentice-Hall. New Jersey, 1975. pp. 7 1 et sey.’’ P. Dyson and D. L1. Hammick.J. Clicwi. Soc.. 1937. 1724: M. R. F. Ashworth, R. P. Daffern, and D. LI. Hammick, ihiti., 1939. 809. ’’)H. Stetter and G. Dambkes, Sjxrhesis. 1977,403; H. Stetter. Angcw. Chem.. Int. Ed. Engl., 1976, 15, 639. 115 Prototropic Routes to I ,3-and 1,5-Dipoles, arid 1,2-Ylides H Scheme 25 - 'Y't-iNa 58 8OoC, 20min CO,H S Scheme 26 decarboxylate in boiling methylene chloride or benzene to give the corresponding decarboxylated imines (Scheme 25, R = R' = alkyl or aryl). Attempts to trap the intermediate, 1,2-ylide with aromatic aldehydes were unsuccessful. Transimination and competitive proton transfer, to give the decarboxylated imine, intervene. However, the 1,2-ylide can be trapped with sulphur to give the corresponding thioamide in excellent yield and this can be achieved in a one-pot reaction from primary or secondary amines, x-keto acid and sulphur, e.g.Scheme 26.*' Further reactions of (53) -(54) are under study. Thus the decarboxyla-tion of a-keto acids uiu imine formation is a facile process and it would be surprising if there are no biochemical processes utilizing this reaction. 5 The Iminium Ion Route to Azomethine Ylides The concept of a 1,5-H shift facilitating dipole formation that proved successful in the oxime case (Scheme 15)52 might, we felt, be applied to the generation of azomethine ylides from unactivated primary and secondary amines as outlined in Scheme 27. M. F. Aly and R.Grigg. J. Ch~m.SIC,..C'liem. Comntim.. 1985. 1523 Grigg (55) "It R R Scheme 27 6 9 */a Scheme 28 Sigmatropic rearrangements in charged systems are generally extraordinarily facile'' but to our knowledge this concept of charge acceleration has not been applied to 1,5-shiftsa2 such as [(55) arrows] (Scheme 27).It proved remarkably simple to generate azomethine ylides from primary and secondary amines and '' H. J. Hansen, B. Sutter, and H. Schmid, Helv. Chim.Acta, 1968,51,828; D. A. Evans and A. M. Golob, J. Am. Chem. SOC.,1975, 97, 4765; M. Koreeda and J. I. Luengo, ibid.,1985, 107, 5572. 82 For a related 1,6-H shift leading to 1,5-dipoles see A. N. Reinhoudt, G. W. Visser, W. Verboom, P. H. Benders, and M. L. M. Pennings, J. Am. Chem. SOC.,1985, 105, 4715. 117 Prototropic Routes to 1,3-and I S-Dipoles, and 1,2-Ylides carbonyl compounds containing the moiety O=C-C=X.83 A survey of carbonyl compounds of this latter type has shown that ninhydrin, isatin, acenaphthaquinone, phenylglyoxaldehyde, ethyl glyoxylate, and pyridine-2-carbaldehyde all function as suitable precursors of azomethine ylides.Examples where X=S (Scheme 27) have yet to be studied. Typical examples of this new route to azomethine ylides are shown in Schemes 28 and 29.83 In each case a single stereoisomer is obtained and in Scheme 29 the reaction is regiospecific, involving only the benzylic methylene group. The stereochemistry of the cycloadducts in Schemes 28 and 29 are assigned by n.0.e. difference spectroscopy except for that at C* in Scheme 28 which is tentative and is assigned in accord with the proposed mechanism.It must be admitted that although these reactions provide a facile route to azomethine ylides, alternative, non-sigmatropic, base-catalysed mechanisms may be operative. Thus 3,5-di-tert- butyl o-ben~oquinone~~ and phenylgly~xaldehyde'~ react with amines to give ketones via prototropy of the intermediate imines and the mammalian and bacterial coenzyme methoxatin (56) functions similarly.86 Thus a non-sigmatropic, base-catalysed process has much to commend it. Dipole stereochemistry in this case would then be controlled by the stabilization afforded by a 1,5-charge interaction (5Q8 6 Metallo-1,3-Dipoles In the general dipole equilibrium (5)e(6) any atom, X, Y, Z, or H could conceptually be replaced by a metal ion and this raises many intriguing possibilities. "H.Ardill, R. Grigg, V. Sridharan,S. Surendrakumar. S. Thianpatanagul, and S. Kanajun,J. Chem. Soc.. Chem. Commun., 1986, 602. 84 E. J. Corey and K. Achiwa. J. Am. Chem. Snc., 1969, 91, 1429. 85 V. Calo, L. Lopez, and P. E. Todesco, J. Chem. SOC..Perkin Truns. I, 1972, 1652. 86 C. L. Lobenstein-Verbeck, J. A. Jongejan, J. Frank, and J. A. Duine, FEBS Left., 1984, 170, 305; Y. Ohshiro, S. Itoh, K. Kurokawa, J. Kato, T. Hirao, and T. Agawa, Tetrahedron Letf., 1983, 24, 3465; S. Itoh. M. Mure, Y. Ohshiro, and T. Agawa, ibid., 1985, 26, 4225. Grigg CO,HI xNy0 0B:o*HX-(56) (57) I M"* Scheme 30 119 Prototropic Routes to I ,3-and I ,5-Dipoles, and 1,2-Ylides Me I Me I CHC02Me LiWC14 or Pd(OAcI2* X- (62) J Scheme 31 We have initially focussed on examples in which H is replaced by a metal ion (58) e(59) and, although we have, as yet, no metallotropic examples we have several examples of (59).29*37A family of metallo-1,3-dipoles (59) can be imagined in which the overall molecular charge will vary with the valency of the metal ion M and the number of associated counterions. In a development of earlier work by Casella et we prepared a series of copper(Ir), zinc(rr), and cadmium(r1) complexes of imines derived from x-keto acids and glycine or alanine.These metal complexes, e.g. (60), undergo stereo- and regio-specific cycloadditions to 1,2-disubstituted electronegative olefins in the presence of weak base at ambient temperature via the metallo-1,3-dipole (61) (Scheme 30).88 Reactions of these metallo imines with methyl acrylate, phenyl vinyl sulphone, and acrylonitrile frequently give mixtures of regio- and stereo-isomers.The stereoisomers arise by isomerization of initial cycloadducts formed by a 47c + 27c concerted process. The reaction of aryl imines of a-amino acid esters with either lithium tetrachloropalladate or palladium acetate gives the corresponding dimeric ortho palladated imines (62) (Scheme 31) in good yield. These imines (62) are readily deprotonated by weak base at ambient temperature and the resulting metallo- 1,3- dipole can be trapped by N-methylmaleimide in good yield (Scheme 31).89 The work described in this article has all developed from the simple idea of 1,2- protopropy in X=Y-ZH systems and the extension of this and related ideas is still developing rapidly.''L. Casella, M. Gullotti, and E. Melani, J. CJiern. Soc., Perkin Trans. 1, 1982, 1827. 88 R. Grigg, V. Sridharan, and S. Thianpatanagul, J. Chem. Soc., Perkin Trans. I, 1986, 1669. B9 R. Grigg and J. Devlin, J. Chem. Soc.. Chem. Commun., 1986, 631. 120 Grigg Acknowledgements. I wish to record my thanks to my co-workers for their unstinting cooperation, hard work, and good humour and to Glaxo (Ware) who sponsored our initial work in this area. Further subsequent support from Gallahers, SERC, and Queen’s University is gratefully acknowledged.

ISSN:0306-0012    

DOI:10.1039/CS9871600089

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Chem. SOC.Rev., 1987, 16, 123-160 Applications of Multinuclear NMR to Structural and Biosynthetic Studies of Polyketide Microbial Metabolites By T. J. Simpson DEPARTMENT OF CHEMISTRY, UNIVERSITY OF EDINBURGH, WEST MAINS ROAD, EDINBURGH EH9 355 1 Introduction The study of biosynthetic pathways received a major new impetus in the early 1970s with the advent of pulsed Fourier-transform n.m.r. spectrometers which greatly facilitated the routine determination of 3C n.m.r. spectra of realistically available amounts of natural products. In addition, precursors enriched with 13C and other stable isotopes were becoming more available. These were timely developments because structures had been determined increasingly by spectroscopic and other physical methods with little or no recourse to degradative chemistry with the result that classical biosynthetic studies, using radioisotopes and necessitating extensive degradative schemes to locate the position of incorporation of isotopic label, were becoming increasingly difficult.In addition, the complexity or limited available amounts of molecules that were the targets for study meant that, at best, only a partial labelling pattern might be determined. These problems were to be largely overcome by 3C-labelling methods which again provided a biosynthetic technique complementary to the methods used for structure elucidation. It should be noted that the early studies using singly 13C-labelled precursors did not provide any information which in principle at least, could not be obtained by classical radioisotope methods: they merely (!) facilitated the determination of information such as complete labelling patterns by observation of enhancements of individual 3C resonances.However these studies soon led to the use of precursors doubly labelled with 13C which inter alia enabled the mode of incorporation of intact biosynthetic units, and the integrity of particular carbonxarbon bonds to be established by observation of 3C-1 3C spin-spin couplings; and bond fragmen- tation and rearrangement processes to be detected by the loss of 13C-13C couplings. This in fact represented the real advance offered by 13C-labelling techniques as this type of information could not be obtained, even in principle, by classical radioisotope methods.Subsequent and equally important developments have involved the use of precursors doubly labelled with 13C together with "0or 2H or I5N which enable ~xygen,~the biosynthetic origins of hydr~gen,~.~ and nitrogen to be determined T. J. Simpson, Chem. SOC.Rev., 1975,4, 497. T. J. Simpson in 'Modern Methods of Plant Analysis', ed., H. F. Linskens and J. F. Jackson, Springer- Verlag, 1986, vol. 2, p. 1. C. Abell in 'Modern Methods of Plant Analysis', ed. H. F. Linskens and J. F. Jackson, Springer-Verlag, 1986, Vol. 2, 60 M. J. Garson and J. Staunton, Chem. SOC.Rev., 1979, 8, 539.'J. C. Vederas, Can. J. Chem., 1982,60, 1637. Biosynthet ic Studies of Polyket ide Microbial Me tab oli tes by observation of isotope-induced shifts (or spin coupling) in 13Cn.m.r.spectra; and by direct observation of the incorporation of label from 2H-or ”N-enriched precursors by direct ’H or 5N~~.m.r.~Some limited success has also been achieved in the use of 170 n.m.r. and 170-enriched precursors.6 Besides these essentially biosynthetic techniques, n.m.r. methodology has developed to permit the rigorous assignment of spectra and of ~tructures,~ both of which are essential prerequisites of biosynthetic studies. In this article the growth and development of biosynthetic studies using stable- isotope labelling methodologies over the past decade will be illustrated by a personal account of a research programme aimed at elucidating details of the biosynthesis of polyketide-derived metabolites. For this reason the work is presented in a more or less chronological order which means that certain molecules will be revisited as developments in methodology are discussed which permitted further information on their biosynthesis to be elucidated.The compounds studied are all metabolites of the lower fungi in which the requirements of high and reliable precursor incorporation rates are more easily (but not it must be emphasized always) achieved, and because the polyketide pathway is particularly characteristic of these and other microorganisms. 2 The Polyketide Biosynthetic Pathway The polyketide pathway is one of the major routes in nature for the formation of aromatic compounds but it also produces many non-aromatic compounds many of which display biological activity as antibiotics, antitumour agents, or mycotoxins. It was first described by Birch and Donovan’ and in common with the other pathways of secondary metabolism it can be considered in terms of a primary or assembly phase followed by a secondary or modification phase.The primary phase produces a relatively small number of compounds and is responsible for the basic unity of the pathway. However, many of these primary products can be subjected to a wide variety of modifying reactions and it is this secondary phase which is ultimately responsible for the amazing diversity of structures produced by this and indeed other pathways. A simplified picture of this which will suffice for present discussions is given in Scheme 1.In essence, varying numbers of acetate units, activated as their coenzyme A thioesters, are condensed * to form enzyme-bound ‘polyketide’ intermediates which then undergo stabilizing reactions, typically cyclization and aromatization, before being released from the enzyme. Thus four acetates give a tetraketide intermediate which can, for example, cyclize to produce orsellinic acid (1) which in turn can be extensively modified to produce inter alia the mycotoxin botryodiplodin (2) in Penicillium roquefortii.’ As will be demonstrated, * The condensation occurs cirr malonyl coenzyme A. See Scheme 21 (p. 153) for further details. K. Nanamori and J. D. Roberts, Acc. Chem. Res., 1983,16,35;R. L. Baxter and S. L.Greenwood, J.Chem. Soc., Chem. Comntun., 1986, 175. R. M. Adlington, R. T. Alpin, J. E. Baldwin, L. D. Field, E. M. M. John, E. P. Abraham, and R. L. White,J. Chem. Soc.. Chem. Commun., 1982, 137. ’R. Benn and H. Gunther, Angew. Chem., Int. Ed. Engl., 1983, 22, 350. A. J. Birch and F. W. Donovan, Ausf. J. Cham., 1953, 6, 360. ’R. Renauld, S. Moreau, and A. Lablanche-Combier, Tetrahedron, 1984, 40, 1823. Simpson ASSEMBLY ' MODiF1CATION -L MeCOSCoA , I Acctat "T elrak tide " Orsellinic Acid : Botryodiplodin (1 1 (2) The POLYKETIDE Biosynthetic Pothway-Scheme 1 stable isotope labelling studies have enabled much invaluable information on both the assembly and modification process to be elucidated." 3 I3C Enrichment Studies The labelling pattern resulting from incorporation of a '3C-enriched precursor is determined by obtaining the p.n.d. 3C n.m.r.spectrum of the labelled metabolite and comparing it with the spectrum of the unlabelled compound. This is illustrated in Figure 1 which illustrates the results of incorporating either [1-l3C]-, [2-'3C]-, or [1,2-' 3C,]acetate into contiguous carbons of a polyketide-derived metabolite. Normally these carbons contain only natural abundance 13C(1.1%) as indicated in Figure la. Incorporation of a singly 3C-labelled precursor will result in an increase of the 13C content at a particular carbon and this manifests itself as an increase in the intensity of the signal due to that carbon in the 13C n.m.r. spectrum of the enriched metabolite (Figure lb and c).As may be seen, a severe limitation to this type of experiment is the existing 13C natural abundance which as a rule necessitates precursor incorporation efficiencies which will produce a doubling of the 13C content if enrichment is to be reliably observed. This means that the maximum dilution of label from precursor into product is ca. 100. These dilutions are more easily obtained in micro-organisms than in plants and it is for this reason that many of the early studies were with micro-organisms. An integral, essential, and often the most difficult part of this type of study is the rigorous assign- ment of the 13C n.m.r. spectrum, although this aspect has tended to be underemphasized in many biosynthetic papers.Incorporation of a precursor in which adjacent carbons are enriched with 13C will lead to the observation of a 3C-1 3C spin coupling being observed in the 3C n.m.r. spectrum of the enriched metabolite if the bond so labelled remains intact lo For regular reviews see, T. J. Simpson, Nut. Prod. Rep., 1985,2, 321, and previous reviews in this series. Biosynthetic Studies of Pofyketide Microbial Metabolites Use of %nmr in Isotope Labellinq Experiments * -Origin of CARBONS precursor Metabolite '&Pm Qbservation N a tura1 abundance (a) CH3COSCoA -signals only n Enhancement-c,-c,-L Enhancement Id)'3CH32C0,Na --c2-c,-13C,13C Coupling I Enhancement * First- Assinn 'k-nmr spectrum Figure 1 Simulated p.n.d, "C n.m.r.spectra of a polyketide-derived moiety (a) at natural abundance, (b) enriched from [1-' 3C]acetate,(c) enriched from [2-' 3C]acetate,(d) enriched .from [1,2-13C,]acetate, and (e) enriched from [1,2-' 3C,]acetate ajler bond cleavage throughout the biosynthetic pathway (Figure Id). If, however, the bond is broken then the derived carbons will give rise to enhanced singlets in the final spectrum. This ability to test the integrity of carbon-carbon bonds during biosynthesis represented the first major advance offered by 3C-labelling studies.' 4 Applications of Single and Double 3C-Labelling Aspergillus variecofor produces a group of xanthone metabolites, the major one being tajixanthone (3). This provided our first experience of the use of 3C n.m.r.to identify the types of carbon present in a molecule." The 13C n.m.r. spectrum of tajixanthone was fully assigned on the basis of simple chemical shift and multiplicity considerations and by shift comparison studies amongst a number of I' K. K. Chexal, C. Fouweather, J. S. E. Holker, T. J. Simpson, and K. Young, J. Chem. Soc., Perkin Trans. 1, 1974, 1584. Simpson closely related derivatives. After much thought and experimentation to work out the feeding protocols and the other requirements necessary to obtain significant I3C enrichment values, incorporation of [1-I3C]-and [2-13C]acetate into tajixanthone was achieved and from the enrichments observed in the 13C n.m.r. spectra of the enriched metabolite, the origins of all the carbons in tajixanthone were deduced as shown.This enabled a biosynthetic pathway (see Scheme 9 below), via oxidative ring-cleavage of an anthraquinone to produce an intermediate benzophenone, to be proposed.'2 Further support for this pathway was provided by the isolation of the variecoxanthones, arugosins, and other related co-metabolites from a number of strains of A. ~ariecolor.'~"~ The spectra which result from incorporation of [1-l3C]- and [2-13C]acetates into deoxyherqueinone (4)in Penicillium herquei lS are shown in Figure 2 for the derived diacetate(11). If high enrichments are obtained, as in this case, the labelled sites are readily apparent from visual inspection of the spectrum. More often, enrichments are lower and identification of enriched sites with certainty may be more difficult.'.2 13C N.m.r.was also used in the structural elucidation of multicolic acid (5) and related tetronic acid metabolites of Penicillium multicolor.16 Their biosynthesis was studied by incorporations of singly and doubly 13C-labelled acetate to provide one of the earliest applications of this then recently described technique." The observations of '3C-13C couplings and more significantly their absence on the '3C resonances of certain carbons led to the proposal that the tetronic acids were biosynthesized via oxidative cleavage of an intermediate containing a benzenoid ring (Scheme 2). These proposals were subsequently confirmed by the incorporation of 6-pentyl-resorcylic acid (6),' * and from '*O-labelling studies.' J.S. E. Holker, R. D. Lapper, and T. J. Sirnpson, J. Chem. SOC.,Perkin Trans. 1, 1974, 2135. I3 J. S. E. Holker, K. Young, and T. J. Simpson, J. Chem. Soc., Perkin Trans. I, 1975, 543. l4 K. K. Chexal, J. S. E. Holker, and T. J. Sirnpson, J. Chem. SOC.,Perkin Trans. 1, 1975, 549. Is T. J. Sirnpson, J. Chem. SOL'.,Chem. Commun., 1975, 258. '' J. A. Gudgeon, J. S. E. Holker, and T. J. Sirnpson, J. Chem. Soc., Chem. Commun., 1974, 636.'' H. Seto, L. Cary, and M. Tanabe, J. Chem. Soc., Chem. Commun., 1973, 867; H. Seto, T. Sato, and M. Tanabe, J. Am. Chem. Soc., 1973, 95, 8461. 18 J. A. Gudgeon, J. S. E. Holker, T. J. Simpson, and K. Young, Bioorg. Chem., 1979, 8, 311. l9 J. S. E. Holker, E. O'Brien, R. N. Moore, and J.C. Vederas, J. Chem. SOL'.,Chem. Commun., 1983, 192. 127 Biosynthetic Studies of Polyketide Microbial Metabolites I I I I I 200 I50 100 50 ppm 0 Figure 2 15.04 MHz p.n.d. '3Cn.m.r. spectra of deoxyherqueinone diacetate (a) at natural abundance, and enriched from (b) [1-'3C]acetate (a)(c) [2-'3C)acetate (*) OH 'C0,H (6) (5) Scheme 2 Incorporation of ['3C2]acetate was next applied to the biosynthesis of aspyrone (7) a metabolite of Aspergillus melleus. The resultant labelling pattern (Scheme 3) suggested that its biosynthesis was either via a ring cleavage pathway or by rearrangement.20 The rearrangement pathway shown was supported by the observation of a two-bond 13C-13C coupling of 6.2 Hz between C-2 and C-8 in the I3C n.m.r.spectrum (Figure 3) of [13C2]acetate-enriched aspyrone.21 This was the first observation of such a coupling in biosynthetic studies. At about this time the idea was conceived that the involvement of a symmetrical 2o T. J. Simpson, Tetrahedron Lett., 1975, 175. T.J. Simpson and J. S. E. Holker, Tetrahedron Lett., 1975,4693; J. Chem.SOC.,Perkin Trans. I, 1981,1397. Simpson Scheme 3 7 6*2Hz I I 150 100 50 6C Figure 3 25.2 MHzp.n.d. 13C n.m.r. spectrum of aspyrone (7) enrichedfrom [1,2-' 3C2]acetate intermediate at any stage in a biosynthetic pathway would result in a random- ization of labelling, e.g. of 13C-13C spin couplings if a double 13C-labelled precursor were used. Griseofulvin (8) was chosen as a model to test this hypothesis and ['3C,]acetate was incorporated using a high-yielding commercial strain of Penicillium patulum.However the results obtained in this study turned out to be very complicated. Rapid metabolic turnover of exogenous acetate resulted in 129 Biosynthetic Studies of Polyketide Microbial Metabolites J A Scheme 4 multiple labelling of individual molecules and therefore the observation of extensive inter-acetate and long range '3C-'3C couplings in addition to the desired intra-acetate couplings. In fact the most efficient route for incorporation of label from acetate was via the C,-pool into the methoxyl carbons.22 However the hypothesis was soon proved to be correct when a study on the xanthone metabolite ravenelin (9) was carried out.Incorporation of ['T,]acetate into ravenelin in cultures of Helminthosporium ravenelii resulted in the predicted randomization of '3C-13C couplings in ring-C consistent with the intermediacy of a symmetrical benzophenone intermediate (Scheme 4), itself derived from cleavage of an anthraq~inone.~ This type of information has subsequently found extensive use in biosynthetic studies. In this st6dy the 13C n.m.r. spectrum of ravenelin was partially assigned by 22 T. J. Simpson and J. S. E. Holker, Phytochemistry, 1977, 16, 229. 23 A. J. Birch, T. J. Sirnpson, and P. W. Westerrnan, Tetrahedron Lett., 1975,4173; A. J. Birch, J. Baldas, J. R. Hlubucek, T. J. Sirnpson, and P. W. Westerman, J. Chem. SOC.,Perkin Trans. 1, 1976, 898.Simpson OMe 1RS Me-COSR c5Me OMe HO Me Scheme 5 analysis of long-range 'H-13C couplings in the fully 'H-coupled 13C n.m.r. spectrum, a technique which was to form the basis of many future studies. It remains one of the best but under-utilized methods for both structural elucidation and spectral assignment studies (see below). This was exemplified by a study of deoxyherqueinone (4) and herqueichrysin (lo), phenalenone metabolites of Penicillium herq~ei.,~ The aromatic ring system of these metabolites could be derived a priori by any one of three foldings of a heptaketide precursor or by numerous possible multi-chain condensations. Deoxyherqueinone was isolated and purified as its diacetate derivative. Due to the tautomeric possibilities in these hydroxyphenalenone structures the actual structure of this diacetate was uncertain.However, analysis of the long range 'H-13C couplings by selective 'H irradiation and D,O exchange experiments simultaneously defined the precise structure (1l), (Figure 4) and simultaneously produced an unambiguous spectral assignment. Similar studies defined the structure of herqueichrysin. Subsequent incorporation experiments with singly and doubly 3C-labelled acetates and malonate and analysis of the resultant enrichments and 13C-13C couplings indicated formation of the phenalenone ring system as shown in Scheme 5 by a specific folding of a single heptaketide precursor. Another study finally established the structure of phomazarin (12), an aza- anthraquinone, produced by the plant pathogen Phoma terrestris, for which numerous structures had been proposed since its original isolation in 1940.The exact structures of phomazarin and its co-metabolite isophomazarin (13), including 24 T. J. Simpson, J. Chem. SOC.,Perkin Truns. 1, 1979, 1233. Biosynthetic Studies of Polyketide Microbial Metabolites Figure 4 Long range 'H-I3C spin-spin couplings observed in the fully 'Hcoupled 15.04 MHz'3C n.m.r. spectrum of deoxyherqueinone diacetate (11) MeCOSCo A 1 0 OH M Me0 OH 2 HO 0 to1 OHew 0 R C02H Bun* I "HJ1 (12) R' = H, R2 = OH (13) R' =OH, R2 =H Scheme 6 the tautomeric form of the 4-hydroxypyridine ring were established using 'H-' 3C couplings and in particular 15N chemical shifts (by INDOR), 'H-I5N, and "N-l 3C couplings in derivatives of biosynthetically 5N-enriched phomazar- in.25,26 Subsequent labelling studies with '3C-labelled acetates and malonate showed that phomazarin was biosynthesized via oxidative ring fission of an anthraquinonoid intermediate itself formed by a specific folding and condensation of a single nonaketide precursor rather than the two-chain pathways that had been previously proposed (Scheme 6).27This study helped to confirm a suspicion that whenever a two-chain pathway is proposed in polyketide biosynthesis the 25 A.J. Birch, D, N. Butler, R. E. Effenberger, R. W. Rickards, and T. J. Simpson, J. Chem. SOC.,Perkin Trans. 1, 1979, 807. 26 R. E. Effenberger and T.J. Simpson, J. Chon. SOL'.,Perkin Trans. 1, 1979, 823. '' A. J. Birch and T. J. Simpson, J. Chem. SOC.,Perkin Trans. 1, 1979, 816. Simpson possibility, however remote, of formation via a single-chain modification should not be excluded. Studies on multicolic acid, aspyrone, ravenelin, and tajixanthone all exemplify this. 5 Monitoring of 'H and l8O by n.m.r. The studies described above mainly concerned determining the origins of the carbon skeletons of metabolites. However, in studying the nature of the intermediates on a biosynthetic pathway and in particular elucidating the de- tailed mechanisms of their interconversions, it is essential to determine the biosyhthetic origins and fate of the hydrogen and oxygen atoms. Studies in recent years have been more concerned with these aspects.Deuterium incorporation can be monitored directly by 2H n.rn.r., or indirectly from isotope-induced shifts in I3C n.m.r.'?, (see below). These methods are essentially complementary. 'H n.m.r. despite several inherent disadvantages has been the nucleus of choice in many biosynthetic studies. Its major limitations are mainly as a consequence of the low magnetogyric ratio, and the relaxation behaviour of the 'H nucleus. Because it is a quadrupole nucleus (spin 1) and thus very efficiently relaxed, the spectral lines are rather broad and this, coupled with the low magnetogyric constant and the small chemical shift range for hydrogen nuclei, often results in poorly resolved spectra.However, the rapid relaxation and lack of any n.0.e. mean that accurate integration of 2H n.m.r. spectra is possible so that the relative enrichment at different sites in a metabolite can be accurately assessed. Another major advantage is that as a consequence of its low natural abundance (0.012%) much greater dilutions are tolerable than in the case of '3C-labelling: a 100% 'H-labelled precursor may be diluted 6 000 fold and still result in a doubling of intensity over the corresponding natural abundance signal. This makes 2H-labelling particularly suitable for studying the incorporation of advanced intermediates on a biosynthetic pathway. The inherent lack of resolution in 'H n.m.r. can be overcome by the use of isotope-induced shifts in 13C n.m.r.The use of 3C as a 'reporter' nucleus for both hydrogen and oxygen represents the great recent advance in biosynthetic studies with stable isotopes and makes use of the observation that substitution of a proton alpha or beta to a 13C by deuterium causes a change (usually upfield) in the 13C chemical shift. Similarly the presence of l80alpha to a 3C atom can be detected by an upfield shift in the 13C n.m.r. spectrum. These effects are summarized in Figure 5. When the deuterium label is directly attached to a 13C nucleus in the precursor molecule, the p.n.d. I3C n.m.r. spectrum of the enriched metabolite shows, for carbons which have retained deuterium label, a series of signals upfield of the normal resonance., The presence of each deuterium shifts the centre of the resonance by 0.34.6 p.p.m.and spin-spin coupling ('JCD) produces a characteristic multiplet, hence CD appears (Figure 5a) as a triplet whereas CD, and CD, would give respectively a quintet and septet. Shifted signals arising from carbons which bear no hydrogen suffer reduced signal-to-noise ratio caused by poor relaxation and lack of n.0.e. enhancement, a disadvantage of the method Biosynthetic Studies of Polyketide Microbial Metabolites Use of 13c-nrnr in Isotope Label\ing Experiments Origin of HYDROGENS and OXYGENS Precursor Metobol i te '36 spectrum Qbserva t ion (a) D D I I ''C :H Coup1ingD~F-CO~N~--c2-c,-D a-Isotope shift (b) D13 ID=C-CO2Na --Cz-C,-8-Isotope shift I D Figure 5 Simu1atedp.n.d.I3C n.m.r. spectru of a polyketide-derived moiety enriched from (a) [2-13C,2H,]acetute,(b) [1-'3C,2H,]ucetate,(c) [1-'3C,'802]a~etate,and (d) "0,gas which is compounded by the multiplicities due to coupling. Deuterium de-coupling2' can assist in this by removing the 13C-,H coupling. However, information not obtainable by direct *H n.m.r. spectroscopy, such as the distribution of label as CH,D, CHD,, and CD, and the integrity of carbon- hydrogen bonds during biosynthesis, may be gained. More recently a pulse sequence has been described which allows the selective observation of deuterated 3C signals by selective suppression of signals from protonated carbons.29 This makes the technique more sensitive but like the simultaneous proton and deuterium decoupling method requires instrumentation and expertise which are not widely available.Many of the problems associated with directly attached deuterium are avoided by placing the deuterium label two bonds away from the 13C reporter nucleus.30 The isotope shift, although reduced, is still observable, and as P-hydrogens only contribute markedly to the relaxation of non-protonated 3C nuclei, the shifted signals otherwise retain any n.0.e. also experienced by the unshifted signals on proton decoupling. As geminal carbon-proton coupling constants are generally small anyway,31 and carbondeuteron couplings are over six times smaller again, the shifted signals are effectively singlets (Figure 5b), even without deuterium 28 C. R. Hutchinson, 1.Kurobane, C. T. Mabuni, R. W. Kurnola. I. G. McInnes, and J. A. Walter, J. Am. Chem. Soc., 1981, 103. 2474. 29 D. M. Doddrell, J. Staunton, and E. D. Laue, J. Chem. Sac., Chcni. C'ommun., 1983, 602. 30 C. Abell and J. Staunton, J. Chem. Snc., Chem. Conirnun., 1981, 856. 3' J. L. Marshall, 'Carbon-Carbon and Carbon-Proton NMR Couplings', Verlag Chernie International, Deerfield Beach, 1983. 134 Simpson Figure6 (a) 360.13 MHz 'H n.m.r. spectrum ofO-methylusparoenone (14), (b) 55.28 MHz 2H n.m.r. spectrum of (14) enriched from [2H,]ucetate decoupling, and this gives a further increase in the signal-to-noise ratio compared with the corresponding x-shift experiment. However, neither of these methods provides reliable information on the stereo- specificity of deuterium labelling.Although 'H n.m.r. spectra are disadvantaged by their inherently low dispersion and broad lines, they do have the advantage of pro-viding information on the stereospecificity as well as regiospecificity of labelling. 'H N.m.r. however does not prove the number of deuteriums incorporated. At about the same time, the first biosynthetic application of "0 isotope-induced shifts in 13C n.m.r. was rep~rted,~'as shown in Figure 5; the "0 may be conveniently introduced via a doubly labelled precursor or by growth in an "0' atmosphere. The resulting shifts are generally not much larger than 0.05 p.p.m. These are very small effects and are the same general size as P-'H isotope shifts and are only readily observed with high field spectrometers.These techniques for elucidating the origins of hydrogen and oxygen provided the basis for much of the work described below. 6 Applications of 'H and "0 Labelling Incorporations of singly and doubly 3C-labelled acetates confirmed the formation of 0-methylasparvenone (14) from specific folding and condensation of a hexaketide precursor in Aspergillus parvulus. 'H N.m.r. analysis (Figure 6) of the ['HJacetate-enriched metabolite showed that 2H label was incorporated specifically into the 10-methyl, 5-, 2-axial, and 3-axial hydrogens with none at C-4. This indicated that oxygen is introduced at C-4 by an aromatic hydroxylation 32 J. C. Vederas and T. T. Nakashima, J. Chern. Soc., Chem. Commun., 1980, 183.Biosynthetic Studies of Polyketide Microbial Metabolites SR 0 0 OH OH-D,C-t02Na + *o D3CWD OD J. OH 0 OH OH Me0 DzHc*D HO 0 D OH Scheme 7 9 -1 202 145 ? I 1, I 1 I I I I s,180 140 100 60 20 Figure 7 90.56 MHz p.n.d. 13C n.m.r. spectrum of 0-methylasparvenone enriched from [1-3C,2H,]acetate process with an accompanying NIH shift of hydrogen from C-4 to C-3 and that reduction from the naphthalene to the dihydroaromatic level occurs with stereospecific trans introduction of hydrogen at C-2 and C-3 (Scheme 7).33 In a 33 T. J. Simpson and D. J. Stenzel, J. Chem. Soc., Chem. Commun., 1981, 239. 136 Simpson 1 3 Figure 8 Signals from the 90.56 h4Hzp.n.d. 'jC n.m.r. spectrum of 0-methylasparuenone (14)partially deuteriated at C-2.Resonances are for (a) C-1 and (b) C-3 further incorporation of [l-'3C,2H3]acetate and analysis of the 2H p-isotope shifts in the resultant 13C n.m.r. spectrum (Figure 7) showed that one hydrogen was lost from the C-10 methyl to indicate formation of the ethyl moiety by a reduction4imination-reduction sequence on the corresponding acetyl group. The magnitude and direction of the p-isotope shifts were observed to depend markedly on the functionality of the reporter 3C nucleus and surprisingly on the stereospecificity of 'H incorporation. This was confirmed by an in uitro experiment when the C-2 methylene hydrogens were exchanged in equimolar MeOH and Me02H to give the spectrum shown in Figure 8. For carbonyl groups the observed shift could be downjiefd or even zero ip contrast to the usually observed upjiefd shifts, thus indicating the necessity for caution in the interpretation of results when carbonyl groups are involved.The incorporation of 2H label from ['H3]acetate into the similar dihydronaphthalene scytalone (15) in Phiufuphoru fagerbergii was 34 T. J. Simpson and D. J. Stenzel, J. Chem. Soc., Chem. Commun., 1982, 1074. Biosynthe tic Studies of Polyketide Microbial Metabolites OH 0 HO 6' [O1 IMe "o,-o [HI 0 , / I OH 0 OH 2' OH 0 OH &\ / OH 0 OMe (18) Scheme 8 also studied by 2H n.m.r. In contrast to 0-methylasparvenone, reduction of the aromatic ring was not stereospecifi~.~~ 2H-Labelling has also been applied to good effect in studies on the biosynthesis of aflatoxin B,.Although averufin (16) was generally held to be an early 35 E. Bardshiri and T. J. Simpson, Tetrahedron,1983, 39, 3539. 138 Simpson intermediate on the biosynthetic pathway to aflatoxin B1 (1S), this had never been rigorously established. Accordingly, [4'-2H2]averufin was prepared and incorporated into aflatoxin B by cultures of Aspergillus Jaws. 2H N.m.r. analysis showed that 'H label was incorporated specifically at C-16 of aflatoxin B1.36 The incorporation of 'H from [l-'3C,ZH3]acetate into averufin, sterigmatocystin (17) and aflatoxin B1 was studied both by direct 'H n.m.r. analysis and by observation of P-isotope shifts. The results showed that one 'H was incorporated stereo-specifically into the C-2' and C-4' positions of the side chain of averufin 37 and that these are retained on conversion of the C6 side chain into the C4-bisfuranoid side chain of the aflat~xins.~' Other important observations included the retention of 2H label at C-6 of sterigmatocystin, so ruling out previously proposed mechanisms for xanthone ring formation requiring the introduction of a phenolic hydroxyl group on this carbon.39 However the appearance of 'H at C-4 of aflatoxin B1 shows that such a hydroxylation with accompanying NIH shift does occur in the biosynthesis of aflatoxin B1.These results are in accord with the biosynthetic sequence shown in Scheme 8. Further studies were carried out on tajixanthone. Incorporations of ['3C2]- acetate and ['HJacetate gave the results summarized in Scheme 9.The absence of 'H label on C-25 and C-5 indicated that cleavage of an anthraquinone rather than an anthrone intermediate occurred and that decarboxylation of the octaketide precursor occurs after cyclization and aromatization. The observed scrambling of 13C-13C couplings in ring c implies the involvement of a symmetrical benzo- phenone intermediate (19) which in turn means that ring cleavage of the anthra- quinone precursor must precede introduction of the C-prenyl residue, CJ ravenelin. The stereospecificity of labelling in the dihydropyran ring, however, suggests its formation from an 0-prenylaldehyde intermediate by a concerted 'ene' rea~tion.~' In order to obtain information on the mechanism of xanthone ring-closure tajixanthone was isolated from A.uariecolor growing under an atmosphere containing *02 using the closed system shown in Figure 9 which allows the oxygen pressure to be kept constant and the oxygen uptake to be monitored. The '*O isotope shifts observed in the 13C n.m.r. spectrum are shown in Figure 10. The intensities of the isotopically shifted signals for carbons 1, 10, and 11 are half of those for the other shifted signals and so are consistent with the intermediacy of a symmetrical benzophenone and a ring-closure mechanism via a Michael addition- elimination process in which a ring c hydroxyl attacks ring A.~~Mass spectral analysis of tajixanthone produced in an '02,1602 mixture also showed that each aerobically derived oxygen atom was derived separately by mono-oxygenation so that previously proposed mechanisms via dioxygenases can be ruled out.In a more recent study, [methyl-H3lchrysophanol (20) has been shown to be a specific 36 T. J. Simpson, A. E. de Jesus, P. S. Steyn, and R. Vleggaar, J. Chem. SOC.,Chem. Commun., 1982, 631. 37 T. J. Simpson, A. E. de Jesus, P. S. Steyn, and R. Vleggaar, J. Chem. SOC.,Chem. Cornmun., 1982,632. 38 T. J. Simpson, A. E. de Jesus, P. S. Steyn, and R. Vleggaar, J. Chem. SOC.,Chem. Cornmun., 1983, 338. 39 T. J. Simpson and D. J. Stenzel, J. Chem. Soc., Chem. Commun., 1982, 890. 40 E. Bardshiri and T. J. Simpson, J. Chem. SOC.,Chem. Cornmun., 1981, 195. E. Bardshiri,C.R. McIntyre,T.J. Simpson, R.N. Moore, L. A. Trirnble,and J. C. Vederas, J. Chem.SOC., Chem. Commun.. 1984, 1404. 139 Biosynthetic Studies of Polyketide Microbial Metabolites c-Me Scheme 9 precursor for tajixanthone. 'H N.m.r. analysis (Figure 11) showed that specific incorporation of label into the aromatic methyl of (3) had occurred.42 42 S. A. Ahmed. E. Bardshiri, and T. J. Simpson, unpublished work. 140 Simpson wash bottles growth flasks Figure 9 Apparatus for growth of fungal cultures in an "0,atmosphere. The wash bottles are arrangedso that thejrst acts as a suck-back trap, the second contains 5 M KOH to absorb CO, produced by the cultures and the third contains cotton woo1 to remove any alkaline spray The work described above on O-methylasparvenone was initiated due to an interest in the biosynthesis of polyketide-derived molecules containing an ethyl side chain. This also promoted an investigation of LL-D253a, a chromanone first isolated from Phoma pigmentivora and subsequently from several other plant pathogens. In the course of 13C assignment studies it became apparent that the previously assigned structure (21) was incorrect and analysis of the fully 'H coupled I3C n.m.r.spectrum (Figure 12) of the diacetate (23) identified the long range 'H-I3C couplings indicated in Figure 13. This effectively defined the structure (22) for LL-D253a which was subsequently confirmed by unambiguous synthesis.43 Its biosynthesis has been studied by incorporation of I3C-, *H-, and '80-labelled acetates and the resulting labelling patterns are summarized in Scheme A particularly interesting feature was the partiaZ randomization of label from singly 13C-labelled acetates between C-10 and C-11 in the hydroxyethyl side chain.On incorporation of [1-'3C,ZH,]acetate two 2H atoms were incorporated at both C-10 and C-1 1 and only one at C-3. Taken along with the l8O labelling (Scheme 10) this indicated that the chromanone ring was formed by conjugate addition of a phenolic hydroxyl to the corresponding aP-unsaturated ketone. As LL-D253x is optically active the ring-closure is stereospecific with respect to C-2, but 2H n.m.r. analysis showed that both hydrogens at C-3 were C. R. McIntyre and T. J. Simpson, J. Cliem. Soc., Clzem. Commun., 1984, 704; C.R. McIntyre. T. J. Simpson, L. A. Trimble, and J. C. Vederas, J. Chem. Soc.. Chem. Commun., 1984, 706. Biosyn the t ic Studies of Polyke t ide Microbial Me taholites 1 J 161 160 153 152 151 150 15 ppm l 1 1 1 1 1 l l l l ~ l , , ~ 65 64 63 62 61 60 59 58 p.p.m. Figure 10 Sections of the 90.56 MH2p.n.d. 13Cn.m.r. spectrum of tajixanthone (3) labelled by 1802 gas Me0 Me0 Me RO OR (22) R =H (23)R =Ac Simpson I I I I I I 1 7 6 5 4 3 2 1 PPM Figure 11 55.28 MHz 2H n.m.r. spectra of tajixanthone (3) (a)producedin a culture medium supplemented with 57; 'H,O, (b) labelled from feeding [methyl-2H,]chrysophanol (20) labelled to an equal extent so that protonation of the intermediate enolate must occur with equal facility from both faces as indicated in Scheme 11.This contrasts with the corresponding chalcone to flavanone ring-closure which is known to be stereospecific with respect to both positions. LL-D253a must be biosynthesized via two preformed polyketide chains. One possibility is shown in Scheme 12. The observed randomization of labelling in 80% of the molecules is accounted for by formation of a symmetrical cyclopropyl intermediate (24) as shown. This intermediate can undergo hydrolytic ring-opening at either the a or p carbon. According to this scheme the 20% of the molecules not undergoing randomization should have the 1 1-hydroxyl derived from the atmosphere and in accord with this, fermentation in an "0, atmosphere resulted in an l8Oisotope shift being observed on the resonance due to C-11 in the 3Cn.m.r.spectrum, the intensity of the shifted peak being ca. 20% that of the unshifted peak. It is not clear whether the randomization is an in uiuo or an in uitro process. The success of these methods in revealing subtle biosynthetic information Biosyn the t ic Studies of Polyket ide Microbial Met a b oli tes x c * * I, 8a 5 7 La L no I rrad tat ion Figure 12 The high frequency region of the fully 'H-coupled 200 MHz 13Cn.m.r. spectrum of LL-D253a diacetate (23), and results of selective low-power 'H decoupling experiments. Positions where decoupling is observed are indicated (*) Figure 13 Long-range 'H--l3C couplings in LL-D253r diacetate (23) selectively removed bylow-power 'H decoupling experiments shown in Figure 12 Simpson OMe 0 OAc OMe 0 Scheme 10 OH0 HO HO Me H R R J.I H R Scheme 11 encouraged a re-examination of the formation of aspyrone (7). Experiments with [1-'3C,'802]acetate and l80,revealed the surprising result that none of the oxygens were derived from acetate, three being derived from the atmosphere and one from the medium.44 As indicated in Figure 14, the lactone carbonyl carbon C-2 showed shifts due to the presence of an aerobically derived l80oxygen in either the 44 S.A. Ahmed,T. J. Simpson, J. Staunton,A. C. Sutkowski, L. A. Trimble, and J. C. Vederas, J. Chem.SOC., Chem. Commun., 1985, 1685.Biosynthetic Studies of Polyketide Microbial Metabolites Figure 14 "0 Isotope-inducedshijis observed in the 100.6 MH2p.n.d. I3Cn.m.r. spectrum of aspyrone (7) labelled by ''0, gas OR 0 HO 20% G*" HOJ?$l. % 40% * OH Simpson 5 l3; D, C 0 N Q"5i' 1 I 79.3 Figure 15 a 'H Isotope-induced shifts observed in the 100.6 MHz 'Hand 'H noise decoupled I3C n.m.r. spectrum of aspyrone (7) labelled from [2-' 3C,2H,]acetate doubly or singly bonded oxygen. Incorporation of C2-l 3C,2H3]acetate gave the spectra shown in Figure 15. As may be seen, deuterium noise decoupling leads to a great simplification of the otherwise uninterpretable results for C-7, which complements previous results 45 for the related co-metabolite asperlactone (25), and makes it unlikely that C-7 was ever part of a double bond.To accommodate these results, a pathway involving epoxide-mediated rearrangement and ring- closure reactions, Scheme 13, was proposed, thus providing a relatively simple model for similar processes which appear to be involved in the formation of the much more complex polyether and ionophore antibiotic^.^^ 7 Polyketide Assembly Processes A longstanding problem is the exact relationship between polyketide biosynthesis and the corresponding pathway in primary metabolism uiz. fatty acid biosynthesis. Labelling studies with 8O and 'H on appropriate polyketide-derived molecules permit indirect information on the processes which must be occurring on the polyketide synthetase enzymes to be obtained and compared with the much better understood processes catalysed by fatty acid synthetases.These studies required molecules with intermediate oxidation levels between the highly oxygenated fully aromatic polyketides and fatty acids to be examined. Incorporation of 3C-, 2H-, and 80-labelled acetates into monocerin (26) by cultures of Dreschleru rauenelii and analysis by 13Cand 2H n.m.r. gave the labelling 45 R. G. Brereton. M. J. Carson, and J. Staunton. J. Cliem. SOC.,Perkin Trans. I, 1984. 1027. 46 D. E. Cane, W. D. Colmer, and J. W. Westley, J. Am. Chem. Soc., 1983, 105, 41 10. 147 Biosynthetic Studies of Polyketide Microbial Metabolites f n'0 *t v '0< 148 Simpson OH 0 Me (26) ? OH 6 Scheme 14 patterns shown in Scheme 14.47 A particularly interesting feature is the retention of two acetate-derived hydrogens at C-10 which suggests that reduction of the p-ketoacyl intermediate to the corresponding P-hydroxyacyl intermediates takes place during chain assembly.2H N.m.r. showed that only one of the diasterotopic hydrogens at C-12 is labelled. Thus the dihydroxy moiety (27) rather than a classical heptaketide can be proposed as the likely enzyme-bound precursor as shown in Scheme 15. The 180-labelling pattern means that the benzopyrone ring must be formed by nucleophilic attack at the terminal carboxy moiety by a hydroxy group at C-9. It is likely that the cyclization takes place on the enzyme-bound thioester to give (28) as the first enzyme-free intermediate.The retention of the acetate carbon-oxygen bond at C-1 1 indicates that the tetrahydrofuran ring is formed by nucleophilic attack of a C-11 hydroxy function on C-8. A mechanism for this would be nucleophilic addition onto a quinonemethide intermediate (30) formed by oxidation of (29), the hydroxylated derivative of (28). Colletodiol (31) is a macrocyclic dilactonic metabolite originally isolated from the plant pathogenic fungus Colletotrichum capsici. The origins of all the oxygen and hydrogen atoms have been elucidated by incorporation of label from [l-3C,1*O,]-and [1-' 3C,2H,]acetates and "0, gas in cultures of a Cytospora sp. and analysis of the resultant *H and l80isotope-induced shifts in the p.n.d.I3C n.m.r. spectra of the enriched metabolites and by ,H n.m.r. analysis.48 The results are summarized in Scheme 16. From these results it can be concluded that the lactone- ring formation occurs by an acyl substitution mechanism as shown in Scheme 17; and that the 1,2-diol formation most likely occurs by epoxidation of a (3-alkene from the a-face, followed by hydrolytic SN2 ring-opening of the epoxide by attack of 47 F. E. Scott, T. J. Simpson, L. A. Trimble, and J. C. Vederas, J. Chem. Sac., Chem. Commun., 1984, 756. T. J. Simpson and G. I. Stevenson, J. Chem. Sac., Chem. Commun., 1985, 1822. 149 Biosynthetic Studies of Polyketide Microbial Metabolites Me / (30) Scheme 15 OH (31) CD? 0 Scheme 16 Simpson Me 0 -H OH I Me 0@D Scheme 17 0 00 MeASR -MeuSR -Me SR -Me SR \ Scheme 18 water from the a-face at C-4, Scheme 17.On the basis of these results the thioesters (33) and (34), Scheme 18, were proposed as the actual enzyme-bound precursors and their formation via the sequence shown in Scheme 18 where the diol (32) in which the C-3 stereochemistry is uncertain was proposed as a common intermediate, trans-elimination of water giving rise to (33) directly whereas ,cis-elimination followed by elaboration of a further C, unit produces (34). The relative timing of the diol formation is uncertain but macrocycle formation to give (35) followed by epoxidation is an attractive possibility. It was recently reported that 3C-labelled hexanoate is incorporated intact into averufin and as a result it was suggested that averufin is not a decaketide but is an 151 Biosynthetic Studies of Polyketide Microbial Metabolites 9 Walonotr-cosco* 01 -0 ’ Drcokct dr’ OH0 WCOSCOA 2 Malonalr I 0 OH Scheme 19 octaketide formed as shown in Scheme 19 from a hexanoate ‘starter’ (from fatty acid metabolism) and 7 malonate chain-extending units.49 However incorporation of [2-’3C]malonate into averufin and analysis of enrichments in the 13C n.m.r.spectrum shows high and equal incorporation at nine positions (Scheme 20) to indicate a clear acetate ‘starter’ effect.” Thus averufin is a decaketide, but the significance of the original observation is that exogenous hexanoate can equilibrate with the enzyme-bound intermediate and so be incorporated without prior degradation.These results, and others, are contributing to an overall picture of polyketide biosynthesis in which a ‘polyketide synthase’ structurally related to fatty acid synthetase assembles the enzyme-bound intermediates as shown in Scheme 21. 49 C. A. Townsend and S. B. Christensen, Tetrahedron, 1983, 39, 3575. I. M. Chandler and T. J. Simpson, J. Chem. Sor., Chem. Commun., 1987, 17. Simpson OH 0 sx000 R W Sn X \H,O 0 0 R& sx R W O H n RASX Scheme 21 Fully aromatic metabolites which retain the oxidation level of a classical poly-p- ketide are built up by a cyclic process (path a) analagous to fatty acid biosynthesis but omitting the reduction4imination-reduction sequence responsible for the loss of acetate-derived oxygen.The majority of metabolites however, show varying degrees of reduction and/or deoxygenation. It is envisaged that after each malonate condensation step the synthase has a choice of which of paths a4 is utilized before the next condensation reaction occurs. In this way 'polyketide' precursors which show varying degrees of reduction and deoxygenation can be assembled in a stepwise manner on the synthase before being released from the enzyme by a stabilizing ring condensation or some other such process. Substitution of acyl CoA starter units, other acetate and methylmalonate, ethylmalonate, etc. as chain-extending units accounts for the other polyketide- derived structural types formed in nature.8 Meroterpenoids A major interest has involved a group of compounds of mixed polyketide- terpenoid origins-the so-called mer~terpenoids.~~Our interest in these compounds began with the reported isolation of andibenin (36) from A. uarie-colo~r.~~Its structure which was elucidated by X-ray crystallography strongly suggested a sesterterpenoid origin. However the results of incorporation experi- ments with 13C-labelled acetates and methionine showed this hypothesis to be in- correct.54 The labelling pattern which resulted was consistent with a biosynthetic pathway in which the key step was alkylation of a bis-C-methylated tetraketide- derived phenolic precursor (42) by farnesyl pyrophosphate to give (43) followed by further cyclization and oxidative modifications as shown in Scheme 22.A number of closely related co-metabolites e.g. andilesin C (37) and A (38) were isolated in the B. Sedgwick and C. Morris, J. Chem. SOC.,Chem. Commun., 1980,96; F. Lynen, Eur. J. Biochem., 1980, 112, 431. 52 J. W. Cornforth, Chem. Br., 1968, 4, 102. "A. W. Dunn, R. A. W. Johnstone, B. Sklarz, and T. J. King, J. Chem. SOC., Chem. Commun., 1976,270. 54 J. S. E. Holker and T. J. Simpson, J. Chem. SOC.,Chem. Commun., 1978, 626. 153 Biosynthetic Studies of Polj’ketide Microbial Metabolites I ;e-?O2Na \ Me OHa* ? xg,Fo0 ‘-0 --_--c (37)R = H (411 (38) R= OH Scheme 22 course of these studies and their structures were assigned by ‘H and 13C spectral comparisons and chemical correlation^.^^ Two further, structurally unrelated but biosynthetically relevant, metabolites were isolated from mutant strains of A.variecolor. These were the bis-C-methylated tetraketide metabolite stellatin (39) whose structure was defined almost entirely from analysis of the fully ‘H-coupled I3C n.m.r. spectrum,56 and the sesquiterpenoid astellolide A (40) whose structure was deduced from ‘H and I3C n.m.r. studies and confirmed by X-ray crystal- lography. 55 T. J. Simpson, J. Chem. Soc., Perkin Trcms. I, 1979, 2118; A. W. Dunn, R. A. W. Johnstone, B. Sklarz, L. Lersinger, and T. J. King. hid, 21 13. 56 T. J. Simpson, J. Chem. Soc., Chem.Commun., 1978, 627. ” R.0.Gould, T. J. Simpson, and M. D. Walkinshaw, Terrahedron Lett.. 1981, 1047. Simpson (44) (45) A further significant metabolite was isolated along with andilesin C from another strain of A. uariecolor. This was anditomin (41) whose structure was deduced by spectroscopic methods and confirmed by X-ray analysis '* and whose biosynthesis was confirmed by '3C-labelling experiment^.^^ It represented an important modification of the meroterpenoid pathway as it was the first metabolite in which the carbocyclic ring of the tetraketide-derived moiety had been fragmented. While this work was in progress, attention was drawn to two further metabolites whose structures could be rationalized by extensions, albeit drastic ones, of the meroterpenoid pathway. These metabolites were austin (44) and terretonin (45) which had been isolated as toxic metabolites of Aspergillus ustus 60 and Aspergillus terreus 61 respectively.Modified terpenoid origins had been suggested for both metabolites. However, incorporation of '3C-labelled acetates and methionine gave results which supported the hypothesis that these were further metabolites of the meroterpenoid pathway formed via (43). The conclusive evidence for the meroterpenoid origins of these metabolites was provided by the synthesis of labelled 3,5-dimethylorsellinic acid (42) 62 and its specific incorporation into andibenin (36),63,64and austin (44) and terretonin (45).65 This was established by 2H n.m.r. analysis of the metabolites enriched from feeding experiments with (42) specifically labelled with 2H in the 5-methyl group.The mode of incorporation of the carbon skeleton of 3,5-dimethylorsellinate into these metabolites is summarized in Scheme 23. Whereas the skeleton is incor- porated intact into andibenin B and andilesin C, and suffers one bond cleavage only on incorporation into anditomin, it is fragmented to an unprecedented degree on incorporation into austin and terretonin. This was the subject of further studies described below. Further evidence for the biosynthetic relationship of austin and T. J. Simpson and M. D. Walkinshaw, J. Chrm. SOC.,Chern. Commun., 1981, 914. "T. J. Simpson, Terrahrdron Lett., 1981, 3785. 6" K. K. Chexal, J. P.Springer, J. Clardy, R. J. Cole, T. W. Kirksey, J. W. Dorner, H. G.Cutler, and W. J. Strawter, J. Am. Cliem. SOC.,1976, 98, 6748. 61 J. P. Springer, J. W. Corner, R. J. Cole, and R. H. Cox, J. Org. Chrm., 1979, 44, 4852. "T. J. Simpson and D. J. Stenzel, J. Chem. Soc., Chem. Camrnun., 1981, 1042; C. R. McIntyre and T. J. Simpson, ihid., 1043. 63 A. J. Bartlett, J. S. E. Holker. T. J. Simpson, and E. O'Brien, J. Chrm. Soc., Perkin Trans. I, 1983, 667. 64 A. J. Bartlett, J. S. E. Holker, E. O'Brien, and T. J. Simpson, J. Chrm. SOC.,Chem. Commun.. 1981, 1198. "C. R. McIntyre, T. J. Simpson, D. J. Stenzel, A. J. Bartlett, E. O'Brien, and J. S. E. Holker, J. Chem. SOC., Chcvn. Commun., 1982, 78 1. Biosynthetic Studies of Polyketide Microbial Metabolites Scheme 23 2-O' 0 0 ;.OAc I MeMe (46) (471 andibenin B was provided by the isolation of both metabolites from A. uariecolor 66, The 13C n.m.r. spectral assignment of austin (44) and the structures of dehydroaustin (46)and iso-austin (47)related metabolites isolated from A. ustus and Penicillium diversum were largely established by detailed analysis of fully 'H-coupled 3C spectra and 'H-13C correlation experiments.66 P. diuersum produces an amazing range of metabolites. Apart from iso-austin, it produces the known polyketides lichenxanthone (48), alternariol monomethyl ether (49)and two new structural types. These are the diversolonic esters (50) whose structure were elucidated by extensive 'H and 13Cn.m.r. studies,67 and a novel isocoumarin (51) whose structure was confirmed by X-ray studies.68 This metabolite is probably biosynthesized by a novel aromatic ring contraction from the known co-metabolite (49).66 T. J. Simpson, D. J. Stenzel, A. J. Bartlett, E. O'Brien, and J. S. E. Holker, J. Chem. Soc., Perkin Trans. I, 1982, 2687. 67 J. S. E. Holker, E. O'Brien, and T. J. Simpson, J. Chem. Soc., Perkin Trans. I, 1982, 1365. 68 J. S. E. Holker, E. OBrien, T. J. Simpson, and M. D. Walkinshaw, unpublished results. 156 Simpson Me 0 OH 0 OH HO GOMe' MeHO (481 (49) (50) (51) The origins of the oxygen atoms in the meroterpenoid metabolites were then studied by incorporation experiments in the presence of 1802 and [l-13C,1802]acetate,to try to elucidate information on the mechanisms by which the extensive modifications observed for the orsellinate-derived moiety in austin and terretonin occurred and also for the formation of the spiro-6-lactone systems in andibenin B and austin.Whereas l80label from acetate was successfully incorporated into andibenin B,69 the low level of incorporation obtained precluded the observation of the necessary isotope shifts for andilesin A and austin. Nonetheless the results from incorporation of label from 1802into austin 70 were consistent with a modification scheme in which the orsellinate moiety undergoes a ring-contraction via an a-ketol rearrangement followed by biological Baeyer- Villiger type of oxygen insertions to form the &lactone moieties found in both the polyketide- and terpenoid-derived portions of the molecules as shown in Scheme 24.The problem of low incorporation of labelled acetate was overcome by synthesizing 3,5-dimethylorsellinate doubly labelled with 13C and ''0 in both the carboxyl carbonyl and at the C-6 position. This was incorporated with high efficiency into austin (Figure 16) to confirm the 1802results,71 and also into andilesin A to rule out the possible involvement of deoxyorsellinate intermediates in the biosynthesis of the andibenins and andile~ins.~~ 69 C. R. McIntyre, T. J. Simpson, R. N. Moore, L. A. Trimble, and J. C. Vederas, J. Chem. Soc.., Chem. Commun., 1984, 1499. 70 T. J. Simpson, D. J. Stenzel, R. N. Moore, L. A. Trimble, and J. C. Vederas, J. Chem.SOC.,Chem. Commun., 1984, 765. 71 F. E. Scott, T. J. Simpson, L. A. Trimble, and J. C. Vederas, J. Chem. SOC.,Chem. Commun., 1986, 214. ''C. R. McIntyre, F.E. Scott, T. J. Simpson, L. A. Trimble, and J. C. Vederas, J. Chem. SOC.,Chem. Commun., 1986, 501. 157 Biosynthetic Studies of Polyketide Microbiul Metabolites 10; Scheme 24 Interestingly, further metabolites related to austin have been isolated from Emericella dent at^,'^ and two unrelated metabolites which are almost certainly further products of the meroterpenoid pathway, fumigatonin (52) and paraherquonin (53), have been isolated from Aspergillus fumigatus 74 and Penicillium par~herquei.~~ It is of interest to note that studies which were initiated on the mistaken assumption of a sesterterpenoid origin for andibenin B have led to the unravelling of a complex, novel, and now apparently widespread biosynthetic pathway. The meroterpenoid pathway as it stands at present is summarized in Scheme 25. This will clearly be an area in which much biosynthetic and synthetic work will be carried out in the future.9 Conclusions The use of stable-isotope labelling methodology has enabled otherwise unobtainable information on both the early and later stages of biosynthetic pathways to be obtained. These results, besides their own intrinsic merit, enable further work using advanced intermediates and cell-free enzyme studies to proceed on a more rational basis. Acknowledgements. The author expresses his gratitude to the many other people who have carried out labelling studies with stable isotopes.The ideas and 73 Y. Maebayashi, E. Okuyama. M. Yamazaki, and Y. Katsube, Chmi. Plinrrn. Bull., 1982, 30, 191 1. E. Okuyama, M. Yamasaki, and Y. Katsube, Tetrahedron Lett., 1984, 3233. " E. Okuyama, M. Yamasaki. K. Kobayashi, and T. Sakurai. Tetraliriirotr Lcti.. 1983, 31 13. Simpson Me Me Me Me ~ 11 ~~l*J * ~ * ~Ill* 1180 160 70'I -6 Figure 16 'O-Zsotopicall,v shifred resonances in the 100.6 MHz p.n.d. I3Cn.m.r. spectrum of austin (44) enriched by ethyl ['3C,1803-3,5-dimethylorsellinate 0 Me Biosynthetic Studies of Polyketide Microbial Metabolites Me OH Fumigat onin A.f*igeCO2H 4 I 4.ustus-A st i A_. variecolor P. d iv ersum Emericella dentata HO 1 1 Puraherquonin paraherquei Terr e to nin A.terreus The Fungal Meroterpenoid Pathwuy Scheme 25 experiments described by them have provided much of the stimulation and rationale for the work described above.Particular thanks must go to some of the collaborators who over the years have contributed to these studies-these include A. J. Birch, J. S. E. Holker, P. S. Steyn, J. C. Vederas, and J. Staunton.

ISSN:0306-0012    

DOI:10.1039/CS9871600123

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Chem. Soc. Rev., 1987, 16, 161-185 TATE AND LYLE LECTURE Structural and Conformational Characterization of Carbohydrate Differentiation Antigens By Elizabeth F. Hounsell APPLIED IMMUNOCHEMISTRY RESEARCH GROUP, MRC CLINICAL RESEARCH CENTRE, WATFORD ROAD, HARROW, MIDDLESEX HA1 3UJ 1 Introduction Recently there has been a resurgence of interest in the chemistry and biochemistry of carbohydrates which have been largely overshadowed in the past few years by the significant advances in nucleic acid technologies and then protein sequencing and synthetic methods. It is now becoming more widely realized that post- translational events, in particular protein glycosylation, also need to be well- characterized at the molecular level. In the carbohydrate field two main areas of research have contributed to this realization.First, improvements in methods of carbohydrate analysis have allowed the characterization of a large number of different structures and studies on their biosynthesis, tissue localization, and cellular distribution. Second, it has been shown that a number of naturally occurring and hybridoma-derived antibodies recognize carbohydrate structures as antigens which change during various stages of cell development and tumourigenesis. The term differentiation antigen was coined to describe cell surface antigens that are restricted to particular lineages or to specific stages within a cell lineage. Antibodies to these surface markers are extremely useful reagents in analysis of different cell types 536 and characterization of the determinants which they recognize can provide significant insight into cell surface biology.The present review is a selective account of the characterization of antibodies which recognize carbohydrate differentiation antigens, highlighting the use of modern chromatographic, n.m.r., and f.a.b.-m.s. methods * in the structural and antigenic assignment of oligosaccharides with particular reference to the charac- terization of fucosylated and sulphated antigens based on the N-acetyllactosamine sequence, Galp( 1-4)GlcNAc. T. Feizi, Immunol. Coniniun., 1981, 10, 127.'T. Feizi, Nuture, 1985, 314, 53. S. Hakomori, Sci. Am., 1986, 254, 32. E. A. Boyse and L. J. Old, Ann. Rev. Gener., 1969, 3, 269. 'Monoclonal Antibodies', ed.P. C. L. Beverley. Churcill Livingstone, 1986. 'Immunocytochemistry', ed. J. M. Polak and S. Van Noorden, 2nd Edn., John Wright, Bristol, 1986. * Abbreviations used: m.s., mass spectrometry; f.a.b.-m.s., fast atom bombardment m.s.; e.i.-m.s., electron impact m.s.; 'H n.m.r., proton nuclear magnetic resonance spectroscopy; h.p.t.l.c., high performance thin layer chromatography; h.p.1.c.. high performance liquid chromatography; g.c., gas-liquid chromatography; Gal, D-galactopyranose; GlcNAc, 2-N-acetamido-~-glucopyranose;Fuc, L-fucopyranose; Man, D-mannopyranose; GalNAc, 2-N-acetamido-~-galactopyranose;Glc, D-glUCOpyranOSe; Asn, asparagine; Ser, serine: Thr, threonine: Cer, ceramide; 3-fucosyl-N-acetyllactosamine,(ronfinued ouer page) Charucterizution of' Carbohjidrate Difrerentiation Antigens A.The Distribution of Carbohydrate Differentiation Antigens.-Carbohydrate antigens at the cell surface occur as oligosaccharide chains covalently linked to protein in glycoproteins and proteoglycans and to lipid in glycolipids. Proteoglycans 'have long sulphated oligosaccharide chains which make up the bulk of the matrix surrounding cells. Glycoproteins * and glycolipids can be found either anchored in the cell membrane by relatively hydrophobic, non-glycosylated regions or as extracellular components. The carbohydrate moieties of these glyco- conjugates surround the cell surface where they are accessible to antibodies '," and other carbohydrate-binding proteins (lectins ').As described below for the antigen termed SSEA-1, the same carbohydrate antigen can exist on different types of glycoconjugate chain and also as part of free oligosaccharides such as those of milk and urine. In addition, carbohydrate antigens can be present in many different tissues and can, for example, show tumour-associated changes where an antigen absent from one type of tissue is expressed on tumour cells derived from it. The antigen SSEA-1 recognized by a monoclonal antibody raised against mouse teratocarcinoma cells is a stage-specific embryonic antigen (acronym SSEA) in mouse embryo development (appearing at the 8-cell stage of the embryo). However, in man this antigen is relatively widespread, the normal human distribution including the spleen, brain, and kidney.' The antigen is absent from other tissues, for example liver, pancreas, skeletal muscle, and non-lactating breast, but in this last organ the antigen appears during tumour development.13 As shown in Table 1, the carbohydrate structure characterized as the SSEA-1 antigen,' 47 3-fucosyl-N-acetyllactosamine, can form part of carbohydrate chains 3FLN.Galp( 1 -4)GlcNAc1 1,3 Fucx LNFP-11, Gala( 1 +3)GlcNAcp( 1 -3)Galb( 1 -4)Glc 1A Fuci LNFP-111, Ga1(3(1 -+4)GlcNAcp(1 --+3)GalP(1-4)Glc t 1.3 Fuci FLNH, Gala( 1 -4)Gl~NAcj3 1 L f 1.3 Galp( 1 +4)GlcFUCX 3 GalP(1+3)GlcNAcp I '? 'M. H88k, L. Kjellan, S. Johansson. and J. Robinson, Ann. Rev. Bioclzem.. 1984, 53. 847. R. Kornfeld and S. Kornfeld, Ann.Rev. Bioc/iem.. 1985, 54, 631.'S. Hakomori, Ann. Rer. Biocliem.. 1981, 50, 733. lo E. F. Hounsell, H. C. Gooi, and T. Feizi, in 'Investigation and Exploitation of Antibody Combining Sites', ed. E. Reid, G. M. W. Cook, and D. J. Moore. Plenum Publishing Corporation, 1985. p. 317. " H. Lis and N. Sharon. Ann. Rec. Bioc'hrm.,1986, 55, 35. '2 D. Solter and B. B. Knowles, Proc.. Nu!. Acad Sci.. 1978, 75, 5565. l3 N. Fox, I. Damjanov, B. B. Knowles, and D. Solter, Cancer Rrs., 1983, 43, 669. l4 H. C. Gooi, T. Feizi, A. Kapadia, B. B. Knowles, D. Solter, and M. L. Evans. Nature, 1981, 292, 156. E. F. Hounsell, H. C. Gooi, and T. Feizi, FEBS Lett., 1981. 131, 279. Hounsell Table 1 Typical carbohydrate chains of glycoproteins, glycolipids, and secreted oligosaccharides bearing the SSEA-1 antigenic structure, 3-fucosyl-N-acetyllactosamine,on backbone sequences attached to diflerent core regions (outlined in boxes) 5 1,3 0-linked chains e.g.GalP(1+4)GlcNAc~1 i GalNAcx(1 +)Ser/Thr Glycolipids e.g. GalP(1-+4)GlcNAcP(1 +3)GalP(1-+4)GlcNAcP( t 193 t 123 FUCX FUC~ Milk oligosaccharides ' e.g. Fuca GalP(1 -4)GlcNAcPl GalP(l+)4Glc1 GalP(l-r3)GlcNAc~l a For references see text (Section 1A). * Glycolipids having both of the Fuc residues shown accumulate in human adenocarcinoma (ref. 23). Those with only the left-hand Fuc are present on human erythrocytes (ref. 22) and the fucosylated pentasaccharide-Cer containing the right-hand side fucosylated pentasaccharide is found, for example, in dog small intenstine (ref.24). The oligosaccharide shown is fucosyllacto-N-hexaose, FLNH.25,53 Characterization of Carbohydrate Differentiation Antigens either N-linked to glycoproteins l6 (e.g. in human secretory component l7 and promyelocytic HL60 leukaemia cells 18), 0-linked to glycoproteins l9 (e.g. in bronchial mucus 2o and human seminal plasma ’), in gly~olipids,~~-~~ or as the oligosaccharides of human milk.’ s-25 B. Characterization of Carbohydrate Antigens.-High molecular weight secreted glycoproteins (mucins), which characteristically have 0-linked chains,26-28 and the oligosaccharides of milk1s.25,29 have been of particular value in the characterization of carbohydrate differentiation antigens because they are a relatively abundant source of oligosaccharides which express many of the antigens of cell membranes detected by monoclonal antibodies.They were used, for example, in the characterization of the Ii antigens of sheep gastric mucins 30*31 and the SSEA-1 antigen.l4*I5 The strategy employed has been to inhibit with structurally defined glycoproteins and oligosaccharides the binding of antibodies to glycoproteins in inhibition radioimmunoassays. 14*30 For structural identi- fication and correct antigenic assignment of oligosaccharides it is first neces- sary to carry out extensive purification (Section 2) and then to determine their complete structure. C. Structural Analysis of 0ligosaccharides.-The structural analysis of oligosaccharides requires determination of the monosaccharide composition, the sequence of monosaccharides, their position of linkage and anomeric con- figuration.As outlined in Table 2 this is usually achieved by the combined use of g.c., m.s., and n.m.r. Modern high field n.m.r. (e.g. 500 MHz ‘H n.m.r.) can achieve a complete structural analysis without recourse to other methods (Section 3), but de nouo determination of previously undocumented oligosaccharides is expensive on instrument and operator time and requires relatively large amounts of material l6 M. D. Snider in ‘Biology of Carbohydrates’ vol. 2, ed. V. Ginsburg and P. W. Robbins, John Wiley and Sons, 1984, p. 163. I’ A. Mizoguchi, T. Mizuochi, and A. Kobata, J. Biol. Chem., 1982, 257, 9612.’’ A. Mizoguchi, S. Takasaki, S. Maeda, and A. Kobata, J. Biol. Chem., 1984, 259, 11949. l9 J. E. Sadler in ‘Biology of Carbohydrates’ vol. 2, ed. V. Ginsburg and P. W. Robbins, John Wiley and Sons, 1984, p. 199. ’O H. Van Halbeek, L. Dorland, J. F. G. Vliegenthart, W. E. Hull, G. Larnblin, M. Lhermitte. A. Boersrna, and P. Roussel, Eur. J. Biochem., 1982, 127, 7. ” F.-G. Hanisch. H. Egge, J. Peter-Katalinic, G. Uhlenbruck, C. Dienst, and R. Fangmann, Eur. J. Biochem., 1985. 152, 343. ’’R. Kannagi, E. Nudelman, S. B. Levery, and S. Hakomori, J. Biol. Chem., 1982, 257, 14865. 23 S.Hakomori, E. Nudelrnan, R. Kannagi,and S. B. Levery, Biochem. BiophJs.Res. Commun., 1982,1#,36. 24 K.-E. Falk, K.-A. Karlsson, and B. E. Samuelson, Arch. Biochem.Biophys., 1979, 192, 191. *’ Y. Tachibana, K. Yamashita, and A. Kobata, Arch. Biochem. Biophys., 1978, 188, 83. ”E. A. Kabat in ‘Carbohydrates in Solution’, Advances in Chemistry Series No. 117, American Chemical Society. 1973, p. 334. ” E. F. Hounsell and T. Feizi, Mrd. Bid, 1982, 60,227. ”E. F. Hounsell, A. M. Lawson, J. Feeney, H. C. Gooi, N. J. Pickering, M. S. Stoll, S. C. Lui, and T. Feizi, Eur. J. Biochem., 1985, 148, 361. 29 L. C. Huang, C. I. Givin. J. L. Magnani, J. H. Shaper, and V. Ginsburg, Blood, 1983, 61, 1020. 30 E. Wood, E. F. Hounsell, J. Langhorne, and T. Feizi, Biochem. J.,1980, 817, 711. ’I E. F. Hounsell, E. Wood, T. Feizi, M. Fukuda, M. E. Powell, and S. Hakomori, Carbohyf. Rex, 1981,90, 283. 164 Hounsell Table 2 Example of the structural analysis of oligosaccharides using g.c., m.s., n.m.r., and chemical or enzymatic methodsfor the oligosaccharide lacto-N-fucopentaose I11 [LNFP-111) of human milk Question asked Method Results Composition G.c.analysis of trimethylsilyl Molar ratio of 2: 1:1:1 of Gal, ethers of methyl glycosides of the Fuc, GlcNAc, Glc constituent monosaccharides" Molecular weight F.a.b.-m.s. of native Mol. wt. 853 (elemental analysis oligosaccharides for 3 hexoses, 1 deoxyhexose, and 1 N-acetylhexosamine I I I Monosaccharide F.a.b.-m.s. and e.i.-m.s. of Hex-0-HexN Ac-0-Hex-0-Hex sequence permethylated oligosaccharides' I ddeoxy-Hed 1,2, 3, are fragment ions of mol. wt. 219, 638, and 842 Y Position of G.c.-m.s.of partially methylated Gal(l+), Fuc(l-+), >IcNAc(I-+) 2linkage alditol acetatesd before and after removal of fucose by mild acid [and (+4)GlcNAc( 1+) after hydrolysis hydrolysis], (-+3)Gal(1+), (-4)Glc Anomeric Oxidation with chromic oxide,/ 1or p configuration degradation with glycosidases of known specificity, n.m.r. -Overal conclusion GalP( 1-+4)GlcNAcP(1+3)GalP(1+4)Glc I 193 FUC'1 o b wOH OHO Oome OH I I II' OH OH HO O HO e NAc Derivatization largely as described by T. Bhatti, R. E. Chambers,and J. R. Clamp, Biochim. Biuphys. Acfa, 1970, 222, 339. * F.a.b.-m.s. is discussed in Section 5. Refs. 94 -98. H. Bjorndal, C. G. Hellerqvist, B. Lindberg, and S. Svensson, Agneu. Chern., in[.Ed.Engl., 1970, 9, 610 K. Stellner, H. Saito, and S.Hakomori, Arch. Biochem. Biuphys., 1973, 155, 464; A. M. Lawson, E. F. Hounsell, and T. Feizi, Int. J. Mass. Specfrum. ion Phys.. 1983, 48, 149. 0.02M,H,SO,, 100 "C,1 h. For example, as described in ref. 21 Characterization of Carbohydrate Differentiation Antigens (>100 nM). N.m.r. analysis of 100 nM samples can identify oligosaccharides for which previous data are available with the added advantage of leaving the sample intact for biological or immunological assays. For oligosaccharides for which n.m.r. data have not previously been documented, n.m.r. analysis gives valuable information which supplements that obtained by g.c. and m.s. methods (<10 nM required) or by enzymatic and chemical degradation of radioactively labelled material followed by chromatographic identification ( < 1nM required).D. Conformational Studies of Oligosaccharide Antigens.-Where 100 nM material is available, n.m.r. analysis can go one step further than providing sequence and linkage information, in giving data which can be interpreted to deduce the conformation in water solution of oligosaccharides (Section 3). Knowledge of the solution conformation is important for understanding the 3D shape recognized by anti-carbohydrate antibodies and lectins: for example, in understanding the differences in fine specificities of monoclonal antibodies which recognize different facets of the same molecule (Sections 4 and 5).This type of information is crucial for obtaining biological information from the use of carbohydrate-binding proteins in studies on the tissue distribution of oligosaccharide sequences which are differentiation antigens and tumour markers.2 The Oligosaccharides of Mucins and Milk :Purification and Antigenic Assignment The field of carbohydrate research presents a unique challenge in purification and analysis because oligosaccharides vary, not only in composition and sequence of their constituent monosaccharides, but also by the positions and anomeric con- figuration of monosaccharide linkage. An abundance of oligosaccharides with closely related composition and of isomeric molecules is particularly found with the oligosaccharide chains of mucins. The carbohydrate, which makes up as much as 85% by weight of these large molecular weight glycoproteins, is arranged as multiple chains consisting of from one to twenty or more monosaccharide^.^^ A.Oligosaccharide Chain Biosynthesis, Structure, and Antigenicity.-Oligo-saccharide chains are built up by stepwise addition of monosaccharides by glycosyltransferases which are specific for substrate, donor, and linkage. In the biosynthesis of mucin oligosaccharide chains 9*32 the initial step is the attachment of a GalNAc residue to the hydroxyl group (0-linked) of Ser or Thr amino acids in the polypetide. The chains are then lengthened by the addition of Gal and GlcNAc residues in a variety of different linkages. The resulting types of core sequences found in mucins of human meconium,28 the bron~hus,~~*~~ and colon 34 are shown in Table 3.Backbone sequences are built up of repeating Gal and GlcNAc residues as shown for sheep gastric m~cins.~l From these latter studies a composite picture of the carbohydrate chains of uncharged mucin glycoproteins can be constructed 32 H. Schacter, Croi. J. Bioclrern. Cdl. Bid., 1986, 64, 163. 33 G. Lamblin, A. Boersma, A. Klein, P. Roussel, H. van Halbeek, and J. F. G. Vliegenthart, J. Bid. Chem., 1984, 259, 9051. 34 D. K. Podolsky. J. Bid. Cliem.. 1985, 260, 15510. 166 Hounsell Table 3 Core region oligosaccliarides isolated from human gastroinstestinal mucin glycoproteins a GalNAc-, GalNAcx(1 -+3)GalNAc+ GlcNAcP(1 -3)GalNAc-GlcNAcP(1 -+6)GalNAc+ GlcNAcP1 .GalNAc-, GalPl ’ Ga@(1 -+4)GlcNAcPl GalNAc-, GlcNAcPl /* a Data taken from refs. 20, 28, 33, and 34 and substantiated by studies on ovarian cyst mucins (e.g.refs. 35, 36). GalNAcr( 1 j3)GalNAc has also been found in sialylated form in humans in mucin-type glycoprotein of rectal adenocarcinoma (A. Kurosaka. H. Nakajima, T. Funakoshi, M. Matsuyama, T. Nagayo, and T. Yamashina, J. Bid. Chem., 1983,258, 11594).Sialic acid is a common component linked to all these cores (~.g.see also refs. 21. 33, 34). Terminal GlcNAc residues are more often found with either Galp( 1+3) or GalP( 1-4) substituents. Oligosaccharide chains are built up from these cores as shown in Figure 1 Periphery Backbone Core- Peptide (Hi Fu~-2 (A) fUG11-2 T Ga I NAcch-3 Ga Ipl -4G IcNAcgl -6 Galhl-3 JGICNcicll-2 =(Galpl-4GlcNAcOl-6) Ga 161-314G IcNA cpl -3GaI pl -314GI cNAc,?1-3\ GlCNAC!ll-4 Figure 1 Composite scheme of the carbohydrate chains of mucins.(H)and (A) are examples of blood group actice substitutions. Backbone regions made up of Ga@(1-4)GlcNAc sequencese.\-press I (hranchecf)and i (linear) antigens. Fucose residues (Fuc) also occur linked to backbone GlcNAc to .form the Lea, and SSEA-1 antigens. The blood group related T antigenGulp(1 -+3)GalNAc and the Tn antigen GulNAcx(1 -+)Ser/Thr are espressed at the core regions in the uhsence of additional glj)cosj-lation. Peripheral sialic ucid residues linked to backbone or core region sequences and sulphute ester groups can occur Mlhich musk antigens associated with internal sequences Characterization of Carbohydrate Dzfferentiation Antigens (Figure 1).This picture is consistent with the data obtained by several groups on the gastrointestinal mucins of man, horse, hog, and rat (reviwed in ref. 27) and human ovarian cyst m~~ins.~~*~~-~~ In addition to the core and backbone regions, a third ‘peripheral’ domain can be identified and, as shown in Figure 1 and discussed in ref. 27, each of these domains is associated with a particular set of antigens. The oligosaccharides of human milk (and for that matter the N-linked chains of glycoproteins and oligosaccharides of glycolipids e.g. see Table 2) express many of the antigenic sequences associated with the backbone and peripheral regions of mucin carbohydrate chains, the difference in milk being that the chains are built up on a lactose core, Galp( 1 +4)Glc (Table l), and only relatively short back bones have so far been characterized. B.Characterization of Oligosaccharide Antigens-Except for SSEA- 1, the antigens discussed in the legend to Figure 1 were originally characterized as the structures recognized by naturally occurring antibodie~.~~.~~,~~.~ 1,37 SSEA-1 was the first hybridoma-defined antigen to be characterized at the molecular The anti- SSEA-1 antibody was found to bind to mucin glycoproteins of non-secretor type (lacking in the peripheral ABH antigens which mask antigens associated with back bone sequences). This binding could be inhibited by mucin oligosaccharides containing the 3-fucosyl-N-acetyllactosamine sequence.l4 However, a very good inhibitor of binding was a preparation of the milk oligosaccharide lacto-N- fucopentose I1 (LNFP-11), having an isomeric non-reducing end trisaccharide sequence Galf3(1 -3)GlcNAc rather than Galp(1 -4)GlcNAcr 154 t 193 Fucx FUCZ It therefore appeared at this stage in its characterization that the anti-SSEA-1 antibody might be relatively unspecific in its recognition of antigen, but it turned out that LNFP-IT purified by classical chromatographic methods contained a significant proportion of contaminant LNFP-I11 having the 3-fucosyl-N-acetyllactosamine non-reducing end sequence.The two isomers were purified by resorting to acetylation and h.p.t.1.c.and in this way it could be proved that LNFP- 111 was the active component.’ C.Purification of 0ligosaccharides.-The characterization of the SSEA- 1 antigen demonstrated the need for efficient purification methods for oligosaccharides. Several studies have now shown that oligosaccharides purified by classical chromatographic techniques, and more recently by gel filtration chromatography on BioGel P4, contain more than one structural isomer or indeed different oligosaccharides of closely related size and composition. BioGel P4 (-400 mesh. BioRad) remains as the material of choice for initial purification because the 3s A. M. Wu, E. A. Kabat. B. Nilsson, D. A. Zopf. F. G. Gruezo,and J. Liao, J. Biol. Chem., 1984.259.7178.36 V. K. Dua, B. N. N. Rao, S.-S. Wu, V. E. Dube, and C. A. Bush, J. Bid. Cheni., 1986, 261, 1599. 3’ W. M. Watkins, Adr. Him. Gerrc~r.,1980, 10, 1 and 379. 168 Hounsell chromatography is based on size exclusion where an acetamido sugar is consistently eluted in twice the volume of a neutral sugar, thus giving useful compositional inf~rmation.~'.~' H.p.1.c. has now largely superseded h.p.t.1.c. as the preferred method for further purification because of the efficiency in time and yield of each chromatographic step. This is important as often more than one type of chromatographic separation is required for oligosaccharide purifi~ation.~~,~' The h.p.1.c. systems widely used for oligosaccharide purification and analysis are reverse-phase octadecylsilyl column packings with water or water-acetonitrile elution, normal-phase chromatography with amine-bonded packings such as aminopropyl silica or anion exchange and water-acetonitrile elution, anion exchange chromatography on amine-bonded and anion exchange column packings eluted with buffers, and cation exchange chromatograph Y.~" A combination of reverse- and normal-phase h.p.1.c. was used to purify the core region oligosaccharides of mucins 20,28,34-36 such as those shown in Table 3.Sialylated oligosaccharides of mucins 33,34 and milk 40.41 and sialylated glycolipids (gangliosides)42 have been separated on amino-bonded column packings with phosphate buffer-acetonitrile elution. H.p.1.c. anion exchange column packings eluted with buffer gradients have been used to separate sialylated and phos- phorylated N-linked oligosaccharides 43 and sulphated oligosaccharides (Section 5).44 The h.p.1.c.anion exchange column packings eluted with water-acetonitrile34.40.45 together with cation exchange ~hromatography,~~ offer additional systems for separation of non-anionic oligosaccharides. The use of more than one column and solvent system for oligosaccharide analysis gives greater assurance that purification has been achieved and knowledge of the different chromatographic behaviour of each oligosaccharide can be used in their structural identification. For previously characterized oligosaccharides, this and n.m.r. analysis serve to identify the structure and purity of an oligosaccharide without recourse to degradative structural methods such as those involving g.c.and m.s. 3 The Structural and Conformational Analysis of Oligosaccharides using 500 MHz 'H N.m.r. High resolution H n.m.r. has emerged in the past few years as a powerful technique in the structural analysis of oligosaccharides. Several groups have now published data obtained at 27&500 MHz for various types of oligosaccharide structures 3H A. Kobata in 'Biology of Carbohydrates' vol. 2, ed. V. Ginsburg, and P. W. Robbins, John Wiley and Sons, 1984, p. 87. 39 E. F. Hounsell, N. J. Jones, and M. S. Stoll. Biochem. Soc. Trans.. 1985, 13, 1061. 40 E. F. Hounsell in 'HPLC of Small Molecules', ed. C. K. Lim. 1986, p. 49. 41 M. L. E. Bergh, P.Koppen, and D. H. van den Eijnden, Carhohyd Res., 1981, 94, 225. 42 G. Gazzotti, S. Sonnino. and R. Ghidoni, J. Chromarogr., 1985. 348. 371. 43 J. U. Baenziger and M. Natowicz. And Biorlieni., 1981, 112. 357. J4 P. Scudder, P. W. Tang. E. F. Hounsell. A. M. Lawson, H. Mehmet, and T. Feizi. Eur. J. Biochem., 1986, 157, 365. 45 S. J. Mellis and J. U. Raenziger, And. Bioc~hem..1981, 114. 276. 4h A. S. R. Donald and J Feeney, C~irhdij~ir.Rcy., in press. including the N-linked chains of glyc~proteins,~’ 50 0-linked chains released from protein by base, borohydride degradati~n,”-~~*~~~~~*~~naturally occurring free olig~saccharides.~~’~~54 chemically synthesized oligosaccharides and glycosides 5s-s7 and gly~olipids.~~.~~ A. An Introduction to N.m.r.Analysis of 0ligosaccharides.-The n.m.r. analyses of oligosaccharides described above were carried out in solution in deuterium oxide (D20). The oligosaccharides were first lyophilized several times in D20 to exchange the OH and NH protons with deuterium. Each of the remaining protons of the glycosidic rings resonates in the applied magnetic field at a specific radiofrequency to give a characteristic signal along the radiofrequency scale of the spectrum (chemical shift, given as p.p.m. of the operating frequency of the instrument). The signal is split into a doublet or multiplet pattern depending on the number of interactions (couplings) with protons on adjacent carbons in the ring and from these splittings coupling constants can be calculated which are characteristic of each monosaccharide type.The chemical shifts of the protons of each monosaccharide are dependent on their local chemical environment and are thus characteristic of monosaccharide sequence and linkage. In general, chemical shifts are comparable for the same oligosaccharide sequences of four or five monosaccharides in different oligosaccharides, enabling a data base for ‘H n.m.r. data to be set up.”’ This is important because n.m.r. analysis relies strongly on the comparison of data with those from standard compounds. An example of the use of the data base is given in ref. 28 for the structural assignment of the core region sequences of human meconium glycoproteins (Table 3). Two of the oligosaccharide sequences could not be assigned in this way as their n.m.r. data had not previously been documented.Further n.m.r. experiments were therefore carried out to give complete proton assignments for these two oligosaccharides using 2D-correlated spectroscopy (COSY) and spin-decoupling (irradiation at the frequency of a proton signal causing ‘decoupling’ of signals from protons on adjacent carbon atoms which can then be traced in the spectrum by observing the collapse of their multiplets). 41 J. F. G. Vliengenthart, L. Dorland. and H. van Halbeek. Ad.. C‘nrhohjdr.. C’horii. Biochc~ni.,1983, 41, 209. 48 K. Bock. J. Arnarp. and J. Liinngren. EW. J. Biochcwi.. 1982. 129, 171. 4y J.-P. Brisson and J. P. Carver. Bioch(vni.~rt’” S. W. Homans. R.A. Dwek, D. L. Fernande macher. Biochim. Biop/ij..s. Ac,rir, 1983.760, 256. 5‘ H. van Halbeek. Bioc/i~w~.Soc. Trms.. 1984, 12. 601 ” B. N. N. Rao, V. K. Dua. and C. A. Bush. Biopo/jmcr.\. 1985. 24, 2207.’’V. K. Dua. K. Goso. V. E. Dube. and C. A. Bush. J. C/?rormfogr.,1985, 328. 259. ”E. F. Hounsell. N. J. Jones. H. C. Gooi. T. Feiri. A. S. R. Donald, and J. Feeney, (’nrhnhj~ilr.Rex. in press. ”C. Auge. S. David. and A. Veyrikres, Noirr. J. Chini.. 1979, 3, 491.’’ R. U. Lemieux. K. Bock. L. T. J. Delbaere. S. Koto. and V. S. Rao, Cirri. J. Cherii., 1980, 58. 631. 57 0. Hindsgaul, T. Norberg. J. LePerdu. and R. U. Lemieux. Ctrrholij~rlr.Res., 1982. 109. 109. ” U. Dabrowski. H. Egge. and J. Dabrowski. Ardi. Rioclrcm. Bioplij,,~.,1983, 224. 254.”T. A. W. Koerner, J. H. Prestegard, P. C. Demou, and R. K. Yu, Bioc/ier~i.stry,1983, 22. 2676.“’ E. F. Hounsell. D. J. Wright. A. S. R. Donald. and J. Feeney. Bioc.hon7.J.. 1984, 223. 129. 61 J. Feeney, T. A. Frenkiel. and E. F. Hounsell. Ctrrhohjdr. Rrs.. 1986. 152. 63. ”A. Bax and L. Lerner, S(,irtic.c,1986, 232, 960. 170 Hounsell Galpl-3GlcNAc,~l-3Gal~31-4Glc-01-11.4 -Galex, Fuco Gal,,,, HOD Galpl-4GlcNAcpl-3Galpl-4G Ic-01 -1,3 -Galcil iucn Gal,,,, HOD HlilFuc n H5 Fuc n H1$ GlcNAc n HlpnGal,”, H4 Galin, n H2 Gal,,, n LI 1 I I I 1 I I I ppm 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 Figure 2 The 500 MHz ‘H n.m.r. spectra of LNFP-11-of und LNFP-111-of Besides giving sequence and linkage information, comparison of the data from ‘H n.m.r.analysis of a series of structurally related oligosaccharides can lead to information on their solution conformations, as described in Sections 3B-D below for the oligosaccharides of milk used in the characterization of the SSEA-1 antigen. B. The Spectra of the Alditols of LNFP-I1 and LNFP-111.-The 500 MHz ‘H n.m.r. spectra of LNFP-11-01 and LNFP-111-01 are shown in Figure 2. Approximately 120pg (140nM) were used for the analysis. The signals that can be readily recognized have been assigned in the figure. These are the structural reporter groups47 which resonate at frequencies away from the main bulk of the proton signals. For example, the ‘H signals for the H-1%and H-5 of Fuc, the H-10 of GlcNAc, and the H-1P of the two galactose residues are to low-field (high Characterization of Carbohydrate DifSerentiarion Antigens radiofrequency) of the bulk of the proton signals. The H-2 signal for the non- reducing end Gal (Galexl) is also readily distinguished (by a decoupling experiment at the H-1 frequency) and is located at a slightly higher field than the bulk region proton signals.The methyl protons of the acetamido group and C-6 of Fuc are also at high-field near the internal standard acetone, which has chemical shift 2.225 p.p.m. with respect to sodium 4,4-dimethyl-4-silapentane-1-sulphonate (DSS) at 295 K (the temperature of the experiments). The H-1 protons marked in the spectra of Figure 2 are doublets (coupling to H-2 only), the H-2 is a quadruplet (coupling to H-1 and H-3) and the H-5’s are octuplets (coupling to H-6, H-6’, and H-4).The H-1P signals can be distinguished because that for GlcNAc characteristically has a larger coupling constant than those of Gal residues. The signals arising from the two Gal residues of each molecule can be distinguished because the chemical shifts for the Gal attached to Glc-01 and Glc are different in the reduced and unreduced oligosaccharides (Table 4). C. Interpretation of H N.m.r. Spectra to Give Structural and Conformational Information.-As can be seen from the chemical shift data given in Table 4, in general comparable residues in the related oligosaccharides have very similar chemical shifts e.g. the internal Gal residue (Galinl), Glca, and GlcP in LNT, LNNT, LNFP-TI, and LNFP-111.The addition of Fuc to LNT and LNNT to give, respectively, the non-reducing end trisaccharide sequence of LNFP-I1 and LNFP-111, leads to differences in the chemical shifts of residues in these sequences as does change of linkage from GalP( 1-+ 3)GlcNAc to GalP( 1+4)-GlcN Ac. As illustrated in Figure 3, the differences in chemical shift for the non-reducing end trisaccharide sequences of LNFP-IT and LNFP-111 have been attributed 56,63,64 to the close proximity of the H-5 of Fuc to the ring oxygen of the external Gal residue (Galexl) and the oxygen of the GalP(1-,3) or GalP(l-+4)GlcNAc glycosidic bonds. The H-1 of GalP(1+3) is then adjacent to the acetamido group whereas that of GalP(1+4) is adjacent to GlcNAc C-6.The H-5 signals of Fuc are significantly deshielded63.64 by close proximity to the two oxygen atoms giving low-field signals of 4.882 and 4.830 p.p.m. (LNFP-I1 and LNFP-111, respectively) as compared for example, with the H-5 of Fuca (1+2) of another isomer, LNFP-I Fucz( 1-+2)Gal~(l-+3)GlcNAc~(l-+3)Gal~(l-+3)Glc which has a Fuc H-5 chemical shift of 4,293 ~.p.m.~~ The similarity in the chemical shifts of the non-reducing/non-reducedend portions of each oligosaccharide/alditol pair can be interpreted as the reducing/reduced end being orientated away from the rest of the molecule as predicted by empirical energy calculation^^^ and shown in Figure 4 for LNFP-111-01. b3 K. Bock, Pure Appl. Chem., 1983, 55, 605. 64 U. Spohr, N.Morishima, 0.Hindsgaul, and R. U. Lemieux, Can. J. Chem., 1985, 63, 2659. 65 M. Biswas and V. S. R. Rao, rnf. J. Quantum Chem., 1981, 20, 99. 172 Table 4 The 'H chemical shifts @.p.m. from DSS) of the structural reporter groups of human milk oligosaccharides and their alditols" LNT LNT-01 LNNT-01 LNFP-I1 LNFP-111-01 FLNH 0 u--0 0 0 0 a-.-.-a 8 o--O-a--o .--.--.--@ A AI '-m\ a--0 o--H- 1 5.028 5.029 5.127 5.131 5.105 H-5 4.882 4.870 4.830 4.842 4.864 H-6 1.180 1.179 1.174 1.175 1.172 H-1 4.44 1 4.442 4.505 4.507 4.440 H-2 3.524 3.529 3.485 3.486 3.524 H-1 4.480 4.479 4.462 4.463 4.452 H-2 3.539 3.536 3.497 3.497 3.496 H-la 4.73 1* 4.731 4.706 4.697 4.730 H-IP 4.726 4.695 4.726 NAc 2.027 2.025 2.032 2.032 2.025 GlcNAc N-1% 4.707 4.708 4.715 4.713 4.638 H-1P 4.703 4.710 4.638 N Ac 2.034 2.034 2.022 2.023 2.052 H-1 4.44 1 4.492 4.437 4.495 4.433 4.489 4.432 4.488 4.431 H-4 4.1 54 4.144 4.155 4.150 4.156 4.152 4.1 56 4.152 4.140 CGlca 0 H-1 5.220 5.220 5.220 ___ 5.2 19 5.219 GlcP H-I 4.662 4.663 4.663 4.662 4.666 H-2 3.279 3.278 3.279 3.277 3.290 Symbols used: A, Fucr( 143);A,Fuca( I +4); 0,GalP(1-3); 0,GalP(144); 0,GlcNAc linked at C-3 by Gal; m, GlcNAc linked at C-4 by Gal; 0,Glc; a! Glc-01.* Signals arising from the x and P anorners of reducing oligosaccharide (anornerization effect e.g. see ref. 90). 'Not determined. Characterization of Carbohjjdrate Differentiation Antigens Fuc~I\ Fuccl.1 ‘31 -GIcNAcP 1 -Gal/$ 1 ’;GI~NA~~ GalPI I Figure 3 The structural formulae, molecular models and outline of the molecular models proposed for the non-reducing end trisaccharide sequences qf LNFP-I1 and LNFP-111.The atoms muking up the molecular models are white, H; light grey, N; dark grey, 0;and black, C Several predictions can also be made about the conformation of FLNH from a comparison of the ‘H n.m.r. chemical shift data in Table 4 (similar data have been obtained by Dua et ~1.~~).The chemical shifts of GlcNAc and non-reducing end Gal, (Gal,,,), in the sequence GalP(1 -+3)GlcNAcP( 1--+3)Gal are essentially identical in LNT and FLNH. The chemical shifts for the Fuc and GlcNAc residues in the sequence Galp( 1 -+4)[Fuc~(1 -+3)]GlcNAc of FLNH are close to those of the Hounsell LNFP-m-01 Gal ill-4 GlcNAc p 1-3 Gal p 1-4 Glc-ol I1,3 FUC(t Figure 4 The sfructural,fiwmulu, molecular model and outline qf the moleculur model proposedfi)r LNFP-111-ol.The atoms appear coloured as described in Figure 3 corresponding shifts of LNFP-111, thus confirming that the single fucose residue is in this 3-fucosyl-N-acetyllactosamine sequence. The differences in chemical shift between the fucosylated terminal trisaccharide unit of LNFP-111 and FLNH can therefore be accounted for by the 3-fucosyl-N-acetyllactosamine sequence being followed by a 143 linkage to Gal,,, in LNFP-I11 and a 1 -+6 linkage to Galint in FLNH. In addition, the chemical shift of the anomeric proton of the fucvsylated GlcNAc is smallcr in FLNH, whcreas that of the N-acetamido methyl group is larger (by 0.074 and 0.029 p.p.ni., respectively).An explanation for this in terms of relative deshielding is given by the molecular model of FLNH depicted in Figure 5. This shows the anomeric proton of GlcNAc adjacent to the hydrogens of C-6 of galactose and the tnethyl protons of the N-acetamido group in close proximity to Characterizution of Carbohydrate Differentiation Antigens FLNH Galp 1-4 GlcNAcp1 ,'FUCrr :Galp 1-4 Glc 0> Galp 1 -3 GlcNAcL3 1 Figure 5 The structural jormula, molecular model and outline of the molecular modelproposed .for FLNH. The atoms appear coloured as described in Figure 3 the ring oxygen of the galactose linked to glucose and the glycosidic oxygen of the Galp(1-+4)Glc bond.D. The Construction of Space-filling Molecular Models Incorporating H N.m.r. Data.-The molecular models shown in Figures 3-5 were constructed using the information obtained from the n.m.r. data as discussed above, together with information from other sources 52*56*57*63 70 obtained by X-ray crystallography, ''J. F. Stoddart. 'Stcreochemistry of Carbohydrates', John Wiley and Sons Inc., 1971. h7 D. A. Rees, Adill.Cbrholijulr. C'lrcm. Bioc,lirvn., 1969, 24, 267. "R. U. Lemieux and S. Koto, Tctrirhc~tlrori,1974, 30, 1933. ") H. Thngersen, R. IJ. Lemieux, K. Bock. and B. Meyer, Can. J. C'hcwi., 1982, 60, 44. 'O R. U. Lemieux and K. Bock, Arch. Bicdicwi. Biophys.. 1983, 221, 125. Hounsell empirical energy calculations, and n.m.r. nuclear Overhauser experiments (measurement of the change in intensity of a signal on irradiation of another resonance caused by a through-space interaction of close protons).62 These studies have shown that in solution oligosaccharides tend to adopt conformations in which D-sugars have the 4C, conformation and L-sugars the 'C, conformation (as shown in Figure 3) and in the most energetically favoured conformers the angles which define the orientation of residues around the glycosidic bonds (the cp and w angles) are such that the anomeric and aglyconic protons of each linkage are on the same face of the molecules (cpH approximately 60"for 0-D-glycosides and approximately -60"for a-D-glycosides 63).Although this is only an approximation to the likely solution conformation of an oligosaccharide at any particular time, the molecular models of structurally similar oligosaccharides are useful in interpreting major differences in their chemical shifts and in envisaging the molecular features recognized by carbohydrate binding proteins as has been discussed previously 54 and is explained further in Section 4.4 Studies of Carbohydrate Antigen Recognition using Space-filling Molecular Models As discussed in Section 2 the anti-SSEA-1 antibody specifically recognizes oligosaccharides having the 3-fucosyl-N-acetyllactosamine sequence, Galp( 1 -4)GlcNAc ? 1-3 FUCZ Oligosaccharides having the isomeric Lea active Galp( 1-,3)GlcNAc? 1.4 FUCO: are not recognized by anti-SSEA- 1.As shown by the molecular models of these two trisaccharides (Figure 3), the significant features which discriminate between the two models are that in the LNFP-11-type structure the Fuc-methyl and GlcNAc N-acetamido group are on different surfaces of the model (top and bottom, respectively) whereas in the LNFP-111-type structure they are in close proximity on the top surface of the molecule. As it is known that the fucose residue and acetamido group are necessary for binding of anti-SSEA-1 (N-acetyllactosamine and 3-fucosyllactose are relatively inactive as inhibitors of binding) it is thought that this part of the molecule is specifically recognized and that it is the orientation of the Fuc-methyl and acetamido groups to each other and to those of other atoms in the molecule, e.g.hydroxy groups of the Fuc and non-reduced end Gal residue, that are recognized by the antibody combining site (Figures 4 and 6). From other studies of oligosaccharide binding by le~tins,~7*71-74 anti-'' R. U. Lemieux in 'Frontiers of Chemistry', ed. K. J. Laidler, Pergamon Press, 1982, p. 3.''U. Spohr, 0. Hindsgaul, and R. U. Lemieux, Can. J. Chem., 1985,63, 2644. 73 0.Hindsgaul, D. P. Khare, M. Bach, and R. U. Lemieux, Cun. J. Chem., 1985,63, 2653. l4 K. A. Kronis and J. P. Carver, Biochemistry, 1985, 24, 834. Char a cterizntioii of' Cnrhohjdrntc D lfferwtiu tion A titigms Table 5 Differing reuc'tion puttcrris of nionocional mriihodie.v wcopiizing 3Tfuco.~yl-N-uc.et~~lluc'tosnmirie Antibody Imnrunogeri AciiiVtj? rz-ith d&fj{iwntoli~o.suc.chari1~e.s 3FLN LNFP-111-01 FLNH@-I @-T\.-a "" 0-0 Anti-SSEA-1 Mouse teratocarcinoma + + + + + + + + cells Vim/Vep Human myeloid cells + ++ NT 3C1B12 EGF receptor -++ + a References as in text (Section 4).ActiLity measured as nM oligosaccharide giving 50",, inhibition of binding; + + + + , < I nM; + + +, <2 nM: + +, <4 nM; + <, 10 nM; NT, not tested. Symbols as in legend to Table 4 bodies,52.54.56.64.7 5-77 and other carbohydrate-binding proteins ''it is thought that areas with a predominance of protons interact with hydrophobic amino acids in the combining site and that surrounding hydroxyl groups form specific hydrogen bonds with polar amino acids. Prediction of the molecular features recognized by carbohydrate-binding proteins can be made by analysis of the inhibition data of a series of proteins with related specificities and a series of oligosaccharides with different inhibitory activities isolated from biological sources or synthesized by site-specific chemical reactions.h4.h9.7 1-7 3.7 5-7 7 For studies on antibody recognition of 3-fucosyl-N- acetyllactosamine there were available three oligosaccharides having this trisaccharide sequence; the trisaccharide itself (3FLN), LNFP-111-01, and FLNH. These had different inhibitory activities towards several antibodies with specificities related to SSEA-1. In addition to the SSEA-1 antibody, other antibodies recognizing the 3-fucosyl-N-acetyllactosamine sequence which have now been characterized include a series of related antibodies belonging to the Vim and Vep series which were raised against human myeloid cell^,'^.'^ and the antibody 3ClB12 raised against the receptor for epidermal growth factor (EGF)." An ''R.U. Lemieux. A. P. Venot. U. Spohr, P. Bird. G. Mandal. N. Morishima, 0.Hindsgaul, and D. R. Bundle, Con. J. Chrni., 1985, 63, 2664.'' E. A. Kabat, J. Liao, M. H. Burzynska. T. C. Wong, H. Thegersen, and R. U. Lemieux, Mol. Inlniunol., 1981, 18, 873. 77 R. U. Lemieux. T. C. Wong, J. Liao. and E. A. Kabat, Mol. Itnt~umd.~1984, 21, 751. 78 F. A. Quiocho, Am. Rev. Biocliorii., 1986, 55, 287. 79 H. C. Gooi. S. J. Thorpe. E. F. Hounscll. H. Rumpold, D. Kraft. 0. Forster. and T. Feizi, Ew.J. It~7nl~irio/.,1983. 13. 306. H. C. Gooi. E. F. Hounsell, A. Edwards, 0.Majdic, W. Knapp, and T. Feizi. Cliri. E\-p. It~iniunol..1985, 60, 151. H. C.Gooi. E. F. Hounsell, 1. Lax, R. M. Kris,T. A. Libermann. J. Schlessinger. J. D. Sato. T. Kawamoto, J. Mendelsohn. and T. Feizi. Bio.sc,i. Rep.. 1985, 5. 83. Hounsell Anti-SSEA-1 Antibodies Virn/Vep Antibody 3ClB12 Figure 6 The outlines-for the molecular models of FLN, LNFP-111-01, and FLNH takenfrom the molecular models shown in Figures 3,4, and 5,respectively, with shading signqying regions containing features recognized by antibody anti-SSEA- 1, antibodies of the Vim and Vep series, and antibody 3C1 B12 raised against the receptor for epidermal growth factor Vor references see text).It is proposed that antibodj SSEA-1 recognizes molecular features in addition to those represented in 3-fucosyl-N-acetyllacetosamine, but which are not present in LNFP-111-01 and FLNH, e.g. p( 1+3)GalP(1+4)GlcNAc rather than P( 1+3)Ga@(1+4)Glc-ol. On the other hand, antibodies of the Vim and Vep series recognize mostly features of 3-fucosyl-N-acetyllactosamine itself and antibody 3C1 B12 may recognize the branched sequence insight into the topographical array of atoms recognized by these antibodies is given by comparison of their relative reactivities with the three different oligosaccharides shown in Table 5, as follows. Anti-SSEA-1 reacts slightly better with 3FLN than LNFP-111-01 and is relatively unreactive with FLNH. This suggests that the glucitol of LNFP-111-01, and even more the GalP(1-+3)GlcNAc sequence of FLNH interfere with antibody binding.Thus, it is proposed that the combining site for SSEA-1 recognizes the complete ‘top’ surface of 3FLN and Characterization of Carbohq~drate Dflerentiation Antigens probably extends recognition beyond this to include for example a GlcNAc residue which is usually present in longer oligosaccharide chains of glycoconjugates in place of Glc-ol of LNFP-111-01 (Figure 6). On the other hand, antibodies of the Vim/Vep series and 3C1B12 react more strongly with LNFP-111-01 than 3FLN, and 3C1B12 shows two times less reactivity with FLNH than LNFP-111-01. These antibodies therefore seem to recognize the internal Gal residues of LNFP-111-01 and FLNH which extend the hydrophobic face of the molecule of Figures 3-6.Some further aspect of the reducing end of LNFP-111-01 and the Galp( 1 -3)GlcNAc sequence of FLNH may also fit into the combining site which indicates that the antibodies may be directed towards branched structures. From additional molecular models 54 and the knowledge that antibody 3ClB12 has some reactivity towards oligosaccharides with non-reducing end GalNAca( 143) and Fuca( 142) linked to the Galp(1-+4)GlcNAc sequence, it is thought that the external Gal residue of LNFP-111-01 and FLNH is not involved in this antibody recognition. 5 Characterization of Sulphated Oligosaccharide Antigens Based on the N-Acetyllactosamine Sequence A1terations in sulphated oligosaccharide sequences of proteoglycans and glycoproteins are being implicated increasingly in cell development and differentiation.For example: specifically sulphated sequences of heparin are thought to be involved in regulation of cellular pr~liferation;’~-~~ several changes in proteoglycan composition are associated with differentiation 85 and age- and disease-related changes in cornea and cartilage; 86,87 sulphated glycoproteins show developmentally regulated changes in the liver and lung of chick embryos; 88 and the sulphation of N-acetyllactosamine sequences of the LFA-1 antigen of lymphocytes is restricted to the T-cell lineage.89 For the study of these and related changes it is becoming increasingly important to have specific antibodies to sulphated sequences and methods available for their characterization.A. Sulphated Antigens of the N-Acetyllactosamine Series.-Among the first sulphated oligosaccharide antigens to be characterized at the molecular level were sulphated poly-N-acetyllactosamine sequences which are the major component of the proteoglycan keratan sulphate. Three hybridoma antibodies raised against keratan sulphate were shown to recognize polysulphated hexa- and larger oligosaccharides isolated from bovine corneal keratan sulphate by endo-p- 82 R. Crum, S. Szabo. and J. Folkman, Science, 1985, 230. 1375. ”J. J. Castellot, J. Choay, J.-C. Lormeau, M. Petitou, E. Sache, and M. J. Karnovsky, J. Cell Biol.,1986, 102, 1979. 84 J. T. Gallagher, M. Lyon, and W.P. Steward, Biochem. J.,1986, 236, 313. 85 R. Kapoor and P. Prehm, Eur. J. Biochem., 1983, 137, 589. 86 N. SunderRaj, J. Willson, J. D. Gregory, and S. P. Darnle, Curr. E-ve Res., 1985, 4, 49, ”A. R. Poole, Biochem. J., 1986, 236, 1. 88 A. Heifetz, W. H. Kinsey, and W. J. Lennarz, J. Biol. Chem., 1980, 255, 4528. 89 N. M. Dahms and G. W. Hart, J. Immunol., 1985, 134, 3978. 180 Hounsell GlcNAcB1-SGal GlcNAcBl-3Gal I6 so; GlcNAcBl-3GalB1-4GlCNAcB1-3Gal I6 I6 16 so; so; so3 GlcNAc~l-3~alB1-4GlcNAcB1-3GalB1-4Gl~NAcB1-3G~~ 16 I6 16 16 16 so; so, so,-so3 so< GlcNAcBl-3GalBl-4GlcNAcf?1-3Gal~1-4GlcNAc~1-3GalB1-4GlcNAcB1-3Ga~ I6 16 16 16 16-16-16 so3 so; so? SOT so3 so3 SO: GlcNAcBl-3GalB1-4GlcNAcB1-3GalB1-4GlcNAc~1-3Ga1B1-4GlcNAc~1-3GalB1-4GlcNAcB1-3Gal 16 16-I6 16 I6 16 16-I6 SO3 so; SO3 so: SO: SO, SO; SO^ SO? Figure 7 The sequences of the major oligosaccharides isolated from bovine corneal keratan sulphate peptidoglycans by endo- P-galactosidase digestion, Bio-Gel P4 chromatography and h.p.1.c.galactosidase digestion of the peptidogly~an.~~.~~*~~ The major oligosaccharides characterized were as shown in Figure 7; a non-sulphated disaccharide, a monosulphated disaccharide, a trisulphated tetrasaccharide, a pentasulphated hexasaccharide, a heptasulphated octasaccharide, and a nonasulphated decasac- charide. The pentasulphated hexasaccharide was the smallest oligosaccharide with antigenic activity with the three antibodies. Activity was lost on desulphation indicating the importance of one or more sulphate groups for antibody recognition.The number and linkage position of the sulphate groups and the backbone sequence were deduced as described below and in references 44, 90, and 91. B. Structural Characterization of Sulphated 0Iigosaccharides.-(i) Chromatography. The oligosaccharides released from keratan sulphate by the enzyme endo-p- galactosidase were purified by gel filtration chromatography on BioGel P4 (-400 mesh) eluted in ammonium bicarbonate buffer and anion exchange h.p.1.c. (Varian AX-4 column eluted with a phosphate buffer gradient from 10-400rnM in 45 min at flow rate lml min-’). From the known specificity of the enzyme92 it could be deduced that GlcNAc-Gal sequences were present terminating in a non-sulphated Gal residue.From the chromatographic elution pattern of the oligosaccharides it could be deduced that these were di- to dodeca-saccharides increasing in size by mono-or di-sulphated N-acetylhexosamine-hexose units. The oligosaccharide composition was confirmed by GC analysis. (ii) Fast A tom Bombardment Mass Spectrometry. The number of sulphates, N-acetylhexosamines, and hexoses present on the major oligosaccharides were 90 E. F. Hounsell, J. Feeney, P. Scudder, P. W. Tang, and T. Feizi, Eur. J. Biochem., 1986, 157, 375. ” H. Mehmet, P. Scudder, P. W. Tang, E. F. Hounsell, B. Caterson, and T. Feizi, Eur. J. Biochem., 1986,157, 385. 92 P. Scudder, P. Hanfland. K. Uemura, and T. Feizi, J. Biol. Chem., 1984, 259, 6586.181 Characterization of' Car holij3dra te Difle rentiution AnIigens calculated from the molecular weight given by their f.a.b.-m.s. spectra. This is a relatively new technique applied to the structural analysis of oligosaccharides as a method for determining the sequence and composition of constituent monosac- charide~.~~Previously, the physicochemical analysis of oligosaccharide sequence had been achieved by e.i. direct probe mass spectrometry of permethylated derivative^.^ An advantage of the f.a.b.ionization method is that it can be used 394~97 for the analysis of non-derivatized oligosaccharides. However, further studies e.g. refs.98,99 have suggested that derivatized oligosaccharides give more useful f.a.b.- m.s.spectra containing fragment ions which provide sequence information. Methylated or acetylated derivatives are the method of choice analysed in positive ion f.a.b. in a 1 : 1 glycerol/thioglycerol matrix or 1 : 1 glycerol/triethylamine matrix. For the series of sulphated oligosaccharides shown in Figure 7, negative ion f.a.b.-m.s. of the underivatized oligosaccharides using a thioglycerol matrix gave fragment ions resulting from the loss of sulphate residues (as their sodium or potassium adducts). No fragmentation due to glycosidic bond cleavage could be detected. However, the pattern of fragment ions given by loss of sulphate were most instructive in assigning the correct molecular weight as the molecular ion was relatively small. The sulphate groups were found not to be stable to methylation or acetylation and therefore additional sequence information could not be obtained by this method.(iii) 7V.m.r. Analysis. For the non-sulphated and mono-sulphated disaccharides of keratan sulphate (Figure 7), complete assignment of all the signals in the spectra could be made using spin decoupling methods. From this analysis it was shown that the mono-sulphate residue was at the C-6 position of GlcNAc linked 143 to Gal. The protons on the sulphated C-6 atom had a characteristically large chemical shift, compared to those of the non-sulphated oligosaccharide, caused by deshielding by the sulphate group. The effect on the chemical shift of the other protons around the sulphated glycosidic ring was roughly proportional to their distance from C-6, suggesting that the sulphate group extended away from the oligosaccharide backbone. Spectra of the tetra- and hexa-saccharides could be interpreted, by the use of 2D-spectroscopy methods and comparison of the data with those for the disaccharides, to give the structures as shown in Figure 7.The larger oligosaccharides, which were initially analysed as mixtures, gave spectra which were consistent with them being of the same 6-sulphated poly-N-acetyllactosamine sequence, but little detailed information could be obtained. For both the f.a.b.-m.s. and H-n.m.r. studies, analysis of the octa-, deca-, and dodeca-saccharides was greatly aided by having an homologous series of oligosaccharides of increasing size.The information obtained y3 A. Dell and C. Ballou. Bionied. Miis.c .Sp(~frot?r..1983. 10. 50. Y4 K.-A. Karlsson, I. Pascher. W. Pimlott. and R. E. Samuelsson. Bioriic~l.Mrrss Spec/roni..1974, 1. 49. 95 K. Watanabe, M. E. Powell, and S. Hakomori, J. Biol. Chon., 1978, 253. 8962. "N. K. Kochetkob. V. A. Derevitskaqa. and N. P. Arbatsky. Eirr.J. Biodirm. 1976. 67, 129. '' M. McNeil, A. G. Darvill. P. Amin. L.-E. Franzen. and P. Albersheim, Merlrorl.\ Etr~~mo~..1982. 83. 3. y8 E. F. Hounsell. M. J. Madigan. and A. M. Lawson, Biochcwi. J., 1984, 219. 947. "S. Naik. J. E. Oates. A. Dell, G. W. Taylor, P. M. Dey. and J. B. Pridharn, Biorhrm. Binpliys. Rrs. C'omiii~iii., 1985, 132, 1. H-1 H-3 H-5 Figure 8 A molecular model .for the penta-sulphated hexasuccharide isolated from bovine corneal keratan sulphate bused on n.m.r.studies and X-ray crystallographic data (refs. 90, 100, 101) from these studies serves as a model for the characterization of other sulphated sequences now increasingly being found in glycoproteins and proteoglycans. The n.m.r. data were consistent with the molecular model for the pentasulphated hexasaccharide based on X-ray crystallographic data 'oo,'o' shown in Figure 8. The anionic sulphate groups are arrayed in pairs along both the top and bottom surfaces of the molecule to give a distinct topography of hydrophilic and hydrophobic areas. The two non-reducing end pairs of sulphates surround a relatively hydrophobic region on the face of the molecule shown in the Figure, including the H-1, -3, and -5 of the non-reducing end GlcNAc, the H-1, -3, -4, and -5 of the Gal to which it is linked, and the H-2, and -4 of the next GlcNAc residue.The fully sulphated GlcNAc-Gal-GlcNAc-Gal sequence is repeated three times on the two faces of the decasaccharide (Figure 9) which was the best inhibitor of antibody binding with two of the antibodies,"' suggesting the importance of this sequence in antibody binding and cooperativity effects. 100 S. Arnott, J. M. Guss, D. W. L. Hukins, 1. C. M. Dea, and D. A. Rees, J. Mol. Biol., 1974, 88, 175. 'O' D. A. Rees, M7P /ti/. R~P.Sci. Biochoni. Sor. 1, 1975, 5. 1. 183 Characterization of Carbohj)drate Differentiation Antigens H2,4 HI, 3,5 H1,3,4, 5 H2,4 H1,3, 5 H1,3,4,5 H2,4 0 Q Figure 9 A schematic diagram of the nona-sulphated decasaccharide isolated from keratan sulphate.The face ofthe hexasaccharide molecule shown in Figure 8 is represented in the upper diagram. The middle diagram shows the reverse side of the molecule and the lower, the conventional structure for this face. (Adopted.from refs. 90, 100, 101). The stippled areas are those having the H-1, -3, -5 of GlcNAc (Gn), the H-1, -3, -4,-5 of Gal(G), and H-2 and H-4 of Gn. The small square is the N-acetamido group and S the sulphate. The tetra-sulphated tetra- saccharide sequence having this relatively hvdrophobic Gn-G-Gn sequence linked to sulphated Gal is absent,from the tetrasaccharide (Figure 7) which had negligible antigenic activity and is present one, two, and three rimes.respectively, in the hexa-, octa-, and deca-saccharides which had increasing antigenic activities, suggesting that a fully sulphated tetra-saccharide is the predominant feature recognized by the antibodycombining site 6 Conclusions There is a considerable diversity of carbohydrate structures possible from a combination of a few monosaccharides-taking into account different monosac- charide sequence, position of linkage, and anomeric configuration. They have, therefore, great potential as biological information molecules. The studies Hounsell described in this review show how changes in glycosylation pattern i.e. 6-sulphation and 3-fucosylation of N-acetyllactosamine sequences, result in different antigens defined by monoclonal antibodies and, further, that the features recognized are topographical arrays of atoms giving both hydrophilic and hydrophobic areas which are thought to interact, respectively, with polar and non-polar amino acids in the antibody-combining site.These studies provide a basic understanding of oligosaccharide antigen conformation and molecular recognition. More detailed characterization using empirical energy calculations, X-ray crystallography, and nuclear Overhauser experiments can be used to give additional insight into carbohydrate-protein interactions (e.g. refs. 52, 56, 57, 63-65, 69-78). The principles established in elucidating the specificities of monoclonal antibodies to cell surface markers are also relevant to future studies on the recognition of carbohydrate receptors by microorganisms,102-104 to studies on carbohydrates as targets for autoantibodie~,~~~~~~~~~and to work on cell-to-cell interactions mediated by endogeneous lectin~.’~~-’~~ Acknowledgements.The personal studies described in this review could not have been carried out without valuable collaboration with Dr. T. Feizi, Dr. A. Lawson, and Dr. J. Feeney and colleagues. The author is also grateful to the Royal Society of Chemistry and Tate and Lyle Ltd. for the 1984 Carbohydrate Chemistry Prize, awarded for the work on which this review is largely based, and to Mrs. M. Runnicles for patient typing of the manuscript. lo2 ‘Microbial Lectins and Agglutinins’, ed. D. Mirelman, John Wiley and Son, 1986. lo’ L. M. Loomes, K. Uemura, R. A. Childs, J. C. Paulson, G. N. Rogers, P. R. Scudder, J.-C. Michalski, E. F. Hounsell, D. Taylor-Robinson, and T. Feizi, Nature, 1984, 307, 560. ‘04 S. H. Barondes, Science, 1984,223, 1259. lo5 ‘The Biology of Glycoproteins’, ed. R. J. Ivatt, Plenum Press, 1985. lo6 ‘Receptors in Cellular Recognition and Developmental Processes’, ed. R. M. Gorczynski, Academic Press, 1986.

ISSN:0306-0012    

DOI:10.1039/CS9871600161

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Chem. SOC.Rev., 1987, 16, 187-238 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction By Donald Craig DEPARTMENT OF CHEMISTRY, IMPERIAL COLLEGE OF SCIENCE AND TECHNOLOGY, SOUTH KENSINGTON, LONDON SW7 2AY 1 Introduction Since its discovery nearly 60 years ago,’ the Diels-Alder reaction has become one of the most commonly used stratagems in organic chemistry. The ability to generate simultaneously up to four chiral centres in a highly stereoselective and largely predictable fashion has resulted in its application to numerous synthetic challenges, often difficultly accessible by other means. The intramolecular version of this process, although over thirty years younger than its bimolecular counterpart,2 has similarly enjoyed widespread use in the construction of polycyclic ring systems with high levels of stereocontrol. Whilst the last ten years have seen a large number of additions to the review literature covering the .intramolecular Diels-Alder (IMDA) rea~tion,~ these have largely simply catalogued published examples of the reaction, classifying cyclization substrates according to such structural features as the nature of substituents on the diene and dienophilic groups, the nature and presence of substituents in the linking chain, and the incorporation of heteroatomic groups in the linking chain.The present review sets out to assess critically the effect of such parameters on the stereochemical outcome of the IMDA reaction, including a brief discussion of some recent theoretical work in the area.Although it is clearly outside the scope of this review to analyse exhaustively all the known examples of the IMDA reaction, particular emphasis has been placed on those instances where the observed reactivity serves to highlight and exemplify an emerging stereochemical trend. As a corollary of this selective analysis, examples of the reaction in which stereochemistry is not apparent, or where the observed selectivity results purely as a consequence of some obvious structural feature have been omitted. The use of the IMDA reaction in steroid synthesis, amply reviewed elsewhere, has not been covered in detail. Because the last major reviews appeared in 1984, all the relevant literature since that date has been reviewed.0.Diels and K. Alder, Justus Liebigs Ann. Cliem., 1928,460, 98. (a)G.Brieger, J. Am. Chem. SOC.,1963, 3783; (b) L.H.Klemm and K. W. Gopinath, Tefrahedron Lelt., 1963,4,1243;(c) H.0.House and T. H. Cronin, J. Org. Chem., 1965,30,1061. (a)W.Oppolzer, Angew. Chem., Int. Ed. Engl., 1977, 16, 10; (b) W.Oppolzer, Synthesis, 1978, 798; (c)R.L.Funk and K. P. C. Vollhardt, Chem. Soc. Rev., 1980,9,41;(6,G. Brieger and J. N. Bennett, Chem. Rel;., 1980,80,63;(e) D.F. Taber, ‘Intramolecular Diels-Alder Reactions and Alder Ene Reactions’, Springer Verlag, New York,1984;(f)E.Ciganek, Org. React., 1984,32,1; (g)A. G. Fallis, Can.J. Chem., 1984,62, 183; (h)M.P.Edwards, Ph.D thesis, University of London, 1982.For a review on mechanistic aspects of the Diels-Alder reaction, see R.Sustrnann and J. Sauer, Angew. Chem., Int. Ed. Engl., 1980,19, 779. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction Since the large majority of recorded uses of the IMDA reaction has resulted in the construction of bicyclo[4.3.0] and bicyclo[4.4.0] ring systems, rather than the possible (though rarely observed) bridged isomers, the review is split into two main sections dealing with each of these topics; further classification into carbo- and heterocyclic ring synthesis is made within each category. 2 Carbocyclic Systems A. Bicyclo[4.4.0]decanes.-IMDA reactions of 1,3,9-decatrienes may proceed via four distinct transition states, giving rise to product types as depicted below. It should be noted that the terms endo- and exo- refer to the orientation of the dienophile-activating group with respect to the diene function.chair * trans-fusedw--X=dienophile-activating group chair es--cis -fused boat (i) Unsubstituted and Terminally Substituted Trienes. Despite the simplicity and ready availability of the IMDA reaction substrate, studies on the cyclization of (a-deca-1,3,9-triene (1) have only recently a~peared.~ Houk and Lin observed that (1) cyclized with very low levels of stereocontrol to give mixtures of cis- and trans-fused bicyclo[4.4.0]dec-2-ene, with product ratios tending towards unity with increasing temperature (equation 1). Y.-T.Lin and K. N. Houk, Telrahedron Lett., 1985, 26, 2269. Craig The small preference for the formation of the cis-fused product in these reactions, taking into account their irreversibility suggests the activation energy for formation of the trans-product to be some 0.3 kcal mol-' higher than for the cis-isomer, as predicted by calc~lations.~~~ Theoretical methods showed the trans- isomer to be 2 kcal mol-' more stable than the cis-,' suggesting that product stabilities may be of limited use in predicting the stereochemical course of IMDA reactions. Substitution of an electron-withdrawing group at the dienophile terminus of 1,3,9-decatriene had little effect on the observed stereoselectivity of the cyclization, although lower temperatures were required for the reaction to proceed, presumably due to a lowering of the energy of the dienophile LUM09 by the ester function (equations 2 and 3)." E!XI 155°C 94% - (2) (21 E 51 49 E = CO,CH, & H (31 H E E 51 49 Dienophile geometry exerted no effect on the product ratio, the marginally major product resulting from a chair-like endo-transition-state for the cyclization of the E,E-triene (2), and from a chair-like em-transition-state for the isomeric triene (3) (Scheme 1).ts-tz-Scheme 1 Secondary orbital interactions are clearly unimportant in determining product ' Products were recovered unchanged after resubjection to thermolysis conditions. 'C. C. Browne and F. D. Rossini, J. Phys. Chem., 1960, 64, 927.'S.-J. Chang, D. McNally, S. Shary-Tehrany, M. J. Hickey, and R. H.Boyd, J. Am. Chem. Soc., 1970,92, 3109.'N. L. Allinger, J. Am. Chem. Soc., 1977, 99, 8127. 1. Fleming, 'Frontier Orbitals and Organic Chemical Reactions', Wiley, Chichester, 1978. lo W. R. Roush and S. E. Hall, J. Am. Chem. SOC.,1981, 103, 5200. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction ratios in these kinetically controlled processes, demonstrating the limited use of the endo-rule in predicting the outcome of thermal reactions. This parallels similar observations in the bimolecular case, where endo-selectivity falls rapidly with increasing temperature. 11,12 Attempts to increase the proportion of the product arising from an endo-transition-state by Lewis acid catalysis resulted only in diene polymerization.Addition of an alkyl substituent to the diene terminus of methyl 2,8,10-decatrienoates left the product ratio from E,E,E-isomer (4) unchanged, although the geometric isomer (5) showed a small bias towards the formation of the trans- fused product (equations 4 and 5).13 16OoC,48h -ipr@i;r*,@ (4)69% iP E E(4) 50 50 E = CO,CH, This small difference in selectivity between (4)and (5) may point towards non- bonded interactions between the terminal diene substituent and the ester grouping in the endo-transition-state leading to the cis-fused bicyclic system from (5) (Scheme 2). Scheme 2 Much more pronounced cis-selectivity was observed in the cyclization of the terminally substituted decatrienoate ester (6) in which formation of the trans- isomer was disfavoured by similar steric effects in the endo-transition-state (equation 6).14 The triene (7), in which an electron-rich diene and an electron-deficient J.Sauer, Angen. Chem., Inr. Ed. Engl., 1967,6, 16. If J. G. Martin and R. K. Hill, Chem. Rev., 1961, 61, 537. l3 W. R. Roush and H. R. Gillis, J. Org. Chem., 1982, 47, 4825. l4 B. S. Joshi, N. Viswanathan, D. H. Gawad, V. Balakrishnan, and W. Philipsborn, Helu. Chim. Actu, 1975, 58, 2295. Craig dienophile are present in the cyclization substrate showed a slight preference for formation of the trans-isomer, seemingly at variance with the result shown in equation 6 (equation 7).15 benzene (7)40"C -Et,N &&..@ E E (7) E = C0,Et 55 45 From a comparison of the thermal conditions required to effect cyclization of trienes (2) and (3), (4) and (5), and (7), it can be seen that a bulky terminal diene substituent attenuates IMDA reactivity whilst a strongly electron-donating group has a rate-enhancing effect.The slight bias towards reaction via an endo-transition- state exhibited by triene (7) may reflect the involvement of secondary orbital interactions at lower temperatures. Unlike unsubstituted trienes (2) and (3), (4) and (5) reacted with high stereoselectivity when treated with Lewis acids (equations 8 and 9).13 endo-Specificity resulting from Lewis acid-enhanced secondary orbital interactions was also exploited in the cyclization of a$-unsaturated amide (8) in the presence of zinc chloride (equation 10).l6 68%(4 t 88 : 12 0 EtAIC12 I CH2C12 -trans-: cis-23"C, 2h (5) t <8 : >92 (91nx TMSCI, Et,N, ZnClt Q@ , 180°C W CH3 (lo) 52% E= C0,Et Is T.-C.Wu and K. N. Houk, Tefrahedron Let!., 1985, 26, 2293. l6 M. Ihara, T. Kirihara, A. Kawaguchi, K. Fukumoto, and T. Kametani, Tetrahedron Lett., 1984,25,4541. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction Zinc may serve the additional role of forming a chelate-type structure uia co- ordinationofthe heterodienol ether andestercarbonyloxygensasshownin Scheme 3. Lithium-chelated species such as (9a) have been invoked to account for the trans- specificity observed in the cyclization of the enone (9) (equation 1l)." Scheme 3 t CHMDS ,THF * "*@ (11) 60% When a trans-fused cyclohexane ring was incorporated into the tether connecting diene and dienophile, the resulting 1,2-diequatorial arrangement of the b-1;? q$pMe0,C-.\ LHMDS, hexane-60% Et20 (12) H C02Me " M. Ihara, M. Toyota, K. Fukurnoto, and T. Karnetani, TetralredrortLett., 1984,25,2167; ibid.,1984,25, 3235. Craig ring gave a product arising from attack by the a$-unsaturated ester moiety at a single diastereoface of the dienolate (equation 12). * Lewis acid-catalysed IMDA reactions via endo-transition states have found application in asymmetric synthesis where extremely mild conditions and highly ordered, reactive intermediates are essential prerequisites for efficient diastereofacial selection.l9 Cyclization of optically pure triene (10) occurred with complete endo- and very high diastereofacial selectivity to yield the trans-fused product (11) (equation 13).20 Me,AICI (1-4 eq .) 94%d.e.(4 Shielding of one face of the rigid chelated intermediate (12) as a result of 7c-stacking interactions between the aromatic group at the 4-position of the chiral oxazolidone function and the dienophile was used to explain the observed selectivity. Thermal reaction of (10) gave a 1 : 1 mixture of cis-and trans-bicyclic products. \/ Similar high levels of stereocontrol have been realized through the use of optically pure camphor-derived N-acyl sultams in asymmetric IMDA reactions2 Substitution of an electron-withdrawing group at the diene terminus gave a 1 : 1 mixture of cis-and trans-cyclization products, whilst attempted Lewis acid- catalysed cycloaddition of triene (1 3) resulted in polymerization (equation 14).22 (13) 1 1 M.Ihara, M. Toyota, K. Fukumoto, and T. Kametani, Tetrahedron Lett., 1985, 26, 1537. l9 For a review of the asymmetric Diels-Alder reaction, see W. Oppolzer, Angew. Chem., hi. Ed. Engf., 1984, 23,876. 2o D. A. Evans, K. T. Chapman, and J. Bisaha, Tetrahedron Lett., 1984,25, 4071. 21 W. Oppolzer and D. Dupuis, Tetrahedron Left., 1985, 26,5437. ” K.N. Houk and Y.-T. Liu-Tetrahedron Lett., 1985, 26,2517. 193 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction The smaller effect of the presence of an electron-withdrawing group on the diene rather than the dienophile terminus was attributed to the smaller effect of such a group on the HOMO coefficients of the diene than on the LUMO coefficientsof the dienophile 23*24 (videinfra).The presence of an electron-withdrawing group within the chain linking diene and dienophile caused a bias towards cis-fused products arising uia an endo- transition-state (equation I 5).25 + trans-isomer (15)cyclisation occursoxidise fQ-in situ Q --OH (at or below room cis-: trans-temperature) --=60:40 to 95:5 Since some of the oxidation reactions were carried out in acidic media, it seems probable that enhanced secondary orbital interactions arising from protonation of the ketone oxygen were responsible for the observed endo-selectivity.Placement of an isopropyl group on the dienophile terminus resulted in complete endo- selectivity, presumably due to unfavourable non-bonded interactions between the alkyl substituent and the diene in the alternative exo-transition-state. In contrast, fluoride-initiated cyclization of tetraene (14) gave the trans- decalone (15) as the sole product (equation 16),26 presumably as a consequence of base-catalysed isomerization of the initially-formed cis-fused isomer. H KF ,CHSOH 62% OSiEt3 The observation that the analogous reaction in [2H,]methanol did not result in any deuterium incorporation in (15) would seem to be at variance with the proposed intermediacy of ketone (16), however. Trienes containing an internal dienophile-activating group and possessing an 23 K.N. Houk, J. Am. Chem. SOC.,1973,95,4092. 24 K. N. Houk, J. Sims, C. R. Watts, and L. J. Luskus, J. Am. Chem. SOC.,1973, 95, 7301. 25 J.-L. Gras and M. Bertrand, Tetrahedron Lett., 1979, 20, 4549. See also: 0.P. Vig, I. R. Trehan, and R. Kumar, Ind. J. Chem., Sect. B, 1977, IS,319; 0.P. Vig, I. R. Trehan, N. Malik, and R. Kumar, ibid., 1978, 16, 449. 26 W. Oppolzer and R. L. Snowden, Tetrahedron Leu., 1976, 17, 4187. Craig allenic terminal diene substituent showed enhanced cis-/endo-selectivity when the IMDA reaction was carried out in the presence of a Lewis acid (equation 17).27 &-s Y TBDMS H 51,CH,CI, (17)T6DMso~5 Et,AICI % a I* 0 0 1 2 The analogous thermal reaction gave a 1 : 1 mixture of products.Although this method accomplished the introduction of an angular methyl group in the trans- fused product, substitution of a methyl group at C-7 resulted in preferential [l,5] sigmatropic hydrogen shift 28 to give the conjugated triene. Tetraenes in which the allenic double bond is within the incipient 6-membered ring underwent IMDA reactions in which a single isomer was formed, regardless of whether the dienophile- activating group was at the chain terminus or within the newly formed cycle. Thus (17) cyclized to give only two out of four possible diastereomeric products (equation Allenic tetraene (18) similarly gave a single diene upon thermolysis (equation 19).30 Presumably the alternative transition-state (19) leading to the isomeric product ’’H.J. Reich and E. K. Eisenhart, J. Org. Chem., 1984, 49, 5282. 28 W. H. Okamura, Acc. Chem. Res., 1983, 16, 81 and references cited therein. 29 G. E. Keck and D. F. Kachensky, J. Org. Chem., 1986, 51, 2487. For closely related work see: E. A. Deutsch and B. B. Snider, J. Org. Chem., 1982, 41, 2682; Tetrahedron Lett., 1983, 24, 3071. 30 B. B. Snider and B. W. Burbaum, J. Org. Chem., 1983, 48, 4370. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction (20) was disfavoured due to non-bonded interactions between H-5 and H-9. (ii) Trienes Containing Internal Olefin Substituents. In sharp contrast to 1,3,9- decatriene, 3-methyl- 1,3,9-decatriene cyclized at 160 "C to give trans-2-methyl- bicyclo[4.4.0]dec-2-ene as the only product in 95% yield.31 Addition of a further methyl substituent at the 9-position of the triene substrate severely attenuated reactivity; whilst the trans-fused ring system was the only cycloadduct isolated, the low (30%) yield presumably arose from competing polymerization/decomposition of starting material under the somewhat harsh reaction conditions.The exclusive formation of trans-product may be attributed to the development of severe non- bonded interactions in the transition-state (21) leading to the cis-isomer. Although substituted triene (22) gave predominantly the trans-fused bicyclic 100°C I -10h 72% % 18O0cI 24h \ moderateyield 1 2(231 31 S. R. Wilson and D. T. Mao, J. Am.Chem. SOC.,1978,100,6289. See also S. R. Wilson and J. C. Huffman, J. Org. Chem., 1980, 45, 560. 196 Craig product upon thermolysis (equation 20), the methylated analogue (23) yielded more of the corresponding cis-isomer (equation 21).32 The tendency towards formation of the cis-product when the dienophile was internally substituted may indicate the presence of non-bonded interactions between the C-3 and C-9 methyl groups in the transition-state (24) giving rise to the trans-fused product; the presence of the fused benzene ring forces the linking chain to adopt a boat-like conformation. O-Quinodimethane species (25) and (26) reacted to give trans-fused tricyclic species with varying stereoselectivity depending on whether or not the internal dienophile was activated (equations 22 and 23).33 [&] -842-65”/0 + (22) 5 1 HEAT The highly reactive triene (27) cyclized at low temperatures to yield exclusively the rrans-fused tricycle, formation of the cis-isomer being disfavoured by non- bonded interactions between the axial C-6 proton and the methylene bridge linking b 6 benzene, 5ouc ~ TBDMSO high yield (23 E 32 S.R. Wilson and D. T. Mao, J. Org. Chem., 1979,44,3093.For a counter-example see D. F. Taber and S. A. Saleh, J. Am. Chem. SOC.,1980, 102,5085. See also S.R. Wilson and R. N. Misra, J. Org. Chem., 1980,45, 5079. 33 K. C. Nicolaou, W. E. Barnette, and P. Ma, J. Org. Chem., 1980,45,1463. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction C-9 and (2-10 (equation 24)34 in a transition-state in which a chair-like linking chain is oriented exo-with respect to the diene.Cyclization of tetraene (28) occurred with regioselectivity depending on the nature of the carboxyl function and the solvent to give only trans-fused products (equation 25).35 E$4 PhMe, 1a"C l8h,80% E H + p (25) E' E = C0,Et When the cyclization was carried out in boiling water, a 2: 3 mixture of (29) and (30) was obtained. This was ascribed to coiling of the lipophilic non-carboxylated diene moiety 36 so as to adopt a conformation disposed towards diene-like rather than dienophilic reactivity. If the free acid or sodium salt corresponding to (28) was cyclized in boiling water, the products corresponding to (29) and (30) were formed in a ratio of 1:8.The predominant formation of (29) in toluene reflects the decreased dienophilic reactivity of trisubstituted olefins. A single diastereomer of (29) arose from the preferred transition-state in which the C-8 methyl group was equatorial in a chair-like linking chain (vide infra). Greater flexibility in this approach may be realized by the use of a removable bulky C-3 diene substituent. Thus cyclization of (31) at elevated temperatures gave a single trans-fused diastereomer (32) (equation 26).37am -5180"C, 24h R ~o-'M, 89% R-E R= (cH2)JoBn (32) 34 A. P. Kozikowski and S. H. Jung, Tetrahedron Lett., 1986, 27, 3227. 35 D. R. Williams, R. D. Gaston, and I. B. Horton 111, Tetrahedron Len,1985, 26.1391. D. R. Williams, M. C. Bremner, D. L. Brown, and J. d'Antoniono, J. Org. Chem., 1985, 50, 2807. 36 D. C. Rideout and R. Breslow, J. Am. Chem. SOC.,1980, 102, 7816. 37 R. K. Boeckman, jun. and T. E. Barta, J. Org. Chenr., 1985, 50, 3241. Craig The trans- and diastereospecificity resulted from the favouredness of transition- state (33) in which non-bonded interactions and A1,3 strain 38 were minimized by the equatorial disposition of the OMOM group in the chair-like linking chain. Although triene (31) was much less reactive towards cyclization than the 'desilylated' analogue,'O the observed specificity represented a 600-fold increase (vide infra). Removal of the trimethylsilyl stereocontrol group was readily accomplished in high yield.Use of bromine instead of silicon at the appropriate position of the diene was less effective in controlling the stereochemistry at the ring junction, although cis-and trans-products (34) and (35) were both formed as single diastereomers (equation 27).39 + R. E= COF R= CH=CHCH,OTMS 55 Formation of cis-fused (35) may proceed via a transition-state (36) in which the benzyloxy group is axial, presumably so as to minimize non-bonded interactions with the bulky halogen. Alternatively a boat-like transition-state (37) may be implicated (vide infra). OBn R-(iii) Trienes With Substituents on the Linking Chain. Substituents within the tether linking diene and dienophile may influence the diastereoselectivity of dienophile addition to the non-equivalent diene faces.Triene (38) derived from (3R)-(+)-citronellol gave a 1:1 mixture of cis-and trans-fused products upon thermolysis, each as a single diastereomer (equation 28).40 The assignment of structure (39) is however questionable, since it would arise via a transition-state (40) in which the C-6 methyl group experiences serious non- bonded interactions with H-9. A likely alternative is (42), arising from the more favoured transition-state (41), although formation of (39) could arguably proceed through a boat-like transition-state in which the C-6 methyl group is pseudo- equatorial. Heterodiene (43) displayed similar diastereospecificity in giving a product 38 F. Johnson, Chem. Rev., 1968, 68,375.39 W. R. Roush and M. Kageyarna, Tetrahedron Lett., 1985, 26, 4327. 40 T. K. M. Shing, J. Chem. Soc., Cliem. Commun., 1986, 49. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction PH Me t-BuO,C bearing an equatorial substituent in the newly formed saturated ring (equation 29).41 Cyclization of dimethylated triene (44)proceeded to give exclusively the product in which the methyl substituents in the newly formed ring were equatorial (equation 30).42 Contrastingly, when the substituents at the corresponding positions were connected to each other, cyclization occurred via a transition-state in which these groups were necessarily 1,3-diaxial (equation 3 i).43 4' J. J. Talley, J. Org. Chem., 1985,50, 1695. See also: G.Sheldrick, Angew. Chem., Int. Ed. Engl., 1980, 19, 134; L. Tietze and G. V. Kiedrowski, Tetmhedron Let(., 1981, 22, 219. 42 A. Ichihara, H. Kawagishi, N. Tokugawa, and S. Sakamura, Terrahedron Lett., 1986, 27, 1347. 43 A. Davidson, C. D. Floyd, A. J. Jones, and P. L. Myers, J. Chem. Soc., Chem. Commun., 1985, 1662. Craig PhMe, 140'C 0 Me0,C 37h1 85% *Me02Cy OMe The cyclic triene (45) gave exclusively the cis-fused tricycle (46) upon thermolysis, in keeping with some other trienes bearing an internal dienophile-activating group (ode supra) (equation 32).44 QMe 0 (45) The observed stereospecificity for the endo-transition-state, in spite of the proximity of the axial C-6 methoxy function to the C-3 methyl substituent, may indicate more serious non-bonded interactions between the latter and the C-5 methoxy and C-9 substituents in the alternative exo-arrangement, as described above (Scheme 4).When the C-3 diene substituent formed part of a flat, conjugated x-system as in 44 K. Shishido, K. Takahashi, Y. Oshio, K. Fukumoto, T. Kametani, and T. Honda, Tetrahedron Lett., 1986, 27, 1339. 201 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction \ vs. Scheme 4 (47), selectivity was reversed, with the ratio of exo-to endo-cyclization products (48) and (49) reflecting the differing steric demand of the group (equation 33).45 (47) (48) (49) 6 1 If the C-6 methoxyl group in (45) was replaced by a much more sterically demanding pivaloyloxy group as in (SO), only the trans-fused tricyclic product (51) was formed upon Lewis acid-catalysed cyclization (equation 34).46 Me,&, CH,CI, Me0 (34) The oxaethano bridge linking C-7 and C-9 in (50) ensured that the bulky C-6 substituent was constrained in an axial disposition.Lewis acid complexation of the enone oxygen may also have served to destabilize the endo-transition-state via Lewis aciddiene non-bonded interactions. Incorporation into a rigid cyclic system of substituents bearing a vicinal PMOM PhMe, sealed tube 220°C,100h, 100% (35) 45 K. Shishido, T. Saitoh, K. Fukumoto, and T. Kametani, J. Chem. Soc., Chem. Commun., 1983, 852; J. Chem. Soc., Perkin Trans. I, 1984,2139. 46 R. H.Schlessinger, J.-W.Wong, M. A. Poss, and J. P. Springer, J. Org. Chem., 1985,50, 3950. Craig relationship resulted in cyclization of the steroidal intermediate (52) to give almost entirely the trans-fused product (equation 35).47 The minor (ca. 20%) amounts of cis-fused products probably arose from contamination of starting material by some Z-triene (vide infra). Oxidation of allylic alcohol (53) using Jones's reagent gave the corresponding enone which spontaneously cyclized under the reaction conditions (equation 36).48 Y H2Cr207,Et,O Q"C,87% 9 1 Whilst the endo-specificity resulted from secondary orbital interactions becoming significant under the acidic condition^,^^ the observed diastereoselectivity indicates a boat-like transition-state in which the bulky isopropyl group is pseudoequatorially disposed (Scheme 5).hJ.-i-Pr product disfavoured Scheme 5 Almost complete endo-selectivity was observed in the cyclization of bicyclic triene (54) in the presence of acid (equation 37).50 PTBDMS TFA, -78OC c 70% + epimer at C -(96:4) When carried out under thermal conditions, the cyclization gave a 3:2 ratio of products, which may imply non-bonded interactions between the dienophile methyl substituent and the methylene unit attached to C-3. Cyclization onto the a-face of the diene resulted from the x-disposition of the side-chain bearing the dienophilic group. 4' M. Ihara, I. Sudow, K. Fukumoto, and T. Kametani, J. Chem. SOC.,Perkin Trans. 1, 1986, 117; J. Org. Chem., 1985, 50, 144.48 D. F.Taber and B. P. Gunn, J. Am. Chem. SOC.,1979, 101, 3992. 49 K. N. Houk and R. W. Strozier, J. Am. Chem. SOC.,1973, 95, 4094. so G. Stork, G. Clark, and C. S. Shiner, J. Am. Chrm. SOC.,1981, 103, 4948. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction Cyclization of the furan (55) was found to be reversible: the ratio of (56) to (57) after six days at room temperature was 8: 1 (61% conversion), whereas heating in boiling benzene for the same time gave a 1 :9 product ratio (50% conversion) (Scheme 6).51 kinetic thermodynamic/I #OX OHL 1 X =TBDMS Scheme 6 Due to the presence within the linking chain of the dienophile-activating group, bond formation between the diene and dienophile termini is at a more advanced stage than internal bond formation in the transition-state. Calculations show 52 that the most stable conformation of the resulting pseudo-ten-membered ring is the boat-chair-boat arrangement giving rise to the kinetic product (56).The reversible nature of the reaction precludes formation of the highly strained products arising from endo-addition of the enone to the furan.This concept of asynchronous bond formation in Diels-Alder reactions will be discussed in more detail below. Strikingly, cyclization of the free alcohol corresponding to (55) was effected by shaking in cold water for 10 min to give exclusively the kinetic Thermolysis of the 3-substituted triene (58) gave a 3.5: 1 ratio of trans- and cis- fused products in which the trans-product consisted mainly of the isomer bearing the axial oxygen substituent (equation 38).54 Use of Lewis acid catalysts resulted in the exclusive formation of (59).The ” L. A. Van Royen, R. Mijngheer, and P. J. de Clercq, Tetrahedron Lett., 1982,23,3283; Bull. SOC.Chern. Belg., 1984, 93, 1019. See also P. J. de Clercq and L. A. Van Royen, Synrh.Cornrnun., 1979, 9, 771. 52 J. B. Hendrickson, J. Am. Chem. SOC.,1964, 86, 4854; ibid., 1967, 89, 7036. 53 L. A. Van Royen, R. Mijngheer, and P. J. de Clercq, Tetrahedron Lett., 1983,24,3145; Tetrahedron, 1985, 41, 4667. 54 R. L. Funk and W. E. Zeller, J. Org. Chem., 1982, 47, 180. 204 Craig preference to form the product in which the t-butyldimethylsilyloxy group is axial was ascribed to a minimization of non-bonded interactions between H-2 and the H-4 substituent, and to the involvement of a transition-state in which the C-4-0 bond is orthogonal to the plane of the adjacent double bond, thereby maximizing ~*~-~-n*overlap and lowering the energy of the dienophile LUMO.With an aldehyde group at the dienophile terminus, Lewis acid-catalysed cyclization proceeded extremely rapidly at low temperatures to give the trans-fused isomer with an axial oxygen substituent as the only product.55 Similar reactivity was displayed when the substituent was allylic with respect to the diene (equation 39), although the nature of the oxygen protecting group had a profound effect on the observed dias tereoselec tivi t y (equation 40).OTBDMS OTBOllllS -78"--40°C OHC (39) (!4 F' Me,AICI, CH,CI, 'GI OHC OR' -78"-90%-23°C R' R@ (40) CHO CHO R=(CH2),0Bn R'z OMOM R'=OTBDMS 95 : : 55 5 Thermal reactions of carboxylic esters corresponding to (60) gave mixtures of cis-and trans-fused isomers depending on dienophile geometry. Thus whilst both E-and 2-dienophilic trienes cyclized to give predominantly cis-fused products in which the preference was for an axial C-7 substituent, E-dienophilic trienes showed 55 (a)J. A. Marshall, J. E. Audia, J. Grote, and B. G. Shearer, Tetrahedron, 1986,42,2893; (6)J. A. Marshall, J. E. Audia, and J. Grote, J. Org. Chem., 1984,49, 5277. See also M. Hirama and M. Uei, J. Am. Chem. Snc., 1982, 104, 4251.Stereochemical Aspects of the Intramolecular Diels-Alder Reaction a tendency towards equatorial C-7 substitution in the trans-isomers, and the Z-isomers towards axial groups at this position." All of the observed selectivities were low, however. The presence of two oxygen substituents at the 7-position resulted in the predominant formation of cis-fused products (equation 4 1). 1 4 Presumably Al,3 strain in the transition-state (61) leading to the trans-product disfavours its formation. Cyclization of diene (62) gave a ca. 2:l mixture of trans- and cis-products (equation 42)." Coplanarity of the C-0 bond with the diene favours the trans- transition-state and lowers the energy of the diene HOMO, explaining the decreased reactivity of (62).0 E =CO,Me E --65 35 conjugated isomers The acetylenic ester (63) cyclized to give a ca. 2: 1 mixture of diastereomers (equation 43).56 The major product presumably arose from a minimization of steric effects in the necessarily boat-like transition-state (64). A methyl substituent at the C-4 position of enal(65) exerted a powerful directing influence on the mode of cyclization in the presence of Lewis acid (equation 44).57 Addition of a C-2 methyl substituent did not affect this specificity, although the more substituted triene was less reactive than (65). The tendency for the C-4 56 S. E. Hall and W. R. Roush, J. Org. Chern., 1982, 47, 4611. For a related case in which no diastereoselectivity was observed, see S. D. Burke, T.H. Powner, and M. Kageyama, Tetrahedron Lett., 1983, 24, 4529. 57 J. A. Marshall, J. E. Audia, and J. Grote, J. Org. Chem., 1986, 51, 1155. Craig OMEM OMEM 165"C,50h (431R' @ R@ C02CH&CI3 COzCH,C13111 Rr"?' 95% nI 7 3 R= OYO (43 A EtAICI, , CHZCI, -78"--23" C, lh 82%OHC OHC (65) substituent to adopt an equatorial disposition was unchanged by the presence of an axial methyl group at C-6 (equation 45). EtAIC12 CHZCI,-78"--23°C -& 05)OHC 70% tLOH6 The observed stereoselectivity was correctly predicted by calculations of the energies of the diastereomeric trans-products, implying a late or product-like transition-state. B. Bicyclo[4.3.0)nonanes.-l,3,8-Nonatrienes may cyclize via two alternative transition states to form trans- or cis-fused bicycloC4.3.01 products.(i) Unsaturated and Terminally-substituted Trienes. Unlike the unsubstituted higher homologue, (0-1,3,8-nonatriene cyclized with moderate selectivity to form a ca. 3: 1 mixture of cis-and transfused products (equation 46).4 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction endp-t trans- fused -X=dienophile-activating group t -cis-fused 73 27 150"C, 24h +*@ @ (47)65% 60:40 E E 180°C , 5hp -@ ..a(48)75% i 65:35 EE lSO"C, +72%40h i -Pr-@(49) i -PrG) ;-Pr f$ E E 72:28 180°C ,5h &i -Prp -75% i-Pr i -Pr*' (50) IH iIH eqs.47-50 : E=CO,CH, E 6733 Craig Whilst the major isomer is thermodynamically more favoured, the kinetically controlled nature of the cyclization was demonstrated by the recovery of unchanged bicyclic products after separation and re-subjection to the thermolysis conditions.With a terminal carboxylic ester as the dienophile-activating group, trans-selectivity was observed (equations 47 and 48); 58 the presence of a terminal diene substituent resulted in a small increase in the proportion of trans-product formed (equations 49 and 50). As with the decatriene case, dienophile geometry did not greatly affect the stereoselectivity of cyclization. E,Z-Diene (66) gave only the cis-fused isomer upon thermolysis, reacting at a rate comparable to that of the corresponding E,E-geometric isomer (equation 51).2cThe latter result contrasted with the differing reactivities in intermolecular Diels-Alder reactions which was used as a means of obtaining pure (66) from a mixture with the E,E-isomer.Cyclization of the nitrotriene (67)proceeded more rapidly and with greater trans-selectivity than the corresponding carboxylic ester, though the Z,E,E-isomer gave a ca. 1 : 1 mixture of products (equations 52 and 53).59 PhH , 80°CQ 30h, 64"h O2N (67) H H Lewis acid-catalysed IMDA reaction of E,E-triene (68) resulted in exclusive formation of the trans-fused bicyclic product (equation 54) whereas the E,Z-isomer (69) cyclized in low yield with poor stereoselectivity (equation 55).58b*60 The same trends were observed for the less reactive trienes in which the diene was terminally substituted, and reflect the insufficient magnitude of Lewis acid- H EtAICI,, CH,CI, ,23"C, 36h E 60X (4 E=COzCH3 E '' (a)W.R. Roush, A. I. KO,and H. R. Gillis, J. Org. Chem., 1980,45,4264; (b)W. R. Roush, H. R. Gillis, and A. I. KO, J. Am. Chem. Soc., 1982, 104, 2269. 59 M. J. Kurth, M. J. O'Brien, H. Hope, and M. Yanuck, J. Org. Chem., 1985, 50, 2626.''W. R. Roush and H. R.Gillis, J. Org. Chem., 1980, 45,4267. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction same conditions t &) & (55)27% E E 'H 52:a i'H enhanced secondary orbital interactions to overcome the tendency of 1,3,8-nonatrienes with this substitution pattern to form trans-fused products. Lewis acid-mediated cyclization of the enamide (69) occurred with good stereoselectivity, again presumably via a chelated intermediate (vide supra) (equation 56).61 Bronsted acid-catalysed cyclization of tetraene (70) gave a single bicyclic diene via an endo-transition-state (equation 57),62 although a stepwise, cationic mechanism may also explain this transformation.H TfOH,C H,CI, ,-23 "C 6min,88" A related transition-state was invoked to explain the exclusive formation of the trans-fused product in the hydrofluoric acid-mediated cyclization of (71) (equation 58).63 M 61 M. Ihara, T. Kirihara, K. Fukumoto, and T. Kametani, Hererocycles, 1985. 23, 1097. 62 P. G. Gassman and D. A. Singleton, J. Am. Chem. Soc., 1984, 106, 6085. 63 W.R. Roush, H. R. Gillis, and A. P. Essenfeld, .I.Org. Chem., 1984, 49, 4674. 210 Craig The failure of the methyl ether corresponding to (71) (TBDMS = Me) to cyclize under the same conditions indicated the intermediacy of a 1,3-dioxolenium cation which directed the subsequent endo-specific ring closure (Scheme 7). Scheme 7 (ii) Trienes Containing Internal OZefin Substituents. Substituted trienone (72) was first reported 64 to give only the cis-fused indenone upon thermolysis, although a later paper described more modest selectivity (equation 59). PhH, 190 C, 13h f& + (59) 100% 7 0 (72) 3 The non-coplanarity of the carbonyl group with the dienophile in the conformation required for orbital overlap with the diene to occur was used to account for the high temperatures needed to effect cyclization, although the C-8 methyl group may also attenuate reactivity.The preponderance of cis-fused product resulted from more advanced peripheral carbon-carbon bond formation in the transition-state, which adopts the more stable cis-skewed conformation of the pseudo-nine-membered ring (vide infra). The tendency towards predominant 64 J. J. S. Bajorek and J. K. Sutherland, J. Chem. Soc., Perkin Trans. 1, 1975, 1559. 65 M. E. Jung and K. M. Halweg, Tetrahedron Left., 1981, 22, 3929. 211 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction formation of cis-products from trienes having an internal dienophile activating group was reversed, however, in the case of triene (73) (equation 60).66 Since the Z-isomer of (73) may only form the cis-fused product upon cyclization (vide supra), the E-isomer actually gave a 20: 1 ratio of trans- to cis-fused products, a consequence of unfavourable non-bonded interactions in the transition-state (74) leading to the latter.Similar reactivity was exhibited by the triene (75) substituted at C-3 of the diene (equation 61).67 PhMe, %O0C 3h , 92% * (75) O The related substrate (76) showed much lower stereoselectivity in favour of the cis-isomer (equation 62).68 The greater proportion of cis-product formed from cyclization of (76) than from (75) presumably reflects the smaller steric bulk of an ethyl ester relative to a 1,3-dioxolane. Activation of the dienophile by two electron-withdrawing groups gave mixtures of trans- and cis-products with ratios depending on dienophile geometry (equations 63 and 64).69 The higher proportion of cis-product in the cyclization mixture of (77) may point towards steric interactions between the diene and the dienophile acetyl and methyl substituents in the trans-transition-state.The highly reactive doubly-activated triene (78) cyclized at low temperatures to give almost exclusively the trans-fused tricyclic product (equation 65).34 66 (a)K. Shishido, K. Airoya, K. Fukumoto, and T. Kametani, Tetrahedron Lett., 1986,27,1167. However, a trans:crs ratio of 3:7 has also been claimed for this cyclization; (b) D. F. Taber, C. Campbell, B. P. Gunn, and I.-C. Chiu, Tetrahedron Lett., 1981, 22, 5141.For a very recent example of high truns-selectivity resulting from a C-3 diene methyl substituent, see K. Takada, M. Sato, and E. Yoshii, Tetrahedron Lett., 1986, 21, 3903. '' A. Ichihara, R. Kimura, S. Yamada, and S. Sakamura, J. Am. Chem. SOC.,1980,102, 6353. 6a M. E. Jung and K. M. Halweg, Tetrahedron Lett., 1981, 22, 2735. "P. D. Williams and E. LeGoff, Tetrahedron Lett., 1985, 26, 1367. Craig 61"C, 72h87% -Q Q (63) AC iC 83 17 llO°C, 180h -6Q (64)+ AC AC 50 50 50°C , 3h -btrans-: cis-(65) xo% >mx X =20:1 E (78) The high selectivity resulted from non-bonded interactions between the C-8-C-9 trimethylene bridge and the linking chain disfavouring the cis-transition-state, and from advanced internal (i.e. C-3-C-7) bond formation in the transition-state favouring the trans-pseudo-cyclopentane ring.(iii) Trienes Containing Substituents in the Linking Chain. Trienes which are disubstituted alpha to the dienophile exhibit enhanced trans-selectivity as a consequence of unfavourable steric buttressing between the bulky geminal substituents and the group at C-3 of the diene. Thus, ketal(79) afforded a ca. 2.5: 1 mixture of trans- and cis-products upon thermolysis in contrast with the related enone (vide supra) (equation 66).65 PhMe ,24h + (66) MeO "w-OMe Me 72 28 The 1,3-dioxane corresponding to (79) gave a similar product mixture,70 whilst a related 1,3-dithiane was less stereoselective (equation 67).7 'O S.A. Bal and P. Helquist, Tetrahedron Lett., 1981, 22, 3933. M. E. Jung and K. M. Halweg, Tetrahedron Lett., 1984,25, 2121. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction 17OoC , 24h 96% 53 47 Dienophile-activated trienes bearing single substituents on the position allylic to the dienophile give mixtures of diastereomers on cyclization. E,E-Triene (80) showed moderate trans-selectivity, although diastereoselectivity for both isomers was poor (equation 68).72 Y H PhMe,24O0C,llh E Oh 67% pm(80> (81) Ratio @):(82)<@): (M) H M @:30:17:13 + + E: CO,CH, Ef83> OBn E (84) In contrast, E,Z-triene (85) showed enhanced trans-selectivity with both products being formed as single diastereomers (equation 69).72 22oOc ,m -& & (ss)+80% OBn OBn (=I E E 4 1 The diastereospecificity clearly resulted from a minimization of Al,3 strain between the ester and benzyloxy groups (Scheme 8).Such interactions are absent in the case of E,E-triene (80), accounting for the low diastereoselectivity; the poorer trans-selectivity may be a consequence of non- bonded interactions between the diene and the ester and the C-3 methyl substituent in the endo-transition-state (cf: equations 63 and 64). Activation of the dienophile by an internal electron-withdrawing substituent which was not part of the linking chain gave predominantly the cis-product 66b,72 despite the presence of a C-3 diene methyl substituent in one of the cases studied.Thermolysis of the substituted cyclopentenone (86) gave exclusively the product in which the newly formed ring junction was cis-oriented (equation 70).73 l2 W. R. Roush and S. M. Peseckis, J. Am. Chem. SOC.,1981, 103, 6696. l3 M. Ihara, A. Kawaguchi, M. Ihichiro, K. Fukumato, and T. Kametani, J. Chem. SOC.,Clzem. Commun., 1986, 671. Craig produd Scheme 8 WH EBBn I I I E=CO,CH, I I I I i This result contrasts with the normally observed tendency for trienes having this substitution pattern to form trans-ring fusions (e.g.equation 65),and may be due to interactions between the diene and the cyclopentenone ring disfavouring the expected endo-transition-state (87). A1.3 strain in the diastereomeric em-transition- state (88) precludes its involvement, and (89) is the preferred conformation.PhS (4 The thermal IMDA reaction of (go), in which the dienophilic group has the Z-geometry gave exclusively the product of em-addition with a trans-ring-fusion, PhMe ,230°C, 72h XOQ 81% (71) X=TBDMS (90) Stereochemical Aspects of the Intramolecular Diels-Alder Reaction the diastereofacial specificity of addition being determined by the stereochemistry at C-4 (equation 71).74 The E,Z-triene corresponding to (90) predictably gave the all cis-fused product (91) upon thermolysis. Enone (92) gave the endo-product (93) as a single isomer upon prolonged heating at high temperatures (equation 72).” 0(&,,, mesitylene, zooc t 0 50h, 47% AcO (93)(94 C-4 stereochemistry determined the diastereospecificity, whilst endo-selectivity was enhanced by diene-trimethylene ring steric interactions in the alternative exo-transition-state.Trienes substituted in the position allylic to the diene cyclize to give mixtures of trans-and cis-fused bicyclic products with varying diastereoselectivity. The terminally substituted triene (94) cyclized under thermal conditions to give mostly the trans-product with moderate diastereoselectivity for both trans- and cis-isomers (equation 73).76 H OBn i:pr.-qJi-Pr@ 115:%110h i -PrJ$ (73) (94) E(95) E (96) Ratio (95):(96) : (97): (98) + fJJ +J@$ 30:s : 13 : 4 i-pr.’ EH E E = CO,CH, (97) (98) 74 S. D. Burke, D. R.Magnin, J. A. Oplinger, J. P. Baker, and A. Abdelmagid, Tetrahedron Lett., 1984,25, 19. 75 K. Shishido, K. Hiroya, Y. Ueno, K. Fukumoto, T. Kametani, and T. Honda, J. Chem. Snc., Perkin Trans. 1, 1986, 829; Chem. Leii., 1984, 1653; K. Shishido, K. Hiroya, K. Fukumoto, and T. Kametani, .I.Chem. SOC.,Perkin Trans. 1, 1986, 837. 76 W. Roush, J. Org. Chem., 1979, 44, 4008; J. Am. Chem. Soc., 1978, 100, 3599: 1980, 102, 1390. 216 Craig The preferred trans-diastereomer resulted from destabilizing Al,3 strain in the alternative transition-state leading to (95), the same reason accounting for the 3 :1 ratio of (97):(98) (Scheme 9). E=C02Me Scheme 9 Cyclization of the isomeric substrate (99) again gave mixtures of products although the predominant trans-product was that in which the benzyloxy group was pseudo-axial.Similar product ratios were obtained upon thermolysis of E,E-nitrotriene (loo),and with a benzenesulphonyl group alpha to the diene complete trans-selectivity was realized with a 9 :1 diastereomeric ratio (equation 74),89 although the major product possessed a pseudo-equatorial benzenesulphonyl group. i-PrGn @(99) (100) O2N COOMe SO2PhPhMe,90°C, 25h -+,&gzphPh (74)0," 77% 'H P 41;" NO-Alkyl substituents at the diene allylic position also have a diastereo-directing influence on IMDA reactions. Triene (101)cyclized to give predominantly the trans-fused product in which the ethyl group was pseudo-equatorial, other isomers forming less than 10% of the product mixture (equation 75).77 endo-Selectivity was better with R = MEM than TBDPS,77" pointing towards the significance of non-bonded interactions between the terminal diene substituent ''((I) M.P. Edwards. S. V. Ley. and S. G. Lister. Tetrcihedrorl Lett.. 1981,22, 361; (h)K. C. Nicolaou and R. L. Magolda, J. Org. Client., 1981,46, 1506; (c)W. R. Roush and A. G. Myers, ihid.,1981,46, 1509. See also S. R. Attah-Poku, F. Chau, V. K. Yadav, and A. G. Fallis, J. Org. Chem., 1985, 50, 3418. 21 7 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction PhMe , 110”- 13OoC 270% (75) I‘ ‘A E = C0,Me RO E R = TBDPS, MEM and the ester in the endo-transition state. Substitution of a bulky trimethylsilyl group at C-8 resulted in diastereo- and endo-specific cyclization uia a transition- state (102) in which A1.3 strain and non-bonded interactions were minimized.37 +>--(102) t-BuO,C (iv) Trienes with geminal Substituents in the Linking Chain.1,3,8-Nonatrienes geminally substituted at the 6-position display enhanced reactivity in relation to the unsubstituted analogues. Trienes (103) underwent thermal IMDA reactions to give solely the trans-fused isomers (equation 76). 78 H 155”C, 1Oh 85% X E: C0,Me X=CO,R , CN, H (103) Isomerization of the double bond occurred under the reaction conditions to give the thermodynamically more stable isomer in which the unsaturation was ‘opposite’ the trans-ring fusion.79 The rate of cyclization was observed to be approximately four times greater than in the unsubstituted case, reflecting the smaller population of unreactive rotameric forms as a result of steric interactions with the geminal substituents.Interestingly, addition of a second ester group to (103) (X = COOR) resulted in a surprisingly small increase in the rate of cyclization; this was interpreted in terms of non-coplanarity of the two ester x-systems (steric inhibition of resonance). The use of very bulky E-dienophilic esters did not affect the trans-specificity, indicating the unimportance of non-bonded interactions between the ester and the butenolide methylene, in contrast to some of the findings described above. This was interpreted in terms of the asymmetric stretch mode of the asynchronicity of the IMDA reaction (uide infra).In contrast, the substituted 2-dienophilic triene (104) gave a 1:1 mixture of cis- and isomerized trans-products (equation 77).80 ” R. K. Boeckman, jun. and S. S. KO, J. Am. Chem. Sor., 1982. 104, 1033.’’(a) R. Burcourt, Bull. SOC.Chim. Fr., 1963, 1262; (b) A. A. Akhrem and A. Yu Titov, ‘Total Steroid Synthesis’, Plenum Press, New York, 1970, pp. 48--50. R. K. Boeckman, jun. and S. S. KO, J. Am. Chem. Soc., 1980, 102, 7146. Craig 1E=C0,Me 1 (104) The formation of some cis-fused product may indeed indicate non-bonded interactions between the acetoxymethyl group and the butenolide methylene in the exo-transition-state giving rise to the trans-fused product. Pure cis-fused tricyclic lactone was formed when the triene (105) was heated (equation 78).81 PhMe,ao %23OoC,32h -p?p(78) 0 hE OAc OAc (105) Compound (105)cyclized about forty times more slowly than the isomeric (104), although [1,5] sigmatropic hydrogen shifts *' did not compete significantly with the cyclization.That the position of the geminal substituents on the chain linking diene and dienophile is important was demonstrated by a comparison of the rates of cyclization of the substituted cyclopentadienes "(106) and (107) (equations 79).'3 160°C, 88h ry 100% 160°C, 2h zg$ 74% OEt EtO EtO (1071 10 1 The stereocontrolling influence of the ethoxyvinyl group allylic to the diene may '' R. K. Boeckman, jun. and T. R. Alessi, J. Am. Chem.Soc., 1982, 104, 3216. 82 D. D. Sternbach, J. W. Hughes, and D. F. Burdi, J. Org. Chem., 1984,49, 201. 83 (a) D. D. Sternbach, J. W. Hughes, D. F. Burdi, and R. M. Forstot, Tetrahedron Lett., 1983, 24,3295; (h)D. D. Sternbach, J. W. Hughes, D. F. Burdi, and B. A. Banks, J. Am. Chem. SOC.,1985,107, 2149. 219 Stereochemical Aspects of' the Intranzolecdar Diels-Alder Reaction be rationalized by a consideration of the diastereomeric transition-states (108) and (109j, of which (108) is preferred due to minimization of Al,3strain. &L OEt Whilst the substituted cyclopentadienes (106) may clearly isomerize via [1,5] hydrogen shifts, only the isomers shown undergo IMDA reactions. The exclusive formation of isomers in which the linking chain is exo-with respect to the diene is similarly ~ell-established.~~ Similar effects ascribable to geminal C-6 substituents were observed in the IMDA reactions of 2-substituted furans.The 1,3-dithiane function in (110) was crucial to IMDA reactivity, as its replacement with a benzyloxy and a methyl group rendered the furan unreactive (equation 80).85 PhH, <2days. 8OoC 100 % Catalysis of the reaction in aqueous medium using 0-cyclodextrin may have been a result of the forced proximity of the reacting centres in the catalyst cavity or of inclusion of the 1,3-dithiane group, generating the effect of two extremely bulky geminal substituents.86 The unique ability of the 1,3-dithiane moiety to accelerate these reactions may stem from its rigidity, and from the larger C-S bond length and smaller Van der Waals radius of sulphur uersus methyl, thereby minimizing non- bonded interactions with the substituent alpha to the diene.87 Cyclization studies of the furan (111j yielded information about the relative stereo-directing tendencies of substituents alpha to the diene and dienophile (equation 81).88 Rh PhH, Mac,2-4days + (89cS&80-95% 84 (a)E.J. Corey and R. S. Glass, J. Am. Chem. SOC.,1967, 89, 2600; (h) E. G. Breitholle and A. G. Fallis, Can. J. Chem, 1976, 54, 1991; J. Org. Chem., 1978, 43, 1964. n5 D. D. Sternbach and D. M. Rossana, Tetrahedron Lett.. 1982, 23, 303. "D. D. Sternbach and D. M. Rossana, J. Am. Chem. SOC..1982, 104, 5853. D. D. Sternbach, D. M.Rossana, and K. D. Onan, Trtmhedrorz Leri., 1985, 26, 591. 88 D. D. Sternbach. D. M. Rossana, and K. D. Onan, J. Org. Chem., 1984, 49, 3427. 220 Craig Less sterically demanding R and R’ groups gave mixtures of diastereomeric tricyclic products, but bulky groups such as tetrahydropyran-2-yl and benzyl promoted the exclusive formation of (1 12) via a transition-state (1 13) in which the C-8 substituent was pseudo-equatorial. OR A similar preference for a pseudo-equatorial OR’ group was displayed by the isomeric furan (1 14). It may be seen from the examples cited that bicyclo[4.4.0] and -[4.3.0] carbocyclic systems may be obtained with high levels of stereocontrol by the cyclization of an appropriately designed triene precursor. A summary of the general stereochemical features of these reactions is presented below. Bicydo[4.4.0J systems.Thermal cyclization reactions of unsubstituted or terminally substituted 1,3,9-decatrienes exhibit low stereoselectivities. For thermal reactions, product ratios are essentially independent of dienophile geometry; secondary orbital interactions do not control product stereochemistry. Lewis acid- and metal enolate-mediated cyclization reactions of trienes containing an electron-withdrawing group on the dienophile are highly stereoselective, giving rise to products formed via transition-states in which the dienophile-activating and diene groups are endo. Product ratios are governed by dienophile geometry, and secondary orbital interactions between the diene and the dienophile account for the observed stereoselectivities. 1,3,9-Decatrien-8-0nes cyclize readily at low temperatures to give cis-fused bicyclic ketones formed via an endo-transition-state.Bulky C-3 diene substituents promote high trans-selectivity. 173,9-Decatrienes possessing substituents at both C-3 and C-9 are less reactive than the monosubstituted analogues. Trienes substituted in the chain linking diene and dienophile generally cyclize via a transition-state in which the substituents are equatorially disposed in a chair-like linking chain. However, oxygen substituents positioned allylically with respect to the diene or dienophile frequently adopt a pseudo-axial disposition. 22 1 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction Bicyclo[4.3.0] systems.Unsubstituted 1,3,8-nonatrienes cyclize under thermal conditions with moderate selectivity to give predominantly the cis-fused isomer. Addition of an electron-withdrawing dienophile substituent reverses the observed selectivity, independently of dienophile geometry. Highly reactive dienophile-activated trienes (and less reactive substrates in the presence of Lewis acids) exhibit high trans-selectivity if the geometry of the dienophile is E; 2-dienophiles show low selectivity. Trienes substituted at C-3 of the diene show enhanced trans-selectivity. Trienes with substituents which are allylic with respect to the diene or dienophile generally give products in which the substituent is pseudo- equatorial.Geminal substitution alpha to the dienophile results in slightly enhanced trans- selectivity relative to the unsubstituted analogues. Geminal substitution beta to the dienophile increases triene reactivity. Both 1,3,9-decatrienes and 1,3,8-nonatrienes possessing a diene group having a Z-internal double bond invariably cyclize to give exclusively cis-fused products. 3 Heterocyclic Systems A. Nitrogen-containing Heterocycles.-(i) Bicyclo[4.4.0] Systems. Oppolzer first observed the stereocontrolling influence of the hybridization of the atoms in the chain linking the diene and dienophile in IMDA reaction substrates. Thus the urethane (1 15) 89 cyclized to give exclusively the cis-fused N-carbomethoxy- hexahydroquinoline (equation 82) whilst the amide (1 16) gave a mixture of trans-and cis-products (equation 83).’O H COZCH, 190°C ,16h 59 % -aH tj PF H P?c3same conditions fyJo62% + (83) H H (116) 2 1 Placement of a methyl group on the dienophile terminus of (1 15) slowed down the cyclization such that elimination became significantly competitive.It was 89 W. Oppolzer and W. Frost], Helv. Chim. Acta, 1975,58,587. 90 W. Oppolzer and W. Frost], Helv. Chim. Acta, 1975,58, 590.For a related example in which chain substituents caused formation of the ck-isomer exclusively, see P. Magnus and P. M. Cairns, J. Am. Chem. SOC.,1986,108,217. Craig argued that the favourable conformations in which all the diene and amide orbitals were parallel were such as to favour endo-cyclization to the cis-product from (113, and exo-cyclization of (116) to the trans-fused isomer.The latter cyclization was said to be less selective due to the endo-effect, which would lead to the formation of the cis-ring-fusion. These arguments are questionable, however; endo-effects due to secondary orbital interactions are unimportant in determining the stereochemistry of cyclizations at such elevated temperatures. If orbital overlap of the nitrogen lone pair with the amide carbonyl introduces some trigonal character at nitrogen, then the favoured transition-states are those in which the C-4 diene proton is vicinally eclipsed by a less sterically demanding acyl, rather than an alkyl carbon atom (Scheme 10).Scheme 10 cis-trans --The observed stereoselectivity was utilized in the synthesis of a pumiliotoxin-C precursor in which the observed diastereospecificity implied a boat-like transition- state (117) (equation 84),91 although the low yield of the cyclization reaction precludes unambiguous assignment of this conformation. PhMe, 215'C ,2Oh, (84)25 % Cyclization of 0-quinodimethanes formed during thermolysis of benzo-cyclobutanes gave varying amounts of cis- and trans-products depending on the position and oxidation state of the nitrogen-containing function in the linking chain (equations 85 and 86).92 The greater trans-selectivity realized from cyclization of (119) (X = H2) than from (118) (X = Y = H2) may arise from the greater degree of steric buttressing between the incipient aromatic ring and a methylene rather than an -NH-group at this position, as in (120).91 W. Oppolzer, W. Frostl, and H. P. Weber, Helc.. Chim.Actu, 1975,58, 593. For application to a synthesis of (+)-chelidonine, see W. Oppolzer and K. Keller, J. Am. Chem. Soc., 1971, 93,3836. 92 W. Oppolzer, Tefruhedron Letr., 1974, 15, 1001. Stereochemical Aspects cf the Intramoleculur Diels-A lder Reaction X=Y =H, 2.7:1 X = 0,Y = H2 1 : 5.2 X=H2,Y=0 1.2 X &fH 180°C,16h (86)dH+dH X = H2 7.3 : 1 x=o 1 :4 In contrast to (118) (X= 0,Y = H2), dienamide (121) gave the trans-fused bicyclic amide upon thermolysis, isomerization to the more stable conjugated enamide taking place in situ (equation 87).93 DMSO,19O0Cl 24h (87)65-81% --dR R=Me,Et , i-Pr Ar Thermolysis of the E,Z,E-diene (122) predictably gave exclusively the cis-fused product with the observed diastereoselectivity resulting from the preferred equatorial disposition of the C-6 methyl substituent." (ii) Bicyclo[4.3.0] Systems.Thermolysis of the benzocyclobutane (1 23) resulted in exclusive formation of the cis-fused y-lactam, paralleling the trend observed for the higher homologues (equation 88).95 y3 S. Handa. K. Jones. C. G. Newton, and D. J. Williams, J. C'hrvn. Soc.. C'/iem.Commun., 1985. 1362. y4 S. Wattanasin, F. G. Kathawala. and R. K. Boeckman, jun. J. Org. Chmi.. 1985, 50, 3810.'' W. Oppolzer, J. Am. Chrm. Soc.., 1971, 93, 3833. Craig qa;,18OoC1 18h = ,,&;in62 % E-NBn E H *A E (1 2 3) In contrast to the analogous six-membered-ring-forming reaction,” amide (124) gave predominantly the cis-fused product (equation 89).96 The lower temperatures required for cyclization of (124) reflect the higher energy of the diene HOMO in the intermediate O-quinodimethane, presumably as a result of the absence of delocalization of the nitrogen lone pair into the carbonyl double bond in the conformation required for cyclization to occur. The intermediacy of an O-quinodimethane species was established by observing the rate of racemization of optically active (124).As expected, terminally activated amide dienophiles show increased reactivity and truns-selectivity. The highly reactive amide (125) cyclized spontaneously upon formation at 0 “C.giving exclusively the trans-product resulting from an endo-transition-state (equation 90).97 W. Oppolzer. J. Atti. Chrtn. Sor.., 1971, 93. 3834. 91 H. W. Gschwend and H. P. Meier. .4ngrw~.C’hrtv., hi. Ed. Engl., (972, 11, 294. 225 Stereochemical Aspects of the htramolecular Diels-Aldvr Reaction The less activated triene (126) gave mostly trans-product upon heating in boiling benzene (equation 91). PhH ,80°C,24hAr @iMe90% 9 ArPPh-NMe (91) (124 Ph Ph 15 2 With 1,2-diaryl dienes (127), similar trends in reactivity were observed, with activating groups on the dienophile promoting increased trans-selectivity (equation 92).98 Ph Me (92) Ph-' X = COOEt, Y = 0,O "C; 100 :0 X = Ph, Y = 0,90 "C, 10 h; 8 : 1 X = H, Y = H,, 140 "C, 12 h; 1 : 5 X = H, Y = 0,llO"C, 8 h; 1:1 When the N-methyl group in (127) (X = COOEt, Y = 0)was replaced with a proton, reactivity decreased sharply.In general, large groups on the amide nitro- gen lowered activation energies for the cyclization reactions, presumably by dis- favouring unreactive rotamers as discussed above. The comparatively unreactive nature of acrylamides not possessing a terminal dienophile-activating group was ascribed to the non-coplanarity of the C=C and C=O double bonds, thereby causing an increase in the LUMO energy of the dienophile, with consequently poorer HOMO diene-LUMO dienophile overlap. As with the all-carbon analogues, substituents in the chain linking the diene and dienophile exert a considerable stereocontrolling influence on IMDA reactions.Cyclization of the Z-diene (128) gave a single product with complete absolute stereochemical control at the three newly-formed chiral centres (equation 93).99 PhMe. llO°C. 40h 95% (93) 98 H. W. Gschwend, A. 0.Lee, and H. P. Meier, J. Org. Chem., 1973. 38, 2169. 99 S. G. Pyne, M. J. Hensel, S. R. Bym, A. T. McKenzie, and P. L. Fuchs, J. Am. Chrm.Soc., 1980,102,5960. For applications to cytochalasin total synthesis. see: S. G. Pyne, M. J. Hensel, and P. L. Fuchs, J. Am. Chem. SOC.,1982,104,5719;S. G. Pyne, D. C. Spellmeyer, S. Chen, and P. L. Fuchs, ihid., 1982,104,5728. Also see M. Yoshioka, H. Nakai, and N. Ohno, ibid..1984, 106. 1133. Craig Consideration of the two possible diastereomeric transition-states reveals considerable non-bonded interactions between the pseudo-axial benzyl group and the diene terminus in the transition-state (129) leading to the unobserved isomer (130). Interestingly, the E-triene corresponding to (128) was totally inert to cyclization under the conditions employed. This result serves to demonstrate the utility of Z-trienes in securing complete cis-and extremely high diastereoselectivity by maximizing non-bonded interactions in the undesired transition-state. Similar diastereospecificity was displayed when the furan (131) cyclized under relatively mild conditions to give a single em-diastereomer (equation 94).'0° R A strong preference for transition-state (132) was implied by this result; addition of a methoxyl substituent at C-3 of the furan rendered the cyclization completely non-diastereoselective in accord with this model.Me High diastereoselectivity may be attained by the use of removable chiral groups, enabling access to IMDA products with high optical purity. Thus the R-phenylglycinol-derived amide (133) underwent internal cycloaddition upon formation of its magnesium salt to give the cyclized product in 76%diastereomeric excess (equation 95). O1 Chelation by magnesium between the hydroxyl and carbonyl oxygens served the dual purpose of rendering the two faces of the internal dienophile diastereotopic, and accelerating the reaction by increasing the proportion of reactive s-cis-rotameric forms.lo2 loo M.E. Jung and L. J. Street, J. Am. Chem. SOC.,1984, 106, 8327. lo' T. Mukaiyama and N. Iwasawa, Chem. Lett., 1981, 29. Io2 T. Mukaiyama, T. Tsuji, and N. Iwasawa, Chem. Lett., 1979, 697. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction I OH 12 B. Oxygen-containing Heterocycles.-(i) Bicyclo[4.4.0] Systems. Trienes (134) containing an ester grouping in the chain linking diene and dienophile were found to be resistant to cyclization, instead isomerizing to the conjugated ester prior to IMDA reaction (equation 96).'03 225 or 295°C (96) Y (134) iIMDA reaction X = EtO,C, Y = H;X = H, Y = COOMe The unreactive nature of (1 34) was explained in terms of an unfavourable lack of overlap of the ester oxygen non-bonding electrons with the carbonyl group in the reactive conformation (135) required for cyclization to occur.1o4 That an ester group was the cause of this lack of reactivity, as opposed to solely an ether oxygen, a carbonyl group, or an unusually facile [1,5] hydrogen shift was established by the ready cyclization of trienes (136), (137), and (1 38) (equations 97, 98, and 99).Y Electron-withdrawing groups on the internal dienophile carbon atom caused preferential formation of the cis-fused isomers as previously observed. R. K. Boeckman, jun. and D. M. Demko, J. Org. Chem., 1982, 47, 1789. '04 M. Simonetta and S. Carra, 'General and Theoretical Aspects of the -COOH and XOOR Groups' in 'The Chemistry of Carboxylic Acids and Esters', ed.S. Patai, Wiley, New York, 1969, p. 13. Craig 170°C I 20h 50 % E E 30 :70 86 %I 20h -&o + f$,17OoC (98) E AHE E (137) 60 :40 17OoCI 20 h 50 Y, E Ec E=COOEt 25 :75 Cyclization of the cyclic trienes (139) occurred via approach of the dienophilic group to a single face of the diene to give product mixtures which varied according to the geometry and substitution of the enone moiety (equation 100).'05 R = R' = H: room temperature 1:6 R = Me, R' = H: 90 "C,several hours 1 : 6 R = H, R' = Me: 80 "C, several hours 3 : 2 R = R' = Me: 130"C 1:l The Z-enone (139) (R = Me, R' = H) surprisingly gave the endo-product predominantly, despite the expected diene-P-methyl non-bonded interactions in the transition state.Equally striking was the preferred cyclization of (139) (R = H, R' = Me) to give the exo-cycloadduct. Here again, steric interactions appeared to be maximized in the transition-state leading to the preferred product. Whilst the predominance of cis-product from cyclization of (139) (R = R' = H) would be predicted on the basis of secondary orbital interactions at room temperature, the observed lo' S. J. Hecker and C. H. Heathcock, J. Org. Chem., 1985, 50, 5159. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction selectivities for the substituted trienes are somewhat puzzling. As expected, disubstitution at the dienophile terminus caused a decrease in reactivity. The acetylenic ketone (140) cyclized at a slower rate than the enones (139) due to the unfavoured boat-like transition-state adopted as a consequence of the linearity of the dienophile (equation 101).A boat-like transition-state was invoked to explain the diastereospecific formation of the cis-fused tricyclic aldehyde upon thermolysis of aldehyde (141) (equation 102). lo6 decalin,8017OoC,1-5h (102)% -a,CW-Of the two possible transition-states for the cyclization of (141), (143) was clearly preferred, with the incipient heterocyclic ring adopting a boat-form. Comparison was made between the implied transition-state conformation and the preferred conformation of the hydrocarbon (144), which suggested that the alternative transition-state (142) would be lower in energy.Since bond formation between the terminal carbon atoms of the diene and dienophile would be expected lo6 M. Koreeda and J. I. Luengo, J. Org. Chem., 1984, 49, 2079. Craig to be at a more advanced stage in the transition-state for cyclization of (141)(uide infra),a consideration of the preferred conformations of 1,3-bridged ten-membered rings might have been more instructive. Cyclization of the heterodienophilic triene (145)occurred readily at or below room temperature to give the endo-product exclusively (equation 1O3).lo7 80 %p&4(4 The methyl group in the linking chain accounted for the diastereospecificity; the reaction proceeded cia a boat-like transition-state (146)in which the methyl group was pseudo-equatorial, 1,2-eclipsing interactions disfavouring the alternative chair-like arrangement (147).'08 0 (ii) Bicyclo[4.3.0]Systems. Cyclic ethers have been generated with high stereo- selectivity via the IMDA reaction.The silylated triene (148)gave only the exo-product upon heating in toluene (equation 104).'09 neat, 120'~ FSrQ 004)67h, 86% -0 Whilst replacing the geminal methyl groups on the cyclohexane ring with hydrogen atoms had no effect on the reactivity of (148), increasing substitution on the dienophilic group slowed cyclization considerably, with elimination of allylic alcohol increasing significantly. Cyclization of the related triene (149)also proceeded predominantly via an exo- transition-state (equation 105). lo Allenyl ethers were shown to be more reactive than the isomeric propargylic compounds.Thus (1 50) underwent base-catalysed isomerization and in situ lo7 S. W. Remizewski, R. R. Whittle, and S. M. Weinreb, J. Org. Chem., 1984, 49, 3243. lo* For a review of the intramolecular imino Diels-Alder reaction, see S. M. Weinreb, Acc. Chem. Rex, 1985, 18, 16. S. D. Burke, S. M. Smith Strickland, and T.H. Powner, J. Org. Chem., 1983, 48, 454. 'lo R. L. Funk, C. J. Mossman, and W. E. Zeller, Tetrahedron Lett., 1984, 25, 1655. 231 Stereoclieniicul Aspects of the In truniolcwlur Diels-A liler. Reactior? PhMe, 165°C -0 4 1 cyclization to give the enol ether product, which was subsequently converted into the tricyclic lactone (151) (equation 106)."' The increased reactivity of the allenic intermediate resulted from the absence of non-bonded interactions between H-3 and the cyclohexane ring.' '' Cyclization of the trienes (152) showed a general tendency towards the formation of truns-fused y-lactones (equation 107).'' xylene,137 OC -+ (107)a,.aY' YXZ 0Y X = Me, Y = CO,Me, Z = H 100:0 X = CO,Me, Y = Me, Z = H 4.3: 1 X = CO,Me, Y = H, Z = Me 4.7: 1 Compound (132) (X = Me, Y = CO,Me, Z = H) in which the dienophile activating groups were sjx to each other was the most reactive isomer; an increase in the steric bulk of the Z-substituent had a negative effect on the rate of cyclization.Anomalously, with a carboxylic acid group at the Y-position, the cis-''' K. Hayakawa.S. Oshuki, and K. Kanematsu. Tcfrdicdrotz /,i,if.. 1986,27, 947. See also K. Hayakawa. Y. Yamaguchi. and K. Kanematsu, Tetrrihdrott Lcff., 1985. 26. 1689. K. Hayakawa. M. Yodo. S. Oshuki. and K. Kanematsu. J. Atti. C/iwi.Soc,.. 1984. 106, 6735. J. D. White and B. G. Sheldon. J. Org. Chtw.. 1981.46.2173: J. D. White. R. G. Sheldon. R.A. Solheim. and J. Clardy, TofrtrhrdronLcf/.,1978. 19. 5189. Craig fused product was obtained exclusively, albeit in low yield. Reversibility of the IMDA reaction was tentatively put forward to explain this peculiarity.' l4 The sorbic acid derivative (153) gave almost entirely the trans-fused product upon heating (equation 108).' O3 135'C 155h 79 76 L 9 1 Cyclization occurred readily in spite of a lowering of the diene HOMO energy due to coplanarity and overlap of the diene with the ester carbonyl.This overlap reduces the demand for ester-oxygen-carbonyl overlap, though molecular models showed the ester-oxygen lone-pair to be skewed only slightly away from the conformation in which maximum overlap could take place. Although cyclization may only take place ilia the disfavoured s-cis-conformation of the ester linkage the energy barrier to rotation about the CO-0 bond is sufficiently small so as not to impede the IMDA reactions.' Although the singly-activated ester (154) failed to cyclize upon heating due to competing elimination and polymerization processes, the mixed fumaric ester (1 55) gave a single cycloadduct (equation 109),'09 formed via an exo-transition-state with respect to the internal ester.TMsq(l54) PhH 120"C, 90h Tw(log)TMspE80%= CO,E t 0*o (155) Similar results were obtained for the more sterically demanding trienes (156) 16*1l7 and (157).' l8 'I4 For similar anomalous behaviour, see A. Ingendoh, J. Becher, H. Clausen, and H. C. Nielsen, Tetraherlron Lett., 1985. 26, 1249. I 'See reference 13 of reference 103. 'Ih P. R. Jenkins. K. A. Menear, P. Barraclough, and M. S. Nobbs, J. Chem. Sac., Chem. Commun., 1984, 1423. 'I' P. Magnus, C. Walker, P. R. Jenkins, and K. A. Menear, Tetrahedron Lerr., 1986, 27, 651. In F. E. Ziegler, B. H. Jaynes, and M. T. Saindane, Tetrnhedron Leff.,1985, 26, 3307. For a related approach to the forskolin ring system, see: K.C. Nicolaou and W. S. Li, J. Chem. SOC., Chem. Commun., 1985. 421. 233 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction OH' S (157)LA The maleic acid derivative (158) cyclized to give two endo-(with respect to the internal ester) isomers (equation 1 10).'16,'l7 Whilst (1 60) clearly resulted from an endu-transition state, (1 59) would appear to be the product of dienophile isomerization prior to cyclization. The non-identity of (159) with the cyclization product of (156) clearly disproved this; (159) was shown E>o* 56%PhH' l5OoC E' + @- 'E@ (''O) 0 3:l 0 b 58) (159) (160) by deuterium incorporation studies to be the epimerization product of the initially formed exo-product (161)."' (161) Et02c" -0zs-0 0 Singly-activated dienophilic trienes with an ester group forming part of the linking chain may undergo IMDA reactions if sufficiently vigorous conditions are employed.The substituted acrylate (162) formed a three-component mixture of cycloadducts upon prolonged thermolysis (equation 1 1 l).' l9@: @:, @$;ill) 0 ~70% HO ox ox Ho ox Ho ox (la) XzTBDMS 40 40 20 The 60: 40 cis-trans product-ratio was in keeping with other cyclizations of trienes with internally substituted dienophilic groups. The diastereospecificity of formation of the trans-isomer was a consequence of Al,3strain in the alternative transition state (163). J. D. White, E. G. Nolen, jun., and C. H. Miller, J. Org. Chem., 1986, 51, 1150.Craig The moderate selectivity associated with cyclization to the cis-isomer nevertheless parallels that observed in carbocyclic bicyclo[4.3.0] systems (uide supra). Sumnzarj). Whilst the cyclization reactions of trienes containing heteroatoms in the linking chain exhi bit many of the stereochemical features of the all-carbon substrates, several additional trends may be summarized as follows. Bicyclo[4.4.0] systems (i) The presence of an amide group within the linking chain has a variable effect on the observed selectivity, depending on its position relative to the diene and dienophile. (ii) Trienes containing non-conjugated ester groups are unreactive, and isomerize prior to cyclization. Bicycle[4.3.O] systems (i) Amides in which either the nitrogen atom or the carbonyl group is conjugated with the diene exhibit cis-selectivity.(ii) Amides and esters which are conjugated with the dienophile double bond exhibit trans-selectivi ty which increases with terminal dienophile activation; the absence of such activation gives rise to zero or moderate cis-selectivity. Amines and ethers show stereoselectivities similar to the all-carbon substrates. 4 Theoretical Aspects It is abundantly clear from the foregoing discussion that a delicate and subtle balance of structural factors affects the stereochemical outcome of the IMDA reactions of triene substrates. Although secondary orbital interactions may become significant at low temperatures and in the presence of Lewis and Brransted acids, the endo-'rule' is of very limited use in predicting isomer distributions in the thermal reactions discussed above. Careful consideration of parameters such as diene/ dienophile substitution, length of the linking chain, and the nature of any heteroatomic functionality present is essential to an understanding of the observed stereoselectivities. Central to this understanding is an appropriate assessment of those steric interactions which are important in determining the energy of the transition-state. Stereochemical Aspects of the Intramolecular Diels-Alder Reaction The concept of the 'concerted but non-synchronous' reaction pathway is a useful one in deciding which transition-state interactions are important. In this model, transition-state bonding is considered to be at a more advanced stage between those two atoms which have the largest coefficient of the frontier molecular orbital.23 Thus A will cyclize via a transition-state in which peripheral bond formation is more advanced and B via a more internally bonded transition-state.EDG EDG=electron-donatinggroup EWG$ EWG-EWG=electron-withdrawing group A B This model does not imply a stepwise reaction; the reaction is concerted in that the two bonds are initiated simultaneously,113 but asynchronous by virtue of the differing rates of formation of the peripheral and internal bonds along the reaction co-ordinate. Two modes of asynchronicity have been put forward to explain some of the stereochemical features of IMDA reactions, and these are outlined below.A. Asymmetric Stretch Asynchronicity.-Considering a triene with a substitution t pattern as in B above. Asymmetric stretch asynchronicity would mean that the internal termini of the diene and the dienophile have moved together concomitant with a moving apart of the peripheral atoms. Consequently, the transition-state has more of the character of the ring formed by connecting the internal termini. This explains why 173,8-nonatrienes substituted as in B give predominantly trans-fused prod~cts,~~*~~since the most stable pseudo-five-membered transition-state is that in which the diene and dienophile are anti with respect to each other. The moving apart of the peripheral termini has been used to explain the unimportance of the steric bulk of the ester alkyl group R in determining the stereospecificity of cyclization of (103) (X = H) to give purely trans-products via an endo-transition- ~tate.'~ $(P(103) (X=H) Craig Conversely, 1,3,8-nonatrienes with internal dienophile-activating groups display more nine-membered ring character in the transition-state, giving predominantly cis-fused products due to the greater stability of a cis-skewed nine-membered Aring.64,65,66b,68.72,80 consideration of the thermodynamic stabilities of cyclodecane conformers accounted for the kinetic cyclization of (55) uia the most favoured 52 boat-chair-boat transition-state.51*53 In the transition-state, peripheral bonding between A and C is more advanced, so the resulting structure acquires some of the character of a ten- rather than a six- membered ring.Conversely, with 1,3,9-decatrienes substituted as in B, the linking chain adopts the most stable chair-like conformation as a result of its pseudo-six- membered ring character. This explains the stereocontrolling influence of substi- tuents in the linking chain which adopt the more stable equatorial dispo~ition.~~-~’ B. Twist Asynchronicity.-In this mode, supported by force-field calculations,’ 2o twisting occurs about the bond which is the more fully formed in the transition- state. In the case of a 1,3,8-nonatriene substituted as in B, twisting occurs about the incipient C-4-C-8 bond which is more fully formed in the transition-state.The torque generated by the distortion of the incipient five-membered ring is such as to reduce the C-54-4-C-84-7 dihedral angle (N) to as near zero as possible. If twisting about C-4-C-8 occurs as a result of this torque, it may be seen that the dienophile twists in an em-direction, away from the diene. With the arrangement D leading to the cis-fused product, the torque is such as to reduce angle N as before but concomitantly with a twisting of the dienophile endo with respect to the diene, such as to increase non-bonded interactions. Thus transition state C is favoured over D, and trans-product predominates. Similar arguments apply to trienes with internal dienophile activating groups. With a tetramethylene linking chain, as in the case of 1,3,9-decatrienes with terminal dienophile-activating groups, there is very little torque about C-44-9, 120 F.K. Brown and K.N. Houk, Tetrahedron Lett., 1985,26, 2297. 237 Stereochemical Aspects of the Intramolecular Diels-Alder Reaction D and very slight changes in stereoselectivity occur upon substitution of an electron- withdrawing group at C-10. Clearly, such notions of asynchronous bond formation must be used with caution when predicting cyclization stereochemistries, as non-bonded interactions and electronic effects may be such as to stabilize or destabilize one or other of the transition-states to such an extent that product distributions are changed or even reversed from those predicted by these models. Nevertheless, the concept of concerted but non-synchronous bond-formation provides a complementary insight into the stereocontrolling factors in intramolecular Diels-Alder reactions.Acknowledgement. The author wishes to thank Professor Steven V. Ley for his encouragement and advice. lZ1 Compare references 65 and 66, for example.

ISSN:0306-0012    

DOI:10.1039/CS9871600187

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Chenz. SOC.Rev., 1987, 16, 239-274 SonochemistryPart 1-The Physical Aspects * By John P. Lorimer and Timothy J. Mason SCHOOL OF CHEMISTRY, COVENTRY POLYTECHNIC, COVENTRY CVl 5FB 1 Introduction Up to a few years ago the use of ultrasound in chemistry was something of a curiosity and the practising chemist could have been forgiven for not having met the term sonochemistry. And yet the use of ultrasound in chemistry is not a new topic; there were publications in primary chemical journals and industrial applications reported in the 1950s. After a period of neglect in the sixties and early seventies however, the subject is undergoing a renaissance which is generally considered to be due to the current wide availability of laboratory ultrasonic equipment in the form of cleaning baths and ultrasonic probes (often marketed as biological cell disruptors).The Royal Society of Chemistry provided a focus for this rapidly increasing area of study by including the first international symposium on sonochemistry at its 1986 Annual Congress held over three days in April 1986 at the University of Warwick.' The meeting brought together research groups whose studies spanned a range of different aspects of sonochemistry and generated considerable academic and industrial interest, so much so that the R.S.C. has now formed a new Subject Group devoted to the topic. It is hoped that this review will serve as both an introduction to the topic and a survey of current trends in sonochemistry. Ultrasound is the name given to sound waves having frequencies higher than those to which the human ear can respond (ie.>16 kHz). The upper limit of ultrasonic frequency is not sharply defined but is usually taken to be 5 MHz for gases and 500 MHz for liquids and solids. Being a sound wave, ultrasound is transmitted through any substance, solid, liquid, or gas, which possesses elastic properties. The movement of a vibrating body (i.e. sound source) is communicated to the molecules of the medium, each of which transmits its motion to an adjoining particle before returning to approximately its original position. It is this continuous movement of molecules, producing areas where they are compressed together, followed by layers where there is a deficiency of molecules, which gives rise to the alternate compression and rarefaction portions of the wave.For liquids and gases, particle oscillation * Part I1 -Synthetic Applications by James Lindley and Timothy J. Mason will appear in Chemical Sociery Rericwr.7, 1987, Issue No. 3 (September).' Special edition covering the R.S.C. Sonochemistry Symposium. Warwick 1986, Wlrrasonics, 1987, 25, January. Sonochemistry. Part I -The Physical Aspects takes place in the direction of propagation and produces longitudinal waves. Solids, however, since they possess shear elasticity can support tangential stresses, and hence tranverse waves in which particle movement takes place perpendicular to the direction of the wave. The use of ultrasound may be divided broadly into two areas.First, low amplitude (high frequency) propagation, which is concerned with the effect of the medium on the wave. Typically, low amplitude waves are used to measure the velocity and absorption coefficient of the wave in the medium. Secondly, high energy (low frequency) propagation, which is concerned with the effect of the wave on the medium. Examples of high energy applications are ultrasonic cleaning, drilling, soldering, chemical processes, emulsification etc. These processes are the result of either the mechanical agitation caused by the wave or are a consequence of cavitation (tiny bubbles) produced in the liquid. Although the field of ultrasound had been established in 1880 with the discovery of the piezoelectric effect by Curie and the ultrasonic whistle by Galton in 1893, the first commercial application of ultrasonics did not appear until 1917 with Langevin’s echo-sounding technique. Langevin’s discovery was the direct result of a competition organized in 1912 to find a method of detecting icebergs and so avoid any repetition of the disaster which befell the Titanic.Echo-sounding consists of sending a pulse of ultrasound from the keel of a boat to the bottom of the sea where the wave is reflected back to a detector which is also situated on the keel. The time interval between issuing and receiving the pulse allows the determination of depth. since depth = 4 x time interval x velocitjt ($sound in the M’uter. Essentially all imaging, from medical ultrasound to non-destructive testing (flaw detection) relies upon the same pulse-echo type of approach but with considerably more advanced electronic hardware.High frequency (> 1 MHz) ultrasound is employed for this work since the much shorter wavelengths involved are able to detect much smaller areas of phase-change i.e. differences in tissue structures in the body, or flaws in a metal. It is only since 1945 with the increased understanding of the phenomenon of cavitation, together with significant developments made in electronic circuitry and transducer design that a rapid expansion in the application of ultrasound to chemical processes has occurred. The last decade has seen sonochemistry come of age and it has become increasingly evident that sonochemistry may be as important a topic within chemistry as photochemistry, thermochemistry, or high pressure chemistry- possibly even more important because of its greater general applicability across the whole breadth of chemistry from polymer science to chemical physics.It has the distinct advantage that the methodology is straightforward with relatively simple apparatus requirements. The aim of this review is to outline how important a tool ultrasound has become to the chemist in studying a range of topics from analysis and relaxation phenomenon (using low amplitude waves) to the acceleration of chemical processes, organic synthesis, and polymerization (high energy waves). Lorimer and Mason 2 General Principles The vast majority of chemical reactions are carried out in the liquid phase under either homogeneous or heterogeneous conditions. This is certainly true of those processes which have been studied in the presence of ultrasound e.g.chemical synthesis, structural determinations, kinetic studies, and polymer degradations. For this reason the following review of the physical effects of ultrasonic irradiation on chemical processes has been restricted to those occurring in the liquid phase. The mathematical treatment has also been kept to a minimum, consistent with the aim of introducing the topic to chemists. However the authors are well aware of the many rigorous mathematical treatises which relate to ultrasound and these can be found in the selection of books and reviews (written predominantly by physicist^).^-'^ For some sections of the following qualitative discussions, where an awareness of the underlying mathematical concepts is considered advantageous, semi-quantitative descriptions have been provided.A. Sound-induced Vibrations.-When an acoustic field is applied to a liquid the sonic vibrations create an acoustic pressure (Pa)which must be considered to be additional to the ambient hydrostatic pressure (Ph)already present in the medium. The acoustic pressure is time (t) dependent and is represented by equation 1 Pa = PA sin 2nft (1) where f is the frequency of the wave (>16 kHz for ultrasound) and PA is the maximum pressure amplitude of the wave. By analogy with electrical vibrations the intensity of the wave (I, the energy transmitted per second per cm2 of fluid) is as described in equation 2 where p is the density of the medium and c is the velocity of sound in that medium.As the wave propagates through the medium the sound-induced oscillations of the molecules about their mean rest-position may be described mathematically in * H. G. Flynn, ‘Physical Acoustics’, Vol. 1 B,ed. W. P. Mason, Academic Press, New York, 1964, pp. 57-172. R. E. Apfel, ‘Ultrasonics’, ed. P. D. Edmonds in ‘Methods of Experimental physics’, ed. E. Marton, Academic Press, New York, 1981, pp. 355-411. A. Basedow and K. H. Ebert, ‘Advances in Polymer Science’, Vol. 22, ed. H. J. Cantow, Springer Verlag, New York, 1978. B. Brown and J.E. Goodman, ‘High Intensity Ultrasonics’, D. Van Nostrand Co. Inc., Princeton, New Jersey. J. Blitz, ‘Fundamentals of Ultrasonics’, Butterworths, London, 1967. ’E. A. Neppiras, Phys. Rep.. 1980, 61, 160. B. E. Noltingk and E. A. Neppiras, Proc. Phjs. Soc. B (London), 1950, 63B, 674.’E. A. Neppiras and B. E. Noltingk, Proc. Phj3. Soc. B (London), 1951, 64B, 1032. lo K. S. Suslick, ‘Modern Synthetic Methods’, vol. 4, Springer Verlag (Berlin), 1986, pp. 1-60. P. Riesz, D. Berdahl, and C. L. Christman, Enciron. Health Persp., 1985, 64,233. l2 A. Henglein, CTirrasonics,1987, 25, 6. l3 L. D. Rosenberg, ‘High Intensity Ultrasonic Fields’, 1971, Plenum Press, New York, pp. 203-491. l4 I. E. El’piner, ‘Ultrasound’, Consultants Bureau, New York, 1964. Ref.5, p. 16. 241 Sonochemistry. Part 1-The Physical Aspects terms of molecular displacement (x), velocity (t’) and acceleration (a) (equations 3-5). .x = xo sin 27cft (3) v = (dx/dt) = 271s~~cos 2~ft (4) a = (du/dt) = -42J2x, sin 2nfr (5) B. Attenuation of Sound in a Liquid Medium.-The intensity of sound is attenuated (i.e. decreases) as it progresses through a medium. As the molecules of a liquid vibrate under the action of the sound wave they experience viscous interactions which degrade the acoustic intensity and some energy is lost in the form of heat. Heating will occur at the sites of compression, and cooling at the sites of rarefaction, but, because of its low compressibility there will be little appreciable heating of the bulk medium from this source.The small bulk heating effect which does occur on passing high power ultrasound through a liquid medium is due to the absorption of degraded acoustic energy. The energy loss is represented in equation 6, I = I. exp (-24 (6) where I is the intensity at some distance 1 from the radiation source and a is the absorption coefficient. Kirchoff derived an equation (7) for the calculation of based upon losses due to viscous forces and heat conduction,’ where qsand qb are the shear and the bulk viscosities of the medium respectively, k’ is thermal conductivity of the medium,C, is the specific heat at constant pressure, and y is the ratio of specific heats. For any given medium, at a given temperature, the value of a/f’ must be a constant and so any increase in sound frequency fmust result in a compensatory increase in a and thus a more rapid attenuation of the sound intensity with distance.This effect is best explained with a specific example. Whereas sound at 20 kHz is reduced to 4 of its intensity after passing through 30 km of water, the distance required to achieve the same reduction of intensity for 118 kHz sound is only 1 km. Calculations such as these demonstrate clearly that in order to achieve identical intensities at a given distance in a medium it will be necessary to use a higher initial power for the source with the higher sound frequency. C.The Formation of Cavitation Bubbles.-Under the influence of a pressure wave the average distance between the molecules in a liquid will vary as the molecules l6 G.Kirchoff, Ann. Phys. (Liepzig), 1868, 134, 177 Lorimer and Mason R Figure 1 Creuice model for stabilizing cavitation nuclei (ref. 11). (a) For external positive pressure. (b)For external negative pressure oscillate about their mean position. If a sufficiently large negative pressure (P,) is applied to the liquid (here it is the acoustic pressure on rarefaction P, = Pa -Ph) so that the distance between the molecules exceeds the critical molecular distance (R)necessary to hold the liquid intact, the liquid will break down and voids will be created i.e. cavitation bubbles will form. For water the critical distance is assumed to be cm and the tensile stress, or pressure involved, can be calculated to be of the order of 10 000 atmospheres (P,z 2a/R where a = surface tension).If the calculation is modified l8 so that allowance is made for the bubbles to be filled with vapour (from evaporation of the liquid) cavitation will still require negative pressures of about 1 000 atmospheres. In practice cavitation occurs at considerably lower applied acoustic pressures due to the presence in the liquid of weak spots which lower the tensile strength. One possible source of weakspots is the presence of gas nuclei in the form of either dissolved gas, minute suspended gas bubbles, or gas bubbles produced as a result of heat fluctuations within the liquid. Evidence for this has been obtained from degassing the liquid 19-” or raising the hydrostatic pre~sure,’~-~~ both of which lead to an increase in the cavitation threshhold. Ultrafiltration 26 is also known to raise the cavitation threshhold of liquids.This suggests that it is the presence of particulate matter, and more especially the occurrence of trapped vapour-gas nuclei in the crevices and recesses of these particles, which is responsible for lowering the cavitation thre~hhold.’~-~~ Nucleation from these sites (and from similar sites on the vessel walls) is easy to visualize (Figure 1). During the rarefaction cycle of the acoustic wave, as the L. A. Crum, IEEE Ultrasound Sjwp., 1982, 1. la Ya. B. Zel’dovich, Zh. E’Ksp. Tevr. Fiz., 1942, 12(11-12), 525. l9 H. N. V. Temperley, Proc. Phys. Soc., 59, 199.’O W. J. Galloway, J. Acoust. Soc. Am., 1954, 26, 849. G. W. Willard, J. Acoust. SOC.Am., 1953, 25, 669.’’E. N. Harvey, J. Colloid Comp. Physiol., 1944, 24, 1. 23 D. C. Pease and L. R. Blinks, J. Phys. Cellular Chem., 1947, 51, 556. 24 M. Strasberg, J. Acoust. SOC.Am., 1959, 31, 163.’’H. J. Naake, K. Tamm, P. Damming, and H. W. Helberg, Acustica, 1958,8, 193. 26 M. Greenspan and C. E. Tschiegg, J. Res. Natl. Bur. Stand., Sect. C, 1967, 71, 229.’’ L. A. Crum, Nature, 1979, 278, 148. R. H. S. Winterton, J. Phys. D: Appl. Phys., 1977, 10, 2041. 2q R. E. Apfel, J. Acoust. SOC.Am., 1970, 48, 1179. 243 Sonochemistry. Part I -The Physical Aspects pressure decreases (P = Pa -Ph), the liquid-gas interface becomes increasingly more convex, its angle of contact decreases, until, at sufficiently low pressure (Pa = PA sin 2nft), it breaks away from the surface to produce a bubble of radius R.It can be shown that the critical (or Blake Threshold) pressure (P,)*q9313 (neglecting vapour pressure and inertial and viscous effects) which must be exceeded by the acoustic pressure (Pa)to provide a bubble of radius R is given by equation 8, where o is the surface tension of the liquid. For large bubbles (P, 2 a/R) the equation may be approximated to equation 9, whereas for small bubbles (2 o/R $= Ph) it takes the form of equation 10. P, = Ph + 0.77 (a/R) (10) Equation 10 can be used in another sense. For bubbles with radii less than l@' cm it provides a good estimate of the limiting tensile strength of water (e.g.for a = 7.25 x 1C2 Nm-', P, x 720 atm).Thus, although cavitation in the strictest sense is the production of empty voids (or, more likely, vapour-filled voids), the inability to remove all gas nuclei from the liquid necessitates the inclusion of gas-filled bubbles in discussions of cavitation phenomena. It is the subsequent fate (see 2E below) of some of these bubbles, as they oscillate in the applied sinusoidal acoustic field, which is the origin of sonochemical effects. It is certain that sonochemical effects cannot be the result of direct coupling of the sound field with the chemical species on the molecular level since the frequencies employed (20 kHz-10 MHz) are too low even for the excitation of rotational motion.There are two forms of cavitation-stable and transient. Stable cavities are those which oscillate, often non-linearly, about some equilibrium size (Ro);such bubbles have an existence of many cycles. Transient cavities generally exist for less than a single acoustic cycle during which time they expand to at least double their initial size before collapsing violently into smaller bubbles (for further treatment of this see E below). It was once thought that the spectacular effects such as erosion, emulsification, molecular degradation, sonoluminescence, and sonochemical enhancement of reactivity were entirely attributable to the collapse of transient cavities. This is no longer believed to be true since the majority of visible bubbles generated in an acoustic field will oscillate in a stable manner and, because they are long-lived, the overall integrated effects of stable cavitation must be significant.Lorimer and Mason Stable bubbles are also capable of being transformed into transient cavities. For these reasons the study of the fate of stable bubbles has become important. (i) Transient Cavitation. Transient cavitation bubbles are voids, or vapour-filled bubbles, produced using ultrasonic intensities in excess of 10 Wcm-*. They exist for one, or at most a few acoustic cycles, expanding to a radius of at least twice their initial size before collapsing violently on compression and often disintegrating into smaller bubbles. (These smaller bubbles may act as nuclei for further bubbles, or if of sufficiently small radius, R, can simply dissolve into the bulk of the solution because of the very large pressure due to surface tension, 2 o/R).During the lifetime of the transient bubble it is assumed that there is no time for any mass flow, by diffusion of permanent gas, into or out of the bubble, whereas evaporation and condensation of liquid is assumed to take place freely.There being no permanent gas to act as a cushion, the implosion leads to a very violent collapse. Theoretical considerations by Noltingk and Neppiras and later by Flynn,2 and separately by Neppiras,' assuming adiabatic collapse of the bubbles, allow for a calculation of the temperature (Tmax,)(equation 11) and pressures (P,,,,)(equation 12) within the bubble at the moment of collapse, where Tois the ambient (experimental) temperature, y is the ratio of specific heats of the gas (or gas vapour) mixture, P is the pressure in the bubble at its maximum size and is usually assumed to be equal to the vapour pressure (P,)of the liquid.[This assumption is a direct consequence of the initial assumption that transient bubbles grow without the influx of gas into the cavity. If gas does enter the cavity the value of P (= P, + P,)will depend upon the value of P, when the bubble is at its maximum size.] P, is the pressure in the liquid at the moment of transient collapse (= P, + Pa). The collapse time T for an empty bubble (equation 13) 30 is normally not longer than one fifth of the period of vibration and therefore P, can be regarded as constant during the collapse. T = 0.915 R,(p/P,)f (13) An estimate of the temperature and pressure (equations 11 and 12) involved in the final phase of the implosion of a bubble containing nitrogen (y = 1.33) in water at ambient temperature (20 "C) and ambient pressure (1 bar), provides values of 4200 K and 975 bar.It is the existence of these very high temperatures within the 30 Lord Rayleigh, Phiios. Mag., 1917, 34, 94. 245 Sonochemistry. Part 1-The Physical Aspects bubble that have formed the basis for the explanation of radical production and sonoluminescence, whilst the release of the pressure, as a shock wave, is a factor which has been used to account for both increased chemical reactivity (due to increased molecular collision) and polymer degradation.(ii) Stable Cavitation. We now turn our attention to stable cavitation, a phenomenon which, at one time, was not thought to be of much significance in terms of chemical effects. Stable bubbles are believed to contain mainly gas and some vapour and are produced at fairly low intensities (1-3 Wcm-2), oscillating, often non-linearly, about some equilibrium size, for many acoustic cycles. The time- scale over which they exist is sufficiently long that mass diffusion of gas, as well as thermal diffusion, with consequent evaporation and condensation of the vapour, can occur, resulting in significant long-term effects. If the rates of mass transfer, across the gas-liquid interface, are not equal, it may result in bubble growth.The mechanism by which small microbubbles in the liquid (which are normally instantly dissolvable due to surface tension) grow, is termed rectified diffusion. In the expansion phase of the acoustic cycle gas diffuses from the liquid into the bubble, whilst in the compression phase, gas diffuses out of the bubble into the liquid. Since the interface area is greater in the expanded phase, the inward diffusion is greater, leading to an overall growth of the bubble. As the bubble grows the acoustical and environmental conditions of the medium will change, the medium becoming acoustically lossier and more compressible. The stable bubble may be transformed into a transient bubble and undergo collapse (see 2E below). The violence of collapse, however, will be less than that for a vapour-filled transient since the gas will cushion the implosion.The cavity will reduce to a minimum size Rmi,,,during compression, after which it will expand to R,,,, and subsequently oscillate between these extremes. On the other hand the bubbles may continue to grow during subsequent cycles until they are sufficiently bouyant to float to the surface and be expelled-this is the process of ultrasonic degassing. Not all bubbles are capable of producing significant cavitational effects. The greatest coupling of the ultrasonic energy will occur, according to Minneart (equation 14),31when the natural resonance frequency vr)of a bubble is equal to the applied ultrasonic frequency.(R,is the resonance radius of the bubble). For applied frequencies greater than the bubble’s natural resonant frequency, oscillations will be complex. However, for applied frequencies less than the bubble’s resonance frequency, collapse can occur (Figure 2). As with transient cavitation, estimates have been made of the temperatures and pressures produced in stable bubbles as they oscillate in resonance with the applied 31 M. Minneart, Philos. Mag., 1933, 16, 235. 246 Lorimer and Mason I I r 1 0.1 0.2 0.3 Time /~s Figure 2 Radius-time curvesfor air bubble in sonicated water at (a) 5 MHz, (b) 15 MHz (ref. 7). R, = 8 x lW5cm; PA = 4 bar; P, = 1 bar;f, = 6.8 MHz (ref. 31) acoustic field. Griffing et al.32derived an expression (equation 15) for the ratio To/Tmax ., where Q is a damping factor equal to the ratio of the resonance amplitude to the static amplitude of vibration of the bubble and P,,,( =Ph + Pa)is the peak pres- sure of the bubble.For a bubble containing a monatomic gas (y = 1.666) and P,/Ph = 3.7 (corresponding to an intensity of 2.3 WcmP2) and assuming a value of Q = 2.5, the Tm,,. for the bubble is deduced to be 1665 K. Calculations33 of the local pressures due to these resonance vibrations has resulted in values which exceed the hydrostatic pressure by a factor of 150000. There is no doubt that the intense local strains in the vicinity of the resonating bubble are the cause of the many disruptive mechanical effects of sound.D. Parameters Effecting Cavitation.-Given the differences in irradiation conditions (frequency, solvents, system vapour pressure, intensities, hydrostatic pressure) it is pertinent to discuss briefly how these parameters affect the distinct stages of acoustic cavitation: namely nucleation, bubble growth, and collapse. Since the dynamics of cavity growth and collapse are dependent upon local environment, one must also consider how cavitation in a homogeneous liquid is modified when it occurs at a liquid-solid interface, as for example in heterogeneous catalysis (see Part 2). 32 M. E. Fitzgerald, V. Griffing, and J. Sullivan, J. Chern. Phys., 1956, 25, 926. 33 F. D. Smith, Philos. Mag., 1935, 19, 1147. 247 Sonochemistry. Part 1-The Physical Aspects U.- - _I .-z lo2 - 2 r lo I I I I I I I 200 LOO 600 800 1000 1200 Frequency I kHz Figure 3 Variation with.frequency of maximum jluid pressure during collapse (ref. 8).R, = 3.2 x cm; PA = 4 bar; adiabatic conditions (i) Frequency. As the ultrasonic frequency is increased 8*34-36 the production of cavitation in liquids decreases. Various explanations 37 have been put forward to explain this observation. In qualitative terms it may be argued that at very high frequency, where the rarefaction (and compression) cycles are very short, the finite time required for the rarefaction cycle is too small to permit a bubble to grow to a size sufficient to cause disruption of the liquid. On the other hand it can be argued that even if a bubble was produced during rarefaction, the time required to collapse that bubble may be longer than that available in the compression half-cycle.(Figure 3 shows the variation of maximum fluid-pressure against frequency for constant pressure amplitude (PA), and bubble radius). Higher frequencies require more power for an equivalent amount of chemical work, since the higher rates of molecular motion at the higher frequencies result in greater power losses. Ten times more power is required to make water cavitate at 400 kHz than at 10 kHz, and it is for this reason that 2&50 kHz frequencies were generally chosen for cleaning purposes and have subsequently been found to be of value in sonochemistry. (ii) Solvent. The formation of voids or vapour-filled microbubbles (cavities) in a 34 G.Muller and G. W. Willard, J. Arousr. SOC. Am.. 1948, 20, 589.’’W. Gaertner, J. Acousr. SOC.Am., 1954. 26. 977. 36 R. Esche. Akust. Beill.. 1952, 4. 208. 37 H. J. Eyring, J. Chrni. Phjx. 1936, 4. 283. 248 Lorimer and Mason Table 1 Soundpressure (P) producing cavitation in various liquids under a hydrostatic pressure of 1 atmosphere Liquid q/Nsrn-* (25 "C) P/atm Castor oil 0.630 3.90 Olive oil 0.084 3.61 Corn oil 0.063 3.05 Linseed oil 0.038 2.36 CCl, 0.001 1.75 t 0 a 1.8 I C0 .-c c.-> 0 I . t I t 0.02 O.OL 0.06 0.08 Equilibrium Gas PressurelMPa Figure 4 Variation of ucoustic cavitation threshold of water with dissolvedgas content (f = 38 kHz; T = 25 "C) (ref.39). (a) Distilled water; (CT= 7.2 x lo-' Nm-I). (b) Aqueous guar gum (100 p.p.m.); CT = 6.2 x lo-' Nm-'. (c) Aqueousphotofiow (80 p.p.m.);o = 4.0 x lo-' Nm-' liquid requires that the negative pressure in the rarefaction region must overcome the natural cohesive forces acting within the liquid and hence cavitation should be more difficult to produce in viscous liquids. Published data 38 indicate that such an effect, albeit small, does occur (Table 1). Conversely, the use of solvents with low surface tensions should lead to a reduction in the cavitation threshold. However Cr~m,~~using non-polar hydrophobic solids to vary the surface tension of distilled water, has observed, at constant gas content, that the cavitation threshold increases with a decrease in surface tension (Figure 4). Solvents with high vapour pressure (P) undergo less intense cavitational effects.This is most easily demonstrated for the maximum temperature on implosion, (equation 12), since any increase in P leads to a decrease in TmaX..The effect of P,,,, 3R L. Bergmann, 'Ultrasonics', G. Bell and Sons, 1938. 39 L. A. Crum, App/. Sci. Rex. 1982, 38, 101. 249 Sonochemistry. Part 1-The Physical Aspects is not so obvious at first glance. For ease of calulation, if it is assumed that y remains constant (an incorrect assumption since y will be lowered by the introduction of vapour into the bubble) and is equal to 1.33 (an air-filled bubble), then P,,,, a Pm4/P2.Thus as P (the solvent vapour pressure) increases, P,,,.rapidly decreases and the bubble collapse is less violent. (iii) Temperature. Increasing the ambient temperature 40-44 will raise the equilibrium vapour pressure of the medium and so lower both T,,,, and Pmax.. However R~senburg~~ observed that, in a number of liquids, the amount of aluminium eroded in a 8 kHz ultrasonic field increased as the temperature increased from -10 "C to 50 "C, and decreased (as expected) from 50 "Cto 90 "C. The maximum (in erosion and hence cavitation intensity) is readily explained by assuming that as the temperature is increased the number of nuclei for cavitation is also increased. However, with continued increase in temperature, the decrease in surface tension and increase in vapour pressure (pressure within the cavity) results in a damping of the shock wave (Pmax.decreases) when the cavity implodes.A further factor which must be considered in cases where large numbers of cavitation bubbles are generated concurrently is the cushioning or dampening effect of these bubbles on the dissipation of ultrasonic energy from the source through the fluid. (iv) Gas Type and Content. According to equations 11,12, and 15, employing gases with large y values will provide for larger sonochemical effects from gas-filled bubbles. For this reason monoatomic gases (He, Ar, Ne) are used in preference to diatomics (N2, air, 0,).It must be remembered that this dependence on y is a simplistic view, since the extent of the sonochemical effects will also depend upon the thermal conductivity of the gas: 46 the greater the thermal conduction of the gas, the more heat (formed in the bubble during collapse) will be dissipated to the Table 2 Rate of formation of free chlorine by irradiation of water containing CCl, in relation to the nature of the saturating gas Reaction rate Thermal conductivity Gas (mM/min) Y (1C2 Wm-' K-' 1 Argon 0.074 1.66 1.73 Neon 0.058 1.66 4.72 Helium 0.049 1.66 14.30 Oxygen 0.047 1.39 1.64 Nitrogen 0.045 1.40 2.52 Carbon monoxide 0.028 1.43 2.72 40 W.Connolly and F. E. Fox, J. Acoust. SOC. Am., 1954, 26, 843. 41 F. G. Blake, Phys. Reo., 1949, 75, 1313. 42 J. P. Horton, J. Acoust. SOC. Am., 1953, 25, 480.43 A. S. Bebchuk, Akusr. Zh., 1957, 3, 90. 44 W. C. Schumb, H. Peters, and L. H. Mulligan, Metals and Alloys, 1937, 5, 126. 45 L. Rosenberg, Ultrasonics News, 1960, 4, 4. 46 F. R. Young, J. Acousr. SOC. Am., 1976, 60,100. 250 Lorimer and Mason surrounding liquid, effectively decreasing Tmax..Unfortunately a strict correlation between conductivity and effect has not been observed (Table 2). Increasing the gas content of a liquid leads to a lowering of both the cavitational threshold (Figure 4) and the intensity of the shock wave released on the collapse of the bubble. The threshold is lowered as a consequence of the increased number of gas nuclei (or weak spots) present in the liquid, whilst the cavitational intensity is decreased as a result of the greater ‘cushioning’ effect in the microbubble.The latter point may be deduced semi-quantitatively from a consideration of equations 11 and 12. In the strictest sense, P should be replaced by P,, (= P, + P,),and increasing the gas content of the liquid increases P,, and hence P,, increases, to provide for decreases in Pmax. and Tmax.. It might be anticipated that employing gases with increased solubility would also reduce both the threshold intensity (by virtue of providing a large number of nuclei in the solvent) and the intensity of cavitation. Indeed there is a definite correlation 4749 between gas solubility and cavitational intensity. The greater the solubility of the gas, the greater the amount which penetrates into the cavitation bubble, and the smaller the intensity of the shock wave created on bubble collapse.A further factor affecting the intensity of collapse may be that the more soluble the gas the more likely it is to redissolve in the medium during the compression phase of the acoustic cycle. (v) External (Applied) Pressure. Increasing the external pressure (Ph) leads to both an increase in the cavitation threshold and the intensity of cavity collapse. Qualitatively it can be assumed that there will no longer be a resultant negative phase of the sound (since Ph -Pa > 0)and so cavitation cannot occur. Clearly a sufficiently large increase in the intensity I of the applied ultrasonic field can produce cavitation even at high overpressures since it will generate larger values of Pa (1CC PA^; Pa = PA Sin 27Cft) making Ph -Pa < 0.In that P, (the pressure in the bubble at the moment of collapse) is approximately Ph + Pa, increasing the value of Ph will, according to equations 11, 12, and 13, lead to a more rapid and violent collapse. The increase in overpressure may even allow cavitation to occur at higher ultrasonic frequencies, since the time for collapse, T, is reduced under these conditions (equation 13). The effect of increasing Ph is somewhat more difficult to visualize for stable bubbles, but strangely it leads to a decrease in Tmax.. (vi) Intensity. In general an increase in intensity (I) will provide for an increase in the sonochemical effects. Since I a PA^, the maximum pressures and temperatures within a transient collapse will increase according to equations 11 and 12 (Pm z Ph + PA).However it must be realized that intensity cannot be increased indefinitely.With increase in the pressure amplitude (PA)the bubble may grow so 4’ H. W. W. Brett and H. H. Jellinek, J. Polym. Sci., 1954, 13, 441. 48 R. 0.Prudhomme and P. Graber, J. Chim. Phys., 1949, 46, 667. 4y R. 0.Prudhomme, J. Chim. Phys., 1950, 47, 795. 25 1 Sonochemistrjv. Part 1-The Physical Aspects large on rarefaction (Rmax,)that the time available for collapse [T = 0.915 R,,,. (p/P,)*] is insufficient (see 2E below). For stable bubbles the quantitative effects of increasing I are not easily visualized. Increasing [leads to an increase in PA(and hence P,) such that there is a decrease in P,/P,. The quantity Q(P,/P,) -1 becomes more negative and the right hand side of equation 15 smaller i.e.T,,,, increases. E. Cavitation Bubble Dynamics.-The fundamental dynamical problem of acoustic cavitation is the determination of the pressure and velocity fields in the two-fold medium (gas-liquid), together with the motion of the bubble wall, when under the influence of a time-dependent (acoustic) pressure. By ignoring mass and heat-flow across the interface, Noltingk and Neppiras 8,9 were able to show that the motion of the cavity wall for a gas-filled bubble may be given by equation 16, 2cJ ---(Po -PA sin 2n/i)] (16)(p0 + ~~J/R~)(R~/R)~~Po R where R is the bubble radius at some time t, R, is the equilibrium bubble radius, Po is the ambient pressure, R is the bubble wall velocity, and is the bubble wall acceleration. This equation adequately describes the motion of stable bubbles over several cycles but it fails for transient bubbles where the bubble wall velocity exceeds of the velocity of sound.Writing R = R, + r and substituting in equation 16 yields equation 17. Where a,is the resonance frequency given by equation 18. Neglecting the effects of viscosity and solvent vapour pressure, equation 18 reduces to equation 19 (for large bubbles) and equation 20 (for small bubbles). It is possible to solve equation 17 (for which equation 21 is the general solution) and generate various r -t curves for given PA and R, values.Lorimer and Mason 1 2 3 5 Time/TA Figure 5 Radius-time curve for a cavity insonated below resonance frequency. Ro .= 2.6 x cm; PA = 0.333 bar; P, = 1 bar. (a) applied frequency (83.4 kHz). (b) Relative radius of bubble w r= ‘A [sin at -o, sin att pRo(wT2 -a*) 1 For small PA/Ph ratios, with R, 2= R,(the resonant bubble radius), oscillations take place at approximately the excitation frequency (Figure 5). For R, > R, bubble oscillation has a strong component of its own natural resonant frequency (Figure 6). However, for very small bubbles, R, < R,, transient conditions are attained as PAincreases beyond Ph (Figure 7,PA = 4 and 10 atm). It may be that as PA is further increased the bubble grows so large in the tension phase that it has insufficient time to collapse before the end of the pressure cycle and collapse occurs at the end of the second positive peak (Figure 7,PA = 25,100,200 atm).Eventually if PA/Ph > > > 1 the bubble may never undergo transient collapse. 3 Relaxation Phenomena Whenever a sinusoidal sound wave propagates through a liquid it induces oscillation of the volume occupied by the molecules and thereby increases, momentarily, the mean translational energy of the molecules. Although, in principle, this translational energy can be transferred in toto to other molecules by elastic collisions, and so increase their translational energy, in reality energy losses will occur due to (a) viscosity effects (motion of one molecule relative to another in the liquid) and (6) thermal effects (heat transfer from regions of high to low translational energy).It is expected therefore that the energy of the wave (0will be attenuated as it passes through the medium.I6 The extent of Sonochemistry. Part 1-The Physical Aspects 3 U .-0 1.0 c m .-5-0.9 mc 1 - . - _._~. 1 2 3 4 5 . 6 7 8 9 1 0 TimelT, Figure 6 Radius-time curve for bubble for a cavity insonated above resonance. R, = 2.6 x lW3 cm; PA = 0.333 bar; Ph = 1 bar. (a) Applied frequency (83.4 kHz). (b)Resonance frequency of bubble (ref. 31). (c) Relative radius of bubble 200 so0Q: 100 25 Po 1.o 2.0 Figure 7 Radius-time curves for an insonated air bubble in water (ref.7).R, = 10-4 cm;f= 500 kHz. The numbers on the curves refer to the ratio PAIPh.Time is measured in units of the period (TA) of the applied acoustic field attenuation has already been discussed in General Principles and is given by equations 6 and 7. Since for any given liquid qs, qb, y, k’, and C, are constant at constant temperature, the value, a/f2 should be independent of the experimental frequency 254 Lorimer and Mason employed to determine a. Experimentally this is not the case for many liquid systems with alf’ decreasing with increase in frequency. This is due to the fact that the total energy content of a liquid is not restricted solely to translational energy, but is the sum of many components including rotational, vibrational, molecular conformational, and structural forms.It is the coupling of the translational energy with these other energy forms which leads to the absorption of sound in excess of that deduced from equation 7, and to the non-constancy of q‘f’ with increasing frequency. The occurrence of this excess absorption is most easily illustrated by considering the fate of a vibrationally excited molecule, produced as a result of the energy interchange between the translation and vibrational modes. Provided the vibrationally excited molecules can be deactivated (by inelastic collisions with other molecules) and returned to the ground state in a time period which is shorter than the period of sound oscillation, the energy will be returned to the system in phase with the sound wave, and no net loss will be observed in the sound energy per cycle.As the frequency of the sound wave increases (i.e.the time period decreases) the return of energy will become increasingly out of phase with the wave and will appear as an energy loss. Ultimately if the period of the wave is decreased sufficiently (i.e. very high frequency ultrasound is applied) a situation will be reached when the perturbation of translational energy occurs so fast that there is no time available for exchange with the other energy forms. Between these two extremes of high and low frequency there exists a condition when the frequency of the fluctuation induced by the sound wave is comparable with the time required for energy exchange.The time lag between the excitation and de-excitation processes is observed as an acoustic relaxation. Since detailed discussions of the theoretical basis of acoustic relaxation have been published elsewhere 50*51 it is sufficient to report here that any relaxation is observable 52 as either an increase in the velocity- frequency curve, a peak in the &-frequency curve, or a decrease 53s4 in the alf’ us. frequency curve. For the latter case the experimental data may be represented by equation 22, where f,is the relaxation frequency, A is the relaxation amplitude, and B is the high frequency residual absorption, which is frequency independent. If more than one relaxation process (i.e.n processes) can occur, equation 22 is more accurately written as equation 23: R.A. Pethrick, J. Macromol. Sci. Revs. Macromol. Chem., 1973, 9, 91. 51 A. M. North and R. A. Pethrick, ‘International Reviews of Science, Physical Chemistry Series l’, ed. A. D. Buckingham and G. Allen, Butterworths, London, 1972. 52 A. J. Matheson, ‘Molecular Acoustics’, Wiley (Interscience), New York,1971. 53 K. F. Herzfeld and T. A. Litontz, ‘Adsorption and Dispersion of Ultrasonic Waves’, Academic Press, New York, 1959. ”R. A. Pethrick, Sci. Prog., 1970, 58, 563. 54a H. 0.Kneser, Ann. Phjx, 1938, 32, 277. Sonochemistry. Part 1-The Physical Aspects o! i=n +Bfl= (1 + Ai Absorption studies have proved important in the investigation of the structural aspects of liquids. Basically liquids may be classified into three groups according to their sound absorption proper tie^.^^ The first in which absorption only slightly exceeds the classical value (equation 7); the second, containing the majority of organic liquids, show large excess absorptions (a/mClass= 3--400).55 These large absorptions have been attributed to thermal relaxation due to the slow interchange of the internal and external energies.The third group, containing associated liquids, have tc/x,,,,, values of approximately 3. The excess sound absorption here is thought to be due to structural, rather than thermal relaxations, since the liquids have negative temperature coefficients of ab~orption.~~ The excess sound absorption characteristics of various binary aqueous especially alcohol-water mixtures, have attracted a great deal of This excess absorption, for a given experimental frequency varies greatly from one alcohol to another,56 depends strongly on the composition of the mixture, and decreases rapidly with rising temperature.With a change in the experimental frequency, the magnitude of the peak in the sound absorption concentration (PSAC) decreases and moves to a lower mole fraction of the non- aqueous component 75 (Figure 8). For all binary systems the existence of a PSAC is interpreted in terms of changes in the H-bonding (i.e. solute-solvent interaction), between like and unlike molecules (AA + WW = 2AW), the transfer equilibrium being displaced by the compression of the acoustic wave. Such displacement is opposed by potential energy barriers, and the molecular translations and reorientations called upon to occur within each half cycle introduce a relaxation which is the source of the excess absorption.55 L. A. Daridovich, A. A. Ivanov, S. Marakamov, L. Pulatova, P. K. Khabibullaev, M. G. Khaliulin, and Sh. Sharinov, Sor. Phys. Acousr., 1973, 19, 26. 56 A. D'Aprano, I. D. Donato, G. D'Arrigo, D. Bertolini, M. Cassettari, and G. Salvetti, Mol. Phys., 1985. 55, 475. "J. Glinski and S. Ernst, Pol. J. Chent., 1982, 56, 339. 58 B. Jezowska-Trzebiatowski, J. Glinski, and S. Ernst, Pol. J. Chem., 1984, 58. 859. s9 S. Nishikawa and T. Yamaguchi, Bull. Chem. SOL..Jpn., 1983, 56, 1585. S. Nishikawa and K. Kotegawa, J. Phys. Chem., 1985, 89, 2896. " T. C. Bhadra and B.Roy, Ulrrasonics, 1980. 18. 62 N. D. T. Dale, P. A. Flavelle, and P. Kruus, Can. J. Chem., 1976, 54, 355. 63 S. Nishikawa and N. Nakao, J. Chem. Soc., Furaday Trans. 1. 1985, 81, 1931. 64 C. J. Burton, J. Acoust. Soc. Ant., 1948, 20, 186. 65 G. Mikhailov and S. B. Gourevitch. Acd. Sci., URSS, 1956, 52, 673. 66 J. Thamsen, Acusricu, 1965, 16. 14. M. J. Blandamer. D. E. Clarke, N. J. Hidden. and M. C. R. Symons, Truns. Furaday Soc., 1968,64,2691. 68 M. J. Blandamer, N. J. Hidden, M. C. R. Symons, and N. C. Trelvar, Truns. Fururkuy SOL..,1968,64,3242. 69 M. J. Blandamer, 'Water: A Comprehensive Treatise, Vol. 2', ed. F. Franks, Plenum, New York. 1973.'"S. Rajagopalan and S. A. Tiwari, Arusric,u. 1985, 58, 98. 71 Y. S. Manucharov and I. G.Mikhailov. Sor. Phys. Acoust.. 1977, 23. 522. 72 L. R. D. Storey. J. Chem. Soc.. 1952, 43. 73 Y. Shindo, M. Nanbu. Y. Harada. and Y. Ishida. rZc~u.s/ic~u.1981. 48, 186. 74 S. Rauh and W. Knoche. J. Clirni. Soc.. Frrrurlaj, Trrms. I. 1985, 81, 2551. '' Y. Shindo and M. Nanbeutal. .4cws/iccr, 1981. 48. 186. Lorimer and Mason 30L ' ' ' ' ' ' ' ' 0.1 0.2 0.3 O.L 0.5 0.6 0.7 0.8 Mole Fraction MeOH Figure 8 Variation of absorption (af) in MeOH-H,O mixtures af 5 "C (ref. 70). (a) 10 MHz. (b) 200 MHz Ultrasonic velocity measurements 76-79 have also been used to study molecular structure 80-82 and interaction. 82-84 At any temperature the ultrasonic relaxation, arising from the perturbation of the equilibrium: where A and B are the two conformers, is accompanied by a variation in velocity according to (equation 24), where Cis the velocity at frequencyf, C, is the velocity at low frequency cf <A), C, is the velocity at high frequency (f % f,) and f, is the relaxation frequency.c,2 -c2 1 -em2-CO2 1 + Cl;(f)' Together with ultrasonic absorption 633-88 they afford a means of calculating 76 R. T. Beyer and S. V. Lecher, 'Physical Ultrasonics', Academic Press, New York, 1969 '-E. K. Baumgartner and G. Atkinson, J. Phys. Chem., 1971, 75, 2336. "Y. Wada, J. Phjs. Soc. Jpn., 1949, 4, 280. ''A. Giacomini, J. Acoust. Soc. Am., 1947, 19, 701. 'O M. R. Rao, Indian J. Phjs., 1941, 9, 682.'' A. Weissler, J. W. Fitzgerald, and I. Resnick, J. Appl. Phys., 1975, 18, 434.''J. Antosiewicz and D.Shugar, J. Solution Chem., 1983, 12. 123. 83 G. K. Joshri and R. C. Misra, Acustica, 1985, 57, 292. 84 A. Juszkiewicz, Pol. .I.Chem., 1984. 58, 11 15. '5 G. Gopal and N. P. Rao, Indian J. Pure Appl. PIiys., 1984, 22, 587. 86 R. Zana, J. Macromol. Sci. Rev., Macromol. Cheni., 1975, C12, 165. J. Emery and S. Gasse, Adv. Mol. Relaxation Interaction Processes, 1978, 12, 47. J. Emery and S. Gasse, ,4custica, 1979, 43. 206. 257 Sonochemistry. Part 1-The Physical Aspects both the kinetic 89790 (k, and k,,) and thermodynamic parameters (AGO, AHO, ASO, A p)for structural 90 and conformational 91 change. Relaxation in polymers may be divided into processes involving segmental motion of the backbone or side groups (independent of RMM) and overall co- operative motion of the whole backbone (RMM-dependent).Prior to the use of acoustic relaxation techniques 52 the study of segmental (and side-chain) motion was restricted mainly to dielectric relaxation studies on polar molecules (dielectric studies are unable to provide information regarding motion of a non-polar molecule), with investigation of whole chain movements 92 restricted to a study of the frequency-dependence of the shear viscosity of the polymer s~lution.~~,~~ Most experimental investigations of polymers use frequencies in the range 100 kHz-500 MHz, with the attenuation determined as a function of temperature, frequency, polymer concentration, and relative molar mass. Equation 23 95*96 is fitted, reiteratively, by computer to the experimental data in the frequency range investigated and the best fit * values of A l,f,l,and B are obtained by assuming that single, double, or multiple relaxation phenomena were involved.In general the dynamic spectrum of a polymer may be divided into two parts. The first is a low-frequency process, with a relaxation time (T,= +I&) which is molecular weight-dependent 97-100 and an amplitude (A)which correlates with the viscosity of the solution. The second is a high-frequency process which is molecular weight-dependent for low molecular weights and independent for higher molecular weights.’O1-lOz Single relaxation models lo3 (i.e. one value of A andf,) have been interpreted in terms of segmental motion of the backbone, whereas two relaxation models (A, andf,,: A, andf,,) have been interpreted in terms of motion of the backbone and the side-groups.For example, the data for several polyvinyl esters ‘04-lo7 have((~/~z)~~~~~~2)c~,c.)) * Error of fit is given by 89 S. Kato, H. Nomura, R. Zielinski, and S. Ikeda, Bull. Chem. SOC.Jpn., 1986, 59, 707. 90 S. Nishikawa, R. Shinohara, and G. Tanaka, Bull. Chem. SOC.Jpn., 1985, 59, 827. 91 P. K. Choi, Y. Naito, and K. Takagi, Chem. fhys. Lett., 1985, 121, 169. 92 J. D. Ferry, ‘Viscoelastic Properties of Polymers’, Wiley, New York, 1971. 93 B. H. Zimm, J. Chem. fhys,, 1956.24, 269. 94 P. E. Rouse, J. Chem. Phys., 1953, 21, 1272. 95 G. Schwarz, Rev. Mod. fhys., 1968, 40, 206; J. Rassing, Acta Chem. Sand., 1971, 25, 1506; G.W. Castellan, Ber. Bunsenges. fhys. Chem., 1963,67,898; P. Schimmel, J. Chem. Phys., 1971,54,4136; G.C.Hammes and W. Knoche, J. Chem. fhys., 1966,454041; G.C. Hammes and A. Park, J. Am. Chem. SOC.,1968, 90,4151. 96 T. Sano and Y. Yasunga, J. fhys. Chem., 1973, 77, 2031. 97 M. A. Cochran, A. M. North, and R. A. Pethrick, J. Chem. SOC., Faraday Trans. 2, 1974,70, 1274. 98 H. Hassler and H. J. Bauer, Kolloidn. Zh., 1969, 230, 194. 99 W. Ludlow, E. Wyn-Jones, and J. Rassing, J. Chem. Phys. Lett., 1972, 13, 477. loo B. Fruelich, C. Noel, and L. Monneric, Polymer, 1979, 20, 529. H. J. Bauer, H. Hassler, and M. Immendorfer, Faraday Discuss. Chem. SOC.,1970, 49, 238. lo2 S. Kato, N. Yamauchi, H. Nomura, and Y. Miyahara, Macromolecules, 1985, 18, 1496.Io3 A. Juszkiewicz, A. Janowski, J. Ranachowski, S. Wartewig, P. Hauptmann, and L. Alig, Acta folmerica, 1985, 36, 147. H. Nomura, S. Kato, and Y. Miyahara, J. Mat. Sci. Jpn., 1972, 21, 476. H. Nomura, S. Kato, and Y. Miyahara, J. Chem. SOC.Jpn., (Chem.Ind. Chem.),1972,1241; 1973,2398. Io6 Y. Masuda, H. Ikeda, and M. Ando, J. Mat. Sci. Jpn., 1971, 20, 675. lo’ 0.Funschilling, P. Lemarechal, and R. Cerf, Chem. fhys. Lett., 1971, 12, 365. 258 Lorimer and Mason been found to fit a double relaxation model yielding two values of A andf,. The low frequencyf, value (3-8 MHz), being almost independent of the length of the side chain, was interpreted as being due to motion of the backbone. The high frequency .f, value (60-150 MHz) decreased significantly with increase in the length of the side-chain and was associated with reorientational motion of the side-chain. A study of the dependence of the acoustic absorption coefficient (a) on polymer concentration (c) has in some cases yielded99~10'~'08~'09 breaks in the a us.ccurves. These break points have been ascribed 'lo to the increased polymer-polymer interactions which occur with the onset of chain entanglement ' ' in the solution. As with pure liquids, studies of the dependence of attenuation with temperature has allowed a determination of the various thermodynamic parameters (AGO, AP, A P,ASo) associated with the various conformational changes,' ' for example, the activation energy for polystyrene in CCl, lo' obtained by plotting the acoustic relaxation time against 1/T is in good agreement (-27.3 kJmol-') with the values obtained from dielectric studies ' in poly(p-chlorostyrene) ( -21 kJmol-') and n.m.r.'l4 measurements in the same solvent. The energies associated with the conformational change, however, depend not only on the nature of the group attached to the backbone, but also upon the configuration (i.e. tacticity '5, of the polymer. Certain configurations will have conformations which require lower activation energies to achieve a particular spacial arrangement than do others. For example, the acoustic energy difference between the conformational states of poly(a-methylstyrene) (PMS), when pre- dominantly syndiotactic, is greater than when the polymer is predominantly isotactic.This PMS value (8.3 kJ mol-') is also greater than that for the less- hindered polystyrene chain (5.4kJ mol-'). For polymethyl methacrylate,' l6 the energy differences for syndiotactic, atactic, and isotactic are 6.3, 6.3, and 3.7 kJ mol-' respectively. Interestingly, the chains with the lowest energy difference are also those for which the solid polymer has the lowest glass transition temperature (T'J. Indeed the Gibbs-Dimarzio energies calculated '' from Tevalues bear a close resemblance to the acoustic segmental conformational energies. Changes in the tacticity of the polymer also appear to have a marked influence on both the position and amplitude of the variation of the absorption coefficient (a) with frequency.' l6 More recently '' ultrasonic attenuation has been used to follow the progress of the emulsion polymerization of polyvinyl acetate.lo' R. Cerf, R. Zana, and S. Candau, C. R. Secinces Acad. Sci., 1961, 252, 2229; 1962, 254, 1061. Io9 P. Row-Chowdhury, Indian J. Chem., 1969, 7, 692. lo9' J. Lang, J. Chim. Phys. Phys.-Chim. Biol, 1969, 66, 88. J. R. Asay, D. L. Lamberson, and A. H. Guenther, J. Appl. Phys., 1969, 40, 1768. H. Nomura, S. Kato, and Y. Miyahara, Nippon Kagaku Zusshi, 1967,88,502; 1968,89,149; 1969,90,250. H. R. Berger, G. Heinrich, and E. Straube, Acfa Polyrn., 1986, 37, 226. 'I2 S. Nishikawa and R. Shinohara, J. Solution Chem., 1986, 15, 221. W. H. Stockmayer, H. Yu, and J. E. Davis, Polq'm. Preprints, 1963, 4, 132.'I4 D. W. McCall and F. A. Borey, J. PoI?;m. Sci., 1960, 45, 530. 'I5 J. H. Dunbar,A. M. North, R. A. Pethrick, and D. B. Steinhauer, J. Chem. SOC., Faraday Trans. 2, 1975, 71, 1478. 'I6 C Tondre and R. Cerf, J. Chem. Phys., 1968, 65, 1105. 'I' R. A. Scott and H. A. Scheraga, J. Chem. Phys., 1966, 44, 3054. 'I8 P. Hauptmann, F. Dinger, and R. Sauberlich, Polymer, 1985, 26, 1741. Sonochemistry. Part 1-The Physical Aspects Polyelectrolytes, combining the properties of polymers (chain flexibility) with those of electrolytes (strong electrostatic interaction) have also been investigated using ultrasonic relaxation methods.86g102 Because of the many processes which, theoretically, could give rise to excess ultrasonic absorption, e.g. segmental motion of backbone and side groups, solvation, proton transfer, and ion-pair formation, caution must be exercised in assigning the relaxations to a particular process.4 Kinetics For many chemical reactions the application of high power ultrasound has led to substantial improvements in both the reaction rate and product yield. The question as to the precise origin of these enhancements has not been fully resolved. The reactions must be the result of one or other (or possibly a combination) of the following: (a) reaction in the actual cavitation bubble,’ ‘9-’24 within which there are very high temperatures and pressures; (b) reaction as a result of secondary reactions125-127 taking place at the gas- liquid interface of the bubbles; (c) reaction as a result of the enormous pressures released on bubble collapse.’ 28-’ 30 What is certain is that all the above are consequences of cavitation. Despite the many experimental studies 14* ’ ’ in which ultrasonic chemical reactions have been investigated, few ’l 9-124,129.1 30*132-1 39 have received any detailed kinetic study of the effects of variations in irradiation frequency or intensity, the type of gas in the system or its concentration, or the solvent type and its solvent vapour pressure.Most have been investigations of the oxidation-reduction 25,127*140reactions of I19 K. S. Suslick, P. F. Schubert, and J. W. Goodale, IEEE Ultrusound S~mp.,1981, 612. 120 K. S. Suslick, J. J. Gawienowski, P. F. Schubert, and H.H. Wang, J. Phys. Chem., 1983, 87, 2299. IZ1 K. S. Suslick, J. W. Goodale, and H. H. Wang, J. Am. Chent. Soc., 1983, 105, 5781.’’’ K. S. Suslick, J. J. Gawienowski, P. F. Schubert, and H. H. Wang, Ultrusonics, 1984, 22. 33. D. J. Donaldson, M. D. Farrington. and P. Kruus, J. Plz~s.Chem., 1979, 83, 3130. P. Kruus and T. J. Patraboy, J. Pltys. Chent.. 1985, 89, 3379.’’’ A. Weissler. J. Am. Cheni. Soc.. 1958, 81, 1077. A. Henglein and C. Kormann, Int. J. Rad Biol., 1985. 48, 251. E. J. Hart and A. Henglein, J. Phy.Y. Cltmt., 1986, 90, 5992; 1986. 90, 5989. M. S. Doulah, Ind. Eng. Cheni., Fundurn., 1979, 18, 76. L29 E. C. Couppis and G. E. Klinzing, AlChE J., 1974, 20, 485.’” J. W. Chen and W. M. Kalback, Inti. Eng. Chmt., Fundurn., 1967, 6, 175.13’ A. Weissler. J. Acoust. Soc. Am., 1953, 25, 651. 132 S. Folger and D. Barnes, Itid. Eng. Chem., Fundmi.. 1968, 7, 222. 133 T. J. Mason and J. P. Lorimer, J. Chew. Soc., Chem. Cotnntutt., 1980, 1135. 134 T. J. Mason, J. P. Lorimer, and B. P. Mistry, T~~trahrdronLett., 1982, 23, 5563; 1983, 24, 4371. 135 T. J. Mason, J. P. Lorimer, and B. P. Mistry, Tetrahedron, 1985, 26, 5201. 13‘ T. J. Mason, J. P. Lorimer, and B. P. Mistry, ‘Ultrasonics International 85, Proceedings’, Butterworth, U.K., 1985. 839. 13’ T. J. Mason, J. P. Lorimer. and B. P. Mistry, J. Chem. Sor., Cliem. Commun., 1986. 611. ’” T. J. Mason and J. P. Lorimer, unpublished work. 13’ S. Witekowa. Actit Chin?.Acnti. Sci. Hung., 1972. 17. 97. 260 Lorimer and Mason aqueous solution and have been concerned with mechanistic 3291253126,141-145 14' rather than kinetic 14' In 1950 Miller aspects.studied the oxidation of air-saturated Fe2+ ions to Fe3+ ions using ultrasound of frequency 500 kHz. The Fe3+ yield was found to be dependent upon the length of insonation for up to 10 minutes duration, beyond this time non- linearity of yield was observed. Miller concluded that the oxidation reaction was an indirect process, due to the reactive HO- radical fragments produced from water (equation 25) and that the non-linearity of yield beyond 10 minutes was due to degassing of the solution. Weissler '25 using a frequency of 400 kHz (I = 2.5 W ern-,) investigated the effect of volatile scavengers (allylthiourea, acrylamide, and formic acid) on the sonochemical yield of hydrogen peroxide in oxygen- and argon-saturated aqueous solutions. The observation that formic acid proved to be a less efficient scavenger than either acrylamide or allylthiourea was unexpected since, being more volatile, it ought to find it easier to enter the vapour in the microbubble. From these experiments it was inferred that radical recombination to yield H,O, took place partly in the liquid phase.Although this view was supported by Henglein 125*126it was in contrast to the findings of Pecht 14' who found that whereas the non-volatile HO-scavengers, thallous and formate ions, did not affect the yield of H,O,, a number of different volatile organic solutes lowered the yield of H,O,.The inference was that radical recombination took place in the bubble phase. The presence of HO-radical has been established by Parke and Taylor 14' who produced ortho, rneta,and para (0> p > rn) hydroxybenzoic acid on irradiating air-, oxygen-, or nitrogen-saturated solutions of benzoic acid at 500, 1 000, and 2 000 kHz (I = 1.2 to 4.1 W cm-'). The authors also reported that hydroxylation took place for toluene, nitrobenzene, and phenol, though not for benzene itself. Anbar and Pecht 14* also showed that when deuterated formate ions were sonolysed in aqueous solutions, HD was produced indicating that Ha atoms were formed during the sonolysis process. Henglein studied the sonolysis of water in the presence of D, as a scavenger and observed that the proportion of HD increased with the amount of D, in the system, thereby indicating the presence of He radicals.At low concentrations of D,, HOD was observed as a consequence of the scavenging of HO. radicals. 14'N. Miller, J. Chem. Soc., Furudaj Trans., 1950, 46, 546. M. Anbar and I. Pecht, J. Phys. Chem., 1964, 68, 352. C. H. Fischer, E. J. Hart, and A. Henglein, J. Phys. Chem., 1986, 90, 222. 143 A. Henglein and C. H. Fischer, Eer. Eunsenges Phys. Chem., 1984, 88, 1196. 144 A. Henglein and R. Schultz, Z. Nuturforsch., 1953, 8, 277. 145 A. Henglein, NaturM.issenschuften, 1956, 43, 277. P. Riesz and S. Rustgi, Rudiat. Pliys. Cliem., 1979, 13, 21. 145b H. S. Frank and D. G. J. Ives, J. Chem. Soc., Quart. Ret.., 1966, 20, 1.146 M. A. Margulis, Soviet Physics-Acoustics, 1971, 16, 361. 14' A. V. Parke and D. Taylor, J. Chem. Soc., 1956,4442. 14'M. Anbar and I. Pecht, J. Phys. Chem., 1964, 68, 1460. 26 1 Sonochemistry. Part 1 -The Physical Aspects Recently Henglein 126*127 has extended his earlier investigations on the effect of organic additives 144 and gas concentration and type 145 on the sonochemical yields of iodine and hydrogen peroxide from aqueous iodide solutions. Using an irradiation frequency of 300 kHz, Henglein 12' observed that the yield of H,02 was at a maximum when the solution was saturated with a 30-70 mixture of O,/Ar. The increase in peroxide concentration with increase in oxygen content was explained in terms of suppression of the combination reaction (26) by reaction (27), with subsequent reaction (28) to yield H,O,, in addition to that formed by (29).Henglein has also been able to conclude, from scavenging experiments with a variety of organic solutes, that although a similarity exists between sonolysis and radiolysis, radiation studies do not explicitly predict the efficiency of a scavenger. More recently Riesz et using spin-trap techniques in conjunction with e.s.r., have provided direct and conclusive evidence for the formation of He and HO. radicals by the sonolysis of aqueous solutions. Of the few groups who have addressed themselves to detailed kinetic studies, most have considered reactions in aqueous media. Several '"-'30,132 have investigated the effect of ultrasound on the acid-catalysed hydrolysis of methyl ethanoate.The increased reaction rates (&lo%) have been attributed to different aspects of cavitation. Folger and Barnes 132 (using 27.5 kHz) considered that the increased reaction rates resulted from temperature effects associated with the microbubbles, whereas Couppis and Klinzing 129 (at 540 kHz and 780 kHz) and Chen and Kalback 130(at 23 kHz) attributed them to increased molecular motion due to the presence of the pressure gradient associated with the bubble. More recently Doulah'28 has provided evidence to suggest that they are a result of increased diffusion within the reacting system. Working at several different experimental intensities Couppis and Klinzing,' 29 and separately Folger and Barnes,13' have also observed an optimum power (at a given temperature) at which a maximum rate constant was obtained.Similar dependencies have been observed by other workers from product studies.' 50-' 53 Couppis and Klinzing '29 have also 149 K. Makino, M. M. Mossoba, and P. Riesz, J. Am. Chem. SOC.,1982, 104, 3537; ihid., J. Phys. Chem.. 1983, 87, 1369; ihid., Radiat. Res., 1983, 96, 416. C. Bondy and K. Sollner, J. Chem. SOC.,Faraday Trans., 1936, 32, 556. Is' S. Kusano, Tohoku J. Exp. Med., 1936, 30, 175. 152 0.Nomoto and S. Okui, J. Phys. SOC.,Jpn., 1948, 3, 47. 153 N. Sata and K. Nakasima, Bull. Chem. Soc. Jpn., 1943, 18, 220. 262 Lorimer and Mason demonstrated that the reaction rate constant decreases with an increase in frequency.Both observations agree with the theoretical predictions outlined in General Principles above. The effect of ultrasonic irradiation on the hydrolysis of 2-chloro-2-methyl- propane in aqueous alcoholic media has been studied in detail by Lorimer and Ma~on.'~~-'~~Initial studies 133 of the reaction in aqueous ethanol as solvent at 25 "Cusing a cleaning bath revealed modest rate enhancements (up to twofold) with the larger values obtained in the more alcoholic media. 1337134 Using a cuphorn device (at 20 kHz), capable of operating at different powers, and by studying the reaction at a variety of different temperatures and solvent compositions, the authors observed that the ultrasonic rate enhancement (up to 20 fold) increased with increase in the alcohol content and a decrease in the reaction temperature,'3s that there existed a maximum'36 in rate enhancement at an ethanol-water composition closely coincident with that thought to be the structural maximum 647141 for such systems, and that there existed an optimum power 136 at which a maximum rate enhancement occurred.The authors failed to obtain a simple relationship between rate enhancement and solvent vapour pressure. '36 Witekowa 139 has studied the effects of frequency, acoustic intensity, temperature, and nature of the gas on a wide variety of aqueous redox reactions. Of the twelve reactions investigated eight were found to proceed, under irradiation, by zero order kinetics, an observation noted by Lorimer and Mason for the aqueous polymerization of N-vinyl pyrrolidinone.'38 Although the redox reaction rates were found to be independent of the frequency employed (15,20,25,500,800,1000, 2 100 kHz), maxima were observed when plotted as functions of temperature and intensity as predicted by theory (see General Principles). In the presence of various gases the authors observed the following sequence of rate constants: kai, > koxygen> kargon> knilrogen.The larger rate constants in the presence of air and 0, were explained in terms of the production of the oxidizing radical, HO,. (equation 27). Several other investigations,' 54-' 56 though not so detailed, have also been reported. Kristol '54 has reported ultrasonically (20 kHz) induced rate enhancements for the hydrolysis of the 4-nitrophenyl esters of a number of aliphatic carboxylic acids. The rate enhancements at 35 "C were all in the range of 1615% and were independent of the size of the alkyl substituent (R = Me, Et, Pr', But) on the carboxylic acid.The authors concluded that the rate enhancements could not be due simply to an increase in the bulk temperature of the system (due to ultrasonic heating effect). This was based on the large differences in the energy of activation for the hydrolysis of each of the substrates which would result in considerable variations in rate enhancements if a simple heating effect alone were responsible for the enhancement. The rate enhancements were thought to D. S. Kristol, H.Klotz, and R. C. Parker, Tetrahedron Letf., 1981, 22, 907."'V. Griffing, J. Chem. Phys., 1952, 20, 939. lS6 W. C. Schumb and E. S. Rittner, J. Am. Ckem. Soc., 1940,62, 3416. Sonochemistry. Part 1-The Physical Aspects be most probably due to the intense localized pressure increase as a result of bubble collapse. Griffing et studied the effect of high frequency ultrasound (2 MHz, I = 6.5 W crn-,) on the acid-catalysed inversion of sucrose and observed no detectable rate enhancements, even though the solution visibly cavitated. The particular reaction was chosen since it proceeds at a reasonable rate at room temperature and has a high temperature coefficient-for this reaction a rise in temperature of 10 "C brings about a threefold increase in rate.Since sucrose has a negligible vapour pressure, hydrolysis must take place in the liquid phase so that the lack of enhancement with ultrasound was interpreted as indicating that there was no appreciable heating at the bubble-liquid interface. Although the first example of sonolysis in a non-aqueous solvent, the de- colorization of diphenylpicrylhydracyl (DPPH) radical in methanol, was reported in 1953,"' it took some 20 years to realize that cavitation could successfully be supported in organic solvents.' 58 The lack of progress in this area was the result of a combination of two factors (i) the failure to observe, in organic media, certain sonochemical reactions which occurred in water and (ii) the knowledge that the addition of organic solutes supressed sonochemically induced aqueous reactions. In hindsight it should have been argued that the lack of success was due to the higher vapour pressures of the organic liquids which, in turn, led to substantial lowering of the cavitational intensities in the organic media.In recent times, with the advent of more powerful instrumentation a resurgence of interest in non-aqueous studies has occurred, most notably in the field of synthetic organic chemistry, the subject of Part 2 of this review. Non-aqueous high intensity ultrasound can be broadly divided into three major areas. These are cavitation- induced decomposition of the solute or solvent, ultrasonically induced free-radical polymerization, and ultrasonic polymer degradation.The last two areas are dealt with in the section on Polymers. Chloroform 143 has been subjected to ultrasonic irradiation of frequency 300 kHz (I = 3.5 W cm-,) to yield a large number of products, the major proportion of which are unsaturated compounds. Decomposition was found only to occur in the presence of mono-or diatomic gases, free radicals being postulated as the intermediates based upon scavenging studies with 0, or cyclohexene. Somewhat earlier, Weissler 159 had confirmed the free-radical nature of such reactions by irradiating CCl, in the presence of Ar, O,, and 1-iodobutane. Recently, direct spectroscopic evidence for free-radical formation in the sonolysis of CCI, has been provided by Rosenthal. '6o According to the theory outlined in General Principles, the maximum temperature reached inside a collapsing transient bubble may be taken to be inversely proportional to the solvent vapour pressure (P,).If it can be assumed that the reaction mechanism in the bubble is governed by the Arrhenius equation, then 1 S7 R. Schultz and A. Henglein. Z. Nrrrui+rsc,/z.. 1953, 8. 160. 158 B. A. Niemczewski, U/trasonic.s, 1980, 18, 107. Is') A. Weissler. I. Pecht, and A. Anbar, Science, 1965, 150, 1288. 160 I. Rosenthal, M. M. Mossoba. and P. Riesz. J. Mogn. Reson.. 1981, 45, 359 264 Lorimer and Mason it follows (from equation 11) that the reaction rate constant (k)decreases with increasing solvent vapour pressure (equation 30). Ink = By combining the use of two dosimeters, Fe(CO), and DPPH, Suslick and co- workers ' '9-' 22,16 ' have evaluated the effectiveness of various solvents in producing cavitational sonochemistry and free-radical formation in particular.Although the authors neglected the effects of viscosity, surface tension, and bond dissociation energy, the correlation between experimental rate-constant and solvent vapour- pressure met with reasonable success.' 20-' 22 The higher the vapour pressure of the solvent medium the lower the rate of decolorization of DPPH. Kruus has also obtained a similar, though somewhat less successful correlation for the polymerization of nitrobenzene, at 20 kHz and 20 W cm-', in the presence of various gaseous and liquid solutes. The reaction rate was not only lowered by the presence of a liquid solute with high vapour-pressure, it was also lowered by the presence of a gaseous solute with a high solubility.Finally, whenever kinetic investigations are undertaken into the effect of ultrasound, care must be exercised in deciding upon the method of monitoring the reaction progress. Previous studies '19,162-164 have shown that the ultrasonic intensity is dependent upon the irradiation depth of the liquid. In a recent investigation into the ultrasonic polymerization of methyl methacrylate, Kruus 124 developed kinetic equations to compensate for the reduction in volume on removing aliquots from a sonicated reaction. This volume compensation, though useful in most circumstances, may not be strictly correct in cases where a substantial lowering of liquid height occurs.5 Sonoluminescence Sonoluminescence is the name given to the light emitted when a liquid cavitates. The emitted light has been detected by a number of methods which include the naked eye,'65 exposure of photographic plates,'66 the use of photo-66p'multipliers,' 69 and image intensification technique^."^^'^' Since its first observation '72 in 1933, many explanations have been offered for the origin of the effect. They fall into two broad categories, thermal and electrical. 16' K. S. Suslick. P. F. Schubert, and J. W. Goodale, J. Am. Cliem. Soc., 1981, 103, 7342. 16' F. G. P. Aerstin, K. D. Timmerhaus, and H. S. Folger, AICIiE J., 1967, 13, 453. 163 S. Folger, Ind. Eng. Cliem., Fundam., 1968, 7, 387.164 B. Pugin, Ultrasonics, 1987. 25. 49. Ih5 L. A. Chambers, J. Chem. Pliys., 1937, 5, 290. lhh R. D. Finch, Ultrasonics, 1964, 1, 87. lh7 C. Seghal, R. P. Steer, R. G. Sutherland, and R.E. Verrall, J. Cliem. Phys., 1979, 70, 2242. lh8 C. Seghal, R. G. Sutherland, and R. E. Verrall, J. Phys. Chem., 1980, 84, 396. Ihy C. Seghal, R. G. Sutherland, and R. E. Verrall, J. Phys. Chem., 1980, 84, 388."'G. T. Reynolds, A. J. Walton, and S. Gruner, Rev. Sci. Instrum., 1982, 53, 1673. L. A. Crum and G. T. Reynolds, J. Acoust. Soc. Am., 1985, 78, 137. N. Marinesco and J. J. Trillat, C. R. Seances Acud. Sci., 1933, 196, 858. Sonochemistry. Part 1-The Physical Aspects A. Thermal Theories.-These include: the hot-spot theory,8" 73 in which the temperatures produced in the microbubbles produce incandescence; the thermochemical theory, according to which the heating of the vapour-gas mixture in a collapsing bubble results in thermal dissociation or ioniza- tion of the water molecules, the light originating from the recombination of radicals '74-1 76 or ions; '77 the mechanico-thermal theory, proposed by Jarman,' 78 in which the collapse of a cavitation bubble is assumed to give rise to high tem- peratures,pressures,and light radiation,similar to thecaseofconvergingshockwaves.B. Electrical Theories.-These have been proposed by Nathanson,' 79 Degrois and Baldo,'" Harvey,18' and Frenkel,'82 the last named suggested that on creation of the cavity (initially lens shaped) charges form on opposite sides of the cavity.Under certain conditions micro-discharges occur to produce light. Although, more recently, Margulis 183 has proposed a new electrical theory which more satisfactorily accounts for the experimental observations than previous theories, 180 the thermal theories appear more acceptable.' 84 There is now sufficient spectral evidence to show that sonoluminescence originates mainly from the recombination of radicals created within the high temperature and pressure environment of both transient and stable cavitation bubbles. A particular example is the emission observed by Verrall 167 from argon- saturated aqueous alkali-metal halide solutions during insonation at 460 kHz. The emission is ascribed to the de-excitation of excited alkali-metal atoms formed by free-radical reduction process.Verrall et have also used sonoluminescence to measure indirectly the intercavity temperature and pressure within a collapsing bubble. The values obtained (3 400 K and 310 atm) were substantially less than those predicted theoretically (9 500 K and 12 400 atm). They ascribed the differences to thermal conductivity of the gas.46 Investigations have also been undertaken into the dependence of sonoluminescent intensity on the nature of the liquid,' 85,186 the nature of the dissolved gas,46,168,187 the liquid temperat~re,'~~*'~~*'~~-'~~ 173 D. Srinivasan and L. V. Holroyde, J. Appl. Phys., 1961, 32, 446. 174 V. Griffing and D. Sette, J. Chem. Phys., 1955, 23, 503.175 V. Griffing and D. Sette, Phys. Rev., 1952, 234. 176 C. Sehgal, R. P. Steer, R. G. Sutherland, and R. E. Verrall, J. Phys. Chem., 1977, 81, 2618. 17' M. A. Margulis, Russ. Acoustic J., 1969, IS, 153. 178 P. D. Jarman, J. Acoust. SOC.Am., 1960, 32, 1459. G. L. Nathanson, Dokl. Akad. Nauk SSSR, 1948, 59, 83. M. Degrois and P. Baldo, Ultrasonics, 1974, 14, 25. la' E. N. Harvey, J. Am. Chem. SOL..,1939,61, 2392. Ya. I. Frenkel, Rum. J. Phys. Chem., 1940, 14, 305. M. A. Margulis, Russ. J. Phys. Chem., 1985, 59, 1497. T. K. Saksena and W. L. Nyborg, J. Chem. Phys., 1970.53, 1722. P. Jarman, Proc. R. Soc. Land., 1959, 73, 628. P. 1. Golubinchii, V. D. Goncharov, and Kh. V. Protopopov, Sou. Phys. Acousr., 1971, 16, 323. lB7 R. 0.Prudhomme, Bull.SOC.Chim. Biol., 1957, 39, 425. V. P. Gunther, W. Zeil, U. Grisar, and E. Heim, Z. Electrochem., 1957, 61, 188. G. Iernette, Acusrica, 1972, 26, 112. 190 P. K. Chendke and H. S. Folger, J. Phys. Chem., 1985, 89, 1673. Lorimer and Mason the presence of impurities,' 8491889191 ultrasonic inten~ity,'~~and fre-quency.' 69 6 Polymers A chemist has at his disposal two types of ultrasonic wave, high intensity (usually low frequency) and low intensity (usually high frequency), which are used for two different areas of investigation. The use of low intensity waves provides information on relaxation phenomena 81,192,193 such as segmental m~tion,'~~~'~~ conforma-tional change,s6 vibrational-translational energy interchange l and polymer- solvent interactions.High intensity waves have been used to effect such chemical changes as polymerization and depolymerization. Applications of the former type of irradiation have been dealt with elsewhere (see Relaxation Studies). A. Degradation of Polymers.-It is now well established 473195-208 that the prolonged exposure of solutions of macromolecules to high energy (>10 W cm-2) ultrasonic waves produces permanent reductions in the solution viscosity. Even after the irradiated polymers are isolated and redissolved, their viscosities remain low in comparison to those of the initial non-irradiated solutions. Schmid 195,196,209 and Mark 210 did not invoke cavitation to explain these observations since degradation still occurred even when the systems were degassed or pressurized.They suggested that degradation occurred as a result of the increased frictional forces developed between the faster moving solvent molecules and the larger, less mobile, macromolecule. Although envisaging different modes of interaction between the solvent molecules and the macromolecule, both authors concluded that the increased frictional forces were sufficient to break an atomic C-C bond. Schmid '95 considered two ideal cases: the first in which the macromolecules were tightly held in solution and the solvent molecules were swept rapidly past them by the applied acoustic field, and a second which involved allowing the macromolecule 19' V. L. Levshin and S. N. Rzhevkin, Dokl. Akad. Nauk SSSR., 1937, 16, 407.192 S. K. Hassun, S. H. F. Al-Madfai, and M. M. F. Al-Jarrah, Br. Polym. J., 1985, 17, 330. 193 M. F. Haque, S. J. Fast. S. S. Yun, and F. B. Stumpf, J. Acoust. SOC.Am., 1985, 77, 2181. 194 A. Juszkiewica, A. Janowski, and J. Ranachowski, Acra Polym., 1985, 36, 147. 19s G. Schmid and 0.Rommel, Z. Phps. Chem., 1939, A185,97. 19' G. Schmid and 0.Rommel, 2. Elektrochem., 1939, 45, 659. G. Schmid, Phjs. Z., 1940, 41, 326. 19' G. Schmid and E. Beutenmuller, Z. Elektrochem., 1943, 49, 325; 1944, 50, 209. 199 H. H. Jellinek and G. White, J. Polpm. Sci., 1951, 6, 745; 1951, 6, 757; 1951, 7, 33. M. A. K. Mostafa, J. Polym. Sci., 1956, 22, 535; 1958, 27, 473; 1958, 28, 499; 1958, 28, 519. A. Weissler, J. Appl. Phys., 1950, 21, 171. '02 A.Weissler, J. Chem. Phys., 1950, 18, 1513. '03 H. W. Melville and A. J. R. Murray, J. Chem. Soc., Faraday Trans., 1950, 46, 996, '04 N. Sata, H. Okuyama, and K. Chujo, Kolloidn. Zh.. 1951, 121, 46. '05 P. E. M. Allen, G. M. Burnett, G.W. Hastings, H. W. Melville, and D. W. Ovenall, J. Polym. Sci., 1958, 33, 213. '06 D. W. Ovenall. G. W. Hastings. and P. E. M. Allen. J. Polym. Sci., 1958, 33, 207."' G. Gooberman, J. Po1j.m.Sci., 1960. 42. 25. '08 G. Gooberman and J. Lamb, J. Polym. Sci., 1960, 42, 35. '09 G. Schmid, 2. Phj~Chem., 1940, 186A, 113. Sonochemistry. Part 1-The Physicul Aspects to move with the solvent molecules under the action of the ultrasound. Mark2'' recognized that molecular configuration would influence the extent of the frictional forces, and so included micro-Brownian motion of the rotating polymer segments as well as the macro-Brownian motion of the whole polymer molecule.Since the frictional forces depend upon the size of the macromolecule, then no matter which interpretation is adopted, both predict that the extent of degradation should decrease with chain size. Based upon experimental data, Schmid 19s9196 was able to show this mathematically for dilute solutions (<0.02M) (equation 31) and for concentrated solutions (equation 32) where dx is the number of chemical bonds broken in unit volume in an irradiation time dt, P,is the degree of polymerization at time t, Po is the initial degree of polymerization and P, is the limit degree of polymerization.Although this limit degree of polymerization has been observed by many worker^,^^^,^' different values have been quoted by different authors for a given p~lymer.'~~,~~~,~ 13*2l4 This discrepancy arises from the early investigators' use of viscosity measurements to determine molar mass ([q] = KM")and the difficulty lS in deciding upon K and u values. There is now a wealth 35,48,49.199,201,207.2 14,216--2 19 of experimental evidence to suggest that degradation is due to cavitation effects. What is debatable, however, is whether the degradation is caused by (i) the hydrodynamic 203*207,208.219 forces of cavitation (i.e. the shock-wave energies produced on bubble implosion), (ii) the shear stresses at the interface of pulsating bubbles,21 or (iii) the associated thermal and chemical effects of both stable and transient cavitation, since all of the above are dependent upon the same factors i.e.intensity, frequency, gas content and type (see General Principles). For instance48~49~'99*201"6'2'79220*221diatomic gases (N2, 02,H2) are found to enhance depolymerization, whereas polyatomic gases (NH,, SO2, CO,), which also have increased solubility as well as decreased y values, inhibit depolymerization. Degassed solutions have been found to exhibit no depolymerization 210 H. F. Mark, J. Acoust. Soc. Am., 1945, 16, 183. *11 M. A. K. Mostafa, J. Polym. Sci.,1958, 33, 295; 1958; 33, 311; 1958, 33, 323. 212 H. Okuyama, Z. Elektrochem.. 1951, 59, 565. 'I3 G. Schmid, C. Schneider, and A.Henglein, Kolloidn. Zh., 1956, 148, 73. '14 N. H. Langton and P. Vaugham, Br. J. Appl. Phys., 1957, 8, 289. 215 V. V. Korshak and S. R. Rafikov, Dokl. Akad. Nauk SSSR., 1949, 64, 211. 2'6 A. Weissler, J. Acoust. Soc. Am., 1951, 23, 370. 'I7 F. Gebert, Angew. Cltem., 1952, 64, 625. '18 G. Schmid, P. Paret, and H. Pfleiderer, Kolloidti. Zh., 1951, 124, 150. 219 M. S. Doulah, J. Appl. Polym. Sci.,1978. 22, 1735.'"A. Botinov, P. Kubeko, and F. Marci, Zh. Fiz. Khim., 1942, 16, 106. 221 A. Henglein and R. Schultz, Z. Naturforsch., B, 1952, 7, 484. Lorimer and Mason a c0 lc1 (b) 1000 a I 1 I (a1 1 0.5 1:o 1.5 2.0 Irradiation Timelh Figure 9 Degradation of 1% poly(styrene) in benzene at dgferent ultrasonic frequencies (ref.211).(a) 1 MHz. (b) 1.25 MHz. (c) 1.5 MHz. (d) 2 MHz Most workers in the field 3s,211,212*222agree that increasing the frequency of the ultrasound leads to a decrease in the extent of depolymerization (Figure 9). This, no doubt, is due in part to the need, at higher frequencies, to employ greater intensities to ensure cavitation. For instance, although Gaertner 35 has observed depolymerization at both 400 kHz and 2 500 kHz, the lower frequency only necessitated an intensity of 0.5 W cm-2 whereas the higher frequency required approximately 2 KW crnp2. Higher frequencies also provide for shorter periods in which bubble growth and collapse can occur (see General Principles). It is likely that at the higher frequencies (at the same intensity) there is insufficient time available to produce cavitation.Although investigating a polymerization process, Henglein 222 confirms this view. He found that the polymerization rate (and degree of polymerization) of acrylamide (in water), at a given frequency, using pulsed ultrasound, depended upon the duration of the pulse. As the duration of the pulse was reduced, the rate of polymerization decreased. In respect of ultrasonic intensity, Gebert’” has shown that an increase in intensity leads to an increase in the extent of depolymerization. Whatever the mechanism involved, depolymerization results in the breakage of an atomic bond in the macromolecule to produce long-chain radical species. The existence of these radical entities is easily established by investigating the depolymerization process 223-226 in the presence of a radical scavenger such as DPPH.227 Spectroscopic analysis of the loss of DPPH = 525 nm) allows both a determination of the depolymerization rate and the number of break points 222 A.Henglein, Makromol. Chem., 1954, 14, 15. 223 A. Henglein, Makromol. Chem., 1955, 15, 188. 224 1. E. El’piner, Akust. Zh., 1959, 5, 133. 225 A. S. Berlin, Dokl. Akad. Nauk SSSR., 1956, 110, 401. 226 J. R. Thomas, J. Phys. Chem., 1959, 63, 254. 227 C. E. H. Bawn and S. F. Mellish, J. Chem. SOC.,Faraday Trans., 1951, 47, 1216. 269 Sonochemistry. Part 1-The Physical Aspects in the macromolecule. (To estimate the number of break points it must be assumed that two DPPH molecules are consumed per bond break.) In the absence of radical scavengers the molecular fragments are free to recombine by the usual termination mechanisms.Combination termination will produce macromolecules of the same, or differing lengths, as those existing just prior to bond breakage depending upon whether the combining molecular fragments are from the same or differing polymer chains. Disproportionation termination between fragments, no matter what their origin, must result in smaller macromolecules. Henglein has investigated the probability of the combination reactions for several polymers.223,228,229 Direct evidence for the formation of macroradicals in the degradation of poly(methy1 methacrylate), polystyrene, and poly(viny1 acetate) has been provided by Tabata230,231 using spin trapping and e.s.r.techniques. From studies in which deuterium-labelled polymers were used it was concluded that degradation took place by main-chain homolysis as a result of ultrasonically induced hydrodynamic action on the polymer. Perhaps one of the distinctive and remarkable effects of these competing degradation and recombination processes is the reduction in the polydis-persity 203,204.21 1,213,232 of a polymer sample (i.e. reduction in the M,:Mnratio). Although the absolute magnitude of a polymers relative molar mass (M, or M,)is important, there is a whole series of physicochemical properties, such as film formation, chemical stability, solution flow etc. which depends upon the degree of polydispersion.According to several workers 204*213*233*234 there is a high probability of breakage of chemical bonds at any site in the molecular chain, on applying ultrasound, provided P 9 P,. This random scission ought to result in a mixture of molecular fragments of various lengths, and an increase in the polydispersity, certainly in the initial periods of irradiation. With the passage of time, the smaller molecular fragments so produced are broken into equal halves4*235,236so that long exposure leads to the attainment of an almost monodisperse solution of the polymer. The present authors can confirm that, for certain macromolecules, degradation takes place with an initial increase in p~lydispersity.'~~Further, they have observed that the shape of the macromolecule, as determined by viscosity studies, changes with irradiation time.Unlike chemical or photodegradation, ultrasonic degradation does not appear to take place predominantly at the points of inherent weakness within the polymer's backbone. For example, Melville 203 has shown that degradation of two 228 A. Henglein, Z. Naturforsch., B, 1955, 10, 616. 22q A. Henglein, Makromol. Chem., 1956, IS, 37. 230 M. Tabata, T. Miyanawa, 0.Kabayashi, and J. Sohma, Chem. Phys. Lett., 1980, 73, 178. 13' M. Tabata and J. Sohma, Eur. Polym. J., 1980, 16, 589. 232 K. Edelmann, FasserJorsch. Textiltech., 1953, 10, 407. 233 P. A. R. Glynn, B. M. E. Van der Hoff, and P. M. Reilly, J. Macromol. Sci., Chem., 1972, A6, 1653. 234 P. A.R. Glynn and B. M. E. Van der Hoff, J. Macromol. Sci., Chem., 1973, A7, 1695. 235 A. Basedow and K. H. Ebert, Makromol. Chem., 1975, 176, 745. 13' A. Basedow and K. H. Ebert, Pol-ymer Bulletin, 1979, 1, 299. Lorimer and Mason separate polymethylmethacrylate (A)-acrylonitrile (B) copolymers (molar ratios of A:B of 40: 1 and 400:1 respectively) yielded almost identical molar masses after irradiation with ultrasound. If it is assumed that the A-B linkages are appreciably weaker than the corresponding A-A or B-B linkages, then, as in the case of thermal degradation, appreciably different molar masses ought to have been obtained. Those readers wishing a more quantitative discussion of depolymerization are referred to articles by Jellinek 237 and Glynn.233,234 B.Polymerization.-It is well known that the structural, physical, and physicochemical characteristics of macromolecules depend not only on the nature of the monomer (homopolymer) or monomers (copolymer) from which they are synthesized, but also on the method of production (e.g. graft, block, or random copolymers). For instance, whereas random copolymerization of two monomers A and B produces a polymer with a property (e.g. solubility, polarity) which is the weighted average of the two constituent monomers, block (or graft) copolymers have properties which are the sum of the two homopolymers. Typically a graft copolymer consisting of water soluble (polyethylene oxide) and oil-soluble (polystyrene) components is capable of dissolving in both solvent types.In the previous section it was shown that ultrasound was capable of producing radical entities. It is not surprising, therefore, that the application of ultrasound to polymer synthesis has attracted the attention of many investigators. Until recently, most of the work involved applying ultrasound to systems containing a mixture of homopolymers in the hope of producing graft or block copolymers, rather than in the initiation of polymerization from monomer. The latter study suffers from the complication that as the polymerization proceeds and the concentration of poly- mer increases, the competing depolymerization reaction will become increasingly more significant. It is also likely that the increase in viscosity accompanying the reaction will lead to a change in the acoustic environment within the system.(See General Principles). Keqiang 38 has successfully produced block copolymers, based upon cellulose, while Henglein 223,228.229 has produced both graft and block copolymers using polystyrene and polymethyl methacrylate. Malh~rta,~~~ employing a variety of homopolymers (rigid and flexible), has met with limited success in the synthesis of block copolymers. In each of the above syntheses degradation of the homo- polymers by ultrasound provides long-chain radicals of each component which terminate by combination. However both homopolymers must have degrees of polymerization greater than PIto ensure production of a radical entity.239 The fact that irradiation by ultrasound leads to the breakage of only a limited number of bonds in the macromolecule, yet the yield of block copolymer may be as high as 90% in some cases, has prompted Berlin 240 to suggest that the macroradical is also capable of degrading a stable macromolecule.The suggestion that a radical could 23’ J. J. G. Jellinek, ‘Degradation of Vinyl Polymers’, Academic Press, New York, 1955 238 C. Keqiang, S. Ye, L. Huilin, and X. Xi, J. Mncromol. Sci., Chem., 1985, A22, 455. 239 S. L. Malhorta, J. Mncromol. Sci., Chem., 1981, A18, 1055. 240 A. A. Berlin, Usp. Wzim., 1960. 29, 1189. 271 Sonochemistry. Part I -The Physical Aspects itself cause degradation of a polymer chain has been supported by Ramsden and McKay 241 who reported that hydroxyl radicals were capable of inducing chemical degradation of polyacrylamide.Block copolymers have also been produced by irradiating a solution containing a homopolymer (from monomer type A) and a monomer (type B).242 In such cases polymerization of the monomer (B) is initiated by the macroradical produced by ultrasonic degradation of the homopolymer. In cases where polymer was absent, no polymerization occurred. Similar findings have been reported 240*243,244 by other workers when attempting to homopolymerize pure vinyl monomers in the presence of ultrasound. Such observations are in direct contrast to the findings of other workers 124,221,222,245,246 including the present authors. Ultrasonic waves (I = 8 W cm-2) have been found to initiate the polymerization of acrylonitrile in aqueous media saturated with N2.245 The initiating species are presumably HO-radicals from the decomposition of water (equation 26).Berlin 247 confirms this opinion in his investigation of the polymerization of polystyrene in the presence of styrene monomer since addition of water to the solvent (benzene) greatly enhanced the yield of polymer. It could be argued, however, that the appearance of water decomposition products (e.g. H,02) led to oxidation of the various impurities, which previously, may have acted as inhibitors. Ultrasonic waves have also been found to increase the rates of emul-sion 221,222,246,248-250 and suspension2 polymerizations. Various explanations have been proposed to explain the increase in rate.These include (i) the oxidation of impurities (see above), (ii) the removal of oxygen (known to inhibit radical reactions) by ultrasonic degassing, (iii) ultrasonic degradation of the polymer to provide more active sites (i.e. autocatalysis), and (iv) prevention of agglomeration between droplets, or the sticking of the droplets to the walls of the reaction vessel, in suspension polymerization. Few workers 130,242.252.253 have investigated the effects of varying such parameters as frequency, intensity, temperature, and the nature of the gas, on the polymerization process. Berlin 242 has shown that for the block copolymerization of polymethyl methacrylate with acrylonitrile, the time required to produce a given amount of polyacrylonitrile in the block decreased with increasing intensity.Kruus 124 has been able to show that there is a propagation rate (R,)dependence, for the bulk polymerization of methyl methacrylate, on the square root of the 241 D. K. Ramsden and K. McKay, P0lj.m. Deg. Stab., 1986, 15, 15. 242 A. A. Berlin and A. M. Dubinskaya, Bysokomole Kulyameje Soedin., 1960, 2, 1426. 243 K. F. Driscoll and A. U. Sridhari, J. Appl. Pofym. Sci., Appl. Pofym.Symp., 1975, 26, 135. 244 H. Fujiwara and K. Kimura. Polym. J., 1981, 13, 927. 245 0. Lindstrorn and 0.Lamm, J. Pli~s.Colloid Chem., 1951, 55, 1139. 246 P. Alexander and M. Fox, J. Polym. Sci., 1954, 12, 533. 247 A. A. Berlin and B. S. El'tsefon, Khini. Nauka Prom., 1957, 2, 667. 248 A. S. Ostroski and R.B. Starnbaugh, J. Appf. Plijs.3 1950, 21, 478. 249 N. Sata and Y. Harisaki, Kolloidti. Zli., 1951, 124, 36. 2so R. Fox, E. Yaeger, and F. Hovorka, J. Acoust. SOC.Am., 1960,32, 1499. 25' Y. Hatate, T. Ikeura, M. Shinonome, K. Kondo, and F. Nakashio, J. Cliem. Eng. Jpn., 1981, 14, 38. 2s2 T. Miyata and F. Nakashio, J. Chem. Engl., Jpn., 1975, 8, 463. 253 J. R. McKee and C. J. Christrnan, Bioclienristry, 1977, 16, 4651. 272 Lorimer and Mason intensity (I*),as is the case for photopolymerization. The present authors have found that at a given temperature and irradiation frequency (T = 60,f= 20 kHz), there is a maximum in the R, us Icurve for the solution polymerization of NVC.138At very high intensities (>10 W cm-2) the conversion is negligible.Henglein 222 has shown that the degree of polymerization decreases when the duration of pulsed ultra- sound is decreased. The growth and collapse of cavitation bubbles require a finite time-they are not instantaneous. Henglein 221 has also shown that the rate (and degree of polymerization) depends upon the nature of the gas used to saturate the system. For the polymerization of methacrylic acid in aqueous solution, a 15 minute irradiation yielded 10.7% conversion in the presence of N,, 1.8% conversion in the presence of 0, (low presumably due to inhibition), and no polymerization in a degassed solution). Kruus'23*'24 is one of the few investigators who has attempted to interpret the results of ultrasonically induced polymerizations in terms of equation 11 (General Principles).For the polymerization of nitrobenzene 123 he has observed, as predicted by equation 30, that the polymerization rate (measured as solution darkening) decreases both in the presence of gases with high solubility (e.g.SO, and CO,) and solutes with high vapour pressures. The model used, although containing serious oversimplifications, allows for a deduction of the minimum and maximum temperature, in the region of bubble collapse, of 600 K to 40000 K. Using a similar model he has been able to explain the conversion of methyl methacrylate (bulk polymerization) in terms of reaction time, reaction volume, and ultrasonic intensity. Polymer yields and molar masses (Y = 3% in 2 h; T = 40 "C;I = 20 W cm-'; M, = 700000) were somewhat lower than those found by the present authors for the solution polymerization of NVC (Y = 30%, T = 60 "C, I = 30 W cm-,; M, > 2 x lo6).Kr~us'~~ has also determined activation energies for the bulk polymerization of methyl methacrylate in the presence of ultrasound. The value obtained (-19 kJ mol-') is similar to that observed for the bulk thermal polymerization reaction (17-20 kJ mol-'), provided the contribution from the initiation step is excluded. This close correspondence in activation energies suggests that the effective activation-energy for the initiation step, in the presence of ultrasound, may be taken to be 0 kJ mol-I, as is the case in photopolymerization. Kruus also studied the polymerization in the presence of the radical scavenger DPPH.Unfortunately the rates of initiation as deduced from both the overall polymerization rate and the rate of DPPH consumption, although of similar magnitude, showed inexplicable differences in temperature dependence. Recently Toppare 2s4 has investigated the use of ultrasound (25 kHz) on the rate of polymerization, and copolymer composition, of the electroinitiated cationic polymerization of isoprene with or-methylstyrene. In the presence of ultrasound the total :< conversion was found to increase with the polymerization potential (E). The authors attributed this to a 'sweeping clean' of the electrode surface due to the action of ultrasound. The proportion of isoprene incorporated in the copolymer, under sonication, was found to pass through a maximum value of 54% when the 2s4 U. Akbulut, L. Toppare, and B. Yurttas, Polymer. 1986, 27, 803. Sonochemis try. Part 1-The Physical Aspects polymerization potential was 2.6 volts. Little work has been performed on the effect of frequency on polymerization rate (and yield). Frequency is a factor which determines cavitation threshold, size of bubble, and the time scale of bubble growth and collapse. It is anticipated that changing frequency will alter the polymerization process.

ISSN:0306-0012    

DOI:10.1039/CS9871600239

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Clzern. Soc. Rev., 1987, 16, 275-311 SonochemistryPart 24ynthetic Applications By James Lindley and Timothy J. Mason SCHOOL OF CHEMISTRY, COVENTRY POLYTECHNIC, COVENTRY CV1 5FB 1 Introduction A large number of articles have been published over the past few years which describe the various applications of ultrasound to chemical synthesis. These have encompassed organic, organometallic, inorganic, and polymer chemistry together with some aspects of catalysis. As a result of this the majority of chemists will be aware of the developing science of sonochemistry, to the extent that some have already been tempted to experiment with ultrasound in their own laboratories. This, the second part of the review, is designed to provide an overview of the synthetic aspects of sonochemistry for chemists in both academic and industrial laboratories.Sonochemistry is not a new subject-it was under active investigation over 50 years ago! There are literature references to applications in polymer and chemical processes in the 1940~.''~The renascence of the subject which has occurred over the past few years is undoubtedly due to the more general availability of commercial ultrasonic equipment. In the 1960s the ultrasonic cleaning bath began to make its appearance in metallurgy and chemical laboratories. Having seen the way in which these baths cleaned soiled glassware and dispersed immiscible organic solvents in aqueous detergent it was not surprising that chemists began to consider using them to enhance chemical reactivity-as indeed we ourselves did in the early 70s.It was not long before some remarkable syntheses were achieved in this manner, one of the first being that reported by Fry in 1978 involving the use of ultrasonically dispersed mercury in acetic acid for the reduction of a,x'-dibromoketones to a mixture of a-acetoxyketone~.~The reaction was performed by dissolving the dibromoketone in acetic acid and dispersing a small amount of mercury in the medium by means of an ultrasonic laboratory cleaning bath, for 1-4 days. After this publication, and others of similar type, interest in the application of ultrasound to chemical synthesis started growing. In the 1970s ultrasonic cell disruptors began to be used on a regular basis in biology and biochemistry laboratories.Such instruments offered the chance of introducing greatly increased ultrasonic power into chemical reactions at a modest cost. A number of reviews on the chemical applications of ultrasound have been published over the past few years.4-' I A. Weissler. J. C'heni. Eiiuc.. 1948, 28. H. Mark, J. Acoust. Soc. Am., 1945, 16, 183. A. J. Fry and D. Herr. Tetrahedron Lrtr., 1978, 19. 1721.'J.-L. Luche, L'actua(ite chirniyue, 1982, 21.'P. Boudjouk, Nadir. Cizeni. Tech. Lab., 1983, 31, 78.'T. J. Mason, Lab. Pracr., 1984. 13. 275 Sonochemistry. Part 2-Synthetic Applications In part 1 * the types of ultrasound which are used in chemistry were broadly divided into power ultrasound, between 20 and 100 kHz, which is used for cleaning, plastic welding, and to affect chemical reactivity and high frequency ultrasound, in the 2-10 MHz range, which is used in medical scanning, chemical analysis, and the study of relaxation phenomena.For the majority of synthetic chemists interest in sonochemistry will be in power ultrasound because this provides a form of energy for the modification of chemical reactivity which is different from that normally used i.e. heat, light, and pressure. Power ultrasound produces its effects via cavitation bubbles. These bubbles are generated during the rarefaction cycle of the wave when the liquid structure is literally torn apart to form microbubbles which collapse in the compression cycle. It has been calculated that pressures of hundreds of atmospheres and temperatures of thousands of degrees are generated on collapse of these bubbles.The synthetic chemist will be mainly concerned with reactions in solution, and the effects of ultrasound in such cases are best summarized in terms of four different reaction types. A. Reactions involving Metal Surfaces.-There are two types of reaction involving metals: (i) those in which the metal is a reagent and is consumed in the process and (ii) those in which the metal functions as a catalyst. It is tempting to explain that the ultrasonically induced enhancements in chemical reactivity which are observed in such heterogeneous reactions are due simply to the well-known cleaning action of ultrasound. It is certainly true that sonication will clean the surface of a metal and that dirty surfaces can inhibit a chemical reaction.It is because of surface contamination that many of the metals used in chemical reactions are cleaned before use e.g. copper is washed with EDTA to remove surface salts and iodine is commonly used in the preparation of a Grignard reagent to remove oxide film and promote magnesium reactivity. In some respects sonication serves a similar purpose to these chemical techniques-it exposes clean or reactive surface to the reagents involved. Examination of irradiated surfaces by electron microscopy reveals ‘pitting’ of the surface of the metal which acts both to expose new surface to the reagents and to increase the effective surface area available for reaction.The pitting is thought to be caused by two possible processes: (i) the implosion of cavitation bubbles formed from seed nuclei on the surface and (ii) microstreaming of a jet of solvent onto the surface when a cavitation bubble collapses in the solvent close to it. In many cases, however, it has been shown that the cleaning effect alone is not * ‘Sonochemistry. Part 1 The Physical Aspects’ by John P. Lorimer and Timothy J. Mason, Chern. SOC. Rev., 1987, 16, 239.’T. J. Mason, Ultrusonics, 1986, 24, 245.’K. S. Suslick, Modern Sjwfhrfic Methods. 1986, 4, 1. K. S. Suslick, Ah Organornet. Cheni., 1986, 25, 73. lo D. Bremner, Chern. Br.. 1986, 22, 633. RSC Sonochemistry Symposium, University of Warwick, 1986, Ulfrusonics. 1986, 25.January. M. A. Margulis, Russ. J. Phys. Chern., 1976, 50, 1. Lindlej) and Mason sufficient to explain the extent of the sonochemically enhanced reactivity. In such cases it is thought that sonication serves to sweep reactive intermediates, or products, clear of the metal surface, thus presenting renewed clean surface for reaction. This sweeping effect would not be so effective under normal mechanical agitation. B. Reactions involving Powders or other Particulate Matter.-In heterogeneous reactions involving solids dispersed in liquids the overall reactivity, just as with the metal surface reactions described above, will depend upon the available reactive surface area. In the case of powders (metallic or non-metallic) ultrasonic ‘pitting’ will lead to fragmentation and consequent particle size reduction.The significant feature of such reductions is that there appears to be an optimum size for the reduction beyond which ultrasound has no further effect. One important benefit of particle size reduction and simultaneous surface activation is the possibility of using sonication in place of a phase-transfer catalyst (PTC) as a means of assisting heterogeneous solid-liquid reactions. C. Emulsion Reactions.-Ultrasound is known to generate extremely fine emulsions from mixtures of immiscible liquids. In such emulsions there is a dramatic increase in the interfacial contact area between the liquids i.e. an increase in the region over which any reaction between species dissolved in the liquids can take place.As with the powder reactions this allows the use of ultrasound in place of a PTC. In some cases, however, it has been found that a combination of sonication and PTC has a better overall effect than either of the two techniques alone. D. Homogeneous Reactions.-Thus far we have attributed ultrasonically enhanced chemical reactivity to the mechanical results of cavitational bubble collapse. That this cannot be the whole reason for the effect of ultrasound on reactivity is clear when we turn our attention to homogeneous reactions. In Part 1, for example, we discovered that light can be emitted from sonicated water (sonoluminescence) and that ultrasound can fragment liquid alkanes or accelerate the solvolysis of 2-chloro- 2-methylpropane in aqueous alcoholic solvents.The answer lies in the actual process of cavitational collapse. The microbubble does not enclose a vacuum-it contains vapour from the solvent and any volatile reagents so that, on collapse, these vapours are subjected to the enormous increases in both temperature and pressure referred to above. Under such extremes the solvent and/or reagent suffers fragmentation to generate reactive species of the radical- or carbene-type, some of which are high enough in energy to fluoresce. In addition the shock wave produced by bubble collapse, or even by the propagating ultrasonic wave itself, could act to disrupt solvent structure and could in this way influence reactivity by altering solvation of the reactive species present.The practising chemist might thus expect to use ultrasound for a range of applications and perhaps achieve one or more of a number of beneficial effects: (1) to accelerate a reaction or permit use of less forcing conditions (2) to reduce the number of steps which are required using normal methodology (3) to make use of cruder reagents (4) to initiate reaction, often without the need for additives (5) to reduce any induction period involved (6) to drive a reaction through an alternative pathway. Sonochemistry. Part 2-Synthetic Applications In the succeeding sections of this article a number of these exciting synthetic prospects will be examined. 2 Synthetic Applications of Ultrasound A. Organometallic Compounds.-The use of ultrasound in the synthesis of organometallic compounds, especially of the soft metals, has seen intense activity in recent years.The first report was published in 1950 by Renaud,13 who obtained improved yields in the direct metallation of alkyl halides with Li, Mg, and A1 in undried diethyl ether using ultrasound (960 kHz, 2 Wcm-’). This method was unsuccessful with Zn, Hg, Ca, and Be. Surprisingly, this work was not followed up for thirty years until Luche and Damanio published the sonochemical preparation of Grignard and organo-lithium reagents, a paper which signalled the renascence of organometallic sonochemistry. l4 In their studies the ultrasonic equipment used was neither a purpose-built ultrasonic generator nor a piece of equipment ‘borrowed’ from other disciplines but a common laboratory cleaning bath (50 kHz).In the case of Grignard reagents initiation occurs instantaneously without the aid of activators and in commercial undried ether. n-Propyl, n-butyl, and phenyl lithium were prepared in >9O”j, yield by reaction of the appropriate bromide with Li wire (or Li-2% Na sand); in these cases the reaction commenced immediately, although with secondary and tertiary alkyl bromides longer periods of sonication were required. EtCH(Br)Me + Mg (1)1))),Et CH( Mg Br)Me Today one of the most common chemical applications of ultrasound is the initiation of a reluctant Grignard reaction by immersion of the reaction vessel in an ultrasonic cleaning bath.This technique has been put on a more quantitative basis with some studies of the induction times for formation of Grignard reagents with various grades of ether (equation 1) (Table 1).l5 In order to induce reaction after the extended periods required under normal conditions, it was necessary to activate the magnesium by crushing pieces of the metal. In no case, however, with or without sonication, was there any significant differencein the yield of organometal, the figures being 65,55, and 55%. This work was performed in an ultrasonic bath and it is significant that prior sonication of the l3 P. Renaud, Bull. Soc. c‘him. Fv.. Scr. S, 1950. 17, 1044. l4 J.-L. Luche and J. C. Damanio. J. Am. Ckem. Soc., 1980, 102, 7926.’’J. D. Sprich and G.S. Lewandos, Inorg. Chi. Actci, 1982, 76, 1241. Lindley and Mason Table 1 Preparation of butan-2-yI magnesium bromide in ether (50 kHz bath at 50 "C) Diethyl ether Method Induction time pure. dried (0.01:< water) non-ujs 6-7 min (0.01% ethanol) uis <10 s reagent grade non-ujs 2-3 h (crushed) (0.52; water) (2.0x, ethanol) uis 3-4 min 50% saturated non-ujs 1-3 h (crushed) (O.OlO,/, ethanol) uls 68 min metal in ether had no effect on the induction time. This clearly eliminates simple surface cleaning as the source of the effect and suggests that sonication removes adsorbed water from the metal surface. Ultrasound facilitates the production of arene radical anion salts of the alkali In a comparative study of several methods for the synthesis of sodium isobenzoquinoline (1) the method using an ultrasonic probe (25 kHz) was found to be superior to the others; the reaction was complete in 45 min compared with 48 h for the non-ultrasonic control. Similarly, rate enhancements were reported for the formation of sodium naphthalene in commercial undried THF using a 36 kHz cleaning bath.I8 Improvements in yields and reaction times have been reported for the preparation of the alkyl aluminium halides.' The yields of isobutenyl aluminium sesquichloride [(2) R = CH,=CMeCH,, X = Cl] from the reaction of A1 and isobutenyl choride were found to be higher in dioxane than in diethyl ether but were unaffected by changes in ultrasound frequency in the range 32-36 kHz.It would appear that the better cavitation which is possible in the higher boiling dioxane is important. In another study 2o a comparison of methods using ultrasonic agitation l6 W. Slough and A. R. Ubbelhode, J. Chem. Soc., 1957, 918. " M. W. T. Pratt and R. Helsby, Nature, 1959, 184, 1694.'*T. Azuma, S. Yanagida, H. Sakurai, S. Sasa, and K. Yoshino, Synlh. Commun., 1982, 12, 137. l9 A. V. Kurchin, R.A. Nurushev, and G. A. Tolstikov, Z. Obshch. Khirn., 1983,53, 2519. 2o K. F. Liou, P. H. Yang, and Y. T. Lin, J. Organomet. Chem., 1985, 294, 145. Sonochernistry. Part 2-Synthetic Applications R /R .'\\ /X \ A\ ,'Al (2) with those using mechanical stirring showed that the reaction of bromoethane with A1 in THF to give ethyl aluminium sesquibromide [(2), R = Et, X = Br] was complete in 19 min with ultrasound at room temperature, while no reaction at all occurred in the mechanically stirred control reaction. Mg, BF30Et,2 Et20.3RX + R3B(90-100"/e) )))I, 15-30min Sonication using a 20 kHz probe gives significant improvements in the synthesis of organoboranes via in situ generated Grignard reagents (equation 2).21 Symmetrical trialkyl boranes such as Pr;B are obtained with this method giving purities >99%, compared with only 93% purity using the usual hydroboration route. The ultrasonic method also has distinct advantages in the synthesis of hindered boranes, thus (l-naphthyl),B is obtained in 93% yield in 15min compared with 91% yield in 24 h in the absence of ultrasound.The formation of disilanes and distannanes from the reaction of trialkyl- chlorosilanes or stannanes with lithium in THF is facilitated by low intensity ultrasound (cleaning bath, 50 kHz).22 The method has been used to prepare the novel tetramesitylsilene (3) in 90% yield. The fact that other workers were able to obtain only cyclic tri~ilanes~~ while trying to repeat this work underlines the importance of specifying all sonochemical parameters (equipment, power, apparatus) when reporting sonication results. The use of low intensity ultrasound (cleaning bath) also leads to increased yields and a reduction in reaction time from 48 to 6 h in the preparation of tris(pheny1dimet hylsi1yl)met hane. 24 '0; I Si H.C. Brown and U. S. Racherla, Tetrahedron Lett., 1985, 26, 431 1.''P. Boudjouk, B. H. Han, and K. R. Anderson, J. Am. Chem. Soc., 1982, 104, 4992. 23 S. Masarnune, S. Murakami, and H. Tobita, Organometaliics, 1983, 2, 1464.''C. Eaborn, P. B. Hitchcock, and P. D. Lickiss, J. Organomef.Chmi., 1984, 269, 235 Lindley and Mason There have been numerous reports of the use of ultrasound to generate organozinc reagent^.''-*^ In many cases the organozinc is formed directly from the metal and organic halide and then reacted in situ with electrophiles. This important simplification in technique for organic synthesis will be described later. A more reliable route to organozinc compounds involves the trans-metallation of zinc halides with organolithium reagents (equation 3).29*30 ZnBrgRX + Li R Li R2Zn (3) Although quite good yields of diarylzinc can be obtained by a one-pot procedure using aryl halide, zinc bromide, and lithium wire in THF in a cleaning bath (50 ~Hz),~~more consistent results are obtained for dialkyl zincs by using a sonic horn (see Equipment section below).30 Toluene containing a little THF was also found to be a better solvent in this reaction, which again suggests that the more powerful cavitation in the higher boiling toluene is beneficial.Using this system quantitative yields of dialkylzinc are obtained in 20-30 min compared with only 75% yield in 2 h without ultrasound. Ultrasound also facilitates the formation of organocopper compounds by transmetallation of copper(1) iodide (equation 4) with in situ generated alkyl-or aryl-lithium in 1: 1 diethyl ether/THF in a cleaning bath (50 kHz, 90W).31 E + Ze- --* E~-RX* RER E = Se,Te R = PhCH2,4-CNC,H,CH, Scheme 1 A novel route to organoselenium and organotellurium compounds involves the 25 P.Knochel and J. F. Normant, Tetrahedron Lett., 1984, 25, 1475. l6 B. H. Han and P. Boudjouk, J. Org. Chem., 1982,47, 751. ’’T. Kitazume and N. Ishikawa, J. Am. Chem. SOC.,1985, 107, 5186.’* T. Kitazume and N. Ishikawa, Chem. Lett., 1982, 137. 29 J.-L. Luche, C. Petrier, J. P. Lansard, and A. E. Greene, J. Org. Chem., 1983, 48, 3837. 30 C. Petrier, J. C. de S. Barbosa, C. Dupuy, and J.-L. Luche, J. Org. Chem., 1985, 50, 5761. 31 J.-L. Luche, C. Petrier, A.L. Gemal, and N. Zirka, J. Org. Chem., 1982, 47, 3805. 28 1 Sonochemistry. Part 2-Synthetic Applications ultrasonic acceleration of the electroreduction of Se or Te to their anions followed by reaction with electrophiles, RX, (Scheme l).32 B. Ligand Displacement Reactions.-Substitution in metal complexes proceeds mainly by dissociation processes, In systems which are coordinatively saturated and kinetically inert ligand dissociation is generally induced either thermally or photochemically. The local high temperatures and pressures which are produced during cavitational bubble collapse have also been shown to be an effective means of promoting these reactions. In a study of the sonolysis of Fe(C0)5 in hydrocarbon solvents Suslick and co-workers 33,34 have obtained results which are different from both the thermal and photochemical methods.The thermolysis of Fe(C0)5 above 100 "C produces mainly finely divided iron, ultraviolet photolysis gives Fez(C0)9 via reaction of the intermediate Fe(CO)4 with Fe(CO)S, whereas sonolysis yields Fe3(C0)12 and finely divided iron in a ratio which is dependent on solvent vapour pressure. The clusterification to Fe3(CO)1 is favoured in high vapour pressure solvents such as heptane in which >82% yield is obtained, whereas in low vapour pressure solvents such as decalin only a 4.7%yield is obtained. These results are clearly related to the energetics of cavitation bubble collapse which is inversely proportional to solvent vapour pressure.The clusterification, being the process of lower activation energy, is the favoured process in the lower boiling point solvents which produce weaker cavitation. The formation of Fe3(C0)12 during sonolysis is considered to arise mainly from the multiple coordinatively unsaturated species Fe(CO),. The principal reactions are shown in Scheme 2. In the presence of added ligands such as phosphines and phosphites substitution occurs to give LFe(CO),, L,Fe(CO),, small amounts of L,Fe(CO), and, only in low vapour pressure solvents, finely divided iron. The ratio of LFe(CO), to 32 B. Gautheron. G. Tainturier, and C. Degrand, J. Am. Chrm. Soc.. 1985, 107, 5579. 33 K. S. Suslick, P. F. Schubert, and J. W. Goodale, J. Am. Clirm. Soc., 1981, 103, 1324.34 K. S. Suslick, J. W. Goodale, P. F. Schubert, and H. H. Wang, J. Am. Clzem. Soc., 1983, 105, 5781. 282 Lindley and Mason L,Fe(CO), remains constant on prolonged sonolysis which suggests that LFe(CO), is inert to further sonochemical substitution. Sonochemical substitution of other metal carbonyl systems such as Mn2(CO),,, Re,(CO),,, Cr(CO)6, Mo(CO),, Wo(CO),, and Ru(CO), illustrates the generality of the te~hnique.~~~,~ The sonochemical substitution of the dimeric Mn,(CO),, and Re,(CO),, proceeds without rupture of the metal-metal bond which is more akin to thermal rather than photochemical substitution. Sonolysis of Mn,(CO),, and Re,(CO),, in halogenocarbon solvents give rise to halogenopentacarbonyl metal complexes due to a secondary reaction with solvent- derived radicals (Scheme 3).2R,C' -R,CCR, 2x' -x, 2X' + x2 + Sonolysis using a cleaning bath (80 W, 50 kHz) at room temperature of Fe,(C0)9 in benzene in the presence of alkenyl expoxides gives good yields of q3-allylironcarbonyl lactone complexes, which are easily oxidized to lactams and lactones (Scheme 4).37 In a similar way sonolysis of Fe,(CO), in the presence of dienes gives good yields of the (q4-diene)Fe(CO), c~mplexes.~~ C. Reactive Metal Powders and Catalysts.-Reduction of metal salts in the presence of ultrasonic fields has been a major area of study. In general the ultrasonic field produces fine dispersions and cavitation phenomena give rise to clean surfaces containing an increased number of dislocations, which are widely considered to be the active sites in catalysis.35 K. S. Suslick and P. F. Schubert, J. Am. Chem. Soc., 1983, 105,6042. 36 G. Wilkinson, Chem. Br., 1983, 986. 37 A. M. Horton, D. M. Hollinshead, and S. V. Ley, Tetrahedron, 1984, 40, 1737. S. V. Ley, C. M. R. Low, and A. D. White, J. Organomer. Chem., 1986,302, C13. 283 Sonochemistry. Part 2-Synthetic Applications R 0 Scheme 4 Scheme 5 Lindley and Mason Reduction of metal halides with lithium in THF at room temperature in the presence of low intensity ultrasound (cleaning bath, 50 kHz) gives rise to metal powders which have reactivities comparable to those of the so-called Rieke powders prepared by reduction of metal halide with potassium in refluxing THF.39,40 Thus powders of Zn, Mg, Cr, Cu, Ni, Pd, Co, and Pb were obtained in <40 min by this ultrasonic method compared with reaction times of 8 h using the experimentally more difficult Rieke method.Reductions with lithium in THF which were mechanically stirred took up to 26 h. In cases where the metal halides are insoluble in THF the addition of naphthalene as an electron-transfer agent is recommended. These powders show enhanced reactivity in organic syntheses involving metals e.g. the Reformatsky and Ullmann coupling reactions. A highly active form of magnesium is formed when magnesium powder in THF is subjected to low intensity ultrasound (cleaning bath) in the presence of anthra~ene.~~The anthracene forms an electron-transfer complex with magnesium and this effectively acts as a phase-transfer agent (Scheme 5).The magnesium produced in this way is an excellent reducing agent for metal salts and when the reduction is carried out in the presence of Lewis base ligands it is a useful route to organo-transition metal complexes, for example q5-cyclopentadienyl complexes Cp,M (M = V, Fe, Co), q3-allyl complexes (M = Co, Ni), alkene complexes (M = Ni, Pd, Pt, Mo), and phosphine complexes (M = Pd, Pt). The magnesium-anthracene complex is also a convenient route to allyl Grignard reagents at temperatures as low as -35 "C. This eliminates the coupling of allyl magnesium halides with the starting alkyl halide which is a common side- reaction with conventional methods (equation 16).42 yield 76-100"/0R' = lo,Z0,3O -alkyl, alkyl, vinyl 15-40 min Reduction of transition metal halides with sodium sand in the presence of CO at low pressure (1-5 atm) at 10 "Cunder prolonged sonication (20 kHz probe, 100W cmP2) in THF gives reasonable yields of metal carbonyl anions [W2(C0),,l2-47%, [MO~(CO),,]~- 54%, [Nb(CO),]- 51%, [v(Co),] -35%.43 Metal halides of low solubility in THF give reduced yields.These results are quite remarkable as such compounds are usually obtained by reduction of metal halides at high temperatures (100-300 "C) and high CO pressures (100-300 atm) in an autoclave. It is postulated that these reactions proceed by a mechanism in which CO traps partially reduced metal species at the sodium surface.It is also j9 P. Boudjouk, D. P. Thompson, W. H. Ohrbom, and B. H. Han, Orgonomefullics, 1986, 5, 1257. 40 R. D. Rieke, Acc. Chem. Res., 1977, 10, 301. H. Bonnermann, B. Bogdanovic, R. Brinkman, D. W. He, and B. Spliethoff, Angew. Chem., In!.Ed. Engl., 1983, 22, 728. 42 W. Oppolzer and P. Schneider, Tetrahedron Lett., 1984, 25, 3305. 43 K. S. Suslick and R. E. Johnson, J. Am. Chem. Soc.., 1984, 106,6856. 285 Sonochemistry. Part 2-Syn thetic Applications conceivable that the reactions proceed uiu excited CO molecules which are produced during the cavitation process. Sonication (35 kHz cleaning bath) is a simple and convenient method for preparing colloidal alkali Thus the typical blue colour of colloidal potassium is produced in a few minutes in toluene or xylene.However, sodium is dispersed in xylene but not in toluene. This is another example of the more powerful cavitation in the higher boiling solvent being an important factor in determining reaction products. These colloidal systems are particularly useful in condensations of the Dieckmann type and in the generation of ylide intermediates in Wittig reactions. Such potassium dispersions are also effective in the desulphurization of s~lphones.~~ Highly dispersed mercury emulsions in acetic acid are conveniently generated by sonication (cleaning bath).3 Such emulsions are efficient in promoting the reductive substitution of =,a'-dibromoketones. Sonication of commercial copper-bronze in DMF at 60°C using a 20 kHz probe reduces the average particle size of the copper to a finite limit of 20 pm and is also an efficient means of cleaning the copper surface by the removal of metal salts.46 Copper treated in this way gives improvements in Ullmann coupling reactions.Reduction of ruthenium chloride with zinc dust in methanol containing 1,5-cyclooctadiene in a 50 kHz cleaning bath gives a 93% yield of (q6-1,3,5-cyclooctatriene)(q2-1,5-cyclooctadiene)ruthenium (4) compared with less than 35% yield using a two-stage non-ultrasonic method.47 Reduction of metal salts in the presence of ultrasound has been widely used in the preparation of heterogeneous catalysts.48 Palladium and platinum blacks prepared by reduction of aqueous solutions of metal salts with formaldehyde in ultrasonic fields of intensities between 0.4 and 14.6 Wcm-' had up to 30%increase in surface area, increased paramagnetism, and higher background intensity of XRD patterns which indicates a higher concentration of atomic phase.These blacks gave increased activity in the decomposition of H,O,, in the hydrogenation of hex-1-ene, and in the oxidation of ethanol. Interestingly the catalytic activity of the platinum blacks increased with increasing frequency (20 kHz, 548 kHz, 3 MHz) 44 J.-L. Luche, C. Petrier, and C. Dupuy. Tetrahedron Lett., 1984, 25, 753. 4s T. S. Chou and M. L. You, Tetrahedron Lett., 1985, 26, 4495. 46 J. Lindley, J. P. Lorimer, and T. J. Mason, Ultrasonics, 1986, 24, 292. "K. Itoh, H. Nagashima, T.Ohshima, N.Ohshima, and N. Nishiyama, J. Urganomef. Chem., 1984,272,179. 48 A. N. Mal'tser, Rum. J. Phys. Chem., 1976, 995. 286 Lindley and Mason of the ultrasound used in their production, whereas the palladium blacks showed the opposite trend; there is no obvious explanation for this. Increased surface area of metals deposited on alumina and silica gels can be obtained using ultrasonic techniques. Thus the reduction of solutions of platinum complexes in the presence of suspended silica gel subjected to ultrasound (440kHz, 5 WcmP2) gave an 80% larger platinum surface on the gel compared with a control sample.49 Alkene hydrogenation catalysts are usually noble metals (Pt, Pd) or specially activated metal powders. High intensity ultrasound has been used to activate nickel powders even at room temperature and pressure. Ultrasound also has a marked accelerating effect on the formation of intercalation compounds of a range of layered solids (e.g.ZrS2, V205, TaS2, and MOO^).^' D. Ultrasound in Organic Synthesis.-(i) Reactions at Carbonyl Functions. Luche and Damanio l4 have observed significant improvements both in yields and simplification of experimental techniques over conventional methodology in the Barbier reaction (equation 16)’’ when the reactions are carried out in a simple ultrasonic cleaning bath (50 kHz). Significant advantages of this method are that the reactions can be carried out in commercial undried THF and are largely free from side reactions such as reduction and enolization, which are common in conventional methodology.Even benzyl halides give yields in excess of 95% and very little Wurtz coupling, which often predominates with non-ultrasonic methods, has been observed. For perfluorohalides the use of in situ sonochemically generated perfluorozinc is preferred to Li or Mg, which are normally used in the Barbier reaction, as perfluoroalk yl derivatives of these metals are prone to p-elimination to give alkenes (equation 17).27,52,53Here it is necessary to use a higher boiling solvent such as DMF, which allows the more powerful cavitation needed to activate the zinc. An elegant application of this method has enabled chiral perfluoroalcohols with 30-66% optical induction to be obtained from the reaction sequence shown in Scheme 6.54 An alternative route to perfluoroalkyl alcohols is via the Barbier reaction of perfluoroaldehydes with in situ sonically generated alkyl or ally1 Grignard reagents (equation 18).55 49 V.I. Shekhobalova and L. V. Voronova, Vestn. Mosk. Univ., Ser. 2: Khim., 1986, 27, 327. 50 K. S. Suslick, D. J. Casadonte, M. L. H. Green, and M. E. Thompson, Ultrasonics, 1987, 25, 56. 51 C. Blomberg and F. A. Hartog, Synthesis, 1977, 18. 52 N. Ishikawa and T. Kitazurne, European Patent 0 082 252 Al, 1982. 53 T. Kitazurne and N. Ishikawa, Chem. Lett., 1981, 1679. 54 A. Solladie-Cavallo, D. Farkharic, S. Fritz, T. Lazrak, and J. Suffert, Tetrahedron Letr., 1984,25, 41 17. 55 N. Ishikawa, M. G. Koh, T. Kitazume, and S.K. Choi, J. Fluorine Chem., 1984, 24, 419. Sonoc hemis try. Part 2-Syn thetic Applications (chiral) Scheme 6 CF,CHO + RX 2. H20l*Mg' CF3RCHOH (18) Ally1 halides readily react under sonication with aldehydes and ketones in the presence of tin in aqueous THF (5: 1) to give high yields of homoallylic alcohols (equation 19).56 This reaction can also be performed non-ultrasonically with Zn but yields are consistently lower. Aldehydes react more quickly than ketones to the extent that in competition reactions and in molecules containing both functionalities reaction occurs almost exclusively at the aldehyde group. Low intensity ultrasound also facilitates the Reformatsky reaction of p-halogenoesters with aldehydes and ketones (equation 20).57 Thus the ultrasonic method gave ethyl 2-hydroxyphenylacetate 98% in 5 min for R = C,H, and R' = H compared with 98% obtained in 1 h using activated zinc powders, 95% in 5 h using the (MeO),B/THF solvent system, and only 61% after 12 h using the conventional methodology.The ultrasonic Reformatsky reaction also gives good yields with perfluoroalkyl aldehydes.55 RR'CO + BrCH2C02Et RR'CH(OHICH2COzEt (20) 56 C. Petrier, J. Einhorn, and J. L. Luche, Tetrahedron Lelt., 1985, 26, 1449. 57 B. H. Han and P. Boudjouk, J. Org. Chem., 1982, 47, 5030. Lindley and Mason Alkali metals and magnesium react with aryl halides and alkyl isocyanates under the sonochemical Barbier conditions to give secondary aryl amides (equation 2l)? * Good yields of the intermediate (5) are obtained when M = Mg, and low yields with Li.The reaction with Na is slow but is greatly accelerated by the addition of 1 equiv. of HMPA. The intermediate (5)can be readily ortho-lithiated when M = Na but complications occur with M = Mg due to Mg-Li exchange. These ortho-lithiated intermediates readily react with a wide range of electrophiles to give ortho-substituted aryl amides (equation 22). NR NHR + RNCO -2N E=RNC0,RCHO (22) The low intensity ultrasonic generation of organolithium reagents and their application in the Bouveault reaction has resulted in higher yields of product aldehydes than in traditional methods (equation 23).59 /Me Me2NC%C H N ‘CHO Non-ultrasonic Bouveault reactions suffer from numerous side reactions, although the method is improved when DMF is replaced by more elaborate (and 58 J.Einhorn and J.-L. Luche, Tetrahedron Lett., 1986, 27, 501. 59 C. Petrier, A. L. Gemal, and J.-L. Luche, Tetrahedron Lefr., 1982, 23, 3361. Sonochemistry. Part 2-Syn thet ic Applications expensive) formamides such as (7). There is no advantage to be gained, however, by using an extra chelating group such as (7) in the sonochemical route since in this case the reaction with DMF is clean. Interestingly, while a change of solvent from THF to THP has little effect on the rate or yields of reactions carried out in a 50 kHz ultrasonic bath, no reaction was observed in diethyl ether under these conditions.60 However, the reaction in diethyl ether was facilitated when ultrasonic irradiation of 500 kHz frequency was employed.The reason for this is not clear but it is tempting to suggest that at this higher frequency the cavitation bubbles, filled with volatile ether vapour, do not exceed the collapse limit radius before the compression cycle. ax+ (71 1. xsLi,)))) 2.Bu"Br 3. Electrophrle (El The Bouveault intermediates (6) derived from aryl halides and formamide with a chelating group such as (7) can be regiospecifically ortho-lithiated. A great simplification of this method is made by sonication of the aryl halide and amide with excess lithium for 15 min followed by the dropwise addition of 1-bromobutane (instead of n-butyllithium), sonication for a further 30 min, followed by addition of the electrophile.For example, when the electrophile is iodomethane, a 70% yield of 2-substituted benzaldehyde [(8),E = Me] is obtained (equation 24).61 Good yields of alkenes are obtained by methylation of carbonyl compounds using zinc and diiodomethane in THF when the reaction is performed in an ultrasonic cleaning bath (53W, 41 kHz) at room temperature (equation 25).62 Higher yields are obtained with aldehydes than with ketones. The Cannizzaro reaction under heterogeneous conditions (solid-liquid) catalysed by barium hydroxide is greatly accelerated by low intensity ultrasound (cleaning bath). Thus 100% yields of disproportionation products are obtained after 10min sonication of benzaldehyde whereas no reaction is observed during this period in the absence of ultrasound (equation 26).63 'O J.Einhorn and J.-L. Luche, Tetrahedron Lett., 1986, 27, 1791. " J.-L. Luche, Ultrasonics, 1987, 25, 40. 62 J. Yamashita, Y. Inoue, T. Kondo, and H. Hashimoto, Bull. Chern. Soc. Jpn.. 1984, 57, 2335. 63 A. Fuentes and J. V. Sinisterra, Tetrahedron Lett., 1986, 27, 2967. 290 Lindley and Mason Ultrasonic acceleration of reaction is also observed in the Strecker synthesis of aminonitriles (9) (equation 27).64 Using a simple cleaning bath the reaction times of these homogeneous reactions for the synthesis of aminonitriles (10) are reduced from 12 d to 2CL-25 h and yields are increased by up to 60%. R = H , Bun, Ph, PhCH2,4-Me -C6H4 NC (ii) Reactions at C-C Multiple Bonds.1,4-Addition to a$-unsaturated carbonyl compounds. Traditionally organocopper reagents are used for these reactions.65 Luche et aL3' have observed significant improvements in yields, rates, and ease of experimental technique when organocopper compounds generated by sonication (bath 50 kHz) of copper(1) compounds, organic halide, and lithium sand in diethyl ether-THF at 0 "C are allowed to react with z-enones (equation 28). 0 0 + RBr p-;Li, Cu. EtZO, THF' H30+_ po R R (28) (R = Bu",89"/0) Ultrasonically generated (cleaning bath) arylzinc compounds are also excellent reagents for the 1,4-addition to a-enones and a-enals in the presence of catalytic quantities of Ni(acac), (equation 29).66 64 J. Menedez, G. G.Trigo. and M. M. Sollhuber, Tetrahedron Lett., 1986, 27, 3285. 65 G. H. Posner, Org. React. (N.Y.),1972, 19, 1. 66 J. C. S. Barboza, C. Petrier, and J.-L. Luche, Tetrahedron Lett.. 1985, 26, 829. 291 Sonochemistry. Part 2-Synthetic Applications Reactions with a-enals are performed at -40 "Cwhereas those with a-enones are carried out at room temperature. Extension of the method to include alkyl halides requires more intense sonication which is provided by a sonic horn (30 kHz) and a better medium for cavitation such as t~luene-THF.~'*~~ Under these conditions good yields of alkyl- substituted ketones are obtained. The method has been successfully exploited to provide an efficient synthesis of P-cupranone (11) (equation 30).68 Hydroboration.Low intensity ultrasound has a marked accelerating effect on hydroborations, which are traditionally very The effect is particularly marked in heterogeneous systems. For example, the preparation of tricyclohexyl- borane by hydroboration with BH34Me, in THF traditionally requires 24 h at 25 "C, however, with irradiation, in an ultrasonic bath (50 kHz, 150 W) the reaction is complete in 1 h (equation 31). Hydrosilation. Dramatic improvements in the platinum-catalysed hydrosilation of alkenes are obtained when reactions are carried out in an ultrasonic cleaning bath at 30 "C,which is the lowest reported temperature for Pt-C catalysis (equation 32).70.71 R3SiH + )=( Pt IC,1-2h R3Si 30 "C,))), Hydroalkylation of alkynes and dienes.Ultrasonically promoted hydroperfluoro- 6' C. Petrier, J.-L. Luche, and C. Dupuy, Tetrahedron Lett., 1984, 25, 3463. 68 A. E. Greene, J. P. Lansard, J.-L. Luche, and C. Petrier, J. Org. Chem., 1984, 49, 931. 69 H. C. Brown and U. S. Racherla, Tetrahedron Lett., 1985, 26, 2187. 'O B. H. Han and P. Boudjouk, Organometallics, 1983, 2, 769.'' B. H. Han and P. Boudjouk, Tetrahedron Lett., 1981, 22, 2757. 292 Lindley and Mason alkylation of alkynes with perfluoroalkylcuprates, which are generated in situ from the reaction of perfluoroalkyl halides with zinc and copper(1) iodide in THF, gives good yields of fluoroalkyl substituted alkenes. The reaction is regiospecific but not stereospecific (equation 33).27,52 Sim i 1ar results are obtained for the perfluoroalkylation of dienes catalysed by Cp,TiCI, (equation 34).27 1.Zn,C p2TiCI21)I RfI + Rf-\ (34)@ ’ 2. H30+ Sonochemically generated highly functionalized ally1 zinc intermediates readily add to alkynes to give dienes which can be used in various cyclizations (equation 35).25 R Cycloaddition. The zinc-promoted cycloaddition of a,cr’-dibromoketones to 1,3- dienes is facilitated by ultrasound; highly hindered bicyclo[3.2.l]oct-6-en-3-ones (12) are easily accessible by this method (equation 36).72 This reaction in the absence of ultrasound gives only low to moderate yields and requires long reaction times (24 h). 2 = CH2,0 (12) (79%) The [2 + 21 cycloaddition of dichloroketene to alkenes is also improved by ultrasound (equation 37).73 72 N.Joshi and H. M. R. Hoffmann, Tetrahedron Lett., 1986, 27, 687. 73 G. Mehta and H. S. P. Rao, Synth. Commun., 1985, 15, 991. Sonochemistry. Part 2-Syn the tic Applicu t ions Short reaction times, good yields, ambient temperatures, and the use of ordinary zinc dust, instead of a zinc-copper couple, are significant advantages of this method. Cyclopropanation. In 1982 Repic described a sonochemical modification of the Simmons-Smith reaction using sonochemically activated zinc which avoided the sudden exotherm normally associated with the reaction. Thus (13) could be produced in 91% yield compared with 51% by the normal route.74 Existing methods for this reaction relied upon activation of the zinc by using zinc-silver or zinc-copper couples and/or the use of iodine or lithium.In the sonochemical procedure no special activation of the zinc was required, indeed equally good and reproducible yields were obtained using zinc dust or even the metal in the form of mossy, rods, or foil. The ultrasonic source was again a cleaning bath (50 kHz). This methodology has been successfully scaled-up to run in a 22 dm3 vessel immersed in a 50 gallon bath.75 For this scale-up the zinc was cast in two 800 g lumps (using 125 cm3 conical flasks as moulds). The reagents were methyl oleate (0.6 kg), diiodomethane (1.3 dm3), and dimethyloxyethane (2.7 dm3). Under nitrogen at 100 "C the reaction yielded (13) 0.5 kg (82%) after 2.25 h (equation 38). The method has several advantages over the normal method of cyclopropanation as a result of changing from zinc powder to the metal: there is a reduction in foaming (normally associated with ethene and cyclopropane formation); the exotherm is more evenly distributed (only a small clean area of metal is available throughout the reaction); the reaction can be controlled by removing the lump of metal from the reaction (this is not unlike the use of fuel rods in a nuclear reactor); the residual metal can be removed from the reaction as a lump.Ultrasound, when used in a solid-liquid reacting system, shows promise as a method of avoiding the use of phase-transfer catalysts. This has been found to be particularly relevant in the generation of dichlorocarbene by the direct reaction between powdered sodium hydroxide and ~hloroform.~~ The reported procedure is both simple and efficient in that irradiation (bath 45 kHz) of a stirred mixture of powdered NaOH in chloroform containing an alkene generates high yields of the corresponding dichlorocyclopropanes in 4 h at 40 "C.The results make it quite '' 0.Repic and S. Vogt, Tetrahedron Lett., 1982, 23, 2729.'' 0.Repic, P. G. Lee, and N. Giger, Org. Prep. Proc. ht., 1984, 16, 25. "S. L. Regen and A. Singh, J. Org. Chem., 1982, 47, 1587. Lindley and Mason clear that both mechanical stirring and ultrasonic irradiation are necessary for high reactivity, thus styrene is converted into (14), 96%in 1 h with both sonication and stirring, but the yield is reduced to 38% (20 h sonication only) and 31% (16 h stirring only) (equation 39).CI Hydrogenation. Formic acid and palladium-on-carbon are an effective couple for the hydrogenation of a wide range of alkenes at room temperature in the presence of low intensity ultrasonic fields (cleaning bath, 50 kHz) (equation 40).77 w PdlC,HC02H,20 OC,*H(40) (95-100'1.) Similarly, the hydrazine-palladium-on-carbon couple is also useful for the hydrogenation of alkenes in ethanol at room temperature using an ultrasonic bath.78 A commercially useful example of a sonochemically enhanced catalytic reaction is the ultrasonic hydrogenation of soybean A three-phase non-aqueous system is used comprising liquid oil, H, gas, and solid catalyst. The catalyst was either 1% copper chromite or 0.1%Nysel(25% nickel) at 115 psig and 180 "C.The method employs a flow-through cell operating at 0.5-2.0 lh-' providing sonication at 20 kHz and leading to a tube reactor of dimension 120 feet x inch. This has considerable advantages over the currently used batch methods which require much longer reaction times.(iii) Coupling Reactions of Organometals and Organic Halides. Ultrasonic radiation has been shown to be effective in promoting the homocoupling of organometallic intermediates. Good yields of homocoupled products obtained by reaction of alkyl, aryl, or aryl halides with lithium wire in THF immersed in an ultrasonic bath (1 17 W, 50 kHz) (equation 41).71,80In the absence of ultrasound little or no reaction occurs. 77 P.Boudjouk and B. H. Han, J. Catal., 1983,79,489. 78 D.H.Shin and B. H. Han, Bull. Korean Chem. SOC.,1985,6, 247. 79 K. J. Moulton, S. Koritala, and E. N. Frankel, J. Am. Oil Chem. SOC.,1983,60,1257. T. D. Lash and D. Berry, J. Chem. Educ., 1985,62,85. 295 Sonochemistry. Part 2-Synthetic Applications Coupling of benzyl halides in the presence of copper or nickel powder generated by lithium reduction of the corresponding halides in the presence of ultrasound gives high yields of dibenzyl (equation 42).39 The yields obtained when sonication is applied throughout the reaction are higher than those obtained in mechanically stirred reactions. (42) Ullmann coupling of activated aryl halides in DMF with high intensity ultrasound from a sonic horn gave a 64-fold increase in rate over a mechanically stirred control reaction (equation 43).46 -Cu DMF 60 OC (43)'NO, NO2 NO2 In this work a fourfold decrease in the particle size of the Cu was observed (see above), however, this alone was insufficient to explain the large rate increases observed when sonication was continued throughout the reaction.It would appear that ultrasound assists in the breakdown of reaction intermediates and/or the desorption of products. An interesting Ullmann-type coupling of aryl sulphonates promoted by in situ generated nickel(0) complexes is also facilitated by ultrasound (equation 44).*'The method works best for triflates (equation 44, R = CF,); for tosylates (R = 4-methylphenyl) the rate is significantly lower.NICI,. Zn, PPh3, Nal, AroSo2R DMF, 60 OC * A'2 (44) Sonication using a cleaning bath (35 or 45 kHz) has a beneficial effect in the cross- coupling reactions of perfluoroalk ylzinc reagents with vinyl, ally], or aryl halides (equations 45 and 46).27*52953 Aryl phosphorus bonds are readily cleaved by lithium in THF in the presence of low intensity ultrasound (cleaning bath) to give lithium dialkylphosphides which T. Yamashita, Y. Inoue, T. Kondo, and H. Hashimoto, Chern. Lett., 1986, 407. Lindley and Mason readily couple with alkyl halides to produce high yields of phosphanes (equation 47).82,83Much higher rates are observed than for reactions using mechanical stirring. Li, THF, R’R2R3P R’R2 P-Ph (47)R1R2P-Li+ y’”’ R’ R~P(cH~)~PR’ R~ (iv) Dehalogenation.Ultrasonic irradiation during the reaction between zinc and ap’-dibromoorthoxylene (15) in dioxane yields a xylylene intermediate (16) which readily adds to any dienophiles in the reaction mixture affording high yields of adducts (18) and (19) as shown in Scheme 7.26 In the absence of dienophile, polymer and about 10% of the dimer (17) are formed, although an 80% yield of the dimer can be obtained by reaction of (15) with Scheme 7 ”T. S. Chou, J.-J. Ying, and C.-H. Tsao, J. Chem. Rex (3,1985, 18. ‘3 T. S. Chou, C.-H. Tsao, and S. C. Hung, J. Org. Chem., 1985, 50, 4329. 297 Sonochemistry. Part 2-Syn the t ic Applicu tions Li (1 equiv.) in an ultrasonic bath.84 There is no reaction in the absence of ultrasound.This technique for the generation of (16) has also been used in carbohydrate chemistry to produce compounds with A ring similarities to anthracycl~nones.~~ Under the influence of ultrasound cyclopropylidines can be generated, without induction period, by the reaction of gem-dihalogenocyclopropanesand lithium, sodium, or magnesium in THF (but not pentane), which again emphasizes the importance of solvent in sonochemical reaction^.^^ All three products (20) (equation 48),(21) (equation 49), and (22) (equation 50) were obtained in <20 min at 20 “C. Similar results were obtained for the less reactive dichloro-compounds using sodium sand in xylene. Good yields of penicillinate esters (24) are obtained by the sonochemical debromination of the 6-bromopencillinate ester (23) with zinc (equation 51).87 CO2R C02R (23) (24) This method is more efficient, cleaner, and less expensive than those employing 84 P.Boudjouk, R. Sooriyakumaran, and B. H. Han, J. Org. Chem., 1986, 51, 2818. 85 S. Chew and R. J. Ferrier, J. Chem. SOC.,Chem. Commun., 1984, 911. 86 L. Xu, F. Tao, and T. Yu, Tetrahedron Lett., 1985, 26. 4231. ”J. Brennan and F. H. S. Hussain, Synthesis, 1985, 8, 749. 298 Lindley and Mason the more usual debrominating agents Bu”,nH or Pd-C/H, recommended for this reaction. Sonically dispersed mercury emulsions are efficient in the reductive debromination of m,a’-dibromoketone (25) in acetic acid to give a-acetoxyketones (26) and (27), (equation 52).3 Using ketones as solvents the products are isopropylidene- 1,3-dioxolan derivatives e.g.(28) (equation 53).88 &+ (52) Br Br OCOR OCOR 0 The rate of electrodechlorination of polychlorobiphenyl to give biphenyl at a stirred mercury pool electrode is enhanced 2-to 3-fold when the reaction is performed in an ultrasonic cleaning bath.89 The reductive dehalogenation of aryl halides with nickel(I1) chloride and zinc in aqueous HMPA is facilitated by low intensity ultrasound (equation 54).90 NiC12, Zn, HMPA, (54)H20.60 OC, X = CI,Br,I Ultrasound also gives substantial rate enhancement in the reductive dehalogenation of aryl halides using lithium tetrahydroaluminate (equation 55).91 Thus a 97% yield of benzene was obtained in 5 h from bromobenzene compared with only 21% in 24 h under non-ultrasonic conditions.LiAlHL ,1,2 -dimethoxyethane.’Q (55) 88 A. J. Fry, G. S. Ginsberg. and R. A. Parante, J. Chcm. Soc., Chcm. Commun., 1978, 1040. “T. F. Connors and J. F. Rusling, Chrmasphere, 1985, 13, 415. 90 T. Yamashita, Y. Inoue, T. Kondo, and H. Hashimoto, Bull. Chem. SOC.Jpn., 1985, 58, 2709. 91 B. H. Han and P. Boudjouk, Terrahdron Lefr.. 1982. 23, 1643. Sonochemistry. Part 2-Synthetic Applications This method has also been extended to good advantage with the synthesis of group IVB element hydrides from the corresponding halogeno, alkoxy, or amino derivatives (equation 56).92 LIAlH4, hexane. R3MX R,MH (56) 40 OC -))I) (R = alkyl,M = Si,Ge,Sn,X = CI,Br) (v) Substitution. Ultrasound facilitates the Friedel-Crafts acylation of aromatics (equation 57).93 PrI2NH, AICI3, Et20, MeopoH(57) R COMe OMe OMe A combined Friedel-Crafts acylation/alkylation is a key step in the synthesis of hexamethylphenalene (29) (equation 58).The use of low intensity ultrasound has enabled the number of steps in the synthesis to be reduced from 15 to 4.94 (29) (58) An interesting change in direction of the alumina-catalysed reaction of benzyl bromide with toluene and potassium cyanide is observed on sonication, Scheme 8.95Thus the mechanically stirred reaction gave 83% of the Friedel-Crafts product (30) and none of the substitution product (31), whereas the ultrasonic method gave no Friedel-Crafts product and 76% of the substitution product (Scheme 8).The probable explanation involves ultrasonic dispersion of KCN on the alumina surface which decreases its Friedel-Crafts activity whilst promoting the nucleophilic displacement of the CN -on its surface. 92 E. Lukevics, V. N. Gevorgyan, and Y. S. Goldberg, Tetrahedron Lett., 1984, 25, 1415. 93 B. M. Trost and B. P. Coppola, J. Am. Chem. SOC.,1982, 104, 6879. 94 P. Boudjouk, W. H. Ohrbrom, and J. B. Woell, Synrh. Commun., 1986, 16, 401. 95 T. Ando, S. Sumi, T. Kawate, J. Ichihara, and T. Hanafusa, J. Chem. SOC.,Chem. Commun., 1984, 439. Lindley and Mason agitation (30) (31I Scheme 8 In the ultrasonic preparation of aromatic acyl cyanides (32) (R = H, 2-Me, 3-Me, 4-Me, 4-Me0) (equation 59) by the reaction of the corresponding acyl chlorides with solid KCN in acetonitrile, good yields of products have been achieved (70-85%) even in the absence of phase-transfer catalysts.96 Under non- ultrasonic conditions this reaction is facilitated by the presence of traces of water but proceeds very slowly, whereas the ultrasonic reactions are not significantly affected by water.A possible rationale for this may be that the role of the water is to attack the crystal lattice to reveal sites which may well be more easily exposed by ultrasound. The preparation of azides from primary alkyl halides and aqueous sodium azide also benefits from low intensity ultrasound (equation 60).97 Higher yields are obtained when R = propargyl or ally1 (60-91%) than for R = alkyl (20%).NaN3, HzO, 60 OC,)))] RX * RN3 (60) Rate.enhancements are noted in several other heterogeneous substitutions which involve the use of phase-transfer catalysis (PTC), in several instances the use of ultrasound enables cheaper PTC reagents to be used. Thus the efficiency of N-96 T. Ando, T. Kawate, J. Yamawaki, and T. Hanafusa, Synthesis, 1983, 637. 97 H. Priebe, Acta Chem. Scand., Ser B, 1984, 38, 895. 301 Sonochemistry. Part 2-Synthetic Applications alkylation of amines with alkyl halides in toluene in the presence of KOH and PEG methyl ether is markedly increased (equation 61).98When R = benzyl and R' = R2 = phenyl the yield is 98% in 1 h at 25-50 "C under sonication compared with only 70% after 48 h under reflux.In the absence of PTC there was no reaction under sonication, emphasizing that the increase in reactivity is not simply a matter of increasing interfacial contact area. Ultrasound also enhances the rate of thiocyanation of alkyl halides using tetra- alkylammonium halides as phase-transfer catalysts.99 Increased yields of products are obtained using ultrasound in the PTC alkylation of the isoquinoline derivatives (33) (equation 62).'0° The generation of the methyl sulphinyl carbanion from sodium hydride and dimethylsulphoxide is facilitated by sonication (800 kHz, 200 W)."' When this reaction is carried out in the presence of isoquinoline good yields of I-methylisoquinoline are obtained (equation 63).'02 This reaction gives only slightly higher yields than existing methods, but for speed and simplicity it is superior.(63) 2 -H20 Me (76%) Ultrasound has been found to give increased rates for the preparation of thioamides by reaction of their respective amides with P,Sl0 in dry THF (equation 98 R. S. Davidson, A. M. Patel, A. Safdar, and D. Thornthwaite, Tetrahedron Leu., 1983, 24, 5907. 99 W. P. Reeves and J. V. McClusky, Tetrahedron Lett., 1983, 24, 1585. 100 J. Ezquerra and J. Alvarez-Builla, J. Chem. Soc., Chem. Commun., 1984, 54. lo' K. S. Sjoberg, Tetrahedron Lerr., 1966, 6383. lo' J. Ezquerra and J. Alvarez-Builla, Org. Prep. Proc. Int., 1985, 17, 190. 302 Lindley and Mason 64).'03 This method has the additional advantage of requiring only 1-1.5 equiv.of P,S,, rather than the large excess used in the traditional method. (vi) Condensations. The rates at which o-hydroxybenzaldehydes condense with p-nitrostyrene derivatives using basic alumina catalyst can be increased by ~onication.'~~The method which uses a 60 kHz cleaning bath is a convenient one- pot route to 3-nitro-2H-chromenes (34) (equation 65). Ultrasound was also found to improve yields and rates for the aldol dimerization of ketones catalysed by basic alumina (equation 66).'05 Some of the conclusions drawn from the above work have, however, proved to be + Low intensity ultrasound (cleaning bath) has beneficial effects in the synthesis of ethers and esters (equation 67).'07 Using this method an 80% yield of ethyl phenyl ether was obtained in 2 h compared with only 44% in a stirred control reaction.KOH, PEG, ROH + R'X ROR' (67) (RC0,H) ))I) (RCO~R') X = CI,Br,I (vii) Hydrolysis. Ultrasound has a pronounced effect on the rate of saponification of carboxylic esters.' O8 Thus methyl 2,4-dimethylbenzoate and sodium hydroxide S. Raucher and P. Klein, J. Org. Chem., 1981, 46, 3558. Io4 R.S. Varma and G. W. Kabalka, Heterocjdes, 1985, 23, 139. '05 B. C. Barot, D. W. Sullins, and E. J. Eisenbraum, Synth. Commun., 1984, 14, 397. Io6 J. Muzart, Synth. Commun., 1985, 15, 285. lo' R. S. Davidson, A. Safdar, J. D. Spencer, and D. W. Lewis, Ultrasonics, 1987, 25, 35. IonS. Moon, L. Duchin, and J. Cooney, Tetruhrdron Lrtr., 1979, 3917.Sonochemistry. Part 2-Synthetic Applications solution (2073 after sonication (20 kHz probe) for 1 h gave a 94% yield of acid whereas only a 15% yield of acid was obtained after refluxing for 1.5 h. Saponification of commercially important substances, such as glycerides, rape seed oil, and wool waxes is greatly accelerated by soni~ation.'~' These heterogeneous reactions can be carried out at much lower temperatures than is usual and lead to products exhibiting less colour. While experiments on a 10 g scale were carried out in an ultrasonic cleaning bath, scale-up was achieved by use of a whistle reactor. (viii) Oxidation. The oxidation of alcohols by solid potassium permanganate in hexane and benzene is significantly enhanced by sonication in an ultrasonic bath (equation 68).' O9 OH 0 Comparisons with mechanical stirring reveal increases in yield at 50 "C for the oxidation of octan-2-01 (R = C,HI3) from 2.6% to 92.8% (5 h) and for 3- phenylprop-2-en-1-01 from 4.5% to 82.8% (3 h). When the KMnO, was supported on alumina, however, normal reactivity was enhanced and ultrasound had no additional effect.Attempted autoxidation of 4-nitrotoluene (35) (Ar = 4-N02C,H,) (equation 69) in the presence of 0, using KOH and PEG 400 as PTC gives a mixture OZ'KOH,ArMe ArC02H + ArCH2CH2Ar + ArCH=CHAr (69) (35) 1 (36) (37) (38) consisting entirely of the dimers (37) and (38) with combined yields ranging from 19.3 to 38.7% depending on 0, prkssure and reaction conditions.Sonication not only reduces reaction times by a factor of three but, more significantly, effects the selectivity of such reactions.' lo At the same temperature (25 "Cj and with reaction times of 1 h the product distribution of the reaction is changed by irradiation such that the carboxylic acid (36) is the main product with yield ?< (acid: total dimer) as high as 43.1% to 2.3% depending on conditions. (ix) Isotopic Labelling. A quantitative isotopic yield of carrier-free [17-'231]heptadecanoic acid is obtained by halogen exchange between the bromoacid and iodine- 123-sodium thiosulphate in butan-2-one at 100 "C under sonication (ultrasonic bath, 50 kHz) for 20 min (equation 70)."' '09 J. Yamakawi, S. Sumi, T. Ando. and T. Hanafusa, Chem.Lett., 1983, 379. 'lo R. Neumann and Y. Sasson, J. Chrm. Sac,.,Clirm. Cammun., 1985, 616."' J. Mertens, W. Vanryckeghem, A. Bossuyt, P. V. den Winkel, and R. Vandendriessche, J. Labelled Comp. Radiopharm., 1984, 21, 843. Lindley and Muson The Raney nickel-catalysed hydrogen-deuterium exchange in cereboside and monosacharides in THF-D,O proceeds under mild conditions in an ultrasonic cleaning bath.lL2 The mild conditions employed lead to enhancement of site selectivity for the exchange. 3 Sonochemistry Equipment A. Ultrasonic Apparatus.-(i) Whistle Reactor. This type of mechanical transducer device is predominantly used for homogenization/emulsification. In a sense these devices can be considered almost as ‘passive’ rather than ‘active’ sonicators in that the power of the sonication is fixed by the flow of fluid across the vibrating plate.Most of the chemical effects observed using these reactors can be attributed to the generation of very fine emulsions rather than the ultrasonic irradiation itself. An obvious benefit of such a system is that it can be used for flow-processing large volumes. (ii) Ultrasonic Cleaning Bath. This is undoubtedly the most accessible and simplest equipment available. There are, however, three factors that should be borne in mind when using this method. (a) The amount of power reaching the ‘reaction’ immersed in the bath is not readily quantifiable because it will depend on the size of the bath, the reaction vessel type (and thickness of its walls), and the position of the reaction vessel in the bath.’ (b)Temperature control is not easy in this system.Most cleaning baths warm up during operation, especially over a prolonged period of use. This is not a problem if a heater is used to establish thermal equilibrium but can lead to inconsistent results when working around room temperature or below. Two solutions are available: (i) operating for very short periods over which the temperature can be assumed to remain essentially constant or (ii) circulating cooling water or adding ice. If ice is used, however, it must be borne in mind that solids will alter the characteristics of sonic wave transmission. Whatever method is chosen it must be emphasized that it is the temperature inside the reaction vessel which must be monitored as this is often a few degrees above that of the bath liquid.(c) Cleaning baths do not all operate at the same frequency and this may well lead to difficulties, particularly in attempts to reproduce results reported in the literature. E. Cioffi and J. H. Prestegard, Tetrahedron Lett., 1986, 27, 415. B. Pugin, Ultrasonics, 1987, 25, 35. Sonochemistry. Part 2-Synthetic Applications (iii) Direct Immersion Sonic Horn. An ultrasonic probe can be placed directly in the reacting system and this is the type of equipment often used for biological cell disruption. It is undoubtedly the most efficient method of transmitting ultrasonic energy into a reaction. The vibrating motion generated by the piezoelectric transducer used in such equipment is normally too low for practical use and so it is necessary to magnify or amplify this motion.This is the function of the horn (or probe) attached to the transducer. Normally the horn is half a wavelength long. The most popular horn designs are shown in Figure 1. Figure 1 Horn designs (a) linear taper (b)exponential taper (c) stepped (a) Linear taper. This is simple to make but its potential magnification is limited to approximately fourfold. (b)Exponential taper. This design offers higher magnification factors than the linear taper but its shape makes it more difficult to manufacture, Its length and the small diameter of the working end makes this design particularly suited to micro applications.Stepped. For this design the magnification factor is in the ratio of the end areas. The potential magnification is limited only by the dynamic tensile strength of the horn material. This is a useful design and easy to manufacture. Gains of up to 16-fold are easily achieved with this type. The material used for the fabrication of acoustic horns should have high dynamic fatigue strength, low acoustic loss, resistance to cavitation erosion, and chemical inertness. The most suitable material by far is titanium alloy. A number of such devices are on the market (normally called cell disruptors), the majority operating at 20 kHz, and a range of different metal probes (horns) are available. The advantages of this method over a bath are threefold: (a)Much higher ultrasonic powers can be used since energy losses during the transfer of ultrasound through the bath media and reaction vessel walls are eliminated. LindIey and Mason (b) These devices can be tuned to give optimum performance in the reaction mixture over a range of powers.(c) The ultrasonic intensity and size of sample to be irradiated can be matched fairly accurately for optimum effect. Although the probe has these advantages over the bath it does suffer from the same difficulties of temperature control and operation at a fixed frequency, plus two additional problems. These are that with direct sonication it is possible to generate radical species by the action of the probe tip on the solvent and that with prolonged use some erosion of the tip occurs which may mean contamination of the reaction under study by small metallic particles.(iv) The Cup Horn. This system (Figure 2) was also originally designed for cell disruption but is both more controllable than a cleaning bath (in terms of power and temperature) and less drastic in action than a sonic horn. The use of such a system allows more quantitative and reproducible studies of sonochemical effects than a cleaning bath. The frequency is fixed and the power is tuneable but, unlike the direct sonic horn, no radicals or fragments of metal are generated in the reaction mixture itself. n OVERFLOW COOLANT OUT ANT Figure 2 Cup horn The major disadvantages of the cup horn compared with the direct immersion sonic horn are (i) the reduction in power and (ii) the restriction in size of the reaction vessel which can be placed inside the cup horn.Sonochem istry. Part 2-Syn thetic Applications B. Reactor Design.-(i) Batch Reactions. Although the direct insertion of a probe into the reaction mixture is by far the most effective method of introducing ultrasound into a reaction, there are a number of problems associated with it. These PTFE SLEEVE GROUND GLASS GLASS ROSET TE Figure 3 Rosette cell PTFE SLEEVE GROUND GLASS INDENTATION Figure 4 Indented cell Lindley and Mason -PTFE COLLAR INLET Figure 5 Pressure reactor centre around the maintainance of temperature stability, vapour tightness, and (where necessary) pressure.Some of the simplest types of laboratory scale reactor are described below. A glass rosette cell with flanged lid is shown in (Figure 3). The design of the rosette cell allows the irradiated reaction mixture to be sonically propelled from the end of the probe around the loops of the vessel and thus provides both cooling (when the vessel is immersed in a thermostatted bath) and efficient mixing. A PTFE sleeve provides a vapour-tight fit for the probe through the glass joint. As an alternative to this an ordinary reaction vessel can be adapted for sonic mixing by providing an indentation on its base which acts to disperse the sonic waves as they are reflected from the base (Figure 4). If the reaction vessel is simply immersed in an ultrasonic bath then it will be necessary to provide additional mechanical stirring.In situations where gas pressures above atmospheric need to be used a useful reactor has been described by Suslick (Figure 5).43 Luche has described a simple apparatus for organometallic preparations involving the direct reaction of metals with a liquid (Figure 6).68 (ii) Flow Systems. An obvious limitation of the electromechanical systems described above is the batch nature of the processing involved. A favourite method of avoiding this is to use a flow-cell in a continuous or circulating system (Figure 7). This bears some relationship to the whistle reactor described above except that the sonication is provided through a probe and is therefore of controllable power.(iii) Large Scale Applications. On a production scale the volumes treated will be very much larger than those considered in the laboratory. Almost certainly the type of process will govern the choice of transducer energy density required and it could well be that some processes would be suited to a low intensity sonication whereas others may need the higher intensity of the probe system. Sonochemistry. Part 2-Synthetic Applications Figure 6 Organometallic reactor HORN -\OVERFLOW 'ORIFICE Figure 7 Flow cell In the case of low intensity treatment the reacting liquids could be flowed in a controlled manner through an ultrasonic tank and out over a weir to the next process. A number of such sonically activated stages could be connected in line.The tanks would be constructed in an appropriate grade of stainless steel, of if plastic tanks were to be used then the transducer could be bonded on to a stainless steel or titanium plate and bolted with a gasket into the tank. Alternatively a sealed submersible transducer assembly could be employed. If high intensity treatment were needed it would be possible to couple a probe Lindley and Mason transducer into a flow pipe by means of a T section. A number of such trans- ducers could be employed in this manner. The actual number and position in the process line would need to have been determined during the process development phase. l4 R.A. Holl, U. S. Patent, 1978, 4,071,225.

ISSN:0306-0012    

DOI:10.1039/CS9871600275

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Chem. SOC. Rev., 1987, 16, 313-338 Product Stability in Kinetically-Controlled Organic Reactions By Sosale Chandrasekhar DEPARTMENT OF ORGANIC CHEMISTRY, INDIAN INSTITUTE OF SCIENCE, BANGALORE 560 012, INDIA 1 Introduction Few organic reactions yield a single product. Therefore, an appreciation of the factors which affect the distribution of products in organic reactions is of great importance. While external variables such as solvent, temperature, catalysts, etc., are expected to be important, it is perhaps natural to wonder whether the stability of a product has any influence on its yield. Indeed, in a reaction where many products are derived from the same reactant, one may expect (perhaps naively) that changes in transition-state structure are mainly influenced by changes in product structure.On the other hand, the concept of thermodynamic and kinetic control implies that, if anything, the more stable product is formed more slowly. An interesting question which then arises is: ‘Just how do most organic reactions behave?’ Many years ago the terms ‘product stability control’ and ‘steric approach control’ were invented in connection with the reduction of ketones with complex metal hydrides. Subsequently, however, it was decided that product stability actually had little influence on the course of the reactions, which proceeded uicl ‘early, reactant-like transition states’. This review addresses the question: ‘How general is this phenomenon?’ A variety of organic reactions, many of synthetic importance, is so considered in the following sections.Clearly, exhaustiveness is impossible, and the author has, therefore, tried to establish general trends. Finally, in this section, the following definition is in order. The term ‘kinetically- controlled reaction’ is used to mean a reaction which is performed away from equilibrium, ie. in one direction only. Under such conditions, the relative yield of a product reflects its rate of formation. 2 Additions to Carbon-Oxygen Double Bonds A. Reductions of Aldehydes and Ketones with Complex Metal Hydrides.-Much is known about the stereochemistry of reduction of various cyclic ketones with complex metal hydride reagents. This area has been authoritatively covered by a number of reviews,’-3 and only an outline of the findings is given below.’ H. 0. House, ‘Modern Synthetic Reactions’, Benjamin, Menlo Park, 2nd Edition, 1972, p. 54. J. R. Boone and E. C. Ashby, Top. Stereochern., 1979. 11, 53. D. C. Wigfield, Tetruheriron, 1979, 35,449. Product Stability in Kinetically-Controlled Organic Reactions The hydride reduction of unhindered cyclohexanones usually yields the more stable equatorial alcohols. Introduction of sterically-hindering substituents at the 3-and 5-positions in the ring, however, increases the proportions of axial alcohols even to the extent of making these isomers predominant (equations 1 and 2). H 37 O/Ll Li Al H, +____+ The accepted explanation is that the predominance of the more stable alcohol is fortuitous and that the stereochemistry of the reduction is mainly controlled by a combination of steric and torsional factors.Formation of the equatorial alcohol requires attack from the axial side of the carbonyl group, where steric interference with the substituents at the 3-and 5-positions in the ring is engendered. However, if these substituents are no larger than hydrogen, it is supposed that such steric interference is less important than the torsional strain involved in equatorial attack. Such strain is thought to arise from the eclipsing of the axial carbon-hydrogen bonds a to the carbonyl group, with the partially-formed bond between the carbonyl carbon atom and the hydride ion. The reduction of many bicyclic ketones also suggests that product stability is unimportant in determining the course of the reaction.2-Norbornanone yields predominantly the less stable endo alcohol (equation 3). Similar considerations apply to the reduction of acyclic aldehydes and ketones, with the product stereochemistry being solely determined by factors controlling the Chandrasekhar approach of the hydride ion to the carbonyl group. In addition to the steric and torsional factors discussed above, electrostatic factors are also thought to be important in the reductions of acyclic aldehydes and ketones bearing polar substituents. However, assumptions have to be made regarding the orientation of the carbonyl group relative to the a-substituents, such orientation usually being unambiguous in cyclic ketones.The above arguments have been used to explain the Rule of Steric Control of Asymmetric Induction.' According to this rule, the acyclic ketone or aldehyde is considered to react in a conformation in which the carbonyl group is staggered between the medium and the smallest r-substituents. The product stereochemistry is then predicted by considering that the hydride ion approaches from the less hindered side of the carbonyl group. Although the relative stabilities of acyclic diastereomers are not easy to predict, it is noteworthy that it is not necessary to invoke product-stability control to explain the course of the reaction. Rei has made a systematic study of the reaction of various cyclic ketones with lithium aluminium hydride and with methyl lithi~m.~ The above author has made the interesting suggestion that product stereochemistry is governed by a combination of steric strain and product stability. Although such a suggestion had been tried and discarded earlier, it appears to explain the stereochemistry of reduction of cyclopentanones, a reaction in which the more stable trans alcohols predominate.Ashby and B~one,**~ and Eliel,6 however, have questioned the usefulness of the concept of product development control in the reduction of ketones with complex metal hydrides. According to these authors, the stereochemistry of reduction of cyclopentanones is best explained by the 'anti-periplanar' effect. 2-Methyl- cyclopentanone, for example, is expected to exist in the half-chair conformation (equation 4).The preference for attack from a direction cis to the methyl group is seen as being due to steric hindrance by the hydrogen on carbon atom 2 to trans attack. Such hindrance is caused by the aforementioned anti-periplanar effect, which is a combination of torsional and orbital distortion effects. M. Rei, J. Org. Chem., 1979, 44, 2760. E. C. Ashby and S. A. Noding, J. Am. Chem. SOC.,1976,98, 2010; J. Org. Chem., 1977,42, 264. E. L. Eliel and Y. Senda, Tetrahedron, 1970,26,2411;D. M. S. Wheeler and M. M. Wheeler, J. Org. Chem., 1962,27, 3796. Product Stability in Kinetically- Controlled Organic Reactions B. Other Reductions of Aldehydes and Ketones.-Both catalytic hydrogenation and the Meerwein-Ponndorf-Verley reduction of cyclohexanones preferentially lead to the axial cyclohexanols, under kinetic conditions. Apparently, in these reactions too, attack takes place from the less hindered, equatorial, side of the carbonyl group.7 C.Kinetically-controlled Aldol Condensations.-These reactions show interesting stereochemical results.* The erythro-threo ratios of the aldol products can vary from &lOO%, depending on experimental conditions. However, even when the more stable isomers predominate, product stability is not the cause. The examples in equations 5-7 are illustrative. It is thought that the erythro-threo ratio is mainly governed by the geometry of the intermediate enolate ion as also by the interactions between the R’ and R3 groups in the transition state, which is usually of the chair form (Figure 1).R’ L Figure 1 D. The Wittig Reaction.-The Wittig reaction between an aldehyde or a ketone and a phosphorus ylide to yield an olefin, takes place uia betaine intermediates, whose formation is usually rate-determining. The nature of these betaine intermediates determines the stereochemistry of the products (Scheme l).9 It is clear from the above scheme that in the absence of thermodynamic control, predominant formation of the erythro betaine (A) would lead to a predominance of the cis olefin. Indeed, cis olefins are preferentially formed in many Wittig reactions. Therefore, there appears to be a kinetic preference for the less stable erythro betaines in these reactions.Either metal cations in the reaction medium or stabilizing r-substituents in the ylide can give rise to thermodynamic control. In both cases, thermodynamic control to afford a mixture richer in threo betaine (B) becomes competitive with olefin formation. However, if the Wittig reaction is carried out under conditions favouring kinetic ’E. L. Eliel, ‘Stereochemistry ofcarbon Compounds’, McGraw-Hill, New York, 1962, p. 243; H. 0.House, ‘Modern Synthetic Reactions’, Benjamin, Menlo Park, 2nd Edition, 1972, p. 20. * D. A. Evans, J. V. Nelson, and T. R. Taber, Top. Stereochem., 1982, 13, 13; D. Fellmann and J. E. Dubois, Tetrahedron, 1978, 34, 1349 C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, and J.Lampe, J. Org. Chem., 1980, 45, 1066; A. I. Meyers and P. J. Reider, J. Am. Chem. SOC.,1979, 101, 2501. H. 0.House, ref. 1, p. 682;M. Schlosser, G. Mueller, and K. F. Christmann, Angew. Chem., In!. Ed. Engf., 1966,5,667;M. Schlosser and K. F. Christmann, Annalen, 1967,708, 1; L. Crornbie, P. Hemesley, and G. Pattenden, J. Chem. Soc. (C), 1969, 1016, 1024; 0. H. Wheeler and H. N. Battelle de Pabon, J. Org. Chem., 1965,30, 1473; B. E. Maryanoff, A. B. Reitz, M. S. Mutter, R. R. Inners, and H. R. Almond, Jr., J. Am. Chem. SOC.,1985, 107, 1068. Chandrasekhar 95 "lo 100 "lo6 pPh + PhCHO 4 8 "lo (7) + 0 OH 52 "lo R'CHO + Ph3P=CHR +HPh,P +pJR';aR' R i 1(A) R("' R yR' Scheme 1 317 Product Stability in Kinetically-Controlled Organic Reactions control, it is generally found that the less stable cis olefins predominate, as shown in equations 8-10.Ph Et Ph Ph3P=CHEt + PhCHO ____* + (8)\ Et a5 01, 4 "I" 60 40 O/O'1'0 Ph Ph + NaOEt Ph3PCH2Ph + PhCHO CI -Ph 35 "I" 4 1 "lo 3 Additions to Carbon-Carbon Double Bonds A. Electrophilic Addition of Acids and Halogens.-The Markownikoff addition of electrophiles to carbon-carbon double bonds leads to the regioisomer which may be the slightly more stable one (equation 11). However, the regiochemistry of the final products is determined in the first step, in which the most stable possible carbonium ion intermediates are preferentially formed. Therefore, product stability control is ruled out." H I RCH=CH, + HBr ---+ R-C-Me (1 1) I Br More interesting is the stereochemistry of electrophilic addition to cyclic olefins.4-t-Butylcyclohexene adds formic acid to yield mainly the less stable axially- '' (a) P. B. D. de la Mare and R. Bolton, 'Electrophilic Additions to Unsaturated Systems', Elsevier, Amsterdam, 2nd Edition, 1982, p. 65;(h) S. Winstein and N. J. Holness, J.Am. Chem. Soc., 1955,77,5562; (c) J. Hine, 'Physical Organic Chemistry', McGraw-Hill-Kogakusha, Tokyo. 2nd Edition, 1962, p. 19. Chandrasekhar substituted product (equation 12).'0",b Addition of hydrogen bromide to 1-cyclohexenecarboxylic acid leads to the less stable cis product (equation 13)." And, addition of bromine to 3-t-butylcyclohexene is presumed to lead initially to the diaxial dibromide in which the cyclohexane ring is in the twist form; this compound then isomerizes to the fully-equatorial compound (equation 14).l2 Mechanistically, these reactions presumably take place via the rate-determining formation of bridged intermediates, which suffer axial attack.Thus, the less stable axial isomers are formed initially. OCHOt Br Br / .jc;-/.-..Br Br Work in the steroid series also offers interesting examples. 5-Cholestene derivatives add electrophiles to yield products with trans ring junctions (equation 15).13*14 However, the nucleophilic parts end-up in axial positions, and that the CI " P.B.D.delaMareand R. Bolton,ref. lOa,p.363;R.CapleandW. R.Vaughan, TelrahedronLelr., 1966,4067. l2 P.B. D. de la Mare and R. Bolton, ref. 10a, p. 164 P. L. Barili, G. Bellucci, F. Marioni, I. Morelli, and V. Scartoni, J. Org. Chem., 1972, 37, 4353. l3 P. B. D. de la Mare and R. Bolton, ref. 10a, p. 156. H. 0.House, ref. 1, p. 426; D. H. R. Barton and R. C. Cookson, Chem. SOC.Rev., 1956,10,44 D. H. R. Barton and E. Miller, J. Am. Chem. Soc., 1950,72, 1066. Product Stability in Kineticallwv-Controlled Organic Reactions products are the less stable isomers is suggested by the rearrangement of similar compounds to cis-fused systems on heating (equation 16).14 Finally, it is known that bromine and chlorine add to 2-and 3-cholestenes preferentially to produce the diaxial dihalides. Br Electrophilic additions to dienes may take place in either 1,2-or 1,4-fashion (equation 17).The less stable 1,2-addition products are known generally to predominate under kinetic conditions.'6 For example, in the addition of electrophiles such as Clz, Br2, ClOAc, and BrOAc, the ratio of 1,2-to 1,4-addition ranges from 1.2 to 6.7. 1,4-Addition does, however, lead to the more stable trans isomer; this is probably because the intermediate carbonium ion prefers a transoid E B. Epoxidations.-The epoxidation of an olefin with a peracid usually takes place from the less hindered side of the double bond and the product formed may be the P. B, D.de la Mare and R. Bolton, ref. 10a,p. 163;G. H. Alt and D.H. R. Barton, J. Chem.SOC.,1954,4284. l6 P. B. D. de la Mare and R.Bolton, ref. 10a, pp. 326,336;V. L. Heasley. G. E. Heasley, R. A. Loghry, and M. R. McConnell, J. Org. Chem., 1972, 37, 2228. l7 K. Mislow and H. M. Hellmann, J. Am. Chem.SOC.,1951,73,244;H. M. Hellmann,J. W. Hellmann, and K. Mislow, ibid., 1954, 76, 1175; K. Mislow, ibid., 1953, 75, 2512. Chandrasekhar more stable one (equation 18).'* However, that product stability is not important in these reactions is suggested by equation 19, where the more electron-rich double bond is preferentially attacked to yield, probably the less stable product.lg Epoxidations of allylic alcohols are dominated by a directing effect of the hydroxyl group. In cyclic systems, this may result in the epoxide ring being cis not only to the hydroxyl group, but also to other groups, which may be as bulky as t- butyl (equation 20).20 +Hobphco3H+H0?4 0 % (20) HO 96 "lo 4 "lo C. Hydrogenations.--The catalysed addition of hydrogen to double bonds is known to be insensitive to product stability, the product stereochemistry being mainly determined by the requirement that the addition take place from the less hindered side of the double bond (equations 21-23).21,22 Pt-C A HH2 l8 H.0.House, ref. 1, p. 303; R. R. Sauers, H. M. How, and H. Feilich, Tetrahedron, 1965, 21, 983.'' H. 0.House, ref. 1, p. 298; L. A. Paquette and J. H. Barrett, Org. Synrh., 1973, Coll. Vol. 5,467;W. Huckel and U. Worffel, Chem. Ber., 1955, 88, 338. H. 0.House, ref. 1, p. 304; H. B. Henbest, Proc. Chem. SOC.,1963,159;P. Chamberlain, M.L. Roberts, and G. H. Whitham, J. Chem. SOC.(B), 1970, 1374. 21 H. 0.House, ref. 1, pp. 5, 10, 19; H. C. Brown and C. A. Brown, J. Org. Chem., 1966,31,3989;C. A. Brown, J. Am. Chem. Soc., 1969,91, 5901. 22 J. A. Marshall, N. Cohen, and A. R. Hochstetler, J. Am. Chem. SOC.,1966, 88, 3408. 32 1 Product Stability in Kinetically-Controlled Organic Reactions D. Hydroboration.-The hydroboration of bicyclic olefins takes place from the less hindered side of the double bond.23 Thus, a-pinene yields the product shown in equation24.The alternative stereoisomer (with the same regiochemistry), which may be of comparable stability, is not formed. Methylenecyclohexanes undergo hydroboration also preferentially to yield the less stable axial products (equation 25).E.Enolate Alky1ations.-Kinetically-controlled alkylations of ketone enolates can yield the less stable products (equations 26-29).24 The stereochemistry of alkylation is thought to be mainly determined by the ease of approach of the alkylating agent to the intermediate enolate ion, as also by stereoelectronic factors, rather than by product stability." LI 0mA n 0 MeI ___* 45 Yo 55 "/, (28) 23 H. 0.House, ref. 1, p. 110 H. C. Brown and G. Zweifel,J. Am. Chem. Soc., 1961,83,2544 ibid., 1964,86, 393; J. Klein and D. Lichtenberg, J. Org. Chem., 1970,35, 2654. 24 H. 0.House, ref. 1, p. 587. E. J. Corey, R. Hartmann, and P. A. Vatakencherry,J. Am. Chem. SOC.,1962,84,2611; H. 0.House and B. M. Trost, J. Org.Chem., 1965,30, 1341,2502; B. J. L. Huff, F. N. Tuller, and D. Caine, J. Org. Chem., 1969,34, 3070. Chandrasekhar 5 5 O/O 10 Oto Likewise, alkylations of acyclic enolates are known preferentially to yield the (presumably) less stable erythro products.26a And, enamines of cyclic ketones, on alkylation, preferentially yield axially-substituted products.26b F. Conjugate Additions.-l,4-Addition of organocopper derivatives to conjugated enones has been well-studied. Stereoelectronic factors appear to control the reaction and the products obtained may be the less stable ones (equations 30 and 3 1).27 (It must be mentioned that some cis-decalin derivatives are actually more stable than their trans isomers.280 Therefore, equation 30 may not rule out product- stability control; equation 3 1, however, does!).R’ R’ 0a, (30) R R H 98 ‘lo Similarly, Michael additions show insensitivity to product stability; the course of the reaction is determined by the requirement that the addition take place from the less hindered side of the conjugated system.28b 4 Pericyclic Reactions Regio- and stereoselectivity in various pericyclic reactions are under orbital symmetry control. Hence, product stability is not important, although there are examples in which the more stable products predominate. 26 (a) W. G. Kenyon, R. B. Meyer, and C. R. Hauser, J. Org. Chern., 1963, 28, 3108; (b)S. Karady, M. Lenfant, and R. E. Wolff, Bull. Soc. Chim. Fr., 1965, 2472. ’’ P. Deslongchamps, ‘Stereoelectronic Effects in Organic Chemistry’, Pergamon Press, Oxford, 1983, p.221; G. H. Posner, Org. React. (N.Y.), 1972, 19, 19; E. Piers and R. J. Keziere, TetrahedronLett., 1968, 583; J. A. Marshall and H. Roebke, J. Org. Chem., 1968,33,840; J. A. Marshall, W. I. Fanta, and H. Roebke, ibid., 1966,31,1016; S. M. McElvain and D. C. Remy, J. Am. Chem. Soc., 1960,82,3960; H. 0. House and W. F. Fischer, Jr., J. Org. Chem., 1968, 33, 949. ’’(a) E. L. Eliel, ref. 7, p. 279; (b)H. 0.House, ref. 1, p. 615. Product Stability in Kinetically-Controlled Organic Reactions Familiar examples are the Diels-Alder reactions of cyclopentadiene, which preferentially yield the less stable endo products (equation 32).29 The accepted explanation for this phenomenon is that secondary orbital interactions stabilize the transition state leading to the endo product.n Regioselectivity in these reactions is also independent of product stability as shown by the preferred formation of the less stable ‘ortho’ adducts (equations 33 and 34).30,31 Such regioselectivity is supposedly due to the preferred overlapping of orbitals of similar size in the transition state. OMe OMe CO, H CO, H Electrocyclic reactions, too, ignore product stability. For example, the disrota- tory cyclization of the octatriene in equation 35 yields the 1,3-cyclohexadiene with the methyl groups mutually disposed in the less stable cis fashion.32 5 Elimination Reactions Eliminations leading to olefins are mainly of three types, El, ElcB and E2.Both the regio- and stereochemistry of the product olefins are important in determining 29 I. Fleming, ‘Frontier Orbitals and Organic Chemical Reactions’, Wiley, London, 1976, p. 106; R. Hoffmann and R. B. Woodward, J. Am. Chem. Soc., 1965, 87,4388. 30 I. Fleming, ref. 29, p. 121; 0.Wichterle, Collect. Czech. Chem. Cornrnun., 1938, 10, 497. 31 I. Fleming, ref. 29, p. 129; K. Alder, M. Schumacher, and 0.Wolff, Annafen, 1949,564,79; K. Alder and K. Heimbach, Chem. Ber., 1953,86, 1312. ” I. Fleming, ref. 29, p. 105; E. Vogel, W. Grimme, and E. Dinnk, Tetrahedron Lett., 1965, 391; E. N. Marvel, G. Caple, and B. Schatz, ibid., 1965, 385. Chandrasekhar stabilities, the more highly substituted, and the trans, isomers being generally more stable.A. El Reactions.-These reactions take place uia the rate-determining formation of carbonium ions, followed by loss of protons, to yield olefins (equation 36). When R is a primary or a secondary alkyl group, the more substituted olefin predominates (Saytzeff product). When R is a tertiary alkyl group, the less substituted olefin, which however is the more stable isomer, predominates. It has been stated as a general rule that, in an El reaction, the most stable possible olefin is formed via the most stable possible carbonium ion.33 X I + __+RCHzCMe2 RCH2CMe2 ____* RCH=CMez + (36) RCHZC =CHZ I Me The simplest explanation for Saytzeff elimination is product-stability control. This also appears to be generally accepted by workers in this area.33,34 B.E2 Reactions.-The regio- and stereochemistry of the products in bimolecular elimination reactions, involving both the substrate and a base in the transition state, vary widely. Both steric and electronic factors are thought to be important in determining regiochemistry in E2 reactions. In the absence of steric effects, Saytzeff orientation, leading to the more stable olefin obtains. However, when steric factors are important, as when the leaving group or the attacking base is bulky, Hofmann orientation leading to the less stable olefin obtains. As an example, consider the dehydrobromination reaction in equation 37.35*36 When the attacking base is the ethoxide ion, the more substituted olefin predominates (81%).However, when the base is the t-butoxide ion, the terminal olefin is also obtained (53%). The effect of a bulky leaving group is shown in equation 38.35a*36 Base EtCHMe -MeCH=CHMe + EtCH=CH, (37)I Br 33 (a)W. H. Saunders, Jr. and A. F. Cockerill, ‘Mechanisms of Elimination Reactions’, Wiley, New York, 1973, p. 212; (b)H. C. Brown and M. Nakagawa, J. Am. Chem. Soc., 1955,77, 3610. 34 D. V. Banthorpe, ‘Elimination Reactions’, Elsevier, Amsterdam, 1963, p. 59. 35 (a)W. H. Saunders, Jr. and A. F. Cockerill, ref. 33, p. 165; (b)M. L. Dhar, E. D. Hughes, and C. K. Ingold, J. Chem. Soc., 1948, 2058. ”E. D. Hughes, C. K. Ingold, G. A. Maw, and L. I. Woolf, J. Chern. Soc., 1948, 2077. Product Stability in Kinetically-Controlled Organic Reactions Et 0-EtCHMe ___* MeCH=CHMe (26°/0) + (38)I + SMep EtCH=CHZ (74 "lo) The reason for these phenomena is supposed to be that, in the absence of steric effects, these reactions are under product-stability control.When steric effects become important, the attacking base deprotonates the least hindered proton to yield the less substituted olefin. The stereochemistry of elimination is also interesting. Generally, the more stable trans olefins predominate, as in equation 39, and product-stability control has been invoked as an e~planation.~~".~' Me Br 51 "lo 18 "lo (39) Other theories have also been proposed to explain the predominance of the more stable olefin in E2 reactions. McLennan has pointed out that the yield of more stable olefin is sometimes much greater than is warranted by its stability.38 Thus, the above author has proposed an alternative explanation to product-stability control.According to this theory, applicable to eliminations induced by weak bases on loose substrates, ground-state steric interactions in the substrate are important. Such interactions, between the substituents on the more substituted P-carbon and the other P'-alkyl group, will be better relieved on going to the more substituted olefin (Figure 2). Figure 2 Steric interactions between the attacking base and the groups (R) on the p-carbon atom are also supposed to destabilize the transition state leading to the less substituted olefin. 37 H. C. Brown and 0.H. Wheeler, J. Am.Chem. Soc.. 1956, 78, 2199. D. J. McLennan, Tetrahedron, 1975, 31, 2999. Chandrasekhar Another important point is that, in E2 reactions, the requirement that the leaving group and the hydrogen being removed be antiperiplanar, usually overrides considerations of product ~tability.~' C. Cyclic Eliminations.-The decomposition of acetates, xanthates, and amine oxides is an important preparative method for olefins; interesting orientation results are found.40 These reactions are all cis-eliminations. Generally, factors other than product stability are thought to be important. In acyclic systems a statistical factor determined by the number of P-hydrogens is supposed to dominate (equation 40).4' However, when an aryl substituent is present, stability is probably important (equation 41).42 I Me Me 76 "lo 24 % H I APhCH2 CMe PhCH =CHMe + PhCHZCH= CH2 (41)I OAc 75 Olo 2 5 OlO In cyclic systems, an axial-equatorial alignment of the eliminating groups is favoured over an equatorial-equatorial alignment.This appears to be the main factor determining product composition (equation 42).43 c=-?( -0".0"(42) SOYSMe 70 OIo 30 'lo However, in acetate and xanthate pyrolyses, the more stable endo olefins are 39 W. H. Saunders, Jr. and A. F. Cockerill, ref. 33, p. 116; E. D. Hughes. C. K. Ingold, and J. B. Rose, J. Chem. SOC.,1953, 3839; E. D. Hughes and J. Wilby, ibid., 1960, 4094; W. Hueckel, W. Tappe, and G. Legutke, Annulen, 1940, 543, 191. 40 W. H. Saunders, Jr.and A. F. Cockerill, rel: 33, pp. 409, 427, 447. 41 D. H. Fremsdorf, C. H. Collins, G. S. Hammond, and C. H. DePuy, J.Am. Chem. Soc., 1959,81,643;W. 0.Haag and H. Pines, J. Org. Chem., 1959, 24, 877. 42 W. J. Bailey and C. King, J. Org. Chem., 1956, 21, 858. 43 F. G. Bordwell and P. S. Landis, J. Am. Chem. Soc., 1958, 80, 6379; W. Hueckel, W. Tappe, and G. Legutke, Annulen, 1940,543,191;R. T. Arnold, G. G. Smith, and R. M. Dodson, J. Org. Chem., 1950,15, 1256; W. J. Bailey and L. Nicholas, J. Org. Chem., 1956, 21, 854. 327 Product Stability in Kinetically-Controlled Organic Reactions predominantly formed (equation 43).44 Product-stability control seems the most likely explanation, although it has been suggested that entropic factors favour the formation of endo olefins.This is because there is a loss of freedom of rotation of the methyl groups in the transition state leading to em ~lefin.~~ 7 5 "I0 2 5 OIO In contrast, the corresponding Cope elimination yields almost exclusively the exo olefin (equation 44).46It is thought that this is because, in the transition state for the formation of the endo olefin, the cyclohexane ring would have to adopt the less stable boat conformation, whereas the e.w olefin can be formed via the chair transition state. ___* (44)0" I 0-Finally, the Cope eliminations in equations 45 and 46 may be mentioned.47 In the trans isomer (equation 46), axial-equatorial elimination can lead to either orientation of the double bond. Whether the predominance of the conjugated Ph Ph &;Me, ___*I 0-2 98 "lo"I0 Ph + NMe2 85 "lo 15 "loI0-44 W.J. Bailey and W. F. Hale, J. Am. Chem. Soc., 1959, 81. 647, 651. 45 D. V. Banthorpe, ref. 34, p. 175. 46 A, C. Cope, C. L. Bumgardner, and E. E. Schweizer, J. Am. Chem. Soc., 1957, 79, 4729. "A. C. Cope and C. L. Bumgardner, J. Am. Chem. Soc., 1957, 79, 960. 328 Chandrasekhar isomer is due to its greater stability or to the greater acidity of the PhC-H hydrogen in the reactant is not clear. 6 Cyclization Reactions Much is known about the thermodynamic and kinetic factors affecting cyclization reactions. Amongst the small and medium rings, six-membered rings are the most stable, followed by five-membered rings.However, five-membered rings are generally formed the fastest, followed by six-membered rings. Thus, the equilibrium constant for the cyclization reaction in equation 47 is about 16, whereas it is about 8 for the analogous reaction leading to a five- membered ring. The equilibrium constants for the corresponding reactions forming three- and four-membered rings are negligible, and for the reactions forming seven- and eight-membered rings, are said to be 0.2 and 0.1 respe~tively.~~ It is interesting to compare these trends with the relative rates of formation of rings of various sizes.48 For the reaction in equation 48, the relative rates for various values of n are as follows: n 3 4 56 71015 krelative 3.12 0.002 100 1.7 0.03 The most striking feature is that the five-membered ring is formed faster than the more stable six-membered ring.Similarly, the three-membered ring is formed faster than the more stable four-membered ring; this is thought to be due to an entropy effect, the ends of a chain of three atoms being closer together than those of a chain of four. However, the dramatic rise in the value of k on going from n = 4to n = 5, may well be due to product-stability control. The strain energies for the 3-, 4-,5, and 6-membered cycloalkanes are 9.2, 6.6, 1.3, and 0.0 kcal mol-’ re~pectively.~~ Thus, the difference in strain energies between the four- and five-membered rings is about twice that between the three- and four-membered rings, which may explain the importance of product stability in the formation of the five-membered ring.In other words, in the formation of five-membered rings, a balance is achieved between the product-stability and entropic factors. 48 R.0.C. Norman, ‘Principles of Organic Synthesis’, Chapman and Hall, London, 2nd Edition, 1978, pp. 23,90; P. R. Jones, Chem. Rev., 1963,63,470 C. D. Hurd and W. H. Saunders, Jr., J. Am. Chem. SOC., 1952,745324; A. A. Frost and R. G. Pearson, ‘Kinetics and Mechanism’, Wiley, New York, 2nd Edition, 1961, p. 297; G. Salomon, Hefv. Chim. Am, 1933, 16, 1361. 49 J. March, ‘Advanced Organic Chemistry’, McGraw-Hill-Kogakusha, Tokyo, 2nd Edition, 1977, p. 145; E. L. Eliel, ref. 7, p. 189. 329 Product Stability in Kinetically-Controlled Organic Reactions Favoured (’3X Disfavoured Scheme 2 Baldwin’s ‘Rules for Ring Closure’ also highlight the unimportance of product stability in cyclization reactions.Preferred modes of cyclization are determined by the structural features of the reactants, rather than by product stability. For example, 5-and 6-endo-tet reactions are disfavoured, whereas 3-and 4-exo-tet closures, leading to strained three- and four-membered rings respectively, are favoured (Scheme 2). However, closures leading to five- and six-membered rings in the exo-tet mode are favoured. Similarly, 3-to 5-endo-trig closures are disfavoured whereas 3-to 7-exo-trig closures are favoured. Again, 3-to 4-exo-dig processes are disfavoured, whereas 3-to 7-endo-dig processes are favoured.These illustrate, in a way, that the stability of a ring is not very important to its rate of formation. Dramatic examples of the formation of the less stable products, in accord with these rules, are shown in equations 49 and 50. 0’ 50 J. E. Baldwin, J. Chem. Soc.. Chem. Commun., 1976, 734. 330 Chandrasekhar 7 Aromatic Electrophilic Substitutions Kinetic and thermodynamic products may be different in aromatic electrophilic substitution reactions. For example, sulphonation of naphthalene under kinetic conditions (80 “C) yields 1-naphthalenesulphonic acid, whereas the thermody- namically-controlled product is 2-naphthalenesulphonic acid (equation 51). Similarly, kinetically-controlled methylation of toluene yields only 0-and p-xylene, whereas the equilibrium composition is 60% m-,20% 0-,and 20% p-xylene (equation 52).’ Mechanistically, these reactions take place via the rate-determining formation of a-complex intermediates. SO3 H I 8 Other Reactions A.Dissolving Metal Reductions.-A variety of functional groups is reduced by dissolving metals. However, only the reduction of conjugated systems is interesting in the context of this review. (Although the reduction of cyclic ketones is known to give the more stable alcohol products, a consideration of the mechanism shows that these reactions are not kinetically ~ontrolled.’~) The Birch reduction of various aromatic systems is known to yield the less stable unconjugated dienes (equations 53-55).’ 3-’5 The reason adduced for this J.Hine, ‘Physical Organic Chemistry’, McGraw-Hill-Kogakusha, Tokyo, 2nd Edition, 1962, p. 380. 52 H. 0.House, ref. 1, p. 150; J. F. Huffmann and J. T. Charles, J. Am. Chem. Sac., 1968, 90, 6486; A. Coulombeau and A. Rassat, J. Chem. Sac., Chem. Commun., 1968, 1587. 53 (a)H. 0.House, ref. 1, p. 188; (b)N. L. Bauld,J. Am. Chem. Sac., 1962,84,4347;D. R. Weyenberg, L. H. Toporcer, and L. E. Nelson, J. Org. Chem., 1968, 33, 1975. 54 A. P. Krapcho and A. A. Bothner-By, J. Am. Chem. SOC.,1959,81, 3658; ibid., 1960; 82, 751. 55 K. C. Bass, Org.Synth., 1962,42,48;F. Camps, J. Coll, and J. Pascual, J. Org. Chem., 1967,32,2563;A. L. Wilds and N. A. Nelson, J. Am. Chem. Soc., 1953, 75, 5360, 5366. 33 1 Product Stability in Kinetically-Controlled Organic Reactions COOH H COOH (55) phenomenon is that, in the highest-occupied molecular orbital of the intermediate anion, electron density is greatest at the middle carbon of the pentadienyl system.Protonation, which is fastest at this site, then leads to the unconjugated product. Similar reactions include electrophilic attack at the middle carbon of the pentadienyl anion, and the deconjugation of u,P-unsaturated Finally, the reduction of 1,3-butadiene is reported to yield 2-butene (equation 56).s3bHowever, in the light of the above discussion, product-stability control is probably unlikely. B. Epoxide Cleavages.-The cleavage of a cyclohexene oxide takes place in such a way as to place the resulting substituents in the trans-diaxial rather than in the trans-diequatorial positions (equation 57).58 I. Fleming, ref. 29, p. 45. 57 H. 0.House, ref. 1, p. 502; H. J. Ringold and S. K. Malhotra, TetrahedronLeft.,1962,669; J. Am. Chem. SOC.,1962,84, 3402; S. K. Malhotra and H. J. Ringold, J. Am. Chem. SOC.,1963,85, 1538; ibid., 1964; 86, 1997; ibid., 1965, 87, 3228. H. 0.House, ref. 1, p. 301; H. B. Henbest, M. Smith, and A. Thomas, J. Chem. SOC.,1958,3293; G. H. Alt and D. H. R. Barton, ibid., 1954, 4284; J. Gorzynski Smith, Synthesis, 1984, 629. Chandrasekhar I OH The opening of epoxides by organometallic reagents has been well-studied. The regiochemistry of the products is determined by the fact that attack is at the less hindered position (equation 5Q5’ OMe Me 2Cu L i 49 OIOw ‘Me + OMe 45 OIo Apparently, there is no evidence for product-stability control in these reactions.C.Photochemical Reactions.-The Paterno-Buchi reaction often yields, probably the less stable, products (equation 59); so does olefin dimerization (equation 60).60 The reason for the observed orientations is that the reactions are under frontier- orbital control; therefore, product stability is unimportant. Ph l p h -k A A PhQ -+ (59) Ph Ph Ph 90 10 -b D. Miscellaneous.-In the Baeyer-Villiger oxidation, the course of the reaction is 59 G. H. Posner, Org. React. (N.Y.),1975,22,287;B. C. Hartmann, T. Livinghouse, and B. Rickborn, J. Org. Chem., 1973, 38, 4346. 6o I. Fleming, ref. 29, p. 213; D.R. Arnold, R. L. Hinman, and A. H. Glick, Tetrahedron Letf.,1964, 1425; D. 0.Cowan and R.L. E. Drisko, J. Am. Chem. Soc., 1970,92,6286. Product Stability in Kinetically-Controlled Organic Reactions determined solely by the nature of the group migrating to electron-deficient oxygen. The less stable product may be formed preferentially (equation 61).61 0 0 LO3 It ____+ PhOCMe Ph iVQ The SN1' reaction of many allylic halides can lead to the predominant formation of the less stable products (equation 62).62 Me2C =CHCH2CI H20 b Me2C-CH=CH2 I OH 15 OIo Allylic halogenation is known to give a predominance of the more stable product. However, this is because of equilibration of the product mixture under the reaction condition^.^^ 9 Summary of Survey of Reactions A variety of organic reaction classes has now been surveyed to ascertain the importance of product stability in determining product composition.The selection of reactions has been representative rather than exhaustive. Examples which are clear-cut or which are of synthetic importance have been chosen. Some of the reactions surveyed, such as additions to carbon-oxygen multiple bonds, additions to carbon-carbon multiple bonds, and elimination reactions, have been subjected to rigorous mechanistic study by various workers. The following general conclusions may be drawn from the survey: (1) There are a large number of reactions in which the less stable products are formed faster. Thus, kinetic and thermodynamic products are different for most organic reactions.Unambiguous examples of product stability determining product composition are rare. In other words, again, product-stability control is the exception rather than the rule. Further, even when the more stable product is 61 H. 0.House, ref. 1, p. 321; R. R. Sauers and R. W. Ubersax, J. Org. Chem., 1965,30,3939;C.H. Hassall, Org. React. (N. Y.), 1957, 9,73. J. March, 'Advanced Organic Chemistry', McGraw-Hill-Kogakusha, Tokyo, 2nd Edition, 1977,p. 307; R. H. de Wolfe and W. G. Young, Chem. Rev., 1956, 56, 753. H. 0.House, ref. 1, p. 485; L. Bateman and J. I. Cuneen, J. Chem. Soc., 1950, 941. Chandrasekhar formed faster, factors other than product stability have been proposed as explanations.And, sometimes, the proportion of the more stable product is greater than warranted by its stability. (2) Elimination reactions provide a few examples of apparent product-stability control. This is especially true of El reactions. Some cyclization reactions could also be under product-stability control. (3) In some reactions, such as electrophilic additions to olefins and epoxide cleavages, the less stable products are apparently the only possible ones, given the mechanisms of the reactions. However, it is interesting that the reactions do not change mechanism to avoid formation of the less stable products. (4)When a reaction takes place via intermediates, the final product-forming step is rarely rate determining. The rate-determining step usually occurs early along the reaction co-ordinate.10 Possible Explanations These intriguing findings pose a challenge to present theories of chemical reactivity, such as transition state theory. By definition, the transition state lies in-between reactants and products. Why then is product stability unimportant? The following qualitative explanations are possible and they can be classified into two general categories: A. Explanations Involving the Position of the Transition State along the Reaction Co-ordinate.-The reduction of ketones with complex metal hydrides is a reaction which serves as a convenient starting point for the discussion. This reaction class, in addition to having attracted attention to the above phenomenon, is also the most thoroughly studied.1--6 The accepted explanation appears to be that such reductions take place via early, reactant-like, transition states.Hence, product stability is thought to be unimportant. The reasons for this are not very clear. One possible reason is that, the reactions being exothermic, the Hammond postulate is applicable. According to this postulate, in exothermic reactions the transition states resemble the reactants in geometry, as these species are closer together along the reaction ~o-ordinate.~~ Although the postulate was actually meant to be applied to reactive intermediates, whose reactions are highly exothermic, it can probably be extended to less exothermic reactions.6 (Two reaction classes to which the Hammond postulate is certainly applicable are electrophilic additions to olefins, and dissolving metal reductions.These reactions take place via carbocations and carbanions, respectively; the transition states for the formation of products are expected to resemble the intermediates rather than the products.) Interestingly, most organic reactions are exothermic. Or rather, organic 64 J. March, ref. 62,p. 194;G.S. Hammond, J. Am. Chem. Soc., 1955,77,334. 335 Product Stability in Kinetically-Controlled Organic Reactions reactions are studied and used mostly in the exothermic directions. Endothermic reactions need to be driven to completion (by removal of a product) and are, therefore, less convenient to perform. It is also noteworthy that saturated systems are generally of lower energy than unsaturated systems.Therefore, in additions to unsaturated systems the transition states would be expected to be reactant-like, as such reactions are generally exothermic. Hence, product stability would be unimportant. However, reactions in which the products are 'more unsaturated' than the reactants, are expected to be endothermic and the transition states to possess some product character; product stability would then be important. Table Is0mers IAE I (kcaIs/mole)(Possible Products) X = OH 0. 4 -0.9 X = halogen 0.25-0.70 x 5 COOH -1.7 -0 2.4(3) (4) PhCHCH Ph II Br Br (meso) 1.4 (5) Xyle ne (0-+ P-) <o. 4 336 Chandrasekhar Table (contd.) isomers IA E I (kcals/mole) (Possible Products) 2.4 -3.0 2.5 3.2 (9) (n=1) (n=2) 2.6 The fact that elimination reactions are generally endothermic agrees with the above arguments.For, these reactions, as a class, offer the largest number of examples of product-stability control. An alternative explanation, not explicitly involving the Hammond postulate, is as follows. The energy of a transition state is assumed to be mainly that of steric repulsion between the colliding reactant molecules. As bonding progresses, the repulsive interactions are gradually offset. Now, bonding interactions are expected to offset repulsive interactions better in exothermic than in endothermic reactions. This is because bonding interactions release more energy in exothermic reactions.The result is that the energy maximum, i.e. the transition state, occurs earlier along the reaction co-ordinate for exothermic reactions. Therefore, the transition state would be expected to be reactant-like, for exothermic reactions. To sum up, then, organic reactions generally involve additions to multiple bonds and are, therefore, exothermic. The transition states for exothermic reactions resemble the reactants rather than the products. Hence product stability is unimportant. Product Stability in Kineticall~)-Controlled Organic Reactions B. Explanations Not Involving the Position of the Transition State along the Reaction Co-ordinate.-Insensitivity to product stability may be due either to the transition state not possessing enough product character, or to the differences in product stability being small.The first of these possibilities was discussed above. The second is now considered below. For differences in transition-state energies to be derived from the differences in product stabilities, the latter energy differences would have to be at least equal to the former. Interestingly, such a relationship is rather rare. Differences in stability of possible products (say, related isomers) are considerable only for olefins. For saturated systems, such energy differences are generally much smaller (less than about 2 kcal mol-'), as seen in the table on pp. 336-337.'0c365 Now, elimination reactions provide the few examples that exist of product- stability control.Hence, the tentative proposal is made that product-stability control is important onfy Hihen the differences in product stability are at least about 2 kcal mol-' (corresponding to the presence of about 95% of the most stable product, at equilibrium at 25 "C). 11 Conclusions Contrary to intuitive expectations, product-stability control is rather rare in organic reactions. In kinetically-controlled organic reactions, it seems that product- stability differences influence product composition only if the differences are at least about 2 kcal mol-'. Apparently, available theories of chemical reactivity do not satisfactorily explain these findings. Perhaps, much further work is needed. 6s E. I. Eliel. ref. 7, pp. 139, 236, 280. 303.

ISSN:0306-0012    

DOI:10.1039/CS9871600313

出版商:RSC    

年代:1987

数据来源: RSC