摘要:

Chemical Society Reviews Vol 11 No4 1982 Page The Mechanism of the Microbial Hydroxylation of Steroids By H. L. Holland 371 Carbonyl Group Transpositions By D. G. Morris 397 TILDEN LECTURE Semistable Molecules in the Laboratory and in Space By H. W. Kroto 435 Silicon-containing Carbonyl Equivalents By D. J. Ager 493 1982 Indexes 523 The Royal Society of ChemistryLondon Chemical Society Reviews EDITORIAL BOARD Professor K. W. Bagnall, B.Sc., Ph.D., D.Sc., C.Chem., F.R.S.C. (Chairman) Professor K. R. Jennings, M.A., D.Phi1, C.Chem., F.R.S.C. Professor G. W. Kirby, M.A., Ph.D., Sc.D., F.R.S.E., C.Chem., F.R.S.C. Professor G. Pattenden, PhD., C.Chem., F.R.S.C. Professor B. L. Shaw, B.Sc., Ph.D., F.R.S. Professor P.A. H. Wyatt, B.Sc., Ph.D., C.Chem., F.R.S.C. Editor: K. J. Wilkinson, B.Sc., M.Phi1. Chemical Society Reviews appears quarterly and comprises approximately 20 articles (ca. 500 pp) per annum. It is intended that each review article shall be of interest to chemists in general, and not merely to those with specialist interest in the subject under review. The articles range over the whole of chemistry and its interfaces with other disciplines. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submit- ted to The Managing Editor, Books and Reviews Section, The Royal Society of Chemistry, Burlington House, Piccadilly, London, W1V OBN.Members of the Royal Society of Chemistry may subscribe to Chemical Society Reviews at 512.50 per annum; they should place their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letch- worth, Herts. SG6 1HN England. 1982 annual subscription rate U.K. f36.00, Rest of World f38.00, U.S.A. $85.00. Air freight and mailing in the U.S.A. by Publications Expediting Inc., 200 Meacham Avenue, Elmont, Nel. Yoik 11003. U.S.A. Postmaster: Send address changes to Chemical Society Reviews, Publi- cations Expediting Inc., 200 Meacham Avenue, Elmont, New York 11003.Second class postage is paid at Jamaica, New York 11431. All other despatches outside the U.K. by Bulk Airmail within Europe, Accelerated Surface Post outside Europe. Note to subscribers. Regrettably publication of the four issues has still not reverted to the usual quarterly dates. The cause of this is a persisting shortage of articles (the production problems of recent years have been largely overcome) but the setting-up of an Editorial Board should result in an increase in the commis- sioning of reviews in 1982. @ Copyright reserved by The Royal Society of Chemistry 1983 ISSN 0306-0012 Published by The Royal Society of Chemistry, Burlington House, London, W1V OBN Printed in England by Eyre & Spottiswoode Ltd, Thanet Press, Margate.

ISSN:0306-0012    

DOI:10.1039/CS98211FP005

出版商:RSC    

年代:1982

数据来源: RSC

ISSN:0306-0012    

DOI:10.1039/CS98211FX009

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

Chemical Society Reviews Vol 11 No 4 1982 Page The Mechanism of the Microbial Hydroxylation of Steroids By H. L. Holland 371 Carbonyl Group Transpositions By D. G. Morris 397 TILDEN LECTURE Semistable Molecules in the Laboratory and in Space By H. W. Kroto 435 Silicon-containing Carbonyl Equivalents By D. J. Ager 493 1982 Indexes 523 The Royal Society of ChemistryLondon

ISSN:0306-0012    

DOI:10.1039/CS98211BX011

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

The Mechanism of the Microbial Hydroxylation of Steroids By H. L. Holland DEPARTMENT OF CHEMISTRY, BROCK UNIVERSITY, ST. CATHARINES, ONTARIO, CANADA, L2S 3A1 1 Introduction The use of a micro-organism to introduce the hydroxy-group into an organic molecule by performing the direct conversion of carbon-hydrogen bond to carbon-hydroxyl with defined regio- and stereo-specificity has given the organic chemist the ability to produce a wide range of compounds which may otherwise severely tax his or her synthetic ingenuity and skill. The first application of this technique was for the synthesis of the anti-inflammatory corticosteroids, and followed the discovery in 1950 by Murray and Peterson that the fungus Rhizopus arrhizus (isolated from the air in Kalamazoo, Michigan) was able to convert progesterone (1) into its 1 la-hydroxy derivative (2) in high isolable yield (Scheme 1).’y2 (1) (2) Scheme 1 The C-lla hydroxylation ofprogesterone’ Since that time, microbial hydroxylation has been extensively applied in the production of steroids on a commercial scale,3 and has also been used to a lesser extent in the research-scale preparation of non-steroid organic molecule^.^ In the steroid field, microbial transformations, of which the hydroxylation reaction is but one example, now constitute a formidable synthetic arsenal.’ The key position of the microbial hydroxylation reaction in this arsenal is assured by the relative inaccessibility of the products by conventional chemical H.C. Murray and D.H. Peterson, US Patent 2 602 769 (July 8, 1952).’G. G. Hazen, J. Chem. Educ., 1980, 57, 291. G. Nomine, Bull. SOC. Chim. Fr., 1980, 11-18, K. Kieslich, ‘Microbial Transformations of Non-steroid Cyclic Compounds’, 1976, Georg Thieme, Berlin. K. Kieslich, Bull. SOC. Chim. Fr., 1980, 11-9. The Mechanism of the Microbial H ydroxylation of Steroids means, and is reflected in the coverage given to this aspect of the subject in several reviews devoted to microbial transformations of steroids6 -’ In spite of the widespread application of microbial steroid hydroxylation in both industry and research over three decades, it is only in recent years that the mechanism of this reaction has been even partially understood. At the present time, our knowledge of the biochemistry of the process is more complete than our understanding of the chemistry concerned; this review will discuss both chemical and biochemical data relevant to the mechanism of the microbial steroid hydroxylation reaction.2 The Reactants A. The Enzymes Involved.-The term microbial hydroxylation has been loosely used to cover transformations carried out by either bacteria or fungi. Of these, the latter group of micro-organisms has been more extensively exploited and is of greater synthetic utility in the steroid field.6,7 However, the hydroxylation reaction may be performed by enzymes from a wide range of sources, including plant and animal tissue. The use of isolated enzymes or enzyme preparations for hydroxylation on a synthetic scale is not widespread; this is attributable to the difficulty of isolation and instability of the enzyme preparations concerned.’ The vast majority of microbial steroid hydroxylations has therefore been performed using either actively growing or resting cultures of Irrespective of the source of the steroid hydroxylating enzyme, the available evidence suggests that it is an iron-containing cytochrome P-450dependent 3species which functions with the stoicheiometry shown in equation ~ ~ ‘*I2 ’ R-H + NADPH + O2-+R-OH + NADP’ + -OH (1) These enzymes, which incorporate one molecule of molecular oxygen into the substrate, are classified as mono-oxygenases.The cytochrome P-450dependent mono-oxygenases are widely distributed among almost all forms of life,” and exist in both soluble and membrane-bound forms.Much of the mechanistic work on this class of enzymes has been performed using soluble enzymes from bacterial sources, such as the camphor hydroxylase from Pseudomonas put id^,'^,' or on enzymes of mammalian origin, but the available evidence suggests that all cytochrome P-450 dependent mono-oxygenases function by a similar W. Charney and H. L. Herzog, ‘Microbial Transformations of Steroids’, 1967, Academic Press, New York. L. L. Smith, in ‘Terpenes and Steroids’, (Specialist Periodical Reports), vol. 4, The Chemical Society, London, 1974, p. 394. C. Vezina and S. Rakhit in ‘Handbook of Microbiology’, vol. 4, ed. A. I. Laskin and H. A. Lechevalier, CRC Press, Cleveland, Ohio, 1974, p.117. H. Iizuka and A. Naito, ‘Microbial Transformations of Steroids and Alkaloids’, University of Tokyo Press, Tokyo, and University Park Press, State College, Pennsylvania, 1967. lo ‘Cytochrome P-450’, ed. R. Sat0 and T. Omura, Academic Press, New York, 1978. K. Breskvar and T. Hudnik-Plevnik, Biochem. Biophys. Rex Commun.,1977, 74, 1192.’’ K. Breskvar and T. Hudnik-Plevnik, J. Steroid Biochem., 1981, 14, 395. l3 L. S. Alexander and H. M. Goff, J. Chem. Educ., 1982,59, 179. 372 Holland mechanism.lo The data obtained from bacterial and mammalian enzymes are therefore relevant in a discussion of steroid hydroxylation mechanisms. The existence of a multitude of hydroxylating enzymes which function with different substrate, regio-, and stereo-specificities, and yet are all dependent on the same cofactors, is now well established in mammalian sy~tems.'~~'~ The close similarity between hydroxylations performed by mammalian and fungal systems16 suggests that a parallel state of affairs may exist in the microbial world.The role of cofactors and polypeptide (apoenzyme) may be distinguished as follows: the cofactors are responsible for the binding of oxygen, its activation, and delivery to the substrate of the oxidizing species; and the apoenzyme is responsible for the binding and (if appropriate) activation of the organic substrate (steroid). The apoenzyme therefore controls the substrate, regio-, and stereo-specificity of the hydroxylation reaction, and it is variation in this portion of the enzyme which is largely responsible for the wide range of substrate specificities and products observed in this reaction.The role of the apoenzyme in interacting with the substrate is the least well understood aspect of the hydroxylation process. Since the interpretation of the mechanistic data relevant to this aspect of the process depends in part on a knowledge of the nature of the catalytic cycle, the latter will be discussed first. B. The Binding and Activation of Oxygen.1o,' -''-The overall features of the catalytic cycle of cytochrome P-450mono-oxygenases appear to be independent II CH CH, I I CH, tH 2 I I COOH COOH (3) l4 M. A. Lang and D. W. Nebert, .I.Biol. Chem., 1981, 256, 12058.l5 M. A. Lang, J. E. Gielen, and D. W. Nebert, J. Biol. Chem., 1981, 256, 12068. l6 R. V. Smith and J. P. Rosazza, J. Pharm. Sci., 1975, 64, 1737. l7 'Molecular Mechanisms of Oxygen Activation', ed. 0.Hayaishi, Academic Press, New York,1974. C. K. Chang and D. Dolphin in 'Bioorganic Chemistry', ed. E. E. van Tamelan, Academic Press, New York, 1978, vol. 4, p. 37. l9 P. Bentley and F. Oesch in 'Foreign Compound Metabolism in Mammals', (Specialist Periodical Reports), vol. 5, The Chemical Society, London, 1979. p. 113. The Mechanism of the Microbial Hydroxylation of Steroids of the source of the enzyme. The active site of cytochrome P-45OCAMfrom P. putida contains an iron haem in the form of iron protoporphyrin IX (3), present in the restivg state of the enzyme in the iron(II1) state.The two axial ligands are provided by the protein; one of these is a cysteine sulphide ion, while the other, which is displaced by oxygen during the catalytic cycle, is currently unidentified but may be the imidazole nitrogen of a histidine residue. The catalytic cycle of cytochrome P-450 dependent mono-oxygenases, which has been deduced largely from a study of the camphor hydroxylase of P. putida, is presented in Scheme 2. A detailed discussion of thas cycle is beyond the S Fe3' Fe3'---S Scheme 2 The catalytic cycle of cytochrome P-450 dependent mono-oxygenases (S = substrate) scope of this review, but the following points are relevant. The first step, substrate binding, is necessary before oxygen can bind to the iron centre; however, the subtrate does not bind directly to the haem unit, but is presumably bound by the apoprotein in close proximity to the cofactor.The two reducing equivalents are provided ultimately by NADPH, and are transferred to the cofactor via a flavin nucleotide, iron-sulphur proteins (ferredoxins) and/or cytochrome b5, depending upon the source of the enzyme. The ultimate oxidizing species, here formulated as (4), has already lost one atom of molecular oxygen to the aqueous medium. The nature of (4)and its subsequent reaction to provide the product will be discussed in more detail in Section 3. C.Binding of the Substrate.-The binding of substrate to a cytochrome P-450 dependent mono-oxygenase is accompanied by changes in both the conformation of the protein2' and the spectral properties of the cofa~tor.'~ It has been H.Shichi, K. Kumaki, and D. W. Nebert. Chem.-Bid. Interact., 1978, 20, 133. 374 Holland proposed that ketosteroids may bind to a protein as imines (via condensation with a primary amino-group)21*22 or thio-ethers (via Michael addition of a thiol to A4-3-ketosteroids).23,24However, hydroxylation of [3-180]testosterone (5) at C-68 or C-lla by Rhizopus arrhizus proceeded with ca. 80% retention of label,25 a result which eliminates from consideration the binding of substrate as an imine with consequent loss of the original C-3 oxygen to the medium. OH The binding of (5) as a thio-ether cannot be eliminated on this evidence, but is unlikely in view of the requirement of the C-6B hydroxylation for an intact A4-3-ketosteroid substrate (vide infra).In the C-6p hydroxylation of (5), and the hydroxylation of related ketosteroids at positions adjacent to carbonyl, it is likely that binding of the substrate occurs in the enol form. This is discussed in greater detail in Section 2.D below. The first indication that a specific relationship may exist between the position of substitution of the substrate and the site of hydroxylation was provided by Usingthe work of Murray et ~21.~~~~’ substituted cyclic and polycyclic substrates they postulated the existence in Sporotrichurn sulphurescens of an enzyme-su!strate complex in which oxygenation occurs at a methylene group about 5.5A away from an electron-rich substituent of the substrate (Figure 1).More recent work28’29 with the same micro-organism (since reclassified as Beauveria bassiana and described2 as Beauveria sulphurescens) using the bridged bicyclic and polycyclic amide substrates (6)-( 12) has established the sites of mono-hydroxylation shown on the corresQonding structures. Since these hydroxylation do not occur systematically 5.5 A away from the carbonyl oxygen, the authors suggest that either the amide nitrogen or lipophilic aromatic ring rather than the carbonyl oxygen may be instrumental in determining the regiospecificity of hydroxylation for these substrates. “ W. F. Benisek and A. Jacobson, Bio-org. Chem., 1975, 4, 41.’’D. C. Wilton, Biochem.J., 1976, 155, 487. ’3 R. C. Fahey, P. A. Meyers, and D. L. DiStefano, Bio-org.Chem., 1980, 9, 293. 24 C.-C. Chin and J. C. Warren, Biochemistry, 1972, 11, 2720. ”H. L. Holland and G. J. Taylor, Can. J. Chem., 1980, 58, 2326. 26 G. S. Fonken, M. E. Herr, H. C. Murray, and L. M. Reineke, J. Am. Chem. SOC., 1967,89, 672. 2’ R. A. Johnson, M. E. Herr, H. C. Murray, and G. S. Fonken, J. Org. Chem., 1968, 33, 3182. 28 R. Furstoss, A. Archelas, B. Waegell, J. Le Petit, and L. Deveze, Tetrahedron Lett., 1980, 21, 451. 29 R. Furstoss, A. Archelas, B. Waegell, J. Le Petit, and L. Deveze, Tetrahedron Left., 1981, 22, 445. The Mechanism of the Microbial Hydroxylation of Steroids E = an electron-rich group L = a lipophilic group which may or may not be part of C C = a cyclic system Figure 1 Hypothetical enzyme-substrate complex for hydroxylation by S.sulphure~cens~~~~~ 5.7 @"KPh"K"0 0 (9) In the steroid field, this approach has been successfully applied over the past decade by the Oxford research group of Sir Ewart R.H. Jones and G. D. Meakins. A preliminary review of this work has appeared.30 By employing steroid substrates with oxygen substituents (hydroxy and/or carbonyl) in defined locations, and varying these locations in a systematic manner, a relationship 30 E.R. H.Jones, Pure Appl. Chern., 1973, 33, 39. 376 Holland II 0 has been established between the position of substitution of the substrate and the site of hydroxylation of the latter for several micro-organisms. Working with the mono-oxygenated Sa-androstane substrates (13)-( 19) and the fungus Calonectria decoru, the pattern of dihydroxylation shown on the structures was establi~hed.~' The major transformation products contained two equatorial hydroxy-groups about 4 A apart, and the sites of hydroxplation bear the approximate geometrical relationship to the position of the carbonyl substituent illustrated in Figure 2.This relationship also holds for several A-nor and ~-homosteroids.~' OH co 4 > OH 7.5 II Figure 2 Dihydroxylation of monoketo Sor-androstanes by C. decora3' 31 A. M.Bell, P. C. Cherry, I. M. Clark, W. A. Denny, Sir Ewart R. H. Jones, G. D. Meakins. and P. D. Woodgate, J. Chem. SOC.,Perkin Trans.I, 1972, 2081. The Mechanism of the Microbial Hydroxylation of Steroids Further with di-oxygenated substrates and C. decora again resulted in equatorial hydroxylations, the predominant products being mono-or di-hydroxylated. The pattern of hydroxylation of the substrate diones or keto- alcohols was not so apparent as in the case of the monoketo substrates (14)-(19), but may be summarized as follows: The presence of a carbonyl or hydroxy-group in the A or D ring exerts a dominant directing influence which results in the introduction of hydroxyl according to the relationship of Figure 2 [e.g., (20), (2111. However, the presence of a carbonyl or hydroxy-group at a site close to a predicted position of hydroxylation appears to inhibit hydroxyl- ation at that position [e.g., C-6a, structure (20)], and substituents in the B or c ring do not show a strong directing influence.Nevertheless, with these constraints, the pattern of hydroxylation of disubstituted androstanes is roughly similar to that shown in Figure 2. The fact that at a given location, both carbonyl [e.g., (14)] and hydroxyl [e.g., (22)] exhibit similar directing effects supports the interpretati~n~~of the enzyme-substrate binding as a hydrophilic interaction (vide supra). The sensitivity of the relationship shown in Figure 2 to changes in substrate geometry is reflected in the deviation from this pattern observed when 3a,5-cyclosteroids, e.g., (23), cf: (19) were used as substrate^.^^ 0 0& HO Oxygenated substituents other than carbonyl and hydroxyl, such as enol ethers and acetals, may also exert a directing influence on hydroxylation by C.decora similar to that of Figure 2, but generally with reduced yield and ~pecificity.~~The directing influence of halogen has also been studied using ’’A.M. Bell, W. A. Denny, Sir Ewart R. H. Jones, G. D. Meakins, and W. E. Muller, J. Chem. SOC.,Perkin Trans. 1, 1972, 2759. 33 V. E. M. Chambers, W. A. Denny, Sir Ewart R. H. Jones, G. D. Meakins, J. 0. Miners, J. T.Pinhey, and A. L. Wilkins, J. Chem. SOC., Perkin Trans. 1, 1975, 1359. 34 J. M. Evans, Sir Ewart R. H. Jones, G. D. Meakins, J. 0.Miners, A. Pendlebury, and A. L. Wilkins, J. Chem. Soc., Perkin Trans. 1, 1975,1356. Ho1land halosteroids as substrates for C.decora, Rhizopus nigricans, and Asperg illus -ochraceu~.~~The position of hydroxylation of monoketohalosteroids by C. decora is controlled by the directing influence of the carbonyl group,35 e.g., (24), cf. (19), and (25), cf. (14), unless halogen is present at a preferred site of location, in which case hydroxylation occurs elsewhere, e.g., (26), cf. (14).36 With R. nigricans (R.stolonifer), hydroxylation may also occur at the preferred site irrespective of the presence of halogen [e.g., (27), (28)],35937 whereas the position of hydroxylation by the C-1 la site-specific hydroxylator A. ochraceus (vide infra) is unaffected by the presence of halogen [(29) and (30)] provided that the latter is not located close to C-11;35*36in this event, hydroxylation occurs elsewhere.With the exception, therefore, of hydroxylation by R. nigricans (stolonifer), the presence of a halogen substituent at C-n has little directing influence; it generally results in hydroxylation remote from that site when C-n is a favoured position of hydroxylation, and has little effect where the favoured hydroxylation site is remote from C-n. F 0& 0& F FF F --Ffl 35 Sir Ewart R. H. Jones, G. D. Meakins, J. 0. Miners, and A. L. Wilkins, J. Chem. Soc., Perkin Trans. I, 1975, 2308. 36 T. G. C. Bird, P. M. Fredericks, Sir Ewart R. H. Jones, and G. D. Meakins, J. Chem. Soc., Perkin Trans. I, 1980, 750. 37 H. L. Holland and E. M. Thomas, Can. J. Chern., 1982, 60, 160. 379 The Mechanism of the Microbial Hydroxylation of Steroids 0Po-'0@OH Several other fungi show a pattern of hydroxylation similar to the relationships deduced for C.decora. Rhizopus nigricans, although giving predominantly C-1la-hydroxylated products with pregnanes such as progesterone (1) (cf: Scheme 1),38 exhibits a substituent directed pattern of hydroxylation with 5a-androstane substrates.39940 Using a series of monoketone, diketone, and keto-alcohol substrates, the relationship shown in Figure 3 was deduced, in which three sites exist on the enzyme which can fulfill either binding or hydroxylating roles. Monoketo substrates, e.g., (32) and (33), are thus dihydroxylated following binding of the substrate carbonyl to one of these sites, whereas di-oxygenated substrates, e.g., (34) and (35) are monohydroxylated at the third site following binding of the substrate to the other two. The possibility exists that the substrate may bind in either 'normal' [e.g., (34)] and/or 'reverse' [e.g., (35)]fashion.Figure 3 Binding and hydroxylation of SIX-androstanesby R. nigri~ans~~.~' 38 D. H. Peterson and H. C. Murray, J. Am. Chem. SOC., 1952, 74, 1871. 39 J. W. Browne, W. A. Denny, Sir Ewart R. H. Jones, G. D. Meakins, Y. Morisawa, A. Pendlebury, and J. Pragnell, J. Chem. SOC., Perkin Trans. I, 1973, 1493. 40 V. E. M. Chambers, W. A. Denny, J. M. Evans, Sir Ewart R. H. Jones, A. Kasal, G. D. Meakins, and J. Pragnell, J. Chem. SOC.,Perkin Trans. I, 1973, 1500. Holland The fungus Rhizopus arrhizus also shows a pattern of hydroxylation of Sa-androstanes similar to that of R.nigricans, but no clear relationship was discernable for hydroxylations performed by Rhizopus circinnans, apart from a tendency for hydroxylation in ring B or c.~’A triangular geometry relating binding and hydroxylation of Sa-androstanes has been proposed for hydroxylation Ophiobolus herpotri~hus,~~ by Wojnowicia grarnini~,~~ Daedalea rufe~cens,~~ Diaporthe cei~strina,~~ and an unspecified fungus species4’ In the case of W.graminis and 0.herpotri~hus,~~the central site appears to have only binding, and not hydroxylating, capability, whereas with D. r~fescens,~~although all three sites have a dual function, the terminal ring sites are considered to be the exhibited a preference for a-face primary hydroxylating entities; D. ~eiastrina~~ hydroxylation within the general framework of a triangular site arrangement.The unspecified fungus isolated from an ant nest (‘Acromyrex fungus’)45 performed a variety of transformations in addition to hydroxylation, but the latter process could again be rationalized by the existence of a triangular arrangement of three enzyme sites, similar to that shown in Figure 3. Site-directed hydroxylation has also been observed with several steroid-related s~bstrates.~~C. decora hydroxylated (36) as shown [cf. (14)], and R. nigricans hydroxylated (37) in the anticipated region of the molecule. Although bicyclic4’ substrates such as (38) were hydroxylated by C.decora and R. nigricans in the HO 41 A. M. Bell, I. M. Clark, W. A. Denny, Sir Ewart R. H. Jones, G. D. Meakins, W. E. Muller, and E. E. Richards, J. Chem. SOC.,Perkin Trans. I, 1973, 2131. 42 V. E. M. Chambers, Sir Ewart R. H. Jones, G. D. Meakins, J. 0. Miners, and A. L. Wilkins, J. Chem. SOC., Perkin Trans. I, 1975, 55. 43 A. M. Bell, Sir Ewart R. H. Jones, G. D. Meakins, J. 0. Miners, and A. Pendlebury, J. Chern. SOC., Perkin Trans. 1, 1975, 357. 44 A. M. Bell, A. D. Bod, Sir Ewart R. H. Jones, G. D. Meakins, J. 0. Miners, and A. L. Wilkins, J. Chem. SOC.,Perkin Trans. 1, 1975, 1364. 45 Sir Ewart R. H. Jones, G. D. Meakins, J. 0. Miners, J. H. Pragnell, and A. L. Wilkins, J. Chem. SOC.,Perkin Trans. I, 1975, 1552. 46 M.J. Ashton, A. S. Bailey, and Sir Ewart R. H. Jones, J. Chem. SOC.,Perkin Trans. 1, 1974, 1658. 47 A. S. Bailey, M. L. Gilpin, and Sir Ewart R. H. Jones, J. Chem. SOC., Perkin Trans. 1, 1977, 265. 381 The Mechanism of the Microbial Hydroxylation of Steroids range 7-9A away from an existing oxygen substituent, the conversions and isolated yields were very low. The use of monocyclic substrates such as cyclododecanone and cyclopentadecanone did not yield useful mechanistic information beyond the generalization that initial hydroxylation occurred at a position remote from the directing carbonyl sub~tituent.~~ Although C. decora, R. nigricans, R. arrhizus, and D.rufescens exhibit the site directed hydroxylation of Sa-androstanes discussed above, these fungi gave complex mixtures and less regio-selective hydroxylation when metabolizing Sa-pregnane substrate^.^' However, general similarities were apparent, so that hydroxylation of a C-n oxygenated 20-ketopregnane usually occurred at the same position as that of a C-n oxygenated 17-ketoandrostane [e.g., (39) with C.decora cf. (21)]. The difference in hydroxylating behaviour between the three Rhizopus species observed for androstane substrates (vide supra) was also present, but less markedly so, for pregnane substrates. Fungi have also been identified which clearly do not have a definite geometrical relationship between substrate substituent(s) and site of hydroxyl- ation. Thus Absidia regnieri and Syncephalastrurn racemosurn, although both active hydroxylators of 5a-androstane derivatives, do not exhibit a clear relationship between site of hydroxylation and substrate str~cture.~' Aspergihs ochraceus, on the other hand, shows a predilection for hydroxylation at C-1ICY of a wide range of substrates in both the androstane51 and ~regnane~~ series, irrespective of the location of substitution in the substrate.D. Activation of the Substrate.-In the hydroxylations at saturated carbon discussed above, (with the possible exception of those by A. ochraceus), it is assumed that no specific activation of the C-H bond concerned is provided by the enzyme, but rather the position of hydroxylation is controlled by the geometrical nature of the active site. However, not all steroid C-H bonds 48 M.J. Ashton, A. S. Bailey, and Sir Ewart R. H. Jones, J. Chem. SOC., Perkin Trans. I, 1974, 1665. 49 Sir Ewart R. H. Jones, G. D. Meakins, T. 0. Miners, R. N. Mirrington, and A. L. Wilkins, J. Chem. SOC.,Perkin Trans. 1, 1976, 1842. 50 A. M. Belf, Sir Ewart R. H. Jones, G. D. Meakins, J. 0. Miners, and A. L. Wilkins, J. Chem. SOC.,Perkin Trans. 1, 1975, 2040. 51 A. M. Bell, J. W. Browne, W. A. Denny, Sir Ewart R. H. Jones, A. Kasal, and G. D. Meakins, J. Chem. SOC.,Perkin Trans. I, 1972, 2930. 52 A. S. Clegg, W. A. Denny, Sir Ewart R. H. Jones, G. D. Meakins, and J. T. Pinhey, J. Chem. SOC.,Perkin Trans. 1, 1973, 2137. Holland are equally reactive towards hydroxylation, and this phenomenon can also play a role in determining the position of microbial hydroxylation.For example, dry ozonation of saturated steroids supported on silica gel, reaction conditions reported to mimic microbial hydr~xylation,~ demonstrate selectivity in oxidation at C-14,54 and hydroxylation at allylic positions of steroidal and related olefins is common.55- 57 Indeed, allylic hydroxylation becomes the dominant pathway of metabolism for the unsaturated substrate (40) whose saturated analogue (41) is hydroxylated (in this case by Fusarium graminearum) at a contiguous but different site.58 Although enzymic C-H bond activation at saturated non-allylic carbon is apparently unnecessary for hydroxylation, and indeed it is difficult to visualise how such activation could occur in an enzymic system, the situation is potentially more complex for hydroxylations which occur adjacent to carbonyl or conjugated carbonyl groups. During the hydroxylation of, for example, progesterone (l), at C-2, -6, -17 or -21, activation of carbon towards electrophilic oxidation can occur by en~lization,~’ shown in Scheme 3 for hydroxylation at C-21.The oxidizing species is shown for mechanistic convenience as ‘+OH’;its exact nature is discussed in Sections 2.B and 3.A. Circumstantial evidence for the involvement of enolic intermediates has existed for some time; thus Scheme 3 Activation of C-21 towards electrophilic attack by enolization 53 A. L. J. Beckwith and T. Duong, J. Chem. SOC.,Chem. Commun., 1978, 413. 54 R. L. Wife, D. Kyle, L. J. Mulheirn, and H.C. Volger, J. Chem. SOC.,Chem. Commun., 1982, 306. 55 T. A. Crabb, P. J. Dawson, and R. 0.Williams, J. Chem. SOC.,Perkin Trans. I, 1980, 2535. 56 T. A. Crabb, P. J. Dawson, and R. 0.Williams, J. Chem. SOC.,Perkin Trans. I, 1982, 571. 5’ R. A. LeMahieu, B. Tabenkin, J. Berger, and R. W. Kierstead, J. Org. Chem., 1970, 35, 1687. 58 G. Defaye, M. H. Luche, and E. M. Chambaz, J. Steroid Biochem., 1978, 9, 331. 59 H. J. Ringold, in ‘Oxygenases’, ed. D. Hayaishi, Academic Press, New York, 1962, p. 227. The Mechanism of the Microbial Hydroxylation of Steroids hydroxylations at the axial C-2/3, -68, and -log (in 1Pnorsteroids) positions of A4-3-ketosteroids are among the most frequently reported, whereas hydroxyl- ations at C-2u, -6a, and -1Ou are quite rare.6*7 Chemical electrophilic attack on the appropriate enolic species leads to preferential axial substitution under stereoelectronic control,609 61 exemplified by the peracid oxidation of A3,5-dienol derivatives to give exclusively 6/3-hydroxy-A4-3-ketones,shown in Scheme 4.62 The facile electrophilic oxidation of steroidal en~ls,~’-~~ and the existence of enzymes which enolize ketosteroids,66 add credence to this mechanistic proposal.Of1 Scheme 4 Peracid oxidation of A3y 5-dienol derivatives The possibility of enolization during the C-2 1 hydroxylation of progesterone (1) by Aspergillus niger has been examined using substrates with one, two, and three deuterium atoms at C-21.67 Using [21-2H3 ]progesterone as substrate, the product (42) was obtained with two deuterium atoms at C-21.Hydroxylation therefore occurred without reversible enolization of the C-20 carbonyl towards C-21 with concomitant loss of label. However, prolonged incubation times can lead to subsequent non-enzymic exchange of label at C-21 of (42) with protium of the medium; the medium pH drops as low as 2.3 in actively growing cultures.68 Substrates with one and two deuterium atoms at C-21 were used to obtain the primary intramolecular isotope effect for C-2 1 hydr~xylation.~~ The value obtained, kH/kD = 1.25, is inconsistent with a mechanism requiring prior enolization (Scheme 3), and suggests that C-21 hydroxylation occurs by direct reaction of the oxidizing species with a C-21-H bond.The microbial C-6/3 hydroxylation of A4-3-ketosteroids by Rhizopus arrhizus has been shown to proceed via binding of the substrate to the enzyme as the A3*’-dienol (43) (Scheme 5).69-74 The earlier report7’ that this reaction 6o J. Romo, G. Rosenkranz, C. Djerassi, and F. Sondheimer, J. Org. Chem., 1954, 19, 1509. 61 P. B. D. de la Mare and B. N. B. Hannan, J. Chem. SOC., Perkin Trans. 2, 1973, 1086. 62 D. N. Kirk and J. M. Wiles, J. Chem. SOC., Chem. Commun., 1970, 518, 1015. E. J. Bailey, J. Elks, and D. H. R. Barton, Proc. Chem. SOC., 1960, 214. 64 P. B. D. de la Mare and R. D. Wilson, J. Chem. SOC., Perkin Trans. 2, 1977, 157. 65 H. L. Holland, E. Riemland, and U. Daum, Can. J. Chem., in press. 66 S. K. Malhotra and H. J. Ringold, J.Am. Chem. SOC., 1965, 87, 3228. 6’ H. L. Holland and B. J. Auret, Can. J. Chem., 1975, 53, 845. H. L. Holland and Jahangir, unpublished data. 69 H. L. Holland and B. J. Auret, Can. J. Chem., 1975, 53, 2041. 70 H. L. Holland and B. J. Auret, Tetrahedron Lett., 1975, 3787. 71 H. L. Holland and P. R. P. Diakow, Can. J. Chem., 1978, 56, 694.’’H. L. Holland and P. R. P. Diakow, Can. J. Chem., 1979, 57, 436. 73 H. L. Holland and P. R. P. Diakow, Can. J. Chem., 1979, 57, 1585. 74 H. L. Holland, Can. J. Chem., 1981, 59, 1651. ”S. Baba, H. J. Brodie, M. Hayano, D. H. Peterson, and 0.K. Sebek, Steroids, 1963, 1, 151. 3 84 Holland OH(43) Scheme 5 C-6p hydroxylation of A4-3-ketosteroids by R.arrhizus preceeded with retention of tritium label at C-6a was originally interpreted as militating against the involvement of the dienol (43), but this work preceeded the investigations of Ringold and co-workers66.76-78 on the stereoelectronic effects operative in the enolization of A4-3-ketosteroids. Since enolization occurs with almost complete retention of the C-6a hydrogen, retention of label at C-6a during C-6B hydroxylation is not inconsistent with an enolic intermediate. The first indication that an dienolic intermediate was involved came from incubation of the A4-3-ketosteroid analogue (44)with R. arrhizus, and from peracid oxidation of the dienol-ether (45).69 Both procedures yielded a mixture of the alcohols (46) and (47) in which (46) was predominant; the formation 0d3 EtO (44) (45) 0 R' R2 (46) R' = H.R2= OH (47) R' =OH, R' = It of this mixture was rationalized by the proposal that both enzymic and chemical oxidation proceeded by stereoelectronically controlled axial addition to the dienols (48) (Scheme 6). For the conformationally constrained steroid, only route B of Scheme 6 is feasible, and so only /? oriented products are obtained. A similar result was obtained using the 19-nor steroid analogue (49).71 The products in this case included the alcohol (50). Hydroxylation at C-10 is also observed with 19-nor-A4-3-ketosteroid substrates,"* 79 presumably via A3*5('0)-dienol intermediates. The use of androst-4-ene-3,17-dione(51) with 76 S. K. Malhotra and H. J. Ringold, J. Am. Chem. SOC.,1963, 85, 1538.77 S. K. Malhotra and H. J. Ringold, J. Am. Chem. SOC., 1964, 86, 1997.''G. Subrahmanyam, S. K. Malhotra, and H. J. Ringold, J. Am. Chern. SOC.,1966, 88, 1332. 79 J. Favero, J. Marchand, and F. Winternitz, Bull. SOC. Chirn. Fr., 1977, 310. The Mechanism of the Microbial Hydroxylation of Steroids (47) (46) Scheme 6 Hydroxylation by axial addition to a dienot H OH 0m 0m deuterium labels at C-4, C-6a, and C-68 as substrates for C-6B hydroxylation by R. arrhizus confirmed the intermediacy of (43) in the C-68 hydroxylation reactions7' The reaction proceeded with complete retention of label at C-4 and C-6a. The C-6B labelled substrate retained 12-15 % of the original label, which was located at C-6a in the product (52). This result is in agreement with the observed retention of 17% label during enolization of C-6B deuterium labelled A4-3-ketosteroids towards C-6,'* and inconsistent with a direct stereospecific reaction of the oxidizing species at C-68.Further evidence for the pathway shown in Scheme 5 was provided by metabolism of the dienol acetate (53) by R. arrhiz~s.~'.~~Co-incubation of (53), and the ketone (51) labelled with deuterium at C-16, indicated that (53) was 386 H o1land transformed to the alcohol (52) faster than was (51). The metabolism of C-6 substituted A'-3-ketosteroids has also been examined, and the results rationalized in terms of the pathway of Scheme 7.73 The C-6p halo-substituted substrates (54) and (55) gave products [(56), (58), and (61)], whose formation could be rationalized by the presence of the dienol (62) and the subsequent reactions shown in Scheme 7.Similar products were obtained upon incubation of the dienol acetate (59) with R. arrhizus, and upon peracid oxidation of the corresponding dienol ether (60). (58) (61) Scheme 7 Metabolism of C-6 substituted A4-3-ketosteroids by R. arrhizus IR ri (54) R = C1 (56) R = C1 (55) R = F (57) R = F The Mechanism of the Microbial Hydroxylation of Steroids 0 0 (59) R= Ac (58) (60) R = Et (61) The assumption that the axial (/I) stereochemistry of hydroxylation at C-6 in substrates such as (l), (5), and (51) is the product of stereoelectronic addition of oxygen to the corresponding dienol (43) is supported by results obtained from the incubations of the B-norsteroids (63) and (64) with R.arrhizus, when both a and B alcohols (65) and (66) were formed.74 The conformation of the B ring in (63) and (64) is such that both a and /I positions at C-6 are stereo- chemically equivalent with respect to the plane of the O-C-3-C-4-C-5-enone system, so that interaction of developing electron density at C-6 from a A3,5-dienol of (63) or (64)will occur equally favourably from both the a and faces, 0 (63) R'+ R2= 0 (65) R' = H, R2= OH (64) R' =OH, R2= H (66) R' =OH, R2= €1 thus giving both (65) and (66) as products. The possibility that C-6p hydroxyl- ation of A4-3-ketosteroids proceeds via the A5 isomer (67) and the hydroperoxide (68)80 has also been examined.72 Incubation of (67) with R.arrhizus gave a mixture of products which included (52) and (58), and which was apparently formed by auto-oxidation of the substrate. There is no direct evidence for the involvement of free (67) or (68) in enzymic C-6p hydroxylation. Brodie et al. have studied the C-6p and C-7p hydroxylation of deuterium labelled estr-4-ene-3,17-dione (69), using Botryodiplodia rnalorurn.81,82 The interpretation of their results is difficult because of lack of homogeneity of label in the substrates, particularly at C-6p,71,83but nevertheless their data for C-6p hydroxylation are not inconsistent with the existence of an enolic intermediate and the route shown in Scheme 5. Hydroxylation at C-7p, however, occurs "P.H. Yu and L. Tan, J. Steroid Biochem., 1977, 8, 825. "H. J. Brodie and C. E. Hay, Biochem. J., 1970, 120, 667. I. Kim, C. E. Hay, and H. J. Brodie, J. Bid. Chem., 1973, 248, 2134. 83 H. L. Holland and G. J. Taylor, Can. J. Chem., 1981, 59, 2809. Holland 0 without loss of label from C-6B, and therefore cannot involve binding of the substrate as (43) unless formation of the latter is reversible and stereoselective, with return of the C-6B deuteron from the enzyme at the end of the reaction. 3 The Hydroxylation Reaction A. The Nature of the Oxidizing Species.-The oxidizing species has been formulated as (4), Scheme 2.84 Its electrophilic character is apparent from the observation that benzylic hydroxylation, and the closely related oxidation of alkyl aryl sulphides to sulphoxides (Scheme 8), a reaction also carried out by OH ICHPR' CHZR' p = -0.4 --1.60-0R R 0 Itg.-43p = -0.16 --0.67 R R Scheme 8 Hammett p valuesfor benzylic hydroxylation and sulphoxidation 84 J.T. Groves, S. Krishnan, G. E. Avaria, and T. E. Nemo, in 'Biomimetic Chemistry', ed. D. Dolphin, C. McKenna, V. Murakami, and I. Tabushi, American Chemical Society, Washington, D. C., 1980, p. 277. 389 The Mechanism of the Microbial Hydroxylation of Steroids R R Scheme 9 Formation of arene oxides during aromatic hydroxylation cytochrome P-450dependent mono-oxygenases,8s both proceed with rates which indicated a negative p value in the Hammett relationship.86 The electrophilic nature of the oxidation is also indicated by studies using olefinic substrates. Hydroxylation of aromatic substrates can proceed via arene oxide intermediates and the well-known NIH shift (Scheme 9),87988while other cytochrome P-450dependent mono-oxygenases epoxidize dehydrosubstrates related to their normal saturated substrate at a rate similar to that of hydroxylation, both transformations occurring at the same enzyme site.89 This is the case for the camphor hydroxylase of P.putida (Scheme lo),’’ and was first established for steroids with the C-9a hydroxylase from Nocardia restrictus.” Scheme 10 Epoxidation and hydroxylation by camphor hydroxylasegO A stereochemical relationship between steroid hydroxylation and epoxidation was deduced by Bloom and Shull, who formulated the proposal that ‘a micro- organism capable of introducing an axial hydroxy-function at C-n of a saturated steroid will also effect the introduction of an epoxide grouping axial at C-n in the corresponding unsaturated Equatorial hydroxylases do 85 Y.Watanabe, T. Iyanagi, and S. Oae, Tetrahedron Lett., 1982, 23, 533. 86 H. L. Holland and I. M. Carter, Can. J. Chem., in press. R. A. Sheldon and J. K. Kochi, ‘Metal-catalysed Oxidations of Organic Compounds’, 1981, Academic Press, New York,p. 248. D. R. Boyd, R. M. Campbell, H. C. Craig, C. G. Watson, J. W. Daly, and D. M. Jerina, J. Chem. SOC., Perkin Trans. 1, 1976, 2438. 89 R. T. Ruettinger and A. J. Fulco, J. Biol. Chem., 1981, 256, 5728. 90 M. H. Gelb, P.Malkonen, and S. G. Sligar, Biochem. Biophys. Res. Commun., 1982, 104, 853. ”F. N. Chang and C. J. Sih, Biochemistry, 1964, 3, 1551. 92 B. M. Bloom and G. M. Shull, J. Am. Chem. SOC.,1955, 77, 5767. Holland not effect similar conversions. This epoxidation may occur because of the spatial resemblance of the .n electron distribution in an unsaturated substrate to the area of maximum electron density in the related axial C-H bond of the corresponding saturated compound, shown for a C-118 hydroxylase in Figure 4. H Figure 4 C-llfl hydroxyIution and C-9(11) epoxidation B. The Stereochemistry of Hydroxy1ation.-Hydroxylation of steroids at unactivated positions occurs exclusively with net retention of configuration. This was first established for C-1 lor hydroxylation of C-11 labelled progesterones (cf.Scheme 1)by R. nigrican~’~,’~and has since been found to be the case for all cytochrome P-450dependent steroid hydroxylations which have been With the exception of a minority of cases, hydroxylation of other substrates also occurs with retention, and is considered the ‘normal’ mode of rea~tion.’~ An isolated report of hydroxylation with net inversion of configuration concerns the alkaloid norpl~viine;’~ however, hydroxylation of related alkaloids occurred with retention or partial retention of c~nfiguration,’~ so that the observed inversion during norpluviine hydroxylation may be attributable to a combination of a stepwise radical hydroxylation mechanism and a large primary kinetic isotope effect (vide infra)? Hydroxylations which occur with loss of configuration are a source of useful mechanistic data, and are considered below.C.Interaction between the Substrate and the Oxidizing Species.-The oxidizing species (4)may react with substrate in two ways (paths A and B, Scheme 11). The observed retention of configuration (Section 3.B) and the ability of (4) to epoxidize unsaturated substrates (Section 3.A) led to the proposal that hydroxylation occurs by direct insertion of the six-electron oxene species into a C-H bond (path A).98 The oxene mechanism of hydroxylation was accepted for many years as being the most consistent with the available 93 E. J. Corey, G. A. Gregoriou, and D. H. Peterson, J. Am. Chem. Soc., 1958, 80, 2338.94 M. Hayano, M. Gut, R. I. Dorfmann, 0.K. Sebek, and D. H. Peterson, J. Am. Chem. Soc., 1958,80,2336. 95 J. T. Groves, Adv. Inorg. Biochem., 1979, 1, 119. 96 I. T. Bruce and G. W. Kirby, J. Chem. SOC., Chem. Commun., 1968, 207. C. Fuganti and M. Mazza, J. Chem. SOC.,Chem. Commun., 1972,936. 98 G. A. Hamilton, J. Am. Chem. Soc., 1964, 86, 3391. 391 The Mechanism of the Microbial Hydroxylation of Steroids J &C-OH t Fe3+/ Scheme 11 Possible routes for hydroxylation at saturated carbon experimental data, but recently the free radical mechanism (route B), proposed by Wiberg" for analogous chemical oxidations, has gained some acceptance. (i) Product and Conjiguration Studies. The first positive indication that hydroxyl- ation may proceed via radical intermediates came from a study of the metabolism of the insecticide dieldrin (70) in mammals.100 The formation of (among others) the bridged metabolite (71) has been rationalized by the mechanism of Scheme 12,'" involving a transannular reaction of the radical intermediate (72).Further evidence for radical intermediates has been provided by the hydroxylation of deuterium labelled norbornanes by a rabbit liver cytochrome P-450system, which can occur with partial epimerization of label at the oxidized carbon,"* and by the observation that the cumene hydroperoxide dependent hydroxylation of labelled cyclohexene (73) by a liver microsomal system proceeded with partial allylic rearrangement.'03 The production of 5-exo-hydroxycamphor from camphor by the camphor hydroxylase of P.putida (Scheme 10) also occurs with partial epimerization at C-5, and a radical intermediate has been proposed.lo4 The production of hydroxy-radicals by cytochrome P-450dependent mono- oxygenase preparations has been inferred in several instances,"' -and the 99 K. B. Wiberg, in 'Oxidation in Organic Chemistry', ed. K. B. Wiberg, Academic Press, New York, 1965, p, 69. loo M. K. Baldwin, J. Robinson, and D. B.Parke, Food Cosmetics Toxicol., 1972, 10, 333. lo' C. T. Bedford, in 'Foreign Compound Metabolism in Mammals', (Specialist Periodical Reports), vol. 4, The Chemical Society, London, 1975, p. 407. lo' J. T. Groves, G. A. McClusky, R. E. White, and M. J. Coon, Biochem.Biophys. Res. Commun., 1978, 81, 154. J. T. Groves, 0.F. Akinbote, and G. E. Avaria, in 'Microsomes, Drug Oxidations and Chemical Carcinogenesis', vol. 1, ed. M. J. Coon, A. H. Conney, R. W. Estabrook, H. V. Gelboin, J. R.Gillette, and P. J. OBrien, Academic Press, 1980, p. 253. lo4 M. H. Gelb, D. C. Heimbrook, P. Malkonen, and S. G. Sligar, Biochemistry, 1982,21, 370. K. Ohnishi and C. S. Lieber, Arch. Biochem. Biophys., 1978, 191, 798. lo6 G. Cohen and A. I. Cederbaum, Arch. Biochem. Eiophys., 1980, 199, 438. lo' M. Ingelman-Sundberg and G. Elkstrom, Biochem. Eiophys. Res. Commun., 1982, 106, 625. lo' F. Hawco, L. Hulett, and P.J. OBrien, in ref. 103, p. 419. Ho1land I c1Cl C1 Scheme 12 Rearrangement during dieldrin metabolism'OO*'O' existence of substrate based radicals during N-oxidation by similar systems has also been lo The epoxidation of trans,trans-1,8-dideutero-1,7-octadiene with inversion of the original olefin geometry, using an enzyme of Pseudomonas oleovorans, has been also cited as supportive of a stepwise oxidation process analogous to radical hydroxylation,' " but since the P.oleo-oorans enzyme does not require cytochrome P-450,the relevance of this finding to the mode of action of other mono-oxygenases is unclear. In experiments specifically designed to test for intermediacy of a substrate radical, Golding and co-workers examined the hydroxylation of cyclopropane and methylcyclopropane by Methylocpccus capsulatus (Scheme 13).' ' * No rearrangement products were detected, indicating that free charged or radical intermediates were not involved.Theoretical calculations for the reaction of singlet carbene' and oxene' l4 with a C-H bond indicate that the preferred pathway does not involve lo9 R. P. Hanzlik and R. H. Tullman, J. Am. Chem. SOC.. 1982, 104, 2048. 'lo B. K. Sinha and A. G. Motten. Biochem. Biophys. Res. Commun., 1982, 105. 1044. 'I1 S. W. May, S. L. Gordon, and M. S. Steltenkamp, J. Am. Chem. SOC.,1977, 99, 2017. 11* H. Dalton, B. T. Golding, B. W. Waters, R. Higgins. and J. A. Taylor, J. Chem. SOC., Chem. Commun., 1981, 482. R. C. Dobson, D. M. Hayes, and R. Hoffmann, J. Am. Chem. SOC., 1971, 93, 6188. A. T. Budzianowski and G. H. Loew, J. Am. Chem. SOC., 1980, 102, 5443. The Mechanism of the Microbial Hydroxylation of Steroids A -A,,Only Scheme 13 Hydroxylation of cyclopropane and methylcyclopropane by M.capsulatus' l2 concerted direct insertion, but proceeds through a linear transition state in which the original C-H distance is little increased. Subsequent rearrangement of atoms can lead directly to products (Scheme 14). Similar calculations for triplet oxene"4 indicate a conventional radical abstraction mechanism. The formation of an oxene intermediate could therefore be consistent with either pathway of Scheme 11; no information on the spin state of such an intermediate in the enzymic reaction currently exists. Scheme 14 Theoretical path for C-H hydroxylation by singlet o~ene''~,'~~ The observation of epimerization or rearrangement in several reactions militates in favour of a radical intermediate which is relatively long lived or loosely bound to the enzyme. However, the failure to observe epimerization at carbon during enzymic hydroxylation may be attributable either to a concerted process (singlet oxene) or to a triplet oxene or radical pathway in which collapse of the intermediate radical pair occurs before significant loss of configuration.Since the majority of hydroxylations occur with retention of configuration, and this situation is clearly not amenable to unambiguous mechanistic interpretation, other experimental parameters are required. (ii) Kinetic Isotope Effect Studies. The rate determining step in the cytochrome P-450cycle (Scheme 2) has been variously reported as the addition of the second electron," and the decomposition of the P-450-substrate-oxygen complex to products.116 It is not clear to what extent the later steps of the cycle of Scheme 2 are kinetically distinct, and this has hampered a clear interpretation of the intermolecular isotope effects observed for hydroxylation.In general, such effects have been determined by product composition analysis following competitive hydroxylation of both labelled and unlabelled substrates. The need to correct for the extent of reaction,'I7 and the possible existence of isotope effects in substrate binding and other non rate-limiting steps' present additional complications. 'I5 P.Shannon and T. C. Bruice, J. Am.Chem. SOC., 1981, 103,4580. Y. Ishimura in 'Cytochrome P-450', ed. R. Sat0 and R. Omura, Academic Press, New York, 1978, p. 211. C. J. Collins and M. H. Lietzke, J. Am. Chem. SOC., 1959, 81, 5379.'" D. B. Northrop, Ann. Rev. Biochern., 1981, 50, 103. Holland Intermolecular isotope effects obtained in this way for steroid hydroxylations at C-6fi,7'91'9C-7a,119,120C-7fi,82 and C-l and also for non-steroid substrates,12' are low (generally kH/kD < 2) and have been interpreted as consistent with a concerted insertion me~hanism.~ The analogous effects for carbene'22 and ~arbenoid'~~ insertions are indeed low (kH/kD I2) but radical abstractions may also involve isotope effects of a similar magnitude.124,' 25 In cases where both inter- and intra-molecular isotope effects have been determined for the same substrate, appreciable differences are apparent.'26 The intramolecular effects are typically large (kH/'kD > 5),84*102exemplified in Scheme 15.'27 The only intramolecular effect so far reported for a steroid PI1 \ Kdb - Y XPh+ phvxphD OHHO D D k,/k, =6-11 Scheme 15 Nydroxylation of 1,3-diphenyl-[ l,l-2H2]propane'27 hydroxylation (kH/kD for C-21 hydroxylation = l.2)6 differs substantially from the values for non-steroid substrates.In view of the complicating factors discussed above, the intramolecular isotope effects are now viewed as potentially more useful than intermolecular effects in providing data for mechanistic inter- pretation.'02."8 The large effects observed are consistent with a radical abstraction process with a transition state in which the hydrogen is approximately equally shared between the atom which it is leaving and the abstracting species,' 28 but are difficult to reconcile with a concerted direct insertion mechanism (vide supra).86 4 Summary Considerable progress has been made in understanding the steroid hydroxylation reaction.The nature of the enzymically activated oxidizing species is now clear, and factors which can control the binding and possible activation of the substrate have been identified. However, the exact mechanism of the hydroxyl- ation step is not yet fully understood. Product and isotope effect studies lend weight to a radical abstraction-recombination mechanism for the hydroxylation of non-steroid substrates, and, by extension, of steroids.The latter, however, is by no means certain and further work in this area is clearly required. I. Bjorkhem, Eur. J. Biochem., 1971, 18, 299. lZo M. J. Frey, H. Jirku, and M. Levitz, J. Labelled Comp. Radiopharm, 1970, 6, 355. R. E. McMahon and H. W. Culp, J. Med. Chem., 1979, 22, 1100. 12' V. Franzen and R. Edens, Justus Liebigs Ann. Chem., 1969, 729, 33. lZ3M. J. Goldstein and W. R. Dolbier, J. Am. Chem. SOC., 1965, 87, 2293. J. T. Groves and M. Van Der Puy, J. Am. Chem. SOC., 1976, 98, 5290. L. B. Harding and W. A. Goddard, J. Am. Chem. SOC.,1980, 102, 439. lZ6 A. B. Foster, M. Jarman, J. D. Stevens, P. Thomas, and J. H. Westwood, Chem.-Biol. Interactions, 1974, 9, 327.''' L. M. Hjelmeland, L. Aronow, and J. R. Trudell, Biochem. Biophys. Res. Commun., 1977, 76, 541. H. Simon and D. Palm, Angew. Chem., Int. Ed. Engl., 1966, 5,920.

ISSN:0306-0012    

DOI:10.1039/CS9821100371

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

Carbonyl Group Transpositions By David G. Morris DEPARTMENT OF CHEMISTRY, UNIVERSITY OF GLASGOW, GLASGOW G12 8QQ 1 Introduction The term carbonyl transposition has been in use for some time and transposition has recently been taken to mean 'the effective movement of functionality within the carbon framework'.'*2 In most of the work cited in this review carbonyl transposition is the only net chemical change, that is the product and the starting material are isomeric e.g. (1) -+ (2) and (162) -+ (163). However, two additional cases are considered; first, those in which introduction of an alkyl group accompanies the carbonyl transposition (the so-called alkylative carbonyl transpositions), and secondly, those in which migration of a double bond takes place together with the carbonyl transposition.In the final section examples of isomerization of ketones are discussed. Although these are not transpositions in a formal sense, they are sufficiently close as to merit inclusion in this review. The most intensively investigated have been the 42 carbonyl transpositions and in this review these have been sub-divided on the basis of the initial functionality introduced (and cross-referenced in those cases in which the same substrate is employed in different reaction pathways). Such sub-division has not proved necessary in the other sections. Despite the prevalence of the carbonyl group in organic chemistry, carbonyl transpositions have not been greatly exploited in synthesis. Many of the methods developed have been of the general methods character, or have been specifically designed for the preparation of say a steroid with a carbonyl group in a novel position with the objective of examining certain spectral properties.2 1,2 Carbonyl Transpositions Much early work on 1,2 carbonyl transposition centred around the synthesis of epicamphor (bornan-3-one) (1) from camphor (bornan-2-one) (2). The first successful synthesis of epicamphor appears to have been that of Lankshear and Perkin3 in which carboxylic acid group functionality was first introduced in an a-position to the carbonyl group of (2) to give (3). The penultimate intermediate of this multi-stage synthesis was (4), from which epicamphor was obtained by oxidation with potassium permanganate. ' P.Brownbridge and S. Warren, J. Chem. SOC., Perkin Trans I, 1977, 1131. W. Tochtermann and P. Rosner, Chem. Ber., 1980, 113, 1584. F. R. Lankshear and W. H. Perkin, Proc. Chem. Soc., 1911, 27, 167. Carbonyl Group Transpositions Shortly afterwards a joint paper by Bredt and Perkin4 described a number of vain attempts to synthesize epicamphor and proceeded to describe two further successful syntheses. In the first of these, bornylene-3-carboxylic acid was converted into the azide (5) from which (1) was obtained by refluxing with hydrochloric acid. In order not to involve the potentially hazardous azide (5), (2) R=H (3) R=COzH an alternative synthesis was devised, in which the carboxylic acid (3) gave bornylene-3-hydroxamic acid (6)after reaction with hydroxylamine and sodium ethoxide.Thermolysis of (6)yielded epicamphor directly, via successive formation of the isocyanate (and water) and the carbamic acid, from which ammonia and carbon dioxide were lost. More controlled thermolysis, to the same end, was achieved with acetyl and benzoyl hydroxamic acids. By means of a similar series of transformations camphor was regenerated from epicamphor. Rather later, pinocamphanone (8) was obtained from verbanone (7) in good yield by way of the corresponding azide (9).’ yo 9’qCoN3‘CONHOH (6) (7) (8) (9) A further method6 of effecting the transformation of camphor to epicamphor involved synthesizing camphorquinone (bornan-2,3-dione) (10)and then making use of the differential reactivity of the two carbonyl groups in (10) brought about by the bridgehead methyl group.Thus, from (10)and aluminium amalgam, 2-hydroxyepicamphor (11)was obtained; sodium amalgam then reduced (1 1) to epicamphor (l),(see also Scheme 9). J. Bredt and W. H. Perkin, J. Chem. Soc., 1913, 103, 2182. G. Komppa, A. Klami, and A. M. Kuvaja, Liebig’s Annalen der Chemie 1941, 547, 185. J. Bredt and M. Bredt-Savelsberg, Chem. Ber., 1929,62, 2214. Morris Arylidene Derivatives.-The read.y reactivitv. in basic solution, of benzaldehyde with ketones bearing an a-methylene group allowed the development of the 1,2 carbonyl transposition sequence indicated in Scheme l.7This procedure was employed for transposition of the carbonyl group in 5a-androstan-17-one ( 12).8 /, ii iii Reagents: i, PhCHO in aqueous alcoholic NaOH; ii, aluminium isopropoxide, xylene; iii, O3 Scheme 1 However, a better method was developed for removal of the 17-0x0 group from the 16-benzylidene derivative (13) using a mixture of LiAlH4 and A1Cl3 that contained the hydride in appreciable excess over the ratio (1:3) required for formation of the postulated reagent AlC1,H.For the transposition of carbonyl @! [&CHPh from C-3 to C-2 in ring A of 5a-androstan-3-one ( 14),8 using now the anisylidene derivative (cf. ref. 9), a modified route as outlined in Scheme 2 proved necessary. In this way 5a-androstan-3,17-dione was also converted into the 2,16-dione in good yield. ’ H. H. Zeiss and W.B. Martin, J. Am. Chem. SOC., 1953, 75, 5935. J. E. Bridgeman, C. E. Butchers, E. R. H. Jones, A. Kasal, G. D. Meakins, and P. D. Woodgate, J. Chem. SOC., (C) 1970, 244; J. E. Bridgeman, E. R. H. Jones, G. D. Meakins, and J. Wicha, Chem. Commun., 1967, 898. M. Fetizon, J.-C. Gramain, and I. Hanna, Compt. Rendu., 1967, 265C, 929. Carbonyl Group Transpositions +ArHca+ii, iii 1 ArHC a1 0 Ac 0 H A 0& i A (14) / iv Reagents: i, p-MeOC,H,CHO; ii, NaBH, ; iii, Ac,O--C,H,N; iv, 0,; v, Zn-HOAc Scheme 2 Bromo Derivatives-A well documented reaction pathway for carbonyl trans- position involves initial formation of an a-bromoketone. This pathway is illustrated by the transformation of cholestan-3-one (15) into the corresponding 2-one (17), mediated by the nitrone/(l6), as shown in Scheme 3'' (see also Scheme 17).In an analogous manner, 2-bromoandrostan-3,17-dionegives androstan-2,17-dione. H H H (17) Reagents: i, Br, ; ii, C5H5N,A; iii, p-Me,NC6H,NO; iv, HCl; v, TsCI; vi, NaI, Me,CO, 160 "C, 17 h; vii, H,, Pt Scheme 3 lo L. Ruzicka, P. A. Plattner, and M. Furrer, Helv. Chim. Acta, 1944, 21, 524. C. Djerassi, R. Yashin, and G. Rosenkranz, J. Am. Chern. Soc., 1950,72, 5750. Morris The first step in the transformation of hecogenin acetate (18) into ll-oxotigo- genin acetate (20) by Cornforth's group, was reaction with bromine which brought about dibromination, the sites being at C-11 in an a-position to the carbonyl group, and on the pyran ring13 (Scheme 4).This second bromine was J/ Br \ 0-H (20) Reagents: i, Br2 ;ii, NaBH, ;iii, KOH; iv, HBr; v, CrO, ;vi, Zn-HOAc-NaOAc Scheme 4 carried through until debromination was effected with buffered zinc and acetic acid. A sequence very similar to that in Scheme 4 was employed by Schmidlin and Wett~tein.'~ The same initial dibromination of hecogenin acetate to give (19)was used in another synthesis of (20).14 However (19) was then transformed into (21) by means of a two-phase system consisting of aqueous sodium hydroxide and dioxan; acetylation of (21), debromination (Zn-HOAc) and bis-deacetylation (Ca-NH3) then yielded 1 1-oxotigogenin. l2 J. W. Cornforth, J. M. Osbond, and G. H. Phillipps, J. Chem. SOC., 1954,907. J. Schmidlin and H.Wettstein, Helv. Chim. Acta, 1953, 36, 1241. "J. Elks, G. H. Phillipps, T. Walker, and L. J. Wyman, J. Chem SOC., 1956, 4330; J. H. Chapman, J. Elks, G. H. Phillipps, and L. J. Wyman, J. Chem. SOC., 1956, 4344. Carbonyl Group Transpositions In further investigations on this system" the ketol (21) was oxidized to the a-diketone (22). From this, reaction with HS(CH2)2SH gave (23) in a reaction at a specific carbonyl of an a-diketone made possible by the disparity of the surrounding molecular structure. Reaction of (23) with Raney nickel yielded 1 1-oxotigogenin. n At the same time, Corey converted 2-bromocholestan-3-one into the bromo- hydrin with NaBH, .I6 Isopropanolic potassium hydroxide then gave 28,3/3- oxidocholestane from the bromohydrin; the epxide reacted with LiAlH4 to give cholestan-2/3-01, although oxidation to cholestan-2-one, the formal product of transposition, was not attempted.In a related methodology, 2-bromo-5a-androstan-3-one yielded both the anti-bromohydrin (24), and its C-3 epimer (from which it was separated by t.1.c.) from reduction with L~AI(OBU'),H.'~ Sa-Androstan-2-one (25) was then obtained by steps very similar to those outlined above.I6 H The same workersI7 prepared a bromohydrin (26), isomeric with (24), by a different route (Scheme 5)and completed the transposition by means of oxidation and debromination. A fortuitous observation by Clarke led to the formation of a steroidal 2-one. In an attempt to carry out a nucleophilic displacement of bromine from 17~-acetoxy-2a-bromo-5a-androstan-3-one(27) by propanethiol, a solution of the ketone was refluxed with excess propanethiol in chloroform to give a 23% yield of the transposed ketone (28).18.19 For this transformation the Is C.Djerassi, H. J. Ringold, and G. Rosenkranz, J. Am. Chem. SOC., 1954, 76, 5533. l6 E. J. Corey, J. Am. Chem. SOC., 1953, 75, 4832. l7 J. E. Gurst and C. Djerassi, J. Am. Chem. SOC., 1964, 86, 5542. R. L. Clarke, J. Org. Chem., 1963, 28, 2626. l9 R. L. Clarke and S. J. Daum, J. Org. Chem., 1965, 30,3786. Morris &j I BrI a}LHoJ-J}TsO A H A O&-A O&]Br ' A (25) Reagents: i, A, collidine or Al,O, ; ii, HOBr; iii, Cr0,-HOAc; iv, Zn-HOAc Scheme 5 author proposed the mechanism shown in Scheme 6.In this, direct displacement was indeed the first step, although no configuration was ascribed to the PrS-group in compound (29), which was then converted into (30) by means of a catalysis induced by HBr liberated in the initial step. Both (29) and (30) when exposed to the reaction conditions experienced by (27) gave the OAc Scheme 6 403 Carbonyl Group Transpositions transposed ketone (28). Under optimized conditions the yields of 2-one and 3-one were both 42%. The latter ketone formed a bisulphite adduct in high yield, whereas the steric influence of the C-19 axial methyl group precluded formation of an adduct of the 2-one; this differential reactivity provided the basis of a separation.'* Oxygen Derivatives.-Only a small number of convenient methods are available for introduction of oxygen in a position alpha to a carbonyl carbon in a saturated system; nevertheless some examples which employ this as the initial reaction have been reported.Thus, in the key step lanost-8-en-3-one (31) gave the diosphenol (32) after reaction with t-butoxide ion in t-butanol under an atmosphere of oxygen (Scheme 7). Alternatively, reaction of (31) with i (3 2) ii, iii 0@ iv AcO Reagents: i, Bu'O-, Bu'OH, 0, ;ii, HI, Pt; iii, Ac,O; iv, Ca-NH, Scheme 7 Pb(OAc),-BF, gave the vicinal acetoxyketone (34). Isomerization to (35) occurred in the presence of basic alumina (Scheme 8) with the last step to (33) executed as shown above.2O :B Scheme 8 2o A.Lablache-Combier, B. Lacoume, and J. Levisalles, Bull. SOC.Chim. Fr., 1966, 897. Morris The diosphenol, catalytic hydrogenation, acetylation route enabled 4,4,14a-trimethylpregn-8-en-3,20-dione(36),to be converted into a mixture of (37) and the 2-0x0-3-acetoxy isomer, the former of which was obtained pure by recrystallization.21 Reduction of (37) with calcium in liquid ammonia and re-generation of the carbonyl group at C-20 yielded (38). An improved synthesis of epicamphor (I) in good yield has been published22 (Scheme 9). The key to this sequence is again the methyl group at C-1 in (10) which enables selective protection of C-3, (39), to be made, after which the carbonyl group at C-2 is removed (see also Introduction).iv -40 (1) Reagents: i, SeO, ; ii, HOCH2CH20H, TsOH, PhH, A; iii, NH,.NH, ; iv, 2M-HCl, aq-MeOH, A Scheme 9 D. H. R. Barton, D. Giacopello, P. Manitto, and D. L. Struble, J. Chem. SOC.,(C), 1969, 1047. 22 S. Thoren, Acta Chem. Scand., 1970, 24,93. Carbonyi Group Transpositions This section is concluded with two examples of enone migration. In the first of these, a synthesis of (fFacorenone-B from (40) is outlined in Scheme the acetoxy-group is introduced with lead tetra-acetate as the first step of an alkylative transposition. OH*0 (41) Reagents: i, Pb(OAc),; ii, excess MeLi; iii, TsOH, PhH, A, lh Scheme 10 In the second, a 1,2 carbonyl migration within a cyclohexenone, though with the double bond ‘on the other side’ of the carbonyl group in the product, has been reported by Reusch’s (Scheme 11).Jiv Reagents: i, alkaline methanolic H,O, ; ii, methanolic KOH; iii, TsNH.NHI ; iv, 2 mol MeLi; v, aq. HCl-THF Scheme 11 ”W. Oppolzer and K. K. Mahalanabis, Tetrahedron Lett., 1975, 341 1. 24 K. M. Pate1 and W. Reusch, Synth. Commun., 1975, 27. Morris Oximes, Nitrcxompounds, and Hydrazones-In the presence of base, a-methylene ketones react with alkyl nitrites to give a-oximino-ketones ;alkyl nitrates give a-nitro-ketones under the same conditions. These derivatives can then be made the basis of successful 1,2 transpositions of the carbonyl group. Alternatively, the ketone can be converted into an arylsulphonylhydrazone which is subsequently functionalized in the a-position.Thus 5ar-androstan-17-one, (12), gave (42)25 (Scheme 12), which was converted into the a-hydroxytosylate (43); this gave the transposed ketone (44) 0 0 OH OTs OTs (43) Reagents: i, K0Bu'-isoamyl nitrite; ii, Zn-HOAc; iii, TsCl-C5H5N; iv, NaBH, ; v, NaOH-MeOCH2CH20H Scheme 12 by base-induced elimination. The authors remarked25 that (42) was produced in good yield from (12) irrespective of whether one or two moles of KOBu' were used, whereas when (45) was the substrate, two moles of this base were necessary' to produce the ketoxime. When only one mole of KOBu' was employed with (45) the reaction took a different course. (45) Alternatively, the a-ketoxime (42), when subjected to mild Huang-Minlon reduction, gave the oxime of (44) from which the ketone was liberated on sequential treatment with bisulphite and acid.26 This latter method was 25 D.Varech and J. Jacques, Bull. SOC. Chim. Fr., 1965, 67. 26 M. N. Huffman, M. H. Lott, and A. Tillotson, J. Bid. Chem., 1955, 217, 107. Carbonyl Group Transpositions employed' ' for the preparation of 3fl-hydroxyandrost-5-en-16-one in good yield from the corresponding 17-one. Corey's group has developed a procedure for 1,2 carbonyl transposition using propiophenone as a substrate, under the particular conditions outlined in Scheme 13.28 The key to this sequence lies in construction of the penultimate intermediate (46) which undergoes both deoximation and bis-deacetoxylation in one pot. N -OAc i -iii IIPhCOCH,Me PhCH-C-Me -% PhCH,COMeI OAc (46) Reigents: i, RONO; ii, NaBH,; iii, Ac,O; iv, chromous acetate in THF-H,O (10 : 11 65 "C,34h Scheme 13 Reaction of cholestan-3-one (15) with n-butyl nitrate in the presence of both -0Bu' and Bu'OH led to a-nitro-ketone (47);'' the nitro-group at C-2 of (48) became the subject of a Nef reaction after removal of the 3-0x0-group (Scheme 14) in the formation of cholestan-2-one (17) in satisfactory overall yield.A similar manipulation was also carried out on a ring D carbonyl gro~p,~' 3fl-hydroxyandrost-5-en-16-onebeing converted into the 17-0x0-isomer. (47) (17) Reagents: i, Bu'N0,-Bu'O--Bu'OH; ii, NaBH,, H', column chromatography; iii, NaBH,, H'; iv, -OH Scheme 14 G.Just and Y. C. Lin, Chem. Commun., 1968, 1350. E. J. Corey and J. E. Richman, J. Am. Chem. SOC., 1970, 92, 5276. 29 A. Hassner, J. M. Larkin, and J. E. Dowd, J. Org. Chem., 1968, 33, 1733. Morris In a general procedure developed explicitly for 1,2 carbonyl transp~sition,~' a toluene-p-sulphonylhydrazonewas dilithiated to give (49) and then converted into (50). This complex intermediate broke down to the vinyl thioether (51) which was hydrolysed in the conventional manner with HgC12 in aqueous acetonitrile to the transposed ketone (52) (Scheme 15). This was the method chosen by Sorensen3 for the preparation of 5-methylcyclohexanone from the 6-methyl isomer. Li Li I 10N -NHTs N -NTs NyN-Ts SMe (49) (50) mo msMenSMe~ ~iv (52) (5 1) Reagents: i, BuLi (2 mol) in TMEDA-THF (1 :2) at low temperature; ii, MeSSMe (1 mol); iii, BuLi (1 mol); iv, HgClz, aq.MeCN Scheme 15 Although the toluene-p-sulphonylhydrazonesof 3-methylcyclohexanone were formed in an E/Z ratio of ca. unity (from 'H n.m.r. spectroscopy), the ratio of 4- and 2-methylcyclohexanones produced was 9: l.30 The reasons for this pronounced preference in favour of the 4-methyl isomer are uncertain although the nature of the solvent may be relevant. Benzene sulphonylhydrazones were used in another generally applicable method,32 illustrated in Scheme 16. As a result of step (iii) two oxiranes (53) (53) (54) Reagents: i, RLi; ii, Me,SiCI; iii, m-CPBA; iv, LiAIH4 ; v, H,CrO,, in two-phase system (ether-water) Scheme 16 30 T.Nakai and T. Mimura, Tetrahedron Lett., 1979, 531 (a review of carbonyl transpositions in Japanese is given by these authors in J. Synth. Org. Chem. Jpn., 1977, 35, 964). 31 R. P. Kirchen, N. Okazawa, K. Ranganayakulu, A. Rank, and T. S. Sorensen, J. Am. Chem. SOC., 1981,103, 597. "W. E. Fristad, T. R. Bailey, and L. A. Paquette, J. Org. Chem., 1978, 43, 1620. 409 Carbonyl Group Transpositions and (54) were formed in a ratio 38:62; these isomers were separable and both 'gave only p-trimethylsilylated alcohol'. Sulphur Derivatives.-These were introduced by Mar~hall,~ who made use of the thioacetal ketone (56), generated from the hydroxymethylene derivative of (55) and TsS(CH,)~STS(Scheme 17). The carbonyl transposition to give (58) proceeded by way of the acetoxy-ketone (57).H (55) iii -v H vi AcO -Reagents: i, HCO,Et, NaH; ii, Ts(CH~)~TS,KOAc; iii, LiAlH,; iv, Ac,O; v, aq. HgCIz; vi, Ca-NH, Scheme 17 In a similar synthesis, a related functionality was introduced in an a-position to the carbonyl group to give (59) with the transposition to (60)completed via a mesylate ester; demesylation was brought about in the last step with chromous (59) (60) (61) X = H2, Y = 0 (62) X = 0,Y = H2ywMeMe 33 J. A. Marshall and H. Roebke, J. Org. Chem., 1969,34,4188. Morris chloride in acetone.34a By means of this approach lycoraminone (61) was synthesized from (62).34b Subsequently, a protocol was developed based on the initial introduction of a single sulphur functionality a to a carbonyl group.” This involved reaction of a suitable enolate with PhSSPh at low temperature (Scheme 18) to give the vinyl thioether (64)[cj (51) and ref.301. Hydrolysis of (64)was brought about by the less common reagent, TiC14, in refluxing aqueous acetic acid. (63) (64) (65) Reagents: i, NaBH, ; ii, TsOH, C6H6. A; iii, TiCl, in aq. HOAc, A Scheme 18 The same authors3’ reported the first transposition of the carbonyl group of an ester, with simultaneous conversion into a ketone, by a slightly modified procedure (Scheme 19). i, ii PhCH,CH,CO,Et -PhCH,CHCH20H -%-PhCH2CHCH,Cl I I SPh SPh V PhCH,COMe t--PhCH =CMe I SPh Reagents: i, LiNR,, PhSSPh; ii. LiAIH,, THF; iii, SOCI, ; iv, -0Bu‘; v, HgCIZ, MeCN-H,O (3 : I), A Scheme 19 Vinyl thioethers, e.g. (67), have also served as the penultimate intermediates in a related procedure for a carbonyl transp~sition.~~ Thus, tetralone yielded the transposed ketone (68) via the initial derivative (66) (Scheme 20) in a pathway reminiscent of that shown in Scheme 15.An extension to alkylative transposition has also been rep~rted.’~ Thus, from cyclopentanone, the a-phenylthioether (69) gave the olefin (70) after Wittig ’*‘Y. K. Yee and A. K. Schultz, J. Org. rhpm.. 1979. 44, 719 34b A. G. Schultz, Y. K. Yee, and M. H. Bergen, J. Am. Chem. SOC., 1977.99, 8065. ’’ B. M. Trost, K. Hiroi, and S. Kurozumi, J. Am. Chem. SOC., 1975, 97, 438; see also S. R. Wilson, G.M. Georgiadis, H. N. Khatri, and J. E. Bartmess, J. Am. Chem. SOC., 1980, 102, 3577. 36 S. Kano, T. Yollomatsu, T. Ono, S. Hibino, and S. Shibuya, J. Chem. SOC., Chem. Commun., 1978,414. 411 Carbonyl Group Transpositions 0 N -NHTs (68) Reagents: i, MeSSMe; ii, TsNH.NH2;iii, MeLi (excess); iv, aq. HgCl, Scheme 20 reaction with Ph3 P=CH2. Following isomerization of the double bond with BuLi, leading to (71), the final step to (72) was executed as in Scheme 20. (69) (70) (71) (72) a-Sulphenylation also featured as the initial step in a high-yield synthesis of ( & ) acorenone-B (41) which also involved alkylative transp~sition~~ (Scheme 21) (cf. ref. 23 and 42). The last step, a conventional method, proved c-i SPh SPh I iii iv (41) -mMeSPh (73) Reagents: i, LiNPr'(cyc1o C6Hll) THF-HMPA, PhSSPh, 25 "C; ii, MeLi(Et,O), -70 "C; iii, TsOH, C6&, A; iv, aq.HgCl, Scheme 21 37 B. M. Trost, K. Hiroi, and N. Holy, J. Am. Chem. SOC., 1975, 97, 5873. Morris troublesome in this instance. After reflux for 48 h with HgC12 in aqueous dioxan, > 50 % of (73) was recovered; the use of an alternative reagent, TiC1, , resulted in extensive decomposition. Grignard Reagents, Alkyl-lithiums, and Metal Hydrides.-These reagents serve to make alcohols; the next step is olefin-forming elimination with one of the olefinic carbons being the original carbonyl carbon. Re-introduction of oxygen, best performed by means of hydroboration, at a carbon in an a-position to the original carbonyl carbon, provides the means of effecting the transposition.Thus alkylative transposition of cyclohexanone has been carried out successfully (Scheme 22); 2-methylcyclopentanone was also synthesized by the same method.38 Reagents: i, PhMgBr; ii, -H,O; iii, B,H, ;iv, H,CrO, Scheme 22 A novel transposition route has been developed for the synthesis of the spirovetivane intermediate (76),39 that devised by Trod having proved inade- quate. Thus, after selective reduction and protection of the carbonyl group in the six-membered ring of (74) had been achieved, the other carbonyl group became one site of an endocyclic olefin (75) (Scheme 23). Regiospecific re- introduction of oxygen was brought about with thexylborane (and subsequent oxidation), although the authors noted that this bulky reagent may not be necessary since regioselective addition of diborane has been observed in a related system.In a transposition made possible by an acid-catalysed hydride shift, the diol (78), itself obtained from reaction of (77) with excess MeLi, gave (80), via the carbo-cation (79); the product (81) was obtained after movement of the double bond into conjugation with the carbonyl The tertiary alcohol from (82) and MeMgI likewise underwent dehydration to the rearranged desmethoxy-ketone (84) via (83) as a purported inter-mediate.41 A similar procedure was employed42 by this research group for the synthesis of (-)-acorenone-B (41) from (85) (see also ref. 23 and 37).38 H. C. Brown and C. P. Garg, J. Am. Chem. Soc., 1961, 83, 2951. 39 K. P. Subrahamanian and W. Reusch, Tetrahedron Lett., 1978, 3789. 40 W. Oppolzer, T. Sarkar, and K. K. Mahalanabis, Helv. Chim. Acta, 1976, 59, 2012. 41 G. L. Lange, D. J. Wallace, and S. So, J. Org. Chem., 1979, 44,3066. 42 G. L. Lange, E. E. Neidert, W. J. Orrom, and D. J. Wallace, Can. J. Chem., 1978, 56, 1628. Carbonyf Group Transpositions (74) iii, iv 1 0 OTDS OTDS OTDS viii, ix (TDS = Me,CSiMe2) 0 (76) Reagents: i, NaBH4 ;ii, Me3CSiMe2CI, imidazole; iii, LiAIH4 ;iv, MeS02CI, C5HSN, A; v, thexylborane; vi, H202, NaOH; vii, CrO,, C,H,N; viii, H30+; ix, C,H7SO3H, C6Hs, A Scheme 23 Me OH POAC0 POH @J-& @ @PhPh Ph Ph Ph Ph Ph Ph Ph Ph Morris Organophosphorus Reagents.-l,2 Carbonyl migration along a side chain which is being simultaneously generated has been reported in a few instances.Such examples represent carbonyl migration associated with homologation and accordingly may be regarded as a special case of alkylative transposition. In particular (86) was converted43 into (88), as a mixture of epimers, with a ratio 7a:7/3 acetyl of 2.9:l (Scheme 24). The key intermediate (87) was produced by a Horner-Emmons reaction using the specifically designed phosphonate MeSCHz P(O)(OEt), .a.-QsMe qo (86) (87) (88) Reagents: i, MeSCH,P(0)(OEt)2 (3 mol) HMPA-DME (1 :4), 62 "C,12h; ii, HgC12 (2 mol),aq. MeCN, 25"C, 3h Scheme 24 In a similar vein, a 30% yield of (90)was obtained from reaction of (89) +-Ph3 P--CHOMe.44 After conversion of the 3-acetoxy-group into a tetra-hydropyranosyloxy derivative, the vinyl ether was readily hydrolysed to the +-aldehyde (91).However, the reagent Ph3P-CHOMe was of only limited utility (89) (90) (91) and the sequence in Scheme 25 was preferred 4s for the formation of (93) from the acyl indole (92). Further uses of organophosphorus reagents in alkylative carbonyl transposition are shown for (72).36 OMe - OMe - Ph,qO)--( i P~,P(O)&OH Li R' R2 R2 OMe Reagents: i, R'R'CO; ii, NaH, THF Scheme 25 43 D. S. Watt and E. J. Corey, Tetrahedron Lett., 1972, 4651. 44 G. R. Pettit, B. Green, G. L. Dunn, and P. Sunder-Plassmann, J. Org. Chem., 1970, 35, 1385. 45 C.Earnshaw, D. J. Wallis, and S. Warren, J. Chem. SOC., Perkin Trans I, 1979, 3099; S. Warren Top. Curr. Chem., 1980, 91, 1. 415 Carbonyl IGroup Transpositions 3 1,3 Carbonyl Transpositions Study of these transpositions is a relatively recent development. The methods so far employed are based, in the main, on the Wharton reaction, a [2,3] sigmatropic rearrangement or some direct bridging between the initial and final carbonyl sites. The Wharton reaction involves a rapid reaction at room temperature between hydrazine and an ~t,P-epoxy-ketone.~~ Although not explicitly used for carbonyl transposition by Wharton, this elegant reaction has been exploited by several groups. i OH OH (95) .1 OH R' 0 R' (96) R' = H, R2= Me (98) R' = H, R2= Me (97) R'= Me, R2= H (99) R'= Me, R2 = H Reagents: i, H202, -OH; ii, H2N*NH,; iii, H,CrO, (or MnO,) Scheme 26 46 P.S.Wharton and D. H. Bohlen, J. Org. Chem., 1961, 26, 3615. Morris The mechanistic interpretation given to the Wharton reaction is indicated in Scheme 26, where ( +)-a-ionone (94) was the ~ubstrate.~' The geometric isomers (96) and (97), formed in a ratio ca. 1:l and separated by g.l.c., were oxidized to give E-a-damascone (98) and its 2 counterpart (99). Evidence in favour of the intermediacy of the vinyl anion (95) was provided by the formation of both geometric isomers (96) and (97), and also the cyclic allylic alcohol (100). (100) Ohlofs group also converted ( f)-pionone (101) into a separable mixture of the epoxy-derivatives (102) and (103).These then gave inter alia, the 2-and E-y-damascones (104) and (105) re~pectively.~' 0 (104) (105) Similarly, the dione (106) gave two alcohols in combined yield of 30 % after chromatographic separation following reaction under Huang-Minlon conditions ; the carbonyl at C-3 was simultaneously reduced to a methylene group.49 The ketones (107) and (108) that formed after oxidation of these alcohols could be equilibrated by either base- or light-catalysed reactions. & &l 0 0 (107) R'= Me, R2= H (108) R1=H, R2 = Me 47 G. Ohloff and G. Uhde, Helv. Chim. Acta, 1970, 53, 531. 48 K. H. Schulte-Elte, V. Rautenstrauch, and G. Ohloff, Helo. Chim. Acta, 1971, 54, 1805. 49 C. Beard, J.M. Wilson, H. Budzikiewicz, and C. Djerassi, J. Am. Chem. SOC., 1964, 86, 269. Carbonyl Group Transpositions In further syntheses using the Wharton reaction a low yield of D-homo-5a-androstan-16-one (111) was prepared from the 17-one (109) via the epoxy- ketone (1 Djerassi’s groups1 converted 5a-androstan-17-one (12) into (1 12), which is capable of base-catalysed epimerization at C-14, and cholestan-1-one (1 13) was obtained from the 3-0ne.~~ X (109)X = 0,Y = H2 (1 11) X = Hz, Y = 0 A similar concept enabled H~ang-Minlon~~ to prepare the exocyclic olefin (1 15) (of unspecified configuration) from (1 14). An epoxy-ketone (1 17), derived from cholest-l-en-3-one, (1 16) was involved in another route to cholestan-1-one (1 13).54This time, however, the epoxy-ketone was hydrogenated catalytically to a pair of diols that were epimeric at C-3; these diols were then selectively acetylated at C-3 prior to elimination of acetic acid (Scheme 27).D. N. Kirk, W. Klyne, C. M. Peach, and M. A. Wilson, J. Chem. SOC., (C), 1970, 1454. 51 C. Djerassi, G. von Mutzenbecher, J. Fajkos, D. H. Williams, and H. Budzikiewicz, J. Am. Chem. Soc., 1965, 87, 817. 52 C. Djerassi, D. H. Williams, and B. Berkoz, J. Org. Chem., 1962, 27, 2205. 53 Huang-Minlon and Chung-Tungshun, Tetrahedron Lett., 1961, 666. 54 P. Streibel and C. Tamm, Helu. Chim. Acra, 1954, 37, 1094. Morris major isomer (1 17) liii OH (1 13) Reagents: i, HzOztNaOH; ii, H2, Pt; iii, Ac,O; iv, CrO,; v, AI,O,; vi, H2, Pt Scheme 27 &o QOH A CHMe9 J iii, iv t--- H Me4S-Ph SPh Me 0 S “Qy4 L PhSO PMeh -(120) HO Me SPh.4 (118) 0 Reagents: i, MeCH-CHMgBr; ii, PhSCI; iii, LiNEt, ;iv, PhSSPh; v, HgCI, Scheme 28 419 Carbonyl Group Transpositions A useful method of 1,3 carbonyl transposition, which gives products in yields of 44--80%, depends on a [2,3] sigmatropic rearrangement as a means of introducing fufictionality into the position which is to become the carbonyl group.55 The rather involved reaction sequence is given for the synthesis of the bicyclic ketone (118) in 70% yield (Scheme 28). A noteworthy point is the regeneration of diphenyl disulphide in the penultimate stage, leading to the thio-ether (120), from the addition of this reagent to the sulphoxide (1 19).In the case of cyclopentenecarboxaldehyde (121), 'however, the allylic anion derived analogously from (122), using now BuLi, was sulphenylated both a and y to the sulphoxide group.5 The former product of sulphenylation underwent rearrangement and desulphenylation analogous to that shown in Scheme 28, whereas the product of y-sulphenylation was isolated unchanged. H Bun Since epoxydihydro-a-ionone and its y-isomer underwent cyclization with hydrazine, an alternative method to the Wharton reaction was developed for the synthesis of B-damascone (124).56 In this, the key feature was intra-molecular migration of oxygen from the oxime of p-ionone (125) to the remote 4 iiiI (124) (128) Reagents: i, 1,-KI, aq.THF, NaHCO, ;ii, Pt-H, ;iii, Na-NH,-Bu'OH Scheme 29 55 B. M. Trost and J. L. Stanton, J. Am. Chem. SOC.,1975, 97, 4018.''G. Buchi and J. C. Vederas, J. Am. Chem. SOC., 1972, 94, 9128. Morris carbon of a conjugated double bond. This oxidation, which was carried out with I2 and KI in aqueous THF buffered with NaHCO,, gave rise to an isoxazole (126) in 90% yield; strong base produced complex mixtures (Scheme 29). The vinylogous amide (127) was reduced to the labile /?-amino- ketone (128) which was then converted directly into /?-damascone (124). The instability of isoxazoles derived from aldehydes limits the starting material to ketones. The regio- and stereo-selectivity of PhSeCl addition to allylic acetates has been made the basis of another 1,3 carbonyl transposition, and is exemplified (Scheme 30) by the conversion of (129) into its optical antipode (133).57" (133) (132) (131) Reagents: i, LiAlH4; ii, MeCOCI, C5H5N; iii, PhSeC1, CH,Cl,, -78 "C; iv, 0,, CH,CI, ; v, Et,NH, CH,CI,, A; vi, 90% HCOOH Scheme 30 Accordingly, (130) was produced with the selenium moiety being delivered to the double bond after initial co-ordination between selenium and carbonyl oxygen.This selenonium ion then gave (131.) as the only observable product; in accord with precedent, elimination from the selenoxide of (131) took place away from oxygen to give (132). The final step is based on work by Lan~bury.~~~ The specifically deuterated cyclopentenone (135) was synthesized from cyclopentenone 57u D.Liotta, G. Zima, and M. Saindane, J. Org. Chem., 1982, 47, 1258. 57b P. T. Lansbury, Acc. Chem. Res., 1972, 5, 311. 421 Carbonyl Group Transpositions (lo-Q,--Q-0 Reagents: i, MeMgBr; ii, pyridinium chlorochromate Scheme 31 An independent procedure for 1,3 alkylative transposition of a carbonyl group has been devised by Dauben." In this, cyclo-oct-1-en-3-one gave (136) (Scheme 31) and, in a reaction related to the 1,2 carbonyl shifts described in references 43-45, cyclohexanone was converted successively into (137) and (138). Acyclic ketones gave appreciably lower yields. A number of methods, collated here on account of their potential utility, are capable of effecting 1,3 transposition although the final step was not executed. Scheme 32 shows how [2,3] sigmatropic rearrangement of the selenoxide (140) enabled the contrathermodynamic isomerization of (139) to (141) to take place; typically yields of ca.80% were enco~ntered.~~ J. tq dN" OH 0 -SeAr Ph (141) Reagents: i, p-NO,C,H,SeCN in C5H5Nwith BuYP; ii, 15% v/v H,O, (20 equiv) Scheme 32 58 W. G. Dauben and D. M. Michno, J. Org. Chem., 1977,42,652. 59 D. L. J. Clive, G. Chittatu, N. J. Curtis, and S. M. Menchen, J. Chem. Soc., Chem. Commun., 1978,770. Morris I‘c-c-c< ’\/ I 0 OH ...‘c-c=c’ I 111 \-,c-c-c’I \ OH ‘0’ Reagents: i, VO (acac),, Bu‘OOH; ii, Et,N, MeS0,CI; iii, Na-NH, Scheme 33 Oxiranes mediate the transformation of allylic alcohols (Scheme 33) such that ( -)-carve01 (142) can be converted into the ( + )-isomer uia the cis-epoxy- alcohol (143)?’ The allylic acetates (144) and (145) are equilibrated in a ratio 1.9: 1 by heating the former at 70 “C for 3h with 3 mol% Pd (OAC)~ and 3 mol PPh, in the presence of KOAc and with t-butanol as solvent.61 Me(CH,),CH =CHCH,OAc Me(CH ) CH( 0Ac)CH =CH A catalytic quantity of mercuric acetate in THF at 25°C enabled the allylic carbamates (146) and (147) to be equilibrated in a ratio 52 f4 % and 41 f3 %,62 together with a small amount of the cis-isomer of (146).OCONMe OCONMe, A. Yasuda, H. Yamamoto, and H. Nozaki, Tetrahedron Lett., 1976, 2621. 61 J. Tsuji, K. Tsuruoka, and K. Yamamoto, Bull. Chem. SOC.Jpn., 1976, 49, 1701.62 L. E. Overman and C. B. Campbell, J. Org. Chem., 1976,41, 3338. Carbonyl Group Transpositions 4 1,4 Carbonyl Transpositions Only a limited number of methods are known for bringing about 1,4-transfer of a carbonyl group, and two of these involve additional bridging. After acetolysis of the ester (148), specifically tritiated at C-1, the product was shown to consist inter aha of trans-4-methoxycyclohexyl acetate (149) (Scheme 34) in which 43% of the label was located at C-4, the remainder6j being at C-1. The assay for label involved successive saponification and oxidation of (149) to 4-methoxycyclohexanone. 1,4 Carbonyl transposition had occurred in that part of the ketone which contained tritium. 0+ ;j.. AcO eoMeiii T i, ii + OMe OMe AcO iv, vi Reagents: i.NaBT,; ii, TsCI, C,H,N; iii, HOAc; iv, -OH; v, CrO, Scheme 34 A C-18 radical (151) was generated by photolysis of the 11-/3 nitrite (150) and subsequent hydrogen abstraction, Scheme 35. In (151) the radical centre is favourably located with the exocyclic carbonyl group to give (152). This electron deficient intermediate can undergo ring opening to give compound (153).64 In an elegantly designed series of reactions Tochtermann’s group executed a 1,4 carbonyl transposition on the oxanorbornadiene dioxolan (154) (Scheme 36).2 Irradiation gave the sensitive quadricyclene derivative (155), which was directly converted into (156) (two valence tautomers) in refluxing toluene. Although deoxygenation of (156) proceeded readily, the formal transposition sequence was frustrated by the inability to ‘de-protect’ the dioxolan (157).63 D. S. Noyce and B. N. Bastian, J. Am. Chem. SOC., 1960, 82, 1246. 64 J. Kalvoda and J. Grob, Helu. Chim. Acta, 1978, 61, 1966. Morris ON-0 I, de (156a) x = -0CI-l *CHzO-(158) (1 57) Reagents: i,hv; ii, A, PhMe; iii, [Rh(CO),Cl], Scheme 36 Carbonyl Group Transpositions Notwithstanding this, however, the lower homologue (158) was subsequently obtained without difficulty by an analogous pr~cedure.~’ In a method of 1,4 carbonyl transposition associated with ring expansion, cyclohexenone yielded (161) by the mechanism, indicated in Scheme 37, which included both a homoallylic cation (159) and a chromate ester (160); the latter is normally a product-forming intermediate in alcohol oxidation by chromic acid.66 Reagents: i, MeLi ;ii, rn-CPBA;iii, pyridinium chlorochromate Scheme 37 5 Transposition of Hydroxy-ketones Transposition of carbonyl and hydroxy-groups can occur in hydroxy-ketones in cases in which the number of carbon-carbon bonds separating the carbons bonded to the oxygen atoms varies between 1 and 6.The reactions are characterized by hydride or, less commonly, carbon-carbon bond migration and although definitive evidence is not available from all investigations, inter- molecular migration appears to be uncommon. A review of earlier work is given in references 67 and 68. 1,2 Transpositions-With NaOH in aqueous methanol 1-hydroxycamphenilone (162) equilibrated with (163); the greater stability of (163), where the gem dimethyl group also forms the methylene bridge, is indicated by its pre-dominance over (162) by 2:l at 31 0C.69 65 W.Tochtermann and H. Kohn, Chern. Ber., 1980, 113, 3249. 66 E. Wada, M. Okawara, and T. Nakai, J. Org. Chern., 1979, 44, 2952. 67 S. Selman and J. F. Eastham, Quart. Rev. Chem. Soc., 1960, 14, 221. N. L. Wendler in ‘Molecular Rearrangements’, ed. P. de Mayo, Interscience, New York, 1963, p, 1114. 6g A. Nickon, T. Nishida, J. Frank, and R. Muneyuki, J. Org. Chem., 1971, 36, 1075. Morris In the course of the synthesis of methyl isomarasmate the transformation of (164) into (166) was effected with 1% methanolic sodium hydr~xide.~' After initial ester hydrolysis to (165) the rearrangement proceeded as shown in (167).(164) R=Ac (165) R=H 1,3 Transpositions.-Base-catalysed hydrolysis of (168) gave an alcohol, which after acetylation, yielded an acetate isomeric with (~8).~'The rearranged acetate was shown to be (169) and this was considered to have arisen via a 1,3 hydride shift at some stage during the hydrolysis (see however ref. 72). /-0 I 0 OAc 0 1,4 Transpositions.-These are more common and occur in ring systems in which hydride can be readily transferred to a transannular carbonyl group. Such was shown to be the case for (170); in DMSO-Bu'OH (95:5) a value E, = 24.5kcal mol-' and an associated primary deuterium isotope effect, kdkD zz 3 were found for the conversion of the potassium salt of (170) into HO 0 'O D.Helmlinger, P. de Mayo, M. Nye, C. Westfelt, and R. B. Yeats, Tetrahedron Leu., 1970, 349. 71 D. A. H. Taylor, J. Chem. SOC. (C), 1970, 336. 72 E. W. Warnhoff, Can. J. Chem., 1977, 55, 1635; E. W. WarnhoK P. Reynolds-Warnhoff, and M. Y. H. Won& J. Am. Chem. SOC., 1980, 102, 5956. Carbonyl Group Transpositions (171).73 It was subsequently pointed out, however (see ref. 76), that the hydroxy-ketone exists in the form of an internal hemiacetal in which the hydroxy-group is more acidic than in a secondary alcohol; accordingly the above activation energy may represent the value for the interconversion of the isomeric hemiacetal salts.More recently formal incorporation of 4 deuterons into (172) under basic conditions in the presence of D20 led to the postulation of a 1,4 hydride shift leading to (173).74 The authors considered that 3 protons are exchangeable in (172) and 1 in (173); however there was no evidence on the relative amounts of (172) and (173) at equilibrium. In the Meerwein-Pondorff-Varley-Oppenauer type reaction which transformed (174) into (175) there was both intra- and inter-molecular hydride transfer.72 Here, in the presence of Pr'OM, the rate of intermolecular hydride transfer increased with increasing Lewis acidity of the cation (M)(A13+> Li' > Ba2+> Na+ > K+). For the intermolecular process the authors therefore invoked a cyclic transition state (176).The transposed ketones (177) and (178) were interconverted by a 1,4 hydride shift; in base the equilibrium mixture contained 98.96 % (177), corresponding 73 P. T. Lansbury and F. D. Saeva, J. Am. Chem. SOC., 1967,89, 1890. '' J. M. Shepherd, D. Singh, and P. Wilder, Tetrahedron Left., 1974, 2743. Morris to this ketone being more stable by 2.7 kcal mol-1.75 In order for this hydride shift, presumably intramolecular, to occur a small standing concentration of the boat conformation is needed in that six-membered ring which contains both oxygen bearing carbons (Scheme 38). This hydride transfer is cu. x lo2 slower than the corresponding 3,7 shift in a related system (188) (vide infru). Anions of a series of ketols (179)-(181), which are held in frameworks of slightly varying rigidity, underwent degenerate rearrangement.76 Solutions of the sodium salts of these ketols in dimethyl sulphoxide exhibited the following barriers, AG*, to rearrangement, as indicated by dynamic 3C n.m.r.spectroscopy: for (179), >21.7 (100°C); (180), 19.0 (100°C); (181), 17.3 (72"C)kcalmol-l. Extension of the methylene bridge has the effect of bringing C-3 and C-3' closer together; this intuitive expectation is reinforced by molecular mechanics calculations. (179) n = 1 3 /OH (180) n =2 '0 1,5 Transpositions.-The first report of a 1,5 hydroxy-ketone transposition appears to have been that of Acklin and Pre10g~~ wherein the cis fused (183) was formed from (182) by means of activated alumina.1,5 Carbonyl trans- positions to cyclohexanone have been reported both in cases in which the 0miHHO-H H H ''I. Watt, Tetrahedron Lett., 1978, 4175. 76 G.-A. Craze and I. Watt, J. Chem. SOC., Perkin Trans 2, 1981, 175. 77 W. Acklin and V.Prelog, Helv. Chim. Acta, 1959, 42, 1239. Carbonyl Group Transpositions migrating hydride (deuteride) is exocyclic, (184)-( 185),78 and also when the hydride is located on an adjacent, and fused, ring (186)-(187).'' In order that intramolecular migration might occur, a boat conformation is required for ring A in the former case, whereas in the latter the preferred twin chair conformation facilitates hydride transfer. A similar conclusion is in order for the isomeric (188);80by means of variable temperature 'H n.m.r.spectroscopy, a value AG * = 19.4 +_ 0.2kcal mol- at 113 "Cwas determined for the 3,7hydride transfer of the sodium salt of (188) in DMSO. It was estimated that the lowest energy position for the migrating hydride places it ca. 1.98, from the carbonyl and locates it behind the orthogonal to the plane of the carbonyl group running through the carbonyl carbon atom. This implies that the hydride approached the carbonyl carbon along the optimum (least energy) direction. Similar considerations are relevant to other additions to carbonyl groups in this review. H 0 1,6 Transpositions.-A mechanism for the 1,6 transfer of hydride within (189) leading to (190) and ultimately to p-hydroxyphenyl-lactic acid (191) was proposed by Plieninger.8 The intramolecular nature of the hydride transfer, established recently by means of labelling experiments,82 is shown in Scheme 39.J. Wicha and E. Caspi, J. Org. Chem., 1973, 38, 1281. 79 W. Parker and J. R. Stevenson, Chem. Commun., 1969, 1289. R. S. Henry, F. G. Riddell, W. Parker, and C. I. F. Watt, J. Chem. Soc., Perkin Trnns 2, 1976, 1549. H. Plieninger, Angew. Chem., lnt. Ed. Engl., 1962, 1, 367. "S. Danishefsky and M. Hirama, J. Am. Chern. Soc., 1979, 101, 7013. Morris II0 0 II An acyclic example of a 1,6 carbonyl transposition (192)-( 193) has also been demonstrated re~ently.’~ 6 Isomerizationof Ketones via Homaenolization In the presence of the strong base, KOBu‘ in Bu‘OH at high temperatures and for prolonged reaction times, often of the order of a week, many bicyclic ketones undergo isomerization.These reactions involve abstraction of protons #? (or occasionally y) to the carbonyl carbon to form homoenolate anions. In some instances, high yield conversions, which are synthetically useful, are achieved. 431 Carbonyl Group Transpositions sheme 40 The formation of homoenolates was first noted by NickonE3 in the racemization of camphenilone (194) by way of (195). Fenchone (196) also underwent a homoenolization reaction, outlined in Scheme 40, wherein two isomeric ketones (197) and (198) were formed after 60-400 h.84 From the homoenolate (199)’ cleavage of bond ‘a’ is favoured over bond ‘b’ by ca. 20: 1. The latter cleavage led to the endo methyl ketone (198) and the exo methyl counterpart in a ratio 3 : 1.Under comparable conditions camphor, (2), was only partially (2.5%) equilibrated to the ketones (200) and (201).85 (200) (201) The bridged norbornanone derivative (202) (brexan-Zone) was completely converted into brendan-2-one (203) (Scheme 41).86 Molecular mechanics calculations indicated the latter ketone to be more stable by 2.90 kcal mol- ’. The three negatively charged species (204)-(206) are considered either to be in equilibrium or to be contributors to a resonance hybrid. At still higher temperatures, 275 “C, longicamphenilone, (207) was converted into an equilibrium mixtGe with (208) which contained these compounds in a ratio 7 :P7 83 A.Nickon and J. L. Lambert, J. Am. Chem. SOC., 1966, 88, 1905. 84 A. L. Johnson, J. B. Stothers, and C. T. Tan, Can. J. Chem., 1975, 53, 212. ”A. Nickon, J. L. Lambert, J. E. Oliver, D. F. Govey, and J. Morgan, J. Am. Chem. Soc., 1976, 98, 2593. 86 A. Nickon, H. R. Kwasnik, C. T. Mathew, T. D. Swartz, R. 0. Williams, and J. B. DiGorgio, J. Org. Chem., 1978, 43, 3904. ”R. M. Coates and J. P. Chen, Chem. Commun., 1970, 1481. Morris Attempts to generate homoenolates from the bicyclo[2.2.2]octane skeleton have only been partially successful. Thus, 400h were necessary to achieve a 30% conversion of (209) into (210).88 However, attempts to generate the common homoenolate ion from (210) were appreciably more difficult, since after the same reaction time, <5 % of (211) had been formed.After 168h, however, the bicyclo[2.2.2]octenone (212) gave rise to two new ketones (213) and (214) in an equilibrium ratio 2:9:9. 06 ** D. M. Hudyma, J. B. Stothers, and C. T. Tan, Org. Magn. Reson., 1974, 6,614. Carbonyl Group Transpositions In a manifestation of the greater stability of the bicyclo[3.3.0]octane ring ~y.stem,~~*~~the ketone (215) gave an 80-90% yield of (216)” (Scheme 42). Two groups reported simultaneously that the birdcage ketone (217) was completely isomerized to (219) oia the homoenolate (218).92,93 0 Homoketonization of (218) is ca. 33000 times more rapid than homoenoliza- tion of (217) at 100°C. In contrast to the previous examples cited in this section, homoenolate (218) is formed by abstraction of a proton from a carbon in a y-position from the carbonyl group.Rather later a further example of abstraction of a y proton was rep~rted.’~ This is indicated in Scheme 43, in which (220) was transformed into (221) by means of proton abstraction from the C-6 endo methyl group. Concurrently with this reaction a B proton on C-7 of (220) was also being exchanged. Abstraction of a proton y to a carbonyl group has also been reported for the C-9 methyl group of camphorg5 and both y proton sites of cis-3,3-dimethyl bicyclo[3.3.0]octan-2- one,” although these do not lead to synthetically useful reactions. 0 89 P. von R. Schleyer, K. R. Blanchard, and C. D. Woody, J. Am. Chem. SOC.,1963, 81, 1358. 90 H. M. R. Hoffmann and H.Vatke-Ernst, Chem. Ber., 1981, 114, 2898. 91 A. L. Johnson, M. W. Petersen, M. B. Rampersad, and J. B. Stothers, Can. J. Chem., 1974, 52, 4143. 92 R. Howe and S. Winstein, J. Am. Chem. SOC.,1965, 87, 915. 93 T. Fukunaga, J. Am. Chem. SOC.,1965,87,916; T. Fukunaga and R. A. Clement, J. Org. Chem., 1977, 42, 270. 94 N. H. Werstiuk, Can. J. Chem., 1975, 53, 2211.

ISSN:0306-0012    

DOI:10.1039/CS9821100397

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

TILDEN LECTURE* Semistable Molecules in the Laboratory and in Space By H. W. Kroto SCHOOL OF CHEMISTRY AND MOLECULAR SCIENCES, UNIVERSITY OF SUSSEX, BRIGHTON BNl 9QJ 1 Introduction This article deals with the production, detection and application of new, unstable or semistable (or perhaps semi-unstable?) molecules. The lifetimes are usually of the order of 1s under the conditions of the experiments, sufficiently long that extensive modifications of standard equipment can often be avoided but usually too short to allow isolation. In some cases, however, the work has shown that certain species are somewhat more stable than previously expected. The instability usually arises because they are unsaturated and in the main contain second- (or sometimes third-) row elements of the periodic table, elements which exhibit a well known reluctance to participate in pn-pn bond formation.This antipathy is perhaps most clearly manifested by the fact that so few such molecules are known and the instability of those that are known. The reason is probably the small contribution to the binding energy obtainable by pn-pn overlap. This tends to be an optimum at the distances which characterize bonds between first-row atoms, becoming less and less favourable when second- or third-row atoms participate and the interatomic distance increases. Not only are the precepts which initiated and governed the experiments explored but so also are some diverse applications to other areas such as mainstream chemistry and radioastronomy. Although the main experimental technique used has in general been microwave spectroscopy, backed up by photoelectron measurements, in several cases nuclear magnetic resonance, infrared spectroscopy, mass spectrometry, X-ray crystallography, and theoretical calculations have been invaluable. There are a few basic ground rules that have governed the research detailed here.The most important come under the three headings A) Chemical Relationships B) Experimental Synergy C) General Implications A. Chemical Relationships.-There are several types of relationship which can usefully be used to extrapolate or interpolate and so conjecture that a certain * This is an expanded version of a lecture that was first presented at a meeting of the Faraday Division of the Royal Society of Chemistry at the Scientific Societies’ Lecture Theatre, London, on 29 October 1981.435 Semistable Molecules in the Laboratory and in Space molecule or group of molecules might exist. In fact it is likely that almost any cluster of atoms one can think of may exist for some period of time, albeit short; it is just a matter of catching it unawares. For our purposes we are interested in species which are not to be found in the average chemist’s bucket, but also not so elusive that we need to use very fast techniques, i.e. not, for instance, free radicals. The relationships which have proven most valuable are i) Mendeleevian or Periodic relationships ii) Isoelectronic relationships iii) Analogous and Homologous relationships To give a feeling for the interplay of these relationships a diagram which shows the family related uia i), ii), and iii) to formaldehyde CH20 is given in Figure 1.On this CH,O cube Mendeleevian relationships are represented by vertical steps, isoelectronic ones by steps to the right, and analogous/homologous ones by steps to the left. Isovalent relationships can be represented by diagonal steps Periodic or Mendeleev ian relations hips H,C=AsH /YIsoelectronic Analogous and relationships homologous relationships Figure 1 Chemical cube showing some molecules related to formaldehyde H,C=O. Periodic group relationships are given by vertical steps, steps to the lejt are possible analogously and homologously related species, and steps to the right are isoelectronically related species.The molecules shaded haue been studied in this work H.W Kroto on the right face etc. It is almost certain that, since the time of Mendeleev, chemists must have at least ruminated about various possibilities. Could for instance Si analogues of ethene such as CH2=SiH2 be made? Not only that, could CH,=PH the P analogue of CH,=NH be made, or for that matter, CH2=S the S analogue of formaldehyde? One can obviously play similar games with other molecules and, in fact, a good deal of the work presented here results from relationships which can be catalogued on the CH20 and HCN cubes. It is likely that games such as these lie at the base of most scientific research whatever the field, and chemists in particular use related concepts to develop new chemistry. One also needs, in good measure, an inalienable faith that should relationships point to a species, then it can be formed.A childish naivety is useful. As an example, after a lesson on the periodic table and one on the nitriles at school one would be quite happy to extrapolate and assume that CH,C=P would be similar to the well known molecule CH3C=N. A more knowledgeable chemist might be aware of the difficulty of forming pn-pn bonds involving second-row elemects and subconsciously aware that he had almost never come across a CEP group and take its non-existence for granted. Early chemists must have attempted to make such compounds and ended up with polymeric products. Some sort of naivety is also useful in developing routes to such species. As an example, it is likely that only a school student would suggest that the reaction (1) might be worthy of study.H C1 / \ R-C-H Cl-P -RC=P+3HC1 \ / H C1 One aim of this review is to show that these simple ideas are not entirely naive and that one must always take care that the more knowledge of chemistry one has the less adventurous one can become because of the hang-ups this knowledge invariably generates. B. Experimental Synergy.-Combining two or more disparate, though com-plementary, techniques can be very rewarding. Although microwave spectroscopy is a very high resolution technique (linewidths ca. 100kHz -0.33 x lop5cm-') its application in this work has often been facilitated by photoelectron studies where features seldom have bandwidths less than 20meV -160cm-' (1eV = 8065 cm-').The interaction has often been two-way and synergistic. The value has been mainly experimental in that a particular molecule may be more readily detectable by one technique and once detected the conditions can be optimized to facilitate detection by the other. C. General Implications.-Spectroscopy has an inherent charisma not only in the beauty of the patterns often produced, but also in the deep insight it gives at Semistable Molecules in the Laboratory and in Space the molecular level and the degree of certainty which it can often bestow on the conclusions.The analysis of microwave spectra can give the most positive molecule identification and some of the most accurate structural data. In addition it can yield : dipole moments, quadrupole moments, vibration-rotation parameters, and associated force-field data such as internal rotation barrier heights. It has been used to further our understanding of maser processes, collisional energy transfer, and interstellar chemistry. Photoelectron spectroscopy yields ionization potentials and, through these, information about the electronic structure of molecules and their associated ions. Apart from these specific virtues of the two techniques, their more general value as probes to initiate new areas of basic chemistry has been the most important factor in this work.Indeed, the major aim has been to show that microwave spectroscopy in particular need not be an esoteric technique whose sole value to chemists is the elucidation of structural information. It can and has been a powerful tool in the development of new areas of organic, inorganic, organometallic, and interstellar chemistry. 2 Experimental Techniques The method used to produce semistable molecules is extremely simple in that a suitable precursor molecule is passed through an 8mm i.d. quartz tube, heated for about 10 cm of its length, to a suitable temperature (up to ca. 1100"C),and the resulting products flow directly into the cell of a microwave or photoelectron spectrometer, Figure 2. In general the rate of loss of the new species by further reactions is slowed considerably because of the low pressures used for these two spectroscopic techniques (ca.1-100 pHg). Furnace Quartz tube Flat-plate Stark cell electrode I/ i -Microwave radiation Sample Figure 2 Schematic diagram of the main production and detection technique. The quartz tube is ca. 0.8cm i.d. and heated for some lOcm of its length. The distance between the furnace and the cell is about 10cm. The cell is made from rectangular cross-section wave guide which has a septum held hay way between the two broad faces by a tejlon spacer/ insulator. This allows Stark modulated signals to be observed. In general the spectrum is displayed so that a positive signal is the field free frequency, and the negative signal that in the presence of the field.See Figure 17 H. W Kroto A. Microwave Spectroscopy.--In general microwave spectroscopy is used to observe the rotational spectra of molecules.’ -The very high resolution available, together with the high degree of pattern specificity allows such moderately complex molecules as ethanol EtOH, glycine NH2CH2COOH and cyanoethene CH2 =CHC EN to be unequivocally identified in extremely complex mixtures. To confirm this one only has to note that some 50 molecules and numerous isotopically substituted modifications have been identified by radio astronomical detection of microwave radiation from the molecular soups which exist in interstellar space (Section 4). The advent of the Hewlett Packard 8460A microwave spectrometer, alas no longer available, for the first time enabled the research worker to obtain microwave spectra which were not only linear in frequency but also obtainable over a wide bandwidth, with high sensitivity.The instrument obviated the technical problems that beset previous microwave research, particularly frequency sweep problems and frequency calibration. At a stroke it was possible to transfer from the technical problem of obtaining spectra and concentrate on the chemical problems involved in producing the species to be studied. As some of the results obtained during this programme display many of the merits of the microwave technique, such as spectroscopic patterns, in a way that hitherto has not been possible a short general introduction to the most important features is given.As in all spectroscopic studies one must use quantum mechanics to develop the energy levels and in this case one can start from the Hamiltonian for a rigid rotating molecule (a very good first approximation in general) given in equation (2) H, = AJj + BJ; + CJZ (2) where JA, JB, and Jc are the components of overall rotational angular momentum (in units of h) along the molecule-fixed principal axes and A, B, and C are rotational constants related to the principal moments of inertia ZA , I,, and Ic by A = 1/21A . . . etc.* By convention IA IB IC and therefore A 2 B > C. The solution of H, depends on the-type of molecule and the results can be summarized as f01lows:~ Linear molecules such as CO, OCS, and HCrC -C=N have B = C and JA -+ 0 and the resulting energy is given by the familiar expression (3) E(J) = BJ(J + 1) (3) where J is the overall angular momentum quantum number.? Symmetric tops * I, = Enm,,(rg + r&, I, = ...etc.where m, are atomic masses and rA etc. are co-ordinates relative to the principal axes of the molecule3 A (MHz) = 505391/IA(amu A’) or A (cm-’) = 16.858/IA(amu A’) t The units of E (and AE for a transition) will be governed in these expressions by the units of the rotational constant, usually Hz or cm-’ C. H. Townes and A. L. Schawlow, ‘Microwave Spectroscopy’, McCraw-Hill, 1955. W. Gordy and R. L. Cook,‘Microwave Molecular Spectra’, Interscience, 1970. H. W. Kroto, ‘Molecular Rotation Spectra’, John Wiley, London, 1975.Semistable Molecules in the Laboratory and in Space such as CH,C=N or SF,Cl wfiich are prolate (i.e. cigar-shaped) have A > B = C, can spin about their symmetry axes with associated quantum number K, and the energy is given by equation (4). E(J, K) = BJ(J + 1) + (A -B)K2 (4) The energy levels for a linear molecule are shown in Figure 3a and those for a prolate symmetric top in Figure 3b. A similar expression to (4), in which A -+C and C -+ A, applies to oblate (discus-shaped) tops such as NH3 and C6Hs. Spherical tops such as CH4 and SF, which have A = B = C are rather complicated and will not be dealt with here as their spectra4 are difficult to detect. Their levels are also governed by equation (3).Asymmetric top molecules are most important, they have A > B > C and their J J J J J J J 5 5 8- 8- 8- 7 4 -7 -4 7- 7- -6 -2 3 7- -6 3 2 6-6--5 6--5~ -4 -45-5-5-3 3 4-4-4-2 -2 3-3-1 3--1 2-2-2-1-1-1-0-0-0-IKI = O 1 2 KA = 0 1 2 (a 1 (b) (C) Figure 3 The rotational levels of (a) a linear molecule, (b)a prolate symmetric top, and (c) a prolate slightly asymmetric rotor. For this diagram A -38 GHz, B ,-.,C -3.06GHz and B-C -0.25GHz. In all cases vertical transitions between adjacent levels in a given manifold may occur (AJ = k1) depending on the dipole moment conditions. In such cases the transitions give rise to equidistantly spaced lines in the linear case or groups of lines in the non-linear case J.K. G. Watson, J. Mol. Spectrosc., 1971, 40,536. 440 H. W Kroto energy levels follow much more complicated expressions. These will not be discussed in detail but one can get some feel for the spectral patterns by summarizing the approximate results that apply in the case of molecules which are not too asymmetric. We will also restrict ourselves to neur prolate molecules which are the most common, at least in the work studied here. In a near prolate molecule A > B -C and perturbation theory yields the relation (5)3 E(J, KA)= BJ(J + 1) + (A -B)K: k+aSK,. -C)J(J + 1) *.. where B = i(B + C) and KA is a good enough quantum number = IK I, which for a symmetric top is almost perfect. An understanding of what the ephemeral ‘good’ quantum number is demands a deeper study of quantum mechanics than is possible here.The first two terms are very closely related to the symmetric top expression, equation (4). The third has a Kronecker delta coefficient which indicates that only the IKI = 1 levels, in the symmetric rotor, limit are split by this factor which is proportional to (B -C)-which is of course a rough asymmetry gauge. Smaller, second-order, terms which shift and/or split other levels have been truncated. They become less important as’ K increases (for a given value of J), i.e. as the top spins more and more quickly about its symmetry axis. The resulting levels are shown in Figure 3c. If a molecule is very asymmetric, the energy level pattern can be very complicated, as can the resulting spectrum.For the asymmetric molecule it is useful to further specify the levels for, as can be seen in Figure 3c, levels of a given (K(or KA are no longer degenerate. It is usual to add also the value of IKI with which the level correlates in the oblate limit, i.e. Kc. Thus a giken level is characterized by JKAKc. For a linear molecule the expression which governs the spectroscopic patterns can be derived from equation (3) using the electric dipole selection rule AJ = k1 to yield equation (6). AE(J)= 2B(J + 1) (6) This gives rise to a set of equally spaced lines separated by 2B. In the symmetric top case the rules AJ = k1 and AK =0 apply and result in the same expression for transitions. Lines with a given IKI have the same frequency and pile up on top of each other.They are, however, usually split apart by centrifugal distortion effects which are observed under high resolution. For asymmetric rotor molecules the most frequently observed transitions often occur for near prolate molecules with dipoles oriented roughly along the long A axis. In this case the main selection rules that apply are AJ = k1 and AKA= 0. Applying these to equation (5) for this slightly asymmetric case yields equation (7). AE(J, KA) = 2B(J + 1) k*dKA, 1(B -C)(J + 1) + ... (7) As B 9(B -C) we can see that the transitions tend to bunch together, in this case, at 2B (= B + C) intervals but with an added factor that each J group is Semistable Molecules in the Laboratory and in Space symmetrically flanked by the two KA = 1 lines, which are separated from the main bunch by+(B -C)(J + 1).This splitting of the KA = 1 lines is the quantum mechanical equivalent of classical wobbling which occurs for an object which is not a good top. Under high resolution this type of splitting is seen to occur also, but to a smaller extent, for KA > 1 lines. It increases with asymmetry and decreases with KA, i.e. as the molecule spins more rapidly about its axis it becomes a better top. A good example of the power of microwave spectroscopy is shown in Figure 4 where the spectra of EtNO are pre~ented.~ The bands of two conformers are 40 36 34 32 30 28 GHz 1 I I I I 1 I I I 1 1 11 J=4+3 Me J=3+2 gauche J = 3+2 111 1 Me ? -I,iicis HI Ill Figure 4 The microwave spectra of EtNO.’ Two sets of spectra are identijied.One set, belonging to the gauche isomer, shows two groups of transitions each with a typical triplet pattern. The outer members of the triplet are the KA = 1 lines and the central member a composite of lines belonging to KA # 1 lines. The central line is usually resolved under high resolution. The second set belongs to the cis isomer which is very asymmetric and the resulting pattern rather more complex and spread out as indicated (compare with Figure 15b). There are many other lines belonging to vibrationally excited molecules and transitions jor which AKA # 0, i.e. cross-stack transitions in Figure 3c. Positive-going lines are zero field frequencies, negative-going lines are Stark shifted frequencies readily distinguished because the spectroscopic patterns depend so strongly on the moments of inertia and they are very different for the two conformers.The conformers are both eclipsed, and one, the gauche conformer, much closer to the prolate symmetric rotor limit than the other, cis conformer. It is this type of enormous change in pattern, as a function of a parameter which does not readily affect other properties, that makes this technique such a powerful structural and also analytical tool. Examples of spectra of linear and symmetric rotors as well as other asymmetric rotors will be presented. B. PhotoelectronSpectroscopy.-Photoelectron spectra are obtained by analysing the kinetic energy of electrons (Ekin)ejected by molecules irradiated by a ’A.P.Cox, J. A. Hardy, H. W. Kroto, M. Maier, and D. R. J. Milverton, to be published. 442 H.W Kroto monochromatic beam of ionizing photons. If the photon energy is E = hv then the ionization energy (Eionization)is given by expression (8). Eionization = hv -&in (8) The electrons tend to bunch together (in energy) giving rise to several bands which often can be identified with electron ejection from individual molecular orbitals. To a first, and often satisfactory, approximation the resulting ionization potentials can be directly equated to molecular orbital energies derived from theoretical calculations, and so this technique yields some of the most valuable information about the electronic structures of molecules from a molecular orbital viewpoint.Perhaps the most important point is that the separations between various bands yield the transition energies of the associated electronic states of the molecular ion. In fact, the technique tends to tell us about the ion rather than the molecule, a fact that should not be overlooked. The application of photoelectron spectroscopy to the study of unstable species has recently been reviewed by Dyke, Jonathan, and Morris.6 C. Combined Application of Microwave and Photoelectron Techniques.-A good example of the synergistic aspects of combining techniques is evidenced in some recent work on high temperature reactions involving S(CN)2. In these experi- ments a new microwave spectrum (Figure 5) was dete~ted.~The spectrum consists of bunches of lines at intervals of roughly 3.25 GHz.Under high resolution the bunches show KA = 1 flanking lines consistent with an asymmetric top and also additional features due to vibrationally excited molecules which complicate the spectrum. After a few guesses and trial moment of inertia calcula- tions it became clear that a thermal rearrangement of the form given in scheme (9) had taken place. The NCNCS molecule is V-shaped as shown in Figure 6 and a good rough estimate of ZB and therefore also B can be made from the approximate scale diagram and dimension shown. The molecule is planar which means that rc = 0 for all atoms and thus the B moment of inertia, summed over all atoms, n, is given by equation (10).1, = C mn(ri + rz)n = C mn(r5)n n n According to the approximate dimensions in Figure 6 we see that: Is = 14(3.0)2+ 12(2.0)2+ 14(0.5)’ + 12(0.5)’ + 32(2.0)2= 308.5amuA2 J. M. Dyke, N. Jonathan, and A. Morris, Int. Rev. Phys. Chem., 1982, 2, 3.’M. A. King and H. W. Kroto, J. Chem. SOC.,Chem. Commun., 1980, 606. 443 2 -.3 J =12+ll J= llCl0 J = 10-9 J= 9-8 s Figure 5 The microwave spectrum of NCNCS.' This spectrum is characteristic ofa slightly asymmetric rotor in that strongest lines lie in bunches at almost equidistant intervals ofca. 2B = B + C. Under high resolution the lines resolve into a complex pattern for a molecule which is rather Jlexible and so has many excited tlibrurional states' H.W Kroto -1 N Figure6 The structure ofNCNCS relative to the A and B principal axes (scale in A units).The molecule is planar with an angle at the central nitrogen of ca. 150".I,, the moment of inertia about the B axis, is determined by Enmn(ri)n as discussed in the text The B rotational constant can now be calculated as B = 505.391/308.5= 1.638GHz and compared with the rough value of B = *(I3 + C) = i(3.25) = 1.625GHz obtained from the spectrum shown in Figure 6. A more accurate analysis shows that the observed value of Bo = 1.628* and the preliminary structure yields Bcalc= 1.623GHz. The fine details of the analysis show that NCNCS has a rather unusual spectrum in that the molecule shows quasi-linear behaviour.Essentially the molecule does not know whether it is linear or bent and this ambivalence is exhibited in the spectroscopic patterns observed under high resolution.* The initial attempt to detect NCNCS by photoelectron spectroscopy (Figure 7b) was unsuccessful, resulting in product peaks which were readily identified with CS2 and C2N2,neither of which have permanent dipole moments and are therefore not detectable by our microwave spectrometer. Parallel experiments using a small quadrupole mass spectrometer confirmed this. The photoelectron and mass spectroscopic data thus immediately indicated that at ca. 1OOO"C very little NCNCS is produced, even though under similar conditions the microwave experiments showed extremely strong lines of NCNCS.As NCNCS was known, from the microwave experiments, to be present, the temperature and flow conditions were varied until new peaks, consistent with NCNCS were found. These are identified in Figure 7c. The products of pyrolysing under the new conditions were trapped and the spectrum of essentially pure NCNCS shown in Figure 7d was obtained on re-vaporization.' In this way the microwave detection had identified, with ease, a species which was much more difficult to observe by the photoelectron technique. The microwave technique had, however, * The rotational constants of a real molecule, which is not of course rigid, depend on vibrational state. The experimentally determined constants for the ground vibration state are labelled by a subscript zero, i.e.A,, B, ,and Co. M. A. King, H. W. Kroto, and B. M. Landsberg, to be published. M. A. King and H. W. Kroto, to be published. Semistable Molecules in the Laboratory and in Space I I I I I I I 910 "c (a) S(CN1, IN, 650 "C (d)I NCNCS I I I I I 10 12 14 16 18 e\ 10 12 14 16 18 e' Figure 7 (a) The p.e. spectrum of S(CN), . (b) The p.e. spectrum of S(CN), pyrdysed at 910 "C.(c) The p.e. spectrum ofS(CN), pyrolysed at 650 "C.(d) The p.e. spectrum obtained by revaporizing NCNCS from a sample produced under the conditions of (c) and trapped' overlooked some other important reaction pathways. In the next sections similar situations are discussed, some of which show the r6les reversed in that the p.e.technique has spearheaded microwave detection. 3 Studies of Semistable Molecules A. Thiocarbonyls and Selenocarbony1s.-It was work on some small thiocarbonyls which originally highlighted the value of joint microwave and photoelectron experiments as general readily applicable techniques for detecting moderately unstable species. There must have been many attempts in the past to make sulphur analogues of formaldehyde, acetaldehyde, and acetone. Indeed Noller" lo C. R. Noller, Chemistry of Organic Compounds', W. B. Saunders Co., Philadelphia, 1957, p. 282. H. w Kroto notes that ‘the odour of thioacetone is so obnoxious that Baumann and Fromm had to abandon their work because of the protests of the City of Freiburg’. This anecdote conjures up a vision of the smell wafting gently over the city fathers as they, holding their noses, march towards the laboratory to find Baumann and Fromm working without a fume cupboard and oblivious to the odour.The present work has its origins in a number of experiments. During flash photolysis experiments on dimethyl peroxide aimed at the detection of the methoxy-radical, MeO, the spectrum of formaldehyde H2C =O was detected (unpublished results). Subsequent experiments aimed at detecting the sulphur analogue, H2C =S, by photolysing MeSSMe proved unsuccessful because the S-S bond was more difficult to break photolytically and the electronic transition sought is very weak. Some experiments by Callear et al.’ did, however, detect a transient spectrum at around 2100 A.The first clear spectroscopic identification was made by Johnson et al.” using flow pyrolysis of MeSSMe and microwave detection. The value of photoelectron spectroscopy, which is also a low pressure (1-50 pHg) technique, for detecting such molecules became clear after experi- ments on CS produced by a discharge in CS2’3-15as well as experiments on H2CS.16 Lifetime data for CS had previously been obtained by Dyne and Ramsay” and the microwave spectrum by Kewley et ~1.’~The synergistic value of combining the two techniques was evidenced by work on F,CS, a molecule which had originally been made by Middleton, Howard, and SharkeyIg by pyrolysing the dimer (CF2S), . Several attempts to detect the microwave spectrum by myselfand others had failed although the molecule was isolable.Subsequent photoelectron detection of the species in a flow-pyrolysis system2’ showed that the molecule was readily formed by this technique and, using an essentially identical set-up and optimized conditions for production, the microwave spectrum of F2CS was finally observed.’l The spectrum was very weak because the dipole moment p(on which rotational intensity depends as p2) was only 0.08 Debye. In addition F,CS reacts very quickly (in the metal wave- guide microwave cell) with adsorbed water to form HF, F,CO, HFCO, and OCS, whose lines are very strong. The flow technique flushes the cell and after a while the strong lines of by-products can be almost eliminated allowing the search for weak lines to proceed efficiently.A very similar two pronged approach finally succeeded in detecting the elusive mixed halide BF2Cl, which is in fact isoelectronic with CF2S. Photoelectron experiments showed clear evidence for the mixed A. B. Callear, J. Connor, and D. R. Dickson, Nature, 1969, 221, 1238. l2 D. R. Johnson, F. X. Powell, and W. H. Khirchhoff, J. Mol. Spectrosc, 1971, 39, 146. l3 G. H. King, H. W. Kroto, and R. J. Suffolk, Chem. Phys. Letts., 1972, 13, 457. l4 N. Jonathan and M. Okuda, Faraday Discuss. Chem. SOC., 1972, 54, 67. l5 D. C. Frost, S. T. Lee, and C. A. McDowell, Chem. Phys. Lett., 1972, 17, 153. l6 H. W. Kroto and R. J. Suffolk, Chem. Phys. Letts., 1972, 15, 545. I7 P. J. Dyne and D. A. Ramsay, J.Chem. Phys., 1952, 20, 1055. R. Kewley, K. V. L. N. Sastry, M. Winnewisser, and W. Gordy, J. Chem. Phys., 1963, 39, 2856. l9 W. J. Middleton, E. G. Howard, and W. H. Sharkey, J. Org. Chem., 1965, 30,1375.*’ H. W. Kroto and R. J. Suffolk, Chem. Phys. Letts., 1972, 17, 213. 21 A. J. Careless, H. W. Kroto, and B. M. Landsberg, Chem. Phys., 1973, 1, 371. Semistable Molecules in the Laborutory and in Spuce species BF2Cl and BFCl, in BF3-BC13 mixtures,22 and reproducing the flow conditions using microwave detection resulted in the observation of some very weak lines of BF2Cl which proved very difficult to detect.23 The studies on CS, CH2S, and F2CS, all of which were known compounds, showed how well microwave and photoelectron techniques could be used to mutual benefit and in particular should enable the detection of new molecules- most obviously new thiocarbonyls.In general, attempts to prepare the smaIler thiocarbonyls result in the production of trithianes which are ring trimers, (R2CS)3. For instance, the reaction of acetaldehyde, CH,CHO, with H2S in acid solution yields 1,3,5-trimethyltrithiane (CH3CHS)3 which has a crown shaped skeleton (1). This compound is sufficiently volatile to allow its photoelectron spectrum to be observed Figure 8a. The sulphur p orbitals overlap to give rise to E and an A highest occupied molecular orbitals with the nodal characteristics [(2)-(4)]. I The degenerate combination is less bonding, possessing a node, and gives rise to the broad first IP at 8.39eV.The more bonding A orbital is more stable and is associated with the second IP at 8.91eV. The intensities are roughly 2:1, in line with the degeneracies. On pyrolysis this spectrum is completely eliminated and replaced by the more simple spectrum of monomeric CH3CH=SZ4 as shown in Figure 8b. The spectrum of CHJCHS has a single peak at 8.98 eV which can be assigned to ionization from a single sulphur lone-pair orbital and a second band at 10.87eV which corresponds to ionization from the C=S 71 bonding orbital. The spectra given in Figures 8a and b show how efficient and complete is the formation of the monomer from the trimer. On the 22 H. W. Kroto, M. F. Lappert, M. Maier, J. B. Pedley, M. Vidal, and M. F. Guest, J. Chem. SOC., Chem.Commun., 1975,810. 23 H. W. Kroto and M. Maier, J. Mol. Spectrosc., 1977, 65, 280. 24 H. W. Kroto, B. M. Landsberg, R. J. Suffolk, and A. Vodden, Chem. Phys. Letts., 1974, 29, 265. H. W Kroto Me,( I,H s. ,s I 1 L I a 10 12 14 16 eV MeCH==S .A 8 10 12 14 16 eV Figure 8 (a) The p.e. spectrum of (CH,CHS), . (b) The p.e. spectrum qf inonovieric CH,CH=S produced by pyrulysing the trimer at 600°C. The jrst and second bands correspond to ionization of electrons from the n(S) and n(C=S) orbitals re~pectirely~~ Semistable Molecules in the Laboratory and in Space basis of these experiments a microwave search for CH3CHS was carried out successf~lly~~and the spectrum of the J = 3 -2 transition is shown in Figure 9.The pattern has the classic structure of a bunch of centrally placed KA # 1 lines flanked by two KA= 1 lines. Here the KA= 1 lines are split by methyl group internal rotation tunnelling into doublets. From these splittings the barrier height V, = 6.578 kJ mole-was determined. In a similar way the photoelectron and microwave spectra of (CH,),CS were observed in the pyrolysis of the trimer (Me,CS), .24 These experiments were refined still further in an attempt to detect thioketene CH2 =C=S. Some evidence for this species as an intermediate had been presented previously by Howard during the pyrolysis of Me3SC=C-H.26 In our experi- ment~~~,~~this species was positively identified by microwave spectroscopy in the pyrolysis of (Me2CS), at 1OOO”C.Krantz and Laureni2’ also detected this molecule by i.r. spectroscopy by a neat route involving the pyrolysis of the thiadiazole, CH =CH-S-N =k. Krantz and Laureni also detected CH,=C=Se by an analogous route.,’ This route is more efficient and has allowed photoelectron spectra to be observed., 1,32 The microwave spectrum of CH2CSe has also been studied using this route3,. As well as thioketene, a second new species was identified when thioacetone trimer was pyrolysed at lo00 “C. This was finally identified as propenethial, CH2 =CHCH =S,34 which had formed by skeleton rearrangement from thioacetone. This molecule had originally been identified by Bailey and Isogawa3’ in the pyrolysis of diallylsulphide (CH2 =CHCH,),S from which it is more efficiently produced.Some preliminary experiments aimed at developing analogous selenocarbonyl species have been carried out. These are much more difficult to handle (i) because there is an ever-present tendency for elemental Se to deposit and (ii) there is a psychosomatic response at the mere hint that such experiments are being carried out. Before the latter problems halted the present work the microwave spectrum of selenoacetaldehyde CH,CHSe was detected and and some circumstantial photoelectron evidence for CH2Se obtained. Some synthetic studies of (CH,Se), have been discussed37 and these methods were modified, with difficulty, to make (MeCHSe), which was successfully pyrolysed to produce CH,CHSe. This species was found to be much less stable and more difficult to 25 H.W. Kroto and B. M. Landsberg, J. Mol. Spectrosc., 1976, 62, 346. 26 E. G. Howard, Chem. Absr., 1962, 57, 13617fi 27 K. Georgiou, H. W. Kroto, and B. M. Landsberg, J. Chem. SOC., Chem. Commun., 1974, 739. K. Georgiou, H. W. Kroto, and B. M. Landsberg, J. Mol. Spectrosc., 1979, 77, 365. 29 A. Krantz and J. Laureni, J. Am. Chem. Soc., 1974, %, 6768. ”A. Krantz and J. Laureni, J. Am. Chem. SOC.. 1977,99,4843.’‘ H. Bock, B. Solouki, G. Bert, and P.Rosmus, J. Am. Chem. SOC., 1977, 99, 1663. 32 H. Bock, S. Aygen, P. Rosmus, and B. Solouki, Chem. Ber., 1980, 113, 3187. 33 B. Bak, 0.J. Nielsen, and H. V. Svanholt, Chem. Phys. Lett., 1978, 53, 374. 34 K. Georgiou and H. W. Kroto, J. Mol. Spectrosc., 1980, 83, 1. 35 W.J. Bailey and M. Isogawa, Polym. Prep. Am, Chem. SOC., Div. Polym. Chem., 1973, 14, 300. 36 M. Hutchinson and H. W. Kroto, J. Mol. Spectrosc., 1978,70, 216. 37 H. J. Bridger and R. W. Pittman, J. Chem. Soc., 1950, 1371. 3 3.8 33.6 334 33.2 33-0 328 32.6 GHz Figure 9 The J = 3 +2 microwave transition of CH,CH=S.25 The outer KA = 1 lines are split into doublets by the eflects of methyl group internal rotation. The central group consisting of the KA = 0 and KA = 2 lines are also split by these eflects. The other lines belong to torsional satellites Semistable Molecules in the Laboratory and in Space detect than CH3CHS. Attempts to produce selenoacetone compounds appear to lead to the deposition of elemental Se." Data on various thio- and seleno-carbonyls have been collected together in Table 1.Table 1 Collected data for thio- and seleno-carbonyls Ionization p/Debye PotentialsleV Other data CH, =S 1.61112 1.647412 9.34 11.7816 CH3CH-S 1.61025 2.3325 8.90 10.87 12.7424 V, = 6578 Jmole-' " (CH3)2C=S --8.60 10.46 12.4024 V3 = 5440 Jmole-' 24 CH2=CHCH=S 1.6134 2.6134 -r(C=C) = 1.34134 r(C-C) = 1.46.A F2C=S 1.59, 0.0802' 10.45 11.34 14.87,' L(FCF) = 107.1" 17.65 r(C-F) = 1.315.A CH,=C=S 1.5542 1.0228 8.9 11.3 12.13' r(C=C) = 1.314.A'' CH3CH=Se 1.75836 --V, = 6859 Jmole-' 36 CH, =C =Se 1.702 0.933 8.7 10.7 11.632 r(C=C) = 1.31333 B. Sulpbidoboron and Selenidoborbn Species.-A family of molecules related to HCN can be assembled and-the resulting cube would have HCN, HBO, and CO along the isoelectronic top edge.The second layer beginning with HCGP, together with the third layer, is shown in Figure 10. The isoelectronically related molecule HB =O has not been detected spectroscopically although the halide ClB=O has been observed by Kawaguchi, Endo, and Hirota in an 02-BCl, di~charge.~' HBS, the sulphur analogue of HBO, was detected by Kirk and Timms in the products of a high temperature reaction (ca. 1000°C) between H2S and crystalline boron using a mass spectrometer4' and further confirmation has come from microwave work by Pearson and M~Cormick~'*~~ and photoelectron ~ork.~~,~~ In Figure 11 the spectrum observed using a fast- flow photoelectron instrument (of the type developed at Southampton by Dyke, Jonathan, and Morris45) is shown.46 The original detection of HB =S initiated a programme to produce substituted analogues by various sensible, though unsuccessful, routes such as the thermal elimination of HCl from BC1,SH.Finally, a simple modification of the original Kirk and Timms route to HBS was attempted which at the time did not seem likely to be fruitful. In the event it worked beautifully. In the first experiment 38 D. S. Margolis and R. W. Pittman, J. Chem. Soc., 1957, 799. 39 K. Kawaguchi, Y. Endo, and E. Hirota, J. Mol. Spectrosc., 1982, 93, 381. 40 R. W. Kirk and P. L. Timms, Chem. Comm., 1967, 18. 41 E. F. Pearson and R. V. McCormick, J. Chem. Phys., 1973, 58, 1619. 42 E. F. Pearson, C. L. Norris, and W. H. Flygare, J.Chem. Phys., 1974, 60, 1761. 43 H. W. Kroto, R. J. Suffolk, and N. P. C. Westwood, Chem. Phys. Letts., 1973, 22, 495. 44 T. P. Fehlner and D. W. Turner, J. Am. Chem. Soc., 1973, 95,7175. 45 J. M. Dyke, N. Jonathan, and A. Morris, Electron Spectrosc., 1979, 3, 189 (Academic Press). 46 T. A. Cooper and H. W. Kroto, to be published. H. W Kroto Periodic or Mendeleevian relationships Figure 10 The HCzN cube with the top layer removed. All the molecules shaded in the second-row layer have been studied in the work discussed in this reriew H2S+rl i.. 10.0 12.0 14.0 16.0 18.0 eV Figure 11 The p.e. spectrum of HB=S detected during fastpow pyrolysis of H,S over solid boron46 453 PVI P 38 36 34 32 30 28 GHi I I I I I I J = 7-6 CI-B=S J= 6-5 J = 5-4 I Figure 12 The wide band scan of C1B=S.49 There are 12 possible isotopic variants involving 35Cl,37Cl,"B, "B, 32S,33S,and 34S.Lines of all twelve appear in the spectrum together with associated vibrational satellites. As the most abundant species 35CI"B32S and 37C111B32Sgive rise to the most prominent lines each J transition appears to be split into two bunches.The higherfrequency bunch associated mainly with 35Clvariants, thP lnwpr frpaupnrv hunch with 37C1variants. The intensities bear a very poor relationship with abundance due to modulation eflects H.W Kroto the reaction of MeSSMe with crystalline boron at ca. 1O0O"C was investigated and the new molecule CH,B=S was readily identified by microwave measure- ment~.~'~~~Of course, with hindsight, a logical mechanism can be formulated such as equation (11) CH3SSCH3 A CH3S.CH,SB -CHJBS (11) where the electron deficient boron surface is attacked by CH3S. radicals following the readily accomplished thermal breakage of the S-S bond. The feasible CH3SB species may then isomerize to the more stable methyl sulphidoboron, CH,B=S. The process is probably more complex than this, involving solid products. Photoelectron studies have not detected this species, indicating that in this case the process produces very small amounts of CH3BS which is detected because microwave spectroscopy is very sensitive to symmetric tops with large dipole moments (p = 2.573 Debye). These experiments led naturally on to the study of the halides by essentially the same technique using disulphur dihalides, equation (12).X2S2 l~"c~XB=S (X = Hal) (12) In Figure 12 the microwave spectrum of C1BS49 is shown. Here the wide band scan shows the profusion of isotopic transitions which can be used to obtain accurate structural data. The photoelectron spectrum of ClBS is shown in Figure 12. In the original photoelectron work on HBS43 and CIBS'' a modified Perkin Elmer P.S.16 spectrometer was used which allowed only modest flow rates to be achieved. With very fast flow rates the much improved data in Figures 11 and 1346 are obtained which indicate that reaction (12) yields a remarkably high conversion rate in these cases. This really seems quite surprising considering all the other possible reactions that might be expected to occur.This work has been extended to the detection of monomeric FBS and BrBS by both photoelectr~n~~,~ The trimers of the and microwave spectro~copy.~~ sulphidoboron species are quite well known, and in fact, some interesting results on the FBS system have been obtained using combined microwave, photo- electron, and mass spectrometric techniques. These have shown that under the right conditions the spectra of FBS, (FBS), ,and (FBS), can be identified in the gas phase." Such species can be formed by high temperature reactions involving SF4-B, SF,-B, or BF,-B,S, as well as the F2S2-B." The sulphidoboron data are collected together in Table 2 and the photo- electron data correlated in Figure 14.This work has recently been extended to the bottom layer of Figure 10 by the detection of C1BSeS2 using a modification of reaction (12) in which Cl,Se2 47 C. Kirby, H. W. Kroto, and M. J. Taylor, J. Chem. Soc., Chem. Commun., 1978, 19. 48 C. Kirby and H. W. Kroto, J. Mol. Spectrosc., 1980, 83, 1. 49 C. Kirby and H. W. Kroto, J. Mol. Spectrosc., 1980,83, 130. 50 C. Kirby, H. W. Kroto, and N. P. C. Westwood, J. Am, Chem. Soc., 1978, 100, 3766. 51 T. A. Cooper, C. Kirby, H. W. Kroto, and N. P. C. Westwood, to be published. 52 T. A. Cooper, M. A. King, H. W. Kroto, and R. J. Suffolk, J. Chem. Soc., Chem. Commun., 1981, 354. 455 Semistable Molecules in the Laboratory and in Space I I I I I I 10.0 12.0 14.0 16.0 18 I Figure 13 The fast pow p.e.of C1B=S.46 ClBS is produced by passing C12S, over solid boron at llOO°C and this spectrum indicates that the resulting vapour phase product is essentially pure CIBS. Note that the 2nd and 3rd ionization potentials coincide closely Table 2 Spectroscopic data on sulphidoboron and selenidoboron species Species r(X-B)/A r(B=S)/A pfDebye Ionization PotentialfeV Ref: HB=S 1.169 1.599 2.098 11.1 13.55 15.84 41 -44 FB=S 1.284 1.606 1.086 10.9 14.2 17.2 19.62 46, 51 ClB=S 1.681 1.606 1.45 10.57 13.55 13.63 16.36 49, 50 BrB=S 1.831 1.608 - 10.42 12.77 13.43 46 CH3B-S 1.535 1.603 2.573 - 48 ClB=Se 1.664 1.751 - - 52 is passed over B at 1100“C. The spectrum is much more difficult to detect than that of ClBS.This is the first example of a selenidoboron compound and there is no obvious reason why other analogues should not be detectable. C. Carbon-Phosphorus Multiple Bonds.-Phospha-alkenes and Phospha-alkynes. In 1961 Gier at Du Pont showed that phosphaethyne, HCEP, the phosphorus analogue of HCN is produced when PH, is passed through a carbon arc di~charge.’~Subsequently Tyler at NRC studied the microwave and the optical spectrum with Johns and Shurvell.’’ The existence of this molecule immediately suggested various possible consequences. Could analogues be made and might there be an associated chemistry parallel to that of the nitriles? The chemistry of the C=P group might be equally, if not even more, 53 T. E. Gier, J.Am. Chem. SOC.,1961, 83, 1769. 54 J. K. Tyler, J. Chem. Phys., 1964, 40, 1170. 55 J. W. C. Johns, €3. F. Shurvell, and J. K. Tyler, Can. J. Phys., 1969, 47, 893. H. W Kroto H-B=S F-B=S CL-B=S Br--B=S eV 11 c/s-==== Tc (B=S) 14 I-, -13 c \ \ -I -r /-/II /I ,-C(B=S) -= / I 15 - I I I 16 17 -1 -, - \ \ \ \ *-\ I I I I I I /-I / )IF-/ // * a(X- B1 18 - \ \ I I preliminary measurement \ I \* I 19- diverse and important relative to that of the nitriles. The possibilities for reactions such as condensation reactions, polymerization processes, inorganic and organometallic complex formation seemed endless. The questions were clear but the techniques for solving them much less obvious. Although nitriles are well known stable systems the doubly bonded imino > C =N’ species are much less so, indeed it is only fairly recently that Johnson and LovasS6 succeeded in identifying the simplest molecule CH, =NH by micro- wave spectroscopy in the products of pyrolysing CH,NH2, This experiment together with the existence of HCEP point to the distinct possibility that phosphaethene CH,=PH might be detectable in the pyrolysis of such species as CH3PH2etc. Indeed some work by Haszeldine and co-~orkers~~*~* postulated 56 D.R. Johnson and F. J. Lovas, Chem. Phys. Lett., 1972, IS, 65.’’ H. Goldwhite, R. N. Haszeldine, and D. G. Rowsell, J. Chem. Soc., 1965. 6875. 58 M. Green, R. N. Haszeldine, B. R. Iles, and D. G. Rowsell, J. Chem. Soc.. 1965.6879. 457 Semistable Molecules in the Laboratory and in Space that species of the type R,C=PX were intermediates in the reactions of certain perfluoroalkylphosphines with bases, in for instance scheme (13). CF, \ (CF3),PH -!!!@l(CF3)ZP-7CF,P=CF, /p-oMeCH,F The combined microwave and photoelectron technique which had already been successful in studying such species as CH, =S16 and CF, =S20*21(isoelectronic with the feasible species CH, =PH and CF, =PH respectively) as well as CS13 and HB=S43 (both isoelectronic with HCcP) thus seemed ideally suited to the detection of the hitherto unknownphospha-alkenes as well as new phospha-alkynes related to the lone species HC=P. Accordingly some exploratory microwave investigations were initiated at Sussex together with John Nixon.These met with immediate success in that three members of the phospha-alkene family, a new structural type, including the simplest, CH2 =PH, were produced and characteri~ed.~’ In addition the first substituted phospha-alkyne, CH3C=P, the phosphorus analogue of acetonitrile was produced.60 At the same time, Becker61 observed a rearrangement in a P-silylated acyl phosphine to form PhP=C(Bu‘)OSiMe, . In the first experiment attempted, the pyrolysis of dimethyl phosphine Me,PH, a microwave transition of the species CH, =PHs9 was detected according to equation (14). (CH,),P 7CH2=PH + CH4 (14) Further evidence for the assignment came with the detection of the same transition in the pyrolysis of CH3PH2 and subsequently, more efficiently, of Me3SiCHzPH2.62,63Furthermore this detection was immediately followeds9 by the identification of CH, =PCl in the reaction (15) CH,PCl, 7CH,=PCI + HC1 (15) and the molecule CF, =PH5’ in the reaction (16) CF3PH2 CF,=PH+HF (16) The microwave spectra for the pyrolysis of CH3PC12 are shown in Figure 15.A second and very important result is also to be found in this spectrum in that at 39.952 GHz the J = 1 t0 transition of HCEP is readily detectable. 59 M. J. Hopkinson, H. W. Kroto, J. F. Nixon, and N. P. C. Simmons, J. Chem. SOC., Chem. Commun., 1976, 513. 6o M. J. Hopkinson, H. W. Kroto, J. F. Nixon, and N. P. C. Simmons, Chem. Phys. Lett., 1976,42,460. 6’ G. Becker, Z. Anorg. Allg. Chem., 1976, 423, 242.62 H. W. Kroto, J. F. Nixon, K. Ohno, and N. P. C. Simmons, J. Chem. Soc., Chem. Commun., 1980,709. 63 H. W. Kroto, J. F. Nixon, and K. Ohno, J. Mol. Spectrosc., 1981, 90, 367. 0 38 36 34 32 30 28 GH2 I I I I I I I I II I (a) MePC$ (b) 1000 pyrolysisOC Figure 15 (a) The wide band scan of the microwave spectrum of CH,PCl,. This molecule is fairly asymmetric and gives rise to a uery complicated multitude of weak rotational lines which fall into few, if any, recognisable patterns. (b) On pyrolysis of CH,PC12 a new group of lines appears which is readily assigned to the J = 4-3 transition of CH,=PCI. In addition the strong J = 1 +--0 line of HC=P appears at 9 39.952GHz indicating that two HCl fragments have been eliminated 3 58 Semistable Molecules in the Laboratory and in Space The second part of these initial investigations relating to the phospha-alkynes was now clear and pyrolysis of the species EtPCl, according to equation (17) CH3CH,PCI, A + CH3CrP+2HCI (17) was immediately confirmed by micr~wave~'?~~ and photoelectron 65 investiga-tions.The microwave spectrum is shown in Figure 16. 40-2 40.1 40.0 39.9 GH I I I I I 1 MeCSP 5. s. /=4-3 I1 '8=3 Ye= 2 1 Figure 16 The J = 4 +-3 transition of MeCEP produced by pyrolysing EtPCI,. The ground vibrational state lines for this symmetric top molecule with K = 0-3 bunch together at ca. 39930MHz. When the lowest vibrational mode, the C-C-P bend, is excited the molecule changes from a symmetric to an asymmetric rotor and the v = 1 vibrational satellite shows a pattern which has characteristics similar to those of a slightly asymmetric rotor.The J = 1+0 line of HCP is also in this region and it shows a nice example of a simple Stark modulated microwave line. The positive line is the zero-field frequency and the negative lobe is the frequency in the presence of the perturbing Jield. For the simple J = 1 +-0 case one only observes a Stark shift. In general one observes splittings when higher values of J are involved (see Figure 17) A careful search for FCP formed by thermally eliminating two HF fragments from CF3PH2 continuing equation (16) was also carried out and the J = 3 +-2 transition, Figure 17, was identified even though it was rather weak.66 When this experiment was modified to prevent the possible back reaction of HF with FCP, by passing the pyrolysed products over solid KOH, it was discovered that HF could be eliminated directly by a reaction between the precursor CF,PH, and KOH-no heating was necessary,66 Figure 17.The reaction (18) CF,PH2 -;EL CF,=PH FC=P (18) takes place at room temperature. These techniques have also confirmed the importance of phospha-alkenes as intermediates in reactions between primary 64 H. W. Kroto, J. F. Nixon, and N. P. C. Simmons, J. Mol. Spectrosc., 1979, 77, 270. 65 N. P. C. Westwood, H. W. Kroto, J. F. Nixon, and N. P. C. Simmons, J. Chem. SOC.,Dalton Trans., 1979, 1405. 66 H. W. Kroto, J. F. Nixon, and N.P. C. Simmons, J. Mol. Spectrosc, 1980, 82, 185. 31.8 31.7 31.6 31.5 GI I I I I r I 11'0 11'0 I00 I of0 02OO cF2 H2 03'0 Figure 17 The J = 3 + 2 microwave transition of FCrP is a beautjful example of a linear molecule rotational spectrum. The ground vibrational state line is assigned (0oO) i.e. (v, = 0, v2 = 0, v3 = 0).The bending vibration v2 is doubly degenerate and the satellite splits into two lines by an interaction called I-type doubling. The efect is loosely related to the asymmetry splitting of KA= 1 lines in asymmetric tops due to the fact that on bending the molecule is no longer linear and B # C. These are the two lines labelled (01'0). The superscript indicates the quantum number for vibrational angular momentum, 1.The 2v2 state gives rise to a state with 1 = 2, i.e. (0220)and a state with 1 = 0 (02'0). ' The 02'0 state is shifed by a Fermi resonance with the vj state (Ool), see Figure 21. The asterisks indicate Stark lobes belonging to the two (01'0) lines. The U-lines are unidentiJed and belong to another species 3 P T: E 8 Semistable Molecules in the Laboratory and in Space or secondary polyfluoroalkyl phosphines with nucleophiles such as alkoxides and amines. In particular the species CF,P=CF, ,postulated as an intermediate in the methanolysis of (CF,),PH, equation (13), has been trapped and identified by n.~.r.~~ The obvious step of treating CF3CF2PH2 with KOH to observe CF3C=P was not successful, though this species has been detected in the pyrolysis products of the precursor in rather low yield.68 Having detected the phospha-alkenes CH, =PH, CH2 =PCl, CF, =PH, and CF,P=CF2 and the phospha-alkynes FCEP, CH3C=P, and CF,C=P in these preliminary experiments, the programme was developed in wider and more general directions. Not only were new members of these two groups sought but more efficient synthetic routes and new chemical applications, for instance as ligands in transition-metal complexes, were explored.In addition, the chemistry of these species is now being studied by several other groups such as those of Becker, Appel, Bickelhaupt, and Issleib. Below, the contributions made by this research programme in collaboration with John Nixon are summarized, with contributions from other groups included where appropriate.Reviews of these systems are now beginning to appear.69- 72 (i) Production of Phospha-alkenes. As indicated above, the thermal elimination route has proven very successful, especially for spectroscopic purposes. Thus, the general scheme shown in equation (19) RCX2PY2 * RCX=PY+XY (19) has led to CH2=PH, CF,=PH, and CH,=PC15’ and Klebach et aL7, have shown that a phospha-alkene is produced according to equation (20). RPC12 -RPClCHPh, -RP=CPh, (R = mesityl) (20) where the resulting compound is stabilized by the substituents. The elimination step can, in the case of CF,PH, and (CF,),PH, be carried out by treatment with base to form CF, =PH and CF,P=CF2 respectively (previous Section). Studies, together with David Walton, of routes involving silyl sub-stituted phosphines are in progress and have resulted in phospha-alkenes by equations (21)-( 24) Me,SiCH,PCI, CH, =PCl Me,SiCH,PF,*Me,SiCH,PH, CH,=PF A CH,=PH (21) (22) (23) Me3SiCH2PBr2 CH2=PBr (24) 67 H.Eshtiagh-Hosseini, H. W. Kroto, J. F. Nixon, and 0.Ohashi, J. Organomet. Chem., 1979, 181, C1. N. P. C. Simmons, H. W. Kroto, and J. F. Nixon, to be published. 69 H. W. Kroto and J. F. Nixon in ‘Phosphorus Chemistry’, ed. L. D. Quin and J. Verkade, A.C.S. Symposium Series 171, American Chemical Society, 1981, p. 283. lo J. C. T. R. Burckett-St. Laurent, T. A. Cooper, H. W. Kroto, J. F. Nixon, 0.Ohashi, and K. Ohno, J. Mol. Struct., 1982, 79, 215.’’ R. Appel, F. Knoll, and I.Ruppert, Angew. Chem., Int. Ed. Engl., 1981, 20, 731. l2 H. W. Kroto and J. F. Nixon, to be published. 73 T. C. Klebach, R. Lourens, and F. Bickelhaupt, J. Am. Chem. Soc., 1978, 100, 4886. H. W Kroto The route (23) to CH2=PH is more efficient than the original one, equation (14), and has allowed an accurate structural study to be made.63 Since this work, CH2=PCI has also been detected in the pyrolysis of CH30PC12 .74 The review by Appel et aL71 contains details of other phospha-alkenes. (ii) Spectroscopic Data on Phospha-alkenes. From the microwave studies accurate structures for the two phospha-alkenes CH, =PH63 and CH, =PC174*75 have been determined (5)and (6)where the bond lengths are in A and angles in degrees. H' (5) (6) In addition to CH2=PH and CH,=PCl, microwave studies have also been carried out on CH, =PF,76 CH, =PBr,77 and CF, =PH.59978 The rotational constants of some of the species studied are given in Table 3 and some of the more Table 3 Rotational constants of phospha-alkenes Species* A,/MHz B,/MHz C,/MHz Ref.CH, =PH 138 503.2 16418.105 14649.084 62, 63 CH,=PD 93 513.75 16098.885 13 701.898 CH2=PF 28 454.9 8890.30 6760.13 76 CH2=P35C1 22712.5 4667.3 1 8 3865.535 59, 75 CH~=p3 7c1 22 657.0 4539.161 3735.677 CH,=P''Br 21 608.48 2904.0 10 2586.750 77 CH, =PBIBr 21 603.06 2879.260 2537.48 CF,=PH CF2 =PD 11 107.108 10 676.036 4766.393 4672.806 3330.7873246.213 59978 * Species containing "C, "P, and I9F important structural parameters (some of which are preliminary) are collected in Table 4.Some dipole moment data are also included in this Table. Ohno .~et ~1 have ~ obtained vibrational frequencies from an i.r. study of CF,=PH:v,(PH stretch) = 2326.9 and v,(C=P stretch) = 1349.5 cm-' (see Section 3Cii). This system has also been studied by n.m.r. (see Section 3Cii). "B. Bak, N. A: Kristiansen, and H. Svanholt, Acta Chem. Scand., Ser A, 1982, 36, 1. 75 H. W. Kroto, J. F. Nixon, 0.Ohashi, K. Ohno, and N. P. C. Simmons, to be published. ''H. W. Kroto, J. F. Nixon, K. Ohno, and D. R. M. Walton, to be published. ''H. W. Kroto, J. F. Nixon, and K. Ohno, to be published. '* H. W. Kroto, J. F. Nixon, and N. P. C. Simmons, to be published. 79 K.Ohno, H. Matsuura, H. W. Kroto, and H. Murata, Chem. Letts., 1982, 981. Semistable Molecules in the Laboratory and in Space Table 4 Structural and dipole moment data for phospha-alkenes r(CP)/A r(PX)/A L(CPX)/o PA PB/Debye Re$ CHz=PH 1.673 1.420 97.4 0.731 0.470 0.869 63 CH,=PF 1.67" 1.58" 104.0 ---76 CH,=PCl 1.658 2.059 103.0 ---75 CH, =PBr 1.65" 2.22" 104 ---77 CF,=PH 1.67" 1.42" (100) 0.705 0.533 0.884 78 (a) preliminary data (iii) Phospha-alkene Complexes. On production of the first phospha-alkenes the possibility of their use as ligands with transition metals was investigated. This has resulted in the synthesis of several organometallic complexes of the form (7). iM The complexes which have been made" are (L = MesP=CPh,): cis-M(CO),L, (M = Cr, Mo, or W) M[CO),L (M = W) RhCl(PPh,)L, RhCl(CO)L,, Rh(C9H7)L, ,PtX,L, (X = C1, I, or Me) PtCl, (PEt, )L The last compound has been the subject of an X-ray structure analysis," from which the main structural parameters are: r(C=P) = 1.668 A, L(C=P-C) = 112", r(Pt-P) = 2.193& L(C=P-Pt) = 120.2'.(iv) Production ofPhospha-alkynes. The original Gier methods3 required a rather complicated cooled carbon arc device to be made and the reaction between graphite and PH, produced a mixture of ca. 4: 1 C,H,:HCP. It appears to be almost impossible to separate these two as their physical properties are very similar. The method of production that has been most fruitful has been the thermal elimination route (25) RCX2PY2 9RCrP (XU = HCl or FH) (25) Using this straightforward method at temperatures of ca.10oO'C or so, the *' H. Eshtiagh-Hosseini, H. W. Kroto, J. F. Nixon, M.J. Maah, and M.J. Taylor, J. Chem. SOC., Chem. Commun., 1981, 199.*'H. W. Kroto, J. F. Nixon, M. J. Taylor, A. A. Frew, and K. W. Muir, Polyhedron, 1982, 1, 89. 464 H.W Kroto molecules HCGP,” FCEP,~~CH3C=P,60.64*6s CF,CGP,~’ and CH2= CHC=PS2 have all been detected by microwave spectroscopy. Photoelectron studies indicate that the yield is good in the case of HCP,83 fair for CH3CP,6s and poor for the rest. Pure HCP can now be produced from CH,PC12 by titrating off the HCI with NH3.83FCP can be produced in good yield by treating CF3PH2 with KOH (see Section 3Cv). During experiments aimed at detecting HC=C-C=P which involved an attempted synthesis of HC=CCH2PC12, the sought species was dete~ted.’~ To produce the precursor, the Grignard of HC=CCH2Cl was treated with PC13 and the resulting products flow pyrolysed, which gave rise to a weak but readily identifiable spectrum of HC,P.The precursor was not, however, HC=CCH2PC12, which did not appear to be formed, but the original starting materials HCGCCH2Cl and PCl, . In fact the strongest spectrum was observed using a 10:1 PCl,: HC=CCH2Cl mixture. This result suggested that HC3P might be formed in reaction (26), HCGC-CH, + Cl,P HC=C-C=P + 3HC1 (26) which indeed turned out to be the case. In fact the reaction, equation (l), has now been generalized with R = HC-C, NEC, and Ph to produce not only HC=C-C=P but also N=C-C=P, and PhCEP.Most recently the molecule NC,P has been detected by equation (27) the first new species to be detected by this route.85 NrC-CrC-CH, + C13P 6NrC-CzC-CzP + 3HC1 (27) N=C-C=P had originally been detected by co-pyrolysing HCP with NCN, ,86 equation (28). NGCN, + HCrP bNrC-CrP + ... (281 The PC1,/CH3CN route is at least as good for spectroscopic purposes. The molecules SiMe,C=P and PhCGP have been produced by pyrolysis of ClP=C(SiMe,)2 and ClP=C(SiMe,)Ph respectively by Appel and Westerhau~,~~’~~Becker et have shown that the stable molecule Bu‘C=P can be produced by equation (29) But \ C=P-SiMe, -:e:& Bu‘CrP /Me,SiO 82 K. Ohno, H. W. Kroto, and J. F. Nixon, J.Mol. Spectrosc., 1981, 90, 507. M. A. King, H.W. Kroto, and J. F. Nixon, unpublished. 84 H. W. Kroto, J. F. Nixon, and K. Ohno, J. Mol. Spectrosc., 1981, 90. 512. M. Durrant, H. W. Kroto, D. McNaughton, and J. F. Nixon, to be published. 86 T. A. Cooper, H. W. Kroto, J. F. Nixon, and 0.Ohashi, J. Chem. Soc., Chem. Commun., 1980, 333. R. Appel and A. Westerhaus, Tetrahedron Lett., 1981, 2159. R. Appel and A. Westerhaus, Angew. Chem., Int. Ed. Engl., 1981, 20, 197. 89 G. Becker, G. Gresser, and W. Uhl, Z. Naturjorsch, Teil B. 1981, 36, 16. 465 Semistable Molecules in the Laboratory and in Space (v) Spectroscopic Data on Phospha-alkynes. Using Gier's original method of producing HC =P numerous spectroscopic investigations were made. The micro- wave spectrum was studied by Tyler,54 the electronic spectrum by Johns et the n.m.r.spectrum by Anderson et al.," the i.r. by Garneau and Cabana,g1 and the p.e. spectrum by Frost et al.92 In some cases, particularly the last two, the acetylene contaminant obscured regions of the spectrum. This problem is obviated by producing HCP from CH3PC12, allowing a p.e. spectrum of pure HCP to be observed.83 It has also enabled the electronic fluorescence spectrum of the HCP+ ion, excited by slow electron bombardment, to be observed, Figure 18.93 Electronic Emission Spectrum HCP+ A"2n-x2n 2 ,z I i22i 640 660 660 700 nl 1 Figure 18 The electronic emission spectrum of HCP' excited by slow electron bombardment of HCPg3 So far, CH3CP,60.64 FCP,65 CF3CP,68 NCCP,86385 HCZCCP,~~,*~ NCCGCCP,~~CH2=CHCP,'* and PhCP85,94 have all been studied by micro- wave spectroscopy.Indeed, all but the last compound were first identified by this technique. The more important data are collected in Table 5. The discovery of reaction (18) enabled a thorough analysis of the microwave spectrum of FCP shown in Figure 17 to be carried out.66 It also enabled the 90 S. P. Anderson, H. Goldwhite, D. KO, A. Letson, and E. Esparza, J. Chem. SOC., Chem. Commun., 1975, 744. 91 J. M. Garneau and A. Cabana, J. Mol. Spectrosc., 1980, 79,502. 92 D.C. Frost, T. Lee, and C. A. McDowell, Chem. Phys. Lett., 1973, 23,472. 93 M. A. King, H. W. Kroto, J. F. Nixon, D. Klapstein, J. D. Maier, and 0. Marthaler, Chem.Phys. Lett., 1981, 82, 543. 94 J. C. T. R. Burckett-St. Laurent, H. W. Kroto, J. F. Nixon, and K. Ohno, J. Mol. Spectrosc., 1982, 92,158. H. W Kroto Table 5 Spectroscopic data on phospha-alkynes Ionization BoIMHz PI Debye r(X-C)lA r(C=P)/A Potentials/ eV Re$ 19 973.67 0.39 1.0667 1.5421 10.79 12.86 54,92 1.11 1.596 93 4991.339 1.499 1.465 1.544 9.89 12.19 64,65 5257.80 0.279 1.285 1.541 10.57 13.55 66,96 1668.5644 - 1.460 1.542 68 2704.4803 3.44 1.382 1.547 86 2656.3944 0.754 1.382 (1S44) 84 873.4803 - 1.382 (1S44) 85 2726.773 1.183 1.432 (1S44) 82 867.6925 - 1.467 (1.544) 8.68 9.60 97 9.87 10.79 - - I - 9.61 11.44 97 p.e. spectrum shown in Figure 19 and the n.m.r.data in Figure 20 to be ~btained.’~The i.r. data of Ohno et aL7’ in Figure 21 give a particularly useful insight into the overall efficiency of this reaction. As well as the earlier p.e. work on HCP,92 CH,CP,65 and FCP,96 more I1 I I I I I I I 1 I I I 10 12 14 16 18 20 e‘ Figure 19 The p.e. spectrum of FCEP produced by $owing gaseous CF3PH2 over solid KOH. The first and second bands correspond to ionizations from the n(CEP) and n(P) orbitals respectivelyg6 95 H. E. Hosseini, J. F. Nixon, H. W. Kroto, S. Browstein, J. R. Morton, and K. F. Preston, J. Chem. SOC., Chem. Commun., 1979, 653. 96 H. W. Kroto, J. F. Nixon, N. P. C. Simmons, and N. P. C. Westwood, J. Am. Chem. Soc., 1978, 100, 446. Semistable Molecules in the Laboratory and in Space -1000 Hz FC =P 4lili (bd CF, PH2 Figure 20 'P (ca.-80 "C) n.m.r. spectra of the products of the reaction of CF3PH2 with KOH at room temper~ture.'~(a) 'H decoupled, (b) 'H undecoupled recently PhCP and t-BuCPg7 have been studied, yielding useful information on the electronic behaviour of the CEP group. In particular, it is worth noting that the zz and n ionization energies for HCN are almost identical, whereas for HCP the n(C=P) is the first at 10.79eV and the P lone pair is the second at 12.86eV." Some ionization potential data are also collected in Table 5. (vi) Phospha-alkyne Complexes. One of the more exciting prospects with phospha-alkynes is the possibility of making transition-metal complexes. A Pt complex of Bu'CrP has been made and its structure, as determined by X-ray analysis, is shown in Figure It is noteworthy that the angle LCCP has bent from 180"-+ 132" and the CEP bond length has increased from ca.1.544A (as in CH,C=P) in the free molecule to 1.672A in the complex reflecting the effects of back-bonding from the zero-valent platinum. The n.m.r. spectrum has also been mea~ured.'~ Seyferth and Henderson have observed dechlorination of RCC1,PCl2 by CO,(CO)~ to form a phospha-alkyne complex.99 A similar complex can be formed from CO,(CO)~ and free t -BuCP. 97 J. C. T. R. Burckett-St. Laurent, M. A. King, H. W. Kroto, J. F. Nixon, and R. J. Suffolk, to be published. '13 J. C. T. R. Burckett-St. Laurent, P. B. Hitchcock, H. W. Kroto, and J.F. Nixon, J. Chem. Soc., Chem. Commun., 1981, 1141. 99 D. Seyferth and R. S. Henderson, J. Organomet. Chem., 1978, 162, C35. H. W Kroto "1 CF.PH assignment W r-(C) FCEP assignment v, 1 1 1 I I 1 I 1 1 2400 2000 1600 1200 800 400 Wavenumber /cm -' Figure 21 The i.r. spectra obtained (a) for CF3PH2,(b)by passing CF3PH2 through a tube packed with KOH, (c) by double passage over KOH.79The strong band at ca. 1170 in (a) is the C-P stretch of CF3PH2.In (b) both CF2=PH and FCP appear and in (c) FCP is more intense relative to CF2=PH, and CF3PH2 has been almost completely eliminated. In (b) the stronger CF2 =PH features are v,(PHstr), v,(C=Pstr), v,(CF,asym str) and v,(CF2sym str). In (c) the FCPfeatwes vl, 2v2,and v3 are identified: v1 appears to be an antisymmetric stretching frequency and v3 a symmetric stretching frequency. Fermi resonance with v3 enhances 2v2.Note the correlation with the microwave spectrum in Figure 17 4 Poly-ynes A.Introduction.-Linear molecules present some most interesting problems in molecular dynamics. If they are very long they flex like a cane and one can visualize rotational energy transfer or vibrational energy transfer depending on whether a collision is near an end or near the chain centre respectively. In general they possess the most simple spectra and the longer they are, the higher is the number of bending vibrations excited at room temperature. These types of intrinsically interesting physical ideas initiated a programme with David Walton aimed at spectroscopic study of poly-ynes.This involved the preparation of a range of simple poly-ynes, some of which are rather unstable, by a combination of traditional synthesis and novel reactions. 469 Semistable Molecules in the Laboratory and in Space Figure22 The results of an X-ray analysis ofthe t-Buc~PPt[P(Ph)~l,n complex.98 LCCP has changed from 180" in the free t-BuCP molecule to 132" in the complex A number of alkynes and polyalkynes were produced and their microwave spectra, and in some cases also their photoelectron, n.m.r., and i.r. spectra, were measured.100 The length of these molecules gives rise to extended vibra- tional satellite structure in their microwave spectra enabling detailed rotation- vibration studies to be made.The study of these species, in particular HC=C-C=C-C=N, coincided with the exciting breakthrough in detection of interstellar molecules by radio- astronomy'"-and the microwave measurements initiated a search for inter- stellar poly-ynes which has led to exciting and perplexing discoveries whose implications have still to be explained. B. Microwave Spectra of Polyacety1enes.-In a typical synthesis, HC5N104 was made as shown in equation (30) ClCH2C=CCH2CI H(C=C),H Et,SnNEt, (30) H(C=C),CH Me3Si(C=C)2CN 4 CNCl Me,Si(C=C),SnEt, The triethyl tin group is preferentially replaced in step 4 resulting in Me3Si(C=C)2CN. This molecule is a symmetric rotor and its microwave spectrum is shown in Figure 23.'05 In this case there are so many lines, due to not loo A. J.Alexander, 'Spectroscopic Studies', BSc. Thesis, University of Sussex, 1975. G.Winnewisser, E. Churchwell, and C. M. Walmsely in 'Modern Aspects of Microwave Spectroscopy', ed. G. Chantry, Academic Press, London, 1979, p. 313. lo' H. W. Kroto, 'Chemistry between the Stars', New Scientist, 1978, 79, 400. H. W. Kroto, 'The Spectra of Interstellar Molecules', Znt. Rev. Phys. Chem., 1981, 1, 309. A. J. Alexander, H. W. Kroto, and D. R. M. Walton, J. Mol. Spectrosc., 1976, 62, 175. A. J. Alexander, H. W. Kroto, and D. R. M. Walton, to be published. H. W Kroto (uU U WU aDU 5: Nm Um Wv) cbm W0 II 7 47 1 Semistable Molecules in the Laboratory and in Space L --1 -I V 111 V I L, 111 0 I I 472 iz 37.5 37.0 36.51 I I I I I I I I I I I I I I I0 J = 14-13 13 15C and N isotopic satellites H-C=C-C=C-C=N abcdef eb a2 d,c "1 1 Figure 25 The J = 14t 13 transitions of HC,N under moderate re~olution.'~~ The bending vibrational satellites march out with exponential intensity to high frequency.On bending the molecule shortens, decreasing the moment of inertia and consequently increasing the average B, value causing the shft to high frequency. The ilarious singly substituted isotopic modifications are also observed, being heavier they lie to low frequency. As the moment of inertia is a function oJmr2 the shift is roughly proportional to the square of the distance of the substituted atom from the centre of mass.To see that this is roughly correct one can assume all the bonds are the same length and that the c. of m. is in the middle of the central triple bond. The distances of atoms d and c, e and b, and f and a are then in the ratio 1 : 3 : 5 respectively. This should result in isotope shifts 3 in the ratio 1 : 9 : 25. From the above spectrum one can see that this is roughly correct as the ratios are ca. 1 : 10.3 : 26.6. The correct analysis 3is discussed in the text and in Table 6. The ground state linesfor tlic isotopically substituted species are identified 5 w2 2 Semistable Molecules in the Laboratory and in Space only IK I degeneracy but also bending vibrational satellites as well as Me,Si group torsional satellites, that each J + 1 +J transition is a very broad band, composed of many hundreds of unresolved lines.The trimethylsilyl group can be readily hydrolysed off to produce cyano- butadiyne HCEC-CEC-CEN whose broad-band microwave spectrum is shown in Figure 24.1°4 The spectrum is so strong, mainly due to the large dipole moment (p= 4.33 Debye), that naturally occurring 13C and I5N isotopically substituted analogues can be seen even though they are only present in ca. 1 % abundance. The structure of the J = 14 + 13 transition is presented in Figure 25 so that the isotopic satellites and the roughly exponentially decaying vibrational satellites can be seen in more detail.In fact, a very accurate structure determination can be made simply and directly from measurement of these lines alone using the Kraitchman relations.,. 106*107 In the simple case of a linear molecule, the Kraitchman relation shows that, if I is the moment of inertia of a particular species (mass M) and I* is that for a singly substituted species (mass M + Am) then the distance of the substituted atom from the c. of m. ofthe parent species (r,) is given by equation (31) where p = MAm/(M + Am). The Kraitchman analysis yields substitution (r,) co-ordinates, and for the transitions shown in Figure 25 is given in Table 6. The reason for giving a detailed analysis is that this is a very good example of what is arguably the most important structure determination procedure for small molecules and does not appear to be well known outside the field of microwave spectroscopy.The standard method, given in all spectroscopy textbooks, involves the solution of sets of complex quadratic equations, a method which in fact gives relatively poor results as discussed by Co~tain.~,~~~ The resulting structural parameters are compared with those of HC3N108 in Table 6. The vibrational satellites of HC,N can also be analysed in detail on the basis of vibration-rotation theory of linear molecules. This has been carried out to as high as eight quanta of the lowest frequency bending vibration."' A symmetric top has a much more complicated spectrum as shown in Figure 26 for CH3-C~C-C~C-CrN."o Instead of a single line, as in the linear case, the ground state transition is, as discussed in Section 2A, split into K + 1 IKI components, Figure 27.The vibrational satellite structure is more complex and difficult to unravel. The same type of 1-type doubling occurs as in CH3CzP, Figure 16, except that here there are many more contributing low- frequency vibrations to confuse the issue. lo6 J. Kraitchman, Am. J. Phys., 1953, 21, 17. lo' C. C. Costain, J. Chem. Phys., 1958, 29, 864. lo' J. K. Tyler and J. Sheridan, Trans. Faraday Soc., 1963, 59, 2661. lo9 M. Hutchinson, H. W. Kroto, and D. R. M. Walton, J. Mol. Spectrosc., 1980, 82, 394. 'lo A. J. Alexander, H. W. Kroto, M. Maier, and D. R. M. Walton, J. Mol. Spectrosc, 1978, 70, 84. H.w Kroto Table 6 Determination of the substitution bond lengths (r,) of cyanobutadiyneH-C=C-C=C-C=N" AE(13y/ Bd/ IP/ AI~I Speciesb MHz MHz amuA2 amuA2 pg r,hlA H-C=C-C=C-C=N 37 276.99 1331.321 379.6162 -~ __ -D-C=C--C=C-C=N 35 589.32 1271.047 397.6179 18.0017 0.992956 4.2579 H-E=C-C=C-C=N 36 306.63 1296.665 389.7622 10.1460 0.9901 11 3.2011 H-C=E-C=C-C=N 36 894.99 1317.678 383.5467 3.9305 0.9901 11 1.9924 H-C=C-E=C-C=N 36 238.39 1329.943 380.0095 0.3933 0.9901 11 0.63026 H-C~C-C&-C~N 36 242.92 1330.104 379.9635 0.3473 0.9901 11 0.59226 H-C=C-C=C-E=N 36908.73 1318.169 383.4038 3.7876 0.990111 1.9559 H-C=C-C=C-C=fi 36 361.62 1298.629 389.1727 9.5565 0.983955 3.1 165 1.0568 1.2087 1.3621 1.2225 1.3636 1.1606 H-C-C-------CVC-----C'='N A 1.058 1.205 1.378 1.159 H-C- c-------c- N A (a)This calculation has been simplified by neglecting centrifugal distortion so the B values in this table are not quite correct (see ref.104).However, because the structure calculation utilises Ai the discrepancies cancel out and yields a very good structure. (b) * Indicates substituted nucleus. (c) Measured frequency of J = 14 + 13 transition, Figure 25. (d) B obtained neglecting centrifugal distortion, i.e. B = AE(J)/ AZ = i* -Z(H1ZCS14N).2(5 + 1). (e) Z/amu A2 = 505391/B(MHz).(1) (9) p = MAm/(M + Am); M = total mass; masses are: 1.007825, 2.014102, 12.0, 13.00335, 14.00307, and 15.00011 for H, D,12C, 13C, 14N and "N respectively. (h) rc = (AZ/p)lI2. C. Interstellar Molecules.-In the period since 1968 when Townes and colleagues' '' discovered NH, emission by radioastronomy from the direction of Orion, there has been a rapid development in the study of interstellar molecules with numerous exciting and surprising results."' -lo3 The black clouds which congregate in the plane of the galaxy have now been shown, by spectroscopy, to harbour vast quantities of molecules.As these clouds are the raw material from which stars and planets form, molecular spectroscopy is the medium through which the earliest stages of star formation can, for the first time, be observed. The field of interstellar molecules has made a significant contribution not only to astronomy through its impact on the Big Bang Theory, the evolution of galaxies, and the birth of stars but also to Chemistry, Physics, and Biology.New types of chemical reactions must now be considered involving the new types of molecules which are now known to exist under the unusual A. C. Cheung, D. M. Rank, C. H. Townes, D. C. Thornton, and W. J. Welch, Phys. Rei:. Lett., 1968,21, 1701. 40 30 36 34 32 30 28 GH I I 1 I I 1 1 1 I I 1 1 I I Me-CEC-C=C-C=N J = 24 23 22 21 20 19 18 17 16 1 1 1 I I I 1 I I 1 I I A Figure 26 Wide-band scan of the microwave spectrum of CH,C=C-C=C-C=N.' loAs in the case of HC,N thefirst line at the RH end of each J group belongs to the vibrational ground state and the rest to bending vibrational satellites. The ground state lines can be resolved into IKI multiplets under high resolution as shown in Figure 27 H.W.Kroto GHz 37 340 37 330 37 3 !O I I I 1I IKI = Od 4 6 5 Figure 27 Part of the IKI structure of the J = 24 +-23 transition of CH3(C~C)2CN.'lo The higher IKI levels are not suficiently populated so the structure peters out at IK( > 10. Note the increased intensity of lines for I KI a multiple of 3 in agreement with C,, statistical weights3 conditions in space. Perhaps the most interesting aspect of these new findings lies in the light that is shed on the origin of the biosphere. The beautiful photograph by Murdin, Allen, and Malin'" shown in Figure 28 gives a nice feel for what a small region in the Constellation of Orion looks like; a conglomeration of stars and nebulae either cold and black or heated to incandescence by nearby hot stars.The dark areas are very important from our point of view. It was only in ''' P. Murdin, D. Allen, and D. Malin, 'Catalogue of the Universe', Cambridge University Press, Cambridge, Massachusetts, 1979, p. 131, Semistable Molecules in the Laboratory and in Space this century that these regions were shown to be clouds of opaque material rather than, as had been thought in ancient times, holes in the star fields through which one could see deep into space. Rather frail circumstantial evidence indicates that the blackening is caused by micron or submicron sized particles of unknown constitution which scatter light at optical wavelengths. The assignment is frail because it is based on very rough scattering data whose characteristics cannot be ascribed to any other entities.The full importance of the scattering constituent has still to be determined though one thing seems clear, the scattering of starlight protects the molecules in the clouds from photodissociation by the starlight that pervades the rest of space. Although the hot regions have been studied for years by optical spectroscopy it is only since 1968 that analysis of rotational radio or microwave emission from molecules has been able to show that the vast black clouds which litter the space between the stars are full of compounds. In fact, to date, more than 50 different molecules have been detected varying from H,, the most abundant, and CO, the next most abundant, through such species as CH3NH, and OCS to species such as CH,CH20H and HC9N.Radio telescopes are essentially glorified radios with large steerable highly directional aerials. The sensitive detectors and amplifiers can tune in to very weak, narrow-frequency signals. In general a search is made by tuning the radio- telescope to the same frequency* as that determined by the laboratory study, pointing the telescope at a suitable interstellar source and integrating the incoming signal to see whether a molecule is emitting the same frequency or preferably set of frequencies. The first experiments were, of course, searches for common molecules whose microwave lines had already been measured. Occasionally during these experi- ments, lines were detected which corresponded to no known laboratory frequency.One of the most prominent of these unidentified lines (U lines), detected by Buhl and Snyder,'13 was assigned by Klemperer to HCO' (protonated CO).'l4 The assignment was confirmed in laboratory measurements by Woods and co-worker~."~ This and other similar results showed that molecules were important probes of the conditions in interstellar molecular clouds and that, in particular, species such as molecular ions and radicals were relatively stable and abundant in the rarified environment and non-equilibrium conditions that existed. Indeed, the detections indicated that the special conditions in space stabilize some molecules that are very difficult indeed to study in the laboratory.A particular example of this is the case of the interstellar poly-ynes, discovered as a result of the laboratory experiments discussed in the previous section which were, of course, initiated for quite a different purpose. * The frequency is usually adjusted slightly to make due allowance for the Doppler shifts arising from the relative motion of the earth and the celestial object being observed. D. Buhl and L. E. Snyder, Nature, 1970, 228, 267. W. Klemperer, Nature, 1970, 227, 1230. R. C. Woods, T. A. Dixon, R. J. Saykally, and P. G. Szanto, Phys. Rev. Lett., 1975, 36, 1269. H.W. Kroto Figure 28 The long bright emission nebula IC434 silhouetting the well known Horsehead dark cloud in the constellation of Orion (taken from Murdin, Allen, and Malin"2 UKSTU). North is up and East is left in this photograph.The bright star at the top end of IC434 is [ Orionis, the left-hand star of the three in Orion's belt. The nebula NGC2024 lies just to the East (left) of ( Orionis. IC434 glows due to the photoionization by 0 Orionis which is the bright star near the Western (L.H.) edge of the picture Semistable Molecules in the Laboratory and in Space Figure 29 The dark clouds in Taurus from Barnards 1927 Survey. The TMC region is near the LH (SE) corner and the co-ordinates are marked on the edge of the picture D. Interstellar Poly-ynes *..C=C-C=C-C=C-CEC*** ?-As it happened, the study of the poly-ynes, in particular cyanobutadiyne HC=C -CzC -C =N, coincided with the exciting breakthrough in detection of interstellar molecules by radioastronomy discussed above.The observation and analysis of the spectrum of HC,N seemed particularly significant when connected with the roughly simultaneous realization that the previous member of the family, cyanoethyne HC~C-CGN, was a relatively abundant interstellar species. This abundance and the knowledge of the radio frequencies obtained from the spectrum in Figure 24 suggested that HC,N might be detectable by radioastronomy and prompted an enquiry to Takeshi Oka, who had been a former colleague at N.R.C. Ottawa, to see whether he was interested in collaborating in such a search.* * He wrote back to say that he was ‘very, very, very, very, very much interested’ H.W.Kroto The J = 4+ 3 transition was subsequently detected in collaboration with Lorne Avery, Norm Broten, and John MacLeod' l6 using the N.R.C. 46 metre telescope in Algonquin Park in Canada. At the time the detection of HC,N was very exciting as it had six heavy atoms, two more than any molecule previously detected (such as HC,N). A semi-quantitative view of the chemical situation at the time (1976) indicated that small molecules with one or two heavy atoms (C, N, or 0)tended to be fairly abundant and that after two, each successive heavy atom tended to reduce the abundance by a factor of ca. 10. This rough rule seemed to make sense in the light of some vague statistical reasoning based on the apparent molecular composition of the interstellar medium.Some doubts, however, about the applica- bility of this rule to the HC,N (a = 1, 3, or 5) family began to creep in. Indeed, searches for these types of molecule (Morris et a!.,' Churchwell et al.,"* and Little et indicated that there were clouds, such as TMCl (Taurus Molecular Cloud 1) with very high HC3N and HC,N abundances. This cloud is in the LH bottom (SE) corner of the photograph (Figure 29) published by Barnard'" in 1927. In this beautiful picture dark clouds, which contain molecules, streak across the sky obscuring the myriads of background stars. The detection of HC5N together with the unexpectedly high abundance clearly promised the possibility of detecting the next poly-yne, HC,N, and urged us accordingly to attempt its synthesis and analysis, which turned out to present some difficulties.The main problem lay in the last step in which the rather involatile and reactive HC,N had to be vapourized into the microwave cell. It was essentially a nip-and-tuck situation in which the sample holder temperature was raised enough to obtain a sufficient cell vapour pressure but not so high that the sample decomposed completely. This turned out to be just feasible. The resulting spectrum, of which part is shown in Figure 30, was in fact decaying because of sample decomposition during this run. The spectrum shows three J + 1 +J transitions consisting of distinct bunches of lines. The strong ground-state lines stand isolated to the RH (low frequency) side of the rest, which are the multitude of bending vibrational satellites.Because the molecule is so long there are several very low frequency bending modes which give rise to satellites with v (and associated combinations) as high as 15. A good estimate of the Bo value can be obtained from the spacing between adjacent ground state lines and a rather better value by dividing a given J + 1 +J frequency by 2(5 + l), neglecting centrifugal distortion corrections which are relatively small. The accurate analysis allowed a successful search for the L. W. Avery, N. W. Broten, J. M. MacLeod, T. Oka, and H. W. Kroto, Astrophys. J., 1976. 205. L173. 'I' M. Morris, B. E. Turner, P. Palmer, and B. Zuckerman. Astrophys. J., 1976, 205, 82.'" E. Churchwell, G. Winnewisser, and C.M. Walmsley, Astron. Astrophys.. 1978, 67. 139. C. T. Little, G. H. Macdonald, P. W. Riley, and D. M. Matheson, Man. Not. R .4stron. Sot,.. 1978, 183, 45. E. E. Barnard in 'Atlas of Selected Regions of the Milky Way'. ed. E. B. Frost and R. Cahert. Carnegie lnstitute of Washington, 1927. 481 Figure 30 Three AJ = + 1 transitions in the microwace spectrum of HC7N.121The RH line in each group belongs to the vibrational ground state: the rest are bending vibrational satellites and there are many of them because the molecule is long and readilyjexes. In the cold clouds the temperature is so low that the vibrational states are not populated and all the intensity crowds into the ground state lines 12' C. Kirby, H. W. Kroto, and D. R. M. Walton, J.Mol. Specrrosc., 1980, 83. 261. H. W.Kroto J = 10 +9 line to be made.* 122 The first oscilloscope trace of this detection is shown in Figure 31. Not only had HC,N been detected but again the intensity was high, suggesting that perhaps there was something special about the chemistry that gave rise to these species. Of course, the next step, the quest for HC9N was obvious though the route to detection much less so. A synthetic scheme could be worked out but the problems which beset us with the last step for HC,N could surely only be compounded for HC9N. Just as the initial synthetic Figure 31 A photograph of the raw data for the initial detection of interstellar HCGC-CEC-C=C-C=N.'~~ Each dot represents data in a 10 kHz wide channel. The spectrum was observed from the cold cloud TMCl which yields very narrow lines no more than lOkHz wide.The range was centred so that the line should lie in one or two of the central three channels. The high signals in the central two channels indicate that radiation at the expected frequency has been detected * Because of the above experimental snags, the experiment to observe the microwave spectrum at Sussex had still not been successful when the earmarked observing session at the Algonguin Observatory started. However, about half-way through the session Colin Kirby back at Sussex finally succeeded and analysed the spectrum to obtain the rotational constants. He telephoned my wife, she telephoned a friend in Ottawa, and he telephoned the observatory and so the priceless B, and Do values were transferred (without error).Together with my Canadian collaborators, we tuned the telescope to a possible frequency and the observing session began. At 01.00 after some six hours of integration during which time only the results of individual 10 minute integrations had been available the signal shown in Figure 31 appeared, for the first time, on the oscilloscope screen. The circumstances had made the experiment exciting. lz2 H. W. Kroto, C. Kirby, D. R. M. Walton, L. W. Avery, N. W. Broten, J. M. MacLeod, and T. Oka, Astrophys. J., 1978, 219, L133. 483 Semistable Molecules in the Laboratory and in Space steps were initiated Takeshi Oka discovered a neat, simple, and surprising empirical technique which enabled the B, value of HC9N to be predicted with quite remarkable accuracy by extrapolating from the known values of HC,N with n = 1, 3, 5, or 7.123The J = 18 -+ 17 (Figure 32) and J = 25 +24 lines were detected and indicated that B, = 290.5185 f0.002 as compared with the predicted value of 290.523MHz!'~~The ratios of HC,N species with n = 3, 5, 7,9 turned out to be 10:5.0: 1.2:0.32re~pectively.'~~HC9N has still not been observed in the laboratory nor is it probably worth the effort as its spectrum is measurable more readily and with higher accuracy by Radioastronomy.It is now clear that even longer species can now be searched for using the extrapolation technique and indeed HCllN has been detected by Bell et al.I2' and there may be no obviously foreseeable limit, though the available signal to noise may provide the most immediate stop.This technique should also work for the related radicals such as C6H and C5N since C2H, C4H, CN, and C3N 0.02-HC,N -J =18-17 y 0.01 ---2 YG krb 0-OOJ v!JUCa# s -0.01 --1 I Figure 32 The spectrum of HC9N detected by radioastronomy. In astronomy the intensity is usually given in terms of the Antenna temperature. The abscissa indicates that the frequency of the signal differs from that in the laboratory by an amount (the Doppler Shift) consistent with a 5.9 kms-' relative velocity of the source and the earth. All signalsfrom TMCl show exactly the same Doppler Shft so the frequency adjustment is known lZ3 T.Oka, J. Mol. Spectrosc, 1978, 72, 172. lZ4 N. W. Broten, T. Oka, L. W. Avery, J. M. MacLeod, and H. W. Kroto, Astrophys. J., 1978,223, L105. lZ5M. B. Bell, S. Kwok, P. A. Feldman, and H. E. Matthews, Nature, 1982, 295, 389. H. w.Kroto have all been observed. An important aspect of the recent studies is that the poly-ynes as well as C3N and C4H seem to be particularly abundant in the expanding gaseous envelope which surrounds the cool carbon star IRC + 10216.103 5 Discussion There are a few general points that seem to be worth making in this summary. Microwave spectroscopy is a technique which has in the past been rather difficult to apply* and in general has been used by chemical physicists to make detailed studies of molecular structure and other molecular parameters such as those obtainable from vibration-rotation analysis.It is, however, a very flexible technique and in recent years a few groups have used it to make significant contributions to other areas: Oka to collisional energy transfer,'26 Legon and Millen to the study of weakly bound complexes,127 Johnson and L~vas~~ as well as Hirota, Saito, and co-workers' 28 to unstable molecules. Cross-field applicationof expertise is in general valuable. In this work the main philosophy has been to study problems of intrinsic chemical interest; essentially to use microwave spectroscopy, backed up synergistically by other techniques such as photoelectron spectroscopy, to carry out main group chemistry on compounds not accessible by standard chemical techniques.It has been traditional to hang on heavy groups in order to stabilize elusive moieties and then use the entity in further reactions. In the present approach, however, the aim has been to find a route to semi- stable species, characterize them and develop techniques for further reaction. The last aim is now being developed as shown by reactions such as (28) in which NCCP was made from HCP on line. It is probably worth noting that the very properties that are smothered by substituent group stabilization may be the most valuable that these moieties have. Indeed, it is probably the differences between related species rather than their similarities that are most important and likely to lead to new chemistry.To force them into some pre-ordained mould may by-pass important features. The low-pressure operational conditions of the microwave and photoelectron techniques have been critical in slowing down the polymerization or decomposi- tion rates sufficiently to facilitate detection. In retrospect there has been a sub- conscious tendency to avoid modifying the equipment and instead tailor experiments by, for instance, apposite precursor synthesis to exploit those virtues of the basic instrument that experience has uncovered. For instance, the micro- wave cell which consists of a 1 metre metal tube allowing (rather difficult) access only at the ends offers outstanding sensitivity. Although it is poor for the * It will again become difficult to apply since Hewlett Packard, the only firm to market, successfully, a commercially viable instrument, no longer makes it.lt6 T. Oka, Adu. At. Mol. Phys., 1973, 9, 127. 12' J. W. Bevan, Z. Kisiel, A. C. Legon, D. J. Millen, and S. C. Rogers, Proc. R. SOC. London, Ser A. 1980, 372, 441. 12* E. Hirota, S. Saito, et al.,Annual Review, Institute for Molecular Science, Okazaki National Research Institutes, Japan, 1980, pp. 38-51; 1981, pp. 29-46. 485 Semistable Molecules in the Laboratory and in Space detection of free radicals, which decay too quickly, it is excellent for species of intermediate stability which last long enough effectively to fill a 1-2 metre active length at moderate flow rates. Technical reasons have prevented the beautiful spectroscopic patterns from being displayed in early microwave studies.The data have, in the past, been presented as inedible tabulations of relatively large numbers which mask the patterns and preclude recognition. Indeed, it is the initial observation, together with abstract pattern recognition, which is the cathartic experience that drives this and many other types of research. As a consequence it has been a very important objective in this work that these patterns be displayed in the literature and in this review a range of textbook examples has been presented. The general result of this work is that the chemistry of: >C=S, >C=Se, -B=S, -B=Se, >C=P-, and -C=P containing species has been either extended or initiated so that they can now take their place beside their well- studied first row counterparts, the carbonyls, imines, and nitriles and be considered as viable functional groups in their own right.Some specific points about the various groups of molecules studied are dis- cussed below. A. Thiocarbonyls and Selenocarbony1s.-As far as thiocarbonyls are concerned they were the first group to be studied and were used to hone the experimental techniques. They were also rather easily handled, after all OCS is a well known species being, apart from the smell, rather well-behaved. Thiocarbonyls seem to be sufficiently close in stability to carbonyls that traditional chemistry can handle them except for the simplest ones such as CH,=S. Even Me,C=S seems to be relatively stable.As well as the thiocarbonyls, the selenocarbonyls can also be studied though with somewhat more difficulty. The major technical problem is probably the incredible persistence of the smell and the apprehension with regard to selenium’s reputation as a poison, a reputation almost entirely based on the properties of H,Se. It is probably the close similarity between Se and S in organic configurations that is responsible for the blocking of metabolic pathways. The results do indicate that with some modification of technique such molecules as CH2=S and MeCH=S could be useful reactants with parallel chemical behaviour to the aldehydes and ketones. B. Sulphidoboron Compounds.-It seems curious that oxoboron molecules seem to be less stable than the analogous sulphidoboron molecules.This is based on the circumstantial evidence that they have not been detected by the techniques that produced the sulphidoborons. The yields of the halides, especially ClBS, are excellent as witnessed by the p.e. data, but rather poor in the case of MeBS which presumably reflects the alternative reactions which the precursor may follow. The structural data indicate that the B=S bond length is relatively constant at 1.604& 0.004A for the analogues studied. The nitriles show a similar degree H.W. Kroto of bond length inflexibility. MeBS presents the first example of a bond between sp3 hybridized carbon and sp hybridized boron. An increase of 0.066 8, occurs in r(C-B) between MeBS and MeBF, where it is 1.534 A and 1.60A respectively.This is in good agreement with the ClBS/C1BF2 system where it increases from 1.6818, in ClBS by 0.047 8, to 1.728 8, in ClBF, . The mechanism for producing sulphidoborons is probably complicated. Detailed searches have not yielded any evidence for XSB isomers which, if formed, would probably be too short-lived for our detection techniques. An alternative mechanism follows from known reactions of C1,S2 and boron. C1,S2 decomposes above 300°C to form C1, and sulphur, and boron reacts with C1, and sulphur at elevated temperatures to form BC13 and B2S2. Further, it is known that BC13 reacts with B203 to form ClB0.12’ Thus, an alternative reaction, equation (32), is possible. C1,S2 A C12 + S BC13 + B2S, A ClBS (32) The photoelectron data on ClBS have provided circumstantial evidence for such a scheme in that large quantities of BC1, are produced at temperatures below those needed to form ClBS.From the analysis of the quadrupole structure of ClBS an estimate of the character of the Cl-B bond can be obtained. This indicates that the bond has 0.5 0 character, 0.23 7t character, and 0.27 ionic character.48 An almost complete, apart from IBS, photoelectron correlation diagram can now be drawn as shown in Figure 14. This shows that for the 7t(B=S) system there is a gradual destabilization with substituent. The order of stability is: H > F > C1 > Br in line with an increase in electron density due to the effects of hyperconfiguration.In the o(B=S) system the introduction of F stabilizes this orbital in line with the expected withdrawing inductive effects. The effect of C1 and Br in this case is negligible. Preliminary theoretical calculations indicate some interesting features about the XB=S system which relate to the question of whether there is a double or triple bond between boron and sulphur. There are two electrons in the o(BS) orbital and four in the degenerate 7t(BS) orbitals, so one might expect a major -+ contribution from a valence configuration such as XB=S implying a build-up of charge on the boron. This does not appear to be the case as the boron, at least according to preliminary Gaussian 70 calculations, is effectively uncharged. It turns out that the electron density in the 7t orbitals resides mainly on the sulphur atom and the two 7t bonds are roughly half-strength, The initial indication is that the net effect is roughly that of a double bond because the 7t orbitals have 50 :50 bonding :non-bonding character.C. Phospha-alkenes and Phospha-a1kynes.-The results on phospha-alkenes and phospha-alkynes have shown that the family resemblance between P and N in multiple bond configurations is considerably closer than chemists realised. In fact lZ9 J. Blauer and M.Forber, Trans. Faraday SOC., 1962, 58, 2090. Semistable Molecules in the Laboratory and in Space it is somewhat surprising, in the light of such results as the ease of production of FCP and the stability of t-BuCP as well as the big hints implicit in the existence of HCEP and phosphabenzene, that the field did not open up much sooner. The reason for the lack of awareness was probably the fact that these compounds are just past the threshold of attack by traditional chemical techniques. They are onlyjust past this threshold as such molecules as MeCP can be retrieved after trapping, but this is not the case for the sulphidoborons which appear to form trimers before revaporizing.In these experiments there has also been no evidence for isomers of the form XPC analogous to the isonitriles. From the general structural study one can obtain the following covalent radii for phosphorus. P C Sum sp 0.94 0.60 1.54 A CH,CGP sp2 1.00 0.67 1.67 A CH,=PH aromatic sp2 1.03 0.70 1.73 A C,H,P sp3 1.07 0.77 1.84 A CHJPHl The photoelectron data indicate that the .n(C=P) orbital is the HOMO which fits in nicely with the fact that n-complexes such as the Pt compound, Figure 22, can be made.In the case of HCN the o and .n orbitals have almost identical ionization energies in line with the co-ordinating properties of nitriles. In some respects, particularly in its co-ordinating ability, HC rP behaves more like HC=CH than HC=N. D. Multiply Bonded Si.-An important series of molecules represented on the CH20 cube in Figure 1 has not featured in the experimental work summarized in previous sections. The sila-alkene family related to CH2=SiH2 is absent, though not for want of trying. As pointed out in Section 1, the techniques applied have not in general involved the custom construction of equipment designed to catch veryelusive species (i.e.species with lifetimes of ca.10-3-10-6 s) but rather are aimed at those which are just fickle (i.e. lifetimes of ca. 1s). Our experiments on Si=X species have indicated that they have very elusive spirits indeed, with reactivities comparable with those of small free radicals. The family resemblance between C and Si is very much less obvious and the generation gap that exists is perhaps most spectacularly exemplified by the difference between a sample of C02 and a sample of Si02. The reluctance of Si=X species to submit to the techniques of Section 2 led to a theoretical study of the problem as a last re~ort.’~’”~’ This showed that Si has a strong tendency to remain divalent which manifests itself critically during attempts to produce multivalent configurations.This tendency is experimentally apparent in the relative stability of SiF2 compared with that of CF2, which readily forms CF2 =CF2. 13* J. N. Murrell, H. W. Kroto, and M. F. Guest, J. Chem. SOC.,Chem. Commun., 1977, 619. lJ1H. W. Kroto, J. N. Murrell, A. Al-Derzi, and M. F. Guest, Astrophys. J., 1978, 218, 886. H. w.Kroto Some early results of Gusel'nikov and Flowers' 32 presented circumstantial evidence for >Si =C :type intermediates in pyrolysis experiments on cyclic silaethenes. More recently Brookes et al.133have succeeded in using large stabilizing groups to form such molecules as (Me,Si),Si =C(OSiMe,)adamantyl which has been characterized by X-ray analysis.A very interesting result was obtained by Leclercq and Duboi~'~~ who detected the transient species CH, =Si during flash discharge experiments in MeSiH,. This observation is in circumstantial agreement with the theoretical prediction that Si prefers to be divalent and that in this case CH,=Si is much more stable than HC=SiH.13' This study also indicates that HN=Si is much more stable than HSi=N, which is of course a reversal of the HNC/HCN situation.'30*'31 E. Poly-ynes.-The original reason for studying the poly-ynes lay in their simplicity and the consequent tractability of their rotational spectra. In addition their dynamic behaviour should be simpler than that manifested by other molecules.The spectra and the basic analysis have already been discussed and the resulting data show some interesting points. The accurate structural study Table 6 provides a textbook example of delocalization in extended conjugated systems. As the conjugated system extends from HC3N to HC5N delocalization increases the lengths of the triple bonds and decreases the lengths of the single bonds, expecially near the middle of the chain. For instance r(CrC) increases from 1.205 8, for HC3N to 1.2225A for HC5N. The bond lengths show a general trend which is manifested by the success of the extrapolation technique used by Oka to estimate the Bo values (previous section). A second indicator of good behaviour is the excellent transferability of structural data.This has recently been shown by N=C-CsC-C=P whose experimental B, value was found to be 873.480MH~.*~ This can be compared with an estimated value of 873.66MHz based on [NrC-CrC] lengths taken directly from the appropriate part of HC,N and a [C-CEP] structure taken from that of N~c-csP. The vibration-rotation analysis for such species is clearly quite severe as indicated by Figures 25 and 30. An analysis for HC5N has been carried out which has shown that the transitions involving highly excited vibrational modes are well explained by the standard theory which governs general vibration- rotation beha~iour.'~' This was a little surprising as the instinctive feeling is that molecules in such states are very bent systems on average, and that a theory based, as this was, on a small amplitude approximation might show signs of breakdown.F. Interstellar Poly-ynes.-The origin of interstellar molecules has been the subject of numerous studies and radio observations have instigated much 132 L. E. Gusel'nikov and M. C. Flowers, J. Chem. SOC., Chem. Commun., 1967, 864. 133 A. G. Brook, F. Abdesaken, B. Gutekunst, G. Gutekunst, and R. K. Kallury, J. Chem. SOC., Chem. Commun., 1981, 191. 134 H. Leclercq and I. Dubois, J. Mol. Specrrosc., 1979, 76. 39. Semistable Molecules in the Laboratory and in Space recent work. In particular, gas phase ion-molecule reactions and grain surface catalysis have been invoked. The detection of long chains, however, has presented severe problems to the acceptance of these processes.It is certainly not clear that ion-molecule reactions can build up such chains preferentially with respect to branched species, especially as branched ions are generally expected to be more stable. Indeed, if there are analogous, branched hydrocarbon species in commensurate numbers with the C, chain molecules, the clouds must contain significantly more molecules than ever considered possible. It is also not at all clear that the chains can be formed on grains as it is seemingly impossible for them to desorb at the low temperatures that exist in clouds such as TMCl (ca. 10-30 K). The chemistry is not clear but the most recent results do indicate that some molecules are formed in the envelopes of cool stars.The cool star IRC+10216, which has a high carbon to oxygen ratio, has now been shown to be pumping out molecules, in particular the chains. In addition, it seems tq be pumping out grains. It may well be that in these stars grains and chains' are formed at roughly the same time but whether there are enough of these stars to account for the colossal quantities of molecules now known to exist is not clear. Suffice it to say, the interstellar studies have shown that some very long molecules exist in the space between the stars. They may be very long indeed and their relationship with grains is far from being understood. In fact, it is only now that a possible relationship can even be ~ontemp1ated.l~~ The long chains may be an intermediate form of carbon, between atoms and small molecules such as C, C2, and C3, which are well known, and particles with high carbon content such as soot.Another factor is that chains of this length must be good scatterers of radiation due to their electronic properties and so it is even possible that they are the grains.lo3 Douglas has suggested that the chains give rise to the so-called Diffuse Interstellar Lines.'35 These are a set of some 40 broad interstellar features in the visible spectroscopic region which have perplexed astronomers for nearly 50 years. The latest data indicate that some new experimental and theoretical work on the mechanism of precipitation of particles from carbon vapour is necessary. The interaction of radiation with these chains also should be studied to see how it might relate to the quantitative interstellar scattering characteristics.Finally, the interesting general point is that these molecular clouds are the raw material out of which stars and particularly planets form. The mechanism of planet formation is still far from clear and indeed the relationship of the molecules in these clouds with those in the earth's atmosphere is even less clear. We now know that molecules are formed in stars and pushed out into space. There are now, therefore, three known ways in which bio-emotive molecules, such as glycine, can be formed: (1) in the biosphere by Urey-Miller type processes; (2) in the cold interstellar clouds by ion-molecule reactions and perhaps also by grain catalysed processes; (3) in reactions in circumstellar shells.135 A. E. Douglas, Nature, 1977, 269, 130. H.W. Kroto There is clearly an inexorable drive to form the molecules that are the building blocks of life. Indeed, the new results suggest that one should consider whether the circumstellar molecules might actually have survived the transition from circumstellar shell to the molecular cloud, protected from photolysis by starlight in a symbiotic relationship with the grains, and perhaps accreted into planetary atmospheres more or less intact during a later cooler phase of planet formation. The new results herald a new look at not only the origin of the biosphere but also a new look at the mechanism of grain formation and grain identity, as well as the formation of larger objects such as planets.Acknowledgements. It is a great pleasure to acknowledge the hard work of my co-workers in this research: Anthony Alexander, James Burckett-St. Laurent, Allan Careless, Terry Cooper, Krini Georgiou, Marcus Durrant, Mike Hutchinson, Mike King, Colin Kirby, Barry Landsberg, Don McNaughton, Mike Maier, Osamu Ohashi, Keiichi Ohno, Nigel Simmons, Roger Suffolk, and Nick Westwood. I should also like to acknowledge the debt I owe to my Sussex colleagues, John Nixon with whom the phosphorus work has been carried out and David Walton with whom the poly-ynes were studied. In addition the help and encouragement of Michael Lappert, Bill McCrea, John Murrell, and Jim Watson have been consistent and invaluable. Finally, it has been a pleasure to collaborate with Takeshi Oka, Lorne Avery, Norm Broten, and John MacLeod in the radio- astronomical work.491

ISSN:0306-0012    

DOI:10.1039/CS9821100435

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

Silicon-containing Carbonyl Equivalents By David J. Ager DEPARTMENT OF ORGANIC CHEMISTRY, ROBERT ROBINSON LABORATORIES, P.O. BOX 147, LIVERPOOL, L69 3BX* 1 Introduction Despite the advances made in the field of organosilicon chemistry and the numer- ous synthetic methods which rely on the properties of silicon, the use of this element in acyl anion equivalents has received little attention compared to other elements such as sulphur. Indeed, the area of acyl anion equivalents and other urnpolung’ reagents has been dominated by sulphur compound^.^-^ It is the aim of this review to discuss the use of silicon reagents in this role; general organosilicon chemistry will not be considered as there are already many excellent For the purposes of this article, only compounds which have the silicon atom bonded directly or through one heteroatom to the carbon atom which is to become the carbonyl carbon and are urnpolung reagents have been considered.This means that 0-silylcyanohydrins are looked at but 0-silylenol ethers have been omitted.’ 2 Vinylsilanes and cx,&Epoxysilanes Vinylsilanes as carbonyl equivalents was one of the first uses for these compounds in organic methodology.12 The large number of methods of preparation and reactions of these compounds’ has made vinylsilanes useful synthetic tools besides providing a method for the synthesis of carbonyl compounds uia cr,/?-epoxysilanes. Vinylsilanes (1) have been prepared from acetylenes by a variety of routes which are summarized in Scheme 1. Silanes have been added to acetylenes in the presence *Present address: Department of Chemistry, University of Toledo, 2801 West Bancroft St., Toledo, Ohio 43606, United States of America.D. Seebach, Angew. Chem., Int. Ed. Engl., 1969, 8, 639; 1979, 18, 239.’B.-T. Grobel and D. Seebach, Synthesis, 1977, 357. 0. W. Lever, Tetrahedron, 1976, 32, 1943. S. F. Martin, Synthesis, 1979, 633. I. Fleming, Chem. Ind., 1975, 449. T. H. Chan, Acc. Chem. Res., 1977, 10, 442.’E. W. Colvin, Chem. Soc. Reti., 1978, 7, 15. * I. Fleming in ‘Comprehensive Organic Chemistry’ ed. D. H. R. Barton and W. D. Ollis, Pergamon, Oxford, 1979. vol 111, p. 541g I. Fleming, Chimica, 1980, 34, 265. lo P. Magnus, Aldrichimica Acta, 1980, 13, 43. I. Fleming, Chem.SOC.Reti., 1981, 10, 83. G. Stork and E. Colvin, J. Am. Chem. Soc., 1971, 93, 2080. l3 T. H. Chan and I. Fleming, Synthesis, 1979, 761. Silicon-containing Carbonyl Equivalents of a platinum catalyst,'2*'4-19 but because of the lack of regioselectively a terminal acetylene which leads to a 1-silylalkene,or symmetrical acetylene have normally been used. The cuprate derived from dimethylphenylsilyl-lithium added to acety-lenes with some regioselective control; this method has the added advantage that the resultant vinylcopper compound can react with a variety of electrophiles to give functionalized vinylsilanes.20 Other organometallic reagents which have been added to silylacetylenes (2) or acetylenes and the resultant vinylmetallic reagent treated with a silyl halide are organocuprates,21*22organoboranes,'6,23*24 R2 ---organo-aluminium compounds,*5,26 and Grignard reagents catalysed by ni~kel.~ Rl R2--Rl - -SiR3 - R2-i-SiR3 R3-=- - SiR3 - (2) Reagents: (i) R' = R3 = Por R' = R2, R3 = H; R3SiH, HzPtC16 (ref.12, 14-18). (ii) R' = R2 or R2 = H; (a) (PhMe,Si),CuLi.LiCN/THF/O"C, (b) R3X (ref. 20). (iii) R' = R3 = H; (a) RZ2CuMgXor R2CuX.MgX/THF, (b) H20 (ref. 21). (iv) R' = RZ= H; (a) R2,CuLi, (b) Me3SiC1 (ref. 22). (v) R' = R2 = H; (a) (c-C6H,,)BH/THF, (b) AcOH/A (c) H,O,/-OH (ref. 23). (vi) R2 = H; (a) (c-C6Hll)BH/THF, (b) MeLi, (c) CuI, (d) P(OEt),/HMPA/R'X (ref. 24). (vii) R2 = H; (a) Dibal-H/R43N, (b) MeLi, (c) R'X (ref. 25). (viii) R2= Me; (u) Ni(acac),/Me,Al/MeMgBr/THF, (b) R'X (ref.27). (ix) R3 = H; (a) Dibal-H, (b) MeLi, (c) R'X (ref. 25, 26). Scheme 1 l4 R. A. Benkeser, M. L. Burrows, L. E. Nelson, and J. V. Swisher, J. Am. Chem. Soc., 1961, 83, 4385. l5 G. Stork, M. E. Jung, E. Colvin, and Y. Noel, J. Am. Chem. SOC.,1974, %, 3685. l6 P. F. Hudrlik, D. Peterson, and R. J. Rona, J. Org. Chem., 1975, 40, 2263. l7 P. F. Hudrlik and C.-N. Wan, Synth. Commun., 1979, 9. 333.'* K. Yamamoto, 0.Nunokawa, and J. Tsuji, Synthesis, 1977, 721. l9 G. H. Wagner, U. S. Patent, 2637738; Chem. Abs., 1954, 48, 8254. zo I. Fleming and F. Roessler, J. Chem. SOC.,Chem. Commun., 1980, 276; I. Fleming, T. W. Newton, and F. Roessler, J. Chem. SOC., Perkin Truns. 1, 1981, 2527. 21 H. Westmijze, J. Meijer, and P.Vermeer, Tetrahedron Lett., 1977, 1823. 22 A. Alexakis, G. Cahiez, and J. F. Normant, Synthesis, 1979, 826. z3 R. B. Miller and T. Reichenbach, Tetrahedron Lett., 1974, 543. z4 K. Uchida, K. Utimoto, and H. Nozaki, J. Org. Chem., 1976,41, 2941; Tetrahedron, 1977, 33, 2987. 25 J. J. Eisch and G. Damasevitz, J. Org. Chem., 1976, 41, 2941. z6 K. Uchida, K. Utimoto, and H. Nozaki, J. Org. Chem., 1976, 41, 2215. "B. B. Snider, M. Karras, and R. S. E. Conn, J. Am. Chem. SOC., 1978, 100, 4624. Ager Silylacetylenes have been reduced to the vinylsilane by hydrogenation in the presence of a poisoned palladium catalyst12 or Raney Vinylsiianes have also been prepared by a Diels-Alder reaction of a silylacetylene with a dieneZ9 or of a silyl-substituted diene with an appropriate dien~phile.~' Vinyl halides have been used as precursors to vinylsilanes; the required trans- formation has been achieved by Wurtz co~pling'~*~~-~~ via the ~inyl-lithium~~,~' (this method has been used to prepare functionalized ~inylsilanes~~),high temperature^,^ or palladium catalysis3' (see Scheme 2). Elimination of a hydrogen halide,39-42 water,43 or an ester44 from an appro- priately substituted silane leads to vinylsilanes.The most useful reaction of this type i or ii1 Reagents: (i) R = Me, R3 = H; Na/Et20/Me3SiC1 (ref. 31--33). (ii) R = Me, R3 = H; (a) t-BuLi/low temp., (b) Me,SiCl (ref. 34, 35). (iii) R = C1, R' = R2 = R3 = H; Si/SnCI2 or CuC1/55O0C (ref. 37). (iv) R = Me,Cl,-, ; (CI3-,Me,Si,)/Pd(PPh,), (ref.38). Scheme 2 ** K. Atsurni and I. Kuwajima, Tetrahedron Lett., 1977, 2001. ''R. F. Cunico, J. Org. Chem., 1971, 36, 929. 30 J. W. Ryan and J. L. Speier, J. Org. Chem., 1966, 31, 2698. 3' M. Kanazashi, Bull. Chem. Soc. Jpn., 1953, 26, 493. 32 A. D. Petrov, V. F. Mironov, and V.G. Glukhovtsev, Zh. Obshch. Khim., 1957,27, 1535; Chem. Abs., 1958, 52, 36689. 33 G. Nagendrappa, Synthesis, 1980, 704. 34 D. Seebach and H. Neumann, Chem. Ber., 1974, 107, 847. 35 H. Neumann and D. Seebach, Tetrahedron Lett., 1976, 4839; Chem. Ber., 1978, 111, 2785. 3h For example: J. S. Swenton and E. L. Fritzen, Tetrahedron Lett., 1979, 1951 and references cited therein; C. Shih and J. S. Swenton, Tetrahedron Lett., 1981, 22, 4217. 37 C. 0.Strother and G.H. Wagner, U. S. Patent, 2532430; Chem. Abs., 1951, 45, 2968e. 38 H. Matsumoto, S. Nagashima, T. Kato, and Y. Nagai, Angew. Chem., Int. Ed. Engl., 1978, 17, 279. 39 F. K. Cartledge and J. P. Jones, Tetrahedron Lett., 1971, 2193. 40 C. L. Agre and W. Hilling, J. Am. Chem. Soc., 1952, 74, 3895. 41 L. H. Sommer, D. L. Bailey, and F. C. Whitmore, J. Am. Chem. Soc., 1948, 70, 2869. "S. N. Ushakov and A. M. Itenberg. J. Gen. Chem., 1937, 7, 2495; Chem. Abs., 1938, 32, 2083. 43 H. Gilman, D. Aoki, and D. Wittenberg, J. Am. Chem. Soc., 1959, 81, 1107. 44 F. A. Carey and J. R. Toler, J. Org. Chem., 1976, 41, 1966. 495 Silicon-containing Carbonyl Equivalents is shown in Scheme 3, although it should be noted that the isomers of the B-hydroxyselenide (3a and 3b) have to be separated.45 R SiMeg OH 1.Bu"Li 2. RCHO R' 'H SeMe SeMe R' R R ' (3a) (3b) P0Cl3 -NEt3 -CH2C12I Me3Si R R Scheme 345 Vinylsilanes have been prepared from ketones via the corresponding sulphonyl- hydrazones (4)46-48(see Scheme 4)and, hence, it is possible to protect a ketone as a vinylsilane. qNHso2Ar , ,R' ArSO NHNH 1. n-BuLi--TMEDA $'R' 2. Me3SiCI R2 R2 (4) (1) Scheme 44648 In addition to the anions produced by the addition of organometallic reagents to silylacetylenes (2)(vide supra),anions derived from vinylsilanes have been used to synthesize other vinylsilanes by reaction with alkyl haiide~,~'-~ carbonyl 45 W. Dumont, D. Van Ende, and A. Krief, Tetrahedron Lett., 1979, 485.46 T. H. Chan, A. Baldassare, and D. Massuda, Synthesis, 1976, 801. 47 R. T. Taylor, C. R. Degenhardt, W. P. Melega, and L. A. Paquette, Tetrahedron Lett., 1977, 159. 48 A. R. Chamberlin, J. E. Stemke, and F. T. Bond, J. Org. Chem., 1978, 43, 147. 49 B.-T. Grobel and D. Seebach, Angew. Chem., Int. Ed. Engl., 1974, 13, 83. 50 B.-T. Grobel and D. Seebach, Chem. Ber., 1977, 112, 867. 51 A. G. Brook, J. M. DufF, and W. F. Reynolds, J. Organornet. Chem., 1976, 121, 293. 52 D. Seyferth, J. L. Lefferts, and R. L. Lambert, J. Organomet. Chem., 1977, 142, 39. 53 G. Zweifel and W. Lewis, J. Org. Chem., 1978, 43, 2739. 54 R. F. Cunico and F. J. Clayton, J. Org. Chem., 1976, 41, 1480. 55 C. Huynh and G. Linstrumelle, Tetrahedron Lett., 1979, 1073.496 Ager corn pound^,^^*^^-^^ a,B-unsaturated carbonyl corn pound^,^^^^^-^^ acid anhydride^,^' or epoxides66 (see Scheme 5). i -is1 Br SiR3 n-Bu3S!iR3./ Reagents: (i) R3 = H; (a) BuLi, (b) R'X (ref. 49-53). (ii) R = Me, R2 = H; R',CuLi (ref. 53). (iii) R = Me; (a) Mg, (b) Cu'/R'X (ref. 55). (iv) R2 = R3 = H; R' = R4RsC(OH)-; (a) BuLi, (b) R4R5C0 (ref. 49, 56, 57, 61). (v) R = Me. R2 = H, R' = CH,R4; (a) t-BuLi, (b) R3CH0, (c) S02C12,(d)R42CuLi (ref. 58,59). (vi) R = Me, R3 = H, R' = CH2R" ;(a)t-BuLi, (b) R2CH0, (c) AcCI/AgCN, (d) R4,CuLi (ref. 58, 60). (vii) R = Me. R' = R6C(0)CH2CR4R5-; (a) t-BuLi or Mg, (b) CuI, (c) R'R5C=CHC(0)R6 (ref. 55. 62-64). (viii) R' = R4CO; (a) t-BuLi or Mg, (b) R2 = R3 = H, R' = -CH(R4)C(OH)R5R6; (a)Mg, (b) R' = R3 = H; (a)n-BuLi/-70 "C, (b)R2X (ref.54). (xi) as (iii) but with RZX (ref. 55). (xii) as (vii) but R2 = R6C(0)CH2CR4R5 (ref. 55, 62-64). (xiii) as (viii) but R2 = R4C0 (ref. 65). Scheme 5 The Peterson reaction,67 the silicon equivalent of the Wittig reaction, provides another method for the preparation of vinylsilanes. The required a-silylanions have been prepared from the parent ~iIane,~'*~* by addition of an alkyl-lithium to a 56 T. H. Chan, W. Mychajlowskij, B. S. Ong, and D. N. Harpp, J. Organomet. Chem., 1976, 107, CI. "T. H. Chan, B. S. Ong, and W. Mychajlowskij, Tetrahedron Lett., 1976, 3253. 5B W. Mychajlowskij and T. H. Chan, Tetrahedron Lett., 1976, 4439. 59 T. H. Chan and B. S.On& J. Org. Chem., 1978, 43, 2994. 6o R. Amouroux and T. H. Chan, Tetrahedron Lett., 1978, 4453. 61 T. H. Chan, W. Mychajlowskij, B. S. Ong, and D. N. Harpp, J. Org. Chem., 1978, 43, 1526. 62 R. K. Boeckman and K. J. Bruza, Tetrahedron Lett., 1974, 3365. R. K. Boeckman and M. Ramaiah, J. Org. Chem., 1977, 42, 1581.'"R. K. Boeckman and K. J. Bruza, J. Ore. Chem., 1979, 44,4781. 65 A. G. Brook and J. M. Duff, J. Organomet. Chem., 1973, 51, 2024. 66 I. Matsuda, Chem. Lett., 1978, 773. "D. J. Peterson, J. Org. Chem., 1968, 33, 780. B.-T. Grobel and D. Seebach, Chem. Ber., 1977, 110, 852. Silicon-containing Carbonyl Equivalents vinyl~ilane~~,~~and by displacement of a suitable (see Scheme 6). This method, however, has the disadvantage that the anions only react cleanly with non- enolizable carbonyl compounds, but this can be overcome by the presence of other functional groups on the ani~n.~'.~~ SiMe7 iiiT SiMe3 SPh Reagents: (i) R' = H or SiMe, ;(a)R4Li, (b) R2R3C0 (ref.49, 68). (ii) R2 or R3= H; R' = R4CH2; (a) R4Li, (b) R'CHO (ref. 49, 69). (iii) (a) LiNaph/THF/-78"C, (b) R2R3C0 (ref. 70). (iv) R' = H or SiMe, ;(a)NaOMe/HMPA, (6) RzR3C0 (ref. 71). Scheme 6 Other routes to vinylsilanes are provided by the ally1 anion of allyltrimethyl-silane (5)73-77 (see Scheme 7), nucleophilic substitution of 1-and 3-trimethyl- silylallyl acetates (6) and (7)78(see Scheme 8), anions derived from a,fl-epoxysilanes (S)," reduction of an a-silyl ester" or thioacetal of an enal," a Diels-Alder 69 D.Seebach, R. Burstinghaus, B.-T. Grobel, and M. Kolb, Annalen, 1977, 830. "D. J. Ager, J. Org. Chem., submitted.'' H. Sakurai, K.-i. Nishiwaki, and M. Kira, Tetrahedron Lett., 1973, 4193. ''K. Sachdev, Tetrahedron Lett., 1976, 4041. 73 D. Ayalon-Chass, E. Ehlinger, and P. Magnus, J. Chem. Soc., Chem. Commun., 1977, 772. 74 K. Yamamoto, M. Ohta, and J. Tsuji, Chem. Lett., 1979, 713. 75 E. Ehlinger and P. Magnus, J. Am. Chem. SOC., 1980, 102, 5004. 76 R.J. P. Corriu, C. Guerin, and J. M'Boula, Tetrahedron Lett., 1981, 22, 2985. ''M. A. Tius, Tetrahedron Lett., 1981, 22, 3335. '* T. Hirao, J. Enda, Y.Ohshiro, and T. Agawa, Tetrahedron Lett., 1981, 22, 3079. 79 J. J. Eisch and J. E. Gable, J. Am. Chem. Soc., 1976,98, 4646.J.-P. Picard, J. Dunogues, N. Duffaut, and R. Calas, J. Chem. Re@), 1977, 54. '' D. Pandy-Szekeres, G. Deleris, J.-P. Picard, J.-P. Pillot, and R. Calas, Tetrahedron Lett., 1980,21,4267. Ager reaction,82 and rearrangement of silyl substituted cyclopropanes (9)83 (see Scheme 9). Me3Si 1. Base E 2. E+ 'Me3Si w (5) Scheme 7 -CRXY Me3Si -%-J CRXY or SiMe3 %Me3 Scheme 878 SiMe? (9) iii1 SiMe3 SiMe, 0 0 II II Reagents: (i) (a) LiNaph, (b) 0 (ref. 84), (ii) (a) 0 , (b) EtZnI/CH212/25"C, (c) NHLCl/H20 (ref. 84). (iii) TsOH/C,H,/20 "C (ref. 84), (iv) A (ref. 83). Scheme 9 a,b-Epoxysilanes (8) have been prepared by epoxidation of the vinylsilane (1) with a peracid' 7~59*85 which is commonly m-chloroperoxybenzoic acid (MCpBA).12,16,64,75,86-89The epoxide (8) was formed stereospecifi~ally'~~~'~~~ 1.Fleming and R. V. Williams, J. Chem. SOC.,Perkin Trans. 1, 1981, 684. 83 L. A. Paquette, G. J. Wells, K. A. Horn, and T.-H. Yan, Tetrahedron Lett., 1982, 23, 263. 84 L. A. Paquette, K. A. Horn, and G. J. Wells, Tetrahedron Lett., 1982, 23, 259. J. J. Eisch and J. E. Galle, J. Org. Chem., 1976, 41, 2615. G. Stork and M. E. Jung,J. Am. Chem. SOC., 1974, %, 3682. 87 T. H. Chan, M. P. Li, W. Mychajlowskij, and D. N. Harpp, Tetrahedron Lett., 1974, 3511. T. H. Chan, P. W. K. Lau, and M. P. Li, Tetrahedron Lett., 1976, 2667. 89 M. Obayaski, K. Utimoto, and H. Nozaki, Tetrahedron Lett., 1977, 1807. 499 Silicon-containing Carbonyl Equivalents (see Scheme 10).It has been found that ketones must be protected during this ~xidation.~~,~~ The epoxides (8) have also been prepared by the use of anions derived from a-chlorosilanes (10);epoxide formation was the preferred pathway rather than 0 Scheme 1OI6 MejSi R~ R~CO THF/ -78 OC C1 R’ BuLi Me3x1Li -C1 H Scheme 11 elimination of the silyl group uia a Peterson reacti~n’~~~~~~’ (see Scheme 11). The anions of some a$-epoxysilanes have been obtained by direct deprotonation.” a$-Epoxysilanes (8) have been hydrolysed to the corresponding carbonyl com- pounds by acid catalysed hydrolysis (see Scheme 12). Many acids have been used 10,12,62.6 3.7 5.93 and in some cases the hydrolysis may proceed via the acetal. In cyclic cases, for example, 1,2-epoxy-l-trimethylsilylcyclohexane(1 l), the diol (12) was formed upon hydrolysis, instead of the ket~ne~~,~~ (see Scheme 13).These results show that vinylsilanes can only be used as masked carbonyl compounds in acyclic cases and suggest that the hydrolysis proceeds by the mechanism shown in Scheme 12 rather than by a concerted attack at the silyl group and ring opening.” 90 C. Burford, F. Cooke, E. Ehlinger, and P. D. Magnus, J. Am. Chem. SOC.,1977, 99,4536. 91 F. Cooke and P. Magnus, J. Chem. SOC., Chem. Commun., 1917, 513. 92 J. J. Eisch and J. E. Galle, J. Am. Chem. SOC.,1976, 98, 4646. 93 G. Stork and M. E. Jung, J. Am. Chem. SOC., 1974,%, 3682. 94 C. M. Robbins and G. H. Whitham, J. Chem. SOC., Chem. Commun., 1976, 697; A.P. Davis, G. J. Hughes, P. R. Lowndes, C. M. Robbins, E. J. Thomas, and G. H. Whitman, J. Chem. Soc., Perkrn Trans. I, 1981, 1934. 95 P. F. Hudrlik, J. 0.Arcoleo, R. H. Schwartz, R. N. Misra, and R. J. Rona, Tetrahedron Left., 1977,591. Ager H I R2R3*:3 R' H20..> HO 0 T1 R3)AR1 R2 H20: Scheme 12 The diols (13) have been converted into trimethylsilyl enol ethers by reaction with potassium h~dride'~ (see Scheme 14). In addition, a$-epoxysilanes have been converted directly or indirectly into carbonyl compounds by pyrolysis' 7-g9 or magnesium salt induced rearrangement' oo*lol but these methods usually produce a mixture of products, the major one leading to a carbonyl compound in which the carbonyl carbon was not derived from the carbon atom to which the silicon was originally bonded.OSiMe3A ~ ~H2S04 O h o H KH/Ct20 H20/THF NaHCO,/ H20 n-ChH13 SiMe3 n-C6HI3 SiMe, Il-ChH 1.7 Scheme 1496 96 P. F. Hudrlik, R.H. Schwartz, and A. K. Kulkami, Tetrahedron Lett., 1979, 2233. 97 P. F. Hudrlik, C.-N. Wan, and G. P. Withers, Tetrahedron Lett., 1976, 1449. 98 A. R.Bassindale, A. G. Brook, P.Chen, and J. Lennon, J. Organomet. Chem., 1975, 94, C21. 99 P. F. Hudrlik and C.-N. Wan, Synth. Commun., 1979, 9, 333. loo P. F. Hudrlik, R. N. Misra, G. P. Withers, A. M. Hudrlik, R. J. Rona, and J. P. Arcoleo, Tetrahedron Lett., 1976, 1453. '01 M. Obayashi, K. Utimoto, and H. Nozaki, Tetrahedron Lett., 1977, 1807. 501 Silicon-containing Carbonyl Equivalents The use of a,p-epoxysilanes has been illustrated by the synthesis of (R)-(+)-frontalin.'o* O2 3 a-Silylsulphides and &Siloxysulphides Unlike acyl anion equivalents which are based solely on sulphur, such as 1,3- dithianes, and are often difficult to hydr~lyse,~,"~ silicon analogues may be hydrolysed under mild conditions (vide infra).The parent compound for this series is phenylthiotrimethylsilylmethane(14). This silane (14) has been prepared by the reaction of sodium thiophenoxide with trimethylsilylmethyl chl~ride''~ or by phenylthiomethyl-lithium with chlorotrimethylsilane. '05-'07 Phenylthiotrimethylsilylmethyl-lithium(15) has been prepared in quantitative yield from the silane (14) with n-butyl-lithium as the base in THF'" or N,N,N',N'-tetrameth yle thylenediamine (TMEDA)-hexane '6,'* as solvents, and alkylated in high yield by primary alkyl bromides and iodides (see Scheme 15); secondary alkyl halides gave only poor to moderate yields, indeed with cyclohexyl bromide, elimination was the only reaction pathway observed.Li R n-BuLi RX PhS-SiMq -PhSASiMe) -PhS Scheme 15 The masked aldehydes (16)have also been made by the addition of alkyl-lithiums to 1-phenylthio-1-trimethylsilylethene(17),'08 reaction of bis(pheny1thio)acetals (18) with lithium naphthalenide followed by chlorotrimethylsilane,'09 and by silylation of a-thioanions' lo and ally1 anions derived from appropriately sub- stituted sulphur compounds"'-"4 (but 1-thio-3-silyl compounds may also be f~rmed''~~"~).The reactions are summa1 ed in Scheme 16.Phenylthiotrimethylsilylmethyl-lithium (is)has been treated with a wide variety of electrophiles;''5 some will be seen below. The reaction of the anion with lo' P. D. Magnus and G. Roy,3. Chem. SOC., Chem. Commun., 1978, 297. lo3D. Seebach, Synthesis, 1969, 17. G. D. Cooper, 3. Am. Chem. SOC., 1954, 76, 3713. lo5 P. J. Kocienski, Tetrahedron Lett., 1980, 21, 1559. lo6 D. J. Ager and R.C. Cookson, Tetrahedron Lett., 1980, 21, 1667. lo' D. J. Ager, 3. Chem. SOC., Perkin Trans. 1, in press. lo' D. J. Ager, Tetrahedrnn Lett., 1981, 22, 587. log D. J. Ager, Tetrahedron Lett., 1981, 22, 2923. 'lo T. M. Dolak and T. A. ryson, Tetrahedron Lett., 1977, 1961. K. Hiroi and L.-M.Chen, 3. Chem. SOC.,Chem. Commun., 1982, 23, 1945. I. Fleming and R.V. Willihms, Unpublished results. " D. J. Ager, Unpublished results. A. Itoh, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1979, 1783. "'D. J. Ager, Tetrahedron Lett., 1981, 22, 2803. Ager (1 7) ii R Reagents: (i) R = RICH2 ; (a) R'Li/TMEDA/Et,O/O "C, (h) NH,CI/H20 (ref. 108). (ii) (a) LiNaph/THF/-78 "C, (b) Me,SiCl (ref. 109). (iii) (a) t-BuLi/THF/HMPA/-78 "C, (b) Me,SiCI (ref. 110). (iv) (a)base, (b) Me,SiCl (ref. 111-114). Scheme 16 epo~ides'~~~''~~'l6 and cr,B-unsaturated ketones' '5~"7*' '*provide useful methods for introducing an aldehyde group (see Scheme 17). The phenylthiotrimethylsilyl-methyl group has been introduced by the reaction of phenyltliotrimethyl- silylmethyl bromide (19a)or chloride (19b) with trimethylsilylenol ethers' 19-121 (see Scheme 18).cr-Silylsulphides(16)have also been prepared from the dianion of benzylthiol'22 and base-induced ring-opening of trimethylsilylmethyl substituted 1,3-dithiane~.'~~B,y-Unsaturated aldehyde derivatives (20)have been prepared by the rearrangement reaction outlined in Scheme 19.' 24 Phenylthiotrimethylsilylmethyl-lithium (15)reacted with carbonyl compounds to give vinylsulphides (21) (see Scheme 20), which are themselves masked aldehydes'15,125,126and useful precursors to 01efins.l~~ 'I6 I. Fleming and C. D. Floyd, J. Chem. Soc., Perkin Trans. 1, 1981, 969. 11' D. J. Ager, J. Org. Chem., submitted. 11* D. J. Ager, J. Chem. Soc., Perkin Trans.1, submitted. 'I9 I. Fleming and S. K. Patel, Tetrahedron Lett., 1981, 22, 2321. 120 I. Fleming and D. A. Perry, Tetrahedron, 1981, 37, 4027. D. J. Ager, Tetrahedron Lett., in press. 122 K.-H. Geifl, D. Seebach, and B. Seuring, Chem. Ber., 1977, 110, 1833. 123 T. A. Hase and L. Lahtinen, Tetrahedron Lett., 1981, 22, 3285. 124 P. J. Kocienski, J. Chem. Soc., Chem. Cornmun., 1980, 1096. F. A. Carey and A. S. Court, J. Org. Chem., 1972, 37, 939. 126 T. Agawa, M. Ishikawa, M. Komatsu, and Y. Ohshiro, Chem. Lett., 1980, 335. B. M. Trost and P. L. Ornstein, Tetrahedron Lett., 1981, 22, 3463. Silicon-containing Carbonyl Equivalents OH SiMe3 LJA R R' R PI1s R = Mc -R 4 R' R' Scheme 17 OSiMc 0 SiMe R' NCS or NBS -PhS X -4 RASiMe3 VSPh R' (1%; X = Br) (19b: X= C1) Scheme 18 (20) Scheme 19124 R2 = alkyl or NR; Scheme 20 Ager Other oxidation states of sulphur have also been used to prepare these systems.1-Trimethylsilyl-1-phenylsulphinylmethyl-lithiumreacted with carbonyl com-pounds (see Scheme 21)lz8but could only be alkylated with methyl a-Silylsulphoxides have also been prepared by treatment of a methyl sulphinate with a Grignard reagent.13' 0 II 0 PhSASiMe3 2. R~R~CO Scheme 21 a-Silylsulphones have been used as masked carboxylic acids and employed in a synthesis of Prelog-Djerassi lactonic acid (22). The relevant steps are summarized in Scheme 22 and a mechanism for the key oxidation step is shown in Scheme 23.13' SiMel ++-__3 11.Ill ** OEt 'OEt -.OEt I HO2C vi, viiviii c--*. 30 -Ho2c& 0 I I I I Reagents: (i) (COCI),/DMSO/NEt,, (ii) PhS(Me3Si),CLi, (iii) MCPBA, (iv) MeLi, (v) PhSeCI, (vi) H,02/H20/THF, (vii) H30+, (viii) Br,/NaOAc/H,O/DMF. Scheme 22 12' F. A. Carey and 0. Hernandez, J. Org. Chem., 1973,38, 2670. 129 This reaction is under investigation at present as it would provide a direct method for the prepara- tion of aldehydes (ref. 113). 130 A. G. Brook and D. G. Anderson, Can. J. Chem., 1968,46, 21 15. 13' M. Isobe, Y. Ichikawa, and T. Cioto, Tetrahedron Lett., 1981, 22, 4287. Silicon-containing Carbonyl Equivalents SiMe 3 ii SiMe3 YSiMe3I PhSe -C --p PhSe-C-4 PhSe-C-I Ci PhS02 PI1so2 PhSO, 0 II HO-C-i" -OH Scheme 23 In contrast to 1,3-dithianes, 1-phenylthio-1-trimethylsilylalkanes(16) cannot be used as precursors to ketones because treatment with a base did not produce the correct anion.Direct deprotonation may be used, however, for the preparation of phenylketones (23)as the correct anion is obtained in this case132 (see Scheme 24). Ph 1. n-BuLi/TMEDA/C6H1J P11s * PhS SiMe,XP1'-PI1 (23) Scheme 2413' This problem has been alleviated by the use of indirect methods for the prep- aration of the acyl anion equivalent and are summarized in Scheme 25. They consist of the addition of an alkyl-lithium to 1-phenylthio-1-trimethylsilylethene(17)' 33 in a manner similar to that used for the synthesis of aldehydes, and displacement of a tin134or sulphur The last method also provides alternative routes and a solution to the problem of diastereoisomers which can occur with the other methods.Another approach which has been used, is to employ the phenylsulphone group to stabilize the anion.' 37 Carey and Court,125 as mentioned above, found that the sulphoxide was difficult to alkylate but this may be due to the ease of the sila- Pummerer rearrangement (vide infra)' ' which does not occur in the sulphone series. Again, a variety of pathways are available and are summarized in Scheme 26; 132 D. J. Ager, Tetrahedron Lett., 1980, 21, 4759. lJ3 D. J. Ager, Tetrahedron Lett., 1983, 24, 95. 134 D. J. Ager, Tetrahedron Lett., submitted. 135 D. J. Ager, Tetrahedron Lett., submitted.136 D. J. Ager, Tetrahedron Lett., submitted. .lii SnBu n3 i PhSASiMe3 iii f--iv Me3SiXSPh RxR SPh PhS %Me3 PhS SiMe3 Reagents: (i) R = R2CH2;(a)R2Li/Et,0/TMEDA/O"C, (b)R'X (ref. 133). (ii) (a)n-BuLi/THF, (b) n-Bu,SnCI (ref. 115). (iii) (a)LDA or KDA/THF/-78 "C, (b)RX (ref. 134). (iv) (a) n-BuLi, (b) R'X (ref. 134). (v) LiNaph/THF/-78"C, (b) Me,SiCl (ref. 136). (vi) (a) LiNaph/THF/-78 "C, (b)R'X (ref. 136). Scheme 25 R R'kR1-PhSxSiMe3 PhSO2 SiMe3 vi Reagents: (i) 2.2 equiv. MCPBA/CH2CI2. (ii) (a)n-BuLi/THF, (b)RX. (iii) (a)n-BuLi/THF, (b)R'X. (iv) Dibal-H/THF. (v) LiAIH4/THF. (vi) (a)n-BuLi/THF, (b)Me,SiCI. Scheme 2613' Silicon-containing Carbonyl Equivalents in addition, it seems to be possible to add alkyl-lithiums to l-phenylsulphonyl- 1-trimethylsilylalkenes and alkylate the resultant anion.' l3 The disadvantage of the sulphone methods is that two extra steps-an oxidation and reduction-are introduced, even though both are invariably high yielding.'37 The masked aldehydes (16) and ketones (24) have been converted into the corresponding carbonyl compounds by a sila-Pummerer rearrangement.The mechanism, as proposed by Brook130 is given in Scheme 27. The reaction provides an excellent method for the conversion of 1-phenylthio-1-trimethylsilylalkanes(16) in to 1-phen ylthio- 1-trime t hy lsilox yalkanes (25), O 5-' O '7 ' (see Scheme 28). In a manner similar to the Pummerer rearrangement itself,'39 the sila-Pummerer rearrangement is subject to stereo and electronic effects' 38 and, there- fore, in some ketone cases the vinylsulphide (21) becomes the major product instead of the required siloxythioacetal(26) (see Scheme 29); this phenomenon has also been observed in the aldehyde series.'05 Although vinylsulphides may be hydrolysed to carbonyl compounds,2 the conditions required are not as mild as those required for the hydrolysis of the acetal(26).This means that the synthesis of branch-chained ketones has two major drawbacks; the alkylations with a secondary halide are only moderate to low yielding and the sila-Pummerer rearrangement can lead to the vinylsulphide (21) as the major product. 13' D. J. Ager, Tetrahedron Lett., submitted. 13* E. Vedejs and M. Mullins, Tetrahedron Lett., 1975, 2017.Ager R' MCPUARxR'"x Rx2PhS OSiMe, and/or PIlS R3PIiS SiMq PhS SiMe, (24) II0 (26) (21) where R = <:HR2R3 Scheme 29140 The sila-Pummerer rearrangement has been used to prepare thiol esters (27) from chloromethyl phenyl'sulphoxide (28) (see Scheme 30);I4l the rearrangement failed when the chlorine was in the 2-position (see Scheme 31), although alternative 0 0 1 J Reagents: (i) LDA/THF/- 78 "C. (ii) RX. (iii) Me,SiC1. (iv) -78 -+ 60°C. Scheme W4' 0 0 Scheme 3175 mechanisms are available in this case." It has also been used for the synthesis of enals (29) from 3-trimethylsilylallylic alcohols as shown in Scheme 32.142 139 G. A. Russell and G. J. Mikal in 'Mechanisms of Molecular Migrations' ed.B. S. Thyagarajam, Interscience, New York, 1968, vol. 1, p. 157; T. Durst, Adc. Org. Chem., 1969, 6, 356; T. Durst in 'Comprehensive Organic Chemistry', ed. D. H. R. Barton and W. D. Ollis, Pergamon, Oxford, 1979. vol. 3, p. 137, and E. Block in 'Reactions of Organosulphur Compounds', Academic, New York. 1978, p. 154. 140 D. J. Ager, Tetrahedron Lett., submitted. K. M. More and J. Wernple, J. Org. Chem., 1978, 43, 2713. 14' I. Cutting and P. J. Parsons, Tetrahedron Lett., 1981, 22, 2021. 509 Silicon-containing Carbonyl Equivalents R' R' R' ?Me3 iii5 R' OSiMe3 SPh R2R2 Reagents: (i) LiAlH4/THF/A. (ii) PhSCl/NEt,/Et,O. (iii) r.t. (iv) AgN03/H20/MeCN. Scheme 32142 Siloxythioacetals [(25) and (26)] have also been prepared from the parent carbonyl compounds by treatment with thiophenol and chlorotrimethylsilane in ~yridine'~~or a thiosilane in the presence of an anionic initiation'44 (this method is not, however, general for ketones) (seeScheme 33).They have also been prepared by the photochemical addition of a-trimethylsiloxythiols to olefins.14' PhS OSiMe3 PhSH/Me3SiCl/pyr (ref. 143) R R' 01phSSiMe3 /KCN/I 8-crown-6 (ref. 144) > (24) Scheme 33 The acetals [(25) and (26)] are more stable to hydrolysis than would be expected from analogous systems. They were, however, cleaved by acid or base hydrolysis or hydrolysis catalysed by metal ions such as copper, silver, and mercury.105*'42~146 Reaction of [(25) or (26)] with an alkyl-lithium in an ethereal solvent yielded the parent carbonyl compound but when the reaction was carried out in HMPA or TMEDA, the thio-group was displaced to give the alcohol (30).'07,148The acetals [(25)and (26)] have also been converted into a-iodosulphides, vinylsulphides,147 143 T.H. Chan and B. S. Ong, Tetrahedron Lett., 1976, 319. 14' D. A. Evans, L. K. Truesdale, K. G. Grimm, and S.L. N. Nesbitt, J. Am. Chem. Soc., 1977, 99, 5009. T. Aida, T. H.Chan, and D. N. Harpp, Angew. Chem., Int. Ed. Engl., 1981, 20, 691. 14' D. J. Ager, Tetrahedron Lett., submitted. 14' T. Aida, D. N. Harpp, and T. H. Chan, Tetrahedron Lett., 1980, 21, 3247. 14* R. S. Glass, Synth. Commun., 1976, 6, 47. 510 Ager and ~ulphides'~~ (see Scheme 34) while a,a'-bis(trimethylsiloxy)sulphides'49 have been converted into ole fin^'^^ (see Scheme 35).Me3SiO R3 RxR, ii Ti viii RnSR2 -Reagents: (i) R3Li/HMPA or THF/TMEDA (ref. 107, 143). (ii) H20. (iii) HCl/H,O/THF (ref. 143, 146). (iv) NaOH/H,O/THF (ref. 146). (v) MX,/H,O/THF, MeCN or Et,O (ref. 105. 142. 146). (vij Me3SiI/CHCl3 (ref. 147, 149). (vii) NEt, or NaOH/H,O/R,NX (ref. '147).' (vii;) LiAIH,/AIC13/Et20 (ref. 148). Scheme 34 "'("YR(Mc3Si)2S TiC13/LiAllfj RCH =CHRRCHO -CN -Me3SiO OSiMe3 TH 1-Scheme 35149*150 The advantages of employing the sulphur-carbon-silicon system as an acyl- anion equivalent are that the hydrolysis is very mild and can be achieved in acidic, neutral, or basic conditions whereas, in contrast, the parent a-thiosilanes are stable to a variety of reagents."* When further transformations of the carbonyl group are required, the system can be converted directly into an alcohol, vinylsulphide, sulphide, acetal, or olefin without isolation of the carbonyl compound.The main disadvantages of the system are that a chiral centre is introduced although the use of bis(pheny1thio)acetaIs may alleviate this to some extent, oxidations in the presence of sulphur can be troublesome and the method cannot be used to synthesize hindered ketones. 149 T. Aida, T. H. Chan, and D. N. Harpp, Tetrahedron Lett., 1981, 22, 1089. T. H. Chan, J. S. Li, T. Aida, and D. N. Harpp, Tetrahedron Lett., 1982, 23, 837. 511 Silicon-containing Carbonyl Equivalents Ti R! SiMe3 SiMe R2HR (R = ti) PhS ASiMc3 viii u-2phOR' Rz SnR, X R.eagents: (i) (a) n-BuLi/THF, (b) Me,SiCI (ref.70). (ii) (a) LiNaph/THF/-78"C, (b) R'R'CO (ref. 70). (iii) (a) n-BuLi, (6) Me,SiCl (ref. 115). (iv) R = Me or Bu"; (a) n-BuLi, (h) R,SnCI (ref. 68, 115). (v) LDA or KDA/THF, (b) R1R2C0 (ref. 68, 115). (vi) (u) n-BuLi/THF, (b) R'R'CO (ref. 68, 151). (vii) RL = H; NCS/R30H (ref. 151). (viii) (a) n-BuLi, (b) RX (ref. 152). Scheme 36 The reactions of anions with two silicon groups and one sulphur group attached to one carbon atom are summarized in Scheme 36, and those for one silicon and two sulphur groups are shown in Scheme 37. As can be seen, a wide variety of products are available, such as vinylsilanes (vide supra), vinylsulphides, thiol esters, B.-T.Grobel, R. Burstinghaus, and D. Seebach, Synthesis, 1976, 121. Is2 D. J. Ager, Tetrahedron Lett., submitted. 153 c.J D. J. Ager, Tetrahedron Lett,, 1980, 21, 4763; 1. Kuwajima, T. Abe, and K. Atsumi, Chem. Lett., 1978, 383. 154 E. J. Corey and D. Seebach, J. Org. Chem., 1966, 31, 4097. 155 P.Blatcher and S. Warren, J. Chem. SOC., Perkin Trans. 1, 1979, 1074. D. Seebach, M. KoIb, and B.-T. Grobel, Chem. Ber., 1973, 106, 2277. 512 Ager R &RCHO R2 R PllSR'HsP1' z 0 0 R' SP1i Me j"ixSiMe3 pc,Ph PilS SPh R' SiMe Reagents: (i) (a) LiNaph, (b) R'R'CO (ref. 70), (ii) (a) n-BuLi/TMEDA (b) Me,SiCl (ref. 113, 153). (iii) PhSH/H+ (ref. 154, 155). (iv) (a) n-BuLi, (b) RX (ref.154). (v) n-BuLi, (b) Me3SiC1 (ref. 152, 156). (vi) as (iv) (ref. 152). (vii) as (v) (ref. 70). (viii) (a) n-BuLi, (b) R'R'CO (ref. 152, 156) (for reactions of anions derived from 1,3-dithianes see ref. 157). (ix) (a) LiNaph, (b) Me,SiCl (ref. 113, 158). (x) TFA (ref. 159, la), (xi) (u) MCPBA, (b) A, (c) hydrolysis (ref. 152). (xii) Ag' or Cu"/R'OH (ref. 161). Scheme 37 15' F. A. Carey and A. S. Court, J. Org. Chem., 1972,37, 1926; D. Seebach, B.-T. Grobel, A. K. Beck, M. Braun, and K.-H. Geiss, Angew. Chem., Znt. Ed. Engl., 1972, 11, 443; P. F. Jones and M. F. Lappert, J. Chem. SOC.,Chem. Commun., 1972, 526; P. F. Jones, M. F. Lappert, and A. C. Szany, J. Chem. SOC.,Perkins Trans. 1, 1973, 2272; N. H. Anderson, Y. Yamamoto, and A.D. Denniston, Tetrahedron Lett., 1975, 4547; S. Danishefsky, R. McKee, and R. K. Singh, J. Org. Chem., 1976, 41, 2934; R. S. Brinkmeyer, Tetrahedron Lett., 1979, 207. 15* T. Cohen and R. B. Weisenfeld, J. Org. Chem., 1979, 44, 3601. 159 D. Seebach and R. Burstinghaus, Synthesis, 1975, 461. A. Mendoza and D. S. Matteson, J. Org. Chem., 1979,44, 1352. 161 S. Masarnune, Y. Hayase, W. Schilling, W. K. Chan, and G. S. Bates, J.Am. Chem. SOC.,1977,99,6756. Silicon-containing Carbonyl Equivalents HO SiMe3 R1R SiMe3sXsR1R'SiMe 3 R-=--SiMe3 OH Br RASiMe3 J (34) Ar (37) \iii PliSe SePliMe3Si -=-SiMe3 -Reagents: (i) (a) MCPBA, (b) A, (c) hydrolysis (ref. 152, for the selenium analogue see ref. 163). (ii) hydrolysis, e.g.HgCl,/MeCN/H20 (ref. 152, 164-166). (iii) HBCl,, (b) Me3N0.2H20/ C6H6 (ref. 167). (iv) R = Ar; AgOAc/Me2CO/EtOH/H20 (ref. 168) or Si0, (ref. 169). (v) R = Ar; X = OR2. (u) Me,SiCl/Mg/HMPA, (b) H,O+ (ref. 170); X = C1, Me3SiSiMe3/ [(q'-C3HS)PdCl]2/P(OEt)3 (ref. 171). (vi) H30+ (ref. 172). (vii) (a) LDA, (b) Me,SiCI (ref. 173). (viii) H30+ (ref. 174, 175). (ix) see Scheme 39. (x) DCC/DMSO (ref. 176) or Cr03/pyr (ref. 162). (xi) t-BuOCI/CCl, (ref. 177). (xii) Mg/Me,SiCl/HMPA (ref. 172). (xiii) (a) PhSCI, (b) MCPBA, (c) xylenelb (ref. 178). (xiv) (u) LDA, (b) Me,SiCI, (c) Na/ Me3SiC1 (ref. 179).(xv)R1 = H; (u)LDA, (b)Me,SiCI, (c)LiNEt,, (d) RX,(e)AcOH (ref. 180). (xvi) R' = H, R2 = Me or EtOCH(Me)-, (u)BuLi, (b) Me3SiC1, (c) BuLi, (d) RX, (e) TFA or H2SOJH20/THF (ref.181, 182). (xvii) (a) LDA, (b) R'X, (c) RCHO (ref. 185). (xviii) (u)BH3.SMe2, (b) Me3N0, (c) H20 (ref. 184). Scheme 38 Ager Me3Si OH iii RxRI -R1v0SiMe3R3 t 0 vii R+ SiMe 'SiMej > RCHO I R* (34) viii R AR,h ii ii RCOzH \Y R' SiMe; SiMe3 \ xviiOSiMe3 (35) ii R R' R Y OSiMe 1 Reagents: (i) TsNHNH,/EtOH/AcOH (ref. 185) or N,H,/AcOH (ref. 186). (ii) see Scheme 38. (iii) LiAlHJEt,O (ref. 176, 187, 188). (iv) R'Li (ref. 176). (v) KH/HMPA (ref. 170) (This is the Brook rearrangement for further examples see ref. 180 and 189). (vi) hv/MeOH (ref. 190). (vii) R = Ar; -OH or -0Et (ref. 168, 191) or KF/H20/DMS0 or HMPA (ref. 192, 193) (viii)R = Ar; KF/18-crown-6/R1X (ref. 194)or KF/R'I/DMSO or HMPA (ref.192). (ix) HOz- (ref. 195), (x) (a) R'-=-Li, (b) R'X, (c) hydrolysis (ref. 180). (xi) PhS0,CHLiR' or R'CHLiCN/THF (ref. 175). (xii) R-RICH,; (u) LDA, (b) R2X (ref. 173). (xiii) R' = PhS; R3Li/Etz0 (ref. 173). (xiv) (u) CH, = CHLi/Et,O, (b) E+ (ref. 180). (XV) A (ref. 196). (xvi) RCH(OR3)3/BF3.Et20 (ref. 197). (xvii) NBu40H (ref. 197). (xviii) NBu,F/HCO,H/ 75°C (ref. 183, 198). (xix) H202/NaOH/THF/H20 (ref. 183). (xx) R = H, R' = PhSe; PhS(O)CH,Li (ref. 173). (xxi) R'H; PhS0,CLiR'R' (ref. 182). Scheme 39 515 Silicon-containing Carbonyl Equivalents and esters. Both of the systems have been used to prepare acylsilanes (34)16*whose methods of preparation are summarized in Scheme 38. Acylsilanes (34) are not strictly umpolung reagents but the numerous synthetic methods which stem from them (see Scheme 39) despite their labile nature,' makes them worthy of inclusion. 4 a-Silylselenides Unlike a-silylsulphides, a-silylselenides have not found such a widespread appli- cation as acyl-anion equivalents.This is due to the selenium analogue of the sila- Pummerer rearrangement leading to the vinylsilane rather than the required 0-trimethylsilylselenoacetal for ketone derivatives. 63 Despite this, a-silylselenides have been used to prepare aldehydes, olefins, and ketones (see Scheme 40)as well as carboxylic acids (see Scheme 23). The synthesis of olefins from a-silylselenides, A. G. Brook, Adv. Organomet. Chem., 1968, 7, 95. 163 H. J. Reich and S.K. Shah, J. Urg. Chem., 1977,42, 1773. 164 D. Seebach and R. Burstinghaus, Angew. Chem., Int. Ed. Engl., 1975, 14, 57. 165 E. J. Corey, D. Seebach, and R. Freedman, J. Am. Chem. SOC.,1967, 89, 434. 16' A. G. Brook, J. M. Duff, P. F. Jones, and N. R. Davis, J. Am. Chem. SOC.,1967, 89, 431. 167 A. Hassner and J. A. Soderquist, J. Organomet. Chem., 1977, 131, C1. 16' A. G. Brook, J. Am. Chem. Soc., 1957, 79, 4373, 16' A. Degl'Innocenti, D. R. M. Walton, G. Seconi, G. Pirazzini, and A. Ricci, Tetrahedron Lett., 1980, 21, 3927. 170 J.-P. Picard, R. Calas, J. Dunogues, N. Duffaut, J. Gerval, and P. Lapouyade, J. Urg. Chem., 1979, 44, 420; J.-P. Picard, R. Calas, J. Dunogues, and N. Duffaut, J. Organomet. Chem., 1971, 26, 183. K. Yamamoto, S.Swzuki, and J. Tsuji, Tetrahedron Lett., 1980, 21, 1653. P. Bourgeois, J. Dunogues, N. Duffaut, and P. Lapouyade, J. Orgunomet. Chem., 1974, 80, 125. 173 H. J. Reich, J. J. Rusek, and R. E. Olson, J. Am. Chem. SOC., 1979, 101, 2225. 174 R. Bourgeois, J. Organomet. Chem., 1974, 76, C1. G. E. Niznik, W. H. Morrison, and H. M. Walborsky, J. Organomet. Chem., 1974, 39, 600. S. R. Wilson, M. S. Hague, and R. N. Misra, J. Org. Chem., 1982, 47, 747, 177 I. Kuwajima, T. Abe, and N. Minami, Chem. Lett., 1976, 993. 17' N. Minami, T.Abe, and I. Kuwajima, J. Organomet. Chem., 1978, 145, C1."'I. Kuwajima, M.Kato, and T. Sato, J. Chem. SOC., Chem. Commun., 1978, 478. H. J. Reich, R. E. Olson, and M. C. Clark, J. Am. Chem. SOC., 1980, 102, 1423. J. C. Clinet and G.Linstrumelle, Tetrahedron Lett., 1980, 21, 3987. I** H. J. Reich and M. J. Kelly, J. Am. Chem. SOC., 1982, 104, 1119. J. A. Miller and G. Zweifel, J. Am. Chem. Soc., 1981, 103, 6217. lE4J. A. Miller and G. Zweifel, Synthesis, 1981, 288. lE5A. G. Brook and P. F. Jones, Can. J. Chem.. 1969, 47, 4353. lE6K.-D. Kaufmann, B. Aurath, P. Trager, and K. Ruhlmann, Tetrahedron Lett., 1968, 4973. J. J. Eisch and J. T. Trainor, J. Urg. Chem., 1963, 28, 2870. "'A. G. Brook, M. A. Quigley, G. J. D. Peddle, N. V. Schwartz, and L. M. Warner, J. Am. Chem. Soc., 1960, 82, 5102. A. G. Brook, Acc. Chem. Res., 1974, 7, 77; I. Kuwajima and M. Kato, J. Chem. SOC.,Chem. Commun., 1979, 708. J. M. Duff and A. G. Brook, Can. J. Chem., 1973, 51, 2869. lgl A.G. Brook, T. J. D. Vandersar, and W. Limburg, Can. J. Chem., 1978, 56, 2758. D. Schinzer and C. H. Heathcock, Tetrahedron Lett., 1981, 22, 1881. D. Pietropaolo, M. Fiorenza, A. Ricci, and M. Taddei, J. Organomet. Chem., 1980, 197, 7. lg4A. Degl'Innocenti, S. Pike, D. R. M. Walton, G. Seconi, A. Ricci, and M. Fiorenza, J. Chem. SOC, Chem. Commun., 1980, 1201. 195 G. Zweifel and S. J. Backlund, Angew. Chem., Int. Ed. Engl., 1976, 15,498. A. G. Brook and J. Harris, J. Organomet. Chem., 1975, 90, C6. Ig7T.Sato, M. Arai, and I. Kuwajima, J. Am. Chem. SOC., 1977, 99, 5827. H. J. Reich and S. K. Shah, J. Am. Chem. Soc., 1977, 99, 263. Ager R %Me3 Me3S;/\SeR1 (34) RCHO viii\ ti / R R R2 SeR' vii I/-I\-YR3Me3Si SeR' R R2 V Me 3 Si%eR' SiMe + + y2Ixiii fix R'Se R2 Me3Si SeR' R' Se R2 R xiv R3 SiMe3 Reagents: (i) (a) LiNEt2, (b) Me,SiCl, (c) HzOz (ref.163). (ii) H202 (ref. 200, 201). (iii) (a) n-BuLi. (b) R2R3C0,(c) H30+ (ref. 202). (iv) R = Ph; (a)LiNEt,, (b) R2X (ref._63).(v) (a)MCPBA, (b) A (ref. 163), (vi) (a) n-BuLi, (b) Me,SiCl (ref. 202, 203) (vii) R = R2(CH2),-; (a) R*Li/Et20, (b) Me,SiCl (ref. 204). (viii) (a)LDA (b) RX (ref. 200, 201). (ix) (a) n-BuLi, (b) RZX (ref. 201). (x) (a) LDA, (b) R2CH0 (ref. 68). (xi) (a) n-BuLi, (b) R2R3C0 (ref. 201, 205). (xii) (a)LDA, (b) RX, (c) n-BuLi, (d) Me3SiC1 (ref. 201). (xiii) (a)LDA, (b) Me3SiC1 (ref. 68, 201). (xiv) KOBu'/THF (ref. 205). (XV) Br,/CCl, (ref. 205). (xvi) HgC12/MeCN (ref.205). (xvii) H202 (ref. 205). (xviii) POC13/NEt,/CH2C12 (ref. 205). Scheme 40 517 Silicon-containing Carbonyl Equivalents in contrast to a-silylsulphides (videsupra),has the disadvantage of the a-silylanion formation step being low yielding."' 5 0-Silykyanohydrins 0-Silylcyanohydrins [(39)and (40)]are readily available from aldehydes or ketones respectively (for a review see reference 206).Their use as acyl-anion equivalents has, however, been limited to the cyanohydrins derived from aromatic aldehydes. These reactions, together with some other useful transformations which do not strictly involve 0-silylcyanohydrins as acyl-anion equivalents, are summarized in Scheme 41. The 0-trimethylsilylcyanohydrinsof a$-unsaturated aldehydes (41) have been alkylated to give, after hydrolysis, en one^^^' (see Scheme 42).They have also been used as acyl-anion equivalents for a three-carbon annelation procedure22 (see Scheme 43) and oxidized with pyridinium dichromate to A2-butenolides227 (see Scheme 44). 6 Other Methods This section considers silicon-containing carbonyl equivalents which do not fall into any of the above sections. lg9 A. Krief, Tetrahedron, 1980, 36, 2531. 'O0 K. Sachdev and H. S. Sachdev, Tetrahedron Lett., 1976, 4223. '01 D. van Ende, W. Dumont, and A. Krief, J. Organomet. Chem., 1978, 149, C10. '02 W. Dumont and A. Krief, Angew. Chem., Int. Ed. Engl., 1976, 15, 161. '03 I. Kuwajima, S. Hoshino, T. Tanaka, and M. Shimizu, Tetrahedron Lett., 1980, 21, 3209.S. Raucher and G. A. Koolpe, J. Org. Chem., 1978, 43, 4252. '05 W. Dumont, D. van Ende, and A. Krief, Tetrahedron Lett., 1979, 485. '06 W. C. Groutas and D. Felker, Synthesis, 1980, 861. 207 S. Hiinig and G. Wehner, Chem. Ber., 1979, 112, 2062. 208 S. Hiinig and G. Wehner, Synthesis, 1975, 391. '09 G. Boche, F. Bosold, and M. Niepner, Tetrahedron Lett., 1982, 23, 3255. 'lo R. Amouroux and G. P. Axiotis, Synthesis, 1981, 270. 'I1 W. Nagata, M.Yoshida, and M.Murakami, Org. Synth., 1972, 52, 96. 'I' F. E. Ziegler and T.-F. Wang, Tetrahedron Lett., 1981, 22, 1179. K. Deuchert, V. Hertenstein, and S. Hiinig, Synthesis, 1973, 777. 'lo K. Deuchert, V. Hertenstein, S. Hiinig, and G. Wehner, Chem. Ber., 1979, 112, 2045. 'lS S. Hiinig and G. Wehner, Synthesis, 1975, 180.'16 J. K. Rasmussen and S. M.Heilmann, Synthesis, 1978, 219. '17 P. G. Gassman and J. J. Talley, Tetrahedron Lett., 1978, 3773. '18-M. Oda, A. Yamamuro, and T. Watabe, Chem. Lett., 1979, 1427. '19 E. J. Corey, D. N. Grouse, and J. E. Anderson, J. Org. Chem., 1975, 40, 2140. 220 S. Hiinig and G. Wehner, Chem. Ber., 1980, 113, 302. 221 S. Hiinig and G. Wehner, Chem. Ber., 1980, 113, 324."'D. A. Evans, G. L. Carroll, and L. K. Truesdale, J. Org. Chem., 1974, 39, 914. 223 I. Fleming and M.Woolias, J. Chem. SOC.,Perkin Trans. I, 1979, 829. 224 G. L. Grunewald, W. J. Brouillette, and J. A. Finney, Tetrahedron Lett., 1980, 21, 219. 225 V. Hertenstein, S. Hunig, and M.oller, Synthesis, 1976, 416. 226 R. M. Jacobson and G.P. Lahm, J. Org. Chem., 1979, 44, 462; R. M. Jacobson, G. P. Lahm, and J. W. Clader, J. Org. Chem., 1980, 45, 395. 227 E. J. Corey and G. Schmidt, Tetrahedron Lett., 1980, 21, 731. Ager R- - 1 R ANMe R3 n OH . Ph CN viii iiiMe3si0YCN-R \ OH R' OSiMe? HO CN Me3SiOxCN,OxCN \I11 iii -RxR1 -R' RH:2OH NH2R R' R R' ,RHr2 J (i:i\ OH NH2 0 "'>r,H2 R:vNH2"$NH2R1 R2vN :vNH2 R' R2 OH Reagents: (i) R = Ar; (a)LDA/DME, (b) R'R2C0, (c) H20 (ref. 207, 208). (ii) R = Ar; (a)LDA, (b) PhzP(0)ONMe2,(c)H30+ (ref. 209). (iii) (a)R2Li, (6) HzO, (c) AcOH/H20 (ref. 210). (iv) KHSO4/130-150"C (ref. 211, 212). (v) R = Ar; (a) LDA/THF/-78"C, (b) RZX (ref. 213-215). (vi) KCN/Me3SiC1/MeCN or DMF/Zn12 (ref.216). (vii) Me3SiCN/CH2ClZor C,H6/Zn12 (ref. 206, 217, 218). (for a preparation of the t-butyldimethylsilyl derivative see ref. 219). (viii) R = Ar; (a) LDA/Et20/-78 "C, (b) PhCOCl (ref. 220). (ix) R = Ar; (a) LDA/Et,O, (b)R1COCH-CR2R3, (c) H30+ (1,Zaddition occurs when THF or DME used as solvent, see ref. 220, 221). (x) LiAlH4/THF (ref. 222, 223). (xi) R = Ar; HCl (ref. 224) (for the t-butyldimethylsilyl analogue see ref. 219). (xii) R = R2CH2;POC13/pyr (ref. 218). (xiii) HCl/HzO (ref. 217). (xiv) (u)H30+ or R,NHF, (b) HO-(ref. 213, 215). Scheme 41 519 Silicon-containing Carbonyl Equivalents OSiMe3 Mc3SiCN ‘qcN1. LDA/?’HT: R9R4A ______) I ZnI 2 2. R4X R3 R3 R‘ 3. hydrolysis ‘Rl (41) Scheme 422 O 0~i~e3 1. LDA/THF/-78 ’C TsOH ___) &R R1Ph Mcfill Scheme 43226 0 Me3SiCN DMFPDC 0 KCN/l8-crown-6Ph Ph (41) Scheme 44227 l-Trimethylsiloxyphosphonates228~229have been alkylated to give the ketone derivatives which, in turn, were easily hydroly~ed~~~ (see Scheme 45).0 0 Scheme 45230 In addition to anions derived from a-chlorosilanes (uide supra), Magnus has employed the anion of methoxymethyltrimethylsilane(42) to prepare methyl enol ether, and consequently aldehydes”*231 (see Scheme 46). 228 M. Sekine, I. Yamamoto, A. Hashizume, and T. Hata, Chem. Lett., 1977, 485. 229 D. A. Evans, K. M. Hurst, L. K. Truesdale, and J. M.Takacs, Tetrahedron Lett., 1977, 2495. 230 M. Sekine, M. Nakajima, A. Kume, and T. Hata, Tetrahedron Lett., 1979, 4475.See also T. Hata, A. Hashimme, M. Nakajima, and M. Sekine, Tetrahedron Lett., 1978, 363.*” P. Magnus and G. Roy, J. Chem. SOC.,Chem. Commun., 1979, 822. Ager 1. s-BuLi/THF/-7ooC KH/THF, I 'gMeA MegSi OMe \ Me3Si OMe Scheme 4623' Trimethylsilyl ethers (43)although not umpolung reagents, may be regarded as carbonyl equivalents as they have been oxidized to the ketone by a variety of methods (see Scheme 47). Oxidation of the ethers (43) derived from primary alcohols gave the ester instead of the aldehyde. Finally, it should be mentioned that a silyl group has been used as a masked anion for the preparation of non-silicon-containing acyl-anion equivalent^.^^ri: ori, iiiii ARl R R (43) \ R'OR R2AOR Reagents: (i) (a) Ph3CBF4/CH2C12, (b) H20 (ref.232). (ii) NOBF4/CH2C12 (ref. 233). (iii) NBS/CC14/hv (ref. 234). (iv) R' = H; RZCHO/NBS/CCl4/hv (ref. 234). (v) R' = H; NBS/CCl,/hv (ref. 200). Scheme 47 232 M. E. Jung, J. Org. Chem., 1976, 41, 1479. 233 G. A. Olah and T.-L. Ho, Synthesis, 1976, 609. 234 H. W. Pinnick and N. H. Lajis, J. Org. Chem., 1978, 43, 371. 235 N. H. Anderson, D. A. McCrae, D. B. Grotjahn, S. Y. Gabhe, L. J. Theodore, R.M. Ippolito, and T. H. Sarkar, Tetrahedron, 1981, 37,4069. 521 Silicon-containing Carbonyl Equivalents 7 Conclusions It has been seen that there are many methods which employ organosilicon reagents for the synthesis of carbonyl compounds. Some of these methods have distinct advantages over more traditional methods.It is to be hoped that silicon- containing carbonyl equivalents find widespread use alongside the more traditional reagents.

ISSN:0306-0012    

DOI:10.1039/CS9821100493

出版商:RSC    

年代:1982

数据来源: RSC