ISSN:0306-0012    

DOI:10.1039/CS97302FX001

出版商:RSC    

年代:1973

数据来源: RSC

ISSN:0306-0012    

DOI:10.1039/CS97302BX003

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

The Growth of Computational Quantum Chemistry from 1950 to 1971 By G. G. Hall UNIVERSITY OF NOTTINGHAM 1 Introduction In the evolution of a science there are often prolonged periods devoid of dramatic discoveries but rich in rewarding results as the theory is thought through, the techniques tamed, and the applications accumulated. For Quantum Chemistry the past 21 years has been such a period. The foundations, such as the Schrodinger equation and the molecular orbital wavefunction, were already laid in the decade after 1925 as were the principal working tools such as variation and perturbation methods, expansions in atomic functions, and group theory. The years since 1950 have seen the building up of a sound theoretical super- structure on these foundations and the development of methods of calculation sufficiently reliable to be programmed and distributed widely for anyone to use.The inclusion of ‘computational’ in the title draws attention to the role of the computer in the subject. Its impact has been crucial, perhaps more so than in any other subject, as calculations that would have taken literally several lifetimes have become feasible. The extension of the subject beyond the limits of one- and two-electron systems to systems of general interest to chemists is really the consequence of having computers. The title is interpreted here as including both ab initio and semi-empirical calculations. In this context, since they often use the same methods and even the same programs, the distinction is not important.Although 1950 is, to some extent, an arbitrary date with which to begin this survey it does represent approximately the point when the subject began its postwar growth by initiating several new approaches. I have also a personal interest in accepting this suggested date since it is the date of my first paper so that I have been involved in the subject throughout the whole of this period. It is not the intention to deal with the details of the thousands of publications appearing during this period. A bibliography of review articles published since 1950 is provided for those who would like such details. Nor will I be concerned with questions of priority or credit which seem to me foreign to the true spirit of science and a source of many injustices and quarrels.2 The Situation in 1950 As mentioned above, the basic elements of Quantum Chemistry were already established in 1950. This is shown most obviously in the introductory textbooks by Eyring, Walter, and Kimball and by Coulson which date from that period and are still valuable references. On the other hand, the subject was difficult to learn to the standard required to begin research since there were few appropriate The Growth of Computational Quantum Chemistryfrom 1950 to 1971 lecture courses and no summer or winter institutes. It was virtually necessary to join, like an apprentice, one of the few existing groups with their ‘oral tradition’ of how things should be done and their collections of theses to serve as advanced textbooks.Even basic mathematical techniques, such as the calculation of eigenvalues and eigenvectors for a matrix, presented major problems since none of the methods now used was known then and the earlier methods were tedious and numerically unstable. The electronic computer had not yet arrived in 1950 and desk calculators were heavy and slow. A calculation on a simple diatomic could take a year, as could a Huckel calculation for a hydrocarbon with about a dozen carbon atoms. In these circumstances calculations were performed only when an important principle had to be established. Most of the time, results had to be obtained by making the maximum use of group theory and by appealing to a variety of crude approximations and analogies. One major factor in the situation which must be mentioned, because of its importance at the time, concerns the status of the subject in most chemistry departments. Apart from such minor matters as the structure of the hydrogen atom and the ultimate nature of the chemical bond, Quantum Theory was thought irrelevant to Chemistry.Chemists, organic chemists in particular, had achieved a systematic synthesis of their subject in terms that seemed final to them and could be seen to have practical point in predicting the properties of complicated compounds, whereas quantum theorists were still in dire trouble over such simple species as water and benzene. Thus Ingold, for example, writing his massive textbook on the ‘Structure and Mechanisms of Organic Chemistry’ in 1953can dismiss quantum mechanics in a few pages.The concepts of electron behaviour used in these explanations were usually qualitative and included electronegativity, ionic-covalent resonance, and the mesomeric and electro- meric effects. The principal hypothesis was that molecular structure determined molecular reactivities and vice versa. Since, consequently, their concepts were based partly on what was known of the structure of the molecule and partly on its susceptibility to reactions of various kinds, it was not possible to relate them all to quantum calculations of the electronic structure of molecules in their ground states. In so far as it seemed to be talking the same empirical language, valence bond theory was thought more relevant to chemistry than molecular orbital theory.The ultimate in theory was represented by Pauling’s book on ‘The Nature of the Chemical Bond‘. The inability of theorists to reply coherently to such simple questions as ‘Is the Coulomb energy always 15% of the exchange energy?’ and ‘Is planarity absolutely necessary for resonance?’ showed up how little they could contribute even when the problems were theoretical! In this situation the quantum chemist was tolerated only because he probably knew more statistical mechanics and he could integrate a kinetic equation from time to time! It must be confessed that Quantum Chemistry in 1950 had also some unfortunate legacies from its own past which retarded its progress.Earlier, imprecise arguments based on Hartree product wavefunctions had suggested that Hall molecular orbital theory was inappropriate for the description of excited states and consequently this area of application was neglected. On the other hand, the prediction of resonance energies and dissociation energies was given top priority without a clear appreciation of the complications involved in their definition, both theoretically and experimentally, because of the changes in nuclear geometry. Semiempirical theories suffered also from the absence of any clear statement of the approximations on which they were based so that no checking of the theories was possible and many of the derivations were suspect since their first principles were obscure.3 Progress made since 1950 Perhaps the most obvious change since 1950 is in the status of the subject. Quantum chemistry now has an honoured place in most chemistry departments and a share in the teaching programme. There are many textbooks propounding the subject and regular Institutes where the interested amateur can receive a concentrated professional training. The subject owes a great deal to those, like Coulson and Lowdin, who pioneered this instructional effort. We have also our own journals, The International Journal of Quantum Chemistry, Theoretica Chimica Acta, and Advances in Quantum Chemzktry though it is still true that papers are scattered through almost every Physics and Chemistry journal and sometimes even wider.This acceptance of Quantum Chemistry is closely related to its use in the analysis and interpretation of molecular spectra of various kinds. Classical descriptions of electronic structure and categories of explanation of electronic behaviour, derived inductively from ground-state observations, did not extend to excited or ionized states whereas explanations and predictions based on simple wavefunctions were remarkably successful. As n.m.r. and e.s.r. apparatus moved into experimental laboratories so it became patently obvious that there were some essential techniques of chemical analysis that could be comprehended only in terms of quantum variables and concepts. It also became intolerable, as Chemical Physics expanded, that the laws governing electrons in chemistry should differ from those governing electrons in physics.In Quantum Chemistry itself perhaps the greatest advance has been in the status of molecular orbital theory. It is now accepted that this theory can be made rigorous and amenable to practical calculations. Its predictions of molecular structure and of one-electron properties have been demonstrated in many examples to be substantially correct and, with a moderate use of configuration interaction, it can also account for electronic spectra. Predictions of two- electron properties and properties depending on a differencing of energies are not yet reliable. While it is the computer with its power and speed which has been the main factor in reaching this situation, it is also the result of careful analysis of the equations and of the methods of evaluating the integrals involved in them.The use of Gaussian basis functions, too, as well as the traditional exponentials has opened up several new ways of solving integral problems. An important achievement which can be ascribed to this period is the The Growth of Computational Quantum Chemistry from I950 to 1971 derivation of theoretical expressions for a large number of molecular properties. Some of these arise from the small relativistic terms in the Hamiltonian of the molecule itself and some from the interaction of the molecule with radiation or other external fields. For the lighter atoms some form of Breit Hamiltonian is sufficient for this purpose and for heavier atoms a radical change in approach is indicated but has not yet been established.In several instances new, specialized forms of perturbation theory have been required for the practical calculation of the properties. Even if the expressions have remained difficult to evaluate accurately, it has been important to trace the origin of each effect to specific terms in the Hamiltonian and to indicate the circumstances in which it will be very large or very small as well as the form of its dependence on such variables as the nuclear spin or the external field. A theoretical subject also advances by recognizing the limitations of some of its approaches. It is now clearly recognized that the arguments originally used to justify the Huckel form of molecular orbital theory are imprecise and inadequate.The theory does have some justification as an approximate treatment though it is not yet clear what limitations must be placed on this since its use of empirical quantities often means that correlation and other effects are implicitly included. Similarly, valence bond theory, in its original form, has been abandoned though not so much because the theory is imprecise or inaccurate as because the proper inclusion of all the overlap integrals produces an unwieldy formalism ill-adapted to calculation and with no natural definition of localization which would lead to a unique semi-empirical interpretation. The essence of the theory persists in localized geminal and pair theories.The use of one-centre expansions for poly- atomic molecules has been widely investigated and, while they continue to have a substantial attraction when considering hydrides, their rates of con- vergence for large molecules are too slow for practical calculations. Numerical analysis has contributed too since it has produced eigenvalue procedures so fast and reliable that earlier methods based on desk machines are super- seded and some pieces of theory whose only purpose was to avoid an eigen- value problem can now be eliminated. 4 Progress still being made There are several areas of Quantum Chemistry where substantial progress has been made but where the issues are not yet finally resolved. The most obvious of these is ‘the correlation problem’.The only generally successful method of obtaining wavefunctions whose accuracy exceeds the single-determinant wave- functions has been the multi-determinant (polydetor) or configuration interaction method. This gives part of the correlation relatively easily but its convergence in energy is slow and the labour required for extra accuracy increases rapidly. The interpretation and use of the complicated wavefunctions that emerge from the computer is also a problem, though analysis into natural orbitals and geminals has simplified part of this problem by making the expressions much more com- pact and providing entities which can be understood physically. Of the alternative approaches, the strongly orthogonal geminal and pair-function Hall theories try to allow for local forms of correlation, the trans-correlated wave- function introduces rla terms into the wavefunction and there are several methods based on field-theoretic techniques of organizing and evaluating the series expansions of perturbation theory.It is still possible that a direct variation of the two-electron density matrix will be the method of the future, though many of us despair of finding conditions for N-representability in a form suitable for molecular calculation. Much of this trying out of techniques and initiating of new and more sophisticated forms of wavefunction may seem futile to a practical chemist who believes ‘helium chemistry’ to be uninteresting but it is an essential part of the theoretician’s professional concern to be building up his stock of methods, and the helium atom has been our most valuable benchmark. Despite considerable progress, and the discovery of a number of practical algorithms, the calculation of molecular integrals remains a significant technical problem.As the number of basis functions in a calculation increases, the number of molecular integrals increases as its fourth power so that, in many calculations, the evaluation of integrals and the collection of them in various ways into matrix elements are the rate-determining steps. The possibility of numerical quadrature is very attractive since it could reduce the fourth power to the second and would allow the use of any type of basis function. Unfortunately, none of the numerical methods yet suggested has sufficiently rapid convergence to be an accurate and reliable procedure.The problem of collecting and sorting integral lists is fundamentally a list-processing problem and will be solved as programs for handling highly structured lists become generally available. The proper treatment of large molecules is still being debated. For many people the only procedure which is advocated as able to give worthwhile results is the semi-empirical one because its severe restrictions on the number of variables in the equations and its elimination of the worst of the integral problems through the use of experimental data make calculations feasible on moderately large molecules. Contemporary methods of this type are much more securely founded than the older methods, but there are still arbitrary features in these methods that have not yet been examined critically enough in circumstances where more exact treatments are available to give standards for comparison.We are still in the situation where each of us has his own semi-empirical method in which he believes but none of us has any trust in anyone else’s method. It has recently become apparent, however, that ab initio calculations can be extended to large systems using an almost minimal basis set of Gaussian functions. In terms of total energy these wavefunctions are poor (-95%) but they do seem to give some properties, especially structural properties, with good accuracy by a balancing of errors and they do not require any experimental data.Perhaps it is a good thing that we should have several modes of attack on the difficulties of large molecules. The quantum mechanical study of the reactions of molecules lags far behind the study of their structure. Few reaction surfaces have been calculated and little is known about how to proceed economically from the shape of the surface to the reaction rate itself. The use of indices calculated from the ground-state l%e Growth of Computational Quantum Chemistry from 1950 to 1971 wavefunction and based on a simplified treatment of one feature of the surface is no longer convincing though some of these indices may retain some empirical value. 5 Prospects for the Future Although it is not the intention of this paper to predict the future of Quantum Chemistry it is appropriate in the light of the past to suggest problems that will have to be faced in the near future.It is to be expected that technical problems will dominate the scene for some time yet. The search for better wavefunctions, for better methods of evaluating integrals and better treatments of molecular properties, including reactivities, will certainly continue. Nevertheless, the continued strengthening of computing facilities and the invention of more adequate list-processing algorithms may in the end be more significant than most of our present numerical experiments. I believe that the greatly improved status of Quantum Chemistry now, as compared with 21 years ago, is recognition of the fact that we have become professionals committed to our subject and convinced of its value instead of amateurs whose first interests are elsewhere.We have developed our techniques to the point where we can tell whether or not a property of a particular molecule can be calculated and, if so, with what functions and what expenditure of effort. In this sense we have an analytical tool which should be applied without further hesitation to solve genuine chemical problems which are difficult to study experimentally, such as structure problems for excited states and short-lived species. We ought also, in my opinion, to be paying more attention to the other uses of theory. Thus, for example, we should be concerned with the &ding of molecules which have some property in extreme form.The search for a molecular superconductor is one example of this. We should be designing new molecules for specific purposes. An example of this might be a molecule to catalyse a specific reaction rather as an enzyme does. We cannot know that we have really under- stood the action of an enzyme until we have successfully invented a new one. Molecules which can store information in such a form that it can be read in and out without being destroyed could even lead to molecular memories in computers and would stimulate interest in the memory systems used by insects and small animals. I am convinced, by the evidence of molecular biochemistry, that, as we move to large molecules, more elaborate molecular ‘systems’ become possible with many interesting co-operative properties that have no analogue in smaller molecules.It should be one of the aims of Quantum Chemistry to lead the way into this fascinating area by suggesting the properties and by investigating them using simplified models. This paper was first presented at the NATO summer school on ‘Computational Quantum Chemistry’ held at Ramsau in September, 1971. The author would like to thank the organisers for their invitation and for their permission to publish this lecture. Hall Bibliography of Review Articles in Quantum Chemistry Advances in Quantum Chemistry All of Volumes 1-5. Advances in Chemical Physics H. C. Longuet-Higgins, 1958, 1,239. P. 0.Lowdin, 1959,2,207.H. Hartmann, 1963, 5, 1. A. D. Liehr, 1963,5,241. 0. Sinanofjlu, 1964, 6,315. J. I. Fernandez-Alonso, 1964,7. R. Daudel, 1965, 8. R. K. Nesbet, 1965,9, 321. J. 0.Hirschfelder, 1967, 12. F. Ferreira, 1967, 13, 55. F. E. Harris and H. H. Nichols, 1967, 13, 205. R. Lefebvre and C. Moser, 1969, 14. J. D. Weeks, A. Hazi, and S. A. Rice, 1969, 16, 283. H. S. Taylor, 1970, 18, 91. A. Carrington, D. H. Long, and T. A. Miller, 1970,18, 149. B. J. Nicholson, 1970, 18, 249. Annual Reviews of Physical Chemistry H. C. Longuet-Higgins and G. W. Wheland, 1950,1,133. G. E. Kimball, 1951, 2, 177. C. A. Coulson, 1952, 3, 1. J. E. Lennard-Jones, 1953, 4, 167. A. D. Walsh, 1954, 5, 163. R. G. Parr and F. 0. Ellison, 1955, 6, 171.W. Moffitt and C. J. Ballhausen, 1956, 7,107. J. W. Linnett and P. G. Dickens, 1957,8, 155. M. Kotani, Y. Mizuno, K. Kayama, and H. Yoshizumi, 1958,9,245. J. A. Pople, 1959, 10, 331. P. 0.Lowdin, 1960, 11, 107. T. Fueno, 1961,12, 303. A. D. Liehr, 1962,13,41. 0. Sinanoglu and D. F. Tuan, 1964,15,251. B. M. Gimarc and R. G. Parr, 1965, 16,451. F. Prosser and H. Shull, 1966, 17, 37. A. Golebiewski and H. S. Taylor, 1967, 18, 353. L. C. Allen, 1969, 20, 315. A. D. Buckingham and B. 0. Utting, 1970,21,287. The Growth of Computational Quantum Chemistry from 1950 to 1971 Advances in Atomic and Molecular Physics G. G. Hall and A. T. Amos, 1965,1, 1. B. L. Moiseiwitsch, 1965, 1, 61. A. Dalgarno and W. D. Davison, 1966,2, 1. D. R. Bates and R. H. G. Reid, 1968,4, 13. R. J. S. Crossley, 1969, 5, 237. Reports on Progress in Physics W. Moffitt, 1954, 17, 173. G. G. Hall, 1959, 22, 1. D. ter Haar, 1961,24, 304. J. Owen and J. H. M. Thornley, 1966, 29, 675. Methods in Computational Physics All of Volume 2 (1963).

ISSN:0306-0012    

DOI:10.1039/CS9730200021

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

Total Syntheses of Prostanoids By P. H. Bentley BEECHAM RESEARCH LABORATORIES, BROCKHAM PARK, BETCHWORTH, SURREY 1 Introduction ‘Prostanoids’ is a recently introduced1 term used to designate the family of natural prostaglandins and prostaglandin-like compounds (cf. ‘steroids’). The prostaglandins have been known for about forty years, but not until 1962 was the structure of prostaglandin El announced by Bergstrom and co-workers.2 Since then at least fourteen more have been isolated from various sources. Few other biologically potent, naturally occurring substances have such diverse bio- logical effects, and it is reasonably certain that some clinical use will be found for at least one member or a synthetic analogue. The need for adequate amounts of the materials has led to several total syntheses of these substances and it is with this aspect that the review is concerned.Literature to April, 1972 is included. For other aspects the reader is referred to a recent review by Horton3 as well as to an earlier chemical re vie^.^ 2 Nomenclature and Structures The structures of the prostaglandins (PG’s) are derivable from prostanoic acid (1). They occur in four series, designated by the letters E, I;, A, and B [partial structures (2)--(5)], depending on the substitution within the ring. (1) I I HO HO E Series F Series A Series 8 Series (2) (3) (41 (5) E. J. Corey, T. Ravindranathan, and S. Terashima, J. Amer. Chem. Soc., 1971, 93, 4326 S. Bergstrom, R. Ryhage, B. Samuelsson, and J.Sjovall, Acta Chem. Scad., 1962, 16, 501 E. W. Horton, ‘Prostaglandins’, Vol. 7 of Monographs on Endocrinology, Springer Berlin, 1972. J. E. Pike, Fortsch. Chem. Ore. Naturstoffe, 1970, 28, 313. TotaI Syntheses of Prostanoidr As well as a 15-hydroxy-group, up to three double bonds may be present in the side-chains. Thus El, E2, and E3 have one, two, and three double bonds respectively in the positions and with the configurations shown in (6)-(8). 0 (6) PGE1, no 5,6 -or 17,18-double bond (7) PGf2,5,6 -cis, no 17,18 -dou b[e bond (8) PGE3,5,6 -cis, 17,18-cis -double bond The 13,14-double bond is trans In the F series the 9-hydroxy-group can be either a,and hence cis to the C-8 side-chain, or p, when it is trans. Only the former occurs naturally.Prosta- glandins with a 19a-hydroxy-group also occur naturally. Structure (6) shows the absolute stereochemistry of PGEl as determined by X-ray analysis. PGEl is therefore (-)-1la,l5(S)-dihydroxy-9-oxo-13-trans-prostenoicacid. The six prostaglandins of the E and Fseries are termed the primary prostaglandins. 3 Chemical Syntheses The salient features of PGEl (6)are the four chiral centres, the /?-ketol function in the five-membered ring, the all-trans arrangement of the three ring substituents, and the allylic alcohol group at C-15. The additional cis-double bonds and the configuration of the 9-hydroxy-group in the Fseries add further problems to the design of a general synthesis. Furthermore, prostaglandins of the E and A series both give rise to B-prostaglandins under basic conditions, whereas under acidic conditions E-prostaglandins dehydrate to A-prostaglandins. Final steps in any synthesis must therefore be conducted under mild conditions. Earlier reductions of the 9-keto function of the E series yielded a separable mixture of the Fa and the biologically less active Fp-prostaglandins. However, more sophisticated reducing agents furnish the desired Fa compounds exclu- sively5so that a synthesis of the E-prostaglandins becomes a more general one.A conversion of a PGAa derivative into a mixture of PGE, and its llp-epimer E. J. Corey and R.K. Varma, J. Amer. Cliem. Soc., 1971, 93, 7319. BentZey by an epoxidation and reduction sequence has also been reported.6 These interconversions are shown in a general form in Scheme 1.0 HO I ___) 42i” QHO +m0 lii\0 0 0“I.;\ ... Ill -A B Reagents: i, LiBHR3 (for Rsee ref. 5); ii, H20 -AcOH or HCI -H20-THF; iii, KOH-MeOH; iv, H202-KOH-MeOH; v, Ct2+ Scheme 1 Commercially it would be desirable for a synthesis to be as adaptable as possible and ideally to provide in high yield all the resolved primary prosta- glandins and desirable analogues from a single intermediate. So far only the latest Harvard synthesis is likely to meet all these requirements. In this review prostanoid syntheses have been divided into those in which the cyclopentane ring is formed from precursors which incorporate at least one of the carbon side-chains and those where both side-chains are elaborated from initially ‘simple’ cyclopentane derivatives.The object of the review is not to be comprehensive but to illustrate the diversity of the schemes and to suggest which are of commercial importance. 4 Prostanoids from Single-chain Precursors It is convenient to subdivide this section according to which carbon-carbon bond of the ring is formed. A. C-8-C-12 Bond Formation.-Historically this section includes the first synthesis of a prostanoid by Samuelsson and Stallberg.’ Base-catalysed cycliza- G. L. Bundy, W. P. Schneider, F. H. Lincoln, and J. E. Pike, J. Amer. Chem. SOC.,1972, 94, 2123. B. Samuelsson and G. Stlllberg, Actu Chem. Scund., 1963,17,810. 31 2 Total Syntheses of Prostanoids tion of (9), followed by ester hydrolysis and decarboxylation, afforded 15-deoxy- 13,14-dihydro-PGB1 (10) and an isomer (1 1) arising from an alternative mode of cyclization.These isomers were critically compared with a degradation product of natural PGE,, the results supporting the earlier proposed structure (6). (9) (10) + Miyano and Darns effected a similar cyclization of (13), available from a condensation of styrylglyoxal and the diacid (12). The product (14) on hydroxyla- tion and cleavage of the side-chain and reduction of the ring double bond afforded the aldehyde (15). This underwent a Wittig condensation with the phosphorane (16) to furnish 15-dehydro-PGE, (17), together with the 118- epimer and small amounts of dehydration products, all separable by chromato- graphy (Scheme 2).Although the selective reduction of the 15-oxo-group in (17) remained to be solved, and recent work@ suggests that this may be possible microbiologically, the small number of steps and good yields make the synthesis otherwise attractive. Syntheses of PGB, are presently of less commercial interest because it has low biological activity and it has not yet been converted into the primary prosta- glandins. A total synthesis was achieved by three groups10-12 utilizing the diketone (19). The latter was prepared either by selective reductionlOJ1 of (18), available from a condensation of 9-oxo-decanoic acid and oxalate, or by cycliza- tion12 of (20) (Scheme 3). Reaction of the corresponding enol ether (21) with the acetylenic Grignard reagent (22), followed by acidic work-up, afforded (23) as a mixture of C-15-epimers.Partial reduction of the latter gave (+)-PGB1 or * M. Miyano and C. R. Dorn, Tetrahedron Letters, 1969, 1615. M. Miyano, C. R. Dorn, F. B. Colton, and W. J. Marsheck, Chem. Comm., 1971,425. lo P. Collins, C. J. Jug, and R. Pappo, Israel J. Chem., 1968, 6, 839. l1 J. Katsube and M. Matsui, Agric. and Biol. Chem. (Japan), 1969, 33, 1078. 1969,17,408.(Japan),Bull.Chem. and Pharm. Ide,J.Y. Yura and 1' Bentley the &-isomer (24), which was isomerized to PGBl by dilute alkali. Use of optically active (22) has also afforded natural PGB1.13 LLPGE, C5H11 HO 0 Reagents; i,PhCH=CHCO-CHO; ii, aq.NaOH; iii, Os04 -NaIOk ;iv, Zn -AcOH; Scheme 2 B.C-ll-C-12 Bond Formation-Two general syntheses by Corey and co-workers were characteristically outstanding in that pure crystalline prostaglandins of the E and Fseries were obtained for the first time and, in the case of PGE1,a resolu-tion step provided both enantiomeric forms. In addition, completely new chemistry of general applicability was devised. The important synthetic concepts of these elegant syntheses were: (i) the use of the 9-nitro-group as a precursor of the 9-keto function, into which it was transformed under mild conditions; (ii) the successful use of the tetrahydropyranyl (THP) protecting group which suggested that the E series might be obtainable from 11,15-bis-THP-prosta-glandin F derivatives, an important concept of the Harvard bicyclic route; and (iii) the use of aldol cyclizations at a late stage of the synthesis, leading directly to the C-11-C-15 ene-diol unit or its equivalent.R. Pappo, P. Collins, and C. J. Jug, Ann. New Yorkhad. Sci., 1971,180,64. 33 Total Syntheses of Prostanoids Reagents: i, Hz-Pd/C-H'; ii,EtCOCl -AIC13; iii, CH2N2 ; iv, Zn -Pb; v, H2 -Lindlar catalyst; vi, aq.NaOH Scheme 3 In the first of these the key intermediate (29) was constructed by a six-stage process commencing with the Diels-Alder addition of (25) and (26), which gave the adduct (27) as the major product. The latter was modified to (28) (Scheme 4), the cyclohexene ring oxidatively cleaved, and the product (29) cyclized using the base (30).Acetylation of the product fwnished (31) along with small amounts of the llb-epimer. Reduction of the ketone function and ketal hydrolysis gave (32), which was dehydrated to (33) under neutral conditions by a new and useful reaction with dicyclohexylcarbodi-imide,catalysed by cupric chloride. On reduction, the enone (33) yielded both C-15-epimeric alcohols, which were further transformed, via (34),to racemic PGE, and its C-15-epimer. After separation PGE, was converted into PGF,,, PGFlP PGA1, and PGBl by reactions shown in Scheme 1. E. J. Corey, N. H. Anderson, R. M. Carlson,J. Paust, E. Vedejs, I. Vlattas, and R. E. K. Winter, J. Amer. Chem. SOC.,1968,90,3245. Bentley HCONH "I ,R vi ,vii C5Hll HCONH HO 0 AcO 0 THPO OTHP (33) x,;i;4'/-PGEl + 150-epimer Reagents: i, A[-Hg (NO2 +NH2); ii, HC02Ac ( NH2 -HCONH); iii, [E: 9 Hg2* (ketal exchange); iv, 0~04;v, Pb(OAc)4; vi, QN (30); vii, Ac20; viii, NaBHb; ix, H'; w x, C6Hl1NCNC6Hl1- CuCI2; xi, ZnBH,; xii, KOH (OAc -OH); xiii, (OH-OTHP); xiv, KOH(CN-CO2H and HCONH-NH,); XY, NBS(NHp NHBr); xvi, OH'(-HBr); xvii, H+( )NH -)O and OTHP+ OH); xviii,chromatography Scheme 4 Total Syntheses of Prostanoids In a second synthesis15 stannic chloride-catalysed cyclization of (39, which reacted as the aldehyde (36), led to the enone (37), essentially free of the llg-epimer (Scheme 5).Other acidic catalysts gave both C-1 l-epimers. Following p2 R IL *C5Hll C5H1 1L L0 HO 0 Reagents: i, SnCl ;ii, ZnBHL;iii, base ; iv, chromatography; v,Al-Hg; vi, HCOzAc, then xiii -xvii of Scheme 4 Scheme 5 reduction of the ketone function in (37) with zinc borohydride, mild base treat- ment of the products placed the nitro-group and C-8 side-chains in the more stable trans-orientation, enabling the C-15-epimers (38) to be separated by chro- matography.The synthesis of PGEl was completed essentially as before, but in addition the amine (39) was resolved and each enantiomer reacted separately. The natural forms of the prostaglandins were thereby obtained for the first time. The later bicyclic route was the result of the need for a general synthesis, particu- larly of the higher prostaglandins (PGE,, PGEs etc.), to which the above routes were not easily adaptable.Several potential PGEl syntheses were described by Morin and co-workers.16 Thus it was envisaged that dialdehyde (40), which had been obtained from l6 E. J. Corey, I. Vlattas, and K. Harding, J. Amer. Chem. Soc., 1969, 91,535. l6 R. B. Morin, D.0.Spry, K. L. Hauser, and R. A. Mueller, Tetrahedron Letters, 1968, 6023. 36 Bentley aromatic precursors, might undergo intramolecular aldol cyclization to furnish (41). In the event no aldols were isolable. Moreover, the alternative mode of cyclization was preferred, so that at best a separable mixture of (42) and (43) was produced. Further reactions of (42) afforded PGB1, but added difficulties were encountered in removing the protecting ketal group, and only low yields were obtained.OR ,,,an nm OGpI" o(y b0 R CHO CHOCHo CHO OH (40)R=(CH2)6CO2Me (41) (421 (43) C.C-10-C-11 Bond Formation.-Strike and Smith1' synthesized a stereoisomeric mixture (47), containing 13,14-dihydro-PGEI, providing the only example in this section. Thus cyclization of the aldehyde (44)furnished the enone (45), which was epoxidized and hydrogenated to (46).Mild acid treatment gave (47).w:;::,e:;:,,-K 0 2 HC5Hll CHO OTHP OTHP OH OR (44) (451 (46)R=THP (47)R=H D. C-9-C-10 Bond Formation.-A route to PGE, methoxime by Finch and FitP will be only briefly discussed. Dieckmann cyclization of the tetraester (48) followed by five more steps afforded the enone (49).Introduction of the 11-hydroxy-group was achieved by allylic bromination to (50), treatment with silver acetate to (51), and methanolysis to (52). Following silylation, which gave (53), hydrogenation afforded the all-cis derivative (54), arising from cis-addition of hydrogen to the face opposite the bulky silyloxy-group. After protecting the 9-keto-group with methoxyamine and subsequent base treatment to place the side-chains in the more stable trans-orientation, eight further steps furnished PGEl methoxime. The protecting group was not successfully removed. E. C-8-C-9 Bond Formation.-No examples in this section have appeared. l7 D. P. Strike and H. Smith, Tetrahedron Letters, 1970, 4393. l* N.Finch and J. J. Fitt, Tetrahedron Letters, 1969, 4639.37 Total Syntheses of Prostanoids ** C02 Me (48) R=(CH2)6C02H X or ester (49) X = H (54) (50) X = Br (51) X = OAc (52) X = OH (53) X = OSiMes 5 Prostanoids from 'Simple' Cyclopentanes A. Monocyclic Cyc1opentanes.-The 1 1 -deoxy-E and -F prostaglandins are currently of interest as possible substrates for microbiological oxidation at C-11 as well as for their intrinsic biological properties. A recent synthesis by Caton Reagents: i, cyclopentanone enamine ; ii, HCI -BuOH; iii, MezC(0H)CN -Na2CO3; iv, Bu\ AIH; v, phosphorane (IS); vi, Cr03-H'; vii, NaBH4 Scheme 6 Bentfey and co-worker~~~ illustrates a relatively simple route to them (Scheme 6). The condensation product of cyclopentanone and the aldehyde (55) was dehydrated by acid to the enone (56; R = CH20H).Reaction of the latter with cyanide ion, provided by acetone cyanhydrin, afforded the nitrile (57; R = CH80H). The alkaline conditions of the reaction favour the formation of the more stable trans-isomer. Di-isobutylaluminium hydride reduced both the keto and nitrile functions of (57), and the product (58), after Wittig condensation, was oxidized at both alcohol groups and finally reduced to give a mixture (60), containing 1 1 -deoxy-PGF,,. The corresponding PGFIBderivative had been prepared earlier by Bagli and BogrPO using (56; R = C02H), which had been synthesized from Z-ethoxy- carbonylcyclopentanone. Thus diacid (61; R = H),obtained by hydrolysis of the corresponding nitrile (57; R = C02H),was selectively esterified to the half-ester (61; R = Me).The elaboration of the C-12 side-chain was then achieved as follows: the acid chloride of (61; R = Me) reacted with hept-l-yne in the presence of aluminium chloride to provide (62) ;methanolic sodium hydroxide afforded the enol ether (63; R = Me), and hydrolysis, the acid (63; R = €3); reduction of the latter by sodium borohydride followed by acid treatment led to the isolation of the enone (64); the configuration of the 9-hydroxy-group was established by other evidence; finally, a second borohydride reduction gave 1 l-deoxy-PGFlp (65) and its 15p-epimer. The enone (56; R = C0,H) was also utilized in two similar syntheses of PGBl by Hardegger and co-workers,21 and by Klok and associates.22 OH t(64)X = CH=CHCO.CSH,l t(65) X = CH=CH$HC,H,I.I I OH M.P. L. Caton, E. C. J. Coffee, and G. L. Watkins, Tetrahedron Letters, 1972, 773. J. F. Bagli and T. Bogri, Tetrahedron Letters, 1967, 5. a1 E. Hardegger, H. P. Schenk, and E. Broger, Helv. Chim.Acta, 1967,50,2501. R. Klok, H. J. J. Pabon, and D. A. Van Dorp, Rec. Truv. chirn., 1968, 87, 813, and for extension to El series: ibid., 1970,89, 1043. Total Syntheses of Prostarioih vii 0 / ? -o-d( viii ~ I 2 OH Q,R 6H dH (67)(73) (74) COCl Reagents : R (69) i, PhCH20CH2CI ;ii, CH;!=C(CI)COCI j iii, NaN3 (COCL-CON3); CI CIiY,heat(CON3-NCO); v, Ht+(>(NCo-xNH2 +)=NH-+O); vi, m -CIC6H4 C03 H; vii, NaOH; viii, K13-NaHC03 Scheme 7 B.Bicyclic Cyc1opentanes.-This section includes three ~yntheses~~-~~ using bicyclic intermediates. The Harvard synthesisz3 has provided intermediates from a3 See references 26-30 inclusive. 24 H. L. Slates, Z. S. Zelawski, D. Taub, and N. L. Wendler,J.C.S. Chem. Comm., 1972,304. 25 U.Axen, J. L. Thompson, and J. E. Pike, Chem. Comw., 1970, 602, and earlier references cited. Bentley which all the primary prostaglandins in resolved form have been obtained. Prostaglandin El is produced in twenty-one steps from cyclopentadiene, and yields are now such that the prostaglandins could soon be available on a sub- stantial scale. Of the other two schemes, the one by Slates and co-worke~s~~ affords natural PGEl in twenty-nine steps from penta-lY3-diene, but yields, although probably not yet optimum, are less good.The Upjohn synthesis,25 which has been discussed in the review by Pike,* has also led to most of the primary prostaglandins and their isomers. It has the advantage of being short, PGEl being produced in thirteen steps from norbornadiene. However, it suffers from poor yields at several stages. Only the Harvard scheme will be discussed in detail. One important intermediate in Corey’s route is the bicyclic iodolactone (74), the preferred synthesis26 of which is shown in Scheme 7. The average yield per step is 85 %. Because the alkylcyclopentadiene (66) is prone to isomerization to (67), it was found essential to carry out the alkylation and Diels-Alder reactions well below 0°C and with as short an isolation time as possible.For large-scale operations the route shown had definite advantages over an earlier process.27 The reaction of (66) with the dienophile led to (68), where the benzyl- oxymethyl substituent is exclusively anti to the carbon bearing the chloro and chloroformyl groups. In particular, no syn or 2 + 2 addition products [e.g.(69)] were formed. Replacement of the two groups by oxygen was achieved as shown without isolation of intermediates. The oxidation of the product (70) afforded (71) exclusively, no epoxide or isomeric lactone being produced. The hydrolysis product (72) was purified as an ammonium salt and if required. Thus the (+)-salt formed with (+)-amphetamine provided the natural prostaglandins, whereas the enantiomeric series would be obtained from the corresponding (-)-salt.It is apparent from the numbering in (72) that the carboxymethyl group ultimately provides the C-8-substituent and the benzyloxymethyl group the C-12-substituent. Reaction of (72) with potassium tri-iodide in aqueous bi- carbonate introduced the 9a-hydroxy-group at (74) via the intermediate (73). The iodolactone therefore contained the desired stereochemistry at all the nuclear centres. Its conversion into the various prostaglandins will now be described. PGF2,.28 Acylation of (74) and deiodination provided (73, which was trans- formed into (78) by the sequence: catalytic hydrogenation to (76), oxidation with chromic oxide-pyridine complex to the aldehyde (77), and Wittig condensation with phosphonate (79) (Scheme 8).In this sequence the p-phenylbenzoyl (PB) group was chosen over simple acetyl since it allowed for easier crystallization and chromatographic separation of the subsequent reduction product (80) from its 15p-epimer. This reduction of (78) was extensively studied. Zinc borohydride produced a 1 : 1 mixture of the epimers. Other reducing agents yielded lesser z6 See ref. 1 and ref. 28. E. J. Corey, U. Koelliker, and J. Neuffer, J. Amer. Chem. SOC.,1971, 93, 1489, and cited references to earlier work. E. J. Corey, S. M. Albonico, U. Koelliker, T. K. Schaaf, and R. K. Varma, J. Amer. Chem. Suc., 1971, 93, 1491. 41 Total Syntheses of Prostanoids C5H11 PBO I I I I PBO HC) OTHP ATHP (75)R= CHzOCH2Ph (80) (76) R= CH,OH (77)R = CHO HO J Me I C-Pri Reagents: i, p-C&C6H&OCI; ii, 8u: SnH; iii, Hz-Pd/C-H+; iv, CrO3-py ;v, (79); vi, (81)-Bu'Li -OP( NMQ~)~- vii,K2C03; viii, 0; ix, Bu~AIH;x, (83);xi,Hf THF; Scheme 8 Bentley amounts of (80) and products arising from a 1,4-reduction of the enone system.However, of several optically active borohydride ions (Li+BR,H), the reagent derived from the borane (81) and t-butyl-lithium in hexamethylphosphoramide-tetrahydrofuran at -120"C,was shown to reduce (78) to (80) and the 15p-epimer in the ratio 4.5 : 1. Commercially it may be more convenient to effect this reaction with less sophisticated reagents since, following separation, the unwanted epimer can be reoxidized to (78) for recycling.An alternative approach to the stereoselective introduction of the 15-hydroxy-group is described later. The ester group of (80) was next hydrolysed and the two hydroxy-groups of the product reprotected as THP-ethers. Reduction to the lactol(82) and Wittig condensation with phosphorane (83) provided (84) with the desired 5,6-cis-double bond. Mild hydrolysis furnished PGF,,. PGF,,, PGE2, PGE,. Scheme 9 shows how intermediate (84) was further HO .OHI OTHP OTHP OTHP OTHP (84) .. ...i, iii Ii II, Ill iPGEZ PGf1 Reagents: i, H,-Pd /C;ii, CrO,; iii, Ht Scheme 9 tran~formed.~~The selective reduction of the 5,6-double bond depended on the screening of the 13,14double bond by the two tetrahydropyranyloxy-groups.More recent work6 has shown that the dimethylisopropylsilyloxy-groupis even more effective in this respect. PGF,,, PGE,. The desired C-12side-chainof these prostaglandins was introduced stereo~pecifically~~by condensation of optically active aldehyde (85) with the ylide derived from the phosphonium salt (86) (Scheme 10). The latter had been E. J. Corey, R. Noyori, and T. K. Schaaf, J. Amer. Chem. SOC.,1970,92,2586. E. J. Corey, H. Shirahama, H. Yamamoto, S. Terashima, A. Venkateswarlu, and T. K. Schaaf, J. Amer. Chem. SOC.,1971,93, 1490. 43 Total Syntheses of Prostanoids 04 04(75) i-iv @ V @ av-THP~aCHO THPO 6H (85) (87) OH /ii \ A H ____) PGF3aIX THPO OTHP (88) VIII,IX PGf31".* I' P h 3 b- w I OH Reagents : i, K2CO3 ;ii, I ;iii, H2-Pd /C -H';0 (86) iv, CrO3-py ; v, (86) -MeLi ;vi, Bu~ALH;vii,(83); viii, Cr03;ix, Ht Scheme 10 prepared from S-( -)-malic acid. The product (87) was transformed as before to a bis-THP derivative (88) and thence to natural PGF,, and PGE,. PGA2. A novel elimination reaction of the iodolactone (74) provided the basis of a high-yielding synthesis31 of the PGA intermediate (94) (Scheme 11). Al-though the A series is available from the E series (Scheme l), this attractive synthesis is of considerable interest. The elimination to (89) was followed by a one-step ether-cleavage and esterification to (go), ester and lactone reduction to (91), methyl acetal formation to (92), and transformation of the latter to (93) and (94) as before.Further reactions of (94) were not described, but a conversion into (94a) would be envisaged, followed by oxidation and hydrolysis to PGA2. a1 E. J. Corey and P. A. Grieco, Tetrahedron Letters, 1972, 107. BentZey OXMQ i-iv (74) -pi -QCHO (89)%*ORR= CHZPh, X= 0 (93) (90) R=Ac,X= 0 (91) R=H, X= OH (92) R=H, X=OMe OH 0 OTHP (94) (94a) Reagents : i, MeS02CI ;ii,Ac20-BF3; iii, BuhAIH; iv, BF3-MeOH; vJr03-p~; vi, (79); vii, ZnBHi; viii, 0;ix,(83); x,Cr03;xi,H+ 0 Scheme 11 Other Prostanoids. Reference has already been made to the importance of the 11-deoxy-prostaglandins. An efficient route to them was developed by Crabb6 and G~zmin~~ using racemic (89).Direct reduction of the double bond in (89) with Raney Nickel produced (99, through simultaneous hydrogenolysis of the aIlylic oxygen33 (Scheme 12). However, the corresponding hydroxy-acid (961, after reduction and re-lactonization, furnished the desired lactone (97). The P. Crabbe and A. Guzmin, Tetrahedron Letters, 1972, 1IS. 33 (95) was subsequently transformed to a 9,ll-bisdeoxyprostaglandin(ref. 34). s4 P. CrabbC, A. Cervantes, and A. Guzmhn, Tetrahedron Letters, 1972, 1123. Total Syntheses of Prostanoids 9",CHZCO,H ,,CH,CO,H qCHpOCH.Ph CH2OCH2Ph CH2OCH2Ph (95) (96) (97) (100) x= CI (98) (101) X= H 04 xii -or 11 -deoxy -PGF2a or Q+/C*Hl1 xii,xiii,xv,xiv) 11 -deoxy-PGE2 I OTHP (99) Reagents: i, Raney Ni; ii, H'; iii, H2-Pd/C-Ht;*iv, Cr03-py; v,C12CHCOCl -Et3N; vi, Zn -AcOH; vii, H202-OH7 viii, Tl (NO&-H'; ix, (79); x, ZnBHA ;xi, xii, Bu~ALH ;xiii, (83); xiv, H'; xv, CrO3 Scheme 12 synthesis was completed along now familiar lines as shown, e.g.(97) -+ (98) -+ (9%-11-deoxy-PGE, or -POF,,. However, this route had probably already been superseded by a novel and Bentley -b0OAcOAc .. ... I 11,111 + &ir fH OAc &/ (107) R= O-OH(103) R = 0 (106) (104) R= a -OH (108) R = 0 (105) R = a -OAc OAc ?Ac v-viii .KC02Me I:H OAc 6Ac (109) (110) R= CHq (111) R= CHqCHCOC5H11 (112) R = CH-CHCHC5H11 3 OH C5Hll xi-xiii,xv,xit OH OH (114) R= a -OH (11 5) R = 0 Reagents: i, On(105): m-Cl*C6H4C03H; ii, HBr; iii, oxidize; iv,CaCO3; v, Os04;vi, Pb(0Ac)A; vii, (79); viii,.ZnBH~,; ix, KOH;x, HCl -MeOH; xi, 0;xii, BuiAlH; xiii, (83);xiv, H+; xv, CrO3 0 Scheme 13 Total Syntheses of Prostanoids simple synthesis by the Harvard who obtained (98) in four steps from cyclohexadiene with an average yield of > 85 %.Thus the adduct (100) from the diene and dichlorketen was dechlorinated to (101) (Scheme 12). Careful oxida- tion provided the desired lactone (1 02), which underwent oxidative ring- contraction with thallium trinitrate to furnish (98). The later stages of the Harvard syntheses of PGF,, and PGEe were also used by Cro~sley~~ to prepare the cyclohexane analogues (1 14) and (115) (Scheme 13).Thus the dione (103), available from a Diels-Alder addition of p-benzoquinone and butadiene, was reduced with sodium borohydride, and the isolated cis-diol (104) was acetylated to (105) and epoxidized. After removing the a-epoxide, the /%isomer (106) was treated with hydrogen bromide to give the bromohydrin (107), oxidized to the bromoketone (108), and dehydrobrominated to (109). Hydroxylation and cleavage of the double bond furnished the aldehyde (110), which underwent Wittig condensation to the enone (1 11). The latter was reduced to the diols (1 12), the three ester groups hydrolysed, and the product lactonized to (113). The remaining steps closely followed the Harvard syntheses and furnished the analogues (1 14) and (115) and their C-15-e~imers.~' An unexpected source of the prostaglandins, which might compete with the syntheses discussed, is the coral Plexaura homomalla, which has been shown to contain PGA2 and its C-15-e~imer;~~ these have been converted into PGE2 and PGF2,.6 Note added in proof: The rapid developments in prostanoid chemistry since April 1972 have seen the following innovations. 1.Conversion of PGF's into PGE's (E. W. Yankee, C. H. Lin, and J. Fried, J.C.S. Chem. Comm., 1972, 1120). 2. Further stereoselective syntheses based on bicyclic intermediates (G. Jones, K. A. Raphael, and S. Wright, J.C.S.Chem. Comm., 1972, 609; and D. Brewster, M. Myers, J. Ormerod, M. E. Spinner, S. Turner, and A. C. B. Smith, ibid, p. 1235). 3. Synthesis from (82), (74), and (96), respectively, of novel prostanoids con- taining: (i) a propadiene group at C-4,5 (P.CrabbC and H. Carpio, J.C.S. Chem. Comm., 1972, 904). (ii) a 10a-hydroxy-group (P.CrabbC, A. Guman, and E. Velarde, J.C.S. Chem. Comm.,1972, 1126). (iii) photoadducts at C-10,ll (P. CrabbC, G. A. Garcia, and C. Rihs, Tetrahedron Letters, 1972, 295 1). The author thanks colleagues at the Beecham and Wellcome Research Laboratories for helpful discussions. 36 E. J. Corey and T. Ravindranathan, Tetrahedron Letters, 1971, 4753. 36 N. S. Crossley, Tetrahedron Letters, 1971, 3327. ~3' Other true analogues include the 7-oxo-PG's. For these and others see: J. Fried, C. Lin, M. Mehra, K. Kao, and P. Dalven, Ann. New York Acad. Sci., 1971,180,38. s8 W.P. Schneider, R. D. Hamilton, and L. E. Rhuland, J. Amer. Chem. SOC.,1972,94,2122.

ISSN:0306-0012    

DOI:10.1039/CS9730200029

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

Lanthanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy By B. C. Mayo DEPARTMENT OF CHEMISTRY, THE POLYTECHNIC OF NORTH LONDON, HOLLOWAY, LONDON N7 8DB 1 Introduction Nuclear magnetic resonance (n.m.r.) spectroscopy is a most valuable technique for structural investigations of complex organic molecules. However, owing to the relatively low sensitivity of proton chemical shifts to changes in the chemical and stereochemical environment, the application of n.m.r. spectroscopy has been severely restricted. Such terms as the ‘methylene, methine envelope’ used fre- quently in connection with the proton n.m.r. spectra of steroids and terpenes illustrate this frequent overlapping of resonance of non-equivalent protons. Shift reagents are used in n.m.r.spectroscopy to reduce the equivalence of nuclei by altering their magnetic environment, and are of two types: aromatic solvents such as benzene or pyridine, and paramagnetic metal complexes. The latter function by co-ordinating to suitable donor atoms in the compound under study, thereby expanding their co-ordination shell and forming a new complex in solution. Apart from effects due to shielding by bonding electrons, the chemical shifts are altered by the paramagnetic metal ion by a transfer of electron spin density, via covalent bond formation, from the metal ion to the associated nuclei (contact shift), or by magnetic effects of the unpaired electron magnetic moment (pseudocontact shift). First-row transition-metal complexes can be used as shift reagents and operate by both contact and pseudocontact mechanisms, although the former predominates owing to the covalent character of these compounds.Unfortunately, these shift reagents exhibit an adverse effect on the resolution of the n.m.r. spectra by causing severe line-broadening. In 1969 Hinckleyl initiated a major advance in this field by introducing the use of a lanthanide-metal complex as a shift reagent and since then it has become established that lanthanide complexes produce far less linewidth broadening and give shifts which are caused virtually exclusively by the pseudocontact mechanism. The complexes found most useful are lanthanide acetylacetonate derivatives, some of which are fluorinated and exhibit greater shifting power. The most common practice is to successively add known amounts of the lanthanide shift reagent (LSR)to the compound under study (substrate) and record the n.m.r.spectrum after each addition. The chemical shift of each proton in the substrate alters, to a greater or lesser degree, with each addition of shift C.C. Hinckley, J. Amer. Chem. SOC.,1969, 91, 5160. Lanthanide Shvt Reagents in Nuclear Magnetic Resonance Spectroscopy reagent and the extent of this lanthanide induced shift (LIS) is measured. A plot of the LIS against the ratio of LSR: substrate is a straight line at low values of this ratio. The slope of this line is characteristic of the compound under study. Apart from spectral clarification, the factors determining pseudocontact shift allow relative distances within the complex to be determined, permitting studies of the stereochemistry of the substrate under examination.The application of LSRs in n.m.r. spectroscopy has permitted the solution of a large number of structural problems and one example of this occurs in the use of chiral lanthanide shift reagents for estimating the composition of mixtures of enantiomers. 2 Substrate-Lanthanide Shift Reagent Interaction The lanthanide shift reagent consists of a six-co-ordinate metal complex which readily expands its co-ordination in solution to accept further ligand~.~~~ The substrate co-ordinates to the LSR by virtue of the requirement that it contains heteroatoms which exhibit some degree of Lewis basicity.Addition of the LSR to a solution of the substrate in a normal n.m.r. solvent leads to the formation of an equilibrium mixture, as shown in equations (1) and (2) K L + s + [LS] KS ES] + s + [LS,] where L and S are the concentrations of the LSR and substrate, respectively, and [LS] the concentration of the complex formed in solution; the ratios of these species depends on K and K2,the binding constants. The latter binding constant K2 is usually assumed negligible (see later), i.e. a 1 : 1 complex is thought to be formed. Owing to the magnetic interactions with the metal ion (Section 3) in the complexed substrate [LS], the n.m.r. positions of associated nuclei in the substrate differ from those in the uncomplexed state. The equilibrium in solution between these species is rapid on the n.m.r.timescale: so that only a single average signal is recorded for each nucleus in the different environments.* This does not mean that the whole spectrum is merely displaced since factors such as the distances of the nuclei from the metal ion cause a differential expansion of the spectrum. Consequently, the foremost use of LSR is in effectively increasing the resolution, in many cases producing first-order spectra. An expression can be derived for the lanthanide induced shift (LIS), denoted by ad,of the nuclei of the substrate before and after addition of the LSR? * Slow chemical exchange is reported5 to occur at -8OOC with a solution of dimethylsulphoxide and the LSR tris-(1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane-4,6-dionato)-europium(II1) [Eu(fod),] in deuteriomethylene chloride.R. G. Charles and R. C. Ohlmann, J. Inorg. Nuclear Chem., 1965, 27, 119. J. E.Schwartzberg, D. R. Gere, R. E. Severs, and K. J. Eisentraut, Inorg. Chem., 1969, 6, 1933. * F.A.Hart, J. E. Newbery, and D. Shaw, Nature, 1967,216,261. D. F.Evans and M. Wyatt, J.C.S. Chem. Comm., 1972, 312. D.R.Eaton, Canud.J. Chem., 1969,47,2645. K[LS] AB (3)6A = 1 + K&S] where & is the LIS of the complexed substrate [LS], i.e. the bound chemical shift, and K the equilibrium constant of expression (1). At low concentration of LSR, a linear concentration dependence of LIS is observed, which is used to control the magnitude of the shift.For the purpose of obtaining shift parameters which are independent of concentration of LSR, Demarco et al. have proposed7 a technique used by many whereby the concentration-shift plots are extrapolated to concentrations where the molar ratio of LSR to substrate is 1 : 1. These LISs at such high concentrations can often not be checked directly owing to the limited solubility of the LSR. The chemical shift of the uncom- plexed substrate can be obtained by a graphical method whereby the chemical shift of each nucleus is plotted against the concentration of LSR and the plot extrapolated to zero concentration of LSR,8s1*-16 a technique useful when individual resonances are part of a complex, multiple adsorption band. How- ever, deviations between extrapolated and observed chemical shifts are cited' even at low concentrations of LSR.17 By studying expression (2), it is apparent that as the concentration of LSR is increased, the deviation from linearity should also increase, as shown in Figure 1.Such curves cannot be produced using the dipivalomethanato LSR So is constant) Figure 1 Relationship of LIS (84)with the concentration of added LSR [L,] and added substrate [So] 'P. V. Demarco, T. K. Elzey, R. B. Lewis, and E. Wenkert, J. Amer. Chem. SOC.,1970,92, 5743. a K. K. Anderson and J. J. Uebel, Tetrahedron Letters, 1970, 5253. H. Hart, and G. M. Love, Tetrahedron Letters, 1971, 625. loC. Beaute, Z. W. Wolkowski, and N. Thoai, Tetrahedron Letters, 1971, 817. l1 Z. W.Wolkowski, Tetrahedron Letters, 1971, 821. Z. W. Wolkowski, Tetrahedron Letters, 1971, 825. l3 M. Witanowski, L. Stefaniak, H. Januszewski, and Z. W. Wolkowski, Tetrahedron Letters, 1971, 1653. l4 A. F. Cockerill and D. M. Rackham, Tetrahedron Letters, 1970, 5149. l6 K. C. Yee and W. G. Bentrude, Tetrahedron Letters, 1971,2775. l6 D. R. Crump, J. K. M. Sanders, and D. H. Williams, Tetrahedron Letters, 1970, 4949. l7 J. Goodisman and R. S. Matthews, J.C.S. Chem. Comm., 1972, 127. Lanthanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy owing to its limited solubility, but they are produced experimentally by: (a) using Eu(N0,),,6D20 in an aqueous solution in a study of 31Pn.m.r. spectra;l* and (b)using Eu(fod), or Pr(fod),, which are fluorinated LSRs having higher solubilitie~.~~ It should be noted that the extrapolation of the linear portions of the curve does not coincide with the line drawn at a 1 : 1 molar ratio.The quantity of LSR needed to reach the flat part of the curve in Figure 1 depends on the Lewis basicity of the substrate, and for weakly basic substrates up to two molar equivalents of the fluorinated LSR are necessary.19 However, when used in a large excess these LSRs give LISs approaching that of the bound substrate. Deviations from the curves expected from expression (3) occur at high con- centrations of LSR, which have been explained by a combination of medium and associated effects.14 The praseodymium complexes are reported to exist as dimers in the solid state,20 varying from 7 to 8 co-ordinate and the consequences of polyfunctional substrates21*22 have yet to be studied in detail.The shift parameters derived by these approaches are somewhat dependent on the initial substrate concentration and an alternative approach has been advocated which provides a method for obtaining quite accurate bound chemical shifts, and also a value for K the binding constant. From the LIS (ad),the uncomplexed chemical shift, and the bound chemical shift dg, the following is derived : From this expression a useful relationship is derived relating K and d~ so(l-z)='T-(;+Lo)SA L~ *& Armitage and co-wo~kers~~ use this expression with an assumption that 6d/& is negligible at low concentration of LSR.Hence: so = Lo AB--($+Lo) 6A In a plot of Soagainst 1/6d the slope equals Lo -d~and the intercept equals 1/K + Lo. Therefore, from the slope, the 'first reliable values' of the bound chemical shift dg are determined. These and other show previous results' to be much too low and provide a more accurate basis for comparison of substrates. As seen from expressions (2) and (4), dilution effects alter the LIS, J. K. M. Sanders and D. H. Williams, Tetrahedron Letters, 1971, 2813. lD R. E. Rondeau and R. E. Sievers, J. Amer. Chem. SOC.,1971, 93, 1522. C. S. Erasmus and J. C. A. Boeyens, Acta Cryst., 1970, B26,1843. p1 H. van Brederode and W. G. B. Huysmans, Tetrahedron Letters, 1971, 1695. 2a I. Fleming, S. W. Hanson, and J. K. M.Sanders, Tetrahedron Letters, 1971, 3733. a3 I. Armitage, G. Dunsmore, L. D. Hall, and A. G. Marshall, Chem. Comm., 1971, 1281. 24 J. Bouquant and J. Chuche, Tetrahedron Letters, 1972.2337. Mayo whereas the bound chemical shift is independent of concentration. The equi- librium constant K can be derived from the intercept, but the values obtained will be upset by the extent of dimerization of the LSR. A twofold advantage exists in measurements at low concentrations of the LSR (a factor favouring the fluorinated LSRs which have greater ‘shifting power’) since (i) this minimizes the possibility of dimerization of the LSR and (ii) that the bulk susceptibility changes caused by the metal ion are minimal. Various papers report values of the equilibrium constants (see Table l), obtained in some cases from slightly different approaches to that described.It is interesting to note that greater values of the equilibrium constant occur with fluorinated as opposed to non- fluorinated LSRs. This phenomenon is the cause of the larger LIS observed Table 1 Equilibrium constants of LSRs and various substrates Substrate LSR Equilibrium Ref. constant (K) Cholestanol Eu(dpm)3 61 24 Neopen t an01 Eu(dpm)3 6* 25 Pyridine Eu(dpm)3 100 26 n-Prop ylamine Wdpm)3 12* 25 Nucleoside phosphates EuIII 4 to 17 27, 28 Neopentanol Eu(fod) loo* 25 t-Butyl alcohol Eu(fod), 280 29 Isopropyl alcohol Eu(f0d)3 97* 30 Tetrahydro furan Eu(fod), 57* 30 But an-Zone Eu(fod)3 32* 30 Isopropeny1 acetate Eu(fod), 27* 30 Ally1 acetate Eu(fod) 26* 30 n-Propylamine Eu(f0d)3 loo* 25 * Values estimated from the technique reported by Armitage and co-~orkers.~~ for the fluorinated reagents and not the value of the bound chemical shift, which is smaller for the dipivalomethanato reagent^.^^^^^ Optically active LSRs, which are used to separate resonances of enanti~mers,~~~~~are thought to distinguish these isomers by forming diastereoisomeric complexes with the LSR which have different binding constants.I. Armitage, G. Dunsmore, L. D. Hall, and A. G. Marshall, Chem. and Ind., 1972, 79. 26 H. Huber and J. Sellig, Helv. Chim. Acta, 1972, 55, 135. 27 C. D. Barry, A. C. T. North, J. A. Glasel, R. J. P. Williams, and A. V. Xavier, Nature, 1971,232,236.as C. D. Barry, A. C. T. North, J. A. Glasel, R. J. P. Williams, and A. V. Xavier, Biochem. Biophys. Acta, 1972, 262, 101. a0 K. Roth, M. Grosse, and D. Rewicki, Tetrahedron Letters, 1972, 435. 30 D. R. Kelsey, J. Amer. Chem. SOC.,1972, 94, 1764. 31 B. L. Shapiro, M. D. Johnston, jun., A. D. Godwin, T. W. Proulx, and M. J. Shapiro,Tetrahedron Letters, 1972, 3233. 38 G. M. Whitesides and D. W. Lewis,J. Amer. Chem. SOC.,1970,92,6979; 1971,93, 5914. 33 H. L. Goering, J. N. Eckenberry, and G. S. Koermer, J. Amer. Chem. Soc., 1971,93, 5913. Lantkanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy One difficulty in determining the intrinsic LIS parameters, namely the bound chemical shift and the binding constant, is the interference by other substrates and impurities in the solution being examined.A possible method of overcoming this difficulty3* employs a reference substrate having a known bound chemical shift and binding constant. From an expression similar to equation (3) the following is derived: where the subscripts refer to the parameters of the investigated substrate 0) 1 1and the reference substrate (m). In a plot of a -against -, the slope and in- aAm tercept should give AB and K of the investigated substrate (i.e. AB~and Kj). Without the knowledge of d~~and Km for the reference substrate, the slope and intercepts are nevertheless used to characterize the compounds examined. Values of these parameters are not reported, but this approach is illustrated by an analysis of a mixture of four compounds.A similar approach is also referred to,86 which is extended to a mixture of (x) substrates. An internal reference signal of examined substrates can also be used to analyse and compare a solution containing two or more substrates.ao For two protons (m and j) in the same substrate: By plotting adj against aAm, slopes which are independent of substrate or reagent concentrations are obtained, which are applied to the analysis of mix-tures of substrates which contain the same internal standard protons, e.g. acetoxy or methoxy. Results showed that for a similar geometric arrangement in a series of compounds, the slopes of such plots are characteristic. Armitage and co-workers have developed a schemeea for evaluating the stoicheiometry of the complex formed in solution.Thus, modifying equation (1) to: KL + nS + &Snl (9) where n is the number of moles of S that combine with one mole of L, then: log S = (l/n) log [LS/L] -(l/n) log K Combination with expression (3) permits evaluation of S, L,and PSI, which by plotting a graph of log S against log [LS/L] gives a slope equal to l/n. Values of unity are calculated with Eu(dpm), for both n-propylamine and neopentanol, although this method is invalid when the binding constant is large.ea Other ** D. E. Williams, TetrahedronLetters, 1972, 1345. J. K. Sanders and D. H. Williams, J.C.S. Chem. Comm., 1972,436. investigations have been made;zB one in particular concludes that pyridine and Eu(dpm), form a 1 :1 complex,2s although the possibility of n = 2 is seriously considered as the pyridine di-adduct, a solid isolable compound, is known,' and dimethyl sulphoxide is thought to form a di-adduct at low temperatures in deuteriochloroform.6 The lowering of the LIS with different solvents are reported;36 one explanation attributes this to competitive inhibition of weakly complexed substrates, particu- larly with donor solvents such as acetonitrile, pyridine, acetone, and dimethyl sulphoxide. Approximate orders of magnitude of the decrease in LIS are 10,20, and 30 % for deuterio-benzene, -chloroform, and -acetonitrile, respectively, when compared with carbon tetrachloride or carbon disulphide using tris(dipiva1o- methanato)europium(m), Eu(dpm),, on alcohols and amines.,* Therefore, the use of donor competing solvents should be avoided when using the tris-p- diketonate LSR, although alternative reagents are available for use in more highly polar solvents (see Section 7),l8p3' and one has been used in aqueous Finally, as the magnitude of LIS is geometry dependent (see Section 5) and lanthanide complexes are predominantly electrostatic, the solvation spheres can influence this geometry so that different solvents may alter shifts.The presence of other donor substrates as impurities can reduce the effective concentration of the LSR39if they form stronger co-ordination complexes than the substrate under study. The presence of water inhibits the LIS in this ~ay,lO,~O as shown by the 60% reduction in the LIS of cholesterol hydrate protons when compared with the anhydrous form,ls owing to competitive co-ordination by water.The presence of moisture in some LSRs can easily be observed by a change in c~lour,~~ e.g. Pr(dpm), and Eu(dpm), are pale green and pale yellow when anhydrous, but yellow and white, respectively, when hydrated. It appears that extremely small amounts of impurity in the LSR, insufficient to cause a change of melting point, nevertheless cause deviations in the LIS, e.g. 30% difference in the LIS of two batches of LSR.42It has been proposed that a standard sub- strate for measurement of the LIS with the LSR be adopted, which could provide a better criterion for measuring purity than melting point.As the LSR is only a weak Lewis acid, steric hindrance reduces the LIS either because of a smaller value of the equilibrium constant or a greater nucleus- cation distance or both. Steroidal acetals, thioacetals, and methoxy-derivatives have been shown3' to co-ordinate selectively to LSRs according to the degree of steric hindrance, e.g. a 3/?-methoxy-steroid co-ordinates to a greater extent than the more hindered 3a-methoxy-steroid. A further report illustrates the effect of the steric hindrance42 in a study of substituted anilines, which shows that a *IJ. K. M. Sanders and D. H. Williams, J. Amer. Chem. SOC.,1971, 93, 641. *' J. E. Hertz, V. M. Rodriquez, and P. Joseph-Nathan, Tetrahedron Letters, 1971, 2949. a* F. A. Hart, G. P.Moss, and M. L. Staniforth, Tetrahedron Letters, 1971, 3389. 39 L. Tomic, Z. Majerski, M. Tomic, and D. E. Sunko, Chem. Comm., 1971, 719. 40 I. Armitage and L. D. Hall, Canad.J. Chem., 1971,49,2770. 41 D. R. Crump, J. K. M. Sanders, and D. H. Williams, Tetruhedron Letters, 1970,4419. 4a L. Ernst and A. Mannschreck, Tetrahedron Letters, 1971, 3023. Lanthanide Shvt Reagents in Nuclear Magnetic Resonance Spectroscopy linear correlation of basicity in terms of pKa with proton LIS is upset when steric hindrance is present, such as with ortho-and N-substitution. In conclusion, the quoting and comparison of LIS or bound chemical shift with different substrates should be made with caution; as seen later, other parameters such as the geometry of the complexed substrate and the particular LSR affect the magnitude of the LIS.A number of comparisons of co-ordinating ability of different substrates, as indicated by the LIS, are discussed in Section 8. 3 Shift Mechanism In the lanthanide-substrate complex, interaction between the paramagnetic metal ion and the nuclei of the substrate causes changes in the chemical shift of the nuclei. Two types of interaction between metal cation and ligand have been proposed, contact and pseudocontact interactions, and the resulting shifts referred to as the contact and pseudocontact shifts. Pseudocontact shift43 is caused by a dipolar interaction between the nucleus and the electron spin magnetization of the paramagnetic metal ion. Two theories have been developed giving expressions for the magnitude of the pseudocontact shift, both of which can be expressed as follows: 6A = x(3 cos 281 -1) ri3 where Oi is the angle between (a) the distance vector, Ti, joining the metal cation to the particular nucleus, i, in the complexed substrate, and (b)the crystal field axis of the complexed substrate, often assumed as the line joining the metal atom to the lone-pair-bearing atom.Now -ps(s + 1)x= 27 kT f(g) from the theory by McConnell and and from the more recent theory of Bleany:6 where p is the Bohr magneton; S the electron spin; k is Boltzmann’s constant; A,0(r2) the crystal field coefficient; and g the g tensors. The value of x is different for each complex studied as it involves the g tensor, which is split into g1and g,,,the tensors perpendicular and parallel to the molecular axis. According to McConnell and Robertson’s theory, the pseudocontact shift arises from a failure of the dipolar interaction to average zero owing to the metal possessing an anisotropic g tensor.However, Bleany 43 P. J. McCarthy, in ‘Spectroscopy and Structure of Metal Chelate Compounds,’ ed. K. Nakamoto and P. J. McCarthy, Wiley, New York, 1968, p. 346. 44 H. M. McConnell and R. E. Robertson,J. Chem. Phys., 1958, 29, 1361. 46 B. Bleaney, J. Magn. Resonance, submitted for publication. Mayo proposes46 a theory in which x encompasses a different set of parameters Rather than attributing pseudocontact shift to the anisotropic g factors, he suggests that the dipolar shift is caused by anisotropy in the susceptibility which occurs in less than cubic geometries.One difference arising from this approach is the temperature dependance, which is P2(except in the cases of Eu3+and Sm3+), as opposed to T-l expected from McConnell and Robertson’s theory. For europium and samarium, effects of the excited states give a more complex temperature dependence, approximating to T-l. Various temperature relation- ships have been reported which vary from T-* for Yb(d~m)~~~ to T-l using Pr(d~m),.~@The shift 6d is also dependent on the distance ri of the nuclei from the metal cation through space and not via the covalent bonds of the molecules, a distinction important in studying the consequences of the various parameters involving the shifts.Furthermore, the shift is dependent on the geometric term (3 cos2 8i -l), a factor neglected in many studies. The expressions (11) and (12), derived for axially symmetric complexes, may not necessarily be applicable to the wide range of complexes of lower symmetries, although it is reported as adequate for at least systems of C2and C2vsymmetry.43 The crystal structures of Ho(dpm),,2(4-pi~oline)~~and E~(dpm),,2(pyridine)~* are not axially sym- metric with respect to the adduct ligands, but possibly in solution an approach to axiality is achieved by rapid ligand exchange. Contact shiftsa3 occur by direct electron-nucleus magnetic interaction as distinct from the classical dipolar interactions.Consequently, shifts occur by movement of unpaired electron spin density from the metal cation to the ligand by covalent bond formation. Hence, this mechanism operates through the metal cation co-ordinating bond and so depends on the degree of covalency in this bond. This interaction is independent of the 3 cos2& -1 term and falls off rapidly with increasing distance except in conjugated systems, which facilitate delocalization of unpaired electrons. The distinction between contact and pseudocontact shift is important for a better understanding of the factors affecting the LIS. The assumption that lanthanides interact by a pseudocontact mechanism is based on their high electropositive character and the shielding of unpaired electrons of thef0rbitals.4~ As the lanthanides form complexes by electrostatic interaction, this precludes the operation of a contact mechanism of the same order of magnitude as those found with first-row transition-block metal complexes,5o but with even as little as 1% covalency contact shift should be Therefore, even with lanthanides, a small degree of contact interaction is possible51 and is seen in deviations from the expression (1l), particularly for protons attached to the 46 C.Beaute, S. Cornuel, D. Lelandais, N. Thoai, and Z. W. Wolkowski, Tetrahedron Letters, 1972, 1099. 47 W. De Horrocks, jun., K. P. Sipe, and J. R. Luber, J. Amer. Chem. SOC.,1971, 93, 5258. 48 R. E. Cramer and K. Seff, J.C.S. Chem. Comm., 1972, 400. 49 F. A. Cotton and G. Wilkinson, ‘Advanced Inorganic Chemistry’, Wiley, New York, 2nd edn. D.R. Eaton, J. Amer. Chem. SOC.,1965,87, 3097. 81 E. R. Birnbaum and T. Moeller, J. Amer. Chem. SOC.,1969, 91, 7274. Lanthanide Sh$t Reagents in Nuclear Magnetic Resonance Spectroscopy carbons nearest the lone-pair-bearing atoms.sa It has been suggested that contact shift is significant for aromatic aminesySs where the presence of conjugation may increase the electron delocalization, thus increasing the degree of contact con- tribution,' but this view is contradicted in a study of quinoline and isoquino- line.s4 Pseudocontact and contact interactions are distinguished in a graphical analysissa using the log of expression (11) [see later, expression (15)], and contact shift is only reported to occur on the protons vicinal to the lone-pair-bearing atom.A similar deviation from an otherwise linear plot of log ri against log 6d is reported by Dernarc~,~who attributes this to the presence of contact shift. The relative magnitude of the g tensors correlates with the direction of shift, as indicated in electron paramagnetic resonance experiments, which show good agreement of the relative magnitudes of gl and gllwith those observed in the shielding or deshielding of the different lanthanides.s5 However, magnetic susceptibility anisotropy data correlate qualitatively with the observed signs of LISs,g6 and Bleany's theory, which excludes the anisotropic g tensor, still calculates shift data having excellent agreement with observed LISs by use of an expression for pseudocontact shift.67 A detailed analysis of trans-4-t-butylcyclo- hexanol and adamantan-2-01 achieves such good correlation using only the pseudocontact term that contact shift is excluded.s8 However, one investigation of such correlations concludes that no experimental results confirm (or disprove), the pseudocontact expression, owing to the wide deviation in the experimental results dealt with.17 The similarity of x in expression (11) for lH and 13Cn.m.r.spectra of borneolSB and the similarity of LIS ratios of aniline and 2,4,6-tri- fluoroaniline in the lH and lSF n.m.r.60 both indicate that and lSFnuclei are subject to predominaatly a pseudocontact interaction. The 31P n.m.r. results of phosphates and phosphonates indicate a significant contact interaction operating18 and the 14Nn.m.r.studies on mine-M(dpm), systems (M is ytter-bium or europium) indicate a predominance of contact intera~ti0n.l~ Nuclei with lone pair electrons P4N, lSN,and *lP)may be expected to interact pre- dominantly by a contact mechanism. 4 Distance-Shift Relationships Assuming the interaction of the lanthanide complexes is predominantly pseudo- contact, the magnitude of the LIS of the ith nucleus is inversely proportional to the cube of the average distance from the metal ion [expression (1l)]. In fact, this distance parameter is often assumed to be the predominant term as the I* C.C. Hinckley, M. R. Klotz, and F. Patil, J.Amer. Chem. Soc., 1971,93,2417.F. A. Hart, J. E. Newbery, and D. Shaw, Chem. Comm., 1967, 45. I4H. Huber and C. Pascaul, Helv. Chim. Acta, 1971,54,913. 55 G. A. Hutchinson and E. Wong, J. Chem. Phys., 1958, 29, 754. 50 W. De W. Horrocks,jun., and J. P. Sipe, J. Amer. Chem. Soc., 1971, 93, 6800. 67 B. Bleaney, C. M. Dobson, B. A. Levine, R. B. Martin, R. J. P. Williams, and A. V. Xavier, J.C.S. Chem. Cornm., 1972,791. S. Farid, A. Ateya, and M. Maggio, Chem. Comm., 1971, 1285. J. Briggs, F. A. Hart, G. P. Moss, and E. W. Randall, Chem. Comm., 1971, 364. 6~ Z. W. Wolkowski, C.Beaute, and R.Jantzen, J.C.S. Chem. Comm., 1972, 619. Mayo remaining factors, namely the angle term, are regarded as constant. Thus expression (11) is simplified to: SA = b/ra (14) where b is assumed as a constant.The distance-shift relationship is clearly illustrated in the proton n.m.r. spectrum of n-heptanol. As seen in Figure 2,61addition of Eu(dpm)s renders 20 15 10 5 0 PPm Figure 2 Proton (60MHZ)n.m.r. spectra of n-heptanol;(a) 0.3 mol I-' in CDCls; (b) with a molar ratio of 0.78 of Eu (dpm),/n-heptanol (Reproduced with permission from Analyt. Chem., 1971, 43, 1599.) the spectrum amenable to first-order analysis, shifting the resonance nearest the hydroxy-group furthest; on increasing distance the LIS is less. Substantial shifts for protons up to 13a from the site of co-ordination have been measured,l smaller shifts (O.lp.p.m.) for distances up to 27A are also reported.' HincMey reported1 the f%st use of a LSR in distance-shift relationships with the steroid cholesterol.The distances of each nucleus from the co-ordinated metal ion in the complex are estimated from Dreiding models. The inverse cube of this distance term is plotted against the values of the LIS for each nucleus and frequently produces a linear response, substantiating this aspect of the relation- ship for pseudocontact shifts. Consequently this approach enables relative distances of the nuclei from the metal ion to be estimated, which can contribute to structural information. This can be applied by altering the possible structural models of the molecule to obtain the best correlation of.the distance-shift data. The presence of more than one co-ordination site in the organic substrate complicates the interpretativn of the measured shifts since these represent sums of the interactions with the LSR at each site,6a although some groups form stronger co-ordination complexes than others.At each co-ordination site, equi- librium constants, and hence pseudocontacts, contribution differ and so result in D.L.Rabenstein, Analyt. Chern., 1971, 43, 1599. 6% A. Ius, G. Vecchio, and G. Carrea, Tetrahedron Letters, 1972, 1543. Lanthanide Sh ft Reagents in Nuclear Magnetic Resonance Spectroscopy different proportionality constants in expression (14). These complications make straightforward plots of the LIS against the inverse cube of the distance in- effective aids in analysis, but fortunately the log of this expression renders an important simplification: IogSd = -3Iogri + logc (15) A plot of log ad against log ri should be linear irrespective of c, a constant.By assuming expression (15) correct, a graphical analysis by this approach allows a distinction between the relative contributions of co-ordination at each site of a bifunctional steroid.62 This approach is only useful when co-ordination sites are far apart so that some protons are only affected by co-ordination at one site. The slope of -3 would be expected but it is not in fact obtained with these graphs, which is attributed to errors in the distance measurement or geometric factors.' One generalized interpretation suggests that molecules which produce slopes greater than three are flexible, but those of slopes less than three are rigid.17 In many cases good linear relationships between the LIS and the inverse square of the distance parameter have been fo~nd.~*~~~-~~ However, an analysis of these different values of the power of the distance termes concludes that too little is known about the detailed nature of the geometry to allow definite structural conclusions to be drawn and crude approximations may not reflect the complex nature of the interactions involved.Deviations from the distance- shift correlations may be due to over-simplification with respect to the shift mechanism or the geometric terms. The angle term is frequently considered reasonably constant in many substrates and if free rotation occurred about the metal ion-heteroatom bond of the labile complexYs7 the angle term may be averaged out.Measurements of the broadening of resonances, caused by the metal ion increasing the transverse relaxation rate (T2),can also lead to estimates of relative distances within the complexed substrate. A simplified form of an expressionesis used to relate the half bandwidth (hi,,) and the inverse sixth power of the distance term (ri) of the ith nucleus, where C is a constant for the particular complex being investigated. This approach was first used with two transition-metal complexes,eB and has since been applied to LSRs,27~28~70in particular those lanthanides which produce appreciable broadening, e.g. gadolinium(Ir1). 63 M. R. Willcott, J. F. M. Oth, J. Thio, G. Plinke, and G. Schroder, Tetrahedron Letters, 1971, 1579.64 L. W. Morgan and M. C. Bourlas, Tetrahedron Letters, 1972, 2631. 65 A. F. Cockerill and D. M. Rackham, Tetrahedron Letters, 1970, 5153. 66 A. J. Rafalski, J. Barciszewski, and M. Wiewiorowski, Tetrahedron Letters, 1971, 2829. 67 R. F. Fraser and I. Y. Winfield, Chem. Comm., 1970, 1471. 6* H. Sternlicht, J. Chem. Phys., 1965, 42, 2250. 6s E. E. Zaev, V. K. Voronov, M. S. Shvartsberh, S. F. Vasilevesky, Yu. N. Molin, and I. L. Kotljarevsky, Tetrahedron Letters, 1968, 617. 7O J. Reuben and J. S. Leigh, jun., J. Amer. Chem. SOC.,1972, 94, 2789. Mayo 5 Consequences of Geometric Factors Deviations from the distance-shift correlations due to neglect of the geo- metric term as in expression (14) are common and by including the term (3~0s' 8i -l), improved correlations are obtained.In order to measure the angle 8i for each nucleus, the position of the metal ion with respect to the substrate needs to be known. This problem has been avoided by some workers by measuring distances of nuclei from either the heter~atom~~p~~ or the perimeter of the lone pair on this atom.14 These results may be sufficient for the cases in hand, but do not contribute to a more complete understanding of the shift mechanism. The orientation of this lone-pair is more predictable in cases of restricted rotation in the carbon-heteroatom bond, e.g. carbonyl groups, but is less predictable for systems which rotate freely, e.g. hydroxy-groups. Table 2 summarizes the positions postulated for the metal ion with respect to the substrate where some estimates are made by comparison with analogous com- plexes studied by X-ray crystallography, others by modifying values of the metal position and evaluating the most linear response to expression (11).The most successful attempts to locate the metal atom, firstly by Briggs, Hart, and and later by ~ther~,~~@+~~~~~ were achieved by varying the metal-atom position and computing the correlation with minimum deviations from expressions (11) and (16) using the LIS and broadening parameters. The results show that for an accurate positioning of the metal ion a set of calculations needs to be worked out for each molecule studied. This approach may be used to calculate the ratio of conformers by computing the percentage contribution of each conformer required to obtain the best correlation.How- ever, a possible disadvantage of this technique is that the ratio of conformers may be altered on co-ordinating to the LSR. A 13Cn.m.r. study of some phos- phorinans does show that the ratio of conformers is altered by the quantity of LSR Conversely, other report~~lg~~ indicate very little change in the ratio of conformers when complexed to the LSR, but presumably this will depend on the energy barrier between the conformers concerned. In certain cases the angle 8i may be sufficiently large that the direction of 'normal shift' is reversed. A plot of the 3cos2 Bi -1 term against angle, as in Figure 3, shows how the LIS can be varied from positive to negative as the angle is altered.Thus with Eu(dpm), shielding as opposed to the 'normal' de- shielding, shifts are produced when the angle 81 is between 54.7 and 125.3 O, but in most cases the angle appears to be below 54.7". Many reports of europium upfield shifts are rep~rted,~~~~~~~~~~~-~~ most of which enable direct interpretation 71 J. Briggs, F. A. Hart, and G. P. Moss, Chem. Comm.,1970, 1506. M.R. Willcott, tert., R. Lankinski, and R. E. Davis, J. Amer. Chem. SOC.,1972, 94, 1742. 'Is M. Ochiai, E. Mizuta, 0. Aki, A. Morimoto, and T. Okada, Tetrahedron Letters, 1972, 3245. W. G. Bentrude, H. W. Tan, and K. C. Yee, J. Amer. Chem. SOC.,1972,94, 3264. 76 S. G. Levine and R. E. Hicks, Tetrahedron Letters, 1971, 31 1. 76 B.L. Shapiro, J. R.Hlubucek, and G. R.Sullivan,J. Amer. Chem. SOC.,1971, 93, 3281. 77 T. H. Siddall, Chem. Comm., 1971,452. 76 P. H. Mazzocchi, H. J. Tamburin, and G. R. Miller, Tetrahedron Letters, 1971, 1819. 7D S. B. Tjan and F. R.Visser, Tetrahedron Letters, 1971, 2833. '0 M.Kishi, K.Tori, and T. Komeno, Tetraheah Letters, 1971, 3525. o\ h, ETable 2 Postulated positions of the lanthanide ion in the complexed substrate ASubstrate Functional Distance Angle MXC Lanthanide Method of group (heteroatom Jdegrew ion assessing to rnetal)/A kiAdamant-1- or -2-01 OH Radii of 115 Eu Estimate 81 8 op0 plus Eu s4-t -Bu t ylcyclo hexanol OH 2.3 139 Eu Computed optimum 58 c Adamant-2-01 OH 3.0 128 Eu Computed optimum 58 3 Borneo1 OH 3.O 126 Pr Computed optimum 71 5 General OH 2.7-0.4 --Computed optimum 58 % Cyclic ketones c=o 2.8 109 Eu Analogy with RCO-HgCIB 82 8 Halogenovinyl ketones CHO 3.O 150 Yb Best linear fit 83 % Indanone and fluorenone c=o 1.5 120 Yb Best linear fit 11 8itSulphoxides s=o 3.5 I Eu Analogy with La(edta) 67 2.Amines NH* 3.O -Yb Best linear fit 10 h Analogous complexes of kno wn stereochemistry 2 Cyclononanone-HgC1a 2.8 Hg -84 s8Yb(acac),,H zO 2.34 Yb X-Ray crystallography 85 8La(edta) 2.55 La X-Ray crystallography 86 8Eu(dPm)3,2PY 2.65 Eu X-Ray crystallography 48 s *l G. H. Wahl, jun., and M. R. Peterson, jun., Chern. Cumrn., 1970, 1167. sP. Kristiansen and T. Ledaal, Tetrahedron Letters, 1971, 2817. 8a* C.Beaute, Z. W. Wolkowski, J. P. Merda, and D. Lelandais, Tetrahedron Letters, 1971, 2473. 20’ S. Dahl and P. Groth, unpublished results. J. A. Cunningham, D. E. Sands, W. F. Wagner, and M. F. Richardson, Znorg. Chern., 1969, 8, 22. J. L. Hoard, B. Lee, and M. D. Lind, J. Arner. Chern. Suc., 1965,87, 1612. Mayo m Figure 3 The variation of 3 COS20i -1 with the angle 8 of structural problems. By altering the solvent or ligand of the LSR, the direction of the shift is often a1tered,37v38s51~87 as these factors can also affect the geometry of the complexed substrate. An alternative explanation for the reversal of the ‘normal’ direction of the LIS is attributed either to the presence of significant contact interacti~n,~~ to changes in magnetic susceptibility gor (although disagreement has been expressed with this latter reason77) or to changes in the sign of crystal field coefficient^.^^ A further point involves the definition of the angle &,which is derived using the crystal field axis as one vector.This axis need not coincide, as is often assumed, with the metal atom-heteroatom bond;88 the difference is not neces-sarily compensated by free rotation around the bond. 6 Lanthanide Metal Ion Transition-metal complexes could be used as shift reagents in n.m.r. spectroscopy if it were not for the excessive linewidth broadening these metal ions exhibit in This phenomenon is related to similar effects caused by oxygen and free radicals when present in solution in the n.m.r.tube. These species provide a mechanism for shortening the relaxation times (T2)of the protons and, therefore, increasing the bandwidth. Europium(m), the most frequently selected lanthanide, is selected by virtue of its anomalously inefficient nuclear spin-lattice relaxation properties.g0 It has a low-lying Russell-Saunders state and a diamagnetic 7F0 ground state, which gives a very small separation of the highest and lowest occupied metal orbitals and which leads to inefficient relaxation; the excited 7F1state presumably contributes to the pseudocontact shift. Q1Thus the presence of such metal ions as europium(n1) in solution causes very little broadening in n.m.r. spectra. H. Donato, jun., and R. B. Martin, J. Amer. Chem. SOC.,1972, 94, 4129.8B C. L. Honeybourne, Tetrahedron Letters, 1972, 1095. 8s A. Carrington and A. D. McLachlan, ‘Introduction to Magnetic Resonance’, Harper and Row, 1967, p. 225. @O J. H. Van Vleck, ‘The Theory of Electric and Magnetic Susceptibilities’, Oxford UniversityPress, 1932. chap. IX. @l S. I. Weissman, J. Amer. Chem. SOC.,1971, 93, 4928. 63 3 Lanthanide Shut Reagents in Nuclear Magnetic Resonance Spectroscopy Table 3 Comparison of the lanthanide- and transition-metal complex proton n.m.r. bandwidths Lanthnide BandwidthsJHza Half-height band- Relative widthsJHz broadening1 Pr 40 5.6 Hz per Hz of shift= 0.005 Nd 16 4.0 Sm 7 4.4 0.02 Eu 10 5.0 0.003 Gd 1500 - Tb 250 96.00 0.1 DY 180 200.00 - Ho 180 50.00 0.02 Er 250 50.00 Tm 400 65.00 - Yb 60 12.00 0.02 Transition nietal Bandwidth JHzd as MIL' Ti 2000 V 25 Cr lo00 Mn 100 Fe 800 Mo 200 Ru 100 a Lanthanide bandwidthssa of t-butyl in M(dpm), in carbon tetrachloride.b Lanthanide half bandwidthss6 of methyl in 2-picoline using M(dpm)B. C Lanthanide relative broadeninel of t-butyl in M(dpm),. d Transition-metal bandwidthss0 of methyl in M(acac),. Several comparisons of the lanthanides for use as LSRs have been reported and Table 3 shows some comparisons of lanthanide broadening properties along- side those of some first-row transition-block metal complexes. Close comparison of these figures is not possible as different ligands and solvents were used in the measurements.Narrow bandwidths are exhibited by the lanthanides praseodymium (Pr), neodymium (Nd), samarium (Sm),and europium (Eu), and moderate broadening is found with ytterbium (Yb),but a notable exception to these characteristics occurs with gadolinium (Gd), which is used explicitly as a broadening pr~be.~**~~~93 Europium and praseodymium are used most extensively and ytterbium also appears satisfactory for use, although it causes greater broaden- *%N.Ahmad, N. C. Bhacca, J. Selbin, and J. D. Wander, J. Amer. Chem. SOC.,1971, 93, 2564. s3 K. G. Morallee, E. Nieboer, F. J. C. Rossotti, R. J. P. Williams, and A. V. Xavier, Gem. Comm., 1970, 1132. 64 Mayo ing. Further comparison of broadening properties have been investigatedsa using M(NO,),(dbbp), where dbbp is 4,4’-di-n-butyl-2,2’-bipridyl and M are various lanthanides.An investigation of these complexes shows that lanthanum, lutetium, and ytterbium cause extensive broadening; cerium, praseodymium, neodymium, and samarium only cause moderate broadening; and europium is cited as the only metal permitting a distinction between three aromatic protons in the complex. A similar 14N n.m.r. studyn4 of the half bandwidths shows a significantly different situation, with dysprosium (Dy) and holmium (Ho) giving the least broadening. A secondary factor in selection of the correct lanthanide as a LSR is the magnitude of the shift produced. Some comparisons of this factor have been made for the lanthanides, as seen in Table 4.The largest shifts are unfortunately Table 4 Comparisons of lanthanide induced shiftsa Metal Shgt caused Shift caused Shift power Shut by by M(dpm),.by M(dpm),. relative to M {OP(NMe,)a MC104) a-methylene y-methylene Eu(dpm), of MeCN /Hzb /Hzb /Hze /Hzd Pr -11.25 -3.7 -1.1 -3.00 Nd -5.55 -1.8 --1.15 Sm -1.35 -0.6 -0.2 -0.27 Eu 2.95 1.8 1.O 1.33 Gd Tb -26.25 -10.9 -5.5 -19.2 -DY -54.00 --17.9 -Ho -51.45 -18.1 -7.0 -17.0 Er 25.55 8.8 -4.4 Tm -44.65 -14.8 6.9 Yb 12.15 4.4 4.0 6.9 -Lu 0.00 0.0 a A more recent survey gives analogous results.56 * The 01 and y groups refer to the methylene protons of cyclohexanone (0.1 mol 1-I) in a saturated solution of M(d~rn)~in CC14.g* C Shift power relative to Eu(dpm), calculated from ‘representative’ selection of lanthanides refer to slopes of concentration vs.shift plots.41 (I Ref. 95. exhibited by the metals which cause greatest broadening, e.g. terbium to thulium, and, therefore, the metals selected for use as LSRs are necessarily a compromise of these factors, with a greater consideration given to the broadening factor. Consequently, europium produces relatively small but adequate shifts and is the lanthanide used most extensively since the first paper was published by Hinck1ey.l This metal ion produces large enough shifts with sufliciently minimal broadening to allow gross multiplet adsorption bands to be resolved at relatively large shifts. M. Witanowski, L. Stefaniak, and H. Januszewski, Chem.Cornrn., 1971, 1573. 65 Lanthanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy Furthermore, the t-butyl resonance of Eu(dpm), occurs upfield of TMS in proton n.m.r. and is, therefore, not interfering with the spectra. In 14Nn.m.r., europium causes three times as much shift as ytterbium,13 reversing the relative shift power found in proton n.m.r. spectroscopy (cf: Table 4). Praseodymium follows europium in its popularity, owing to two factors: (i) the shifts are larger than those caused by europium, in proton n.ni.~.,~~ compensating for the slightly poorer broadening properties ; (ii) praseodymium causes upfield shifts and is, therefore, a useful complimentary reagent. A disadvantage of praseodymium and other shielding LSRs, however, is the added complication of crossing over of resonances, which confuses analysis in some cases.A series of papers,10~11~76~ 96 largely by Beaute and Wolkowski, advocates the use of ytterbium and holmiumS7a owing to their relatively greater shifting powers (cf: europium), but these advantages are balanced by their greater bandwidths. Thulium has been used as a LSR,40but although shifts are greater than those caused by europium, drastic broadening again limits its application. In 13C n.m.r. the praseodymium/ europium shift-ratio and the terbium/europium LIS ratios are given as 1.8 and 8.6, resp~ctively,~~but as usual the advantage of terbium has to be balanced against its extensive broadening properties. The reference to a LSR as de- shielding or shielding refers to its use under ‘nornial’ conditions (as a p-di- ketonate complex, in fairly non-polar solvents and with angle 81 outside the 54.7 to 125.3 O limits).Finally, diamagnetic lanthanum is usedD7b in LSR studies although the shifts produced are probably due to changes in shielding by bonded electrons and not indicative of any pseudocontact shift. The main use of lan- thanum may, therefore, lie in taking accurate measurements of the LIS due to pseudocontact shift only, by subtracting shifts caused by the lanthanum complex from the LIS caused by a paramagnetic LSR.67 7 Lanthanide Shift Reagent (LSR) Lanthanide tris(#?-diketonates), often air stable and soluble in organic solvents, are known to expand their co-ordination by accepting further ligand~~~ and have a very simple n.m.r.spectrum, i.e. factors desirable in a shift reagent. The simplest #?-diketonates, the acetylacetonates, are used with first-row transition- block metals as shift reagents, but these ligands are hygroscopic and the co- ordinated water leads to weak complexation with further ligands, giving poor shifts.36 The t-butyl derivative dipivaloylmethanate is a more satisfactory LSR, whose proton n.m.r. spectra in CDC13consists of only one singlet which is shifted to higher field by approximately -0.7 p.p.m. when co-ordinated to a substrate such as an alcoh01.~ Bulky ligands in the LSR are an advantage as this restricts mobility in the complex, preventing the susceptibility tensors being averaged out by a combination of different configurations (see Section 3).47 The dipivaloyl- Or, J.Briggs, G. H. Frost, F. A. Hart, G. P. Moss, and M. L. Staniforth, Chem. Comm., 1970, 749. O6 C. Beaute, Z. W. Wolkowski, and N. Thoai, Chem. Comm.,1971,700. O’aL. Tomic, Z. Majerski, M. Tomic, and D. E. Sunko, Croat. Chem. Acta, 1971, 267. 07bE. Wenkert, D. W. Cochran, E. W. Hagaman, R. B. Lewis, and F. M. Schell, J. Amer. Chem. Soc., 1971, 93, 6271. 66 methanato-complex of europium was first used by Hinckleyl as the dipyridine adduct Eu(dpm),,2py. This was later improved by Sanders and Williamso8 by use without the associated pyridine, rendering the complex more amenable to expanding its co-ordination and accepting substrates, which effects a fourfold increase in shifts. These complexes are available commercially, but they can be prepared in the laboratory from the metal nitrate.Bs The complexes have only a limited solubility in the normal n.m.r.solvents, which prevents a 1 :1 molar ratio being reached. In the absence of the substrate, Eu(dpm), has a maximum concentration of approximately 40mg ml-l in deuteriochloroform,7 and solubi- lity increases with co-ordination to a basic substrate, e.g. concentrations of 200 to 300mg ml-l are obtained with alcohols in chloroform or deuteriobenzene, but only 100 mg ml-l in carbon tetra~hloride.,~ It is probable that the substrates less basic than alcohols will not permit such comparatively high concentration of the LSR.However, the dipivaloylmethanato-complexes are widely used reagents which give quite satisfactory shifts even at the low concentrations governed by their limited solubility. Other similar reagents with no particular advantage over the dipivalomethanates have been reported, e.g. tris(dibenz~ylmethanate)~~~~~~ and t ris-( 1-benzoylace t onate) .lO O The introduction of fluorine atoms on the p-diketonate ligand overcomes the solubility problem and has led to new superior LSRs. One such complex, the 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane~,6-dionato(fod) lanthanide,' apart from having improved solubility (of the order of 400 mg ml when com- plexed to a substrate), has a more acidic metal ion owing to the electron- withdrawing power of the fluorines.This greater Lewis acidity causes a stronger association with the substrate and thus extends its range to less basic groups; although the bound chemical shift is smaller for these fluorinated LSRS,~~the observed LIS is larger because of the stronger binding in the complex. However, an alternative method for comparing the shifting power of LSRs, by measuring their vinylic proton shifts,lol allows a comparison of the shifting power of various fluorinated LSRs with the non-fluorinated reagents,loa Eu(fod), > Eu(pfd), > Eu(fhd), > Eu(dpm)s where (pfd) represents 1,1,1,2,2-pentafluoro-6,6-dirnethylheptane-3,5 and (fhd) represents 1,1,l-trifluoro-5,5-dimethylhexane-2,4-dione.Various LSRs appear to exhibit different degrees of contact interaction with aromatic sub- strates, and a series of the reagents with an increasing degree of contact inter- action operating is reported :loS J.K. M. Sanders and D. H. Williams, Chem. Comm.. 1970,422. O°K. J. Eisentraut and R. E. Severs, J. Amer. Chem. SOC.,1965, 87,5254. looG. V. Smith, W. A. Boyd, and C. C. Hinckley, J. Amer. Chem. SOC.,1971,93, 6319. lol H. E. Francis, Ph.D. Thesis, University of Kentucky, Lexington, Kentucky, 1972. lo*H. E. Francis and W. F. Wagner, Org. Magn.Resonance, 1972,4189. lo9B. F. G. Johnson, J. Lewis, P. M. Ardle, and J. R. Norton, J.C.S. Chem. Comm., 1972, 535. 67 Lanthanide ShiJt Reagents in Nuclear Magnetic Resonance Spectroscopy Pr(fod), < Yb(fod), -c Eu(dpm), < Er(dpm), < Eu(fod)s increasing contact interaction Finally, one disadvantage in using the fluorinated LSR is that the t-butyl resonance occurs in the 1-2 p.p.m. region when complexed, hence interfering with proton resonances in this region.Optically active LSRs such as tris-[3-(t-butylhydroxymethylene)-( + )-cam-phorato]europium(rr~) have been developed for the purpose of determining enantiomeric Once again the idea of using fluorinated ligands to improve the relative shifting power of these LSRs has been applied to these reagents and has led to tris-[3-(trifluoromethylhydroxymethylene)-(+)-cam-ph~rato]-~~and tris- [3-(heptafluoropropylhydroxymethylene)-(+ )-camphoratol-europium- and -praseodymiurn-(~rr)~~~ which are used* to distinguish resonances of a number of enantiomorphs.These LSRs are assumed to distinguish between enantiomorphs by forming diastereoisomeric complexes which have either different stability or just a different magnetic environment.sS Further LSRs used mainly for application in highly polar solvents include europium trichloride, reported to co-ordinate to polyfunctional steroids in dimethyl sulphoxide, causing upfield shifts,37 and praseodymium and europium nitrate hexadeuterium oxide, used successfullyL8 in deuterioacetone for investiga- tion of phosphate and phosphonates by 31Pn.m.r. The use of praseodymium perchlorate in deuterium oxide is reported3* in the study of carboxylic acids, and a poorer reagent, M (N(CH,CO,), )(HzO)3,where M is a lanthanide, is also used in studying carboxylic acids as their sodium salts.Table 5 shows the structures of some lanthanide shift reagents. 8 Organic Functional Groups As already pointed out, greater shifts are caused by functional groups which are most basic, and this aspect has been investigated by Ernst and Mannschreck, who an almost linear correlation of pKa with LIS for a series of substi- tuted anilines. The basicity factor appears a most important criterion on which to judge the effectiveness with which a group will give a LIS, although factors such as steric hindrance cannot be ignored. Alcohols are the most widely used functional group, followed by ketones and esters, which give slightly smaller shifts. These groups, together with quinones,lo6 aldehyde^,^^^*^ acetal~,,~ lactones,1a8 tetrahydrofurans,lO ether^,^^^^^epoxide~,6~~~~~ carboxylicparticularly rnethoxide~,~~~~~~~~~ and a number of phos- * A simple method for the preparation of these reagents is reported.lo6 lo4R.R. Fraser, M. A. Petit, and J. K. Sanders, Chem. Comm., 1971, 1450. loSV. Schurig and R. Israel, Tetrahedron Letters, 1972, 3297. loBJ. Grandjean, Chem. Cumm., 1971, 1060. lo' L. H. Keith, Tetrahedron Letters, 1971, 3. lo8F. I. Carroll and J. T. Blackwell, Tetrahedron Letters, 1970,4173. looA.F. Bramwell, G. Riezebos, and R.D. Wells, Tetrahedron Letters, 1971, 2489. Maya Table 5 Lanthmide shgt reagents Acetylacetone (acac) Tris(acety lacetonato) europium(HI) IEU(acac ) 1 r 1 r 1 30 0 L '3 Tris(dipival0ylmethanato Tris(dibenzoylmethanato) europium(111) IEu(dpm)3l europium(111) IEu(dbm) I 1 Eu F,$T 1 F F 3 -13 Tris -( 1,l,1,2,2,3,3 -heptaf luoro Tris -W(t-butylhydroxymethylene)-7,7-dimenthyloctane-4,6--(+)-camphoratoleuropium(rr~)dionato)europium(111) IE~(fod)~l (continired overleaf) Lanthanide Shvt Reagents in Nuclear Magnetic Resonance Spectroscopy Table 5 continued . ;Eu -Eu/ F--tFF$F FF 'F 3 3 Tris -I 3-( heptafluoro-n-propyl-Tris -I3 -(trifIuoromethyIhydroxy-hydroxymethylene)-.(+) -methyhe) -(+ camphorat01camphoratoleuropium (111) europium(III) phorous oxides,15~1s~74~110-113 all give LISs useful for spectral clarification.A wide range of comments and comparative investigations have been made on the preferred selective co-ordination of oxygen-containing groups, which necessarily involves either a comparison of LISs in different monofunctional molecules or a study in polyfunctional molecules.These observations are largely empirical and the factors which affect the shift should be considered in each case (steric hindrance, geometry, etc.). Only the alcohol in a difunctional hydroxy-ester is reported22 to co-ordinate at low concentrations of LSR, as expected. By increas- ing the LSR concentration, co-ordination eventually occurs at the carbonyl of the acid group, presumably only at a stage when co-ordination is complete at the hydroxyl-function. A detailed graphical analysis of a hydroxy-keto-~teroid~~ separates the relative contribution of the shift from co-ordination at each group, a method which could be developed for a wider range of polyfunctional mole- cules.Conversion of carbohydrates into the 5-O-acetate and 5-deoxy-analogues of methyl-2,3-O-isopropylidene-p-~-ribofuranosideshows a decrease in shift by 40 to 50 % and 10 to 20 %, respectively.llS Ketones are reported to co-ordinate better than ethers and esters, although only 35 to 40% as well as alcohols.B8 Quinones also give a satisfactory LIS, the carbonyl group being regarded as the preferred site of co-ordination in com- parison with an aromatic methoxy-group.loe A wide range of oxygen compounds are compared in a variety of intra- and inter-molecular competition experiment^,^ where tetrahydrofuran-acetone co-ordinate comparatively in a ratio of 8 :1; dimethyl ether-acetone, 7 :3; dioxanxyclohexane-1 ,4-dioneY 6 :4; and dioxan-methyl acetate or -acetone, 5 : 1.The presence of conjugation decreases T. M. Ward, I. L. Allcox, and G. H. Wahl, jun., Tetrahedron Letters, 1971,4421. l11 B.D.Cuddy, K. Treon, and B. J. Walker, Tetrahedron Letters, 1971,4433. 11s J. R.Corfield and S. Trippett, Chem. Comm.,1971,721. 11* R.F.Butterworth, A. G. Pernet, and S. Hanessian, C~mad.J. Chem., 1971,49,981. co-ordination in an up-unsaturated ether, and if oxygen is part of a furan ring, co-ordination is very Investigations of esters in polymers indicates preferred co-ordination to the carbonyl and not the ether ~xygen.~~~~~~~ In the case of functional groups consisting of two possible donor atoms, co-ordination is thought to occur mainly with the oxygen atom when present.As amides protonate preferentially at the o~ygen,~~~~~~~ the nitrogen lone pair being delocalized, preferential co-ordination of the LSR to the oxygen is ex- pected. This is found with amidess6~11s s6 azoxyben~enes,’~~and also oxime~,’~~ trimethylene sulphites,120 sulph~xides,~~ hemithioacetalsYs7 thiadecalones,lZ1 phosphate^,^^^^^ and the phosphoryl oxygen in pho~phorinans.~~~~~ However, the converse is thought to occur with oximes,12z where results indicate preferred co-ordination to the nitrogen lone pair. The carboxylate ion gives a greater shift to associated protons than the basic amine group when in an aqueous solvent?a Phenols, hydroxy, and, particularly, carboxylic compounds can be studied with normal LSRs, but these may decompose the complexed substrate on standing.Together with sulpho~ides,~~~~ which co-ordinate 25 to 30% less than alcohol^,^ thioamide~,~~~J~~ and thiocarbamate all give appreciable s~lphinyls,~~~ LISs, as well as hemithi~acetals,~~ which co-ordinate via the oxygen. The sulphonyl oxygen (R,SO,) co-ordinates less than the sulphinyl oxygen (R,SO), which is analogous to the nitro (RNO2) and amine oxide (RzNO) systems.80 Aminesl0JZ6 give larger shifts than alcohols;z3 and amides,l18Ja7 oximes,1aS1z2 q~inolines,~~ all give pyrazines,loB pyridines,1° and nitroso-amino-carbanions1z8 reasonable LISs; N-oxides give slightly smaller shifts;66~103~1zB pyrroles and nitriles96 only give small shifts and imines, azobenzenes, and nitro-compounds remain ~nperturbed~~~~~ by LSRs.In I4Nn.m.r., a survey13of nitrogen substrates shows that largest shifts are caused by alkylamines and pyridines; acetonitrile has less interaction with LSRs owing to its poorer basicity. Surprisingly, co- ordination is reportedlsO to occur preferentially with a phosphine in a phosphine- amine compound. The effect of deuteriating the substrate is shown to increase J. E. Guillet, I. R. Peat, and W. F. Reynolds, Tetrahedron Letters, 1971, 3493. A. R. Katritzky and A. Smith, Tetrahedron Letters, 1971, 1765. n6T. Birchall and R. J. Gillespie, Canad. J. Chem., 1963,41, 148. 11’ R. L. Middaugh, R. S.Drago, and R. J. Niedzielski,J. Amer. Chem. SOC.,1964,86,388. 118 L. R. Isbrandt and M. T. Rogers, Chem. Comm., 1971,1378. IIOR. E. Rondeau, M. A. Berwick, R. N. Steppel, and M. P. Serve, J. Amer. Chem. Soc., 1972,94,1096. laoG. Wood, G. W. Buchanan, and M. H. Miskow, Canad.J. Chem., 1970,50,521. A. van Bruijnsvoort, C. Kruk, E. R. de Waurd, and H. W. Huisman, Tetrahedron Letters, 1972, 1737. la5K. D. Berlin and S. Rengaraju,J. Org. Chem., 1971,36,2912. Ia3 W. Walter, R. F. Becker, and J. Thiem., Tetrahedron Letters, 1971, 1971. lZ4J. L. Greene, jun., and P. B. Shevlin, Chem. Comm.,1971, 1092. lZ6 R. A. Bauman, Tetrahedron Letters, 1971,419. la6 H. Burzynska, J. Dabrowski, and A. Krowczynski, Bull. Acad. polon. Sci., S&r.Sci.chim., 1971, 587.la’ A. H. Lewin, Tetrahedron Letters, 1971, 3583. lasR. R. Fraser and Y. Y. Wigfield, Tetrahedron Letters, 1971, 2515. lZ8R. A. Fletton, G. F. H. Green, and J. E. Page, Chem. and Ind., 1972, 167. laoR.C. Taylor and D. B. Walters, Tetrahedron Letters, 1972, 63. 71 Lanthanide Sh$t Reagents in Nuclear Magnetic Resonance Spectroscopy the ~hift,~~J~~~~~~-~~~ possibly owing to an increase in base strength caused by the deuterium. Alkyl halides, olefins. and saturated hydrocarbons. as expected. co-ordinate weakly or not at Some general conclusions have been made concerning comparisons of co-ordinating ability of different functional groups. The co-ordinating power of thiols, thio-ethers, and arylphosphines are generally much less than their oxygen and nitrogen analogues.lS The following series of functional groups have been put in order of their ability to co-ordinate and cause a LIS: phosphoryl > carbonyl > thiocarbonyl > thiophosphoryPO ethers > thioethers > ketones > esters@ amines > hydroxyls > ketones > aldehydes > ethers > esters > nit rile^^^ (for RCH,X) (Note: there are contradictions with respect to relative shifts, e.g.ketones and ethers) 9 Application of Lanthanide Shift Reagents By applying the principles outlined in the review, apart from spectral simplifica- tion, a great deal of information can be gained by using LSRs. This varies from producing spectra amenable to first-order analysis to configurational and *82s83conformational analysisll ,21+v3 9 lo8#134a using the dis tance-shift and distance-broadening relationships.A unique application is apparent when, for example, upfield shifts are produced by Eu(dpm), in fairly non-polar solvents, which is peculiar to structures which are often described as ‘f~lded’~~~~* and have the angle 81 between 54.7 and 125.3’. Shift reagents are used in spectral simplification of aliphatic systemsB5, and are also applied to their configuration and conformational analysis, e.g.oximes,lz thioarnide~,~~~,~~~and thiocarbamate Monocyclic systems are studied either in order to clarify spec tra7 9 36 9 or in c~nfigurational~~ @ 639 76 9 lS69 137 and conformational analysi~.~~.~~~~ The proton n.m.r. of heterocyclic systems are also simplified, e.g.pyrazines,lo@ pyridine~,~~~ pyridine N-oxides,12@ carbo-hydrate~,~~~J~~b~~~~ and examples of conformational and alky1idenefuranonesy7@ elucidation are cited with valerolactones,108 dioxaphosphorinan~,~~~~~and thia- decalones.12‘ Bicyclic systems, bicyclononanes in partic~lar,~~J~~~~~~ are studied alongside other rigid molecules chosen to simplify analysis of the distance and lalA. M. Grotens, C. W. Hilbers, and E. de Boer, Tetrahedron Letters, 1972, 2067. A. M. Grotens, J. Smid, and E. de Boer, Tetrahedron Letters, 1971, 4863. 133 D. A. Lightner and G. D. Christiansen, Tetrahedron Letters, 1972, 879. lsaaM.R. Vegar and R. J. Wells, Tetrahedron Letters, 1971, 2847. lsrbD. Horton and J. K. Thomson, Chem.Comm., 1971, 1389. 136 P. Belanger, C. Freppel, D. Tizane, and J. C. Richer, Chem. Comm., 1971, 266. 136 C. Casey and R. A. Boggs, Tetrahedron Letters, 1971, 2455. 13’ C. Freppel, D. Tizane, and J. C. Richer, Cunad. J. Chern., 1971, 49, 1984. 13* K. E. Stensio and U. Ahlin, Tetrahedron Letters, 1971,4729. 13@I. Armitage and L. D. Hall, Chem. and Ind., 1970, 1537. lrOL.F. Johnson, J. Chakravaty, R. Dasgupta, and U. R. Ghatak, Tetrahedron Letters, 1971, 1703. 72 Mayo geometric factors and allow correlation of the LIS with the pseudocontact shift expression. Thus the LIS of all protons in the n.m.r. spectra of adamant-1-01~~ and -2-01,~~J' 2-hydroxy-l-(2-hydroxyethyl)adamantane,6sborne~l,~.~~and iso- bomeo17 have been reported, as well as that for the methyl resonances of (+)-camphor.141 The 13Cn.m.r.spectra of borne01,~~ is~borneol~~~, cycl~pentanols,~~~ have been similarly assigned using and rib0-5-phosphatel~~ LSRs. Stereochemical problems have been solved in a wide range of compounds including pe~ticides~~~~~~~ Inone such structural elucida- and natural prod~cts.~~J~~ tion of a new diterpene, trachyl-oban-19-01,~~~ 32 proton resonances were assigned with the aid of LSRs. Steroids are another group of compounds ~t~died;~~~~~~~~~J~~,~~~one result indicates the position of the C17 side-chain in solution.86 References on the application of LSRs to conformational analysis are numerous.63~7s~82~83~108Detailed investigation of polyfunctional substrates are less common, although an example of a satisfactorily assigned spectrum of a di-functional sys tem is reported for 2-hydr ox y- 1-(2-hydrox ye t hy1)adaman t ane.65 However, complicated molecules can be simplified before using the LSR by reducing the number of functional groups available; one paper suggests the conversion of an alcohol into a trifluoroacetic ester, a group with very poor basicity, as an effective blocking group.16 Formation of first-order spectra with LSRs permits the measurement of coupling constant^,^^^^^^^^^ although com- plexation of the substrate with the LSR is reported to alter this parameter.150a Lanthanide shift reagents have been used as structural probes in studying co-ordination sites of enzymes by observing the shifts of acetamido and glyco- sidic methyl groups.93 The distinction of the resonances of iso-, hetero-, and syno-tactic polymers with LSRs has been applied in an analysis of poly(methy1 metha~rylate),ll~,~~~and is even used in molecular weight determinations.160b The optically active LSRs are used to distinguish enantiorn~rphs;~~ the fluorinated reagents appear to have a wider appli~ation~~J~~-one case cites the separation of enantiotropic protons at a prochiral centre.151 Application of LSRs to 14N n.m.r.spe~froscopy~~~~~is restricted by the large extent of broadening, but it is 141 C. C. Hinckley, J. Org. Chem., 1970,35,2834. 14a 0.A. Gansow, M. R. Willcott, and R. E. Lenkinski, J. Amer. Chem. SOC.,1971,93,4295. 143 W. B. Smith and D.L. Deavenport, J. Magn. Resonance, 1972, 6,256. lP4M. Christl, H. J. Reich, and J. D. Roberts, J. Amer. Chem. SOC.,1971, 93, 3463. 146 B. Birdsall, J. Feeney, J. A. Glasel, R. J. P. Williams, and A. V. Xavier, Chem. Comm., 1971,1473. lIe J. D. McKinney, L. H. Keith, A. Alford, and C. E. Fletcher, Cunad. J. Chem., 1971, 49, 1992. 147 0.Achmatowiez,jun., A. Ejchart, J. Jurczak, L. Kszerski, and J. St. Pyrek, Chem. Comm., 1971, 98. 14* P. V. Demarco, T. K. Elzey, R. B. Lewis, and E. Wenkert, J, Amer. Chem. Soc., 1970, 92, 5737. 14* D. G. Buckley, G. H. Green, E. Ritchie, and W. C. Taylok, Chem. and Ind., 1971, 298. laoaF. Floyd and L. Ho, J. Polymer Sci., Part B, Polymers Letters, 1971,9,491. lsobB.L. Shapiro, M. D. Johnston, jun., and R.L. R. Towns, J. Amer. Chem. Soc., 1972, 94, 4381. lS1 M. R. Frazer, M. A. Petit, and M.Miskow, J. Amer. Chem. Soc., 1972, 94, 3253. Lunthanide Shvt Reagents in Nuclear Magnetic Resonance Spectroscopy useful to use the LIS to characterize the mode of nitrogen bonding. More useful is 31P n.m.r.,f8 and as aHn.m.r. has been used with transition-metal reagents,162 there is a further possible application of LSRs with this nucleus. 10 Practical Aspects A widely used method for studying shifts is by addition of portions of LSR, as a solid or a solution, so that the gradual shifts of each resonance can be followed. This permits identification of peaks, initially part of a complex adsorption band, by reverse extrapolation to zero concentration of LSR, and is also one method of measuring the shift parameter. However, an alternative approach23 gives more accurate shift parameters or bound chemical shifts, by starting with a solution of the LSR in the n.m.r.tube and adding portions of the substrate. A plot of substrate concentration against the inverse of the LIS gives a slope equal to (L~B),where dg is the bound chemical shift;2a see Section 2. The internal standard from which chemical shifts are measured is also displaced by the LSR, albeit a fairly small shift. This is a consequence of changes in the bulk magnetic susceptibility of the solution, which shifts the TMS signal by up to 1.4 p.p.m. in one case.37 However, these shifts are linear, with respect to the LSR concentration, so that no drastic errors in structural conclusions should arise, noting that the magnitude of these shifts is invariably smaller than the shifts of the substrate.Acetonitrile has been used as an internal standard; the lack of broadening at high concentration of LSR indicates a minimal shift;l* benzene1l5 and cyclohexanes have also been used, the latter being shifted 3 Hz in the concentrations studied. Alternative standards such as chloroform are proposed to avoid interference by the LSR resonances in the 1 p.p.m. region.14 The effect of changes in bulk magnetic susceptibility may also cause displacement of the nucleus being studied, but such variables need only be considered in detailed measurements. Use of the temperature-shift relationship is reported either in just improving or in substituting the concentration-shift studies.g2 Sensitivity of instruments may be enhanced by increasing the radiofrequency field, as the limit of saturation could be increased by the presence of the paramagnetic ions even though these LSRs have fairly inefficient spin relaxation properties. The author wishes to thank Dr. A. P. Johnson for many useful discussions. lpoA. Johnson and G. W. Everett, jun., J. Amer. Chern. SOC.,1970,92,6704.

ISSN:0306-0012    

DOI:10.1039/CS9730200049

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

Insect Attractants of Natural Origin By D. A. Evans DEPARTMENT OF CHEMISTRY, THE UNIVERSITY, SOUTHAMPTON, SO9 5NH C. L. Green TROPICAL PRODUCTS INSTITUTE, 56-62 GRAY’S INN ROAD, LONDON, W.C.l 1 Introduction and Scope During the past decade, the interdisciplinary investigations of biologists and chemists have established the importance and complexity of chemosensory communication amongst many marine and land anima1s.l The insect world bas been the subject of the most intense study and many facets of insect behaviour have been shown to be regulated by chemical stimuli. The current outcry over indiscriminate use of insecticides has provided much of the motivation for this work since the species-specificity and high potency of many naturally occurring chemosensory substances hold great promise for manipulation and control of insect populations.The objectives of this review are to offer a current and critical survey of the most widely studied area, namely insect attraction. We define an insect attractant as a compound or mixture of compounds which stimulates in an insect a be- havioural response of orientation and locomotion to the source of the attractant. This definition is necessarily a convenient oversimplification of an incompletely understood biological process in which other factors can play an important contributing role in producing behavioural responses. Natural insect attractants fall broadly into two categories: (i) secretions of insect origin which produce responses for mating, aggregation, and foraging within a single species :the term ‘pheromone’ applies to this type of intra-species attractant; (ii) volatile constituents of plant- or animal-hosts utilized by insects in searching for food and egg-laying (oviposition) sites.Wilson2 has classified pheromones and related stimuli into two distinct types, termed ‘releasers’ and ‘primers’. A releaser pheromone elicits an immediate behavioural response upon reception, and insect pheromone attractants fall within this category. In contrast, primer pheromones cause physiological changes which ultimately result in a behavioural response, e.g. the pregnancy block induced in mice by the odour of strange males. A consideration of primer stimuli is outside the scope of this review. A great number of pheromone and host attractants have been reported in the ‘Communication by Chemical Signals’, ed.J. W. Johnston, jun., D. G. Moulton, and A. Turk, Appleton Century Crofts, New York, 1970.* E. 0.Wilson, Science, 1960,149, 1064. Insect Attractants of Natural Origin entomological literature3 but the number of chemical identifications is compara-tively small. This survey is primarily concerned with insect attractants of which the chemical identity has been rigorously established, and where the synthetic material has been successfully field-tested. Recent advances in the techniques of microscale structure elucidation which have enabled rapid progress in this field are presented. Brief discussions are devoted to artificial lures discovered by the screening of synthetic compounds, and to the practical and economic uses of insect attractants.Other types of insect secretions, e.g. mating aphrodisiacs, defence secretions employed to repel predators, alarm pheromones secreted by social insects to warn a colony of attack, are not considered here. In a research field which engenders the most formidable practical difficulties, it is inevitable that a number of structural hypotheses are erroneous. Indeed, several discrepancies are currently manifest in the literature and mention is made of such instances. 2 Sex Attractant Pheromones A. Function.-A sex attractant pheromone is secreted externally by an adult insect to stimulate attraction over a distance of a member of the opposite sex of the same species.At short range the pheromone arrests the insect and induces copulatory movements. This method of intra-species communication over a distance may be vital for the species survival of low-density populations of some non-social insects. The sex pheromone may comprise one or more components, and is secreted by the virgin adult in many cases soon after emergence from the pupae. In species where mating occurs only once, pheromone production ceases after cop~lation.~ B. Lepidoptera (Moths and Butterflies).-Whereas most species of butterfly (superfamily Papilionoidea) appear to rely upon a visual system of communication over a distance, many of the moth species that have been studied rely upon the production of sex pheromones by the female of the species.Secretion of sex pheromones by males of some lepidopterous species during the courtship stage has been reported, but these are now considered to act as ‘aphrodisiacs’ to aid in stimulating and arresting females.s Such aphrodisiacs are effective only at short range and are not considered further here. However, mention must be made of one of the male pheromones of the greater wax moth, Gafferiameffoneffu M. Jacobson, ‘Insect Sex Attractants’, Wiley (Interscience), New York, 1965; M. Jacobson, N. Green, D. Warthen, C. Harding, and H. H. Toba, in ‘Chemicals Controlling Insect Behaviour’, ed. M. Beroza, Academic Press, New York, 1970, p. 3; K. Eiter, Fortschr. Chem. org. Naturstofe, 1970,28,204; C.G. Butler, ref. 1, p. 37. C. F. So0 Hoo and R. J. Roberts, Nature, 1965,205, 724; M. L. Bobb, J. Econ. Entomol., 1964,57,829; C. G. Butler, ref. 1, p. 40. M. Birch, Animal Behaviour, 1970, 18, 310; J. Meinwald, W. R. Thompson, and T. Eisner, Tetrahedron Letters, 1971, 3485 and references cited therein; C. G. Butler, ref. 1, p. 42. Evans and Green Table 1 Sex attractants for males of the Lepidoptera (a) Sex pheromone attractants -identity rigorously proven Structure 0 2 4 6 8 10121416184...................... -/LAo-.......................Lo--== ....................... ...d................... -A0-....................... ....................... K, ....................... ...A....................-AoA-....................... -JOJ ... ................... -fi0-+ JOJ -....................... HO ....................... ....................... . .0 . . .6 .8 .,.*.l.*.1.4.l.6 .,.e +0+ Insect Species Pine emperor moth a (Nudaurelia cytherea cytherea) Cabbage looper moth b (Trichoplusia ni) Oriental fruit moth C (Grapholitha molesta) Grape berry moth d (Paralobesia viteana) Red-banded leaf roller e (A rgyrotaenia velut inana) Oblique-banded leaf f roller (Choristoneura rosaceana) European corn-borer g Ostrinia nubilalis, Iowa) Tortricid moths 11 (Adoxophyes orana and A. fasciata) Indian meal moth i (Plodia interpunctella) Almond moth (Cadracautella) Southern armyworm j moth (Prodenia eridania) Silkworm moth k (Bornbyx mori) Tiger moths (7 species) I (Artiidae) Gypsy moth m (Porthetria dispar) 77 Insect Attractants of Natural Origin Table 1 (continued) (b) Proposed sex pheromone attractant structures- awaiting successful and unambiguous field testing Structure Insect Species Ref: 2 0 2 4 6 8 1012 1416184.......................Codling moth n HO (Laspeyresia pomonella)...o. ................... False codling moth 0 A0-(A rgyr oploce leuco treta) ....................... Pseudoplusia includens, RadQlusia ou, PLo-Autographia biloba. Autographa 4...; ................... calvornica -Fall armyworm moth r4-(Spodoptera ....................... frug&erda) Mediterranean flour S moth (Anagasta kuehniella) Beet armyworm moth t ,i, .. . . .r.o . l.4.1.60 ,08 (Spodoptera exigua) (c) Sex attractrants identified by the EAG method 2 0 2 4 6 8 1012 1416 18 4....................... Codling moth U HO-/ (Laspeyresia pomonella) ....................... Larch bud moth Y (Zeiraphera diniana) ....................... 4 2 0 2 4 6 8 1012 941658 (a) H. E. Henderson, F. L. Warren, 0.P. H. Augustyn, B. V. Burger, D. F. Schneider, (in part) P. R. Boshoff, and H. S. C. Spies, and H. Geertsema, J.C.S. Chem. Comm., 1972, 686; (b)R. S. Berger, Ann. Entomol. SOC.Amer., 1966,59,767; (c) W. L. Roelofs, A. Comeau, and R. Selle, Nature, 1969, 224, 723; (d) W. L. Roelofs, J. P.Tette, E. F. Taschenberg, and A. Comeau, J. Insect Physiol., 1971, 17, 2235; (e) W. L. Roelofs and H. Am, Nature, 1968, 219, 5 I3 ;cf)W. L. Roelofs and J. P. Tette, Nature, 1970,226, I I72 ;(g)J. A. Klun and T. A. Brindley, J. Econ. Entomol., 1970,63,779;(h) Y. Tamaki, N. Noguchi, T. Yushima, C. Hirano, K. Honma, and H. Sugawara, Kontyu, 1971, 39, 338; Y. Tamaki, H. Noguchi, T. Yushima, and C. Hirano, Appl. Ent. Zool., 1971, 6, 139; C. M. Meijer, F. J. Ritter, C. J. Persoons, A. K. Minks, and S. Voerman, Science, 1972, 175, 1470; (i) Y. Kuwahara, C. Kitamura,S.Takahashi, H. Hara, S.Ishii, and H. Fukami, Science, 1971,171, 801 ;U. E. Brady, J. H. 78 Evans and Green which has been shown to be n-undecanal.6 This is reported to perform the dual role of attraction of females over a distance and provision of a stimulus at short range for copulation.The study of lepidopterous sex attractants was pioneered by Butenandt et al.,’ who identified a pheromone of the female silkworm moth Bornbyx muri as hexadeca-trans-lO,cis-l2-dien-l-olin 1961 after some twenty years of pains- taking research. This remarkable accomplishment was achieved with only 12 mg of pheromone extracted from some half-million virgin females, and without the aid of modern sophisticated instrumentation. Table l(a) lists the structures of sex pheromone attractants which have been rigorously proven by isolation and structure elucidation by chemical and spectroscopic methods, and have been confirmed by successful attraction in the field using a synthetic sample of the pheromone.Some cases which await successful and unambiguous field-testing are listed in Table l(b). Recent research has provided a more rapid method of sex attractant identifica- tion involving the screening of candidate compounds by electrophysiological study of the responses of insect antennae. This ‘electroantennogram’ technique (abbreviated as EAG) is frequently used as a bioassay method, and its applica- tions are fully discussed in Section 8. Combined field and EAG screening pro- grammes have allowed recognition of sex attractants for a number of species, and a recent review8 provides an excellent discussion of results for over eighty lepidopterous species, together with taxonomic correlations. However, it is dangerous to assume that a highly potent sex attractant is the natural pheromone until identity has been established by chemical or spectroscopic means.Table l(c) contains two examples of sex attractants identified by the EAG method for which there exists supporting chemical evidence of identity with a natural pheromone. Most lepidopterous sex attractants so far identified are monoene or diene straight-chain fatty alcohols or acetates of C12or C,, chain length. The most H. Roller, K. Biemann, J. S. Bjerke, D. W. Norgard, and W. H. McShan, Acta Ent. Bohemoslov., 1968, 65, 208. See Table 1, ref. k.* W. L. Roelofs and A. Comeau, Proceedings of the Second International Congress on Pesticide Chemistry, IUPAC, Tel Aviv, 1971, p.91. Tumlinson, R. G. Brownlee, and R. M. Silverstein, ibid., 1971, 171, 802; 0)M. Jacobson, R. E. Redfern, W. A. Jones, and M. H. Aldridge, Science, 1970, 170, 542; R. E. Redfern, E. Cantu, W. A. Jones, and M. Jacobson, J. Econ. Entomol., 1971,64,1570; (k)A. Butenandt, R. Beckman, and D. Stamm, 2.physiol. Chem., 1961, 324, 84; (I) W. L. Roelofs and R. T. Carde, Science, 1971,17,684; (m)B. A. Bierl, M. Beroza, and C. W. Collier,J. Econ. Entomol., 1972,65,659; (n) L. M. McDonough, D. A. George, B. A. Butt, J. M. Ruth, and K. R. Hill, Science, 1972, 177, 177; (0)J. S. Read, F. L. Warren, and P. H. Hewitt, Chem. Comm., 1968, 729; (p) R. S. Berger and T. D. Canerday, J. Econ. Entomol., 1968, 61, 452; (q) H. H. Shorey, L. K. Gaston, and J. S.Roberts. Ann. Entomol. SOC.Amer., 1965, 58, 600; (r)A. A. Sekul and A. N. Sparks, J. Econ. Entomol., 1967, 60, 1270; (s) Y. Kuwahara, H. Hara, S. Ishii, and H. Fukami, Agric. and Biol. Chem. (Japan), 1971,35,447; (t)U. E. Bradey and M. C. Ganyard, Ann. Entomol. SOC.Amer., 1972, 65, 898; (u) W. L. Roelofs, A. Comeau, A. Hill, and G. Milicevic, Science, 1971, 174, 297; (v) W. L. Roelofs, R. Carde, G. Benz, and G. von Salis, Experientia, 1971, 27, 1438. Insect Attractants of Natural Origin diverse structural types encountered to date occur in the superfamily Noctuoidea where, in addition to unsaturated fatty alcohols and acetates, a hydrocarbon and an epoxide have been found. The sex pheromone of the pine emperor moth, Nudaurelia cytherea cytherea, is novel both for its short chain length and its 3-methylbutanoate ester m~iety.~ For the majority of species where pheromone structures have been identified, only one compound is necessary to attract males.However, several instances have been recognized where two compounds are essential to elicit attraction, for example, the tortricid moths (Adoxophyes species),l0 and the southern armyworm moth (Prudenia eridania).ll In the case of the latter, attraction to synthetic pheromones in the field has been reported to be relatively poor, but it is possible that this may have been the result of a formulation problem. Two groups have reported research into the attractant of the codling moth Laspeyresia pomonella. Roelofs et al. suggest that dodeca-trans-8,trans-10-dien-1-01 [Table l(c)] may be a natural pheromone on the basis of EAG and field screening experiments.’* McDonough et al.report the presence of cis-2,- trans-6,7-methyl-3-propyl-deca-cis-2,trans-6-dien-1-01Fable 1(b)] as one of at least seven natural pheromone^,^^ but were unable to confirm the presence of Roelof’s attractant. Comparative field-testing experiments may resolve this problem. The proposed structures for the sex pheromones of both the false codling moth Argyroploce leucotreta14 and the fall armyworm moth Spodoptera frugi- perda15 are suspect because the synthetic compounds fail to produce convincing attraction in the field. The structure (1;‘propylure’) first proposed16 for the pheromone of the pink bollworm moth Pectinuphora gossypiella now appears to be incorrect.In field- testing, propylure and various formulations in conjunction with its reputed natural synergist NN-diethyl-m-toluamide (Deet) were found to be markedly less potent than compound (2; ‘hexalure’), discovered by screening experiments, which possesses a more conventional sex attractant Jacobson et al. assigned structure (3; ‘gyptol’) to the sex pheromone of the gypsy moth Por- thetria dispar, and reported that its homologue (4; ‘gyplure’) was also very active as a sex attractant.l* However, this work has been subsequently shown to be erroneous and the reputed biological activity ascribed to a highly potent See Table 1, ref. a. loSee Table 1, ref. h. l1 See Table 1, ref.j. la See Table 1, ref. u. lS See Table 1, ref. n. l4 See Table 1, ref. 0. l6 See Table I, ref. r. l6 W. A. Jones, M. Jacobson, and D. F. Martin, Science, 1966, 152, 1516; W. A. Jones, and M. Jacobson, ibid., 1968, 159,99. J. C. Keller, L. W. Sheets, N. Green, and M. Jacobson, J. Econ. Entomol., 1969, 62, 1520. M. Jacobson, M. Beroza, and W. A. Jones, J. Amer. Chem. SOC.,1961, 83, 4819; M. Jacobson and W. A. Jones, J. Org. Chem., 1962,27,2523; R. M. Waters and M. Jacobson, J. Econ. Entomol., 1965, 58, 370. Evans and Greeri 0 (1) propylure AP-----(2) hexalure contaminant.lO The situation has recently been clarified by the identification and successful field-testing of cis-7,8-epoxyoctadecane [Table 1(a), ‘dispar- The practical difficulties involved in the investigation of the biogenesis of lepidopterous sex attractants have not been surmounted to date. It is significant in this context that many species do not feed as adults and lipid catabolism is a plausible route for attractant biosynthesis.C.Sex Attractants of Other Orders.-In comparison with the Lepidoptera, far fewer sex attractants have been identified in other orders. Those which have been identified and confirmed by field-testing are listed in Table 2. The sole identification of a dipterous pheromone is of that produced by the female housefly, Musca domesticu.21 ‘Muscalure’ (cis-9-tricosene) is far less potent than many other known sex attractants but its ease of synthesis offers promise for use as a lure.l9 M. Jacobson, R. M. Waters, and M. Schwarz, J. Econ. Entomol., 1970, 63, 943. *O See Table 1, ref. rn. 41 See Table 2, ref. a. Insect Attractants of Natural Origin Table 2 Sex pheromone attractants for males of non-Iepidopterous species Structure Insect Species Ref. C8Ht7 \3/ C13H27 Diptera: Housefly a (Musca dornestica) b (Apis mellvera) and related species 0 - Coleoptera: 0 Me0 " 0 - 2 1 Black carpet beetle (Attagenus megatoma) Dermestid beetle c d HO + (Trogoderma inclusum) Sugar beet wireworm eHOA/v (Limonius californicus) Grass grub beetle f (Costelytra zealandica) aO" (a) D. A. CarIson, M. S. Mayer, D. L. SiIhacek, J. D. James, M. Beroza, and B. A. Bierl, Science, 1971,174,76; (b)C.G. Butler and E. M. Fairey, J. Apicufr.Res., 1964,3,65; (c) R. M. Silverstein,J. 0.Rodin, W. E. Burkholder, and J. E. Gorman, Science, 1967,157,85; (d)J. 0. Rodin, R. M. Silverstein, W. E. Burkholder, and J. E. Gorman, Science, 1969, 165, 904; (e) M. Jacobson, C. E. Lilly, and C. Harding, Science, 1968, 159, 208; cf) R. F. Henzell and M. D. Lowe, Science, 1970,168,1005. Among the Hymenoptera, the honeybees provide an example of social insects where an extremely complex pheromone system has evolved.22 The so-called 'queen substance', one component of which is 9-oxodec-trans-2-enoic acid, of the honeybee functions as both a primer and releaser pheromone. In the hive it regulates ovary development of workers and also queen replacement. During the mating flight, the queen substance, together with the 9-hydroxy-derivative, acts as a sex attractant for the drones.Furthermore, cohesion of swarms is co-ordinated by an interplay of the secretions of two castes: the pheromones of the queen together with the Nassanoff gland secretions of the workers.Bs It is Ref. 1, p. 35. 19 R. A. Morse and R. Boch, Ann. EntomoZ. SOC.Amer., 1971,64,1414. 82 Evans ad Green noteworthy that queens of some species of termites are reported to utilize 9-oxodec-trans-2-enoic acid as a pheromonal secretion.2* It is likely that second- ary pheromones operate in conjunction with queen substance in specific behavioural contexts . The sex pheromone attractants of the beetles (Coleoptera) are structurally diverse and may be produced by the male or female of the species.The female stored-product beetles (Trogodermaand Attagenus species) utilize fatty alcohols or acids, and unidentified secondary pheromones are also suspected to be involved.25 The attractant of the sugar beet wireworm Limonius californicus is reported to be valeric acid26 and, apart from its unusually short chain length, its great abundance in the female (greater than 100 pg) is remarkable. The sex pheromone attractant of the grass grub beetle Costelytria zealandica is phenol,27 which is believed to be produced by the action of symbiotic bacteria, possibly upon tyrosine, within the collaterial glands of the female.28 Interestingly, 2,6-dichlorophenol (5) has been isolated from females of the lone star tick Amblyomma americanum (an Arachnid) and is suspected as being its sex phero- mone attractant.2a The allene (6) or a closely related structure is suggested as a component of the sex attractant secreted by the male dried bean beetle A canthoscelides obtec t us.3 The structure (7) proposed by Jacobson et aL3' for the sex attractant of the female American cockroach Periplanata americana (Dictyoptera) has been OH (5) M S.Sannasi and C. J. George, Nature, 1972,237,457. M. See Table 2, ref. d. *a See Table 2, ref. e. s7 See Table 2, ref.f. *@ C. Hoyt, G. 0. Osborne, and A. P. Mdcock, Nature, 1971,230,472. *O R. S. Berger, Science, 1972, 177, 704. 8o D. F. Horler, J. Chem. Suc. (0,1970, 859. M. Jacobson, M.Beroza, and R. T. Yamamoto, Science, 1963, 139,48. Insect Attractants of Natural Origin firmly disproved by Whiting’s rational synthesis of (7) in conjunction with bio- assay testing.3a Much of the reported chemistry remains inexplicable and clarification of the whole situation is awaited. D. Sex Attractant Specificity.-The most extensive studies in this area have been with the Lepidoptera, but the conclusions are probably widely applicable. Two aspects must be considered separately in relation to pheromone sex attractants : Structurd Specificity. Studies of the effects of structural modification of the sex attractants of several species demonstrate that simple changes result in dramatic reduction or even complete loss of activity.The cabbage looper the gypsy and the red-banded leaf roller have been carefully studied in this respect and the results for the last are summarized in Table 3. Such structure-activity relationships have been used to probe olfaction mechanisms (Section 7). Species Specificity. The avoidance of cross-mating (i.e. the maintenance of reproductive isolation) of species is dependent on factors such as differences in seasonal or geographic distributions and by genetic or physiological incom- patibility. However, when similarity occurs in these biological factors, the evolution of species-specific sex pheromone attractants has provided an addi- tional mechanism for reproductive isolation. Tables l(a--c) reveal that many species, and especially those which are closely related, utilize the same compound.However, it has been demonstrated that in some such cases, differences in attraction behaviour can be observed in close proximity to the attractant source. Some species are believed to have evolved secondary pheromones which, although inactive alone, augment the potency of the natural pheromone and modify short-range attraction when concentrations are relatively high. Conclusive identification of secondary pheromones has not yet been reported. Both the red- and oblique-banded leaf roller moths employ tetradec-cis-ll-enyl acetate as a natural sex pheromone, but the addition of dodecyl acetate as a synergist dramatically enhances attraction of the former, but reduces trapping of the latter.36 The natural occurrence of secondary phero- mones is probably more frequent than has been revealed by laboratory bio- assays, particularly where simple fatty alcohol or acetate attractant pheromones are involved.In contrast to species where only one compound is required to achieve attraction, several cases are known where a dual pheromone system is utilized and both components are essential to achieve attraction. This phenomenon has been found with two species of tortricid moths [Adoxophyes orunu and A. A. C. Day and M. C. Whiting, Proc. Chem. SOC., 1964,368; A. C. Day and M. C. Whiting, J. Chem. SOC. (C),1966,464 and references cited therein. aa R. S. Berger and T. D. Canerday, J. Econ. Entomol., 1968, 61, 452; M. Jacobson, H. H. Toba, J.Deboult, and A. N. Kishaba, ibid., 1968, 61,84. 31 V. E. Adler, M. Beroza, B. A. Bierl, and R.Sarmiento, J. Econ. Entomol., 1972, 65, 665, 679. W. L. Roelofs and A. Comeau, J. Insect Plrysiol., 1971, 17,435, 1969. W. L.Roelofsand A. Comeau, Science, 1969,165,398. Evans and Green Table 3 Eflects of structural modification on attraction of the male red-banded leaf roller (Argyrotaenia velutinana)" 0 2 4 6 81 0 1 214 O a . . o . . . . . . . * * . . . Natural pheromone *................ J-Very weak 4 attractant ................ (R =H, CHO, EtCO) Inhibitors O................ AO \ A 0................. Synergist O................ II Inactive (both cis and trans) ................0 2 4 6 8 101214 aW. L.Roelofs and A. Comeau, J. Insect Physiol., 1971, 17, 435. fasciata, Table 1(a)].I0 Field screening experiments have also revealed cases where a mixture of both an unsaturated fatty alcohol and the corresponding acetate derivative is required to achieve attraction, e.g. CZepsis meZaZeucana.8In contrast, in single component systems where the natural pheromone is an acetate, it has beenobserved that the corresponding alcohol causes inhibition in the field.s6 Significantly, there are several reported instances involving morphologically similar species, previously classified as being identical, where one species responds to a cis-isomer of a sex attractant whereas its 'twin' is attracted to the trans-85 Insect Attractants of Natural Origin isomer.*J6 For example, the European corn-borer Ustrinia nubilalis in Iowa is attracted to tetradec-cis-1 l-enyl a~etate,~' whereas in New York it is attracted to the trans-isomer.8 3 Population Attractants A.Function.-Population attractants assemble large numbers of both sexes of a species at a particular site for mating and subsequent egg-laying. In general, the behavioural sequence is initiated by one sex being attracted by the volatile constituents of a suitable host-plant. The pioneer insects secrete pheromones, usually after feeding, which attract large numbers of both sexes of the species. Such pheromones are found to be sex-selective in that they attract predominantly, but not exclusively, members of the opposite sex to that of the pioneer insects.Such a system of colonization is most widely employed by the beetles, and to date the Scolytid genera have been studied most closely. B. Chemistry and Specificity.-The aggregation pheromone of the stored- product beetle Trogoderma granarium consists largely of a mixture of the ethyl esters of palmitic, linoleic, oleic, and stearic acids together with methyl 01eatc.~* The majority of aggregation pheromones identified, however, are terpenoids. The male boll weevil Anthonomus grandis is attracted by the volatile terpenoid constituents of the cotton bud of which (-)-a-pinene, (-)-limonene, (-)-/% caryophyllene, (+)-/%bisabolol, and caryophyllene oxide have so far been rec~gnized.~~After feeding, the males secrete an aggregation attractant which has been identified as a synergistic mixture of four novel terpenoids (9)--(12).40 s7 J.A. Klun and T. A. Brindley, J. Econ. Entomol., 1970, 63, 779; J. A. Klun and J. F. Robinson, ibid.. 1970, 63, 1281. 38 U. Yinon, A. Shulov, and R. Ikan, J. Insect Physiol., 1971, 17, 1037. ae J. P. Minyard, D. D. Hardee, R. C. Gueldner, A. C. Thompson, G. Wiygul, and P. A. Hedin, J. Agric. Food Chem., 1969, 17, 1093. *O J. H. Tumlinson, D. D. Hardee, R. C. Gueldner, A. C. Thompson, P. A. Hedin, and J. P. Minyard, Science, 1969, 166, 1010. Evans and Green The probable biosynthetic route to these pheromones is metabolic transformation of ingested cotton terpenes (8)-+(9)-(12).41a Field trapping with the synthetic pheromone mixture ('grandlure') produced catches of only 50-80 % of those of live males.Although this may merely be a formulation problem, the possibility exists that unidentified secondary pheromones are secreted by the males.4a The bark beetles (Scolytidae) are major forestry pests and achieve aggregation by a complex interplay of pheromonal secretions and volatile terpenoids of the host tree.41b,43a In the monogamous Dendroctonus species, females initiate the attack on a suitable host, whereas males perform the task in the polygamous Ips species. The pioneer beetles release pheromones which act in combination with the volatile terpenes of tree resin exudate to signal the suitability for mass attack. Table 4 lists the combinations of the several compounds involved.It appears that the Ips species utilize solely male pheromones, in contrast to Dendroctonus species where secretions from both sexes effectively balance the sex-ratios of attacking beetles. The release of exo-brevicomin (14) by D. brevi-comis females attracts a predominance of males, whereas secretion of frontalin (13) produces a counterbalancing effect by selectively attracting females of this species. In contrast, the related D. frontalis females attract predominantly the males of their species with frontalin, and the males compensate by release of a male inhibitor, verbenone (19), after alighting and feeding. The review of Renwick and VitC is recommended for a more detailed discussion of this complex sy~tem.~lc Frontalin is present prior to feeding in emergent adult females of D.frontah and is presumed to be a product of lipid catab~lism,~~C and exo-brevicomin probably has an analogous biosynthetic origin. The pheromones trans-verbenol (18) and verbenone (19), although recognized as constituents of certain trees, could plausibly arise by metabolic oxidation of ingested a-pinene [(17)+(18)+ (19)].41a In contrast to Dendroctonus species, the Ips pheromones are not secreted until after several hours feeding by males. Their origin is probably by metabolic transformation of ingested terpenes, but this hypothesis is in dispute."4 A high degree of structural specificity is exhibited by the bark beetle pkero- mone~.~l~ possess both Individual pheromones and host-tree terpene~~l~,~~ 41 'Symposium on Population Attractants', Contributions from the Boyce Thompson Institute, 1970,24, No.13. (a) D. D. Hardee, p. 315; (b) G. L. McNew, p. 251; (c) J. A. A. Renwick and J. P. VitC, p. 283; (d)J. A. A. Renwick, p. 337; (e) H. Oksanen, V. Perttunen, and E. Kangas, p. 299; cf) T. L. Payne, p. 275; (8)J. P. VitC, p. 343. 42 D. D. Hardee, G. H. McKibben, R. C. Gueldner, E. B. Mitchell, J. H. Tumlinson, and W. H. Cross, J. Econ. Entomol., 1972,65,97. 43 'Control of Insect Behaviour by Natural Products', ed. D. L. Wood, R. M. Silverstein, and M. Nakajima, Academic Press, New York, 1970. (a) D. L. Wood, p. 301; (b) J. C. Moser, p. 161; (c) V. G. Dethier, p. 21; (d) T. Sakan, S.Isoe, and S. B. Hyon, p. 244; (e) T. Muto and R. Sugawara, p. 189; cf) M. Jacobson, p. 11 1 ;(glR. M. Silverstein, p. 285. 44 J. H. Borden, K. K. Nair, and C. E. Slater, Science, 1969, 166, 1626. 45 H. J. Heikkenen and B. F. Hruffiord, Science, 1965, 150, 1457. Insect Attractants of Natural Origin Table 4 Bark beetle population attractants Species Pheromones Host-tree Ref. Female Male attractants Dendroctonus species: D. frontalis D. brevicomis (13) + (1 8) (1 3) + (14) + (1 8) (19) (1 3) + (19) (1 7) (8)+(16)+(23) a a,b D. ponderosae (1 8)D.pseudotsugae (1 3) + (1 5) Ips species: I. confusus - (14) I (20)+ (21)+ (22) (1 7) (1 7) ? a C d I. grandicollis I. calligraphis -- (22) (20)+ (21) (8)+(18)+(24) ? e f (a) J.A. A. Renwick and J. P. Vit6, Contributions from the Boyce Thompson Institute, 1970, 24, 283; (6) W. D. Bedard, P. E. Tilden, D. L. Wood, R. M. Silverstein, R G. Brownlee,and J. 0. Rodin, Science, 1969, 164, 1284, and references cited therein; W. D. Bedard, R. M. Silverstein, and D. L. Wood, ibid., 1970, 167, 1638; (c) G. W. Kinzer, A. F. Fentiman,jun., R. L. Foltz, and J. A. Rudinsky, J. Econ. Entomol., 1971, 64,970; J. Rudinsky, Science, 1969, 166, 884; (d) R. M. Silverstein, J. 0. Rodin, and D. L. Wood, Science, 1966, 154, 509; D. L. Wood, R. W. Stark, R. M. Silverstein, and J. 0.Rodin, Nature, 1967, 215, 206; (e) J. P. Vit6 and J. A. A. Renwick, J. Insect Physiol., 1971, 17, 1699; R. A. Werner, ibid., 1972, 18, 423, 1403; cf> J.A. A. Renwick, and J. P. Vite, J. Insect Physiol., 1972, 18, 1215. Evans and Green sex- and species-selectivity, and reproductive isolation of species is achieved by the specific action of a combination of the pheromones and host-tree terpenes. 4 Trail Pheromones A. Function.-Among the complex chemosensory communication systems evolved by social insects, trail following is one of the most highly developed responses triggered by pheromone~.~~~~~ Trail marking is usually performed only by successful foragers on returning to the nest in order to recruit and guide other members to the food source. Trail pheromones are also believed to be involved in controlling colony migration, e.g. in the swarming of honeybees. B. Chemistry and Specificity.-The trail pheromones of most social insects appear to consist of complex multicomponent systems, and there exists at present Table 5 Trail pheromones Structure Insect Species Ref.(25) geraniol, R1= CH20H; R2= H 7 (26) geranial, R1= CHO; Ra = H (27) neral, R1= H; R2= CHO a (28) geranic acid, R1= C02H; R2 = H (29) nerolic acid, R1= H; R2= C02H Citral, i.e. (26) + (27) Stingless bee (Trigona subterranea) Leaf-cutting ant H (Atta texana) Zootermopsis nevaciensis H02C-(termite) Southern subterranean termite eHQa(Reticulitermes virginicus) -(a) C. G. Butler and D. H. Calam, J. Insect Physiol., 1969, 15, 237, and references cited therein; (6) M. S. Blum, R. M. Crewe, W. E. Kerr, L. H. Kieth, A.W. Garrison, and M. M. Walker,J. Insect Physiol., 1970, 16, 1637; (c) J. H. Tumlinson, J. C. Moser, R. M. Silverstein, R. G. Brownlee, and J. M. Ruth, J. Insect Physiol., 1972, 18, 809; (d) H. Hummel and P. Karlson, Z.physiol. Chem., 1968, 349, 725; (e) F. Matsumura, H. C. Coppel, and A. Tai, Nature, 1968, 219,963; A. Tai, F. Matsumura, and H. C. Coppel, J. Org. Chern., 1969,34, 2180. Insect Attractants of Natural Origin little chemical information in this area. Table 5 summarizes current knowledge and the compounds listed are best regarded as being the principal active com- ponents of pheromones. Whereas most of the trail markers listed refer to com- pounds used to lay ground trails, the bee pheromones discussed here are airborne markers, effective only over a very short range.The origin of some trail pheromones appears to be direct utilization of plant constituents rather than by biosynthesis in specialist organs. For example, citral which is employed by honeybees is almost certainly of phytochemical origin;46 and the fatty alcohol trail pheromone of the southern subterranean termite (Table 5) is present in the fungus-infected wood of its diet.47 The isoprenoids (30) and (31), extracted from Santalum spicatum wood oil, have been shown to possess trail-marking activity for several Nasutiterrnes species of termites.4s However, the natural trail pheromone is considerably more potent, and structural studies indicate that it is a monocyclic diterpene. The few trail pheromones studied exert some degree of inter-species response and structural analogues of the natural pheromones possess some degree of activity.5 Host Attractants A. Function.-Olfaction is an important means by which many insects locate sources of food plants and other animals on which they prey. However, the potency of such host attractants is often of a lower order than that of pheromone attractants. A very close relationship frequently exists between host-food attraction and insect reproduction behaviour, particularly in relation to egg-la~ing.*~c Mention has already been made of some aspects of these relationships with respect to population assembly of bark beetles (Section 3). Additionally it is of interest that many species of moths do not feed as adults, but nevertheless females are attracted to suitable oviposition sites by the volatile constituents of a host plant, the latter being suitable for the feeding of the larvae.Frequently, the same host attractants are used by the larvae to seek food. 46 M. S. Blum and G. E. Bohart, Ann. Entomol. SOC.Amer., 1972,65,274. 47 See Table 5, ref. e. See also F. L. Carter, L. A. Dinus, and R. V. Smythe, J. Insect Physiol., 1972,18, 1387, and references cited therein. 48 A. J. Birch, I<. B. Chamberlain, B. P. Moore, and V. H. Powell, Austral. J. Chem., 1970, 23, 2337. 90 Evans and Green B. Chemistry.-TabIe 6 reveals that great structural diversity is encountered in animal- and plant-host attractants. Again, it is certain that complex mixtures are involved, and the attractants listed are best regarded as a principal component in host attractant complexes.Table 6 Some examples of host-food and host-prey attractants Attractant Insect Host Ref. Food Attractants Honey bee Clovers of various H02C- A\ mellvera) (APiS types (isolated from pollen) R-N=C=S Vegetable Plants of the (e.g. R =CH2=CH---CH2-; weevil Cruciferae C6H 5CHS-i C 6H 5CH,CH2-) (Listoderes obliquus) Sweet clover weevil Sweet clover (Sitona (Melitotus cy lindricollis) oficinalis) Oviposition Attractants Rice stem borer Rice d moth (Chilo suppressalis) Onion maggot onions b (Hylemya antiqua) Prey Attractants Me(CH2)ll-CH-(CH2)1,MeI Microplit is croceipes Larvae of the corn earworm moth e Me (parasite) (Heliothis zea) (a) C.Y. Hopkins, A.W. Jevans, and R. Boch, Canad. J. Biochem., 1969, 47, 433; (b) Y. Matsumoto, in ‘Control of Insect Behaviour by Natural Products’, ed. D. L. Wood, R. M. Silverstein, and M. Nakajima, Academic Press, New York, 1970, p. 133; (c) H. Hans and A. J. Thorsteinson, Ent. Exp. and Appl., 1961, 4, 165; (d)T.Saito and K. Munakata, ref. (b), p. 225; (e)R. L. Jones, W. J. Lewis, M. C. Bowman, M. Beroza, and B. A. Bierl, Science, 1971,173,843. Insects which prey upon or parasitize others are attracted to the odour of their host victims. The female yellow fever mosquito Aedes aegypti is attracted to carbon dioxide and L-lactic acid when simultaneously the latter being inter alia a component of human perspiration.Several insects that prey 49 F. Acree, R. B. Turner, H.K. Gouck, M. Beroza, and N. Smith,Science, 1968,161, 1346. Insect Attractants of Natural Origin upon the larvae of bark beetles are known to be attracted by the aggregation pheromones of the beetle adults.60 Some plants exert sex-specific attraction, which suggests that the volatile phyto-attractant resembles a pheromone of the insect.s1 Eugenol dimethyl ether (32) from the golden shower blossom Cassia fistula attracts the males of the oriental fruitfly Dacus d0rsa1i.s.~~ Male lacewings (Chrysopa species) are attracted to and feed upon the Japanese plant Actinidia pofygama, and among its most potent attractant constituents are neomatatabiol (33) and iridodiol (34).43dIn this context, it is noteworthy that the Iridomyrmex ants employ such compounds at a higher oxidation state [e.g.iridodial(35)J as defence-secretion~.~~ OH U (34) (35) Many attractants of fungal origin have been observed, but little chemical information is available.However, the fly-agaric mushroom Amanita muscaria which attracts houseflies has been extensively studied and the attractant has been shown to be 1,3-diolein (36).43e954 The flies die as a result of consumption of the mushroom fruiting body and it is possible that (36) is closely related to another housefly attractant. An interesting relationship has been observed between the mating behaviour of the polyphemus moths Antheraea polyphemus and the red oak, Quercus ~ubra.~~The volatile leaf constituent hex-trans-2-enal is suspected to trigger the release of sex pheromone by the female.F. B. Camors and T. L. Payne, Ann. Entomol. Sac. Amer., 1972, 65, 31; W. D. Bedard, P. E. Tilden, D. L. Wood, R. M. Silverstein, R. G. Brownlee, and J. 0. Rodin, Science, 1969, 164, 1284. 51 B. S. Fletcher, Nature, 1968, 219, 631. 5* Y.Kawano, W. C. Mitchell, and H. Matsumoto, J. Econ. Entomol., 1968, 61, 986, and references cited therein. G. W. K. Cavil1 in ‘Cyclopentanoid Terpene Derivatives’, ed. W. I. Taylor and A. R. Battersby, Marcel Dekker, New York, 1969, p. 203. ha T. Muto and R. Sugawara, Agric. and Biol. Chem. (Japan), 1965,29,949. L. Riddiford, Science, 1967, 158, 139.Evans and Green The possible biogenetic relationship between plant-food constituents and insect pheromones has been remarked upon in earlier sections of this review. BochSs has pointed out the similarity of the honeybee attractant in clover pollen [(37) and Table 61 to the queen bee substance [(38) and Table 21 and has suggested a metabolic inter-relationship. CH;!-O-CO-CI~H~~I CH-OH 6 Artificial Lures Considerable effort has been devoted to the screening of synthetic compounds for attractant activity in pursuit of methods of insect control. Recent reviews provide a fuller coverage of the extensive research in this area.s7 Artificial lures are structurally diverse but can be conveniently subdivided into two types. Some possess structures analogous to those of natural attractants, e.g.eugenol used for the attraction of the Japanese beetle PopiZZia japunica.68 The other category comprises compounds which are totally unrelated to natural products, e.g. trimedlure (39), which attracts male Mediterranean fruitflies, (Ceratitis ~apitata).~~ s5 0 (39)mixture of four isomers 7 Insect Olfaction Mechanisms The current understanding of insect olfaction is limited and only the salient 50 See Table 6, ref. a. 67 M.Beroza and N. Green, Ah. Chern. Ser., 1963, no. 41, p. 11; M. Beroza, in ‘Chemicals Controlling Insect Behaviour’, ed. M. Beroza, Academic Press, New ,York, 1970, p. 145. 56 H. F. Goonwardene, J. H. White, A. E. Grosvenor, and D. B. Zepp, J. Econ. Entomol., 1970,63,1289.5@M. Beroza, N. Green, S. I. Gertler, L. F. Steiner, and D. H. Miyashita, J. Agric. Food Chern., 1961,9, 361; T. P. McGovern and M.Beroza, J. Org. Chem., 1966,31, 1472. 93 Insect Attractants of Natural Origin features are discussed in this review. Interested readers are referred to the article of Schneider for a more detailed treatment.so The olfactory receptor cells of insect antennae are categorized either as ‘specialist’ or ‘generalist’. Typical odour specialists are the sex pheromone attractant receptors of male moths which are absent in the females. The generalist receptors respond to a wide variety of stimuli, and the food odour receptors of most insects are of this type. Where a single compound can elicit attraction, for example with the majority of male moths, triggering of a single type of specialist receptor induces the behavioural response. Where two compounds having disparate structures are necessary for attraction, e.g.tortricid moths and the bark beetlesY4lf it is likely that triggering of two different types of specialist receptors is required. Qualitative and quantitative evaluation of the electrical responses produced by receptor cells on stimulation by different compounds can be measured by insertion of microeIectrodes at the base and tip of the antennae, i.e. the electro- antennogram (EAG) method.61 Recording the overall slow responses of receptor cells by this technique is widely employed as a bioassay to assist attractant identification. EAG studies have demonstrated that the impact of a single pheromone molecule upon specialist antenna1 receptors of some male moths is sufficient to trigger a response.Communication distances for moth sex attractants have been calculated by this method to be in excess of 100 metres,6a and this figure is in good agreement with that suggested by field Several theories have been proposed to rationalize the structure-activity relationship of attractants. The Dyson-Wright theorys4 suggests an inter-relationship between olfactory response and molecular vibrations in the 50-500 cm-1 region of the far infrared spectrum of the pheromone molecule, but experimental testing has failed to support this hypothesks5 An alternative theory proposed by Amoore relates elements of molecular structure and stereo- chemistry to activity,66 and in this context Roelofs and Comeau have proposed an ‘induced fit’ theory bearing analogy to enzyme-substrate binding, where the pheromone molecule binds to a receptor 8 Attractant Identification and Bioassay A.Materials and Methods.-Two major problems confront a natural product chemist working in this field: locating the attractant and any synergists among the numerous components present in a plant or animal extract, and structure 60 D. Schneider, Science, 1969, 163, 103 1. 61 D. Schneider, 2. vergl. Physiol., 1957, 40, 8. 68 L.L. Sower, L. K. Gaston, and H. H. Shorey, Ann. Entomol. SOC.Amer., 1971,64, 1448. e3 A. N. Kishaba, H. H. Toba, W. W. Wolf, and P.A. Vail, J. Econ. Entomol., 1970, 63, 178. 64 R. H. Wright, Nature, 1963, 198, 455; 1972,239,226; Canad. Entomol., 1966, 98, 1083. 65 R.E. Doolittle, M. Beroza, I. Keiser, and E. L. Schneider, J. Insect Physiol., 1968, 14, 1697. 66 J. F. Amoore, J. W. Johnston, and M. Rubin, Scientific American, 1964,210,42. Evans and Green elucidation on minute quantities of material. The yields of pheromone sex attractants can range from as little as five nanograms per virgin female in moths to the order of micrograms in beetles. Excision of insect glands responsible for pheromone production is rarely practicable, and instead larger clippings of the appropriate body portions are generally used. In beetles, pheromones are found in the hindgut, and excreta can profitably be used as a pheromone source.Cuticular washings have also provided active samples. Air entrainment over living insects rarely provides sufficient material for chemical study. The classical procedure for the rigorous chemical characterization of an attractant may require up to 500000 insects, but this requirement is being continually reduced by progress in instrumentation techniques. In a typical case, the active components are located by chromatography monitored by bioassays. Since attractants possess per se a degree of volatility, both gas chromatography and mass spectrometry are ideally suited to this type of structural identification, particularly when interfaced as a combined system. Microscale chemical de- gradations (e.g.location of olefinic bonds by microozonolysis) monitored by gas chromatography are employed to confirm structures, and ancillary spectroscopic techniques are used where sufficient material is available.The methodology of identification of insect attractants has been the subject of recent review articles.41g943f,43g,67 B. Bioassays.-The bioassay is the lynch-pin of all chemical investigations. Ideally, the bioassay should be based on a knowledge of the behaviour under natural conditions. A full behavioural bioassay of orientation and attraction over a distance is desirable, but this is frequently impossible under laboratory conditions. Many investigators employ simple bioassays based upon observa- tion of excitory behaviour in an insect on exposure to a candidate sample (‘flutter test’).This method is of dubious reliability in that it fails to differentiate between true attractants and other compounds to which the antenna1 receptors respond (e.g. inhibitors and aphrodisiacs). Also, synergists can be overlooked since in isolation they fail to produce responses. The inadequacy of this type of laboratory bioassay partly explains a number of incorrect structures for sex pheromones reported in the literature. The development of the EAG technique (Section 7) has greatly facilitated attractant identification, and its advantages and limitations have been reviewed.8 EAG screening of gas chromatographic fractions of crude extracts aids rapid location of both attractants and synergists.The development of a simultaneously recording gas chromatography-EAG instrument is especially useful, particularly for the location of synergists which may be overlooked by other laboratory bioassay techniques.s8 67 M. Beroza, Toxicol. Environ. Chem. Rev., 1972, 1, 1. 68 J. E. Moorehouse, R. Yeadon, P. S. Beevor, and B. F. Nesbitt, Nature, 1969, 223, 1174. 95 4 Insect Attractants of Natural Origin C. EAG Techniques in Structural Studies.-The most powerful application of the EAG technique is in theprediction of sex attractant structure.8~6B This is only possible in cases where there exists a uniformity of attractant structure, e.g. within related species of the Lepidoptera. The first stage of this process involves location of an active component of the natural extract by EAG-gas chromato- graphy.For lepidopterous attractants, retention time data with respect to known standards provide a clue to approximate chain-length, functionality, and un- saturation. EAG screening of a 'library' of appropriate synthetic compounds leads to prediction of exact chain-length and position and configuration of double bonds by observation of maximum response for variation along a particular series. The Figure shows the antenna1 responses of the male grape berry moth Paralobesia viteana to various cis- and trans-mono-unsaturated dodecenyl w 3mvrmz x-cis ---Itrans n2 cn w h"/U a L \\ Z Z F2 a *5 7 9 11 IN0 POSITION Figure Antenna1 responses of the male grape berry moth (GBM) (Paralobesia viteana) to various cis- and trans-mono-unsaturated dodecenyl acetates. The naturally occuring sex pheromone is dodec-cis-9-enyl acetate.(Reproduced by permission from J. Insect Physiol., 1971, 17, 2235.) acetates, from which it is evident that dodec-cis-9-enyl acetate is a potent stimulant. Proof of identity with a natural pheromone requires confirmation of the actual presence of the attractant in the insect by 'classical' methods. How- ever, under these circumstances, this process is greatly facilitated and Roelofs et al. have succeeded in comparative identification using only 50-200 in~ects.~~~~ The ultimate proof of a proposed attractant requires field-testing using a synthetic sample which should achieve attraction to a degree comparable to the 69 See Table 1, refs.u and Y. Evans and Green natural source. Several workers have emphasized the importance of the purity of synthetic attractants in field-testing or bioas~ays.~~ As little as five per cent of the ‘wrong’ geometrical isomer can lead to masking of response. 9 Economic Uses of Attractants The potential economic and environmental importance of biological pest control is currently undergoing experimental e~aluation,~~ and the successful use of natural insect attractants has been reported by several groups.7* Insect at- tractants have been used to reduce pest populations by employing attractant- baited traps. Sex pheromone attractants have also been used in the ‘confusion technique’ whereby normal mating behaviour is disrupted by permeating the atmosphere with synthetic sex at tract ants .These methods of pest control have considerable advantages over the use of conventional insecticides. The relatively small amounts of synthetic attractant required minimizes the possibility of environmental pollution, and the species- specificity of many natural attractants reduces the risk of destroying beneficial insects such as predators, parasites, and pollenators. Furthermore, the evolution of strains of pest populations resistant to natural attractants is very unlikely. The most general application of insect attractants probably lies in integrated control measures as population survey tools to probe the degree of infestation.Limited application of chemical pesticides would then suffice in areas of in- tolerable infestation, and the need for blanket spraying programmes throughout the season, with its attendant hazards, would be obviated. In conclusion, it should be emphasized that this Review has attempted to survey only a minute area of the field of chemosensory communication in animals. At present, more rapid progress is being made in the chemical aspects than in the understanding of the biological aspects. The efficient exploitation of these substances, such as in insect control programmes, can only be achieved when a full understanding of their role in animal behaviour is achieved. The authors wish to thank their colleagues at the University of Southampton, the Tropical Products Institute and the Centre for Overseas Pest Research for their valuable comments, and also many workers in this field who have provided information.W. L. Roelofs and A. Comeau, Nature, 1969, 220, 600. ‘l M. Beroza, in ‘Pest Control: Strategies for the Future’, Nat. Acad. Sci. Publication No. 1945, 1972, p. 226, and references cited therein. D. Hamilton, J. Econ. Entomol., 1971, 64, 150; D. Hardee, ibid., p. 928; H. H. Shorey,L. K. Gaston, and L. L. Sower, California Agriculture, 1971,25, 11; M. Beroza and E. F. Knipling, Science, 1972, 177, 19.

ISSN:0306-0012    

DOI:10.1039/CS9730200075

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

The Chemistry of Transition-metal Carbene Complexes and their RoIe as Reaction Intermediates By D. J. Cardin, B. Cetinkaya, M. J. Doyle, and M. F. Lappert SCHOOL OF MOLECULAR SCIENCES, UNIVERSITY OF SUSSEX, BRIGHTON BNI 9QJ 1 Introduction The title compounds have the formula (1). They were discovered during the past decade,’ although the Chugaev salts, first prepared in 1915,2 were recently3s4 recognized to contain carbene complexes (e.g. see Figure l).3Nevertheless there have now been more than 200 publications and the topic is one of the fastest growth areas in organometallic chemistry (30 papers in 1971). Initially, interest centred on synthesis and structures, but subsequently much was also learned of the chemistry of the co-ordinated carbene ligands, and of other reactions of carbene complexes.These thenies continue to be elaborated, but a further development is the identification of transition-metal carbene complexes as reactive intermediates in various (organic) syntheses. We may therefore consider two main approaches to the study of transition- metal carbene complexes. One is to examine stable compounds; the other is to investigate those transition-metal systems in which carbene complexes are inter- mediates, including transition-metal-catalysed organic reactions. The former aspect has been comprehensively reviewed5 (and accounts of the contributions from E. 0. Fischer’s laboratory are available6s7) and we now lay more emphasis on the second topic. E. 0.Fischer and A. Maasbol, Angew. Chem.Internat. Edn., 1964,3,580. a L. Chugaev and M. Skanavy-Grigorizeva, J. Russ. Chem. SOC.,1915, 47, 776. a W. M. Butler and J. H. Enemark, Znorg. Chem., 1971, 10, 2146. G. Rouschias and B. L. Shaw, J. Chem. SOC.(A), 1971, 2097. D. J. Cardin, B. Cetinkaya, and M. F. Lappert, Chem. Rev., 1972, 72, 545; see also F. A. Cotton and C. M. Lukehart, Progr. Inorg. Chem., 1972, 16,487. E. 0. Fischer, Rev. Pure Appl. Chem., 1970,24,407; ibid, 1972, 30, 353; C. G. Kreiter and E. 0. Fischer, ‘XXIIIrd International Congress of Pure and Applied Chemistry (Boston)’, Butterworths, 1971, Vol. 6, p. 151. ‘IM. Ryang, Organometallic Chem. Rev. (A), 1970, 5, 67; A. Nakamura, Kagaku No Ryoiki Zokan, 1970,89,285. The Chemistry of Transition-metal Carbene Complexes 2 Stable Transition-metal Carbene Complexes A.Survey of Compounds and their Classification.-Carbene complexes are now known for many of the later transition metals. Metal electron configurations range from d3to dlO,with d5and dgas yet unrepresented, oxidation states from 0 to + 4, and co-ordination numbers from 2 to 7 [taking (r-C5H6)as providing a single co-ordination position]; the corresponding configurations around the metal include linear, square planar, tetrahedral, trigonal bipyramidal, and octahedral. These data are summarized in Table 1 and typical examples are shown in Table 2. Systematic (I.U.P.A.C.)nomenclature for these compounds uses the suffix -ylidene, the ligand being regarded as neutral with respect to the metal oxidation state; thus (OC),Cr-C(0Me)Me is called pentacarbonyl- (1-methoxyethylidene)chromium(O), but trivially is methoxy(methy1)carbene- pentacarbonylchromium(0). The majority of carbene complexes are neutral, mononuclear, and have a single co-ordinated carbene.However, cationic species are known, as are a number of di- and tri-nuclear derivatives. To date no anionic carbene complexes have been reported, although the acyl-metallates (LM-C0R)-are intermediates in a number of syntheses [see Section 2C(i)]. Oligocarbene complexes LM(carbene)n (n = 14) have been prepared (e.g. the mercury compound in Table 2) and also complexes with a chelating dicarbene ligand (e.g. Figure l).a Me H2 H3 ‘1 2/N-N\ yM= H/N-c\ /C-N\, CI/pd\ c1 Figure 1Approximately square-planar around Pd (CW) :Pd-C = 1.86 A, C-l-N-1 = 1.45 A, N-2-N-3, C-1-N-2 = 1.38 A, and Pd-Cl = 2.38 %i (see ref.3) The majority of carbene ligands are terminal and unidentate (e.g. Figures 7and 10) although a few bridging examples (Figures 2--4)8~Bp12are reported. In this review a metal carbene complex, whether terminal or bridging, is defined as a species having the ligand CXY with an approximately spa-hybridized Ccarb, attached to the metal without a formal Cc8r-X or Ccarb-Y multiple bond. Consequently, compounds such as those shown in Figures 4, 5, and 9 are not classified as carbene complexes, whereas Figure 3 represents a bridging carbene (SP2-Ccarb).Generally the co-ordinated ligands (CXY) are ‘tertiary’, neither X nor Ybeing hydrogen atoms, but there are some example^^^^^^^ of secondary carbenes.Stable methylene complexes are unknown at present. trans-cis Isomerism, arising 100 Table 1 The occurrence of carbene complexes" d3 d4 ds d7 d0 d10 CrO(6, n; 4, nC) Mn0(6,n,d) Fe0(5,n; 6, n, d, br; Ni0(4, n, t) 7, n, t, br)MnI(4,n) Cor(4, n;d 5, n) FeIJ(4, n;b 4, nc) NbII(5, n, d, br) MoII(5, n, or cl) Mo0(6,n; 4, nc) UY4, n)RuII(4, cl) WO(6, n; 4, nc) ReI(4, n) PdII(4, n or cl) AuI(2,n) $ IrI"(6, n) PtII(4, n or c1, c2) Hg'I(2,c2) $ PtIV(6, n, cl) Y9 Numbers in parentheses indicate metal co-ordination number [(n-C5H5)taken as occupying a single site], and abbreviations are: n, neutral; cl, s' cationic (+ 1); c*, cationic (+ 2); d, dinuclear; t, trinuclear; br, bridging carbene.*This refers to Fe(CO)(NO),CXY. CThis refers to 8 (n-C,H,)M(CO)(NO)CXY. d This refers to CO(CO)~(NO)CXY. k Note: oligocarbene complexes, LM(carbene)n, are known as follows: n = 2, M = CrO, Wo, FeII, RhI, PdII, PtII, and HgII; n = 3, M = IrI, Rh', Q NiII, and PtII; n = 4, M -Pt. b% k!! % b88 "L The Chemistry of Transition-metal Carbene Complexes Table 2 Typical carbene compZexes Complex Ref. (Me,SiCH2)4Nb 2(CSiMe3),a 6 A 21 17 Ph (.rr-C5H &OC) ,Mn-C(OMe)Me 22 [(~-C,H,)(OC)(Ph,P)Fe-C(OEt)Me] + 23 I(7r-C &)(OC),(R,P)Mo--C( OEt)MeJ 23 cis-(OC),(Ph,P)Mo-C(0Me)Me 24 [(T-C,H,)(OC)(R,P)RU-C(OE~)M~]+-23 I,(OC)Rh-C(Ph)N(Me)C(Ph) :NMeC 9,25(OC) ,W-C(NHMe)Me 16 (.rr-C5H5)(0C),Re-C(OMe)Me 26 CI,(Ph,P),Ir-C(H)NMe, 13 [Mez(F3C)(Me*PhP)*Pt-C()1 Oa 27 I ICIdPt -C(NMeH)NHNHC(NMeH) 28 (OC),Mn,--C(OMe)Ph 29 Me 30 Me [(OC),Fe-C(:O)Ph (OC),Fe-(OC),Fe(H)(CNMe,)Fe(CO), 1la (OC),(ON)Co-C(Et)NMe 31 Ph,Sn(OC),Co-C(0Et)Ph 32 Ph CI(PhiP)7Rh--Cf] N 33 Ph C1 ,(PhNC)Pd-C(NHPh)OMe 34 CI,Pd-C(NMeH)NHNHC(NMeH)e 3 102 Cardin, Cetinkaya, Doyle, and Lappert Complex Ref.Phf N &-and irons -CI,(Et,P)Pt -c: 13,14'3 N Ph trans-[Me(Me,As),Pt-C(OMe)Me] +PF6-35 trans-[(EtNC)(PMe,Ph),Pt-C(SCH,Ph)NHEt 1, + 36 [(OC)Ni--C(OMe)Ph l3 37 ClAu-C(OMe)C ,H ,Me-p 38 2+ 39[+$,I a Figure 2. b Figure 10. C Figure 6. Figure 3. Figure 1. f Figures 7 and 8. 8C.K. Prout, T. S. Cameron, and A. R. Gent, Actu Cryst., 1972, B28, 32; M. L. H. Green and J. R. Sanders, J. Chem. SOC.(A), 1971, 1947. O P. B. Hitchcock, M. F. Lappert, G. M. McLaughlin, and A. J. Oliver, to be published. lo F. Huq, W. Mowat, A. C. Skapski, and G. Wilkinson, Chem. Comm., 1971, 1477. l1 P. F. Lindley and 0. S. Mills, J. Chem. SOC.(A), 1969, 1279. ll@ R. Greatrex, N.N. Greenwood, I. Rhee, M. Ryang, and S. Tsutsumi, Chem. Comm., 1970, 1193. lP A. W.Parkins, E. 0. Fischer, G. Huttner, and D. Regler, Angew. Chem. Internat. Edn., 1970, 9, 633. l3 B. Cetinkaya, M. F. Lappert, and K. Turner, J.C.S. Chem. Comm., 1972, 851. 13a P. M. Treichel, J. P. Stenson, and J. J. Benedict, Inorg. Chem., 1971, 10, 1183. l4 D. J. Cardin, B. Cetinkaya, M.F. Lappert, Lj. ManojloviC-Muir, and K. W. Muir, Chem. Comm., 1971,400. l6 D. J. Cardin, B. Cetinkaya, E. Cetinkaya, M. F. Lappert, Lj. ManojloviC-Muir, and K. W. Muir, J. Organometallic Chem., in the press. E Moser and E. 0. Fischer, J. Organometallic Chem., 1969, 16, 275. l7 H. W. Wanzlick, Angew. Chem. Internat. Edn., 1962, 1, 75. laG. Huttner, S. Schelle, and 0. S. Mills, Angew. Chem. Internat. Edn., 1969,8,515; K. Ofele, ibid., 1968, 7, 950. lo G. N. Schrauzer, H. N. Rabinowitz, J. A. K. Frank, and I. C. Paul, J. Amer. Chem. SOC., 1970, 92, 2 1 2. IDJ. Cooke, W. R. Cullen, M. Green, and F. G. A. Stone, J. Chem. Soc. (A), 1969, 1872. I1 F. A. Cotton and C. M. Lukehart, J. Amer. Chem. SOC.,1971,93,2672. E. 0. Fischer and A. Maasbol, Chem.Ber., 1967, 100, 2445. lS M. L. H. Green, L. C. Mitchard, and M. G. Swanwick, J. Chem. SOC.(A), 1971, 794. s4 E. 0.Fischer and R. Aumann, Chem. Ber., 1969,102, 1495. *5 M. F. Lappert and A. J. Oliver, J.C.S. Chem. Comm., 1972, 274. es E. 0. Fischer and A. Riedel, Chem. Ber., 1968, 101, 156. "M. H. Chisholm and H. C. Clark, J. Amer. Chem. SOC.,1972, 94, 1532. *8 A. L. Balch, J. Organometallic Chem., 1972, 37, C19. *s E. 0. Fischer and E. Offhaus, Chern. Ber., 1969, 102,2449. 30 K. Ofele, Angew. Chem. Internat. Edn., 1969, 8, 916. s1 E. 0.Fischer, F. R. Kreissl, E. Winkler, and C. G. Kreiter, Chem. Ber., 1972, 105, 588.'* D. J. Darensbourg and M. Y. Darensbourg, Inorg. Chem., 1970, 9, 1691. 33 D. J. Cardin, M. J. Doyle, and M. F. Lappert, J.C.S.Chem. Comm., 1972, 927. s4 B. Crociani, T. Boschi, and U. Belluco, Inorg. Chem., 1970, 9, 2021. s6 M. H. Chisholm, H. C. Clark, and D. H. Hunter, Chem. Comm., 1971,809; M. H. Chisholm and H. C. Clark, Inorg. Chem., 1971, 10, 171 1. a8 H. C. Clark and L. E. Manzer, Inorg. Chem., 1972, 11, 503. 57 E. 0. Fischer and H. J. Beck, Angew. Chem. Internat. Edn., 1970, 9, 72. I* F. Bonati and G. Minghetti, Synth. Inorg. Metal-org. Chem., 1971, 1, 299. H. J. Schonherr and H. W. Wanzlick, Chem. Ber., 1970,103, 1037. The Chemistry of Transition-metal Carbene Complexes Figure 2 Nb-1-C-1 = 1.995 A, Nb-2-(2-1 = 1.954 A, arrd Nb-1-Nb-2 = -n2.897 A; Ca-2 = 85.6', Ne-2 = 94.4", Nb-1C-1 Si = 119.8", Aand Nb-2 C-1 Si = 142.4' (Nb-1 and Nb-2 and C-1 and C-2 are related by a centre of symmetry inside the ring)lO Ru2 Figure 3 Both metalshave a distorted octahedral Figure 4 Ru-1, Ru-2, Ru-3, and environment and lie in a crystaliographic mirror C-1 to C-7 alI coplanar, with Ph plane: Fe-24-5 = Fe-245' = 1.945 A, ringperpendicular to this plane, C-54-5 = 1.262A, Fel-0-5 = Fe-14-5' ring 1-6 shows marked bond-= 1.967 A, and Fe-1-Fe-2 = 2.568 A: Iength alternation: Ru-347 n-n = 2.09A (see reJ 12)Fe-2 C-5 0-5 = llQ", C-2 Fe-2 C-5 =.8.41" (see reJ 11) from alternative arrangements of ligands around a central metal, is established for square-planar PdII and PtlI (e.g. Figures 7 and 8)l4Jsand geometrical isomerism due to alternative arrangements within the carbene ligand is known for Cro, Moo, Wo,and PtI1 [e.g.(2) and (3)].'* Cardin, Cetinkaya, Doyle, and Lappert Me. PhC1/"\ \I /C2Ph -Rh-N2 Et0' I \MeI Figure 5 Mo-C-1 = 2.08 81and Mo-N-1 = 2.11 8, (see ref. 8) Figure 7 Square-planar environment around Pt: Pt-C = 2.020A, Pt-C1 = 2.31 1 A, Pt-P = 2.291 8,, Ccarb-N = 1.348 A, and N-Ph = 1.403 8, (see refs. 14 and 15) Ph Fe' (CO), Ph Figure 9 Fe-1-C-1 = 2.089 A, Fe-2-C-1 = 1.96981, Fe2-C-2 = 2.069A, Fe-1-S = 2.243 A, and Fe-1-Fe-2 = 2.533 A (see re$ 19) Figure 6 Approximate octahedral en- vironment around Rh: Rh-C-1 = 1.97 A, Rh-N-2 = 2.05 A, C-1-N-1 = 1.33 A, N-14-2 = 1.43 A, and C-2-N-2 = 1.30 8, (see ref. 9) Figure 8 Square-planar environment around Pt :Pt-C = 2.0098,, Pt-Cl-1 = 2.362 81, Pt-c1-2 = 2.381 81, Pt-P =2.234A, Ccarb-N = 1.327& N-Ph = 1.395 A (see ref.15) Figure 10 Approximate octahedral en- vironmentaroundcr: Cr-C-l= 2.05A, C-2 or C-3-Ph = 1.45 A, Cr-CO = 1.88-1.92A, and C-2-C-3 = 1.35%L (see ref. 17) 105 The Chemistry of Transition-metal Carbene Complexes Me H I I (OC)&r-C /N\ H (OC)&r -c /N\ Me\ \Me Me (2) (3) All the authenticated stable carbene complexes so far described (more than 300 compounds) have X and/or Y capable of conjugating with the electrophilic Ccarb and, except for three compounds with the ligand 2,3-diphenylcyclopropene (e.g.Figure 10),17haveX and/or Y as an oxy-, thio-, seleno-, or amino-substituent ; ligands are listed in Table 3.Hence, existing complexes may be said to originate from nucleophilic carbenes.18 A single electrophilic carbene structure (4) remains to be verified;20 an alternative structure, (Ph2MeP),(0C)IrCC1(CF,),, is possible. Cl Cationi~~~p~~and anionic carbene complexes may alternatively be regarded as metallo-carbonium ions or -carbaniom. For example, in the compound formu- lated as trans-[Me(Me,As),Pt-C(OMe)Me]+PF6-in Table 2, the positive charge may be largely localized on either Pt or Ccsrb. The carbonium ion symbolism has been useful for rationalizing some of the reactions of such complexes.3sA mercury dicationic compound (see Table 2) may more reasonably be formulated74 as shown. Ph Ph Ph Ph Table 3 Carbene ligands* (i) Acyclic carbenes Non-chelated R'(R20)C-R1R2N(R30)C-R1R2C :N(R30)C- R'(R2S)C-R1(R2Se)C-R'(H2N)C-R1(R2NH)C-R' (R2 2N)C- R1NH(R2NH)C-R' ,N(R2NH)C- R1(R2R3C: N)C- (ii) Cyclic carbenes Carbene R' @c-R' 1 R2 c,I c--R2N' CC-R' Cardin, Cetinkaya, Doyle, and Lappert Footnote Bidentate or chelated Footnote a -O(R1)C- m b -CNMe2- n C -C(MeNH)NR1 -(MeNH)C- 0 d -C(MeNH) -NR1 -NH(MeNH)C- p e f -CH SNMe -CH, .NMe CH--NR1C(R2)NHR'(R2)C- r 4 gh i i k I Footnote Carbene Footnote R' S [>c- W R' Fi' t c;c- X N R' R' U N+ "4II c-- Y R' Ph Ph V z References occur on next page 107 The Chemistry of Transition-metal Carbene Complexes * Footnotes show the identity of groups R1, R1, and R8 excepting that simple alkyl and aryl groups [Me, Et, Pr, Bu, and (0, m, P)-C&,.X (X= H, Me, OMe, NMe,, F, C1, Br, or CFJ] are not listed separately in the footnotes, but are denoted by the symbol R; fu = 0(X= 0, S, or NR)., PhCi C,48 CH8:CH,44 I-naphthyl,46 ferr~cenyl,~~ a ~.aap,z R' = C8F5y4' C6C15,41 PhCHzYPz fU,44*46or CH2SiMe,;46 Ra = H,23986 fu,44,46 SiMe3,47 Li,48,40 or CpTiC1. b R.81,50-51 c R.68 d R;54*55 R' = f~4~945or SiMe3.56 8 R.6 f R;54,57 R1 = fu,44,46 0 R;64,68,50 Rl = CHz:(MeO)C Me(O:)C, or Me(MeO),C.609e* R;68,68,68 R1 = H. f R.1~,~~160,66.66f ~-67k ~,682 ~1 = N3s C,H,N, or MeO(0 :)C.46 m R.11946 See ref. 1 la. 0 R.6gP R1 = H or C(:O)NH,.4 Q R.s6 r See ref.13a. R.70 R' = Ph(Me0); R* = C6H11.60~6aSee refs. 21, 27, and 71. U R.l5W R.aots' 2 R.14p16133. fl R.7a R* = OR, NHEt, Ph, or Nn0 .78 W 40 E. 0. Fischer, H. J. Beck, C. G. Kreiter, J. Lynch, J. Miiller, and E. WinkIer, Chem. Ber., 1972,105, 162. J. A. Connor, E. M. Jones, and J. P. Lloyd, J. Organometallic Chem., 1970,24, C20; G. A. Moser, E. 0.Fischer, and M. D. Rausch, ibid., 1971,27, 379. I1M. Y. Darensbourg and D. J. Darensbourg, Inorg. Chim. Actu, 1971, 5, 247. E. 0.Fischer and F. R. Kreissl, J. Organomerallic Chem., 1972, 35, C47. I4J. A. Connor and E. M. Jones, J. Chem. Sac. (A), 1971, 1974. 45E.0. Fischer, C. G. Kreiter, H. J. Kollmeier, J. Muller, and R. D. Fischer, J. Organo-metallic Chem., 1971, 28, 237. 4a 3. A. Connor and E.M. Jones, Chem. Comm., 1971,570; J. Chem. SOC. (A), 1971, 3368. E. Moser and E. 0. Fischer, J. Organometallic Chem.. 1968, 12, P1. aa E. 0.Fischer and V. Kiener, J. Organometallic Chem., 1970, 23, 215. E. Hadicke and W. Hoppe, Acta Cryst., 1971, B27, 760. E. M. Badley, J. Chatt, and R.L. Richards, J. Chem. SOC.(A), 1971, 21 ;E. M. Badley, B. J. L.Kilby, and R. L. Richards, J. Organometallic Chem., 1971, 27, C37. 61 E. 0. Fischer and H. J. Kollmeier, Angew. Chem. Internat. Edn., 1970, 9, 309. 6a U. Schollkopf and F. Gerhart, Angew. Chem. Internat. Edn., 1967, 6, 560. O3 M. F. Lappert and J. McMeeking, to be published. 64 U. Klabunde and E. 0. Fischer,J. Amer. Chem. Soc., 1967,89,7141; R. J. Hoare and 0.S. Mills, J.C.S. Dalton, 1972, 653.S6 E. 0. Fischer, M. Leupold, C. G. Kreiter, and J. Miiller, Chem. Ber., 1972, 105, 150. 56 B. Cetinkaya and M. F. Lappert, to be published. 67 E. 0. Fischer and H. J. Kollmeier, Chem. Ber., 1971, 104, 1339. 68 J. A. Connor and E. 0. Fischer, J. Chem. SOC.(A), 1969, 578. 59 E. 0.Fischer, B. Heckl, and H. Werner, J. Organometallic Chem., 1971, 28, 359. 60 R. Aumann and E. 0.Fischer, Angew. Chem. Internat. Edn., 1967, 6, 879. G. Huttner and S. Lange, Chem. Ber., 1970,103, 3149. 6a R. Aumann and E. 0. Fischer, Chem. Ber., 1968, 101, 954. 68 J. A. Connor and E. 0. Fischer, Chem. Comm., 1967, 1024. 64 P. M. Treichel and W. K. Dean, J.C.S. Chem. Cornm., 1972, 804. 65 F. Bonati, G. Minghetti, T. Boschi, and B. Crociani, J. Organometallic Chem., 1970,25,255; F.Bonati and G. Minghetti, ibid., 24, 251. O6 R. J. Angelici and L. M. Charley, J. Organometallic Chem., 1970, 24, 205. 67 U.Schollkopf and F. Gerhart, Angew. Chem. Internat. Edn., 1967, 6, 970. 68 L. Knauss and E. 0. Fischer, Chem. Ber., 1970,103,3744; J. Organometallic Chem., 1971, 31, C68. 60 J. Muller, A. L. Balch, and J. H. Enemark, J. Amer. Chem., SOC., 1971, 93,4613. '0 K. Ofele, J. Organometallic Chem., 1970, 22, C9. 71 C. P. Casey and R. L. Anderson, J. Amer. Chem. SOC., 1971,93, 3554. K. Ofele and C. G. Kreiter, Chem. Ber., 1972, 105, 529. 73 C. W. Rees and E. V. Angerer, J.C.S. Chem. Comm., 1972,420. 74 C. J. Cooksey, D. Dodd, and M. D. Johnson, J. Chern. SOC.(B), 1971, 1380. Cardin, Cetinkaya, Doyle, and Lappert B.Structureand Bonding.-It has been noted (see Section 2A) that stable metal carbene compIexes are derived from nucleophilic carbenes and that Ccarb is highly electrophilic. This results in multiple bonding with the heteroatoms (X or Y) of the ligand [see (Sa)] and not in (d-ph (back bonding) with the metal. As a ligand,* we can therefore describe the co-ordinated carbene as a strong 0-donor, but a weak n-acceptor. In this context the polarity clearly differentiates it from +-the 'ylide' (e.g., R,P-CH,), structure. The conclusion that (5a) and (5b) are the principal canonical forms implies (i) the absence of a bond order significantly greater than unity in M-Ccarb, (ii) the considerable multiple bond character in Cmrb-x, (iii) the electrophilic character of Ccarb, (iv) the analogy between Ccarb-oR or Ccarb-NR'R' and Cacyi-OR or Cacyl-NRIRa, rather than Cal~l-OR or Ca1e1-NR1R2 organic compounds, and (v) an electronic effect of the carbene ligand on M... .. Hi /x /x-LM-d -LM-CLGI-C \ \ \ v Y Y (5d (5W (5d The clearest evidence for (i), (ii), and (iv) is crystallographic. X-Ray results are now available for more than fifteen compounds. The first such study was on a chromium complex (Figure 11);75some other data are summarized in Figures 1-9. Figure 11Essentially octahedral environment for Cr;Ph at 90"toplane Of Sp2-&b Cr-C-1 = 2.04 A, G1-0 = 1.33 A, 0-Me = 1.46 A, C-l-Ph = 1.47 A, A nCr-C-2 = 1.87 A, andCr-C-3 = 1.86-1.91 A; Cr C-1 0 = 134",Cr C Ph = -122", 0C-1 Ph = 104", and Cme = 121"(see ref.75) It is manifest that z(M-c!carb) (Z denotes bond length) is not particularly short: e.g.,from Figure 11 note that Z(Cr--Ccarb) > Z(Cr-CO); and from Figures 7 and 75 0.S. Mills and A. D.Redhouse, Angew. Chem. Internal. Edn., 1965,4,1802; J. Chem. SOC. (A), 1968, 642. The Chemistry of Transition-metal Carbene Complexes 8 Z(Pt-C) w Z(Pt--C,,a) in trans-[CI(Ph,MeP),Pt--CH,SiMe,] (2.079 A).?, On the other hand, ((Ccarb-x) is significantly shorter than expected for a single bond: e.g. from Figure 11 note that l(Ccarb-0) is shorter even than the Cacyl- OR bond in an ester such as MeC0,Et (1.36 A) and from Figures 7and 8 that /(Ccarb--N) is shorter than in an amide such as MeCONHPh (1.35 A).'? Supporting testimony for (i) is chemical.Thus, there are scarcely any reactions of carbene complexes which suggest M=Ccarb double-bond character (see Section 2C), but insertion reactions with PhSeH or C,HllNC may convenient- ly, although not inevitably, be interpreted as proceeding via such a structure. Nuclear magnetic resonance studies of rotation about Ccarb-NR'R2 or Ccarb-OR bonds show that the energy barriers are considerable and indeed higher than in carboxylic acid amides or esters, thus providing further demonstra- tion of (ii) and (iv). In (OC),Cr-C(OMe)C,H,.OMe-o, -m,or -p, dGt = 13.2, 11.9, or < 8 kcal mol-l, respectively, and in (OC),Cr-C(OMe)C,H, CF3-0, -m,or -p is 13.5, 12.1, or 12.3 kcal mol-l, re~pectively:~~~~~ these trends support the view that the high barrier is due to CO bond multiplicity rather than inversion at oxygen.In (OC) ,Cr-C(OEt)Me, (OC) ,Cr-C(NMe,)Me, (OC) ,Cr-C(0Et)- NMe,, and (OC),Fe-CfNDMe),, dGt values are 13.6 (about CO), > 25 (about CN), 20.8 (about CN;< 8 about CO), and 16.6 (about CN) kcal mol-l, respect-ively., Such data show that barriers to rotation are greater about CN than about CO (and hence probably that N-Ccsrb -?*q occursto a greater extent than Sccarb) and that when both the groupsX and YarecapabIe-of.rr-bondingwith Ccarb, CX and CY bond multiplicities are lower than is the case when only X or Yhas this capacity. Consistent with (ii), (iii), and (iv) are the reactions of the co-ordinated carbene ligand. These have been most clearly demonstrated for alkoxycarbenechromium- (0) compounds (see Figure 13).Nucleophilic substitution reactions at Ccarb and electrophilic substitution at the contiguous carbon in LM-Ccarb(OMe)CH,R are particularly significant. Also relevant to (iii) and (iv) are some n.ni.r. data. 13C chemical shifts, 8(13C), which promise to provide a useful diagnostic tool for metal carbene complexes, show that Ccarb is substantially deshielded. Values of 8(13C) (in p.p.m., relative to Me,% in CDCl,) for various complexes are: (OC),Cr-C(OMe)Me, 362.3 ;79 (OC) ,Cr-C( OMe)Ph, 3 54.5 ; (OC) ,Cr-C(NHMe)Me, 284.8 ; (OC)&r-C(NMe,)Ph, 277.5 ;79 (OC),W-C(OMe)Ph, 322.8 (OC),W--C(OMe)Me, 332.9;81(OC),W-C(SMe)Me, 332.5 ci~-(0C)~Cr- [C(NMeCH,),],, 141.0;s2 (OC),Fe-C(NMeCH ,) ,, 213.O ;82 trans-[Cl,(Bun3P)Pt-C(NMeCH2) ,I, 178.0;s2 '6 M.R. Collier, C. Eaborn, B. JovanoviC, M. F. Lappert, Lj. ManojIoviC-Muir,K. W. Muir, and M. M. Truelock, J.C.S. Chem. Comm., 1972, 61 3. 77 'Tables of Interatomic Distances', Chem. SOC. Special Publication No. 11, 1958; C. J. Brown, Acta Cryst., 1966, 21,442. C. G. Kreiter and E. 0.Fischer, Angew. Chern. Internat. Edn., 1969, 8, 761. 79 L. F. Farnell, E. W. Randall, and E. Rosenberg, Chem. Comm., 1971, 1078. 80 J. A. Connor, E. M. Jones, E. W. Randall, and E. Rosenberg, J.C.S. Dalton, 1972,2419. 81 C. G. Kreiter and V. Formacek, Angew. Chem. Internat. Edn., 1972, 11, 141. 81 D. J. Cardin, B. Cetinkaya, E. Cetinkaya, M. F. Lappert, E. W. Randall, and E. Rosenberg,J.C.S.Dalton, 1973, in the press. Cardin, Cetinkaya, Doyle, and Lappert cis-[C1,(Bun,P)Pt-C(NMeCH2),], 196.5;sz and trans-[Cl(Et,P),Pt-C(NMe-CH,)]+ BF4-, 191.82The values are similar to those found for carbonium ions: e.g., 8(13C)of Me,C+ is 273 p.p.m. to lower field than in Me,CC1.83 Of eighteen organometallic compounds reported in ref. 79,Cmrb in (OC),Cr-C(0Me)Me has by far the lowest 8(13C), although Cacvi in (n-C,H,)(OC),FeCOMe is not far removed. For a range of secondary carbene complexes having the H(Me,N)C- ligand, 8(lH) for C&bH is at T = -1.2 to + 0.9.l3Other more peripheral data (from electric dipole moments, vibrational force constants, ionization potentials, electronic spectra, and other aspects of lH n.m.r. spectra) have been used to discuss the electronic nature of the carbene ligands.g The trans influence (defined as the tendency of a ligand to weaken the bond trans to itself)s4 of several carbene ligands in PtI* complexes is similar to that of a tertiary pho~phine.~~,~~ This may be illustrated by the Z(Pt-Cl) and Z(Pt-P) data of Figures 7 and 8.Supporting evidence comes from v(Pt-CI) and J(195Pt-31P) of such compounds,16,60 and J(1g5Pt-1H) in trans-{PtMe(Y)L2}+PF6-;Y is the trans ligand, including R(RIO)C-, and L is a tertiary phosphine or ar~ine.~~ C. Synthesis and Reactions.-Transition-metal carbene complexes have been obtained from three classes of precursors, (i)-(iii) in Figure 12. (i) Syntheses from Metal-Carbon Compounds. The metal carbonyl route is illustrated in equation (1).The tungsten compounds (6; R = Me or Ph) were the ,OLi LiRW(C0)e +(0C)S w -c,/ [Me4Nlf* I (0C)sW -CORI- INMe41' \R first stable transition-metal complexes to be prepared; methylation then involved diaz0methane.l The synthesis was improved by using oxonium salts,60 and was extended to other transition metals (Cry Mo, Mn, Fe, Ru, and Re)10~22924J6~29948 and other ligands (Table 3). Grignard reagents have been employed, but they are less reactive than the lithium Neutral acyl compounds may likewise be converted into carbene complexes [equations (2)23986and (3)52], and such intermediates, (7) and (8), are probably formed in reactions (4)21and (5).72 83 G. A. Olah, E. B. Baker, J. C. Evans, W. S. Tolgyesi, J.S. McIntyre, and I. J. Bastein, J. Amer. Chem. SOC.,1964, 86, 1360. 84 A. Pidcock, R. E. Richards, and L. M. Venanzi, J. Chem. SOC.(A), 1966, 1707. M. L. H. Green, and C. R. Hurley, J. Organometallic Chem., 1967, 10, 188. 111 The Chemistry of Transition-metal Carbene Complexes 1i,RLi ii,H+-CH2N2 or R30t LMCO LM-CNX 0 II LM-C-X NR' II LM-CX n.-U /xLM-C '* X Y X' /LM-C db 'YY .-L'M-CW \Y '/2CXY=CUY Na2(LM)*' (-2NaHal)Hal2 CXY or L' M (L' Hal,IL) (e.g.Scheme2) IHCXY 1' LMH (-Hq) or LMCl (-HCI) Figure 12 Principal synthetic routes to transition-metal carbene complexes Cardin, Cetinkaya, Doyle, and Lappert (n-C5H ,)(OC),Fe-COMe + HCI -[(n-C,H,)(OC),Fe-C(0H)Me ] +C1- (2) Hg(CONRLR2)2+ 2[Me,0]+[BF4]--[Hg{C(OMe)NR1R2},]2+[BF,],-(3) Co-ordinated isonitriles react with alcohols, primary amines, and sodium bor~hydride~~~ ~e~to yield carbene ~~mpleThe first example is .~ shown in equation (6);50others refer to PdII, PtII, HgII, and FeII.Isonitrile complexes of CrO and Moo as well as PdI2(ButNC), (in contrast to the correspond- ing chloride8') were unreactive.88 The preparation of Chugaev salts is of this as illustrated for (9) in equation (7).*The chelating anionic (mono- carbene ligand in (9) is clearly related to the neutral bidentate (dicarbene) ligand of Figure 1. CiS-Cl,(Et3P)P t-CNPh + EtOH -+ c~s-CI4Et3P)P t-C(0Et)NHPh (6) Neutral imidoyl compounds niay also be converted into carbene com-88 A.Burke, A. L. Balch, and J. H. Enemark, J. Amer. Chem. SOC.,1970,92,2555. G.A. Larkin, R. P. Scott, and M. G. H. Wallbridge, J. Organometallic Chem., 1972.37, C21. J. A. Connor, E. M. Jones, G. K. McEwen, M. K. Lloyd, and J. A. McCleverty, J.C.S. Dalton, 1972, 1246. 113 The Chemistry of Transition-metal Carbene Complexes plexe~,~~, as shown in equation (8).89 The formation of cationic PtII complexes from acetylenes [equation (9)] is critically dependent on the nature of the acetylene, ligands Q, and solvent, and on the reaction ~onditions.~~~~~~~~~~~ “HII+[PFII-trans-I(Ph,P),Pt-C(: trans-[I(Ph,P),Pt-C(NHMe)-NMe)Ph -PhI+(PFsl-(8) i, Ag+[PFJ-trans-ClQ,MePt + R1CfCR2-trans- [MeQ,Pt-C(0Me)- ii, MeOH CHR1R2]+[PFs]- (9) (ii) Syntheses froin Metal-Carbene precursors.Reactions of the co-ordinated carbene ligand have been most widely studied for methoxycarbenechromium(0) complexes, and are shown, with other reactions of such compounds, in Figure 13. Some of these (also found for Mo, W, and Mn) illustrate the analogy mentioned earlier between alkoxycarbenes and carboxylic esters, namely the rections with ammonia, primary and secondary amines, ketimines, and thiols [equation (lo)]. It is noteworthy that not all protic compounds behave similarly [see Figure 13 and Section 2C(iv)]. Both the ~tereochemistry~~~~~~ and the kinetic^^^^^^^ of the aminolysis reaction have been studied. The latter revealed that the reaction proceeds by initial protonation at OMe, [equation (lo)], followed by co-(OC),Cr-C(0Me)R + HA -MeOH + (OC),Cr-C(A)R ordination of a nucleophile and finally reaction of R2NH [= HA in equation (lo)].Deprotonation affords LM-C(NR2)R1. In paraffinic solvents R2NH is capable of acting both as proton donor and acceptor. Clearly Ccarb is an electrophilic centre; this is further demonstrated by the protonic character of the a-hydrogens P. M. Treichel, J. J. Benedict, R. W. Hess, and J. P. Stenson, Chem. Comm., 1970, 1627. D. F. Christian, G. R. Clark, W. R. Roper, J. M. Waters, and K. R. Whittle, J.C.S. Chem. Comm., 1972,458. 91 M. H. Chisholm and H. C. Clark, Inorg. Chem., 1971, 10, 2557. 92 P. E. Baikie, E. 0.Fischer, and 0.S. Mills, Chem. Comm., 1967, 1199. 93 E. 0.Fischer and R. Aumann, Chem.Ber., 1968, 101, 963; Angew. Chem. Internat. Edn., 1967, 6, 181. 9p E. 0.Fischer and V. Kiener, Angew. Chem. Internat. Edn., 1967, 6,961. st, E. 0. Fischer and A. Maasbol, J. Organometallic Chem., 1968, 12, P15. 96 E. 0. Fischer, E. Louis, W. Bathelt, E. Moser, and J. Muller, J. Organometallic Chem., 1968, 14, P9. 97 H. Werner and H. Rascher, Inorg. Chim. Acta, 1968, 2, 181 ;Helv. Chim. Acta, 1968, 51, 1765. E. 0.Fischer and L. Knauss, Chem. Ber., 1969, 102,223. g9 C. G. Kreiter, Angew. Chem. Internat. Edn., 1968, 7, 390. looL. Knauss and E. 0.Fischer, J. Organometallic Chem., 1971, 31, C71. lol J. A. Connor and P. D. Rose, J. Organometallic Chem., 1970, 24, C45. loaE. 0. Fischer and K. H. Dotz, J. Organometallic Chem., 1972, 36, C4.lo3E. 0.Fischer, B. Heckl, K. H. Dotz, J. Muller, and H. Werner, J. Organometallic Chem., 1969, 16,P29. lo4E. 0. Fischer and K. H. Dotz, Chem. Ber., 1970, 103, 1273. lo5 E. Moser and E. 0. Fischer, J, Organometallic Chem., 1968, 15, 147. lo6H.Werner, E. 0.Fischer, B. Heckl, and C. G. Kreiter, J. Organometallic Chem., 1971,28, 367. Cardin, cetinkaya, Doyle, and hppert Ref NH3 NH2Mc NHMe2 * --- Cr-C(NH2)R Cr -C(NHMe)R Cr-C(NMe2)R 54,57 58,92 63 NHPri2 HNZCPh;! MeCHO-NH3 HONH2 H2NNMe2 -e *-Cr-C(NHPr i)R Cr-C( N:CPh*) Cr-C(N:CHMe)R, Cr-NH: C(0Me)R Cr -Ni CMe Cr- C(NH2)R 58,63 68 68 93 93 H0N:CHPh Cr -NH:CHPh, Cr-N ICPh 68 Cr -C(SR')R 54,55 I PhSeH rn Cr -Se/Ph 94 'CH !OMe)R Cr-py, (OC)4Cr(py)2, Et0CH:CH; 95 cr-c,i(oMe)c H+ Cr-C, ,COMe Cr lC(0Me)R CNC6H11 m MeOH NHC6H11 ,C(OMe);!Me 60,62 'N-c6H11 Cr-C, I PX3 (X=Br or I) PH1 ---cis-(OC)~Cr(PH3)2, MeOCH: CH2 cis 40C)~(R13P)Cr-C(OMe)R, cis-(OC)4 Cr(P R1g ) Cr-PX3 NHC6H11 1 96 97 98 HI- "Me&)+ (Cr -1-0)- (NMe4)' 6 McOD -MeONa* Cr -C(OMe)C03 99 Me3OBF4 -MeONa Cr-C(OMe)Et, Cr-C(0Me)CHMez 99 Li[AIH(OBut)i 7 Cr-C(OMe)CH:CHCH:C(OMe)Me 100 EtjSiH Et 3SiCH(OMe)R 101 Ph;! SiHCH(0Me)R 102 Ph( Me0)C :C (0Me)Ph 103 py-HMeC:C(CO7Me)H 104 *In catalytic amount.?Refers to (OC),Cr-C(OEt)Me Figure 13 Reactions of alkoxycarbenechrornium(0) complexes Cr-C(0Me)R (R = Me or Ph), such as (OC),Cr-C(0Me)Me in (OC),Cr-C(OMe)CH,, as shown by the facile conversion (OMe--MeOD) into (OC),Cr-C(OMe)CD, or (OC),Cr-C(OMe)CHnMe,-n (n = 1 or Z).as An interesting reaction of a co-ordinated carbene is shown in equation (11).7s Displacement reactions of either neutral or anionic ligands from transition- 115 5 The Chemistry of Transition-metal Carbene Complexes metal carbene complexes may provide a method of synthesis of further carbene complexes.This is demonstrated by equation (12),13 and has also been used in CrO (e.g. Figure 13), Moo, Wo,RhI, Pd", and PtlI (e.g. Figure 14) chemistry. trans -Br2(Et PIPt-C (NMeCH2)2 frans -Mez(Et3P)P t-C(NMeCH2)Z trans cis -CIz(Et3P)Pt -C(NMeCH2.2 trans -ICI(Et3P)zPt -C(NM~CHZ)~I'[BFLI' trans -CI(H)(Et3P) -Pt -C(NMeCH2)z Me /N\Figure 14 Reactionsllo of trans-Cl,(Et,P)Pt-C I\" Me Additionally, for RhI compounds, it has been possible to displace one carbene Iigand by another [e.g.equation (13)].33Nucleophiles may, however, react in other ways [e.g. Figure 13; for C,H,,NC see also Section 2C(iv)]. Some PtI1 carbene complexes are converted into Ptm derivatives by reaction with chlorine.28 EtaP C13(Ph,P) ,Rh-C(NMeJH +C13(Et3P),Rh--C( N MeJH (12) IC€WG~M*P)CHJ~),C1(PhsP)aRh-C m(Ph)CH,], _______+ Cl(Ph,P),Rh-C [N(C6HI-Me-p)CH,], (13) Two examples of carbene ligand transfer from one metal to another one are known37J07 [e.g. equation (14)].37 It is possible that this proceeds via an electron-rich olefin by analogy with reaction (15).66 WCQ.(?r-CsHs)(ON)(OC)Mo-C(OMe)Ph -+(OC)4Fe-C(OMe)Ph (14) hv Me Me Me N [,;C=C<) FC( COI 5 -(OC),,Fe -C, N Me MU Me K.ofele and M.Herberhold, Angew.Chem. Intwnut. an., 1970,9, 739. Cardin, Cetinkaya, Doyle, and Lappert Square-planar d8complexes trans-Hal,QM-CXY rearrange thermally to &e the thermodynamically more stable cis-isomers [M = Pd or Pt ;Hal = C1 or Br ; NS\Q = RsPorR&; = C(NPhCH&, C(NMeCH,),, or C-MeN--C6H,s](PdIIreacts more readily than PtII).16 (iii) Syntheses from Organic Carbene Precursors. Electron-rich olefins, such as (lo), are good nucleophileslOs and have exceptionally low first ionization poten- tials (ca. 6 eV).lo@They react with certain transition-metal substrates which are responsive to nucleophilic attack to furnish carbene complexes. The first example of this reaction is shown in equation (16) (R = Ph).14 Other carbene complexes to have been made by this procedure are complexes of Cr0,66Feo,6s Rh1,33966 PdI1,l6Jlo and PtII,14~1s~110 and include dicarbene complexes [from Rh,Cl,(CO)4 or Cr(CO), olefins to have been employed are [:CN(R)CH,], (R = Me, Ph, /s\or C6H4.Me-p), [:C-MeN-C,H4-oJ2, and C2(SMe),.Imidazolium salts have been used (Scheme 1) to obtain complexes of CrO, FeO,and Hga+.30,38,72 Electron-rich gem-dichlorides, in which the C4I bonds have appreciable ionic X -CHCr(C0)5]-, R P Me3' / * (OC)5Cr -C(NRCH), Scheme 1 lo' R. W. Hoffmann,Angew. Chem. Internat. Edn., 1968,7, 754; N. Wiberg, ibid., p. 766. meB. etinkaya, G. H. King, S.S.Krishnamurthy, M. F. Lappert, and J.B. Pedley, Chern. Comm., 1971, 1370. B. etinkaya, E. Cetinkaya, and M. F. Lappert, J.C.S. Dalton, in the press. TIe Chemistry of Transition-metal Carbene Complexes character, combine with dianions,as shown in equation (13, the earliest example of such a reaction;,O other reports relate to M%NCHCla and either Na,Cr(CO), Ph Ph + Na2Cr(CO),-(OC)&-C 3-+ 2NaCl (17) Ph Ph or Na2Fe(CO)4.13 Such dichlorides have also been used with co-ordinately unsaturated low-oxidation-state substrates (RhI, IrI, or PtII complexes13 or Pd meta170). This procedure gives carbene complexes by a three-fragment oxidative- addition process, a sequence first postulated in order to account for the reaction products from imidoyl chlorides and RhI complexes (eg.Scheme 2). [Me,NCHCl ]+C1-,ls [(PhNH),CCl]+Cl- (Scheme 2)>, and 2,3-diphenyl-l,1- dichlorocyclopropene have been used. 70 R' N-C-NR' CI3(Ph,P),Rh--C: R R 1NHR' (Ph3P)3RhCl C13( Ph3P)zRh-C, R\\ I(PhNH12CCl)'Cl; 'Cf3( Ph3 P)2Rh- C(NHPh)Z Scheme 2-Three-membered-ring compounds LM-COS [e.g. (n-C,HJ(OC),-Mo-C(NMe,)S and (Et,P)ClPt-C(SMe)S] are known for X = SMeKBand NMe,.64 (iv) Other Reactions. The reactions of transition-metal complexes may be divided into those in which (a) another carbene complex is formed [see Section 2C(ii)], (b) the carbene ligand is transformed, but its constituents remain within the co-ordination sphere of the metal, and (c) the carbene ligand is displaced. Illus- trations are provided in Figures 13 and 14.A number of protic compounds do not behave according to equation (10). These include HONH,, HONHPh, H,NNMe,, PhSeH (Figure 13), and HN, {on [Me4N]+ [(OC),Cr-C(O-)CH,SiMe, ] to give (OC)5Cr-NCMe}.46 All these reagents afford metal-nitrogen co-ordination compounds :the forma- tion of isonitrile complexes may involve an initial methoxy displacement asshown in equation (10) and subsequent rearrangement [e.g. (ll)]. The reactions with PhSeH and CBHl1NC are essentially insertions into the Cr-Cmb bond (Figure Cardin, cetinkaya, Doyle, and Lappert 13). There is a single example of conversion of a co-ordinated carbene into a substituted methyl complex [equation (18)].23 A related reaction is the reversible conversion of Cl,(Ph,P)Pd-C(0Me)NHPh with base into the imidoyl complex [Cl(Ph,P)PdC(OMe)(: NPh) NaBH,-EtOH [(n-C,H,)(Ph,P)(OC)Fe-C(0Et)Me ]+____+ (n-C5H5)(Ph3P)(OC)Fe-CH(OEt)Me (1 8) From Figure 13 it is evident that the carbene ligand may be displaced from chromium by a suitable nucleophile such as pyridine or a phosphine.Similar, but less extensive, results are available for complexes of Moo,Wo, RhI, and HgII: an example is in equation (19).l12Especially noteworthy are those reactions in Hg[C(NPhCH)2]a2++ HZS +HgS + 2[HC(NPhCH),]+ (19) which the carbene ligand is trapped, by dimerization, rearrangement [e.g. Me(Me0)C: 4MeOCH=CH,], or a trapping agent. Because stable metal carbene complexes are derived from nucleophilic carbenes, olefins such as cyclohexene are not particularly good reagents for this purpose, and hence the use of compounds such as $-unsaturated esters.lo4 Silanes and related hydrides are particularly effective: the carbene inserts into the M-H bond101#102(but see Figure 14).3 Metal Carbenes as Reaction Intermediates or Transition States. Several reactions are known for which metal carbene complexes have been postulated as intermediates or transition states. This section describes such reactions, some of which are synthetically important. Figure 15 summarizes details of organic and transition-metal reactants and products for the types of reactions outlined in Sections 3A-E, and Scheme 3 gives a particular example for Section 3D. The evidence in favour of intermediate carbene complexes in the reactions shown in Figure 15 is not equally strong in all cases.Thus, whereas the metal- catalysed decomposition of diazoalkanes (Section A) and the alkylation of carbonylmetallates (Section B) leaves little room for doubt concerning such 111 B. Crociani and T. Boschi, J. Organometallic Chem., 1970, 29, C1. lla H. W. Wanzlick and H. J. Schonherr, Angew. Chem. Internat. Edn., 1968,7,141. The Chemistry of %arition-metal Carbene Complexes XYCN2 M', especially Cur and Pd*' /x LiR RR' CXY Cr Iraq. q.MeCBr2Me Strained various metal catalysts carbocyc'ics 1C.g. Scheme 31 Olefin Dismuted dismutat ion olefins e.g. R'ZN, ,NRZ ,c=c, R: N NR2 Figure 15 Reactions proceeding via carbene-metal complexes products including products -including Scheme 3 Cardin, Cetikaya, Doyle, and Lappert intermediates, the role of the metal in the cyclopropanation reactions (Section C) is rather different.As to Section D, many strained-carbocyclic rearrangements certainly do not involve complexed carbenes, although there is a wealth of circumstantial evidence in favour of such a mechanism in other cases. In terms of Scheme 3 we are here concerned only with reactions proceeding via species analogous to ((12)-(13)] (path b) i.e. carbene complexes or metallo- carbonium ions, and not via metal-substituted carbonium ions, (path a) in which the metal is at a site remote from the carbon with greatest positive charge. Finally, attention is drawn to some reactions which proceed through unstable carbene species but are not of general synthetic utility and are not outlined in Figure 15.These include [braces { } denoting those which have not been iso- lated] {(?r-c,H,)(OC),Fe-CH,+) (see Section C), {(n-C5H5)(OC),Mo--CH2-}, and {(?r-CSH6)(OC), [(C,H, Me-p),CN]Mo-C(C,H, Me-p), 1, which are de- tailed here. The reaction of(T~-C,H,)(OC),MON~with ClCH,SiMe, surprisingly afforded (n-C,H,)(OC),Mo-Me, and not the expected silylmethyl derivative.l13 Deuter- ium labelling studies exclude the possibility of Me migration (from SiMe,). The reaction proceeds via the silyl derivative, as in equation (20), but subsequent (m-C,H,)(OC),Mo-Na+-THF (T~-C~H~)(OC),M~-CH,SiMe3 + room temperature {(?T-C,H,)(OC),M~-~H,-N~+} -+(.rr-C,H,)(OC),Mo-CH, (20) (14) attack by (v-C,H,)(OC),Mo- gives rise to (14); this is presumably because (i) anchimeric assistance by the cyclopentadienyltricrbonylmolybdenum group facilities CH,-Si bond cleavage (unusual at room temperature) and (ii) the negative charge in (14) is substantially delocalized. A metallocarbene inter- mediate (15) has been proposed in the reaction between (n-C6H,)(OC),MoC1 and LiN:C(C,H,* Me-p), (Scheme 4).l14 An intermediate of this type is entirely (IT-C~H~)(OC)~MOCIt 2LiN:CRz-1 R = Ph or p-tolyl Scheme 4 11* M.R.Collier, B.M. Kingston, and M. F. Lappert, Chem. Comm., 1970, 1498. *14 H. R. Keable and M. Kilner, J.C.S. Dalton, 1972, 153. The Chemistry of Transition-metal Carbene Complexes possible; the reaction of a lithium ketimide with co-ordinated carbonyl has been shown to afford carbene complexes [equation (21)],6a but here the subequent reaction is not possible.i, LiNCPh, (OC),Cr -(OQCr-C(0Et)NCPhii, [Et,O]+[BFJ-A. Metal-catalysed Carbene Generation from Diazoalkanes.-The influence of metals in reactions of diazo-compounds XYCN2 has been known for many years,116 particular attention having been paid to catalytic decomposition by copper derivatives. The reactions afford nitrogen, and in many cases the products are those to be expected from the intermediacy of free carbenes. The reactions with metal and metalloid derivatives have been reviewed;lls only those believed to involve carbene-metal species are considered here.As well as transition-metal carbene complexes (LM-CXY), other proposed intermediates include LM(CXYN2) and LM(CXYN,CXY) (LM = catalyst). A few stable compounds having such compositions have been isolated,lls but this does not necessarily imply that they play a role in the catalysed reaction path. Examples of these are (i) (T-C,H,)(OC),W-N: N-CH,SiMe, from (m-C5H6)- (OC),WH and Me3SiCHN2117 and (ii) cis-(Ph,P),Pt [(CF,),C: No N: C(CF,),] from (Ph,P),Pt and (CF3)gCN2.14 Differences in the reactions undergone by the :CXY groups led to the proposal that complexed carbenes were true reaction infermediates,ll* rather than the free carbenes. This proposal has been examined in detail for reaction (22),llS which is homogeneous.It has been observed that, in reactions of this type, the ratios of exolendo products are very different from the photochemical and metal- initiated reactions.12o Since the photochemical mechanism clearly cannot involve metal, these differences were taken as evidence for the intermediacy of copper-carbene complexes. Moser1l9 found that the thermd reaction affords products, the exolendo ratios of which lie closer to those of the metal-modified reactions, implying that these ratios are not sufficient evidence of LM-CXY intermediates. Better evidence for such intermediates has now been obtained by a study of the lls A. Loose, J. puakt. Chem., 1909, 79, 507. M. F. Lappert and J. S. Poland, Adv. Organometallic Chem., 1970,9, 397.117 M.F. Lappert and J. S. Poland, Chem. Comm., 1969, 1061. 11* P. Yates, J. Amer. Chem. SOC.,1952, 74, 5376. lleW.R.Moser, J. Amer. Chem. SOC.,1969, 91, 1135, 1141. lB0P. S. Skell and R. M. Etter, Chem. and Znd., 1958, 624. 122 Cardin, Cetinkuya, Doyle, and Lappert results of changing electronic or steric effects of substituents on the metal catalyst.llB In summary, it was found that increasing the size of the phosphite [in (RO),PCuCl ] favours formation of the endo-isomer (16), additionally electron- withdrawing groups favour a higher proportion of the endo-product (17).Addition-ally, use of the optically active (-)-tribornyl phosphitecopper(1) chloride gave two optically active cyclopropanes with optical yields of 3.2% (18) and 2.6% (19) [equation (23)].From the results, including an Arrhenius treatment of the reaction studied at various temperatures, it was concluded (i) that the ha1 transition state (20 or 21) leading to products involves olefin, metal, and the carboxymethylene, (ii) that the transition state is asymmetric, and (iii) that any intermediate leading to it decomposes unimolecularly to products. A mechanism incorporating these factors has been proposed,lle and is shown in Scheme 5. "2N2HC02Et + I(RO)~PCUCLI~-~(RO)~PCUC~+(RO)3PCuCl*CHC02 Et I I, olefin ii,NZCHCOzEtI-\ )I/J /H (20)8x0 bC02Et (21) endu \ C02Et Scheme 5 123 The Chemistry of Trmition-metal Carbene Complexes The effect of electronegative ligands (favouring formation of the endo-product) has been rationalized in terms of increased steric hindrance in (20) leaving (21) relatively unaffected.The dissociation of the copper phosphite is based on kinetic data.181 Finally, probably the best evidence for copper-carbene complexes as intermediates is the induction of asymmetry at the cyclopropanes, and the linear correlation of exolendo ratios with normal (Hammett) a-constants of substituents in the aromatic ring using triaryl phosphite-copper complexes. Good correlations of this type are not common in catalytic reactions. In a studylea comparing thermaI, photolytic, and metal-initiated decomposition of diazoalkanes with copper or silver salts, both olefins and cyclopropanes were formed [equation (24)] and evidence for metal carbene intermediates emerged.Asymmetric induction in cyclopropanes similar to that using norbornyl phosphite complexes has been demonstrated using an optically active chelate (22) of copper (Scheme In this case the optical yields were rather higher Ph* CHMe H I N=C IH Ph*CHMe (-6%) than with tribornyl phosphitecopper chloride, as one might have predicted with an asymmetric centre closer to the metal. In this case the reaction was inhibited by addition of co-ordinating bases such as pyridine. Scheme 6 also shows asymmetric induction with an oxetan.18a Another chelate, acetylacetonatocopper(n), has been examined with benzoyl-diaz~methane.~~~~~~~Here, metal complexation was believed to account for lS1 A.G. Witenberg, I. A. D’yakorov, and A. Zindel, Zhur. org. Khim., 1966, 2, 1532. W. Kirmse and K. Horn, Chem. Ber., 1967, 100,2698. la*H. Nozaki, S. Moriuti, H. Takaya, and R. Noyori, Tetrahedron Letters, 1966, 5239. lapM. Takebayashi, T. Ibata, H. Kohara, and Bu Hong Kim, Bull. Chem. SOC.Japan, 1967, 40,2392. M. Takebayashi, T. Ibata, H. Kohara, and K. Ueda, Bull. Cham. SOC.Japan, 1969, 42, 2938. Cardin, Cetinkaya, Doyle, and Lappert Ph C02R Ph N2CHC02R + PhCHzCH;! Scheme 6 reduced carbene reactivity. A number of copper salts catalysed a cycloheptatriene synthesis from aromatic In one study,128 with Cu, Hg, or Co catalysts, a mercury intermediate129 was isolated and its subsequent reaction demonstrated. Reactions catalysed by zinc halides, especially ZnI,, are of particular interest because of the possible similarity between intermediate species in this and in the Simmons-Smith reaction (see Section 3C).Kinetic studies with Ph2CN2 show that two intermediates are involved, the first of which may be a carbene complex. In subsequent reactions, ZnI, differs from the chloride and bromide.laO~lal De-composition of the same diazo-compound and analogues by CuBr, in acetoni- trile yields the diary1 ketone and ketazine. Kinetic studies point to the reaction pathway of Scheme 7, which shows only the essential metal ligands. The fast -N2 fastAr2CN2 -t'CuBr; +Ar2CNZ'CuBr-ArZC-CuBr CAr2C*Cu*N2*CAr2+ 6r' Br-/slow 1z:Nz 1::Nz Ar2C:0 Ar&: N * N :CAr2 Scheme 7 kinetic evidence, including spectroscopic, indicates the intermediate formation of CuII-carbene complexes, but the diazoalkane complex is inferred from stopped- flow data on the initial phase of the reaction.lal la6E.Miiller and H. Fricke, Annalen, 1963, 661, 38. la' E. Miiller, H. Kessler, H. Fricke, and W. Kiedaisch, Annalen, 1964, 675, 63. la8T. Saegusa, Y. Ito, T. Shimim, and S. Kobayashi, Bull. Chem. SOC.Japan, 1969, 42, 3535. lagA. N. Nesmeyanov and G. S. Powch, Ber., 1934,67,971. D. Bethell and K. C. Brown, Chem. Comm., 1967, 1266; J. C. S. Perkin 11, 1972, 895. 181 D. Bethel1 and M. Eeeles, personal communication. The Chemistry of Transition-metal Carbene Complexes By contrast with the above catalytic decompositions, ethyl diazoacetate reacts with the organic ligand of bromo-7T-allylnickel(r),affording butadiene derivatives, mainly isomers of (23).lSa A possible reaction scheme involves the carbene intermediate (24). It is proposed that the carbene then inserts into the adjacent Ni-C bond (cf: carbon monoxide) to form, e.g., (23).Decomposition of ethyl CHz=CH -CH=C(H) C02Et (23) diazoacetate by an allylpalladium complex (25) has also been examined;lS3 here reaction with co-ordinated ally1 was not observed. The proposed mechanism (Scheme 8) involves the carbene species (26), an analogue of (24). In this study, Scheme 8 comparison between (25) and copper salts as catalysts was made. Thus for reactions of N,CHCO,Et with but-2-yneY (25) is an effective catalyst at 0-lO”C, whereas copper derivatives required temperatures of 65-l2O0C, and curiously, whereas the former afforded mainly diethyl fumarate in the dimerization reaction, diethyl maleate was the major product in the latter case.In another comparative study, catalytic decomposition of the unusually stable diazotetrachlorocyclo- pentadiene by (25) in acetylenes (as solvents) was examined.I3* When carried out in tolan or 3-hexyne at 75-82°C using copper or copper sulphate, the spiro[2,4]- heptatrienes (27; R = Me or Ph) were obtained. However, with the palladium 13* I. Moritani, Y. Yamamoto, and H. Konishi, Chem. Comm., 1969, 1457. lS3 R.K. Armstrong, J. Org. Chem., 1966, 31, 618. lS4 E. T. McBee, G. W. Calundann, and T. Hodgins, J. Org. Chem., 1966,31,4260.Cardin, Cetinkaya, Doyle, and Lappert complex at 1O-2O0C, low yields of the adducts with two acetylene molecules (28; R = Me or Ph), but no cyclopropane derivatives, were isolated, together with 50-60 %of the mine (29) (not detected with copper catalysts). The proposed CI Cl ‘ CI Nc[@CL Cl R mechanism for the Pd-catalysed system (Scheme 9) involves both a carbene complex(31) and a butadiene complex (30);the latter is postulated to account for the unique feature, namely lack of reaction with solvent acetylene. (30) I (3’) r R valence isomerization Scheme 9 [The decomposition of CHBNBby Ni(CO), is described in the following section, and the use of diazoalkanes in mechanistic studies relevant to carbocyclic rearrangements is described in Section 3D.3 B. Synthesis of Organic Carbonyl Compounds using Metal Carbony1s.-In the syntheses of the Group VIA-metal carbene complexes first used by Fischer and co-workers,Bs7 acylmetallates (32) are intermediates. These may be regarded as anionic carbene complexes, and such a view has been widely accepted. However, the contribution of forms such as (33) cannot be ignored (see Table 3 and ref. 49). In a number of reactions intermediate carbonylmetallates react with organic reagents forming alkyl- or aryl-(carbene) complexes (OC)nM-C(OR)Ph which The Chemistry of Transition-metal Carbene Complexes decompose to products: in this section both ions and neutral species are regarded, formally, as carbenes. As we have seen, the acylmetallates derived from RLI and a Group VIA-metal hexacarbonyl are stable complexes which require rather good alkylating agents [e.g.CH2 then H+, or (Et30)+BFa-] for conversion into neutral carbenes. By contrast the carbonyls Fe(CO), and Ni(CO), are more reactive to organolithium reagents (the latter reacts exothermically at -70 "C), forming rather unstable salts, sensitive to air and moisture. They are, however, useful intermediates in organic syntheses by virtue of their reactions with olefins, alkyl halides, and other organic substances. Such syntheses are exemplified in equations (25)-(34). (ref. 135) (25) (ref. 136 ) (26) (ref. 137) (27) RCO*CH(OH)R (R-aryl) (ref. 138) (28) f H+ Ph&==CH-CHPhLi + M(CO)s -+ (Li [(OC),M-C(O)CHPh*CH=CPh,]}--f PhCH(CHO)CH=CPhs (ref.140) (33) (M = Group VIA metal; routes to unsaturated aldehydes are relatively un- common) 13b M. Ryang, I. Rhee, and S. Tsutsumi, Bull. Chem. SOC.Japan, 1965,38, 330. lacy.Sawa, M. Ryang, and S. Tsutsumi, unpublished work cited in ref. 7; Tetrahedron Letters, 1969, 5189. Is' Y. Sawa, I. Hashimoto, M. Ryang, and S. Tsutsumi, J. Org. Chem., 1968, 33, 2159. lsrY. Sawa, M. Ryang, and S. Tsutsumi, J. Org. Chem., 1970, 35, 4183. la@M. Ryang, S. K. Myeong, Y. Sawa, and S. Tsutsumi, J. Organometallic Chem., 1966, 5, 305. 140 E. 0.Fischer and A. Maasbol, G. P. 1214233/1966. Cardin, Cetinkaya, Doyle, and Lappert HmS LiNMe, + Ni(C0)4 + (LiN(MeaC0 *Ni(CO)3 1 -+ Me,NCO.CO.NMe, + Hg + 2LiCl (ref.141) (34) The intermediate salts of Fe and Ni are too reactive to permit structural studies. They are believed to be mono- and di-nuclear respectively; thus, products from the coupling of two organic groups are formed from the nickel derivatives. The proposed mechanism137 for an acyloin and stilbenediol diester are shown in Scheme 10; the use of this route for direct addition of acyl groups to conjugated enones has been described.lqe The reaction of diphenyldiazomethane with Ni(CO), is extremely vigorous. Catalytic amounts of the carbonyl afford mainly benzophenone azine together with nitrogen, ethylene, and small quantities of other nitrogen-containing com- pound~.~~~With excess nickel, carbonylation takes place. The proposed mechan- ism, equation (39, involves a metal-carbene intermediate.Reaction of CO with free carbene is not known. -+ -co --NS R,C-NrN + Ni(CO), -R2-G-Ni(C0)s -+ R&-Ni(CO)s 3. (35)I+N {Ni(CO),) + Formation of ketazine may well involve the carbene intermediate (and R2CNa), a view in harmony with the dependence on the concentration of metal carbonyl. C. Carbene Transfer Reactions, Especially to 0lefins.-A number of ‘CXY’ transfer reactions (in which the carbene is derived from a diazo-compound) have been described in Section A; others are detailed here, including the synthetically important dihalogenocarbene reactions. Unusually mild conditions (dilute HCl, room temperature) are required for the cleavage of the ether linkage in (34), shown in equation (36).14‘ Similar behaviour is typical of acetals where hydrolysis is favoured by c---O double-bond forma- HCI (7r-C6Ha)(OC)8Fe-CH20CHs-(7r-C5HJ(0C),Fe-CH2C1 (36)MeOH-NaOH (34) (35) tion.An attractive is that reaction (36) is facilitated by carbene formation (stabilization, ‘double-bond’ formation with Fe). Support for this view has been obtained by reaction of (35) with AgBF,: AgCl may be filtered off, after which the filtrate reacts with cyclohexene affording norcarane, presumably 141 S. K. Myeong, Y.Sawa, M. Ryang, and S. Tsutsumi, Bull. Chem. SOC.Japan, 1965,38,330. lP1E. J. Corey and L. S. Hegedus, J. Amer. Chem. SOC.,1969,91,4926. lP3C. Ruchardt and G. N. Schrauzer, Chem. Ber., 1960, 93, 1840. lP4 M. L. H. Green, M.Ishaq, and R. N. Whiteley, J. Chem. SOC.(A), 1967, 1508. 129 The Chemistry of Transition-metal Carbene Complexes Ni(CO),+ LiPh-I PhCH2X/ 0/"\Ph 0 Ph I I0-c c-0I I R' R' Ph >c=c /Ph R'OCO \OCOR' stilbenediol diester Ph 0 LiO CH2Ph PhCOC(0H)PhI CH2Ph (os-benzvlacvloin 1 Scheme 10 Cardin, Cetinkaya, Doyle, and Lappert from the intermediate { [(T-C,H,)(OC)~F~CH~]+BF~-1 (36).14, Without the separation step norcarane yields of 46 % were obtained, and using cis- and trans- but-Z-enes trapping was stereospecific. The compounds isolated in the absence of traps were (T-C,H,)(OC),FeCH, and [(rr-C,H,)(OC),Fe(CH2=CH2)I+, both of which are clearly plausible products from further reaction of (36).Trapping experiments were positive also in the reaction of (n-C,H,)(OC)s-MoCH20Me with acids and in similar but much slower reactions with Re and Mn met hoxymethyl species. 46 Since the discovery of reactive dihalogenocarbenes from halo form^^*^,^^^ and from the Simmons-Smith reagent IZnCH21,148,14e there has been much interest in carbene transfer reactions. A number of studies have suggested a transition state (37) involving methylene and metal, but the species does not come within (37) our definition of a carbene complex (see refs. 146-157). The subject has been authoritatively reviewed.162 The reduction of gem-dihalides by chromium(n) sulphate has been shown to proceed via chromium-carbene intermediate^.^^^ Kinetic data, products, and reactivity sequences support a reduction involving carbenes derived from an initially formed a-halogenomethyl radical : R~R~CX~ *CP+]3R~RZ~X+ cr2+ -+F~R~c(x).-.x*. + CrX*+ (37) followed by R1R2k+ Cra+---+ [R1R2C-CrIa+ -+ R1R2C+ CrXa+ I 3. (38)X [R1R2CCr]*+ (38) 146 P. W. Jolly and R. Pettit, J. Amer. Chem. SOC.,1966, 88,5044. 146 W. von E. Doering and A. K. Hoffinann, J. Amer. Chem. Soc., 1954,76,6162. lQ7 G. Kobrich, H. Buttner, and E. Wagner, Angew. Chem. Internat. Edn., 1970,9, 169. 148 E. P. Blanchard and H. E. Simmons, J. Amer. Chem. SOC.,1964, 86, 1337. 14@ H. E. Simmons, E. P. Blanchard, and R. D. Smith, J. Amer. Chem. SOC.,1964,86, 1347. lSoT. L. Gilchrist and C. W. Rees, ‘Carbenes, Nitrenes, and Arynes’, Nelson, London, 1969.lS1 G. L. Closs and R. A. Moss,J. Amer. Chem. SOC.,1964,86,4042. 16* D. Seyferth, Accounts Chem. Res., 1972, 5, 65. usD. Seyferth and J. M. Burlitch, J. Amer. Chem. SOC.,1964, 86, 2730. lti4W. von E. Doering and W. A. Henderson, J. Amer. Chem. SOC.,1958, 80, 5274. 166 D. Seyferth, J. Y.-P. Mui, and J. M. Burlitch, J. Amer. Chem. SOC.,1967, 89,4953. 16a D. Seyferth, M. E. Gordon, and K. V. Darragh, J. Organometallic Chem., 1968,14,43. lb7D. Seyferth, J. Y.-P. Mui, and R. Damrauer, J. Amer. Chem. SOC.,1968, 90, 6182. 168 C. E. Castro and W. C. Kray, J. Amer. Chem. SOC.,1966, 88,4447. The Chemistry of Transition-metal Carbene Complexes Reduction takes place by proton transfer: [RlRZCCr ?+ Hi-3 [R1RZHC-Cr(OH)I2+ -+R1RaCHCr2++ Cra+ (39)c+ .gR~R~CH+ erg+3.etc. Carbenes have been trapped in this reaction; with 3-butenol and Me,CBr, the cyclopropyl product was obtained in 39% yield [equation (40)].These results indicate a carbene of rather reduced reactivity, presumably species (38). YezCBr;! + Cr2*+ CH2-CH.CH2-CH20H -CHz-CHCH3 +CH3 CH2CH3 1 3*lo 4 OJO CHzCHzOH (40) f Me2CH(OH) + x,.44 '10 Me 39'10 D. Valence Isomerizations of Strained-ring Carbocyclic Compounds.--+) Nature of the Reaction. A number of remarkable a-bond rearrangements in highly strained ring compounds are catalysed by transition-metal ions or their com-plexes. Examples are shown in the equations (41)--(47); the bonds specified are those cleaved. -A9* " (ref.161) (42) (43) (42) 160 L.Cassar, P. E. Eaton, and J. Halpern, J. Amer. Chem. SOC.,1970,92,6366. L. Cassar, P. E. Eaton, and J. Halpem,J. Amer. Chern. Soc., 1970,92,3515. L. A. Paquette and J. C. Stowell, J. Arner. Chern. SOC.,1971,93, 2459. I32 Cardin, Cetinkaya, Doyle, and Lappert*Me Me lelMe \ H Me H Me H# Me + Me# Me tie Me H Me (50) 46% (51) 50% (52) BU' cototysts + 6+ @J \ But But But (57) (59) (tsym-ismr)ro (ref.168) (61) (62) (63) (refs. 165,169) (46b) G. L. Closs and P. E. Pfeffer, J. Amer. Chem. Soc., 1968, 90, 2452. 16a P. G. Gassmann and F. J. Williams,J. Amer. Chem. SOC.,1970,92, 7631. 160 M. Sakai and S. Masamune, J. Amer. Chem. SOC.,1971, 93,4610. 166 P. G. Gassmann, T. J. Atkins, and F.J. Williams, J. Amer. Chem. SOC.,1971, 93, 1812; P. G. Gassmann and T. J. Atkins, ibid., p. 4597; but see also B. S. Solomon, C. Steel, and A. Weller, Chem. Comm., 1969, 927; ref. 181. lee P. G. Gassmann and T. Nakai, J. Amer. Chem. SOC.,1971, 93, 5897. 16' K. L. Kaiser, R. F. Childs, and P. M. Maitlis, J. Amer. Chem. SOC.,1971, 93, 1270. m6 K. B. Wibert and G. Szeimies, Tetrahedron Letters, 1968, 1235. leeL. A. Paquette, G. R. Allen, and R. P. Henzel, J. Amer. Chem. SOC.,1970, 92, 7002; see also L. A. Paquette, R.P. Henzel, and S. E. Wilson, ibid., 1971, 93,2335. The Chemistry of Transition-metal Carbene Complexes (67) (ref. 170) (47) Particular attention has been given to AgI, RhI, and PdII catalysts, among others, and in some cases simple Lewis acids are effective.The Agl catalyses have been reviewed.171 The driving force for these reactions is the relief of the high ring strain initially pre~ent,~~~J~~ and the role of the transition metal is tc provide a low-activation-energy pathway which is otherwise inaccessible, owing to the constraints of orbital ~ymmetry.~~~,~~~ Attention is drawn to the hybrid (69) shown in Scheme 11with both the carbene (69b)and metallo-carbonium ion Me" -MN 1-MN hydrogen shift Scheme 11 170 J. Wristers, L. Brenner, and R. Pettit, J. Amer. Chem. Soc., 1970,92, 7499. 171 L. A. Paquette, Accounfs Chem. Res., 1971, 4, 280. 17' K. B. Wiberg, Adv. Alicyclic Chem., 1968, 2, 185. 17s M. G. Evans, Trans. Faraday SOC., 1939, 35, 824. 17' R. B.Woodward and R. Hoffmann,Angew. Chem. Internat. Edn., 1969,8,781. Cardin, Cetinkaya, Doyle, and Lappert (69a) contributors. Further evidence for (68) and (69) comes from trapping experi- ments with nucleophiles (see below). The derivatives (70) and (71) were produced when the fRh(CO),CI], catalysis of (60) was conducted in methanol, and significantly in the same ratio when sulphuric acid was used in place of the metal ~ata1yst.l~~These experiments support both the stepwise nature of the reaction and the intermediacy of carbonium ions, but do not provide conclusive evidence for (69); some related systems have been rationalized in terms of the parallel with conventional carbonium ion chemistry.17 A similar charge-transfer (cation radical) intermediate has been proposed for the prismane rearrangement [equation (45)].ls7We may contrast conditions of the thermal (unchanged 3 h, 150 "C; 86% recovery after gas-phase pyrolyses 1 s, 500 "C)and catalysed (quan- titative conversion, -c 3 min, 40 "C) reactions analogous to equation (42) for the (saturated) bis(methylcarboxy1ate) of compound (42).Kinetic factors are presumably also responsible for the contrasting behaviour of (64)with AgBF,, the anti-isomer being inert under the same conditions [equation (47)l. Finally we note the synthetic utility of some reactions :equation (44)shows a novel route to azulenes,16s and the first preparations of semibullvalene were based on a bis-homocubyl rearrangement.176 (ii) Mechanisms. A large amount of evidence supports the existence of carbene intermediates or 'metallo-carbonium ions' in many of these reactions, having the structural feature shown.The evidence includes (a)satisfactory product identifica- tion, (b) kinetic data, (c) labelling experiments, (d) trapping experiments both internally and with additives, and (e) studies with model systems. Point (a) is illustrated with reference to equation (46b); the thermal reaction (46a) follows a different course (and, probably, a different mechanism). The product ratios are dependent on the catalyst employed, of which there are many (including Rh, Pd, Cu, Ag, Zn, and Hg derivatives) having the common feature 176 L. A. Paquette,J. Amer. Chem. SOC.,1970,92,5765; R. Askami, Tetrahedron Letters, 1970, 3349; L.Cassar, P. E. Eaton, and J. Halpern, J. Amer. Chem. SOC.,1970,92,6367. 176 M. Sakai, H. H. Westburg, H. Yamaguchi, and S. Masamune, J. Amer. Chem. SOC.,1971, 93, 461 1. 17' J. E. Byrd, L. Cassar, P. E. Eaton, and J. Halpern, Chem. Comm., 1971,40. 77ie Chemistry of Transition-metal Carbene CompIexes of Lewis acidity. A common intermediate (68) has been proposed, which can account easily for the observed products of Scheme 11. Kinetic data (6) relating to bicyclobutane systems [especially equation (46) J have shown that the reactions are not concerted processes and that the derived rate law16g is consistent with the following mechanism: +interrdiate + Ag+ Ccomplexl (48) products + Ag' Kinetic studies with cubane and a norbornene derivative17e also establish stepwise pathways.Point (c) is illustrated by reference to equation (43). Different bonds are cleaved in the thermal reaction162 (43a) from those in catalysed path~ays~~~J~* (43b and c); the ambiguity (C-1-C-3 and C-2-C-3 or C-1-C-4 and C-2-C-3) in pathway (43b) was resolved by a labelling study D( = D; (43b)l. The C-1-C-3 cleavage was also rigorously established for the Ag+-initiated rearrangements18o of exqexo-and endo,endo-l,4-dimethylbicyclo[1,l,O ]butanes which are, respect- ively, largely and highly stereospecific. The methylated analogue (44;X = Me) gives an almost statistical distribution of products [equation (43)], but the isomeric 2,2,4,4-tetramethyl derivative, which has no 2- or 4-hydrogen atom available for migration after the skeletal change, afforded (72) only.lSs This might imply a new bond-breaking sequence, but a more attractive explanation is that Me the unchanged sequence leads to (73) [cf.(69)], which subsequently undergoes a vinyl migration. Studies on migratory aptitudes to carbenoid centres show an order H > vinyl > methyl.l*l Further support for (73) is provided by the low- temperature decomposition of (74) catalysed by the same RhI species, which affords (72) as the only volatile 178 L. Cassar, P. E. Eaton, and J. Halpern, J. Amer. Chem. SOC.,1970,92,3515, 6366. lTeT.J. Katz and S. A. Cerefice, J. Amer. Chem. SOC.,1969, 91, 6520. 180 M. Sakai, H. Yamaguchi, H. H. Westburg, and S. Masamune, J.Amer. Chem. SOC.,1971, 93, 1043. lnl H. Shechter, personal communication quoted in ref. 182; see also D. M. Lemal and K. S. Shim,Tetrahedron Letters, 1964, 323; G. L. Closs and R. B. Larabee, ibid., 1965, 287. 136 Cardin, cetinkaya, Doyle, and Lappert Trapping reactions (d) have been widely used in other systems as evidence for intermediate carbene species. Particularly interesting in this context is the internal benzene into norcaradiene conversion, a typical carbene reaction, believed to take place in the rearrangement of (52) [equation (a)].The proposed reaction scheme is presented in Scheme l2.l" Me H Ph Ph Scheme 12 A (carbonium ion) precursor to the metal carbene complex has been detected in the 1,2,2-trirnethylbicyclo [1,1 ,O]butane system by intermolecular trapping with methanol.las These experiments confirm the stepwise nature of the process, and establish that C-2-C-3 bond rupture precedes C-1-C-3 scission in the reaction (see labelling experiments above), as shown in Scheme 13.The methoxy-deriva- tive was obtained at a rate (97%, 1 min, 25 "C) comparable to that of the Tlte Chemistry of Transition-metal Carbene Complexes Mu Me I (M= Rh) MK MuO Me e Scheme 13 rearrangement. Acid catalysis was eliminated (control experiments) but the possibility that methanol solvent promotes a different mechanism from that in chloroform, although improbable and without experimental foundation, could not be ruled out.le6 Synthesis of the proposed carbene intermediates in these reactions from model compounds and a study of their subsequent reactions have tended to confirm the proposals for some systems only.It is known that the metal-catalysed decompo- sition of diazo-compounds proceeds via carbene complexes (see Section 3A) and this reaction has been used to provide the required intermediates. [One example, (74), has been mentioned above. ] In the palladium-catalysed rearrangements of bicyclobutanes, two bond- breaking pathways are known, as shown in Scheme 14; the intermediate (75) Scheme 14 Cardin, Cetinkaya, Doyle, and Lappert corresponds to (73) in the RhI-catalysed reactions. The percentage distribution of products is very sensitive both to the catalyst and to substituents in the substrate.Diazo-compounds were synthesized, such that their decomposition would lead to corresponding carbonium ion analogues of the general intermediate (75),lS4 Bicyclobutanes with the appropriate diazo-models are shown below. For the palladium-catalysed [(PhCN),PdCI,] reactions of the bicyclobutanes the product distribution was similar or identical to that obtained with the relevant model, strongly supporting a carbene (metallo-carbonium ion) intermediate. However, the silver-catalysed decompositions led to entirely different ~ati0s.l’~ It seems here that an initial C-l-C-2 heterolysis is followed by a cyclopropyl- to allyl-carbinyl rearrangement and loss of metal Evidence for this using traps has been presented above. In conclusion, we may consider for which systems and metals carbene-metal complexes may be intermediates.There is clear evidence for these both from trapping experiments (especially internal insertion into benzenelS6) and from suitable models for several bicyclobutane rearrangements catalysed by both rhodiumls5 and palladium.lS4 For the Ag+ catalyses, evidence for metallo- carbenes is no more than circumstantial, although two aspects have been clearly established: (i) the stepwise nature involving different bonds in the carbon framework from the thermal reactions and (ii) the involvement of carbonium ions, possibly inetal-containing but conceivably at a site remote from greatest positive charge. E. Olefin Dismutation (or Metathesis).-The reaction is illustrated in equation (49), in which X and/or Y are H, alkyl, or some other univalent atom or group.Catalysis may be heterogeneous, the catalyst comprising a ‘promoter’, a metal oxide (e.g. MOO,) and a ‘supporter’, an oxide or phosphate (e.g.Al,O,). We are concerned principally with homogeneous systems : catalysts include WC16- 2BunLi, [(Ph,P),CI,-W(NO),]-(Me,AI,C1,),and (Ph,P),RhCI (for electron-rich olefins). Reviews are a~ailable,l~~-~~~ but these do not consider the role of metal-carbene complexes. There is increasing evidence for the participation of such 188 G. C. Bailey, Catalysis Rev., 1969, 3, 37; M. L. Khidekel’, A. D. Shebaldova, and I. V. Kalechits, Russ. Chem. Rev., 1971,40,669; S. Yoshitomi, Sekiyu Gakkai Shi, 1970,13,92; C. Inoue and K.Hirota, Yuki Gosei Kagaku Kyokai Shi, 1970,28,744; J. Tsuji, Kagaku No Ryoiki Zokan, 1970, 89, 169. F. D. Mango and J. H. Schachtschneider, in ‘Transition Metals in Homogeneous Catalysis’, ed. G. N. Schrauzer, Marcel Dekker, New York, 1971,223. lS4 N. Calderon, Accounts Chem. Res., 1972,5, 127; N. Calderon, E. A. Ofstead, J. P. Ward, W. A. Judy, and K. W. Scott, J. Amer. Chem. SOC.,1968,90,4133. The Chemistry of Transition-metal Carbene Complexes 1 + 2,”0ZF uu species in the reaction, as discussed below and summarized schematically in Figure 16, in which LM represents the transition metal with ancillary ligands. Support for a metal-carbene intermediate comes from kinetic data on the hetero- geneous Co-Mo catalysis of (a)CH2N2 decomposition into N, and C2H4 and (b) the dismutation of C3Hs into C2H4 and CH3CH:CHCH3;186 the rates for (a) and (6) are similar and, as discussed in Section 3A, (a) very probably involves a metal-CH, species. 18s J.J. Rooney and P.P.O’Neill, J.C.S. Chem. Comm., 1972, 104. Cardin,cetinkaya, Doyle, and Lappert 2cx,:cY, +cx,:cx, + CY,:cY, (49) It will be convenient to classify organometallic species according to the number of active M-C sites: the 4-C systems are (76),lS4 (77),lS6 and (78);lS7 the 3-C is (81);33 the 2-C is (79);s3 and the l-C is (80).33 A fou-carbon-metal species is consistent with the results of labelling experi- ments1s8~1sg as exemplified by equation (50).and product characterizati~n,~~~-~~~ However, in several systems products are formed which are not so readily explained(e.g.see refs.189 and 190). For instance, the dismutation of oct-l-ene, catalysed by WCI,-EtAICI,, affords not only the expected ethylene and Me(CH,),CH: CH(CH,),Me but also olefins having odd numbers of carbon atoms (C7-C15), especially at high catalyst con~entration.~~~ It is well knownthat transition-metal complexes often cause the isomerization of olefins, and this affords a possible rationalization of the results [e.g.equation (51)]; however, the possibility of a carbene intermediate has been considered,lgl presumably of type (80). 2CH3-CH=l4CH, +14CH#4CH2 + CH,-CH=CH-CH, (50) CH,=CH(CH&,CHs +C2H4 + CH,(CH,),CH=CH(CHJbCH, 11 CH,CH=CH(CH,),CH, +CHFCH(CH,)~CH~ (51) + CH,(CH,),CH=CHCH, A quasi-cyclobutane intermediate, (76), was first suggested for hetero- geneous but now appears unlikelylS6 because (i) cyclobutanes are not detected in dismutation experiments and (ii) dismutation catalysts do not trans- form cyclobutanes into olefins.These experiments were taken to imply that a so-called ‘tetramethylene complex’ (77) was involved.lss In (77), the four CX, or CY, fragments, formed by simultaneous scission of both 0-and rr-bonds of C2X4 and C2Y4, are co-ordinated to M by the overlap scheme of Figure 17, each carbon utilizing hybrid orbitals approximating to sp3.Thus, (77) is not a metal carbene complex, as defined in Section 2A (sp2-C being required). Further evidence for a four-carbon-metal species, and especially (77), comes from experiments on dismutation of non-4-ene by the d6 complex (n-MePh)- W(CO)3.186In order to form such a species, taking each of CX, or CY, as a two- electron donor to the metal, it is necessary that both toluene and at least one CO ligand be displaced from the metal, unless the metal is to exceed its complement of 18 valence electrons.No dismutation occurred when carbon monoxide loss was prevented, and inhibition was noted when excess of toluene was present. lB6G. S. Lewandos and R. Pettit, J. Amer. Chem. SOC.,1971, 93, 7087. le7 R. H. Grubbs and T. K. Brunck, J. Amer. Chem. Soc., 1972, 94, 2538. J. C. Mol, J. A. Moulijn, and C. Boelhouwer, Chem. Comm., 1968, 633. lag A. Clark and C. Cook,J.Catalysis, 1969,15,420; G. V. Isagulyants and L. F. Rar,Bull. Acad. Sci. U.S.S.R.,1969, 1258. lB0 F. F. Woody, M. J. Lewis, and G. B. Wills, J. Catalysis, 1969, 14, 389. K. Hummel and W. Ast, Naturwiss., 1970, 57, 245. lo*R. L. Banks and G. C. Bailey, Ind. and Eng. Chem. (Proc. Res. and Development), 1964,3, 170; C. P. C. Bradshaw, E. J. Howman, and L. Turner, J. Catalysis, 1967,7,269. The Chemistry of Transition-metal Carbene Complexes Figure 17Orbital overlap for a Vetramethylene complex' (77) The four-carbon metallocyclic species (78) was suggested for systems such as those catalysed by WC16-2BunLi (see ref. 193), as a consequence of the experi- ments on (i) ineso-l,4-dilithio [2,3-2H2]butane, illustrated in Scheme 15,1*' and (ii) the &compound which gave CH2=CHD (88 %), trans-CHD=CHD (6%), and C2H4 (6%).Scheme 15 J. Wang and H. R. Menapace, J. Org. Chem., 1968, 33, 3794. Cardin, cetinkaya, Doyle, and Lappert The metallocycles were not isolated, but as a class such compounds are known. Their interconversion requires a symmetrical transition state or intermediate, e.g. (77), although a [1,3] shift has also been considered.18s The pathways a and 01‘ (for the minor product) were suggested.lS7 However, the possibility of steps /?and p, via two-carbon fragments (79),is now proposed. This allows for alternative competing pathways, such as a and p. Additionally, it provides a plausible route to the origin of the metallocycles in Figure 16. olefin LM + olefin +n-complex (82) +(79) FA(78)-olefin The dicarbene (79) may form via a wolefin complex (82); these are, of course, well-known.As described in Section 2C(iii), electron-rich olefins yield one-carbon complexes (go), probably via (82) and a free carbene.However, it is also possible to isolate a dicarbene complex (79) [equation (52)].56It may be significant that Group VIA hexacarbonyls are considered to be active dismutation catalysts only if a mechanism exists which provides for the loss of two or more CO ligands (e.g. by irradiationlg4). Me Me.. Recently a three-carbon metallocyclic species (81) has been suggested, and definitive evidence for a one-carbon species (80) (a metal-carbene complex) has been presented in the homogeneously catalysed dismutation of the electron-rich olefins (83).ss A mixture of (83a) and (83b) at 140 “C in xylene for 2 h in the presence of a rhodium(1) complex L(Ph,P),RhCl (L = PhsP or CO) underwent a dismutation reaction to produce (83c) in yields approaching the statistical (50%).R1 R2 (83a) R’=Rz-Ph N N = CX2CX2 or CY2CY2 (83b) R’=R~=~-toi“;c=c: N] 1 (83c) R’=Ph R’ R2 = CX2CY2 R2=P’ to[ The suggested mechanism is shown in the lower part of Figure 16. The evidence rests on: (i) the isolation of the monocarbene complexes of type (80a), E.S.Davie, D.A. Whan, and C. Kernball, J. Curakjwis, 1972,24,272. The Chemistry of Transition-metal Carbene Complexes L(PhSP)Rh(CX2)CI, from the reaction of C2X4 with L(Ph3P),RhCI under dismutation conditions; (ii) the demonstration that compounds (80)also catalyse (83b)the dismutation; and (iii) the conversion (80a) -3(80b) for L = Ph,P.Addition- ally, (iv) the oxidative addition step seems plausible because other oxidative addition reactions of Rhl carbene complexes can be demon~trated,~~~ whereas (v), the carbene complex (Et,P)CI,Pt-C~(Ph)CH,],, which is known to be unreactive with regard to oxidative addition, is not a dismutation catalyst under the conditions employed. The possibility of a metal-dicarbene complex (79) in this system is not ruled out (see above). Such a compound has been isolated by reaction of an olefin of type (83) with [Rh(C0)2C1]2.66 At present, whether the dismutation of simple alkenes is related to that of electron-rich olefins remains an open question.4 Addendum Although selective in nature, this section brings the literature coverage up to the end of 1972.The existence of transient anions derived by proton abstraction from co-ordinated carbenesgg has been confirmed by generation at low temperature and affords useful The intramolecular cyclization reaction?' has been extended to cationic and neutral compounds having 2-heteroatom substitu- ents.lg7 Reactions of nucleophiles with the electrophilic Ccarb of :C(OMe)Ph bound to a Group VI metal have been studied: the secondary phosphine HPMe, co-ordinates through phosphorus to Ccarb affording a substituted ylide ~tructure,~~~but phosphonium ylides cleave the carbene and afford a route to vinyl ethers.lSD Two developments in syntheses of carbene complexes from neutral precursors are noteworthy.viz. a general synthesis, particularly of oligo- carbene derivatives using electron-rich olefhs,eoo and diphenylcarbene complexes of rhodium prepared from Ph2CN0 or Ph,C=C=O, which are among the very few co-ordinated carbenes not stabilized by a hetero-substituent on CCBrb.201For recent developments in the mechanism of metal-catalysed rearrangements of strained-ring compounds see references 202 and 203. Wethank Dr. D. Bethell for unpublished data and the S.R.C. for their support. D. J. Cardin, M. J. Doyle, and M. F. Lappert, to be published. lo* C. P. Casey, R. A. Boggs,and R. L. Anderson, J. Amer. Chem. Soc., 1972,94, 8947. M. Green, J. R. Moss,I. W. Nowell, and F. G. A.Stone, J.C.S. Chem. Comm., 1972, 1339. lo*F. R. Kreissl, C. G. Kreittr, and E. 0.Fischer, Angew. Chem. Internat. Edn., 1972,11,643. C. P. Casey and T. J. Burkhardt, J. Amer. Chem. SOC.,1972, 94, 6543. 'O0 B. Cetinkaya, P. Dixneuf, and M. F. Lappert, J.C.S. Chem. Comm., 1973, in the press. *01 P. Hong,N. Nishii, K. Sonogashira, and N. Hagihara, J.C.S. Chem. Comm., 1972,993. *O* L. A. Paquette, R. P. Henzel, and J. E. Wilson, J. Amer. Chem.Soc., 1972, 94, 7780 and references therein. *Oa P. G. Gassman and T. J. Atkins, J. Amer, Chem. Soc., 1972, 94, 7.

ISSN:0306-0012    

DOI:10.1039/CS9730200099

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

INDEXES Volume 2, 1973 The indexes in this issue cover Volumes 1 and 2 Index INDEX OF AUTHORS Ahluwalia, J. C., 2, 203 Baker, A. D., 1, 355 Bentley, P. H., 2,29 Braterman, P. S., 2, 271 Breslow, R., 1, 553 Brundle, C. R., 1, 355 Carabine, M. D., 1, 411 Cardin, D. J., 2, 99 Carless, H. A. J., 1, 465 Cetinkaya, B., 2,99 Chatt, J., 1, 121 Chivers, T., 2, 233 Corfield, G. C., 1,523 Cornforth, J. W., 2, 1 Coulson, E. H., 1,495 Coyle, J. D., 1,465 Cross, R. J., 2, 271 Doyle, M. J., 2, 99 Drummond, I., 2, 233 Evans, D. A,, 2, 75 Fry,A., 1, 163 Green, C. L., 2,75 Griffiths, J., 1,481 Grossert, J. S., 1,1 Groves, J. K., 1, 73 Guilford, H., 2, 249 Gutteridge, N. J. A., 1, 381 Hall, G.G., 2, 21 Harmony, M. D., 1,211Hartley, F. R., 2, 163 Henderson, J. W., 2,397 Jamieson, A. M., 2, 325 Jotham, R. W., 2,457 Kennedy, J. F., 2, 355 Kresge, A. J., 2,475 Lappert, M. F., 2, 99 Leigh, G. J., 1, 121 Linford, R. G., 1,445 Lipscomb, W. N., 1,319 Maitland, G. C., 2, 181 Maret, A. R., 2, 325 Mason, R., 1, 431 Mayo, B. C., 2,49 Menger, F. M., 1,229 Moore, H. W., 2, 415 Mulheirn, L. J., 1, 259 North, A. M., 1,49 Page, M. I., 2, 295 Ramm, P. J., 1,259 Rattee, I. D., 1, 145 Sarma, T. S., 2,203 Smith, E. B., 2, 181 Stacey, M., 2, 145 Sutherland, R. G., 1,241 Thomas, T. W., 1, 99 Thompson, M., 1, 355 Tolman, C. A., 1, 337 Underhill, A. E., 1, 99 Waltz, W. L., 1, 241 Whitfield, R. C., 1,27 Index INDEX OF TITLES Acylation, Friedel-Crafts, of alkenes, 1, 73 Alkenes, the Friedel-Crafts acylation of, 1, 73 Atmosphere, interactions in, of drop- lets and gases, 1,411 Azidoquinones and related com-pounds, chemistry of, 2,415 Azobenzene and its derivatives, photo- chemistry of, 1,481 Biomimetic chemistry, 1,553 Biosythesis of sterols, 1,259 Brsnsted relation -recent develop- ments, 2,475 Carbohydrate-protein complexes, gly- coproteins, and proteoglycans,of human tissues, chemical aspects of, 2,355 Carbonium ions, carbanions, and radicals, chirality in, 2,397 Carbonyl compounds, photochem- istry of, 1,465 Catalysis, homogeneous, and organo- metallic chemistry, the 16 and 18 electron rule in, 1,337 CENTENARYLECTURE.Biomimetic chemistry, 1,553 CENTENARYLECI-URE.Three-dimen-sional structures and chemical mechanisms of enzymes, 1,319 Chemical aspects of aEinity chroma-tography, 2,249 Chemicals in rodent control, 1, 381 Chemistry-a topological subject,2,457 -of azidoquinones and related compounds, 2,415 -of dyeing, 1, 145 -of homonuclear sulphur species, 2,233 -of transition-metal carbene com- plexes and their role as reaction intermediates, 2,99 Chirality in carbonium ions, car-banions, and radicals, 2,397 Chromatography, affinity, aspects of, 2,249 Cis-and trameffects of ligands, 2, 163 Conformational studies on small mole-CUleS, 1,293 Cyclopolymerization, 1, 523 Dielectric relaxation in polymer solu- tions, 1, 49 Droplets and gases, interactions in the atmosphere of, 1,411 Dyeing, chemistry of, 1, 145 Echinoderms, 1, 1Education, chemical, a reassessment of research in, 1, 27 Electron spectroscopy, 1,355Elimination reactions, isotope effect studies of, 1, 163 Energetics of neighbouring group participation, 2,295Enzymes, the logic of working with, 2, 1 -, three-dimensional structures and chemical mechanisms of, 1, 319 Experimental studies on the structure of aqueous solutions of hydro-phobic solutes, 2,203 Fixation, of nitrogen, 1,121Forces between simple molecules, 2, 181 Friedel-Crafts acylation of alkenes, 1, 73 Gases, and droplets, interactions in the atmosphere of, 1,411Glycoproteins, proteoglycans, and car- bohydrate-protein complexes of hu-man tissues, chemical aspects of, 2,355Growth of computational quantum chemistry from 1950 to 1971, 2, 21 HAWORTHMEMORIAL TheLECTURE.consequences of some projects ini- tiated by Sir Norman Haworth, 2,145 Homogenous catalysis, and organo- metallic chemistry, the 16 and 18 electron rule in, 1,337Hydrophobic solutes, experimentalstudies on the structure of aqueous solutions of, 2,203 Insect attractants of natural origin, 2, 75 507 Interactions, in the atmosphere of droplets and gases, 1,411 -, met al-met a1 , in transit ion-met a1 complexes containing infinite chains of metal atoms, 1, 99 Isotope effect studies of elimination reactions, 1,163 Lanthanide shift reagents in nuclear-magnetic resonance spectroscopy,2, 49 Laser light scattering, quasielastic, 2, 325 Ligands, cis-and trans-effects, 2, 163 Mechanisms, chemical, and three-dimensional structures of enzymes, I, 319 MELDOLA ChemicalMEDALLECTURE. aspects of glycoproteins, proteo- glycans, and carbohydrate-protein complexes of human tissues, 2, 355 Metal-metal interactions in trans-ition-metal complexes containing infinite chains of metal atoms, 1, 99 Natural products from echinoderms, 191 Neighbouring group participation, en- ergetics of, 2,295 Nitrogen fixation, 1,121NucIear magnetic resonance spectro- scopy, lanthanide shift reagents in, -2,49 Organometallic chemistry and homo- geneous catalysis, the 16 and 18elec-tron rule in, 1,337drgano-transition-metal complexes: stability, reactivity, and orbital correlations, 2,271 Phase boundaries, reactivity of organic molecules at, 1,229Photochemistry, of azobenzene and its derivatives, 1,481 -, of carbonyl compounds, 1,465 -, of transition-metal co-ordina- tion compounds-a survey, 1,241Polymer solutions, dielectric relaxation in, 1,49Prostanoids, total syntheses of, 2, 29 Quantum chemistry, computational, growth of from 1950 to 1971, 2,21 Index Quantum mechanical tunnelling in chemstry, 1,211Quasielastic laser light scattering,2,325 Reactivity of organic molecules at phase boundaries, 1,229Research in chemical education: a re- assessment, 1, 27 ROBERTROBINSON The logic LECTURE.of working with enzymes, 2, 1 Rodent control, chemicals in, 1, 381 16 and 18 Electron rule in organo- metallic chemistry and homogen- eous catalysis, 1,337Small molecules, conformation studies 09, 1,293Solids, surface energy of, 1,445Some recent developments in chemis- try teaching in schools, 1,495 Spectroscopy, electron, 1,355Stability, reactivity, and orbital cor- relations of organo-transition-metalcomplexes, 2,271 Sterols, biosynthesis of, I, 259 Structure of aqueous solutions of hyd-rophobic solutes, experimentalstudies on, 2,203Sulphur species, homonuclear, chem- istry of, 2,233Surface energy of solids, 1, 445 Sytheses, total, of prostanoids, 2, 29 Teaching, of chemistry in schools,some recent developments in, 1,495Three-dimensional structures and chemical mechanisms of enzymes,1,319TILDEN LECTURE. Valence ir, trans- it ion-me t a1 complexes, 1,431Topological subject-chdstry, 2,457Transition-metal, carbene complexes, chemistry and role as reaction inter- mediates, 2, 99 -complexes, containing infinite chains of metal atoms, metal-metal interact ions in, 1,99-complexes, valence in, 1,431 -co-ordination compounds,photochemistry of, 1,241 Valence in transition-metal complexes, 1, 431

ISSN:0306-0012    

DOI:10.1039/CS9730200505

出版商:RSC    

年代:1973

数据来源: RSC