ISSN:0306-0012    

DOI:10.1039/CS98413FX001

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

Chemical Society Reviews Vol 13 No 1 1984 Page CENTENARY LECTURE Organic Reaction Paths: A Theoretical Approach By M. Simonetta HAWORTH MEMORIAL LECTURE Synthesis of Complex Oligosaccharide Chains of Glycoproteins By H. Paulsen 15 New Insights into Aliphatic Nucleophilic Substitution Reactions from the use of Pyridines as Leaving Groups By Alan R. Katritzky and Giuseppe Musumarra 37 Light-induced Tautomerism of P-Dicarbonyl Compounds By Peter Markov 69 Reactive Intermediates in Enzyme-catalysed Reactions By Colin T. Suckling 97 The Royal Society of ChemistryLondon

ISSN:0306-0012    

DOI:10.1039/CS98413BX003

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

HAWORTH MEMORIAL LECTURE* Synthesis of Complex Oligosaccharide Chains of Glycoproteins By H. Paulsen INSTITUTFUR ORGANISCHECHEMIE UND BIOCHEMIE, UNIVERSITAT HAMBURG, D-2000 HAMBURG 13, WEST GERMANY 1 Introduction The selective chemical synthesis of complex oligosaccharides has made remarkable progress over the past five years.’ Biologically interesting oligosaccharides with different building blocks and different types of linkage at the anomeric centres can now be systematically synthesized. Improved methods of reaction selectivity, new catalyst systems, and new separation and analytical techniques have made this possible. In particular, high-field n.m.r. spectroscopy in conjunction with two- dimensional n.m.r. spectroscopy permits excellent monitoring of reaction sequences and a complete analysis of n.m.r.spectra of complex oligosaccharides, in deblocked form also, is now possible. The synthesis of specific oligosaccharide segments is of most interest in the glycoconjugates class, especially glycoproteins* and glycolipid~.~ In glycoproteins and glycolipids, the oligosaccharide section is frequently the determinant that defines the biological function of the substance, and there can be interaction between these carbohydrate structures and other protein^.^ Examples of such interaction include antigen-antibody reactions or other receptor reactions, as well as interactions that are involved in cell communication, where the molecular structure of the carbohydrate sequence is of great significance as it determines the selectivity of the reaction with the protein or agglutinin. With synthesized carbohydrate determinants or haptens and modified structures derived from them, information about the type of bonding between the carbohydrate residue and the protein can be obtained.Available data indicate that in this interaction predominantly hydrophobic attractive forces play a greater part than do hydrogen bondss By linking a synthesized carbohydrate chain to a solid * Delivered at the Spring Meeting of The Royal Society of Chemistry Carbohydrate Group on 28th March 1983 at Heriot-Watt University, Edinburgh H. Paulsen, Angew. Chem., 1982, 94, 184; Angew. Chem., Int. Ed. Engl., 1982, 21, 155. J. Montreuil, Adv. Carbohydr. Chem. Biochem., 1980, 37, 157.C. C. Sweeley and B. Siddiqui, in ‘The Glycoconjugates’, ed. M. 1. Horowitz and W. Pigman, Academic Press, New York, 1977, Vol. 1, p. 459. ‘Carbohydrate-Protein Interaction’, ed. 1. J. Goldstein, ACS Symposium Series no. 88, Washington, D.C., 1979. R. U. Lemieux, in ‘IUPAC Frontiers owhemistry’, ed. K. J. Laidler, Pergamon Press, Oxford and New York, 1982, p. 3; 0. Hinsgaul, T. Norberg, J. Le Pendu, and R. U. Lemieux, Curbohydr. Res., 1982, 109. 109. Synthesis of Complex Oligosaccharide Chains of Glycoproteins substrate, an absorber can be obtained on which the protein involved in the interaction can be selectively absorbed, purified, and isolated. This process can be used to obtain agglutinins and enzymes; in addition, the selectivity of lectins can be investigated.If the synthesized carbohydrate determinants are coupled to protein substrates, the resulting synthetic antigens make immunostimulation possible, or even the development of monoclonal antibodies. There are thus numerous areas of use, of great biological interest, for selectively synthesized complex oligosaccharides. In this article are described the basic methods for the selective synthesis of oligosaccharides that are found in carbohydrate segments, in 0-glycoproteins as well as in N-glycoproteins. 2 Methods of Glycosidic Linkage to Oligosaccharides For selective glycosidic linkage in an oligosaccharide synthesis, three fundamental procedures, depending on the desired anomeric linkage, have proved to be particularly suitable: (i) the neighbouring-group-assisted procedure (Scheme l), by which p-glycosidic linkages in the D-ghC0 and D-galacto series and a-glycosidic linkages in the D-manno series can be synthesized; (ii) the in situ anomerization procedure (Scheme 2), which permits an a-glycosidic linkage in the D-gluco and D-galact0 series; and (iii) the heterogeneous catalyst procedure (Scheme 3), by which p-glycosidic linkages in the D-manno series can be synthesized.Overall, the glycosyl halides have proved to be the most successful starting materials for all types of reaction. In the neighbouring-group-assistedprocedure (Scheme l), it is, as a rule, the more stable a-D-halide with a neighbouring-group-active substituent at C-2, e.g.an 0-acetyl group, that is substituted. There then results, via a carboxonium ion, a stabilized cyclic acyloxonium intermediate that can be opened at the anomeric centre by a nucleophile only in a direction trans to the substituent at C-2 (1,2-trans type). As can be seen in Scheme 1, in the D-gluco series this opening results in the p-D-glucopyranoside; analogously, in the D-galacto series the reaction results in the fl-D-galactopyranoside. Since, however, in the D-manno series the substituent at C-2 has an inverted configuration, the result is also an inverted cyclic acyloxonium intermediate. The corresponding trans opening (1 ,2-trans type) results in this case, as can be seen in Scheme 1, in the a-D-mannopyranoside, also inverted.The catalysts that are generally used are listed in Scheme 1; as the intermediate is polar, the solvent should be polar or have medium polarity. It should be mentioned that even in modified form the neighbouring-group- assisted procedure gives very good results if a B-~-l-O-acetate group is substituted instead of the halide, whereby the 1-0-acetate group with neighbouring-group support functions as a leaving group.6 The analogous cyclic acyloxonium intermediates thus formed react correspondingly. In this case Lewis acids are used as catalysts. Trimethylsilyl triflate has proved to be particularly effective. This 'H. Paulsen, M. Paal, and M. Schultz, Tetrahedron Lett., 1983, 24, 1759. 16 Paulsen P-D-glucO 1,2 -trans -TypeACOQr Z!?L AcO + R70"$0: -AcO0OAcOAc 4 d-D-gluCO CH3 p-0-gluco d -0-ma nno 1,2 -t rans -FJBr___c Atop) + RPH -OAc AcO -Br-OAc 0 OAc AcO Ad AcO d-D-manno a!-0 -ma nno Catalyst : Hg(CN)? ,HgClz .AgCIO4 . Ag triflate Neiahbourina Group Assisted Procedure Scheme 1 method, however, requires an especially stable system of protecting groups, especially with acyl residues, as otherwise side-reactions and degredation take place. In the in situ anomerization procedure a neighbouring-group non-active substituent must be present at C-2. Use is made here of the possibility of producing an equilibrium, via suitable catalysts, between the a-halide and the P-halide that establishes itself quickly across ion pairs (see Scheme 2).' As the P-D-halide (top right) is destabilized by the anomeric effect, there is great excess of a-D-halide (top left) in the thermodynamically controlled equilibrium.If the kinetics of the glycosidation reaction are considered, however, it is found that the reaction of the unstable B-D-halide to give the a-D-glycoside (right path in Scheme 2) is fast in comparison to the conversion of the more stable a-D-halide into the P-D-glycoside (left path in Scheme 2). Under certain reaction conditions this difference in reaction rate can be used such that the reaction proceeds almost exclusively along the fast path from the P-D-halide to the desired a-~-glycoside.~~* This also happens if there is a low concentration of the required P-D-halide, but provision is made for it to be re-formed quickly by an effective catalyst across the prescribed equilibrium.In this way selective a-D-glycoside synthesis (1,2-cis type) is possible in the D-gluco and D-galucto series. Aside from trialkylammonium halides, the most suitable catalysts for starting from a-~-halides in the in situ anomerization procedure are mercury salts and silver perchlorate and silver triflate. In this connection modified compounds, too, could ' R. U. Lemieux, K. B. Hendriks, R. V. Stick, and K. James, J. Am. Chem. Soc., 1975, 97,4056.* H. Paulsen and (5. Kolai, Chem. Bet-., 1981, 114, 306. Synthesis of Complex Oligosaccharide Chains of Glycoproteins axOR 4%J-O-gluCo x p-0-qluco x-// tl OR OR ll OR d-0-gluc0 1,2 & TY P.'0-R' R J OR OR =OR' OR in situ Anomrrisation Procedure P-0-gluco (Without Neighbouring Group Participation) d-0-gluco OR' Scheme 2 react as intermediates in place of pyranosyl halides, e.g. pyranosyl perchlorates or pyranosyl triflates. For those intermediates, however, ail the corresponding stabilities and rates of reaction would be valid so that Scheme 2 is likewise applicable. The scheme was therefore drawn up in a general form. Completely corresponding selectivities regarding the formation of a-D-glycosides are observed with these very much more effective catalysts. Difficulties in selectivity can occur in very reactive hydroxy-groups as the difference between the rate of formation of the cr-D-glycosides and of the P-D-glycoside becomes smaller.9* lo The best selectivities are achieved with hydroxy-groups of medium rea~tivity.~ The in situ anomerization procedure would also yield the a-D-mannopyranoside in the D-mannO series completely analogously to Scheme 2, as the P-D-mannopyranosyl halide is likewise destabilized by the anomeric effect (Scheme 3).In the D-manno series the neighbouring-group-assisted procedure and the in situ anomerization procedure thus likewise yield the a-D-mannopyranoside and not the P-D-mannopyranoside. In order to achieve this, neighbouring-group reaction and any catalyst of the in situ anomerization procedure must therefore be strictly avoided. Only a heterogeneous, insoluble catalyst, which must be applied in the heterogeneous phase under neutral conditions, should be used.Besides other silver catalysts, the very reactive silver silicate catalyst is particularly suitab1e.I l* * With this catalyst an r-D-mannopyranosyl halide reacts by inversion to the fl-D-mannopyranoside (Scheme 3, 1,2-cis type). A very reactive halide and a 'H.Paulsen and 0. Lockhoff, Chrm. Ber., 1981, 114, 3079. lo H. Paulsen and J.-P. Holck, Carhohydr. Res., 1982, 109. 89. H.Paulsen and 0. Lockhoff, Chem. Ber., 1981, 114, 3102. H.Paulsen, W. Kutschker, and 0.Lockhoff, Chem. Ber., 1981, 114, 3233. Paulsen in situ Anomerisation + ROH -d-D-manno -D-manno Silver silicate + d-0-manno p-D-manno Hotorogonic Catalyst Procoduro (Wilhout Noighbouring Group Participation) Scheme 3 hydroxy-group of good to medium reactivity are necessary for this heterogeneous catalyst procedure; otherwise selectivity decreases.' All three linkage methods are used in the synthesis of the oligosaccharide chains of glycoproteins. For every glycosidic linkage reaction, however, the three parameters given in the Table must be carefully assessed and balanced,' namely the reactivity of the halide, that of the catalyst, and that of the hydroxy- component. The reactivity of the pyranosyl halide varies within wide limits with variation of the blocking-group. Ether-substituted compounds are always more reactive than acyl-substituted compounds, The scale of reactivity of the catalysts is also extraordinarily wide. None of the catalysts given in the Table should, of course, be used in the heterogeneous-catalyst procedure. The reactivity of the hydroxy-group is unfortunately the most difficult to assess, even though this very group is often of considerable importance for the course of the reaction.In the linkage step it is always the reactions of polyfunctional compounds that are involved, for which reactivities depend very much on the kind of blocking system. The result of this is that for each glycosidic linkage step optimum conditions should be chosen carefully from the parameters given in the Table in order to find the best compromise between high selectivity and' satisfactory yield. 3 0-Glycoproteins The basic structure of the carbohydrate part of the 0-glycoproteins is shown in Figure 1.It can be seen that the N-acetylgalactosamine is linked a-glycosidically to the hydroxy-group of serine or threonine in the peptide chain. As a further saccharide unit, a galactose unit is linked j?(1 +3)-glycosidically to it. In addition, one or two neuraminic acid residues are linked to this disaccharide unit. This fundamental structure is found in most 0-glycoproteins. 19 Synthesis of Complex Oligosaccharide Chains of Glycoproteins Table Reactivity parameters determining selectivity and yield in oligosaccharide syntheses Halogen Catalyst Alcohol R -Bzl> BZ 5AC X -I > Br> CI 6-OH > >3-OH > 2-OH >4-OH Glycophorin, the main glycoprotein of the erythrocytes, is an interesting compound.It contains a chain of 131 amino-acids of which the hydrophobic part, amino-acids 71-90, is anchored in the membrane. The part of the peptide chain, amino-acids 1-70, that extends into the exocellular space contains 16 0-glycoprotein side-chains and one N-gfycoprotein side-chain. There are two Figure I Fundamental structure of the oligosaccharide chain of 0-glycoproteins different types, whose terminal amino-acids 1-5 are shown in Figure 2. The structure with L-Leu as end group has N-antigen character and the structure with L-Ser as end group has M-antigen character.13 If glycophorin is treated with neuraminidase, the neuraminic acid residues are cleaved off. T-Antigenicity is ascribed to the disaccharide fundamental structure thus exposed.The synthesis of these kinds of sequences and segments is of great interest. The production of the wglycosidic linkage of D-galactosamine to L-serine would indicate the use of the in situ anomerization procedure. The two azido-sugars shown in Figure 3 are suitable as neighbouring-group non-active halides.'O This reaction demonstrates very well the complications of the process that arise when a very reactive hydroxy-component is present, as in the primary hydroxy-group of L-serine. In Figure 3 it can be seen that in the reaction of the a-D-halide with a serine derivative the in situ anomerization procedure yields a highly unsatisfactory selectivity of a:p-product, of only 2: 1. For better selectivity it would be necessary to reduce the reactivity of the halide, which in this case, however, is not possible l3 M.Tomita, H. Furthmayer, and V. T. Marchesi, Biochemistry, 1978, 17, 4756. Paulsen L-Leu L-Sor 0 t P I p-0-Ghl(l~3)-d-D-G~lNAc(140)-L-Sor p0-Gal(l--3) -d-0-Gal NAc (1 -0)-L -Sor f P I 'F 0 p-0-Gal(1-3)-d-0-GalNAc(1-0)-L-Thr p-0-Gal(1-3)-d-O-GhlNAc(l--O)-L-Thr 7 P I 7 P 1 p-D-Gal(l--3)-d-D-GalNAc(1-0)-L-Thr p-D-Gal(1-3) -d-D-Gal NAc( 1 -c 0)-L-Thr I L-Glu I Peptidr Peptide chain chain N -Antigen M-Antigen Figure 2 End groups of glycophorin of the N-antigen and M-antigen types [! = or-~-NeuSAc(2-+3)-, p = a-~-Neu5Ac(2-.6)-] since all the hydroxy-groups are already occupied with acyl groups that lower reactivity. The 4-D-chloride, which is directly isolatable in this case, can be substituted for bromide in the reaction.Figure 3 shows that the selectivity of the reaction with 4-D-chloride is indeed better but not yet completely satisfactory, with an a:b-product ratio of 7:2 to 9:2.14 The reason for this is that during the reaction chloride partially anomerizes to a-D-chloride, which by inversion then yields ,the undesired 4-D-glycoside. By the addition of toluene to the non-polar solvent dichloromethane, which is generally used, it is possible to suppress anomerization. O Despite the consequent lowering of the reaction rate, the selectivity of a$-product (19:1) is now very good (Figure 3). O Using the process it is now possible to synthesize an equivalent 0-glycopeptide (Scheme 4). The reaction of D-D-halide (I) with the serine derivative (2) results in the a-glycosidically linked product (3), which can be converted via compound (4) into the corresponding derivative (5).O In a neighbouring-group-assisted procedure a-D-halide (6) of D-galactose can now be linked to the 3-OH group of compounds (5) to form the P-D-glycosidically linked disaccharide (7). By deblocking, the fundamental structure (8), the so-called T-determinant, attached to serine can be obtained from compound (7).1° A completely analogous reaction sequence can be carried out with threonine.1° For the synthesis of larger oligosaccharides, block syntheses in which di- or tri-saccharide halides are applied have in general proved to be very successful.1s In this way larger saccharide units are obtained more quickly, and with a reduction l4 B.Ferrari and A. A. Pavia, Carbohydr. Res., 1980, 79, CI. lJH. Paulsen and A. Bunsch, Carbohydr. Res., 1982, 100, 143. 21 Synthesis of Complex Oligosaccharide Chains of Glycoproteins Product CataI ys t Solvent Temp d :p Ac 0 N3 -19:l AgCIOb/Ag~COj CHzCl2 I -7 O Toluene 1:l Figure 3 Reaction 0s3,4,6-tri-O-acetyl-2-azido-2-desox-y-~-galactopyranos~lhalides with N-benzyloxycarbonyl-L-serinebenzylester in various conditions in the number of necessary separation processes. A synthesis block of /?-D-Gal(1 -+3)-~-GalNAcwould therefore be very desirable. This synthesis block could then be used for direct linking to hydroxyamino-acids and could possibly be linked to larger peptides as well.In the linking step the stereoselectivity of the reaction with the reactive hydroxy-group of serine or threonine would again be very important. It became obvious that the production of the desired block could be brought about by reaction of the halide (6) with the easily obtainable derivative (9) (Scheme 5). Unfortunately, however, the expected disaccharide (10) is obtained in low yield only, and with bad selectivity. Surprisingly, the 3-OH group is extraordinarily unreactive in compound (9).6 A solution to this important problem was found in a completely new synthesis route (Scheme 6).6To begin with, the azidonitrate (1 I), which can be obtained easily by azidonitration of D-galactal,' is converted with sodium methoxide directly into 8-D-methylglycoside (I 2).Selective benzoylation can be carried out with compound (12), resulting in product (13), in which only the 3-OH group has not been substituted. In compound (I 3) there are now only acyl protecting groups so that glycosidation of (13) with the penta-acetate (14) in the presence of trimethylsilyl triflate via the modified neighbouring-group-assisted procedure is successful.6 In this way the desired disaccharide (1 5) can be obtained in 85%yield. The methylglycoside (1 5) can be relatively easily acetolysed to the a-acetate (16), from which by reaction with titanium tetrabromide in anhydrous conditions' the newly functionalized synthesis block can be obtained as the a-bromide (17).6 Excellent results were obtained for this new synthesis block (17) with the serine derivative (2) or the corresponding threonine derivative.6 From the reaction '' R.U. Lemieux and R.M.Ratcliffe, Can.J. Chem., 1979, 57, 1244. 22 Paulsen RO /NHZHo-CH-CH 'CO~etl L-Scr(L-Thr NCH-CH121 'C0282l(3) R =Ac (L) R =HI Ph ACO HO Ad ,NHZ@+ Ox&-CHBr (6) (5) 'COzBd $0 It AcOAcoaom P-D-Gal(l+3)-d-D-GdNAc(l-O)-L-Srr (L-Thr) (6) Scheme 4 Scheme 5 Synthesis of Complex Oligosaccharide Chains of Glycoproteins AcO A c0 OM. AcO AcO 0Ac (17t Scheme 6 (Scheme 7) between compounds (17) and (2) in the presence of silver perchlorate/silver carbonate, the desired glycojxptide (18) is obtained directly from the a-D-bromide via the in situ anomerization procedure in over 80% yield.The formation of a fl-glycosidic product is not observed in this case. The glycopeptide (8) can be obtained by deblocking. With the corresponding threonine derivative the reaction proceeds in exactly the same way, with corresponding selectivity. It is remarkable that the glycoside synthesis from the a-D-bromide (1 7) proceeds completely stereoselectively even though the reactive hydroxy-group of serine is again available. The reason for this is that the reactivity of the disaccharide block Paulsen H AcO 020 I ,NHZ 1 A)*'HO-CH-CH H P-D-Gal(1-3)-d-D-GalNAc(l-O)-L-Sor (L-Thr) Scheme 7 (17) is considerably lower than that of the monosaccharide halides in Figure 3.In this way it becomes feasible to use the in situ anomerization procedure since the difference in reaction rate leading to the a- and fi-glycosidically linked product is again large enough to achieve good selectivity in favour of the a-glycosidic product. The lower reactivity of the disaccharide halide (17) which is tuned exactly to the reaction, can be attributed on the .one hand to the additionally linked galactose residue but on the other hand also to the presence of two benzoyl groups. In compound (17), therefore, an excellent synthesis block is available from which high selectivities in the reaction with hydroxyamino-acids can be expected. To check the reaction with peptides, the derivative of L-Leu-L-Ser (19) was allowed to react with the synthesis block (17) (Scheme 8).6 The coupling reaction proceeds similarly with high selectivity and produces exclusively the a-glycosidic glycopeptide (20) in 70% yield.Deblocking (20) results in compound (21), which contains the terminal structural element of glycophorin of the N-antigen type (Figure 2). It is of the greatest interest to test whether the synthesis block also reacts with several hydroxy-groups of corresponding serine- or threonine-containing peptide chains. In fact it has been possible to allow the derivative of L-Ser-L-Ser (22) to react with 2 moles of the synthesis block (17) in a stereoselectively simultaneous reaction (Scheme 9) to form the glycopeptide (23) with two carbohydrate chains6 In this case, too, as proved by careful two-dimensional n.m.r.spectroscopy, the reaction proceeds completely stereoselectively. Components of /?-products are not detectable. This demonstrates impressively the efficiency and the high selectivity of Synthesis of Complex Oligosaccharide Chains of Glycoproteins L Q, m I 0 -3 3-I J Paulsen I 9 / I 0 I I 0 I I I I 0I + 0 0 c1c I 27 Synthesis of Complex Oligosaccharide Chains of Glycoproteins I I I I I I I I I I I I t I I I I I 1 I I I I I I I , I I 1 1 tI Y z r-03 t Y V 4 z -0 (3I c3I h* 1 Y C -7I I I 0 I II 1I I I I I I I I % .h d Paulsen the synthesis block (17) and it is evident that it can react correspondingly with any serine- or threonine-containing peptide chains.The reaction with longer peptide chains would cause some difficulties concerning their solubility in dichloromethane, which is the solvent of glycoside syntheses. In this case, a step- by-step synthesis of 0-glycopeptides with mixed substituted amino-acid derivatives, following the methods of the peptide synthesis, is possible to obtain higher 0-glycopeptides which are part of the glycophorin. 4 N-Glycoproteins Figure 4 shows the fundamental structure of the oligosaccharide chain as it generally occurs in N-glycoproteins of the lactosamine type.The chain is linked 8-N-glycosidically to the amide group of asparagine, which itself is part of the total peptide chain. The first unit on asparagine is a chitobiose unit, to which the particularly interesting branched middle section consisting of three mannose units is attached. In the lactosamine type, lactosamine antennae, which contain neuraminic acid end-groups, are linked to both mannose residues. In the so-called mannose type of N-glycopiotein, the same core structure of chitobiose and branched mannose trisaccharide exists. In this case, though, further mannose groups of different chain lengths are linked to the mannose units. There are numerous variants in which the basic framework is the same but additional branches are present.* The main problem of the synthesis of such an oligosaccharide sequence lies in the production of the P-D-mannosidic linkage in the partial sequence fi-D-Man(1 -+4)-~-GlcNAc(residues 3 and 2 in Figure 4).Until now it has not been possible to prepare this unit by direct linkage, but only indirectly by first of all preparing (J-D-G~c( 1 -+4)-~-GlcNAc and then subsequently converting the glucose unit in several steps into a mannose unit.” For direct preparation of this key disaccharide the heterogeneous-catalyst procedure should be suitable (Scheme 3) in which, in particular, the reactive silver silicate catalyst could be tested. The reaction (Scheme 10) in the presence of silver silicate catalyst, however, of the reactive mannose halide (25) with the easily available glucosamine derivative (26) (containing a free 4-OH group) slowly yields a strong preference for the undesired a-D-glycoside (27).18 It is known that the 4-OH group in derivative (26) is particularly unreactive and therefore should be responsible for the slow reaction.The reaction clearly proceeds to some extent via in situ anomerization or via the direct formation of a carboxonium ion, both of which should preferentially result in the a-D-glycoside (27). It was thus necessary to increase the reactivity of the 4-OH group. This is possible since the inverse conformation, as in the 1,6-anhydro-c0mpound (29), can be made to react (Scheme 1 1). The now free axial 4-OH group has higher reactivity, and in this case the heterogeneous-catalyst procedure in the presence of a silver silicate catalyst does in fact result in satisfactory selectivity, as a p:a-C.Auge, C. D. Warren, R.W. Jeanloz, M. Kiso, and L. Anderson, Carbohydr. Res., 1980, 82, 85. H. Paulsen, R. Lebuhn, and 0.Lockhoff, Carbohydr. Res., 1982, 103, C7. 29 Synthesis of Complex Oligosaccharide Chains of Glycoproteins + (251 (26) A c H P BzlO (27) Scheme 10 product ratio of 7:1 is found, and the desired 8-glycosidic product (30) can be isolated in 65% yield.18*19 The crucial key disaccharide, which was most suitable for all further synthesis reactions, was thus synthesized. If the key disaccharide (30) is deacetylated to compound (33), coupling with the mannose halide (35) can be achieved at the liberated 6-OH group in a neighbouring-group-assisted procedure (Scheme 12).The trisaccharide (31) is then obtained by the production of a new a-glycosidic link to mannose. Hence the free trisaccharide (32), which contains the additional mannose residue in an a( 1-+6)-glycosidic link, can be obtained via a series of de-blocking steps.18*19 If the basic disaccharide (30) is deallylated, primarily to compound (34), which is deblocked at the 3-OH group, a corresponding coupling with the mannose derivative (35) to the trisaccharide (36) is possible. The corresponding deblocking then yields the trisaccharide (37), in which an additional mannose residue is linked a( 1-3)-glycosidically to the disaccharide. * *a1 If in the disaccharide (30) both the 6-OH and the 3-OH groups are free, compound (38) is obtained.In a neighbouring-group-assisted procedure there are now two residues of the mannose halide (35) to be linked to compound (38) in a simultaneous reaction (Scheme 13), and the branched tetrasaccharide (39) can be obtained in one step. In a sequence of deblocking steps the desired tetrasaccharide (40),i.e. the central branching structure of the core sequence, can be obtained.' **19 These examples show that, in principle, all sequence fragments can be synthesized. As the following sequence in the oligosaccharide chain of the lactosamine type of N-glycoprotein, in each case a lactosamine unit is linked to the two terminal mannose groups, as shown in Figure 4. It would be very useful if here, too, a block synthesis could be carried out in order to link the lactosamine in one step.From lactosamine an excellent, reactive synthesis block (42) is available.20 This halide contains a 2-phthalimido-grouping. In a neighbouring-group-assisted reaction this bulky grouping ensures stereoselective glycosidation to a fi-D-glycoside. A P-glycosidic linkage with lactosamine with the 2-OH group of the terminal mannose unit is desired. In a trial reaction (Scheme 14), therefore, the trisaccharide (41), which has a free 2-OH group and is easily produced by deacetylation of lo H. Paulsen and R. Lebuhn, Liehigs Ann. Chem., 1983, 1047. 2o J. Arnap and J. Lonngren, J. Chem. Soc., Perkin Trans. I. 1981, 2070. Paulsen N m b e w h) 1) PdC12IAc OH IH20 2) CFJ COtH I Ac20 d dMan(l-,G)P Man(l44)GlcNAc3) Pd IH2 4)Ac2O (32) 0JQo 5) NaOCH3 CI [ 35) Silver triflato Scheme 12 Paulsen 2x Bz10f4BZlO (38I (351 c'/Ag triflate 2.) PdlHZ 4) NaOCHj a-0-Manll-6) p -D-Man[l-L)-D-GlcNAca-0-Manll-3)' (401 Scheme 13 compound (31), was allowed to react with the synthesis block (42) in the presence of silver triflate/collidine. In this way, the desired pentasaccharide (43) is obtained, which contains all the required a-and /?-glycosidic linkages.In a series of deblocking reactions the free pentasaccharide (44) can be prepared from compound (43). An obvious substitution is that of the branched tetrasaccharide (45), which has two free 2-OH groups on the mannose residues and can be easily produced by deacetylation of compound (39), for the reaction with the lactosamine synthesis block (42) (Scheme 15).In fact two moles of (42) can be linked simultaneously to the 2-OH group of (45) under the same conditions in one reaction step, and the desired octasaccharide (46) synthesis is achieved in 70% yield.21*22It should be noted that in this case it is not the condensation step that presents the real difficulty. The series of difficult deblocking steps must be undertaken with great care in order not to threaten the newly formed glycosidic links. The cleavage of phthalimido- groups takes place in methanol with hydrazine under very mild conditions.In the 21 H. Paulsen and R. Lebuhn, Angew. Chem., 1982, 94, 933; Angenl. Chem., lnt. Ed. Engl., 1982, 21,926. 22 H. Paulsen and R. Lebuhn, Carbohydr. Res., 1984, 125, in press. 33 Synthesis of Complex Oligosaccharide Chains of Glycoproteins L m U a Z G U C 0 T c I h CD t + - 0 - U t mU- c v-0 0 Ic N m m 34 1) NaOCH3 PhthN 2) NYNHzAcO OAc 3) Ac2O/Pyr 4)CF3 CO$i/Ac20 5) PdlH2 6) Ac2O/Pyf Ac 0 7)K2COjICHjOH PhthN J P-Gal (l--&)-P- GlcNAc(l--2)-d-Man(l-r6), ,P-Man(1 --t)-GlcNAc p-Gal(1 d4I-p-GlcNAc(l+Z)-d-Man(1-+3) (471 Scheme 15w m Synthesis of Complex Oligosaccharide Chains of Glycoproteins opening of the l&anhydro-ring of the reducing unit with trifluoroacetic acid/ acetic anhydride, the acid component must be measured out very accurately so that no further hydrolyses take place.Deblocking proceeds in the prescribed way, and the free octasaccharide (47), which contains the central structure shown in Figure 4, can thus be obtained.21*22 Studies were also made to examine the possibility of lengthening the oligosaccharide chain shown in Figure 4 to the asparagine end. For these studies the starting point was again the key disaccharide (30), from which by modification of the protecting groups compound (48) was obtained. After conversion of the azido-group into a phthalimido-group (Scheme 16), the 1,6-anhydro-ring in the resulting compound (49) can be opened by acetolysis with trifluoroacetic acid/acetic anhydride.23 The acetolysis ,yields the fl-acetate (50), which can be functionalized with titanium tetrachloride to the halide (51).In a neighbouring- group-assisted procedure compound (5 1) can be coupled with the glucosamine derivative (53) to the trisaccharide (52).23This trisaccharide contains the chitobiose unit, which is linked directly to asparagine. The trisaccharide (52) is, moreover, a good starting product for further synthesis reactions. After removal of the two ally1 groups, two further mannose residues should be able to link x-glycosidically to the 3-OH and 6-OH groups of the mannose This would be the route to the synthesis of the general saccharide core structure as it occurs both in the N-glycoproteins of the lactosamine type and in those of the mannose tY Pee The described reaction sequences indicate that in principle all sequences that occur in N-glycoproteins can be chemically synthesized.This is, of course, also the case for all partial sequences that are contained in structures (47) and (52). 5 Neuraminic Acid Oligosaccharides It would also be highly desirable to discover methods for linking N-acetyl- neuraminic acid to the terminal oligosaccharide chains of glycoproteins, as shown in Figure 4, and of particular interest here is the trisaccharide unit a-~-Neu5Ac(2--+6)-fl-~-Gal(1-+4)-~-GlcNAc. This sequence occurs (see Figure 4) as the terminal segment in the oligosaccharide chain of N-glycoproteins of the lactosamine type.Because of considerable difficulties encountered in synthesizing glycosides by the use of N-acetylneuraminic acid, the prospects for a linkage with a reactive 6'-OH group from lactosamine were still the most promising. A corresponding building block was therefore produced from the easily obtained derivative of 2-azido- 2-desoxy-lactose (54) (Scheme 17).24 The halide (54) was first of all converted into the benzylglycoside (55) and then, by variation of the protecting groups, into compound (56). Hydrolysis yielded compound (57), now containing two free hydroxy-groups, 4'-OH and 6'-OH,25 of which the 6'-OH group should be much more reactive than the 4'-OH group. One would therefore expect preferential 23 H. Paulsen and R. Lehuhn, Carbohydr.Res., in press. 24 H. Paulsen and J.-P. Holck, Liebigs Ann. Chem., 1982, I I2 1. 25 H. Paulsen and H. Tietz, Angew. Chem., 1982, 94, 934; Angew. Chem., In!. Ed. Engl., 1982, 21, 927. 36 Paulsen + Scheme 16 reaction with the 6'-OH group, and (57) is therefore suitable as substrate for the reaction with an N-acetylneuraminic acid halide. Glycoside syntheses using the halide of the neuraminic acid (59) therefore present considerable difficulties, as the dominating reaction in the presence of virtually all catalysts is elimination with HCl cleavage to give the unsaturated neuraminic a~id.~~,~~ The yield of neuraminic acid-containing oligosaccharides is therefore extraordinarily low. It has now been discovered that, with the use of the mercury catalysts (mercury cyanide/mercury bromide) under controlled conditions, the undesired eIimination reaction can be considerably suppressed (Scheme 18).Under these conditions, the halide of the neuraminic acid (59)reacted with the lactosamine building block (57) at 50% yield to form rieuraminic acid-containing oligosaccharides. 5*26 The reac- tion does not proceed stereospecifically; the two anomeric compounds (58) and (60) are obtained, in an a$-product ratio of about I: 1. Both the anomers (58) and (60) can, however, be separated by chromatographic means and can therefore be isolated in this way, both at about 25% yield. Complete deblocking of both z6 H. Paulsen and H. Tietz, Carbohydr. Res., 1984, 125, in press. z1 'Sialic Acids', ed.R. Schauer, Cell Biology Monographs Vol. 10, Springer Verlag, Wien and New York, 1982. Synthesis of Complex Oligosaccharide Chains of Glycoproteins \% Paulsen -m" Y5 UU c -NOD nI u, 0u r-e+ Synthesis of Complex Oligosaccharide Chains of Glycoproteins Ph I Ph A c OAcO t:' i 2 C w o XCOzCH3 AcHN OAc no PhthNz3-OBzl OAc OBrl (65) A cAcO o; H 2 cCOtCH3 ~ I O ~ o s ~ B z I O ~ ACHN 0Ac AC0 PhthN OAc ezio At0 OBzl OAc 0At (67) AcO AcOH2C AcHN OAc 0AC OBzt 91-D-Neu5 AC-(2- 6)-p-D-Gal(l- 4I-p -D -GIcNAc(l 2)-0-Man (69) 40 Scheme 19 Paulsen neuraminic acid trisaccharides was possible.2 5926 From the a-product (60) the free trisaccharide (61) is obtained in this way, and it represents the terminal unit of the saccharide chain of N-glycoproteins as shown in Figure 4.The direct introduction of N-acetylneuraminic acid into larger oligosaccharides remains a problem.27 It would therefore be useful to develop a neuraminic acid- containing synthesis block by means of which the anomeric unit could be converted into a reactive form that would permit linking to any oligosaccharides. The lac- tosamine residue in (60) could be most suitable in this respect if it were converted into the corresponding phthalimido-compound. With regard to the effectiveness of a glycosidic linkage, a functionalized phthalimido-compound has very good prop- erties. Therefore, the modified lactosamine derivative (63), which contains a phthalimido-group, was produced (Scheme 19) from compound (62).The building block (a),which is similarly suitable for reaction with the N-acetylneuraminic acid halide (59),is obtained by cleaving the ally1 glycoside (63) followed by acetylation and hydrolysis of the benzylidene group. The reaction of (64)with (59) under analogous conditions affords in corresponding yield the two anomeric trisaccharides, which can also be separated chromatographically.28 The a-D-compound (65) produced in this way now has at the anomeric centre of the reducing unit an acetyl group that is once more functionalizable. To this end it is necessary first of all to cleave off the benzyl ether groups in compound (65) by hydrogenation and to substitute them with acetyl groups. In this way a more stable compound is obtained that can be used directly in a gly- cosidation step under the conditions of the trimethylsilyl triflate method (see Scheme 6).28A new neuraminic acid-containing synthesis block is available for this.In a test reaction, the B-acetate compound (66) was allowed to react with the mannose derivative (67), which has a free 2-OH group. In the presence of trimethyl triflate in a neighbouring-group-assisted procedure, the desired tetrasaccharide (68) is obtained by attachment of the new P-glycosidic link to mannose.28 From (68) the tetrasaccharide chain (69) becomes accessible, representing the terminal sequence of one arm of the lactosamine antennae in the formula shown in Figure 4.This example shows that the block is suitable for further glycoside syntheses. It can thus serve to introduce neuraminic acid into oligosaccharides, with which other- wise practically no reaction would be possible. 6 Conformations of Oligosaccharide Chains In several cases the oligosaccharide chain of glycoconjugates represents the biolog- ical determinant, so therefore the molecular shape (and also conformation) of the chain is of great interest. The molecular shape of the terminal oligosaccharide sequence determines the specificity of the reaction with proteins. Conclusions about the interaction with protein receptors can be drawn from data regarding the conformation of the oligosaccharide chain.For determining the conformation of 28 H. Paulsen and H. Tietz, to be published. 41 Synthesis of Complex Oligosaccharide Chains of Glycoproteins the oligosaccharide chain, two methods are considered: a theoretical calculation, in which the mutual steric interactions of the saccharide units are taken into account, and the use of the modern methods of high-field n.m.r. spectroscopy, which yield information about the conformation in solution. In the method of HSEA (hard-sphere exo-anomeric effect)29 or GESA (geo- metric ~accharide)~~ calculations, the pyranose ring is accepted to be in a rigid chair form, and corresponding data for the chair conformation are inferred from X-ray structure analyses.Further, the atomic radii and the exo-anomeric effect are taken into consideration. Rotations to give various conformations are carried out about the different anomeric linkages, and for anomeric linkages with secondary OH groups two angles (4 and $) can be varied. By varying both angles the energy minimum can be calc~lated,~~~~~ and for glycosidic linkages with secondary hydroxy-groups the minimum was found to be relatively steep so that, in this kind of linking, one conformation is strongly preferred. For anomeric linkages with 6-OH groups, a further rotation about the C-5 -C-6 axis is possible. Taking into account this third variability of rotation, with this kind of linkage, therefore, more minima result, so that variable parts of conformations are present here.The most important minima in this case are a gg (gauche-gauche) and a gt (gauche-trans) conf~rrnation.~~~~~ For conformation analysis by the n.m.r. method, the 'H n.m.r. spectrum of the substance being analysed must be assigned completely. This is very difficult for deblocked oligosaccharides as there is extensive overlapping of the ring protons of the various saccharide units. An assignment can be made by intensive use of the new methods of two-dimensional n.m.r. spectroscopy. The assignment can be backed up more by the determination of relaxation times and by observation of particular deshielding effects. If a solution to the spectrum has resulted, a difference n.0.e. (nuclear Overhauser effect) spectrum is set up and searched for inter- glycosidic n.0.e.effects between protons of various saccharide units. Provided that these interglycosidic n.0.e. effects can be observed, statements regarding the dis- tance of the observed protons can be made, from which experimental indications of the conformation occurring in solution can be obtained. The results of the n.m.r. investigations must then be compared with the theoretical calculations. Both methods described above were applied to the octasaccharide (47), which represents the key element in the oligosaccharide chain of the N-glycoprotein shown in Figure 4. A GESA calculation established that within the pen- tasaccharide section, in which the lactosamine residue is linked at 0-3, one con- formation is very much preferred.31 In the lactosamine group, which is linked as a branch at 0-6, there is, however, a mixture of gt and gg conformations. The energy calculation of the minima predicts that in this case the gt conformation should predominate; this preferred gt conformation is represented in Figure 5.The line drawing (bottom) shows the arrangement of the eight individual pyranose rings; the space-filling atomic model (top) represents the molecule in exactly the '' H. Th#gersen, R. U.Lemieux, K. Bock, and B. Meyer, Can. J. Chem., 1980, 58, 631. 30 B. Meyer, to be published. 31 H. Paulsen. T. Peters, V. Sinnweli, and B. Meyer, Liebigs Ann. Chem., in press. 42 Paulsen Figure 5 Conformation of the octasaccharide (47), calculated from the GESA program.Bottom: line drawing showing the arrangement of the pyranose rings; top: space-filling molec- ular model with corresponding conformation same position and to the same scale as the line dra~ing.~ In both models the two divergent lactosamine antennae can be clearly recognized. N.m.r.studies of the octasaccharide (47) in D,O are now possible for the first time, because the amounts of material necessary for such measurements are avail- able by synthesis, leading to results that agree very well with theoretical calcu- lations. The conformations that are preferred according to the calculations should also be preferred in solution, as the interglycosidic n.0.e. effects of the correspond- ing protons can be reconciled very well with the conformations calculated by Synthesis of Complex Oligosaccharide Chains of Glycoproteins Figure 6 Schematic diagram of the structure of immunoglobulin IgGl means of the GESA The n.m.r.studies also indicate that for the lactosamine unit linked to 0-6 there is a mixture of gg and gt conformations. Similarly, the data can best be interpreted in favour of the gt c~nformation.~~ By very lucky chance, an X-ray structure analysis for the octasaccharide (47) is also available. The octasaccharide itself, of course, cannot be crystallized. H~ber,~however, managed to crystallize immunoglobulin IgGl , isolated pure from human serum, and carried out a complete X-ray structure analysis. In addi- tion to several peptide chains in the so-called Fc section, IgGl contains a small carbohydrate chain.A schematic diagram of the structure of immunoglobulin IgGl is shown in Figure 6, in which the carbohydrate chain at the C,2 fragment can be seen. The structure of this carbohydrate chain actually matches to a great extent that of the synthesized octasaccharide (47). The X-ray structure analysis gave not only the positions of all the amino-acids but also the positions of the atoms of the carbohydrate chain. Thus there is now also available an X-ray structure analysis of the octasaccharide sequence (47). This curious situation arises 32 R.Huber,Klin. Wochenschr., 1980, 58, 1217. 45

ISSN:0306-0012    

DOI:10.1039/CS9841300015

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

New Insights into Aliphatic Nucleophilic Substitution Reactions from the use of Pyridines as Leaving Groups* By Alan R.Katritzky DEPARTMENT OF CHEMISTRY, UNIVERSITY OF FLORIDA, GAINESVILLE, FL. 3261 1, USA Giuseppe Musumarra ISTITUTO DIPARTIMENTALE DI CHIMICA E CHIMICA INDUSTRIALE, UNIVERSITA DI CATANIA, CATANIA 95100, ITALY 1 Introduction Since 1976, our group has developed a pyrylium-mediated transformation of amines into other functionalities by a two-step process (Scheme 1). The first step involves the reaction of the primary amine with a pyrylium salt to give a corresponding pyridinium derivative, and the second step is a nucleophilic substitution reaction in which the N-substituent is transferred from the pyridine nitrogen atom to the nucleophile.The first step can be carried out at 20°C in CH,Cl, in high yields,2 and using superior leaving groups, the second step can be carried out in solution at 50-100 0C.3 The preparative utility of these reactions is con~iderable,~but will not be considered here. The present account is concerned with the light that information from the kinetics of N-substituent transfer can shed on the mechanism of aliphatic nucleophilic substitution in general. 2 The Background The fundamental difference between the SN2 and S,l reaction mechanisms in aliphatic compounds was first described by Ingold. Winstein expanded this distinction by pointing out that there was evidence that the SNlmechanism took place in distinct variations involving intimate ion-pairs, solvent-separated ion- pairs, and free carbocation (Scheme 2).6 Sneen put forward the hypothesis that all SN2mechanisms took place over intimate ion-pairs formed reversibly in a pre- * Based on lectures delivered (by A.R.K.) 1982-83 at the Universities of Erlangen, Jordan, Heidelberg and Zurich, Rice University (Texas), La Trobe University (Australia), UCLA, King's College (London), 185th ACS National Meeting (Seattle), and elsewhere.* J. B. Bapat, R.J. Blade, A. J. Boulton, J. Epsztajn, A. R.Katritzky, J. Lewis, P.Molina-Buendia, P. L. Nie, and C. A. Ramsden, Tetrahedron Lett., 1976, 2691. A. R. Katritzky, R. H. Manzo, J. M. Lloyd, and R. C. Patel, Angew. Chem., Int. Ed. Engl., 1980, 19, 306. (a)A. R. Katritzky and S.S. Thind, J. Chem. Soc., Perkin Trans. I, 1980, 1895; (b) Ibid., 1981, 661. For a review see A. R. Katritzky, Tetrahedron, 1980, 36, 679. See C. K. Ingold, 'Structure and Mechanism in Organic Chemistry', 2nd Edn., Bell, London, 1969. S. Winstein, B. Appel, R. Baker, and A. Diaz, in 'Symposium on Organic Reaction Mechanisms', Chemical Society (London), Special Publication No. 19, 1965, p. 109. New Insights into Aliphatic Nucleophilic Substitution Reactions -J&R-NH, + Ar + NU-R Ar Ar Ar Ar ArI R Scheme 1 intimate solvent-separated free I Nu1 k, ion-pair ion-pair carbeni1.1 m (Nu1 kz /[Nu1 ion Products I INu’Products Products Products Scheme 2 equilibrium followed by rate-determining nucleophilic attack on the intimate ion- pair.’ Schleyer and Bentley have emphasized the concept of variable nucleophilic assistance by solvent.8 Recently it has been suggested, and amply demonstrated, that electron transfer may cause nucleophilic s~bstitution.~ A perennial difficulty in the interpretation of nucleophilic substitution reactions with a halide, tosylate, or similar leaving group, is that such substrates are neutral and during the reaction charge is created in an S,l type reaction.This means that such reactions may not take place in non-polar solvents, and in those solvents where they do occur the possibility arises that the solvent is acting as nucleophile, rather than just as a polar medium, and this complicates considerably the interpretation. The advent of substituted pyridines as neutral leaving groups changes this.Here the substrates start off by being positively charged, and no charge is created in the bond heterolysis which produces R+ and a neutral leaving group. Hence, such S,1 reactions are expected to be much less affected by solvent polarity and can be studied in non-polar media where there is no doubt that the solvent is acting truely as a solvent and not as a nucleophile. Because of this, interpretation is simpler and findings from the non-polar solvents can be extrapolated to polar solvents, thus shedding light on the whole question of the reaction mechanisms. (a) R. A. Sneen, Acc. Chem. Res., 1973,6,46; (b)R. A. Sneen and J. W. Larsen, J. Am. Chem. SOC., 1969, 91, 362; (c) R. A.Sneen and J. W. Larsen, J. Am. Chem. Soc., 1969, 91, 6031. 8 (a)T.W.Bentley and P.v. R.Schleyer, J. Am. Chem. SOC., 1976, 98, 7658; (b) F. L. Schadt, T. W. Bentley, and P.v. R.Schleyer, J. Am. Chem. Soc., 1976,98, 7667; T. W. Bentley and P. v. R. Schleyer, Adv. Phys. Org. Chem., 1977, 14, 1. (a)I. P.Beletskaya and V. N. Drozd, Russ. Chem. Rev.(Engl. Transf.)1979,48,431; (b) M. Chanon and M. L. Tobe, Angew. Chem., Int. Ed. Engl., 1982, 21, 1. 48 Katritzky and Musumarra 3 The Kinetic Investigation of Nucleophilic Displacements with Pyridines as Leaving Groups Kinetic investigation of reactions of the type depicted has shown the following characteristics: (a) Whereas salt effects are found in non-polar solvents for charged nucleophiles, the neutral nucleophiles show clean kinetics under second order or, very conveniently, under pseudo first-order conditions.(b) A wide range of solvents can be used, e.g. PhCl, MeCN, pentanol, DMSO. (c) Changing the gegen ion from BF4- to C104- has no influence on the reaction rate. (d) A wide range of N-substituents, leaving groups, and nucleophiles can be studied. (e) Temperature and pressure can be conveniently varied to give AH', AS*, A V'. (f) Rates can be followed either spectrophotometrically ot conductometrically, although the former is normally the more convenient method. A typical spectrophotometric determination of rate is shown in Figure la from which the data in Figure 1b were plotted to give the kobsvalue.As can be seen, very good straight line plots are obtained for kobsunder pseudo first-order conditions. Figure 2 shows the result of plotting kobsagainst nucleophile concentration for the three different nucleophiles piperidine, morpholine, and pyridine with 1-benzyl-2,4,6-triphenylpyridiniumat 100 "C in chlorobenzene solution. For each nucleophile, a straight line is found which passes through the origin, showing that the reaction is first order in the nucleophile. Separate experiments show that it is also first order in substrate. In other words, overall it is a second-order reaction characteristic of the sN2 mechanism. The second-order rate-constant is proportional to the slope of the line in the plot, and is as expected greatest for piperidine, less for morpholine, and by comparison very much smaller for pyridine, which is a much less powerful nucleophile.1° However, a dramatically different result is found for the N-isopropyl analogue in Figure 3.Here, although three straight lines are found, they do not pass through the origin, but give a significant intercept at zero nucleophile concentration. This shows clearly that alongside the second-order component there is also a first-order component, which is independent of the amount and nature of the nucleophile. In other words, we have alongside our SN2 reaction, an S,l component.'O Such behaviour is typical for substrates with secondary alkyl groups. Figures 4 and 5 show results in which now the nucleophile is kept constant as piperidine, but the N-substituent is varied for the monocyclic series (Figure 4), and for the tricyclic series (Figure 5).It can be seen that in Figure 4 methyl, ally], benzyl, and p-methylbenzyl all give results, in the monocyclic series, that are (within experimental precision) completely second order and no first-order component can be detected. lo A. R.Katritzky, G. Musumarra, K. Sakizadeh, S. M. M. El-Shafie, and B. Jovanovic, Tetrahedron Lett., 1980, 21, 2697. New Insights into Aliphatic Nucleophilic Substitution Reactions \. \. c\\. \\i\1. \ s CI b Y .-C E Y Q,E i= > Katritzky and Musumarra 130 8 120. 110 100 90 / / Morpholine-8oI 70 60 50 40 I / / 'vri dine 0.4 f 1:200 1:300 [Nu] (mol I-'1 Figure 2 Nucleophilic substitution by S,2 reaction only: kobs for 1 -benzyl-2,4,6-triphenylpyridinium cation (1.6 x 10-3M) plotted vs.nucleophilic concentration (chloro- benzene solution, 100 "C) By contrast all the secondary alkyl derivatives (isopropyl, secondary butyl, cyclopentyl, and cyclohexil) show a clear first-order component. * The same pattern is repeated for the tricyclic series. Here, the benzoquinoline is a much more active leaving group, and rates at the same temperature of 100"Care much greater. We can now follow the rates for the primary alkyl groups other than methyl, and see that they react essentially only by the SN2mechanism, but at relatively slow rates.' * I' A.R. Katritzky, K. Sakizadeh, Y. X. Ou, B. Jovanovic, G.Musumarra, F. P. Ballistreri, and R. Crupi, J. Chem. SOC.,Perkin Trans. 2, in press. New Insights into Aliphatic Nucleophilic Subst it ution React ions 00-70 -6.0-5.0-4.0-X VI n -to Q- Pyr idine I I I I I I I 0 f0.1 f 0.2 f 0.3f 0.4 f 0.5 0.6 f 150 1:lOO 1:150 1:200 1:300 1:LOO [Nu] (mol I-') Figure 3 Nucleophilic substitution by simultaneous S .I and' SN2 reactions: kobSfor 1-isopropyl-2,4,6-triphenylpyridiniumcation (I .6 x 10-31Lfj plotted vs. nucleophilic concen-tration (chlorobenzene solution, 100"C) 4 Activation Parameters It has long been known that the magnitude of the activation entropy is character-istically less negative for SNl than for SN2 reactions.We have measured the activation parameters for a number of the reactions depicted in Figures 4 and 5, and the results are given in Table 1. It will be seen that the expected pattern is reproduced. l* 5 RHO Star Plots p*-Plots have been used particularly by Schleyer and Bentley to gain evidence regarding the degree of solvent participation in solvolysis reactions.* A series of secondary alkyl substrates (e.g. tosylates) are used and p* is defined as the slope of a plot of the logarithms of the solvolysis rates (keeping the same solvent) against '*A. R. Katritzky, G. Musumarra, and K. Sakizadeh, J. Org. Chem., 1981, 46,3831. Katritzky and Musumarra Ph Ph Ph I R X 1 I I I 00-0.1 0.2 0.3 0.4 0.5 [Piperidine] (mot I-') Figure 4 Rate variation with N-substituent: k for reactions of N-substituted-2,4,6-triphenylpyridinium cations (1) (1.6 x 10-3M)wit?$iperidine in chlorobenzene at 100 "C the sum of the c* of each of R' and R2 in the groups R1R2CHX used.The value of o* for an alkyl group is a measure of its electron donor ability. Hence the sum (~*~i+ 0*~2) is a measure of the stabilization afforded by R' and R2 to R1R2CH+. The argument is that the greater the solvent assistance the less will be the necessity of the developing carbonium ion centre to rely on electron donation from R' and R2. Hence the p* should be high for solvents affording little solvent assistance and low for solvents offering much assistance. 53 New Insights into Aliphatic Nucleophilic Substitution Reactions [Piperidinel (mot I -’) Figure 5 Rate variation with N-substituent: kobsfor reactions of N-substituted-2,4-diphenyl-5,6-dihydrobenzo[h]quinolinium cations (2) (6.4 x 10-sM)with piperidine in chlorobenzene at 100 “C Table 1 Activation parameters AH+373 AG73 Ring N-Substituen t Reaction (kcal mol-I) (cal mol-’ K-’) (1) Benzyl SN2 16.3 f0.6 -26.2 (1) p-MeC,H,CH, SN2 16.4 f0.2 -24.6 13.6 k3.1 -30.4 (1) p-MeOC6H,CH2 {:; 22.3 k0.5 -7.0 %.Methyl 14.0 f4.0 -31 f13(2)(2) Isopropyl {;; 19.4 k 2.1 -17+6 25.6 k0.8 -4+2 (2) Benzyl SN2 15.8 f1.5 -19k.5 Katritzky and Musumarra Figure 6 Rho star plots of solvolysis rates at 100"C of l-(sec-allyl)-2,4-diphenyl-5,6-dihydrobenzo[h]quinolinium cations (2): A -tripuoroacetic acid, A ---acetic acid, 0 ----pentanol, 0--chlorobenzene However, Figure 6 shows that this simple picture is incomplete, because the p* plot in chlorobenzene solution (which can be obtained for the substrates shown, but not of course for tosylates) is considerably less than that for trifluoroacetic acid.A. R. Katritzky, J. Marquet, and M. L. Lopez-Rodriguez, J. Chem. SOC.,Perkin Trans. 2, 1983, 1443. New Insights into Aliphatic Nucleophilic Substitution Reactions Ph J 1 Same proportions (ca. 1:l) Ph Scheme 3 Product analysis (l 3C n.m.r.) This finding led us to study the product analysis (Scheme 3) of some of these rea~ti0ns.l~We found that both 2-pentyl and 3-pentyl substrates underwent solvolysis in trifluoroacetic acid to give the same mixture of 3-pentyl and 2-pentyl trifluoroacetates.This indicates a carbocation mechanism where the carbocation has time to equilibrate. By contrast the same two substrates undergo acetolysis in acetic acid to give only the 2-pentyl acetate from the 2-pentyl substrate, and only the 3-pentyl acetate from the 3-pentyl substrate showing that here no jiee carbocation is involved. The solvolyses in hexafluoroisopropanol (Scheme 4) are still more revealing. l4 Again, both the substrates undergo solvolysis to yield the same mixture of the 3-pentyl and the 2-pentyl hexafluoroisopropyl ethers, showing reaction through a free carbocation. When some morpholine is added to this solvent, it is found that there is no large rate acceleration.However, morpholine is able to intercept the pentyl carbocation and the major product is now a N-pentylmorpholine. Significantly, the 3-pentyl derivative gives only 3-pentyl morpholine, and the 2-pentyl gives only 2-pentylmorpholine. This indicates that no free carbocation is formed, and the evidence together strongly suggests that the solvolysis occurs through an intimate ion-molecule pair. Morpholine is a sufficiently strong nucleophile to intercept the pentyl carbocation at the ion-molecule pair stage, whereas in the absence of morpholine, the pair drifts apart to generate a free carbocation, which then equilibrates before reaction with a solvent molecule. A plot of p*against ET as a measure of solvent polarity (Figure 7) indicates that as the solvent polarity increases the p* value becomes less negative. There are two main exceptions to this correlation: acetic acid and pentan-1-01.We believe that this indicates that substantial solvent assistance is being given by pentan- 1-01 and l4 A. R. Katritzky, M. L. Lopez-Rodriguez, and J. Marquet, J. Chem. SOC.,Perkin Trans. 2, 1984, 349. Katritzky and Musumarra IjC-CH-CF3 H CH dH3 F3C\ ,c5 F3C\ ,CF3 OCH\ OCHI + I H3C\ ,CH\ ,CH3 /CH\ /cH2\H2c CH* H3C CH2 CH3 Ph F3C-CH-CF3 A /CH\ /CH2\ H3C CH2 CH3 Scheme 4 Solvolyses in hexaj?uoroisopropanol (at 100"C) acetic acid in these reactions, which are thus essentially of SN2type, but that in the other solvents we have essentially SN1 solv~lysis.~~ 6 Other Evidence For Intimate Ion-Molecule Pairs Both a-methylallylamine and y-methylallylamine react with 2,4,6-triphenyl-pyrylium to give the expected pyridinium cations.However, the N-a-methylallyl- pyridinium cation, on gentle heating in an inert solvent, rearranges to the y-methylallyl analogue (Scheme 5a). This reaction must take place via an intimate ion-molecule pair rearrangement. 15 Furthermore, when optically active or-phenylethylarnine reacts with 2,4,6-'' A. R.Katritzky, Y. X. Ou, and G. Musumarra, J. Chem. Soc., Perkin Trans. 2, 1983, 1449. New Insights into Aliphatic Nucleophilic Substitution Reactions P* -1 -A Pentan-1-01 -2 -3 -Chlorobenzene AAcetic acid -4 --5.--6 --1,1,1, 3,3,3-Hexaf luoroisopropanol -7 I I 1 I I I I 1 35 40 45 50 55 60 65 70 ET Figure 7 Plot of p* vs.E, triphenylpyrylium cation in acetic acid solvent the initially formed pyridinium is so reactive that it immediately gives the corresponding acetate. However, the a-phenylethyl acetate is formed with complete inversion. This reaction is likely also to occur via an intimate ion-molecule pair (Scheme 5b).* To summarize, the evidence so far indicates we have distinguished between two types of sN1 reaction; that via the free carbonium ion and that involving an intimate ion-molecule pair as intermediate. We now go on to distinguish between the two types of bimolecular mechanism: the classical &? reaction and the SN2 reaction on the intimate ion-molecule pair. 7 The Pressure Criterion for Mechanistic Distinction between SN2Classical and S 2 Intimate Ion-Molecule Pair Reaction Pathways de classical sN2 reaction should be rate enhanced by pressure; i.e., the AV' is expected to be negative, because the two reactants will be pushed close together.This naive interpretation receives support from several pieces of evidence in the literature. '' (a)T.Asano and W. J. Le Noble, Chem. Rev., 1978,78,407; (h)M. Okamoto, M.Sasaki, and J. Osugi, Rev. Phys. Chem. Jpn., 1977. 47, 33. Katritzky and Musumarra m r 0 v=v I I/ hl N'I-5 In a i n + 'mI 'Xm 0 0 New Insights into Aliphatic Nucleophilic Substitution Reactions By contrast an sN2 reaction on an intimate ion-molecule pair involves a pre- equilibrium of the type RX+%R+...-X, for which we should expect a large positive d p.In other words, the equilibrium will be pushed considerably to the left by increasing pressure. Although the second stage of the reaction R+ * --X + Nu ---+ NuR+ + X should have a negative A Vf the magnitude should be smaller; thus overall the reaction rate should be decreased by pressure. 1-p-Methoxybenzyl-2,4,6-triphenylpyridiniumperchlorate shows (Figure 8) a reaction rate which clearly decreases with pressure indicating that this reaction involves an intimate ion-molecule pair (this reaction was carried out at temperatures at which the only measurable reaction is second order.)" Still more interesting is the result for the N-benzylpentacyclic derivative, seen in Figure 9.Here the reaction rate first decreases with increasing pressure, but then passes through a minimum and starts to increase. This clearly indicates a change in mechanism and furthermore that the reaction at normal and fairly low pressure is via the intimate ion-molecule pair, but that at higher pressures reaction by the classical &2 process takes over. ' -10.51 I I I 10 20 40 60 80 160 1iO P(MPa1 Figure 8 Reaction via intimate ion-molecule pairs: reaction of I -p-methoxybenzyl-2,4,6-triphenylpyridinium perchlorate (1) (2.0 x 10-5M)with piperidine (0.1M) at 30 "C in chlorobenzene solution at varying pressures (activation volume A V' + 18.9 & I cm3/mole) 8 Reaction by an Electron Transfer Mechanism We have shown that N-substituents are transferred from pyridinium cations to the carbon atom of nitro-alkane anions.'* For reasons detailed below we believe that this reaction involves an electron transfer mechanism, but not of the normal radical chain variety.17 A. R. Katritzky, K. Sakizadeh, W. J. Le Noble, and B. Gabrielsen, J. Am. Chem. SOC.,in press. 18 A. R.Katritzky, G. Z. de Ville and R. C. Patel, Tetrahedron Lett., 1980, 21, 1723. 60 Katritzky and Musumarra Ph Ph (3) 3Activation volume + 22 cm /mol (Second-order reaction on inti mate ion -molecule pair ) II 0-'. n / *O /'/= -9.0 ,/ 1 1 1 I 50 100 150 P ( MPa) Figure 9 Competing reactions at high pressure: the pseudo first-order rate-constant for the reaction of N-benzyl-5,6,8,9-tetrahydro-7-phenyl-bis-benzo~a,hJacridinium tetrajuoroborate (3) (2.0 x 10-5M)with piperidine (2.0 x 10-3M) at 30°C in chlorobenzene as a function of pressure The reaction is very fast for the N-benzyl substituent.Figure 10a shows the overall spectral changes for a reaction taking place at 25 "C in DMSO.l9 These data give a good second order plot when kobsis plotted under pseudo first-order conditions against nucleophile concentration (Figure 1 Ob). Here there is no evidence for the formation of any intermediate. However, when the N-substituent is N-n-butyl, at 25 "C in DMSO, although a change occurs in the ultra-violet spectrum (Figure 1 l), no product is formed (as shown by preparative experiments).Evidently an intermediate is formed in equilibrium in the starting materials. However, when the mixture is heated up above 60 "C,product formation begins at an appreciable rate and at 100"C the rate is quite fast as shown in Figure 12.19 l9 (a) A. R. Katritzky, M. A. Kashmiri, G. Z. de Ville, and R. C. Patel, J. Am. Chem. so[., 1983, 105, 90;(b)M. A. Kashmiri, unpublished. 02 X v) n 2co t i h. 5 -Wavelength (nm) Figure 10 Reaction of 1-benzyl-2,4,6-triphenylpyridiniumwith sodium propane-Znitronate in DMSO at 25 "C: (a) Spectral changes (pyridinium 6.597 x 10-5m/l,CMe,NO,-(1.320 x 10-3m/l; time intervals 3 min). (b) Plot of kobsvs.concentrations of CMe,NO,- Katritzky and Musumarra -Wavelength (nm) Figure 11 Formation of charge-transfer intermediate radical pair: reaction of 1-n-butylpyridinium (6.597 x 10-sm/l) with CMe,NO,-(1.320 x 10-3m/l) in DMSO at 25 "C We believe that these observations can be explained by the reaction mechanism presented in Scheme 6. The pre-equilibrium involves formation of an intermediate which can be considered either as a radical pair or a charge-transfer complex. This Ph R Radical pair or CT complex Ph Ph Scheme 6 Proposed radicaloid non-chain mechanism then breaks down to products. In the case of the N-benzyl substituent the breakdown process is fast even at 25 "C and no build up of intermediate is seen. In the case of the N-n-butyl substituent, at low temperatures we get the equilibrium formation of a charge-transfer complex, which then breaks down only at higher temperatures.Although the rate of formation of a charge transfer is usually fast, examples are known of CTC formation at measurable rates.20 2o (a)C. Walling and C. Zhao, Tetrahedron, 1982, 38, 1105; (6) D. P. N. Sdtchell, brsonal commu-nication. c I Y m2 X In n 0 -L --Wavelength (nm) Figure 12 Reaction of I-n-buty1-2,4,6-triphenylpyridinium(6.597 x 10-Sm/l) with sodium propane-2-nitronate in DMSO at 100 "C:(a) Spectral changes at time intervals of 30 min (CMe,NO,-= 1,320x 10-3m/l). (6)Plot of kobsvs. nucleophilic concentration Katritzky and Musumarra As this reaction mechanism proposed is an unusual one, it is important to summarize the evidence that has caused us to eliminate the mechanisms with more precedents.9 Evidence Against a Chain Mechanism for the Reaction with Nitronate Anions We believe that a chain reaction can be eliminated for the following four reasons: (a) The kinetic dependence expected for a radical-chain mechanism is generally complex (see for example ref. 21): although a radical mechanism in which chain initiation and termination rates were identical could give simple kinetics, these could not persist over a variety of conditions. (b) Radical non-chain mechanism should indeed give simple kinetic dependence. Examples are known, including the decomposition of phenyldiimide (PhN,H) into benzene and nitrogen.22 (c) Light, which acts as an initiator for many radical-chain reactions, has no effect on the rate of these reactions.19 (d) Inhibitors such as di-t-butyl nitroxide and rn-dinitrobenzene have little effect on rates of these reactions.10 Evidence Against a Cyclic Mechanism for the Reaction with Nitronate Anions We believe the mechanism depicted in Scheme 7 can be rejected for the following reasons: RCMeZN0, Scheme 7 Possible cyclic mechanism (a) Pyridinium cations normally add nitronate at the 4-position to form a C-4 bond, rather than at the 2-po~ition.~~ (b) The transposition depicted in the scheme is unfavourable on orbital grounds. (c) Complexes formed do not show the n.m.r. expected for such an adduct, unlike 24the complexes formed with methoxide or cyanide (d) Bulky groups at a-position do not inhibit reaction, and in fact compounds of type (1) react particularly well and quickly.21 J. Hine, 'Physical Organic Chemistry', 2nd Edn., McGraw Hill, New York, 1962, pp. 42W38. 22 P.C. Huang and E. M. Kosower, J. Am. Chem. SOC..1967, 89, 3910. 23 S. W. H. Damji, C. A. Fyfe, D. Smith, and F. J. Sharom, J. Org. Chem., 1979, 44,1761. 24 Unpublished work with J.-L.Chen. 65 New Insights into Aliphatic Nucleophilic Substitution Reactions 11 Evidence in Favour of a Radicaloid rather than a Heterolytic Mechanism for the Reaction with Nitronate Anions A. Structure of Products.-It is well known that the alkylation of nitronate anions by halides or tosylates, which are ionic reactions, give exclusively O-alkylation as shown in Scheme 8.25 0 R-X + Me2cN0, ----c Me2C2N''OR Scheme 8 The few previous examples of free-radical alkylation of nitronate anions, which have utilized either very specially substituted alkyl groups @-nitrobenzyl or similar)26 or mercury do indeed give C-alkylation. The fact that our reaction gives exclusively C-alkylation even with the neopentyl derivatives strongly indicates a free-radical mechanism. B.Rate Dependence on N-Substituents.-As shown in Figures 4 and 5, the S,2 reaction with piperidine is far faster for benzyl than for N-methyl and far faster for N-methyl than for N-isopropyl substituents. By contrast we find that, for reactions with the nitronate ion from 2-nitropropane, although the rate for N- benzyl is still the most rapid, that for N-isopropyl is nearly as fast and is far higher than the rate for N-methyl.This change in rate dependence on the N-substituent is not compatible with the ionic mechanism, but is very readily compatible with a free-radical mechanism. Moreover, for a series ofpara-substituted benzyl groups at nitrogen the second- order rate-constants for displacements vary quite differently for the reaction with piperidine than for the reaction with the anion from 2-nitropropane, as shown in Table 2. In the ionic reaction the rate is greatest for the electron-donor methoxy- group, intermediate for hydrogen, and least for the electron-acceptor nitro-group.By contrast, for the radical reaction the rate is least for hydrogen, and higher for all substituents, particularly for the electron-acceptor nitro-group. Again this behaviour is consistent with that expected for a free-radical reaction mechanism. Table 2 Second-order rate-constants for displacement reactions of 1-(p-substituted benzyl)- 2,4,6-triphenylpyridiniumcations with piperidine and with nitroalkane anions R OMe Me H C1 NO2 k, x lo3 18.0 8.52 4.95 5.88 2.96 k2 4.2 4.1 3.30 5.9 12.4 For reaction with piperidine in chlorobenzene solution at 100 "C,1 mol-Is-'. Extrapolated for values at 70°C. For reaction with CMe,NO, in DMSO solution at 25T, 1 rnol-*s-l 25 L. Weisler and R. W. Helmkamp, J. Am. Chem. Soc., 1945, 67 , 1167.26 (a)N. Kornblum, Angew. Chem., inr. Ed. Engl., 1975,14,734; (b)cf: N. Kornblum, S. C. Carlson, and R. G. Smith, J. Am. Chem. SOL'.,1979, 101, 647. 27 G. A. Russel., J. Bershberger, and K. Owens, J. Am. Chem. Soc., 1979, 101, 1312. Katritzky and Musumarra C. Absolute Comparisons of Kinetic Rates and Activation Parameters- A straight comparison of the second-order rate-constants in dimethyl sulphoxide at 25 "Cfor the reaction of 1-benzyl-2,4,6-triphenylpyridiniumcations with piperidine and with the anion from 2-nitropropane shows that the former is 1.16 x I mol-s-whereas the latter is 3.30 I mol-s-l. Such a large difference in rates would not be expected, particularly in the direction shown, if both reactions are going by the same mechanism.Ig Moreover, the activation parameters are quite different.We find for the S,2 reaction with piperidine a AS' of -26 f2, whereas for the radicaloid reaction with a nitronate anion a AS' of -58 & 2. 12 Conclusions Evidence has been presented in this review that nucleophilic displacement of N-substituents in pyridinium cations can proceed by the five mechanisms shown in Scheme 9. Only time will tell how far these conclusions apply to nucleophilic Ar hAr I I;, Arradical- pair ~ collapse R-NU & 2nd order + h-,r kinetics Ar R 1tNu- Ar IR Ar 2nd order SNZ displacementNu--R-Nu+hArAr kinetics k2 % Jpa Ar (i) 2nd orderk2 Nu displacement kinetics+ Jf&on intimate J, R-NU (ii) 1st order molecule-ion pair Ar Ar kinetics Ar hAr R+ Scheme 9 Nucleophilic substitutions with pyridine leaving groups New Insights into A lipha t ic Nucleophilic Subst it ution React ions displacements at sp3-hybridized carbon atoms in general.However, the results discussed here certainly suggest that we must take very seriously the concept of competitive distinct individual pathways for nucleophilic substitution reactions. Acknowledgements. We thank all our co-workers mentioned in the References, and particularly Drs. M.Lopez-Rodriguez and K. Sakizadeh. A.R.K. is grateful to many colleagues who have vigorously discussed these results with him where he has presented them and to Professor W. le Noble for his collaboration with the pressure measurements.

ISSN:0306-0012    

DOI:10.1039/CS9841300047

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

Light-induced Tautomerism of /?-Dicarbonyl Compounds By Peter Markov DEPARTMENT OF ORGANIC CHEMISTRY, UNIVERSITY OF SOFIA, 1, A. IVANOV AVENUE, SOFIA 1126, BULGARIA 1 scope The idea of tautomerism was introduced by Laar in 1885.’ The dual reactivity of /3-dicarbonyls is believed to be due to uncertainty in the position of one double bond, caused by the intramolecular oscillation of a hydrogen atom within the framework of the three-centre unsaturated system: A=B-CeA-B=C IIHH This state of the molecule has been defined as ‘tautomeric’. By the turn of the century it was generally accepted that the properties of /3-dicarbonyl compounds could be related to the tautomeric equilibrium: I I-c=c-*-c-c-I II I0-H OH This was the earliest in a long series of examples that were to prove the versatility and generality of the phenomenon.Later, the concept of tautomerism was extended to comprise all types of rapidly and reversibly equilibrated transformations (see, for examples, refs. 2 and 3). Since these early days the tautomeric equilibria in solutions of /I-dicarbonyl compounds have been the subject of continuous interest. Various aspects of this subject have received extensive treatment in several review articles.’- The group of /3-dicarbonyls comprises compounds such as (a), (b), and (c). C. Laar, Chem. Ber., 1885, 18, 648. M. 1. Kabachnik, Zh. Vses. Khim. Ova., 1962, 7, 263. C. K.Ingold, ‘Structure and Mechanism in Organic Chemistry’, Cornell University Press, Ithaka, New York, 1953, Chapter 11.S. Forsen and M.Nilson, in ‘The Chemistry of the Carbonyl Group’, Vol. 11, ed. J. Zabicky, Interscience, New York, N.Y., 1970, pp. 157-240. 0. Ya. Neiland, Ya. P. Stradyn, E. A. Silin’ysh, D. A. Balode, S. P. Vatere, V. P. Kadysh, S. V. Kalinin, V. E. Kampar, I. B.Mazheina, and L. F. Taure, ‘Stroenie i Tautomernie Perevrashcheniya 8:Dikarbonylnykh SoedineniiYStructure and Tautomeric Conversions of 8-Dicarbonyl Compounds), Zinatne, Riga, 1979. V. 1. Minkin, L. P. Olekhnovich, and Y. A. Zhdanov, Arc. Chem. Res., 1981, 14, 210. Light- induced Taut omer ism of /?-Dicar bon y I Compounds 0 0 0 II I1 c c Cx/ \ / \y 2' 'z2 ii0 \Z2 (a) ( b) X,Z = R, OR, H (C) Open-chain p-dicarbonyl compounds [type (a)] with at least one hydrogen atom at a-position (Z' = H) can, in principle, exist in the following forms: keto form (a), chelated enols (la), (2a), and non-chelated enols (3a), (4a).The free energies of the keto and enol forms differ only slightly and the tautomeric equilibrium constants are fairly easy to determine. The influence of the structural features on the keto-enol equilibrium cannot be traced in a unique manner since the effects on the keto and enol forms are difficult to disentangle and solvent effects are often marked. However, it seems that the electron-withdrawing substituents at the a-carbon atom tend to increase the stability of the enol form. If present at all, the trans-enol forms constitute less than about 3% of the tautomers.The most striking feature of all studies in this field is that they are exclusively directed to the ground-state properties of the 8-dicarbonyl compounds. A limited number of widely scattered and isolated data on the photochemistry of the compounds under consideration is now available. As shown in Figure 1, the characteristic phototransformations include a-cleavage, decarbonylation, 1,3-shift, and conformational changes. Prolonged irradiation of benzoylacetaldehyde yields acetophenone and C0.7 Non-enolizable /?-diketones undergo 1,3-shift and decarbonylation. 2,2-Dimethylcyclohexane-1,3-diones undergo 1,3-shift upon irradiation in benzene (Scheme 1).* ' R. A. Finnegan and A. W. Hagen, 7etrahedron Lett., 1963, 365. H. Nozaki, Z. Yamaguti, T.Okada, R. Noyori, and M. Kawanisi, Tetrahedron, 1967, 23, 3993. Markov / 1!.= I / Figure 1 Photoreactions of 8-dicarbonyl compounds Scheme 1 Propyl bromide enhances the reaction rate, indicating a heavy atom acceleration of the intersystem crossing to the reactive triplet state. Nozaki and co-workersg have studied several bicyclic non-enolizable /?-diketones. They found that 1,3-shift products were formed with extremely high yields. An nn* triplet state is assumed to be responsible for these reactions. Gorodetsky et al.‘‘-I2 have studied the photochemistry of different types of cyclic, steroidal, and acyclic enol benzoates and acetates. Irradiation causes an intramolecular 1,3-shift. A simple example is provided by the conversion of vinyl benzoate into benzoyl acetaldehyde in 6% conversion in benzene solution.’ Irradiation in transparent solvents produces decarbonylation with formation of acetophenone (Scheme 2).H. Kato, N. Miyamoto, M. Kawanisi, and H. Nozaki, Tetrahedron, 1970, 26, 2975 lo M. Feldkimel-Gorodetsky and Y. Mazur, Tetrahedron Lett., 1963, 369. M. Gorodetsky and Y. Mazur, Tetrahedron, 1966, 22, 360. A. Yogev, M. Gorodetsky, and Y. Mazur, J. Am. Chem. SOC.,1964, 86, 5208. Light-induced Tautomerism of /I-Dicarbonyl Compounds Scheme 2 Exceptions to this behaviour are observed with compounds such as (5) which additionally form products of a-cleavage, followed by hydrogen abstraction or dimerization. (5) According to Houk’ the photochemical reactions of non-enolizable b-diketones and enol esters, can be rationalized on the basis of biradical intermediates, formed by a-cleavage from nn*-excited states.Unlike the /I, y-unsaturated ketone and aldehydes, the a-cleavage of B-diketones seems to involve triplet states in many cases. Two basic types of 1,3-shift for non-enolizable p-dicarbonyls may be envisioned: concerted reactions or intermediate formation of radical pairs. Berson and Salem14 have suggested that the transition state of orbital symmetry forbidden reactions should be stabilized with respect to radical pairs or biradicals involved in stepwise mechanisms. From a phenomenological point of view, light-induced tautomerism has to be associated with the large area of intramolecular proton transfer in electronically excited molecules.In 1931 Weber” showed the link between the fluorescent intensity of some fluorescent species and the acidity of the media. Forster16-18 suggested that such a dependence is probably due to the differences in electron distribution for the fluorescent molecules depending on their electronic states. Weller’ -’’ was first to show experimentally that the pH values of several organic compounds possessing an acidic hydrogen atom are closely related to their electronic states. The concept of photo-induced hydrogen migration was originally put forward in order to explain the photochemical behaviour of salicylic acid and some related l3 K. N.Houk, Chem. Rev., 1976, 76, I. l4 J. A. Berson and L.Salem, J. Am. Chem. Soc., 1972, 94,8917. K. Weber, 2. Phys. Chem., 1931, B 15, 18. T. Forster, Nufurwissenschuffen, 1949, 36, 186. T. Forster, 2.Elektrochem., 1950, 54, 42. T. Forster, Z. Elektrochem., 1950, 54, 531. Iq A. Weller, Z. Elekfrochem., 1952, 56, 662. A. Weller, Z. fhys. Chem., N. F., 1955, 3, 238. A. Weller, Z. fhys. Chem., N.F., 1958, 15, 438. Markov corn pound^.^^.^^ Cohen, Hirschberg, and Schmidt24 showed that the photochromic properties of salicylidene anilines are due to intramolecular proton transfer in an excited state. Later, Wette~mark~~ found experimental evidence of photo-induced intramolecular hydrogen migration for some substituted acetophenones. During the last few years interest has been growing in the field of light-induced enolization and related transformations. 26 -29 Photoenolization is a very general phenomenon that occurs with a wide variety of substrates.The first present-day study in this area was carried out by Huffman et~l.,~'with some chromone derivatives as an example. They showed that irradiation produces dienol species (Scheme 3): Scheme 3 The process could be reversed by a non-photochemical dark reaction. Several important topics of this field have been reviewed.31 Thus far, where compounds show intramolecular excited state proton transfer this is known to be related to the presence of molecular fragments of the type (6) and (7) in which hydrogen transfer takes place in the 6-centre system in the direction of the existing hydrogen bond (Scheme 4).22 A. Weller, Z. Elektrochem., 1956, 60,1144. 23 A. Weller, Naturwissenschaften, 1955, 42, 175. 24 M. D. Cohen, Y. Hirschberg, and G. M. J. Schmidt, 'Hydrogen Bonding', Symposium in Ljubliana, Pergamon, New York, 1959, p. 293. z5 G. Wettermark, Photochem. Photobiol., 1965, 4, 621. 26 D. I. Schuster and M. D. Goldstein, Mol. Photochem., 1976, 7, 209. 27 J. A. Barltrop and J. Wills, Tetrahedron Lett., 1968, 4987. 2a A. Pawda, A. Au, and W. Owens, J. Org. Chem., 1978,43, 303. 29 E. Hadjoudis, Mol. Cryst. Liq. Cryst., 1971, 13, 233. 30 K. R. Huffman, M. Loy, and E. F. Ullman, J. Am. Chem. Soc., 1965, 87,5417. 31 P. Sammes, Tetrahedron, 1976, 32, 405. Light-induced Tautomerism of B-Dicarbonyi Compounds hV Scheme 4 2 Spectra Until the advent of n.m.r.spectroscopy, ultraviolet and infrared spectroscopies were the most useful techniques for the study of tautomeric molecules and even now they are still invaluable as diagnostic tools. Among the many applications are structure determination^,^^-^^ kinetic measurement^,^^.^^ determinations of equilibrium constant^,^'-^^ mechanistic -45 and analysis of isomer mixtures.46 The present brief discussion will be restricted to the advancement in this area, related to the effect of ultraviolet and visible light on tautomeric equilibria. The strong absorption in the 250-300nm region of the u.v.-spectra of enolizable P-dicarbonyl compounds is due to the B-hydroxyvinyl carbonyl system (8). oiH50 '2 4'' R3d/C\3,C,'C (8) Theoretical PPP47and CNDO/S48studies on this molecular fragment indicate that the high-intensity band should be assigned to a n -+ n* transition in the CO conjugated ethylene system.Numerical calculations49 predict, however, two n -+n* transitions in the visible or near-ultraviolet region. The position of the high-intensity band is virtually independent of the type of aliphatic substituents 32 S. J. Rhoads, J. C. Gilbert, A. W. Decora. T. R. Garland, R. J. Spangler, and M. J. Urbigkit, Tetrahedron, 1963, 19, 1626. 33 S. Forsen, F. Merenyi, and M. Nilson, Acta Chem. Scand., 1967, 21, 620. 34 S. Forsen, F. Merenyi, and M. Nilson, Acta Chem. Scand., 1964, 18, 1208. 35 P. Courtot, J. Le Saint, and N. Platzer, Bull.Soc. Chim. Fr., 1969, 3281. 36 Y.Hoppilliard, G. Bouchoux, and P. Jaudon, Nouv. J. Chim., 1982, 6, 43. 37 H. Baba and T. Takemura, Tetrahedron, 1968, 24, 4779. 38 T. Takemura and H. Baba, Tetrahedron, 1968, 24, 531 1. 39 A. Yogev and Y.Mazur, J. Org. Chem., 1967,32, 2162. 40 J. Billmann, S. Soyka, and Ph. Taylor, J. Chem. Soc., ferkin Trans. 2, 1972, 2034. 4* J. Burdett and M. Rogers, J. Am. Chem. SOC.,1964, 86, 2105. 42 J. Burdett and M. Rogers, J. Phys. Chem., 1966, 70, 939. 43 J. S. Chickos, D. W. Larsen, and L. E. Legler, J. Am. Chem. Soc., 1972, 94,4266. 44 J. S. Splitter and M. Calvin, J. Am. Chem. Sor., 1979, 101, 7329. 4s J. H. Clark, J. Chem. Soc., ferkin Trans. 2, 1979, 1326. 46 C. A. Erastov, C. N. Ignatieva, and Z. G. Gabulin, Izv.Acad. Nuuk SSSR, Ser. Khim., 1969, 1620. 47 F. Fratev, P. Markov, and R. Vasileva, Izv. Otd. Khim. Nauk, BAN, 1974, 7, 737. ** P. Markov and F. Fratev, C. R. Acad. Bulg. Sci.,1975, 28, 771. 49 W. Hug, J. Kuhn, K. J. Seibold, H. Labhart, and C. Wagniere, Helv. Chim. Ada, 1971, 54, 1451. Markov R', R2,and R3.Somewhat more noticeable is the influence of the benzyl radical (R'= PhCH,), resulting in a bathochromic shift of the absorption maximum. The introduction of alkyl substituents at the a-carbon atom produces similar spectral changes. Aromatic substituents in 2- and 4-positions of the b-hydroxy-carbonyl system give rise to a new absorption band in the 250-260 nm range, assignable to the aroyl group of the ketonic form. At higher concentrations of the enol tautomer ( moll-') a low-intensity absorption band can be found in the 290--410nm region.The exact position of the band depends strongly on the structural peculiarities of the /?-dicarbonyl compound. The accumulated datas0 show that the 240-270 nm excitation is ineffective in giving rise to luminescence. Conversely, excitation in the long-wave band range produces emission lines. The excitation and emission spectral maxima for some /?-dicarbonyl compounds are presented in Table 1. Table 1 Luminescence spectral data for R'-CO -CH, -CO -R2in cyclohexane solutions, C = 1 x 10-2moi1-' Compound max (nm) R' RZ excitation emission Me OEt 300 390 Ph OEt 350 440 Me OC6H4 310, 340 370 Me OCH,CH:CHPh 252, 327 308, 375 Ph Ph 380 520 Ph Me 400 510 Me Me - - The long-wave absorption (AN)of concentrated solutions of /?-dicarbonyls is due to the formation of molecular associates, nM=N where M is a monomeric enol molecule and N is molecular associate.From the linear dependenceS0 A, = (ENKN)-1/n (ANn-1)-I/n + one can find the association constant KNand molar absorptivity E~ of the dimer molecules (N). The numerical value of KN for MeCOCH,CO,CH,CH:CHPh (Table 1) is 8.39 x lo4. This corresponds to a free energy change of AG = -6.6 kcalmol-'. The assumption of the existence of dimeric species is in agreement with the results of n.m.r. studies on similar molecular system^.^^*^^ Since the long-wave absorption band coincides with the respective excitation band, the process N b.b.,N* ,Nhvfl is likely to occur. In this sense, the emission observed is to be unequivocally related to the presence of dimeric associates. It should be noted that long-wave luminescence, due to dimeric associates, has been reported elsewhere. 53 50 P. Nikolov, F. Fratev, I. Petkov, and P. Markov, Chem. fhys. Left., 1981, 83, 170. 51 M. T. Rogers and J. L. Burdett, Can. J. Chem., 1965, 43, 1516. 52 C. Giessner-Prettre, C. R.Acad. Sci. (Paris), 1960, 250, 2547. 53 K. C. lngham and M. A. El-Bayoumi, J. Am. Chem. Soc., 1974, 96, 1674. 75 Light-induced Tautomerism of /3-Dicarbonyl Compounds 3 Reversible Photochemistry A. Enolizable b-Dicarbonyl Compounds.-Studies up to 197 I had demonstrated the influence of ultraviolet light on the prototropic equilibria of B-dicarbonyl corn pound^.^^.^^ Figure 2 shows the change in intensity of the 246nm absorption band in the u.v.-spectrum of ethyl acetoacetate after successive irradiation of its heptane solution. 200 250 hnm I't I I11lI.I Figure 2 U.V.spectra of ethylacetoacetate in cyclohexane (ca.1.5 x moll-')measuredat diferent times after the start of U.V. (254 nm) irradiation Ultraviolet light also causes changes in the i.r.-spectral characteristics. The respective absorption bands in the 6 region found for the ethyl acetoacetate before (curve a), immediately after 8 h of U.V. irradiation (curve b), and 16 h after the end of irradiation (curve c) are presented in Figure 3.1800~m-~16001600 1800~m-~1600 -18OO~rn-~ cc-. -Figure 3 1.r. spectra of a cyclohexane solution of ethyl acetoacetate (0.95 x 10-2mol I-')(a) before irradiation, (6) after 8 h exposition to 254 nm U.V. irradiation, (c) 16 h after the end of irradiation 54 P. Markov, L. Shishkova, and Z. Zdravkova, Tetrahedron Lett., 1972, 39, 4017 55 P. Markov, L. Shishkova, and A. Radushev, Terrahedron, 1973, 29, 3203. Markov Absorptions due to the enolic form at 1640 and 1660cm- decrease, with a parallel absorption increase at 1718 and 1742cm-', related to the ketonic form. Similar spectral changes have been obtained with structural analogues of the reference compound. The enol forms of benzoylacetone, dibenzoylmethane and other similar compound are sensitive towards s~nlight.'~ The spectral changes in the u.v.-spectrum of dibenzoylmethane after successive exposures of the solution are shown in Figure 4.200 250 300 hnm Figure 4 U.V.absorption spectrum of dibenzoylmethane in heptane (ca.0.25 x 10-4mol 1-') curve 1, before exposure to sunlight; curve 2, after a 60 min exposure; curve 3, after a 120min exposure The spectral changes caused by ultraviolet irradiation are reversible, i.e. the original solution spectra are restored in the dark. Available spectral data (for example refs. 59-61) for /3-dicarbonyl compounds reveal that the observed spectral changes are due to a shift of the keto-enol equilibrium towards the keto form. Kinetic studies of photoketonization together with quantum yields have been de~cribed.'~*~~ In the region of high optical densities (c' = 1 x moll-I), the photoinduced transformation follows zeroth-order kinetics.At lower concentrations of the enolic form (ce = 0.5 x 10-4mo11-') the process is described by the function lnc; -Inc: = kr which is a solution of the rate equation for first-order kinetics. Under high- intensity pulsed-laser irradiation, a hyperbolic relationship between transmittance (9 and time of irradiation (t) was found.62 In this case the rate of photoketonization is given by I. Petkov and P. Markov, Rev. Roum. Chim., 1982, 27, 847. 57 P. Markov and I. Petkov, Tetrahedron, 1977, 33, 1013. s8 P. Markov, I. Petkov, and D. Jeglova, J. Photochem., 1978, 8, 277. sQ R.A. Morton, A. Hassan, and T. C. Calloway, J. Chem. Soc., 1934, 883. ao R. Rasmussen and R. Brattain, J. Am. Chem. SOC.,1949, 71, 1075. 61 L. J. Bellamy, 'Infrared Spectra of Molecules', Moscow, 1957, p. 221. 6z W. Majewski, W. Skubizak, T. Kotovuski, S. Dinev, P. Markov, and 1. Petkov, Mol. Photochem, 1979, 9, 463. 77 Light-induced Tautomerism of /3-Dicarbonyl Compounh dc=-Ige b dt ~l 'at2+ bt where a,b are constants, I is optical length, and t is time of irradiation. A considerable body of evidence shows that the type of the substituents R', R2, and R3has no marked effect on the photoketonization rate in its first (zeroth-order kinetics) and second (first-order kinetics) stages. In some cases, however, the k, and k, values are particularly dependent on some structural features of the enolizable species. The presence of a ring system such as (9) reduces considerably the rate of photoconver~ion.~~ A similar effect is produced by the replacement of enolic hydrogen with deuterium.56 .~~Veierov et ~1have tested the photoisomerization kinetics for the enol form by flash photolysis. In their view these species undergo facile photoisomerization to the corresponding non-chelated short-lived forms. The photoprocess obeys the first-order reaction law. The relevant energies associated with the hydrogen migration within the framework of the three-centre unsaturated system of the enol form vary with the structure peculiarities from 5 to 8 kcal mol- 65 Quantum yield measurements show that the photoinduced hydrogen transfer seems to occur with a nearly constant quantum yield.The variation of the /?-ketoester structure produces minor differences in the @-values. The oscillator strength for the S, tSo transition in the C =0 conjugated system seems to be related to the respective rate constants and quantum yields. A logical extension of the studies in the area under consideration has been .~~recently made by Getoff et ~1They were the first to report on triplet-sensitized prototropy of ethyl acetoacetate in solution. The ketonization of this /?-dicarbonyl compound was found to be sensitized by benzene, toluene, and p-xylene, used as energy donors. The quenching of the donor fluorescence was studied and the Stern-Volmer constants were determined.On the assumption that sensitized ketonization takes place subsequent to energy transfer from the donor triplet state, the donor triplet quantum yield has been calculated. The lowest excited state of 63 P. Markov and E. Radeva, J. Photochem., 1975,4, 179. 64 D. Veierov, T. Bercovici, E. Fischer, Y. Mazur, and A. Yogev, J. Am. Chem. Soc., 1977, 99, 2723. 65 P. Markov, unpublished data. 66 G. Kittel, G. Kohler, and N. Getoff, J. P~JXChem., 1979, 83, 2174. 78 Markov ethyl acetoacetate in its enolic form is of nn* nature and it is not observed by absorption spectroscopy in dilute solutions. CNDO/S calculation^^^ gave 3.382eV, corresponding to 365nm for its vertical energy. According to Getoff et al., the 3nn* and nn*-states have to be expected at energies below 3 eV (410 nm).In such a case benzene and its derivatives should be efficient triplet energy donors for ethyl acetoacetate, since their relaxed triplet energy is higher than 3.4eV.67 In 1973 Courtot and Le Saint6' showed that the ultraviolet irradiation causes interconversions between chelated enolic species of diaroylacetic acids. More recently Courtot et al. have studied in detail the photochemical properties of tria~ylmethane~'and some nitrogen-containing analogue^.^' It is concluded that Z +E isomerization takes place directly by rotation around the olefinic double bond of the enolic chelate system after cleavage of the intramolecular hydrogen bond. In this case the intermediate formation of ketonic species as a result of photoinduced hydrogen transfer cannot be ruled out.Until recently no information concerning the possible influence of y-irradiation on tautomeric equilibria was available. Getoff and Fratev" have shown that 60Co-irradiation causes a decrease in the concentration of the enol form of ethyl acetoacetate in solution, yielding the keto form. As already mentioned, the thermodynamic ratio between the two tautomeric forms is completely restored in the dark. The rate of re-enolization (dark reaction) depends on several factors, including the presence of specific catalysts and the duration of the irradiati~n.~~ The experimental data in the case of base-catalysed re-enolization satisfy the function InvC" -co = ktc -c Co and C" denote the initial and the equilibrated concentrations of the enol form and C is the concentration t seconds after starting the kinetic run.A plot of C" -ln-covs. t at different concentrations of the catalyst (n-amylamine) is C" -C presented in Figure 5. The rate of the reverse process gradually increases as a result of repeatedly performed photoketonization, when tertiary amine is used as a catalyst (Figure 6). The initial k value is 15-times smaller than that obtained after six prototropic interconversions (photoketonization+nolization). The accelerating effect of ultraviolet irradiation occurs only in the case when tertiary amine is used as a catalyst. 67 J. B. Birks, 'Photophysics of Aromatic Molecules', Wiley-Interscience, London, 1970.P. Courtot and J. Le Saint, Tetrahedron Lett., 1973, 33. 69 B. Couchouron, J. Le Saint, and P. Courtot, Bull. Soc. Chim. Fr., 1981, 11, 381. 70 R. Pichon, J. Le Saint, and P. Courtot, Tetrahedron, 1981, 37, 1517. 71 N. Getoff and F. Fratev, Z. Phys. Chem., N. F., 1977, 104, 131. l2 P. Markov, J. Photochem., 197677, 6, 91. Light-induced Tautomerism of 8-Dicarbonyl Compounds b 0 15 30 L5 60 75 90 Figure 5 Plot of In[(CW-Co)/(Cm-C')]vs. t at di erent concentrations (C,) of the catalyst (n-amylamine): 1, 0.08 x 2, 0.32 x 10-P-; 3, 1.30 x 4, 5.00 x lo-'. C(' = 0.2 x 10-4moll-', h,,, = 246nm f (mid Figure 6 Plot of ln[(Cm-Co)/(Cm-C')]vs. t after successive 20min irradiations. Basic catalyst, triethylamine (C,= 0.5 x 10-7mo11-') Theoretical Considerations.In the theoretical analysis of tautomeric interconversions an energy value can be assigned to each tautomeric form. Since in a molecule of many atoms there are several geometrical variables and the energy depends on all of them, the total energy of the respective tautomer can be represented as a hypersurface over the multi-dimensional space of the internal co-ordinates. The tautomerism of P-dicarbonyl compounds corresponds to the paths of minimum energy of these hypersurfaces, while stable conformations and transition states are represented by minima and saddle points, respectively. Markov During the last few years, energy surfaces for the interaction between small molecules or ions have become available by ab inirio LCAO MO calculations.The most extensive of these studies73 -77 claim to have an accuracy of a few kcal mol- relative to the energy minimum over the most important parts of the surface. For large molecules such as p-dicarbonyls, however, the orthodox approach is not practicable. The calculation of the energy surface becomes possible if the number of geometrical variables is reduced on the basis of a well-founded model for the transition In the common case, the principle of least motion" and orbital symmetry conservation rules" have to be considered. The main assumption in the case of proton transfer within the framework of the t hree-cen t re unsaturated sy stem I I-c=c-g -c-c-I II I0-H OH of a tautomeric molecule is that the nature of the potential surface depends exclusively on the internal co-ordinate of the migrating particle. The most probable path of the system during the tautomeric interconversion can be represented by a line on the surface that follows the lowest possible energy contours between the U AE t w X H Figure 7 Energy diagram for proton-transfer reaction 73 G.H. F. Diercksen, Theor. Chim. Acta., 1971, 21, 335. 74 G. H. F. Diercksen and W. P. Kraemer, Chem. Phys. Lett., 1970, 5, 570. 75 H. Popkie, H. Kistenmacher, and E;Clementi, J. Chem. Phys., 1973, 59, 1325. 76 E. Clementi and H. Popkie, J. Chem. Phys., 1972, 57, 1077.'' 0. Matsuoka, E. Clementi, and M. Yoshimine, J. Chem. Phys., 1976, 64, 1351. 78 M.Simonetta, Fortschr. Chem. Forsch., 1973, 42, 2. 79 M. J. S. Dewar, Chem. Br., 1975, 11, 97. L. Salem, Acc. Chem. Res., 1971, 4, 322. J. W. McJver, Acc. Chem. Res., 1974, 7, 72. 81 Light- induced Taut omer ism of /3-Dicarbony 1 Compounds initial and the final state, so that a two-dimensional diagram like Figure 7 represents a section of the energy surface. The two curves represent the potential energies of the two separate tautomers X-H and Z-H as a function of the position of the hydrogen atom, migrating between two centres X and Z. The reaction co-ordinate has a simple significance, namely, the distance of the proton from either X or Z. The energy of the transition state is given by the point of intersection between two potential energy curves.Some insight into the type of transition involved and the direction of the main internal co-ordinates may be obtained from the kinetic features of the photoinduced tautomerism and from the theoretical data on the two tautomers. As already mentioned, the photoactivated prototropic change follows zero (at high optical densities) and first (at low optical densities) order reaction law. Consequently, the photoinduced ketonization, taking place under suitable experimental conditions (inert aprotic solvent and absence of catalyst), is to be ascribed to intramolecular hydrogen atom migration. There are arguments showing that the process does not go along the hydrogen bond of the chelated form. The photoexcitation of the enol tautomer produces important changes in the electron density distribution of the #I-hydroxyvinyl carbonyl system.Calculated CNDO/S values of the total charge density of each atom and the respective bond indices of the planar enol form in the ground and the first excited state are presented in Figure 8. Q804 6.2 68 0.969 3.7 89 0.960 I I H H 0.969 0.994 0.802 (b) 6.151 0 (P,6.197 0.843I0.964 HH’l H 0.970 0.984 Figure 8 Electron density distribution in (a) the ground state and (6) the excited state of ethyl acetoacetate 0.969 c4.125 H\cyc c 4.0900-H I (bl 00 &-w Figure 9 Possible reaction pathways for the photoinduced intramolecular hydrogen transfer: (a) through-space transfer (b) through-bond transfer 2 Light-induced Tautomerism of p-Dicarbonyl Compounds The population analysis shows the presence of a positively charged oxygen atom (dq = +0.060) indicating that in the excited state there is no intramolecular hydrogen bond in the cis-enolic species.Evidently, migration of a positively charged hydrogen to the carbonyl oxygen is improbable. There are two possible reaction pathways for the photoinduced intramolecular hydrogen transfer, under aprotic conditions, leading to the keto form. These pathways are: (i) Through-space transfer (Figure 9a) which involves a change in the hybridization scheme of the C'-atom as a result of twisting the carbon-carbon double bond. (ii) Through-bond transfer (Figure 9b) involving a 'jump' of a proton to the n-orbital of the neighbouring oxygen atom and subsequent localization of the hydrogen atom at the C'-atom with a prior or subsequent change in the hybridization of this carbon atom so as to attain the final keto form.In order to distinguish between the two pathways, the orbital symmetry conservation rules (OSCR) have been applied.82 The parameter r was used to represent the rupture (r = 0) or formation (r = 1) of bonds during the photoketonization process. The results from the tests of these two reaction paths are illustrated by Figures 10a and b. I/------2 -0 0.2 0.40.6 OB 1.0 -2 0 0.2 OX 0.6 0.8 1.0 -r Figure 10 Correlation diagrams for ethyl acetoacetate: (a) through-bond transfer (b) through-space transfer It is seen that ketonization is orbitally allowed in the ground state and the first excited state by the through-space mechanism and forbidden by the through-bond variant.82 G. St. Nikolov and P. Markov, Annuaire de I'Universite de Sofia Faculte de Chimie, 1977-78.72, 109. 84 Markov An important consequence of this finding is that the change in C'-atom hybridization is possible only if the OH group is out of the plane of conjugation in the enol tautomer. It is known that the barriers to internal rotation about C -0 bonds are in the range of 8-10 kcal mol- The twisting of the ethylenic double bond depends on the bond order. PPP-calc~lations~~ show that the singlet state bond orders C2-C3 and C3 -C4 have nearly the same magnitude. Since twisting of the ethylenic quasi-double bond is an important mode to lose quanta,83 this path should be preferred.Experimental evidence for the twisting mechanism could be the photoisomerization of the enol form. As already mentioned, spectroscopic data concerning such a process have been recently published by Veierov et uZ.~~It may be thus concluded that the orbital restriction on overlapping between the 2p-orbital of the C3-atom and the Is-orbital of the hydrogen atom is possibly lifted as a result of twisting about the C2-C3 bond in the excited state of the enol tautomer. A model of the transition state of the photoprocess, based on the above- mentioned assumptions, is presented in Figure 1 1. Figure 11 Assumed (C3=C4, C4 -05,O5-H') and calculated (C3-H') bond distances in the unchelated sickle form of the enol.pth carbon and oxygen are assumed to be sp2hybridized.Calculated: = 68.84", c$2 = 8.84 . X denotes the reaction co-ordinate. (6) Assumed (C3-C4, C4 =Os,C3-H') and calculated (0'-H') distances in the keto,form. H' and H2 ate above and Flow the molecular plane and H' is their projection on this plane 6,= 66.56 , q54 = 47.55 It can be seen that the formation of a transition state with the shape of a distorted trapezium is assumed. The reaction co-ordinate is taken along the direction between the OH hydrogen atom and C3-carbon atom. As the reaction co-ordinate is invariant to rotation about the C2 -C3 bond the choice of the configuration does not affect the final results.It seems likely that the photoinduced hydrogen shift within the framework of the model presented, consists of an intramolecular radiationless H-migration. The idea that photochemical reactions are radiationless relaxation processes has emerged from earlier concepts concerning non-radiative transitions. 84-86 During the last 83 A. Devaquet, J. Am. Chem. SOC.,1912, 94,5160. 84 R. M. Langer, Phys. Rev., 1929, 34,92. 0. K. Rice, Phys. Rev., 1929, 34, 1451. 86 N.Rosen, J. Chem. Phys., 1933, 1, 319. 85 Light-induced Tautomerism of P-Dicarbonyl Compounds few years this approach has successfully been applied in the field of photochemical hydrogen abstraction processes, particularly in the cases of excited ketone^.^'*^^ The basic problem is whether these reactions should be treated as radiationless transitions or as hydrogen atom transfer over a potential energy bar~ier.~~-~~ That and some similar problems can be solved, at least in principle, on the basis of general theoretical considerations (see, for instance, refs.94 and 95). Such theories can be extended to interpret photochemical reactions with the ultimate aim of finding structure-reactivity relationships in the electronically excited states. However, the complex nature of this approach, as well as the necessity to introduce physical and mathematical approximations connected with the application of the theory, reduces its efficiency considerably. It is reasonable to presume on the other hand that in the case of hydrogen migration there will be an important digression from the classical behaviour of a moving particle.The wave associated with the motion of the hydrogen atom has a wavelength in the 10-8-10-9cm range. Since the barriers on the pathways of chemical reactions have a total width of a few Angstrom units, one can expect the tunnel effect to be of some importance. This was suggested at an early date by a number of author^.^^-'^ More recently, experimental evidence has been forthcoming and there has been renewed interest in the part played by the tunnel effect in the transfer of protons or hydrogen atoms and in other phenomena. According to Kasha, tunnelling arises since the construction of the potential energy surfaces implies a separation of the electronic and vibrational motions.In this sense the tunnel-effect theory considers hydrogen transfer reactions with electronically excited carbonyl compounds as radiationless transitions. loo -O2 Its application to the photoketonization of P-dicarbonyl compounds has been discussed elsewhere. lo3 In order to assess the relative contributions of both tunnelling and over-the-barrier processes for photoketonization the Gamow factorlo4 can be compared to the Boltzmann one. For enol-keto interconversion (ethyl acetoacetate) the energy barrier is 3.5 kcal mol- and the Gamow factor is significantly higher. Consequently, the contribution of the over-the-barrier process can be neglected. From an experimental point of view, the quantum tunnelling is J.C. Scaiano, J. Photochem., 1973-74, 2, 81. S. G. Cohen, A. Parola, and G. H. Parsons, jun., Chem. Rev., 1973, 73, 141. 89 W. G. Dauben, L. Salem, and N. J. Turro, Arc. Chem. Res., 1975, 8, 41. S. J. Formosinho, J. Chem. SOC.,Faraday Trans. 2, 1976, 72, 1313. 91 A. Hailer, Mol. Photochem., 1969, 1, 257. 92 R. C. Dougherty, J. Am. Chem. SOC.,1971, 93,7137. 93 C.M. Previtali and J. C. Scaiano, J. Chem. Soc., Perkin Trans. I, 1972, 1667. 94 J. Jortner, S. A. Rice, and R. M. Hochstrasser, Adv. Photochem., 1969, 7, 149. 95 S. A. Rice, Adv. Chem. Phys., 1971, 21, 153. 96 S. Roginsky and L. Rosenkewitsch, Z. Phys. Chem., 1930, B10,47. 97 E. Wigner, Z. Phys. Chem., 1932, B19,203. 98 R. P. Bell, Proc. R. SOC.London, Ser. A, 1933, 139,466. 99 S. G.Christov, Ann. Univ. Soja, Far. Phys. Math., 1945-46, 42,69. loo S. J. Formosinho, J. Chem. Soc., Faraday Trans. 2, 1974, 70,608. lo' S. J. Formosinho, J. Chem. SOC.,Faraday Trans. 2, 1978, 74, 1978. lot S.J. Formosinho, Mol. Photochem., 1977, 8, 459. lo3 G. St. Nikolov and P. Markov, J. Photochem., 1981, 16, 93. lo4 G. Gamow, Z.Phys., 1928,51, 204. 86 Markov well founded by the significant isotope effect of the process under c~nsideration.'~ The rate of photoconversion, enol+ ketone, is given by''' k, = k,exp -%(2~D)~dx " 1 The quantities presented in the equation are illustrated in Figure 12. Figure 12 Illustration of the quantities involved in the description of the crossing of the two potential energy curves: Vp,for the products; V,,for the reactants; X,the reaction co-ordinate; R, the displacement of the two parabolas For intramolecular processes the transmission factor k, is taken to be 10-'3s-1.Potential energy curves V,and Vpare estimated for harmonic oscillators 0-H and C -H. As can be seen, the rate of photoketonization is strongly dependent on the barrier width (Ax), Ax along with the barrier height (D) being a function of the displacement of the potential energy curves (R) and the energy gap (LIE). As Ax decreases with increasing LIE, it becomes evident why excitation of the enolic species excitation enables formation of the keto tautomer. The contribution of 0-H and C =0 oscillators along the direction of the bond to be formed (C -H), depends on the presumed geometry of the transition state (Figure 11).From this point of view the good agreement between the calculated1 O3 and experimentally fo~nd'~,~~characteristics of the photoinduced tautomerism lends support, to a certain extent, to the basic assumptions concerning its mechanism. In spite of the marked reproducibility of the experimental data assuming a singlet state of the reacting species, the nature of the reactive excited state is still controversial. Generally speaking the higher singlet reactivity is entirely accounted for by a higher electronic energy value, which produces smaller energy barriers and Light-induced Tautomerism of P-Dicarbonyl Compounds barrier widths. Since the difference E6 -ET is probably constant and not too large, the possibility of a triplet precursor formed as a result of intersystem crossing (S, + T,) cannot, however, be avoided.The lifetimes of the first excited singlets for the enol forms are very small (approximately 2 x 10-9s). Consequently, the internal conversion leading to the population of the first excited triplet must occur in a very short time interval at a very high rate. The internal conversion rate constant kisf is knownlo5 to be in order of 10-7-10-" s-l which is sufficiently high compared with the lifetime of the first excited singlet. According to El- Sayedlo6 carbonyl compounds, such as those considered here, undergo efficient intersystem crossing. That is why it seems reasonable that photoketonization can proceed from the triplet state of the excited enol as well.Strong evidence of a triplet-sensitized ketonization of ethyl acetoacetate was recently obtained by Getoff et ~1.~~ There is, however, yet another possibility: the primary photoproduct can be a short-lived rotamer (presumably trans) of the enol form which undergoes fast thermal conversion into the keto form. Since the tautomerism of 8-dicarbonyls is also a thermal reaction such an idea is considered as promising. It was first explained in ref. 47. Later, Veierov et~l.~~proposed the mechanism F%E14% hv where E is chelated enol, El is non-chelated enol, and K is the keto form. There is, however, no experimental evidence for the process El -+K. In order to get a further insight into the link between the processes of photoisomerization and phototautomerism, the photochemical behaviour of some cyclic P-ketoesters was studied (see ref.63). In spite of any possibility for a photoisomerization via rotation about the C2-C3 bond, the keto-enol equilibrium was observed to be shifted to the keto form when solutions of these compounds were irradiated. It becomes evident that the phototautomerization occurs independently: plSES$ A It is also clear, however, that other rotational or vibrational motions lifting the orbital restriction for hydrogen migration are indeed possible. Recently an independent mechanism for the formation of photoisomerization and phototautomerization products was proposed by Courtot et for the case of P-tricarbonyl compounds.Metal Derivatives of P-Dicarbonyl Compounds.-Some Remarks on the Concept of Metallotropy. The preparation of alkali-metal derivatives of P-dicarbonyl Io5 N. J. Turro, 'Molecular Photochemistry', Benjamin, New York, 1965. Io6 M. A. El-Sayed, J. Chem. Phys., 1963, 38,2834. Markov compounds was described by Wislicenu~’~~ as early as 1877. After this pioneer work, interest in the structure and reactivity of the metal salts of /3-dicarbonyls has been steadily increasing. Michael”* has demonstrated their dual reactivity towards alkyl halides, i.e. the formation of both 0-and C-alkyl derivatives of ethyl acetoacetate. The logical explanation of such a phenomenon was the assumption of the existence of a metallotropic (prototropic-like) equilibrium: I I-c=c-g -c-c-I I1 IOM OM Enolate Carbeniate Regardless of the efforts in this field, however, no direct experimental evidence in favour of such an equilibrium has ever been found.It was for this reason that in the late fifties the ‘non-existence’ of a metallotropic equilibrium in solutions of metal derivatives of the fi-dicarbonyl compounds was postulated. In his fundamental work ‘Theoretical Backgrounds of Organic Chemistry’ (Leipzig, 1952) Huckel noted: ‘The numerous efforts for argumentation of this idea theoretically or experimentally undoubtedly has showed its inacceptability. The notation tautomerism is inapplicable to the case of metal derivatives of keto-enols . . .’ (Chapter 5.8.1.). In his book ‘Theoretical Problems of Organic Chemistry’ (Moscow, 1956), Reutov remarks: ‘There is no example of a structure type isomerism in the case of metal derivatives of keto-enols depending on the position of the metal atom’ (Chapter X).An attempt to elucidate the dual reactivity not involving the idea of metallotropy was made in 1948 by Nesmeyanov and associates.lo9 For the first time they drew attention to the importance of the ‘shift of the reaction centre’ during the reaction. In fact, the metallotropic tautomerism was found to be irrelevant. Since the type of migrating species is in principle not critical, the lack of a logical background for such a conclusion becomes apparent. From a general point of view, two extremes of the situation may be considered.If the potential function representing the enolate-carbeniate transformation is of a double-minimum type with a barrier high above the ground state of the normal modes for the skeletal vibrations in the metallotropic forms, it would be reasonable to treat the metallotropic conversion as an ordinary chemical reaction. If the potential barrier is, however, comparable with the ground state vibration energies, quantum-mechanical tunnelling is likely to occur. On the other hand, if the potential barrier is of a single-minimum type, there will be no different metallotropic forms. In this case, it would be somewhat inadequate to speak about a metallotropic equilibrium or interconversion. From this point of view the unsuccessful attempt to prove experimentally the metallotropy of alkali-metal derivatives of /I-dicarbonyls should be attributed to the very low energy barrier between the two tautomeric forms, relative to the high electropositivity of the metal atom. lo’ J.Wislicenus, Annulen, 1877, 186, 161. lo* A. Michael, J. Prukt. Chem., 1887, 37, 473. lopA. N. Nesmeyanov, V. A. Sazonova, and E. B. Lander, DAN (SSSR), 1948, 63, 395. Light-induced Tautomerism of P-Dicarbonyl Compounds Spectroscopic proof for the existence of a metallotropic equilibrium in magnesium ethyl acetoacetate solutions was first reported in 1964' lo (Scheme 5). MeI 0 0 Mg/2IIMe-C-CH-C0,Et //C-O,HC Mg/2 GMdf2 + 'C=O'.' I OEt 0 Scheme 5 The quantitative description of the metallotropic process has been given in the paper.'" It was later shown that calcium and copper derivatives of ethyl acetoacetate also possess such a property. '' The latest studies in this field' l3 extend the area of known metallotropic transformations to the nickel and cobalt derivatives of ethyl acetoacetate and the ethyl ester of benzoylacetic acid.Since 1964 there have been a number of very extensive studies on reversible metallotropic-type rearrangements (for example, refs. 114, 1 15). Metallotropic equilibria in solutions of mercury derivatives of fi-dicarbonyl compounds have been thoroughly studied.' 16-120 The estimated free-energy change in these cases is about 10kcalmol-'. The activation energy is found to be 9kcalmol-'. It is supposed on this basis that a metallotropic process proceeds as an intramolecular reaction. The geometrical parameters of the various metallotropic forms have been determined using X-ray diffraction.I2 Subsequently, Nakamoto and co-workers'22 have confirmed that the frequencies above 1600cm-' in the carbonyl region of i.r.spectra of metal derivatives of j-dicarbonyl compounds are due to the presence of the respective carbeniate form. A number of interesting studies on the structure and reactivity of metal derivatives of keto-enol systems has been performed by Gaudemar and I1O P. Markov, C. Ivanov, and M. Arnaudov, Chem. Ber., 1964, 97, 2987. III B. Jordanov, C. Ivanov, M. Arnaudov, and P. Markov, Chem. Ber., 1966. 99, 1518. 112 C. Ivanov, M. Amaudov, P.Markov, and L. Shishkova, Izv. Otd. Khim. Nauk BAN, 1980, 13, 198. 113 I. Petkov, K. Roumyan, C. Ivanov, and P. Markov, 'Annuaire de I'Universite de Sofia, Faculte de Chimie', in press. 11* M. Kirilov and G. Petrov, Ber., 1967, 100, 3139. 1l5 A. B. Bogatski, T. K. Tchumatchenko, A. E. Kojuchina, and M. B. Grenadirova, J. Gen. Chem. (Russ.), 1972, 42, 403. 'I6 K. Flatau and H. Musso, Angew, Chem., 1970, 82, 390. 11' F. Bonati and G. Minghetti, J. Organomet. Chem., 1970, 22, 5. R. Allmann, K. Fiatdu, and H. Musso, Chem. Ber., 1972, 105, 3067. 119 R. H. Fisch, J. Am. Chem. Soc., 1974,%, 6664. R. H. Fish, R. E. Lundin, and W. E. Hadden, Tetrahedron Lett., 1972, 921. Iz1 R. Allmann and H. Musso, Ber., 1973, 106, 3001. IZ2 G. Behnke and K. Nakamoto, Inorg.Chem., 1967, 6, 433, 490. Markov associates.'23-'25 On the basis of i.r. and n.m.r. data, they have found evidence for the presence of carbeniate-, enolate- and chelate-type species in solutions of Reformatsky reagents. Their results provide support that the ratio between the different forms depends strongly on the solvation ability of the solvent used. Various examples of reversible migration of an element included in an organic group in tautomeric systems have been studied by Lutzenko et al. (see for example refs. 126-128). Photoinduced Metallotropic Interconversions. The influence of ultraviolet light on some metal derivatives of /?-dicarbonyl compounds (10) in non-polar aprotic solvents was first described in refs.129,130. Contrary to known examples where (10) M = Cu,Ca.Mg,Co,Ni; 1R = Me, Phi R2 = various aliphatic radicals their photoreductive destruction takes place in polar media,' 31-'33 it was found that under these conditions the changes caused by ultraviolet irradiation are fully reversible. In some cases, a significant spectral change occurs in the course of time after dissolving the metal salt. The observed alterations in the U.V. spectrum of copper ethyl acetoacetate are presented in Figure 13. 123 M. Gaudemar, Bull. SOC.Chim. Fr., 1966, 31 13. Iz4 M. Gaudemar and M. Martin, C. R. Acad. Sci. (Paris), 1968, 267C, 1053. M. Bellassoued, F. Dardereze, F. Gaudemar-Bardone, M. Gaudemar, and N. Goasdoone, Terrahedron, 1976, 32, 271 3. lZ6 1.F. Lutzenko, Yu. T. Baukov, 0.V. Dudukina, and E. N. Karamoarova, J. Organomef. Chem., 1968, 11, 35. lZ7 I. F. Lutzenko, Yu. I. Baukov, I. Yu. Belavin, and A. N. Tworgov, J. Organomef. Chem., 1968, 14, 229. I. F. Lutzenko, Yu. I. Baukov, and I. Yu. Belavin, J. Organomet. Chem., 1970, 24, 359. lz9 P. Markov, I. Petkov, and C. Ivanov, C. R. Acad. Sci. (Paris), 1978, 286C, 505. I3O P. Markov, I. Petkov, and C. Ivanov, J. Organomet. Chem., 1979, 173, 211. 131 N. Filipescu and H. Way, Inorg. Chem., 1969, 8, 1863. 132 H. D. Gafney and R. Lintvedt, Inorg. Chem., 1970, 9, 1728. 133 H. D. Gafney and R. Lintvedt, J. Am. Chem. Sor., 1970,92, 6996. Light- induced Tautomerism of p-Dicarbonyl Compounds 300 hnr t 0.8 Figure 13 U.V.spectra of copper ethyl acetoacetate in heptane (ca. 0.5 x 10-4mo11-') measured at different times after solution (1)0, (2)1, (3)7, (4)20h The ultraviolet irradiation of the stabilized (constant U.V.spectral characteristics with time) heptane solutions produces profound spectral changes (Figures 14-15). Figure 14 U.V.spectra of copper ethyl acetoacetate in heptane (ca. 0.5 x 10-4mo11-') at different times after the start of the U.V. (254 nm)irradiation Markov nm2 0.8 3 0.6 c b 0.4 0 2 0.24 0 Figure 15 U.V. spectra of CU(~-C~C,H,COCH,CO~E~)~in heptane (ca. 0.5 x lo-, moll-') at dzferent times afer the start of the U.V. irradiation (3 13 nm) The linear dependences between 290 and 250nm peaks of some metal derivatives (R' = Ph), measured after different durations of ultraviolet irradiation, are given in Figure 16.0.6 0.4 0.2 0.2 0.4 0.6 0.8 1.0 1.2 290 A Figure 16 Dependence between the absorbances A,,, and A,,, of compounds I, 11, and Ill measured at different times afer the start of U.V. irradiation (3 13 nm). Initial concentrations 0.5 x lo-, moll- '. (I), Cu(m-MeC H,COCH,CO,Et),; (II), Cub-ClC,H,COCH,CO,Et),; (III), Cu(p-MeC,H,COCH,eO,Et), Efforts to obtain a theoretical interpretation of the u.v.-spectra of some metal chelates of B-dicarbonyl compounds have been made by Basu and Chatterji. * 34 According to Belford et al. 35 the 254 nm absorption band in the U.V. spectrum of copper ethyl acetoacetate is due to a 7~ -+ n* transition in the CO-conjugated system of the chelate form.Substantially different results-two bands at 239 and 134 S. Basu and K. K. Chatterji, J. Phys. Chem., 1958, 209, 360. 135 R. L. Belford, A. E. Martell, and M. Calvin, J. Inorg. Nucl. Chem., 1956, 2, 11. 93 Light-induced Tautomerism of p-Dicarbonyl Compounds 269 nm-have been reported by Sen and Thankarajan.'36 Previosuly the Pariser-Parr-Pople scheme4' and CNDO/S method4* were used to study the ground- and excited-state properties of the enol form of acetoacetic acid. The energy of the n +n* transition, calculated for the chelate form is 5.00 eV (248 nm). On the other hand it has been shown experiment~!ly~~ that the open (non-chelated) form absorbs at 228nm. Consequently, it may be concluded that monochromatic (254 nm) irradiation of metal salts solutions of ethyl acetoacetate (R'-aliphatic radical) shifts the metallotropic equilibrium hv hvchelate == enolate ecarbeniate to the carbeniate form. This conclusion gains support also from the available i.r.spectral data (Figure 17). 1500 1800 cm'' 1,500 l8qO cm-1 (a) (b) c The strong i.r. absorption near 1530 and 1600cm-', attributed to the chelate complex, decreases in intensity during irradiation while the intensity of the 1720 and 1740 absorption bands (carbeniate form) increases. Accordingly, new maxima appear at 1640 and 1660 cm; ' (enolate). In the case of metallo-derivatives of benzoylacetic acid ethyl ester (R' = C6H,), the diminishing intensity in the 280-310nm region is accompanied by the appearance and enhancement of a new absorption band at 245-255 nm (Figure 14).The presence of isobestic points in the successive U.V. spectra of irradiated solutions and the linear relationship found between the absorbances of two forms (Figure 17) undoubtedly show the existence of a photometallotropic interconversion producing predominantly the carbeniate form. 136 D. N. Sen and N. Thankarajan, Indian J. Chem., 1968, 6, 746. 94 Markov The kinetics of the photometallotropic process depends on the type of the metal in~luded."~The quantum yields vary from 0.017 to 0.029. As it was pointed out, spectrophotometric assays of the solutions after irradiation show a gradual restoration of the chelate concentration. This reversibility implies that no destructive photoprocesses ensue under the chosen experimental conditions.It is as yet difficult to rationalize the effect of U.V. light on the metallotropic equilibria. The available experimental data are insufficient to allow the discussion of the possible involvement of electronically excited states of the metal chelate in the process of photoactivated metallotropy. As far as this transformation is effected as a thermal reaction, it seems probable that an open enolate form is the resulting species. This assumption implies that the rate of the photoactivated process must depend on the stability of the respective metal chelate. However, the dependence of the rate of photoactivated metallotropy on some structural peculiarities of the ligand system and on the nature of the metal cannot be clearly traced.A correlation exists between the values of the rate constants and the respective quantum yields. 30 The substitution of electron-releasing atoms or groups at the para-position in benzene ring tends to increase the oscillator strength due to the lengthening of the conjugate system. Other Tautomeric Compounds.-The nitrogen-containing analogues of ethyl acetoacetate, the ethyl ester of 3-aminocrotonic acid and its N-substituted derivatives, are photosensitive compounds. The alteration found137 in the i.r. and U.V.spectra show that the irradiation gives rise to a photoinduced hydrogen transfer from the nitrogen to the carbon atom (Scheme 6): HNR OR2 NR OR2II hV I1 I-c=c-c=o --c-c-c=o /\R11 H R' Scheme 6 More recently, 38 supporting evidence for photoinitiated hydrazine-hydrazone isomerization, as shown in Scheme 7, has also been obtained.R2NHN OR' R,N-N OR211 -It I -c=c-c=o --c-c-c=o I /\R' H R' Scheme 7 13' P. Markov, 1. Petkov, and M. Arnaudov, Mol. Photochem., 1979, 9, 295. 138 1. Petkov and P. Markov, to be published. 95 Light-induced Tautomerism of fi-Dicarbonyl Compounds 4 Conclusion Three obvious areas for further development in the field of photoinduced tautomerism of b-dicaibonyl compounds can be outlined: Mechanistic Aspects. Further efforts in tracing the path of the migrating particle may show more clearly the roles of excitation, solvents, and catalysts. Synthetic Aspects.The thermal chemistry of p-dicarbonyls has been an active field of research for a very long time. Such studies have covered several areas of synthetic applications. It can be foreseen that their photochemical variants will be used in new synthetic pathways. Biochemical Aspects. Photoinduced tautomerism is an interesting phenomenon since it may play an important role in photochemical processes of biological significance.

ISSN:0306-0012    

DOI:10.1039/CS9841300069

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

Reactive Intermediates in Enzyme-catalysed Reactions* By Colin J. Suckling DEPARTMENT OF PURE AND APPLIED CHEMISTRY, UNIVERSITY OF STRATHCLYDE, 295 CATHEDRAL STREET, GLASGOW GI IXL 1 Introduction It has often been remarked that enzymes catalyse reactions in a subtle manner, making full use of the inherent reactivity of their substrates. Although the reactions mediated by enzymes are sometimes surprising at first sight, a closer study reveals that the mechanisms involved are closely akin to those found in solution reactions. Training in organic chemistry emphasizes the mechanistic relationships between solution reactions and a major part of such generalizations centres upon reactive intermediates. The factors that influence the reactivities of carbanions, radicals, carbocations, and carbenes are familiar fare.Similarly the relationship between the stability of a reactive intermediate and the rate of a reaction is also familiar; since such intermediates are high energy species, they will usually be closer in character to the transition state for the reaction than either the starting materials or the products. Hence, if the intermediate can be stabilized in some way, a lowering in energy of the transition state will probably result also, and the reaction will be accelerated. In the last ten years, significant advances have been made in our understanding of the basis of enzymic catalysis. The essence of catalysis by enzymes is to have the right reactants together at the right time and in the right place.This summarizes the entropic component of enzymic catalysis, that is enzyme-catalysed reactions are essentially made intramolecular by the ability of the enzyme to bind reactants at its active site. Several recent reviews deal with this However, once reaction is in progress at the active site, an enzyme still has to deal with the formation and utilization of reactive intermediates. It has been known for many years how enzymes deal with the problem of stabilizing carbanions but only recently have the enzyme chemistries of radicals, carbocations, and carbenes been placed upon a firm experimental basis. *This review is based upon one section of an Irvine Review Lecture given at the University of St. Andrews, November, 1982, and it is the author’s hope that the presentation of the topic through the familiar frame of the reactive intermediate will be instructive to the general reader and will also offer the practising organic chemist a new perspective on the important topic of enzymic catalysis.Many of the subjects described are considered in more detail in ‘Enzyme Chemistry, Impact and Applications’, ed. C. J. Suckling, Chapman and Hall, London, 1984 and references to appropriate chapters will be cited in this review. * R. Kluger in ‘Enzyme Chemistry, Impact and Applications’, ed. C. J. Suckling, Chapman and Hall, London, 1984, chapter 2. A. J. Kirby in ‘Comprehensive Organic Chemistry’, vol. 5, ed. E. Haslam, Pergamon, Oxford, 1979 p. 389. W. N. Lipscomb, Acc. Chem. Res., 1982, 15, 322.U -0 b bH 'P' Acyl carrier protein (ACP-SH) 177 amino-acids (E.co/i)] (2) Figure 1 Coenzyme A and Acyl Carrier Protein Suckling This article discusses some modern aspects of the chemistry of these reactive intermediates at enzyme active-sites and draws parallels, where appropriate, with synthetic chemistry or with topics of current mechanistic significance. 2 Carbanions Condensation reactions involving carbanions form one of the largest classes of synthetic methods for constructing the carbon skeleton of an organic compo~nd.~.~This is as true of biosynthetic reactions as of laboratory synthesis. The chief contrast between the two fields is that biological reactions substitute for the controlling techniques of low temperatures and sterically hindered bases typical of modern synthetic organic chemistry the ordered precision of the enzyme’s active site.Although an enzyme can exert considerable control upon the course of possible reactions of its substrate, it still has to overcome the problem of generating carbanions. Strong bases are, of course, not available from the side-chains of protein amino-acids and consequently, when carbanions are required, enzymes must ensure that the anions are stabilized to achieve catalysis. Three coenzymes are especially important in this regard, coenzyme A (CoA) and the related acyl carrier protein (ACP), thiamine pyrophosphate (TPP) and pyridoxal phosphate (PLP). The salient features df these coenzymes have been understood for some time and have been extensively A.Coenzyme A and Acyl Carrier Protein.-The familiar Claisen ester condensation is one of the fundamental base-catalysed synthetic reactions of organic chemistry. Formally, there are close parallels between the carbon-carbon bond forming reactions in the biosynthesis of fatty acids and polyketides and this condensation. However, the enzyme reactions employ thiol esters in place of alcohol esters and the thiols are provided by CoA (1) or ACP (2) (Figure 1). With respect to their oxygen-containing analogues, thiol esters are more readily attacked at the carbonyl group and the a-protons are more acidic. In an alcohol ester, the non-bonded electrons of the alcohol oxygen atom can be considered to be delocalized into the carbonyl group.In the sulphur analogue, however, delocalization of the more diffuse 3p non-bonded electrons is less effective and consequently the carbonyl group of a thiol ester has reactivity more typical of a ketone than an ester. In quantitative terms the difference can be seen in the pK, values of related 8-dicarbonyl compounds: a typical /3-ketoester 10.5; a P-diketone 8.2-8.9, and a P-ketothiolester 8.5.9 It was therefore tempting to rationalize the R. K. Mackie and D. M. Smith, ‘Guidebook to Organic Synthesis’, Longmans, London, 1982, pp. 83-93. R. 0.C. Norman, ‘Principles of Organic Synthesis’, 2nd edn., Chapman and Hall, London, 1978, p. 225. H. C. S. Wood in ‘Comprehensive Organic Chemistry’, vol.5, ed. E. Haslam, Pergamon, Oxford, 1979, p. 489. H. Dugas and C. Penney, ‘Bioorganic Chemistry’, Springer Verlag, New York, 1981. K. E. Suckling and C. J. Suckling, ‘Biological Chemistry’, Cambridge University Press, Cambridge, 1980. T. C. Bruice and S. J. Benkovic, ‘Bioorganic Mechanisms’, vol. 1, Benjamin, New York, 1966, p. 297. Reactive Intermediates in Enzyme-catalysed Reactions biosynthesis of fatty acids as involving carbanions in the chain-extending reaction (Scheme 1) and it came as a surprise when Lynen, who had played a major role MeCOSACP + CH,COSCoA iMeCOCH,COSACPI + cozCO, H iik"ADpHNADP+ MeCH=CHCOSACPa MeCH(0H) CH-COSACP t MeCH,CH,COSACP etc. Scheme 1 in elucidating the significance and general chemical characteristics of thiol esters, showed that carbanions were not intermediates in this reaction." He was able to isolate the required enzyme and to prepare malonyl-ACP, the chain-extending unit. Consistent with the ease of ionization of the protons a to the thiol ester, it was found that these protons rapidly exchanged with deuterium in D,O. If a carbanion is formed in the enzyme-catalysed reaction, it would be expected that an isotope effect on the reaction rate would be observed when the deuteriated substrate was used.None was found. A further piece of evidence against the formation of carbanions was that no tritium was incorporated into the product when the reaction was run in tritiated water. As the equation shows (Scheme 1, reaction l), this reaction also involves a decarboxylation and loss of carbon dioxide can provide the nucleophilic reactivity required for condensation.Lynen argued that the isotope experiments showed that decarboxylation and condensation are concerted events in the enzyme-catalysed reaction. It is often easy to draw formal analogies between the mechanisms of simple chemical reactions and biochemical ones but, as in this case, there can be substantial differences. There are, however, coenzyme A mediated reactions in which carbanions do appear to be involved. The stereochemistry of dehydration of hydroxyacyl-CoAs, analogous to step 3 in the biosynthesis of fatty acids (Scheme I) suggests that an EICB-type mechanism is operating' and significant primary deuterium isotope effects have been measured for the reactions catalysed by malate and citrate synthases (Scheme 2).13-15 lo K.-I. Arnstadt, G.Schindbleck, and F. Lynen, Eur. J. Biochem.. 1975, 55, 561. P. Willadsen and H. Eggerer, Eur. J. Biochem., 1975, 54, 247. IZ B. Sedgwick, C. Bacquet, and S.J. French, J. Chem. Soc., Chem. Commun., 1978, 193. l3 J. W. Cornforth, J. W. Redmond, H. Eggerer, W. Buckel, and C. Gutschow, Nature, 1969,221, 1213. l4 J. Luthy, J. Retey, and D. Arigoni, Nature, 1969, 221, 1213. J. Retey, J. Seibl, D. Arigoni, J. W. Cornforth, G. Ryback, W. P. Zeylemaker, and C. Veeger, Eur. J. Biochem., 1970, 14, 232. Suckling + CoASH CH2 Cog (3"'COSCoA citrate I -'2'--OH + CoASH + -O~CCOCH,CO,-synthase I CH,CO,' Scheme 2 Until very recently, this pattern of behaviour was generally accepted but Douglas has awakened some possibilities that have lain dormant for many years.l6 He has shown that some thiolesters can undergo acyl transfer reactions via ketene intermediates (Scheme 3) and suggests that electrocyclic addition of a ketene to an CH,COCH,COSCoA =CH3COcHCOSCoA INuH -CH,COCH=CCH,COCH,CONu =O malate CH3C0SCoA synthase*? CH CO -I2 -/f\HO C02-L Scheme 3 aldehyde or ketone might be a reasonable mechanism for the reactions catalysed by malate and citrate synthases. Such a sequence would involve the formation of lactones, as was first suggested in 1943 by Martius." Although the stereochemistry of the reactions can be accounted for in this way, the lactone intermediates must undergo hydrolysis to obtain the product and this reaction would require catalysis by the enzyme.Thus the synthases would have to exhibit condensing and hydrolysing activity: catalysis of more than one reaction by an enzyme is not l6 K. T. Douglas, M. Alberz, G. R. Rullo, and N. F. Yaggi, J. Chem. Soc., Perkin Trans. 2, 1982, 1675, 1681. C. Martius, Hoppe Seyler's 2. Physiol. Chem., 1943, 279, 96. Reactive Intermediates in Enzyme-catalysed Reactions unusual. The ketene mechanism has also been considered in the context of fatty acid biosynthesis. The facility with which thiol esters undergo condensation reactions has not passed unnoticed by synthetic chemists. For reactions in which conventional acylations are inefficient, such as the synthesis of macrolides, it has been found that thiol esters provide an efficacious solution' 9-24 (Scheme 4).Reactions have been 0 Hg= * or Agl 25 OC RCoNa+ Mg(O2CCH2COSBut), -RCOCH~COSBU~ Scheme 4 successful both with simple alkyl compounds and with highly functionalized molecules such as precursors to antibiotic macrolides. Also, close analogues of the chain-extending unit of fatty acid biosynthesis have been used to construct functionalized carbon chains. Several further synthetic transformations modelled upon other enzyme-catalysed reactions will be described below. B. Thiamine Pyrophosphate.-In all of the reactions involving thiol esters, the carbonyl group acted as an electrophile; it was therefore easy to construct carbon skeletons with carbonyl groups fl to each other.Such reactivity cannot, however, be used to prepare a-dicarbonyl systems. The first chemical reaction to achieve this was the benzoin reaction in which cyanide acts as a catalyst. The condensation is effective because the cyanohydrin can form a carbanion stabilized by the cyano- group and this anion then adds to a second molecule of the aldehyde. Is L. Jaenicke and F. Lynen in 'The Enzymes', ed. P. D. Boyer, H. Lardy, and K. Myrback, 2nd edn., Academic Press, New York, 1960, vol. 3, p. 62. I9 G. E. Wilson, jun. and A. Hess, J. Org. Chem., 1980, 45, 2766. 2o S. Masamune, S. Kamata, and W. Schilling, J. Am. Chem. Soc., 1975, 97, 3515.zL S. Masamune, Y. Hayase, W. Schilling, W. K. Chan, and G. S. Bates, J. Am. Chem. Sac., 1977, 99, 6756. 22 E. J. Corey and D. J. Brunelle, Tetrahedron Lett., 1976, 3409. 23 H. Gerlach and A. Thalman, Helv. Chim. Ada, 1974, 57, 2661. 24 S. Masamune, Aldrichimica Acta, 1978, 11, 23. Suckling PhCHO + CN-ePhCH(0H)CN ePhC-(0H)CN PhC-(0H)CN + PhCHO -P PhCH(0H)COPh + CN-It was many years before this catalytic device was developed into a synthetic strategy known as ‘umpol~ng’,~~*~~ but meanwhile, a good understanding of the related biochemical system had been stimulated by Breslow’s experiments on thiamine pyrophosphate. 27 Thiamine pyrophosphate is an N-alkylthiazolium salt and Breslow’s key observation was that the C-2 proton underwent unusually rapid exchange for deuterium in D,O solution (Scheme 5).This observation was Thiamine pyrophosphate TPP H D R-C-0’ I H R Scheme 5 interpreted as being consistent with the formation of a carbanion at C-2, an ylide in fact, since the molecule also has a positively charged nitrogen atom. Formation of carbanions a to heteroatoms in heterocyclic rings is a normal occurrence but N-alkylthiazolium salts are particularly reactive due both to the positive charge and to the sulphur atom. In this way, a nucleophilic intermediate that can add to carbonyl groups can be generated. The parallel between the reactivity of such adducts and synthetic acyl anion equivalents can then be readily seen. In all cases, the carbonyl derivative bears an acidic proton that can yield a stabilized carbanion 25 Ref.4, p. 98. 26 D. Seehach, Angew. Chem., Int. Edn. Engl., 1979, 18, 239. 27 R.Breslow, J. Am. Chem. SOC.,1958,80, 3719. 103 Reactive Intermediates in Enzyme-catalysed Reactions (Scheme 5). In bacteria, such intermediates are formed in the synthesis of acetoin, analogous to the benzoin condensation, but a more significant contribution of thiamine pyrophosphate is in the pyruvate dehydrogenase-catalysed conversion of pyruvate into acetyl-CoA, the link between glycolysis and the citric acid cycle. The nature of this enzyme differs widely between organisms but the initial reaction of TPP with pyruvate and its subsequent decarboxylation is common to all of these enzymes (Scheme 6).The success of TPP in this reaction can be readily recognized 430,OH 0 Jliii 0 -N, S II +v & HS SH S SH Reagents: (i)-(iv), pyruvate decarboxylase; (v), dihydrolipoate transacetylase; (vi), dihydrolipoate dehydrogenase (requires NAD' + FAD) Scheme 6 in its ability to accept electrons from the C-C bond cleaved in decarboxylation. This affords an acetyl anion equivalent, which in the enzyme-catalysed reaction acylates lipoic acid before being transferred to CoA. Two types of thiazolium derivatives have been exploited in synthesis.28 Firstly, the direct analogue of the enzymic intermediate has been used in condensation reactions (Scheme 7)29 and secondly, the oxidation product of this intermediate, S.Shinkai in 'Enzyme Chemistry, Impact and Applications, ed. C. J. Suckling, Chapman and Hall, London, 1983. chapter 3. l9 R. C. Cookson and R. M. Lane, J. Chem. Soc., Chem. Commun., 1976, 804. Suckling R = CH2Ph 1-H20 (b) ;OR’+ R’CHO + R‘CON~ NuH = HzO, ROH, HONH,, RSH Scheme 7 a 2-acylthiazolium salt, has been shown to be capable of providing a means for the transformation of an aldehyde into a variety of carboxylic acid derivatives including esters, hydroxamic acids, and thiol esters (Scheme 7).30,31 Although TPP effectively stabilizes a carbanion, there is still work for the enzyme to do to catalyse anion formation. The importance of stereoelectronic effects in controlling the courses of non-enzymic reactions is well e~tablished~~ and it has been realized that the same factors are important in enzyme-catalysed reactions.One of the first cases to be described in detail concerned PLP, which will be discussed briefly in a moment, but the same arguments apply to TPP.’ The essence of stereo-electronic control in these cases is that bond breaking to form a stabilized carbanion will be favoured if the bond to be broken lies in the same plane as the p-orbitals of the conjugated ring (Scheme 8). The conformation shown is co2-Scheme 8 30 F. G. White and L. L. Ingraham, J. Am. Chem. Soc., 1962, 84, 3109. 31 H. Inoue and K. Higashiwa, J. Chem. Soc., Chem. Commun., 1980, 549. 32 R. W. Alder, R. Baker, and J. M. Brown, ‘Mechanism in Organic Chemistry’, Wiley Interscience, New York, 1975.p. 21. 105 Reactive Intermediates in Enzyme-catalysed Reactions optimal for decarboxylation and the enzyme achieves this arrangement by binding the reactants with a suitably disposed anionic side-chain of an amino-acid at the active site. C. Pyridoxal Phosphate.-PLP is involved in a much wider range of reactions than TPP, three of which are illustrated for the amino-acid ~erine~~ (Scheme 9). In these CHO L i (" 'HCHO' + PLP+ -@O -HOCH,CH,NH, + PLP H&H, co; H+ + co, B o a o H t HO/Kcoc 'N CH, 0 pyridoxamine phosphate Scheme 9 reactions, the carbanion is formed by deprotonation of the first intermediate, an imine (Scheme 10). The enzymes can take advantage not only of stereo-electronic effects to catalyse carbanion formation but can also use them to control the reaction course.As with TPP, the heterocyclic ring stabilizes the carbanion, in this case by delocalization on to the positively charged nitrogen atom. Amino-acids are typical substrates for pyridoxal-dependent enzymes; in some cases, such as serine (Scheme 9), there are three possible bonds that can be broken to give the carbon. D~nathan~~was the first to point out that which bond is broken can be controlled 33 Ref. 7, p. 419; ref. 8, p. 82. 34 H. C. Dunathan, L. Davis, P. G. Kury, and M. Kaplan, Biochemisfry, 1968, 7, 4532. 106 Suckling XCH2 NH2 + CH,X 7%-fI HZ 7&0-H+ H X = HI CO, HOCH2, etc.I Scheme 10 by the conformation of the adduct at the enzyme’s active site; the stereo-electronic requirement is the same as with TPP (Scheme 10).Another feature of this group of enzymes that attracted Dunathan’s attention was the very close similarity between enzymes with quite different metabolic functions. He envisaged that all PLP-dependent enzymes have evolved from a common progenitor, through slight changes in binding sites, whilst maintaining essentially the same catalytic mechanism. This widely held concept is most attractive chemically because it suggests that PLP-dependent enzymes might be prepared to accept non-natural substrates and be applied to synthesis. One early example of this was the preparation of chiral isotopically labelled glycine using aspartate-pyruvate ammonia tran~ferase:~’ the pro-R hydrogen readily undergoes exchange for a heavier isotope in the appropriate medium.Such applications are useful for the synthesis of small quantities of research chemicals, but in Japan, a PLP-dependent enzyme has found use in the industrial synthesis of L-tryptophan (Scheme 11); the + + 73 CH,CH73 + H20+ HOCHZCHoJ = 0-J‘c0,-H ‘co; H Scheme 11 enzyme was used in immobilized form.36 A third aspect of PLP chemistry, with respect to synthesis, is the mimicking of the biological process as was discussed for 35 P.Besmer, Dissertation No. 4435, E.T.H. Zurich, 1970. 36 s. Fukai, S. Ikeda, M. Fujimura, H. Yamada, and M. Kumagai, Eur. J. Biochem., 1975, 51, 155. 107 Reactive Intermediates in Enzyme-catalysed Reactions TPP.Rapoport3’ has stripped PLP of those features necessary for binding to the enzymes (the hydroxymethyl phosphate) and has concentrated the reaction into 4-formyl-N-methylpyridiniumsalts (Scheme 12) thus emphasizing the carbanion stabilizing features. With this compound, it was possible to promote transaminations of amines to aldehydes and ketones in good yield, a useful reaction because many alternative oxidations of amines to carbonyl compounds employ less selective reagents. PLP-dependent enzymes also feature in medicinal chemistry. Since they catalyse a great many important metabolic reactions, these enzymes become prime targets for inhibition by drugs in the treatment of pathological conditions. In particular, the concept of mechanism-based, so-called ‘suicide’ inhibitors, has been extensively in~estigated.~~A good understanding of the mechanism of action of an enzyme is an excellent start for the design of an inhibitor and in the case of the PLP enzymes, the ability of the coenzyme to stabilize a carbanion was the focus for attention. It was realised that it might be possible to divert the normal course of reprotonation of the stabilized carbanion through the loss of a good leaving group or through protonation at a more remotely conjugated site (Scheme 13).The products from such reactions are respectively a,P-unsaturated carbonyl equivalents, to which Michael addition may occur, or allenes, which will readily undergo acid-catalysed nucleophilic addition.If the addend is a nucleophilic group from the enzyme’s active site, PLP becomes covalently bound to the enzyme which is thereby inhibited. Of the large number of inhibitors of this type, perhaps the most notable is y-vinyl-GABA, studied by the Merrell This compound is an effective and selective inhibitor of GABA-transaminase, the enzyme that initiates the catabolism of the inhibitory neurotransmitter, GABA. Inhibition in vivo causes brain GABA levels to be elevated and the compound is undergoing clinical trials as a potential treatment for epilepsy. 3 Radicals and Carbenes When thinking about organic reaction mechanisms, it is easiest to consider extremes, a fact that has led to much protracted controversy. Thus the advocate of polar mechanisms can easily pay insufficient attention to the possibility that a 3’ T.F. Buckley and H. Rapoport, J. Am. Chem. Soc., 1982, 104, 4446. 38 C. Walsh, Tetrahedron, 1982, 38, 871. 39 B. Lippert, 8. Metcalfe, M. Jung, and P. Casara, Eur. J. Biochem., 1977, 74, 441. I08 Suckling EnzNuTj $R EnzNu V H a--aH+ H+ / R = CH2CH2COzH Y-vinyl-GABA - EnzNuhR rN Q( H+ H+ Scheme 13 radical mechanism might be operating and, of course, vice versa. Although polar mechanisms are most frequently discussed in the chemistry of enzymes, a remarkable wealth of radical chemistry exists principally through the involvement of transition metal complexes and through the radical character of the ultimate oxidant, oxygen. The fields in which radical intermediates are important extend well beyond the organic chemist's first preoccupation with such species in enzyme- Reactive Intermediates in Enzyme-catalysed Reactions catalysed reactions, namely in oxidative coupling reactions in bio~ynthesis.~' The oxidation of a phenol to a phenoxy radical, in which the unpaired electron density is delocalized on oxygen and the ortho and para carbon atoms, allowed the interpretation of a very large number of biosynthetic processes leading to alkaloids and phenolic fungal metabolites (Scheme 14).Many of these reactions can be 0' Me0 J Me0Me0q How :NMe BuIbocapnine OMe Cularine Morphine Scheme 14 40 R. B. Herbert in 'Comprehensive Organic Chemistry', vol. 5, ed.E. Haslam, Pergamon, Oxford, 1979, p. 1068. I10 Suckling reproduced synthetically using transition-metal ion ~xidants.~l-~~ Interest in radical chemistry in enzyme-catalysed reactions then turned to a remarkable series of rearrangement reactions catalysed by coenzyme B, ,. More recently, the question of the involvement of radical intermediates in flavin- and nicotinamide coenzyme-mediated reactions has been under active research. Some of the flavin-dependent enzymes are hydroxylation catalysts and parallel research into the chemistry of hydroxylating metalloenzymes, especially cytochrome P-450; additionally, the possibility of carbene intermediates in the latter’s reactions has been suggested. A discussion of some aspects of the chemistry of each of these systems follows.However, none of these reactions is more important than the reduction of oxygen at the termini of electron transport chains that complete the energy producing process known as oxidative pho~phorylation.~~ A. Coenzyme B,,.-Vitamin B12,or cyanocobalamin, is converted in vivo into the enzymically active coenzyme, adenosyl cobalamin that is responsible, amongst other things, for promoting a number of important double 172-rearrangements (Scheme 15). Much evidence from both enzymic and model experiments is consistent with the involvement of radical intermediates in B, ,-mediated reactions45 but, as is frequently the case with any mechanistic study, direct evidence has been very difficult to obtain. It has, however, been well established that coenzyme B,, and related model compounds can exist in three oxidation states.These can be understood as arising formally from heterolytic cleavage of the Co-C bond to give cobalt(1) and an organic cation, heterolytic cleavage to cobalt(I1) and a radical or the second possible heterolytic cleavage giving cobalt(m) and a carbanion. Each can be brought about under appropriate conditions but the photolability of the Co-C bond to give cobalt(I1) and a radical is a particularly facile reaction. One line of evidence that has led to the belief that radical intermediates are likely in the enzyme-catalysed reactions is the study of the stereochemical course of the rearrangement reactions using isotopic labels. The reaction catalysed by ethanolamine ammonia lyase is an interesting case in which racemization of the substrate takes place; an unusual event in an enzyme whose metabolic function is not racemi~ation~~.~’(Scheme 16). The results were consistent with a mechanism in which homolysis of the Co-C bond leads to an adenosyl radical, which abstracts a hydrogen atom from the substrate to initiate rearrangement.The reaction is terminated by the reverse abstraction of a hydrogen atom from the adenosyl methyl group by the substrate but evidently, before this happens, there is sufficient time for the substrate to racemize by rotation. There has been much effort to understand the detailed nature of the rearrangement step and 41 D. H. R. Barton and G. W.Kirby, J. Chem. SOL..,1962, 806. 42 M. A. Schwartz and R. A. Holton, J. Am. Chem. SOC.,1970, 92, 1090. 43 M. A. Schwartz and I. S. Mami, J. Am. Chem. SOC.,1975, 97, 1239. 44 B. G. Malmstrom, Ann. Rev. Biochem., 1982, 51, 21. 45 B. T. Golding in Comprehensive Organic Chemistry’, vol. 5, ed. E. Haslam, Pergamon, Oxford, 1979, 549. 46 J. Retey, C. J. Suckling, D. Arigoni, and B. M. Babior, J. Biol. Chem., 1974, 249, 6359. 47 D. Gani, 0.C. Wallis, and D. W. Young, Eur. J. Biochem., in press. Reactive Intermediates in Enzyme-catalysed Reactions HO OH -NHZ HC-CH,I Coenzyme B,, Some rearrangements catalysed by coenzyme B12-dependent enzymes - CH3 CH -CH I I 2 CH,CH,CHO + H,O OH OH - H&CH,-CH~OH - CH,CHO + NH&+ CH3CHCOSCoA CHtCOSCoA I I CO, H CH~CO, H Scheme 15 cobalt-n-complexes have been popular intermediates.More subtle suggestions involving electrocyclic reactions of the coenzyme ring have also been made.48 Whilst not attracting great support, the proposition of this alternative makes it clear that a satisfactory understanding of these reactions has not yet been reached. 48 E. J. Corey, N. J. Cooper, and M. L. H. Green, Pmc. Nat. Acad. Sri. USA., 1977, 74, 81 1. I12 Suckring CHZAd I NH, + CH,CHO H3N<H 'CH,AdH L (Con) KO=) I I I c / + J OH H,N OH Scheme 16 B. Reactions Mediated by Flavin and Nicotinamide Coenzymes.-The heterocyclic coenzymes containing nicotinamide or flavin systems are the mainstays of biological oxidation reactions at the level of organic substrates.Consequently there has been a great deal of interest in the mechanisms of action of these compounds in enzyme catalysed reactions. Additionally, chemists have been intrigued by the' possibility of mimicking the biological reactivity with model systems.28 Although this pursuit has led to much interesting chemistry, it has also fermented controversi concerning the mechanisms of action of the coenzymes at the enzymes' active site. The centre of the discussion has concerned the possible intermediacy of radicals and a few words on the current position for nicotinamide and flavin coenzymes follows. In the case of nicotinamide coenzymes, two of the chief candidate mechanisms are summarized in Scheme 17.There have been several reliable reports of one- electron transfer reactions from reduced nicotinamide coenzymes (NADH) analogues to sufficiently strong oxidants such as ferricyanide but the situation has been confused by a large number of studies of reactions with but weakly oxidizing substrates that have been interpreted as indicating radical intermediate^.^^ Very few experiments, however, have addressed themselves to the more difficult task of probing the enzyme's mechanism itself. The best way to tackle this problem was to use a molecule that would report the intermediacy of radical intermediate and 49 For an extensive list of references and critical discussion see M. F. Powell and T. C. Bruice, J. Am. Chem. SOC.,1983, 105, 1014.113 Reactive Intermediates in Enzyme-catalysed Reactions Nicot in am ide adenine dinucIeotide (oxidised form) CONH, R' + \ c=o ==== 21 I R CONH2 R' 'r'-0-R2/I R 1Probe of enzyme mechanism: R = H, R2 = cyclopropyl not observed Scheme 17 this has been done for alcohol dehydr~genase~' and for lactate dehydr~genase.~ The principle of the probe is that if a radical forms, the cyclopropane ring will undergo ring opening which can be detected by isolating the products of the reaction. In neither case was any ring opening found, and related model reactions showed the same behaviour. 1*52 The current concensus is that nicotinamide- I. MacInnes, D. C. Nonhebel, S. T. Orszulik, and C. J. Suckling, J.Chem. SOC.,Chem. Commun.,1982, 121. 51 D. C. Nonhebei, S. T. Orszulik, and C. J. Suckling, J. Chem. SOC.,Chem. Commun., 1982, 1146. 52 J. C. T. van Niel and U. K. Pandit, J. Chem. SOC.,Chem. Commun., 1983, 149. 114 Suckling mediated oxidations and reductions take place through hydride transfer mechanisms. With flavins, the situation is more complex because these molecules are very effective one-electron oxidants and reductants as well as undergoing hydride-like two-electron reactions. As Walsh has aptly put it, flavin coenzymes are at the crossroads of biological redox chemistry. 53 One further major difference between flavins and nicotinamide coenzymes is that the reduced form of the former can be oxidized directly by oxygen whereas the latter cannot.In fact, many flavin-mediated reactions involve oxygen as a co-substrate. In some cases such as amino-acid oxidases and hydroxy-acid oxidases, there is good evidence for the formation of carbanions at the substrates, although the nature of the oxidation step is still uncertain (Scheme 18). For substrates lacking the anion-stabilizing R = H riboflavin ?H = P03H f lavin monophosphate FMN 0-0--I I -'P/O\POO\adenosineII II0 0 flavin adenine dinucleot ide FAD 0 oxidized form lactate oxidase: R H+ R LHO-T-CO~H II CH3 0 reduced form ,CO2H o=c 'CH3 Scheme 18 53 C. Walsh, Acc. Chem. Res., 1980, 13, 148. Reactive Intermediates in Enzyme-catalysed Reactions carbonyl group such as amines in amine oxidases, radical mechanisms may be involved.Indeed Bruice has obtained evidence from model studies that the oxidation of carbanions by flavins takes place through one-electron steps. 543 An alternative reaction of flavins with oxygen leads to incorporation of one atom of the dioxygen molecule into the substrate. Oxygen activation is thought to proceed through electron transfer from the reduced flavin to oxygen followed by combination of the radical pair. This leads to a 4a-hydroperoxyflavin which is the prime candidate for the biological hydroxylating agent (Scheme 19).53Bruice has R R R R I I OH RH = e.g. RCHO-RC0,H HO' Scheme 19 shown that the properties of this molecule belong to the same general series as alkyl hydroperoxides and per acid^;'^ the mechanism by which subsequent hydroxylations take place, however, are not yet established. Arguments have been presented for direct oxygen tran~fer,'~'~~ for radical recombination^,^^ and for N-5-0xides.~~In such discussions, it is important never to forget the nature of the substrate and it is highly probable that the mechanism of hydroxylation of aromatic compounds may be quite different from the oxidations of aldehydes and ketones to carboxylic acid derivative^.'^ Nevertheless, the activity in the chemistry 54 M.Novak and T. C. Bruice, J. Am. Chem. SOC.,1977, 99,8079. 5s T. C. Bruice, AN. Chem. Res., 1980, 13, 246. 56 T. C. Bruice, J. Chem. Soc., Chem. Commun., 1983, 14. s7 B. Entsch, D. Ballou, and V.Massey, J. Biol. Chem., 1976, 251, 2550. 58 J. W. Frost and W. H. Rastetter, J. Am. Chern. SOC.,1981, 103, 5242. 59 C. Walsh, 'Enzymatic Reaction Mechanisms', Freeman, San Francisco, 1979, chapters 11 and 12. 116 Suckling of flavins has led to the development of a useful mild epoxidizing agent that has some similarities with the reactivity of flavins. As Bruice has pointed out, the oxidizing ability of flavin 4a-hydroperoxides can be ascribed chiefly to the low pK, of the hydroperoxide (9.1-9.5). A similar situation exists in the hydroperoxyhydrate of hexafluoroacetone60*61 and this property has been harnessed for an effective synthetic reagent (Scheme 20). 0 AR hR OH OHI I CG-C-CF CF3-C -CF3I I OHOOH x H2° "2O2 CHZCLCH2Cl reflux in presence of Na2HPOL anhydrous Scheme 20 C.Reactions Mediated by Cytochromes P-450.--Cytochrome P-450 is the name commonly given to a class of haemoproteins that catalyses hydroxylation reactions. A wide variety of organic molecules can act as substrates, some endogenous and some foreign to the organism, including steroids, smaller alicyclic hydrocarbons, benzenoid, and polycyclic hydrocarbons. The enzyme operates by a cyclic mechanism (Figures 2 and 3). Self destruction as a result of generating reactive hydroxylating species is prevented by the requirement that a molecule of substrate binds to the active site before oxygen. The stoicheiometry of the cycle and the shunt by which organic hydroperoxides can short circuit it are well established but the nature of the hydroxylating species is still a topic of active research.As was discussed for the flavin-dependent enzymes, there is a great variety of substrates for cytochromes P-450 and it would not be surprising, therefore, if the mechanisms of action reflected the reactivity of the substrates as well as the catalytic properties of the enzyme. Nevertheless, an essential part of all P-450species appears to be a thiolate ligand from the protein which co-ordinates to an axial position of the iron opposite the oxygen. It is most probable that this excellent donor ligand has the job of stabilizing an electrophilic hydroxylating agent generated at the iron. The connection between cytochromes P-450 and radical and carbene intermediates was first discussed by Hamilton6' who suggested that the potent hydroxylating ability of these enzymes might be due to the generation of a highly electrophilic oxygen species, oxene, which would insert into a carbon-hydrogen 6o R.P.Heggs and B. Ganem, J. Am. Chem. SOC.,1979, 101, 2486. 6L A. J. Bileski, R. P. Heggs, and B. Ganem, Synthesis, 1980, 810. 62 G. A. Hamilton in 'Molecular Mechanisms of Oxygen Activation', ed. 0.Hayaishi, Academic Press, New York, 1974, p. 405. """' Reactive Intermediates in Enzyme-catalysed Reactions Flavoprotein Iron (EII) sulphur P450 Fer'GHZO NADPH Flavoprotein Iron (II)sulphur (oxidised) protein ROH Figure 2 The cytochrome P-450system of adrenal steroidogenic tissue RH RH"il H2° sI MT Figure 3 Proposed mechanism for cytochrome P-450.(a) RH binds to low-spin Fe"'P-450.converting it into a high-spin complex. (b)One electron enters from the P-450reductase, giving an Fe" state. (c) Oxygen binds and a second electron enters, forming the formal Fell-0, -complex. (d) The active form of oxygen is generated, hydroxylation takes place and the products, ROH and water, diffuse off the complex, leaving it in its initial state bond in an analogous manner to singlet ~arbenes.~~ This suggestion, although attractive, has not received much experimental support and the balance of evidence now seems to favour radical pathways, especially for aliphatic hydroxylation. The first results pointing strongly in this direction were from model studies.Following earlier work showing that metalloporphyrins are potent autoxidation initiators, Groves discovered that tetraphenylporphyrin-metal complexes together with iodosobenzene as a source of oxygen have a lot in common with the enzymes 63 W. Kirmse, 'Carbene Chemistry', 2nd edn., Academic Press, New York, 1971. Suckling them~elves.~~-~'He has been able to establish that the complex formed after oxygen is transferred to the iron from iodosobenzene is able to abstract hydrogen from a substrate yielding a radical which then recombines with the hydroxy-group co-ordinated to iron as if on a rebound (Scheme 21). The characteristics of the 0 PhIO II Fem(TPP) CI -FeY(TPP) CI OH IRH I ROH + Fe*(TPP)CI -FeX(TPP)C1 + R' Scheme 21 reactions of this system with such substrates as alkenes leading to allylic rearrangements and cyclopropanes leading to ring opening are also consistent with the intermediacy of radicals.A related mechanism may operate with the enzymes themselves and the observation of a substantial kinetic isotope effect in the oxidation of norbornane is consistent with this vie^.^**^^ However, there have been strong suggestions that in the reaction with oxygen itself, a complexed acyl hydroperoxide is an intermediate (Scheme 22). Homolytic cleavage of this complex RH RH t-""" ___f S-Fe-0-OCOL(P450l-J R' - RH S-Fe--0. HOC S-Fe-O* *OCO L(P450)----f3 Scheme 22 64 J. T. Groves in 'Metal Ion Activation of Dioxygen', ed.T. G. Spiro, Wiley, New York, 1980, p. 125. 65 J. T. Groves, T. E. Nemo, and R. S. Myers, J. Am. Chem. SOC.,1979, 101, 1032. J. T. Groves, W. J. Kruger, jun., and R. C. Haushalter, J. Am. Chem. Soc., 1980, 102, 6375. 67 J. T. Groves, R. C. Haushalter, M. Nakamura, T. E. Nemo, and B. 1.Evans, J. Am. Chem. SOC.,1981, 103, 2884. J. T. Groves, G. A. McClusky, R. E. White, and M. J. Coon, Biochem. Biophys. Res. Commun., 1978, 81, 154. 69 M. J. Coon and R. E. White in 'Metal Ion Activation of Dioxygen', ed. T. G. Spiro, Wiley, New York, 1980, p. 73. 119 Reactive Intermediates in Enqvrne-catalysed Reactions leads to two radicals at the active site, one of which abstracts hydrogen leaving the complexed oxygen able to bond to the substrate radical pr~duced.~'-~~ This pattern of reactivity seems to be consistent with the hydroxylation of cumene, camphor, and cyclohexane and also indirectly with the oxidation of cyclopropyl benzene to benzoic acid in which three sequential oxidation steps seem to occur.73 Aromatic compounds offer more mechanistic ambiguities than aliphatic substrates as can be seen by the effect of exchanging oxygen for sulphur in the demethylation of arylmethyl ether^.^^,^' It has been found that a large primary hydrogen-isotope effect accompanies the demethylation of a series of substituted an is ole^^^*^^ and this result has been interpreted to indicate rate-determining hydrogen abstraction from the methyl group.However the analogous series of thioethers showed no such isotope effect. Instead, a correlation between the one- electron oxidation potential of the thioether and the rate of demethylation was observed.In this case, it was argued that the rate-determining step involves electron transfer from substrate to the haem complex. There is also evidence that aromatic hydroxylation occurs through addition to the aromatic ring and not through abstraction or insertion mechanisms (Scheme 23). The well known NIH3X X hydroxylatenzyme ing ~ 'NIy;:ift'+ @ D D HO Scheme 23 shift has been a major technique for diagnosing addition-rearrangement mechanisms: as indicated in Scheme 23, rearrangement of an intermediate epoxide leads to substantial retention of isotopic label (limited by the kinetic isotope effect).This behaviour is characteristic of cytochromes P-450and of a few model systems in which a strong oxidant is present.77 The metabolism of warfarin in vivo in rats is thought to proceed through a mechanism of this type.78 One of the consequences of the generation of radical intermediates by cytochromes P-450at their active sites is that side reactions in which the radicals attack the porphyrin ligand can take place. This phenomenon has been observed 'O R. E. White, S. G. Sligar, and M. J. Coon in 'Biochemistry, Biophysics and Regulation ofCytochrome P-450'. ed. J.-A. Gustaffson, Elsevier North Holland, 1980, p. 307. R. C. Blake 11 and M. J. Coon, in ref. 70, p. 315. '* S. G. Sligar, M. Besman, M. Gelb, P.Gould, D. Heimbrook, and D. Pearson, in ref. 70, p. 379. 73 K. E. Suckling, C. G. Smellie, I. E. Ibrahim, D. C. Nonhebel, and C. J. Suckling, FEBS Lett., 1982, 145, 179. l4 Y. Watanabe, T. Iyanagi, and S. Ode, Tetrahedron Lett., 1982, 23, 533. l5 Y. Watanabe, S. Ode, and T. Iyanagi, Bull. Chem. SOC.Jpn., 1982, 55, 188. l6 J. R. Lindsay Smith, R. E. Piggott, and P. R. Sleath, J. Chem. SOC.,Chem. Commun., 1982, 55.'' L. Castle and J. R. Lindsay Smith, J. Chem. SOC.,Chem. Commun., 1978, 704. E. D. Bush and W. F. Trager, Biochem. Biophys. Res. Commun., 1982, 104, 626. 120 Suckling with a variety of substrates including substituted cyclopropylmethylamines.79*80A further ramification of this reaction concerns the oxidation of halogen-containing anaesthetics and related compounds in the liver, a major location of cytochrome P-450.8 The generation of trichloromethyl radical by microsomes containing cytochrome P-450and in rat liver has been demonstratedE2 but such results by no means prove a relationship between the formation of radicals and liver damage.Nevertheless, there seems little doubt that the adventitious generation of radicals in vivo is a major cause of tissue damage and the relationship between lipid peroxidation and ageing has received considerable attention.8 Although the reactions of cytochrome P-450 discussed above have been interpreted chiefly in terms of radical mechanisms and not oxenoid intermediates, there is conclusive evidence for the formation of carbene complexes related to cytochrome P-450from X-ray analysis (Scheme 24).83This phenomenon led recrystallite Fen(TPP) + CC!, -Cl,C=Fe(TPP) -C12C=Fe(TPP)OH2 studied by X-ray crystallography Scheme 24 Mansuy and Ullrich to investigate the cause of the synergism of 1,3-benzodioxoles with insecticide^.^^ They found that a dichlorobenzodioxole reacts with tetraphenylporhinatoiron(I1) (Scheme 24)and, on addition of butyl thiolate, a spectrum resembling that of the enzyme treated with the synergist resulted.This reaction causes inhibition of the enzyme. Since hydroxylation by cytochrome P-450 is a major detoxification route for foreign compounds in many organisms, the synergism of the benzodioxoles could well be due to the blocking of the insects’ detoxification pathways.In view of the extensive hydroxylating ability of cytochromes P-450and other metal-containing oxygenases, it is not surprising that attempts have been made to mimic their reactivity with simpler chemical rnodekE5 One goal of research has been to match the catalytic efficiency of the enzymes and this has best been attained 79 R. P. Hanzlik and R. H. Tullman, J. Am. Chem. Sor., 1982, 104, 2048. *O T. L. Macdonald, K. Zirvi, L. T. Burka, P. Peyman, and F. P. Guengerich, J. Am. Chem. Soc., 1982, 104, 2050. ‘Free Radicals in Biology’, vol. 4, ed. W. A. Pryor, Academic Press, New York, 1980. 82 P. B. McCoy, T. Noguchi, K.-L. Fong, E. K. Lui, and J. L. Poyer, in ‘Free Radicals in Biology’, vol. 4. ed. W. A. Pryor, Academic Press, New York, 1980, p.157. 83 D. Mansuy, M. Lange, J.-C. Chottard, J. F. Bartoli, B. Chevrier, and R. Weiss, Angew. Chem., fnt. Edn. Engl., 1978, 17, 781. 84 D. Mansuy, J. P. Battioni, J.-C. Chottard, and V. Ullrich, J. Am. Chem. Sor., 1979, 101, 3971. 85 T. Matsuura, Tetrahedron., 1977, 33, 3971. 121 Reactive Intermediates in Enzyme-catalysed Reactions using manganese tetraphenylporphyrin complexes as catalysts for hydroxy-lationse6 and epoxidation~.~~*~~ Alternatively, emphasis has been placed upon attaining enzyme-like regioselectivity in hydroxylati~n.~~~~~ The achievement of high selectivity with high catalytic efficiency has yet to be reached for the latter. D. Reactions Catalysed by other Haernopr0teins.-A second group of haemoproteins in which oxygen is caused to react with organic substrates to generate radicals is concerned in the formation of hydraperoxides.A particularly H eCozH11 1L arachidonic acid / \ y OOH -'0-0' H I COz H H OH leukotriene A a prostaglandin (PGG) Scheme 25 86 I. Tabushi and N. Koga, J. Am. Chem. Soc., 1979, 101, 6456. E. Guilmet and G. Meunier, Tetrahedron Lett., 1980, 4449. 88 D. Mansuy, M. Fontcave, and J.-F. Bartoli, J. Chem. Soc., Chem. Commun., 1983, 253. 89 C. J. Suckling, ind. Eng. Chem., Prod. Res. Dev.,1981, 20, 434. C. J. Suckling, J. Chem. Res., 1981, (S) 280, (M) 3279-3291. 122 Suckling important reaction is the conversion of cis,cis-1,6pentadienes, a common feature of polyunsaturated fatty acids, into the cis,tuans conjugated hydroperoxide (Scheme 25).Such a reaction is characteristic of a radical mechanism and evidence for the intermediacy of radicals in vivo has been obtained.82 The significance of these reactions lies in their participation in the biosynthesis of prostanoids including prostaglandins, prostacyclins, thromboxanes, and leukotrienes (including the so-called slow-reacting substances of anaphylaxis). All of these compounds are derived from oxidation reactions of arachidonic acid (Scheme 25), which contains two pairs of cis double bonds. Oxidation at C-5 leads to leukotrienes whereas oxidation at C-1 1 leads to prostaglandins. Since arachidonate metabolites have a wide range of biochemical actions-including inflammation, the control of blood platelet aggregation, and the control of the reproductive cycle-chemical manipulation of the pathway has become an attractive proposition for medicinal chemist^.^^^^^ To illustrate an approach to manipulating these biosynthetic pathways, Corey’s extensions of his original leukotriene synthesis are rele~ant.~~.~~ The design strategy was to generate specific inhibitors for either prostaglandin or the leukotriene branch by replacing one of the double bonds by an acetylene.In the hydroperoxide-forming reaction, an allylic hydroperoxide would result at the site determined by the enzyme. If this site held an acetylene, an allenic hydroperoxide would form instead, fragmentation of which would lead to reactive radicals that would inhibit the enzyme (Scheme 26).It was J Scheme 26 found that both 11,12- and 14,15-dihydroarachidonicacids were potent inhibitors of prostaglandin biosynthesis, whereas the 5,6-isomer inhibited leukotriene biosynthesis selectively, as would be expected from the mechanism. 4 Carbocations Whereas the scope of organic-radical intermediates in enzyme-catalysed reactions is large, chemistry relating to carbocations chiefly concerns the biosynthesis of B. Hesp and A. Willard in ‘Enzyme Chemistry, Impact and Applications’, ed. C. J. Suckling, Chapman and Hall, London, 1984, chapter 5. 92 J. Ackroyd and F. Scheinemann, Chem. SOC.Rev., 1982, 11, 321. 93 E. J. Corey and H. Park, J. Am. Chem. SOC.,1982, 104, 1750. 94 E. J.Corey and J. E. Munroe, J. Am. Chem. SOC.,1982, 104, 1752. 123 Reactive Intermediates in Enzyme-catalysed Reactions isoprenoid corn pound^.^^*^^ In this field, a number of striking rearrangement processes have been shown to occur with a high degree of stereospecificity and some are shown in Scheme 27.A great deal of elegant chemistry using isotopically -PPi H + H2cH3c*F@o Gtranyl pyrophosphate Scheme 27 labelled molecules has established the stereochemical course of such reactions. Since most of the stereospecific reactions then known related to SN2 and E2 reactions, it was natural for chemists to formulate such biosynthetic reactions in similar terms. For the interconversion of isopentenyl and dimethyl ally1 pyrophosphates (Scheme 27), this interpretation took the form of an enzyme nucleophile (SMe) that both stabilized an incipient positive charge and then acted as a good leaving group.This, and similar rationalizations, found wide acceptance. No experimental evidence was available to test the hypothesis, however, largely because of difficulties in obtaining sufficiently pure samples of the appropriate enzymes. The first experimental questioning of the nucleophile hypothesis came showedwhen P~ulter~~’~~that the behaviour of fluorinated analogues of isopentenyl pyrophosphate (see Scheme 27) and other isoprenoids was not consistent with the addition-elimination mechanism demanded by the participation of a nucleophilic group on the enzyme’s active site. For example, if the analogue shown in Scheme 27 underwent reaction by the hypothesized pathway, loss of a proton to eliminate the enzymic nucleophile would be impossible because of fluorine substitution.Hence the compound should act as an q5 J. W. Cornforth, Quart. Rev., 1969, 125. 96 J. R. Hanson in ‘Comprehensive Organic Chemistry’, vol. 5, ed. E. Haslam, Pergamon, Oxford, 1979, p. 989. 97 C. D. Poulter, E. A. Marsh, J. C. Argyle, 0.J. Muscio, and H. C. Rilling, J. Am. Chem. Soc., 1979, 101, 6761. 98 C. D. Poulter and H. C. Rilling, in ‘Biosynthesis of Isoprenoid Compounds’, vol. I, ed. J. W. Porter and S. L. Spurgeon, Wiley Interscience, New York, 1981, p. 161. 124 Suckling irreversible inhibitor. Although the fluorinated analogues bind to the enzyme well, no irreversible inhibition was observed.On the basis of this and other evidence, Poulter argues that the addition-elimination mechanism should be abandoned. Many years earlier, some provocative papers by Sneeng9 advocated the idea that even SN2 reactions take place not by concerted processes but through tight ion pairs, which kinetically are equivalent to the undissociated substrate (Scheme 28). Rt + X-RY + X' R-X (RtX-) solvent scparated Scheme 28 The extension to the S,l mechanism is obvious. One attractive feature of this point of view is that the transition between SN1 and SN2 behaviour can be envisaged as reflecting the tightness of the ion pairing, a situation that would be strongly dependent upon the reaction conditions.Indeed with regard to cyclization reactions in terpene biosynthesis, evidence has been presented to suggest that a spectrum of cyclization mechanisms from concerted to ionic through degrees of ion pairing is possible. 'O0 The enzymic counterpart of these experiments has begun to emerge recently, chiefly through the work of Cane.10'*'02 With the aid of l8O labels, his group has established that the enzyme-catalysed cyclization of several acyclic isoprenoids occurs without loss of the label (Scheme 29). Indeed in some cases, the labelled oxygen does not even exchange by rotation about the P-0 bond. Thus the best current interpretation of these results is that enzyme-catalysed cyclizations take place through a series of tight ion pairs.The phosphate leaving-group remains, presumably co-ordinated to magnesium at the active site, and the rearrangement takes place with the positive charge remaining virtually within bonding distance of the phosphate. This obviates the need for an additional electron-donating group to stabilize the cation in a most economical fashion. There are, however, cases in which the structure of the enzyme has a specific capability for stabilizing cationic intermediates. The classic example of this phenomenon concerns the enzyme lysozyme which hydrolyses amino-polysaccharides (Scheme 30). Cationic mechanisms for such reactions are favoured by the ability of the adjacent oxygen atom to stabilize the positive charge,Io3 but even a delocalized cation must have a counter ion.In lysozyme, X-ray crystallography has shown that an aspartate residue is positioned close to the site 99 R. A. Sneen and J. W. Larsen, J. Am. Chem. Soc., 1969.91, 362, 6031. loo C. D. Poulter and C. H. R. King, J. Am. Chem. SOC.,1982, 104, 1420, 1422. Iol D. E. Cane in 'Enzyme Chemistry, Impact and Applications', ed. C. J. Suckling, Chapman and Hall, London, 1984, chapter 7. Io2 D. E. Cane, A. Saito, R. Croteau, J. Shasko, and M. Felton, J. Am. Chem. Soc., 1982, 104, 7274. Io3 L. Hough and A. C. Richardson in 'Comprehensive Organic Chemistry', vol. 5, ed. E. Haslam, Pergamon, Oxford, 1979, p. 714. Reactive Intermediates in Enzyme-catalysed Reactions Geranyl pyrophosphate Scheme 29 OH NHAc CH,CHC02H CH3CHCO2H Lysozy me cleaves here of generation of positive charge in hydrolysis.O4 The electrostatic interaction contributes to catalysis by this enzyme. A quantitative estimate of the catalytic advantage of such a charge neutralization has been obtained by Sinnott"' who studied the hydrolysis of glycosylpyridinium salts by P-galactosidase. These reactions proceed unambiguously through an S,l pathway with no covalent participation by the enzyme. Compared with the non-enzymic reaction, p-galactosidase causes a rate enhancement of 104-105 due to charge neutralization. *04 A. Warshel, Proc. Nai. Acad. Sci. USA., 1978, 75, 7250. lo5 C. C. Jones, M. L. Sinnott, and L. J. Souchard, J. Chem. SOC.,Perkin Trans. 2, 1977, 1191. Suckling 5 Transition-state Stabilization At the beginning of this article, I reminded readers about the relationships between the stabilities of transition states and reactive intermediates. Since this relationship has proved a most fruitful one in the chemistry of enzymes, especially their inhibitors, some discussion is worthwhile. The first explicit connection between transition-state structure and enzymic catalysis was made by Pauling' O6 who extended Fischer's lock and key metaphor to suggest that an enzyme's active site is complementary to the transition state for the reaction that it catalyses.The concept has been further developed, primarily by W~lfenden,'.''~ and a wide range of inhibitors that are analogues of a presumed transition state, or perhaps more closely, of a probable reactive intermediate has been described.The parallels between inhibitor and reactive intermediate structure make satisfying organic chemistry. To revert to a reaction discussed earlier, pyruvate decarboxylase is inhibited by a phosphonate analogue of pyruvate (Scheme 31a). Although the coenzyme, TPP, adds to the carbonyl group, the adduct so formed cannot, of course, undergo decarboxylation and it blocks the active site."* The use of a phosphonate, which is a stable tetrahedral anionic group, to imitate a transient tetrahedral intermediate of an acyl group hydrolysis has also been a productive device. For example, a phosphonate analogue of a typical dipeptide substrate of carboxypeptidase is a potent inhibitor (Scheme 31b).'09 In this case, it is believed that the structure of the inhibitor matches the negatively charged phosphonate accurately, allowing bonding to the zinc ion at the enzyme's active site.The shape of a molecule alone can also provide a sufficiently close relationship to the binding preferences of an enzyme to cause inhibition. Thus, in racemization of a chiral centre, at some stage in the reaction a planar configuration is likely to be reached. An early example of a transition-state analogue showed this feature; the racemization of proline was inhibited by pyrrole-2-carboxylic acid; a planar analogue of the substrate' ' (Scheme 3 lc). A great merit of the transition-state analogue concept is that it offers a rational approach to the design of potent specific inhibitors of enzymes from mechanistic information or even from speculation.The relationship between inhibitors '9'' designed on the basis of transition-state structure is, of course, very close to the design of suicide inhibitors mentioned above. in the former case, the inhibitor is a molecule closely related to a structure on the normal reaction path: in the latter, the enzyme's normal mechanism is followed only part of the way until a branch that leads to destruction is reached. Finally, moving to the very earliest moments of the transformation of a substrate molecule bound at an enzyme's active site, there has been much discussion over the years about whether an enzyme distorts its substrate on binding. Undoubtedly lots L.Pauling, Nature, 1948, 161, 707. lo' R. Wolfenden, Acc. Chem. Res., 1972, 5,10. lo* R. Kluger and D. C. Pike, J. Am. Chem. SOL'.,1979, 101, 6425. lop N. E. Jacobsen and P. A. Bartlett, J. Am. Chem. Soc., 1981, 103, 654. 'lo G. J. Cardinale and R. H. Abeles, Biochemistry, 1968, 7, 3970. Reactive Intermediates in Enzyme-catalysed Reactions (a) Pyruvate decarboxylase inhibition CH~-C -OHI CH~-6-OH I P=O / \o-Me0 c 0// \o - inhibitor intermediate (b) Carboxypeptidase inhibition inhi bitor i n ter mcd iat e (c) Proline racemase inhibition c f. Qco;H H H2 inhibitor substrate Scheme 31 both enzyme and substrate molecules have some flexibility and it would be surprising if mutual adjustments were not made on binding.If a substrate undergoes such a distortion along the reaction co-ordinate, then distortion on binding may contribute to catalysis, as has been argued for lysozyme. Recently, using spectroscopic techniques, it has been possible to detect enzyme-substrate interactions in solution before the chemical transformation takes place. For example, strong evidence for the Lewis acid activity of the zinc ion in horse liver alcohol dehydrogenase has come from a resonance Raman spectroscopic study of the binding of 4-dimethylaminobenzaldehyde to the enzyme. l1 This compound has a carbonyl stretching frequency at 1664cm-' that is lost on binding to the I" P. W. Jagodzinski and W. L. Peticolas, J. Am. Chem. Soc., 1981, 103, 234. Suckling enzyme and is similarly lost by the model reaction of complexing with zinc ions in an organic solvent.The result was interpreted as evidence for the polarization of the carbonyl group of the substrate by zinc prior to hydride transfer from 1-53.11 1NADH.~ Fourier transform infrared spectroscopy has detected a 19cm- ' shift to lower frequency in the carbonyl absorption of dihydroxyacetone phosphate bound to triose phosphate isomerase. * Knowles has argued that this shift is due to a distortion of the carbonyl C-C-C bond angle by 9 O towards a single bond, as required in the reaction product glyceraldehyde 3-phosphate. 6 Conclusion The foregoing discussion has concentrated upon only one aspect of catalysis by enzymes, that relating to reactive intermediates.The convenience in discussion permitted by this limitation, however, should not be allowed to obscure the contribution of the whole enzyme molecule to catalysis in its natural environment. A minimum requirement in this regard is that the whole enzyme molecule must be soluble in its working environment, which may be aqueous, as in intracellular solution, or hydrophobic, as in lipid membranes. ' ' The stabilization of reactive intermediates by enzymes and coenzymes is, of course, advantageous for catalysis but its effect is simply to transfer the onus of the rate-limiting step from bond making and breaking to the association and dissociation of reactants from the enzyme's active site. The ultimate biological catalyst, as Knowles and Albery first pointed out,'I4 is an enzyme in which all the chemical steps proceed at optimal rates and hence diffusion becomes rate-limiting.When this situation has been reached, the only way in which an organism can improve the efficiency of its cnemistry is to bring together enzymes required for a particular biosynthetic pathway into an organized multi-enzyme complex.113 The construction of such a system clearly depends upon intermolecular interactions between enzyme molecules. As has been described above, although uncertainties remain, much is known about the chemistry of the insides of enzymes, the active sites; much remains to be discovered about the chemistry of their outsides. 112 J. G. Belasco and J. R. Knowles, Biochemistry, 1980, 19, 472. 'I3 N. C. Price and L.Stevens 'Fundamentals of Enzymology', Oxford University Press, Oxford. 1982. J. R. Knowles and W. J. Albery, AN. Chent. Res.. 1977, 10, 105.

ISSN:0306-0012    

DOI:10.1039/CS9841300097

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

INDEXES Volume 13, 1984 The indexes in this issue cover Volumes 1-13 (Figures in bold type refer to the volume number) Index INDEX OF AUTHORS Aarons, L. J., 5,359 Ackroyd, J., 11,321 Ager, D. J., 11,493 Ahluwalia, J. C., 2,203 Allen, N. S. 4,533 Angyal, S. J., 9,4 15 Ambroz, H. B., 8,353 Atkinson, D., 8,475 Attygalle, A. B., 13,245 Baker, A. D., 1,355 Barnfield, P., 13,441 Barker, B. E., 9,143 Bartle, K. D., 10, 113 Bartlett, P. D., 5, 149 Baxendale, J. H., 7,235 Beattie, I. R., 4, 107 Beddell, C. R., 13,279 Bell, R. P., 3, 513 Belson, D. J., 11,4 1 Bentley, P. H., 2,29 Berkoff, C. E., 3,273 Bird, C. L., 10,49 Bird, C. W., 3,309 Blandamer, M. J., 4,55 Blundell, T. L., 6, 139 Boelens, H., 7, 167 Bradshaw, T.K., 6,43Braterman, P. S., 2,271 Breslow, R., 1,553 Brown, D. H., 9,217 Brown, I. D., 7, 359 Brown, K. S.,jun., 4, 263 Brundle, C. R., 1,355 Buchanan, G. L., 3,41 Burdett, J. K., 3,293; 7, 507 Burgess, J., 4, 55 Burnett, M. G., 12, 267 Burrows, H. D., 3, 139 Burtles, S. M., 7,201Butterworth, K. R., 7, 185 Cadogan, J. I. G., 3, 87 Carabine, M. D., 1,411 Cardin, D. J., 2,99 Carless, H. A. J., 1,465 Casellato, U., 8, 199 Cetinkaya, B., 2,99 Chamberlain, J., 4,569 Chatt, J., 1, 121 Chesters, J. K., 10,270Chivers, T., 2,233 Clark, G. M., 5,269 Clark, R. J. H., 13,219 Collins, C. J., 4, 251 Colvin, E. W., 7, 15 Connor, J. N. L., 5, 125 Corfield, G. C., 1,523 Cornforth, J.W., 2, 1 Cotton, F. A., 4,27; 12, 35 Coulson, E. H., 1,495 Cowan, J. M., 8,419 Cox, B. G., 9,381 Coyle, J. D., 1,465; 3,329; 4,523 Cragg, G. M. L., 6,393 Cramer, R. D., 3,273 Crammer, B., 6,43 1 Cross, R. J., 2,271; 9, 185 Curthoys, G., 8,475 Dack, M. R. J., 4,211 Dainton, F. S., 4,323Dalton, H., 8,297 Davies, D. I., 8, 17 1 de Rijke, D., 7, 167 de Silva, A. P., 10, 181 de Valois, P. J., 7, 167 Dickinson, L. C., 12, 387 Dobson, J. C., 5,79 Dowle, M. D., 8, 171 Doyle, M. J., 2,99 Drummond, I., 2,233 Dunkin, I. R., 9, 1 Duxbury, G., 12,453 Elliott, M., 7, 473 Emsley, J., 9, 91 Eschenmoser, A., 5,377 Evans, D. A., 2,75 Evans, J., 10, 159 Fenby, D. V., 3, 193 Fensham, P. J., 13, 199 Fenton, D.E., 6,325; 8, 199 Ferguson, L. N., 4,289 Fisher, L. R., 6,25 Fleming, I., 10, 83 Flygare, W. H., 6, 109 Forage, A. J., 8,309 Fox, M. F., 9, 143 Frazer, M. J., 11, 171 Fry, A., 1, 163 Funk, R. L., 9,41 Garson, M. J., 8,539 Georghiou, P. E., 6,83 Gheorghiu, M. D., 10, 289 Gibson, K. H., 6,489 Gilbert, J., 10, 255 Gilchrist, T. L., 12, 53 Gillespie, R. J., 8, 315 Goodings, E. P., 5,95 Gordon, P. F., 13,441 Gorman, A. A., 10,205 Gray, B. F., 5,359 Green, C. L., 2,75 Greenhill, J. V., 6, 277 Greenwood, N. N., 3,231; 13,353 Grey Morgan, C., 8,367 Grice, R., 11, 1 Griffiths, J., 1,481 Grimshaw, J., 10, 181 Grossert, J. S., 1, 1 Groves, J. K., 1,73 Guilford, H., 2,249 Gutteridge, N.J. A., 1, 38 1 Haines, R. J., 4, 155 Hall, G. G., 2,21 Hall, L. D., 4,401 Hall, T. W., 5,43 1 Halliwell, H. F., 3, 373 Hamdan, I. Y., 8, 143 Hamer, G., 8,143 Harmony, M. D., 1,211 Harris, K. R., 5,215 Harris, R. K., 5, 1 Harrison, L. G., 10,491 Hartley, F. R., 2, 163 Hartshorn, S. R., 3, 167 Hathway, D. E., 9,63,24 1 Hayward, R. C., 12,285 Heelis, P. F., 11, 15 Henderson, J. W., 2, 397 Hepler, L. G., 3, 193 Hilburn, M. E., 8,63 Hinchliffe, A., 5,79 Holbrook, K. A., 12, 163 Holland, H. L., 10,435; 11,37Holm, R. H., 10,455 Hore, P. J., 8,29Horton, E. W., 4,589Hudson, M. F.,4,363 Huntress, W. T.,jun., 6, 295 Hutchinson, D. W., 6,43 Ibers, J. A., 11,57 Ikan, R., 6,43 1 Isaacs, N.S., 5, 181 Isbell, H. S., 3, 1 Jaffk, H. H., 5,165 James, A. M., 8,389 Jamieson, A. M., 2,325 Janes, N. F., 7,473 Jencks, W. P., 10,345 Jenkins, J. A., 6,139 Johnson, A. W., 4, 1; 9, 125 Johnson, S. P., 5,441 Johnstone, A. H., 7,3 17; 9,365 Jones, J. R., 10,329 Jones, P. G., 13,157 Josh, C. G., 8,29 Jotham, R.W., 2,457 Kalyanasundaram, K., 7, 453 Katritzky, A. R., 13,47 Keenan, A. G., 8,259 Kemball, C., 13, 375 Kemp, T. J., 3, 139; 8, 353 Kennedy, J. F., 2,355; 8, 22 1 Kennewell, P. D., 4, 189; 9,477Kenny, A. W., 4,90 King, G. A. M., 7,297 Kirby,G. W.,6, 1 Kitaigorodsky, A. I., 7, 133 Koch, K. R., 6,393 Kolar, G. F., 9,241 Korpela, T., 12,309Kresge, A. J., 2,475 Krishnaji, 7,219 Kroto, H., 11,435 Kriiger, H., 11,227 Kuhn, A.T., 10,49 Lappert, M. F., 2,99 Lee, M. L., 10, 113 Lee-Ruff, E.,6,195 Leigh, G.J., 1, 121; 4, 155 Lemieux, R. U., 7,423Leznoff, C. C., 3,65 Lindberg, B., 10,409Lindsay, D. G., 10,233 Lindoy, L. F., 4,421 Linford, R. G., 1,445 Lipscomb, W. N., 1,319 Liu, M. T. H., 11,127 Lynch, J. M., 3,309 Lythgoe, B., 9,449Makela, M. J., 12, 309 McCleverty, J. A., 12, 33 1 McKean, D. C., 7,399 McKellar, J. F., 4,533 McKervey, M. A., 3,479 Mackie, R. K., 3,87 McLauchlan, K. A., 8,29 McNab, H., 7,345 Maitland, G. C. 2, 18 1 Maitlis, P. M., 10, 1 Manning, P. G., 5,233 Maret, A. R., 2,325 Markov, P., 13,69 Maslowsky, E., 9,25 Mason, R., 1,431 Mayo, B. C., 2,49 Meadowcroft, A.E., 4,99 Menger, H. W., 2,415 Midgley, D., 4,549 Millen, D. J., 5,253 Mills, R., 5, 2 15 Moore, D. S., 12,415Moore, H. W., 2,415; 10, 289 Morgan, E. D., 13,245 Morley, R., 5,269 Morris, D. G., 11,397 Morris, J. H., 6, 173 Muetterties, E. L., 11, 283 Mulheirn, L. F., 1,259 Munn, A., 4,87Murphy, W. S., 12,213 Musumarra, G., 13,47 Newman, J. F., 4,77 Nightingale, W. H., 7, 195 Norman, R. 0.C., 8,l North, A. M., 1,49 Oakenfull, D. G., 6,25 Overton, K. H., 8,447 Page, M. I., 2,295Paulsen, H., 13, 15 Pelter, A., 11, 191 Perkins, P. G., 6, 173 Pickford, C. J., 10,245 Pletcher, D., 4,471Poliakoff, M., 3,293; 7,527 Index Prakash, V., 7,219 Pratt, A. C., 6,63 Puddephatt, R. J., 12,99 Ramm, P.J., 1,259 Rao, C. N. R., 5,297; 12, 36 1 Ratledge, C., 8,283Rattee, I. D., 1, 145 Redl, G., 3,273 Redpath, J., 12,75 Richards, D. H., 6,235 Ritch, J. B., jun., 5,452 Roberts, M. W., 6,373 Robinson, F. A., 5,3 17 Robinson, S. D., 12,415 Roche, M., 5,165 Rodgers, M. A. J., 7,235 Rose, A. E. A., 6,173 Rouvray, D. H., 3,355 Rowlinson, J. S., 7,329; 12,251 Sanders, J. K. M., 6,467 Sarma, T. S., 2,203 Satchell, D. P. N., 4,231; 6,345 Satchell, R. S., 4,231 Scheinmann, F., 11,321 Schlegel, W., 7,177 Scriven, E. F. V., 12, 129 Self, R., 10,255 Senthilnathan, V. P., 5, 297 Shorter, J., 7, 1 Simonetta, M.,13, 1 Simpson, T. J., 4,497 Singh, S., 5,297 Slorach, S. A., 10,280 Smith, E. B., 2, 181 Smith, K., 3,443Smith, K.M., 4,363 Smith, W. E., 6, 173; 9, 217 Snell, K. D., 8,259 Somorgai, G. A., 13,321 Stacey, M., 2,145 Staunton, J., 8,539 Staveley, L. A. K., 13,173 Stevens, M. F. G., 7,377 Stoddart, J. Fraser, 8,85 Stokes, R. H., 11,257 Strachan. A. N.. 11.41 Suckling; C. J., 3,387; 13.97 Suckling, K. E., 3,387 49 1 Index Sutherland, J. K., 9, 265 Tolnian, C. A., 1, 337 Sutherland, R. G., 1, 241 Trost, B. M., 11, 141 Sutton, D., 4, 443 Traux, D. R., 5,411 Swan, J. S., 7, 201 Twitchett, H. J., 3, 209 Swindells, R., 7, 212 Tyman, J. H. P., 8, 499 Symons, M. C. R., 5, Underhill, A. E., 1, 99; 337; 12, 1, 387; 13, 9,429van Dort, J. M., 7, 167393 Takken, H. J., 7, 167 vand der Linde, L. M., Taylor, J.B., 4, 189; 9, 7, 167 Varvoglis, A., 10, 377477 Taylor, S. E., 10, 329 Vaughan, K., 7,377 Theobald, D. W., 5, Vidali, M., 8, 199 203 Vigato, P. A., 8, 199 Thomas, T. W., 1, 99 Vollhardt, K. P. C., 9, Thompson, M., 1, 355 41 Thornber, C. W., 8, 563 Wain, R.L., 6, 261 Tincknell, R.C., 5, 463 Walker, E. R. H., 5, 23 Toennies, J. P., 3, 407 Walker, I. C., 3, 467 Waltz, W. L., 1, 241 Ward, I. M., 3, 231 Ward, R. S., 11, 75 Watkins, D. M., 9, 429 Wattanasin, S., 12, 213 White, A. J., 3, 17 Whitfield, R. C., 1, 27 Wieser, H., 5, 41 1 Wiesner, K., 6, 413 Williams, D. H., 13, 131 Williams, G., 7, 89 Williams, R. J. P., 9, 281, 325 Wilson, A. D., 7,265 Wise, S. A., 10, 113 Yoffe, A.D., 5, 51 Zeelen, F. J., 12, 75 Index INDEX OF TITLES A biotic receptors, 12, 285 Absorption bands in the spectra of stars, a crystal approach, 5, 233 Acidity of solid surfaces, 8,475 Across the living barrier, 6, 325 Acylation and alkylation catalysts, 4-dialkylaminopyridines, super,12, 129 -by ketens and isocyanates, a mechanistic comparison, 4, 23 1 Acylation, Friedel-Crafts, of alkenes 1, 73 Adamantane rearrangements, 3, 379 Affinity chromatography, chemical aspects of, 3, 249 Alcohols and amines, conformational analysis of, 5,411 Aliphatic nucleophilic substitution reactions, new insights into, from the use of pyridines as leaving groups, 13,47 Alkali-metal complexes in aqueoussolution, 4,549 Alkaloids, aconite, synthesis of, 6,413 Alkenes, the Friedel-Crafts acylationof, 1, 73 Aluminium phosphates, the chemistry and binding properties of, 6, 173 Amines and alcohols, conformational analysis of, 5, 411 Analysis of trace constituents of the diet, organic and inorganic,10, 245, 255 Analytical methods, modern, for en-vironmental polycyclic aromatic compounds, 10, 113 Anionic cyclization of phenols,12, 213 Ants, chemicals from the glands of, 13, 245 Aphids and scale insects, their chem- istry, 4, 263 Application of electrochemical tech-niques to the study of homogeneous chemical reactions, 4,471 Applications of e.s.r.spectroscopy to kinetics and mechanism in organic chemistry, 8, 1 Application of research findings to the development of commercial flavourings, 7, 177 Aqueous mixtures, kinetics of reac-tions in, 4, 55 Aqueous mixtures, kinetics of reac-tions in, 4, 55 Aqueous solution, micelles in, 6, 25 Aryl cations-new light on old inter- mediates, s, 353 halides, photochemistry and p h ot oc ycliza ti on of, 10,181 Aryldiazonium cations, co-ordination chemistry of, 4, 443 Aryliodine (111) dicarboxylates, 10, 377 Atmosphere, interactions in, of drop- lets and gases, 1,411 Autocatalysis, 7,297 Azidoquinones and related corn-pounds, chemistry of, 2,415 Azobenzene and its derivatives, photochemistry of, 1,481 Benzene compounds, substituted, synthesis from acyclic com-pounds, 13,441 Bile timents, 4, 363 Binding of heavy metals to proteins, 6.139 Binding properties and chemistryof aluminium phosphates, 6, 173 Bio-active molecules, structural studies on, 13, 131 Biological surfaces, molecular aspects of, 8, 389 Biomimetic chemistry, 1,553 Biosynthesis of sterols, 1, 259 Biosynthetic products from arachidonic acid, 6,489 studies, carbon-I3 nuclear mag- netic resonance in, 4,497 Bis(dipheny lphosphino)methane,chemistry of, 12,99 Blood groups, human, and carbohy- drate chemistry, 7,423 Bond strengths, CH, in simpleorganic compounds: effects of conformation and substitution, 7, 399 valences-a simple structural model for inorganic chemistry,7,359Boron reagents, carbon-carbon bond formation involving, 11, 191 Bredt’s rule, 3, 41 Brarnsted relation-recent develop-men ts, 2,475Butadiene, polymerization and copolymerization of, 6, 235 Index Calciferols, hormonal: chemistry of ‘Vitamin’ D, 6, 83 Calorimetric investigations of hydro- gen bond and charge transfer com- plexes, 3, 193 Cancer and chemicals, 4, 289 Carbohydrate chemistry and human blood groups, 7,423 Carbohydrate-directed macromole-cules, transition-metal oxide chel-ates of, 8, 221 Carbohydrate-protein complexes, gly- coproteins, and proteoglycans, of human tissues, chemical aspects of, 2,355 Carbohydrates to enzyme analogues, 8, 85 Carbonxarbon bond formation in-volving boron reagents, 11, 191 Carbon-13 nuclear magnetic resonance in biosynthetic studies, 4,497 Carbonium ions, carbanions, and radi- cals, chirality in, 2, 397 Carbonyl clusters, metal, relationship with supported metal catalysts,10, 159 compounds, photochemistry of, 1, 465 equivalents, silicon-containing,11,493 group transpositions, 11, 397 Carcinogens, chemical, mechanisms of reaction with nucleic acid, 9,24 1 Catalysis and surface chemistry, new perspectives, 6, 373 Catalysis, homogeneous, and organo- metallic chemistry, the 16 and 18 electron rule in, 1, 337 -of the olefin metathesis reaction, 4, 155 Catalysts, supported metal, rela-tionship with metal carbonyl clus- ters, 10, 159 CENTENARY LECTURE.Biomimetic chemistry, 1, 553 CENTENARY LECTURE. Cyclo-pentanoids: a challenge for new methodology 11, 141 CENTENARYLECTURE. Hydrocarbon reactions at metal centres, 11, 283 CENTENARYLECTURE.Light scatter-ing in pure liquids and solu-tions, 6, 109 CENTENARYLECTURE.Metal Clusters in biology, 10,455 CENTENARYLECTURE. Molecular In-gredients of heterogeneous cataly- sis, 13, 321 CENTENARYLECTURE. Organic re-action paths: a theoretical ap-proach, 13, 1 CENTENARY LECTURE. Quadruple bonds and other multiple metal to metal bonds, 4, 27 CENTENARYLECTURE. Reactivities of carbon disulphide, carbon dioxide, and carbonyl sulphide towards some transition-metal systems, 11, 57 CENTENARYLECTURE. Rotationally and vibrationally inelastic scattering of molecules, 3, 407 CENTENARY LECTURE. Systematic development of strategy in the synthesis of polycyclic poly-substituted natural products: the aconite alkaloids, 6,413 CENTENARYLECTURE.Three-dimen- sional structures and chemical mechanisms of enzymes, 1, 319 Charge transfer and hydrogen bond complexes, calorimetric investiga-tions of, 3, 193 Chemical applications of advances in Fourier transform spectroscopy,4, 569 ~ aspects of affinity chrom-atography 2, 249 _____ of glycoproteins, proteogly- cans, and carbohydrate-proteincomplexes of human tissues, 2, 355 Chemical education, conceptions,misconceptions, and alternative frameworks in, 13, 199 ______ research: facts, findings, and consequences, 9, 365 ~ interpretations of molecular wavefunctions, 5, 79 ___ models of enzymic transimin-ation, 12, 309 -processes on heterogeneouscatalysis, 13, 375 Chemically-induced dynamic electron polarization (CIDEP), role in chemistry, 8, 29 Chemicals from the glands of ants, 13, in rodent control, 1, 381 which control plant growth,6, 261 Chemistry and binding properties of aluminium phosphates, 6, 173 CHEMISTRY AND FLAVOUR I Molecular Structure and Organ- oleptic Quality, 7, 167 I1 Application of Research Findings to the Development of Commercial Flavourings, 7, 177 III Safety Evaluation of Natural and Synthetic Flavourings, 7, 185 IV The Influence of Legislation on Research in Flavour Chemistry,7, 195 V The Development of Flavour in Potable Spirits, 7, 201 VI The Influence of Flavour Chemistry on Consumer Accept- ance, 7,212 and the new industrial revolu-tion, 5, 317 , a topological subject, 2, 457 -of aphids and scale insects,4, 263 of azidoquinones and related compounds, 2,415 -, of dental cements, 7, 265 of dyeing, 1, 145 ~ of the gold drugs used in the treatment of rheumatoid arthritis, 9, 217 of homonuclear sulphur species, 2, 233 of long-chain phenols of non-isoprenoid origin, 8,499 __ of the production of organici socyana tes, 3, 209 of transition-metal carbene complexes and their role as reaction intermediates, 2, 99 ~ of ‘Vitamin’ D: the hormonal calciferols, 6, 83 , some considerations on the philosophy of, 5, 203 Chirality in carbonium ions, car-banions, and radicals, 2, 397 Chlorophyll chemistry, n.m.r.spectral change as a probe, 6, 467 Chromatography, affinity, chemical aspects of, 2, 249 Cis-and trans-effects of ligands,2, 163 Clathrates and molecular inclusion phenomena, 7, 65 Collisional transfer of rotational energy and spectral lineshapes,7, 219 Compartmental ligands: routes to homo-and hetero-dinuclear com-plexes, 8, 199 Index Complex formation between sugarsand metal cations, 9,415 hydride reducing agents, the functional group selectivity of, 5, 23 Complexes, alkali-metal, in aqueoussolution, 4, 549 homo-and hetero-dinuclear, routes via compartmental ligands, 8, 199 ---, I-D metallic, 9,429 Complexes, square-planar, isomer-ization mechanisms of, 9, 185 Computer resolution of overlappingelectronic absorption bands,9, 143 Conductivity and superconductivity in polymers, 5, 95 Conformation and substitution, effects of, on individual CH bond strengths in simple organic com-pounds, 7, 399 -of rings and neighbouring group effects, development of Haworth’s concepts of, 3, 1 Conformational analysis of some alcohols and amines: a comparison of molecular orbital theory, rota-tional and vibrational spectros-COPY, 5,411 studies on small molecules, 1, 293 Contribution of ion-pairing to ‘memory effects’, 4, 251 Contributions of pulse radiolysis to chemistry, 7, 235 Conversion of ammonium cyanateinto urea-a saga in reaction mech- anisms, 7, 1 Co-ordination chemistry of aryl-diazonium cations: aryldiazenato(arylazo) complexes of transition metals, and the aryldiazenato-nitrosyl analogy, 4, 443 Corrin synthesis, post-BI 2 problemsin, 5, 377 Crystal field approach to absorption bands in the spectra of stars, 5, 233 Crystal structure determination: a critical view, 13, 157 Crystals and molecules, organic, non- bonded interactions of atoms in, 7, 133 Current aspects of unimolecular reactions, 12, 163 Index Cyanocobalt(rI1) complexes, the syn-thesis of mononuclear, 12, 267 Cyanoketenes: synthesis and cyclo-additions, 10, 289 Cyclization, initiation of, using 3-methylcyclohex-2-enone derivatives, 9, 265 of phenols, anionic, 12, 213 Cyclopentanoids: a challenge for new methodology, 11, 141 C yclopol ymerization, 1, 523 Dental cements, chemistry of, 7, 265 Designing drugs to fit a macro-molecular receptor, 13, 279 Development of flavour in potablespirits, 7, 201 4-Dialkylaminopyridines: super acyl-ation and alkylation catalysts,12, 129 Diazirines, the thermolysis and pho- tolysis of, 11, 127 P-Dicarbonyl compounds, light-induced tautomerism of, 13, 69 Dielectric relaxation in polymersolutions, 1, 49 Diffusion in liquids, the effect of iso- topic substitution on, 5, 215 Difluoroamino-radical, gas-phasekinetics of, 3, 17 Droplets and gases, interactions in the atmosphere of, 1,411 Drug design, isosterism and molecular modification in, 8, 563 -___ ,quantitative 3, 273 Dyeing, chemistry of, 1, 145 Echinoderms, 1, 1 Education, chemical, a reassessment of research in, 1, 27 7 _____ , review of research and development in the U.K., 1972-1976, 7, 317 Effect of isotopic substitution on diffusion in liquids, 5, 215 Electrochemical techniques, applica-tion of to study of homogeneous chemical reactions, 4,471 Electron as a chemical entity, 4, 323 scattering spectroscopy, thresh- old, 3, 467 -spectroscopy, 1,355 Electronic absorption bands, over-lapping, computer resolution of, 9, 143 496 Electronic properties of some chain and layer compounds, 5, 51 -transitions, vibrational intensities in, 5, 165 Electrons, solvated, in solutions of metals, 5,337 Electron spin resonance of haemo-globin and myoglobin, 12, 387 Electrophilic aromatic substitutions, non-conventional, and related reac- tions, 3, 167 C-nitroso-compounds, 6, 1 Elimination reactions, isotope effect studies of, 1, 163 Enaminones, 6, 277 Energetics of neighbouring groupparticipation, 2, 295 Enumeration methods for isomers, 3, 355 Environmental lead in perspective,8, 63 polycyclic aromatic compounds, modern analytical methods for, 10, 113 -protection in the distribution of hazardous chemicals, 4, 99 -regulation: an international view, 5,431 Enzyme analogues from carbo-hydrates, 8, 85 Enzymes, immobilized, 6, 215 in organic synthesis, 3, 387 --, the logic of working with, 2, 1 three-dimensional structures aid chemical mechanisms of, 1, 319 Enzyme-catalysed reactions, reactive intermediates in, 13,97 Enzymic reactions, stereochemical choice in 8, 447 E.s.r.spectroscopy, applications to kinetics and mechanism in organic chemistry, 8, 1 Experimental Studies on the structure of aqueous solutions of hydro-phobic solutes, 2,203 FARADAY The electron as a LECTURE. chemical entity, 4, 323 FARADAYLECTURE. The molecular theory of small systems, 12, 251 Fast reactions, techniques for the kinetic study of, 11, 227 Fats grown from wastes, 8, 283 Fe(C0)4, 7, 527 5-Substituted pyrimidine nucleosides and nucleotides, 6, 43 Fixation, of nitrogen, 1,121 Flavins (isoalloxazines), the photo-physical and photochemicalproperties of, 11, 15 Forces between simple molecules, 2, 181 Foreign compounds in mammals,importance of non-enzymic chem- ical reaction processes to the rate of, 9, 63 Formation of hydrocarbons by micro- organisms, 3, 309 Fourier transform spectroscopy,chemical applications of advances in, 4, 569 Four-membered rings and reaction mechanisms, 5, 149 Friedel-Crafts acylation of alkenes, 1, 73 Functional group selectivity of complex hydride reducing agents,5, 23 Gas-phase kinetics of the difluoro-amino-radical, 3, 17 Gases, and droplets, interactions in the atmosphere of, 1,411 Glass transition: salient facts and models, 12, 361 Glycoproteins, proteoglycans, and car- bohydrate-protein complexes of human tissues, chemical aspectsof, 2, 355 Glycoproteins, synthesis of complexoligosaccharide chains of, 13, 15 Gold drugs used in the treatment of rheumatoid arthritis, chemistry of,9, 217 Growth of computational quantum chemistry from 1950 to 1971, 2, 21 Haemoglobin and myoglobin, electron spin resonance of, 12, 387 Handling toxic chemicals-environ-mental considerations, 4, 77 HAWORTH MEMORIAL LECTURE.The consequences of some projects in- itiated by Sir Norman Haworth, 2, 145 HAWORTH MEMORIAL LECTURE. The Haworth-Hudson controversy and the development of Haworth’s con- Index cepts of ring conformation and of neighbouring group effects, 3, 1 HAWORTH MEMORIAL LECTURE.Human blood groups and carbo-hydrate chemistry, 7, 501 HAWORTH LECTURE.MEMORIAL Struc-tural studies of polysaccharides,10, 409 HAWORTH MEMORIAL LECTURE. Synthesis of complex oligosacchar- ide chains of glycoproteins,13, 15 Hazards in the chemical industry- risk management and insurance, 8,419 Health hazards to workers from in- dustrial chemicals, 4, 82 Heterogeneous catalysis, chemical processes on, 13, 375 High resolution laser spectroscopy,12,453 Homogeneous catalysis, and organo- metallic chemistry, the 16 and 18 electron rule in, 1, 337 Homogeneous chemical reactions, application of electrochemical techniques to the study of, 4,471 Human blood groups and carbo-hydrate chemistry, 7,423 Hydrocarbon formation by micro-organisms, 3, 309 -reactions at metal centres, 11, 283 Hydrogen bond and charge transfer complexes, calorimetric investiga-tions of, 3, 193 -bonded liquids, thermodynamics of, 11, 257 ___ bonding, very strong, 9, 91 ___ isotope effects, kinetic, recent advances in the study of, 3, 513 Hydrophobic solutes, experimentalstudies on the structure of aqueoussolutions of, 2, 203 Imines, photochemistry of, 6, 63 Immobilized enzymes, 6, 215 Importance of (non-enzymic) chemical reaction processes to the fate of foreign compounds in mammals,9, 63 Importance of solvent internal pres- sure and cohesion to solution phenomena, 4,211 497 index Inclusion phenomena, molecular, and cla t hra tes, 7, 65 Individual CH bond strengths in simple organic compounds: effects of conformation and substitution, 7, 399 Industry, chemical, hazards in: risk management and insurance, 8, 419 Influence of favour chemistry on consumer acceptance, 7,212 Influence of legislation on research in favour chemistry, 7, 195 Infrared and Raman vibrational spec- troscopy in inorganic chemistry,4, 107 INCOLD LECTURE. Four-membered rings and reaction mechanisms, 5, 149 INGOLDLECTURE.How does a reaction choose its mechanism? 10, 345 Initiation of cyclization using 3-methyl- cyclohex-2-enone derivatives, 9, 265 Inorganic chemistry, bond valences, a simple structural model for, 7, 359 Inorganic pyro-compounds Ma[0<20 7)bI, 5, 269 Insect attractants of natural origin,2, 75 Insecticides, a new group of: syntheticpyre throids, 7,473 Interactions in the atmosphere of droplets and gases, 1,411 ion-solvent, thermodynamicsof,’ 9, 381 , metal-metal, in transition-metal complexes containing infinite chains of metal atoms, 1, 99 , non-bonded, of atoms in or-ganic crystals and molecules, 7, 133 Introducing a new agricultural chem- ical, 4, 77 Ion-molecule reactions in the evolution of simple organic molecules in interstellar clouds and planetaryatmospheres, 6, 295 Ion-pairing, contribution to ‘memory effects’, 4, 251 Ion-solven t interactions, t hermo- dynamics of, 9, 381 Isocyanates and ketens, a mechanistic comparison of acylation by, 4, 231 -, organic, chemistry of the produc- tion of, 3, 209 isocyanic acid, preparation and prop- erties of, 11,41 Isomer enumeration methods, 3, 355 Isomerization mechanisms of square- planar complexes, 9, 185 Isosterism and molecular modification in drug design, 8, 563 Isotope effect studies of elimination reactions, 1, 163 Isotopic hydrogen exchange in purines: mechanisms and applications, 10, 329 -substitution effects on diffusion in liquids, 5, 215 JOHN JEYES LECTURE.Chemicals which control plant growth, 6,261 KELVIN LECTURE.Across the livingbarrier, 6, 325 Ketens and isocyanates, a mechanistic comparison of acylation by, 4, 231 Kinetics and mechanism in organicchemistry, applications of e.s.r.spec- troscopy to, s, , gas-phase, of the difluoroamino- radical, 3, 17 of reactions in aqueous mixtures, 4, 55 P-Lactams, synthetic routes to, 5, 181 Lanthanide shift reagents in nuclear magnetic resonance spectroscopy,2, 49 Laser light scattering, quasielastic,2, 325 Laser spectroscopy of ultra-trace quan- tities, 8, 367 Lasers, tunable, 3, 293 Lead, environmental, in perspective,8, 63 LENNARD-JONESLECTURE.Recent ex- perimental and theoretical work on molecularly simple liquid mix-tures, 13, 173 Leukotrienes; a new class of biologically active compounds including SRS-A, the synthesis of, 11, 321 Ligands, cis-and trans-effects of, 2, 163 , compartmental: routes to homo- and hetero-dinuclear complexes,8, 199 Light-induced tautomerism of P-dicar- bony1 compounds, 13, 69 Lignans and neolignans, the synthesis 0f, 11, 75 Liquid mixtures, recent experimentaland theoretical work on molecularly simple, 13, 173 Liquid, surface of, 7, 329 LIVERSIDGELECTURE.On first looking into nature’s chemistry: I The r6le of small molecules and ions: the transport of elements, 9, 281 I1 The r6le of large molecules, especially proteins, 9, 325 LIVERSIDGE Recent advances LECTURE.in the study of kinetic hydrogenisotope effects, 3, 513 LIVERSIDGE The surface of a LECTURE. liquid, 7, 329 M acrocyclic ligands, synthetic, transi- tion-metal complexes of, 4, 421 Macromolecular receptor, designingdrugs to fit a, 13, 279 Main-group elements, ring, cage, and cluster compounds of, 8, 315 Matrix isolation technique and its application to organic chemistry, 9, 1 Mechanisms, chemical, and three-dimensional structures of enzymes, 1, 319 , isomerization, of square-planar complexes, 9, 185 of the microbial hydroxylation of steroids, 11, 371 , of reaction between ultimate chemical carcinogens and nucleic acid, 9, 241 MELDOLA MEDAL LECTURE.Chem- ical aspects of glycoproteins, pro- teoglycans, and carbohydrate-pro-tein complexes of human tissues, 2, 355 MELDOLAMEDAL LECTURE. Fe(C0)4,7, 527 MELDOLAMEDAL LECTURE. Molecular collisions and the semiclassical ap- proximation, 5, 125 MELDOLA MolecularMEDAL LECTURE.shapes, 7, 507 MELDOLA MEDAL LECTURE. N.m.r. spectral change as a probe of chlorophyll chemistry, 6,467 MELDOLAMEDAL LECTURE. The rela- tionship between metal carbonylclusters and supported metal cata- lysts, 10, 159 Meldrum’s acid, 7, 345 Index Metal carbonyl clusters, relationship with supported metal catalysts,10, 159 centres, hydrocarbon reactions at, 11, 283 clusters in biology, 10,455 Metal-metal bonding and metallobor- anes, 3, 231 bonds of various orders, synergic interplay of experiment and theory in studying, 12, 35 Metal-ion-promoted reactions of organo-sulphur compounds, 6, 345 1-D Metallic complexes, 9, 429 Metalloboranes and metal-metal bonding, 3, 231 bonds, multiple (especially quad- ruple), 4, 27 interactions in transition-metal complexes containing infinite chains of metal atoms, 1, 99 Metals, binding to proteins, 6, 139 Methyl group removal in steroid biosynthesis, 10,435 Micelle-forming surfactant solutions,photophysics of molecules in, 7,453 Micelles in aqueous solution, 6, 25 Microbes, use in the petrochemicalindustry, 8, 297 Micro-organisms, protein production by7 8, 143 Mixed-valence complexes, the chem- istry and spectroscopy of, 13, 219 Molecular aspects of biological sur-faces, 8, 389 beam reactive scattering, 11, 1 collisions and the semiclassical approximation, 5, 125 orbital theory, comparison with rotational and vibrational spec-troscopy in conformational ana-lysis of alcohols and amines 5, 411 -shapes, 7, 507 tectonics, the construction of polyhedral clusters, 13, 353 structure and organoleptic qual- ity, 7, 167 theory of small systems, 12, 251 wavefunctions, chemical inter-pretations of, 5, 79 Molybdenum and tungsten; alkoxy,amido, hydrazido, and related com- pounds of, 12, 331 Monoalkyltriazenes, 7,377 Index Morphogenisis, biological, the physical chemistry of, 10,491 Motion, molecular, and time-cor-relation functions, 7, 89 Multistability in open chemical reaction systems, 5, 359 Myoglobin and haemoglobin, electron spin resonance of, 12, 387 Natural products from echinoderms, 1, 1 --,polycyclic polysubstituted, systematic development of strategy in, 6,413 Neighbouring-group effects and ringconformation, development of Haworth’s concepts of, 3, 1 participation, energetics of, 2.295 New insights into aliphatic nucleo-philic substitution reactions from the use of pyridines as leaving groups, 13,47 New perspectives in surface chemistry and catalysis, 6, 373 Nitrogen fixation, 1,121 Nitroso-alkenes and nitroso-alky-nes, 12, 53 C-Nitroso-compounds, electrophilic, 69.1 N.m.r. and vibrational spectroscopicstudies, structure in solvents and solutions, 12, 1 Non-bonded interactions of atoms in organic crystals and molecules,7, 133 Non-conventional electrophilic arom- atic substitutions and related reac-tions, 3, 167 Nuclear magnetic resonance and the periodic table, 5? 1 __--,carbon-13, in bio-synthetic studies, 4,497 __--methods (new) for tracing the future of hydrogen in biosyn thesis, 8, 539 __-~smctral change as a probe of chlorophyll chemistry,6.467 --__ spectroscopy, ’Ian-thanide shift reagents in, 2, 49 ----: spin-latticerelaxation, 4,401 Nucleic acid, mechanisms of reaction with ultimate chemical carcinogens, 9, 241 Nucleosides and nucleotides, pyrim- idine, 5-substituted, 6, 43 Nutritional chemistry of inorganic trace constituents of the diet, 10,270 NYHOLM LECTURE.MEMORIAL Chemical education research: facts, findings, and consequences, 9, 365 NYHOLM LECTURE.MEMORIAL Concep-tions, misconceptions, and alternative frameworks in chemical educa-tion, 13, 199 NYHOLM LECTURE.MEMORIAL Forward from Nyholm’s March on Lecture, 3, 373 NYHOLM LECTURE.MEMORIAL Growth, change, challenge, 5, 253 NYHOLM MEMORIAL LECTURE.Ring, cage, and cluster compounds of the main group elements, 8, 315 NYHOLMMEMORIAL SolvingLECTURE. chemical problems, 11, 171 NYHOLM LECTURE.MEMORIAL Synergicinterplay of experiment and theory in studying metal-metal bonds of vari- ous orders, 12,35 Olefin metathesis and its catalysis,4, 155 Olefinic compounds, photochemistry of, 3, 329 On first looking into nature’s chemistry: I The r6le of small molecules and ions: the transport of the ele-ments, 9, 281 Il The r6le of large molecules, especially proteins, 9, 325 Organic chemistry of superoxide,6, 195 Organic reaction paths: a theoretical approach, 13, 1 Organoboranes as reagents for organic synthesis, preparation of, 3, 443 Organoborates in organic synthesis: the use of alkenyl-, alkynyl-, and cyano- borates as synthetic intermediates, 6, 393 Organometallic chemistry and hom-ogeneous catalysis, the 16 and 18 electron rule in, 1,337Organomethyl compounds, synthesis, structure, and vibrational spectra,9, 25 Organosulphur compounds, metal-ion- promoted reactions of, 6, 345 Organo-transition-metal complexes:stability, reactivity, and orbital cor- relations, 2, 271 Oxygen, singlet molecular, 10, 205 PEDLER LECTURE.Porphyrins and related ring systems, 4, *1 Phase boundaries, reactivity of organic molecules at, 1, 229 Phenols, anionic cyclization of, 12, 213 , long-chain, of non-isoprenoidorigin, 8,499 Philosophy of chemistry, some con-siderations, 5, 203 Phosphates, aluminium, the chem-istry and binding properties of, 6, 173 Phosphorus compounds, tervalent, in organic synthesis, 3, 87 Photochemistry of azobenzene and its derivatives, 1,481of carbonyl compounds, 1, 465 of imines, 6, 63 of olefinic compounds, 3, 329 of organic sulphur compounds, 4, 523 of the uranyl ion, 3, 139 of transition-metal co-ordination compounds-a survey, 1, 241 Photocyclization and photochemistry of aryl halides, 10, 181 Photodegradation and stabilization of commercial polyolefins, 4, 533 Pho tophysical and photochemicalproperties of flavins (isoal-loxazines), 11, 15 Photophysics of molecules in micelle- forming surfactant solutions, 7, 453 Plant growth, control by chemicals, 6, 261 Platinum metal complexes, q 5-cyclo-pentadienyl and q6-arene as pro-tecting ligands towards, 10, 1 Polyhedral clusters, the construction 0f, 13, 353 Polymer solutions, dielectric relaxation in, 1, 49 supports, insoluble, use in organic chemical synthesis, 3, 65 Polymerization and copolymerization of butadiene, 6, 235 Polymers, conductivity and supercon- ductivity in, 5, 95 Polyolefins, commercial, photo-Index degradation and stabilization of, 4, 533 Polysaccharides, structural studies of, 10, 409 Porphyrins and related ring systems, 4,.1 Post-BIZ problems in corrin synthesis, 5,377 Preparation of organoboranes: reagents for organic synthesis, 3, 443 and properties of isocyanic acid, 11,41 PRBIDENTIALADDRESS1976. Chemistryand the new industrial revolution, 5, 317 Properties and syntheses of sweetening agents, 6,431Prostaglandins, tomorrow's drugs,4. 589 ,thromboxanes, PGX: biosynthetic products from arachidonic acid, 6,489Prostanoids, total syntheses of, 2, 29 Protecting ligands, q '-cyclopentadienyland q6-arene towards platinum metal complexes, 10, 1 Protein production by micro-organ- isms, 8, 143 Proteins, binding of heavy metals to, 6, 139 Proteins, r6le of in nature's chemistry, 9, 325 Pulse radiolysis, contributions to chern- istry, 7, 235 Purines, isotopic hydrogen exchange in, mechanisms and applications,10, 329 Pyridines as leaving groups, new insights into aliphatic nucleophilic substitution from the use of, 13, 47 Pyrimidine nucleosides and nucleotides, 5-substituted, 6, 43 Pyro-compounds, inorganic, Ma[@20 7)b], 5, 269 Quadruple bonds and other multiple metal to metal bonds, 4, 27 Quantitative drug design, 3, 273 Quantum chemistry, computational,growth of from 1950 to 1971, 2, 21 mechanical tunnelling in chern- istry, 1,211 Quasielastic laser light scattering, 2,325 Radical cations in condensed phases, 13, 393 501 Index Radioactive and toxic wastes: a com- parison of their control and dis-posal, 4, 90 Radiolysis, pulse, contributions to chemistry, 7, 235 Raman and infrared vibrational spec- troscopy in inorganic chemistry, 4, 107 R.A. ROBINSON LECTURE.MEMORIAL Thermodynamics of hydrogen-bonded liquids, 11, 257 Reaction mechanisms, four-membered rings and, 5, 149 , the conversion of ammonium cyanate into urea, 7, 1 Reactive intermediates in enzyme-cat a1 ysed reactions, 13,97 Reactivities of carbon disulphide,carbon dioxide, and carbonyl sul- phide towards some transition-metal sys tems, 11, 57 Reactivity of organic molecules at phase boundaries, 1, 229 Recent advances in the study of kinetic hydrogen isotope effects, 3, 513 Recent syntheses in the Vitamin D field, 9, 449 Research in chemical education: a reassessment, 1, 27 RESOURCES CONSERVATION BY NOVEL BIOLOGICAL PRO-CESSES I Grow Fats from Wastes, 8, 283 II The Use of Microbes in the Petrochemical Industry, 8, 297 III Utilization of Agricultural and Food Processing Wastes contain- ing Carbohydrates, 8, 309 Review of chemical education research and development in the U.K., 1972-1 976.7, 317 Ring, cage, and cluster compounds of the main group elements, 8, 315 ROBERT ROBINSON Post-B12LECTURE. problems in corrin synthesis,5, 377 ROBERTROBINSON The logic LECTURE. of working with enzymes, 29.1 ROBERT ROBINSON LECTURE.Vitamin B12. Retrospect and pros-pects, 9, 125 Rodent control, chemicals in, 1, 381 Role of chemically-induced dynamic electron polarization (CIDEP) in chemistry, 8, 29 Rotationally and vibrationallyinelastic scattering of molecules, 3, 407 Safety evaluation of natural and synthetic flavourings, 7, 185 Scale insects and aphids, chemistry of, 4, 263 Semistable molecules in the laboratory and in space, 11,435 Silicon compounds in organic synthesis, some uses of, 10, 83 containing carbonyl equiva-lents, 11,493 -in organic synthesis, 7, 15 16 and 18 Electron rule in organometal- lic chemistry and homogeneouscatalysis, 1,337 Small molecules, conformation studies on, 1, 293 Solids, surface energy of, 1, 445 Solute-solvent interactions, spectro-scopic studies of, 5, 297 Solution phenomena, the importance of solvent internal pressure and co- hesion, 4,211 Solutions of metals: solvated elec-trons, 5,337 Solvent internal pressure and cohesion, importance to solution phenomena, 4,211 Solving chemical problems, 11, 171 Some considerations on the philosophy of chemistry, 5, 203 Some recent developments in chemistry teaching in schools, 1,495 Spectra of stars, absorption bands in, a crystal field approach, 5, 233 Spectral lineshapes, collisional trans- fer of rotational energy with, 7, 219 Spectroscopic studies of solute-solvent interactions, 5, 297 Spectroscopy and chemistry of mixed- valence complexes, 13, 219 Spectroscopy, electron, 1,355 , Fourier transform, chemical applications of advances in, 4, 569 , laser, of ultra-trace quantities, 8, 367 -, rotational and vibrational, com- parison with molecular orbital theory in conformational analysis of alco-hols and amines, 5,411 -, threshold electron scattering,3,467 Spin-lattice relaxation: a fourth dimen- sion for proton n.m.r.spectroscopy, 4, 401 Square-planar complexes, isomeriza-tion mechanisms of, 9, 185 SRS-A, the synthesis of leukotrienes: a new class of biologically active compounds including, 11, 321 Stability, reactivity, and orbital correla- tions of organo-transition-metalcomplexes, 2, 271 Stereochemical choice in enzymic reac- tions, 8, 447 Stereoselective synthesis of steroid side- chains, 12,75 Steroid biosynthesis, methyl groupremoval in, 10,435 , the mechanism of the microbial hydroxylation of, 11, 371 , routes to by intramolecular Diels-Alder reactions of 0-xyly-lenes, 9, 41 side-chains, stereoselective syn- thesis of, 12, 75 Sterols, biosynthesis of, 1, 259 Structure in solvents and solutions- N.m.r.and vibrational spectroscopic studies, 12, 1 of aqueous solutions of hydro- phobic solutes, experimental studies on, 2, 203 Substitution and conformation, effects of, on individual CH bond strengths in simple organic compounds,7, 399 Sugars, complex formation with cations, 9,415 Sulphoximides, 4, 189 Sulphoximides-an update, 9, 477 Sulphur compounds, organic, photo- chemistry of, 4, 523 organic compounds of, metal-ion- promoted reactions of, 6, 345 species, homonuclear, chemistry of, 2, 233 Superconductivity and conductivity in polymers, 5, 95 Superoxide, organic chemistry of, 6, 195 Surface chemistry and catalysis, new perspectives, 6, 373 energy of solids, 1,445 modified electrodes, 8, 259 of a liquid, 7, 329 Surfaces, biological, molecular aspects of, 8, 389 Index , solid, their acidity, 8,475 Sweetening agents, properties and syn- theses of, 6,431 Syntheses and properties of sweetening agents, 6,431 of mononuclear cyanocobalt(1II) complexes, 12, 267 , recent, in the Vitamin D field, 9, 449 , total of prostanoids, 2, 29 Synthesis and cycloadditions, cyanok- etenes, 10,289 and synthetic utility of halolac- tones, 8, 171 , of corrins, post-B12 problems in 5, 377 -of complex oligosaccharide chains of glycoproteins, 13, 15 of leukotrienes: a new class of biologically active compounds in- cluding SRS-A, 11, 321 of lignans and neolignans,11, 75 of polycyclic polysubstitutednatural products, systematic de-velopment of strategy in, 6, 413 , organic, enzymes in, 3, 387 -, organic, preparation of organo-boranes as reagents for, 3, 443 , organic, silicon in, 7, 15 -, organic, some uses of silicon compounds, 10,83 , organic, tervalent phosphoruscompounds in, 3, 87 , organic, use of inorganic polymer supports in, 3, 65 -, organic, the use of organoboratesas synthetic intermediates, 6, 393 , structure, and vibrational spectra of organomethyl compounds, 9, 25 ~ of substituted benzene compounds from acyclic precursors, 13, 441 Synthetic pyrethroids.A new group of insecticides, 7,473 routes to p-lactams, 5, 181 Systematic development of strategy in the synthesis of polycyclic poly- substituted natural products: the aconite alkaloids, 6,413 TATEAND LYLE LECTURE. From carbo- hydrates to enzyme analogues,8, 85 TATEAND LYLE LECTURE. Spin-latticerelaxation: a fourth dimension for proton n.m.r. spectroscopy, 4, 401 index TATEAND LYLE LECTURE. Transition-metal oxide chelates of carbohydrate- directed macromolecules, 8, 221 Teaching of chemistry in schools, some recent developments in, 1,495Techniques for the kinetic study of fast reactions in solution, 11, 227 Tervalent phosphorus compounds in organic synthesis, 3, 87 Thermal, photochemical, and transi-tion-metal mediated routes to ster- oids by intramolecular Diels-Alder reactions of o-xylylenes (o-quinodi- methanes), 9, 41 Thermodynamics of ion-solvent inter-actions, 9, 381 Thermolysis and photolysis of diazir- ines, 11, 127 Three-dimensional structures and chemical mechanisms of enzymes,1, 319 Threshold electron scattering spectro- SCOPY, 3,467 Thromboxanes, prostaglandins, PGX: biosynthetic products of arachidonic acid, 6,489TILDENLECTURE.Alkoxy, amido, hy- drazido, and related compounds of molybdenum and tungsten, 12, 331 TILDEN Applications of e.s.r.LECTURE. spectroscopy to kinetics and mech- anism in organic chemistry, 8, 1 TILDEN Carbon<arbon bond LECTURE. formation involving boron re-agents, 11,191TILDEN Chemistry and Spec- LECTURE. troscopy of mixed-complexes,13, 219 TILDENLECTURE.Concerning stereo- chemical choice in enzymic reactions, 8, 447 TILDENLECTURE.q '-Cyclopentadienyland q6-arene as protecting ligands towards platinum metal com-plexes 10, 1 TILDENLECTURE. Electrophilic C-nitroso-compounds, 6, 1 TILDEN Initiation of cycliza- LECTURE. tion using 3-methylcyclohex-2-enonederivatives, 9, 265 TILDENLECTURE. Molecular beam reactive scattering, 11, 1 TILDEN New perspectives in LECTURE. surface chemistry and catalysis,6, 373 TILDENLECTURE.Semistable molecules in the laboratory and in space,11,435TILDEN Some uses of silicon LECTURE. compounds in organic synthesis,10,83 TILDENLECTURE.Structural studies on bio-ac ti ve molecules, 13, 131 TILDEN Valence in transition- LECTURE.metal complexes, 1,431 Time-correlation functions and mole- cular motion, 7, 89 Topological subject-chemistry,2,457Trace constituents of the diet, chemical aspects, 10, 233 organic constituents of the diet, sources and biogenesis, 10, 280 Transimination, chemical models of enzymic, 12, 309 Transition-metal carbene complexes,chemistry and role as reaction intermediates, 2, 99 complexes, containing infinite chains of metal atoms, metal-metal interactions in, 1, 99 -complexes of synthetic macro-cyclic ligands, 4,421 complexes, valence in, 1, 431 -co-ordination compounds,photochemistry of, 1, 241 hydride complexes, 12,415 -systems, reactivities of carbon disulphide, carbon dioxide, and car- bony1 sulphide systems towards,11,57 -oxide chelates of carbohydrate- directed macromolecules, 8, 221 Tunable lasers, 3, 293 Unimolecular reactions, current aspects of, 12, 163 Uranyl ion, photochemistry of, 3, 139 Use of insoluble polymer supports in organic chemical synthesis, 3, 65 Utilization of agricultural and food processing wastes containing car-bohydrates, 8, 309 Valence in transition-metal complexes, 1, 431 Valences, bond, a simple structural model for inorganic chemistry,7, 359 Index Very strong hydrogen bonding, 9,91 Vibrational and n.m.r.spectroscopicstudies, structure in solvents and solutions, 12, 1 -, infrared, and Raman spectro-scopy in inorganic chemistry,4. 107 intensities in electronic transi-tions, 5, 165 -spectra, synthesis, and structure of organomethyl compounds, 9, 25 Vibrationally and rotationally inelastic scattering of molecules, 3, 407 Viologens, electrochemistry of, 10, 49 Vitamin BIZ, retrospects and pros-pects, 9, 125 Yitamin D, chemistry of: the hormonal calci ferols, 6, 83 Vitamin D, recent syntheses in, 9, 449

ISSN:0306-0012    

DOI:10.1039/CS9841300489

出版商:RSC    

年代:1984

数据来源: RSC