摘要:

Chemical Society Reviews Editorial Board Professor H. W. Kroto FRS (Chairman) Professor M. J. Blandamer Dr. A. R. Butler Dr. E. C. Constable Professor B. T. Golding Professor M. Green Professor D. M. P. Mingos FRS Professor J. F. Stoddart Consulting Editors Dr. G. G. Baht-Kurti Professor S. A. Benner Dr. J. M. Brown Dr. J. Burgess Dr. N. Cape Professor A. Hamnett Dr. T. M. Herrington Professor R. Hillman Professor R. Keese Dr. T. H. Lilley Dr. H. Maskill Professor Dr. A. de Meijere Professor J. N. Miller Professor S. M. Roberts Professor B. H. Robinson Dr. A. J. Stace Staff Editors Mr. K. J. Wilkinson Dr. J. A. Rhodes Dr. M. Sugden University of Sussex University of Leicester University of St. Andrews University of Cambridge University of Newcastle upon Tyne University of Bath Imperial College London University of Birmingham University of Bristol Swiss Federal Institute of Technology, Zurich University of Oxford University of Leicester Institute of Terrestrial Ecology, Lothian University of Newcastle upon Tyne University of Reading University of Leicester University of Bern U n ivers ity of Sh eff ieId University of Newcastle upon Tyne U n iversity of G ott ingen Loughborough University of Technology University of Exeter University of East Anglia University of Sussex Royal Society of Chemistry, Cambridge Royal Society of Chemistry, Cambridge Royal Society of Chemistry, Cambridge It is intended that Chemical Society Reviews will have the broad appeal necessary for researchers to benefit from an awareness of advances in areas outside their own specialities.Deliberate efforts will be made to solicit authors and articles from Europe which present a truly international outlook on the major advances in a. wide range of chemical areas. It is hoped that it will be particularly stimulating and instructive for students planning a career in research. The articles will be succinct and authoritative overviews of timely topics in modern chemistry. In line with the above, review articles will not be overly comprehensive, detailed, or heavily referenced (ca.30 references), but should act as a springboard to further reading. In general, authors, who will be recognized experts in their fields, will be asked to place any of their own work in the wider context. Review articles must be short, around 6-8 journal pages in extent.In consequence, manuscripts should not exceed 20-30 A4/American quarto sheets, this length to include text (in double line spacing), tables, references, and artwork. An Instruction to Authors leaflet is available from the Senior Editor (Reviews). Although the majority of articles are intended to be specially commissioned, the Society always considers offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. @ The Royal Society of Chemistry, 1993 All Rights Reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic or mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Servis Filmsetting Ltd. Printed in Great Britain by B lack bear Press Ltd.

ISSN:0306-0012    

DOI:10.1039/CS99322FX013

出版商:RSC    

年代:1993

数据来源: RSC

ISSN:0306-0012    

DOI:10.1039/CS99322BX015

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Catalytic Antibodies: Mechanistic and Practical Considerations Jon D. Stewart and Stephen J. Benkovic Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, U.S.A. ~~ 1 Introduction The field of catalytic antibodies has been amply reviewed -recently. Its origins, key underlying tenets, and the range of reaction types presently known to be susceptible to antibody catalysis have all been described. Initial efforts at defining the mechanism of action of these agents have also been summar- ized.2 In order not to be merely repetitious, we will focus primarily on two issues: first, what are we learning about catalysis in general from a study of these agents; and secondly, how do these agents rank relative to other biological catalysts in terms of their present catalytic efficiency and in their potential for improvement? We have chosen to address these issues by examining, in turn, the characteristics of abzymes that catalyse the hydrolysis of various esters and amides and the properties of selected catalytic antibodies in facilitating stereospecific transformations.2 Hydrolytic Reactions The induction of antibodies capable of facilitating the hydrolysis of amide and ester bonds has been based on transition-state analogues that mimic the tetrahedral intermediates anticipated to be involved in these proce~ses.’.~~~ Since enzymes appear to have active sites that are electronically and geometrically com- plementary to the transition states involved in the rate-limiting step of the substrate to product conversi~n,~Jj potent inhibitors of many hydrolytic enzymes have been created through the synthesis of stable tetrahedral intermediate analogue^.^ Fore-most among these inhibitors for hydrolytic enzymes have been compounds containing either charged tetrahedral phosphorus or secondary alcohols to substitute for the carbonyl of the scissile amide or ester b~nd.~?~ These compounds in turn have been used to elicit antibodies capable of catalysing various reactions.Examples of several catalytic antibodies generated to phos- pho,iate, phosphonamidate, and secondary alcohol transition- state analogues are listed in Table l.4,10--16In all cases the reported data were obtained from a single monoclonal antibody characterized from a panel of ca.25-50 monoclonal antibodies that were selected owing to their high affinity for the correspond- Jon D. Stew,art, born in Elmira, N.Y.in 1964, receivedhis B.S. and M.S.degrees in chemistryfrom Bucknell University in 1986 andhis Ph.D. from Cornell Un- iversity in 1991. He is currently a post-doctoral fellow of the Helen Hay Whitney Founda- tion in Professor Benkovic’s laboratory where he has used protein engineering techniques to investigate catalytic anti-body mechanisms. He has accepted a position as an assis- tant professor in the Chemistry Department at the University of Florida. 213 ing hapten in an ELISA (enzyme-linked immuno-assay) assay. High affinity, however, is no guarantee of catalytic power since, for example, only one out of forty antibodies generated against hspten (4)showed activity against the anilide substrate.This behaviour is another manifestation of the diversity of the immunological response and the myriad ways of tightly binding a particular hapten. Given the presence of aromatic elements which provide strong binding determinants in all the hapten structures in Table 1, we can imagine hapten-antibody com-plexes where the tetrahedral mimic is either excluded from the binding pocket or so protected that the carbonyl centre of the corresponding substrate might not be accessible to water. There are two general indices based on steady-state kinetic analyses that are used to assess the catalytic efficiency of an antibody:kcat/kUncatand k,,,/KM.The steady-state kinetics for all abzymes obey the Michaelis-Menten rate expression for both KM (the concentration of substrate that produces one-half the maximal catalytic rate) and kcat(the rate constant for product formation under conditions when the antibody is saturated with substrate). Note that the KM parameter also represents an approximate measure for the dissociation of the abzyme-sub- strate complex. The meaning of the first index -kcat/kuncat, where k,,,,, is the rate constant for the same chemical process in the absence of antibody -is obvious and for enzymes may exceed lolo.(For hydrolytic reactions both k,,, and kuncathave the same units since the activity of water is set equal to unity.) The second index of efficiency, the ratio kc,,/KM,represents a measure of the kinetic barrier encountered commencing with the combination of antibody and substrate and proceeding along the reaction coordinate to the transition state of highest energy.This ratio has a limit of approximately lo7M-I s-I when the reaction is limited by diffusion together of the substrate and antibody.” The values of kcat/kuncatin Table 1 span a range from 70 to 106. This spread also encompasses all the antibody-catalysed chemical transformations reported to date. If one accepts our initial premise that antibodies owe their catalytic activity to their Stephen J. Benkovic was born in Orange, New Jersey in 1938 and received his undergraduate degree at Lehigh and his Ph.D.at Cornell. After a period as postdoctoral research associate at U.C.-Santa Barbara, he joined the faculty at Penn State University in 1965. He now holds the rank of Evan Pugh Professor, and holds the Eberly Chair in Chemistry. He has been recog- nized by numerous national and international awards, and was elected a member of the Natio- nal Academy of Science in 1985. Benkovic’s research has em- phasized the study of the mech- anisms of enzyme-catalysed reactions either through model- ling of the reaction in physical organic studies or experiments on the enzymes themselves. 214 Table 1 Hapten Substrate 0 12 (PH 8 5) 20 (PH 8 0) 7 7 x 10 (R) 15x10 3(S) (PH 90) 83x10 (PH 90) 25 (PH 93) 12x10 (pH 8 5) D isomer 8 7 x 10 (2x1Asp) 93 x 10 3(Asp) (pH 8 5) D succinimide 12x10 (PH 7 5) CHEMICAL SOCIETY REVIEWS I993 625~10~30x104 13x10 82 x lo4 2000 38 x 10 6(R) d 1600 2000 I9 x 10 (s) 15~105 37x105 22x10 6 ef 27x 104 53~104 047 70 ND 63x10' g 70 ND 36x10 h 290 ND 39x10 2250 26 33x10 ti a K M Shokat M K KO T S Scanlan L Hochersperger S Yankovic S Thaisrivongs andP G Schultz Angew Chem Int Ed Engl 1990 29 1296 h J W Jacobs P G Schultz R Sugsawara and M Powell J Am Chem Soc 1987 109 2174 A Tramontano A A Ammann and R A Lerner J Am Chem Soc 1988 110 2282 d K D Janda S J Benkovic and R A Lerner Sczence 1989 244 437 e K D Janda D Schloeder S J Benkovic and R A Lerner Sczenre f1988 241 1188 R A Gibbs P A Benkovic K D Janda R A Lerner and S J Benkovic J Am Chem Soc 1992 114 3528 R A Gibbs S Taylor and S J Benkovic Sczence 1992 258 803 * L J Liotta P A Benkovic G P Miller andS J Benkovic J Am Chem Soc 1993 115 350 ability to stabilize the transition state for their respective reac- tion, kcatand kuncatcan be inter-related through a thermodyna- mic cycle to the KMfor the substrate and K, (the dissociation constant for the hapten from the antibody-hapten complex), Scheme 1 The K, term is presumed to be an approximation of the hypothetical and unmeasurable disocciation constant, KtAbSx,describing binding of the transition state, S,to the antibody The relationship is thus (kcat/kuncat)=(KM/K,) Scheme 1 For hydrolytic antibodies raised against haptens (l), (2), (39, and (4) this equation is largely satisfied, in addition some eighteen other anti-phosphonate catalytic antibodies exhibit kinetic parameters that are also within an order of magnitude of the KM/K,ratio l9 On the other hand, for haptens (3R)and (6), the values of KM/Klis smaller than kcat/kuncat,but only by an order of magnitude [the K, value for (5) is not yet determined] These discrepancies may be more a consequence of an inaccur- acy in the K, values, for example, the K,for antibody induced by (4)has been revised from 10 to 10 after direct titration by hapten Thus, despite the uncertainties inherent in presuming that K, for the hapten accurately reflects transition-state bind- ing, the relationship of the kcat/kUncatto KM/K, for a given catalytic antibody is fairly well satisfied Nevertheless, this agreement may mask a greater complexity in the antibody's catalytic mechanism This is indeed the case for an antibody induced by hapten (4)described below, whose mechanism has been studied in detail Examination of the values for kcat/kuncat and kcat/KM for the hydrolytic reactions listed in Table 1 reveals that antibody catalysis generally is less than optimal Antibody 43C9 [induced to hapten (4)]is one of the most reactive antibodies, and it has been the object of extensive experimental scrutiny to discern its mechanism of action Studies of the pH-dependence of k,,, and kcat/& for both the p-nitroanilide and p-nitrophenyl ester substrates exhibited an apparent pKa w 9, which was not attri- buted to the ionization of a binding site residue but rather to a change in the rate-limiting step of the process around a central, transient antibody-substrate-generated intermediate O In sup- port of that postulate were the differential solvent deuterium isotope effects and electronic effects encountered at high and low pH when the substrates were expanded to include a series of p-substituted phenyl esters l4 *l Specifically,kHzo/kDzox 3 8 for amide hydrolysis at pH <9 but -1 at pH >9 0 In addition, the p value of +2 3 at pH >9 0 (against Hammett 0)is particularly diagnostic of an acylation reaction involving a neutral nitrogen CATALYTIC ANTIBODIES MECHANISTIC AND PRACTICAL CONSIDERATIONS-J D STEWART AND S J BENKOVIC 215 nucleophile contributed by the antibody binding site but is inconsistent with a general base mechanism, such as one involv- ing formation of a bound tetrahedral intermediate from base- assisted attack by water The recent cloning and sequencing of the heavy and light chains of 43C9 revealed the presence of two histidines, one in the heavy and one in the light chain 22 Computer modelling of this sequence with the hapten (4) docked in the antibody binding site suggests that the light chain histidine is proximal to the phos- phonamidate phosphorus atom (within 3 A) and by implication the substrate carbonyl 23 The imidazole of this histidine is then a likely candidate for the nucleophile that is acylated and deacy- lated in the course of the hydrolysis reaction A kinetic scheme consistent with these collective observations is presented in Scheme 2 OH-Ab + S =AbS =Abl -AbPieP2 *AbeP2 + Pi *Ab + Pi + P2 X=NH,O PI = H02C& NH Scheme 2 The individual steps in the kinetic sequence of Scheme 2 were evaluated from a combination of steady- and pre-steady-state methods and the data transformed into a free-energy reaction coordinate diagram (Figure 1) There are several salient features which are instructive with respect to our opening inquiry It is clear that for both the ester and anilide substrates at pH 7 0, the deacylation step [Ab'I -+ AbP, .P2] is primarily rate-limiting At higher pH (owing to the rate of deacylation being first order in hydroxide ion) the barrier between Ab * I +AbP, P, decreases so that product desorption (ester substrate) and/or acylation (anilide substrate) become rate-limiting At no pH value does Ab * I accumulate since the slow loss of P, favours the return of Ab I to Ab * S It is highly probable that this profile will be typical for most catalytic antibodies, neither the chemical or product release steps should be optimized since the immunologi- cal response evolves simply to maximize binding and then stops A more optimal situation would balance the differences in dG between the external and internal ground states and their respective transition states, so that no single AG barrier would be egregious 24 Perhaps we should be more astonished by the richness of the kinetic sequence that pertains to the catalytic activity of anti- body 43C9 The phosphonamidate transition state analogue has 15-10-h 'T-5-i2-8 0-Y, a4-5--10-U -15 Ab*P,*P, Figure 1 Reaction AG profile for antibody-catalysed ester (-) and anilide (----) hydrolysis at pH 7 The ground-state energy of the anilide was set 5 kcal mole lower than the arbitrarily fixed value for the ester The free-product ground-state energies for protonated acid and neutral p-nitrophenol and p-nitroaniline were fixed at 0 kcal mole and were not corrected to pH 7 The standard states of all substrate and products are 1 M The uncertainty in the forward rate constant for Ab-I formation from the ester is highlighted by the dotted line The arrows indicate that transition states set at their maximum free energy values (Reproduced with permission from Science, 1990,250, 1135) induced an active-site pocket that contains at least one nitrogen nucleophile proximal to the substrate carbonyl which is capable of reversible acylation In this case, the acylimidazole is hydro- lysed to complete the cycle, unlike many macrocyclic systems that react stoichiometrically However, as a consequence, the transition-state analogue is no longer an ideal mimic of the tetrahedral intermediates anticipated in the hydrolytic reaction, suggesting that the catalytic activity of 43C9 may be further improved The generation of a covalent antibody-substrate intermediate is not an isolated example There is strong kinetic evidence2 to implicate an acyl-antibody intermediate in the transesterifica- tion reaction of 21H3 (Scheme 3), vzz a pre-steady-state burst of p-nitrophenol formation equivalent to the antibody concent- ration and steady-state ping-pong kinetics This antibody also exhibits an induced fit by the second substrate to activate the acyl intermediate for subsequent chemical reaction Although 21H3 is unusually reactive as a transesterification agent (kcat/ kuncatis estimated as >, lo6),it is a poorer catalyst for hydrolysis, presumably owing to a rate-limiting deacylation Consequently nucleophilic catalysis per se is insufficient to provide a kcdt/kUncdt ratio greater than KM/K, On the other hand, the induction of antibodies using a reaction pathway involving an acyl-antibody intermediate is not a general immunological response to the tetrahedral phos- phorus-containing haptens For example, hapten (1) induces a catalytic antibody that does not function via such an acyl intermediate, as its pH rate profile for the hydrolysis of p-OH NO* Scheme 3 CHEMICAL SOCIETY REVIEWS, 1993 n I 0or L D 01 L-ASP Scheme 4 nitrophenyl acetate is simply first-order in hydroxide ion throughout.Hapten (5) represents the first successful attempt to generate abzymes which catalyse a succeessive two-step process (Scheme 4).l53I6 The deamidation of an Asn-Gly peptide is known to proceed through a succinimide and this intermediate can be opened by the attack of water at either carbonyl.The two hydrolytic pathways yield either the Asp-Gly or the Isoasp-Gly peptide as the final products. Furthermore, electronic effects favour formation of the Isoasp product over the Asp product by a factor of 3.6. Three classes of catalytic antibodies which hydrolysed the Asn-Gly substrate were isolated: those selective for the D-isomer, those selective for the L-isomer, and those which cata- lysed the hydrolysis of both isomers. This latter property was demonstrated by a change in the Isoasp/Asp product ratio to values either greater (16) or lower (1) than the normal back- ground (3.6)reaction, and was dependent on the given antibody as well as the stereoisomer being processed.To further investigate this reaction, kinetic measurements were made for the antibody-catalysed hydrolysis of both D-and L-isomers of synthetic succinimide. These studies indicated that both tetrahedral mimics of hapten (5)-the phosphinate as well as the secondary alcohol -induced complementary binding pockets within the antibodies which were capable of catalysing reaction at both carbonyls of the succinimide intermediate. Note that either the D-or L-isomers of the succinimide could conceiva- bly occupy the binding site of a single antibody since the only difference is the location of the N-acetyl group (Figure 2). A direct comparison of the rate constants for partitioning by a given antibody of the succinimide to the two products suggests that the charged phosphinate moiety is some 6-8-fold more effective in inducing a catalytic active site than a secondary alcohol.Similarly the antibodies generated in response to the secondary hydroxy hapten (6) are less reactive, coincidentally by an order of magnitude, than those to the phosphinate (1). The above study illustrates that the structure of the transition- state mimic is crucial for producing antibodies with high cata- lytic activity. Although existing transition-state mimics have provided antibodies with fair turnover relative to the sponta- neous reaction, the full power of the technology may not be realized until other structural mimics are explored. 3 Stereospecific Transformations Several recent examples of reactions catalysed by antibodies that are attractive in a synthetic sense are listed in Table 2.The first Figure 2 Schematic illustration of D-and L-succinimide binding to the active site of an antibody generated against phosphinate (5). A. Bound @phosphate hapten Antibody binding pocket Ls""l B. Bound Dsuccinimide C. Bound L-succinimide CATALYTIC ANTIBODIES: MECHANISTIC AND PRACTICAL CONSIDERATIONS-J. D. STEWART AND S. J. BENKOVIC 217 Table 2 KM Hapten Substrate(s) Product(s) 01M) kcatlkuncat Ref. m30yCH3 0 "hH300 1.1 x 103 a N40H 0 HO (7) (as racemate) 100 70 b + QLOH0 OH 0 (14) (13) 400 -POH ArHpAx (17) 1200 290 d (1 mM NaBH,) 0-(9) 0 0 0 H N SOO(19) 5.3 x lo4 e 300 (20) (1 J.-L.Reymond, K. D. Janda, and R. A. Lerner, J. Am. Chem. SOC.,1992,114,2257. J.-L. Reymond, K. D. Janda, and R. A. Lerner, Angew. Chem., Int. Ed. Engl., 1991,30, 171 1. K. D. Janda, C. G. Shevlin, and R. A. Lerner, Science, 1993,259,490. G. R. Nakayama and P. G. Schultz, J. Am. Chem. SOC.,1992,114, 780. R. Jacobsen, J. R. Prudent, L. Kochensperger, S. Yonkovich, P. G. Schultz, Science, 1992,256, 365. p entry features an enantioselective protonation; the same anti- body also catalyses the hydrolysis of the aryloxytetrahydro- pyran acetal (13).26327Another antibody catalyses the cycliza- tion of the hydroxy epoxide (16) preferentially to a 6-end0 product, a disfavoured reaction.28 A third, induced by hapten (9), facilitates the stereospecific reduction by NaCNBH, of an a-ketoamide, (18).29 Finally, an antibody elicited by hapten (10) promotes formation of a 3'-ester linkage in the 2'-deoxy sugar (19).30 All five reactions exhibit the high reaction stereospecificity and substrate diastereo- or enantioselectivity anticipated for antibody-catalysed processes.For example, hydrolysis of enol ether (1 1) to aldehyde (12) proceeds in 96% enantiomeric excess; the reduction of a-ketoamide (18) to alcohol (19) by NaCNBH, in the presence of antibody yields the S-isomer in 99% diastereo-meric excess. Another attractive use for catalytic antibodies is to divert reaction pathways away from those favoured in solution to those desired in synthesis. In the first such example, Janda and co-workers reported the conversion of epoxy-alcohol (16) into the 6-endo (17) rather than the normally-favoured 5-exo pro-duct.Note that the latter is the only product found in the absence of antibody. Since the abzyme-catalysed and uncata- lysed reactions yield different products, a kcat/kUncatratio cannot be evaluated for this case. It is instructive to predict the reaction courses based on the kinetic parameters assigned to these antibodies, since we antici- pate that such modelling will be generally useful in judging whether the efficiency of a given catalytic antibody is sufficient for it to determine the outcome of the reaction. Using a kinetic simulation program, we first generated the expected extent of product formation for the simple, single substrate reaction time course described in Scheme 5 where P, is the desired product formed by an antibody-catalysed pathway and P, is an unde- sired product resulting from a spontaneous, uncatalysed reac- tion of the substrate.The critical parameter in these simulations is [P2]/[S], the fraction of substrate converted into the desired product when the reaction is run to completion. The time course Scheme 5 218 CHEMICAL SOCIETY REVIEWS, 1993 101 1 Time (s x lo5) Figure 3 Kinetic simulation of the mechanism shown in Scheme 5 with a KM value for substrate of 1 mM The on rate for substrate binding to the antibody was assumed to be diffusion controlled (1 x los M-ls-') and k,,,,, was fixed at 1 x lo-%-' The substrate concent-ration was 100 pM and the antibody concentration was 1 pM The time courses shown utilized (starting from the bottom)k,,t/k,ncatratios of lo2, lo3,lo4, and lo5 Time (s x lo5) Figure 4 As in Figure 3 except that KM for substrate was set at 0 1 mM was run at a typical concentration of [S](100 pM) and of [Ab] (1 pM) and at varying ratios of kcat/kuncatThe result IS shown in Figure 3 for a KMvalue of 1 mM Figure 4repeats this exercise at a ten-fold lower KM value (100 pM) We then extended our simulations to the two substrate situation shown in Scheme 6, where the binding of S, and S, was presumed to be a random process [The antibody induced by hapten (10) follows a random sequentla] process ] The time courses generated from the above kcat/kUncatratios at two different KMl and KM2values are given in Figures 5 and 6 The simulations were indexed to antibody concentrations of 1 pM, since this represents a reasonably obtainable concentration Scheme 6 "0 1 2 3 4 5 6 7 8 9 10 Time (s x lo5) Figure 5 Kinetic simulation of the mechanism shown in Scheme 6 with KM values for both substrates set at 1 mM The on rates for substrate binding to the antibody were assumed to be diffusion controlled (1 x los M-ls-') and k,,,,, was fixed at 1 x lo'%-' The concent- rations of both substrates were 100 pM and the antibody concent- ration was set at 1 pM The time courses shown utilized (starting from the bottom) kCa,/k,,,,,ratios of lo2,lo3, lo4,and lo5 Time (Sx lo5) Figure 6 As in Figure 5 except that KMvalues for both substrates were set at 0 1 mM of catalyst given the technology for producing antibodies Decreasing the level of antibody would reduce proportionately the P,/S ratio A base-line of k,,,,, = s-l was chosen, which approximates the values for the reactions listed in Table 2 Obviously, increasing the value of kuncat (and keeping the same kcat/kuncatratio) would shorten the time axis accordingly, but would not change the final P,/S ratio Inspection of Figures 3 and 4reveals that the extent of conversion into P, (the desired product) is strongly dependent on the kcat/kUncat ratio and is also quite sensitive to the value of KM Thus, kcat/kuncatratios of > lo4 and KM < 0 1 mM are clearly desirable for antibodies to have practical utility as catalysts The same ratios are necessary in the bimolecular case (Figures 5 and 6) as well In addition, bimolecular reactions should be more subject to product inhibi- tion because the transition-state mimic generally contains frag- ments of both S, and S, in P, The antibody-catalysed reactions in Table 2 exhibit KM values between 0 1-1 mM and kcat/kuncat ratios of 70-1000 and therefore should follow product (P,/S) time courses in the intermediate ranges of our simulations While the antibody catalysing the bimolecular aminoacylation reaction (20) + (21) +(22) exhibits particularly desirable kinetic para- meters, its effectiveness is compromised by strong product CATALYTIC 4NTIBODIES MECHANISTIC AND PRACTICAL CONSIDERATIONS-J D STEWART AND S J BENKOVIC 2 19 inhibition by (22) Expansion of Scheme 6 to include the observed product inhibition by (22) (K,= 0 2 pM)followed by simulation illustrates its effect on the yield of the product (Figure 7) Likewise, a simulation of the antibody-catalysed epoxide opening (1 6) -+ (1 7) using the steady-state kinetic parameters reported by Janda and co-workers shows that 1 pM antibody is sufficient to direct approximately 95% of the substrate to the desired 6-end0 product We used a value of 2 2 x s-for the conversion of (16) into the five-membered ring product for these simulations Unfortunately, the impact of product inhi- bition on this simulation could not be evaluated since the affinity of the abzyme for the reaction-products was not reported t/ I 08k/t/ I uO 1 2 3 4 5 6 7 8 9 10 Time (sx lo5) Figure 7 Kinetic simulation of the aminoacylation reaction (19) + (20) --* (21) using the reported steady-state kinetic parameters with an antibody concentration of 1 pM and both substrate concent- rations set at 100 pM (a) Top curve reaction time course in the absence of product inhibition by (21) (b) Bottom curve reaction time course incorporating the observed product inhibition by (21) (K,= 0 2 PM) 4 Conclusion It would appear that to further increase the catalytic efficacy of antibodies, it will be necessary to improve the opportunities for general acid-base chemistry at the substrate binding site of the antibody Antibodies exhibiting favourable kinetic parameters appear to operate through complex kinetic sequences caused by such active-site-substrate chemistry Appropriate side-chain residues can be introduced vza site-directed mutagenesis of specific amino acids, by replacing whole chains,32 or by con- structing binding sites for metal ions or other cofactors 33 Obviously, the objective would be to increase the kcat/kUncatratio consistently to values > lo4and also to maintain a low KM value for substrate This increased substrate binding, however, is a two-edged sword, since tighter binding of substrate most likely will be associated with tighter binding of product Inhibition by product may be overcome by changes in transition state analo- gue design or through the use of substrates that are not spatially congruent with the analogue at a distance from the reaction centre-a more general version of bait and switch catalysis 34 We are optimistic that by building upon unique antibody frameworks, sculptured by nature to complement closely our transition analogues, the desired increase in catalytic efficacies will be achieved 5 References 1 R A Lerner, S J Benkovic, and P G Schultz, Science 1991, 252, 659 2 S J Benkovic, Ann Rev Biochem 1992,61,29 3 D Hilvert, Pure Appl Chem , 1992,64, 1103 4 K M Shokat, M K KO, T S Scanlan, L Hochersperger, S Yankovic, S Thaisnvongs, and P G Schultz, Angew Chem Int Ed Engl , 1990,29, 1296 5 L Pauling, Am Sci , 1948,36, 51 6 R Wolfenden, Annu Rev Bzophys Bzoeng , 1976,5,271 7 R Wolfenden, Acc Chem Res , 1972, 5, 10 8 P A Bartlett and C K Marlowe, Biochemistry, 1983, 22, 4618 9 J V N Vara Prasad and D H Rich, Tetrahedron Lett, 1990, 31, 1803 10 J W Jacobs, P G Schultz, R Sugsawara, and M Powell, J Am Chem SOC , 1987,109,2174 11 A Tramontano, A A Ammann, and R A Lerner, J Am Chem SOC, 1988,110,2282 12 K D Janda, S J Benkovic, and R A Lerner, Sczence, 1989, 244, 437 13 K D Janda,D Schloeder,S J Benkovic,andR A Lerner,Science, 1988,241, 1188 14 R A Gibbs, P A Benkovic, K D Janda, R A Lerner, and S J Benkovic, J Am Chem SOC , 1992,114,3528 15 R A Gibbs, S Taylor, and S J Benkovic, Science, 1992,258,803 16 L J Liotta, P A Benkovic, G P Miller,and S J Benkovic,J Am Chem SOC, 1993,115,350 17 k,,, for enzymes, kcat/& for enzymes 18 S J Benkovic, A D Napper, and R A Lerner, Proc Nut1 Acad Sci USA, 1988,85,5355 19 J W Jacobs, Biotechnology, 1991,9,258 20 S J Benkovic, J A Adams,C L Borders,K D Janda,andR A Lerner, Science, 1990,250, 1135 21 K D Janda, J A Ashley, T M Jones, D A McLeod, D M Schloeder, M I Weinhouse, R A Lerner, R A Gibbs, P A Benkovic, R Hilhorst, and S J Benkovic, J Am Chem Soc , 1991, 113,291 22 R A Gibbs, B A Posner, D R Filpula, S W Dodd, M A J Finkelman, T K Lee, M Wroble, M Whitlow, and S J Benkovic, Proc Nut1 Acad Sci USA, 1991,88,4001 23 V A Roberts, J Stewart, S J Benkovic, and E D Getzoff, J Mof Bzol, submitted 24 W J Albery and J R Knowles, Biochemistry, 1976, 15, 5631 25 P Wirsching, J A Ashley, S J Benkovic, K D Janda, and R A Lerner, Science, 199 1,252, 680 26 J -L Reymond, K D Janda, and R A Lerner, J Am Chem Soc , 1992,114,2257 27 J-L Reymond,K D Janda,andR A Lerner, Angew Chem Int Ed Engl, 1991,30, 1711 28 K D Janda, C G Shevlin, and R A Lerner, Science, 1993, 259, 490 29 G R Nakayama and P G Schultz, J Am Chem SOC , 1992, 114, 780 30 R Jacobsen, P R Prudent, L Kochensperger, S Yonkovich, and P G Schultz, Science, 1992, 256, 365 3 1 C G Shevlin, personal communication 32 W D Huse, L Sastry, S A Iverson, A S Kang, M Alting-Mees, D R Burton, S J Benkovic, and R A Lerner, Science, 1989,246, 1275 33 B L Iverson, S A Iverson, V A Roberts, E D Getzoff, J A Tainer, S J Benkovic, and R A Lerner, Science, 1990,249, 659 34 R A Lerner and S J Benkovic, BzoEssays, 1988,9, 107

ISSN:0306-0012    

DOI:10.1039/CS9932200213

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Catalysis by Metal Ions in Reactions of Crown Ether Substrates R. Cacciapaglia and L. Mandolini Centro CNR di Studio sui Meccanismi di Reazione and Dipartimento di Chimica, Universita La Sapienza, 00185 Roma, Italy 1 Introduction During the last two decades macrocyclic polyethers have made an impressive impact upon the scientific community, mostly because they have properties in common with the naturally occurring ionophores. They bind alkali and alkaline-earth metal ions, and by virtue of their lipophilic structure are capable of promoting ion extraction and transport in biological and liquid- liquid membranes. The basic concept of the fit between metal ion and macrocyclic cavity size has guided the synthesis of a host of synthetic macrocyclic ligands and, in turn, has stimulated the investigation of the properties of a proportional number of metal complexes.2 This has led not only to a better understand- ing of the mechanism of action of the naturally occurring ionophores in biological systems, but has also disclosed novel properties which are interestingper se and have been used in a number of useful app1ications.l Among these we have been interested in systems where metal ion complexation by a multi- dentate ligand is a major factor in controlling the reactivity of the ligand itself.Recognition of the simple principle that coordi- native interaction between polyether chains and alkali or alka- line-earth metal ions is an effective force for catalysis led us to the design of simple functionalized crown ethers that were used in studies of metal ion catalysis of acetyl transfer and methyl transfer reactions.2 The Template Effect Our earliest interest in crown ethers dates back to the mid- seventies. In those times our group was involved in a thorough research programme on ring-closure reactions of bifunctional chain^.^ The fact that in many reports on the synthesis of crown ethers there were strong indications that ring closure was facilitated by alkali metal ions4 captured our attention. The very idea that simple and featureless chemical species such as Na+ or K+ could enhance rates of macrocyclic ring closure was fasci- nating. Our kinetic investigations of the template effect in the formation of crown ethers have been briefly reviewed.s Hence we will touch here only briefly on some aspects which proved to be relevant to subsequent investigations of metal ion catalysis. Roberta Cacciapaglia, born in Rome in 1960, received her laurea degree in Chemistry from the University ‘La Sa- pienza’, working in thejeld of ion pairing eflects on reactivity under L.Mandolini. Since 1991 she has been a research fellow of the ‘Consiglio Nazio- nale delle Ricerche’ (CNR) at the ‘Centro di Studio sui Mec- canismi di Reazione ’, Rome. Her research interests are focused on reactivity and cata- lysis in supramolecular systems. 22 1 The first approach to the problem was to investigate the influence of added metal ions on the rate of the base-induced closure of B18C6 (i.e.benzo-18-crown-6) in water solution from a phenolic precursor having an ortho polyether side chain with an w-bromo leaving group.6 It was soon apparent that the template effect was a kinetically detectable phenomenon. Ring closure was accelerated by Na+ and K+, but not by Li+ ion. Most strikingly, the divalent ions Sr2+ and Ba2+ proved to be even more efficient promoters than the monovalent ones. But more importantly, there was established a powerful technique of kinetic investigation that has been used ever since for our studies on the catalysis and inhibition by metal ions of the reactions of anionic nucleophiles. More detailed investigations of the template effect were carried out afterwards, both in 990/0aqueous Me,SO (v/v)’ and in MeOH.* Figure 1 shows the influence of added alkali metal bromides on the first-order rate constant kobsfor cyclization of the tetramethylammonium salt of O-HOC,H~(OCH~CH,)~B~ to B18C6 in 99% Me,SO.In these experiments the initial reactant concentration was kept very low (ca. 0.1 mmol dm-3) in order to make any contribution from second-order dimeriza- tion negligible, and to keep to a minimum the amount of metal ions sequestered by the anionic reactant. Known concentrations of metal ions in the kinetic runs were obtained by adding variable amounts of alkali metal bromides, which behave as strong electrolytes in Me2S0 solution. It is apparent from Figure 1 that all of the metal ions but Li+ are rate enhancing, and that the magnitude of rate-enhancement is a marked function of cation concentration and nature.The contrasting behaviour of the corresponding set of rate profiles related to the first-order formation of catechol dodecamethylene ether from the parent 12-bromododecyloxy phenoxide (Figure 2) is strik- ing. Here metal ions exert a negative influence in all cases. Strictly similar behaviours were displayed by the intermolecular alkylations of guayacolate and o--OC,H~(OCH~CH,)~OCH~ with butyl bromide.’“ Clearly, rate enhancements are only Luigi Mandolini, born in Pesaro in 1943, was educated in Chemistry in Rome under G. Illuminati. He began his academic career as an assistant to G. Illuminati (1970-1980) and lecturer in Organic Reaction Mechanisms (1971-1980) at the University ‘La Sapienza I, Rome, where he has been since 1980 Professor of Organic Chemistry and since 1987 Director of the ‘Centro di Studio sui Mecca- nismi di Reazione ’ of CNR.He was awarded the 1979 Ciami- cian Medal of the Organic Chemistry Division of the Ita- lian Chemical Society for his contributions to the field of macrocyclization reactions. His principal research interests lie in physical and mechanistic organic chemistry and supra- molecular science. 222 CHEMICAL SOCIETY REVIEWS 1993 ArO- -05 Figure 3 Distribution scheme according to classical kinetics -1 0 independent kinetic contributions from free and cation-paired anions (Figure 3) was suggested, inter aha, by the unmistakable //Lsaturation behaviour displayed by the profiles of the Na +,K +,-1 5 Rb+, and Cs+ reactions reported in Figure 1 The data were accommodated to a good precision by the binding isotherm in 3-20 Q,--2 5 -3 0 -3 5 -5 -4 4 -2 -1 lo!3[M+ 1 Figure 1 Effect of tetraethylammonium and alkali-metal bromides on the rate of formation of B18C6 in 99% Me,SO at 25 0°C(koba in s I) The horizontal line represents the rate coefficient In the absence of added salts (Reproduced by permission from J Am Chem Soc , 1983 105, 555 ) -2 0 -2 5 L0 O --35 -40 Figure 2 Effect of tetraethylammonium and alkali-metal bromides on the rate of formation of catechol dodecamethylene ether in 99% Me,SO at 25 0 "C(kobsin s l) (Reproduced by permission from J Am Chem Soc , 1983, 105 555 ) possible when the intramolecular character is combined with the multidentate ligand character in the same system 2.1 The Distribution Scheme Interpretation of the above data in terms of association of the anionic reagent with the alkali metal counter ion, and of equation 1, which is easily derived from the distribution scheme reported in Figure 3, and has the familiar form of a rectangular hyperbola Since the mean activity coefficient yh was easily calculated from an extended Debye-Huckel equation and k,was accurately measured, numerical values for the unknown quanti- ties k,, and KIPwere determined by a non-linear least-square fit of equation I to the data The most interesting feature of the data related to the forma- tion of B18C6 is the fact that K+ is the best promoter both in 99% Me2S0 and in MeOH (Table 1) Incidentally, we note that use of MeOH as a solvent permitted determination of the catalytic efficiencies of the alkaline-earth metal ions Ca2 +,Sr2+, and Ba2+ under the same conditions used for the monovalent ions The more than lo3 rate enhancement measured with Sr2 + was admittedly unexpected, but nevertheless gratifying It taught us that the amount of binding energy translated into catalysis in reactions promoted by hard metal ions can be very large Table 1 Template effects on the formation of B18C6 in 99% Me2S0 and in MeOH at 25°C Metal ion 99% Me,SO' kpik1 MeOH" Na + 61 60 7 K+ 100 199 Rb + 43 48 7 cs + 19 17 1 Ca' + 51 6 Sr2 + I190 BaZ+ 334 Data from ref 7rr Data from ref 8c 2.2 The Hole-Size Relationship When ring sizes other than 18 were considered, ordering among cations changed in a way that was decidedly suggestive of the importance of the match of the metal ions to the cavity of the ring-shaped transition states 7b This is clearly shown, for ex- ample, by the set of rate profiles related to the formation of B21 C7 in 99% Me2S0 (Figure 4) Clearly, optimum efficiency is obtained here not with K +,but with the larger Rb + and Cs ,the+ small Na+ acts as an inhibitor However, with B15C.5, Na+ turns out to be the best promoter, K+ ranks next, and Rb+ and Cs+ follow in the given order Not surprisingly, equilibrium constants for association of alkali metal ions to the benzo-crown ether products revealed as a general trend that a metal ion which associates strongly with a crown ether is also a good ternplating agent in the formation of that crown ether, and that the magnitude of the template effect is basically related to those factors which govern the strength of binding to the reaction product CATALYSIS BY METAL IONS IN REACTIONS OF CROWN ETHER SUBSTRATES-R CACCIAPAGLIA AND L MANDOLIN1 223 -1 0 --1 5 ---20 3m-25 --0 -30 --35 -40 t Figure 4 Effect of tetraalkylammonium and alkali-metal bromides on the rate of formation of B21C7 in 99% Me,SO at 25 0°C(/cobs in s ')(Reproduced by permission from J Am Chem Soc , 1984,106, 168 ) 2.3 Ion Pairing and Reactivity Inhibition by metal ions, rather than catalysis, clearly occurs for all of the reactions whose rate profiles have a negative first derivative Figures 1,2,and 4 show that in all cases, with the sole exception of the Na+ profile drawn in Figure 4, the curvature is negative, which is a consequence of the fact that the quantity (k,p/k,)K,py$[M'3 appearing in the numerator of equation 1 is much smaller than unity throughout the investigated concent-ration ranges and a good fit of the data is obtained with the simplified equation 2 In these cases the only productive route is the free ion pathway, the ion pair being totally unreactive In contrast, for the Na+ profile drawn in Figure 4 an inflection point occurs in the neighbourhood of 0 01 mol dmP3,above which the curvature becomes positive and the data tend to saturation This is a clear consequence of the fact that there is an increasingly greater contribution from the ion pair pathway, which renders the quantity (klp/kl)Klpy$[M +I significant with respect to unity in the high metal-ion concentration region For the case dt hand, klp/klturned out to be 0 27 When we started our studies of the template effect, the notion that ion pairs are less reactive than free ions in SN2reactions was well established We soon realized, however, that knowledge in the fieldwas based mainly on evidence that was either qualitative or semiquantitative in nature In addition to the scarcity of ion-pairing constants available in the literature, severe limitations to such studies are ascribable to the serious difficulty of a mean-ingful separation of ion pair from free ion contributions to the overall rate, particularly when k,, is much smaller than k, But we also realized that we had developed a useful technique for the investigation of ion pairing effects on reactivity The basic feature of the technique is that the relative propor-tions of cation-associated and unassociated nucleophile are varied over a wide range by virtue of the mass law effect exerted by varying amounts of added strong electrolytes As a conse-quence, ion pairing effects on rates become so large that their recognition is easier and their assessment considerably more Et4N-1 -2 0.-3 d LI 22 Sr -0 k 4 a 1 I 1 -3 -2 -1 log[salt] Figure 5 Effect of tetraethylammonium and metal salts on the rate of intramolecular C-alkylation of the anion of ethyl (5-bromopenty1)-acetoacetate in 99% Me,SO at 25 0°C(/cobs in s l) (Reproduced by permission from J Org Chem , 1988,53,2579) precise In practice, the mere occurrence of an inflexion point in a rate profile with negative first derivative may be taken as convincing evidence for the occurrence of significant contribu-tions from the ion pair pathway Self-consistency is another feature of our technique, which does not rely upon ion pairing constants from other sources, but can in fact be considered d valuable tool for the determination of ion pairing constants In addition to phenoxide~,~~our self-consistent approach hasOU been applied to ion pairing effects on alkylation reactions of carboxylates' Ob and malonates, O' and to C-Od and 0-alkyld-tionslOeof acetoacetic ester derivatives Although the main goal of this short review article is not the discussion of these studies, a glance at the rate profiles plotted in Figure 5 will suffice to illustrate the potential of the technique The reaction under investigation is the intramolecular alkylation of the dnion derived from ethy1 (5-bromopenty1)acetoacetate (equd tion 3) Analysis of rate data by means of equation 1 showed that k,,/k, is 40x 10P3forLi+,16x10-*forBa2+,30x10 3forSr2+, 1 0 x for Ca2+,and 1 7 x loP5for Mg2+ 2.4 The Caesium Effect A brief comment on the so-called caesium effect is in order here The term refers to the supposedly beneficial influence of Cs+ compared with the smaller alkali metal ions in alkylation reactions of anionic nucleophiles and, notably, in their intramo-lecular versions leading to macrocyclic compounds This notion has been challenged l2 No special property of Cs+ emerges from our studies but, rather, a situation where its influence on rates is very similar to those of its next congeners K+ and Rb+,as clearly shown, for instance, by the data plotted in Figure 2 Furthermore, lactonization of 1I -bromoundecanoic acid In the presence of alkali metal carbonates revealed a close correspondence between ion pairing effects on lactonization, as disclosed by the kinetics and yields of the 12-membered lactone.It was concluded that the myth that Cs+ favours macrocycliza- tion by directing the reaction in an intramolecular fashion, possibly via a 'rolling mechanism' at the surface of the large Cs + ion,' was based on little data and some imagination. 2.5 Ion Triplets and the Two-metal-ion Pathway The reactivity and UV spectra of aryloxide ions in DMF are affected by the addition of either Li+ or Na+ ions in a way that suggests the occurrence of weak ion triplets M+A-M+ in addition to free ions and ion pairs.loa Weak ion triplets of the same kind were also detected in DMF with carboxylate ions. Ob In Me,SO solution these phenomena are hardly noticeable because of its high dielectric constant (Me,SO, E, = 46.7; DMF, E~ = 36.7).In the presence of ion triplets, a more expanded distribution scheme has to be taken into account (Figure 6). ArO-4 -Product ArO-M + Figure 6 Distribution scheme involving ion triplets. Whenever both ion pairs and ion triplets are unreactive, as is usually the case, the drop in kobsupon increasing [M '3 is much steeper than predicted by equation 2. Different situations occur with the templated cyclizations leading to benzo-crown eth- ers. Oa>l The influence of increasing amounts of KClO, on the rate of cyclization Of O--oC6H4(OCH2CH2)6Br to B21C7 in a medium composed of equal volumes of 99% Me,SO and dioxane is shown by the bell-shaped profile of Figure 7.On increasing the concentration of K+ the rate increases first because of the accumulation of the reactive ion pair, but a marked reduction in the extent of catalysis is observed in the high concentration region. This is a consequence of the gradual replacement of the ion pair by the less reactive ion triplet (kit < kip). This is not surprising, as there is obviously no room for two K+ ions in the cavity of the ring-shaped transition state leading to B21C7. But when the ring becomes larger, as in B30C10, a steep increase in reactivity is found in the concent- ration region where a reactivity drop is observed with B21C7. This behaviour has been interpreted as being due to the superpo- sition of an additional contribution from the ion triplet, with kIt> kip: It has been suggested 7b,13 that the two K+ ions are hosted In the 30-membered ring transition state, as schemati- cally depicted in Figure 8.2.6 Modelling the Transition State According to transition state theory, equation 1 can be written in the form (4) where KTi, operationally defined as has the meaning of the formal equilibrium constant for conver- sion of the transition state which does not contain Mz+ into one which contains Mz+, i.e.,the ion pairing association constant of the transition state (Figure 9).8cOn the basis of equation 5 the problem of the influence of the metal ion on reactivity resolves itself into questions of the response to the metal ion of the relative ligation abilities of reactant and transition state.This is well illustrated for the template formation of B18C6 in MeOH CHEMICAL SOCIETY REVIEWS, 1993 12 10 8 5 sp 6 830C10 4 2 4 3 -2 -1 Log QClO, Figure 7 Effect of added KClO, on the rate of formation of B2 1C7 and B30C10 in dioxane/99% Me,SO (2:l) at 25°C. (Data from ref. 13.) Figure 8 Schematic picture of the transition state for the two-metal-ion pathway in the formation of B30C10. ArO-T'It I+M' Kip M /KT> Product -A~O-M+ -T*M+ Figure 9 Distribution scheme according to transition state theory. by a comparison of KT' values calculated from rate data with equilibrium constants for association of the metal ions with the three polyether ligands involved in the reaction, namely, ArOH, ArO -,and B18C6 (Figure 10).These are all sexadentate oxygen ligands, but belong to different structural types. The open-chain ligands ArOH and ArO- differ in the presence of the negative charge that is responsible for the increased complexation power of the latter. On the other hand, the cyclic nature of B18C6 is clearly responsible for its being a much stronger ligand than its acyclic counterpart (a macrocyclic effect). Figure 11 clearly shows that the transition state T* is the best ligand out of the four species ArOH, ArO-, B18C6, and T*for all of the given metal ions. This is understandable, since T* is both cyclic and negati- vely charged. The effect of the variation of cation on the stability CATALYSIS BY METAL IONS IN REACTIONS OF CROWN ETHER SUBSTRATES-R.CACCIAPAGLIA AND L. MANDOLIN1 225 4 _I__* (OCH,CH,),Br / (OCH,CH,),Br=a-ArOH ArO' Figure 10 Distribution scheme involving fully coordinated structures. 7-la 1 K 1 Rb Cs 1 -l :a I Sr I Ba 9 8 7 t7 k6 =-O-I0 818CI35 5fi4 4\ Am-13 2 Ar On 1.0 1.2 1.4 1.6 1.0 1.2 1.4 Ionic radius (A) Figure 11 Log K for association of metal ions with the sexadentate oxygen ligands involved in the B 18C6-forming reaction in MeOH solution. of the T*Mz+ complexes roughly parallels the corresponding effect on the stability of the B18C6.MZ+ complexes, showing that the geometry of the ring-shaped transition state is close to that of the ring product. We note further that the stabilizing effect of the negative charge is stronger in the reactant state complexes than in the transition state complexes, because the negative charge is essentially localized on the aryloxide oxygen in the former, but significantly more spread in the latter.It appears therefore that a representation of the transition state for the metal-templated formation of B 18C6, which is consistent with all of the above data, is one involving a fully coordinated structure (Figure 12). 3 The Poly(oxyethy1ene) Side Arm The basic ingredients of the transition state complex depicted in Figure 12 are (i) a metal ion, (ii) a (somewhat delocalized) negative charge, and (iii) a poly(oxyethy1ene) side arm. Transi- tion state stabilization by the metal ion occurs through co- I T*W+ Figure 12 Transition state for the metal-templated formation of B18C6.operation of electrostatic binding to the negative charge and coordinative binding to the polyether moiety. Now the import- ant question arises as to whether this type of catalysis by alkali and alkaline-earth metal ions is peculiar to crown ether forming reactions or has a more general scope. To answer this question, one should imagine a situation where a polyether moiety is proximal to the negatively charged reaction zone of an anion- neutral-molecule reaction. Unlike the crown ether forming substrates, here the polyether moiety does not bear a reacting group. It should serve the sole, important purpose of providing additional binding sites for complexing the metal ion, thereby increasing the stability of the metal-bound transition state.3.1 Enhancing Rates of Acetyl Transfer In a first approach to the problem, we have inve~tigated'~ the influence of added alkali (Na, K) and alkaline-earth (Sr, Ba) metal bromides on the rate of acetyl transfer from o-acetoxyphe- nyl 3,6,9,12-tetraoxatridecylether to MeO- in MeOH at 25 "C (equation 6). 0- CHEMICAL SOCIETY REVIEWS, 1993 I I Me Me I II Figure 13 Schematic pictures of the transition state for the metal-ion assisted methanolysis of phenyl acetate The results largely fulfilled our expectations All of the added salts increased the rate of reaction according to standard binding isotherms having the general form of equation 4 The order of catalytic efficiency is Na+ < K+ << Sr2 < Ba2+,a maximum + rate acceleration of nearly 10, being observed with the latter metal ion The finding that the corresponding reaction of the parent phenyl acetate is unaffected by Na+ and K+, and accelerated only slightly by the divalent metal ions demonstrates that substantial contributions to the stability of the transition state of the metal-ion assisted path arise from interaction of the metal ion with the oxygen donors of the side arm 3.2 Nucleophilicity of Alkaline-earth Metal Methoxides Analysis by means of equation 4 of the rate data obtained in the reactions of phenyl acetate14 gives log KIP= 1 78 and 1 64, and log KTi = 2 45 and 2 21 for Sr2 + and Ba2 + respectively These figures are translated by means of equation 5 into a k,,/k,value of 4 7 for Sr2 and one of 3 7 for Ba2 ++ A rationale for the finding that the transition state binds Sr2 + and Ba2 + more strongly than methoxide ion, in spite of the fact that a more concentrated negative charge is present in the latter, is offered by the chelate structure I (Figure 13) having the form of a four-membered contact ion pair, but it is clear that the six- membered solvent-shared forms I1 and I11 are equally consistent with the kinetics The fact that the metal-bound methoxide is inore reactive than free methoxide is apparently at variance with the wide- spread belief that ion pairs are less reactive than free ions This is what is usually observed in nucleophilic substitutions at satur- ated ~arbon,~ but a contrasting behaviour has been recently reported for reactions of carbon-, phosphorous-, and sulfur- based esters ' 3.3 Enhancing Equilibria in Hemiacetal Anion Formation The simple strategy based on the poly(oxyethy1ene) side arm that has been used to enhance rates can also be used to enhance equilibria The simplest example is offered by the increase in apparent acidity of ArOH (Figure upon metal ion com- plexation An additional example is found in a quantitative study' of the influence of alkali and alkaline-earth bromides on the equilibrium for the addition of methoxide ion to 2-(1,4,7,10,13-pentaoxatetradecyl)benzaldehydein MeOH at 25 "C(equation 7) Whereas alkali metal ions have no effect, the apparent equilibrium constant is increased by about 420 and 150 times upon addition of 0 1 mol dm SrBr, and BaBr,, respecti- vely No effect of this sort is observed with benzaldehyde, for which addition of MeO- turned out to be unaffected not only by alkali but also by alkaline-earth metal salts OMe (7) FHO H.3 0-C' I Me 111 4 More Preorganized Substrates The role of preorganization in host-guest chemistry is well recognized It is a consequence of the simple principle that conformational changes of the host upon binding to the guest are to be kept to a minimum Clearly, this condition is poorly fulfilled by the poly(oxyethy1ene) side arm, on account ofits high conformational mobility In order to increase the available binding energy and, hope- fully, the fraction of this binding energy which can be utilized in catalysis, we have turned our attention to more structured substrates such as macrocyclic polyethers containing a 1,3-xyleneyl unit in the macrocyclic backbone, with a functional group X attached to the 2-position of the aromatic ring (Figure 14) The binding properties of these host molecules can be modulated within wide limits by changing the length of the pol yether bridge 4.1 Acetyl Transfer Reactions The effect of alkali (Na, K, Rb, and Cs) and alkaline-earth (Sr, Ba) metal ions on acetyl group transfer to methoxide ion by a series of crown ether acetates, ranging from 2-Ac0-15C4 to 2- Ac0-27C8 (equation S), has been investigated in MeOH solu- tion at 25 "C l7 For each substrate a complete set of rate profiles was obtained An example is shown in Figure 15 In all cases the effect of metal ions is rate enhancing, maximum observed accelerations ranging from 2- to 20-fold with the inonovalent ions, and from 2 to 3 orders of magnitude with the divalent ions CH,CO,Ar + Me0 --* CH,C02Me + ArO (8) Treatment of rate data for the monovalent ions was carried out by means of equation 9, which is clearly of the same form as equation 4, apart from the y$ term which does not appear in the numerator of the right-hand side of equation 9 because the experiments were run at constant ionic strength Here kobsis the second-order rate constant measured in the presence of added salt, k, refers to reactions run in the presence of tetraalkylammo- nium ion as the sole counter ion, and Ks is the equilibrium constant for binding metal ions to the crown ether substrates The results of the treatment are summarized in graphical form as a plot of log KTt vs log Ks (Figure 16) It should be noted that the extent of catalysis for each substrate-cation combination is simply given by the vertical difference between the representa- tive point and the origin-intercepting line of unit slope Not unexpectedly, considerable scatter is apparent in the plot, show- ing that the relation between binding and catalysis is a complex one Nevertheless, there is an undeniable tendency for KTt to increase with increasing Ks, which indicates that there is a certain degree of resemblance betweeen the alterered substrate in the transition state and the unaltered substrate in the reactant state (9) In some cases, two metal ions can be accommodated in the macrocyclic cavity of the transition state, giving rise to well defined two-metal-ion pathways, which have been kinetically + +detected in the Na and K reactions of 2-Ac0-24C7 and in the CATALYSIS BY METAL IONS IN REACTIONS OF CROWN ETHER SUBSTRATES-R.CACCIAPAGLIA AND L. MANDOLIN1 227 n = 4 2-Ac0-15C4 2,6-bis[(2-ME)M]PA n =5 2-Ac0-18C5 n = 6 2-Ac0-21 C6 n =7 2-Ac0-24C7 n =8 2-Ac0-27C8 la b c d K + and Rb reactions of 2-Ac0-27C8. Thus, there seems to be a + close parallel between the two-metal-ion pathway in the tem- plated formation of large ring benzo-crown ethers and the present case.It is worth stressing that the metal ions that can be doubly hosted by 2-Ac0-24C7 are Na+ and K+, but for the larger 2-Ac0-27C8 it is K+ and Rb+ that can be doubly accommodated. No effect of this sort was observed with Cs+. These observations point to the existence of a definite correla- tion between cation size and fit to the macrocyclic cavity. 1000 4 100 < 3 10 0.001 0.01 0.1 t =it1 Figure 15 Effect of alkali and alkaline-earth metal bromides on the rate of basic methanolysis of 2-Ac0-18C5 at 25 "C. n = 5 2-Me0-18C5 n = 5 2-Me02C-18C5 la b Treatment of rate data obtained in the presence of Sr2+ and Ba2+ requires an appropriate binomial accounting for associa- tion of the metal ion with methoxide to be included in the denominator of equation 9.This leads to equation 10,which fits remarkably well to all of the data.The relevant parameters are summarized in Table 2. The much greater catalytic power of the divalent ions as compared with the monovalent ions is not only 51 4 I catalysis 0 cs7 Rb7 / ~a5 '$8. K4 *Rb4 ~8 OCS4 Na6/ 0 1 2 3 Log Ks Figure 16 Transition state stabilization vs. reactant state stabilization for the alkali metal ion assisted methanolysis of crown ether aryl acetates 2-Ac0-3(n + 1)Cn. The numbers attached to the datum points indicate the number of oxygens in the crown ether bridge. The origin-intercepting line of unit slope is the borderline between the catalysis and inhibition domains.Table 2 Alkaline-earth metal ion assisted acetyl transfer in MeOH at 25'Ca KS KT' (kobslko)maxh(mol-' dm3) (mol-' dm3) 2,6-bis[(2-ME)M]PA Sr -2.8 x 10, 7.0 Ba -1.7 x lo2 5.6 2-Ac0- 15C4 Sr -1.2 x 103 4.0 x 10 Ba -2.4 x 103 9.3 x 10 2-Ac0- 18C5 Sr -9.1 x 103 2.3 x lo2 Ba -2.0 x 104 7.6 x lo2 2-AcO-21C6 Sr -3 8.5 x 103 1.9 x lo2 Ba 50 3.2 x 104 2.5 x lo2 2-Ac0-24C7 Sr 8 2.2 x 104 3.5 x 102 Ba 260 4.4 x 104 1.0 x 102 2-Ac0-27C8 Sr 5 1.3 x 104 2.5 x lo2 Ba 74 2.6 x 104 1.6 x lo2 K,p(mol-I dm3) for association with methoxide is 27 f5 for Sr2 and 19 i4+ for Ba2 . * Maximum observed rate enhancing effects. Whenever a rate + maximum is absent, the rate data refer to 0.1 mol dm-3 added salt.due to a much larger electrostatic stabilization of the transition state, but also to a better utilization in catalysis of the binding energy due to coordinative interactions with the polyether bridges. This is clearly shown, for example, by a comparison of data for reaction of the model compound 2,6-bis[(2-ME)M]PA with the corresponding data reported for 2-Ac0-15C4 and 2- AcO- 18C5. As substrate binding is negligibly small in all cases, the only initial-state stabilization by metal ions which has to be paid for is that of methoxide ion. This means that, unlike the alkali-metal ion reactions of the same substrates, the additional binding energy rendered available in the cyclic substrates, relative to the open-chain model, shows up in the transition states only, and is fully utilized in catalysis.As a variation on the theme of macrocyclic structures incor- porating a 1,3-xyleneyl unit, a series of macrocyclic compounds (1) and open-chain models (2) (Figure 14) incorporating a 2,6- dibenzyl-4-nitrophenyl acetate moiety have been synthesized and tested for Sr2+ and BaZ+ catalysis of transacylation.l* Small rate enhancements were measured in MeO-/MeOH, but remarkably high catalytic factors and novel kinetic features were observed in the EtO -/EtOH base-solvent system. Evidence was obtained that ethoxide ion is completely bound to the metal ion (equation 11). This leads to a simple kinetic treatment, as the metal-bound ethoxide is treated kinetically as a single species (equation 12).Rate data are summarized in the upper part of Table 3. All of the investigated reactions are promoted by Sr2 + and Ba2 +,but it is apparent that more favourable situations are met with the larger macrocycles (lc) and (Id), and with the open chain analogue (2b). These data point once more to the import- ance of a polyether chain which is available for binding to metal ions, and pose the question as to why the divalent metals are more efficient in EtOH than in MeOH. To answer this, ester cleavage of 2-Ac0- 1 5C4, 2-Ac0- 18C5, and 2-Ac0-2 1C6 was investigated in Et0-/EtOH.l9 The rate data listed in the lower part of Table 3 clearly reveal dramatic accelerations by metal ions, the largest effect being displayed by 2-Ac0-21C6, which reacts with EtOBaBr half-a-million times faster than with EtONMe,. The conclusion was reached that these huge rate enhancements are a consequence of the fact that both electro- CHEMICAL SOCIETY REVIEWS, 1993 Table 3 Rate data for acetyl transfer reactions from aryl acetates to ethoxide ion in EtOH at 25 OC" Substrate EtOSrBr EtOBaBr KS kM/ko KS kdk,(mol-dm3) (mol-dm3) pNPOAch -8.0 -7.0 (2a) -24.8 -18.5 (2b) 39 279 25 188 (la) -16.7 -14.1 (lb) -14.2 -15.1 (W 12 46.6 20 91.3 (14 11 249 23 69 1 POAcr -62 -45 2-Ac0- 15C4 48 2 300 54 7 200 2-Ac0-18C5 57 48 000 121 46 000 2-Ac0-21C6 89 41000 1450 500000 Data from ref.18 (upper part) and ref. 19 (lower part).pNPOAc = p-1nitrophenyl acetate. POAc = phenyl acetate. static binding and coordinative binding in the metal- bound transition state are much more efficient in EtOH than in MeOH. EtONMe, + MBr, -P EtOMBr + Me4NBr (1 1) v = kMIEtOMBr][S] (12) 4.2 The Ternary Complex and the Question of Detailed Mechanism In addition to the exciting crescendo of catalytic factors shown in Table 3, our studies of metal ion catalysis of acetyl transfer in EtOH solution disclosed a kinetic feature that bears directly on the important question of the detailed or microscopic mechan- ism of catalysis (and inhibition) by metal ions in anion-neutral- molecule reactions. For some of the compounds, plots of kobsvs [EtOMBr] were strictly linear over a wide concentration range, but a negative curvature was present in the other cases, which were analysed in terms of the mechanism in equation 13, where the substrate S associates in a reversible fast step with EtOMBr to give what might be called a ternary complex (substrate + ethoxide + metal ion), which decomposes into products in a slow mono- molecular step.KS kcatS + EtOMBr F! S.EtOMBr Products (13)--t Analysis of rate data for all the compounds showing a non-linear dependence upon [EtOMBr] gave the Ks values listed in Table 3. Since it seemed unlikely that the fact that some of the substrates follow a certain kinetic equation whereas the others follow a different equation implied a mechanistic change along the series, we assumed that the mechanism of equation 13 applied also to substrates exhibiting linear dependence upon [EtOMBr].In these cases the ternary complex presumably resembles an inher- ently unstable random complex, but it is clear from the data in Table 3 that an increasing number of oxygen donors increases the stability of the associated species to the point where a true complex accumulates such as to affect the kinetics. In general terms, we believe that the dualism between the ion- pair mechanism, in which a cation-paired nucleophile reacts with a free substrate, and the pre-association mechanism, in which a free nucleophile reacts with a metal-bound substrate,20 can be overcome, at least conceptually, if one assumes that in all cases the reaction proceeds through what, in the language of the enzyme kineticist, is known as a random sequential mechanism (Figure 17).Here the key intermediate is a ternary complex that is formed from reactants and metal ion with no obligatory order of combination. CATALYSIS BY METAL IONS IN REACTIONS OF CROWN ETHER SUBSTRATES-R CACCIAPAGLIA AND L MANDOLIN1 229 MZ+S Nu-M" Figure 17 Random sequential mechanism From an operational point of view, it should be stressed that here, as in other cases where the reagents are in mobile equili- brium, the question of detailed mechanism, as pointed out by Harnmett,,I ' is ambiguous because the question is In any event it is irrelevant to any presently observable phenomena' These arguments explain our preference for equation 10 in the treatment of data which, in terms of classical kinetics, are subject to a mechanistic ambiguity I4 l7 Equation 10 is based on transition state theory and, consequently, bears no relation whatsoever to the microscopic or detailed mechanism by which the transition state is attained 4.3 Methyl Transfer Reactions Metal ion catalysis is by no means restricted to acetyl transfer Rdtes of methyl transfer from 2-Me0-18C522 and 2-Me0,C- 18C523 to a-toluenethiolate (equations 14 and 15) are greatly enhanced by alkali metal counter ions in a way that is highly dependent upon the substrate-cation combination (Table 4) When the metal ion is sequestered by criptand 222, any rate enhancing effect disappears The crucial role of the crown ether bridge is once again demonstrated by the model compounds 2,6- dimethylanisole and methyl 2,6-dimethylbenzoate, whose demethylation reactions are in fact inhibited, not accelerated, by Table 4 Cleavage of methyl 2,6-dimethylbenzoate, 2-Me0,C- 18C5, 2,6-dimethylanisole, and 2-Me0-18C5 by C,H,CH2S- M + M+ kr,, Methyl 2 6-dimethylbenzodte" K+[222] lh Li 0 54+ Na 0 57+ K+ 0 66 cs 0 43+ 2-Me02C- 18C5" K+ [222] 1 Li 15+ Nd 7+ K+ 7 cs+ 44 2 6-Dimethylanisoled K+[222] I' Lit 0 25 Na + 0 43 K+ 0 43 cs 0 42+ 2-Me0- 18C5" K+[222] I' L1+ 26 Nd 565+ K+ 826 cs 146+ In DMF (+ 1 6 mol dm H,O) at 35°C Data from ref 23 h=35xIO 4m~l'dm3s k=32x10 4m01 'dm3s In DMF (+ 33 mol dm H,O) at 60°C Ddtd from ref 22 X=89x 10 'mol 'dm3s ' k=46x 10 'mol 'dm3s alkali metal counter ions Dissection of metal ion effects into reactant state and transition state contributions was not carried out for these reactions Nevertheless, there is no doubt that metal-ion binding is strongest in the transition states C,H,CH,S-+ MeOAr -+ C,H,CH,SMe + ArO (14) C,H,CH,S-+ Me0,CAr +C,H,CH,SMe + ArCO, (1 5) Peak reactivity occurs both with 2-Me0-18C5 dnd 2-Me0,C- 18C5, but K+ is the best promoter with the former, and Na+ with the latter This seems to be a consequence of the hole-size relationship, as suggested by the naive pictures of the transition states involving fully coordinated structures (Figure 18) The cavity defined by the polyether bridge and the bulkier methoxy- carbonyl group is somewhat smaller than the corresponding cavity in the crown ether anisole and, consequently, more suitable to host the smaller Na+ ion L Figure 18 Transition states for the cleavage of 2-Me0-18C5 and 2-Me02C-18C5 We further note that metal ion effects are about an order of magnitude larger in the demethylation of the crown-anisole, which is believed to arise from a stronger electrostatic binding in the metal-bound transition state Here the negative charge transferred from the thiolate nucleophile is essentially localized on a single oxygen atom, but spread over both oxygens of the methoxycarbonyl group in the reactions of 2-Me0,C- 18C5 5 Acetyl Transfer in Calixarene Systems The monoacetylated derivative (4) of p-tert-butylcalix[4]arene-crown-5 (3), constitutes a further step toward more preorgd- nized structures (Figure 19) 24 Ionization of the phenolic hyd- roxyl of (4) has the potential for providing an additional binding site for holding a metal ion in the crown ether cavity very near to the acetoxy group Deacetylation of (4) in Me,NOMe/MeOH (3)X=Y=OH (4) X = OH, Y = OAC (5) X = 0-,Y = OAC (6) X = OH, Y = 0-(7) x = 0-,Y = 0-rol, Figure 19 230 occurs very slowly at 25"C, with a second-order rate constant k,,,,, of 3 4 x 10-mol -dm3 s -By way of an example, the half-life in a I mmol dm Me,NOMe solution is 34 weeks, but drops astonishingly to 8s upon addition of 1mmol dm-BaBr, Strontium bromide promotes the reaction, but to a somewhat smaller extent Much lower, yet still remarkable rate enhance- ments are brought about by monovalent ions Methanolysis in 40 mmol dm-3 Me,NOMe is accelerated 3300-fold by 40 mmol dm KBr, and 220-fold by 43 mmol dm RbBr Combination of kinetic and UV spectroscopic data shoMs that in the absence of metal ions attack of MeO- takes place on the non-ionized form (4), but in the presence of metal ions the reactive form is the metal complex of the ionized form (5), which is present in significant amounts by virtue of the acidity- enhancing effect of the metal ions (equation 16) Thus, the simple replacement of the ionizable proton of (4) with a metal ion converts an unreactive species into a very labile one The metal ion, hosted in the cavity delimited by the crown ether bridge and the aryloxide oxygen, activates the carbonyl group toward nucleophilic attack, as depicted in (8) Analysis of rate data showed that kcat/kuncatis 1 2 x lo6 for SrBr, and 2 1 x lo7 for BaBr,, which are translated into transi- tion state stabilizations of 8 3 and 10 0 kcal mol- I, respectively (1 cal = 4 184 J) To the best of our knowledge, these are the most striking examples of electrophilic catalysis by these ions Me0 Me0 k,,, (4) + M2+ C_(5) M2+ -Product (1 6) 5.1 A Novel Nucleophilic Catalyst with Transacylase Activity The acidity enhancing properties of divalent metal ions, coupled with their rate-enhancing properties in acyl transfer reactions, can be put to the purpose of developing a nucleophilic catalyst with transacylase activity When properly activated by Ba2+ under mild basic con- ditions, (3) acts as a transacylation catalyst in the methanolysis of p-nitrophenyl acetate (pNPOAc) in a medium composed of 90% MeCN and 10% MeOH (v/v) at 25 "C * The results of a typical set of kinetic experiments are plotted in Figure 20 The slow liberation of p-nitrophenol (pNPOH) due to background methanolysis (ti ca 5 days) is unaffected by addition of (3), but significantly accelerated by an equimolar mixture of (3) and BaBr, The initial burst of pNPOH release is followed by a linear portion where the reaction order is zero and the slope is above an order of magnitude larger than background The linear portion extrapolates back to an initial burst which corresponds nearly to the initial concentration of (3) The occurrence of a catalyst- substrate covalent intermediate in the catalysis pathway was 0 80 II bl n0 60E E v 040 zn-020 000 0 10 20 30 40 50 60 70 80 90 t(min) Figure 20 Appearance of pNPOH during methanolysis of pNPOAc (30 mmol dm 3, In MeCN/MeOH (9 1) in the presence ofdiisopropyleth- ylamine bromide salt buffer ([B]/[BHBr] = 3 I) Curve (a) V back-ground reaction measured in the presence of buffer alone, 0 buffer plus 0 46 mmol dm (3) Curve (b) buffer plus 0 46 mmol dm (3)0 46 mmol dm BaBr,, the full line is calculated (Reproduced by permission from J Am Chem Soc , 1992,114 10956 ) CHEMICAL SOCIETY REVIEWS, 1993 strongly suggested by the phenomenological behaviour typical of ping-pong kinetics,2 and directly confirmed by HPLC analy- sis The turnover number is 5 5 x lop3min-', which means a catalyst turn over rate of eight times per day In the presence of Ba2 +,about 1/6 of (3) is in the farm of the neutral barium complex (7) BaZ+,the rest being probably in the form of (6) Ba2+ The kinetics indicate that the active form of the catalyst is the barium complex of the doubly ionized form (7), and that the entire catalytic cycle takes place as shown in Figure 21 In the active complex (7) Ba2+,the negative poles and the polyether bridge act as working units that perform co- operatively in providing the driving force for the formation of the complex itself, and the barium ion serves as an electrophilic catalyst both in the acylation and in the deacylation steps AcOMe MeO-(7)*Ba2+ (5).Ba2+ pNPOAc pN PO- MeO-AcOMe Figure 21 The barium salt of (3) as a nucleophiliccatalyst with transacyl- ase activity The design and synthesis of organic catalysts that possess some of the attributes of enzymes is a major challenge in supramolecular chemistry Much work has been done on syn- thetic catalysts with transacylase activity, but significant success has been achieved more in the acylation than in the deacylation step 27 It appears, therefore, that the supramolecular complex (7) Ba2+ can be viewed as a prototype catalyst, from which it is hoped that more sophisticated structures capable of displaying enzyme-like transacylase activity can be derived 6 Concluding Remarks The results presented in this account show to what an extent the rates of reactions of anionic nucleophiles with neutral molecules, including their intramolecular versions, are influenced by alkali and alkaline-earth metal ions Rate effects measured under carefully controlled conditions span over I2 orders of magni- tude, ranging from the rate inhibition observed in the alkylation of the magnesium derivative of P-ketoenolates to the lo7 rate enhancement found in the cleavage of the barium complex of p-tert-butylcalix[4]arene-crown-5monoacetate Dis- cussion has been focused on transition state stabilization by metal ions, and on the beneficial influence of additional binding energy rendered available by a polyether moiety proximal to the reaction zone Our work in this field widens considerably the scope of group 1 and group 2 metal ions as effective catalysts of CATALYSIS BY METAL IONS IN REACTIONS OF CROWN ETHER SUBSTRATES-R CACCIAPAGLIA AND L MANDOLIN1 231 transacylation processes, which have potential for further investigation and development in the field of supramolecular catalysis Ackno~ledgements The contributions of the colleagues whose names appear in the cited references are deeply acknowledged 7 References I ‘Crown Ethers and Analogs’, ed S Patai and Z Rappoport, J Wiley New York, 1989.G Gokel, ‘Crown Ethers and Cryptands’, The Royal Society of Chemistry, Cambridge, 1991 2 R M Izatt, K Pawlak, J S Bradshaw, and R L Bruening, Chem Re\ , 1991.91, 1721 3 G Illuminati and L Mandolini, Acc Chem Res .1981, 14, 95, L Mandolini, Adr Phys Org Chem , 1986,22, 1 4 D N Reinhoudt and F de Jong, in ‘Progress in Macrocyclic Chemistry’, ed R M Izatt and J J Christensen, J Wiley and Sons, New York, 1979, vol 1, p 176 5 L Mandolini, Pure and Appl Chem , 1986,58, 1485 6 L Mdndolini dnd B Masci, J Am Chem Soc , 1977,99,7709 7 (a)G Illumindti, L Mandolini, and B Masci, J Am Chem Soc , 1983, 105, 555, (h)L Mandolini and B Masci, J Am Chem Soc , 1984,106, 168 8 (a) G Ercolani, L Mandolini, and B Masci, J Am Chem Soc, 1981, 103, 2780, (b) 1981, 103, 7484, (c) 1983, 105,6146 9 J E Gordon, ‘The Organic Chemistry of Electrolyte Solutions’, J Wiley.New York, 1975 10 (a)M Crescenzi, C Galli, and L Mandolini, J Chem Soc Chem Commun , 1986, 551, (b) J Phys Org Chem, 1990, 3, 428, (c) C Galli and L Mandolini, J Chem SOC Perkzn Trans 2, 1984, 1435, ((0R Cacciapaglia and L Mandolini, J Org Chem , 1988,53,2579, (e) Tetrahedron, 1990,46, 1353 11 A Ostrowicki, E Koepp, and F Vogtle, Top Curr Chem, 1992, 161,37 12 C Galli and L Mandolini, J Org Chem , 1991,56, 3045, C Galli, Org Prep and Proc Int , 1992, 24, 285 13 C Antonini Vitali and B Masci, Tetrahedron, 1989,45, 2213 14 G Ercolani and L Mandolini, J Am Chem Soc . 1990, 112,423 I5 M J Pregel and E Buncel, J Org Chem . 1991, 56, 5583 and previous papers in the series See also K J Msayib and C I F Watt Chem Soc Rev, 1992,2,237 16 G Doddi, G Ercolani, P Mencarelli, and C Scalamandre, J Org Chem, 1991,56,6331 17 (a) R Cacciapaglia, S Lucente, L Mandolini, A R van Doorn, D N Reinhoudt, and W Verboom, Tetrahedron, 1989,45,5293.(h) R Cacciapaglia, A R van Doorn, L Mandolini, D N Reinhoudt and W Verboom, J Am Chem Soc , 1992,114,261 1 18 D Kraft, R Cacciapaglia, V Bohmer, A A El-Fadl, S Hdrkemd, L Mandolini, D N Reinhoudt, W Verboom, and W Vogt, J Org Chem , 1992,57,826 19 R Cacciapaglia, L Mandolini, D N Reinhoudt, and W Verboom, J Phys Org Chem, 1992,5,663 20 J -M Lefour and A Loupy, Tetrahedron, 1978,34,2597 21 L P Hammett, ‘Physical Organic Chemistry’, McGraw-Hill, New York, 1970. p 118 22 R Cacciapaglia, L Mandolini, and F S Romolo, J Phis Org Chem , 1992,5,457 23 R Cacciapaglia, L Mandolini, and V Van Axel Castelli, Red Trav Chim Pay-Bas, 1993, 112, 347 24 R Cacciapaglia, A Casnati, L Mandolini, and R Ungaro, J Chem Soc Chem Commun , 1992, 1291 25 R Cacciapaglia, A Casnati, L Mandolini, and R Ungaro, J Am Chem Soc, 1992,114, 10956 26 A Fersht, ‘Enzyme Structure and Mechanism’, W H Freeman and Co , New York, 1985, Chapter 4 27 (a)R Breslow, G Trainor, and A Ueno, J Am Chem Soc , 1983, 105,2739, (b)D J Cram, P Y -S Lam, and S P Ho, J Am Chem Sac ,1986,108,839,(c)J M Lehn and C Sirlin, NeM J C‘hem ,1987, 11, 693, (d)J Suh, Bzoorg Chem , 1990, 18, 345, (e) F Diederich, ‘Cyclophanes’, The Royal Society of Chemistry, Cambridge, 199 1, Chapter 8, (f) J Murakami, J Kikuchi, and Y Hisaeda, ‘Inclusion Compounds’, ed J L Atwood, J E D Davies, and D D Mdc Nicol, Oxford University Press, New York, 1991, Vol 4, Chapter 1 1

ISSN:0306-0012    

DOI:10.1039/CS9932200221

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

The Physiological Role of Nitric Oxide Anthony R. Butler Chemistry Department University of St. Andrews Fife KY16 9ST Scotland D. Lyn H. Williams Chemistry Department University of Durham South Road Durham DH I 3LE England 1 Introduction Even six years ago a review of nitric oxide in biology would have been very brief but after the initial reports in 1987 of the necessary role of nitric oxide in vascular muscle relaxation there has been an explosion of activity. At present more than 50 papers a month are published reporting the role of nitric oxide in a variety of physiological pathways and these papers appear in a wide range of journals from medical and physiological to biochemical. The topic has been reviewed a number of times and among the most recent and significant is that by Moncada Palmer and Higgs.' In this review we will attempt to alert chemists to some of the remarkable developments in physiology linked to the chemistry of nitric oxide. A short explanation will be given of some terms to assist those unfamiliar with the vocabulary of physiology. In view of the large number of papers published and the limited number of references permitted in this review much important work will not be mentioned or will be inadequately referenced. It is hoped however that a sufficient number of references is provided to allow the interested reader to gain access to the relevant literature. In 1994 there should be an extensive review with greater emphasis on biological aspects by Hodson ofThe Wellcome Research Laboratories in Natural Product Reports. 2The Properties of Nitric Oxide We will consider first the physical and chemical properties of nitric oxide which are relevant to its physiological action but excluding its role in nitrosation and its properties as a ligand complexed with transition metals which are discussed in Sections 4 and 6 respectively. Nitric oxide is a colourless gas at room temperature with bp -151.8"Cand mp -163.6"C.The liquid and solid are also colourless when the material is pure (contrary to some literature reports which ascribe to it a blue colour no doubt due to the presence of some N,O,). The solubility in water at 25°C and 1 atmosphere pressure is 1.8 x lop3 mol dm- which is unchanged within the pH range 2-13. For its physiological action nitric oxide is always present as an aqueous solution. Anthony R. Butler studied chemistry at King's College London and obtained his Ph.D. for work with Professor Victor Gold. After post-doctoral work with ProfessorTom Bruice at Cornell University and Prof- essor Colin Eaborn at Sussex University he joined the staflof St. Andrews and has been Reader in Chemistry since 1983. His principal research interest is the application OJ physical organic chemistry to problems in medicinal chem- istry. Nitric oxide is one of the simplest odd-electron species and its structure has been the subject of much interest and debate. In valence bond terms it is best represented by the canonical forms shown.The presence of the unpaired electron effectively reduces the bond order to -2.5 (it is much closer to 3 in NO+) and the reluctance of nitric oxide to dimerize is related to the geometrical distribution of the odd-electron and also to the fact that the bond order would be virtually unchanged in the dimer. Nitric oxide is of course paramagnetic and its reactions with atoms and free radicals have been much studied. Its use as a free radical trap in gas-phase reactions is also well-known and it is an efficient quencher of excited singlet states. Pt-Rh4NH + 50 -4N0 + 6H,O (1) N + 0 = 2N0 AGO = 173 kJ mol-' (2) In the laboratory nitric oxide can conveniently be prepared by the reduction of nitric acid (e.g. with Cu) or of nitrous acid (e.g.with iodide ion or ascorbic acid). On the industrial scale it is made by the catalytic oxidation of ammonia (equation 1).The bulk of nitric oxide made in this way is then oxidized to nitrogen dioxide and reacted with water to give nitric acid. The direct formation of nitric oxide from nitrogen and oxygen (equation 2) is thermodynamically unfavourable but can be achieved to a small extent at high temperatures such as in lightning discharges and more importantly in the internal combustion engine. In the absence of catalytic converters (which reduce NO back to N,) the nitric oxide produced in this way is partially oxidized in air to nitrogen dioxide and produces air pollution problems (often ascribed to NO,) in industrialized countries.The presence of nitrogen oxides in the air can cause major photochemical smogs exemplified by the situation much of the time in the greater Los Angeles basin and in other places. There is also concern regard- ing the depletion of the ozone layer by reaction with nitric oxide emitted by the engines of supersonic aircraft. Lyn Williams was educated at University College London and obtained his Ph.D. in 1960 working with the late Professor P. B. D. de la Mare. After a short periodas an ICI Fellow at University College Swansea he was appointed Lecturer in Dur- ham University. He is currently the Head of Department and was promoted to a Chair in 1991. His research interests have always been in mechanis- tic organic chemistry more re- cently in the chemistry of nitro-sation reactions and of nitroso compounds. 233 The most well-known and studied reaction of nitric oxide is its oxidation to nitrogen dioxide which could of course occur m vzvo In the gas phase it is the classical example of a third order reaction second order in [NO]The observed rate constant decreases with increasing temperature The generally accepted explanation is that there is an initial equilibrium formation of a dimer (with a negative AHo value) which then reacts with oxygen in the rate limiting step (equation 3) but other explanations (such as that outlined in equation 4) have also been put forward 2NO*N,O %2N02 (3) NO NO+O,+NO -NO (4) The oxidation has also been studied kinetically in aqueous solution where the product is either nitrous acid or nitrite ion depending on the pH but no nitrateThe rate law for reaction in water3 is the same as that found for gas-phase reaction and the most reasonable explanation (outlined in equations 5) is that NO is oxidized to NO which reacts with more NO to yield N,O the anhydride of nitrous acid The value for the third order rate constant is -5 x lo6 dm6m01-2~-1,3 which is unchanged in the pH range 1-13 The rate equation holds when either NO or 0 is in excess Calculations based on these results show that even in an aqueous medium saturated with oxygen NO at a concentration of 10 8Mhas a half-life of approximately 3 hours The yield of nitrate is undetectably low if precautions are taken to remove all traces of NO Nitric oxide generated by the spontaneous decomposition of S-nitroso-N-acetylpenicilla-mine (SNAP) (1) in an aqueous buffer at pH -7 also yields nitrite qudntitatively S-NO I C(CH3)2 SNAP I H&CONH-CH-C02H NO + 40 = NO NO +NO = N,O (5) N,O + H,O = 2HN0 = 2H+ + 2N0 It is perhaps surprising at first sight that nitrite ion is the sole product from aerobic aqueous NO given that the hydrolysis of its oxidation product NO yields an equimolar mixture of nitrite and nitrate It must be that the reaction of NO with NO is much faster than the hydrolysis of NO Pulse radiolysis studies have shown that this is the case since the rate constant for the reaction NO + NO = N,03 is very close to the diffusion controlled limit In aqueous solution the equilibrium favours N,03 while in the gas phase the opposite applies Recent work4 has cast doubt on the interpretation based on the intermediacy of N203howeverThe results of scavenging experiments using azide ion are not consistent with the pub- lished rate constants for the reaction of N,O with N -and for the hydrolysis of N,O However to date no alternative structure has been put forward which would account for all of the known results 3 Physiology of Smooth Muscle Relaxation According to structure contractile properties and control mechanism there are three types of muscle skeletal smooth and cardiac Sheets of smooth muscle surround hollow organs and tubes most significantly blood vessels Contraction of vascular smooth muscle is one of the many factors controlling resistance to blood flow in the arterial system and sustained contraction in the absence of compensation elsewhere in the body can lead to high blood pressure (hypertension) Work by Murad in the early 1980s established that smooth muscle relaxation (which is a CHEMICAL SOCIETY REVIEWS 1993 positive process rather than just the absence of contraction) requires activation of the enzyme guanylate cyclase and is accompanied by the conversion of guanosine triphosphate (GTP) (2) into cyclic guanosine monophosphate (cGMP) (3) 0 -0 cl OH (3) The process of relaxation can be triggered by a number of substances which occur in the body such as acetylcholine and bradykinin and it had been generally assumed that these chemicals act directly on the muscle cells of the vascular system but a serendipitous discovery by Furchgott and Zawadzki6 showed that this was not the caseThey were examining the effect of acetycholine on isolated rings of rabbit aorta (a major blood vessel coming direct from the heart) and found that the relaxing effect of acetylcholine (vasodilator action) was greatly attenuated if the endothelial cells (cells lining the inside of the aorta) had inadvertently been removed or damaged during preparationT$ey concluded that acetylcholine[CH3CO-O-CH,CH,-N(CH3)3]acted not upon the muscle cells but upon the endothelium which in turn produced a 'second messenger'This diffused from the endothelium into the underlying muscle cells and activated guanylate cyclaseThe second messenger became known as the endothelium-derived relaxing factor or EDRF During the succeeding years there was much speculation about the chemical identity of the EDRF and there were several claims which were later disproved or could not be substantiated In fact there was enough information around to identify the EDRF correctly and the answer came to several people active in the field of muscle physiology at about the same time It had been known for some time that a group of compounds all containing the NO group in some form or other [glyceryl trinitrate (4) amyl nitrite (9,sodium nitroprusside (6) and nitric oxide itselfJ activate guanylate cyclase in vitro and it CHz-ONO,I CH-ONOz GTN I CH2-ON02 (4) H3C ,CH-CH2-CH2-ON0 amyl nrtrde H3C Na2[Fe(CN)5NO] SNP (6) THE PHYSIOLOGICAL ROLE OF NITRIC OXIDE-A R BUTLER AND D L H WILLIAMS was only a small but highly significant step to suggest that nitric oxide is the EDRF the endogenous activator of guanylate cyclaseThat this was indeed the case was established' in 1987 independently by Palmer Ferrige and Moncada at The Well- come Research Laboratories and by Ignarro et ul Both groups found that in a bioassay NO and the EDRF behaved identically Identifying the EDRF as NO also explained why the lifetime of the EDRF was prolonged by addition of the enzyme superoxide dismutase (SOD) (superoxide reacts with NO) and why the action of the EDRF was destroyed by hdemoglobin (it binds NO very strongly)The most direct evidence that NO is formed zn vivo also reveals the substrate from which NO is formed and comes from a study by Palmer Ashton and Moncada Cultured endothelial cells were fed with L-drginine labelled with 5N at the terminal position perfused with a biological buffer and the perfusate purged with helium which was passed into a mass spectrometer After stimulation of the endothelial cells with bradykinin (H-Arg-Pro-Pro-Gly-Phe- Ser-Pro-Phe-Arg-OH) the helium was found to contain NO labelled with 5N Reports of this and related work led to a flurry of activity on the L-arginine-to-NO pathway and some of this activity will be summarized in a later section of this reviewThe enzyme or more probably the family ofenzymes responsible for effecting the conversion is known as nitric oxide synthase (NO- synthase) A somewhat simplified view of what occurs when an endothelial cell is stimulated by the arrival of an endothelium- dependent vasodilator like acetylcholine is shown in Figure 1 NITROVASODILATOR I NO ENDOTHELIUM \SMOOTH MUSCLE '.soluble guanylatecyclase GTP cGMPn DEPENDENT VASODILATOR proteirkmase phospt rylated Figure 1 The identity of the EDRF as NO has been questioned That the final process in the activation of guanylate cyclase is transfer of NO to the enzyme cannot be doubted but NO could approach the enzyme not as free NO but bound to something else For example Myers et af suggested that the EDRF is S-nitrosocys- teine but the validity of the experiments must be questioned as it is difficult to isolate S-nitrosocysteine in a pure formThe search for an alternative to NO as the EDRF seems motivated partly by d distrust of a gas in solution as a messenger molecule but NO has all the necessary qualities it is small and therefore very mobile it is soluble in both water and lipid as a radical species it is highly reactive but in isolation it is perfectly stable and lastly another gas ethene is effective as a messenger molecule It is possible that NO is stored in the muscle cell as an S-nitroso- compound and Stamler et al lo have reported that nitrosated thiol groups on proteins provide a vasodilator which is more stable than NO itself However it is not clear how the thiol groups dre nitrosated because NO itself is not a nitrosating agent (see Section 4) Alternatives to NO as the EDRF are discussed in detail by Moncada Palmer and Higgs In the judgment of the authors of this review there is no need to look beyond NO as the EDRF but the ability of the oxides of nitrogen to act as nitrosating agents is worthy of further discussion It is relevant to the role of NO as a vasodilator and as a carcinogen (see later) There appears to be another process which stimuldtes reledse of NO from the endothelium it is shear stressThere is evidence that increased flow of blood automatically results in vascular smooth muscle relaxation and enlargement of the blood vessel and presumably enhancement of protection against blood clots (see Setion 8) 4 Oxides of Nitrogen as Nitrosating Agents12 For electrophilic nitrosation the oxides of nitrogen must act as sources of NO + When pure and in particular when totally free from oxygen nitric oxide is not an electrophilic nitrosating speciesThus with secondary amines no reaction occurs when oxygen is rigorously excluded but nitrosamines are rdpidly formed when air is admitted to the system A lot of confusion has arisen in the past because reactions were carried out when all the oxygen had not been removed In the presence of copper(r1) salts or molecular iodine however nitrosation of dmines occurs readily even in the absence of oxygen and is brought about by the intermediacy of a copper-nitrosyl complex and nitrosyl iodide respectively Nitric oxide forms complexes with dmines the so-called Drago complexes which can upon aerial oxidation lead to nitrosamine products l4 Nitroso products can also be obtained from nitric oxide and sources of free radicals particu- larly carbon radicals One example is the formation of the oxime of cyclohexanone via the nitroso product arising from the reaction with the free radical derived from cyclohexdne (equd- tion 6)The reverse process could be a model for the in \zvo production of NO from N-hydroxyarginine (see Section 13) 0 Because of nitrite formation (see Section 2) nitric oxide in aerated aqueous solution yields an effective nitrosating species and has been used to diazotize sulfanilamide and to nitrosdte N-methylaniline and thiols Alkyl Grignard reagents react with nitric oxide (or with nitrosyl chloride) to yield C-nitroso products vzu it is believed the intermediacy of N-nitrosohydroxylamines Dinitrogen trioxide N,03 is an effective nitrosating agent In the gas phase it breaks down to NO and NO but exists ds d molecular species in the liquid solid and solution forms In water nitrous acid exists in equilibrium with N203(equation 7) and the currently accepted value of the equilibrium constant is 3 0 x 10-3dm3mol-At reasonably high nitrous acid concent- rations the blue colour of N203may be detected by eye In aqueous solution N203 is a nitrosating agent and dt high concentrations of nitrous acid at low acidity it is the main reagent for the nitrosation of a range of substrates as shown by the second-order kinetic dependence upon [HNO,] It is a very reactive nitrosating species in water reacting for example with amines with pK > 5 with a rate constant close to the diffusion limit For some of the most reactive substrates (eg aniline and azide ion) N,O formation from HNO is the rate limiting step 2HNO,*N,O + H,O (7) Liquid N203 and solutions of N203in non-aqueous solvents such as toluene and ether and also in aqueous alkali have all been used preparatively as reagents for effecting nitrosation for a wide variety of substrates including amines carbonyl compounds alcohols thiols and alkenesThese appear to be electrophilic reactions although no detailed mechanistic studies have been reported Some reactions of N203 in solution (and also in the gas phase) lead to nitro compounds no doubt formed by way of free radical attack by NO produced by dissociation of N203 The chemistry of N,O is closely linked with that of NO since both species are related by the much studied equilibrium reac- tion given in equation 8 Below the freezing point ( -1 1 2 "C) the solid consists entirely of N204 molecules and its structure is well-known as a planar molecule containing the N-N bondThe NO content increases with the temperature being about 0 1YO at the boiling point (21 5 "C) in the liquid phase and I5 9% in the gas phase At 135°C there is virtually no molecular N,OThe unpaired electron in NO is more localized on the nitrogen atom than it is in NO which may account for the greater ability of NO to dimerize Many reactions are initiated by NO giving rise to nitro products by way of a free-radical pathway In addition how- ever other reactions are best rationalized in terms of a heteroly- tic fission to give either NO or NO+ (equation 9)The latter + reaction is of interest in terms of nitrosation This ionization mode is evident in media of high dielectric constant and studies in concentrated sulfuric and perchloric acids show that the conversion is virtually complete For example the Raman spectrum of N204 in sulfuric acid clearly shows the NO+ frequency of 2300 cm-' and also NO+ salts can be made from N2°4 N,O,=NO + NO N20 G= NO+ + NO (9) N204 solutions in solvents such as CCl or ether at low temperaturess have been much used synthetically to introduce the NO group using amines amides alcohols and thiols Reaction with an alkene in liquid ethane-propane solvent results in the formation of the nitroso nitrate adduct probably via an electrophilic nitrosation reaction Passing NO gas into an aqueous solution of a thiol gives immediately the characteris- tic red colour of the thionitrites RSNO l6These are unstable materials which are difficult to isolate the product normally obtained is the disulfide Interestingly the same reaction with NO (with oxygen rigorously excluded) gave no colour evidence of the formation of the thionitritesThe result with NO suggests that enough N204is present in solution to effect nitrosation There have been suggestions that the reactive nitrosating species derived from N204 is in fact an isomer ONONO This is an attractive idea but as yet there is no firm physical evidence for its involvment A much favoured preparative procedure for effecting nitrosation generally used by early workers was to pass 'nitrous fumes' into a solution containing the substrate These were generally prepared from nitric acid and a reducing agent or from sodium nitrite and nitric acid The composition has never been established but clearly will be a NO,/NO mixture which in solution could act as a nitrosating agent via the N,O or the N204 pathway 5 Activation of Guanylate Cyclase Guanylate cyclase the enzyme responsible for vascular mus- cle relaxation is found in most cells and throughout the animal kingdom It exists in two forms a soluble enzyme inside the cell and in a membrane-associated (particulate) formThe relative amounts of each within the cell vary with the cell type and its physiological state Normally purified soluble guanylate cyclase can be activated zn vztro by NO-donating compounds such as sodium nitroprusside However if the purification is sufficient to remove the haem component of the enzyme activation is markedly reduced It can be restored by addition of haematin in CHEMICAL SOCIETY REVIEWS 1993 the presence of a reducing agent It is generally assumed that NO activates guanylate cyclase by binding to the iron of the haem component and moving the iron out of the plane of the porphyrin ring Once the enzyme has been activated there is accumulation of cGMP which in muscle cells is accompanied by muscle relaxation In other cells the accumulation of cGMP is accompanied by different physiological effects as will be des- cribed later 6 Nitric Oxide as a Ligand NO-complexes of transition elements have been known for a long time but there was a major expansion of interest in the 1960s and 1970s principally because of their potential use as homogeneous catalysts for a range of reactions Well-known examples are the 'brown-ring' complex [Fe(H,O),N0I2 + in the classic test for nitrates Roussin's red and black salts and the nitroprusside anion [Fe(CN),N0I2 Major reviews appeared in the 1970s more recently a book has been published' devoted to these complexes Nitrosyl complexes have now been synthesized and character- ized for a large number of transition elements including Fe Mn Cr Co Rh Ir Ni Ru Pt V MoTe W and Re Synthesis is usually by direct reaction with nitric oxide or a nitrosonium salt but sometimes other sources of the nitroso group such as acidified sodium nitrite alkyl nitrites N-nitroso compounds or nitrosyl chloride have been successfully used Much effort has been directed at the establishment of the detailed structure and bonding of metal nitrosyls using in particular X-ray crystallo- graphy vibrational spectroscopy photoelectron spectroscopy electron spin resonance spectroscopy and 5N-NMR spectro- scopy When NO is bound for example to the Fe" atom in haem derivatives it still has an unpaired electron and therefore can be detected by EPR *This use of a 'spin-labelled' ligand has been used to probe electronic structures of haem and other deriva- tives Ideas have been developed correlating the shape of the complex (e g linear or bent NO configuration) with the ability to transfer NO+The NO group can in some cases be oxidized by molecular oxygen in the presence of Lewis bases to give the corresponding nitro or nitrato complexes Other reactions are described in reference 17 A number of nitrosyl complexes can act as direct electrophilic nitrosating agents Since this can be achieved in neutral or basic solution there is some synthetic potential here for situations where acidic conditions need to be avoidedThe most widely studied complex in this regard is the nitroprusside anion [Fe(CN),N0I2-(SNP) and the reactions particularly with amines have been studied mechanistically l2 The rate law is given in equation 10 and has been interpreted in terms of a mechanism in which a complex between SNP and the amine is rapidly and reversibly formed which then breaks down in competing reactions by reaction with either another amine molecule or with water Similarly ketones yield the correspond- ing oximes but S-nitrosation does not occur with thiols which is puzzling in view of the vasodilator action of nitroprusside (see Section 7) Rate = k,[SNP][Amine] + k,[SNP][AmineI2 (10) Ruthenium and some other transition metal nitrosyls can also act as a source of NO+,and reactions with azide ion hydrazine hydroxylamine amines alcohols and p-diketones have all been recorded l2 Often the final product of nitrosation remains bound to the metal but can sometimes react further For example in the reaction with primary aromatic amines the bound diazonium group can bring about the normal azo cou- pling reaction with /$naphthol Nitrosyl haems can give nitrosa- mines from reaction with secondary amines l2 It is certain that a haem function is a requirement for activation of guanylate cyclase (see Section 5) by NO and so it is very probable that a nitrosyl complex is first formed One such complex (7) is shown and has been characterized as the dimethyl THE PHYSIOLOGICAL ROLE OF NITRIC OXIDE-A R BUTLER AND D L H WILLIAMS Me esterThe Fell form of protohaems generally react readily with NO (or HNO,) to yield such complexes One familiar example is the pink coloured material which occurs in cured meats when treated with sodium nitrite An interesting reaction occurs between NO and oxyhaemoglobin (equation 11) which rapidly yields nitrate anion and methaemoglobin 2oThis reaction is the basis of the analytical procedure using difference spectrophoto- metry which allows the determination of NO down to 1 nM Incidentally there is a recent review2 of analytical procedures for NO which includes chemiluminescence assay diazotization assay use of EPR the nitrosyl-haemoglobin method and microelectrode analyses +3 HbOZ+NO +MetHb +NO 7 Nitrovasodilators Long before NO was identified as the EDRF a number of NO-donating compounds were recognized as vasodilators (sub- stances which enlarge blood vessels) and used in the treatment of diseased conditions where increased blood flow will relieve the symptoms In the case of angina pectoris arteries of the heart become constricted and the heart is unable to function effecti- vely as a pump because of lack of oxygen When this happens physical activity is accompanied by intense pain in the chest and arm Sufferers are often given glyceryl trinitrate (4)and this was prescribed for Alfred Nobel who had made a fortune by incorporating it into porous silica as the explosive dynamite Amy1 nitrite (5)and isosorbide dinitrate (8) have similar vasodi- latory effects Nitrovasodilators act by by-passing the NO- generating system in the endothelium and delivering NO direct to muscle cells in the walls of the artery Organic nitrates and nitrites undergo a series of enzymatic transformation in the presence of thiol groups with eventual release of NOThey are not effective as vasodilators unless given to whole animals 22 On the other hand some NO-donating compounds such as S-nitroso-N-acetylpenicillamine(SNAP) (1) and sodium nitro- prusside (SNP) (7)23are effective in ex vzvo experiments such as those involving pieces of isolated artery or a frog’s heartThe former compound releases NO in straightforward fission reac- tion the other product of reaction is a disulfide 2RS-NO +RS-SR +2N0 (12) The action of sodium nitroprusside is more difficult to under- stand as the only reaction leading to direct release of NO is photochemical decomposition In experiments using a frog’s heart it was found that the action of SNP was greatly enhanced by exposure to light from a laser 23 It is known that in a fairly isosorbide dinitrate ONO (8) slow reaction NO is also released from SNP on reaction with thiols 24 As SNP is often used for inducing low blood pressure (hypotension) during surgery on the vascular system it is possible that the lighting in the operating theatre may play some part in providing NO although there is also a non-photochemi- cal reaction A compound containing a large number of NO ligands in each ion is the anion of Roussin’s Black Salt (RBS) [Fe,S,(NO),] This ion decomposes with release of NO by both chemical and photochemical routes and ex vzvo experiments have shown it to be a highly effective vasodilatorThe effect of SNAP and SNP in such experiments is transient but with RBS relaxation may persist for as long as six hoursThis is a consequence of the unusual solubility of RBS which although ionic is more soluble in organic solvents than in water RBS is rapidly taken into the endothelial cells because of its lipid solubility and remains there for several hours slowly releasing NO 25 8 Platelet Aggregation NO is involved in another important aspect of the blood supply In blood there are numerous colourless cell fragments contain- ing granules known as plateletsThey are much smaller than red blood cells When a blood vessel is damaged excessive bleeding is prevented by platelet aggregation to form a plug which adheres to the wall of the blood vessel Further aggregation occurs in blood coagulation to form a clot which is the essential defence against bleeding after injury Myocardial infarction (‘heart attack’) may be caused by abnormal clotting of the blood in a coronary vessel coated with atherosclerotic plaque (a coating on the inside of a blood vessel containing quantities of cholesterol) Concurrently with the discovery of the role of NO in effecting vascular muscle relaxation came the discovery that NO inhibits both platelet aggregation and adhesion 26 Prosta-cyclin and NO act synergistically to inhibit platelet aggregation and to disaggregate platelets but there is no parallel synergism in platelet adhesion 26The role of NO in this area seems to be as a feedback mechanism to counteract the effect of substances in the body produced after injury which promote aggregation and adhesion The NO utilised by the platelets is derived from endothelial cells with which the platelets come in contact but there is also an enzyme system in the platelets themselves which acts on arginine to produce NO 9 Macrophage Activity The immune response is the body’s reaction by which foreign matter both living and non-living is neutralized or destroyed The non-specific immune response non-selectively protects against foreign substances or cells without having to recognize their specific identities and a key part of that response comes from a set of cells known as macrophages which are found in virtually all organs and tissues their structure varying somewhat from location to location For macrophages to respond they have to be activated by substances known as cytokinesThe role of macrophages is quite extensive and includes engulfing foreign matter (phagocytosis) and if necessary killing it by injection of cytotoxic substances Macrophages can also kill invading microbes by contact without phagocytosis It is the killing process which appears to involve nitric oxide Before this was discovered it had been known for some time that there is a correlation between activity of the immune system and elevated nitrate levels in the urine More recent work2’ had shown that cultured macrophages from a mouse generate sub- stantial amounts of both nitrite and nitrate after activation It had also been shown that the cytotoxicity of macrophages against tumour target cells depended upon the presence of L-arginine (9) and that activity was again accompanied by the formation of nitrite and citrulline (1 0) Once the production of NO from L-arginine in endothelial cells had been established it became clear that a similar process occurs in activated macro- phages and that both nitrite and nitrate come from the common precursor NO However in view of the recently reported exclusive formation of nitrite from NO in oxygenated aqueous solution this view may have to be modified (see Section 8) but nitrate is readily formed from nitrite by oxidation in blood NO production was confirmed independently by three groups29 and it now seems certain that in activated macrophages there is a process occurring which parallels that taking place in endothe- lial cells Nature appears to have been economical in using the same enzyme system for two entirely different tasks but clearly the properties of NO are special enough to make this profitable However it does pose a problem If any part of the body suffers from a massive infection there will be much macrophage activityThe NO produced as a consequence will have not only substantial cytotoxicity I e it kills the invading cells but will also bring about massive hypotensionThis condition is known as septic shock and can be fatal Now that the nature of the species responsible for septic shock may have been identified there is a chance that improved treatment can be developed Why is NO toxic towards invading bacteria and unhealthy host cells? It could be that as a radical species NO is destructive towards the lipid cell membrane and that this alone is sufficient to explain its action but there is at the moment little direct experimental evidence to substantiate this view Beckman et af 30 suggested that NO reacts with superoxide also produced during macrophage activity in the following way NO + 0; +ON00 ONOO-+ H+ +ONOOH (13) ONOOH +NO + HO Peroxynitrite (ONOOH) is a weak acid and the anion will be protonated at physiological pH and could then fragment to give nitrogen dioxide and hydroxyl radicals which are known to be very destructive towards lipid membranes and DNA However peroxynitrite also rearranges to the more stable and non-toxic nitrate and so the generation of hydroxyl radicals by this route remains speculative A third possibility is that NO reacts with an enzyme iron-sulfur centre that is essential for metabolic activity to give an iron-sulfur cluster nitrosyl In solution iron-sulfur cluster nitrosyls may dissociate to give EPR-active species and analysis of these spectra3 * has permitted detection of similar species in tumour target cells co-cultured with activated macro- phages 32 Similar EPR signals are obtained when NO from activated macrophages acts upon aconitase an enzyme in the citric acid cycle which is known to contain an iron-sulfur centre 10 Neutrophils Another part of the body’s immune system is the collection of cells in blood known as leukocytes or white blood corpuscles Human neutrophils are one type of leukocyte and are known to produce a substance which inhibits platelet aggregation 33The biological significance of NO production in neutrophils has yet to be elucidated 11 NO as a Carcinogen Although NO can be cytotoxic towards early tumour cells it seems that it can also act as a carcinogen or cancer-causing agent It is known that under physiological conditions NO can nitrosate natural secondary amines to form carcinogenic N-nitroso compounds From a chemical point of view this is somewhat puzzling as NO is not a nitrosating agent but how it might be converted into a positive nitrosation species is dis- cussed in Section 4 Also there appears to be another more direct cancer-inducing process for which NO is responsible Keefer et af 34 have shown that NO can effect mutagenesis (a change in base-pair sequence in DNA) in Salmonella typhzmur- ium by the conversion of 5-methylcytosine into thymine (equa- tion 14)This is nitrosative deamination and must again involve conversion of NO into an electrophilic nitrosating agent CHEMICAL SOCIETY REVIEWS 1993 In a similar way incubation of a human cell line with NO leads to mutation 35 It is difficult at the moment to define precisely the physiological conditions under which NO will act either as a cause of or a cure for cancerThe role of NO as a carcinogen has environmental consequences (see Section 2) It is present at quite high concentrations in cigarette smoke but as there are so many other carcinogens present already an addi- tional one hardly elevates the health risk significantly but it could contribute to the dangers of passive smoking 12 NO as an Antiparasitic Agent In the same way as NO is toxic towards bacteria as part of the body’s immune system so NO will kill non-bacterial parasites and there is some evidence that it is part of the body’s natural defence mechanism Macrophages from a mouse incubated with the cytokine interferon-y are effective in killing the protozoal parasite Leishmania major and the effect is diminished if an inhibitor of NO synthase is added 36 NO itself did not inhibit the growth of the malarial parasite Plasmodzum falciparum but S-nitrosocysteine and S-nitrosoglutathione are effective at very low concentrations 37 Nitroprusside and Roussin’s Black Salt are also toxic towards Pfasmodzum bergher with the former being the more effective although NO is more readily obtained from the latter If NO is part of the body’s natural defence against the malarial parasite it is a matter of great importance as it could initiate a new class of antimalarial drugs desperately needed in view of the catastrophic increase in the incidence of falciparum malaria particularly in Africa and Southeast Asia 13 NO-Synthase The enzyme responsible for the production of NO zn vivo has been the object of considerable scrutinyThe enzymes from the brain,38umacro phage^,^^^ and neutrophil~,~~~ inter aha have been isolated and purified and more recently the enzyme has been the target for the techniques of modern molecular biology Fair quantities are now available for studyThere are two or more probably three distinct enzymes which can effect NO formationThe exact nature of the enzyme depends on the tissue from which it was obtained Although there is a large measure of homology the different members of the family exhibit important physiological differences All show a degree of homology with P-450 reductaseThe substrate for the enzymes is L-arginine (9) and the products of reaction are citrulline (10) and NO Definitive insight on the mechanism of enzyme action has come from Moncada and co-workers 39They have shown that the source of oxygen in both NO and citrulline is molecular oxygen (Figure 2) and so NO synthase is correctly described as a dioxygenase This discovery eliminated a number of pathways which had been proposed previously It is known that W-hydroxy-L-arginine is a vasodilator and so it is assumed that this molecule is an intermediate on the pathway A number of oxidizing agents are known to convert N-hydroxy-L-arginine Figure 2 Isotopic study of the enzyme NO-synthase THE PHYSIOLOGICAL ROLE OF NITRIC OXIDE-A R BUTLER AND D L H WILLIAMS + H2NYNHoH fNH N -hydroxy-L-arginine H3N CO,1 (1 I) into citrulline and NO Compounds related to arginine are effective inhibitors of NO-synthase (Figure 3) and their use has proved invaluable in many investigations on the biology of NO NH N-monomethy-L-arginine (L-NMMA) NH N-nltro-L-arginine methyl ester (L-NAME) NH N-cyclopropyl-L-arginine Figure 3 Some inhibitors of NO-synthase NO-synthase in endothelial cells is a constitutive enzymeThis means it is present all the time and responds rapidly to activa- tion There appears to be a basal production of NO from endothelial cells which continuously acts against constriction of the vascular smooth muscle On the other hand the enzyme in macrophages is inducible that is it is not present until the macrophages have been activated by a cytokineThere is a delay of some hours between activation and the appearance of nitrate and nitrite indicative of macrophage activity Other differences between the inducible and the constitutive enzyme are shown in Table 1 (modified from reference 1) Table 1 Similarities and differences between the two NO-synthases Constitutive Inducibie Diox ygenase Dioxygenase NADPH dependent NADPH dependent +Ca2 /calmodulin dependent Ca2 /calmodulin independent + Picomoles NO released Nanomoles NO released Short-lasting release Long-lasting release Inhibited by L-arginine analogues Inhibited by L-arginine analogues Some of the differences between the two enzymes can be understood in terms of their different physiological roles NO is cytotoxic only when large quantities are produced and this explains why the NO used to activate guanylate cyclase in muscle cells has no adverse effects Macrophage activity must necessarily be long-lasting to rid the body of infection but in order to respond to the rapidly changing needs of the body the effect of NO in muscle cells must be short-term Calmodulin is a protein which binds calcium ions and most enzymes which are activated by calcium ions are also calmodulin dependent Very recent work suggests that the apparent Ca2 +/ calmodulin independence of the inducible enzyme may be due to the very strong binding between the enzyme and calmodulin so strong that it is impossible to obtain the enzyme without calmodulin There is much activity in the design of inhibitors of both the inducible and constitutive enzymes If the former could be selectively inhibited then the condition of septic shock could be managed Equally selective stimulation of the constitutive enzyme in blood platelets could be an approach to the treatment of clotting without overstimulating the immune systemThere should be many exciting developments during the next few years 14 Central Nervous System Messages are conveyed along nerve cells as electrical impulses but for movement across the gaps between nerve cells (syna- pases) there are chemical messengers known as neurotransmit- ters When a synapse increases the activity in a postsynaptic nerve cell it is known as an excitatory synapse Among the major excitatory neurotransmitters are the amino acids aspartate and glutamate It has been known for some time that within the central nervous system activity in excitatory pathways leads to enhanced levels of cGMP paralleling what occurs during relax- ation for vascular smooth muscle It was also known that arginine is the endogenous precursor for activation of rat forebrain guanylate cyclase In view of the similarities with smooth muscle relaxation it seemed reasonable to look for NO In 1988 Garthwaite et a1 40 reported that cultured brain cells produced an EDRF-like substance when stimulated by N-methy1-D-aspartate and in 1989Knowles Palacios Palmer and Moncada4' isolated from the rat forebrain an enzyme which catalyses the formation of NO from arginine Confirmation of this pathway in the brain came from a study by Bredt and Snyder42 of the activation and inhibition of NO-synthase in brain slicesThat the role of NO is intercellular was shown by Southam and Garth~aite~~ by the inhibiting action of haemog-lobin which is an extracellular agent It appears that NO in the brain acts in two ways In the first NO is formed in the postsynaptic nerve cell following activation by an amino acid neurotransmitter NO does not act upon guanylate cyclase within the cell where it was produced but diffuses out and acts upon one or more neighbouring structures including the presynaptic nerve cell and so strengthening the connection between the cells on the two sides of the synapse Thus NO is part of a feedback loop or a retrograde messenger In one model of brain activity such a retrograde messenger is the way in which long term memory is built up NO is not the only candidate as the retrograde messenger and so we must wait for further investigation before we can be certain that NO is involved in the process of memoryThe second role of NO in the brain is more like that of a normal neurotransmitter in that it acts upon nerve cells other than the presynaptic nerve cell It also seems probable that NO in the brain plays some part in the cerebral blood supply It has also been suggested that overpro- duction of NO could be responsible for brain damage and certain degenerative conditions such as senile dementia because of its radical nature or because it can generate hydroxyl radicals As well as in the brain NO appears to have role in the peripheral nervous systemThere is a set of nerves in the body known as NANC nerves (non-adrenergenic non-cholinergic an inelegant description as it merely specifies what the neurotrans- mitter is not) in which the neurotransmitter has not been identified with any certainty but evidence is growing that in some cases it is NO Recent studies of the canine colonic sphincter muscle a valve in the gut that is activated by a NANC nerve have demonstrated that stimulation is the result of the release of NO 44 In this instance release of NO is prompted by an electrical impulse in the nerve rather than a chemical messenger (acetylcholine) as in the case of relaxation of vascular smooth muscleThe role of NO in NANC nerve cells may turn out to be a very general phenomenonThe male penile erection is brought about by relaxation of muscles in the corpus cavernosum and the inflow of blood A NANC nerve is responsible for this process and there is now direct evidence that the arginine-to-NO path- way is directly involved Muscle relaxation in the corpus caver- nosum can be effected by NO-donor drugs 45 15 Other Sources of NO Although it may already seem that NO is unexpectedly wide- spread in the body there are further experimental observations to suggest that it occurs even more generally Kupffer cells (another part of the non-specific immune system) produce NO when stimulated with lipopolysaccharide Some muscles although normally activated by NO produced in proximate endothelial cells appear also to contain an inducible NO- synthase but its effect may not be observed for some hours Adrenal glands produce NO but the reason for this is not clear NO appears to play some part in vision and the fluid in arthritic joints has an abnormally high level of nitrite Details of these little-explored areas of NO activity can be found in the review of Moncada Palmer and Higgs NO formed in the liver has been trapped as a complex with diethyldithiocarbamate and identi- fied by ESR spectroscopy 46 16 Clinical Aspects It is unlikely that a discovery of such fundamental importance as that of the role of NO in human biology will not have a profound effect on the drugs used to treat a number of diseased conditions Because of the large number of drugs already available for the treatment of high blood pressure it is unlikely that there will be a major impact in this area Platelet aggregation and adhesion are more fruitful topics As NO has so many roles it is difficult to see how an NO-donor drug affecting only one metabolic function could be devised One of the major challenges to medicinal chemists is the simplicity of the NO molecule How do you modify such a simple molecule to make its action more specific? On the other hand NO binds to a number of metals (see Section 6) and there may be possibilities for inorganic drugs containing NO as a ligand There have already been some clinical uses made of NOThe NO-synthase inhibitor L-NMMA will bring about a decrease in blood pressure in the human forearm and this effect has been used in a study of essential hypertension (elevated blood pres- sure due to a fault in the basal production of NO) 47 Inhaled NO has been used successfully in the treatment of severe adult respiratory distress syndrome (ARDS) although the toxicity of NO make this an unattractive clinical procedure 48 One of the biggest clinical challenge is the management of the hypotension associated with septic shock What may be required is control of the amount of NO present rather than its complete removal and this will not be easy to achieve 17 Conclusion Few subjects have grown as rapidly in importance as has the biological role of NO If only half the results now appearing stand the test of time NO is still a major mediator of physiologi- cal control NO has appeared in the quality press in January 1993 it was featured as ‘Molecule of the Month’ in the Science and Medicine page ofThe Independent and it has been men- tioned in Cosmopolztan In October 1993the third international conference on nothing but NO in biology takes place in Col- ogne What the future holds is difficult to predict greater insight into how our bodies work and some progress and also some false hopes in new drugs or new clinical procedures Although research on NO is now worldwide much of the early pioneering work when a biological role for NO seemed unlikely took place CHEMICAL SOCIETY REVIEWS 1993 in Britain and this is something of which British science should be proud 18 References 1 S Moncada R M J Palmer and E A Higgs Pharmacol Rev 1991,43 109 2 W A Seddon and H C SuttonTrans Farad SOC 1963,59,2323 3 V L Progrebnaya,A P Usov,A V Baranov,A I Nesterenko,and P L Bezyuzychnyi J Appl Chem USSR (EngTrans1 ) 1975,43 1004 4 D A Wink J F Darbyshire R W Nims J E Saavedra and P C Ford Chem ResToxic01 1993 6 23 H H Awad and D M Stanbury Int J Chem Kinet 1993,25 375 5 J McAninly and D L H Williams unpublished observations 6 R F Furchgott and J V Zawadzki Nature 1980 288 373 7 R M J Palmer A G Ferrige and S Moncada Nature 1987,327 524 L J Ignarro G M Buga K S Wood R E Byrns and G Chaudhuri Proc Natl Acad Sci USA 1987,84,9265 8 R M J Palmer D S Ashton and S Moncada Nature 1988,333 664 9 P R Myers R L Minor R Guerra J N Bates and D G Harrison Nature 1990,345 161 10 J S Stamler,D I Simon,J A Osborne,M E Mullins,O Jaraki,T Michel D J Singel and J Loscalzo Proc Natl Acad Sci USA 1992,89,444 11 G M Rubanyi J C Romero andP M Vanhoutte Am J Physiol 1986,250 H1145 12 D L H Williams ‘Nitrosation’ Cambridge University Press Cambridge 1988 13 B C Challis and S A Kyrtopoulos J Chem SOC PerkinTrans 1 1979,229 14 R 0 Ragsdale B R Karstetter and R S Drago Inorg Chem 1965,4,420 15 R G Coombes in ‘Comprehensive Organic Chemistry’ ed I 0 Sutherland Pergamon Oxford 1979 Vol 2 p 310 16 W A Pryor D F Church C K Govindan and G Crank J Urg Chem 1982,47 156 17 G B Richter-Addo and P Legzdins ‘Metal Nitrosyls’ Oxford University Press NY 1992 18 M F Perutz Ann Rev Biochem 1979,48 327 19 J C Maxwell and W S Caughey Biochemistry 1976,15,388 20 M P Doyle and J W Hoekstra J Inorg Biochem 1981,14 351 21 S Archer FASEB Journal 1993,7 350 22 M Feelisch Eur J Pharmacol 1987 142,456 23 F W Flitney and G Kennovin J Physiol l987,392,43P 24 A R Butler A M Calsy-Harrison C Glidewell and P E Serrensen Polyhedron 1988,7 I197 25 F W Flitney I L Megson D E Flitney and A R Butler Brit J Pharmacol 1992,107,842 26 R M J Palmer S Moncada and M W Radomski Brit J Pharmacol ,1987,92,181 M W Radomsky R M J Palmer and S Moncada Brit J Pharmacol 1987 92 639 27 D J Stuehr and M A Marletta Cancer Res 1987,47 5590 28 J B Hibbs Z Vavrin and R RTaintor J Immunol 1987 138 550 29 M A Marletta P S Yoon R Iyengar C D Leaf and J S Wishnok Biochemistry 1988,27,8706 J B Hibbs R RTaintor Z Vavrin and E M Rachlin Biochem Biophys Res Commun 1988 157 87 D Stuehr S S Gross I Sakuma R Levi and C F Nathan J Exp Med 1989,169 101 1 30 J S Beckman,T W Beckman J Chen,P A Marshall and B A Freeman Proc Natl Acad Sci USA 1990,87 1620 31 A R Butler C Glidewell A R Hyde and J C Walton Po1.v hedron 1985,4 303 32 J -C Drapier C Pellat and Y Henry J Biol Chem 1991 266 10162 33 D Salvemini G de Nucci R J Gryglewski and J R Vane Proc Natl Acad Sci USA 1989,86 6328 34 D A Wink K S Kasprzak C M Maragos R K Elespuru M MisraT M DunamsT A Cebula W H Koch A W Andrews J S Allen and L K Keefer Science 1991 254 1001 35 T Nguyen,D Brunson,C L Crespi,B W Penman,J S Wishnok and S R Tannenbaum Proc Natl Acad Sci USA 1992,89,3030 36 F Y Liew S Millott C Parkinson R M J Palmer and S Moncada J Immunol 1990,144,4794 37 K A Rockett M M Awburn W B Cowden and I A Clark Infection and Immunity 1991 59 3280 38 (a)D S Bredt and S H Snyder Proc Natl Acad Sci USA 1990 87 682 (b)J M Hevel K A White and M A Marletta J Biol THE PHYSIOLOGICAL ROLE OF NITRIC OXIDE-A R BUTLER AND D L H WILLIAMS 24 1 Chem 1991 266 22789 (c) Y Yui R Hattori K Kosuga H 43 E Southam and J Garthwaite Neurochemutry 1991 2 658 Eizawa K Hiki S Ohkawa K Ohnishi S Terao and C Kawai J 44 H Bult,G E Boeckxstaens,P A Pelckmans,F H Jordaens,Y M Biol Chem 1991,266 3369 Van Maercke and A G Herman Nature 1990,345,346 39 A M Leone R M J Palmer R G Knowles P L Francis D S 45 F Holmquist H Hedlund and K -E Anderson Acta Physzol Ashton and S Moncada J Biol Chem 1991,226,23790 Scand 1991,141,441 40 J Garthwaite S L Charles and R Chess-Williams Nature 1988 46 L N Kubrina W S Caldwell P I Mordvintcev I V Malenkova 336,385 and A F Vanin Biochem Biophys Acta 1992 1099,233 41 R G Knowles M Palacios R M J Palmer and S Moncada Proc 47 P Vallance J Collier and S Moncada Lancet 1989,ii 997 Natl Acad Sci USA 1989,86,5159 48 C Frostell M D Fratacci J C Wain R Jones and W M Zapol 42 D S Bredt and S H Snyder Proc Nut1 Acad Sci USA 1989,86 Circulation 1991 83 2038

ISSN:0306-0012    

DOI:10.1039/CS9932200233

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Cholaphanes et a/#;Steroids as Structural Components in Molecular Engineering Anthony P. Davis Department of Chemistry Trinity College Dublin 2 Ireland 1 Introduction One of the ultimate aims of Chemistry must be to establish itself as (or give birth to) an engineering discipline within which molecular-scale artefacts may be devised and assembled with the confidence which is currently possible at the macroscopic level. This goal may be some way off but it provides orientation for an increasing proportion of chemical research in which synthetic targets often of some complexity are chosen by rational design to serve theoretical or practical purposes. Some of the most interesting challenges of this type involve the assembly of quite elaborate extended structures in which spatially separated elements combine to achieve an overall effect. Examples might be molecules which can recognize and bind others ‘artificial enzymes’ which can catalyse transformations in bound mole- cules and systems which can reproduce themselves or otherwise store and process information at the molecular level.] In all of these areas one of the central problems is the flexibility of most organic molecules.The desired properties will result not only from the presence of the various elements but also from their relative dispositions in space and the three-dimensional shape of the overall assembly. Hence for most applications there will be a requirement for molecules with well-defined geometries in which conformational freedom though probably not elimi- nated is kept under close control. This criterion can be met in principle by designs based on flexible frameworks in which the necessary restraint is achieved by careful adjustment of non-covalent interactions (the most obvious example being in proteins). However the difficulty of predicting the end result in such cases suggests that in practice there will always be a strong reliance on covalent bonds to provide structural definition. Unfortunately we are supplied with rather few rigid units to use as building blocks and it is therefore sensible that the potential of each should be explored in depth. When we first surveyed the area a few years ago it seemed that one fragment which had been under-utilized was the steroid nucleus. It is one of the largest rigid units which is readily Tony Davis was born in Watford Hertfordshire in 1954. He receiveda B.A. in Chemistry from Oxford University in 1977 then stayed onfor a D.Phi1. under Dr. G. H. Whitham and two years postdoctoral work with Prof essor J. E. Baldwin. In 1981 he moved to the ETH Zurich as a Royal Society European Ex- change Fellow working with Professor A. Eschenmoser then in 1982 was appointed as a Lecturer in Organic Chemistry atTrinity College Dublin. In 1993 he was elected to a Fellowship of the College. His research interests include ‘molecular engineering’ (as dis- cussed in this article) and the application of organosilicon reagents to organic synthesis. 243 available presents two options for substitution (axial or equa- torial) at most positions and occurs in homochiral form. Moreover because of the importance of steroids in biochemistry and medicine their chemistry is understood in great detail.Thus the ‘molecular engineer’ can access extensive information on potential transformations spectroscopic properties etc. & OH There are many steroids which are commercially available and might be chosen as starting materials for more elaborate frameworks. However there are two which stand out on grounds of cost cholesterol (1) at LO. 12/g and cholic acid (2) at LO. 16/g(prices from the current Aldrich catalogue). Cholic acid in particular will feature strongly in this article. Cholesterol is functionalized at one end and can easily be appended to a structure; moreover oxidative degradation of the side chain gives a second point of attachment allowing the nucleus to be used as a rigid spacer. However the lack of functional groups in the central portion of the framework limits cholesterol’s poten- tial. In contrast cholic acid has four functional groups which are fairly evenly spaced around the molecule. Of course little could be done if it were not possible to differentiate between these groups and at first sight the fact that three are secondary hydroxyls might appear to present difficulties. However another valuable feature of the steroid nucleus is its inherent asymmetry. No two positions are equivalent and it is often possible to exert a surprising degree of control in synthetic transformations. In the case of (2) the C3-OH is equatorial while the others are axial allowing the former to be derivatized selectively.The C7 and C12 hydroxyls are more difficult to distinguish but as will be described later the problem was solved many years ago as part of classical steroid chemistry. 2 Steroids as Appendages and Rigid Spacers For most of its scientific history (outside the biomedical area) the steroid nucleus has been viewed principally as a ‘rigid lump of grease’. It is valuable for promoting liquid crystallinity2 and is also useful in the study of hydrophobic aggregates such as lipid CHEMICAL SOCIETY REVIEWS 1993 Me0 H0"' H (5) membranes It continues to be employed for both purposes sometimes in quite sophisticated systemsThus recent reports describe (a) the cholesteryl crown ether (3) as a component of liquid crystalline phases which responded enantioselectively to the inclusion of chiral anion^,^ (b) redox-responsive vesicle formation by ferrocene derivative (4),5 and (c) the use of cholanoate units to position the cationic cyclophane (5) in a bilayer An elegant application is the use of the steroidal appendages in (6) to position the porphyrin nucleus at a certain depth within a bilayer membrane giving a system capable of promoting the regioselective oxidation of matching substrates The use of steroid-based spacers to study long-range intramo- lecular interactions also has a long history As far back as 1965 the rigid dimeric framework in (7) was employed to separate donors and acceptors of excitation energy,8 and simpler mono- meric spacers have been used in several investigations of intra- molecular electron transfer 3 Functionalized Steroids in Biomimetic Chemistry The potential of the steroid nucleus for organizing functional group arrays has perhaps been less widely appreciated How-ever in the field of biomimetic chemistry it was realized some years ago that by combining both water-solubilizing and cata- I NH (7) R R = donor + acceptor lytic groups on a steroidal framework it might be possible to achieve realistic modelling of enzyme action By mobilizing the framework in the aqueous phase the water-solubilizing groups would allow the hydrocarbon surfaces to bind substrates by hydrophobic interactions and correctly positioned catalytic groups would then induce the desired transformations Early examples were the 'synthetic acylases' (8) and (9) reported respectively by the groups of F M Menger'O and J P Guth-rie Both molecules caused substrate-selective accelerations in the hydrolysis of certain p-nitrophenyl esters but were limited by their inability to encapsulate their substrates and a related tendency to aggregate in aqueous solution 0 0 H (9) The use of a dimeric framework was a fairly obvious step forward It would allow a single molecule of the model enzyme to surround its substrate promoting the formation of 1 1 complexes at the expense of micelles etcThe complexes would presumably have better structural definition and provided that the catalytic groups could be positioned appropriately one might expect greatly improved activity and selectivity An initial move in this direction was made by J McKenna and co-workers who described models derived from the head-to-head linkage of 0A3 CHOLAPHANES ET AL STEROIDS AS STRUCTURAL COMPONENTS IN MOLECULAR ENGINEERING-A P DAVIS OH OH cholic acid as in (10) or connessine as in (1 1) In comparison with monomeric analogues these structures displayed enhanced abilities for nan-micellar binding of organic molecules in aqueous media However they were not supplied with catalytic functionality and no attempt was made to demonstrate true enzyme mimicry Meanwhile the group of Guthrie extended the work on imidazolyl-substituted steroids by synthesizing dimeric versions culminating in (1 2)This system showed consider- able improvement over monomeric analogues such as (9),giving impressive accelerations for the hydrolysis of selected esters (up to 550-fold relative to imidazole) It was on the other hand clearly quite troublesome to prepare thus illustrating a principle which has also governed our own experience while the steroid nucleus has undoubted potential as an ‘engineering component’ its exploitation requires synthetic effort which though often rewarding IS rarely trivial In McKenna’s cholanic dimer (lo) the cholic acid units were used in much the same way as they are by nature I e to provide a hydrophobic environment for binding organic molecules (cholic acid is the principle ingredient of the bile salts which are employed as surfactants in living organisms) More recently it was recognized by C J Burrows that it might be used in an inverse fashion in organic media with the hydrocarbon surface controlling solubility and the cofacial hydroxyl groups provid- ing binding sites for polar moleculesThe dimeric structure (1 3) was prepared and variable temperature NMR studies indicated that it was indeed capable of binding an organic-soluble glyco- side to an unquantified extent in CDCl l4 4 Steroid-derived Macrocycles; ’Cholaphanes‘ The foregoing section serves as a good introduction to our own contributions We also have been hoping to mimic nature by constructing synthetic analogues of enzymes and receptors basing our strategy on the use of steroid-derived frameworks to organize functional group arrays We were drawn to cholic acid OH OH for the reasons described in Section 1 and also because a ‘side- on’ view of the molecule [as in (14)] suggested that it might be susceptible to incorporation in macrocyclic structuresThe linear dimeric systems described above suffer from the lack of an enforced cleft or cavity for substrate binding limiting their ability to bind strongly and selectively and also to position catalytic groups accurately on either side of the substrate Macrocyclic structures would have far less freedom and could be designed to be highly rigid and pre-organized if so desired In cholic acid there is a cis-ring junction between rings A and B which imparts a curvature to its skeleton and means that an equatorial substituent at C3 is directed at ca 90” to the main portion of the nucleus It seemed that a rather natural develop- ment of the structure would be to introduce a C3a spacer group and then use the carboxyl group at the far end to form cyclodimers as in (1 5) By controlling the substitution pattern at C7 and C12 of the monomer units it should be possible to position up to four different binding/catalytic groups around the periphery of the cavity giving a versatile system for studies in biomimetic and/or supramolecular chemistry In the initial work it made sense to retain the 7a-and 12a- oxygens and aim for organic-soluble macrocycles with converg- ing polar functionality Our first instinct was to keep the 3a-oxygen atom as well and introduce the spacer by making an ether linkage (e g to a benzyl unit) However we soon recog- nized that any such plan would result in a rather flexible framework and that the dzrect attachment of a rigid spacer to the steroid would be far preferableThe obvious choice for the spacer was a para-substituted benzene ring apart from being structurally suitable one might hope that the ring would induce useful NMR effects when we came to study the properties of the systemThis raised questions perhaps more typical of a project in natural product synthesis than in supramolecular or biomi- metic chemistryThe aryl unit would need to carry functionality for use in the cyclodimenzation and a complementary group would be required in the steroidal side-chain Bearing these CHEMICAL SOCIETY REVIEWS 1993 points in mind how might the spacer be introduced at C3 with (a) the correct stereochemistry and (b) acceptable chemo- selectivity? One of our answers is shown in Scheme 1 We chose to use amide bond formation for the cyclodimerization partly because it is easily accomplished and partly because the macrocycle would be chemically robustThis required retention of the side- chain carboxyl in suitably protected form and incorporation of a protected amino group in the spacerThe new carbon-carbon bond was formed with the help of one of the newer types of organometallic reagent an organomanganese derivativeThis had the advantage of being completely inert to ester groups so that acetyl protection could be used at positions 7 and 12 (vide infra) and critically the side-chain carboxyl could be carried through as its methyl esterThe stereochemistry was controlled by a traditional method I e catalytic hydrogenation of the less- hindered face of a double bondThe final step cyclodimeriza- tion to ‘cholaphanes’ (1 7) was the one which initially caused us the greatest concern The shortest route around the macrocyclic framework encompasses 38 atoms Although ring closure would be assisted by the rigidity of the monomeric units (reducing the activation entropy for cyclization) we were still afraid that much hard-won material might be lost as polymer In fact the transformation proved to be remarkably easy It could be accomplished in stepwise fashion via a linear dimer (demonstrat- ing that products lacking C symmetry could be made if required) or as shown directly from a monomer unitThe most effective method employed pentafluorophenyl ester interme- diates (as illustrated) and gave up to 90% yield of crystalline macrocycle The sequence in Scheme 1 was carried out for two series of compounds Initially we worked from the diacetoxy ketone (I 6a) through to tetraacetoxycholaphane (17a) and then (after treatment with hydroxide) to tetrahydroxycholaphane (1 7b) It is worth noting that although several steps were involved the overall yield of (1 7a) from cholic acid was nearly 40% For the second series our aim was to show that we could control the substitution pattern at carbons 7 and 12 and thus differentiate between the two faces of the macrocycle As mentioned in Section 1 the problem of distinguishing between the axial 7a- and 12a-OH groups in cholic acid is non-trivial but had been solved in the ‘classical’ period of steroid chemistry Acetylation of methyl cholate (1 8) with acetic anhydride/pyridine gives the 3,7-diacetate (19) with reasonable ~electivity,~ allowing isola- tion of the crystalline product in ca 65% yield (Scheme 2)The preferential acylation at position 7 as opposed to 12 is actually quite curious as the former is apparently the more hindered due to the axial orientation of C4 (with respect to ring B) Indeed under other acylation conditions the 12u-OH is the more reactive (a fact which we were later able to exploitls) and the formation of (19) seems to be a particular quirk of the pyridine-catalysed reaction l9 Benzylation of (19) gave (20) which was converted (15) A D = bindinglcatalytic functionaldy X = spacer into (1 6b) and thenceforth to cholaphane (1 7c) Selective depro- tection could be accomplished at either face giving two further macrocycles (1 7d) and (17e) (Scheme 1) During the early phases of this work our main concern was to show that the cholaphane framework could be assembled with reasonable ease and was thus a viable starting point for artificial enzymes etc However we came to realize that our ‘demon- stration models’ (17) might in themselves have quite interesting properties Molecular modelling indicated that if they adopted an open conformation they would enclose a cavity of cross- sectional area 40-50 A2 (see eg Figure 1) Including the annular amides the cavity would be surrounded by SIX polar functional groups in a fully three dimensional arrangement which might be likened to a (highly) distorted octahedronThe cholaphanes might therefore be well suited to act as receptors for small molecules with a 3D array of divergent functionalityThe obvious targets were carbohydrate nuclei In spite of the import- ance of these units as carriers of biological there was little work reported on modelling their recognitionThe only successful system was the resorcinol-aldehyde tetramer (21) investigated by Aoyama and co-workers,21 however this molecule was clearly incapable of encapsulating a carbohydrate and apparently operated via face-to-face interactions (the report of referred to above appeared soon after we started our work) Accordingly we used NMR to investigate the interaction of (17a-e) with the organic-soluble glucoside (22) in CDCI 22 Although none of the acetylated macrocycles showed any sign of binding we were delighted to find that addition of the glucoside caused significant changes in the spectra of (17b) and (17d) Spectra from an experiment involving tetra01 (1 7b) are shown in Figure 2 As glucoside is added (moving up the Figure) the signal at 6 5 67 (NH)moves sharply downfield the AB system at 6 4 3-4 5 (CH2N) separates and the HN-CH vicinal couplings change dramatically Analysis of the movements was consistent with 1 1 complex formation with a binding constant of 1740 ( f200)M -Similar effects were observed with dibenzyloxy diol (1 7d) yielding a binding constant of 700 (f100)M In the latter case it was interesting to note that the AB quartet due to the 0-benzyl methylene protons also moved appreciably While we have no direct proof that the glucoside head-group was entering the cavities of the macrocycles several factors point in this direction First the size of the binding constants suggests that several hydrogen bonds are being formed Secondly the NMR movements suggest major changes in the conformation of the macrocycles which in the case of (17d) at least involve widely-separated parts of the molecule Finally computer-based molecular modelling confirmed that the hypothesis is reason- able Making the assumption that both annular amides were acting as H-bond donors (supported by the NH NMR move- ments and also by IR data) we were able to devise the configu- ration shown in Figure 3 Based on a relatively unstrained CHOLAPHANES ET AL. STEROIDS AS STRUCTURAL COMPONENTS IN MOLECULAR ENGINEERING-A P. DAVIS OMe 0 (16a) R'= R2=AC (16b) R' = Ac. R2 = CH2Ph (11) (CF3C0)20. CF3C02H OMe OMe (I) NaOH. MeOH.THF (11) (BOC)20.THF. EiPr'zN (111) DCC. CsF50H NHBOC (I) CF,CO,H (11) BaseI Q Q (17a)~l=R~=AC NaOH (1%) R' = R2 = H (17C) R' = Ac R2 = CHZPh NaOH L 1Scheme 1 (I7d) R' = H. R2 = CH2Ph H PdlC CHEMICAL SOCIETY REVIEWS 1993 AcO H Scheme 2 OHT\ OH HO i conformation oi the macrocycle the modelled complex is held together by six intermolecular hydrogen bonds Although it may well be a figment of our (computer-aided) imagination with no basis in reality one can reasonably argue that it can only be superseded by an even more favourable arrangement If the carbohydrate was indeed entering the cavities of (1 7b/ d) an expected consequence was that the binding constants should be quite sensitive to a change in substrate We felt that an interesting test might be to investigate binding to a complete set of stereoisomeric glucosides (u/Pand D/L) Results from experi- ments employing (17b) and the octyl glucosides are shown in Table 1 23 Not only was there significant diastereoselectivity (ca 5 5 1 compare entries for p-D and a-D) but also appreciable enantioselectivity (ca 3 1 /I-D us /3-L)The latter is of course made possible by the chirality of the macrocyclic framework The level of selectivity compares poorly with that found in natural systems but considering the flexibility of (17) has to be seen as encouraging Considering the next phase of our cholaphane programme we focused on two medium-term objectives One was to develop carbohydrate receptors with improved potency and controllable selectivity and the other was to carry the macrocycle into aqueous solution where realistic enzyme modelling might be attempted For both purposes it was clear that major alterations would be required to framework (17) First we would need to increase the rigidity of the structure so that derivatives would be more pre-organized to bind target substrates less able to adapt themselves to other guests and less able to find collapsed conformations in which guests are excluded (relevant to aqueous solution where hydrophobic forces would tend to bring the HO organic surfaces together) We were also aware that unless conformational flexibility could be reduced there was little prospect of predicting binding/catalytic behaviour in a rational fashion Secondly we needed a method of controlling the solubility of the framework For studies in chloroform the tetraol(l7b) had barely sufficient solubility (2lmM) and there was every likeli- hood that increasing the rigidity would make the problem worse A rigid molecule moving from the solid state into solutions gains just translational and rotational entropy a flexible molecule acquires other freedoms and thus gains more from undergoing such a transition Any plan for increasing cholaphane rigidity should therefore make provision for the introduction of flexible solubilizing substituents oriented in such a way as not to interfere with the organized core of the framework For studies in water it was clear that polar or ionic substituents would be necessary and again it would be desirable that they should be directed away from the centre There was one alteration which appeared synthetically feas- ible and which seemed likely to improve matters in both the above respects Considering the sequence in Scheme 1 it was apparent that we were being somewhat wasteful of the function- ality at C3 of our starting materials (16) In principle there was an opportunity to introduce two substituents at this centre an aryl spacer in the equatorial orientation and a solubilizing group in the axial orientation If the latter were fairly bulky it would restrict rotation about the C-aryl bond such that the spacer would be positioned as shown in partial structure (23)This would remove some of the conformational freedom of the macrocycle (calculations indicated that rotation about the CHOLAPHANES ET AL STEROIDS AS STRUCTURAL COMPONENTS IN MOLECULAR ENGINEERING-A P DAVIS Figure 1 Computer-generated space-filling model of tetrahydroxycho- laphane (17b)This structure is one of 36 energy minima within 4 5 kcal mol of baseline located in a search employing the QUANTA/ CHARMm software package Although their shapes varied consider- ably all were open conformations enclosing substantial cavities C-aryl bonds in (17) should be relatively unrestricted)pd also give a well-defined surface to the cavity The idea was first realized as shown in Scheme 3 24 Satisfying features of this sequence were the chemo- and stereoselectivity of the reactions used to introduce the spacerThe Knoevenagel reaction to give (24) could be performed under very mild Ho 0 C12H25 A B. 11IL I ,.I...,I..,.,,. I. 70 65 60 55 50 45 40 35 PPm Figure 3 A possible conformation for the complex of (17b) and methyl /3-D-glucopyranoside (acting as a model for (22)) Intermolecular hydrogen bonds are shown as white dotted lines accompanied by the corresponding distances Table 1 Binding constants for stereoisomeric octyl glucosides with cholaphane (17b) in CDCl at 25 "C as determined by H NMR titration experiments Ka(M I) P-D 3100 (f14%) a-L 1030 (f10%) *Separate experiment conducted dt end of series to check reproducibility Figure 2 IH NMR spectra from d titration experiment involving cholaphane (1 7b) and glucoside (22) with CDCl as solvent In the initial spectrum of (1 7b) [1 1 mM spectrum (a)] the amide NH A' dppears at 5 67 p p m ,while the benzylic protons 'B,C' are quite closely grouped around 4 4 p p m and show roughly equal couplings to the NH In the presence of (22) at increasing concentrations [0 31 mM in spectrum (b) 0 86 mM in (c) and 2 92 mM in (d)] signal A moves downfield towards an estimated limiting value of 6 75 p p m Signal B moves downfield (estimated limiting A6 0 32 p p m )and shows increased coupling to A while signal C moves upfield (est A6 0 44 p p m )and shows decreased coupling to AThe shifts clearly suggest major conformational changes in the macrocyclic skeleton consistent with complex formationThe doublet 'D' due to the anomeric proton of the carbohydrate moves very slightly downfield during the experiment As the proportion of carbohydrate bound is at its greatest at low concentrations it can be inferred that this proton experiences a weak shielding effect within the complex CHEMICAL SOCIETY REVIEWS 1993 I X =(a) luncttonalised (b) relatively bulky conditions the organocuprate (25) was inert to the ester groups in (24) and the aryl group was introduced almost exclusively from the equatorial direction. It was also pleasing that the final product (26) could be analysed by X-ray crystallography which showed the spacer groups in the expected orientation and confirmed the ability of the framework to encompass small guest molecules (Figure 4). We were less happy about the use of oxygen-based functionality in organometallic (25).This arose because we were unable to find a form of N-protection compat- ible with both the cuprate and its Grignard precursor (for further discussion see Section 6). However the replacement of oxygen for nitrogen proceeded smoothly and in good yield. A more serious problem concerned the dicyanomethyl groups in cholaphane (26).There were a number of ways in which we had hoped to elaborate them into either flexible or ionic substi- Figure 4 X-Ray crystal structure of cholaphane (26) shown in space- filling mode.The cavity includes two molecules ofTHF positioned by N-H.a-0 hydrogen bonds. 0 I-butyl removal 0-sulphonyialion displacement with azide ion etc. Scheme 3 CHOLAPHANES ET AL STEROIDS AS STRUCTURAL COMPONENTS IN MOLECULAR ENGINEERING-A P DAVIS 25 1 tuents but they proved disappointingly inert (possibly because of their unusually hindered environment)The obvious solution was to employ an alternative to malononitrile in the initial condensation Here again we met with unexpected difficulties (re)discovering that high-yielding Knoevenagel condensations on cyclohexanones are the exception rather than the rule However one of the exceptions is provided by cyanoacetate reagents and recent work has shown that (16a) may be con- verted into (27) and thenceforth via arylcuprate addition de- ethoxycarbonylation etc to cholaphane (28) Although the cyanomethyl groups in (28) are less bulky than their dicyano relatives they seem to be more tractable and we are hopeful that the methodology will prove viable for the synthesis of a range of externally-functionalized cholaphanes I OAc attach water-solubilizing functionality at two points on the framework but it is likely that more will be required An option which seems attractive in principle is to replace the 7,12a-OH groups in cholic acid by /3-directed NH; units via SN2 displace- ments Although this transformation has proved less easy than we might have hoped we have been able to achieve a workable procedure using azide as the nucleophile and sulphonate leaving groups 26 Water-soluble cholaphanes are thus a realistic goal for the future 5 Steroid -derived Macrocycles; Directly- linked Oligo-cholane Units Formula (15) does not of course represent the only way of assembling cholane units into macrocyclic structures An alter- native is to make a direct linkage between two steroidal compo- nents and complete the macrocycle with a third fragment (which may or may not be derived from the steroid) We have been exploring some possibilities of this type as discussed below However most of the running has been made by R P Bonar-Law who synthesized cholaphanes (1 7) as his Ph D work in Dublin and then moved to Cambridge to collaborate with J K M Sanders Structures investigated by the Cambridge group are the steroid-capped metalloporphyrin (30),2 ’and the ‘cyclocholates’ (3 1)28 and (32) 29 In (30) the two cholic acid units are joined by formation of a bis-lactone the resulting cap having two hydroxyl groups which can interact with substrates bound to the metalThe molecule showed interesting selectivity for binding of hydroxyamines and was rapidly monoacylated by a 3-carboxypyridine derivative Macrocycles (3 1) were formed by direct cyclo-oligomerization of 7,12-diprotected cholic acid derivatives and applied to the binding of alkali metal cations in organic media Cyclocholates (32) were prepared in an analo- gous fashion from starting materials which had been subjected to a Beckmann rearrangement at the steroidal C12 It was shown OAc that they could self-associate into tubular dimers by amide- fiLCN“H I OAc amide H-bond formation It has also proved possible to con- 0 In (26) and (28) which might be described as ‘second-generation’ cholaphanes only modest progress has been made towards a rigid predictible macrocyclic framework However for the third generation we plan a modification which should effectively complete the journeyThere are practical large-scale methods for shortening the side-chain of cholic acid by two carbons and with such ‘bis-nor’ derivatives as starting materials macrocycles of the general form (29) should be accessible Computer-based molecular modelling suggests that these struc- tures should have very little flexibility indeed and could prove very informative in studies of molecular recognition and enzyme action A final point for this section concerns the move into aqueous solutionThe ‘second-generation’ methodology allows us to struct a tetrameric cyclocholate bridged on one face by a metalloporphyrin giving an elegant bowl-shaped structure with inward-directed hydroxyl groupsThis molecule has been found to bind morphine by a combination of H-bonding and nitrogen-metal ligation 30 Although the simple cyclocholate frameworks are readily accessible they are rather flexible for use in pre-organized receptors (unless supplied with extra constraints as in the porphyrin described above) However analogous molecules derived from ‘bis-nor’ cholic acid have been prepared by the Cambridge group and appear to have considerable potential 31 An approach of our own also involves the bis-nor steroidThe 3a-OH has been replaced by an amino group and two units have then been linked by amide bond formationThe resulting dimers may be seen as consisting of two rigid blocks connected by a fairly flexible hinge We hope that by completing the macrocycle with spacers of varying lengths we will be able to generate a family of host molecules of the form (33) Spacers B will be used to introduce functionality and control solubility as well as to tune the size of the cavity 6 Concluding Remarks; Spin-offs and Future Prospects Molecular engineering as illustrated in this article consists of a collaboration between organic synthesis and physical or physi- cal-organic chemistry For most chemists the ultimate justifica- tion would probably lie in the latter area- it is the demonstration of a novel and interesting property which gives the work its meaning However as progress continues it is likely that the synthetic aspect will be of increasing importance Structures will become more elaborate their designs will be subject to more precise constraints and their syntheses will present greater difficultyTo the physical-organic chemist this may seem a bleak prospect but to the synthetic chemist it is an exciting challenge 0 H 0"0" 'OR /H (31) R = H CH20CH2CH20CH COCH,O(CH2CH20)2CH L' If as seems likely work in the area begins to converge with natural products synthesis it will also yield some of the benefits of the latter In particular it will highlight general problems of methodology and will stimulate the finding of solutions In a small way this has already happened within our own pro-gramme For example our experience in introducing p-amino-methylphenyl spacer groups (Schemes 1 and 3) has-made us aware of the paucity of N-protecting groups which are compat-ible with strongly basic reagents N,N-Bis(trimethylsily1) was satisfactory in the first sequence but was too unstable to be truly convenientThis prompted the development of the 'Benzosta-base' protecting group as in (34)32 In the synthesis of (26) we found that Si-based groups were incompatible with the organo-cuprate (probably because of N-basicity) and we were forced to resort to the 0-substituted reagent (25) However we later developed the use of the pyrrole ring as in Scheme 4 this probably stands as the only group which is compatible with organometallic centres essentially non-basic and removable under reasonably non-aggressive conditions As illustrated in the foregoing sections the steroid nucleus can be employed to construct a variety of complex extended mole-CHEMICAL SOCIETY REVIEWS 1993 0 0 cular frameworks It hardly needs saying that its potential is not yet exhausted and that many further applications may be expected However two points are worth making concerning prospects for the futureThe first is a general one relating to the use of steroids to construct molecular receptors As mentioned in the introduction a particular feature of the steroidal frame-work is its asymmetryThus in a C2-symmetric cholaphane such as (17) or (26) there are 24 steroidal carbons which are different from each other and which therefore give distinct identifiable NMR signals Because of the prevalent sp3 hybridi-zation these carbons carry ca 30 distinguishable proton types almost all of which should be assignable to 'H NMR signals (after performing this exercise for (17a) the only uncertainties were between pairs of protons in four methylene groups) Many of these protons are directed into the cavity and may be seen as sensors positioned within the interior wall Provided that the receptor is able to bind its substrate in a single well-defined orientation one should be able to obtain remarkably precise structural information on the complex using intermolecular NOES and other effects The second and final point relates specifically to cholic acid Most of the work on this molecule has involved its assembly into large oligomeric structures capable of encapsulating substrate molecules However there may well be unrealized potential in the single cholic acid unit given its supply of differentiable co-directed functionality A wide range of molecules of the general CHOLAPHANES ET AL STEROIDS AS STRUCTURAL COMPONENTS IN MOLECULAR ENGINEERING-A P DAVIS Scheme 4 w (351 form (35) should be readily accessible and various applications can be envisaged A recent paper by Kahne demonstrates one option describing the glycosylation of the axial hydroxyls to give ‘facially amphiphilic’ molecules 34 We are actively consi- dering the possibilities of systems (35) in molecular recognition with particular emphasis on the achievement of enantioselecti-vity vzu three-point binding Acknouledgements For the work performed in Dublin I have to thank my co-workers Richard Bonar-Law Michael Orchard Brian Murray Bnan DorganTom Egan Khadga Bhattarai and a number of others who are currently ‘on steroids’ We are grateful to the groups of Pat McArdle (Galway) and David Williams (Imperial College London) for X-ray crystallography to Manfred Reetz for collaboration on the Benzostabase N-protecting group to Jeremy Sanders for help obtaining mass spectra and to Andy Derome for advice concerning NMR spectra Funding has been provided by Eolas (the Irish Science andTechnology agency) BioResearch Ireland and (in support of our molecular graphics facility) Loctite Corporation Finally thanks are due to Diamalt Gmbh for a generous supply of cholic acid References For leading references see J Rebek Jr ,Ang Chem Int Ed Engl 1990 29 245 J -M Lehn Angew Chem Int Ed Engl 1990,29 1304 F N Diederich ‘Cyclophanes’ Royal Society of Chemistry Cambridge 1991 P L Anelli P R Ashton R Ballardini V Balzani M Delgado MT Gandolfi T T Goodnow A E Kaifer D Philp M Pietraszkiewicz L Prodi M V Reddington A M Z Slawin N Spencer J F Stoddart C Vicent and D J Williams J Am Chem Soc 1992 114 193 C See1 and F Vogtle Angew Chem Int Ed Engl 1992,31 528 P J Collings ‘Liquid Crystals’ Adam Hilger Bristol 1990 Leading reference J -H Fuhrhop and J Mathieu Angew Chem Int Ed Engl 1984,23 100 S ShinkaiT Nishi and T Matsuda Chem Lett 1991,437 J C Medina,I Gay,Z Chen L Echegoyen,andG W Gokel J Am Chem Soc 1991,113 365 J Kikuchi C Matsushima K Suehiro R Oda and Y Murakami Chem Lett 1991 1807 J T Groves and R Neumann J Am Chem Soc ,1987,109,5045 J Org Chem 1988,53,3891 J Am Chem SOC,1989,111,2900 S A Latt H T Cheung and E R Blout J Am Chem Soc 1965 87,995 9 see e g ,J R Miller L T Calcaterra and G L Closs J Am Chem Soc 1984 106 3047 Y Kobuke M Yamanishi I Hamachi H Kagawa and H Ogoshi J Chem Soc Chem Commun ,199 1,895 S -z Zhou S-y Shen Q-f Zhou and H -J Xu J Chem Soc Chem Commun 1992,669 10 F M Menger and M J McCreery J Am Chem Soc ,1974,96,121 11 J P Guthrie Can J Chem 1972 50 3993 J P Guthrie and Y Ueda J Chem Soc Chem Commun 1973,898 12 J McKenna J M McKenna and D WThornthwaite J Chem Soc Chem Commun 1977,809 13 J P Guthrie J Cossar B A Dawson Can J Chem ,1986,64,2456 and refs cited therein 14 (a)C J Burrows and R A Sauter J Inclusion Phenomena 1987,5 117 (b) J F Kinneary T M Roy J S Albert H Yoon T R Wagler L Shen and C J Burrows J Inclusion Phenomena 1989,7 155 15 R P Bonar-Law and A P Davis J Chem Soc Chem Commun 1989 1050 16 G Cahiez and J F Normant in ‘Modern Synthetic Methods’ Vol 3 ed R Scheffold Wiley Chichester 1983 p 173 17 L F Fieser and S Rajagopalan J Am Chem Soc ,1950,72,5530 18 R P Bonar-Law A P Davis and J K M Sanders J Chem Soc PerkznTrans 1 1990,2245 19 R T Blickenstaff and J Baker J Org Chem 1975,40 1579 and refs cited therein 20 see e g ,T W Rademacher R B Parekh and R A Dwek Ann Rev Biochem 1988 57 785 S -1 Hakomori Adv Cancer Res 1989,52,257 N Sharon and H Lis Chem Br 1990,26,679 21 Y Aoyama Y Tanaka H Toi and H Ogoshi J Am Chem Soc 1988,110,634,Y Kikuchi Y Tanaka S Sutarto K Kobayashi H Toi and Y Aoyama J Am Chem Soc ,1992,114 10303 and refs cited therein 22 R P Bonar-Law,A P Davis,andB A Murray,Angeir Chem Int Ed Engl 1990,29 1407 23 K M Bhattarai R P Bonar-Law A P Davis and B A Murray J Chem SOC Chem Commun 1992,752 24 A P Davis M G Orchard A M Z Slawin and D J Williams J Chem Soc Chem Commun 1991 612 A P Davis and M G Orchard J Chem Soc PerkznTrans I 1993,919 25 (a)A P Davis T J Egan M G Orchard D Cunningham and P McArdle Tetrahedron 1992 48 8725 (b) A P Davis and T J Egan Tetrahedron Lett 1992,33 8125 and refs cited therein 26 A P Davis and M G Orchard Tetrahedron Lett 1992,33 51 11 27 R P Bonar-Law and J K M Sanders J Chem Soc Chem Commun 199 1,574 28 R P Bonar-Law and J K M Sanders Tetrahedron Lett 1992,33 207 1 29 R P Bonar-Law and J K M Sanders Tetrahedron Lett 1993,34 1677 30 R P Bonar-Law L G Mackay and J K M Sanders J Chem Soc Chem Commun 1993,456 31 R P Bonar-Law personal communication 32 R P Bonar-Law A P Davis and B J Dorgan Tetrahedron Lett 1990,31,6721 R P Bonar-Law A P Davis B J Dorgan M T Reetz and A Wehrsig Tetrahedron Lett 1990,31 6725 33 Y Cheng,D M Ho,C R Gottheb,D Kahne,andM A Bruck J Am Chem Soc 1992,114,7319

ISSN:0306-0012    

DOI:10.1039/CS9932200243

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Interactions of Metal Ions with Nucleotides and Nucleic Acids and their Constituents Helmut Sigel University of Basel Institute of Inorganic Chemistry Spitalstrasse 51 CH-4056 Basel Switzerland 1 Introduction Enzymatic reactions involving nucleotides have a general depen- dence on metal ions; this also applies to the biosynthesis of nucleic acids.For example all enzyme-catalysed reactions with 5‘-ATP,+ including those involving DNA and RNA polymer- ases need divalent cations usually Mg2+.An additional diva- lent metal ion may also be sometimes Hence it is not surprising that nucleotide-metal-ion interactions have fasci- nated coordination chemists for more than three decades especially since Szent-Gyorgyi3 postulated not only phosphate binding to 5’-ATP for Mg2+,but also an interaction with the nucleic base moiety. As a result of their ambivalent proper tie^,^ nucleotides (see Figure l)5u-6 present a true challenge to coordination chemists. 4.5,7 -O A metal ion may interact with the phosphate group(s) the sugar moiety or the base residue of a nucleotide. Moreover such a base residue is itself ambivalent; for example an adenine residue offers the N-1 N-3 and N-7 sites to a metal ion for binding. It is the aim of this short review to clarify the binding properties of the various constituents which are of course largely identical for both (low molecular weight) nucleotides and (high molecular weight) nucleic acids. Some composites of these constituents in particular mono-nucleotides will also be con- sidered.The phosphate group(s) will be dealt with first because their interaction with metal ions determines to a large part the stability of nucleotide-metal-ion complexes. At this point it is worth mentioning that only a few acidity constants (of protonated ligands) and stability constants (of the corresponding complexes) will be summarized. However the literature citations for these equilibrium constants will be given Helmut Sigel is Professor (Extraordinarius; 1978) at the Institute of Inorganic Chemistry University of Basel Switzerland where he has been Dozent since 1967 and where he also earned his Ph.D. (1964) with the late Prof. Dr. Hans Erlenmeyer; in 1968169 he u~~sa Visiting Staf Member at Cornell University in Ithaca (N.Y. U.S.A.j. Dr. Sigel is on various Editorial Boards of inter-nationaljournals editor -together with Astrid Sigel- ofthe series ‘Metal Ions in Biological Systems’ and chairman of the pro- gramme on the Chemistry of Metals in Biological Systems of the European Science Foundation (Strasbourg) . He is the recipient of the 1977 Alfred Werner Award of the Swiss Chemical Society the 1985 Brotherton Visiting Research Professor at the University of Leeds (U.K.) and for the years 1992-5 named Visiting Professor at the Zhongshan (Sun Yat-Senj University in Guangzhou (China). His present research interestsfocus on the stability structure and reactivity of sim-ple and mixed ligand metal ion complexes of nucleotides amino acids peptides and other bio-ligands. 255 where appropriate. Any constant actually presented is defined as given below 2 Stability of Phosphate-Metal Ion Complexes 2.1 Phosphate Monoesters and Phosphonate Derivatives In simple phosphate monoesters RMP2- where R represents a non-coordinating organic residue R indirectly affects the metal ion binding properties of the phosphate group by altering its basicity. It is well known that for families of structurally related ligands straight lines are observed if log I& is plotted versus pG,,l and the same is to be expected for phosphate monoester ligands. Indeed the data pairs log KE(RMp)/pG(RMp)for phenyl phosphate 4-nitrophenyl phosphate methyl phosphate n-butyl phosphate and even hydrogen phosphate for a given metal-ion complex all fit on a straight line. Some examples are shown in Figure 2l 2-14 and it is worthwhile emphasizing that simple phosphonate ligands like methyl phosphonate and ethyl phos- phonate also fit on the same straight lines. For the metal ions Mg2+,Ca2+,Sr2+,Ba2+,Mn2+,Co2+ Ni2+,Cu2+,Zn2+,or Cd2 + and their complexes with phos- phate monoesters and phosphonates straight line equations have been established. Hence it is possible to calculate the stability constants of the corresponding metal ion complexes for any phosphate or phosphonate derivative with a non-interacting group R if the pK value is known. An interesting result borne out from these studies is that 5’-CMP2- 5’-UMP2-,and 5’-dTMP2 -form complexes with the mentioned divalent metal ions and for these the data pairs fit on the reference lines defined above (see Figure 2).12This means that cytidine uridine and thymidine residues do not participate in complex formation. For 5’-CMP2 -this may seem particu- larly surprising because it is well known that cytidine can bind metal ions via N-3.16 However 5’-CMP2 -,like 5‘-UMP2 -and 5’-dTMP2-,exists predominantly in the anti conformation in aqueous solution6a such that N-3 is pointing away from the phosphate group (see Figure l) and therefore simultaneous coordination of the metal ion to both the phosphate residue and N-3 is only possible through adoption of the less favoured syn conformation (cf. also reference 17).The uracil and thymine residues become attractive for metal ions after deprotonation of the H(N-3) unit (see also Sections 4.1 and 5.1). t Abbreviations Note listed below are only those abbreviations which do not logically follow from either the definitions given in Figure 1 and its legend or in the legend of Figure 2. Ado = adenosine; 2’-AMP2 -= adenosine 2‘-monophosphate; 3’-AMP2-= adenosine 3’-monophosphate; Cyd = cytidine; DHAP2-= dihydroxyacetone phosphate = HOCH,C(O)CH,OPO -;dThd = thymidine; E = dielectric constant; 5’-GMP2 - 5‘-GDP3- 5’-GTP4-= guanosine 5’-mOnO- phosphate 5‘-diphosphate 5‘-triphosphate; GI P2-= glycerol 1 -phosphate = HOCH,CH(OH)CH,OPO:-; Guo = guanosine; I= ionic strength of a solu-tion; Ino = inosine; K = acidity constant (see also equation I); L = general ligand with an undefined charge; M*+ = general metal ion; RMP2-= phosphate monoester (R may be any organic residue e.g. phenyl or nucleosidyl; in some instances also phosphonate derivatives RPO -,are included in this abbreviation); RNA = ribonucleic acid;TuMP2- = tubercidin 5’-monophosphate (= 7-deaza-5’-AMP2-; i.e. N-7 of the adenine residue is replaced by a CH unit); Urd = uridine. CHEMICAL SOCIETY REVIEWS. 1993 Figure 1 Chemical structures of various nucleosides (Ns) and their corresponding nucleoside 5'-mOnO- 5'-di- and 5'-triphosphates (5'- NMP2- 5'-NDP3- and 5'-NTP4-) As examples at the top are shown adenosine 5'-triphosphate (5'-ATP4 ) and cytidine 5'-triphos- phate (5'-CTP4-) in their dominating anti c~nformation,~~together with the labelling system for the triphosphate chain note the phos- phate groups in the NTPs are labelled a ,9 and y where y refers to the terminal phosphate groupThe analogous NMPs and NDPs have the corresponding structures with one or two phosphate groups respecti- velyThe adenine and cytosine residues in the structures given at the top for 5'-ATP4 -and 5'-CTP4 -,respectively may be replaced by one of the other nucleic base residues shown above if this substitution is done in the way the bases are depicted within the plane then the anti conformation will also result for the corresponding nucleoside 5'- phosphates For reasons of clarity the 5' label is used only in the top two examples however in the text this specification is always given when necessary NH 5'-ATP" 2.2 Diphosphate andTriphosphate Monoester Ligands In nucleoside 5'-triphosphates (5'-NTP4 -) the terminal 7-phos- phate group is relatively far removed from the nucleosidyl residue and consequently its basicity is largely unaffected by the base residues Indeed pK&NTP) = 6 50 f0 05 in aqueous soh- tion (I = 0 1 M NaNO or NaClO 25 "C) for H(5'-ATP)3 - H(5'-ITP)3- H(5'-GTP),- H(5'-CTP),- H(5'-UTP)3 - and H(5'-dTTP)3 -,l l8 the pK value for monoprotonated methyl triphosphate is also within the given limits lac Again 'HNMR shift experiments,l in agreement with spectrophotometricZ0 and kinetic studies,21 reveal that for 5'-CTP4- 5'-UTP4- and 5'-dTTP4- the affinity for the divalent metal ions mentioned in Section 2 1 is solely determined by the properties of the triphos- phate residue (the single exception being the CU(~'-CTP)~ complex cf reference 17) 5'-CTP" R= -ribose -rlbOSYl 5'-monophosp hate -ri bosyI 5'-dip hosphate -ribosyl 5'-triphosphate Ado AMP^- ADP~ ATP~ R 3 Ino IMP2- IDPs ITP& Guo GMP" GDP3- GTP" CMP2- CDPs CTP" R Urd UMP2- UDPs UTP" R' = -2'deoxyribose -2'-deoxyribosyl5'-mono phosphate -2'-deoxy nbosyI 5'-diphosphate -2'-deoxy nbosyl 5'-triphosphate dThd dTMP2- dTDP2- dTTP2- NUCLEIC ACID CONSTITUENT-METAL ION INTERACTIONS-H 5 -AMP 2-AMP 1 3-AMP 0 28 70 HPK H(R-MP) Figure 2 Relationship between log G(RMP) for the 1 1and pG(RMP) complexes of Mg2 +,Zn2+,and Cu2+ with some simple phosphate monoester ligands (RMP2 -) 4-nitrophenyl phosphate (NPheP2 -) phenyl phosphate (PheP2 -) uridine 5‘-monophosphate (UMP2 -) D-ribose 5’-monophosphate (RibMP2-) thymidine 5’-monophosphate (dTMP2-) and n-butyl phosphate (BuP2-) (from left to right( (0) The least-squares lines are drawn through the corresponding six data sets which are taken from ref 12 the equations for these base lines are taken fromTable V of ref 12 (see alsoTable I of ref 13)The points due to the complexes formed with 2’-AMPZ 3’-AMP2- and 5‘-AMPZ-(0)are inserted for comparison and they provide evidence for an enhanced stability of several of the M(AMP) complexes the corresponding equilibrium constants are taken fromTables 2 and 3 and ref 14 All points for the complexes with 5’-CMP2 -(= C) (a>)(see ref 12) andTuMP’ -( =T) (@) fall within the error limits on the reference lines the log stability constants of the M(TuMP) complexes are plotted versus the microconstant pk:;: = 6 24 and these data are taken from Table I11 and Figure 2 of ref 13 respectively All plotted equilibrium constants refer to aqueous solutions at 25 “C and I = 0 1 M (NaNO,) Our knowledge of nucleoside 5’-diphosphates (5’-NDP3 -) is considerably scarcer 22 It appears that the acidity constants for various H(5’-NDP)2-species vary somewhat i e = 6 2 to 6 4 22 23 This variation may be taken as an indication that the nucleosidyl residue affects the basicity of the P-phosphate group in the 5’-NDP3- species to some extent However from lHNMR shift experiments in D20 (I = 0 1 M NaNO 27 0C)23 it is clear that in the M(S’-CDP)- and M(5‘- UDP)- complexes with Mg2 +,Zn2+,or Cd2 + no metal-ion- base interaction occurs this is probably also true for most other divalent metal ions The observations for the M(5‘-CTP)2 - M(5’-UTP)2-,M(5‘-dTTP)2- M(S‘-CDP)- and M(S’-UDP)- complexes may be explained as discussed in Section 2 1 in nucleotide complexes containing the uracil or thymine residues no metal ion inter- action with the nucleic base moiety is feasible as long as the H(N- 3) site is not deprotonated (cf also Section 4 l) aside from the fact that the anti conformation dominates as is also true for 5’-CTPJ and 5’-CDP3 -5d In this anti conformation the N-1- C- 6 bond of pyrimidines projects onto or near to the ribose ring and N-3 is directed away from the phosphate moietyThe energy barrier between the syn and anti conformations of 5’-CTP4- has been estimated’ to be about 6 kJ mol- Recommended stability constants for M(5‘-NTP)2 -com-plexes are listed in reference 17 values for M(S‘-NDP)- species are given in references 22 and 23 2.3 Structural Aspects of Phosphate-Metal Ion Interactions How do metal ions interact with phosphate groups? For the complexes of poly(cytidy1ate) [ = poly(C)] which contains phos- SIGEL 257 phate diester groups with a single negative charge on the phosphate unit with Mg2 +,Co2+,Ni2+,or Zn2 + very similar stability constants have been observed 24This observation is taken as evidence that these metal ions are bound to poly(C) mainly by electrostatic interactions with little or no inner-sphere coordination an outer-sphere coordination with water between the metal ion and the phosphate oxygens is suggested 24 Such an outer-sphere interaction is also proposed for Mg2 + /poly(adeny-late( [ = poly(A)] complexes while metal ions like Co2 +,Ni2+ and Zn2 + also form inner-sphere species with poly(A) (see also Sections 5 2 and 5 5) For doubly negatively charged phosphate monoester ligands (RMP2-) it has been tentatively concluded12 by considering the slopes of the aforementioned reference lines (see also Figure 2) that in aqueous solution four-membered chelate rings are rarely formed -despite their (albeit infrequent) occurrence in the solid state sb 25 -and that the dominating binding mode is monoden- tate inner-sphere phosphate oxygen coordination (see also Section 5 2) possibly together with a six-membered ‘semi-che- late’ ring involving both a metal ion-coordinated water molecule and a hydrogen bond l2This conclusion agrees with a recent examination25bof phosphate-metal ion interactions in the solid state based on the Cambridge Structural Database metal ions display preferentially a monodentate out-of-plane coordina- tion stereochemistry However one has to add that in aqueous solution pure outer-sphere complexation may also play a role 26 Moreover a crystal structure study of the barium-adenosine 5’-monophosphate heptahydrate complex2 revealed that Ba2 + is coordinated to eight water molecules without direct interaction with 5‘-AMP2- and that seven of the eight water molecules from the Ba2+ hydration shell are hydrogen bonded to phos- phate groups three of these water molecules are also hydrogen bonded to other suitable acceptor sites on the base (N-1 and N-7) and ribose (0-3’) entities Consequently ‘isomeric’ equilibria regarding the phosphate-metal ion binding mode have to be expected in solution the position of which will also depend on the kind of metal ion involved Indeed for complexes of methyl phosphate it has previously been concluded that the extent of outer-sphere complexation depends on the metal ion 26a How-ever clearly more research is needed on the degree of formation of these various species For di- and triphosphates the formation of inner-sphere complexes will certainly be more pronounced owing to the increased negative charge of these ligands (see also Section 5 5) This conclusion agrees with an earlier one,26b namely ‘the lower the charge the more predominant are outer-sphere complexes’ 2.4The Effect of a Decreasing Solvent Polarity on Complex Stability Nowadays it is well established that in proteins28 and the active- site cavities of enzymes29 the ‘effective’ or ‘equivalent solution’ dielectric constant is reduced compared to the situation in bulk water I e ,the activity of water is decreased30 due to the presence of aliphatic and aromatic amino acid side chains at the protein- water interface Estimates for the dielectric constants (E) in such locations range from about 30 to 70 28 29Therefore it should be emphasized In the present context that metal ion-phosphate group interactions increase considerably with decreasing solvent polarityThis effect is well established for both phosphate31 and triphosphate monoester3 Iigands for example the stability of the Cu2 + complex of phenyl phosphate (PheP2 -) increases by nearly a factor of ten in going from water (c = 78 5,33 log G:(phep) = 2 77) to an aqueous solution con- taining 30% (v/v) 1,4-dioxane (€ = 52 7,33 log @:(ph,p) = 3 72) 31 Straight-line plots were constructed of log versus pG(,,,) for the Cu2+ complexes of simple phosphate mono- ester ligands in water containing 20 30 40 or 50% (v/v) 1,4-dioxane (I = 0 1 M NaNO 25°C) (see also Figure 3 in Section 3) For the solvents containing 30 and 50% 1,4-dioxane it was also shown that the data pairs for the complexes of simple phosphonate ligands fit on these straight lines34 (see also Section 2 1) As before the stability constant for the corresponding Cu2+ complex can be calculated from these straight-line equa- tion~~'~~and the pK value of a phosphate monoester or a phosphonate derivative 3 Interactions of Metal Ions with Sugar Resi d ues Complexes between carbohydrates or sugar-type ligands and metal ions have recently been reviewed 3s Structural studies showed 35 that simple carbohydrates can bind Ca2 + only if they can provide three or more hydroxy groups in a geometrical arrangement fitting the coordination sphere of calcium 36 Another example involving a transition metal ion stems from an X-ray structure study of a polymeric Cu2 + complex of guano- sine 2'-monophosphate that revealed an axial Cu-O(5') bond with the ribose 37 In this case Cu2+ has a distorted [4 + 21-octahedral coordination sphere in which the Cu-O(5') bond (2 474 A) is 0 138 8 longer than the opposite Cu-0 bond to a coordinated water molecule with a bond length of 2 336 8 The two examples clearly indicate that the interactions between divalent metal ions and simple sugar residues are weak This is different of course for sugars containing an amino or carboxylate group as well as for macromolecular carbohydrates In line with the above conclusions are the results of a recent study3* dealing with dihydroxyacetone phosphate (DHAP2 )and glycerol- 1-phosphate (GlP2 -) By employing the straight- line equations mentioned in Section 2 1 it was established for aqueous solutions that the stability of the M(DHAP) and M(G1P) complexes where M2+= Mg2+,Ca2+ Sr2+ Ba2+ Mn2+ Co2+ Ni2+ Cu2+ Zn2+ or Cd2 +,is governed by the basicity of the phosphate group of DHAP2- and G1P2- there are no indications for the participation of the oxygen atom of either the carbonyl or hydroxyl groups at C-2 of these ligands in complex formation which would be possible on steric grounds However measurements with Cu2 + and DHAP2- or G1P2 in water containing 30 or 50% (v/v) 1,4-dioxane show -as is nicely seen in Figure 3 from the increased complex stabilities -that to some extent seven-membered chelates involving these oxygen atoms may be formed 38This may also be surmised for the other divalent metal ions listed above under appropriate conditions By using the results summarized in Figure 3 it was possible to quantify the position of the following intramolecular equilibrium 0 O,o-c,OP-0-C-C-R OP C-R I I \ I (3)I I0 0 OM 0 M The degree of formation of each of the chelated species of Cu(DHAP) and Cu(G1P) is approximately 0 15 and 45% in water water/30% (v/v) 1,4-dioxane and water/50% (v/v) 1,4- dioxane respectively 38These results nicely demonstrate that the weak binding sites of sugar residues become important when the solvent has poorer solvating properties than water a con- dition that exists in the active-site cavities of enzymes as indicated in Section 2 4 4 Metal Ion Binding Sites in Nucleoside Cornplexes 4.1 Some Considerations on Uridine/Th ymidine and InosinelGuanosine Scanning the six nucleic base structures shown in Figure 1 reveals that the base moieties of uridine (Urd) and thymidine (dThd) offer to metal ions no strong binding sites -aside from the weakly coordinating carbonyl groups -as long as the H(N-3) unit is not deprotonated a reaction that will occur only excep- tionally in the physiological pH range under the influence of metal ions because the acidity constants are high CHEMICAL SOCIETY REVIEWS 1993 50 45-3 40-Ck334 35-0-30-50 55 60 65 70 75 80 HPKH(R-MP) Figure 3 Evidence for an enhanced stabilitv of Cu(DHAP) and ku(G1P) in mixed dioxane-water solvents based on the relationship and pG(RMP) between log G(RMP) for the Cu2 + 1 1 complexes of 4- nitrophenyl phosphate (I) phenyl phosphate (2) D-ribose 5'-mono- phosphate (3) n-butyl phosphate (4),uridine 5'-monophosphate (9,and thymidine 5'-monophosphate (6) in water and in water containing 30 or 50% (v/v) 1,4-dioxaneThe least-squares lines are drawn in each case through the data sets shown the equations of these reference lines are availableThe points due to the Cu2 + 1 1 complexes formed with DHAP2 and GIP2- (a)in the three mentioned solvents are inserted for comparison these data are fromTable I11 of ref 38The vertical broken lines emphasize the stability differences to the corres- ponding reference lines these differences equal log dCu(RMP)as defined in Section 5 2 by equation (7) All the plotted constants refer to 25 "C and I = 0 1 M (NaNO,) (Reproduced by permission from J Am Chem Soc 1992 114 7780 ) (pG@Jrd)= 9 19 pG(dThd) = 9 69 I= 0 1 M NaNO 25"C H Sigel results to be published) The situation with inosine (Ino) and guanosine (Guo) (see Figure 1) is quite similarThe H(N-1) sites are in general not available at a pH of about 7 (PK&,,~) = 8 76 pK&,, = 9 22 H Sigel results to be published) for metal ion binding this leaves N-3 and N-7 as binding sites Among these N-7 is the predominant site,7c while binding to N-3 is observed only exceptionally (see Section 5 3) The two base entities that show a large degree of ambivalent behaviour are clearly adenine and maybe more surprisingly cytosineTherefore we shall consider adenosine and cytidine in somewhat more detail 4.2The N-1 versus N-7 Dichotomy of Adenosine The adenine residue offers metal ions N- 1 occasionally N-3 (see Section 5 3) and N-7 as binding sites (cf Figure 1) Conse- quently for adenosine (Ado) this leaves a dichotomy in metal ion binding of N- 1 versus N-7 a problem first addressed by Kim and Martin s6 39 The development of log KELversus pGL reference lines for imidazole-like or N-7 type ligands and for pyridine- like or N-1 type ligand~,~~ as well as the evaluation of the steric inhibitory effect of the o-amino group on the complexation tendency of the N-1 site in adenosine by studying the complex forming properties of tubercidin (Tu)~~ (inTu the N-7 of Ado is replaced by a CH unit) brought some further progress to the resolution of the problem 42 Indeed this information together with an improved estimate for the pK value of the H+(N-7) site in rnonoprotonated adenosine (which is not directly accessible by experiments because N-7 is less basic than N- l) allowed the conclusion that Ni2+ and Cu2+ (to approximately 70°/0) and most probably also Co2+ and Cd2 +,prefer to coordinate to adenosine via the N-7 site for Zn2 + a more even distribution between the N-1 and N-7 sites appears to occur while Mn2 + possibly prefers the N-1 site which is indubitably strongly predominant for the binding of NUCLEIC ACID CONSTITUENT-METAL ION INTERACTIONS-H. H +.For further details reference 42 should be consulted where the corresponding equilibrium constants are also listed. It may be added that similar treatment has been carried out for the dichotomy present in H(N- 1) deprotonated xanthosine (pK = 5.47).40 4.3The Ambivalent Properties of Cytidine The establishment of reference lines (log GLversus pGL)42 for o-amino pyridine-like ligands (Section 4.2) allowed a quantifica- tion of the coordination tendency of N-3 of cytidine (Cyd) as well as of the stability enhancing effect of the neighbouring 2- carbonyl group in M(Cyd) complexes.'This effect increases + within the series Co2+ -Ni2+ (no effect) < Mn2+-Zn2+ (0.25 log unit) < Cd2+ (-0.55) < Cu2+ (-1.05); a positive effect is also observable for the M(Cyd)2 + complexes of Mg2 + and Ca2+. However in most instances the coordination tendency of the o-carbonyl group is not able to compensate completely for the steric inhibitory effect of the o-amino group (see Figure 1). It is concluded16 that in Co(Cyd)2+ and Ni(Cyd)2+ the 2- carbonyl group does not participate to any appreciable extent in metal ion binding; in the M(Cyd)2 systems with Zn2 +,Cd2+,+ or Cu2 + chelates involving N-3 and a more weakly bound 0-2 are formed at least in equilibrium . These chelates could be four- membered such as those observed in the solid state (see citations in reference 16) but a metal ion-bound water molecule might also participate in aqueous solution and six-membered chelates would result from this partial outer-sphere coordination; a binding type sometimes termed semi-chelation. In contrast it should be pointed out that the stabilities of the M(Cyd)2+ complexes with Mn2 +,Mg2+,and Ca2 + are apparently deter- mined to a large part by the metal ion affinity of the 0-2 of the carbonyl group. For further details especially the related stability constants reference 16 should be consulted. 4.4 Conclusions Regarding Nucleic Acids Some provisional conclusions regarding the metal ion binding properties of single-stranded RNA or DNA based on studies of the indicated type are given in reference 7c. For the neutral pH range the following overall order of affinity for the metal ion- binding of the sites available in the base residues in single- stranded nucleic acids may be tentatively proposed N-7; GUO2 N-3; Cyd Z N-7; Ado Z N-1; Ado > N-3; Ado GUO. Some metal ions e.g. Cu2+,may also be able to partially replace H from the neutral H(N- 1) unit in the guanine moiety + (cf. Figure 1) or from the H(N-3) site of the uracyl or thymine residues in the neutral pH range sb,19,43 (see also Section 4.1). The position of these negatively charged N sites in the preceding series of metal ion affinities is as yet undetermined. Regarding the consequences of metal ion binding to base residues upon certain degradation reactions see Section 7. Of course the so-called hard or class a metal ion^,^.^^ like Na +,Mg2+,AI3+,Mn2+ or Fe3 +,preferably interact with the hardoxygen sites of the phosphate groups of nucleic acids; these metal ions have only a low affinity for the base residues. Clearly the soft or class 6 e.g.,Cd2+ Hg2+ Pd2+ Pt2+ as well as the borderline e.g.,Fez+,Co2+,Cu2+,Zn2+,Pb2+,metal ions have a rather pronounced affinity for the borderline aromatic N-sites of the nucleic base residues; however it should be noted that many of these metal ions e.g.Cut +,Zn2+,Cd2+ or Pb2 +,also bind significantly to phosphate groups (see also Sections 5 and 7). 5 Nucleot ide-M eta I Ion Interact ions 5.1 Some Introductory Remarks It was pointed out in Sections 2.1 and 2.2 that in the case of the pyrimidine nucleoside phosphates the stability of the resulting complexes is determined by the metal ion affinity of the phos- phate group(s) and that there is no significant metal ion-nucleic SIGEL 259 base interaction (at least as long as the H(N-3) site of the uracil or thymine is not ionized);17 the only exception known so far is CU(CTP)~- of which about 30% exist in the form of a macrochelated isomer involving N-3 (see also equili- brium 4 below). 'Therefore the following parts in this section will concentrate on the complexes of purine nucleoside phosphates. There is one important aspect that needs to be emphasized and that has to be kept in mind when dealing with purine derivatives.They all show a pronounced tendency for self- association which occurs via stacking of the purine rings.' 9~23,4s As a result experiments aimed at determining the properties of monomeric metal ion complexes of purine nucleosides or their phosphates should not be carried out in concentrations higher than M; in fact to be on the safe side it is recommended that a maximum concentration of only 5 x M is used (cf e.g.,references 7c 13-1 5,41). Consequently most of the results to be discussed in the following sections were obtained by potentiometric pH titrations of solutions that had a nucleotide concentration of 3 x loa4 M. To prevent erroneous conclusions7c it is very important to be aware of the aforementioned self-stacking proper tie^,^ which n~~~may be favoured via either metal i ~ 9323 or proton46 binding. ~ Moreover such self-stacking also affects the acid-base qualities of nucleosides and nucleotides which can be studied as a function of c~ncentration.~~ 5.2 Macrochelate Formation Involving N-7 in Metal Ion Complexes of Adenosine 5'-Monophosphate (5'-AMP2 -) The biologically most important compound among the adeno- sine monophosphates (see Figure 4in Section 5.3) is probably 5'-AMP2-. In the case when a metal ion is coordinated to the phosphate group of this nucleotide the ion may also interact with N-7 of the adenine residue because in the dominating anti conformation N-7 is orientated towards the phosphate group (while N-1 is pointing away; see Figure I).This then gives rise to the following intramolecular equilibrium b as e -e The degree of formation of the macrochelated or 'closed' species which we designate as M(NMP),I is independent of the total concentration of complex present because the intramolecu- lar equilibrium constant Kl as defined by equation 5 where M(NMP) refers to the 'open' species in equilibrium 4 is dimensionless KI may be calculated' 1,1 3,19 via equation 6 log A = log G(NMp) -log G(NMP) (7) If a further identification of log A is necessary it is given by indices; e.g. log !M(S*-AMp) refers to the stability difference as expressed in equation 7 for M(5'-AMP) complexes.The remain- ing definitions are given in equations 8 through 10 CHEMICAL SOCIETY REVIEWS 1993 Table 1 Comparison of the measured stability G(5 of the M(5'-AMP) complexesa with the calculated stability Ki(s AMP), for an isomer with only M2 +/phosphate coordination,b and extent of the intramolecular macrochelate formation (equilibrium 4)in the M(5'-AMP) complexes at 25 "C and I = 0 1 M (NaNO,) ZqTg)tMP) log Gi.5AMP),p log A KI Yo M(S'-AMP),I +M2 (Eq 9) (Eq 7) 0% 6) (Eq 4 11) Mg2 I 60 f0 02 1 57 f0 04 0 03 f0 04 007fOlO 0 (7 f9/< 15)+ Ca2+ 146f001 1 46 f0 05 0 00 f0 05 OOOfO12 0 (< 11)Sr2 124f001 1 24 f0 05 0 00 f0 05 ooo*o 12 O(< 11) +Ba2 117*002 116*005 0 01 f0 05 002*0 13 O(< 13) Mn2+ 223f001 2 16fO07 0 07 f0 07' 0 17 f0 19' 15f 14e co2 2 23 f0 02 1 94 f0 07 0 29 f0 07 0 95 f0 33 49 f9+ Ni2+ 2 49 f0 02 1 95 f0 06 0 54 f0 06 2 47 f0 50 71 f4 cu2 3 14 f0 01 2 87 f0 08 0 27 f0 08 0 86 f0 35 46f 10 + Zn2 2 38 f0 07d 2 12f008 026fO 11 0 82 f0 45 45f 13 + Cd2+ 2 68 f0 02 2 44 * 0 06 0 24 f 0 06 0 74 f0 25 43 f8 Determined in aqueous solution by potentiometric pH titrationsThe errors given are either 3 times the standard error of the mean or the sum of the probable systematic errors whichever is largerThe acidity constants of H,(5 AMP)* are pG AMP = 3 84 f0 02 and pG AMP = 6 21 f0 01 l3 Calculated with pfi AMP = 6 21 and the baseline equations given inTable 1 of ref 13 l2 the error limits correspond to 3 times the standard deviations (SD)given in the column at the right inTdble 1 of ref 13 See also the information summarized in Section 2 1The errors given here and in the other two columns at the right were calculated dccording to the error propagation after Gauss by using the errors listed in the second and third columns In this connection the in part increased stability of several M(5 AMP) complexes shown in Figure 2 should also be noted the vertical distance of a datum point to the reference line corresponds in each case to log AM AMP Regarding experimental difficulties see ref 13The log K$i AMP values determined in aqueous solution with NaNO and NaCIO as background electrolyte (I=0 1 M) were 2 41 k0 10 and 2 34 i0 06 respectively the value given above is the overall average This result is in all probability significant with 2 u as error limits the data are logdMns AMP = 0 07 f004 K = 0 I7 f0 11 and % M(5 AMP) = 15 f8 l3 (Reprinted by permission from J Am Chem SOC 1988 110 6857 ) complexes (see Figure 2 in Section 2 1 andTable I) are actually due to the formation of macrochelates involving N-7 was proved Equation 6 follows from equation 10b The overall stability by studying the M2 + complexes of tubercidin 5'-monophos- (equation 10a) is experimentally accessible phate (TuMP2 = 7-deazaAMP2 ,I e N-7 is replaced by a CH constant G(NMP)and e g for M(5'-AMP) systems values for K&s AMP) (equa-group) l3 Indeed M(TuMP) complexes show no increased tion 9) are calculated by employing the reference-line equations stability I e TuMP2 behaves as a simple phosphate mono- described in Section 2 1 and the acidity constant of H(S'-AMP)- ester ligand and its data pairs fit within the error limits on the (PG(~ = 6 21),13 hence log dM(5 AMP) becomes known reference lines (see also Figure 2) and thus via KIthe position of the intramolecular equilibrium 4 In the previously mentioned M(S'-AMP),I macrochelates i e the percentage of the closed or macrochelated species both binding sites I e the phosphate group and N-7 may bind follows from equation 11 to a metal ion in an inner-sphere manner l3This conclusion is also supported by kinetic studies (mainly with Ni2+ and CO~+),~~and agrees with suggestions based on space-filling molecular models s1 Moreover the following results for other This calculation procedure outlined now for M(NMP),I applies purine nucleoside 5'-monophosphates are also in line kinetic to all corresponding systems discussed in Section 5 Further-and product studiess2 for the reaction between cw-Pt(NH,)z + more to provide the reader with all the data involved in such a and 5'-(2'-deoxy)GMP2 or 5'-GMP2 indicate a direct coordi- calculation in a single example those for various M(5'-AMP) nation a suggestion also confirmed in NMR studiess3 for 5'-systems are summarized inTable 1 IMP2 and other related purine nucleotides Furthermore From column 4 of Table 1 it is evident that the stability there is evidence that in D20the MoiVof the (ys-C,H,),Mo2 + increase log AMP) is zero within the error limits for various unit coordinates directly to both N-7 and the phosphate group M(5'-AMP) complexes and therefore at the most only traces of of 5'-(2'-deoxy)AMP2 thus forming a macrochelate 54 In base-backbound isomers can occurThe increased complex agreement with these results are the properties observed for the stability with the 3dmetal ions and Zn2 + or Cd2 + demonstrates M2+ complexes of 1,N6-ethenoadenosine 5'-monophosphate (E-that the macrochelated isomers (equilibrium (4))are formed in AMP2 ) l3 Of course these summarized proofs for inner- appreciable amounts (column 6 of Table 1) The smaller stability sphere binding in these macrochelates do not exclude the enhancement observed for Cu( 5'-AMP) in comparison with that possibility that in aqueous solution macrochelates with a (par- for Ni(5'-AMP) indicates that the geometry of the coordination tial) outer-sphere binding also occur to a certain degree (see also sphere of the metal ion is playing a role Assuming that Cu2 + Section 5 5) adopts a Jahn-Teller distorted octahedral coordination sphere with a strong tendency to coordinate donor atoms equator- ial]~,~*there are three equatorial positions left in a phosphate- 5.3 Complexes of 2'-AMPZ and 3'-AMP2 :Evidence for coordinated Cu2+ but for steric reasons only the two CIS Metal Ion-(N-3) Interactions positions are able to interact with N-7 In the octahedral Figure 2 in Section 2 1 demonstrates that the stability of some coordination sphere of Ni2 + four of the five positions left after M(2'-AMP) and possibly also though certainly to a lesser phosphate coordination are sterically accessible Hence Ni2 + extent M(3'-AMP) complexes is enhanced What types of backbinding to N-7 is statistically favoured by a factor of 2 macrochelates are possible with 2'-AMP2 and 3 -AMP2 3 By corresponding to 0 3 log units and indeed this is comparable to considering the structures of the ligands shown in Figure 4 it is the larger stability enhancement of 0 27 log units (= log AN,(^ evident that N-7 though crucial for the properties of the M(5 -AMP) -log AcU(sAMP) = 0 54 -0 27Table 1) for the Ni2 + com-AMP) complexes is for steric reasons clearly not accessible to a plexThe near identity of the stability enhancements (log A) of metal ion already bound to either the 2'- or 3'-phosphate group the complexes with Co2+,Zn2+,and Cd2 + (Table 1) reflects the instead one might be tempted to postulate chelate formation similar affinity of these ions toward imidazole-type nitrogen with the neighbouring OH groups of the ribose ring for both donors 49 AMPS However this is apparently not the case the steric That the observed increased stabilities of various M(5'-AMP) conditions for 2'-AMP2 and 3'-AMP2 to form such seven- NUCLEIC ACID CONSTITUENT-METAL ION INTERACTIONS-H. 00 R3' R2 Figure 4 Chemical structures of the adenosine monophosphates (AMPs) considered in Section 5.3.The AMPs are shown in their dominating anti conformation.6b membered chelates are identical (Figure 4) and therefore equiva- lent properties for both series of complexes are expected but this is not observed as can be seen from Figure 2 as well as from the results listed in columns 2 and 3 ofTable 2. Table 2 Extent of intramolecular macrochelate formation according to equilibrium (4) in M(AMP) complexes expressed as the percentage of M(AMP),I formed in aqueous solution at 25 "C and I = 0.1 M (NaNO,)" M*+ '/O M(2'-AMP),l '/O (M(3'-AMP) YOM(5'-AMP),I Mg' + Ca*+ 0 0 0 0 7f9(< 15) 0 Sr2+ 0 0 0 Ba' + 0 0 0 Mn'+ co2 +Ni2 + 11 f15(<24) 11 f16(<24) 13 f13 (< 25) 0 0 13 f13 (< 25) 15f 14h 49 f9 71 f4 Cu*+ 45f 10 17% 16(<30) 46f 10 Zn' + Cd2+ 15 f 17 (< 29) 13 f 13 (< 25) 0 0 45* 13 43 f9 Abstracted from Table 4 of ref. 14. * See comment in footnote e of Table 1. Different structural qualities of the ligands must be respon- sible for the different properties of the M(2'-AMP) and M(3'- AMP) complexes the obvious conclusion is that in Cu(2'-AMP) (see column 2 ofTable 2) as well as possibly in some of the other M(2'-AMP) species macrochelates are formed by an interaction of the phosphate-coordinated metal ion with N-3 of the adenine residue. Indeed 2'-AMP2 -in its preferred anti conformation (Figure 4) is perfectly suited for this type of macrochelate f0rmati0n.l~That metal ions may interact with N-3 of a purine moiety has become more and more clear during the past few years through X-ray structure studies of Pt" complexes of guanine derivative^,^ of Rh' complexes of 8-azaadenine deriva- tive~,~~and also of Ni" complexes formed with neutral ade- nine.57 It may be added that very recently chelate formation involving N-3 has also been proposed for M2 + complexes of the dianion of the antiviral AMP2 -analogue 9-(2-phosphonyl- methoxyethy1)adenine (PMEA2 -)* and that a Rh"' binding to N-3 of adenine residues of DNA was tentatively assigned.58 The presented conclusions regarding the M(2'-AMP) com- plexes also explain why the tendency to form chelates is further reduced for 3'-AMP2- (see column 3 ofTable 2).14 In M(3'- AMP) complexes an interaction of the phosphate-coordinated metal ion with N-3 only becomes possible when the nucleotide adopts the less favoured syn conformation. Though it appears highly likely that the stability increases observed for M(2'-AMP) and (possibly also) M(3'-AMP) systems14 (Figure 2) are due to SIGEL 26 1 base-backbinding of the phosphate-coordinated metal ion to N- 3 as discussed above the additional occurrence of even smaller concentrations of seven-membered chelates involving the phos- phate-coordinated metal ion and the neighbouring OH group of the ribose ring cannot be ruled out completely; however in the light of the results presented in Section 3 such chelation appears to be rather unlikely. In any case it is clear that the degree of formation of the closed species (equilibrium 4) decreases in the order M(5'-AMP),I > M(2'-AMP) > M(3'-AMP)cI (seeTable 2).Preliminary results have also been obtained for M2+ com- plexes of 2'-GMP2 -,3'-GMP2-,and 5'-GMP2 .59 They paral- -lel those described for 2'- 3'- and 5'-AMP2- the maximum degree of formation of macrochelated species for all metal ions occurs with 5'-GMP2-; i.e. YO M(5'-GMP),I > YO M(2'-GMP),I > YOM(3'-GMP),,; 3'-GMP2- shows at most only a small tendency to form chelates. In M(5'-GMP),I base-back- binding occurs to N-7 (see Section 5.4) and it is now also suggested that it occurs in M(2'-GMP) most probably to N-3 of the guanosine residue. 5.4The N-7 Backbinding Properties in Complexes of Inosine (5'-IMPZ-) and Guanosine 5'-Monophosphate (5'-GMPZ -) The results summarized in Table 3 for various M2 + complexes of purine nucleoside 5'-monophosphates show that macrochela- tion according to equilibrium 4 is also important for the M(5'- IMP) and M(5'-GMP) complexes.6o In addition a closer com- parison of the results reveals that the percentages of the closed species increase from the M(5'-AMP) to the M(5'-IMP) and further to the M(5'-GMP) complexes. Table 3 Extent of intramolecular macrochelate formation according to equilibrium 4in M(5'-AMP) M(5'-IMP) and M(5'-GMP) species expressed as the percentage of M(NMP),I formed in aqueous solution at 25 "C and I = 0.1 M (NaNO,)" M*+ '/' M(S'-AMP) '/' M(5'-IMP),l Yo M(S'-GMP) MgZ+ CaZ+ 7f9(< 15) 0 21 f8 9f 11 26 f8 15k 10 Mn2+ 15f 14 29f 12 40f 10 Co*+ 49 f9 78 f4 83 f3 Ni2+ 71 f4 89 f2 93 f1 Cu2+ 46f 10 69 f6 81 f4 Zn*+ 45f 13 62 f7 72 f5 Cd2+ 43 f8 64 f5 70 f4 The data for M(5'-AMP) are fromTable 1 those for M(5'-IMP) and M(5'- GMP) from references 60a and 60b,c respectively. Though further studies are necessary for the 5'-IMP2 -and 5'-GMP2-systems,60 the stability increase log AM(NMp) as defined by equation 7 is accessible via the experimentally measured stability constant Kg(NMP) which quantifies the overall stability of the M(NMP) complexes and KE(NMp)op which describes the stability of the complex with a sole phosphate coordination; this latter value is calculated via the straight reference-line equations as indicated in Section 2.1 As metal ion backbinding occurs to N-7 in M(5'-AMP) M(5'- IMP) and M(5'-GMP) complexes one might expect that the extent depends on the basicity of this site. In other words a plot of the stability increase log AM(NMp) versusthe pK of the N-7 site in these three 5'-NMPs might reveal further insights.42 In a relative sense the basicity of the N-7 site in 5'-AMP2 - 5'-IMP2-,and 5'-GMP2 -should be reflected by the pK values of the corresponding nucleosides (Ns) adenosine (Ado) inosine (Ino) and guanosine (Guo) i.e. by pk;(,- Ns).The values P~(lno) pk~(N-7= Ino) = 1.06 * 0-04 and P&(cuo) = pki(N-7 Guo) = 2.1 1 f0.04 were mea~ured,~' and the one for pk,(,- Ado) = -0.2 was recently estimated.42 1 07i /I 1 011 7T /IAdo I no Guo 35 0 05 10 15 20 H pk H(N-7INs) Figure 5 Relationship between log dM(NMp) (equation (7)) for the Cu2 + (W ) and Cd2 (0)1 1 complexes of 5’-AMP2- 5’-IMP2- or 5’-+ GMP2 and pk& ,Ns) of the corresponding nucleosides (Ns) adeno- sine (Ado) inosine (Ino) and guanosine (Guo) For details including the origin of the data (25“C,Z = 0 1 M NaNO,) see ref 42 (Reproduced by permission from Comments lnorg Chem ,1992,13,35 ) Though the data for only a few metal ion systems are as yet available it is clear from the results shown in Figure 5,13 6o 61 where log AM(NMP)versus the mentioned pk& 7/Ns) values are plotted for the Cu(5‘-NMP) and Cd(5‘-NMP) systems that straight lines are obtained 42This observation allows two conclusions (1) macrochelate formation in the M(5‘-NMP) complexes depends on the basicity of N-7 (11) the carbonyl oxygen at C-6 in 5‘-IMP2- and 5’-GMP2- (see Figure 1) has apparently very little effect on the stability increase log AM(NMp) this observation argues against the formation of five-membered chelates involving N-7 and O(C-6) next to the mentioned macrochelates However the structural aspects of the formation of macrochelates (seeTable 3) with alkaline earth ions warrant further studies In the present context a recent IUPAC publication22 on ‘Stability Constants for Nucleotide Complexes with Protons and Metal Ions’ has to be mentioned This compilation is very helpful for finding access to the literature regarding equilibrium constants and (in part) their connected enthalpy changes How- ever great care should be exercised with regard to the advice given in this publication z e differentiating between the values which are recommendedand those not recommended To give Just a single example “The values of (references) are tentatively recommended for Cd(5’-CMP) for Cd(5‘-UMP) and for Cd(5’-dTMP)The value of (reference) for Cd(5’- GMP) is much larger than the above values and is not recom- mended” For the reader who ‘digested’ Section 2 1 and the results presented above in this section (as well as those described in Sections 5 2 and 5 3) the apparent discrepancy is quite clear the stability of the Cd2+ complexes with the aforementioned three pyrimidine nucleoside 5’-monophosphates is solely deter- mined by the basicity of the corresponding phosphate groups I e there is no nucleic base-metal ion interaction while the stability of Cd(5’-GMP) is significantly increased z e log ACd(5 GMP) = 0 53 f0 06 (see Figure 5),‘-j1owing to considerable base- backbinding to N-7 (see also Section 5 2) of the phosphate- coordinated Cd2 +,indeed Cd(S‘-GMP),I is formed to 70 f4% (Table 3) It is evident that most unfortunately users of the IUPAC compilation22 have to make their own judgements in selecting stability constants to prevent being misguided’ 5.5 Isomeric Equilibria in Complexes of Adenosine 5’-Triphosphate (5‘-ATP4 -) Stability constants measured by potentiometric pH titration for M(5’-ATP)2-complexes are in a number of instances larger than those of the corresponding complexes formed with pyrimi- dine nucleoside 5’-triphosphates (PNTP4-) As the stability of CHEMICAL SOCIETY REVIEWS. 1993 M(PNTP)2-species is solely determined by the binding proper- ties of the triphosphate chain (see also Section 2 2) this allowed the definition of log (equation 7) and the calculation of the percentages of the closed form M(S’-ATP)$ according to equilibrium 4 in the way described in Section 5 2The detailed results of potentiometric measurements including those of various research groups are given in references 7b and I7 In the present context it is important to note that other determinations of the percentages of M(S‘-ATP);( by UV difference spectrophotometry’*‘ 2o and ‘H NMR shift experi- ment~’~gave smaller values for YOM(S’-ATP):( than those obtained via potentiometric measurementsThis apparent dis- crepancy is especially clear-cut for Mg(5’-ATP)2 -and Ni(5’- ATP)2- where approximately 0 and 30% respectively for the closed species were deduced in contrast to the 11 f6% and 56 f4% obtained via the potentiometric pH titrations Taking into account that ultraviolet absorption and nuclear magnetic resonance spectroscopy techniques which detect perturbations in the adenine ring are sensitive mainly to inner- sphere coordination of the ring by a metal ion the above observation has led to the sugge~tion~~ that outer-sphere chelates are also formed It is evident that the stability increase detected by potentiometric pH titrations encompasses both inner-sphere and outer-sphere coordination of N-7 z e M(5’-ATP),2,,, (see column 2 ofTable 4) hence the difference between YOM(5’-ATP)zl~ and the percentage determined by the spectroscopic methods sensitive mainly to inner-sphere coordination z e to M(S‘-ATP)& should provide the percent- age of the N-7 outer-sphere coordinated species M(S‘-ATP)& Of course the difference between 100% and YOM(S’-ATP),‘,tot (= YOM(S‘-ATP)& + YOM(5’-ATP)&) gives the percentage of the open complex M(5’-ATP)&Tentative and simplified struc- tures of the two macrochelated species are shown in Figure 6 Figure6 Tentative and simplified structures for the macrochelated inner- sphere (A = M(S’-ATP)~,,;) and outer-sphere (B = M(S‘-ATP);,;) isomers of M(ATP)2 species It should be noted that the terms inner- sphere and outer-sphere are used here only with regard to the M2+/N-7 coordination (for further details ref 7b should be consulted) (Reproduced with permission from Eur J Bzochem 1987,165,65 The results summarized inTable 4 are the ‘best’ values presently available At this time only indirect evidence for the formation of N-7 outer-sphere macrochelates can be presented However it should also be emphasized that in some of the examples76 the differences between M(S’-ATP& and M(5’- ATP)$ are certainly beyond the experimental error limits e g for the complexes with Ni2+ and Mg2+ Interestingly the percentages of the inner-sphere closed forms (third column in Table 4)follow the usual stability series for dispositive 3d metal ions2 62 including the stability constants for imidazole bind- 1ng44a49 and the relative placements of Zn2 and Cd2 + + It may be added that recent NMR evidence has been presen- ted536 that in dilute neutral D20 solutions czs-Pt(ND2CH3); + coordinates to purine nucleoside 5’-triphosphates via N-7 and NUCLEIC ACID CONSTITUENT-METAL ION INTERACTIONS-H SIGEL 263 Table 4 Estimates for the degree of formation of N-7 inner-sphere M(S‘-ATP)& and outer-sphere macrochelates M(S’-ATP)& as well as for the ‘open’ species M(S’-ATP)& in aqueous solution (-25 “C,I z0 1 M)The degree of formation for M(5‘-ATP)2cljt,t which encompasses both inner-sphere and outer-sphere coordination to N-7 as determined from potentiometric pH titrations is given for comparisona Estimates for M2 Yo M(S’-ATP),~,I % M(S’-ATP),??; Yo M(S‘-ATP),??; Yo M(S‘-ATP)&+ +Mg2 11 f6/13 f6 0 10 90 Cd2 2f6 --0 10 15 100+ Mn2+ 17f 10 -25 10 0 80 co2 38 f9/35 f10 60+ Ni2+ 56 f4/58 30 25 45 cu2 67 f2/68 f4 67 -0 33+ Zn2+ 28 f7/26 f5 15 15 70 Cd2+ 46 f4/50 f6/52 30 20 50 These ddtd dre abstracted fromTdble 4 of ref 7b The data listed in the second column resulted from potentiometric pH titrdtions where two or more vdlues dre given in a row they dre based on independent determinations 7h For further details references 7h and 17 should be consulted the y-phosphate group in forming a macrochelate A further mentioned that the percentages for M(S‘-ADP)i were calculated interesting result is the evidence63 that in Mg(5’-ATP)2 -phos-such that rather lower limits resulted 23 However despite all phate binding occurs as a mixture of P,y-bidentate and a,P,y-shortcomings these results suggest that the total extent of tridentate complexation (see also Section 2 3) Finally there are macrochelate formation for the metal ions studied depends on ~ndications~~that for Cu2+ in strongly alkaline media the the number of phosphate groups and varies in the series % hydroxy groups in the ribose residue -due to deprotonation -M(S’-AMP),I < YOM(S’-ADP)i > YOM(5’-ATP)zl-This order become important binding sites possibly indicates that the macrochelates of M(S’-ADP)-are That N-7 coordination is the ‘weak’ point in macrochelate less strained than those of M(5‘-AMP) and that they also form formation of the M(5’-ATP)2 -complexes is not surprising 7‘ more easily than those of M(5‘-ATP)z ,a result that may be due Indeed the release of N-7 upon mixed ligand complex formation to the denticity of the different phosphate residues in solution has been demonstrated with ligands as different as For M(5’-ITP)zl and M(5‘-GTP)zi the preliminary results OH-,65 NH3,656 imida~ole,~~~66 2,2’-bipyridy1,65a67 1,lO-phe-available are listed in columns 5 and 6 ofTable 5 respect-and trypto~hanate,~~~ nanthrolir~e,~~~ 68 and has also been ively 6oa 70 Surprisingly the degree of formation of the macro- confirmed for the solid state 69 These results suggest that the chelates for a given metal ion with the three purine nucleoside 5’-binary M(5’-ATP)2 -complex bound to an enzyme may exist as triphosphates including M(5‘-ATP)zl- ,do not vary consider- a closed macrochelate only when no enzyme groups coordinate ably (columns 4-6 ofTable 5) This is different from the directly to the metal ion observations made with the corresponding monophosphates (Table 3) which were discussed in Section 5 4 At this stage it is difficult to provide a conclusive explanation for the different 5.6 Comparison of the Extent of Macrochelate Formation in properties of the M(5‘-NMP) and M(5‘-NTP) complexes M(5‘-AMP) M(5’-ADP) ,M(5‘-ATP)’- M(5’-ITP)’ maybe the higher basicities of N-7 in the inosine and guanosine and M(5‘-GTP)2 -Systems residues are better suited for an inner-sphere coordination For the M(5’-AMP) species it appears that macrochelate forma- whereas the adenosine residue (possibly due to the 6-NH2 tion to N-7 predominantly occurs in an inner-sphere fashion group) allows a higher degree of outer-sphere complex forma- (Section 5 2) l3 However for the other complexes mentioned in tion and this leads to similar overall percentages for the M(5‘- the above headline aside from M(5’-ATP)2 - practically no NTP)zi- species of a given metal ion such information is available and therefore all the following comparisons rely on results for M(N),I (= M(N)cl,tot) where N = nucleotide as obtained via potentiometric pH titrations 6 Solvent Influence on Metal Ion-( N-7) though there are indications that in the case of M(S‘-ADP)- (cf Base- Backbinding references 20 and 23) similar isomeric equilibria exist as dis-The importance of a decreasing solvent polarity on the metal ion cussed in Section 5 5 for M(5‘-ATP)2 -systems binding properties of phosphate groups has already been In columns 2 3 and 4 ofTable 5 the available data for % pointed out in Section 2 4(cf also Figure 3) a decreasing solvent M(S’AMP), M(S‘-ADP)i and M(5‘-ATP)zi- respectively are polarity considerably favours phosphate-complex stability’ Of listed The data for M(S’-ADP)- are incomplete and it may be course with the results on macrochelate formation discussed in Table 5 Comparison of the extent of macrochelate formation according to equilibrium 4for various complexes of 5‘-nucleotides (N) expressed as the percentage of M(N),l formed in aqueous solution at 25 “Cand I = 0 1M (NaNO,) M2 + ‘/O M(S‘-AMP),I O/O M(S’-ADP) YOM(S‘-ATP):j- ‘/O M(S’-ITP)$ Oh M(S’-GTP),?I Mg2+ Ca2+ Mn2+ 7f9 0 15f 14 0 55 11 f6 2f6 17 f10 0 (<5) 0 (<3)37f 15 95 13 0(<7) 38% 14 co2 + 49 f9 60 38 f9 41 f4 52 f5 N12 + 71 f4 80 56 f4 60 f4 74 f3 cu2 + 46f 10 94 67 f2 55 f7 67 f7 Zn2+ Cd2+ 45f 13 43 f8 67 28 f7 46 *4 26 f9 55 f6 28 f10 51 f4 Ref 13 23 17 60a 60c Section 5 in mind the question arises is macrochelate formation also affected by a decreasing solvent polarity? So far only a very limited amount of data is available71 and these refer to Cu(5’-AMP) and CU(S‘-ATP)~ complexes in -water-dioxane mixturesThe corresponding results are depicted in Figure 7 The surprising result is certainly the obserkation that the degree of formation of Cu(S‘-AMP),l passes through a minimum with increasing concentrations of 1,4-dioxane in waterThe same observation has also been reported recently for the Cu2 + complex formed with the dianion of 9-(2-phosphonyl- methoxyethy1)adenine (PMEA2 ) 34 Even though three iso- meric complexes occur in this system,’ 34 the chelated isomer with a Cu2+-adenine interaction also passes through a mini- mum upon the addition of increasing amounts of 1,4-dioxane to an aqueous solution containing Cu(PMEA) 34 Of course in accord with previous experience (see Section 2 4) the overall stability of the Cu(5’-AMP) Cu(PMEA) and CU(S‘-ATP)~ complexes which is mainly determined by the metal ion affinity of the phosphate residues increases considerably for all three complexes with increasing amounts of 1,4-dioxane despite the evident changes in the degree of formation of the macrochelates 70-60-50-40-30-20-10-OJ,0 10 20 30 40 50 % (vh) Dioxane-Water Figure7 Degree of formation of the macrochelates (equilibrium 4) in the Cu(5‘-AMP) (0)and Cu(S‘-ATP)*-(0)complex systems as a function of the percentage of 1,4-dioxane added to the aqueous reagent mixtures at 25 “Cand Z = 0 I M (NaNO,) (Reproduced by permission from Znorg Chem 1990,29,3631) Why does the degree of formation of the macrochelate for Cu(5’-AMP) (see Figure 7) and also for CU(PMEA),~~ pass through a minimum?This observation is difficult to explain but there have to be two opposing effects which result from the addition of 1,4-dioxane to an aqueous solution containing the complexes It could be for example that low amounts of 1,4- dioxane lead to a hydrophobic (lipophilic) solvation of the purine fraction of the nucleotides by the ethylene groups of 1,4-dioxane and that in this way the binding site N-7 is shielded to some extent Upon addition of larger amounts of 1,4-dioxane to the aqueous solution no further shielding occurs but the activity of water decreases to the point where poor solvation results for those metal-ion sites not occupied by the phosphate group(s) of the nucleotides consequently this poorer solvation leads to an increased affinity of these metal ion sites for other ligating groups z e for N-7 Along these lines the observations made with Cu(5’-AMP) and also Cu(PMEA) could be explained Clearly should this explanation be correct then for Cu(5’- ATP);]-such a minimurn at higher 1,4-dioxane concentrations should also be observable unfortunately solubility problems prevent such a study In any case the above observations are meaningful -and they CHEMICAL SOCIETY REVIEWS. 1993 are also to be expected for other metal ion-nucleotide complexes -considering the substrate and product structures in enzymic reactions it is evident that at a protein-water interface subtle polarity changes are enough to favour either one of the struc- tures shown in equilibrium 4 72 Moreover one wonders how far metal ion binding to nucleic acids1° 73 (Section 4 4) e g 74 of Pt2+,is also affected by changes in the polarity of the surround- ing solvent? In this respect it should be noted that not only the nucleic base parts alter their coordinating properties but as pointed out above the metal ion affinity of phosphate residues also increases drastically with a decreasing solvent polarity (Section 2 4) Finally the influence of such solvent changes on the reactivity has already been proven9a75 for the metal ion facilitated dephosphorylation of 5‘-ATP 7 Some Reflections on Reactions Involving Metal Ion-Nucleic Base Interactions The role of metal ions and their interaction with N-7 as well as the importance of self-stacking for the promoted dephosphory- lation of 5’-ATP has recently been reviewedThis reaction +proceeds in the presence of e g Cu2 or Zn2 + via a dimeric species in which one 5’-ATP orientates via N-7 the metal ion and the other 5’-ATP such that a reactive state is achieved In other words 5’-ATP can be considered as its own ‘enzyme’ in the metal ion facilitated hydrolysisThe role of the structuring 5’-ATP4 can also be taken over by 5’-AMP2-These obser- vations have led to the question gb have 5‘-ATP4- and related purine nucleotides played a role in early evolution? Clearly in contemporary biochemistry 5’-ATP is still the most important energy-rich intermediate in metabolic processes Maybe 5‘-ATP has conserved its eminent role for life over billions of years It should also be emphasized in the present context that intramolecular equilibria of the type discussed in Sections 5 and 6 often involve only small changes in free energy (AGO)The existence of 20% of a certain species in rapid equilibrium with the other isomers may be more than enough for a given enzymic reaction to proceed however the connected energy change is very small z e AGO = -0 6 kJ mol-l 7c l1 It is evident that here Nature has a tool to achieve high selectivity by connecting various such equilibria without creating high energy barriers 72 Another interesting aspect is the following one more than 25 years ago it was shown that the copper-catalysed disproportio- nation of H202 does not proceed via free HO radicals but occurs7677 in the coordination sphere of Cu2 + Consequently peroxidase-like reactions can be carried out in the coordination sphere of Cu2 + (cf reference 78) and the Cu2 +/H202 system can be used to probe the structures of complexes in solution 77 79 For example evidence for base-backbinding in monomeric Cu2+ complexes of nucleoside 5’-triphosphates was provided by this method many years ago 77 *O Quantification of the peroxi- dase-like activity in such systems z e degradation of the nucleic base residues within the coordination sphere of Cu2 + by H202 leads to the bell-shaped curves shown in Figure 8 In a certain pH range the activity increases with increasing pH due to backbind- ing of the nucleic base moiety to Cu2+ and then it decreases again at higher pH due to the formation of hydroxo complexes which lead to a release of the base moiety from the coordination sphere of the metal ion (see Section 5 5)The bell-shaped curve in Figure 8 for the Cu2 +/5’-ATP/H202 system passing through a maximum at a pH of about 8 5 can be easily understood in this wayThe observation of the reactivity maximum at a pH of about 9 5 in the corresponding systems with 5’-ITP and 5’-GTP is connected with a deprotonation of the H(N-1) group 43 Similarly 5‘-UTP and 5‘-dTTP also undergo base backbinding at pH > 8 due to deprotonation of the H(N-3) unit 43 Finally in the case of CU(S’-CTP)~ only small amounts of a macrochelate -are formedI7 and consequently the degradation of the base residue is not very pronounced in this case (see Figure 8) The Cu2 +/H202 systems can also be used to probe macromo- lecules 77 For example native DNA coordinates Cu2+ in neutral or slightly alkaline aqueous solution preferentially via NUCLEIC ACID CONSTITUENT METAL ION INTERACTIONS-H SIGEL h -006 004 000 PH Figure 8 Peroxidase-like activity ([H202]= 8 x 10 M) for the Cu2+ complexes (4 x M) of 5’-ATP (a),5’-ITP (a),5‘-GTP (O),5‘-5’-UTP (a),and 5’-dTTP (0)CTP (e) ([NTP] = 4 x 10 M) at 22°C and natural ionic strengthThe degradation of the nucleic bases was followed spectrophotometrically by measuring the decreasing absorption at the maximum or in the case of pH dependent spectra at the isosbestic point and by quantifying the reactivity via the calcula- tion of the pseudo-first order rate constant k‘ (min-l) For details see ref 80 and in part also 77 (Redrawn by permission from Helv Chim Acta 1967,50 582 ) the phosphate groups Addition of H202gives rise to a catalase- like activity as well as to the formation of ternary peroxo complexes as observed by spectrophotometry,81 but there is no evident degradation of the nucleic bases under these conditions However if Cu2+ is added to DNA and the solution is kept at room temperature for 1 5 days Cu2 + penetrates into DNA and coordinates to the base residues (cf also Section 44) Addition of H,02 to such a solution leads then not only to a catalase-like activity but also to a peroxidase-like degradation of the nucleic base residuesThis can be followed by measuring the decreasing absorption at 260 nm 82 By such experiments both native and denatured DNA can be distinguished RNA with its less com- plete base-pairing offers even in the native form nucleic base sites for Cu2 + binding and consequently base degradation occurs in the presence of H202 77 82 DNA may be denatured in acidic solutions due to protonation of certain sites of the nucleic bases similarly in the alkaline pH range deprotonation of certain nucleic base sites occurs that again leads to denaturation and opening of the double helix These various events may also be nicely probed with the Cu2+/ H202 system as seen in Figure 9 83 Moreover metal ion binding to the phosphate groups inhibits the protonation of the base residues and consequently stabilizes the double helix whereas this kind of metal ion binding hardly affects deprotonatzon of the basesThe corresponding effects of Li +,Na + ,and K + are also seen in Figure 9 It may be added that a 100 times lower Mg2+ concentration (5 x lop4M) has the same stabilizing effect on DNA as the mentioned monovalent ions in 0 05 M solutions an observation which corresponds approximately to the expected differences in phosphate-complex stability between the alkaline M ions and Mg2 +The indicated stabilizing effect of Mg2 ++ on DNA is well known lo In this context a recent studys4 on the interaction of Cu2 with DNA and the observed antagonism of + various other metal ions should also be mentioned A final point of interest which is indirectly connected with self- stacking properties of nucleic bases (see Section 5 1) is their interaction with other aromatic entitiesThe stabilization of such interactions by a metal ion bridge was first shownsS for the mixed ligand complex formed between Cut +,2,2‘-bipyridyl and 5’-ATP4- Meanwhile many more systems with such intra- molecular stacks have been studied and in various instances the positions of the connected intramolecular equilibria quanti- fied 72 86 Such interactions between nucleic base residues and 4 5 6 7 8 PH Figure 9 Denaturation of DNA under the influence of the pH of the solution (slow stirring for 16 hours) at 22 “C and natural ionic strength ( O) and the stabilizing effect of Li+ (@) Na+ (0),and K+ (0)The peroxidase-like activity was used to characterize the extent of dendtu- ration of DNA under the various conditions ([DNA] = 0 01‘/o i e 7 5 mg DNA were solved in 15 mL H20),i e after the dddition of Cu2+ (10-4M)andH202 (8 x lop3M)therateofdegraddtionofthe nucleic bases was measured at 260 nm in 2 mm quartz cells and expressed as the pseudo-first order rateconstant k’ (min l)The alkali ions (0 05 M) when present were added as chlorides For details see references 83 and 77 (Redrawn by permission from Biochim Biophjs Acta 1968 157 637 ) amino acid side chains can also occur in mixed hgand-metal ion complexes containing a nucleotide and an amino acid residue In all these cases the nucleic base moiety is released from the coordination sphere of the metal ion upon formation of the intramolecular stack in the mixed ligand complex (Section 5 5) 66 86 Moreover this type of interaction shows a significant degree of selectivity for example the affinity of M(5’-ATP)2- for the following amino acids decreases in the order tryptopha- nate > leucinate > alaninate 68 72The importance of such inter- actions regarding the selectivity observed in Nature is evident AcknowledgementsThe technical assistance of Ms Rita Baum- busch in the preparation of the manuscript and the financial support for the research of my group on the complexes of phosphates nucleosides and nucleotides by the Swiss National Science Foundation are gratefully acknowledged 8 References 1 A S Mildvan Magnesium 1987 6 28 2 J J R Frausto da Silva and R J P Williams ‘The Biologicdl Chemistry of the Elements’ Clarendon Press Oxford 199 1 3 A Szent-Gyorgyi in ‘Enzymes Units of Biological Structure and Function’ ed 0 H Gaebler Academic Press New York 1956 p 393 4 ‘Metal Ions in Biological Systems’ Vol 8 Nucleotides and Deriva- tivesTheir Ligating Ambivalency ed H Sigel M Dekker New York 1979 5 (a)R B Martin and Y H Mariam Met Ions Biol Sj rt 1979 8,57 (b) R B Martin Acc Chem Res 1985 18 32 (c)R B Martin Met Ions Biol Syst 1988,23 3 15 6 (a) D B Davies P Rajani and H Sadikot J Chem Soc Perkin Trans 2 1985 279 (b) R Tribolet and H Sigel Eur J Biochem 1987 163,353 7 (a)H Sigel Chimia 1987,41 11 (6) H Sigel Eur J Biochem ,1987 165 65 (c)H Sigel in ‘Metal-DNA Chemistry’ ed T D Tullius ACS SJmp Series 402 American Chemical Society Washington D C 1989 p 159 8 (a) K Aoki in ‘Bioactive Molecules ,Vol 8 Metalloproteins ed S Otsuka andT Yamanaka Elsevier Amsterdam 1988 p 457 (h)K Aoki in ‘Landolt-Bornstein Band 1 Nukleinsauren Teilbdnd b Kristallographische und strukturelle Daten II’ ed W Saenger Springer Verlag Berlin 1989 p 17 1 (c) H Lonnberg in ‘Biocoordi- nation Chemistry’ ed K Burger Ellis Horwood London 1990 p 284 9 (a) H Sigel Coord Chem Rev,1990 100,453 (h)H Sigel lnorg Chim Acta 1992 198-200 1 CHEMICAL SOCIETY REVIEWS 1993 10 J A Cowan Comments Znorg Chem 1992,13,293 11 R B Martin and H Sigel Comments Znorg Chem 1988,6,285 12 S S Massoud and H Sigel Inorg Chem 1988,27 1447 13 H Sigel S S Massoud and R Tribolet J Am Chem Soc 1988 110,6857 14 S S Massoud and H Sigel Eur J Biochem 1989,179,451 I5 H Sigel D Chen N A Corfu F Gregaii A Holy and M Straiak Helv Chim Acta 1992 75 2634 16 Y Kinjo L -n Ji N A Corfu and H Sigel Znorg Chem ,1992,31 5588 17 H Sigel RTribolet R Malini-Balakrishnan and R B Martin Inorg Chem 1987,26,2149 18 (a)H Sigel J Znorg Nucl Chem 1977 39 1903 (b)H Sigel Y Kinjo N A Corfu and R Tribolet results to be published (c) P W Schneider H Brintzinger and H Erlenmeyer Helv Chim Acta 1964,47,992 19 K H Scheller F Hofstetter P R Mitchell B Prijs and H Sigel J Am Chem Soc 1981,103,247 20 Y H Mariam and R B Martin Znorg Chim Acta 1979 35 23 21 (a)C M Frey and J E Stuehr Met Ions Biol Syst 1974,1 51 (b) C M Frey and J E Stuehr J Am Chem Soc ,1978,100,134,(c)C M Frey and J E Stuehr J Am Chem Soc ,1978,100,139 (d)J C Thomas C M Frey and J E Stuehr Znorg Chem 1980 19 505 22 R M Smith A E Martell and Y Chen Pure Appl Chem 1991 63 1015 23 K H Scheller and H Sigel J Am Chem Soc 1983,105,5891 24 K S Dhathathreyan and H Diebler Ber Bunsenges Phys Chem 1991 95 880 see also H Diebler F Secco and M Venturini Biophys Chem ,1987,26,193 D Porschke Bzophys Chem ,1976,4 383 25 (a)R W Gellert and R Bau Met Ions Bzol Syst 1979 8 1 (6) R S Alexander Z F Kanyo L E Chirlian and D W Christian- son J Am Chem Soc 1990,112,933 26 (a)H Brintzinger Helv Chim Acta 1965,48,47,(b)H Brintzinger and G G Hammes Znorg Chem ,1966,51286 (c)TTheophanides and H A Tajmir-Riahi NATO ASI Ser Ser C 1984,139 137 27 H Sternglanz E Subramanian J C Lacey Jr and C E Bugg Biochemistry 1976 15 4797 28 (a)D C Rees J Mol Bzol 1980,141 323 (6) G R Moore FEBS Lett 1983 161 171 (c) N K Rogers G R Moore and M J E Sternberg J Mol Biol 1985 182,613 29 (a)H Sigel R B Martin RTribolet U K Haring and R Malini- Balakrishnan Eur J Biochem 1985 152 187 (b) see also the comment in the footnote on p 258 in M Bastian and H Sigel Znorg Chim Acta 1990 178 249 30 L De Meis Bzochem Biophys Acta 1989,973 333 31 (a)G Liang N A Corfu and H Sigel Z Naturforsch B 1989,44 538 (b)M C F Magalhies and H Sigel J Indian Chem Soc ,1992 69 437 (c) M Bastian and H Sigel Znorg Chim Acta 1991 187 227 32 R ,ribolet R Malini-Balakrishnan and H Sigel J Chem Soc Dalton Trans 1985,2291 33 G Akerlof and 0 A Short J Am Chem Soc 1936,58,1241 F E Critchfield J A Gibson Jr ,and J L Hall J Am Chem Soc 1953 75 1991 G Akerlof and 0 A Short J Am Chem Soc 1953,75 6357 34 D Chen F Gregafi A Holy and H Sigel submitted for publication 35 K Burger and L Nagy in ‘Biocoordination Chemistry’ ed K Burger Ellis Horwood London 1990 p 236 36 N S Poonia and A V Bajaj Chem Rev 1979,79,389 M L Dheu-Andries and S Perez Carbohydr Res 1983 124 324 cf also H Einspahr and C E Bugg Met Ions Biol Syst 1984 17,51 37 W S Sheldrick Acta Cryst B 1981,37 1820 38 G Liang D Chen M Bastian and H Sigel J Am Chem Soc 1992 114,7780 39 S -H Kim and R B Martin Inorg Chim Acta 1984,91 19 40 Y Kinjo RTribolet N A Corfu and H Sigel Inorg Chem ,1989 28 1480 41 L -n Ji N A Corfu and H Sigel J Chem Soc Dalton Trans 1991 1367 42 H Sigel N A Corfu L -n Ji and R B Martin Comments Inorg Chem 1992 13 35 43 H Sigel J Am Chem Soc 1975,97 3209 44 (a)R B Martin Met Ions Biol Syst 1986,20,21 (b)R B Martin in ‘Handbook onToxicity of Inorganic Compounds’ ed H G Seller H Sigel and A Sigel M Dekker New York 1988 p 9 45 H Sigel Biol Trace El Res 1989 21 49 46 R Tribolet and H Sigel Biophys Chem 1987,27 119 R Tribolet and H Sigel Eur J Blochem 1988 170 617 N A Corfu R Tribolet and H Sigel Eur J Biochem 1990 191 721 47 N A Corfu and H Sigel Eur J Biochem 1991,199,659 48 H Sigel and R B Martin Chem Rev 1982,82 385 49 N Saha and H Sigel J Am Chem Soc ,1982,104,4100,L -n Ji N A Corfu and H Sigel Znorg Chim Acta 1993 206 215 50 R S Taylor and H Diebler Bioznorg Chem 1976,6,247,A Peguy and H Diebler J Phys Chem 1977,81 1355 H Diebler J Mol Catalysu 1984 23 209 5 1 H Sigel and K H Scheller Eur J Biochem 1984,138,291 See also the comment in footnote (55) of ref 13 52 D J Evans M Green and R van Eldik Znorg Chim Acta 1987 128,27 M Green and J M Miller J Chem Soc Chem Commun 1987 1864 for a correction see zbid 1988,404 53 (a) M D Reily and L G Marzilli J Am Chem Soc 1986 108 8299 (b) M D ReilyT W Hambley and L G Marzilli J Am Chem Soc 1988,110,2999 54 L Y Kuo M G Kanatzidis and T J Marks J Am Chem SOC 1987 109,7207 55 G Raudaschl-Sieber H Schollhorn U Thewalt and B Lippert J Am Chem Soc 1985 107 3591 56 W S Sheldrick and B Gunther Inorg Chim Acta 1988 152,223 57 A Ciccarese D A Clemente A Marzotto M Rosa and G Valle J Inorg Biochem 1991,43,470 A Marzotto G Valle and D A Clemente ‘Abstracts of the 29th Internat Conf on Coordination Chem ’ Lausanne Switzerland July 19-24 1992 p 72 (No P182) 58 R E Mahnken M A Billadeau E P Nikonowicz and H Morrison J Am Chem Soc 1992,114,9253 59 (a)M C F Magalhdes,S S Massoud,N A Corfu,andH Sigel J Znorg Biochem 1989 36 295 5045 (b)M C F Magalhiies S S Massoud N A Corfu and H Sigel ‘Abstracts of the Fall-Assembly of the Swiss Chemical Society’ Berne Switzerland October 20 1989,p 99 60 (a) Y Kinjo N A Corfu S S Massoud and H Sigel J Inorg Biochem 1991,43,463,(b)S S Massoud and H Sigel ‘Abstracts of the XXVIth Internat Conf on Coordination Chem ’ Porto Portu- gal Aug 28-Sept 2 1988 C49 (c) N A Corfu Y Kinjo S S Massoud and H Sigel ‘Abstracts of the XXVIIIth Internat Conf on Coordination Chem ’ Gera GDR August 13-18 1990 Vol 2 pp 1-90 61 S S Massoud and H Sigel Bull Chem Soc Ethiop 1988,2,9 62 H Sigel and D B McCormick Ace Chem Res 1970,3,201 63 HTakeuchi H Murata and I Harada J Am Chem Soc 1988 110,392 64 G Onori Biophys Chem 1987,28 183 65 (a)H Sigel K H Scheller and R M Milburn Znorg Chem 1984 23 1933 (b) RTribolet R B Martin and H Sigel Znorg Chem 1987,26,638 66 H Sigel R Tribolet and 0 Yamauchi Comments Znorg Chem 1990,9 305 67 (a)P R Mitchell B Prijs and H Sigel Helv Chim Acta 1979,62 1723 (b)H Sigel F Hofstetter R B Martin R M Milburn V Scheller-Krattiger and K H Scheller J Am Chem SOC ,1984,106 7935 68 H Sigel B E Fischer and E Farkas Znorg Chem 1983,22,925 69 P Orioli R Cini D Donati and S Mangani J Am Chem Soc 1981 103 4446 W S Sheldrick Angew Chem 1981 93 473 Angeu Chem Znt Ed Engl 1981 20 460 W S Sheldrick Z Naturforsch B 1982,37 863 70 N A Corfu Y Kinjo RTribolet and H Sigel J Znorg Biochem 1989,36,295 71 G Liang and H Sigel Znorg Chem I990,29 363 1 72 H Sigel Pure Appl Chem 1989,61,923 73 E L Andronikashvili V G Bregadze and J R Monaselidze Met Ions Biol Syst 1988,23 331 74 S J Lippard Pure Appl Chem 1987,59 731 S E Sherman and S J Lippard Chem Rev 1987 87 1153 J Reedijk Pure Appl Chem 1987,59 181 J Reedijk A M J Fichtinger-Schepman A T van Oosterom and P van de Putte Structure & Bondzng 1987,67 53 J Reedijk Znorg Chrm Acta 1992 198-200 873 75 H Sigel and R Tribolet J Inorg Biochem 1990,40 163 76 H Sigel and U Muller Helv Chim Acta 1966 49 671 H Sigel C Flied and R Griesser J Am Chem Soc 1969 91 1061 R Griesser B Prijs and H Sigel J Am Chem Soc ,1969,91,7758 77 H Sigel Angeu Chem 1969,81,161 Angeu Chem Int Ed Engl 1969,8 167 78 H Erlenmeyer C Flierl and H Sigel J Am Chem Soc 1969,91 1065 79 H Erlenmeyer U Muller and H Sigel Helv Chzm Acta 1966,49 681 80 H Sigel Helv Chim Acta 1967 SO 582 NUCLEIC ACID CONSTITUENT-METAL ION INTERACTIONS-H. 81 H. Sigel and H. Erlenmeyer Helv. Chim. Acta 1966 49 1266. 82 H. Sigel B. Prijs and H. Erlenmeyer Experientia 1967,23 170. 83 H. Erlenmeyer R. Griesser B. Prijs and H. Sigel Biochem. Biophys. Acta 1968 157.637. 84 J.-L. Sagripanti P. L. Goering and A. LamannaToxicol. Appl. Pharmacol. 1991 110,477. 85 C. F. Naumann B. Prijs and H. Sigel Eur. J. Biochem. 1974 41 SIGEL 267 209; C. F. Naumann and H. Sigel,J. Am. Chem. SOC. 1974,96,2750. 86 S. S.Massoud R. Tribolet and H. Sigel,Eur.J. Biochem. 1990,187 387; S. S. Massoud and H. Sigel Chimia 1990 44 55; M. Bastian and H. Sigel J. Coord. Chem. 1991 23 137; D. Chen M. Bastian F. Gregaii A. Holjl and H. Sigel,J. Chem. SOC.,Dalton Trans. 1993 1537.

ISSN:0306-0012    

DOI:10.1039/CS9932200255

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

The Lower Oxidation States of Indium Dennis G. Tuck Department of Chemistry and Biochemistry University of Windsor Windsor Ontario Canada N9B 3P4 1 Introduction Although interest in the coordination chemistry of the Main Group metallic elements has grown in parallel with the develop- ment of transition element chemistry progress in the former was relatively slow during the years in which rapid advances were made in the latter area due in part to the lack of experimental and theroetical probes analogous to those provided by ligand field theory magnetochemistry and electronic spectroscopy. The structural investigation of colourless diamagnetic com- pounds depended largely on a mixture of intuition and vibra- tional spectroscopy until the ready availability of X-ray crystal- lographic methods revealed the real range of preparative and structural problems which challenge the worker in Main Group chemistry. The availability and sophistication of information on the chemistry of indium typifies this situation. In 1963 it was realistic for D. C. Bradley to summarize what was then known about the stereochemistry of indium in the + 3 oxidation state by stating simply and correctly that the coordination number might be either four or six. In the intervening years a number of review articles have testified to the increasingly sophisticated and detailed information which has become available on the inorganic and coordination chemistry the properties of complexes in ~olution,~and organometallic chemistry of this element. Even so most of the published material refers to the chemistry of indium (111) and only in recent years has there been any significant interest in the structure and properties of the oxidation states + 1 and + 2. Again this situation is similar to that for other Main Group metals where much of the attention has been on the generally more easily accessible higher oxidation states.The present article reviews the main features of the inorganic and organometallic chemistry of indium(1) and (11) and of the concomitant coordination chemistry and some possible areas for future development are suggested. 2The Inorganic Chemistry of Indium(i) 2.1 Binary Halides A major hindrance to the development of indium(1) chemistry has undoubtedly been the absence of readily available starting materials.The chalcogenides have been known for some time Professor Dennis Tuck is a graduate of the University of Durham and much of his early research work was in the field of radio-chemistry. Appointments in the University of Nottingham and Simon Fraser University pre- ceded a period as Head of the Department of Chemistry and Biochemistry at the University of Windsor where he now holds the position of University Pro- fessor. His present research in- terests ure in Main Group chemistry in preparative elec- trochemistry and in the redox reactions chemistry of Main Group elements. He received the RSC Main Group Chemistrj? Award in 1986. but have not apparently been useful in synthesis and the indium(1) halides although easily prepared are insoluble in all the commonly available solvents and in the presence of water or other bases rapid disproportionation gives indium metal and the corresponding indium(II1) species.This reaction 3InX -+ Ino + InX (1) is a characteristic and all too frequent feature of indium(1) chemistry and in some circumstances may provide a useful test of the absence of other competing reactions (see below). An interesting feature of the indium(1) halides is that they are generally obtained as coloured solids (red to black depending on the preparation) which may indicate the presence of either impurities or other oxidation states of the metal. The solid state structuresof InBr and In1 are both of theTI1 type in which each M + ion has X- neighbours at five of the corners of a distorted octahedron while InCl has a distorted NaCl lattice. Some of the important thermochemical properties of the monohalides are given in Table 1. In view of the later discussion this Table also contains some important information derived from thermochemical and spectroscopic evidence on the proper- ties of InX molecules in the gas phase and calculated AH values for equation 1. The earlier conclusions of Barrow have been recently supported by independent spectroscopic evidence and it is clear that these molecules are strongly bonded in the gas phase.4 There is some evidence for dimer formation in the case of InCI. 2.2 Other Indium(r) Compounds In addition to the binary halides and chalcogenides a number of indium(1) derivatives of inorganic acids have been prepared.The reaction of cyclopentadienylindium (CpIn see below) with weak acids results in ligand exchange. CpIn + HL +CpH + InL (2) giving rise to compounds in which L is a singly charged bidentate anion such as quinoline-8-olate. A more general route depends on the method of direct electrochemical synthesis in which a sacrificial metal anode is oxidized in a non-aqueous solution of a ligand or ligand precursor to give the appropriate MX com- pound.6 Since the starting point is the metallic element the technique is especially useful for synthesizing low oxidation species and indium gives a nice example of this behaviour; for example the oxidation of indium in the presence of CH,X (X = Br,I) gives InX as the primary product whose subsequent in situ reactions give derivatives such as X,InCH,X X,InCH,PPh et~.~In these syntheses the formation of indium(1) species at the anode can generally be inferred from the number of moles of metal dissolved per Faraday of charge but the reactivity of these initially formed species is sometimes such that the final product is in fact the corresponding indium(rI1) compound. It seems probable that these species are formed through electron transfer processes following the electrochemi- cal reactions cathode HL + e -+ L-+ +H (3) anode L- + In +InL + e (4) solution InL + HL -+ InL + +H (5) InL + HL -+ InL + $H (6) 269 270 CHEMICAL SOCIETY REVIEWS 1993 Table 1 Some important properties of indium(1) halides M pt/"C DjkJmol lU r(In-X)(g) jAh -AH,OjkJ mol InCl 225 428 2 40 186 InBr 235 385 2 54 175 In1 351 330 2 86 116 R F Barrow ref 4(a) * A H Barrett and M Mandel Pk~sRei 1955 99 666 and refs 4 (b) (c) Values from V V Losev so that InL is the only product recovered from the solution The electrolytic oxidation of indium into solutions of thiols gives InSR In(SR) or In(SR) depending on R indium(1) species are obtained for R = C2H5 or n-C,H and the stabiliz-ing effect of these groups has been discussed in terms of the charge distribution and its effect on the reactivity of the lone pair of electrons * An unusual series of compounds arises from the electrolytic oxidation of indium in solutions of aromatic 1,2-diols R(OH) where the products are of the type In'[O(OH)R] and with aliphatic dithiols R(SH) the similar products are In'[S(SH)R]The reactions of these substances are very similar and are summarized in Scheme I Et,NH[ In'(E,R)] AEt3NH[l2In"'(E2R)] IEhNI... 12In'[E(EH)R] -I,ln"'[E(EH)R] Br4C602oIIn1"[E(EH)R](Br4C602) Scheme 1 A related indium(1) compound has been preparedlo by the reaction of 2,4,6-tris(trifluoromethyl)phenolwith InCp to gihe the dimer (I) in which the two phenyl rings are almost in a plane and perpendicular to the In,O ringThe average In-0 bond distance of 2 320 8 is significantly longer than that in indium(m) complexes It is worth noting that all of the neutral indium(1) speciesdiscussed in this section involve ligands which are known to be either chelating or bridging and it may well be that the acknowledgement that monomeric species will be difficult to prepare is the key to further developments in this area Another novel indium(1)species which also requires a biden-tate ligand can be prepared by direct reaction between equimo-lar quantities of the element and a solution of 3,5-di-t-butyl-172-benzoquinone (dbbq) in refluxing toluene," the product is a solution of the corresponding semiquinone derivative Inl(dbbsq ) whose reactions are outlined in Scheme 2Two important features not normally encountered in Main Group chemistry are the strong colour and the paramagnetic resonance due to the semiquinone Iigand and analysis of the electron spin resonance (ESR) spectrum leads to the hyperfine constant for coupling to 51n(I = 9/2) which is of the order of 9-10 G for In' oxidation to In"' causes this to drop to -5-7 G depending on the ligands present and similar values have been found for other indium(lI1) species (see below)The energetics of the In/ In'(dbbsq*) 12 AH,OlkJ [3InX(s) -,InX,(s) + 21no(s)] 21 96 110 ref 14 * 1,ln(dbbsq> In'(dbbsq')(phen) \ [In'(pc),]+dbbsq' -Ph4PCII Ph4P[In'(dbbsq?(phen)Cl] Scheme 2 Y4a0 + Scheme 3 dbbq reaction are obviously an interesting balance of effects since the analogous reaction between indium and the tetrahalo-geno-o-benzoquinones (Y,C,02-o Y = C1,Br) produces deri-vatives of indium(I1) catecholate formulated as the dimers (In(O,C,Y,)L) (L = 1,10-phenanthroline 4-picoline)The ESR evidence shows the presence of semiquinone species in the reaction media and hence the initial reactions are presumably those shown in Scheme 3 rather than the reaction shown in equation 7 In + dbbq -+ In(dbbsq) (7) Such differencesare in keeping with the known stronger oxidiz-ing power of the Y,C,O,-o compounds relative to dbbq and parallel that found in the reactions of these o-quinones with indium(1) halides (see below)The spectroscopic properties of In(dbbsq) make it attractive for the study of the non-aqueous solution chemistry of indium(1) 2.3 Indium (I) Complexes Much of the chemistry of indium(1) is concerned with its oxidation reactions in which electrons are lost but there are also THE LOWER OXIDATION STATES OF INDIUM-D GTUCK a number of species which show that indium(1) compounds can act as electron pair acceptors these will be briefly treated in the order neutral cationic and anionic Indium(1) halides are reported to form ammine complexes InX nNH (n = 1,2) which disproportionate upon heating to In NH and InX yNH Adducts with aniline and morpholine of the type [InL,]X and [InL,]X (X = Cl,Br,I) have also been identified but in neither study was structural characterization possible ' while adducts of In'(dbbsq) within 1,lO-phenanthro- line were isolated in studies of that compound l1 Solutions of indium(1) halides in mixtures of aromatic solvents and organic bases yield solid adducts of the formula InX 0 Stmen (X = Rr I tmen = N,N,N',N'-tetramethylethanediamine) although this does not appear to be the predominant solution phase species To summarize a small number of adducts with nitrogen bases are known but no structural information is available due in part to the inherent instability of such compounds towards disproportionation which occurs readily and in some cases with explosive violence in the presence of donor ligandsThe calculated enthalpy change for the parent InX/InX systems is positive for X = CI Br or I (Table l) so that the instability of the adducts of InX is presumably enhanced by the enthalpy of complexation of InX As in much of this area of chemistry detailed dnalysis is impossible because of the lack of thermody- namic data but it seems safe to conclude that stable adducts of InX with hard donor ligands will be difficult if not impossible to prepare because of the stability of the corresponding indium(II1) species iind soft ligands may offer a better reward in this context Cationic complexes of indium(1) can be obtained by using In'[In111X4] [X = CI Br I) or similar species as starting mater- ials the structure of these indium(r1) compounds is discussed below (Section 6 I) but for the moment it is sufficient to note the presence of In+ cations in the solid state Prolonged treatment with either 6,7,9,10,17,18,20,21-octahydrodibenzo(h,k]-[ 1,4,7,10,13,I6]hexaoxacyclo-octadecane(dibenzo-18-crown-6) or 1,4,8,11 -tetraazacyclotetradecane (cyclam) yielded [InL)InX (L = crown ether or cyclam X = C1 Br I) and similarly InAlCl gave [InL]AlCIThese are complexes of the In cation stable in the solid state but decomposing in common + organic solvents by loss of ligand and deposition of InX Similar compounds were identified in the Inl(dbbsq ) system where the addition of a large (-100-fold) excess of 4-picoline gave a solution of free dbbsq and a cation presumed to be [In(pic),] + The study of these cationic complexes has been hindered by the absence of starting materials other than In2X4 It seems clear that the stabilization of In + as [InL,] is helped by the suppres- + sion of disproportionation in the case of L = crown ether or cyclam the corresponding indium(Ir1) cationic complex is unlik- ely to be stable and decomposition in fact yields InX and InX L (see below) Given the range of multidentate complexing agents now dvdilable it should be possible to design a system in which the balance of complexation and lattice forces will allow the stabiliziition of salts of crystalline In speciesThe stabilization + of In+ in aromatic solvents is discussed below (Section 2 5 2) Both simple and complex anionic indium(1) derivatives are knownThe treatment of InX with [bpyMe,-4,4']* (X ) gives+ salts of InXi isoelectronic with SnX and formulated as mononuclear C species on the evidence of vibrational spec- troscopyThe related [NEt,][InX,] salts can be prepared by the reaction InCp + NEt,X + HX -+ CpH + [NEt,][InX,] (8) for X = CI Br or I and the iodo species can also be obtained electrochemically Metathesis yields the corresponding [In(NCO),] and [In(NCS),] ,and [In(NCS),I2 -has also been prepared but none of these apparently simple species has been structurally characterized The ease of preparation and the apparent stability is probably aided by the fact that the disproportionation 27 1 3InX -+ InXi-+ 21n0 (9) is hindered by a high energy of activation More complicated anions have also been prepared The complexes I[O(OH)R] and In[S(SH)R] both involve anions with an -OH or -SH group on the ligand and treatment of these with NEt results in proton transfer to give the salts (eg ) [NEt,H]+ [InS,R]-in which the oxidation state of the metal has been confirmed by reaction with IThe coordination number of indium(r) in such anions is not known but it seems unlikely that these are simple mononuclear complexes Another anion is [In(dbbsq )(Cl)phen] stabilized as the PPh; salt and in general it seems likely that a series of anionic complexes with different mono- or bidentate ligands could be prepared as stable molecules so that the full range of accessible structures could be established The question of the stereochemical effect of the 'lone pair' of electrons in indium(1) complexes could then be properly addressed 2.4 Solution Chemistry Given the ready disproportionation of indium(1) compounds in the presence of donor Iigands it is not surprising that there have been few studies of the behaviour of this state in aqueous solutionThe electrochemical aspects of the problem have been discussed by Losev ' Despite the experimental difficulties In+(aq) species have been generated by the in sztu reduction of the metal and the kinetics of their oxidation by Fe"' investi- gated The kinetics of the disproportionation process have been used to derive stability constants for In+/X systems for which X= F logp = 246 c1 log K' = 2 37 Br log K = 1 56 log p2 = 2 11 Not surprisingly these tentative values imply only weak forma- tion of the InX in aqueous media Despite the fact that disproportionation is enhanced by basic ligands indium(1) halides are soluble in mixtures of aromatic solvents and basesThe original studies' involved toluene/tmen mixtures in which InBr and In1 form solutions whose stability against disproportionation depends on the temperature At -20 "C the solubility of InBr also depends on the concentration of tmen reaching a maximum of 15 7 f0 02 mmol dm (3 06 mg cm-,) when [tmen] = 0 15 mol dm The dependence on [tmen] at low concentrations implies that the solution species is InBr 3tmen but addition of light petroleum in this solution precipitated InBr 0 Stmen When the temperature was allowed to rise above O'C disproportionation to 21n0 + InX,L occurred giving products whose nature depended on the properties of the base L The nature of the solute species is unclear other than the obvious fact that coordination (I c solvation) by tmen or other bases is crucial as is the presence of an aromatic as opposed to any other hydrocarbon solvent but the degree of association of the solute has not been established The rich variety of structures that has been identified in com- pounds of(say) lithium with organic bases suggests that it would be unwise to speculate on the basis of stoichiometry aloneThe main advantage of these solutions is that they allow the study of a number of oxidative processes which might otherwise be inaccessible 2.5 Cyclopentadienylindium (I) and Analogues 2 5 1 Preparation and Structural At several points the absence of readily available inorganic indium(1) compounds has been emphasized and the consequent problems have made the existence of cyclopentadienylindium(1) a welcome fact of lifeThis compound was first prepared by Fischer and Hofmann,' in a reaction between InCl and excess NaCp InCp is obtained by sublimation together with trace amounts of InCp Later experiments showed that substituting LiCp for the more reducing NaCp enhances the formation of InCp and the production of InCp in the original reaction may be due to the reduction of InCp Methylcyclopentadienylin-dium(1) was also prepared via In(MeCp) but the indenyl analogue could not be isolated A more convenient synthesis of InCp involves the metathesis of LiCp and InCl in diethyl ether,l and another routel involves the co-condensation of metal vapour and CpH at 77 KThe substance is sensitive to oxygen but unaffected by water InMeCp is much more air-sensitive The chemistry of this fascinating molecule is a direct reflection of its structure although that structure itself raises some chal- lenging questions The structure of crystalline InCp is that of a linear homopolymer with each indium atom lying between two C,H rings on the ring C axis with r(In4entre) = 3 19(10) A This form of packing is in keeping with the substantial dipole moment but an unusual feature is that although the rings are orthogonal to the In-In axis there is an angle of 137 O at centre- In-centre The inter-chain In-In distance is 3 99 A which is long compared to the In-In bond distance of 2 775(2) 8 in In,Br,I 2tmen (see below)The structure of InCp in the gas phase determined by electron diffraction is that of a half- sandwich with C symmetry (r(1n-C) = 2 621(5) 8 and r(C- C) = 1 427(7) A) the hydrogen atoms of the CSH ring are bent away from the metal by 45 O The bonding in this molecule is covalent not ionic and early CNDO calculations provided a description involving the interaction of the p orbitals of the ring-carbon atoms with both a hybrid sp orbital and thep andp orbitals of the metal and also correctly predicted the presence of a large dipole moment (calcd 4 75 D found 2 2 D at 40 "C in toluene) which was identified with the existence of a metal-atom lone pair of electrons perpendicular to the ring Two photoelec- tron spectroscopic investigations' l9 of InCp are in substantial agreement with each other but sophisticated SCF methods20 21 were required to obtain an MO scheme in agreement with the spectroscopic results In this treatment the HOMO is a doubly degenerate MO formed from the ep orbital of C,H andp and pL of InThe lone pair which is an important feature of the chemistry of InC,H is then the next highest orbital involving indium 5s (or 5s + 5p,) interacting with the a ligand n-orbital It is worth emphasizing that either oxidation or complexation (see below) causes a change in hapticity from five to one so that any alteration in the electron density at the metal and especially in the lone pair has concomitant effects on the metal-ligand interactions apparently destroying the n-interactions which are critically important in the q5-bonding mode Our knowledge of the structural behaviour of organoin- dium(1) compounds has recently been considerably enhanced by the work of Beachley and his colleagues,22 who have prepared and structurally characterized crystalline In(C Me,) In(C,H,Me) In(C,,H,SiMe,) and In(C,H,Bu') A related member of this series is In[C,(CH,Ph),] 23 Electron diffraction results have also been reported for In(C,Me,] and In(C,H,Me) The predominant feature is still the half-sandwich structure with the indium situated on a C axis but there are fascinating differences in the ways in which these molecules pack together in the solid stateThe zigzag homopolymeric form of In(C,H,) has been confirmed and this structure is also found for In(C,H,Me) in both cases In-In distances of 3 986(1) 8 are observedThe zigzag infinite chains are also found in In(C,H,- SiMe,) and In(C,H,Bu') but in these cases there are no close In-In contacts Finally In C,(CH,Ph),] is a q~asi-dimer,~~ with In-In contacts of 3 631 s while In(C,Me,) in the solid state forms a hexamer in which indium atoms are at the corners of an octahedron with the C,Me rings on the outside one important detail is that vectors from the centres of the rings through the indium atoms do not point at the centre of the octahedron The main structural features of these molecules have been summar- ized by Beachley 22p In addition to the question of the molecular structure and bonding in these compounds the X-ray results reveal a series of challenging intermolecular arrangements which have prompted CHEMICAL SOCIETY REVIEWS 1993 much discussion Dimer formation has been discussed in terms of In-In interactions involving lone-pair -'p donation 24 A much more detailed analysis of M-M bonding (M = In,TI) has been given by Janiak and Hoffman,25 who emphasize the importance of considering both metal and ligand in solid-state packingTheir treatment leads to a rational explanation of the intermolecular interactions in InCp and its congeners Perhaps the most important theme of this long and important paper is that the structural chemistry of organoindium(1) and related compounds is too subtle to be treated by simplistic arguments Until recently InCp and its derivatives were the only stable organoindium(1) compounds known but Cowley26 has recently reported the synthesis of [(Me,Si),C]In by the metathesis of the lithio compound and InClThe crystal structure unfortunately did not refine but indicates the presence of a tetrameric unit with indium atoms at the corners of a tetrahedron (r(1n-In) -3 0 A 2 5 2 Indium(I) Arene Solvates Organotransition metal chemists have brought order into their work by organizing ligands in terms of the number of electrons which each may contribute to the 18-electron formalism This scheme has not been widely used in Main Group chemistry which is surprising because it can lead to useful rationalizations A case in point is InCp which is an 18-electron system if one counts 4d1° + 4s2 + 5p' + 5(Cp) a simpler and equally useful formalism is the EAN rule 49 + 5 = 54 (Xe) Such an approach emphasizes the bonding relationship between InCp and (say) CpSnC1 and between cyclopentadienyl compounds and arene solvates The solubility of In,X,(and Ga2X,) compounds (see Section 6 1) in aromatic solvents is in sharp contrast to the insolubility in other hydrocarbonsThis has been correctly attributed to the formation of [M(arene),]+ MX solute species and in recent years stable crystalline derivatives have been obtained Given the complexity of the solid state chemistry of the cyclopentadie- nyl derivatives discussed above it is not surprising that there are some challenging problems in this area The only indium(r) compound studied crystallographically is [(1,3,5-Me,C6H,),In]1nBr in which In+ is coordinated by two q6-arene units whose planes are at an angle of 47 3" two bromine atoms from the pseudo-tetrahedral InBr anion are also in the coordination shell Such compounds are only formed with substituted benzenes Similar bis-arene complexes have been reported with Ga,X but here there is also a mono-q6- arene species [(Me,C,)Ga]GaBr in which Gal resides on the six-fold axis of the C ring and this despite the (so far) non- existence of GaICp or derivatives No doubt in this area as with the C5 compounds a complex set of solid state and bonding interactions awaits elucidation 2 5 3The Reactions of Organoindium(r) Compounds While there can be little doubt as to the reality of the structural problems outlined in Section 3 1,there is equally no doubt that the reactions of InCp and of other indium(1) species can be rationally discussed by acknowledging the presence of an avail- able pair of electrons Regardless of whether or not these constitute a stereochemically active lone pair they do behave as a reactive lone pair and this is implicitly accepted in the remainder of this review In addition to the oxidation processes discussed in detail below the lone pair gives InCp Lewis-base properties so that the compound forms adducts with BX (X = F,Cl,Br,Me) and in so doing according to the infrared evidence changes to ql-C,H,In BXThis change is in keeping with the MO schemes discussed above since the donation of electron density results in the destabilization of the M-ring interaction It also follows that other organoindium(1) compounds should have some Lewis- base activity although no direct evidence of this has been reportedThe use of InCp in metathetical reactions was dis- THE LOWER OXIDATION STATES OF INDIUM-D G TUCK cussed earlier and these and other processes are summarized in Scheme 4 -q5-cpln1 0x3 ql-Cpln BX3 Et4NII Scheme 4 Beachley et al have used the acid hydrolysis of In'R species as a means of characterization InR + 3H -,In3 +(aq) + H,(g) + RH (10)+ but in each case the yield of H is ca 95% of theoretical suggesting that the process may go via InR + H+ -+ In+(aq) + RH (1 1) In+(aq)+ 2H,O -,In(OH),(aq) + H+ + H (12) In(OH),(aq) + 3H+ -+ In3+(aq)+ 3H20 (13) in which case there will be a competing disproportionation 3In+(aq) -+ In3+(aq)+ 21n0 (14) which is related to equations I and 9The deposition of indium metal during the hydrolysis is in agreement with this 2.6 Oxidation Reactions of Indium(r) Compounds Not surprisingly a characteristic reaction of indium(1) com- pounds is oxidation to either indium(r1) or (111) The simplest of these is oxidation by iodine (see Schemes 1,2 and 4) to give the corresponding XInI compounds and this reaction produces readily identifiable indium(II1) complexes under the appropriate conditions We should note that in the case of InCp these indium(I1r) species all involve r] -ligation again emphasizing the importance of the available pair ofelectrons in stabilizing the y5-mode of bonding An important class of reactions is that involving oxidative addition of InX to various substrates Despite the view that such reactions lie exclusively in the domain of organo-transition metal chemistry there is ample evidence of oxidative addition (or insertion) with many low oxidation state Main Group inorganic and organometallic compounds (using the term with- out prejudice as to the detailed mechanism of the reaction)The reaction of InBr or In1 with the corresponding RX (R = Me Et n-Bu t-Bu allyl CH,Ph) gives RInX in good yield at rates which depend markedly on the nature of R and X A mechanism which supposes the participation of various indium sub-halides has been proposed but the evidence for this is indirect and research is needed to establish the mechanism since radical species may be invoked (cf o-quinone oxidations below)The reactions are very useful methods for the preparation of organo- indium(II1) halides A related reaction involves the insertion of In' into E-E bonds an early example being the opening of the S-S bonds of the dithiete ring by InX (X = Cl,Br,I) or InCp (Scheme 5) to produce InS,C ring systems with typical indium(II1) coordina- tion chemistry These heterogeneous reactions of InX were later extended' by using InX/toluene/tmen solutions with Ph,S Ph,Se PhCO,O,CPh or Co,(CO) in which case the products were (e g ) XIn(SPh) isolated as adducts with monodentate donors (Scheme 6) although a number of substrates including Ph,P Ph,Pb 2,4-dinitrophenylhydrazine,Mn,(CO) and [(C,H,)Fe(CO),] failed to react under these conditions In related studies Ph,SnX (X = Cl,Br,I) or Ph,SnOAc gave Ph,SnInX tmen (etc ) as the product but again no reaction was detected with Me,SnCl Ph,SnH Ph,GeCl Ph,PbCl or Ph,PCl 28 It is possible to rationalize these results by a model in which the transfer of electrons is accounted for without allowing any inference about the detailed mechanism and which presumes that the substrate must have both donor and acceptor properties Given the significance of one-electron transfer in other oxidation processes with InX it is also possible that a free radical mechanism would equally well explain the results and this is being explored Scheme 5 J Y~I~"I~"(x)Y Xln"'( SR)* R Scheme 6 Two other oxidation reactions lend themselves to explanation via an oxidative addition mechanism When InX (X = Cl,Br,I) is refluxed with pentane-2,4-dione (Hacac) the product is a mix- ture of In(acac) and InX,(acac) the latter being isolated as the adduct InX,(acac)L (L = bpy etc ) Similarly In'[qno = quino-line-8-ato anion) and excess Hqno yielded In(qno) while with Hacac the product was In(qno)(acac)The reactions can be seen as the result of the reactions InL + HL -+ HInL HInL -,H + InL 2InL -+ InL + InL (17) followed by elimination of hydrogen (2H -+ +H2) and the dimer- ization and disproportionation of the resultant indium(i1) spe- cies probably via the mechanism discussed belowThis is in keeping with the zn sztu conversion of electrochemically pro- duced In1 species by similar processes in the presence of excess HL (see Section 2 2) 2.7 General Conclusions It will be clear from the review of the inorganic chemistry coordination chemistry and organometallic chemistry of indium(1) that this is in fact a well-established area of Main Group chemistry and merits something more than the cursory treatment which it normally receives in textbooksThe redox chemistry is an area full of promise both in the scope of the reactions which can be studied and the mechanistic problems which need to be unravelled Much the same comments can be made about the low oxidation state chemistry of a number of the other heavier p-block elements and there is much to be done to understand the details of the structures and reactions involved 3 Indium(l1) Chemistry 3.1 Indium(r1) Halides The structure of the crystalline indium dihalides stoichiometry InX2(X = Cl,Br,I) is a classical problem in Main Group chemistry as is that of the analogous gallium compoundsThe bromide and compounds can be readily obtained by controlled halogenation of the metal by reduction of InX by the metal or by the reaction of InX with InX The chloride is not accessible by these reactions and there is considerable doubt about the very existence of this compound There is a long history to this matter in which phase studies have played a part that has been reviewed elsewhere' 29 as has the question of the other sub- halides such as In,Cl In,X7 and In,Br 25 Since the dihalides are all diamagnetic they cannot be monomers as the In2 + ion must be paramagnetic leading to the postulation of either X,InInX or In'[InlllX,] structures It is important to stress here that simplistic but nevertheless credible arguments show that the M-X bonds in a mononuclear MX molecule should be reasonably strong so that the non-existence of such species must be ascribed to the kinetic reactivity of the unpaired electron rather than to any thermodynamic instability There is a challenging problem in the possible stabilization of a stable complex of monomeric InX in a structure which would minimize this reactivity by appropriate electronic and steric effects For crystalline In214 the structure has been shown by X-ray crystallography to be built up from InI tetrahedra which are organized around the In cation to give eight-fold coordination + of the latter by iodineThe structure of In2Br is apparently similar since Raman spectroscopy establishes the presence of InBr in the solid stateThe solubility of those compounds in aromatic hydrocarbons due to solvation was discussed earlier The apparent non-existence of InCI coupled with the existence of In,CI In,CI and In7C1 can be perhaps understood in the following way Indium(u1) is six-coordinate in crystalline InCI and this appears to be the most stable coordination state with chloride ligands since InC12 -is the most readily formed anionic complex InCI and InCI are only found in salts with large organic cations It is therefore not unreasonable that In1-[InI1'C1,] should not be a stable lattice and that the simplest mixed-oxidation state crystalline solid is In\[Inll'C1,] which is in fact found for In,Cl Similarly In,Cl can be written as Ini[In$llC1,] again containing six-coordinate indium(IrI) while the recently reported In7Cl can be described as a derivative of InCl with In"' appropriately substituted into the lattice As in so many other cases X-ray crystallography has illuminated a formerly murky area of Main Group chemistry A similar clarification of the species present in molten indium dihalides would be equally welcomeThere is in summary no evidence for In-In bonding in any of these halides in the solid state CHEMICAL SOCIETY REVIEWS 1993 3.2 Complexes of Indium(r1) Halides Neutral adducts of In,X can be prepared either by treating the dihalide with a range of neutral donors at low temperatures or by the oxidative insertion of InY into an X,In-X bond in the presence of a donor (18) Anionic derivatives In,Xg -have been obtained by treating In,X with 2R,NX in aromatic solventsThese anions are stable in the solid state but llsIn NMR spectroscopy showed that disproportionation occurs in non-aqueous solution and this process is obviously the inverse of equation 18(1) 1*-x. F,X In + tnI()(;In-tnFX -y 1-x bx xyx X The only structural information on these anions comes from vibrational spectroscopy but the analogous gallium(1r) species are certainly based on M-M bonding and there is no reason to doubt the validity of the proposed structure It has been argued elsewhere3 that the stability of these neutral and anionic In-In bonded molecules depends not so much on the strength or weakness of the In-In bond whose dissociation energy is estimated to be of the order of 85 kJ mol l but rather on the ease of halide transfer between the two metal centres (z e ,the inverse of equation 18(1) or the analogue of equation 20) It follows that while uncoordinated X21n-InX species do not exist in the solid state for X = halide it should be possible to prepare similar molecules if X is a poor leaving group and in keeping with this argument [(Me,Si),CH],InIn[CH(SiMe3)2]2 has been prepared and ~haracterized,~~ the In-In bond distance is 2 828( 1) A and r(1n-C) = 2 19( 1) A and the coordination at indium is almost planar trigonal Similar distances are found in (RF),InIn(R~) (RF = 2,4,6-(CF,),C,H,) for which r(1n-In) = 2 744(2) 8 and r(1n-C)(av) = 2 22 A this latter molecule also shows evidence of intramolecular In-F interactions 33 Stabiliza-tion by adduct formation stabilizes the In-In structure in a similar way since halide transfer is prevented by blocking the metal through coordinative saturation to give the anionic or neutral derivatives noted above One of the latter In,Br,I -2tmen has two five-coordinate indium(I1) centres linked through an In-In bond for which r(In-In) = 2 775(2) 8 34 As with other topics discussed in this review there is no reason to suppose that further In-In species cannot be prepared given careful choice of ligandsThermochemical measurement of the dissociation energy of this bond would be especially welcome We should also note that the chemistry of Sn-Sn bonded Sn2L species shows somewhat analogous behaviour in that the halide species are unstable against disproportionation while the organic compounds are reasonably stable and it may well be that the conclusions about the intramolecular mechanism of dissociation are of general application in Main Group chemistry 4 ElectronTransfer Processes in Indium Chemistry The oxidation of various indium(r) species has been discussed in earlier sections with the general conclusion that these processes could be viewed as addition reactions in which the pair of electrons at indium is transferred THE LOWER OXIDATION STATES OF INDIUM-D GTUCK This equation is parallel to that written for association in the system but the reverse processes the reductive elimination reactions of InX species are unknown (with the possible exception of the thermal decomposition of InCp to InCp) Despite the ready acceptance of equations such as 22 which can be found in every elementary textbook there is essentially no evidence as to the mechanism in the case of Main Group compounds and the assumption that a pair of electrons is transferred in some concerted fashion seems to have been based on the lack of anything better A few years ago in the course of investigating such reactions with indium(1) halides we examined their oxidation by substi- tuted o-quinones and in particular Y4C6O,-o (Y = C1,Br) and 3,5-di-tert-butyl-o-benzoquinone(dbbc) We found the expected formation of the indium(rI1) halide-catecholate complex whose coordination and structural chemistry showed all the established features of an indium(II1) compound Such reactions are in fact common to other low oxidation state complexes of the p-block elements and we have subsequently studied similar reactions withTlX GeX SnX PbX PR SbR andTeR compounds In each case electron spin resonance (ESR) spec- troscopy has shown the formation of an intermediate in which the o-semiquinonate ligand is attached to the central element the ESR spectrum typically contains the characteristic free- radical spectrum with evidence of coupling to the p-block element The indium case was one of the first to be investigated in detail and the reaction pdthway has been explained in terms of indium(1) (II) and (111) species in the solution phaseThe first step in the reaction between InX and a quinone Q is presumed to be a one-electron transfer (cf Scheme 3) InX + Q -,XIn (SQ ) (24) and the subsequent reactions of this indium(r1) diradical species depend essentially on the unpaired electron at indium and not that on the radical-anion ligand so that here as in the corres- ponding SnX,/Q reaction addition of +I2 produces XInI(SQ) Such species would be expected to be thermodynamically stable (see above) and in fact it proved possible to synthesize an indium(lr1)-semiquinone compound by the route DIC where pic = 4-methylpyridineThe molecular structure of this adduct was established by X-ray crystallography and proved to be that of a six-coordinate indium(m) compound with an InO,N,Br kernel and the X-ray results identified the C-0 bond distance in the SQ ligand as 1 28(2)& which is close to the generally accepted value for o-semiquinones The ESR spectrum of the molecule was also in agreement with this formulation and in particular yielded a hyperfine coupling constant Al -6 G significantly lower than that for Inl(SQ )(see Section 2 2) The ESR spectrum of the InX/Q reaction mixture shows that both indium(1) and indium(II1)-semiquinone species are present and while there are some important unresolved details in the explanation of these results the overall scheme is essentially thdt shown in Scheme 7 A key step is the dimerization of the XIn (SQ ) units to give an In-In bonded molecule which disproportionates by the halide transfer process discussed above to give Inl(SQ ) and In"'X,(SQ ) For the most strongly oxidiz- ing Y,C60 -0 these intermediate species cannot be identified and the final products are derivatives of In111(Y4C60,]X 112 12 Q+ In' -(SQ')I?X -(SQ')I n1''(X)I t t (SQ*)Xln"l n"X( SQ.) (SQ')lnl'l(X)IL L(SQ')ln' + (SQ')ln1''X2 -(SO')In1''X2L Scheme 7 It is satisfying to find that these interesting systems can be understood in terms of the known coordination chemistry of indium in each of its oxidation states Furthermore such reactions are apparently typical of the p-block elements -for example the reactions of SnX closely parallel those just described and the Sn-Sn bonded diradical can be identified from the ESR spectrum -and two important questions then arise about the proposed mechanismThe first is why such one- electron processes have not been previously postulated in Main Group redox chemistry and the answer to this is probably that most of the two-electron oxidants used (eg halogen) react so rapidly that the spectroscopic identification of the one-electron intermediate is impossible by present techniquesThe second which follows in part from this concIusion is whether one can identify hitherto unexplored oxidation reactions in which radi- cal intermediates might be involved One possible system which is presently being investigated involves the reaction InX + RX -+ RInX (26) which has been known for several years (see Section 2 6) A possible initial step in a reaction scheme based on one-electron transfer is XIn + R-X-+X,In + R (27) and in fact it has already been suggested from the synthetic work that low oxidation indium species are involvedThese could obviously be formed by and one obvious confirmation of the scheme would be by direct identification of the organic radical R Other reactions in Scheme 6 also offer interesting possibilities for mechanistic investigations 5 Postlude The chemistry of indium exemplifies much that is valid for other Main Group elements- the coordination chemistry of the higher oxidation states still retains from a distance a deceptive air of simplicity while the chemistry of the lower oxidation states is largely unexplored Perhaps the best advice to the prospective researcher is to ignore the generalized and comforting indica- tions found in some textbooks to the effect that this is a tranquil region lacking in challenge and to explore instead the many topics which merit the attention of modern inorganic and organometallic chemists 6 References 1 (a) K Wade and A J Banister in ‘Comprehensive Inorganic Chemistry’ ed A FTrotman-Dickenson Pergamon Press Oxford 1973 vol 1 p 993 (6) A J Carty and D GTuck Prog Znorg Chem 1975,19,245,(c)D G Tuck in ‘Comprehensive Coordina- tion Chemistry’ ed G Wilkinson R D Gillard and J A McCle- verty Pergamon Press Oxford 1987 vol 1 p 153 2 D G Tuck Pure Appl Chem 1983,55 1477 3 D G Tuck in ‘Comprehensive Organometallic Chemistry’ ed G Wilkinson F G A Stone and E W Abel Pergamon Press Oxford 1982 vol 1 p 683 4 (a) R F Barrow Trans Faradaj Soc 1960 56 952 (b) S N Vempati and W E Jones J Mol Spectrosc 1988,119,405,(c) S N Vempati and W E Jones J Mol Spectrosc 1988 127 232 5 R G Edge11 and A F Orchard J Chem Soc FaradatTrans ZZ 1978 1179 6 D G Tuck in ‘Molecular Electrochemistry of Inorganic Bioinorga- nic and Organometallic Compounds’ ed A J L Pombeiro and J A McCleverty Kluwer Dordecht 1993 pp 15 31 7 T A Annan D G Tuck M A Khan and C Peppe Organometal-lrcs 1991 10 21 59 8 J H Green R Kumar N Seudeal and D G Tuck Znorg Chem 1989,28 123 9 (a)H E Mabrouk and D G Tuck Can J Chem 1989,67,746 (6) C Geloso H E Mabrouk and D G Tuck J Chem Soc Dulton Trans 1989 1759 10 M Scholz M Noltemeyer and H W Roesky Angel* Chem Int Ed Engl 1989,28 1383 11 T A Annan D H McConville B R McGarvey A Ozarowski and D G Tuck Znorg Chem 1989,28 1644 12 T A Annan and D G Tuck Can J Chem 1989,67 1807 13 C Peppe D G Tuck and L Victoriano J Chem Soc Dalton Trans 1982 2165 14 V V Losev in ‘Standard Potentials in Aqueous Solution’ ed A J Bard R Parsons and J Jordan Marcel Dekker New York 1985 Chap 9 p 240 15 E 0 Fischer and H P Hofmann Angelt Chem 1957,69,639 16 C Peppe D GTuck and L Victoriano J Chem Soc Dalfon Trans 1981 2592 18 R G Egdell I Fragala and A F Orchard J Electron Specrrosc Relat Phenom 1978 14,467 CHEMICAL SOCIETY REVIEWS 1993 19 S Craddock and J Duncan J Chem Soc Faradat Tians 2 1978. 74 194 20 M Lattman and A H Cowley Inoig Chem 1984,23,241 21 E Canadell 0 Eisenstein and J Rubio Organomerallzc~,1984. 3 759 22 (a)0 T Beachley Jr ,R Blom M R Churchill J Fettinger J C Pazik and L Victoriano J Am Chem Soc 1986 108 4666 (b) 0 T Beachley Jr R Blom M R Churchill K Faegri Jr J C ~ Fettinger J C Pazik and L Victoriano Organomerullrcs 1989 8 346 (c) 0T Beachley Jr J C Pazik T E Glassman M R Churchill J C Fettinger and R Blom Organometallrcs 1988 7 1051 (4 0 T Beachley Jr J F Lees T E Glassman M R Churchill and L A Buttrey Organometallrcs 1990 9 2488 (e) 0 T Beachley Jr J F Lees and R D Rodgers J Oiganomet Chem 1991,418 165 23 H Schumann C Janiak F Gorlitz J Loebel dnd A Dietrich J Organomet Chem 1989 363,243 24 P H M Budzelaar and J Boersmd Reel Trui Chrm Puts-Bas. 1990 109 187 25 C Janiak and R Hoffman J Am Chem Soc . 1990. 112 5924 26 A H Cowley J Coord Chem ,in press 27 (a) J Ebenhoch G Muller J Reide and H Schmidbaur Angeir Chem Inr Ed Engl 1984.23 386 (6)H Schmidbaur R Nowak B Huber. and G Muller Pol Jiedron 1990 9 283 28 T A Annan and D G Tuck J Organomet Chem 1987,325,83 29 M J Taylor ‘Metal-to-metal Bonded States in the Main Group Elements’ Academic Press London 1975 30 H P Beck and D Wilhelm AngeM Chem Znt Ed Engl 1991,30 824 31 D G Tuck Polihedron 1990,9 377 32 W Uhl M Layh and W Hiller J Organometal Chem 1989,368 139 33 R Schluter A H Cowley D A Atwood R A Jones M R Bond and C J Carrano J Am Chem Soc 1993 115,2070 34 M A Khan C Peppe and D G Tuck Can J Chem 1984,62,60 35 (a)T A Annan and D G Tuck Can J Chem 1988,66 2935 (b) T A Annan R K Chadha P Doan D H McConville B R McGarvey A Ozarowski and D G Tuck Inorg Chem 1990,29 3936 36 D G Tuck Coord Chem Ret~ 1992 112,215

ISSN:0306-0012    

DOI:10.1039/CS9932200269

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Interplay of Theory and Experiment in the Determination of Transition -state Structure Ian H. Williams School of Chemistry University of Bath Bath BA2 7AY U.K. 1 Introduction The transition state (TS) is of strategic importance within the field of chemical reactivity. Owing to its location in the region of the highest energy point on the most accessible route between reactants and products (Figure l) it commands both the direction and the rate of chemical change. Questions of selecti- vity (‘Which way is it to the observed product?’) and efficiency (‘How easy is it to get there?’) may be answered by a knowledge of the structure and properties of the TS. There are important practical reasons for investigating the nature of TS structure. Mechanisms-based approaches to drug design are directed towards the synthesis ofTS analogues as inhibitory substrates for enzymes controlling key biochemical processes; this requires knowledge of the TS structure to be mimicked. The design of synthetic catalysts for specific chemical processes is aided by knowledge of the TS structure in order that its structural complement may be constructed; likewise selec- tion of catalytic antibodies requires a hapten adequately mim- icking the TS for the reaction to be catalysed which presupposes a knowledge of the TS structure and properties. +*-TS analogue TS complement as enzyme inhibitor as catalyst Scheme 1 In a sense a TS is not a single physical entity in itself but rather is a collection of species populating a range of energy levels encountered in the vicinity of a saddle point on the potential energy surface (PES) governing transformation of a chemical Ian Williams obtainedhis B.Sc. (1974) andPh.D. (1978) degrees from the University of Shefield under the supervision of James McKenna. Following postdoctoral research with Richard L. Schowen at the University of Kansas he held a Royal Society Pickering Research Fellowship at the University of Cambridge (1980-1985) and a SERC Advanced Fellowship at the University of Bristol (1985- 1989) in the Department of Theoretical Chemistry. He was appointed as Lecturer in Organic Chemistry at the Uni- versity of Bath in 1989 and has been Reader in Physical Organic Chemistry since 1991. His research interests in theor- etical organic chemistry range from atmospheric reactions to enzyme catalysis but focus upon the role of the transition state in reactivity. ’R I I I I Figure 1 Saddle-shaped potential energy surface in the region of a transition state $. A vertical cut through the surface in (b) along the minimum energy path interconnecting reactants (R) and products (P) gives the potential energy profile (a). Horizontal cuts through the surface give the energy contours (c). system from reactants to products.The actual saddle point is associated with a particular molecular entity with a definite structure. Commonly the term ‘transition state’ is used ambi- guously to refer both to the quasi-thermodynamic state of the reacting system and to the molecular structure at the saddle point.This colloquial usage is perhaps not merely the result of muddled thinking but reflects a deeper ambiguity between different concepts of what is meant by the term ‘transition state’ deriving either from an experimental or from a theoretical viewpoint. In order to refer specifically to the molecular entity at the saddle point it may be useful to speak of either the activated complex or the transition structure (see below). By its very nature theTS is elusive to direct experimental study. Recently it has become possible using sophisticated spectroscopic techniques to study the structure and dynamics of molecular systems as they pass through the TS region between reactants and products for some simple gas-phase processes. Zewai12 has described laser experiments capable of probing the dynamics of elementary reactions on the femtosecond (10-l s)timescale and Moore3 has recently reported evidence for the energy levels of theTS for dissociation of ketene these are indeed direct observations of TSs in the sense of activated complexes. However the study of TSs for ordinary organic reactions in solution is still obliged to be via indirect methods 277 such as kinetic isotope effects (KIEs) and structure-reactivity correlations The interpretation of these kinetic data in terms of TS structure is as yet far from straightforward The purpose of this brief review is not only to sketch the outlines of the theoretical and empirical concepts ofTS structure and to signal some of the problems raised by each approach but also to lay down a few pointers as to how computation and experiment may interact in a complementary way in the elucidation of TS structure 2 Early ideas The essential notion that properties of the saddle point region of a PES hold the key to fundamental understanding of reaction kinetics is due to Eyring and Polanyi who showed that the heat of activation for a simple triatomic reaction (eg H +H,) could be identified with the height of the saddle point The term ‘transition state’ was introduced by Polanyi and Evans5 in papers which included discussion of the mechanism of displace- ment reactions X- +RY +XR +Y -At this stage it was clear that a reaction rate constant k could be regarded as the product of some generalized rate constant k (roughly independent of temperature and the nature of the medium or the structure of the reactants) and a quantity K*with most of the properties of an equilibrium constant for formation of theTS from the reactants The significant step forward was made by Eyring who proposed that kf = kT/hand that K*for the TS should be evaluated using partition functions lacking a factor for motion along the reac- tion coordinate Thus the TS was from the start an essentially theoretical concept and the question of TS structure was a problem for quantum-mechanical theory Right from the outset the scope of the TS theory was greater than the ability of practitioners to produce reliable PESs and to characterizeTS structures the quantitative inadequacies of the methods available at that time were fully apparent to those involved in the development of the TS theory Nonetheless the idea of a TS structure whose properties were responsible for (and in some way could be related to) the observed kinetic behaviour of organic reactions in solution was immediately appealing Ingold first referred to a TS in 1936,’ and the next year his classic papers on the mechanism of Walden inversion contained the following statement “inver- sion of configuration is presumed to be the rule for bimolecular substitutions (SN2 and SE2) primarily because the transition state (l) which leads to inversion will have a smaller energy ”than that (2) which corresponds to retention X Y The idea of theTS had captured the imagination of experi- mental chemists and was already proving to be a very useful means of explaining details of reaction mechanisms Indeed it was not long before the issue of finding the mechanism for an organic reaction became essentially a matter of defining the TS (or TSs) occurring along the path between reactants and products At the Faraday Society Discussion9 on ‘Reaction Kinetics’ in 1937 Hinshelwood observed that there were two completely different approaches to the topic mathematical and empirical and Moelwyn-Hughes pointed out that the former approach (TS theory) was seriously limited by the fact that chemists were interested in systems for which partition functions were not available In response Polanyi remarked that precise numerical agreement between theory and experiment was of less signifi- cance than the insight given into chemical reaction mechanisms CHEMICAL SOCIETY REVIEWS 1993 and Hammett commented that it was most important “to distinguish the very valuable qualitative and conceptual accom- plishments of these new theories from the quantitative ”inadequacies which they may still possess 3Theoretical Approaches The problem of determining TS structure by theoretical calcula- tions divides into two parts first how to construct a reliable PES to describe a particular chemical reaction second how to locate and characterize a saddle point on a multidimensional PES In regard to the former suffice it to say here that the original semi- empirical valence-bond approach of Eyring and Polanyi4 was superseded by developments occurring in several different direc- tions ab znztzo wavefunctions of increasing sophistication a totally empirical approach in the form of the bond-energy/bond- order (BEBO) method O and semi-empirical molecular-orbital (MO) theories Early explorations of PESs employed either exhaustive point-by-point searches in multidimensional space -an approach doomed to futility -or else techniques based only upon energy minimization A breakthrough came with the publication by McIver and Komornicki” of a method for locating saddle points on surfaces by minimization of the gradient normThese authors not only reported a calculatedTS structure for the electrocyclic ring-opening of cyclobutene to butadiene (Figure 2) but they also clearly stated the criteria which any proposed theoretical TS structure must satisfy it must be a stationary point on the PES with zero gradient its matrix of force constants must have one and only one negative eigenvalue corresponding to the lack of a restoring force along the reaction coordinate it must be the highest energy point on a continuous line connecting reactants and products and it must be the lowest such point satisfying these conditions Milestones in the applications of ab rnrtio MO theory were the development of analytical methods for evaluation of the first and second derivatives of the energy a variety of efficient algorithms are now available for saddle-point searches thus providing a range of powerful tools for studies of reactivity An excellent example of what may currently be achieved by means of theoretical approaches is provided by Houk’s recent review ofTS structures for hydrocarbon pericyclic reactions Although there is now extremely good agreement between ab inrtio theory and experiment for the kinetics of the prototypi- cal reaction H +H it is still exceedingly difficult to calculate the barrier height for even F +H to within ‘chemical accuracy’ (-4 kJ mol l) of the experimental value and the TS structure for this particular reaction is quite sensitive to subtle refinements of the wavefunction l4 Of course in the absence of structural data from experiment it is difficult to judge whether a predicted TS structure is correct or not’ Nonetheless theoretical studies have now been carried out upon a great number of chemical reactions and in general it has been found that as increasingly sophisticated (and expensive) methods are used convergence of molecular geometry with respect to method is obtained con- Figure 2 CalculatedTS structure for electrolytic ring-opening of cyclo- butene to butadiene the arrows represent relative motions of the atoms in the reaction-coordinate vibrational mode (Adapted with permission from ref 11 Copyright 1972 American Chemical Society ) TRANSITION STATE STRUCTURE INTERPLAY OFTHEORY AND EXPERIMENT-I siderably more readily -even for a TS -than is convergence of the calculated barrier height The molecular geometry corresponding to a saddle point on a PES is often referred to by computational chemists as a transz-tzon structure (cf reference 12)in order to distinguish it from the geometry corresponding to the maximum along the free-energy profile for an elementary step which is the TS In many cases these two geometries may not be sensibly different A theoretical evaluation of an activation barrier must however take account of the contributions to AG* from sources other than the poten- tial-energy difference de* these include differences in zero- point energy thermal energy the pressure-volume term and entropy It is easy to compute these additional terms for a particular temperature and standard state at least within the ideal-gas rigid-rotor harmonic-oscillator appro~imation,'~ H WILLIAMS provided that the second derivatives of the energy are obtained However there are probably also many cases where the geo- metry at the maximurn along the free-energy profile is signifi- cantly different from that at the saddle point in other words the TS structure is temperature dependent Doubleday et a1 l7 have reported an example in the radical-radical disproportionatlon (equation 1) At the saddle point on the PES for this reaction H + CH,CH -+H + CH2=CH2 (1) LheC2H moiety resembles the ethyl radical (I e the transitron structure is reactant-like) but at the maximum on the free-energy profile for high temperatures (> ca 900 K) this group more closely resembles ethene (Ee theTS structure is product-like) Since the products are appreciably 'tighter' than the reactants there is a decrease in entropy along the reaction coordinate once the transition structure has been passed the potential energy falls but the free energy may continue to rise to a maximum (Figure 3) In general theTS structure shifts in the direction of lower entropy as the temperature is raised Improved agreement between calculated and observed reaction rate constants is obtained by using varratzonalTS theory,ls in which the reaction 'bottleneck' is associated not with the PES saddle point (as in conventional TS theory) but rather with the free-energy maxi- mum along the reaction path It has been suggested that for reactions with low or flat barriers (A€* < ca 5kT) no claimedTS structure should be believed unless it has been obtained by a variational search 4 Empirical Approaches It may be coincidental that the very issue of Chemical Reviews which contained Eyring's seminal paper on TS theory6 also contained an article by Hammett on rate-equilibrium relation- ships,19 but the link between these two topics was recognized immediately the existence of linear free-energy relationships implying the complete interchangeability of equilibrium and rate constants was taken to be one of the simplest and strongest supports of TS theory On the basis of simple energy profiles it was noted moreover that the more thermodynamically favoured a member of a family of related reactions is the faster it should proceed and the earlier itsTS should occur along the reaction coordinate conversely a thermodynamically un-favourable reaction would be slower and its TS would occur later (cf Hammond's postulatez0) LeHer proposed that the slope of a linear correlation between log k and log K (I e of dG* vs AG,,,) could be identified as a parameter measuring the degree of resemblance of the TS to the products as compared with its resemblance to the reagents 21 Thus a slope ,8 e 0 for a Brernsted correlation (Act= PdG,,,) would indicate a reactant- like TS in which essentially no proton transfer had occurred from the acid to the base 6 zz 1 would indicate a product-likeTS in which proton transfer was essentially complete and ,8 z 0 5 would indicate a TS in which the proton was about half transferred In this way the value of the rateeequilibrium coefficient came to be interpreted as a qualitative measure of TS structure 300 K "W-FTOKPotential energy 1 I I I 1 16 15 14 13 12 H H*/A Figure 3 (a) Free energy curves (1 M standard state) for the reaction in equation 1 at various temperatures each curve is separately refer-enced to the free energy of reactants at the given temperature (b) Molecular structure at the saddle point [indicated by dotted line in (a)] (c) Molecular structure at H,H = 1 2 8 [indicdted by dashed line in (a)] near to free-energy maximum for temperatures > 900 K (d) Schematic contour map showing free-energy bottleneck ( W ) between saddle point (0)and products at temperatures > 900 K (Adapted in part with permission from ref 17 Copyright 1985 Ameri- can Chemical Society ) A problem with many structure-reactivity correlations -in which the effect of a substituent upon the rate of reaction is compared with its effect upon the equilibrium of either the same or some standard reaction -is that the substituent may not merely perturb the energetics of the PESfor the reaction but may significantly alter the shape of the PES In this case what was intended as a probe forTS structure may actually change the mechanism the act of observation affects the object in such a way as to render its original state inscrutable A KIE may be regarded as the most subtle form of substituent effect in that it arises by substitution only of neutrons which (within the Born- Oppenheimer approximation) do not affect the PES in any way the observed effect upon the rate arises solely from the difference in the non-potential-energy term d(G -c)* due to the presence of a heavier isotope It is often attempted to relate the magnitude of primary hydrogen KIEs in a family of reactions to the extent of hydrogen transfer in theTS 22 Variation in TS structure from asymmetric and reactant-like through symmetric to asymmet- ric and product-like is accompanied first by an increase and then by a decrease in the magnitude of the primary KIE as the transferring hydrogen isotope moves between the donor and acceptor.23 Secondary hydrogen KIEs are also commonly employed as probes ofTS structure; their magnitudes are often assumed to range approximately from unity for a very reactant- like TS to some extreme value -approaching the equilibrium isotope effect which may be either less than or greater than unity -for a very product-like TS and thus to provide a measure of progress along the reaction c~ordinate.~~ 5 Bridge- buildi ng Exercises 5.1 Rate-Equilibrium Correlations The use of slopes derived from structure-reactivity correlations (particularly Brransted p and Hammett p) as measures of TS structure has come under severe criticism in recent years but has also been thoughtfully defended with appropriate cautionary notes.26 It has long been recognized that there is a fundamental incompatibility within the body of ideas which have sprung from the fount ofTS theory if the slope of a linear rate-equilibrium relationship is interpreted as some index of TS structure it must reflect some constant property of the TS for the entire family of reactions used to construct the correlation; however the Leffler principle,2 Hammond postulate,20 and related notions2' all suggest that changing the reaction energetics should cause variation in TS structure within this same family. Modern computational chemistry offers a means by which this paradox may be resolved. For a particular reaction of a series of substituted compounds the energetics and geometries of reac- tantsTSs and products may be obtained from calculated PESs. Rate-equilibrium relationships may be constructed from plots of calculated AGt vs. AGS, (or AHi vs. AH,,,) values. The merit of this approach is that the TS structure deduced indirectly from the slopes of these plots may be compared with those deter- mined directly. An initial attempt to realize this goal in an ab initio self-consistent field (SCF) theoretical study of addition of neutral protic nucleophiles to carbonyl compounds was unsuc- cessful for good reason.2s The TS for addition with concerted proton transfer (equation 2) contains a four-membered ring a structural feature not present in either the reactants or product theTS is not structurally intermediate between reactants and products and thus its properties are not modelled by any combination of their properties in the manner assumed by Leffler.2 (X = CN CI H Me NMe,; IQ = isoquinoline) The variation in TS structure resulting from the polar effect of a remote substituent has been simulated theoretically for the addition of a range of 4-substituted pyridines to N-methoxycar- bony1 isoquinolinium (equation 3) by using the semi-empirical AM1 MO method.29 Each nucleophile -and the nucleofuge -was satisfactorily mimicked by an ammonia molecule whose gas-phase basicity was modulated by a suitably located dipole to reproduce the experimental proton affinity relative to ammo-nia of a particular substituted pyridine. A plot of calculated -AHz vs. -AH, values revealed a very good linear correla- tion despite being constructed from data forTSs of variable structure! The slope of this correlation might be interpreted as a measure of either the bond order BNC of the making bond between the nucleophile and the acyl carbon or of the develop- ing charge q on the nucleophile (0 for reactants + 1 for the tetrahedral adduct). Figure 4a shows how the normalized values (change between reactants and TS divided by change between reactants and adduct) of these important structural variables CHEMICAL SOCIETY REVIEWS. 1993 vary with AH,,, the more basic the nucleophile the more reactant-like is the TS in accord with the Hammond postulate. If a linear rate-equilibrium relationship is not after all incom- patible with the Hammond postulate its constant slope /3 cannot be interpreted simply as a measure ofTS structure. A similar theoretical approach has recently been taken30 to simulate the elementary steps of proton transfer and methyl transfer between reactant and product encounter complexes. A curved Brernsted correlation is found for proton transfer (equa- tion 4 R = H) the slope of which at any given point being similar in magnitude to the value of either the normalized bond order BNH(for the making bond between the base and the transferring proton) or the normalized charge q on the basic moiety (Figure 4b). In contrast a linear rateeequilibrium corre- lation is obtained for methyl transfer (equation 4 R = CH,) the slope of which does not agree with the varying indices ofTS structure BNcand q (Figure 4c). These two reacting systems differ significantly in the magnitudes of their intrinsic barriers (the value of AHt at AH, = 0) a very low value (-5 kJ mol- l) for proton transfer -for which p does provide an approximate :Is0.4 Om2t AH, / kJ mol-1 1 I 1 I I -60 -40 -20 0 1.0 r AHnn / kJ mol-1 I I I I I 1 I -15 -10 -5 0 5 10 15 AH / kJ mol-1 I I I I IJ I -60 -40 -20 0 20 40 60 Figure 4 AM 1calculated rate-equilibrium coefficient fl (B),normalized change in bond order for making bond to nucleophile or base (A),and normalized change in charge on nucleophile or base (0)as a function of heat of reaction for (a) nucleophilic addition (equation 3) of substituted pyridines to methoxycarbonyl isoquinolinium (b) proton transfer (equation 4,R = H) between substituted pyridines and (c) methyl transfer (equation 4,R = CH,) between substituted pyridines. TRANSITION STATE STRUCTURE INTERPLAY OFTHEORY AND EXPERIMENT-I H WILLIAMS 28 1 measure of TS structure -and a rather high value (-152 J mol-l) for methyl transfer -for which p does not measure TS structure The sign and magnitude of the slope p of a Hammett correla- tion between log k and the substituent constant o are used widely as a diagnostic tool for the determination of reaction mechanism in a completely empirical fashion but a question arises whether p also provides a measure of charge development in theTS McLennan has argued that this may be the case provided that raw p values are corrected for variation in the efficiency of transmission of charge from a reacting centre in a molecule to a substituent group 31 According to this view a small value of p for a Michael addition (equation 5) as determined by an aryl substituent at the a-carbon would be interpreted as indicating an early TS with little charge development at C a large value for p would on the other hand indicate a late TS with substantial charge development at C Hoz~~has recently challenged this traditional interpretation in the light of 3C chemical shift correlations and a qualitative valence-bond curve-crossing analysis of the Michael addition process by proposing that a large p signifies an earlyTS and vzce versa He argues that an early TS for this reaction (equation 5) has diradical character (not present in either reactants or product) with an electron occupying a delocalized MO such that the C substituent readily senses the build up of electronic charge in contrast a late TS resembles the Michael adduct in which the negative charge at C is not readily transmitted to the substituent at C There is scope here for a careful theoretical study to examine these suggestions It is of importance to know not only the nature of the TS structure itself but also the manner in which TS structure changes in response to changes within the reacting system and its environment e g substituent and solvent effects changes in either acidi t y/ basici ty or nucleophilici t y/electrophilici ty of reacting moieties Physical organic chemists have developed empirical methods for rationalization of observed trends as determined by experimental probes forTS structure including structure-reactivity correlations and kinetic isotope effects and have adopted these methods for predictive purposes *' Of particular popular use has been the empirical construct some- times known as the Albery-More O'Ferrall-Jencks (AMJ) diagram 33 this is a two-dimensional 'map of alternative routes' with an implied third dimension of energy assumed to have the form of a saddle thus representing the TS region of a PES for a reacting system A change in say the acidity of a catalytic proton-donor group causes changes in the relative energies of one or more corners or edges of the diagram the consequences forTS structure are deduced by consideration of the resultant of effects parallel and perpendicular to the reaction coordinate Figure 5a shows an AMJ diagram describing the hydride transfer and hydron transfer components of the concerted reduction of a carbonyl to an alcohol (equation 6) in which the hydride donor is dihydropyridine (HPy H) and the hydron donor is imidazolium cation (Im+) It is of interest to enquire how the TS structure for this reaction varies as the base strength of the Im moiety is increased This change stabilizes HIm+ and so lowers the energy of the whole left-hand side of the AMJ diagramThe Hammond (parallel) effect of this change in exoergicity along A? HN~CHH-F-O-H N*NH -H w the reaction coordinate is to shift the TS towards the top-right corner and the anti-Hammond (perpendicular) effect is to shift the TS towards the top-left corner since the energy of the +unfavourable (HPy CH,O -HIm +) intermediate is reduced The resultant of these component shifts leads to the prediction that increasing basicity of Im should cause a significant increase in the degree of hydride transfer in the TS with very little change in the degree of hydron transfer Systematic modification of the gas-phase basicity of the Im group does indeed cause the AM 1-calculated TS structure (Figure 5b) to vary in this manner the transferring hydride moves from an early to a more central location between HPy and CH,O whereas the position of the transferring hydron remains unaltered 34This computational result serves to validate the use of AMJ diagrams as empirical tools for predictions of TS structural changes 5.2 Kinetic Isotope Effects Substitution of the transferring proton in the above reaction (equation 6) by a deuteron results in little change in the AM1 calculated value for the semi-classical primary kinetic isotope H resultant change in TS structure1 hydron 9 dihydropyridtne"-.-. :1 73A I Q il'l / 1 I reoction Coordinate I vibrational mode / d imidazole 24 22 20 18 16 950 1000 Proton affinity/kJ mol-' Figure 5 (a) Albery -More O'Ferrall -Jencks diagram for concerted reduction of carbonyl to alcohol (equation 6),showing location ofTS and predicted change in structure in response to increase in basicity of imidazole (b) AM1 calculated TS structure for reaction (equation 6) (c) AM 1 calculated semi-classical primary deuterium kinetic isotope effects for hydron transfer and hydride transfer in this reaction as a function of imidazole base strength Points on the left of the diagram correspond to unsubstituted imidazole CHEMICAL SOCIETY REVIEWS I993 effect kH/kD [‘hydron (ME),’] as the proton affinity of Im is raised consistent with little or no structural change in this component of the reaction; however substitution of the trans- ferring protide by deuteride results in a steady increase in the calculated value for kH/kD[‘hydride (KIE),’] with increasing basicity in accord with a structural change from an asymmetric to a more nearly symmetricTS for the hydride transfer compo- nent (Figure 5c).34 A recent experimental study of general-acid- catalysis of the reduction of p-benzoquinone by an NADH analogue suggests a single TS for concerted hydride and hydron transfer and also shows some evidence that the magnitude of the substrate (hydride) kinetic isotope effect increases with pK within a family of related catalysts.35 Schowen has pioneered a method for obtaining semi-quanti- tative relative structural information about a series of TSs by a combination of experimental kinetic isotope effect measure- ments with theoretical modelling of isotope effects based upon the BEBO approach.The initial ap~lication~~ was to methyl transfer from sulfur to oxygen and the TS structures were characterized in terms of Pauling bond orders Bco and Bcs for the making and breaking bonds; all other structural features of the TSs were related to these two parameters by means of various assumptions. For a particular isotope effect (eg. k(CH,)/k(CD,)) the predicted effects as a function of Bco and Bcs form a surface which may be projected as a contour map of constant isotope effects upon which may then be traced a figure representing the experimental isotope effect together with its estimated error (Figure 6a). To the extent that the calculational procedure is reliable such a figure contains the space ofTS structures ‘allowed’ by the experimental measurement. Super- imposition of similar maps constructed for other isotope effects (e.g. k(12CH3)/k(13CH3),Figure 6b) then leads to a reduced space of ‘allowed’ TS structures simultaneously consistent with all the experimental isotope effects (Figure 6c). Comparison of the ‘allowed’ structures for enzymic and non-enzymic methyl transfers led Schowen and co-workers to conclude that the making and breaking CO and CS bonds are shorter in the TS for the former than for the latter and to suggest that the methyl transferase enzyme exerts compression upon the TS in order to Figure 6 (a) Map of kinetic isotope effects k(CH,)jk(CD,) for methyl transfer between sulfur and oxygen calculated using BEBO approach as a function of bond orders B and Bcs to nucleophile and leaving group. (b) Similar map of calculated kinetic isotope effects k(’2CH,)/ kCH,). (c) Superposition of (a) and (b) showing spaces of ‘allowed’TS structures for non-enzymic (dark shading) and enzymic (light shad- ing) methyl transfer; the limits of these spaces are set by the experi- mental kinetic isotope effects for reaction of methoxide with a methyl sulfonium salt (k(CH,/k(CD,) = 0.97 f0.02 k(12CH,/k(’3CH,) f 1.080 = 0.012) and reaction of 3,4-dihydroxyacetophenone with S-adenosylmethionine catalysed by catechol 0-methyl transferase [k(CH,)/k(CD,) = 0.83 f 0.05 k(’2CH3)/k(’3CH3)* 1.09 sk 0.021. (Adapted with permission from ref. 36. Copyright 1982 American Chemical Society.) 0.0 0.0 Bcs Bcs 4 & 0.5 0.5 1.o 1.o0.5 1.o 0.0 BCO + Bco -(a) achieve catalysis.36 Independent theoretical support for this hypothesis was obtained from ab initio SCF calculations upon mechanically compressed and uncompressedTSs for methyl tran~fer.~’ Murray has recently used the isotopic mapping method to characterize the TS for general-base-catalysed addition of alco- hols to a~etaldehyde,~~ here the maps were constructed as functions of bond orders Bco and BOH for the making bonds between the nucleophile and the carbonyl group and between the catalyst and hydroxylic proton respectively. It was con- cluded that a reaction coordinate with essentially equal contri- butions of proton and heavy-atom motion was most consistent with the experimental solvent deuterium kinetic isotope effects for additions of different alcohols. The use of KIEs as probes ofTS structure is most convincing when multiple isotopic substitutions are performed as in Sin- nott’s studies of acid-catalysed hydrolysis of methyl a-and @-glucopyranosides (3) where seven different KIEs were mea- ~ured.~~There may be several possible TS structures (modelled using say the BEBO approach) which are consistent with experimental KIEs for substitution at only one or two positions but agreement with multiple KIEs provides a much more stringent test for any proposed TS structure. In Sinnott’s work theory was used to assist experimental interpretation in another way by providing estimates for equilibrium isotope effects which were not easily accessible to experiment.Thus ab initio SCF MO equilibrium isotope effects calculated for models of glucosyl cation formation were used to calibrate the experimen- tal KIEs in order to determine the degree of oxocarbonium ion character in the TS. (3) 6 Theory as an Aid to Experimental Interpretation Theory and experiment are sometimes viewed as opposites and computational chemistry is sometimes portrayed as an alterna- tive to experiment. Although it is necessary to perform definitive calculations upon benchmark systems to demonstrate the accur- acy of theoretical methods this competitive mode of operation should perhaps be regarded as the exception rather than the rule. 0.0 Bcs 4 0.5 1.o 0.5 1.o 0.0 Bco - 0.5 1.o (b1 (c1 TRANSITION STATE STRUCTURE INTERPLAY OFTHEORY AND EXPERIMENT-I H WILLIAMS Besides the enormous value of theory for generating insight into chemical phenomena not least in the area of reactivity there is a vital role for theory as a tool complementary with experiment a co-operative mode in which the aim is not so much to provide an answer in place of performing an experiment but rather to provide a sound framework within which experimental results may be interpreted reliably and new experiments suggested The TS remains an elusive entity for most chemical reactions of interest in condensed media While there is considerable progress in theoretical techniques for describing solvated systems and enzymic reactions these methods alone are unlikely to solve all the problems However theory and experiment working together offer an exceedingly powerful combination 7 New Horizons Computational molecular modelling has developed over the past fifteen years or so into a powerful tool for the study of chemical behaviour complementary with experimental meth- ods Most of the activity in this area may be characterized as exploration of valley bottoms on energy surfaces governing chemical equilibria for example molecular modelling in the pharmaceuticals industry has mainly focused on determination of conformation and binding properties of drug molecules with receptors In contrast questions of reactivity -the making and breaking of chemical bonds -require study of the mountain passes on these energy surfacesTwo adjacent energy minima on a surface are separated by just one saddle point but a little thought shows that a surface containing multiple minima is likely to possess at least as many saddle points a rectangular egg-carton containing six holes for example has seven saddle points separating adjacent pairs of minimaTo the extent that molecular modelling has hitherto tended to concentrate upon equilibrium properties of molecules in valley bottoms it has neglected a good half of chemistry I e the top half where all the mountain passes are to be found’ The current importance of such issues as stereospecific synthesis and catalysis where rational design requires the use of computational modelling to assist experimental endeavour makes it imperative to turn the spotlight upon modelling of transition states Many exciting developments are in prospect upon this horizon 5 References 1 Structure and Dynamics of ReactiveTransition States’ Faradaj Discuss Chem Soc 91 1991 2 A H Zewail Science 1988 242 1645 3 E R Lovejoy S K Kim andC B Moore Science 1992,256,1541 4 H Eyring and M Polanyi Z physik Chem B 1931,12,279 5 R A Ogg and M Polanyi Trans Faraday SOC ,1935,31,604 M G Evans and M Polanyi Trans Faraday Soc 1935,31 875 6 H Eyring J Chem Phys 1935,3 107 Chem Rev 1935 17 65 7 E D Hughes C K Ingold and U G Shapiro,J Chem Sue 1936 225 8 W A Cowdrey E D Hughes C K Ingold S Masterman and A D Scott J Chem Soc 1937 1252 9Trans Faraday SOC 1938,34 pp 1-268 10 H L Johnston Adv Chem Phyy 1961,3 131 11 J W McIver and A Komornicki J Am Chem SOC 1972,94,2625 2 K N Houk,Y Li,and J D Evanseck Angew Chem Int Ed Engl 1992,31,682 3 J V Michael J R Fisher J M Bowman and Q Sun Science 1990 249,269 4 H F Schaefer J Phys Chem ,1985,89,5336 R J Bartlett J Phis Chem 1989,939 1697 5 C D Chalk B G Hutley J McKenna L B Sims dnd I H Williams J Am Chem Soc 1981 103. 260 I H Williams D Spangler,D A Femec,G M Maggiora,andR L Schowen J Am Chem SOC 1983 105 31 16 M C Flanigan A Komornicki and J W McIver in Modern Theoretical Chemistry vol 8 Semiempirical Methods of Electronic StructureTheory Part B Applications’ ed G A Segal Plenum Press New York 1977 p 1 17 C Doubleday J McIver M Page and T Zielinski J Am Chem Soc 1985 107,5800 18 D G Truhlar Ace Chem Res 1980 13 440 D G Truhlar and M S Gordon Science 1990,249,491 19 L P Hammett Chem Rev 1935,17 125 20 G S Hammond J Am Chem Soc 1955,77 334 21 J E Leffler Science 1953,117 340 J E Leffler and E Grunwdld ‘Rates and Equilibria of Organic Reactions’ Wiley New York 1963 22 J P Klinman in ‘Transition States of Biochemical Processes’ ed R D Gandour and R L Schowen Plenum New York 1978 p 165 23 R A More O’Ferrall in ‘Proton-Transfer Reactions’ ed E F Caldin and V Gold Chapman and Hall London 1975 p 201 24 I M Kovach J P Elrod and R L Schowen J Am Chem Soc 1980 102 7530 25 A Pross and S Shaik Nouv J Chim 1989,13,427 26 W P Jencks Bull SOC Chim Fr 1988 218 27 E KThornton and E R Thornton in ‘Transition States of Biochemical Processes’ ed R D Gandour and R L Schowen Plenum New York 1978 p 3 W P Jencks Chem Rev 1985,85 51 1 28 I H Williams D Spangler G M Maggiora and R L Schowen J Am Chem Soc 1985 107 7717 29 I H Williams Bull Soc Chim Fr 1988,192 R B Hammond and I H Williams J Chem SOC Perkin Trans 2 1989 59 30 I H Williams and P A Austin (manuscript submitted to J Am Chem Soc) 3 I D J McLennan Tetrahedron 1978,34,2331 32 S Hoz Acta Chem Scand 1992 46 503 Z Gross and S Hoz Tetrahedron Lett 199 1,32,5 163 Can J Chem 1992,70 1022 33 W J Albery Prog React Kinet ,1967,4,353 R A More O’Ferrall J Chem SOCB 1970,274 W P Jencks Chem Rev 1972,72,705 34 J Wilkie and I H Williams J Am Chem Sue 1992 114 5423 35 C A Coleman J G Rose and C J Murray J Am Chem Soc 1992 114,9755 36 J Rodgers D A Femec and R L Schowen J Am Chem Soc 1982 104 3263 37 I H Williams J Am Chem SOC 1984 106,7206 38 C J Murray and T Webb J Am Chem SOC,1991 113 1684 39 A J Bennett and M L Sinnott J Am Chem Soc ,1986,108,7287

ISSN:0306-0012    

DOI:10.1039/CS9932200277

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Thermodynamics of Solvation in Mixed Solvents W. Earle Waghorne Department of Chemistry University College Dublin Belfield Dublin 4 Ireland In the development of chemical processes chemists have tradi- tionally made use of a wide range of solvents; however it is often startling to realize just how profound the effect of changes in solvent can be on chemical systems. Figure 1 which shows the variation in the equilibrium constant for the simple dispropor- tionation of cuprous ions (reaction El) as a function of solvent composition in aqueous acetonitrile mixtures provides one illustration of this. Thus in water the text book disproportionation reaction occurs but on transferring the reaction to acetonitrile there is a change in the equilibrium constant of some 26 powers of ten (lo6 to 10-20); moreover this change is a markedly non-linear function of solvent composition with a change of twelve orders of magnitude occurring between pure water and an acetonitrile mole fraction of 0.05. Confronted by results such as this it is only natural to ask how the replacement of one clear colourless liquid by another can cause such a dramatic change in the chemistry of simple reac- tions. It is also obvious that the ability to predict such changes in chemical reactivity would be of considerable importance in the optimization of chemical processes. In the early 1970s the available quantitative solvation theories simply could not account for such effects.There were however a number of important qualitative observations. Among these were Parker’s2 demonstration that poor anion solvation resulted in the marked increases in the rates of nucleophilic reactions in aprotic solvents Reichardt’s3 and Gutmann’s4 work showing that the solvation could be correlated with parameters which gave a measure of the solvent’s acidity or basicity and Strehlow’s5 studies showing the existence of prefer- ential solvation in mixed solvent systems. All of this work pointed to the dominance of solute to near neighbour solvent molecule interactions in determining the chemical changes which result from changes in solvent. Simply if these interactions were strong the solute would be well solvated while it was poorly solvated (and hence more reactive) if they were weak. In mixed solvents the solute was preferen- tially solvated by the component with which it interacted more strongly. The observation of preferential solvation in mixed solvents was particularly striking and suggested that solvation in these media was analogous to complexation with the better solvent Earle Waghorne w’as born in Canada and received his B.Sc. from the University of Guelph in 1969. He then studied with Professor A.J. Parker obtain- ing his Ph.D. from the Austra- lian National University in 1973. He is currently a lecturer in Chemistry at University College Dublin where he has continued his research into the eflects of changes in solvent on the properties of chemical systems. 285 10.0 5.0 0.0 -5.0 %& -10.0 -0 -15.0 9-20.0 -25.0 0.0 0.2 0.4 0.6 0.8 1.o Mole Fraction Acetonitrile Figure 1 Variation in the logarithm of the equilibrium constant for the disproportionation of cuprous ions (equilibrium E1) in aqueous acetonitrile mixtures. taking the role of the ligand.This analogy was supported by the isolation of crystalline solvates of a number of electrolytes and by the determination of stability constants for the complexation of a number of cations by common solvents.’ These results raised the obvious question as to the extent to which changes in the thermodynamics of solvation result simply from changes in the composition of the solute’s coordination or inner solvation sphere. The simple coordination model which results from this 1~6,7 assumes that all of these thermodynamic changes result from the successive replacement of the molecules of one solvent say A by those of a second solvent B in the coordination sphere of the solute.Thus it takes no account of changes in solvent -solvent interactions nor of changes in the interactions of coordinated solvent molecules with the surrounding medium. It also takes no account of the effect of changes in the permittivity of the solvent system although this contribution could be included. This leads to a set of relatively simple equations for the thermodynamic transfer parameters of a solute.Thus the free energies of transfer of a solute d,G* from some solvent A to some second solvent B and to mixtures of A and B are given by equations 1 and 2 respectively. Throughout n is the coordination number of the solute n the number of molecules of i in the coordination sphere and the /3:s are the equilibrium products for the equilibria MA + IBHMA B + IA (E2) written in terms of the mole fractions of A and B (xAand xB respectively)These equations are formally identical to those derived by Covington et a1 * except that the latter include a term to take account of changes in the solvent permittivity The composition of the coordination sphere of the solute is similarly calculable from the ,f3 values vza Clearly relationships for the enthalpies and entropies of transfer AtHeand dtSOcan be derived by the appropriate differentiation of equation 2 with respect to temperature More directly if the enthalpy changes for the successive replacement of A by B can be taken to be constant AtHOis given by A+B A,H+=(!!E~A H* (4) which requires the determination of the enthalpy of transfer A+B from A to B A HO,as well as the 8 values A more elegant route to these parameters comes from the recognition that A J* simply reflects the fact that preferential solvation results in a non-random distribution of solvent mole- cules within the systemThus the proportions of A and B molecules in the solute's coordination sphere differ from those in the bulk solvent Clearly the compositions of the bulk solvent and coordination sphere are the same (x = n,/n = 1) in the single component solvent systems and the corresponding entropy is zero in theseThus AtSOto mixtures of A and B is given by (5) while that to pure solvents is zero d,H* is calculable as A,HO= A,GO+TA,Se (6) with dtH* between pure solvents equal to the corresponding dtGe Thus this simple coordination model leads to a self-consistent set of equations for the composition of the coordination sphere of the solute and the transfer free energies enthalpies and entropies moreover the only parameters required for these calculations are the 8 and n for the system This model is formally restricted to solvent systems which form ideal liquid mixtures since it assumes that the observed changes result solely from changes in the composition of coordi- nation sphere of the solute It is of course possible to modify equations 2 and 3 to take account of non-ideality of the solvent system by replacing the x values by the corresponding Raoult's law activities however additional factors have to be included in the relationship for the transfer enthalpies and entropies (see below) Testing this model requires experimental values of the appro- priate 8:and of the transfer parameters or some measure of the variation of the composition of the coordination sphere of the solute in a reasonably ideal mixed solvent system Dimethylsulf- oxide (DMSO) and the propylene carbonate (PC) form almost ideal liquid mixtures and have the advantages that there is a large difference between their basicitiesThe latter leads to large changes in cation solvation and experimentally accessible values of 8;for the complexation of several cations by DMSO in PC Additionally since both solvents are aprotic changes in anion solvation should be minimalThis approximation is supported by the fact that the transfer parameters for the silver halides in these media are within experimental error indepen- dent of the anion Figure 2 shows the experimental dtG* d,H* and dtSO(as CHEMICAL SOCIETY REVIEWS 1993 300 I 7-I0 10000 ** 0 A ° 3 E 10 0 200 300 z<-400 -500 -60 0 000 020 040 060 080 100 Mole Fraction Dimethylsulfoxlde Figure 2 Comparison of calculated (lines) and experimental (points) transfer free energies (0)enthalpies (0)and entropies (as -TAtSe) (A) of sodium (open symbols) and silver (filled symbols) chloride from propylene carbonate to propylene carbonate + dimethylsulfox ide mixtures -TdJ*) values for the transfer of AgCl and NaCl from PC to DMSO + PC mixtures along with the corresponding values for Ag and Na +,calculated vza equivalents 1-6 using the experi- + mental 8 values for Ag+-DMSO and Na+-DMSO complexes in PCThe results for LiCl are similar and have been omitted for clarity The agreement between the calculated and experimental transfer parameters is in all cases close to the limits of experi- mental precision and provides striking support for the simple coordination model Thus the cations are preferentially solvated by DMSO leading to monotonic decreases in dtG*and A,He with the latter decreasing more rapidly at low DMSO mole fractions and the values converging for transfer from PC to DMSO Preferential solvation also accounts for the relatively large maxima in -TdJ* (minima in AJ*) which result from the differences in the compositions of the coordination sphere and bulk solventThese provide an obvious marker for signifi- cant preferential solvation in mixed solvents Unfortunately there are no data which provide direct infor- mation about the composition of the coordination spheres of the ions in these media although the agreement shown in Figure 2 strongly argues for the applicability of equation 3 There are however 23Na-NMR chemical shift data available in a number of mixed solvent systems and these do provide a method for estimating these changes loThe DMSO + acetonitrile MeCN system is one for which there are NMR data and although there are no directly determined B values available there are A,Ge data Assuming that the values are related statistically it is straightforward to recover a value of PL(l/") This in turn can be used to calculate the individual values provided that the coordinating number n is available a value of six consistent with the results of molecular dynamics calculations,' was chosen in this case Figure 3 shows the corresponding plots of the experimental and calculated values of nD/n,the fraction of the coordination sites occupied by DMSO and dtG* for Na+ as a function of solvent composition in this system Again the agreement between the calculated and experimental results is excellent Thus for these relatively simple solvent systems we arrive at a simple predictive model for the effect of changes in solvent in THERMODYNAMICS OF SOLVATION IN MIXED SOLVENTS-W E WAGHORNE 287 00 300 -50 200 T--100 I-1 v vvla 10 0 -7-15 0 5 +--20 0 t 0 0--10-25 0 a ?d 0 \\+ t-300 xd -20 -350 I\I I I I I I ~ 00 02 04 06 08 10 Mole Fraction Dimethylsulfoxide Figure 3 Comparison of calculated (lines) and experimental (points) values for the composition of the solvation shell (0),left hand scale) and transfer free energy (0,right hand scale) of the sodium ion in acetonitrile + dimethylsulfoxide mixtures which the dominant interactions are those between the solute and its coordination sphere of solvent moleculesThe compo-sition of the coordination sphere varies with solvent compo-sition according to simple equilibrium process with the compo-nent solvents acting as ligands competing for coordination sites around the solute and changes in solvent composition act by altering the relative concentrations of these ligands The obvious response to the success of the simple coordina-tion model is to test its applicability to more complex solvent systems that is those which do not form ideal liquid mixtures Initially this involved measuring fi and dtG*values for a range of systems Inconveniently the measurement of 8 values for anions is relatively difficult and these studies concentrated on cations particularly Ag+,and involved single ion dtGe values estimated using an extrathermodynamic assumption ' The results of these studies were remarkable in that equation 1 and 2 reproduced the dtG*data practically to experimental error in a wide range of solvent systems However when the studies were extended to the d,H* and dtSe data9 there were systematic deviations between the experimental data and those predicted by equations 3-6This was a much more interesting situation Figure 4 shows the experimental and calculated transfer parameters for silver chloride from methanol MeOH to MeOH + MeCN mixtures which is a good example of the situation In this system Ag+ is preferentially solvated by MeCN and C1-by methanolThe fi; values for the Ag+-MeCN complexes are available from the literature,' however these are unusual in that only three constants were recovered while the coordination number of Ag+ is generally found to be fourThus the fourth equilibrium constant was assumed to be unity corresponding to random solvation at the fourth site (this gives PIvalues of2 51 x lo2,6 31 x lo4 1 00 x lo6,and 1 00 x lo6) The corresponding values for the C1-MeOH complexes are not available and were estimated by first calculating the d,G* values for Ag+ via equations 1 and 2 and subtracting these from the experimental dtG*data to give those for C1 equation 1 was used to estimate fiE which was in turn used to calculate the ,f3; values assuming that the coordination number of C1-was fourThe values recovered in this way were 1 04 x lo2 3 62 x lo3 418 x lo4,and4 18 x lo4 There are several striking aspects to the results shown in Figure 4 First despite the fact that the MeOH + MeCN mixtures form non-ideal liquid mixtures the simple coordina-tion model accurately predicts dtG* for AgCl and by impli-cation those of the individual ions Moreover the predicted AI I-400 I I I I 00 02 04 06 08 10 Mole Fraction Acetonitnle Figure 4 Comparison of calculated (lines) and experimental (points) transfer free energies(0),enthalpies (A) and entropies (as -TdtS") (V) for silver chloride from methanol to methanol + acetonitrile mixtures Dashed lines are values calculated using equations 1 7 and solid lines those calculated using equations 8 and 7 (see text) maxima in -TdtS8,and sharp changes in d,H* at high and low MeCN mole fractions are clearly observedThus the basic picture is similar to that in the simpler DMSO + PC system with the Ag+ and Cl-ions being preferentially solvated by MeCN and MeOH respectively in the mixed solvents The most intriguing features of the results shown in Figure 4 are the systematic deviations between the experimental -Td,S* and dtH* data and those predicted by the simple coordination model Two things can be said immediately about these devi-ations (1) they reflect some factor not included in the simple coordination model and (11) they compensate in each other exactly or very nearly so in d,G* Now the principal limitation imposed on the simple coordi-nation model is that it takes no account of changes in solvent-solvent interactionsThus it is reasonable to ask whether these changes could result in the observed deviations It is also reasonable to ask whether the effects of changes in solvent-solvent interactions should contribute only to the -Td,S* and dtH* data and compensate each other in d,G* This second question has been addressed by Ben-Naim,14 who showed on the basis of statistical mechanical arguments that provided the solute is at infinite dilution solute-induced structural changes in the solvent will contribute to the enthalpies and entropies of solution but will cancel each other exactly in the free energy of solution Clearly any contributions which cancel in the free energies of solution will also cancel in dtG* sincethis is simply the difference between the free energies of solution in the reference and target solvents Hence Ben-Naim's result supports the view that the observed deviations result from solvent-solvent interactions Extension of the simple coordination model to take account of the effects of changes in solvent-solvent interactions is relatively straightforward and has been described in detail elsewhere Briefly the solute occupies a cavity in the solvent structure surrounded by its coordination sphere of n solvent molecules In order to complex to the solute each of these n molecules will have broken some fraction a of their bonds to other solvent molecules resulting in an endothermic enthalpy change of -andH where AH is the average enthalpy of solvent solvent bonding Additionally there may be a modifica-tion of solvent-solvent bonds around the coordination sphere affecting N (note N 2 n) solvent molecules By postulating that the resulting enthalpy change is proportional to AH we can set it equal to -/3NAH where /3 is the average proportionality constant for the modified bonds and is negative if the bonds are strengthened (leading to an exothermic contribution to the enthalpy of solution) After introducing the approximation that the values of a and /3 are constant over a range of solvent compositions and some manipulation this leads to and for the enthalpies and entropies of transfer In equations 7 and 8 x are mole fractions L,and s,the relative partial molar enthalpies and entropies of the components of the mixed solventThe parameters AAHo* and Adso* represent the differences between the enthalpies and entropies of interaction of the pure solvents and are calculable from the enthalpies and entropies of vaporization (the latter corrected for volume effects 6 The remaining model parameters reflect the solvation of the solute in the mixed solvent systemThe parameter p which is defined by (9) accounts for preferential solvation and in the simplest case is equal to the mean stability constants for the equilibria E2 [I e p = /3n(l/")] The effect of the solute on the solvent-solvent interactions is accounted for by the composite parameter (an+ /3N) with an resulting from the formation of the cavity to accommodate the solute and /3N from any further modification of the solvent structure around the cavity The parameters dA HY2and Ad S:,represent the differences between the enthalpies and entropies of solute-solvent interac- tions in the pure solvents A and B Thus equation 7 contains three model parameters A AH (an + /3N),and p and equation 8 the corresponding parameters Ads (an + PN) andp and the additional parameter N which corresponds closely to the solvation number of the solute Clearly the value of p is the same in each of these equations At first sight it would appear that the values of (an + PN) would also be common to the entropies and enthalpies however this need not be the caseTo see the reason for this we consider for example a water molecule which has hydrogen bonds to four near neighbour water molecules If this molecule becomes the near neighbour of a solute it must break initially one of these bonds to allow the formation of the cavity with an increase in enthalpy equal to 25% (aH = 0 25) however the remaining three hydrogen bonds continue to restrict the motion of the solvent molecule in particular its rotational freedom leading to a much smaller increase in its entropy (as 40 25) Similar considerations apply to the /3 values which result from restruc- turing of the solvent around the cavity We will consider the significance of this point in more detail below CHEMICAL SOCIETY REVIEWS 1993 By now the reader will have formulated the obvious question as to whether these equations do in fact predict the experimen- tal values of AtH* and AtSOUltimately this is the only valid test of any theory We can address this question by considering again the data for AgCl in the MeOH-MeCN systemThe necessary value of p is simply calculated from the value ofpias indicated above and the values recovered are 17 8 and 0 0700 for Ag + and C1- respecti- vely both written for coordination by MeCN in MeOH (Note that the value for C1- calculated this way is the inverse of that for the coordination by MeOH in MeCN ) Using Ben-Niam's compensation principle we can set the value of d~IHfi)~equal to that of A,G* since the other contribu- tions to A,H* result from solvent-solvent interactions and so disappear from dtGO(The individual values fror Ag+ and C1- calculated via equation 1 are -28 5 and 26 3 kJ mol respectively ) Thus for dtHOfrom MeOH to pure MeCN equation 7 reduces to and setting A AHo* equal to the difference between the enthal- pies of condensation of the pure solvents we calculate a value of 2 45 for (an + /3N) Thus we have values for all of the necessary model para- meters without recourse to the AtH* values in the mixed solvents except that we have no a przorz method of separating (an + PN) into its individual ionic contributionsThis seems to be an acceptably small degree of flexibility The variation in A,H* across the entire range of solvent compositions calculated using (an + /3N)values of I 00 and 1 45 for Ag+ and C1- and the values of -TA,S* calculated from these and the calculated A tGe values are shown as solid lines in Figure 4The agreement between these and the experimental data is satisfactory Similar agreement is found between the predicted and calculated AtH* data for the other silver halides in this solvent system Given the success of this treatment it is worth considering equations 7 and 8 in slightly more detailThe first point which can be made is that the model separates the direct solute-solvent and solvent-solvent contributions to A,H* and dJ* the latter residing entirely in those terms containing (an + /3N) This separation allows the rigorous testing of Ben-Naim's compensation principle I4This has been anticipated slightly in the above but warrants further comment If we consider solva- tion in a mixed solvent which has a non-zero excess free energy then two possibilities arise (1) there is exact compensation of the solvent-solvent contributions to AtG* in which case the values of (an + /3N) for the enthalpies and entropies must differ or (11) the (an + /3N) value is common to the two parameters in which case exact compensation cannot occur This situation was investigated previously,' where the A tH* and d,S* data for the alkali metal halides in aqueous methanol systems were fitted to equations 7 and 8 giving the correspond- ing (an + /3N) values These results are shown for LiCl and NaI (the best and worst cases respectively) in Figure 5 Again the agreement is good but in these cases the calculated values reflect the ability of the model to reproduce rather than predict the dataThe values of (an + /3n)recovered from the fits are listed inTable 1 along with the ratio of the (an + /3N)values obtained from the enthalpy and entropy data It is clear from the results listed in Table 1 that the values of (an + PN) recovered from the entropy data are systematically lower than those from the entropy data and that the ratio of these values is substantially the same for all of the electrolytes Thus in these systems at least case (11) does not obtain The solvation of these simple electrolytes in the aqueous methanol system is essentially random (z e ,p = 1) and in this case AtH* and AtSeare simply related to the excess enthalpies and entropies of the solvent system since 289THERMODYNAMICS OF SOLVATION IN MIXED SOLVENTS-W E. WAGHORNE One goal of the development of theoretical models such as 50.01Ithose discussed above is the prediction of the thermodynamic I 30.0 20.0 10.0 0.0 ‘-.Al0.*i \ -20.0 -30.0 YI I I I-40.0 / I I -I 0.0 0.2 0.4 0.6 0.8 1.o Mole Fraction Methanol Figure 5 Comparison of calculated (lines) and experimental (points) transfer free energies (0),enthalpies (0),and entropies (as -TA,Se) (A) for lithium chloride (open symbols) and sodium iodide (filled symbols) from water to water + methanol mixtures. Table 1 Values of (an + PN)for alkali metal halides in aqueous methanol solvents from A,H* and A,S* data LiCl 5.6 4.7 1.19 NaCl 6.1 4.7 1.30 KCl 5.7 4.3 1.33 RbCl 5.6 4.2 1.33 CSCl 5.9 4.7 1.26 NaBr 8.0 6.3 1.27 NaI 10.1 8.0 1.26 Average 1.28 and exact compensation between the solvent-solvent contribu- tions to A,He and A,Se requires that the ratio of the correspond- ing (an + PN)values is equal to that of -TASEto AHE. In the aqueous methanol system this ratio increases slightly across the range of solvent compositions (from 1.18 to 1.63) with an average value of 1.36 for the composition at which the experi- mental data were obtained.These values are in reasonable agreement with the ratio of the (an +PN) values lending support to the compensation principle [case (i) above] but more work is required to test this thoroughly. Acceptance of Ben-Naim’s compensation principle has one immediate consequence. Equations 7 and 8 are derived using the approximation that the (an + PN) values are constant over a range of solvent compositions. If the compensation principle is to hold this situation cannot obtain for the (an + PN)from both enthalpies and entropies where there are varying ratios between the enthalpies and entropies of solvent-solvent interactions. consequences of changes in the solvent system. A second approach is to use the model equations analytically to obtain information about the fundamental solvation process.Thus for example A,He or A,S* data may be fitted to equations 7 or 8 respectively and the corresponding model parameters recovered. Enthalpy data are far more numerous in the literature and in general are the more easily measured. The application of equation 7 to d,He data for electrolytes is complicated by the fact that two solutes the cation and anion are involved each with their own set of model parameters.This is simplified if as in the aqueous methanol system the p values are similar for these in which case one set of parameters referring to the whole electrolyte are recovered. It is also tractable where the p values are available from other measure- ments as for AgCl in the MeOH-MeCN system or where the solvation is dominated by one of the ions. In the main however six parameters provide rather too much flexibility for unambi- guous information to be obtained from the simple fitting of experimental data to equation 7. At first sight at least this problem is simplified when consider- ing solutes which are non-electrolytes since only one set of model parameters is recovered from the analysis. Correspond- ingly the solvation of a number of simple non-electrolytes has been investigated in this way. One example of this approach is shown in Figure 6 where the experimental dtH* data for a series of non-electrolytes from MeOH to MeOH-MeCN mixtures are shown along with the corresponding fits to equation 7; the parameters recovered from these analyses are listed inTable 2 (note that for clarity not all of the data are shown in Figure 6). The first point to be made about the data shown in Figure 6 is that equation 7 satisfactorily reproduces all of the experimental data across the whole range of solvent compositions despite the marked variations in the A,H* against composition profiles 15 I t I II lot I I I+ -10 0.0 0.2 0.4 0.6 0.8 1 .o Mole Fraction Acetonitrile Figure 6 Comparison of calculated (lines) and experimental (points) enthalpies of transfer of water (A) propan-1-01 (A),formamide (a) N-methylformamide (0),N,N-dimethylformamide ( +) dimethyl-sulfoxide (V) and propylene carbonate (M) from acetonitrile to acetonitrile + methanol mixtures. Table 2 Solvation parameters for solutes in acetonitrile- methanol mixturesa Soluteh P 18*03 14503 -22k5H2O PrOH 20+05 08It03 -16It5 TBA 15&03 07*03 -14+4 OcOH 204Z05 08f06 -17f5 PC 074Z02 084Z02 14Z3 DMSO 24It04 40~t04 -3Of5 DMA 15*03 41*08 -33f7 DMF 16503 284Z04 -21*3 NMF 184Z04 254~04 -2OIt4 Form 16k03 27f03 -24f4 Calculated using acetonitrile as the reference solvent p > 1 indicates preferential solvation by methanol * Solutes are PrOH propan-I -01 TBA,2,2-dimethyhlpropan-2-ol,t-butyl alcohol OcOH octan- 1-01 Pc propylene carbonate DMSO dimethylsulfoxide DMF N N- dimethylformamide NMF N-methylformamide Form formamide again providing support for the extended coordination model Consideration of the various solutes studied shows that the interpretation of the model parameters is somewhat less straightforward than the one naively first believedThus considering for example N,N-dimethylformamide the solute presents a variety of different surfaces including the basic -C=O carbonyl and the relatively non-polar -C-H and N-CH groups to the surrounding solvent and the parameters recovered are the sums [(an+ PN) and ddH7,] or the weighted means (p)of those for these different groups A second point which must be recognized is that these polyatomic solutes may undergo conformational changes with changing solvent composition with corresponding intramolecu- lar contributions to AtHeTo a first approximation these intramolecular contributions will follow changes in the compo- sition of the coordination sphere of the solute paralleling the first term in equation 7 and appearing in ddHFThis makes interpretation of this parameter relatively treacherous How-ever if the compensation principle holds it may provide an opportunity to investigate these intramolecular effects since the enthalpy of direct solute-solvent interaction may be equated to dtGe kaving the intramolecular contribution as the difference between AtGe and the measured ddH7,value In the MeCN + MeOH system the interpretation of the model parameters is not difficultThis has been discussed in detail elsewhere,17 and we can restrict ourselves to the main features The values of (an + PN) reflect the contribution of solvent- solvent effects to A tHe,with positive values resulting from a net breaking or weakening of solvent-solvent bonds In the metha- nol-acetonitrile system these are positive for all of the solutes studied moreover these increase systematically in the order water alcohols propylene carbonate < formamides < N,N-dimethylacetamide DMSO The first point to be noted is that the values for the hydroxyl solutes are independent of the size of the alkyl groupThus while for example the cavity required to accommodate the n- octyl group (octan- 1-01) must be larger than that for the propyl group (propan-1-01) this does not affect (an + PN) This can be understood by recognizing that dtHe is sensitive only to those contributions to the enthalpy of solvent-solvent bonding which vary with solvent composition In this system the contribution from hydrogen bonding of the methanolic -OH group will be composition dependent but those from interac- tions of the other non-polar surfaces of the solvent molecules may be much less soThus the enthalpies of solvent-solvent bonding reflected in the L and ddHo*values are likely to be dominated by the changes in the hydrogen bonding of the methanolic -OH groups in which case the (an+ PN) values will CHEMICAL SOCIETY REVIEWS 1993 indicate only the extent to which the solute disrupts theseThis suggests that these solutes are solvated with their -OH groups interacting with those of the methanol molecules and their alkyl residues accommodating in a cavity surrounded by acetonitrile molecules and the methanolic -CH groups In this case forma- tion of the cavity for the solute alkyl residue would make little contribution to dtHO,although it would make a significant but composition independent contribution to the enthalpy of solution Support for this view comes from the relatively low value of (an + PN) for PC which will not hydrogen bond strongly to methanol and so not disrupt the methanol-methanol hydrogen bonds in effect the solvation PC then would be similar to that of the alkyl groups The insensitivity of the (an + PN) values to the size of the alkyl groups greatly simplifies their interpretation since they can reasonably be attributed to the effect of the polar groups on the hydrogen bonded network of methanol molecules The interpretation is further simplified by noting that (an + PN) is essentially the same for the three formamids indicating that hydrogen bond formation to the amide -N-H protons doesn't involve disruption of this networkThis is easily understood since at most only half of the methanol oxygen lone pairs are involved in methanol-methanol hydrogen bonding leaving a large reservoir of these basic sites available for hydrogen bonding to the -N-H protons Thus we can focus on the (an + PN) values for two types of functional groups the R-OH of the hydroxylic solutes and the aprotic -C=O or -S=O of the amides or DMSO Solvation of the R-0-H group can be accomplished by insertion into the hydrogen bonded network without perturb- ing it significantly and so results in a relatively small value of (an + PN)In contrast hydrogen bonding to the -C=O or -S=O groups involves breaking the network Now hydrogen bonding in extended networks such as that formed by MeOH in these systems is cooperative and there is evidence that the hydrogen bonds to terminal molecules in such networks are weaker than the average hydrogen bonds in the networkThus solvation of these groups will involve not only a breaking of methanol- methanol hydrogen bonds (an > 0) but a weakening of hydro- gen bonds near the point where the network is broken giving a further endothermic contribution to dtHe (PN> 0) Support for this comes from considering the (an + PN) values for the amides Infra-red studies indicate that the formamides form on average about 1 5 hydrogen bonds to their -C=O groups in pure methanol while the acetamides form close to 2 such bonds,lg 2o thus leading to an increase in (an + PN) from 2 5 to 4This increase in the extent of hydrogen bond formation is consistent with the extra basicity of the acetamides relative to the formamides and combined with the (an + PN) values suggests that DMSO also forms a maximum of two hydrogen bonds to methanol Despite the earlier comment one can cautiously note that the A A Hy,values are entirely consistent with this interpretation Thus that of PC is close to zero indicating roughly equal interaction enthalpies with methanol and acetonitrile while those of the other solutes are negative and those for the more basic DMA and DMSO significantly more so indicating stronger interactions with methanol than acetonitrile Thus consideration of the model parameters leads to a remarkably detailed picture of the solvation of the species with the non-polar alkyl groups surrounded by methanol -CH groups and acetonitrile molecules and the polar groups hydro- gen bonded to the methanol -OH groupThis latter interaction results in the preferential solvation by methanol the variation in the (an + PN) values and arguably that in ddH The fact that the model allows the recovery of these insights into solvation in what are relatively complex systems from measurements effectively made with a Dewar flask and a ther- mometer is both startling and gratifying However the Holy Grail of all work in the area of solvation chemistry is to provide a THERMODYNAMICS OF SOLVATION IN MIXED SOLVENTS-W. E. WAGHORNE 29 1 15.0 II5.O 3’ 1T 0.0 -5.0 0.0 0.2 0.4 0.6 0.8 1.o Mole Fraction Propan-1-01 Figure 7 Comparison of calculated (lines) and experimental (points) transfer enthalpies for N-methylpyrrolidinone (V),N,N-dimethylfor-mamide (O),N-methylformamide(A) formamide(0),and urea (0)from water to aqueous propan-1-01 mixtures. Solid lines represent the fits to the water rich domain dashed lines those to the organic rich domain (see text). better understanding of aqueous solutions. Correspondingly we can conclude by briefly considering some of the results obtained in mixed aqueous solvents. Figures 7 and 8 show dtH* for several amides and related solutes in aqueous mixtures with propano12 and acetonitrile.22 The plots for the other aqueous alcohol systems are similar and are reported elsewhere.2 The most obvious feature ofthe results shown in Figures 7 and 8 is that two sets of model parameters are required to produce the experimental data one in the water-rich mixtures and the other at higher concentrations of the organic co-solvent.This is also the case for these solutes in the aqueous methanol and ethanol systems;20 however as is clear from above this transi- tion in the solvation parameters is not found for the amides in the non-aqueous mixed solvents so far studied nor for the alkali metal halides in aqueous methanol. The parameters recovered for the water-rich and organic-rich composition ranges are listed inTable 3 those for the same solutes in the aqueous methanol ethanol and 2-methyl-2- propanol (TBA) systems show the same general features. These results pose an obvious question. What change might occur in these aqueous solvent systems which could lead to the changes in their solvating properties? Since no corresponding transitions are observed in the purely non-aqueous solvent systems it is reasonable to assume that they reflect some change specific to the aqueous media. The principal difference between the parameters for the water- rich and organic-rich domains lies in the (an + Prv) values. In the organic-rich regions these are similar to those in the purely non- aqueous systems; that is they are relatively insensitive to the size of the solute. In contrast the values in the water-rich domains increase systematically with the size of the non-polar alkyl residues on the solute and for the bulkier solutes are relatively large. These results combined with those from studies of aqueous- 10.0 %. U 5.0 0.0 -5.0 f I i I I -I 0.0 0.2 0.4 0.6 0.8 1.o Mole Fraction Acetonitrile Figure 8 Comparison of calculated (lines) and experimental (points) transfer enthalpies for N,N-dimethylacetamide(+) N,N-dimethyl-formamide (V),N-methylformamide (A),and formamide (0)from water to aqueous acetonitrile mixtures. Solid lines represent the fits to the water-rich domain dashed lines those to the organic-rich domain (see text). organic mixtures,’ led us to attribute the change in the solva- tion parameters to a change in the solvent structure from one based on the three-dimensional hydrogen-bonded water struc- ture to one of lower order based on that of the organic component. Thus in the water-rich domain introduction of the solute requires disruption of the hydrogen-bonded water structure principally to create the cavity necessary to accommodate the solute and this disruption will be greater for the larger solutes. Beyond the structural transition the solvent structure will more closely resemble those of the non-aqueous mixed solvents and the non-polar surfaces of the solute will correspondingly make less contribution to (an + PN). The A,H* against composition profiles of the amides are similar to those for a range of solutes including the tetraalkyl- ammonium and t-butyl alcoholz7 (as solute) in mixed aqueous solvents.Thus in each case A,H* rises markedly as the concentration of the organic component increases from zero and then varies relatively gently over the remaining composition range.This is typical of solutes with significant non-polar surfaces; that is those solutes which are commonly referred to as hydrophobic. It is clear from Figures 7 and 8 that the initial rise in A,He becomes more extreme as the size of the non-polar surfaces increases and from the parameters listed inTable 3 that it is associated with increases in (an + PN).This is also the case for the tetraalkylammonium halides in aqueous propanol and t- butyl Thus these variations in AtH* in the water-rich domain reflect a net disruption of the solvent structure [(an+ PN)> 01 with the extent of this disruption increasing with the size of the non-polar groups.This result doesn’t preclude the possibility of rigidification of the water structure around these surfaces (PN < 0) but shows that any such contribution to A,H* is outweighed by that from the formation of the cavity required to accommodate the solute (an > 0). 292 Table 3 Solvation parameters for solutes in aqueous propan- 1-01 and acetonitrile mixturesa Soluteh P (an + PW AAHy,/kJmol-Water-Rich Region Propan-1-01 + Water Urea 10f03 47f05 -26*3 Form 10f03 45f02 -14f 1 NMF 06f03 78f03 -12f2 DMF 064103 12 1 f05 -5*10 NMPY 06603 178f09 -16f 10 Acetonitrile + Water Form 063102 6f 1 90 41 20 NMF 07f01 14f 1 244* 16 DMF 07f01 23 f2 405 f 20 DMA 04f01 21 f2 413 f 30 Organic-Rich Region Propanol-1-01+ Water Form 054Z02 59f15 15 f 5 NMF 03f01 234~15 -1*5 DMF 02*01 07f 1 8k5 NMPY 02fO 1 OOf 1 1 f 10 Acetonitrile + Water Form 04f02 2f 1 35 f 10 NMF 04f02 2f 1 36f 15 DMF 07f01 2Lt 1 35 f 10 DMA 05*01 35f05 604I 10 0 Calculated using acetonitrile as the reference solvent p > I indicates preferential solvation by methanol or dcetonitrile ?3oIutes dsinTable 2 except NMPY N-methylpyrolidinone It is interesting to note that the (an + PN) values for the amidic solutes in the water-rich domain (Table 3) increase almost linearly with the area of the non-polar -CH groups of the solute z1This is consistent with independent solvation of these groups and suggests that it may be possible to develop a group contributions approach to predicting d,He However this needs further investigation and the corresponding variations for the tetraalkylammonium bromides,z4 for which the (an + /3N) values are far larger are markedly non-linear A slightly surprising feature of the model parameters for these systemsz1 is that the p values indicate slight preferential hyd- ration with this increasing with the size of the non-polar -CH groupsThis result has been observed consistently for a range of solutesThe origin of this isn’t clear and requires further study in particular by other techniques which can probe the solvation of these groups directly It is clear from these few examples that analysis of the thermodynamic transfer parameters in this way can give remarkable insights into solvation in mixed solvents Combin- ing these with the results of studies using other techniques particularly those that probe the solvation of individual func- tional groups will sharpen these images furtherThis IS particu-larly exciting in the study of complex solutes where the solva- tion of different functional groups will differ markedly The ultimate goal of formulating a complete predictive theory for the thermodynamic changes which result from changes in solvent remains tantalizingly beyond our grasp CHEMICAL SOCIETY REVIEWS 1993 However the broad features of such a theory are clearThe principal interactions of significance are the near neighbour solute-solvent and solvent-solvent interactions with the former dominating the free energy and the latter contributing to the enthalpies and entropies Preferential solvation is the norm and although in many cases it is relatively weak it affects the variations in all of the transfer parameters in mixed solvent systems The above has concentrated for obvious reasons on one series of developments Of course this isn’t unique and other theoretical approaches have been and continue to be pur- sued 28 However the basic picture of solvation which these paint is essentially similar to the above with the apparent differences reflecting differences in the mathematical rather than the chemical approach adopted References I B G Cox A J Parker and W E Waghorne J Phqs Chem 1974 78 1731 2 A J Parker Quart Re\ 1962 16 163 3 C Reichardt Agner Chem Int Ed Engl 1965,4 29 4 V Guttmann Chem Brit 1971,7 102 5 H Schneider and H Strehlow Z Phjs Chem 1966,49,44 6 B G Cox W E Waghorne and K C Pigott J Chem Soc FaradayTrans I 1979,75 227 7 B G Cox and W E Waghorne Chem Soc Rev 1980,9,381 8 A K Covington and K E Newman Pure Appl Chem 1979 51 2041 9 B G Cox and W E Waghorne J Chem Soc Faradai Trans I 1984,80 1267 10 R H Erlich M S Greenberg and A I Popov Spectrochim Acta 1973,29A 543 11 K Heinzinger Pure and Applied Chem 1985,57 103 1 12 G Clune B G Cox and W E Waghorne J Chem Soc Faradai Trans I 1976,72 1294 13 S E Manahan and RT Iwamoto J Electroanal Chem 1967,14 213 14 A Ben-Naim J Phis Chem 1978,82 874 15 D Feakins E de Valera and W E Waghorne J Chem Soc Faradaj Trans I 1983,79 1061 16 D Feakins E de Valera and W E Waghorne J Chem Soc Faraday Trans I 1985,81,2703 17 A Costigan D Feakms I McStravick C O’Duinn J Ryan and W E Waghorne J Chem Soc Faraday Trans 1991,87,2443 18 M C R Symons in ‘Water and Aqueous Solutions’ ed G W Neilson and J E Enderby Adam Hilger Bristol 1986 p 41 19 G Eaton and M C R Symons J Chem Soc Faradaj Tians I 1988,84 3459 20 G Eaton M C R Symons and P P Rastogi J Chem Soc Faradaj Trans I 1989,85 3257 21 G Carthy D Feakins C O’Duinn and W E Waghorne J Chem Soc Faraday Trans 199 1,87,2447 22 D Feakins P Hogan C O’Duinn and W E Waghorne J Chem Soc Faradaj Trans 1992,88,423 23 F Franks and J Desnoyers Water Sci Re1 1985 1 170 24 G Carthy D Fedkins and W E Waghorne J Chern Soc Faiada) Trans I 1987,83 2585 25 J Juillard J Chem Soc Faradaj Trans I 1982 78 37 26 R K Mohanty T S Sharma S Subramaniam and J C Ahluwa- ha J Chem Soc Faradaj Trans I 1971,67 305 27 D Feakins J Mullally and W E Waghorne J Soh Chem . 1990 19,401 28 Y Marcus J Chem Soc Faradaj Trans I 1989,85 3019

ISSN:0306-0012    

DOI:10.1039/CS9932200285

出版商:RSC    

年代:1993

数据来源: RSC