摘要:

ISSN 0306-0012 CSRVBR 25(4) 229-296 Chemical Society Reviews Volume 25 Issue 4 Pages 229-296 August 1996 A Radical Reappraisal of Gif Reactions By M. John Perkins (pp. 229-236) Various iron-catal ysed procedures for the functionalisation of saturated hydrocarbons have been designated 'Gif' reactions. These were originally conceived as biomimetic models for non-haem oxidase systems, and a mechanism in which high-valent iron-oxo species interact with the hydrocarbon has been adduced in support of this analogy. This review examines the evidence against an alternaiive free-radical mechanism. It concludes that plausible radical schemes are available for the interpretation of most, if not all, of the Gif data, but that more information is required before any unambiguous mechanistic interpretation can be justified.On the Mechanism of Gif Reactions By Derek H. R. Barton (pp. 237-239) Gif chemistry converts saturated hydrocarbons selectively into ketones. On a limited conversion of up to about 25%,the yield is quantitative. Two manifolds can be distinguished: Fe1I1-FeV and Fe1'-FeIV. The first manifold, with a few exceptions, does not involve radical chemistry. The second always affords carbon radicals. However, for both manifolds, the K.I.E. is identical at about 2.1 and the selectivity for secondary positions is the same. The activation process, in both cases, requires the presence of an appropriate carboxylate ligand and affords a species which reacts faster with saturated hydrocarbons than with substrates which are traditionally more easily oxidized.Application of Fluorescence Microscopy to a Study of Chemical Problems By R. S. Davidson (pp. 241-253) The review outlines the photophysical properties that a compound should possess if it is to be of value as a reagent for fluorescence microscopy. Applications of fluorescence microscopy and related techniques to the study of the uptake of dyes by fibres, the photodegradation of dyes and polymers (eg.wool and lignin) and for determining the softening temperatures of polymers are described. Assembly and Encapsulation with Self-complementary Molecules By Julius Rebek, Jr. (pp. 255-264) Molecular assemblies provide a means of evaluating intermolecular forces and chemical information involved in recognition processes. Self-complementary molecules are especially useful in this regard, and here are described synthetic structures inspired by sports equipment.These molecules dimerize through hydrogen bonding to generate pseudo-spherical capsules. Their assembled states are capable of reversible encapsulation of smaller molecules of complementary size and shape. The unusual thermodynamic parameters observed for the encapsulation process suggest a host-hostage relationship. The capsules show promise as reaction chambers. New Approaches to Chemical Patterns By Barry R. Johnson and Stephen K. Scott (pp. 265-273) Approximately40 years ago, Alan Turing predicted that the coupling of diffusion to complex chemical kinetics could give rise to the spontaneous development of chemical patterns.Several challenges have stood in the way of the experimental realisation of this prediction, but these have recently been overcome. Several new experimental configurations for studying the progress of reactions in space and time are now available to the chemist. INGOLD LECTURE: Reactive Intermediates: Carboxylic Acid Enols and Other Unstable Species By A. J. Kresge (pp. 275-280) Newly developed flash photolytic methods for generating the unstable enol isomers of simple aldehydes and ketones, under conditions where they can be observed directly and accurate new information about their chemistry can be obtained, are extended to the considerably less stable and much shorter-lived enols of selected carboxylic acids and their functional derivatives. Photoelectron Spectroscopy in a New Light: Zero Kinetic Energy (ZEKE) Photoelectron ~125 I Spectroscopy with Coherent Vacuum Ultraviolet Light By John W.Hepburn (pp. 281-287) The combination of coherent vacuum ultraviolet light sources with zero kinetic energy photoelectron spectroscopy (ZEKE-PES) is discussed in this review. The generation of coherent light with photon energies up to 19 eV is described, followed by a general description of ZEKE-PES. These general remarks are followed by some specific examples, which illustrate some unusual features of ZEKE-PES. The Changing Face of Arene Oxide-Oxepine Chemistry By Derek R. Boyd and Narain D. Sharma (pp. 289-296) Improved methods of arene oxide synthesis by direct oxidation of arenes, and by multistep conversion of vicinal cis-diol and halohydrin precursors, provide entry to a new range of heterocyclic arene oxides (benzofuran, benzothiophene, indole, quinoline, isoquinoline, acridine).Factors which determine both the rate of interconversion and the equilibrium ratio of arene oxide-oxepine tautomers have been elucidated. Recognition that enzyme- mediated epoxidation can occur on arene oxide, oxepine, phenol and trans-diol, metabolites of arenes has led to renewed interest in the biological effects of these novel epoxide metabolites. Articles that will appear in forthcoming issues include Designing New Lattice Inclusion Hosts Roger Bishop Potential Energy Surface Crossings in Organic Photochemistry Fernando Bernadi, Michael Robb and Massimo Olivucci Specificity and Versatility in Erythromycin Biosynthesis Rembert Pieper, Camilla Kao, Chaitan Khosla, Guanglin Luo and David E.Cane Glutamate and 2-Methyleneglutarate Mutase: From Microbial Curiosities to Paradigms for Coenzymes B ,,-dependent Enzymes Wolfgang Buckel and Bernard T. Golding Nitrous Acid and Nitrile in the Atmosphere Gerhard Lammel and J. Neil Cape Environmentally Friendly Catalytic Methods James H. Clark and Duncan J. Macquarrie ‘Covalent’ Effects in ‘Ionic’ Systems Paul A. Madden and Mark Wilson Non-porphyrin Photosensitisers in Biomedicine Mark Wainwright Scanning Transitiometry Stanislaw L. Randzio Inhibitors of Glycosphingolipid Biosynthesis Thomas Kolter and Konrad Sandhoff The Chemistry of the Semiconductor Industry Sean O’Brien An Odyssey from Stoichiometric Carbotitanation of Alkynes to Zirconium-catalysed Enantioselective Carboalumination of Alkenes Ei-ichi Negishi and Denis Y. Kondakov Photo- and Redox-active [ 21Rotaxanes and [2]Catenanes Andrew C. Benniston

ISSN:0306-0012    

DOI:10.1039/CS99625FP013

出版商:RSC    

年代:1996

数据来源: RSC

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\ Overburdened?Too much to do and too little time? AnnualReports in the Progrew of Chemistry offers an easy, inexpensive way to keep up with chemical research. ..... . . .... . .... . . ... . . . . . . .. . Subscribe now and reduce your workload at a stroke. Section A: Inorganic Chemistry Section B: Organic Chemistry Section C: Physical Chemistry Europe and World 5122.00 Europe and World 5116.00 Europe and World 5122.00 USA $220.00 USA $210.00 USA $220.00 Europe and World 5324.00 USA $583.00 Avalaible in September 1996. To order please contact: For further information please contact: The Royal Society of Chemistry Stella Green Turpin Distribution Services Ltd The Royal Society of Chemistry Blackhorse Road, Letchworth Thomas Graham House, Herts SG6 lHN, United Kingdom Science Park, Milton Road, Tel: +44 (0)1462 672555 Cambridge CB4 4WF, United Kingdom Fax: +44 (0)1462 480947 Tel: +44 (0)1223 420066 Fax: +44 (0)1223 423429 E-mail: sales@rsc.org WWW: http://chemistry.rsc.org/rsc/ RSC Members should order through the Membership Administration Department at our Cambridge address.Two of the most distinguished and widely respected names in chemical publishing, The Royal Society of Chemistry and the American Chemical Society have joined forces to co-publish this exciting new journal, which seems sure to become the first point of reference in its field. Organic Process Research & Development is a bi-monthly journal which will contain comprehensive reviews of developments IN EACH ISSUE YOU’LL FIND 0Substantive articles and reports from leading researchers 0Reports on original work in process chemistry 0Reports on scale up of process to pilot plant, with discussions of safety and environmental issues 0Special focus on the design of chemical processes, and their development and scale up from laboratory to manufacture 0Current R&D in the fine organic and speci a Iity chem ical indu stries relating to the batch and semi-batch chemical process industries, keeping you up-to-date with the very latest in fine organic chemical and speciality chemical industries including pharmaceuticals, electronics, agrochemicals, intermediates and speciality polymers -subjects never previously covered in depth by any existing sc ience jou r n a I.Editor Trevor Laird Scientific Update East Sussex, UK Associate Editors John F Arnett J. F. Arnett & Associates West Chester, PA, USA Richard Pariza, C&P Associates North Zion, II, USA The first issue of Organic Process Research & Development will be available in January 1997. ORDER YOUR COPY TODAY To order, please contact: xTHE ROYAL UK & Europe USA & Rest of World TI-RYSOCIETY OF The Royal Society of Chemistry The American Chemical Society s Turpin Distribution Services Ltd Customer Service and Sales Blackhorse Rd, Letchworth 1155 Sixteenth Street, NW Herts SG8 1HN Wahington, DC 20036 USA Tel +44 (0) 1462 672555 Tel +1 202-776-8100 Fax +44 (0) 1462 480947 Fax +1 202-872-6067 Irihrrnatiun OIServices RSC & ACS Members are enttled to a discount. Please contact your society for further details 8

ISSN:0306-0012    

DOI:10.1039/CS99625BP015

出版商:RSC    

年代:1996

数据来源: RSC

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The Royal Society of Chemistry Chemical Society Reviews Editorial Board Professor H. W. Kroto FRS (Chairman) (University of Sussex) Professor M. J. Blandamer (University of Leicester) Dr. A. R. Butler (University of St. Andrews) Professor E. C. Covlstable (University of Basel, Switzerland) Professor T. C. Gallagher (University of Bristol) Professor D. M. P. Mingos FRS (Imperial College London) Consulting Editors Dr. G. G. Balint-Kurti (University of Bristol) Dr. J. M. Brown (University of Oxford) Dr. J. Burgess (University of Leicester) Dr. N. Cape (Institute of Terrestrial Ecology, Lothian) Professor B. T. Golding (University of Newcastle upon Tyne) Professor M. Green (University of Bath) Professor A. Hamnett (University of Newcastle upon Tyne) Dr.T. M. Herrington (University of Reading) Professor R. Hillman (University of Leicester) Professor R. Keese (University of Bern, Switzerland) Dr. T. H. Lilley (University of Sheffield) Dr. H. Maskill (University of Newcastle upon Tyne) Professor A. de Meijere (University of Gottingen, Germany) Professor J. N. Miller (Loughborough University of Tech no Iog y ) Professor S. M. Roberts (University of Liverpool) Professor B. H. Robinson (University of East Anglia) Professor M. R. Smyth (Dublin City University, Republic of Ireland) Professor A. J. Stace (University of Sussex) Chemical Society Reviews aims to foster current progress in the chemical sciences and related disciplines. The journal has the broad appeal necessary to enable scientists to benefit from recent advances made in research outside their immediate interests.In particular, students embarking on a research career should find Chemical Society Reviews a particularly Chemical Society Reviews (ISSN 0306-0012) is published bimonthly by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, UK CB4 4WF. All orders accompanied by payment should be sent directly to The Royal Society of Chemistry, Turpin Distribution Services Ltd., Blackhorse Road, Letchworth, Herts., UK SG6 1HN. Neb.Turpin Distribution Services Ltd., distributors, is wholly owned by The Royal Society of Chemistry. 1996 annual subscription rate: EEA f120.00; Rest of World f123.00; USA $225.00.Customers in Canada will be charged the Rest of World price plus a surcharge to cover GST.Customers should make payments by cheque in sterling payable on a UK clearing bank or in US dollars payable on a US clearing bank. Second-class postage is paid at Jamaica, NY 1141-9998. Airfreight and mailing in the USA by Publications Editorial Staff Managing Editor Martin Sugden Editorial Production Peter W h ittington Editorial Secretary Debbie Halls Editorial Office The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cam bridge UK CB4 4WF Telephone +44 (0)1223 420066 Facsimile +44 (0) 1223 420247 Electronic Mail (Internet) csr@rsc.org or su g den m@ rsc.0 rg h ttp://c h em ist ry. rsc.org/rsc/ Advertisement sales Telephone +44 (0)171 287 3091 Facsimile +44 (0) 171 494 1134 Typeset by Servis Filmsetting Ltd.Printed in Great Britain by Black Bear Press Ltd. stimulating and instructive springboard to further reading. The Editorial Board encourages an international and interdisciplinary approach to science, which is reflected in the succinct, authoritative articles commissioned. The Board members welcome comments and suggestions; these should be directed to the Managing Editor Expediting Services Inc., 200 Meacham Avenue, Elmont, NY 11003, and at additional mailing offices. US Postmaster: send address changes to Chemical Society Reviews, c/o Publications Expediting Services Inc., 200 Meacham Avenue, Elmont, NY 11003. All despatches outside the UK by Bulk airmail within Europe and Accelerated Surface Post outside Europe. PRINTED IN THE UK. 0 The Royal Society of Chemistry, 1996. All rights reserved. No parts of this publication may be repro- duced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, recording, or other- wise, without the prior permission of the publishers.

ISSN:0306-0012    

DOI:10.1039/CS99625FX017

出版商:RSC    

年代:1996

数据来源: RSC

ISSN:0306-0012    

DOI:10.1039/CS99625BX019

出版商:RSC    

年代:1996

数据来源: RSC

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A Radical Reappraisal of Gif Reactions M. John Perkins Department of Chemistry, Brunel University, Uxbridge UK UB8 3PH Selective alkane functionalisation is achievable by a variety of natural enzymic systems. Perhaps the most extensively studied of these are the cytochrome P-450 enzymes,] in which the active site contains an iron atom coordinated with a tetradentate porphyrin ligand. The mechanism of alkane functionalisation catalysed by P-450 enzymes has widely been accepted as involving the so-called ‘oxygen rebound’ mechanism,’” in which an iron (IV)-OXO inter-mediate* is generated which removes hydrogen from the hydro- carbon substrate [eqn. (l)]; the resulting alkyl radical immediately removes hydroxyl from iron to form alcohol and regenerate a low- valent iron species [eqn.(2)l.Very recent studies,’( depending upon the use of cyclopropylcarbinyl radical ‘clocks’2 have attempted to ‘time’ the rebound process. 0 ONH dH Less well studied than the P-450s, but attracting considerable attention recently, are those non-haem iron-based oxidases3 in which the iron ligands are principally substituents in amino acid residues of the enzyme. These include the methane monooxy- genases,3(l which catalyse the oxidation by air of methane to methanol, isopenicillin-N cyclase ,3/’ prol yl-4-hydroxylase,3c and y-butyrobetaine hydroxylase.3“ Uniquely amongst these, but in common with certain other redox iron enzymes, the methane mono- oxygenases incorporate a di-iron-containing active centre.In addition to investigations of structure and mode of action of the non-haem iron-based enzymes, attempts have been made to replicate their selective oxidising characteristics in model experiment^.^ Among examples of these model studies is the work of Que and his colleagues who, in exploiting the tetradentate tris-(2-pyridyl methy1)amine ligand 1,have provided direct spectroscopic evidence for the formation of an unstable binuclear species in which one iron atom is in an oxidation state greater than III.~ John Perkin5 ,Professor Emeritus in the University of London, has been Aswciate Professor at Brunel since taking early retirement in I992 from the London chair which he had held for 20 years. Following his PhD with D. H. Hey he has worked principally in the area of free radicals, for which his early research was recognised with the award of a Corday-Morgan Medal by the Chemical Society. He has contributed to, and edited volumes in WileyS Organic Reaction Mechanism5 series, and is responsible for a short text, Radical Chemistry, pub -lished recently by Ellis Horwood.1 This review focuses primarily upon another, more extensively reported, and superficially simpler set of model studies, begun in the early 1980~~by D. H. R. Barton and his colleagues. The essential features of these new oxidation processes, which were whimsically designated inter alia ‘Gif’ and ‘GoAgg’ reaction systems after the geographical locations of the investigators, are the use of an oxygen source or other oxidising agent, a reducing agent, and a (catalytic) source of ferric iron.7 Until very recently, the solvent has invariably been a mixture of pyridine and acetic acid, in which the pyridine, present in large excess, was originally included as a simple iron- coordinating species (eqn.(3)].In the earliest investigations the substrate was commonly cyclohexane. Predominantly, this is oxid- ised not to cyclohexanol, but to cyclohexanone [eqn. (4) I. ox0-6 (4) Table 1 Some ‘Gif’ oxidation systemsa GiP“ FeO/Oz GiPV ZnO;Feli(cat.)/O, Gif-Orsay e-(cathode);Feii(cat.)/O, GoAggl Feii;KO,/argon GoAgg” Feill:H,O, GoAgglil Fe”l;added ligandh/H20, GoAggiV FeiIi;BufOOH GoAggV Feill;added ligandhlBufOOH All of these systems utilise pyndine-acetic acid (10 Iv v) as solvent, and air is not normally excluded Usually picolinic acid Table 1 lists some of the Gif family of reaction systems, the mechanisms of each of which has been investigated to a greater or lesser extent.In one of their more recent publications, Barton and his colleagues have acknowledged that the proliferation of names for these systems is unwelcome.8 However, ‘Gif’ has now come to be accepted by a number of authors to embrace many of these oxida- tions, as well as those variants in which other reagents are added in order to intercept intermediates. In what follows, I shall occasion- ally specify some of the oxidation systems using names listed in the Tab1 e . Central to Barton’s discussion of these oxidation reactions has been the conclusion that, at least where secondary carbon isfunc- tionalised, the results cannot be accommodated in terms of simple free-radical processes.The object of the present article is to * Since, in the iron(iv) species, the porphyrin ligand is oxidised to a radical cation, the whole has sometimes been represented as incorporating iron(v) 229 attempt to provide a critical reexamination of the arguments against radical intermediates in Gif chemistry One problem which ames in so doing is that the totality of the evidence which has cul- minated in a global (non-radical) mechanism embracing many of these reactions has been culled from individual systems Thus, data for, say, one of the early Gif systems has been used in explain- ing a GoAgg reaction The exceptions to this involve reactions listed at the foot of Table 1, in which the oxidising agent is tert-butyl hydroperoxide Although these represent a relatively recent development in the history of Gif chemistry, many investigators would now contend that they are better understood Nevertheless, their consideration here is deferred until towards the end of this review The global mechanism which is currently favoured for methylene functionalisation depends on the formation of an iron(v)-oxo species which inserts into the C-H bond of the substrate, sub sequently, oxygen transfer to carbon leads to the product These essential features are outlined in Scheme la This is the first time in a review article that the case against an alternative free radical mechanism has been the subject of critical examination Other reviews have presented the iron-xo mechanism4 and have usually7 accepted that the evidence against radicals is over whelming \V VOH-Fe=O + RH -lFe< / /R v OH \In --Fe-!FC( + ROH IR / Scheme la Scheme lb One of the earliest reasons to believe that Gif Chemistry is quite different from established radical processes, and might indeed have some synthetic importance, was the observation that, when adamantane was the substrate for oxidation in place of cyclo- hexane? there was a very much larger yield of adamantan-2-one than of adamantan-1-01 This prompted the conclusion that the secondary position of adamantane was much more reactive than the tertiary position Allowing for the statistical factor of three (there are twelve secondary hydrogens but only four tertiary hydrogens in adamantane), these early results suggested that, per hydrogen, the secondary position is more reactive than the tertiary by cu 7 1 This is in sharp contrast to familiar radical reactions of adamantane (or of almost any other aliphatic hydrocarbon), where (per hydrogen) the tertiary position is normally at least as reactive CHEMICAL SOCIETY REVIEWS, 1996 as the secondary lo This radical selectivity is markedly dependent upon the reacting radical, with ratios (tertiary/secondary) close to unity for the most reactive radicals such as hydroxy1,II but rising to cu 20 for the relatively unreactive bromine atom Unfortunately, however, the Gif result with adamantane was incomplete Whereas the secondary position was predominantly oxidised to ketone (with much smaller amounts of adamantan 2 ol), P I *-----JX-2 0v it was later discovered that the tertiary position is functionalised not only by hydroxylation, but also by the adamantylation of pyridine (to give 2a and 27) l2 When this was taken into account, the per hydrogen reactivity ratio now favoured tertiary by ca 3 I, firmly in the range expected of radical chemistry, although suggestive of a rather reactive abstracting radical *+ But why should the tertiary intermediate behave so differently from the secondary' The non radical interpretation is simple, if somewhat contrived radicals are involved In functionalising the tertiary position, they are not involved in functionalising the secondary position The difference is attributed to the relative strengths of iron+arbon bonds The tertiary alkyl-to-iron bond is proposed to be so weak that it dissociates into radicals, the secondary alkyl to iron bond is considered to be suffi ciently strong that there is negligible dissociation within the life time of the intermediate 71* This analysis seems to find support from experiments (vide infra) in which sources of the two isomeric adamantyl radicals, when decomposed in pyridine-acetic acid mix- tures, both give adamantylpyridines l5 But could there be an alter native and purely radical interpretation? We shall reconsider these important results when some further aspects of Gif chemistry have been presented In addition to the revision of the reactivity ratios for adaman- tane, it also proved necessary to revise the mechanistic rationalisa- tion for these alkane functionalisations as more information became available For example, early proposals, which invoked a binuclear iron complex similar to those of the methane mono- oxygenases, were modified16 when it was discovered that, if GoAggIl oxidation (see Table I) of I 'C-ennched cyclohexane was monitored by I 'C NMR spectroscopy cyclohexyl hydroperoxide was revealed as a major long-lived intermediate l6l7 The concentration of this intermediate at first grew, but then dimin ished as it was replaced by the previously reported cyclohexanone This result prompted our own short contribution'* to this story, in which 180-incorporation experiments were carned out in order to investigate whether the oxygen of the product (and by implication that of the intermediate hydroperoxide) was derived from the hydrogen peroxide, as required by the then current mechanistic proposal, or from molecular oxygen The finding that it came sub- stantially from molecular oxygen led us to propose that the inter- mediate hydroperoxide might be none other than the product of a * It is important to be clear whether per hydrogen reactivity or simply site reactivity ratio is being presented Clearly the statistical factor is incorporated into one of these Unfortunately the early reports are not entirely self consistent in this regard In this article per hydrogen relative reactivities are used throughout unless explicitly stated otherwise + The early work was also in error in using data which were uniquely based on aroyloxyl radicals' 'to provide a reference value for the secondaryitertiary competition ratio expected for hydrogen abstraction from adamantane by oxygen centred radicals Although this was doubly flawed in that not only does selectivity vary markedly from radical to radical but also the assumed abstraction by aroyloxyl radicals is probably contaminated by aryl radical chemistry the comparison has been perpetuated in a very recent report from the Barton group IJ A RADICAL REAPPRAISAL OF GIF REACTIONS-M.J. PERKINS radical autoxidation.* However, when this isotope-incorporation result was corroborated in Barton's own laboratory,I7 it simply led to yet another revision of the nun-radical mechanism, essentially to its current form? i4 shown in Scheme lb (which fleshes out Scheme la). In this, the observed hydroperoxide is in equilibrium with a species in which molecular oxygen has inserted into the Fe-C bond of the organo-iron intermediate (A). The proposalIs of a radical autoxidation pathway presented the problem of what species could be responsible for the 3:1 selectivity in adamantane functionalisation. Our suggestion was that catalysed decomposition of hydrogen peroxide would generate hydroxyl ,and catalysed decomposition of intermediate al kyl hydroperoxides would give alkoxyl radicals. Both of these radical types are known to abstract hydrogen from alkanes, the former with almost neglig- ible selectivity,' the latter with a tertiary to secondary reactivity ratio of ca.4-5: 1 .I9 Clearly, the observed ratio lies between these limits. A very similar argument can be usedi8 to accommodate the modest kinetic isotope effects which have been obtainedgo for cyclohexane versus [2HI Jcyclohexanet. The essential features of the radical mechanism are outlined in Scheme 2.* slow Fe"' + H2& H+ + HOO.-Fe++ + veryfast Fe+* + H& HO-+ HO.-Fe++++ a(Fenton Reacbon) R-+ 02 -ROO ROO + H202 ROOH__t -Fe"* IFe'* + ROOH + HO-+ [ROD Scheme 2 A problem with the hydroxyl-alkoxyl interpretation is that, in the cyclohexane functionalisation, the product from cyclohexyloxyl radicals would be cyclohexanol.This is reported by Barton's group to be only a minor product, and not to be oxidised in situ to cyclo- hexanone, yet in our hands, under GoAgg" conditions, this trans- * At the time of our report, we considered ~nsitu reduction of molecular oxygen to H,O, to be unlikely This neglected the sequence outlined below which is a plausible source of the hydroxypyndines discussed later (see Scheme 4).but which would gen- erate insufficient H,O, to be competitive with the H,O, originally present (and isomers) 1H2O2 U + These explanations of the adamantane reactivity pattern, and of the isotope-effect data, would appear to require that the quantitative results should be a function of the progress of reaction, since at the commencement the dominant hydrogen-abstracting species must be hydroxyl, whilst at a later stage in the reaction the more selective alkoxyl must assume much greater importance This does not appear to have been tested* In our experiments, in which a GoAgg" oxidation of cyclodecane was carned out under an atmosphere of I8O,, the ]*Omcorporation into ketone was ca 50% It should be noted, however, that I6O2is available from termination reactions involving the peroxyl radicals in Scheme 2 (or by oxidation of HOO.) Indeed (in isotopically normal expenments) the ketone yield was little affected by changing from an air atmosphere to one of N, Only with a brisk N, purge was ketone formation almost eliminated 23 I formation appeared to be efficient.We have experienced other prob- lems of accurate reproducibility using hydrogen peroxide in these oxidations, including ones between individual investigators in this laboratory. These problems are hinted at in one published report?O which included inter alia the observation that in a GoAgg" system a 15"C temperature rise altered peroxide consumption from zero to 98%.Another possible difficulty is the fact that oxygen gas is gener- ated within the system. In the absence of adequate agitation, this could result in reaction mixtures which are supersaturated with respect to oxygen.Clearly, therefore, the physical procedure may be critical in determining the relative concentrations of vital compo- nents of these reaction systems. What, then, could be a radical interpretation of the pyridine- adamantylation results described earlier? In discussing a possible solution to this, it should first be noted that tertiary alkyl radicals are generally insufficiently reactive to alkylate simple benzenoid aromatics in significant yields. The exception to this is the alkyla- tion of protonated pyridines, extensively studied by Minisci and his colleagues.21 These reactions are characterised by the strongly facilitating influences of electron-donating substituents in the proto- nated pyridine, and they have been interpreted as having transition states with substantial charge-transfer character in which the alkyl radical becomes carbocation-like (Scheme 3).If this is so, then it is0 Q+R--R'+ I 1.Rb+QR Scheme 3 easy to see that tertiary alkylation might be facilitated to a greater extent than secondary alky1ation.s Any misgivings that this might not be the case for the bridgehead tertiary adamantyl system should be dispelled by the knowledge that the 1-adamantyl cation is more stable than its (secondary) 2-is0mer.~~ Were adamantyl radicals to be generated in partially protonated pyridine which contained dis- solved oxygen, we should then expect competition between alkyla- tion of the abundant pyridinium cation, and peroxyl radical formation [eqn.(5)and (6)].This should occur for both secondary H and tertiary radicals, but the reaction with oxygen, because it is essentially diffusion-controlled, will have almost the same rate con- stant for both radicals. On the other hand, it seems plausible, from the reasoning just presented, that the rate of reaction of the tertiary radical with the pyridinium ion might be appreciably greater than that of the secondary one, and therefore k,/k, may be correspond- ingly greater for the tertiary radical.§ This implies that at certain oxygen concentrations tertiary adamantylation of pyridinium may compete effectively with peroxyl production whereas secondary adamantylation might be negligible. It is actually possible to argue that Barton's results with the authentic adamantyl-radical precursors mentioned earlier tend to Absolute rate data for reaction of alkyl radicals with protonated pyridine are few Whilst butyl and tert-butyl radicals were reported to react at roughly the same rate?, the tert-butyl data were complicated by reversibility, and a marked steric factor was evident Therefore extrapolation to the adamantane radicals is difficult 232 support the above interpretation. N-Acyloxypyridine-2-thiones3 and 4 were the precursors used in these experiments;15 in the hv -adamantylpyridines Pyndine-Acetic Acid 3 4 Ii-7 absence of oxygen, both gave adamantylpyridines, but as each reac- tion was repeated with increasing concentrations of molecular oxygen present, the pyridine adamantylation products were replaced by adamantane oxidation products. However, whilst the 2-adamantylpyridines(5aand 5y) from 4 were virtually eliminated by oxygen concentrations corresponding approximately to GoAgglJ conditions, the same oxygen concentrations reduced the yield of I-adamantylpyridines (201.and 2y) from 3 by only ca. 50%.* Furthermore, Barton has very recently reportedt4 a model radical experiment in which butoxyl radicals, generated by di-tert-butyl peroxyoxalate decomposition in a pyridine solution of adamantane containing HCI (from the oxalyl chloride used in situ to prepare the peroxide) and under oxygen, yielded the 2 isomers, but apparently not the 5 isomers!t In the GoAgg" system, a key point of controversy, of much wider significance than in Gif chemistry alone, is whether or not an iron(II1) system can catalyse the production of hydroxyl radicals from hydrogen peroxide (the Haber-Weiss reaction).That it can has been argued by and is now widely accepted in a biolog- ical context. The manner whereby this is thought to happen involves a slow reaction which generates iron(I1) followed by a very rapid Fenton-type reaction in which the iron(rr) is re-oxidised (Scheme 2). A probe for participation of hydroxyl radicals in biological systems is the pattern of hydroxylation of added aromatic amino acids, such as phenylalanine.25 Added to the GoAggll system, phenylalanine does indeed show this pattern.I* The chemistry of hydroxyl radicals has been extensively studied, especially by pulse-radio1 ysis techniques, which have yielded a large number of rate constants for hydroxyl radical attack on organic mo1ecules.I' It can be deduced from these that if some 50% of the GoAggI oxidation of cyclohexane is initiated by hydroxyl radicals, then there should be a significant amount of hydroxylation of the solvent.In fact, the rate of reaction with most monocyclic aromatic compounds appears to be at least an order of magnitude slower than that with cyclohexane, so that reaction with cyclo- hexane will not be swamped by the large excess of pyridine. Are hydroxypyridines formed? Not only is the answer 'yes', but they are accompanied by bipyridyls,26 expected products of pyridine hydroxylation by the mechanism outlined in Scheme 4.The picture is further complicated by the instability of the hydroxypyridines under the reaction conditions: one possible fate may involve * Clearly, these results suggest that the rate of reaction of 1-adamantyl radicals with protonated pyridine is indeed greater than that of the corresponding reaction with 2-adamantyl. Indeed, based on reasonable assumptions regarding the concentration of oxygen in Barton's experiments, it is possible to argue that the 1-adamantyl rate is approximately one order of magnitude greater than that published for rert-butyl (see footnote 5 on previous page). + Though it should be recorded that secondary-alkylpyridineswere detected in a similar experiment with cyclooctane as substrate.CHEMICAL SOCIETY REVIEWS, 19% (andisomers) dimerimtion H Scheme 4 oxidation by iron(m).* This would presumably constitute an alter- native route to iron(II), and it is interesting that the reaction appears to have an induction period. This is evident in the initial slow build- up of hydroperoxide in cyclohexane 0xidation.1~ Especially in more recent work, the Gif systems have been extended by incorporating a variety of additional reagents, and the results obtained have been construed as affording further evidence against the possibility of radical pathways. One of the earliest of these variations incorporated diphenyl diselenide into a GiPV oxida- tion of cy~lohexane.~~~~~~~~ The product was no longer cyclohexa- none; instead, cyclohexyl phenyl selenide was obtained.However, it was reported that under the reaction conditions the diselenide was reduced to benzeneselenol (which could be intercepted by methyl iodide, giving methyl phenyl selenide). Since benzeneselenol was known to reduce secondary alkyl radicals to alkane with a rate con- stant approaching the diffusion it was concluded that cyclo- hexyl radicals could not be involved. Unfortunately, this rationalisation appears to have overlooked the high acidity of ben- zeneselenol, which exceeds that of acetic acid [ ~K,(PhseH)<5;*~ pK,(H,Se) = 3.731, so that the predominant species in the pyridine solvent must have been the conjugate base, PhSe-. Indeed, in the presence of zinc salts, it seems likely that it may be coordinated to zinc.Reaction of alkyl radicals with the benzeneselenolate anion would be expected to give the observed products, in a reaction which finds a close parallel in S,, processes [eqn. (7)]. The less acidic benzenethiol is not deprotonated under compar- able conditions, and addition of it, or of diphenyl disulfide (which is also reduced), lowers the yields of oxygenation products, but no alkyl phenyl sulfide is formed.I8 In these cases, the simple radical interpretation is that the thiol is intercepting alkyl radical to regen- rate a1 kane .I A subsequent modification, with results which again could appar- ently not be explained in terms of radical intermediates, involved the GifV oxidation of cyclohexane in the presence of trimethyl phosphite.The unexpected product of this reaction was cyclohexyl dimethyl phosphate.30u A 'control' experiment emphasised in sub-sequent reviews of this work showed that cyclohexyl hydroper- oxide is quite rapidly reduced to cyclohexanol by trimethyl phosphite, the latter being oxidised to trimethyl phosphate. But a key element may be seen to be absent from this control, namely * Iron(iii) is also a plausible candidate for the oxidant in Scheme 4 (but see footnote * on previous page). This diminution in yield is very close to that calculated taking known rate con- stants for reaction of secondary alkyl radicals with oxygen and with PhSH,and making a reasonable assumption regarding the oxygen concentration in the reaction mixture (M.Newcomb, personal communication). A RADICAL REAPPRAISAL OF GIF REACTIONS-M J PERKINS iron A wholly plausible reaction sequence in the presence of iron Se0-R-+ CO SW-RCO* salts is set out in Scheme 5 Iron(1i)-catalysed decomposition of the -h Radical Interpretahon OOH Meo\. PMeo---o n Me01 Meo-P-0MeO-P==O Nucleophde 0/ / Scheme 5 hydroperoxide would generate cyclohexyloxyl radicals Since alkoxyl radicals are known to add to phosphite to generate phos- phoranyl radicals, it seems reasonable to suppose that the tetra- alkoxyphosphoranyl radical 6 would be formed and that this would be particularly susceptible to one-electron oxidation, there is ample precedent for S,2 displacement (in this case of one of the small methyl groups) on the resulting tetraalkoxyphosphonium ion Critical to the evaluation of this reinterpretation is the determina- tion of the relevant rate constants for destruction of the hydroper- oxide, and an estimate of the iron(I1) concentration, but it is interesting that in the original work an additional control experi- ment, generally neglected in subsequent discussion, was carried out in the presence of an iron salt Under these conditions, the mixed phosphate was indeed produced 300 A parallel rationalisation is available for the formation of chloro- cyclohexane when triyhenylphosphine is added 30b (Scheme 6) Cr' Scheme 6 A thorough discussion of a reaction proceeding via a similar mechanism, i e one which also involves one-electron oxidation of an alkoxyphosphoranyl radical followed by nucleophilic displace- ment of alkyl from the resulting alkoxyphosphonium ion, was given recently by Kampmeier and Nalli 31 The presence of carbon monoxide in a cyclohexane oxidation gives cyclohexanecarboxylic acid, interpreted as arising by carbon monoxide insertion into the alkyliron intermediate 32 In radical chemistry, cyclohexylcarbonyl radicals might be expected to decar- bonylate, but there is in fact precedent in the literature for a process seoRCO.+ Fe"' sec~RC0' + Fe++ Scheme 7 such as that outlined in Scheme 7, in which the acyl radical, formed reversibly, is intercepted by one-electron oxidation 33 In all of these modifications, the radical mechanism assumes that the alkyl radical intermediate is intercepted by the added reagent, whereas the iron-oxo mechanism assumes that it is the intermediate iron alkyl (A in Scheme lb) which is diverted to product One strat egy which could perhaps allow these mechanisms to be differentiated would be competitive interception of the intermediate using systems for which the competition for alkyl radicals is well established Such competition was investigated for a number of systems in which the product was alkyl halide Two different types of competitive study were carried out with halogen donors * 34 One of these followed the strategy outlined above, with a single cycloalkane and two different halogen donors The other, which produced some particularly dramatic results, examined the competitive halogenation of two different hydro- carbons Arguably, these series of experiments provide some of the most compelling evidence against radical participation in the Gif oxidations For example, when judged by the bromination yields, using bromotrichloromethane as halogen donor, cyclohexane has a per hydrogen reactivity greater than that of any other cycloalkane examined, and sign$cantlv greater than the reactivrty of tertiary hydrogen in 2,3-dimethylbutane [C,H,, -H/Me,CHC(Me),-H = 10 21 The dimethylbutane result seems particularly damaging to the radical argument, in view of the earlier comments on relative reactivities of tertiary and secondary hydrogens The apparently lower reactivity of, e g cyclopentane when compared with cyclo-hexane is also out of line with radical behaviour, where radical reactivities can be analysed in terms of relative strain factors in the sp3 cycloalkane and the derived sp2 cycloalkyl radical Perhaps these results deal a fatal blow to the case for radicals However, there was apparently no attempt to obtain a total product balance in these experiments It is not impossible that the concentration of bro- motrichloromethane was at such a level that it competed effectively with oxygen for secondary alkyl radicals, but that it w~asinsuficient entirely to suppress reaction of the tertiary 2,3-dirnethyL-2-butyl radicals with protonated pyridine These tertiary radicals would be expected to be intercepted more slowly by the BrCCI,, but would be particularly reactive with respect to protonated pyridine The result might then be the observed depletion in the bromination yield Many other inconsistencies with behaviour expected of radical chemistry are claimed for relative reactivities for halogenation Space does not permit a full discussion of these, though it must be pointed out that relative substrate reactivities depend on the halogen-abstracting species For example, if bromination by BrCCl, added to Gif systems is not a chain process, reactivity pat- terns may be quite different from those found when the chain carrier is CCI, (although this would not, of course, explain the low tertiary reactivity found with dimethylbutane) It was noted earlier that Barton's group had accepted that the functionalisation of the 1-position of adamantane in Gif reactions does involve radicals Presumably the same is accepted as applying to the functionalisation of the tertiary sites in dimethylbutane The greater reactivity of cyclohexane is then attributed to the interven- tion of the non-radical mechanism, in which the cyclohexyliron intermediate (A in Scheme 1b) is formed relatively rapidly, and is then intercepted by BrCCl, One possible approach to resolving the question of whether or not the alkyl fragment in Gif oxidations has a discrete existence as a radical might be to employ the 'free-radical clock' method * For this, a suitable substrate must be found which, if oxidised to a radical, would then undergo rapid, unimolecular and character- istically radical rearrangement, competitively with inter- molecular trapping.Among the best alkyl-radical clocks are cyclopropylcarbinyl radicals which rearrange more or less rapidly to allylcarbinyl, depending upon the substituents present [eqn. (S)]. The fastest of these rearrangements occur on a timescale approaching that of molecular vibrations. When devising an experiment designed to use this approach, it is essential to ensure not only that the rearrangement is sufficiently rapid, but also that ionic or other non-radical pathways cannot result in formation of the expected rearrangement products. Thus, when 3-carene 7 was 0 8 subjected to Gif oxidation?5 the products included 9.However, the most likely derived radicals 8 are allylic, and probably, as with a-cyclopropylbenzyl radicals, cyclopropane ring-opening is thermodynamically unfavourable. Whilst radical autoxidation of 7 is known to give ring-opened products, it seems likely that the ring-opening involved cationic rearrangement of the initial prod- uct~.~~More recently, Newcomb’s group have subjected the GoAggI’l system to scrutiny with 1-methyl-2-phenylcyclo-propane; no products of oxidation at the methyl group were iso- lated which had nut rearranged.37* In this case, the free (2-phenylcyclopropy1)carbinyl radical is known to undergo very rapid rearrangement (k = 3 X 1011s--1),28yet, in marked contrast, when the same hydrocarbon was oxidised using a methane mono- oxygenase preparation, the only products of the enzyme-catal- ysed oxidation at the methyl were ~nrearranged!~~ Finally, we turn our attention to the recent work in which GoAgg systems have been modified by the replacement of hydrogen per- oxide by tert-butyl hydroperoxide (see Table 1) .8-39 An interesting distinction between these and the earlier H,O, systems is that the cycldkane substrate may be functianalised by reactions in which the alkyl intermediate is captured by an added nucleophile.For example, when the catalytic iron salt in cyclohexane oxidation is CHEMICAL SOCIETY REVIEWS, 1996 reaction of the alkyl radical with the nitroxide completely masked any reaction with the nucleophilic iron(II1) halide. Barton also pointed out a distinction between the experimental techniques of the two laboratories.This is that in the Italian work somewhat higher temperatures are employed, under which conditions alkyl-iron intermediates would be more prone to dissociate into radicals. Minisci’s group also noted that butoxyl radicals may be inter- cepted by nucleophilic alkenes, e.g. styrene, added to the system, followed by ligand-transfer oxidation of the resulting adduct radi- cals.42 Whilst the dkyl hydroperoxide systems have the advantage that reaction of possible alkoxyl radical intermediates with pyridine solvent would be negligible (in contrast to hydroxyl), in situ forma- tion of molecular oxygen cannot be excluded, since hydrogen abstraction from the hydroperoxide could form peroxyl radicals; dimerisation of these is a well documented source of 0,.In addressing Minisci’s mechanistic proposals, which depend essentiallyupon iron( 11)-promoted decomposition of hydroperoxide (cf. Scheme 2),Barton has investigated reactions in which hydro- carbon oxidation by H,O, or tert-butyl hydroperoxide is promoted in pyridine-acetic acid by added iron(I1) salts, and has now accepted that hydrocarbon activation in the ButOOH systems involving either iron(r1) or iron(rI1) does involve butoxyl radicals. On the other hand, he has proposed that with iron(I1) and H,O, an iron(Iv)-oxo intermediate is the active species which abstracts hydrogen, but that this does also give free alkyl radicals.43 It is, of course, pertinent to note that, if the tert-butyl hydroper- oxide chemistry with iron(II1) is accepted as radical, then it might be difficult to refute radical character at least for a part of the GoAgg reactions with hydrogen peroxide, i.e.that part which occurs sub-sequent toformation of intermediate alkyl hydroperoxide. I have emphasised here the work deriving directly from Barton’s original observations. Discussion of complementary approaches to alkane functionalisation, such as those of Que6;34 and of Sawye+ and their colleagues, have been almost completely neglected, as has work in which the iron is successfully replaced by other transition Both Que and Sawyer have argued that mechanisms similar to that of Scheme 1b are operating in their experiments, and have presented evidence for the formation of high-valent iron species; but evidence that these are directly involved in alkane activation is less compelling, and has begun to be questioned in recent p~blications.4~ In one of these, a relatively well-controlled system originating in Que’s laboratory was selected for experi- mental scrutiny.This employed tert-butyl hydroperoxide as oxidant, acetonitrile as solvent, and a tris-(2-pyridylmethyI)amine 1 iron complex as cataiyst. When the rerr-butyl hydroperoxide was replaced by 2-methyl- 1-phenyl-2-propyl hydroperoxide 10, high iron(II1) chloride, a significant product is chlor~cyclohexane.~~ Similarly, with added nucleophiles such as aide or thiocyanate, the corresponding cyclohexyl derivatives are formed.A1though ini-tially perceived by Barton asan extension of the methane monooxy- genase biomimetic pmcess, this has been interpreted by Minisci in terms of a well-established mechanism involving ligand-transfer oxidation of cyclohexyl radicals [eqn. (9)].“O Evidence for alkyl- radical intermediates came from their interception by added quino- line, the protonated form of which is more reactive towards alkylation than is protonated pyridine. The cyclohexyl radicals from cyclohexane oxidation, as well as the methyl radicals from butoxyl fragmentation, were trapped as alkylquinolines. Indeed, in the absence of a halide counter-ion, cyclohexylpyridines were found. Minisci’s interpretation was immediately ~hallenged;~’ one argu- ment wasthat during cyclohexane oxidation in the presence of both halide and a stable nitroxide, halogenation of cyclohexane pre- dominated aver radical trapping by nitroxide, but when, instead, a typical alkyl radical precursor was used, the diffusion-cantrolled * The possibility that this result might be interpreted in terms of cationic ring-opening of an initially formed cyclopmpylmethanol was excluded when authentic (2-phenylcyclopropy1)methanol gave no rearrangement pfoduct under GoAggI“ conditions and was largely (90%)recovered unchanged.37 Me Me\‘“,Y,,-cFf” p~+.-PhCHr .+ c=o hile Me Me’ 10 yields of products arising via benzyl radicals were formed, strongly suggestive of the intermediacy of alkoxyl radicals which, in this case, rapidly fragment.It was argued that if the mechanism advanced by Que, involving an iron-oxo intermediate and by- passing radicals, were operative, then there should be no significant difference between the reactions with the two hydroperoxides.* The report concluded by suggesting ‘that each claim for alkyl hydroper- oxide-derived high-valent metal-oxo species as oxidising agents should at least be checked using 2-methyl- 1-phenyl-2-propyl hydroperoxide as a mechanistic probe.’47u Interestingly, in one recent case in which a metal-oxo species does appear to react as an ‘oxyl’ radical, its reactivity was very much lower, and its selectivity correspondingly greater, than are those of terr-butoxyl: the metal-oxo species in question is chromyl Where measurements have been made, the enzyme systems are also more selective. * At present, the possibility that a small amount of radical fragmentation might redi-rect the overall process cannot be dismissed.A RADICAL REAPPRAISAL OF GIF REACTIONS-M J PERKINS A final point may be made by further reference the P-450mech-anism One, at one time puzzling, feature was the absence of any significant kinetic isotope effect in competition between oxidation by the enzyme of deuteriated and undeuteriated substrates There is, however, a marked intramolecular isotope effect when partially deuteriated substrates are oxidised Ih This difference can easily be rationalised if the rate-limiting step is transfer of the hydrocarbon substrate into the binding pocket of the active site within the enzyme structure * And, of course, it is within the constraints of this site that the oxygen rebound occurs so rapidly Without those con- straints, the radical organic chemist might anticipate some contribu- tion from geminate recombination within the solvent cage if an iron-oxo species were to abstract hydrogen in a simple chemical model, but would expect also that the majority of any radicals formed would diffuse away from their site of formation This simple picture may not always apply in organometallic instances, relatively efficient cage recombination has been reported in some systems where there is no greater constraint than the solvent cage of a non- viscous solvent This may add a further dimension to Gif chem- istry In conclusion, it has been the purpose of this short review to evaluate some of the evidence against radicals in the continually broadening spectrum of Gif chemistry (where the solvent system chosen for much of the early work has probably played a uniquely complicating role), and to argue that a radical interpretation of much of the data, for at least some of these oxidation systems, remains a tenable alternative to that favoured in other review articles Inevitably, space restrictions have precluded comprehensive report- ing, and well-informed readers will recognise a certain selectivity, designed to establish the view that the case against radicals is unproven Nevertheless, it IS seldom, in recent chemistry, that so much experimental information may seem capable of more than one explanation, and this adds a particular savour to the Gif problem Not infrequently, when this situation has prevailed during earlier scientific investigations, the truth has been found to comprise ele- ments of both of the conflicting analyses Mechanistic hypothesis undoubtedly has a major role to play in addressing the problem -but investigators are bound to consider all possible interpretations of their results, and should not overlook the fact that, as scientists, 'we are dedicated to the discovery of truth 'sl Note added in proof Since this review was submitted, a summary of the work of the Milan group on the use of tert-butyl hydroper-oxide as a Gif oxidant has been published (F Minisci, F Fontana, S Araneo, F Recupero and Lihua Zhao, Synlett, 1996, 119), as have the results of Newcomb et a1 on the use of cyclopropyl- carbinyl radical clocks to investigate GoAggili system (M Newcomb, P A Simakov and S -U Park, Tetrahedron Lett, 1996,37,8 19) In the latter work, further evidence is adduced for the occurrence of aromatic hydroxylation in these reactions Other significant publications include the following D W Snelgrove, P A MacFaul, K U Ingold and D D M Wayner, Tetruhedron Lett, 1996,37, 823, D H R Barton, Bin Hu, D K Taylor and R U Rojas-Wahl, Tetrahedron Lett, 1996, 37, 1133, J Kim, R G Harrison, C Kim and L Que,J Am Chem Soc , 1996,118, 4373, D T Sawyer, A Sobkowiak and T Matsushita, Acc Chem Res , 1 996,29,407 Acknowledgements I am indebted to Professors K U Ingold, Martin Newcomb and Lawrence Que Jr ,and to Dr B P Roberts for helpful comments, and to Professor Newcomb for permission to quote unpublished results from his laboratory, to Dr D D M Wayner and to Roderick Aliazas for stimulating discussions relating to their own analyses of this problem, and to a referee for drawing my attention to the papers by Tulley et a1 (ref 49) The interesting question arises here as to what intramolec ulur isotope effect would be expected tor a diftusm controlled hydrogen abstraction in a mobile solvent e ,g by hydroxyl radicals from C,H,D, Apparently experimental data do not exist The value of unity noted earlier was obtained by companng liquid phase rate data for C,H,, and for C,DI, This was appropriate tor comparison with the Gif experiments There are however gas phase data for hydrogen abstraction from alkanes by HO which not only give a kinetic isotope effect ot ((I 2 hui ulto 3hou (I rhreejold prejerence (ut 2Y4 K) for uh5truc tion of tertruri ruthrr than tei ondur\ h\dro,gen -lv References 1 (a) Cytochrome P 450 Structure, Mechanism, and Biochemistry ed P R Ortiz de Montellano, Plenum Press, New York, 1986, (b) J T Groves,G A McClusky, R E White and M J Coon, Biochim Biophys Res Commun , 1978, 81, 154, (c) J K Atkinson and K U Ingold, Biochemistry, 1993, 32, 9209, for a very recent discussion, see M Newcomb, M H Le Tadic Biadeatti, D L Chestney, E S Roberts and P F Hollenberg,J Am Chem Soc ,1995,117,12085 2 D Griller and K U Ingold, Acc Chem Res , 1991, 24, 139, V W Bowry, J Lusztyk and K U Ingold,./ Am Chem SOC ,1991,113,5687, D C Nonhebel, Chem Soc Rev, 1993,22,347 3 E g (a)M P Woodland,D S Patil and R Camrnack, Biochim Biophys Acta, 1986,2330, (6)J E Baldwin, J Heterocycl Chem ,1990,27,71, (c) K I Kivirkko, R Myllyla and T Pihalajaniemi, FASEB, 1989, 3, 1609, (d)D L Ziering and R A Pascal,./ Am Chem SOC ,1990,112, 834 4 A L Feig and S J Lippard, Chem Rev, 1994,94,759,see also T H Peterson, Acc Chem Res , 1995,28, 154, R H Crabtree, Chem Rev, 1995,95,987 5 R A Leising,B A Brennan,L Que,B G Fox and E Munck,J Am Chem SOC , 1991, 113, 3988, Y Dong, H Fujii, M Hendrich, R A Leising,G Pan,C R Randall,E C Wilkinson,Y Zang,L Que,B G Fox, K Kauffmann and E Munck,J Am Chem Soc , 1995,117,2778 6 D H R Barton, M J Gastiger and W B Motherwell, J Chem SOC , Chem Commun , 1983,41 7 D H R Barton and D Doller, Ace Chem Res , 1992, 25, 504, G Belavoine, D H R Barton, Yu V Geletii and D R Hill, in The Activation of Dioxygen and Homogeneous Catalytic Oxidation, ed D H R Barton, A E Martell and D T Sawyer, Plenum Press, New York, 1993,p 225,D H R BartonandD K Taylor,Ru~~Chem Bull, 1995,44,575 8 D H R Barton,W Chavasir1.D R HillandB Hu,NewJ Chem ,1994, 18,611 9 (a) D H R Barton, J Boivin, W B Motherwell, N Ozbalik, K M Schwartzentruber and K Jankowski, Nouv J Chim ,1986,10,387,(h) G Belavoine, D H R Barton, J Boivin, A Gref, P Le Coupanec, N Ozbalik, J A X Pestana and H Riviere, Tetrahedron, 1988,44,1091 10 K U Ingold, in Free Radical$, ed J K Kochi, Wiley, New York, 1972, vol 1,p 37 11 G V Buxton,C L Greenstock, W P HelmanandA B Ross,./ Phys Chem Ref Data, 1988,17,513 12 G Belavoine, D H R Barton, J Boivin, P Le Coupanec and P Lelandais, New J Chem , 1989,13,691 13 J Fossey, D Lefort, M Massoudi, J Y Nebelec and J Sorba, Can J Chem , 1985,63,678 14 D H R Barton, A H Beck and D K Taylor, Tetrahedron, 1995,51, 5245 15 D H R Barton, F Halley, N Ozbalik, M Schmitt, E Young and G Belavoine,J Am Chem SOC 1989,111,7144 16 D H R Barton, E Csuhai, D Doller and G Belavoine, J Chem SOC , Chem Commun ,1990,1787 17 D H R Barton, S D Beviere, W Chavasiri, E Csuhai, D Doller and W G Liu,J Am Chem Soc ,1992,114,2147 18 C Knight and M J Perkins,J Chem Soc ,Chem Commun ,1991,925 19 C Walling and B B Jacknow, J Am Chem SOC ,1960,82,6108 20 S B Kim, K W Lee, Y J Kim and S I Hong, Bull Korean Chem SOC , 1994,15,424 21 E g F Minisci and A Citterio, Adv Free Radical Chem ,1980,6,65 22 A Citterio, F Minisci and V Franchi, J Org Chem ,1980,45,4752 23 G A Olah, G Liang and G D Mateescu,J Org Chem ,1974,39,3750 24 C Walling, R E Partch and T Well, Proc Natl Acad Sci USA, 1975, 72,140 25 J Z Sun, H Kaur, B Halliwell.X Y Li and R Bolli, Circ Res , 1993, 73,534 26 D H R Barton, S D Beviere, W Chavasiri, D Doller, W G Liu and J H Reibenspies, New J Chem , 1992,16,1019 27 D H R Barton, J Boivin and P Le Coupanec,J Chem Soc ,Chem Commun .1987, 1379 28 M Newcomband M B Manek, J Am Chem SOC , 1990,112,%62 29 See T B Rauchfuss in, The Chemistry of Organoselenium and Tellurium Compounds. vol 2, ed S Patai, Wiley, Chichester, 1987,p 339 30 (a) D H R Barton, S D Beviere and D Doller, Tetrahedron Lett, 1991 ,32,4671, (6)D H R Barton and S D Beviere, Tetrahedron Letr , 1993,34,5689 31 J A KampmeierandT W Nalli,J Org Chem , 1993,58,943 32 D H R Barton, E Csuhai and D Doller, Tetrahedron Lett, 1992,33, 4389 33 D D Coffman, R Cramer and W E Moebel, J Am Chem Soc ,1958, 80 2882 236 34 D H R Barton, E Csuhai and D Doller, Tetrahedron Lett, 1992,33, 3413 35 K -W Lee, S -B Kim, S -B Kim and D H R Barton, Buff Korean Chem SOC ,1991,12,459 36 D A Baines and W Cocker, J Chem SOC ,Perkin Trans I, 1975,2232 37 M Newcomb, S -U Park and P A Simakov, unpublished results 38 K E Liu, C C Johnson, M Newcomb and S J Lippard, J Am Chem SOC,1993,115,936 39 D H R Barton, S D BCvikre, W Chavasiri, D Doller and B Hu, Tetrahedron Lett ,1993,34,187 1 40 F Minisci and F Fontana, Tetrahedron Lett, 1994,35, 1427 41 D H R Barton and D R Hill, Tetrahedron Lett, 1994,359,1431 42 F Minisci, F Fontana, S Araneo and F Recupero, Tetrahedron Lett, 1994,35,3759,J Chem SOC ,Chem Commun ,1994,1823 43 C Bardin, D H R Barton, B Hu, R Rojas Wahl and D K Taylor, Tetrahedron Lett ,1994,35,5805 44 R A Leising, J Kim,L Q Perez and L Que, J Am Chem SOC ,1993, 115,9524, T Kojima, R A Leising, S Yan and L Que, J Am Chem SOC , 1993, 115, 11328, S Menage, E C Wilkinson, L Que and M Fontecave, Angew Chem ,Int Ed Engl ,1995,34,203,M Lubben, A Meetsma, E C Wilkinson, B Feringa and L Que, Angew Chem ,fnt Ed Engf ,1995,34,1512 CHEMICAL SOCIETY REVIEWS, 1996 45 H -C Tung, C Kang and D T Sawyer, J Am Chem SOC , 1992,114, 3445, C Kang, C Redman, V Cepak and D T Sawyer, Bioorg Med Chem ,1993,1,125,A Sobkowiak,A Qui, X Liu, A Llobet and D T Sawyer, J Am Chem SOC , 1993, 115, 609, D T Sawyer, C Kang, A Llobet and C Redman, J Am Chem SOC , 1993,115,5817,D T Sawyer, X Liu, C Redman and B Chong, Bioorg Med Chem ,1994, 2,1385,C Kang, A Sobkowiak and D T Sawyer, lnorg Chem ,1994, 33,79, D T Sawyer, J P Hage and A Sobkowiak, J Am Chem SOC , 1995,117,106 46 E g Yu V Geletii, V V Lavrushko and G V Lubimova, J Chem SOC , Chem Commun, 1988, 936, D H R Barton, D Doller and Yu V Geletii ,Mendefeev Commun ,1991, 1 15 47 (a)I W C E Arends,K U Ingoldand D D M Wayner,J Am Chem SOC ,1995,117,4710,(6)ARabion,S Chen,J Wang,R M Buchanan, J L Seris and R H Fish, J Am Chem SOC , 1995,117,12356 48 G K Cook and J M Mayer, J Am Chem SOC .1995,117,7139 49 F P Tulley, J E M Goldsmith and A T Droege.J Phvs Chern, 1986,90,5932, A T Droege and F P Tulley, J Phvs Chem ,1986,90, 5937 50 T W Koenig, B P Hay and R G Finke, Pofvhedron, 1988, 7, 1499 5 1 J F Bunnett, Acc Chem Res ,1982,15,267

ISSN:0306-0012    

DOI:10.1039/CS9962500229

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

On The Mechanism of Gif Reactions Derek H. R. Barton Department of Chemistry, Texas A&M University College Station, TX 77843-3255, USA The foregoing review article' makes extensive reference to Gif chemistry and involves the role that oxygen and carbon radicals may play in this phenomenon. In brief, Gif chemistry permits the conversion of saturated hydrocarbons into ketones at room temper- ature under nearly neutral conditions. There is also a surprising chemoselectivity where saturated hydrocarbons are more reactive than would be expected. Thus, ketones were originally2 formed in the presence of H2S, normally much more easily oxidized. Over the years, our theory, which originally was an hypothesis, has evolved to explain all the facts that we have observed.Other suggestions about mechanism are always welcome, but they must explain all of the facts and not just a small selection of data. From the beginning it has been important to distinguish between oxygen- and carbon-radicals and mechanisms which do not involve radicals. Fortunately, great progress has been made in the last two years in distinguishing the role of radicals in Gif chemistry from that important mechanism where they are not involved. Amongst many indications which are mechanistically helpful we would underline the following techniques. (i) The coupling of carbon radicals to pyridine as pioneered by Hey3 and later by Mini~ci.~This technique has always proved reliable. (ii)The reac- tion of carbon radicals with chloride bonded to Fel" to afford R-CI and Fell.This well known reaction' has played an important role in distinguishing between Fe" and Fellr chemistry. Finally, we would emphasize the importance of distinguishing between Fell and Fell' by simple chemical titration.6 In Gif chemistry, we recognize that Fell activated by superoxide and Fe"1 activated by nucleophilic displacement by H202 afford the Professor (Sir) Derek H. R. Barton was born on September 8, I918 in Gravesend. Kent. His first academic appointments (I 945-1 949) were as Lecturer in Inorganic and then Physical Chemistry at imperial College. After a stint at Harvard (I 949-1 950), which pro- duced eventually (1969) a Nobel Prize, he was appointed Reader at Birkbeck College, then Professor, and in 1954 was elected FRS.After two years (1955-1957) as Regius Professor in Glasgow, he returned to Imperial College (I 957-1 978) as, eventually. Hofmann Professor of Organic Chemistry. His career became more interest- ing when he was appointed as 'Directeur de l'lnstitut de Chimie des Substances Naturelles ',a large CNRS Laboratory in Gif-sur-Yvette, France. in 1986, he became a European retirement refugee at Texas A&M University where he is currently very happy as Dow Professor of Chemical Invention. He was elected an Honorary member of the National Academy in 1970 and received the Priestley Award of the American Chemical Society in 1995. His experience of working in three countries spanning two continents is probably unique.As he has commented before, 'the older you are the harder you have to work because the time left to work is diminishing.' His current schedule of 3-00 a.m. to 8:00 p.m., seven days a week is probably at his limit, pending transfer to another, celestial laboratory where perhaps you can work 24 hours a day forever! Imagine what the literature must be like! 237 Fe"+ HOz-Fe"+ H202-Fe"' + H202 Fell'-OOH Fell-OOH+ + Fev=O Fe"=O+ + Fev-CHR1 R2 Few-C+HR1 R2 + O=CR'R~ Fe"' + 'CHR'R' Scheme 1 same FeI"-OOH species (Scheme 1). Postulated evolution to an FeV oxenoid species and reaction with a saturated hydrocarbon CH2RlR2 affords an Fev species with an Fev-carbon bond. Eventually this affords ketones selectively, showing preferred inser- tion into secondary C-H bonds.A second route to activation is provided by the nucleophilic dis- placement of H,O, on Fell to furnish FeII-OOH from which an FelV oxenoid species results. This shows similar reactivity towards satu- rated hydrocarbons and affords an FeIV species which rapidly breaks down to Fell1 and a carbon radical (Scheme 1). We have good evi- dence that hydroxyl radicals are not involved in Gif chemistry in pyridine? Indeed hydroxyl radical attack could not explain the selectivity for secondary attack nor the fact that all systems have the same kinetic isotope effect of 2.1 (cyclohexanevs. perdeuteriocyclo-hexane) and the same selectivity for adamantane functionalization. This is always close to 1.O for C2/C3where C2 represents the sum (in mmol) of all secondary products and C3 is the same for all tertiary products.For tert -butoxyl radicals, in pyridine, the C2/C3is 0.3.This is a new value determined with care and not a quotation from the lit- erature.x In Scheme 1 we now distinguish two manifolds: Fe1I1-FeV, the non-radical producing manifold and FeI1--FelV, the radical mani- fold.8 In principle, electron transfer between valence states could remove these differentiations. Fortunately, the chemistry of Fell + H202is completely different from that of Fe1I1 + H20,. Also, the Fell or Fell1 + equivalent H202in both manifolds can be varied widely without any change in efficiency. So electron transfer here is not a fast process.The conclusion that iron-carbon bonds were involved in Gif chemistry came from early studies9 on the oxidation of adamantane using a superoxide +Fell system (ZnO as reductant) in pyridine-acetic acid. On reducing the oxygen pressure coupling of the tertiary position to pyridine was detected, but not at the sec- ondary position. Later work showed'O that genuine secondary radi- cals from adamantane showed the same competitive reaction as did genuine tertiary radicals. Hence, there was a difference which was most easily explained (Occam's Razor) by the formation of iron-carbon bonds at both positions. In the tertiary case the bond was so weak that spontaneous fragmentation to carbon radicals took place. It has not been easy to detect iron-carbon bonds in Gif systems.They may be present in low concentrations. The best evidence comes from recent work by Newcombll who has shown that a number of hyperactive traps do show the presence of radicals in Gif oxidation If iron-carbon bond formation precedes further chem- istry, then the structural driving force for the rearrangement may well weaken the iron-carbon bond to the point where it dissociates to give radicals In the discussion of Professor Perkins as to whether cyclohexa- no1 or cyclohexyl hydroperoxide is the precursor of the ketone, we have studied the rate of oxidation of cyclohexanol It is very slow in the Fe1I-Zno-pyridine-acetic acid system, but somewhat faster with the Fe1I1-H2O2 procedure There is, however, good evidence that the main source of the ketone, as long as pyridine-acetic acid is the solvent, is the hydroperoxide Professor Perkins suggests that the hydroperoxide, by reaction with Fell, is the source of the cyclohexyloxyl radical and hence of the alcohol He has overlooked the study that we madel, to show that with FeI1Cl2 in pyridine-acetic acid cyclohexyl hydroperoxide is converted rapidly (2 min ) and quantitativelv into cyclohexanone No cyclohexanol is formed In the FeIl-Zn" system the addition of increasing amounts of tri-phenylphosphine changes formation of ketone to formation of alcohol However, the total of ketone +-alcohol is constant over a wide range of Ph,P concentration l2 This important experiment shows that alkoxyl and alkylperoxyl radicals are not present, that the activated iron species reacts faster with the hydrocarbon than with Ph,P and that the activation to give hydroperoxide, which was then reduced to alcohol, was constant Similar studies were made with quenching experiments (benzenethiol with or without oxalic acid) In the Fe111-H202 series a l3NMR experiment proved that the hydroperoxide preceded the ketone Quenching experiments with oxalic acid demonstrated that ketone came mainly from hydroper- oxide and not from alcohol After reference to this work Professor Perkins comments on some difficulty in reproducing oxidation results obtained using hydrogen peroxide In fact, there are many articles by Sawyer on the H,O,-pyridine-acetic acid system, in one of which we were co- authors l3 l4 There was no difficulty in obtaining reproducible results The same applies to the extensive work of Professor Ulf Schuchardt and his colleagues Is This work on the oxidation of cyclohexane has examined in depth the FeI1-Zno-pyridine acetic system and the Fe1"-H,02 system with various ligands The results are always as good as ours and sometimes better with respect to yield In a comparison of iron and ruthenium chemistry,16 work on the repetition of the FeJ1-Zno process gave a turnover number of 1000,similar to our own results A communication from Geletii17 using H,O,-Fe"l in pyridine-acetic acid reported that cyclohexa- none was formed by a non-radical reaction and not via cyclohexa- no1 Similar results were obtained with Cull salts An interesting study of cyclohexane oxidation to cyclohexanone using the Fe111-H,02-pyridine-acetic acid system has been reported l8 The various variables were analysed including the kinetics There was no difficulty in repeating the Gif-type chemistry by these authors We have detected one factor that can influence yield in H20, experiments Some, but not all, metal syringes catalyse the decomposition of H,02 to oxygen and water This is usually obvious from the oxygen bubbles However, it would be normal practice to carry out the blank experiment to make sure that the H202drawn into the syringe is, in fact, delivered intact into a solu- tion of the solvent actually being used The non-existence of hydroxyl radicals in pyridine has already been commented upon earlier It is suggested by Professor Perkins that hydroxylated pyridines would be oxidized by H,O,-Fe"I In pyridine as solvent all the hydroxy-pyridines are recovered intact l9 Of course, the 2- and 4-hydroxypyridines are really amides, so oxidation would not be expected With regard to the interesting reaction2" which converts saturated hydrocarbons into dimethyl phosphates by using FeI1-Zno in pyri-dine-acetic acid in the presence of trimethyl phosphite, the follow- ing comments are relevant Trimethyl phosphite is well known to react with alkylhydroperoxyl radicals to reduce them to alkoxyl rad- icals which in turn are reduced to alkyl radicals A blank experiment with trimethyl phosphite, oxygen and cyclohexyl radicals was carried out in a previously cited paper I* In the blank experiments with trimethyl phosphite, cyclohexyl hydroperoxide and Fell, CHEMICAL SOCIETY REVIEWS, 1996 approximately equal amounts of cyclohexanone, cyclohexanol and dimethylcyclohexyl phosphate were formed No cyclohexane was observed in these accurate I3C studies In order for the Scheme 5 of Professor Perkins to be operative, the Fell1 oxidation of the inter- mediate radical would have to be favourable thermodynamically It is doubtful if this can be true The product of the proposed Arbusov reaction that makes the dimethylcyclohexyl phosphate has recently been identified by I3C NMR It is methyl acetate and not an N-methylpyridinium salt In any case, the initial addition of the cyclohexyloxyl radical postulated by Professor Perkins should have lead to immediate deoxygenation to afford a cyclohexyl radical (vide supra) The proposal in the Scheme 6 of Professor Perkins is even less likely to explain the experimental facts As above, the addition of the cyclohexyloxyl radical to triphenylphosphine would lead at once to deoxygenation to the corresponding cyclohexyl radical Over a number of years we had carried out Gif Fe1I1-H,O, oxida- tion of saturated hydrocarbons to give ketones in the presence of chloride and bromide anion without seeing a trace of alkyl chloride or bromide It was, therefore, a surprise when the addition of hydro- gen peroxide to FeCI, in the presence of triphenyl phosphine in pyridine-acetic acid gave smooth formation of cyclohexyl chloride instead of the ketone which was normally produced in the Fe1I1-FeV manifold 22 Clearly the activation of the alkane was nearly as great as it was for the usual ketone formation After a helpful publication by Mini~ci,2~ we realized that alkyl chloride formation was due to production of Fell In fact, whilst triphenylphosphine reduces Fell1 to Fe" only slowly, the addition of H202 produces a fast formation of Fell and of Ph,P=O The Fel1-FelV manifold then proceeds to activate the hydrocarbon and to make carbon radicals These combine with the chloride bonded to Fell1 to make the observed chloride In principle, this reaction reforms Fell However, there is another oxidation reaction with H,O, which oxidizes Fell to Fe"' in competition with the chlorination reaction and eventually all the Fell is reconverted to Fell1 These reactions provide a valuable proof that the Fell1 + H20, reaction makes the ketone by a non-radical mechanism * If one adds H,O, portionwise to an Fell salt in pyri-dine-acetic acid containing chloride ion, alkyl chloride is first formed However, as soon as all the Fell is converted into Fell1 (titra- tion) chloride formation ceases and the Fe1I1-FeV manifold more slowly produces ketone If more Fell is added, rapid alkyl chloride formation recommences, then ceases and is replace by ketonisation when all the Fell has been converted into Fell1 Most experiments have been done with cyclohexane We have, of course, shown by suitable blank experiments that cyclohexyl chloride is inert under the Fe111-H202 oxidation conditions and is not the source of cyclo- hexanone When all the Fell has been converted to Fell1 there is still a large excess of chloride ion present, some of which is bonded to Fell1 So if the FelI1-H,O, system were producing carbon radicals it would still be making alkyl chloride Indeed the alkyl chloride reac- tion is much faster than the ketonisation process 24 The comparison of Professor Perkins of radical bromination and Gif bromination fails to mention certain important facts Citation is made of the preliminary communication,2s but not of the full paper26 In the latter, mass balances are given for all the hydro- carbons that are not too volatile These are satisfactory mass bal- ances and there is no reason to think that the very volatile hydrocarbons (cyclopentane and 2,3-dimethylbutane) would not follow the same reactions More important is the failure to mention the comparative bromination of cyclohexyl bromide Radical bromination affords I ,2-dibromides as major products, whereas in Gif bromination 1,2-dibromides are very minor and 1,4-dibrorno- cyclohexanes are the major product This bromination in the 4-posi- tion corresponds to Schuchardt's observationI5 that the ultimate oxidation product of cyclohexanone is cyclohexane- 1,4-dione As far as tert-butyl hydroperoxide (TBHP) reactions are con- cerned, these have a kinetic isotope effect of about 7, very different from the 2 1 found for Gif chemistry It is clear that these reactions are largely radical in nature The slow formation of chloride and other congeners from cy~lohexane~~ is probably due to radical chemistry produced by reduction of a small amount of Fell1 to Fell If the reaction is started using Fell then the derivative formation is ON THE MECHANISM OF GIF REACTIONS-DEREK H R BARTON fast28 and we agree involves carbon radical formation by reaction with tert-butoxyl radicals The contrast between H202 and TBHP chemistry finds a possible explanation in the importance of the ligands in Gif chemistry All the Gif reactions are only seen when the right kind of carboxylate ligand is present 2429 This chemistry probably involves an Feiii-O-O-Feiii functionality stimulated by carboxylate bridging This peroxyl function is not possible with TBHP Finally, I would point out that if you consider the whole body of evidence, carbon radicals, when present, can be detected easily In those reactions where carbon radicals cannot be detected an alter- native mechanism must be proposed Gif chemistry is a well estab- lished experimental fact But if any other theory can be advanced to explain all of the facts, we shall be happy to consider it Such a theory must explain also the Gif paradox How is it possible to generate an iron species which attacks selectively saturated hydro- carbons in the presence of PPh,, (MeO),P, H2S, even PhSeH etc , reagents which by conventional standards are much more easily oxidized’ We have offered an explanation in the as yet unappreci- ated nature of iron-hydrogen peroxide derived species References M J Perkins,Chem Soc Rev,19%,229 D H R Barton, M J Gastiger and W B Motherwell.J Chem SOC Chem Commun , 1983,41 D H Hey, C J M Stirling and G H Williams, J Chem Soc ,1955, 3963,and references there cited F Minisci and A Citterio, Adv Free Radical Chem , 1980, 6, 65, F Minisci Acc Chem Res , 1975,8, 165 J K Kochi, in Free Radicals, ed J K Kochi, Wiley, New York, 1973, pp 591-683 L J Clark, Anal Chem . 1%2,34,348 D H R Barton,S D Beviere,W Chavasiri,D Doller,W G Liuand J H Reibenspies,New J Chem ,1992,16,1019,D T Sawyer,C Kang, A Llobet and C Redman, J Am Chem SOC, 1993, 115, 5817, J P Hage, A Llobet and D T Sawyer, Bioorg Med Chem , 1995,3.1383 C Bardin, D H R Barton, B Hu, R Rojas Wahl and D K Taylor. Tetrahedron Lett , 1994,35,5805 D H R Barton, J Boivin, W B Motherwell, N Ozbalik and K M Schwartzentruber, Nouv J Chim 1986,10,387 10 D H R Barton, F Halley, N Ozbalik, M Schmitt, E Young and G Balavoine, J Am Chem Soc ,1989,111,7144 11 M Newcomb, P A Simakov and S V Park, Tetrahedron Lett ,in press 12 D H R Barton, S D Beviere, W Chavasiri, E Csuhai, D Doller and W G Liu,J Am ChemSoc, 1992,114,2147,DH R Barton,E Csuhai, D Doller and G Balavoine J Chem SOC Chem Commun ,1990, 1787 13 C Sheu, A Sobkowiak, L Zhang, N Ozbalik, D H R Barton and D T Sawyer, J Am Chem SOC ,1989,111,8030 14 C Sheu, A Sobkowiak, S Jeon and D T Sawyer, J Am Chem Soc , 1990, 112, 879, C Sheu, S A Rickert, P Cofre, B Ross, A Sobkowiak, D T Sawyer and J R Kanofsky, 1990,112,1936,C Sheu and D T Sawyer, 1990 112,8212, and later papers from the Sawyer group15 Summanzing article U Schuchardt, W A Carvalho and E V Spinace, Svnlett, 1993,713,and references there cited 16 G Powell, D T Rickens and L Khan, J Chem Res (S),1994,506 17 Y V Geletii,V V LavrushkoandG V Lubimova, J Chem Soc Chem Commun , 1988,936 18 S B Kim, K W Lee, Y J Kim and S 1 Hong, Buff Korean Chem SOC, 1994,15,424,S B Kim and K W Lee, Korean J Chem Eng , 1995,12, 188, and prior references there cited 19 D H R Barton, B Hu and R U ROjaS Wahl, unpublished observations 20 D H R Barton, S D Beviere and D Doller, Tetrahedron Lett , 1991, 32,4671 21 D H R Barton and D K Taylor unpublished observations 22 D H R Barton and S D Beviere, Tetrahedron Lett , 1993,34,5689 23 F Minisci and F Fontana, Tetrahedron Lett .1993,35, 1431 24 D H R Barton, B Hu, D K Taylor and R U Rojas Wahl, J Chem Soc Perkin Trans 2,1996,1031 25 D H R Barton, E Csuhai and D Doller, Tetrahedron Lett, 1992,33, 3413, 26 D H R Barton, E Csuhai and D Doller, Tetruhedron, 1992, 48, 9195 27 D H R Barton, S D Beviere. W Chavasiri, D Doller and B Hu, Tetrahedron Lett , 1993,34, 1871, D H R Barton and W Chavasiri, Tetrahedron. 1994,50. 19,D H R Barton. S D Beviere and W Chavasiri, Tetrahedron, 1994.50,31, D H R Barton and W Chavasiri, Tetrahedron. 1994,50,47 28 D H R Barton,B Chab0t.N C Delanghe,B Hu,V N LeGloahec and R U Rojas Wahl, Tetrahedron Lett, 1995,36,7007 29 D H R Barton,B Hu,D K Taylorand R U Rojas Wahl, Tetrahedron Lett, 1996,37,1133 30 D H R Barton and D Doller,Acc Chem Res ,1992,25,504

ISSN:0306-0012    

DOI:10.1039/CS9962500237

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Application of Fluorescence Microscopy to a Study of Chemical Problems R. S. Davidson Department of Chemistry University of Kent Canterbury UK CT2 7NH 1 Introduction This review aims to show the reader how the use of fluorescence microscopy using a conventional or modified fluorescence micro- scope may be used to study chemical problems such as the photo- degradation of naturally occurring polymers photoinduced reactions the dyeing of fibres and the measurement of Tg (glass transition temperature) values. Hitherto the use of fluorescence microscopy has been the domain of the biologist but now there are opportunities available to the chemist. Fluorescence may be defined as light which is emitted when an electronically excited state relaxes to an electronic state of lower energy and possessing the same spin state. For organic species in solution and in the solid state the fluoresence observed is usually associated with relaxation from the first excited singlet state to the ground state.' Needless to say this is only one of the ways that an electronically excited singlet state can relax and these processes are usually shown pictorially by means of a Jablonski diagram (Fig. 1). A wide range of compounds exhibit fluorescence. One of the features that marks highly fluorescent compounds is that they possess rigid structures. Examples include polycyclic aromatic hydrocarbons (e.g.anthracene) and dyes2 which are based on a fused aromatic ring system (e.g.fluorescein 1 the coumarin derivative 2 Fig. 2). The rigid structure prevents the electronically excited state de- activating via undergoing intramolecular isomerisation (e.g. as exemplified by stilbenes which undergo cis-trans isomerisation3) or conformational changes (e.g. twisting about the 1-1' C-C bond in 1 ,l'-binaphthyl). In some cases intramolecular motion can lead to a new emitting species which does not possess an equivalent R.S. Davidson gained an ARICfrom Leeds College of Technology in hv -hip (fluorescence) -hv (phosphorescence) or A or a 'I I Figure 1 Jablonski diagram (A. Jablonski Nature 1933 131 839; Z. Phys. 1935,94,38). Fluorescein 1 A coumarin laser dye 2 Figure 2 Some fluorescent dyes. by bond rotation1958 and then curried out research for a PhD degree under the supervision of Professor B. Lythgoe FRS at the University of Leeds. This work led to a successfil synthesis of tachysterol and the award of the J. B. Cohen prize from the University of Leeds. Having spent a year working with Professor R. B. Woodward (Harvard University) on a synthesis of vitamin B he took up the post of lecturer in organic chemistry at the University of Leicester (I964)where he pursued his interests in photochemistry. Particular interests at this time were photoinduced electron-transfer reactions and photo-oxidation reac- tions. He was awarded a DSc degree from the University of Leeds in 1978. He moved to the City University London in 1979 to take up the chair of organic chemistry. It wus whilst in this post that his inter- est in microscopy and the photodegradation of natural polymers was awakened. In 1990 he moved to the University of Kent where he is currently Professor of Applied Chemistry. Most of his research is concerned with radiation curing (photoinitiated poly-merisation processes) and he is also investigating ways to prevent the photoyellowing of papers made from high yield pulps. He had the title of Emeritus Professor of Organic Chemistry conferred upon him by City University in 1993. He has over 200 publications in the field of photochemistry. 3 Twisted S state of 1 ,l-binaphthyl Almost planar relaxed S state of 1 .I-binaphthyl Figure 3 Relaxation of the initially created excited singlet state of 1 ,l'-binaphthyl by bond rotation. (MFM Post J. Langelaar and J. D. Van Voorst Chem. Phys. Lett. 1975,32,59). stable ground state i.e. emission occurs from the almost planar form of 1 ,I'-binaphthyl 3 (Fig. 3). As a consequence the fluorescence spectrum of 1,l '-binaphthyl shows a broad structureless band at lower energy than that expected from the primarily excited species i.e. the intramolecular motion has generated a sizeable Stokes shift. Compounds which exhibit such shifts and possess high quantum yields of fluorescence are par- ticularly valuable as fluorescence probes4 and no more so than when the probes are used in fluorescence microscopy. Many compounds exhibit fluorescence in solution which does not emanate from the initially created excited singlet state but rather may be attributed to the excited state undergoing solvation (thereby giving rise to solva- tochromic shifts) deprotonation or protonation intramolecular charge transfer etc. If the fluorescence spectrum of a compound is sensitive to solvent polarity then such a material may be used to probe the polarity of cell membranes etc.5 and such a process can be visualised by means of fluorescence microscopy. The phenome- non of excited singlet states undergoing protonation and deprotona- tion is well established6 and is well illustrated by the hydroxy coumarin 4' (Fig. 4). 24 1 HO Figure 4 Some protonation and deprotonation reactions exhibited by 4 Fluorescent species which are sensitive to pH have found application in determining the pH of intracellular material * A topic which is currently attracting much attention is that of intramolecular charge transfer and fluorescence spectroscopy has been used exten- sively to study the dynamics of the process Perhaps the most fre- quently studied compound which exhibits this phenomenon is 4-dimethylaminobenzonitrile This compound exhibits a broad structureless emission band which shifts to lower energy and exhibits a decrease in quantum yield as the solvent polarity increased Such behaviour is the hallmark of an excited state which possesses a considerable amount of charge transfer and conse- quently has a high dipole moment Many experimental results support the view that excitation of the aminobenzonitrile leads to rotation about the C-N single bond with concomitant electron transfer from the amino to the cyanobenzene moiety (Fig 5)thereby leading to a twisted intramolecular charge transfer (TICT) Figure 5 Formation of a twisted intramolecular charge transfer complex Many compounds have been found to behave in a similar fashion to the aminobenzonitrile and compounds of particular value in fluo-resence analysis (eg end group determination of peptides using the Edman degradation)lO and fluorescence microscopy are sulfonated amino naphthalenes such as 1-dimethylaminonaphthalene-5-sul-fonic acid4 Since the formation of a TICT complex involves a change in molecular conformation it is not surprising to find that the efficiency of the process is dependent upon solvent viscosity Thus such compounds have found use as probes for monitoring the change in viscosity which occurs when materials such as acrylates undergo polymerisation I The occurrence of charge transfer in excited states is not limited to examples where the donor is directly linked to the acceptor group Thus many examples are known of compounds which exhibit excited state charge transfer in which the donor and acceptor groups are separated by a rigid spacer group or a flexible chain '2 Compounds having a donor and acceptor group separated by rigid spacers (eg 5 Fig 6) of varying dimensions have been used to show that electron transfer can occur over large distances eg 25 A For compounds having donor and acceptor CH CN CH 5 Figure 6 A rigid compound which exhibits long distance electron transfer (N Paddon Row and J W Verhoeven New J Chem ,1991,15 107,J W Verhoeven Pure Appl Chem 1990,62,1585 CHEMICAL SOCIETY REVIEWS 1996 OH groups linked by a flexible chain the efficiency of excited complex formation can in part or wholly be dominated by the conformational flexibility of the chain For compounds such as 6 (Fig 7) it is 6 Figure 7 Formation of an intramolecular excited charge transfer complex necessary for the donor group (the amine) to interact with the T-electron system of the aromatic hydrocarbon acceptor group l2 Another requirement for compounds such as 7 to exhibit excited charge transfer complex formation is that the amino group is able to donate an electron This is cleaily impossible when the amino group is protonated or if the lone pair of electrons is part of a dative bond This simple fact has been used to design compounds which will act as molecular switches and signalling devices Compound 7 (Fig 8) 7 Intrarnoleculs?r excited state charge transfer complex Intramolecular excirrer formation Figure 8 A compound which exhibits both excimer and exciplex formation exhibits intramolecular excited charge transfer complex formation in neutral solution eg ethanol but in the presence of acid the formation of an excited charge transfer process is switched off and is replaced by intramolecular excimer formation I3 Since the two types of complex emit at different wavelengths they can be readily distinguished Compounds have been designed which exhibit intra- molecular excited charge transfer complex formation and which have been used as molecular switches in which the on-off process is regulated by pH l4 In many cases intramolecular electron transfer leads to fluorescence quenching and consequently if in these com- pounds the donor ISan amino group protonation or involvement of APPLICATION OF FLUORESCENCE MICROSCOPY TO A STUDY OF CHEMICAL PROBLEMS-R S DAVIDSON 8 9 Figure 9 Compounds which exhibit an increase in fluorescence yield when the lone pair electrons on nitrogen are involved in bonding the nitrogen lone pair in complexation leads to enhancement of the fluorescence quantum yield Protonation of the nitrogen atom in 8 (Fig 9) leads to a spectacular increase in quantum yieldls and in the case of compound 9 (Fig 9) complexation with potassium led to a 47-fold increase in fluorescence intensity I6 A process which is somewhat similar to quenching of fluo- rescence by intramolecular complex formation is that of quench- ing via the heavy atom effect Quenching by halogen atoms increases in efficiency as the atomic mass of the halogen atom is increased and consequently bromine is a more efficient quencher than chlonne For quenching to be observed the halogen atom may be directly attached to the fluorogenic chromophore or it may be linked to the chromophore via a flexible chainI8 or alternatively may be present in solution as part of the solvent Where the atom is present in the molecule its removal via ground- or excited-state reactions will lead to an increase in fluorescence yield An example which illustrates such a process is afforded by reactive dyes 10 11 and 12 (Fig 10) These dyes become covalently attached to wool via nucleophilic displacement of a halogen group by the €-amino group of lysyl groups present in the wool It was found that this process in itself did not remove all the halogen atoms and that further reaction with external reagents such as water or an amine was necessary for the dyes to exhibit their maximum fluorescence intensity l9 L1 10 2 Fluorescence Spectrometers and Microscopes For the routine recording of fluorescence spectra a spectrometer which contains the basic elements shown in Fig 11 can be used It is a relatively simple task to replace the sample accessory (3) by one which will accommodate solid samples 20 In order to decrease the influence of scattered light upon the emission spectrum it is best to avoid the right angle configuration and to have a system whereby the angle of the sample with respect to the excitation beam can be varied In this way the angle can be varied so as to find the one which gives the least disturbed and highest intensity signal With a spectrometer such as the one shown in Fig 11 the monochromators are equipped with entrance and exit slits and by appropriate choice of slit widths maximum spectral resolution can be achieved If the fluorescence spectrum of the sample does not exhibit a Stokes shift t Ia Figure 11 Layout of the components of a spectrofluorimeter (1) Light source usually Xe or Hg/Xe arc lamp (2) Excitation monochromator (3) Sample shown as a quartz cuvette in which the emission is observed at right angles to the exciting beam (4) Emission monochromator (5)Photomultiplier tube (6) Amplifier (7) Data recording device great care has to be taken to ensure that scattered exciting light does not affect the spectrum and that the emission spectrum is not per turbed by some of the fluorescence being absorbed by the sample (inner filter effect) When weakly emitting samples are being exam- ined better sensitivity can be achieved by operating the detection system in the photon counting mode 21 With such a spectrometer it is possible to use the exciting light as a means of bringing about photochemical reactions in the sample and if those reactions cause a change in fluorescence intensity or spectral shift the course of the reaction can in principle be monitored in real time This can be dif- ficult to achieve in practice since usually it is necessary to employ large slit widths for the excitation monochromator which can lead to difficulties in recording the spectra However it is a relatively simple job to record spectra after set illumination times by chang- ing the slit widths In this way the photodimerisation of styrylpyridinium groups (Fig 12)appended to a poly(viny1 alcohol) (PVA) was monitored 22 The spectra in Fig 13 show that the excimer emission exhibited by the films of modified PVA decreases 11 $03 *a IBr 'S03Na IBr Figure 10 Reactive dyes which are non fluorescent but which become flu0 rescent upon removal of the halogen atoms via nucleophilic displacement Figure 12 The photodimerisation of a styrylpyridinium salt I4O I 360 380 400 420 440 460 480 hInm Figure 13 Fluorescence spectra recorded during irradiation of styrylpyridin-ium groups pendant to a poly(viny1 alcohol) chain. in intensity as reaction proceeds. At the end of the reaction some styrylpyridinium groups remain and these are presumably groups which do not have a neighbour that is sufficiently close to enable the chemical reaction to occur. Many of the benefits which accrue from using a fluorimeter of the type shown in Fig. 11 are due to the presence of the two monochromators. If these are replaced by filters the recording of spectra becomes impossible and for emission to be observed it requires that the excitation and observation wavelengths are suffi- ciently well separated. The conventional fluorescence micro- scope23 relies upon the use of filters and consequently fluorescence probes etc. being examined via the microscope should exhibit large Stokes shifts. The examples cited (i.e.com-pounds 1-12) possess this property and many well utilised probes exhibit fluorescence properties which are due to the photophysical processes displayed by compounds 1-12. Microscopes such as the one shown in Fig. 14 are the standard work-horse of immunology laboratories where fluorescent labels are used to detect particular interactions. In order to obtain sufficiently high light levels for visual observation a super-high-pressure mercury lamp is the usual source of excitation. A filter is used on the excitation side which either transmits a wavelength associated with one of the main emission lines of the lamp e.g. 365 nm or transmits a spectrally wide band of light. The dichroic mirror (Fig. 15) reflects the excitation light onto the sample but transmits the fluorescence pro- duced by the sample. With the advent of charge coupled device (CCD) cameras it is possible to observe very low light intensities and such cameras can be mounted onto the microscope so as to increase the sensitivity of fluorescence detection. When the microscope is being used for studying chemical reactions it is often advantageous to mount either a photomultiplier tube or a monochromator equipped with a photomultiplier tube on the microscope. In this way fluorescence CHEMICAL SOCIETY REVIEWS 1996 0Viewing Optics I i----Optional filter! I iSample Figure 14 Diagram showing the parts of a fluorescence microscope associ- ated with revealing the fluorescence of the sample. intensity changes during irradiation can be recorded and if the monochromator is properly equipped fluorescence spectra can be recorded. Such a system can be enhanced further if a continuous wave (cw) e.g. an argon ion or helium cadmium laser replaces the lamp. By placing a timed shutter between the laser and the micro- scope the system can in principle be used for determining fluo- rescence lifetimes (provided the photomultiplier tube is operating in the single photon counting mode) and to carry out bleach recovery experiments (see later). The layout of such a system is shown in Fig. 16. Such an experimental set-up is ideal for examining samples and for carrying out photochemical reactions. The high intensity excitation beam can be used simultaneously to bring about a photochemical reaction and also monitor fluorescence changes which occur during the reaction (real time fluorescence spec- troscopy). However if the sample requires heating or if the sample is to be reacted in solution there is insufficient room between the microscope objective and the sample to allow positioning of the necessary equipment. This problem can be overcome by the use of an inverted fluorescence microscope. In such a microscope all the optical parts are sited below the microscope stage thereby leaving space between the stage and the ceiling of the room in which the microscope is being used to house any equipment. For purposes outlined later we have constructed two accessories which fit on the top of the stage and which allow polymer films and similar samples to be heatedz4 and another in which materials can be sub- jected to chemical treatment.25 These accessories are shown in Fig. 17. A very useful commercially available accessory is a micro- injector which enables metered amounts of material (e.g. a dye) to be injected into a sample being examined on the stage of the micro- scope. iilnrn i./nrn Mirror for visible light excitation. Mirror for UV light excitation. Figure 15 Spectral characteristics of a dichroic mirror used in a fluorescence microscope. APPLICATION OF FLUORESCENCE MICROSCOPY TO A STUDY OF CHEMICAL PROBLEMS-R S DAVIDSON P-Computer -Oigitiserx-Amplifier Photomultipliertube L Shutters -Pockel cell ns ’ -Acoustooptical AlA-I. t. /Sample open shut A (ms) Figure 16 Diagram of a fluorescence microscope adapted for recording spectra fluorescence lifetimes and for carrying out bleach recovery experiments (a) Copper_ blocks Peltier pump Copper block .. Hole for Insulation sample holder Top face Slide UV cured polymer -Dye crystals I \Irradiated (bottom face hv Figure 17 Accessones for use with an inverted fluorescence microscope (a) for heating a polymer film (b) for carrying out chemical reactions 3 Some Examples of the Use of Fluorescence Microscopy to Study Chemical Problems 3.1 The Chemistry of Wool The structure of a wool fibre is very complex and Fig 18 shows in diagrammatic form some of its components The cuticle is normally only one cell thick except where the cells overlap and is rich in cystine Whilst most of the fibril structure is made up from keratin (a protein) molecules the cortical cells are separated from each other by a cell membrane complex which is largely composed of lipids The cell membrane complex also separates the cuticle cells from the underlying cortical cells Whilst much of the chemistry of wool is based on the fact that it is a proteinaceous fibre it is clear that this is very much an oversimplification of the real case Like other natural polymers wool is affected by light The most obvious effect is that of photoyellowing caused by wavelengths <380 nm photobleaching is caused by wavelengths >380 nm The photo- degradation processes also lead to an increase in the fluorescence of wool fibres26 (Fig 19) Clearly the colour changes indicate that photochemical reactions proteln molecule posslbly comprlslng three polypeptide chains helices) twistedlogether hellcat rrrmgement of proteln molecules nuclear remnant 1 mlcrollbrll p.r.cortex mrcrollbrll orthoconexcotllcalCI Figure 18 Sketch of a broken section of fine wool fibre showing the major cellular components and the detailed structures within them are occurring but in addition to these others occur which lead to the wool fibres losing their strength These changes are exacerbated when the wool has been subjected to treatments such as oxidative bleaching or the application of fluorescent whitening agents (FWAs) It has been known for some time that wool possesses an intrinsic fluorescence the origin of which is far from understood When sections of wool fibres are examined by fluorescence microscopy it was very evident that the tips were far more fluo- rescent than the roots 26 By measuring the fluorescence intensity along the length of a 60 mm fibre (obtained from Merino sheep) it was found that most of the fluorescence was exhibited in the first 5 mm from the tip of the fibre 27 Given that the fleece is densely packed this result is not surprising When a fibre from a more open- structured fleece was used the difference in fluorescence intensity at the root and tip was not so marked 28 Fluorescence spectra of the tips and roots of Merino wool (obtained by microspectrofluorim- etry) were found to be very similar which suggested that the same species are present in tips and roots which give rise to the fluo- rescence A further finding which substantiated this deduction is that the bleach-recovery profiles for the tips and roots are similar In this type of experiment the sample is irradiated for a short time CHEMICAL SOCIETY REVIEWS 19% Figure 19 Wool fibres before irradiation (left hand side) and after irradiation (right hand side). (e.g. 1 ps),the intensity of fluorescence measured and then the fluo- rescence intensity measured after the sample has remained in the dark some time e.g. 2 ms. If the fluorescent species undergoes reduction to give a leuco species oxidation of this species in the dark period will regenerate the fluorescence. In other cases recov- ery of the fluorescence can be due to fluorescent species migrating into the viewing area of the microscope during the dark period. Such an experiment carried out with the tips and roots of a fibre showed that the fluorescent species was destroyed upon irradiation and that the destruction occurred over a similar time period for tips and roots. The origin of the fluorescence of wool has been the subject of much debate. Conventional fluorimetry has been used to show that several species are responsible for fluorescence. When the wool is excited at 300 nm most of the emission (Amax 350 nm) emanates from tryptophan. Excitation with light of wavelength >300 nm generates fluorescence having maximal intensity at >350 nm; e.g. excitation at 375 nm generates fluorescence having a A, at 430 nm. Species which may be responsible for this long wavelength emission include carbolines and other compounds which are derived by degradation of tryptophan. It is clear from the bleach- recovery experiments that these compounds are destroyed to non- fluorescent products upon irradiation and this is clearly the origin of the photobleaching effect. The destruction process can be accom- plished chemically under both oxidising and reducing conditions which suggests that there is not a unique photodestruction process. It has also been established that the fluorescence of these com- pounds is quenched by the disulfide bonds present in cystine and this phenomenon may contribute to the lack of fluorescence exhib- ited by the root of the fibre (where little photooxidation of cystine has occurred) and the much greater fluorescence intensity of the tips (where much of the cystine and tryptophan has been oxidised26). The dyeing of wool usually utilises the fact that it contains free amino groups (the €-amino groups of lysine) and to a lesser extent sulfhydryl groups (present in cysteine and can be chemically pro- duced by reduction of cystine). The presence of the amino groups means that anionic dyes (usually containing sulfonic acid groups) and reactive dyes (which rely upon the amino group acting as a nucleophile and thereby forming a covalent bond with the dye viu a Michael addition reaction and in other cases via a nucleophilic sub- stitution reaction). Since the wool fibres are more open at the tips due to photodegradation etc.,dyeing occurs preferentially at the tips thereby leading to uneven dyeing. This problem can be overcome by the use of levelling agents which aid migration of the dye within the fibre. In an alternative approach to obtaining level dyeing wool has been treated with chitosan (an amino-polysaccharide) .29 It was expected that the chitosan would adhere to the surface of the wool fibres and that the presence of the amino group would lead to rapid adsorption of anionic dyes. Having obtained a high concentration of dye on the surface the normal processes whereby the dye is taken into the fibre were expected to take over. Fluorescence microscopy was used to demonstrate that chitosan-treated wool fibres when treated with a fluorescent whitening agent underwent rapid dyeing at a lower temperature and that most of the dye was located on the exterior of the fibre. By raising the temperature of the dye-bath the dye on the surface of the fibre migrated into the interior of the fibre leading to a greater degree of level dyeing than was observed with wool that had not been treated with chitosan. By construction of the appropriate accessory (Fig. 17) and using it with an inverted microscope it proved possible to follow the dyeing of wool in situ.I9 To follow the dyeing of a fibre in situ it is essential that the dye-bath solution does not fluoresce (or at least is only weakly fluorescent) so that the fluorescence of the fibre can be readily detected by the dye or if the intensity of fluorescence is being monitored that the detection device is only seeing fluo- rescence from the fibre. This requirement was accommodated by the dyes 12 (Fig. 10)and N-(9-acridinyl)maleimide. Both dyes react with primary amines and sulfhydryl groups but selectivity can be obtained by control of pH. Nucleophilic attack upon the bromo- acrylamido group present in 12 leads to loss of bromine thereby removing the internal quenching group and rendering the stilbene dye fluorescent. The maleimido group present in N-(9-acridiny1)maleimide quenches the fluorescence of the acridinyl group and consequently where the maleimido group is converted to a succinimido group via nucleophilic attack of an amino or sulfhydryl group the fluorescence of the acridinyl group is restored. The dyeing of wool fibres by these dyes was carried out on the microscope stage and the process of the dyeing followed by record- ing the change in fluorescence intensity of the fibres with time. Figs. 20 and 2 1 show the results obtained in this way and Figs. 22 and 23 show photographs of the wool fibres before and after dyeing. Figs. 20 and 21 demonstrate that the dye-bath solution exhibits little fluorescence that the wool fibres exhibit an increasing amount APPLICATION OF FLUORESCENCE MICROSCOPY TO A STUDY OF CHEMICAL PROBLEMS-R.S. DAVIDSON 140 250 120 c.-C3 $ 100 C3 v200 .-E *O vl a,w .S 60 8 c ' 40 rr 150 9 Tipfibre 12 A Middle fibre 1G 20 V Tipfibre2+ Middle fibre 2 0 Background0 I I I I I I 100 0 1 2 3 4 5 6 tlh Figure 21 Change in fluorescence intensity of wool fibre present in a dye- bath solution containing N-(Pacridinyl) malemide as a function of time. of fluorescence as their immersion time in the dye-bath increases 50 and that the cut end of the fibres takes up the dye more rapidly than the centre portion of the fibre. This latter observation can be attrib- uted to some of the dye entering the fibre via the exposed centre of Solution the fibre rather than through the cuticular layer. Such experiments Ppave the way for a more detailed investigation of how different parameters e.g. varying the amount and consistency of dye-bathI I I I I 1 2 3 4 5 agents such as surfactants and levellers affect the dyeing process. tlh In order to achieve the whiteness required by customers fluo-rescent whitening agents (FWAs) are applied to wool. These colour- Figure 20 Change in fluorescence intensity of a fibre present in a dye-bath less dyes absorb ultraviolet radiation and emit blue light thereby containing 12 as a function of time. making up for the blue light which is absorbed by the yellow coloured species which are responsible for the wool having an off-white colour. Unfortunately FWAs photodegrade to give yellow products via singlet oxygen and radical mediated reactions and in Figure 22 Wool fibres before dyeing. Figure 23 Wool fibres after dyeing with 12 for 6 h at 80 "C. the process increase the rate of yellowing of the wool. This process can be readily monitored using a fluorescence microscope. Fig. 24 shows that wool fibres treated with an FWA exhibit little fluo- rescence after they have been exposed to light. The degradation of FWAs on the surface of wool has been mon- itored in real time using fluorescence microscopy. Wool was dyed with FWAs based on the stilbene and pyrazoline chromophores and then irradiated on the stage of a fluorescence microscope with simultaneous recording of the fluorescence intensity of the sample.30 Using this technique the ability of additives such as CHEMICAL SOCIETY REVIEWS 1996 Blankit D (80%formaldehyde sulfoxylate) and thiourea dioxide to arrest the degradation of the FWAs was investigated. A diagram-matic representation of one of the many results is shown in Fig. 25. It was found that the degradation of the FWAs was preceded by an induction period which was attributed to the wool protecting the FWA by reaction of its cystyl residues with any generated singlet oxygen. However the protective action of the cystyl residues is sacrificial by nature since in the process it becomes oxidised with the final product being cysteic acid. Once the cystyl residues in the wool (particularly the cystyl-rich cuticle) have been consumed degradation of the FWAs commences. The role of singlet oxygen is not as great for the stilbenes as it is for the pyra- Figure 24 Wool fibres treated with an FWA before irradiation (left hand side) and after irradiation (right hand side) APPLICATION OF FLUORESCENCE MICROSCOPY TO A STUDY OF CHEMICAL PROBLEMS-R S DAVIDSON Tirne/mins Figure 25 Degradation of an FWA as monitored by real time fluorescence spectroscopy Real time degradation of pyrazoline H treated wool in the presence and absence of a 2% solution of thiourea dioxide where r IS the time for the fluorescence intensity to decrease by lo%,rso is the time for the fluorescence intensity to decrease by 50% and r4' = r -I, zolines and there is evidence that a significant part of the degrada tion of the stilbenes involves a reductive interaction between the wool and the FWA 3.2 The Photobleaching and Photoyellowing of Paper Containing Lignin The mechanical strength of plant materials is due to the laying down of a polymer Iignin in the cell walls Lignin is derived from phenyl tyo" co :t120H I -YH CH2W 6 alanine via a series of enzymatically induced hydroxylation and oxidation reactions It does not have a unique structure and the chemical structure of an extracted lignin will reflect the nature of the species from which the lignin was extracted and the season in which the lignin was laid down Despite the complexity of the material several important structural motifs have been identified (Fig 26) and many of these contain photoactive chromophores such as the a-0-4 and p-0-4 units quinones and phenolic residues If pulp produced from wood without extracting the lignin is converted into paper the product has a light brown appearance Bleaching of the pulp can be used to produce papers having an acceptable white ness but such papers readily undergo photoyellowing As with wool the yellowing is largely produced by light wavelengths <396 nm with longer wavelength light leading to photobleaching There IS abundant evidence to support the view that the lignin is to a large extent responsible for the photoyellowing Extensive detailed work has unravelled many of the processes which lead to the formation of coloured products but as yet little precise information is available as to the structure of the degradation products 31 Lignin is ff uorescent and consequently the structure of a sample of wood can be examined by fluorescence microscopy By use of the chemical reactor shown in Fig 17 the in situ delignification of wood using a Kraft liquor at 95-100 "C was continuously moni tored The loss of lignin was readily apparent and after a 4 h treat-ment some lignin still remained attached to the cellulosic t12COH tI p r II tIC -co I CHOtl CII3 I I cu,o 0-HC -ftl H,CO 4 b -'HFoH I I 0-$H OCH OH C-0 I OH ti a phenylcoumarin unit fphenolic OH group b a 0 4 linkage g methoxy group c p 0 4 linkage h p 1 linkage -0d 5 5' bond biphenyl unit i methylene quinone bond -0 e pinoresinol unit Figure 26 Structure of lignin after Freudenberg (C K Freudenberg and A C Neish Mol Bra1 Biochem Biophysrcs 1968,2 103) -framework The fluorescence of this lignin was different in appear-ance to that observed prior to the Kraft liquor treatment which would indicate that it has a different structure Whether this struc- ture has been produced by the chemical treatment or not is not clear The presence of lignin in the wood structure can also be detected by staining with dyes such as Basocryl gold and Astrazon red Since lignin is fluorescent it is not surprising to find that papers made from high yield pulps i e pulps produced without delignifying the wood also exhibit fluorescence 32 The wavelength distribution of the fluorescence is highly dependent upon the excitation wave- length that is used and this shows that more than one chromophore is responsible for fluorescence When such papers were subjected to bleach-recovery experiments (using the modified fluorescence microscope) with an argon ion laser operating at 488 nm as the illumination source it was found that the recovery was relatively slow (>2 s) This is attributed to lignin diffusing into the area where the lignin had previously been photodegraded and is an indication of the lignin being a relatively mobile species Chemical and photo- chemical reduction of papers made from high yield pulps increased the overall fluorescence intensity of the papers and fluorescence spectra showed that this was due principally to species emitting at 400 nm It is possible that the reduction process has transformed species which act as inner filters or quenchers of fluorescence into innocuous products e g quinones into dihydroxybenzenes coniferaldehyde into coniferyl alcohol These changes are unfortu- nately not permanent and upon illumination these reductively bleached papers undergo rapid photoyellowing Fluorescence microscopy and microspectrofluorimetry have been used to study these and related processes 33 Of particular value was the use of sequential irradiation In this procedure the sample is irradiated with UV light (broad band pass filter centred at 365 nm) with continuous monitoring of fluorescence intensity for a set period and then it is irradiated with visible light (450-490 nm) with continu- ous monitoring of fluorescence intensity for a set period This pro- cedure is facilitated by the microscopes having the appropriate filters fitted and therefore change of excitation and monitoring wavelengths can be readily accomplished A typical result is shown in Fig 27 Initial cycle s-dSecond cycle Irradiation Blue light irradiation 30 ' 10' ' ' ' 5 ' ' ' ' tlmin Figure 27 Changes in fluorescence intensity caused by sequential UV and visible irradiation of a paper made from a high yield pulp (SGWP) Irradiation with UV light leads to a decrease in fluorescence intensity as does irradiation with visible light However following irradiation with visible light it is found that the initial intensity of the UV-stimulated fluorescence is substantially greater than that recorded at the end of the first UV excitation period Irradiation of the paper with UV light in the second cycle leads to an increase in the intensity of the fluorescence initially recorded in the second cycle of irradiation with visible light These observations are most readily accommodated by the view that lignin exhibits photochrom- ism and that the photochromic process exhibits fatigue (Fig 28) That the observed changes in fluorescence are due to lignin is attested by the fact that sections of wood when subjected to the sequential irradiation procedure exhibits the same characteristics as the paper When either the paper or wood is subjected to oxidative or reductive bleaching the intensity of the UV-stimulated fluo-rescence increases markedly Not only is this apparent when the sequential irradiation procedure is employed but also the CHEMICAL SOCIETY REVIEWS 1996 M-B M-B -Lignin mohf affectedby 365nm radiation affectedby vislbIe radiation M-V-Lignin mohf 1 p;Oducts Products Figure 28 Photochromic behaviour exhibited by lignin irreversible destruction of the chromophores giving rise to the UV- stimulated fluorescence Some differences were however observed between the behaviour of reduced wood and paper since the paper contains species which fluoresce in the visible which are not reduced by borohydride These species are thought to be stilbenes which are produced during pulping via a mechanochemical process The stilbenes are remarkably chemically active and represent an important seat of photochemical instability 33 Determination of TgValues The chemical characterisation of a crosslinked synthetic polymer is usually difficult since normally the material is insoluble in most solvents A property of some importance is its Tg value i e the temperature at which the polymer softens thereby allowing some molecular movement Techniques such as differential scanning calorimetry (DSC) and dynamic mechanical thermal analysis are frequently used but they have their limitations A method employ- ing fluorescence microscopy has been developed which allows the Tgof films including thin films and fibrous materials to be deter- mined The basis of the method lies in the technique of disperse dyeing which 1s used to dye synthetic fibres such as polyesters and polyamides In this mode of dyeing the substrate is heated in a dye-bath the temperature of which is sufficiently high as to cause the substrate to soften The dye which is present in the dye-bath in dispersed form enters the softened fibre In the attachment for the inverted fluorescence microscope shown in Fig 17 a polymer film or other substrate is laid down on the top of a few dye crys- tals It is important that the dye used is reasonably soluble in the softened polymer and that it exhibits characteristic easily visible fluorescence In our hands perylene and 3,7-bis(4-n-propoxyphenyl)benzo[ 1,2-6 4 5-b']difuran-2,6-dione have proved to be very suitable Using the attachment shown in Fig 17 the film is heated slowly When the Tg is reached the dye enters the polymer imparting a beautiful colour to the polymer (Figs 29 and 30) Tg values of several UV-cured films have been determined (Table 1 p 252) To ensure that the technique was reliable the Tgof the poly(iso- bornyl acrylate) film was also determined by DSC and was found to be very similar In another check the Tgof a commercial sample of polystyrene was determined by both techniques with the same result Given the system of heating the sample there was some concern that the heat flow from the surface nearest the heater to the surface farthest away from the heater may be so slow that accurate Tgvalues would only be obtained by ramping the temperature at an incredibly slow rate To test this point the Tgof a polyester fabric was determined both as a single and triple layer and the fact that similar results were obtained suggests that heat transfer in the system is not a problem The technique has been used to show that UV-initiated polymerisation of isobornyl acrylate produces a film having a Tgof 69 "C and that if films of isobornyl acrylate contain- ing increasing amounts of ethoxylated phenol acrylate are polymer- ised the Tgof the resulting films decreases as the amount of the latter is increased (Table 2 p 252) In many UV-initiated free radical polymensation processes the photoinitiator system consists of an aromatic ketone admixed with a tertiary amine The triplet state of the aromatic ketone reacts with the amine to give an a-aminoalkyl radical which then initiates polymensation There has been some evidence presented which supports the view that if the amines are used at a sufficiently high APPLICATIDN OF FLUORESCENCE MICROSCOPY TO A STUDY OF CHEMICAL PROBLEMS- R.S. DAVIDSON 25 1 Figure 29 Polymer film together with crystals of a benzodifuranone dye before migration of the dye has occurred. Figure 30 Polymer film together with crystals of a benzodifuranone dye showing the dye dissolving in the polymer film. concentration they can act as plasticisers. This contention is to study the migration of fluorescent species in films and across the admirably supported by the results shown in Table 3 where it can points of contact between one pdymer and another. be seen that use of ethyl 4-dimethylaminobenzoate at a concentra- Acknowledgements The work described would not have been pos- tion of >2% m/m leads to a decrease in the Tgvalues of the cured sible without the sterling efforts and intellectual input of many of films. my research students postdoctoral fellows and colleagues in indus-Undoubtedly the technique described will undergo further try. Similarly without the financial input from the SERC the developments,e.g.automation and also undergo modification so as International Wool Foundation the Australian Wool Corporation 252 CHEMICAL SOCIETY REVIEWS 1996 the EEC (contracts MAlB 0127 -C (EDB) and MA2B0018) the Table 1 Tgvalues of UV-cured films using fluorescence technique Groupemente de Recherche Papiers et DCrivCs (CNRS CTP Reactive diluents Film formed TJT Grenoble) Du Pont Demours Deutschland SmithKline Beecham Ltd and the Cancer Research Campaign it would have been impos- Isobornyl acrylate Very hard brittle film 69 sible to carry out the work Epoxidised soya bean oil Very flexible rubbery film 44 Polyester acrylate Flexible strong film 53 4 ReferencesPoly (propy lene glycol) Dye migrated at room 1 C A Parker Photoluminescence of Solutions Elsevier Amsterdam monoacrylate Very soft flexible film temperature 1968 E J Bowen Luminescence in Chemistry Van Nostrand London Ethoxylated 1968 phenol Dye migration at room 2 The Chemistry and Application of Dyes ed D R Waring and G Hallas monoacrylate Soft flexible film temperature Plenum Press New York 1990 Urethane 3 For a description of isomerisation processes exhibited by excited states oligomer/ see N J Turro Modern Molecular Photochemistry Benjamin/ poly(ethy1ene Cummins Menlo Park California 1978 glycol 200) 4 R S Davidson and M M Hilchenbach Photochem Photobiol 1990 diacrylate 75/25 Very flexible strong film 63 52,43 1 Urethane 5 B S Hudson D L Harris R D Lucheser A Ruggier A Cooney- oligomed Freed and S A Cavalier in Applications of Fluorescence in the et hoxy I ated Biomedical Sciences ed D L Taylor A S Waggoner R F Murphy F phenol Lamni and R R Birge A R Liss New York 1986 p 159 monoacry late 6 A Weller Progr React Kinet ,1%1,1,187 75/25 Very flexible strong film 40 7 G S Beddard S Carlin and R S Davidson J Chem Soc ,Perkin Urethane Trans 2,1977,262 oligomerl 8 L Tanasugarn P McNeil G Reynolds and D L Taylor J Cell Biol Tri (prop ylene 1984,98,717 glycol) diacrylate Strong film slightly 9 2 R Grabowski K Rotkiewicz A Siemarczuk J Cowley and W 75/25 flexible 60 Baumann Nouv J Chim 1979,3,443 W Rettig Angew Chem ,Int Poly (ethylene Ed Engl 1986,25971 glycol 200) 10 R S Davidson and J B Hobbs in Natural Products ed J Mann R S Davidson J B Hobbs D V Banthorpe and J V Harborne Longman diacrylate Weak flexible film 64 Poly(ethy1ene Harlow 1994 ch 3 p 131 glycol 400) 11 J C Song and D C Neckers American Chemical Society Division of diacrylate Soft flexible film 28 PMSE Papers I994,71,71 1 6-Hexanediol Brittle film slightly 12 R S Davidson In Molecular Association I ed R Foster Academic diacrylate flexible 52 Press 1975 p 215 Tn( propylene 13 G S Beddard R S Davidson and TD Whelan Chem Phys Lett glycol) diacrylate Hard film slightly flexible 59 1977,56,54 14 A P de Silva and H Q N Gunaratne J Chem Soc ,Chem Commun 1990,186 15 S A Jonker,F Ariessand J W Verhoeven Recl Trav Chim Pays-Bas 1989,108,109 S A Jonker K Van Dijk K Goubitz C A W Reiss W Schuddeboom and J W Verhoeven Mol Cryst Liq Cryst 1990 183,273 16 A P de Silva and S A de Silvo J Chem Soc ,Chem Commun ,1986 Table 2 Effect upon Tgof films produced from a mixture of 1707 E U Akkaya M E Huston and A W Czamik J Am Chem isobornyl acrylate and ethoxylated phenol acrylate Soc ,1990,112,3590 17 M Kasha J Chem Phys ,1952,20,71 Poly(isobomy1 18 R S Davidson R Bonneau J Joussot Dubien and K R Trethewey,acry1ate)lethoxylated Chem Phys Lett 1980,74,318 phenol acrylate TfC 19 R S Davidson G Ismail and D M Lewis J SOC Dyers Colourists 1oo/o 69 1988,104,86 9515 63 20 J F McKellar and N S Allen Photochemistry of Man-made Fibres 90110 58 Applied Science Publishers Barking Essex 1979 85/15 45 21 J W Longworth in Creation and Detection of the Excited State /A ed 80/20 34 A A Lamolo Marcel Dekker New York 1971 p 343 75/25 Dye migrated at room temperature 22 E S Cockburn R S Davidson and J E Pratt,J Photochem Photobiol A Chem ,1996,94,83 23 F W D Rost in Fluorescence Microscopy vol I Cambridge University Press Cambridge 1992 24 R S Davidson L Merritt and G Bradley in Aspects of Analysis Proceedings of a Conference organised by the Paint Research Association Egham Surrey 1994 25 G Bradley S Collins and R S Davidson Rev Sci lnstr ,in the press Table 3 Effect of added amine upon the Tgof cured isobornyl 26 S Collins R S Davidson P H Greaves M Healey and D M Lewis acrylate films J Soc Dyers Colourisrs 1988,104,348 27 S Collins R S Davidson and M E C Hilchenbach Dyes and N Methyldiethanolamine Ethyl 4-dimethylaminobenzoate Pigments 1994,24,15 I Amine (%) TJ0C 7'pI.C 28 K Schafer J Soc Dyers Colourists 1993,109,202 0 22 43 29 R S Davidson and Y Xue J Soc Dyers Colourists 1994,110,24 1 -53 30 S Collins and R S Davidson J Photochem Photobiol A Chem 2 31 65 1994,77,277 4 35 42 31 C Heitner in Photochemistry of Lignocellulosic Materials ACS Symp 6 38 35 Ser 53 1 ed C Heitner and J L Scaiano American Chemical Society 8 20 31 Washington DC USA 1993 p 2 A Castellan L'Actualite Chimique 10 20 30 1994 Supplement 7,148 32 R S Davidson L A Dunn A Castellan and A Nourmamode J Photochem Photobiol A Chem ,1991,58,349 APPLICATION OF FLUORESCENCE MICROSCOPY TO A STUDY OF CHEMICAL PROBLEMS-R S DAVIDSON 33 H Choudhury S Collins and R S Davidson J Photochem Photobiof H Choudhury. R S Davidson and S Greher J Photochem Photobiol A Chem 1992 69 109 A Castellan and R S Davidson A Chem 1994,81 117 A Castellan H Choudhury R S Davidson J Photochem Photobiol A Chem 1994 78,275. A Castellan and S Grelier J Photochem Photobiol A Chern 1994,81,123

ISSN:0306-0012    

DOI:10.1039/CS9962500241

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Assembly and Encapsulation with Self-complementary Molecules Julius Rebek, Jr.+ Massachusetts Institute of Technology, Department of Chemistry, Cambridge, MA 02139, USA 1 introduction Molecular recognition is a branch of chemistry that is concerned with complementarity. By this term is meant complementarity of size, and shape and chemical surfaces: the 'goodness of fit' between two molecules like the fit between a foot and a hand-made shoe. Molecular recognition defines this goodness of fit, and explores the intermolecular forces, the weak attractions that act over short dis- tances between molecules. These forces -hydrogen bonds, aro- matic stacking, polar and van der Waal's interactions -are the ones that bring molecules together into complexes. Such complexes are temporarily and weakly held groups of two or more molecules. More complicated complexes -assemblies -are also possible.These structures may be made up of complementary molecules or multiple copies of a self-complementary molecule. They form and dissipate on a timescale that varies from microseconds to hours: time intervals long enough for many types of chemistry to occur between them. Assemblies have captured the attention of many research groups involved in molecular recognition because new phenomena fre- quently emerge whenever more than one copy of an entity is present. It is often as impossible to predict what emerges as it is to predict the hexagonal shape of a honeycomb from the study of a single bee. Biochemistry abounds with examples: allosteric enzymes, channel-forming peptides and viral coat proteins are all assemblies of multiple copies of a molecule that give rise to super- structures with functions that are unique to their assembled states: functions such as regulation, transport, replication and encapsula- tion.But simpler molecules, available through chemical synthesis, are also able to exhibit unique behaviour through assembly. This review is concerned with such molecules and is limited in its scope to systems that show sharply defined features of size and shape in solution. Specifically excluded are aggregates such as micelles, liquid crystals and the like as well as assemblies that emerge pri- marily in the solid state. A two-dimensional system of three molecules illustrates some of the features of self-complementarity involved in assembly.The structure designed and synthesized by Zimmerman (Fig. 1)' pre-sents a pattern of hydrogen bond donors and acceptors on one edge + Present address The Skaggs Institute for Chemical Biology, at the Scnpps Research Institute, 10550North Torrey Pines Road, La Jolla, California, 92037, USA Julius Rebek, Jr. received his undergraduate education at the University of Kansas 1966, and obtained the PhD degree fiom the Massachusetts Institute of Technology (1970) for studies in peptide chemistry with Professor D. S. Kemp. At the University of California at Los Angeles he used the 'three-phase test' to detect reactive intermediates. In 1976 he moved to the University of Pittsburgh where new systems for molecular recogni- tion were developed.In I989 he returned to M.I.T. and devised self-replicating and selj-assem- bling molecules. In June of 1996, he moved to La Jolla where he is the director of the new Skaggs Institute for Chemical Biology at Scripps. that is complementary to the pattern on the other functioning edge. Accordingly, assembly at one level can be predicted. The orienta- tion in space of the atoms capable of hydrogen bonding at the two edges of the molecule is fixed at almost exactly 120"Cby the rigid- ity of the aromatic centrepiece of the structure. The information, the code, for the assembly is written into the hydrogen bond pat- terns of the edges and their angular orientations with respect to each other.In solution a trimer is formed, and assembly takes place in the manner expected. But entropy also has its say: linear aggre- gates intrude on the well-ordered cyclic trimer. A cooperative, self-assembling trimer m R 3 H 'R R and R Figure 1 Self-complementary hydrogen bonding sites lead to trimers and oligomers Two-dimensional hydrogen bonded arrays are enormously popular in supramolecular chemistry? For the most part, the systems use rigid, flat, heterocyclic compounds. The resulting assemblies resemble practically infinite sheet^;^ crinkled tapes;4 twisted ribbon^;^ ingenious rosettes: to name just a few. The principles of molecular recognition can also be used to assemble three-dimensional structures, but additional structural requirements must be met.The most important is curvature. This is beautifully illustrated with the constructs of Ghadiri? These structures take the self-complementary hydrogen bonding pat- terns featured by peptide p sheets and wrap them into a macro- cyclic format (Fig. 2). The resulting assembly is a hollow cylinder, a peptide nanotube, and is an early example of an assem- bly that actually shows function. Transport of glucose through the nanotube and across a lipid bilayer membrane was demon- strated. The systems we have worked with at MIT are literally mini-malistic: they involve only two copies of the same molecule. But it is the single molecule that holds the key, loaded with the information and what it promises for assembly.Rene Wyler synthesized the first CHEMICAL SOCIETY REVIEWS, 1996 I I Complementary distances between acids and bases 4 )r 0‘ ‘0 \ Cyclizing a bsheet structure... gives a self-assembled peptide nanotube Figure 2 Curvature increases the complexity of self-complementary assemblies such molecule la from diphenylgl ycoluril and tetrabromodurene.8 The cis-fusion of the two five-membered rings of the glycoluril forces a fold at either end of the molecule. Curvature along the length of the skeleton is caused by seven-membered rings on either side of the central benzene unit. When all of the glycoluril substituents appear on the same face of the molecule, a low energy conformation that features self-complementarity can be obtained.Specifically, the 0-0 distance indicated is appropriate for two hydrogen bonds to form to the ends of another molecule. The stereochemical features impart the necessary curvature for the dimeric assembly, while the hydrogen bonds provide the cohesive force, just as the stitching along the seam of a baseball holds the two pieces together. Spectroscopic studies in CDCI, indicated that a single species was present in solution which showed extensive hydrogen bonding. We were fortunate that this solvent (the industrial standard for studies in molecular recognition) was a poor fit for the interior of the capsule, as most of the encapsulation phenomena described in this review owe their very existence to two characteristics of a solvent. Foremost, it must dissolve reasonable concentrations of the assembly’s components.Secondly, it must compete so poorly for the interior of the capsule that the encapsulation of solute guest molecules can be observed. In other words, the solvent’s superior concentration -relative to an intended guest’s -must be overcome by the goodness of fit. This observation was made earlier by Still and used with tremendous success by Cram in his incarceration of ‘convicts’ in covalently bound capsules .9 The IH NMR spectrum of this ‘baseball’ (la-la) in CDC1, saturated with methane is shown in Fig. 4to illustrate some of the advantages of NMR for the study of assembly and encapsulation. The spectrum displays a sharp singlet at the unusual chemical shift of 6 -0.9 representing encapsulated CH,,l0 in addition to the resonance for free methane at 6 0.2 (the ethane signal at 6 0.82 and the characteristic pattern of propane at 6 0.9 and 1.3 are a measure of the purity of natural gas ‘on line’ at MIT).The separa- tion of the free and bound signals for both host and guest places limits on the rates of exchange into and out of the capsule: the rates are slow on the NMR timescale but fast on the human time- scale. The crystal structure of dimeric lc was solved by Toledo,II and it is shown, shorn of its ethyl esters in Fig. 5. The crystal of 1.1 appears to contain a disordered guest species in its cavity, although it was not possible to determine unambiguously the identity of the 1-1 Figure 3 Two identical molecules give a closed-shell ‘baseball’ CH,CH, CH4 bound CbCH, bound CH4 1.2 0.8 0.4 -0.0 -0.4 -0.8 PPm Figure 4 Unusual chemical shifts are observed for encapsulated small molecules guest.It was possible, however, to locate and refine a carbon atom at two positions with assigned occupancy factors of 0.55 and 0.45. This leads us to believe that this guest species is a methanol mole- cule with a highly disordered oxygen atom. There are eight (car- bony1 oxygen) good hydrogen bond acceptors along the seam of the capsule, and it is possible that the hydroxy group of methanol is dis- ordered about eight positions. It was desirable to find more soluble versions of the glycoluril subunit and the family of esters available from dihydroxytartaric acid were settled on.Their enhanced solubility in organic media and the possibility of functional group manipulations (e.g.hydrazinolysis) to water-soluble glycolurils are promising. The p-dimethylamino- diphenylglycoluril derivative lb and the capsule derived from it offer control of the assembly process by events that take place on the periphery of the structure rather than on the inside. Encapsulation of xenon in dimethyl formamide (DMF) solution can be directly observed in the i29Xe NMR spectrum.’* Neil Branda showed that the presence of xenon actually causes nucleation, the formation of the capsule. The basic sites of the dimethylamino function are subject to ASSEMBLY AND ENCAPSULATION WITH SELF-COMPLEMENTARY MOLECULES -JULIUS REBEK, JR.Synthesis of glycolurils H"K~-H 0 1-1 Figure 5 Synthesis of soluble glycolurils and the methane-selective capsule protonation with strong acids, and at high acidities the guest is released. Neutralization with bases reverses the processes: the guest is again encapsulated (Fig. 6). The simplest interpretation (though still unproved) is that the multiple positive charges that build up on protonation of the periphery force the two halves of the capsule apart through coulombic repulsion. The influence of acidity on dimeriza- tion suggests that it may be possible to make multicomponent systems in which assembly is fine-tuned to subtle changes in pH.Xavier Garcias showed it was also possible to alter the environ- ment inside the cavity. The hydroquinone 2 and quinone 3 spacers present either electron rich or electron deficient surfaces to encap- sulated guests (Fig. 7). The affinity of some small molecules to the capsules derived from these, compared to the original capsule, are given in Table 1.13 The studies of the fluorinated methanes were inspired by recent calculations by KollmanI4 that predicted CF, to be an appropriate guest for these capsules, but experiment and computation for the affinity of CF, have yet to be reconciled. Qualitative evidence for the encapsulation of nitric oxides in 3-3 was also obtained. 2 Other Shapes and Sizes In molecules 1,2 and 3, the glycoluril functions at the end of the molecule and the connecting spacer elements, which determine the dimensions and the overall shape of the dimer, remain constant.It was not unexpected to find that heterodimers formed readily when 3:E = C02(~-CqHg) Figure 7 Electron rich and electron poor capsules show altered selectivities Table 1 Association constants KJmol -I I, (298 K), for encapsulation of guests in dimers lc-lc, 2-2, and 3-3 (K,,,, = [N-guest-Nj/[N-N] X [free guest]). Host lc -lc 2-2 3-3 Guest CH4 33 70 10 C,% 51 51 13 CH3F 1.0 17 <0.3 CF4 0.7 0.6 <0.2 the various components were present in the same solution. Can dimerization still take place if the spacers are varied? The monomers 4,5 and 6 contains ethylene, naphthalene and a bridged anthracene, respectively, as their spacer elements.If good hydro- gen bonds are to be formed in the dimers, the 'length' of the spacer should complement the 'width' of the glycoluril. The energy-min- imized structures of the corresponding dimers, as generated by an MM2 for~efield,'~ are provided in Fig. 8, and the calculated 0-0 distances of the monomers are shown.ll The dimerization leads to unusual pseudo-spherical structures with cavities smaller or larger than that of 1-1. Obviously, 4.4 is smaller than 1.1;calculations indicate that the cavity formed by 4.4 (41 A3) is approximately 18% smaller than that of 1.1 (50 A3). Carlos Valdks showed that dimer 4.4 does bind small molecules, and displays a remarkable selectivity: ethane, which binds to 1.1, was not measurably encapsulated by 4.4.However, a price is paid for the discrimination: the affinity of methane for 4.4 is approximately 70 times lower than for 1.1. What are the consequences for 'miscegenation'? Molecular models indicate that three heterodimeric combinations are espe- cially likely to form: hybrid structures 1-4, 1-6 and 5-6.16The energy-minimized heterodimers are shown in Fig. 9. In the experiment, Urs Spitz observed heterodimers when two different Figure 6 Control of encapsulation is possible with changes in acidity 258 4.09 A 0-Y Figure 8 Dimensions and shapes of new capsules dimers were present in the same solution. The formation of hybrid capsules showed that structurally related molecules that are self- complementary are often complementary to each other. The 'recombination' of the homodimers to form hybrids is an equilibrium process, and opens access to new capsule shapes.The hydrogen bonds in the homodimers are expected to be superior to those of the heterodimers; the disproportionation observed must, to some extent, be driven by the entropy of mixing. The recombina- tions (disproportionation equilibria) of the dimers depended strongly on the solvent.ll For example, in the case of 1 with 4, the CHEMICAL SOCIETY REVIEWS, 1996 6.14 A 0--0K 0 6 0 7.17 A 0' '0 disproportionation constant K,, is large in CDCl,, CDBr, and Cl,DCCDCl, but is an order of magnitude smaller in CD,Cl,.The former three solvents are too large to fit the cavity of any of the three species present in the equilibrium, but CD,CI, is of appropriate size for 1.1. The CD,CI, provides a motivation, the driving force, for the formation of 1.1. The goodness of fit again determines the favoured species. Of the various possible capsules, only 6.6 appears large enough to accommodate Cl,DCCDCl,. Accordingly, only traces of hetero- dimer 1.6 are present in solutions of this large solvent. The current ASSEMBLY AND ENCAPSULATION WITH SELF-COMPLEMENTARY MOLECULES-JULIUS REBEK, JR. Figure 9 Hybrid or heterodimeric capsules form when exposed to Complementary guest solvents state of predictions regarding the energetics and geometry of hydro- gen bonds is far from ideal, and to predict the magnitude and the sign of the thermodynamic parameters for hybrids 1-6 and 5.6 without knowledge of the number of species being encapsulated or released is tenuous.3 Larger Volumes Robert Meissner and Jongmin Kang, with the collaboration of Javier de Mendoza developed a new system shown as 7 in Fig. 10.’’ The overall architecture involves a tape-like structure of 13 fused and one bridged ring systems. The ring fusions provide the gentle curvature required for the pseudo-spherical assembly. When viewed on edge, as shown in the Fig. 10, the somewhat exaggerated curvature of the structure can be seen. Compared to the ‘baseball’ the new system is a larger ‘softball’. The compound did show the expected NMR spectroscopic earmarks of a dimer in some aromatic solvents.But in chloroform the molecule produces a gel-like phase. Apparently, a polymeric assembly takes place; the molecule expresses its self-complementarity in an unexpected arrangement. The large solvent [2H,,I-p-xylene permitted the encapsulation of guests of considerable size and shape in the dimeric form. Adamantane is a particularly good fit and even tetramethyl-adamantane can be accommodated. Again, the widely separated and relatively sharp signals for free and encapsulated guest in the NMR spectra indicate that exchange of guests in and out of the capsule is slow on the NMR timescale. The numerous polar and polarizable atoms that line the inner surface can also stabilize complementary functional groups on guests, such as those on adamantaneamine and adamantanedicarboxylic acid.These proved to be the most tightly bound guests. Because higher order aggregates were also observed with 7a, it was necessary to find modifications by which the assembly process 0 0 7a R = phenyl, X = H 7b R = COZ-i-pentyl, X = H 7c R = 4-n-heptylphenyl, X = OH Figure 10 Self-complementary ‘softballs’ feature up to sixteen hydrogen bonds could be better controlled. For example, in 7c additional hydrogen bonding sites are provided by the phenolic functions. As these sites are positioned along the seam and can provide up to eight additional hydrogen bonds to stabilize the capsule, dimerization is favoured over other processes.I The encapsulation behaviour of this system proved surprising. The data for adamantane and ferrocene with 7c-7~in [2H,,]-p-xylene are given in Table 2. Table 2 Thermodynamic parameters for guest encapsulation by the 7c-7~dimer in [2Hlo]-p-xylene. The temperature range was from 298 to 343 K (K = association constant as defined in ref. 18; 1 cal = 4.184 J). AGlkcal AHlkcal ASlcal Guest K,,, mol-' mol -I mol-I K-' Adarnantane 1.7 X lo3 2 90 -4.6 2 0.2 2.2 2 0.1 22.6 2 1.1 Ferrocene 3.3 X 10' 2 170 -5.0 -+ 0.3 2.3 2 0.1 24.4'2 1.2 The most significant observation is that guest encapsulation iricreases with temperature. Now, most processes involving host-guest association are entropically unfavourable but enthalpi- cally favourable, and much has been written about the compensat- ing effects of entropy and enthalpy in complex f0rmati0n.I~ For 7c.7~the inclusion of guests involves an enthalpic cost compen-sated by a larger entropic gairz.Such entropy-driven binding is rem- niscent of the classical hydrophobic effect, wherein release of bound water to the bulk solvent compensates for the association of solutes In organic media such behaviour is not frequently detected,I8 even though liberation of solvent must be a universal feature of molecular recognition phenomena. How can this anom- alous behaviour be interpreted? A single solvent molecule appears too small to fill the cavity of the capsule 7c -7c; more than one CDCl, or p-xylene is required to maximise the intermolecular forces -the van der Waal's interac- tions -between the convex surfaces of the guests and the concave surface of the host's interior.The answer came from a simple set of experiments. In either [2H,]benzene or fl~oro[~H,]benzene the NMR spectra of compound 7b are characteristic of a single dimeric species. When the spectra was recorded in a mixture of the two sol-vents it became clear that three species were present.20 The most economical interpretation is that the third species is the capsular form that contains one of each solvent molecule (Fig. 11). Figure 11 Three distinct softballs are observed in a mixture of two solvents It is reasonable that single molecular guests which fill the cavity and offer chemical and structural complementarity are preferred to multiple solvent molecules; one guest releases the two solvent mole- cules inside the capsule (as well as the retinue of solvents associated with the guest outside).Consequently, the encapsulation of adaman- tanes or ferrocenes by 7c.7~increases entropy, since more than one encapsulated solvent is released to the bulk solution (Fig. 12). What are the limits on the capacity, i.e. what fraction of the space in these capsules can be occupied? What is the volume? Using MACROMODELIS the capsule's volume is calculated to be about 400 A3,or 4 X dm3. Two benzenes or two toluenes can easily be accommodated in this space. This suggested that the cavity was CHEMICAL SOCIETY REVIEWS, 1996 Figure 12 Encapsulation is entropy driven since two solvent molecules are 1iberated roomy enough to accommodate the transition state geometry of a typical Diels-Alder reaction.When both p-quinone and cyclohexa- diene are present in solution with 7a, a single well-defined complex emerges in the NMR spectrum. Integration shows one molecule of quinone is present within this complex. but no signals unique to encapsulated cyclohexadiene can be assigned. Nonetheless it must also be present, since the encapsulated Diels-Alder adduct is observed by NMR within one day (Fig. 13).21 The rate of this reac- tion in bulk solution is so slow at these concentrations that reaction must be taking place within the capsule. The effective molarity of the reactants inside is ca. 1 mol 1-I.This is a promising figure for the future use of capsules as reaction chambers for bimolecular processes. Figure 13 The softball as a reaction vessel for a Diels-Alder cycloaddition 4 Flattened Spheres Other geometric changes that can be made on the original design involve higher symmetries and one such improvement was pro- vided by a triphenylene spacer. This dimer features D,, symmetry, but it resembles -in shape and size comparisons relative to the base- ball and softball -a jam ('jelly) doughnut. This structure 8 was syn- thesized by Robert Grotzfeld (Fig. 14).22 The ceiling and floor of the assembled capsule consist of aromatic r-surfaces; 12 strong hydrogen bonds hold the two halves together. Titration experiments with benzene in CDCI, reveal a direct competition between benzene and CDCl, for the cavity of 8-8.Titration in [2H,,]-p-xylene solu-tion (an uncomfortable guest for 8.8) with cyclohexane revealed a new upfield (6 -0.87) signal in the 1H NMR spectrum for the encapsulated aliphatic guest.ASSEMBLY AND ENCAPSULATION WITH SELF-COMPLEMENTARY MOLECULES -JULIUS REBEK, JR. 26 1 H H 11 x2 Figure 14 The ‘jelly doughnut’ 8.8 has an ideal cavity for cyclohexane encapsulation A depth-shaded view of the complex with cyclohexane reinforces the notional and functional aspects of the jam (jelly) doughnut description. Unlike the other capsules, which take up and release guests at a rate that is fast on the human timescale, 8.8 takes hours to equilibrate with cyclohexane.This guest probably requires a large fraction of the host’s hydrogen bonds to break before passage into and out of the cavity is permitted. 5 Assembly with a Macrocycle Ken Shimizu proposed and synthesized the self-complementary calixarene 9a. It forms a dimeric capsule of yet another shape. The overall architecture of the assembly 9a.9a is that of two hemi- spheres ‘zippered’ together along the equator by hydrogen-bonded ureas (Fig. 15)?3 This hydrogen-bonding pattern of ureas has been well established, particularly in the solid state, where X-ray crys- tallography has shown that the head-to-tail arrangement is a common geometry. Their inviting bowl-like shape and their syn- thetic availability have made calixarenes attractive scaffolds for applications in supramolecular chemistry.24 The calix[4]arene systems synthesized in the research groups of Reinh~udt?~ Ungaro26 and Shinkai27 to assemble by hydrogen bonding are par- ticularly relevant.For the dimerization at hand, the ureas can be hydrogen-bonded in this fashion with the carbonyl oxygens buried into the NH’s of the preceding urea. All eight ureas may be fixed in same direction forming up to 16 hydrogen bonds. The hydrogen-bonding slows rotation about the calixarene-urea bond resulting in an isomer of D s mmetry. 4dEvydence for the existence of calixarene as a hydrogen bonded dimer 9a.9a comes from the encapsulation of solvent molecules inside the assembled cavity. Inclusion was initially apparent in mixed solvent systems where two distinct calixarene assemblies were observed by lH NMR.Direct observation of the encapsulated guests by ‘H NMR is also possible, given some time.Z8 For example, when excess benzene is added to the solution of 9b-9bin [2H,,J-p-xylene, a new signal for encapsulated benzene appears at 6 4.02 and gradually grows in over the course of ca. 40 min. The interleaved geometry of the assembly prevents visiting guests from leaving or entering quickly. 9aR=H 9bR=F 9a-9a Ar = C6H5 9b-9b Ar = CeH4p-F Figure 15 The head-to-tail ureas drive the formation of new capsules 9.9 Other guests have also been directly observed, such as fluoro- benzene, p-difluorobenzene and pyrazine. Blake Hamann observed remarkably different chemical shifts for encapsulated fluorobenzene; the para and ortho protons are separated by > 2 ppm, suggesting that a particular orientation is favoured by this guest within the cavity.The orientation shown in 10 (Fig. 16), where the ortho and metu hydrogens are directed at the 7~ faces of the calixarene while the para hydrogen and the fluorine are directed at the belt of ureas, is consistent with the chemical shifts. Competition studies of guests with benzene were undertaken and the affinity of the calixarene dimer for these, relative to benzene, is given in Table 3. Addition of other ureas such as the phenyl-a-phenylethyl deriv- CHEMICAL SOCIETY REVIEWS, 1996 R R R RI I I /Figure 16 'Denaturation' of the capsule and liberation of p-fluorobenzene by competing urea functions ative to the solution results in the liberation of guests and a new calixarene species 11 appears.This is most likely a result of the 'denaturation' of the calixarene dimer by the urea through compet- itive hydrogen bonding (Fig. 16), a process analogous to the denat- uration of proteins with urea. Table 3 Relative affinities of guests in competition experiments with benzene Guest Affinity (25 "C) Guest Affinity (25 "C) C6H6 1.o C,H,OH 0.83 C,H,F 2.6 C,H5NH, 0.32 p-C,H,F, 5.8 Pyrazine 3.2 C,H,CI 0.30 Pyridine 1.2 C,H,CH3 <0.1 The high affinity observed for pyrazine is also suggestive of a conformation that directs the nitrogen lone pairs at the urea hydro- gens within the complex.A recent study by Sherman29 also finds pyrazine a favoured guest. The system involves a belt of strong hydrogen bonds (phenol with phenolate) and structures closely related to calixarenes (Fig. 17). k k k Figure 17 Hydrogen bonding holds hemispheres together for guest encapsulation The volume of the cavity was estimated to be ca. 210 A3, and most guests appear to fill ca. 50%or less of the available space in the cavity. By comparison, in a typical liquid 70% of space is filled. The shape of the cavity within 9.9 is difficult to visualize, but a geometric simplification is shown in Fig. 18. Each calix[4]arene is represented by a square pyramid with its tri- angular facets corresponding to the outside of the aromatic sur- faces.In the dimer, the pyramids are offset by 45", and the corners are cut off to represent the eight interleaved ureas which encircle the equator. 2 Square Pyramids ( 45"offset ) 7-8A 7-8& Figure 18 Schematic representations of the cavity formed by the dimeriza- tion of tetraureas 9,and vertical and horizontal cross sections Cross sections of the molecular model are in agreement with the gem-like geometric representation. A horizontal slice through the plane of the ureas yields an octagonal cavity, while a vertical slice gives a diamond-shaped cavity, having different angles and lengths for the top and bottom sections. The representations shown in Fig. 18 suggest that cubane is a ASSEMBLY AND ENCAPSULATION WITH SELF-COMPLEMENTARY MOLECULES- JULIUS REBEK, JR.reasonable three-dimensional complement for the cavity shape. The energy-minimized structures for the complexes with cubane are shown in Fig. 18, again with the cavity walls cut away for ease of visualization. In the experiment, cubane was added to a solution of 9b-9bin [*H,,]-p-xylene and the formation of a I: 1 complex was again observed by NMR. Figure 19 Cut-away views of CPK representations of the calixarene dimer with encapsulated cubane In conclusion, the behaviour and functions of molecular assem- blies can, to some extent, be controlled -either by solvation effects or by nucleation by guests. The energetics for such complexes invariably pit intermolecular forces against the decreased freedom of the included guest.These forces are the van der Waals' interac- tions and hydrogen bonds between the exterior surface of the guest and the interior surface of the host. In addition, special entropic effects can emerge when more than one solvent molecule is present in the capsules. Guests, or better, hostages, which more closely fit the host's cavity in size and shape and leave no empty space are favoured.30 The acceleration of a Diels-Alder reaction augurs well for the long-term goal of using these capsules as reaction chambers. In the meantime, we continue to explore the behaviour of 'mole- cules within molecules .'3I Acknowledgements I am indebted to the members of my research group for their inspired designs and experiments.Their names appear on the original publications. I am grateful to the National Institutes of Health for financial support. 6 References 1 S. C. Zimmerman and B. F. Duerr, J. Org. Chem., 1992,57,2215. 2 J.-M. Lehn,Angew. Chem., Int. Ed. Engl., 1990,29,1304;J. S. Lindsey, New J. Chem.,1991,15, 153; G. M. Whitesides, J. P. Mathias and C. T. Seto, Science, 1991,254, 13 12. 3 C. T. Set0 and G. M. Whitesides,J. Am. Chem. Soc.. 1990,112,6409:F. Garcia-Tollado, S. J. Geib, S. Goswami and A. D. Hamilton. J. Am. Chem. SOC., 1991,113,9265. 4 J. A. Zerkowski, C. T. Seto, D. A. Wierda and G. M. Whitesides, J. Am. Chem. SOC., 1990, 112, 9025; J. Zerkowski, J. P. Mathias and G. M. Whitesides, J. Am. Chem. SOC.,1994,116,4305. 5 M.Simard, D. Su and J. D. Wuest,J. Am. Chem. Soc., 1991,113,4696; J. Am. Chem. SOC., 1994, 116 1725; Y. Ducharme and J. D. Wuest, J. Org. Chem., 1988,53,5787;C. Fouque, J.-M. Lehn and A. M. Levelut, Adv. Mater., 1990,2,254; J. Yang, J.-L. Marendaz, S. J. Geib and A. D. Hamilton, Tetrahedron Lett., 1994,35,3665. 6 J. P. Mathias, C. T. Seto, E. E. Simanek and G. M. Whitesides, J. Am. Chem. Soc.. 1994, 116, 1725; J. P. Mathias, E. E. Simanek, J. A. Zerowski, C. T. Seto and G. M. Whitesides, J. Am. Chem. Soc., 1994, 116,4316. 7 M. R. Ghadiri, J. R. Granja, R. A. Milligan, D. E. McRee and N. Khazanovich, Nature, 1993,366,324; J. R. Granja and M. R. Ghadiri, J. Am. Chem. SOC., 1994,116, 10785; K. Kobayshi, J. R. Granja, R. K. Chadha and D. E. McRhee, Angew.Chem., Int. Ed. Engl., 1995.34, 93. 8 R. Wyler, J. de Mendoza and J. Rebek, Jr. Angew. Chem., Int. Ed. Engl., 1993,32,1699. 9 K. T. Chapman and W. C. Still, J. Am. Chem. Soc., 1989, 111,3075; M. L. C. Quan and D. J. Cram,./. Am. Chem. SOC.,113,2754. 10 N. Branda. R. Wyler and J. Rebek, Jr. Science, 1994, 263, 1267; for methane complexation inside a cryptophane: L. Garel, J.-P. Dutasta and A. Collet, Angew. Chem., Int. Ed. Engl., 1993,32, 1169. 11 C. ValdCs, U. P. Spitz, L. Toledo, S. Kubik and J. Rebek, Jr., J. Am. Chem. SOC., 1995,117,12733. 12 N. Branda, R. M. Grotzfeld, C. ValdCs and J. Rebek, Jr., J. Am. Chem. SOC.,1995,117,85. 13 X. Garcias and J. Rebek, Jr., Angew. Chem., Int. Ed. Engl., 1996, in press. 14 T. Fox, B.E.Thomas, M. McCarrick and P. A. Kollman,J. Phys. Chem., submitted for publication. We thank these authors for helpful corre-spondence and a preprint of their manuscript. 15 Molecular modelling was performed using MACROMODEL 3.5X (MM2" force field); F. Mohamadi, N. G. Richards, W. C. Guida, R. Liskamp, M. Lipton, C. Caufield, G. Chang, T. Hendrickson and W. C. Stil1,J. Comput. Chem., 1990,11,440. 16 C. Valdes, U. P. Spitz, S. Kubik and J. Rebek, Jr., Angew. Chem., Int. Ed. Engl., 1995.35.1885. 17 R. Meissner, J. de Mendoza and J. Rebek, Jr., Science, 1995,270.1485. 18 J. Kang and J. Rebek, Jr., Nature, in press. For other cases involving covalent J. Canceill, M. Cesario, A. Collet, J. Guilhem, L. Lacombe, B. Lozach and C. Pascard, Angew.Chem., Int. Ed. Engl.. 1989,28. 1246; D. J. Cram, H.-J. Choi. J. A. Bryant and C. B. Knobler, J. Am. Chem. SOC., 1992, 114. 7748; D. J. Cram, M. T. Blanda, K. Paek and C. B. Knobler, J. Am. Chem. Soc., 1992,114,7765. 19 J. D. Dunitz, Chem. Bio., 1995, 2,709; B. R. Peterson, P. Wallimann, D. R. Carcangue and F. Diederich, Tetrahedron, 1995,51,401; M. S. Searle, M. S. Westwell and D. H. Williams,J. Chem. Soc., Perkin Trans 2,1995,141. 20 R. Meissner, X. Garcias and J. Rebek, Jr., Angew. Chem.. submitted for publication. For other unique encapsulation phenomena, see: D. J. Cram and M. E. Tanner, Angew. Chem., Int. Ed. Engl., 1991, 30, 1024; P. Timmerman, W. Verboom, F. C. J. M. van Veggel, J. P. M. Duynhoven and D. N. Reinhoudt, Angew. Chem., lnt.Ed. Engl., 1994,34,2345; R. G. Chapman, N. Chopra,E. D. Cochien and J. C. Sherman,./. Am. Chem. Soc., 1994,116,369. 21 J. Kang and J. Rebek, Jr., unpublished. 22 R. Grotzfeld and N. Branda and J. Rebek, Jr., Science, 1996,271,487. 23 K. D. Shimizu and J. Rebek, Jr. Proc. Natl. Acad. Sci. USA, 1995,92, 12403. 24 For recent reviews see: V. Bohmer,Angew. Chem., Int. Ed. Engl.. 1995, 34, 713; P. Linnane and S. Shinkai. Chem. Ind., 1994, 811; C. D. Gutsche, Aldrichim. Acta, 1995, 28, 3; S. Shinkai, Tetrahedron. 1993, 49, 8933; P. Timmerman, W. Verboom and D. N. Reinhoudt. Tetrahedron, 1996,52,2663. CHEMICAL SOCIETY REVIEWS, 1996 25 J. D.van Loon, R. G. Janssen, W. Verboom and D. N. Reinhoudt, 30 For examples of covalently linked hemispheres see: T.A. Robbins, Tetrahedron Lett. 1992,33,5125;P.Timmerman,K.G.A.Nierop,E.A. C. B. Knobler, D. R. Bellow and D. J. Cram, J. Am. Chem. Soc., 1994, Brinks, W. Verboom, F. C. J. M. van Veggel, W. P. van Hoorn and D. N. 116,lll;A.IkedaandS.Shinkai,J.Chem.Soc.,PerkinTrans.I,1993, Reinhoudt, Chem. Eur. J., 1995,1, 132. 2671 ;L. Garel, J. P. Dutasta and A. Collet, Angew. Chem., fnt. Ed. Engl., 26 A. Arduini, F.Fabbi, M. Mantovani, L. Mirone, A. Pochini, A. Secchi 1993,32, 1169; J. Canceill, L.Lacombe and A. Collet, J.Am. Chem. and references therein. For a review of molecules and R. Ungaro, J.Org. Chem., 1995,60,1454. SOC.,1986,108,4230, 27 For two-component assemblies based on calixarenes see: K. Koh, K. with large interior cavities see: C. See1 and F. Vogtle,Angew. Chem., Int. Araki and S. Shinkai, Tetrahedron Lett., 1994,44,8255. Ed. Engl., 1992,31,528. 28 B. C. Hamman, K. D. Shimizu and J. Rebek, Jr., Angew. Chem. tnt. Ed. 31 D. J. Cram, Lecture at the C. David Gutsche Symposium, Washington Engl., 1996,35,1326. University, St. Louis, Missouri, May 5, 1990. 29 R. G.Chapman and J. C. Sherman, J.Am. Chem. Soc., 1995,117,9081.

ISSN:0306-0012    

DOI:10.1039/CS9962500255

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

New Approaches to Chemical Patterns Barry R. Johnson and Stephen K. Scott School of Chemistry, University of Leeds, Leeds, UK, LS2 9JT 1 Introduction For many people, the patterns of ‘chemical gardens’, rock strata and their laboratory equivalents Liesgang Rings are as an important a part of the early attraction of chemistry as ‘smells and bangs.’ These ‘reaction4iffusion structures’ arise from a cooperation between molecular transport through diffusion and chemical kinetics. In recent years there has been considerable interest in the study of chemical patterns fuelled by an almost casual suggestion4 of one of Britain’s more enigmatic mathematicians and made possible by rapid advances in technology driven by several groups of imagina- tive chemists. In this review, we survey the various new observa- tions made along the route to taming of so-called ‘Turing Structures’ in the laboratory and attempt to set these in the context of their relevance in chemistry and other areas of science.2 Background concepts 2.1 Chemical Feedback In all but the simplest (elementary) reaction systems many different species become involved during the course of the conversion of the initial reactants to the final products. Species which are formed in early stages but then react further are termed intermediates and are frequently more reactive than their precursors. In such systems, we can still define a reaction rate in terms of the rate at which the concentration of one of the initial reactants is decreasing in time or as the rate at which the concentration of one of the final products is increasing.The way in which this rate varies during the reaction can be examined by plotting it against the extent or fractional conver- sion of the initial reactant. In some cases, these rate-extent curves have one of the shapes shown in Fig. l(a).These correspond to so-called deceleratory kinetics, as the reaction rate falls steadily throughout the whole course of the reaction, having its maximum value at the very start. Such rate-extent curves are often represented by simple n-th order rate laws, with n = 1 for a first-order reaction, n = 2 for second-order and so on. The rate-extent curves in Fig. l(b) have a different form in that they show the reaction rate increasing with the extent, at least in the early stages, and so have an acceleratory phase, before attaining a maximum when perhaps half of the reactants have been consumed.0 0.5 1 extent of reaction, 5 0 0.5 1 extent of reaction, 5 Figure 1 (a) Dependence of reaction rate on extent of conversion, 6, for different order of deceleratory reactions. The rate is normalised to the maximum rate, R,,,, which for these systems corresponds to 6 = 0. (b) Reaction rate dependence on the extent of conversion for (i) quadratic and (ii) cubic autocatalysis, and (iii) an exothermic reaction illustrating the different positions of maximum reaction rate for feedback systems. Stephen Scott is Professor of Mathematical Chemistry and currently Head ofPhysica1 Chemistry at the University of Leeds where he and Dr Barry Johnson run the ‘Nonlinear Kinetics Laboratory’.Both authors are Leeds graduates: Scott has had periods in Australia (postdoc) and USA (Fulbright Professor); Johnson was a postdoc at Stanford. Our research areas include oscillating reactions, chem- ical waves and the applications of chaos theory in which areas we have written several books in recent years. Barry R. Johnson Stephen K. Scott 265 Such curves indicate the existence of some chemical feedback process in the reaction mechanism. A simplified but very useful representation of chemical feedback based on autocataly~is~imag-ines a reaction in which some chemical A is converted to a product B but for which the reaction rate increases as the product concentra- tion increases as if B plays the role of a catalyst for its own produc- tion.Two basic forms are often exploited: quadratic autocatalysis A + B -2B rate = kqab (1) cubic autocatalysis A + 2B -3B rate = k,ab2 (2) where a and b are the concentrations of the reactant and autocatalyst and k, and k, are rate constants. Whilst there is almost certainly no actual chemical reaction in which such a conversion occurs in a single elementary step, the rate-extent curves for a considerable (and ever-growing) class of reactions can be fitted by one or other of these caricatures (or by a combination of the two). The autocatalyst B is frequently referred to as thefeedback species or activator.In some cases it is relevant to identify an inhibitor species from amongst the reactants, whose removal has an overall accelerating effect on the reaction. 2.2 Examples of Systems showing Chemical Feedback Chemical feedback forms the kinetic clockwork driving various ‘exotic’ types of reaction behaviour, including oscillations. At the time of Alan Turing’s paper (1952) there was no well-established example of an oscillatory reaction although Boris Belousov had made an initial attempt the previous year to publish his observations concerning the reaction that now bears his name in conjunction with Anatol Zhabotinsky. The ‘BZ’ reaction is now a familiar lecture demonstration with its repetitive red-blue-red oscillations that last for several hours in a well-stirred beaker and many other chemical reactions with feedback are now very well-characterised: feedback is far from a rarity in chemical kinetics.The BZ reaction3 involves the oxidation of a suitable organic sub- strate, often malonic (propane- 1,3-dioic) acid with an acidified bromate solution in the presence of a transition metal redox catalyst such as the ferroin-ferriin couple, in which Fe is complexed with 1,lo-phenanthroline and oscillates between the red Fell and blue Fe*I1 states. The important features of the mechanism of the BZ system are now relatively firmly established: there are essentially three important overall processes: an inhibition phase involving bromide ion, an autocatalytic phase in which the redox catalyst is oxidised, and a clock-resetting phase in which bromide ion is pro- duced as the redox catalyst is reduced. The autocatalytic species has been identified as HBrO,, and the autocatalytic phase has the overall stoichiometry: BrO; + HBrO, + 3H+ + 2Fe” -2HBrO, + 2Fe”’ + H,O rate = k [BrO;l[HBr0,1[H+12 thus exhibiting the quadratic-type of kinetics in eqn.(l),with the reactant A corresponding to bromate ion. If a solution of BZ reagents is spread as a thin layer in a Petri dish, waves of the oxidation reaction spread out from certain pacemaker sites? which perhaps correspond to sites where the local pH varies from that of the bulk (these may arise from dust particles or defects in the dish surface). The waves appear as thin blue reaction zones moving across a red background often as concentric circles (target patterns) or as spiral waves, examples of which are shown in Fig.2. Spirals and targets occur more widely in chemistry and biology: recent work has shown that the reaction of CO with 0 atoms on some Pt crystal planes occurs through spiral waves on the crystal surface;6 spirals and targets have very recently been reported in gas-phase reaction;’ the slime mould Dictyostelium discoideum responds to starvation by changing from a colony of individual single cells into a multicellular organism? with the cells coming together under the influence of chemical signalling and chemotaxis in a spiralling migration; spirals and their three-dimensional counterparts, scroll waves, are implicated in disorders of the heart and may be associated with epileptic seizures .9 CHEMICAL SOCIETY REVIEWS, 1996 Despite their names, these are not chemical ‘patterns’ in the Turing sense; the exact spatial distribution depends crucially on the chance locations of the pacemaker sites rather than just the under- lying kinetics and the reaction zone size.They are, nevertheless, attractive and important examples of chemical spatiotemporal organisation. A second solution-phase reaction that has become increasingly exploited for studies of spatial patterning is the CIMA (chlorite-iodide-malonic acid) reactionlo or its close cousin the CDIMA (chlorine dioxide-iodine-malonic acid) system. These differ only in the precise chemical form in which the oxychlorine and iodine reagents are supplied: in the CIMA system, the initial CIO; and 1-are almost completely consumed during a pre-oscilla- tory induction phase during which C10, and I, are the major ‘reac- tant’ species with chlorite and iodide acting as the ‘intermediates’. The Lengyel-Rabai-Epstein’ I mechanism for this reaction involves three component processes: (CIMA1) MA + I, -IMA + I-+ H+ rate = ~,,[MAI[I,l/(k,, + [I,] (CIMA2) c10, + I--(210; + HI, rate = k,(ClO,][I-] (CIMA3) C10; + 41-+ 4H+ -21, + C1-+ 2H,O rate = k3,[C10; J[I-]H+ + k3,[C10;I[1,1[I-l/(a + [I-],) The empirical rate laws for each of these overall stoichiometries indicate that there is a complex role for I, in (CIMAI) and that I, acts as an autocatalyst in (CIMA3) in which iodide ion is an inhibitor.Under the normal reaction conditions, I, is present in excess and its concentration is effectively constant, so the inhibitory role of I-is the dominant feedback route. The CIMA reaction also exhibits oscillations in well-stirred batch reactors and target ‘patterns’ in unstirred systems: using starch as an indicator the reaction varies between blue (reduced state) and clear/pale yellow (oxidised state). 23 Diffusion-driven Instabilities: lbring Patterns In most simple situations, diffusion has a ‘smoothing out’ effect which serves to produce uniform spatial distributions of chemical species as time progresses: a simple example is the spread of a drop of ink in a beaker of water to produce a dilute, uniform ink solution.The possibility of the reverse process, all the ink particles spontane- ously gathering together in some small region of the solution and leaving the bulk colourless, is usually viewed as that most heinous of suggestions -a violation of The Second Law of Thermo- dynamics. Alan Turing’s startling prediction4 was that if diffusion is coupled with chemical feedback, then something similar to this spatial organisation can indeed occur spontaneously, without invok- ing demons or violating the Second Law. Subsequent theoretical work by Prigogine’s group in Brussels and by others elsewhere showed that chemical reactions would be an ideal hunting ground for Turing Patterns. The basic requirements for a system to decide to self-organise from an initially uniform distribution of all concentrations into a situation where some species have concentrations that vary with position are that: (i)the feedback process be sufficiently strong that it can support oscillations under well-stirred conditions and (ii)the diffusion coefficient for the feedback species should be less than that for the inhibitor-reactant species, i.e.we require D,/D, < 1. It might be imagined that some reactions might meet this naturally (e.g.if they involve molecules of distinctly different molar masses), but in general the need selectively to control one diffusion coeffi- cient in a reacting system has presented a problem that has only recently been resolved. There are some subsidiary requirements: diffusion is a relatively weak process and the frail chemical patterns that arise from its cou- pling with feedback kinetics are readily disrupted by fluid motion whether imposed or arising as a consequence of the chemistry.The latter situation can arise relatively easily in reactions as a result of density changes accompanying the reaction that, in turn, may be caused by a reaction that is exothermic and thus having local self- NEW APPROACHES TO CHEMICAL PATTERNS-BARRY R. JOHNSON AND STEPHEN K. SCOTT Figure 2 (Top) Target patterns formed in a thin layer of BZ reaction mixture, 7.25 min after mixing. There are three random pacemaker sites in the 9 cm diameter Petri dish. (Bottom) Spiral waves formed by breaking target patterns. Each spiral rotates with the same period (30 s) and has the same frequency. heating where the reaction rate is highest or if there is a change in the molar volume in going from reactants to products.In either case, the density changes will lead to convective motion of the solution; this itself can give rise to some interesting spatial phenomena, and chemical reactions which have suitable colour changes can be used to reveal such induced convection, but it is separate from the diffu- sion-dri ven Turing mechanism. A second requirement is for a continuous supply of fresh reac- tants (and a matching removal of products if the volume of the system is not to grow). This flow allows the system to sustain a pattern indefinitely, driven by the free energy change accompany- ing the reaction; in the absence of flow, patterns may develop during the reaction but they are inevitable transient phenomena and the system returns to spatial uniformity as the system approaches its chemical equilibrium state.These two different requirements -the provision of a continuous supply but also the suppression of fluid motion -are, to some extent, contradictory and represented a considerable challenge to the experimental verification of Turing’s predictions. Systems that meet the various conditions set out above should show spontaneous spatial organisation to produce chemical patterns that have a ‘natural wavelength’ that depend on the reaction kinetic parameters (rate constants etc.) and on the diffusion coefficients. The wavelength is mainly independent of the size of the reaction CHEMICAL, SOCIETY REVIEWS, 1996 I 1 Reservoir 2 Figure 3 The Gel Strip reactor and the first experimental Turing Pattern in the CIMA reaction (left) Sketch of the reactor Reagents are well mixed in the reservoirs, 1 and 2 and diffuse into the gel from the longest edges (right) Contrast enhanced picture of Turing pattern several rows of clear spots where dark regions correspond to reduced state, clear regions correspond tooxidised state Experimental conditions temperature 7 "C, boundary feed conditions (concentrations in moll-1) [NaCIO,] = 2 6 X [KI] = 3 X lop3,[NaOH] = 3 X low3,[Na,SO,] = 3 X 10 3, [CH,(COOH), = 9 X 10 3, [H,SO,] = 1 X 10 2 (Reproduced with permission from Castets et af I3 0The American Physical Society) zone, although there is a need for this to exceed some minimum dimension in order that at least one half-wavelength can be accom- modated If this condition is met, then patterns may be expected provided the concentrations of the major reactant species lie in certain ranges, 1 e patterns are only found over finite ranges of experimental conditions Any patterning that does develop needs to be recorded in some way The technology for such image capturing and processing has been brought to a very sophisticated state based on video camera + frame digitisation techniques pioneered in the chemical context by the group of Benos Hess, Stefan Muller and The0 Plesser at Dortmund l2 These provide essentially spatially and temporally resolved spectrophotometry with intensity levels as a function of position and time that can be converted to absolute concentrations if required or simply used as grey-scale monitors of changes in signal 3 The First Experimental Observations of Turing Patterns Various new experimental configurations have been designed and tested in order to satisy the demands listed in the previous section Central to the success in the search for Turing Patterns has been the use of gels instead of an aqueous solution phase These were pri- marily adopted to reduce the tendency for natural convective motion and also to allow streams of fresh reactants to flow past the reaction zone without disrupting the diffusive transport within the matrix 3.1 The Gel Strip Reactor The Gel Strip Reactori3 devised by the group of Jacques Boissonade and Patrick De Kepper in Bordeaux consists of a narrow, rectangu- lar piece of polyacrylamide hydrogel approximately 20 mm in length and 3 mm wide (with a thickness of 1 mm) The two long edges are placed in contact with separate reservoirs of reactant species, as indicated in Fig 3, in which the concentrations are main- tained constant by continuous flow Diffusion of the individual reac- tant species occurs across the strip, so there are natural concentration gradients in this system perpendicular to the reser- voirs, but not in a direction parallel to the long edges Reaction occurs in the gel strip where the concentrations of all species are non-zero In order to render the development of the reaction visible by eye and to a standard video camera imaging system, the gel can be loaded with suitable indicators such as starch or thiodene This apparently simple device has an initially unsuspected advantage The feedback species for the CIMA reaction is I-which in the pres- ence of I, forms 1, This species complexes with the starch or other indicator which itself is a large molecule and which has a low mobility in the gel matrix The I, indicator complex thus has a reduced effective diffusion coefficient14 whilst other species have diffusion coefficients that are substantially higher (the diffusivities of 'normal size' molecules in the gel are approximately equal to their solution-phase values) In this way, the system is arranged to satisfy the Turing requirement in terms of differing diffusivities The first experimental examples of a Turing Pattern obtained in this wayi3 are shown in Fig 3 The spatial structure perpendicular to the long edges is, as explained above, driven at least in part by the imposed chemical gradients, but the spatial inhomogeneity along the strip, right-to-left in the figure must arise from a Turing mechanism based on feedback reaction and selective diffusion The wavelength scale of the pattern is of the order of 0 2 mm and hence much smaller than the reactor dimensions, suggesting that the strip geometry has no determining role in the pattern By varying the concentrations of individual reactants in the reser- voirs, different spatial structures can be obtained,' as indicated in Fig 4 In this figure, the main change with composition lies in the number of 'fronts', i e changes from oxidised to the reduced state, lying parallel to the reservoirs (so the spatial structure is parallel to the imposed concentration gradients), with the Turing Pattern-type spots only occurring in region IV The investigation of other types of Turing Pattern has been pursued with a different type of gel reactor 3.2 The Gel Disk Reactor A variation on the Gel Strip Reactor developed by Qi Ouyang and Harry Swinney in Texas involves a disk of the gel matrix separating different reactant reservoirs of constant concentration l6 I (main-tained by continuous flow), with the reaction then monitored by video camera as indicated in Fig 5(a) A i \Z 1.5 -/cu 9 x A I7E.1-I 0A A i 0.5 -\ A A -10-0 1 2 3 [KI]x 103/M Figure 4 Phase diagram of sustained patterns Section in the plane (iodide-malonic acid) Regions I single front pattern, I1 triple front pattern, 111 multiple front pattern, IV spot pattern Numbers next to symbols indicate the number of rows Experimental conditions tempera- ture 4"C, other parameters as for Fig 3 (Reproduced with permission from Castets et a1 Is 01990The American Physical Society) NEW APPROACHES TO CHEMICAL PATTERNS-BARRY R. JOHNSON AND STEPHEN K. SCOTT aspirator aspirator U/.\reservoir reservoir waste sulfuric acid malonic acid, iodide chlorite, sodium hydroxide Figure 5 Schematic diagrams of open spatial reactors fed by cstrs.(a) Two- side fed reactor and (b) one-side fed reactor. (Reproduced with permis- sion from Ouyang et a1.l6J7(a) 01991 American Institute of Physics, (b) 01992 Elsevier Science BV) A further variation on this is the single-side feed, Fig. 5(b),in which the reactants are mixed prior to entering the chamber above the gel in which the mixture has a relatively short residence time. Again, an indicator can be incorporated into the gel although polyvinyl alcohol gels are self-indicating and also play the role of reducing the mobility of the feedback species. The system is viewed along the imposed concentration gradients and so any patterns that are observed lie perpendicular to these gradients and arise from the Turing mechanism.As shown in Fig. 6, changing the reservoir concentration can cause the pattern to change from a hexagonal arrangement of ‘spots’ to ‘stripes’ much as predicted in the Turing theory. Rhombic arrangements of spots and ‘zig-zag’ arrangements of stripes have also been observed as the reactant concentrations are varied.I8 Subsequent studies by Agaldze el a1.I9 in which the reaction occurs in capillary tubes have indicated that the precise form of the gel is not vital for Turing patterns, and even that the patterns can arise without a gel, indicating that the starch-iodine complex is suf- ficiently less mobile than 10, in aqueous solution for the require- ment of different diffusivities to be met, 4 Patterning in Reaction Fronts and Flames The kinetics required to support oscillatory behaviour in batch systems represent one degree of complexity up from the simple one- off feedback processes represented in eqns.(1) and (2). A single autocatalytic process can, however, support a one-off clock reaction in which there is a rapid reaction event at the end of a long induc- tion period. If such a system is conducted in an unstirred solution and the reaction is initiated locally in a small region, then a one-off reaction-diffusionji-ont can emerge in which the diffusion of the autocatalyst triggers reaction in the surrounding region. Such fronts are isothermal analogues of flames in which the primary feedback arises thermally from the exothermicity of the reaction.In the simplest circumstances, fronts propagate as circles or spheres (in 2D and 3D reaction zones) or as a planar front. However, if the diffusivities of the reactant and feedback species can be made to differ, there can be a spontaneous development of more complex wave front geometries. This effect was first observed and analysed in flame systems, but has also recently been demonstrated*’J experi- mentally for a chemical feedback system. The reaction between iodate and iodide ion in acidified solution in the presence of the suit- Figure 6 Stationary chemical patterns formed in the two-side fed open reactor with a polyacrylamide gel: (a) and (c) hexagons; (b) and (d) stripes.The bar beside each picture represents I mm. The concentrations (in mol I-’) in reservoirs A and B were (a) [I-] = 3.0 X [CH,(COOH), = 1.3 X lo-* and (b) 11-1 = 5.0 X [CH,(COOH),] = 8.3 X 10-2 with the other parameters held fixed at [Na,SO,J = 4.5 X lop3,[C102-] = 1.8 X lop2,(H,SO,I, = 5 X lo-,, [H2S0,], = 1 X 10-2, temperature 5.6 “C.(Reproduced with permission from Ouyang and Swinney.Ih 01991 American Institute of Physics) CHEMICAL SOCIETY REVIEWS, 1996 0.0L I 0.0 1.0 2.0 3.0 4.0 0.0 0.0 1.0 2.0 3.0 4.0 xicm xicm II. I 0.0 1.0 2.0 3.0 4.0 0.0 1.0 2.0 3.0 4.0 x/cm xicm Figure 7 Initial front evolution from a symmetrical perturbation with [a-cyclodextrinl, = 0.33 mol I-' for (a) and (b), and [a-cyclodextrin], = 0.04 mol I-' for (c) and (d).(a) Behaviour at t = 23 min following initiation at the interface between product and reactant zones; (b) development of front at t = 343 min after initiation showing the appearance of a cusp separating two symmetrical cells; (c) behaviour at t = 23 min following initiation at the interface between product and reactant zones; (d) development of front at t = 10h after initiation showing the diffusive smoothing of the perturbation. Experimental conditions (concentrations in mol ]-I): [IO;] = 4.8 X lop3,[As"'] = 1.6 X lo-*, [SO:-1 = 0.32, [HSO,] = 4.8 X lo-*, [Ag+] = 6.5 X 10-5, pH = 2.35. (Reproduced with permission from Horvath and Showalter.20 01995 American Institute of Physics) able reductant (typically HSO; or H,AsO,) is known as the Landolt reaction and follows an approximately cubic autocatalytic rate law (2) with A = 10; and B = I-.When performed in a polyacrylamide gel in which a-cyclodextrin, which forms a relatively immobile complex with I-, has been incorporated, non-planar fronts develop from small perturbations if the concentration of the complexing agent is sufficiently large, but such perturbations decay and a planar front is re-established with lower concentrations, Fig. 7. If the iodate-reductant system is augmented with ferrocyanide, the kinetics are able to support oscillations in flow reactors. This system has been studied in the Gel Disk Reactor in which complex 'serpentine patterns' have been observed.The 'pattern' is obtained by providing relatively large amplitude perturbations locally at points on the membrane, from which propagating redox fronts emerge. These propagate towards each other until they are separ- ated by a critical distance, when they then stop. The fronts emerg- ing from the various initiation sites eventually produce a structure that fills the spatial domain, with a typical development shown in Fig. 8. Several additional features have also been found, including the 'birth' of new spots as a large spot divides and 'death' as two spots coalesce. Once established by a suitable initial perturbation, this dynamic spatial structure is self-sustaining as long as the flow of reactants is maintained.21,22 5 Gel-based Studies of the Belousov-Zhabotinsky reaction Some of the earliest applications of continuous-flow unstirred reac- tors based on gels were to studies of the spatial structures of the BZ reaction:23 the targets and spirals mentioned earlier.The Annual Gel Reactor is formed from a circular annulus of gel with one stream of reactants flowing around the outer circumference and the second stream flowing through the central hole in the gel. A pacemaker site at some point on the gel will initiate a pair of waves, one travelling clockwise, the other counterclockwise. These waves will meet each other at some point across the annular diameter where they will mutually anihilate. (It is a characteristic feature of these chemical waves that they do not pass through each other.) If the transit time for the waves is long compared with the rate of firing of the pace- maker, several pairs of waves may be established at any one time propagating around the gel.By providing a barrier to the propaga- tion of waves close to, and on one side of, the pacemaker, the waves propagating in one of the two senses can be eliminated, leaving say just the clockwise propagating fronts. If the pacemaker can also be then eliminated, these waves will simply continue to run laps around the gel, forming a chemical pinwheel as indicated in Fig. 9 (A similar response with a slightly different origin was predicted in Turing's original paper?) Subsequent studies have also exploited the Gel Disk Reactor Figure 8 Time evolution of a pattern in the iodate-ferrocyanide-sulfite system initiated by a perturbation with intense ultraviolet light at the left boundary.The pattern achieved 3 h after the localised perturbation was removed is essentially stationary. The pattern was visualised with Bromothymol Blue pH indicator (1.5 X mol I-!) so white regions correspond to low pH and black regions to high pH. Experimental condi- tions (concentrations in moll- I): [NaIO,] = 7.5 X lo-*, [Na,SO,] = 8.9 X lo-,, [K4Fe(CN);3H,O] = 2.5 X [H,SO,] = 4.5 X (NaOH] = 2.5 X lop4;temperature 30.0 ? 1 .O "C.(Reproduced with per- mission from Lee et ~1.2~01991 The American Physical Society) NEW APPROACHES TO CHEMICAL PATTERNS-BARRY R. JOHNSON AND STEPHEN K. SCOTT 27 I Figure 9 A five-armed pinwheel on a ring-shaped polysulfone membrane 1 h after its initiation. The fixed catalyst is bathoferroin with the ring dimensions inner diameter 24 mm; and outer diameter 37 mm.BZ solution: [CHBr(COOH),] = 0.19 rnol I-', [NaBrO;] = 0.12 rnol I-I, [H2S0,1 = 0 47 mol I-' (Reproduced with permission from Noszticzius et ~21.~501987 Macmillan Magazines Ltd) using a PVC-silica membrane impregnated with a polyacrylamide gel .24,25 In the simplest cases, the spiral waves observed are almost identical to those found for similar reactant concentrations in Petri dishes, only now sustained indefinitely by the flows. It is possible to initiate and stabilise a single spiral rather than counter-rotating pairs of spirals. Waves can be initiated in such systems by exposure to UV light and masks can produce waves of varying initial shape.The advantages and challenges presented by the use of gels with reactions such as the BZ system have been considered by Yamaguchi et a1.26Several new approaches, particularly in relation to producing pinwheels, have been developed by No~zticzius.~~ 5.1 Immobilised Catalyst Systems In the various Gel Reactors described above, all of the components of the BZ system are able to diffuse relatively freely, with diffusion coefficients approaching those appropriate to aqueous solution. With other possible reaction matrices, it is possible effectively to immobilise the redox catalyst, e.g. by employing a cation exchange resin either in the form of beads or a membrane. (The redox cata- lyst is not an autocatalytic or inhibitor species in the BZ reaction so this is a different situation from the Turing systems described in Section 3.) This approach has been particularly exploited by Ken Showalter and Jerzy Masleko in West Virginia.28 In their original study, a thin layer (0.5mm) of small cation exchange beads (38 pm to 75 pm diameter) loaded with ferroin was spread in a Petri dish and covered with a 1.6 cm deep solution of the remaining BZ reagents.At low bromate and H+ concentrations, simple target pat- terns were established and each bead was uniformly either red or blue depending on its position relative to the waves. As the reactant concentrations were increased, however, more complex responses developed, with waves breaking as they propagated away from their initiation sites, giving rise to asymmetric spiral pairs.These propa- gated so that the merging wavefront collided with itself, Fig. 10,and eventually produced essentially concentric circular fronts. This is an important aspect: in homogeneous solutions, spiral waves do not evolve spontaneously, but there is a growing body of evidence that shows that they can be expected to develop where inhomogeneities exist. Part of the explanation of this for the bead system relates to the fact that the speed of a wave depends on the curvature of the wave. As the curvature increases (which, for a circular wave, means as the radius decreases), so the speed decreases from that of a plane wave.At some sufficiently small radius, the speed becomes zero and the wave ceases to propagate. This, in turn, means that there is a critical nucleation sizefor BZ waves. The beads at the lower end of the size distribution used in the study of Maselko et al.have radii less than this critical size and hence do not initiate waves: only the larger beads act as sources. The critical nucleation size decreases as [H+]or [BrO;] increase, so at higher concentrations of these reac- Figure 10 Intensity difference images of a target pattern with a broken spiral centre 132 min after mixing the reagents, produced from two images collected at 4-40nm and 10.0s apart. The dark bands represent the distance that the wave has travelled between image shots.Image size 19.3 X 19.3 mm. Experimental conditions: [KBrO,] = 0.3 rnol I-', [H,SO,l = 0.25 rnol I-', [CH2(COOH),] = 2 5 X lop2rnol I-', 1.O X lop5rnol g-I immobilised on >400 mesh size Bio-Rad Analytical Grade 50W-X4 cation exchange resin. (Reproduced with permission from Maselko et ~21.~~01989 The American Chemical Society) CHEMICAL SOCIETY REVIEWS, 1996 tants the system becomes more ‘active’ with more beads able to act as initiation sites. Small beads and vacancies in the layer due to imperfect packing, however, can act as ‘wave breaks.’ The random arrangement of the beads in the layer means that wave breaks are likely to occur in some directions but not others, giving rise to the formation of wave ‘ends’ that develop into spirals.With larger cation exchange beads, 0.5-1.4 mm diameter, spirals can actually be observed unwinding and then rewinding as they propagate over the surface of individual beads in the form of a chemical rotor. The precise form of these waves has provided a challenge to theory from which a different geometric form has been predicted. 5.2 Immobilization on Membranes Cation exchanges can also be obtained in thin films. An example is Nafion, a perfluorinated sulfonic acid derivative used widely in the electrolytic production of NaOH. If a Nafion membrane is loaded with ferroin and immersed in the BZ reagents, spiral waves can develop spontaneously on the solution-membrane interface. The solution can be fed through the reactor so providing a continuous feed of the reagents and the reaction is thus sustained over an extended period.The spirals propagate more slowly than in solu-tion, partly reflecting the lower diffusifity of HBrO, in the mem- brane. The anionic reactants, BrO; and Br-, are unable to penetrate the Nafion matrix, which has a net negative charge, so the reaction is restricted to the membrane surface. Spiral waves can develop on each of the surfaces of the thin strips29 and, most interestingly, the diffusion of neutral species such as the autocatalyst HBrO, through the matrix, from one face to the other, allows the spatial structures to communicate. The strength of this coupling can be varied by changing the ferroin loading (high loading gives weak coupling).Coupling between two layers of waves can also arise in gel-based BZ systems in which there is an 0, concentration gradient,’O as oxygen reacts with some of the organic intermediates. Some very complex entrainment patterns have been observed in this configura- tion, Fig. 1 I, and this form of coupling is of real interest as a simple analogue of the chemical signalling that occurs across biological membranes in vivo. In a simpler ar~angement,~’ in which only one membrane surface is in contact with the solution, the initial development of spiral waves in the region behind an initial reaction front has been fol- lowed. The development of the broken waves which subsequently evolve into rotating spirals can be explained in terms of the spatially inhomogeneous recovery of the membrane.Recovery corresponds to the system returning to the reduced state some time after the oxidation wave has passed over a given point in the membrane and so locations further behind the advancing front are more recovered than those over which the front has passed more recently. Only once the system is sufficiently recovered can it support the passage of another wave, so if a stimulus is applied relatively close to the back of a wave, it is only likely to initiate waves propagating away from the original front and so produce a pair of wave ends that will evolve into spirals. This phenomenon is known as vulnerabilit_vin the cardiac literature where it is strongly implicated in the development of spiral and other types of wave structure associated with cardiac arrhythmias. 6 Further Exploitation of the Techniques The various experimental methods and techniques developed for spatial systems over the past ten years provide many more general possibilities for studying reactions in the reaction-diffusion (or other mode of transport) contexts.The classic Liesegang Ring phe- nomenon involves a different mechanism from the Turing instabil- ity: a periodic precipitation of an insoluble salt formed as one chemical species diffuses through a gel impregnated with a second reactant has recently been revisited.32 Some complex patterns Figure 11 Chemical waves propagating on the surface of a ferroln-loaded Nafion membrane suspended in a cstr pumped with BZ reaction mixture.lmag shows the intensity of light transmitted through a membrane 0.18 mm In thickness, 4.5 h after initiation, residence time of 56.93 min; field of view is 6. X 4.7 mm. Nafion loading 38.7%. Reactant concentrations (mol I-’) in cstr: [NaBrO,] = 0.19, IH,SO,l = 0.24, [CH,(COOH)2] = 1.9 X lo-’. [ferroin = 5.8 X [KBrj = 8.7 X temperature 25.0 “C (Reproduced with permission from Winston et af.2y01991 Macmillan Magazines Ltd) NEW APPROACHES TO CHEMICAL PATTERNS-BARRY R JOHNSON AND STEPHEN K SCOTT include radial dislocations in the concentric precipitation rings obtained in a thin layer of gel into which a high concentration of one of the chemicals is introduced at a ‘point’ Other patterns include helical precipitation bands in which the precipitate pitches on a screw axis as it propagates down a test tube On the basis of detailed experimental observations, a more comprehensive theory has been developed which combines the original Ostwald hypothesis based on supersaturation and nucleation with the mechanism proposed by Ortoleva involving a reasonably homogeneous initial precipitation with subsequent spatial development due to the growth of larger particles at the expense of smaller ones (the Lifshitz-Slyozov ins tabili ty ) If the ferroin redox catalyst in the BZ reaction is replaced by the Ru(bipy).:+ (bipy = 2 2’-bipyridine) complex, the ability of the matrix to support wave propagation can be varied by ill~mination~~ which produces an electronically excited form of the catalyst that reacts directly with bromate ion to form the inhibitor bromide ion locally This allows for an element of ‘spatial control’ over the reac- tion and has been exploited to remove spiral centres by causing them to collide with each other or with the reactor walls and to produce novel spatial patterns with multi-armed spirals Intricate spatial domains can be readily constructed with the redox catalyst either preloaded onto a membrane that is then cut into the desired ‘floor plan’ or, most imaginatively, by replacing the ink in a pen plotter with ferroin and then drawing complex patterns onto membrane supports that are then immersed in the BZ reagent In this way, the propagation of waves through mazes can be used to find the shortest path subject to various constraints or the fundamental building blocks, logic gates, for construction of a chemical com- puter 34 35 The understanding developed through such studies should help other situations, such as the transport and reaction of species incor- porated into water droplets or small ice particles of relevance in the cloud chemistry associated with acid rain formation We can also expect to see attacks on more complex transport problems such as those in combustion where the chemistry interacts with and causes significant convective effects even in the absence of imposed flows Perhaps the main area of application, and that in which Turing’s speculations were first proposed, for these advances in knowledge, however, will lie in their significance for biological systems in which chemical kineticists, especially those with backgrounds that encompass nonlinear feedback, have much to contribute 7 References 1 Chemical Waves and Patterns, ed R Kapral and K Showalter Kluwer, Dordrecht.1995 2 Dynamism and Regulation in Nonlinear Chemical Systems (Physica DM), ed M A Marek, S C Muller, T Yamaguchi and K Yoshikawa North Holland, Amsterdam, 1995 3 S K Scott, Oscillations Waves and Chaos, Oxford University Press, 1994 4 A M Turing, Philos Trans Roy Soc ,1952, B327,37 5 A T Winfree, Science, 1974,175,634 6 S Nettesheim, A von Oertzen, H H Rotermund and G Ertl, J Chem Phvs ,1993,98,9977 7 H Pearlman, Combustion and Flame, 1996,in press 8 J D Murray, Mathematical Biology, Springer, Berlin.1990 9 L Glass and M C Makey, From Clocks to Chaos the Rhythms of Llfe, Princeton University Press, 1988 I0 P De Kepper, J Boissonade and I R Epstein, J Phys Chem ,1990,94, 6525 1 I I Lengyl, G Rabai and I R Epstein, J Am Chem Soc . 1990. 112, 4606,9104 12 S C Muller, Th Plesser and B Hess, Science, 1985, 230, 661, Naturwissenschaften. 1986,73,165 13 V Castets, E Dulos, J Boissonade alid P De Kepper, Phvs Rev Lett , 1990,64,2953 14 I Lengyl and I R Epstein, Science, 1991,251,650 15 P De Kepper. V Castets, E Dulos and J Boissonade, Physica, 1991, D49,161 16 Q Ouyang and H L Swinney, Chaos, 1991,1,411 17 Q Ouyang and H L Swinney, Nature, 1991,352,610 18 Z Noszticzius, Q Ouyang, W D McCormick and H L Swinney, J Phys Chem , 1992,96,6302 19 K Agladze, E Dulos and P De Kepper,J Phys Chem ,1992,96,2400 20 D Horvath and K Showalter, J Chem Phys , 1995,102,2471 21 K J Lee, W D McCormick, J E Pearson and H L Swinney, Nature, 1994,369,215 22 K J Lee, W D McCormick, Q Ouyang and H L Swinney, Science, 1993,261,192 23 Z Nosztrcius, W Horsthemke, W D McCormick, H L Swinney and W Y Tam, Nature, 1987,329,619 24 W Y Tam, W Horsthemke, Z Noszticzius and H L Swinney, J Chem Phvs ,1988,88,3395 25 G Kshirsagar, Z Noszticzius, W D McCormick and H L Swinney, Physica, 1991, D49,5 26 T Yamaguchi, L Kuhnert, Zs Nagy Ungvarai, S C Muller and B Hess,J Phys Chem, 1991,95,5831 27 A Lazar, Z Noszticzius, H D Forsterling and Zs Nagy Ungvarai, Physica, 1995,D84, 112 28 J Maselko, J S Reckley and K Showalter, J Phys Chem , 1989,93, 2774 29 D Winston, M Arora, J Maselko, V Gaspar and K Showalter, Nature, 1991,351,132 30 A M Zhabotinsky, S C Muller and B Hess, Physica, 1991, D49,47 31 S K Scott,J D B Smithand B W Thompson,J Chem Soc ,Faraday Tram , 1996,92,325 32 A A Polezhaev and S C Muller, Chaos, 1994,4,631 33 M K R Reddy, Zs Nagy Ungvarai and S C Muller,J Phys Chem , 1994,98,12255 34 0 Steinbock and K Showalter, Science, 1995,269,418 35 A Toth and K Showalter, J Chem Phys ,1995,103,2058

ISSN:0306-0012    

DOI:10.1039/CS9962500265

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

INGOLD LECTURE. Reactive Intermediates: Carboxylic Acid Enols and Other Unstable Species A. J. Kresge Department of Chemistry, University of Toronto, Toronto, Ontario, Canada M5S 3H6 1 Introduction Enols are the tautomeric isomers of carbonyl compounds through which many important chemical and biological reactions occur, and, if we wish to understand these reactions, and through understanding to control them, we must understand the chemistry of enols. Most enols, however, are also quite unstable, both thermodynamically and kinetically, and their lifetimes in solution are usually very short. This has impeded their study. Enols have been known for more than a century,' but very little hard quantitative information about the rates and equilibrium constants of their reactions was available for very nearly all of that time. The situation changed dramatically about 15 years ago when we and others developed methods for generating enols in greater than equilibrium amount under conditions where they could be observed directly and their reactions studied in detail.This has produced a wealth of reliable new information about en01 isomers of simple aldheydes and ketones.* That work is now being extended to the more difficult task of examining the much more labile enols of carboxylic acids, esters, and amides. This review will begin with a short description of some of our work on enols of aldehydes and ketones in order to illustrate the methods that we have used and the kinds of information that can be obtained.That will then be followed by an application of these methods to enols of carboxylic acids and their derivatives. 2 Methods We have found flash photolysis to be an especially useful technique for studying the chemistry of short-lived enols. An example of this method is provided by the Norrish type I1 photoelimination of 5-hydroxypentan-2-one1,eqn. (1).3 Irradiation of this substance leads to hydrogen abstraction from the y-position by the oxygen atom of the photoexcited carbonyl group to give the diradical2, which then Jerry Kresge received his undergraduate education at Cornell University and obtained a PhD in synthetic organic chemistry at the University of Illinois working with Nelson Leonard. He then spent the next four years learning physical organic chemistry, jirst as a Fulbright Scholar with Hughes and Ingold at University College London and then as a Postdoctoral Fellow,jrst with H.C. Brown at Purdue and then with C. G. Swain at M. I. T. Kresge 'sjrst independent research position was as Associate Chemist at Brookhaven National Laboratory. From there, he moved to an academic post at the Illinois Institute of Technology, and, some twenty years ago, he moved again, to Toronto, where he is now Emeritus Professor of Chemistry. Kresge has worked in a number of areas of physical organic chemistry, using kinet- ics, acid-base catalysis, and isotope efSects a5 principal investigative tools. His accom-plishments have been recog-nized by a number of honours: he has held Guggenheim, Killam, and Yamada Fellow- ships, and has received the Syntex Award and the Morley Medal; he has also been visiting professor at many universities.1 2 3 4 fragments to the enol of acetone 3 and the enol of acetaldehyde 4. These reactions occur very rapidly, and, if the process is initiated by a sufficiently short and intense burst of light in a flash photolysis apparatus, the enols can be generated much faster than they keton- ize to their carbonyl isomers. The ketonization reactions can then be monitored by following changes in UV absorbance of the enols. Ketonization of acetone enol is about two orders of magnitude faster than ketonization of acetaldehyde enol, and accurate rate con- stants for both enols can easily be obtained.We have also made enols by the flash photolytic oxidation of alcohols and reduction of carbonyl compounds: as is illustrated in eqn. (2) for acetone. Irradiation of acetone in the presence of iso-propyl alcohol leads to an intermolecular analogue of the Norrish type I1 reaction, giving a pair of ketyl radicals 5;these then dispro- portionate, producing the enol of acetone and regenerating the alcohol. Photohydration of acetylenes, eqn. (3), is another useful method OH 0 of generating en01.s.~ The thermal hydration of acetylenes is known to occur through enol intermediates, but, in the strongly acidic solu- tions needed to effect this process, the enol ketonizes as fast as it is formed and consequently cannot be observed.Photoexcitation, however, greatly enhances the reactivity of acetylenes towards electrophilic addition, and now the enol is generated much more rapidly than it is consumed; its reactions may therefore be moni- tored. The photohydration of acetylenes occurs through vinyl cation intermediates such as 6, and vinyl cations can also be produced by photoionization of vinyl halides. We have consequently found that we can generate enols by the flash photolytic solvolysis of vinyl chlorides as well: as is illustrated in eqn. (4). Me rvre Me Me Paramount among the things one would like to know about enols is the magnitude of the equilibrium constants for their formation 275 from keto isomers. Such keto-enol equilibrium constants, KE, have traditionally been determined by the Kurt Meyer halogen titration method, which uses the fact that enols react with halogens whereas their keto isomers do not.This method works well when enol con- tents are not too low, as is the case, for example, with P-dicarbonyl compounds. With most monofunctional aldehydes and ketones, however, the method fails badly because enol contents here are in the parts-per-million or even parts-per-billion range, and impurities that react with halogen must be excluded at better than these levels. This difficulty may be avoided by determining keto-enol equi- librium constants as ratios of rate constants: those for enolization, k,, divided by those for ketonization k,: KE = k,/k,. Values of k, are easily obtained by long-established methods such as halogen scavenging of the enol as it forms, and values of k, may be supplied by the flash photolytic methods we have developed.This technique produces keto-enol equilibrium constants whose accuracy is limited only by that with which the component rate constants can be determined, and it can give good results no matter how small the value of K, actually is. Another important property of enols is the acid strength of their hydroxy groups. Standard methods for determining acidity con- stants of stable acids cannot, of course, be applied to short-lived enols, but accurate estimates of enol pK, values may nevertheless be obtained from the way their rates of reaction change with pH.Fig. 1 shows a typical enol ketonization rate profile. At high acidity 1o5 1o4 1o3 3 lo2 10' 1oo Figure 1 Rate profile for the ketonization of the enol of indan-I-one in aqueous solution at 25 "C there is an acid-catalysed process that involves rate-determining protonation of the enol on its @-carbon by hydronium ion; this is represented by the diagonal segment with slope = -I on the left side of Fig. 1. As the acidity drops, this reaction gives way to keton- ization by @-carbon protonation of the very much more reactive enolate ion; since this process produces a hydronium ion in an initial pre-equilibrium step and then uses it up in the rate-determining step, the overall reaction is independent of acidity and it consequently appears as the 'uncatalysed' segment of slope = 0 near the centre of Fig.1. At still lower acidities, the concentration of hydronium ions is too low to sustain this process and @-carbon protonation of enolate ion by solvent water takes over; since the hydronium ion produced in the pre-equilibrium is now not used up in the rate-deter- mining step, the rate of reaction becomes inversely proportional to hydronium ion concentration and directly proportional to hydrox- ide ion concentration, giving the region of apparent hydroxide ion catalysis represented by the segment of slope = +1 on the right side of Fig. I. Eventually, however, the position of the pre-equilibrium shifts from enol to enolate, and the advantage of converting a less reactive to a more reactive substrate is lost; hydroxide ion catalysis then becomes saturated and the rate levels off to a constant value giving the second 'uncatalysed' segment of slope = 0 at the far right of Fig.1. Straightforward analysis of rate data in the region of transition from hydroxide ion catalysis to catalysis saturation gives both the rate constant for the carbon protonation step and the equi- librium constant for the prior equilibrium step. The latter, of course, CHEMICAL SOCIETY REVIEWS, 1996 is the acid dissociation constant of the enol. We have used this method to determine pK, values of very short-lived enols, some with lifetimes of only a microsecond. As shown in eqn. (3,keto-enol isomerization and acid ioniza- Ph,C& + H* tion of the enol form two legs of a thermodynamic cycle whose third member is ionization of the keto form as a carbon acid.Once the equilibrium constants K, and KF for the first two legs have been determined, therefore, that for the third member, KF, can be calcu- lated as the product K,K:. In some cases the keto isomer is suffi- ciently acidic to allow Kf to be determined directly, and then the cycle serves as a test of the internal consistency of the data, for the pK values should sum to zero around the cycle. The diphenyl- acetaldehyde system, shown in eqn. (5), provides an especially good example of such a situation, for here we were able to measure each of the three constants by two independent methods.' The results obtained, pK, = 0.98 5 0.04, pK: = 9.40 ? 0.01 and pK5 = 10.42 ? 0.02, do sum up to a value that is less than the rather small combined experimental uncertainty of the individual measurements: ZpK = 0.04 ? 0.05.A sample of results we have obtained for representative simple aldehydes and ketones is presented in Table 1. It may be seen that Table 1 Equilibrium constants for some simple aldehyde and ketone systems in aqueous solution at 25 "CU Substrate QK, PKE QK,KP 6.23 10.50 16.73 8.33 10.94 19.27 7.96 10.34 18.31 Ph 3.86 11.63 15.49 0.98 9.40 10.42phFoPh 6.39 11.70 18.09d "Ionic strength = 0.10 mol I-'; acidity constants are concentration quotients at this ionic strength. K, for acetaldehdyde is very small: less than 1 ppm of en01 is in equilibrium with the keto form.The enol content of acetone is even lower, by some two orders of magnitude. This difference between acetone and acetaldehyde may be attributed to stabilization of the keto isomer of acetone by its additional methyl group, and the next entry in Table 1 shows that phenyl is just about as good as methyl in this respect. Methyl substitution in the @-position, as in iso-butyraldehyde, on the other hand, raises KE, which may be under- stood in terms of alkyl group stabilization of the enol double bond. Phenyl groups in this position are even better than methyls, as shown by the relatively large enol content of diphenylacetaldehyde. A conformational effect appears to operate in the case of cyclo- hexanone, for its enol content is considerably greater than that of corresponding acyclic ketones and also greater than that of cyclo- pentanone and cycloheptanone.4 The acid strength of these enols is similar to that of phenols, as might be expected from the vinyl alcohol structures they have in REACTIVE INTERMEDIATES CARBOXYLIC ACID ENOLS AND OTHER UNSTABLE SPECIES-A J KRESGE common There is not much variation in pK: with structure for the group of substances shown in Table 1, much less than that in pK, or pKt Structural effects on pKt, moreover, appear to parallel those on pK,, and there is in fact a fairly good linear relationship between these two quantities for a substantial number of aldehydes and ketones 3 Mandelic Acid and Derivatives As is illustrated by the examples provided above, the enol isomers of simple aldehydes and ketones are usually highly labile and thermodynamically unstable substances Carboxylic acid enols are even more labile and unstable This is apparent, for example, from a comparison of the keto-enol transformation of acetaldehyde, eqn (6),with that of acetic acid, eqn (7) For acetaldehyde, pK, = 6 23 q04==(a 0) OH OH and the hydronium ion catalytic coefficient for ketonization of the enol is k; = 33 mol I 1 s Neither of these quantities has as yet been measured directly for acetic acid, but reliable estimates can be made Guthrie has presented several different arguments that lead to the consistent result pK, = ca 20p and k; = 10s-lo9 mol I I s-I, may be estimated on the basis of the experimentally determined value k; = 7 X lo5mol 1 s I for the dimethyl ether of acetic acid enol, CH2=C(OMe),,Io and the fact that methyl vinyl ethers are one to two orders of magnitude less reactive than the corresponding enols This comparison shows that the enol content of simple car- boxylic acids with no enol-stabilizing substituents can be expected to be many orders of magnitude smaller than that of simple alde- hydes and ketones and that the rates of ketonization of these car- boxylic acid enols will be so fast as to approach the diffusion controlled limit Daunting realizations such as these have directed studies of car- boxylic acid enols to systems in which special structural features stabilize the enol One such approach uses bulky aromatic substitu- ents to block access to the enol double bond, through whose proto- nation ketonization must take place This is a technique that has produced remarkably stable enols of aldehydes and ketones, as shown in work pioneered by Fuson some 50 years ago and lately elaborated by Rappoport Its application to carboxylic acid systems has produced enols with lifetimes as long as several hours, l2 but these long lifetimes have also produced complications in the form of radical-producing oxidation reactions of the very elec- tron-rich enols Our own approach has been to increase the lifetime of the enol somewhat less by introducing subctituents that we know, from our studies of aldehyde and ketone systems, stabilize enols through their electronic effects When we began our work, there were reports in the literature that irradiation of esters of benzoylformic acid 7 leads to a Norrish type I1 reaction, eqn (8), which produces 7 8 hydroxy(pheny1)ketene8 l4 We reasoned that in aqueous solution this ketene would be hydrated to an enol 9, eqn (9),and that the p-OH and P-Ph groups of this enol might slow its ketonization to 9 10 mandelic acid 10 sufficiently so that the enol would decay more slowly than it was formed and thus be observable We found that flash photolysis of benzoylformic acid esters in aqueous solution did indeed produce transient species which, through solvent isotope effects and the form of acid-base catalysis, we could identify as a rapidly reacting ketene and a somewhat more stable but still rapidly reacting enol The rate profile for ketonization of mandelic acid enol is shown in Fig 2 It is similar to rate profiles for the ketonization of simple log I 1”o3 w 102 tuu L“”’lo1 lo3 105 10’ log 10” 10j3 toi5 WyM Figure 2 Rate profile for the ketonization of mandelic acid enol in aqueous solution at 25 “C aldehyde and ketone enols (cf Fig I), with the exception that the bend representing acid ionization of the enol comes at a lower acidity because this enol is a stronger acid (pKt = 6 62) This is typical of carboxylic acid enols and may be attributed to the pres- ence of the second, geminal hydroxy group, a similar acid-strength- ening effect may be seen in going from ethanol 11,with pK, = 15 9, to acetaldehyde hydrate 12,with pK, = 13 6 4-OH 11 12 In order to obtain a keto-enol equilibrium constant for the man- delic acid system by the rate constant ratio method (KE= k,/k,), we measured rates of acid-catalysed enolization of the acid This reac- tion proved to be very slow, and we had to resort to high tempera tures (140-155“C) in order to get conveniently measurable rates Extrapolation of these data to 25 “C then gave a rate constant, which, when combined with the acid-catalysed rate of ketonization, provided the result pK, = 15 4 Combination of that value with pKk = 6 6 then produced pKE = 22 0 for mandelic acid ionizing as a carbon acid These results show the enol content of mandelic acid to be very low but still significantly greater than the estimate pK, = 20 for acetic acid The difference may be attributed to the p-OH and p-Ph groups of mandelic acid enol, for such substituents are known to stabilize enol isomers in simple aldeheyde and ketone systems 2 Our characterization of the mandelic acid keto-enol system, in addition to being of general chemical interest, has proved to be of specific value to biological chemists in connection with the enzy- matic racemization of mandelic acid by mandelate racemase, and the current controversy over whether the enzyme achieves its effi- ciency by an electrostatic effect or by formation of a strong hydro- gen bond We hdve written the acid ionization of mandelic acid enol, eqn (lo), as involving one of the geminal hydroxy groups, specifically that trans to phenyl, because we found the trans-enol of phenyl-acetaldehyde, 13,to be a stronger acid than the cwisomer 14 l7 In principle, however, the ionization of mandelic acid enol might also 278 A Ph PhoH u 14 involve the hydroxy group a to phenyl.In order to investigate this matter, we wished to examine an enol for which such ionization is blocked by conversion of this hydroxy to methoxy, and we hoped to be able to make that substance, 15, by hydration of the ketene generated through the photo-Wolff reaction shown in eqn. (11). 16 15 Flash photolysis of methyl phenyldiazoacetate 16 did produce a transient species which we identified as an enol, but the product of the reaction was methyl mandelate 17 rather than the expected methyl ether of mandelic acid 18, eqn.( 12).Is We postulate that this MeOH: - p h M G (12) Ph OH 18 substance was formed by insertion of the methyoxycarbonylcar- bene 19, formed by loss of nitrogen from methyl phenyldiazo- acetate, into an O-H bond of solvent water. Such carbene insertion reactions are well known, and a number of different mechanisms have been proposed for them, all of which involve only the carbenic carbon. Our detection of an enol intermediate in the process indi- cates that the carbonyl group is involved as well and that the reac- tion occurs as shown in eqn. (1 3); the process might therefore be 17 more accurately described as conjugate addition of water across the entire carbonylcarbene functional group.We have since found other examples of such conjugate additions, in the cyclic system shown in eqn. (14)and also in the amide system N2 OH OH CHEMICAL SOCIETY REVIEWS, 1996 shown in eqn. (15). This has taken us into the chemistry of enols of carboxylic acid esters and enols of carboxylic acid amides. 4 Phenylcyanoacetic Acid We have found that the enol20 of phenylcyanoacetic acid 21 can be generated from a diazo compound precursor, 22, eqn. ( 16).19 In this K CN 22 20 21 case flash photolysis gives the Wolff rearrangement rather than con- jugate addition of water to a carbonylcarbene, and the ketene so pro- duced is hydrated to the enol.The rate profile for ketonization of this enol, shown in Fig. 3, is \b pK':=8.70 1o2 ioo tw100 -104 L.,.. ,, 4L*'*L'L 12 [H*W Figure 3 Rate profile for the ketonization of phenylcyanoacetic acid enol in aqueous solution at 25 "C somewhat different from those of Figs. 1 and 2 in that there is an additional bend at the high acidity end. Through solvent isotope effects and the form of acid-base catalysis, we have been able to assign this bend to ionization of the first O-H group of the enol ,and the bend at [H+] = ca. mol 1-I to ionization of the second O-H group. The plateau before the first bend then represents reac- tion through pre-equilibrium ionization of the enol followed by rate- determining carbon protonation of the enolate ion, and the diagonal segment of slope = -I represents the same reaction with enolate ion as the initial state.Near [H+] = lop6mol I-', carbon protona- tion of the more reactive dianion by water takes over, with reaction first starting from the monoanion as the initial state, giving a region of apparent hydroxide-ion catalysis, and then reaction starting from the dianion as the initial state, leading to catalysis saturation. With the aid of rates of enolization measured by bromine scav- enging, we were able to characterize the phenylcyanoacetic acid keto-enol system completely. The results are presented in Scheme 1. It may be seen that the enol is quite strongly acidic with pK: = 0.99 CN CN PKE = 7.22-l'h&O$-I OH 0.99 -+ Ht Scheme 1 REACTIVE INTERMEDIATES CARBOXYLIC ACID ENOLS AND OTHER UNSTABLE SPECIES-A J KRESGE for its first ionization, this makes the enol more acidic than the car- because their conjugate bases are stabilized by delocalization of boxylic acid group of its keto form’ Even in its second ionization, negative charge into the five-membered ring, which produces with pK’F = 8 70, this enol is more strongly acidic than the enols of an aromatic cyclopentadienyl anion The enol contents are high simple aldehydes and ketones (cf Table l), which attests to the strong acidifying effect of the cyano group The difference between the first and second pK,, ApK, = 7 7, is not unlike that for the first and second ionization of carbonic acid, ApK, = 6 4 The cyano group also stabilizes the neutral enol strongly, raising the enol content of phenylcyanoacetic acid over that of mandelic acid by eight orders of magnitude 5 Cyclopen tadienecarboxy lic Acid and Derivatives The cyclopentadiene moiety also stabilizes enols strongly, and this effect has been used in studies of aldehyde and ketonez0 as well as carboxylic21-23 acid systems The enol 23 of cyclopentadiene-carboxylic acid itself 24, was made by hydration of the ketene 25, which was generated in two ways by photo-Wolf reaction of the corresponding diazo compound, 26, and also by photo-induced elimination of HBr from 2-bromophenol, 27, as shown in eqn 17 This enol and that of mandelic acidi5 were the first carboxylic acid enols to be Characterized in aqueous solution, unfortunately, however, there are problems with some of the originally published data on the cyclopentadienecarboxylic acid system,21b and revised values have not yet been made public The monobenzo B2Ib’*and dibenzo 2923 analogue of cyclo- pentadienecarboxylic acid enol have also been investigated The 29 30 former is of some commercial importance to the photolithographic industry, for the diazonaphthoquinone 30 precursors of its deriva- tives are constituents of photoresistsz4 and the enols are intermedi- ates in the photolithographic process 22 It may be seen from the results obtained, summarized in Table 2, that these enols are quite strongly acidic, this is Table 2 Summary of results for cyclopentadienecarboxylicacid keto-enol systems0 PK,E 13 19 22 PK ’,” 8 7h 83 96 PKF 8 46 93 95 PK E 5oh 66 83 pK ’,“ 13 7 15 2 17 9 uIonic strength = 0 10 mol I I, acidity constants are concentration quotients at this ionic strength Equilibnum constants are as defined in Scheme 1 hRevised value provided by Professor Wirz as well because the enols are stabilized by fulvenoid aromatic delocalization It IS significant that the acids become somewhat weaker and the enol contents somewhat smaller with increasing benzo substitution, for the resonance energy of the cyclo- pentadienyl ring can be expected to decrease with benzo sub stitution 6 Acetoacetic Acid Keto-enol tautomerism in P-keto esters has been investigated almost since the beginning of enol chemistry, and these systems provide some of the most extensively documented examples of such isomerism available today In striking contrast, very few studies of tautomerism in P-keto acids have been carried out, and only one of these has dealt with the prototype substance, acetoacetic acid 25 The acetoacetic acid system is especially interesting because two different enols may be formed, the carboxylic acid enol31, and the ketone enol32, eqn (1 8) The ketone enol might be expected to be 31 32 the much more stable of the two and the overwhelmingly pre- dominant enol form in solution, for keto-enol equilibrium constants for simple ketones are very much greater than those for simple acids cf pK, = 8 for acetone vs pK, = 20 for acetic acid Much of this difference between acetone and acetic acid, however, must be an initial-state effect, inasmuch as the keto form of acetic acid is stabilized by conjugation of its carbonyl group with the adjacent hydroxy substituent, eqn (19), whereas such conjugative initial state stabilization is not possible in the case of acetone Initial state effects, of course, have no bearing on the relative abundance of the two enols of acetoacetic acid, for both are in equilibrium with the same initial state keto form [eqn (18)] The relative amounts of the two enols will be determined, rather, by the intrinsic stabilities of the enols themselves, and this may well be not as disparate as SUE- gested by the acetone-acetic acid comparison It is difficult to address this matter experimentally because the enol content of acetoacetic acid is small (pK, = 2 25, vide infru) and the enol(s) are short-lived We have therefore performed ab initio calculations on the system at the MP2/6-3 11+G** level The results show an energy difference of AE = 11 kcal mol I (1 cal = 4 184 J) between the two enols, with the ketone enol as the more stable isomer z6 This result is thus qualitatively consistent with the prediction made from the acetone-acetic acid comparison It is sig nificant, however, that the calculated energy difference is less than the 16 kcal mol I that corresponds to the pK, difference for acetone-acetic acid We obtained the enol of acetoacetic acid by hydration of acetylketene33, eqn (20), which was generated by flash photolysis of 2,2,6-trimethyl-4H-1,3-dioxin-4-one34, eqn (21) 27 The rate profile for ketonization of the enol showed bends that could be attributed to ionization of its two acidic groups and from which the pK, values shown in eqn (22) were obtained The first of these, pK, = 4 05, shows the carboxylic acid group of the enol to be consider- ably more acidic than the value, pK, = 5 67, that can be predicted from a correlation of acidity constants of substituted acrylic acids z8 34 + 2H++H+ The difference may be attributed to the hydrogen bond formed between the hydroxy group of the enol and the carbonyl group of the acid, which is not taken into account by the correlation, this hydrogen bond will become stronger as the acid ionizes, thus stabi lizing the ionized state This hydrogen bond also stabilizes the unionized state of the second ionization, making the enol a weaker acid than it would otherwise be This enol, with pK: = 13 18, is in fact unusually weakly acidic cf pKf = 9 48 for ionization of the enol of the corresponding methyl ester, eqn (23) 29 Another factor contributing to the weak acidity of the enol of acetoacetic acid is electrostatic repulsion between the two negative charges in the dian- ionic product In the only other investigation of the acetoacetic acid keto-enol system,25 rates of enolization were determined by bromine scav- enging, and combination of those with our results for ketonization leads to pK, = 2 25 This is a rather low value for a P-dicarbonyl system, for example, pK, = 1 10 for tautomerism of the corre- sponding methyl ester, eqn (24) 29 The difference may again be attributed to hydrogen bonding, this time in the initial state of the acetoacetic acid reaction, eqn (18), an effect that is absent from the methyl ester system Acknowledgements I am grateful to the Natural Sciences and Engineering Research Council of Canada, the United States National Institutes of Health, and the Petroleum Research Fund administered by the American Chemical Society for financial support of our work CHEMICAL SOCIETY REVIEWS, 1996 7 References 1 E Erlenmeyer, Chem Ber ,1881,14,320 2 See, e g Z Rappoport, The Chemistry of Enols, Wiley-Interscience, New York, 1990 3 Y Chiang, M Hojatti, J R Keeffe, A J Kresge, N P Schepp and J Wirz, J Am Chem SOC ,1987,109,4000 4 J R Keeffe, A J Kresge and N P Schepp, J Am Chem SOC , 1990, 112,4862 5 Y Chiang, A J Kresge, M Capponi and J Wirz, Helv Chim Acta, 1986,69,1331 6 A J Kresge, and N P Schepp, J Chem Soc ,Chem Commun ,1989, 1548 7 Y Chiang, A J Kresge and E T Krogh, J Am Chem Soc ,1988,110, 2600 8 J R Keeffe and A J Kresge, in The Chemistry of Enols, ed Z Rappoport, Wiley-Interscience, New York, 1990,ch 7 9 J P Guthrie, Can J Chem , 1993,71,2123, J P Guthrie and Z Liu, Can J Chem ,1995,73,1395 10 A J Kresge and M Leibovitch, J Am Chem SOC ,1992,114,3099 11 This work IS reviewed by H Hart, Z Rappoport and S E Biali, in The Chemistry of Enols, ed Z Rappoport, Wiley-Interscience, New York, 1990,ch 8 12 P O’Neill and A F Hegarty,J Chem SOC ,Chem Commun ,1987,744, B M Allen, A F Hegarty, P O’Neill and M T Nguyen, J Chem Soc , Perkin Trans 2, 1992,927 13 J FreyandZ Rappoport,J Am Chem Soc ,1995,117,1161,1996,118, 5182 14 M V Encinas,E A Lissi,A Zanocco,L C StewartandJ C Scaiano, Can J Chem ,1984,62,386 15 Y Chiang, A J Kresge, P Pruszynski, N P Schepp and J Wirz, Angew Chem ,lnt Ed Engl ,1990,29,792 16 J P Guthrie and R L Kluger, J Am Chem SOC , 1993, 115, 11 569, G L Kenyon, J A Gerlt, G A Petsko and J W Kozarich, Acc Chem Res ,1995,28,178 17 Y Chiang A J Kresge, P A Walsh and Y Yin, J Chem SOC ,Chem Commun ,1989,869 18 Y Chiang,A J Kresge,P Pruszynski,N P ScheppandJ Wirz,Angew Chem ,/nt Ed Engl ,1991,30,1366 19 J Andraos, Y Chiang, A J Kresge, I G Pojarlieff, N P Schepp and J Wirz, J Am Chem Soc , 1994,116,73 20 M P Harcourt and R A More O’Ferrall, J Chem Soc , Chem Commun ,1987,822,J Chem SOC ,Perkin Trans 2,1995,1415 21 (a)B Urwylerand J Wirz,Angew Chem ,Inr Ed Engf ,1990,29,790, (6)J I Kim,B Urwylerand J Wirz,J Am Chem SOC ,1994,116,954 22 J Andraos, Y Chiang, C G Huang, A J Kresge and J C Scaiano, J Am Chem SOC , 1993,115,10605 23 J Andraos, PhD Thesis, University of Toronto, 1992 24 See, eg E Reichmanis, in Polymers for Electronic and Photonic Applications, ed C P Wong, Academic Press, New York, 1993, pp 67-117 25 K J Pedersen,J Phys Chem, 1934,38,999 26 S Hoz and A J Kresge, unpublished work 27 Y Chiang, H X Guo, A J Kresge and 0 S Tee, J Am Chem SOC , 1996,118,OOOO 28 D D Perrin, B Dempsey and E P Sergeant, pKa Predictions for Organic Acids and Bases, Chapman and Hall, New York, 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ISSN:0306-0012    

DOI:10.1039/CS9962500275

出版商:RSC    

年代:1996

数据来源: RSC