Ciba Foundation Symposium 158 ____ ~

~ - -

HOST-GUEST MOLECULAR

INTERACTIONS: FROM CHEMISTRY

TO BIOLOGY

A Wiley-lnterscience Publication

1991

JOHN WILEY & SONS

Chichester . New York . Brisbane Toronto . Singapore _ _ ~~

HOST-GUEST MOLECULAR

INTERACTIONS. FROM CHEMISTRi

TO BIOLOGY

The Ciba Foundation is an international scientific and educational charity. It was established in 1947 by the Swiss chemical and pharmaceutical company of ClBA Limited - now CIBA-GEIGY Limited. The Foundation operates independently in London under English trust law.

The Ciba Foundation exists to promote international cooperation in biological, medical and chemical research. It organizes about eight international multidisciplinary symposia each year on topics that seem ready for discussion by a small group of research workers. The papers and discussions are published in the Ciba Foundation symposium series. The Foundation also holds many shorter meetings (not published), organized by the Foundation itself or by outside scientific organizations. The staff always welcome suggestions for future meetings.

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Ciba Foundation Symposium 158 ____ ~

~ - -

HOST-GUEST MOLECULAR

INTERACTIONS: FROM CHEMISTRY

TO BIOLOGY

A Wiley-lnterscience Publication

1991

JOHN WILEY & SONS

Chichester . New York . Brisbane Toronto . Singapore _ _ ~~

OCiba Foundation 1991

Published in 1991 by John Wiley & Sons Ltd. Baffins Lane, Chichester West Sussex PO19 IUD, Ergland

All rights reserved.

No part of this book may be reproduced by any means, or transmitted, or translated into a machine language without the written permission of the publisher.

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Suggested series entry for library catalogues: C'iba Foundation Symposia

Ciba Foundation Symposiuin 158 i x+278 pages, 80 figures, 21 tables, 15 structures

1,ibrarv of Congress Cataloging-in-Publication Data Host-guest molecular interiictions: l'rom chemistry to biology.

p. cm.-(Ciba Foundation symposium; 158) Proceedings of the Symposium on Host-Guest Molecular Interactions:

from Chemistry to Biology held at the Ciba Foundation, London, Jul. 3-5, 1990.

Includes 'bibliographical references and index. ISBN 0-471-92958-1 I , Ligand binding (Biochemistry)-Congresses. 2. Drugs-Design-

Congresea. 3 . Protein engineering-Congresses. 4. Protein binding-Congresses. I . Symposium on Host-Guest Molecular Interactions: from Chem:,stry to Biology (1990: Ciba Foundation) I I . Series. QP517.L54H67 1990 574.19 ' 245-dc20 91-330

CIP

British Library Cafalogrrinp in Publication Data Host-guest molecular interactions: from chemistry

to biology.-(CIBA Foundation Symposia) I . Sutherland, I . 0. 541.2

ISBN 0 471 92958 I

11. Series

Phototypeset by Dobbie Typesettinl: Limited, Tavistock, Devon. Printed and bound in Great Britain by Biddles Ltd., Guildford.

Contents

Symposium on Host-Guest Molecular Interactions: from Chemistry to

Editors: Derek J . Chadwick (Organizer) and Kate Widdows

Biology, held at the Ciba Foundation, London 3-5 July 1990

1. 0. Sutherland Introduction 1

J. F. Stoddart Molecular self-assembly processes 5 Discussion 17

G. W. Gokel Self-assembly in supramolecular systems 23 Discussion 3 1

General discussion I Flexibility or rigidity? 39

D. N . Reinhoudt, W. F. Nijenhuis and P. D. van der Wal Host-guest interactions in thin membranes: selective ion transport and transduction into electronic signals 42 Discussion 5 1

W. J . Albery Molecular recognition and molecular sensors 55 Discussion 67

J. P. Waltho and D. H. Williams The natural design of vancomycin family antibiotics to bind to their target peptides Discussion 87

73

General discussion I1 Crystals as supramolecules 92 Molecular devices and sensors 95

J. Rebek Clefts as receptor and enzyme analogues 98 Discussion 109

R. Breslow Enzyme mimics 115 Discussion 122

V

vi

M. J. Waring Binding of antibiotics to DNA 128 Discussion 142

Contents

T. Montenay-Garestier*, C. HClCne and N. T. Thuong sequence-specific bi runctional nucleic acid ligands

Design of 147

M. H. Caruthers, G. Beaton, L. Cummins, D. Graff, Y.-X. Ma, W. S. Marshall, H . Sasmor, P. Norris and E. K. Yau Synthesis and biochemical studies of dithioate DNA Discussion 166

158

G. C. K. Roberts Conformational flexibility and protein specificity 169 Discussion 182

R. I. Carey, K.-H. Altmann and M. Mutter Protein design: template- assembled synthetic proteins 187 Discussion 199

General discussion I11 Transition state theory and energy requirements for reaction 204

A. B. Edmundson, D. L. Harris, G. Tribbick and H. M. Geysen Binding of peptides to proteins: an exercise in molecular design Discussion 225

213

R. U. Lemieux, L. T. J . Delbaere, H. Beierbeck and U. Spohr Involvement of water in host-guest interactions Discussion 245

23 I

J. G. Vinter and M. It. Sauriders Molecular modelling approaches to host-guest complexes 249 Discussion 262

1. 0. Sutherland Summing-up 266

Index of contributors 269

Subject index 271

*Dr Montenay-Carestier was unable to attend the symposium. Her paper was presented by Dr Michael Waring.

Participants

W. J. Albery University College, Oxford OX1 4BH, UK

C. I. BrandCn Swedish University of Agricultural Sciences, Department of Molecular Biology, Uppsala Biomedical Center, PO Box 590, S-751 24 Uppsala, Sweden

E. Breslow Department of Biochemistry, The New York Hospital-Cornell Medical Center, 1300 York Avenue, New York, NY 10021, USA

R. Breslow Department of Chemistry, Columbia University, New York, NY 10027, USA

R. I. Carey Institut de Chimie Organique, UniversitC de Lausanne, Rue de la Barre 2, CH-1005 Lausanne, Switzerland

M. H. Caruthers Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA

A. Collet StCrCochimie et Interactions MolCculaires, Ecole Normale Superieure de Lyon, 46 AllCe d’Italie, F-69364 Lyon cedex 7, France

M. J . Crumpton Imperial Cancer Research Fund Laboratories, PO Box 123, Lincoln’s Inn Fields, London WC2A 3PX, UK

J. D. Dunitz Laboratorium fur Organische Chemie, ETH-Zentrum, Universitatstrasse 16, CH-8092 Zurich, Switzerland

A. B. Edmundson Harrington Cancer Center, 1500 Wallace Boulevard, Amarillo, TX 79106, USA

G. W. Gokel Department of Chemistry, University of Miami, Coral Gables, FL 33124, USA

C. D. Gutsche Department of Chemistry, Texas Christian University, Fort Worth, TX 76129, USA

vii

Vll l Participants

A. D. Hamilton Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA

R. M. Kellogg Department of Organic Chemistry, University of Groningen, Nijenborgh 16, Groningen 9747 AG, The Netherlands

0. Kennard University Chemical Laboratories, University of Cambridge, Lensfield Road, Cambridge CB2 lEW, UK

R. U. Lemieux Department of Chemistry, Faculty of Science, University of Alberta, E5-52 Chemistry Building East, Edmonton, Alberta, Canada, T6G 2G2

W. Miiller Institute o f Organic Chemistry, University of Mainz, J J Becher Weg 18-22, 11-6500 Mainz 1, Federal Republic of Germany

D. Parker Department of Chemistry, Science Laboratories, University of Durham, South Roa.d, Durham DHl 3LE, UK

J . Rebek Departmenl, of Chemistry, Massachusetts Institute of Technology, Building 18-207, 77 Massachusetts Avenue, Cambridge, MA 02139, USA

D. N. Reinhoudt Laboratory of Organic Chemistry, Twente University, PO Box 217, NL-7500 AE Enschede, The Netherlands

G. C. K. Roberts Department of Biochemistry, University of Leicester, Adrian Building, University Road, Leicester LEI 7RH, UK

C. Sacht (Ciba Founddion Bursar) Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7700, Cape Province, South Africa

J . F. Stoddart Department of Chemistry, University of Sheffield, Sheffield S3 7HF and The School of Chemistry, University of Birmingham, Edgbaston, Birmingham B 15 2TT, UK

I. 0. Sutherland (Chairman) Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK

J. G. Vinter Molecular Recognition Unit, University Chemical Laboratories, University of Cambridge, Lensfield Road, Cambridge CB2 1EW and Department of Chemistry, University College London, 20 Gordon Street, London WClH OAJ, UK

Participants

J. P. Waltho Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK

M. J. Waring Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 lQJ, UK

IX

lntrodu ction Ian Sutherland

Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK

This meeting is ambitious in its breadth; it ranges from biology to chemistry, but I suspect the actual scope of the meeting will be defined by the papers and the interests of the participants. Otherwise, it would be impossibly broad. The origins of the meeting date back to my postgraduate days in the 1950s, when, unknown to me, many of the foundations of molecular biology were being laid down in nearby laboratories. At that time, the crystal structures of proteins were being examined and the double helix of DNA was discovered. Molecular biology really took off from there and has grown explosively ever since. A number of molecular biologists are here to represent the biological end of the spectrum. I believe that the basic principles are chemical and that there is complete overlap of biology and chemistry, but I have to recognize that different people emphasize different aspects of our topic. In the 1950s, again unknown to me, work on clathrates was proceeding in Oxford. H.M. Powell began the work on clathrates and host-guest chemistry in the solid state, and this is now an active and expanding area. At this meeting we are not going to talk much about clathrates, but we will talk a great deal about complexes in solution. Also in the 1950s, Fritz Cramer was working on cyclodextrins. Cyclodextrin chemistry was the first example of host-guest chemistry using relatively small host molecules, but this work did not attract as much attention at the time as it deserved.

Organic chemists became interested in the field of host-guest chemistry after the discovery of crown ethers in 1967. The impact crown ethers had was quite considerable, but the ripple created then has since grown enormously. Crown ethers have sparked off a great deal of synthetic effort and imagination in the chemical community; new compounds and families of compounds have appeared, many of which will feature in this meeting.

It certainly seemed appropriate to bring these areas together in a single meeting. Intermolecular interactions and molecular assemblies will play an extremely important role in chemistry in the future. For biologists, of course, they have always been the most important thing-all biology is based on molecular assemblies-but they are now coming into the orbit of the synthetic chemist. We shall hear about methods for making organized assemblies of synthetic molecules, which may have specific purposes. New materials and molecular electronics are certainly going to require synthetic molecular assemblies

1

2 Sutherland

and possibly also assemblies based on biomolecules. Measurement science is related to this area and molecular sensors are particularly relevant. These involve transport, response, selective detection and a process that is termed transduction. Transduction has its counterpart in biology, but biology has a wider range of transduction processes I han I believe are currently used in molecular sensors, so maybe we shall hear some interesting comments from our molecular biology colleagues about transduction and response. At this stage, sensors use both synthetic host molecules and biomolecules; responses can be optical or electrical, but electrical responses will probably feature more prominently in discussion than optical responses. Work on sensors may also provide ideas for those of us who are becoming interested in molecular electronics as a science of the future.

The underlying theme of this meeting is molecular recognition involving small molecules and large molecules. We shall range from ionophores and ions, perhaps the simplest system of recognition but nevertheless quite difficult to achieve, through host--guest chemistry involving synthetic hosts, to the vancomycin group of antibiotics, host molecules that Nature has made, which are comparable in size to those made by synthetic chemists but which function in a more elegant way. Proteins and DNA, it goes without saying, play a major role in molecular recognition. A number of chemists still regard these recognition processes as essentially ‘lock and key’, a term that has been with us for a long time. The lock and the key are of course much more complex than a real lock and key, not only because they are molecular, which might define their dimensions and fit, but also because they have dynamic properties-they do not necessarily exist in single conformations.

Virtually everything we shall look at takes place in solvents, and solvation must play a very important role in molecular recognition. I hope that we shall be able to shed some light on solvation effects during the meeting. These are difficult effects to discuss in detail because they involve charges. All of us who are interested in putting molecules together are aware of charge distribution and charge-charge interactions, as well as solvation. That takes us into the real world, as opposed to the simplified model of molecules interacting in the gas phase.

We can’t avoid thermodynamics if we are to understand intermolecular interactions. Ultimately, virtually all science is based upon numbers, and the numbers that characterize the binding between molecules have their basis in enthalpy and entropy, areas often avoided by organic chemists. I hope that there are participants here who can enlighten us about the details of intermolecular interactions, particularly regarding solvation effects and charge distribution, which are key factors &hen molecules come together.

We shall hear about recognition by small molecules. Although someone may describe a more elegant performance by a small molecule, I think that the vancomycin antibiotics itre extremely well designed host molecules. The credit in this case has to go to evolution and not to the chemist, but chemists have

Introduction 3

also been smart in their molecular design. I draw your attention to synthetic molecular clefts and ditopic systems; these are simple strategies which generate good complexes, guest recognition and catalysis of reaction-things that chemists hope to achieve with their synthetic host molecules. A lot of progress has been made in this area even if we haven’t quite reached the level of sophistication of vancomycin.

Molecular recognition by large molecules will also feature. I don’t think that many of us are able to design large molecules comparable with DNA or proteins. We tend to think of DNA as a double helix, but of course it is also an interesting host molecule, although Nature may not have had that in mind when evolving its structure. DNA is an excellent host molecule because it possesses a lot of ‘sticky’ functional groups on its surface.

I believe that no chemist can yet design proteins that will act as hosts. Possibly we shall eventually be able to design protein sequences that are different from natural sequences, and we shall hear some approaches to this. We know a lot about the structure of proteins in the solid state and, through NMR studies, about structures of proteins in solution. We even know something about the dynamics of proteins and we can model protein dynamics, given large enough computers and good enough graphics. Despite this, although a lot of progress has been made, we are still unable to predict from a sequence exactly how a protein will fold. Folding is a difficult topic because it involves kinetics as well as equilibria. How do proteins fold and how can they select the conformation that they eventually find from the millions of potential conformations that exist? There is no possibility of equilibrium-the process has to be controlled by kinetics. This is a problem that people like myself who work with simple molecules never have to face, yet it is obviously a serious one for protein chemists. I doubt whether we can solve this problem here, but we may well hear some views on the subject, and on how close we are to protein design. Studying synthetic peptides is one approach to understanding proteins. 1 believe that we shall find it possible to predict peptide-peptide interactions and approach protein folding using this information.

Last, but certainly not least, we come to molecular models. All scientists use models of varying complexity. In chemistry, we are forsaking the classical space- filling molecular models that we used to hold in front of us at meetings, because they are cumbersome and are not numerate-they are good analogue computers but they don’t provide numbers. We are now adopting the more sophisticated molecular modelling provided by computer graphics. We will not cover quantum chemistry, although it provides us with the parameters for molecular mechanics and dynamics, but we shall certainly hear about models that are based on mechanics and dynamics.

I have already referred indirectly to the problem of conformational space. We are perplexed by the amount of conformational space that is available to even the small flexible molecules that we make. Some of us, perhaps wisely,

4 Sutherland

concentrate on molecules in which conformational space is restricted by structural rigidity. I have referred already to charge distribution and solvation. These may feature in our models, but in some cases our models are related more to the gas phase. Molecular models will certainly appear from time to time during the meeting, and we shall hear an account of molecular modelling at the end. The question I put to you is, how successful are we in making predictions using our models? Such predictions, I believe, are less common than the rationalization of the experimental facts that we learn in the laboratory.

I have covered the content of our meeting, but I am sure you all have your own ideas about what we should discuss. The scope is, to me, frighteningly broad. As a chemist, I view biology as impossibly complex, but there may be some molecular bio1ogisi.s here who are not entirely happy with synthetic organic chemistry! We shall see how we get on with one another.

Molecular self-assem bly processes J. Fraser Stoddart

Department of Chemistry, The University, Sheffield S3 7HF, UK*

Abstract. A logical and stepwise approach to the establishment of the concept of self-assembly in the synthesis of wholly unnatural products is proposed. The approach is based on the use of irreversibly interlocked molecular systems in the shape of catenanes and rotaxanes as the vehicles through which to transfer from host-guest chemistry the knowledge and experience gained on relatively small molecules to much largtr molecules including polymers in which the molecular components are reversibly intertwined. The proposal presents a manifesto for making the transformation from supramolecular to polymolecular chemistry. A number of recent template-directed syntheses of catenanes and rotaxanes are presented as examples of structure-directed synthesis, to illustrate that there are inherently simple ways of making apparently complex unnatural products from appropriate substrates without the need for reagent control or catalysis.

1991 Host-guest molecular interactions: from chemistry to biology. Wiley, Chichester (Ciba Foundation Symposium 158) p 5-22

The art of chemical synthesis is about to undergo one of the most profound changes of a conceptual nature that it has witnessed during its long and impressive development as a scientific discipline. The reason for this renaissance is that more and more chemists are beginning to appreciate that the conventional synthetic methodology of making compounds atom by atom and group by group, employing reagents or catalysts to make or break covalent bonds and so manipulate functional groups and transform molecular structures is not going to be enough. In all its many synthetic pathways and transformations, Nature does not have to rely on the use of protecting groups in the manner and practice of synthetic organic chemistry. Indeed, most biological systems contain the information that is necessary for their own chemical formation and physical organization. One of the keys to the efficient operation of biological systems is their ability to self-replicate and self-assemble. In essence, the chemist needs to learn, in principle at least from Nature, how to assemble compounds molecule by molecule from molecular components. Physicists with an eye to the future and looking particularly to the age of the molecular computer have been imploring

'Present address: The School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

5

6 Stoddart

chemists to address the problems of self-assembly and self-replication for some time now. In his search tor a modular chemical approach to molecular electronic devices Carter (1984) commented that ‘this challenge will probably only be mastered when we have learned the principles of self-organization and self- synthesis from the biological world and have applied them more broadly to both organic and inorganic chemistry’. There is little doubt that a new science-call it molecular cybernetics if you wish-awaits development. It will be involved intimately with a fundamental investigation of the chemical sciences, which will enable the future development of mechanoelectrical and photoelectrical communication system:; and devices (Lehn 1988, Balzani & Scandola 1990).

I am convinced that it is from an appreciation of host-guest molecular inter- actions (Cram 1988) that a modular chemical approach to the construction of new materials will emerge in the near future. The approach will be based on the idea of assembling carefully designed molecular components in a template-directed manner. The molecular ,components will have to be held together not by classical covalent bonds, but rather by non-convalent bonds. However, the problem with the best-understood chemical systems that display host-guest interactions is that they are small compared with the biological systems that exhibit molecular recognition. Some kind of bridge or scaffolding between the biological and chemical worlds has to be built. It occurred to us that the kind of self-assembly process employed in biological systems might be easier to establish in chemical systems i f the relatively small molecules contained an element of irreversible mechanical entanglement in addition to the non-covalent bonding interactions that would also have to be present between the molecular components of the man-made assemblies. It seemed prudent to begin by exploring the mechanical principles of interlocking between molecular components and then go on to relax this irreversible mode csf molecular association to the more reversible ones of threading and intertwining. By following this logical thought process we were led inexorably to consider the possibility that molecular compounds known as catenanes and rotaxanes (Schill 197 1, Dietrich-Buchecker & Sauvage 1987) could serve as prototypes for the construction of large, ordered and structured molecular assemblies. When a guest is complexed by a host (Fig. la), the 1:l complex is usually in equilibrium in solution with the molecular components. On the other hand, formation of a rotaxane (a ring compound with a chain through it that is terminated by large groups) by either a threading (Fig. lb) or a clipping (Fig. lc) process will be irreversible, as will the formation of a catenane (a linked-ring compound) by a clipping process (Fig. Id). I shall now show how weak, non- covalent bonding interactions between molecular components not only preside over the synthesis of molecular assemblies, but also persist in these molecular assemblies that they help to create. This is an obvious, but nevertheless important, feature of these new chemical systems. The order they acquire during their formation can obviously become the basis for the subsequent storage and transfer of information at a molecular level.

Molecular self-assembly processes 7

I--

Ill1 1111 -la /

FIG. 1. Diagrammatic representation of (a) formation of a reversible 1: l complex between a host (shaded) and a guest, maintained by non-covalent interactions that are illustrated as vertical striations; (b) production of a rotaxane, a compound formed by a threading process in which an extended guest is covalently capped with large groups (filled circles) after it has threaded itself through the ring-shaped host, preventing reversal; (c) production of a rotaxane by a clipping process in which the complete guest molecule complexes with a partially formed ring, which is then closed; (d) production of a catenane composed of two linked macrocyclic rings from a complete ring and a clipped ring (shaded) which is completed after complexation.

Background

We had established during the 1980s that the redox-active bipyridinium dication (Summers 1980) paraquat [ PQT] 2 + forms a 1 : 1 complex with the cyclophane- like macrocyclic polyether, bisparaphenylene-34-crown-10 (BPP34C 10) (Fig. 2; Stoddart 1988). The stability constant (K, = 730 M- l) in acetone for this deep orange-coloured complex, which is formed at room temperature when the counter ions are soft hexafluorophosphates (PF6-), corresponds to a complexation free energy of 16.3 kJmoI- I . The complex [BPP34C10.PQTI2+ is stabilized by (i) electrostatic interactions, including [ C-H - - -01 hydrogen bonding between the guest dication and the crown ether oxygen atoms in the host and (ii) dispersive forces, including charge transfer interactions between the

8 Stoddart

111

111 Me

[BPP34C1 O.PQlJ*+

ouou~LPuo Me ~_________--_- .

U 111

I I I [BBIPYBIXYCY.1/4DMBJ4+

OMe

0 0 0 0 0

I I

FIG. 2. The host-guest chemistry behind the design of a [2]catenane. The formation of complexes between PQT and BPP34C10 and between BBIPYBIXYCY and 1/4DMB suggested a strategy for the production of a [ 21 catenane (bottom), I [21- [BPP34ClO] - [ BBIPYBIXYCY] -catenane14+ (see Fig. 3 for the synthesis of this catenane). BPP34C10, bisparaphenylene-34-crown-10; PQT, paraquat; BBIPY BIXYCY, a bisbipyridinium- bixylylcyclophane; 1 /4DMB, 1,4-dimethoxybenzene.

7r-electron-accepting bipyridinium moiety of the [ PQT] 2 + dication and the 7-

electron-donating hydroquinol rings of BPP34C 10. The charge transfer interactions account for the deep orange colour of the crystalline 1 : 1 complex, which has been fully characterized by X-ray diffraction studies in the solid state.

Molecular self-assembly processes 9

The centrosymmetrical structure has a rotaxane-like character with the [PQTI2+ dication inserted through the middle of the BPP34C10 ring; such structures can be termed pseudorotaxanes. The distance between the mean planes of the parallely aligned ?r-donating hydroquinol residues and the ?r-accepting bipyridinium ring system is 3.7 A.

The next question we asked ourselves was (Fig. 2) whether we could reverse the roles of the paraquat residues and the hydroquinol rings by incorporating the former in a host tetracation such as [ BBIPYBIXYCYI4+ (bisbipyridinium- bixylylcyclophane) and including the latter in the form of a simple neutral guest like 1 ,Cdimethoxybenzene ( 1 /4DMB). The tetracationic cyclophane [BBIPYBIXYCYI4+ was synthesized (Ode11 et a1 1988) and was found to complex weakly with one molar equivalent of 1/4 DMB (Ashton et a1 1988). The K, value of 17 M- in acetonitrile at room temperature corresponds to a free energy of complexation of 6.9 kJ molt I . On the basis once again of an X-ray crystal structure, it may be concluded that the [ BBIPYBIXYCY. 1/4DMB] 4 +

tetracationic complex is probably stabilized by weak edge-to-face interactions (Jorgensen & Severance 1990) between the 1MDMB and the orthogonally aligned paraphenylene units in the [ BBJPYBIXYCY] 4 + tetracation (with the hydrogen of one aromatic ring pointing towards the centre of the neighbouring aromatic ring), as well as by the dispersive interactions associated with ?r-stacking. Similar edge-to-face T-geometry has been observed (see, for example, Gould et a1 1985) in crystals of benzene, naphthalene and anthracene as well as in proteins that are rich in aromatic amino acids, in which about 70% of the side chains of phenylalanine and tyrosine residues exhibit stabilizing edge-to-face interactions (Burley & Petsko 1988). Clearly, the electrostatic component is not so significant in stabilizing the [ BBIPYBIXYCY. 1/4DMB] 4 + tetracationic complex because of the lack of polyether chains (see below). The solid state structure of the 1 : 1 complex formed between [ BBIPYBIXYCY] [ PF6] and 1/4DMB shows that once again the guest is inserted pseudorotaxane-like through the centre of the tetracationic macrocycle.

The observations that BPP34C10 forms a complex with the [PQTI2+ dication (Fig. 2) and that the tetracationic cyclophane [ BBIPYBIXYCY] 4+ forms a complex with 1/4DMB suggested the possibility of combining these different features in the design of a [2]catenane (Ashton et a1 1989).

Template-directed synthesis

When equimolar amounts of the bis(pyridinium) salt [ BBIPYXY ] [ PF6] (BBIPYXY, bispyridiniumxylyl) and bis(bromomethy1)benzene (BBB) were stirred in acetonitrile at room temperature in the presence of three molar equivalents of BPP34C10, the [ 21 catenane shown in Figs. 2 and 3 was isolated in the remarkably high yield of 70% as a crystalline tetrakishexafluorophosphate after purification by column chromatography and counter ion exchange with

10 Stoddart

.i

Br *- Br

BBB

-- MeCN

Room temp 24 h

L 4PF,

{[2]-[BPP34clo]~[BBlPvBlxYcyl- catenane)[ PF,],

FIG. 3. A [2]catenane made to order. llsing the features of the complexes shown in Fig. 2, a [ 21 catenane was constructed from BPP34Cl0, [ BBIPYXY ] + and BBB, bis(bromomethy1)benzene.

ammonium hexafluorophosphate. In the absence of BPP34C10 the maximum yield of [BBIPYBIXYCY][ PF6j4 that we have ever managed to isolate is 12%, and that was only after heating the acetonitrile solution containing the [ BBIPYXY] [ PF61 and BBB for several days under reflux. Thus, it is much easier to construct the ([2l-[BPP34ClO] - [BB1PYB1XYCYl-~atenane)~+ tetracation than i t is to make one of its components, namely the tetracationic cyclophane [BBIPYBIXYCYI4+, by itself. The implications of this observa- tion are considerable and augur well for the future of self-assembly processes employing this kind of i.emplate-directed synthesis. The [2] catenane acts as a template for its own formation. The first nucleophilic substitution between the [ BBIPYXY] 2 i dication and BBB produces a trication (Fig. 3), which, because of its similarity to the [I’QTI2+ dication, will thread its way through the centre of the BPP34C10 macrocycle. The second nucleophilic substitution is then favoured entropically and possibly even enthalpically. Whatever the precise details of the mechanism, the reaction is amazingly efficient. What is more, dynamic ‘H NMR spectroscopy indicates that the non-covalent bonding order, which presided over the formation of the [ 21 catenane in the first place, ‘lives on’ when the compound is dissolved in polar solvents such as acetonitrile and acetone. In a relatively slow site-exchange process involving ‘inside’ and ‘alongside’ hydroquinol rings, the BPP34C 10 macrocycle feeds its way through the tetracationic cyclophane [ BBIPYBIXYCY] 4 + and in so doing experiences a free energy of activation ( A c t ) of 65 k J mol-I. Simultaneously, in a faster exchange process involving ‘inside’ and ‘alongside’ bipyridinium rings, the neutral macrocycle is pirouetting around the tetracationic cyclophane with a

Molecular self-assembly processes 11

AG$ barrier of 51 kJ mol-I. The solid state structure of the1[2]-IBPP34ClO]- [ BBIPYBIXYCY ] -catenanel + tetracation reveals both a-stacking and edge- to-face interactions involving the appropriate aromatic rings, that is, the structure is that of a highly ordered [ 21 catenane. This order is maintained in the crystal beyond the molecule in the form of an alternating stack of the a-electron-rich and a-electron-deficient aromatic rings repeating continuously in one of the crystallographic directions. This supramolecular order, coupled with a little imagination, suggests possible molecular designs for the construction of polyrotaxanes and double helicates.

Molecular modelling indicates that by replacing the phenylene rings in the tetra- cationic cyclophane [ BBIPYBIXY] 4 + with biphenylene units it should be possible to thread two BPP34CIO rings simultaneously through the centre of this 'expanded' tetracationic cyclophane. Indeed, it is possible to isolate f [ 31 - [ BPP34C101- [ BBIPYBIBTCY ] - [ BBP34C101 -catenanel [ PF,] (BBIPYBIB- TCY, bispyridiniumbisbitolylcyclophane) in 20% yield after reacting equimolar amounts of the bis(bipyridinium) salt [ BBIPYBT] [ PF6] with 4,4'-bisbromo- methylbiphenyl (BBBP) in the presence of a three molar excess of BPP34C10 and subsequent chromatography and counter ion exchange (Fig. 4; P. R. Ashton,

0 r -

BBBP

1. MeCN Room temp 4 days

t n n n m m n n -

0 0 0 0 0 0 0 0 0 0 n n n m m n n -

([3]-[EPP34Cl O]-[EElPYElETCv]-[BPP34Cl O]catenane)[PF,],

FIG. 4. A [ 31 catenane made to order. Expansion of the tetracationic cyclophane by incorporating a biphenylene unit permits threading through of two BPP34ClO rings to form a [ 31 catenane. [ BBIPYBT] + , bispyridiniumbitolyl; BBBP, bisbromomethylbiphenyl.

12 Stoddart

C. L. Brown, E. J . T. (Chrystal, T. T. Goodnow, A. E. Kaifer, K. P. Parry, A. M. Z. Slawin, N. Spencer, J. F. Stoddart & D. J. Williams, unpublished work 1989). The fact that this [3]catenane can be prepared with such relative ease is all the more remarkable when it is recognized that all attempts to obtain [BBIPYBIBTCY][PF6]4 by itself have so far been unsuccessful. Here is an intriguing example of a molecular assembly being made despite the fact that its central molecular component has yet to be isolated and characterized; molecular self-assembly is a highly desirable event. The solid state structure indicates that this [ 31 catenane, like the [ 21 catenane, is highly ordered. However, an interesting additional feature of this assembly is the loss of the alternating pattern of a-donors (D) and a-acceptors (A) observed in the [2]catenane. The a-stacking is associated with a DADDAD sequence in the [ 31 catenane and, what is more, the sequence extends beyond the molecule throughout the crystal, producing a continuously stacked array. Although once again the molecular order persists in solution (as indicated by the temperature dependence of the ‘H NMR spectrum) a process in which both BPP34C10 macrocycles are revolving simultaneously around the tetracationic cyclophane [ BBIPYBIBTCY] 4+, so exchanging the sites of the hydroquinol rings ‘inside’ and ‘alongside’ the tetracation, is occurring with the relatively low free

t HO-0-0

I CHzCIz

temp Br Br 7 Davs

BBB

HO-0-0 1 + + +

+ +

t [BBIPVBIXYCY][PF&

FIG. 5 . The template-directed synthesis of a molecular component. Synthesis of the tetracationic cyclophane [BBIPYBIXYCY ] 4 + is facilitated by the use of BHEEB, bishydroxyethyleneoxyethyleneoxybenzene, as a template. The template molecule can be separated from the product and recycled.

Molecular self-assern bly processes 13

energy of activation of 45 kJ mol- Placing two hydroquinol rings inside the [BBIPYBIBTCYI4+ in the [3]catenane would seem to be less favourable than placing one hydroquinol ring inside the tetracationic cyclophane [BBIPYB1XYCYl4+ in the [2] catenane.

A possible approach to the synthesis of the tetracationic cyclophanes that are difficult to prepare on their own is to employ a neutral compound as a template and then remove it from the charged macrocycle by unthreading when the reaction is complete (P. L. Anelli, P. R. Ashton, N. Spencer, A. M. Z. Slawin, J. F. Stoddart & D. J. Williams, unpublished work 1989). Although 1/4DMB is ineffective as a template in the synthesis of [BBIPYBIXYCY][ PF,],, compounds in which the hydroquinol rings carry polyether chains do act as neutral molecule templates. For example, BHEEB (bishydroxyethyleneoxy- ethyleneoxybenzene) increases the yield of the tetracationic cyclophane from 12% to 35% (Fig. 5 ) . A pure sample of [BB1PYBIXYCY][PF6l4 can be separated easily from the template (BHEEB), which can be recycled by continuous liquid-liquid extraction of an aqueous solution of the highly coloured 1 : 1 complex with dichloromethane. As the extraction proceeds to completion, the colour is dispelled from the aqueous solution. When acetonitrile is replaced by dimethylformarnide in the reaction scheme outlined in Fig. 5 and a catalytic amount of sodium iodide is added, the yield of the tetracationic cyclophane is increased to 45%. Finally, on carrying out the same reaction at ultra high

+ +

+ +

7 0

BHEEB 0 (Me,CH),SiOTf

Me Q Me

MeCN then

NH,PF,

2

I I Hz0

[BBIPYBlXYCY][PF&

I I lo= Si(CHMe,),

([2]-[BSEEB]-[BBlPYBIXYCY]- rotaxane][PF,],

FIG. 6. A [2] rotaxane madc to order by the threading procedure. { [2] - [ BSEEB] - [ BBIPYBIXYCY ] -rotaxanel + was prepared by treatment of BHEEB, bishydroxy- ethyleneoxyethyleneoxybenzene, with triisopropylsilyl triflate in acetonitrile containing BBIPYBIXYCY and lutidine.

14 Stoddart

ZPF,

--n (Me,CH),SIO 0 0 0

BSEEEB a O~O-~lUOSi(CHMe,),

MeCN Room temp

Days

Br

Si(CHhAe,),

' 0 < 4PFF

2

[[2]-[BSEEEB]-[BBIPYBiXYCY]- rotaxaneJ[PF,],

FIG. 7. A [2]rotaxane made to order by the clipping procedure. BSEEEB, BBI PY XY and BBB, bis(1xomomethyl)benzene were used to prepare { [ 21 - [ BSEEEB] - [ BBIPYBIXYCY J -rotaxme) 4 + .

pressures (10 kbar) a yield of 62% of [ BBIPYBIXYCY] [ PF6] is obtained. When BHEEB was treated with triisopropylsilyl triflate [ (Me,CH),SiOTf] in acetonitrile contahing a molar equivalent of [ BBIPYBIXYCY] [ PF6I4 and a suitably hindered base (lutidine), I [2] - [BSEEB] - [ BBIPYBIXYCY] - rotaxane) [ PF6] was isolated following counter ion exchange (Fig. 6). This is an example of the preparation of a [ 21 rotaxane by the threading procedure (Fig. 1 b). Although it is not possible to prepare the [ 21 rotaxane incorporating BSEEB (bissilyloxyet hyleneoxyethyleneoxybenzene) by the clipping procedure (Fig. lc), { [2] - [ BSEEEB] - [ BBIPYBIXYCY] -rotaxanel [ PF6] was obtained in 14% yield by reacting [ BBIPYXY 1 [ PF6] and BBB in acetonitrile in the presence of three molar equivalents of BSEEEB followed by counter ion exchange in the usual manner (Fig. 7). The solid state structures of the [ 21 rotaxanes indicate that in both cases the hydroquinol ring is placed centro- symmetrically inside the tetracationic cyclophane. Following on from the characterization of these [2] rotaxanes, the design and synthesis of a highly ordered molecular shuttle has been achieved and its operation has been demonstrated by dynamic IH NMR spectroscopy (P. L. Anelli, P . R. Ashton, N. Spencer, A. M. Z. Slawin, J . F. Stoddart & D. J . Williams, unpublished work 1989). The basis for the design is a [ 23 rotaxane composed of a polyether

Molecular self-assembly processes 15

[BBIPYBIXYCY][PF&

+ 0 0 0 0

MeCN

c-

[BBIPYBlXYCY.3HQ][PF614 4' FIG. 8. The self-assembly of a molecular bead, [BBIPYBIXYCYI4+, and a molecular thread, 3HQ, an acyclic polyether containing three hydroquinol rings and terminated by benzyl groups.

chain interrupted by two symmetrically placed n-electron-rich hydroquinol rings and terminated by triisopropylsilyl end groups and the tetracationic cyclophane [ BBIPYBIXYCY] + . Using 'H probes in both components of the [2] rotaxane, a barrier of about 44 kJ mol- to the shuttling process of the tetracationic cyclophane back and forth between the two hydroquinol rings has been calculated. This molecular shuttle may be looked upon as a prototype for a new range of molecular mechanical and electronic devices.

It is also highly encouraging that pseudorotaxanes will self-assemble spontaneously. An example is given in Fig. 8, which involves the tetracationic cyclophane [ BBIPYBIXYCY] 4 + and an acyclic polyether (3HQ) containing three hydroquinol rings and terminated by benzyl groups. The 1 : 1 complex [BBIPYBIXYCY .3HQ] [ PF,] has been fully characterized (P. L. Anelli, P. R. Ashton, N. Spencer, A. M. Z. Slawin, J. F. Stoddart & D. J. Williams, unpublished work 1989). The X-ray crystal structure suggests that polyrotaxanes and double helicates should self-assemble spontaneously from the appropriate molecular components. If this next stage in the research programme is successful, then we will have demonstrated that highly ordered catenanes and rotaxanes are the ideal vehicles at the small molecule level around which to experiment with a view to designing larger systems that will self-assemble in not only a spontaneous but also in a reversible mode. In this way, information can be transferred at the molecular level as well as stored.

16

Reflections

Stoddart

All the examples of template-directed synthesis discussed in this paper illustrate the principle of structure-directed synthesis (Kohnke et a1 1989) which states that:

There are inherently simple ways of making apparently complex unnatural products from appropriate substrates without the need for reagent control or catalysis.

It implies that the required stereoelectronic information is preprogrammed into the substrates of a chemical reaction; this allows the efficient and precise spontaneous self-assembly of these ‘intelligent’ substrates, thus yielding either large molecules with completely defined superstructures or, as in the case of the catenanes and rotaxanes made to order, an organized molecular assembly composed of unique molecular components. The concept of structure-directed synthesis challenges the dogma of present day synthetic chemistry, which is often viewed as a search for more sophisticated reagents and catalysts to carry out well-known chemical reactions. It calls for a change in our thinking about the art of synthetic chemistry which I suggest now has to undergo a major conceptual revolution with fundamental implications for the practice of chemical synthesis as we have perceived it in the classical and traditional sense. Following the examples provided by Nature, we must begin to learn how to build large molecules and molecular assemblies molecule by molecule in addition to the familiar atom-by-atom and group-by-group approaches involving the time- consuming and often not so efficient functional group manipulations and transformations that rely upon the delicate and intricate use of protecting groups.

A ckno wledgernents

I am deeply indebted to Drs Neil Spencer and Pier Lucio Anelli for leading the research programme I have described in this paper with such drive and success, to Mr Peter F.. Ashton for his imaginative and intuitive use of fast atom bombardment mass spectrometry in the characterization of high molecular weight complexes and assemblies, and to Dr David J . Williams and Miss Alexandra M. Z. Slawin (Imperial College, London) for their apparently effortless solutions to many extremely demanding X-ray crystal structure problems. WI: were all admirably supported by many talented contributions from postgraduate research students, namely Christopher L. Brown, Douglas Philp, Mark V. Reddington, and Cristina Vicent. I thank the Science iind Engineering and the Food and Agricultural Research Councils for their generous financial support. The intellectual input of senior scientists at both ICI Agrochemicals (Drs Keith P. Parry and Ewan J . T. Chrystal) and Shell Research (Dr Barbara Odell) contributed greatly to everyone’s understanding.

Molecular self-assern bly processes 17

References

Ashton PR, Odell B, Reddington MV, Slawin AMZ, Stoddart JF , Williams DJ 1988 Isostructural alternately-charged receptor stacks. The inclusion complexes of hydroquinone and catechol dimethyl ethers with cyclo(paraquatppheny1ene). Angew Chem Int Ed Engl 27:1550-1553

Ashton PR, Goodnow TT, Kaifer AE et a1 1989 A [2]catenane made to order. Angew Chem Int Ed Engl 28:1396-1399

Balzani V , Scandola F 1990 Supramolecular photochemistry. Ellis Horwood, Chichester Burley SK, Petsko GA 1988 Weakly polar interactions in proteins. Adv Protein Chem

Carter FL 1984 The molecular device computer: point of departure for large scale cellular automata. Physica lOD:175-194

Cram DJ 1988 The design of molecular host, guests, and their complexes (Nobel Lecture). Angew Chem Int Ed Engl 27:1009-1020

Dietrich-Buchecker CO, Sauvage J P 1987 Interlocking of molecular threads: from the statistical approach to the templated synthesis of catenands. Chem Rev 87:795-810

Could RO, Gray AM, Taylor P , Walkinshaw MD 1985 Crystal environments and geometries of leucine, isoleucine, valine and phenylalanine provide estimates of minimum nonbonded contact and preferred van der Waals interaction distances. J Am Chem SOC 107:5921-5927

Jorgensen WL, Severance DL 1990 Aromatic-aromatic interactions: free energy profiles for the benzene dimer in water, chloroform, and liquid benzene. J Am Chem SOC

Kohnke FH, Mathias JP , Stoddart J F 1989 Structure-directed synthesis of new organic materials. Angew Chem Int Ed Engl Adv Mater 101:1129-1136

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Odell B, Reddington MV, Slawin AMZ, Spencer N, Stoddart JF , Williams DJ 1988 Cyclobis(paraquat-p-phenylene): a tetracationic multipurpose receptor. Angew Chem Int Ed Engl 27:1547-1550

39: 125-189

112:4768-4774

Schill G 1971 Catenanes, rotaxanes, and knots. Academic Press, New York Stoddart J F 1988 Conception and birth of new receptor chemistry from

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DISCUSSION

Ron Breslow: Could I raise the question of function? You talked about the need to develop these new classes of synthetic molecular assemblies because of their interesting potential functions. What are you going to do that cannot be done already?

Stoddart: One example concerns catalysis. By and large, Nature has devised large molecular assemblies, in the form of the enzymes, to preside over catalytic events. I t could be by putting some effort into the self-assembly of high molecular weight synthetic receptors that we shall be able to improve on the catalytic performances and reaction selectivities of synthetically derived enzyme mimics. You, of course, are one of the world’s leading authorities in the area