From Non-Covalent Assemblies to Molecular Machines

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Edited by Jean-Pierre Sauvage and Pierre Gaspard From Non-Covalent Assemblies to Molecular Machines

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Edited by Jean-Pierre Sauvage and Pierre Gaspard

From Non-Covalent Assemblies to Molecular Machines

The Editors Prof. Jean-Pierre Sauvage Université de Strasbourg Institut de Chimie 4, rue Blaise Pascal 67070 Strasbourg Cedex France

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for

Prof. Pierre Gaspard Université Libre de Bruxelles Center for Nonlinear Phenomena and Complex Systems Code Postal 231, Campus Plaine 1050 Brussels Belgium Cover Image The drawing was prepared by Alex Bosoy, a graphic artist working in the Mechanostereo chemistry group (Northwestern University, USA). His contribution is gratefully acknowledged.

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliograﬁe; detailed bibliographic data are available on the Internet at . © 2011 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microﬁlm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not speciﬁcally marked as such, are not to be considered unprotected by law. Cover Adam-Design, Weinheim Typesetting Toppan Best-set Premedia Limited, Hong Kong Printing and Binding Strauss GmbH, Mörlenbach Printed in the Federal Republic of Germany Printed on acid-free paper ISBN: 978-3-527-32277-0

V

Contents Preface XIII List of Contributors XV Description XIX Opening Session XX The International Solvay Institutes XXIII Solvay Scientiﬁc Committee for Chemistry XXV 21st Solvay Conference on Chemistry XXVI

Part One Noncovalent Assemblies: Design and Synthesis

1

1

Introduction and Deﬁnition of Noncovalent Assemblies 3 Julius Rebek Jr References 6

2

Noncovalent Assemblies: Design and Synthesis 7 Makoto Fujita and Takashi Murase Introduction 7 Landmarks in Self-Assembly Fields 8 Hydrogen-Bonded Assemblies 15 Coordination Assemblies 17 Function Through Architecture 21 Conclusions 27 References 27

2.1 2.2 2.3 2.4 2.5 2.6

3

Discussion 1.A 31 Chairman: Julius Rebek Jr

4

Noncovalent Synthesis of Molecular Receptors 35 David N. Reinhoudt Introduction 35 Noncovalent Synthesis 35 Supramolecular Chirality 38

4.1 4.2 4.3

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

VI

Contents

4.4

Optical Ampliﬁcation in Dynamic Supramolecular Systems Acknowledgments 41 References 42

5

Cucurbiturils: New Players in Noncovalent Assembly 43 Kimoon Kim Acknowledgments 48 References 48

6

Comment on the Possible Presence of Bubbles Inside Self-Assembled Molecular Cages 51 Josef Michl References 56

7

Discussion 1.B 57 Chairman: Julius Rebek Jr

Part Two Template Synthesis of Catenanes and Rotaxanes 8 8.1 8.1.1 8.2 8.3 8.3.1 8.3.2 8.3.3 8.3.4 8.3.5 8.3.6 8.3.7 8.3.8 8.4 8.5 8.5.1 8.5.2 8.5.3 8.6 8.7 8.8 8.9

65

A Short History of the Mechanical Bond 67 John-Carl Olsen, Kirsten E. Grifﬁths, and J. Fraser Stoddart Introduction 67 Historical Perspective 69 Donor/Acceptor Templated Systems 72 Charged Hydrogen Bond-Templated Systems 80 Reverse Recognition in Rotaxane Synthesis 82 Threading-Followed-by-Stoppering Protocols 83 Clipping Protocol 84 Slippage 86 Ring Shrinkage 87 Threading Accompanied by Swelling 87 Other Mechanically Interlocked Molecules 88 Molecular Switches 89 Anion-Templated Synthesis 90 Neutral Hydrogen Bond-Templated Systems 93 Catenanes 94 Rotaxanes 99 Novel Catenane and Rotaxane Architectures 103 Metal-Containing Catenanes and Rotaxanes 106 Solvophobically Driven Templation 115 Applications 122 Conclusions 127 References 128

40

Contents

9

Discussion 2.A 141 Chairman: Fritz Vögtle

10

Dynamic Combinatorial Approaches to Catenanes Jeremy K. M. Sanders Notes Added After the Conference 149 References 149

11

Discussion 2.B 151 Chairman: Fritz Vögtle

147

Part Three Molecular Machines Based on Catenanes and Rotaxanes 12 12.1 12.2 12.2.1 12.2.2 12.2.3 12.2.4 12.2.5 12.2.5.1 12.2.5.2 12.2.5.3 12.3 12.3.1 12.3.2 12.3.2.1 12.3.2.2 12.3.2.3 12.3.2.4 12.3.3 12.3.3.1 12.3.3.2 12.3.4 12.3.4.1 12.3.4.2 12.3.5 12.4 12.4.1 12.4.2 12.4.3

157

Molecular Machines Based on Rotaxanes and Catenanes 159 Vincenzo Balzani, Alberto Credi, and Margherita Venturi Introduction 159 Molecular Machines: History and Overview 160 General Concepts 160 Natural Devices and Machines 161 Artiﬁcial Molecular Devices and Machines 161 Mechanical Motion in Artiﬁcial Molecular-Scale Systems 163 Energy Supply 165 Chemical Energy 165 Light Energy 165 Electrical Energy 166 Molecular Machines Based on Rotaxanes 166 Introduction 166 Chemically Driven Movements 169 Rotaxanes Based on Macrocyclic Crown Ethers 169 Rotaxanes Based on Metal Complexes 172 Rotaxanes Based on Cucurbituril and Cyclodextrin 172 Other Systems 174 Electrochemically Driven Movements 175 Rotaxanes Based on Tetracationic Cyclophanes 175 Rotaxanes Based on Metal Complexes 176 Photochemically Driven Movements 178 Systems Based on Photoinduced Electron Transfer 178 Systems Based on Photoisomerization Reactions 181 Allowing/Preventing Ring Motion 183 Molecular Machines Based on Catenanes 187 Introduction 187 Chemically Driven Processes 188 Electrochemically Driven Processes 189

VII

VIII

Contents

12.4.4 12.4.5 12.5 12.5.1 12.5.2 12.5.3 12.5.4 12.5.5 12.6

Photochemically Driven Processes 190 Unidirectional Ring Rotation in Catenanes 192 Performing Functions with Molecular Machines 196 Beyond the Solution Phase: Ordering and Addressing 196 Molecular Valves 197 Molecular Muscles 198 Photoinduced Transport of Liquid Droplets 199 Interlocked Compounds in Solid-State Electronic Devices 200 Perspectives 204 Acknowledgments 205 References 206

13

Discussion 3.A 213 Chairman: David A. Leigh

14

Rearrangement of a Surface-Deposited [2]catenane by Coordination to Copper(I) at the Single-Molecule Level 219 Jean-Pierre Sauvage Conclusions 222 References 222

15

A Toroidal Oxidation Catalyst 225 Alan E. Rowan, Johannes A.A.W. Elemans, and Roeland J.M. Nolte References 230

16

Discussion 3.B 231 Chairman: David A. Leigh

Part Four Molecular Machines Based on Non-Interlocking Molecules 17

17.1 17.2 17.3 17.3.1 17.3.2 17.3.3 17.3.4 17.3.5 17.3.6 17.4 17.4.1

241

Synthetic Molecular Machines Based on Non-Interlocked Systems: From Concept to Applications 243 Wesley R. Browne, Dirk Pijper, Michael M. Pollard, and Ben L. Feringa Introduction 243 Design Concepts 244 Synthetic Molecular Rotors 246 Metal Complexes as Rotors 246 Correlated Rotation Through Steric Interactions 250 Molecular Gyroscope in the Solid State 253 Rotary Motion Controlled by an External Input 254 Electrically Driven Rotors and Machines 256 Molecular Rotation on Surfaces 258 Synthetic Molecular Motors and Machines 263 Biased Brownian Motion 264

Contents

17.4.2 17.4.3 17.4.4 17.4.5 17.5 17.5.1 17.5.2 17.5.3 17.6 17.7

Chemically Driven Molecular Motors 265 Light-Driven Molecular Machines Based on Azobenzenes 268 Light-Driven Molecular Rotary Motors 269 Second-Generation Light-Driven Molecular Motors 272 Molecular Machines: Putting Motors to Work 274 Light-Driven Machines 274 Photochemically Driven Mechanical Changes in Crystals and Polymers 276 Molecular Motors Operating on Surfaces 279 Molecular Motors at Work 282 Conclusions and Outlook 283 References 285

18

Discussion 4.A 291 Chairman: Takuzo Aida

19

Comment on Molecular Machines Based on Non-Interlocking Molecules (Other Than Catenanes and Rotaxanes) 297 Josef Michl References 300

20

A Few Hints Towards Artiﬁcial Active Macroscopic Systems 301 Jacques Prost Active Molecules 301 Active Gels 302 Expected Properties 304 Acknowledgments 304 References 305

20.1 20.2 20.3

21

21.1 21.2 21.3 21.4 21.5 21.6

22

Fluctuation Theorem, Nonequilibrium Work, and Molecular Machines 307 Pierre Gaspard Introduction 307 Fluctuation Theorem 308 Nonequilibrium Work Relations 308 Application to the F1-ATPase Molecular Motor 309 Perspectives 310 Note Added after the Conference 310 Acknowledgments 311 References 311 Discussion 4.B 313 Chairman: Takuzo Aida

IX

X

Contents

Part Five Towards Molecular Logics and Artiﬁcial Photosynthesis 317 23

Chairman’s Comments A. Prasanna de Silva References 320

24

Towards Molecular Logic and Artiﬁcial Photosynthesis 321 Devens Gust, Thomas A. Moore, and Ana L. Moore Introduction 321 Artiﬁcial Photosynthesis 321 Natural Photosynthesis 322 Realizing Artiﬁcial Photosynthesis 324 Mimicking the Reaction Center 324 Artiﬁcial Antenna Systems 333 Using the Stored Energy 336 Molecular Logic 337 What is Molecular Logic? 337 Simple Switches 338 Chemically Operated Logic Gates 339 Photochemical Logic Gates and Related Devices 340 Combinations of Logic Gates 343 Reconﬁgurable Molecular Logic Devices 344 Ultrafast Switching 346 Communication Among Molecular Switches 347 Are There Applications for Molecular Logic? 348 Final Comments 350 References 350

24.1 24.2 24.2.1 24.2.2 24.2.2.1 24.2.2.2 24.2.2.3 24.3 24.3.1 24.3.2 24.3.3 24.3.4 24.3.5 24.3.6 24.3.7 24.3.8 24.3.9 24.4

319

25

Discussion 5.A 355 Chairman: A. Prasanna de Silva

26

Artiﬁcial Photosynthesis: Oxygen Evolution from Photochemical Water Splitting 361 Vincenzo Balzani Introduction 361 Oxygen Evolution 362 Lessons from Nature 363 Proton-Coupled Electron Transfer 364 References 364

26.1 26.2 26.3 26.4

27 27.1 27.2

Potential Applications of Molecular Logic Alberto Credi Introduction 367 Discussion 368 Acknowledgments 373 References 374

367

Contents

28

Discussion 5.B 377 Chairman: A. Prasanna de Silva

Part Six From Single Molecules to Practical Devices 29 29.1 29.2 29.2.1 29.2.2 29.2.3 29.2.4 29.2.5 29.2.6 29.2.7 29.3 29.3.1 29.3.2 29.3.3 29.3.4 29.3.5 29.3.6 29.3.7 29.3.8 29.4 29.4.1 29.4.2 29.4.3 29.4.4 29.4.5 29.5

379

From Single Molecules to Practical Devices 381 Jean-Pierre Launay Introduction 381 Devices Based on Mechanical Effects 382 Molecules as Tools on Surfaces 382 Transport by Molecules on Surfaces 382 Rotors and Motors on Surfaces 385 Gears 389 Racks and Pinions on Surfaces 390 The Challenge of Unidirectional Rotation (Mostly in Solution) 391 Vehicles on Surfaces 393 Devices Based on Electronic Effects 397 Preliminary: How to Connect Wires to a Single Molecule 398 Overview of the Different Transport Regimes 400 Wires 405 Connecting Elements to Metal Electrodes: Importance of the Atomic Precision 408 Rectiﬁcation 409 Single Electron Storage 411 Negative Differential Resistance Devices 412 Single-Molecule Transistors 414 Devices Based on a Combination of Mechanical and Electronic Effects 416 Switches 416 Ampliﬁer with C60 418 Molecular Ammeter 419 Morse Manipulator 421 Quantum Logical Gate 422 Conclusions 424 Acknowledgment 426 References 426

30

Discussion 6.A 429 Chairman: Enrico Dalcanale

31

A Spring-Loaded Device 435 Dariush Ajami and Julius Rebek Jr Notes After the Conference 440 Acknowledgments 441 References 441

XI

XII

Contents

32

From Electrochemically-Driven Conformational Polymeric States to Macroscopic Sensing and Tactile Muscles 443 Toribio F. Otero References 452

33

Controlling Self-Assembly in Space and Time Ben L. Feringa Introduction 453 Low-Molecular-Weight Gelators 453 Dynamic Control of Gelation 455 Concluding Remarks 460 References 460

33.1 33.2 33.3 33.4

34

Discussion 6.B 463 Chairman: Enrico Dalcanale

Index

467

453

XIII

Preface It was a great honor and a real pleasure to chair the 21st Solvay Conference on Chemistry. The prestigious Solvay Conferences on Physics or on Chemistry are all known by the various scientiﬁc communities as major events, with a historical impact that is universally recognized. It is obvious to all of us that these conferences had a strong inﬂuence on the way physics and chemistry evolved during the course of the past hundred years or so. The spirit and the organization of the conference on chemistry “From Monovalent Assemblies to Molecular Machines” were in accordance with those of the previous conferences. The format was indeed unique: no classical lectures, a pre-eminence of questions and comments and, as a testimony for the widest possible community and for the future scientists interested in the ﬁelds discussed during the event, detailed proceedings gathering the various general lectures (“reports”), short presentations (“prepared comments”) and, last but not least, discussions on the prepared comments. The theme of the Conference was relatively wide, since, a priori, noncovalent assemblies have almost no relationship with controlled dynamic systems (molecular machines). However, at the same time it was relatively focused since, historically, these two ﬁelds are tightly linked. The ﬁrst area is an important subﬁeld of supramolecular chemistry, the development of which has been spectacular during the course of the past 30 years or so. In the particular context of the Conference, transition metals and hydrogen bonds played a special role. The second ﬁeld, related to molecular motion, is more recent and, to a large extent, has derived from the ﬂourishing ﬁeld of interlocking compounds (“catenanes and rotaxanes”), the synthesis of which has undergone a spectacular revival during the past 20 years or so. Of course, the creation of interlocking ring structures relies on the ability of molecular chemists to assemble precisely deﬁned multicomponent ediﬁces before making the desired catenanes or analogous species, which was the ﬁrst topic of the conference. Functional interlocking compounds – the constitutive elements of which are held together only by “mechanical bonds” rather than covalent bonds – are conceptually particularly well adapted to the study of large-amplitude molecular movements, as the various fragments of catenanes and rotaxanes can move with almost no constraints. A ring can spin around the axle on which it has been threaded, and it can also glide over large distance along the same axis. From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

XIV

Preface

Triggering and studying molecular motion is not restricted to interlocking systems. In this context, noninterlocking compounds have also turned out to be of high interest, especially as far as rotary motions are concerned. For both classes of molecules, ingenious chemists have been able to set given fragments of the molecule in motion by using various types of stimulus (light pulse, electrochemical signal, heat, modiﬁcation of the solvent, etc.). The relation between molecular biology and the numerous motor proteins found in Nature is obvious, as is the connection to physics and Brownian molecular machines, which are of utmost importance in biology. The use of complex molecular systems, which are able to behave as switches or to display novel properties in relation to molecular logic or artiﬁcial photosynthesis, seems to be promising and, even if these research topics are not strictly speaking part of the molecular machine ﬁeld, they were sufﬁciently close from a conceptual viewpoint to form part of the themes discussed during the Conference. The high level of interaction between the scientists classiﬁed as belonging to a given subﬁeld was a demonstration that it is indeed important to allow various communities to meet and work together. Finally, a critical point is to know whether applications might be expected in the near future or, at least, to consider possibilities related to practical devices. Some of us have already started to envision important applications, and also to realize highly promising devices from a practical standpoint. It was important to compare the points of view of these investigators with those of more basic-science-oriented researchers. Single-molecular devices, as well as ordered or condensed states of matter consisting of the various molecular systems discussed during the Conference, are certainly to be considered with respect to various applications. Consequently, a special session was devoted to single molecules and their potential, mostly in relation to information storage and processing. All of the participants at the 21st Solvay Conference on Chemistry are extremely grateful to the Solvay family for their very generous support. The tradition started by this family so long ago is highly beneﬁcial to the scientiﬁc community in general, as the Conferences have a scientiﬁc impact that goes much beyond the meeting itself. In addition to the generous sponsors whose support made the Conference possible, I would also like to thank all of the participants for their great contributions, as well as the younger colleagues who took care of all the practical aspects of the conference, who gathered the various written reports and comments, and who transcribed the oral presentations, comments, questions and answers. Without their important contribution, the preparation of this book would never have been possible. Jean-Pierre Sauvage

XV

List of Contributors Dariush Ajami The Scripps Research Institute The Skaggs Institute for Chemical Biology and Department of Chemistry 10550 North Torrey Pines Road La Jolla, CA 92037 USA

Alberto Credi Università di Bologna Dipartimento di Chimica “G. Ciamician” Via Selmi 2 40126 Bologna Italy

Vincenzo Balzani Università di Bologna Dipartimento di Chimica “G. Ciamician” Via Selmi 2 40126 Bologna Italy

Johannes A.A.W. Elemans Radboud University Nijmegen Institute for Molecules and Materials Toernooiveld 1 6525 ED Nijmegen The Netherlands

Wesley R. Browne University of Groningen Stratingh Institute for Chemistry & Zernike Institute for Advanced Materials Faculty of Mathematics and Natural Sciences Nijenborgh 4 9747 AG, Groningen The Netherlands

Ben L. Feringa University of Groningen Stratingh Institute for Chemistry & Zernike Institute for Advanced Materials Faculty of Mathematics and Natural Sciences Nijenborgh 4 9747 AG Groningen The Netherlands

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

XVI

List of Contributors

Makoto Fujita The University of Tokyo School of Engineering Department of Applied Chemistry 7-3-1 Hongo, Bunkyo-ku Tokyo 113-8656 Japan

Jean-Pierre Launay Center for Materials Elaboration and Structural Studies (CEMES) CNRS 29 rue Jeanne Marvig 31055 Toulouse Cedex 04 France

Pierre Gaspard Université Libre de Bruxelles Center for Nonlinear Phenomena and Complex Systems Code Postal 231, Campus Plaine 1050 Brussels Belgium

Josef Michl University of Colorado Department of Chemistry and Biochemistry Boulder, CO 80309-0215 USA and

Kirsten E. Grifﬁths Northwestern University Department of Chemistry 2145 Sheridan Road Evanston, IL 60208 USA Devens Gust Arizona State University Center for Bioenergy and Photosynthesis Department of Chemistry and Biochemistry Tempe, AZ 85287 USA Kimoon Kim Pohang University of Science and Technology National Creative Research Initiative Center for Smart Supramolecules and Department of Chemistry San 31 Hyojadong Pohang 790-784 Republic of Korea

Academy of Sciences of the Czech Republic Institute of Organic Chemistry and Biochemistry Flemingovo nam. 2 16610, Prague 6 Czech Republic Ana L. Moore Arizona State University Center for Bioenergy and Photosynthesis Department of Chemistry and Biochemistry Tempe, AZ 85287 USA Thomas A. Moore Arizona State University Center for Bioenergy and Photosynthesis Department of Chemistry and Biochemistry Tempe, AZ 85287 USA

List of Contributors

Takashi Murase The University of Tokyo School of Engineering Department of Applied Chemistry 7-3-1 Hongo, Bunkyo-ku Tokyo 113-8656 Japan Roeland J.M. Nolte Radboud University Nijmegen Institute for Molecules and Materials Toernooiveld 1 6525 ED Nijmegen The Netherlands John-Carl Olsen Northwestern University Department of Chemistry 2145 Sheridan Road Evanston, IL 60208 USA Toribio F. Otero Universidad Politécnica de Cartagena Centre for Electrochemistry and Intelligent Materials 30203 Cartagena Spain Dirk Pijper University of Groningen Stratingh Institute for Chemistry & Zernike Institute for Advanced Materials Faculty of Mathematics and Natural Sciences Nijenborgh 4 9747 AG, Groningen The Netherlands

Michael M. Pollard University of Groningen Stratingh Institute for Chemistry & Zernike Institute for Advanced Materials Faculty of Mathematics and Natural Sciences Nijenborgh 4 9747 AG, Groningen The Netherlands Jacques Prost Physicochimie Curie (CNRS-UMR168) Institut Curie, Section de Recherche 26 rue d’Ulm 75248 Paris Cedex 05 France and Ecole Supérieure de Physique et de Chimie Industrielles (ESPCI) 10 rue Vauquelin 75231 Paris Cedex 05 France Julius Rebek Jr. The Scripps Research Institute The Skaggs Institute for Chemical Biology and Department of Chemistry 10550 North Torrey Pines Road La Jolla, CA 92037 USA David N. Reinhoudt University of Twente MESA+ Institute for Nanotechnology Laboratory of supramolecular Chemistry and Technology Drienerlolaan 5 7522 NB, Enschede The Netherlands

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List of Contributors

Alan E. Rowan Radboud University Nijmegen Institute for Molecules and Materials Toernooiveld 1 6525 ED Nijmegen The Netherlands

A. Prasanna de Silva Queen’s University School of Chemistry and Chemical Engineering Belfast, BT9 5AG, Northern Ireland UK

Jeremy K. M. Sanders University Chemical Laboratory Department of Chemistry Lensﬁeld Road Cambridge, CB2 1EW UK

J. Fraser Stoddart Northwestern University Department of Chemistry 2145 Sheridan Road Evanston, IL 60208 USA

Jean-Pierre Sauvage Université de Strasbourg Institut de Chimie Laboratoire de Chimie Organo-Minérale 4, rue Blaise Pascal 67070 Strasbourg-Cedex France

Margherita Venturi Università di Bologna Dipartimento di Chimica “G. Ciamician” Via Selmi 2, 40126 Bologna Italy

XIX

Description 21st Solvay Conference on Chemistry Hotel Metropole (Brussels), 28 November–1 December 2007

“From Noncovalent Assemblies to Molecular Machines” Chair: Professor Jean-Pierre Sauvage

The 21st Solvay Conference on Chemistry took place in Brussels between 28 November and 1st December 2007, according to the tradition initiated by Lorentz at the 1st Solvay Conference on Physics in 1911 (“Premier Conseil de Physique Solvay). The Conference was followed on 2nd December by a public event, during which J.-M. Lehn delivered a public lecture entitled “De la Matière à la Vie: la Chimie? La Chimie!” and a panel of scientists (B. Feringa, V. Heitz, J.-P. Launay, J.-M. Lehn, D. Leigh, A. Moore, J.-P. Sauvage and F. Stoddart) answered questions from the audience. The organization of the 21st Solvay Conference has been made possible thanks to the generous support of the Solvay Family, the Solvay Company, the Belgian National Lottery, the “Université Libre de Bruxelles”, the “Vrije Universiteit Brussel”, the “Communauté française de Belgique”, the David and Alice Van Buuren Foundation, the Wiener Anspach Foundation and the Hotel Metropole.

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

XX

Opening Session Opening address by Marc Henneaux

Dear colleagues, dear friends, In the name of the International Solvay Institutes, it is my great pleasure to welcome all of you to the 21st Solvay Conference on Chemistry. This is the ﬁrst Solvay Conference on Chemistry to be held in the 21st century. Since I have only a few minutes, I will be brief. I thought it would be of interest to give you some historical background on the Solvay Conferences on Chemistry. The history of the International Solvay Institutes started in 1911, with the ﬁrst Solvay Conference on Physics. I am sure that you have all seen the famous photograph where Marie Curie, Lorentz, Poincaré, the young Einstein and other celebrities surround Ernest Solvay. In view of the success of the 1911 conference, Ernest Solvay created the Institute of Physics in 1912 and the Institute of Chemistry in 1913, which have now merged into the “International Institutes for Physics and Chemistry, founded by Ernest Solvay”, or the “International Solvay Institutes” for short. One central mission of the Solvay Institutes is periodically to organize the famous Solvay Conferences. The list of all the conferences that have taken place in chemistry is as follows: 1. 1922 Cinq Questions d’Actualité Chair : William Pope (Cambridge) 2. 1925 « Structure et Activité Chimique » Chair : William Pope (Cambridge) 3. 1928 « Questions d’Actualité » Chair : William Pope (Cambridge) 4. 1931 « Constitution et Conﬁguration des Molécules Organiques » Chair : William Pope (Cambridge) 5. 1934 « L’Oxygène, ses réactions chimiques et biologiques » Chair : William Pope (Cambridge)

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

Opening Session

6. 1937 « Les Vitamines et les Hormones » Chair : Fred Swarts (Gand) 7. 1947 « Les Isotopes » Chair : Paul Karrer (Zurich) 8. 1950 « Le Mécanisme de l’Oxydation » Chair : Paul Karrer (Zurich) 9. 1953 « Les Protéines » Chair : Paul Karrer (Zurich) 10. 1956 « Quelques Problèmes de Chimie Minérale » Chair : Paul Karrer (Zurich) 11. 1959 « Les Nucléoprotéines » Chair : A.R. Ubbelohde (London) 12. 1962 « Transfert d’Energie dans les Gaz » Chair : A.R. Ubbelohde (London) 13. 1965 « Reactivity of the Photoexited Organic Molecule » Chair : A.R. Ubbelohde (London) 14. 1969 « Phase Transitions » Chair : A.R. Ubbelohde (London) 15. 1970 « Electrostatic Interactions and Structure of Water » Chair : A.R. Ubbelohde (London) 16. 1976 « Molecular Movements and Chemical Reactivity as conditioned by Membranes, Enzymes and other Molecules » Chair : A.R. Ubbelohde (London) 17. 1980 « Aspects of Chemical Evolution » Chair : A.R. Ubbelohde (London) 18. 1983 « Design and Synthesis of Organic Molecules Based on Molecular Recognition » Chairs : Ephraim Katchalski (Rehovot) and Vladimir Prelog (Zurich) 19. 1987 « Surface Science » Chair : Frederik W. de Wette (Austin) 20. 1995 « Chemical Reactions and their Control on the Femtosecond Time Scale » Chair : Pierre Gaspard (Brussels) A striking feature of the subjects of the conferences is their diversity, ranging from physics to biology. The previous conference on chemistry took place in 1995. With the organization of the 21st Conference, 12 years after the 20th one, we are happy, at the Solvay Institutes, to revive a tradition that has been dormant since then. I would like to

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Opening Session

express our deepest thanks to the Solvay Scientiﬁc Committee for Chemistry, represented here by its Professors Stuart Rice (chair), Graham Fleming, Henk Lekkerkerker, Jean-Marie Lehn and Albert Goldbeter (secretary), who chose the subject of the conference, and to Professor Jean-Pierre Sauvage from the University of Strasbourg who accepted to chair it. In preparing my speech, I was informed by Professor Franklin Lambert (VUB) that there are, in fact, many historical links between the University of Brussels and the Solvay Institutes on the one hand, and the University of Strasbourg on the other hand. These links go back to the early days of the Institutes, after the First World War. The physicist Pierre Weiss, known for his important work on magnetism, was a cornerstone of this cooperation. It is interesting to note that Pierre Weiss, as early as in 1920, pushed for an exchange program between professors and lecturers of both Brussels and Strasbourg Universities, and even suggested an equivalence of degrees and diplomas … it was the Bologna program before the Bologna program but without the bureaucracy. Pierre Weiss himself came many times to Brussels to give lectures, and received a golden medal from the University. With the 21st Solvay Conference on Chemistry, we are pleased to renew the tradition of cooperation with Strasbourg. I wish you a very fruitful meeting, and I am very happy to give the ﬂoor to Jean-Pierre Sauvage.

XXIII

The International Solvay Institutes Board of Directors Members Mr Solvay†

President

Professor Franz Bingen Emeritus – Professor VUB

Vice-President and Treasurer

Professor Rosette S’Jegers Vice-rector VUB and Professor VUB

Secretary

Professor Françoise Thys-Clément Honorary Rector and Professor ULB Mr Philippe Busquin European Deputy and Former European Commmissioner Baron Daniel Janssen Honorary Chairman of the Board of Directors of Solvay S.A. Mr Jean-Marie Solvay Member of the Board of Directors of Solvay S.A. Mr Eddy Van Gelder President of the Administrative Board of the VUB Professor Jean-Louis Vanherweghem President of the Administrative Board of the ULB Honorary Members Professor Irina Veretennicoff Professor VUB

Baron Jaumotte Honorary Rector and Honorary President ULB †

Honorary Director

Deceased April 29, 2010.

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

XXIV

The International Solvay Institutes

Mr Jean-Marie Piret Attorney General of the Supreme Court of Appeal and Honorary Principal Private Secretary to the King Guests Professor Marc Henneaux Professor ULB

Director

Professor Franklin Lambert Professor VUB

Deputy Director

Professor Albert Goldbeter Professor ULB

Scientiﬁc Secretary of the Committee for Chemistry

Professor Alexandre Sevrin Professor VUB

Scientiﬁc Secretary of the Committee for Physics

Mr Pascal De Wit Adviser Solvay S.A. Professor Niceas Schamp Secretary of the Royal Flemish Academy for Sciences and Arts

XXV

Solvay Scientiﬁc Committee for Chemistry Chair Professor Stuart Rice, University of Chicago, USA Members Professor Manfred Eigen Max-Planck Institut, Göttingen, Germany

Professor Graham Fleming University of Berkeley, USA Professor Harold W. Kroto University of Sussex, Brighton, UK Professor Jean-Marie Lehn Collège de France, Paris, France Professor Henk N.W. Lekkerkerker Utrecht Universiteit, the Netherlands Professor Mario J. Molina Massachusetts Institute of Technology, Cambridge, USA Professor K.C. Nicolaou University of California, San Diego, USA Professor Kurt Wüthrich Institut Fédéral Suisse de Technologie, Zurich, Switzerland Scientiﬁc Secretary Professor Albert Goldbeter Université Libre de Bruxelles, Belgium

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

XXVI

21st Solvay Conference on Chemistry Participants Takuzo

Aida

University of Tokyo, Japan

Harry

Anderson

University of Oxford, UK

R. Dean

Astumian

University of Maine, USA

Vincenzo

Balzani

Università di Bologna, Italy

Paul

Beer

University of Oxford, UK

Albert M.

Brouwer

University of Amsterdam, The Netherlands

Alberto

Credi

Università di Bologna, Italy

Enrico

Dalcanale

Università di Parma, Italy

A. Prasanna

de Silva

Queen’s University Belfast, UK

Luigi

Fabbrizzi

Università di Pavia, Italy

Ben L.

Feringa

University of Groningen, The Netherlands

Graham

Fleming

University of California Berkeley, USA

Makoto

Fujita

University of Tokyo, Japan

Devens

Gust

Arizona State University, USA

Akira

Harada

Osaka University, Japan

Valérie

Heitz

Université de Strasbourg, France

Christopher

Hunter

University of Shefﬁeld, UK

Christian

Joachim

CEMES-CNRS, France

Kimoon

Kim

Pohang University of Sciences and Technology, Korea

Jean-Pierre

Launay

CEMES-CNRS, France

Jean-Marie

Lehn

Université de Strasbourg, France

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

21st Solvay Conference on Chemistry

David A.

Leigh

University of Edinburgh, UK

Henk

Lekkerkerker

Utrecht University, The Netherlands

Josef

Michl

University of Colorado, USA

Ana L.

Moore

Arizona University, USA

Thomas A.

Moore

Arizona University, USA

Roeland

Nolte

University of Nijmegen, The Netherlands

Toriobio F.

Otero

Universidad Politécnica de Cartagena, Spain

Jacques

Prost

Ecole Supérieure de Physique et de Chimie Industrielles (ESPCI)

Kenneth

Raymond

University of California, USA

Julius

Rebek

The Skaggs Institute for Chemical Biology, USA

David N.

Reinhoudt

University of Twente, The Netherlands

Stuart

Rice

University of Chicago, USA

Rolf W.

Saalfrank

Universität Erlangen-Nürnberg, Germany

Jeremy K. M. Sanders

University of Cambridge, UK

Jean-Pierre

Sauvage

Université de Strasbourg, France

Christoph A.

Schalley

Freie Univesität Berlin, Germany

Abraham

Shanzer

Weizmann Institute of Sciences, Israel

Seiji

Shinkai

Kyushu University, Japan

Mitsuhiko

Shionoya

The University of Tokyo, Japan

J. Fraser

Stoddart

University of California, USA

Fritz

Vögtle

Universität Bonn, Germany

Krzysztof

Wozniak

Warsaw University, Poland

XXVII

XXVIII

21st Solvay Conference on Chemistry

Auditors Kristin

Bartik

ULB

Jacques

Reisse

ULB

Davide

Bonifazi

FUNDP

Christian

Hasselt

Steven

De Feyter

KULeuven

Ven den Broeck Vincent

Stéphanie Durot

Stéphane

FUNDP

Strasbourg Scientiﬁc Secretary of the Conference Kritstin Bartik ULB

Pierre

Gaspard

ULB

Paul

Geerlings

VUB

Yves

Geerts

ULB

Johan

Hofkens

KULeuven

Ivan

Jabin

ULB

Alain

Jonas

UCL

Fanny

Kirsch

ULB

René

Lefever

ULB

Paul

Mandel

ULB

Jose

Martins

Ghent

Administrative Secretary of the Conference Dominique Bogaerts Solvay Institutes

Cécile

Moucheron

ULB

Isabelle

Stéphanie

Durot

Strasbourg

Yves

Geerts

ULB

Ivan

Jabin

ULB

Fanny

Kirsch

ULB

Cécile

Moucheron

ULB

Sergey

Sergeyev

ULB

Juif

Solvay Institutes

1

Part One Noncovalent Assemblies: Design and Synthesis

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

3

1 Introduction and Deﬁnition of Noncovalent Assemblies Julius Rebek Jr

It is my very pleasant duty as Session Chairman to open this Solvay Conference on Chemistry and welcome you, the participants, to “Noncovalent Assemblies.” It is not a very pleasant a duty to deﬁne this ﬁeld – after all, every crystal is a selfassembly, every monolayer, membrane, vesicle and micelle is a self-assembly, and every metal–ligand interaction is also a self-assembly. In fact, at some level, every synthesis is a self-assembly. But, unfortunately, as we cannot include them all, some must be excluded. As there is no graceful way to do this, I will deﬁne our work this morning arbitrarily as “ﬁnite systems that persist in solution.” Yet, even that term is unsatisfactory – although crystalline urea-based inclusion compounds and cholic acid complexes have been known for decades, they must persist at some level in solution, even though we are not yet able to analyze them on the timescales and instrumentation available today. Likewise, in this morning’s presentations we can exclude zeolites and the newer Metal Organic Frameworks, even though they demonstrate enviable functions in the solid state. I mention this in an attempt to focus and stimulate discussion on those noncovalent assemblies that do show function. The early solution assemblies which used metal–ligand interactions or hydrogen bonds had no apparent function – they merely ﬁlled space (Figure 1.1). But, we shall see that function arises from the proper ﬁlling of space: we all know that Nature abhors a vacuum, and a price must be paid to create one. Nonetheless, there are rewards waiting for those can who manipulate molecules into ﬁxed spaces. Today, I have invited those who have taken these enormous steps, and many strides beyond the Werner coordination complexes, such that a century later we are aiming at different targets (see Figure 1.2). Parallel developments with hydrogen-bonded systems also moved the focus from space ﬁlling to function;

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

4

1 Introduction and Deﬁnition of Noncovalent Assemblies

O O

N' Zn'

N O

N

N

Zn

X

X

N

N

N

N

X

X

X

N O O n

O O N

N'

N

O

O X

N

O

O

X

N

O

N

N

N

O

N Cu+

O

X

N

O

O

N

X

n = 0, 1, 2, 3; X = H Figure 1.1 Upper section. Left: A catenane self-assembled by Sauvage and coworkers [1], using Cu as a template; Right: A schematic cartoon of a helicate with two Zn metals, as

X

N

N

N

N

X

X

= Cu+ devised by Fuhrhop and colleagues [2] in 1976. Lower section. The self-sorting series of helicates as created by Lehn and Rigault [3], in 1988.

Stabilization of Reactive Species

Raymond (2000) Figure 1.2 Left: Raymond et al.’s [4] capsule represented schematically. A phosphine/ acetone adduct was stabilized inside and isolated from the bulk solvent. More recently, iminimum ion-reactive intermediates have

Fujita (2000) been stabilized in the same capsule. Right: A cartoon of Fujita and colleagues’ [5] “ship-in-a-bottle”-type synthesis of a silanol inside a capsule. Neither encapsulated product is stable outside the capsule.

1 Introduction and Deﬁnition of Noncovalent Assemblies

5

indeed, the melamine/cyanuric acid pattern was tailored for ﬁnite assemblies (see Figure 1.3): O

R''

N

R'' = CH2C6H4C(CH3)3

N R'' R'

Br N N N N

R'

R' = CH2CH2C(CH3)3

N H

O

H O R' N OH

O

N H

H

N N N

N N

H O H H N N N N N

H H H

O N O

H H H

O N O

N N H N H N N

R'

O O

H H

H

N N O

H

N N N

Br R'

R'

Figure 1.3 The melamine/cyanuric acid hydrogen-bonding recognition pattern as adopted by

Seto and Whitesides [6], which creates a 3 : 1 assembly.

and also for rosettes (Figure 1.4):

O

O NH2 N HN

NH2

N

N

N NH

N N

HN

NH

N H

N

O

O O

O

H N

H

+ O

O H

2 O

N

N

N HN

N

H

O

N

O

H

H

N

H

N

O

O

N

O

H

H

O

N

O

H N

H N O N H H H N N

N

HN N OH

N H

O

H

H

H

N

O

N

H

O

H

N

N H

H

N

N H N N

N

H O

O

H N

N

N O

O

O

H

O

N

H

N

H

H N

O

H

N

N

N N

H

O

O O

H

O

Figure 1.4 The melamine/cyanuric acid pattern presented on calixarene platforms as a rosette

discovered by Reinhoudt and coworkers [7], that has encapsulation properties.

H N

O

O

6

1 Introduction and Deﬁnition of Noncovalent Assemblies

while recent activity in the cucurbiturils also warrants discussion (Figure 1.5):

Figure 1.5 Two guests encapsulated in a cucurbit[10]uril by Isaacs et al. [8] (left), and an inverted version by Kim, Isaacs and colleagues [9] (right).

The good news is that I have invited some of the research workers featured above – including Ken Raymond, Kimoon Kim and David Reinhoudt – to highlight their investigations and to stimulate the discussion that will be held during the second half of this session, on noncovalent assemblies. For now, among those who have been invited, the ﬁrst to report their ﬁndings will be Makoto Fujita. So, without any further introduction, let me turn things over to Makoto – if you don’t know who he is, then you have wandered into the wrong hotel room! So, fasten your seatbelts and turn off your cellphones!

References 1 Dietrich-Buchecker, C.O., Sauvage, J.-P., and Kern, J.-M. (1984) J. Am. Chem. Soc., 106, 3043–3045. 2 Struckmeier, G., Thewalt, U., and Fuhrhop, J.H. (1976) J. Am. Chem. Soc., 98, 278. 3 Lehn, J.-M. and Rigault, A. (1988) Angew. Chem., 100, 1121. 4 Dong, V.M., Fiedler, D., Carl, B., Bergman, R.G., and Raymond, K.N. (2006) J. Am. Chem. Soc., 128, 14464. 5 Yoshizawa, M., Kuskawa, T., Fujita, M., and Yamaguchi, K. (2000) J. Am. Chem. Soc., 122, 6311–6312. 6 (a) Seto, C.T. and Whitesides, G.M. (1990) J. Am. Chem. Soc., 112, 6409.

(b) J.P. Mathias, E.E. Simanek, C.T. Seto, G.M. Whitesides, Angew. Chem., 1993, 105, 1848–1850. 7 Kerckhoffs, J.M.C.A., ten Cate, M.G.J., Mateos-Timoneda, M.A., van Leeuwen, F.W.B., Snellink-Ruël, B., Spek, A.L., Kooijman, H., Crego-Calama, M., and Reinhoudt, D.N. (2005) J. Am. Chem. Soc., 127, 12697–12708. 8 Huang, W.-H., Liu, S., Zavalij, P.Y., and Isaacs, L. (2005) J. Am. Chem. Soc., 127, 16798–16799. 9 Isaacs, L., Park, S.-K., Liu, S., Ko, Y.H., Selvapalam, N., Kim, Y., Kim, H., Zavalij, P.Y., Kim, G.-H., Lee, H.-S., and Kim, K. (2005) J. Am. Chem. Soc., 127, 18000–18001.

7

2 Noncovalent Assemblies: Design and Synthesis Report Makoto Fujita and Takashi Murase

2.1 Introduction

The analysis of a keyword search for “self-assembly” using the SciFinder program shows the obvious initiation of this ﬁeld around 1990, and the subsequent remarkable progress which has been made over the past two decades. In 2006, the term “self-assembly” was employed several thousand times each year in scientiﬁc journals (Figure 2.1). Typically, the curved line which reveals the development of a scientiﬁc ﬁeld would be expected to progress along an S-shaped curve, with a clear point of inﬂection. However, it is clear from Figure 2.1 that self-assembly is still a relatively young scientiﬁc ﬁeld that has not yet reached the point of inﬂection, but continues to offer “hot” topics. During the 1980s, the term “self-assembly” was used mainly in biology, to describe the spontaneous generation of biological structures; in this case, it was used, without deﬁnition, as a general rather than a scientiﬁc term. By contrast, in the ﬁeld of chemistry, the term “self-assembled monolayers (SAMs)” [1] was the most frequently used, although the chemistry of SAMs is not related to the synthesis of molecules and materials to any substantial degree. The main driving force of self-assembly is the weak interaction (weak bond) [2]. Although, typically, self-assembly will not occur if the interactions are too weak, a kinetically distributed mixture of products will be formed if the interactions are too strong. In Nature, the self-assembly of various biological structures is induced by the combination of many weak interactions, such as hydrogen bonding, hydrophobic interactions, aromatic interactions, and electrostatic interactions. Inspired by the elegant self-assembly processes conducted by Mother Nature, chemists have designed and achieved the process of “artiﬁcial self-assembly,” where both hydrogen bonds and coordination bonds are utilized as the major driving force. Strangely, although coordination bonds are infrequently used in Nature, they demonstrate a higher modularity in their bond strengths and angles compared to hydrogen bonds. Although, from a conceptual viewpoint, self-assembly covers a very wide range of substances, in this chapter attention will be focused on discrete self-assemblies, From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

2 Noncovalent Assemblies: Design and Synthesis 5539

4528

3695

The frequency of usage

8

3011

“Self-assembly”

2290 1826 1492 1274 884

70 92 96 128 179

221

281

412 498

678

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 Year Figure 2.1 SciFinder search on “self-assembly.”

the chemical structures and solution chemistry of which can be strictly deﬁned. In particularly, two self-assemblies will be investigated – hydrogen-bonded assemblies and coordination assemblies. Unfortunately, due to the limited space available, structurally undeﬁned assemblies such as micelles, vesicles, bilayers, gels, liquid crystals, hydrogen-bonded networks, coordination networks, and surface assemblies will be not discussed at this point.

2.2 Landmarks in Self-Assembly Fields

Several landmarks of the self-assembly ﬁeld can be identiﬁed that date back to the 1980s, with the origins being ascribed to the pioneering studies of Pedersen, Lehn, and Cram on the chemistry of crown and related compounds [3]. In 1981, Ogino reported a self-assembled cyclodextrin rotaxane 1 (Figure 2.2) [4]; in this case, the spontaneous threading of a cyclodextrin on aliphatic diamines, followed by the capping of both strand ends with cobalt (III) stoppers, led to the production of rotaxane 1 in surprisingly efﬁcient fashion. It is remarkable that, rotaxanes which today are situated at the forefront of chemistry, were prepared only by self-assembly during those very early times. The explosive development of the chemistry of catenanes and rotaxanes was triggered in 1983 by the template synthesis of a catenane by Sauvage et al. [5]. In

2.2 Landmarks in Self-Assembly Fields

Figure 2.2 Molecular modeling of cyclodextrin rotaxane 1 [4].

Figure 2.3 Molecular modeling of catenane 2 [5].

this method, the orthogonal assembly of two phenanthroline units around a copper (I) template, followed by ring closure, led to the production of a catenane 2 in very high yields (Figure 2.3). The main scientiﬁc signiﬁcance of these studies, however, was related not only to the ﬁrst high-yield synthesis of catenanes but also to the use of transition metals in prototypical molecular self-assembly processes. The Cu(I)-templated catenane precursor, which was the minimal unit of doublehelical structures, was in fact then extended to di- and trinuclear precursors of a molecular knot, and to a doubly interlocked catenane. In 1986, Maverick reported the details of a macrocyclic compound 3 which incorporated two copper (II) centers within the cyclic framework [6]. This metallomacrocycle showed high binding afﬁnities for diamines such as diazabicyclooctane (Figure 2.4), and was the ﬁrst example of the self-assembly of a synthetic host molecule, despite the basic cyclic framework having been reported some years earlier, in 1984 [7]. In 1987, Lehn’s double-helical Cu(I) complex 4 clearly demonstrated the principle and power of coordination-driven self-assembly, and this in turn had an

9

10

2 Noncovalent Assemblies: Design and Synthesis

Figure 2.4 X-ray crystal structure of macrocyclic compound 3 [6].

Figure 2.5 X-ray crystal structure of double helicate 4 [8].

enormous impact on molecular synthesis (Figure 2.5) [8]. On this basis, Lehn deﬁned the term “self-assembly” in the ﬁeld of chemistry, and distinguished it from “self-organization,” depending on whether the assemblies created showed functions that the individual components did not possess. The term was deﬁned from a synthetic chemistry viewpoint, and was therefore quite different from Nicolis and Prigogine’s concept, which was viewed from a physical chemistry aspect [9]. Both, helical and double-helical coordination assemblies were also investigated by Constable et al. [10]. In 1988, by applying a three-dimensional (3-D) cage framework, Saalfrank et al. described the creation of an M4L6-type coordination assembly 5 that would be formed spontaneously from a di-α-keto acid ligand and a metal ion (Figure 2.6)

2.2 Landmarks in Self-Assembly Fields

Figure 2.6

X-ray crystal structure of M4L6 cage 5 [11].

Figure 2.7 Chemical structure of A3D3 rosette 6 [14].

[11]. The M4L6 cage framework was later expanded by inserting spacers into the ligand [12]. In 1990, Whitesides emphasized that self-assembly represented one of the most efﬁcient methods for the bottom-up construction of nanometer-scale structures [13]. In this case, well-deﬁned structures including A3D3 “rosettes” 6 could be formed spontaneously by utilizing complementary hydrogen-bonding between cyanuric acid and melamine (Figure 2.7) [14]. In 1990, the self-assembly was reported of an M4L4 square complex 7 in which Pd(II) coordination block provided a 90 degree angle at every corner of the square (Figure 2.8) [15]. Since that time, a variety of square structures have been reported

11

12

2 Noncovalent Assemblies: Design and Synthesis

Figure 2.8 X-ray crystal structure of M4L4 square 7 [15].

Figure 2.9 Molecular modeling of hydrogen-bonded assembly of “tennis ball” 8 [16].

where transition metals occupy every corner. The scientiﬁc signiﬁcance of these studies was the ﬁrst demonstration of not only polygon self-assembly but also the function of the metal-containing discrete assembly. Notably, the self-assembled square complex 7 showed a molecular recognition ability for neutral organic molecules in water. In 1993, a cavity that recognizes small guest molecules was also elegantly created by the hydrogen-bonded assembly of the “tennis ball” 8 by Rebek et al. (Figure 2.9) [16]. In this case, complementary amide hydrogen bonds that were previously employed for the assembly of two-dimensional (2-D) architectures were used for an efﬁcient formation of the 3-D assembly. As discussed above, during the 1980s and 1990s both coordination and hydrogen bonds were proven to be powerful driving forces for the self-assembly of welldeﬁned architectures. The data in Figure 2.1 also indicate that these earlier studies triggered an explosive development of molecular self-assembly after 1990. In fact, even during the late 1990s new trends in self-assembly were being developed in a variety of original investigations. In the past, cucurbituril, a classical macrocylic compound, has attracted minimal attention as a synthetic host, mainly because of its poor solubility. However, Kim

2.2 Landmarks in Self-Assembly Fields

O tBuO

N H

O

O

O

12-helix

N H

N H

N H

N H

N H

O

O

O

O

O

O

O tBuO

12

OCH2Ph

N H

N H

N H

N H

N H

N H

N H

O

O

O

O

O

13

N H

14

14-helix

Figure 2.10 X-ray crystal structure of 12- and 14-helical foldamers [19, 20].

et al. were able to solubilize this compound by cation complexation, and to demonstrate its unique binding capabilities [17]. Subsequently, the compound has been used as an essential building block for the self-assembly of many supramolecular structures, such as cyclic and acyclic polyrotaxanes [18]. The concept of foldamers, which are oligomers and polymers that adopt a predictable conformation, was originated by Gellman et al. [19] and Seebach et al. [20]. In particular, Gellman succeeded in preparing the 12- and 14-helix structures from synthetic β-peptides that contained ﬁve- and six-membered rings in the frameworks, via intramolecular hydrogen bonding (Figure 2.10). In 1991, Seeman et al. showed that DNA is not merely a secret of life, but that the prominent characteristic of DNA to form double-helical duplexes could be employed artiﬁcially for the self-assembly of rationally designed nanoscale architectures [21]. A cube and a truncated octahedron were, for example, constructed by the combination of self-assembly and ligation by DNA ligases. These and related studies conducted by Seeman et al. were hugely important in initiating the ﬁeld of DNA nanotechnology. Since the early 1990s, Harada et al. have demonstrated the use of cyclodextrin in the preparation of a variety of polyrotaxanes, in which cyclodextrins are threaded onto polyethylene glycols and related linear polymers [22]. Likewise, the cyclodextrin rings of the polyrotaxanes were linked covalently to form cyclodextrin nanotubes [22b]. Covalent bonds can be also formed in self-assembly, provided that the bond formation is a reversible process. Boronic acid ester formation from diols and boronic acids have been frequently used for covalent self-assembly since Shinkai’s

OCH2Ph

14

2 Noncovalent Assemblies: Design and Synthesis

Figure 2.11 X-ray crystal structure of molecular Borromean ring 9 [26].

initial studies on sugar recognition by a bis(boronic acid) receptor [23]. Sanders et al. showed that even ester formation or S–S bond formation can be used for the thermodynamic formation of guest-templated receptor structures, giving the concept of a dynamic combinatorial chemistry [24]. Schiff-bases (C=N bonds) are also reversible covalent bonds, while C=N bond-based polymer materials have been reported by Lehn et al. [25]. One recent fascinating example of self-assembly exploiting reversible Schiff-base formation was the high-yield preparation of the Borromean ring 9 as reported by Stoddart et al. (Figure 2.11) [26]. Whitesides et al. have demonstrated self-assembly on the millimeter to centimeter scale, by using polygonal plastic pieces made from placing alternative coatings of hydrophobic and hydrophilic compounds onto the lateral faces [27]. When the modiﬁed pieces were ﬂoated on a water–perﬂuoroalkane interface, and shaken moderately, honeycomb structures would be constructed spontaneously due to the lateral hydrophobic interactions. Similarly, two pairs of complementary pieces that mimic DNA base pairs were manufactured. By connecting these pieces, oligonucleotide models were also prepared on the centimeter scale [28]. This result provides a fascinating example of the ability to realize molecular-level phenomena on the macro scale. To summarize, representative studies conducted during the 1990s, when the concept “noncovalent assembly” was ﬁrst established, have been overviewed. It is quite possible that these studies triggered the subsequent boom of self-assembly, although since then hydrogen-bonded and coordination assemblies have made major progress during this decade.

2.3 Hydrogen-Bonded Assemblies

2.3 Hydrogen-Bonded Assemblies

As noted in Section 2.1, this chapter is focused on a system where well-deﬁned and stable structures are self-assembled. Hydrogen bonding is most frequently used as the driving force of self-assembly – as seen in Nature – although the dimerization of carboxylic acids represents a traditional hydrogen-bonded assembly, and there was no concept of self-assembly until the hydrogen-bonded assembly of the “tennis ball” 8 was realized by Rebek et al. in 1993 (see Figure 2.9) [16]. This capsule-like closed structure is composed of two parts of molecules, the shapes of which resemble the leathers of tennis balls. This was the ﬁrst example to show the 3-D construction of a hydrogen-bonded self-assembly. The “tennis ball” compound 8 has subsequently proved to be the origin of a variety of hydrogen-bonded hollow host compounds, such as “soft ball,” which has an expanded cavity [29], a cavitand [30], and a cylindrical capsule [31]. A number of capsule-like molecules have been identiﬁed that are composed of calix[4]resorcinarenes. Kobayashi et al. have demonstrated the creation of a selfassembled dimeric capsule 10 of calix[4]resorcinarene tetracarboxylic acids by employing a bridge formation of two carboxylic acid molecules through four aminopyridines (Figure 2.12) [32]. Huge hollow compounds can be prepared by the elegant design of hydrogenbonding motifs. For example, the calix[4]resorcinarene hexamer 11, as produced by Atwood et al., is the hydrogen-bonded capsule with the largest cavity (Figure 2.13) [33]. The spontaneous assembly of such a huge hollow structure, which is held together by a total of 60 hydrogen bonds, clearly illustrates the power of hydrogen bonding. R

O O

N

H

N

N N

H H

O O

O

H

N

O

O

O

H

N

H O

N

H

N

H H

O O

N

H H N

O O

O H

O

O O

R

O O

O O O H O

H

N

R

R

H O

N H

O O

O O

O

O

R

R

R

R

10 Figure 2.12 X-ray crystal structure of calix[4]resorcinarene dimeric capsule 10 [32].

15

16

2 Noncovalent Assemblies: Design and Synthesis

Figure 2.13 X-ray crystal structure of calix[4]resorcinarene hexameric capsule 11 [33].

Figure 2.14 Molecular modeling of peptide nanotube 12 [37].

Helical structures constructed only by using hydrogen-bonding have also been identiﬁed. For example, in 1994 Hamilton et al. assembled the minimum unit of a partial helical structure using hydrogen-bonding [34]. Artiﬁcial oligopeptides designed by Lehn and Huc et al. represent fascinating compounds that show an interconversion of two states between single and double helices [35]. In this case, a stable double-helical structure at low temperature is changed to an entropically favored monomer structure at high temperature.

2.4 Coordination Assemblies

The main driving force of the secondary structure formation of proteins is the hydrogen bonding between amide bonds [36]. This is actively conducted in the ﬁeld of peptide technology, to prepare unique structures from various artiﬁcial peptides, based on the ability of polypeptides to form self-assembled secondary structures. Ghadiri et al. reported that macrocyclic peptides having alternate arrangements of d- and l-amino acids were able to form cylindrical β-sheet structures that would self-assemble to form peptide nanotube structures 12 (Figure 2.14) [37] that could function as artiﬁcial ion channels by burying themselves into the vesicle membranes. Likewise, Matile et al. reported that oligo(phenylene) rod arrays with oligopeptides at the lateral sides, were able to self-assemble into tube structures, in the same way that β-barrels are created via the formation of β-sheet structures [38]. Moreover, the propensities of the inner and outer surfaces of these pores can be controlled by designing the peptide sequences [39]. In one such example, a functional tube with catalytic activity was prepared by directing the functional groups towards the inner face [40]. More recently, DNA nanotechnology has achieved signiﬁcant progress since the breakthrough in the creation of DNA-nanoachitectures made by Seeman et al. [41]. In an example of this, a nanoscale DNA octahedron was prepared by folding a long, single-stranded DNA, without causing any knotting [41a].

2.4 Coordination Assemblies

Much like hydrogen-bonded assemblies, great advance have been made in the production of coordination assemblies with hollow closed structures. For example, a self-assembled M6L4 octahedral cage 13 was prepared by the complexation of an exo-tridentate triangular ligand, 2,4,6-tris(4-pyridyl)-1,3,5-triazine, and a 90° unit block, [enPd(II)]2+ (Figure 2.15) [42], this being the ﬁrst example of a self-assembled

Pd

12+

N N

N

N

N

N

N

N

Pd

Pd

N N N

N

Pd N

N

N

N

N

Pd

N

N

N N

N

Pd

NH2 H2N Pd

N

N

Pd

12NO3–

13

Figure 2.15 X-ray crystal structure of M6L4 octahedral cage 13 [42].

17

18

2 Noncovalent Assemblies: Design and Synthesis

Figure 2.16 X-ray crystal structure of M4L6 anionic cage 14 [44].

hollow structure with a hydrophobic cavity. The 12+ total charges of the metal centers render the cage 13 highly water-soluble, enabling it to strongly encapsulate neutral organic molecules within the cavity via a hydrophobic interaction in water. As noted below, many novel functions and reactions have been created, based on the high ability of molecular recognition. The 90° end-capping unit, [enPd(II)]2+, is extremely efﬁcient for the discrete self-assembly of several compounds with hollow structures [43]. By combining this metal unit with pyridyl building units, a variety of 3-D structures, such as capsule, tube, bowl, and catenane structures, were quantitatively constructed. An anionic hollow complex 14 with M4L6 composition was designed by Raymond et al. (Figure 2.16) [44], and which was capable of recognizing cationic guests and neutral hydrocarbons in a polar solvent. As shown in hydrogen-bonded assemblies, capsule-like structures can be prepared by the dimerization of either resorcinarene or calixarene units. Recently, Dalcanale et al. [45] and Shinkai et al. [46] have made use of the coordination of Pd(II) ions with cyano and pyridyl groups, respectively. Notably, Shinkai et al. have demonstrated that the self-assembled capsule was encapsulating a C60 fullerene within its cavity [46]. Shionoya et al. have created an artiﬁcial metallo-DNA by the replacement of complementary hydrogen-bonded base pairs in natural DNA with metal complexes (Figure 2.17) [47]. By using a suitable ligand design and sequence program, the Cu(II) and Hg(I) ions can be aligned at will [48]. As the development of reversible bond formation and template synthesis, Sanders et al. proposed the notion of dynamic combinatorial chemistry [26]. In this case, when a guest molecule is added into the system where some host frameworks are at equilibrium, a particular host framework that is interacting with the guest will be assembled selectively and stabilized. Initially, this notion was veriﬁed in a reversible ester reaction [49], but later a prototype of dynamic combinatorial chemistry in self-assembly driven by coordination bonds was achieved (Figure

2.4 Coordination Assemblies

Figure 2.17

Molecular modeling of artiﬁcial metallo-DNA [47, 48].

N H2 ONO2 N Pd N ONO2 H2

+

N

M

M3L2

L

M6L4

N

oligomers

Guest

M3L2

Figure 2.18 Guest-induced dynamic coordination assembly from a Pd capping block and a ﬂexible tridentate ligand [50a].

2.18) [50]. A mixture of many structures can be generated from the complexation of a Pd block and a ﬂexible tridentate ligand. Moreover, addition of the correct guest molecule to this dynamic system will induce self-assembly of the most suitable host structure, and lead to the quantitative formation of the M3L2 cage structure [50a]. Lehn et al. have also demonstrated the similar dynamic self-assembly in the formation of a circular helicate [51], where ﬁve tris(2,2′-bipyridine) ligand strands and ﬁve equivalents of FeCl2 were self-assembled to an M5L5 circular doublehelicate 15 in which a Cl− ion was located at the center (Figure 2.19) [51a]. In the case of SO2− 4 as a counter-anion, an M6L6 circular helicate would be preferentially formed [51b]. The guest molecules are able to select the best host framework from

19

20

2 Noncovalent Assemblies: Design and Synthesis

Figure 2.19 X-ray crystal structure of M5L5 circular helicate 15 [51a].

24

12 Pd2+

Figure 2.20 X-ray crystal structure of furan-based M12L24 spherical complex 16a [57].

an inﬁnite number of MnLn libraries. Some other examples of dynamic selfassembly have been noted which depend on the presence or absence of guests, and also on the stoichiometric ratio of the metal ions and ligands. Examples of these include a cage–helicate structural conversion reported by Raymond et al. [52], and a cage–capsule structural conversion by Shionoya et al. [53]. A huge spherical hollow structure represents one of the most attractive forms among metal-driven self-assemblies. Although the M12L8 complex reported by Robson et al. [54], and the M24L24 complexes reported by Yaghi et al. [55] and Zaworotko et al. [56], are representative spherical cages, their crystal structures were most likely only discussed because of their poor solubility and stability in solution. Subsequently, a self-assembled M12L24 spherical complex 16, that was highly stable in solution, was successfully created – in quantitative fashion – by making use of a kinetically labile Pd(II)–pyridine bond (Figure 2.20) [57]. In this

2.5 Function Through Architecture

case, the symmetry of the M12L24 complex 16 was delineated by a cubo-octahedron, that was formed by truncating each of the eight vertices and 24 equivalent edges triangular faces. The 12 equivalent vertices and 24 equivalent edges of the cubooctahedron could then be superimposed on the 12 Pd(II) centers and 24 bent ligands. The solution structure of the furan-based M12L24 complex 16a, as determined using nuclear magnetic resonance (NMR) and coldspray ionization mass spectrometry (CSI-MS) proved to be in agreement with the crystal structure [57].

2.5 Function Through Architecture

As manifested by DNA and proteins in Nature, their 3-D structures are determined by the molecular sequences, and in turn the structures determine the materials’ biochemical properties and functions. Therefore, it is believed that elaborate designs and the judicious choice of organic small molecules and metal ions will lead to unprecedented architectures and novel properties and functions that cannot otherwise be obtained by using conventional methods. Whilst numerous selfassembled structures have hitherto been reported by many research groups, most of them are structurally unique and fascinating, while their functionalities remain unexplored and unclear. Clearly, the next step of noncovalent self-assemblies seemed to lie in “function thorough architecture.” In 1989, Kato and Fréchet demonstrated a new type of liquid crystalline system 17 through intermolecular hydrogen bonding between pyridine and carboxylic moieties (Figure 2.21) [58]. The 1 : 1 mixture of these two mesogens allowed the formation of a new extended mesogen and mesophase stabilization. At about the same time, Lehn et al. prepared the mesogenic supramolecular species 18 from an equimolar mixture of non-mesogenic complementary compounds, using triple hydrogen bonding (Figure 2.21) [59]. Cavity-directed chemical transformations represent one of the most important features of 3-D hosts. In 1997, pioneering investigations of these reactions were conducted by Rebek et al., who employed the hydrogen-bonded “soft ball” as a microreactor and achieved a 200-fold acceleration of a Diels–Alder reaction by encapsulating the reactants within the cavity (Figure 2.22) [60]. This rate

Figure 2.21 Chemical structures of hydrogen-bonded liquid crystals 17, 18 [58, 59].

21

22

2 Noncovalent Assemblies: Design and Synthesis

Figure 2.22 Acceleration of a Diels–Alder reaction within the hydrogen-bonded “soft ball”

[60].

Figure 2.23 Pairwise selective recognition of guest molecules in a cylindrical capsule [31].

enhancement was ascribed to the effective concentration of the reactants and their close proximity inside the capsule. The pairwise selective recognition of guest molecules is a useful method because it brings about selective reactions and allows the orientation of substrates to be controlled, depending on the cavity involved. As an example, one benzene molecule and one xylene molecule were preferentially encapsulated together in pairs within a cylindrical capsule of hydrogen-bonded dimer (Figure 2.23) [31]. Such encapsulation led to an acceleration of the 1,3-dipolar cycloaddition between phenylacetylene and phenyl azide. Synthetic receptors based on resorcinarene units have been widely used by Rebek et al. to conduct cavity-directed and unique chemical reactions. For example, an alkane molecule was folded within a hydrophobic cavitand in water [61], while

2.5 Function Through Architecture

a labile hemiacetal intermediate was stabilized and observed in a cavitand that had an inwardly directed aldehyde moiety on the rim [62]. Coordination assemblies also demonstrate unique properties and functions through their architectures. For example, Raymond et al. described the M4L6 anionic host complex 14 which, in water, would efﬁciently trap and stabilize reactive guests which included a tropylium cation [63], phosphine-acetone adducts [64], iminium cations [65], and organometallic intermediates [66]. Moreover, guest encapsulation within a self-assembled cage can have a dramatic effect on the properties of the entrapped guest. For example, the anionic host 14 favors protonated species over neutral species on encapsulation, yet when a protonated amine is stabilized in the host 14 it becomes more basic than when in free solution. Based on this phenomenon, Raymond et al. have demonstrated that the anionic host 14 enables the protonation of orthoformate, HC(OR)3 (R: alkyl or aryl group), even in basic solution, and also catalyzes the hydrolysis reaction (Figure 2.24) [67].

H2O HC(OR)3

+ HC(OR)3

OH–

OR + RO

H OR

H 14

H2O + OH H

OR 2 ROH

+ OH H

OR

+ 2 RO– – H 2O

O ROH

+ H

O–

Figure 2.24 Acid-catalytic orthoformate hydrolysis in basic solution in the presence of the anionic host 14 [67].

23

24

2 Noncovalent Assemblies: Design and Synthesis

As shown in the above examples, cavities isolated from the exterior by the frameworks of complexes offer an unusual chemical environment that differs from the solution state and may serve as a unique reaction space. It was found that the coordination cage 13 would demonstrate both stereo- and regiocontrol of the intermolecular [2+2] photodimerizations of oleﬁns, as well as accelerating the reactions [68]. These ﬁndings indicate that the orientation of the encapsulated molecules is being strictly controlled, depending on 3-D shapes of the cavities. In 2006, it was found that the M6L4 cage 13 could induce highly unusual regioselectivity and stereoselectivity in the Diels–Alder reaction of anthracene and maleimide guests, and would provide exo-selective syn adduct bridging at a terminal (1,4-position) rather than at a central (9,10-position) anthracene ring (Figure 2.25) [69]. The unusual 1,4-adduct that formed resulted from the geometric con-

Figure 2.25 Unusual Diels–Alder reaction of anthracene and maleimide guests within the

cage 13 [69].

2.5 Function Through Architecture

straint of the guests within the cage 13 before the reaction. This was the ﬁrst example of a cavity-directed unusual chemical reaction. Subsequently, a similar bowl-shaped host was shown to efﬁciently catalyze the usual Diels–Alder reactions of a variety of anthracene and maleimide derivatives. In situ X-ray crystallography provides a powerful means of determining the unambiguous structure of a reactive unstable intermediate. Within the cavity of M6L4 cage 13, stable Cp′Mn(CO)3 (Cp′ = methylcyclopentadienyl) released one CO molecule upon photoirradiation in the crystalline state, to generate Cp′Mn(CO)2 (Figure 2.26) [70]. This proved clearly that the geometry of the coordinatively unsaturated Cp′Mn(CO)2 was a pyramidal structure. The complexation of two 2,4,6-tris(4-pyridyl)-1,3,5-triazine and three 4,4′bipyridine ligands with six 90° end-capping [enPd(II)]2+ units yields a prism-like pillared cage 19 (Figure 2.27) [71] which can accommodate two planar guest molecules, in a stacked manner. The room-temperature and solution-state observation (a)

(b)

pyramidal structure

CO

Figure 2.26 Direct crystallographic observation of the coordinatively unsaturated Cp′Mn(CO)2 within the cage 13. X-ray crystal structures: (a) before and (b) after ultraviolet (UV) light irradiation at 100 K [70].

N

Pd

N

2

N

Pd N N

3

N N

N

N

N

12+

N

N

N

N

N Pd N

N

Pd

N

NH2

6

H2N Pd ONO2

Pd

N Pd N

ONO2

Figure 2.27 Self-assembly of a prism-like pillared cage 19 [71].

N

N

19

N

N N

Pd

12NO3–

25

26

2 Noncovalent Assemblies: Design and Synthesis

24 12 Pd2+ R' X N

X

: none,

X R

N

,

16 Figure 2.28 Self-assembly of M12L24 complex 16 with 24 peripheral and endohedral functional groups [57, 76].

of the mixed-valence state of a radical dimer cation [(TTF)2]+•, which is not commonly detected, proved to be successful [72]. A metal–metal d–d interaction through the discrete stacking of MII(acac)2 (where M = Pt, Pd, Cu) was clearly demonstrated within the complex 19 [73]. Large planar aromatic molecules such as porphines may also be encapsulated by using host–guest π-stacking interactions. The dimeric assembly of CuII-porphine molecules within the cage 19 induced intermolecular spin–spin exchange interactions (triplet state, S = 1) [74]. The number of stacking planar molecules can be ﬁnely controlled by the length of the aromatic pillars. M12L24 molecular spheres 16 are versatile scaffolds that can be used for a precise functionalization. The attachment of a functional group to the convex or concave side of each ligand leads to a 24-fold peripheral or endohedral functionalization of the sphere 16, respectively (Figure 2.28). In fact, it was shown that large functional groups, such as fullerene [57], porphyrin [57], and oligosaccharide [75], could be introduced on the surface of the M12L24 complex 16. Notably, the clustered oligosaccharides were seen to be effectively bound to lectins which recognized the conformation of the saccharides [75]. An acetylene spacer is indispensable for the endohedral functionalization of M12L24 complex 16 [76]. A “pseudo-nanoparticle” of poly(ethylene oxide) (PEO) with a total of 120 (= 5 × 24) ether oxygen donor atoms can show a reversible uptake of metal ions [76]. Consequently, an efﬁcient capsule polymerization was demonstrated where 24 methyl methacrylate units were concentrated at the core of the complex 16 [77]. In an amino acid-containing capsule, the chilarity of each amino acid was transferred to the spherical shell that, in itself, had no asymmetric points [78].

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O Pd

N

N

Pd

F2C CF2 F2C CF2 F2C CF3 16b Figure 2.29 Molecular drawing of ﬂuorous sphere 16b prepared by combining the X-ray

crystal structure of the shell framework and the optimized C6F13(CH2)2 – side chains. The side chains are depicted as CPK representation [79].

In 2006, a distinct endoﬂuorous environment was created in an M12L24 spherical complex 16 where 24 perﬂuoroalkyl chains resided (Figure 2.29) [79]. The ﬂuorous core of complex 16b is able to take up perﬂuoroalkane guest molecules, depending on the length of the perﬂuoroalkyl chain that is introduced. A subsequent X-ray crystallographic analysis revealed the rigid shell framework and amorphous interior to closely resemble a “raw egg,” where the ﬂuorinated segments were able to furnish a ﬂuid-like or “nanodroplet” environment in the complex 16b.

2.6 Conclusions

The well-deﬁned self-assembly of small molecules using noncovalent interactions represents an easier and more efﬁcient approach than the direct synthesis of a similar covalent structure. The self-assembly of molecules is a ubiquitous strategy for the creation of functional assemblages in Nature. For example, a highly symmetrical virus capsid is in fact an assembly of asymmetric protein subunits that have been folded to speciﬁc conformations and show functionalities that depend on those conformations. In this context, Nature sets good examples from which scientists can learn valuable lessons. Clearly, “self-assembly” is a keyword for the new design, synthesis, and function of a molecule.

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2 Noncovalent Assemblies: Design and Synthesis 59 Brienne, M.-J., Gabard, J., Lehn, J.-M., and Stibor, I. (1989) J. Chem. Soc., Chem. Commun, 1868–1870. 60 Kang, J. and Rebek, J., Jr (1997) Nature, 385, 50–52. 61 Trembleau, L. and Rebek, J., Jr (2003) Science, 301, 1219–1220. 62 Iwasawa, T., Hooley, R.J., and Rebek, J., Jr (2007) Science, 317, 493–496. 63 Brumaghim, J.L., Michels, M., Pagliero, D., and Raymond, K.N. (2004) Eur. J. Org. Chem., 22, 5115–5118. 64 Brumaghim, J.L., Michels, M., and Raymond, K.N. (2004) Eur. J. Org. Chem., 22, 4552–4559. 65 Dong, V.M., Fiedler, D., Carl, B., Bergman, R.G., and Raymond, K.N. (2006) J. Am. Chem. Soc., 128, 14464–14465. 66 Fiedler, D., Bergman, R.G., and Raymond, K.N. (2006) Angew. Chem. Int. Ed., 45, 745–748. 67 Pluth, M.D., Bergman, R.G., and Raymond, K.N. (2007) Science, 316, 85–88. 68 (a) Yoshizawa, M., Takeyama, Y., Kusukawa, T., and Fujita, M. (2002) Angew. Chem. Int. Ed., 41, 1347–1349; (b) Yoshizawa, M., Takeyama, Y., Okano, T., and Fujita, M. (2003) J. Am. Chem. Soc., 125, 3243–3247. 69 Yoshizawa, M., Tamura, M., and Fujita, M. (2006) Science, 312, 251–254.

70 Kawano, M., Kobayashi, Y., Ozeki, T., and Fujita, M. (2006) J. Am. Chem. Soc., 128, 6558–6559. 71 Yoshizawa, M., Nakagawa, J., Kumazawa, K., Nagao, M., Kawano, M., Ozeki, T., and Fujita, M. (2005) Angew. Chem. Int. Ed., 44, 1810–1813. 72 Yoshizawa, M., Kumazawa, K., and Fujita, M. (2005) J. Am. Chem. Soc., 127, 13456–13457. 73 Yoshizawa, M., Ono, K., Kumazawa, K., Kato, T., and Fujita, M. (2005) J. Am. Chem. Soc., 127, 10800–10801. 74 Ono, K., Yoshizawa, M., Kato, T., Watanabe, K., and Fujita, M. (2007) Angew. Chem. Int. Ed., 46, 1803–1806. 75 Kamiya, N., Tominaga, M., Sato, S., and Fujita, M. (2007) J. Am. Chem. Soc., 129, 3816–3817. 76 Tominaga, M., Suzuki, K., Murase, T., and Fujita, M. (2005) J. Am. Chem. Soc., 127, 11950–11951. 77 Murase, T., Sato, S., and Fujita, M. (2007) Angew. Chem. Int. Ed., 46, 1083–1085. 78 Suzuki, K., Kawano, M., Sato, S., and Fujita, M. (2007) J. Am. Chem. Soc., 129, 10652–10653. 79 Sato, S., Iida, J., Suzuki, K., Kawano, M., Ozeki, T., and Fujita, M. (2006) Science, 313, 1273–1276.

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3 Discussion 1.A Discussion on the Report by M. Fujita Chairman: Julius Rebek Jr

Chairman: Thank you so much, Professor Fujita. Your abilities to do justice to this ﬁeld are very much appreciated and admired. Professor Fujita’s report is now open for discussion. Do we have any questions? J.-P. Sauvage: That was a great lecture. I have a quick question on the CF2 containing cages. When you have many CF2 groups inside, did you try to dissolve dioxygen? M. Fujita: We want to try that, but unfortunately we have not yet done so. It is very challenging, but we would like to incorporate the oxidation catalyst to promote the oxidation with molecular oxygen. J.-P. Sauvage: My point was related to artiﬁcial blood. Correlated molecules have a certain afﬁnity for O2, and it has been suggested that they can be used to make artiﬁcial blood. In fact, I think it is already used in some parts of the world – perhaps you could have just a tiny droplet of artiﬁcial blood. M. Fujita: Yes, that’s a fantastic idea. R. Nolte: I am not sure if we should start this discussion now, but ﬁrst I must thank you very much for the really beautiful lecture – it was a great overview. What I perhaps missed is the link with the metal–organic frameworks, which are currently receiving so much attention and for which so many possible applications can be foreseen. I am not sure whether you left those out deliberately, or you don’t see any future for them. Or is this something that will be mentioned in the next part of the conference? M. Fujita: The applications of what? R. Nolte: Of the metal–organic frameworks, which are of course different from your beautiful applications, but are receiving much attention in the journals Nature and Science. You didn’t discuss those in your lecture.

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

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3 Discussion 1.A

M. Fujita: Yes, indeed, much work has been devoted to these structures, such as self-assemblies. However, they are not discrete structures and I could not include the inﬁnite systems in my talk. But that’s another very interesting story. R. Nolte: Thank you. Chairman: Yes, when talking about discrete systems that have ﬁnite lifetimes in solution, that is an arbitrary deﬁnition of self-assembly, but it was chosen to focus the discussion. The original host and guest labels were applied by Louis Fieser to the cholic acid–organic complexes in 1950.1 Eight cholic acids dissolve in water, and dissolve one molecule of naphthalene. However, at least on the arbitrary timescales that we can use to characterize these things, they are not discrete assemblies, they are too dynamic. One day, by using faster spectroscopic techniques, they may be deﬁned as ﬁnite structures. Likewise, the inﬁnite structures of the solid state are really beyond this scope, but you can certainly ask questions about them. They have enormous functions. This is also the case for zeolites, but they are not represented here today. Are there any other questions? E. Dalcanale: I would like to identify with something that Roeland Nolte said. One interesting option for self-assembly is to attach discrete molecules on surfaces in a very high-ﬁdelity way, if you can apply such a term. That might also be a point of discussion, to see how the catalysis can be also transferred on heterogeneous systems, and which could prove to be even more useful. M. Fujita: The reason that I focused only on discrete systems is because we can design and synthesize them. With regards to the surface assemblies or crystalline assemblies, it is very difﬁcult to design the assembly structures, and therefore I would like to focus on molecular chemistry. That’s the reason why I focused on discrete systems, but of course, surface assembly has yielded much excellent information. D.N. Reinhoudt: I have a question about principles. Self-assembly, as you presented it, always seems to give thermodynamical equilibrium conditions. There is basically no fundamental difference between covalent and noncovalent chemistry, it all depends on kinetic barriers. Have you any experience with discrete assembly formation under kinetic control? M. Fujita: That is a very interesting topic in self-assemblies. In my group, we have some results on kinetic self-assembly, and by using relatively inert chemical metal interactions, we can trap the intermediate during the self-assembly processes. To answer your question, I think that some groups have reported kinetic selfassemblies. In protein self-assemblies, proteins are also considered to assemble through kinetic pathways. Indeed, it is a very interesting topic in this ﬁeld. K. Raymond: A slightly different topic – C60 is a supermolecular species, I would say, at 3000 K, and it’s a question of where you have dynamic equilibrium. My 1) Fieser, L.F. and Rajagopalan, S. (1950) J. Am. Chem. Soc., 72, 5530.

3 Discussion 1.A

second comment concerns topics such as crystal habit and crystal growth – these are essentially kinetic phenomena, so that in different solvents there will be different appearances because the rate of deposition on the surface is different – one develops and one doesn’t. I am not sure whether that is within the scope of this meeting, but those are self-assembly issues. M. Fujita: I agree with you. Fullerene is a good example of kinetic self-assembly. D.N. Reinhoudt: Of course, we are talking about the conditions under which organic molecules exist and we can do self-assembly. One point that has bothered me for some time is whether, in supramolecular chemistry, we always go for thermodynamic equilibrium and we always present it as an advantage. But it is also a limitation, of course, and that’s why I brought the subject up. S. Shinkai: Simply said, in this chemistry there are two aspects: one concerns individual component structures, and the other concerns the resulting size of the assembly. You raised many examples of structure-dependent functions, but there are very few examples available of size-dependent functions. In Nature, many functions are correlated with the size of the assembly or the particle; for example, a virus must be of a speciﬁc size in order to show its original function. Are there any examples of size dependence of this sort in your system? M. Fujita: In recent examples of self-assemblies, the assembled size covers a large range. Concerning the discrete systems, their size ranges from one to several nanometers, so there is no major difference. If I were to include more ambiguous assemblies, there would be more room for discussion, but when it comes to discrete systems there are no real differences, and I cannot recognize any signiﬁcant size effects. Would anyone else have an opinion on this? S. Shinkai: Maybe we could add something more to this system? Chairman: Many of the people mentioned in Professor Fujita’s lecture today are here to speak for themselves. I am pleased to say that four of them will give brief presentations after the coffee break, and will get a chance to say these things in their own words. So, before we break off, please join me in thanking Makoto Fujita once again for his brilliant lecture.

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4 Noncovalent Synthesis of Molecular Receptors Prepared Comment David N. Reinhoudt

4.1 Introduction

In Nature, noncovalent interactions between molecules are essential to create structure and function. The increasing awareness of chemists of the importance of noncovalent interactions in Nature has led to a paradigm shift in organic chemistry. It was realized during the early 1990s that the rational design and synthesis of molecular receptor molecules for guest species, which was more complex than that of simple cations and ions, was hardly successful [1]. Hence, the carefully planned and executed covalent synthesis of molecular receptors led to molecules that had a perfectly preorganized cavity but did not complex with the steroid molecule for which they were designed (Figure 4.1).

R

O O O O O

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H

H

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O O

H H

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O

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O

O

O

ON

N H O O O O O

R

O O H O O O OO

R

R

O N

H

R

Figure 4.1 A molecular receptor for steroids [1].

4.2 Noncovalent Synthesis

As an alternative, a strategy was focused on the assembly of receptors from small building blocks that were composed of relatively simple molecules that carried From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

4 Noncovalent Synthesis of Molecular Receptors

36

O

O

O O O

O

O

CDCl3 toluene benzene

O

O

O

O

O

O

O

O

O

O

O

O

O

O

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O

O

O

O

O O

O O

O

O

O

O

36 H-bonds -

O

O

diss. < 10-4 M

Figure 4.2 Assembly of a double rosette.

the structural information to be assembled into deﬁned supramolecular structures [2, 3]. H-bonding was selected to carry this structural information in barbiturates (or cyanurates) and melamines. The complementarity of the six H-bond donors and acceptors led to a so-called “rosette motif” in which three molecules of each were assembled into a hexagon. As H-bonds are generally weak, multivalency was required to achieve thermodynamic stability. For example, whereas single rosettes, having 18 H-bonds, dissociate at room temperature in chloroform below 10−2 M, double rosettes are much more stable [4] (Figure 4.2). The structure of these double rosettes was characterized using 1H NMR, Ag+-assisted mass spectrometry (MS) and X-ray analysis [5] (Figure 4.3). It has been shown that chirality in the components controls the topological chirality of the assembly. Either one chiral center in the barbiturates (or the cyanurates) or two chiral centers in the calix[4]arene bismelamines (see Figure 4.2) allows a complete control of the P or M chirality in the assembly [6]. These double rosettes can either function as either exo or endo receptors. When the double rosettes have ureido functionalities both at the top and the bottom of the double rosettes, they are capable of complexing acidic phenols. Both, 1H NMR titrations and Ag+-assisted MS have been used to verify the structure as 6 : 1 complexes [7]. When aromatic guests with acidic phenol functions such as alizirin were added to the double rosettes, the latter behaved as endo receptors, with three molecules forming a trimer that was not present in detectable concentrations in chloroform,

4.2 Noncovalent Synthesis a

b O

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e

f

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OO O

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N

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5000

H

H

H N

N N

N

N N

H N H

N H H

0 1000

2000

3000

4000

5000

6000

7000 m/z

Figure 4.3 Characterization of double rosettes.

but rather was encapsulated in the cavity that was formed in the double rosette which then changed from a staggered to a symmetrically eclipsed structure. The structure of the assembly, which brought together 3 + 3 + 6 different molecules in a completely stereochemically deﬁned manner, was proven using 1H NMR spectroscopy and X-ray analysis [8] (Figure 4.4). Upon the addition of butylcyanurate to the complex, the barbiturates were replaced by the cyanurate, and this in turn led to release of the encapsulated guest [9] (Figure 4.5). Extensive investigations have been conducted to determine how the binding in these noncovalent receptors could be optimized, and for this purpose libraries of double rosettes and alizarin derivatives have been assembled [10] Combinatorial chemistry represents a very efﬁcient way by which to optimize host–guest interactions, an example being to identify the most potent inhibitor of an enzyme function. In supramolecular chemistry, virtual libraries can be generated simply by mixing components. About ten years ago, the present author’s group showed that, in H-bonded assemblies, the binding of guests could be optimized by adding guest molecules to a mixture of functional double rosettes [11]. Moreover, as H-bonding would lead to kinetically labile assemblies, all equilibria would be formed instantaneously. The same strategy has since been applied to optimize the binding of alizarins [12]. Clearly, during the past 40 years, supramolecular chemistry has developed from a structural role to a functional role [13].

8000

38

4 Noncovalent Synthesis of Molecular Receptors

Figure 4.4 X-ray structures of a double rosette (left) and its alizarin complex (right).

H-bonded OH (alizarin) RR

6

RR

R

R

BuCYA

R

R

RR

R

+ 3

Free OH

complex

R

15

14

13

12

11

10 δ (ppm)

+ 6 DEB

Figure 4.5 Release of alizarin from the complex.

4.3 Supramolecular Chirality

One aspect which deserves a more detailed discussion is the extremely important role of chirality in these complex self-assembly processes [14]. Self-assembly plays an important role in the formation of many (chiral) biological structures, such as DNA, and the α-helices or β-sheets of proteins. More recently, this process has also begun to play a signiﬁcant role in nanotechnology, to construct functional structures of nanometer dimensions. The control of chirality in synthetic selfassembled systems is very important, an example being to mimic the catalytic

4.3 Supramolecular Chirality

Figure 4.6 Different stereomeric double rosettes.

activity of enzymes. As noted brieﬂy above, it was found that these double rosette assemblies represented the perfect example of chirality control in self-assembly. The calix[4]arene bismelamines (Figure 4.6) can assemble from either the staggered or the eclipsed conformation, leading to three different diastereoisomers D3, C3h, and Cs. As the D3 conformer has no elements of symmetry, it is formed as a mixture of two enantiomers [15]. Thus, when a chiral center is present in either the calyx[4]arene bismelamine or the barbiturate, one diastereoisomeric assembly is formed in excess. The diastereoisomeric excess (d.e.) values will be small in the case of barbiturates, but very large in the case of chiral cyanurates. Moreover, the d.e.-values are strongly solvent-dependent, with the largest values being found in apolar solvents such as toluene. As cyanurates can replace the barbiturates in these assemblies (simply because the H-bonds are weaker with barbiturates), it was possible to replace chiral barbiturates with nonchiral cyanurates, thereby converting the diastereoisomers into enantiomers. The ﬁrst example of an enantiomerically pure H-bonded supramolecular system was obtained in this way [16]. Notably, the rate of racemization was slow at room temperature, and could be determined quantitatively by measuring the decrease in optical activity as a function of time and temperature. In more complex tetrarosettes, where the assembly is held together by 72 rather than 36 H-bonds, the rate of racemization was much slower and the assemblies behaved as “covalent” enantiomers at room temperature in solution.

39

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4 Noncovalent Synthesis of Molecular Receptors

The fundamental difference between a “covalent” compound and these supramolecular assemblies is that, in the former case, the atoms are linked by permanent covalent bonds, whereas in supramolecular assemblies the component molecules may be exchanged. The rate of such exchange is determined by the activation energy required to rupture the H-bonds in the system, while the amount of energy required will depend on how many H-bonds must be broken. In the case of double rosettes, the barbiturates (or cyanurates) will form six H-bonds, whereas the calix[4]arene bismelamines will dissociate only after the cleavage of 12 H-bonds. It is the H-bond cleavage that always serves as the rate-determining step for racemization.

4.4 Optical Ampliﬁcation in Dynamic Supramolecular Systems

The dynamic nature of the double rosette assemblies leads to them serving as ideal models for chiral systems that are in a non-equilibrium state [17]. For example, when the P- and M-enantiomers of the same components (barbiturates and chiral bismelamines) were mixed, it was found that they would mix without exchanging the chiral bismelamines; in other words, the R,R,R- and S,S,S-enantiomers were present, but not a mixed diastereoisomer. On mixing, the optical activity was seen to decrease from 100% for the pure R,R,R (or S,S,S) -enantiomer to 0% for the 1 : 1 mixture (Figure 4.7), and in this sense the enantiomers were considered to be behaving as covalent enantiomeric molecules.

Figure 4.7 Complete enantioselective self-resolution of chiral rosettes.

Acknowledgments

Figure 4.8 Chiral ampliﬁcation in mixtures of chiral and achiral rosettes under

thermodynamic equilibrium.

Yet, the dynamic nature of these assemblies allows for their mixing. For example, when chiral rosettes (in which chirality had resulted from the barbiturates) and chiral (racemic) rosettes in different ratios were mixed, the optical activity of the mixture was reduced from 100 to 0%. However, the reduction did not occur in a linear fashion (Figure 4.8), and in all cases the optical activity of the mixture was higher than would be expected on the basis of the chiral content of the components. This result has been elucidated on the basis of the “sergeant and soldiers principle,” in that once a chiral center is present in the rosette, a difference in energy will exist between the two diasteriomeric P- and M-helices. This explains why a more than proportional chirality results in the mixture [14]. The situation becomes even more complex when the chirality originates from chiral cyanurates. As the kinetic stability of cyanurate-based rosettes is much higher, mixing and racemization take place much more slowly than in the case of barbiturates, and this results in a much higher than expected chiral content of the mixtures. These processes have been described in a quantitative model, in which the most important parameters are the rates of dissociation of the components of the rosette [17].

Acknowledgments

The author is very grateful for the crucial contributions made to these studies by his former colleagues Dr M. Crego Calama and Prof. P. Timmerman, and all of the former group members who are mentioned in the references.

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References 1 Timmerman, P., Verboom, W., Van Veggel, F.C.J.M., Van Hoorn, W.P., and Reinhoudt, D.N. (1994) An organic molecule with a rigid cavity of nanosize dimensions. Angew. Chem. Int. Ed. Engl., 33, 1292–1295. 2 Vreekamp, R.H., Van Duynhoven, J.P.M., Hubert, M., Verboom, W., and Reinhoudt, D.N. (1996) Molecular boxes based on calix[4]arene double rosettes. Angew. Chem. Int. Ed. Engl., 35, 1215–1218. 3 Reinhoudt, D.N., Stoddart, J.F., and Ungaro, R. (1998) Supramolecular science. Where it is and where it is going. Chem. Eur. J., 4, 1349–1351. 4 Prins, L.J., Reinhoudt, D.N., and Timmerman, P. (2001) Noncovalent synthesis using hydrogen bonding. Angew. Chem. Int. Ed., 40, 2382–2426. 5 Timmerman, P., Jolliffe, K.A., Crego Calama, M., Weidmann, J.-L., Prins, L.J., Cardullo, F., Snellink-Ruël, B.H.M., Fokkens, R.H., Nibbering, N.M.M., Shinkai, S., and Reinhoudt, D.N. (2000) Ag+ labeling: a convenient new tool for the characterization of hydrogen-bonded supramolecular assemblies by MALDITOF mass spectrometry. Chem. Eur. J., 6, 4104–4115. 6 Prins, L.J., De Jong, F., Timmerman, P., and Reinhoudt, D.N. (2000) An enantiomerically pure hydrogen-bonded assembly. Nature, 408, 181–184. 7 Kerckhoffs, J.M.C.A., Ishi-I, T., Parachiv, V., Timmerman, P., Crego-Calama, M., Shinkai, S., and Reinhoudt, D.N. (2003) Complexation of phenolic guests by endo- and exo-hydrogen-bonded receptors. Org. Biomol. Chem., 1, 2596–2603. 8 Kerckhoffs, J.M.C., Van Leeuwen, F.W.B., Spek, A.L., Kooijman, H., Crego Calama, M., and Reinhoudt, D.N. (2003) Regulatory strategies in the complexation and release of a noncovalent guest trimer by a self-assembled molecular cage. Angew. Chem. Int. Ed., 42, 5717–5722. 9 Mateos Timoneda, M.A., Kerckhoffs, J.M.C.A., Crego Calama, M., and Reinhoudt, D.N. (2005) Ditopic

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complexation and release of neutral guest molecules by a hydrogen-bonded “endo-exo” receptor. Angew. Chem. Int. Ed., 44, 3248–3253. Crego Calama, M., Hulst, R., Fokkens, R., Nibbering, N.M.M., Timmerman, P., and Reinhoudt, D.N. (1998) Libraries of non-covalent hydrogen-bonded assemblies; combinatorial synthesis of supramolecular systems. Chem. Commun., 1021–1022. Kerckhoffs, J.M.C.A., ten Cate, M.G.J., Mateos-Timoneda, M.A., Van Leeuwen, W.B.F., Snellink-Ruël, B., Spek, A.L., Kooijman, H., Crego-Calama, M., and Reinhoudt, D.N. (2005) Selective self-organization of guest molecules in self-assembled molecular boxes. J. Am. Chem. Soc., 127, 12697–12708. Kerckhoffs, J.M.C.A., Mateos Timoneda, M.A., Reinhoudt, D.N., and Crego Calama, M. (2007) Dynamic combinatorial libraries based on hydrogen-bonded molecular boxes. Chem. Eur. J., 13, 2377–2385. Funeriu, D.P. (2005) Angew. Chem. Int. Ed., 44, 6442. Mateos-Timoneda, M.A., Crego-Calama, M., and Reinhoudt, D.N. (2004) Supramolecular chirality of selfassembled systems in solution. Chem. Soc. Rev., 33, 363–372. Prins, L.J., Jolliffe, K.A., Hulst, R., Timmerman, P., and Reinhoudt, D.N. (2000) Control of structural isomerism in noncovalent hydrogen-bonded assemblies using peripheral chiral information. J. Am. Chem. Soc., 122, 3617–3627. Prins, L.J., Huskens, J., De Jong, F., Timmerman, P., and Reinhoudt, D.N. (1999) Complete asymmetric chirality in a hydrogen-bonded assembly. Nature, 398, 498–502. Prins, L.J., Timmerman, P., and Reinhoudt, D.N. (2001) Ampliﬁcation of chirality: the “sergeants and soldiers” principle applied to dynamic hydrogenbonded assemblies. J. Am. Chem. Soc., 123, 10153–10163.

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5 Cucurbiturils: New Players in Noncovalent Assembly Prepared Comment Kimoon Kim

In the recent past, macrocycles have greatly contributed to the development of supramolecular chemistry, with crown ethers, cyclodextrins and calixarenes representing three major classes of macrocycles to be used extensively as key components in both noncovalent self-assembly processes and molecular recognition. Recently, however, a new class of macrocycles – the cucurbiturils – has added an exciting new dimension to this ﬁeld. Brief details of the cucurbiturils will be provided in the following sections, in addition to information relating to the noncovalent assemblies that may be built with these materials. The cucurbit[n]urils (CB[n]), a family of macrocyclic compounds that comprise n glycoluril units, are self-assembled via the acid-catalyzed condensation reaction of glycoluril and formaldehyde (Figure 5.1). Although the synthesis of the parent compound, CB[6] was ﬁrst reported by Behrend et al. in 1905 [1], its chemical nature and structure remained unknown until 1981, when a full characterization was reported by Mock and co-workers [2]. The pumpkin-shaped CB[6] molecule has a hydrophobic cavity and two identical carbonyl-laced portals. When extensive studies were conducted by Mock and others on the host–guest behavior of CB[6] [3], the hydrophobic interior was shown to provide a potential inclusion site for nonpolar molecules, while the polar ureido carbonyl groups at the portals allowed CB[6] to bind ions and molecules through charge–dipole and hydrogen-bonding interactions. The unique structure and recognition properties of CB[6] make it attractive not only as a synthetic receptor, but also as a building block for the construction of supramolecular architectures. Subsequently, a wide variety of supramolecular species, including rotaxanes, catenanes, and molecular machines incorporating CB[6], have been reported [4]. In 2000, the discovery was reported of other members of the CB family, CB[n] (where n = 5–11) and the successful isolation of CB[n] (n = 5, 7, and 8) [5], and this has broadened the scope of CB chemistry enormously. Within a few years, the host–guest chemistry of the CBs, as well as the novel supramolecular assemblies built with CB[n] have been extensively studied by the present authors and others [6, 7]. In particular, the discovery of the formation of a stable charge-transfer (CT) complex inside CB[8] [8] led to the building of a number of supramolecular From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

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5 Cucurbiturils: New Players in Noncovalent Assembly (a)

(b) O N

N

R

CH2

R

N

N O

CH2 n

Figure 5.1 (a) Structural formula of CB[n] (n = 5–10); (b) X-ray crystal structure of CB[8].

Figure 5.2 Supramolecular assemblies built with CB[8]-stabilized charge-transfer interactions [9].

assemblies based on this chemistry. The CB[8]-stabilized CT complexes proved to be thermodynamically stable, but could be readily disassembled into their components when treated with redox stimuli. The high thermodynamic stability of the CB[8]-stabilized CT interactions allowed various supramolecular assemblies to be built, ranging from molecular necklaces to vesicles. Furthermore, the reversibility of the CT complex formation inside CB[8] led to the design of redox-driven molecular machines, such as molecular loop locks, based on this chemistry (Figure 5.2) [9]. Although the discovery of other members of the CB family led to their supramolecular chemistry being as rich as that of other celebrity host families, their practical applications remained somewhat limited, mainly because of their poor solubility in common solvents and difﬁculties in introducing functional groups onto their

5 Cucurbiturils: New Players in Noncovalent Assembly

surfaces. In particular, unlike other host families, the functionalization of these molecules proved to be a daunting task. However, the recent discovery of a direct functionalization method of CB[n] [10] allowed the relatively easy synthesis of a wide variety of CB derivatives and, in turn, the investigation of many possible applications. Today, applications such as ion channels, vesicles, polymers, ionselective electrodes incorporating CB[n], and CB-immobilized solid surfaces and silica gel have been reported, while numerous other uses continue to be explored [11]. In this chapter, attention will be focused on the vesicle formation of amphiphilic CB[6] [12]. When medium-sized poly(ethylene glycol) (PEG) units were attached at the periphery of the rigid CB[6] framework, it became sufﬁciently amphiphilic as to form a vesicle, the most interesting property of which was that the vesicle surface could easily be modiﬁed using host–guest chemistry, as the vesicle membrane was composed of a synthetic receptor CB[6] with an accessible cavity (Figure 5.3). The exceptionally high afﬁnity of CB[6] towards polyamines means that it would be possible to decorate the vesicle surface with a speciﬁc tag, simply by treating the vesicle with a tag-attached polyamine. As a consequence, because very many accessible CB[6] molecules were present in the vesicle membrane, the noncovalent interactions could be used to introduce a large number (and a wide variety) of tag moieties onto the vesicle surface, where they would interact with speciﬁc receptors in a multivalent manner. A potential use for such surfacedecorated vesicles was demonstrated by the receptor-mediated endocytosis of folate-decorated vesicles into human oral cancer cells (KB cells), on the surfaces

Figure 5.3 Vesicle formed by functionalized CB[6] and noncovalent modiﬁcation of its surface

[12]. The receptor-medicated endocytosis of a folate-decorated vesicle is illustrated.

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5 Cucurbiturils: New Players in Noncovalent Assembly Table 5.1 Binding constants and relevant thermodynamic parameters for the complexation of

CB[7] with ferrocene derivatives [13, 14].

Fe

R1

R1

Guest

Kexp (M−1)

∆H°exp (kJ mol−1)

T∆S°exp (kJ mol−1)

3

(3.2 ± 0.5) × 109 0.5) × 109

−90 ± 2

−36 ± 2

4

(4.1 ± 1.0) × 1012

−90 ± 1

−18 ± 2

5

(3.0 ± 1.0) × 1015

−90 ± 1

−2 ± 2

R2

R2

3 -CH2OH

-H

4 -CH2N (CH3)3 -H 5 -CH2N+(CH3)3 -CH2N+(CH3)3 +

of which folate receptors were overexpressed. Such an outcome would suggest that these vesicles might be useful for applications in targeted drug delivery [12b]. Much effort has been expended recently in the development of synthetic molecular recognition pairs with a high binding afﬁnity that matches that of the avidin– biotin complex. This biological system, which has an extremely high binding afﬁnity (∼1015 M−1) that is effected via noncovalent interactions, is important not only for the acquisition of a deeper understanding of noncovalent interactions, but also for practical applications. Recently, CB[7] has been shown to form a very stable complex (K = 3 × 109 M−1) with hydroxymethylferrocene (3) [13]. The subsequent introduction of a terminal positive charge onto the ferrocene residue (4) led to a sizeable increase in the binding constant (measured as K = 3 × 1012 M−1) for the CB[7]-4 pair (Table 5.1). Having identiﬁed this effect, it was considered that if another positively charged sidearm were to be introduced to the other cyclopentadiene ring of ferrocene, the value of K might be increased by a factor of thousand; consequently, guest 5 was prepared and its binding afﬁnity to CB[7] measured [14]. Indeed, the K-value for 5 was shown to be approximately 3 × 1015 M−1, which matched – and might even have exceeded – that of the biotin–avidin pair [14]. The biggest surprises, however, were the enthalpy and entropy changes associated with the binding. Although a very large enthalpic gain of −90 kJ mol−1 was achieved (see Table 5.1), there was essentially no entropic penalty, presumably because the large negative conﬁgurational entropic penalty – which most host– guest pairs pay on binding – was almost completely compensated by the equally large positive entropy of desolvation in 5. Thus, this system largely deviates from the enthalpy–entropy compensation trend observed in many natural and synthetic ligand–receptor systems (Figure 5.4). So, perhaps it is not simply a coincidence that the avidin–biotin pair also shows a large deviation from the enthalpy–entropy compensation plot? It was concluded, therefore, that the extremely large binding afﬁnity of the host– guest pair (CB[7] and [5]) was driven by a huge enthalpic gain that had originated from the tight ﬁt of the ferrocene core to the rigid CB[7] cavity, yet was critically

5 Cucurbiturils: New Players in Noncovalent Assembly

Avidin-Biotin

100

T∆S (kJ mol–1)

5-CB[7] 50

0

–50

Protein-Ligand CDs-Guest

–100 –150

–100

–50

0

50

100

∆H (kJ mol ) –1

Figure 5.4 The thermodynamic data obtained for complexation of guests 3, 4 and 5 with

CB[7], which signiﬁcantly deviates from the enthalpy–entropy compensation plots for protein–ligand and cyclodextrin–guest complexation [14].

assisted by the entropic gain arising from dehydration of the guest and the CB[7] portals [14]. A “take-home” message here is perhaps that, if there is a need to design a tight-binding synthetic receptor–ligand pair, then it is important to consider not only how to achieve a large enthalpic gain, but also how to reduce the entropic penalty upon binding. The present system suggests a possible solution to the problem! Finally, the strong and speciﬁc interaction displayed by the avidin–biotin system has led to its widespread use in many applications, including immunological assays. Unfortunately, however, the system also suffers certain shortcomings, including denaturation by organic solvents or elevated temperatures, as well as its large size and high cost. Thus, the development of a synthetic ligand–receptor pair to replace the biotin–avidin system would be important for practical applications. Based on the above results, a novel noncovalent method was recently reported by which a protein could be immobilized onto a solid surface by using the CB[7]– ferrocenemethylammonium (FA) pair (Figure 5.5) [15]. As a proof of concept, the immobilization of ferrocenylated glucose oxidase (GOx) enzyme on a CB[7]anchored gold substrate, and its use as a glucose sensor, have been demonstrated. In principle, this approach could be applied to the immobilization of any biomolecule, including nucleic acids, on any surface such as glass, silicon, silica, and polymers. Thus, a synthetic host–guest pair with exceptional afﬁnity, chemical robustness, simple preparation and easy handling may, in time, replace the biotin–avidin system not only for the immobilization of biomolecules on solid surfaces but also in other applications, such as afﬁnity chromatography and immunoassay.

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5 Cucurbiturils: New Players in Noncovalent Assembly

Biomolecule

Avidin-Biotin complex

CB[7]-FA complex

Figure 5.5 Immobilization of biomolecules using CB[7]–ferrocene pair; this represents a potential replacement of the avidin–biotin system [15]. FA, ferrocenemethylammonium.

In summary, within the new millennium, the cucurbiturils have become new and important players in supramolecular chemistry, as witnessed by the heightened interest in this ﬁeld over the past few years. Indeed, they have already achieved levels never before reached with other synthetic host molecules. Yet, noncovalent assembly is but one ﬁeld of chemistry to have beneﬁted from the unique structures and exceptional recognition properties of the cucurbiturils. Clearly, many more opportunities lie ahead with this new host family.

Acknowledgments

The author gratefully acknowledges those people who have contributed to the development of CB chemistry, especially, Profs Y. Inoue, L. Isaacs, A.E. Kaifer, and M.K. Gilson. These studies have been supported by the Creative Research Initiative and the Brain Korea 21 Program of the Korean Ministry of Education, Science and Technology.

References 1 Behrend, R., Meyer, E., and Rusche, F. (1905) Justus Liebigs Ann. Chem., 339, 1. 2 Freeman, W.A., Mock, W.L., and Shih, N.-Y. (1981) J. Am. Chem. Soc., 103, 7367. 3 Mock, W.L. (1996) in Comprehensive Supramolecular Chemistry, vol. 2 (ed. F. Vögtle), Pergamon, Oxford, p. 477. 4 Kim, K. (2002) Chem. Soc. Rev., 31, 96. 5 Kim, J., Jung, I.-S., Kim, S.-Y., Lee, E., Kang, J.-K., Sakamoto, S., Yamaguchi, K., and Kim, K. (2000) J. Am. Chem. Soc., 122, 540. 6 Lee, J.W., Samal, S., Selvapalam, N., Kim, H.-J., and Kim, K. (2003) Acc. Chem. Res., 36, 621.

7 Lagona, J., Mukhopadhyay, P., Chakrabarti, S., and Isaacs, L. (2005) Angew. Chem. Int. Ed., 44, 4844. 8 Kim, H.-J., Heo, J., Jeon, W.S., Lee, E., Kim, J., Sakamoto, S., Yamaguchi, K., and Kim, K. (2001) Angew. Chem. Int. Ed., 40, 1526. 9 Ko, Y.H., Kim, E., Hwang, I., and Kim, K. (2007) Chem. Commun., 1305. 10 Jon, S.Y., Selvapalam, N., Oh, D.H., Kang, J.-K., Kim, S.-Y., Jeon, Y.J., Lee, J.W., and Kim, K. (2003) J. Am. Chem. Soc., 125, 10186. 11 (a) Kim, K., Selvapalam, N., Ko, Y.H., Park, K.M., Kim, D., and Kim, J. (2007) Chem. Soc. Rev., 36, 267; (b) Kim, D.,

References Kim, E., Kim, J., Park, K.M., Baek, K., Jung, M., Ko, Y.H., Sung, W., Kim, H.S., Suh, J.H., Park, C.G., Na, O.S., Lee, D.-K., Lee, K.E., Han, S.S., and Kim, K. (2007) Angew. Chem. Int. Ed., 46, 3471; (c) Park, K.M., Suh, K., Jung, H., Lee, D.-W., Ahn, Y., Kim, J., Baek, K., and Kim, K. (2009) Chem. Commun., 71; (d) Kim, S.K., Park, K.M., Singha, K., Kim, J., Ahn, Y., Kim, K., and Kim, W.J. (2010) Chem. Commum., 692; (e) Kim, E., Kim, D., Jung, H., Lee, J., Paul, S., Selvapalam, N., Yang, Y., Lim, N., Park, C.G., and Kim, K. (2010) Angew. Chem. Int. Ed., 49, 4405; (f) Kim, D., Kim, E., Lee, J., Hong, S., Sung, W., Lim, N., Park, C.G., and Kim, K. (2010) J. Am. Chem. Soc., 132, 9908. 12 (a) Lee, H.-K., Park, K.M., Jeon, Y.J., Kim, D., Oh, D.H., Kim, H.S., Park, C.K., and Kim, K. (2005) J. Am. Chem.

Soc., 127, 5006; (b) Park, K.M., Lee, D.W., Sarkar, B., Jung, H., Kim, J., Ko, Y.H., Lee, K.E., Jeon, H., and Kim, K. (2010) Small, 6, 1430. 13 Jeon, W.S., Moon, K., Park, S.H., Chun, H., Ho Ko, Y., Lee, J.Y., Lee, E.S., Samal, S., Selvapalam, N., Rekharsky, M.V., Sindelar, V., Sobransingh, D., Inoue, Y., Kaifer, A.E., and Kim, K. (2005) J. Am. Chem. Soc., 127, 12984. 14 Rekharsky, M.V., Mori, T., Yang, C., Ko, Y.H., Selvapalam, N., Kim, H., Sobransingh, D., Kaifer, A.E., Liu, S., Isaacs, L., Chen, W., Moghaddam, S., Gilson, M.K., Kim, K., and Inoue, Y. (2007) Proc. Natl Acad. Sci. USA, 104, 20737. 15 Hwang, I., Baek, K., Jung, M., Kim, Y., Park, K.M., Lee, D.-W., Selvapalam, N., and Kim, K. (2007) J. Am. Chem. Soc., 129, 4170.

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6 Comment on the Possible Presence of Bubbles Inside Self-Assembled Molecular Cages Prepared Comment Josef Michl

Ever since the metal ion-directed self-assembly of large molecular cages in solution was popularized by investigators such as Fujita [1], Stang [2], and others, many a chemist has surely wondered whether, under ambient conditions, those that are large enough to contain several solvent molecules inside are indeed ﬁlled with solvent, or whether they are empty (i.e., whether they contain a bubble of solvent vapor). Little, if any, experimental or theoretical evidence seems to exist on the issue. As every scientist is taught early in life that Nature abhors a vacuum, the natural response is to assume that the cages are ﬁlled with liquid solvent, perhaps structured to some degree. On second thought, however, the answer may be less obvious, as many common solvents will form bubbles at various nucleation centers spontaneously, and at temperatures only a little higher than ambient. Could it be that in some solvents bubbles will be present in the molecular cages at equilibrium already at temperatures lower than the boiling point? Of course, depending on the details of intermolecular interactions, it is also possible that solvent molecules will prefer to stay inside the cages even at temperatures above the boiling point. The speculation may not be merely a matter of idle curiosity. If solvent vapor bubbles are present in these molecular cages, then their formation will be a part of the initial cage self-assembly, and may affect it. The choice of solvent and counterions might then play an unsuspected role in the kinetics and thermodynamics of cage formation and decomposition. If the presence of internal bubbles were related to solvophobic effects, it might be particularly easy to ﬁll the bubble with additives that exhibit an afﬁnity for its inside walls, including templates. During the course of investigating the properties of the highly positively charged trigonal prism shown in Figure 6.1, which was self-assembled in nitromethane from three equivalents of an electroneutral, cross-shaped connector with a pyridine ligand at each arm end and six equivalents of the triﬂate salt of the (Me3P)2Pt2+ dication [3], a curious observation was made. Whilst the cage was large enough to contain a dozen solvent molecules, and its walls contained openings through which the solvent molecules could easily pass, the observation was most simply interpreted by postulating that, under ambient conditions, the molecular cage From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

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6 Comment on the Possible Presence of Bubbles Inside Self-Assembled Molecular Cages

N

N

N

12+

N

N N

Co

Co

N

N

12 –OTf N

N

Figure 6.1 A self-assembled molecular cage. The six corner dots represent (Me3P)2Pt2+ ions.

contained a bubble of nitromethane vapor, and most of the time it was completely empty [4]! Although, many more experiments must be conducted before this interpretation can be considered as established, the proposal attracted sufﬁcient curiosity to warrant its presentation at a discussion forum, as might be offered by a Solvay conference. The observation which prompted the proposal that, in nitromethane solution under ambient conditions, the cage shown in Figure 6.1 would contain a solvent bubble, was the ﬁnding of a highly peculiar Eyring plot for the kinetics of edge interchange in the pyridine ligands attached to the Pt2+ ions located at the vertices. The two edges of each pyridine were inequivalent in 1H NMR spectra, and standard dynamic NMR techniques could be used to extract the rate constant k of their interconversion. When log k was plotted against 1/T, the Eyring plot was bilinear and consisted of two highly linear segments (Figure 6.2). Below a certain temperature, which was dependent on the choice (and, in the case of triﬂate, also on the concentration) of anions in the solution, the slope and abscissa corresponded to a set of activation parameters that were quite reasonable for a somewhat hindered rotation of a pyridine ligand around a N–Pt2+ bond. The sensitivity of the rate constant of the counterions present was attributed to effects of ion pairing, and it was concluded that a rotation of the pyridine ring was facilitated when a counterion was tightly associated with the Pt2+ cation. When − , ∆H‡ = 16 ± 3 kcal mol−1 and the counterion was the carborane, HCB11Me12 ‡ −1 ∆S = −2 ± 1 cal mol ·K, independent of the anion concentration and of that of any triﬂate added. From the measurement of diffusion constants by gradient − NMR, it appeared that, under the conditions of the experiments, one HCB11Me12 2+ anion was always associated with Pt , and not displaced by triﬂate. The constancy

6 Comment on the Possible Presence of Bubbles Inside Self-Assembled Molecular Cages –21 –22

In (k/T)-In (Kg/h)

–23 –24 –25 –26 –27 –28 –29 –30 2.7

2.8

2.9

3

3.1 3.2 100/T (k–1)

Figure 6.2 Eyring plots for the pyridine edge

exchange reaction in the cage of Figure 6.1 in nitromethane solutions containing 12 equivalents of TfO− (open black squares) or − HCB11Me11 (open black circles) counterions, and solutions containing an added salt, with

3.3

3.4

3.5

3.6

total numbers of anion equivalents equal to 30 TfO− (open green squares), 60 TfO− (open − red squares), 12 TfO− + 12 HCB11Me11 (open − blue circles), and 60 HCB11Me11 (open red circles). Reproduced with permission from Ref. [4].

of the activation parameters observed for the carborane anion was then understandable, and the small value of ∆S‡ ﬁtted a unimolecular process. When the counterion was triﬂate, ∆H‡ = 11–14 (±2) kcal mol−1 and ∆S‡ = −10 to −18 (±6) cal mol−1·K, depending on the triﬂate concentration. In this instance, the analysis was more complicated, and it was not possible to deconvolute unique values of activation parameters for the rotation step from reaction parameters describing ion-pairing equilibria. However, it was qualitatively reasonable that the observed ∆S‡ should be more negative for what is effectively a bimolecular process in which a counterion needs to be brought up from the solution. The abrupt change in the slope of the Eyring plot above a certain temperature suggested a change of mechanism. Since the results for the carborane anion were again unaffected by added carborane or triﬂate salts, it seemed unreasonable to attribute the difference to a shift from a reaction which predominantly involved one ion-paired species to a reaction that predominantly involved another ionpaired species. It is difﬁcult to escape the conclusion that the reacting species was the same, but a new reaction path characterized by a higher ∆H‡ and also a higher ∆S‡ had become accessible and dominant at higher temperatures. The effects of the changes in ∆H‡ and ∆S‡ were largely compensated, such that the resulting rate constant remained essentially unchanged, and the reaction was still observ-

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6 Comment on the Possible Presence of Bubbles Inside Self-Assembled Molecular Cages

able by using the NMR technique. The observed values were ∆H‡ = 38 ± 3 kcal mol−1 and ∆S‡ = 62 ± 9 cal mol−1·K. The values observed for the triﬂate salts were similar, and all attempts to ﬁt the results for the triﬂate salt to schemes that included ionpair equilibria led to a similar conclusion. That is, in the high-temperature regime, at least one kinetic step resulting in a pyridine edge exchange would have Eyring parameters similar to those observed for the carborane salt. The values of these activation parameters were striking, particularly considering that only a very simple reaction – the interchange of the two edges of a pyridine ring – was involved. The high value of ∆H‡ can be rationalized readily if it does not correspond to a conformational change but rather to a bond-breaking process. The weakest bonds in the molecule are undoubtedly the N–Pt2+ coordination bonds. Since their breaking is surely accompanied by a simultaneous stabilizing interaction with a molecule of the solvent (or, more likely, a counterion), the observed ∆H‡ value is probably sufﬁcient for the breaking of two of these bonds. This would cause the cage to unravel, producing a structure in which two pyridine rings could rotate freely until the N–Pt2+ bond closed again. If only a single N–Pt2+ bond were to break in the transition state, then one pyridine ring would still rotate. Either way, the reaction path proposed was closely related to the reverse of the last step anticipated for the original cage self-assembly. It is difﬁcult to offer a similarly acceptable rationalization of the extreme value of ∆S‡. This is essentially unprecedented, except for the values observed for certain protein unfolding reactions in water, and it corresponds to the simultaneous fragmentation of the cage into a half-dozen pieces. Yet, there was no indication that the cage was unstable under the conditions of these experiments. No amount of increased ﬂexibility provided by a unimolecular transformation in which one or two bonds were broken could account for the result, and there seemed to be no particular justiﬁcation for postulating a dramatic change in ion pairing. It seemed inevitable that a drastic change in the structure of the solvent was involved. The nature of this change in the entropy of solvation between the initial and the transition state was not obvious, and consequently help was sought from theory. The result of a classical molecular dynamics simulation of the cage in a small drop of nitromethane, using the admittedly very approximate universal force ﬁeld (UFF) [5] and the locally developed TINK computer program [6], was quite spectacular. Starting with an approximately equal density of solvent outside and inside the cage, it only took about 30 ps for a bubble to form inside (Figure 6.3). At least at this level of theory, at equilibrium the cage was essentially empty, and was only occasionally inhabited by a lone solvent molecule passing through. In one of the dynamics runs, in which the N–Pt2+ bonds were represented by Morse potentials, one of these bonds broke, and the opening was followed by a collapse of the vapor bubble as the solvent molecules rushed back in. The breaking of a second bond has never been observed during the time span of the runs completed, but as the cage then would be completely unraveled there is little doubt that it could not support a bubble, either. The solution to this puzzle, as suggested by molecular dynamics, was then tested by an order-of-magnitude calculation of the entropy of cavitation, using the theory

6 Comment on the Possible Presence of Bubbles Inside Self-Assembled Molecular Cages (a)

(b)

Figure 6.3 View of the cage of Figure 6.1

of its behavior in a drop of nitromethane at room temperature. The solvent molecules contained at least partially inside the cage are drawn in thick blue lines. Reproduced with permission from Ref. [4].

approximately along (upper panel) and perpendicular to (lower panel) its threefold symmetry axis, at 3 ps (a) and 30 ps (b) after the start of a molecular dynamics simulation

of hydrophobic interactions that had been elaborated for water. In this case, it was necessary to make some very crude assumptions; for example, assuming that the bubble was spherical and that only the solvent was present on its walls. This calculation yielded a value of 3.9 nm3 for the size of a bubble, the collapse of which yielded an increase in entropy equal to 62 cal mol−1·K, while the internal volume of the cage estimated from molecular models was 3.6 ± 0.5 nm3. Although the perfect agreement was, of course, accidental, the result lent credence to the proposal that, under ambient conditions in nitromethane solvent, the cage would contain a vapor bubble at equilibrium, and that the bubble would collapse when the cage opened, allowing one or two pyridine rings to rotate more or less freely before the cage reclosed. There are various ways in which this proposal could be tested, both by an examination of the effects of variables on the rate of pyridine rotation, and by examining other properties such as ultrasound absorption. Some of the external variables were pressure and a variation of counterion nature and solvent composition. It is possible that nonpolar additives would collect inside the bubble as liquids or solids,

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6 Comment on the Possible Presence of Bubbles Inside Self-Assembled Molecular Cages

and that this would be revealed in their spectra and reactivity. Assuming that the presence of a solvent vapor bubble was conﬁrmed, it would be important to ask why the phenomenon occurs, and how general it is. One likely reason for bubble formation may be the amphiphilic nature of the cage. The 12 positive charges provide the cage with an afﬁnity for the polar solvent, yet its faces are lipophilic. Whilst it is difﬁcult to be sure about this until the generality of the phenomenon is established, it is conceivable that a relationship exists between the cage opening and providing solvent access to previously excluded regions, and certain biological processes in water. Examples include the unfolding of proteins uncovering hydrophobic regions and providing water with access to pockets from which it was previously excluded, and perhaps also the recently proposed bubble formation in biological ion channels, with implications for general anesthesia. Conceivably, the cage may ultimately be shown to be a smallmolecule model for some important and complex biological processes.

References 1 Kawano, M. and Fujita, M. (2007) Coord. Chem. Rev., 251, 2592. 2 Seidel, S.R. and Stang, P.J. (2002) Acc. Chem. Res., 35, 972. 3 Caskey, D.C., Yamamoto, T., Addicott, C., Shoemaker, R.K., Vacek, J., Hawkridge, A.M., Muddiman, D.C., Kottas, G.S., Michl, J., and Stang, P.J. (2008) J. Am. Chem. Soc., 130, 7620.

4 Vacek, J., Caskey, D.C., Horinek, D., Shoemaker, R.K., Stang, P.J., and Michl, J. (2008) J. Am. Chem. Soc., 130, 7629. 5 Rappe, A.K., Casewit, C.J., Colwett, K.S., Goddard, W.A., III, and Skiff, W.M. (1992) J. Am. Chem. Soc., 114, 10024. 6 Vacek, J. and Michl, J. (1997) New J. Chem., 21, 1259.

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7 Discussion 1.B Discussion on the Prepared Comments by D.N. Reinhoudt,1) K. Kim,2) K. Raymond,3) and J. Michl4) Chairman: Julius Rebek Jr

Chairman: The communications are now open for discussion and comments, but ﬁrst, let me ask David Reinhoudt a question. When you try to bind cholesterol in your huge receptor molecule, do you believe that if you had a faster timescale for measuring the binding in and out, you might be able actually to observe the complex between cholesterol and your receptor? That is a timescale which is slow on the NMR chemical shift, and is purely arbitrary. But if you could speed up the rate at which the pictures are taken, might you have seen the complex for which you designed the molecule? D.N. Reinhoudt: That is an interesting question, and it also relates to what Josef Michl has just shown. We also conducted molecular dynamic calculations on the solvation of the inner sphere of such a large cavity, which is about 1000 Å3 – that’s about 1 nm in diameter. From the start of the calculations, four chloroform molecules are seen to jump into the cavity, and are so nicely solvated that a guest molecule – even with the entropy gain expected – would be unable to replace it because the ﬁt is perfect and the windows are large enough for entry. If you open up the cavity, by leaving the roof off, the cholesterol complexation can be seen. So it is preorganized, as Donald Cram used to say, when designed for desolvation and binding. However, the molecules were only preorganized for solvation, and that’s completely different in the case of water-soluble systems. I think this is a fundamental problem. Also in Josef Michl’s case, with such a nicely solvated cavity, I wonder if a guest molecule ever enters? And what would be the gain if a guest molecule were to enter? Would you expect a guest molecule to be bound in that cavity? 1) The prepared comment by D.N. Reinhoudt was on the noncovalent synthesis of molecular receptors (see p. 35). 2) The prepared comment by K. Kim was on cucurbiturils as new players in noncovalent assembly (see p. 43).

3) The prepared comment by K. Raymond was on [M4L6]12− tetrahedral nanozymes. 4) The prepared comment by J. Michl was on the possible presence of bubbles inside self-assembled molecular cages (see p. 51).

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

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7 Discussion 1.B

Chairman: Before Josef Michl answers, let me say what we have done is try to get around the problem of the huge concentration advantage that the solvent has. For example, chloroform is about 10 M, and you cannot really get 10 M cholesterol. So, what we can do is to ﬁnd solvents that are too large to ﬁt into the cavity that do not have to compete with the low concentration. By using the largest commercially available deuterated solvent (mesitylene), we can get things into our cavities quite easily. D.N. Reinhoudt: That works very well for cavities where lean molecules can ﬁt in, but in our case there is no solvent one can think of that would be unable to enter the windows. Those windows are also necessary in order to allow cholesterol molecules in and out. J. Michl: First of all, we have not yet made any study of binding. This is a relatively new discovery – in fact it is a relatively new interpretation of what has been puzzling us for some time, and that may be a more honest way of describing it. I don’t have any numbers for binding constants, but if at equilibrium there is actually a bubble in there that’s because the internal faces of the prism are solvophobic – that is, they are hydrophobic. We don’t use water – we use a different solvent and, in a way, the hydrophobic interactions that we are familiar with from water are manifest in this system. So, the reason that the highly polar nitromethane solvent does not want to be inside, and that there is bubble in there, is because it does not want to be next to the nonpolar solvophobic surfaces; it can solvate the charges much better from the outside. Our expectation is, however, if we now add a guest that is nonpolar, it will be bound beautifully inside the cage. It will not suffer from any solvophobic effect, there will be solvophilic interactions with the face. So, the question I ask myself is whether this is just one exception among thousands, or is it very common for those cages that can bind nonpolar guests very well also to have bubbles in them? We don’t know how general this is. Have I answered your question, or not? D.N. Reinhoudt: I think the difference with water is that, when water is desolvated from a hydrophobic cavity, there is of course an enormous gain in enthalpy when the water returns and is re-bound in the water matrix. That is what makes water very special. It is much more difﬁcult to compete in nonaqueous solutions because organic molecules as such are hydrophobic and easily solvated by organic solvent molecules. A. Shanzer: I would like to ask Professor Raymond a question about the difference between the design of covalent interactions – where we generally know where we are going – compared to the design of noncovalent interactions. To what extent is that a serendipity effect to obtain a particular structure, and how can that be controlled? K. Raymond: One of many slides I didn’t show was the calculated structure that we created for this naphthalene-ligand structure compared to the crystal structure. When we ﬁrst started these studies, some 10 to 12 years ago, these things were

7 Discussion 1.B

quite common, and the calculated structure always came after the crystal structure. But in our case, the calculated structure preceded the crystal. We really designed these molecules, and the key is to have a limited stereochemical ﬂexibility for the components. The difﬁcult part – and that’s what simple mechanical modeling was able to do – is to get the angles right between the axes of interaction. It is especially difﬁcult to do that by hand. A. Shanzer: How do you decide whether to do that right-handed or left-handed? K. Raymond: The right-handed and left-handed would have equal amounts, and you would have to resolve the structure. But, remember that we are not making enantiopure components – we are making something that is racemic and will be resolved at a later stage. R.W. Saalfrank: May I comment on both Raymond’s and Shanzer’s interpretations? I think the design is only possible when you have, perhaps, a different structure already, so that the synergistic effect of serendipity and rational design is focused on newer complexes. I think what we would do there might be termed the “lead sheet approach.” This is related to chess – what we have is ligands, geometries and the connectivity of the metals ions. Comparing this with chess, you will have the harmony, the rhythm, the melody, and a process. This is how we use this chemistry in order to come up with a new system. K. Raymond: Yes, and of course the reality is that the larger the cluster, and consequently the more ﬂexible the linker you have, the more difﬁcult it is to control the system and to force the structure that you want to make. J.-P. Sauvage: I have a question for the “capsules” people that relates to chemical reactions. In a few examples, the capsules can be used as containers to perform catalysis, to catalyze certain types of reactions. To me, it is really striking that Diels–Alder reactions or 2+2 photo-cycloaddition reactions – which are normally conducted under high pressure – can be carried out in a catalytic way in a capsule which is, at the same time, relatively labile, possibly exchanging ligands and metals. For me it is difﬁcult to understand how high pressure can be replaced by a cage that is perhaps not so strictly preserved from a structural viewpoint. Chairman: I can start to answer that point based on my own experience. The volume of these capsules is in the order of hundreds of cubic Ångströms – which means that a single molecule inside will enjoy concentrations of 4–5 M. If you calculate or measure what the rate would be under those circumstances, outside in bulk solution, then there is no surprise as to the rate of the reactions going on inside. The other way to look at this – at least, one that I ﬁnd useful – is that in the bulk solution, when two molecules diffuse together into a diffusion complex, the effect lasts on the order of a nanosecond. But, inside the capsule, the lifetimes are on the order of 1 second. Then, if they can reach the right geometry for a transition state, they have plenty of time to do so. Perhaps Professors Fujita and Raymond may have different perspectives on this?

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M. Fujita: In terms of the concentration effect, I soon recognized that the geometry ﬁxation at the correct position is very important. So, in our 2+2 photo-additions, the reactions do not always proceed if substrates are not ﬁxed at the correct position. The reaction centers should be very close, and the original geometry should be very close to the transition state. Therefore, we should design the geometry of the substrate prior to the reactions. K. Raymond: That is exactly what Nature has done with enzymes such as chorismate mutase, which recognizes a speciﬁc conformer and, in effect, concentrates it so that the reaction is superbly accelerated. J.-P. Sauvage: I fully agree with what you say, but something which I ﬁnd a bit contradictory is that some of those cages are dynamic – they are exchanging pieces and parts with the outside. You mentioned times of the second scale, or a range of seconds – this would imply that the ligand exchange or the exchange rate for the various parts of the cage would be slower. Is this correct? Chairman: It is on about the same timescale. Another way of looking at this is that very often, during the change from the ground state to the transition state, a change of solvation will take place, and this entropy effect causes a slowing down of the reaction, or contributes much to the activation energy. You could think of these cages as being ﬁxed solvent molecules – which is really what they are – so that if they are arranged they cannot get away, they do not have to move, and essentially they can “shrug” to accommodate the transition state. The downside is that very often in these reactions, the product is the best guest, especially in condensation reactions. As a result, you get classic enzymological product inhibition. D.N. Reinhoudt: I am in support of Julius Rebek’s statement that concentration effects are responsible, even if I can imagine that if you had a very strained cavity where a transition state cannot be reached, a reaction would not take place. There is an analogy, when reactions are conducted on surfaces under conditions of microcontact printing, which means that there is no solvent present and that the molecules are less well organized but are brought into very close proximity in a conﬁned space. In this way, 200 000-fold rate accelerations are observed. Such an effect on an organic chemical reaction that would normally be performed at 10 mM, when changing to a 5 M local concentration for a bimolecular reaction, would represent an enormous acceleration. Therefore, a general explanation, in terms of high local concentrations, is probably very valuable. T.A. Moore: Could I ask Prof. Raymond regarding the comment he made about his system running backwards: Can you start with products, and reach equilibrium? K. Raymond: I am not quite sure what you mean. We have not run these reactions backwards although, in principle, I think you could, because we do not want product inhibition. In the case of the diene reaction, that is a reversible reaction, and it normally happens quite rapidly. We would certainly be catalyzing the reverse

7 Discussion 1.B

reaction as well, and what drives that reaction in one direction in this case is the hydrolysis of the generated Schiff base cation. B.L. Feringa: I have a small comment to Prof. Sauvage about the effects of acceleration. We should not forget that when you take two components, for instance in the Diels–Alder reaction, and you add a tiny amount of a Lewis acid, these two components bind to the Lewis acid metal center, are conﬁned in space, and give a million-fold acceleration. But if you take the components just in water, you will get tremendous acceleration by conﬁning them more or less in space. I am very happy to hear Josef Michl talk about these solvent effects, as they are very simple ways to achieve tremendous accelerations. My question also concerns what David Reinhoudt said about conﬁnement on surfaces, where the molecules can move together and become closer. Could I also ask a more general question to the speakers. I was very impressed by the fantastic capsules and components that self-assemble. I heard Prof. Kim talk about binding constants of 1015, which is very impressive, and better than some of the binding constants that you ﬁnd in Nature. But in the case of natural systems there is an awful lot of dynamics. For example, actin ﬁlaments are assembled, and then disassembled, so that in the enzyme cavity there are always things moving. I was wondering, in general, how will we be able not only to achieve high binding constants but also to tune those binding constants – for example, to go from high to low binding, or vice versa, in a dynamic way. We know how to do that to a certain extent, for instance, in rotaxanes where we can shovel things (and we shall hear a lot about this in the upcoming discussions), but in my opinion, there seems to be a tremendous challenge for the future in ﬁguring out how this can all be done in a dynamic way. It is this aspect of tuning and controlling the binding to obtain dynamic capsules not only in an equilibrium situation, but also by being able to trigger it that would be fantastic. So I would not mind hearing some comments from the experts in the ﬁeld of self-assembly. Chairman: In our experience, you can control the equilibria and also the rate of formation and dissipation of these capsules with solvent. This is if you have solvents that can compete, say for the hydrogen bonds, you can lower the afﬁnities of things for them and also make their exchange rates more rapid. However, this is not really what you would like to do. You would like to do everything in water if you are going to the biomimetic end of things. So in that respect, there really is a challenge. B.L. Feringa: When you look at how Nature does it, you see small conformational changes in places and, suddenly, the binding even remote is changed dramatically and things are released or accepted. A. Shanzer: There is a way of doing that in the opposite way, which means taking something very active and making it less reactive. We did that in several cases where a model binds too strongly to be a sensor – for example, it would serve as a sensor that could be used only for a single time. In order to change this, you would

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have to change the nature of the receptor itself, making it increasingly less effective. You would then arrive at a point where there would be a sufﬁcient interaction, but a “puff of air” could release the substrate and you would regain the sensor. Alternatively, you could change the solvent and remove it completely, and you are back at the start again. A major question here is how to improve the process – that’s the most difﬁcult part, because once the receptor has been made, how can it be made better? That’s generally the main problem. R.W. Saalfrank: Prof. Raymond’s system is a stable one, which has four times ∆ and four times Λ. It is a racemic mixture that must be separated, but you must take into consideration the fact that the metal centers can undergo a Bailar twist. Although this is often a very simple process, it is locked in Raymond’s case because the atropenantiomerization around these bonds is blocked. However, if this system is mobile, it will undergo – spontaneously – four Bailar twists and six atropenantiomerizations. So, if this is without any association, it will go from four times ∆ to four times Λ. The systems do not have to be really rigid, but they can be mobile in themselves and change chirality, for instance. J. Sanders: I just wanted to pick up on Ben Feringa’s point, and also Rolf Saalfrank’s. Nature achieves much higher binding constants, much higher rate constants than we do by making much more ﬂexible systems that are then able to respond and reach the optimum geometry. So anything that we design is almost certainly imperfect and, if it is too rigid and imperfect, then it would not be able to achieve an optimum geometry to stabilize the transition state that is needed to get a good catalysis. So, what we must do is to create systems which are sufﬁciently ﬂexible that can be chosen to obtain the correct conformation, because only then will they be effective. R. Nolte: Yes, I was also going to say something on this topic, but I would like to raise an even more general question. To what extent are we dealing with turnover catalysis in the systems that have been designed? Is this possible? It seems so, but what do we really have to do to get real catalysis? Do we have to go to more ﬂexible systems, such as adapting the system to the situation it is in? Do the systems discussed by Professors Fujita and Raymond show real turnover catalysis? An afﬁrmative answer was given by Prof. Raymond. Do you indeed? Why is this so? Is this because the product is expelled? What is the turnover exactly? K. Raymond: Well at least several hundreds. We have not waited long enough, but there is no inhibition of the catalyst. We routinely run these reactions with 1% of the catalyst, but I am sure if we were more patient we could do it at 0.1%, or maybe 0.01%. M. Shionoya: I have a comment. Very recently, we have found an interconvertible system between the capsule and the cage of metal-assembled complexes. We discovered this purely by chance and, in the future, I would like to be able to give a more general answer to your question. As Prof. Fujita showed us, a discrete number of molecular building blocks tend to form very beautiful, highly sym-

7 Discussion 1.B

metric structures. Probably, our next goal is to create less symmetric structures – for instance, a stepwise self-assembly using inert metal species and labile metal species may be useful for the construction. Alternatively, the use of a programming molecule, such as DNA, could prove to be very useful. I would greatly appreciate any comments you might have on this point. J.-P. Sauvage: I fully agree with the production of more complex and less symmetrical – but sadly less beautiful – structures. This, however, is no longer going to be self-assembly, because I think you will need kinetically inert transition metals in some parts. It will be a construction of the molecules. K. Raymond: Yes, if you look at Nature as an example, materials such as cellulose are rather irregular, but are also limited in function in terms of them largely being only structural. In contrast, viral capsids, ferritin, or other individual macromolecules that Nature creates through self-assembly have a high symmetry. The reason for that is because if you want to make one thing, with one volume, then the only way to do it is with high symmetry. E. Dalcanale: Returning to your point, may I remind you that Chad Mirkin has already made an interesting contribution to the inert towards less inert complexation metals, and has obtained very interesting results which move in the direction that Ben Feringa also proposed – that a system should be partly mobile and maybe also partly ﬁxed. Although it is true that Nature acts in a ﬂexible manner, it does not always do so completely. Some type of inner structure must remain in order to allow the dynamic behavior. J. Michl: I would like to raise a different point, and one that we have been led to by contemplating the results I have just reported. The reaction that leads to the collapse of a bubble can be viewed as the inverse of the last step in the synthesis, in the self-assembly of the cage. The question is, how much is actually known concerning the mechanism of the assembly of these wonderful cages? K. Raymond: In my case, far too little, but not for lack of trying! I would like to reﬂect a question back to you if I may – on a completely different topic. Your bubbles should have a natural frequency to them. Are you able to perform ultrasound, or the Einstein equations? You should see a resonance. J. Michl: Thank you – we shall add this to the list of 101 experiments we need to do! You should see, for instance the effect of pressure, the effect of adamantane addition to the solvent on the NMR results, on the rate constant and such like. There is a countless number of really exciting experiments that we ought to perform. R. Nolte: May I ask a question about your bubbles, as I didn’t understand it precisely. Is there a vacuum or an air bubble – the picture was not completely clear to me? J. Michl: I am sorry – it would have been clearer had I been brave enough to show my slides, but I was worried I would lose the movie if I did that. The three or four

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cubic nanometers inside the prism are at equilibrium, and are either completely empty or every now and then they contain one or two molecules of solvent dashing across. I would not say it is a vacuum – I would rather say it was vapor, an equilibrium vapor of the solvent. K. Raymond: Just a quick follow-up: the density is going from something close to 1 inside your cluster to something that must be 100 or so – is that correct? So, on a practical level, is not it closer to a vacuum? J. Michl: The density of the solvent that is known experimentally is 1.14 kg l −1 (the density of nitromethane). In the model that we use, the UFF potential used in the calculations does not reproduce that exactly. Depending on the size of the drop that is being calculated, the ﬁgure is between 1.05 and 1.1 kg, which is slightly less than 1.14 kg. So, the calculated liquid is almost at the experimental density. At the start of the movie we had the same density outside and inside, but as equilibrium is reached in 30 ps or so, the solvent molecules ﬁrst reorient, and then actually begin to leave the inside. Ultimately, the density is very close to zero. On average, you have one molecule in those 4 nm3. Chairman: I would like to close the morning session and leave you with a warning to come back early if you are coming to do some presentations this afternoon. Thanks to all of you.

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Part Two Template Synthesis of Catenanes and Rotaxanes

From Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

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8 A Short History of the Mechanical Bond Report John-Carl Olsen, Kirsten E. Grifﬁths, and J. Fraser Stoddart

8.1 Introduction

Students learn about the nature of the chemical bond [1] – covalent, ionic, and metallic – early on in their scientiﬁc education as the means by which atoms are held together in molecules. In particular, the selective formation, under both kinetic and thermodynamic control, of covalent bonds has proven to be an ongoing challenge for synthetic chemists as they strive to make a wide variety of molecules with functions. However, by utilizing weaker inter- and intramolecular interactions, such as van der Waals forces, hydrogen bonds, dipole–dipole, pole–dipole, and pole–pole attractions, it is now possible for chemists to achieve more precise control over kinetic and thermodynamic processes. It has transpired that, by exploiting these weak interactions, chemists have been able to construct a new class of molecules containing a distinctive kind of chemical bond called the “mechanical bond” [2]. Mechanically interlocked molecules [3–37] (Figure 8.1) contain two or more distinctive collections of atoms within discrete components which, were it not for the mechanical bond(s), would normally fulﬁll the classical deﬁnition of molecules on their own. These new mechanically interlocked compounds do indeed fulﬁll the deﬁnition of a single molecule. They require the breaking of at least one covalent bond to allow the molecule’s components to separate, one from the other. Thus, in a mechanically interlocked molecule, the union between any two contiguous components equates with a strength that is commensurate with that of the weakest covalent bond in the molecule. The concept that mechanically interlocked compounds are made up of molecules, rather than assemblies of separate entities, was ﬁrst proposed in an article by Frisch et al. [38] in 1961. It should also be noted that mechanically interlocked compounds have structural and functional properties which differ signiﬁcantly from those of their individual components. The simplest mechanically interlocked molecules are [2]catenanes and [2]rotaxanes, consisting either of two interlocked rings or of one ring and a dumbbell component, respectively. While structurally distinct, both structures may be preFrom Non-Covalent Assemblies to Molecular Machines. Edited by Jean-Pierre Sauvage and Pierre Gaspard © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32277-0

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8 A Short History of the Mechanical Bond

Figure 8.1 Five types of mechanically interlocked molecules (clockwise, from top left) which have been prepared by chemists: [2]rotaxanes [3–8]; suit[2]anes [9, 10];

[2]catenanes [3–8]; pretzelanes [15–21]; trefoil knots [28–37]; Borromean rings [22–27]; and Solomon links [11–14].

pared from a common intermediate known [39] as a pseudorotaxane – that is, a supramolecular species in which a linear thread-like molecule is encircled by a ring. Using modern techniques, the threading of a linear component through a ring is driven thermodynamically by dint of noncovalent bonding interactions to create the most stable complex in solution. While chemically interesting in their own right, pseudorotaxanes are dynamic entities which may undergo decomplexation when subjected to changes in solvent or temperature, or on the addition of competitive guests. It is possible, however, to ﬁx a pseudorotaxane kinetically by either: (i) stoppering both ends of the thread to form a rotaxane; or (ii) covalently connecting the ends together by means of supramolecularly assisted macrocyclization to form a catenane [40]. The name rotaxane [38, 41–43] is derived from the Latin word for a wheel (rota) and an axle (axis). Rotaxanes are molecules comprised of a linear dumbbell-shaped component encircled by one or more rings. The stoppers attached at the ends of the dumbbell must be large enough to trap the ring(s) mechanically, thus preventing them from dethreading. A standard piece of nomenclature has been established wherein the number of components which comprise the rotaxane appears in square brackets before the term. Thus, an [n]rotaxane is a molecule comprised of a dumbbell and (n − 1) ring components. In a similar fashion, catenanes [38, 44, 45] are comprised of two or more mechanically interlocked rings, their name being derived from the Latin word for a chain (catena). Catenanes also utilize a naming convention wherein the number of rings, which comprise the molecule, appears in square brackets before the term. Thus, an [n]catenane is a molecule comprised of n rings. Despite their conceptual similarity, catenanes are considered to be topologically nontrivial, whereas rotaxanes are considered to be topologically trivial [46]. This difference exists since a catenane’s topology cannot be altered, for no matter how the rings become distorted, the structure remains mechanically interlocked unless a ring is broken. In a rotaxane, by comparison, if the ring is stretched like an elastic band, it can dethread by slipping over one of the stoppers, resulting in two topologically trivial components. Thus, a rotaxane is topologically identical to its equiva-

8.1 Introduction

lent free dumbbell and ring(s), while a catenane and its equivalent rings are topologically isomeric. In addition to catenanes and rotaxanes, a wide variety of molecules containing mechanical bonds have been identiﬁed and synthesized subsequently by chemists. These compounds include the trefoil knot [28–37], the simplest nontrivial knot which contains only three crossing points and is inherently chiral. The Solomon links [11–14] and the Borromean rings [22–27] are mechanically interlocked molecules consisting of either two or three rings, respectively, wherein the rings cross in a pattern that sustain alternating nodes. In both of these compounds, if one ring is cleaved then the mechanical integrity of the molecule will be lost completely, and the components will disassemble. An important difference between the two compounds is that in the Solomon link the two rings are doubly interlocked (it is, in fact, a special type of [2]catenane), whereas in the Borromean rings no two rings are interlocked, yet the molecule as a whole is interlocked. More recent additions to the “family” of mechanically interlocked molecules include the pretzelanes and the suitanes. Pretzelanes [15–21] are related to catenanes in so far as they are essentially [2]catenanes, the rings of which are linked by a bridge. However, unlike their molecular sibling, pretzelanes are considered to be topologically trivial species. Similarly, suit[2]anes [9, 10] may be considered to be the “internally stoppered” variant of a [2]rotaxane, since dethreading of the polycyclic component is prevented by steric bulk at the center of the thread, rather than at its termini. Nonetheless, both suitanes and rotaxanes are considered (Figure 8.1) to be topologically trivial. 8.1.1 Historical Perspective

The study of mechanically interlocked compounds is thought by most chemists to have begun in 1960, when Wasserman [44] described in the literature what is commonly believed to be the ﬁrst wholly synthetic [2]catenane (Figure 8.2). In order to obtain this catenane, a statistical synthetic methodology in which macrocyclizations of alkyl chains containing 34 carbon atoms in length were used in order to complete the syntheses. In Wasserman’s synthesis, statistically less than 1% of the starting materials react in a mechanically interlocked co-conformation [47], leading to the isolation of only a very small quantity of the catenane. This initial research was followed in 1961 by a landmark paper from Wasserman and Frisch [38] entitled “Chemical Topology.” Capturing the imagination of many synthetic chemists, this treatise explored the possibility of statistical knotting and/ or linking during the macrocyclization of long alkyl chains to create molecules such as trefoil knots and catenanes. While the statistical approach to the synthesis of mechanically interlocked compounds heralded the creation of a new ﬁeld of research, its development was hindered by the low yields and the limited structural diversity and scope of the compounds isolated initially. The early pioneers in the ﬁeld, Lüttringhaus and Schill [45], recognized the limitations of the statistical synthesis of catenanes and,

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8 A Short History of the Mechanical Bond

Historical Perspective – Mechanically Interlocked Molecules

Reactions Methods

1950

Chi Chiu

Sauvage Hunter Harada Leigh Smithrud Harriman Grubbs Beer Kim Jeppeson Fujita Balzani Seeman Credi Goddard Agam Wasserman Ogino Wenz Heath Smith Schill Walba Stoddart Vögtle Loeb Böhmer AndersonCoutrot Frisch Tian Sanders Busch Gibson Schalley Godt Zilkh Zilkha

Applications

People

Puddephatt

Structu ures

70

Molecular Electronics NanoActuators Gas Storage Drug Delivery NanoFluidics RGB Displays Bioimaging

Statistical Methods Kinetic Reactions

Templated Methods Covalent

Metal-Directed Charged H-Bonding Anion Donor-Acceptor Solvophobic Neutral H-Bonding

Active Metal

Wittig Pd-catalyzed ‘Click’

SN2

Thermodynamic Reactions

Dynamic Imines Metathesis SN2

Metal-Ligand

Disulfides Thioesters

Catenanes Rotaxanes

Trefoil Knots Daisy Chains Suitanes Solomon Knots Shuttles Borromean Rings Elevators

1960

1970

1980

1990

2000

2010

Figure 8.2 A list of timelines which describe, in collective fashion, the explosive progress in the ﬁeld of mechanically interlocked molecules, based on citing the dates of important concepts and practices, as well as key developments and the prime players.

in 1964, attempted to prepare appreciable quantities of them using dynamic covalent bonds to template their formation. In this strategy, steric control provided by well-designed covalent bonds prevents the extra-annular ring closures which plague the statistical method of catenation, thus increasing the yield of the desired pre-catenane precursor. The desired [2]catenane is then formed by breaking the templating covalent bonds, such that the two rings are no longer connected covalently. As this approach requires lengthy synthetic pathways, it still results in low yields overall. Working without a good understanding of the noncovalent bonding interactions associated with the more intricate templation methods, these early attempts to make catenanes were a testament to the synthetic skills of the chemists at the time. The simplicity of statistical methods prevailed again in 1967 with the synthesis of the ﬁrst wholly synthetic rotaxane by Harrison and Harrison [41–43]. In order to produce a rotaxane in appreciable quantities, these investigators attached a 30-carbon-containing ring to a resin and then ingeniously passed a pyridine/ dimethylformamide (DMF) solution containing decane-1,10-diol (thread) and triphenylmethyl chloride (stopper precursor) over the resin no less than 70 times. As the solution passes over the resin, some of the threads become stoppered at both of their ends while they are threaded through the tethered rings, thus creating a [2]rotaxane after cleaving the product from the resin and purifying it further. Despite having run the reaction some 70 times, the authors were able to report

8.1 Introduction

only a 6% yield. Although exceptionally clever and groundbreaking at the time, these statistical synthetic methods have since been entirely surpassed and replaced by template-directed synthetic methods which rely on molecular recognition and self-assembly. The synthesis by Harrison and Harrison was followed soon thereafter by the covalent template-directed synthesis of a [2]rotaxane by Schill and coworkers [48, 49]. Subsequently, chemists [40] have discovered the power of molecular recognition and self-assembly to overcome the poor yields associated with the traditional methodologies, by using noncovalent template-directed synthetic strategies. These strategies depend upon noncovalent bonding interactions to direct the assembly of complexes or pseudorotaxanes, wherein the components are mutually interwoven. These supramolecular assemblies [50–56] are then able to undergo postassembly covalent modiﬁcation, which may be either dynamic or kinetic in nature, to form the desired mechanically interlocked compounds. In these strategies, a template complexes with another component (usually a ring) by means of coordinative or noncovalent bonding interactions that include: (i) donor–acceptor forces; (ii) metal–ligand coordination; (iii) hydrogen-bonding; (iv) π−π stacking; (v) solvophobic repulsion; and/or (vi) electrostatic forces. The use of noncovalent bonding interactions to direct the synthesis of mechanically interlocked molecular compounds has real advantages in that it is possible to prepare complex mechanically interlocked molecular compounds in high yields, while employing fewer synthetic steps than would be required using the comparable covalent template-directed, or statistical approaches to synthesis. As an area of investigation, the inception of which can only be traced back seriously to the 1960s, the promise of the mechanical bond is only now being appreciated. New investigators (Figure 8.3) from varied backgrounds that include biology, chemistry, physics, and engineering are currently conducting research into innovative applications at the intersections of the traditional scientiﬁc disciplines. Beginning with the ﬁrst statistical syntheses of [2]rotaxanes and [2]rotaxanes in the 1960s and 1970s, chemists have sought different ways to create molecules with mechanically interlocked components. However, it was not until supramolecular assistance to covalent synthesis was conceptually uncovered during the early 1980s, with the use of metal-templation to produce a [2]catenate, that chemists had the conceptual toolbox ready to be implemented. Subsequently, throughout the 1980s and 1990s, chemists began to ﬁll this toolbox with a range of useful techniques, including an improved understanding of noncovalent bonding interactions, a greater control of molecular motions, an appreciation of kinetic versus thermodynamic processes, and a collection of covalent bond-forming reactions suitable for use in systems wherein the compounds are in dynamic equilibrium. Today, a whole collection of new synthetic tools is just beginning to be employed to create families of mechanically interlocked molecules with potential applications that range from cancer therapy and bioimaging to molecular electronics and electronic displays. With applications branching into diverse disciplines, it is no wonder that scientists the world over are sitting up and taking notice of the mechanical bond as it breaks upon the scene.

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Chemists of the Mechanical Bond Macartney Swager Fitzmaurice Hunter Nolte Rowan Stoddart Seeman Puddephatt Cooke Becher Anderson Sanders Jeppeson Branda Smithrud Beer Leigh Sauvage Lehn Vögtle Wozniak Garcia-Garibay Loeb Kato Atwood Kim Fujita Stang Grubbs Shinkai Heath Tian Ti Goddard Rebek

Sessler Busch

Smith Godt Credi Diederich Kaifer Coutrot Balzani Gibson Schalley

Chiu Harding Gunter Langford Willner

Figure 8.3 A map of the world displaying the global distribution of chemists whose research programs have encompassed the investigation of molecules containing mechanical bonds.

8.2 Donor/Acceptor Templated Systems

Template-directed synthesis, which is donor/acceptor based, began with the pairing of π-electron-rich rings with π-electron-deﬁcient rods which thread through the rings to form thermodynamically stable pseudorotaxanes [57–59]. The earliest recorded example of a donor/acceptor-based pseudorotaxane was reported in 1987 [57, 58]. In this example, an electron-rich macrocyclic polyether, bis-p-phenylene[34] crown-10 (BPP34C10), binds the electron-deﬁcient paraquat dication. The complex is held together by: (i) π−π stacking interactions between the complementary aromatic units; and (ii) [C–H…O] interactions between the hydrogen atoms – [CH3–N+] and [CH–N+] – in the positions α with respect to the positively charged nitrogen atoms in the bipyridinium unit and the crown ether oxygen atoms located in the polyether loops of the BPP34C10. The assembly of the BPP34C10/paraquat pseudorotaxane can be extrapolated to an inverse recognition system, wherein the host is constructed from two paraquat dications and the guest species is a hydroquinone unit, carrying ethylene glycol chains. This receptor system was reported by the present authors [59] in 1988, with the isolation and characterization of cyclobis(paraquat-p-phenylene) cyclophane (CBPQT4+), a promiscuous π-electrondeﬁcient receptor if there ever was one. Building on this recognition motif, the ﬁrst donor/acceptor-based templatedirected synthesis of a [2]catenane and a [2]rotaxane were reported in the literature

8.2 Donor/Acceptor Templated Systems

in 1989 and 1991, respectively [60, 61]. The mechanisms for the synthesis of both of these mechanically interlocked molecules are conceptually very similar. The synthesis of the donor/acceptor-based [2]catenane involves [60] the mixing of an acetonitrile solution of BPP34C10 with 1,4-bis(bromomethyl)benzene and the pyridylpyridinium salt, as shown in Scheme 8.1. The proposed mechanism for this reaction involves the pyridylpyridinium dication reacting ﬁrst with the bis(bromomethyl)benzene. Although this dication is not known to form a complex with BPP34C10, once a fully ﬂedged bipyridinium unit is formed within the thread, this intermediate trication threads through the BPP34C10 ring to form a pseudorotaxane, which is a more thermodynamically stable species than any of the other components individually. Once this 1 : 1 complex has formed, the hydroquinone units align themselves so as to template the formation of the second covalent bond, leading to the cyclization and formation of the CBPQT4+ ring. This ﬁnal step yielded the catenane in an astounding 70% yield with its built-in πacceptor/π-donor/π-acceptor/π-donor stack. It is this π–π sandwiching that leads to the [2]catenane being formed in such a highly efﬁcient manner. This mechanism, however, is less efﬁcient in the synthesis of the [2]rotaxane [61], as the dumbbell component is less preorganized on account of its increased conformational ﬂexibility. Thus, the analogous [2]rotaxane was formed in only 32% yield. Yet, compared to the previous approaches when creating rotaxanes, this yield was a windfall. The alignment by stacking of the π-acceptor and π-donor units in these interlocked molecules has been established using 1H NMR spectroscopy and by X-ray crystallography [60–62].

Donor/acceptor template-directed synthesis of a [2]catenane (top) and a [2] rotaxane (bottom).

Scheme 8.1

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More recently, Sanders and coworkers [7, 63–73] have introduced a πcomplementary donor/acceptor templation method involving neutral components. In this system, pyromellitic diimide (PmI) and naphthyl diimide (NpI) function as electron-poor recognition units, while dioxynaphthalene usually serves as the complementary electron-rich recognition site. Being more robust than the charged and strained bipyridinium moiety of CBPQT4+, the diimides tolerate a wider range of reaction conditions. The synthesis of one of the ﬁrst mechanically interlocked compounds to be made by this neutral templation strategy relied on an oxidative acetylenic coupling reaction, and afforded [63] an NpI-containing [2]catenane in 52% yield (Scheme 8.2). Grubbs alkene metathesis [64], zinc(II)-bipyridyl ligations [67], and Mitsunobu alkylation [68] have also been used for catenane synthesis. Rotaxanes, too, have been synthesized by neutral templation [69–74].

Scheme 8.2 A catenane synthesized by donor/acceptor templation, using neutral

components.

Following the development of these efﬁcient charged and neutral templatedirected methods, the dynamic processes associated with their interlocked products were studied. For example, by employing variable-temperature 1H NMR spectroscopy, it is possible to follow the motion of the CBPQT4+ ring as it shuttles back and forth between two identical hydroquinol recognition sites on the dumbbell component of a degenerate [2]rotaxane [61]. Subsequently, efforts were made to control this motion, using both chemical and electrochemical inputs. This goal was accomplished with the construction of a donor/acceptor-based [2]rotaxane, wherein one of the recognition sites is a much better π-electron-donating site for the π-electron-accepting CBPQT4+ ring than the other recognition site. The ring sits preferentially on the more attractive of the two sites in the ground state until a chemical or electrochemical stimulus is applied, so as to alter the π-electrondonating abilities of the two recognition sites and, consequently, the preferred location of the ring. In an ideal system, it is possible to move the ring reversibly back and forth between two or more recognition sites over many cycles [75–77].

8.2 Donor/Acceptor Templated Systems

A high level of control of this shuttling process was reported in an article in Nature [78] in 1994, following the synthesis of a bistable [2]rotaxane composed of a CBPQT4+ ring and a dumbbell containing both benzidine and biphenol recognition sites. Subsequent 1H NMR spectroscopic investigations showed that the CBPQT4+ ring prefers to occupy the benzidine site over the biphenol one to the extent of 5.25 : 1 in the ground state at 229 K [78, 79]. It is then possible to switch the recognition such that the stronger π-electron-donating unit becomes weaker than the second unit. In order to effect this change, the benzidine unit can either be oxidized electrochemically or protonated with an acid such as triﬂuoroacetic acid (TFA) to form, respectively, the radical cation or the dication. The result is that the positively charged benzidine unit repels the CBPQT4+ ring, which moves to 100% occupation of the biphenol π-electron-donating recognition site. As soon as the benzidine unit is reduced or deprotonated, the CBPQT4+ ring returns to encircling it for the most part since it is once again the stronger π-electrondonating unit. The molecular shuttle, as illustrated in Scheme 8.3, was synthesized by ﬁrst assembling the dumbbell and then clipping the components which comprise the CBPQT4+ ring around the dumbbell, under template control. A different system was designed using a reverse recognition-based bistable [2] rotaxane where the dumbbell contains two π-electron-withdrawing recognition

Scheme 8.3

An electrochemically and chemically switchable [2]rotaxane.

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sites – a PmI site and a NpI site – that is, the Sanders type of recognition units [71, 72]. The stoppers on the dumbbell were carefully chosen such that a DN38C10 ring is able to slip onto the axle of the dumbbell only at elevated temperatures to form the [2]rotaxane. When the dumbbell and crown ether macrocycle were heated to 60 °C in chloroform : methanol (95 : 5) in the presence of lithium ions (which enhance binding of the π-electron-donating DN38C10 to the dumbbell), the bistable [2]rotaxane was isolated in 60% yield. This compound has been shown (Scheme 8.4) to undergo switching, both electrochemically and chemically. In the ground state, the DN38C10 ring resides exclusively (to all intents and purposes) on the NpI unit, as determined by variable-temperature 1H NMR spectroscopy. The chemical switching process involves the addition of a source of lithium cations (in the form of LiBr or LiClO4) such that they form a strong 2 : 1 co-complex with the PmI unit and DN38C10 macrocycle. In order to reverse the switching, an excess of [12]crown-4 is added to the solution to sequester the Li+ ions and return the [2]rotaxane to its ground-state translational isomer. It is also possible to switch the rotaxane electrochemically, such that the NpI unit undergoes a oneelectron reduction and is deactivated so that the DN38C10 ring is obliged to move to the PmI recognition unit. It is possible thereafter to oxidize the system back to its ground state, and then continue to switch through multiple cycles. Finally, all recognition between the dumbbell and the ring can be turned off by reducing both the NpI and PmI units to their radical anions, such that both the recognition sites and the DN38C10 ring are π-electron-rich and, thus, are no longer involved in any donor–acceptor interactions.

Scheme 8.4 Switching of a neutral [2]rotaxane via binding of Li+ ions.

8.2 Donor/Acceptor Templated Systems

The translational isomerism of a bistable [2]catenane has been investigated by making one unit in the π-electron-donating ring of the catenane electrochemically active [80, 81]. This goal has been achieved most successfully by substituting a tetrathiafulvalene (TTF) unit for one of the 1,5-dioxynaphthalene (DNP) units in DN38C10, followed by clipping this crown ether with 1,4-bis(bromomethyl)benzene and the appropriate dicationic precursor to form an interlocked CBPQT4+ ring and, thus, a nondegenerate [2]catenane [82, 83]. This catenane is bistable with the lower energy isomer having the CBPQT4+ ring encircle the TTF unit (Scheme 8.5). However, when the TTF unit is oxidized to its radical cation or dication, the charged CBPQT4+ ring is repelled and the crown ether undergoes circumrotation, such that the DNP unit is encircled by the cyclophane. After reduction of the TTF moiety back to its neutral state, the crown ether relaxes slowly back to its ground state co-conformation, where the CBPQT4+ ring encircles the TTF unit.

An electrochemically switchable [2]catenane based on the π-electron-deﬁcient cyclophane, CBPQT4+, and its association with the π-electron-donating recognition units, TTF and DNP, in a crown ether ring.

Scheme 8.5

In addition to designing even more exotic molecular switches, recent research has been focused on increasing the efﬁciencies expressed during the templatedirected synthesis of mechanically interlocked molecules. With increased efﬁciencies, it is possible to construct even more complex molecular switches, or to synthesize the known compounds in yields sufﬁcient for their use in larger-scale applications. It is clear that synthetic chemists are becoming more adept at utilizing kinetically and thermodynamically controlled reactions to increase the yields of desired target compounds. While, historically, the ﬁrst method of choice for the preparation of charged donor/acceptor [2]rotaxanes involved [60] the clipping of the CBPQT4+ ring (or a derivative thereof) around a crown ether, it has been shown recently that it is also possible to trap kinetically a pseudorotaxane obtained (Scheme 8.6) from a glycolappended naphthalene thread encircled by a CBPQT4+ ring, using high-yielding reactions, such as the Cu(II)-mediated Eglinton coupling or the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition [84–89]. These reactions are particularly attractive because they are typically high-yielding and efﬁcient; additionally, they proceed under neutral, oxidative and non-nucleophilic conditions at room temperature. It was discovered that, when the dialkyne-appended naphthalene glycol was subjected to Cu(OAc)2 for four days, the two terminal alkynes underwent oxidative coupling, affording the resulting [2]catenane in 14% yield. The yield in this reaction was raised to 21% (Scheme 8.6, top) by using microwave irradiation for

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Scheme 8.6 Kinetically controlled reactions that have been used to synthesize [2]rotaxanes in

high yield. Top: Cu(II)-mediated Eglinton coupling; Bottom: Huisgen 1,3-dipolar cycloaddition.

20 min. In a similar fashion, by employing a Huisgen 1,3-dipolar cycloaddition (an extremely high-yielding and robust kinetically controlled reaction which has earned the name “click chemistry” as a result), it was found that the 1,5-dioxynaphthalene derivative containing glycol chains – one terminated with an azide function and the other with an alkyne – assembles efﬁciently with the CBPQT4+ ring to form a pseudorotaxane which cyclizes when exposed to CuSO4 for 24 h at room temperature, affording (Scheme 8.6, bottom) a [2]catenane in 41% yield. While neither of these reactions surpasses the yields in terms of those attained by clipping the CBPQT4+ ring around the equivalent π-electron-rich macrocycle, these new kinetically controlled methods are attractive because of their simplicity and brevity, and will undoubtedly prove to be highly useful in the synthesis of more complex mechanically interlocked compounds. Building on these successful results in the template-directed synthesis of [2]rotaxanes, “click chemistry” was promptly applied to the synthesis of bistable [2]rotaxanes containing TTF and DNP recognition units encircled by a CBPQT4+ ring [87–90]. By means of the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction, stoppers appended with a terminal alkyne functionality were reacted with a pseudorotaxane terminated by azide groups in the presence of CuSO4·5H2O and ascorbic acid (Scheme 8.7) to form the desired bistable [2]rotaxane in an impressive 60% yield. This example of the threading-followed-by-stoppering approach to the synthesis of a bistable [2]rotaxane beneﬁts from the full thermodynamic binding of the CBPQT4+ ring to the pseudorotaxane of interest, as the cyclophane is fully formed at the outset of the reaction. This strategy differs from the clipping one, in which the binding interactions are weaker between the intermediary cationic pyridinium oligomers and the dumbbell. In addition, the reaction can be performed at −10 °C in order to increase the concentration of pseudorotaxane with respect to free thread and free CBPQT4+ ring present in solution. Recently, a thermodynamic method has been applied [90] to the production of the “original” degenerate catenanes – namely, the CBPQT4+ ring interlocking

8.2 Donor/Acceptor Templated Systems

Synthesis of an electrochemically switchable [2]rotaxane synthesized in high yield, using “click chemistry.”

Scheme 8.7

either BPP34C10 or DN38C10 rings – in high yields by utilizing a set of errorchecking and proof-reading processes (Scheme 8.8) to provide, ultimately, the energetically most favorable species. The proposed mechanism of equilibration involves the nucleophilic attack by iodide (I−) anion on the CBPQT4+ ring at one of its four benzylic methylene centers, displacing one of the positively charged bipyridinium groups, opening the cyclophane and, in so doing, relieving a considerable amount of ring strain. This linear intermediate is then able to complex with a free crown ether, forming a pseudorotaxane in solution, followed by a reverse nucleophilic attack by the pyridyl nitrogen lone pair to displace the leaving group (I−) and hence generate the degenerate [2]catenane. This method has been coined a “magic ring” approach, as the synthesis begins with two closed macrocycles and

Proposed mechanism for the synthesis of a donor/acceptor [2]catenane under thermodynamic control.

Scheme 8.8

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results in a [2]catenane in the presence of a small amount of the catalyst, tetrabutylammonium iodide. Furthermore, it was found that the CBPQT4+/BPP34C10 catenane could be isolated in 46% yield from a 1 : 1 solution of the starting materials. The equilibrium was much more favorable in the case of the formation of the CBPQT4+/DN38C10 catenane, which was formed in 93% yield. Finally, it is important to note that other nucleophilic catalysts such as dimethylaminopyridine and tributylphosphine were ineffective because they reduced and degraded CBPQT4+, and that 4,4′-bipyridine and KI were inert – in the case of KI, most likely because of its limited solubility in the acetonitrile solvent.

8.3 Charged Hydrogen Bond-Templated Systems

Since Pedersen’s early discovery [91–94] that crown ethers complex with both organic and metal cations, numerous investigations [95–98] have been carried out on the binding of ammonium and primary alkylammonium ions with macrocyclic polyethers. The complexes formed from these cations are face-to-face in character, they exhibit 1 : 1 stoichiometries, and they do not result in threaded geometries. Building on this initial research, it was ﬁrst reported in the literature in 1995 by Busch [99] and ourselves [100] that secondary dialkylammonium ions will form pseudorotaxanes by the insertion of R2NH2+ ions through a macrocyclic polyether, provided that the ring is large enough. For example, in the case of dibenzo[24] crown-8 (DB24C8) and dibenzylammonium hexaﬂuorophosphate (DBA+), it has been shown [100–104] that a strong 1 : 1 threaded complex is formed (Figure 8.4a) in the solution state when equimolar amounts of each compound are dissolved in a poor hydrogen-bonding solvent. In CD3CN at room temperature, three sets of signals appear in the 1H NMR spectrum corresponding to free DB24C8, free DBA+, and the 1 : 1 complex. Signals for the complexed DBA+ and benzylic methylene protons are shifted considerably upﬁeld because of [N+–H…O] and [C–H…O] hydrogen-bonding interactions, respectively, with the encircling crown ether oxygens. The presence of both the free and complexed species in equilibrium implies that the rates of complexation and decomplexation are slow on the NMR (a)

(b)

(c)

(d)

Figure 8.4 Pseudorotaxanes containing (a) dibenzylammonium, (b) 4,4′-bipyridinium, (c) 1,2-bis(pyridinium), and (d) bis(benzimidazolium) threads are encircled by DB24C8.

8.3 Charged Hydrogen Bond-Templated Systems

timescale. Based on the results of X-ray crystallography conducted on single crystals, it is also possible to observe the presence of these hydrogen bonds in 1 : 1 complexes in the solid state. In addition, π−π stacking interactions are observed between the phenyl rings of the DBA+ thread and the catechol rings of the DB24C8 macrocycle. Further evidence for this 1 : 1 complex was provided by mass spectrometry and elemental analysis. In summary, the formation of this 1 : 1 complex can be attributed to, (i) hydrogen-bonding interactions involving the charged and/ or activated donors and neutral acceptors, (ii) electrostatic pole–dipole interactions between the ammonium center and precisely positioned ligating atoms, and (iii) in some instances, dispersive interactions, including stabilizing π–π and/or CH–π interactions. By using 1H NMR spectroscopy, an association constant (Ka) of 27 000 M−1 in CDCl3 between DB24C8 and DBA·PF6 was determined, using the single-point method. Additionally, it was shown [105] that when the DBA+ thread is para-substituted with electron-donating groups, such as OMe or Me, a weaker binding is exhibited towards DB24C8; in contrast, if the substituent is electronwithdrawing, such as NO2 or CO2H, then binding of the macrocycle by the thread is enhanced. Furthermore, Busch and coworkers [105] have conducted a detailed study of the binding of a variety of other dialkylammonium threads to DB24C8 in acetone. Soon after the development of ammonium-based threads for DB24C8, a second, weaker binding station was sought so that it could be incorporated into switchable catenanes and rotaxanes. The 4,4′-bipyridinium cation (Figure 8.4b) was investigated [106, 107] and found to be suitable, and binding between it and DB24C8 was considerably weaker than that between DB24C8 and DBA+, but stronger (presumably because of [C–H…O] hydrogen bonding as well as π−π stacking interactions) than the binding between neutral DBA and DB24C8. Because of these different binding afﬁnities, it was possible to synthesize a two-station, acid–base-switchable [2]rotaxane. In this system, DB24C8 initially resides exclusively on the DBA+ station, until deprotonation and subsequent movement of the macrocycle to the 4,4′-bipyridinium station. Reprotonation causes the macrocyle to return to its initial position on the DBA+ station. In 1998, Loeb and coworkers [108] described a new, isomeric pyridinium-based binding site (Figure 8.4c), namely 1,2-bis(pyridinium)ethane, which shortens the distance between the pyridinium nitrogen atoms to 3.75 Å, from 7.00 Å in the 4,4′-bipyridinium unit. This change in geometry allows for a strong complex to be formed between the bis(pyridinium)ethane dication and DB24C8 as a result of eight [C–H…O] hydrogen bonds, eight [N+…O] interactions, and π–π stacking interactions between the catechol rings of the crown ether and the electron-poor aromatic rings of the pyridinium unit. This system was found to be particularly susceptible to changes in the functional groups at the 4-positions of the pyridinium rings. In solution, when X = H, the Ka was found to be 180 M−1 in MeCN at 298 K with BF4− counterions, while the introduction of an electron-withdrawing group (X = COOEt) resulted in a Ka value of 1200 M−1 under the same conditions. Recently, yet another recognition unit for the DB24C8 ring was developed [109], in this case, around a bis(benzimidazolium) cation (Figure 8.4d). In contrast to

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the bis(pyridinium)ethane dication, the self-assembly of the imidizolium-based pseudorotaxane is largely attributed to charge-assisted [N+–H…O] rather than to the neutral [C–H…O] interactions present in the Loeb system. This system also utilizes strong ion–dipole and π–π stacking interactions during its self-assembly. On account of the conjugated nature of the benzimidazolium cation, it is possible to vary the strength of these interactions by changing the nature of the substituent groups on the axle. Speciﬁcally, substitution of the thread with an electronwithdrawing group (COOEt) increases the amount of pseudorotaxane formation in solution, while substitution with an electron-donating group (Me) decreases it. By using 1H NMR spectroscopy, it was found that the PF6− salt of the parent bis(benzimidazolium) thread with X = H has association constants (Ka values) at 298 K of 670 M−1 in CD3CN and 3050 M−1 in CD3NO2 with DB24C8. While these four structural types represent the most widely used charged hydrogen-bonding motifs reported to date, variations, combinations and novel structures for use as building blocks in the template-directed synthesis of mechanically interlocked molecules are continually being developed [110]. 8.3.1 Reverse Recognition in Rotaxane Synthesis

In contrast to the standard recognition motif, in which a hydrogen bond-donating thread is encircled by a hydrogen bond-accepting macrocycle, it has been shown [111] that the reverse recognition motif can also be employed in the templatedirected synthesis of mechanically interlocked molecules. It is possible to synthesize (Scheme 8.9) a macrocycle containing two secondary dialkylammonium centers which are available for complexation. Subsequently, when presented with a glycol thread, the ﬂexible chain inserts itself through the macrocycle, forming a stable pseudorotaxane as the glycol chain wraps itself around the two −NH2+ − centers to form [C–H…O] interactions and [N+–H…O] hydrogen bonds. The ends of the thread can then be reacted with triphenylphosphine to provide the desired rotaxane in 15% yield. While the standard recognition motif between the −NH2+ − centers in secondary dialkylammonium ions and the oxygen atoms present in

The template-directed synthesis of a [2]rotaxane utilizing an “inside-out” recognition motif, employing charged hydrogen-bonding interactions.

Scheme 8.9

8.3 Charged Hydrogen Bond-Templated Systems

crown ethers has been widely exploited, the reverse recognition motif with macrocycles containing −NH2+ − centers has been studied less extensively. 8.3.2 Threading-Followed-by-Stoppering Protocols

The traditional method for synthesizing [2]rotaxanes is by the threading-followedby-stoppering protocol, in which a thermodynamically stable pseudorotaxane is formed between a macrocycle and a thread, and the 1 : 1 complex is subsequently reacted with stoppers in order to prevent the macrocycle from dethreading. This method of rotaxane formation has been shown to be effective in the synthesis of a variety of charged hydrogen-bonding-based systems. For example, in the synthesis (Scheme 8.10) of 1,2-bis(pyridinium)ethane-based rotaxanes, Loeb and coworkers [112–117] showed that it is possible to obtain a metallo[2]rotaxane quantitatively by adding [Pd{C6H3(PhSCH2)2}(MeCN)]BF4 and 3 equiv. of DB24C8 to 1 equiv. of the 1,2-bis(pyridinium)ethane thread. In particular, this stoppering strategy is highly successful, a point reﬂected in the fact that it proceeds in excellent yield

Scheme 8.10 The template-directed synthesis of a 1,2-bis(pyridinium)ethanebased metallo[2]rotaxane using the threading-followed-by-stoppering protocol. The [2]rotaxane is shown as a Newman

projection in order to emphasize the four stabilizing [C–H…O] interactions responsible for the self-assembly of the DB24C8 macrocycle with the 1,2-bis(pyridinium) ethane unit.

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and permits a variety of termini to be appended to the [2]pseudorotaxane, without perturbing its self-assembly. 8.3.3 Clipping Protocol

While clipping reactions to form donor/acceptor [2]rotaxanes and [2]rotaxanes are extremely common, clipping is less common in hydrogen bond-based systems, as the electron-rich macrocycle tends to be a ﬂexible crown ether which does not contain the preorganization necessary to undergo efﬁcient clipping reactions. However, several systems have been developed which employ an error-checking process made possible through reversible covalent bond formation. This approach allows a ﬂexible macrocycle to encircle a macrocycle or dumbbell containing an ammonium center, despite the conformational freedom of the ring precursor. Performing clipping reactions under thermodynamic control has proven to be an efﬁcient method of synthesizing mechanically interlocked compounds templated by hydrogen-bonding interactions [118]. Oleﬁn metathesis mediated by functional group-tolerant ruthenium alkylidene catalysts is regarded as an excellent reversible reaction. This reaction has been employed to yield both [2]rotaxanes and [2]catenanes [119] as a result of the clipping of an oleﬁn-containing crown ether-like macrocycle (Scheme 8.11). This

Scheme 8.11

metathesis.

“Magic ring” synthesis of a [2]rotaxane and a [2]catenane, using oleﬁn

8.3 Charged Hydrogen Bond-Templated Systems

reaction is another example of the “magic ring” approach to the formation of mechanically interlocked molecules. The reaction proceeds from an empty closed ring to a ring being linked in at least a 95% yield with an ammonium-containing stoppered dumbbell or macrocycle as if by magic, or more speciﬁcally in this case, by oleﬁn metathesis. While the metathesis reaction yields a mixture of cis and trans double bonds, it is possible to simplify this mixture by hydrogenation (H2/PtO2) of the double bonds. Thus, it is possible to use ammonium centers to template the cyclization of an oleﬁn-appended glycol chain to form mechanically interlocked compounds, in good yields. The dynamic nature of imine bond formation has also been exploited [120, 121] to clip [24]crown-8-like macrocycles around ammonium threads already appended with stoppering groups (Scheme 8.12). This system was designed such that a ﬂexible bis(2-aminophenyl)ether will undergo reaction with an appropriate dialdehyde to form dynamic imine bonds. In the absence of a template, a library of different dynamic oligomers is formed, but if a secondary dialkylammonium template is present, then the bis(2-aminophenyl)ether will wrap itself around the −NH2+ − center via hydrogen-bonding interactions such that, on reaction with the dialdehyde component, a [2]rotaxane is formed. This [2]rotaxane is dynamic until the imine bonds are chemically reduced; consequently, the rotaxane is no longer susceptible to hydrolysis and can be isolated in 70% yield.

Scheme 8.12

Template-directed synthesis of [2]rotaxanes, using reversible imine bond

formation.

Building on previous systems, a new method was recently developed which involves the reaction of 2,6-diformyldipyridine with two short amine linkers to form a dynamic combinatorial library (DCL) consisting of a mixture of different oligomers. It was shown that, when a template is introduced to the DCL, the

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reversible imine bonds equilibrate to such an extent that a [24]crown-8-like macrocycle is formed around a secondary dialkylammonium ion template in 35% yield, as measured with 1H NMR spectroscopy [122]. Exchange experiments involving the addition of 4-chloro-2,6-dipyridine were performed, verifying that the resulting [2]rotaxane remains a dynamic species in solution: a mixture of nonchlorinated, mono-chlorinated and di-chlorinated [2]rotaxanes could be observed by 1H NMR spectroscopy. 8.3.4 Slippage

Several investigations into the assembly of charged hydrogen bonding-based [2] rotaxanes using a slippage protocol have been reported [123–125]. This method requires matching the size of the macrocycle and the stoppers of the dumbbell such that, at elevated temperatures, the macrocycle will slip over the sterically hindering stoppers. It is not possible to distinguish [2]rotaxanes formed by slippage deﬁnitively from kinetically stable pseudorotaxanes. For example, if cyclohexyl units are appended to a dialkylammonium center (Scheme 8.13), then assembly of the two components will require the heating of a dichloromethane (DCM) solution containing the dumbbell and DB24C8 to 40 °C for 36 days until the equilibrium state, in which >97% of the threads are encircled by a ring, is reached. It has also been shown [126] that, as a consequence of the negative volumes of activation associated with slippage, it is possible to accelerate the threading process by using ultra-high pressure. Conversely, if this assembly is then placed in an electrondonating solvent, such as DMSO, which disrupts hydrogen bonding, the complex will dissociate into its components over 18 h at 20 °C. This “schizophrenic” type of behavior means that the assembly behaves as a rotaxane in one environment, but in another environment it will show all the characteristics of a pseudorotaxane. Thus, for this class of mechanically interlocked molecules, a “fuzzy” domain exists between the realms of supramolecular assemblies and molecular entities obtained using the slippage approach.

Scheme 8.13 Synthesis of a dialkylammonium/DB24C8 kinetically stable [2]pseudorotaxane

with cyclohexyl stoppers.

8.3 Charged Hydrogen Bond-Templated Systems

8.3.5 Ring Shrinkage

In a method which conceptually is somewhat related to both clipping and slippage mechanisms, it is possible to form a [2]rotaxane using a mechanism (Scheme 8.14) which has been described in the literature as “shrinkage.” In this mechanism, a macrocycle which is easily able to slip over the bulky stoppers of a dumbbell component does so, and forms a pseudorotaxane in solution. However, with the addition of a transition metal (e.g., palladium or nickel) to this 1 : 1 complex, a strong coordination occurs between a salophen [N,N′-o-phenylenebis(salicylideneiminato) dianion] moiety in the macrocycle and the metal, such that the effective diameter of the macrocycle is reduced. If this reduction in diameter is sufﬁcient to prevent the dumbbell from dethreading, a [2]rotaxane is formed. Yields of isolated rotaxanes in the range of 26–30% have been reported using this approach [127, 128].

Scheme 8.14 Synthesis of a [2]rotaxane by contracting the size of the template macrocycle via metal coordination.

8.3.6 Threading Accompanied by Swelling

Recently, Chiu and coworkers [129] described an elegant method by which a [2]rotaxane was synthesized simply by heating a solution containing a macrocycle and a dumbbell (Scheme 8.15). The reaction proceeds as a result of the complexation of a dialkylammonium thread with a hydrogen bond-accepting ring component. When heated, the terminus of the thread, a cis-1[(Z)-alk-1′-enyl]2-vinylcyclopropane moiety, undergoes a Cope rearrangement to produce a “swollen” – and, thus, sterically bulkier – cycloheptadiene moiety. At ambient temperatures, the cycloheptadiene unit is large enough to prevent dethreading of the macrocycle, yielding the desired [2]rotaxane in 86% isolated yield. This approach may prove to be very useful in certain contexts, as it does not require the addition of any reagents to effect stoppering. However, as the reaction must be heated to 70 °C, such a relatively high temperature may result in some decomplexation of the parent pseudorotaxane, causing a lowering of the rotaxane yields.

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Scheme 8.15 An example of the threading-accompanied-by-swelling approach to [2]rotaxane

formation.

8.3.7 Other Mechanically Interlocked Molecules

In addition to the archetypal catenanes and rotaxanes, a new class of mechanically interlocked molecules has recently been designed in which two separate components – a body with two or more limbs that are rigid and protrude outward, and a single-component “suit” which encompasses the torso of the body – are held together as a single molecule by the inability of the “torso” to escape the conﬁnes of the suit. Referred to as “suitanes,” these molecules are considered to be internally stoppered, with the steric bulk and rigidity of the limbs preventing decomplexation of the guest and suit present in the center of the thread. This effect is augmented by a semi-rigid “suit” component. This class of molecule may be expanded to encompass bodies with many limbs, such that a body with n limbs protruding from a suit would be termed a suit[n]ane [9]. A suit[2]ane [9] (Scheme 8.16) and a suit[3]ane [10] which were ﬁrst described in 2006 relied on the binding of secondary dialkylammonium centers to dipyrido[24]crown-8, a macrocycle that can be substituted symmetrically with formyl groups for further elaboration. When the crown ether and torso components are combined, the macrocycles thread spontaneously onto −NH2+ − centers to form [3]- or [4]pseudorotaxanes. The peripheral formyl groups can then undergo reaction with an aromatic di- or tri-aminobenzene linker, forming reversible imine bonds which stitch together the suit around the torso, so as to form a suit[2]ane or suit[3]ane, respectively. The formation of suitanes using this mechanism allows

Scheme 8.16

product.

A suit[2]ane synthesized as the most thermodynamically stable reaction

8.3 Charged Hydrogen Bond-Templated Systems

for reversibility and error-checking in the assembly process, a phenomenon which allows the assembly of these complex molecules to proceed in high (>95%) yields. 8.3.8 Molecular Switches

When constructing complex mechanically interlocked molecules using a templatedirected synthesis, it is advantageous to incorporate additional functionality into the molecules. In particular, the ability to control the translational motion of the components within a mechanically interlocked molecule is of considerable interest – and possibly also value. By using the variation in pKa of different charged hydrogen-bonding donors, it is possible to protonate/deprotonate hydrogen bonddonating stations selectively, such that the different stations possess different binding afﬁnities within a range of pH values for hydrogen bond-accepting macrocycles [130]. By using the ability to change the hydrogen bonding character of the binding stations, a variety of pH-responsive molecular shuttles have been designed and constructed [131]. The ﬁrst charged hydrogen bonding-based molecular shuttle was described in 1997 [106, 107]. In order to construct the shuttle, a pseudorotaxane was assembled by mixing a thread containing a secondary dialkylammonium center with DB24C8. On subsequent reaction of the pseudorotaxane with 3,5-di-tert-butylbenzylbromide, the thread was stoppered and a 4,4′-bipyridinium station formed (Scheme 8.17) as a result. When the −NH2+ − center in the [2]rotaxane is protonated, the DB24C8 macrocycle is bound to this center with a selectivity of at least 98% over a temperature range of between −80 °C and +31 °C. On deprotonation of the secondary dialkylammonium center with a base (such as iPr2NEt), however, the ring shuttles to the more weakly binding 4,4′-bipyridinium station. The shuttling motion of the macrocycle can be reversed by the addition of TFA, which reprotonates the −NH2+ − center so that is binds the DB24C8 macrocycle strongly once more. This addition of acid returns the shuttle to its initial state, rendering it fully reversible, as observed by 1H NMR spectroscopy. Building on this initial success, a C3-symmetric tripodal structure containing three shuttles, joined by a 1,3,5-substituted phenylene unit and threaded through three DB24C8 rings fused to a triphenylene core, was constructed and referred to as a molecular elevator [132]. The molecular elevator was synthesized using a threading-followed-by-stoppering protocol in which a stable 1 : 1 complex was formed between the fused crown component and the trisammonium tripod. Assembly of the 1 : 1 complex results from a combination of strong [N+–H…O] hydrogen bonding and weak [C–H…O] interactions, ampliﬁed by π−π stacking forces between the components. On the addition of 3,5-di-tert-butylbenzylbromide, each leg of the tripod becomes stoppered, forming the desired compound in 74% yield. This molecular machine operates analogously to the simple molecular shuttle described in Scheme 8.17. Although the hydrogen bond-accepting ring component prefers to encircle the −NH2+ − centers, it moves to occupy the 4,4′-bipyridinium sites upon deprotonation of the −NH2+ − centers with a base. Reprotonation of these centers by acid restores the molecular elevator to its original state.

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Scheme 8.17 Synthesis and reversible shuttling of a charged hydrogen bonding-based

molecular shuttle.

The operation of such an elevator has been demonstrated over 10 shuttling cycles, and generates approximately 200 pN in force, while the ring component travels approximately 0.7 nm. Clearly, with dimensions of only about 2.5 nm × 3.5 nm, the molecular elevator is a complex structure capable of performing well-deﬁned mechanical movements under the actions of external inputs.

8.4 Anion-Templated Synthesis

Although other types of templation (e.g., metal-directed, donor/acceptor, solvophobic, hydrogen-bonding) emerged during the 1980s and 1990s as powerful methods for the synthesis of mechanically interlocked compounds, anionic methods were not employed successfully until about 1999. This lag in the development of aniontemplated syntheses of mechanically interlocked compounds can be attributed to

8.4 Anion-Templated Synthesis

the intrinsic properties of anions. Notably, their diffuse nature, pH sensitivity and relatively high energies of solvation have resulted in very different challenges in terms of both design and synthesis. Nonetheless, the wide variety of anionic templates currently found in general in supramolecular systems points to a strong potential for anion-templation as a highly controllable method for the synthesis of mechanically interlocked compounds [133, 134]. The seminal studies in this area were conducted by Vögtle and coworkers [135], who ﬁrst showed that it is possible to template the synthesis of [2]rotaxanes in high yield by arranging for noncovalent bonding interactions between negatively charged molecules and charge-neutral, hydrogen-bonding moieties. In this case, templation is envisaged (Scheme 8.18) to take place through the formation of a phenolate–wheel semirotaxane complex between a sterically hindered phenolate anion and the amide groups of a macrolactam macrocycle. This complex was shown to form in near-quantitative yield in solution. The supramolecular intermediate is then able to act as a nucleophile to displace the bromide anion from a semiaxle component, by means of an SN2 reaction, thus forming the desired [2]rotaxane in yields of up to 95%. The mechanism of this reaction differs from that of other template-directed systems, in than it proceeds through a semirotaxane rather than a pseudorotaxane intermediate. This situation occurs because the axle is not threaded through the ring when the thermodynamically stable supramolecular intermediate is formed. Building on the approach ﬁrst introduced by Vögtle, Schalley and coworkers [136] subsequently re-engineered the axle component of the [2]rotaxane such that it contained a phenolate anion that was centrally placed in order to mediate the

Scheme 8.18 The anion template-directed synthesis of a [2]rotaxane semirotaxane intermediate, as described by Vögtle and coworkers [135].

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template effect, and also had two terminal functional (NH2) groups, suitable for attaching bulky stoppers (Scheme 8.19). It was found that the phenolate anion could be formed by treating the axle component and macrocyclic lactam with Schwesinger’s P1 base to form the desired pseudorotaxane. Interestingly, other bases, such as K2CO3/18-crown-6 or NaH, proved ineffective. The primary amine groups at the termini of the axle were then able to undergo substitutions with acid chloridefunctionalized stoppers to form the desired [2]rotaxane. This rotaxane differs from that ﬁrst synthesized by Vögtle [135], in that the dumbbell component still has strong hydrogen-bonding interactions with the macrocycle after formation of the rotaxane. Yet, this recognition element between the dumbbell and ring may prove to be useful for the future development of molecular motors, as has been noted for other classes of mechanically interlocked molecules formed by templation.

Scheme 8.19 Synthesis of a mechanically interlocked [2]rotaxane, using the threading-

followed-by-stoppering approach and relying on an anion-templated assembly of a pseudorotaxane, as reported by Schalley and coworkers [136].

More recently, Beer and coworkers [137, 138] have developed an anion-templation motif by utilizing a noncovalently bound chloride anion template in place of the covalently bound phenoxide anion template. The noncovalent nature of the association between the anion and the hydrogen-bonding groups makes this system analogous to the metal-templated systems of Sauvage, while the covalently bonded ion templates of Vögtle and Schalley more closely resemble the charged hydrogenbonding systems. The interwoven assembly of the two components is based (Scheme 8.20) on three different sets of noncovalent bonding interactions, namely: (i) anionic binding between the chloride ion and the hydrogen atoms of the amide moieties; (ii) π−π stacking between the pyridinium and phenylene rings; and (iii) hydrogen bonding between the acidic methyl protons and the electronegative oxygen atoms of the polyether tails. The assembled structure was then shown to undergo ring-closing metathesis (RCM) in 78% yield from a 1 : 1 mixture of the PF6− and Cl− salts. The authors were also able to show that the anion-templation

8.5 Neutral Hydrogen Bond-Templated Systems

Scheme 8.20 The synthesis of a [2]catenane via the self-assembly of a supramolecular intermediate as a consequence of [Cl−…H–N] interactions, eight [C–H…O] hydrogen bonds, and π-stacking interactions between

the phenylene and pyridinium aromatic rings. The supramolecular aggregate undergoes RCM in the presence of a Grubbs ﬁrstgeneration catalyst, in 78% yield.

was essential for the assembly of the supramolecular intermediate, since, when only the PF6− components were subjected to RCM, the [2]catenane was formed in only a 16% yield. This templation motif has also been shown to be effective in the synthesis of [2]rotaxanes by clipping the macrocyclic precursor around a functionalized dumbbell using RCM in 47% yield [139, 140]. Anion-templated synthesis represents one of the most recent supramolecular motifs among the chemist’s arsenal that can be used to create mechanically interlocked molecules. Moreover, it continues to exhibit considerable promise, and is likely to remain a highly effective synthetic method, based on the high yields obtained and the high speciﬁcity of the noncovalent bonding interactions involved during templation.

8.5 Neutral Hydrogen Bond-Templated Systems

A new approach to the templated synthesis of mechanically interlocked molecules was discovered [3, 15, 141–143] during the early 1990s whereby, in contrast to the use of anions, metal cations, or charged organic species as templates, neutral

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components are used, and the method relies primarily on the concerted action of multiple hydrogen bonds. This method is versatile, and also provides access to a variety of catenanes and rotaxanes, while the robust nature of the amide and sulfonamide functionalities involved allows for post-assembly modiﬁcations. Further exploitation of this methodology has produced a variety of knots [35], as well as stimuli-responsive switches, shuttles, and machines [144, 145]. New examples of calixarene–catenane and calixarene–rotaxane hybrids, based on a urea-binding motif, have been reported as the ﬁeld continues to expand. The discovery of hydrogen bond templation in 1992 and the development of the technique up to the present day are discussed in the following sections, with attention focused on the fundamental architectures, synthetic methods, and binding motifs. 8.5.1 Catenanes

While attempting to synthesize a tetralactam macrocycle for binding studies with benzoquinone, Hunter [146] instead uncovered an octaamide catenane as a sideproduct in 34% yield (Scheme 8.21, top). The mechanical bonding in the catenane

Scheme 8.21 Synthesis and structure of Hunter’s original amide-based [2]catenane [146]. Top: synthesis of the octaamide [2]catenane; Bottom left: The intended tetraamide macrocyclic target; Bottom right: The X-ray crystal structure of the catenane

with all hydrogens omitted for clarity except those (light blue) involved in intracatenane hydrogen bonding (red). One amide of each macrocycle is ﬁxed within the center of the other macrocycle by three hydrogen bonds.

8.5 Neutral Hydrogen Bond-Templated Systems

was established using elegant two-dimensional (2-D) NMR studies, while a subsequent X-ray crystal structure (Scheme 8.21, lower right) showed [147] each macrocycle hydrogen bonding to one amide of the other. In each amide guest, the carbonyl oxygen interacts with two amide hydrogens of an isophthaloyl subunit of an encircling macrocylic host, so as to form an unusual bifurcated hydrogen bridge in which the hydrogen bonds are orthogonal to the carbonyl lone pairs. More typical hydrogen bonds are present between the hydrogens of the bound amides and the carbonyl oxygens of the encircling macrocycles. Overall, to furnish the six hydrogen bonds in the octalactam catenane, one amide of each macrocycle is inverted, having its carbonyl oxygen pointing toward the middle of a ring. In other words, one isophthaloyl subunit per macrocycle is cisoid and one transoid, to produce the same type of macrocycle conformations as were deduced from the initial solutionphase NMR experiments. These results emphasized the importance of hydrogen bonding in catenane templation, a process that has been examined in many further studies. While investigating the synthesis of basket-shaped host molecules, Vögtle and coworkers [148] discovered a simple, one-step synthesis of a similar octaamide catenane, but which had methoxy substituents (Scheme 8.22). These results were reported very shortly after Hunter’s initial disclosure, and followed [149] by a report of the step-wise syntheses of isomeric octaamide catenanes that were monomethoxy-functionalized in one or both macrocycles. Discrete catenane

Scheme 8.22 Synthesis of catenane isomers. Top: The Vögtle group’s one-step synthesis [148] of a methoxy-substituted octaamide catenane; Middle: The in and out catenane isomers obtained when one macrocycle is

substituted with a methoxy group; Bottom: The in/in, out/in, and out/out isomers obtained when each macrocycle is substituted with one methoxy group.

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isomers were accessible on account of the presence of the bulky cyclohexylidene moieties, which prevented circumrotation of the interlocked rings. Depending on the sequence of reactant addition, different isomers were produced. For example, catenanes with one methoxy-substituted isophthalamide subunit gave rise to in and out isomers, whereas catenanes having both macrocycles monomethoxyfunctionalized led to in/in, out/in, and out/out isomers. The Vögtle group proposed a templation process for catenane formation in which a diacid chloride (or monoacid–monoamide) nestles within the wheel of a fully formed macrocycle, and reacts with a diacid chloride to close a second macrocycle and produce a catenane. Later, the poor binding of acid chlorides by tetralactam macrocycles was demonstrated experimentally, with emphasis being placed instead on the intermediacy of a complexed monoacid–monoamide as the precursor to catenane formation. Other structural variants, including [2]rotaxanes with a sulfamide functionality in the macrocycles or with aliphatic segments in one macrocycle, were also synthesized [150, 151] (Scheme 8.23, top). The successful construction of the latter showed that π–π interactions were not necessary for templation, and that hydrogen bonding was the key interaction. The post-assembly modiﬁcation of a sulfonamidecontaining catenane afforded [152] the ﬁrst pretzel-shaped molecule (Scheme 8.23, bottom).

Scheme 8.23 Sulfonamide-containing catenanes and a molecular pretzel. Top left: The prototype catenane with sulfonamide functionality; Top right: A sulfonamide

catenane with aliphatic segments in one ring; Bottom: A pretzel-shaped molecule obtained by dialkylation of a [2]catenane.

8.5 Neutral Hydrogen Bond-Templated Systems

In 1995, a new type of amide catenane was reported by Leigh and coworkers [153]. This discovery was, again, fortuitous as the intended target of the designed synthesis was a tetraamide macrocycle to be used for CO2 binding studies. Although no free macrocycle was produced, a benzylamide catenane was isolated in 20% yield – a surprisingly high recovery considering that an eight-molecule condensation was required for its one-step assembly (Scheme 8.24).

Scheme 8.24 The benzyl amide macrocycle and [2]catenane. Top left: Leigh’s original synthetic target macrocycle [153] intended for CO2 binding studies; Bottom: One-step synthesis of the benzylic amide catenane.

The crystal structure of Leigh’s catenane revealed one inverted amide in each macrocycle, echoing the solution-phase structures of the Hunter and Vögtle catenanes. One amide of each macrocycle was bound to the other macrocycle by three hydrogen bonds, for an intramolecular total of six. As a result of careful consideration of the X-ray crystallographic data, the authors proposed [154] that “… the driving force for catenane formation is hydrogen bonding between the newly formed 1,3-diamide units and carbonyl groups on the acid chloride or other intermediates.” The catenane-forming reaction itself was tolerant of structural variation in both the aromatic 1,3-dicarbonyl component and the benzylic spacer, affording products in 15–27% yields. Recently, a detailed molecular mechanics study was performed [155] on a series of bimolecular adducts including short linear oligomers of the dibenzylamine and diacid chloride building blocks of the [2]catenane. Adducts involving the free macrocycle and short oligomeric guests were also analyzed. The relative stabilities of these possible supramolecular intermediates provided an insight into the mechanism of formation of [2]catenanes. It was determined that the self-assembly of benzylic amide [2]rotaxanes involves the intertwining of acyclic oligomer chains, followed by two macrocyclizations, rather than the independent formation of one macrocycle followed by axle threading and a second macrocyclization, as was

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proposed for catenanes of the Hunter and Vögtle type. Nevertheless – and consistent with the latter mechanism – the calculations conﬁrmed the importance of hydrogen bonding. The driving force for the assembly of the smaller benzylic amide catenanes was found to be the formation of bifurcated hydrogen bonds, with π-stacking playing only a minor role. Using a modiﬁed synthesis, two adjacent amides in each ring of the catenane were replaced with esters linked by aliphatic chains (Scheme 8.25, top). In the X-ray crystal structure of this modiﬁed catenane, the same characteristic type of amide hydrogen bonds was observed, but no π-stacking interactions were found. This abservation led the authors to suggest [156] that “… such [π–π] interactions are, after all, of limited importance in the catenane assembly process.”

Scheme 8.25 Synthesis of [2]rotaxanes containing aliphatic and alkenyl segments. Top: A reaction producing a [2]catenane with aliphatic segments; Bottom: A “magic ring”

reaction – an oleﬁn metathesis in which the catenane and its free macrocycle are in equilibrium, and in which the catenane is favored at high concentrations.

A similar [2]catenane with oleﬁn functionality was templated [157] by using, in lieu of a kinetically controlled condensation of amines and acid chlorides, a thermodynamically controlled metathesis reaction of the corresponding free macrocycle (Scheme 8.25, bottom). Speciﬁcally, a ruthenium catalyst was added to a 0.2 M solution of the macrocycle, and the system allowed to equilibrate to provide a 95% yield of the product catenane. This “magic-rings” approach to amide-based catenanes is analogous to Fujita’s self-assembly of palladium(II)containing [2]catenanes (as described in Section 8.6), in the sense of being under thermodynamic control.

8.5 Neutral Hydrogen Bond-Templated Systems

8.5.2 Rotaxanes

With reference to their proposed threading mechanism for catenane formation, Vögtle’s group [158–161] synthesized rotaxanes by using a four-component (two stoppers, one macrocycle, and one diacid chloride) threading-followed-bystoppering technique, with the macrocycle functioning as a template (Scheme 8.26).

Scheme 8.26 An illustration of Vögtle’s four-component “threading-followed-bystoppering” approach to rotaxane synthesis [158–161]. Terephthaloyl chloride reacts with an aniline stopper to form a monoacid monochloride “semi-axle”; this then threads

the macrocycle template to give a pseudorotaxane. This complex, which is held together by three hydrogen bonds, reacts with another aniline stopper to furnish a [2]rotaxane.

When a variety of sulfonic and carboxylic acid dichlorides was used to form [2]rotaxanes (Figure 8.5), aliphatic dichlorides proved to be effective and showed that π–π interactions were unnecessary for rotaxane templation. A one-pot reaction produced [160] an unsymmetrical [2]rotaxane which had one porphyrin and one trityl stopper, while the alkylation of a [2]rotaxane afforded [161] an unusual, selfcomplexing [1]rotaxane. The ﬁrst amide-based [3]rotaxane was also synthesized [162] in this way. Dichlorides could also be replaced by diisocyanides which reacted [163] with phenol or aniline stoppers to form, respectively, urea- or carbamatecontaining threads (data not shown). Related studies with rotaxanes synthesized by threading-followed-by-stoppering, and having urea-binding stations, have recently been reported by Chiu [164]. In order to investigate the mechanism of the rotaxane synthesis even further, Vögtle’s group [165] performed 1H NMR titration experiments in CD2Cl2 to measure the binding of various pseudoaxle guests by macrocycles. When downﬁeld shifts of wheel and axle protons were used to determine the binding constants, secondary amides were found to be the preferred guests over esters, acid chlorides, or tertiary amides. The downﬁeld shifts of macrocycle isophthalamide protons indicated the formation of hydrogen bonds to the carbonyl oxygens of guests. The downﬁeld shifts of the protons of secondary amide guests suggested

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Figure 8.5 Rotaxanes via neutral templation. Top: Rotaxanes with varied diamide and sulfonamide axles. Middle left: A rotaxane with an unsymmetrically stoppered axle. Middle right: A self-complexing [1]rotaxane. Bottom: The ﬁrst amide-type [3]rotaxane.

at least some “back-bonding” with the inverted carbonyl oxygens of transoid isophthalamides of the macrocycles. A monosulfonamide trislactam ring and a dithiamide macrocycle were shown to bind pseudoaxles, but without the characteristic shift of the guest amide protons; this observation indicated that the phenylsulfonyl and dithiaamide moieties were not acting as binding sites. Neither did a linear tetralactam oligomer bind the pseudoaxles. The results of these studies supported the hypothesis that the crucial intermediate during rotaxane synthesis is a semirotaxane, composed of a semiaxle ﬁxed inside a wheel by hydrogen bonds (Scheme 8.27, top). As a test of this mechanism, a rotaxane having an amide in the axle was obtained in 69% yield, whereas an analogous rotaxane that contained a much more

8.5 Neutral Hydrogen Bond-Templated Systems

Scheme 8.27 [2]rotaxanes via threading-followed-by-stoppering. Top: Amide and ester rotaxanes formed by way of the key macrocycle–semiaxle complex; Bottom: A cartoon representation of rotaxanes containing aliphatic segments in the thread component.

weakly binding ester was templated in only 4% yield. The successful synthesis of several more rotaxanes with aliphatic axle segments conﬁrmed that hydrophobic arene–arene interactions were not necessary for assembly. An investigation of the binding abilities of macrocycles containing parasubstituted pyridyl rather than isophthaloyl rings has been conducted by Jeong [166]. Afﬁnities for a diamide axle ranged in value over three orders of magnitude (Ka = 70 to 24 000 M−1) when comparing macrocycles with, respectively, para electron-donating groups such as dimethylamino to para electron-withdrawing groups such as nitro. The Leigh group [167] ﬁrst embarked on rotaxane synthesis (Scheme 8.28) as a means to isolate their benzyl amide macrocycle as a free species. The four macrocyclic components could be clipped around an isophthalamide-containing axle template to yield a rotaxane in 28% yield. The free macrocycle was then recovered from the rotaxane in quantitative yield, following transesteriﬁcation to remove the bulky stoppers and precipitation of the macrocycle itself. The next generation of rotaxanes (on this occasion, synthesized for their own sake) employed an axle with a glycylglycine motif. This peptidic segment has a spatial arrangement of hydrogen bonding sites similar to that of the transoid 1,3-aromatic diamides [168]. Following the one-step clipping protocol, a glycylglycine rotaxane was isolated in 62% yield, with the higher recovery being testament to the greater complementarity of the hydrogen bond acceptor sites in the peptide template. An even more dramatic template effect was demonstrated [169] with fumaramide axles. Having less steric bulk and a near-ideal preorganized hydrogen bond acceptor array with two fewer rotational degrees of freedom than the peptide motif, the fumaramide axle – in a

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Scheme 8.28 [2]Rotaxanes via clipping. Top: The ﬁve-component assembly reaction for a

rotaxane having an isophthaloyl unit in the axle; Bottom: Rotaxanes with other binding motifs in their axles.

one-step, ﬁve-component clipping reaction – set an undisputed “world record” 97% yield for amide-based [2]rotaxane synthesis. In fact, the preorganized arrangement of the fumaryl motif proved to be so effective that even the weaker hydrogen bondaccepting ability of fumaryl esters was capable of templating (Scheme 8.28) the formation of rotaxanes, albeit in lower yields of 35% and 3%. Tertiary amide and bis-nitrone axle motifs were also effective [170, 171]. The robust fumaramide motif was also capable of templating a rotaxane having a macrocycle with inverted amides [155]. In addition to the clipping protocol, the Leigh group [172] has developed a thermodynamically controlled synthesis of rotaxanes analogous to their “magic rings” approach to catenanes. In a “magic rod” reaction, an axle containing an internal oleﬁn and 5 equiv. of a macrocycle were submitted to metathesis conditions to give a [2]rotaxane and a [3]rotaxane in 52% and 43% yields, respectively (Scheme 8.29). Removal of the ruthenium catalyst was all that was needed to secure the kinetically stable products.

8.5 Neutral Hydrogen Bond-Templated Systems

Scheme 8.29

(a)

The “magic rod” approach to peptidic [2]- and [3]rotaxanes.

(b)

Figure 8.6 Stick representations of a urea-functionalized calix[4]arene dimer showing the

hydrogen-bonding pattern (red) that forms between the monomers (blue and light blue). Hydrogens and templating solvent have been omitted for clarity. (a) Side view; (b) Top view.

8.5.3 Novel Catenane and Rotaxane Architectures

It is well known that urea-functionalized calix[4]arene monomers will dimerize [173] under apolar/aprotic conditions to form capsules. This self-assembly is the result of a seam of hydrogen bonds that forms between monomers and the templation effect of nonpolar guests such as benzene (Figure 8.6).

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Using the tetraurea calix[4]arene components shown in Figure 8.7, the Böhmer group [174–181] recently synthesized a collection of highly interlocked multiple catenanes and rotaxanes with capsular structures. With a tetraalkene-functionalized calixarene and a preformed bisloop calixarene, heterodimers were formed at high dilution. Subsequent oleﬁn metathesis and hydrogenation produced [176] a bis[2]catenane in 97% yield (Scheme 8.30, top). Homodimers of the bisloop calixarene did not form due to unfavorable steric interactions between the macrocyclic loops, and homodimers of the tetraalkenefunctionalized calixarene did not form because heterodimerization maximized the hydrogen bonding between ureas and was therefore more energetically favorable. By using an eightfold alkene-functionalized calixarene and a tetraloop calixarene, the same synthetic strategy of heterodimerization followed by metathesis and hydrogenation gave [177] a highly interlocked [8]catenane product in 58% yield (Scheme 8.30, middle, and Figure 8.8).

Scheme 8.30 Synthetic reactions for interlocked capsules. Top and middle: Formation of calixarene catenane structures by heterodimerization, followed by metath-

esis and hydrogenation; Bottom: Heterodimerization followed by a Diels–Alder stoppering reaction to form a fourfold calixarene–rotaxane.

Hybrid calixarene–rotaxane structures have also been synthesized (Scheme 8.30, bottom). In this case, a tetraloop calixarene and a succinimide-functionalized calixarene were dimerized [178] to form a pseudorotaxane-like structure which, when stoppered by a Diels–Alder reaction between the succinimides and the anthracene, gave a fourfold [2]rotaxane in 45–50% yield. These interlocked capsules possess unprecedented connectivity, and might exhibit novel host–guest properties. Referring to their bis[2]catenane, the authors speculated [176] that “… the rate of guest exchange might be controllable through

8.5 Neutral Hydrogen Bond-Templated Systems

Figure 8.7 ChemDraw and cartoon

representations of components for highly interlocked calixarene–catanane and calixarene–rotaxane capsules. Top two rows, left to right: A fourfold alkene-functionalized calixarene, a preformed bisloop calixarene,

and a calixarene with eight alkenes. Bottom two rows, left to right: A succinimidefunctionalized calixarene, an electron-rich anthracene, and a preformed tetraloop calixarene.

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(b)

Figure 8.8 Space-ﬁlling representations of an [8]catenane with hydrogens omitted. (a) Top view with methoxy substituents of one calixarene pointing toward the reader; (b) Side view.

the lengths and the structures of these intertwining rings.” More studies no doubt lie ahead in this area.

8.6 Metal-Containing Catenanes and Rotaxanes

Metals have been incorporated into catenanes and rotaxanes in a variety of interesting ways, including within the subcomponents [182, 183] of catenanes, or as part of the stoppers [160] for rotaxanes. In this section, attention is focused on metalcontaining catenanes and rotaxanes that have been synthesized by the so-called “templation” or “self-assembly” methods of Sauvage and Fujita, respectively, in which the metals play a central and indispensable synthetic role. To be clear, it is certainly true that the term “self-assembly” can be applied to aspects of Sauvage’s approach, and that “templation” can be used to describe features of Fujita’s techniques, but because these somewhat imprecise terms are in such common usage they have been retained here, although for clarity the two synthetic methods are illustrated and distinguished with numerous examples. Attention has also been focused on the more fundamental structures, such as [2]rotaxanes and [2]catenanes, with attempts being made to provide a succinct yet thorough survey of the past 25 years of the ﬁeld, by highlighting as many important studies as possible. In 1983, the Strasbourg trio of Dietrich-Buchecker, Sauvage, and Kintzinger reported [184] the ﬁrst practical, high-yielding synthesis of catenanes. The key to their strategy was the use of the tetrahedral copper(I) cation as a template. In a one-pot version of the method, the copper(I) cation functioned [185] as a central locus for gathering two “convergent turns” [186] (in this case, appropriately functionalized phenanthroline ligands) around itself in an orthogonal fashion. Subsequent ligand cyclizations with a diiodide linker provided the catenane in 27% yield (Scheme 8.31). Since the initial report, copper(I) has been used [187–198] to synthesize a variety of catenanes and rotaxanes, and over the past 25 years the use of

8.6 Metal-Containing Catenanes and Rotaxanes

Scheme 8.31

A copper(I)-templated synthesis of a [2]catenane.

metals as templates has developed into a general strategy for the synthesis of mechanically interlocked molecules. Today, transition metals with well-deﬁned coordination geometries appear to be the most useful, although a few examples of catenanes [199] and rotaxanes [200–202] templated by main group metals have also been reported. A selection of [2]rotaxanes that have been synthesized with different transition metals, coordination geometries, and ligand sets is shown in Figure 8.9. The tetrahedral geometry is represented by a Sauvage-type complex having two bidentate phenanthroline ligands surrounding copper(I). This complex differs from the original copper-templated catenanes, in that the macrocycles (and also the interlocked structure itself) were formed by oleﬁn metathesis which today has become [203] a reaction of choice for catenane synthesis, based on its superior and often near-quantitative yields. In fact, the ligand macrocyclization steps for all of the catenanes shown in Figure 8.9 relied on oleﬁn metathesis, with or without subsequent hydrogenation of the alkene product. The neutral, square planar catenane in Figure 8.9 was synthesized by the Leigh group [204], and relies on a palladium(II) template with one monodentate and one tridentate ligand, a system which was also developed [205–207] subsequently for the synthesis of rotaxanes. Also shown is a rare example of a catenane templated by a trigonal bipyramidal metal [208], in this case zinc(II), with one bidentate and one tridentate ligand. Octahedral metals with different ligand sets have also been proven as [209–215] effective templates. For example, ruthenium(II) was used [210–212] to prepare catenanes with either one tetradentate and one bidentate ligand or, alternatively, two tridentate ligands. Usually, the metal-containing catenanes (i.e., the “catenates”) can be demetallated with potassium cyanide to furnish the all-organic “catenands”; however, there is at least one example of a catenate that ultimately was too stable for demetallation [210]. Recent, and particularly versatile, syntheses of catenanes [216] and rotaxanes [217] based on octahedral metal templates have been reported by the Leigh group. The method for [2]metallorotaxane synthesis is shown in Scheme 8.32, where the experimental design features included: (i) the use of a preformed macrocycle to preclude catenane formation; and (ii) the incorporation of aniline rather than benzylamine groups in the thread, to prevent the formation of stable complexes between the metal and two threads. Simple mixing of the starting materials at

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Figure 8.9 Metal templation geometries (tetrahedral, square planar, trigonal bipyramidal, and octahedral) for [2]catenane synthesis, with corresponding examples.

Scheme 8.32 Five-component self-assembly of [2]rotaxanes, using octahedral metal(II)

templates.

8.6 Metal-Containing Catenanes and Rotaxanes

room temperature under thermodynamic control produced [2]rotaxanes in good to excellent yields, using a variety of transition metal templates. Leigh and coworkers [218–222] have further advanced the ﬁeld of mechanical bond formation by introducing catalytic and stoichiometric “active metal” templation methods. Here, a transition metal functions as a template as well as a promoter or catalyst for the reaction that ultimately produces a mechanically interlocked product. To date, several systems have been developed [223] for rotaxane synthesis, such as a palladium(II)-catalyzed Heck reaction of aryl boronic acids and alkenes to produce [218] [2]rotaxanes in moderate to good yields, with as little as 1 mol% palladium catalyst. The proposed catalytic cycle for this system is shown in Scheme 8.33. A different way of using metals for catenane synthesis was pioneered by Fujita [224–233] during the 1990s, and further developed by his group and others. In this so-called “self-assembly” approach, the metals are no longer the central loci for ligand gathering and orientation, but are incorporated directly into the molecular backbone where their reversible and directional bonding properties – aided and abetted by other noncovalent bonding interactions – allow the thermodynamically controlled assembly of interlocked catenane products. As reported in the initial study [224], simply stirring a palladium(II) complex and a dipyridyl ligand in water gave a mixture of a catenane and a macrocycle, with the former favored at higher concentrations of palladium complex and ligand (Scheme 8.34). Under aqueous conditions the inter-aryl attractions were important, and favored catenane formation in cases of higher solvent ionic strength. Fujita dubbed the whole process a “magic rings” synthesis (this was the ﬁrst use of the term, as applied to interlocked compounds) in analogy to the well-known illusionist’s trick of interlocking seemingly solid metal rings. This type of metal-promoted self-assembly appears to be a fairly general (though sometimes unexpected) phenomenon that is also useful for rotaxane construction [234–237]. Several examples of self-assembled [2]rotaxanes with different metals in their backbones are shown in Figure 8.10. Beer and coworkers [238] discovered that catenane A (Figure 8.10) self-assembles in 93% yield upon oxidation of the corresponding copper(II) dithiocarbamatebased macrocycle with iron(III) chloride. The lability of the copper(II) dithiocarbamate bond allows an interlocking of the rings, while chemical oxidation promotes the formation of a mixed-valence structure in which the successive copper atoms are Cu(II) and Cu(III). The naphthyl spacers provide the ideal distance for maximizing donor–acceptor interactions between the electron-rich and electron-poor metal centers. Similar mixed-metal [2]catenanes containing copper(II) and gold(III) can also be synthesized [245, 246]. Since the mid-1990s, several other types of self-assembled catenanes containing gold have been reported [13, 239, 247–255]. The most structurally versatile class consists of gold(I) acetylides and diphosphine ligands, and was discovered by the group of Puddephatt [13, 239, 249–255]. Structure B [239] (Figure 8.10) is an example of this type; with its carbon–gold(I) bonds, it is a true organometallic catenane which exists as a colorless, air-stable solid that is soluble in organic

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Scheme 8.33 The proposed catalytic cycle for the palladium active-template oxidative Heck cross-coupling synthesis of rotaxanes. The catalytically active complex undergoes transmetallation with a boronic acid. Ligand substitution of an acetate for an alkene gives

a π complex, which undergoes migratory insertion followed by β-hydride elimination to give an interlocked intermediate. Loss of palladium(0) yields a [2]rotaxane. Some of the corresponding non-interlocked thread is also formed in the reaction.

8.6 Metal-Containing Catenanes and Rotaxanes

Scheme 8.34 Dynamic self-assembly of a metallo[2]catenane and its corresponding free macrocycle. aNet concentration of Pd(II).

solvents such as dichloromethane. Novel gold(I)–gold(I) “aurophilic” interactions (worth 7–11 kcal mol−1) [256–258] provide some structural stabilization and driving force for catenane formation, although they are not strictly necessary. Similar gold-containing catenanes having a greater number of methylene spacer groups in the diphosphine component were also easily synthesized, but lacked aurophilic interactions. Puddephatt and coworkers [245] cited the low steric hindrance associated with the linear gold(I) acetylides, and the inter-aryl attractive forces as the most important features contributing to the facile formation of this class of molecules. The latter also include [13] a doubly-braided [2]catenane – that is, a Solomon Knot – the ﬁrst to be characterized using X-ray crystallography. Structure C [240, 241] in Figure 8.10 is a rare example of a catenane assembled using a main group metal, and the ﬁrst of this type to lend itself to X-ray crystallographic analysis [240]. The combination of two divalent barium cations and two dianionic organic ligands results in an overall charge-neutral structure that is soluble in organic solvents. Catenane C is also a rare example of a quadruply stranded helicate. Wisner and coworkers [242, 259, 260] have taken advantage of both ﬁrst- and second-sphere ligand coordination to the square planar palladium(II) cation in the

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Figure 8.10 Selected examples of self-

assembled metallo[2]rotaxanes. (A) Beer’s mixed-valence Cu(II)/Cu(III)-templated catenane [238]; (B) Puddephatt’s organometallic gold(I) catenane [239]; (C) Rees’s rare Group II metal-templated catenane [240,

241]; (D) Wisner’s Pd(II)-containing catenane templated by ﬁrst and second-sphere metal coordination [242]; (E) Fujita and Sauvage’s “mixed-motif” Pd(II)/Cu(I)-templated catenane [243, 244].

carefully designed syntheses of rotaxanes and catenanes. An X-ray crystal structure of catenane D in Figure 8.10 revealed [242] ﬁrst-sphere coordination between the pyridyl groups of the organic ligand and the palladium(II) centers which were part of the macrocyclic backbones. A second-sphere coordination was present between the amides of the organic ligand and the residually nucleophilic chloride ions bound to the metal. Despite the presence of normally labile pyridine–palladium bonds, the structure was surprisingly stable; it maintained its integrity in a 50 : 50 mixture of CDCl3:CD3OD, but dissolved to form the free macrocycle in the same proportions of CDCl3 and CD3SOCD3. Eventually, Fujita and Sauvage fruitfully combined [12, 243, 244] their template and self-assembly approaches. Catenane E [243, 244] in Figure 8.10 was produced in 85% yield in a one-pot reaction after the successive additions of copper(I) and palladium(II) metal salts to a solution of the corresponding free organic ligand. The catenane was formed as the thermodynamic product because of the substitutional lability of the copper(I) and, especially, the palladium(II) complexes. In contrast to Fujita’s original catenane (see Scheme 8.34), the formation of which was accompanied by varying proportions of the corresponding free macrocycle, catenane E was obtained quantitatively, regardless of the concentrations of the palladium salt and organic ligand. Its stability is attributed to the excellent ﬁt of

8.6 Metal-Containing Catenanes and Rotaxanes

the ligand for palladium(II) coordination, and the appropriate length of the four sides of each constituent macrocycle. The Quintela group [261] in Coruña in Spain has exploited the reversible nature of both metal–ligand coordination bonds and π–π donor–acceptor interactions to allow the dynamic self-assembly of a [3]catenane from six separate components (Scheme 8.35). In this structure, two palladium(II) complexes hold two bipyridine ligands together to form a dinuclear octacationic metallomacrocycle, which is interlocked by two dioxoaryl cyclophanes. X-ray crystallography revealed six π–π stacking interactions as well as hydrogen bonding. There are [C–H…π] interactions between protons of the internal hydroquinols and the π systems of the bipyridine rings, and [C–H…O] interactions between α-CH bipyridine hydrogens and oxygen atoms of the dioxoaryl cyclophane. Like catenane E (see Figure 8.10), this structure represents the successful implementation of combined assembly motifs.

Scheme 8.35 Synthesis of a [3]catenane from a dioxoarylcyclophane and a dicationic bipyridine ligand.

Multiply-interlocked “catenanes” have also been built using metal templation. These structures are less chain-like, more complex, and showcase the power of metal-templated self-assembly. Fujita’s cage-like catenane, which forms spontaneously from ten components, is a prime example (Figure 8.11). With the aid of retrosynthetic analysis and a consideration of both attractive π–π aryl interactions and square planar metal coordination, a synthetic route incorporating platinum(II) and two types of pyridine ligand was designed and executed. The thermodynamically driven assembly was achieved [262] by heating the component mixture in water at 100 °C for three days to afford the product cage in 65% yield. A second example of a structure with the same topology was synthesized by Hardie and coworkers [263], who fashioned a triply interlocked catenane by using a bipyridine-functionalized cyclotriveratrylene (CTV) ligand and either zinc(II) or cobalt(II) nitrate. Crystals of the catenane were grown in 63% yield by diffusing acetone vapors into a dimethylsulfoxide (DMSO) solution of the CTV ligand and 2 equiv. of zinc(II) nitrate. An X-ray crystal structure showed two bipyridyl ligands and a nitrate anion coordinated to each metal, giving rise to a distorted octahedral geometry. Each of the two bowl-shaped CTV ligands coordinates three equivalent zinc(II) centers, forming a trigonal bipyramidal M3L2 cage structure, while each cage contains three “windows” through which another cage can interlock (Figure

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Figure 8.11 Fujita’s cage-like, multiply-interlocked [2]catenane [262].

Figure 8.12 One of the two cage components of Hardie’s multiply-interlocked metaltemplated [2]catenane [263]. Two of these cages interlock to form the complete structure.

8.12). Unlike Fujita’s interlocked cages, this structure shows no intramolecular face-to-face π–π stacking interactions. However, multiple [C–H…O] interactions are present between the cages that involve aryl and methyl hydrogens of the bipyridyl ligands and oxygens of the methoxy substituents and nitrate anions. Each cage contains both enantiomers of the CTV ligand, yet all six metal complexes in the [2]catenane have the same handedness. The molecule is chiral and crystallizes as a racemic mixture.

8.7 Solvophobically Driven Templation

8.7 Solvophobically Driven Templation

Solvophobic interactions drive the formation of many important biochemical molecular structures that are essential to life [264]. For example, in a folded protein [265, 266], many hydrophobic residues pack against each other in the core of the protein as a consequence of their being repelled by the surrounding water molecules. Hydrophobic molecules tend to be nonpolar, and thus prefer to associate with other neutral molecules and nonpolar solvents, whereas hydrophilic molecules are polar or polarizable and are able to form hydrogen bonds with water molecules in solution. While an individual hydrogen bond is relatively weak, the sum total of a solution containing an inﬁnite network of hydrogen bonds is very strong, as the network tries to expel adjacent, energetically unfavorable molecules that might disrupt the integrity of the solvent [267]. In a fashion similar to that employed by Mother Nature, chemists have worked to utilize this powerful noncovalent bonding interaction to drive the formation of molecular assemblies. These supramolecular complexes can then undergo subsequent reaction(s) to form mechanically interlocked molecules. In this context, both cyclodextrins (CDs) [268–270] and curcubiturils (CBs) [271–276] have been studied as a consequence of their ring-shaped structures, nonpolar interior cavities, and polar external surfaces, all of which contribute to the unique properties of these materials as hosts. As the application of solvophobicity to template-directed synthesis has been studied extensively, and reviewed thoroughly [277–280], the discussion in this section will be limited to key developments in the synthesis of rotaxanes and catenanes. The CDs [268–270] are cyclic oligosaccharides comprising α-1,4-linked Dglucopyranosyl residues which constitute a toroidal shape, with secondary hydroxyl groups on the wider side and primary hydroxyl groups on the narrower side. The CDs have a hydrophobic inner cavity, and are readily soluble in water and other polar solvents. In such solvents, hydrophobic and van der Waals interactions drive all hydrophobic guest molecules of complementary size into the cavity of the torus, where they are bound to varying extents. Generally, the better a guest ﬁlls out the CD’s cavity, the higher the binding constant of the complex. The CDs may consist of six, seven, or eight glucopyranosyl residues, and are referred to as α-, β-, or γCDs, respectively, having cavities that range from 5.7 to 9.5 Å in diameter (Figure 8.13). In order to synthesize CD-based rotaxanes in high yield by the threadingfollowed-by-stoppering approach [277–280], several practical synthetic requirements must be met. First, the axle component must form a stable pseudorotaxane with the CD ring(s). Once this supramolecular intermediate complex has assembled in aqueous solution, the axle must be long enough to react with stoppering groups that are large enough to prevent the ring(s) from dethreading from the axle of the dumbbell. However, successful stoppering reactions are limited as they must take place in good yields in highly polar solvents, such as water, DMSO, or DMF, in order to prevent the complex from disassociating. Further compounding this problem is the fact that both the stoppering component and the desired rotax-

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Figure 8.13 Structural representations of (left to right) α-, β-, and γ-cyclodextrins.

ane must be soluble in polar solvents, so that homogeneous conditions can be maintained through the course of the reaction. Finally, it must also be possible to purify and isolate the desired rotaxane from the aqueous reaction mixture, despite the rotaxane’s intrinsic polarity. In addition to the threading-followed-by-stoppering approach to CD-based rotaxane synthesis, the slippage approach to rotaxane formation has also been implemented successfully. This approach is subject to many of the same limitations described above, as the components must be soluble in polar solvents, the stoppers must be large enough to prevent dethreading of the CD ring(s), and the ﬁnal rotaxane must be amenable to isolation. In addition, the stoppers of the dumbbell must be large enough to prevent the CD ring(s) from dethreading under ambient conditions, yet small enough to allow for threading at elevated temperatures and/ or pressures. This ﬁnal requirement is seldom met, however, and attempts often result in the formation of kinetically stable pseudorotaxanes – a situation which may or may not be suitable for potential applications. At the present time there is no reported synthesis of a CD-based rotaxane using the clipping approach. This is a consequence of the structure of the CD being poorly suited to this type of reaction. Despite the synthetic complications mentioned here, CDs are nonetheless easily functionalized, water-soluble, biocompatible, and available in both good yield and high purity. Consequently, their incorporation into mechanically interlocked compounds has undergone extensive investigation. The ﬁrst CD-based [2]rotaxane was reported [281] in 1981 by Ogino. A linear diaminoalkane was included (Scheme 8.36) in either α- or β-CD, and a [2]rotaxane was formed (best yield, 19%) when equimolar amounts of 1,12-diaminodecane and α-CD were reacted with 2 equiv. of cis-[CoCl2(en)2]Cl in DMSO. The relatively low yield obtained in this synthesis was thought to be a consequence of: (i) the formation of many Co(III)-containing side-products; and (ii) the smaller thermodynamic driving force for complexation between the hydrophobic thread and the CD ring in DMSO solution versus that in water. Subsequently, other stoppering methods that rely on strong metal–ligand interactions [282–285] have been shown to lead to stoppering. Both electrostatic stoppering via strong ionic interactions

8.7 Solvophobically Driven Templation

Scheme 8.36 Synthesis of a [2]rotaxane by the threading-followed-by-stoppering approach, in which metal coordination acts to prevent the α- or β-CD from dethreading.

[286–288] and covalent stoppering [289–292] have also been applied successfully to the synthesis of a variety of CD-based rotaxanes. Having successfully threaded a single CD onto a hydrophobic thread, it was shown subsequently [293] that it is possible to thread a number of CDs onto a single thread. For example, multiple α-CDs will complex readily with polyethylene glycol (PEG) chains as a result of both hydrophobic and van der Waals interactions. In 1992, this multiple threading phenomenon was demonstrated by Harada and coworkers [294–297] in the synthesis (Scheme 8.37) of a CD-based polyrotaxane. In order to accomplish this goal, a saturated aqueous solution of α-CD was mixed with a PEG-bisamine to form a polypseudorotaxane, with approximately 20 CD rings threaded onto each polymer chain. This complex was then dried and a large excess of 2,4-dinitroﬂuorobenzene added with some DMF and left to stir at room temperature overnight. After puriﬁcation, the polyrotaxane was isolated in 60% yield, and no free dumbbell or CD was present. While the authors were unable to determine explicitly how the adjacent CDs are oriented relative to each other, the fact that polyrotaxane is not water-soluble at neutral pH demonstrates that strong hydrogen bonds exist between the contiguous α-CD rings. This observation also suggests that, most likely, the α-CD rings alternate in their orientation along the backbone of the dumbbell. Subsequent studies have shown that it is possible to synthesize CD-based polyrotaxanes by a step-growth polymerization of 1 : 1 pseudorotaxane complexes, followed by stoppering in aqueous media [298–301]. This ability to produce CD-containing pseudopolyrotaxanes and polyrotaxanes has led to extensive investigations into the formation of hydrogels and networks [302–308] and nanoporous ﬁlms [309, 310] from these exotic polymers. This research has resulted in the creation of new materials with unique properties based on their mechanically interlocked nature. Like CDs, the cucurbiturils (CBs) [271–276] are water-soluble polycyclic macrocycles with a hydrophobic interior. However, unlike CDs, the CBs have highly symmetrical structures with equal-sized portals rimmed by a row of polar carbonyl

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Scheme 8.37 Synthesis of a polyrotaxane from α-CD and PEG.

groups that allow the CBs to bind ions and molecules through charge–dipole interactions. CBs are obtained from an acid-catalyzed condensation reaction between glycouril and formaldehyde. The most commonly studied derivative is cucurbit[6]uril (CB[6]), with a cavity of approximately 5.7 Å. CB[6] is known to form a strong (Ka = ∼105–106) 1 : 1 host–guest complex with protonated diaminoalkanes, such as diaminopentane and diaminobutane. The formation of this complex is attributed to two noncovalent interactions, namely: (i) the hydrophobic interactions between the internal methylene groups and the inside of the cavity; and (ii) the strong charge–dipole and hydrogen-bonding interactions between the protonated amines and the portal carbonyl groups. Based on this simple type of complex, a CB[6]-based [2]rotaxane (Scheme 8.38) was synthesized and ﬁrst reported in 1996 by Kim and coworkers [311]. In this case, the hydrochloride salt of spermine (a linear tetraamine) was mixed with CB[6] in water to form a pseudorotaxane, which was stoppered with dinitrophenyl groups in the presence of 2,6-lutidine and dinitroﬂuorobenzene. The desired [2]rotaxane was isolated in 83% yield. Following the successful syntheses of [2]rotaxanes containing CD and CB, methods for controlling the position of the ring on the dumbbell were explored. In one example, a [2]rotaxane was synthesized (Scheme 8.39) [312, 313] in which an α-CD ring preferentially sits over a trans-azobenzene recognition site. On

8.7 Solvophobically Driven Templation

Scheme 8.38

Synthesis of a CB[6]-based [2]rotaxane.

Scheme 8.39

Photoisomerization of an azobenzene-containing rotaxane.

photoirradiation at 360 nm, the azobenzene isomerizes to the cis conﬁguration, which forces the CD ring away from the azobenzene unit and onto the methylenespacer of the rotaxane’s backbone. On irradiation at 430 nm, the azobenzene isomerizes back to the trans conﬁguration, and the CD ring returns to the azobenzene recognition site. A variety of other reversible, photo-driven molecular shuttles have been developed [314–318] based on this system. Despite early attempts during the 1950s by Lüttringhaus, Cramer, Prinzbach, and Henglein, the ﬁrst successful synthesis of [2]- and [3]catenanes incorporating a CD ring was not reported until 1993, by the present authors [319–321]. In order

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to synthesize the [2]- and [3]catenanes (Scheme 8.40), a 1 : 1 complex was ﬁrst assembled in water by placing heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DM-βCD) and a hydrophobic, rigid bibenzyl core carrying hydrophilic glycol arms. Driven by hydrophobic interactions, the pseudorotaxane which assembles can be trapped kinetically, using the Schotten–Baumann reaction, by adding a bifunctional acid chloride-linking unit to the complex in the presence of a base. This reaction was chosen as the key ring-closure step as it does not require any external reagent or catalyst that could interfere with the complexation process; moreover, the reaction proceeds readily in water. From the reaction mixture, it was possible to isolate a range of cyclic reaction products that included moderate amounts of the free macrocycles, and small amounts of catenanes, including both the inseparable head-to-head and head-to-tail isomers of the [3]catenane and two different [2]rotaxanes. It is important to note that, since the CD component does not act as a template for cyclization, the catenation is no more energetically favorable than a simple macrocyclization, and might even be inhibited by unfavorable steric interactions.

Scheme 8.40 Synthesis of [2]- and [3]catenanes incorporating DM-β-CD.

Mechanically interlocked compounds have been exploited for the ability of either the CD or the CB ring to shield the portion of the molecule encompassed in its cavity – a phenomenon that has been described as “molecular insulation” [322,

8.7 Solvophobically Driven Templation

323]. Speciﬁcally, a molecular component within the cavity of a CD or CB experiences a well-deﬁned, unreactive, nonpolar environment, preventing it from undergoing undesirable side reactions. This effect is particularly pronounced in rotaxanes because the ring(s) are restricted to remain permanently around the dumbbell of the rotaxane, protecting its linear axle. This capability has been used to: (i) improve the quantum yields of dye molecules; (ii) shield them from degradation; and (iii) adapt their solubilities for easier processing [324–332]. The concept has been extended to the production of insulated molecular wires by surrounding extended π-electron systems with CD rings in order to improve drastically their stabilities and solubilities [333–337]. As a means of creating new molecular topologies and functional materials, mechanically interlocked components can be connected by transition metals to create metal–organic rotaxane frameworks (MORFs) [338–342]. When constructing MORFs, CBs, rather than CDs, have been the preferred ring components, simply because of their higher degree of symmetry that simpliﬁes the analysis of NMR spectra and the acquisition of single-crystal X-ray structural data. In order to incorporate CB rings into metal-containing molecular frameworks, the termini of the axle component of the CB-pseudorotaxanes are functionalized so as to act as metal ligands which, when mixed with transition metals in polar solvents, selfassemble to create the novel MORF architectures. The use of pseudorotaxanes as ligands was initially successful [343–346] when creating (Figure 8.14) a family of CB[n] molecular necklaces (MNs), that is, topological isomers of linear oligocatenanes. Although considered to be zero-dimensional, MNs are interesting as a consequence of their potential use as molecular machines in nanotechnological applications. Building on this research, it is now possible [347–351] to extend the molecular framework into a linear one-dimensional (1-D) strand by synthesizing a polyrotaxane or a polycatenane. The structures and properties of these polymers can be changed by varying the metal ions, counterions, or the axle component employed. Similarly, by varying the transition metal and/or ligand functionality, it is possible to attain a variety of 2-D [338, 341] and three-dimensional (3-D) MORFs [339, 340, 342]. These polyrotaxanated nets provide an intriguing example

Figure 8.14 A variety of molecular architectures which can be achieved using pseudorotaxanes (blue threads encircled by yellow CB rings) as ligands for metals (green balls).

Left to right: A 0-D [5]molecular necklace [343–346]; a 1-D polypseudorotaxane [347–351]; a 2-D MORF [338, 341]; a 3-D MORF [340].

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of chemical topology and, in addition, provide insights into the construction of novel porous, solid-state materials.

8.8 Applications

A new stage of development is under way in the ﬁeld of the mechanical bond. Although, some 15 years ago, fundamental research was still largely driven by the novelty and intrinsic beauty of mechanically interlocked molecules, today’s investigators are starting to identify innovative applications for these “academic curiosities” in diverse areas such as analyte detection, bioimaging, biofuel cells, molecular electronics, organic synthesis, microﬂuidics, and drug delivery. For example, the Chiu group [200, 201, 352, 353] has used rotaxanes and pseudorotaxanes as metal ion sensors, by relying [352] a molecular cage molecule that binds (Scheme 8.41) strongly to dimethyldiazapyrenium (DMDAP) and quenches its ﬂuorescence, even at equimolar concentrations as low as 1 × 10−5 M. Despite this tight binding, it was found that calcium ions could displace DMDAP, restoring its ﬂuorescence. As other cations, including Li+, Na+, K+, and Mg2+, are at least tenfold less effective at displacing DMDAP, the pseudorotaxane provides a sensitive and selective probe for measuring concentrations of the biologically important calcium ion.

Scheme 8.41 A [2]pseudorotaxane for calcium ion detection. A molecular cage (red) complexes and quenches the ﬂuorescence of DMDAP (blue). Calcium ions displace DMDAP to restore its ﬂuorescence and allow an indirect detection of the calcium ions themselves.

Elsewhere, Bradley Smith and his team [354–357] at Notre Dame University have developed squaraine rotaxanes as near-infrared (NIR) ﬂuorescent dyes for cell imaging. Unprotected squaraine dyes tend to aggregate and self-quench, and

8.8 Applications

are also vulnerable to attack by common biological nucleophiles such as amines and thiols, a property which limits their stability and the duration of imaging experiments. The Smith group solved both of these problems by protecting squaraine ﬂuorophores with Leigh-type benzylic amide macrocycles to produce bright, chemically stable [2]rotaxane ﬂuorescent probes (Figure 8.15). Additionally, by varying the stoppers, the dyes can be targeted [355] to different cellular locations. For example, a rotaxane with hydrophobic stoppers was used to visualize the endoplasmic reticulum, whereas one with hydrophilic stoppers was used to brighten intracellular aqueous compartments and image cell-trafﬁcking processes. Cationic stoppers afforded a rotaxane that is selective for the outer membranes of bacteria. It has been used to image Staphylococcus aureus and Escherichia coli infections in mice. Clearly, this versatile new class of dyes presents many new opportunities for biological experimentation. Willner and coworkers [358, 359] have used redox-active rotaxanes for the construction of efﬁcient electrodes. One such electrode (Scheme 8.42) was used as a component in a bioelectrolytic cell, whereby the rotaxane contained cyclobis(paraquat-p-phenylene) (CBPQT 4+), an electron-rich para-iminobenzene binding site for CBPQT 4+, and a ﬂavin adenine dinucleotide (FAD) stopper on which the enzyme glucose oxidase (GOx) was reconstituted [358]. The other “stopper” was the gold surface of the anode on which the whole assembly was tethered. When glucose was added to the electrolytic cell and a −0.4 V potential (versus saturated calomel electrode; SCE) was applied, the enzyme and cofactor oxidized glucose to gluconic acid. As a consequence, electrons were relayed from FAD to CBPQT 4+, which shuttled them to the anode surface. The CBPQP4+ then returned to the p-iminobenzene binding site near the FAD–enzyme complex to be re-reduced. This cyclical shuttling process allowed the bioelectrocatalytic

Stable, ﬂuorescent [2]rotaxanes for in vitro and in vivo imaging. Different stoppers allow for the staining of different biological targets.

Figure 8.15

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8 A Short History of the Mechanical Bond

Scheme 8.42 A rotaxane-modiﬁed anode.

(a) Components of the surface-bound rotaxane including the thread, CBPQT4+ macrocycle, and FAD stopper; (b) A cartoon representation of the mechanism of electron

shuttling. The GOx enzyme transfers electrons from glucose to CBPQT4+ via FAD. The CBPQT4+ macrocycle shuttles electrons from the diiminobenzene binding station to the gold anode.

Figure 8.16 (a) A bistable [2]rotaxane used for the construction of molecular switch tunnel junctions (MSTJs); (b) A high-resolution scanning electron micrograph of MSTJs in a crossbar array of silicon and TiO2 nanowires. Scale bar = 250 nm.

oxidation of glucose to occur at a low negative potential (−0.4 V), close to the thermodynamic potential of FAD (−0.51 versus SCE at pH 8.0). Such an efﬁcient, nanostructured electrode might be useful as a component of a glucose sensor or as a biofuel cell. In the area of molecular electronics, prototype memory devices have been constructed [360, 361] during a collaboration between the present authors’ laboratory and the Heath laboratory, using switchable, bistable catenanes and rotaxanes. For example, an electrochemically switchable [2]rotaxane was assembled [361] (Figure 8.16) at the junctions of a crossbar array of silicon and titanium oxide nanowires.

8.8 Applications

Switching of the conductance states of the rotaxanes between low (“0”) and high (“1”) was achieved by applying voltages across the individually addressed junctions. The states of the rotaxanes – a