From Non-Covalent Assemblies to Molecular Machines

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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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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

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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

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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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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.

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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

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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].

References

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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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

32

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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35

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

N N O O O

O N H

R

R

H

H

O

R

O O O O

O O

H H

O

N O

O O

O

N O

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

O O

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

O

e

f

O

O

O

a

b

O

c

e

O

O

c

d d O O O

a

14

f

O

b

13

12

11

Counts

15

37

10

9

8

7

6

5

3 4 δ (ppm)

25000 20000

O

O H

4278.3 (calcd. 4276.1)

N

N

H

O

15000 O

OO O

10000 H N

N

N N

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

40

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.

41

42

4 Noncovalent Synthesis of Molecular Receptors

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

10

11

12

13 14

15

16

17

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

44

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.

45

46

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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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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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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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 – and therefore of the junctions – were “read” by applying smaller voltages and measuring the tunneling currents. This device functions as a defect-tolerant memory with a density of 1011 bits cm−2, which corresponds to the 2020 node for memory on the International Technology Roadmap for Semiconductors. The architectures of both rotaxanes and pseudorotaxanes have recently been used [362–365] for the design and synthesis of asymmetric catalysts. Nishibayashi and coworkers [363] have attached a ruthenium complex to a dibenzo[24]crown-8 ether to build a pseudorotaxane catalyst for asymmetric hydrogenation of enamides (Scheme 8.43). The conversions were uniformly quantitative, and the product enantiomeric excess (ee) values were in the region of 90%.

Scheme 8.43

A [1]pseudorotaxane catalyst for the asymmetric hydrogenation of enamides.

Interestingly, Leigh and coworkers [366], on the other hand, have coaxed liquid to flow uphill. For this piece of work, bistable [2]rotaxanes (Scheme 8.44) were grafted onto self-assembled monolayers of 11-mercaptoundecanoic acid on Au(111). The rotaxanes contained E-furamide and tetrafluorosuccinamide binding stations. In the ground state, a benzylamide macrocyle preferentially encircles the furamide station. Subsequent irradiation with 254–400 nm light induces an E to Z isomerization of the furamide and shuttling of the macrocycle to the tetrafluorosuccinamide station. With a greater proportion of the tetrafluorosuccinamide stations concealed, the entire surface becomes more polarophilic. When a drop of diiodomethane is placed on an inclined surface, and light shone on the uphill side of the drop, the interaction with the more polarophilic uphill surface causs a greater wetting and initiats an uphill spreading of the drop. The coherence of the drop assures its movement uphill, as a whole. This type of photo-induced trans-

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Scheme 8.44 (a) A bistable, light-responsive [2]rotaxane; (b) An illustration of light-induced

liquid transport on a surface coated with this rotaxane.

portation of liquids (albeit most likely on a level surface) could eventually be used for delivering analytes in lab-on-a-chip environments. The present authors’ collaboration with the Zink group has resulted (Scheme 8.45) in the creation of stimuli-responsive mesoporous silica nanoparticles that might serve as drug-delivery agents [367–370]. The nanoparticles bear pores on their surfaces that can be loaded with various molecular cargoes and then closed with sterically bulky rotaxanes. An appropriate stimulus causes the rotaxanes to be disassembled, and the pores to open and release their cargo. When the particles are loaded with the fluorescent dye, Rhodamine B [369], the addition of pig-liver esterase caused the stoppers to be cleaved from the rotaxane pore-caps, and the dye to be released. The application of this store-and-release mechanism, together with further modifications of targeting moieties and specific triggering mechanisms, could result in the nanoparticles providing an effective vehicle for the delivery of drugs to tumors and/or other sites of tissue pathology.

8.9 Conclusions

Scheme 8.45 Controlled release of rhodamine B from a mesoporous silica “snaptop” nanoparticle. The pores of the particle are capped by rotaxanes comprised of

α-cyclodextrin (α-CD) macrocycles and adamantyl stoppers. The stoppers are cleaved by an esterase, which releases the rhodamine B cargo.

8.9 Conclusions

After 50 years, or thereabouts, the chemistry of the mechanical bond could be considered to have reached “middle age.” Yet, despite the impressive progress that has been made, there remains a need to identify applications for the mechanical bond in chemistry, and beyond. Since the groundbreaking studies of the 1960s, the pace of discovery and innovation has accelerated. The initial statistical methods with yields of less than 1% have now been far surpassed by templation approaches which, in some cases, deliver on a quantitative basis. With regards to templation, “reverse recognition” was the earliest concept to be developed, while mixed templation motifs [12, 239, 249, 261], such as metal–ligand/organic donor–acceptor [261] and active metal templation strategies [218–222, 371] have been more recent innovations. Today, solvent-free methods for mechanical bond formation are also available, as this type of chemistry goes “green” [372–374]. In terms of structure, the [2]catenanes and [2]rotaxanes are relatively “tame” members of a growing menagerie of trefoil knots, pretzelanes, suitanes, Solomon knots, Borromean

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rings, and other exotic topologies that defy easy categorization. Both, a recent report of novel, hybrid, organic–inorganic rotaxanes [375], and an article describing pseudorotaxane formation within a metal organic framework [376], have suggested that the development of the chemistry of the mechanical bond may be entering a new phase. Currently, for the purposes of analysis and prediction, computational methods based on density functional theory are being specifically tailored for modeling interlocked compounds [377]. Finally, these molecules are not only aesthetically appealing – they can also be both dynamic and functional, and are beginning to roam “fancy free” into other fields such as materials science, computing, and even medicine. A recent example of this was the description of a strategy to use rotaxanes as prodrugs [378]. Clearly, this form of chemistry is the product of a burgeoning international community of scientists. In this chapter, besides chronicling synthetic developments, structural achievements, and promising applications, an attempt has been made to convey some of the excitement that abounds in this vital area. Indeed, if this field of research is new to the reader, this review should serve as a cordial invitation to join in the fun!

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9 Discussion 2.A Discussion on the Report by J.F. Stoddart Chairman: Fritz Vögtle

Chairman: Thank you very much, Professor Stoddart – that was a fantastic, graphical and colorful lecture summarizing nearly everything I could imagine. We should have a general discussion to clarify questions about the type of chemistry that we do – this is the topic “templating.” Would there be a general question to address? L. Fabbrizzi: My question/comment is very general. Some people, including you, Professor Stoddart, wanted to distinguish between a kinetic template effect and a thermodynamic template effect. In my opinion, a template effect should be only thermodynamic in the sense that, if you have a template, you need a fast and reversible reaction rearranging things – in a fast way, in the best way, in the most stable way – and thereafter you can have a kinetic process. You can have a ring closure which can be kinetic so that the very heart of the process is thermodynamic. That’s my feeling. J.F. Stoddart: Yes, I agree that the heart of the process is thermodynamic, but Daryle Busch, who is not here to defend himself – and I respect his words on this subject – has been talking about both kinetic and thermodynamic effects for the past 50 years almost. In my opinion, when you get to big molecules – and I know that we are reaching this in terms of some of the work that we are doing – essentially, if you look at the functional groups, you say “yes,” we are operating under thermodynamic control. But, once you have brought together a dozen, say, imines, in a vast structure, there seems to be a point at which kinetics effectively starts to impinge and takes over from the thermodynamic process. So, I think we must face up to this fact as structures get bigger. I am not going to argue about what is happening at the very small molecular level, because I think you take your pick and this is an almost philosophical point. Quite honestly, we just do not know the mechanism of these thermodynamically driven reactions. This is a field of huge ignorance compared with those that we studied for years under kinetic control. But I am ready to witness, experimentally, the intervention of kinetic control when things get big.

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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J. Rebek: On a related note, which is directed more to our Chairman, to Chris Hunter, and to those people who create these interlocked systems making amide bonds, I noticed that acid chlorides are much admired in this synthesis. Can I first ask, do you ever use activated esters in your synthesis? And do they work? D.A. Leigh: Yes, you can use activated esters, but chlorides are rather privileged anions in this case. I think that’s because they help to solubilize the amide intermediates. J. Rebek: Yes, but another reason why they may be important is that, some 40 years ago, amide formation between acid chlorides and amines was shown to be autocatalytic. Actually, the product catalyzes the breakdown of the tetrahedral intermediate so that, apart from the template effect, you may actually be seeing an acceleration of the reaction because the amide is helping to force out the chloride. But the amide must be in the right place for the catenane to form. D.A. Leigh: Sure, that could be the case – but they are pretty fast reactions anyway. I am sure there are complex answers as to why this is so. Chairman: May I add a little to this story? We performed many studies with activated esters of all types, but we have never achieved results better than with acid chlorides. J. Rebek: That’s because most activated esters show very limited amide catalysis. Chairman: We got absolutely the best results with acid chlorides. R.D. Astumian: You had suggested that perhaps we should go in the direction of using hard rigid structures to make machines at the nanoscale. In biology, most of the motors are “soft,” and to do things in the same way as we do macroscopically, with bicycles and play toys, then hard is probably better. But if you want to work with the thermal environment of the system, then soft is probably better. J.F. Stoddart: Yes, I was just being devil’s advocate. Maybe many of you know that I am not the chemist who has been bioinspired, at least to date, to the extent that bio is the be-all and end-all in the chemistry that I do. This may change with my next venue, but I think we can be at least bioinspired conceptually, and we are of course in the way of making catenanes and rotaxanes using all these weak forces. I am not sure in hunting out devices that will bring widgets to the market place in the next, say, five to ten years. If I have confidence that staying in the “squelchy” world – in the wet world – is going to deliver, I think that it is a much longer-term activity that may be many decades away. But of course we have got to start, and I am now at the stage of life where I am looking to a termination at some point, that is not too far away. So, I have to make choices and I am just arguing that if, as chemists, we look at what has been successful across the board, it has been in device land, applications, and so forth – that is, it has been robust things rather than squelchy things.

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R.D. Astumian: Why do you contrast between robust and squelchy? Many things made from soft and dense matter are very robust. J.F. Stoddart: Yes, there is of course no cut-off between the two. The systems of Jim Heath, that I described, are like liquid crystals in between two electrodes, so that they are called solid-state devices. But we are looking at something that is like liquid crystals. I think I am just saying a robust architecture, a robust surrounding, outside the practice of healthcare and pharmaceuticals. That is where we have had our biggest successes so far. I am just being provocative – I want some people to disagree with me! M. Shionoya: Interlocking systems have provided many successful examples, in particular, in terms of directional control of the movement. How can we control the rate of movement of the molecules that use mechanical bonds. Do you have any ideas? J.F. Stoddart: We are always going to be encumbered by the fact that there are moving nuclei. If we are comparing their movement with that of electrons, for example, it is a slow world, but that doesn’t worry me. I think we can have very successful widgets, gadgets, machines, switches – whatever you want to call them – that are acting quite slowly. We can of course cover quite a large range of magnitude – I would say two, three, four or five times, depending on the environment where you put a particular molecule. Again, from my own experience, if we take molecules that have been put into crossbars, then there is a range of 10 000 between the solution rate and the rate in the actual device. Therefore, environment has a rather big effect on rates. So, while we can play around with the molecules and make the ring bigger and floppier, that certainly increases the rate. For example, a BPP 34-crown-10 ring will fly back and forward between a bipyridinium twostations 300 000 times each second in a degenerate rotaxane. For the much tighter cyclophane addressing to a hydroquinone unit, that is 500 times a second. Here, there are differences by orders of magnitude just by changing structures. But you have also a huge influence by changing the environment, and we are going to have to entertain these differences, because if we are going to take these molecules and make them work for us, then my feeling is that we will need ensembles. Therefore, we must go to surfaces, to interfaces, or – as I am advocating today – we have to go to three-dimensional structures. That’s my take on it. Chairman: You mentioned Wasserman’s rotaxanes, and you possibly doubted that it is correct. When I visited Gottfried Schill in Freiburg, he told me he does not believe it is correct. If one repeats this it will not be successful, I guess. J.F. Stoddart: I have heard Jean-Pierre Sauvage questioning it too, and I have also been reading some of Schill’s papers. You do not have to read much between the lines to come to the conclusion that this was not made by Wasserman. A. Credi: Professor Stoddart, I am very much intrigued by your idea of introducing mechanical switches into these metal–organic frameworks. We know that, for many of the switching systems studied so far, the solvent plays an important

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role as the mechanical rearrangements are assisted by the solvent. But very often, counterions have also to enter and leave. Would these processes still be possible in a solvent-free environment? J.F. Stoddart: I am sorry. I did not elaborate enough. Borrowing the term from Stephen Loeb, these metal–organic frameworks, or MOFs, are quite capable of being absolutely full of solvent if the struts are big enough. They are sponges – even those that are around at the moment. Maybe they don’t provide the type of environment you would have in solution, but the beautiful thing is that they are going to be so insoluble that you can introduce them to water, to dichloromethane, or to dimethylsulfoxide. You can really work, I think, in a fairly rapid way compared to what we are used to just by working in solution. For me, that’s the best of all worlds, because if it allows you to work in the gas phase. I take very much from these very highly porous materials, but perhaps this community hasn’t been impacted by it as much as I have. It was Omar Yaghi who showed that picture from BASF of huge cuboids of MOFs being held – and this is a little sexist, I know – by women on one hand. They are as light as feathers, and they are absolute sponges for gases, for liquids, and probably for other solutes that you want to add. Therefore, I think that they show a lot of promise – but that’s just my feeling. J.-P. Sauvage: Professor Stoddart, first, I would like to compliment you on your lecture. It was a very difficult task and you did it remarkably well. J.F. Stoddart: I thought you were going to say I should have not come. J.-P. Sauvage: I would have punished you. You made a very provocative statement at some stage. You said that “… if we just restrict ourselves to making such molecules without finding applications, the field does not go anywhere”. Maybe you can imagine that I do not entirely agree with that. Let me take an example: Somebody in 2004 made the Borromean rings. I don’t know if you have heard of this remarkable piece of work, which is a landmark in my opinion. In a way, this is bringing new concepts into molecular chemistry, and I think that in itself this is very important. Of course, if you can find applications for what we are doing – exactly as you are doing with Jim Heath and others – it is a bonus, it is a plus. But in my opinion, applications may come later on, possibly in other directions which are not exactly the way we had foreseen in our minds. I think if we are satisfied intellectually or conceptually with what we do, we can be happy. Don’t you agree on that? J.F. Stoddart: I think you can be happy if you are confident that the support for your research program will continue to be provided. I don’t pretend just to be the sole advocate trying to go for applications, but the point is that, in the United States, it is very very difficult. I haven’t got a dollar yet – I wrote up something quite small on the Borromean rings and sent it to the American Chemical Society, and it went down. You know, you really have got to argue your case for potential applications on that continent. I am just perhaps rather influenced by the environment I’m in, but I have got to bootstrap in order to make something like a Borromean ring or a suitane, or whatever it happens to be. I enjoyed doing it and I share your

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enjoyment there. By the same token, I have enjoyed immensely what I have done with Jim Heath – it has been an eye-opener in terms of expanding my scientific horizons, and it has produced a good deal of controversy which I think we have more or less killed off by doing a huge amount of physical organic chemistry. Anyone who has read our reports must now accept that the switching is molecular in the devices that we make. We are still compared to our supposed early-on collaborators who used a different form of switching, but what the community which wants to make such a comparison does not seem to appreciate is that the environment is all-important, and that it really does come down to polysilicon and titanium in order for these molecules to work at the molecular level. But if you put gold, platinum, or palladium – which is what they do – you see a physical effect. I have often said that scientists have seen this before with NMR spectroscopy. Physicists came along and saw huge effects in the magnetic field of resonance of hydrogen, fluorine, phosphorus, or whatever. Then, the organic chemists – and particularly bio-organic chemists – came along in the mid-1980s and found that, by working with this ten parts per million difference, this very, very small effect – this needle in a haystack – was providing a huge amount of information about molecules. So, I think I have been involved in some very interesting things as a result of going to a potential application, that I would not have got into if I had stayed with Borromean rings. There are many intellectual types of challenge that come from trying to pursue in a sort of targeted way. To say you would make a molecular computer – which you might never do – is not a bad thing to take on board if you are making Borromean rings and suitanes. J.-P. Sauvage: You made a provocative comment on purpose. That was to trigger discussion and somebody has to react, you know. J.F. Stoddart: Yes, and I thought more people would react, this time. I wanted some good arguments. J. Sanders: Can I follow on, can I react? I understand that one needs science in the long run to deliver practical technological applications, but there is a political danger in saying now that this kind of supramolecular chemistry or this kind of approach is going to deliver something. Our political paymasters work on much shorter time scales than we do, and if we say we can deliver catalysis, molecular computers, or whatever, and we do not deliver something that is competitive with the PC in the next four or five years, they might actually then rebound on us. J.F. Stoddart: Yes, sure. J. Sanders: There is a danger, I think, in saying too soon that “… this science will lead to practical applications.” J.F. Stoddart: I totally agree. I think that if you enter the room of hype and build something up too far, then you lose all credibility with your peers, and you probably lose the support of your funding bodies. But that still does not take away from us the challenge that we must meet, of attempting to address applications. There is not a seamless divide between this “blue sky” research and the application-driven

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one – there is as much intellectual stimulation to come out of a project that has some sort of goal and an applied nature, than one that is just being done for the hell of it. F. Vögtle: There is a last remark by Ben Feringa before the coffee break. B.L. Feringa: Yes, thank you. One area of applications is polymers. As I recall, ten years ago or so, there was quite some excitement about new polymers, all kinds of smart polymers based upon rotaxanes, catenanes, and so on. You did mention them as far as I recall, but is there still a future for this field? J.F. Stoddart: Yes, I do think there is a future, but I think it is a classical example of where the people practicing in this area must now reflect during the next decade or 15 years. I think we must now wonder whether we will be allowed to go on thanks to government funding – or wherever the funding is coming from – just making these things and speculating that they are going to do something useful. We must try to design something with the intent of demonstrating some form of use. But that’s a huge step, and we are not trained to do it – we have all been trained just to be classical academicians and to think of making Borromean rings or suitanes, or whatever is the joy of our life. I think that we must switch as a community, with part of us driven by applications. I don’t know if I’ll try to build up my involvement into the polymer area – I may do, but it will need to be driven by applications. If we make a particular polymer that is interlocked in some way, then it will need to have an application. Chairman: Thank you again, Professor Stoddart, for this outstanding contribution to the conference. We will have more time for discussion after the coffee break.

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10 Dynamic Combinatorial Approaches to Catenanes Prepared Comment Jeremy K. M. Sanders

The classical approach to creating receptors or molecules with interesting topologies such as catenanes is to design the structure and then try to synthesize it. By definition, this approach, when it is successful, leads to predictable structures. By contrast, dynamic combinatorial chemistry (DCC) uses a template to direct the synthesis of its own receptor. By using reactions that are under thermodynamic control, it is possible to generate equilibrating mixtures of unknown structures, from which the template can amplify complementary receptors [1, 2]. Thus, the successful structures cannot always be predicted. Indeed, the philosophical question that inspires this approach is “How do we discover the things we didn’t know we didn’t know?” Catenane synthesis appears intrinsically improbable, and is generally considered to be difficult. It therefore requires a molecular recognition event – templating – to bring the components together in high effective concentration and in the correct orientation. The first syntheses of catenanes used the design approach [3], and primed the investigators’ minds so that when an unexpected catenane was first produced from a dynamic combinatorial library (DCL), it was possible to recognize what had been made [4]. By using a simple peptide building block and hydrazone chemistry, it was discovered that acetylcholine chloride could act as an effective template for the production of a [2]catenane, in yields of 70% or more (Figure 10.1) whereas, in the absence of a template, only simple macrocycles were detected. The product catenane consists of two interlocked macrocycles, each containing three hydrazone-linked building blocks. The template, which appears to be clasped between aromatic rings in the two macrocycles, does not necessarily actively catalyze or accelerate the formation of the catenane; rather, it simply captures and stabilizes the product molecules as they are formed. However, the fact that the template successfully amplifies this hexameric product from a mixture of small stable macrocycles is testament to the absolute and relative strength of its binding to the catenane. In this case, the acetylcholine is a template in the classical architectural sense – that is, it is used as a guide to make something accurately, and can then be removed, so that it leaves no trace in the final molecule. Thus, it is difficult to imagine a prediction that such an unlikely and large flexible structure would serve as a good receptor for acetylcholine. 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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H

N H O

N H N N

O O

R

O

H N

N

O

N

ACh NHNH2

O

O

NMe3 Cl

O

R

H O

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N O

CHCl3:DMSO 95:5

MeO

N N HN

OMe

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O

O NH O H

HN

O N

N H O HN O O R NH O N

H O

HN

O

R NH

N

O R

NH N O H

Figure 10.1 Acetylcholine-templated formation of a [2]catenane from a peptide-hydrazone

dynamic combinatorial library [4].

OOC

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Figure 10.2 The use of a self-templating approach may allow discovery of the unexpected.

The alternative type of templating is self-templating, where a building block both directs the assembly of components around it and forms an integral part of the final structure. By using this approach, the present author’s group and others have prepared catenanes using dynamic covalent chemistry. In other words, predictable catenanes (and rotaxanes) are produced as the thermodynamically favored products of reversible chemical reactions such as alkene metathesis and imine exchange. However, even when using the self-templating approach, it is possible to discover the unexpected, as summarized in Figure 10.2 [5]. In this case, hydrophobic, van der Waals and possibly donor–acceptor interactions are used in water, with disulfide chemistry as the reversible reaction, to generate a diverse library that contains at least one catenane. Again, the long flexible side chains allow access to a wide variety of unexpected products that might be difficult to design. Three major conclusions can be drawn from these investigations: •

The synthesis of catenanes using building blocks that pack together well and displace solvent efficiently is actually quite easy.

References

•

Dynamic combinatorial chemistry gives ready access to unpredictable molecules, and opens up entirely new and unexpected areas in chemical structure space.

•

That, as originally articulated 10 years ago [6]: “The fear of entropy has taken supramolecular chemists too far in the direction of rigidity and pre-organisation, … the future may lie in more flexible systems that rely on non-covalent interactions to impose order on three-dimensional structure.”

This final conclusion was perhaps always obvious if a closer examination had been made as to how Nature achieves selectivity and strong binding in biology, although additional supporting evidence is now available from within the supramolecular world.

Notes Added After the Conference

The dynamic combinatorial approach has recently proved to be very successful for the discovery of new unpredictable catenanes [7].

References 1 Corbett, P.T., Leclaire, J., Vial, L., Wietor, J.-L., West, K.R., Sanders, J.K.M., and Otto, S. (2006) Chem. Rev., 106, 3652–3711. 2 Lehn, J.M. (2007) Chem. Soc. Rev., 36, 151–160. 3 Raehm, L., Hamilton, D.G., and Sanders, J.K.M. (2002) Synlett, 1743–1761. 4 Lam, R.T.S., Belenguer, A., Roberts, S.L., Naumann, C., Jarrosson, T., Otto, S., and

Sanders, J.K.M. (2005) Science, 308, 667–669. 5 Au-Yeung, H.Y., Pantos, G.D., and Sanders, J.K.M. (2009) Proc. Natl Acad. Sci. USA, 106, 10466–10470. 6 Sanders, J.K.M. (1998) Chem. Eur. J., 4, 1378–1383. 7 Au-Yeung, H.Y., Pantos, G.D., and Sanders, J.K.M. (2009) J. Am. Chem. Soc., 131, 16030–16032.

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11 Discussion 2.B Discussion on the Prepared Comments by M. Fujita,1) J. Sanders,2) and D.A. Leigh3) Chairman: Fritz Vögtle

Chairman: I think that all the presentations today – the long one and the shorter ones – should inspire discussions and questions. For example, I have the idea that the historic synthesis of macrocycles should possibly be repeated, if they look good, in the direction of catenanes and rotaxanes, because those people had rigid building blocks partly, and maybe some of their products, as just noted by Professor Makoto Fujita, could also be catenanes. Of course, new template synthesis should be designed that should be of high yield. Nevertheless, there is no doubt that the combination of templates with catalysis has also very good future aspects. J. Michl: My question relates to Professor Fujita’s talk. We had a similar experience of a catenane forming without particularly being intended to form, and trying to make molecular rectangles. We found that with smaller anions we are actually not making simple rectangles; rather, they are catenated – two of them together. But with larger anions – specifically polyalkylated carborane anions that apparently filled the inside of the rectangle – we suddenly got ordinary simple rings or rectangles. So, my question is, how important is the nature of the counterion in this whole process? Chairman: Certainly, there are rotaxane syntheses where the counterions play an important role, I think. Also, if there is a wide space and nothing fits into the cavity, there is the danger that you get a molecule threaded through it. J. Michl: Actually in our case, the solvent could fit very nicely. Chairman: Then you should modify the solvent. If you take a too-large solvent molecule that cannot penetrate into the cavity, then possibly your component reactant would thread through. 1) The prepared comment by M. Fujita was on template synthesis versus “by chance” synthesis. 2) The prepared comment by J. Sanders was on dynamic combinatorial approaches to catenanes (see p. 147).

3) The prepared comment by D.A. Leigh was on the “active template” synthesis of mechanically interlocked architectures.

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R.W. Saalfrank: I have a question for Professor Sanders. Your presentation was very interesting – particularly, the sentence “… gives away the actual responsibility to the molecules”. Could you please comment on that sentence a little more? J. Sanders: We have all been to lectures by synthetic or medicinal chemists who show us molecules they have designed, and which have successfully inhibited this enzyme or that transport, or saved peoples’ lives. At the end of the lecture, they say “… we designed this molecule, we made it, and it was successful.” Although this is true, they have also often designed hundreds or thousands of other molecules, which they have successfully synthesized, but which did not work, and so they were not mentioned. The lesson I draw from this is that we are really not very good at designing molecules that are successful. We are good at designing molecules, but not very good at predicting how they will behave, or how they will act. So, I decided that it was best to give that design responsibility to the molecules. When designing an experiment, the point of dynamic combinatorial chemistry is to set up the experiment, not the molecule. Then, if it’s possible to create a successful system on that basis, it will be created, and all we have to do is to find out what we have made afterwards. What I mean by giving intellectual responsibility to the molecules is that I am letting the molecules, the template, or the building blocks choose which are the most stable and most successful species, rather than imposing my will on them, because I am not very good at that. I don’t know if that answers your question? R.W. Saalfrank: So you are asking for more dialogue between the chemist and the experiment? J. Sanders: Late at night, some of us do talk to our molecules! No, of course, you do not have a dialogue with the molecules, you simply let things go and see what happens. Chairman: One important aspect of templating is to produce as yet inaccessible molecules, because new architectures and new structures usually yield new functions, with which you can do new chemistry. J. Sanders: To me, the attraction is that the products obtained are not limited by my imagination, or by my research group’s imagination. That’s how we can discover the things we did not know we could make – and how we can discover things we don’t know. Two hundred years ago, nobody knew that DNA existed – in fact, they didn’t even know that they didn’t know DNA existed. But look at how important it is now. I accept Fraser Stoddart’s point that we must perform applicable science, but we must also perform science in such a way that it enables us to discover the things that we cannot currently imagine, that our governments cannot currently imagine, and that the chief executives of companies cannot currently imagine. That’s what we must do. D.N. Reinhoudt: Just to follow on from Jeremy Sanders’ talk. In most of your examples, you have one building block and you make a dimer, a trimer, or a

11 Discussion 2.B

tetramer – that is, you make symmetrical molecules. But we discussed earlier that perhaps nonsymmetrical molecules might be far better. So, what do you see as the limitation in taking multiple building blocks and finding the really good molecule for a specific guest? A priori, I think it is not the symmetrical molecule that is always the best. J. Sanders: My colleague Sijbren Otto is not here, but he has some wonderful results with very much more complicated libraries than I have mentioned here. He has many different building blocks in one mixture, with thousands of molecules that you can identify with HPLC. So, you can amplify very effective compounds, which contain more than one or more than two types of building block, and which are no longer symmetrical. In the long run, that’s it, but in part it’s once again the fear of entropy that stops us jumping to these hugely complex mixtures. However, if you are a good analytical chemist, you can handle complicated mixtures and find the molecules that are fitter, those that are better, and those that are no longer simple and symmetrical, similar to those I have shown here. S. Shinkai: I also have a question for Jeremy Sanders, which is related to the oxidation of SH groups to form cyclic compounds. We once tried to synthesize crown-type compounds from disulfide compounds containing ethylene glycol. Then, of course, the ring-size product distribution was template dependent, and the product was also time-dependent in the isolation process. The distribution always changed so that we couldn’t differentiate between the kinetic control and the thermodynamic control. In a sense, as Makoto Fujita demonstrated, acid exchange is always taking place under some reaction conditions. So, how can you discriminate between the thermodynamic control and the kinetic control? J. Sanders: We have had several examples where we see kinetic products formed initially, but they then go away and we get what we believe to be thermodynamic products. Of course, you could never know whether you reached thermodynamic equilibrium. The acetylcholine binding catenane I showed reaches its maximum concentration after about 40 days. It may be that, if we waited for 40 years, we would get something that was even better, but I couldn’t persuade the student to stay that long! What we do find is that we always get to a stable situation. We often start the reaction from different points – from a pre-formed dimer or a preformed tetramer – to be sure that we end up reaching the same equilibrium. But it sounds as though you are not getting complete oxidation. Once you have complete oxidation to disulfides, and there are no thiolate anions present, then there would be no exchange. But if you don’t have complete oxidation, then the exchange will continue. Usually, we find that the opposite is true – we get to complete oxidation too soon, so that you have to add a little reducing agent or a little thiolate anion to restart the process and make sure you get to equilibrium. S. Shinkai: In our case, it is a very flexible ring system. so that the ∆Gs between different compounds are very, very similar. Consequently, the exchange is quite easy because the stabilities of the monomers, dimers, or trimers are similar, as the rings are so flexible.

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J. Sanders: But you should still reach a steady state – unless you have discovered an oscillating system, which would be really exciting! R. Nolte: Another question for Jeremy Sanders. The dynamic combinatorial approach is very interesting of course. What you mentioned is that if you add a template, you don’t go to the lowest energy state of a particular compound, but to the lowest free energy of the complete mixture. My point is, if you have a limited number of building blocks, you possibly select the species you would like to have; however, if you increase the number of building blocks this becomes problematic, because you get to the lowest free energy of the system in the presence of the template. You are not sure you’re really getting the compounds you would like to have – that is, the host system that fits the guest best. For two or three component molecules that can form a host, your approach is probably OK. But, suppose that you mix 12, 15, or 20 building blocks, and that you would like to select a host that fits the guest best. Then, you’re not sure that you’ll really have that particular host, because it’s the free energy of the system of the complete mixture, of different combinations of hosts and guests, that counts. J. Sanders: There are two separate questions mixed up in there. One is clearly that, if you have too many building blocks, the concentration of each species in solution is very, very low. At the point where it is below one over the association constant, you wouldn’t be able to amplify the product because there would not be sufficient binding. So, you cannot have too many building blocks at once. Nonetheless, it’s quite easy to set up a hundred different experiments simultaneously, so that you can screen many different mixtures. You are unlikely to ever isolate a receptor that has got several different types of building block in, although in principle you could. That is one point: you can’t have a too-complicated mixture, because the concentrations are too low. The other possible worry is the following, and this was a worry that we had when we first started out on this 15 years ago. If the mixture is too complicated, will it take too long to reach equilibrium? Does it take too long to explore all the different possible structures? In fact, I employed a mathematician to carry out simulations for me, and then I discovered that Stuart Kauffman in New Mexico had done those calculations already during the 1980s. As you make the system more complicated, the number of pathways increases faster than the number of products. Therefore, whilst it is counterintuitive, it doesn’t take any longer to reach equilibrium if you have more building blocks in solution than less. R. Nolte: Yes, that’s a good point. A. Shanzer: I would like to emphasize your point when you say we don’t know how molecules react. In practice, that’s probably correct, as I’m sure everybody here has experienced planning one thing and getting something else. So, why don’t we do just the opposite and learn how molecules work by taking your experiment and asking the questions: What type of molecules did we get, rather than just the one that works? What types of molecule did we get from a very, very small mixture of say three or four components? Perhaps we would acquire some new knowledge, which is probably there, and then you can go back to the design.

11 Discussion 2.B

J. Sanders: As with the other speakers, I was allowed only three slides, so I was unable to explore that question. But obviously, that’s a very important component of what one is doing. In the end, you learn how molecules behave and, yes, that’s something that we do, but I didn’t talk about it. J. Michl: I would like to take two issues with what Jeremy Sanders is proposing. One of them has already been just addressed, the proposal being to give the intellectual responsibility to the molecules. But clearly, that’s really not what you truly mean, this is just the first step. J. Sanders: No, it isn’t what I mean – it’s what I’ve been accused of. J. Michl: OK, it is merely a first step in trying to learn how to do things better and ultimately taking over the intellectual control yourself – that’s clear. The other issue is that you are not really giving up the intellectual responsibility, you are just shifting it to a different level. Instead of trying to design the distances between the binding groups that are just right to achieve an enzymatic catalysis and so on, you will be faced with the responsibility for selecting the one, two or three products from the very large number that you get, and deciding what they are good for. Because of the way that you described it, you have really no particular objective in mind in the synthesis – you are creating compounds with the objective of deciding later what they might be useful for, after you’ve identified them. J. Sanders: Yes, that’s correct. C. Hunter: Professor Sanders, you made a throwaway comment that “… you just have to characterize the molecules”. In reality, how easy is it to do that, especially, given that we are considering structure resolution with X-ray crystallography as the only good tool for determining such structures? J. Sanders: That’s a good point. We don’t have any crystal structures from these dynamic combinatorial projects. We are doing nineteenth century chemistry – disulfide chemistry, hydrazone chemistry – but solving structures using twentyfirst century analytical chemistry. In particular, mass spectrometry is very important to us when determining molecular weights and connectivities, especially when it comes to catenanes with multiple possible structures. But we do have examples where it takes a long time to find out what the structure is. In the case of the acetylcholine binding catenane, I think we were only able to determine its structure because my mind was prepared. We were trying to make catenanes by other routes and failing, so catenanes were in my mind. Many people would have never seen a catenane, and it would never have crossed their minds. But this problem exists because we don’t have the X-ray structures. Chairman: Are there any further questions? J.-P. Sauvage: This question is totally unrelated to the interesting discussion we have just had. I come back to Fritz Vögtle’s earlier lecture, where you referred to kDNA. I remember that, maybe 15 years ago, there was a series of publications describing the DNA of parasitic organisms – I don’t remember their names. There

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were claims being made that such DNA had exactly the same type of topology as the one you showed. So, my question is, do we know more about that? Is it now sure and proven? Chairman: I am sorry, I just took the picture from the literature, I don’t know the answer to that question. J.-P. Sauvage: Perhaps some biologists would know? I ask because it is really fascinating to realize that Nature possibly is creating such complicated topologies, but for which aim, and for which purpose? Chairman: It must also be a quite elastic material. J.-P. Sauvage: So this is a no-answer question! T.F. Otero: I am an electrochemist working with conducting polymers, and am fascinated by the many beautiful molecules that you are working with. At the end of the day, you were talking about applications and different possibilities, and so we are probably only hearing things about molecules and molecular properties. However, it’s very difficult to arrive at properties if we don’t talk about the properties of collectives. What happens when we put all of these molecules together? When we produce films and monolayers, new properties and new possibilities appear. But what happens when those molecules work in solid state, when they work in liquids, or when they work as a collective? From my point of view, most of the money being spent in this field arrived when Moore’s law predicted that, in a few years, chips will be available in molecular dimensions. Although much work has been done – and very well done – on this subject, I can’t see where the point of contact occurs between people working with traditional microtechnologies and those working with wonderful molecules. In order to meet each other, surely it is necessary to talk about the collective properties? That’s the point I wanted to stress here today. J.F. Stoddart: Yes, I think that point has been well made, and it’s the one I was trying to address. I didn’t spend a lot of time talking about the properties that emerge when you start working with collections of molecules at interfaces or on surfaces, but I totally agree. And this is where a lot of the science is to be found. This morning, we were directed towards synthesis of the noncovalent type almost exclusively, though of course with some overlap into the covalent world. And this afternoon, we were living with the synthesis of compounds with mechanical bonds. But of course you are right, and I did raise the prospect that – as my colleague Jim Heath used to say over and over again – synthesis does not begin and end with just making molecules. It continues into the device fabrication and into the measurements that you make with collective bundles of molecules. I totally agree. Chairman: Well, I think we have discussed quite a lot here, so I would like to join with you all in applauding today’s speakers and commentators, and then to close the session. Thank you very much.

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Part Three Molecular Machines Based on 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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12 Molecular Machines Based on Rotaxanes and Catenanes Report Vincenzo Balzani, Alberto Credi, and Margherita Venturi

12.1 Introduction

Chemistry is one of the oldest sciences which, initially, involved not only watching the spontaneous transformation of substances but also causing changes in their properties. During the nineteenth century, the occurrence of chemical reactions was explained on the basis of the atomic nature of matter and the properties of atoms. However, during the twentieth century chemistry progressively became the science of molecules – whether of natural molecules discovered in the world in which humankind lives, or of artificial molecules developed by chemists in their laboratories. Until 10 years ago, it was indeed thought that “…the most creative act in chemistry was the design and creation of new molecules” [1]. In the meantime, the concept of supramolecular chemistry [2] – particularly in its broader sense of the chemistry of multicomponent systems [3] – began to permeate the chemical community, whereupon the idea began to arise [4–6] that the concept of macroscopic devices and machines could be transferred to the molecular level. During the past 20 years, the marriage of an engineering mentality with the use of photonic, electronic, and chemical inputs to stimulate supramolecular systems [7] has led chemists to construct a variety of molecular devices and machines capable of processing energy and signals [8–24]. Clearly, at the start of the twenty-first century, the “old flasks” of chemistry are in the process of being refilled with the “new wine” of nanoscience and nanotechnology.

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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12.2 Molecular Machines: History and Overview 12.2.1 General Concepts

In the macroscopic world, devices and machines are assemblies of components designed to achieve a specific function. Each component of the assembly performs a simple act, while the entire assembly performs a more complex, useful function, characteristic of that particular device or machine. In principle, the macroscopic concepts of a device and a machine can be extended to the molecular level [12, 24]: •

A molecular device can be defined as an assembly of a discrete number of molecular components designed to achieve a specific function. Each molecular component performs a single act, while the entire supramolecular assembly performs a more complex function, which results from the cooperation of the various components.

•

A molecular machine is a particular type of device in which the (molecular) component parts can display changes in their relative positions as a result of some external stimulus (for more details, see Section 12.2.4).

The extension of the concepts of a device and a machine to the molecular level is of interest not only for basic research, but also for the growth of nanoscience and the development of nanotechnology. During the past 50 years, the outstanding development of information technology has been strictly related to the progressive miniaturization of the components employed for the construction of devices and machines. Miniaturization at the micrometer level is currently pursued by the “top-down” approach, which leads physicists and engineers to manipulate progressively smaller pieces of matter by photolithography and related techniques. Until now, this approach has operated in an outstanding way; however, it is becoming increasingly apparent that it is rapidly moving towards the upperlimits of its capabilities [25–27]. In particular, the conventional scaling methods of the semiconductor industry are being subjected to drastic technical and economical limitations as device features are pushed towards the deep sub-100 nm regime. An alternative strategy towards technology at the nanometer scale is offered by the “bottom-up” approach, which starts from atom or molecules and builds up to nanostructures. The idea that atoms could be used to construct nanoscale devices and machines was first raised by R. P. Feynman in 1959 [28], and then depicted by K.E. Drexler in an exciting and visionary way during the mid-1980s [29, 30]. The atom-by-atom approach to miniaturization – which seems so appealing to physicists – does not convince chemists [31, 32], however, who believe that molecules are much more convenient building blocks than atoms when constructing nanoscale devices and machines. Indeed, molecules are components that already

12.2 Molecular Machines: History and Overview

exhibit distinct shapes, carry device-related properties (e.g., the properties that can be manipulated by photochemical and electrochemical inputs), and can selfassemble or be easily connected so as to create larger structures. 12.2.2 Natural Devices and Machines

In nature, a variety of molecular devices and machines are already present, and function work very well [33–35]. Indeed, Nature provides living systems with complex molecules (proteins) that convert chemical energy into power. It is because of these biological devices and machines that humankind can walk, talk, and even think. In fact, it has been estimated that around 10 000 different types of nanomachines are at work in the human body [33]. The design and construction of artificial molecular devices and machines can take great benefit from the knowledge of the working principles of their natural counterparts. Nature shows, indeed, that nanoscale devices and machines can hardly be considered as “shrunken” versions of macroscopic counterparts, because some of the intrinsic properties of molecular-level entities are quite different from those of macroscopic objects [34]. Biomolecular machines are made from nanometer-size floppy molecules which operate at constant temperature in the soft and chaotic environment produced by the weak intermolecular forces and the ceaseless and random molecular movements. Gravity and inertia motions are familiar concepts in everyday life, but are fully negligible at the molecular scale; typically, viscous forces resulting from intermolecular interactions (including those with solvent water molecules) largely prevail, and directed motion is very difficult. This means that while the bottom-up construction of a nanoscale device can be described as an assembly of suitable (molecular) components (by analogy with what happens in the macroscopic world), it should not be forgotten that the design principles and operating mechanisms at the molecular level are quite different. The working mechanism of biomolecular machines can be described as a “random walk” [36], with transitions from one state to another occurring by thermal activation over energy barriers [37]. Biomolecular machines are actuated by Brownian motion, and the role of the energy input (ATP hydrolysis) is to give direction to these undirected processes by lowering the energy profile along a specific motion coordinate (as shown schematically in Figure 12.1). When destabilization of the initial, more-stable conformation has occurred, the motion itself is driven by thermal activation over the (decreased) barrier. Reset occurs when the input energy ends, or upon the action of an opposite input. 12.2.3 Artificial Molecular Devices and Machines

As in the macroscopic world, molecular-level devices and machines need energy to operate and signals to communicate with the operator [38].

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E

Destabilize

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Figure 12.1 Schematic representation of the role played by the energy input in giving a

direction to the random walk of biomolecular machines [37].

As molecular devices and machines are chemical systems, they can operate by means of chemical reactions that, broadly speaking, imply both electronic and nuclear rearrangements. In some cases, however, the function performed is essentially based on the transfer of electrons or electronic energy, without substantial nuclear rearrangements. In other cases, the operation is based on the occurrence of extensive nuclear displacements. The energy needed for the operation of a molecular device or machine can be supplied in the form of: (i) a chemical fuel (i.e., a reagent); (ii) an absorbed photon; or (iii) the addition or subtraction of an electron. In view of the shortage of chemical fuels and increasing environmental problems, the ideal primary energy source would be sunlight [39], while the worthiest processes are those that do not form waste products. In order to control and monitor the operation of a molecular device or machine, a suitable signal is needed. Since at least one molecular component of the system changes its state on performing the required function, any signal related to such a component can be used. In this regard, a variety of chemical and physical techniques can be valuable. Both, a device and a machine must function by repeating cycles, which means that “reset” is an important requirement. Consequently, any chemical reaction involved in the operation must be reversible. Although no chemical reaction is fully reversible, this requirement is reasonably well met by energy transfer, electron-transfer (redox), and proton-transfer (acid–base) processes, and also by some types of photoisomerization and metal–ligand coordination reactions. The operation time scale of a molecular device can range from less than picoseconds to days, depending on the nature of the processes involved. The functions that can be performed by molecular devices and machines are various. They may be related to signal transfer (in the form of energy, electrons, protons, etc.), information processing (e.g., by molecular-level logic gates), energy conversion (e.g., conversion of light into chemical or electrical energy), and a wide range of mechanical-like aspects (e.g., transportation of a cargo through a membrane).

12.2 Molecular Machines: History and Overview

12.2.4 Mechanical Motion in Artificial Molecular-Scale Systems

It is not easy to define the functions related to artificial molecular motions, and comparison with the functions performed by molecular-level biological moving systems is difficult for several reasons: •

The natural systems are very complex from a structural viewpoint.

•

They usually combine different motions and functions.

•

Sometimes. motions in artificial molecular systems have no counterpart in Nature.

•

The function performed by an artificial molecular-level system depends on the way in which the system is operated; for example, an ordered molecular array can carry out functions that the same molecules, when randomly distributed in a solution, cannot perform [40].

A simple and immediate categorization of artificial molecular motions is usually based on an iconic comparison with motions taking place in macroscopic systems (e.g., braking, locking, shuttling, rotating). Such a comparison presents the advantage of an easy representation of molecular devices by cartoons that can clearly explain their mechanical functions. However, it also implies the danger of overlooking the above-discussed, substantial differences between the macroscopic and molecular worlds. To establish a nomenclature is always a difficult and controversial issue, particularly in the case of a new and emerging field that involves different disciplines such as chemistry, physics, and biology, as is the case of mechanical motion at the molecular level [12, 17, 21]. It is suggested that the following minimum set of terms and definitions be used: • • •

Mechanical device: A particular type of device designed to perform mechanical movements. Machine: A particular type of mechanical device designed to perform a specific mechanical movement under the action of a defined energy input. Motor: A machine capable of using an energy input to produce useful work.

Clearly, there is a hierarchy here. A motor is also a machine, and a machine is also a mechanical device, but a mechanical device might not be a machine or a motor, and a machine might not be a motor. For the sake of simplicity, in general discussions, the term molecular machines will include molecular motors. The distinctions among the three types of device will be further discussed when describing examples of moving rotaxanes and catenanes. Mechanical movements at the molecular level result from nuclear motions caused by chemical reactions. Of course, any type of chemical reaction involves some degree of nuclear displacement, though only large-amplitude, nontrivial motions leading to the real translocation of some component parts of the system

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are considered. Particularly interesting nuclear motions from the viewpoint of artificial molecular systems are those related to: • • •

isomerization reactions involving –N=N–, –C=N–, and –C=C– double bonds in covalent supramolecular structures; acid–base or redox reactions that cause the making or breaking of intermolecular bonds (including hydrogen bonds); and metal–ligand reactions causing the formation or disruption of coordination bonds.

In the Brownian ratchet model discussed above for biomolecular machines, the interaction energy resulting from mechano-chemical coupling is a property of the system as a whole, without any specific structural origin [37]. The motion is described as a thermally activated stochastic process. The system is at chemical equilibrium, and there is no crucial conformational step that can be identified as the point at which energy transduction occurs. This stochastic model is unsuitable for simple artificial systems in which the energy of the input, delivered in a very short time, is localized in a well-defined site of the system, and the motion is confined in a specific degree of freedom. Indeed, only a mechanical (i.e., deterministic) model is conceivable when the motion is produced by the photoexcitation of a clearly identifiable molecular component with the sudden formation of a highenergy, much less-excited state (Figure 12.2) [41]. It has been pointed out that, in principle, the distinction between a mechanical model and the Brownian model for biomolecular motors could find an experimen-

*

* Excited state

E

hv Ground state

Figure 12.2 Schematic representation of the

role played by a pulsed (e.g., photonic) and localized energy input to cause a motion confined in a specific degree of freedom in a supramolecular system. Excitation causes the sudden formation of a high-energy,

well-less-excited state that can undergo fast relaxation, leading to a different molecular structure. A typical example may be represented by the E→Z photoisomerization of azobenzene [41].

12.2 Molecular Machines: History and Overview

tal basis [37]. For example, by observing in the same experiment at the singlemolecule level an individual ATP hydrolysis event, followed by the completion of a step of the motor along its track, it should be possible to determine the distribution of time lapse between these two events. In the case of a Brownian motor mechanism, the time between ATP hydrolysis and completion of the step should be randomly distributed, rather than deterministic. This type of investigation should be easier to perform on simple artificial molecular machines, particularly those powered by light pulses. A very important feature of molecular machines, related to energy supply (vide infra) and cyclic operation, is their capability to exhibit an autonomous behavior; that is, to keep operating, in a constant environment, as long as the energy source is available [42]. Although, natural motors are autonomous, most of the artificial systems reported to date have not been autonomous since, after the mechanical movement induced by a given input, they require another (opposite) input in order to reset. Clearly, the operation of a molecular machine is accompanied by the partial degradation of free energy into heat, regardless of the chemical, photochemical, and electrochemical nature of the energy input. 12.2.5 Energy Supply

Under equilibrium conditions, Brownian motion arising from thermal energy cannot be exploited to drive the organized movement of a machine or a motor, even if anisotropy features are embedded in the system [43, 44]. To make a molecular machine move, energy must be supplied, and the most obvious way of supplying energy to a chemical system is by adding a reactant (fuel) that is capable of causing a desired reaction. There are, however, alternative, more convenient, ways of powering artificial molecular machines. 12.2.5.1 Chemical Energy If an artificial molecular machine is to function by the input of chemical energy, it will require the addition of fresh reactants (“fuel”) at any step of its working cycle [21, 24, 45]. It should be noted that even cycling between two stable forms of a molecular-level system under the action of chemical inputs, implies the formation of waste products. For example, if the forward reaction is caused by an acid input, the successive addition of a base will return the system to its original form, but the acid–base reaction will generate waste products. Any accumulation of waste products will inevitably compromise the operation of the machine, unless they are removed from the system, as occurs both in natural machines and in macroscopic internal combustion engines. 12.2.5.2 Light Energy In Nature, light energy is not used as such to produce mechanical movements, but rather to produce a chemical fuel, namely ATP, which is suitable for feeding natural molecular machines. Light energy, however, can directly cause

165

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12 Molecular Machines Based on Rotaxanes and Catenanes

photochemical reactions that involve large nuclear movements. A simple example is a photoinduced isomerization from the lower-energy E form to the higherenergy Z form of a molecule containing a –N=N– double bond, followed by a spontaneous or light-induced back-reaction [41]. In supramolecular species, photoinduced electron-transfer reactions can also cause the major displacement of molecular components [12, 21, 24, 46]. When working with suitable systems, an endless sequence of cyclic molecular-level movements can, in principle, be performed by making use of light-energy inputs, without generating waste products. Whilst, compared to chemical energy inputs, photonic energy does not generate waste products, it also has certain other advantages, [12, 24, 45, 46]: •

light can be switched on/off easily and rapidly;

•

lasers provide the opportunity of working in very small space and very short time domains;

•

photons, besides supplying the energy needed to make a machine work, can also be useful to “read” the state of the system and thus to control and monitor the operation of the machine.

12.2.5.3 Electrical Energy An electrical potential can be used to create redox reactions involving large structural changes in supramolecular systems [47–49]. By working on a reversible redox couple, it is possible to fuel the forward reaction and, by reversing the potential, to return to the reactant – that is, to cause a switching process without the formation of waste products [12, 21, 24]. The main advantage of using an electrochemical energy input in place of chemical redox inputs is that it can be switched on and off easily and rapidly. Moreover, electrochemical techniques can also provide a useful means of monitoring the operation of the machine, while electrodes represent one of the best ways of interfacing molecular-level systems with the macroscopic world.

12.3 Molecular Machines Based on Rotaxanes 12.3.1 Introduction

A rotaxane [50–53] (Figure 12.3) is a supramolecular [54] species composed of a dumbbell-shaped component threaded by a ring which is trapped mechanically around rod-like portion of the dumbbell-shaped component by two bulky stoppers. The two components cannot, therefore, dissociate from one another, even though they are not linked covalently. The general strategy for preparing rotaxanes in high yields is based on the template effect [50–53, 55, 56], which relies on the presence of molecular recognition sites between the components to be assembled.

12.3 Molecular Machines Based on Rotaxanes (a)

(b)

Figure 12.3 Schematic representation of the rotation (a) and shuttling (b) movements of the ring component of a rotaxane.

In a rotaxane, the wheel component can either rotate around (Figure 12.3a) or shuttle along (Figure 12.3b) the axle component1). These movements, however, are conditioned by the presence of recognition sites on the dumbbell and ring components. The most common template syntheses usually lead to the cases depicted in Figure 12.4, namely: (i)

The dumbbell component contains only one recognition site, and the ring component possesses two identical recognition sites (Figure 12.4a); these systems can undergo degenerate co-conformational change [57] when the ring circumrotates.

(ii)

Both, the dumbbell and the ring components contain two identical recognition sites (Figure 12.4b); in such a case, the system can undergo degenerate co-conformational changes when the macrocycle circumrotates or moves along the dumbbell.

(iii) The dumbbell component contains only one recognition site, and the ring component possesses two different recognition sites (Figure 12.4c); these systems can occur in two different rotational isomers. (iv)

The dumbbell component contains two different recognition sites, and the ring component possesses two identical recognition sites (Figure 12.4d); in such a case, the system can occur in two different translational isomers.

In a diagram of potential energy against a coordinate expressing the orientation of the ring relative to the thread or the position of the ring along the thread, cases (i) and (ii) correspond to an energy profile such as that shown schematically in Figure 12.5a, while cases (iii) and (iv) correspond to an energy profile as shown in Figure 12.5b. For the molecular machine viewpoint, that is, movements caused by external stimuli, the cases of interest are (iii) and (iv). In fact, very few investigations have been conducted on compounds of type (iii) (this type of switching motion is often termed “pirouetting” [58–60]). Most of the investigations have indeed concerned systems in which the ring component is forced by external 1) The cartoons shown in the figure, while providing a simple structural and topological representation, are somewhat misleading because they give the impression that rotaxanes and catenanes are made of rigid molecular components, which is not the case for the vast majority of the systems reported so far. However, in order

to obtain clear-cut mechanical movements the molecular components should exhibit at least some stiffness. As will be evidenced by the examples in the following sections, this feature for molecular machines is most commonly fulfilled by utilizing molecular components that possess rigid subunits in their structures.

167

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12 Molecular Machines Based on Rotaxanes and Catenanes (a)

(b)

(c)

State 0

State 1

(d)

State 0

Figure 12.4 Schematic representation of

rotaxanes composed of: (a) a dumbbell containing only one recognition site and a ring containing two identical recognition sites; (b) a dumbbell and ring components both containing identical recognition sites; (c) a dumbbell containing only one recognition site and a ring containing two

State 1

different recognition sites; (d) a dumbbell containing two different recognition sites and a ring containing two identical recognition sites. The interconversion between the possible rotational and/or translational isomers is also shown. Asterisks are used to highlight the exchange of position of identical units.

stimuli to shuttle between two different recognition sites (“stations”) located on dumbbell component [as in case (iv)] [61, 62]. Two-station rotaxanes can exist as two different equilibrating co-conformations (state 0 and state 1), the populations of which reflect their relative free energies, as determined primarily by the strengths of the two different sets of noncovalent bonding interactions. In appropriately designed systems, protonation– deprotonation, oxidation–reduction and other processes can be exploited to alter, reversibly, the stereoelectronic properties of one of the two stations. This will affect their relative capacities to interact with the ring, and induces ring displacement towards the station offering the strongest interaction. By switching the recognition

12.3 Molecular Machines Based on Rotaxanes (a)

(b) State 0

E

State 1

E

Ring orientation around the thread

Ring orientation around the thread

or

or

Ring position along the thread

Ring position along the thread

Figure 12.5 Potential energy curves for degenerate (a) and nondegenerate (b) ring-pirouetting or shuttling motions in rotaxanes. Curves (a) and (b) refer to systems like those shown in Figure 12.4a–d, respectively.

properties of one of the two stations off and on again, a reversible shuttling process can be obtained which is under the control of chemical, electrochemical, or photochemical stimulations [9–16, 18–24, 63, 64]. The controlled shuttling movement is interesting not only mechanically, but also for information processing (binary logic). Interestingly, the dumbbell component of a molecular shuttle exerts on the ring motion the same type of directional restriction imposed by the protein track for linear biomolecular motors (an actin filament for myosin and a microtubule for kinesin and dynein) [35]. It should also be noted that interlocked molecular architectures are largely present in natural systems; typical examples include DNA catenanes and rotaxanes [53]. Many processive enzymes – that is, enzymes which remain attached to their biopolymer substrates (DNA, RNA or proteins) and perform multiple rounds of catalysis before dissociating – are thought to exhibit a rotaxane structure; this has been confirmed, for example, by observations of the crystal structure of DNA λ-exonuclease [65]. Clearly, the unique aspect of the rotaxane architecture – that is, the mechanical binding of the catalyst with the substrate which leaves the former free to displace itself along the latter, without losing the system’s integrity – is utilized by Nature to enhance the activity of processive enzymes. In the following discussion, the systems have been subdivided on the basis of the predominant stimulus (chemical, electrochemical, photochemical) that causes ring displacement. Due to limited space, only paradigmatic examples will be illustrated at this time, and in all cases the investigations have been performed in solution. Those systems in which the molecular motions are interfaced with the macroscopic world are described in Section 12.5. 12.3.2 Chemically Driven Movements 12.3.2.1 Rotaxanes Based on Macrocyclic Crown Ethers Rotaxane [1H]3+ incorporates a dialkylammonium and a bipyridinium recognition site in its dumbbell-shaped component (Figure 12.6) [66]. The macrocyclic crown

169

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12 Molecular Machines Based on Rotaxanes and Catenanes

O

O +

+

N

O N O H2 O O O

O

N

+

H+

[1H]3+

+ i-Pr2NEt

+ H+

12+

Figure 12.6 The acid–base-controllable molecular shuttle [1H]3+ [66].

ether, namely a dibenzo [24]crown-8, resides exclusively around the ammonium recognition site in (CD3)2CO at 298 K, as a result of a combination of [+N–H…O] and [C–H…O] interactions between the [CH2NH2+ ] hydrogen atoms of the dumbbell and the oxygen atoms of the macrocycle. On the addition of excess of i-Pr2NEt to a (CD3)2CO solution of [15H]3+, deprotonation of the ammonium recognition site occurs. As a result, the intercomponent hydrogen bonds are destroyed and the macrocycle shuttles to the bipyridinium recognition site. The original coconformation is restored by addition of CF3CO2H. The shuttling process is quantitative, and can be followed using 1H NMR and UV-Vis spectroscopy, and also electrochemical techniques [66, 67]. Extending the idea of a one-dimensional (1-D) two-station dumbbell (vide supra) to a three-dimensional (3-D) system [68] enabled preparation of the trifurcated compound [2H3]6+, which contains two stations in each of its three arms (Figure 12.7a) [69]. Threading of [2H3]6+ into the tritopic receptor 3, in which three benzo [24]crown-8 macrorings are fused on to a triphenylene core, yielded the complex [3·2H3]6+ which was then converted into the interlocked species [4H3]9+ by functionalization with bulky groups. This compound, which behaves like a nanometerscale elevator, is approximately 2.5 nm in height and has a diameter of about 3.5 nm. It consists of a tripod component containing two different notches – one ammonium center and one 4,4′-bipyridinium unit – at different levels in each of its three legs. The legs are interlocked by the tritopic host, which plays the role of a platform that can be made to stop at the two different levels. Initially, the platform resides exclusively on the “upper” level – that is, with the three rings surrounding the ammonium centers (Figure 12.7b, state 0; because the molecular elevator operates in solution; i.e., with no control of the orientation of the molecules relative to a fixed reference system, the words “upper” and “lower” are used only for descriptive purposes). On addition of a strong, non-nucleophilic phosphazene base to an acetonitrile solution of [4H3]9+, deprotonation of the ammonium center occurs and, as a result, the platform moves to the lower level – that is, with the three crown ether rings surrounding the bipyridinium units (Figure 12.7c,

12.3 Molecular Machines Based on Rotaxanes (a)

+

N

N O

N

+

O

+

+

O

O

O

O

O O

O [3 2H3]6+

O 3

O

Self-assembly

O H2N +

[2H3]6+

O O

O N

O

O

NH2

H2 N

+

O

O Stoppering

O

O O

O

O

N

N

+

O O O O O H2N+ O O

(c)

(b) [4H3]9+

46+

+N

H+ H+

171

_

O O O O H2N+ O O O O

O O

O O +NH2 O O O O

N+

N+

3H+

+N

H+

+N

+ 3H+ N+

[4H3]9+ State 0

State 1

Figure 12.7 (a) Self-assembly of the triply threaded supramolecular bundle [3·2H3]6+ and subsequent synthesis of the triply interlocked species [4H3]9+; (b,c) Schematic representation of the operation of [4H3]9+ as an acid–base-controlled molecular elevator [69].

state 1). The distance traveled by the platform is about 0.7 nm, and the potential force that can be generated is 200 pN – more than an order of magnitude greater than that generated by natural linear motors such as kinesin. This structure is stabilized mainly by charge-transfer interactions between the electron-rich aromatic units of the platform and the electron-deficient bipyridinium units of the tripod component. The subsequent addition of acid to 46+ restores the ammonium centers, and the platform moves back to the upper level. The “up-and-down” elevator-like motion can be repeated many times, and may be monitored using 1H NMR spectroscopy, electrochemistry, and absorption and fluorescence spectroscopy [69]. Detailed spectroscopic investigations have shown that the platform operates by taking three distinct steps associated with each of the three deprotonation processes. In this regard, the molecular elevator is more reminiscent of a legged animal than it is of a passenger or freight elevator. The base–acid-controlled mechanical motion in [4H3]9+ is associated with interesting structural modifications, such as the opening and closing of a large cavity (1.5 nm × 0.8 nm) and the control of the positions and properties of the bipyridinium legs. This behavior can, in principle, be used to control the uptake and release of a guest molecule, which is a function of interest for the future development of drug-delivery systems.

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12 Molecular Machines Based on Rotaxanes and Catenanes

The concept of rotaxanes as carriers [45] for changing the properties of a system on the basis of mechanical movement at the molecular level has been recently exploited (J. Li et al., unpublished results). For example, in a two-station rotaxane such as that shown in Figure 12.6, a calix[4]arene appended to the macrocycle can upload a K+ ion, which is then unloaded by the addition of [18]crown-6. 12.3.2.2 Rotaxanes Based on Metal Complexes Metal complexes have been extensively used as templates to obtain rotaxanes [50, 51, 53]. A unique feature of this approach is that the template can easily be removed on completion of the synthesis whereas, in other strategies based on organic fragments, an interaction between the template and the components of the final rotaxane structure is usually maintained. The presence of the metal ion, however, is essential for obtaining controlled movements. An exciting development in the field of linear artificial molecular machines has been the construction of a rudimentary molecular-scale muscle [70–72]. The idea [70] starts from the topology of a pseudorotaxane dimer which, when suitably designed, can undergo contraction and stretching movements. The synthesized system [6·Cu2]2+ (Figure 12.8) is a rotaxane dimer that contains two Cu(I) metal ions and two identical ring-and-string components 5. Each component 5 consists of a ring containing a bidentate phenanthroline-type unit, and a string containing a bidentate phenanthroline, a terdentate terpyridine, and a bulky stopper unit. Each of the two Cu(I) metal ions present in the rotaxane dimer is coordinated to two bidentate chelates, because Cu(I) prefers a four-coordination arrangement. Under these conditions, the system is “extended” [length 8.3 nm, as estimated from a creatine phosphokinase (CPK) model]. On the electrochemical oxidation of Cu(I), it was expected that the system would contract, because Cu(II) prefers a five-coordination arrangement and should, therefore, be surrounded by a bidentate and a terdentate ligand. This change in the coordination environment had, in fact, been previously observed for rotaxanes and catenanes of the same family (vide infra) [15, 60]. In [6·Cu2]2+, however, electrochemical oxidation had apparently no effect; however, a contraction could be obtained (Figure 12.8) by the extraction of Cu(I) with a large excess of KCN (CH2Cl2–H2O, room temperature) and successive remetallation of the free ligand 6 with Zn(NO3)2 (CH2Cl2–CH3OH). Both, demetallation of [6·Cu2]2+ and remetallation of 6 to obtain [6·Zn2]4+ (the length of which was estimated as 6.5 nm) were quantitative. Transformation of the contracted [6·Zn2]4+ species to the extended [6·Cu2]2+ species could be achieved by the addition of [Cu(CH3CN)4·PF6] in CH2Cl2–CH3CN [70]. The above-discussed principle of the rotaxane dimer has been recently extended to trimeric and tetrameric species (termed “bidimensional muscles”) [73]. Another system mimicking the function of muscle at the molecular level is described in Section 12.5.3. 12.3.2.3 Rotaxanes Based on Cucurbituril and Cyclodextrin Cucurbit[6]uril (usually referred to as cucurbituril; CB) is a hexameric macrocyclic compound that is self-assembled from an acid-catalyzed condensation reaction of

12.3 Molecular Machines Based on Rotaxanes

N

N O

O O

O O

O H3C O

N

N

CH3 O

N

N

N

O

5

[6 Cu2]2+ + CN

_

6

+ Zn(II)

[6 Zn2]4+

Figure 12.8 The component 5 of the rotaxane dimer [6 · Cu2]2+ and the contraction of

[14 · Cu2]2+ on demetallation with CN− and remetallation with Zn2+ [70].

173

174

12 Molecular Machines Based on Rotaxanes and Catenanes

O N

N CH2 H N CH2

H N O

6

[7H3]3+ +

N H2

_ H+ +

N H2

[7H2]2+ H N

NH3 +

+

+H

Yellow, fluorescent

+

N H2

NH3 +

Violet, non-fluorescent 3+

Figure 12.9 The cucurbituril-based molecular shuttle [19H3] , and its switching scheme [75].

glycoluril and formaldehyde [64, 74]. It has a cavity of ∼5.7 Å diameter, accessible from the exterior through two carbonyl-laced portals of ∼4 Å diameter. Cucurbituril forms very stable 1 : 1 host–guest complexes with protonated diaminoalkanes [64, 74] (see, e.g., compound [7H2]2+ in Figure 12.9 [75]), because of charge–dipole and hydrogen-bonding interactions between the protonated amino group and the portal carbonyl groups, and hydrophobic interactions between the internal methylene units and the inside wall of the cavity. When appropriate triamine compounds are employed as molecular threads, the position occupied by the CB macrocycle along the thread can be controlled by changing the pH of the solution. Pseudorotaxanes of this type behave as pH-driven molecular shuttles [75, 76], and can thus be included among rotaxanes as far as molecular movements are concerned. Cyclodextrins (CDs) are cyclic oligosaccharides shaped like truncated cones. The most commonly available CDs are those with six, seven, and eight glucose units, and are referred to as α-, β-, and γ-CD, respectively. Polyrotaxanes in which many CDs are threaded on to a polymer chain (“molecular necklaces”) have been prepared starting from poly(ethylene glycol) (PEG) and α-CD by capping the end chains with bulky stoppers (e.g., dinitrophenyl groups) [77]. In these types of polyrotaxanes, one or two rings can be displaced along the polymer chain by using the tip of a scanning tunneling microscope [78]. 12.3.2.4 Other Systems A very interesting movement of a ring along a polymer chain occurs in processive catalytic rotaxanes [79], which mimic DNA polymerase [33]. These synthetic rotaxanes consist of a cavity-containing porphyrin macrocycle (Figure 12.10) which, after the insertion of a manganese center, is threaded onto a polybutadiene polymer. The macrocyclic catalyst moves along the polymer while, in the presence of an oxygen donor, catalyzing conversion of the polymer double bonds into the corresponding epoxide functions. In a rotaxane consisting of a macrocycle threaded in a dumbbell containing a succinamide and glycylglycine stations and a fullerene and a diphenyl as stoppers,

12.3 Molecular Machines Based on Rotaxanes (a)

(b) N N MnIII N N

O

O O O

O

O O O

Product N

O N

N N

O

Substrate (polymer)

Catalyst

Figure 12.10 (a) A cavity-containing porphyrin macrocycle with a manganese center;

(b) Schematic representation of the catalytic action of the processive catalyst [79].

+

H3CO

H3CO

O

O

O

O

O

N

N

+

O

S

S

S

S

S

SCH3

O O

H3CO

+

N

N

O

O

N

+

O

O O

O

O

84+

Figure 12.11 In rotaxanes such as 84+ there is an equilibrium between translational isomers [82]. In the isomer represented in the figure, the tetracationic cyclophane moves away from the TTFP unit on one-electron oxidation of this station [81].

the translocation of the macrocycle can be triggered by changing the solvent, or by changing the redox state of the fullerene stopper. When two ferrocene units are appended to the macrocycle, a photoinduced electron transfer from ferrocene to fullerene takes place, whereby the lifetime of the resulting charge-separated state depends on the position of the macrocycle along the thread [23]. 12.3.3 Electrochemically Driven Movements 12.3.3.1 Rotaxanes Based on Tetracationic Cyclophanes Electrochemically induced shuttling in suitably designed rotaxanes based on Stoddart’s tetracationic cyclophane cyclobis(paraquat-p-phenylene) [80], known as the “blue box”, has long since been reported [62]. A recent example [81] is that concerning rotaxanes consisting of the blue box macrocycle and a dumbbell containing monopyrrolotetrathiafulvalene (TTFP) and 1,5-dioxynaphthalene (1,5-DMN) units (e.g., 84+, Figure 12.11 [81a]), which have been investigated in acetonitrile solution. Both, TTFP and 1,5-DMN are potential stations for the tetracationic cyclophane, because they can establish charge-transfer interactions with its electron-accepting bipyridinium units. On the basis of the redox properties of the two stations, a strong preference might be expected of the tetracationic cyclophane for the TTFP station compared to the 1,5-DMN station. Interaction of the

175

176

12 Molecular Machines Based on Rotaxanes and Catenanes

cyclophane with electron-donating units depends also on other factors, however, including the extension of the [π …π] stacking and the formation of hydrogen bonds. A comparison with the behavior of suitable model compounds and of the free dumbbell components has provided evidence that two-station rotaxanes of this type have complex electrochemical and spectral features that cannot simply be related to the presence of the two expected translational isomers. It seems that, owing to their length (ca. 5–6 nm) and flexibility, such compounds can fold up in the solvent used to maximize the charge-transfer interactions. It seems also that the two stoppers (notably the dendritic form) play a much more active role than do the simple bulky groups. The presence of a bulky thiomethyl substituent on the TTFP unit, when situated in between the two stations (as in the case of 84+) slows down the shuttling movement [82]. Folding in solution has also been evidenced for similar rotaxanes in which the TTFP station has been replaced by a tetrathiafulvalene (TTF) unit [83]. Back-folding effects, however, are minimized on incorporation of a rigid spacer which links the two stations [81b]. Rotaxanes of this type have been used to construct two-dimensional (2-D) molecular electronic circuits (see Section 12.5.5). A recent investigation [84] performed on a rotaxane consisting of the blue box macrocycle and a dumbbell containing a fullerene stopper, a light-harvesting porphyrin, and TTF and dioxynaphthalene stations, has shown indeed that the properties of the system cannot be easily rationalized solely on the basis of its functional units. As the structural complexity increases, the overall properties no longer depend simply on the “primary” structure of the system, but also on higher level effects, as occurs for the properties of biomolecules. 12.3.3.2 Rotaxanes Based on Metal Complexes In suitably designed rotaxanes, the pirouetting-type movements of the wheel around the axle can be electrochemically driven. Rotaxane [9·Cu]+ has a structure (Figure 12.12) in which Cu(I) is coordinated tetrahedrically by the phenanthroline present in the axle and the phenanthroline contained in the wheel [60a]. The electrochemical oxidation of the Cu(I) center in solution leads to a transient tetracoordinated Cu(II) species that, by pirouetting of the wheel around the axle, rearranges in tens of seconds to a structure in which the Cu(II) center reaches its most stable environment, being pentacoordinated by the phenanthroline of the axle and the terpyridine of the wheel ([9·Cu]2+, Figure 12.12). On electrochemical reduction of Cu(II), a transient pentacoordinated Cu(I) species is obtained which rearranges on a millisecond time scale by means of a second pirouetting of the wheel to the most stable structure, with Cu(I) tetrahedrically coordinated. An improvement in the pirouetting rate was obtained by keeping the ligand set around the copper center less hindered, and the metal center more accessible [60b–d]. Rotaxane [10·Cu]+ (Figure 12.13) has a phenanthroline and a terpyridine unit in its dumbbell-shaped component [85]. It also incorporates a Cu(I) center coordinated tetrahedrally by the phenanthroline ligand of the dumbbell, together with the phenanthroline ligand of the macrocycle. On oxidation of the tetracoordinated

12.3 Molecular Machines Based on Rotaxanes

+

O

O

O

O

N N CuI N

O

O

N

O

O N

N

N

[9 Cu]+

_ e_

+e

_

[9 Cu]2+

Figure 12.12 Rotaxane [9 · Cu]+ and wheel pirouetting induced by the copper oxidation– reduction cycle [60a]. The dark and light circles represent Cu(I) and Cu(II), respectively.

O

O

O

+

O

O

O N N CuI N N

O

N

N

N

O

[10 Cu]+

O

_ e_

+e

_

[10 Cu]2+

Figure 12.13 Shuttling of the macrocyclic component of [10 · Cu]+ along its dumbbell-shaped

component can be controlled electrochemically by oxidizing–reducing the metal center [85]. The dark and light circles represent Cu(I) and Cu(II), respectively.

177

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12 Molecular Machines Based on Rotaxanes and Catenanes

Cu(I) center of [10·Cu]+ (+1.0 V relative to SCE, CH3CN solution), the macrocycle shuttles away from the bidentate phenanthroline ligand of the dumbbell to encircle Cu(II) with a terdentate terpyridine ligand. In this species, the Cu(II) center adopts a pentacoordination geometry that is significantly more stable than the tetracoordination form associated with the original co-conformation. A second electrolysis (−0.03 V) of the CH3CN solution of the rotaxane reduces the pentacoordinated Cu(II) center, and leads back to the original structure. The shuttling rate is increased by orders of magnitude when the highly shielding and hindering phenanthroline moiety contained in the ring is replaced with a nonhindering biisoquinoline unit [86]. The shuttling in compound [10·Cu]+ can also be induced by a bimolecular electron-transfer reaction. [85b]. 12.3.4 Photochemically Driven Movements 12.3.4.1 Systems Based on Photoinduced Electron Transfer To achieve photoinduced ring-shuttling in rotaxanes containing two different recognition sites in the dumbbell–shaped component, the carefully designed compound 116+ shown in Figure 12.14 was synthesized [87]. This consists of the electron-donor macrocycle R, and a dumbbell-shaped component which contains [Ru(bpy)3]2+ (P2+) as one of its stoppers, a p-terphenyl-type ring system as a rigid spacer (S), a 4,4′-bipyridinium unit ( A 12+ ) and a 3,3′-dimethyl-4,4′-bipyridinium unit ( A 2+ 2 ) as electron-accepting stations, and a tetraarylmethane group as the second stopper (T). The stable translational isomer is the one in which the R component encircles the A 12+ unit, as expected because this station is a better electron acceptor than the other. The electrochemical, photophysical, and photochemical (under continuous and pulsed excitation) properties of the rotaxane, its dumbbell-shaped component, and some model compounds were then investigated and three strategies devised to obtain the photoinduced abacus-like movement of the R macrocycle between the two stations A 12+ and A 2+ 2 [88]: (i) an intramolecular mechanism (Figure 12.14, center), based on processes involving only the rotaxane components; (ii) a sacrificial mechanism (Figure 12.14, left), which requires the help of external reactants that undergo decomposition; and (iii) a relay mechanism (Figure 12.14, right), which requires the assistance by an external species that undergoes a reversible redox process. The intramolecular mechanism (Figure 12.14, center) is based on the following four operations [87]:

(a) Destabilization of the stable translational isomer: Light excitation of the photoactive unit P2+ (step 1) is followed by transfer of an electron from the excited state to the A 12+ station, which is encircled by the ring R (step 2), with the consequent “deactivation” of this station; such a photoinduced electrontransfer process must compete with the intrinsic decay of the excited state of P2+ (step 3).

12.3 Molecular Machines Based on Rotaxanes P2+ N N

S

N

N

O

e

P3+

8

S

e

Products

P2+

A22+

P3+

S

e

c' A1 +

S

9

O2

e

_

T

A22+

3

A12+

4

A1+

5

R

Intrinsic decay

_

a

R

S

2+

T

A22+

_

T

O

_

2

P

b'

A12+

R

h

R

O

6+

1

4

O

N O + O O O

N +

O

N

O

O

O N +

CH2 N +

11

tea _ e

6+

A22+

Ru II N

A2

ptz

b

R T

2+

e

_

A2

Products S

A22+

4

P3+

ptz+

S

e

R

T

A22+

_

5

b"

A1+

11

e

_

ptz

c A1+

2+

R

T P2+

6

R 2+

10

_

ptz+

S

T

e

A1+

5

R P3+

P

A22+

d

7

A12+

c" A1+

S

T

a

Figure 12.14 Rotaxane 116+ and schematic representation of the intramolecular (center), sacrificial (left), and relay (right) mechanisms for the photoinduced shuttling movement of macrocycle R between the two stations A 12+ and A 2+ 2 [87, 88].

(b) Ring displacement: The ring moves from the reduced station A 1+ to A 2+ 2 (step 4), a step that must compete with the back-electron-transfer process from A 1+ (still encircled by R) to the oxidized photoactive unit P3+ (step 5). This is the most difficult requirement to meet in the intramolecular mechanism. (c)

179

Electronic reset: A back electron-transfer process from the “free” reduced station A 1+ to P3+ (step 6) restores the electron-acceptor power to the A 12+ station.

(d) Nuclear reset: As a consequence of the electronic reset, back movement of the 2+ ring from A 2+ 2 to A 1 occurs (step 7). Each absorbed photon could, in principle, cause the occurrence of a forward and back ring movement (i.e., a full cycle), without generating any waste product. In practice, the efficiency is very low, because 84% of the excited *P2+ species undergoes deactivation (step 3) in competition with electron transfer (step 2), and 88% of the reduced A 1+ species undergoes back-electron transfer (step 5) before ring displacement (step 4) can occur [89]. The somewhat disappointing quantum efficiency for ring shuttling (2%) is compensated by the fact that the investigated system is a unique example of an artificial linear nanomachine, because it gathers together the following features: (i) it is powered by visible light (in other words,

12

e

ptz+

_

T ptz

180

12 Molecular Machines Based on Rotaxanes and Catenanes

sunlight); (ii) it exhibits autonomous behavior, like motor proteins; (iii) it does not generate waste products; (iv) its operation can rely only on intramolecular processes, allowing (in principle) operation at the single-molecule level; (v) it can be driven at a frequency of ∼1 kHz; (vi) it works in mild environmental conditions (i.e., fluid solution at ambient temperature); and (vii) it is stable for at least 103 cycles. Much higher efficiencies are obtained when the system operates by the sacrificial or relay mechanisms. The sacrificial mechanism [87] is based on the use of external redox reactants (a reductant such as triethanolamine, and an oxidant such as dioxygen) that operate as illustrated on the left of Figure 12.14. Destabilization of the stable translational isomer occurs as in the intramolecular mechanism. Because the solution contains a suitable reductant, a rapid reaction of this species with P3+ (step 8) competes successfully with the back-electron-transfer reaction (step 5); the originally occupied station thus remains in its reduced state A 1+ , and a displacement of the ring R to A 2+ 2 (step 4), although slow, does occur. Restoration of the electron-acceptor power of the A 12+ station is achieved by oxidizing A 1+ with a suitable oxidant such as dioxygen (step 9), and nuclear reset occurs as in the previous mechanism (step 7). Under these conditions, the efficiency of the photoinduced ring displacement is 0.16, which corresponds to the quantum yield of the photoinduced electron transfer (step 2). The relay mechanism (Figure 12.14 right) [88] is based on participation to the process of a species capable of undergoing a reversible redox reaction. When photoexcitation of 116+ is performed in the presence of phenothiazine (ptz), the photoinduced electron transfer (step 2) is followed by a diffusion-controlled reaction between ptz and P3+ with formation of ptz+ and regeneration of P2+ (step 10). As a consequence, the intramolecular back-electron transfer (step 5) can no longer occur, and ring displacement (step 4) must compete only with the much slower intermolecular back-electron-transfer reaction between ptz+ and A 1+ (step 11). Under the experimental conditions used, ring displacement (step 4) occurs with 76% efficiency, while both electron (steps 11 and/or 12) and nuclear (step 7) reset processes occur quantitatively. Therefore, 116+ behaves as an autonomous molecular shuttle which consumes only photons of visible light with an overall efficiency of 12%. The role played by ptz is that of an electron relay with a “negative” kinetic effect. Another light-driven molecular shuttle which relies on an external electron relay has been reported [90]. Rotaxane 12 (Figure 12.15) consists of a benzylic amide macrocycle that surrounds an axle featuring two hydrogen-bonding stations − a succinamide and a naphthalimide unit − separated by a long alkyl chain. Initially, the macrocycle resides on the succinamide station, because the naphthalimide unit is a much poorer hydrogen-bonding recognition site. Excitation with light at 355 nm (step 1) in acetonitrile at 298 K generates the singlet excited states of the naphthalimide unit, which then undergoes high-yield intersystem crossing to the triplet excited state. Such a triplet state can be reduced in bimolecular encounters by an electron donor (1,4-diazabicyclo[2.2.2]octane; DABCO) added to the solution in a sufficiently large amount (step 2). Because the back-electron-transfer process

12.3 Molecular Machines Based on Rotaxanes

O

O NH

1

HN

O

hν

O N H

O N [CH2]10N H O O NH HN 12 O O

N O H NH O

O 6

N H

N O

[CH2]10

N O HN NH

O

O DABCO 2 DABCO +

DABCO

DABCO

5

3

DABCO +

DABCO +

O O

O NH

N O H NH O_

HN O

N H O

_O N [CH2]10N OH O NH HN O

O 4

N H

N O

[CH2]10

12

_

N O HN NH

O

O

Figure 12.15 Light-induced reversible shuttling of the macrocyclic component of the

hydrogen-bonded rotaxane 12 [90]. The operation of this system relies on the use of DABCO as an electron relay.

(step 3) is spin-forbidden, and thus slow, the photogenerated ion pair can dissociate efficiently. Because the naphthalimide anion is a much stronger hydrogenbonding station compared with the succinamide, on reduction of the naphthalimide unit the macrocycle shuttles from the latter to the former station (step 4). The time required for ring shuttling (∼1 µs) is much shorter than the lifetime of the naphthalimide radical anion (∼100 µs). After charge recombination (step 5), the macrocycle moves back to its original position (step 6). The device can be cycled at a frequency which depends on the charge recombination rate of the rotaxane radical anion. It can be estimated that if the shuttle is pumped by a laser at the frequency of its “recovery stroke” (step 5) – that is, 104 s−1 – this molecular-level machine generates approximately 10−15 W of mechanical power per molecule [90]. 12.3.4.2 Systems Based on Photoisomerization Reactions The geometrical photoisomerizations of azobenzene and stilbene have been used extensively to cause movements of CD and CB beads along the dumbbell components of simple rotaxanes [91–93]. More complex systems based on azobenzene and stilbene photoisomerization have recently been reported [94–97]. Rotaxanes containing two different photoresponsive stations and either one [96] or two [97] macrocyclic rings behave as multistate–multifunctional switches. For instance, rotaxane 13 (Figure 12.16) [97] is a quite interesting species because it contains several photoactive units in its axle component. These are an azobenzene and a stilbene groups as the stations,

181

182

12 Molecular Machines Based on Rotaxanes and Catenanes E,E-13

Stopper A

Stopper B

SO3Na H2N

O

O N

NaO3S

SO3Na

α-CD

N

O

N

N O SO3Na

SO3Na H2N hν 380 nm

hν " 450 nm or ∆

O

O N

NaO3S

N

O

N

O

H2N

O N

O

N

NaO3S O

N

NaO3S

O

Z,E-13

O N O

N

N

O

E,Z-13 NaO3S

SO3Na

NaO3S

NH2

O

Z,Z-13

hν ' 313 nm

hν ' 313 nm

SO3Na

SO3Na

N

hν "' 280 nm or ∆

N

O

O

O

N

N

hν "' 280 nm

N

N

hν " 450 nm N

NaO3S

hν 380 nm

O SO3Na NH2

Figure 12.16 Interconversion scheme between the four possible geometric isomers of rotaxane 13 on photoisomerization of its azobenzene and stilbene stations [97].

It should be noted that light irradiation affords photostationary states (PSS) containing all four isomers in different proportions.

and two slightly different naphthalimide stoppers (A and B) that fluoresce at distinct wavelengths (λmax = 520 and 395 nm, respectively). The ring is an α-CD macrocycle. The azobenzene and stilbene units can be photoisomerized by using light at different wavelengths in the UV-visible region, albeit with limited selectivity because of substantial spectral overlapping between the absorption bands of these units. Therefore, photostationary states (PSS) containing all four geometric isomers of 13 in different proportions are obtained on photoirradiation. The interconversion scheme between such isomeric forms is shown in Figure 12.16. At room temperature in dimethylsulfoxide (DMSO) solution, the stable (starting) state is E,E-13, characterized by a fast (on the NMR timescale) shuttling of the α-CD ring between the two stations. Irradiation at 380 nm causes an isomerization of the azobenzene unit, leading to the formation of Z,E-13, in which the α-CD ring is trapped on the E-stilbene station. Further irradiation at 313 nm causes

12.3 Molecular Machines Based on Rotaxanes

isomerization of the stilbene unit, leading to the formation of Z,Z-13, in which the α-CD ring encircles the central biphenyl group. On the other hand, irradiation of E,E-13 at 313 nm leads to formation of the E,Z-13 isomer, in which the α-CD ring is trapped on the E-azobenzene unit; further irradiation at 380 nm affords Z,Z-13. As indicated in Figure 12.16, the photochemical reactions are fully reversible (but never complete; PSS are obtained, vide supra) on light irradiation or heating. The starting state and the three photostationary states were characterized by NMR and UV-visible absorption and luminescence spectroscopy. Interestingly, each state has a different fluorescence spectrum because the emission intensity of a stopper group is enhanced when the α-CD ring is located close to it, possibly owing to steric effects exerted on the fluorophore by the macrocycle. The absorption and fluorescence spectral changes related to the interconversion between the four states of the system can be interpreted in terms of AND and XOR binary logic functions. As a consequence, rotaxane 13 can perform as a reversible half-adder device with all-optical input and output signals [97]. It has been shown recently [98] that photoinduced proton-transfer processes between molecular switches in solution can also be exploited to operate acid–basecontrolled molecular machines with light. 12.3.5 Allowing/Preventing Ring Motion

By clever functionalization of the thread, it is possible to allow/prevent shuttling motions of the ring. An interesting example is given by compound 14 (Figure 12.17) [99], in which the two stations are structurally identical (but distinguishable because of the different stoppers), and a bulky silyl ether acts as a barrier which prevents the ring from moving between them. The system starts out statistically unbalanced for synthetic reasons. Removal of the silyl ether “links” the two stations, thus switching on a dynamic exchange of the macrocycle between them and enabling the system to move towards equilibrium. Applying the silyl ether again does not affect the position of the macrocycle because the system is now statistically balanced. In the case of compound 15 (Figure 12.18) [99], the system starts statistically balanced (85% of macrocycles on the fumaramide station, 15% on the succinamide station) and unlinked because of the presence of the silyl group. When the balance is broken by light excitation that causes E→Z isomerization, and the kinetic barrier is removed, the system moves towards the new equilibrium. Restoring the barrier produces a system that is balanced, but not in equilibrium, because shuttling cannot occur. Applying a thermal stimulus that causes a Z→E backisomerization makes the system statistically unbalanced, unlinked, and not in equilibrium. In this rotaxane, the thread performs the task of directionally changing the net position of the macrocycle. The same principle has been exploited to obtain the first example of a molecular information ratchet [100]. The described system is rotaxane 162+ (Figure 12.19), which consists of a macrocycle based on dibenzo[24]crown-8 mechanically locked

183

12 Molecular Machines Based on Rotaxanes and Catenanes

R= O

O NH

HN

R O

O N OH NH HN

N H

Distribution of the rings

O

O

H N

N

O O

CH3 Si CH3

N

14

100% 0% Ring position

1. _ R 2. + R

Distribution of the rings

184

50%

50% Ring position

Figure 12.17 In rotaxane 14, a removable bulky silyl ether acts as a barrier which prevents the ring from moving between the two stations [99].

onto a linear thread. Along the thread there are two stations for the ring − a dibenzyl-ammonium (DBA) and a monobenzyl-ammonium (MBA) unit; these bind the ring with comparable affinities, but are distinguishable for the purpose of monitoring the system. An α-methylstilbene unit divides the thread asymmetrically into two compartments, each of which contains a station. When the stilbene unit is in the E form, the macrocycle can move randomly along the full length of the thread, whereas when it is in the Z form the ring is trapped in one of the two compartments. Hence, the stilbene unit plays a role of a photoswitchable gate for the ring movement between the two stations. When the stilbene unit is in the E form (i.e., the gate is open), an equilibrium distribution of the ring between the two stations of 65(DBA) : 35(MBA) is established (Figure 12.19a). To drive the system away from equilibrium, two requirements should be concurrently obeyed: (i) the gate should be closed for most of the time to avoid fast equilibration; and (ii) the gate should be opened preferentially when the macrocycle occupies

12.3 Molecular Machines Based on Rotaxanes

R= O

O NH

HN

R O

O N OH NH HN

N H

Distribution of the rings

O

O

H N O

O

CH3 Si CH3

N

N

15

85% 15% Ring position

Distribution of the rings

1. _ R 2. + R

1. _ R 2. hν (E →Z isomerization) 3. + R 4. ∆ (Z → E isomerization)

56%

44% Ring position

Figure 12.18 In rotaxane 15, movement of the ring caused by E→Z photoisomerization is made irreversible by insertion of a barrier after E→Z photoisomerization. This results in a change in the net position of the macrocycle [99].

a specific position (in this case the DBA station), so as to change the original distribution. The first requirement is achieved by adding to the solution a suitable photosensitizer (benzil); this leads to a photostationary state that is rich in the Z form of α-methylstilbene (82 : 18, Z : E under the conditions employed) by intermolecular triplet sensitization. The second requirement is accomplished by appending another photosensitizer (benzophenone) to the macrocycle; this is capable of causing the Z→E photoisomerization of the stilbene gate by intramolecular triplet sensitization. Benzophenone was chosen because it leads to a photostationary state that is richer in the E form of α-methylstilbene (55 : 45, Z : E) compared to benzil. A key feature of the system is that the DBA station is very close to the stilbene gate, whereas the MBA station is far from the gate. Therefore, it can be expected that intramolecular (benzophenone) sensitization (i.e., gate

185

12 Molecular Machines Based on Rotaxanes and Catenanes

(a)

(b) +

O O

O

O

O

CH3

8

O

9

O

hν

E-162+

O O O O O H2 N+ O O O

O

O

O O Closes gate

E

+

E

Opens gate

O H3C

Benzo- O phenone

8

O

Gate open

hν

O

O

O E-α-Methylstilbene

CH3 O

+

+

8

O

9

O N O H2 O O O

N H2

DBA

O

O O

hν

H2 N +

E

O Closes gate O

O +

O

O

8

H3C O

N H2

9

Z-162+

(c)

O

hν

Benzil

O

MBA

+

O N O H2 O O O

N H2

hν

Gate closed

186

Z-α-Methylstilbene

O

9

O N O H2 O O O

E

O

hν O

Figure 12.19 Scheme for operation of a molecular information ratchet based on the photoisomerizable bistable rotaxane 162+ [100]. The dashed arrows indicate processes that are unlikely to occur.

opening) is more efficient when the macrocycle is in the DBA compartment, whereas the efficiency of intermolecular (benzil) sensitization should be independent of the location of the macrocycle. The conditions are chosen so that the benzophenone-sensitized isomerization dominates (gate open) when the ring is in the DBA compartment – that is, held near to the gate (Figure 12.19b) – whereas the benzil-sensitized reaction dominates (gate closed) when the ring is in the MBA compartment – that is, held far from the gate (Figure 12.19c). The system starts with the stilbene gate open (E) and an equilibrium ring distribution of 65(DBA) : 35(MBA). When a suitable concentration of benzil is used, excitation of both photosensitizers leads the system to a 80 : 20, Z : E photostationary state. Under this condition, the ring distribution becomes 45(DBA) : 55(MBA); in other words, about one-third of the macrocycles which occupied the more energetically favorable DBA compartment at equilibrium have been moved to the less-favorable MBA compartment. Ultimately, the different photoreactivity of the various interconverting isomers of 162+ (Figure 12.19) leads to a ring distribution between the two compartments under light irradiation, which is different from that observed at the equilibrium in the dark. It should be pointed out that, in this system photons are not used to modify the binding energy between the ring and either station, but rather to power an information transfer process, as shown schematically in Figure 12.20 [21]. In other words, driving the ring distribution away from its equilibrium value is ensured only by the fact that macrocycle “signals” its position to the gate, which opens (or closes) accordingly. The similarity of these processes with the hypothetical task performed without an energy input by a “demon” in Maxwell’s famous thought experiment has been extensively discussed [21].

12.4 Molecular Machines Based on Catenanes

E

Figure 12.20 Schematic representation of an

information ratchet mechanism for the directional transport of a Brownian particle along a potential energy surface. If the

particle signals its position in a distancedependent manner, then only the barrier closer to the particle may be lowered.

12.4 Molecular Machines Based on Catenanes 12.4.1 Introduction

As for rotaxanes, the general strategy for preparing catenanes in high yields is based on the template effect, which relies on the presence of molecular recognition sites (usually involving metal ion coordination [50, 51, 53, 55, 56], electron donor– acceptor [51, 53, 55, 56] and hydrogen-bonding [51–53, 55, 56] interactions) between the components to be assembled. In most cases, this type of synthesis leads to catenanes in which: (i) both the ring components carry two identical recognition sites (Figure 12.21a); or (ii) one of the ring carries two identical recognition sites while the other ring carries two different recognition sites (Figure 12.21b)1). In the first case, the system can undergo degenerate co-conformational change when a macrocycle circumrotates, whereas in the second case the system can occur in two different co-conformations (state 0 and state 1) that can be interchanged by the use of appropriate stimuli (chemical, electrochemical, and

187

188

12 Molecular Machines Based on Rotaxanes and Catenanes (a)

(b)

State 0

State 1

Figure 12.21 Schematic representation of catenanes composed of: (a) two rings each containing two identical recognition sites; (b) one ring containing two identical recognition sites, and one ring containing two

different recognition sites. The interconversion between the possible rotational isomers is also shown. The asterisks highlight the exchange of position of identical units.

photochemical in nature). Such a bistable behavior (Figure 12.21b) is reminiscent of that of controllable molecular shuttles (see Section 12.3, Figure 12.4d). It should be noted that repeated switching between the two states does not need to occur through a full rotation. In fact, because of the intrinsic symmetry of the system, both movement from state 0 to state 1 and from state 1 to state 0 can occur with equal probabilities along a clockwise or anticlockwise direction. This type of switching motion is often termed “circumrotation.” A full (360°) rotation movement can occur only in ratchet-type systems – that is, in the presence of dissymmetry elements which can be either structural or functional in nature. 12.4.2 Chemically Driven Processes

Catenanes 174+ and 184+ (Figure 12.22) incorporate the blue box tetracationic cyclophane and a π-electron-rich macrocyclic polyether comprising a TTF group and either a 1,4-dioxybenzene or a 1,5-dioxynaphthalene unit [101]. The 1H NMR spectra (CD3CN, 298 K) of 174+ and 184+ indicate that the TTF unit resides preferentially inside the cavity of the tetracationic cyclophane, whereas the dioxyarene unit is positioned alongside. The tendency of o-chloroanil 19 to stack against TTF can be exploited [101] to “lock” this unit alongside the cavity of the tetracationic cyclophane. On addition of a mixture of Na2S2O5 and NH4PF6 in H2O, the adduct formed between the TTF unit and o-chloroanil is destroyed, and the original coconformation with TTF inside the cavity of the tetracationic cyclophane is then restored. The molecular motion associated with catenanes 174+ and 184+ can also be controlled electrochemically by a reversible oxidation–reduction of the TTF unit [101].

12.4 Molecular Machines Based on Catenanes O +

N

O

O N

S

S

S

S

+N

O

+

O

N+ O

O O

O O

+ S2O52 174+ 184+

Figure 12.22 Circumrotation of the macrocy-

clic polyether component of catenanes 174+ and 184+ can be controlled reversibly by adding or removing o-chloroanil (19) which

_

+

Cl

Cl Cl

Cl

O O

19 19

forms a charge-transfer adduct with the tetrathiafulvalene unit of these catenanes [101]. The adduct can be disrupted by reducing o-chloroanil with Na2S2O5.

By analogy with what occurs with rotaxanes (see Section 12.3.2.2), in catenanes based on Cu(I) [50, 51, 53] and in other phenanthroline-containing catenates ring, circumrotation is observed on demetallation–metallation or on demetallation– protonation [102]. 12.4.3 Electrochemically Driven Processes

Catenane 204+ (Figure 12.23) incorporates a 1,4-dioxybenzene-based macrocyclic polyether and a tetracationic cyclophane comprising one bipyridinium and one E-1,2-bis(4-pyridinium)ethylene unit [103]. The 1H NMR spectrum of 204+ in (CD3)2CO at 243 K contains the signals for two distinct co-conformations in a ratio 92 : 8. In the major isomer, the bipyridinium unit is located inside the cavity of the macrocyclic polyether, and the E-bis(pyridinium)ethylene unit is positioned alongside. The first two reduction waves in the cyclic voltammogram of the free tetracationic cyclophane occur at −0.31 and −0.43 V (relative to SCE). These correspond to the first monoelectronic reductions of the bipyridinium and the E-bis(pyridinium) ethylene units, respectively. In the catenane, these two waves are shifted to more negative potentials and occur at −0.39 and −0.49 V. Such observations indicate that the bipyridinium unit is located preferentially inside the cavity of the macrocyclic polyether (Figure 12.23), and its reduction is more difficult than for the free tetracationic cyclophane. When this unit is reduced, however, the tetracationic cyclophane circumrotates through the cavity of the macrocyclic polyether, moving the E-bis(pyridinium)ethylene unit inside, as shown by a comparison of its reduction

189

190

12 Molecular Machines Based on Rotaxanes and Catenanes 204+ O +

N

O O O N

O

+

+e

+

_

N+

N O

O O O

O

_ e_

Figure 12.23 Circumrotation of the tetracationic cyclophane component of the catenane 204+

can be controlled reversibly by reducing or oxidizing its bipyridinium unit electrochemically [103].

potential with that of a catenane model compound [103b]. The original equilibrium between the two co-conformations associated with catenane 204+ is restored on oxidation of both units back to their dicationic states. Electrochemically driven switching processes have been observed for several metal-based catenanes [15, 104–106], including heterodinuclear bis-macrocyclic transition-metal complexes [107]. Catenane [21·Cu]+ (Figure 12.24) incorporates two identical macrocyclic components comprising terpyridine and phenanthroline ligands. The Cu(I) ion is coordinated tetrahedrally by the two phenanthroline ligands, whereas the two terpyridine ligands are located well away from each other [106]. On electrochemical oxidation of [21·Cu]+, or on treatment with NOBF4, the tetracoordinated Cu(I) center is converted into a tetracoordinated Cu(II) ion, which has preference for a coordination number higher than four. As a consequence, one of the two macrocycles circumrotates through the cavity of the other, affording a pentacoordinated Cu(II) ion. Subsequently, the other macrocycle undergoes a similar circumrotational process, yielding a hexacoordinated Cu(II) ion. Electrolysis (−1.0 V) of an acetonitrile solution of the catenane reduces the hexacoordinated Cu(II) center leading back to the original co-conformation, in quantitative fashion. 12.4.4 Photochemically Driven Processes

Catenanes 222+ and 232+ (Figure 12.25) were synthesized using an octahedral Ru(II) center as template [108]. Compound 222+ consists of a 50-membered ring

12.4 Molecular Machines Based on Catenanes O

+

O

N

N

N

N

N

CuI

N

N

_ e_ N

N

N

O

O

[21 Cu]+

+e

_

[21 Cu]2+

Figure 12.24 Circumrotation of the macrocyclic components of catenate [21 · Cu]+ can be

controlled reversibly by oxidizing or reducing the metal center [106]. The dark and light circles represent Cu(I) and Cu(II), respectively.

2+

O

O

O

N

O

N O

O

O

O

O

O

O

O

N RuII

O

O

N N

O

N O

O

O

O

O

N

O

N O

O

O

O

N RuII

O

O 222+

2+

O

232+

N N

N

O O

Figure 12.25 Structure formulas of photoactive catenanes 222+ and 232+ [108].

O

O

191

192

12 Molecular Machines Based on Rotaxanes and Catenanes

which incorporates two phenanthroline units and a 42-membered ring which contains a 2,2′-bipyridine (bpy) unit. Compound 232+ contains the same bpyincorporating ring as 222+, but the other ring is a 63-membered ring. Clearly, 232+ is better suited to molecular motions than 222+, which has a relatively tight structure. Excitation of the Ru-based complex with visible light causes dissociation (via a ligand field-excited state) of the bpy ligand, which is replaced by two chloride ions [108]. The bpy-incorporating ring is thus disconnected from the metal ion and is free to circumrotate. The connection can be restored by a thermal back reactions. The co-conformational motion electrochemically induced in Cu(I)-based catenanes (see Section 12.4.3), which exploits the preference of Cu(I) and Cu(II) for tetra- and penta-coordination, respectively, can also be stimulated by intermolecular photoinduced electron-transfer reactions [104b]. 12.4.5 Unidirectional Ring Rotation in Catenanes

Unidirectional rotation in a catenane requires a careful design of the system [21, 45, 109]. A bistable catenane can be a starting point to make a rotary motor, but an additional control element must be added, as illustrated in Figure 12.26 [18]. The “track” ring of the catenane should contain, besides two different recognition sites A and B, a hindering group K and a blocking group X. In the starting coconformation (I), the “moving” ring surrounds the most efficient site (A) on the track ring. On application of the stimulus S1, site A is switched off (A′) and the ring moves from it. The system has to reach the new stable co-conformation II, wherein the ring surrounds site B. The presence of a blocking group X makes the anticlockwise rotation faster compared to the clockwise rotation. At this stage, the application of stimulus S2 causes cleavage of the blocking group, and a reset stimulus S–1 restores the recognition ability of site A. The system has now to reach the starting co-conformation wherein the moving ring surrounds site A. Again, the presence of the hindering group K makes the anticlockwise rotation faster than the clockwise rotation. The original catenane structure is then obtained with a reset stimulus S–2, by which the blocking group X is put back in place. Unidirectional rotation in such a catenane occurs by a “flashing ratchet” mechanism [37, 111], which is based on a periodic change of the potential energy surface viewed by the moving part (Figure 12.26) by orthogonal (i.e., independent) reactions. It is worth noting that the direction of rotation can be inverted by reversing the order of the two input stimuli. This concept was cleverly realized using light as a stimulus with catenane 24 (see Figure 12.27a) [110]. The larger ring of 24 contains two recognition sites for the smaller ring – namely, a photoisomerizable fumaramide unit (A) and a succinamide unit (B) – and two bulky substituents that can be selectively detached– reattached – namely, a silyl (X1) and a triphenylmethyl (X2) group. In the starting isomer (I in Figure 12.27b), the smaller ring surrounds the fumaramide site. On E→Z photoisomerization of such a unit with 254 nm light and subsequent

12.4 Molecular Machines Based on Catenanes

A'

A' K

X

K

X

A

B

B

K B

A ')

S2 (_ X) S_ 1 (A' A)

S 1 (A

E

S_ 2 (+X) _

90°

0°

90°

180°

A K

I

360°

270°

A

A' X

K

B

Figure 12.26 Design of a bistable catenane

that performs as a molecular rotary motor controlled by two pairs of independent stimuli. The working scheme is based on the potential energy changes expected for the

II B

Rotation angle

X

K B

chemical reactions and co-conformational rearrangements brought about by stimulation with independent inputs. For further details, see the text.

desilylation (II), the smaller ring moves in a clockwise direction to surround the succinamide site. At this point, a silyl group is reattached at the original position (III). Piperidine-assisted back-isomerization of the maleamide unit to the fumaramide unit, followed by removal of the triphenylmethyl group (IV), causes another half-turn of the smaller ring in the clockwise direction to surround the fumaramide unit. Reattachment of a triphenylmethyl substituent regenerates the starting isomer (I). The overall result is a net clockwise rotation of the smaller ring about the larger ring. Exchanging the order in which the two blocking groups are manipulated produces an equivalent anticlockwise rotation of the smaller ring. The structures of the compounds obtained after each of the above reaction steps, and particularly the position of the smaller ring, were determined with 1H NMR spectroscopy [110]. This system is more complex than that described in Figure 12.26, because it contains two independently addressable blocking groups. Hence, unidirectional rotation is achieved with three pairs of different stimuli (one to drive the co-conformational rearrangement, and two for ratcheting the energy barriers).

193

12 Molecular Machines Based on Rotaxanes and Catenanes

194

(a)

(b)

A'

A 254 nm A A'

O

O HN

NH

A

HO N

X2

H N O

NH

_X 1

X2

II

B

HN

O

X1

I

O

B

(CH2)8

(CH2)8

+ X1

+ X2

X2 O O

O

N H

A

O

O

H N

B

O

A' piperidine A' A

X1

O

IV

O Si

24

_X 2

X2

X1

III

B

B

Figure 12.27 (a) Structure of catenane 24; (b) Schematic representation of the processes that enable unidirectional ring rotation [110].

(a)

(b) O NH

O

HN

350 nm A A'

O A

O

O

O

A

(CH2)12

H3C (CH2)4

254 nm B B'

O

C

N H

N (CH2)12 25

I N O

O

O

B

C

(CH2)4

O

II

N OH NH HN

N H

NH

A'

O

C

B A'

B CH3

III A',B'

A,B

C

B'

Figure 12.28 (a) Structure of catenane 25; (b) Stimuli-induced sequential movement of the small macrocycle between three different stations located on the large macrocycle [111].

Other strategies to obtain unidirectional ring rotation in catenanes have been explored. Catenane 25 (Figure 12.28a) consists of a benzylamide macrocycle threaded into a larger macrocycle which carries three different binding sites (stations) [111]. Stations A and B are two photoisomerizable fumaramide units with different macrocycle binding affinities. Station B, as a methylated fumaramide residue, has a lower affinity for the macrocycle than station A. The third station C (a succinic amide ester) is not photoactive, and is intermediate in terms of its macrocycle binding affinity between the two fumaramide stations (E ) and their

12.4 Molecular Machines Based on Catenanes

maleamide (Z) counterparts. In the initial co-conformation (I in Figure 12.28b), the small macrocycle resides on the nonmethylated fumaramide station A. This station is located next to a benzophenone unit, which enables its selective, photosensitized isomerization by irradiation at 350 nm (A→A′). The photoisomerization of station A destabilizes the system, and the macrocycle finds its new energy minimum on station B (form II). The subsequent direct photoisomerization of this station by irradiation with light at 254 nm (B→B′) moves the macrocycle onto the succinic amide ester station C (III). Finally, heating the catenane (or treating it with photogenerated bromine radicals or piperidine) results in the isomerization of both Z-olefins back to their E-forms, so that the original order of binding affinities is restored and the macrocycle returns to its original position (I). The 1H NMR spectra for each diastereoisomer show excellent positional integrity of the small macrocycle in this three-way switch at all stages of the process, though the rotation is not directional. Over a complete sequence of reactions, an equal number of macrocycles go from A, through B and C, back to A again in each direction. As discussed for catenane 24, in order to bias the direction that the macrocycle takes from station to station in 25, kinetic barriers are required to restrict Brownian motion in one direction at each stage. Such a situation is intrinsically present in [3]catenane 26 (Figure 12.29a) [111], which contains the same large macrocycle of catenane 25. In this case, however – and in contrast to what occurs for 25 – the isolated amide group incorporated in the macrocycle (D in Figure 12.29a), which can make fewer hydrogen bonding contacts than A, B, and C, plays a significant role. In the initial co-conformation (I in Figure 12.29b), the two small macrocycles reside on the fumaramide stations, A and B. Irradiation at 350 nm switches off station A and causes an anticlockwise (as drawn) rotation of the macrocycle M1 to the succinic amide ester station C (II). Photoisomerization with 254 nm light of the remaining fumaramide (B→B′) causes the other macrocycle M2 to relocate to the single amide station D (III), and again this occurs anticlockwise because the clockwise direction is blocked by the other macrocycle. This “follow-the-leader” process, in which each macrocycle in turn moves and then blocks a direction of passage for the other macrocycle, is repeated throughout the sequence of transformations shown in Figure 12.29b. After three diastereoisomer conversions, the E,E form of 26 is again obtained, but a 360° rotation of each of the small rings has not yet occurred; rather, they have only swapped places (IV in Figure 12.29b). Complete unidirectional rotation of both small rings occurs only after the threestep sequence leading from structures I through IV has been completed twice (structures IV, V, VI, and back to I). In this system, the yield of direction fidelity is high (>99%), but the efficiency of the motor is poor (<1% based on absorbed photons). The time scales and numbers of reactions involved for unidirectional ring rotation in catenanes 24 and 26 make their operation as rotary motors somewhat unpractical. Nevertheless, an analysis of the thermodynamic and kinetic aspects of the operation mechanisms provides a fundamental insight into how energy inputs can be used to harness thermal fluctuations and drive unidirectional motion.

195

196

12 Molecular Machines Based on Rotaxanes and Catenanes

(a) O

O NH

D

26

O A

O

O

M1

HN

N OH NH HN

N H

O

O

NH

(CH2)4

O

(CH2)4

O O

O

O

C

(b)

NH

(CH2)12

H3C

N H O

N O

(CH2)12

O

M2

N O

N

N H

HN

B H CH3

M1

A

A'

A'

D

I

B

M2

M2

M2 350 nm A A'

D

II

D

B

M1 A',B'

B'

C

C

C

III

254 nm B B'

B

A,B

M1 A',B'

A,B

M2

A

A'

A' M1

M1

D

VI

B'

D

B

V

254 nm B B'

B

M2

D

IV

B

350 nm A A'

C

C

M1

C M2

Figure 12.29 (a) Structure of [3]catenane 26; (b) Schematic representation of the processes that enable unidirectional ring rotation [111].

12.5 Performing Functions with Molecular Machines 12.5.1 Beyond the Solution Phase: Ordering and Addressing

Most of the studies on rotaxanes and catenanes have been performed in solution. Under such conditions, the investigated systems contain a huge number of molecules which behave independently from one another, because they cannot be addressed individually, and hence controlled. In spite of this limitation, these

12.5 Performing Functions with Molecular Machines

studies have unraveled a number of very interesting concepts concerning molecular-level movements controlled by external inputs. Incoherence, however, remains a major impediment to designing and realizing systems capable of performing useful functions. Thus, it seems reasonable that for several real applications the molecular machines must be interfaced with the macroscopic world by ordering them in some way, so that they can behave coherently and be addressed in space [40, 112]. In this regard, a variety of approaches can be followed, namely: (i) organization at interfaces [113] and on surfaces [114–119]; (ii) incorporation into liquid crystals [120–122] and polymers [123]; or (iii) immobilization into membranes [124] or porous materials [125–127]. To realize the summation of motion at the molecular level to achieve macroscopic motion is a major challenge. The approaches taken include changes in surface properties (e.g., surface tension), a direct translation of molecular to macroscopic motion, and signal collection by suitably designed architectures. Investigations into rotaxanes and catenanes on surfaces and at interfaces have been recently conducted by several research groups [40]. Some paradigmatic examples will be briefly described in the following subsections. 12.5.2 Molecular Valves

The construction of a valve at the molecular scale requires the integration of a stable and inert nanocontainer with an appropriate moving part that can act as a gatekeeper to regulate the molecular transport into and out of the container. The construction of functioning nanovalves can be useful for controlling drug delivery, signal transduction, nanofluidic systems, and sensors. The photoinduced isomerization of spyropyran [124] and azobenzene [126] units in carefully designed systems has recently been used to construct light-actuated nanovalves. An alternative approach is that based on the controlled stimulation of mechanical movements in rotaxanes [127]. The redox-switchable bistable rotaxane 274+ has been attached to mesoporous silica nanoparticles. As illustrated in Figure 12.30, the silica nanopores can be closed and opened by moving the mechanically interlocked ring component of rotaxane 274+ closer to and away from the orifices of the pores, respectively [128]. When the ring sits on the preferred TTF station, access to the interior of the nanoparticles is unrestricted, and diffusion of solutes from the surrounding solution can occur. A chemically induced oxidation of the TTF unit results in a shuttling of the ring closer to the solid surface, thereby blocking the access to the pores and trapping any solute molecule inside. Reduction of the TTF unit reverses the mechanical motion, thus releasing the guest molecules and returning the system to its initial state. More recently, it has been shown that the properties of these rotaxane-based valves can be fine-tuned by changing the length of the linkers between the surface and the rotaxane molecules and the location of the movable components on the nanoparticles [129]. A pH-driven nanovalve has also been constructed by threading/dethreading a surface-bonded pseudorotaxane [130].

197

198

12 Molecular Machines Based on Rotaxanes and Catenanes

+

+

N

O O O

274+

N S S

S S

O O O

O O O

O O O N

+

Loading or recharging

N

O O HN

O Si O O

+

Close valve

Open valve

Release of guest molecules

Figure 12.30 A molecular valve based on redox-switchable bistable rotaxane 274+ [128].

12.5.3 Molecular Muscles

As discussed in Section 12.3.2.2, molecular muscle-type contraction and stretching movements at the molecular level have been obtained by using a Cu(I)-based rotaxane dimer. Cumulative nanoscale movements within surface-bound “molecular muscles” based on another type of rotaxanes have been harnessed to perform large-scale mechanical work. The investigated system [131] consists of the palindromic bistable rotaxane 288+ with two rings and four stations, namely two TTF and two oxynaphthalene (OXN) moieties (Figure 12.31). Tethers attached to each ring anchor the whole rotaxane system as a self-assembled monolayer to the gold surface of the microcantilever beams. Each microcantilever was covered with

12.5 Performing Functions with Molecular Machines (a)

(b) N+

+N

O O

S S

O

S S

+N O SS

O

O

O

+N

O O

O O

N+

S S

S S

288+ O

O

N+

+N S + O S

S + S

O

O

+ 4e

+N

O

O

O

O

O

O SS

N+

O O N+

O O

_

O O +N

SS

O N+

+N

_ 4e _

O O

O

N+

O

S + S

S + S

O

O O

N+

+N O

O

O

O SS

Figure 12.31 A molecular muscle based on a self-assembled monolayer of the palindromic

bistable rotaxane 288+ (a) anchored on the gold surface of microcantilever beams (b) [131].

approximately 6 billion randomly oriented rotaxane molecules, and the set-up then inserted into a fluid cell. Oxidation of the ring-preferred TTF station with ferric perchlorate results in a shuttling of the two rings onto the OXN station, significantly shortening the inter-ring separation (from 4.2 to 1.4 nm). This change in inter-ring distance induces a tensile stress on the gold surface of the microcantilever, which in turn causes an upward bending of the beam by about 35 nm, whereas a monolayer of the dumbbell alone is inactive. Reduction with ascorbic acid returns the cantilever to its original position. The process can be repeated over several cycles, though with gradually decreasing amplitude. 12.5.4 Photoinduced Transport of Liquid Droplets

Changes in the molecular properties of bistable species mounted on surfaces can strongly affect the surface macroscopic properties [132]. A photoinduced transport of droplets on a surface has been achieved by light excitation of the two-station rotaxane 29 (Figure 12.32a) when physisorbed onto a modified gold surface (Figure 12.32b) [133]. The system comprises a ring that can move along a thread which contains a photoactive fumaramide (FUM) station and a tetrafluorosuccinimide (TFS) station. The former station has a high binding affinity for the ring, which can be switched off by photoisomerization to the maleamide (MAL) isomeric form. Consequently, when in the dark the ring surrounds the fumaramide station, but on light excitation it moves to surround the TFS station (Figure 12.32a). The shuttle movement that occurs is used to expose or conceal the fluorinated moiety of the dumbbell, thereby changing the surface tension (Figure 12.32b). When the area near the droplet of liquid is switched, the liquid is attracted to the irradiated zone, and so moves across the surface. The collective action of a monolayer of

199

12 Molecular Machines Based on Rotaxanes and Catenanes

200 (a)

N

N

O

O

O NH

HN O

O F F H N

FUM

N OH HN NH

N H

F F N N H H F F O HN NH

(CH2)9

N H

MAL

HN O

NH O

O

(CH2)9 N H F F O

29

O

O

O NH

h (254 nm)

TFS

O

O

N Hydrophobic

FUM

TFS

COOH

COOH

TFS

COOH

COOH

COOH

FUM

COOH

h (240-400 nm)

S

TFS

MAL

COOH

COOH

COOH

TFS

COOH

COOH

COOH

COOH

COOH

FUM

MAL

COOH

TFS

TFS

COOH

COOH

FUM

COOH

COOH

TFS

COOH

TFS

FUM

COOH

COOH

COOH

FUM

Less hydrophobic

COOH

(b)

N

S

S

S

S S

S S

S S

S S

S S

S

S

S

S

S

S

S

Au(111)

S

S

S

Glass or mica

Figure 12.32 (a) Structural formula of rotaxane 29 and its operation as a lightcontrolled molecular shuttle; (b) Schematic representation of the photoinduced change

of the hydrophobic/hydrophilic character of a gold surface covered with a self-assembled monolayer of rotaxane 29/11-mercaptoundecanoic acid [133].

these molecular shuttles has sufficient power to move a 1 µl droplet of diiodomethane on a millimeter scale up an incline of up to 12°. Liquid transportation using photoresponsive surfaces may prove useful for delivering analytes in lab-on-a-chip environments, or for performing chemical reactions on a tiny scale without a reaction vessel, by bringing individual drops containing different reactants together. 12.5.5 Interlocked Compounds in Solid-State Electronic Devices

The results obtained with electrical conductance measurements performed with scanning tunneling spectroscopy on gold-supported monolayers of the bistable catenane 184+ (Figure 12.22) [134] encouraged attempts to incorporate rotaxanes [135] and catenanes [136] in electrically addressable solid-state devices. In a leading experiment [136], a Langmuir monolayer consisting of the catenane 184+ and its amphiphilic dimyristoylphosphatidyl (DMPA−) counteranions was transferred onto a photolithographically patterned polycrystalline silicon electrode (Figure 12.33, top). The patterning was such that the film was deposited along

12.5 Performing Functions with Molecular Machines

Ti/Al electrode Monolayer of catenane 184+ Poly-Si electrode

Figure 12.33 Schematic representation of a solid-state device based on junctions consisting

of a monolayer of catenane [184+][DMPA−]4 sandwiched between polysilicon and Ti/Al electrodes [136]. The structure of 184+ is shown in Figure 12.22.

several parallel lines of poly-Si on the electrode. A second set of orthogonally oriented wires was then deposited on top of the first set, such that a “crossbar” architecture was obtained. This second set of electrodes consisted of a 5 nm-thick layer of Ti, followed by a 100 nm-thick layer of Al. The bottom poly-Si electrode of the molecular sandwich was 7 µm wide, and the top Ti/Al electrode 10 µm wide. By this approach, an array of junctions, each of which was addressable individually, was constructed (Figure 12.33, bottom). The mechanism for conduction was by electron tunneling through the single-molecule-thick layer between the junction electrodes. Thus, any change in the electronic characteristics of the inter-electrode medium would be expected to affect the tunneling efficiency and change the resistance of the junction. It should be noticed that such devices are conductors, but not capacitors. A series of experiments were carried out by applying different voltage pulses (between +2.0 and −2.0 V) and reading, after each pulse, the current

201

202

12 Molecular Machines Based on Rotaxanes and Catenanes

through the device at 200 mV (a potential that does not affect switching) (Figure 12.34a). The current (read)–voltage (write) curve displayed a highly hysteretic profile (Figure 12.34b), suggesting that the catenane junction device might have a potential use in random access memory (RAM) storage. The current–voltage curve was interpreted on the basis of the mechanism illustrated in Figure 12.35, which is derived from the behavior of the same catenane 184+ in solution [101, 137]. Co-conformation I is the “switch-open” state, and coconformation IV the “switch-closed” state of the device. When 184+ is oxidized (+2 V), the TTF unit is ionized in state II and experiences a coulombic repulsion inside the tetracationic cyclophane component. This results in a circumrotation of the crown ether and the formation of co-conformation III (note that, in solution at +2 V, TTF undergoes two-electron oxidation and the dioxynaphthalene unit is also oxidized [101]). When the voltage is reduced to near-zero bias, a metastable co-conformation IV is obtained which, however, does not return to co-conformation

(a) 1.2

Write

E (V) 0.8

Read

0.4

0 Pulse number

(b)

0.8 I (nA) 0.4

0 _ 2.0

0

+2.0

Ewrite (V) Figure 12.34 (a) A perturbing (“write”) potential is applied across the device, the state of which is then observed by measuring the current flow at the (“read”) potential of

200 mV; (b) Plot of the “read” current as a function of the “write” voltage for the device based on catenane 184+ [136].

12.5 Performing Functions with Molecular Machines E (V)

+

+

+2

II

III _e

_

+e

_

0

I

IV _ 2e_

+ 2e

_

–2

VI

V

Figure 12.35 Proposed molecular-level mechanism for the operation of solid-state electronic

devices based on catenane 184+ [136, 138].

I. The initial co-conformation can in fact be restored only via states V and VI, in which the bipyridinium units of the cyclophane component are reduced (in solution, at the potential value used, −2 V, the bipyridinium units undergo two-electron reduction [101]). Most likely, the reduction of the bipyridinium units weakens the charge-transfer interaction with the dioxynaphthalene unit, thereby decreasing the barrier for its escape from the cyclophane cavity. The same behavior was observed for solid-state devices containing TTF-based bistable rotaxanes such as 304+ and 314+ (Figure 12.36) [138], and interpreted on the basis of an analogous mechanism. Because these results and their interpretation gave rise to some controversy [139, 140], intensive efforts were undertaken in order to characterize the mechanical rearrangement associated with redox switching in bistable catenanes such as 174+ and related bistable rotaxanes [83, 85, 141], as well as their structural organization in monolayers [142, 143] and the molecule–electrode interface [142, 144]. The metastable state corresponding to co-conformation IV (Figure 12.35) was in fact observed for a number of different bistable rotaxanes and catenanes in a variety

203

204

12 Molecular Machines Based on Rotaxanes and Catenanes O + N O

O

S S

O

O

O

O

O O

O

OCH3

+ N S S

S S

O O

O O O

O O O

O O O N +

OCH3

O O

304+

N +

+ N

OCH3 O

O

S S

N +

O O O

O

+ N

N +

314+

O

O

OCH3

O

O

O

OCH3

OCH3

O O

Structure formulas of bistable rotaxanes 304+ and 314+, used to construct switchable electronic junctions for memory and logic function purposes [138].

Figure 12.36

of environments (solution, self-assembled monolayer, solid-state polymer matrix) [145]. The conductance switching in these systems was also extensively investigated by theoretical calculations [146]. Furthermore, the color change associated with the redox-driven switching of TTF-based bistable catenanes and rotaxanes in a polymer matrix can be exploited to make solid-state electrochromic devices [147]. Very recently, by use of the same paradigms described above, a molecular electronic memory with an amazingly high density of 1011 bits cm−2 was constructed by sandwiching a monolayer of the bistable rotaxane 314+ (Figure 12.36) between arrays of nanoelectrodes in a crossbar arrangement [148]. The realization of this device relies on a novel method for producing ultra-dense, highly aligned arrays and crossbars of metal or semiconductor nanowires with high aspect ratios [149]. It was estimated that each junction acting as a memory element consisted of approximately 100 rotaxane molecules. For practical reasons, only 128 (16 × 8 contacts) of the 160 000 memory cells (400 × 400 nanowires) contained in the circuit were tested [148]. However, the measurements showed that 25% of the tested cells displayed good and reproducible switching, while 35% failed because of bad contacts or shorts, and the remaining 40% showed poor switching. This work is a compelling demonstration that a combination of top-down and bottomup nanofabrication methods can lead to outstanding technological achievements. Nonetheless, several aspects – such as stability, reliability and ease of fabrication – need to be optimized before these systems can find real industrial applications [150].

12.6 Perspectives

The extension of the concept of a machine to the molecular level has been one of the most important advances in the field of chemistry during the past 20 years.

Acknowledgments

A wealth of novel systems have been designed, synthesized, and operated, showing that the molecule-by-molecule bottom-up approach opens virtually unlimited possibilities concerning the construction of artificial molecular-level machines. This new frontier of science – which gives a new meaning to the term “chemical engineering” – is of interest not only for basic research, but also for the development of nanotechnology. Furthermore, it can provide invaluable contributions towards a better understanding of the molecular-level aspects of the extremely complicated machines that are responsible for biological processes. Rotaxanes and catenanes are particularly interesting structures when constructing artificial molecular machines. However, whilst there are enormous opportunities in this field, there are also hurdles and challenges, most of which concern any type of artificial molecular machine: (a)

There is a need to find new types of active components (rings, stations and stoppers in the case of rotaxanes and catenanes) that are capable of undergoing fully reversible chemical processes.

(b) Research should be addressed preferentially towards systems powered by light or electricity, in order to avoid the accumulation of waste products. (c)

Light-powered machines require photoactive species with well-designed, excited-state properties (energy level, lifetime, stability, redox potentials).

(d) An autonomous behavior can be required for some applications. (e) A very interesting point to be elucidated is whether, and when, in a molecular machine the energy input is coupled with the mechanical motion by a deterministic or stochastic process. (f)

More efficient strategies should be devised to obtain a fast, unidirectional motion in catenanes.

(g) More interesting systems would arise from coupling linear and rotary motions. (h) Investigations carried out in solution are quite useful for understanding mechanisms, but for several applications the molecular machines must be interfaced with the macroscopic world by ordering them in some way at interfaces, or on surfaces. (i)

Techniques should be developed to address single machines in space.

Acknowledgments

The authors thank Professor J. Fraser Stoddart and his group for a longlasting and fruitful cooperation, and all of their collaborators and coworkers, whose names appear in the reference list. Financial support from the EU (Biomach project), Ministero dell’Università e della Ricerca (PRIN 2008), Ministero degli Affari Esteri

205

206

12 Molecular Machines Based on Rotaxanes and Catenanes

(DGPCC), Regione Emilia-Romagna (PROMINER) and Fondazione Garisbo is gratefully acknowledged.

References 1 Breslow, R. (1997) Chemistry Today and Tomorrow – The Central, Useful, and Creative Science, American Chemical Society, Washington DC. 2 Lehn, J.-M. (1995) Supramolecular Chemistry: Concepts and Perspectives, Wiley-VCH Verlag GmbH, Weinheim. 3 (a) Balzani, V. and Scandola, F. (1996) Comprehensive Supramolecular Chemistry, vol. 10 (ed. D.N. Reinhoudt), Pergamon Press, Oxford, p. 687; (b) Balzani, V., Credi, A., and Venturi, M. (1999) Supramolecular Science: Where It Is and Where It Is Going (eds R. Ungaro and E. Dalcanale), Kluwer, Dordrecht, p. 1; (c) Balzani, V., Credi, A., and Venturi, M. (2002) Chem. Eur. J., 8, 5525. 4 Joachim, C. and Launay, J.-P. (1984) Nouv. J. Chim., 8, 723. 5 Balzani, V., Moggi, L., and Scandola, F. (1987) Supramolecular Photochemistry (ed. V. Balzani), Reidel, Dordrecht, p. 1. 6 Lehn, J.-M. (1988) Angew. Chem. Int. Ed. Engl., 27, 89. 7 Gale, P