From Non-Covalent Assemblies to Molecular Machines

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

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Edited by Jean-Pierre Sauvage and Pierre Gaspard

From Non-Covalent Assemblies to Molecular Machines

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

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

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

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

V

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

Part One Noncovalent Assemblies: Design and Synthesis

1

1

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

2

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

2.1 2.2 2.3 2.4 2.5 2.6

3

Discussion 1.A 31 Chairman: Julius Rebek Jr

4

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

4.1 4.2 4.3

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

VI

Contents

4.4

Optical Amplification in Dynamic Supramolecular Systems Acknowledgments 41 References 42

5

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

6

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

7

Discussion 1.B 57 Chairman: Julius Rebek Jr

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

65

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

40

Contents

9

Discussion 2.A 141 Chairman: Fritz Vögtle

10

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

11

Discussion 2.B 151 Chairman: Fritz Vögtle

147

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

157

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

VII

VIII

Contents

12.4.4 12.4.5 12.5 12.5.1 12.5.2 12.5.3 12.5.4 12.5.5 12.6

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

13

Discussion 3.A 213 Chairman: David A. Leigh

14

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

15

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

16

Discussion 3.B 231 Chairman: David A. Leigh

Part Four Molecular Machines Based on Non-Interlocking Molecules 17

17.1 17.2 17.3 17.3.1 17.3.2 17.3.3 17.3.4 17.3.5 17.3.6 17.4 17.4.1

241

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

Contents

17.4.2 17.4.3 17.4.4 17.4.5 17.5 17.5.1 17.5.2 17.5.3 17.6 17.7

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

18

Discussion 4.A 291 Chairman: Takuzo Aida

19

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

20

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

20.1 20.2 20.3

21

21.1 21.2 21.3 21.4 21.5 21.6

22

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

IX

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Contents

Part Five Towards Molecular Logics and Artificial Photosynthesis 317 23

Chairman’s Comments A. Prasanna de Silva References 320

24

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

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

319

25

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

26

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

26.1 26.2 26.3 26.4

27 27.1 27.2

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

367

Contents

28

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

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

379

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

30

Discussion 6.A 429 Chairman: Enrico Dalcanale

31

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

XI

XII

Contents

32

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

33

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

33.1 33.2 33.3 33.4

34

Discussion 6.B 463 Chairman: Enrico Dalcanale

Index

467

453

XIII

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

XIV

Preface

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

XV

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

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

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

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

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

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


XVI

List of Contributors

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

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

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

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

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

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


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

XIX

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

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

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


XX

Opening Session Opening address by Marc Henneaux

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


Opening Session

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

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Opening Session

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

XXIII

The International Solvay Institutes Board of Directors Members Mr Solvay†

President

Professor Franz Bingen Emeritus – Professor VUB

Vice-President and Treasurer

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

Secretary

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

Baron Jaumotte Honorary Rector and Honorary President ULB †

Honorary Director

Deceased April 29, 2010.


XXIV

The International Solvay Institutes

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

Director

Professor Franklin Lambert Professor VUB

Deputy Director

Professor Albert Goldbeter Professor ULB

Scientific Secretary of the Committee for Chemistry

Professor Alexandre Sevrin Professor VUB

Scientific Secretary of the Committee for Physics

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

XXV

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

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


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



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


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


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;


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.


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


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


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)


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


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


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


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


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].


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


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


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


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].


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


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


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


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].


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


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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31

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.


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.

33

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


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


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


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


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.

47

48


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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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).


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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


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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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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


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].


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.


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


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.


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


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


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.


8.3.5 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


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.


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.


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.


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.


8.5.2 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


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.


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


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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8 A Short History of the Mechanical Bond (a)

(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


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.


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.


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


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


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


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


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,


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.


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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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dynamic combinatorial library [4].

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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


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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.


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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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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).


12.2.4 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].


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

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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

168

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


(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

170


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,


+

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.

172


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


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,


(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


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


+

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

178


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


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


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


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


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


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


R= O

O NH

HN

R O

O N OH NH HN

N H


O

O

H N O

O

CH3 Si CH3

N

N

15

85% 15% Ring position


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


(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


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


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


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


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 (98% cis double bonds) using iodosylbenzene as oxidant and a 500-fold excess of tbpy. For comparison, the same experiment was also performed with meso-tetrakis 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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15 A Toroidal Oxidation Catalyst (a)

(b)

Figure 15.1 (a) X-ray structure of the DNA polymerase III (upper, top view; lower, side view;

see Ref. [3]); (b) Blueprint of a synthetic processive catalyst.

(2-methoxyphenyl) porphyrin (MnTMPP), which is electronically related to Mn1 but does not possess a binding cavity. Mn1 was found to be a slower catalyst than MnTMPP, which was in line with expectation as the reaction with polybutadiene is forced to take place inside the cavity of the former catalyst. The reaction could be inhibited by the addition of viologen (Kass >105 M−1), which competitively binds inside the cavity and prevents the substrate from entering. Further proof that the reaction took place on the inside of Mn1 came from the cis–trans ratio of the product of the reaction, that is, polybutadiene epoxide. While the toroidal catalyst Mn1 produced 80% trans- and 20% cis-epoxide polymer from polybutadiene, MnTMPP gave predominantly the cis-product (78% cis, 22% trans). As a model compound, a polymer–porphyrin rotaxane catalyst was also synthesized, in which compound the rotaxane architecture with the manganese(III)–porphyrin enclosing the polybutadiene substrate was enforced by capping the ends of the polymer with stoppers. Catalytic experiments with this catalyst revealed the same high trans:cis ratios as obtained with Mn1 and free polybutadiene, confirming that the catalysis had indeed taken place preferentially on the inside of Mn1 (Figure 15.2b) [5]. The above studies have provided only indirect evidence that the Mn1 complex threads onto the polymer and moves along it during catalysis. Furthermore, the precise relationship between motion and catalysis, and whether the catalysis proceeds sequentially processive or via a hopping mechanism, remain unknown. It was decided, therefore, to study in more detail the threading behavior of H21 (the free base derivative of Mn1). To this end, a series of polymers (polybutadiene and polytetrahydrofuran) of well-defined length were synthesized that contained a thermodynamic trap (N,N′-dialkyl-4,4′-bipyridinium) at one side of the polymer chain, and a blocking group (a 3,5-di-tert-butylphenyl group) and an open end at

15 A Toroidal Oxidation Catalyst (a)

(b)

Figure 15.2 (a) Cavity containing a manganese(III) porphyrin catalyst (Mn1), which reacts with a low-molecular-weight alkene substrate (S) either on the inside or

on the outside, depending on the type of axial ligand applied to activate the catalyst; (b) Mn1 complex epoxidizing the double bonds of polybutadiene via a gliding process.

the other side. As H21 is unable to slip over the bulky blocking group, it must traverse the entire polymer chain from the open side in order to reach the trap (Figure 15.3). This process can be followed by recording the change in fluorescence of the porphyrin as a function of time, because such fluorescence will be quenched as soon as the viologen becomes bound into the cavity of porphyrin H21 (Note: Mn1 cannot be used for this purpose because it does not display fluorescence) [6]. The fluorescence quenching studies revealed that the threading reaction followed second-order kinetics, whereas the de-threading reaction proceeded accord-

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15 A Toroidal Oxidation Catalyst

Figure 15.3 Schematic representation of the threading of H21 on a polymer chain. Complex formation is only possible via the open end of the polymer.

Figure 15.4 Threading of a (bio)polymer through an opening, according to the nucleation

model (see Ref. [7]).

ing to first-order kinetics. Based on the results of experiments conducted at different temperatures, the kinetic and thermodynamic parameters were derived. The study results showed clearly that compound H21 is able to thread onto, and then completely traverse, the polymers. A length-dependent barrier, which increased with 61 J nm−1 must be overcome in order to reach the viologen trap. The threading process was found to be much slower for polybutadiene (ca. 40-fold) than for polytetrahydrofuran, most likely due to the presence of both 1,2 and cis-1,4 alkene units in the former polymer, which increases the bulkiness of the polymer chain as compared to polytetrahydrofuran. In order to be able to accept H21, the polymer must stretch and partly unfold, thus creating an entropic barrier. The threading mechanism may be similar to that proposed for the transportation of DNA through the opening in a virus particle [7]. After having found the opening, the DNA chain must thread through a certain critical length before the process can continue (the nucleation mechanism; see Figure 15.4). According to this mecha-


nism, the barrier that must be overcome is entropic in origin, and depends on the length of the polymer chain. Kinetic data acquired at different temperatures revealed a similar behavior, with the entropy of activation being strongly negative and increasing in absolute value when the polymer chain length became larger (polymer length, in nm; ∆Son ≠ /JK−1 mol−1): 21 (−88), 37 (−94), and 54 (−97). In contrast, the enthalpy of activation remained constant, within experimental error. As Mn1 could not be used in the fluorescence quenching experiments, its zinc analog (Zn1) was synthesized and the threading behavior of this compound compared with that of H21 [8]. An analysis of the kinetic data obtained from experiments with polytetrahydrofuran as polymer revealed that the threading of Zn1 occurred more slowly than that of H21. The initial suggestion was that this difference was due to a coordination of the zinc ion to the oxygen atoms in the polytetrahydrofuran chain, which slowed down any movement of the porphyrin macrocycle. However, when the ∆Gon≠ values were plotted against the polymer length, this was found not to be the case, as similar slopes were obtained for Zn1 and H21 [8]. Within error, the enthalpy and entropy values of the movement along the polymer chain were also identical for the two porphyrin macrocycles. Hence, it was concluded that the mechanism of motion was the same for H21 and Zn1 (and hence probably also for Mn1), and that the metal center had no additional interaction with the polymer chain. Further studies showed that the slower threading was the result of blocking of the cavity of Zn1 by a solvent molecule, which must first be removed before the threading can start. As all of these experiments were carried out in mixtures of chloroform and acetonitrile, molecules of the latter solvent may bind to the zinc ion and act as a competitive species for the polymeric guest. This suggestion was confirmed by experiments in which pyridine was added as a competing species. This ligand, which binds strongly within the cavity of Zn1 (Kass = 1.1 × 105 M−1), was found to cause a considerable slowing down of the threading process, and might even completely block it at sufficiently high concentrations. Interestingly, the addition of tbpy to Zn1, which is known to bind to the outside of this porphyrin cage compound, increased the rate of threading, because it induced the release of the coordinated acetonitrile molecule from inside the cavity of Zn1, opening it for threading by the polymer. Based on the kinetic data presented above, the speed of movement of the catalyst along the polymer thread can be roughly estimated. This amounts to 750 pm s−1 for the combination H21 and polytetrahydrofuran, and 14 pm s−1 for the combination of H21 and polybutadiene. These speeds are much higher than the translocation velocity calculated from the rate of catalytic oxidation when assuming a sequentially processive process, that is, approximately 1 pm s−1. This comparison suggests that the catalytic oxidation of polybutadiene by Mn1 most probably occurs in a random sliding fashion, with the catalyst hopping from site to site on the polymer chain, while at the same time converting double bonds into epoxide functions [6]. The above-described approaches to mimic the action of naturally occurring toroidal enzymes such as the DNA polymerases has resulted in the development

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of a new class of rotaxane catalysts not previously described. Processive catalysis represents a new phenomenon in organic and polymer chemistry, and opens interesting possibilities for the post-polymerization modification of various functional polymers, either synthetic or biological. Further studies are required to fine-tune the speed of movement of the catalyst, in order to match the catalytic conversions and make the process truly sequentially processive, as in Nature.

References 1 Benkovic, S.J., Valentine, A.M., and Salinas, S. (2001) Annu. Rev. Biochem., 70, 181–208. 2 Trakselis, M.A., Alley, S.C., Abel-Santos, E., and Benkovic, S.J. (2001) Proc. Natl Acad. Sci. USA, 98, 8368–8375. 3 Wang, J., Sattar, A.K.M.A., Wang, C.C., Karam, J.D., Koningsberg, W.H., and Steitz, T.A. (1997) Cell, 89, 1087–1099. 4 (a) Elemans, J.A.A.W., Bijsterveld, E.J.A., Rowan, A.E., and Nolte, R.J.M. (2000) Chem. Commun., 2443; (b) Elemans, J.A.A.W., Bijsterveld, E.J.A., Rowan, A.E., and Nolte, R.J.M. (2007) Eur. J. Org. Chem., 751–757.

5 Thordarson, P., Bijsterveld, E.J.A., Rowan, A.E., and Nolte, R.J.M. (2003) Nature, 424, 915–918. 6 Coumans, R.G.E., Elemans, J.A.A.W., Nolte, R.J.M., and Rowan, A.E. (2006) Proc. Natl Acad. Sci. USA, 103, 19647–19651. 7 Muthukumar, M. (2001) Phys. Rev. Lett., 82, 3188–3191. 8 Hidalgo Ramos, P., Coumans, R.G.E., Deutman, A.B.C., Smits, J.M.M., de Gelder, R., Elemans, J.A.A.W., Nolte, R.J.M., and Rowan, A.E. (2007) J. Am. Chem. Soc., 129, 5699–5702.

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16 Discussion 3.B Discussion on the Prepared Comments by R.D. Astumian,1) J.-P. Sauvage,2) J.F. Stoddart,3) and R. Nolte4) Chairman: David A. Leigh

Chairman: The session is now open for some discussions. R.D. Astumian: I would first like to address a question to Fraser Stoddart. You mentioned that biology is very complex, and I think that the lesson we can learn from biology is the following. If you consider the environment, being in water at a temperature of about 300 K with lots of squishiness, huge amounts of inertia, and if you try to consider how you might accomplish things in a macroscopic way – pushing them here, pushing them there – then inevitably you will confront what Richard Smalley had called beautifully and eloquently “the fat sticky finger problem.” You simply cannot do things in a liquid environment at the nanoscale, in the way you do things macroscopically, by pushing them – it just doesn’t work. The lesson that we take from biology is much less the idea of trying to imitate it, but much more of figuring out ways of using thermal noise in a constructive fashion to facilitate self-assembly, molecular motors, and such things. You also mentioned the term “complexity,” which is often talked about with regard to proteins. In fact, I think the dynamics of proteins is far simpler than that of macroscopic scale systems, but we confuse “unfamiliarity” with “complexity” because we don’t have an intuitive sense of how things work at that scale. So, I would like to get your feedback on those thoughts. J.F. Stoddart: Well, my brain is turning over because I guess we are on slightly different wavelengths, Dean Astumian. I approach my science very much from a practical level, and this is what I have been saying these past two days. I am looking for a means to use some of the science that we ourselves and many in this 1) The prepared comment by R.D. Astumian was on swimming in molasses and walking in a hurricane. 2) The prepared comment by J.-P. Sauvage was on the rearrangement of a surface-deposited [2]catenane by coordination to copper(I) at the single molecule level (see p. 219).

3) The prepared comment by J.F. Stoddart was on the differences between the biological and artificial chemical systems. 4) The prepared comment by R. Nolte was on a toroidal oxidation catalyst (see p. 225).


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16 Discussion 3.B

room have generated over the past quarter of a century to not just make beautiful things such as Borromean rings or Solomon knots. I purposely refer to the topics we have worked on ourselves, because I want to get over the message that I also like working on beautiful things – and my students do even perhaps more than I. However, I am looking for practical ways to get to something on a fairly short timescale. Like everybody else, I am inspired by biology, and influenced by what I have learnt from my physics. What I am trying to find are relatively simple ways to get to functioning materials. I don’t see a very quick route to imitating the complexity of Nature and devising a gadget that is going to be useful to humankind at this time. Are some of us thinking that we can create an animal that would look like a horse, and give it four legs so we can get this thing to start walking around this room as a kind of robot that is built of molecules at the nanoscopic level? I think not. If we are going to do that, we can already do it from an engineering and macroscopic point of view. So, if I extrapolate down to the nano-level world, I still want to take the rigidity in a sense that the horse conveys, although it would be a robotic one with pretty hard legs, body, and so on. If I put my little nano switches, machines, motors, or whatever you want to call them in that environment, can I get them to start doing something that is useful? I don’t know if we are engaging or not, but we are probably on slightly different wavelengths. R.D. Astumian: I think our ultimate goals are the same, but perhaps we have different perspectives of what is most likely in the near future. J.F. Stoddart: What do you think is likely in the future? R.D. Astumian: To make things move at the nanoscale. You may well be right if you want to scale things up to macroscopic levels. However, if you want to do things by moving and synthesizing molecules by chemical … J.F. Stoddart: Sorry to interrupt, but what is the point ultimately about being able to move molecules in an ordered kind of way at the nanoscale at this time? I think maybe in a century’s time it will be an appropriate thing to do, but I just don’t see the link with the world that we live in. I think we should try to make the quick journey from the nanoscale, molecular, subnanoscale world – if we are talking about molecules – to either a micro-world or a macro-world. As I said at the start of my presentation, I don’t have enough time left to start doing the type of thing that is too imitative of Nature. I have to look for short cuts, and I think these short cuts are to get onto surfaces, to get into membranes or between electrodes, or to get into some sort of three-dimensional networks. That is where I am aiming to go. Even if you could move molecules around in the way you are describing, I just don’t see what use it would be to man or beast in the next three years if you want to get the venture capitalists interested? But maybe that’s not important. J.-P. Sauvage: I would like to come back to the issue of Nature and its influence on chemical molecular systems. I would like to ask a general question to the audience, but before that I have just a few points. I think a few people believe that biomolecular machines are a tremendous source of inspiration, not the fragments

16 Discussion 3.B

or the components as such, but more the function. In our group and in others, we would like to be able to transport matter (Nature does it very well), to compress molecules (chaperones do it very well), that is, to perform chemical reactions. I think chemical reactions constitute the main point, so any molecular machine in Nature is a catalyst; basically, there is no molecular machine (except retinal) that is not a catalyst. This brings me to my next point, about autonomous molecular machines, which was addressed this morning by Vincenzo Balzani. If we want to fabricate autonomous molecular machines, they will have to be catalytic systems. In a way, we already have lots of molecular machines, which we don’t regard as molecular machines, but which could probably be converted to more classical molecular machines in our sense. Going back to my original point, in Nature, molecular machines are catalysts – they are all driven by ATP hydrolysis, more or less. Now, if you take a normal catalyst based on organometallic chemistry or, as Roeland Nolte beautifully demonstrated, based on manganese porphyrins – perhaps not so much with porphyrins, but with Wilkinson’s catalysts and the other classical catalysts – you have ligand exchange processes taking place. You have the phosphine which can go out and come back, so that you can already identify this as being an autonomous machine, or very close to becoming one. Now, if you incorporate this phosphine into one ring, and the rhodium catalyst in another ring, you have a catenane which will behave as an autonomous catalyst. So, my question is, have you already started working on that? Chairman: I am not seeing any answers. What you are saying is how can one make a chemically driven motor, or a directionally driven chemical system using the principles that Dean Astumian talked about. If you made such a catenane, and just put in some fuel, you should be able to directionally rotate the rings using that sort of system. J.-P. Sauvage: I must confess that we have been working for the past ten years to achieve a good design for such a system, especially with copper, as we know copper relatively well. You can also consider glucose plus O2 giving gluconic acid, and the copper should move around. But perhaps some other systems could be thought of? I leave you with that thought. D.N. Reinhoudt: We are not working on those machines, but I want to make a remark about the comparison between the biotic and abiotic worlds. Roeland Nolte showed beautifully how you can epoxidize using a porphyrin derivative. We should keep in mind that, in Nature and in our bodies, 3% of hemoglobin is degraded and replaced every day. Thus, there is no absolute durability in living systems without the machinery to replace what has been broken. It doesn’t make too much sense to say that, in Nature, everything is ideal and works for ever. We are the best examples that it does not! So I think it’s a little useless to say that we have to imitate Nature, or take it as an example, or go to completely artificial systems. We spent a lot of time in our group in order to realize what other people have promised in supramolecular chemistry. These are very simple devices such as sensors. If you have a sensing principle, you synthesize a molecule in roughly a year, but after

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that it takes ten years to convert that molecule and incorporate it into a sensor that is in continuous contact with water and will work for nine months. Therefore, the translation of molecular principles into practical applications will be more the engineering part – that is, including the molecules into solid matrices or attaching them to surfaces. That was my comment, but now I have a question for Dean Astumian. You use a bipolar surface, and I was very pleased that you were the first to introduce not just the molecule, but also its combination with the surface. But I’m wondering why you didn’t use a gradient surface instead of a bipolar one. If you had used a gradient surface, which is essentially chemical energy, would your model have been different? By a chemical gradient, I mean that you go from 100% of one functionality to 0%. In this case, would your model be the same? R.D. Astumian: Frankly, the reason I didn’t go in that direction is that, in this case, transport is trivial from a theoretical standpoint. Whenever you have a gradient you can always go up or down the gradient with an appropriate design. D.N. Reinhoudt: But the trivial solutions are the best. R.D. Astumian: Yes, from the point of view of a device. My model doesn’t mimic a microtubule, which is composed of repetitive subunits. I think that it would perhaps be more difficult to make, although everyone else in this room is much more able to address that than I would be. D.N. Reinhoudt: I can assure you that an undergraduate student in my laboratory is capable of making gradient surfaces with a two-step synthesis in probably one hour. R.D. Astumian: But would they be polymers? D.N. Reinhoudt: No – they would be solid surfaces functionalized for instance with aldehyde groups in our case, and where molecules with minor end-groups such as dendrimers can walk. You can visualize and see them walking from A to B. If you could reverse the polarity, for instance by protonation (in other cases than ours), then it might walk back. R.D. Astumian: But something would have to be used up as the motor goes in one direction. D.N. Reinhoudt: No. I think it is just the chemical energy by forming bonds, and there is a gradient which is the driving force for the process. Thermal energy in the system is enough to make it move, and the directionality is given by the chemical gradient. R.D. Astumian: But ultimately something would have to be used up. D.N. Reinhoudt: Sure. If you want to reverse it, you have to change the gradient into another gradient, but the process itself is autonomous. R.D. Astumian: But you couldn’t have a surface and keep introducing material on the left, and have it all move to the right, and keep introducing more

16 Discussion 3.B

on the left and keep it going onto the right. That would be a violation of the second law. D.N. Reinhoudt: I am not a physicist, but it can be done. R.D. Astumian: That is OK, the second law holds anyway! Chairman: Fraser Stoddart wants to make a point. J.F. Stoddart: Two quick points. Catalysis came up, and again if we’re being bioinspired, lets recall that an Olympic athlete consumes a ton of ATP a day in order to function at that level. I have forgotten what we consume as lethargic layabouts. Chairman: I consume about a ton! J.F. Stoddart: Well, I just wanted to make that point. The other point is the following. If we come to catalysis in a practical world, heterogeneous catalysis on metal surfaces and using zeolites has far outstripped anything that organic, inorganic, organometallic chemists have ever brought to the scene. J. Michl: It seems to me that there is less of a chasm between the views expressed by Dean Astumian and Fraser Stoddart. Dean Astumian is calling for the recognition of the essential role that is played by thermal or Brownian motion. However, in chemistry essentially everything we do is thermally activated. Thus, we are already using that random motion to our advantage all the time. Fraser Stoddart’s laboratory and everybody else’s laboratory does that. I also wanted to support the view expressed by Fraser Stoddart that it would be highly desirable – at least at this time – to organize our motors, machines, or rotors on a surface or in three dimensions. In our own work, we have actually always used surfaces, but we have also worked with MOFs, and I can tell you that we have a MOF in which dipolar rotors turn, driven by an electric field. The trouble is that the variety of structures that you can get for these MOFs is limited. For instance, if you wish to have a ferroelectric system, you can’t use a cubic system, and most of these things are just not suitable. Therefore, we’ve spent most of our time trying to find the type of MOF structure that would position objects in space the way that we want them to, so that they would interact with each other properly. J.F. Stoddart: I think I am particularly privileged to be beside one of the experts in the world, not just at producing cubic structures, but almost anything that geometry has brought to the field of these three-dimensional structures. I think that’s the type of area that’s worthwhile exploring. If we continue to wallow around in solution until kingdom come, we’ll be rather limited in what we can deliver to this world. I am not saying we wouldn’t deliver anything, but we could have severe limitations. I think, as chemists we’ve got to get ourselves out of this wet solution world, whether it is water or an organic solvent, and move into other worlds. It is absolutely needed. If this community doesn’t do it, I don’t know who is going to do it in chemistry. I think Josef Michl gave us a very early lead. I remember being at a meeting in Paris in 1991, where he was flying little propellers on surfaces, probably not through experiments as much as through just conceptually laying

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a platform out to people. But I can say that he was almost two decades ahead of the rest of us. J. Michl: That was not my point! F. Vögtle: In this session so far, catenanes and rotaxanes have been considered as a structural basis for molecular motors or machines. But what about molecular knots? They look more complicated and they might be less synthesizable at the moment, but over the next five to ten years I think they could become readily available. The motion inside knots is very nice, because every atom can move along the chain so that we have no real overall translational movement, as occurs in rotaxanes. It would be very elegant, so perhaps this should also be considered. T.F. Otero: I have two comments and one question. Let me translate a general idea from the north west of Spain which says that “the best things are the main enemies of the good things”: in other words, the best machines are the main enemies of the good machines. Here, we have good molecular machines, and it’s necessary to extract all the knowledge about it. The best things are in the domain of God, and the good things in the domain of human beings. The second comment is related to complex systems. We are dealing with a very large research area that extends from single molecules to complex systems. It includes, for instance, conducting polymers and molecular machines with solvent and counterions, where the reactions change all the intermolecular and intramolecular interactions in doing mechanical work, changing color or porosity, storing or releasing chemicals – that is, it is almost mimicking biological systems. We only have to use all our physical, chemical and engineering backgrounds in order to improve our general knowledge and arrive at devices. I have a question to Professor Astumian. Why do you use probabilistic concepts in kinetics? R.D. Astumian: I think that, first of all, the probabilistic point of view is actually simpler than a deterministic chemical kinetic point of view. It is less familiar, but when you work things out, it is really far easier to come up with good theoretical constructs and, thus, with good proposals for design based on probabilistic concepts, rather than kinetic ones. For example, one striking misleading point that has been made by some chemical kinetic models is the idea that you have a forward reaction where you hydrolyze ATP and move a step forward, and a reverse reaction where you move a step backwards and synthesize ATP. But that’s just not the case. When you look at a probabilistic point of view, you recognize that, when you hydrolyze ATP, there is also a certain probability that you will step backwards. T.F. Otero: That is included in the chemical equilibrium. You have the chemical methodology from the eighteenth century to determine the constant. R.D. Astumian: Unfortunately, when you combine chemistry and mechanics, which are two processes such as oxidation–reduction and protonation– deprotonation, the way in which the word “backwards” is used in chemistry is in fact the reverse reaction – it’s not the backward reaction. There are four reactions

16 Discussion 3.B

when you have two coupled processes, but that’s not normally taken into consideration in chemical kinetic models. G. Fleming: The point was made earlier that you don’t want to start with atoms, you want to start with molecules. I would like to ask a heretical question: are you sure you want to stop there? When computer chip engineers design a new version of the Pentium chip, they do not work out the doping levels of silicon. Instead, they take components and assemble them in some way to make a device that has a function. Roughly speaking, this is the philosophy of a field called synthetic biology – which I haven’t heard mentioned so far – as distinct from synthetic chemistry. If you want to make devices that really work, do you want to start at the molecular level, or do you want to just take things that we know work, and combine them in new ways to make functions that are better or different than what exists in Nature? I know it is heretical for this conference to take this point of view, but I’m curious to hear what the reaction is to that. I do take seriously – in fact, I shall talk about it tomorrow – the damage that occurs to real biological machines as part of their function, so you would have to deal with that. However, it is not obvious to me that, if you really want to make something that carries out a real function, you want to start always at the molecular level. Chairman: Well, just answering from our own group, we don’t want to mimic biology despite what is being said, and to make a horse that will walk along. G. Fleming: I wasn’t talking about mimicking biology, I was talking about creating a function that doesn’t exist right now. Chairman: There are many ways that you can go forward in this field, but I think the advantage of chemists is that we can go beyond Nature. We have more building blocks that we can use than DNA or proteins – we can use far more elements, far more building blocks, and in the end we’ll be able to make things that are very different functionally to Nature. However, at the same time, if you’re going to try building a racing car that is like a Ferrari, as McLaren found out, the best way to do that is to steal the ideas of Ferrari and see how it works. That is the sort of thing that we try and do – to learn lessons from how biology tackles these problems and use those to then construct something that’s so different that the F1 designers can’t tell that’s what is in our cars. R. Nolte: Just answering this question, I fully agree that we should go to complete systems, but that’s one step too far at the moment. What we are currently doing is combining synthetic organic chemistry and polymer chemistry with synthetic biology. We take a virus particle, use its empty capsid, and modify it to perform catalysis with these biological systems. But, in general, this is one step too far at the moment – that would be the approach for the future, the approach of Nature, whereas this is something that we simply can’t do at the moment. It will take more time. S.A. Rice: I would like to follow up on Graham Fleming’s remark, but from a slightly different point of view. There is a danger in stealing the ideas of Ferrari

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to make a better Ferrari, because as biological beings have evolved, they have often – through evolution – achieved very complex solutions to problems which can only be understood, not in a completely logical sequence, but by following the evolution. Nobody can understand how to design or look at a human kidney without seeing how the kidney evolved through the mammalian species. You wouldn’t do it that way and I think that, at a certain functional level, there is a danger in taking the ideas of the current understanding, because they may have evolved in a fashion which is less than optimal. They work, but they may not represent the best way of doing it. B.L. Feringa: I would like to make a comment on catalysis in the hard and soft worlds. I appreciate very much the remarks made by Jean-Pierre Sauvage regarding this issue. This whole discussion reminds me a lot about the talks that have been going on for many years between the heterogeneous and homogeneous catalysis worlds, whereby there is always this debate about the stability, robustness, function, and so on. It also slightly resembles the debate about natural systems and synthetic systems. What you see nowadays in several places is that the heterogeneous and homogeneous communities have met each other. The interface between these two communities results in tremendous opportunities by taking advantages of some aspects from either heterogeneous or homogeneous catalysis. Therefore, it gives us a whole lot of new opportunities. I think this is also what Fraser Stoddart was mentioning, and I really appreciate his comments on that. On the other hand, we shouldn’t forget that there are tremendous numbers of industrial processes on the large scale that work perfectly based on homogeneous catalysis, and yet these are small molecules that work beautifully as tiny machines. I think this comment is worthwhile making, I’ll be commenting on this more tomorrow during my presentation. Furthermore, I think there is a huge effort at the moment from several people in the catalysis community, who are looking at mother Nature and asking how she performs catalysis in the living cell. This is a cascade of catalytic steps – look for instance at the way fatty acids are produced in cells – this is fantastic machinery where several catalysts, all of which are spatially positioned at the nanoscale, operate in well addressable ways. Today, a huge effort is being made to see how cascades of catalytic events can be made. This is very difficult because you have to spatially address the catalysts, separate them, and balance their activity, the diffusion, the transport, and so on. I think this will offer tremendous opportunities in the future to advance in the field of molecular machines because you can learn a lot from that community. We must take advantage of solid-state chemistry, catalysis, and biology. In bringing all these aspects together, we can progress enormously with what we learn from these fields. R.D. Astumian: I would like to follow up on the idea of catalysis. Jeremy Knowles studied evolutionary pathways to optimize enzyme catalysis, and I’m reminded by a beautiful title of an article he wrote about fifteen years ago: “Enzyme catalysis: not different, just better”.5) Thus, at least with regard to a single protein 5) Knowles, J.R. (1991) Nature, 350, 121.

16 Discussion 3.B

and asking how can this function as a really good catalyst, you can study what principles has Nature adapted to make this as good a catalyst as it possibly can be, and how can we take maybe less-complicated molecules but ones that can be synthesized more readily and use those principles to get really good catalysts. With regard to motors, machines and the like, similar ideas using what we learn from biology – but not slavishly attempting to mimic them – constitutes a very good approach. J.-P. Launay: On the issue of whether or not to imitate Nature, I think at first we shouldn’t try to directly imitate Nature. The most important thing is to understand a few basic principles that are fundamental, and to use them in different ways. I was struck this morning by Professor Nolte’s speech, because I suddenly realized that there is a big difference in the machines that we discuss: machines could be characterized as one-, two-, and three-dimensional. Those presented by Professor Nolte are one-dimensional machines, which are easy to understand in a way because the reagent or double bonds and waste products remain on the chain, preventing back motion. Therefore, it’s a marvelous example to teach students, to demonstrate to them the motions of this porphyrin on the thread. If we consider machines in two dimensions on the surface, the motions are already much more complex. And in three dimensions, there is a huge variety of motions so that it’s extremely difficult to predict what will happen, because there are so many degrees of freedom for the molecules themselves, the reagents, and the waste products. Therefore, perhaps we should think about these very general principles and try to understand simpler systems before expanding out to higher complexity. Chairman: Of course, the way that Nature has addressed that problem is to use tracks and axis so that it can restrict the dimensionality. I realize that we’ve gone on for a long time, and I apologize for that, but I would like to thank all of the speakers for their participation in this session, and also those people who have joined in on the debate, which was really great.

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Part Four Molecular Machines Based on Non-Interlocking Molecules


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17 Synthetic Molecular Machines Based on Non-Interlocked Systems: From Concept to Applications Report Wesley R. Browne, Dirk Pijper, Michael M. Pollard, and Ben L. Feringa

17.1 Introduction

From antiquity, we have wondered at the enormity of Nature’s diversity and pondered as to the source of vital energy that animates matter; since the days of Galileo and van Leeuwenhoek, we have marveled as its complexity as has been exposed first, by optical microscopy and, over the past half-century, by ever-more sophisticated methods to reveal the inner architecture of the cell, the ubiquity of molecular machines, and the chemical-driven motors contained therein. The more we have learnt about how we “work,” about how the concerted action of innumerable molecular machines in our body translates to macroscopic movement and provides us with awareness of the world around us [1], the more we have been inspired to apply the art of chemical design and synthesis and engineering of nanosize functional architectures to construct and use synthetic molecular motors and machines [2, 3]. Indeed, the state of the art of wholly synthetic systems, although still primitive, demonstrates that concerted action at the nanoscale can drive macroscopic phenomena [2]. In this chapter, the conception and development of these truly synthetic molecular machines is discussed – but first, perhaps, a moment should be taken to consider just what a molecular machine is! This is arguably one of the toughest of questions to ask of the field of synthetic molecular machines and devices. In the macroscopic world, a whole lexicon of terms is used to describe machinery. For instance, the term “diesel-electric train” describes a locomotive engine in which chemical energy is first converted to electrical and subsequently to kinetic energy. In the microscopic world, such a succinct definition of a particular machine is, exasperatingly, elusive [4]. Is a system which uses biased Brownian motion (like biological motors) a machine, or must a microscopic machine use a chemical, light, heat, an ion or proton gradient or electrical fuel source? In the broadest possible terms, a machine – molecular or otherwise – is a thing which performs a task. In the present chapter, the discussions will be focused on a tighter definition of a machine, to those devices that either feature a 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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motor element to convert a source of energy to kinetic energy or use Brownian motion to perform a task [5, 6]. But first, a brief comment should be made on what is defined as a “molecular motor” [2–4]. That bastion of the English language, the Oxford English Dictionary [7], defines the term motor as “… a thing that imparts motion.” However, this definition poses a problem when taken from a molecular perspective [4]. Brownian motion [5] places all molecular systems in a state of virtually perpetual motion; hence, a more useful term for a molecular motor would be that which uses energy, in whatever form, to impart a change in molecular structure in a controlled, cyclic and continuous manner, or which retards Brownian motion in a specific manner so as to achieve directional motion. The forces that dictate the movement of macroscopic objects – for example, gravity – hold little relevance to movement at the nanoscale. The chaotic thermally driven movement Brownian motion, which causes all components to vibrate, rotate, and translate incessantly at temperatures above 0 K, is the dominant factor at the molecular level. Therefore, the overriding challenge in designing molecular motors does not lie in achieving motion, but rather in controlling their operation, and especially their directionality [4, 6]. In order to control movement in this turbulent environment, Brownian motion must be either exploited [8], or overcome [9]. A brief comparison with biological molecular motors, such as the kinesin and myosin translational motors or ATPase and bacterial flagella rotary motors, is pertinent to illustrate some of the enormous challenges ahead in designing artificial molecular motors [3, 6, 7]. The complex dynamics of these systems involve, among other factors, autonomous and repetitive motion, movement along a track or at least control of directionality, a time scale of motion, control mechanisms to operate the motor properly, and the execution of useful functions that allows the motor to perform work. An essential element that should be taken into account is that Nature exerts its dynamic functions also at different hierarchical levels, through intricate coupling and amplification mechanisms [10].

17.2 Design Concepts [11]

In designing molecular machines, perhaps the most basic requirements that should be considered are: the energy input; the motor unit; the actuator; and the output work (Figure 17.1). The choice of both energy input and output determines the type of motor unit employed. A central requirement in any design, however, is that fundamental issues regarding dynamics, friction, wear, transmission, efficiency, fuel, motion, work and interactions with the environment, must be considered from a molecular perspective, and not by analogy with the macroscopic world. Furthermore, a primary design consideration is the function or the nature of the work to be performed by the machine. For example, is controlling the distance between two molecular entities sufficient (as in the azobenzene systems; Figure 17.1), or is continuous repetitive rotation or translation required? These

17.2 Design Concepts

requirements determine the type of “motor” component to be employed, while other considerations – such as the environment in which the machine will operate – determine the necessity, or otherwise, of incorporating additional functional components such as anchors for immobilization on surfaces, cage units to isolate a rotor component, or hydrogen bonding units or alkyl chains to enable self-assembly. Ultimately, however – as in the macroscopic world – a central consideration must be the fuel source. Should chemical, electrochemical or light fuel be used, and how should it be used? From the macroscopic world of machines, perhaps the natural instinct would be to use fuel to fight the incessant Brownian motion, but a leaf could also be taken out of Nature’s book [11, 12] and the fuel used to bias Brownian motion [6a, 11, 13–15].

(a)

(b) N N

O

N

N

N

O

N

N

O O

N

O

hn

hn

O

O

hn′

hn′ O

O

O

O

O

O

O

O O

O

O

Figure 17.1 (a) A simple molecular machine – the cis-trans isomerization of an azobenzene unit is used to control the interaction of two functional groups; (b) Two

int

crown ether units can be brought together or separated by the action of the azobenzene unit, allowing ion binding and transport powered by light [16] (see text for details).

er fac e

switches

s function sensors

Machines & devices fuel

rs actuato

motors

Figure 17.2 Making a molecular machine work: Conceptual illustration of some parameters to be considered in the design and functioning of molecular machines.

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A machine is more than a motor, however important that motor function may be. Further design considerations include the delivery of fuel to the molecular machine, the removal of waste products, the transmission of movement (actuation), the coupling of motions, and the effect of environment – for example, surface, packing, solvation, on molecular function (Figure 17.2). Indeed, an added factor that must be considered is that each of the components cannot be dealt with in isolation; that is, changes in their own component will almost certainly have an effect on other components in these complex dynamic systems. In this chapter, the principles and advances made in the area of molecular motors and machines based on non-interlocked systems will be discussed. In the present discussion, interlocked systems – that is, rotaxanes, catenanes and systems involving gels, polymers and DNA-based motors, as well as nanodevices that are not molecular-defined – will not be discussed [17].

17.3 Synthetic Molecular Rotors

The simplest concept of a machine is perhaps that of the Brownian rotor. However, whereas Nature is able to bias the rotary action of Brownian rotors to extract a function from their action, synthetic molecular rotor systems have, to date, focused primarily [18, 19], albeit not exclusively, on so-called technomimetic [20] rotor systems in which no control over the directionality or actual rate of rotation can be achieved [21–26]. Indeed, although the rotary motion around a carbon–carbon single bond can be extremely fast (exceeding 100 MHz; vide infra), albeit with no control over the directionality of the rotation [22], it should be realized that molecular machines and molecules are not rigid entities in the macroscopic sense, but rather undergo changes in shape (conformational flexibility) incessantly – which is a key aspect in their functioning. 17.3.1 Metal Complexes as Rotors

Sandwich complexes such as the metallocenes, and in particular ferrocene-based systems [27], have formed the basis of a wide range of molecular rotor systems often referred to as carousels, in which two flat units rotate with respect to one another with a metal ion acting as a “ball bearing.” In the case of the ferrocenebased systems (such as those shown in Figure 17.3), the rotation of the cyclopentadienyl rings around the Fe(II) pivot in ferrocene has been the subject of several studies, and a barrier to rotation of 9.6 kJ mol−1 has been determined at 68 K [28]. A recent gas-phase experimental and theoretical study of a ferrocene derivative, substituted with a carboxylic acid on both cyclopentadienyl rings, showed that intramolecular rotation can be induced through protonation and deprotonation cycles also [29]. The conformation of the dianion is locked in the trans conformation, to minimize coulombic repulsion of the negative charges. Protonation of one

17.3 Synthetic Molecular Rotors t

Bu

t

Fe

Ph

Fe t

Ph

Fe

Ph

Ph

Ph

Ph

t

Bu

Bu

1

Ph

Ph

Bu

2

3

O

O

+H+

-

O

O

+H+

-

O

O 4a

Br

Br

Br Br N N

Ru N B H

O-

4b

Figure 17.3 (a) Ferrocene and substituted ferrocenes 1, 2, and 3 as molecular rotor components. The barrier to rotation can be increased by the introduction of bulky groups onto the cyclopentadienyl rings; the introduction of two tert-butyl groups on each ring in 2 increases the barrier to rotation to 54.7 kJ mol−1 [30]. The concerted rotary movement of multiple substituents on the metallocene has been examined

N

N

5

Figure 17.4 (a) Organometallic molecular turnstile 5, in which the rotation about the ruthenium axle and the rotation of the phenyl substituents are coupled; (b) Cerium(IV) bis(porphyrinato) complex 6 bearing pyridine

N CeIV N N N N

N

N N

N N N N

Br N N

in the cog-wheeling rotation of the phenyl substituents in bis(tetraphenylcyclopentadienyl)iron(II) 3 [31], where the barrier to rotation (37.6 kJ mol−1) was found to be much lower than anticipated; (b) pH-dependent rotary movement in a ferrocene dicarboxylic acid 4a/4b. In this example, the protonation locks the conformation of the molecule in one of two states [29]. N

N

H

O

N

N N

N

N N N CeIV

N N

HO

N

HO

N N N N

N

N

O O

6 substituents, of which the rotation of the two porphyrins about the metal axle can be locked or accelerated by the addition of dicarboxylic acid substrates or silver ions, respectively.

of the carboxylic acid groups results in a rotary movement around the metal center, with the complex being locked in the cis conformation due to intramolecular hydrogen bonding. The ruthenium sandwich complex 5 (Figure 17.4), a so-called “organometallic molecular turnstile,” consists of a pentakis(p-bromophenyl)cyclopentadiene deck

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and a deck consisting of a hydrotris(indazolyl)-borate group. The barrier to rotation of the cyclopentadienyl ligand is less than 41.8 kJ mol−1 [32]. There appears to be a good fit of the indazolyl groups of the lower deck into the pockets created by the phenyl substituents on the upper deck, as evidenced by NMR spectroscopy; hence, it was proposed that the phenyl groups twist out of their perpendicular arrangement to allow the indazolyl rings to pass – creating a geared mechanism of rotation. The rotation involved with double-decker complexes based on porphyrin ligands with either cerium or zirconium metal ions has been shown to be much slower than that of the smaller metallocenes and, indeed, in several systems rotation could not be observed even at elevated temperatures [33]. The rate of rotation was found to depend on the steric bulk of the substituents and the size of the central metal atom, and the addition of acid-accelerated rotation [34]. Later, it was shown that the redox state of the metal center, as well as the porphyrin ligands, has a significant influence on the rate of rotation [35]. The rotation in the cerium(IV)– porphyrin-complex 6 bearing pyridine substituents (Figure 17.4) could be locked by the addition of dicarboxylic acids that bind the two pyridines on opposite porphyrin decks [36]. Indeed, the binding constant for the diacids was found to increase for the subsequent binding of dicarboxylic acids (cooperative effect). This was suggested as being due to a reduction in the enthropic cost of the binding by the locking out of rotary movement: the (loss of) supramolecular rotation leads to a positive allosteric effect. With a complex analogous to 6, however, bearing pmethoxyphenyl substituents, the binding of silver ions to the concave π-clefts (three Ag+ ions per cerium double-decker) actually increased the rate of rotation [37]. The silver ion binding was proposed to induce conformational changes in the system that reduces steric interactions, or increases the distance, between the two decks, thus facilitating rotation. An extension of this concept towards a molecular carrousel is the so-called “molecular ball-bearing,” in which three silver ions are coordinated between two disk-like ligands 8 [38]. In compound 8, the tolyl groups serve to force the thiazolyl groups out of the plane of the central benzene ring for more efficient binding to silver. The sandwich complex appeared to have a distinct helical shape (by X-ray analysis), in which the interconversion between P and M helicity was shown to be fast (by NMR spectroscopy). Using a hetero-complex of 8 and 9 (Figure 17.5), a reversible partial rotary movement with a rotational barrier of ∼58.5 kJ mol−1 was observed. The two stable helical forms, where the silver ions are coordinated to two thiazolyl nitrogens (one from each disk), interconvert via a state where the silver ions coordinate to three nitrogens (one from the upper disk and two from the lower disk) [39]. An alternate approach to molecular rotors are the molecular gyroscopes based on the free rotation of a R-Rh–CO rotor in a 25-membered macrocycle that constitutes the three-spoke stator (Figure 17.6). was reported by Gladysz et al. [40]. When R is as small ligand – for example, chlorido as in complex 10 – the rotation is fast in solution, but a bulky ligand such as a p-tolylacetylene present in 11 effectively halts the rotary motion (this is analogous to the turnstiles, as discussed


S

N

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S S

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8

3x Ag+

S

N

N

9

S

S

N

N

S N

S S

N

Figure 17.5 Self-assembly of polythiazolylbenzene disks 8 and 9 with three silver ions,

forming molecular ball-bearings.

O

O

O

P

10 : R = Cl R

Rh

CO

11 : R =

P

O

O O

Figure 17.6 “Giant” rhodium-based molecular gyroscopes 10 and 11.

above). The flexible open structure of these systems results in an intercalation of neighboring molecules or solvent between the spokes in the solid state; hence, bulky groups must be introduced in order to restrict access to the molecule’s interior space. A major advantage of these systems towards gyroscopic functionality may lie in the large dipole of the rotor unit that might allow for control over the rotary motion. Although inorganic complexes – and, in particular, transition-metal ions – provide considerable flexibility and versatility in the development of rotor systems, it

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should not be forgotten that biological rotor systems rely on wholly organic compounds. The twin rotor system 12 shown in Figure 17.7 is a typical example of the numerous organic rotor systems that have been studied over the past half-century [19]. This twin-rotor system is based on a radialene frame, while the rate of rotation around the butatriene axis can be controlled by variation of the substituents. For example, the slowest rotation rate is observed with fluorene rotors (i.e., X = 0; 12a), whereas thioxanthene and dihydroanthracene rotors give a much faster rotation. Again, the system is typical for rotors in that, although rotation can be very fast, it is not possible to control its speed, other than by temperature or by structural variation in the rotor unit, and the direction of rotation is essentially random. 17.3.2 Correlated Rotation Through Steric Interactions

Conformational dynamics involving rotary motion are extremely fast in organic molecules, with a typical barrier to free rotation around the central C–C single bond in butane being 4.5 kcal mol−1 [41]. By enhancing the steric hindrance, as in biphenyls (Figure 17.8a) and in particular substituted biphenyls (Figure 17.9), the

Figure 17.7 The twin rotor based on a radialene frame.

(a)

(b) hn′ hn′

13 14 Figure 17.8 (a) Free rotation around C–C single bonds in alkanes and biphenyls; (b) Double

bond rotational isomers.


(a)

Mirror plane a

d

d

b

c

c

CO2H HO2C

b

O2N NO2

a

R

R

(c)

X

(b)

X

R R

+

R 16

15

R

17a : x = S 17b : x = O 17c : x = C = O

Figure 17.9 (a) Atropisomerism (chirality due to restricted rotation) with biphenyls and dinitro-substituted diphenic acid 15; (b) Triarylcarbonium ions 16 adopting a

R 18

propeller conformation and the concerted rotation encountered in “cogwheel-like” systems 17a-c; (c) Triptycene-based molecular gear 18.

rate of rotary motion can be decreased. Alkene-based rotary isomers rely on tuning the steric parameters, as is also the case in sterically overcrowded alkenes (Figure 17.8b) [42]. Biphenylic molecules can exhibit molecular chirality, a phenomenon first established in the resolution of the enantiomers of the biphenyl-based compound 13 (Figure 17.8a) [43]. However, this is only possible in systems that adopt a twisted conformation of one of the phenyl rings with respect to the other, and where rotation around the central aryl–aryl bond is hindered (Figure 17.9a). This ability of compounds to possess chirality due to restricted rotation is called atropisomerism [44] (from the Greek tropos, meaning to turn or rotate). During the mid-1960s, with the advent of NMR spectroscopy, the observation that triphenylcarbonium ion 16 adopts a propeller conformation, and that rotation in these gear-like systems is hindered, led to the discovery that the rotation of one part of the molecule could induce rotation of other parts, in a correlated fashion (Figure 17.9b) [45]. Over the following decade, numerous studies on the so-called “cog-wheel” effect in these and related systems (16–18) have been reported [46, 47]. The first examples of truly geared rotation were the ditriptycyl systems [48], which consisted of two, three-toothed gears, as in 18 and 19 (Figures 17.9c and 17.10) [49]. In the first of these systems, the energy barriers to rotation were sufficiently low to allow “slippage” of the gears to a certain extent, but intermeshing of the phenyl rings of the two triptycenes resulted in little or no slippage, even at elevated temperatures [50].

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17 Synthetic Molecular Machines Based on Non-Interlocked Systems Me Me

19

Me Me

tBu

gears CO2H

tBu

20

propellers Me

Me Me

Me

Figure 17.10 Molecular propellers and gears. Adapted from Ref. [49]; © ACS, 2004.

21 : R = H 22 : R = CH2OCH3 19 : R = H2C O

R

R

Figure 17.11 Molecular turnstiles.

These geared systems form the basis of a “molecular turnstile,” in which a substituted p-diethynylbenzene group is attached to the interior of a phenylethynyl macrocyclic framework (Figure 17.11) [51]. The rotation of the internal phenylene group was studied as a function of the size of its substituents (R), using dynamic NMR spectroscopic techniques. For the nonsubstituted 21, rotation is too fast to


measure, even at very low temperatures. However, the introduction of a substituent, as in 22, allowed the barrier to rotation to be determined as 56.0 kJ mol−1, yielding a rotation rate at room temperature of 320 rotations per second. In the case of 23, rotation was blocked effectively, even at elevated temperatures. 17.3.3 Molecular Gyroscope in the Solid State

The immobilization of molecular rotor systems is seen as being key to both appreciating fully the rates of rotation that can be achieved, and in fixing the stator unit to a macroscopic frame of reference. This can be achieved either by immobilization on a surface (vide infra), or by entrapping rotors in the solid state. Garcia-Gariby and coworkers have taken this latter approach to develop aryl-acetylene-based systems [21], such as those shown in Figure 17.12. Here, the solid state allows for the confinement of a chemically bound system in a fully enclosed cavity. In the crystal lattice, the framework is held static and shields the rotor part from steric interactions with adjacent molecules in the crystal, allowing it to orient under the influence of external electric or magnetic fields. The introduction of substituents onto the phenylene rotor, thus creating a dipole, could allow it to be addressed by an external electric field, although these studies have not yet been reported [52]. Molecular motion and dynamics can be restricted severely in the crystal lattice compared to that in the liquid and gas phase, due to packing of both the molecule

Figure 17.12 (a) Molecular gyroscope 24; (b) Parallel packing of two gyroscope molecules in

the crystal lattice, creating a sufficient spacing for the phenyl rings to rotate with a barrier of only 18.0 kJ mol−1. Adapted from Ref. [55]; © ACS, 2002.

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and solvent of crystallization (to fill voids) [53]. However, the rate of rotation in the crystalline phase of for example, methyl groups, can reach values as high as those observed in the gas phase. Similarly, while the rotation of the phenylene rotator around single bonds is virtually barrierless in solution, retardation observed in the solid state may be assigned to steric contacts with the triptycene units of the stator or with neighbors in the crystal lattice. Initial studies on crystals grown from a system similar to 24, albeit lacking the methyl substituents, showed a reduced rate of rotation due to interdigitation of the triptycene units causing contact between the rotor and a neighboring triptycene unit [54]. In these and other systems, the inclusion of a solvent in the crystal lattice also hinders rotation. In 24, the methyl groups prevent the interdigitation of adjacent molecules in the lattice, providing a local cavity for the rotor unit (Figure 17.12) [55]. This favorable packing arrangement allows nearfree rotation of the phenylene unit, with a remarkably low activation barrier of only 18.0 kJ mol−1, resulting in a rate of rotation of 1.9 × 103 MHz [22]. 17.3.4 Rotary Motion Controlled by an External Input

In discussing metal complexes as rotors (vide supra), it was shown how the binding of guest molecules, a change in redox state, or the size of substituents or metal ions (used as ball bearings), could each affect the rotational dynamics of a particular molecular system. Conformational changes in ligand geometry due to metal binding is, of course, a well-known phenomenon [56], and the principle has also been used in the context of controlling rotary motion. The control of free rotation around a molecular axle can be achieved by using “molecular brakes,” that increase the barrier to rotation. An elegant example of such a molecular brake is through the use of the reversible coordination of metal ions to restrict molecular conformational freedom (25; Figure 17.13) [57]. Kelly et al. have employed Hg2+ ions (which can be removed by addition of a thiol) to lock the conformation of a molecular rotor based on a triptycene stator linked to a polypyridyl rotor via an ethynyl axle. Although the rotation around the axle was relatively free, binding of the Hg2+

Me

Me N

N

N

activate brake

25a Figure 17.13

N M2+

M2+

Molecular brake 25 induced by metal-ion binding.

25b


ion the system was locked as the phenanthrene unit of the rotor interacted with the triptycene stator so as to halt rotation. A similar approach has been taken by Jog et al., who used the oxidation of a thiol side chain of an N-arylindolinone to increase the barrier to rotation around the N-aryl bond [58]. Control over the rate of rotation around an aryl–aryl single bond can be achieved by increasing and decreasing the steric hindrance to rotation through a switchable second component. For example, a bi-component system, comprising an optical switch and a biaryl propeller, in which the rotation around an aryl–aryl single bond could be controlled by light, which induced a change in steric hindrance is shown in Figure 17.14. In this system, the naphthyl unit can be brought into or out of proximity with the rotor group [42]. The rate of rotation around the aryl–aryl single bond (indicated by a double arrow) was expected to be different for the two geometrical isomers (cis and trans) of the molecular switch 26. Somewhat counterintuitively, the rate of rotation was found to be faster in the cis isomer (with a barrier to rotation of 79.4 kJ mol−1) than in the trans isomer (with a barrier to rotation of 82.3 kJ mol−1). Apparently, the naphthalene unit is flexible enough to bend away from the phenyl rotor, while the methyl group on the other side of the upper half is held in position, more rigidly presenting a significant steric barrier, as seen in (M)-trans-26. A similar principle was used in the “molecular gearbox” shown in

S

S

(a) H H

hn

S

S (M)-trans- 26

(P)-cis- 26 S

(b) Me

S (2′R)-(M)-trans- 27 Figure 17.14 (a) Variation of the kinetic

barrier to rotation around an aryl–aryl bond by isomerization of the double bond in overcrowded alkene 26; (b) Molecular

gearbox 27, in which the barrier for rotation of the o-xylyl rotor is different in each of the four possible diastereoisomers.

255

256


Figure 17.14b, in which a unidirectional molecular motor unit 27 effects the rotary speed of an attached biaryl rotor (vide infra). 17.3.5 Electrically Driven Rotors and Machines

In the preceding examples of molecular rotors, although the potential of systems based on rotation about molecular axes is apparent, the systems are driven by ambient thermal energy and, as such, are chaotic both in rate and in directionality. A conceptually simple approach to control rotor systems can be achieved through the use of electrochemical stimuli to drive motion. The recent investigations of Hawthorne et al. showed that a change in redox state is sufficient to drive a molecular rotor 28 [25]. In this system (Figure 17.15), the preferred conformation of a nickel bis-carborane complex is cisoid in the Ni(IV) oxidation state, but transoid in both the Ni(III) redox state and in the photoexcited state of the Ni(IV) complex. This opens the possibility of both electro- and photo-chemically driven rotary motion. Although, the initial and final states in such a system (cisoid/transoid) are well defined, the actual rotary motion induced in switching between the states is directionally random. An approach proposed to remedy this, is to introduce asymmetry, and possibly to use chirality, via the R1 and R4 groups, and to immobilize the rotor system on a surface. An alternative approach proposed by Launey and coworkers makes use of a ruthenium-based rotor system (vide supra) decorated by ferrocene units as electroactive groups (EGs) to develop a true rotary-based machine [20, 59]. In this proposed system (Figure 17.16), the ferrocene-decorated rotor is placed in a nanojunction between two electrodes that are biased so as to oxidize and reduce the ferrocene units. The electrostatic repulsion between the ferrocenium ion and the positive electrode would then drive the rotation around the central ruthenium axis.

0

–1

R2 Ni(IV)

R

1

e–

R3 R4

–e–

Ni(IV)

R1 R2

Ni(III)

Ni(III) R3 R4

28 Figure 17.15 Carborane nickel complex 28 as an electrochemically driven molecular rotor (white circles = carbon atoms; gray circles = boron atoms, R1–R4 = H. Adapted from Ref. [57].

17.3 Synthetic Molecular Rotors eStep 1: Oxidation of the electroactive group (ferrocene) closest to the anode.

+

EG

EG

-

Anode

Cathode EG EG

B H

EG

Step 2: The oxidized form is pushed back by electrostatic repulsion towards the cathode. A rotation of one fifth of a turn occurs.

+

EG

+ EG

-

Anode

Cathode EG EG EG

eStep 4: A new rotation of one fifth of a ture occurs after the electrostatic repulsion of the ferricinium cation.

+

+ EG

EG

-

Anode

Cathode EG EG EG

Figure 17.16 Schematic representation of a

molecule placed between the two electrodes of a nanojunction (EG = electroactive group, e.g., a ferrocene unit). The transfer of electrons from the cathode to the anode through successive oxidation and reduction

Step 3: The ferricinium ion closest to the cathode is reduced, while a new ferricinium ion is generated at the anode.

eEG

+

EG

+

Anode

Cathode

EG

EG EG

processes is expected to result in the clockwise rotation of the entire upper part of the molecule. This figure represents one-fifth of a turn, corresponding to the movement induced by the transfer of one electron. Reproduced from Ref. [58]; ACS 2003.

Although conceptually very elegant, such a system would be unlikely to work in practice for such a small system, due to the high rates of heterogeneous electron transfer typical of ferrocene units over relatively large distances, and the weakening of electrostatic interactions by effective charge compensation of the ferrocenium ion by the electrolytes present in a working system. Nevertheless, such a conceptual machine points towards intriguing possibilities of redox-driven rotary machines. Redox processes also offer an attractive alternative to light-controlled nanomechanical valves [2], due to the possibility of their integration into nanoelectronic devices. A quite simple, yet elegant, example of such a molecular valve is based on cyclophanes (large molecular rings), where oxidation can be used to open a cavity and reduction to close it [60]. Although the channel itself is very small when compared with the protein-based systems described below, this system does hold potential for the development of fully synthetic molecular valves. Another approach to changing molecular structure is to use changes in coordination modes to driven changes in supramolecular structures. Lehn and coworkers have shown that a contraction and expansion between a linear to a helix structure, with a concomitant fivefold decrease (increase) in length, can be achieved by metal binding in 29 (Figure 17.17a) [61]. The redox-driven translocation of metal ions between different ligand binding sites has been demonstrated in a number of systems (Figure 17.17b). In an elegant approach, Shanzer used multidentate ligand 30 to achieve the reversible movement of iron based on redox cycling between the Fe2+ and Fe3+ states with a concomitant change in ligand binding [62]. This principle is frequently employed in interlocked mechanical systems – that is, metallorotaxanes and catenanes [4].

257

258

17 Synthetic Molecular Machines Based on Non-Interlocked Systems 10 CF3SO3H 10 CF3SO3–

N

N

10 HNEt3 10 NEt3

R

R

R

R

10+

N

N N PbII N

N

N PbII N

N

N PbII N

N N PbII N

N

N PbII N

O

–e , –3H

FeIII O

N

O O

N

N

N O NH O HN O NH +e–, +3H+ O O O – +

30 R

N N N II N Fe N

N

N

NH

NH N

HN

O

O

NH

O HN

O

HN

OO O N HO N N HO OH O

O

NH

NH

O

HN

N

Figure 17.17 (a) Ion- (29) and (b) redox- (30) driven systems. Adapted from Ref. [61];

© NAS USA 2002; and Ref. [62].

17.3.6 Molecular Rotation on Surfaces

The rotor systems described above demonstrate the concept of a molecular rotor. However, as in any system, their application requires that the rotor is interfaced with the macroscopic world, and the functioning of molecular motors and machines on surfaces represents one of the most challenging aspects of this field. Besides the interface between the nano- and macro- worlds, and the restriction of Brownian motion, there are several key issues that range from relative to absolute directionality in motion, addressing the motor or machine, exploiting surface texture, concentration gradients, adhesion and friction and control of functions in a solid environment or at the solid–liquid interface. Many of these issues deal with a balancing of the molecular interactions. Closely associated issues include the challenge of organizing molecular motors or machines, without losing their dynamic functions, as well as movement along defined trajectories. A relatively simple approach is to immobilize a rotor on a surface, and Michl, Tour and others have taken this approach when designing and immobilizing rotors, both azimuthally (where the axis of rotation is normal to the surface) and altitudinally (where the axis of rotation is parallel to the surface). The surface-bound azimuthal rotor of Tour and coworkers is designed to be attached to the surface via a rigid tripod – a sort of molecular wind vane 31 (Figure 17.18) [63]. The tripod should bind to the gold surface via thiol anchors, and the rotor unit is asymmetrically functionalized with a donor (Me2N-) and an acceptor (NO2) group. This provides a permanent dipole moment which, potentially, can be manipulated by an electric field. Although, the design and synthesis of this system were first reported some years ago, its actual immobilization and characterization on a surface has yet to be reported 31. An altitudinal rotor system reported by Michl and coworkers that has made it to surface is shown in Figure 17.19 [24, 64]. In this case, the approach taken in the previous system, to introduce a strong dipole moment in the rotor unit, is taken here also. As with the azimuthal rotor 32, the altitudinal rotor of Michl and coworkers was anticipated to be controllable by application of an electric field. The system assembled on a gold surfaces was characterized using ultra-high-vacuum


N

Me2N

NO2

31 Si

S

S S

Figure 17.18 Design for a surface-bound azimuthal rotor 31.

F Ph

S

S

F F

F

Ph

Ph

Ph Co Hg Hg S S Hg Hg Hg S S S

S

S

S

S

S

32 Ph

Ph Co Hg Hg S S Hg Hg Hg S S S

S

S

S

Figure 17.19 Surface-bound altitudinal dipolar rotor 32.

scanning tunneling microscopy (UHV-STM), in particular to ascertain if the application of an electric field (via the STM tip) could influence the rotor unit. Indeed, the application of an electric field resulted – for a fraction of the molecules examined – in a change in molecular orientation. However, in the case of rotors that did not possess a dipole moment, no effect was observed. It should be noted that 32 can exist as three diastereomeric pairs of enantiomers with a helical conformation. Molecular dynamics calculations predicted that, for one of the three diastereoisomers, the response to the alternating electric field would be blocked. The calculations also showed that, in the other two conformations, the response would be a rotation of the rotor in a unidirectional fashion.

259

260


However, this held true only at a very low temperature, since at higher temperatures any random thermal interconversion between the stereoisomers would overwhelm the unidirectional rotation event. In an alternate approach to the covalent binding of rotors to a surface, the physisorption of flat molecules (e.g., HB-DC 33; Figure 17.20) in which rotation can be controlled and characterized by using STM has been reported. For example, individual molecules, consisting of a flat decacyclene core decorated with six bulky tert-butyl groups, were “trapped” in a self-assembled monolayer (SAM) matrix. However, by using an STM tip these molecules could be positioned in a void within the lattice, and fast rotation induced (Figure 17.20) [65]. The fast rotation of surface-adsorbed zinc porphyrins has been demonstrated in systems where the surface/molecule interaction has been weakened by the addition of a ligand, which inserts itself between the zinc and the surface [66]. Zinc porphyrin 34 (Figure 17.21) was functionalized with sterically demanding groups that decouple the molecular π-electron system from the surface, providing a relatively weak molecule–surface interaction. The four individual substituents were still apparent as a four-lobed species in the STM images (Figure 17.21). The addition of 4-methoxypyridine, a bifunctional ligand that is known to interact with the zinc atom via the pyridine and with the silver surface through the O→Ag interaction, resulted in a substantial change in the shape of the porphyrins in the STM images. The objects now appeared toroidal, indicating that the rotation of the porphyrins with respect to the surface was fast. Recently, the rotary movement, using an STM tip, of a single propeller-shaped hexa-arylbenzene along the boundary of a SAM domain composed of these molecules was reported [67]. The six aryl substituents in the molecule comprised five phenyl groups and one pyrimidine, which acted as a STM-detectable “tag” to enable a determination of the orientation of the molecule. The molecule that acts as a six-toothed cogwheel can be translated parallel to the SAM domain boundary when pinned under the STM tip (Figure 17.22). It was proposed that interdigitation of the aryl substituents of the moving molecule with the aryl groups at the t-Bu

t-Bu

(a)

t-Bu

(b)

t-Bu

t-Bu

t-Bu

33 Figure 17.20 Hexa-tert-butyl decacyclene (HB-DC) 33 and STM images of a monolayer of HB-DC on a Cu(100) surface. (a) The molecule indicated with a black circle, in registry with the 2-D crystal, is imaged as a

six-lobed structure; (b) After the molecule is translated to a void in the 2-D crystal lattice, it is imaged as a torus. Adapted from Ref. [65]; © Science, 1998.


(a)

(b)

R

N

N R

Zn

R N

(c)

0 5 10 15 20 25 30 35 Apparent width / Å

0 5 10 15 20 25 30 35 Apparent width / Å

N

R R = 1,3-di-tert-butylphenyl 34 Figure 17.21 (a) Zinc porphyrin 34, and STM images, line profiles and structural diagrams for

(b) zinc porphyrin 34 on Ag(100) and (c) after addition of 4-methoxypyridine, which inserts between the zinc porphyrin and the surface, inducing fast rotation of 34. Adapted from Ref. [66]; © John Wiley & Sons, Inc., 2007.

(b) (a)

(c)

Figure 17.22 (a) Illustration of a macro-

scopic rack-and-pinion; (b) STM image of the border of a SAM domain of the hexaarylbenzene and a single molecule adsorbed on its side acting as the rack and the pinion, respectively; (c) Schematic representation of the molecular rack-and-pinion device: one of

the six aryl substituents is a pyrimidine tag (white dot), which allows the orientation of the molecule to be monitored, while the white arrow indicates the direction of the translation of the molecule induced by the STM tip. Adapted from Ref. [67]; © Nature, 2007.

edge of the domain would cause the translated molecule to rotate with respect to the direction of the monolayer. Recently, the translational motion of large, surface-adsorbed molecules bearing functionalities that have been proposed to operate as molecular wheels, has captured the imagination of several groups. In the macroscopic world, the friction between wheels and the surface of a road is essential to allow a vehicle to move forward through rolling. This is advantageous over translation through sliding, when there is a low coefficient of dynamic friction between the surface and the

261

262


object (e.g., a snowboard on snow). At the molecular level, the forces involved in surface–object interactions and the concept of translation is much less clear. Indeed, a crucial question that arises is whether translational movement occurs via a desorption/adsorption process, or via a direct horizontal translation. In the case of the latter mechanism, at the molecular level the translation would be expected to be quantized, but the consequence of such quantization on the movement of nanoscale objects remains an open question. An example was reported recently in which the rotary motion of surface-adsorbed molecular wheels was proposed to result in directing the translational movement of a large molecule over a surface. The attachment of four fullerenes to a central flat scaffold, 35, resulted in a system where directionality of the translational motion over the surface was proposed to be provided by a rolling of the fullerenes (Figure 17.23) [68]. At room temperature, these molecular structures – dubbed “nanocars” – would lie stationary on the surface due to the strong charge transfer interaction between the fullerenes and the gold surface. However, at 200 °C the molecules would move in a direction perpendicular to their axis. Movement of the molecules could also be achieved by manipulation with the STM tip, and again only motion in the direction perpendicular to the axles was facile. In the case of a system where three instead of four fullerenes were attached to a central scaffold, a pivoting motion rather than a translation over the surface was observed. Both of these observations suggested that, as for the macroscopic world, the translational motion of the system over a surface would be guided by a rotation of the fullerenes acting as wheels. A caveat to such a conclusion however should be made. An essentially flat molecule, an anthraquinone, was shown recently to diffuse in a straight line across a flat surface [69], and even be capable of the binding and transport of a molecule of CO2 as cargo. This suggested that a controlled and directed movement over a surface at the molecular level would not necessarily require mediation by nanoscale wheels (Figure 17.24). It is important to note, however, that with all of the surface-adsorbed systems discussed here, the rotation takes place only under UHV conditions. Indeed, this

(a)

C12H25

C12H25

H

(b)

H N

N

N

N

H

H

C12H25

C12H25

35 Figure 17.23 (a) Nano-car 35 containing four fullerene wheels; (b) A space-filling model of 35 on a surface. The arrows indicate the direction of the STM-imaged fullerene-assisted rolling motion. Adapted from Ref. [68b]; © ACS, 2006.

17.4 Synthetic Molecular Motors and Machines (a)

(b)

1

Ib

2

C

3

II O

H

Ia

4

Cu

Figure 17.24 Transport of CO2 across a surface by an anthraquinone. (a) STM images; (b)

Schematic diagram. Adapted from Ref. [69]; © Science, 2007.

appears to be necessary in order to ensure that the interactions between the molecules and the surface remain sufficiently strong. It is, therefore, highly unlikely that such systems could ever operate at the solid–liquid interface, where there would be a constant equilibrium between the molecules being dissolved in the solvent or adsorbed on the surface. In other words, the hopping mechanism for translational movement, presumably, would dominate. Hence, it may be envisaged that the molecules would first need to be attached to the surface before they could be used at the solid–liquid interface. The attachment may not need to be covalent, however, but could also take advantage of balanced and specific intermolecular interactions, as demonstrated so elegantly by myosin motors walking on actin filaments in muscle cells.

17.4 Synthetic Molecular Motors and Machines

It is difficult to imagine what Galileo, van Leeuwenhoek and those many other pioneers of modern sciences would have made of the complexity of the machinery of life contained within the cells that they examined with the earliest of optical microscopes. Certainly, they would have been oblivious to the role of a simple inorganic phosphorus–oxygen bond being at the heart of the fuel which makes life happen. The deceptive ease with which Nature uses chemical energy to drive the molecular motors and machines of the living cell, continues to set synthetic chemists a major challenge in matching these systems in terms of design, speed, efficiency, and function. In the rapidly expanding field of nanotechnology, it is tempting to simply use the motors provided by Nature to perform tasks within a nanotechnological setting [70]. A key disadvantage of their application ex vivo arises from their complexity and inherent instability outside of their natural environment. Therefore, artificial nanoscale devices that mimic these biological systems, but which are simpler in design and able to tolerate a broader range of operating conditions, would be highly desirable. Having said this of course, it should not be forgotten that Nature’s molecular machines – its enzyme factories – are employed extensively in industry and society, from industrial processes to biologic washing powders to the production of lactose-free milk! For the free rotors described above, a control over the speed of the thermal rotary motion could be exerted through the use of metal ion binding, structural factors,

263

264


and the incorporation of switching units. Yet, making the step from the rotor systems described above to true molecular motors would require incorporating an ability to convert one form of energy into directed motion. The ability to control the rate at which such processes take place would be equally important. In the case of rotary motors, the conversion of energy – chemical or otherwise – to a unidirectional continuous rotary motion should be considered as being fundamentally different to the movement of macroscopic rotary motors. The movement of molecular motors, and indeed of all molecules, is quantized and relies on the oscillatory vibrational movement which, by default, means the movement is not continuous but rather stuttered. Even for the biotic rotary motor, F1-ATPase rotation in the wrong direction (by as much as 120°) is a frequent occurrence during its “unidirectional” operation [71]. Less-kinetically favored pathways to a thermodynamic minimum are occasionally taken, and background thermal energy will also cause the molecular components to move, even when no stimuli are applied, the direction of this non-biased Brownian motion being random. For this reason, the term “biased rotary motion” perhaps would be more appropriate. Over recent years, a number of systems have been developed that meet the basic requirements of most definitions of a molecular motor. These systems are either driven by chemical energy, similar to the numerous biological systems driven by ATP, by light, or by a combination of these energy sources. 17.4.1 Biased Brownian Motion

The conversion of energy from an external source in an attempt to achieve unidirectionality in molecular motion has been illustrated elegantly by Kelly with rotor 36 (Figure 17.25b). This system, at first sight, should be able to convert random thermal Brownian motion into unidirectional rotation, based on its resemblance to a macroscopic ratchet-and-pawl system. The chiral helical structure of 36 (which perhaps is most apparent in the space-filling model shown in Figure 17.25c) is reminiscent of a macroscopic ratchet-and-pawl (Figure 17.25a) and, intuitively, tells us that rotation within this molecule should take place in an analogous fashion [72]. ∆H‡

Me (a)

(b)

(c)

36 Figure 17.25 (a) Schematic illustration of a macroscopic ratchet and pawl; (b) Attempted design of a molecular ratchet and pawl (36); (c) Space-filling model showing the helical twist of the helicene imparting chirality to the

(d)

∆H

0

40

80 q/°

120

system; (d) Schematic representation of the calculated enthalpy changes for rotation in 36. Adapted from Ref. [72]; © John Wiley & Sons, Inc., 1997.


The rotor is composed of a triptycene and a benzophenanthrene unit connected covalently; the helicene half of the molecule plays the role of the pawl in attempting to direct the rotation of the trypticene. The enthalpy changes calculated for rotation showed an asymmetric potential energy profile (Figure 17.25d). However, back in 1963, Feynman had already shown that such a molecular ratchet system could not work, as it would violate the second law of thermodynamics [73]. NMR experiments indeed confirmed Feynman’s assertion that rotation in 36 takes place in both directions, with equal frequency. The rate of molecular transformation was seen to depend on the energy of the corresponding transition state, which was identical for rotation in both directions. Any imbalance in this system at equilibrium, caused by a higher rate of rotation in one of the two directions, would have violated the second law of thermodynamics [74, 75]. Thus, a crucial requirement for unidirectional rotary motion is the input of energy to drive the system from equilibrium [76]. 17.4.2 Chemically Driven Molecular Motors

The first fully synthetic chemically driven molecular rotary motor, albeit capable of only a 120° rotation (Figure 17.26), as reported by Kelly and coworkers, was based on rotor 36 (vide supra) [77]. The steric interactions between the stator and rotor units of 37 prevent free rotation around the axis, the triptycene–aryl bond. However, by introducing amino and alcohol functionalities in the two units,

NCO

NH2 O Cl

slight rotation

Cl

O

O

O

HO

HO

HO

high-energy conformation urethane formation

irreversible rotation over Eact

NaBH (OEt)3

O

NCO

NH2 (hydrolysis urethane)

HO

NH O

O

NH O

O

O

O high-energy conformation

Figure 17.26 Chemical-driven molecular motor 37, capable of a controlled unidirectional 120°

rotation around its central axis.

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266


respectively, a controlled 120° rotation could be achieved using a high-energy fuel source (phosgene), in much the same manner that Nature uses ATP to drive biological molecular motors. The addition of phosgene and triethylamine first converts the amine functionality connected to the triptycene unit to an isocyanate. After a slight rotation of the triptycene with respect to the helicene to a higher-energy rotamer, this isocyanate reacts with a hydroxypropyl tether on the helicene to form a urethane linkage. The undesirable strained conformation in which the molecule is “caught” after formation of the urethane linkage is responsible for the subsequent unidirectional rotation step, in which the helicene unit slips past the part of the triptycene to which it is connected, to result in a more stable conformation. In the final step, the urethane bond is hydrolyzed, to produce the rotamer of the original atropisomer. This relatively simple system represents a proof of principle for the possibility to obtain unidirectional rotation, albeit only over 120°. Despite considerable effort, 360° unidirectional rotation has not yet been achieved with this particular approach [78]. An alternative approach to a chemically driven molecular motor 38 was reported recently by Dahl and Branchaud, based on a biaryl system (Figure 17.27) [79]. Again however, the undirectionality of rotation in a repetitive full rotary cycle is a key issue that needs to be addressed. Indeed, in the present authors’ system (the details of which were reported virtually simultaneously), this problem was overcome to provide the first example of a

1) diastereoselective ring-opening O

+90°

OH

Nu

HO2C

+180° 2) chemoselective lactonization

(M,S)-38b

O

O OMe

O

O

HO2C

NuO2C

O

(S)-38a

OMe

Nu

HO2C

–90°

OH

(S)-38c

OMe

–180° (P,S)-38b OMe

3) chemoselective hydrolysis A prototype chemically driven molecular motor 38, based on the concept of hindered rotation around a bifunctional biaryl lactone.

Figure 17.27


synthetic molecular motor that was fueled by a sequence of chemical conversions and capable of performing a full 360° rotation, in repetitive fashion [80]. The sense of rotary motion is governed by the choice of chemical reagents that control the rotor movement through four distinct stations. The use of a chiral reagent, (S)-2methyl-CBS-oxazaborolidine and BH3.THF [81], to accomplish an enantioselective reduction of the lactone (steps 1 and 3), which discriminates between the two dynamically equilibrating helical forms of 39a and 39c, results in a stereoselective ring opening of the lactone towards one atropisomer [78]. Due to the steric barriers involved, free rotation around the central bond connecting the two halves of the molecule in the chiral biaryl system in 33b and 33d does not occur. Employing the principle of orthogonal chemical reactivity, a series of protection/deprotection steps ensures the selective ring closure of the lactone (steps 2 and 4) by which unidirectionality is achieved (Figure 17.28). Although 39 demonstrates the principle of repetitive unidirectional rotation driven by chemical fuel through a full 360° rotary cycle, the requirement of a sequence of incompatible chemical reagents reduces the usefulness of this system in practice. The design of a system which would be capable of continuous rotation upon the addition of one specific chemical fuel, preferentially based on catalytic steps, would represent a major leap forward. Although not a rotary motor, a similar approach has been taken recently in the use of dihydrogen peroxide as a chemical fuel to drive the autonomous movement of microparticles. Although, the majority of systems reported to date are based on metallic units [82], which decompose H2O2 to dioxygen and water, a synthetic molecular-based catalytic system has proven to be very versatile, both in terms of the range of surfaces on which it can be immobilized, and its efficiency and stability [83].

Hb

Ha

Hb

Top-down view

Ha

step 1 PMBO

O

A PMBO

O

39a (station a)

AllylO

B 1)

39b (station b)

step 4 Ha

OAllyl CO2H

2)

step 2 Ha

Hb OPMB CO2H

AllylO

Hb OPMB

step 3

39d (station d)

4)

O

39c (station c)

3) D

C

Figure 17.28 (a) Chemical structures and reaction scheme corresponding to the unidirec-

tional rotary cycle of chemically driven rotary motor 39; (b) Schematic representation of the rotary process.

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17.4.3 Light-Driven Molecular Machines Based on Azobenzenes

Although better known as a “photochromic switch,” the relatively large structural change which azobenzene undergoes upon cis-trans interconversion has made it a unit of choice in many designs for synthetic molecular mechanical devices. The first example of the use of what is essential a two-state switch as a power-strokedelivering component in a true synthetic device was reported by Shinkai and coworkers (Figure 17.1b) [16]. In this system, the azobenzene unit separated and brought together, reversibly, two crown ether components to take up and release potassium ions, selectively. Subsequently, the utility of azobenzenes has been demonstrated in many systems, and a few examples are described in the following subsection. Aida and coworkers have combined two components discussed above into a single device, the first example of which is the “molecular scissors” 40 (Figure 17.29). This consists of an azobenzene moiety (which acts as the power unit), a ferrocene unit (a molecular rotor to act as the pivot point), and two phenyl groups (the blades) [84]. The conformational changes induced by cis-trans isomerization of the azobenzene switch, through alternating irradiation with ultraviolet (UV) and visible light, are translated into a rotational movement around the metal center of the ferrocene rotor unit. Notably, the molecular scissors is intrinsically chiral, and in each enantiomer the rotary movement induced is, in principle, unidirectional. Recently, it was shown that the photochemical response upon irradiation with UV light is altered after oxidation of the ferrocene unit, and reversible rotary motion induced by a combination of redox and UV light was demonstrated [85]. This concept has been extended to increase functionality and to amplify the effect of the cis-trans isomerization of the azobenzene by covalent attachment of two zinc porphyrins to the phenyl blades in 41 [86]. The zinc porphyrins can each bind to a one of the nitrogen atoms of 4,4′-bisisoquinoline 42 (Figure 17.28). Subsequent cis-trans isomerization of the azobenzene unit induces changes in the orientation of the two porphyrins, via rotation of the ferrocene pivot. These lightinduced conformational changes in the host–guest complex 42.41 in turn leads to a mechanical twisting of the coordinated 4,4′-bisisoquinoline guest rotor molecule in one particular direction. The motion of several units coupled in a multicompo-

FeII

350 nm

N N

trans-40 Figure 17.29

Molecular scissors 40.

N

FeII

N

>400 nm

cis-40


Ar

N

Zn

N

Ar Ar

FeII

N

42

N

350 nm N

N Zn N

cis-41

N

N

N

N

Ar N N Zn N N Ar

trans-41

N

>420 nm

42 Ar

N

FeII

N N Zn N N Ar

N

N N

Ar

42-trans-41

42-cis-41

Figure 17.30 Conformational changes of two porphyrin moieties in a host–guest complex

induced by the light-induced scissoring motion in 41 lead to a mechanical twisting of the guest rotor molecule 42.

nent system, together with the stepwise transmission of motion which, again, is unidirectional due to the chirality of the system, enables this system to operate in a machine-like fashion (Figure 17.30). The changes in size, which accompany the cis-trans isomerization of azobenzenes (a change in distance between the para positions of the arene termini of 0.35 nm), when incorporated along the backbone of a polymer chain, can be used to change the modulus of elasticity of the polymer chain itself, as demonstrated by Gaub and coworkers (Figure 17.14) [87]. The forces associated with the contraction and expansion of the polymer chain upon alternating UV and visible irradiation, and the light-induced work against an atomic force microscope tip were measured using scanning probe techniques (Figure 17.31). 17.4.4 Light-Driven Molecular Rotary Motors

Changes in molecular configuration upon the cis-trans isomerizations of double bonds, especially the photochemically induced isomerization of stilbenes [88] and azobenzenes [89], have been the focus of many studies over the past few decades. In these systems, a double-bond isomerization is induced by an external stimulus that constitutes a 180° rotation of the molecule, albeit with no control over directionality. This is not necessarily always the case, however. For the chiroptical switches based on sterically overcrowded alkenes [90] (e.g., 43), the strong steric interactions between the two halves of these molecules precludes slippage of the naphthalene group in the upper-half past the lower part of the molecule, and this results in a folded structure of a particular helicity (Figure 17.32). Furthermore, the helicity of the molecules dictates the directionality of the photochemically induced cis-trans isomerization of the central alkene bond, as the naphthalene is forced to remain at one specific side of the lower part (Figure 17.32). This results in a controlled and unidirectional rotary movement, over approximately 120°.

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270

17 Synthetic Molecular Machines Based on Non-Interlocked Systems (a)

O NH

AFM tip

H2 N

Au

S

O HN

O

N N

HN 4 O

HN NH

O

(b)

Force

O

N

O Si O O

Glass slide

(c) Afm Cantilever Azobenzene polymer

Extension

Flint glass

Excitation in TIR Figure 17.31 Reversible contracting a photochromic polymer. (a) Attached to an AFM tip; (b) Attached to a surface; (c) Irradiation with UV or visible light results in a contraction or relaxation of the polymer. Adapted from Ref. [87]; © Science, 2002.

Figure 17.32 Unidirectional rotation over approximately 120° involved with a photochemically induced cis-trans isomerization of a chiroptical switch based on a sterically overcrowded alkene.

Achieving full and continuous unidirectional rotation requires the incorporation of a further chiral element. Over the past decade, the photochemical and thermal isomerization processes observed for biphenanthrylidenes [91] has been examined intensively, and this has led to the development of the first synthetic rotary molecular motor, capable of controlled and repetitive unidirectional rotary motion around a carbon–carbon bond [92]. The sterically overcrowded alkene (3R,3′R)-(P,P)-trans1,1′,2,2′,3,3′,4,4′-octahydro-3,3′-dimethyl-4,4′-biphenanthrylidene 44 can perform a full 360° rotation of one half of the molecule relative to the other half, in a unidirectional fashion, upon irradiation with light. The important features of this molecule, which are the control elements governing the unidirectional rotation, are: (i) the intrinsic helicity of the overcrowded alkene; (ii) the central carbon–


Meax

step 1

Meeq

l > 280 nm 5 : 95

Meax

stable (3R,3′R)-(P,P)-trans 44

step 4

Meeq

unstable (3R,3′R)-(P,P)-cis 44

thermal helix inversion 60°C


Meeq

step 2

Meax l > 280 nm

Meeq

90 : 10

Meax

step 3 unstable (3R,3′R)-(P,P)-trans 44

stable (3R,3′R)-(P,P)-cis 44

Figure 17.33 Photochemical and thermal isomerizations involved with the unidirectional

rotary cycle of light-driven molecular motor 44.

carbon double bond connecting the two identical halves of the motor, acting as the axis of rotation; and (iii) the two stereogenic centers bearing methyl substituents that dictate the direction of rotation. For the stable isomers, these methyl groups adopt a pseudo-axial conformation to minimize steric interaction with the other half of the molecule. The rotary cycle of 44 can be considered as an alternating sequence of four steps, including two photochemically and two thermally driven steps (Figure 17.33). Irradiation of the stable form (3R,3′R)-(P,P)-trans-44 with UV light (λ >280 nm) initiates a photochemical trans→cis isomerization around the central double bond (Figure 17.33, step 1). This isomerization results in an inversion of the molecule’s helicity (P,P→M,M). A key factor leading to the unidirectionality of the rotation process is the fact that in the unstable (3R,3′R)-(M,M)-cis-44 formed, the methyl substituents are forced to adopt a strained pseudo-equatorial orientation. In this conformation, the methyl groups experience steric crowding, with the naphthalene rings flanking the opposite side of the double bond. As a result, this photochemically induced isomer is thermally unstable and a helix-inversion step occurs spontaneously at room temperature, releasing the strain in the molecule (step 2). In

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this step, the methyl groups and naphthalene moieties of the upper and lowerhalves pass each other, and the methyl groups regain their energetically more favorable pseudo-axial conformation, thus generating stable (3R,3′R)-(P,P)-cis-44. The large difference in free energy between the isomers is responsible for the unidirectionality of this process by ensuring complete, irreversible conversion of the unstable form to the stable form. Subsequent irradiation (λ > 280 nm) of the stable (3R,3′R)-(P,P)-cis-44 initiates a cis→trans isomerization, inverting the molecule’s helicity to generate unstable (3R,3′R)-(M,M)-trans-44, in which the stereogenic methyl groups again adopt a highly strained pseudo-equatorial conformation (Figure 17.33, step 3). This strained molecule requires gentle heating (60 °C) to facilitate the last step of the rotary cycle, where another helix inversion releases the conformational strain and regenerates stable (3R,3′R)-(P,P)-trans-44 with axially oriented methyl substituents (step 4). In these systems, the direction of circumrotation is determined by the absolute stereochemistry of the molecule, the enantiomer with an S configuration at both stereogenic centers rotates in the opposite direction. The repetitious nature of its rotary behavior, which occurs upon the input of light energy, provides this lightdriven molecular motor with a considerable advantage over other rotary motor systems. The conversion from stable to unstable form by the absorption of a photon of light takes place on the picosecond timescale; however, the rate-limiting step in the sequence is the relaxation of the unstable to stable forms, which limits the maximum rotation rate achievable for 44. Indeed, at room temperature the high energy barrier to relaxation of the unstable trans-44 to the stable isomer (step 4 in Figure 17.33) results in an average rotational rate on the per week scale. Increasing the rotary speed of this type of light-driven molecular motor requires modifications to the basic molecular design. 17.4.5 Second-Generation Light-Driven Molecular Motors

Merging of the molecular structure of the symmetrical biphenanthrylidene-based molecular motors (i.e., 44) with that of the chiroptical molecular switches developed earlier [93, 94], resulted in the development of so-called “second-generation” light-powered rotary motors. These consist of distinct upper and lower halves, which can be considered as the rotor and stator components of the motor [95]. Whereas, the upper half is structurally similar to that of the first-generation motors, the lower half is now derived from a symmetric tricyclic unit (Figure 17.34). The rotary cycle of these systems is essentially similar to that of the firstgeneration type motors (e.g., 44), with the exception that the direction of rotation is controlled by a single stereogenic center (Figure 17.35). This change offers several practical advantages in terms of synthesis, including the possibility to introduce functional groups selectively into the upper or lower half. As the energy barrier to both thermal helix inversions (which are the rate-limiting steps in the

17.4 Synthetic Molecular Motors and Machines X rotor

axle

stator Y Figure 17.34 General structure for second-generation light-driven molecular rotary motors.

S

S

step 1

Meax

Meeq

l = 365 nm MeO

MeO 14 : 86 S stable (2′R)-(M)-trans- 45

S unstable (2′R)-(P)-cis 45


step 4


S

step 2

S l = 365 nm

Meeq MeO

89 : 11 S

unstable (2′R)-(P)-trans 45

Meeq MeO

step 3

S stable (2′R)-(M)-cis 45

Figure 17.35 Rotary cycle of second-generation molecular motor 45.

rotary cycle) are almost equal, the rate of rotation of these systems becomes easier to tune via structural modifications. Approaches to control the rotary speed include the tuning of electronic and steric parameters in both first- and second-generation motors. In this way, unidirectional rotary motors, in which the rotary speed can be enhanced several million fold, were obtained. Light-driven rotary motors that rotate at speeds comparable with the speed of natural ATPase (135 revelations per second) are now at hand [96].

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The concept of interlocking molecular components in a geared system (Figure 17.14) was revisited recently using a second-generation light-driven motor as the switching unit [97]. The rate of rotation around the arene–arene single bond was measured for the individual diastereoisomers of the motor transstable (shown in Figure 17.35), cisunstable, cisstable, and transunstable. As was the case for the switchable molecule 26, the barrier to rotation around the arene–arene bond was higher for the cis isomer than for the trans isomer. Furthermore, for both geometric isomers the barrier was found to be higher in the unstable isomer than in the stable isomer. This was due to the increased steric hindrance between the o-xylyl moiety and the upper-half of the motor molecule in the unstable states; for instance, by the methyl substituent adopting a pseudo-equatorial orientation in transunstable. The ability of 27 to be switched between four states, each with a different rate of rotation of the o-xylyl rotor, qualifies this system as a “molecular gearbox.”

17.5 Molecular Machines: Putting Motors to Work

With an extensive molecular toolbox and parts kit in hand, it is now possible to discuss how molecular motors, and the machines that contain them, can be made to perform useful work. In terms of dynamics/movement, switches, rotors, rotary and translation motors in several forms have become available in recent years (vide supra). The fuels that can be used to drive such motion include light and heat, ion gradients, pH and redox changes, and chemical energy. Interfacing molecular components by their attachment to surfaces to control catalysis and recognition [98], interfacial electron transfer [99], biomaterials [100], transport of liquids [101], and mimicking of muscle functions [87, 102] incorporation into nanochannels [103, 104], polymers [105, 106], and as dopants [107] in liquid crystals (LCs) allows for their molecular function to be translated and even amplified or manifested as rotation, translational, and bending [108, 109] on both a molecular and macroscopic level, through coupled motion. The first stage of any molecular motors action is, at a fundamental level, a switching step between two distinct structural states. Figure 17.36 shows the structures of the most frequently encountered molecular switches used to date, together with a collection of functions that have been addressed with these dynamic structures. 17.5.1 Light-Driven Machines

A few examples of how photo-induced switching has been incorporated through functional components in devices will be discussed in the following subsections. A very simple, yet powerful, example of how a photoswitchable unit can be applied as part of a functional device can be seen in the work of Willner and coworkers (Figure 17.37) [110]. In this system, the mechanical changes which accompany the


Figure 17.36 Molecular toolbox to address functions. (a) Structures of common photochro-

mic switches which undergo photo-controlled changes in molecular structure; (b) Functions that can be addressed by incorporating these molecular trigger elements.

+

S

O S

N O

NO2

N

S

+

+

–0.5 –1

+

Cyt. Cred

b

–1.5

a

–2 –0.3 –0.2 –0.1 0 E/V

UV

1.2 0.9 0.6 0.3 0.0

0 1 2 3 45 67 8 cycle number

0.1

0.2

N

S

+

N H N

S

e

+

Vis

Au electrod

–

N

S

c 0

+

N H N

0.5

Cyt. Cred

Icatalythe /µA

S

Au electrod

+

N

I / µA

S

+

+

N+

+

O S

N

S

N

+ Cyt. Cred

NO2 HO

Figure 17.37 Switchable enzyme-based redox system based on a spiropyrans-modified gold electrode which can be switched between a polar and apolar state, by light. Adapted from Ref. [110]; © Elsevier, 1997.

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actual switching event are not used, but rather the change in surface properties; that is, polarity and inhibition or the enhancement of electron transfer between the surface and a redox-active cytochrome enzyme. Although it may be difficult to describe this as a molecular machine, it should be remembered that each component (the switching unit, the tether, the surface and the enzyme) are essential to achieve the function of the device. Another example of how light-driven changes in molecular polarity can be used to drive changes in the operation of a nanodevice is the light-driven opening and closing of a nanovalve [109]. Again, the spiropyran-mercyanine system was used (Figure 17.38). The mechanosenstive channel protein of large conductance (MsCl) serves as a kind of safety (pressure release) valve to certain cells. In response to a build up of osmotic pressure or membrane tension, the tightly closed membrane-embedded protein complex opens a 3 nm pore to allow material to flow out of the cell. Incorporating cysteines to each of the protein units in the pentamer complex provides anchors to introduce light-switchable molecular units at predetermined sites. The photochemical ring-opening of a spiropyran to a merocyanine induces sufficient changes in the protein conformation and hydrophilic nature of the constriction zone to achieve opening of the channel. The externally triggered reversible opening and closing could be demonstrated by using patch–clamp techniques. By incorporating the hybrid photoactive protein channel into the bilayer of a giant vesicle, it was shown that the content of the vesicle could be released upon irradiation. This system holds potential for controlled drug delivery through the use of such switchable nanovalves. A different approach to photochemical valve control involves a biohybrid system in which movement through a channel is controlled allosterically [104b]. A semisynthetic ligand – a gated ion channel that can be turned on and off by UV and visible light irradiation – has been developed using an azobenzene (see Figure 17.1) optical switch. The azobenzene switch is attached both to the protein and the glutamate residue, which is specific for the allosteric site (a signal binding site on the protein, which regulates the operation of a separate remote functional component) that is responsible for closing of the protein channel. The point of attachment is, naturally, critical to its operation, and in contrast to the previous example the switching unit is attached to the outside of the channel rather than to the inside. The trans → cis photo-isomerization of the azobenzene unit results in a large geometric change in the molecule and, as a consequence, glutamate binds to the receptor and the channel opens. In this nanomechanical valve several structural units and functions operate in concert to allow reversible channel gating controlled by light. 17.5.2 Photochemically Driven Mechanical Changes in Crystals and Polymers

Perhaps the simplest of approaches to achieving concerted actions in ensembles of molecules is to incorporate them into polymer materials or in single crystals


Figure 17.38 Light-driven opening and closing of a biohybrid nanovalve.

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[105, 106]. Although there are already many examples of systems where these approaches have been taken, two are discussed here that demonstrate the principle elegantly. Gaub and coworkers [109] have incorporated azobenzene units into polypeptide polymer chains; subsequently, contraction of the polymer chain upon optically induced conversion from the trans to the cis form results in a change in the length (or, more precisely, the elasticity) of the polymer chain, which can be measured by connecting one end of the polymer chain to a surface and the other end to an AFM tip (Figure 17.31). An alternative approach is to make use of differences in the unit cell dimensions of two different molecular states, which interconversion can be induced by light. Irie [105], Uchida, Feringa and coworkers [106] have shown that thin single crystals of photochromic diarylethenes can be made to bend and even “roll up” and uncurl by the application of UV and visible light, respectively. This system works by taking advantage of what is otherwise seen as a problem in the photochromic switching of solid materials. For a solid material, photochromic switching from a colorless to a colored state is limited by inner filter effects which arise from conversion of the top layer of a material [111]. Hence, the irradiation of a thin crystal will cause only the molecules on one side to change shape (i.e., to contract), which induces the crystal to bend (and eventually to roll up). The reverse process – that of ring opening of the diarylethene – leads to a transparent state, so that a complete recovery of the open stretched state can be achieved (Figure 17.39). The transmission of motion from the molecular to the mesoscopic or macromolecular level is extremely relevant within the context of biological motors, and for the development of smart materials. A fascinating example of the transmission of rotary motion of a membrane-bound molecular motor to a polymer is seen in

(a) UV UV

Vis.

(b)

F6 H N H3C

O

F6 H N

CH3 S HC 3

hn ′

S O

H N

hn ′ CH3

Figure 17.39 Bending crystals. (a) UV irradiation of a crystal leads to conversion on one side to a closed ring isomer which has a smaller unit cell. Inner filter effects create a gradient of conversion through the crystal and result in one side being contracted more

H3C

O

H N

CH3 S HC 3

S O

CH3

than the other, causing the crystal to curl up. Irradiation with visible light leads to complete conversion to the open state, such that the crystal unrolls; (b) The diarylethene photochemical switch used in this system.


the bacterial flagella motor, which ultimately converts molecular rotary motion into a translational motion, allowing the bacterium to swim. Recently, a system was reported in which the change in chirality of a wholly synthetic molecular rotary motor during rotation was transmitted to a change in the folding of a helical macromolecule [112]. In this design, a dynamic helical polymer, polyhexylisocyanate, was employed. An optically active amide-substituted trans molecular motor 46 was used as an initiator in the polymerization of isocyanates, which resulted in a polymer which showed random helicity. Photoisomerization of the molecular motor unit to the unstable cis-form resulted in conversion to a M-helical polymer, while subsequent thermal isomerization of the motor to the stable cis-form triggered helix inversion in the macromolecule, to the P-helical polymer. Next, a photochemical isomerization followed by a thermal isomerization reset the whole system. The motor typically functions as a multistage molecular switch, and the motion of the molecular motor is coupled with the motion of the dynamic polymer. The triggering of polymer folding, as well as the transmission of chiral information from a single molecule to a macromolecule, offers exciting opportunities in addressable materials and thin films. However, perhaps the most important feature of this system is that, under conditions of continuous irradiation with light and thermal energy, a steady state is reached but helix inversions still take place; such that the system is continuously driven out of thermodynamic equilibrium (Figure 17.40). 17.5.3 Molecular Motors Operating on Surfaces

Whereas, changes in molecular properties such as charge and polarity can be used to modify interfacial properties in a passive sense, a real challenge rests in using

1) hu 2) ∆ R N O

(M)-cis-46

preferred P helix racemic polymer

∆

R N O (M)-trans-46 R = poly-isocyanate

Figure 17.40 Structure of polymer-modified

second-generation rotary motor 46, and schematic illustration of the reversible induction and inversion of the helicity of a polymer backbone by a single light-driven molecular motor positioned at the terminus. Irradiation of the photochromic unit leads to a preferred helical sense of the polymer

hu

preferred M helix

backbone. A thermal isomerization of the rotor unit inverts the preferred helicity of the polymer chain. Subsequent photochemical and thermal isomerization steps regenerate the original situation with a random helicity of the polymer backbone. Adapted from Ref. [102b]; © John Wiley & Sons, Inc., 2007.

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the actually mechanical non-Brownian movement of molecules to drive macroscopic movement. It has been envisioned that two key issues must be addressed to harness work from these light-driven molecular motors. First, the movement should be sufficiently pronounced to overcome the surrounding Brownian motion; and second, the movement of ensembles of molecules should be concerted or the movement of a single molecule be amplified to translate the effect from the nanoto the micro- and macroscopic world. In many regards, the immobilization of responsive molecules that exhibit motor-like functions onto surfaces and into ordered media is essential to create useful devices. Another issue that needs to be addressed is to gain both positional and orientational order of the molecules. All of the systems discussed above operate in solution, and one approach to overcome the random Brownian motion surrounding the systems would be to bring about order by immobilizing the motors on a surface. As a first step towards these surface-immobilized systems, a secondgeneration light-driven motor was immobilized successfully on a gold nanoparticle, to yield the azimuthal motor 47 (Figure 17.41a) [112]. The use of nanoparticulate surfaces allows for spectroscopic studies to be performed; these are essential to demonstrate the retention of the molecular motor’s unidirectional rotary behavior upon immobilization, in solution, which greatly facilitates the analysis. In this system, the lower half of the motor truly becomes the stator component, as this part is connected to the surface via two thiol-functionalized legs, whereby it is prevented from rotating freely with respect to the surface (the use of only one attachment point would of course still allow uncontrolled free rotation of the entire system with respect to the surface). 1H NMR spectroscopy confirmed that the two photo-induced cis-trans isomerizations of the central double bond, each followed by the thermal helix inversion, induced a full and unidirectional 360° rotation of the propeller with respect to the surface-mounted lower half of the system. A slightly higher barrier to the thermal helix inversions was found for the surfacebound motor compared to the same molecular motor operating freely in solution. This effect was attributed to a reduction in the degrees of freedom due to it being

S

S

(a)

(b)

(c)

rotor axle stator

legs

S O C8H16 S

47 O C8H16 S

O

O HN Si O O

NH

O

48

Si O O

Quartz gold particle

Au

Figure 17.41 Second-generation light-driven rotary molecular motors 47 and 48. (a) Immobilized on a gold nanoparticle via thiol-functionalized tethers; (b) Grafted onto a 3-aminopropyltriethoxysilane-coated quartz plate. Adapted from Ref. [112]; © Nature, 2007.


grafted to a surface. In a subsequent study, instead of studying the rotation with respect to the nanoparticles that still rotate and translate freely through solution due to thermal Brownian motion, the true absolute rotation of the rotor upper-half of the motor relative to a planar surface was studied [113]. The length and nature of the connecting legs were found to be critical factors with the use of a gold surface, which is known to be able to act as an excited-state quencher [114]. Therefore, the distance of the photochromic unit from the gold must be sufficiently large to permit the photochemical steps to be effective. Avoidance of the problems encountered with gold surfaces concerning electronic excited-state quenching suffered by the motor molecule was achieved by grafting motor 48 onto a quartz surface (Figure 17.41c). Furthermore, the study of such a monolayer of motors by spectroscopic methods is much more difficult compared to solution studies, due to the low signal-to-noise ratio involved. Verification that the lower (stator) half of the molecule was grafted to the surface through two points of attachment was proven using X-ray photoelectron spectroscopy (XPS). Correlation of the photochemical and thermal behaviors of the motor in the monolayer to its counterpart in solution, using circular dichroism (CD) spectroscopy, was consistent with the molecular motor’s unidirectional rotary cycle. In a recent attempt by Tour and coworkers to use these light-driven rotary motors to propel a multicomponent molecular device across surfaces, the motors described above were incorporated into the framework of prototype molecular “car” 49 [115]. In this design, four carborane groups that can interact with and roll over a metallic surface, due to their pseudo-spherical three-dimensional structure, acted as “wheels” and were attached covalently to the central motor unit. A unidirectional rotation of the central motor unit was anticipated to drive the molecular car forward over the surface, by paddling. Although the function of the molecular motor unit itself was verified in solution, to demonstrate the functioning lightdriven movement of this system over a surface proved to be a considerable challenge that, as yet, has not been met. A possible difficulty that might be encountered with this light-driven molecular car is quenching of the photochemistry by the metallic surface, similar to that observed with the light-driven molecular motors grafted covalently to gold surfaces (vide supra). It is tempting to speculate that if it were possible to orient the motors linked covalently to the surface in the same direction, then the collectively harnessed actions of this large number of motors, operating in a concert, might generate forces large enough to drive processes on the macroscopic level. This principle of macroscopic motion, induced by collectively harnessed changes in molecular structure, is the fundamental basis of muscular movement. Inspiration for this idea includes several examples where surfaces modified with molecular switches led to the generation of systems that could perform work – in these cases, the movement of large-scale objects. The reversible photochemically induced switching of surface grafted azobenzene [111b] or spiropyran [116] -based molecular switches generated surface energy gradients that were used to translate liquid droplets deposited on top of this modified surface. However, it must be noted that a distinction should be drawn between the “physical” motion of the molecular

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motor/switch and the effect of changes in molecular – and hence surface – properties that arise simply as a function of a change in the state of the system.

17.6 Molecular Motors at Work

The control in a dynamic way of the organization and color of LC materials is a goal in the design of novel display materials. Chiral molecular motors are excellent dopants for a variety of nematic LC phases, resulting in twisted nematic (induced cholesteric) phases. The change in helicity of the motor molecule 49 during the four-step rotary process induces a reorganization of the helical-twisted nematic LC film and, as a consequence, a reversible color change in the material (Figure 17.42). In this way, color pixels covering the entire visible spectrum can be readily achieved. The first demonstration of work performed by light-driven unidirectional rotary molecular motors was described recently. The reversible rotation of a surface texture and a microscale object deposited on top of this surface was generated with a second-generation version of these motors embedded in a LC film [117]. Due to the intrinsic helical shape of the motor, it is very effective in inducing a dynamic helical organization in the LC film. The change in intrinsic helicity of the motor upon photo-isomerization is amplified by the LC matrix. As a result, the irradiation of a LC film doped with molecular motor 49 leads to a clockwise or anticlockwise rotational reorganization, depending on the chirality of the motor molecule, and on its polygonal texture (as observed using polarizing microscopy; Figure 17.43), which is reverted following the thermal isomerization step of the molecular motor. As the orientation of a surface relief of 20 nm (observed by non-contact AFM) is also altered along with the rotational reorganization of the film, a torque is gener-

365 nm ∆, t1/2 = 9.88 min (RT)

430 nm

49

a time (s)

0

6

12

20 30

40 50

70

6.8 wt% motor in E7, irradiation at 365 nm

b time (min)

1.30 2.20 4.00 5.35 6.46 8.09 10.40 13.00 16.46 21.02 32.35

Same sample, thermal step back at T = 22C. Figure 17.42 Color changes of an LC film comprising a motor guest (49) in an E7 liquid crystal host compound. Adapted from Ref. [116]; © John Wiley & Sons, Inc., 2007.

17.7 Conclusions and Outlook

Figure 17.43 Pictures of the polygonal

fingerprint texture of a LC film doped with a second-generation light-driven rotary molecular motor 49 (1 wt%) and a glass rod (5 × 28 µm) deposited on top of it, taken at

15 s time intervals after the start of UV irradiation. Note the rotational reorganization of the LC film, and how the glass rod rotates along with the film. Adapted from Ref. [117]; © Nature, 2006.

ated that is sufficient to achieve a unidirectional rotation of any microscopic objects placed on top of the film. In this way, by harvesting the light energy and the collective action of these nanomotors, objects that exceed them in size by three orders of magnitude can be rotated in unidirectional fashion. This macroscopic rotation, however, cannot be induced in a continuous way, as it is halted when the photostationary state is reached, and reverted by the subsequent thermal isomerization of the molecular motor.

17.7 Conclusions and Outlook

During the development of molecular motors and machines, much inspiration has been drawn from the biological world. Hence, with a rapidly expanding toolbox of functional components to construct nanomechanical devices, and with the first genuine molecular motors at hand, it seems appropriate to close the chapter with a brief comparison of natural and synthetic molecular motors (Figure 17.44). The elegance of Nature’s design and the complexity of the functions of biological motors stands out in sharp contrast to the rather primitive systems that have been designed thus far. On the other hand, the basic principles of rotary and translational motion with synthetic molecular motors have been demonstrated, and the first examples of useful functions with such artificial systems reported. Although tremendous opportunities exist for the exploitation of protein- and DNA-based molecular motors [68], issues associated with their robustness and operation outside their natural environment might ultimately prove to be decisive factors. Although the use of biohybrid systems or modified proteins (as already seen in biocatalysis) offers amazing opportunities, the unlimited building blocks available to today’s synthetic chemist to generate stable structures and novel functions can be considered a distinct advantage in the long term. Nonetheless, the field is clearly at a stage of development, and only imagination and time will reveal to what extent molecular motors and machines can be

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α

β

α

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rotor

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Natural motors - nearly every important biologic process - wide variety of functions - complex structures - very limited building blocks

gold particle

Synthetic motors - very limited function - applications, materials&medicine - primitive structures - unlimited building blocks

Figure 17.44 Natural versus synthetic motors.

exploited. At this point, a number of pressing issues remain to be resolved. In the case of chemically driven motor systems, a catalytically driven system needs to be developed that is capable of continuous rotary behavior upon the input of one chemical energy source. Based on light-driven motors, faster movements over longer time frames need also to be established. Eventually, the challenge will remain to develop nanomechanical systems based on these artificial rotary molecular motors that can drive directional movement along a certain trajectory, and even transport certain types of cargo. The construction of functioning nanovalves, with movable molecular control units to regulate the flow of substances, represents a significant step towards the development of real nanomachines. However, such nanovalves are attractive components in themselves, for example in drug-delivery systems with controlled release, in signal transduction, in sensors, and in nanofluidic systems. By making only a small step into the future of molecular machines, it is easy to realize that new systems will be required to demonstrate repetitive and directional movements within distinct time frames, and with a precise control of speed. The control of mechanical processes and functions at different length scales is another important issue. Furthermore, interfacing the hard and soft world of, for example electrodes and motors, remains a major contemporary challenge. One pertinent question that the designer of any of these systems should ask is: What problems require a molecular machine for their solution? In the context of practical devices, additional important questions with regards to stability and continuous operation, efficiency and integration in multicomponent, complex devices, have been raised. In time, it should also be possible to envision other features that are common to natural systems and which must be overcome, including mechanisms for both repair and replication. Ultimately, then, might it be possible to build molecular (nano-size) robots that are self-propelled by molecular motors? Indeed, although currently in the realm of nanoscience fiction, this is not

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109 Uchida, K., Sukata, S.I., Matsuzawa, Y., Akazawa, M., de Jong, J.J.D., Katsonis, N., Kojima, Y., Nakamura, S., Areephong, J., Meetsma, A., and Feringa, B.L. (2008) Chem. Commun., 326–328. 110 Katz, E., Willner, B., and Willner, I. (1997) Biosens. Bioelectr., 12, 703–719. 111 de Jong, J.J.D., Browne, W.R., Walko, M., Lucas, L.N., Barrett, L.J., McGarvey, J.J., van Esch, J.H., and Feringa, B.L. (2006) Org. Biomol. Chem., 4, 2387–2392. 112 van Delden, R.A., ter Wiel, M.J.K., Pollard, M.M., Vicario, J., Koumura, N., and Feringa, B.L. (2005) Nature, 437, 1337–1340. 113 Pollard, M.M., Lubomska, M., Rudolf, P., and Feringa, B.L. (2007) Angew. Chem. Int. Ed., 46, 1278–1280. 114 Zhang, J., Whitesell, J.K., and Fox, M.A. (2001) Chem. Mater., 13, 2323–2331. 115 Morin, J.-F., Shirai, Y., and Tour, J.M. (2006) Org. Lett., 8, 1713–1716. 116 Rosario, R., Gust, D., Garcia, A.A., Hayes, M., Taraci, J.L., Clement, T., Dailey, J.W., and Picraux, S.T. (2004) J. Phys. Chem. B, 108, 12640–12642. 117 (a) Eelkema, R., Pollard, M.M., Vicario, J., Katsonis, N., Ramon, B.S., Bastiaansen, C.W.M., Broer, D.J., and Feringa, B.L. (2006) Nature, 440, 163; (b) Eelkema, R., Pollard, M.M., Katsonis, N., Vicario, J., Broer, D.J., and Feringa, B.L. (2006) J. Am. Chem. Soc., 128, 14397–14407.

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18 Discussion 4.A Discussion on the Report by B.L. Feringa Chairman: Takuzo Aida

Chairman: The session is now open for discussion. E. Dalcanale: I found your amplification of the molecular movement in liquid crystals extremely interesting. I would like to go on and say that building from a molecular motion to a collective behavior is a very nice strategy. B.L. Feringa: Yes, you are absolutely right, and we are now trying to figure out what exactly the mechanism is. I have proposed a mechanism here, but in fact I think it’s a little more complicated, because a lot depends on the interaction of the soft material with the interface – what happens at the surface – and how these rod-like molecules anchor to the surface. Returning to your question about amplification, indeed we need to find out to what extent one can continue to amplify these effects – that is, how you go from a limited number of molecules to the collective action of a large number of molecules. This is really fascinating, and you can see that in our case we doped it with 1, 2, or 3% – it’s not due to the fact that the motor moves, it’s due to the fact that the state changes and that the whole orientation and organization at the level of the mesoscopic material has to change. So, it follows the change in chirality and it involves a lot of self-unwinding and rewinding. There’s a lot going on at the level of mesoscopic material, but I think we can explore that in other systems as well, such as gels and other materials, when they arrive at smart surfaces. R.D. Astumian: I have one comment and one question. I think it’s important to clarify that the movie of kinesin was not actually a molecular dynamic simulation. It is an animation, and it has many flaws with regards to the representation of the dynamics of motion at the microscale – it has inertia, it bounces, and there is no deposition of energy when a flash of light comes in to represent ATP hydrolysis. So, in that context, I wanted to ask a question. You were showing a molecular dynamic simulation on the same slide of your rotor. Was that done in the presence of water, or was there any input of Brownian dynamics, or did you simply solve Newtonian equations with light?


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B.L. Feringa: No, this was not done in a solvent, but we are working on this in the solvent. I completely agree that the pictures of these biological motors – motility motors such as the flagella motor and the like – are used to illustrate that it is not a very smooth motion, and we are still quite a long way from reality. There is a lot more motion when you look at the level of the protein itself, but it’s not exactly that picture. Just to be clear, it’s a stepwise motion and not smoothly running. So, yes, it’s true that the reality is a little more complex. C. Joachim: I would like to make a comment and ask a question. Normally, on a steam engine, you have of course the path, the piston, the pipe and so forth, but you also have a transmission to open up the valve along with a small program on the machine to synchronize all of that. All of your chemical examples showed the programs, transmissions and microscopic aspects on the outside, because you have to synchronize all the sequences of the cycle on the computer. Do you think we have enough space in the molecule to put this imaging, such as the transmission, the program and the synchronization? B.L. Feringa: Absolutely, in fact I didn’t have time to talk about it in more detail. When it comes to molecular machines, or from molecules to systems, I’ve put forward a whole range of challenges and features that need to be worked on. I agree that, in those systems, we have to build in functions where you have transduction loops transferring information until something else happens at a certain stage because it receives information. For instance, with the capsules that I have shown, we put in a protein as a first attempt to make a capsule that can be opened and closed on command. In this case, we have to use external light to trigger it, but we have also put in a pH-sensitive group. Then, if the capsule goes somewhere and senses a pH difference of even one pH unit, it will open or close – and these results have actually been published. The next step would be to connect it to something that detects whether the concentration is too high, whereupon you would get an effect as the capsule starts to open, to release something, and if the releases must be stopped after a certain moment – say after 10% has been released – the concentration is raised so much that it feeds back the signal. This isn’t easy, but we must consider these types of feedback loop if we want to move towards more complex machinery systems. So, either external signaling, sensing, or building in these autonomous functions is necessary. We can build in autonomous movement, but not yet other functions. C. Joachim: But you have to put the program on the machine. B.L. Feringa: You have to program the machine, more or less. C. Joachim: I mean on the machine. A lot of people forget that the steam engine has a small metal plate with small holes, which synchronizes the up-and-down motion of the valve, depending on speed and temperature, and this is on the machine itself. B.L. Feringa: OK, I am not actually a mechanical engineer.

18 Discussion 4.A

C. Joachim: When I went to Glasgow with David Leigh, I visited a museum and I was surprised to see that there was actually a program on the machine! B.L. Feringa: With regards to the kind of feedback of information-driven machines, I think David Leigh has the most beautiful examples at this stage, where he introduces the function and, indeed, something is recognized creating the possibility for feeding back information. That, in my opinion, is a really important step forward. As I emphasized yesterday, we could incorporate more of the principles of catalysis because, in that field, we have turnovers and a process that continues for hundreds and thousands of times without failure. So, if you could connect the catalytic cycles this would be a very promising approach. There certainly is plenty of promise to make it a reality. In this regard, we can also consider playing with such things as concentration gradients and catalysis speed, as the rate of catalysis can be tuned rather easily. So, I think there is a bright future there. J.F. Stoddard: My advocacy of robustness is coming back to haunt me, so I just want to defend myself! I am not saying that in switching or machine-like environments the molecules are in a robust environment, and I have just given an illustration of this. I am always pained to say that the monolayers we put into them for example are molecular electronics devices. But please, would the community think of these as being liquid crystalline – they are highly mobile! Not only does a moving component move in what I would call a co-conformational manner – that is, like a ring slipping down a rod – but the actual rod undergoes a huge change in its own conformation. So, I would just like to make the point that when I refer to robustness, I mean putting molecules into a robust environment – the molecules themselves may, more often than not, behave in a liquid crystalline type of manner, which I think is the norm. B.L. Feringa: I think your point is extremely well made. Be it either solids, polymers or liquid crystals, every time you talk with people in the industry about devices or applications, these are the key issues – how stable is it, and how can we get it working? It has to do with the fatigue of the systems, robustness, and mechanical strength. You are the prime example of how to cope with that: how to have a robust system on the surface, yet still have sufficient mobility to do the job. When you work with molecules, we usually cannot work in crystals. I showed you a good example of a crystal, but I don’t know if you can ever make a device from it because it might break. However, when you move away from crystals to the interface of the soft and hard worlds, then you need this fine balance, and that’s what I wanted also to emphasize. The fine balance of the mobility, as well as the stiffness and the robustness, are the key issues at stake. With robustness, if you ever want to go to an electronic device or to a polymer, an industry will never do anything with your smart polymer if you can’t make a nice stable film and you can’t sustain it for more than a few weeks or so. And this is a very important issue of course. F. Vögtle: For the rotation of the micrometer rod in the liquid crystalline phase, is it necessary to have rotating molecules, or would chiral azobenzene with a dynamic increase/decrease of chirality possibly do it?

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B.L. Feringa: The point is that you have to have large changes in your liquid crystal organization, and you will also need a complete change. If you want to really spin it in rotation – as we do several times – you have to completely inverse the helicity of your helical systems, but this is an issue at stake. You can use switches, as we and others like Ikeda have done for many years, to change the helicity to a certain degree. In principle, the switching function is sufficient, but if you want to go from a switching function to a completely inversed helicity, then there aren’t many systems that can do it. So, I wouldn’t necessarily say that it has to be a rotor, but it must fulfill the requirements of complete helical inversion in the liquid crystal, in a dynamic sense. That is the crucial thing. A. Schanzer: I want to challenge you. B.L. Feringa: Sure. A. Schanzer: Imagine if you have a racemic mixture made of two components, to which you have attached a chiral molecule which is spinning in one direction, and a chiral molecule that spins in the opposite direction. Would you separate the mixture? B.L. Feringa: That’s an interesting experiment, and one that I often discuss with my students. Two of whom have independently tried to do something on chiral separation by spinning, but the original attempts failed because, at the time, the students had motors that were too slow. If you turn once a minute or once a second, then you’ll never separate anything. But now we have these very fast motors. A. Schanzer: But, in any NMR machine, you have a very fast phase-changing system with thousands of megaHertz. B.L. Feringa: That’s correct, but what we wanted to do is to use a molecular motor and see if, after irradiating, it would spin on opposite sides and move on different tracks. A. Schanzer: And in the same tube, one would move in one direction, and the other in the opposite direction. J. Prost: But that’s not enough – you have to pay attention to symmetry. In order to look at a symmetry argument, you need to consider a vector field. B.L. Feringa: A vector? J. Prost: Yes. B.L. Feringa: That’s correct, and that’s why our original attempts failed. You can think of these experiments – as one of my students recently said, “OK, I’ll do the following trick – I’ll put them on silica, put a lamp on it, and they’ll move to different trajectories.” But you need to break the symmetries that are put into the trajectories. Nowadays, we’re working in electric fields, such as gel electrophoresis, where you have a directionality. But basically, I would say that there is no fundamental law that would prevent it.

18 Discussion 4.A

A. Schanzer: Yes, it’s a challenge. B.L. Feringa: But a challenge that I like very much – we picked it up already, but we haven’t been at all successful. We were struggling at the start, with the speed and breaking of the symmetry. It’s not easy to convince students to do this type of thing – they prefer to do syntheses or physical measurements – but I think that, basically, it can be done. We may be able to use a molecule with a tail-like polymer that could give more momentum to the system, and there’s certainly a possibility with the helix-inverted polymer. Chairman: Thank you.

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19 Comment on Molecular Machines Based on Non-Interlocking Molecules (Other Than Catenanes and Rotaxanes) Prepared Comment Josef Michl

Probably the largest group of molecular machines that have been prepared and investigated are molecular rotors. A recent review [1] that excluded catenanes and rotaxanes included many hundreds of references, and further reports have emerged since then. In this chapter, attention will be drawn only to a pair of publications. The first of these reports described the synthesis of an altitudinal surface-mounted rotor, the dipole of which could be flipped by electric field provided by the tip of a scanning tunneling microscope [2]. The second report used molecular dynamics to determine whether an electric field alternating at microwave frequencies would induce unidirectional rotation in the rotor [3]. The chemical structure and models of three conformations of the rotor molecule are shown in Figure 19.1. The rotor compound was prepared in two flavors, with and without a dipole perpendicular to the axis of rotation. It was attached to an Au(111) surface from solution through adhesion of its ten flexible tentacles, and characterized by several techniques, primarily scanning tunneling microscopy (STM), ellipsometry, X-ray photoelectron spectroscopy (XPS), and infra-red (IR) spectroscopy. The field between the STM tip and the gold surface can easily be made so huge that it would be expected to hold the ∼4.5 debye dipole of the rotator in a fixed direction almost all the time, even at room temperature. A reversal of the field polarity should then cause a flipping of the direction of its dipole if the latter were truly mobile and not blocked by any interaction with the surface, with one of its own tentacles, or with some surface impurity. In the absence of an electric field, a rotor that is not blocked would then undergo rapid spontaneous flipping at room temperature. In order to determine whether the rotor was flipping its direction upon reversal of the field vector, differential barrier height-imaging (BHI) measurements we performed. In this case, the distance between the tip and the surface was modulated at 5 kHz, and both the dc and ac components of the tunneling current were measured. The slope of the linear relationship between these components provided a measurement of the local work function of the surface. Ordinary STM imaging then produced a picture in which the location of the rotors was apparent, while simultaneous differential BHI imaging revealed which of the rotors was 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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responding to the direction of the electric field by changing their work function dramatically. About one-third of the rotors were free to flip, and over dozens of minutes some of those that were originally able to turn lost their mobility, while some that initially were not mobile began to turn. These variations were attributed to slow changes in the adsorbed molecules, and especially in their flexible tentacles. The molecular dynamics calculation of the response of the gold surface-mounted rotor molecule was performed at 10 K for all three conformations of the rotor, in a strong alternating electric field directed along the normal to the conducting surface. The minimum energy orientation of the rotating dipole in two of the conformations had the dipole pointing either almost exactly at the surface or away from it, and the sense of the flip induced by the field was more or less random. In the third conformer (as shown in the center of Figure 19.1), the equilibrium direction of the dipole made an angle of about 25° with the normal, and in this case the rotation induced by a sufficiently strong alternating field proceeded always in the same sense. When the amplitude of the field was large enough and its frequency low enough, the rotor completed a full 360° turn each time the field went through a full 2π phase change, and the molecule behaved like a synchronous motor. At a somewhat lower field amplitude or higher frequency, the rotor performed only a 180° turn during the first half of the 2π field cycle, and did not turn during the second half. If the field was lower still, the rotor failed to follow the field altogether. The results can be summarized in a phase diagram (Figure 19.2). The rotor thus behaves as a single-molecule parametric oscillator, and at higher temperatures the driven and the Brownian regimes can be clearly differentiated (Figure 19.3). With strong fields (the driven rotor limit), where the cold rotor was

(a)

(b)

F

F F

F

Co

Co RSHg RSHg

HgSR HgSR HgSR

RSHg RSHg

HgSR HgSR HgSR

Figure 19.1 (a) Chemical structure and (b) top views of three conformers of the molecular

rotor, which differ in the helicity of the terminal tetraphenylcyclobutadienes and the central biphenyl moiety. The computations described here were performed for the middle conformer.


synchronous

½ synchronous

90

Amplitude (108 V/m)

80 70 60

1/4 synchronous

50 40 30 20 10

25

50

100 75 125 Frequency (GHz)

Figure 19.2 Computed response of the rotor of Figure 19.1 as a function of the amplitude and frequency of electric field perpendicular to an Au(111) surface to which the rotor is

150

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random attached. Blue = synchronous motion; yellow = half-synchronous motion; orange = quarter-synchronous motion; red = random motion.

1

a

10 K 100 K 200 K 300 K

0.5

0

2

3

4

6 5 E (GV m–1)

7

8

Figure 19.3 The probability a that the rotor of Figure 19.1 will miss a unidirectional turn as a function of the amplitude of a 90 GHz electric field at various temperatures.

synchronous, an increase in the temperature led to a degradation in its performance, while the probability that a field cycle would be skipped grew from zero to a finite value, as random thermal fluctuations interfered with the regular driven motion. At weak fields (the Brownian rotor limit), where the cold rotor did not turn at all, an increase in the temperature improved its performance and made it follow at least some of the field cycles, as random thermal motion helped the rotor to leave the potential energy minimum in which it was stuck. We do not have experimental evidence that would confirm the calculated result, namely directional rotation. Experiments to distinguish unidirectional rotation

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from random flipping are more readily envisaged for rotors carrying at least three blades, and not only two, and they currently represent an interesting challenge.

References 1 Kottas, G.S., Clarke, L.I., Horinek, D., and Michl, J. (2005) Chem. Rev., 105, 1281. 2 Zheng, X., Mulcahy, M.E., Horinek, D., Galeotti, F., Magnera, T.F., and

Michl, J. (2004) J. Am. Chem. Soc., 126, 4540. 3 Horinek, D. and Michl, J. (2005) Proc. Natl Acad. Sci. USA, 102, 14175.

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20 A Few Hints Towards Artificial Active Macroscopic Systems Prepared Comment Jacques Prost

In this chapter, some of the problems to be solved for synthesizing artificial linear molecular motors are discussed, and the argument proposed that it should be significantly easier to make artificial “active gels.” This new type of matter has the capacity of self-propulsion, and can also be interesting for the possibility of an external control of its viscosity over a very large range of values.

20.1 Active Molecules

The number of original chemical architectures reported during this conference is really impressive, with catenane, rotaxane, and related constructions giving rise to some fascinating molecules and structures. For most of the time, original architectures go hand in hand with original properties. Very often, the subject involves switches or actuators for which no applications have yet been reported, although these are likely to be developed in the near future. Notably, G proteins – which essentially are switches – play a major role in cell biology [1]. Next to switches come molecular motors, the synthesis of which in a completely artificial form represents a very tempting goal. However, it is first necessary to understand how motion can be generated without the use of any external force or gradient. It has been shown that, by placing a particle in a potential flashing between two different “ratchet like” asymmetric, periodic realizations, long range motion of the particle can be generated [2–4]. The validity of this concept was subsequently verified by various experiments conducted with colloidal particles [5, 6]. Some years later, the concept has been transposed at the molecular level, in the case of a rotary molecular motor which is a real “tour de force” [7]. The synthesis of a linear motor is much more difficult. Indeed, whilst it is possible to obtain a “one-way” rotation around a single covalent bond, by cleverly playing with angular ratchet potentials, there are many more requirements for linear motors. First, it is necessary to synthesize a track, which must be a linear 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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rigid polymer or a one-dimensional crystal (e.g., whisker-like), with spatial polarity. The polarity is essential as it represents the difference between the plus and minus directions, which inform the molecule which way to go. It should be noted that it need not be an electric polarity, but rather a chemical and geometric polarity; moreover, some cellulose whiskers have the correct symmetry. The next stage is to prepare a molecule which may have at least two conformations that are sufficiently different one from another, and which experience very different interaction potentials with the track. The transitions between the two conformations must be driven out of equilibrium by an energy source. Biological molecular motors are driven by ATP hydrolysis, although photons or redox sources would function equally well, and may be even better as they involve larger driving energies. The main difficulty here stems from the fact that efficient molecular motors are dimers which literally “walk” on either microtubules or on actin filaments [8]. Mimicking these motors would require the synthesis of molecules that are able to: •

dimerize

•

have a size matching equal to that of the track period such that: –

at any time only one monomer sticks to the track

–

a conformational change switches monomer roles

– its interaction with the track is large enough that the dimer does not fly off, but low enough that it does not prevent the conformational change (typically a few tens of thermal energy). Whilst evolution has taken billion years to achieve such a goal, man-made chemistry will be faster – but not easy! An easier approach would be to return to the original proposal [2] which is less efficient, but simpler. Ultimately, an almost perfect illustration of this mechanism would be provided by a single-headed kinesin [9]. In such a case there would be no need to synthesize a molecule capable of dimerization; rather, only two conformations would be required: • •

one capable of seeing the track structure; and one capable of seeing an essentially flat interaction profile.

The interaction energies should again be of the order of a few tens of thermal energy, and such a molecule would be more likely to be synthesized than the typical dimeric motor [10, 11]. Notably, the collection of such motors would be equally efficient as their dimeric counterparts [12].

20.2 Active Gels

The synthesis of “active gels” would probably be easier, as these are physical gels in which suitably utilized energy sources can permanently reshuffle the crosslink

20.2 Active Gels

positions [13–15, 17]. They have original properties (these are discussed briefly in the following section), but in particular they are self-propelling. A typical realization of an active gel is provided by the actin–myosin system in vivo. In this case, actin networks are synthesized at the cell surface and crosslinked by appropriate proteins. The myosin II motors, which are bundled into oligomers similar to small muscles, can grab actin filaments and move the crosslinks. Such permanent activity will require an energy source of ATP, which is recognized as the “fuel” of living systems. The actin gel, which can be isotropic in vitro but often anisotropic in vivo, is the essential element, providing plasticity and motility to the cell. The de novo synthesis of active gels may involve telechelic oligomers or polymers. Telechelic polymers are widely used in industry to control the shear behavior of paints, while the monomeric building blocks should contain one or several actuators (as described in this conference) and hydrophilic groups, such that the main chain would be water-soluble. Both extremities of the polymer/oligomer should be prepared from hydrophobic and highly flexible blobs, and presumably, the most difficult step would be to insert the actuator into the polymerizing unit. In order for the system to be interesting from a practical standpoint, the actuator should be capable of breaking the telechelic bonds upon conformational change. In turn, the strength of such bonds can be controlled directly by the size of the blobs. A second generic possibility for active gel creation would be to use the knowledge acquired with side chain-associating polymers. In this case, the actuators could be distributed either on the main chain or on the side chain, while requirements relating to bond strength are similar to those of the telechelic polymers. A third synthetic possibility involves mimicking more closely the actin–myosin system. In this case, each actuator is assumed to be hydrophilic (respectively, hydrophobic), and should be bound covalently (or “strongly enough”) to a hydrophobic (respectively hydrophilic) tail, in such a way that it forms micelles. Optimally, the micelles would have to be elongated, although spherical micelles would also be appropriate. Such a micellar solution could be mixed with almost any associating polymer, and the interaction between the polymer and the active micelle could be of any form. However, hydrogen bonds or hydrophobic interactions would serve as good candidates as their strength can be fine-tuned by correctly adjusting the solvent. In all of these systems, the energies involved in the association of the polymers and the actuators should be of the order of a few tens of thermal energy. Values of energies comparable to that of covalent bonds would not be functional, as the actuator would be so strong that it would destabilize any bond. Neither would values of the order of thermal energies function well, since the effects would barely emerge from noise. A straightforward extrapolation based on the actin–myosin system has suggested cycling frequencies between the two conformations of the actuators in the kilohertz range. In fact, a faster cycling would be better, allowing regimes to be reached that cannot be achieved by living systems.

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20.3 Expected Properties

The synthesis of active gels would be valuable for essentially two reasons. First, totally artificial systems would be able to mimic the important aspects of cell dynamics. It would also be possible to vary parameters under well-controlled conditions over wide ranges, and thus to validate the concepts which have been proposed during recent years [15, 16] for describing the actin–myosin system. An important question in this regard would be to demonstrate the existence of a transition by which such an active gel might set itself in motion, beyond a critical energy consumption threshold [18]. This transition is reminiscent of (but different from) the well-known “Frederiks” transition in liquid crystals. In a conventional Frederiks transition, if a nematic liquid crystal is initially homogeneously aligned and then submitted to the action of an external magnetic field, it will acquire a distorted state beyond a well-characterized critical field value. It is this transition which serves as the basis for liquid crystal display devices [19]. In an anisotropic active gel, there would be no need for an external field. However, an increase in energy consumption beyond a critical value would be sufficient to induce the distorted state and, more interestingly, to set the gel in motion. Whilst the transition is not currently recognized as having any physiological role, it provides the clearest manifestation of the active nature of the gel. In slightly more complex geometries, the theory predicts wave-emitting instabilities [20]. Again, beyond a well-defined energy consumption threshold, the gel would be expected to start emitting shear waves, as has been observed in lammellipodia [21]. More generally, the actin–myosin instabilities are expected to play an important role in areas such as cell oscillations, mitosis, and axone pearling [22–24]. Whether such phenomena could lead to useful applications or not remains an open question. However, by varying the crosslinking density it would be possible to vary the gel elastic modulus E, from hundreds of pascals (Pa) to hundreds of kPa. Moreover, the lifetime, τ, of the crosslinks with energies of the order of 50fold thermal energy would easily be of the order of hours to days and, as a result, the long-term viscosity (η = Eτ) could range from a few MPa·s up to hundreds of GPa·s. With strong actuators, the activity would break the crossslinks, and the relevant time would become the actuator cycle time of, perhaps, milliseconds, while the viscosity would fall to values one million-fold smaller! On this basis, it would be possible to imagine strong glues that would melt away under the correct illumination, but could be used reversibly in systems such as microfluidic devices.

Acknowledgments

The authors is grateful to J.M. Lehn, J. Malthête, and J.F. Joanny for their stimulating discussions, and to Prof. J.P. Sauvage for organizing a wonderful meeting.

References

References 1 Alberts, B., et al. (2002) Molecular Biology of the Cell, 4th edn, Garland, New York. 2 Ajdari, A. and Prost, J. (1992) C. R. Acad. Sci. Paris, 315, 1635. 3 Jülicher, F., Ajdari, A., and Prost, J. (1997) Rev. Mod. Phys., 69, 017. 4 Astumian, R.D. (1997) Science, 276, 1269. 5 Rousselet, J., Salome, L., Ajdari, A., and Prost, J. (1994) Nature, 370, 446. 6 Faucheux, L., Bourdieu, L.S., Kaplan, P.D., and Libchaber, A.J. (1995) Phys. Rev. Lett., 74, 1504. 7 Kelly, T.R., De Silva, H., and Silva, R.A. (1999) Nature, 401, 150. 8 Yildiz, A., Tomishije, M., Vale, R.D., and Selvin, P.R. (2004) Science, 303, 676. 9 Okada, Y., Higushi, H., and Hirokawa, N. (1997) Nature, 424, 574. 10 Lehn, J.M. Personal communication. 11 Malthete, J. Personal communication. 12 Jülicher, F. and Prost, J. (1995) Phys. Rev. Lett., 75, 2618. 13 Kruse, K., Joanny, J.F., Jülicher, F., Prost, J., and Sekimoto, K. (2004) Phys. Rev. Lett., 92, 078101.

14 Kruse, K., Joanny, J.F., Jülicher, F., Prost, J., and Sekimoto, K. (2005) Eur. Phys. J. E, 16, 5. 15 Julicher, F., Kruse, K., Prost, J., and Joanny, J.F. (2007) Phys. Rep., 449, 3. 16 Kruse, K., Joanny, J.F., Jülicher, F., and Prost, J. (2006) Phys. Biol., 3, 130. 17 Narayan, V., Ramaswamy, S., and Menon, S. (2007) Science, 317, 105. 18 Voituriez, R., Joanny, J.F., and Prost, J. (2005) Eur. Phys. Lett., 70, 404. 19 de Gennes, P.G. and Prost, J. (1993) The Physics of Liquid Crystals, 2nd edn, Clarendon, Oxford. 20 Basu, A., Joanny, J.F., Jülicher, F., and Prost, J., unpublished results. 21 Giannone, G., et al. (2004) Cell, 116, 431. 22 Salbreux, G., Joanny, J.F., Prost, J., and Pullarkat, P. (2007) Phys. Biol., 4, 268. 23 Paluch, E., Piel, M., Prost, J., Bornens, M., and Sykes, C. (2005) Biophys. J., 89, 724. 24 Pullarkat, P., Dommeresnes, P., Fernandez, P., Joanny, J.F., and A. (2006) Ott. Phys. Rev. Lett., 96, 048104.

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21 Fluctuation Theorem, Nonequilibrium Work, and Molecular Machines Prepared Comment Pierre Gaspard

A brief review is presented of recent advances in nonequilibrium statistical thermodynamics, leading to the so-called fluctuation theorems and nonequilibrium work relations. These new results concern the forward and reversed fluctuations of molecular machines driven out of equilibrium by energy sources, as illustrated with the F1 -ATPase rotary motor.

21.1 Introduction

We could paraphrase Professor Noyori [1] and say that the science of molecular machines is four-dimensional chemistry, as their three-dimensional (3-D) structure (x, y, z) is coupled to their motion and kinetics (t). In condensed phases at equilibrium, the motion is erratic, with equal probabilities of moving forward or backward according to the principle of detailed balance. Therefore, unidirectional motion is possible if the machine is driven out of equilibrium by some chemical, electrochemical, electronic, or photonic energy source [2–7]. In performing the conversion of energy into motion, the molecular machine is the stage of dissipative processes taking place at the nanoscale in the presence of thermal fluctuations. Accordingly, molecular machines are ruled not only by the laws of thermodynamics but also by the statistical laws of fluctuations ubiquitous at the nanoscale. Remarkably, major results have been recently discovered which combine the thermodynamic and statistical laws into general relationships valid in nonequilibrium nanosystems such as molecular machines. The aim of this chapter is to provide a brief summary of these new results – which are referred to as “fluctuation theorems” and “nonequilibrium work relations” – and to illustrate their application to the F1-ATPase molecular motor.


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21 Fluctuation Theorem, Nonequilibrium Work, and Molecular Machines

21.2 Fluctuation Theorem

Several versions of the fluctuation theorem have been proved for different types of situation [8–17]. This theorem rules the fluctuating fluxes flowing through a system driven out of equilibrium by thermodynamic forces, also known as De Donder affinities [18–20]. The affinities are defined as the free enthalpy changes of the reactions powering the machine from the outside: Aγ = ∆Gγ = Gγ − Gγ,eq. They are not fluctuating because they are fixed by the concentrations of the chemical species in large amounts within the environment of the molecular machine. The affinities are associated with the catalytic cycles driving the machine [21]. These thermodynamic forces generate fluctuating fluxes Jγ, which can be the rates of chemical reactions, the velocity of a linear molecular motor, the rotation rate of a rotary molecular motor, or the electric current in conducting devices. In the case of a chemical reaction, the flux is given by Jγ = (1/t)∆Nγ (t) in terms of the number ∆Nγ (t) of molecules transformed by the reaction over the time interval t. The fluctuation theorem asserts that the probability distribution P ({ Jγ}) of the fluxes in some statistically stationary regime is larger than the probability P ({−Jγ}) of finding the opposite values of the fluxes, by a factor growing exponentially with the time t and the magnitudes of the affinities and the fluxes according to:   t P ({ J γ } ) = exp  Aγ J γ  ∑ P ({− J γ }) k T   B γ

for t → ∞

(21.1)

where kB is Boltzmann’s constant and T is the temperature [12, 15]. At equilibrium, where the affinities vanish, a detailed balance between the forward and reversed fluctuations is recovered. It should be noted that the rate of exponential growth is equal on average to the thermodynamic entropy production: diS 1 = ∑ Aγ J γ ≥ 0 dt st T γ

(21.2)

where 〈−〉 denotes the statistical average in the stationary regime [18–20]. This shows that the fluctuation theorem deeply relates the statistics of fluctuations to the second law of thermodynamics. The surprising result is that the fluctuation theorem is valid away from equilibrium, and allows new relationships extending Onsager’s reciprocity relations to the nonlinear response properties to be derived [12, 16]. This theorem also applies to ion channels and the counting statistics of electrons through quantum dots and single molecules [22, 23].

21.3 Nonequilibrium Work Relations

Further results have been obtained for systems driven by some time-dependent control parameter λ(t) varying between λ1 and λ2. This parameter can be an external force as in atomic force microscopy (AFM) experiments unfolding mechani-

21.4 Application to the F1-ATPase Molecular Motor

cally a single molecule of RNA [24]. Because of the fluctuations, the work W performed on the molecule is statistically distributed. The probability distribution PF(W) of the work performed during forward driving λ1 → λ2 can be compared with the distribution PR (W) corresponding to the reversed driving λ2 → λ1, starting in both cases from their respective equilibrium canonical distribution at the temperature T. Their ratio is ruled by Crooks’ fluctuation theorem [25]: PF (W )  W − ∆F  = exp   K BT  PR ( −W )

(21.3)

where ∆F = F2 − F1 is the free energy difference between the thermodynamic equilibria at λ2 and λ1. A consequence is Jarzynski’s nonequilibrium work theorem [26]:  W   ∆F  exp  − = exp  −  kBT   kBT 

(21.4)

allowing the measurement of free energy landscapes with single-molecule force spectroscopy [27]. Extensions to quantum systems have also been obtained [28]. Moreover, Jarzynski’s theorem implies Clausius’ thermodynamic inequality: W ≥ ∆F

(21.5)

Furthermore, the mean work performed on the molecular machine is given by [29]: W = ∆F + kBT ∫ dqdpUF (q, p, t )ln

UF ( q, p, t ) UR ( q, − p, t )

(21.6)

in terms of the phase-space probability distributions of the positions q and momenta p of the particles at some intermediate time t during the aforementioned protocol. Equation (21.6) of statistical mechanics nicely completes Clausius’ thermodynamic inequality [Eq. (21.5)].

21.4 Application to the F1-ATPase Molecular Motor

ATP is synthesized by rotational catalysis in the F1 part of mitochondrial FoF1ATPase [30–32]. The F1 protein complex is a barrel composed of three large α- and β-subunits arranged in circular fashion around a smaller γ-subunit which plays the role of the shaft. Professor Kinosita and coworkers have succeeded in observing the rotation of the shaft, with a resolution into substeps of about 90° upon ATP binding, followed by the release of ADP and Pi during an extra rotation of about 30° [33, 34]. Therefore, a full revolution of 360° corresponds to the hydrolysis of three ATP molecules. The chirality (handedness) of the molecular complex is essential for its unidirectional rotation under nonequilibrium conditions. Compared to molecular machines such as rotaxanes and catenanes [2], the F1 molecular motor is much heavier, and its large molecular architecture allows

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the separation of the catalytic sites in the β-subunits from the rotating γ-subunit. Nevertheless, the F1 motor remains affected by the thermal fluctuations. According to the fluctuation theorem [35], the probability of backward substeps is given by P (−s) = P (s) exp [−sA/(6kBT )] in terms of the affinity: A = −3∆G 0 + 3kBT ln

[ ATP] ADP [ ][Pi ]

(21.7)

with the standard free enthalpy of hydrolysis ∆G0 ≅ −50 pN nm at pH 7 and 23 °C [34]. The cycle of the motor corresponds to the full revolution with s = 6 substeps. Under physiological conditions, the motor runs in a highly nonlinear regime with a Michaelis–Menten kinetics and an affinity A ≥ 40 kBT [35, 36]. In this regime, the fluctuation theorem shows that the backward substeps are very rare, explaining that unidirectional motion can overwhelm erratic Brownian motion as the motor is driven away from equilibrium.

21.5 Perspectives

The new results provide the foundations for a statistical thermodynamics of nonequilibrium nanosystems, allowing a description of the unidirectional motion of molecular machines. These machines can be driven either by time-dependent control parameters, or autonomously along a catalytic cycle. In both cases, the unidirectional motion is possible on the basis of the nonequilibrium drive by some energy source, and the efficiency of the energy conversion can be characterized. During the reactions, the molecular machine undergoes a cycle of intramolecular transformations, in which its 3-D structure changes with time [37]. Most remarkably, the new results of statistical thermodynamics explain that temporal ordering such as unidirectional motion can be the feature of systems driven out of equilibrium, and showing that the second law of thermodynamics can generate dynamical order and information [38]. Future applications of the new results to molecular machines can be foreseen; to further single-molecule pulling experiments on RNA, DNA, proteins, and other polymers to determine their free-energy landscapes; or to the counting statistics of single-molecule reactive events, possibly using the technique of single-molecule fluorescence spectroscopy [39].

21.6 Note Added after the Conference

Since December 2007, several reviews have been published on the fluctuation theorems and their implications [40–43]. In the light of the fluctuation theorems, significant advances have been carried out in the present understanding of the nonlinear response properties of single and coupled transport processes [44–50]. The chemo-mechanical coupling of molecular motors such as kinesin has been

References

studied on the basis of the fluctuation theorem for the two currents, which are the velocity and the ATP hydrolysis rate [51–53], and by using network representations of the motor dynamics [54, 55]. In a related context, fluctuating copolymerization processes have been shown to generate information based on the directionality provided by nonequilibrium conditions [56, 57]. Moreover, anholonomy in cyclically driven stochastic processes has been investigated [58–60], which is relevant to experiments with catenane or rotaxane molecules in chemical environments undergoing slow cyclic changes induced by external parameters [6, 61, 62].

Acknowledgments

These studies were supported financially by the “Communauté francaise de Belgique” (contract “Actions de Recherche Concertées” No. 04/09-312).

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15 Andrieux, D. and P. Gaspard (2007) J. Stat. Phys., 127, 107. 16 Andrieux, D. and Gaspard, P. (2007) J. Stat. Mech.: Th. Exp., P02006. 17 Kurchan, J. (2007) J. Stat. Mech.: Th. Exp., P07005. 18 De Donder, T. and Van Rysselberghe, P. (1936) Affinity, Stanford University Press, Menlo Park, CA. 19 Prigogine, I. (1967) Introduction to Thermodynamics of Irreversible Processes, John Wiley & Sons, Inc., New York. 20 Nicolis, G. and Prigogine, I. (1977) Self-Organization in Nonequilibrium Systems, John Wiley & Sons, Inc., New York. 21 Hill, T.L. (2005) Free Energy Transduction and Biochemical Cycle Kinetics, Dover, New York. 22 Andrieux, D. and Gaspard, P. (2006) J. Stat. Mech.: Th. Exp., P01011. 23 Harbola, U., Esposito, M., and Mukamel, S. (2007) Phys. Rev. B, 76, 085408. 24 Collin, D., Ritort, F., Jarzynski, C., Smith, S.B., Tinoco, I., Jr, and Bustamante, C. (2005) Nature, 437, 231. 25 Crooks, G.E. (1999) Phys. Rev. E, 60, 2721. 26 Jarzynski, C. (1997) Phys. Rev. Lett., 78, 2690. 27 Hummer, G. and Szabo, A. (2005) Acc. Chem. Res., 38, 504.

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21 Fluctuation Theorem, Nonequilibrium Work, and Molecular Machines 28 Mukamel, S. (2003) Phys. Rev. Lett., 90, 170604. 29 Kawai, R., Parrondo, J.M.R., and Van den Broeck, C. (2007) Phys. Rev. Lett., 98, 080602. 30 Boyer, P. (1993) Biochim. Biophys. Acta, 1140, 215. 31 Walker, J.E. (1998) Angew. Chem. Int. Ed. Engl., 37, 2308. 32 Wang, H. and Oster, G. (1998) Nature, 396, 279. 33 Yasuda, R., Noji, H., Yoshida, M., Kinosita, K., Jr, and Itoh, H. (2001) Nature, 410, 898. 34 Kinosita, K., Jr, Adachi, K., and Itoh, H. (2004) Annu. Rev. Biophys. Biomol. Struct., 33, 245. 35 Andrieux, D. and Gaspard, P. (2006) Phys. Rev. E, 74, 011906. 36 Gaspard, P. and Gerritsma, E. (2007) J. Theor. Biol., 247, 672. 37 Togashi, Y. and Mikhailov, A.S. (2007) Proc. Natl Acad. Sci. USA, 104, 8697. 38 Gaspard, P. (2007) C. R. Physique, 8, 598. 39 Roeffaers, M.B.J., De Cremer, G., Uji-i, H., Muls, B., Sels, B.F., Jacobs, P.A., De Schryver, F.C., De Vos, D.E., and Hofkens, J. (2007) Proc. Natl Acad. Sci. USA, 104, 12603. 40 Sevick, E.M., Prabhakar, R., Williams, S.R., and Searles, D.J. (2008) Annu. Rev. Phys. Chem., 59, 603. 41 Seifert, U. (2008) Soft Matter: From Synthetic to Biological Materials (eds J.K.G. Dhont, G. Gompper, G. Nägele, D. Richter, and R.G. Winkler), Forschungszentrum Jülich GmbH, Jülich, pp. B5.1–B5.30. 42 Esposito, M., Harbola, U., and Mukamel, S. (2009) Rev. Mod. Phys., 81, 1665. 43 Gaspard, P. (2010) Nonlinear Dynamics of Nanosystems (eds G. Radons, B. Rumpf, and H.G. Schuster), Wiley-VCH Verlag GmbH, Weinheim, pp. 1–74.

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22 Discussion 4.B Discussion on the Prepared Comments by S. Shinkai,1) M. Shionoya,2) J. Michl,3) J. Prost,4) and P. Gaspard5) Chairman: Takuzo Aida

Chairman: The session is now open for discussion and comments. R.D. Astumian: The question is for Professor Michl. You mentioned that, as you increase the electric field strength, you get more and more fidelity with regard to the motion. Do you ever reach a point where it decreases as a function of field strength, because it is surprising to me that with an infinite field you have only one symmetry and therefore no possible rotary motion. J. Michl: You are absolutely right. I was careful to say that you get regular motion when the field is “appropriately strong.” If the asymmetry in the potential that the rotor sees becomes negligible relative to the interaction strength with the electric field, then the motion becomes random again. The reason why the rotor undergoes a unidirectional motion – although the field itself is normal to the surface, and does not distinguish clockwise and counterclockwise – is the asymmetry in the favored orientation of the dipole which, in that particular conformer – where the phenyl rings on both stands are forcing the rotor away from being normal to the surface, which would otherwise be the electrostatically favored orientation – the rotor makes an angle of about 25° with the normal when it is at its minimum. You can of course add 180° to that if you flip it over. When that potential difference becomes negligible relative to the interaction with the electric field, you lose the directionality. So indeed, you are absolutely right. 1) The prepared comment by S. Shinkai was on molecular machines from the past (1979) to the future, and what is still missing. 2) The prepared comment by M. Shionoya was on chemical binding in non-interlocking molecular machines. 3) The prepared comment by J. Michl was on molecular machines based on non-

interlocking molecules (other than catenanes and rotaxanes) (see p. 297). 4) The prepared comment by J. Prost was on a few hints towards artificial active macroscopic systems (see p. 301). 5) The prepared comment by P. Gaspard was on the fluctuation theorem, nonequilibrium work, and molecular machines (see p. 307).


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J.-P. Sauvage: I would like to take the defense of molecular machines in solution. We have been extensively discussing the interest of organizing them on surfaces, making crystals, gels, polymers, and so on. However, I would like to come back very briefly to the point I made yesterday, that catalysts can be regarded as molecular machines to some extent. On the other hand, we can use molecular machines as catalysts in solution by turning the catalyst on or off, for instance, to obtain “intelligent” catalysts. Therefore, molecular machines alone can be interesting as a means of performing molecular chemistry in solution. R.D. Astumian: Since we are talking about molecular machines in solution, I wanted to make one observation about a beautiful paper that was written back in 1977 by Ed Purcell, entitled “Life at Low Reynolds Number,” published in the American Journal of Physics.6) Purcell discusses the problem that bacteria would face trying to swim in a directive way, given that there is no inertia – that is, no glide that you might get after a forcing motion. He draws up a wonderful cycle of diagrams with three sticks, but if you look at this as a chemist you can’t help but think of the chair-to-boat transition of cyclohexane. The physical motions of the organic molecules that we are all familiar with from sophomore organic chemistry are those that can – in principle, if put in the right typology – be exactly those that can be used to drive directed motion and swimming at low Reynold’s number. B.L. Feringa: Let me continue a little further with these remarks about catalysis. Jean-Pierre Sauvage has mentioned it and is challenging us! I was mentioning yesterday about the cascades of catalysts, and I think that there is a big challenge when it comes to switching a catalyst on and off in a really controlled manner, so that you can tune a cascade of chemical steps to go from a very simple to a complex molecule, for instance. On the other hand, if you look at some of the polymerization catalysts that have been developed for stereoregular olefin polymerization or olefin CO insertion reactions, you see a real mechanical movement in the ligand maintaining control due to the different steps during a complete single catalytic cycle. It is beautiful and, like a machine, it performs a rotary movement where it positions the ligand in different orientations with respect to the incoming substrate or the outgoing product. This rotary movement is extremely important to make the catalyst function, for instance, to alternate and insert CO and ethylene in this structure. Thus, there are plenty of comparisons possible with machines functioning at the molecular level. E. Dalcanale: I have a question for Ben Feringa. If you look at bacteria, they typically move forward in a chemical gradient. In your system with hydrogen peroxide, can you envisage a way of making them move in one direction, whereby they would follow some kind of signal? B.L. Feringa: Absolutely. I am really fascinated by the idea to make a gradient. Of course, you could think of many ways of making a gradient. One way that we 6) Purcell, E.M. (1977) Am. J. Phys., 45, 3.

22 Discussion 4.B

are currently trying to do that is to take a photochemically protected glucose and to deprotect it. In that way, we can have a laser beam that the moving particle will more or less follow, because with the laser we deprotect the glucose fuel and the glucose is consumed by the glucose oxidase and is catalyzed. Hopefully, we will generate enough fuel to get propulsion, and we could follow it along a trajectory which is dictated by the light beam. This is our first approach, but I am sure there are others. You could think about gradients – of course, bacteria use gradients, they swim towards or away from them. If they encounter a dangerous chemical, they sense it and swim away, so that they can clearly sense the gradient. It is fascinating because, as chemists, we can make concentration gradients without any problem. The difficult part is to make something that moves in the gradient, but I think it’s possible if you think about it. M. Fujita: Coming back to Jean-Pierre Sauvage’s suggestion, I was just thinking about transition metal-catalyzed cross-coupling reactions. Let us suppose that a catalyst adopts conformation A at the oxidative addition step, conformation B at the transmetallation step, and finally conformation C at the reductive elimination step. Accordingly, it should repeat the conformations A, B, C, but not A, C, B. My question is the following: if the catalyst is chiral, can we define that this is a unidirectional motion? Can we say that the conformational changes A, B, C, A, B, C, … in a chiral fashion is a unidirectional motion? B.L. Feringa: With these catalysts, I don’t think it is a unidirectional motion. I didn’t say it is a motor, and I don’t think that Jean-Pierre Sauvage said it is a motor, either. It is a type of machine-like function, but there is probably no directionality. M. Fujita: But I am talking about conformational changes starting from A, B, C. For these conversions, we can think about the mirror image movement. J.-M. Lehn: I have two points to raise. My first point concerns oriented reactions. The ribosome is an oriented catalyst. The reactions you mentioned are not unidirectional, but the ribosome is indeed unidirectional. If you look at the motion in the ribosome, it goes out one way and a number of very specific chemical processes occur so that it is driven one way. The other point I want to make concerns unidirectional systems involving transport of matter. Such a system goes down the concentration gradient, and that is oriented. If you have a membrane separation, you spontaneously go down the gradient and things will follow it down the gradient. You can pump compounds by a difference in pH for instance, and different aspects of such processes have been studied as long as 40 years ago. So, these types of orienting system can be used to drive the directional flow of substances, and in fact have already been used for chemical separations. There are apparatus available where you purify a mixture by just going down the gradient and performing sequential extractions. So, one might use such processes to drive a system one way simply by establishing a concentration difference and creating a chemical potential difference.

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R.D. Astumian: I was actually going to comment on Professor Lehn’s paper that he published on an imine motor (which is just the A to B to C).7) Here, you have an imine that is planar in the ground state and is preferred in the cis rather than the trans. If you shine light on it, it goes into the nonplanar excited state and comes down with equal probability cis and trans. If cis is favored, then it has to make a transition back to the favored cis state. That is truly autonomous breaking of microscopic reversibility – since it goes A, B, C – and if you put it on a surface you break macroscopic reversibility as well. It is perhaps the simplest example that I have seen. Chairman: Coming back to the point of Jean-Pierre Sauvage, I would also like to raise one example, which has been reported by Bob Waymouth a couple of years ago. He used an asymmetric metallocene catalyst for propylene polymerization. According to his proposal, the metallocene is rotating and the stereospecificity changes during the rotations. He can thus obtain a multiple-block copolymer with different stereoregularities and, as a result, the polymer shows elasticity. If there are no further comments, I would like to thank you very much. 7) Lehn, J.-M. (2006) Chem. Eur. J., 12, 5910.

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Part Five Towards Molecular Logics and Artificial Photosynthesis


319

23 Chairman’s Comments A. Prasanna de Silva

Let’s try a little quiz. Think of the top ten one-word issues that concern our world today. The hedonistic among you will probably have “sex,” “drugs,” and “rock-nroll” on your list. The socially conscious might have “food,” “water,” “peace,” and “climate.” But in the final analysis, I would bet that most of us would choose “energy” and “information.” This session of the meeting concerns both of these issues. Our information age depends on logic gates for data processing which is currently dominated by semiconductors. However, the success of silicon-free lifeforms reminds us that molecular information handling is by no means second to semiconductor technology. While engineers and physicists deal with the latter, molecular logic and computation [1] is a suitable field for the efforts of chemists and biologists, with the opportunity for cross-fertilization. The world energy currency of fossil fuels is the result of green plant photosynthesis of previous aeons. Artificial photosynthesis [2] is, therefore, a valuable goal as energy sources become more precious, and chemists can productively aim for molecular systems to achieve this. Diversions of natural photosynthesis to produce usable energy are also of great interest. Interestingly, both of these fields have benefited greatly from photochemical ideas. Artificial photosynthesis requires such ideas as a matter of definition and, as molecules operate in nanometric spaces barred to semiconductor devices, we can command and control molecules in the easiest way with light. Notably, luminescence from even single molecules is detectable [3]. Although green plant photosynthesis depends crucially on photoinduced electron transfer (PET) [4], PET is also a widely used design in luminescent molecular logic devices and switches [5]. Although another meeting session will cover devices, it is worth noting that applications concerning the principles of molecular logic and artificial photosynthesis are already available in blood diagnostics [6], object recognition [7], and dye-sensitized solar cells [8], respectively. This meeting session centers on a report by Devens Gust, who has contributed to both fields under discussion [9, 10], including the achievement of the first longlived charge separation in a molecular triad [11]. His report will be supported by four three-slide presentations by Vincenzo Balzani [12], Graham Fleming [13], 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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Alberto Credi [14], and Avi Shanzer and colleagues [15]. So, let’s look forward to a stimulating session.

References 1 de Silva, A.P. and Uchiyama, S. (2007) Nat. Nanotechnol., 2, 399. 2 Collings, A.F. and Critchley, C. (eds) (2005) Artificial Photosynthesis, WileyVCH Verlag GmbH, Weinheim. 3 Holman, M.W. and Adams, D.M. (2004) ChemPhysChem, 5, 1831. 4 Balzani, V. (ed.) (2001) Electron Transfer in Chemistry, vols 1–5, Wiley-VCH Verlag GmbH, Weinheim. 5 de Silva, A.P., Gunaratne, H.Q.N., Gunnlaugsson, T., Huxley, A.J.M., McCoy, C.P., Rademacher, J.T., and Rice, T.E. (1997) Chem. Rev., 97, 1515. 6 Tusa, J.K. and He, H. (2005) J. Mater. Chem., 15, 2640. 7 de Silva, A.P., James, M.R., McKinney, B.O.F., Pears, D.A., and Weir, S.M. (2006) Nat. Mater., 5, 787. 8 Gratzel, M. (2005) Inorg. Chem., 44, 6841.

9 Gust, D., Moore, T.A., and Moore, A.L. (2006) Chem. Commun., 1169. 10 Moore, A.L., Gust, D., and Moore, T.A. (2007) Acta Chim., 50–56, 308. 11 Moore, T.A., Gust, D., Mathis, P., Mialocq, J.C., Chachaty, C., Bensasson, R.V., Land, E.J., Doizi, D., Liddell, P.A., Lehman, W.R., Nemeth, G.A., and Moore, A.L. (1984) Nature, 307, 630. 12 Balzani, V., Venturi, M., and Credi, A. (2003) Molecular Devices and Machines, Wiley-VCH Verlag GmbH, Weinheim. 13 Engel, G.S., Calhoun, T.R., Read, E.L., Ahn, T.-K., Mancal, T., Cheng, Y.-C., Blankenship, R.E., and Fleming, G.R. (2007) Nature, 446, 782. 14 Credi, A. (2007) Angew. Chem. Int. Ed., 46, 5472. 15 Margulies, D., Felder, C.E., Melman, G., and Shanzer, A. (2007) J. Am. Chem. Soc., 129, 347.

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24 Towards Molecular Logic and Artificial Photosynthesis Report Devens Gust, Thomas A. Moore, and Ana L. Moore

24.1 Introduction

Whilst the two topics of this chapter – molecular logic and artificial photosynthesis – are seemingly disparate, they have a number of fundamental chemical and physical processes in common. As will be illustrated, both molecular logic operations and bioinspired solar energy conversion can use photoinduced electron transfer (PET) and excitation energy transfer to enable the useful exchange of energy and/or information among chromophores and donor and acceptor moieties. The two research areas are immense, and the scientific literature reports a very large number of studies, many of which are interesting and important. It is impossible to comprehensively review either field in the space available here, let alone both together. Consequently, only a brief overview of the history of each area, recent developments, and future directions will be presented, and these will be illustrated with some examples from the laboratory and the literature. Unfortunately, space constraints require that many important papers are overlooked.

24.2 Artificial Photosynthesis

Artificial photosynthesis is the conversion of sunlight to useful forms of energy inspired by the natural photosynthetic process. Photosynthesis is responsible for essentially all energy used by living things, and is the source of the energy stored in fossil fuels such as coal, petroleum, and natural gas. It is also responsible for the oxygenated atmosphere of the Earth, and is a major component of the carbon cycle. Thus, an understanding of the photosynthetic process and the application of similar photochemistry to solar energy conversion for technological purposes has long been a dream of chemists. In 1912, a prescient article by Giacomo Ciamician, one of the fathers of modern photochemistry, revealed the promise of 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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artificial photosynthesis [1]. Although this promise has yet to be realized, significant progress has been made, as exemplified in the following subsections. 24.2.1 Natural Photosynthesis

Before discussing artificial photosynthesis, a short review of the natural process is indicated. In green plants, algae and cyanobacteria, solar light energy is used to reduce carbon dioxide to carbohydrate and other carbon compounds. The electrons required for this process are obtained from water oxidation, and the oxygen produced is released to the atmosphere. (The burning of fossil fuels represents a reversal of this process, releasing carbon dioxide to the atmosphere.) Thus, plant photosynthesis involves the linear electron flow from water to reduced carbon, powered by light. A closely related type of photosynthesis occurs in photosynthetic bacteria, where the process is cyclic in electrons but results in the conversion of solar energy into chemical potential that fills the energy needs of the organism. Photosynthesis occurs in lipid bilayer membranes, wherein reside the photosynthetic proteins. Photosynthesis begins with the absorption of light by antenna chromophores, followed by singlet–singlet energy-transfer processes that move the excitation to another pigment–protein complex called the reaction center. Many antenna chromophores donate excitation to each reaction center. The antennas are “tuned” to the spectrum of sunlight available to the particular organism in its particular environment. In addition, the antenna system performs regulatory functions. Sunlight is a diffuse energy source and, under dim light conditions, an organism maximizes its utilization of sunlight by establishing large antenna arrays for each reaction center. However, if the sunlight becomes brighter (e.g., due to cloud movement or another change in shading), the photosynthetic machinery may be overdriven because some of the metabolic reactions cannot keep up with the influx of photosynthetic energy. Under such conditions, reactive intermediates such as radicals and triplet states may be produced, and these will injure or even kill the organisms. Photosynthesis protects against such damage via a variety of regulatory and photoprotective mechanisms, several of which involve the antenna system. For example, photoprotection can reduce the flow of excitation energy to the reaction center, and thereby limit photodamage. When the excitation energy reaches the chlorophylls in the reaction center, it is converted to electrochemical potential energy via the process of PET. In bacteria, an excited bacteriochlorophyll “special pair” donates an electron to a metal-free bacteriochlorophyll (bacteriopheophytin) via an “accessory” bacteriochlorophyll molecule. This all happens within about 4 ps of excitation, and preserves some of the photon energy as electrochemical potential in a charge-separated state. Recombination of this charge-separated state, with concurrent loss of the stored energy as heat, is precluded by a charge-transfer reaction, wherein an electron is shifted from the bacteriopheophytin to a quinone. Finally, an electron migrates on to a second quinone near one side of the photosynthetic membrane. The positive charge, or


“hole”, left on the special pair migrates to a cytochrome redox system on the other side of the membrane. In water-oxidizing organisms, the process is similar, but in this case two photosystems operate in series, and in one of them, photosystem II, the hole is used to oxidize water at a special manganese-containing site in the protein complex. The relatively complex series of electron-transfer events in the reaction center is designed to stabilize the charge-separated state temporally, so that the energy may be converted to other forms rather than be lost by recombination of the electron and hole. This stabilization is accomplished by moving the electron through a series of donor–acceptor species, each located farther from – and consequently less electronically coupled to – the special pair. Each step of this multistep electron transfer sequence is short range, and therefore rapid, but the result is a large spatial separation of the hole and electron. This leads to weak electronic coupling interactions and a long lifetime for charge separation. The result of the reaction center function is charge separation across the photosynthetic membrane. The next component of the system, the cytochrome bc1 complex in bacteria, uses the redox energy stored by the reaction center to pump protons across the membrane, generating a pH imbalance. This proton-motive force (pmf) consists of both a concentration gradient and a membrane potential (measured in volts), and is the common denominator of bioenergetics used by all organisms. In photosynthetic organisms, the pmf is produced using energy from sunlight via the reaction center; in all organisms, it is generated using energy from the oxidation of carbohydrates or other reduced species. As a result of the function of the bc1 complex and associated proteins, the redox potential generated by the reaction center in bacteria drives proton translocation across the membrane, but the electrons themselves return to the reaction center in a cyclic fashion. Although the pmf may be used by organisms for many purposes, photosynthetic bacteria use it to drive the production of adenosine triphosphate (ATP) by ATP synthase. (The pmf is also coupled to the oxidation of carbon sources to provide the electrons for use in biosynthesis.) This transmembrane protein allows protons to flow through it, across the membrane, in the thermally spontaneous direction of the proton gradient established by the bc1 complex. The energy released is used to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate. The ATP is then used by the organism for its various metabolic needs. Green plant photosynthesis differs in that the electron flow is not cyclic, but vectorial. Electrons from water oxidation are used in the synthesis of carbohydrate and other reduced carbon compounds from CO2. Biology is the best example of functional nanotechnology. Most biological systems work via nanoscale molecular devices that function together to accomplish the task at hand. Photosynthesis is an excellent example of natural nanotechnology. The antenna system is a photonic device at nanoscale; the reaction center is a photovoltaic; the cytochrome bc1 complex is a transmembrane pump; and ATP synthase is a nanoscale chemical factory. ATP synthase is also a molecular motor, as the flow of protons through it results in a rotary motion of peptide residues that is coupled to ATP synthesis.

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24.2.2 Realizing Artificial Photosynthesis

The fundamental processes of photosynthesis are therefore: 1) Light absorption by antennas that cover the useful solar spectrum (∼400–850 nm). 2) Excitation energy transfer to move the excitation energy from the site of light absorption to the reaction center. 3) PET to convert the sunlight stored as excitation energy into electrochemical potential energy. 4) Utilization of chemical potential to generate protonmotive force, ATP, redox potential and, ultimately, reduced carbon compounds. Artificial photosynthesis research endeavors to use these same chemical processes to convert the energy of sunlight to technologically useful forms of energy, and in the process to learn more about how natural photosynthesis works. Whereas all four of the above areas are amenable to bioinspired approaches, the present discussion will begin with attempts to mimic the basic reaction center function, because this is the real “heart” of the energy conversion process. 24.2.2.1

Mimicking the Reaction Center

Porphyrin-Quinones and Related Systems The simplest approach to an artificial reaction center is to mix a chlorophyll and an electron acceptor such as a quinone (Q) together in solution, and irradiate with light. This is easily done, although synthetic porphyrins (Ps) are typically used in place of chlorophyll because they are usually more stable and more readily prepared in the laboratory. The idea is that excitation will generate the porphyrin first excited singlet state (1P), which will then donate an electron to a quinone, forming a P•+, Q•− charge-separated state. However, this approach turns out to be too crude, as the first excited singlet state of a metallated porphyrin has a lifetime of only a few nanoseconds, and decays by various photophysical processes of internal conversion, intersystem crossing to the triplet, and fluorescence. The rate of PET to the quinone will be limited by diffusion, which is too slow to compete well with the unimolecular decay processes at realistic concentrations. Excited triplet states have longer lifetimes, but are of lower energy than singlets, and in general are formed with a lower quantum yield, thus limiting energy conversion efficiency. In addition, with this approach, donor– acceptor distances and orientations cannot be strictly controlled. It is important to do so, as the rates of PET, the recombination of charge-separated states, and energy-transfer processes are all sensitive functions of these parameters. A more fruitful approach to artificial photosynthesis is to covalently link donor and acceptor so as to fix, or at least limit, separations, orientations, and electronic coupling. When donors and acceptors are linked in this way, electronic coupling, which affects the electron-transfer rates, usually occurs through the linkage bonds by the superexchange mechanism, wherein linkage orbitals mix with those of the


donor/acceptor. In linked systems, experimental data and/or theoretical molecular modeling can use structural information to provide a detailed electronic structure and a mechanistic description of the electron transfer. This information may then be used to fine-tune the structure in order to achieve the desired thermodynamic and kinetic parameters for a particular solar energy conversion scheme. The first example of this approach using chromophores related to those in reaction centers was molecular dyad 1, prepared by Loach and coworkers [2, 3]. The molecule consists of a porphyrin light absorber and electron donor linked to a quinone electron acceptor. A similar molecule was reported by Tabushi and coworkers in 1979 [4]. The photochemistry of such molecules will be exemplified by that of P-Q dyad 2 in Figure 24.1 [5]. Figure 24.2 shows the relevant states of the molecule and interconversions among them. Excitation of the porphyrin populates the first excited singlet state of the porphyrin, 1P-Q. Relaxation of this state by internal conversion, intersystem crossing and fluorescence occurs with a time constant of 7.7 ns (krel = 1.3 × 108 s−1). In the dyad, however, the lifetime of 1P-Q in dichloromethane solvent is only 100 ps because of rapid PET to the quinone (kPET = 9.9 × 109 s−1). The resulting P•+-Q•− charge-separated state preserves a significant fraction of the excitation energy as electrochemical potential, and is formed in high quantum yield (Φ = 0.99). Thus, this simple dyad mimics some of the initial photochemical processes in the reaction center, converting light to a potentially more useful form of energy. A very large number of P-Q dyads have been reported [6–16]. By studying these and other donor–acceptor molecules, a huge amount has been learned about the effects of thermodynamic factors, electronic coupling, solvent and reorganization energy, and temperature on the rate constants for PET. Much of these data can be interpreted in terms of the electron-transfer theories originally proposed by Marcus [17–20], Hush [21–23], and Levich [24], and later greatly expanded by others. This body of work has established many of the basic principles necessary for the rational design of artificial reaction centers. From the point of view of artificial photosynthesis, however, these and related dyads have one vexing drawback. The very electronic coupling and thermodynamic factors that favor formation of charge-separated states by rapid PET also result in

Figure 24.1 Structures of porphyrin-quinone dyad early photosynthetic reaction center model compounds.

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Figure 24.2 Transient states of porphyrin-quinone dyads that are relevant for artificial

photosynthetic function, and their interconversion pathways.

a rapid charge recombination to the ground state, with consequent loss of the stored energy as heat. For example, kCR for dyad 2 (Figure 24.2) is on the order of 1 × 1010 s−1. It is very difficult to devise methods for harvesting and stabilizing the electrochemical energy stored in the P•+-Q•− state that successfully compete with recombination on such a time scale, and for some years this factor has greatly limited the progress made in artificial photosynthesis. However, by examining the structure and photochemistry of natural reaction centers, a strategy for overcoming this problem can be identified. As mentioned above, reaction centers use a series of short-range, rapid and efficient electrontransfer steps to move electrons across the width of the lipid bilayer membrane, thereby separating the electron and hole, and stabilizing the charge-separated state for a much longer time. During the early 1980s, the implementation of this strategy in artificial photosynthesis was reported [25, 26], where molecular triad 3 (Figure 24.3) consists of a P and a Q similar to those of 2, but the P bears a


Figure 24.3 The first carotene-porphyrin-quinone triad artificial photosynthetic reaction center, 3. This molecule uses a multistep electron-transfer strategy to increase the lifetime of the C•+-P-Q•− charge-separated state.

carotenoid polyene (C). Carotenoids fill a variety of roles in photosynthesis and artificial photosynthesis; in 3, the carotene acts as a secondary electron donor. The photochemical behavior of 3 (Figure 24.4) begins with PET from the porphyrin excited singlet state (C-1P-Q) to generate the charge-separated state C-P•+-Q•−, just as occurs in dyad 2. Competing with the rapid charge recombination of C-P•+-Q•−, however, is a charge-shift reaction in which an electron migrates from the carotenoid to the porphyrin radical cation, yielding C•+-P-Q•−. The lifetime of this final state is 300 ns in dichloromethane, and up to 2 µs in more polar solvents. Thus, the lifetime of the final charge separated state in the triad is at least three orders of magnitude longer than that in the corresponding dyad. This long lifetime is due to several factors. First, the electronic coupling between the radical ions of C•+-P-Q•− is much weaker than that in the dyad, due to the intervening porphyrin moiety, and this inhibits recombination directly to the ground state (CR2 in Figure 24.4). Second, the reaction occurs in the “inverted” region of the Marcus rate constant versus free energy relationship [18, 19], wherein charge recombination with a high thermodynamic driving force is inhibited. Alternatively, recombination by a two-step process, wherein C•+-P-Q•− returns to C-P•+-Q•−, followed by rapid recombination, is slow because the first step is endergonic [27]. Biology thus provides a solution to the conundrum of rapid charge recombination in artificial photosynthesis. Carotenoids were used to implement this multistep or “triad effect” strategy because, during the course of extensive studies of energy transfer in carotenoidporphyrin dyads, it had been observed that holes produced by pulse radiolysis in these dyads rapidly localized on the carotenoid moiety. It was proposed, in 1981, that the merger of a carotenoid-porphyrin dyad with a P-Q dyad to form a triad could lead to charge shift and a long-lived, highly energetic redox species. Another triad, P-Q-Q (4) was also reported during the early 1980s (Figure 24.5) [28]. This molecule was designed to exhibit a stepwise electron transfer from the porphyrin excited state to the chloroquinone, to yield a final P•+-Q-Q•− state. The lifetime of this state, 300 ps, was indeed longer than that reported for related dyad 5 (130 ps). This extended lifetime was attributed to a larger spatial separation

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Figure 24.4 Transient states of carotenoid-porphyrin-quinone triads that are relevant for

artificial photosynthetic function, and their interconversion pathways.

Figure 24.5 A porphyrin-diquinone triad, 4, and porphyrin-quinone dyad model compound, 5.

between the radical ions in 4 than in 5, although the improvement was less than threefold. The reason for the relatively rapid charge recombination in 4 compared to 3 is likely internal rotations about the carbon–carbon single bonds in the linkages, which allow the porphyrin and chloroquinone to approach one another closely [29]. This and similar experiments have highlighted the advantages of using conformationally rather rigid linkages to join the redox centers of artificial reaction centers. Such linkages not only retard charge recombination, but also allow the


Figure 24.6 A successful molecular pentad artificial photosynthetic reaction center, 6. The arrows indicate the directions of electron transfer (ET), singlet–singlet excitation energy transfer (SS), and triplet–triplet energy transfer (TT).

ready estimation of donor–acceptor separations and orientations, with consequent application of electron-transfer theories to molecular design. The initial investigation with triads was followed by many studies of triads and more complex molecules with multiple donors and acceptors [6–16, 30]. An example of one of the more structurally complex systems is pentad 6 (Figure 24.6) [31, 32]. The C-P-P-Q-Q pentad consists of a linear arrangement of two porphyrins, one of which bears a diquinone electron-accepting unit, and the second a carotenoid electron-donating moiety. In the zinc-containing version of the pentad, excitation of the zinc porphyrin is followed by singlet energy transfer to the free base porphyrin to yield C-P-1P-Q-Q, which may also be produced by direct excitation of the free base. Subsequent PET yields an initial charge-separated state C-P-P•+Q•−-Q. Charge shift reactions move an electron to the terminal quinone, and the hole to the zinc porphyrin, and then on to the carotenoid to give a final C•+-P-PQ-Q•− state. This species is formed with a quantum yield of 0.83 and has a lifetime of 55 µs. In the free base form of the pentad, which contains no zinc, the lifetime of the corresponding state is 340 µs. These pentads and a variety of other molecules synthesized by several different research groups have amply demonstrated that the multistep electron transfer approach can yield charge separated states that rival natural reaction centers in terms of quantum yield, fraction of energy stored, and lifetime. Inorganic Chromophores The examples given thus far all employ porphyrins as the primary electron donors, and so do not stray too far from the natural chlorophyll chromophores. Alternatively, metal complexes – especially ruthenium trisbipyridyls – may be used as the chromophores and electron-donor species [33, 34]. Three of many examples are shown in Figure 24.7. In the first of this class of molecules, 7, which was reported in 1987 by Meyer and coworkers [35], the visibleabsorbing ruthenium complex is attached to a viologen-like electron acceptor and a phenothiazene (PTZ) secondary electron donor. Although the details of the charge separation process in 7 are a slightly different from those in triad 3, the

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Figure 24.7 Three examples of artificial photosynthetic reaction centers based on ruthenium

complexes.

overall process is also a series of sequential electron transfers that isolate the radical ions on the acceptor and secondary donor, thus reducing the electronic coupling between these radical ions. The result is a charge-separated state with a lifetime of 160 ns and a quantum yield of 0.26. One complication with molecules such as 7 is the propeller-like conformation of the tris-chelate at ruthenium, which gives rise to chirality and the possibility for stereoisomerism. Although the resulting stereoisomers are usually difficult to separate, one solution to this problem is a complex such as that in 8 [36]. Whilst the terpyridine complexes have different photophysical properties from the bipyridine complexes, the two terpyridine ligands are orthogonal, thus eliminating chirality and some possibilities for isomerism. Triad 9 is a recent example that combines two ruthenium complex structural motifs [37]. Fullerenes as Electron Acceptors The quinone-based artificial reaction centers discussed above typically feature charge-recombination reactions for the initially formed charge-separated state, the rate constants of which are comparable to, or sometimes larger than, those of the formation of these states via PET. This is a consequence of the relatively large quinone reorganization energy for electron transfer which, in accord with Marcus theory, tends to locate the PET reactions on the initial part of the Marcus curve, where the reactions are slower. Additionally, the charge recombination reactions are located close to the top of the curve, where the rate constants are large. Electron acceptors with lower reorganization energies therefore offer potential advantages, as discussed below. In 1994, the first example was reported of the use of a fullerene as an electron acceptor for a porphyrin excited state donor, dyad 10 (Figure 24.8) [38]. Since that


Figure 24.8 The first porphyrin-fullerene artificial reaction center, 10, and a carotenoidporphyrin-fullerene triad molecule, 11.

time, a large variety of multicomponent artificial reaction centers based on fullerene acceptors have been reported [39–48]. Here, triad 11 (Figure 24.8) will be used to exemplify the photochemistry of this class of molecules [49, 50]. In this C-P-C60 triad, the fullerene fulfills the role of the quinone in triad 3. In 2-methyltetrahydrofuran solution, excitation of the porphyrin yields C-1P-C60, which decays by PET to the i− with a quantum yield fullerene with a time constant of 32 ps, providing C-Pi + -C60 of 0.99. Competing with charge recombination (τ = 3.3 ns) is a charge shift to the i− with an overall quantum yield of 0.95. The carotene (τ = 125 ps), to yield Ci + -P-C60 charge-separated state has a lifetime of 57 ns. A closely related C-P-C60 triad has a lifetime for charge separation of 170 ns at ambient temperature, and ∼1 µs at 77 K [50]. This triad and similar fullerene-based artificial reaction centers have photochemical characteristics that differ markedly from those of quinone-based molecules with related structures. Most obvious is the fact that although the energetics of electron transfer for quinone-based 3 and for 11 are roughly similar, PET is i− is more than 10-fold slower faster in 11, but the charge recombination of C-Pi + -C60 •+ •− than that of C-P -Q . In addition, PET in 3 and other quinone-based molecules ceases when the solvent is frozen, but in fullerene-based systems it still occurs below 10 K [51]. Finally, although charge recombination of C•+-P-Q•− yields the ground state, a recombination of 11 and related triads usually gives the carotenoid triplet state, 3C-P-C60 [50–56]. Recombination to yield triplets is a characteristic of bacterial photosynthetic reaction centers [57–65], but is uncommon in artificial systems [66]. All of these unusual behaviors are consistent with two closely related ideas: (i) the low reorganization energy of fullerenes in electron transfer [43, 67, 68]; and (ii) the low sensitivity of the fullerene radical anion to solvent stabilization [69, 70]. A small reorganization energy for the fullerene relative to quinone, coupled with low reorganization energies for the other electron transfer components, has the effect of shifting the maximum of the Marcus electron-transfer rate constant versus free energy change relationship toward smaller thermodynamic driving

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force values. Other things being equal, this will speed up the PET reaction, slow down charge recombination, and favor recombination to a triplet state over recombination to the ground state. A lower sensitivity to solvent stabilization of the radical ions means that less driving force for PET is lost when polar solvents freeze and lose mobility at low temperatures. The loss of mobility prevents solvent dipoles from rotating to stabilize the charge-separated state, and it is this loss of driving force that is primarily responsible for the disappearance of PET behavior in quinone and related systems when the solvent becomes glassy. As with quinone-based artificial reaction centers, elaborate multicomponent molecules based on fullerene acceptors have been prepared. One of many examples is tetrad 12 (Figure 24.9) [71]. Long Charge Separation Lifetimes in Low-Molecular-Weight Dyads Very recently, extremely long charge separation lifetimes have been reported in low-molecularweight dyad molecules. The primary example is dyad 13, the 9-mesityl-10methylacridinium ion shown in Figure 24.10 [72, 73]. Photoexcitation of 13 is followed by a charge-shift reaction, PET from the mesitylene moiety, to yield an electron-transfer state, the lifetime of which at 77 K is reportedly almost infinite. The unprecedentedly long lifetime was ascribed in part to the very high energy of the electron-transfer state (2.37 eV), which places the decay reaction far into the inverted region of the Marcus relationship. However, the interpretation of these experiments has been seriously questioned, and alternative explanations

Figure 24.9 A tetrad fullerene-containing artificial reaction center that demonstrates long-lived charge separation.

Figure 24.10 The 9-mesityl-10-methylacridinium ion, which has been reported to undergo a

photoinduced charge shift reaction to produce an extremely long-lived charge-separated state.


suggested [74–77]. If other examples of this phenomenon are discovered, it will be a significant advance. From the point of view of artificial photosynthesis, the use of such molecules would require implementation of this effect with larger chromophores that absorb throughout the visible region of the solar spectrum. 24.2.2.2 Artificial Antenna Systems As discussed earlier, natural photosynthesis employs antenna systems to feed excitation energy from light of various wavelengths to the reaction center. Many approaches to artificial antenna systems have been investigated, including arrays of porphyrins or chlorophyll molecules organized by covalent linkages, or by selfassembly. Energy transfer among the antenna chromophores occurs by the Förster mechanism, the Dexter mechanism (which requires overlap between donor and acceptor orbitals), or some combination thereof. Many motifs for covalently linked porphyrin arrays exist; a few examples of cyclic structures are hexad 14 [78, 79], molecular square 15 [80], and dodecamer 16 [81] (Figures 24.11 and 24.12). Linear antennas also exist, including a novel ladder-like structure that acts as a twophoton antenna [82]. Of course, such porphyrin arrays are only useful for artificial photosynthesis if they are coupled to reaction centers, so that energy absorbed by the array migrates to the primary electron donor. An example of such a structure is hexad 17 [83] (Figure 24.13), which consists of a four-zinc-porphyrin antenna covalently linked

Figure 24.11 Two examples of cyclic porphyrin arrays. Molecules of this type can model some

aspects of photosynthetic antenna function. Light is absorbed by one porphyrin chromophore and excitation migrates around the ring via singlet energy transfer.

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Figure 24.12 A very large cyclic porphyrin array, which can also mimic aspects of antenna

function.

Figure 24.13 A porphyrin-fullerene antenna-artificial reaction center construct. Light is absorbed by the zinc porphyrins, and excitation migrates to the free base porphyrin, which initiates photoinduced electron transfer to the fullerene.

to a free base porphyrin-fullerene artificial reaction center. Excitation of a zinc porphyrin of 17 in 2-methyltetrahydrofuran solution is followed by migration of excitation energy through the zinc porphyrin array (τ = 50 ps), and ultimately to the free base porphyrin, the excited state of which is lower in energy than those


of the zinc porphyrins (τ = 30 ps). The free base porphyrin excited state donates an electron to the fullerene acceptor (τ = 25 ps) to form an initial charge-separated state. Because the zinc porphyrins are more easily oxidized than the free base, the hole migrates out into the zinc porphyrin system (τ = 380 ps) to form a final charge-separated state, which has a lifetime of 240 ns. The overall process occurs with a quantum yield of 90%, which shows that it is possible to efficiently combine antenna function with PET within the same molecule. In general, porphyrins – like their chlorophyll relatives – do not absorb light strongly throughout the visible part of the solar spectrum. This means that porphyrins or chlorophylls by themselves do not comprise an ideal antenna system. In photosynthetic organisms, auxiliary chromophores such as carotenoid polyenes, phycoerythrins and phycocyanins are employed to cover the entire visible range; this suggests that artificial antennas employing chromophores other than porphyrins and their relatives could be useful. Heptad 18 (Figure 24.14) illustrates the coupling of nonporphyrinic antennas to an artificial reaction center [84, 85]. The five antennas of 9,10-bis(phenylethynyl) anthracene, together with the porphyrin-fullerene charge-separation unit, are all organized by a central hexaphenylbenzene core that imparts a high degree of structural rigidity to the molecule. Energy transfer from the five antennas to the porphyrin occurs in less than 10 ps, with a quantum yield of 1.0. Comparisons with model compounds and theory have suggested that the Förster mechanism plays a major role in the extremely rapid energy transfer, which occurs at rates

Figure 24.14 An artificial antenna-reaction

center construct with non-porphyrin antennas. The bis(phenylethynyl)anthracene moieties absorb light in a spectral region

similar to that of carotenoids, and transfer the excitation to the porphyrin-fullerene reaction center in picoseconds.

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comparable to those seen in some photosynthetic antenna systems. The throughbond, electron-exchange mechanism also contributes. The porphyrin excited i− chargesinglet state donates an electron to the attached fullerene to yield a Pi + -C60 separated state, which has a lifetime of 15 ns. The quantum yield of charge separation based on light absorbed by the antenna chromophores is 96%. 24.2.2.3 Using the Stored Energy Although considerable progress has been made in the design and preparation of artificial photosynthetic reaction centers and antennas, investigations of the incorporation of such systems into useful devices for solar energy conversion are much less advanced. Two general approaches are electricity production, and the synthesis of fuels. By analogy with solid-state solar cells, artificial reaction centers (which are molecular photovoltaics) could be used in principle to produce electricity for technological purposes. However, electricity alone cannot fill all of society’s energy needs; some form of energy storage is also required. Thus, better batteries, or the use of artificial reaction centers to produce fuels such as methanol or hydrogen will also be necessary. Many approaches to this problem are being investigated, and discussing them is beyond the scope of this chapter. In addition to functionality, practical applications of these approaches to artificial photosynthesis will have to address questions of the stability, cost and large-scale availability of materials.

Figure 24.15 A light-driven artificial biological power plant. Light absorption by the triad artificial reaction center spanning the membrane of a liposome drives vectorial proton transport across the membrane to generate the proton-motive force (pmf). The

hydrogen ions are transported by a quinone/ hydroquinone redox-powered shuttle molecule. The natural ATP synthase enzyme uses the pmf to generate ATP from ADP and inorganic phosphate (Pi).

24.3 Molecular Logic

Given the resemblance between artificial reaction centers and their natural counterparts, it might be considered whether these artificial systems could be made to produce biological forms of energy. Indeed, this is possible. For example, artificial reaction centers related to triad 3 have been vectorially inserted into the membranes of liposomes, the spherical lipid bilayers of which isolate an aqueous interior from an external aqueous environment [86] (Figure 24.15). The membranes also contain a quinone that serves as a redox-based shuttle to transport protons across the membrane. In operation, light excitation of the triad initiates vectorial transmembrane proton pumping to produce a pmf. In this way, the system functionally mimics the reaction center and bc1 complex of natural photosynthesis. When natural ATP synthase enzymes are incorporated into the liposomes, the pmf generated by the artificial reaction center system drives the production of ATP, thus completing mimicry of the bacterial photosynthesis system [87].

24.3 Molecular Logic 24.3.1 What is Molecular Logic?

Digital computers perform mathematics by using combinations of simple twostate (on or off, 0 or 1) electronic switches. By linking these switches in various ways, it is possible to create logic gates that perform the various Boolean logic operations necessary for digital mathematics. As there are many different types of two-state switches, there are in principle many ways to build a computer. The major goals in computer hardware development have been – and continue to be – increased speed and capability coupled with reduced size, cost, and power consumption. The basic limitations to further development using current materials and fabrication methods have spurred interest in alternative platforms for computing. Hence, molecules are natural candidates for such applications, given their size and versatility. Indeed, the possibility of using atoms and molecules in this fashion was first suggested by Feynman, way back in 1960 [88]. Any molecule that can be transformed reversibly between two (or more) states by a stimulus may be thought of as a type of molecular switch, and thus a candidate for molecule-based logic or data storage. An initial state could represent off, for example, and a second state on. To be of any use, an input to switch the molecule on, a reset operation to turn it off, and a readout to determine the state of the switch are necessary. Examples of inputs and/or outputs are addition of chemicals, light, electrochemical operations, electric fields, magnetic fields, and heat. Approaches to molecular logic using many of these have been investigated [89–99]. Chemical approaches to molecular logic are interesting because the human brain is also a chemistry-based logic machine. For potential application in devices, the

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use of light as inputs and outputs offers several advantages. The physical addition of materials as inputs is avoided, and there is no build-up of reaction products after many logic cycles. Photochemical reactions are usually very rapid, permitting, in principle, high data processing speeds. The remote delivery of inputs and sensing of outputs is possible, from a scale of kilometers down to nanometers. Unlike the situation with the usual electronic circuits, 3-D architectures are possible, leading potentially to high device densities. Multiplexing is also possible, where more than one type of device can occupy the same volume element, yet be addressed by different frequencies of light. In this brief introduction, most of the examples of molecular logic (but not all) will be drawn from photochemical implementations. 24.3.2 Simple Switches

Figure 24.16 shows an example of a simple photochemical switch based on a photochromic molecule. Photochromes exist in two metastable states that may be interconverted by photoisomerization, and sometimes thermally. The photochrome in the figure, as reported by Lehn and coworkers [100], is a member of the dithienylethene family of molecules, which has been extensively studied by Irie and colleagues [101, 102]. The open, noncyclic form of the dithienylethene shown on the left of Figure 24.16 absorbs in the ultraviolet (UV) portion of the spectrum. Irradiation in this spectral region (e.g., at 365 nm) results in photoisomerization to the closed form shown on the right. This more-planar structure absorbs strongly in the visible, and visible irradiation will revert the molecule to the open form. Of course, because the two forms are constitutional isomers, they differ in all of their chemical and physical properties. One property of interest is the oxidation potential, which is 0.90 V versus SCE (standard calomel electrode) in the open form, but 0.34 V in the closed form. Such differences in properties can be exploited for readout signals, or for communication with other molecular components. Several photochemical switches may be combined within the same molecule; an example is shown in Figure 24.17. Here, the molecule contains two dithienylethene molecular switches, and all three of the states shown can be accessed photochemically [103]. Great care must be taken in the design of molecules containing multiple photochromes, or photochromes with other chromophores. Although electronic interactions between chromophores can be useful for

Figure 24.16 A simple dithienylethene-based photochemical molecular switch.


Figure 24.17 The three states of a molecular switch consisting of two covalently linked

dithienylethenes.

Figure 24.18 A molecular AND gate with chemical inputs and fluorescence readout.

device design (vide infra), such interactions can also quench photochemistry and preclude photoisomerization [104]. 24.3.3 Chemically Operated Logic Gates

Single-molecule multi-input Boolean logic gates of some complexity may be constructed by combining two or more molecular switches covalently. The switches interact with each other, or with a third moiety, so as to generate an output that exhibits the required logic properties. A common and useful example is the AND gate. This gate has two inputs, either of which may be either on or off, and a single output. The output is initially in the off state, when both inputs are off. Neither input, by itself, turns the gate on, but when both inputs are switched on, the output produces an on response. Figure 24.18 illustrates a chemically operated AND gate molecule [105] consisting of an anthracene fluorophore linked to an amine and a crown ether. Here, the anthracene fluorescence represents the output of the molecular device. In the neutral form of the molecule, both the amine and the

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crown ether quench the anthracene fluorescence via electron-transfer phenomena, and the gate is off. The addition of acid (input A) eliminates quenching by the amine via protonation, but anthracene fluorescence is still quenched by the crown ether, and the output remains off. Alternatively, the addition of sodium to the neutral molecule (input B) forms a complex with the crown ether, and this eliminates fluorescence quenching by the ether. However, anthracene fluorescence is still not observed due to quenching by the amine. Nonetheless, if both sodium ions and acid are added to a solution of the molecule, both quenching mechanisms are abolished, and the anthracene fluoresces, generating an on output signal. Thus, the molecule fulfills the requirements of an AND logic gate. Many other chemically operated logic gates have been reported, and even “molecular machines” and shuttles have been designed as logic gates. An exclusive OR (XOR) gate, for example, also features two inputs and a single output. With no inputs on, the output is off. Either input alone turns the gate on, but when both inputs are applied simultaneously, the gate remains off. A pseudorotaxane-based XOR gate has been described [106] where the inputs of acid and base control the threading/unthreading operations that in turn affect fluorescence, the gate output. 24.3.4 Photochemical Logic Gates and Related Devices

As noted above, molecular logic devices with photonic inputs and outputs represent a fertile area of research, with numerous examples having been reported [52, 107–124]. Molecule 19 (Figure 24.19) is an example of an all-photochemical AND gate [115], where the molecule comprises a porphyrin linked to both dihydroindolizine (DHI) and dihydropyrene (DHP)-type photochromes. By virtue of having two photochromic moieties, 19 can exist in four isomeric forms (exclusive of any stereochemistry arising during the photoisomerization process). In order to realize the AND gate function with 19, an experimental protocol for placing the majority of the molecules in a sample into any of the four states by application of combinations of external stimuli must be found. This has been accomplished using light and heat. Typically, input A is defined as heating for 30 min at 55 °C (or pulsed infrared laser irradiation), and input B is red light (590 nm < λ < 900 nm) irradiation. The gate output is strong fluorescence from the porphyrin (e.g., at 720 nm). The molecule, dissolved in 2-methyltetrahydrofuran, is initially set in the state DHP-P-BT, where BT signifies the open, zwitterionic form of the DHI photochrome (Figure 24.19). The molecule was converted to this initial state, and reset after each logic operation, by irradiation with light at 366 nm followed by 254 nm. When the molecule is in this form (19a), the BT moiety strongly quenches the porphyrin first excited singlet state by photoinduced electron transfer. (The time constant for this process is 43 ps, and the unquenched porphyrin singlet excited state lifetime is 11 ns.) The DHP moiety also quenches the porphyrin first excited singlet state (likely also by PET [115]), with a time constant of 1.8 ns. Thus, the porphyrin fluorescence of DHP-P-BT is strongly quenched by both of the appended photochromes, and only weak emission is observed. The fluorescence output is


Figure 24.19 The four photoisomers of triad molecular gate 19. Solutions highly enriched in each of these isomers may be prepared photochemically.

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below a threshold level, and the AND gate output is off. If neither input is applied, the gate remains off, as thermal isomerization at room temperature is slow. If input A is applied, BT is converted to DHI, yielding DHP-P-DHI (19b). The DHI does not quench porphyrin fluorescence, but the DHP is still an active quencher, so the gate output remains off. Alternatively, if input B is turned on, DHP is isomerized to CPD-P-BT (19d), where CPD denotes the cyclophanediene form of the DHP photochrome. The CPD moiety does not quench fluorescence, but BT is essentially unaffected by the amount of red light employed, and continues to quench porphyrin fluorescence, maintaining the gate in the off state. Finally, applying both inputs isomerizes both photochromes, yielding CPD-P-DHI (19c). Neither photochrome quenches the porphyrin excited singlet state, and strong fluorescence is observed, signaling that the output is in the on state. Thus, the molecule meets the criteria for an AND gate, namely that fluorescence output is only observed when both inputs have been turned on. The experimental porphyrin emission intensities at 720 nm for 19 in its various states as an AND gate are shown in Figure 24.20, where the dotted line is a threshold value. Fluorescence intensities above this line represent an on response, and those below the line an off output. Although an “ideal” digital device is either on or off, any real device requires a threshold to define when it is in each state. This is true of the usual electronic switches, as well as molecular and other systems. In fact, much current development activity in electronics is devoted to reducing

Figure 24.20 Response of a solution of 19 used as an AND gate, following combinations of inputs, as listed on the abscissa. Emission from the porphyrin at 720 nm was monitored. The horizontal dashed line

represents a typical threshold value. Fluorescence intensities above this threshold signify an on output, whereas those below the threshold are an off output.


the threshold value for transistors, and thereby reducing power requirements and heat generation by digital circuits. The AND gate 19 can be cycled through its various states many times while still retaining a sufficient signal-to-noise ratio to allow detection of the state of the output. However, in common with most photochromic molecules, repeated cycling does lead to some decomposition, which limits the number of useful cycles. Photodecomposition of this and most other photochromes is promoted by oxygen, and scrupulous removal of oxygen vastly improves performance. In 19 and other molecular logic gates, each component has a vital function, and cooperativity is important to this function. With 19, each of the photochromes responds to a different input, changing its properties via photoisomerization. It also remains in its new isomeric state until reset, serving as a time-independent record of the application of the input. The porphyrin communicates electronically with each of the photochromes, correlating their molecular states in a way that generates the appropriate output pattern for the logic gate function. 24.3.5 Combinations of Logic Gates

Just as switches may be combined to form logic gates, logic gates may be combined to form more complex logic devices. A half-adder, for example, can add two binary digits. This consists of a combination of an AND gate and an XOR gate that share the same two inputs. Molecular triad 20 is an example of an all-photonic molecular half-adder [118]; this consists of three covalently linked photochromic moieties – a spiropyran and two quinoline-derived dihydroindolizines (Figure 24.21). The AND function is based on the absorption properties of the molecule, whereas the XOR function is based on an off-on-off response of the fluorescence to the inputs that results from interchromophore excited state quenching interactions. As indicated in Table 24.1, the inputs are two identical light beams at 355 nm.

Figure 24.21 A photochemical half-adder consisting of three photochromes. The partial

structures at the right show the response of the photochromes to inputs.

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24 Towards Molecular Logic and Artificial Photosynthesis Table 24.1

Truth table for the half-adder.

Input A λ = 355 nm

Input B λ = 355 nm

Output X (A @ 581 nm) AND gate (carry digit)

Output Y (Em. @ 690 nm) XOR gate (sum digit)

Binary sum

0 1 0 1

0 0 1 1

0 0 0 1

0 1 1 0

00 01 01 10

Triad 20 can exist in six stereoisomeric forms due to isomerization of the three photochromes, all of which are isomerized to their open forms that absorb in the visible (by 355 nm irradiation), and all three revert thermally to their colorless, spiro forms with time constants of a few seconds at ambient temperatures. Thus, when the molecule is exposed to UV irradiation, a photostationary distribution of all six isomers results. However, only one of the six isomers demonstrates spiropyran emission, where the spiropypran is in the open, merocyanine form and the two DHI chromophores are in the spiro form. In all others, the spiropyran emission is either absent or quenched by the other photochromes in their open, betaine forms. This interchromophore communication enables the XOR function [118]. The AND function, the output of which is absorption of the open spiropyran moiety at 581 nm, depends on the fraction of spiropyran in the merocyanine form, which in turn depends on the total light intensity as provided by the inputs. The half-adder is simple to operate, and can be cycled many times. 24.3.6 Reconfigurable Molecular Logic Devices

Molecular logic devices may demonstrate multiple functionality. Photonic systems can be reconfigured in situ by changing their initial state, inputs, and outputs. This could be a major advantage in some applications, because the same physical device could be made to function in multiple ways by simply changing the input characteristics. For example, molecular triad 19 has been implemented as an INHIBIT gate [115], a 2 : 1 digital multiplexer [122], and a 1 : 2 digital demultiplexer [123]. This aspect of molecular logic will be illustrated with the digital multiplexer. A multiplexer is much like a mechanical rotary switch, in that it directs any of several different inputs to a single output. The truth table of a 2 : 1 digital multiplexer is shown in Table 24.2. The two data inputs, A and B, as well as the control input S may be off (0) or on (1), as may be the output. When S is in the off state, the output reports on the state of input B, ignoring the state of input A. After switching S to the on state, the output reports the state of input A, rather than B. When configured as a multiplexer, only three of the four isomers shown in Figure 24.19 are required: CPD-P-DHI, DHP-P-DHI, and CPD-P-BT. The

24.3 Molecular Logic Table 24.2

Truth table for a 2 : 1 multiplexer.

Input A (heat)

Input B (red light)

Input S (green light)

Output (fluorescence)

0 1 0 1 0 1 0 1

0 0 1 1 0 0 1 1

0 0 0 0 1 1 1 1

0 0 1 1 0 1 0 1

function of triad 19 as a digital multiplexer was evaluated using a solution in 2-methyltetrahydrofuran. The initial state was the thermally stable DHP-P-DHI, while input A was heat and input B was red light. An on state for the switching input S was generated by green light. The multiplexer output was porphyrin fluorescence-excited at 590 nm and measured at 653 nm. When the control input was not applied (S = 0), and both A and B were off, the molecule remained in the thermally stable DHP-P-DHI form. Because porphyrin fluorescence in this isomer is quenched by DHP, porphyrin fluorescence is below a threshold level, resulting in an output of 0. Switching on input A by heating the sample has no effect, as the molecule is already in its thermally stable form, and the output remains 0. Alternatively, turning on input B results in absorption of the red light by DHP and photoisomerization to yield CPD-P-DHI. The porphyrinexcited singlet state is no longer quenched, strong fluorescence is observed, and the output of the multiplexer turns on. Finally, applying both inputs A and B to DHP-P-DHI also leads to net isomerization to a distribution containing mainly CPD-P-DHI (as heat has no effect), and the output of the multiplexer again turns on. An examination of the data in Table 24.1 shows that this behavior is exactly that required of the multiplexer with S = 0. The output of the multiplexer reports the state of input B, without regard to that of input A. Next, an identical solution of DHP-P-DHI was subjected to green light, switching control input S to the on state. This irradiation converts the sample to a photostationary distribution consisting mainly of CPD-P-BT. If inputs A and B are both off, then porphyrin emission is quenched by the BT moiety, and the output is also off. However, if heat is then applied (input A on), the sample is converted to CPD-P-DHI, strong porphyrin fluorescence is observed, and the output is on. If instead, input B is turned on (red light for 3.5 min), the molecule remains in the CPD-P-BT form, as photoisomerization of BT to DHI with light of these wavelengths is slow. The output remains off. Finally, if both inputs are applied, isomerization to CPD-P-DHI occurs, and porphyrin fluorescence is again observed (output on). In the context of Table 24.1, after control input S has been applied the output

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now tracks the state of input A, and is insensitive to input B. Thus, the triad solution performs as a 2 : 1 digital multiplexer. The porphyrin fluorescence intensity reports on the state of either input A or input B, depending on the state of control input S. 24.3.7 Ultrafast Switching

The various isomeric states of the photochromic logic gates discussed above are stable for long periods, so that the various switching and measurement operations may be conveniently carried out on a relatively slow time scale. As suggested above, the photoisomerization reactions themselves typically occur on the time scale of a few picoseconds, as do the various interchromophore energy and electrontransfer processes; thus, these devices could in principle switch very rapidly. Similarly, the time scale for thermal isomerization is determined by the temperature. It is possible to prepare and study molecular switches in which the lifetimes of all of the various states are extremely short. An example is molecular triad 21 (Figure 24.22), which is an ultrafast bidirectional switch consisting of a donor chromophore (D) linked to two electron acceptors (A1, A2) [125]. Excitation of the donor is followed by PET to acceptor A1, yielding A1•−-D•+-A2. Excitation of A1•− during its short lifetime initiates electron transfer to A2, giving a final A1-D•+-A2•− charge-separated state. All excitation, PET and charge recombination steps occur in 0

~ 0.6 mm I

~ 5 mm

~ 0.6 mm

17 nm

Au pad

Ga/In Au pad

V +

+ Ga/In

–

–

+ –

+

+ –

–

–

+

+

+ –

–

–

+

+

+ –

–

enhanced electron flow 2.3 nm under forward bias

Au layer (50 nm thick) Cr adhesion layer glass substrate

Figure 29.23 An experimental realization of the Aviram–Ratner conjecture using donor–acceptor molecules oriented as a Langmuir–Blodgett monolayer with symmetrical contacting by Au. The molecules are derivatives of quinolinium tricyanoquinodimethanide equipped with a long aliphatic chain on the quinolinium side. Note that the

measurement bears on a large number of molecules addressed in parallel. In addition, the coupling with the two electrodes is different, due to the presence of the long alkyl chain. Reprinted with permission from Ref. [45]; © 2003, American Chemical Society.

29.3.7 Negative Differential Resistance Devices

Experiments in nanopores conducted by Reed and Tour during 1999 led to the discovery of an important effect, negative differential resistance (NDR), and this triggered a large number of subsequent studies [48]. NDR manifests as a peculiar

29.3 Devices Based on Electronic Effects F

F

S

S F

Figure 29.24 A molecular nanojunction with a single molecule connected by the break junction technique. The two parts of the molecule can be considered as acceptors but

(c)

z (Å)

4

(d)

0

(e)

Au–

0 1 (f)

2

2

15Å × 15Å

with different acceptor properties, and the central dimethyl biphenyl group (which is twisted by sterical interaction) ensures a weak coupling.

e - eF(eV)

(b)

Au0

e - eF(eV)

(a)

Au

F

0

1 PDOS

Figure 29.25 Single electron storage. A gold atom is deposited on an ultrathin NaCl surface (two atomic layers) itself lying on Cu(111). Upon application of a voltage pulse with the tip of a scanning tunneling microscope (with the tip negative), the isolated Au atom is reduced to Au− and remains in this state after the end of the

z (Å)

Au

2

1 2

1 0

15Å × 15Å

0

0

PDOS

1

pulse because it is stabilized by relaxation of the underlying NaCl layers (polaron effect). (a) Scheme of a neutral Au atom on NaCl; (b) Partial density of states for s-orbital of Au; (c) STM image; (d–f) Same elements for the Au anion state. Reproduced with permission from Ref. [47]; © 2004, AAAS.

current–voltage curve where the slope dI/dV is negative in some ranges of voltage, giving a peak-shaped I-V characteristic. This behavior has long been known in conventional electronics, and has been used to create a variety of devices by a proper circuitry, although the NDR element is a two-terminal system. Thus, memory cells, oscillators, microwave components and even logic gates are common applications of NDR. From the point of view of interpretation, NDR is usually the signature of a resonance effect between some electronic levels, and occurs for instance in resonant tunnel diodes. In the case of the Reed–Tour experiments, the molecules were of the phenyleneethynylene family with NO2 and NH2 groups, and a thiol group on one end to ensure fixation on the gold atoms of the bottom of the pore. A strong NDR effect was observed with an abrupt fall of the current in a very narrow potential range (Figure 29.26). However, the results reported by different groups (switching thresholds, on-to-off ratios, etc.) were spread over a large range, and the interpretation revealed difficulties. It was initially suggested that a conformational change would occur for a given voltage, with the phenylene groups adopting a

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29 From Single Molecules to Practical Devices

Gold

H 1.2 1.0 I (nA)

414

0.8

NO2

0.6 H2N

0.4 0.2 0.0 0.0

0.5

1.0 V (V)

1.5

2.0

S

Gold Figure 29.26 The negative differential resistance (NDR) observed at 60 K with a phenylene-

ethynylene molecule bearing amino and nitro groups in a nanopore disposition. Reproduced with permission from Ref. [48]; © 1999, AAAS.

perpendicular disposition with electronic decoupling. Another explanation was based on charge injection, with eventually molecular relaxation; that is, mechanisms either of the polaron type, or the Coulomb staircase/blockade type. Related experiments have been performed in SAMs, with bipyridyl-dinitrooligophenylene-ethynylene dithiol (BPDN-DT) as the active molecule. Detection was carried out using the scanning tunneling microscope tip which, in principle, selects a single active molecule for the measurement. This arrangement also allows measurements either in a “dry” environment, or in an electrolyte [49]. The conclusion was that a change in the oxidation state of the molecule had occurred, which favored an interpretation by the polaron mechanism. Subsequent theoretical assessments suggested that this mechanism could indeed explain the experimental results obtained [50]. 29.3.8 Single-Molecule Transistors

The next step in complexity is to realize a three-terminal device, that is, to achieve the topology of a transistor, with a gate electrode controlling the electron transport between a source and a drain. The difficulty is extreme because the three electrodes and the molecule must be in close proximity and accurately positioned with respect to each other.

29.3 Devices Based on Electronic Effects NCS

SCN

N N

N

Co N

N

DRAIN

SOURCE

N

M SiO2

S

S

Si

Au GATE Figure 29.27 Single-molecule transistor

using a cobalt complex, where cobalt can evolve between oxidation states II and III. The cobalt complex is equipped with thiocyanate groups which react spontaneously on gold with cleavage of the S–CN

bond and fixation of the resulting thiolate functions on gold electrodes. The device is built so that a gate electrode (Si) is capacitively coupled to the molecule through an insulating SiO2 layer. Adapted from Ref. [52].

By using the electromigration method, Tour, Natelson, et al. have reported a single-molecule transistor, where the third electrode is a silicon substrate capacitively coupled to the source–molecule–drain system through a 200 nm SiO2 layer [51]. The molecule used was BPDN-DT, and experiments were performed at 10 K, with a statistical procedure (as usual) with electromigration-made devices. Of particular importance was the detection of a gate potential-dependence of the current; this was indeed observed on some samples, with hysteretic switching between high and low conductance states. However, the switching mechanism was not clear, and may have been due to polaron formation, or to a more important geometric change of the molecule (bond angle change), or even a change in the molecule–metal interface. Using a cobalt complex as the molecule in the junction (see Figure 29.27) gives different results, however, with the system now behaving as a single-electron transistor [52]. This corresponded to a Coulomb staircase/blockade regime, with a variation of the charge state of the molecule, because the cobalt atom could evolve between oxidation states (II) and (III). In this situation, the role of the third electrode would be to facilitate (or not) the conversion to the Co(III) state [52]. In addition, these particular systems produced inelastic electron tunneling effects, as well as a strong Kondo effect. The latter is a manifestation of the presence of unpaired electrons, in this case when Co is present as high-spin Co(II), with S = 3/2. The Kondo effect is usually interpreted as a many-body effect, where the unpaired spins of an impurity couple by exchange to the conduction electrons in the leads. Thus, in the present case, the high strength of the Kondo effect would be an indication of a good molecule–metal electronic coupling.

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29.4 Devices Based on a Combination of Mechanical and Electronic Effects

In this section, systems are considered for which a large geometric change occurs (not only the common bond length changes or molecular vibrations associated to a polaron formation). This geometric change may be conformational when, for instance, a single bond is twisted, or it may be an isomerization when a double bond is involved; in any such case, the result is an important change in the electronic couplings and structure. In some cases, a complete rearrangement may even occur, giving rise to a different isomer with very different electronic properties. It should be noted here that there is no silicon-device analogy (except for some unwanted phenomena such as electromigration or component failure). The possibility to undergo a large-amplitude atomic motion represents the specific behavior of molecule-based devices. 29.4.1 Switches

The “molecular switch” has for many years been one of the cornerstones of molecular electronics. The most direct way to achieve such switching is to harness a photochemical interconversion between two isomers; in this case, the corresponding isomers are stable when the illumination has been switched off, and an intrinsic bistability is obtained. Additional requirements are a chemical stability, fatigue resistance and, above all, the existence of markedly different electronic structures. As the photochromic unit is destined to be inserted somewhere in an electron path, it is desirable that one of the isomers can be considered as “conducting,” and the other as “insulating.” Among the extreme variety of photochromic systems, the family of dithienylcyclopentenes has undergone particularly scrutiny [53] (see Figure 29.28 for an example). These molecules present a photocyclization/ring-reopening process with distinct advantages, including stability, reversibility, high quantum yield, very different electronic properties (one isomer can be considered as composed of two weakly coupled thiophene units, the other as a conjugated octatetraene) and, consequently, very different absorption spectra. The cyclization is triggered by UV light, and reopening by illumination with visible light. In addition, although the electronic structures are different, the geometric structures are not so different; consequently, a limited motion occurs during the photoisomerization process, which can persist in semi-rigid matrices or assemblies. Solution studies conducted by the present author have characterized the switching ability of the dithienylcyclopentene moiety. It was introduced in a mixedvalence structure with redox sites of the ruthenium-cyclometallated family, and the switching “on” or “off” of an intramolecular intervalence electron transfer was observed [54]. As mentioned above, this process constitutes for mixed-valence system the equivalent of the conductance for a nanojunction.

29.4 Devices Based on a Combination of Mechanical and Electronic Effects F F

F F

F F 2+

N

N

OFF N

e-

S

S

N

Ru N

N

N

OPEN (OFF)

Ru

N

UV

VIS

F F

F F

N N

F F 2+

e-

N

Ru N

The switching concept and its illustration with the case of the photochromic dithienyl-perfluorocyclopentene moiety bridging two ruthenium atoms. The

Figure 29.28

S

N

N

ON

N

S

N

N

Ru

CLOSED (ON) N

N N

electronic coupling between Ru atoms can be monitored by the intensity of an intervalence band in the mixed-valence Ru(II)–Ru(III) state.

The incorporation of dithienylcyclopentene systems in a nanojunction has been achieved in at least two investigations. Feringa et al. succeeded in contacting such a photochromic switch (equipped with thiol groups) in a break junction, and studied the response to illumination. A switching in one direction only (from cyclized “on” towards reopened “off”) was obtained due to the quenching effect of the metal surface [55]. In a second study conducted by the same group, the molecule was thiolated on one side only, and a phenyl group spacer inserted with meta linking, to partially decouple the molecule from the surface and thus reduce quenching effects [56]. The molecule was deposited on a Au(111) surface, together with dodecanethiol molecules, to form a SAM; subsequently, STM was used to identify and study the individual molecules embedded in the matrix. A switching effect was established because the apparent contrast was different from the two isomers. On the basis of partial decoupling from the surface, the switching was observed in both directions. By using a variant of the breakjunction technique (see Section 29.3.3), Lindsay et al. reported the precise electrical characterization of a photochromic molecule in the two isomeric states [57] (see Figure 29.29). The nanojunction resistance was found as 526 MΩ for the open form (off) versus 4 MΩ for the closed one (on), and the ratio of these values could be reproduced by ab initio calculations. Here also, the switching could be performed in both directions. At present, it is not entirely clear why in some cases only unidirectional isomerization is possible. Nonetheless, the phenomenon seems very sensitive to subtle effects such as changes in molecular structure by the use of different spacers, or the method of attachment to the metal surface.

417

418


F

F

F

F

F

F

SURFACE

TIP HS

S

S

Figure 29.29 Testing the dithienylperfluorocyclopentene switch in a nanojunction. The switching unit is equipped with thiol groups for fixation on gold. The measurement is performed here with a STM

SH

version of the break junction, and yield junction resistance values of 4 MΩ and 526 MΩ for the molecule in the ON and OFF states, respectively. Adapted from Ref. [57].

In a quite different approach that was not based on photochromism, Meyer, Joachim, et al. studied a switching event on a special porphyrin molecule deposited on a Cu(211) surface, with triggering of the process achieved by the mechanical action of a scanning tunneling microscope tip at low temperature (15 K) [58]. The use of a 211 surface was particularly well premeditated, because this surface has properties intermediate between those of 100 surfaces, for which the four “legs” of the porphyrin lie perpendicular to the surface, and those of 111 surfaces, for which the legs are flat on the surface. On the Cu(211) surface, some porphyrin molecules are adsorbed with three legs flat on a facet, and the fourth on a step edge with two states of almost equal energy: one with the leg perpendicular to the surface, and the other with the leg parallel. The barrier can be overcome by pushing on the leg by the tip apex of the scanning tunneling microscope. These two states lead to very different couplings between the tip and the surface through the molecule. Thus, a high current (on state) is obtained when the leg is perpendicular, and a low current (off state) when the leg is parallel, with nanojunction resistance values of 670 MΩ and 2100 MΩ, respectively (Figure 29.30). To realize the transformation at will in both directions, the principle is to use either a lateral or a vertical mode of manipulation. 29.4.2 Amplifier with C60

As noted above, a geometric change of the structure modifies of course the conductance of the nanojunction, by changing the T(E) coefficient. In the case of C60, the mechanical compression by the tip of a scanning tunneling microscope alters the current so drastically that it is possible to achieve an amplifier unit by means of proper circuitry. C60 has a unique electronic structure that is characterized by several orbital degeneracies, bearing in particular on the HOMO and LUMO [59]. There is a manifold of orbitals with the same energies, but different symmetries, so that the phase relation of the wavefunction between extreme atoms can be reverted from

29.4 Devices Based on a Combination of Mechanical and Electronic Effects STM Tip N N Cu N N OFF

Figure 29.30 A switch made of a porphyrin

molecule deposited on Cu(211). The ON and OFF states are defined by the position of one of the leg either parallel (OFF) or perpendicular (ON) with respect to the surface.

ON

Junction resistance values are respectively 2100 MΩ and 670 MΩ. The switching in both directions is performed by either a lateral or a vertical manipulation with the scanning tunneling microscope tip.

one orbital to the other. In such circumstances, destructive interferences can occur, yielding a low T(E) and, thus, a low conductance. However, this is an accidental situation, because when compressing C60 (see Figure 29.31) the degeneracy is raised, giving rise to a very rapid increase of the tunnel current because an almost perfect compensation disappears. Although, of course, the system is a twoterminal, the introduction of a piezo electric actuator in the overall device allows it to be considered as a three-terminal device. Consequently, a net gain (of about 5) was obtained when comparing the input voltage necessary to activate the piezoelectric actuator and the output voltage across a load resistor. Overall, this procedure results in a molecular amplifier or, more correctly, an amplifier the active unit of which has the dimension of a C60 molecule – that is, only 9 Å in diameter. Electrical simulations have shown that, in principle, it is possible to design simple hybrid processors by associating C60 “transistors” with an ensemble of cantilevers to perform compression. 29.4.3 Molecular Ammeter

The detection of the current passing through a molecule is by no way trivial, because the standard theory of nanojunction conductance is based on an elastic process inside the junction. Electrons are assumed to cross by tunneling or enhanced-tunneling, at constant energy, and to dissipate their energy only in the metal leads.

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STM Tip (tungsten)

10 mV

0.1 nm C60

copper surface

current Figure 29.31 The active part of the C60 amplifier. After contacting with a STM tip, a C60 molecule is deposited on a Cu surface and progressively compressed. This lifts a degeneracy of molecular levels which was responsible of an almost perfect compensa-

tion of current contributions, and a considerable current increase is observed. When taking into account the energy necessary to compress the C60 through a piezoelectric actuator, a net gain is obtained.

Some inelastic processes may occur, however, when the molecule is large and sufficiently complex that the transit time of an electron becomes long enough that an interaction with molecular vibrations can develop. Starting from the pure enhanced-tunneling regime, this situation heralds the apparition of the polaron mechanism, although in this case the inelastic process is a relatively inefficient event. A small proportion of the electron transfers through the molecule release a small amount of energy to the molecule, via the virtual time-dependent occupation of some orbitals, but an overall effect may result because of the large number of electrons crossing the nanojunction per second. Consequently, the final effect may be a geometric change which, in theory, is measurable. Hliwa, Joachim et al. proposed a molecular nanoscale ammeter [60] that is based on a phenyl-pyrene molecule deposited between two electrodes, such that the phenyl ring is lying flat on a terrace (electrode 1). The pyrene unit interacts weakly with the second electrode (#2) such that, for sterical reasons, the two parts of the molecule present a dihedral angle close to 50° or 130°. The barrier for interconverting the two conformers is calculated as about 7 kcal mol−1 in the adsorbed molecule. A third electrode, located above the junction, is used to detect any geometric change by monitoring variations in the current circulating between electrodes 1 and 3 (see Figure 29.32).


Im 3 Vm θ

2

1

I

V

Figure 29.32 The molecular ammeter. In this

theoretical study, a phenyl-pyrene nonplanar molecule is contacted by two electrodes, 1 and 2. When a current crosses the system,

inelastic effects lead to a net force, driving the phenyl-pyrene moiety towards planarity. This effect is detected by the third electrode (3).

When a current crosses the system between electrodes 1 and 2, energy is deposited onto the molecule by the above inelastic mechanism (heating). Although the pyrene ring appears to oscillate around its equilibrium position, this is not the dominant effect. In fact, theory shows that a time-averaged (“inelastic”) force emerges and drives the pyrene unit out of equilibrium in a defined direction, which corresponds to an increase in current. In the present case, the dihedral angle will decreases (i.e., the system becomes more planar) and the pyrene unit moves away from electrode 3, thus reducing the detection current between electrodes 1 and 3. It should be noted that this system necessitates the calculation of a tunnel current between two particular electrodes of a three-terminal device, taking into account the quantum nature of the molecule in the nanojunction. This is achieved through an extension of the ESQC method (see Section 29.3.2), termed N-ESQC [61]. This method is also the key theoretical tool for the next two examples. 29.4.4 Morse Manipulator

As seen above in Section 29.3.4, the quality of the connection between a molecule and a metallic electrode can be measured by the modification of the surface Shockley waves, the perturbation extending far from the contact point. This situation, which is reminiscent of the early days of radio transmission, led to the concept of the Morse manipulator [62]. In this case, a specially designed molecule is constructed from two rigid boards, allowing the geometry the system to be changed by pushing with the tip of a scan-

421

422


Figure 29.33 The Morse manipulator. The active molecule is made of two rigid parts connected by a hinge. Pushing the upper level with a scanning tunneling microscope (STM) tip forces a terminal phenyl ring to

contact the upper terrace. This changes the pattern of surface Shockley waves of the type shown in Figure 29.21, and the effect can be detected far from the manipulator.

ning tunneling microscope [62]. The lower board ensures fixation on the lower terrace, while the upper board extends over the upper terrace. According to the tip position, it is possible to force a terminal phenyl ring to make contact with, or not contact, the upper terrace (Figure 29.33). This would result in a change of the Shockley standing waves pattern that can be detected far away from the Morse molecule. In theory, this is made possible by using two extremely close tips and monitoring the corresponding junction resistance, which is dependent on the surface local density of states. In future, such experiments should be possible by using commercial four-probe ultra-high-vacuum (UHV) systems. The synthesis of the Morse molecule is currently under way. 29.4.5 Quantum Logical Gate

As molecules are inherently quantum objects, it might be interesting to explore their potentiality to perform computations in a quantum manner. In the past, a huge amount of work has been devoted to quantum computing, a method in which the input information is introduced as “qubits.” Contrary to normal input bits, which can take only 0 or 1 values, qubits can exist as a superposition of states, and it is hoped that this fundamental property would confer to quantum calculation a massively parallel character. To fix ideas with a concept familiar to chemists, a nuclear spin can be used to encode a qubit, because it can exist as “spin up,” “spin down,” or any combination, when placed in a non-stationary state by pulsed NMR methods. To date, however, the chemical realization of quantum computing has been achieved with populations of molecules, addressed by a macroscopic NMR experiment. In a theoretical study, Duchemin and Joachim proposed a quantum gate based on a single molecule, in which the principle differed from that of the usual quantum computing systems. In this so-called quantum Hamiltonian computa-


Figure 29.34 The quantum Hamiltonian

half-adder gate. In this theoretical work, a dinitro[1,3]anthracene molecule is studied from the point of view of its dynamic response to an electron uptake, according to the position of the NO2 groups. The NO2 dihedral angles are assumed to be externally

fixed at either 0 or 90°, coding binary inputs 0 and 1, respectively. After an electron introduction in location IN, the time evolution can be read by the appearance of the electron at locations AND and XOR corresponding to the half-adder operation.

tion (QHC) [63], the molecule is not divided in qubits, and the input information is not introduced as an electronic property (e.g., an electron spin state) but rather in a Hamiltonian driving the intramolecular quantum evolution by way of controlling the geometry. The proposed molecule, dinitro[1,3]anthracene (Figure 29.34), should function as a half-adder according to the following truth table: Input Bit 1

Input Bit 2

Output XOR

Output AND

0 0 1 1

0 1 0 1

0 1 1 0

0 0 0 1

Thus, the half-adder provides an output XOR, which is the sum modulo 2 of the input bits, while the output AND constitutes the carry. The (classical) input would be introduced as values of the θ1 and θ2 angles between the respective planes of the NO2 groups and the anthracene plane. (It is assumed that these angles can be experimentally controlled, for instance by using the tip of a scanning tunneling microscope.) The code here is that θ = 0 corresponds to 0, and θ = 90° corresponds to 1. The system is then prepared in a nonstationary state by injecting, for instance, an electron in a particular location, denoted |Φin>. The quantum evolution is then computed as a function of time, and the electron moves along the system of π orbitals in an almost periodic fashion with, from time to time, a localization in a given location such as |ΦAND> and

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|ΦXOR> (see Figure 29.34). The result of calculation can be read in these particular locations. For instance, if θ1 = 0° and θ2 = 90° (code 0 1), the electron has a high probability of appearing on the output |ΦXOR>, and never appears on the location denoted |ΦAND>. Thus, a simple single molecule is, in principle, able to perform a half-adder logic function. The logic function is based on the dynamic evolution as a result of quantum interference effects. It should be noted that there is no claim of a massively parallel way of functioning, although incidentally this claim in the case of the “normal” quantum calculation can also be questioned. The main advantage of QHC is the possibility of its implementation in an extremely small volume, thus taking full advantage of the monomolecular nature of the device. In addition, this approach is adapted to the future possibilities of connecting a molecule to several electrodes at the atomic scale. For instance, a disposition might be considered in which the NO2 groups would be independently turned by selective heating (as in the molecular ammeter described above), and a connection by three electrodes would be performed on the input and the two outputs.

29.5 Conclusions

Today, a wide variety of molecules is available for testing the possibility of building functional molecular devices, with the ultimate goal of achieving a given function with just one molecule. However, immense problems persist, as broadly ranked below according to the outline of this chapter. When using molecules for mechanical effects, we are faced with the flexibility of most molecules, which is frequently neglected or even ignored in naïve reasoning. Thus, their shape can easily vary, especially by bond flexion or torsion (which are soft modes), and it is difficult to conceive how a precise and sophisticated mechanism could survive under these circumstances (cf. Salvador Dali’s “soft watches”). In addition, many linkers contain too many rotation possibilities, leading to complex and even unpredictable shapes upon folding. It is essential, in the present state of our knowledge, to devise molecules with as few degrees of internal rotation as possible. Another problem is the possible occurrence of quantum effects. Molecules are quantum objects, and as such their dynamic behavior can be very different from common experience. Of course, the larger the molecules, the more classical their behavior, and quantum effects are generally neglected for large objects such as proteins. However, for small objects and low temperatures quantum effects cannot be ignored. A favorable circumstance, however, is that we are concerned here with molecules that are not isolated in space but rather interact with a surface. Under these conditions, the interaction restores some classical character to the system’s behavior. Those molecules to be used as pieces of mechanisms must be fed with energy, and thus a real problem is to bring energy to the correct location. Order-of-

29.5 Conclusions

magnitude calculations have shown that these amounts of energy may be quite large at the molecular scale, and thus may have deleterious effects on the shape or even integrity of the molecule. Some ways of introducing energy, in particular through photon absorption, are not at all focused in space, and thus are subject to unwanted side effects. Hence, selectivity in energy feeding is a key issue. When using molecules as electronic components, the main approach to date has been a hybrid technology; that is, to connect molecules to intermediate metallic conductors where the electrons are thermalized. This has the advantage of keeping the decomposition of a complex circuit into simple elements (diodes, resistors, etc.), with each element capable of being characterized by its own current–potential characteristics. Unfortunately, molecular devices have poor characteristics, because the quantum of resistance (12.9 kΩ) is quite large by electronic standards, and in fact many “wires” lead to nanojunction resistances in the MΩ range. As a result, it appears difficult to “cascade” the devices. Thus, there is a great need for studies in device architecture. There are certainly some alternatives to the common architecture that we were taught from the start of our high-school studies, but we have not been used to considering them! Among these, we can quote an integrated architecture (i.e., performing all operations in the same molecule), a quantum architecture (although this will certainly differ from the usual concept of quantum computing), or perhaps a combination of both. At this stage, it is interesting to compare the cases of single molecules used for mechanical or for electronic effects. In the case of electronic effects, a singlemolecule device is easy to conceive, because the standard experiment relies on the measurement of an electron flux (a current) through a molecular junction. This provides a built-in interface between the nanometer scale and the macroscopic scale by averaging the behavior of many electrons. There is no analog in the case of single molecules used for mechanical purposes. To prove that the molecule is functioning, it is necessary to perform a measurement (usually spectroscopic) that involves a large number of molecules. Unless resorting again to a STM-type measurement, the realization of a device with a macroscopic mechanical motion requires also a large number of molecules, as in the muscle action. Devices based on a combination of mechanical and electronic effects certainly show much promise, because they exploit the great specificity of molecules when compared to the usual materials and devices used in electronics: their possibility to evolve at the same time in geometric space and in the state space, with a change in electronic structure. These combined effects are used, for instance, in switches based on photoisomerization, or in the propositions of molecular ammeters or even logic gates, in the sense that a change in geometry triggers a change in electronic properties. However, the reverse process could also be considered, by changing the shape of a molecule with an electrical signal. Curiously, this aspect has been much less considered than for instance photochemical processes, at least in the case of small molecules (although it is used in large interlocked molecules such as catenanes and rotaxanes). But in a very general way, we must not forget the huge size difference between a nanometer-sized object and objects of our macroscopic world. The factor is at

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least 1 million, and this leads to the problem of nanocommunication. How to get reliable signals, which ultimately are translated as the motion of a needle on a dial or a pixel onto a screen? How to send orders in the reverse direction? The scanning tunneling microscope represents a marvelous tool for jumping directly across this dimension gap. It would be useful to dispose of miniaturized versions, to shrink the dimensions of piezoelectric actuators and feedback electronics, in order to define intermediate scales for communication and the integration of nanoscale devices.

Acknowledgment

The author is very grateful for the helpful discussions conducted with C. Joachim.

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30 Discussion 6.A Discussion on the Report by J.-P. Launay Chairman: Enrico Dalcanale

Chairman: Thank you Jean-Pierre Launay for the fascinating lecture. The session is now open for discussion. R.D. Astumian: Professor Launay, I think that it is interesting that you used the term “surmount” when you described the squishy watch of Salvador Dali. I want to make the point that, if we understand deeply how Nature does it, it is not a matter of surmounting the problems associated with thermal noise and squishiness to achieve macroscopic-world, mechanical-like behavior, but rather of figuring out how it is that Nature does it, and do it in an entirely different way that we conceive of mechanically, not by pushing things around – as I would push this here and there – but rather by using Brownian motion in a controlled way. We do this in chemistry, where we always use thermally activated processes in a controlled fashion in order to achieve a synthesis which gives us a high yield, rather than a process where we have the temperature way too high and gives all sorts of products in addition to the one that we want to achieve. J.-P. Launay: Yes, you are right. In the case of mechanical properties, the gap is so big between our nanoscopic and macroscopic objects that we certainly need some intermediate goal, and this could be to make something useful with these objects, and something which could occur at the mesoscopic scale, in a first step. I was struck yesterday by the talk of Ben Feringa, about the possibility of depositing molecular motors on nanoparticles, so that these nanoparticles could have some motion if the deposition and the system are correctly devised. We could trigger a particular motion, and we had a specific example yesterday with the small bar rotating on the liquid crystal, but at even smaller sizes it should also be possible to move yet smaller objects. One possible application of the molecular motion is in the domain of microfluidics, for sorting molecules for example. So, achieving analytical systems could be an intermediate goal. V. Balzani: It seems to me that, when you move a molecule on the surface by using a scanning tunneling microscope tip, the real device is the tip, and not the molecule. Giving a molecule energy by a photon or a chemical reaction is not the 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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30 Discussion 6.A

same compared to a tip, as the tip takes a molecule by the hand, and the molecule does what the tip wants it to do. When you give a photon to the molecule, the molecule does what itself likes to do. So, I think that using a tip is a very different concept than using other kinds of energy for molecular devices. J.-P. Launay: What we use at the moment is a way to study the interaction of molecules with surfaces. It is mainly for understanding what happens. V. Balzani: I understand that the molecule is not so important because you can move any kind of molecules. Of course, you can also have certain specific patterns, but the real device is the tip in such cases, I believe. J.-P. Launay: Could you repeat your comment? V. Balzani: I was just commenting that, in these systems, the tip is more important than the molecule. In other kinds of molecular devices, it is the molecule that plays the most important role. You give energy to the molecule, and the molecule decides which movement it will do. In the case of an STM system, the molecule moves according to what you are doing on it by the tip. It seems to me that this is conceptually very different from what we usually consider a molecular device. C. Joachim: I think I have to add a comment. First of all, when you say that a photon is given to a molecule, you never give a photon to a molecule. In fact, you apply an electromagnetic field to a bunch of molecules. Physically speaking, you never focus one photon on one molecule. My second point concerns the STM tip: it is clear that we don’t yet have a full device, but we are first trying to understand the mechanics. We are discovering the mechanics of a single molecule on the surface, and others will later understand everything. After understanding it, we shall try for example to make a gear with two molecules, a big one and a small one. As any physicist or chemist, we have to follow normal routes which are stepby-step processes, understanding what happens for a single object, such as a molecule. The tip is one way of doing it, but the next step will be to have a new technology – which is evolving in laboratories across the world – where one can have access to a single molecule thanks to multiple electrodes or atomic wires. Maybe in this case, someone will succeed in making the full rotation of a single molecule controlled by an external field, or else. However, at the single-molecule level, the first step is really to understand what this molecule is doing, and what the physics of this molecule is. One example of trying to change the idea of how to use a molecule is in electronics. If you look carefully, the first concept of molecular electronics was a device mimicking a transistor or a rectifier in order to make a full circuit. Nowadays, given that we know that electron transfer is so inefficient in a molecular wire, we try to kill and cancel all the wires, so we are now making better use of what the molecule is capable of doing – which is quantum mechanics – in order to try to perform computation. For this purpose, you first need to understand and image the molecular orbitals, to see the physics going on inside the molecule, before doing the full circuit or full computation. In this case, we are discovering step by step what a single molecule can do. One day when technology

30 Discussion 6.A

will enable us to attach five, ten or twenty electrodes to a single molecule at the atomic scale, maybe we will use it as a computer or a logic gate. However, as I said, we have first to understand what the single molecule can do quantum mechanically for you, and we are now at this stage. J.-P. Sauvage: I have a question related to Vincenzo Balzani’s remark. People are using C60, which looks beautiful, is spherical, and will mimic a wheel at the nanoscale. So, if people make cars on the surface and push them with the tip or heat in order that the car moves, would it make any difference if you replaced the C60 with a big cube – for instance, cubane, which is much smaller than C60? J.-P. Launay: I don’t know why they choose C60. It has the specific drawback that the wheels are extremely smooth; there is no asperity on the wheel. So, how do we get something to roll? If you are driving with glossy tires, you could get stopped by the police! Assuming that you use cubane, perhaps this type of wheel could engage the asperity of the surface in a more effective way. In our case, we use triptycene, which is even worse because there are three parts, forming extremely irregular wheels. In the case of James Tour’s experiment, there was indirect evidence that the wheels were rolling because the motion keeps definite angles with respect to the orientation of the surface. They took this as an indication that the wheels were rolling because in some directions the wheel could engage the asperity, and in others the molecule could skid sideways. We have difficulties in translating at this scale our concepts of everyday life. Talking about the wheel for a system which is extremely irregular, of course raises a problem. J.-P. Sauvage: I am sorry, but I would like to rephrase my question. In fact, my original question was more general. Are not we misled by our macroscopic intuition? This is a very simple and general way of putting it. Chairman: I would like to comment with regard to your cubane device. Probably, cubane is rotating so rapidly to resemble a spherical object, which would not make any difference. V. Balzani: But I believe that it is very difficult to rotate cubane on the surface because of its interaction with the surface. Chairman: Yes, but it would be the same for C60 and cubane. J.-P. Launay: Yes, and also the role of gravity is different, because gravity and inertial forces are much less important at this scale. Thus, it is likely that a mobile system on the surface into which we deposit too much energy will jump into the air like a flea, for instance. Analogy with common life is a way to fix ideas and a means for rapidly explaining things, but of course it must not be taken too literally. R.D. Astumian: Does anyone happen to know whether the surface diffusion coefficient of molecules such as C60 or cubane is governed predominantly by the size or geometry?

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30 Discussion 6.A

Chairman: I may have an answer for you. In the past, we have been studying the behavior of the plastic crystal phase of C60 with neutron scattering. As you know, C60 is a plastic crystal, say, at 100 K. If you add a small tip by introducing a cyclopropane ring on C60 and you do neutron scattering, you will see that the movement is not longer isotropic, but it actually becomes anisotropic, though only in one direction. Therefore, I would say it is more the case of the shape, at least in the solid state. P. Gaspard: I would like to say that Pablo Jensen and coworkers have studied the diffusion of nanoparticles on crystalline surfaces, showing that a crucial parameter for diffusion is the mismatch between both lattices.1 This mismatch will control the diffusion coefficient. A. Credi: There is no doubt that these experiments are extremely interesting, and I really like them. However, it seems to me that these systems are the farthest away from any applications, at least on planet Earth at the moment, because all of these effects are observed at a few degrees Kelvin of temperature, in high-vacuum conditions and, as Professor Balzani mentioned, you need very complicated and sometimes specific instrumentation. So, I wonder if you could comment on how this field could evolve in order to have some real handleable applications. J.-P. Launay: When it comes to particular applications, of course we are very far off because it is all very fine to work in ultra-high-vacuum, but this doesn’t lead to anything that useful at the moment. Currently, we are trying to understand the basics of what happens and, thereafter, we can devise systems which would be practical. I was thinking for instance about some type of sensor, because in a sensor you have to combine information from a chemical or biochemical point of view and transform that into an electrical current. Therefore, it would be some type of sensor where we would have a special molecule that recognized a substrate and changed its conformation, followed by an electronic system where a current would pass through the molecule and produce a signal. But, the question is whether we need a single molecule to perform that. It seems more likely that, in any sensor application, we would put many molecules in parallel just for reliability. The process would occur at the single-molecule scale, but the signal would average a large amount of molecules. That could be one application, but another type of application I can more or less foresee is in the field of microfluidics, sorting molecules, making them move – some form of sophisticated chromatography with a gradient of a property on a surface, for instance. Maybe we could have such systems, but it will be necessary anyway to understand what happens when the molecule interacts with the surface. J. Michl: Could you elaborate a little further on the difference between two of the systems that you described in your general classification? You were talking about Coulomb staircase and the polaron, but what exactly is the difference between the two? 1) Deltour, P., Barrat, J.-L., and Jensen, P. (1997) Phys. Rev. Lett., 78, 4597.

30 Discussion 6.A

J.-P. Launay: What the polaronic and the Coulomb staircase mechanisms have in common is that, at some instant, some charge is localized on the molecule inside the junction. These two concepts came from different types of experiments. The Coulomb staircase or Coulomb blockade came from experiments by Likharev et al. during the 1990s. At that time, the central part was not a molecule but a small metallic island, and they elaborated what they called an “orthodox theory” in which the basic ingredient is the capacitance of the system. It was a mesoscopic theory according to which, if you put an electron on the central island, you change the charging energy of the capacitor, and this avoids a second electron from arriving immediately thereafter. With regard to the polaron, it is a more chemical description. We make a redox process and the molecule rearranges as a function of its oxidation or reduction state. Now, there is a tendency to attempt to mix the two concepts because in molecules there is also some interelectronic repulsion, so that we could apply the concept of Coulomb staircase, probably at the molecular level. For some situations, in particular when there are staircases on the current– voltage curve, it could occur from the interelectronic repulsion described by the U parameter. It could also stem from the succession of molecular orbital energies. So, a complete study should take all of this into account. It is most probable that, for high-level theories, the two concepts will mix. J. Michl: So, the main difference, as you define it, is the size of the island? J.-P. Launay: Yes. Usually, Coulomb blockade or Coulomb staircase is described for a small metallic island, which anyhow is much larger than a molecule. However, as a molecule is smaller, interelectronic repulsion effects are larger, so that the Coulomb blockade should occur in a more important way. There is a big difference between the Coulomb blockade and the polaron mechanism in so far as, with the polaron mechanism, the molecule distorts as a result of the oxidation or reduction and there is a change in geometry. In the Coulomb blockade mechanism, there is no change in geometry which is involved; it is mainly an electrostatic effect. A. Shanzer: I would like to refer once again to the question of the contact between the fullerene and the surface. I would like to suggest an experiment that could maybe show the difference. Instead of fullerene, C60, we use the higher fullerene such as C76, which I think is chiral. If the two front wheels shared the same chirality, the vehicle should move in one direction. However, with the opposite chirality, the vehicle should not be able to move at all! J.-P. Launay: That’s very true – we could have very strange effects. A similar problem would occur if we think about a nanoparticle covered by molecular motors. If all of the molecular motors were of the same chirality, the gearing mechanism would be impossible because some rotors (gears) would be required to move in one direction, and others in the opposite direction. So, perhaps we should ask ourselves if we need to use either a racemic mixture, a single enantiomer, or a mixture of enantiomers but in a proportion different from 50/50, so we would have at some point a rotor moving in the reverse direction so as to

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facilitate the whole rotation. There are many interesting consequences and ideas that we could investigate. A. Shanzer: So, what about the idea of C76 fullerene? D.A. Leigh: But that can’t work, because it would violate the second law unless you are putting energy in it. It can’t be that, thermally, you can just rotate in one direction and not against the other axis. You can’t do that. A. Shanzer: But if you take a C76 fullerene-type of structure, there is an axis which would go through the wheel and there would still be a tilt, because it is taken like a ribbon and overlapped, so that you can always come 90°. There is always an axis and it is a C1 axis. D.A. Leigh: But you can’t have a situation where it rotates in only one direction and not the other on those cars, unless you are putting power in with light or something else. A. Shanzer: Maybe I didn’t understand the question – could you repeat it? D.A. Leigh: Because, if that was true, then it would violate the second law; it would rotate in one direction and not the other at a constant temperature. R.D. Astumian: This is an almost perfect analogy with Feynman’s ratchet. I think the problem here is that your macroscopic intuition suggests that gravity is holding the car down on the surface, which is of course not true. It is actually jiggling up and down, it is increasing and decreasing its diffusional mobility. If you take into account the correlations between when the chiral molecule is down or up and the hopping, you will see that the mechanism that drives it forward with respect to the chiral thing rotating and pushing it forward will work exactly backwards when you take into account the up-and-down motion on the surface and the increase in surface diffusion. You should look carefully at the ratchet example given by Feynman in volume I of his lectures – it’s a beautiful example that illustrates exactly why our macroscopic intuition is just so awful when it comes to thinking about how molecules are going to work. A. Shanzer: I completely accept what you are saying but the question is different. Do we need a fullerene, or can we use a tert-butyl group? As far as you are concerned there is no difference. Chairman: At least, we have reached a consensus on that! Let us thank once again our rapporteur, and all of you for the participation.

435

31 A Spring-Loaded Device Prepared Comment Dariush Ajami and Julius Rebek Jr

Almost three decades ago, some biaryl molecules were introduced that acted as rotors. A bipyridyl system was used to reduce the Pauling principle of maximum binding to a transition state to practice in a chemical model [1]. Subsequently, bipyridyl [2, 3] and biphenyl [4, 5] crown ether compounds became the first models for the allosteric effects of enzymology (Figure 31.1). Binding at one site would transmit information to a remote site through conformational changes [6]. During the past few years, a number of biaryl rotors have been developed as nanodevices [7], particularly in the context of unidirectional rotation [8–10]. Recently, however, an alternative was engineered when instead of a rotor, the new system involved linear motions of expansion and contraction under the control of acids and bases. This was referred to as a “spring-loaded” device. The new system takes advantage of the conformational possibilities of normal alkanes, their extended and compressed shapes. Earlier, it was shown that the cylindrical capsule 1 (Figure 31.2) self-assembles in the presence of suitable guests, or combinations of guests, to produce encapsulation complexes in organic solvents [11, 12]. These complexes are reversibly formed, and have lifetimes on the order of 1 s, which is fast on the human timescale but slow on the NMR chemical shift timescale. Whilst a number of studies with this capsule have defined its capacity as a host [13], the most peculiar guests encountered to date have been the normal alkanes [14] – guests that adopt shapes complementary to their hosts. Although alkanes as long as tetradecane (n-C14) are encapsulated in 1, longer alkanes, such as n-C15, are not accommodated at all, and there is no way they can contort to fit inside. Even C14 cannot fit in an extended conformation; instead, it must adopt a compressed conformation [15] that reduces its length by about 5 Å, which is just enough for it to be accommodated, and to make the guest molecule shorter and thicker. As a result, attractive CH–π interactions are established between hydrogens on the alkane’s surface and the 16 aromatic subunits that define the lining of the capsule (Figure 31.3). This coiling is not without an energetic penalty, because each gauche interaction (in the liquid phase) [16] costs some 0.55 kcal mol−1. Evidently this price is paid by the attractive forces that result in the encapsulation of the alkane. The specific conformation was deduced from 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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31 A Spring-Loaded Device

Figure 31.1 Molecular rotors as allosteric

effectors in chemistry. Upper: Binding of transition metals at the bipyridine restricts the conformation of the crown ether and alters the ether’s transport selectivity for

H

2

H H N N

N O O O

O

NN

N

N

OO

O

O

R

O

alkali ions. Lower: Binding of an ion at one site fixes the biaryl dihedral angle and organizes the second site for enhanced binding.

H O

N O O

N

NN

O

OO

RR

R

R=C11H23 1 Figure 31.2 Chemical formula, ball-and-stick model and cartoon representations of the

self-assembled capsule 1. The self-complementary upper rim of imides of the cavitand creates eight bifurcated hydrogen bonds that hold the dimeric capsule form together.

two-dimensional (2-D) NMR studies which show the close proximity of hydrogens on C1 to C5, C2 to C6, and so on. These indicated a coiled, helical conformation [17]. Recently, it was shown that glycoluril derivatives could insert into the capsule tetradecane complex by forming a new belt of hydrogen bond donors and acceptors


437

C7

C6 20.0 Å

C5

15.5 Å C3

C1 C2 Figure 31.3 Dimensions of n-C14 in extended (left) and encapsulated (center) conformations.

The relevant crosspeaks of the 2-D NMR spectra are color-coded on the model of a helically coiled conformation (right).

H Ar H N N O

O N N H Ar H

24 Å

17 Å R=PhOC8H17 R=PhOC12H25 R=PhN(BU)2 425 Å 2 Figure 31.4 The original capsule 1 and its expansion to 2 by the incorporation of four glycoluril units. Only one of the enantiomers of the latter is shown, and the peripheral

alkyl and aryl groups have been deleted for clarity. The sizes and shapes of their cavities are modeled in yellow.

at the center of the structure [18]. This increased the length by some 7 Å, and the volume by almost 50% (Figure 31.4). Accordingly, tetradecane relaxes into an extended conformation in the expanded capsule 2, and this change is evident in the NMR spectrum. The methylenes of the alkane in the new capsule move away from the walls and toward the center of the structure, while their NMR signals move downfield. The C14 in the original and expanded capsule shows very different NMR spectra, as featured in Figure 31.5. The insertion of four glycolurils very much resembles the insertion of a leaf in a dining table, with the arrangement of the added glycolurils constricting the

620 Å3

438


(b)

(a)

0.0 ppm

–1.0

–2.0

Figure 31.5 The coiled and extended

conformations of n-C14 in (a) capsule 1, and (b) expanded capsule 2. The upfield regions of the NMR spectra are shown below each capsule sketch. In (b), the signals move

–3.0

–4.0

downfield as the C14 is extended and the methylenes move away from the capsule’s walls and toward its center. The chiral nature of the expanded assembly is reflected in the diastereotopic protons of the methylenes.

center of the cavity and creating a chiral nanoenvironment. This is reflected in the diastereotopic protons seen, for example, at C2. The system could be reverted to the original capsule through the addition of a guest such as benzanilide, which is nearly ideal in size for 1. These changes take place within a few seconds at the millimolar concentrations used for the NMR studies. The gauche interactions of the coiled alkane must exert some force on the capsule as the alkane tries to extend to the lower energy conformation of antiperiplanar C–C bonds. The next stage was to control the coiling and extension of the alkane by the external addition of acid and bases. For this, a glycoluril was prepared that had remote basic sites, a dibutylanline derivative [19], and which showed excellent solubility in the solvent of choice for these NMR studies, the largest commercially available deuterated solvent mesitylene- d12. The coiled alkane in the original capsule is not unlike a compressed spring, and the addition of the glycoluril allows it to extend in the longer capsule 2. However, when HCl gas is bubbled into the NMR tube, it protonates the basic sites of the glycoluril and causes the latter to precipitate. This treatment regenerates the original capsule 1 with the coiled alkane inside. Next, trimethylamine was introduced; this base liberates the glycoluril from its salt, which re-enters the solution and expands the capsule. Acid is then added to regenerate 1. Some six cycles of acid/base treatment were possible in a single NMR tube before the build-up of trimethylamine hydrochloride began to distort the


Base

Acid Figure 31.6 The reversible compression and expansion of encapsulated C14. The glycolurils (blue cartoons) insert under basic conditions and allow the guest to relax in 2. Acid precipitates the glycoluril and regenerates the capsule 1 with the coiled C14 inside.

Figure 31.7 A modeled structure of anandamide (the ethanolamide of arachidonic acid) in 3, a capsule extended with two belts of glycoluril modules.

NMR spectra. The acids and bases controlled the reversible compression and relaxation of C14 (Figure 31.6). Whilst it came as no surprise that the expanded capsule could accommodate normal C15, C16, C17, C18, and C19, what was unexpected was the emergence of yet another new capsule in the presence of C19. A new capsule was formed that involved two belts of glycolurils; thus, a double expansion had taken place [20]. This new hyperextended capsule 3 (Figure 31.7) also accommodated some natural products such as anandamide, the endogenous ligand for the cannabanoid receptor of the brain [21]. When even longer hydrocarbons such as C24 to C29 were tested, another encapsulation complex was found which involved three glycoluril belts (Figure 31.8). The complete assembly comprised 15 molecules, and there was evidence of coiling

439

440


35Å 980Å3

28Å 810Å3

22Å 620Å3 15Å 450Å3

Figure 31.8 Energy-minimized structures

and approximate dimensions of capsules extended by glycolurils. The length refers to the accessibility of methyl groups in the inner

space, as determined by semi-empirical methods. The peripheral groups have been removed for viewing clarity.

with the longer guests, suggesting that spring-loaded capsules of additional complexity might be devised in the future. For the present, however, the preliminary results confirmed that even longer capsules could be prepared using a simple recipe of 1, glycoluril and ever longer alkanes. So, is there a limit to this situation? There is, at present, no reason to think that a limit exists; however, the multitude of forces that drive such self-assembly are currently under investigation at the present authors’ laboratories, and details will be reported in due course.

Notes After the Conference

Over the past two years, much progress has been made on evaluating the nature of the pressure inside the self-assembled capsules. One method involved the use of encapsulating gases such as cyclopropane [22]. Overall, these measurements showed that attractive forces between the hydrocarbons and the interior walls allowed remarkable pressures to be achieved. A second method, which involved the use of coiled alkanes in extended capsules, demonstrated that the effects of the gauche interactions could exert 2–3 kcal mol−1 on the interior [23]. Finally, two reviews have produced describing the general behavior of molecules in these small spaces [24], and the use of these capsules as molecular flasks [25].

References

Acknowledgments

The authors thank the Skaggs Institute for Research for financial support.

References 1 Rebek, J. and Trend, J.E. (1978) On binding to transition states and ground states: remote catalysis. J. Am. Chem. Soc., 100, 4315. 2 Rebek, J., Wattley, R.V., Chakravorti, S., and Trend, J.E. (1979) Allosteric effects in organic chemistry: site-specific binding. J. Am. Chem. Soc., 101, 4333. 3 Rebek, J. and Wattley, R.V. (1980) Allosteric effects: remote control of ion transport selectivity. J. Am. Chem. Soc., 102, 4853–4854. 4 Rebek, J., Jr, Wattley, R.V., Costello, T., Gadwood, R., and Marshall, L. (1980) On binding in subunit systems. J. Am. Chem. Soc., 102, 7398–7400. 5 Rebek, J., Jr, Wattley, R.V., Costello, T., Gadwood, R., and Marshall, L. (1981) Allosteric effects: binding cooperativity in a subunit model. Angew. Chem. Int. Ed. Engl., 93, 584–585. 6 (a) Rebek, J., Jr and Marshall, L. (1983) Allosteric effects: an on-off switch. J. Am. Chem. Soc., 105, 6668–6670; (b) Onan, K., Rebek, J., Jr, Costello, T., and Marshall, L. (1983) Allosteric effects: structural and thermodynamic origins of binding in cooperativity in a subunit model. J. Am. Chem. Soc., 105, 6759–6760. 7 (a) Kottas, G.S., Clarke, L.I., Horinek, D., and Michl, J. (2005) Artificial molecular machines. Chem. Rev., 105, 1281–1376; (b) Balzani, V., Credi, A., and Venturi, M. (2003) Movements related to opening, closing, and translocation functions, in Molecular Devices and Machines Wiley-VCH Verlag GmbH, Weinheim, Germany, Chap. 12, pp. 288–328; (c) Kay, E.R., Leigh, D.A., and Zerbetto, F. (2007) Synthetic molecular motors and mechanical machines. Angew. Chem. Int. Ed., 46, 72–191. 8 Kelly, T.R., Harshani De Silva, H., and Silva, R.A. (1999) Unidirectional rotary

9

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motion in a molecular system. Nature, 401, 150–152. Vicario, J., Walko, M., Meetsma, A., and Feringa, B.L. (2006) Fine tuning of the rotary motion by structural modification in light-driven unidirectional molecular motors. J. Am. Chem. Soc., 128, 5127–5135. Dahl, B.J. and Branchaud, B.P. (2006) 180° unidirectional bond rotation in a biaryl lactone artificial molecular motor prototype. Org. Lett., 8, 5841–5844. Heinz, T., Rudkevich, D., and Rebek, J., Jr (1998) Pairwise selection of guests in a cylindrical molecular capsule of nanometre dimensions. Nature, 394, 764–766. Heinz, T., Rudkevich, D.M., and Rebek, J., Jr (1999) Molecular recognition within a self-assembled cylindrical host. Angew. Chem. Int. Ed., 38, 1136–1139. (a) Rebek, J., Jr (2005) Simultaneous encapsulation: molecules held at close range. Angew. Chem. Int. Ed., 44, 2068–2078; (b) Chen, J. and Rebek, J., Jr (2002) Selectivity in an encapsulated cycloaddition reaction. Org. Lett., 4, 327–329. Schramm, M.P. and Rebek, J., Jr (2006) Moving targets: recognition of alkyl groups. Chem. Eur. J., 12, 5924–5933. Scarso, A., Trembleau, L., and Rebek, J., Jr (2003) Encapsulation induces helical folding of alkanes. Angew. Chem. Int. Ed., 42, 5499–5502. Eliel, E. and Wilen, S.H. (1994) Conformation of acyclic molecules, in Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, Chap. 10, pp. 597–664. Scarso, A., Trembleau, L., and Rebek, J., Jr (2004) Helical folding of alkanes in a self-assembled, cylindrical capsule. J. Am. Chem. Soc., 126, 13512–13518.

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31 A Spring-Loaded Device 18 Ajami, D. and Rebek, J., Jr (2006) Expanded capsules with reversibly added spacers. J. Am. Chem. Soc., 128, 5314–5315. 19 Ajami, D. and Rebek, J., Jr (2006) Coiled molecules in spring loaded devices. J. Am. Chem. Soc., 128, 15038–15039. 20 Ajami, D. and Rebek, J., Jr (2007) Longer guests drive the reversible assembly of hyperextended capsules. Angew. Chem. Int. Ed., 46, 9283–9286. 21 Ajami, D. and Rebek, J., Jr (2007) Adaptations of guest and host in expanded self-assembled capsules. Proc. Natl Acad. Sci. USA, 104, 16000–16003.

22 Ajami, D. and Rebek, J., Jr (2008) Gas behavior in self-assembled capsules. Angew. Chem. Int. Ed., 47, 6059–6061. 23 Ajami, D. and Rebek, J., Jr (2009) Compressed alkanes in reversible encapsulation complexes. Nat. Chem., 1, 87–90. 24 Rebek, J., Jr (2009) Molecular behavior in small spaces. Acc. Chem. Res., 42, 1660–1668. 25 Yoshizawa, M., Klosterman, J.K., and Fujita, M. (2009) Functional molecular flasks: new properties and reactions with discrete, self-assembled hosts. Angew. Chem. Int. Ed., 48, 3418–3438.

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32 From Electrochemically-Driven Conformational Polymeric States to Macroscopic Sensing and Tactile Muscles Prepared Comment Toribio F. Otero

A single chain of a conducting polymer can be considered as an electro-chemomechanical molecular motor [1] that is able to go through n consecutive mechanical and chemical equilibrium steps (fundamental conformational energetic states) in a progressive and reversible way, under electrochemical control. The reaction promotes chemical changes: the breaking of double bonds; conjugation generation (decreasing rotational degree of freedom in-between monomeric units); and charge storage along the chains. Simultaneously, important changes in the intraand intermolecular interactions (forces), notably intra-chain, chain–solvent, chain ions, and ion–solvent, occur under this electrochemical control:

H N

N H

H N

N H

H N

- 2 e−

H N

N H

H N

N H

H N

The reaction proceeds, considering a linear ideal chain of conducting polymer (CP) constituted by m monomeric units, through n consecutive oxidation (energetic conformational states, with increasing conjugated planar segments) steps (m > n): 1) 2) 3) 4) 5) n)

CP + (A−)solv ↔ (CP+)A− + e− (CP+ ) A − + (A − )solv ↔ (CP2 + ) A2− + e− , (CP2 + ) A2− + (A − )solv ↔ (CP3+ ) A −3 + e− , (CP3+ ) A3− + (A − )solv ↔ (CP4 + ) A −4 + e− , (CP4 + ) A 4− + (A − )solv ↔ (CP5+ ) A5−, + e− , … [CP(n −1)+ ] An− −1 + (A − )solv ↔ (CPn + ) An− + e−

The n consecutive conformational states are useless when the chain is in solution and submitted to free rotation and molecular collisions (Figure 32.1a). If one of the chain ends is attached to a metallic electrode both, electrochemical and thermal energy at the ambient conditions can be transformed to an electrical molecular machine, giving a prevalent one-dimensional movement (Figure 32.1b). This is equivalent to a Maxwell demon [2]. 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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32 Electrochemically-Driven Conformational Polymeric States

(a)

ox

red

5e–

5e–

(b)

M ETAL

S O L U T IO N

(a)

5e–

ox red

5e–

(b)

Figure 32.1 Oxidation–reduction-induced conformational movements in a conducting

polymer chain. (a) In solution with free rotation; (b) With one of the chain ends attached to a metal electrode.


Polymeric chains Polymeric chains

Conducting material Conducting material

Figure 32.2 Sarcomere-like molecular structure based on monodisperse chains of conducting polymers and two nanometric electrodes.

a)

b)

Figure 32.3 (a) Solution/reduced film/metal; (b) Oxidized and swollen film/metal.

A sarcomere-inspired anisotropic molecular structure can be envisaged by grafting linear monodisperse chains in-between two nanometric electrodes (Figure 32.2). The flow of an anodic current should promote a lineal expansion of the device inside the electrolyte, while cathodic currents should control its linear contraction. Present day technology cannot tell us how these structures can be produced. Amorphous and partially crosslinked films of conducting polymers can be produced by electrochemical synthesis. When used as electrodes in (aqueous) solution, the electrochemical reactions induce quasi-isotropic changes of the above-described noncovalent interaction variations. The generation of free volume, and the entrance of balancing counterions and water with a uniform change of volume, is achieved as a consequence of the electrochemical stimulation of the conformational changes (Figure 32.3). The oxidation reaction of the threedimensional (3-D) structure occurs under conformational relaxation kinetic control of the chains, or under diffusion kinetic control of the counterions inside the polymer film [3]. So, whatever be the intermediate oxidation state of a chain, it

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maintains a chemical equilibrium and the electric potential responds to the Nernst equation along an oxidation process. In this way, it is possible to know which of the entangled chains of a macroscopic film is to get stimulated simultaneously, by electrochemical reactions (the so-called “fat finger paradox”) so as to achieve an individual response from every individual conformational energetic state of a chain (the “stick finger paradox”). Those consecutive energetic states submitted to the thermal energy produce an almost isotropic volume change: notably, a free film in a solution produces a 3%

Figure 32.4 (a) Polypyrrole/tape bilayer. Induced stress gradients by electrochemical

reactions; (b) Macroscopic movements during current flow, 1, 2, and 3 indicate the anodic current; 1, 4, and 5 indicate the cathodic current.


length variation under oxidation–reduction cycling which is stable for thousand of cycles [4]. In order to induce the anisotropy required to generate macroscopic machines, a conducting polymer–tape interface – referred to as a “Maxwell demon” – was constructed [5] (Figure 32.4a). This is a transducer of local isotropic free volume generation to macroscopic stress gradient variations between both polymeric films to give macroscopic angular movements (Figure 32.4b). The “demon” stores (as charges in chains) more than two-thirds of the involved energy. Although the macroscopic muscle is not the best (most efficient) expected structure based on a molecular machine, it will provide a satisfactory 3-D arrangement of molecular motors to initiate the scientific exploration and investigate the technological applications for these new reactive, dense, and entangled molecular motors. During the above n consecutive reaction steps, counterions and water penetrate from the (0.1 M) solution attaining 3 to 6 M concentration inside the polymer. The oxidized polymer counterion composition changes in a continuous way (“giant nonstoichiometry”) from zero to 30–60% (w/w), with the latter being a soft, wet, dense, nonstoichiometric [6] and reactive material. The above-described device is reminiscent of an artificial muscle which links, via electric pulses, a series of chemical reactions, as well as stimulating conformational movements, ion and water interchange, and a change in volume. The electrodic potential (the muscle potential) will follow a progressive increase, in accordance with the chemical equilibria, along n consecutive energetic states during a constant angular movement (Figure 32.5a–d). Any physical or chemical variable (temperature, weight of objects trailed by the muscle, salt concentration, magnetic fields, etc.) that act on the chemical process will influence the muscle’s potential [7].

(b) 1)

2)

4)

Figure 32.4 (Continued)

3)

5)

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32 Electrochemically-Driven Conformational Polymeric States (a) 1600

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Figure 32.5 Evolution of the muscle potential along the movement described in Figure 32.4

(b1) to 32.4 (b3), under a constant current of 5 mA. (a) At different temperatures; (b) Trailing different steel weights; (c) With different concentrations of electrolyte; (d) Evolution of the consumed electrical energy in panel (c).

32 Electrochemically-Driven Conformational Polymeric States (c) 1000

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b)

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4 devices Figure 32.5 (Continued)

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32 Electrochemically-Driven Conformational Polymeric States 1400

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Figure 32.5 (Continued)

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32 Electrochemically-Driven Conformational Polymeric States (b) SOLVAY

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Figure 32.6 (a) A triple layer (polypyrrole/ tape/polypyrrole) advances under a constant current of 5 mA, touches the obstacle, and pushes it; (b) Evolution of the muscle

potential. When the muscle meets the obstacle, a potential step is observed. The initial position of the muscle is recovered by a flow of −5 mA.

This new simultaneous actuating and sensing paradigm, which is based on molecular motors, allows the construction of tactile muscles (Figure 32.6a,b) [8]. When the advancing muscle meets the obstacle, a potential step – which is proportional to the obstacle weight – is observed. Hence, the pathway has been opened to explore the construction of intelligent devices, with the transfer of intelligence from software (which today includes the technologies of independent sensors and actuators) to devices. Tactile muscles are linked to consecutive conformational chemical states obtained by reversible electrochemical reactions. By applying chemical kinetics methodologies to reactive conducting polymer gels, the activation energy attained will be a linear function of the initial packed conformational state of the chains obtained by electrochemical reduction at rising cathodic potentials (Figure 32.7) [9]. Any point of this linear variation is totally reproducible, as the conformations will store energetic memory in a continuous manner, and can be read by an ionic flow generated by an electrochemical reaction (thus mimicking ionic flow responses through the ionic channel in neurons). Clearly, the route is now open to explore the possibility that memory can be written in the conformational energetic states of the proteins that constitute ionic channels and different parts of neurons.

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32 From Electrochemically-Driven Conformational Polymeric States to Macroscopic Sensing and Tactile Muscles 22000

Experimental Ea Theoretical Ea

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Figure 32.7 (a) Evolution of the activation

energy for the oxidation of a film of conducting polymer after reduction by cathodic polarization, for a constant time, to different cathodic potentials; (b) The

Reaction pathway

activation energy includes the terms: constant chemical activation energy (Ea) and the conformational energy (Ec), that increases linearly with the initial state conformational packing.

References 1 Otero, T.F. (2008) Artificial muscles, sensing and multifunctionality from the electrochemical properties of conductive polymers, in Intelligent Materials (eds M. Shahinpoor and H.-J. Schneider), RSC, Cambridge, pp. 142–190. 2 Leigh, D.A., Zerbetto, F., and Kay, E.R. (2007) Angew. Chem. Int. Ed., 46, 72–191. 3 Otero, T.F. (1999) Conducting polymers, electrochemistry and biomimicking processes, in Modern Aspects of Electrochemistry, vol. 33 (eds J. O’m Bockris, R.E. White, and B.E. Conway), Plenum Press, New York, pp. 307–434.

4 Francois, B., Mermilliod, N., and Zuppiroli, L. (1981) Synth. Methods, 4, 131–138. 5 Otero, T.F., Angulo, E., Rodríguez, J., and Santamaría, C. (1992) J. Electroanal. Chem., 341, 369–375. 6 Otero, T.F. and Boyano, I. (2003) ChemPhysChem, 4, 868–872. 7 Otero, T.F. and Broschart, M. (2006) J. Appl. Electrochem., 36, 205–214. 8 Otero, T.F. and Cortés, M.T. (2003) Adv. Mater., 15, 279–282. 9 Otero, T.F. and Santos, F. (2008) Electrochim. Acta, 53, 3166–3174.

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33 Controlling Self-Assembly in Space and Time Prepared Comment Ben L. Feringa

33.1 Introduction

The control of assembly processes by external stimuli is of tremendous current interest, due to the important role of dynamic assembly in biological systems and the challenge to design smart and responsive supramolecular materials [1]. Gels represent an intriguing class of soft materials, and can form the basis for responsive self-assembled systems as they combine fluid and solid behavior with viscous and elastic properties [2]. The archetype of a biological responsive gel is found in the cytoskeleton, which consists of highly dynamic network comprising microtubules and actin filaments in an aqueous phase. The cytoskeleton is arguably one of the most sophisticated gels, and the dynamic processes involved result in many complex functions that include growth, self-organization, and cell division and movement [3]. An important feature is the continuous assembly and disassembly of mictotubules and actin filaments in the gel. The design of gelators – and, in particular, of responsive low-molecular-weight organogelators, that allow the control of an assembly process in a fully dynamic and reversible way – will be briefly discussed.

33.2 Low-Molecular-Weight Gelators

Responsive gels can be divided into chemical gels and physical gels. In chemical gels, which usually are polymers, a three-dimensional (3-D) network is present as a result of covalent crosslinks that provide robustness to the materials. In a responsive chemical gel, a physical or chemical stimulus can change the shape, size, viscoelastic properties, and so on. The interaction between the network filaments or between filament and solvent is also often highly sensitive to the environment.


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33 Controlling Self-Assembly in Space and Time

Stimulus

gel

solution • Temperature • pH • Light • mechanical stress • electrical field

Figure 33.1 Schematic representation of a physical gel, and change in response to an external

stimulus.

In a physical gel, the network is built from subunits that are held together by multiple noncovalent interactions. Responsiveness is an intrinsic property of physical gels, all of which have a characteristic gel–sol phase transition at moderate temperature that involves an assembly–disassembly process (Figure 33.1). Although several physical gels are based on polymers or proteins, low-molecularmass organogelators (LMOGs) represent an attractive class of materials as they have the propensity to gel a variety of liquids at concentrations frequently well below 1 mass%. The LMOGs and hydrogelators are an emerging class of materials with fascinating properties [4]. They comprise a family of compounds with wide structural diversity, but the common property that they readily assemble into fibers in solution. The fibers form entangled networks and, as a result, can convert a range of liquids into gels. The LMOG gels can change their properties by for example, the number of junctions, the extent of assembly into fibers or their structure, their geometry, or the number and nature of noncovalent interactions. Furthermore, interaction with additives, the nature of the solvent, the pH or temperature, or mechanical stress can all lead to a response and a change in the association of the components in the gel network. Photoresponsive gel systems constitute a particular attractive class of responsive LMOGs, as a noninvasive stimulus (light) transforms the gelator molecules, and this results in a change in gelation behavior [5]. Specifically, the introduction of

33.3 Dynamic Control of Gelation

light-switchable functions to synthetic low-molecular-weight (LMW) gelators allows for reversible control over the self-assembly process to be achieved.


To achieve dynamic self-assembly or aggregation with control in space and time in response to an external trigger, the LMOGs are particular effective. It should be noted that “intrinsic factors” such as solubility, concentration or temperature also lead to responsive behavior. Several organogelators have been reported that respond to chemical triggers, including pH change, host–guest complexation, metal-ion binding, gas uptake (notably carbon dioxide), ligand binding, and mechanical stress (i.e. thixotropic behavior). In this chapter, attention is focused on the basic principle of light-responsive gels. The presence of a photoresponsive group in the gelator system provides a very attractive means to change the gel properties in a reversible manner, as the group can be addressed in a selective and/or a noninvasive manner. Several factors will contribute to the response observed, including the chemical changes that occur upon irradiation, and the structural and hierarchical level at which the photoresponsive effect will be expressed. Photoresponsive effects in gels LMOGs can be observed through changes in the phase (gel–liquid) transitions, viscosity, nature, size and extent of aggregate formation, pH change, spectroscopic properties including fluorescence and circular dichroism, patterning, and so on. As the formation of gels based on LMOGs is the result of supramolecular organization and self-assembly of molecules at different hierarchical levels, the presence of phototriggers allows also the study of responses from the nano- to the micro/macroscale, in a time-dependent manner. The dynamics of such responsive self-assembled systems represents one of the most challenging aspects of supramolecular chemistry. Azobenzenes are among the most widely used photoactive compounds in the design of photoresponsive gelators [5]. In the system discussed here, dithienylethenes are used as trigger elements (Figure 33.2), and undergo a reversible switching between open and closed forms, using ultraviolet (UV) and visible irradiation, respectively. The dithienylethenes usually do not interconvert thermally, and show excellent fatigue resistance and stability over multiple switching cycles. The difference in conformational flexibility between the open and closed forms is exploited in the design of photoresponsive gelators, as shown in Figure 33.2. In the open form, the two thienyl units are not conjugated, and can freely rotate around the bond that connects them with the cyclopentene bridging moiety. In contrast, in the closed form, the conjugation extends through the whole chromophore and the rotational freedom is lost, such that a rigid core is present. The introduction of peripheral amide groups allows the formation of multiple hydrogen bonds and, in the presence of several R-substituents (notably those containing aryl moieties),

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Figure 33.2 Photoresponsive gelator based on a bisamide-substituted diarylethene. Hierarchi-

cal assembly; multiple hydrogen bonding results in stacks that aggregate into fibers to form a network-encapsulating solvent to give a gel.

stable gels are obtained with a variety of solvent LMOGs. The photochemical switching at the molecular level is attended by a major change in conformational flexibility and, as a consequence, a change in the aggregation behavior is observed. Both, the open and closed photoresponsive gelator molecules form gels with distinct differences in fiber structure, as revealed using transmission electron microscopy (TEM) and phase behavior (Figure 33.3). The gelators in the closed form exhibit significantly increased gel–sol transition temperatures, and the enhanced stability of the fibers is attributed to the more rigid core of the molecule. The propensity to modulate the stability and nature of the supramolecular structures by photochemical ring-opening or ring-closure of the central dithienyl moiety in the core unit was exploited in holographic patterning. In this case, there is a delicate balance of competing processes in a dynamic system that can be addressed by light (Figure 33.4) [6]. Under the appropriate concentration and temperature regime, the fibers can be assembled and disassembled on demand, by using either UV or visible light irradiation. This results in mass transport to UV-irradiated areas during formation of the closed-state and, as a consequence, more stable aggregates. The control of aggregate formation by reversible photoinduced self-assembly can then be used to


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generate a dynamic gel pattern. As illustrated in Figure 33.5, simultaneous irradiation with two (laser) light sources, employing a suitable mask, leads to the generation of holographic patterns in a fully dynamic manner. When chiral amide substituents are incorporated in these photoresponsive gelators, the interplay of chirality and self-assembly can be studied, providing a system with remarkable gelation behavior [7]. Despite the presence of the chiral amide

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Figure 33.4 Balancing competing processes in photoresponsive organogelators.

2gel

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Figure 33.5 Dynamic pattern formation by reversible photoinduced self-assembly.

groups, the molecular system in its open form consists in solution of a dynamic equilibrating mixture of P and M helices of the central dithienyl core. As a consequence, photochemical ring closure leads to equal amounts of the corresponding diastereoisomers, whereas when photochemical ring closure is carried out in the gel state, only a single diastereoisomer is formed. This remarkable stereoselection


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Figure 33.6 Reversible control of chirality and supramolecular assembly, leading to four distinctive states comprising unstable and stable gels.

is attributed to the exclusive incorporation of one of the two dynamic diastereoisomeric conformations in the aggregates. Detailed studies of the gel formation, fiber structure and photochemical and thermal processes by employing for example, TEM, NMR and circular dichroism (CD) techniques, have revealed that both the open and closed forms of the photoswitchable gelator will create two distinct supramolecular aggregated states, these being metastable and stable gel states. As a result, there are in total four aggregation states in a full cycle which can be addressed by light and temperature changes. An important feature here is that the photochemical ring-opening or closing reaction will change the rigidity and chirality (fixed or dynamic) of the core unit and, as a consequence, the stability of the fibers. However, once assembled in a fiber structure, the supramolecular chirality is preserved in the photochemical steps. The four-state switching cycle and the change in supramolecular assembly are summarized in Figure 33.6. In fact, there is mutual control of chirality at different hierarchical levels and the whole system is reversible due to the chiral photoresponsive group present in the LMOG molecule: Solution Gel

RR:SS diastereomeric ratio 1 : 1 RR:SS diastereomeric ratio 98 : 2

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Of paramount importance in this system is that metastable chiral aggregates can be obtained in a fully reversible manner. This gel system is particular illustrative in showing how the interplay of molecular communication (chiral recognition) and self-assembly operate in a dynamic way. Furthermore, it should be noted that the use of chiral switches allows the control of self-assembly, supramolecular chirality and the viscoelastic properties of these soft materials

33.4 Concluding Remarks

The design of small-molecule gelators with addressable functions allows the control of supramolecular self-assembly processes in a fully dynamic manner. By using photochemical switches, external triggering and typical responses such as gel–sol transitions are readily achieved. However, such stimuli can also induce a variety of other changes in properties and functions, such as chirality, the structure of the aggregates, a propensity to encapsulate hosts, and/or optical or redox properties. The ability to control assembly in space and time at different hierarchical levels will be crucial in the context of future systems’ chemistry. These responsive gel systems also hold great promise for the development of “smart materials,” including systems for sensing, drug delivery, actuators, and as dynamic biohybrid matrices.

References 1 (a) Lehn, J.-M. (1995) Supramolecular Chemistry, Wiley-VCH Verlag GmbH, Weinheim; (b) Feringa, B.L. (ed.) (2001) Molecular Switches, Wiley-VCH Verlag GmbH, Weinheim. 2 (a) R.G. Weiss and Terech, P. (eds) (2005) Molecular Gels: Materials with SelfAssembled Fibrillar Networks, Springer/ Kluwer; (b) van Esch, J.H. and Feringa, B.L. (2000) Angew. Chem. Int. Ed., 39, 2263; (c) Terech, P. and Weiss, R.G. (1997) Chem. Rev., 97, 3133. 3 Goodsell, S. (1996) Our Molecular Nature, The Body’s Motors, Machines and Messages, Springer-Verlag, New York. 4 de Loos, M., Feringa, B.L., and van Esch, J.H. (2005) Eur. J. Org. Chem., 3615–3631. 5 (a) Lin, Y., Kachar, B., and Weiss, R.G. (1989) J. Am. Chem. Soc., 111, 5542; (b) Brotin, T., Utermohlen, R., Fages, F.,

Bouaslaurent, H., and Desvergne, J.P. (1991) J. Chem. Soc., Chem. Commun., 416; (c) Murata, K., Aoki, M., Nishi, T., Ikeda, A., and Shinkai, S. (1991) J. Chem. Soc., Chem. Commun., 1715– 1718; (d) Murata, K., Aoki, M., Suzuki, T., Harada, T., Kawabata, H., Komori, T., Ohseto, F., Ueda, K., Shinkai, S., and Ahmed (1994) J. Am. Chem. Soc., 116, 6664; (e) Ahmed, S.A., Sallenave, X., Fages, F., Mieden-Gundert, G., Muller, W.M., Muller, U., Vogtle, F., and Pozzo, J.-L. (2002) Langmuir, 18 (19), 7096; (f ) Ayabe, M., Kishida, T., Fujita, N., Sada, K., and Shinkai, S. (2003) Org. Biomol. Chem., 1, 2744; (g) Frkanec, L., Jokic, M., Makarevic, J., Wolsperger, K., and Zinic, M. (2002) J. Am. Chem. Soc., 124, 9716; (h) van der Laan, S., Feringa, B.L., Kellogg, R.M., and van Esch, J.H. (2002) Langmuir, 18, 7136.

References 6 de Jong, J.J.D., Hania, P.R., Pygzlys, A., Lucas, L.N., de Loos, M., Kellogg, R.M., Feringa, B.L., Duppen, K., and van Esch, J.H. (2005) Angew. Chem. Int. Ed., 44, 2373. 7 (a) de Jong, J.J.D., Lucas, L.N., Kellogg, R.M., van Esch, J.H., and Feringa, B.L.

(2004) Science, 304, 278; (b) de Jong, J.J.D., Tiemersma-Wiegman, T.D., van Esch, J.H., and Feringa, B.L. (2005) J. Am Chem. Soc., 127, 13804.

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34 Discussion 6.B Discussion on the Prepared Comments by J. Rebek,1) T.F. Otero,2) T. Aida,3) B.L. Feringa,4) and J.F. Stoddart5) Chairman: Enrico Dalcanale

R.D. Astumian: So having seen this flying demonstration, I just want you to think about the wonderful helicopter, which has already been drawn by Leonardo da Vinci, and how catastrophically it would fail if we attempted to fly it at 30 000 feet, where there are very few molecules for the helicopter blades to push off. That would be an illustration of what happens when we attempt to use principles that apply in one set of circumstances to an entirely different regime of motion. I think it is important to point out that the regime we are trying to go into – that of liquids with small things like molecules – is very very different from the one that we are used to in the macroscopic world. If we try and simply translate those principles that we have developed, for example from mechanics, we are doomed to ultimate catastrophic failure, I would say. I want to illustrate one of the philosophical problems that drew me to this field in the first place. Of course, you can easily control the rotation of a chemical bond: you can add a ligand and shape it one way, then remove the ligand and it will turn into a different shape. However, if you think of a simple organic molecule such as ethane, with three different substituents on each carbon, you will see that you get three distinct conformers for that. From any one conformer, you can go to another conformer by a clockwise rotation or to the other conformer by the counterclockwise rotation around the carbon–carbon bond. So, you get three states – let’s call them A, B and C – that form a triangle if you draw up a kinetic diagram. That was the system studied in 1931 by Onsager, to illustrate the principle of microscopic reversibility. You can put it in any temperature you like, at any constant pressure, or any constant chemical potential of a ligand, but under no circumstances you will ever have a directed rotation in which 1) The prepared comment by J. Rebek was on a spring-loaded device (see p. 435). 2) The prepared comment by T. F. Otero is entitled “From electrochemical driven conformational polymeric states to macroscopic sensing and tactile muscles” (see p. 443).

3) The prepared comment by T. Aida was on photomechanical actuators. 4) The prepared comment by B. L. Feringa was on controlling self-assembly in space and time (see p. 453). 5) The prepared comment by J. F. Stoddart was on molecular computing.


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34 Discussion 6.B

you see – from a single molecule point of view – A, then B, then C, then A, then, B then C, more likely than the reverse. Therefore, the philosophical question is as follows: How do you get it to go in one direction by simply changing the environment back and forth, by binding a substrate and then releasing a product – that is, how do you get it to go in a single direction with chemistry? That was the original intellectual problem that drew me to this field, and when I saw David Leigh’s beautiful paper in Nature with the two-ring catenane and three bases, this is exactly Onsager’s model. How can we drive rotation with chemistry? Chairman: So he did it, that is fine! R.D. Astumian: Well, actually he didn’t do it, and it is interesting to see why he didn’t do it as he describes that he got perfect positional integrity. However, when he tried it with the two-ring system, it didn’t go around preferentially in any one direction. When it went from A to B, it was just as likely that it would go from A directly to B as it were if it went from A through C and then to B. There was no rotation in the two-ring system, and the way that he was able to modify the system to get directed rotation is remarkable and creative. I think ultimately, that holds the key to understanding how we can get continuous rotation by chemistry. Chairman: I think, if you gave him time, he will do it. I am sure! P. Beer: It is just a completely different question, if that’s OK, for Ben Feringa. Have you ever considered your materials for sensors? Your gel fiber materials have applications; you have the amide groups on your materials, and if you throw in anions for example of different shapes, you might get some beautiful sol–gel changes. B.L. Feringa: Given all the fantastic work on anion binding, we have considered that. We have not studied it in much detail, as we’ve instead focused heavily on seeing if we could release something, but this anion binding may well be a very good option. What we have done so far is mainly photochemical control; the other system, that we have published in Angewandte Chemie, is with a dual system where we have an enzymatic reaction. We actually have amphiphilic molecules and gelators that together form an independent trading network. Then, by using an enzyme we can trigger the release because we’ve changed the network, so what we have tried to sense is an enzyme activity. But it would be very interesting to sense anion differences, pH differences, and there are many more options, some of which I’ve already touched upon. I think this field is still open for tremendous discoveries. T.F. Otero: In relation to Dean Astumian’s question, I think it is quite complex from a chemical point of view. However, if you use chemistry and electrochemistry together, you can have two fields: one generated by the current, and another generated from the chemical considerations. You can actually see in the case of conducting polymers that you avoid conformational coarsening in the statistical sense, but you can force the unidirectional movement. Concerning rotation, we don’t have a perfect 3-D structure – that everyone is asking for – that is related to the construction of the devices and puting together all the different molecular motors. However,

34 Discussion 6.B

conducting polymers are associated with wire like structures so that they have two possibilities. First, they can control the conformations, and second they have the possibility, for bridging two polypyrrole wires with a molecular motor, or by substituting a molecular motor in place of one of the hydrogens in the pyrrole unit of the polymer backbone, and using this as the 3-D structure in order to control not only the conformations of the lateral molecular motor but also the rotations of the main chain. This is just a suggestion. With regard to your question, any of the polymers – whether they are conducting or not – can act simultaneously as actuators and sensors. The problem is how to obtain the information from nonconducting polymers. From gels, it can be obtained by the potential of the membrane. Moreover you can put different functions inside a system, like those molecular machines. Having different structures, each providing specific attraction for one of the ions in the media, then you can have a perfect actuator sensing only one of the ions present while working, which is also my suggestion. J.-P. Sauvage: I have a different question for Professor Harada, if he doesn’t mind my asking. I suspect a few of us here remember some very nice work which you reported a few years ago, with cyclodextrins threaded like beads onto a small molecular string – such as tetraethylene or pentaethylene glycol – that you studied using STM. You were able to move the molecules, push the beads, unthread them, and fold the entire assembly. As far as I can remember, you had four beads that you described as some type of abacus. Personally, I was very impressed, but I would like to know whether you went further, and if you have a more complex system with more beads potentially in a abacus? A. Harada: We are very interested in the dynamic aspects of threading and movement, and of course the unidirectional movement. According to Feynman, it is impossible to extract the direction from the fluctuations. Of course, that’s correct and we accept the second law. Now, when looking for a way to change direction, an important example is catalysis, because we can use chemical energy in order to perform mechanical energy. Certainly, catalysis is the next step that we are heading towards, although I’m not sure where we are going at the moment. Any ideas would be appreciated. Chairman: I have a small question for Professor Aida. In the last two movies you presented, what was the difference between kicking the nanoparticle of gold and the silica nanoparticle? One exhibits slow movement, but the other goes really fast. So what was the difference? T. Aida: I wonder if this depends on the elastic property of the particle, but apart from that, I have no idea at present. Chairman: Was it done in a different solvent or a different medium? T. Aida: I don’t think so. R.D. Astumian: Was it really in solvent, or on the surface? T. Aida: It was on the surface.

465

466

34 Discussion 6.B

Chairman: I would like to thank all the contributors to this last session – please join me in thanking them. Finally, as the last Chairman of the meeting, I would like to take the opportunity, on behalf of all of you, to thank Jean-Pierre Sauvage for having organized such a wonderful conference, and inviting us all to participate. Thank you.

467

Index a accelerated Diels–Alder reactions 21, 22 acetylcholine-templated catenanes 147, 148, 153, 155 acid–base controllable molecular machines 169–171 actin filaments 61 actin–myosin system 303, 304 activation energy 54, 452 active gels 302–304 active macroscopic systems 301–305 active metal templation 109 addressing in molecular machines 196, 197 AFM, see atomic force microscopy alizarins 37, 38 all-photonic molecular half-adders 343, 344, 347 altitudinal rotors 258, 259, 385, 387 amide-based rotaxanes 99, 100 ammeters 419–421 amplifiers 418–420 anandamide 439 AND logic gates 339–344, 368, 369, 372, 423 anion binding 464 anion templated synthesis 90–93 anionic cage frameworks 18 antenna systems 333–336 anthracene guest reactions 24, 25 artificial blood 31 artificial metallo-DNA 18, 19 artificial photosynthesis 319, 321–337 – antenna systems 333–336 – applications 356 – charge separation lifetimes 332, 333 – definitions and concepts 321, 322, 361, 362 – discussion 355–359, 377, 378

– – – – – – – –

economic/political factors 357–359 electron-proton transfer 363, 364 fullerenes as electron acceptors 330–332 fundamental processes 324 inorganic chromophores 329, 330 low-molecular-weight systems 332, 333 mimicking the reaction center 324–333 natural photosynthesis 322, 323, 336, 337, 355, 363, 378 – oxygen evolution 355, 361–365 – photoinduced electron transfer 321, 324, 325, 327, 329–332 – porphyrin–quinone systems 324–329 – proton-coupled electron transfer 364 – utilizing stored energy 336, 337 asymmetric catalysts 125 atomic force microscopy (AFM) 308, 309, 381 atomic precision 408–410 ATP hydrolysis – artificial photosynthesis 359 – fluctuation theorem 309–311 – molecular machines 161, 165, 214, 236 – non-interlocked systems 244, 291, 302 ATP stimulation 368–370 ATP synthase 323, 336, 337, 391, 392 atropisomerism 251 avidin–biotin complex 46, 47 azimuthal rotors 258, 259, 280, 385, 387, 388 azobenzenes 245, 268, 269, 276, 278, 281, 293, 294, 347, 348, 455, 456

b bacterial glycolysis 314, 315 Bailar twists 62 ball bearings 246, 248, 249 barbiturates 35–39, 41


468

Index barrier height imaging (BHI) 297, 298, 386, 387 barrows 394 benzophenanthrenes 392, 393 benzylamides 97, 194–196 BHI, see barrier height imaging biased Brownian motion 264, 265 binary logic functions 183, 204 – see also molecular logic binding affinities 46, 194, 195 binding constants 58, 61, 62 biochemical machines 225–230 biohybrid systems 276, 277, 283 biological ion channels 56 biomimetics 61, 215 biomolecular machines, see natural devices and machines bipyridyl systems 435, 436 bipyridyl-dinitro-oligophenylene-ethynylene dithiol (BPDN-DT) 414, 415 9,10-bis(phenylethynyl)anthracene 335, 336 bistable catenanes 193, 203, 204 bistable rotaxanes 75, 76, 124, 125, 198, 199, 203, 204 boronic acid esters 13, 14 Borromean rings 68–70, 144, 145 bottom-up approaches 160, 161, 204, 205 BPDN-DT, see bipyridyl-dinitrooligophenylene-ethynylene dithiol brakes 254 break junction method 399, 405, 409, 417, 418 bubble formation 51–56, 58, 63, 64

c cage frameworks 51–56 – activation parameters 54 – binding constants 58 – bubble formation 51–56, 58, 63, 64 – design and synthesis 10, 11, 17–21, 23–26 – edge exchange reactions 52–54 – entropy of solvation 54, 55, 60, 61 – Eyring plots 52–54 – molecular dynamics 54–55, 64 – stepwise self-assembly 62, 63 – template synthesis 113, 114 calixarene–based hybrids 94, 103–106 calixarenes 15, 16, 18, 36, 39, 40 capsules – catalysis and reactions 59–61 – design and synthesis 15, 16, 18, 22, 23, 26

– spring-loaded devices 436–440 – stepwise self-assembly 62, 63 – synthesis 4, 6 carbon nanotubes (CNTs) 381 carboranes – cage frameworks 52, 53 – dynamic combinatorial chemistry 151 – molecular devices 397 – non-interlocked systems 256 carotene–porphyrin–fullerene systems 331, 332 carotene–porphyrin–quinone systems 326–328 carousels 246–248 catenanes – analytical methods 219–221 – anion templated synthesis 93 – applications 124, 125, 156 – asymmetrical synthesis 153 – binding affinities 194, 195 – bistable 193, 203, 204 – charged hydrogen bond templated systems 84 – chemical energy supply 188, 189, 233, 234 – coordination geometries 107, 108 – cucurbiturils 43 – design and synthesis 8, 9 – discussion 151–156 – donor/acceptor template synthesis 72–74, 77–80 – dynamic combinatorial chemistry 147– 149, 151–156 – electrochemical energy supply 189–191 – future developments 204, 205 – historical perspective 69–71 – mechanical bonds 67–70 – mechanical motion 188 – metal-containing 106–114 – molecular machines 187–196, 236 – neutral hydrogen bond templated systems 94–98 – nonequilibrium work relations 311 – novel architectures 103–106 – ordering and addressing 196, 197 – photochemical energy supply 190–192, 195 – rearrangement by copper(I) coordination 219–223 – recognition sites 187, 188 – self-templating approach 148 – solid-state electronic devices 201–204 – solvophobically driven templation 119, 120

Index – structure and coordination 4 – surface-deposited 219–223 – switchable 77–79 – unidirectional ring rotation 192–196 cavity-directed chemical transformations 21, 22, 24–26, 225–227 chaperonins 368, 369 charge separation lifetimes 332, 333 charge-transfer (CT) complexes 43, 44 charged hydrogen bond templated systems 80–90 – clipping protocol 84–86, 102 – molecular switches 89, 90 – other mechanically interlocked molecules 88, 89 – reverse recognition 82, 83 – ring shrinkage 87 – slippage 86, 116 – threading-accompanied-by-swelling 87, 88 – threading-followed-by-stoppering 83, 84, 89, 92, 99, 101, 115–117 chemical energy supply 165, 169–175, 188, 189, 213, 214, 216, 217, 233, 234, 265–267 chemical gradients 314, 315 chemically operated logic gates 339, 340 chemically switchable rotaxanes 75, 76 chirality – molecular devices 433, 434 – molecular receptors 38–41 – non-interlocked systems 293, 294, 315 – self-assembly 457–460 – spring-loaded devices 438 choleic acid complexes 3 choleic acid–organic complexes 32 cholesterol 57, 58 chorismate mutase 60 circular helicate structures 19, 20 click chemistry 77, 78 clipping protocol 84–86, 102 CMOS, see complementary metal-oxide-semiconductor CNTs, see carbon nanotubes cogwheel-like systems 251 coherent transport 403, 404 combinatorial chemistry 37 complementary metal-oxide-semiconductor (CMOS) transistors 367 conducting polymers (CP) 443–452, 465 conformational polymeric states 443–452 coordination assemblies 10–12, 17–21, 23–26, 219–223

copper-templated catenanes/rotaxanes 106, 107, 112, 176–178 copper(I) coordinated catenanes 219–223 Coulomb blockade 433 Coulomb staircase 401, 402, 404, 433 covalent bonding 13, 14 CP, see conducting polymers crown ethers 169–172 crystal bending 278 CT, see charge-transfer CTV, see cyclotriveratrylene cubanes 431, 432 cubic structures 235, 236 cucurbiturils 43–49 – capsules 6 – design and synthesis 12, 13 – discovery and development 43–45 – molecular machines 172–174 – noncovalent assembly 43–49 – structure 44 – template synthesis 115, 117–122 – vesicle formation 45–48 cyanurates 37, 40, 41 cyclic porphyrin arrays 333–335 cyclodextrins – applications 126, 127 – cucurbiturils 46, 47 – molecular devices 465 – molecular machines 172–174 – self-assembly 8, 9, 13 – solvophobically driven templation 115–122 cyclophanes 77, 257 cyclotriveratrylene (CTV) ligand 113, 114

d DCC, see dynamic combinatorial chemistry DCL, see dynamic combinatorial libraries De Donder affinities 308 demultiplexers 344–346 destabilization of translational isomers 178, 180 devices, see molecular devices di-α-keto acids 10, 11 diagnostic applications 370–372 Diels–Alder reactions 21, 22, 24, 25, 59, 61, 104 diffusion complexes 59, 60 digital multiplexers 344–346 dioxygen 31, 355, 361–365 1,5-dioxynaphthalene units 77, 78, 175, 176

469

470

Index disordered clusters 222 dithienylcyclopentadienes 416–418 DMN, see 1,5-dioxynaphthalene DNA-based nanotechnology 368, 369 DNA ligases 13 DNA replication 225, 226 DNA structure 13, 38, 39, 155, 156, 169 DNP, see 1,5-dioxynaphthalene donor/acceptor templated systems 72–80 double helical complexes 9, 10, 16 double rosettes 36–39 drug delivery 126, 127, 171, 172, 276 dynamic combinatorial chemistry (DCC) 18–20, 147–149, 151–156 dynamic combinatorial libraries (DCL) 85, 86, 147 dynamic control of gelation 455–460 dynamic self-assembly 111 dynamic supramolecular systems 40, 41

e edge exchange reactions 52–54 Eglinton coupling reactions 77, 78 electrochemical energy supply – molecular devices 443–452 – molecular machines 166, 175–178, 189–191 – non-interlocked systems 256–258 electrochemical switching 75, 76, 78, 79 electrodic potentials 447–451 electromigration 399 electron ionization-mass spectrometry (ESI-MS) 219, 222 electron-proton transfer (EPT) 363, 364 electron-scattering quantum chemistry (ESQC) 404, 421 electronic reset 179 electronically driven molecular devices 397–425 elevators 89, 90, 170, 171 endocytosis 45 endofluorous environments 27 endohedral functionalization 26 energy production 319 energy supply – active macroscopic systems 303 – molecular machines 165, 166, 169–183, 188–192, 213–217, 233, 234, 245, 256–258, 264–279, 303 enhanced tunneling regimes 402, 403 enthalpy–entropy compensation plots 46, 47 entropy of solvation 54, 55, 60, 61 EPT, see electron-proton transfer

error-checking processes 79, 84 ESI-MS, see electron ionization-mass spectrometry ESQC, see electron-scattering quantum chemistry Eyring plots 52–54

f F1-ATPase molecular motors 309, 310 FA, see ferrocenemethylammonium facile multiplexers 348 fat finger paradox 446 feedback control 292, 293 ferritins 63 ferrocenemethylammonium (FA) pair 47, 48 ferrocenes – cucurbiturils 46–48 – molecular devices 388, 389 – molecular machines 175 – non-interlocked systems 246–250, 256 flashing ratchet mechanism 192 fluctuation theorem 307–311 fluorescence quenching 227–229 fluorescent dyes 122, 123, 174 fluorous spheres 27 folate-decorated vesicles 45 foldamers 13 Frederiks transitions 304 fullerenes – artificial photosynthesis 330–332 – design and synthesis 18, 26, 32, 33 – molecular devices 396, 397, 418–420, 431–434 – non-interlocked systems 262, 263 function through architecture 21–27 furan-based spherical hollow structures 20, 21

g gearboxes 251, 252, 255, 256, 389 glycoluril derivatives 436–440 glycolysis 233, 314, 315 gold-templated catenanes 111, 112 Grätzel cells 358, 359 Grover’s algorithm 377 gyroscopes 248, 249, 253, 254

h half-adders 343, 344, 347, 422–424 helical foldamers 13 helicenes 264, 265 hepsin 369 heterodimerization 104

Index heterogeneous catalysis 235, 238 homogeneous catalysis 238 honeycomb structures 14 Huisgen 1,3-dipolar cycloadditions 77, 78 hybrid technology 398, 425 hydrogen bonding 3–5 – molecular receptors 35, 37, 40 – self-assembly 11–13, 15–17, 21–23 – see also charged hydrogen bond templated systems; neutral hydrogen bond templated systems hydroxymethylferrocene 46, 48

i inclusion compounds 3 incoherent transport 403 information ratchet mechanisms 186, 187 INHIBIT gates 344 inorganic chromophores 329, 330 insulation 120, 121 intermolecular photodimerizations 24 intramolecular electron transfer mechanism 178–180 ion channels 56 ion-driven molecular machines 257, 258 isolated protrusions 222

k keypad locks 349 kinetic control – dynamic combinatorial chemistry 153 – molecular machines 236, 237, 254, 255 – template synthesis 141 kinetic self-assembly 32 Kondo effect 415

l landers 382, 383, 408–410 Langmuir–Blodgett films 409, 412 LDOS, see local density of states LHCII, see light harvesting complex II light, see photochemical light harvesting complex II (LHCII) 378 light-responsive gels 455–459 light-responsive rotaxanes 125, 126 linear motors 301, 302 liquid crystal films 282, 283, 291, 293, 294 LMOGs, see low-molecular-mass organogelators local density of states (LDOS) 400 logic functions, see binary logic functions; molecular logic

low-molecular-mass organogelators (LMOGs) 453–455 low-molecular-weight artificial reaction centers 332, 333

m machines, see molecular machines macrocyclic compounds 9, 10 macrocyclic crown ethers 169–172 macroscopic sensing 443–452 magic ring approach 79, 80, 84, 85, 98, 109 magic rod approach 102, 103 maleimide guest reactions 24, 25 manganese(III)–porphyrin catalysts 225–230 Maxwell demons 443, 447 MCID, see molecular computational identification mechanical bonds – historical perspective 69–72 – research programs 71, 72 – structure and types of interlocked compounds 67–69 – see also catenanes; rotaxanes; template synthesis mechanical motion – molecular devices 382–397, 416–424, 425, 429, 430 – molecular machines 163–165, 167, 169– 188, 214, 215, 217 mechanical work 213 melamine/cyanuric acid pattern 5 melamines 35–38 memory devices 124, 125, 202, 348 9-mesityl-10-methylacridinium ion 332, 333 metal-containing catenanes 106–114 metal-containing rotaxanes 106–114, 172, 176–178 metal–organic frameworks (MOFs) 3, 31, 32, 143, 144, 235 metal–organic rotaxane frameworks (MORFs) 121 metallocenes 246–250, 256, 316 microfluidics 429, 432 MNs, see molecular necklaces MOFs, see metal–organic frameworks molecular ammeters 419–421 molecular amplifiers 418–420 molecular ball bearings 246, 248, 249 molecular barrows 394 molecular brakes 254 molecular cages, see cage frameworks molecular carousels 246–248

471

472

Index molecular computational identification (MCID) 372, 373 molecular devices 381–428 – ammeters 419–421 – amplifiers 418–420 – atomic precision 408–410 – catalysis 465 – combined mechanical and electronic effects 416–425 – conformational polymeric states 443–452 – definitions and concepts 160–163, 381, 382 – discussion 429–434, 463–466 – dynamic control of gelation 455–460 – electrochemical-driven 443–452 – electronic effects 397–425 – gears 389 – low-molecular weight gelators 453–455 – macroscopic sensing 443–452 – mechanical motion 382–397, 416–425, 429–430 – Morse manipulators 421, 422 – muscles 443–452 – negative differential resistance 400, 412–414 – quantum logical gates 422–424, 431 – rack-and-pinion devices 390, 391 – rectification 409–411, 412 – rotors and motors 385–389, 392 – self-assembly 453–461, 464–465 – single electron storage 411–413 – single-molecule transistors 414, 415 – spring-loaded 435–442 – surface-bound 382–391 – switches 416–418 – tools for modifying surfaces 382 – transport agents/regimes 382, 383, 400–405 – unidirectional ring rotation 387, 391–393, 465 – vehicles 393–397 – wires 398–400, 405–407, 430 – see also molecular machines molecular dynamics – cage frameworks 54, 55, 64 – molecular receptors 57 – non-interlocked systems 259, 260, 291, 297–300 molecular elevators 89, 90, 170, 171 molecular gearboxes 251, 252, 255, 256, 389 molecular gyroscopes 248, 249, 253, 254 molecular half-adders 343, 344, 347, 422–424 molecular insulation 120, 121

molecular keypad locks 349 molecular logic 319, 321, 337–350 – applications 348–350, 367–375 – chemically operated logic gates 339, 340 – combinations of logic gates 343, 344 – communication among molecular switches 347, 348 – definitions and concepts 337, 338 – discussion 356, 357 – DNA-based nanotechnology 368, 369 – molecular computational identification 372, 373 – photochemical logic gates 340–343 – photoinduced electron transfer 346, 371, 372 – quantum logical gates 422–424, 431 – reconfigurable devices 344–346 – semiconductor devices 367, 368 – sensory/diagnostic applications 370–372 – simple switches 338, 339 – ultrafast switching 346, 347 molecular machines 159–212 – active macroscopic systems 301–305 – allowing/preventing ring motion 183–187 – applications 171, 172, 197–207, 282, 283 – biased Brownian motion 264, 265 – binding affinities 194, 195 – catalytic systems 235, 238, 239 – catenanes 187–196, 236 – correlated rotation through steric interactions 250–253 – cucurbiturils 43, 172–174 – cyclodextrins 172–174 – definitions and concepts 160–162 – design concepts 244–246 – discussion 213–218, 231–234, 291–295, 313–316 – electron transfer mechanisms 178–181, 217 – energy supply 165, 166, 169–183, 188– 192, 213–217, 233, 234, 245, 256–258, 264–279 – fluctuation theorem 307, 308, 309–311 – functions 162, 163, 196–204 – future developments 204, 205, 283–285 – historical context 160, 161 – kinetic control 236, 237, 254, 255 – macrocyclic crown ethers 169–172 – mechanical changes in crystals and polymers 276–279 – mechanical motion 163–165, 167, 169– 187, 188, 214, 215, 217 – metal-containing rotaxanes 172, 176–178 – metallocenes 246–250, 256

Index – molecular logic 340 – nanoscale synthesis 232, 233 – non-interlocked systems 243–289, 291– 295, 297–300, 301–305, 307–312, 313–316 – nonequilibrium work relations 307, 308–311 – ordering and addressing 196, 197 – photoinduced transport of liquid droplets 199–200 – photoisomerization reactions 181–186, 195 – polymers 215, 216, 276–279, 303 – rotary motion controlled by external input 254–256 – rotaxanes 166–187, 236 – slippage 251 – solid state molecular gyroscopes 253, 254 – solid-state electronic devices 200–204 – surface-bound molecular rotors 258–263, 279–282, 297–300 – synchronization and feedback control 292, 293 – tetracationic cyclophanes 175, 176, 189, 190 – unidirectional ring rotation 192–196, 264–267, 269–272, 280, 294, 295, 299–300, 313–316 – see also molecular devices; natural devices and machines molecular motors – applications 282, 283 – azobenzene units 268, 269, 276, 278, 281 – biased Brownian motion 264, 265 – chemically driven 265–267 – definitions and concepts 163 – fluctuation theorem 309, 310 – mechanical work 213, 216 – non-interlocked systems 244, 263–274 – nonequilibrium work relations 309, 310 – photochemical energy supply 268–279 – second-generation 272–274, 280, 282, 283 – surface-bound 279–282, 385–389 – unidirectional ring rotation 264–267, 269–272, 280, 294, 295 molecular muscles 172, 198, 199, 443–452 molecular nanojunctions 398 molecular necklaces (MNs) 121 molecular propellers 251, 252 molecular receptors 35–42 – cholesterol 57, 58 – dynamic supramolecular systems 40, 41 – noncovalent synthesis 35–38 – optical amplification 40, 41 – supramolecular chirality 38–41

molecular rectangles 151 molecular rectifiers 409–411, 412 molecular rotors 246–263 – correlated rotation through steric interactions 250–253 – electrically driven 256–258 – metallocenes 246–250, 256 – rotary motion controlled by external input 254–256 – solid state molecular gyroscopes 253, 254 – spring-loaded 435 – surface-bound 258–263, 279–282, 297– 300, 385–389, 392, 393 – unidirectional ring rotation 299, 300, 313–316, 392, 393 molecular scissors 268, 269 molecular shuttles – acid–base controllable 169, 170 – allowing/preventing ring motion 183–187 – electrochemically driven 176–178 – pH-driven 174 – photochemically driven 178–183 – template synthesis 75, 89 molecular switch tunnel junctions (MSTJs) 124, 125 molecular switches – applications 348 – chiral 460 – combined mechanical and electronic effects 416–418, 425 – communication among 347, 348 – mechanical motion 216 – non-interlocked systems 255 – photochemical 338, 339, 356, 357 – photochromic 416–418 – template synthesis 89, 90, 143, 144 – three-way 194, 195 – ultrafast switching 346, 347 – see also molecular logic; switchable catenanes; switchable rotaxanes molecular turnstiles 247, 252–253 molecular vacuum cleaners 384 molecular valves 197, 198, 257 molecular vehicles 393–397 molecular wires 398–400, 405–407, 430 MORFs, see metal–organic rotaxane frameworks Morse manipulators 421, 422 motors, see molecular motors MSTJs, see molecular switch tunnel junctions multiplexers 344–346, 348 multiply-interlocked catenanes 113, 114 muscles 172, 198, 199, 443–452

473

474

Index

n nanocars 262, 281, 396, 397 nanocommunication 426 nanoelectronic devices 257 nanojunctions 398 nanometric electrodes 445 nanopore method 399, 400 nanoscale synthesis 232, 233, 244, 262, 263 nanotubes 16 nanovalves 276, 277 natural devices and machines – catenanes and rotaxanes 161, 164, 165, 169, 214, 225–233, 237–239 – non-interlocked systems 243, 244, 283– 285, 291, 292, 302, 314, 315 NDR, see negative differential resistance near-field optical microscopy 381 near-infrared (NIR) fluorescent dyes 122, 123 necklaces 121 negative differential resistance (NDR) 400, 412–414 NEGF, see non-equilibrium Green functions neutral hydrogen bond templated systems 93–106 – catenanes 94–98, 103–106 – novel architectures 103–106 – rotaxanes 98, 99–106 NIR, see near-infrared non-equilibrium Green functions (NEGF) 404 non-equilibrium statistical mechanics 217 non-interlocked systems – active macroscopic systems 301–305 – applications 282, 283 – biased Brownian motion 264, 265 – correlated rotation through steric interactions 250–253 – design concepts 244–246 – discussion 291–295, 313–316 – electrically driven rotors and machines 256–258 – energy supply 245, 256–258, 264–279 – fluctuation theorem 307, 308, 309–311 – future developments 283–285 – kinetic control 254, 255 – mechanical changes in crystals and polymers 276–279 – metallocenes 246–250, 256 – molecular machines 243–289, 291–295, 297–300, 301–305, 307–312, 313–316 – molecular motors 244, 263–274 – molecular rotors 246–263

– nonequilibrium work relations 307, 308–311 – photochemical energy supply 268–279 – rotary motion controlled by external input 254–256 – solid state molecular gyroscopes 253, 254 – surface-bound molecular rotors 258–263, 279–282, 297–300 – synchronization and feedback control 292, 293 – threads 109, 110 – unidirectional ring rotation 264–267, 269–272, 280, 294, 295, 299, 300, 313–316 nonequilibrium work relations 307–311 NOT logic gates 372, 373 nuclear reset 179 nucleation mechanism 228, 229

o octahedral cage frameworks 17, 18 olefin metathesis 84, 85, 98 olefin polymerization catalysts 314–316 oligosaccharides 26 optical amplification 40, 41 OR logic gates 369 ordering in molecular machines 196, 197 organic–inorganic hybrid rotaxanes 128 orthoformate hydrolysis 23 oxygen evolution 355, 361–365

p pairwise selective recognition 22 palladium-templated catenanes 107, 110–113 PASS logic gates 372, 373 penicillin G amidase (PGA) 368, 370 peptide nanotubes 16 PET, see photoinduced electron transfer PGA, see penicillin G amidase pH-driven molecular machines 174, 197, 292 phenanthroline 9 phenolate–wheel semirotaxanes 91 phenothiazines (PTZ) 329, 330 photochemical energy supply – logic gates 340–343 – molecular machines 165, 166, 178–186, 190–192, 195, 216, 217 – molecular switches 338–339, 356, 357 – non-interlocked systems 268–279 – water splitting 355, 361–365 photochromic switches 268–270, 274–276, 278, 416–418 photocycloaddition reactions 59, 60

Index photoinduced electron transfer (PET) – artificial photosynthesis 319, 321, 324, 325, 327, 329–332, 346 – molecular logic 371, 372 – molecular machines 178–181, 217 photoinduced self-assembly 455–459 photoinduced transport of liquid droplets 199, 200 photoisomerization – artificial photosynthesis 356 – molecular devices 416 – molecular machines 181–186, 195 – non-interlocked systems 279 – template synthesis 118, 119 photoresponsive gels 455–459 photostationary states (PSS) 182, 183, 186 photosynthesis 319, 322, 323, 336, 337, 355, 363, 378 – see also artificial photosynthesis photosystem II (PSII) 363, 364 photovoltaics, see artificial photosynthesis planar STM configuration 399 polaron mechanism 420 polaronic regimes 402, 433 polyamines 45 polymerization catalysts 314–316 polymers – active macroscopic systems 303 – electrochemical-driven conformational states 443–452 – molecular machines 215, 216, 234, 237, 276–279 – self-assembly 465 – toroidal oxidation catalysts 227–229 polypeptides 17 polypyrrole/tape bilayers 446, 447, 451 polyrotaxanes 13, 117, 118, 121, 122, 146 polythiazolylbenzene disks 248, 249 porphines 26 porphyrin arrays 333–335 porphyrin–dihydroindolizine–dihydropyrene systems 340–346 porphyrin–diquinone systems 327, 328 porphyrin–fullerene systems 330–332, 334–336 porphyrin–quinone systems 324–329 porphyrins – design and synthesis 26 – molecular devices 418, 419 – molecular machines 175, 233 – non-interlocked systems 247, 248, 260, 261, 269 – toroidal oxidation catalysts 225–230 practical devices, see molecular devices

pretzelanes 68, 69, 96 prism-like pillared cages 25, 26 processive catalytic rotaxanes 174, 175, 225–230 prodrugs 128 proof-reading processes 79 propellers 251, 252 proteins 17, 32, 46, 47, 56 proton-coupled electron transfer 364 pseudoaxles 99, 100 pseudo-nanoparticles 26 pseudorotaxanes – applications 122, 125 – charged hydrogen bond templated systems 80, 83, 89 – donor/acceptor template synthesis 71–73, 77, 78 – historical perspective 71 – mechanical bonds 68 – molecular logic 340 – solvophobically driven templation 116, 118, 120, 121 PSII, see photosystem II PSS, see photostationary states PTZ, see phenothiazenes pyridylpyridinium salt 73, 74

q quantum Hamiltonian computation (QHC) 422–424 quantum logical gates 422–424, 431

r rack-and-pinion devices 261, 390, 391 radialene frames 250 random access memory (RAM) 202 random rotation 214 random walk processes 161 ratchet-and-pawl systems 264 ratchet-like periodization 301, 302 RCM, see ring-closing metathesis read–write memory 202 rearrangement by copper(I) coordination 219–223 receptors, see molecular receptors recognition sites 166–169, 187, 188 reconfigurable molecular logic devices 344–346 rectangles 151 rectifiers 409–411, 412 redox-active rotaxanes 123, 124, 176, 177, 197, 198 redox-driven molecular devices/ machines 257, 258, 274–276, 443–447

475

476

Index relay electron transfer mechanism 178–181 resorcinarenes 18, 22, 23 reverse recognition 82, 83, 127 reversible bond formation 18 rhodium-based molecular gyroscopes 248, 249 ribosomes 315 ring displacement 179 ring shrinkage 87 ring-closing metathesis (RCM) 92, 93 rosettes 5, 11, 36–41 rotaxane dimers 172, 173 rotaxanes – allowing/preventing ring motion 183–187 – anion templated synthesis 91–93 – applications 122–127, 171, 172 – binding constants 61 – bistable 75, 76, 124, 125, 198, 199, 203, 204 – charged hydrogen bond templated systems 80–88, 102 – chemical energy supply 169–175 – coordination geometries 107, 108 – cucurbiturils 43 – design and synthesis 8–9 – donor/acceptor template synthesis 72–79 – dynamic combinatorial chemistry 148, 151 – electrochemical energy supply 175–178 – electron transfer mechanisms 178–181 – future developments 127, 128, 204, 205 – historical perspective 70, 71 – mechanical bonds 67–70 – mechanical motion 167, 169–187 – metal-containing 106–114, 172, 176–178 – molecular machines 166–187, 236 – neutral hydrogen bond templated systems 98, 99–103 – nonequilibrium work relations 311 – novel architectures 103–106 – ordering and addressing 196, 197 – photochemical energy supply 178–186 – photoinduced transport of liquid droplets 199, 200 – photoisomerization reactions 181–186, 195 – processive catalytic 174, 175 – rate of movement control 143 – recognition sites 166–169 – solid-state electronic devices 203, 204 – solvophobically driven templation 115–122 – switchable 75, 76

– tetracationic cyclophanes 175, 176 – toroidal oxidation catalysts 225–230 – two-station 168, 169, 170 rotors, see molecular rotors ruthenium sandwich complexes 247, 248 ruthenium-templated catenanes 107 ruthenium trisbipyridyls 329, 330

s sacrificial electron transfer mechanism 178–180 SAMs, see self-assembled monolayers sandwich complexes, see ferrocenes; metallocenes sarcomere-like molecular structures 445 scanning tunneling microscopy (STM) 219–222 – molecular devices 381, 383, 384, 386, 387, 390, 391, 393–400, 406, 408–411, 417, 418, 422, 429–431 – non-interlocked systems 259–263, 297, 298 SCF, see self-consistent field Schotten–Baumann reaction 120 scissors 268, 269 second-generation molecular motors 272– 274, 280, 282, 283 self-assembled monolayers (SAMs) 7 – molecular devices 398–400, 414, 417 – non-interlocked systems 260–263 self-assembly – coordination assemblies 10–12, 17–21, 23–26 – covalent bonding 13, 14 – definition 3 – discussion 31–33 – dynamic control of gelation 455–460 – function through architecture 21–27 – hydrogen bonding 11–13, 15–17, 21–23 – kinetic 32 – landmark developments 8–14 – low-molecular weight gelators 453–460 – molecular devices 453–461, 464, 465 – molecular machines 170, 171 – photoinduced 455–459 – research fields 7–8 – size/structure dependence 33 – stepwise 62, 63 – template synthesis 106, 109, 111–113 self-consistent field (SCF) theory 405 self-templating approach 148 semiconductor devices 319, 367, 368 semirotaxanes 91 sensing devices 443–452

Index sensory applications 370–372 ship-in-a-bottle synthesis 4 shrinkage 87 shuttles, see molecular shuttles single electron storage 411–413 single-molecule transistors 414, 415 slippage 86, 116, 251 soft ball chemical transformations 21, 22 solid-state electronic devices 200–204 solid-state molecular gyroscopes 253, 254 Solomon links 68–70 solvation entropy 54, 55, 60, 61 solvent bubbles 51–56, 58, 63, 64 solvophobically driven templation 115–122 spherical hollow structures 20, 21, 26, 27 spider molecule 382, 383 spiropyran-merocyanine systems 275, 276, 281, 282 spiropyrans 344, 347, 348 spring-loaded devices 435–442 squaraine rotaxanes 122, 123 square complexes 11, 12 statistical mechanics 217 stepwise self-assembly 62, 63 steroids 36 STM, see scanning tunneling microscopy stoppering 83, 84, 87–89, 92, 99, 101, 115–117 suit[2]anes 68, 88 sulfonamide-containing catenanes 96 supramolecular bearings 385 supramolecular chemistry 37, 159 supramolecular chirality 38–41 surface-bound molecular devices/ machines 258–263, 279–282, 297–300, 382–391 surface-deposited catenanes 219–223 – analytical methods 219–222 – rearrangement by copper(I) coordination 219–223 surface-modifying tools 382 swelling 87, 88 switchable catenanes/rotaxanes 75–79 switches, see molecular switches synchronization 292, 293 synthetic biology 237 synthetic receptors 22, 23

t template synthesis 18 – acid chlorides/activated esters 142 – anion templated synthesis 90–93 – applications 122–127, 144–146 – cage frameworks 113, 114

– charged hydrogen bond systems 80–90, 102 – clipping protocol 84–86, 102 – coordination geometries 107, 108 – discussion 141–146 – donor/acceptor systems 72–80 – dynamic combinatorial chemistry 151, 152 – error-checking/proof-reading processes 79, 84 – future developments 127, 128 – hard/soft structures 142, 143 – historical perspective 69–72 – mechanical bonds 67–139 – metal-containing catenanes and rotaxanes 106–114 – molecular elevators 89, 90 – molecular shuttles 75, 89 – molecular switches 89, 90 – neutral hydrogen bond systems 93–106 – novel catenane and rotaxane architectures 103–106 – other mechanically interlocked molecules 68–70, 88, 89 – reverse recognition 82, 83 – ring shrinkage 87 – slippage 86, 116 – solvent-free synthesis 127–128, 144 – solvophobically driven templation 115–122 – structure and types of interlocked compounds 67–69 – thermodynamic control 78–80, 141 – threading-followed-by-stoppering 83, 84, 89, 92, 99, 101, 115–117 tennis ball structures 12, 15 tetracationic cyclophanes 175, 176, 189, 190 tetrarosettes 39 tetrathiofulvalene (TTF) units 77, 78, 175, 176, 189, 197–199 thermal energy supply 213, 214, 216, 217, 234, 271 thermal jittering 391 thermally activated stochastic processes 164 thermodynamic control 78–80, 141, 153 threading-accompanied-by-swelling 87, 88 threading-followed-by-stoppering 83, 84, 89, 92, 99, 101, 115–117 threading reactions 228, 229 three-way molecular switches 194, 195 top-down approaches 160, 204, 205 toroidal oxidation catalysts 225–230

477

478

Index transport agents/regimes 382, 383, 400–405 trefoil knots 68–70 triflate salts 52–54 tripods 258 triptycenes 265, 266, 392–395 TTF, see tetrathiofulvalene tunneling regimes 401–406 turnstiles 247, 252, 253 twin-rotor systems 250 two-station rotaxanes 168–170

u ultrafast switching 346, 347 unidirectional ring rotation – molecular devices 387, 391–393, 465 – molecular machines 192–196, 264–267, 269–272, 280, 294, 295, 299, 300, 313–316 urea-based inclusion compounds 3

v vacuum cleaners 384 valves 197, 198, 257

vehicles 393–397 vertical STM configuration 398, 399 vesicle formation 45–48

w Wasserman’s synthesis 69, 143 Werner coordination complexes 3 wireless communications 348 wires 398–400, 405–407, 430

x X-ray photoelectron spectroscopy (XPS) 219–222 XOR logic gates 339, 340, 343, 344, 423

y YES logic gates

372–373

z zeolites 3, 32, 235 zinc–porphyrin catalysts

229, 230, 333–335

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