Dendrimers: Towards Catalytic, Material and Biomedical Uses

Dendrimers Dendrimers Towards Catalytic, Material and Biomedical Uses ANNE-MARIE CAMINADE, CÉDRIC-OLIVIER TURRIN, RÉ...

Author: Anne-Marie Caminade | Cedric-Olivier Turrin | Regis Laurent | Armelle Ouali | Beatrice Delavaux-Nicot

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Dendrimers

Dendrimers Towards Catalytic, Material and Biomedical Uses

ANNE-MARIE CAMINADE, CÉDRIC-OLIVIER TURRIN, RÉGIS LAURENT, ARMELLE OUALI and BÉATRICE DELAVAUX-NICOT Laboratoire de Chimie de Coordination du CNRS Toulouse, France

A John Wiley & Sons, Ltd., Publication

This edition first published 2011 © 2011 John Wiley & Sons Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com. The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Dendrimers : towards catalytic, material, and biomedical uses / Anne-Marie Caminade ... [et al.]. p. cm. Includes bibliographical references and index. ISBN 978-0-470-74881-7 (cloth) 1. Dendrimers. I. Caminade, Anne-Marie. TP1180.D45D47 2011 668.92–dc23 2011014028 A catalogue record for this book is available from the British Library. Print ISBN: 9780470748817 ePDF ISBN: 9781119976523 oBook ISBN: 9781119976530 ePub ISBN: 9781119977575 Mobi ISBN: 9781119977582 Set in 10/12 pt Times by Toppan Best-set Premedia Limited

Dedicated to Jean-Pierre Majoral on the occasion of his 70th birthday

Contents

Preface Part 1 1

2

xv Generalities, Syntheses, Characterizations, and Physicochemical Properties

Syntheses of Dendrimers and Dendrons Anne-Marie Caminade

1 3

1.1 Introduction: What Are Dendrimers and Dendrons? 1.2 Syntheses of Poly(propyleneimine) Dendrimers (PPI) 1.3 Synthesis of Poly(amidoamine) Dendrimers (PAMAM) 1.4 Syntheses of Poly(ether) Dendrimers 1.5 Syntheses of Poly(ester) Dendrimers 1.6 Synthesis of Poly(lysine) Dendrimers 1.7 Syntheses of Silicon-Containing Dendrimers 1.8 Syntheses of Phosphorus-Containing Dendrimers 1.9 Syntheses of Carbon-Based Dendrimers 1.10 Syntheses of Dendrimers Constituted of Nitrogen Heterocycles 1.11 Syntheses by Self-Assembly 1.12 Accelerated Syntheses 1.13 Conclusion References

3 5 5 7 10 14 15 16 17 19 21 26 30 30

Methods of Characterization of Dendrimers Anne-Marie Caminade

35

2.1 2.2

35 36 36 40 41 42 43 44

Introduction Spectroscopy and Spectrometry 2.2.1 Nuclear Magnetic Resonance (NMR) 2.2.2 Mass Spectrometry 2.2.3 X-ray Diffraction 2.2.4 Infrared (IR) and Raman Spectroscopy 2.2.5 Ultraviolet–Visible (UV–vis) Spectroscopy 2.2.6 Fluorescence 2.2.7 Chirality, Optical Rotation, and Circular Dichroism (CD)

45

viii

3

Contents

2.2.8 Electron Paramagnetic Resonance (EPR) 2.2.9 Electrochemistry 2.2.10 Magnetometry 2.2.11 Mössbauer Spectroscopy 2.2.12 X-ray Spectroscopies 2.3 Scattering Techniques 2.3.1 Laser Light Scattering (LLS) 2.3.2 Small-Angle Neutron Scattering (SANS) 2.3.3 Small-Angle X-ray Scattering (SAXS) and Wide-Angle X-ray Scattering (WAXS) 2.4 Microscopy 2.4.1 Transmission Electron Microscopy (TEM) 2.4.2 Atomic Force Microscopy (AFM) 2.4.3 Polarizing Optical Microscopy (POM) 2.5 Rheology and Physical Characterizations 2.5.1 Intrinsic Viscosity 2.5.2 Differential Scanning Calorimetry (DSC) 2.5.3 Dielectric Spectroscopy (DS) 2.5.4 Dipole Moments 2.6 Separation Techniques 2.6.1 Size Exclusion Chromatography 2.6.2 Electrophoresis 2.7 Conclusion References

45 46 46 46 47 47 47 47

Luminescent Dendrimers Anne-Marie Caminade

67

3.1 3.2

67 68 68 69

Introduction Dendrimers with Fluorescent Terminal Groups 3.2.1 Fully Substituted Dendrimers 3.2.2 Partially Substituted Dendrimers 3.3 Luminescent Group at the Core of Dendrimers and Energy/Light-Harvesting Properties 3.3.1 Organic Fluorophores as Cores 3.3.2 Porphyrins and Phthalocyanines as Cores 3.3.3 Metallic Cores 3.4 Fluorescent Groups inside the Structure of Dendrimers 3.5 Intrinsically Fluorescent Dendrimers 3.5.1 Fluorescent Groups throughout the Dendrimeric Structure 3.5.2 Fluorescence of Dendrimers without Known Fluorophores 3.6 Two-Photon-Excited Fluorescence of Dendrimers 3.7 Conclusion References

48 48 49 49 50 50 50 50 51 51 52 52 53 53 54

74 74 77 78 79 81 81 86 86 89 90

Contents

4

Stimuli-Responsive Dendrimers Anne-Marie Caminade 4.1 4.2

5

6

99

Introduction Photoresponsive Dendrimeric Structures 4.2.1 Azobenzene-Containing Dendrimers and Dendrons 4.2.2 Other Types of Photoresponsive Dendrimers 4.3 Thermoresponsive Dendrimeric Structures 4.3.1 Thermoresponsive Properties of Dendrimers 4.3.2 Thermoresponsive Properties of Dendrons and Dendronized Polymers 4.4 Dendrimers Responsive to Solution Media Changes 4.4.1 pH-Responsive Dendrimers 4.4.2 Dendrimers Disassembly 4.5 Conclusion References

99 100 101 108 110 110

Liquid Crystalline Dendrimers Anne-Marie Caminade

125

5.1 Introduction 5.2 Mesogenic Groups as Terminal Functions of Dendrons 5.3 Mesogenic Groups as Terminal Functions of Dendrimers 5.4 Mesogenic Groups as Branches of Dendrimers 5.5 Conclusion References

125 126 131 134 135 136

Dendrimers and Nanoparticles Cédric-Olivier Turrin and Anne-Marie Caminade

141

6.1 6.2

141 142 142 147 149 151

Introduction Dendrimers or Dendrons for Coating Nanoparticles 6.2.1 Dendronization of Nanoparticles by Ligand Exchange 6.2.2 Direct Synthesis of Dendronized Nanoparticles 6.2.3 Dendrimer Coated Nanoparticles 6.2.4 Nanocomposites with Interdendrimer Nanoparticles 6.3 Dendrimers as Templates for the Synthesis of Dendrimer-Encapsulated Nanoparticles (DENs) 6.3.1 Catalysis with Dendrimer-Encapsulated Nanoparticles 6.3.2 Other Uses of Dendrimer-Encapsulated Nanoparticles 6.4 Conclusion and Perspectives References Part 2 7

ix

Applications in Catalysis

Terminal Groups of Dendrimers as Catalysts for Homogeneous Catalysis Armelle Ouali and Anne-Marie Caminade

112 114 114 115 117 118

152 153 154 154 155 163 165

Contents

x

7.1

General Introduction 7.1.1 The “Dendrimer Effect” 7.1.2 Recycling the Catalysts 7.2 Catalytic Organometallic Sites as Catalysts for Homogeneous Catalysis 7.2.1 Formation of C–X Bonds (X = C, N, O) 7.2.2 Addition Reactions on a C=X Double Bond (X = C, O) 7.2.3 Oxidation Reactions 7.3 Organocatalysis with Dendrimers 7.4 Conclusion References 8

10

167 167 175 177 178 178 179

Catalytic Sites inside the Dendrimeric Structure for Homogeneous Catalysis Armelle Ouali and Anne-Marie Caminade

183

8.1 8.2

183 184

Introduction Catalytic Sites as the Core of Dendrimers 8.2.1 Dendrimers Bearing a Transition-Metal-Based Complex at the Core 8.2.2 Dendrimers Bearing an Organocatalyst at the Core 8.3 Catalytic Sites inside the Branches of Dendrimers 8.3.1 Formation of C–X Bonds (X = C, N, O) 8.3.2 Addition Reactions on a C=C Double Bond: Olefin Hydrogenation 8.4 Conclusion References 9

165 165 166

184 188 191 191 192 192 193

Dendrimers as Homogeneous Enantioselective Catalysts Armelle Ouali and Anne-Marie Caminade

197

9.1 9.2

Introduction Catalytic Organometallic Sites as Catalysts for Homogeneous Catalysis 9.2.1 Formation of C–X Bonds (X = C, N, O) 9.2.2 Addition Reactions on a C=X Double Bond (X = C, O) 9.3 Organocatalysis with Dendrimers 9.3.1 Aldolizations 9.3.2 Aza–Morita–Baylis–Hillmann Reactions 9.3.3 Transaminations 9.4 Conclusion References

197

Catalysis with Dendrimers in Particular Media Régis Laurent and Anne-Marie Caminade

215

10.1 10.2

215 216

Introduction Two-Phase (Liquid–Liquid) Media

198 198 204 209 209 209 210 210 210

Contents

11

10.3 Catalysis in Ionic Liquids 10.4 Catalysis in Supercritical Media 10.5 Catalysis in Aqueous Media 10.6 Conclusion References

219 220 221 234 234

Heterogeneous Catalysis with Dendrimers Régis Laurent and Anne-Marie Caminade

239

11.1 11.2

239 240 240 248

Introduction Catalysis with Dendrons Synthesized from a Solid Material 11.2.1 Silica as an Inorganic Support 11.2.2 Polymers and Resins as Organic Supports 11.3 Catalysis with Dendrons or Dendrimers Grafted on to a Solid Surface 11.4 Catalysis with Insoluble Dendrimers 11.5 Conclusion References Part 3 12

Applications for the Elaboration or Modification of Materials

254 257 260 261 267

Dendrimers inside Materials Régis Laurent and Anne-Marie Caminade

269

12.1 12.2

269 270

Introduction Dendrimers for the Elaboration of Gels 12.2.1 Dendrimers for the Elaboration of Supramolecular Hygrogels 12.2.2 Dendrimers for the Elaboration of Polymer-Type Hygrogels 12.2.3 Dendrimers for the Elaboration of Organogels 12.3 Dendrimers inside Silica Gels 12.4 Dendrimers inside Other Types of Materials 12.5 Dendrimers for the Elaboration of OLEDs 12.5.1 Fluorescent Dendrimers for the Elaboration of OLEDs 12.5.2 Phosphorescent Dendrimers for the Elaboration of OLEDs 12.6 Conclusion References 13

xi

270 273 276 280 285 288 290 295 298 299

Self-Assembly of Dendrimers in Layers Béatrice Delavaux-Nicot and Anne-Marie Caminade

313

13.1 13.2

313 314 316

Introduction Langmuir–Blodgett Films of Dendrons and Dendrimers 13.2.1 Poly(benzyl ether) Derivatives 13.2.2. Poly(amidoamine) and Poly(propyleneimine) Derivatives 13.2.3 Azobenzene Derivatives

319 320

xii

14

Contents

13.2.4 Poly(carbosilane) Dendrimer Derivatives 13.2.5 Fullerene C60 Derivatives 13.2.6 Other Examples 13.3 Assemblies of Dendrons and Dendrimers on Solid Surfaces 13.3.1 Assembly of Dendrons and Dendrimers on Gold Surfaces 13.3.2 Assembly of Dendrons and Dendrimers on Silicon Substrates or Related Substrates 13.4 Several Routes for the Formation of Dendron or Dendrimer Multilayers 13.5 Nanoimprinting with Dendrons and Dendrimers on Solid Surfaces 13.5.1 Dendrimer-Based Self-Assembled Monolayers as Resists for Scanning Probe Lithography 13.5.2 Microprinting, Transfer Printing, and Dip-Pen Nanolithography with Dendrimers 13.6 Conclusion References

321 322 325 326

Dendrimers as Chemical Sensors Anne-Marie Caminade

361

14.1 14.2

361 362

Introduction Dendrimers as Chemical Sensors in Solution 14.2.1 Porphyrins and Other Macrocyclic Derivatives as the Core or Branches of Dendrimeric Sensors 14.2.2 Terminal Groups of Dendrimers as Sensors in Solution 14.3 Dendrimers as Electrochemical Sensors 14.4 Dendrimers on Modified Surfaces as Chemical Sensors 14.4.1 Dendrimers on Surfaces at the Interface with a Solution 14.4.2 Dendrimers on Surfaces at the Interface with a Vapor 14.5 Conclusion References 15

327 330 334 342 342 344 350 351

362 363 365 367 367 368 370 370

Dendrimers as Biological Sensors Anne-Marie Caminade

375

15.1 15.2 15.3 15.4 15.5 15.6 15.7

375 375 378 380 383 384

Introduction Dendrimers as Sensors in Solutions of Biological Media Detection by Electrochemical Methods Dendrimers or Dendrons for DNA Microarrays Dendrimers for Other Types of Biomicroarrays Dendrimers on Other Types of Support Dendrimers as Multiply Labeled Entities Connected to the Target 15.8 Conclusion References

385 386 387

Contents

Part 4 16

17

Applications in Biology/Medicine

393

Dendrimers for Imaging Cédric-Olivier Turrin and Anne-Marie Caminade

395

16.1 16.2

Introduction Magnetic Resonance Imaging with Dendrimers 16.2.1 Paramagnetic Dendrimer-Based Contrast Agents 16.2.2 PARACEST Dendrimer-Based Contrast Agents 16.2.3 Superparamagnetic Dendrimer-Based Contrast Agents 16.2.4 Dendrimer-Based 129Xe HYPER-CEST MRI Contrast Agents 16.2.5 19F Dendrimer-Based MRI Contrast Agents 16.3 Other Types of Imaging with Dendrimers 16.3.1 Dendrimers for Optical Imaging 16.3.2 Dendrimers for Nuclear Medicine (NM) Imaging and Computed Tomography X-Ray Imaging (CT) 16.4 Conclusion and Perspectives References

395 395 398 402 402

Dendrimers as Transfection Agents Cédric-Olivier Turrin and Anne-Marie Caminade

413

17.1 17.2

413 415 415 416 418

Introduction Gene Transfection with PAMAM Dendrimers 17.2.1 Pioneering Results 17.2.2 Gene Transfection with Surface-Modified PAMAM 17.2.3 Gene Transfection with Core-Modified PAMAM 17.2.4 Gene Transfection with PAMAM-Functionalized Nanoparticles 17.2.5 Gene Transfection with PAMAM-Like Hyperbranched Polymers 17.3 Gene Transfection with Other Dendrimers 17.3.1 Gene Transfection with PPI Dendrimers 17.3.2 Gene Transfection with Peptide-Based Dendrimers 17.3.3 Gene Transfection with Phosphorus-Based Dendrimers 17.3.4 Gene Transfection with Silane-Based Dendrimers 17.4 Conclusion and Perspective References 18

xiii

403 403 403 403 405 407 407

419 420 421 421 422 423 424 426 426

Dendrimer Conjugates for Drug Delivery Cédric-Olivier Turrin and Anne-Marie Caminade

437

18.1 18.2 18.3

437 438 440 440 442

Introduction Improving Bioavailability with Dendrimers Passive Targeting in Tumors with Dendrimer–Drug Conjugates 18.3.1 Dendrimer–Drug Bioconjugates and the EPR Effect 18.3.2 PEGylated Dendrimeric Scaffolds

xiv

Contents

18.4

Active Targeting with Site-Specific Dendrimer–Drug Conjugates 18.4.1 Addressing with Folic Acid (FA) 18.4.2 Addressing with Tumor-Homing Peptides 18.4.3 Addressing with Monoclonal Antibodies 18.5 Dendrimers for Photodynamic Therapy (PDT) 18.6 Dendrimers for Boron Neutron Capture Therapy (BNCT) 18.7 Conclusion and Perspectives References 19 Encapsulation of Drugs inside Dendrimers Cédric-Olivier Turrin and Anne-Marie Caminade 19.1 19.2 19.3 19.4 19.5

Introduction From Dendritic Boxes to Dendrimer-Based Formulations Improving Bioavailability with Dendrimers? Toxicological Issues Dendrimer-Based Formulations for Drug Delivery 19.5.1 Nontargeted Formulations 19.5.2 Supramolecular Assemblies Involving Surface Ionic Interactions 19.5.3 Targeted Formulations 19.6 Conclusion and Perspectives References 20

21

Unexpected Biological Applications of Dendrimers and Specific Multivalency Activities Cédric-Olivier Turrin and Anne-Marie Caminade

446 446 448 449 449 451 452 453 463 463 464 464 465 466 466 473 475 477 477 485

20.1 20.2

Introduction Dendrimers and Multivalency 20.2.1 Multivalent Effects and Dendrimeric Effects 20.2.2 Glycodendrimers 20.3 Antimicrobial Dendrimers 20.3.1 Polycationic Dendrimers 20.3.2 Polyanionic Dendrimers 20.4 From Immunomodulation to Regenerative Medicine 20.4.1 Immunomodulation and Anti-Inflammation 20.4.2 Dendrimers and Regenerative Medicine 20.5 Conclusion and Perspectives References

485 486 486 487 488 489 491 494 494 498 501 502

General Conclusions and Perspectives Anne-Marie Caminade

511

Index

515

Preface

The tree-like architecture seems to be the structural solution that accompanies the increasing complexity of life. It appears that the dendritic structure, found within plant matter and other organic tissues, adapts to their development and is compatible with their metabolic requirements. Indeed, when a dimension characteristic of a living entity grows by a factor n, volume and mass are multiplied by n3, whereas an associated surface, if it is perfectly smooth, is multiplied only by n2. Thus, favoring exchanges which are essential for life necessitates multiplying the exchange surface, and nature seems to have chosen the branching solution. The dendritic structure is frequently found in nature on various scales: on the metre scale in the branches of trees, on the centimetre scale in the roots of these trees, on the millimetre scale in topologies of the circulatory system of the human anatomy (lungs, kidneys, or the liver), and finally on the micrometric scale in dendrites of the neurons of the brain or in dendritic cells. One can also find examples of natural dendritic-like supramolecular entities such as glycogen. These natural tree-like structures are true sources of inspiration for chemists who reproduce the dendritic shape on a nanometric scale and who are able to synthesize macromolecules of well-defined ramified structure: the dendrimers. These compounds are chemical object fruits of two sister disciplines: the chemistry of polymers and organic synthesis. This book is mainly focused on the properties and uses of dendrimers, dendrons, and dendrimerica species. After more than twenty years of research, the time has come to find some uses for these highly sophisticated macromolecules. This book is intended as a reference book about dendrimer applications and so does not cover all aspects of the topic, but it should give the reader a unique overview of what is currently being done with dendrimers, giving numerous references and illustrations. I hope you will appreciate the scientific content of this book, even if the field of dendrimers is now so large that some specialized works have been regretfully omitted. When necessary, a comparison with hyperbranched polymers will be given. This book is divided into four main parts: Part 1: Generalities, Syntheses, Characterizations, and Physicochemical Properties; Part 2: Applications in Catalysis; Part 3: Applications for the Elaboration or Modification of Materials; and Part 4: Applications in Biology/Medicine.

a

The dendrimer community (including ourselves) has adopted the adjective “dendritic”, which is confusing with regard to the field of biology, in particular in connection with the well-known “dendritic cells”. We have decided all along in this book to adopt the adjective “dendrimeric”, which is less confusing and was used in some cases in the literature.

xvi

Preface

Part 1. This book begins with a description of the main dendrimer characteristics and the most popular methods of syntheses (Chapter 1). Then we discuss the main methods for characterizing these compounds, which pertain both to the molecular world and to the polymer world (Chapter 2). Following chapters emphasize some specific families of dendrimers which have generated an important body of work. These include fluorescent dendrimers (Chapter 3), stimuli-responsive dendrimers (Chapter 4), liquid crystalline dendrimers (Chapter 5), and dendrimers as templates for nanoparticles (Chapter 6). Chapter 6 concludes with catalytic uses of nanoparticles and serves as a link with the following series of chapters, which concern catalytic dendrimers. Part 2. The first chapter of this series concerning catalysis describes homogeneous catalysis, which is the most important field of research about dendrimeric catalysts; examples given concern mainly organometallic catalysts, but also feature organic catalysts. Generally, the catalytically active entities constitute the terminal groups of dendrimers (Chapter 7), but they can also be included in the internal structure at the core or within the branches (Chapter 8). After these general chapters, we focus on some attractive special types of catalyses, in particular enantioselective catalyses (mostly asymmetric hydrogenations) (Chapter 9), catalyses in special media such as supercritical fluids or water (Chapter 10), and finally heterogeneous catalyses (Chapter 11), which will ensure the transition to the next series of chapters, concerning materials. Part 3. This part of the book discusses some of the applications of dendrimers. Several types of dendrimers were used to elaborate diverse types of materials, such as organogels, hydrogels, and silica gels. One particular application concerns the elaboration of organic light emitting diodes (OLEDs) (Chapter 12). However, dendrimers can also be used to modify the surface of existing materials. This can be obtained from Langmuir–Blodgett films or by the direct assembly of a monolayer of dendrimers, linked either covalently or by electrostatic interaction to a solid surface. Some consequences of these works such as nanoimprinting and the elaboration of nano-objects are described in Chapter 13. Another consequence is the elaboration of sensitive sensors, explored in Chapter 14, which concerns chemical sensors with detection in particular by fluorescence or electrochemistry, while Chapter 15 discusses biological analyses, including DNA and protein microarrays, which are also based on surface modifications of materials. This chapter provides the transition to the last part of this book, about biological/medical uses of dendrimers. Part 4. Numerous fields of research are related to biological/medical uses of dendrimers. A small part concerns medical imaging, for which one important activity provided by the dendrimer is a reduced clearance, due to their large size (Chapter 16). Most of the research related to biology concerns drug delivery in a broad sense. Numerous cationic dendrimers were used as transfection agents for various types of oligonucleotides, genes, or plasmid DNA or siRNA in various types of cell and these are covered in Chapter 17. Drug delivery has also been attempted using drugs covalently linked to the terminal groups of dendrimers, with the aim of producing an entity able to target precise cells such as an antibody, but the problem of drug release exists in the case of covalent grafting (Chapter 18). To try to overcome this problem, noncovalent encapsulation of drugs inside the structure of dendrimers has been attempted (Chapter 19). Some dendrimers were shown to possess biological properties by themselves, properties that the terminal functions they bear do not possess as monomers. This is a rare and unique property of dendrimers (Chapter 20).

Preface

xvii

Finally, Chapter 21 offers conclusions and tentative perspectives about the applications of dendrimers. I would like to add more personal reflections. Perhaps you are attracted to dendrimers because of their pleasant aesthetics. This was indeed the initial reason for my involvement in the field of dendrimers, when I saw for the first time in December 1992 a full page chemical structure of a fourth generation dendrimer. At first glance, it appeared to me to be a molecular crochet lace mat, before I realized it had a three-dimensional structure. In that instant, I decided to change the topic of my work, from macrocycles to dendrimers. After having convinced Jean-Pierre Majoral (the head of the research group at that time) of the appeal of this emerging topic, he offered constant scientific, material, and friendly help for years. If I gave the initial impulsion, there is no doubt that he greatly contributed with constancy to the expansion of this field worldwide. Without him, our contribution (about 250 publications in common to date) would never have been so large. This book is dedicated to him, with my deepest thanks. With the passing of time, several researchers have gained a permanent position in our group: first Régis Laurent (since 1996), then Cédric-Olivier Turrin (since 2001), then Béatrice Delavaux-Nicot (since 2008), and finally Armelle Ouali (also since 2008). They are all authors of one to six chapters of this book; I am deeply indebted to them, not only for their contribution to this book but also for their enthusiasm in research. I also thank the numerous PhD students and post-docs who spent a few months or several years in our group. I also don’t forget all our colleagues in France or in foreign countries, with whom we have had friendly collaboration for years. Anne-Marie Caminade, Toulouse, February 14, 2011

Part 1 Generalities, Syntheses, Characterizations, and Physicochemical Properties

1 Syntheses of Dendrimers and Dendrons Anne-Marie Caminade

1.1

Introduction: What Are Dendrimers and Dendrons?

The word “dendrimer” was created by D. A. Tomalia1 from two Greek words: dendros (tree) is associated with their shape and meros (part) is reminiscent of their chemical structure, constituted of associated monomers. Due to their repetitive structure, dendrimers pertain to the polymer world, even if they are never obtained by polymerization reactions. They have a perfectly defined structure, in contrast to classical polymers, as shown in Figure 1.1. The synthesis of dendrimers is always carried out step by step, but two synthetic approaches can be used. The most intuitive, which was the first one proposed (by the group of F. Vögtle)2 and is currently the most widely used, is the divergent process. Starting from a multifunctional core possessing most generally two to six chemical functions, the first step is generally its activation or modification. Then, x equivalents (x is the number of functions of the core) of a branched monomer, which is generally of type AB2 (sometimes of type AB3), are coupled to the activated core and afford the first generation of the dendrimer. The next step is the deprotection or activation of the first generation. Then the activated dendrimer reacts with 2x equivalents of the AB2 branched monomer (or 3x equivalents with an AB3 monomer) to afford the second generation (Figure 1.2). Each time a new layer of branching units is created, a new generation is obtained; the number of the generation corresponds to the number of branched layers from the core. The surface is easily functionalized and modified at will at each step. The main drawback of the divergent process is the possible presence of defects for high generations, when the number of individual reactions required on a single molecule is high (several hundreds or even several thousands). Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

4

Dendrimers

Figure 1.1 Different types of polymers. All are obtained by polymerization reactions, except the dendrimer

Figure 1.2 Comparison of divergent and convergent processes for the synthesis of dendrimers

The second type of method used for the synthesis of dendrimers is the convergent process, first proposed by the group of J. M. J. Fréchet.3 In this case, surface groups (generally two) are coupled to an AB2 monomer, in which A is protected or nonactive at this step. The surface groups will not be modified up to the end of the synthesis of the dendrimeric structure. After deprotection/activation of the core, this compound is coupled through its core with an AB2 monomer, to afford the first generation “dendron”, that is a dendrimeric wedge. The synthetic process can be repeated to give larger generation dendrons. These dendrons can be coupled in the final step to a multifunctional core to afford a “true” dendrimer (Figure 1.2). The advantage of the convergent process is that only a very small number of reactions occur at each step on each molecule (only one or two reactions depending on the synthetic step considered); thus the purity is easily controlled. There are two main drawbacks in this process; the first one is that very high generations are not attainable, due to the steric hindrance at the core when the dendrons become large (generally at the fifth generation), and the second one is the difficulty to modify the terminal groups. It must be noted that some dendrons are synthesized by a divergent process;4 in this case, the advantages and drawbacks are those of the divergent process.

Syntheses of Dendrimers and Dendrons

5

In the next paragraphs of this chapter, we will display the pioneering and the most widely used methods of synthesis of dendrimers – those that have led to the various applications that will be emphasized in the other chapters. The chosen examples do not pretend to give an exhaustive overview of the synthesis of dendrimers but a flavor of what has been done in this topic; several other examples can be found in a recent review about the divergent processes.5

1.2

Syntheses of Poly(propyleneimine) Dendrimers (PPI)

The first synthetic compound having a true dendrimeric structure was obtained by the group of F. Vögtle in 1978, which named it a “cascade” structure.2 Starting from a diamine core, the first step of the divergent synthesis is a Michaël-type addition in the presence of acrylonitrile in excess. The second step is the reduction of the nitrile functions, which affords primary amines, suitable to repeat the synthetic process. Compounds were isolated in poor yields (for instance 24% in the reduction step); thus this synthesis was stopped at the second generation (Figure 1.3, upper part). Fifteen years after this pioneering work, this synthetic process was improved independently by the groups of E. W. Meijer6 and R. Mülhaupt7 (from a different core: ammoniac) to obtain these dendrimers in nearly quantitative yields, thus enabling the synthesis to be carried out up to higher generations (at least generation 5) and in a large scale (several kilograms) (Figure 1.3, lower part). This type of dendrimer can be found under different names, in particular PPI (for polypropyleneimine), DAB (for diaminobutane), and POPAM (for polypropylene amine). We will use PPI, which is the most used name for these dendrimers. Recently, polyamino dendrimers reminiscent of PPI but in which the branches are elongated by ether functionalities were synthesized by the group of N. Jayaraman8 by a five-step process based on two alternate Michaël additions and two alternate reduction reactions. A bisnitrile used as the core was first reduced to afford NH2 groups, which were added on to tert-butylacrylate. The third step is the deprotection of the esters, followed by the reduction of the peripheral carboxylic acids with LiAlH4 to alcohol in the fourth step. The fifth step is the Michaël addition to acrylonitrile, affording nitrile terminal groups (Figure 1.4). This synthesis was carried out up to the sixth generation of PETIM (poly(propyl ether imine)) dendrimers.9

1.3

Synthesis of Poly(amidoamine) Dendrimers (PAMAM)

The most widely used type of dendrimers was synthesized by the group of D. A. Tomalia before 1985.1 It was the beginning of the success story of dendrimers, because these compounds were synthesized up to high generations (generation 10, one of the two highest generations synthesized for any type of dendrimers) and were readily commercialized (with various cores and various terminal groups). Their availability worldwide and very early ensured their popularity, not only among chemists but also among biologists and physicists.

6

Dendrimers

Figure 1.3

Two methods of synthesis of polypropyleneimine (PPI) dendrimers

Figure 1.4

Synthesis of poly(propyl ether imine) (PETIM) dendrimers

Syntheses of Dendrimers and Dendrons

Figure 1.5

7

Synthesis of poly(amidoamine) PAMAM dendrimers

The synthetic process necessitates the repetition of two steps, starting from ammoniac as shown in Figure 1.5 (upper part) or more generally from ethylene diamine (Figure 1.5, G4 in the lower part). The first step is a Michaël-type addition to methylacrylate, which occurs with excellent yields and selectivity. The second step is the reaction with ethylene diamine, which affords primary amines terminal groups, suitable to repeat the first step. The presence of two identical functions in ethylene diamine necessitates its use in very large excess, to try to avoid the coupling between two branches or two dendrimers. It is even used as solvent for high generations. These compounds were first called Starburst dendrimers, but they are universally known as PAMAM (for polyamidoamine) dendrimers.

1.4

Syntheses of Poly(ether) Dendrimers

The same year as D. A. Tomalia, the group of G. R. Newkome proposed the synthesis of “arborols”,10 in which the number of terminal groups is multiplied by 3 at each generation,

8

Dendrimers

Figure 1.6

Synthesis of poly(ether amide) dendrimers (PEA)

instead of by 2 for the previous examples and in most cases up to now. The synthesis is a multistep process, but not really repetitive. This method afforded poly(alkyl ether amide) dendrimers, but was carried out only up to the second generation. This method was later on replaced by Newkome and coworkers by another synthesis of poly(ether amide) dendrimers (PEA), in which the number of terminal groups is also multiplied by 3 at each generation. This method necessitates three steps to grow one generation. Alkylester terminal groups are cleaved with NaOH to afford carboxylic acid terminal groups, transformed into acid chloride with SOCl2. The third step is the grafting of the AB3 branching unit, which creates the amide linkages, affords a new layer of ethers and again alkylester terminal groups, suitable to undergo a new synthetic cycle. This reaction was carried out up to the fourth generation, starting from suitably functionalized pentaerythritol (Figure 1.6).11 However, the first fully polyether dendrimer was synthesized by the group of D. A. Tomalia in 1987,12 using a four-step process and also a threefold increase at each generation. In the first step, the potassium salt of 4-hydroxymethyl-2,6,7-trioxabicyclo[2.2.2] octane (HTBO) was grafted on to the core C(CH2Br)4. Hydrolysis of the bicyclic orthoformate groups to three alcohol functions in methanol hydrochloric acid was the second step. The alcohols were converted to tosylates with p-toluene sulfonic chloride in the third step. Replacement of tosylate by bromide using sodium bromide was the fourth step. This synthesis was carried out up to the third generation (Figure 1.7). Other polyaliphatic ether dendrimers were synthesized; two selected examples will be given below. A two-step convergent method was proposed by the group of J. M. J. Fréchet,13 which afforded dendrons based on 2-hydroxymethyl-1,3-propanediol building blocks. The chlorides of methallyl dichloride were reacted with functional alcohols in a

Syntheses of Dendrimers and Dendrons

Figure 1.7

Figure 1.8

9

The first synthesis of fully polyether dendrimers

Two-step convergent synthesis of poly(alkyl ether) dendrons

Williamson ether synthesis; this was the growing step. Derivatization of the double bond at the core of the dendron via hydroboration/oxidation was the activation step. Both steps were carried out up to the fifth generation dendron. It must be emphasized that in these types of synthetic processes, there are only two functions that react during the first step and only one during the second step (Figure 1.8). Both glycerol-type pseudo dendrimers (hyperbranched polymers) and dendrimers were synthesized by the group of R. Haag, starting from tris(hydroxymethyl)ethane.14 Even though this book is focused on dendrimers, Figure 1.9 displays both the synthesis of dendrimers and of hyperbranched polymers, because the latter have found more applications. In the case of the dendrimers, a two-step iterative process was used. This implies allylation with allyl chloride, followed by dihydroxylation. This process was repeated up to the third generation PGly-G3. The first step of the synthesis of the dendrimers was also the starting

10

Dendrimers

Figure 1.9 (PGly)

Synthesis of dendrimer and hyperbranched polymer of type polyglycerol

point for the synthesis of the hyperbranched polymer, using dihydroxylation and opening of epihydroxyhydrin. Poly(arylalkyl ether) dendrimers were first obtained by the group of Fréchet3 using a convergent process. This was the very first example of a convergent process applied to the synthesis of dendrimers. The first step is a dialkylation reaction of 3,5-dihydrobenzyl alcohol (AB2) with benzylbromide (these aryl groups will be at the surface of the dendrimer). The second step is an activation of the benzyl alcohol by CBr4, which affords a benzylbromide function at the core of the dendron, suitable to undergo a new sequence of reactions beginning with the use of the AB2 monomer. In the last step, the dendrons can be coupled to a core such as 1,1,1-tris(4′-hydroxyphenyl)ethane to obtain a dendrimer of type PBzE (polybenzyl ether) (Figure 1.10).3 This method of synthesis of dendrons is frequently used by numerous researchers. Later on, several other types of poly(arylalkyl ether) dendrimers were synthesized. We will indicate only one, in which the number of branches is multiplied by 3 at each generation. It was obtained by the group of D. Astruc using a divergent process.15 Four steps are needed to obtain one generation. Starting from allyl terminal groups, the first step is a hydration which generates alcohols; the second step is the transformation of the alcohols into alkyl iodides; the third step is a mesylation, affording OSO2Me terminal groups; the fourth step, which induces multiplication by 3 of the terminal groups is the grafting of the triallylphenol monomer of type AB3 affording poly(arylalkyl ether) dendrimers (PAAE) (Figure 1.11).

1.5

Syntheses of Poly(ester) Dendrimers

Polyesters, as polyethers, are an attractive structure for the synthesis of biocompatible dendrimers and have generated numerous types of dendrimeric compounds. The first

Syntheses of Dendrimers and Dendrons

11

Figure 1.10 Synthesis of poly(benzyl ether) dendrons and dendrimers (PBzE) by a convergent process

Figure 1.11

Synthesis of poly(arylalkyl ether) dendrimers (PAAE) by a divergent process

12

Dendrimers

Figure 1.12

Synthesis of aliphatic polyester dendrimers

aliphatic polyester dendrimeric hyperbranched polymers were synthesized early16 whereas the related dendrimers were synthesized some years later, using a convergent method.17 A. Hult and coworkers developed a three-step process using 2,2-bis(hydroxymethyl) propionic acid as the building block of dendrons. The focal point of the dendrons was protected by a benzyl ether group, which was deprotected by catalytic hydrogenolysis, affording a carboxylic acid. This acid was converted to acid chloride in the second step, and the third step was the esterification (reaction of the acid chloride with the alcohol groups of the protected monomer unit). This synthesis was carried out up to the fourth generation dendron, which was then coupled to 1,1,1-tris(hydroxyphenyl)ethane, used as the core to obtain the corresponding dendrimer (Figure 1.12).17 Closely related polyester dendrimers were synthesized by a divergent process by the group of J. M. J. Fréchet.18 Dendrimers possessing both ester and ether linkages were synthesized by the group of M. W. Grinstaff,19 using a two-step process. A tetra alcohol was coupled in the first step to a carboxylic acid possessing two masked alcohol functions. The second step is the deprotection of the acetal to generate again alcohol functions. This sequence of reactions was repeated up to the third generation (Figure 1.13). The same group has reported the synthesis of polyester dendrimers using a closely related method of synthesis.20 Very recently, a new methodology for the synthesis of polyester dendrimers possessing additional internal functions was proposed by the group of M. Malkoch.21 This original work is based on a AB2C monomer. The divergent growth approach includes first the esterification of trimethylol propane (the core) with a carboxylic acid (the A function) and then the deprotection of the diol (the B functions) in acidic conditions. Repetition of the esterification and deprotection was carried out up to the fourth generation, which possesses 16 alcohol groups as terminal functions and 16 alkyne groups as internal functions (Figure 1.14).

Syntheses of Dendrimers and Dendrons

Figure 1.13

Figure 1.14

13

Synthesis of mixed aliphatic polyether/polyester dendrimers

Synthesis of polyester dendrimers bearing internal alkyne groups

The first polyarylester dendrimers were synthesized by T. X. Neenan and T. M. Miller in 1991,22 using a convergent process. The synthesis of the dendrons used the iterative sequence of esterification between phenol and acid chloride, followed by hydrolysis of hydroxyl groups protected with the tert-butyldimethylsilyl group. The synthesis of the dendrons was carried out up to the third generation and then three equivalents of dendrons were coupled to the 1,3,5-benzenetricarbonyl chloride to afford the corresponding poly(aryl ether) dendrimers, depending on the generation of the dendrons used (Figure 1.15). Several other methods of synthesis of poly(aryl ether) dendrimers were proposed, in particular using divergent processes. For example, the group of P. C. Taylor23 proposed a two-step process. The first step is an esterification between an acid chloride and a phenol; the second step is the hydrogenolysis of the benzyl groups (Bn), which affords again phenol groups. The synthesis was carried out up to the third generation with the core shown in Figure 1.16 and to the fourth generation with a difunctional core.

Dendrimers

14

Figure 1.15 Synthesis of polyester dendrons and dendrimers by a convergent process

Figure 1.16

1.6

Synthesis of poly(arylester) dendrimers

Synthesis of Poly(lysine) Dendrimers

The very first patented compound having the structure of a dendrimer was obtained by the group of R. G. Denkewalter in 1981.24 It was a polypeptide dendrimer (called highly branched homogeneous compounds) built from a benzhydrylamine core by the repetition of a sequence of protection/deprotection, using N,N′-bis(tert-butoxycarbonyl)-L-lysine nitrophenyl ester as reagent (Figure 1.17). This synthesis was carried out up to the tenth generation (PLys-G10). The synthesis of these compounds was not published in traditional media, but their characterization was published by another group, with authentic samples from the inventors.25

Syntheses of Dendrimers and Dendrons

Figure 1.17

Figure 1.18

1.7

15

Synthesis of poly-L-lysine dendrimers (PLys)

The first example of synthesis of polysiloxane dendrimers

Syntheses of Silicon-Containing Dendrimers

The extraordinary diversity of heteroatom chemistry has stimulated their use for the synthesis of dendrimers.26 The first heteroatom-containing dendrimers (polysiloxanes) were proposed by the group of A. M. Muzafarov.27 The synthesis consists of the repetition of two steps starting from a trifunctional core (methyltrichlorosilane). The first step is a nucleophilic substitution of the chlorosilyl groups by diethoxyhydroxymethylsilane sodium salt; the second step is the reaction of SOCl2 with the ethoxysilane end groups to yield Si–Cl end groups. The repetition of these two steps was carried out up to the fourth generation (Figure 1.18).

16

Dendrimers

Figure 1.19

Synthesis of polycarbosilane (PCSi) dendrimers

However, polysiloxanes are not perfectly stable in water; thus the preferred siliconcontaining dendrimers are of type carbosilane. They are synthesized in very good yields by using alternate alkenylation with Grignard reagents and hydrosilylation. Several types of carbosilane dendrimers were obtained: the branch length depends on the length of the alkyl chain of the Grignard reagent used and the branching multiplicity depends on the type of hydrosilylating agent (HSiCl3 or HSiCl2Me) that is used (Figure 1.19). In the case of a multiplication by 3 of the number of terminal groups at each generation, the highest generation obtainable in each case depends on the length of the alkenyl group.28 The seventh generation dendrimer is the largest one, obtained only with the decenyl derivative. The allyl derivative allows the synthesis of the fifth generation,29 whereas the synthesis with the vinyl derivative has been carried out up to the fourth generation.30 This method of synthesis allows several types of modifications (Figure 1.19). In particular, dichloromethylsilane can be used instead of trichlorosilane.31 These types of dendrimers in which the number of terminal groups is multiplied by two at each generation is the most widely used type of carbosilane dendrimers (PCSi).

1.8

Syntheses of Phosphorus-Containing Dendrimers

Phosphorus-containing dendrimers are the other very important family of heteroatomcontaining dendrimers. The very first example was synthesized by the group of Engel in 1990;32 it was based on phosphonium salts at each branching point, which induced a multiplication by 3 of the number of terminal groups at each generation. However, the

Syntheses of Dendrimers and Dendrons

17

Figure 1.20 Synthesis of poly(phosphorhydrazone) (PPH) dendrimers, built either from the trifunctional core P(S)Cl3 or the hexafunctional core (N3P3Cl6)

type of phosphorus dendrimers that has generated the most important work due to their numerous applications is the one that A. M. Caminade, J. P. Majoral, and coworkers proposed in 1994.33 It consists in applying a two-step reiterative process using successively 4-hydroxybenzaldehyde in basic conditions and H2NNMeP(X)Cl2 (X = O, but mainly S) as branching units (Figure 1.20). Both steps generate only NaCl and H2O as by-products and are quantitative. This process was first carried out up to the fourth generation,33 then to the seventh generation,34 the ninth,35 and finally to the twelfth generation,36 starting from the trifunctional core P(S)Cl3. This twelfth generation (PPH(PS)-G12) is the highest wellcharacterized generation obtained up to now for any type of dendrimer. This two-step method of synthesis can be applied to a large number of different cores, provided they possess either several P–Cl or CHO functional groups. In particular this reaction was carried out from the hexafunctional cyclotriphosphazene core (N3P3Cl6) and up to the eighth generation (PPH(PN)-G8).37 Salamonczyck and coworkers38 developed the use of phosphoramidites as building blocks for the synthesis of polyphosphate dendrimers. The first step is the reaction of a triol with a phosphoramidite possessing acetate groups, followed by oxidation with elemental sulfur. The second step is the deprotection of the acetates to afford the polyols of the next generation. The repetition of both steps was carried out up to the fifth generation. It is even possible to build dendrimers possessing a different type of phosphate at each generation, chosen between P=S, P=Se, and P=O, affording layered dendrimers39 (Figure 1.21).

1.9

Syntheses of Carbon-Based Dendrimers

Dendrimers constituted of only carbon and hydrogen atoms differ from all other types of dendrimers by their rigidity. The first examples were provided by the group of J. S. Moore,

18

Dendrimers

Figure 1.21

Synthesis of phosphate (or thio- or seleno-phosphate) dendrimers

Figure 1.22

Synthesis of poly(phenylacetylene) dendrimers

first for the synthesis of dendrons40 and then of dendrimers,41 both obtained by a convergent process. The repeat unit is based on 1-ethynyl-3,5-disubstituted benzene. These series of compounds have a true fractal structure, with the length of the branches increasing when the number of branches decreases. The synthesis of these poly(phenylacetylene) dendrimers was carried out up to the fifth generation (Figure 1.22). Polyphenylene dendrimers are another type of rigid dendrimer, which were synthesized by the group of K. Müllen via Diels–Alder cycloaddition of an alkyne dienophile to an activated diene at 200 °C. The second step is the deprotection of the silylated alkynes with H4NF, Bu4NF affording primary alkynes as terminal groups, suitable to undergo a new

Syntheses of Dendrimers and Dendrons

Figure 1.23

19

Synthesis of polyphenylene (PPhen) dendrimers

Diels–Alder cycloaddition. The synthesis of these highly aromatic compounds was carried out up to the third generation (PPhen-G3) (Figure 1.23).42 However, by intercalating three aromatic groups in each branch of the monomer, the synthesis was carried out up to the sixth generation. Of course, these dendrimers with elongated arms are more flexible than the ones shown in Figure 1.23.43

1.10

Syntheses of Dendrimers Constituted of Nitrogen Heterocycles

We have seen above several examples of dendrimers having some aromatic groups in their structure, but there also exist some examples of dendrimers in which all the branches are constituted of aromatic nitrogen heterocycles. V. Balzani and coworkers have reported the synthesis of homo- or heterometallic dendrimers based on the complexation of 2,3-bis(2pyridyl)pyrazine. Starting from a core in which three pyridines are methylated, the first step is the deprotection with DABCO (1,4-diazabicyclo[2.2.2]octane), which affords three potential chelating sites. The second step is the complexation of these sites with a metallic complex in the presence of AgNO3, which affords the first generation of poly(bispyridyl) pyrazine (Pbpp-G1) complexes. Repetition of the deprotection and complexation steps allowed the synthesis up to generation 3 (Figure 1.24).44 This synthesis has been done with only one metal (Ru)45 or two (Ru and Os)46 at different levels. Melamine is another type of nitrogen heterocycle that has been used for the synthesis of dendrimers. E. Simanek and coworkers47 described both the use of a convergent and

20

Dendrimers

Figure 1.24

Synthesis of poly(bispyridyl)pyrazine (Pbpp) dendrimer complexes

divergent way to obtain these dendrimers. The convergent way is based on the addition of cyanuric chloride to two dendrons followed by the reaction of p-amino benzylamine with the remaining Cl, in an iterative fashion. The synthesis was carried out up to the third generation. In the last step, the dendrons were coupled to ethylenediamine used as the core, to generate the corresponding dendrimers (Figure 1.25). As constituents of the branches of dendrimers, 1,2,3-triazoles are obtained by “click” reactions based on copper-catalyzed reactions between azides and alkynes. This method has been recently used for the synthesis of various types of dendrimers, but the first example was proposed by C. J. Hawker, K. B. Sharpless, V. V. Fokin, and coworkers.48 It is a convergent process in which an AB2 monomer (A = Cl, B = alkyne) is reacted with an azide in the first step and Cl is replaced by an azide using NaN3 in the second step. The dendrons are grown by repeating both steps and finally they are coupled to a trialkyne core to afford the corresponding dendrimers, up to generation 4 (Figure 1.26). Some macrocycles have been used as branches of dendrimers. The first example was proposed by the group of S. Shinkai.49 It concerns 1,10-diaza-18-crown-6, in which the NH functionalities are sequentially used to react with acid chlorides. The monomeric macrocycle (macro) possesses one NH group and two protected carboxylic acids. The first step is the reaction of NH with the acid chloride of the core. The second step is the deprotection of the carboxylic acids, which are then converted to acid chlorides. The synthesis was carried out up to the second generation (nine macrocycles) (Figure 1.27).

Syntheses of Dendrimers and Dendrons

21

Figure 1.25 Synthesis of melamine dendrimers (PMel) by a convergent method

Figure 1.26

1.11

Convergent synthesis of triazole-containing dendrimers via “click” chemistry

Syntheses by Self-Assembly

We have seen in all the previous paragraphs that the synthesis of dendrimers is always a long and tedious work, requiring two to five steps to build a single generation; thus many attempts to shorten the synthetic processes were proposed. One of the most elegant ways

22

Dendrimers

Figure 1.27

Synthesis of polymacrocyclic dendrimers

consists in applying the concept of “self-assembly” to the elaboration of dendrimeric structure. This topic was recently reviewed by one of the pioneers in the field.50 The first example was proposed by S. C. Zimmerman et al.51 who elaborated a “Fréchet-type” dendron (PBzE) having bisisophthalic acid as the core, suitably positioned to induce the self-assembly of six dendrons, spontaneously in CDCl3 through hydrogen bonding. However, as in all cases of self-assembly, this process is a dynamic process and is totally reversible in THF (Figure 1.28). A somewhat related work was reported by F. van Veggel, D. N. Reinhoudt, and coworkers.52 Dendrons built by coordination chemistry were functionalized at their core by barbituric residue. These dendrons self-assemble by hydrogen bonding in a rosette structure associating three dendrons and three phenyl melamine derivatives, as shown in Figure 1.29. The group of V. Percec53,54 has carried out important work about the self-assembly of liquid crystalline dendrons of AB3 type possessing semi-rigid benzyl ether branches, aliphatic terminal groups, and an ester as the core. The shape of the supramolecular assemblies depends on the size of the dendrons. The generations 1 and 2 of dendrons selforganize into cylindrical lattices, whereas the third generation self-assembles into a spherical dendrimer-like structure (Figure 1.30). The development of the self-assembly process led A. Hirsch and coworkers55 to the complete synthesis of dendrimers based on noncovalent interactions. For this purpose, a

Syntheses of Dendrimers and Dendrons

23

Figure 1.28 First example of a dendrimer synthesized by self-assembly of dendrons

Figure 1.29

Self-assembly of three dendrons with three phenyl melamine derivatives

core possessing three receptor sites (C), branching elements possessing two receptor sites and a complimentary cyanuric acid substrate (AB2), and end caps possessing a complimentary cyanuric acid substrate and “Frechet-type” dendrons (D) were synthesized. Reaction of the core with three equivalents of the end cap led to the first generation of discrete supramolecular dendrimers. Then, the stoichiometric mixing of one core unit, three branching elements, and six end caps was attempted, as well as other experiments using a 1 : (3 × 2n−3) : (3 × 2n) ratio for the same elements. Pulse field gradient NMR spectroscopy proved the existence of discrete dendrimers in chloroform (Figure 1.31).

24

Dendrimers

Figure 1.30 generation

Results of the self-assembly of liquid crystalline dendrons, depending on the

Figure 1.31 Supramolecular assemblies of discrete dendrimers using hydrogen bonding between the core (C), the branching elements (AB2), and the end caps (D)

Despite the interest of the supramolecular assemblies shown in the previous paragraphs, none of them can encompass the efficiency of the association of the DNA double helix by hybridization. This supramolecular phenomenon is due to bases pairing, in which purine bases (Adenine and Guanine) are hydrogen-bonded to complementary pyrimidine bases (Cytosine and Thymine), creating A–T pairs (two hydrogen bonds) and G–C pairs (three

Syntheses of Dendrimers and Dendrons

25

Figure 1.32 Synthesis of dendrimeric nucleic acid structures (called 3DNA) by hybridization of linear oligonucleotides

Figure 1.33 Synthesis of dendrimers using monomers elaborated from three oligonucleotides

hydrogen bonds). Thus DNA was used for the synthesis of DNA dendrimers, a recently reviewed field.56 T. W. Nilsen et al.57 described the first example of dendrimers exclusively composed of oligonucleotides associated by hybridization. A heterodimer composed of two single-stranded nucleic acid oligomers possessing a central double-stranded waist and four single-stranded arms for binding was used as the monomer. The assembly of the dendrimer proceeds in layers, as shown in Figure 1.32. This method was applied up to generation 6 (2916 single-stranded arms). These DNA dendrimers were commercialized under the name of 3DNA. Another series of nucleic acid dendrimers was obtained later on by Y. Li et al.58 using a relatively analogous way. This method is based on single-stranded oligonucleotides having partial complementary sequences, which afforded Y-shaped DNA as the core. Using the same principle, an AB2 monomer (also Y-shaped DNA) was elaborated. Assembly by ligating three equivalents of AB2 with one equivalent of the core affords the first generation dendrimer. The synthesis was carried out up to the fifth generation (Figure 1.33). The last way reported up to now to self-assemble dendrimers is based on pseudorotaxane formation, using a core with elongated arms, and dendrons built with a macrocycle or its precursor as the core, both having the suitable complementary functional groups. H. W. Gibson et al.59 reported the interaction between a homotritopic guest possessing three

26

Dendrimers

Figure 1.34 Two examples of self-assembly of pseudo-rotaxane dendrimers. Dendrons are of the type shown in Figure 1.10

RNH2+CH2Ph groups and a “Fréchet”-type dendron (PBzE, see Figure 1.10) possessing a dibenzo-24-crown-8 as core. 1 : 1, 1 : 2, and 1 : 3 complexes were formed, but the selfassembly was cooperative and only the dendrimers of 1 : 3 stoichiometry were finally obtained (Figure 1.34, upper part). Dendrons of generations 1, 2, and 3 were used, and it was shown that the solubility of the dendrimers increased with the generation of the dendrons. In another approach, the group of J. F. Stoddart60 reported the synthesis of mechanically interlocked dendrimers. In this case, the dendrons have a dialdehyde as the core, and they were reacted with a semi-crown diamine in the presence of a trivalent core carrying R–NH2+CH2C6H3(OMe)2 centers on their side arms. The condensation occurs across these ammonium centers to generate diimine-containing [24]crown-8-macrocycles (Figure 1.34, lower part). Reduction of the imine bonds affords kinetically stable interlocked dendrimers.

1.12 Accelerated Syntheses The self-assembly processes shown in the previous paragraphs are seductive, but they have generally not led to practical uses (with the exception of 3DNA) due to the fragility and the dynamic of the interactions between the subunits. In consequence, other approaches are needed to accelerate the synthesis of dendrimers. The first example was proposed by the group of J. M. J. Fréchet61 and was called the “double-stage convergent growth approach”. It consists of the synthesis by a convergent process of a dendron having protected terminal groups. Then three equivalents of this dendron were grafted to a core through its focal point, and the terminal groups of the resulting dendrimer were deprotected. In the last step dendrons (identical to the previous one or different) are reacted to this “hypercore”. In particular a dendrimer of generation 7 was obtained in one step from a D-G4 dendron and a G3 dendrimer used as the hypercore (Figure 1.35).

Syntheses of Dendrimers and Dendrons

Figure 1.35

27

Illustration of the “double-stage convergent approach”

An analogous strategy was applied later on to the grafting of phosphorus-containing dendrons to the surface of phosphorus-containing dendrimers, allowing direct synthesis of a generation 8 dendrimer from a generation 3 dendrimer and 24 equivalents of a generation 5 dendron.62 Directly related to the concept of “hypercore”, the concept of “hypermonomer”, that is the use of ABx monomers with x > 3, was in particular disclosed by the group of J. M. J. Fréchet for the synthesis of dendrons.63 For instance, the A(Bp)4 compound shown in Figure 1.35 is a “hypermonomer”. Another potential improvement was proposed by C. L. Wilkins, J. S. Moore, and coworkers,64 which was called “double exponential growth”. In this case, the growing of the dendron was carried out bidirectionally, that is to say both at the focal point and at the periphery. This type of strategy could be interesting for the rapid synthesis of high generation dendrimers, but it was applied only to middle size dendrons, for which the number of synthetic steps is not drastically diminished. For instance, a fourth generation dendron was obtained in six steps instead of eight classically (Figure 1.36). The classical synthesis of dendrimers generally necessitates at least two steps, one of which allows the number of terminal groups to multiply while the other one introduces the suitable chemical function for performing the branching step again. One possibility to multiply more rapidly the number of terminal groups consists in using a branched monomer for all synthetic steps. An example of this concept was proposed by K. Yamamoto et al.65

28

Dendrimers

Figure 1.36

Figure 1.37

Illustration of “double exponential growth”

Synthesis of poly(phenylazomethine) dendrimers (DPA)

Dendrimeric poly(phenylazomethines) (DPAs) were synthesized by a convergent method via the condensation of aromatic ketones with aromatic amines in the presence of TiCl4.66 Obviously, the self-condensation between the monomers cannot be totally prevented; thus the yields in isolated dendrons are not excellent (Figure 1.37). To face this problem, the use of two types of branched monomers was proposed, namely AB2 and CD2, where B reacts with C and A reacts with D, resulting in layered dendrimers. This concept was called “orthogonal coupling strategy”.67 It generally requires a set of completely independent protecting groups; thus at least one of these functions needs to be activated at each step using another reagent. A. M. Caminade, J. P. Majoral, and coworkers68 reported the first example of orthogonal coupling strategy in which the A, B, C, and D functions are specifically chosen to react spontaneously, without the need of any activating agent. The fourth generation of the layered phosphorus dendrimer was obtained in only four steps, using two types of quantitative reactions: the condensation of phospho-

Syntheses of Dendrimers and Dendrons

29

Figure 1.38 A generation 4 layered dendrimer synthesized in four steps using AB2 and CD2 branched monomers

Figure 1.39 Synthesis of dendrimers using AB5 and CD5 monomers and a comparison of the number of terminal groups obtained after three synthetic steps, depending on the method used

rhydrazide (A) with aldehydes (D) and the Staudinger reaction of phosphines (B) with azides (C). These reactions generate only water and N2 as by-products, respectively; they were performed also in a one-pot (but multistep) process, affording the fourth generation with practically the same purity (Figure 1.38). Furthermore, this method of synthesis introduces in the dendrimeric structure P=N–P=S linkages, which can be activated later on using strong electrophiles to generate new dendrimeric branches inside the structure, leading to particularly original dendrimeric macromolecules.69 This concept of “two branched monomers” was coupled later on with the concept of “hypermonomer”, using cyclotriphosphazene as the branching element. The reactivity of one function among six could be differentiated, leading to AB5 and CD5 monomers. The synthetic process was carried out up to the third generation, obtained in only three steps. This dendrimer possesses 750 terminal groups.70 Of course the AB5 monomer can be used in combination with CD2 monomers, as well as the AB2 monomer with the CD5 monomer. Besides the synthesis, Figure 1.39 displays the comparison of the number of terminal groups obtained after three steps using different methods.

30

1.13

Dendrimers

Conclusion

This chapter has illustrated the rich diversity of the structure of dendrimers and dendrons, as well as the treasures of imagination developed for their synthesis. It must be emphasized that this chapter is absolutely not exhaustive but it gives a flavor of the synthetic aspects (a recent review by Newkome et al.71 only dedicated to 1→3 connectivity includes more than 1200 references). Despite all the work already done about the synthesis, there is still plenty of room for improving the synthetic processes, in particular for shortening the time needed at the bench. On the other hand, in view of the repetitive structure of dendrimers, it is easy to foresee that their characterization is never trivial, particularly when the size increases. It will be the topic of the forthcoming chapter.

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(15) V. Sartor, L. Djakovitch, J. L. Fillaut, F. Moulines, F. Neveu, V. Marvaud, J. Guittard, J. C. Blais, and D. Astruc (1999) Organoiron route to a new dendron for fast dendritic syntheses using divergent and convergent methods. J. Am. Chem. Soc., 121, 2929–2930. (16) C. J. Hawker, R. Lee and J. M. J. Fréchet (1991) One-step synthesis of hyperbranched dendritic polyesters. J. Am. Chem. Soc., 113, 4583–4588. (17) H. Ihre, A. Hult, and E. Soderlind (1996) Synthesis, characterization, and H-1 NMR selfdiffusion studies of dendritic aliphatic polyesters based on 2,2-bis(hydroxymethyl)propionic acid and 1,1,1-tris(hydroxyphenyl)ethane. J. Am. Chem. Soc., 118, 6388–6395. (18) H. Ihre, O. L. P. De Jesus, and J. M. J. Fréchet (2001) Fast and convenient divergent synthesis of aliphatic ester dendrimers by anhydride coupling. J. Am. Chem. Soc., 123, 5908–5917. (19) M. A. Carnahan and M. W. Grinstaff (2001) Synthesis and characterization of polyether-ester dendrimers from glycerol and lactic acid. J. Am. Chem. Soc., 123, 2905–2906. (20) M. A. Carnahan and M. W. Grinstaff (2001) Synthesis and characterization of poly(glycerolsuccinic acid) dendrimers. Macromolecules, 34, 7648–7655. (21) P. Antoni, Y. Hed, A. Nordberg, D. Nystrom, H. von Holst, A. Hult, and M. Malkoch (2009) Bifunctional dendrimers: from robust synthesis and accelerated one-pot postfunctionalization strategy to potential applications. Angew. Chem. Int. Ed. Engl., 48, 2126–2130. (22) E. W. Kwock, T. X. Neenan, and T. M. Miller (1991) Convergent synthesis of monodisperse aryl ester dendrimers. Chem. Mater., 3, 775–777. (23) D. M. Haddleton, H. S. Sahota, P. C. Taylor, and S. G. Yeates (1996) Synthesis of polyester dendrimers. J. Chem. Soc.-Perkin Trans. 1, 649–656. (24) R. G. Denkewalter, J. Kolc, and W. J. Lukasavage (1981) Macromolecular highly branched homogeneous compound based on lysine units. US Patent 4289872 A 19810915. (25) S. M. Aharoni, C. R. Crosby III, and E. K. Walsh (1982) Size and solution properties of globular tert-butyloxycarbonyl-poly(α,ε-L-lysine). Macromolecules, 15, 1093–1098. (26) J. P. Majoral and A. M. Caminade (1999) Dendrimers containing heteroatoms (Si, P, B, Ge, or Bi). Chem. Rev., 99, 845–880. (27) E. A. Rebrov, A. M. Muzafarov, V. S. Papkov, and A. A. Zhdanov (1989) Space-network polyorganosiloxanes. Doklady Akademii Nauk SSSR, 309, 376–380. (28) A. W. van der Made and P. W. N. M. van Leeuwen (1992) Silane dendrimers. J. Chem. Soc.Chem. Commun., 1400–1401. (29) A. W. van der Made, P. W. N. M. van Leeuwen, J. C. Dewilde, and R. A. C. Brandes (1993) Dendrimeric silanes. Adv. Mater., 5, 466–468. (30) D. Seyferth, D. Y. Son, A. L. Rheingold, and R. L. Ostrander (1994) Synthesis of an organosilicon dendrimer containing 324 Si–H bonds. Organometallics, 13, 2682–2690. (31) L. L. Zhou and J. Roovers (1993) Synthesis of novel carbosilane dendritic macromolecules. Macromolecules, 26, 963–968. (32) K. Rengan and R. Engel (1990) Phosphonium cascade molecules. J. Chem. Soc.-Chem. Commun., 1084–1085. (33) N. Launay, A. M. Caminade, R. Lahana, and J. P. Majoral (1994) A general synthetic strategy for neutral phosphorus-containing dendrimers. Angew. Chem. Int. Ed. Engl., 33, 1589–1592. (34) N. Launay, A. M. Caminade, and J. P. Majoral (1995) Synthesis and reactivity of unusual phosphorus dendrimers – a useful divergent growth approach up to the 7th generation. J. Am. Chem. Soc., 117, 3282–3283. (35) M. Slany, M. Bardaji, M. J. Casanove, A. M. Caminade, J. P. Majoral, and B. Chaudret (1995) Dendrimer surface-chemistry – facile route to polyphosphines and their gold complexes. J. Am. Chem. Soc., 117, 9764–9765. (36) M. L. Lartigue, B. Donnadieu, C. Galliot, A. M. Caminade, J. P. Majoral, and J. P. Fayet (1997) Large dipole moments of phosphorus-containing dendrimers, Macromolecules, 30, 7335–7337. (37) N. Launay, A. M. Caminade, and J. P. Majoral (1997) Synthesis of bowl-shaped dendrimers from generation 1 to generation 8. J. Organomet. Chem., 529, 51–58. (38) G. M. Salamonczyk, M. Kuznikowski, and A. Skowronska (2000) A divergent synthesis of thiophosphate-based dendrimers. Tetrahedron Lett., 41, 1643–1645.

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(39) G. M. Salamonczyk, M. Kuznikowski, and E. Poniatowska (2002) Dendrimers bearing three types of branching functions. Tetrahedron Lett., 43, 1747–1749. (40) J. S. Moore and Z. F. Xu (1991) Synthesis of rigid dendritic macromolecules – enlarging the repeat unit size as a function of generation permits growth to continue. Macromolecules, 24, 5893–5894. (41) Z. F. Xu and J. S. Moore (1993) Stiff dendritic macromolecules. 3. Rapid construction of large-size phenylacetylene dendrimers up to 12.5 nanometers in molecular diameter. Angew. Chem. Int. Ed. Engl., 32, 1354–1357. (42) F. Morgenroth, E. Reuther, and K. Müllen (1997) Polyphenylene dendrimers: from threedimensional to two-dimensional structures. Angew. Chem. Int. Ed. Engl., 36, 631–634. (43) C. G. Clark, R. J. Wenzel, E. V. Andreitchenko, W. Steffen, R. Zenobi, and K. Müllen (2007) Controlled megaDalton assembly with locally stiff but globally flexible polyphenylene dendrimers. J. Am. Chem. Soc., 129, 3292–3301. (44) S. Serroni, G. Denti, S. Campagna, A. Juris, M. Ciano, and V. Balzani (1992) Arborols based on luminescent and redox-active transition-metal complexes. Angew. Chem. Int. Ed. Engl., 31, 1493–1495. (45) S. Serroni, G. Denti, S. Campagna, M. Ciano, and V. Balzani (1991) A decanuclear ruthenium(II)–polypyridine complex – synthesis, absorption-spectrum, luminescence and electrochemical-behavior. J. Chem. Soc.-Chem. Commun., 944–945. (46) G. Denti, S. Campagna, S. Serroni, M. Ciano, and V. Balzani (1992) Decanuclear homometallic and heterometallic polypyridine complexes – syntheses, absorption-spectra, luminescence, electrochemical oxidation, and intercomponent energy-transfer. J. Am. Chem. Soc., 114, 2944–2950. (47) W. Zhang and E. E. Simanek (2000) Dendrimers based on melamine. Divergent and orthogonal, convergent syntheses of a G3 dendrimer. Org. Lett., 2, 843–845. (48) P. Wu, A. K. Feldman, A. K. Nugent, C. J. Hawker, A. Scheel, B. Voit, J. Pyun, J. M. J. Fréchet, K. B. Sharpless, and V. V. Fokin (2004) Efficiency and fidelity in a click-chemistry route to triazole dendrimers by the copper(I)-catalyzed ligation of azides and alkynes. Angew. Chem. Int. Ed., 43, 3928–3932. (49) T. Nagasaki, M. Ukon, S. Arimori, and S. Shinkai (1992) Crowned arborols. J. Chem. Soc.Chem. Commun., 608–610. (50) B. M. Rosen, C. J. Wilson, D. A. Wilson, M. Peterca, M. R. Imam, and V. Percec (2009) Dendron-mediated self-assembly, disassembly, and self-organization of complex systems. Chem. Rev., 109, 6275–6540. (51) S. C. Zimmerman, F. W. Zeng, D. E. C. Reichert, and S. V. Kolotuchin (1996) Self-assembling dendrimers. Science, 271, 1095–1098. (52) W. T. S. Huck, R. Hulst, P. Timmerman, F. van Veggel, and D. N. Reinhoudt (1997) Noncovalent synthesis of nanostructures: combining coordination chemistry and hydrogen bonding. Angew. Chem. Int. Ed. Engl., 36, 1006–1008. (53) S. D. Hudson, H. T. Jung, V. Percec, W. D. Cho, G. Johansson, G. Ungar, and V. S. K. Balagurusamy (1997) Direct visualization of individual cylindrical and spherical supramolecular dendrimers. Science, 278, 449–452. (54) V. Percec, M. Glodde, T. K. Bera, Y. Miura, I. Shiyanovskaya, K. D. Singer, V. S. K. Balagurusamy, P. A. Heiney, I. Schnell, A. Rapp, H. W. Spiess, S. D. Hudson, and H. Duan (2002) Self-organization of supramolecular helical dendrimers into complex electronic materials. Nature, 419, 384–387. (55) A. Franz, W. Bauer, and A. Hirsch (2005) Complete self-assembly of discrete supramolecular dendrimers. Angew. Chem. Int. Ed., 44, 1564–1567. (56) A. M. Caminade, C. O. Turrin, and J. P. Majoral (2008) Dendrimers and DNA: combinations of two special topologies for nanomaterials and biology. Chem.-Eur. J., 14, 7422–7432. (57) T. W. Nilsen, J. Grayzel, and W. Prensky (1997) Dendritic nucleic acid structures. J. Theor. Biol., 187, 273–284. (58) Y. G. Li, Y. D. Tseng, S. Y. Kwon, L. D’Espaux, J. S. Bunch, P. L. Mceuen, and D. Luo (2004) Controlled assembly of dendrimer-like DNA. Nature Mater., 3, 38–42.

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(59) H. W. Gibson, N. Yamaguchi, L. Hamilton, and J. W. Jones (2002) Cooperative self-assembly of dendrimers via pseudorotaxane formation from a homotritopic guest molecule and complementary monotopic host dendrons. J. Am. Chem. Soc., 124, 4653–4665. (60) K. C. F. Leung, F. Arico, S. J. Cantrill, and J. F. Stoddart (2005) Template-directed dynamic synthesis of mechanically interlocked dendrimers. J. Am. Chem. Soc., 127, 5808–5810. (61) K. L. Wooley, C. J. Hawker, and J. M. J. Fréchet (1991) Hyperbranched macromolecules via a novel double-stage convergent growth approach. J. Am. Chem. Soc., 113, 4252–4261. (62) V. Maraval, R. Laurent, B. Donnadieu, M. Mauzac, A. M. Caminade, and J. P. Majoral (2000) Rapid synthesis of phosphorus-containing dendrimers with controlled molecular architectures: first example of surface-block, layer-block, and segment-block dendrimers issued from the same dendron. J. Am. Chem. Soc., 122, 2499–2511. (63) S. L. Gilat, A. Adronov, and J. M. J. Fréchet (1999) Modular approach to the accelerated convergent growth of laser dye-labeled poly(aryl ether) dendrimers using a novel hypermonomer. J. Org. Chem., 64, 7474–7484. (64) T. Kawaguchi, K. L. Walker, C. L. Wilkins, and J. S. Moore (1995) Double exponential dendrimer growth. J. Am. Chem. Soc., 117, 2159–2165. (65) K. Yamamoto, M. Higuchi, S. Shiki, M. Tsuruta, and H. Chiba (2002) Stepwise radial complexation of imine groups in phenylazomethine dendrimers. Nature, 415, 509–511. (66) M. Higuchi, S. Shiki, and K. Yamamoto (2000) Novel phenylazomethine dendrimers: synthesis and structural properties. Org. Lett., 2, 3079–3082. (67) K. L. Wooley, C. J. Hawker, and J. M. J. Fréchet (1994) A branched-monomer approach for the rapid synthesis of dendrimers. Angew. Chem. Int. Ed. Engl., 33, 82–85. (68) L. Brauge, G. Magro, A. M. Caminade, and J. P. Majoral (2001) First divergent strategy using two AB2 unprotected monomers for the rapid synthesis of dendrimers. J. Am. Chem. Soc., 123, 6698–6699. (69) C. Galliot, C. Larré, A. M. Caminade, and J. P. Majoral (1997) Regioselective stepwise growth of dendrimer units in the internal voids of a main dendrimer. Science, 277, 1981–1984. (70) V. Maraval, A. M. Caminade, J. P. Majoral, and J. C. Blais (2003) Dendrimer design: How to circumvent the dilemma of a reduction of steps or an increase of function multiplicity? Angew. Chem. Int. Ed., 42, 1822–1826. (71) G. R. Newkome and C. Shreiner (2010) Dendrimers Derived from 1→3 Branching Motifs, Chem. Rev., 110, 6338–6442.

2 Methods of Characterization of Dendrimers Anne-Marie Caminade

2.1

Introduction

As shown in the first chapter, dendrimers are synthesized step by step, but they have a repetitive structure; thus they are just in between small molecules and polymers. Due to their numerous properties and uses, there is a critical need for techniques of characterization of dendrimers, but this task is never trivial due to their peculiar structure. Indeed, not only their chemical composition and weight have to be known, as for all classical molecules, but also their morphology, their shape, their size, and their homogeneity. In particular, their theoretically perfect and monodisperse structure is always questionable, especially for dendrimers built by a divergent process, and it has to be proven. Indeed, even starting from a perfect dendrimer at a given generation, the yield in perfect dendrimer at the next step depends on the percentage of conversion per terminal group. High generations are only attainable if the percentage of conversion per terminal group is higher than 99.99% (Figure 2.1). Pertaining both to the molecular world and the polymer world, dendrimers and dendrons should benefit from analytical techniques derived from both worlds for their characterization. This is indeed the case, and several thousands of publications are related to the characterization of dendrimers. Among them, only very few general reviews have appeared, essentially one in 1999 from the group of E. W. Meijer1 and one in 2005 from that of A. M. Caminade and J. P. Majoral.2 The techniques for characterizing dendrimers are very diversified, but they can be gathered under a limited number of types of method. The quantity of publications related to some techniques is extremely high in some cases, as, Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Dendrimers

Figure 2.1 Variation of the yield in a perfect dendrimer at each generation (not cumulated) depending on the percentage of conversion (from 90% to 99.999%) of each individual function and with only one synthetic step from a perfect dendrimer

for example, for characterizations by nuclear magnetic resonance (NMR). Only selected examples, generally the first ones published or the most representative, will be given for each technique. Of course, elemental analyses are usually performed with dendrimers, but due to their repetitive structure, this technique is uninformative to detect the presence of defects, especially for high generations.

2.2

Spectroscopy and Spectrometry

These techniques are mostly used to find access to the chemical composition of dendrimers, in some cases to their three-dimensional structure, and also to detect the presence of defects in the structure. 2.2.1

Nuclear Magnetic Resonance (NMR)

NMR is the most frequently used technique for characterizing dendrimers. All types of dendrimers are characterized by 1H NMR, frequently also by 13C NMR, and, depending on the chemical structure of the dendrimer to be studied, by 31P or 29Si NMR; 2H, 11B, 15N, 19 F, 119Sn, 195Pt are also used as the need arises. Routine NMR analyses are especially useful for characterizing the step-by-step growth of dendrimers, even up to high generations. Indeed, they afford information about the transformation undergone by the terminal groups. 1H and 13C NMR are the most used for organic dendrimers. For instance, these techniques are very powerful to follow the extent of amine alkylation by methyl acrylate in PAMAM (poly(amidoamine)) dendrimers,3 and also to detect and assign structural failures in the outermost PPI (poly(propyleneimine))

Methods of Characterization of Dendrimers

37

dendrimer generation. Indeed, in the 1H NMR spectra of NH2-terminated PPI dendrimers, the presence of a triplet at δ = 2.85 ppm, which corresponds to NCH2CH2CN, is characteristic for defects in the outermost generation. Incompletely cyanoethylated PPI dendrimers display additional signals in 13C NMR spectra; the products of retro-Michael addition can be detected also by 13C NMR.4 The completion of the condensation step in the synthesis of poly(phosphorhydrazone) (PPH) dendrimers is easily demonstrated by 1H NMR, with the disappearance of the aldehyde signal.5 In some cases, more complex pulse sequences, in particular two-dimensional experiments, are needed for a better assignment of signals. 1H,1H-COSY-45 (correlation spectroscopy at 45 °) and J-resolved experiments were used for the complete assignment of signals in the 1H NMR spectrum of a G3 poly(phenylacetylene) dendrimer.6 NOESY experiments (nuclear Overhauser effect/enhancement spectroscopy) connect resonances from spins that are spatially close. This technique was used to indicate that no PEG chains linked to the surface of PAMAM (polyamidoamine) dendrimers penetrated inside the dendrimeric structure.7 TOCSY NMR experiments (total correlation spectroscopy) were used to confirm that the coupling of chelates (salicylate, catecholate, or 3,2-hydroxypyridinonate) to the surface of PAMAM or PPI dendrimers was exhaustive8 and also to reveal the thiol–disulfide exchange on the surface of melamine dendrimers.9 The structure of polyamido dendrimers having 2,6-diaminopyridine units close to the core was fully assigned using several two-dimensional NMR techniques, including NOE difference, COSY, TOCSY, and EXSY (exchange spectroscopy) experiments. Co(II) was used as an external paramagnetic 1H NMR probe, binding to the 2,6-diaminopyridine units, which were specifically located.10 Heteronuclear correlations were also found useful for the full characterization of dendrimers. HSQC (heteronuclear single-quantum coherence) is most generally applied to 1 H–13C correlations. The assignment is generally completed using HMQC (heteronuclear multiple-quantum coherence), which is selective for direct C–H couplings, and HMBC (heteronuclear multiple-bond coherence), which affords longer range couplings (2–4 bonds coupling). These techniques, in particular three-dimensional experiments, were applied to probe the structure of PPI dendrimers, using HMQC–TOCSY11 or NOESY– HSQC.12 TOCSY, COSY, NOESY, HSQC, and HMBC techniques were also used for the full characterization of a series of carbosilane dendrimers.13 In addition to 1H and 13C NMR, heteroatom-containing dendrimers are generally characterized by the resonance of the heteroatom. This heteroresonance can afford very valuable information, especially in the case of phosphorus-containing dendrimers. Indeed, 31P NMR is so sensitive to subtle changes in the environment of the nucleus that it allows one to differentiate each layer up to the fourth generation,14 and at least the three most external layers for larger dendrimers up to the twelfth generation15 of PPH (polyphosphorhydrazone) dendrimers. Highly sophisticated phosphorus compounds, in which two types of branches coexist in the same dendrimeric structure, were also fully characterized by 31P NMR, as shown in Figure 2.2.16 Despite the very low amount of 29Si in silicon derivatives, silicon-containing dendrimers are generally characterized by 29Si NMR. For instance, this method was applied to polysiloxane dendrimers,17 to polycarbosilane (PCSi) dendrimers,18 to dendrimers with an N–Si–C framework,19 and to ferrocenyl dendrimers having carbosilane linkages at one layer.20 Two-dimensional 29Si–29Si INADEQUATE (incredible natural abundance

38

Dendrimers Me Ph CH N N C P 0 N P1 O H2 Ph N

(NP0)3 O

S

P′1 O

Me Me H H C N N P2 O C N N P3 O 22 2 S S Me Ph Me Ph H H C N N C P′2 N P′3 O C N N C P′1 N P′2 O H2 H2 Ph S Ph S

222

2 6

P″3

P2

P″2 P″1

P′3 P′2

55

50

45

PNP NP N

P″0

P′1

60

CHO

P′4

P3

65

Me Ph CH N N C P′3 N P′4 O H2 Ph S

P0 40

35

30

25

20

15

10

P1 5

0

–5

–10 –15 ppm

Figure 2.2 31P NMR spectrum of a phosphorus dendrimeric structure, possessing two types of branches

double-quantum transfer experiment) was used to confirm the structure of a first generation polysilane dendrimer.21 Three-dimensional 1H–13C–29Si triple resonance experiments were used to probe the structure of first and second generations of hydride-terminated carbosilane dendrimers.22 Tin-containing dendrimers were characterized by 119Sn NMR,23 as shown for a multiheteroatom-containing second generation dendrimer having tin at each branching point, but also for a dendrimer built from a carbosilane core, having tin at the first generation and germanium as terminal groups.24 15N NMR has been rarely used, but it helped in characterizing PPI dendrimers,25 in particular for detecting their selective protonation first on the surface of a second generation, then at the core, and then at the level of the first generation.26 The cis–trans isomerization of azobenzene groups used as branches of phosphorus-containing dendrimers was recently characterized by a gradient enhanced GHNMQC (gradient hydrogen–nitrogen multiple-quantum coherence) 1H–15N technique.27 Different types of dendrimers exist containing in their structure other types of nucleus detectable by NMR, not used as branching points but as substituents somewhere in the structure. Fluorine can be used instead of hydrogen as an additional marker, affording fluorinated dendrimers.28 For instance, perfluorinated polyphenylene dendrimers were characterized by 19F NMR.29 This technique was also used for characterizing fluorinated substituents linked to the surface of carbosilane dendrimers30 and PPH dendrimers.31 The signal corresponding to CF3 groups incorporated in the structure of chiral polyether dendrimers revealed constitutional heterotopicities caused by substituents that are separated from the fluorine nuclei by up to 15 bonds.32 PAMAM dendrimers covalently modified by heptafluoroacyl groups on the surface spontaneously self-assemble in nanoparticles of high fluorine spin density. They were used for noninvasive images obtained with 19F magnetic resonance imaging of the mouse systemic circulation.33 Other nuclei include 11B NMR,

Methods of Characterization of Dendrimers

39

which allowed characterizing boron clusters linked to C=C bonds in the branches of an all organic dendrimer,34 and also 195Pt NMR for phosphorus dendrimers complexing platinum by diphosphine chelate ligands35 and for carbosilane dendrimers complexing Pt by phosphine groups.36 Special NMR techniques related to relaxation times allowed the morphology or dynamics of dendrimers to be characterized in solution. The spin–lattice relaxation time (T1) of protons indicated, for instance, that azobenzene-containing dendrimers possess a nonconstrained interior and a stiff exterior shell,37 that the density in PBzE (polybenzyl ether) dendrimers radially increases from the core to the outer shell,38 and that polyaryl ether dendrimers have a compact interior and a more mobile exterior shell.39 The T1 values of terminal 13C of PAMAM dendrimers from generation 1 to 10 indicate a gradual increase in segment density and show that the terminal groups are not densely packed, even for the high generations.40 The same technique applied to PPI dendrimers having hydrophilic or hydrophobic long chains as terminal groups shows that the conformation depends on the solvent41 and that dendrimeric boxes also based on PPI dendrimers have a soft interior and a hard external shell.42 The spin–spin relaxation time (T2) was used together with T1 to measure the chain mobility in PAMAM dendrimers, which were labeled on the terminal groups by 2H.43 Pulse field-gradient spin echo (PGSE or PFGSE) 1H NMR may afford access to the size of dendrimers in solution. Indeed, this technique is useful for determining molecular diffusion coefficients because the results are independent of the concentration of the analyte (if it has no tendency to aggregate) and of the kinematic viscosity of the solution. The molecular diffusion coefficient is obtained using the Stejskal–Tanner equation, from which an estimation of the hydrodynamic radii can be obtained using the Stockes–Einstein equation, assuming a spherical shape for the dendrimers. This technique was in particular applied to aliphatic polyesters in chloroform,44 to PAMAM dendrimers ending with several hydrophobic chains in water,45 to PPI dendrimers in methanol,46 to carbosilane dendrimers in chloroform,47 to PPH dendrimers in water,48 and to peptide dendrimers.49 Pulse field 19F NMR spectroscopy was used to compare the free diffusion coefficient of partly fluorinated PAMAM dendrimers in water and in bicontinuous cubic phases composed of hydrated lipids.50 All these techniques are particularly useful for probing the structure of dendrimeric entities based on noncovalent interactions. For instance, PPI dendrimers functionalized by thiourea terminal groups can act as multivalent hosts for guest molecules containing an urea–glycine unit. The host guest interactions were investigated using NOESY NMR and T1, T2 relaxation measurements.51 The same techniques were used to investigate the encapsulation of Reichardt’s dye in poly(glycerol succinic acid) dendrimers.52 The metallodendrimeric assemblies of octaammonium core dendrimers with a catalytically active aryl palladium complex tethered by a sulfonate group were studied by various NMR techniques, including NOESY and ROESY methodologies and PGSE NMR diffusion measurements.53 The structure of PPI dendrimers having cationic ruthenium derivatives as terminal groups with PF6− as the counter ion was investigated by multidimensional and multinuclei NMR techniques, including diffusion NMR experiments, 19F,1H-HOESY (heteronuclear Overhauser effect spectroscopy) NMR experiments; these techniques show that the counterions are positioned mainly on the surface of these dendrimers.54 Besides experiments in solution, some dendrimers have been characterized by NMR in the solid phase. Magic angle spinning (MAS) NMR was used for studying shape-persistent

40

Dendrimers

poly(phenylene) dendrimers.55 Some examples of dendrimers, in which deuterium was used instead of hydrogen, were characterized by 2H NMR in the solid state. For instance, using DCl instead of HCl for the quaternarization of nitrogen branching points of PAMAM dendrimers up to generation 9 allowed the development of a self-consistent and complete picture of the dendrimeric structure, using deuteron quadrupole echo line shapes.56 The mobility of small stilbenoid dendrimers having liquid crystalline properties and selectively deuterated functions was studied by means of 2H solid-state NMR spectroscopy.57 Analogous experiments were carried out with liquid crystalline carbosilane dendrimers.58 Polybenzyl ether dendrons possessing a fluorine atom at the core and labeled by 13C at one selected generation were analyzed by 13C–{19F} rotational-echo double-resonance (REDOR) NMR experiments in the solid state. Inward folding of chain ends with increasing generation number was observed.59 A few examples also reported the solid-state NMR spectra of dendrimers included in solids, in particular in silica. The presence of phosphorus dendrons in mesoporous silica was ascertained by solid-state 31P HPDEC (high-power decoupling) NMR experiments.60 13 C CP MAS NMR spectroscopy was used to confirm the integrity of PPI dendrimers ended by ferrocenes after their incorporation into MCM-41 silica.61

2.2.2

Mass Spectrometry

Mass spectrometry techniques should afford information about the molecular mass and the presence of defects in the dendrimeric structures. Classical mass spectrometry techniques such as chemical ionization or fast atom bombardment (FAB) are usable only for small dendrimers, whose mass is generally <3000 D.62 Techniques developed for the characterization of high molecular weight compounds such as polymers and proteins should also be useful for characterizing dendrimers. Electrospray ionization (ESI) is usable for dendrimers that can form stable multicharged species. It has been applied to PPI dendrimers. In the sample analyzed, the fifth generation possesses a dendrimeric purity of approximately 20%, which corresponds to a polydispersity of approximately 1.002.63 This technique was also applied to PAMAM dendrimers up to the tenth generation, and was used to determine the polydispersity of these systems.64 The capability of this technique was extended using Fourier transform ion cyclotron resonance (FT-ICR MS) also applied to PAMAM dendrimers.65 However, the most widely used mass spectrometry technique to determine the purity of dendrimers is the MALDI-ToF technique (matrix-assisted laser desorption ionization time of flight), which is theoretically able to analyze unlimited masses. It was used to characterize many types of dendrimers, including aromatic polyesters,66 polybenzylacetylenes,67 PAMAM,68 PBzE,69 PCSi,70 and phosphorus-containing dendrimers.71 Polyphenylene dendrimers were characterized using ultrahigh-mass MALDIToF, equipped with a superconducting cryodetector, which extended the sensitivity into the MDa range.72 Imperfections were detected in many cases and were primarily attributed exclusively to chemical defects. However, the supposed mildness of the MALDI-ToF technique is questionable. The spectra obtained are highly dependent on the type of matrix used.73 For instance, it was shown for persulfonylated dendrimers that MALDI-MS gave false negative results due to reactions with acidic matrices, which were not observed when using the ESI technique.74 It was also shown for PPH dendrimers that the strong UV laser

1500

2000

2500

Intensity/units

1.0 S P O

Me C N N P O H S

3418.23 (M+H)+

3084.93 2752.13

2420.34

2087.12

1754.48

1422.33

Methods of Characterization of Dendrimers

Me C N NP O H S

41

(a)

MALDI-ToF UV 2,5-DHB matrix

3500 3000 Mass (m/z) M + Na CHO

22

3

4000

4500

5000 (b)

MALDI-ToF IR glycerol matrix

0.5

0.0 2000

3000 m/z

4000

Figure 2.3 MALDI-ToF spectra of a second generation PPH dendrimer, using either a UV laser (337 nm) or an IR laser for desorption on the same sample

light used for desorption was not only absorbed by the matrix but also by the dendrimer, inducing fragmentation and rearrangements.75 Figure 2.3 displays the dramatic difference obtained with a second generation PPH dendrimer analyzed by MALDI-ToF using (a) a UV laser and (b) an IR laser on the same sample of dendrimer. 2.2.3

X-ray Diffraction

This technique should allow precise determination of the chemical composition, size, and shape of dendrimers. However, even if most dendrimers are solids, they are generally obtained as amorphous powders, which lack long-range order in the condensed phase. Consequently, the structure of dendrimers is generally impossible to determine by X-ray diffraction, except for the first generation (as, for example, for polyester dendrimers76), or the second generation in the case of polysilane dendrimers.77 The structure of a second generation PCSi dendrimer was also obtained, but large thermal motions of the peripheral atoms were observed for this relatively large and flexible compound.78 The presence of aromatic groups should help in obtaining single crystals of dendrimers. Indeed, the structure of large compounds, but pertaining to the first generation, was obtained for polyphenylene dendrimers possessing 2479 or 3080 phenyls as terminal groups. Various types of first generation phosphorus-containing dendrimers were also characterized by X-ray diffraction, in particular the first generation of PPH dendrimers built from the trifunctional core P(S)Cl3,81 a related first generation dendron,82 and a series of very large first generation dendrimers having a 12-membered heteroalkyl chain as the core, and functionalized with methyl83 or allyl groups.84 The main types of dendrimers characterized by X-ray diffraction are gathered in Figure 2.4.

42

Dendrimers

Figure 2.4 crystals

2.2.4

Characteristic examples of dendrimers analyzed by X-ray diffraction on single

Infrared (IR) and Raman Spectroscopy

Infrared spectroscopy is mainly used for the routine analysis of the chemical transformations occurring at the surface of dendrimers. It can be performed in solution, but more frequently in the solid state. For instance, the disappearance of the nitrile groups in the reduction step of PPI dendrimers,85 the occurrence of hydrogen bonding in glycine functionalized PPI dendrimers,86 and the disappearance of the aldehyde groups in the condensation step during the synthesis of PPH dendrimers87 were in particular characterized and monitored by IR spectroscopy. Detailed IR analyses combined with DFT calculations were also done for these PPH dendrimers of various generations88 and built from various cores.89 An additive behavior was observed for increasing generations.90 Near-IR spectroscopy was used to characterize delocalized Π–Π stacking interactions between end groups of PAMAM modified with cationically substituted naphthalene diimides.91 Raman spectroscopy gave relevant information about the degree of cyclodehydrogenation of polyphenylene dendrimers92 and the characterization of PPI dendrimers.93 AntiStokes Raman spectroscopy was used to determine the Boltzmann temperatures of iron porphyrins bearing two polyarylether dendrons.94 In the case of PPH dendrimers, the FT–Raman (10–3500 cm−1) spectra of generations 0 to 10 were recorded and analyzed. Experimental Raman spectra of generations higher than four are similar. The lowfrequency Raman spectra were used to investigate the vibrations of terminal groups. From the different Raman spectra of dendrimers it could be deduced that for generations higher than six, steric congestion disturbed the conformations of terminal groups, information that could not be obtained before with any other technique.95 The Raman spectra

Methods of Characterization of Dendrimers

43

of PPH dendrimers built from an octa-substituted metal-free phthalocyanine core were also recorded. The different IR and Raman spectra of molecules built from the thiophosphoryl and phthalocyanine cores with the same repeating units and terminal groups were studied in order to underline the role of core functionality on the dendrimer architecture.96

2.2.5

Ultraviolet–Visible (UV–vis) Spectroscopy

UV–visible spectroscopy can be used to monitor the synthesis of dendrimers. Indeed, the increasing number of chromophoric groups when the generation number increases generally obeys to the Beer–Lambert law; thus the intensity of the absorption band is essentially proportional to the number of chromophoric units. It was used as a test for the purity of PPI dendrimers having azobenzene as terminal groups,97 for phosphorus dendrimers having azobenzenes within the branches,98 and in general for most dendrimers having azobenzenes in their structure.99 It was also recently used to confirm the existence of defects in large ferrocenyl dendrimers.100 However, deviations from the Beer–Lambert law were not always attributed to the presence of defects. The decrease observed for G4 and G5 PPI dendrimers having methylorange as end groups was attributed to the locally high concentration of methylorange units.101 On the contrary, the molar extinction of polyphenylene dendrons having a binaphthyl core increased over 5 times from generation 0 to generation 2 when the number of chromophore units was increased only 4 times.102 UV–vis has also been used to define morphological information. Attaching a solvatochromic probe at the core of polybenzylether dendrimers from G0 to G6 shows a dramatic change in the absorption maximum from G3 to G4, consistent with a transition from an open to a more globular shape.103 The hypochromicity observed for PBzE dendrimers having a zinc tetraporphyrin core and CO2− end groups in aqueous solution upon increasing the ionic strength or lowering the pH value was attributed to the shrinkage of the hydrophobic dendrimer framework.104 An octa-substituted metal-free phthalocyanine used as the core of phosphorus dendrimers was a sensor and a probe for analyzing the properties of the internal structure. UV–visible spectra show both a hyperchromic and bathochromic effect on the Q-bands of the phthalocyanine (Pc) with increasing generation, indicating that the chromophore is more isolated and that the dendrimeric shell mimics a highly polar solvent. This result is shown in Figure 2.5 in which the variation of the λmax value of the Q-band for generation 0 analyzed in various solvents was plotted against the polarity of the solvent (ET(30) Reichardt’s parameters105). Variation of the λmax value of the Q-band for generations 1, 3, and 4 in CHCl3 indicated that the branches of both Pc-G3 and Pc-G4 mimics the influence of a highly polar solvent such as DMF toward the core.106 UV–visible spectroscopy was also used to monitor the stepwise radial complexation in phenylazomethine dendrimers by Sn2+; four changes in the isosbestic point were observed during the titration of the G4 dendrimer, indicating that the complexation occurred not randomly but stepwise.107 UV–visible spectroscopy is also studied in all cases of fluorescent dendrimers. Indeed, fluorescence is induced by irradiation with a wavelength that can be absorbed by the compound to be studied (the particular case of multiphoton absorption will be evoked in Chapter 3).

44

Dendrimers O O N O O

O N NH N N HN N

O

H Me S C N N P O

H Me S C N N P O

CHO 2 2 2

8

Pc-G3

N O O

H Me S C N N PO

706 λmax nm 704

Pc-G3, Pc-G4 in CHCl3

702 Pc-G1 in CHCl3

700

D

M

F*

2

Py ri Ph din N e O

l3 C H C

D

696

TH F

io xa ne

698

694 35

36

37

38

39

40

41

42

43

44

Figure 2.5 Structure of the third generation of a phthalocyanine dendrimer (Pc-G3). Bold straight line: variation of the λmax value of the Q-band of Pc-G0 in various solvents versus their ET(30) Reichardt’s parameter. DMF*: Pc-G0 has a single Q-band; the corresponding data are not plotted. Dotted horizontal lines: λmax of the Q-band of Pc-G1, Pc-G3, and Pc-G4 in CHCl3. Dotted vertical lines: estimation of the polarity induced by the branches, deduced from the intercept with the bold line

2.2.6

Fluorescence

Chapter 3 is dedicated to fluorescent dendrimers, so we will presently focus on the use of fluorescence for characterizing dendrimers. The high sensitivity of fluorescence has been used to quantify defects during the synthesis of dendrimers, such as unreacted CO2H groups in arborol dendrimers,108 but its main use is to characterize the structure of dendrimers having photochemical probes covalently linked to one particular section. Pyrene moieties selectively attached to the surface of PPI dendrimers showed that the pyrene increasingly aggregates with increasing generation, indicating a closer proximity.109 Changes in the fluorescence spectra of a fluorescent unit attached to the core of dendrimers or dendrons, resulting from changes in size and shape, were observed after a certain generation for PBzE104 or polyphenyl110 dendrimers. A progressive isolation of the fluorescent core of PBzE111 or arborol112 dendrimers was also detected. The large free space available inside dendrimers was shown by the formation of excimers for pyrene linked to the internal branches of PPH dendrimers.113 Internal quenching experiments in dendrimers bearing chromophores at various layers of their structure were also studied. Polyamide dendrimers built from a porphyrin core and terminated by anthraquinone groups displayed a substantial quenching of porphyrin fluorescence, but the quenching decreased as the generation increased from G1 to G3.114 On the contrary, the fluorescence of a maleimide group linked off-center to the core of a series of phosphorhydrazone dendrimers was progressively quenched as the generation increased, indicating a detrimental effect of the branches towards this particular fluorophore.115 Visualizing single molecules by optical microscopy was successfully carried out for dendrimers having a fluorescent core using confocal microscopy. The fluorescence of a

Methods of Characterization of Dendrimers

45

single molecule of third generation PBzE dendrimer built from a dihydropyrrolopyrroledione core116 and of a polyphenylene dendrimer having peryleneimide as end groups117 was observed by this technique. An atomic force microscope having a probe with an aperture to localize the molecule and to carry out optical measurements through the aperture (nearfield scanning optical microscopy, NSOM) was used to observe metallodendrimers built from rhodamine B as the focal point.118 2.2.7

Chirality, Optical Rotation, and Circular Dichroism (CD)

The combination of chirality and dendrimers is described in several specialized reviews,119–122 but we will describe here only the structural information obtained by optical rotation and circular dichroism. Various chiral amino acids linked to the surface of PPI dendrimers induce a dramatic decrease of optical rotation on going from G1 to G5, which is accompanied by small changes in the UV–vis spectra. The rigidity of the external shell for high generations induced by multiple hydrogen bonding of the amide and carbamate groups, which leads to a number of frozen conformations, is presumably responsible for the vanishing of the optical activity.123 However, rigid para cyclophanes on the surface of PPI dendrimers have a nearly constant optical activity with increasing generations124 whereas chiral benzylamine125 or chiral ferrocenes126 linked to the surface of PPH dendrimers simply give additive optical rotation values, demonstrating the absence of interaction between the terminal groups. It was observed that the optical rotation of a single chiral group such as aminophenylpropanediol127 or binaphthyl128 located at the core of PBzE dendrimers decreases with increasing generations. This effect was ascribed to the steric effect upon the conformational equilibrium of the central core, which increased with increasing dendrimer generation. On the contrary, the molar rotation of a series of fully chiral polyether dendrimers up to G4 is approximately proportional to the number of chiral units.129 For phosphorhydrazone dendrimers having one layer of chiral ferrocenes located inside the structure, the chiroptical properties are not sensitive to the location of the chiral units inside the dendrimers, up to G11.130 Circular dichroism (CD) is able to afford information about the geometrical structure of chiral dendrimers. For instance, the variation of the dihedral angle θ of the binaphthyl derivatives at the core of PBzE dendrons was measured and found to depend on the steric hindrance induced by the dendrimeric branches.131 For fully chiral dendrimers (throughout the structure), the chiroptical properties of two series of chiral polyaryl ether dendrimers from generation 0 to 3 (up to 45 stereogenic centers)132 and of dendrimers based on dihydroxypyrrolidine133 showed that the CD spectra changed dramatically, indicating conformational substructures in the branches. On the other hand, the CD spectra of a series of fully chiral dendrimers of phenylalanine type up to G2 showed little steric interaction, but molar rotation divided by the number of stereogenic centres decreased with increasing size of the dendrimeric structure.134 2.2.8

Electron Paramagnetic Resonance (EPR)

EPR or ESR (electron spin resonance) is used for studying compounds having one or more unpaired electrons. Besides metallic radicals, which are mainly characterized by electrochemistry (see Section 2.2.9), the most widely used radicals are various nitroxides. EPR

46

Dendrimers

was used for the quantitative determination of the substitution efficiency on the surface of PAMAM dendrimers by nitronyl nitroxide radicals135 or was able to detect interactions between the nitroxyl end groups of large PPI dendrimers.136 In the latter case, it was shown that the relaxativity increased as a function of dendrimer generation.137 In addition, paramagnetic probes can be used for investigating the structure of dendrimers. For instance, positively charged nitroxide radicals were used for probing hydrophilic and hydrophobic binding sites of PAMAM dendrimers terminated by carboxylate groups138 and the complexation ablility of Cu(II) by a series of PPI dendrimers ended by maltose or maltotriose groups was assessed by EPR.139 2.2.9

Electrochemistry

When redox entities are linked somewhere in the structure of a dendrimer, electrochemistry may afford mainly three types of information. Exhaustive coulometry was used to measure the number of electroactive groups. It was mainly applied in the case of ferrocenes (or more generally metallocenes), linked to the surface of PPI,140 poly(aryl ether),141,142 eventually having lengthened tethers,143 or PPH dendrimers,144 and also for naphthalene groups linked to PAMAM dendrimers.145 Most dendrimers having redox entities in their structure (including at all generations146) were analyzed by cyclic voltametry, but this technique is particularly interesting for studying the degree of burying of electroactive groups inside dendrimers.147 A progressive decrease of the electron-transfer rate constant was observed in most cases for electroactive groups located at the core of dendrons,148 PPH dendrimers,149 or large PBzE dendrimers,150 but not for smaller PBzE dendrimers.151 Electrochemistry gave information about the possibility of interaction152 (or not, most generally) of electroactive end groups between them, traducing a close proximity. Electrochemistry was also useful for detecting molecular recognition, most generally using metallocene terminal groups,153 but also TTF derivatives.154,155 2.2.10

Magnetometry

When “magnetic atoms” are included in the structure of dendrimers, they may help in characterizing them. This was done in particular for melamine dendrimers capped with either Fe(III) or Cr(III) salen/salophen complexes,156 and also for PPH dendrimers capped with gadolinium(III).157 The magnetic properties of dendrimeric polyalkyl aromatic polyradicals were also analyzed, showing that the samples consisted of complex mixtures of polyradicals, and not precisely defined compounds.158 One of the most sensitive types of magnetometry is SQUID (single/superconducting quantum interface device) magnetometry, which was also used for studying polyradicals generated throughout the structure of dendrimeric polyaryl methane; it was found that the spin values are lower than expected, presumably due to defects that disrupt the ferromagnetic couplings.159 2.2.11

Mössbauer Spectroscopy

Mössbauer spectroscopy is based on the recoil-free resonant absorption of γ -quanta by nuclei of the same kind as the emitters. At room temperature, only the 14.4 keV transition

Methods of Characterization of Dendrimers

47

of 57Fe and the 23.87 keV of 119Sn have sufficient Mössbauer probability. In the case of dendrimers, this technique was used for some iron-containing dendrimeric molecules, in particular for ferrocenium terminated dendrimers,160 for iron triflate or tosylate complexed by benzyl ether dendrons having either triazole161 or carboxylic acid162 as the core, and for detecting the encapsulation of ferrocenuim hexafluorophosphate in polyphenyl azomethine dendrimers.163 In all cases, the 57Fe Mössbauer spectra afforded information about the local environment within the system. 2.2.12

X-ray Spectroscopies

X-ray fluorescence (totally different from classical fluorescence) may be observed when an X-ray with sufficient energy strikes a sample, ejecting the inner electrons. The excited atoms can emit characteristic radiation during the de-excitation process, affording information about the elemental composition of the sample. This technique was in particular applied for determining the ratio of cobaltocenium to ferrocene units in PPI dendrimers having both types of units as terminal groups.164 X-ray photoelectron spectroscopy (XPS) was used for determining the chemical composition of dendrimers such as poly(aryl ether) dendrons165,166 or PPH dendrimers,167 even if this technique is most generally used for the characterization of layers.

2.3

Scattering Techniques

Scattering techniques are based on deflection of a beam of an electromagnetic wave or particles away from the straight trajectory after its interaction with the structure to be analyzed. They give information about the size and shape of structures. 2.3.1

Laser Light Scattering (LLS)

In most cases, the laser light scattering technique is used as a detector coupled to a size exclusion chromatography apparatus (see Section 2.6.1) to determine the hydrodynamic radius of dendrimers. However, in some cases, it has also been used for the direct analysis of samples of dendrimers in solution; for instance, the molecular weight (MW) of PPI dendrimers was evaluated with small-angle LLS.168 Dynamic LLS was used to measure the expected increase in the hydrodynamic radius with increasing generation numbers of a series of maltose-modified PPI dendrimers; no aggregate was found.169 Dynamic LLS was applied to detect aggregates of PBzE dendrimers having a phthalocyanine core170 and to vesicles formed by the self-assembly of some water-soluble PPH dendrimers.171 2.3.2

Small-Angle Neutron Scattering (SANS)

The SANS technique also gives access to the radius of gyration and may reveal more accurate information than LLS or SAXS (see Section 2.3.3) about the internal structure of the entire dendrimer. The SANS technique may indicate the molecular weight of

48

Dendrimers

dendrimers; such experiments were conducted with PPI,172 PBzE,173 and PAMAM dendrimers.174 In the latter case, the conformational changes induced by pH variations and the change in the radius of gyration were determined with SANS.175 The location of the end groups was also determined by SANS experiments conducted with PAMAM dendrimers and PPI dendrimers having labeled (deuterated) or unlabeled terminal groups; in the former case, the end groups are concentrated near the periphery,176 whereas in the latter cases the end groups are located throughout the structure.177 The SANS technique was applied to study the counterion effects on the molecular conformation and structure of PAMAM dendrimers ended by ammonium groups in water.178 In the case of neutral PAMAM dendrimers (G4 to G6), the SANS experiments allowed the intramolecular space to be quantified by evaluating the number of guest water molecules. The overall available internal cavity was seen to increase as a function of increasing dendrimer generation, but the fraction of water accessible volume was found invariant for the three generations studied.179 Neutron spin-echo (NSE) is viewed as an extension of the SANS technique, which provides an extremely high resolution in the analysis of small energy changes on scattering. It was applied to G5 PAMAM dendrimers with different terminal groups and it was found that the dynamics of PAMAM dendrimers in solutions depends on the concentration but not on the type of end groups.180 2.3.3 Small-Angle X-ray Scattering (SAXS) and Wide-Angle X-ray Scattering (WAXS) The SAXS technique is often used for the characterization of polymers, including hyperbranched polymers;181 applied to dendrimers it gives information about their average radius of gyration (Rg) in solution. The intensity of the scattering as a function of angle also provides information on the arrangement of polymer segments, and hence on the segment density distribution within the molecule. This technique was applied to fluorinated carbosilane dendrimers30 and PAMAM dendrimers182 to afford their Rg values. The angular dependence of the scattered intensity indicated a relatively diffuse, open boundary for G3 PAMAM and a very sharp outer boundary for G10, with a gradual transition from star-like (G3) to sphere-like (G10) entities.183 In the case of PAMAM G3 terminated by carboxylate groups in solution in water, the SAXS spectra indicated the presence of a long-range structural order in the system due to interparticle interaction in solution.184 Combinations of time-resolved SAXS and SANS experiments allowed the study of the chemical reactions and self-assembly processes that occurred during the reduction of palladium ions in the template provided by the self-assembly of PAMAM dendrimers.185 The difference between the WAXS and SAXS techniques concerns the value of the scattering angle 2θ: close to 0 ° for SAXS and larger than 5 ° for WAXS. The WAXS technique was relatively rarely applied to the characterization of dendrimers. However, it was applied to carbosilane dendrimers ended by perfluoroalkyl groups, which form thermotropic phases; the WAXS technique evidenced that the mesophase structure was layered.186

2.4

Microscopy

Three types of microscopy techniques, very different in principle, have been used for imaging dendrimers. In transmission microscopy, electrons or light produce images that

Methods of Characterization of Dendrimers

49

Figure 2.6 Evolution of the diameter of PAMAM and PPH dendrimers depending on the generation measured by TEM

amplify the original, with a resolution ultimately limited by the wavelength of the source. In scanning microscopy such as atomic force microscopy (AFM), the images are produced by “touch contact” at a few angstroms of a sensitive cantilever arm with the sample. In polarized optical microscopy, it is not directly molecules of dendrimers that are detected, but their arrangement when they possess liquid crystalline properties. 2.4.1 Transmission Electron Microscopy (TEM) Transmission electron microscopy (TEM) allowed images of individual dendrimer molecules from G3 to G10 to be observed for PPH dendrimers having gold covalently attached to each terminal group.187 A strict linear correlation was observed between the size and the logarithm of the molecular weight, as well as for PAMAM molecules also seen by TEM from G5 to G10188 (Figure 2.6). TEM images of the G4 azomethine dendrimers were also obtained.189 2.4.2 Atomic Force Microscopy (AFM) Atomic force microscopy (AFM) was often used for the characterization of dendrimeric macromolecular films. In the case of a wavy surface, individual dendrimers can be detected,190 but we will focus on the visualization of isolated molecules. The spin coating technique applied to generations 5 to 10 of PAMAM dendrimers allowed the visualization of isolated dendrimer molecules by AFM. For all generations, the measured diameters were always larger than the heights, showing that when deposited on a surface the dendrimers are not spherical.191 A high generation PAMAM (G9) was also imaged at the liquid/ solid (water/mica or graphite) interface using tapping mode AFM.192 Large dendrimeric structures bearing lengthening ferrocenyl tethers were also imaged by AFM; the height of dendrimers in each generation was quite uniform and the width of each AFM spot was relatively regular, indicating that agglomeration rather than individual dendrimers were observed.100

50

2.4.3

Dendrimers

Polarizing Optical Microscopy (POM)

Contrary to TEM and AFM, polarizing optical microscopy (POM) is not used for characterizing single dendrimers, but for characterizing the self-assembly of liquid crystalline dendrimers or dendrons. As Chapter 5 is dedicated to liquid crystalline dendrimeric compounds, only a few selected examples are given here. Hexagonal columnar mesophases of PPI dendrimers ended by discotic triphenylene moieties,193 right-handed helixes from fullero dendrons,194 or Janus-type fullero dendrons195 were characterized by POM. Lamellar mesomorphism and columnar mesomorphism were observed with ionic thermotropic liquid crystal dendrimers based on PAMAM and PPI dendrimers.196

2.5 2.5.1

Rheology and Physical Characterizations Intrinsic Viscosity

Rheology, and particularly dilute solution viscosimetry studies, can be used as an analytical probe of the morphological structure of dendrimers. Dendrimers should exhibit a maximum in the dependence of the intrinsic viscosity [η] on generation because the volume grows faster with generation than the molecular weight for the first generations, whereas the opposite occurs after a certain generation. This behavior was experimentally observed for several series of dendrimers. The maxima of the intrinsic viscosity occurs at different generations: generations 2 or 3 for PbzE dendrimers, depending on the density of branches,197,198 generation 3 for phosphorus dendrimers with two types of end groups (free phosphines or phosphines complexing BH3),199 generation 4 for PAMAM dendrimers,200 and generation 5 for PPI201 with two types of end groups (amine or cyano) (Figure 2.7). Very recently, a model for the anomalous intrinsic viscosity behavior of dendrimer was proposed; it is a two-zone model based on the radial segmental density profile. The maximum of [η] versus generations corresponds to the maximum capacity of dendrimers to drag solvent molecules.202 The only exception to this behavior comes from polylysine dendrimers, which showed constant intrinsic viscosity over nine generations;203 this might be due to the geometrical asymmetry of the branches, enabling very close segmental packing.204 2.5.2

Differential Scanning Calorimetry (DSC)

The DSC technique is generally used to detect the glass transition temperature (Tg), which depends on the molecular weight, entanglement, and chain-end composition of polymers. In the case of dendrimers, Tg is affected by the terminal group substitutions and by the molecular mass as shown for PBzE dendrimers205 and dendrons.206 Tg correlates with ne/M (ne is the number of chain ends).207 The same behavior was observed for phosphorus dendrimers,199 and to a lesser extent for PPI dendrimers,208 whereas the generation has practically no influence on the Tg values of liquid crystal dendrimers based on poly(phenyl acetylene)209 or carbosilazane dendrimers.210 DSC and temperature modulated calorimetry (TMC) were also used to detect physical aging of PPH dendrimers.211 DSC is also fre-

Methods of Characterization of Dendrimers

51

Figure 2.7 Variation of intrinsic viscosity with generation for various types of dendrimers (and corresponding references)

quently used not only for characterizing the self-assembly of dendrons (for instance dendrimeric peptides212) but also of many liquid crystalline dendrimers and dendrons, in association with OPM (see Section 2.4.3). 2.5.3

Dielectric Spectroscopy (DS)

Dielectric spectroscopy gives information about molecular dynamic processes in polymers (α-, β-, γ-, and δ-relaxation). This technique was applied to various types of dendrimers, and it was generally found that the α-relaxation values obtained by DS agree well with those obtained in differential scanning calorimetry measurements. Carbosilane,213 arborols,214 poly(etheramide),215 PPH,216,217 carbosilazane,218 polyphenylene,219 and PAMAM220 dendrimers were analyzed by DS; in most cases, both α- and β-relaxations were obtained and identified. 2.5.4

Dipole Moments

In connection with the dielectric properties, dipole moment values of some dendrimers were calculated, in particular from measurements of capacitance and refractive index. It may seem that fully symmetrical entities such as dendrimers should have 0 as the dipole moment value. However, application of an electric field results in significant distortion of the molecules because the polar units of the structure may align in the direction of the field. The first measurements were made with polyarylether dendrimers obtained by grafting two polyarylether dendrons to a core. This method allowed either fully symmetrical

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Figure 2.8 Variation of dipole moment values (μ) for PPH dendrimers with the generation (left) and dipole moment ratio versus generation Dr = μ2/N(μ0)2 with N = number of momomer units and μ0 = 3.03 D (right)

dendrimers or Janus dendrimers to be obtained. The dipole moment values varied from 2.66 to 12.1 D for the fully symmetrical series while going from G1-G1 to G5-G5, and from 4.54 to 17.6 D for the Janus series while going from G0-G1 to G4-G5.221 In the case of phosphorhydrazone dendrimers (PPH) terminated by P(S)Cl2 or CHO functions, it was shown that the dipole moment values increased exponentially from 8.43 D for G1 up to 328 D for G11. Moreover, plotting the dipole moment ratio Dr = μ2/N(μ0)2 (where μ is the dipole moment of the dendrimer, N is the number of polar monomeric units, and μ0 is the dipole moment of the monomeric units) versus the molecular weight gives a constant (Dr = 2.3) (Figure 2.8).15 Another example of dipole moment measurements concerned monolayers of azobenzene dendrons, which were compared with the values obtained from semi-empirical molecular orbital calculations.222

2.6 2.6.1

Separation Techniques Size Exclusion Chromatography

Size exclusion chromatography (SEC), also called gel permeation chromatography (GPC), allows the separation of molecules depending on their size. It can be used for analytical purposes as well as for purification on a preparative scale. For analyses, a detector such as a differential refractive index or an LLS detector (see Section 2.3.1) is connected to the SEC apparatus for the determination of the polydispersity, which must be very close to unity for pure dendrimers. Most types of dendrimers were characterized by SEC, even self-assembled dendrimers.223 The calibration generally uses linear polymers but, due to the very different morphology, an increasing deviation was observed between the experimental mass values obtained by SEC and the theoretical mass values of dendrimers when the generation number (the molecular weight) increased, as shown for PBzE62 (Figure 2.9, left) or various phosphorus-containing dendrimeric structures82 (Figure 2.9, right); thus

Methods of Characterization of Dendrimers

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Figure 2.9 Variation of the retention volume (left) or retention time (right) with molecular weight for PBzE dendrimers (left) and phosphorhydrazone dendritic structures (right) compared to polystyrene standards

well-characterized PAMAM dendrimers were used as standards for polyether dendrimers.224 SEC was also used to monitor size changes of arborol dendrimers with pH variance.225 Besides SEC, HPLC analyses were carried out with PPI dendrimers.226 2.6.2

Electrophoresis

Gel electrophoresis is widely used in biology for the routine analysis and separation of biopolymers such as proteins and nucleic acids. This technique was used for the assessment of purity and homogeneity of several types of water-soluble and charged dendrimers such as PAMAM dendrimers having NH3+ or CO2− terminal groups,227 PPI dendrimers,228 or nucleic acid dendrimers.229 Capillary electrophoresis was used not only for determining the purity of phenylacetylene dendrimers230 and of triazine dendrimers231 but also for the separation of PAMAM dendrimer generations232 and for analyzing the molecular heterogeneity of multifunctional PAMAM dendrimers.233 However, gel electrophoresis is mainly used for studying the interaction between positively charged dendrimers and DNA, in view of transfection experiments (see Chapter 18). It was found that formation of the complex depends both on the generation (size), the charge ratio for PAMAM dendrimers234 and poly(ethyleneglycol)-block-poly(L-lysine) dendrimers,235 but also of the type of terminal ammonium groups of phosphorus dendrimers.236 However, it was recently shown that the effectiveness of the DNA binding given by this technique is not directly related to the transfection efficiency.237

2.7

Conclusion

We have shown in this chapter the most widely used methods for characterizing dendrimers, together with more peculiar methods usable only for some types of dendrimeric

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structures. Most of these methods are issued from methods well known for the characterization of small molecules, in particular all the spectroscopic and spectrometric techniques. On the other hand, most scattering techniques, microscopy methods, and rheological methods are issued from the work on macromolecules such as polymers of proteins. Despite the large number of techniques and methods shown in this chapter, they are not fully exhaustive. One may find some more particular techniques, such as, for example, velocity sedimentation.238,239 It must be also emphasized that most of these techniques are not only used for characterizing dendrimers but also for characterizing their interactions with their environment, for example for creation of networks, for the encapsulation of guests, or for the interaction with biological entities (in particular DNA), as will be shown in most of the forthcoming chapters.

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(189) M. Higuchi, S. Shiki, K. Ariga, and K. Yamamoto (2001) First synthesis of phenylazomethine dendrimer ligands and structural studies. J. Am. Chem. Soc., 123, 4414–4420. (190) B. Miksa, S. Slomkowski, M. M. Chehimi, M. Delamar, J. P. Majoral, and A. M. Caminade (1999) Tailored modification of quartz surfaces by covalent immobilization of small molecules (gamma-aminopropyltriethoxysilane), monodisperse macromolecules (dendrimers), and poly(styrene/acrolein/divinylbenzene) microspheres with narrow diameter distribution. Colloid Polym. Sci., 277, 58–65. (191) J. Li, L. T. Piehler, D. Qin, J. R. Baker, D. A. Tomalia, and D. J. Meier (2000) Visualization and characterization of poly(amidoamine) dendrimers by atomic force microscopy. Langmuir, 16, 5613–5616. (192) T. Muller, D. G. Yablon, R. Karchner, D. Knapp, M. H. Kleinman, H. B. Fang, C. J. Durning, D. A. Tomalia, N. J. Turro, and G. W. Flynn (2002) AFM studies of high-generation PAMAM dendrimers at the liquid/solid interface. Langmuir, 18, 7452–7455. (193) M. D. McKenna, J. Barbera, M. Marcos, and J. L. Serrano (2005) Discotic liquid crystalline poly(propylene imine) dendrimers based on triphenylene. J. Am. Chem. Soc., 127, 619–625. (194) S. Campidelli, P. Bourgun, B. Guintchin, J. Furrer, H. Stoeckli-Evans, I. M. Baez, J. W. Goodby, and R. Deschenaux (2010) Diastereoisomerically pure fulleropyrrolidines as chiral platforms for the design of optically active liquid crystals. J. Am. Chem. Soc., 132, 3574–3581. (195) J. Lenoble, S. Campidelli, N. Maringa, B. Donnio, D. Guillon, N. Yevlampieva, and R. Deschenaux (2007) Liquid-crystalline janus-type fullerodendrimers displaying tunable smectic-columnar mesomorphism. J. Am. Chem. Soc., 129, 9941–9952. (196) R. Martin-Rapun, M. Marcos, A. Omenat, J. Barbera, P. Romero, and J. L. Serrano (2005) Ionic thermotropic liquid crystal dendrimers. J. Am. Chem. Soc., 127, 7397–7403. (197) T. H. Mourey, S. R. Turner, M. Rubinstein, J. M. J. Fréchet, C. J. Hawker, and K. L. Wooley (1992) Unique behavior of dendritic macromolecules – intrinsic-viscosity of polyether dendrimers. Macromolecules, 25, 2401–2406. (198) M. S. Matos, J. Hofkens, W. Verheijen, F. C. De Schryver, S. Hecht, K. W. Pollak, J. M. J. Fréchet, B. Forier, and W. Dehaen (2000) Effect of core structure on photophysical and hydrodynamic properties of porphyrin dendrimers. Macromolecules, 33, 2967–2973. (199) S. Merino, L. Brauge, A. M. Caminade, J. P. Majoral, D. Taton, and Y. Gnanou (2001) Synthesis and characterization of linear, hyperbranched, and dendrimer-like polymers constituted of the same repeating unit. Chem.-Eur. J., 7, 3095–3105. (200) P. R. Dvornic and S. Uppuluri (2001) Rheology and solution properties of dendrimers, in Dendrimers and Other Dendritic Polymers (eds J. M. J. Fréchet and D. A. Tomalia), John Wiley & Sons, Ltd, Chichester, chap. 14, pp. 331–358. (201) R. Scherrenberg, B. Coussens, P. van Vliet, G. Edouard, J. Brackman, E. de Brabander, and K. Mortensen (1998) The molecular characteristics of poly(propyleneimine) dendrimers as studied with small-angle neutron scattering, viscosimetry, and molecular dynamics. Macromolecules, 31, 456–461. (202) Y. Lu, T. Shi, L. An, L. Jin, and Z. G. Wang (2010) A simple model for the anomalous intrinsic viscosity of dendrimers. Soft Matter, 6, 2619–2622. (203) S. M. Aharoni, C. R. Crosby, and E. K. Walsh (1982) Size and solution properties of globular tert-butyloxycarbonyl-poly(α,ε-L-lysine). Macromolecules, 15, 1093–1098. (204) D. A. Tomalia, M. Hall, and D. M. Hedstrand (1987) Starburst dendrimers. 3. The importance of branch junction symmetry in the development of topological shell molecules. J. Am. Chem. Soc., 109, 1601–1603. (205) P. J. Farrington, C. J. Hawker, J. M. J. Fréchet, and M. E. Mackay (1998) The melt viscosity of dendritic poly(benzyl ether) macromolecules. Macromolecules, 31, 5043–5050. (206) W. D. Jang, D. L. Jiang, and T. Aida (2000) Dendritic physical gel: hierarchical selforganization of a peptide-core dendrimer to form a micrometer-scale fibrous assembly. J. Am. Chem. Soc., 122, 3232–3233. (207) K. L. Wooley, C. J. Hawker, J. M. Pochan, and J. M. J. Fréchet (1993) Physical properties of dendritic macromolecules – a study of glass-transition temperature. Macromolecules, 26, 1514–1519.

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(208) B. M. Tande, N. J. Wagner, and Y. H. Kim (2003) Influence of end groups on dendrimer rheology and conformation. Macromolecules, 36, 4619–4623. (209) D. J. Pesak and J. S. Moore (1997) Columnar liquid crystals from shape-persistent dendritic molecules. Angew. Chem. Int. Ed., 36, 1636–1639. (210) R. Elsasser, G. H. Mehl, J. W. Goodby, and M. Veith (2001) Nematic dendrimers based on carbosilazane cores. Angew. Chem. Int. Ed., 40, 2688–2690. (211) E. Dantras, J. Dandurand, C. Lacabanne, A. M. Caminade, and J. P. Majoral (2002) Enthalpy relaxation in phosphorus-containing dendrimers. Macromolecules, 35, 2090–2094. (212) M. Peterca, V. Percec, A. E. Dulcey, S. Nummelin, S. Korey, M. Ilies, and P. A. Heiney (2006) Self-assembly, structural, and retrostructural analysis of dendritic dipeptide pores undergoing reversible circular to elliptical shape change. J. Am. Chem. Soc., 128, 6713–6720. (213) B. Trahasch, B. Stuhn, H. Frey, and K. Lorenz (1999) Dielectric relaxation in carbosilane dendrimers with perfluorinated end groups. Macromolecules, 32, 1962–1966. (214) S. K. Emran, G. R. Newkome, C. D. Weis, and J. P. Harmon (1999) Molecular relaxations in ester-terminated, amide-based dendrimers. J. Polym. Sci. Part B – Polymer Physics, 37, 2025–2038. (215) K. Huwe, D. Appelhans, J. Prigann, B. I. Voit, and F. Kremer (2000) Broadband dielectric spectroscopy on the molecular dynamics in dendritic model systems. Macromolecules, 33, 3762–3766. (216) E. Dantras, C. Lacabanne, A. M. Caminade, and J. P. Majoral (2001) TSC and broadband dielectric spectroscopy studies of beta relaxation in phosphorus-containing dendrimers. Macromolecules, 34, 3808–3811. (217) E. Dantras, J. Dandurand, C. Lacabanne, A. M. Caminade, and J. P. Majoral (2004) TSC and broadband dielectric spectroscopy studies of the alpha relaxation in phosphorus-containing dendrimers. Macromolecules, 37, 2812–2816. (218) L. Tajber, A. Kocot, J. K. Vij, K. Merkel, J. Zalewska-Rejdak, G. H. Mehl, R. Elsässer, J. W. Goodby, and M. Veith (2002) Orientational order and dynamics of nematic multipodes based on carbosilazane cores using optical and dielectric spectroscopy. Macromolecules, 35, 8601–8608. (219) M. Mondeshki, G. Mihov, R. Graf, H. W. Spiess, K. Mullen, P. Papadopoulos, A. Gitsas, and G. Floudas (2006) Self-assembly and molecular dynamics of peptide-functionalized polyphenylene dendrimers. Macromolecules, 39, 9605–9613. (220) J. Mijovic, S. Ristic, and J. Kenny (2007) Dynamics of six generations of PAMAM dendrimers as studied by dielectric relaxation spectroscopy. Macromolecules, 40, 5212–5221. (221) K. L. Wooley, C. J. Hawker, and J. M. J. Fréchet (1993) Unsymmetrical 3-dimensional macromolecules. Preparation and characterization of strongly dipolar dendritic macromolecules. J. Am. Chem. Soc., 115, 11496–11505. (222) T. Manaka, D. Shimura, and M. Iwamoto (2002) Determination of dipole moment of azobenzene dendrimer by Maxwell-displacement-current measurement for Langmuir monolayer. Chem. Phys. Lett., 355, 164–168. (223) F. W. Zeng, S. C. Zimmerman, S. V. Kolotuchin, D. E. C. Reichert, and Y. G. Ma (2002) Supramolecular polymer chemistry: design, synthesis, characterization, and kinetics, thermodynamics, and fidelity of formation of self-assembled dendrimers. Tetrahedron, 58, 825–843. (224) A. B. Padias, H. K. Hall, D. A. Tomalia, and J. R. Mcconnell (1987) Starburst polyether dendrimers. J. Org. Chem., 52, 5305–5312. (225) G. R. Newkome, J. K. Young, G. R. Baker, R. L. Potter, L. Audoly, D. Cooper, C. D. Weis, K. Morris, and C. S. Johnson (1993) Cascade polymers – pH-dependence of hydrodynamic radii of acid terminated dendrimers. Macromolecules, 26, 2394–2396. (226) S. van der Wal, Y. Mengerink, J. C. Brackman, E. M. M. de Brabander, C. M. JeronimusStratingh, and A. P. Bruins (1998) Compositional analysis of nitrile terminated poly(propylene imine) dendrimers by high-performance liquid chromatography combined with electrospray mass spectrometry. J. Chromatography A, 825, 135–147. (227) H. M. Brothers, L. T. Piehler, and D. A. Tomalia (1998) Slab-gel and capillary electrophoretic characterization of polyamidoamine dendrimers. J. Chromatography A, 814, 233–246.

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(228) C. F. Welch and D. A. Hoagland (2003) The electrophoretic mobility of PPI dendrimers: Do charged dendrimers behave as linear polyelectrolytes or charged spheres? Langmuir, 19, 1082–1088. (229) R. H. E. Hudson and M. J. Damha (1993) Nucleic-acid dendrimers – novel biopolymer structures. J. Am. Chem. Soc., 115, 2119–2124. (230) D. J. Pesak, J. S. Moore, and T. E. Wheat (1997) Synthesis and characterization of watersoluble dendritic macromolecules with a stiff, hydrocarbon interior. Macromolecules, 30, 6467–6482. (231) S. Lalwani, V. J. Venditto, A. Chouai, G. E. Rivera, S. Shaunak, and E. E. Simanek (2009) Electrophoretic behavior of anionic triazine and PAMAM dendrimers: methods for improving resolution and assessing purity using capillary electrophoresis. Macromolecules, 42, 3152–3161. (232) P. Sedlakova, J. Svobodova, I. Miksik, and H. Tomas (2006) Separation of poly(amidoamine) (PAMAM) dendrimer generations by dynamic coating capillary electrophoresis. J. Chromatography B, 841, 135–139. (233) X. Y. Shi, I. J. Majoros, A. K. Patri, X. D. Bi, M. T. Islam, A. Desai, T. R. Ganser, and J. R. Baker (2006) Molecular heterogeneity analysis of poly(amidoamine) dendrimer-based monoand multifunctional nanodevices by capillary electrophoresis. Analyst, 131, 374–381. (234) J. F. Kukowska-Latallo, A. U. Bielinska, J. Johnson, R. Spindler, D. A. Tomalia, and J. R. Baker (1996) Efficient transfer of genetic material into mammalian cells using Starburst polyamidoamine dendrimers. Proc. Natl Acad. Sci. USA, 93, 4897–4902. (235) J. S. Choi, E. J. Lee, Y. H. Choi, Y. J. Jeong, and J. S. Park (1999) Poly(ethylene glycol)block-poly(L-lysine) dendrimer: novel linear polymer/dendrimer block copolymer forming a spherical water-soluble polyionic complex with DNA. Bioconjugate Chem., 10, 62–65. (236) C. Padié, M. Maszewska, K. Majchrzak, B. Nawrot, A. M. Caminade, and J. P. Majoral (2009) Polycationic phosphorus dendrimers: synthesis, characterization, study of cytotoxicity, complexation of DNA, and transfection experiments. New J. Chem., 33, 318–326. (237) S. P. Jones, G. M. Pavan, A. Danani, S. Pricl, and D. K. Smith (2010) Quantifying the effect of surface ligands on dendron–DNA interactions: insights into multivalency through a combined experimental and theoretical approach. Chem.-Eur. J., 16, 4519–4532. (238) G. M. Pavlov, E. V. Korneeva, K. Jumel, S. E. Harding, E. W. Meijer, H. W. I. Peerlings, J. F. Stoddart, and S. A. Nepogodiev (1999) Hydrodynamic properties of carbohydrate-coated dendrimers. Carbohydr. Polym., 38, 195–202. (239) G. M. Pavlov, N. Errington, S. E. Harding, E. V. Korneeva, and R. Roy (2001) Dilute solution properties of lactosylated polyamidoamine dendrimers and their structural characteristics. Polymer, 42, 3671–3678.

3 Luminescent Dendrimers Anne-Marie Caminade

3.1

Introduction

Light emission in the UV, visible, or IR domains is called luminescence. If the emission of light occurs very rapidly after irradiation/excitation, the phenomenon is called fluorescence. If the emission of light is delayed, the phenomenon is called phosphorescence. The Jablonski diagram shown in Figure 3.1 displays the different electronic states and the related transition states between each of them, indicating that fluorescence occurs from a singlet state whereas phosphorescence occurs from a triplet state. Numerous dendrimers bear at least one luminescent group in their structure, in most cases a fluorescent group. One review has emphasized the importance of luminescence to investigate dendrimer properties.1 Both purely organic and organometallic luminescent derivatives were grafted on to dendrimeric structures. The position of the chromophore(s) is generally dictated in function by the desired aim. In fact, a large variety of types and locations of the luminescent groups exists and both parameters have a tremendous influence on the luminescence properties. Fluorescence and phosphorescence are very powerful techniques for many purposes, including the elaboration of sensors, of organic light emitting diodes (OLEDs) or for biological imaging. This chapter will give selected examples of luminescent dendrimers, with emphasis on fluorescent dendrimers, and of light harvesting properties. It will end with an emerging topic concerning fluorescence induced by two-photon absorption.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 3.1

3.2

Jablonski diagram displaying the origin of fluorescence and phosphorescence

Dendrimers with Fluorescent Terminal Groups

Modifying the terminal groups of dendrimers is the easiest way to introduce luminescent functions. However, in this case nonnegligible electronic interaction between adjacent chromophoric units may happen both in the ground state and in the excited state. The second problem that is frequently encountered when grafting fluorescent groups on to the surface of dendrimers is an important decrease in the solubility, in particular in water, which precludes in many cases their use in the field of biology.2 This problem is often overcome by grafting statistically a reduced number of fluorophores as terminal groups, whereas the remaining terminal groups are used for ensuring the solubility in water and also for bringing new properties, for instance by grafting drugs and targeting entities. 3.2.1

Fully Substituted Dendrimers

Various types of dendrimers are used as supports for fluorescent groups. Polypropylene amine (PPI) dendrimers from generation 1 to generation 5 were decorated by dansyl derivatives (from 4 to 64 dansyls, respectively). The fluorescence quantum yield and the excited state lifetime of generation 5 and of the corresponding monomer are practically identical, showing that there is no appreciable interaction among the dansyl groups.3 The same behavior was also observed in solution for PPI dendrimers terminated by oligo(pphenylene vinylene) groups.4 Dansyl groups were also used as terminal groups of polyly-

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sine dendrimers. It was shown that a single lanthanide ion (Nd3+ or Eu3+) per dendrimer is able to quench the fluorescence of all the 24 dansyl units,5 as well as Co2+.6 Naphthyl units were grafted as terminal groups of polybenzylether dendrimers built from a cyclam core. The fluorescence of the naphthyl units is quenched by exciplex formation with the cyclam nitrogen, but complexation with Zn2+ induces the disappearance of the exciplex band, with a concomitant increase in the naphthyl localized emission.7 Two series of polybenzylether dendrons were synthesized having either pyrenyl groups8 or benzophenone9 as terminal groups. In both cases, light-harvesting properties were observed (see Section 3.3 for more examples of light-harvesting properties). Eight perylene imide units were grafted as terminal groups of polyphenylene dendrimers.10,11 The position of these substituents is ambiguous, due to the two possible regiochemically different courses of the Diels–Alder reaction that allows its grafting. Photophysical studies show that the fluorescence quantum yield decreases from 0.8 for the monomeric perylene imide to 0.65 for the second generation dendrimer, and that strong electronic interactions exist between several perylene imide chromophores within one dendrimer.12 A first generation of polyphenylene dendrimer bearing two types of perylene imide chromophores was also synthesized.13 Various types of fluorescent groups (naphthyl, pyrenyl, dansyl) were grafted to the surface of PAMAM dendrimers from generation 0 to generation 5 (128 terminal groups). Their fluorescent behavior strongly depends on the generation, and correlates with the transition from an extended structure at low generations to a three-dimensional globular shape at high generations.14 Naphthalimide groups were also grafted as terminal functions of the generation 3 PAMAM dendrimer, and this compound was used as a sensitizer for Eu3+.15 A last example was provided by phosphorus-containing dendrimers ended by pyrene groups, from generation 1 to generation 4 (from 6 to 48 pyrenes, respectively) (Figure 3.2). These phosphorus compounds were used for elaboration of OLEDs (organic light-emitting diodes).16

3.2.2

Partially Substituted Dendrimers

Only a few examples of dendrimers having a limited but perfectly defined number of fluorophores linked to the terminal branching points have been elaborated, because they are generally difficult to synthesize. Asymmetrically substituted polyphenylene dendrimers having a single fluorescent perylene unit on the periphery were synthesized up to the second generation.17 A large poly(L-lysine) dendrimer constituted of two halves and having on one side 16 free porphyrins and on the other side 16 zinc porphyrins displayed intramolecular fluorescence energy transfer from the zinc porphyrins to the free porphyrins.18 Dansyl derivatives and ammonium groups used as terminal groups of polyarylamide dendrimers afford a water-soluble compound. These fluorescent dendrimers, incubated with HeLa cells, were found to form aggregates near the cell nucleus, as determined by confocal fluorescence microscopy.19 The same concept was used for the elaboration of another fluorescent and water-soluble dendrimer, which possesses three different types of functional groups precisely placed on the surface: oligoethyleneglycol chains that ensure solubility in water, dansyl derivatives for the fluorescence, and dicarboxylic acid groups, which can be used as bidentate ligands for pharmaceutical relevant metals like Pt (Figure 3.3).20

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Figure 3.2 Various types of dendrimers having fluorescent groups as all terminal groups. (R1) design an alternative position of substituents R1

However, these highly sophisticated structures are synthetically tedious to elaborate. Thus the statistical grafting of a few fluorophores as terminal groups of water-soluble dendrimers, and particularly PAMAM dendrimers, has gained an increasing importance for biological experiments. A few types of fluorophore were used for such a purpose, in particular the closely related compounds Oregon Green 488 (OG 488) and derivatives of fluoresceine, mainly fluoresceine isothiocyanate (FITC) (Figure 3.4). The fluorophore OG 488 was also statistically linked to the surface of PEG-based dendrons having lysine as branching moities, and was used for defining the endocytosis process.21 The PAMAMFITC dendrimers (positively and negatively charged) were used for investigating the

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Figure 3.3 Three types of well-defined dendrimers possessing fluorescent derivatives and one or two other types of function as terminal groups

Figure 3.4

Types of fluorophores statistically linked to the surface of dendrimers

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Figure 3.5 Statistical grafting of drugs and fluorophores as terminal groups of PAMAM dendrimers

internalization and subcellular trafficking in cell monolayers.22 FITC was also used to label the surface of phosphorus-containing dendrimers ended by phosphonic acids for determining the type of immune cells that were targeted by this dendrimer, and then to distinguish its intracellular route after its internalization by monocytes.23 PAMAM dendrimers linked to a few porphyrins (TAMCPP, see Figure 3.4) provide an original light-inducible gene delivery system.24 This concept of statistical grafting has been extended in recent years to introduce a third, or a fourth, or a fifth type of terminal group on the dendrimeric structure, starting in most cases from PAMAM dendrimers. N-acetyl-L-cysteine (AC, an antioxidant and antiinflammatory agent) was grafted to G4-PAMAM dendrimer ended by either NH2 or CO2H functions and conjugated to FITC.25 G4-PAMAM dendrimer ended by OH groups was conjugated with FITC and with approximately 12 methyl-prednisolone functions (MP, a corticosteroid used for the treatment of asthma).26 Analogously, approximately 58 Ibuprofen groups (Ib, a nonsteroidal anti-inflammatory drug) were grafted to G4-PAMAM–OH.27 Figure 3.5 displays several examples of dendrimers having three different types of terminal groups. The concept of statistical grafting was also applied to dual imaging using compounds having four different terminal groups. Fluorescence and magnetic resonance imaging were obtained using G6-PAMAM dendrimers ended by NH2 groups also bearing as terminal groups diethylenetriamine pentaacetic acid (DTPA, a chelating agent for Gd(III), widely used as an NMR contrast agent) and Cy5.5 as fluorophore. Such compounds were used in particular for localizing by both methods the sentinel lymph node in mice.28 Another series of compounds also built from G6-PAMAM dendrimers possess 120 DTPA chelates, one of them being labeled with radioactive 111In, and four fluorescent groups, either of type Cy5, or Alexa660, or Alexa680, or Alexa700, or Alexa750 (Figure 3.6A). All these compounds injected simultaneously allowed dual-modality scintigraphic and five-color nearinfrared optical lymphatic imaging in mice.29 Several other examples of tetrafunctional PAMAM dendrimers include in particular the functionalization with a reporting fluorochrome (FITC), a targeting agent (folic acid), a chemotherapeutic agent (methotrexate), and various types of surface groups ensuring solubility in water (NH2, CO2H, OH, NHAc) (Figure 3.6B). Such compounds have a rapid and specific binding and internalization within tumour cells, and improve the cytotoxic response of the cells to methotrexate a hundredfold over the free drug.30,31 An analogous procedure was used to graft the anti-HER2 monoclonal antibody (herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2) instead of folic acid as the targeting agent.32 Two recent examples in this field described the synthesis and use for targeted drug

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Figure 3.6

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Several types of dendrimers having statistically four types of terminal function

delivery and imaging of a G5-PAMAM-FITC dendrimer ended by NH2 terminal groups and conjugated to acetamide and biotin,33 and a G3-PAMAM-FITC dendrimer also ended by NH2 terminal groups and conjugated to lauroyl chains and propanolol.34 Using the same principles, one of the terminal substituents can be replaced by an oligonucleotide; if two complementary oligonucleotides are used, their hybridization affords dendrimeric structures having on one side the fluorescent groups (FITC) and on the other side the targeting agent (folic acid) (Figure 3.6C).35 FITC is certainly the most widely used fluorescent group linked to PAMAM dendrimers for biological purposes, but a few other types of fluorophores were also used. They include in particular Alexa fluor 488 and Cy5.5. In the first case, the dendrimer has either the doubly cyclized peptide RGD-4C for targeting tumor angiogenic vasculature36 or the monoclonal antibody Anti-HER2.37 In the second case, both an anticancer drug (paclitaxel) and a synthetic analog of LHRH peptide targeted to receptors over-expressed on the membrane of cancer cells were linked to the fluorescent dendrimer (Figure 3.6D).38

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Figure 3.7

Five different functions linked statistically to PAMAM dendrimers

A few types of engineered dendrimeric nanodevices possess up to five different terminal groups. They were obtained using PAMAM dendrimers having NH2 (partly or totally acetylated) or OH terminal groups, linked to folic acid as targeting groups, to FITC as fluorescent groups, and bearing anticancer drugs, in particular methotrexate (MTX)39,40 or taxol41 (Figure 3.7). An analogous concept was used for obtaining a nanocluster of dendrimers usable as a tumor-targeted fluorescent and magnetic resonance imaging contrast agent.42

3.3

Luminescent Group at the Core of Dendrimers and Energy/Light-Harvesting Properties

Most of the work carried out for having a luminescent group at the core of dendrimers or dendrons was done for studying energy/light-harvesting properties. This idea has generated numerous publications that will constitute the main parts of Sections 3.3.1 to 3.3.3. Several reviews have emphasized the study of these properties,43–46 generally carried out with the aim of using these compounds as artificial antennae for the photochemical conversion of solar energy, mimicking natural photosynthetic systems. In these cases, not only is the fluorophore of the core important but also the nature of the branches and of the terminal functions. In several cases, a second type of fluorophore is used as terminal groups, chosen to absorb the light and to reemit light with a modified wavelength, absorbable by the fluorophore at the core, inducing intradendrimer FRET (Förster resonance energy transfer), a mechanism that is a relatively long-range dipole–dipole coupling. A few other purposes have led to the synthesis of dendrimers and dendrons having a single luminescent group at the core. In the case of organic fluorophores, the aim is often to use the branches to protect the core against quenching effects, due, for instance, to π-stacking or to an interaction with a quencher (for instance water). In the case of a metallic core, the metal also allows the assembly of dendrons around it. 3.3.1

Organic Fluorophores as Cores

The particular case of porphyrins and phthalocyanines used as core of dendrimers will be emphasized in the next section (3.3.2). The other cases can be divided into two different types: either the fluorophore is linked by one functional group to the core of a dendron

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(also called the off-center position) or the fluorophore is used as the core of a dendrimer. Some fluorescent molecules were grafted at the core of dendrons to study their photophysical properties and to detect the influence of the branches, with some contradictory results. The quantum yield of fluorescence of a dansyl group used as the core of polyalkylamide dendrons increased on going from generation 1 to generation 3, correlating with a favorable decrease in polarity of the microenvironment.47 On the contrary, the quantum yield of fluorescence of a maleimide group attached to the core of a phosphorus dendron decreased with increasing generations, from G0 to G2.48 A pyrenyl group at the core of a small polyamide dendron ended by long alkyl chains and encapsulated in a cyclodextrin induced a cooperative assembly that led to nanotubes.49 A polyethylglycol dendron ended by guanidinium and having rhodamine as the core was used as a “molecular glue” to stabilize microtubules.50 In both cases the nano/microtubes were detected by fluorescence. In the case of dendrimers, the fluorescence of a viologen-type core of polybenzyl ether dendrimers was completely quenched as a result of donor–acceptor interactions between the branches and the core.51,52 On the contrary, a perylene core of a first generation polyphenylene dendrimer ended by multiple amino groups was employed successfully as a fluorescent dye for specifically staining the extracellular matrix of animal tissues.53 However, as indicated previously, most of the work concerns the synthesis of lightharvesting antennae, in particular for dendrons having a second type of fluorophores as terminal groups. Polybenzyl ether dendrons having Coumarine 343 as the core and Coumarine 2 as terminal functions were shown to possess FRET properties. Indeed, λmax for Coumarine 2 is 365 nm and λem is 435 nm, an emission wavelength absorbable by Coumarine 343 for which λmax is 446 nm. The efficiency of the energy transfer through space was demonstrated by the strong emission at 490 nm, corresponding to Coumarine 343 when the dendron was irradiated at 343 nm (Figure 3.8A).54,55 Other types of polybenzyl ether dendrons having diarylaminopyrene terminal groups and a benzthiadiazole as the core were also shown to possess energy and electron transfer properties,56 as well as benzyl ether dendrimers constituted by a perylene bis(dicarboximide) core bearing two dendrons ended by Coumarine 2.57,58 Single-layer OLED systems were elaborated with polybenzyl ether dendrons having either Coumarine 343 or a pentathiophene as the core and diarylnaphthyl amine as terminal groups. The arylamine acted as a hole transporter and loci of exciton formation, charge transport occurred through the branches, and the fluorescent core acted as the electroluminescent entity.59 The same properties were observed with the corresponding dendrimers.60 The rigidity of polyphenylene dendrimers was used for intramolecular directional FRET. In particular, the photophysical properties of a dendrimer built with a terrylene dimide core and perylene monoimide terminal groups were detected by single-molecule spectroscopy (Figure 3.8B).61 The influence of O2 on the fluorescence of a polyphenylene dendrimer having a perylenediimide as the core and triphenylamine terminal groups was also detected by single-molecule spectroscopy.62 A review has gathered the energy and electron transfer properties of polyphenylene dendrimers.63 Several types of polyphenylene dendrons having a fluorescent core (generally a perylene) were also synthesized. In the first examples, the conjugated branches were symmetrical (Figure 3.9A). It was shown that the light-harvesting properties of such compounds increased with the number of generations, and hence with the number of phenylacetylene moieties, which are the energy-collecting sites. However, the efficiency of the energy

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Figure 3.8

Figure 3.9 core

Structure of two light-harvesting dendrimeric compounds

Structure of two types of polyphenylene dendrons having a perylene as the

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transfer decreased.64 Two symmetrical phenylacetylene dendrons were used to assemble in a single macromolecule the various components necessary to constitute an electroluminescent diode. Indeed, a bifunctional anthracene was used as the core and luminophore, the phenylacetylene branches were used as energy transfer segments, and the terminal groups (triaryalamines) were used as hole trapping groups.65 The influence of unsymmetrical branching on other types of polyphenylene dendrons was studied (Figure 3.9B). It was found that the photophysical properties are substantially different. In particular these compounds are efficient light absorbing antennae in the nearUV and in the blue part of the spectrum.66 The energy transfer pathways in analogous dendrons were extensively studied.67 3.3.2

Porphyrins and Phthalocyanines as Cores

A recent review has gathered the important work already done with all types of “dendrimers, porphyrins and phthalocyanines”,68 in particular with those having such functions at the core. The dendrimeric branches can be linked in various ways to porphyrin and phthalocyanine cores, as shown in Figure 3.10. In most cases, the types “a+b” for porphyrins and “a” for phthalocyanines are the most widely used. A few porphyrin- and phthalocyanine-cored dendrimers were synthesized with the aim of using them as probes for exploring the properties of the interior of the dendrimeric structure. By encapsulating such entities, one may expect an enhancement of their fluorescence properties by suppressing collisional quenching of their excited states. In many cases, such as benzyl ether (type “a+b”)69 or polyphenylene (type “a+b”)70 dendrimers having a porphyrin as the core, this effect was in fact not observed. In contrast, the fluorescence of phthalocyanine cores is generally enhanced when they are encapsulated in dendrimers. This was in particular observed for polyetheramide (PEA) dendrimers (type “a”)71 and polyphosphorhydrazone dendrimers (type “b”)72,73 having a phthalocyanine as the core.

Figure 3.10 Possible locations of dendrimeric branches having a porphyrin or a phthalocyanine as the core

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Some possible uses of such compounds have been proposed. A dendrimeric iron porphyrin (type “a”) ended by short PEG groups was synthesized with the aim of mimicking globular heme proteins; it was shown that the branches created a hydrophobic microenvironment around the iron porphyrin.74 The electrostatic assembly of positively and negatively charged polybenzyl ether dendrimers was detected by modification of the fluorescence properties of the porphyrin they had as the core (type “a+b”).75 Mn(III), Fe(III), Ni(II), or Cu(II) dendronized porphyrins (type “a”) to which was attached C60 displayed mutual interactions between the redox-active constituents.76 An Mn(III) porphyrin (type “a+b”) surrounded by polyarylester branches was used as a shape-selective oxidation catalyst.77 A series of dendrimeric polyglutamic Pd porphyrin (type “a+b”) was found to be strongly luminescent in deoxygenated solutions, but the phosphorescence was quenched by O2.78 This property was used later for oxygen imaging in biological systems.79 Several types of porphyrins metallated or not were also synthesized for light-harvesting purposes. Polybenzylether branches grafted to a Zn-porphyrin (type “a+b”) were used to demonstrate long-range photoinduced electron transfer through the dendrimeric framework when interacting with methylviologen used as a quencher of the porphyrin fluorescence.80,81 Polyphenylene branches linked to a porphyrin core (type “a+b”) were highly efficient light-harvesting antennae70 and the corresponding iron complexes were efficient catalysts for olefin oxidation.82 Somewhat related to the work with porphyrins, dendrimers surrounded by naphthyl units and having a cyclam (tetranitrogen macrocycle) core were able to complex Ru2+ and also displayed light-harvesting properties.83,84

3.3.3

Metallic Cores

Some examples of metallic complexes of various macrocycles were shown in the previous section; in this one, we will see other cases of luminescent metallic complexes at the core of dendrimers or dendrons. Study of the photophysical properties of Ru2+ complexed by three bipyridine ligands, one or three of them bearing two polybenzylether substituents, demonstrated that the presence of six dendrons efficiently protected the fluorescence of the core against quenching by O2.85 Analogous compounds in which one of the bipyridine ligands has two glycerodendrons as substituents was used for sensing different lectins, which induced changes in the fluorescence quantum yield of the Ru2+ core.86 Dendrons functionalized by fullerene used as branches for a copper bisphenanthroline complex induced a dramatic decrease of the fluorescence of the core, due to site isolation.87 However, as in the previous cases, most of the work carried out with dendrons or dendrimers having a metallic core was for their light-harvesting properties. Various types of metals were used for such a purpose, including lanthanides. Indeed, Er3+, Tb3+, and Eu3+ were complexed by three polybenzyl ether dendrons having a carboxylic acid as the core. The site isolation of the lanthanide combined with a large antennae effect of the branches induced a large enhancement of the luminescence properties.88 In many cases, an organic fluorophore is used as terminal groups and the complexation of the metallic core occurs through nitrogen ligands, mainly of type pyridine or bipyridine. Ru2+ complexed by three bipyridine units surrounded by small Coumarine 450 dendrons was shown to have an increased fluorescence thanks to light-harvesting properties of the structure and also an increased fluorescent lifetime.89 Several examples of iridium com-

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Figure 3.11

79

Various types of dendrimeric phosphorescent emitters

plexes used as core assembling three dendrons (often small) were already shown to be useful phosphorescent entities for the elaboration of OLEDs (more information about OLEDs will be found in Chapter 12). Depending on the type of dendrons, the color of the electrophosphorescence can be adapted. Polyphenylene dendrons90 and carbazole-based dendrons91 afford green emitters, triphenylamine dendrons92 afford pure red emitters, and biphenyl dendrons93 afford deep blue emitters. Their structures are shown in Figure 3.11.

3.4

Fluorescent Groups inside the Structure of Dendrimers

As in the previous section, most types of dendrimers possessing fluorescent groups inside their structure, either as branches or linked to the branches, were synthesized for energy transfer experiments. However, a series of such compounds was elaborated for probing the accessibility to the internal structure of polybenzyl ether dendrons. A single anthracene group was incorporated in a specific location of the dendron (Figure 3.12A displays five different dendrons). The accessibility of a quencher (hexalethyltris(2-aminoethyl)amide) to the anthracene moiety in each type of dendron was determined by measurement of fluorescence quenching.94 A PPI dendrimer surrounded by benzyl ether dendrons, possessing eight dansyl groups inside the structure and 32 naphthalene units as terminal groups (Figure 3.12B), displayed the expected antennae effect. Upon irradiation, strong dansyltype fluorescence was observed, whereas the fluorescence of the naphthyl units was almost totally quenched.95 An important part of the work about fluorescent groups inside dendrimers was carried out with porphyrin derivatives; we have seen in Section 3.3.2 their use as cores. Large dendrimeric multiporphyrin arrays having one free porphyrin as the core and several layers of Zn-porphyrins as branches surrounded by benzyl ether dendrons were synthesized by a convergent process (Figure 3.13). These compounds display light-harvesting properties from the photoexcited Zn-porphyrins to the free core, but the efficiency depends on the type of structure. The efficiency of cone-shaped multiporphyrin dendrons considerably decreased as the generation increased (from 86% for G1 to 19% for G3), whereas all

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Figure 3.12 Examples of dendrimers having fluorescent derivatives precisely located inside their structure

Figure 3.13 Example of a dendrimer having one free porphyrin at the core and 3 layers of Zn-porphyrins

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multiporphyrin dendrimers displayed high-efficiency energy transfer.96,97 In the case of multiporphyrin dendrons having a fullerene as the core, electron transfer from the Znporphyrins to the fullerene was observed, inducing a large quenching of the porphyrins fluorescence.98 Another series of dendrimers having a single layer of Zn-porphyrins either at the level of the first, second, or third generation and surrounded by small benzylether wedges were also synthesized.99 Most of the compounds shown above possess two different types of fluorophores. Some dendrimers also exist possessing three different types of luminescent groups linked at different levels of their structure. One example possesses a free porphyrin as the core, eight naphthopyranones linked to the branches of the first generation, and sixteen coumarin3-carboxylates linked to the surface (Figure 3.14A). When exciting the dendrimer at 335 nm (excitation of coumarin) an almost unique emission was observed at 651 and 715 nm, corresponding to the porphyrin.100 Another dendrimer possessing three different types of chromophores was elaborated with a polyphenylene scaffold. This compound has a terrylene tetracarbodiimide as the core, four perylene dicarboximide linked to the first generation, and eight naphthalene dicarboximide as terminal groups (Figure 3.14B). The wavelengths of excitation and emission of the three chromophores were chosen for an efficient energy transfer. Indeed, upon excitation of the dendrimer periphery, a very strong emission of the core was observed, more intense by a factor of three than the fluorescence induced by direct excitation of the core.101,102 The combination of heterometallic chromophores (Ru and Os complexes) and purely organic chromophores (pyrenyl) is also shown in Figure 3.14C. It was shown that the light energy absorbed by the Ru-based chromophores and the pyrene units is quantitatively channeled to the Os core.103

3.5

Intrinsically Fluorescent Dendrimers

Different types of dendrimers possess luminescent groups throughout their structure, either as constituents of the branches or as branching points; thus they are intrinsically fluorescent. However, some examples also exist of dendrimers that do not possess known fluorescent groups in their structure, but which were surprisingly found to be fluorescent. 3.5.1

Fluorescent Groups throughout the Dendrimeric Structure

The first examples concern polypyridine complexes built with 10 ruthenium or a mixture of osmium and ruthenium centers as branching points and core. In the case of two metals, depending on the location of Os (core or periphery) the excitation energy can be channeled in the desired direction (Figure 3.15).104 Two reviews have gathered the work done with luminescent dendrimers based on polypyridine transition metal complexes.105,106 Multiporphyrin dendrimers built from a free porphyrin as the core and Zn-porphyrins as branching points were synthesized up to generation 3 (Figure 3.15). It was shown that the overall arrival time of energy at the trapping site (free porphyrin) increased with the number of Zn-porphyrins from 45 ps with one Zn-porphyrin to 222 ps for the dendrimer with 20 Zn-porphyrins.107

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Figure 3.14 Dendrimers having three types of chromophores at three levels of their structure (surface, branches, core)

A porphyrin was also used as the core of polycarbazole dendrimers. It was shown that the light collected by the carbazole chromophores was quantitatively transferred to the porphyrin core (Figure 3.16A).108 In the case of polycarbazole dendrons, it was shown that the fluorescence was red-shifted on going from the first to the second generation, but practically did not change on going from the second to the fourth generation (Figure 3.16B).109 In triarylamine dendrimers, it was shown that the absorption

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Figure 3.15

Figure 3.16

83

Luminescent metal complexes throughout the structure of dendrimers

Two types of carbazole dendrimeric structures and a triarylamine dendrimer

was associated with a state that is delocalized over most of the dendrimer structure, and the energy migration process was probed by ultrafast fluorescence anisotropy (Figure 3.16C).110 Several types of purely organic dendrimers also possess fluorescent properties. For instance, the polyphenylene dendrons shown in Figure 3.9 are fluorescent even in the

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Figure 3.17

Triarylethene dendrimer and interlinked triphenylene dendrimer

absence of a fluorescent group at the core, as shown both for the symmetrical64 and the unsymmetrical dendrons.66,111 Triarylethene dendrimers are also intrinsically fluorescent and the fluorescence quantum yield increased from 0.024 for G1 to 0.62 for G3 (Figure 3.17A).112 Variations around polyphenylene dendrimers have led to the synthesis of dendrimers constituted of interlinked triphenylene units (Figure 3.17B) emitting a blue photoluminescence. The quantum yields are low, but increased on going from the first generation (0.066) to the third generation (0.352).113 Polyphenylene dendrimers were also used as scaffolds to introduce highly fluorescent perylene imide chromophores as branches. All the compounds in this series display very high fluorescence quantum yields (0.94–0.98) (Figure 3.18B).114 Polypyrene dendrimers are another type of fully aromatic dendrimer. All the compounds in this series also possess high fluorescent quantum yields (0.69–0.72) irrespective of the generation (Figure 3.18A).115 A series of polytruxene dendrimers was synthesized in which the truxene groups are either linked through benzene groups116 or through thienylethynylene linkages117 (Figure 3.19). In the first case, the photoproperties indicate that the large torsion angle between the truxene moieties and the benzene rings affect the full π-delocalization of the whole molecule. In the second case, the different length of the oligo(thienylethynylene) linkages leads to an increasing effective conjugation from the dendrimeric rim to the core. These compounds display an excellent energy funneling ability, as shown by an energy transfer efficiency of over 95%. Polythiophene dendrimers show very broad absorption spectra, but narrower fluorescent spectra, which maximum wavelength shifts to longer wavelengths as the generation increases (Figure 3.20A). These results are drastically different from those obtained with linear oligothiophenes and polymers.118 The importance of the dendrimeric structure was

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Figure 3.18

85

Polypyrene and perylene imide polyphenylene dendrimers

Figure 3.19

Two types of poly(truxene) dendrimers

also shown in the case of folded dendrimers elaborated from aminobenzamide linkages. Significantly lower fluorescence quantum yields were observed for these dendrimers relative to simple 2-aminobenzamides and might be due to the deviation of the amides in the dendrimeric structures from periplanarity inducing nonradiative processes (Figure 3.20B).119

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Figure 3.20 linkages

3.5.2

Polythiophene dendrimer and dendrimer having ortho-aminobenzamide

Fluorescence of Dendrimers without Known Fluorophores

Background fluorescence was noted early for PAMAM (polyamido amine) dendrimers, but it was considered to be negligible.120 The fluorescence of carboxylate-terminated PAMAM dendrimers was studied in detail, and it was proposed that the fluorescent emission could be due to an n→π* transition from the various amido groups.121 Later on, the blue luminescence observed after oxidation of OH- or NH2-terminated PAMAM dendrimers was not attributed to the backbone but to the terminal groups.122 Such an assertion was rapidly contested and a strong dependence of the fluorescence with the pH was reported (higher fluorescence in acidic conditions).123 In contrast, the fluorescence of PAMAM dendrons forming macrogels was stronger in basic conditions.124 Recently, it was reported that not only PAMAM but also PPI (polypropyleneimine) dendrimers have analogous fluorescence in water. This observation suggests that the fluorescence is due to a common functional group, which is the amine. Furthermore, the fluorescence was strongly enhanced when bubbling air instead of nitrogen in the solutions of dendrimers, suggesting an oxidation of the amine, increased in acidic conditions.125 An analogous behavior was also recently reported for poly(propyl ether imine) dendrimers126 and for polylysine dendrimers ended by NH2 groups.127 It appears from all these data that the intrinsic fluorescence of these compounds is highly dependent on the conditions used both for their stocking and their study.

3.6 Two-Photon-Excited Fluorescence of Dendrimers Two-photon absorption (TPA) is a third-order nonlinear process in which simultaneous absorption of two photons excites a molecule from the ground state to a higher energy state. The energy difference between the lower and upper states of the molecule is equal

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to the sum of the energy of the two photons. TPA is generally used for two-photon-excited fluorescence, which necessitates the high intensity of lasers, and more preferably of pulsed lasers. If a dye has good TPA properties, its excitation would occur at approximately two times the wavelength at which one-photon excitation would have occurred, i.e., for instance, in the near-infrared region instead of the ultraviolet region. Such a property is potentially useful for imaging the human body, which is more transparent in the IR region. The efficiency of the absorption is generally characterized by the TPA cross-section (σ2). Two reviews have gathered several examples of dendrimers for TPA.128,129 A few types of fluorescent dendrimers shown on the previous pages possess TPA properties, for instance the polythiophene dendrimers shown in Figure 3.20 (but without the C6H13 chains).130 However, most dendrimers possessing TPA properties were specially engineered for such a purpose. In several cases, the whole structure possesses TPA properties. For instance, alkyl ruthenium dendrimers (Figure 3.21A) were shown to possess third-order nonlinear

Figure 3.21 Four types of dendrimers in which the whole structure possesses two-photonexcited fluorescent properties

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Figure 3.22 A dendron with TPA terminal groups and various types of TPA chromophores used as terminal groups of free or metalated porphyrins

optical properties,131 TPA properties,132 and even three-photon absorption properties.133 Dendrimer possessing phenylenevinylene connecting units and electron-donating (amino) peripheral groups (Figure 3.21B),134 as well as dendrimers having triphenyl amine as ramification nodes (Figure 3.21C),135 possess TPA properties, and also have optical power limiting applications. Polyfluorene/truxene dendrimers (Figure 3.21D) also possess TPA properties.136 Besides dendrimers whose full structure is able to absorb two photons, there are also several types of dendrimers and dendrons in which only the terminal functions have TPA properties. For instance, a derivative of a conjugated triphenyl amine was grafted as terminal groups of polybenzyl dendrons (Figure 3.22). No deleterious interaction of the chromophore was observed; the two-photon absorbing capacity increased with the dendron generation and hence with the number of chromophores.137 Various types of TPA chromophores were used as terminal groups of dendrimers having a porphyrin as the core, with the aim of generating singlet oxygen via two-photon-excited FRET. Indeed, it is well known that porphyrins have the ability to generate 1O2, suitable for the photodynamic therapy of cancers, but they have low TPA properties. Fluorene derivatives having an emission spectrum overlap with the absorption of porphyrins could be particularly useful for such a purpose. The concept was first demonstrated with a metal-free porphyrin,138 then with metallated porphyrins (AlCl, Zn, Ag),139 and finally with free porphyrin having also PEG derivatives as terminal groups to ensure the solubility in water.140 Pt porphyrinbased phosphorescent dyes are useful for biological oxygen measurements (3O2 is able to quench the phosphorescence); the grafting of TPA derivatives of coumarin as terminal groups of a Pt-porphyrin was carried out for this purpose, but the solubility of this compound was very low141 (Figure 3.22). Various types of phosphorus-containing dendrimers having TPA chromophores in various parts of their structure were elaborated (see Figure 3.23). In a first attempt, fluorophores derived from fluorene were used as terminal groups. The ability of these dendrimers

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Figure 3.23 Various types of phosphorus dendrimers possessing two-photon absorbing fluorophores in their structure

as two-photon absorbing compounds increased with the generations and hence with the number of chromophores, and the TPA cross-section (efficiency) of the fourth generation (55 900 GM at 705 nm) is comparable to the σ2 values of the best quantum dots (inorganic nanoparticles).142 The grafting of stilbazole chromophores as terminal groups of phosphorus dendrimers allowed cooperative two-photon absorption enhancement to be demonstrated through space interactions.143 A derivative of fluorene was also used as the core of phosphorus dendrimers. The grafting of ammonium terminal groups ensured the solubility in water. The second generation of this series was injected intraveneously to a rat and allowed the imaging of its olfactory bulb by two-photon-excited fluorescence.144 The same core was used as a support of other TPA fluorophores linked as terminal groups of several generations of dendrimers. Comparison between the spherical series and this “dumbbelllike” series having the same terminal TPA chromophores pointed out the importance of geometry in such compounds.145

3.7

Conclusion

This chapter has emphasized the large diversity of structures of luminescent dendrimers, and particularly of fluorescent dendrimers. At the beginning, most of these compounds were synthesized for photophysical studies, for sensing the structure of dendrimers, for determining the influence of the dendrimeric structure upon the fluorophores, or the influence of the close proximity of several fluorophores. Very early, it was also recognized that many dendrimeric structures were suitable for light (or energy) harvesting, from the surface to the core, in view of mimicking natural photosynthetic systems. Several other

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uses of fluorescent dendrimers were proposed later on, for instance as components in organic light-emitting diodes (OLEDs). Such a property will be emphasized in Chapter 12. However, the most popular use of fluorescent dendrimers concerns biology. Indeed, when coupled with drugs or targeting entities, such compounds allowed imaging of cells or of trafficking inside cells. Also in the field of biology, dendrimers having two-photon absorption properties have a promising future for imaging, as shown in particular by the imaging of the blood vessels of living animals.

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(126) G. Jayamurugan, C. P. Umesh, and N. Jayaraman (2008) Inherent photoluminescence properties of poly(propyl ether imine) dendrimers. Org. Lett., 10, 9–12. (127) K. T. Al-Jamal, P. Ruenraroengsak, N. Hartell, and A. T. Florence (2006) An intrinsically fluorescent dendrimer as a nanoprobe of cell transport. J. Drug Targeting, 14, 405–412. (128) H. Ma and A. K. Y. Jen (2001) Functional dendrimers for nonlinear optics. Adv. Mater., 13, 1201–1205. (129) C. Andraud, R. Fortrie, C. Barsu, O. Stephan, H. Chermette, and P. L. Baldeck (2008) Excitonically coupled oligomers and dendrimers for two-photon absorption. Adv. Polym. Sci., 214, 149–203. (130) M. R. Harpham, O. Suzer, C.-Q. Ma, P. Bauerle, and T. Goodson (2009) Thiophene dendrimers as entangled photon sensor materials. J. Am. Chem. Soc., 131, 973–979. (131) C. E. Powell, J. P. Morrall, S. A. Ward, M. P. Cifuentes, E. G. A. Notaras, M. Samoc, and M. G. Humphrey (2004) Dispersion of the third-order nonlinear optical properties of an organometallic dendrimer. J. Am. Chem. Soc., 126, 12234–12235. (132) M. P. Cifuentes, C. E. Powell, J. P. Morrall, A. M. McDonagh, N. T. Lucas, M. G. Humphrey, M. Samoc, S. Houbrechts, I. Asselberghs, K. Clays, A. Persoons, and T. Isoshima (2006) Electrochemical, spectroelectrochemical, and molecular quadratic and cubic nonlinear optical properties of alkynylruthenium dendrimers. J. Am. Chem. Soc., 128, 10819–10832. (133) M. Samoc, J. P. Morrall, G. T. Dalton, M. P. Cifuentes, and M. G. Humphrey (2007) Twophoton and three-photon absorption in an organometallic dendrimer. Angew. Chem. Int. Ed., 46, 731–733. (134) O. Mongin, J. Brunel, L. Porres, and M. Blanchard-Desce (2003) Synthesis and two-photon absorption of triphenylbenzene-cored dendritic chromophores. Tetrahedron Lett., 44, 2813–2816. (135) B. Xu, H. H. Fang, F. P. Chen, H. G. Lu, J. T. He, Y. W. Li, Q. D. Chen, H. B. Sun, and W. J. Tian (2009) Synthesis, characterization, two-photon absorption, and optical limiting properties of triphenylamine-based dendrimers. New J. Chem., 33, 2457–2464. (136) Q. D. Zheng, G. S. He, and P. N. Prasad (2005) pi-Conjugated dendritic nanosized chromophore with enhanced two-photon absorption. Chem. Mater., 17, 6004–6011. (137) A. Adronov, J. M. J. Fréchet, G. S. He, K. S. Kim, S. J. Chung, J. Swiatkiewicz, and P. N. Prasad (2000) Novel two-photon absorbing dendritic structures. Chem. Mater., 12, 2838–2841. (138) W. R. Dichtel, J. M. Serin, C. Edder, J. M. J. Fréchet, M. Matuszewski, L. S. Tan, T. Y. Ohulchanskyy, and P. N. Prasad (2004) Singlet oxygen generation via two-photon excited FRET. J. Am. Chem. Soc., 126, 5380–5381. (139) M. A. Oar, W. R. Dichtel, J. M. Serin, J. M. J. Fréchet, J. E. Rogers, J. E. Slagle, P. A. Fleitz, L. S. Tan, T. Y. Ohulchanskyy, and P. N. Prasad (2006) Light-harvesting chromophores with metalated porphyrin cores for tuned photosensitization of singlet oxygen via two-photon excited FRET. Chem. Mater., 18, 3682–3692. (140) M. A. Oar, J. A. Serin, W. R. Dichtel, and J. M. J. Fréchet (2005) Photosensitization of singlet oxygen via two-photon-excited fluorescence resonance energy transfer in a water-soluble dendrimer. Chem. Mater., 17, 2267–2275. (141) R. P. Brinas, T. Troxler, R. M. Hochstrasser, and S. A. Vinogradov (2005) Phosphorescent oxygen sensor with dendritic protection and two-photon absorbing antenna. J. Am. Chem. Soc., 127, 11851–11862. (142) O. Mongin, T. R. Krishna, M. H. V. Werts, A. M. Caminade, J. P. Majoral, and M. Blanchard-Desce (2006) A modular approach to two-photon absorbing organic nanodots: brilliant dendrimers as an alternative to semiconductor quantum dots? Chem. Commun., 915–917. (143) F. Terenziani, V. Parthasarathy, A. Pla-Quintana, T. Maishal, A. M. Caminade, J. P. Majoral, and M. Blanchard-Desce (2009) Cooperative two-photon absorption enhancement by through-space interactions in multichromophoric compounds. Angew. Chem. Int. Ed., 48, 8691–8694.

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(144) T. R. Krishna, M. Parent, M. H. V. Werts, L. Moreaux, S. Gmouh, S. Charpak, A. M. Caminade, J. P. Majoral, and M. Blanchard-Desce (2006) Water-soluble dendrimeric twophoton tracers for in vivo imaging. Angew. Chem. Int. Ed., 45, 4645–4648. (145) O. Mongin, A. Pla-Quintana, F. Terenziani, D. Drouin, C. Le Droumaguet, A. M. Caminade, J. P. Majoral, and M. Blanchard-Desce (2007) Organic nanodots for multiphotonics: synthesis and photophysical studies. New J. Chem., 31, 1354–1367.

4 Stimuli-Responsive Dendrimers Anne-Marie Caminade

4.1

Introduction

The concept of “stimuli-responsive” dendrimers needs first to be defined. Indeed, taken in a wide sense, all dendrimers (and most chemicals) are able to give a “response” after a stimulus, for instance in the form of an NMR signal when submitted to a magnetic field. In this chapter, we will consider only the dendrimers that undergo a physical change (modification of size and/or shape) or a chemical change (for instance disassembly) upon the influence of an external stimulus. Numerous examples inducing physical changes concern photoresponsive dendrimers, which generally incorporate somewhere in their structure a double bond able to undergo trans/cis isomerizations under the influence of light. Obviously the location of the photoresponsive bond(s) is of crucial importance for inducing more or less important size and shape changes. This is in particular the case for azobenzene-containing dendrimers. Besides light, another external stimulus is temperature. The grafting of well-known thermoresponsive polymers as terminal groups of dendrimers affords thermoresponsive dendrimers that have some interesting properties for drug delivery. Modification of the solution media may also modify the size of the dendrimer as well as the chemical properties, in particular when modifying the pH of solutions of protonable dendrimers. This may also lead to dendrimer disassembly. All of these properties will be explained in this chapter. There is no general review about stimuli-responsive dendrimers, but a recent review has displayed their utility as drug delivery systems1 (see Chapters 18 and 19 for dendrimerbased drug delivery systems). There are also some specialized reviews (in particular concerning photoresponsive dendrimers and dendrimer disassembly); they will be indicated in the corresponding sections. Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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4.2

Photoresponsive Dendrimeric Structures

Practically all cases of photoresponsive dendrimers and dendrons concern photoisomerizations.2 The controlled response to light has a large potential of applications, because this noncontact manipulation inducing changes at the molecular level may cause important modifications at the macroscopic level. The highly organized or congested microenvironment created by the dendrimeric structure may modify the responsiveness, depending on the location of the photoresponsive bond(s). Figure 4.1 displays the various types of location of photoresponsive bonds inside dendrimers and dendrons. They can be located everywhere in the surface of dendrimers (A) and dendrons (B), but also only in some parts of the surface, either specifically (C and D) or statistically (E). The photoresponsive bond can be located only at the core (F, G, and H), or at one or some layers of branches (I and J), or even at all levels of the structure (K and L). This figure mainly concerns the case of azobenzene photoresponsive bonds (N=N), but several cases correspond also to stilbene derivatives (C=C).

Figure 4.1 Schematized examples of dendrimers and dendrons incorporating one or several photoresponsive group(s) in their structure. Case C corresponds to a specific functionalization and case E to a random functionalization

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4.2.1 Azobenzene-Containing Dendrimers and Dendrons Including azobenzenes in the structure of dendrimers is very attractive, since their photoisomerization process (trans (E)→cis (Z)) is one of the cleanest photochemical processes known to date. It is fully reversible (thermally or photochemically) and thus azobenzene can undergo innumerable reaction cycles (Figure 4.2). Isomerization of azobenzenes induces very large changes in conformation and size, which are amplified in the case of dendrimeric structures. One recent review has gathered all the known examples of azobenzene dendrimers and dendrons,3 and some earlier reviews concerned in part4 or totally5 azobenzene dendrimers. In this section, we will show representative examples of azobenzene-containing dendrimers and dendrons, organized according to the location of the azobenzene group(s), and their photoresponsive properties. As for most other types of function, the easiest way to introduce azobenzenes in the structure of dendrimers consists in grafting them as terminal groups. Obviously, few geometrical changes are expected in this case upon irradiation. The very first example of an azobenzene-containing dendrimer pertains to this category, even if it is a rare example in which not all the terminal groups but specifically half of them are azobenzene groups (Figures 4.1C and 4.3). Upon irradiation, photostationary equilibrium was reached after 5 minutes.6 In this first case, the internal structure is composed of aryl amines, but most of the following examples concerned the surface functionalization (Figure 4.1A) of poly(propylenimine) (PPI) dendrimers. Figure 4.3 displays representative examples. The azobenzenes were linked to the dendrimer via an amide in a para or meta position of an aryl group,7 or through an amidoalkyl chain,8 eventually used in random mixtures (Figure 4.1E),9 or through a sulfonate linkage.10 These compounds are composed of a hydrophilic interior and hydrophobic exterior, and thus have a tendency to associate either at the air– water interface or to form giant multibilayer vesicles, particularly in the case of the presence of long alkyl chains. Laser light irradiation of the vesicles induces the trans→cis isomerization, which leads to a temporal distortion of the bilayer, rendering it permeable to protons.11 The PPI dendrimers having the simplest azobenzene terminal groups are able to host eosin, the cis isomer being more efficient than the trans isomer.12 Analogous experiments were carried out with dendrimers having naphthalene and azobenzene terminal groups in a strict 1 : 1 ratio (Figures 4.1C and 4.3), but the results are different. In this case, the trans form is able to host eight eosin molecules, with only six for the cis form.13

Figure 4.2

Isomerization of azobenzene

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Figure 4.3 First example of an azobenzene dendrimer (left) and examples of PPI dendrimers with azobenzenes as terminal groups

Figure 4.4 groups

Some examples of dendrimers having azobenzene derivatives as terminal

Surprisingly, few examples of PAMAM dendrimers ended by azobenzene groups were reported, and in most cases the azobenzene groups were created on the surface of the dendrimers and not grafted, contrary to what was done with practically all the other types of dendrimers. In most cases, such methodology did not result in perfectly defined dendrimers. Some of these compounds were used for the release of 5-aminosalicylic acid, obtained by cleavage of the N=N bond.14 Original polybenzyl ether dendrimers having only three azobenzene terminal groups were obtained by a convergent route (Figure 4.4). A decrease of 6.1% of the hydrodynamic volume of the second generation was measured after irradiation.15 The photochemical behavior of a series of azobenzene-functionalized poly(alkylaryl ether) dendrimers was investigated. At the photostationary equilibrium, 85–92% of the cis isomer was obtained in solution.16 Silicon-containing dendrimers, in particular carbosilane and siloxane den-

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drimers, were used to afford a large palette of azobenzene terminal groups. Most of them, which bear long alkyl chains, display liquid crystalline properties, as for instance the series of carbosilane dendrimers17,18 shown in Figure 4.4. The first generation forms a smectic A phase (see Chapter 5 for the definition), which is transformed upon irradiation into an anisotropic state.19 The other well-known type of heteroatom-containing dendrimers (phosphorus dendrimers) was also used as a support for azobenzene groups (Figure 4.4). The isomerization process could be observed by 1H NMR on the CHO terminal groups. After irradiation, the all-trans form was recovered after 5 days in the dark.20 The presence of azobenzene as terminal groups of dendrimers has only a marginal influence on their size and shape upon irradiation. A different behavior is expected for dendrimers having a single azobenzene at the core (Figure 4.1F), but also for dendrons (Figure 4.1G). In most cases, dendrons having a single azobenzene as the core were obtained from poly(benzyl ether) dendrons; they possess various types of terminal groups. The first dendron had methoxy groups as terminal functions,21 while other series have terminal long alkyl chains.22 The azobenzene at the core can be functionalized, for instance, by a methoxy group,23 or a benzyl alcohol,24 or a crown ether22 (Figure 4.5). Some of these compounds were studied as Langmuir and Langmuir–Blodgett films (see Chapter 13). The surface area of layers of dendrons having long alkyl chains as terminal groups changed after UV exposure for G2 but not for G0 (too small an area change), and not for G3 (too dense packing to allow structural changes).22 The presence of the benzyl alcohol at the core allowed the attachment of the dendron to the pores of silica particles and to silica films. Large changes in the rate constant for the cis→trans isomerization of the azobenzene group were observed depending on the generation. Similar results were obtained in solution.24 Polyamide dendrons having an azobenzene as the core were also reported (Figure 4.5). The small dendrons terminated by alkyl chains associate in vesicles in aqueous solutions, which exhibit a photocontrolled release of guest molecules. Upon irradiation, the vesicle membrane displays an enhanced permeability.25 Photoreversible organogels were obtained with the polyamide dendron terminated by benzyloxy groups. The solution state can be recovered by heating or irradiating for inducing the trans→cis isomerization.26

Figure 4.5

Several examples of dendrons having an azobenzene as the core

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The presence of an azobenzene at the core of dendrimers is expected to produce the largest changes of the structure. Numerous examples of such compounds are known (Figure 4.1F), many of them being built with poly(benzyl ether) branches. The aryl groups linked to the N=N function have either a single dendrimeric substituent in the para position,27,28 or two dendrimeric substituents in the meta position.21,29 Another dendrimer having flexible branches issued from isopropylidene furanose rings was also synthesized30 (Figure 4.6). The photoisomerization properties of these compounds were studied depending on the generation. In the case of the dendrimer having isopropylidene furanose branches, the rate of both the trans→cis photoisomerization and the cis→trans thermal isomerization decreased with increasing generation.30 In contrast, with two benzylether dendrons in the meta position, the relative rates of the trans→cis isomerization are 1 : 1 : 0.5 for generations 0, 1, and 3, respectively, whereas the cis→trans isomerization was almost independent of the generation.29 Furthermore, a remarkable behavior was observed by the group of Aida21 for the highest generations of the series terminated by OMe substituents. On exposure to IR radiation (1597 cm−1) the cis isomers of G3 and G4 isomerize to the trans isomers 260 times as high as in the dark, a phenomenon observed neither with the lowest generations (G0, G1, G2) nor with the corresponding dendrons. The IR wavelength corresponds to a stretching vibration of the aromatic rings; it was deduced that the large dendrimer matrix serves to insulate the interior units from collisional scattering and functions as an efficient IR photon-harvesting antennae.21 Besides the examples shown in Figure 4.6 possessing flexible branches, some examples of dendrimers having a rigid framework linked to both sides of the azobenzene group were also reported. These examples include polyarylalkyne dendrimers28 and polyphenylene dendrimers31 (Figure 4.7). The behavior of the rigid polyarylalkyne dendrimers was compared with that of the flexible polybenzyl ether dendrimers. The efficiency of the trans→cis isomerization of the G0 is Φ = 0.30 for the flexible structure and Φ = 0.041 for the rigid compound. A decrease of the hydrodynamic volume upon irradiation was observed for all generations of both series of dendrimers, but the difference is higher for the rigid dendrimers (for instance 12% for G2 flexible and 29% for G2 rigid).28 Even a larger decrease in

Figure 4.6 Representative examples of dendrimers having an azobenzene as the core and flexible branches

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Figure 4.7

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Examples of dendrimers having an azobenzene as the core and rigid branches

the hydrodynamic volume was observed with the rigid polyphenylene dendrimers (38%, 37%, and 24% for G2, G3, and G4, respectively).31 Several examples of dendrimers possessing azobenzene groups at one layer of their structure (Figure 4.1J) are known. In most cases these compounds were obtained by a convergent process, by associating dendrons having a single layer of azobenzenes (Figure 4.1I). This is in particular the case for the benzyl ether dendrimers having azobenzene groups at the level of the first15,32 or second generation.33 Selectively placing azobenzenes at a single layer in dendrimers could allow multiple discrete states to be distinguished. The presence of three azobenzene groups leads to four discrete states upon irradiation (EEE, EEZ, EZZ, and ZZZ), which possess distinct macroscopic properties.32 The presence of six azobenzenes leads to seven discrete states concerning the number of E and Z isomers, but some isomers have two different constitutions. For example, the E2Z4 isomer can have both E azobenzene on the same dendron or on two different dendrons. Therefore 10 diastereoisomers are expected and indeed observed.33 The dendrimer with two azobenzenes “off-center”34 (Figure 4.1H) and also a folded polyarylamide dendrimer35 were synthesized by a convergent process (Figure 4.8). Upon irradiation, this folded dendrimer behaves differently from all the other types of azobenzene derivatives. Indeed, the trans→cis isomerization induces an increase of the hydrodynamic volume.35 Contrary to all the previous cases, phosphorus dendrimers possessing a single layer of azobenzene were built by a divergent process.20 The isomerization process becomes more difficult as the “burying” of the azobenzene increases.36 The percentage of Z isomer decreases from 62% for G1 and 52% for G2 to 42% for G3.20 In most cases, dendrons possessing azobenzene groups inside their structure have them at all layers (Figure 4.1K) and they are of the polyester type, as illustrated in Figure 4.9. A large series of compounds built with tertiary amines as branching points was synthesized; these compounds were used for elaborating Langmuir–Blodget films.37,38 The effect of the isomerization on the shape of the dendrons having a phosphate as the core was determined in the solid state by transmission electron microscopy (TEM).39 The series of dendrons with a benzyl alcohol core was used to determine the influence of the generation on the efficiency of the isomerization upon irradiation. As expected, the

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Figure 4.8

Figure 4.9 structure

Examples of dendrimers having azobenzenes at one layer of their structure

Examples of dendrons having azobenzene groups at each level of their

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Figure 4.10

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Examples of dendrimers having azobenzenes at all layers of their structure

percentage of isomerization decreases when the generation increases, on going from 87% of the cis isomer for the first generation to 61% for the fourth generation.40 Many examples of dendrimers possessing azobenzene groups at all layers (Figure 4.1L) have a polyester structure and were built by grafting the corresponding dendrons to a core. One example is shown in Figure 4.10 in which four dendrons were grafted to an azobenzene core.40,41 In this case also, the percentage of cis isomer obtained by irradiation decreases from 77% for the first generation to 36% for the third generation.41 Analogously, four azobenzene dendrons of the polyamide type were grafted to a calix[4]arene.42 Compounds of this series are less hindered than the previous ones, but a decrease in the percentage of cis isomer obtained upon irradiation was also observed on going from the third (80%) to the fourth (65%) generation.43 Phosphorus-containing dendrimers possessing azobenzene derivatives at all layers were synthesized by a divergent process, either from a tri- or hexafunctional core (Figure 4.10). The influence of the core (which modifies the density) on the percentage of cis isomer after irradiation was detected with these compounds. In the case of the trifunctional core, 63% of the cis isomer was obtained for the first generation and 21% for the third generation. In the case of the hexafunctional core (which affords a more crowded dendrimer), the percentage of cis isomer is only 47%

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for generation 0 and 12% for generation 2 (the same number of azobenzene groups for generation n of the first series and generation n − 1 of the second series).20 It is worth noting that in practically all cases the percentage of isomerization was monitored by UV–visible spectroscopy, whereas 31P and 1H NMR were used in the case of the phosphorus dendrimers. A rich diversity of dendrimeric structures possessing at one or several layers an azobenzene derivative has already been proposed and their photoresponsive properties were studied in most cases, emphasizing the detrimental influence of the steric hindrance on their isomerization properties. Azobenzene dendrimers constitute the most important type of photoresponsive dendrimers, but some other examples are known, which will be presented in the next section. 4.2.2

Other Types of Photoresponsive Dendrimers

The photochemical and photophysical behavior of stilbene is well known (Figure 4.11), but it cannot be compared to the isomerization of azobenzene, since it usually cannot take place by an inversion mechanism, but can occur by rotation around the double bond. Stilbene dendrimers, particularly when the stilbene is located at the level of the core, should allow a study to be made of the isomerization process. Contrarily to most azobenzenes, stilbene derivatives are generally fluorescent (see Chapter 3); this property might give access to the dynamic behavior in the excited state, but in many of these cases only the fluorescence was studied and not the isomerization process.44,45 However, it is also known that stilbene derivatives can undergo a photocyclization reaction, but can lead also to photooligomers besides photoisomerization (Figure 4.11). Furthermore, a two-photon ionization process may also lead to a stilbene radical cation, as illustrated in the case of a benzyl ester dendrimer.46 Undoubtedly, the photoresponsiveness of stilbene is a less clean process than that of azobenzene. This fact certainly explains the lower number of papers concerning stilbene dendrimers than azobenzene dendrimers. Both fields were reviewed together several years ago.47 As in the case of azobenzenes, the presence of stilbene at the core of dendrimers (Figure 4.1F) is expected to furnish the most important effects. For polyphenylene dendrimers the quantum yield of trans→cis isomerization is estimated to be 0.14, to be compared to the

Figure 4.11

Isomerization and photoreactivity of stilbene

Stimuli-Responsive Dendrimers

Figure 4.12

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Examples of dendrimers having stilbene as the core

value for stilbene (0.35); the trans to cis isomer ratio at the photostationary state was determined to be 8 : 92 for the first generation and 25 : 75 for the second generation.48 The cis to trans photoisomerization was studied in another paper.49 Various examples of stilbene dendrimers built with benzyl ether branches and having different types of terminal groups are known (Figure 4.12). The photoisomerization quantum yields measured for the dendrimer terminated by benzyl groups varied from 0.32 for G0 to 0.24 for G4. The diffusion coefficients D measured for the trans and cis forms display a larger difference for the highest generations, as expected.50 In view of fluorescence experiments, it was proposed that the photoisomerization of the C=C bond in the excited state may proceed by a volumeconserving novel mechanism, rather than by the conventional 180 ° rotation around the C=C bond.51 Modification of the terminal groups of the same dendrimers up to G3 by carboxylates induces solubility in water. The reaction quantum yields are lower than in the case of the neutral form.52,53 The isomer ratios of poly(glutamate) dendrimers at the photostationary state (trans/cis) were determined both for those terminated by ester groups (20 : 80 and 26 : 74, for G1 and G2, respectively) and for those terminated by carboxylate (16 : 84 and 15 : 85, for G1 and G2, respectively). It was noted that the cis isomer produced by photoisomerization generally undergoes either isomerization to the trans isomer or a cyclization reaction to give dihydrophenanthrene-type compounds.54 In the case of the poly(benzyl ether) dendrimer having stilbene derivatives, both at the core and as terminal groups (Figure 4.12), besides the trans→cis isomerization, both intramolecular and intermolecular CC bond forming was observed upon irradiation.55 Stilbene derivatives were also grafted on to the surface of dendrimers (Figure 4.1A). In the case of PPI dendrimers, the surface was covered by stilbene and benzene sulfonyl units in a nonstatistical 1 : 1 ratio (Figure 4.1C). The quantum yield of the trans→cis photoisomerization was 0.30 and the cis/trans ratio at the photostationary state was 9 : 1. The presence of excimers between the stilbene units was noted, as well as a photocyclization leading to phenanthrene.56 In another example, the grafting of functionalized stilbene or distyryl benzene on all the terminal groups of PPI dendrimers led to oligomerization/ cross-linking, inducing the disappearance of the typical fluorescent properties.57 The same type of observation was done by starting from small PAMAM and benzylether dendrimers ended by stilbene units.58 Several examples also exist of dendrimers possessing stilbene units in the whole structure (Figure 4.1L), but they were generally not used for studying their photoisomerization properties but their fluorescence properties.

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Figure 4.13

Two examples of photoresponsive dendrons affording gels

A few other types of photoresponsive dendrimers and dendrons are also known. For instance, an amino acid-based dendron having a nitrobenzylcinnamate core can selfassemble in organic solvents to form fibrous networks, inducing the gelation of the solution. Irradiation of the gel at 365 nm induces a gel to sol transition, due to the photodimerization of the nitrocinnamate group. This reaction and physical transition are both reversible by irradiation at 254 nm.59 In another example, UV light irradiation of dendrons having a spiropyran core induces their assembly in nanoparticles, due to the transformation of the core into the open merocyanine form, which leads to gel formation60 (Figure 4.13). PAMAM dendrimers (G3 to G5) terminated by nitrobenzyl groups were used to encapsulate salicylic acid and adriamycin. Irradiation of these dendrimers induced cleavage of the terminal groups and accelerated the release of the encapsulated drugs.61 However, this last work is not representative of the use of dendrimers as nanocontainers for drug delivery, which is most generally carried out with thermoresponsive dendrimers, as will be emphasized in the next section.

4.3 Thermoresponsive Dendrimeric Structures Some types of polymers are known to possess thermoresponsive properties. For instance, poly(N-isopropylacrylamide) (PNIPAAm) exhibits a temperature-dependent solubility, characterized by the lower critical solution temperature (LCST). These polymers have been extensively investigated for their potential as drug delivery devices.62 Thus it was tempting to generate such polymers as terminal groups of dendrimers or at the core of dendrons. However, besides polymers, several other types of functions are able to afford thermoresponsive dendrimeric structures, as will be illustrated in the next pages. 4.3.1 Thermoresponsive Properties of Dendrimers In most cases, the thermoresponsive properties of dendrimers are due to the presence of particular terminal groups, generally constituted of liner polymers. Dendrimer-based star polymers were obtained very early,63 but no thermoresponsive properties of these compounds were reported. The first example of dendrimers ended by PNIPAAm chains was obtained by free radical polymerization of N-isopropylacrylamide on a G3 PPI dendrimer, modified to have SH terminal functions. The resulting PPI-PNIPAAm star polymer was

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Figure 4.14 Schematized effect of temperature on the size of a dendrimer covalently covered by PNIPAAm chains (their structure is shown on the right)

used to encapsulate cobalt phthalocyanine complexes, which were used as catalysts for thiol oxidations. A very important decrease in the catalytic activity was observed compared to nonencapsulated phthalocyanines, but a 3 times increase of the turn over frequency was observed when the temperature was increased from 34 to 36 °C. This phenomenon is probably connected to structural changes in the dendrimeric host, favoring the accessibility of the substrate to the catalytic sites.64 Thermoresponsive star structures were also obtained from PAMAM dendrimers ended by PNIPAAm chains, and their properties were compared to those of linear PNIPAAm.65 Small polyester dendrimers ended by dithioesters were modified by PNIPAAm chains using reversible addition-fragmentation chain transfer (RAFT) polymerization. It is known that PNIPAAm chains collapse at T > 32 °C, because at this temperature water becomes a poor solvent for these chains; this induces a temperature dependence of the average hydrodynamic radius of the dendrimer–PNIPAAm structure. For instance, a decrease from 19 to 10 nm was observed when the temperature increases from 24 to 38 °C, due to shell shrinking; this modification is fully reversible upon cooling66 (Figure 4.14). Larger polyester hyperbranched polymers (not pure dendrimers) were also decorated by PNIPAAm chains, functionalized at their extremity by a thiol, which was used to covalently graft gold nanoparticles. Shrinkage upon increasing temperature was also observed, inducing a red shift of the surface plasmon resonance, characteristic of the decrease of relative distance between gold nanoparticles and of an enhanced interparticle coupling.67 These hyperbranched polyesters ended by PNIPAAm chains were later used as supports of a second thermoresponsive layer. Indeed, 2-(dimethylamino)ethyl methacrylate was also polymerized by RAFT from the PNIPAAm terminal function. This thermoresponsive double corona undergoes a two-phase transition temperature corresponding to the two types of polymers, at 32 °C for the PNIPAAm part and at 40–50 °C for the PDMA part. Two-stage thermally induced collapse was observed; this process is reversible with a twostage re-swelling.68 Besides thermoresponsive synthetic polymers, several types of oligopeptides were grafted as terminal groups of a small amidoester dendrimer,69 of small70 and large71 PAMAM dendrimers, to afford collagen mimetic dendrimers. In all cases, formation of triple helix structures was detected by circular dichroism. The effect of temperature on

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these compounds is not a phase transition, but a change in helix formation. It is known that collagen undergoes an irreversible transition to become gelatin at a melting temperature that depends on the sequence; in the case of the dendrimer–collagen, an unprecedented thermal reversibility was observed. These compounds were also used for the encapsulation and release of Rose Bengal (RB) as a model of drug. It was shown that the release was effectively suppressed at low temperature.71 Even smaller functional groups can afford thermosensitive dendrimers. For instance, phenylalanine residues grafted as terminal groups of PAMAM dendrimers induce changes in water solubility depending on the temperature. These compounds are soluble at low temperature, but become water-insoluble at temperatures above a specific threshold, which also depends on the pH of the solution.72 Isobutyramide (IBAM) groups were also grafted to the surface of PAMAM and PPI dendrimers. In these cases also, a turbidity change of the solutions in water took place at specific temperatures as the temperature was raised; these dendrimer solutions became transparent again when the temperature was decreased. The lowest LCST were obtained for the highest generations. The influence of the internal structure was determined by comparing the behavior of PAMAM and PPI dendrimers having the same number of IBAM groups. It was shown that PPI-based dendrimeric structures exhibit LCST at a much lower temperature than PAMAM, despite their lower molecular weight.73 Other types of alkylamide groups were used with PAMAM dendrimers and also afforded thermoresponsive structures.74 The encapsulation and release of Rose Bengal (RB) was studied with some of these dendrimers. It was shown that the amount of RB encapsulated in the dendrimer interior affected their temperature sensitivity.75 Phosphorus dendrimers ended by Girard’s reagents (cationic hydrazides) form hydrogels in water, even at low concentrations.76 In the presence of KI, the hydrogels are thermoreversible and the sol–gel transition temperature can be easily used in a wide range of temperatures (2–80 °C), depending on the dendrimer generation and concentration, and the quantity of salt.77 A few examples of dendrimers for which the thermoresponsive properties are at least in part due to the internal structure are known. For instance, the presence of carboranes at one layer inside the structure of aliphatic polyester dendrimers ended by alcohols induces lower critical solution temperatures (LCSTs). Precipitation occurs by heating the water solution of dendrimer G3 (4 carboranes, 32 OH) at 52 °C, of G4 (58 carboranes, 64 OH) at 83 °C, and of G5 (16 carboranes, 128 OH) at 63 °C.78 4.3.2 Thermoresponsive Properties of Dendrons and Dendronized Polymers A few examples of dendrons were shown to possess thermoresponsive properties. In particular, biaryl-based amphiphilic dendrons bearing pentaethylene glycol internal chains and decyl chains as terminal groups exhibit a generation-dependant LCST, at 42 °C for G1, 32 °C for G2, and 31 °C for G3.79 Oligothiophene dendrons bearing internal aliphatic substituents display reversible thermochromic behaviors, changing their color from red to yellow with increasing temperature. This behavior was observed for G2 and G3 but not for G1 or linear compounds.80 In fact, most examples concern dendronized polymers that are dendrons linked by their core to a linear polymer. Three main types of structures are known. In the first one, a dendron constitutes one end of the linear polymer (Figure 4.15A); such compounds are

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Figure 4.15 Different types of thermoresponsive dendronized polymers

generally synthesized by using the core of the dendron as the starting point of the polymerization reaction. In the second type of structure, both ends of the linear polymer are functionalized by dendrons (Figure 4.15B); such compounds are generally obtained by grafting two dendrons to a presynthesized polymer. The third type of structure corresponds to most popular type of dendronized polymers, in which the main linear chain is covered by dendrons (Figure 4.15C); such compounds can be obtained either by polymerization of the core of the dendrons or by grafting the dendrons by their core to a functionalized linear polymer. As an illustration of the thermoresponsive properties of structures of type A (Figure 4.15), the core of a poly(benzyl ether) dendron was used to elaborate a PNIPAm linear chain. These compounds form micelles, and the thermoresponsive collapse of the PNIPAm chain was shown to occur by a two-stage process, the first one occurring gradually between 20 and 29 °C, with the second one (main collapse) taking place at 29–31 °C.81 An example of a type B compound is afforded by a thermoresponsive PNIPAAm chain grafted with a biodegradable PLLA (poly(L-lactic acid)) and capped on both ends of the PNIPAAm chain by poly(L-lysine) dendrons. The LCST of these compounds is at about 30 °C.82 Interestingly, these compounds were used for thermally targeted and sustained delivery of pro-apoptotic ceramide C6 to solid tumor. The delivery displayed a bimodal pattern: an initial fast release within the first two days, followed by a slow release up to 33 days. The release was faster at temperatures below the LCST than above.83 Dendronized polymers of type C (Figure 4.15) were elaborated from oligoethyleneglycol dendrons possessing a terminal alcene at the core, used for the polymerization that creates the linear polymethacrylate polymer. The size of the dendrons and also the nature of their terminal groups have an influence on the LCST, which lies in a physiologically interesting temperature range (30–36 °C).84 Aggregation of the dendronized polymers with increasing temperature was observed, affording stable and rather monodisperse mesoglobules, for which the size depends on the heating rate.85 A deeper understanding of the thermal response of these compounds was recently obtained by using a spin probe detected by EPR.86 Poly(amido amine) dendrons having an ammonium as core and ended by short alkyl chains were grafted to an alternating copolymer of styrene and maleic anhydride. The resulting dendronized polymers possess thermo- and pH-dual responsive properties. The pH sensitivity is afforded by the tertiary amines of the PAMAM dendrons. The LCST values increased from Poly-G1 to Poly-G3. The pH values influence the LCST: on going from pH 6.0 to pH 10.0, the LCST values increase from 33.1 to 49.0 °C.87 PAMAM dendrons possessing a terminal alcene at the core were polymerized to afford dendronized poly(methacrylate). They also possess dual responsive properties. The highest LCST could be achieved either by increasing the size of the dendron or by decreasing the molecular

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weight of the dendronized polymer. The LSCT also increased significantly when the pH decreased below 7.0.88

4.4

Dendrimers Responsive to Solution Media Changes

In most cases, the media change concerns the pH of aqueous solutions of dendrimers, as will be emphasized in the next section. However, a few examples also exist in which the media change concerns the addition of a miscible organic solvent to water. In particular, addition of THF to a water solution of a phosphorus-containing dendrimer induced an expansion of the volume of 150%. This effect was due to the hydrophobic character of the interior of this dendrimer, which is shrunk in water to expose only the hydrophilic terminal groups to water. THF penetrates inside the structure of the dendrimer and induces its expansion.89 4.4.1

pH-Responsive Dendrimers

It is worth noting that this phosphorus dendrimer, which possesses a phthalocyanine as the core, is also a sensor for pH. Indeed, deprotonation or protonation induces dramatic changes in the UV–visible spectra.90 An analogous behavior was previously observed, for instance, for porphyrin and tetrabenzoporphyrin dendrimers.91 It was very early observed that pH changes induce drastic changes on the hydrodynamic radius of various types of dendrimers, depending in particular of the type of their terminal groups.92,93 Such behavior was found useful in particular for using dendrimers as controlledrelease systems (for more examples of drug-delivery systems, see Chapters 18 and 19). In many cases, these systems are based on PAMAM or PPI dendrimers, and the terminal groups are often modified to enhance the properties. However, even unmodified PPI dendrimers are able to encapsulate pyrene in aqueous basic solutions and to release it in acidic conditions, in which the environment becomes sufficiently polar to repel pyrene molecules.94 PPI dendrimers ended by quaternary ammonium groups were also used for the pH-controlled release of pyrene.95 Another modification of the terminal functions of PPI dendrimers consisted in adding a layer of PAMAM dendrons. In this case also, pyrene was dissolved inside the dendrimer at basic pH and released at acidic pH96 (Figure 4.16). Several examples of PPI dendrimers ended by some PEG groups also display pH-sensitive release properties. Among the 64 NH2 terminal functions, four or eight were modified by PEG derivatives and were used for solubilizing pyrene or betamethasone (valerate or dipropionate forms). Protonation of the tertiary amines of PPI does not induce a release of the encapsulated guests in this case, contrary to the previous cases.97 Together with the presence of four PEG chains, the remaining NH2 terminal groups were modified by guanidinium moieties. These compounds display acid- and salt-triggered release properties. Protonation modifies the location of the pyrene but does not induce its release in water, which is, however, achieved upon addition of sodium chloride (Figure 4.16). The same treatment also induces the release of betamethasone valerate.98 The presence of bis(mphenylene)-32-crown-10-functions as terminal groups of PPI dendrimers allows the for-

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Figure 4.16 Influence of pH on the structure of PPI or PAMAM dendrimers and on the trapping/release of guest molecules

mation of pseudo-rotaxanes by interaction with paraquat diol. Protonation of the internal structure of PPI induced an increase of the quantity of crown interacting with paraquat diol. This effect was attributed to a rigidification of the structure upon protonation, which renders the crown binding sites more accessible.99 In the case of PAMAM dendrimers, several examples concern unmodified terminal groups. It was shown that modification of the pH induced conformational changes and a slight increase in the radius of gyration at low (acidic) pH.100 In addition, using 5-(dimethylamino)-1-naphthalene sulfonic acid as the probe demonstrated an unusual pHdependent polarity change.101 It was shown that 2-naphthol binds preferentially to the tertiary amino groups in the interior of the dendrimeric structure and that it can be released by lowering the pH of the solution.102 Several examples of lipophilic drugs were dissolved in water by PAMAM dendrimers. The solubility of ketoprofen (a nonsteroidal antiinflammatory drug) was the highest at high pH and when using high generations of PAMAM dendrimers.103 The solubility of nifedipine (a calcium channel-blocking agent, poorly soluble in water) was greater in the case of PAMAM dendrimers ended by esters than ended by NH2, due to a lower degree of protonation.104 The influence of pH was also studied for PAMAM dendrimers coupled to Gd(III) complexes of ethylene propylenetriamine N,N,N′,N″,N″-pentaacetic acid. This compound is potentially a magnetic resonance imaging (MRI) contrast agent (see Chapter 16 for other examples of MRI agents). It was shown that the relaxivities of these complexes show a strong and reversible pH dependency.105 The same behavior was observed for PAMAM dendrimers coupled to Gd(III)-cyclen derivative complexes.106 4.4.2

Dendrimers Disassembly

This topic is connected to the previous one, in the sense that addition of a single reagent to a solution of dendrimer or an external event (heat, irradiation) can induce the disassembly of the dendrimer, either entirely or only of the terminal functions. The field of degradable dendrimers has been reviewed recently.107 One of the most famous examples concerns the thermal degradation of PAMAM dendrimers, which affords fractured

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dendrimers, commercially named SuperFect. These compounds have an undefined structure, but they display an increased efficiency for transfection experiments compared to native PAMAM.108 In early experiments, several methods were used for the cleavage of dendrimers. In particular, enzymatic degradation of a chiral polyester dendrimer was obtained in 1996,109 photoinduced covalent fragmentation of polyester dendrimers was reported in 2000,110 and several series of dendrimers built with biocompatible building blocks, such as glycerol, succinic acid, phenylalanine, or lactic acid, were found susceptible to both acid/base and enzymatic degradation in 2002.111 In all these early cases, the fragments of dendrimers were ill defined. In 2003, three independent groups reported the controlled cleavage of relatively small dendrons.112 An initial stimulus triggers a subsequent cascading destruction of the dendron into a number of smaller fragments. The group of D. V. McGrath reported the disassembly of benzylether dendrons initiated by allyl deprotection, which proceeded from the surface toward the core113 and also from the core toward the surface.114 In the other two cases, the triggering event occurs at the core and propagates toward the surface. The group of F. M. H. de Groot reported that a chemical reduction of a nitro group at the core of dendrons with Zn-AcOH triggers the cascade of self-elimination, inducing the release of four paclitaxel groups.115 The group of D. Shabat reported that tert-butoxy carbonyl (Boc) as the trigger group at the core of dendrons can be chemically removed by trifluoacetic acid, and after addition of NEt3, induced the release of 4-nitroaniline116 (Figure 4.17). This group has reported numerous other examples of dendrimer disassembly. This includes in several cases an enzyme substitute as the trigger, which can induce the release of drugs like doxorubicin117 or camptothecin.118 In these early examples, the dendrons are of generation 0, but the same concept was also developed toward the idea of selfimmolative dendrimeric amplifiers, in which the whole structure is broken through a domino-like chain fragmentation initiated by a single cleavage at the core. This concept was illustrated by the release of a reported fluorophore such as 6-aminoquinoline,119 aminomethylpyrene,120 or p-nitroaniline.121 The same type of method was applied for the direct

Figure 4.17 Structure of three dendrons for which an initial stimulus triggers a subsequent cascading destruction

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detection of triacetone triperoxide, which could be detected on a microgram scale,122 and also for the diagnostic assay for detection of penicillin-G-amidase.123 Other examples of biocompatible and degradable dendrimers were recently reported. One can cite in particular the degradation of dendrimers built with triazaadamantane as branching units, which hydrolyze under physiological conditions, leading to its basic precursors.124 An interesting concept was proposed by D. K. Smith and M. A. Kostiainen, who reported the interaction of dendrons ended by spermine derivatives with DNA and the subsequent optically triggered degradation of the surface groups, inducing the release of DNA.125 This concept was then developed with a fully degradable dendron.126 Besides the cleavage of the whole structure of dendrimers, several examples concern the cleavage of only the terminal groups. PPI dendrimers terminated by tBOC-protected L-phenylalanine derivatives constitute a dendritic box in which Bengal Rose and pnitrobenzoic acid were encapsulated. Hydrolysis of the tBOC groups with formic acid perforated the dendritic box, inducing the release of the encapsulated guests.127 Other early examples concern the PAMAM dendrimers terminated by carboxynitrobenzyl derivatives, which were cleaved by photolytic reactions,128 polybenzyl ester dendrimers ended by tBOC removable by trifluoroacetic acid, which were used in resist formulation for lithography,129 hydrolysis of imine terminal functions of phosphorus dendrimers, inducing the release of the insecticide fipronil,130 and reversible thermal cleavage of terminal Diels– Alder adducts of small polyester dendrimers.131 More recent examples concern in particular doxorubicin-functionalized bow-tie dendrimers in which doxorubicin is linked to the surface of the dendrimer through hydrazone linkages, which are cleaved in a pH-dependent manner (rapidly at pH = 5.0, slowly at pH = 7.0).132 PPI dendrimers were used for the conjugation of nitric oxide to secondary amine terminal groups and the release of NO under physiological conditions.133 The cleavage of 2-carbamoylbenzoate groups, also from the surface of PPI dendrimers, induced the release of volatile tertiary alcohol.134 Irradiation by one or two photons of PAMAM dendrimers ended by 2-methylthiane adducts induced the release of 1,3-dithiaheterocycles and generated diaryl ketones as terminal groups, inducing a seventeenfold increase in fluorescent intensity.135

4.5

Conclusion

Stimuli-responsive dendrimers offer a rich diversity not only of structures but also of properties. The stimulus is essentially light, heat, or pH variation. Depending on the chemical structure of the dendrimers (or dendrons), such stimuli induce different effects, in particular the modification of size, for azobenzene-containing dendrimers upon irradiation, for thermoresponsive dendrimers upon the influence of heat, and for protonable dendrimers upon pH variations. However, the most surprising property is certainly the disassembly of dendrimers. Indeed, the synthesis of dendrimers being long and tedious, it may appear strange to induce their disassembly into their elemental building blocks. Nevertheless, this property is particularly desirable in the case of in vivo uses of dendrimers. Despite a growing interest in this field, it is clear that numerous efforts have still to be done to attain a subtle balance between the stability necessary to reach the biological target and deliver the active

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substance and the disassembly needed to favor the rapid clearance from the body. Furthermore, the individual constituents issued from the disassembly must be chosen to be nontoxic and noninterfering with the biological system. This is another challenge.

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5 Liquid Crystalline Dendrimers Anne-Marie Caminade

5.1

Introduction

Liquid crystalline phases are a state of matter that has properties between that of crystalline solids and amorphous liquids. The different types of liquid crystalline phases can be distinguished by their different optical properties, in particular when viewed under a microscope using a polarized light source. Liquid crystalline phases can be divided into thermotropic (which occurs in a certain temperature range), lyotropic (which depends on the concentration in a solvent), and metallotropic phases (which are based on low-melting inorganic phases). The various liquid crystalline (LC) phases are called mesophases, and the mesogens are the molecules that create the mesophase. The main types of mesogens are calamitic (rod-like) and bowlic or discotic. In many cases, they are composed of aromatic rings linked to a long aliphatic chain. The classification of the various mesophases is based on the order and symmetry of the different molecular arrangements, in particular for thermotropic LCs. The thermotropic phases are stabilized by intermolecular interactions (dipolar, electrostatic, hydrogen bonding, van der Waals). Several types of thermotropic phases exist, in particular the nematic phases (N), the smectic phases (Sm), and the columnar phases (Col). The nematic phases (N) are one of the most common and the simplest LC phase. It is characterized by one-dimensional orientation order of the molecules; both calamitic and discotic mesogens can afford nematic phases (Figure 5.1A). The smectic phases are generally constituted by calamitic mesogens. They consist of the superposition of equidistant molecular layers that are ordered along one direction. The simplest smectic phase is the smectic A phase (SmA) in which the molecules are oriented along the layer normal. In the smectic C phases (SmC) the molecular direction is tilted with respect to the layer normal (Figure 5.1B). Other types Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 5.1

Examples of liquid crystalline phases; n is the director

of smectic phases exist, in particular the hexatic smectic phases. The columnar phases generally result from the stacking of bowlic or discotic molecules into columns, which are packed parallel, eventually organized into hexagonal (Colh), rectangle (Colr), oblique (Colo), or square (Cols) columnar phases (Figure 5.1C). The use of chiral mesogens induces chiral mesophases in which the director is forced to process through the phase, describing a helix. The chiral mesophases are noted with *, for example N* or SmC*. Liquid crystals are widely used in information display technology. To increase the functional capabilities of liquid crystals, the design of new types of self-assembled structures is important.1 Introducing mesogen groups as constituents of the structure of dendrimers (or dendrons) should lead both to self-organizing processes inside the dendrimers and to self-assemblies between dendrimers, which may afford new types of mesophases with uncommon morphologies. Such an idea has generated a lot of work, and several reviews have already emphasized the synthesis and the properties of the earliest examples of liquid crystalline dendrimers.2–5 This chapter will display a choice of the most salient examples. It will be organized depending on the location of the mesogenic groups in the structure of dendrimers and dendrons, essentially as terminal groups and rarely as branches. The liquid crystalline properties will be indicated in each case.

5.2

Mesogenic Groups as Terminal Functions of Dendrons

Most of the work in this field was carried out by the group of V. Percec, which has developed the original concept of self-assembly of dendrons with preprogrammed shapes into supramolecular cylindrical and spherical pseudo dendrimers, inducing their selforganization into various types of liquid crystalline mesophases.6 This group has developed a complete library of different generations of dendrons, from generation 0 to generation 5, but with a preference for the low generations (1 to 3). Figure 5.2 displays the most important units (types of terminal groups, branching units, and focal points) used for generating this very large library of mesogenic dendrons, and the main references. The terminal groups are most generally long aliphatic chains linked to 4-benzyl ether groups. Examples with a single aliphatic chain generally include a C12 chain,7–9 but also a C4, C6, C8, C1010 or C1611 chain, a chiral dimethyl C8 chain,10 and a partly fluorinated C12 chain,12 linked in all cases to a benzyl ether. Other examples of terminal groups are the C12 alkyl chain linked to an aryl group prolonged by a propyl ether,13 or to a series of two or three

Liquid Crystalline Dendrimers

Figure 5.2 dendrons

Examples of terminal groups, branching units, and focal points of Percec’s

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benzyl alcohols,14 or to a diphenyl propylether.15 In some cases, two C12 chains in the 3,4 position,16 or three C12 chains in the 3,4,5 position,17 linked to a benzylether, or three partly fluorinated C12 chains linked to a benzylether were also reported.18 The length of the three chains has also been varied from C4 to C16.19 The branching units are most generally 3,4-20 or 3,5-21dihydroxybenzyl alcohol and 3,4,5-trihydroxybenzyl alcohol,22,23 but some variations include the presence of a propylether13,24 or a series of two25 or three14 benzyl alcohols, or two aryl groups.15,26 The core functionality is often a methylester, a benzyl alcohol, or a carboxylic acid,7–9 but other functionalities are possible, such as a propylester,24 a series of three benzyl alcohols,10,14 a crown ether,12 an alkene group polymerized to polystyrene or polymethacrylate,20 an alkyne group polymerized into polybenzylacetylene,27,28 or various dipeptides;29–33 two dendrons were also grafted to a U-shaped core.34 Most generation 1 dendrons have a flat tapered fan, a semi-discoid or even a discoid shape, favoring the Colh phases. The importance of temperature upon the type of phase has been shown. Increasing the temperature induces the shrinkage and the conversion of a cylindrical shape into a spherical shape.35 The influence of the core functionality is of crucial importance for the induction or stabilization of the mesophases with these low generation dendrons; it follows the order: CO2H > CH2OH > CO2Me. These small dendrons having a polar core and aliphatic terminal groups aggregate into infinite supramolecular columns, which self-organize into rectangular and/or hexagonal lattices. A different behavior is observed with larger dendrons. Indeed, they have generally a conical shape, in particular with the most branched architectures in which a restricted cooperative rotation of the external benzyl ether induces the conical shape. These dendrons self-organize into hemi-spherical and pseudo-spherical shapes, and the largest dendrons (in particular generation 5) become a single sphere. These spheres or pseudo-spherical shapes at their turn self-organize into different liquid crystalline phases, in particular cubic and tetragonal lattices (Figure 5.3).14 Such processes are driven in most cases by H-bonding interactions,

Figure 5.3 Main types of LC arrangements obtained with small dendrons and larger dendrons by the group of V. Percec (Sm = smectic, Col = columnar, Cub = cubic, Tet = tetrahedral)

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intramolecular microsegregation, and steric constraints, and were also studied by atomistic simulations.36 It is interesting to note that a new mesophase was discovered with a third generation dendron (see the first line of Figure 5.2 for its structure). It consists of a tetragonal three-dimensional unit cell, composed of ca. 30 globular pseudo dendrimers, each of them resulting from the self-assembly of ca. 12 dendrons.9 Also a liquid quasi-crystalline phase, which is a new mode of organization of soft matter, was obtained in the case of a second generation dendron.21 The nature of the function at the core is also important. In the case of the crown ether, the self-assembling process is increased after complexation with NaOH.37 Among the various types of core functions, one has to mention in particular the dipeptides, which induce the self-assembly of dendrons into helical pores through a complex recognition process; proton transport measurements established that these pores are functional.29 The presence of a polymerizable function at the core (styrene or methacrylate) led to dendronized polymers,20 which generally self-organize into helical conformations; this field was recently reviewed.38 A few other types of dendrons having liquid crystalline properties were also synthesized by other groups (Figure 5.4). For instance, a third generation dendron based on natural amino acids was used as an organogelator, but it also displayed lyotropic liquid crystalline properties in benzyl alcohol. At about 6 wt%, spherulites and oily streaks appeared. When increasing the concentration, a polygonal texture was observed.39 A folic acid dendron built with oligo(glutamic acid) moieties and lipophilic terminal chains exhibit a thermotropic hexagonal columnar phase and a cubic phase. The organization is guided by the formation of a hydrogen-bond tetramer between the core functionalities.40 An amphiphilic polyether dendron having C18 alkyl chains as terminal groups and a long polyethyleneglycol chain as the core (Figure 5.4) exhibit multiphases that combine the influence of the linear polymer with that of the dendritic system, depending on the temperature. This thermotropic behavior includes crystalline lamellar, micellar, hexagonal columnar, continuous cubic, and disordered phases.41 It was shown that the phase behavior, in particular the crystallinity, was dependent on the generation of the dendron. The first generation did not display any liquid crystalline phase.42 A nanohybrid was obtained by combining this dendron with aluminosilicate by a sol-gel process.43

Figure 5.4

Other types of dendrons having liquid crystalline properties

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A large series of dendrons/dendrimers having a fullerene (C60) as the core was also shown to display liquid crystalline properties; this field was recently reviewed.44 The main idea for the synthesis of such compounds was to combine the electrochemical and photophysical properties of fullerene with the self-assembling properties of liquid crystals, toward the elaboration of novel molecular devices. The grafting of C60 at the core follows two main strategies: either via malonate derivatives leading to methanofullerenes or via 1,3-dipolar cycloadditions, giving rise to fulleropyrrolidines. The supramolecular organization of the fullero-dendrons is practically similar to that of the corresponding malonate precursor, as a consequence of the burying of C60 within the dendrimeric structure. The only exception concerns a very small dendron, where the nematic phase was replaced by a smectic A phase upon the addition of C60 via a methanofullerene. The other generations display a smectic A phase in both cases.45 Another type of dendrimeric methanofullerene containing ferrocenees in the branches and cholesteryl derivatives as terminal groups displayed an enantiotropic smectic A phase46 (Figure 5.5). The same terminal groups were

Figure 5.5

Some examples of liquid crystalline dendrimeric fullerenes

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also grafted on to a small polyarylester dendrimer.47 The use of 1,3-dipolar cycloadditions allows the grafting of two types of dendrons (Janus-type compounds), such as cyanobiphenyl on one side and ferrocene48 or oligophenylenevinylene49 on the other side; both compounds exhibit a Smectic A phase. Another example was afforded by the grafting of two mesomorphic polyether dendrons functionalized either with cyanobiphenyl groups (inducing lamellar mesophases) or alkyl chains (displaying columnar mesomorphism). Depending on the relative size of each dendron, the liquid crystalline properties of these Janus compounds could be tailored, from smectic (A or C phases) to columnar phases. The C60 unit did not influence the type of mesophase formed.50 Optically active fulleropyrrolidine dendrimeric liquid crystals having a chiral carbon at the point of junction between the fullerene and the mesogenic moieties were also synthesized. These compounds exhibit supramolecular helicoidal organizations that are right- or left-handed depending on the diastereoisomer used.51

5.3

Mesogenic Groups as Terminal Functions of Dendrimers

Among the first examples of dendrimers having liquid crystalline properties thanks to their terminal groups, those obtained from carbosilane dendrimers, first52 and second53 generations, constitute a special class. The combination of the flexible carbosilane scaffold with rigid mesogenic units (cyanobiphenyl) led to a smectic A phase. Other examples of siliconcontaining dendrimers were proposed. They include a small carbosilane ended by bananashaped mesogenic units, which led to polar smectic phases. On applying a strong electric field, a ferroelectric state was observed.54 A first generation carbosilane dendrimer built from an octasilsesquioxane core (Si8O12) and ended by a laterally substituted mesogen afforded enantiotropic chiral nematic, disordered hexagonal columnar, and disordered rectangular columnar phases.55 Carbosilazane dendrimers modified with mesogenic terminal groups display enantiotropic nematic phases (Figure 5.6).56 Several other types of flexible dendrimers terminated by mesogenic groups were synthesized. Small dendrimers having a vanadyl group at the core were certainly the first

Figure 5.6 properties

Examples of carbosilane and carbosilazane dendrimers having liquid crystalline

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examples of liquid crystalline dendrimers, even if they were not claimed to be dendrimers. These compounds exhibit an unusual inverted phase behavior with a more ordered phase at high temperature.57 Other examples of LC dendrimers include aliphatic polyesters leading to ferroelectric smectic C liquid crystalline phases.58 The grafting of cyanobiphenyl mesogens as terminal groups of several generations of PPI dendrimers afforded smectic A mesophases in all cases,59 whereas discotic triphenylene moieties led to a rectangular columnar mesophase for the first generation and to hexagonal columnar mesophases for generations 2 to 5.60 PAMAM dendrimers terminated by a mixture of two types of promesogenic units afforded various types of LC mesophases, depending on the ratio of both units, in particular smectic (A and C) and columnar phases.61 Comparison between properties of PPI and PAMAM dendrimers terminated by the same type of mesogenic units derived from salicylaldimine shows that the mesomorphic properties are, on average, improved in the PAMAM compounds,62,63 in particular a wide mesophase temperature range. In both cases, the type of arrangements depends on the number of alkyl chains for mesogenic units; one chain favors the smectic mesomorphism (A and C), whereas increasing the number of alkyl chains favors the formation of columnar structures.64 Various complexes (Cu2+, Ni2+, Zn2+) of small generation (1 and 2) polyethyleneimine dendrimers terminated by long alkyl chains gave an original example of hexagonal columnar mesophase.65 Polyaryl ether dendrimers functionalized by mesogenic terminal groups through the complexation of gold show smectic (A and C) phases and columnar hexagonal phases; their formation is governed by steric and dipolar interactions66 (Figure 5.7). Some particular dendrimeric compounds having flexible structures were also synthesized. Several examples of Janus-like dendrimers were obtained by connecting two dendrons differing in their chemical constitution and generation number. The mesomorphic properties could be tuned by varying the size of the hydrophilic wedge (hydroxyl terminal groups) and of the hydrophobic wedge (aliphatic terminal groups), inducing columnar or cubic phases.67 Additional examples of Janus dendrimers were already shown in Figure 5.5 in the case of fullerene cores. A first generation dendrimer constituted of ethyleneglycol chains and having a bistable rotaxane derivative as the core associates in smectic A phases over a wide temperature range, including at room temperature (Figure 5.8).68 Besides highly flexible dendrimers, some rigid dendrimers were also used as support of promesogenic terminal groups. Generations 1 to 3 of rigid phenyl acetylene dendrimers functionalized with isophthalic and short PEG chains as terminal groups exhibit columnar discotic liquid crystalline phases over a wide temperature range. However, the corresponding fourth generation was found to be amorphous.69 Stilbenoid dendrimers, which also have a rigid skeleton terminated by long alkyl chains, generate various types of discotic phases (hexagonal, rectangular, oblique).70 Generations 1 and 2 have a disk-like shape, inducing columnar liquid crystalline phases; the higher generations (2 to 5) have a cylindrical shape and no LC properties.71 The photochemistry and fluorescence properties of the first generations were investigated in the different LC phases.72 The second generation polyphenylene-based rigid dendrimeric porphyrin terminated by long alkyl chains led to rectangular columnar mesophases, whereas the first generation has no LC properties73 (Figure 5.9). The last type of dendrimer in which the surface affords the mesogenic properties was obtained by noncovalent interactions with PAMAM and PPI dendrimers. The primary amine terminal groups of these dendrimers were reacted with a carboxylic acid group bearing a long alkyl chain as a substituent, leading to ammonium/carboxylate saline

Liquid Crystalline Dendrimers

Figure 5.7 structure

Some examples of liquid crystalline dendrimers having a flexible internal

Figure 5.8 Some particular structures of flexible dendrimeric structures having liquid crystalline properties

133

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Dendrimers

Figure 5.9

Some examples of liquid crystalline dendrimers having a rigid internal structure

Figure 5.10

Ionic liquid crystalline dendrimers

species. These compounds exhibit thermotropic liquid crystalline behavior, and tend to assemble in smectic LC phases. The only exception comes from the fifth generation PPI dendrimer, which self-assembles into a columnar supramolecular structure.74 The same method was used for interacting PPI dendrimers with two different carboxylic derivatives, one with an alkyl chain and the other with a perfluoroalkyl chain. With a majority of one of these terminal functions, incompatible ionic terminal groups tend to segregate, but the presence of the majority groups obscurs the minority groups effect, and conventional lamellar phases (smectic A phases) were obtained. When the quantity of both groups is similar, no long-range order was observed75 (Figure 5.10).

5.4

Mesogenic Groups as Branches of Dendrimers

In contrast to the large number of dendrimers and dendrons terminated by mesogenic groups, dendrimers in which the whole structure is constituted of mesogenic groups (often

Liquid Crystalline Dendrimers

Figure 5.11

135

Two examples of main-chain liquid crystalline dendrimers

called main-chain liquid crystalline dendrimers) are rare. An amplification of the LC properties is expected for such dendrimers. The first example was based on terphenylene monomeric units. Three generations of dendrimers were obtained by grafting three dendrons on to a tribenzoic core. They form enantiotropic N and smectic phases,76 which were attributed to particular chain conformations, implying that all the subunits lie parallel to each other, giving an overall rod-like shape.77 Small generation dendrimers based on branches containing mesogenic units afford mesophases whose morphology depends on the number of terminal chains per terminal group. The dendrimer bearing a single chain per terminal unit has an elongated rod shape and exhibits smectic A and B phases.78 In contrast, the dendrimer having two or three chains79 per terminal unit adopts a wedge-like conformation, which leads to a self-assembly into (supra)molecular disk and columnar phases (Figure 5.11).

5.5

Conclusion

Most of the work concerning dendrimers and dendrons having liquid crystalline properties was carried out up to now for fundamental purposes. These compounds led to classical mesophases such as nematic, lamellar, columnar, or cubic phases, but also to less common phases and to the discovery of new types of mesophases. Indeed, liquid crystal dendrimers present some features different to those of conventional LCs, because the promesogenic

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units are arranged in a highly congested environment, with a restricted mobility. In many cases an enhancement of the mesophase stability was observed. Most of the work has been done with thermotropic liquid crystalline dendrimers. Lyotropic liquid crystalline dendrimers have not been described as extensively, probably because materials for advanced technologies need LCs in the bulk phase. In view of the numerous uses of classical liquid crystals, it is expected that liquid crystalline dendrimers may lead to uses in nano- and biotechnologies. However, the examples are still rare, even if several recent patents have claimed such uses.

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(51) S. Campidelli, P. Bourgun, B. Guintchin, J. Furrer, H. Stoeckli-Evans, I. M. Baez, J. W. Goodby, and R. Deschenaux (2010) Diastereoisomerically pure fulleropyrrolidines as chiral platforms for the design of optically active liquid crystals. J. Am. Chem. Soc., 132, 3574–3581. (52) S. A. Ponomarenko, E. A. Rebrov, A. Y. Bobrovsky, N. I. Boiko, A. M. Muzafarov, and V. P. Shibaev (1996) Liquid crystalline carbosilane dendrimers: first generation. Liq. Cryst., 21, 1–12. (53) K. Lorenz, D. Holter, B. Stuhn, R. Mulhaupt, and H. Frey (1996) A mesogen-functionalized carbosilane dendrimer: a dendritic liquid crystalline polymer. Adv. Mater., 8, 414–416. (54) G. Dantlgraber, U. Baumeister, S. Diele, H. Kresse, B. Luhmann, H. Lang, and C. Tschierske (2002) Evidence for a new ferroelectric switching liquid crystalline phase formed by a carbosilane based dendrimer with banana-shaped mesogenic units. J. Am. Chem. Soc., 124, 14852–14853. (55) I. M. Saez, J. W. Goodby, and R. M. Richardson (2001) A liquid-crystalline silsesquioxane dendrimer exhibiting chiral nematic and columnar mesophases. Chem.-Eur. J., 7, 2758–2764. (56) R. Elsasser, G. H. Mehl, J. W. Goodby, and M. Veith (2001) Nematic dendrimers based on carbosilazane cores. Angew. Chem. Int. Ed., 40, 2688–2690. (57) A. G. Serrette and T. M. Swager (1993) Controlling intermolecular associations with molecular superstructure. Polar discotic linear-chain phases. J. Am. Chem. Soc., 115, 8879–8880. (58) P. Busson, H. Ihre, and A. Hult (1998) Synthesis of a novel dendritic liquid crystalline polymer showing a ferroelectric SmC* phase. J. Am. Chem. Soc., 120, 9070–9071. (59) M. Baars, S. H. M. Sontjens, H. M. Fischer, H. W. I. Peerlings, and E. W. Meijer (1998) Liquid-crystalline properties of poly(propylene imine) dendrimers functionalized with cyanobiphenyl mesogens at the periphery. Chem.-Eur. J., 4, 2456–2466. (60) M. D. McKenna, J. Barbera, M. Marcos, and J. L. Serrano (2005) Discotic liquid crystalline poly(propylene imine) dendrimers based on triphenylene. J. Am. Chem. Soc., 127, 619–625. (61) J. M. Rueff, J. Barbera, B. Donnio, D. Guillon, M. Marcos, and J. L. Serrano (2003) Lamellar to columnar mesophase evolution in a series of PAMAM liquid-crystalline codendrimers. Macromolecules, 36, 8368–8375. (62) J. Barbera, M. Marcos, and J. L. Serrano (1999) Dendromesogens: liquid crystal organizations versus starburst structures. Chem.-Eur. J., 5, 1834–1840. (63) M. Marcos, R. Gimenez, J. L. Serrano, B. Donnio, B. Heinrich, and D. Guillon (2001) Dendromesogens: liquid crystal organizations of poly(amidoamine) dendrimers versus starburst structures. Chem.-Eur. J., 7, 1006–1013. (64) B. Donnio, J. Barbera, R. Gimenez, D. Guillon, M. Marcos, and J. L. Serrano (2002) Controlled molecular conformation and morphology in poly(amidoamine) (PAMAM) and poly(propyleneimine) (DAB) dendrimers. Macromolecules, 35, 370–381. (65) U. Stebani, G. Lattermann, M. Wittenberg, and J. H. Wendorff (1996) Metallomesogens with branched, dendrimeric amino ligands. Angew. Chem. Int. Ed. Engl., 35, 1858–1861. (66) C. Cordovilla, S. Coco, P. Espinet, and B. Donnio (2010) Liquid-crystalline self-organization of isocyanide-containing dendrimers induced by coordination to gold(I) fragments. J. Am. Chem. Soc., 132, 1424–1431. (67) I. Bury, B. Heinrich, C. Bourgogne, D. Guillon, and B. Donnio (2006) Supramolecular selforganization of “Janus-like” diblock codendrimers: synthesis, thermal behavior, and phase structure modeling. Chem.-Eur. J., 12, 8396–8413. (68) I. Aprahamian, T. Yasuda, T. Ikeda, S. Saha, W. R. Dichtel, K. Isoda, T. Kato, and J. F. Stoddart (2007) A liquid-crystalline bistable [2]rotaxane. Angew. Chem. Int. Ed., 46, 4675–4679. (69) D. J. Pesak and J. S. Moore (1997) Columnar liquid crystals from shape-persistent dendritic molecules. Angew. Chem. Int. Ed. Engl., 36, 1636–1639. (70) H. Meier and M. Lehmann (1998) Stilbenoid dendrimers. Angew. Chem. Int. Ed., 37, 643–645. (71) H. Meier, M. Lehmann, and U. Kolb (2000) Stilbenoid dendrimers. Chem.-Eur. J., 6, 2462–2469. (72) M. Lehmann, I. Fischbach, H. W. Spiess, and H. Meier (2004) Photochemistry and mobility of stilbenoid dendrimers in their neat phases. J. Am. Chem. Soc., 126, 772–784.

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(73) M. Kimura, Y. Saito, K. Ohta, K. Hanabusa, H. Shirai, and N. Kobayashi (2002) Selforganization of supramolecular complex composed of rigid dendritic porphyrin and fullerene. J. Am. Chem. Soc., 124, 5274–5275. (74) R. Martin-Rapun, M. Marcos, A. Omenat, J. Barbera, P. Romero, and J. L. Serrano (2005) Ionic thermotropic liquid crystal dendrimers. J. Am. Chem. Soc., 127, 7397–7403. (75) S. Hernandez-Ainsa, M. Marcos, J. Barbera, and J. L. Serrano (2010) Philic and phobic segregation in liquid-crystal ionic dendrimers: an enthalpy–entropy competition. Angew. Chem. Int. Ed., 49, 1990–1994. (76) V. Percec, P. W. Chu, G. Ungar, and J. P. Zhou (1995) Rational design of the first nonspherical dendrimer which displays calamitic nematic and smectic thermotropic liquid-crystalline phases. J. Am. Chem. Soc., 117, 11441–11454. (77) J. F. Li, K. A. Crandall, P. W. Chu, V. Percec, R. G. Petschek, and C. Rosenblatt (1996) Dendrimeric liquid crystals: isotropic-nematic pretransitional behavior. Macromolecules, 29, 7813–7819. (78) L. Gehringer, C. Bourgogne, D. Guillon, and B. Donnio (2004) Liquid-crystalline octopus dendrimers: block molecules with unusual mesophase morphologies. J. Am. Chem. Soc., 126, 3856–3867. (79) L. Gehringer, D. Guillon, and B. Donnio (2003) Liquid crystalline octopus: an alternative class of mesomorphic dendrimers. Macromolecules, 36, 5593–5601.

6 Dendrimers and Nanoparticles Cédric-Olivier Turrin* and Anne-Marie Caminade

6.1

Introduction

The use of dendrimers to design nanoparticles (NPs) is highly related to the bottom-up approach in nanotechnologies. Actually, dendrimers can be finely tuned in size, topology, and functionality at the nanometer scale, and thus provide a high degree of control on the interface created between dendrimers or dendrimeric architectures and other nano-objects. This point is often crucial in the systemic approach to the design of complex nano-objects, where both the nature of all components and the way they interact matter. In this regard, the study of the interactions between dendrimers (or dendrons) and metallic or metal oxide NPs is flourishing, and the number of publications related to this field has been multiplied by a factor of thirtyfold over the last decade according to Web of Sciences™. The synthesis of systems comprising dendrimers and NPs is strongly influenced by the size and shape of the dendrimeric stabilizer (see Figure 6.1), although many other parameters play a crucial role, like the metal/dendrimeric ligand ratio or the nature of the metallic precursor or reducing agent if applicable. In fact, dendrimeric architectures can be equipped with a large variety of donor ligand systems, providing a densely functionalized and stabilizing outer shell that plays a crucial role in the stabilization of NPs, which can occur during the direct synthesis of NPs by reduction of metal salts or by postsynthesis treatment through ligand exchanges. These routes gave rise to relatively well-defined dendrimer-stabilized nanoparticles (DS NPs) with relatively small dendrimers as well as interdendrimeric composite architectures with higher generation dendrimers where the metallic species and dendrimeric ligands are

* Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 6.1 Dendronized NPs or nanoparticle-cored dendrimers (A), dendrimer-stabilized NPs (B), interdendrimeric composite architectures (C) and dendrimer-encapsulated NPs (D)

intimately connected.1 Alternatively, the use of dendrons led to dendronized NPs or nanoparticle-cored dendrimers (NCDs). Finally, the inner structure of dendrimers can also provide a suitable environment for the stabilization of nanoparticles, which can be in this case directly synthesized in situ from metal salts. Actually, the interior of dendrimers is highly ramified and offers tiny pockets surrounded by a high number of heteroatoms, which are commonly involved in the design of ligand systems (nitrogen, oxygen, phosphorus, sulfur). This strategy has been initially reported in 1998 by the groups of R. M. Crooks,2 L. Balogh,3 and K. Esumi,4 whose seminal works in this field led to the concept of dendrimer encapsulated nanoparticles (DENs) and paved the way for elegant and efficient stepwise procedures to produce such systems, which are finding expanding areas of applications, in particular catalysis, which is partly discussed in chapters 10 and 11.5–7

6.2 6.2.1

Dendrimers or Dendrons for Coating Nanoparticles Dendronization of Nanoparticles by Ligand Exchange

Dendrons having at their focal point a strong metal binding function, like a mercapto group, have been early assayed as NP coating agents. In this case the dendrimeric architecture provides a steric stabilization and can also provide other peculiar properties that may not be systematically brought by the dendron itself, but may result from its selfassembly around the metallic core. In a pioneering example, the group of D. Astruc has reported on gold NPs partially covered with redox active dendrons by ligand exchange.8,9 These systems having peripheral ferrocenes were found to selectively recognize and titrate H2PO4− and ATP2− anions, even in the presence of other anions, and the recognition properties were enhanced by the clusterization of recognition sites on the outer shell of the dendronized gold NPs. Recently, the group of B. Donnio has reported on the synthesis of a second generation Fréchet-type dendron having a thiol function at the focal point, which can partially substitute dodecanethiol ligands on the surface of small gold NPs10 (average diameter 2.1 nm, σ = 0.5 nm). The resulting dendronized gold NPs were assumed to be polyhedrons covered in a very compact fashion by 41 dendrons and 56 dodecanethiols as

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Figure 6.2

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Dendronized mesogenic gold NPs10

determined by NMR, and the average surface coverage was calculated at 18.1 ± 0.5 Å2. Interestingly, although none of the components of the system is mesomorphic, the dendronized gold NPs were found to self-assemble as a thermotropic cubic mesophase in the bulk or as a two-dimensional hexagonal lattice on the surface. This point was rationalized by the authors on a dendron design basis. Actually, each structural part of the latter plays a precise role: the dodecyl spacer allows the dendrimeric specie to approach the gold NP surface initially covered by a dodecanethiol protecting layer, the aromatic rings provide rigidity and cone-like conformation in order to favor interactions between particles, and the four alkyl tails give fluidity to the system (see Figure 6.2). The displacement of linear dodecanethiols that are bonded to the gold surface (S–Au bond strength energy 45 kcal mol−1)11 and tightly interacting through van der Waals lipophilic interactions (a few kcal mol−1 per CH2) by a sterically demanding ligand was not rationalized, although the large excess of dendrimeric ligand used in these ligand exchange experiments could be the main driving force. The strong binding force between sulfur headgroups and metals has led to several examples of dendronized metallic or bimetallic NPs obtained by ligand exchanges, in particular with NPs having weaker ligand systems. The now commercially available cystamine cored PAMAM bisdendrimers12 are of great interest for these purposes, as they can be readily reduced to thiol-cored PAMAM dendrons. The latter were successfully used to prepare dendronized gold and CdSe/CdS (core–shell) quantum dots13 (QDs) by displacement of their citrate protecting shell. A collection of dendrons of generation 1 to 3 with different end groups (carboxylic acid, hydroxyl, amine, and protected amine) was used. In the case of gold NPs (average core size 5 nm), the Au/SH ratio was adjusted to 1 : 0.78. Since TEM images only dense metallic cores, this technique could not afford precise information concerning the size modifications as a function of the dendron generation, but gel electrophoresis (PAGE) allowed the authors to evidence the size increase from generation 1 to 3. In the case of CdSe/CdS quantum dots (average core size 4 nm), the thiol/metal ratio was set to 1, and it was clearly found that the first generation dendron could not efficiently stabilize the QDs as massive irreversible aggregation was observed upon

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concentration whereas the generation 2 PAMAM dendron allowed a tenfold concentration of the reaction solutions. In all cases, all mixtures were stable enough to allow removal of unreacted dendrons as well as released citrate by washings or purification by size exclusion chromatography on a Sephadex column. The luminescent spectrum of the dendronized QDs showed about 60% quenching in comparison to the native citrate protected QDs, which could impair them from certain fields of application where high concentrations of QDs with strong luminescent properties are required. Although the nature of the hybrid interface in terms of ligand coverage and the influence of the surface function of the dendrons were not studied by the authors, the system could be improved by changing the nature of the anchoring focal point and the nature of the dendron.14 Actually, hydroxylterminated poly(alkyl ether) dendrons (generations 1 and 2) equipped with a triaryl phosphine at their focal points were synthesized with protected pentaerythritol moieties for this purpose, and the resulting dendronized QDs did not show any fluorescent quenching. Although their stability toward aggregation upon concentration was not thoroughly studied, the dendron capping was found to protect the metallic cores efficiently from chemical and oxidative degradation, and such water-soluble systems can be considered as fairly good candidates for biological purposes. Remarkably, the dendrons used in this study were equipped with a short oligoethylene glycol spacer to move the anchoring phosphine away from the dendron structure and reduce the steric hindrance at the surface of the metallic core. This slight chemical modification is supposed to facilitate the ligand exchange and, in the light of the work by Donnio et al.,10 it could also be responsible for the enhancement of the stability properties. The surface coverage was not evaluated but the luminescent properties enhancement (in comparison with thiol focal point functionalized PAMAM dendrons) was assumed to be clearly influenced by the phosphine anchoring point, and not to other structural parameters like the nature of the dendrons interior or their surface groups. Highly stable luminescent CdSe/CdS core–shell nanocrystals isolated in a dendron box were also prepared by the group of X. Peng in an elegant fashion by means of dendron ligands having polymerizable ethylene end groups and a thiol function at the focal point, which remains masked by a trityl group during the divergent procedure.15 In a mixture of methanol and chloroform, all stabilizing primary amines and/or trioctylphosphine oxide ligands capping the QDs (average core size 3.5 nm) were totally displaced by thiol dendrons, as evidenced by 1H NMR. This complete ligand replacement may appear contradictory with the bulkiness of the dendron wedge that surrounds the anchoring thiol functions; nevertheless, the possibility that some tertiary amines or even some terminal vinyl groups may participate to some extent to the overall electronic stabilization of the QD surface cannot be excluded. Again, the photoluminescent properties were found to be quenched (by a factor of 80%), presumably because of the presence of the sulfur anchor. The elegant peculiarity of these dendronized QDs resides in the possibility to crosslink the terminal vinyl groups of the dendrons (see Figure 6.3) using a Grubbs catalyst, in order to produce what the authors coined as “box nanocrystals”, that is a dendron box around an isolated nanocrystal. Remarkably, the properties of the semi-conducting core were not affected by the metathesis polymerization, and only isolated box nanocrystals were obtained, as no crosslinking between each entity could be observed thanks to the close packing nature of the double bonds at the surface of the dendron monolayer coatings. The HCl digestion of these box nanocrystals allowed the authors to recover “empty” dendron boxes containing

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Figure 6.3 From dendronized NPs to box nanocrystals and hollow boxes (insert: calcination)

15 to 50 dendrons units, as revealed by mass spectrometry. Interestingly, the quantum dots sealed in dendron boxes possessed a superior stability toward chemical, photochemical, and thermal treatments and the photoluminescence properties could even be enhanced by controlled oxidation of the metallic core. The same group also reported on the preparation of CdSe/CdS core–shell box nanocrystals prepared via the so-called dendrimer bridging strategy, which consists in the covalent wrapping of surface alcohol functions of dendrons with a generation 2, amine-terminated, PPI dendrimer in the presence of N,N´-disuccinimidyl carbonate.16 The resulting dendrimerbridged, water-soluble box nanocrystals were obtained as individual species and exhibited a high stability under harsh chemical, thermal, and photochemical conditions and the photoluminescence properties were found to follow similar trends to those observed through the ring-closure metathesis procedure described above. The amine-wrapped box nanocrystals were successfully conjugated with biotine, and the photoluminescent properties of these water-soluble systems were kept constant for at least several months under ambient conditions. Another strategy to coat Cd/Se nanocrystals involves the use of oligothiophene dendrons having a phosphonic acid at their focal point (see Figure 6.4).17 The coordination of the anchoring point was clearly established by FT–IR studies, but required an intermediary ligand exchange with pyridine. It was evidenced that phosphonic acids were not condensed on the surface, as shown by the existence of the P–OH bands (in the 1010 cm−1 region) after ligand exchange, and a Lewis acid coordination mode to cadmium atoms was assumed in the light of the decrease of intensity of the P=O stretching vibration (1180 cm−1). With both generation 1 and 2 dendron ligands, the photoluminescence properties of resulting dendronized Cd/Se QDs were completely quenched, possibly because of electron transfer between the ligands and the nanocrystals. Nevertheless, these dendronized QDs were successfully spin-coated on to ITO (and characterized by AFM on mica) to produce a simple one-layer photovoltaic device that showed a power conversion of 0.29%.17 The coordination properties of phosphonic acids at the focal point of dendrons have also been studied toward maghemite NPs.18 For this purpose, small mesogenic dendrons containing linear oligo(phenylene vinylene) units (OPV) and aliphatic tails were built by palladium-catalyzed Heck coupling reactions. The phosphonate moiety was added by a Pd-catalyzed phosphonation of an aromatic sulfonate located at the focal point, and it was easily converted to the corresponding phosphonic acid by treatment with

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Figure 6.4

Oligiothiophene dendrons with a phosphonic acid core

bromotrimethylsilane and subsequent methanolysis. Surfactant-free ferrite NPs were easily functionalized with the mesogenic and luminescent dendrons in dilute THF solutions. The average number of dendrons on these 39 nm NPs was determined either indirectly by UV–vis titration of the nongrafted ligands or by thermogravimetric analysis (TGA) of the final system, the organic part being fully decomposed at 250–300 °C. According to the latter method, it was found that the full coverage of NPs was possible with linear ligands or a generation 0 dendron, and the coverage rate dropped to 78% and 66% with generation 1 dendrons having 1 or 2 OPV units in their structure, respectively. The 100% surface coverage was calculated by normal projection of the alkyl chain crosssections of the ligands to the ferrite surface, and then compared to the number of dendrons per NP obtained by TGA. These results were roughly confirmed by UV–vis titrations, and they highlight the fact that steric demand really rules rigid dendrimeric ligands arrangements around NPs and that the grafting efficiency is better with linear or slightly conical ones than with dendron-like ones. Unexpected was the absence of mesomorphic properties of the dendronized NPs, contrary to the free dendrons, while the luminescent properties of the OPV-containing dendrons were still observed after grafting, albeit modified by the presence of the iron oxide cores. Finally, the ferrimagnetic properties of the latter were not affected by the grafted dendrons. Optionally, dendrons can be directly grafted on19 or grown from the surface of a nanoparticle equipped with a suitable function. The grafting strategy has been developed by the group of E. R. Gillies on azide-capped superparamagnetic iron oxide (SPIO) NPs that can be clicked on with acetylene-cored polyester dendrons having guanidinium surface functions.19 The resulting systems showed promising cellular uptake on glioma cells. The

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direct growing strategy has also been successfully applied on magnetite nanoparticles (average diameter 8 nm).20 The reactive starting point was introduced by reaction of 3-aminopropyl-trimethoxysilane on the magnetite surface, and the amine group was used to grow PAMAM dendrons up to generation 5. The growing of this dendron could not be fully monitored or characterized. IR analysis afforded clear information concerning the covalent bonding of the dendrons on the magnetite surface. Elemental analysis and competitive ELISA (enzyme-linked immuno assay) on streptavidine modified dendronized magnetite NPs showed that the dendrimer growth was not complete for generations higher than 3, probably because of steric interference and particle agglomeration. The same methodology was applied to core–shell silica-coated magnetic Fe3O4 NPs.21 The silica coating afforded a higher stability toward coagulation and allowed the growth of PAMAM dendrons up to generation 3. Again, the outgrowth was found to be dramatically incomplete from generation 2, as shown by thermogravimetric analysis (TGA) and elemental analysis of the phosphine functionalized dendrons. Nevertheless, the rhodium complexes of the latter were successfully used to catalyze hydroformylation of styrenes with high selectivity and rates of conversion after five runs. Analogous PAMAM-coated magnetic NPs have been successfully used as gene delivery systems into cancerous cells.22 6.2.2

Direct Synthesis of Dendronized Nanoparticles

Dendronized NPs can be directly synthesized by reduction of a metallic precursor in the presence of the stabilizing dendrons and possibly additional stabilizers like alkylamines. This strategy, if used in the absence of additional ligands, advantageously provides with systems that are not “polluted” by an excess of small free ligands. Additionally, the final systems can possibly be designed taking into account simple geometrical parameters that will rule the assembly and compaction of rather rigid dendron ligands for which the focal point is the only stabilizing or metal-interacting moiety. Actually, small dendrons will lead to rather stable small NPs with a highly passivated surface while greater dendrons will lead to less stable, bigger NPs, with a much less passivated surface (see Figure 6.5).

Figure 6.5

Direct synthesis of dendronized NPs

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A pioneering example involved pyridinone-cored Fréchet-like dendrons23 (generation 1 to 3) as the stabilizing agent during the reduction of hydrogen tetrachloroaurate with sodium borohydride in the presence of quaternary ammonium salt as the phase transfer agent to facilitate the reduction, according to the Brust reaction.24 Excess of free ligand could be easily removed by precipitation and TEM imaging revealed that the size of the crystalline gold NPs increases from 2 to 5.1 nm with increasing generation number (from 1 to 3). Elemental analysis allowed the number of dendrons around the NPs to be rationalized and, as mentioned above, it was found that the NPs obtained with the biggest dendrons were less stable. This finding was attributed to the rather weak interactions between the pyridinone and the metal surface and the authors mentioned the possibility to work with thiol-cored dendrons to circumvent the problem. This was done concomitantly by the group of K. Kim with thiol-cored Fréchet-type dendrons25 that afforded stable Au NPs with a narrow size distribution. The second generation dendron was found to be much more efficient than generation 1 and generation 3 dendrons to produce stable and monodisperse Au NPs, but this peculiar property was only justified by a so-called “magic size” of the dendron. Although expected, no further work was published to explain these odd results, which are quite contrasting with the report by the group of K. Esumi one year later,1 with thiol-cored PAMAM dendrons. They showed that the stability of the gold nanocomposites was not increased by the presence of thiol focal groups, particularly when reactive thiol groups are hindered by bulky dendrons. Interestingly, the addition of small alkanethiols on the nanocomposite drastically modified the particle size distributions in all cases. The group of D. Astruc also reported on dendron-modified gold nanoparticles.26 The reduction of hydrogen tetrachloroaurate in the presence of alkane thiols and dendrons having a thiol core and ferrocenes on the surface yielded gold nanoparticlecored composites containing up to about 200 ferrocenyl groups at the dendrons periphery. These systems were reported to recognize and titrate oxo-anions and ATP2− by cyclic voltammetry.27 Large Fréchet-type polyaryl ether dendrimeric wedges having a disulfide core have also been used for the same purpose, without an additional alkanethiol ligand. The resulting gold NPs have been fully characterized.28 Although the core sizes exhibit a relatively wide distribution, without clear information on the shape by HRTEM imaging, the average core size increases with dendrons of generation 1 to 4 from 2.0 to 3.9 nm and then decreases to 2.6 nm with a generation 5 dendron. TGA analysis and NMR measurement revealed the entrapment of up to 5% residual tetraoctylammonium bromide (except in the case of the first generation dendron), used as a transfer agent during the reduction step. No free dendron was identified and the nanoparticles were found to be structural units of so-called NCDs (nanoparticle-cored dendrimers) and not trapped or encapsulated in dendrimeric pockets. The density of dendrons on the gold surface was calculated at 2.2 units per nm2 in the case of the second generation dendrons and 0.3 units per nm2 in the case of the fifth generation dendron. These figures highlight the high percentage of unpassivated gold atoms on the surface of the NPs dendronized with rather bulky dendrons and the possibility to use these systems in catalysis. This possibility was explored on analogous Pd NPs obtained by the Brust reaction with the generation 3 Fréchet-type polyaryl ether dendritic wedge having a disulfide core.29 The resulting system efficiently catalyzed Heck and Susuki reactions but no hydrogen reaction could be performed, probably because of the hydrogenolysis of carbon sulfur benzylic bonds and subsequent metal coalescence. This

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issue was solved with Pd NPs capped with Fréchet-type polyaryl ether dendrons having a diarylphosphine core, which were successfully recycled as catalysts for the Susuki– Myura reaction and hydrogenations.30 Interestingly, analogous dendronized gold NPs were obtained with ester terminated Fréchet-like dendrimeric wedges, and the saponification of the ester functions led to water-soluble gold NPs able to encapsulate pyrene,31 opening the way to water-soluble catalytic systems based on dendronized NPs. A highly stable system was also obtained by reduction of HAuCl4 and Fréchet-type wedges having diazonium cores, leading to dendronized NPs with Au–C bonds.32

6.2.3

Dendrimer Coated Nanoparticles

Small generation dendrimers are nonsymmetrical architectures that present a rather flexible surface that can adapt the curvature of the NP surface. This geometrical consideration has been early pointed out by the pioneering authors in this field1,33–36 to rationalize the possible interactions between dendrimers and NPs either by ligand exchange or by direct synthesis. In the case of small generation PAMAM dendrimers having their surface partially functionalized either with a thiol group or hydrophobic aliphatic chains, it was clearly evidenced on gold NPs and CdSe NPs, respectively, that the flexibility of the branches was responsible for the wrapping of the metallic surface and subsequent stabilization of the NPs. Nevertheless, it was also shown in the pioneering work on gold NPs that removal of free dendrimer ligand was deleterious to the stability of the NPs.37 The ligand displacement can also be accompanied by a rearrangement of the metallic cores. In the case of Au55(PPh3)12Cl6 clusters, the use of thiol-terminated phosphorhydrazone containing (PPH) dendrimers has led to the formation of microcrystals composed of naked Au55 entities.38 Recently, the stochastic functionalization of the surface has also been applied to hyperbranched PAMAM structures with PEG derivatives and the resulting systems have been used to transfer a series of hydrophobic NPs (CdSe, Au, and Fe3O4) from chloroform phase to water by ligand exchange. These PEG-functionalized hyperbranched PAMAM provided the CdSe NPs with low cytotoxicity, as reported by MTT assays and a good endosomial cellular uptake,39 the cell’s nucleus being out of reach for these systems. The group of J. Baker has developed an efficient method that combines layer-by-layer (LBL) self-assembly techniques with dendrimer chemistry to coat Fe3O4 NPs.40 Actually, positively charged magnetic NPs (8.4 nm in diameter) lacking stabilizing agents can be coated with polystyrene sulfonate sodium salt (PSS) in water and the resulting negatively charged NPs can be coated with positively charged PAMAM dendrimers (Figure 6.6). The dendrimer coating step involved a generation 5 PAMAM dendrimer with random surface functions comprising a fluorescein tag, folic acid (FA) moieties as an optional targeting agent, and free amine functions. The final step of these stepwise coating was the acetylation of the free amine functions that were not involved in the electrostatic interactions with the PSS layer.40 The process was fully monitored by zeta potential measurement, and interestingly the zeta potential of the final composite NPs remained positive, indicating that a free portion of hindered free amines could not be acetylated. Interestingly, this elegant approach leads to biologically functional NPs provided with a surface charge that is not expected to alter

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Figure 6.6

LBL coating of magnetic NPs with PSS and multifunctional dendrimers

the interaction of targeting FA with cell receptors, as is the case for negatively charged NPs. It was found that these NPs are biocompatible at Fe concentrations up to 150 μg mL−1 on KB cells (a human epithelial carcinoma cell line). The data collected from confocal microscopy, TEM imaging, flow cytometry, and magnetic resonance imaging (MRI) indicated that NPs coated with dendrimers having the option FA targeting moieties were much more efficiently addressed to KB cells over expressing an FA receptor than NPs lacking the FA, and that the internalization of the NPs was mediated through the FA receptors. Nevertheless, these systems were found to accumulate in the liver of mice and this finding was putatively correlated to a poor mechanical stability. This strategy was then improved by increasing the number of polymer layers by the LBL technique, using multilayers of poly(glutamic acid) and poly(L-lysine) that are chemically crosslinked with a peptide coupling agent before the dendrimer capping step.41 In vivo and in vitro MRI showed that these systems can specifically target tumor cells that overexpress FA receptors and an FA receptor expressing a tumor model of small dimension, and validated the proof of concept of this approach for tumor imaging. The same group also described the removal of oleic acid stabilizing hydrophobic superferromagnetic iron oxide NPs with randomly functionalized G5 PAMAM having on average 5 folic acids, 3 fluorescent probes, and 102 acetylated amines. A phase transfer to water solution successfully occurred and led to biocompatible NPs whose size and shape was unaffected by the ligand exchange, even after drying in air. The presence of folic acids was found pivotal for this phase transfer ligand exchange as NPs lacking the FA did not produce a phase transfer.42 The targeting capabilities of these NPs were verified and the stability was enhanced compared to the bilayer coating system. The group of J. Baker also reported on straightforward preparation of multifunctional gold NPs in water/methanol solutions by acetylation of amine-terminated PAMAM dendrimers (generation 5) complexed with 7 to 10 AuCl4− ions.43 The dendrimers can even be functionalized with FA and fluorescent tag according to the stochastic method.44 In the case of dendrimers fully capped with glycidol hydroxyl groups, the formation of gold NPs is induced by a simple mixing at room temperature. This strategy without additional reduc-

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ing agent45 leads to functionalized isolated gold NPs with a relatively narrow size distribution (a few nanometers in diameter), which are stable for months in physiological media after extensive removal of free dendrimer by dialysis, and represents an attractive alternative to the hydrazine reduction chemistry route involving the same precursors.46 They can bind in vitro to an FA receptor overexpressing cancer cells thanks to the FA grafted on dendrimers and could be applicable for phototherapy treatments. Although less extensively explored, hyperbranched polymers47,48 like hyperbranched polyglycerols (HPG) or polyamidoamine hyperbranched polymers (HYPAM) have appeared as a valuable alternative for the stabilization of NPs in organic solvents and aqueous systems,49–51 and promising results have been obtained in catalysis52 with HYPAM and smart temperature and pH sensors have been obtained from gold NPs coated with HPG.53

6.2.4

Nanocomposites with Interdendrimer Nanoparticles

The reduction of metal salts in the presence of dendrimers can also lead to much less defined systems where the NPs can be reticulated by dendrimers. Although these systems are difficult to analyze and describe, they can find valuable applications.32 The formation of such nanocomposites with interdendrimer NPs is generally related to the dendrimer/ metal ratio and the dendrimer size, as early pointed out by K. Esumi and coworkers.4 The lack of perfection of these systems, which also comprise isolated NPs, does not preclude them from attractive applications. For example, aqueous solutions of PAMAM– and PPI–metal (Ag, Pd, Pt) nanocomposites have a catalytic activity for the reduction of 4-nitrophenol in the presence of sodium borohydride,54 with a strong effect of the dendrimer type and concentration according to the metal of the composite. In the absence of a reducing agent, aqueous mixtures of PAMAM dendrimers and AgNO3 can also lead to silver interdendrimer NPs made of Ag and Ag2O,55 and increasing temperatures (from 60 to 100 °C) resulted in bigger NPs (from 5 to 20 nm). Analogous systems coined as mesosilver–PAMAM complexes have been used to treat textile fabrics for antimicrobial purposes.32 The dendrimer spacing of NPs can also be controlled in order to produce dendrimer-mediated self-assembly of NPs, as described by the group of V. Rotello. The interparticle spacing can be controlled by dendrimer generation,56 and it was shown, for instance, that the lowering of magnetic decoupling with increasing generation modulated the collective magnetic behavior of iron oxide NPs57 or the plasmon resonance of gold nanoparticles.58 Tin oxide nanocomposites have been prepared by bubbling carbon dioxide in aqueous or ethanolic solutions of hyperbranched PEI, fourth generation PAMAM, and PPI dendrimers complexing sodium stannate. With an optimal dendrimer/stannate molar ratio of 1 : 4, the reaction with CO2 led to various nanocomposites whose size was related to the surface function of the dendrimeric host. For instance, small isolated NPs (2 nm in diameter) were obtained with amine-terminated PPI and PAMAM, while large (50 nm in diameter) interdendrimeric NPs were obtained with the hydroxy-terminated analogues.59 The hyperbranched PEI polymer led to relatively small nanocomposites, with a large diameter distribution that suggests the presence of mixed isolated (or encapsulated) NPs as well as interdendrimeric NPs. Remarkably, no benefits were observed with the use of supercritical carbon dioxide.

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Figure 6.7 TEM image of Pt nanodendrites obtained with PPH dendrimers equipped with terminal triolefinic azamacrocycles

Fifteen-membered triolefinic azamacrocycles as end groups of PPH dendrimers have also been used for obtaining stable interdendrimer Pt nanocomposites under mild conditions and in the absence of a reducing agent.60–62 Although the underlying mechanisms of formation remain unclear, the higher the dendrimer generation, the bigger the Pt NPs networks are formed, and a very unique organization of organic dendrimeric structures interweaved with inorganic dendrimeric structures (Figure 6.7) can be obtained. Pd NPs generated with the same PPH dendrimers were succefully assayed as recoverable catalysts in the Mizoroki–Heck reaction, under homogeneous and heterogeneous conditions.60 The influence of the morphology of these systems has not been explored to date, but it has been recently reported that the morphology of Pt nanodendrite can improve their catalytic activity for an oxygen reduction reaction.63

6.3

Dendrimers as Templates for the Synthesis of Dendrimer-Encapsulated Nanoparticles (DENs)

The use of dendrimers as templates for the synthesis of DENS (dendrimer-encapsulated NPs) has generated a large and increasing number of reports. Dendrimers have been early used as boxes to encapsulate host molecules64 or metal ions,65 and the reduction of metal ions trapped into dendrimer structures has been early explored. As pointed out by R. M. Crooks,66 dendrimers offer a series of advantages for the templating of small NPs (from 1 to a few nm): (i) the perfect structural definition of dendrimers offers a unique mold for the production of well-defined NPs, (ii) the NPs are shielded within the dendrimers, which prevent agglomeration of metallic cores, but the DENs can self-organize through dendrimer interdigitation to control the NPs interdistances,67 (iii) the physical entrapment of NPs in the structures leaves a portion of their surface unpassivated, (iv) the end groups of the dendrimers can be modified at will for any purposes,68 and (v) the NPs entrapped in dendrimers are accessible to small molecules.

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Figure 6.8

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General strategy for the preparation of DENs

DENs are produced in a stepwise procedure by reduction of metal ions complexed within dendrimers (Figure 6.8).69–74 The complexation of metal species by the surface groups must be avoided by adjusting the pH75 or surface modification with noncomplexing functions in order to prevent the formation of interdendrimer nanocomposites, which is also related to the size of the dendrimer and the metal : dendrimer ratio.33,34 Methods to characterize DENs are numerous and include electron and atomic force microscopy techniques, X-ray methods (EXAFS,76,77 EDS, XPS), EPR and NMR,73,78 UV–vis, and ATR–IR spectroscopies. They have been exhaustively listed in the case of bimetallic DENs.6 The synthetic approach has matured to a high degree of sophistication and offers the possibility to produce monometallic DENs79 with or without additional reductive agent, and bimetallic DENs.80,81 The properties of these systems can be tuned by modifying the surface of the dendrimer without modifying the integrity and the inherent properties of the metallic core,82 and they can be solubilized in water,83 organic solvents,84 or extracted as monolayer-protected NPs out from the dendrimer via a biphasic treatment with surfactants, the dendrimer playing literally the role of a recyclable mold for the synthesis of NPs.85,86 An intradendrimer metal displacement reaction can also be used to prepare DENs of nobles metals (Ag, Au, Pt, Pd) from Cu DENs.87 Finally, DENs can be deposited on surfaces,88 integrated by sol-gel techniques in metal oxide matrixes,89,90 or dispersed in polymer networks,91 while current investigations still aim at rationalizing the mechanism of formation of DENs.76,92 6.3.1

Catalysis with Dendrimer-Encapsulated Nanoparticles

This field of research has been extensively reviewed by several authors.6,7,66,93–95 DENs appear as an attractive system for homogeneous catalysis in which the dendrimer stands as a nanoreactor that can filter reactants. The recycling of these mesoscopic systems can be done by trivial phase separation or a more technical approach such as supercritical fluids or nanofiltration. Alternatively, DENs can be integrated in solid supports and serve as heterogeneous catalysts81,96 which are easier to recycle. From simple hydrogenation97 to more sophisticated coupling reactions, DENs are generally highly effective catalysts in terms of the rate of conversion and selectivity, the latter being possibly tuned by the surface functions of the dendrimers.98 Despite their performance and the possibility to recycle them, DEN-based catalytic technology is still expensive compared to commercial catalysts, which are sometimes more efficient.99 Moreover, ultrafiltration, which is one of the most industrially appealing solutions for recycling DENs, is still demanding advances in

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membrane technology.100 Nevertheless, these systems are often pointed out as model systems because of their high degree of uniformity and their tunable topology, and are generating an increasing number of publications. Recent advances include the development of bimetallic DENs,6 as alloys or as core–shell structures, immobilization on solid supports,101,102 and the study of size and composition effects of DENs on electrocatalytic reduction of oxygen.103,104 In this context, the development of ultrasmall DENs,105 as for example subnanometer platinum clusters encapsulated in phenylazomethine dendrimers, have recently led to very efficient catalysts for the four-electron reduction of oxygen molecules and offer promising perspectives to make fuel cells more economically viable.106 6.3.2

Other Uses of Dendrimer-Encapsulated Nanoparticles

One of the most striking examples of the benefits of coating or embedding NPs in dendrimers, apart from stability issues, resides probably in the possibility to design the dendrimer in a rational approach in order to make the overall system biocompatible and biologically multifunctional, which is not the case with simple monolayer protected NPs. This point has been recently illustrated by the group of J. R. Baker, who has extended the use of randomly functionalized dendrimeric platforms (see Chapter 18) for the preparation of multifunctional gold DENs.107 The synthesis of such systems is possible by reduction of gold salts trapped within PAMAM dendrimers equipped with a range of surface functions including fluorescent tags, targeting agents (FA or RDG peptides), and acetylated amines.44,108,109 Alternatively, these systems can be produced by functionalization of the surface of dendrimers of the DENs after NP synthesis.110 Both routes seem to offer comparable results since the production of gold NPs inside multifunctional dendrimers does not affect the functions of the latter, and reciprocally the functionalization of such gold DENs with fluorescent tags or targeting agents does not alter the metallic cores. These systems were successfully assayed to image cancer cells in vitro and show comparable results to those obtained with the corresponding dendrimers lacking the NPs or dendrimerstabilized NPs obtained with analogous dendrimer platforms (see Section 6.2.3). Other fields of applications of these systems are related to the intrinsic properties of the metal cores, which can be in some cases increased by the presence of the dendrimeric structure. Highly antimicrobial gold or silver DENs have been prepared with hyperbranched PAMAM-like polymers containing piperazine moieties (HPAMAM), which serve both as stabilizing and reducing agents.111 These composites showed good solubility and stability in water solution and the size of the NPs was directly related to the metal : HPAMAM ratio and could inhibit the growth and multiplication of gram-positive or gram-negative bacteria and fungi. This biocide effect was attributed to both the metal part and the cationic terminations of the HPAMAM. Comparable results have been obtained earlier with DENs comprising PAMAM dendrimers and silver.112

6.4

Conclusion and Perspectives

Dendrimers and metallic (or metal oxide) NPs appear as complementary nano-objects whose interplay often results in increased properties by synergetic or compensatory (still

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advantageous) effects. Fields of research related to the subject are becoming more and more interdisciplinary, and gather scientists with various expertises for the advent of these exciting systems. The exploration of dendrimer-encapsulated subnanometer NPs is bringing new progress in this field113 and NPs are becoming “tunable” nano-objects thanks to dendrimer capping. The promising applications in catalysis are illustrated by the growing number of publications, although some critical issues still demand intense research to reach semi-pilot validation. Some biomedical applications have led to new dendrimer-based tools for nanomedicine,114 and the proof of concept has been successfully reached in certain cases. The generally admitted fact that the biomedical world is less constrained by costs is sometimes accompanied by great expectations. Nevertheless, there is an urgent need for more data related to the safe use of these “nanothings”, like pharmacokinetics, toxicology, or ecotoxicology. Actually, it may represent a severe blocking point for these systems comprising two nano-objects (dendrimers and NPs) for which there is an obvious lack of data in these fields, probably because the fancy they represent is relatively recent.

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(71) M. F. Ottaviani, F. Montalti, N. J. Turro, and D. A. Tomalia (1997) Characterization of Starburst dendrimers by the EPR technique. Copper(II) ions binding full-generation dendrimers. J. Phys. Chem. B, 101, 158–166. (72) M. S. Diallo, S. Christie, P. Swaminathan, L. Balogh, X. Y. Shi, W. Um, C. Papelis, W. A. Goddard, and J. H. Johnson (2004) Dendritic chelating agents. 1. Cu(II) binding to ethylene diamine core poly(amidoamine) dendrimers in aqueous solutions. Langmuir, 20, 2640–2651. (73) P. J. Pellechia, J. X. Gao, Y. L. Gu, H. J. Ploehn, and C. J. Murphy (2004) Platinum ion uptake by dendrimers: an NMR and AFM study. Inorg. Chem., 43, 1421–1428. (74) M. L. Tran, L. R. Gahan, and I. R. Gentle (2004) Structural studies of copper(II)-amine terminated dendrimer complexes by EXAFS. J. Phys. Chem. B, 108, 20130–20136. (75) J. Zheng, M. S. Stevenson, R. S. Hikida, and P. G. Van Patten (2002) Influence of pH on dendrimer-protected nanoparticles. J. Phys. Chem. B, 106, 1252–1255. (76) M. R. Knecht, M. G. Weir, V. S. Myers, W. D. Pyrz, H. C. Ye, V. Petkov, D. J. Buttrey, A. I. Frenkel, and R. M. Crooks (2008) Synthesis and characterization of Pt dendrimerencapsulated nanoparticles: effect of the template on nanoparticle formation. Chem. Mater., 20, 5218–5228. (77) S. V. Myers, A. I. Frenkel, and R. M. Crooks (2009) X-ray absorption study of PdCu bimetallic alloy nanoparticles containing an average of similar to 64 atoms. Chem. Mater., 21, 4824–4829. (78) M. V. Gomez, J. Guerra, A. H. Velders, and R. M. Crooks (2009) NMR characterization of fourth-generation PAMAM dendrimers in the presence and absence of palladium dendrimerencapsulated nanoparticles. J. Am. Chem. Soc., 131, 341–350. (79) R. W. J. Scott, H. C. Ye, R. R. Henriquez, and R. M. Crooks (2003) Synthesis, characterization, and stability of dendrimer-encapsulated palladium nanoparticles. Chem. Mater., 15, 3873–3878. (80) Y. M. Chung and H. K. Rhee (2004) Dendrimer-templated Ag–Pd bimetallic nanoparticles. J. Colloid Interface Sci., 271, 131–135. (81) R. W. J. Scott, O. M. Wilson, S. K. Oh, E. A. Kenik, and R. M. Crooks (2004) Bimetallic palladium–gold dendrimer-encapsulated catalysts. J. Am. Chem. Soc., 126, 15583–15591. (82) X. Y. Shi, I. Lee, and J. R. Baker (2008) Acetylation of dendrimer-entrapped gold and silver nanoparticles. J. Mater. Chem., 18, 586–593. (83) R. C. Hedden, B. J. Bauer, A. P. Smith, F. Grohn, and E. Amis (2002) Templating of inorganic nanoparticles by PAMAM/PEG dendrimer-star polymers. Polymer, 43, 5473–5481. (84) Y. H. Niu and R. M. Crooks (2003) Preparation of dendrimer-encapsulated metal nanoparticles using organic solvents. Chem. Mater., 15, 3463–3467. (85) O. M. Wilson, R. W. J. Scott, J. C. Garcia-Martinez, and R. M. Crooks (2005) Synthesis, characterization, and structure-selective extraction of 1–3-nm diameter AuAg dendrimerencapsulated bimetallic nanoparticles. J. Am. Chem. Soc., 127, 1015–1024. (86) J. C. Garcia-Martinez and R. M. Crooks (2004) Extraction of Au nanoparticles having narrow size distributions from within dendrimer templates. J. Am. Chem. Soc., 126, 16170–16178. (87) M. Zhao and R. M. Crooks (1999) Intradendrimer exchange of metal nanoparticles. Chem. Mater., 11, 3379–3385. (88) F. Grohn, X. H. Gu, H. Grull, J. C. Meredith, G. Nisato, B. J. Bauer, A. Karim, and E. J. Amis (2002) Organization of hybrid dendrimer–inorganic nanoparticles on amphiphilic surfaces. Macromolecules, 35, 4852–4854. (89) R. Velarde-Ortiz and G. Larsen (2002) A poly(propylene imine) (DAP-Am-64) dendrimer as Cu2+ chelator for the synthesis of copper oxide clusters embedded in sol-gel derived matrixes. Chem. Mater., 14, 858–866. (90) J. Huang, K. Sooklal, and C. J. Murphy (1999) Polyamine−quantum dot nanocomposites: linear versus Starburst stabilizer architectures. Chem. Mater., 11, 3395–3601. (91) F. Grohn, G. Kim, A. J. Bauer, and E. J. Amis (2001) Nanoparticle formation within dendrimercontaining polymer networks: route to new organic–inorganic hybrid materials. Macromolecules, 34, 2179–2185.

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(92) E. V. Carino, M. R. Knecht, and R. M. Crooks (2009) Quantitative analysis of the stability of Pd dendrimer-encapsulated nanoparticles. Langmuir, 25, 10279–10284. (93) D. Astruc and F. Chardac (2001) Dendritic catalysts and dendrimers in catalysis. Chem. Rev., 101, 2991–3023. (94) D. Astruc, F. Lu, and J. R. Aranzaes (2005) Nanoparticles as recyclable catalysts: the frontier between homogeneous and heterogeneous catalysis. Angew. Chem. Int. Ed., 44, 7852–7872. (95) R. W. J. Scott, O. M. Wilson, and R. M. Crooks (2005) Synthesis, characterization, and applications of dendrimer-encapsulated nanoparticles. J. Phys. Chem. B, 109, 692–704. (96) L. Sun and R. M. Crooks (2002) Dendrimer-mediated immobilization of catalytic nanoparticles on flat, solid supports. Langmuir, 18, 8231–8236. (97) M. Q. Zhao and R. M. Crooks (1999) Homogeneous hydrogenation catalysis with monodisperse, dendrimer-encapsulated Pd and Pt nanoparticles. Angew. Chem. Int. Ed., 38, 364–366. (98) S. K. Oh, Y. H. Niu, and R. M. Crooks (2005) Size-selective catalytic activity of Pd nanoparticles encapsulated within end-group functionalized dendrimers. Langmuir, 21, 10209–10213. (99) M. Bernechea, E. de Jesus, C. Lopez-Mardomingo, and P. Terreros (2009) Dendrimerencapsulated Pd nanoparticles versus palladium acetate as catalytic precursors in the Stille reaction in water. Inorg. Chem., 48, 4491–4496. (100) E. de Jesus and J. C. Flores (2008) Dendrimers: solutions for catalyst separation and recycling – a review. Ind. Eng. Chem. Res., 47, 7968–7981. (101) W. Huang, J. N. Kuhn, C. K. Tsung, Y. Zhang, S. E. Habas, P. Yang, and G. A. Somorjai (2008) Dendrimer templated synthesis of one nanometer Rh and Pt particles supported on mesoporous silica: catalytic activity for ethylene and pyrrole hydrogenation. Nano Lett., 8, 2027–2034. (102) A. Siani, O. S. Alexeev, D. S. Deutsch, J. R. Monnier, P. T. Fanson, H. Hirata, S. Matsumoto, C. T. Williams, and M. D. Amiridis (2009) Dendrimer-mediated synthesis of subnanometersized Rh particles supported on ZrO2. J. Catal., 266, 331–342. (103) H. Ye, J. A. Crooks, and R. M. Crooks (2007) Effect of particle size on the kinetics of the electrocatalytic oxygen reduction reaction catalyzed by Pt dendrimer-encapsulated nanoparticles. Langmuir, 23, 11901–11906. (104) H. C. Ye and R. M. Crooks (2007) Effect of elemental composition of PtPd bimetallic nanoparticles containing an average of 180 atoms on the kinetics of the electrochemical oxygen reduction reaction. J. Am. Chem. Soc., 129, 3627–3633. (105) T. Mizugaki, T. Kibata, K. Ota, T. Mitsudome, K. Ebitani, K. Jitsukawa, and K. Kaneda (2009) Controlled synthesis of Pd clusters in subnanometer range using poly(propylene imine) dendrimers. Chem. Lett., 38, 1118–1119. (106) K. Yamamoto, T. Imaoka, W. J. Chun, O. Enoki, H. Katoh, M. Takenaga, and A. Sonoi (2009) Size-specific catalytic activity of platinum clusters enhances oxygen reduction reactions. Nature Chemistry, 1, 397–402. (107) X. Shi and S. H. Wang (2008) Dendrimer-entrapped and dendrimer-stabilized metal nanoparticles for biomedical applications, in Dendrimer-Based Nanomedicine (eds I. J. Majoros and J. R. Baker), Pan Stanford Publishing Pte. Ltd., Singapore. (108) R. Shukla, E. Hill, X. Y. Shi, J. Kim, M. C. Muniz, K. Sun, and J. R. Baker (2008) Tumor microvasculature targeting with dendrimer-entrapped gold nanoparticles. Soft Matter, 4, 2160–2163. (109) X. Y. Shi, S. H. Wang, I. Lee, M. W. Shen, and J. R. Baker (2009) Comparison of the internalization of targeted dendrimers and dendrimer-entrapped gold nanoparticles into cancer cells. Biopolymers, 91, 936–942. (110) X. G. Shi, S. H. Wang, S. Meshinchi, M. E. Van Antwerp, X. D. Bi, I. H. Lee, and J. R. Baker (2007) Dendrimer-entrapped gold nanoparticles as a platform for cancer-cell targeting and imaging. Small, 3, 1245–1252. (111) Y. W. Zhang, H. S. Peng, W. Huang, Y. F. Zhou, and D. Y. Yan (2008) Facile preparation and characterization of highly antimicrobial colloid Ag or Au nanoparticles. J. Colloid Interface Sci., 325, 371–376.

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Part 2 Applications in Catalysis

7 Terminal Groups of Dendrimers as Catalysts for Homogeneous Catalysis Armelle Ouali* and Anne-Marie Caminade

7.1

General Introduction

Catalysis is one of the very first published use of dendrimers1 and has gained an increasing interest, to become nowadays one of the major applications of dendrimers. Many reviews dedicated to the use of dendrimers in catalysis have been published during the last two decades.2–14 Because of the well-defined molecular architecture of dendrimers, the catalyst localization can be precisely controlled. Therefore, the catalyst can be placed at the periphery of the dendrimer (Figure 7.1(a)) or within the dendrimer, at the core or more seldom in the branches (Figure 7.1(b)). In both cases, immobilization of the catalyst on to dendrimers gives rise to certain properties that are not possible in the case of the parent monomeric catalyst, and which can be described as a “dendrimer effect”. 7.1.1 The “Dendrimer Effect” In the literature, this term has generally been employed to explain phenomena that arrive when the generation increases.13 For peripheral modifications (Figure 7.1(a)), such a “dendrimer effect” can be a consequence of the high local concentration of catalysts. The proximal interaction of catalytic sites can also be at the origin of cooperative effects or, on the contrary, at the origin of catalyst deactivation. In addition, unexpected selectivities can also result from the steric crowding of catalytic groups at the surface. As far as encap* Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 7.1 Different dendrimeric architectures: catalyst located (a) at the periphery or (b) within the dendrimer

sulation of catalysts inside the dendrimer is concerned (Figure 7.1(b)), steric shielding of the active site can enable catalyst stabilization and shape selectivity. Noteworthy is the fact that core-modified dendrimers can offer substrate binding opportunities and thus behave as biomimics with the specific nanoenvironment created by dendrimeric structures showing great similarity to biological systems such as enzymes. Accumulation of the substrates into the macromolecules so near the catalytic sites can lead to a “concentrator effect”, giving rise to increased efficacy.13 In addition, by isolating the catalytic site at the core of a dendrimer, interactions between catalytic sites and further formation of inactive dimeric complexes can be avoided. All of these kinds of “dendrimer effects” will be illustrated in the following chapters. 7.1.2

Recycling the Catalysts

Beyond the possibility of displaying unexpected catalytic behavior compared to monomeric species, dendrimeric catalysts can be easily recovered from reaction mixtures because of their nanometric size. Therefore, they combine the advantages of both homogeneous and heterogeneous catalysis. Main techniques to recover and recycle the catalysts involve filtration through membranes, precipitation, or column chromatography (Figure 7.2).7 An important technological improvement with membrane nanofiltration was pioneered by Kragl and coworkers, who reported in 1996 the separation of the dendrimeric catalyst in a continuously operating chemical membrane reactor (Figure 7.2(a)).15 Since then, continuous-flow membrane reactors have been used for a wide range of reactions. It is noteworthy that continuous reactors can allow an improvement of the selectivity for reactions that have to be stopped at low conversion because side reactions occur at high conversion. An alternative use of nanofiltration techniques involves batch processes in which the dendrimeric catalyst is separated once the reaction has been completed.7,16 Separation of the catalyst can also be achieved by precipitating the catalyst from the product solution (Figure 7.2(b)). For periphery-functionalized dendrimers, the functional

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Figure 7.2 Different methods for catalyst recycling: (a) nanofiltration techniques, (b) precipitation, or (c) column chromatography

groups on the surface, often organometallic complexes, determine the solubility and the miscibility.7 Many dendrimers ended by organometallic compounds do not dissolve in apolar solvents, so addition of a nonpolar solvent on the reaction mixture allows the precipitation of the dendrimeric catalyst, which can be further reused. The catalyst recovery can also be achieved by column chromatography on silica for example (Figure 7.2(c)). The different methods of recycling will be illustrated in the following chapters.

7.2

Catalytic Organometallic Sites as Catalysts for Homogeneous Catalysis

The catalytic entities are linked to the surface so that a large number of catalytic sites are in close proximity in a single entity. It is worth noting that most catalytic dendrimers have organometallic entities as catalytic sites. They were used as catalysts in numerous types of reactions involving the formation of a C–X bond (X = C, N, O: cross-couplings, metathesis, polymerizations, etc.) or an addition on a C=X double bond (X = C, N, O: hydrogenations, hydroformylations, Kharasch reaction, etc.) and also in oxidation reactions. 7.2.1 7.2.1.1

Formation of C–X Bond (X = C, N, O) Cross Couplings

Palladium catalysts are the most frequently used catalysts in synthesis since they are able to promote numerous reactions such as Sonogashira, Suzuki, Stille, or Heck couplings, hydrovinylation of styrene, or allylic amination – to name but a few. The Sonogashira reaction, coupling of aryl or vinyl halide and terminal alkynes, is a useful methodology for the preparation of arylalkynes and enynes. Palladodendrimeric complexes involving either biscyclohexylphosphines or bis-tert-butylphosphines have been prepared up to the third generation and reported to catalyze the Sonogashira coupling of iodobenzene or bromobenzene and phenylacetylene (Figure 7.3).4,17,18 The tert-butyl

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Figure 7.3 PPI-based dendrimeric diphosphines as ligands for Pd in Sonogashira couplings: example of the third generation

catalyst allowed almost quantitative yields to be reached (100% for G1, 93% for G2, and 96% for G3) and was revealed to be much more efficient than the cyclohexyl catalyst (17% for G1, 15% for G2, and 6% for G3). It is noteworthy that the latter displayed a negative dendrimeric effect resulting from an increase in the steric hindrance around the active metal centres as the generations advanced. The dendrimeric complexes could be recycled by precipitation and reused five times without loss of activity. The Suzuki reaction, coupling between an aryl halide and phenylboronic acid, is a convenient and useful methodology for the preparation of biaryls. K. G. Jayaraman and coworkers prepared three generations (generation 0 to 2) of poly(ether amine) dendrimers decorated with palladium complexes (catalytic moieties) present in varying numbers within a given generation dendrimer (Figure 7.4).19 The catalysts were tested in Suzuki reactions and in each reaction the dendrimeric catalysts having more than one catalytic site within the molecule are considered in multiples of one catalytic site. It was thus shown that (i) the activity of an individual catalytic site is better in catalysts presenting more than one catalytic site within the molecule; (ii) across the generations, the individual catalytic sites in higher generations are more active than the same individual catalytic sites involved in lower generations; and (iii) a cis-oriented catalytic site displays a better activity than the trans-oriented one. Other dendrimeric catalysts have been reported to promote Suzuki reactions or Sonogashira couplings in aqueous media; this topic will be detailed in Chapter 10.20–22 The Stille reaction is a versatile C–C bond-forming reaction between stannanes and halides or pseudohalides. The group of A.-M. Caminade and J.-P. Majoral synthesized three generations of phosphorus-containing dendrimers capped with iminophosphine (first generation)23 or diphosphine (up to the third generation)24 ligands (Figure 7.5). The resulting palladium complexes were tested in Stille couplings and their efficiency was found to be better or slightly lower than that of the monomeric parent complex, depending on the nature of the substrates. However, in all cases, the dendrimeric catalysts could be successfully recovered and reused using the precipitation strategy. No significant loss of activity was observed in three consecutive runs. NMR analysis on the isolated dendrimer complex clearly indicated that no degradation had occurred. The Heck reaction consists in the C–C coupling between aryl halides or vinyl halides and activated alkenes. Pd-diphenylphosphine-terminated PPI dendrimers

Terminal Groups of Dendrimers as Catalysts for Homogeneous Catalysis

Figure 7.4 Poly(ether amine) dendrimers decorated with palladium complexes as catalysts for Suzuki and Heck couplings: example of the first generation

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Figure 7.5 Phosphorus dendrimers decorated with iminophosphines or diphosphines as ligands for Pd in Stille couplings (only the first generations are represented)

(PPI-dendr-[N(CH2PPh2)2]16) have been used by the group of M. T. Reetz in a Heck reaction of bromobenzene and styrene, giving stilbene.25 The dendrimers showed larger turnover numbers than the monomeric parent complexes, which was ascribed to the higher thermal stability of the dendrimeric complexes. For the first time, the dendrimeric catalysts were recovered and recycled through a precipitation procedure. (P,N)-ligands were also grafted to PPI dendrimers and the resulting PPI-dendr-[1,2-N=CHC6H4PPh2)]32 and PPIdendr-[1,2-NH-CH2C6H4PPh2)]32 palladium complexes were found to activate electronrich aryl bromides in tertiary amine/acetic acid (1 : 1) mixtures as the solvent.26 Jayaraman also tested the poly(ether amine) dendrimers decorated with palladium complexes previously mentioned in the Heck reaction (Figure 7.4). Analogous multivalent effects than in the case of Suzuki coupling could be observed.19 PAMAM scaffolds bearing phosphinoferrocenyl termini (generations 1 to 4) were also shown to catalyze the Heck coupling of butyl acrylate with bromobenzene, the higher generations displaying higher activity and better stability.27 As far as hydrovinylation of styrene is concerned, Rossell and coworkers reported the preparation and catalytic activity of palladium complexes involving phosphanyl-terminated carbosilane dendrimers.28 The activity was found to be lower than for the parent palladium complex but the selectivity toward 3-phenyl-1-butene was high. Besides, allyl amines, starting materials for the synthesis of numerous compounds, can be obtained by allylic substitution reactions of allylic acetates with amines. Phosphanefunctionalized carbosilane dendrimers with (Si(CH3)2CH2CH2PPh2) terminal groups have been associated with palladium and the resulting complexes shown to catalyze the allylic amination reaction between crotyl acetate and piperidine. These dendrimeric catalysts were found to be stable and large enough to enable their application in a continuous-flow membrane reactor with a retention of 98.5–99%.29 Another procedure to recover the catalyst in such reactions involves the use of thermomorphic systems, i.e. systems that enable the temperature-induced phase separation of the homogeneous catalyst solution from a product phase.30 This strategy supposes that the catalyst has a strong phase preference, which ensures that it ends up in one phase at low temperature. This can be achieved by using PPI dendrimers decorated with bisdiphenylphosphine–Pd complexes. The latter are indeed soluble in the allylic amination conditions (homogeneous mixture of DMF/

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Figure 7.6 Phosphine ligands assembled to the periphery of a urea adamantyl functionalized PPI dendrimer (fifth generation); application in palladium-catalyzed allylic amination

heptane at 75 °C) but quantitatively transferred to DMF and thus separated from reaction products that are soluble in heptane by cooling to room temperature. Moreover, these dendrimers show high stereoselectivity in the allylic amination of cis-3-acetoxy-5carbomethoxycyclohexyl-1-ene with morpholine. This dendrimer effect has been ascribed to the surface congestion of dendrimers. In most systems reported so far the catalyst is covalently linked to the dendrimer. An interesting alternative approach consists in the noncovalent anchoring of catalyst to the soluble dendrimeric support,31 for example via ionic interactions or hydrogen bonds. J. N. H. Reek, E. W. Meijer, and coworkers reported the application of noncovalently functionalized dendrimers based on multiple interactions in palladium-catalyzed allylic amination (Figure 7.6).32 Phosphine ligands were indeed attached on the surface of a fifth generation urea adamantyl PPI dendrimer by ionic interactions in combination with multiple hydrogen bonds. The supramolecular dendrimeric corresponding palladium complexes were found to display the same activity and selectivity as their unbound monomeric analogs in the allylic amination of crotyl acetate and piperidine (92% yield for a phosphine/Pd ratio of 2 : 1; 71% yield for a 1 : 1 ratio). The dendrimeric catalysts can moreover be operated in a continuous setup that allows its efficient separation from the reaction mixture (retention of 99.4% in a continuous-flow membrane reactor). Although this strategy appears to be really appealing since it opens the way to multipurpose supports that could be functionalized and refunctionalized by different catalytic systems, very few examples of efficient noncovalently bound catalysts have been reported so far. Palladium-based catalysts are efficient and widely used in coupling reactions but palladium remains expensive, relatively toxic, and often requires the use of toxic ligands (mainly phosphines). The involvement of cheaper and less toxic metals is highly desirable, and in this line copper has been shown to efficiently catalyze C–N, C–O, and C–C bond formations. However, only a few copper-based dendrimeric catalysts have been reported so far.33,34 Nevertheless, J.-P. Majoral, M. Taillefer, and coworkers have reported a very positive dendrimeric effect in copper-catalyzed arylation of N- and O-nucleophiles (Figure 7.7).33 Imino-pyridine-ended phosphorus-containing dendrimers have been shown to

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Figure 7.7 Phosphorus dendrimers ended with imino-pyridine ligands displaying a very strong dendrimeric effect in copper-catalyzed arylation of pyrazole

confer to copper a very good catalytic activity in the coupling arylation of phenols and pyrazole by aryl iodides and bromides, whereas the parent monomer is totally inefficient. All dendrimers enabled the quantitative conversion of substrate into product within 20 h at 80 °C when starting from iodobenzene. When starting from less reactive bromobenzene, the best catalytic activity was obtained in the presence of the third generation dendrimeric ligand, phenylpyrazole being obtained in 80% yield after 20 h at 80 °C. The authors also demonstrated specific advantages for copper(I) catalysis of the very important O- and N-arylation and vinylation of phenols and pyrazole using these dendrimeric complexes, for which very high yields could be obtained in extremely mild conditions. 7.1.2.2

Metathesis

Olefin metathesis is an organic reaction that entails redistribution of alkylene fragments by the scission of carbon–carbon double bonds in olefins. Since its discovery, olefin metathesis has gained widespread use in research and industry for making products ranging from medicines and polymers to enhanced fuels. Its advantages include the creation of fewer side products and hazardous wastes. The group of A. H. Hoveyda grafted mononuclear Ru–benzylidene catalysts involving either an imidazolin-2-ylidene carbene ligand (Figure 7.8) or a tricyclohexylphosphine ligand on the branch termini of carbosilane dendrimers.35 Both catalysts were applied in the RCM of diallyl tosylamine (1.25%, CH2Cl2, 40 °C, 15 minutes) and recycled five times by column chromatography on silica using dichloromethane to isolate the expected cyclic product and ether for the elution of the dendrimeric catalyst. The separation was much more efficient than in the case of the monomeric Ru complex, probably because the presence of multiple polar organometallic sites on the dendrimer surface results in stronger adsorption interactions between the dendrimeric catalyst and the silica, and thus a better separation from the product. It is noteworthy that, although the activities remained high, the Ru catalysts were released from the dendrimeric support during the reaction and therefore these catalysts could not be used in continuous processes.

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Figure 7.8 Ru–benzylidene catalysts involving a carbene ligand on the branch termini of carbosilane dendrimers: application in RCM of diallyl tosylamine and recycling by column chromatography

Along the same lines, D. Astruc and coworkers designed polyamine PPI dendrimers ended by bisphosphines with two cyclohexyl groups as ligands for Hoveyda’s ruthenium– benzylidene metathesis catalyst (dendrimeric phosphine is represented in Figure 7.1).4,7,36,37 The three first generations obtained were found to be very efficient catalysts for the ROMP of norbornene under ambient conditions giving dendrimer-cored stars. In this case, the dendrimer displayed a higher activity than the parent monomer, which was explained by a more rapid dissociation of the alkyl phosphine in the dendrimer than in the monomer. This decoordination of the phosphine is a key step in the catalytic process since it permits the interaction of the olefinic substrate with the Ru monophosphine center. It is noteworthy that the efficiency of the catalysts decreased upon the dendrimer generation, which could result from a more difficult access to the metal center due to the increasing steric effect at the periphery. 7.2.1.3

Oligomerizations and Polymerizations

Metallocene catalysts find widespread application in the polymerization of α-olefins. Note that the active form of the catalysts in metallocene-mediated polymerizations is cationic and typically generated by a cocatalyst such as methylaluminoxane (MAO: complex condensate derived from water and AlMe3) or perfluorophenylborane B(C6F5)3 (Figure 7.9). The interaction between the ion pair affects the activity, stereoregularity, chain transfer, termination rate, and lifetime of the metallocene catalyst and, generally, less nucleophilic anions are highly suited. In this line, carbosilane dendrimers bearing alkyltris(pentafluorophenyl)borates on the surface have been used as cocatalysts in ethylene polymerization and copolymerization with propene or 1-hexene (Figure 7.9).38 The dendrimeric polyanions are able to abstract a methyl group from zirconium-based precatalyst (R′ = Me) and to thus generate the catalytically active metallocene cations in a very efficient manner. Moreover, high activities could be obtained in aliphatic solvents such as n-hexane, whereas the use of toluene, an unsuitable solvent for industrial polymerizations, is usually required. The high stability of dendrimeric anions (no loss in activity at reaction times greater than 40 minutes) compared to small molecule anions was referred as a positive dendrimeric effect thought to arise from the specific and unique interaction between the active cationic zirconocene and the crowded anionic surface of the dendrimer.13 It is

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Figure 7.9 Carbosilane dendrimers bearing alkyl-tris(pentafluorophenyl)borates on the surface as cocatalysts in ethylene polymerization and copolymerization with propene or 1-hexene

noteworthy that this system involving ion-pairing interactions can be considered as one of the most efficient noncovalently functionalized dendrimeric catalysts ever reported. Besides, several authors have studied the use of metallodendrimers in which the metal centers are catalysts of olefin polymerization. In this line, carbosilane dendrimers with peripheral zirconocene, hafnocene, and titanocene groups were applied in ethylene polymerization, in olefin copolymerization, and in silane polymerization using MAO as the cocatalyst.3 For example, E. de Jesus, J. C. Flores, and coworkers reported the preparation of carbosilane dendrimers (up to the third generation) decorated with imino-pyridine– Ni(II) complexes and their activity in ethylene polymerization using MAO as the cocatalyst. The size of the dendrimer was found to regulate the production of ethylene insertion products (oligomer versus polymer), the oligomer chain-length distribution, and the branching density, molecular weight, and polydispersity of the polymers.39 Carbosilane metallodendrimers with bis(imino)pyridyl–Fe(II) complexes at the periphery were also shown to catalyze the polymerization of ethylene using modified methylaluminoxane as the cocatalyst and to allow the production of much higher molecular weight polymers than the corresponding mononuclear complex.40 7.2.1.4

Miscellaneous Reactions

Several dendrimers decorated with organometallic complexes at their periphery were used as Lewis acids in different reactions, such as aldol condensations, Michael additions, Knoevenagel reactions, to name but a few. Some representative examples are mentioned above. G. van Koten and coworkers reported that cationic cyclopalladated carbosilane dendrimers can act as a Lewis acid in aldol condensation between benzaldehyde and methylisocyanoacetate. The rate of the reaction was found to decrease with increasing steric congestion at the dendrimer periphery.41 On the contrary, the close proximity of NCNpincer palladium(II) molecular tweezers immobilized on the surface carbosilane dendrimers was responsible for rate enhancements in the same aldol condensation.42 Along the

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same line, analogous NCN-pincer Pd(II) dendrimeric complexes were shown to efficiently catalyze the double Michael reaction between methyl vinyl ketone and α-cyanoacetate.43 Moreover, due to its macromolecular size, the catalyst could be used under continuous reaction conditions in a nanofiltration membrane reactor and showed excellent retentions. Besides, phosphorus-containing dendrimers decorated with diphenylphosphino–ruthenium dihydride complexes were also found to be active catalysts for the diastereoselective Michael addition of ethyl cyanoacetate to diethyl ethylenemalonate. The dendrimeric catalyst displayed similar activity and selectivity to the parent monomeric Ru complex RuH2(PPh3)4 and could be successfully recycled and reused two times through precipitation without loss of activity and selectivity, even when only 1% mol. of the catalyst is used.24 The same dendrimeric Ru complexes also showed high activity and analogous efficient recoverability in the Knoevenagel reaction.24 It is noteworthy that van Koten and coworkers reported one example of the use of noncovalently bound Pd(II) dendrimeric complexes in catalysis. The above-mentioned NCN-pincer palladium(II) complexes were indeed functionalized with sulfonated anionic tails and anchored at the periphery of polycationic dendrimers via ion-pairing interactions. The resulting complexes were successfully applied as a Lewis acidic catalyst, which performs comparably to the unsupported metal complex.44 Besides, L. J. Prins and coworkers reported the preparation of dendrons and dendrimers functionalized at the periphery with triazacyclononane, a ligand able to form a strong complex with Zn(II).45 These multivalent dendrimeric structures showed very high activity in the cleavage of the RNA model compound HPNPP. The catalytic activity was found to be highly dependent on the valency of the structure and this dendrimeric effect was explained by an intrinsic consequence of clustering catalytic units in the multivalent structure. Indeed, the catalytic activity results from the simultaneous action of two Zn(II) metal ions on the substrate. These dendrimers thus behave as enzyme-like catalysts. 7.2.2 Addition Reactions on a C=X Double Bond (X = C, O) 7.2.2.1

Hydrogenations

Hydrogenation, the addition of H2 on an unsaturated C=X bond, gives rise to alkanes from alkenes (X = C) or alcohols from carbonylated compounds (X = O). Palladium- and rhodium-based complexes are widely used to catalyze hydrogenation reactions. For example, K. Kaneda and coworkers prepared palladium complexes from PdCl2 and PPItype dendrimeric phosphines (PPI-dendr-[N(CH2PPh2)2]16). These complexes were shown to be selective catalysts for hydrogenation of dienes to monoenes under an atmospheric pressure of H2. Their catalytic activity is higher than that of the corresponding monomeric palladium complex and the dendrimeric catalyst can easily be recovered and reused without any loss of activity.46 L. H. Gade and coworkers used tripodal-terminated phosphine carbosilane dendrimers as ligands for rhodium in hydrogenation of styrene and 1-hexyne under an atmospheric pressure of H2. The resulting dendrimeric complexes displayed a catalytic activity similar to the monomeric complex and were sufficiently robust to be recycled several times.47 The reduction of C=C, C=O, and C=N bonds can also be achieved by replacing hazardous and expensive gaseous H2 by hydrogen donors such as alcohols or silanes. In this way,

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Figure 7.10 Diphosphine-capped carbosilane dendrimers as ligands for Rh(I) in the hydroformylation of 1-octene: an enhanced selectivity due to steric crowding at the periphery

van Koten and coworkers reported the anchoring of sulfonate-functionalized metal monocarbene Rh complexes on polycationic dendrimers via ion pairing. The resulting dendrimeric complexes were able to convert cyclohexanone into the corresponding alcohol using diphenylsilane as the hydrogen donor with, however. lower activities than the corresponding monomeric parent complex.48 7.2.2.2

Hydroformylations

D. J. Cole-Hamilton and coworkers reported that Rh-phosphine-terminated carbosilane dendrimers based on polyhedral silsesquioxane (POSS) cores and bearing 16 diphenylphosphines at the periphery are able to catalyze the hydroformylation of cyclooct-1-ene (Figure 7.10) with higher linear selectivities over branched isomers (linear/branched, l/b = 13.9) than their small analogs involving two or four PPh2 groups (linear/branched = 3.8 and 5.2, respectively,).49–51 An explanation for this positive dendrimer effect involves the steric crowding at the dendrimeric periphery.13 Indeed, the latter is thought to promote constrained bidentate binding of adjacent phosphines to the Rh(I) center, thus producing an analogous ligand environment than the one occurring with bidentate phosphine ligand known to favor the linear isomer (examples are Xantphos, bis(diphenylphosphinomethyl) biphenyl).51 The same authors reported carbosilane dendrimers still based on polyhedral silsesquioxane cores but decorated with alkylphosphines on the surface. The latter were catalytically active in hydroformylation, yielding alcohols instead of aldehydes. The dendrimeric catalyst bearing 24 PEt2 end groups was slightly more selective than the monomeric ligand (linear/branched = 3.1 over 2.4, respectively).52 7.2.2.3

Kharasch Reaction

Van Koten and coworkers prepared carbosilane dendrimers with, at the periphery, diaminoarylnickel(II) groups that catalyze the Kharasch addition of polyhalogenoalkanes on to C=C double bonds,1 the Kharasch reaction being an anti-Markovnikov addition involving a radical mechanism. This was the first example of catalysis with dendrimers. The dendrimeric catalysts were shown to be much less active than the parent Ni-pincer

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Figure 7.11 Ni-pincer complexes at the surface of carbosilane dendrimers: negative dendrimeric effect in the Kharasch reaction

complex, with the ToF decreasing from 163 h−1 to 39 h−1 for G1 (Figure 7.11), and an even larger decrease in activity was observed on using larger dendrimers (2 h−1 for G2).53,54 Molecular models showed that the accessibility of the catalytic sites was similar for dendrimers and monomers, and it was thus proposed that lower rates were due to high local concentrations of nickel centers. The authors suggested that catalyst deactivation was caused by surface congestion leading to an unsuitable interaction between neighboring Ni(II) and Ni(III) catalysts. The decrease in the catalytic activity was ascribed to formation of a mixed-valence Ni(II)/Ni(III) complex on the dendrimer periphery that competes for reaction with substrate radicals. These dendrimeric catalysts could, however, be successfully applied in a continuous process using a membrane reactor.55 Note that amino-acidbased dendrimeric wedges functionalized by up to four Ni(II)–NCN-pincer complexes were also able to catalyze the Kharasch reaction and no significant influence of the sterically different and more polar amino acid skeleton was observed.56 7.2.3

Oxidation Reactions

Schiff-base–manganese complexes are widely used as catalysts in oxidation reactions using hydrogen peroxide, organic peroxides, or molecular oxygen. Six generations of PAMAM dendrimers were thus functionalized by Schiff bases on their branch termini, complexed to Mn and tested in the epoxidation of cyclohexene under 1 atm. of O2.57 Good activities of the dendrimeric complexes were obtained but the reaction proved to be poorly selective, the major product being the 7-oxabicyclo[4.1.0]heptane-2-one obtained in 49% yield in the best cases. It is noteworthy, that this constitutes one of the rare examples of a surface-functionalized dendrimeric oxidation catalyst. Indeed, as will be highlighted later, most of Mn-, Co-, Zn-, or Ru-based oxidation catalysts have been incorporated at the core of dendrimers. In addition, dendrimeric polyoxometalates assembled by ionic bonding were reported to be very efficient and reusable oxidation catalysts for the epoxidation of alkenes in aqueous media; this topic will be presented in more detail in Chapter 10.58,59

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7.3

Organocatalysis with Dendrimers

As mentioned above, most catalytic dendrimers involve organometallic entities as catalytic sites. However, some examples also exist of dendrimers used as organocatalysts. One of the most famous examples of very efficient dendrimeric organocatalysts has been reported by J. L. Reymond and coworkers, who have described a series of peptide-based dendrimers that are models for lipases. The peptide dendrimers, prepared by solid-phase synthesis with various amino acid branching units, exhibit an enzyme-like esterolytic activity with a strong positive effect resulting from selective substrate binding and rate acceleration in aqueous media.60 Catalytic activity increases with generation despite steric crowding of catalytic groups at the periphery occurring in higher generation dendrimers. The effect of increasing dendrimer size rather induces catalytically productive interactions such as the creation of a hydrophobic microenvironment allowing substrate binding.61 Similar phenomena were observed by other authors.62 This topic will be detailed in Chapter 11 dealing with dendrimeric catalysis operating in aqueous media. Another interesting example in the field of organocatalysis was reported by M. R. Detty and coworkers and concerns the synthesis of Fréchet-type dendrimers decorated with selenides and tellurides and their application in the oxidation of cyclohexene into anti-1,2dibromocyclohexane or anti-2-bromocyclohexanol.63,64 Interestingly, in the case of selenide-capped dendrimeric catalysts, the rate of catalysis was increased by a factor of 80 from monoselenides to dendrimer-supported selenides (this factor was obtained from the relative constants for catalysis of each phenylseleno group (krel/SePh) with n arms terminating in SePh groups). This large dendrimer effect was ascribed to cooperativity between adjacent phenylseleno groups, leading to an autocatalysis at the surface of dendrimers. These reactions are performed in biphasic media and will be reviewed in more detail in Chapter 11. Several other examples of organocatalysts have been reported. For example, J. G. Verkade and coworkers prepared azidoproazaphosphatrane-capped PPI dendrimers, the first example of dendrimers bearing highly basic phosphine sites at their surface.65 The catalytic activity of these dendrimeric organocatalysts was tested in a tandem Michael/ aldol reaction and the expected products were obtained in good yields. No recycling experiment was reported in this example.

7.4

Conclusion

In this chapter, numerous examples of peripherally modified dendrimeric organometallic catalysts based on different backbones have been reported. Terminal groups of dendrimers were also used as organocatalysts but fewer examples were highlighted in the literature. For both, many “dendrimer effects” in catalysis have been observed, including increased/ decreased activity, selectivity, and stability. These “dendrimer effects” could arise from the high local concentration of catalysts, from unexpected interactions between neighboring catalytic sites, or from steric crowding at the dendrimer periphery. Organometallic catalysts could often be recovered and reused several times using various techniques such as nanofiltration, precipitation, or column chromatography. However, the recovery and

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re-use is not systematic and improvements have probably to be achieved in this field. Progress has also still to be performed to develop dendrimeric organocatalysts, very promising in terms of sustainable development because they are free from any metal. Hopefully, the variety of dendrimeric structures and topologies as well as the possibility to modify the dendrimer generation provide an almost infinite number of opportunities to improve catalyst supports.

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Dendrimers carbosilane-supported arylnickel(II) catalysts: observation of active-site proximity effects in atom-transfer radical addition. J. Am. Chem. Soc., 122, 12112–12124. R. A. Gossage, J. T. H. B. Jastrzebski, J. van Ameijde, S. J. E. Mulders, A. J. Brouwer, R. M. J. Liskamp, and G. van Koten (1999) Synthesis and catalytic application of amino acid based dendritic macromolecules. Tetrahedron Lett., 40, 1413–1416. Z.-W. Yang, Q.-X. Kang, H.-C. Ma, C.-L. Li, and Z.-Q. Lei (2004) Oxidation of cyclohexene by dendritic PAMAMSA–Mn(II) complexes. J. Mol. Catal. A, 213, 169–176. L. Plault, A. Hauseler, S. Nlate, D. Astruc, J. Ruiz, S. Gatard, and R. Neumann (2004) Synthesis of dendritic polyoxometalate complexes assembled by ionic bonding and their function as recoverable and reusable oxidation catalysts. Angew. Chem. Int. Ed., 116, 2984–2988. M. V. Vasylyev, D. Astruc, and R. Neumann (2005) Dendritic phosphonates and the in situ assembly of polyperoxophosphotungstates: synthesis and catalytic epoxidation of alkenes with hydrogen peroxide. Adv. Synth. Catal., 347, 39–44. A. Esposito, E. Delort, D. Lagnoux, D. Djojo, and J. L. Reymond (2003) Catalytic peptide dendrimers. Angew. Chem. Int. Ed., 42, 1381–1383. E. Delort, T. Darbre, and J. L. Reymond (2004) A strong positive dendrimeric effect in a peptide dendrimer-catalyzed ester hydrolysis reaction. J. Am. Chem. Soc., 126, 15642–15643. I. K. Martin and L. J. Twyman (2001) Acceleration of an aminolysis reaction using a PAMAM dendrimer with 64 terminal amine groups. Tetrahedron Lett., 42, 1123–1126. C. Francavilla, M. D. Drake, F. V. Bright, and M. R. Detty (2001) Dendrimeric organochalcogen catalysts for the activation of hydrogen peroxide: improved catalytic activity through statistical effects and cooperativity in successive generations. J. Am. Chem. Soc., 123, 57–67. M. D. Drake, F. V. Bright, and M. R. Detty (2003) Dendrimeric organochalcogen catalysts for the activation of hydrogen peroxide: origins of the “dendrimer effect” with catalysts terminating in phenylseleno groups. J. Am. Chem. Soc., 125, 12558–12566. A. Sarkar, P. Ilankumaran, P. Kigansa, and J. G. Verkade (2004) First synthesis of a highly basic dendrimer and its catalytic application in organic methodology. Adv. Synth. Catal., 346, 1093–1096.

8 Catalytic Sites inside the Dendrimeric Structure for Homogeneous Catalysis Armelle Ouali* and Anne-Marie Caminade

8.1

Introduction

Dendrimers possessing the catalytic entities (generally organometallic entities but also organocatalysts) inside their structure, at the core, or within the branches were synthesized with the aim of taking profit of the confinement on the catalytic activity (see Chapter 7, Figure 7.1(b)).1–12 In this chapter, the influence of the confinement of the catalyst inside the dendrimers on the catalyst activities and selectivities will be discussed. Indeed, placing the catalytic group at the core of a dendrimer results in a steric shielding of the active site, enabling catalyst stabilization or shape selectivity in some cases. Moreover, the interior region can provide a localized environment suitable for binding and catalysis and, for example, dendrimers with hydrophobic interiors can bind substrates and catalyze the reaction between hydrophobic guests (enzyme mimics). In addition, by isolating the catalytic site at the core of a dendrimer, interactions between catalytic sites and further potential deactivation can be avoided. Note that although many examples of corefunctionalized dendrimeric catalysts can be found in the literature (Section 8.2), only a few examples of dendrimers bearing catalytic groups in their branches have been reported (Section 8.3).

* Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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8.2

Catalytic Sites as the Core of Dendrimers

8.2.1 8.2.1.1

Dendrimers Bearing a Transition-Metal-Based Complex at the Core Formation of C–X Bonds (X = C, N)

Cross-Couplings. As in the case of surface-decorated dendrimers, palladium catalysts are the most frequently used in this type of cross-coupling. Therefore, L. Canovese, G. Chessa, and coworkers reported the grafting of pyridyl-dithioether ligands on the core of pyridine-based dendrimers and the corresponding palladium(II) allyl complexes were fully characterized and tested in allylic amination reactions. The kinetic and thermodynamic behaviour of the species were not affected on going from the model molecule to the second generation dendrimeric substrate. Only the third generation dendrimeric wedge showed a different behaviour in terms of rate and ligand displacement constants. According to the authors, the steric hindrance induced by the third generation dendrimer on the allyl fragment and the distorsion of the main coordination plane around the metal could explain these results.13 P. W. N. M. van Leeuwen and coworkers reported the preparation of three generations of carbosilane dendrimers bearing bis(diphenylphosphino)ferrocene at their core.14 The resulting palladium(II) complexes were tested in the allylic alkylation of 3-phenylallyl acetate with diethyl-2-sodio-2-methylmalonate. The increase of the size of the second and third generation dendrimers resulted in a more difficult mass transport, leading to the decrease of yields. Moreover, increased steric bulk of the larger dendrimers hinders the nucleophilic attack on the palladium, which favors the formation of the branched product. The apolar microenvironment within the larger carbosilane dendrimers could also contribute to this change in selectivity. R. J. M. Klein Gebbink and coworkers developed Dendriphos ligands (Figure 8.1), Fréchet-type dendrons combining the triphenylphosphine moiety at their focal points and six ammonium groups as permanent cationic substituents in the branches.15 The zero (benzyl), first, and second generation dendrons (G0, G1, and G2) were tested as palladium ligands in Suzuki–Miyaura couplings of aryl bromides and chlorides with phenylboronic acid. For coupling of aryl chlorides, the G0 ligand was found to confer to Pd a much better activity than other conventional triarylphosphine-based ligands. The six permanent cationic charges in the backbone are thought to induce a significant interligand Coulombic repulsion and to play a crucial role in the bulky behaviour of this class of ligands. The authors propose that the steric hindrance of these systems facilitates the formation of the catalytically active species, a coordinately unsaturated Pd(0)L (L = G0, G1, G2). In addition, a very positive dendrimer effect was observed when using ligands of higher generations G1 and G2, indicating an increased ability of higher ligand generations to stabilize the active species due to steric effects. Y. Tsuji and coworkers developed triarylphosphines with dendritically arranged tetraethylene glycol moieties (TEG) at the periphery (9 TEG for the first generation and 18 TEG for the second generation).16 These dendrons were also found to be efficient ligands in a palladiumcatalyzed Suzuki–Miyaura coupling reaction of aryl chlorides and phenylboronic acid in the presence of K2CO3. It is noteworthy that in the same conditions (THF, 60 °C), the corresponding triphenylphosphine–Pd complex is inactive. The TEG moieties are thought to play a crucial role in the course of the reaction by chelating the K+ ion of the base and/ or the arylboronic acid. Therefore, both the transmetallation and the oxidative addition

Catalytic Sites inside the Dendrimeric Structure for Homogeneous Catalysis

185

Figure 8.1 Palladium-catalyzed Suzuki–Miyaura coupling of p-nitrochlorobenzene and phenylboronic acid in the presence of Dendriphos ligands: a positive dendrimer effect

steps would be accelerated cooperatively because of the strong interaction of the TEG moieties surrounding the catalyst center. Apart from palladium-catalyzed cross-couplings, other reactions such as Diels–Alder reactions, Michael additions, or oligomerizations allow for the formation of C–C bonds. Some examples involving core-functionalized dendrimeric catalysts are described below. Diels–Alder Reactions. Diels–Alder reactions allow the formation of C–C bonds and constitute an easy access to highly functionalized molecules in one step. H.-F. Chow and coworkers prepared four generations of dendrimers bearing bis(oxazoline)–copper(II)triflate complexes at their core and tested their catalytic activity in the Diels–Alder reaction of cyclopentadiene and a crotonyl imide.17 The aim was to determine the extent to which the dendrimer ’s polarity and steric factors affected the kinetics of catalysis. The binding of the dienophile to the catalyst could be quantified by determining the binding constant. The latter was found to decrease as the dendrimers got bigger, which could be explained by steric factors that distorted the geometry of the ligand.4 Moreover, the rate constant remained the same for generations 0 to 2 but was found to decrease in the case of the third generation. This was ascribed to a sudden change of dendrimer conformation, which occured between generation 2 and 3. The same authors also demonstrate that the dendrimers could provide steric selectivity, with smaller dienophiles reacting much faster than larger ones.18 Michael Addition Reactions. Michael reactions consist in the addition of a nucleophile on to an electron-poor carbon–carbon double bond (Michael acceptor). Phosphorus dendrons involving a single ruthenium metallic center located at the core were found to

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Dendrimers

efficiently catalyze the diastereoselective Michael addition of ethylcyanoacetate on to diethyl ethylidene malonate.19 The dendron could be recycled and reused three times without loss of activity using the precipitation strategy. No difference in the activity was observed when comparing this dendron with phosphorus dendrimers having several ruthenium centres as terminal groups. Oligomerization of Ethylene. Nickel complexes bearing P, O ligands such as o-phenylphosphinophenols are known to promote polymerization reactions. However, these complexes have a strong tendency for the formation of bis-(P, O)nickel complexes, which are inactive. Van Leeuwen and coworkers proposed a second generation carbosilane dendrimeric P, O ligand which was efficient in Ni-catalyzed ethylene oligomerization in toluene (with an average turnover frequency of 7700 h−1 against 3600 h−1 for the parent monomeric complex).20 The site isolation of the Ni complex within this dendrimeric structure would be at the origin of these increased stability and activity. Noteworthy is the fact that the dendrimeric complexes are even active in methanol, a solvent in which the dimerization is usually favored (with an average turnover frequency of 3242 h−1 in methanol) and in which the parent monomer–Ni complex is inefficient. 8.2.1.2 Addition Reactions on a C=X Double Bond (X = C, O) Dendrimeric catalysts bearing the active species at the core were reported for hydrogenation, hydrosilylation, and hydroformylation reactions. For example, the J. N. H. Reek and P. W. N. M. van Leeuwen group has reported the use of Ru complexes of the diphenylphosphinoferrocene (dppf) carbosilane-based dendrimeric ligands in hydrogenation of dimethyl itaconate in a continuous-flow membrane reactor. Catalytic activities were found to be similar to those obtained with the monomeric complex, but higher retentions could be reached in the case of the dendrimeric catalysts (99.8% instead of 97% for the dppf– rhodium complex).21 Similar observations were reported for the use of these catalysts in hydroformylation reactions.21 Besides, N-heterocyclic carbenes (NHC) rhodium complexes are known to promote hydrosilylation of ketones but their use is often limited by a weak stability of the complexes. Tsuji and coworkers reported the synthesis of NHC chelating carbenes bearing Fréchet-type dendrimeric frameworks.22 Their catalytic activity in Rh-catalyzed hydrosilylation of acetophenone and cyclohexanone was found to be enhanced compared to the parent monomeric ligand. Moreover, a positive dendrimer effect could be highlighted (Figure 8.2), the yields of expected alcohols improving when the generation was increased. This effect was attributed to the folding of the dendrimer around the catalytic active site, which allows an improvement of the catalyst stability.11 Bis-NHC rhodium complexes have also been used in the hydrosilylation of 2-cyclohexen-1-one, but no dendrimer generation effect was observed in this case.23 8.2.1.3

Oxidation Reactions

Epoxidation Reactions. As highlighted in Chapter 7, most oxidation catalysts have been incorporated at the core of dendrimers. The core-functionalized dendrimeric oxidation catalysts have mainly been applied in epoxidations and sulfide oxidations. Therefore, J. S. Moore, K. S. Suslick, and coworkers prepared ester-linked dendrimers with metalloporphyrin cores up to the second generation.24,25 The catalytic activity of the correspond-

Catalytic Sites inside the Dendrimeric Structure for Homogeneous Catalysis

187

Figure 8.2 Rhodium-catalyzed hydrosilylation of ketones (example of acetophenone) in the presence of Fréchet-type dendrimeric N-heterocyclic carbenes as ligands: a positive dendrimer effect

ing manganese complexes was tested in epoxidation of alkenes using iodosylbenzene as the oxygen donor in dichloromethane. The dendrimeric catalysts showed significantly greater regioselectivity than the corresponding unhindered parent metalloporphyrin complex. For example, in the case of substrates containing two separated alkene functionalities, the least substituted functionality was preferentially oxidized. Moreover, easily oxidized electron-rich alkenes such as cyclooctene exhibited lower reactivity than less hindered simpler alkenes, which are usually less reactive. To rationalize these results, molecular modelling was performed and showed that the top access of the porphyrin was extremely limited. This steric restriction was thus thought to be at the origin of the observed shape selectivity of the substrate. It is noteworthy that the dendrimeric oxidation catalysts were found to be very stable (only 10% of the catalyst activity has degraded after 1000 turnover cycles). Fréchet-type dendrimeric ruthenium porphyrins were also prepared by C.-C. Che and coworkers and their catalytic activity was tested in epoxidation and cyclopropanation reactions.26 The chemo- and diastereoselectivities obtained in the epoxidation of aromatic alkenes and unsaturated steroids were found to increase with an increase in the generation number of the dendron or the number of dendrons attached to the core. Dendrimeric polyoxometalates were also reported to be efficient and reusable epoxidation catalysts in aqueous media, a topic that will be presented in more detail in Chapter 10.27,28 Sulfide Oxidations. M. Kimura and coworkers incorporated cobalt(II)–phthalocyanine complexes at the core of dendrimers and showed that dendrimeric shielding was responsible for slowing electron transfer reactions at the centre of the dendrimers.29 The latter were efficient catalysts for oxidation of 2-mercaptoethanol into the corresponding disulfide and they displayed enhanced stability due to the shielding effect of the dendrimeric structure. Such improvement of the oxidation catalyst stability was also reported by F. Diederich and coworkers in the case of iron(III) porphyrins incorporated at the core of dendrimers (generations 0 to 2).30 In these systems, dendrimeric encapsulation mimics the function of

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Dendrimers

the protein shell in the natural heme proteins. These dendrimeric catalysts were found to be efficient and selective in sulfide oxidations. For sulfide oxidation, dendrimeric polyoxometalates also proved to be efficient and reusable catalysts in aqueous media.27,28,31 Miscellaneous Reactions. As illustrated before, placing the catalyst at the core of dendrimers may enable the steric environment around the active centre to be modified and to provide protection of the metallic centre. This has been the case for cobalt(II)–porphyrin complexes encapsulated by a large and radical tolerant poly(aryl) ester dendrimeric cage of the third or fourth generations reported by T. Aida and M. Uyemura.32,33 Azobisisobutyronitrile(AIBN)-initiated alkylation of cobalt(II) within the dendrimers was highly chemoselectively achieved with an alkyne. Due to its steric hindrance, the cage was found to prohibit the access of two cobalt porphyrin molecules, thereby protecting the interior alkylated product from subsequent isomerization. Unexpected behavior of metal centers placed at the core of large dendrimers has also been reported by J. M. J. Fréchet, S. J. Lippard, and coworkers in the case of dinuclear iron(II) complexes prepared from third generation dendrimer-appended carboxylate ligands.34 The oxygenation of such complexes into the mixed-valent complexes Fe(II)–Fe(III) was found to be retarded by about three-hundredfold compared with that of related compounds sterically less demanding, such as the simple terphenyl carboxylate. Dendritic encapsulation would suppress simple dioxygen-initiated outer-sphere one-electron oxidation. These dendrimers were efficient to oxidize anthrone to anthraquinone in the presence of O2. 8.2.2

Dendrimers Bearing an Organocatalyst at the Core

Organic catalysis is a growing area and several examples of dendrimers bearing an organocatalyst at their core have been reported. They have been used in many reactions such as aldolisations, Baylis–Hillman reactions, esterifications, polymerizations, or different redox processes, to name but a few. 8.2.2.1

Formation of C–X Bonds (X = C, N)

F. P. Cossio, X. Lopez, and coworkers have reported the synthesis of three generations of dendrimers incorporating a tertiary alkyl amine at their core and their application as catalysts for the nitroaldol (Henry) reaction between 2-nitroethanol and benzaldehyde.35 The catalytic activity of dendrimers decreased as the generation number and/or the degree of branching increased. The catalytic behavior of the dendrimers could be quantified in terms of their molecular weight and reagent-accessible surface. Still in the line of nitrogencontaining organocatalysts, 4-(N,N-dimethylamino)pyridine (DMAP) was incorporated at the core of dendrimers and the catalytic activity of the latter was tested in a Baylis–Hillman reaction of arylaldehydes with methylvinyl ketone or acrylonitrile at 60 °C. By carrying out the reaction in the thermophoric binary system dimethylformamide/cyclohexane (1 : 1, v/v), the dendrimeric catalysts could be recovered in the cyclohexane phase after cooling the temperature from 60 °C to room temperature and further successfully reused.36 Fréchet and coworkers prepared dendrimers bearing three DMAP groups at their core.37 The dendrimeric architecture involved either benzyl ether (Fréchet-type dendrimers) or aliphatic ester moieties, and both were functionalized with long alkyl chains on the branch termini.

Catalytic Sites inside the Dendrimeric Structure for Homogeneous Catalysis

189

Figure 8.3 Iodide-catalyzed Mukaiyama aldolization: stabilization of anionic intermediates within the polycationic quaternized PPI dendrimer interior

Catalysis experiments in esterification of linalool indicated that the nanoenvironment created by the dendrimeric interior played a crucial role in determining the activity. Such influence of the dendrimer architecture on the catalytic activity was also highlighted by K. Kaneda and coworkers in the case of lipophilic tetraalkylammonium iodide dendrimers. The periphery of third generation PPI dendrimer was functionalized with either C10 or C16 acyl chains and the nitrogen atoms of the interior were quaternized with methyl iodide to afford lipophilic tetraalkylammonium iodide dendrimers (Figure 8.3).38 This study shows that iodide-promoted Mukaiyama aldol reactions of 1-methoxy-2-methyl-1(trimethylsilyloxy)propene with various aldehydes were much more efficiently catalyzed by dendrimeric iodides than by “small molecule” sources of iodide. The concentration of multiple cationic charges within the dendrimeric interior would be at the origin of the unique stabilization of the reactive anionic intermediates.11 By analogy, positively charged transition states or planar cationic intermediates encountered in SN2- or E1-type reactions can be stabilized with polar groups present within the interiors of dendrimers. Fréchet and coworkers indeed reported the synthesis of unimolecular dendrimeric inverted micelles possessing polar CH2OH groups within their interiors.39 These polar substituents provided a stabilizing region within the dendrimer and were found to accelerate greatly the alkylation of pyridines with various alkyl halides via SN2 nucleophilic substitution as well as the preparation of alkenes from secondary and tertiary alkyl halides via E1 elimination. The dendrimers could be recovered and reused many times. Apart from stabilizing intermediates, the globular dendrimeric architecture around a catalytically active site also functions to bind guest molecules, which is another key to success in catalysis. This aspect is reminiscent of molecular transformations achieved by enzymes in which the substrate binding features determine the selectivity. Pyridoxamine PAMAM dendrimers (generations 1 to 6) were applied in the transamination of pyruvic acid and phenylpyruvic acid in aqueous buffer.40 It was found that the substrate binding ability and the reaction rates were improved by increasing the generation number. Substrate binding opportunities offered by dendrimer interiors were also shown to provide selectivity in polymerization reactions. For example, a Fréchet-type poly(aryl ether) dendrimer bearing an alkoxide at its core has been used as the initiator in anionic ring opening

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Dendrimers

polymerizations.41 High molecular weight polymers with narrow polydispersities were obtained whereas simple metal alkoxides provide broad molecular weight distributions. This was explained by the fact that the reactive alkoxide group prefers to stay within the bulky dendrimeric interior, which allowed for avoidance of intramolecular “backbiting” side reactions. Fréchet and coworkers used a similar approach to control a living polymerization in which the radical initiator TEMPO was placed at the dendrimer ’s centre.42 Polymers were also obtained with low polydispersities but low molecular weight, which was explained by the low solubility of the growing polymer dendrimer conjugate. 8.2.2.2

Redox Processes

The substrate-binding opportunities created by dendrimeric nanoenvironments were also highlighted in the field of redox processes. In this field, X. Zhang, J. Liu, and coworkers reported the synthesis of three generations of Fréchet-type poly(aryl ether) dendrimers with a diselenide core and their use as glutathione peroxidase (GPx) mimics. GPx is a mammalian antioxidant selenoenzyme protecting membranes from oxidative damage by catalyzing the reduction of various hydroperoxides (ROOH) using glutathione (GSH) as the reducing substrate.43 The catalytic activities of different dendrimers were tested in the reduction of hydrogen peroxide H2O2 in water in the presence of thiophenol (Figure 8.4). The activities were found to increase greatly from the first to the third generation. This effect was ascribed to a more efficient binding in larger dendrimers that were able to provide the more hydrophobic nanoenvironment suited for this reaction.11 Still on the subject of dendrimers with redox properties, porphyrin-functionalized pyrimidine dendrimers were found to be active catalysts for the photooxidation of alkenes with oxygen. The catalyst displayed high stabilities compared to peripheral porphyrin units, which are more sensitive to photodegradation, and they were efficiently recycled by nanofiltration technology.44

Figure 8.4 Hydrogen peroxide reduction by dendrimeric diselenides (0.01 μM) in the presence of thiophenol in a CHCl3/CH3OH/H2O (3 : 6.5 : 0.5) mixture: increase of the initial rate ν0 with increasing generation number

Catalytic Sites inside the Dendrimeric Structure for Homogeneous Catalysis

8.3

191

Catalytic Sites inside the Branches of Dendrimers

Only a few examples of dendrimers bearing catalytic sites within their branches have been reported in the literature. Moreover, in most cases, the catalytic moieties were noncovalently bound to the dendrimeric support. These facts can probably partly be explained by the relative synthetic difficulties in functionalizing the dendrimer interiors.45 Some representative examples of dendrimeric catalysts displaying catalytic groups in their branches are presented hereafter. 8.3.1

Formation of C–X Bonds (X = C, N, O)

Kaneda and coworkers prepared catalysts using a self-assembly approach from decanoylterminated PPI dendrimers (G2 to G4) and 4-diphenylphosphinobenzoic acid as ligand for the metal center (Figure 8.5).46 The acid–amine ion pair ensured selective catalyst placement at the interior of dendrimers. Addition of [PdCl(C3H5)]2 allowed the generation of the supramolecular active catalyst whose activity was tested in the Heck coupling of iodobenzene and n-butylacrylate. The reaction rate was found to increase with increasing generation, and with 1,4-diiodobenzene as the substrate a good selectivity for the monoadduct (mono : di = 92 : 8) was obtained in the presence of G4 whereas the monomeric parent complex displayed little selectivity (mono : di = 45 : 55). These results could indicate that catalysis occurred inside the dendrimer. The former Pd complexes were also shown to catalyze the allylic amination of cinnamyl methyl carbonate with morpholine, but their activity was found to decrease with increasing generation. However, the formation of the linear product was favored for larger dendrimer catalysts (linear/branched = 9.0 for G4 and

Figure 8.5 Palladium-catalyzed allylic amination of cinnamyl methyl carbonate with morpholine: the acid–amine ion pair ensured the placement of the catalyst inside the dendrimer

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Dendrimers

only 5.1 for the monomeric parent complex). This could be explained by a significantly more polar nanoenvironment within G4, polar media (such as DMSO) being known to induce higher linear to branched ratios. Other dendrimeric palladium catalysts were also used to catalyze C–C bond formation via aldolization. Therefore, R. J. M. Klein Gebbink, G. van Koten, and coworkers reported the preparation of various ionic core–shell polybenzyl aryl ether dendrimers with an octanionic core and their use as supports for NCN pincer palladium complexes bearing tethered sulfato groups.47 The resulting supramolecular palladium catalysts were able to promote the aldol condensation between benzaldehyde and methyl isocyanoacetate in dichloromethane. The minor effect of the size and nature of the dendrimeric supports on the catalytic activity and product selectivity illustrated the good accessibility of Pd(II) sites to reactants within the assemblies. Van Koten also reported the preparation of cationic palladium complexes involving NCN-pincer ligands covalently bound within the branches of the dendrimeric structure.48 These macrocyclic Pd(II) complexes were found to be active catalysts (1 mol %) in the aldol condensation of benzaldehyde and methyl isocyanoacetate to form oxazolines at room temperature. The polycationic dendrimeric system turned out to have a slightly higher activity than the corresponding mononuclear model compound. 8.3.2 Addition Reactions on a C=C Double Bond: Olefin Hydrogenation A. K. Kakkar and coworkers designed dendrimers containing phosphorus ligands at the branching points and the catalytic activity of the corresponding rhodium complexes was evaluated in olefin hydrogenation.49 Whatever the generation, the activity was found to be similar to that of the parent monomeric complex in terms of TON (200) and TOF (400 h−1). The fourth generation was recovered and reused one time and the catalyst was found to be still active with only a 5% decrease of the conversion of decene. D. L. DuBois and coworkers also reported the preparation of dendrimers involving phosphorus atoms at each branching point.50 The corresponding palladium complexes exhibited catalytic activity for the electrochemical reduction of CO2 to CO.

8.4

Conclusion

In this chapter, numerous examples of core-functionalized dendrimeric organometallic and organic catalysts based on different backbones have been reported. As in the case of peripherally modified dendrimers, “dendrimer effects” in catalysis have been observed, including increased/decreased activity, selectivity, and stability. These “dendrimer effects” could arise from steric shielding of the catalyst within the dendrimer interior, from site isolation, or from the nanoenvironment created close to the active site, which allows for substrate binding and preconcentration or also for stabilization of intermediates. It is noteworthy that few examples of dendrimers bearing catalysts in their branches have been reported so far, probably because the functionalization of dendrimer interiors is somewhat more difficult. More research has obviously still to be performed in this field because such dendrimers could combine the advantages encountered for peripherally modified and core-

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functionalized dendrimeric catalysts. Indeed, high local concentration of catalysts could be achieved within the specific nanoenvironment of the dendrimer interior, which could lead to unexpected “dendrimer effects”. Core-functionalized dendrimeric catalysts could often be recovered and reused several times using nanofiltration or precipitation. However, the recovering and reuse is not systematic and, here also, improvements probably need to be achieved.

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(18) H.-F. Chow and C. C. Mak (1997) Dentritic bis(oxazoline)copper(II) catalysts: synthesis, reactivity and substrate selectivity. J. Org. Chem., 62, 5116–5127. (19) V. Maraval, R. Laurent, A.-M. Caminade, and J.-P. Majoral (2000) Phosphorus-containing dendrimers and their transition metal complexes as efficient recoverable multicenter homogeneous catalysts in organic synthesis. Organometallics, 19, 4025–4029. (20) C. Müller, L. J. Ackerman, J. N. H. Reek, P. C. J. Kamer, and P. W. N. M. van Leeuwen (2004) Site-isolation effects in a dendritic nickel catalyst for the oligomerization of ethylene. J. Am. Chem. Soc., 126, 14960–14963. (21) G. E. Oosterom, S. Steffens, J. N. H. Reek, P. C. J. Kamer, and P. W. N. M. van Leeuwen (2002) Core-functionalized dendrimeric mono- and diphosphine rhodium complexes; application in hydroformylation and hydrogenation. Top. Catal., 19, 61–73. (22) T. Fujihara, Y. Obora, M. Tokunaga, H. Sato, and Y. Tsuji (2005) Dendrimer N-heterocyclic carbine complexes with rhodium(I) at the core. Chem. Commun., 4526–4528. (23) T. Fujihara, Y. Obora, M. Tokunaga, and Y. Tsuji (2007) Rhodium(III) complexes with a bidentate N-heterocyclic carbene ligand bearing flexible dendritic frameworks. Dalton Trans., 1567–1569. (24) P. Bhyrappa, J. K. Young, J. S. Moore, and K. S. Suslick (1996) Dendrimer-metalloporphyrin: synthesis and catalysis. J. Am. Chem. Soc., 118, 5708–5711. (25) P. Bhyrappa, J. K. Young, J. S. Moore, and K. S. Suslick (1996) Shape selectivity epoxidation of alkenes by metalloporphyrin-dendrimers. J. Mol. Catal. A, 113, 109–116. (26) J.-L. Zhang, H.-B. Zhou, J.-S. Huang, and C.-C. Che (2002) Dendritic ruthenium porphyrins: a new class of highly selective catalysts for alkene epoxidation and cyclopropanation. Chem. Eur. J., 8, 1554–1562. (27) S. Nlate, D. Astruc, and R. Neumann (2004) Synthesis, catalytic activity in oxidation reactions, and recyclability of stable polyoxometalate-center dendrimers. Adv. Synth. Catal., 346, 1445–1448. (28) S. Nlate, L. Plault, and D. Astruc (2006) Synthesis of 9- and 27-armed tetrakis(diperoxotungsto) phosphate-cored dendrimers and their use as recoverable and reusable catalysts in the oxidation of alkenes, sulfides and alcohols with hydrogen peroxide. Chem. Eur. J., 12, 903–914. (29) M. Kimura, Y. Sugihara, T. Muto, K. Hanabusa, H. Shirai, N. Kobayashi (1999) Dendritic metallophtalocyanines – synthesis, electrochemical properties, and catalytic activity. Chem. Eur. J., 5, 3495–3500. (30) P. Weyermann and F. Diederich (2002) Dendritic iron porphyrins with a tethered axial ligand as new model compounds for heme monooxygenases. Helv. Chim. Acta, 85, 599–617. (31) C. Jahiez, S. S. Mal, U. Kortz, and S. Nlate (2010) Dendritic zirconium-peroxotungstosilicate hybrids: synthesis, characterization, and use as recoverable and reusable sulfide oxidation catalysts. Eur. J. Inorg. Chem., 1559–1566. (32) M. Uyemura and T. Aida (2002) Steric control of organic transformation by a dendrimer cage: organocobalt dendrimer porphyrins as novel coenzyme B12 mimics. J. Am. Chem. Soc., 124, 11392–11403. (33) M. Uyemura and T. Aida (2003) Characteristics of organic transformations in a confined dendritic core: studies of the AIBN-initiated reaction of dendrimer Co(II) porphyrins with alkynes. Chem. Eur. J., 9, 3492–3500. (34) M. Zhao, B. Helms, E. Slonkina, S. Friedle, D. Lee, J. DuBois, B. Hedman, K. O. Hodgson, J. M. J. Fréchet, and S. J. Lippard (2008) Iron complexes of dendrimer-appended carboxylates for activating dioxygen and oxidizing hydrocarbons. J. Am. Chem. Soc., 130, 4352–4363. (35) A. Zubia, F. P. Cossio, I. Morao, M. Rieumont, and X. Lopez (2004) Quantitative evaluation of the catalytic activity of dendrimers with only one active center at the core: application to the nitroaldol (Henry) reaction. J. Am. Chem. Soc., 126, 5243–5252. (36) N.-F. Yang, H. Gong, W.-J. Tang, Q.-H. Fan, C.-Q. Cai, and L.-W. Yang (2004) Phase selectively soluble dendritic derivative of 4-(N,N-dimethylamino)pyridine: an easily recyclable catalyst for Baylis–Hillman reactions. J. Am. Chem. Soc., 126, 5243–5252. (37) B. Helms, C. O. Liang, C. J. Hawker, and J. M. J. Fréchet (2005) Effects of polymer architecture and nanoenvironment in acylation reactions employing denritic (dialkylamino)pyridine catalysts. Macromolecules, 38, 5411–5415.

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(38) T. Mizugaki, C. E. Hetrick, M. Murata, K. Ebitani, M. D. Amiridis, and K. Kaneda (2005) Quaternary ammonium dendrimers as Lewis base catalysts for Mukaiyama–Aldol reaction. Chem. Lett., 34, 420–421. (39) M. E. Piotti, F. Rivera, R. Bond, C. J. Hawker, and J. M. J. Fréchet (1999) Synthesis and catalytic activity of unimolecular dendritic reverse micelles with “internal” functional groups. J. Am. Chem. Soc., 121, 9471–9472. (40) L. Liu and R. Breslow (2003) Dendrimeric pyridoxamine enzyme mimics. J. Am. Chem. Soc., 125, 12110–12111. (41) K. Matyjaszewski, T. Shigemoto, J. M. J. Fréchet, and M. Leduc (1996) Controlled/”living” radical polymerization with dendrimers containing stable radicals. Macromolecules, 29, 4167–4171. (42) L. Gitsov, P. T. Ivanova, and J. M. J. Fréchet (1994) Dendrimers as macroinitiators for anionic ring-opening polymerization. Polymerization of ε-caprolactone. Macromol. Rapid. Commun., 29, 387–393. (43) X. Zhang, H. Xu, Z. Dong, Y. Wang, J. Liu, and J. Shen (2004) Highly efficient dendrimerbased mimic of glutathione peroxidase. J. Am. Chem. Soc., 126, 10556–10557. (44) S. A. Chavan, W. Maes, L. E. M. Gevers, J. Wahlen, I. F. J. Vankelecom, P. A. Jacobs, W. Dehaen, and D. E. De Vos (2005) Porphyrin-functionalized dendrimers: synthesis and application as recyclable photocatalysts in a nanofiltration membrane reactor. Chem. Eur. J., 11, 6754–6762. (45) S. Hecht (2003) Functionalizing the interior of dendrimers: synthetic challenges and applications. J. Polym. Sci. Part A: Polym. Chem., 41, 1047–1058. (46) L. Ooe, M. Murata, T. Mizugani, K. Ebitani, and K. Kaneda (2004) Supramolecular catalysts by encapsulating palladium complexes within dendrimers. J. Am. Chem. Soc., 126, 1604–1605. (47) R. van de Coevering, A. P. Alfers, J. D. Meeldijk, E. Martnez-Viviente, P. S. Pregosin, R. J. M. Klein Gebbink, and G. van Koten (2006) Ionic core–shell dendrimers with an octanionic core as noncovalent supports for homogeneous catalysis. J. Am. Chem. Soc., 128, 12700–12713. (48) G. Rodriguez, M. Lutz, A. L. Spek, and G. van Koten (2002) New mono- and tricyclopalladated dendritic systems with encapsulated catalytic sites. Chem. Eur. J., 8, 45–57. (49) P. Petrucci-samija, V. Guillemette, M. Dasgupta, and A. K. Kakkar (1999) J. Am. Chem. Soc., 121, 1968–1969. (50) A. Miedaner, C. J. Curtis, R. M. Barkley, and D. L. DuBois (1994) Inorg. Chem., 33, 5482–5490.

9 Dendrimers as Homogeneous Enantioselective Catalysts Armelle Ouali* and Anne-Marie Caminade

9.1

Introduction

As a complement to both of the previous chapters, this one will emphasize enantioselective catalytic reactions. As in both Chapters 7 and 8, Chapter 9 involves two main parts respectively dealing with the dendrimeric organometallic catalysts, on the one hand, and with the dendrimeric organic catalysts, on the other hand.1–10 Several examples of reactions allowing the formation of C–C bonds (allylic alkylations, aldolisations, Henry, Michael or Diels–Alder reactions, to name but a few), C–N bonds (allylic aminations or αhydrazinations), and C–O bonds (herero Diels–Alder reaction) have been reported. Note that metal-catalyzed asymmetric hydrogenations constitute the main part of enantioselective catalyses carried out with dendrimers. Various types of unsaturated bonds such as ketones, but essentially alkenes, were hydrogenated, using either H2 or chemical hydrogen donors. As in the case of nonenantioselective transformations, very few examples of dendrimers involving organocatalysts have been reported. For all of the above-mentioned reactions, the catalysts were placed at the core or on the surface of dendrimers and, in some cases, the dendrimeric support modified the catalyst activities and enantioselectivities (the “dendrimer effect”).

* Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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9.2

Catalytic Organometallic Sites as Catalysts for Homogeneous Catalysis

9.2.1

Formation of C–X Bonds (X = C, N, O)

9.2.1.1 Allylic Alkylations and Aminations Several types of dendrimers bearing palladium complexes as end groups were shown to catalyze allylic alkylation reactions efficiently and selectively. For example, chiral ferrocenyl diphosphines were grafted to the branch termini of dendrimers involving different cores (benzene-1,3,5-tricarboxylic acid trichloride or cyclo-tri- and tetraphosphazene).11,12 The palladium complexes obtained by reaction with Pd(dba)2 were tested in the allylation of soft carbon nucleophiles with allylic acetate ([Pd] = 1 mol %, dichloromethane, room temperature). Enantioselectivities afforded by the zeroth and first generations were relatively good but the second generation was not soluble enough.13 Along the same lines, J.-P. Majoral, A.-M. Caminade, E. Manoury, and coworkers reported the preparation of a series of phosphorus dendrimers involving phosphino ferrocene derivatives on their surface.14 The corresponding palladium complexes obtained by reaction with [PdCl(allyl)]2 were found to be efficient catalysts in the reaction of rac-1,3-diphenylprop-2-enyl acetate and dimethylmalonate ([Pd] = 2 mol %, dichloromethane, room temperature). The selectivities were not dependent on the generations and no problems of solubility were observed. However, attempted reuse of these catalysts was unsuccessful, due to a significant decrease of efficiency and enantioselectivity. On the contrary, the palladium allyl complexes involving phosphorus dendrons bearing chiral iminophosphines on their surface were found to be efficient catalysts for the same reaction ([Pd] = 2.5 mol %, dichloromethane, room temperature) and could be easily recovered by precipitation and reused at least two times.15 Dendrimers were also used as ligands in palladium-catalyzed allylic aminations. For example, PAMAM and PPI dendrimers decorated with (diphenylphosphino)pyrrolidines (Pyrphos) were complexed to [PdCl2(NCPh)2] and the resulting catalysts tested in the reaction of morpholine and 1,3-diphenyl-1-acetoxypropene in DMSO at 45 °C. All the catalysts displayed better selectivities than the unselective corresponding monomeric catalysts (enantiomeric excess (ee) = 9%) and a strong dependence on the dendrimer skeleton and generation was highlighted. In the case of PPI dendrimers, an increase of the enantioselectivity was observed on going from the monomeric parent complex to generations 0 and 1, but for generations 2 to 4 a plateau was attained (ee ∼40%). On the contrary, PAMAM dendrimers gave better results and a continuous increase of the enantioselectivity from the zeroth to the fourth generations, with the G′ dendrimer reaching an enantiomeric excess of 69%.16 9.2.1.2

Benzoylations

J.-P. Majoral, O. Reiser, and coworkers have reported the preparation of azabis(oxazoline) decorated phosphorus dendrimers from generations 1 to 3 (Figure 9.1). These macromolecules were evaluated in the copper(II)-catalyzed asymmetric benzoylations starting from two different diols. Dendrimers of first and second generations afforded good yields and enantioselectivities in both cases, whereas the third generation had a detrimental influence

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Figure 9.1 Copper-catalyzed asymmetric benzoylations involving phosphorus dendrimers decorated with azabis(oxazolines)

on the enantioselectivity. The copper(II) catalysts could be readily recovered and reused in several cycles.17 Other dendrimeric catalysts involving oxazoline–copper(II) complexes at their core or on their surface were used in reactions allowing the creation of C–C bonds such as aldolizations (Section 9.2.1.3) or Henry reactions (Section 9.2.1.4), and also the creation of C–N bonds such as the α-hydrazination of a β-keto ester (Section 9.2.1.4). 9.2.1.3 Aldolizations Q.-H. Fan, X.-M. Chen, and coworkers designed and prepared a series of three generations of Fréchet-type dendrons bearing chiral bis(oxazoline) ligands at their core. The corresponding copper(II) complexes were found to catalyze the enantioselective Mukaiyama aldolization of benzaldehyde efficiently with a silyl enol ether (water/ethanol/THF (2:9:9) at 0 °C). Good yields were achieved (78–81%), which were similar to that obtained in the presence of the parent monomeric complex (74%). However, in terms of enantioselectivities, the second generation dendrimer proved more efficient than the monovalent complex and than dendrimers of the first and third generations (ee = 64% instead of 60, 57, and 54%, respectively).18 9.2.1.4

Henry Reactions and α-Hydrazination of a β-Keto Ester

L. H. Gade and coworkers attached bis- and trisoxazolines bearing an alkynyl linker to second generation carbosilane dendrimers and prepared the corresponding copper(II) complexes.19 The latter were immobilized in dialysis membrane bags and their catalytic activity was tested in two reactions: the Henry reaction of 2-nitrobenzaldehyde with nitromethane and the α-hydrazination of a β-keto ester. For the Henry reaction, dendrimeric catalysts involving bis(oxazoline) ligands gave higher ee values than the corresponding mononuclear complexes, whereas the tris(oxazoline)-based catalysts proved less efficient in terms

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of activity and selectivity. Concerning the α-hydrazination, bis- and tris(oxazoline)-based catalysts displayed the same activities and selectivities as the corresponding monomeric model complexes and the bisox-based ligands afforded slightly higher ee values (3–4%) than the trisox-based ligands. The bisox-based dendrimeric catalysts provided the basis of a catalytic “tea bag” and could be successfully recycled several times. 9.2.1.5

Michael Reactions

The Michael reaction consists in the addition of a nucleophile on to an electron-poor C=C double bond with the creation of an asymmetric carbon.20 Dendrimeric catalysts have been used to promote this reaction in an enantioselective manner. For example, H. Sasai and coworkers reported the preparation of dendrimers decorated with BINOL units at their periphery and of the heterobimetallic Al–Li and Ga–Na corresponding complexes (10 mol % catalysts, THF, room temperature).20 Al–Li-based complexes catalyzed the Michael reaction of 2-cyclohexanone and dibenzyl malonate in high levels of enantioselectivies (ee >91%) but in low yields (<63%). Addition of sodium tert-butoxide allowed an increase in the reaction yield to 79% (with a slight ee decrease to 89%). The Ga–Na-based catalysts proved to be more efficient and selective than their Al–Li analogs since they allowed a yield of 83% and an ee value of 97% to be reached. 9.2.1.6

Diels–Alder Reactions

Diels–Alder reactions allow the formation of C–C bonds and constitute an easy access to highly functionalized molecules in one step. K. Ding, J. Meng, and coworkers reported an example of dendrimeric catalyst promoting such reaction enantioselectively.21 They indeed synthesized a first generation Fréchet-type dendrimer involving a 2-amino-2hydroxy-1,1′-binaphthyl-derived Schiff base ligand at its core. The latter was further used as a ligand in titanium-catalyzed hetero-Diels–Alder reactions of Danishefsky’s diene (1-methoxy-3-(trimethylsilyloxy)buta-1,3-diene) and various aldehydes (10 mol % [Ti], 20 mol % Schiff base, toluene, room temperature). The dendrimer displayed higher activities and enantioselectivities than the corresponding mononuclear complex (quantitative yields and ee > 90%). The catalyst could, moreover, be quantitatively recovered by precipitation/filtration and reused for up to four cycles with only a slight loss of activity (10%) and of ee value (2%). 9.2.1.7

Hydrolytic Kinetic Resolution

E. N. Jacobsen and coworkers have immobilized salen–cobalt complexes at the surface of PAMAM dendrimers and tested these catalysts in the hydrolytic kinetic resolution of vinylcyclohexane epoxide and 1,2-epoxyhexane (Figure 9.2).22 At 0.5 mol % [Co], much higher reaction rates (relative rates from 1 to 24 depending on the dendrimer; Figure 9.2) and enantioselectivities similar to those of the monomeric parent complex were obtained. Moreover, for low catalyst loading (0.025 mol %), a dramatic enhancement of the activity was observed since the conversion increased from 0 to 50% on going from the parent mononuclear complex to the third generation dendrimer G3 within 20 h. These enhancements of activity were ascribed to cooperative effects between neighboring catalytic sites. Indeed, these reactions are thought to proceed via both substrate and nucleophile activation by two different metal–salen units.

Dendrimers as Homogeneous Enantioselective Catalysts

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Figure 9.2 Cobalt-catalyzed hydrolytic kinetic resolution of vinylcyclohexane epoxide: dendrimer effect due to cooperative effects between neighboring Co catalytic sites

9.2.1.8 Addition of Diethylzinc A wide range of core- or surface-functionalized chiral dendrimeric catalysts were tested in the enantioselective addition of diethylzinc to aldehydes or imines. It is noteworthy that, in most of the cases, the dendrimers were revealed to be less selective than the corresponding monomers. D. Seebach and coworkers published a series of papers that have investigated the catalytic properties of dendrimers involving chiral TADDOL [(R,R)α,α,α′,α′-1,3-dioxolane-4,5-dimethanol] ligands at their core.23 These dendrimers were constructed by adding Fréchet-type dendrons from generation 0 to 4 to the tetraphenol TADDOL core unit. These dendrimers were tested in the addition of diethylzinc to benzaldehyde in the presence of Ti(O-iPr)4 (1.2 equivalents) in toluene at −20 °C. In this reaction, the dendrimeric structure had an influence on the outcome and a decrease of yield was observed when increasing the generation number (100% yield for TADDOL, 99% for G0, 97% for G1, 96% for G2, 94% for G3, 47% for G4). This effect could be attributed to steric problems associated with mass transport and substrate access to the catalytic site. The different behavior between G3 and G4 was attributed to a change in the structure from roughly planar to globular and densely packed. Enantioselectivities were also affected but to a smaller extent (ee = 99% for TADDOL, 98% for G0, 98% for G1, 98% for G2, 96% for G3, 94% for G4). Besides, the same authors reported the preparation of dendrimers still involving a TADDOL core but containing chiral groups within their branches. The aim of this work was to determine whether remote chiral groups could influence or not the selectivity of the reaction occurring at the core of dendrimers. However, the stereochemical outcome of the reaction was the same as in the case of dendrimers with achiral Fréchettype peripheral units.24 Other diols such as BINOL (binaphtol) were used as ligands in

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Figure 9.3 Addition of diethylzinc to benzaldehyde in the presence of monomeric or phenylacetylene-based dendrimeric (S)-BINOL: enhancement of the catalytic activity with dendrimers

Ti-promoted addition of diethylzinc. For example, Q.-H. Fan and coworkers prepared different kinds of chiral BINOL derivatives bearing Fréchet-type dendrimeric wedges located at 3,3′-, 3-, 6,6′- and 6-positions of the binaphthyl backbone.25 The aim of this study was to evaluate the effect of the linking positions and of the generations of dendritic wedges on the catalytic activity. The dendrimeric wedges at the 6,6′-positions of BINOL gave rise to the most selective catalyst (ee = 87% at 20 mol %) for the addition of diethylzinc to benzaldehyde in the presence of Ti(O-iPr)4 (0.8 equivalents) in toluene at 0 °C. In a similar study, L. Pu and coworkers designed rigid phenylacetylene-based dendrimers involving a BINOL ligand at their core (Figure 9.3).26 These chiral dendrimers were able to catalyze the addition of diethylzinc to benzaldehyde with much higher activity than the corresponding monomeric (S)-BINOL (98.6% for G2 instead of 37% conversion within 24 h at room temperature in toluene at 5 mol %). Enantioselectivities were low in both cases and an opposite enantiomeric product was obtained. The Zn–(S)-BINOL complexes formed during the reaction are thought to exist as aggregates through intermolecular Zn–O–Zn bonds, which resulted in a decrease of the Lewis acidic character of the metal center. The bulkiness and rigidity of the dendrimeric (S)-BINOL could prevent the forma-

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203

tion of such aggregates, which could explain the observed dramatic enhancement of the catalytic activity. By combining the dendrimeric (S)-BINOLs (20 mol %) and Ti(O-iPr)4 (1.4 equivalents), high conversions and enantiomeric excesses could be obtained in toluene within 5 h at 0 °C (100% conversion and 89% ee). In that case, no difference was observed between monomeric and dendrimeric (S)-BINOL, probably because the monomeric Ti– (S)-BINOL complex did not generate dimeric or oligomeric structures, unlike the reaction performed in the absence of titanium. The dendrimer could be recovered by precipitation with methanol. Other groups adopted a similar approach and C. Bolm and coworkers reported, for example, the preparation of Fréchet-type dendrimers bearing chiral pyridyl alcohol at their core.27 These dendrimers were used as chiral ligands (5 mol %) in addition of diethylzinc to benzaldehyde. The enantioselectivities reached for these macromolecules (ee = 85–86%) were similar to that obtained with the monomeric chiral pyridyl alcohol (ee = 88%) but the dendrimeric catalysts could be successfully recovered and reused. Periphery-functionalized chiral dendrimeric catalysts were also designed to promote the Ti-catalyzed addition of diethylzinc to aldehydes. Seebach and coworkers, for example, prepared Fréchet-type dendrimers bearing TADDOL units at their branch termini and tested them in the ethylation of benzaldehyde in the presence of 1.2 equivalents of MeTi(OCHMe2)3 in toluene (0.2 equivalent of TADDOL units per Ti).28 When the TADDOL ligand was placed at the core of analogous dendrimers, yields were lower than when using the mononuclear Ti-TADDOLates, but the enantioselectivies were high for all the dendrimeric systems (94% ee for the larger dendrimer and 96–98% ee for other systems). The dendrimeric catalysts were recovered through silica column chromatography but they could not be reused. Besides, E. W. Meijer and coworkers functionalized the surface of PPI dendrimers with chiral amino alcohols and tested the resulting dendrimers in the addition of diethylzinc to benzaldehyde.29 The dendrimers displayed high activities but moderate enantioselectivities, even for smaller generations. Moreover, ee values decreased with increasing generation number, an effect that could be caused by multiple interactions between adjacent chiral end groups on the surface of the dendrimer. Such interactions could lead to a dense packing of chiral units and result in the existence of different conformations. PAMAM dendrimers decorated with chiral amino alcohol groups were also reported by K. Soai and coworkers.30 These dendrimers (50 mol %) allowed the addition of diethylzinc to N-diphenylphosphinylimines in toluene at room temperature. As previously, lower enantioselectivities were obtained in the case of dendrimers (ee = 43% for G0 and 39% for G1 in the case of N-diphenylphosphinylbenzaldimine) than in the case of the parent monomeric amino alcohol (ee = 92%). The activities were also found to decrease on going to larger ligands (46% for the monomer, 18% for G0, 8% for G1). The same group designed (1R,2S)-ephedrine-capped carbosilane dendrimers, which were also used as chiral auxiliaries in asymmetric addition of diethylzinc to N-diphenylphosphinylimines.31 The dendrimeric catalyst could be recovered using thinlayer chromatography and reused with slight loss in enantioselectivity. Carbosilane dendrimers decorated with analogous (1R,2S)-ephedrine were tested in the addition of diethylzinc on aldehydes and the recycling could also successfully be achieved using thin-layer chromatography.32

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Dendrimers

9.2.2 Addition Reactions on a C=X Double Bond (X = C, O) 9.2.2.1

Hydrogenations

Hydrogenation reactions give rise to alkanes from alkenes (X = C) or alcohols from carbonylated compounds (X = O). If performed in an enantioselective manner, chiral alkanes or alcohols can be obtained, all these products being key intermediates in life science and polymer industries. Numerous dendrimeric organometallic catalysts designed for enantioselective catalysis have been used in hydrogenation reactions. They mainly involve rhodium, ruthenium, and iridium complexes. Hydrogenations with H2. The first example of tentative enantioselective catalysis concerned dendrimers bearing chelating phosphines at their core, which were surrounded by space-filling branches involving optically active groups.33 H. Brunner suggested that in a complex of such dendrimeric ligand a catalytic reaction could take place in the same way as in the pocket of an enzyme and thus called these expanded chelating phosphines “dendrizymes”. The corresponding rhodium complexes were tested in the hydrogenation of (α)-N-acetamidocinnamic acid under H2 pressure (20 bars). Hydrogenation occurred easily but low enantioselectivities were obtained, perhaps owing to the high flexibility of the substituents. It was moreover shown that the reaction rate depended on the steric hindrance close to the catalytic centers.34 The approach consisted in placing the chiral substituents within the dendrimeric structure and in this case proved to be deceptive in terms of asymmetric induction. However, J. R. Parquette and coworkers demonstrated the first example of a dendrimeric catalyst that successfully directed the selectivity of the catalytic process by dynamically transferring the conformational chirality of the dendrimer structure to the catalytic active site.35 For this purpose, they designed several first generation dendrons at the 3 and 3′ positions of a 2,2′-bis(diphenylphosphinoxy)biphenyl scaffold (Figure 9.4). These dendrons, involving either (S)-(1-methoxypropan-2-yl)-2-acylaminobenzoate or oxazoline termini, exist in highly mobile helical conformations and interconvert among at least six diastereomeric conformations. Rhodium was then coordinated to the diphosphine present at the core of oxazoline-terminated dendrons and the resulting complex tested in the hydrogenation of (Z)-methyl 2-acetamido-3-phenylacrylate. An ee of 91% could be obtained in toluene at −20 °C (0.3 mol % [Rh], 50 psi H2). This shows that remote chirality within a dendrimeric catalyst can be efficiently relayed over 12 bonds to control the enantioselectivity of a reaction. This was explained by a chiral relay mechanism that propagates the local chirality present at the branch termini of the dendron to the axial chirality of the biphenyl core via the helical secondary structure of the dendron. Most of the examples of chiral dendrimeric hydrogenation catalysts involve dendrons possessing large dendritic wedges and chiral mono- or bisphosphines at their core. For example, Q.-H. Fan, A. S. C. Chan, and coworkers reported a BINAP (2,2′-bis(diphenylphosphino)-1,1-binaphthylene) ligand linked to the core of three generations of poly(aryl ether) Fréchet-type dendrons.36 The activity conferred by these ligands to ruthenium was tested in the hydrogenation of 2-[p-(2-methylpropyl)phenyl]acrylic acid in methanol–toluene mixtures (0.8 mol % [Ru], 80 atm. H2), leading to ibuprofen. All dendrimeric catalysts showed higher enantioselectivities than the parent monomeric BINAP complex. The rate of the reaction increased when using higher generation catalysts (from 6.3 h−1 to 21.4 h−1 for G3). The third generation catalyst could be recovered and

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Figure 9.4 Rhodium-catalyzed hydrogenation in the presence of oxazoline-capped dendrons: remote chirality within the dendrimeric structure controls the enantioselectivity

reused three times by using the precipitation strategy with no loss of activity and enantioselectivity. Four generations of analogous BINAP-cored dendrimers were also used as ligands for iridium-catalyzed hydrogenation of quinolines in THF at 15–20 °C (0.01 mol % [Ir], 45 atm. H2; Figure 9.5).37 The enantioselectivity was similar for all dendrimeric catalysts (ee = 87–89% for G1 to G4) and was significantly improved compared to the monovalent Ir–BINAP complex (ee = 71% only). The catalytic activity was found to increase gradually with increasing generation number (conversions of 43, 50, 75, 79, and > 95 for BINAP, G1, G2, G3, and G4, respectively). The recyclability of the third generation was successful at least five times with a similar enantioselectivity but a slightly lower activity (80% instead of 95% for the fifth run). The same authors also used BINAP-functionalized dendrons as ligands for ruthenium in hydrogenation of aromatic ketones (0.2 mol % [Ru], 40 atm. H2).38 The dendron generation was not found to influence the enantioselectivity (ee = 75%) and the third-generation complex could be recovered twice with no loss of efficacy. Fréchet-type dendrimers involving chiral 3,4-bis(diphenylphosphino)pyrrolidines instead of BINAP at their focal point were also reported by Fan, Chan, and coworkers.39 The asymmetric hydrogenation of a series of β-ketoesters was carried out with the corresponding rhodium complexes in a methanol–toluene (2:1, v/v) mixture (0.125–1 mol % [Rh], 60 atm. H2). The enantioselectivity slightly decreased on going from the nondendritic ligand to generation 1 and to

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Figure 9.5 Iridium-catalyzed hydrogenation of quinaldine in the presence of dendrimeric BINAP ligands

further generations. In an extension of this work, the same group reported the synthesis of dendrimeric chiral monodentate phosphoramidate ligands at the core of poly(aryl ether) Fréchet-type dendrimers.40 A series of (α)-dehydroamino acid esters was hydrogenated asymmetrically by the corresponding rhodium complexes in CH2Cl2 at room temperature (0.1–1 mol % [Rh], 10–20 atm. H2). Higher or comparable enantioselectivities were achieved as compared to that obtained with the monomeric parent rhodium complex. According to the authors, the steric shielding by the dendrimer could stabilize the rhodium complex against decomposition. The lower catalytic activity of the third generation dendrimeric catalyst was attributed to the encapsulation of the catalytically active centre by the dendrimeric wedge. Peripherically functionalized dendrimeric catalysts have also been used in hydrogenation reactions. For example, the rhodium complexes of dendrimers bearing chiral ferrocenyl ligands at their periphery were shown to catalyze efficiently the hydrogenation of dimethylitaconate in methanol (1 mol % [Rh], 1 bar H2), constituting the first example of phosphino dendritic end groups for asymmetric catalysis.11 The obtained enantioselectivities were slightly lower compared to the parent Josiphos monomeric complex. Preliminary nanofiltration experiments showed complete retention of the rhodium-complexed dendrimers. Gade and coworkers also reported the preparation of C2-chiral pyrphos (3,4-bis(diphenylphosphino)pyrrolidines) ligands surrounded by PPI dendrimers.41 The corresponding rhododendrimers could be obtained up to the fourth generation and their catalytic activity was tested in asymmetric hydrogenation of dimethylitaconate. A loss in activity and selectivity was observed on going to the dendrimeric macromolecules containing a high surface density of cationic metal complexes. This effect was ascribed to the high flexibility of the dendrimer core, which favored the bending back of the attached rhodium complexes to the dendrimeric interior, thus reducing the accessibility of the catalytic centers and rendering their immediate environment less uniform than originally envisaged. More recently, O. Rossell and coworkers reported the preparation of carbosilane dendrimers decorated with P-stereogenic diphosphines and showed that their corre-

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sponding rhodium complexes catalyzed the asymmetric hydrogenation (0.2 mol%, 10 bars H2) of dimethyl itaconate, but with low enantiomeric excesses (7–8%).42 Transfer Hydrogenations. Hydrogen transfer (H-transfer) catalysis, which consists in using H-donors (alcohols, formiates, or silanes) instead of hazardous molecular H2, is an attractive methodology. Some dendrimeric catalysts have been used in this type of reactions. For example, J.-G. Deng and coworkers anchored 1,2-diphenylethylenediamine (DPEN) and (S,S)-N-arenesulfonyl-1,2-diphenylethylenediamine (TsDPEN) on several dendrimeric structures. The first family of ligands prepared bore TsDPEN on the surface of dendrimers and was tested in ruthenium-catalyzed reduction of acetophenone in the presence of formic acid and triethylamine (1 mol % [Ru]). This catalyst was found to be as selective as the parent monomeric complex but its recycling was difficult.43 The authors also designed a hybrid dendrimer combining two different dendrons, the first one bearing the catalyst at the branch termini and the second one consisting of a nonfunctionalized Fréchet-type dendron.44 The enantioselectivity of this catalyst was similar to the surfacefunctionalized catalyst but it could be recycled twice. The best recyclability was obtained when the TsDPEN moiety was placed at the core of a single Fréchet-type dendron (good activities and enantioselectivities up to five cycles).45 G. Rothenberg and coworkers used analogous Fréchet-type dendrons bearing TsDPEN at their core and showed that the corresponding ruthenium complexes were able to catalyze efficiently the asymmetric H-transfer of acetophenone with 2-propanol in the presence of iPrOK as the base at 25 °C (Figure 9.6).46 A conversion of 65% could be obtained within 48 h and a very good ee of 95% could be reached. The reaction could also be performed in a two-layered ceramic membrane cylinder that allowed the diffusion of reactants and products in and out, but kept the dendrimeric catalyst inside. Therefore, this “cat-in-a-cup” approach enabled recycling experiments and for the first two different runs identical conversions, selectivities, and reaction rates could be obtained. It is noteworthy that the reduction of ketones can also be achieved via hydrosilylation (the hydrogen transferred coming from a silane in this case) and further hydrolysis. Gade and coworkers reported the preparation of two series of PPI and PAMAM dendrimers

Figure 9.6 Ruthenium/TsDPEN-catalyzed hydrogenation of acetophenone in a twolayered ceramic membrane cylinder allowing the diffusion of reactants and products in and out but keeping the dendrimeric catalyst inside

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bearing glutaroyl–AMINAP ligands at their branch termini (glutaroyl–AMINAP ligands being BINAP fixed to the dendrimer via a CH2–NH–C(O)–(CH2)3–C(O)NH linker).47 The resulting ligands could contain up to 64 bisphosphines on their surface. They could act as ligands in copper-catalyzed hydrosilylation of ketones in THF–toluene (8:3, v/v) mixture at −78 °C. The enantioselectivities were found to be higher than those obtained with the unfunctionalized BINAP. The same group also prepared PPI dendrimers decorated with carbo–BINAP ligands (carbo–BINAP ligands being BINAP ligands fixed to the dendrimer via a simple C(O)–NH linker).48 In that case, the enantioselectivities were found to greatly increase as the generation number increased (from ee = 34% for G1 to ee = 90% for G5). Note that the highest generation could be recycled and reused several times with no loss of activity and selectivity. 9.2.2.2

Reductions with Boranes

Bolm and coworkers investigated the asymmetric reduction of ketones with BH3.SMe2 and several Fréchet-type dendrons bearing chiral amino alcohols (S)-p-OC6H4CH2C(NH2) C(OH)Ph2 at their core.49 The dendrimeric catalysts (10 mol %) displayed good activities (75–82% yields) and enantioselectivities (81–96%) in the reduction of several prochiral ketones in THF at room temperature. They allowed for better ee values to be reached than the parent monomeric amino alcohol (91% instead of 87% in the case of acetophenone). Along the same lines, G. Zhao and coworkers reported the synthesis of analogous Fréchettype dendrons bearing prolinol at their core.50 The dendrimeric catalysts also promoted the reduction of prochiral ketones with BH3.SMe2 in THF (1–10 mol %) at 20 °C or reflux with high yields (93–99%) and selectivities (ee = 90–97%). Dendrimer-supported catalysts could be recovered at least five times with little or no loss of activity and selectivity. In both previous examples, the ligand was placed at the core of dendrons. However, I. Rico-Lattes and coworkers prepared four generations of peripherally D-gluconolactone functionalized PAMAM dendrimers and reported their use as ligands for the sodium borohydride reduction of prochiral ketones either homogeneously in water or heterogeneously in THF.51 In the latter case, the third generation dendrimer enabled very good enantioselectivities to be achieved and could be recovered by nanofiltration and reused up to ten times with no loss of activity and selectivity. 9.2.2.3

Hydrovinylation of Styrene

The hydrovinylation of styrene, the codimerization of ethene and styrene, is an attractive reaction insofar as it provides chiral building blocks from cheap carbon feedstock. The problems of this reaction are the stability of the catalyst as well as its selectivity, with oligomerization and isomerization of the product occurring. Keeping conversion low by performing this reaction continuously allows the selectivity to improve.52,53 This could be achieved by using hemilabile P,O-ligands grafted on to the surface of carbosilane dendrimers. Retention of these dendrimers bearing four to twelve palladium complexes in the membrane reactor was at least 85% and the selectivity to the desired chiral 3-phenylbut1-ene was very high in the continuous hydrovinylation of styrene. However, the rate of the reaction decreased upon time due to decomposition of the dendrimeric catalyst. The asymmetric hydrovinylation of styrene could also be carried out using allylpalladium complexes involving chiral phosphine-decorated carbosilane dendrimers bearing Si(CH2)

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PR1R2 terminal groups.54 The best result in terms of ee (79%) was obtained for the thirdgeneration dendrimer with phenyl as the R1 group and biphenyl as the R2 group.

9.3

Organocatalysis with Dendrimers

Organic catalysis is a blossoming area and several examples of dendrimers bearing chiral organocatalysts at their core or on their surface have been reported. They have been used in different reactions such as aldolizations, Baylis–Hillman reactions, or transaminations, to name but a few. 9.3.1 Aldolizations G. Kokotos and coworkers prepared five generations of PPI-dendrimers capped with prolines, well-known organocatalysts widely used in asymmetric catalysis.55 These dendrimers were tested in the aldolization of acetone and 4-nitrobenzaldehyde (20 mol % in proline moieties) in DMF at room temperature, conditions in which the free proline afforded the aldol product in 63% yield and 69% ee after 16–18 h. The second generation dendrimers involving eight terminal proline groups led to a yield of 61% within 2 h with an enantiomeric excess of 65%, comparable to those obtained with the monomeric organocatalyst. However, the first, third, fourth, and fifth generation catalysts afforded good yields but lower ee values. This negative “dendrimer effect” was ascribed to steric hindrance between the proline end groups. In the case of higher generations surface-crowded dendrimers, the approach of the enamine intermediate to the Re face of the aldehyde carbonyl group seemed not to be as favoured as in the case of less hindered proline derivatives. No explanation for the surprising behavior of the first generation dendrimer was, however, provided. In addition, loading of the catalyst was found to influence both the chemical yield and the enantioselectivity. Other proline derivatives were used in asymmetric aldolizations. For example, J.-L. Reymond and coworkers prepared libraries of peptide dendrimers with aldolase-active residues such as lysine or proline at their core or on their surface, respectively.56 These dendrimers constituted synthetic models for aldolase enzymes. The dendrimers (1 mol %) were tested in the model aldol condensation of acetone and 4-nitrobenzaldehyde in a DMSO/acetone (4:1, v/v) mixture at room temperature. Organocatalysts bearing lysine at their core were found to be inactive whereas those decorated with prolines displayed high activities and moderate selectivities (up to 61%). Higher activities and selectivities could be reached when performing the aldolization in aqueous media, such conditions better mimicking those of the enzyme-catalyzed reaction. 9.3.2 Aza–Morita–Baylis–Hillmann Reactions Aza–Morita–Baylis–Hillmann reactions allow for the formation of C–C bonds and, if performed in an enantioselective manner, give access to enantiopure β-amino carbonyl compounds bearing an α-alkylidene group. M. Shi and coworkers reported the preparation of a series of polyether dendrimers bearing a chiral phosphino alcohol at their core. The

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latter were used as Lewis bases to catalyze the asymmetric Morita–Baylis–Hillmann reaction of N-sulfonated imines with methyl vinyl ketone, ethyl vinyl ketone, and acrolein in THF at −20 or −30 °C. Very good enantioselectivities could be reached (76–97%) and the dendrimeric catalysts could be recovered and reused.57 9.3.3 Transaminations In Chapter 8, it was reported that R. Breslow and coworkers applied PAMAM dendrimers (generations 1 to 6) involving a pyridoxamine core in the transamination of pyruvic acid and phenylpyruvic acid in aqueous buffer.58 It was found that the substrate binding ability and the reaction rates were improved with increasing generation number. In an extension of this work, they designed PAMAM dendrimers still involving a pyridoxamine core but displaying moreover chiral amino groups at their surface.59 Transaminations to form phenylalanine and alanine from their corresponding keto acids could then occur enantioselectively thanks to an induction by the remote chiral caps. Indeed, computer models indicated the existence of a folding of the dendrimer chains back into the core region.

9.4

Conclusion

In this chapter, numerous examples of core- or surface-functionalized dendrimer-catalyzed asymmetric transformations have been reported. In some cases, better enantioselectivities could be obtained compared to the parent monomeric complex. Such positive “dendrimer effects” could be observed in allylic aminations, Henry reaction, hydrolytic kinetic resolution, additions of diethylzinc, and hydrogenations or hydrovinylation of styrene. Explanations for these effects were sometimes proposed and the latter were, for example, ascribed to cooperative catalysis between neighboring sites or, on the contrary, to site isolation of the catalyst leading to an improvement in its stability. Decreases of the enantioselectivity in comparison to monomeric catalysts were also observed, for example, in ethylations of aldehydes or hydrogenation reactions. In some cases, the packing of chiral end units on the surface of dendrimers was thought to be at the origin of the loss of enantioselectivity. It is noteworthy that dendrimeric catalysts could often be recovered and reused with an efficiency depending on the dendrimers involved. Interestingly, in some examples, the chirality was transferred from the dendrimeric backbone to the catalyst placed at the core.59 This approach recently gave very good inductions in hydrogenations35 and will probably give rise to further studies. Note that most of the dendrimers used in enantioselective transformations involve organometallic catalysts. Only a few examples of dendrimeric organocatalysts have been reported and progress has still to be made in this field.

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10 Catalysis with Dendrimers in Particular Media Régis Laurent* and Anne-Marie Caminade

10.1

Introduction

Certainly, the use of environmentally benign solvents constitutes one of the leading research areas connected with green chemistry;1 it has been developed in particular with the need for molecular catalytic systems that combine the advantages of high activity and selectivity of homogeneous catalysts with the facile recovery and recycling characteristics of the heterogeneous ones. Therefore different nonconventional reaction media have been introduced, including water, aqueous biphasic systems, fluorous biphasic systems, ionic liquids, and supercritical fluids (mainly CO2); such systems provide the opportunity to recycle the catalyst through the relatively facile technique of liquid–liquid phase separation. Dendrimers have taken a considerable role in the development of recyclable homogeneous catalysts easily separated from the reaction mixture, especially in the field of organometallic catalysis and recently in organocatalysis as reported in the previous chapters. To improve the ease of separation and as the solubility of dendrimers can be easily tuned with the correct choice of their peripheral groups, dendrimeric catalysts have been involved in these nonconventional reaction conditions. Relatively few works have been carried out in this field up to now, but it should become more important with increasing environmental concerns. Additionally, the use of water as the reaction media for dendrimers is closely associated with the biological applications of these macromolecules; among them, catalytic enzyme-like properties were studied. We will try to give an overview of these fields.

* Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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10.2 Two-Phase (Liquid–Liquid) Media The use of biphasic media to recycle homogeneous catalysts has been extensively studied in the last three decades:2–4 the case of aqueous mixtures (water alone or in combination with an organic solvent) will be treated in Part 4, so we will focus here on other biphasic systems and primarily on biphasic fluorous/organic systems.3 Dendrimeric catalysts have been designed to be used in such conditions: grafting of perfluorinated groups at the dendrimer periphery enhances the affinity of dendrimers for fluorous solvents.5 A pioneering work was carried out by R. M. Crooks and coworkers with Pd nanoparticles encapsulated within the interior of the amine-terminated fourth generation PAMAM dendrimer;6 they were noncovalently modified with perfluoropolyether monocarboxylic acids and found to be soluble in FC-75 (perfluoro-2-butyltetrahydrofuran). Alkene hydrogenation reactions were performed in a biphasic THF/FC-75 mixture under vigorous stirring, showing good activity for the Pd dendrimer-encapsulated nanoparticle (DEN) catalyst; the methodology is very simple, the catalysts being easily separated from the product and recycled (after separation of the THF phase containing the products, the FC-75 solution could be recycled 12 times without appreciable loss of catalytic activity). Crooks and coworkers have also prepared poly(propylene imine) (PPI) dendrimers covalently modified with perfluoropolyether chains;7 in comparison with fluorous-soluble Pd DENs previously prepared by ionic assembly, covalent attachment of the chains to the dendrimer scaffold further enhanced the thermal stability of the catalytic species. The Heck coupling reaction was investigated in a fluorocarbon/hydrocarbon solvent-based system working at 90 °C instead of 120 °C generally used for colloidal Pd(0) particles (Figure 10.1). Fluorous-phase soluble Pd DENs were active in the Heck coupling reaction involving iodoarene derivatives and nbutylacrylate. Fourth and fifth generation PPI dendrimers were considered, with the higher generation dendrimer giving the more active catalytic system, with up to 70% yield (easier access to the catalytic particles due to less confining space was proposed to explain the difference). Regioselective catalyses were obtained with 100% selectivity in the trans

Figure 10.1

Heck cross-coupling reaction catalyzed by fluorous phase soluble Pd DEN6,7

Catalysis with Dendrimers in Particular Media

Figure 10.2 amination8

217

Dendrimeric Pd(0) complexes used in the thermomorphic mixture for allylic

isomer in contrast to the 74–98% reported with fluorous-phase soluble Pd(0) complex: a sterically confined environment within the dendrimer was proposed to explain this high selectivity. At 90 °C the reaction proceeds in a homogeneous fluorocarbon/hydrocarbon solvent phase; cooling down the temperature at the end of the reaction induces a phase separation. As the fluorous phase retains the dark colored catalyst and the organic phase remains colorless (there is no detectable precipitation, flocculation, or formation of Pd black on the glassware), the recovery of the Pd(0) catalyst was easy, but a decrease in the catalytic activity was obtained. Biphasic systems using the thermomorphic mixture4 of two organic solvents (DMF/ heptane, for example, characterized by two immiscible phases at room temperature and by only one phase at elevated temperature) have been used with dendrimeric catalysts by K. Kaneda and coworkers. They have introduced diphosphine ligands on the surface of PPI dendrimers (first and third to fifth generation) and prepared corresponding Pd(0) dendrimeric complexes.8 Allylic amination of cinnamyl acetate with dibutylamine was studied using the DMF/heptane thermomorphic mixture (Figure 10.2); the two phases became homogeneous during the reaction and could be easily separated by cooling. The DMF phase containing the dendrimeric catalyst could be reused and high activity was still obtained after four uses (99%). Allylic amination in a DMF/heptane mixture was also studied with dendrimeric catalysts prepared by encapsulating palladium complexes within dendrimers: phosphine ligands were introduced in the interior space of surface-modified PPI dendrimers through ionic bonds between the internal tertiary amino groups of the dendrimer and the carboxyl group of 4-diphenylphosphinobenzoic acid.9 Palladium complexes were subsequently introduced inside these nanoreactors. The terminal primary amino groups were modified with 3,4,5-triethoxybenzoyl chloride affording solubility in polar solvents like DMF and insolubility in aliphatic hydrocarbons. N. F. Yang and coworkers have considered the use of a DMF/cyclohexane mixture for organocatalysis and more precisely the Baylis–Hillman reaction catalyzed by dendrimeric 4-(N,N-dimethylamino)pyridine; working at 60 °C in an homogeneous mixture, high yields were obtained with aryl aldehydes having electronwithdrawing substituents.10 Upon cooling down the temperature to 25 °C, a phase separation occurred and, taking advantage of the presence of alkyl chains on its surface, the dendrimeric catalyst could be recovered in the cyclohexane phase and reused up to five

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Dendrimers

times without loss of activity (nevertheless a reactivation process to regenerate a free nitrogen atom on the pyridyl ring is necessary between each consecutive run). In their approach, R. Haag and coworkers have considered a methanol/heptane mixture to perform a hydrogenation reaction catalyzed by Pt nanoparticles stabilized by dendrimeric core–mutishell architectures (hyperbranched polyglycerol functionalized with alkyl and polyethylene glycol chains).11 Stirring was applied during the reaction; as soon as it was stopped, phase separation occurred and the methanol phase containing the dendrimeric catalyst was recovered and reused. Recycling was demonstrated up to 14 times with a very low metal leaching during the process (full conversion can be obtained for each run but with a decrease in the TOF). A. S. C. Chan, Q. H. Fan, and coworkers have used dendrimeric Ru–BINAP catalysts for asymmetric hydrogenation in an ethanol/hexane mixture, a miscible solvent pair in the conditions used, but upon addition of a small amount of water, phase separation was observed; this strategy constitutes an easy way to recover the catalyst (Figure 10.3).12 The dendrimeric BINAP ligands used were synthesized by grafting polyether dendrons end-capped with alkyl long chains on 5,5′-diamino BINAP. Dendrimeric Ru–BINAP catalysts were prepared in situ; complete conversions were obtained with a high enantiomeric excess (similar to those obtained with the Ru–BINAP catalyst). By addition of water (2.5%) there was a phase separation and the hexane one that contained the dendrimeric

Figure 10.3

Hydrogenation catalyzed by second generation dendrimeric Ru–BINAP12

Catalysis with Dendrimers in Particular Media

219

catalyst was recovered and reused; after four runs, similar conversions were obtained with a slight decrease in enantioselectivity. A similar strategy was adopted with the dendrimeric pyrphos ligand for Rh(I)-catalyzed enantioselective hydrogenation reactions (methanol/ cyclohexane mixture)13 and with a dendrimer-bound osmium complex for osmiun-catalyzed olefin dihydroxylation reactions (t-BuOH/MeCN/H2O/hexane mixture); in this case, the dendrimeric catalysts have been used up to 10 times without noticeable deactivation and with reduced osmium leaching (less than 5 ppm).14 Recently, PPI dendrimers (first to fifth generations) were functionalized with glyceryl moieties introduced at the surface level; these dendrimers were found to be soluble in glycerol, which can be considered as an environmentally friendly solvent having close similarities with water.15 These dendrimers were tested as homogeneous organocatalysts in the ring opening of 1,2-epoxydodecane with dodecanoic acid. Even if the glyceryl groups have a negative influence on the activity of the PPI dendrimers, recycling processes were easily carried out by liquid–liquid phase extraction of the product with ethyl acetate, the dendrimers being retained in the glycerol phase; the latter was then reloaded with reactants. The immobilization of the catalyst in the glycerol phase was the more efficient, with the higher generation glyceryl end-capped PPI dendrimers leading to a better recycling process; the parent PPI gave bad recycling efficiency.

10.3

Catalysis in Ionic Liquids

The use of ionic liquid (IL) as a novel reaction media offers a convenient solution to the catalyst recycling problem, especially for organometallic catalysis; their negligible vapour pressure represents an attractive feature related to the green catalytic process.16 The first report concerning the use of dendrimeric catalysts in IL media dealt with the dendrimer encapsulated palladium nanoparticles;17 the dendrimers used were PAMAM dendrimers, which were dissolved in polar IL, 1-(2-hydroxyethyl)-3-methylimidazolium tetrafluoroborate ([C2OHMIM][BF4]). Using carboxylate-terminated PAMAM dendrimers (G5.5– COO−), Pd DENs were prepared and the hydrogenation of styrene studied: the efficiency of the catalyst was maintained for up to 12 recycles. The use of IL was also reported with dendrimers decorated with cationic Rh(I) complexes.18 PPI and PAMAM dendrimers were functionalized with pyrphos ligand; then [Rh(NBD)2] BF4 was used to produce cationic dendrimeric pyrphos rhodium (norbornadiene) [pyrphos–Rh(NBD)] complexes. They have been used in two phase-reaction mediums consisting of the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate {[BMIM] [BF4]} and isopropyl alcohol; enantioselective hydrogenation of Z-methyl-αacetamidocinnamate was studied (Figure 10.4). In these conditions, the substrate and the product were soluble in isopropyl alcohol, and the cationic dendrimeric pyrphos–rhodium (norbornadiene) complexes were soluble in the IL phase. To take advantages of the thermotropic behavior of the solvent mixture, the catalytic tests were carried out at 55 °C. A negative “dendrimeric effect” with regard to the activity, the stereoinduction, as well as the reusability was observed. Hyperbranched polyethyleneimine (PEI) was used as support in the same conditions; similar results were obtained (decrease in activity and enantioselectivity with increasing size of the macromolecular species). However, this decrease was less pronounced.

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Dendrimers

Figure 10.4

10.4

Hydrogenation with dendrimeric Rh complexes in ionic liquid18

Catalysis in Supercritical Media

Due to its physical properties, carbon dioxide is the most frequently used supercritical fluid (a particular advantage is its low critical point of Tc of 31.1 °C and Pc of 73.8 bars). Supercritical carbon dioxide (scCO2) is an attractive solvent as an alternative reaction medium to organic solvents: CO2 is both inexpensive and environmentally benign (noninflammable and with a low toxicity).19 Nevertheless, to be used in catalysis in such conditions, solubility of the catalytic species in the reaction media is needed. Few examples reported the use of dendrimer-modified catalysts in scCO2. Perfluoro-functionalized poly(propyleneimine) dendrimers have been used as a phase transfer catalyst for the halogen exchange reaction of benzyl chloride into benzyl bromide and for the esterification of oxalic acid with pentafluorobenzylbromide.20 The perfluoroalkyl tails make the dendrimers soluble in scCO2. The model SN2 halogen exchange reaction of benzyl chloride into benzyl bromide was performed in a two-phase system consisting of an aqueous phase with a large amount of KBr and a CO2 phase with the functionalized poly(propyleneimine) dendrimer and benzyl chloride (benzyl chloride is not soluble in water and bromide ion is not soluble in carbon dioxide). Dendrimers were used to extract the bromide ions from the aqueous phase to the carbon dioxide phase and consequently the bromide ions were exchanged with the chloride. A high reaction rate was obtained for the halogen exchange and it was found that the rate of reaction depends on the generation number of the dendrimer, the worst results being obtained with the high generation dendrimer (it is more difficult for the substrate to migrate from the bulk carbon dioxide phase to the interior of the dendrimer or for the product to leave the interior of the dendrimer). The same trends were obtained for the esterification reaction.

Catalysis with Dendrimers in Particular Media

Figure 10.5

221

Heck cross-coupling reaction of iodobenzene in scCO222

If perfluoro chains permit the solubility of a compound in scCO2 to increase, some other alternatives exist, such as the use of polysiloxane or trimethylsilyl groups.21 E. de Jesus and coworkers have synthesized first generation carbosilane dendrons end-capped with dimethylethylsilyl groups, and used them to prepare dendrimeric phosphine core ligands with, respectively, 1, 2, and 3 dendrimeric wedges:22 the corresponding Pd(II) complexes were obtained by reaction with [PdCl2(COD)]. The solubility of the complexes in scCO2 increases with the number of dendrimeric wedges on the phosphine ligand; the corresponding nondendrimeric complex [(Ph3P)2PdCl2] was insoluble in these conditions. The Heck cross-coupling reaction of iodobenzene in scCO2 was studied: the complex [(Ph3P)2PdCl2] was inefficient in these conditions whereas the improved solubility of the dendrimeric Pd(II) complexes allowed a conversion close to 40% (Figure 10.5). No recycling process was reported. O. Rossell and coworkers have also used metallodendrimers with carbosilane scaffold as the catalyst in scCO2.23 Dendrimeric ligands were prepared through the grafting of a P-stereogenic phosphine on the surface of first generation carbosilane dendrimers and the corresponding Pd complexes were tested in the enantioselective hydrovinylation of styrene carried out in the presence of Na+[BArF4]−. Unfortunately conversions were lower than those obtained for a catalytic reaction carried out in dichloromethane as the solvent; nevertheless, selectivity and enantiomeric excess were comparable. PPI dendrimer-encapsulated iron nanoparticles were used in scCO2 to produce efficiently carbon nanotubes from carbon tetrachloride decomposition; if high pressure exerted by the CO2 was beneficial for the CCl4 decomposition, the use of dendrimer-encapsulated iron nanoparticles catalysts has permitted control of the nanotube structure.24

10.5

Catalysis in Aqueous Media

The use of dendrimers as catalysts in aqueous media was reported for the first time by W. T. Ford and coworkers in 1994.25 Their approach was based on the reported catalytic properties of cationic polyelectrolytes, especially those able to form polymeric micelles;

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Dendrimers

Figure 10.6

Polycationic dendrimers having catalytic activity in water26,28

they were considered as enzyme models.26 Polycationic dendrimers (of arborol type with peripheral ammonium groups, described as “unimolecular micelles”27) have been involved in biologic model reactions, ester decarboxylation, and phosphate hydrolysis reactions, and rate accelerations were obtained. Later on, they have proposed polycationic PPI dendrimers, which have afforded very high reaction rates for these types of reactions (Figure 10.6).28,29 With the aim to consider the dendrimer itself as a water-soluble catalyst, J. L. Reymond and coworkers have prepared catalytic peptide dendrimers that have shown enzyme-like behavior.30 The synthetic strategy has led to a large library of peptide dendrimers depending on the position in the dendrimeric framework (core, branches, surface) of the amino acid used and on the chemical nature of the diamino acid connector chosen.31–35 Ester hydrolysis activity was especially investigated, leading, when histidine residues were located at the surface, to a rate acceleration up to kcat/kuncat = 2400.31 When dendrimers were synthesized (first to fourth generations) with histidine-serine residues along the dendrimeric framework, an impressive positive dendrimeric effect was obtained for the ester hydrolysis activity (kcat/kuncat = 39 000 for the pyrene trisulfonate propyl ester hydrolysis with the fourth generation) (Figure 10.7).36 A peptide dendrimer with a single catalytic site at the core level was also prepared: the catalytic activity in ester hydrolysis was dependent on the compactness of the dendrimeric species around the catalytic site, which is related to the chemical nature of the surface.37 Other studies where dendrimers were considered as enzymes models and therefore their catalytic activity in aqueous media was investigated have been reported: F. Diederich and

Catalysis with Dendrimers in Particular Media

Figure 10.7

223

Ester hydrolysis with peptide dendrimers36

coworkers have introduced dendrimeric branches on cyclophane derivatives as mimics for pyruvate decarboxylate, but a decrease in the catalytic activity was observed.38 R. Breslow and coworkers have studied a transamination reaction catalyzed by dendrimeric pyridoxamine prepared by PAMAM dendrimer growth (up to generation 6) from protected pirydoxamine.39 The surface was functionalized with the dimethylamino group and the core deprotected to obtain the catalytic species, where 100-, 300-, and 1000-fold rate enhancements were obtained respectively with the first, third, and sixth generations compared to pyridoxamine alone. In a subsequent work, they have grafted a chiral amino group to study enantioselective transamination.40 Metallodendrimers have been also studied as enzyme-like catalysts. P. Scrimin and coworkers have peripherally functionalized PPI dendrimers (third generation) with triazacyclononane moieties and tested its nuclease-like activity in the presence of Zn(II) ions; the cleavage of 2-hydroxypropyl-p-nitrophenyl phosphate (HPNPP), a standard model of an RNA-phosphodiester, was efficiently catalyzed by the dendrimeric system and it was shown that the high catalytic activity was due to a cooperative effect between two Zn(II) metal ions on the substrate.41 Peptide dendrons and dendrimers of increasing generation functionalized at the periphery with triazacyclononane have been prepared by the same group and their Zn(II) corresponding complexes exhibited high activity in the cleavage of HPNPP: a dendrimeric effect was observed (kcat/kuncat going from 700 to 80 000 when

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Dendrimers

the dendrimer generation increases).42 The nuclease-like activity was also observed with triazacyclononane end-capped dendrons species bound to a polymer resin support;43 when compared to the activity of the corresponding soluble dendrons in solution, the resin-bound dendrons gave better results correlated to a stronger substrate binding in this case. Ford and coworkers have also studied the behavior of metallodendrimers as enzyme models,44 especially with PPI dendrimer complexes of Cu(II), Zn(II), and Co(III), while L. D. Margerum and coworkers have considered PAMAM dendrimer complexes of Co(II).45 Using a supramolecular approach, a peroxidase mimetic dendrimeric system has been proposed for which PAMAM dendrimer and hemin were noncovalently associated.46 In their approach, the group of M. R. Detty has developed the synthesis of dendrimeric organochalcogen catalysts (selenides and tellurides) for the activation of hydrogen peroxide (selenides and tellurides mimic enzymes that activate hydrogen peroxide, such as horseradish peroxidase). They have considered polyether dendrimers with phenylselenides or tellurides on the surface (first to third generations with respectively 3, 6, and 12 terminal organochalcogen groups on the surface). These dendrimeric macromolecules, which have shown a poor solubility in water, have catalyzed the oxidation of bromine (NaBr) with hydrogen peroxide to give positive bromine Br+ species that can be captured by cyclohexene in two-phase systems.47–49 Dendrimeric effects were observed only for the selenide derivatives for which the catalytic activity exceeds the sum of the activities of each individual selenide group, illustrating cooperative effects between the peripheral groups (Figure 10.8). These dendrimeric effects were correlated to an increase of the rate of oxidation with the number of phenylselenide groups on the surface due to the autocatalysis process in the formation of the Br+.

Figure 10.8 peroxide49

Dendrimeric organoselenides as catalysts for the activaton of hydrogen

Catalysis with Dendrimers in Particular Media

Figure 10.9

225

Lipase enzyme grafted on poly(phenylenesulfide) dendrimer50

Not only enzyme-like behavior was reported for dendrimers; they have also been used as support for enzymes. T. Imae and coworkers have grafted a Lipase enzyme in a covalent way on the surface of poly(phenylenesulfide) dendrimers (second and third generations); the immobilized enzyme has shown a wider pH and temperature range than the free enzyme and has been used for up to 20 times in the hydrolysis of olive oil (Figure 10.9).50 Dendrimers have not been processed in water only for these “biocatalytic” applications. Aqueous phase organometallic catalysis has been largely developed during the last three decades with the aim to develop green catalytic systems; as dendrimeric catalysts have been successfully involved in transition metal catalyzed reactions they are excellent candidates to be used in such aqueous phase conditions. The Ruhrchemie/Rhône–Poulenc oxo process is one of the most important industrial applications of biphasic organometallic catalysis in water; trisodium tris(m-sulfonatophenyl) phosphine was used as a water-soluble ligand. Two-phase aqueous hydroformylation of olefins using water-soluble dendrimeric ligands was introduced by F. Xi and coworkers.51 They have used PAMAM dendrimers and partially functionalized them with a phosphino group using Ph2P(CH2OH)2Cl to obtain water-soluble dendrimeric ligands; to increase the loading of the phosphino groups and keep the water solubility, the remaining amino groups were transformed to alkylsulfonato groups. This strategy, for which charges and phosphino groups were randomly grafted to the surface of PAMAM dendrimers, does not afford well-defined dendrimeric ligands. Rhodium complexes were prepared in situ with the different ligands prepared, leading to moderate catalytic activity; selectivity for the branched aldehyde was obtained in the hydroformylation of styrene, contrary to the

226

Dendrimers

monomeric hydrosoluble phosphine ligand used, which gave the linear aldehyde. Metal leaching in the organic phase was observed and no reuse of the catalyst was reported. The grafting of some hydrophobic alkyl end groups to enhance the solubility of the olefins in water was not productive. In their approach, A. M. Caminade, J. P. Majoral, M. Peruzzini, and coworkers have prepared well-defined dendrimeric catalysts bearing a ligand (or organometallic complex) and a permanent positive charge on each terminal group.52 1,3,5-triaza-7-phosphaadamantane (PTA, a well-known water-soluble phosphine easily alkylated at one nitrogen) was grafted on to the surface of PPH dendrimers (generation 1 to 3) end-capped with an alkylating group (benzylic chloride), leading to well-defined dendrimeric ligands (PTA dendrimers). Ruthenium complexes were prepared and used in the hydration of alkynes in a water/isopropanol mixture. If the first generation dendrimeric Ru(II) complex showed better activity than the momoneric Ru(II) complex analog (58% conversion and 41%, respectively), a decrease was observed for the second and third generations (45% and 25%, respectively). Nevertheless, a slight increase in the ketone toward aldehyde selectivity was obtained on going from the monomer to the third generation (91%, 95%, 98%, and 98%, respectively). The use of the Ru(II) dendrimeric complexes (1 mol % of Ru catalysts) was also reported for the isomerization of allylic alcohols carried out in a mixture of water–heptane (1:1) at 75 °C, with 2% of Cs2CO3 as the cocatalyst: isomerization of 1-octen-3-ol into octan-3-one was studied and no reaction was observed in the absence of water (Figure 10.10). A clearly positive dendrimeric effect was

Figure 10.10 Allylic alcohol isomerization catalyzed by Ru(II) dendrimeric complexes based on PPH dendrimers52

Catalysis with Dendrimers in Particular Media

227

Figure 10.11 Recycling process for allylic alcohol isomerization catalyzed by first generation Ru(II) dendrimeric complexes52

observed for the conversion, on going from 38% with the momoneric Ru(II) complex analog to 98% with the third generation (63% and 94% conversions were obtained respectively for the first and second generations). A recycling process was reported (Figure 10.11): before stirring, octanol is in the organic phase, the cocatalyst in water, and the dendrimer both in the aqueous phase and at the interface. Upon vigorous stirring both phases mix. The recycling is performed very simply by decantation and removal of the organic phase, followed by addition of heptane and 1-octan-3-ol. In the first three catalytic runs the percentage of conversion remains 100%, whereas it begins slightly to decrease at the fourth run. The group of D. Astruc has reported the synthesis of water-soluble polyphenylene dendrimers with sodium salt of phosphonic acid on the surface and used them to prepare polyperoxophosphotungstates.53 Their catalytic activity was tested in water/acetonitrile mixture for epoxidation of alkenes with hydrogen peroxide. After phase separation, the dendrimeric catalyst was recovered from the water phase and reused with no observable loss of activity. To obtain water-soluble dendrimeric catalyst, R. Haag and coworkers have chosen instead of charges to use poly(ethylene glycol) chains; they have functionalized hyperbranched polyglycerol with azide functions and then added by “click” chemistry an imidazolium salt bearing an alkynyl group and a methoxypoly(ethylene glycol) chain.54 They finally obtained water-soluble hyperbranched polyglycerol derivatives functionalized with N-heterocyclic carbene palladium complexes and used them in a Suzuki–Miyaura crosscoupling reaction (Figure 10.12). These hyperbranched/dendrimeric catalysts have shown

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Dendrimers

Figure 10.12 complexes54

Water-soluble hyperbranched polyglycerol N-heterocyclic carbene Pd

high stability and activity; a dialysis technique was applied to separate the catalyst from the product and it was reused successfully 5 times. The catalytic activity was compared to those of linear analogs bearing a PEG chain, N-heterocyclic carbene, and triazole moieties, particularly in the case of a cross-coupling reaction involving pyridylboronic acid derivatives; hyperbranched/dendrimeric catalysts have exhibited higher activities than the monomeric counterpart for which catalytic recycling was not efficient. To develop water-soluble dendrimeric catalysts, the group of K. I. Fujita has chosen to introduce the ligand (and the organometallic complex) at the core level of a dendrimeric species.55 By coupling polyether dendrons on a phosphorus precursor and subsequent transformation, they have prepared dendrimeric phosphine core ligands having carboxylic acid end groups and used the potassium carboxylate derivatives in a Pd-catalyzed Suzuki– Miyaura coupling reaction in pure water (Figure 10.13). A positive dendrimeric effect was observed with an improved yield on going from the zeroth to the third generation. To analyze these results, catalytic reactions were carried out with the zeroth generation dendrimeric ligands and an additional amount of monomeric potassium benzoate to reach the same number of potassium carboxylate moieties present in the surface of the first, second, and third generation dendrimeric ligands; lower conversions were obtained in comparison to those reported for the reactions using first, second, and third generation dendrimeric ligands. The amphiphilic nature of these dendrimeric ligands was essential to afford the solubilization in water via the hydrophilic peripheral groups and to ensure a hydrophobic domain inside the structure for the phosphine group. As the use of these dendrimeric ligands was not possible in acidic or neutral conditions, in a similar approach dendrimeric phosphine core ligands having tri(ethylene glycol) (TEG) end groups were prepared and gold(I)-catalyzed hydration of alkynes in aqueous media was studied.56 For non-water-soluble alkynes, even if the TEG end-capped dendrimeric ligands were water soluble, no reaction was observed in pure water and water/methanol mixtures were needed; moderate to good conversions were obtained for the hydration reaction carried out in acidic media with the first generation dendrimeric ligand. A negative den-

Catalysis with Dendrimers in Particular Media

Figure 10.13

229

Dendrimeric phosphine core ligands55,56

drimeric effect was observed with a higher catalytic activity obtained for the first generation dendrimeric ligand; increased steric hindrance around the phosphorus coordinating atom with an increase of the generation dendrimeric ligand was proposed to explain this result. For water-soluble alkynes, pure water can be used and the hydration reaction proceeds with high conversion with all the dendrimeric ligands (first to fourth generations). A recycling process of the gold catalytic species was reported using membrane filtration: by means of nanofiltration of the aqueous reaction mixture, the dendrimeric catalyst was recovered and reused up to four times without deactivation. The same group has reported the synthesis of dendrimeric 2,2′-bipyridine core ligands57,58 through the coupling of 4,4′-dihydroxy-2,2′-bipyridine and polyether dendrons having hydrophobic (methoxy or benzyloxy) end groups or hydrophilic (tri(ethylene glycol), or TEG) ones; these ligands were used in the copper-catalyzed three-component condensation reactions with aldehydes, o-anisidine, and nucleophiles in pure water. For ethylene glycol units having interaction with copper, low conversions were obtained with the TEG end-capped dendrimeric ligands, even if they had shown good water solubility. The non-water-soluble dendrimeric ligands gave a better conversion in this Mannich-type reaction; moreover, the conversions obtained in pure water were greater than those obtained in dichloromethane solution, which could be connected with the hydrophobic effects. A positive dendrimeric effect (increase of the yield with the generation of the dendrimeric ligand) was observed;

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Dendrimers

it was proposed that the hydrophobic environment around the copper catalyst was responsible for this effect. Y. Tsuji and coworkers, who have also reported the synthesis of dendrimeric phosphine core ligands with TEG end groups and their use in the Pd-catalyzed Suzuki–Miyaura coupling reaction with aromatic chloride, found that a very low conversion was obtained in pure water (9%), whereas the biphenyl product was prepared in high yield in THF.59 The use of non-water-soluble dendrimeric ligands in an aqueous reaction media was also reported by other groups, with the introduction of the ligands on the surface or the core of dendrimers, but in this case the easy catalyst recovery by only simple phase separation was nonefficient and other processes had to be used. For example, Astruc and coworkers have used diphosphine end-capped PPI dendrimers and their corresponding Pd(II) complexes (first to third generations) in a Suzuki cross-coupling reaction in a THF/ water mixture.60 These conditions have been chosen to ensure the solubilization of the base, the reactants, and the catalyst, but during the course of the reaction a demixion process was observed; therefore the aqueous phase could be separated and pentane added to the organic phase to induce the precipitation of the catalyst and consequently its reuse was possible. Coupling products were obtained with a broad range of halogenoarene and especially aryl chloride; a negative dendrimeric effect was observed, with a first generation dendrimeric Pd(II) complex being the more active. The dendrimeric catalysts were stable (tolerant to air and water); contrary to monomeric analogs, they could be recovered and reused but a loss of reactivity was observed. The same group has developed the synthesis of dendrimeric polyoxometalate (POM) catalysts and used them in biphasic (CDCl3/water) conditions for the oxidation of different substrates (olefins, sulfides, alcohols) with aqueous H2O2 oxidant. Two strategies have been developed: the first one involved the ionic bonding of dendrons with an ammonium group at the focal point to anionic POM species leading to POM-cored dendrimers,61,62 whereas in the other case the surface of an ammonium end-capped dendrimer was noncovalently functionalized with anionic POM species through ionic interaction (Figure 10.14).63,64 Recovery of the catalysts in all cases was performed by adding an additional organic solvent to induce its precipitation; the POMcored dendrimers have shown greater air stability. Some pioneering works in this field were reported by G. R. Newkome and coworkers.65 Caminade, Majoral, Peruzzini, and coworkers have functionalized phosphoruscontaining dendrimers with diphosphine ligands (first to third generations) and used them in a Pd-catalyzed cross-coupling reaction in a water/acetonitrile mixture.66 The phosphine end-capped dendrimers have been shown to be tolerant to water and oxidation. If the first generation dendrimeric ligands have afforded more efficient catalytic systems than the monomeric analogs, the activity for the higher generations was decreased for nearly all the systems. No recycling experiments were reported. Hydrophobic dendrimeric 1,2-aminosulfonamidecyclohexane core ligands were used in Rh- and Ru-catalyzed asymmetric transfer hydrogenation in an aqueous system with HCOONa as the hydrogen source.67 These dendrimeric ligands have been prepared by the coupling of polyether dendrons (first to fourth generations) to 1,2-aminosulfonamidecyclohexane. High conversion and enantiomeric excess were obtained, with the Rh systems being the more efficient; moreover, these dendrimeric ligands have been shown to have less efficient catalytic activity when dichoromethane was used as the solvent and HCOOH–Et3N as the hydrogen source. The recovery of the catalytic systems has been performed by precipitation induced

Catalysis with Dendrimers in Particular Media

Figure 10.14

231

Dendrimeric polyoxometalate (POM) catalysts61–64

Figure 10.15 Dendrimeric 1,2-aminosulfonamidecyclohexane core ligands in Rh-catalyzed asymmetric transfer hydrogenation in water67

by addition of hexane to the reaction mixture: enantioselectivity was not affected after six runs (Figure 10.15). A fluorinated dendrimeric TsDPEN ligand was prepared by coupling fluoroaryl endcapped polyether dendron (second generation) with TsDPEN (N-(p-tolylsulfonyl)-1,2diphenylethylenediamine) derivative;68 it was used successfully in the Ru(II)-catalyzed asymmetric transfer hydrogenation of prochiral ketones in aqueous media (complete conversion and excellent enantioselectivity were obtained). The catalyst/product separation was performed via the solvent precipitation method using hexane here also; the dendrimeric catalyst was reused more than 26 times without significant loss of activity and

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no appreciable ruthenium leaching into the hexane phase was observed. The special stability and recyclability was attributed to the fluorine atoms present on the surface of the dendrimeric species. Bisoxazoline ligands have been functionalized with hydrophobic Fréchet-type dendrons and used in a copper-catalyzed enantioselective aldol reaction in aqueous media (H2O/EtOH/THF).69 Moderate to good conversion and enantiomeric excess were obtained but recovery of the catalyst by precipitation using methanol was not efficient. Another dendrimeric system offers the opportunity to have water-soluble catalysts: it concerns the dendrimer-encapsulated metal nanoparticles for which solubility can be easily tuned regarding the nature of the peripheric end groups. The group of Crooks was the pioneer in this field: using hydroxyl-terminated PAMAM dendrimers (fourth to sixth generations), they have carried out Pt and Pd salt complexation and subsequent chemical reduction of the metal ions to obtain water-soluble dendrimer-encapsulated Pt and Pd nanoparticles.70 These have been considered as catalysts for hydrogenation of allyl alcohol and N-isopropyl acrylamide in water. The activity was correlated with the size of dendrimers, the fourth generation giving the best results due to easier access to the nanoparticles for the substrate. Even if stability of the dendrimeric catalysts was claimed, no recovery experiment was reported. Later on, it was demonstrated that for a given generation of PAMAM dendrimer the activity of the PAMAM-encapsulated Pd nanoparticles was related to the steric crowding at the surface level, which was modulated by the nature of the peripheral group.71,72 PAMAM-encapsulated Pd nanoparticles were also efficient for Suzuki cross-coupling reactions in aqueous media, as reported by M. A. El Sayed and coworkers who have pointed out the dendrimer generation influence on the catalytic activity, with the third and fourth generations giving the best results.73 Astruc and coworkers have used PAMAM- and PPI-encapsulated Pd nanoparticles in a Suzuki reaction carried out at 80 °C. The water/CH3CN mixture was considered and no difference related to the dendrimer nature was observed.74 Recovery and reuse was possible due to the water solubility of the palladium DENs, but with a decrease in the activity. Stille cross-coupling reactions were also catalyzed by Pd DENs in water, as described by de Jesus and coworkers;75 the catalytic activity was generally lower than those of Pd(OAc)2. Nevertheless, when dendrimeric catalytic systems were used, homocoupling product formation was suppressed and catalyst recycling was possible. Astruc and coworkers have reported the use of sulfonated “click” dendrimer-stabilized palladium nanoparticles in Suzuki and hydrogenation reactions;76 in this case, nanoparticles had a larger size than those in the case of DENs, the stabilization occurring in a different way (interdendrimer versus intradendrimer stabilization). Silicon-based dendrimer peripherically functionalized with an azide group was used to obtain, via the “click” reaction, water-soluble 1,2,3-triazolylsulfonated dendrimers. After potassium tetrachloropalladate (K2PdCl4) complexation and metal ion reduction, the dendrimer-stabilized Pd nanoparticles were obtained. They have shown high catalytic activity (0.01% mol Pd) in Suzuki cross-coupling with aryl iodide and allylic alcohol hydrogenation reactions carried out at room temperature in water/ethanol mixtures and pure water, respectively. For aryl bromide derivatives, Suzuki cross-coupling reactions were performed at 100 °C (Figure 10.16). Crooks and coworkers have also developed some water-soluble dendrimer-encapsulated heterobimetallic nanoparticles (Pd/Pt) as an efficient catalyst for hydrogenation of allylic alcohol.77 Finally, metallic nanoparticles can be encapsulated inside hyperbranched poly-

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Figure 10.16 Olefin hydrogenation in water catalyzed by sulfonated dendrimer-stabilized Pd nanoparticles76

mers and used in an aqueous phase catalytic process. For instance, poly(amidoamine) hyperbranched polymers developed by J. D. Marty and coworkers have been used to stabilize Pt nanoparticles;78 hydrogenation reactions were performed. R. Neumann and coworkers have considered alkylated polyethyleneimine to stabilize Pd nanoparticles also involved in hydrogenation of alkenes;79 high conversions were obtained for cyclic and linear alkenes, easy recovery and reuse processes were reported without loss of activity, and competition reaction studies have shown a lack of activity for hindered alkenes, a biphasic media (alkene/water phase) being more efficient than a monophasic one (alkene/ water/methanol). To develop a green catalytic system without the use of metal as in organometallic catalysis, an aqueous phase organocatalytic process80 has also been studied in recent years in order to improve the recovery of the organocatalyst from the reaction mixture or to take the benefits of hydrophobic effects induced by the use of water with a non-water-soluble organocatalyst. Proline and its derivatives have been largely used as organocatalysts for various chemical transformations; therefore some examples of dendrimeric proline derivatives used in aqueous media were proposed. Chiral amphiphilic dendrimeric organocatalysts composed of a proline catalytic core surrounded by hydrocarbon dendrons have been employed for asymmetric aldol and nitro Michael reactions;81 using water as solvent, emulsion formation was promoted by the presence of the dendrimeric wedges on a proline derivative. These emulsions were in part responsible of the catalytic results. Increasing the size and the number of hydrophobic dendrons used was of benefit for obtaining higher enantioselectivity. Recycling experiments were reported using an extraction process with a heptane/methanol mixture (the dendrimeric catalyst being recovered in the heptane phase); when the recovered catalyst was used in different reactions no cross-contamination was observed. Positive effects on the enantioselectivity of an aldol reaction were also

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obtained with the dendrimeric catalyst bearing the active site on the surface.82 PAMAM dendrimers themselves have been used to catalyze Knoevenagel and Mannich reactions in water.83

10.6

Conclusions

Dendrimeric catalysts have been applied in several reactions using particular media with an emphasis on the use of water, biphasic aqueous media, and thermomorphic biphasic systems. The use of ionic liquids as supercritical fluids has for the moment not been fully developed. In numerous cases, some easy recovery processes have been proposed and good activity was retained after several runs: therefore, stability of dendrimeric catalysts in such conditions was demonstrated with reduced metal leaching. Nevertheless, one can argue that as the attachment of water-soluble groups, fluorous groups, or changes to a monomeric catalyst are sufficient to allow an efficient recycling process using liquid– liquid phase separation techniques, the use of dendrimers is not necessary. Contrary to this point, the results obtained up to now have already shown the real specificity of dendrimers, especially in aqueous media for organometallic catalysis with the intention of producing a positive dendrimeric effect or multivalent effect; in numerous cases stability of the dendrimeric organometallic complexes was increased, in comparison with a monomeric catalyst. Additionally, a specific domain concerns the use of dendrimer encapsulated metallic nanoparticles (DENs) in catalysis, for which the easy attachment of the peripheral groups on the dendrimer allowed the user the choice of a better media for a given catalyzed reaction. Of course the use of hyperbranched polymers is of great importance as they can offer a cheaper alternative to dendrimers and therefore have to be developed specially in the context of green chemistry. These points mainly concern the use of dendrimers in organometallic catalysis and organocatalysis and are in good agreement with the green chemistry preoccupations. However, the specific nature of dendrimers also gives the opportunity to consider them as enzyme mimics and therefore to develop their use in biocatalysis.

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(70) M. Zhao and R. M. Crooks (1999) Homogeneous hydrogenation catalysis with monodisperse, dendrimer-encapsulated Pd and Pt nanoparticles. Angew. Chem. Int. Ed., 38, 364–366. (71) Y. Niu, L. K. Yeung, and R. M. Crooks (2001) Size-selective hydrogenation of olefins by dendrimers-encapsulated palladium nanoparticles. J. Am. Chem. Soc., 123, 6840–6846. (72) S. K. Oh, Y. Niu, and R. M. Crooks (2005) Size-selective catalytic activity of Pd nanoparticles encapsulated within end-group functionalized dendrimers. Langmuir, 21, 10209–10213. (73) Y. Li and M. A. El Sayed (2001) The effect of stabilizers on the catalytic activity and stability of Pd colloidal nanoparticles in the Suzuki reactions in aqueous solutions. J. Phys. Chem. B, 105, 8938–8943. (74) J. Lemo, K. Heuze, and D. Astruc (2006) Synthesis and catalytic activity of DAB dendrimer encapsulated Pd nanoparticles for the Suzuki coupling reaction. Inorg. Chem. Acta, 359, 4909–4911. (75) M. Bernechea, E. de Jesus, C. Lopez-Mardomingo, and P. Terreros (2009) Dendrimerencapsulated Pd nanoparticles versus palladium acetate as catalytic precursors in the Stille reaction in water. Inorg. Chem., 48, 4491–4496. (76) C. Ornelas, J. Ruiz, L. Salmon, and D. Astruc (2008) Sulphonated “click” dendrimer-stabilized palladium nanoparticles as highly efficient catalysts for olefin hydrogenation and Suzuki coupling reactions under ambient conditions in aqueous media. Adv. Synth. Catal., 350, 837–845. (77) R. W. J. Scott, A. K. Datye, and R. M. Crooks (2003) Bimetallic palladium–platinum dendrimerencapsulated catalysts. J. Am. Chem. Soc., 125, 3708–3709. (78) J. D. Marty, E. Martinez-Aripe, A. F. Mingotaud, and C. Mingotaud (2008) Hyperbranched polyamidoamine as stabilizer for catalytically active nanoparticles in water. J. Colloid Interface Sci., 326, 51–54. (79) M. V. Vasylyev, G. Maayan, Y. Hovav, A. Haimov, and R. Neumann (2006) Palladium nanoparticles stabilized by alkylated polyethyleneimine as aqueous biphasic catalysts for the chemoselective stereocontrolled hydrogenation of alkenes. Org. Lett., 8, 5445–5448. (80) M. Gruttadauria, F. Giacalone, and R. Notoa (2009) Water in stereoselective organocatalytic reactions. Adv. Synth. Catal., 351, 33–57. (81) C. M. Lo and H. F. Chow (2009) Structural effects on the catalytic, emulsifying, and recycling properties of chiral amphiphilic dendritic organocatalysts. J. Org. Chem., 74, 5181–5191. (82) K. Mitsui, S. A. Hyatt, D. A. Turner, C. M. Hadad, and J. R. Parquette (2009) Direct aldol reactions catalyzed by intramolecularly folded prolinamide dendrons: dendrimer effects on stereoselectivity. Chem. Commun., 3261–3263. (83) G. R. Krishnan, J. Thomas, and K. Sreekumar (2009) Organocatalysis by poly(amidoamine) dendrimers; Knoevenagel and Mannich reactions catalyzed in water. Arkivoc, 106–120.

11 Heterogeneous Catalysis with Dendrimers Régis Laurent* and Anne-Marie Caminade

11.1

Introduction

The attachment of homogeneous catalysts to insoluble supports (inorganic or organic) has been studied intensively with the objective to combine the practical advantages of heterogeneous catalysis with the efficiency of homogeneous systems.1,2 Where easy separation and recycling of the catalyst from the reaction mixture are generally obtained, supported catalysts often suffer from lower activities and selectivities when compared with their nonsupported analogs (diffusion effects, accessibility of the catalytic sites by the reagents in solution, and site heterogeneity are in part responsible for these results). Previous chapters have shown that the use of dendrimers as soluble supports for catalysts can afford some very efficient catalytic systems having their own specificity due to the particular structure of these macromolecules. Therefore to take advantage of this structure, catalytically active dendrimers have been linked to a solid or used in a solid state with the aim of suppressing the main inconvenience of heterogeneous catalysis, which is the poor compatibility of the liquid phase (containing the reagents) with the solid phase.3–5 The dendrimeric structures can be synthesized step by step on the solid surface or synthesized in a liquid phase and then grafted to the solid surface; the solids studied were inorganic materials (silica), organic polymers or copolymers, metallic nanoparticles, and carbon nanotubes. In this way, the catalytic sites are linked to the solid, but are remote enough from it to behave almost like in solution. A few examples of insoluble catalytic dendrimers will be also given. When possible, a comparison between the advantages and inconveniences of homogeneous and heterogeneous catalyses with dendrimers will be discussed. * Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Catalysis with Dendrons Synthesized from a Solid Material

Two main families of supports were considered for the dendrons synthesis: inorganic or organic supports. Among the inorganic ones, silica has been the most used and while for the organic ones, different types of polymeric resins were used. 11.2.1

Silica as an Inorganic Support

The group of H. Alper introduced the concept of heterogenization of a metallodendrimeric catalyst.6 Their first strategy was to construct in a divergent way PAMAM dendrimers on silica up to the fourth generation, starting from amino-functionalized silica (Figure 11.1). Therefore diphosphine ligands were introduced on the PAMAM-dendronized silica using diphenylphosphinomethanol and finally Rh complexes were prepared. These heterogeneous supported dendrimeric catalysts were tested in a hydroformylation reaction (Figure 11.2). Low-generation supported dendrimeric catalysts (zeroth to second generations) gave high activity at room temperature and a very marked selectivity toward the branched aldehydes in the hydroformylation of arylolefins and vinyl esters; the heterogeneous supported dendrimeric catalysts can be recovered and reused without significant loss of activity. High-generation supported dendrimeric ligands (third and fourth) were only active at 75 °C with a decrease in the selectivity; these results were explained on the basis of the low degree of rhodium complexation beyond the second generation due to incomplete functionalization of the PAMAM-dendronized silica arising from steric hindrance (Figure 11.2). To improve the efficiency of these heterogeneous supported rhodium dendrimeric catalysts, the chain length of the diamine used in the synthesis of the PAMAM dendronized silica was extended: ethylenediamine was substituted by 1,4-diaminobutane, 1,6-diaminohexane, or 1,12-diaminododecane, leading to a lower amine content and then

Figure 11.1

Preparation of PAMAM-dendronized silica6

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Figure 11.2 Hydroformylation of styrene using Rh complexes supported on PAMAMdendronized silica (Rh content for the dendrimeric catalysts)6

to a lower congestion at the surface level, allowing a better catalyst loading for the higher generations.7 The efficiency of the supported dendrimeric catalysts in terms of activity and recyclability was increased with the chain length of the diamine and excellent results were obtained with the diaminohexane-based fourth generation catalyst (Figure 11.3). Alper and coworkers also prepared a number of Pd-based supported dendrimeric catalysts using the PAMAM dendronized silica bearing diphosphine ligands and tested them in carbonylation reactions such as alcoxycarbonylation of iodoarene,8 intramolecular amidocarbonylation (synthesis of six- to eight-membered fused heterocyclic lactams,9 synthesis of large ring macrocycles,10 and synthesis of medium ring tricyclic lactams11), olefin hydroesterification,12 intramolecular hydroesterification and hydroamidation (synthesis of lactones and lactams).13 For intramolecular hydroesterification, palladium(II)–PCP type complexes supported on dendronized silica were also used.14 As for rhodium, a decrease in the degree of palladium complexation was observed upon the dendron generation increase when ethylenediamine was used to obtain the PAMAM dendronized silica; to get high loading of metal for high generations, long-chain diamine (C6) was needed. It was also demonstrated, for intramolecular amidocarbonylation for example (Figure 11.4),9 that a better recyclability of the catalyst was obtained when long-chain diamine (C6) was used to prepare the PAMAM dendronized silica. For the methoxycarbonylation of iodoarene8 catalyzed by Pd(II) complexes supported on PAMAM dendronized silica (ethylenediamine as the diamine linker), the activity of the

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Dendrimers

Figure 11.3 Hydroformylation of styrene using Rh complexes supported on fourth generation PAMAM-dendronized silica7

Figure 11.4 Intramolecular carbonylation catalyzed by Pd complexes supported on third generation PAMAM-dendronized silica9

catalyst was analyzed per Pd equivalent loading, showing an increase of the TON with the generation (138, 179, and 234 for, respectively, the first, second, and third generation dendrimeric catalyst; the Pd loading was decreasing at the same time). A lower leaching of Pd from the silica supported dendrimeric catalyst was also observed upon the increase in the dendrimer generation. For all the reactions studied, the supported dendrimeric cata-

Heterogeneous Catalysis with Dendrimers

Figure 11.5

243

Palladium content for the various Pd-based supported dendrimeric catalysts17

lysts could be recycled and reused; nevertheless, in some cases a moderate recyclability was obtained. Pd-based supported dendrimeric catalysts using PAMAM dendronized silica have also been used in a Heck cross-coupling reaction of aryl bromide with butyl acrylate and styrene; moderate to good yields were obtained and the catalyst can be recycled and reused.15 Selective hydrogenation of dienes to monoolefins was reported: the second generation dendrimeric catalyst issued from diaminododecane-based PAMAM-dendronized silica could be reused up to eight times without a significant loss in selectivity.16 The oxidation of terminal alkenes to methyl ketones was also studied.17 Pd content (determined by ICP analysis) was given for different supported dendrimeric catalysts with regard to their generation or the nature of the diamine used for the synthesis of the PAMAM dendronized silica: it increased with spacer length and decreased for higher generations (Figure 11.5). For the C2 diamine spacer, the efficiency of the catalyst decreases with the increase of the generation. The second generation supported dendrimeric catalyst based on the C6 diamine spacer was the most efficient. Oxidation was selective toward the terminal double bond versus an internal one. S. Kawi and coworkers have considered PAMAM dendronized silica as a support for manganese salen-type complexes.18 The PAMAM dendrimers were synthesized on an amino-functionalized silica having a lower amine content (0.4 mmol NH2/g) than the material used by Alper (0.9 mmol NH2/g). Salicylaldehyde was then reacted with PAMAM dendronized silica (zeroth to fourth generations) to introduce salicylimine on the dendrimer surface, which was used to complex manganese. The Mn content was found to increase with the generation; in the epoxidation of styrene they obtained an increase in the yield with the supported dendrimeric catalyst generation (Figure 11.6). The importance of the amine function loading on the amino-functionalized silica used to prepare the PAMAM dendronized silica was also demonstrated by H. K. Rhee and coworkers, who have prepared silica supported dendrimeric chiral auxiliaries and used them for the enantioselective addition of diethylzinc to benzaldehyde, which affords chiral

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Dendrimers

Figure 11.6 Epoxydation of styrene catalyzed by Mn complexes supported on PAMAMdendronized silica18

secondary alcohol.19 They have shown that the construction of the PAMAM dendrimer on the amino-functionalized silica was more efficient when a low loading of the amino group was considered (the difference between the theoretical and the observed amino group content on the surface of the dendrimers was greater when a high loading of the amino group on the starting amino-functionalized silica was used). (1R,2S)-ephedrine was then grafted on to PAMAM dendronized silica (zeroth to fourth generations). With the silica supported dendrimeric chiral auxiliaries prepared from a low loading of aminofunctionalized silica, an increase in the conversion, chemoselectivity, and enantioselectivity with the generation was observed (Figure 11.7). For the second type of silica supported dendrimeric chiral auxiliaries prepared from a high loading of amino-functionalized silica, a negative dendrimeric effect was obtained (a decrease in the conversion, chemoselectivity, and enantioselectivity with the generation). Furthermore, the silica supported dendrimeric chiral auxiliaries can also be recycled and reused without a loss of catalytic activity (conversion, chemoselectivity, enantioselectivity). Even if silica supported dendrimeric catalysts were found to be highly efficient and easily recoverable and recyclable in different examples, several drawbacks are connected

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245

Figure 11.7 Enantioselective addition of diethylzinc to benzaldehyde catalyzed by (1R,2S)-ephedrine grafted on to PAMAM dendronized silica SiO2–Gn–E19

with the nature of the amorphous silica support (small pore size and irregular pore structure). Silica with more appropriate pore structures, periodic mesoporous silicas (PMSs) or ordered mesoporous silicas (OMSs), were studied in order to increase the catalyst loading through the use of higher generation dendrimers. Alper and coworkers have considered the use of large-pore (6.5 nm) MCM-41 silica as the support for the synthesis of PAMAM dendrons.20 Compared to amorphous silica, the large-pore MCM-41 silica showed a higher degree of growth and a higher yield of formation of supported dendrimers: the growth of the dendrimer occurred inside the channels of the MCM-41 silica, leading to a complete filling of the pore with the third generation dendron (the surface areas, pore volumes, and pore sizes decreased along with the increase of the generations, indicating that the dendrimers were constructed on the channel surfaces of the MCM-41 silica). Therefore functionalization with diphosphine ligands and subsequent complexation of rhodium were only performed with the zeroth to second generation PAMAM dendronized MCM-41 silica, and it was demonstrated that the zeroth and first generation PAMAM dendronized MCM41 silica incorporated much more metal than the second generation. Consequently, only the zeroth and first generation catalyst materials were found to be excellent recyclable catalysts for olefin hydroformylation. For the hydroformylation of 1-octene at 70 °C, the higher turnover frequency (TOF) (1800 h−1) was obtained with the zeroth generation supported dendrimeric catalyst (Figure 11.8). The same group has also used Davisil large-pore silica (18 nm) as the support for the synthesis of PAMAM dendronized silica up to the third generation:21 in this case the functionalization with diphosphine ligands and subsequent complexation of rhodium was possible with all the generations (zeroth to third) of PAMAM dendronized Davisil silica. Contrary to the MCM-41 silica series, the Davisil silica series showed excellent activity for the hydroformylation reaction, even for the third

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Dendrimers

Figure 11.8 Hydroformylation of 1-octene catalyzed by Rh complexes supported on PAMAM dendronized MCM-41 silica20 and PAMAM dendronized Davisil silica21

generation supported dendrimeric catalyst; nevertheless, the first generation dendrimeric catalyst was the more active – in particular, the first generation dendrimeric catalyst was more active than the zeroth generation (Figure 11.8). The nature of the support also has an influence on the recyclability: for the Davisil silica series, none of the catalyst could be recycled. The metal leaching is less pronounced for the MCM-41 silica or amorphous silica due to a higher sterically encumbered environment for these supports. Kawi and coworkers have used SBA-15, a different OMS support with a larger pore size than MCM-41, for the synthesis of PAMAM dendronized SBA-15 silica (zeroth to third generations).22,23 They have prepared Rh complexes (grafting of Wilkinson’s catalyst) and used the dendrimeric catalytic materials in the hydroformylation of styrene. They have studied the influence of the passivation of the silanol goups located outside the SBA-15 mesopore channels and shown superior catalytic performance for passivated SBA-15 supported catalysts toward the nonpassivated ones. These functionalized mesoporous dendrimeric silica have also been used in organocatalysis: D. F. Shantz and coworkers have synthesized melamine-based dendrimers (zeroth to second generations) starting from MCM-41 and SBA-15 silicas.24 They have obtained amine functionalized materials and tested them in a nitroaldol reaction. The better activity reported for the SBA-15 silica series was related to the pore size of the parent silica, 3.5 nm for MCM-41 and 7.8 nm for SBA-15. Transesterification of glyceryl tributyrate to afford methyl esters was studied: the dendronized mesoporous silicas are much more active and stable catalysts than simple amine attached to mesoporous silica. M. P. Kapoor and coworkers have used PAMAM and melamine-base dendrimers of functionalized mesoporous silica as very effective catalysts for the Knoevenagel reaction.25,26

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Figure 11.9 Allylic alcohol hydrogenation catalyzed by Pd(0)–PAMAM dendronized SBA-15 silica27

Q. M. Gao and coworkers used PAMAM dendronized SBA-15 silica (zeroth to fourth generations) to stabilize Pd(0) nanoparticles:27 they introduced Pd(II) salts into the dendrimers in the channels of PAMAM dendronized SBA-15 silica and then reduced the Pd(II) salts to form Pd(0) nanoparticles (Pd(0) particles are quite monodisperse in the channels of PAMAM dendronized SBA-15). These dendrimeric materials were tested in the hydrogenation of allylic alcohol and very high catalytic activity was obtained (Figure 11.9). The selectivity toward the hydrogenation product was increased when increasing the generation of the PAMAM dendronized SBA-15 silica. Recyclability of the catalytic dendrimeric materials was demonstrated; the Pd(0)–PAMAM dendronized SBA-15 silica was stable enough to retain the activitity for one month. Metal nanoparticles and more precisely magnetic nanoparticles (Fe2O3 coated with a silica shell) have also been used as solid support for the synthesis of PAMAM dendrimers (up to the third generation);28 organometallic complexes were grafted to these dendronized magnetic nanoparticles to produce dendrimeric catalytic materials easily separated from the reaction media after magnetization with a permanent magnetic field. Even if this process was very efficient to produce highly active, selective, and reusable catalyst for the hydroformylation, the dendronizing process in this case enhances the solubility of the support. Nanoparticles of alumina were considered by Kawi and coworkers as support for PAMAM dendrimers to produce a supported dendrimeric rhodium catalyst for the styrene hydroformylation (grafting of the Wilkinson catalyst).29 These nano-Al2O3 supported dendrimeric catalysts were more efficient (activity and selectivity) than the analog SBA-15

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Dendrimers

silica supported dendrimeric catalysts prepared by the same group.22,23 (For other examples of dendrimers interacting with nanoparticles and used for catalysis, see Chapter 6.) 11.2.2

Polymers and Resins as Organic Supports

Polymer and resin supports have been largely used to prepare supported dendrimeric catalysts. The Alper group was also one of the pioneers in this area; they prepared dendrimeric rhodium complexes on a polystyrene-based resin (Rink amide MBHA resin) for hydroformylation reactions.30 After the solid-phase synthesis of dendrimers (based on 3,5-diaminobenzoic acid-derived peptide-like monomer) up to the third generation, diphosphine ligands were introduced and hence rhodium complexes (Figure 11.10). The second and third generation catalysts were more active than the first generation one and could be recycled a number of times without a loss of activity.

Figure 11.10 Hydroformylation of styrene catalyzed by Rh complexes supported on dendronized polymer resin30

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249

In an elegant way, diphosphine ligands and then rhodium complexes were introduced at the branch level of a dendronized polymer resin: if the activity is similar for the system having the rhodium complexes at the dendrimer surface level, there is an increase in recyclability.31 Immersing a catalytic site inside a dendrimeric structure could improve its stability and at the same time preserve its activity by preventing the leaching of the metal. Some very efficient catalytic systems incorporating lysine moieties in the dendrimeric branches have been prepared: hydroformylation of various olefins has been carried out at room temperature with a high selectivity and excellent yields, even up to the tenth cycle.32 Cooperative effects between interior and exterior catalytic sites located in the dendrimeric structure could explain these results. The same resin supported dendrimeric rhodium complexes have been used successfully in ring expansion of aziridine to β-lactam.33 Wang resin was used as the support by M. Portnoy and coworkers to build polyether dendrimers up to the third generation; the dendronized supports were functionalized with phosphine ligands and the corresponding cobalt complexes were synthesized.34 A remarkable increase in activity and selectivity in the intramolecular Pausond–Khand reaction was obtained using the second and third generation polymer supported Co dendrimeric complexes (Figure 11.11). Starting from the same first to third generation polyether dendrimer functionalized polystyrene resin, Pd complexes were prepared and tested in the Heck cross-coupling reaction of bromobenzene.35 An increase in catalytic activities and selectivity from the zeroth to the third generation was obtained through the introduction of the dendrimeric spacer between the support and the ligands (Figure 11.12). The influence of the dendrimeric backbone nature was studied and showed a better activity for the polyether-based dendrimers than the polythioether or polyamine ones.36 Moreover, it was demonstrated that the use of a linear spacer between the support and the Pd complex was not able to enhance its activity contrary to the dendrimeric spacer (Figure 11.13). The Suzuki cross-coupling reaction was also studied with success.36 A diphosphine ligand functionalized dendronized polymer support was used in the Heck cross-coupling reaction (Figure 11.14).37 In an opposite way to that of monophosphine ligand functionalized dendronized polymers a negative dendrimeric effect was obtained. The different behavior was attributed to the crosslinking occurring during the palladium complexation with the monophosphine ligand, which was less efficient with chelating diphosphine ligands. However, if these diphosphine ligand functionalized dendronized polymers were used in an amidocarbonylation reaction of bromobenzene with diethylamine, better performances were demonstrated with second and third generation dendrimeric supported catalysts showing a positive dendrimeric effect. Here the results seem to be related to the need for high electron density on Pd for the carbonylation reaction and the chelating diphosphine ligand favored this feature. Crosslinked polystyrene was also used as the support for the synthesis of PAMAM dendrimers; K. Sreekumar and coworkers have reported the synthesis of PAMAM dendronized crosslinked polystyrene up to the third generation and subsequent manganese complexation.38 Different degrees of crosslinking were considered for the support, the higher degree giving a slower reaction rate for the synthetic process. The supported dendrimeric complexes were found to catalyze the oxidation of alcohols efficiently: a positive dendrimeric effect was observed with an increase in the stability and catalytic efficiency

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Dendrimers

Figure 11.11 Pauson–Khand reaction catalyzed by Co complexes supported on dendronized resin34

of the dendrimer–Mn complex with the generation. Additionally, there was no drop in the activity of the catalyst up to the fourth recycling cycle and practically no metal leaching was observed. PAMAM dendrimers were also used to prepare crosslinked polystyrene supported dendrimeric Sn(II) complexes (first to third generation), which have been used in the Baeyer–Villiger oxidation of ketones with hydrogen peroxide.39 Even if the metal content decreased with the generation, an increase of the TON with the generation was observed; recycling of the dendrimeric catalysts was an easy process with relatively low loss of activity. PAMAM dendronized polystyrene was also used in the Pd-catalyzed hydrogenation reaction of five-membered heterocycles.40 M. Weck and coworkers have prepared dendronized polystyrene resin and used them to support R,R-salen-type ligand; cobalt complexes were prepared and used for the hydrolytic kinetic resolution of terminal epoxides giving high catalytic activities and enantioselectivities.41 In addition,

Heterogeneous Catalysis with Dendrimers

Figure 11.12 resin35

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Heck cross-coupling catalyzed by Pd complexes supported on dendronized

Figure 11.13 Influence of the support for the Suzuki cross-coupling catalyzed by Pd complexes supported on resin.36 The structure of resin–G3–Pd is given in Figure 11.12

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Dendrimers

Figure 11.14

Diphosphine ligand functionalized dendronized polymer support37

the supported catalysts can be recycled and reused with comparable enantioselectivities. Cooperativity between two metal centers was hypothesized to explain these results as it was done in homogeneous conditions with R,R-(salen)–Co catalyst grafted on to PAMAM dendrimers42 or hyperbranched polymers.43 Organocatalysis was studied using polymer supported dendrimers. The group of Portnoy was the pioneer in this field.44 They decorated polyether dendrimers dendronized Wang resins with proline moieties via “click” methodology and evaluated the efficiency of these supported catalysts in the asymmetric aldol reaction (Figure 11.15). An increase in the yields and in enantioselectivity with the generation was obtained; enantioselectivity was even better than that achieved in solution with proline. Nevertheless, the recycling process was disappointing as, even if the enantioselectivity was not affected, the activity decreased significantly, especially for the higher generations. They also demonstrated that the length of the spacer is not responsible for the dendrimeric effect but its branched nature, pointing out the importance of the proline group proximity to the obtained high yield and enantioselectivity.45 The same Wang resin supported polyether dendrimers have been used to prepare polymer supported bifunctionnal catalysts (Lewis acid and H-donor capabilities) via the grafting of chiral diamines; carbamate or urea connecting units were created to graft the chiral diamine, leading to aminocarbamate or aminourea moieties at the surface of the dendron.46 Enantioselective nitro-Michael addition of acetone to nitroolefins was tested: the number of H-bond donors in the proximity of the amine and the length of the tether to the support influenced the activity and the selectivity of the catalyst. Supported

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Figure 11.15 Proline supported on the dendronized support as the organocatalyst in an asymmetric aldol reaction44

N-alkylimidazole end-capped dendrimers were used as efficient heterogeneous catalysts for the Baylis–Hillman reaction; the positive influence of the dendrimeric spacers and of water (used as the cosolvent) has been demonstrated.47 Polystyrene supported PAMAM dendrimers (zeroth to third generations) have been used as reusable base catalysts in Knoevenagel condensation of carbonyl compounds with methylene compounds.48 The best results were obtained with polar solvents (alcohol, even water); this was representative of the role of the polar dendritic wedges as polystyrene supported catalysts normally favour nonpolar solvents. As the third generation catalyst gave better results than the lower generation one under identical reaction conditions (the equivalence of amino groups was the same for experiments carried out with the different generation supported dendrimeric catalyst), it was assumed that catalytic species situated at the periphery of a dendrimer exhibit cooperative interaction. Supported third generation

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Dendrimers

dendrimers and unsupported first generation PAMAM dendrimers have the same number of peripheral amino groups; even if the unsupported first generation dendrimer is more active, removal and recycling of the catalyst was difficult and required chromatographic separation. The advantage of easy removal and multiple recycling of the supported catalyst (up to ten times) might compensate for the longer reaction time. Polystyrene-supported PAMAM dendrimers were also found to be efficient organocatalysts in the nucleophilic ring opening of epoxides by anilines.49 The third generation catalyst was the more active of the supported catalysts and was also more active than the unsupported ones. As mentioned in the previous chapter, enzyme-like behavior of dendrimers has been studied in particular by J. L. Reymond and coworkers: they have reported the synthesis of peptide dendrimers on Tentagel resins (Tentagel resins are grafted copolymers consisting of a low crosslinked polystyrene matrix on which polyethylene glycol (PEG or POE) is grafted) and the peptide dendrimer library obtained was screened to find catalytic peptide dendrimers for an ester hydrolysis reaction.50–52 Commercially available Tentagel MAP4 and MAP8 resins (Tentagel resins functionalized with a lysine-based dendron backbone – Tentagel-NH-Lys{Lys[Lys(Fmoc)2]2}2 and Tentagel-NH-Lys[Lys(Fmoc)2]2, respectively) were also considered as support: triazacyclononane was grafted on to the resins and the corresponding Zn complexes have shown a catalytic activity in the hydrolysis of 2-hydroxypropyl-p-nitrophenyl phosphate (the standard model of an RNA-phosphadiester).53

11.3

Catalysis with Dendrons or Dendrimers Grafted on to a Solid Surface

Another approach to prepare heterogeneous dendrimeric catalysts consists of the direct immobilization of “ready-made” dendrimers or dendrons on a solid support. H. K. Rhee and coworkers adopted this strategy to prepare a silica-supported dendrimeric chiral catalyst for the enantioselective addition of diethylzinc to aldehyde54 (Figure 11.16). They deposited PAMAM dendrimers on silica modified with epoxyde function, introduced a long alkyl spacer and finally the chiral auxiliary.54 The immobilization of a preformed dendrimer was supposed to reduce more efficiently the unfavorable racemic reaction caused by the silica surface silanol groups than the growth of a dendrimeric species from a silica surface, but no evidence was given. Nevertheless, without the long alkyl spacer, conversion and enantiomeric excess decreased with the generation, indicating a restriction on the access of reagents to the active sites and a negative interaction between the end groups. Catalytic performances were enhanced by the use of the long alkyl spacer. The efficiency of dendrimer encapsulated nanoparticles (DENs) as catalysts has been demonstrated in a very large number of cases (see previous chapters and in particular Chapter 6) and independently the immobilization of nanoparticles on solid supports is considered as an important step in the fabrication of a practical heterogeneous catalyst.55 Therefore the preparation of supported DENs was studied extensively. For example, G. A. Somorjai and coworkers prepared, using the PAMAM dendrimer, Rh and Pt DENs and deposited them on to an SBA-15 mesoporous silica support through electrostatic and hydrogen bonding interactions between the dendrimers and the silica support (Figure 11.17).56

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Figure 11.16 Enantioselective addition of diethylzinc to benzaldehyde catalyzed by (1R, 2S)-ephedrine grafted on PAMAM dendronized silica SiO2–PGn–E and SiO2–PGn–ac–E54

Catalytic activity was reported for ethylene and pyrrole hydrogenation; the nature of the support is of great importance as it prevents any pretreatment of the catalyst. In their approach K. J. Stevenson and coworkers used a carbon nanotube as the support for Pt DENs and produced an oxygen reduction catalyst.57 Pd DENs supported on a carbon nanotube were also prepared and used for electrocatalytic hydrazine oxidation.58 DENs have been used as precursors to obtain supported metallic nanoparticles: after deposition of the DENs on the support, thermal treatment was applied to remove the dendrimers.59 The

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Figure 11.17

PAMAM DEN supported on SBA-15 silica56

nanoparticles formation can occur also after grafting the dendrimer on the support, as demonstrated by R. M. Crooks and coworkers, who deposited PAMAM dendrimers on the surface of highly oriented pyrolytic graphite (HOPG) and then produced catalytically active Pd DENs.60 N. Jayaraman and coworkers reported the covalent grafting of phosphinated poly(propyl ether imine) dendrimers on silica, subsequent palladium (II) complexation, and finally reduction to produce Pd(0) nanoparticles stabilized by silica supported dendrimeric phosphine.61 They have been tested as a hydrogenation catalyst of olefins and have shown the possibility to be recovered and reused. E. Murugan and coworkers have considered PPI dendrimers (second generation) to crosslink poly(vinyl)pyridine polymers and the heterogeneous support thus obtained was used to stabilize Au nanoparticles.62 In their approach, S. Nlate, K. Heuze, and coworkers used nanoparticles as the support for a dendrimeric catalyst: a metallodendron end-capped with palladium complexes was grafted on to a core–shell superparamagnetic nanoparticle, γ-Al2O3/polymer.63 These systems were efficient catalysts for the Suzuki cross-coupling reaction involving iodo-, bromo-, and chloroarene. The recovery process was very simple using magnetic separation and dendrimeric catalysts were still active after 25 cycles. Heterogeneous reusable dendrimeric organocatalysts were prepared by trapping PAMAM dendrimers inside poly(p-xylylene) nanotubes (PPX nanotubes);64 to obtain a persistent assembly, a fifth generation dendrimer was necessary otherwise leaching of the dendrimers from the nanotubes occurred. The fifth generation PAMAM dendrimer entrapped in PPX nanotubes has shown good activity for the Knoevenagel condensation of malonitrile with benzaldehyde; the dendrimeric catalyst was successfully reused nine

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times without loss of activity. Postsynthesis modification of the PAMAM dendrimer entrapped in the PPX nanotube was possible; TEMPO moieties were introduced on the surface of the dendrimer and the resulting dendrimeric material was active as a reusable catalyst in the oxidation of benzylic alcohol to benzaldehyde.

11.4

Catalysis with Insoluble Dendrimers

Another approach for the heterogenization of a dendrimeric catalyst consisted of the crosslinking of soluble homogeneous dendrimers. This approach was introduced by D. Seebach and coworkers, who prepared dendrimerically substituted TADDOLs with peripheral styryl groups and then copolymerized them with styrene to obtain dendrimerically crosslinked TADDOL ligands; therefore, loading with Ti complexes has led to dendrimeric polymer beads incorporating Ti–TADDOLate centers (Figure 11.18).65–67 Enantioselective catalytic efficiency of these dendrimerically crosslinked catalysts was similar to that of the homogeneous monomeric analogs in the addition of diethylzinc to aldehyde. The activity of the dendrimerically crosslinked Ti–TADDOLs was compared favorably to that of the dendrimerically substituted Ti–TADDOLs (no crosslinking with polystyrene). Some comparisons have also been made with catalytic systems obtained from “linear” crosslinked TADDOL ligands; these systems were found to be less efficient in terms of activity and selectivity. Immobilization of 1,1′-bi-2-naphthol (BINOL) by crosslinking copolymerization of styryl end-capped dendrimerically substituted BINOL with styrene was also considered; Ti and Al Lewis acid mediated additions of diethylzinc and trimethylsilylcyanide to aldehydes and of diphenyl nitrone to enol ether were studied, showing good performances over

Figure 11.18 Dendrimerically crosslinked Ti–TADDOLate catalyst Ti–Dcl–G1–TADDOL65–67

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Figure 11.19 Polymer immobilization of bis(oxazoline) ligands using dendrimers as crosslinkers70

many catalytic cycles (the activity was comparable with those of soluble analogs and remained constant after many recycling processes).68 In a similar way, dendrimerically substituted Salens with peripheral styryl groups were copolymerized with styrene; the corresponding manganese and chromium complexes were used in enantioselective epoxidations and hetero-Diels–Alder reactions.69 The presence of the dendrimeric groups enabled isolation of the catalyst center and reduced steric congestion at the catalytic site, leading to significantly improved enantioselectivities for the catalyst. Bis(oxazoline) ligands were also immobilized on polymer using dendrimeric species as crosslinkers (Figure 11.19) to produce efficient copper catalysts for cyclopropanation reactions: the use of dendrimers as crosslinkers has allowed a better copper functionalization of the polymer and accessibility of the catalytic centers.70 A new strategy was proposed by S. P. Kato and coworkers in order to prepare palladium nanoparticles captured in microporous polymers; they functionalized first the surface of PAMAM dendrimers with a methacrylate function, mixed the dendrimer with Pd(OAc)2, and then copolymerized the dendrimer with ethylene glycol dimethacrylate in polymerization-induced phase separation conditions (Figure 11.20).71 Palladium nanoparticles were formed during the copolymerization process without any additional reducing reagent. These palladium nanoparticles containing microporous polymers have shown excellent catalytic performances for the Suzuki cross-coupling reaction in water: very high TONs were obtained and recyclability was demonstrated up to eight times without significant loss of activity. For palladium nanoparticles containing microporous polymers prepared without dendrimers, Pd agglomeration took place during the catalytic experiment and therefore recycling is less efficient (a gradual decrease in the catalytic activity). In their approach to heterogeneous dendrimeric catalysts, T. D. Tilley and coworkers have considered dendrimers as nanoscopic building blocks to prepare high surface area dendrimer-based xerogels and used them as catalyst supports.72,73 The synthetic process involved carbosilane dendrimers decorated with trialcoxysilyl terminal groups and their

Heterogeneous Catalysis with Dendrimers

Figure 11.20 dendrimers71

259

Pd nanoparticles encapsulated in microporous polymers using PAMAM

subsequent incorporation in a porous network via the sol-gel process. Treatment with titanium complexes has afforded active dendrimeric catalytic materials for the epoxidation of olefins with no metal leaching from the gel; compared to the industrially used Shell catalyst (a titanium-based catalyst with silica as the support), a higher yield and selectivity were obtained. The sol-gel process was also applied to produce mesoporous titanosilicate and vanadosilicate oxidation catalysts using PAMAM dendrimers as templating agents.74 In a similar way, PAMAM dendrimers act as the template for the synthesis of the mesoporous ZnWO4 photocatalyst.75 Dendrimers have been also used as the template for encapsulating an enzyme within silica nanoparticles; water-soluble PAMAM dendrimers were mixed with the enzyme (nitrilase) and then catalysed the condensation of Si(OH)4 to produce the immobilized biocatalyst with a catalytic activity similar to the free enzyme.76 They have been used in the synthesis of nicotinic acid starting from 3-cyanopyridine. Ten consecutive experiments were reported, centrifugation being used to recover the catalyst. A quite different strategy was proposed by M. T. Reetz and coworkers, who prepared crosslinked scandium-containing dendrimers, the crosslinking of the individual dendrimer unit being promoted by scandium itself; the Lewis acid properties of these catalytic materials was successfully involved in the Mukaiyama aldol reaction, the Diels–Alder reaction, and the Friedel–Crafts reaction (Figure 11.21).77 These stable, effective, and environmentally benign heterogeneous catalysts can be handled in air, applied in aqueous or organic medium, and are easily recycled and reused without any appreciable loss of catalytic activity. One of the key factors governing the good catalytic activity was the swelling of the material that allows the efficient transport of reaction components into the inner part of the solid catalyst.

Dendrimers

260

Figure 11.21 Dendrimerically crosslinked scandium-based heterogeneous catalyst77

11.5

Conclusion

Different approaches have been developed to prepare supported or/and heterogeneous dendrimeric catalysts. Concerning the supported ones, silica and polymers (or copolymers or resins) were first considered and remained the most used; nevertheless, some new supports have emerged as carbon nanotubes or magnetic nanoparticles. The nature of the supports has a great influence on the catalytic performance of the heterogeneous catalyst, and therefore their choice has to be pertinent to obtain an efficient grafting allowing the active catalytic species to be in the best environment as possible: specific surface, pore volume, and chemical functionality have to be well controlled. This fine tuning of the catalyst–support interface has also to be completed by catalytic reaction mechanism considerations. Up to now, even if some negative results have been obtained, the grafting of dendrimeric catalytic systems on to solid supports has afforded heterogeneous catalysts showing high activity and stability: in many cases the activity was comparable to the

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equivalent monomeric homogeneous systems and even better in some cases. The recyclability of the catalyst has been demonstrated to be up to 20 cycles in some cases. Some of these heterogeneous systems have been used in aqueous media. While activity was preserved, selectivity and even enantioselectivity have been increased in numerous examples, in particular when heterogeneous dendrimeric catalysts were prepared via the use of dendrimers as crosslinkers or template agents. Cooperativity phenomena have also to be considered to explain some results. Not only was organometallic catalysis (including nanoparticles) concerned with the heterogenization process but also organocatalysis and biocatalysis. The examples presented here tend to support the fact that it is possible to overcome the problems associated with the poor compatibility between the solid phase (catalyst) and the liquid phase (reactants) in order to obtain high reactivities in heterogeneous conditions.

References (1) S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer, and S. J. Taylor (2000) Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation. J. Chem. Soc. Perkin Trans. 1, 3815–4195. (2) Q. H. Fan, Y. M. Li, and A. S. C. Chan (2002) Recoverable catalysts for asymmetric organic synthesis, Chem. Rev., 102, 3385–3465. (3) A. S. H. King and L. J. Twyman (2002) Heterogeneous and solid supported dendrimer catalysts. J. Chem. Soc. Perkin Trans. 1, 2209–2218. (4) A. Dahan and M. Portnoy (2005) Dendrons and dendritic catalysts immobilized on solid support: synthesis and dendritic effects in catalysis. J. Polym. Sci., Part A: Polym. Chem., 43, 235–262. (5) T. Kehat, K. Goren, and M. Portnoy (2007) Dendrons on insoluble supports: synthesis and applications. New J. Chem., 31, 1218–1242. (6) S. C. Bourque, F. Maltais, W. J. Xiao, O. Tardif, H. Alper, P. Arya, and L. E. Manzer (1999) Hydroformylation reactions with rhodium-complexed dendrimers on silica. J. Am. Chem. Soc., 121, 3035–3038. (7) S. C. Bourque, H. Alper, L. E. Manzer, and P. Arya (2000) Hydroformylation reactions using recyclable rhodium-complexed dendrimers on silica. J. Am. Chem. Soc., 122, 956–957. (8) S. Antebi, P. Arya, L. E. Manzer, and H. Alper (2002) Carbonylation reactions of iodoarenes with PAMAM dendrimer–palladium catalysts immobilized on silica, J. Org. Chem., 67, 6623–6631. (9) S. M. Lu and H. Alper (2005) Intramolecular carbonylation reactions with recyclable palladiumcomplexed dendrimers on silica: synthesis of oxygen, nitrogen, or sulfur-containing medium ring fused heterocycles, J. Am. Chem. Soc., 127, 14776–14784. (10) S. M. Lu and H. Alper (2008) Sequence of intramolecular carbonylation and asymmetric hydrogenation reactions: highly regio- and enantioselective synthesis of medium ring tricyclic lactams. J. Am. Chem. Soc., 130, 6451–6455. (11) S. M. Lu and H. Alper (2007) Synthesis of large ring macrocycles (12–18) by recyclable palladium-complexed dendrimers on silica gel catalyzed intramolecular cyclocarbonylation reactions. Chem. Eur. J., 13, 5908–5916. (12) J. P. K. Reynhardt and H. Alper (2003) Hydroesterification reactions with palladium-complexed PAMAM dendrimers immobilized on silica. J. Org. Chem., 68, 8353–8360. (13) R. Touzani and H. Alper (2005) PAMAM dendrimer–palladium complex catalyzed synthesis of five-, six- or seven membered ring lactones and lactams by cyclocarbonylation methodology. J. Mol. Catal. A – Chem., 227, 197–207.

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(14) R. Chanthateyanonth and H. Alper (2004) Recyclable tridentate stable palladium(II) PCP-type catalysts supported on silica for the selective synthesis of lactones. Adv. Synth. Catal., 346, 1375–1384. (15) H. Alper, P. Arya, S. C. Bourque, G. R. Jefferson, and L. E. Manzer (2000) Heck reaction using palladium complexed to dendrimers on silica. Can. J. Chem., 78, 920–924. (16) P. P. Zweni and H. Alper (2006) Silica-supported dendrimer–palladium complex-catalyzed selective hydrogenation of dienes to monoolefins. Adv. Synth. Catal., 348, 725–731. (17) P. P. Zweni and H. Alper (2004) Dendrimer–palladium complex catalyzed oxidation of terminal alkenes to methyl ketones. Adv. Synth. Catal., 346, 849–854. (18) J. Bu, Z. M. A. Judeh, C. B. Ching, and S. Kawi (2003) Epoxidation of olefins catalyzed by Mn(II) salen complex anchored on PAMAM–SiO2 dendrimer. Catal. Lett., 85, 183–187. (19) Y. M. Chung and H. K. Rhee (2002) Dendritic chiral auxiliaries on silica: a new heterogeneous catalyst for enantioselective addition of diethylzinc to benzaldehyde. Chem. Commun., 238–239. (20) J. P. K. Reynhardt, Y. Yang, A. Sayari, and H. Alper (2004) Periodic mesoporous silica-supported recyclable rhodium-complexed dendrimer catalysts. Chem. Mater., 16, 4095–4102. (21) J. P. K. Reynhardt, Y. Yang, A. Sayari, and H. Alper (2005) Rhodium complexed C-2-PAMAM dendrimers supported on large pore Davisil silica as catalysts for the hydroformylation of olefins. Adv. Synth. Catal., 347, 1379–1388. (22) P. Li and S. Kawi (2008) SBA-15-based polyamidoamine dendrimer tethered Wilkinson’s rhodium complex for hydroformylation of styrene. J. Catal., 257, 23–31. (23) P. Li and S. Kawi (2008) Dendritic SBA-15 supported Wilkinson’s catalyst for hydroformylation of styrene. Catal. Today, 131, 61–69. (24) Q. Wang, V. V. Guerrero, A. Ghosh, S. Yeu, J. D. Lunn, and D. F. Shantz (2010) Catalytic properties of dendron–OMS hybrids. J. Catal., 269, 15–25. (25) M. P. Kapoor, Y. Kasama, T. Yokoyama, M. Yanagi, S. Inagaki, H. Nanbu, and L. R. Juneja (2006) Functionalized mesoporous dendritic silica hybrids as base catalysts with volatile organic compound elimination ability. J. Mater. Chem., 16, 4714–4722. (26) M. P. Kapoor, H. Kuroda, M. Yanagi, H. Nanbu, and L. R. Juneja (2009) Catalysis by mesoporous dendrimers. Top. Catal., 52, 634–642. (27) Y. J. Jiang and Q. M. Gao (2006) Heterogeneous hydrogenation catalyses over recyclable Pd(0) nanoparticle catalysts stabilized by PAMAM-SBA-15 organic–inorganic hybrid composites. J. Am. Chem. Soc., 128, 716–717. (28) R. Abu-Reziq, H. Alper, D. S. Wang, and M. L. Post (2006) Metal supported on dendronized magnetic nanoparticles: highly selective hydroformylation catalysts. J. Am. Chem. Soc., 128, 5279–5282. (29) P. Li, W. Thitsartarn, and S. Kawi (2009) Highly active and selective nanoalumina-supported Wilkinson’s catalysts for hydroformylation of styrene. Ind. Eng. Chem. Res., 48, 1824–1830. (30) P. Arya, N. V. Rao, J. Singkhonrat, H. Alper, S. C. Bourque, and L. E. Manzer (2000) A divergent, solid-phase approach to dendritic ligands on beads. Heterogeneous catalysis for hydroformylation reactions. J. Org. Chem., 65, 1881–1885. (31) P. Arya, G. Panda, N. V. Rao, H. Alper, S. C. Bourque, and L. E. Manzer (2001) Solid-phase catalysis: a biomimetic approach toward ligands on dendritic arms to explore recyclable hydroformylation reactions. J. Am. Chem. Soc., 123, 2889–2890. (32) S. M. Lu and H. Alper (2003) Hydroformylation reactions with recyclable rhodium-complexed dendrimers on a resin. J. Am. Chem. Soc., 125, 13126–13131. (33) S. M. Lu and H. Alper (2004) Carbonylative ring expansion of Aziridines to beta-lactams with rhodium-complexed dendrimers on a resin. J. Org. Chem., 69, 3558–3561. (34) A. Dahan and M. Portnoy (2002) Dendritic effect in polymer-supported catalysis of the intramolecular Pauson–Khand reaction. Chem. Commun., 2700–2701. (35) A. Dahan and M. Portnoy (2003) Remarkable dendritic effect in the polymer-supported catalysis of the Heck arylation of olefins. Org. Lett., 5, 1197–1200. (36) A. Dahan and M. Portnoy (2007) Pd catalysis on dendronized solid support: generation effects and the influence of the backbone structure. J. Am. Chem. Soc., 129, 5860–5869.

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(37) A. Mansour, T. Kehat, and M. Portnoy (2008) Dendritic effects in catalysis by Pd complexes of bidentate phosphines on a dendronized support: Heck vs. carbonylation reactions. Org. Biomol. Chem., 6, 3382–3387. (38) G. R. Krishnan and K. Sreekumar (2009) Polystyrene-supported poly(amidoamine) dendrimermanganese complex: synthesis, characterization and catalysis. Appl. Catal. A: Gen., 353, 80–86. (39) C. L. Li, Z. W. Yang, S. Wu, and Z. Q. Lei (2007) Chloromethyl polystyrene supported dendritic Sn complexes, preparation and catalytic Baeyer–Villiger oxidation. React. Funct. Polym., 67, 53–59. (40) Z. Guo, H. Feng, H. C. Ma, Q. X. Kang, and Z. W. Yang (2004) Hydrogenation of fivemembered heterocycles of polymer-supported palladium catalyst at normal temperature and pressure. Polym. Adv. Technol., 15, 100–104. (41) P. Goyal, X. Zheng, and M. Weck (2008) Enhanced cooperativity in hydrolytic kinetic resolution of epoxides using poly(styrene) resin-supported dendronized Co-(salen) catalysts. Adv. Synth. Catal., 350, 1816–1822. (42) R. Breinbauer and E. N. Jacobsen (2000) Cooperative asymmetric catalysis with dendrimeric[Co(salen)] complexes. Angew. Chem. Int. Ed., 39, 3604–3607. (43) M. Beigi, S. Roller, R. Haag, and A. Liese (2008) Polyglycerol-supported Co- and Mn-salen complexes as efficient and recyclable homogeneous catalysts for the hydrolytic kinetic resolution of terminal epoxides and asymmetric olefin epoxidation. Eur. J. Org. Chem., 2135–2141. (44) T. Kehat and M. Portnoy (2007) Polymer-supported proline-decorated dendrons: dendritic effect in asymmetric aldol reaction. Chem. Commun., 2823–2825. (45) K. Goren, T. Kehat, and M. Portnoy (2009) Elucidation of architectural requirements from a spacer in supported proline-based catalysts of enantioselective aldol reaction. Adv. Synth. Catal., 351, 59–65. (46) L. Tuchman-Shukron and M. Portnoy (2009) Polymer-supported highly enantioselective catalyst for nitro-Michael addition: tuning through variation of the number of H-bond donors and spacer length. Adv. Synth. Catal., 351, 541–546. (47) K. Goren and M. Portnoy (2010) Supported N-alkylimidazole-decorated dendrons as heterogeneous catalysts for the Baylis–Hillman reaction. Chem. Commun., 46, 1965–1967. (48) G. R. Krishnan and K. Sreekumar (2008) First example of organocatalysis by polystyrenesupported PAMAM dendrimers: highly efficient and reusable catalyst for Knoevenagel condensations. Eur. J. Org. Chem., 4763–4768. (49) G. R. Krishnan and K. Sreekumar (2008) Ring opening of epoxides catalysed by poly(amidoamine) dendrimer supported on crosslinked polystyrene. Polymer, 49, 5233–5240. (50) A. Clouet, T. Darbre, and J. L. Reymond (2004) A combinatorial approach to catalytic peptide dendrimers. Angew. Chem. Int. Ed., 43, 4612–4615. (51) A. Clouet, T. Darbre, and J. L. Reymond (2006) Combinatorial synthesis, selection, and properties of esterase peptide dendrimers. Biopolymers, 84, 114–123. (52) J. Kofoed, T. Darbre, and J. L. Reymond (2006) Artificial aldolases from peptide dendrimer combinatorial libraries. Org. Biomol. Chem., 4, 3268–3281. (53) G. Zaupa, L. J. Prins, and P. Scrimin (2009) Resin-supported catalytic dendrimers as multivalent artificial metallonucleases. Bioorg. Med. Chem. Lett., 19, 3816–3820. (54) Y. M. Chung and H. K. Rhee (2002) Design of silica-supported dendritic chiral catalysts for the improvement of enantio selective addition of diethylzinc to benzaldehyde. Catal. Lett., 82, 249–253. (55) D. Astruc, F. Lu, and J. R. Aranzaes (2005) Nanoparticles as recyclable catalysts: the frontier between homogeneous and heterogeneous catalysis. Angew. Chem. Int. Ed., 44, 7852–7872. (56) W. Huang, J. N. Kuhn, C. K. Tsung, Y. Zhang, S. E. Habas, P. Yang, and G. A. Somorjai (2008) Dendrimer templated synthesis of one nanometer Rh and Pt particles supported on mesoporous silica: Catalytic activity for ethylene and pyrrole hydrogenation. Nano Lett., 8, 2027–2034.

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(57) G. Vijayaraghavan and K. J. Stevenson (2007) Synergistic assembly of dendrimer-templated platinum catalysts on nitrogen-doped carbon nanotube electrodes for oxygen reduction. Langmuir, 23, 5279–5282. (58) Y. Shen, Q. Xu, H. Gao, and N. N. Zhu (2009) Dendrimer-encapsulated Pd nanoparticles anchored on carbon nanotubes for electro-catalytic hydrazine oxidation. Electrochem. Commun., 11, 1329–1332. (59) H. F. Lang, R. A. May, B. L. Iversen, and B. D. Chandler (2003) Dendrimer-encapsulated nanoparticle precursors to supported platinum catalysts. J. Am. Chem. Soc., 125, 14832–14836. (60) L. Sun and R. M. Crooks (2002) Dendrimer-mediated immobilization of catalytic nanoparticles on flat, solid supports. Langmuir, 18, 8231–8236. (61) G. Jayamurugan, C. P. Umesh and N. Jayaraman (2009) Preparation and catalytic studies of palladium nanoparticles stabilized by dendritic phosphine ligand-functionalized silica. J. Mol. Catal. A: Chem., 307, 142–148. (62) E. Murugan and R. Rangasamy (2010) Synthesis, characterization, and heterogeneous catalysis of polymer-supported poly(propyleneimine) dendrimer stabilized gold nanoparticle catalyst. J. Polym. Sci. Part A: Polym. Chem., 48, 2525–2532. (63) D. Rosario-Amorin, X. Wang, M. Gaboyard, R. Clerac, S. Nlate, and K. Heuze (2009) Dendron-functionalized core–shell superparamagnetic nanoparticles: magnetically recoverable and reusable catalysts for Suzuki C–C cross-coupling reactions. Chem. Eur. J., 15, 12636–12643. (64) J. P. Lindner, C. Roben, A. Studer, M. Stasiak, R. Ronge, A. Greiner, and H. J. Wendorff (2009) Reusable catalysts based on dendrimers trapped in poly(p-xylylene) nanotubes. Angew. Chem. Int. Ed., 48, 8874–8877. (65) P. B. Rheiner, H. Sellner, and D. Seebach (1997) Dendritic styryl TADDOLs as novel polymer cross-linkers: first application in an enantioselective Et2Zn addition mediated by a polymerincorporated titanate. Helv. Chim. Acta, 80, 2027–2032. (66) H. Sellner and D. Seebach (1999) Dendritically cross-linking chiral ligands: high stability of a polystyrene-bound Ti–TADDOLate catalyst with diffusion control. Angew. Chem. Int. Ed., 38, 1918–1920. (67) H. Sellner, P. B. Rheiner, and D. Seebach (2002) Preparation of polystyrene beads with dendritically embedded TADDOL and use in enantioselective Lewis acid catalysis. Helv. Chim. Acta, 85, 352–387. (68) H. Sellner, C. Faber, P. B. Rheiner, and D. Seebach (2000) Immobilization of BINOL by crosslinking copolymerization of styryl derivatives with styrene, and applications in enantioselective Ti and Al Lewis acid mediated additions of Et2Zn and Me3SiCN to aldehydes and of diphenyl nitrone to enol ethers. Chem. Eur. J., 6, 3692–3705. (69) H. Sellner, J. K. Karjalainen, and D. Seebach (2001) Preparation of dendritic and non-dendritic styryl-substituted salens for cross-linking suspension copolymerization with styrene and multiple use of the corresponding Mn and Cr complexes in enantioselective epoxidations and hetero-Diels–Alder reactions. Chem. Eur. J., 7, 2873–2887. (70) E. Diez-Barra, J. M. Fraile, J. I. Garcia, E. Garcia-Verdugo, C. I. Herrerias, S. V. Luis, J. A. Mayoral, P. Sanchez-Verdu, and J. Tolosa (2003) Polymer immobilization of bis(oxazoline) ligands using dendrimers as cross-linkers. Tetrahedron Asymm., 14, 773–778. (71) S. Ogasawara and S. Kato (2010) Palladium nanoparticles captured in microporous polymers: a tailor-made catalyst for heterogeneous carbon cross-coupling reactions. J. Am. Chem. Soc., 132, 4608–4613. (72) J. W. Kriesel and T. D. Tilley (2000) Synthesis and chemical functionalization of high surface area dendrimer-based xerogels and their use as new catalyst supports. Chem. Mater., 12, 1171–1179. (73) J. W. Kriesel and T. D. Tilley (2001) Carbosilane dendrimers as nanoscopic building blocks for hybrid organic–inorganic materials and catalyst supports. Adv. Mater., 13, 1645–1648. (74) M. C. Rogers, B. Adisa, and D. A. Bruce (2004) Synthesis and characterization of dendrimertemplated mesoporous oxidation catalysts. Catal. Lett., 98, 29–36.

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Part 3 Applications for the Elaboration or Modifications of Materials

12 Dendrimers inside Materials Régis Laurent* and Anne-Marie Caminade

12.1

Introduction

The development of nanomaterials is one of the major challenges for this new century with an increasing demand for nanosized molecules to be used in a bottom-up approach. Dendrimers have been considered as one of the most promising molecular objects to elaborate nanostructured materials; then inclusion of dendrimers inside materials was developed. More generally, encapsulation of the dendrimers occurs during the elaboration of the material; this was the case for gels (organogels or hydrogels), generally obtained by tridimensional self-assembly of dendrimers in solution. Numerous reports also concern the inclusion of dendrimers inside silica gels (often highly porous silica), generally obtained by a sol-gel process. Other examples of inclusion of dendrimers in various materials such as titanium or cerium alkoxides, as well as their inclusion inside polymers, were reported to modify the properties of the materials. Finally, an emerging use of dendrimers included in materials concerns the elaboration of organic light-emitting diodes (OLEDs), which emit light in various colors, depending on the dendrimer used. Hybrid materials synthesized by the grafting of preformed dendrimers on a solid support or by the stepwise growth of dendrimeric wedges from a solid support will not be discussed here. Uses of such materials can be found in Chapter 11 for catalysis, in Chapter 13, and Chapters 14 and 15 for sensors. * Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Dendrimers

Dendrimers for the Elaboration of Gels

Molecular self-assembly of carefully designed building blocks has become an essential methodology for the preparation of nanostructured materials and, over the last few decades, low-molecular-weight hydrogels1 and organogels2,3 have attracted much research interest. These gel materials are generally composed of a three-dimensional network and can immobilize the organic solvents, referred to as an organogel, or water, referred to as a hydrogel. In these gel materials, small molecules self-assemble into organized nanostructures through intra- and/or intermolecular noncovalent interactions such as van der Waals interactions, hydrogen bonds, and π–π stacking; they can be referred to as supramolecular gels. The ability of dendrimer-derived structures to form supramolecular gels, hydrogels, or organogels, was recently recognized by several groups. Different strategies were developed using dendrimers alone or in combination with a second partner.4,5 Nevertheless, although this way of preparation of hydrogels is attractive, the classical way involves a crosslinking process with polymers and/or small molecules.6 Dendrimeric species have also been involved in this kind of process to produce hydrogels, where polymer-type gels were obtained. 12.2.1

Dendrimers for the Elaboration of Supramolecular Hydrogels

The first example of supramolecular hydrogel was reported by G. R. Newkome and coworkers.7 They prepared bola-formed bisarborols characterized by a flexible lipophilic apolar chain functionalized on both ends with hydrophilic alcohol groups endcapped dendrimeric arborol species (Figure 12.1); these bola-amphiphiles acted as hydrogelators. The self-assembly process was governed by the hydrophobicity and the flexibility of the spacer together with the hydrogen bonding ability of the alcohol peripheral groups. The influence of the arborol linker and size of arborols on the water gelification process was studied later.8,9 This strategy was used by M. Jørgensen and coworkers who introduced a tetrathiafulvalene unit inside the arborol linker to prepare electroactive materials;10 the group of M. R. Bryce has also tried to develop such materials.11 Alcohol end-capped dendrons synthesized by G. J. Boons and coworkers through the introduction of melibiose hemithioacetal have also shown hydrogelation properties; for

Figure 12.1

Bola-amphiphile water gelators7

Dendrimers inside Materials

Figure 12.2

Figure 12.3

271

Ambidextrous gelators of water and organic solvents13

Phosphorus-containing dendrimeric hydrogelators14

these glycodendrons the influence of the branch length on the hydrogelation behavior was studied.12 L-Glutamate-based dendrons containing aromatic cores (phenyl, naphthyl, anthryl) prepared by M. H. Liu and coworkers have demonstrated their ability to selfassemble in water, leading to hydrogels; the same dendrons have also formed organogels with hexane, exhibiting ambidextrous gelation properties (Figure 12.2).13 Hydrogen bonds between the amide functions and π–π stacking were proposed to explain this behavior. When naphthyl or anthryl groups were located at the core of the dendron, fluorescence emission was obtained for the gels with a greater intensity than for the corresponding compounds in solution. Moreover, a thermally driven chiroptical switch has been reported using the gels and the ability to obtain, as a result of the self-assembly, molecular chirality transfer of L-glutamate to the chromophore. A. M. Caminade, J. P. Majoral, and coworkers have reported the ability of polycationic phosphorus-containing dendrimers to act as a hydrogelator.14 These dendrimers were synthesized from aldehyde end-capped dendrimers by condensation of Girard T or P reagents, leading to ammonium or pyridinium end-capped dendrimers, respectively (Figure 12.3). Hydrogels were obtained by a prolonged heating (several hours to several weeks at 65 °C) of an aqueous solution of polycationic dendrimers (1.8%). These hydrogels are rigid, they do not flow, and they can even be crushed into pieces. Freeze-fracture electron microscopy of the gels has shown fragments of chains made of dendrimers, imprisoning large pockets of water. The dendrimer network was due to supramolecular interactions between the end groups of the dendrimers: hydrogen bonds, π–π stacking, and hydrophilic/hydrophobic interactions can occur, since these phosphorus dendrimers have a hydrophobic interior and a

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hydrophilic surface. Freeze-drying of the gels affording aerogel was reported. Remarkably, the gelation time was dramatically shortened in the presence of hydrosoluble components such as buffer (TRIS, tris(hydroxymethyl)aminomethane), metal salts (Ni, Y, Er acetates), acids (citric, ascorbic, lactic, l-tartric), dithioerythritol (DTE), and sodium salt of ethylenediaminetetraacetate (EDTA); these gels were able to encapsulate large amounts of these substances, up to 30% in weight for nickel acetate. Therefore these gels have been proposed to be used for the controlled delivery of active substances. Later it was demonstrated that the addition of salt to aqueous solutions of polycationic dendrimers could induce their self-assembly to produce thermoreversible hydrogels under controlled conditions (salt and dendrimer concentration); the cohesion forces in this case were less strong than in the previous case, illustrating a change in the self-assembly process induced by the addition of salts.15 The formation by flocculation under the flow of macroscopic fibers, characterized by microscopic fibrillar substructures, was also reported.15 Hydrogels developed by the group of K. Kono were also proposed to be used for drug delivery.16 They used a fourth generation PAMAM dendrimer and a collagen model peptide, (Pro–Pro–Gly)5, to produce a collagen-mimic dendrimer. Collagen, the most abundant protein in mammals, has classically been used as a biomaterial, in particular collagen gels are useful for long-term slow-release drug delivery applications. However, as the release from collagen gels is generally uncontrollable, functional collagen materials are desired. A thermally reversible formation of collagen-like triple helix was demonstrated for the collagen-mimic dendrimer and attributed to the clustering of the collagen peptide at the surface of the dendrimer; it was also shown that this dendrimer could act as a thermosensitive drug carrier. Hydrogel was formed by cooling an aqueous solution of the collagen-mimic dendrimer, which melted at 35 °C; then it could be used as a potential cellular matrix for controllable drug release. Self-assembly of larger sized systems was also studied; dendrimeric-lineardendrimeric triblock copolymers were used to obtained thermoreversible hydrogels.17 Poly(ethyleneglycol) was considered as a core material and decorated with carboxylic acid end-capped polyester dendrimeric wedges (first and second generations) (Figure 12.4). Encapsulation of small molecules was reported and potential use as drug delivery systems proposed.18 The same group has reported other dendrimeric–linear–dendrimeric triblock copolymers for which no hydrogels were obtained; poly(ethyleneglycol) was still considered as the linear component, but with silicon-based dendrimeric species.19

Figure 12.4

Dendrimeric–linear–dendrimeric copolymer water gelator17,18

Dendrimers inside Materials

Figure 12.5

273

Polymer–dendrimeric copolymer water gelator20,21

S. I. Stupp and coworkers have considered polymer–dendrimeric diblock copolymer constituted of polylactic acid mono end-functionalized with cholesteryl unit and L-lysine dendron and observed the formation of lamellar structures for the hydrated species (Figure 12.5).20,21 12.2.2

Dendrimers for the Elaboration of Polymer-Type Hydrogels

The strategy here is to use dendrimers (or dendrons) as multivalent crosslinking units to obtain three-dimensional networks. The most representative examples were given by M. W. Grinstaff and coworkers; their first strategy was to carry out photo-crosslinking reactions on a poly(glycerol-succinic acid) dendrimers with acrylate groups on the surface (Figure 12.6).22 Upon exposure to visible light in the presence of a photoinitiating system (eosin Y, 1-vinyl-pyrrolidinone, triethanol amine), aqueous solution of the dendrimers crosslinked to produce hydrogel; photolysis using an argon ion laser was considered to promote the radical free polymerization of the methacrylate moieties on the surface. The same process was carried out with dendrimeric–linear–dendrimeric triblock copolymers built using poly(ethyleneglycol) (Figure 12.6).23 The hydrogels obtained have been involved in ophthalmic applications mainly as an adhesive to replace or supplement suture in the repair of corneal wounds (see also Chapter 20).24 In this domain the second strategy developed does not require light for the crosslinking process, which is of interest for clinicians. They have developed a peptide ligation approach: lysine-based dendrons with cysteine end groups (second generation) were made to react with poly(ethyleneglycol) dialdehyde affording a three-dimensional network through the formation of thiazoline linkage (Figure 12.7).25 These two components were mixed at room temperature and then applied to an incision. The crosslinked hydrogel adhesive is transparent, adhesive, elastic, hydrophilic, and can be considered as a physical protective barrier to the ocular surface.26 Using photochemical or chemical ligation crosslinking of dendrimeric macromolecules, hydrogel sealants were formed and used to repair corneal laceration and perforation, seal cataract incision, secure a corneal transplant, and close LASIK (laser assisted in situ keratomileusis) flaps.27,28

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Figure 12.6 Second generation poly(glycerol-succinic acid) dendrimers and hydrogel formation via photo-crosslinking22,23

The same group has considered the photo-crosslinkable dendrimeric–linear–dendrimeric triblock copolymer as cartilage tissue repair.29 They have encapsulated chondrocytes inside hydrogel during the crosslinkage process and observed cartilaginous extracellular matrix production. The use of dendrimeric species with multivalent branched structure was of benefit to enable the production of high crosslink densities, even for low concentrations; consequently high mechanical strength (with low swelling after the crosslinking process) and high water content required for cartilage repair were obtained. The introduction of carbamate functions in the dendrimeric parts of the crosslinkable dendrimeric–linear– dendrimeric triblock copolymer has lead to new hydrogels with compressive stiffness and viscoelasticity comparable to those of native articular cartilage. The carbamate-linked dendrimeric system was injected in an osteochondral defect and, upon photo-crosslinking, the hydrogel formed to fit the size and the shape of the defect and remain fixed in the defect.30 Other types of dendrimer-based hydrogels have been proposed for tissue engineering. H. Yang and coworkers have functionalized PAMAM dendrimers (third generation) with

Dendrimers inside Materials

Figure 12.7

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Hydrogel formation via peptide ligation25

PEG chains and acrylate groups: amine or carboxylic acid end groups were considered.31 Photo-crosslinkage in the presence of a photoinitiator led to hydrogels; it was shown that the hydrogel formation was dependent on the PEG chain length, the degree of PEGylation, and the distribution of acrylate groups on the dendrimer surface. Acrylate groups were also introduced in a surface of a hyperbranched poly(amine-ester) to induce crosslinkage via radical polymerization and consequently hydrogel was obtained; their uses as multidrug delivery systems were proposed.32 H. Sheardown and coworkers have proposed the use of PPI dendrimers as crosslinkers for the preparation of collagen hydrogel; a second generation PPI dendrimer with eight amino groups on the surface was reacted with glutamic and aspartic acid residues on the collagen in the presence of a water-soluble carbodiimide compound.33 Optical transparency was obtained for these collagen gels, which were also mechanically stronger and more biocompatible than those obtained with conventional linkers such as glutaraldehyde. Potential applications for tissue engineering were therefore envisaged.34 Considering the great importance of PEG polymers to obtain hydrogels via association of PEG chains, different types of dendrimeric species were used as crosslinkers for these PEG chains: hydrogels obtained by Grinstaff with polylysine dendrons are a representative example.25 PAMAM dendrimers have also acted as crosslinkers for PEG diepoxide: zeroth, second, and fourth generation PAMAM dendrimers were considered and it was shown that the ratio of dendrimer end groups to the linear precursor end group was the most significant parameter governing the equilibrium swelling in water.35 Highly branched poly(ethyleneimine) (PEI) was also considered.36 I. Gitsov and coworkers have prepared

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hydrogels working with PEG diepoxide or PEG diisocyanate and amino group end-capped poly(benzylether) dendrimers (zeroth to third generations).37 The basic nature of the network interior was demonstrated together with the study of the binding and release capabilities of the gel: if the highest binding capacities were obtained with the third generation dendrimers, the fastest release was obtained with the zeroth generation. The use of these gels as a biosensor matrix for histochemical and cytochemical tests was proposed. C. J. Hawker, M. Malkoch, and coworkers have developed the accelerated growth of dendrimers using Thiol-Ene esterification reactions; the UV initiated reaction of PEG dithiol with a third generation allyl end group dendrimer was carried out in THF and after solvent to water exchange a transparent hydrogel was obtained.38 The group of R. Sanyal has proposed the synthesis of functionalizable hydrogels: they have considered a dendrimeric–linear– dendrimeric triblock copolymer composed of linear poly(ethyleneglycol) as the core and an alkyne end-capped poly(ester) dendrimeric species (Figure 12.6).39 Hydrogel was obtained via a [3+2] Huisgen “click” reaction between the dendrimeric–linear–dendrimeric triblock copolymer with PEG diazide. The remaining alkyne groups present in the hydrogel were used in a subsequent [3+2] Huisgen “click” reaction to prepare functionalized hydrogel; dye molecules were introduced as well as streptavidin. Dendrimeric species could be used to crosslink other types of polymers than PEG to prepare hydrogels; for example, a PAMAM dendrimer (sixth generation with amine end groups) was considered as a crosslinker agent for poly(vinyl alcohol) (PVA), leading to PVA hydrogel with higher swelling ratios and a faster reswelling rate due to the hydrophilicity of the PAMAM dendrimer.40 In a quite different strategy, PAMAM dendrimers were used to prepare semiinterpenetrating polymeric mixture with poly(N-isopropylacrylamide) (PNIPA).41 The polymerization of N-isopropylacrylamide (NIPA) was conducted in the presence of a sixth generation PAMAM dendrimer and a temperature-sensitive PAMAM/PNIPA hydrogel was obtained: the responsive properties were increased by the dendrimer introduction. M. Kawa and coworkers have prepared fluorescent hydrogel using NIPA and a terbium-cored poly(benzyl ether) dendrimer functionalized with a vinyl group at the surface level: copolymerization was carried out in DMSO, affording a colorless DMSO gel and, after DMSO/ water exchange, a clear colorless fluorescent hydrogel.42

12.2.3

Dendrimers for the Elaboration of Organogels

The ability of dendrimers to act as gelators for organic solvents was reported for the first time by T. Aida and coworkers; they prepared peptide-core poly(benzyl ether) dendrimers (first to third generations) (Figure 12.8) and observed the gelation process in different organic solvents (CH3CN, CHCl3, CH2Cl2, acetone, ethyl acetate).43 The self-assembly process is induced by hydrogen bonding interactions of the dipeptide core together with interactions between the dendrimeric scaffolds: no gelation occurs with a nondendrimeric dipeptide or the first generation dendrimer. Fine elementary fibrils were formed, which were assembled via van der Waals forces to generate bundles of micrometerscale dendrimeric fibers. Later Aida and coworkers pointed out some requirements to obtain gels for these dendrimers (high generation, ester functionalities on the surface, control of the dendrimeric wedges linkage on the dipeptide core).44 W. D. Jang and cow-

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Figure 12.8 Second and third generation peptide-core poly(benzyl ether) dendrimer organogelators43

Figure 12.9

Photopolymerizable second generation poly(amide) dendron gelator48

orkers reported the formation of liquid crystals gels when long alkyl chains were introduced at the dipeptide core level.45 Poly(benzyl ether) dendrons with dimethyl isophthalate groups on the surface were also able to gel organic solvents.46 In the work of Aida the organogels were formed starting from one component: this strategy has been largely used as, for example, in the case of amphiphilic poly(amide) dendrons and dendrimers with peripheral alkyl tails, which were demonstrated to interact through hydrogen bonding of the amide groups as well as van der Waals interaction between the alkyl tails to form thermoreversible gels in organic solvent (THF, CHCl3).47 A linear analog was not able to form gels. By introducing diacetylene fragments at the level of the peripheral alkyl tails, it was possible to stabilize the supramolecular structures obtained by self-assembly through photopolymerization (Figure 12.9).48

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S. P. Rannard and coworkers have prepared first generation poly(amide) dendrimers and observed an ability to gel organic solvents depending on the surface functionality.49 The group of E. E. Simanek has reported the ability of triazine-based dendrimers to form gels with organic solvents in acidic media.50 In their approach H. F. Chow and coworkers have used α-amino acids to prepare layerblock carboxylic acid or ester-cored dendrons.51 Different α-amino acids were introduced along the synthesis of the dendrons: the nature and the order of introduction of the α-amino acids influenced the gelation properties together with the nature of the focal point. Peptidebased dendrimers were also used to obtain gels: some structural and morphological differences were observed depending on the nature of the core.52 The groups of X. R. Jia, Y. Wei, and coworkers have also used amino acids in the synthesis of dendrimeric gelators: they have prepared poly(glycine-aspartic acid) dendrons (first to third generations) with a Boc-protected amino group at the focal point.53 Both hydrogen bonding and aromatic stacking were proposed to be responsible for the aggregation, which arises in a nonconventional way: addition of a third solvent (AcOEt) on the dendron solution prepared with a solvent mixture (CHCl3/CH3OH). The third generation dendron self-assembles into a ramified network of intertwined fibers; for the first and second generations no gelation process was observed using these conditions. After this first report, the same group has shown that the second generation poly(glycine-aspartic acid) dendron with a Boc-protected amino group at the focal point could afford hydrogel using the conventional method (heating/cooling); moreover, they illustrated the influence of the chemical nature of the group located at the focal point on the gelation properties.54 The second generation dendron with an acrylate group at the focal point was able to gel greater number of solvents and some differences were observed on the structure of the gel. They have also pointed out the influence of the amino acids used for the synthesis: poly(glycine-glutamic acid) dendrons (first to third generations) with a Boc-protected amino group at the focal point were prepared.55 The higher efficiency in gel formation was obtained for the third generation dendron (the first generation being inactive) and the deprotected dendrimeric species failed in the gelation process. Poly(amidoamine) dendrons with butylamide end groups were also reported as organogelators.56 Remarkably, a photoreversible dendrimeric organogel was prepared from a second generation poly(glycine-aspartic acid) dendron with azobenzene moieties located at the focal point level: once the gel was obtained (by a heating/cooling conventional procedure), UV irradiation at 365 nm converted the gel into a clear solution and reformed as gel after exposure of the solution to visible light (Figure 12.10).57

Figure 12.10

Photoisomerizable dendrimeric organogelator57

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Photoresponsive organogel was also obtained using a poly(glycine-aspartic acid) dendron with a p-nitrocinnamate group at the focal point: gel obtained at room temperature was converted to clear solution upon UV irradiation at 365 nm and the gel was reformed upon irradiation at 254 nm.58 Photodimerization of the cinnamate fragment and photocleavage of the dimer was responsible for the photostimuli behavior. A photoresponsive organogel with switchable fluorescence using spiropyran/merocyanine isomerization was reported by G. X. Zhang, Q. H. Fan, and coworkers.59 Organogels with a strong fluorescence emission were obtained with p-terphenylene cored dendrimeric species; they have been prepared starting from poly(benzyl ether) dendron (first to third generations) with carboxylic acid at the focal point, introduction of an amide function by the reaction of bromoaniline, and subsequent association of two dendrons via Suzuki coupling with 1,4-phenyldiboronic acid.60 The cooperative effect of the π–π stacking, hydrogen bonding, and van der Waals forces were proposed to explain the ability of these dendrimeric species to gel different kinds of organic solvents. Moreover, gelation-induced fluorescence enhancement was observed: for the second generation system, the fluorescence intensity was more than 800 times stronger in the gel than in the solution. With a careful design of the dendrimeric systems used, V. Percec and coworkers have obtained organogel displaying thixotropic behavior: twin-dendrimeric species with a weak lateral interaction in the bulk has been privileged.61 The self-assembly of amphiphilic bisdendrimer composed of one long alkyl chain end-capped poly(amide) dendrimeric part and one alcohol end-capped poly(ether) dendrimeric part was reported (Figure 12.11); multiple intermolecular hydrogen bonds between the amide and hydroxyl groups were proposed to be responsible for the organogel formation.62 An asymmetric bisdendrimer constituted of an azobenzene dendrimeric moiety and an aliphatic amide dendrimeric moiety was used as an organogelator with a rapid and reversible gel-sol transition induced by light.63 S. I. Stupp and coworkers have also considered a precise architecture for the dendrimeric organogelators they have developed: dendron rod coils.64 These systems are composed of a flexible (coil) polymer unit attached to a well-defined linear rigid rod unit on which a

Figure 12.11

Amphiphilic bisdendrimer organogelator62

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Dendrimers

dendrimeric fragment is grafted. Spontaneous gelation was reported with the formation of nanoribbons for 2-propanol, for example, but longer times might be necessary; the gelation was reported for extremely dilute solutions (0.2 wt/vol%). To obtain gels, it was shown that the presence of at least four alcohol functions on the dendrimeric species was necessary, higher generation for the dendrimeric species were ineffective, the rigid rod required a sufficient number of biphenyl ester units, and a long coil was necessary.65,66 They have exploited these self-assembled nanostructures as scaffolding for the toughening of polymeric materials,67,68 for the preparation of CdS nanohelices,69 and for the preparation of electroactive materials with the introduction of oligo(thiophene), oligo(phenylenevinylene), or oligo(phenylene) as the rigid unit.70 Nanoribbon-like structures were also obtained via the self-assembly of copolymers composed of dendrimeric species and helical polypeptide.71 H. F. Chow and coworkers have proposed dendronized polymers as organogelators: they prepared dendrons with both azide and an acetylenic group at the level of the focal point and used a “click” Huisgen [3+2] reaction to obtain poly(triazole) decorated with dendrimeric wedges (branched alkyl chains).72 As these dendrimeric species can be linked through an amide or ester connecting unit, it was shown that gelation can be obtained for the system using amide connectivity. Hyperbranched polymers with organogelation properties were also reported.73 All the systems presented until now can be considered as a one-component supramolecular organogelator; D. K. Smith and coworkers have proposed a two-component dendrimeric organogelator composed of carboxylic acid cored peptide-based dendrons and a linear aliphatic diamine.74 The first step in their system was the acid–base interaction between the two components and then the self-assembly process took place to form fibrous gel-phase aggregates. They have proposed a detailed study analysing the effects of different factors on the gelation properties: length of the alkyl chain for the diamine partner and nature of this spacer,75,76 generation of the dendrons partner,77 ratio of the two partners,78 solvent,79 stereochemistry,80 peripheral groups on the dendrimeric species,81 nature of the hydrogen bonding unit,82 and solubility of the partners.83 They have also prepared a one-component organogelator and compared the efficiency of the two strategies; as the one-component organogelators present an additional amide group (introduced for the covalent association of the dendrimeric part and the amine) they have shown better gelation properties and a dendrimeric effect was observed (Figure 12.12).84 Nevertheless, for the two-component organogelators better control of the chiral organization during the fiber formation was obtained. The synthesis of a peptidic dendrimer with a cystamine core was reported and used as a onecomponent organogelator.85 Gold nanoparticles have been prepared within the gel-phase network,86 and when alkene groups were introduced at the surface, a crosslinking process using Grubbs’metathesis reaction has led to robust swellable gels.87

12.3

Dendrimers inside Silica Gels

Nanostructured materials with well-defined and tunable porosities have attracted considerable attention in chemistry and materials science due to their potential applications in several areas (catalysis, optical devices, separations, etc.).88–90 Consequently, the prepara-

Dendrimers inside Materials

Figure 12.12

281

Two-component and one-component dendrimeric organogelators84

tion of hybrid organic–inorganic nanocomposites has exploded during the 1980s with the development of soft inorganic chemistry processes, mainly the sol-gel process, which allows the mixing of organic and inorganic components at the nanometer scale. Silica- and/ or siloxane-based hybrid organic–inorganic materials have been studied considerably, the final materials exhibiting both properties associated with the organic moiety and with the inorganic framework. To obtain nanostructuration, nanoscopic molecular building blocks are desired and dendrimers were considered. Inclusion of any type of dendrimer inside a material during its elaboration is generally carried out to take advantage of the confinement of the functional groups present on the dendrimer, to organize the inorganic component, and to generate nanoporosities (after removal of the dendrimers). One of the first reports describing the insertion of dendrimers inside silica gels was proposed by Y. Chujo and coworkers; they have carried out an acid-catalyzed sol-gel reaction of tetramethoxysilane in the presence of PAMAM dendrimers.91 Only ester end-capped dendrimers were successfully introduced in the silica network with the intention of obtaining transparent and homogeneous polymer hybrids. These hybrids were subjected to pyrolysis at 600 °C to remove the organic dendrimeric part; porous silica materials were obtained (200– 610 m2 g−1). The pore size of the silica materials was shown to correspond to the size of the parent dendrimer used during the synthesis. The same observation was done by G. Larsen and coworkers, who prepared silica hybrid materials with hydrolysis/ polycondensation of tetraethyl-ortho-silicate (TEOS) in the presence of PAMAM or DAB (PPI) dendrimers; removal of the dendrimer template was performed by calcination.92,93 PAMAM dendrimers have been involved in the hydrothermal process to obtain nanoporous silica; a high temperature and long reaction time were needed.94 Even if a somewhat good

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Dendrimers

Figure 12.13 dendrimers96

Organic/inorganic hybrid material via the sol-gel process using carbosilane

control in the pore size of the material was obtained, this approach normally suffers from poor structural control. The functionalization of dendrimers with trialcoxysilyl groups was then developed via a nonhydrolyzable bond to prepare hybrid materials. The first example was proposed by M. J. Michalczyk and coworkers using only a star-shaped monomer.95 Then R. J. P. Corriu and coworkers prepared carbosilane dendrimers (first to second generations) with trimethoxysilane groups on the surface (Figure 12.13); hydrolysis– polycondensation by a sol-gel process has yielded hybrid materials only from the second generation dendrimer.96 Depending on the dendrimer core, porous xerogel materials could be obtained; removal of the dendrimeric framework was not successful with a poor homogeneity of the size of the pores due to the highly flexible skeleton. T. D. Tilley and coworkers used the same approach to prepare xerogels with high surface areas; they used the xerogels as the catalyst support for Ti-catalyzed epoxidation of olefins.97,98 Trimethoxysilyl end-capped PAMAM dendrimers were prepared and involved in a hydrolysis– polycondensation sol-gel process in the presence of tetraethyl-ortho-silicate (TEOS); the SiO2–PAMAM dendrimer hybrid has a compartmentalized structure due to the presence of PAMAM compartments and its stability increases with the increasing amount of inorganic network precursor.99 Copper metal ion complexation was shown to be related to the size of the dendrimer. The group of P. R. Dvornic has developed the synthesis of radially layered copolymeric poly(amidoamine-organosilicon) dendrimers (PAMAMOS dendrimers) with different kinds of alcoxysilane groups on the surface: they have developed their use to obtain nanostructured networks through the sol-gel process.100–102 As some dendrimers also have alkenyl groups on the surface together with the alcoxysilane groups, the sol-gel hydrolysis/ condensation was completed with a free-radical coupling process. They have also shown that the introduction of both the alcoxysilyl groups and polyhedral oligosilsesquioxanes could afford hybrid materials with good film processability.103 The PAMAMOS dendrimer has been used by M. H. Schoenfish and coworkers to develop an optical sensor film suitable for the quantitative detection of nitroxyl.104 Another strategy to incorporate dendrimeric species inside a silica gel material was to introduce the trialcoxysilyl group at the core level of a dendron; it was introduced by A. M. Caminade, J. P. Majoral, C. Reye and coworkers.105 Two types of dendrons were prepared in a divergent way with the triethoxysilyl group at the focal point level (Figure 12.14): whereas the silicon moiety was present in the core molecule used for the first

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283

Figure 12.14 Organic–inorganic hybrid material via the sol-gel process using phosphoruscontaining dendrons105

family, for the second one the silicon moiety was introduced at the last step of the synthesis allowing easy surface functionalization. The sol-gel process was carried out in the presence of TEOS; various sizes of dendrons (first to third generations) possessing various types of end groups were considered. A large variety of dendron-silica xerogels were obtained and some of them were found to be mesoporous with a narrow pore size distribution. R. J. Jeng and coworkers have used this strategy to prepare dendronized organic– inorganic NLO hybrid materials; the triethoxysilyl group was introduced at the focal point of dendron (up to the second generation) having disperse red 1 (DR1) chromophores at the surface.106 Hydrolysis–polycondensation in the presence of phenyltriethoxysilane has produced hybrid materials; thin films with excellent homogeneity, NLO properties, and temporal thermal stability were obtained. A. Kakkar and coworkers have considered alcohol end-capped dendrimers synthesized using 3,5-dihydroxybenzyl alcohol as templates in the construction of hybrid silica networks; reaction of the dendrimers with Si(NMe2)4 followed by hydrolysis and polycondensation has yielded highly crosslinked silica-based materials.107 The dendrimer moieties were subsequently removed by the treatment of HCl. If ClSi(NMe2)3 was used instead of Si(NMe2)4, a one-pot procedure could be proposed (HCl being liberated during the network buildup) affording nevertheless a lower surface area. The surface of these network materials was found to be hydrophobic with a hydrophilic interior. Later the free-dendrimer silica networks were used to obtain silver oxide nanoparticles, whereas if residual dendrimers were still present silver nanoparticles could be obtained upon UV irradiation.108 J. Y. Chane-Ching, A. M. Caminade, J. P. Majoral, and coworkers109 proposed the use of dendrimers and surfactants simultaneously to obtain periodic mesoporous organosilicas110 of type MCM-41; they have used polycationic phosphorus-containing dendrimers with cetyltrimethylammonium bromide (CTAB) and showed that it was possible to incorporate large amounts of the dendrimeric species (up to 26% by weight) in the hexagonal silica phase without modification of the honeycomb structure of the MCM-41.109 The cationic surfactant could be selectively removed to liberate the pores while keeping the dendrimer fully accessible inside the material. R. Haag and coworkers have proposed the use of hyperbranched poly(glycerol) as a nonsurfactant template to prepare mesoporous silica materials: large surface areas, pore volumes, and narrow pore size distribution were

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Figure 12.15

Synthesis of periodic mesoporous dendrisilica113

obtained.111 The template could be completely removed by water extraction; the pore diameters of the pure silica samples were still centered at 3.8 nm. H. Peterlik and coworkers have synthesized monolithic inorganic–organic hybrid materials via sol-gel processing of an ethylene glycol end-capped carbosilane dendrimer in the presence of the nonionic copolymer Pluronic P123; SAXS measurements were used to analyze the structure of the material obtained.112 G. A. Ozin and coworkers have prepared carbosilane dendrimers with triethoxysilane groups on the surface (first and second generations); periodic mesoporous dendrisilicas were formed through the hydrolysis of the trialkoxysilyl groups and subsequent condensation of the dendrimer around a surfactant template (octadecyltrimethylammonium bromide for the first generation and a triblock copolymer for the second generation), leading to ordered template-dendrisilica nanocomposites (Figure 12.15).113 The templates could be removed by washing. A surface area as high as 1102 m2 g−1 and a mesopore diameter of about 2.5 nm were obtained for the first generation whereas the second generation had a given surface area of 775 m2 g−1 and an average pore size of 9.1 nm. PAMAM and PPI dendrimers have also been involved in the formation of silica nanospheres; the amino groups on the surface of the dendrimers initiate the condensation of silicic acid (Si(OH)4) and then the formation of the silica nanospheres; particles with diameters from 95 to 400 nm were produced with PAMAM dendrimers (zeroth generation to sixth generation) whereas particles with diameters from 170 to 260 nm were produced with PPI dendrimers (first generation to fifth generation).114 The size of the nanospheres could be controlled by the defined concentrations of phosphate buffer and main group

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285

metal chloride salts.115 If dendrimer-encapsulated metallic nanoparticles were used, encapsulated nanoparticles into discrete nanosphere composites were produced.116 CdSe/ZnS core–shell semiconductor nanoparticles could be entrapped as well as enzymes.117 Hyperbranched poly(ethyleneimine) has also been involved in the synthesis of silica nanospheres, which have been then employed for the removal of toxic water contaminants (metal ions and polycyclic aromatic hydrocarbons).118 Hybrid materials synthesized by the grafting of preformed dendrimer on the silica surface or by the stepwise growth of dendrimeric wedges from the silica surface have found applications mainly in heterogeneous catalysis, as shown in the previous chapter, and as stationary phases in separation processes.119

12.4

Dendrimers inside Other Types of Materials

Dendrimers have participated in the elaboration of different kinds of complex functional nanoarchitectures. Due to their structure and presence of specific functional groups at their surface or in their internal cavities, they have been used to control the nanostructuration of the desired materials or/and to introduce specific properties. In contrast to silicate materials, the elaboration of organic–inorganic hybrid materials built from nonsilicate precursors is often difficult to control; therefore strategies based on the assembly of nano building blocks (ANBB) with well-defined structures are useful and it was applied by C. Sanchez, A. M. Caminade, J. P. Majoral, and coworkers to prepare mesoscopically ordered hybrid materials.120 When alcohol or carboxylic acid end-capped phosphorus-containing dendrimers (first generation) were mixed with the cluster [Ti16O16(OEt)32], a hybrid gel made of dendrimers and clusters was obtained with the respective individual internal structure conserved. The organic–inorganic interfaces were obtained by transalcoholysis between some ethoxy groups of the cluster and some alcoholic groups of dendrimer or by nucleophilic substitutions coupled with a proton transfer from the carboxylic acid end groups, giving bridging carboxylates (Figure 12.16). These solid gels are mesostructured hybrid materials in which clusters are regularly spaced by the dendrimers. The same group has also reported the synthesis of metal oxobased hybrid materials using a carboxylic acid end-capped dendrimer (fifth and seventh generations) and metal alkoxides (Ti(OR)4, Ce(O–iPr)4).121 The complexation of the metal centers by the acidic functions of the dendrimers occurs first through bridging carboxylates, and then these sites act as anchoring points for the development of the inorganic network all around the dendrimer, which acts as a template, affording the hybrid material. After thermal decomposition, the pore packing observed by TEM is sponge-like with mesopores of 9–30 Å; macroporosities are also detected. A similar approach was used by N. R. Choudury with amine or alcohol end-capped PAMAM dendrimers.122 D. W. Wright and coworkers have prepared nanoparticles of TiO2 and GeO2 using PAMAM and PPI dendrimers,123 with a similar approach developed to prepare silica nanospheres.114 Hybrid dendrimeric–mesoporous titania nanocomposite films have been prepared from fluorescent phosphorus-containing dendrimers and nanocrystalline mesoporous titania thin film; it was used as an optical sensor for the detection of phenolic moieties through quenching of the fluorescence.124 Confinement of the fluorescent probe inside the

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Dendrimers

Figure 12.16

Titanium-based dendrimeric mesostructured hybrid materials120

titania pores increases their spatial proximity and makes the formation of a hydrogen bond easier between the hydroxyl moiety of the quencher and the carbonyl group of the dendrimer. C. M. Paleos and coworkers have used triethoxysilane end-capped PPI dendrimers and triethoxysilane-decorated PEI hyperbranched polymers to prepare organosilicon dendrimeric networks in porous ceramics for water purification: following hydrolysis of the triethoxysilyl moieties to Si–OH, polycondensation occur affording Si–O–Si together with Si–O–Ti bridges when a titanium dioxide ceramic filter was subjected to treatment with the dendrimeric species.125,126 The group of Jeng developed the preparation of nanoscale organic/clay hybrids based on the intercalation of dendrons into montmorillonite layered silicates; ion exchange reactions were used to this end.127–130 Dendrons with different end groups (aromatic, alkyl chain, azo compound) could be intercalated; first to third generations were generally considered. Starting from an interlayer of about 12 Å in a parent clay compound, the intercalation of phenyl end-capped dendrons, first to third generations, has induced an increase in the interlayer distance, which was measured at 38, 77, and 115 Å, respectively. Hyperbranched poly(ester-urethane-urea) was used to prepare hybrid composite with K10 clay.131 New organic–inorganic hybrid assemblies based on a layered double hydroxide (LDH) with a carboxylate end-capped PAMAM dendrimer were prepared by two different routes using either the direct coprecipitation at constant pH or the anion exchange procedure.132 LDH is an anionic clay-type compound with a lamellar structure; PAMAM dendrimers were intercalated inside the interlayer space. Some hybrid dendrimeric systems are obtained with the insertion of dendrimers or dendrons in the polymeric network.133 The group of T. S. Chung developed the insertion of a PAMAM dendrimer in polyimide membranes via the cross-link process.134,135 The insertion of a dendrimeric domain inside the 6FDA-durene polyimide membrane has resulted in a decrease in permeabilities for most of the gases studied, due to a decrease in the gas diffusion coefficient upon the crosslinking process; this process induced a reduction

Dendrimers inside Materials

Figure 12.17

287

DAB dendrimer as a crosslinker for polyimide membranes136,137

in the intersticial space among chains, chain mobility, and free volume. The separation properties were related to the duration of the crosslinking process. An increase in the CO2 permselectivity was observed due to a significant increase in the solubility of CO2 in the crosslinked polymer. DAB dendrimers (first to third generations) were also inserted in polyimide membranes, with the first generation giving the higher degree of crosslinking (Figure 12.17).136,137 PAMAM dendrimers were also introduced in a phenolphthalein poly(ether ether ketone) (PEK-C) ultrafiltration membrane.138 J. R. Parquette and coworkers have incorporated dendrimers into dental composite resins and obtained reinforced materials: the flexural strength of the composite containing 2.5% of the dendrimeric species was improved by up to 35%.139 Polymer networks have been prepared with dendrimers as the crosslinker: E. J. Goethals and coworkers used the amine end-capped PPI dendrimers with bifunctionnal living polytetrahydrofuran (polyTHF) to prepare segmented polymer networks. Films of polyTHF–dendrimer were prepared.140 The crosslinking process could be carried out with difunctional monomer, as described for PEI hyperbranched polymers by J. Rademann141 or for hyperbranched poly(amine-ester) by B. K. Zhu:142 in the latter case, crosslinking of the terminal hydroxyl groups of the polymer with glutaraldehyde has afforded film formation. Some specific devices could be prepared as described by X. G. Peng and coworkers: they considered alcohol end-capped dendrons having a thiol function at the focal point to stabilize CdSe or CdSe/CdS nanocrystals, and then used second generation PPI dendrimers as crosslinkers to produce amine box nanocrystals with high chemical, thermal, and photochemical stability.143 To demonstrate the possible use of these species for bioapplications (in particular biodetection using semiconductor nanocrystals), biotin has been coupled on to these amine box nanocrystals and an avidin-biotin/box nanocrystal conjugate

288

Dendrimers

was obtained. The same methodology was used with a gold surface instead of nanocrystals.144 When suitable surface functionalizations were carried out it has been possible to crosslink a dendrimeric species to produce new materials. For example, S. C. Zimmerman and coworkers have developed the preparation of organic nanoparticles using a homoallyl group end-capped poly(ether)-based dendrimer; by using the ring closing metathesis (RCM) reaction it was possible to obtain an intramolecular crosslinking. This strategy was first used to perform molecular imprinting inside the dendrimer; hence when the dendrimer is prepared and the RCM reaction is carried out, the core molecule (porphyrin, aromatic compound) was removed.145–147 The crosslinking process has been shown to produce compact and more rigid particles: the uncrosslinked dendrimer can flatten on a mica surface, contrary to the crosslinked dendrimer, which stands rididly.148 Starting from the metalated porphyrin-cored poly(ether) dendrimers with homoallyl surface groups, it was possible to assemble the dendrimer through the metal core using succinic acid as a bridging ligand; the RCM reaction could be subsequently carried out intermolecularly to form an “organic nanotube”, from which the internal porphyrin fragment could be removed to obtain the free “organic nanotube”.149 S. C. Zimmerman, R. Haag, and coworkers have used this methodology with hyperbranched polyglycerol to prepare nanocarriers for guest binding and controlled release.150–152

12.5

Dendrimers for the Elaboration of OLEDs

Many efforts in the field of organic light-emitting diodes (OLEDs) have been made during recent years motivated by their potential applications in display technology (in particular for large-area flat panel displays) and lighting; when few volts were applied to a thin-layer film of a specific material light is emitted. Although the first OLED was fabricated with anthracene crystals in 1965 (poor performance),153 interest in this field was revived in 1987 when the preparation of a green light-emitting diode fabricated with 8-hydroxyquinoline aluminum (Alq3) was reported.154 It was later found in 1990 that an LED prepared with poly(p-phenylene vinylene) (PPV) also emitted green light on a positive bias potential application.155 Since then the development of OLEDs has concerned the following two types of materials: small molecule OLEDs156 with well-defined structures and excellent purity are generally processed using high-temperature vacuum evaporation techniques while for a polymer-based LED157 simple processes can be used such as spin coating and ink-jet printing due to their solubility in organic solvents. Nevertheless, a polymer-based LED can suffer from less defined structures and therefore batch-to-batch reproducibility can be problematic. Moreover, to develop light-emitting materials and obtain in particular a full-color display, accurate control of their optical and electronic properties is necessary. Due to the controlled molecular synthesis of dendrimers their electronic, optical, and processing properties can be tuned and optimized in such a way that they are now regarded as the third class of materials for use in OLEDs combining the potential advantages of both small molecules and polymers. Dendrimer light-emitting diodes, DLEDs, have been the subject of numerous reports.158–161

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Figure 12.18

289

Schematic representation of electroluminescent devices

For an organic light-emitting diode, an emissive material layer has to be sandwiched between two electrodes: electrons injected at the cathode and holes injected at the anode move through the layer under the applied electric field and then recombine on the emitter molecules to form excited states (singlet and triplet excitons) that can emit light. Electroluminescent devices will use a single- or a multi-layered structure. For the first one, the material considered will have emissive properties together with good charge (electrons and holes) transport properties, while for the second one, additional layers will be incorporated to improve the charge transport properties (Figure 12.18). The layers have to be chemically stable and transparent to the light emission. The development of DLEDs has mainly concerned the incorporation of dendrimers in the emitting material layers of single- or multilayer devices and some strategies used in this context will be presented. Nevertheless, dendrimers or hyperbranched polymers have also been involved in the hole-transport layer of multilayer systems with, for example, the synthesis of triphenylamine-based dendrimers,162,163 carbazole end-capped dendrimers,164 hyperbranched polymers incorporating carbazole moieties,165 or in the electron-transport layer with, for example, the synthesis of diphenylquinoline group end-capped dendrimers.166 We will focus on the use of dendrimers as emitters. To incorporate a dendrimer in an emitting material layer they should present fluorescence properties; different dendrimeric species were considered where chromophores have been introduced at the level of the core, within the dendrimeric scaffold, or on the surface. Nevertheless, dendrimers having the chromophores at the level of the core were the most developed; in this case the periphery and the branches were used to improve the charges transport properties and to tune the solubility of the dendrimer for solution processing (spin coating, for example). One of the key features associated with the introduction of the chromophore at the core is the reduction of its fluorescence quenching and excimer emission. When the chromophore is introduced at the surface level, the opposite case was generally observed, with an increase in the self-quenching process in the solid state; it was demonstrated in the case of a PAMAM dendrimer decorated with ruthenium complexes.167 For phosphorus dendrimers decorated with pyrene moieties on the surface, excimer emission was only observed in the solid state; high threshold tension (caused by electron trapping within the dendrimeric structure) has to be used to obtain very low blue light

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emission.168 A pyrene decorated multifunctional phosphorus compound (N3P3Cl6) has been reported as the emitting material; the efficiency of the device depends on the spacer length used to graft pyrene moieties and on the composition of the emitting layer, but here too some aggregation phenomena were reported.169 Therefore we will focus here on the chromophore cored dendrimers. A key point in the development of DLEDs was the preparation of phosphorescent dendrimers, mainly with the phosphorescent emitter at the core level. In this case both singlet and triplet excitons will be used in the light-emission process, contrary to the fluorescent emitter for which only a singlet exciton is considered. Full color LED displays may be constructed in different ways, such as filtering white light for a specific color, applying different bias potentials to LEDs using efficient dyes to convert colors, or patterning pixels for the three principle colors (blue, green, red) independently. As blue light can be converted to green or red with proper dyes, while green or red cannot be converted to blue, deep-blue LED is a challenging area as alone it may generate all colors. 12.5.1

Fluorescent Dendrimers for the Elaboration of OLEDs

One of the first reports dealing with fluorescent dendrimers for the elaboration of an electroluminescent device has concerned poly(phenylacetylene) dendrimers having a (diphenylacetylenyl) anthracene chromophore at the core level and tert-butyl groups on the surface (Figure 12.19).170 Strong intermolecular interaction of the chromophore in the solid state was supposed to be responsible for the poor efficiency of the DLED prepared, the acetylene linkers giving an open and planar structure. Subsequent substitution of the tert-butyl groups by diphenyl amine groups (holetransport properties) or oxadiazole fragments (electron-transport properties)171 were unsuccessful. New dendrimers with acetylene linkers were prepared, starting from a pyrene core:

Figure 12.19

Poly(phenylacetylene) dendrimers for DLEDs applications170

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Figure 12.20

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DLED device using a fluorene/carbazole dendrimer172

they have carbazole units as divergent points and fluorene units in the branches (Figure 12.20).172 Carbazoles are used to improve the hole–transport properties and the fluorene units to improve the film-forming properties. Depending on the generation and on the number of fluorene units in the monomer used, color of the emissive light was changed, the more active DLED device exhibiting a yellow light emission with a maximum brightness of 5590 cd m−2 at 16 V, a high current efficiency of 2.67 cd A−1 at 8.6 V, and a best external quantum efficiency of 0.86%. Poly(phenylene vinylene)-based dendrimers have been largely studied as light-emitting components of electroluminescent devices, in particular by the groups of P. L. Burn and I. D. W. Samuel. They have prepared dendrimers up to the third generation with a distyrylbenzene core (fluorescent emissive core) and trans-stilbenyl moieties (for charge transport) within the branches (Figure 12.21).173 They have shown that the efficiency of the DLED devices (which give a blue color) was dependent on the generation, the first generation giving the worse efficiency: excimer emission due to aggregation occurs more easily in this case. Nevertheless, this excimer emission is reduced compared to the neat distyrylbenzene for which no emission was reported in the solid state. If dendrimeric wedges are able to prevent excimer formation, they can also decrease the charge mobility and hence have a negative influence on the efficiency of the device. In this family, the second generation gave the higher external quantum efficiency. In a detailed study using tris(distyrylbenzyl)amine-centered dendrimers

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Figure 12.21

Poly(phenylene vinylene) dendrimers used to prepare DLEDs173–175

the opportunity to tune the mobility of the charges by the correct choice of the dendrimer generation was indicated; in this case it was demonstrated that reducing the mobility had a positive influence on the charge capture and hence on the quantum efficiency.176 They prepared corresponding tris(distyrylbenzyl)benzene-centered dendrimers and showed that the aggregation behavior and hence the excimer emission were correlated to the degree of delocalization across the core unit.177 They have also reported the possibility of tuning the color of the emissive light by considering, instead of the distyrylbenzene core, anthryl or porphyrinyl analogs (Figure 12.21).174,175 Tris(distyrylbenzyl)benzene-centered and tris(distyrylbenzyl)amine-centered dendrimers also differ, giving respectively blue and green emissions. The introduction of diphenylquinoline groups on the surface of the tris(distyrylbenzyl)benzene-centered dendrimers has changed the properties of the electroluminescent device, giving a yellow emission due to the peripheral groups; moreover, these new dendrimers have been used in the electron-transport layer.166 The same group has shown that the deposition of an emissive heterolayer consisting of a tris(distyrylbenzyl) amine-centered dendrimer film and a second film of the same dendrimer with an electrontransporting dopant molecule [2-(4-biphenyl)-5-phenyl-1,3,4-oxadiazole, ph-PBD] could improve the efficiency of the DELD device.178 The same strategy was used for a conjugated dendrimer consisting of three distyrylbenzene units linked by a central nitrogen atom as the core and alkyl chains on the surface (Figure 12.22):179 when the dopant content was

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Figure 12.22 DELD device obtained with a conjugated dendrimer bearing distyrylbenzene179

Figure 12.23 Perylene-3,4,9,10-tetracarboxydiimides with aromatic dendrimeric arms180 and poly(terphenylene) dendrimers181

optimized the DELD device has reached a maximum brightness of 4100 cd m−2 and an electroluminescence quantum efficiency of 0.17%. K. Müllen and coworkers have prepared conjugated dendrimers for DELD applications using pentaphenylene dendrimeric wedges linked to perylene derivatives, which act as the emissive component (Figure 12.23); they have prepared a single-layer electroluminescent device giving a red–orange emission.180 Recently they have proposed the use of poly(triphenylene) dendrimers to obtain blue light-emitting materials (Figure 12.23).181 Oligothiophene derivatives have been used as an emissive partner in DELD; the length of the polythiophene moiety will determine the color of the emissive light. The dendrimeric partner presents carbazole units and triarylamine and then the dendrimer is considered as a hole-transporting emissive layer in the DELD device: blue luminescence was obtained with dithiophene (DTP) and yellow luminescence with pentathiophene (PTP) (Figure 12.24).182

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Figure 12.24

Carbazole-based dendrimers with an oligothiophene core182

Truxene rigid π-conjugated dendrimers were also considered in the elaboration of the DELD device as reported by J. Pei and coworkers;183 they prepared deep-blue emitting systems in particular and studied the influence of the annealing process on the lightemission efficiency.184 Conjugated dendrimeric species incorporating carbazole, thienyl units, and end-capped with diphenylamine groups has been integrated in a DELD device producing deep-blue emissions with a brightness of 2121 Cd m−2, an external quantum efficiency of 1.73%, a luminous efficiency of 1.10 lm W−1 at a current density of 100 mA cm−2.185 Nonconjugated dendrimeric species have also been considered for DELD materials; Fréchet-type poly(ether) dendrons were commonly used to decorate a chromophore as M. S. Wong and coworkers did for distyrylbenzene.186,187 Generally poor results were obtained with these systems, the dendrimeric branches becoming more insulating with the generation increase. Then, some effort has been made to introduce some charge-carriers on these systems; J. M. J. Fréchet and coworkers prepared triarylamine end-capped dendrimers with oligothiophene or coumarine dye at the core (Figure 12.25).188 Green light was produced with the oligothiophene derivative and blue light with the coumarine dye. If a DELD device was prepared with the two dendrimers in the same film, as no or reduced energy transfer between the cores occurs, blue and green emissions were obtained simultaneously. Without the dendrimeric framework, the mixing of oligothiophene and coumarine dyes produces only green fluorescence. Later the influence of the generation was demonstrated in the fine tune of the color of the emitting light.189 Blue electroluminescence was obtained from blends of two solution-processible light-emitting dendrimers having the same dendrimeric part and respectively a bisfluorenyl core and a (fluorenyl-thiophenyl) one. The identical nature of the dendrimeric parts in the two partners insures a perfect mixing of the two species and therefore an efficient tunable electroluminescence from the near-UV to blue-green.190 Some naphthalimide cored dendrimers191 were prepared for which the core was surrounded by Fréchet-type dendrimeric wedges decorated with carbazoles (hole-transport properties) or oxadiazoles (electron-transport properties) and also perylenediimide.192 Conjugated polymers are generally used for polymer-based LEDs: the synthesis of dendronized polymers193 have been also studied for the elaboration of new active materials

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Figure 12.25

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Triarylamine end-capped dendrimer encapsulated dyes188

for the LED device. The group of Müllen has reported the preparation of polyfluorenes decorated with pentaphenylene dendrimeric wedges:194,195 the incorporation of the branched structure has been used to prevent the aggregation of the polymer chains and to improve their solubility in organic solvents. The dendronized polyfluorenes have been used as emitting components in the LED device. The synthesis of dendronized poly(pphenylenevinylene) and codendronized poly(p-phenylenevinylene) considering different types of dendrimeric wedges has been reported and here too the attached dendrimeric species have generally increased the solubility of the corresponding linear polymers.196–198 Hyperbranched polymers were also studied as active components for electroluminescent devices, and in many cases as charge-transport species: some examples dealt with their uses as emitting components.199–205 12.5.2

Phosphorescent Dendrimers for the Elaboration of OLEDs

The search for a more efficient DELD has prompted the groups of Burn and Samuel to synthesize phosphorescent dendrimers in order to take the benefits of both singlet and triplet excitons generated in the material and also to be able to use the solution process to prepare the electroluminescent devices (organometallic complexes (of Ir, Pt, Ru, Os, Re) have been largely used in this field206,207). Their first attempt involving a platinum porphyrin cored stilbene dendrimer was not successful;208 they have then developed the synthesis of fac-tris(2-phenylpyridine) iridium-cored dendrimers with 2-ethylhexyloxy groups on the surface (Figure 12.26).209–211 They used first the pure dendrimer in the emitting layer and observed some prejudicial intermolecular interactions that led to luminescence quenching in neat films; the same quenching process was obtained with the second generation

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Figure 12.26

DLED device with fac-tris(2-phenylpyridine) iridium-cored dendrimers209–211

Figure 12.27

Red and blue emitting iridium-cored dendrimers213–215,217

dendrimer, so it was proposed that the opened structure of the complex was not suitable to prevent these intermolecular interactions. Their strategy was then to blend the dendrimer with a second component, a host (which has here some hole transporting properties – 4,4′-bis(N-carbazolyl)biphenyl, CPB, for example), in order first to space the emitting species and also to optimize the recombination rate of all the injected charge pairs. The performance of the device was sensitive to the nature of the blends together with the choice of the electron-transporting layer (hole-blocking properties). Different systems were proposed, leading to very efficient green electroluminescent devices. Later a single-layer system was proposed by mixing the emitting layer with a combination of a hole transporting and an electron transporting compound.212 By changing the position of the dendrimeric wedge on the 2-phenylpyridine ligand or by changing the ligand around the iridium center it was possible to change the color of the emitted light: red (A)213,214 and sky blue (B)215 electroluminescent devices were proposed (Figure 12.27). It was demonstrated also that the mixing of the green and the red emitters in the same emitting layer in a controlled way can be used to tune the color of

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the emitted light.216 A triphenylamine end-capped iridium cored dendrimer (C) (Figure 12.27) prepared by W. Y. Wong, Z. Y. Xie, and coworkers has given a pure red emission in an efficiency among the highest ever reported for a solution-prepared device;217 green photoluminescence was obtained with an iridium-cored dendrimer composed of Fréchettype poly(ether) decorated benzoimidazole ligand,218 and with analogs having a fluorenyl group on the surface of the Fréchet-type poly(ether).219 The influence of the nature of the dendrimeric wedge was studied and different iridiumcored dendrimers were prepared. First highly branched dendrimeric species (Müllen-type dendrons) were attached to the iridium complex to limit the intermolecular interaction: this approach has revealed the importance of the dendrimer solubility to perform efficient spin-coating, but no improvement concerning the luminescence quenching process was observed and the use of the host was necessary.220 K. Müllen, G. Zhou, and coworkers have recently developed the divergent synthesis of iridium-cored poly(phenylene) dendrimers up to the fourth generation and studied the influence of the dendrimer size on the electroluminescence efficiency, the third generation giving the best results.221 Carbazole units have been introduced in the dendrimeric framework to take advantage of their holetransporting properties and moreover the host used in the phosphorescent electroluminescent devices (CBP, TCTA, for example) could be carbazole derivatives. Different structures were proposed222,223 – in particular, a highly efficient green emitting device developed by Y. X. Cheng, L. X. Wang, and coworkers for which carbazole units act as a divergent point in the dendrimeric framework.224 The first generation (D-1st) presents three carbazole units and the second generation (D-2nd) nine carbazole units (Figure 12.28). The iridium-cored dendrimers were used alone in the emitting layer (no host), giving an external quantum efficiency of 6.8% for the first generation and 10.3% for the second generation, and respectively a maximum luminous efficiency of 23.2 (first) and 34.7 (second) cd A−1 and a maximum brightness of 6570 (first) and 7840 (second) cd m−2. Nevertheless, the electroluminescence efficiency doubled when a host was used. Later they reported a more dense system for which the first generation presents six carbazole units (E-1st) (Figure 12.28).225 The efficiency of the green luminescence was improved (doubled in comparison with D-1st) and they obtained an external quantum efficiency of 13.4% and a maximum luminous efficiency of 37.8 cd A−1. They also studied the behavior of heteroleptic

Figure 12.28 Green-emitting phosphorescent iridium-cored dendrimers based on carbazole224,225

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Figure 12.29

Host-free phosphorescent iridium-cored dendrimers228,229

complexes.226 Burn, Samuel, and coworkers have proposed the synthesis of iridium-cored dendrimers based on carbazole using 2-phenylpyridine as the ligand and analysed the influence of the carbazole units on the charge transport.227 The influence of the compactness of the dendrimeric species around the iridium center on light emission was also demonstrated by Burn, Samuel, and coworkers for the factris(2-phenylpyridine) iridium-cored dendrimers:228 a dendrimeric wedge was introduced on the pyridyl ring of the ligand, resulting in a more compact encapsulation of the iridium complex (Figure 12.29). No self-quenching was observed for the film of F, and consequently a host-free green emitting device was obtained with high efficiency (external quantum efficiency of 13.6% at 4.8 V, maximum luminous efficiency of 47 cd A−1, and a maximum brightness of 110 cd m−2). By changing the nature of the ligand around the iridium center a new iridiumcored dendrimer G was prepared and used to elaborate a host-free blue phosphorescent electroluminescent device.229 A deep red light-emitting phosphorescent device was prepared from carbazole end-capped iridium-cored dendrimers with a benzothiophenylpyridine ligand at the core.230

12.6

Conclusion

Exploiting the unique nature of the dendrimeric architecture, their tunability and their multiplicity of functionality, new materials were created with improved properties or some new specific properties. By using self-assembly processes, soft materials were produced, hydrogel or organogels, with an organization of the matter directly connected to the shape and nature of the dendrimeric precursors (nanoribbons, fibres). Some of these processes have been charac-

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terized by a reversible behavior and encapsulation has also been reported, allowing in particular controlled drug release to be developed. Moreover, by the precise incorporation of a specific trigger, stimuli-responsive materials were prepared; “smart” gelator systems thus obtained would find applications not only in drug release but also in imaging, sensors, etc. Chemical or photochemical crosslinking processes of dendrimeric species (alone or in combination with other partners) have been largely used to obtain new biomaterials with unique properties for which the multivalent nature of these macromolecules are in part responsible; dendrimeric species played an important role in the control of hydrophobic/hydrophilic balance and the mechanical properties of the materials. With applications for tissue repair or cartilage tissue engineering, ophthalmic sealents are now very well documented, showing the real appeal of dendrimeric species in biotechnology applications. The crosslinking process has also been used to prepare dendrimeric networks for different purposes, including materials for gaz membranes, for water purification, and for molecular recognition (molecular imprinting): in these areas, connected to ecological considerations, hyperbranched polymers were also involved. Other domains were concerned by these materials as electronics or sensors. The dendrimeric domains incorporated in the material were used to modify or create specific spatial arrangements inside the material or/and to introduce specific functions using in particular the container properties offered by the cavities of the dendrimeric species. Using the sol-gel process (a “chimie douce” process), hybrid organic–inorganic materials were prepared with the introduction of nanodomains inside the inorganic network. The dendrimeric species has been used to control the structure of the solid; the versatility of dendrimers was demonstrated as they can be used not only as a templating agent (with the possibility of their removal not only by calcination but also by washing) but also incorporated in the inorganic walls of the materials. Multifunctional hybrid materials were prepared and used as sensors, photochromic glasses, catalysts, etc. The electronic and optoelectronic properties of dendrimers have been used in different domains (photovoltaic cells, optical amplifiers, lasers, nonlinear optics, etc.) and, among these, dendrimers were revealed to be particularly well suited for the development of DLEDs. The device preparation process has benefitted from the easy surface functionalization for carrying out the solution process and moreover it will be possible to offer to the light-emitter component a special environment in the dendrimeric structure suitable to ensure good efficiency in light production. At the same time, charge-transporting properties can be introduced in the dendrimeric structure to improve the device efficiency. Color tone was possible: green, red, blue, and white emitters can be produced. The development of phosphorescent DLEDs is particularly impressive, even if stability and lifetime need to be improved.

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13 Self-Assembly of Dendrimers in Layers Béatrice Delavaux-Nicot* and Anne-Marie Caminade

13.1

Introduction

Owing to their hyperbranched well-defined structures whose constituent elements and physicochemical properties could be tuned, dendrimers appear as very attractive candidates for chemistry at the interface.1,2 In particular, on one side they can be grafted to, or in contact with, a solid surface and on the other side they can react with, or be connected to, another species or interface. The fabrication of new materials from molecules often requires the formation of thin films. Therefore, for the two last decades, chemists interested by the potential of dendrimers in this research field have solved that problem by creating such films using self-assembly of dendrimers in layers. Two main approaches have been considered, which are the development of Langmuir–Blodgett (LB) films at the air–solid interface following the formation of their corresponding Langmuir (L) film at the air– liquid interface, and the development of self-assembled monolayers (SAMs) on various solid surfaces. These films have been made with different dendrons and dendrimers belonging to well-known families of dendrimers, but also with other original dendrimeric derivatives. The Langmuir–Blodgett technique allows the formation of high-quality and well-structured monolayers, which is very important for the development of nanotechnologies. However, it requires some special equipment and more restricting procedures when compared to the formation of films by SAMs. In this chapter, the results relative to LB films are classified according to the family of studied compounds, while a classification according to the substrate, taking into account the nature of the film formation, has been preferred for SAMs. Multilayers, i.e. the superimposition of monolayers, can be spontaneously produced by using these two techniques or can be prepared by different routes, which * Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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will be illustrated by some examples. Special attention has been brought to multilayers formed by electrostatic interactions between layers of positively and negatively charged dendrimers. Indeed, these layers can provide very interesting opportunities to create nanometric objects such as nanotubes or microcapsules, with a perfectly controlled shape and composition. The development of nanotechnologies also needs the elaboration of thin films with controlled properties. That implies, in particular, the control of patterning of chemical functional groups on the surface. Among the patterning methods, two nanoimprinting methods have led to remarkable results – first, the lithographic methods that rely on using scanning probe instruments, electron beams, or molecular beams to remove materials (SAMs or other resist layers) for subsequent processing or adsorption steps and, second, soft lithography such as microprinting and dip-pen nanolithography that allow one to directly transport molecules to a definite substrate. The chosen examples will give an overview of the state of the art in the concerned research field through numerous evoked points: the design of appropriate dendrimers, the formation, characterization, and use of their films by different techniques, the research of various applications, etc. The reported work also evidences the fact that thin films also play an important role at the interface with biology, as shown for instance by the creation of dendri-stamps and also that of modified surfaces for obtaining molecular sensors and various biomicroarrays. These latter subjects will be more specifically treated in the appropriate Chapters 14 and 15.

13.2

Langmuir–Blodgett Films of Dendrons and Dendrimers

New materials and devices often require a peculiar organization of active moieties. The Langmuir–Blodgett (LB) technique is a frontier method for the deposition of ultrathin and homogeneous films with several specificities, such as a predetermined architecture, composition, thickness, and usually with a resulting elevated level of anisotropy, obtained from amphiphilic materials spread on to aqueous subphases. The deposition of suitable substance involves several key steps. First, the generation of a floating layer of the substance (such as a fatty acid) – monomolecular in thickness and therefore denominated monolayer – should occur at the air–water interface. One such monolayer is spread from a volatile organic solvent containing some aliquot of the amphiphile on to the aqueous subphase (generally pure water). In this way, the solution expands quickly over the entire water surface before the solvent evaporates, producing a floating layer on the water surface. In the second step, by employing movable barriers, the monolayer is compressed at the air– water interface until the formation of a condensed film, highly organized with a twodimensional regular arrangement of the molecules, which is the Langmuir (L) film (Figure 13.1, left). The formation of the monolayer is associated with a decrease of the surface tension of the subphase. The various phase transitions formed during compression can be detected from the dependence of surface pressure, Π, versus surface area, A, available on the surface water. Typically, three main transitions occur (Figure 13.1, right). At large areas per molecule, the interaction between molecules is negligible and the surface pressure is null. It is called the gaseous state phase. Upon compression, the intermolecular interactions increase, the monolayer suffers a phase transition to a liquid-condensed phase, and an

Self-Assembly of Dendrimers in Layers

Figure 13.1 (right)

315

Langmuir film formation (left) and classical shape of a Langmuir isotherm

increase in pressure with the change in area is observed. Further reduction of the area on the water surface brings about the condensed-solid phase, usually the steepest region of the Langmuir isotherm (Figure 13.1, right). The two-dimensional close-packed film, or L film, is obtained (it is noteworthy that the interpretation of the isotherms is not straightforward). Upon further compression, when a sudden drop in the surface pressure occurs, the collapse point is reached, fragments of the film move, and the monolayer is destroyed. In the final step, the transfer and deposition of the two-dimensional Langmuir film on to a solid support (glass, silicon, etc.) is carried out by simple immersion and withdrawal of a substrate through the monolayer, as illustrated, for example, by Figure 13.2.3 The Langmuir–Blodgett film (LB) is thus obtained. The fabrication of three-dimensional ordered multilayers by subsequent transfers of a single monolayer by repeated down- and upstrokes through the floating layer is sometimes possible.4 The analysis of the Langmuir isotherm allows the determination of the surface pressure at which a highly organized Langmuir film can be obtained. The practical objective is to affect the transfer – monolayer by monolayer (LBL) – at a constant pressure and, accordingly, to fabricate a threedimensional array. Of course, the structure of the multilayer depends on the transfer conditions, and obtaining good-quality films requires optimization of numerous experimental conditions. To reproduce the homogeneity of the film and to investigate its formation and properties, many characterization techniques including modern electronic microscopies are employed.5 LB films have important applications in the fields of molecular engineering,6 microlithography resists,7 highly conductive multilayers,8 electroluminescence,9 thermochromic10 and photochromic devices,11 chemical sensors,12 etc. Throughout the world, different groups have designed and synthesized dendrons or dendrimers in order to obtain high-quality LB films. Various aspects, from their characterization, formation mechanism, to their properties and applications, have been investigated. In this section, via compounds belonging to the main representative families of dendrimers, we aim to provide a short overview of the interests and obtained results in this research area.

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Figure 13.2 Transfer of a Langmuir film monolayer from an air–water interface on to a solid support (in grey) to obtain the corresponding LB film (top) and formation of a multilayer of LB films (bottom)

13.2.1

Poly(benzyl ether) Derivatives

The design synthesis and surface chemistry of amphiphilic dendrimers in L and LB films are attracting increased attention. P. M. Saville, J. W. White, and coworkers13,14 carried out initial studies of dendrimers at the air–water interface using convergent Fréchet-type poly(benzylether) (PBzE) dendrons. These dendrons have a hydrophilic alcohol moiety at the focal point and hydrophobic benzyl groups at their periphery. L films were prepared from homologous series of dendrons ranging from generation 2 ([G2]-OH) through generation 6 ([G6]-OH). Within the same series, only the ([G2]-OH) through to the ([G4]-OH) exhibited surfactant-like behavior. It was suggested that the focal point of the larger dendrons is sterically shielded within the interior of the molecule and, as a result, is inaccessible for association with the water surface. This group elucidated the structure of dendrimer L films based on 3,5-dihydroxybenzyl alcohol in the air–water surface by Π-A isotherm and neutron reflectivity measurements.14 The alcohol at the focal point is associated with the surface of the water, while the peripheral benzyl groups are located on the outside of the molecule and away from the water interface. A collapse of the fourth generation monodendron [G4]-OH has been evidenced to a bilayer structure. The molecules of the layer in contact with air were spherical while those next to the water were ellipsoidal (prolate shape) in structure due to compression and contained a volume fraction of about 25% water. The observed behavior suggests that the bottom dendrimer layer acts as a hydrophobic barrier

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317

and prevents water from penetrating the other layer. C. J. Hawker, J. W. White, and coworkers explored the effect of peripheral group chemistry on the surface activity of dendrimers at the air–water interface.15 The prepared PBzE dendrons included a single alcohol at the focal point and either hydrophilic nitrile or methyl ester functional groups at their periphery. The Π–A isotherm measurements and neutron reflectivity studies indicated that the formed monolayers were different from those of the unfunctionalized hydrophobic counterparts. Indeed, the new peripheral groups increased the affinity of the molecule for the water surface, leading to more spreading as the molecules flattened across the interface. The films were thinner and, under high compression, the formation of a bilayer film was not observed as the more polar dendrons tended to move into the water subphase. C. J. Hawker, C. W. Frank, and coworkers, using Fréchet-type PBzE monodendrons functionalized with benzyl ether groups at the periphery, examined the effects induced by changing the nature of the focal point.16 By incorporating hydrophilic oligo(ethylene glycol) chains of varying length at the focal point into [G3] and [G4] dendrons, they showed that the stability of the monolayer formed increased with the chains length as the chains extended into the water subphase. However, it was concluded that the stability trends for the dendrimer monolayers depended on the relative size between the hydrophobic dendron and the hydrophilic focal point chain, as opposed to the absolute size of the oligo(ethylene glycol) unit. Moreover, examining the [G3] through to [G5] molecular areas as a function of molecular weight for dendrimers possessing a hexakis(ethylene glycol) chain as the focal point, they observed a linear relationship. However, this measured trend is much smaller than that predicted for dendrons assuming a spherical shape. It was confirmed that, once a certain size is reached, PBzE dendrons possess and maintain an overall globular shape, which can range from spherical to ovoid depending on the circumstances of their environment. This conclusion was already highlighted by Saville and coworkers with the same dendrons bearing a single hydroxy group at the focal point.13,14 V. J. Percec, P. A. Heiney, and coworkers studied L films of a series of second and third generation monodendrons containing functionalized benzyl ether units at the air–water interface by X-ray reflectivity and Π–A isotherm measurements.17 These dendrons were substituted with crown ether moieties or oligo(ethylene glycol) units at the focal point and functionalized with hydrophobic dodecyl chains at the periphery. The structure of the L monolayers consists of a hydrophilic focal point at or beneath the water surface and a high-density region above the surface consisting of the dendritic block and peripheral alkyl chains extending upwards from the surface. Other L films of PBzE dendrons and dendrimers have been studied.18–21 One of them, using a third generation dendrimer incorporating a diarylethene unit at the focal point, is the first report about the monolayer formation of a photofunctionalized dendrimer.18 It could be transferred to solid supports giving a homogeneous film. Dendrons incorporating an oligophenylenevinylene (OPV) unit terminated by a hydroxyl polar head group and linked to PBzE branches bearing aliphatic chains (npropyl and n-dodecyl) were also prepared for optical and electronic potential applications.20 Recently, the L films of a third-generation carbazole-terminated poly(benzyl ether) dendrimer was investigated and its LB films were deposited on a gold surface and investigated by AFM.21 It is noteworthy that its molecular configuration depended on its concentration at high surface pressure, as shown in Figure 13.3, left. To understand the self-assembling mechanism of a fan-shaped dendron (Figure 13.4) at the air–water interface, its LB films were examined by H.-T. Jung and coworkers.22 Surface

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Dendrimers

Figure 13.3 Two possible configurations of dendrimers on a solid surface (left) and representation of dendrons and dendrimers bearing hydrophilic groups at the air–water interface (right)

Figure 13.4

Asymmetric fan-shaped dendron of type PBzE

pressure–area isotherms, Brewster angle microscopy (BAM), and electron diffraction (ED) measurements, and also atomic force microscopy (AFM) or transmission electron microscopy (TEM) images, were performed in order to propose a schematic model of the molecular organization from the gaseous phase to high surface pressure for the formed mono- and multilayers. At the air–water interface, the CO2C3H7 core group of the fan-

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shaped second generation dendrimer makes contact with the water surface. The condensed monolayers reveal that the molecules bearing dodecyl alkyl tails form edge-on oriented monolayers with hexagonal packing, suggesting a fractional cylindrical configuration at the air–water interface. The condensed monolayer is transformed into a multilayer upon further compression, and the interfacial structure becomes planar morphology. Following the same approach, D. Sohn and coworkers showed how the orientation of two lowgeneration (G1 and G2) PBzE dendrons with an anthracen-9-yl-benzoic acid head group was sensitive to surface anchoring at the bulk state and to the flexibility of the molecule due to increased generation number.23

13.2.2

Poly(amidoamine) and Poly(propyleneimine) Derivatives

A series of poly(amido amine) (PAMAM) dendrimers that has been functionalized at the periphery with hydrophobic alkyl chains of varying length has been initially prepared by D. A. Tomalia and coworkers.24 Examining their behavior at the air–water interface, it was found that the length of the hydrophobic end group, when varied from hexyl to dodecyl, did not significantly influence the molecular area of the dendrimer at the collapse point in the isotherm. Hawker and coworkers,16 reexamining Tomalia’s data concerning this series of epoxyalkane functionalized dendrimers, showed that in contrast to the behavior of the more hydrophobic Fréchet-type dendrons, the molecular area for the PAMAM dendrimers was found to be much larger than expected for a spherical model. It appears that the PAMAM dendrimers assume a flattened, or oblate, conformation when assembled into a Langmuir monolayer. R. M. Leblanc and coworkers have studied LB films formed with disk-shaped amphiphilic PAMAM dendrimers bearing hydroxydodecanoic acid chains (HA) at the periphery.25,26 The topography of the monolayers was observed by BAM at the air–water interface and by environmental scanning electron microscopy (ESEM) for LB films. In the latter case, the edge-on arrangement was proved by a column-like structure observed in AFM images of the LB films. Using an aza-C6-PAMAM dendrimer with an aza crown core, hexyl spacer, and methyl ester terminals spread at the air–silver nanoparticle suspension in the water interface, T. Imae, R. M. Leblanc, and coworkers demonstrated that composite films and composite aggregates could be prepared.27 E. N. Meijer and coworkers reported the synthesis of PPI dendrimers modified with terminal apolar alkyl chains that formed stable LB monolayers.28 It is noteworthy that similarly to PAMAM dendrimers, PPI dendrimers possess a relatively hydrophilic interior due to the presence of a large number of aliphatic tertiary amines. As for Tomalia’s PAMAM dendrimers, an oblate shape was proposed for the PPI dendrimers at the air–water interface. Indeed, the molecules minimize their free energy by association of their polar interior with the water surface and extending upwards the hydrophobic chain ends of the dendrimers away from the water surface. However, when the PPI dendrimers were functionalized by adamantyl groups, multilayers were obtained at the air–water interface. The molecular area of these molecules demonstrated a nonlinear dependence on molecular weight. It was concluded that this dendrimer adopts a shape-persistent spherical conformation due to the significant steric constraints resulting from the incorporation of bulky peripheral adamantyl groups. PPI dendrimers functionalized with peripheric π-conjugated oligophenylenevinylene (OPV) units may also form stable monolayers at the air–water interface with a face-on arrangement.29 Optical spectra from these LB films indicated

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Dendrimers

interaction between their OPV units. Preparing PPI dendrimers substituted by dialkyl sulfide chains with NHCOR (R = CH3(CH2)9S(CH2)10) end groups, D. N. Reinhoudt and coworkers30 demonstrated that different surface architectures, such as “flattened orientation” versus “standing-up” architecture, could be tuned on a gold surface, depending on the preparation methods, respectively by adsorption SAMs (self-assembled monolayers, see the next section) and LB methods. In the first case, the flattened structure can be attributed to adsorption to the gold surface of not only part of the sulfide moieties in the alkyl chains but also part of the tertiary amines in the core. In contrast, LB films on gold largely retain their original shape with closely packed alkyl chains pointed to the air and the core exposed to the surface. Recently, highly ordered LB films of amphiphilic PPI dendrimers were obtained when using dendrimers modified by attaching dodecanoyl chains as terminal functions.31 The corresponding monolayers were transferred on newly cleaved mica by the LB method. High-resolution AFM images clearly evidenced tetragonal order of a two-dimensional crystal with alkyl chain-to-chain spacing of 0.4–0.5 nm. Differential scanning calorimetry experiments indicated glass transitions of the bulk dendrimers in the range of −12 to −60 °C and endothermic transitions from more ordered to less ordered molecular packing at higher temperatures. 13.2.3 Azobenzene Derivatives Azobenzene-containing dendrimers attracted growing interest32,33 for light-driven experiments (see Chapter 4). V. V. Tsukruk and coworkers prepared azobenzene-containing amphiphilic PBzE-like dendrons to fabricate photosensitive monolayers. These dendrons have long terminal alkyl chains providing hydrophobicity and are directly connected to the azobenzene unit bearing a crown moiety as the polar head.34 LB films of the G1 dendrons (Figure 13.5) were deposited on silicon wafers and quartz plates.35 The molecular thickness obtained by ellipsometry (2.5 ± 0.3 nm) was smaller than the length of the molecule, indicating a “flat-on” orientation within the monolayer. The photoinitiated trans–cis isomerization of the photochromic film results in microstructural reorganization and changed the nature and the macroscopic surface properties. Interestingly, a photoresponsive LB film based on the fifth generation PPI dendrimer ramdomly substituted with palmitoyl- and azobenzene-containing alkyl chains in a 1 : 1

Figure 13.5

Chemical formula of the photochromic G1 dendron

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321

ratio was designed and presented a structure capable of forming photoresponsive L and LB films that can be used as active surface materials.36 The perfect tuning of the dendrimer structure allows the azobenzene units to be anchored and hence prevents microphase separation of the azobenzene moieties within monolayers, thereby faciliting reversible cis– trans isomerization. Dendrons and dendrimers behaving azobenzenes in their structures at one or all levels of the branches were also able to form monolayers on the water surface.37 Orientation of the azobenzene units was determined by polarized absorption spectrum measurements. Different orientations were observed depending on the nature of the studied molecule, whereas sometimes no evidence of orientation was found in the LB films. Molecular dynamics was used to model these films.38 LB films of one of these compounds was deposited on indium–tin oxide coated glass substrate and studied by the Maxwell displacement current technique. This demonstrated that the induced charge at trans–cis photoisomerization decreased with temperature39 and that the dendrons had a uniaxial dipolar structure.40 A Langmuir film of a fourth generation siloxane core-based dendrimer bearing 48 azobenzene groups at the periphery was obtained at the air–water interface and showed a reversible photoswitching behavior by isomerization of the azobenzene groups.41 LB films were also sometimes used to measure the nonlinear optical properties of dendrons possessing azobenzene groups as intrinsic constituents of the branches.42,43 In the first case, mixing the dendrons with arachidic acid allowed a significant increase in the second harmonic generation (SHG) intensity. In agreement with theoretical calculations,44 it was shown that the molecular hyperpolarizability (β) of the dendrons increased coherently to the number of chromophore units in the dendron, and were much larger than those of individual chromophores.45 In the second case, the increase of the β values was due to the presence of an NO2 substituent on each azobenzene group of the previous dendrons.43,46,47 The geometric structures of four generations of azobenzene dendrimers in chloroform solution and a model of the monolayer LB film have been calculated by using a molecular dynamic method.48,49 It was found that the first-order hyperpolarizability values (β) of the dendrimers in the films are smaller than those in the solution because azobenzene chromophores in the film have staggered conformations. For further updated literature data concerning azobenzene LB films the reader is referred to the review of A.-M. Caminade and coworkers.33

13.2.4

Poly(carbosilane) Dendrimer Derivatives

Thin-film organic semiconducting materials are considered for development in microelectronic devices, including organic light-emitting diodes (OLEDs) and field-effect transistors. In this context, carbosilane dendrimers bearing a complexing group at the periphery attracted attention.50–52 The group of S.-B. Jung fabricated LB films of fourth generation dendrimers bearing 48 pyridinealdoxime50 and pyridylpropoxy51 functional end groups and studied their current–voltage characteristics after deposit on a glass slide. In the second case, trying to complex LB films with Pt4+, larger current values were obtained when using a subphase containing the cation than those obtained when dendrimers/Pt4+ mixtures were spread on pure water. When adding Fe2+ cations and using the LB method, the current values were proportional to the iron concentration. S. Chandra and coworkers reported the synthesis of Si[(CH2CH2CH2SiMe2CH2CH2(SiMe(OCH2CH2)4O)]4 dendrimers end-grafted

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Dendrimers

Figure 13.6

Chemical formula of the MD2-COOH dendron

with hydrophilic silacrown groups, which allowed the formation of LB films.52 Up to five layers were deposited on crystal silicon and studied by AFM. A family of hydrophobic bithiophenesilane monodendrons with terminal hexyl chains [MDn], n = 0–3, was functionalized by a carboxylic group at the focal point to produce the amphiphilic counterparts [MDn-COOH] (Figure 13.6).53 Tsukruk and coworkers demonstrated that adding branched thiophene fragments in the COOH-containing compounds resulted in achieving a hydrophobic–hydrophilic balance sufficient to form stable, uniform, and elastic Langmuir monolayers with a thickness of 2–3 nm at the air–water interface at a modest surface pressure (<10 mN m−1) easily transferrable to a solid substrate.53 Multilayers were deposited by the LB method and below a thickness of 18 nm a high photoluminescence is preserved as π–π interactions are still weak in the molecular packing. 13.2.5

Fullerene C60 Derivatives

C60 and their derivatives display a wide range of physical properties that make them attractive building blocks for supramolecular assemblies and advanced materials. In particular, their thin films have been investigated as these materials could find application in microsensors or in optoelectronic devices. In 2002, a review indicating the major references in the field was dedicated to Langmuir–Blodget films of C60 and C60 materials.54 Pure C60 tends to form an ill-defined film of three-dimensional fullerene aggregates at the air–water interface rather than a monomolecular layer. To overcome this aggregation tendency, a

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variety of amphiphilic fullerene derivatives with hydrophilic head groups attached to the lipophilic fullerene core for enhanced interactions with the water subphase have been prepared.55 It has been evidenced that the size of the head group should be large and bulky enough to prevent strong C60–C60 aggregation without disrupting their interaction. To illustrate this concept, C60 dendrimers with one or two bulky glycodendron head groups were prepared and formed stable, ordered Langmuir layers at the air–water interface.56 Absence of aggregation was proved by using UV–vis and BAM. X-type LB films were successfully obtained after being transferred on to quartz slides. Potential applications for optical technology and as biosensors for glycoproteins were envisaged. J.-F. Nierengarten and coworkers showed that the encapsulation of the fullerene sphere in a cyclic addend also prevents the aggregation encountered with amphiphilic derivatives,57 and amphiphilic dendrimers with peripheral bismethano fullerene units58,59 have also been investigated. Some of them59 can be easily transferred on to silicon or glass substrates covered with a monolayer of octadecyltrichlorosilane and yielding high-quality LB films. The hydrophobic–hydrophilic balance of amphiphilic diblock dendrimers with a bismethano C60 core has been systematically modified by changing the size of the polar head group in order to investigate the role of the amphiphilicity both at the air–water interface and during the deposition process on to solid substrates.60 These dendrimers have been formed by cyclization of dendrimeric bismalonate derivatives at the carbon sphere. Because of a better anchoring on to the water surface, the compound with the largest size of polar head group adopts the more compact structure, and the transfer of the L film on the solid surface is more efficient. It is worth noting that the fullerene chromophores are almost isolated from external contacts by the dendrimeric structure, thus paving the way toward ordered thin films of isolated functional molecular units. This appears to be an important finding for future nanotechnological applications, in particular for data storage at a molecular level. Other attempts were made by this group in order to modulate and to control the design of the molecule architecture.61–63 In the case of encapsulated C60 compounds, both the nature, size of the polar head, number and length of the surrounded chains were changed to influence the resulting physical properties. Numerous and good LB films were obtained efficiently on a solid support as quartz slides. The results illustrate how sensitive the molecular design is to molecular arrangements and to conformation of the molecules in the film. An unexpected inner substructure of a L film with micelle-forming molecules was even formed. An original amphiphilic diblock Janus dendrimer containing a dendron with five fullerene units, one at the core and four at the periphery, and attached to a Fréchet-type dendron functionalized with ethylene glycol chains, constitutes a perfect example of a hydrophobic– hydrophilic balance for the formation of stable Langmuir films (Figure 13.7).64 The excellent quality of the LB films formed with this latter molecule was confirmed by grazing incidence X-ray diffraction and by the plot of their UV–vis absorbance as the function of the layer number, indicating an efficient stacking of the layers. This approach shows that functional groups such as fullerenes, not well adapted for the preparation of LB films, can be attached into the branching shell of dendrimeric structures and thus incorporated in thin ordered films. C60(Gn-COOMe) fullerodendrons incorporating a C60 unit linked to an antracenyl poly(amidoamine) dendron with methyl ester terminals of different generations (G), were prepared by Imae and coworkers and gave thin LB films.65 Their structural characterization

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Dendrimers

Figure 13.7 Amphiphilic diblock dendrimer containing five bismethanofullerene units

was performed by X-ray reflectometry. With the lower generations (n = 0.5, 1.5) the fullerene moieties exist in the interior of the LB film, which is a double layer of the molecules, whereas for n = 2.5 the fullerene moieties are at the air side and the dendron moieties are at the substrate side (silicon). At the air–water interface, the monolayer formation ability increases with increasing generation as the amphiphilic properties become superior to the fullerene–fullerene attractive interaction that prevents the monolayer formation. The UV light irradiation of the LB films shows that the molecular arrangement also affects their electrochemical properties. The G1,5 dendron has been successfully used for the fabrication of a field-effect transistor (FET) device (Figure 13.8).66 For the LB film composed of five layers, the value of the studied field effect mobility is twice as high as that for the FET with spin-coated films of C60 dendrons, thus showing the influence of ordered π-conduction network of C60 moities. LB and cast films of a first generation alkoxy-phenylenevinylene pyrazolino[60]fullerene dendron have been successfully prepared and studied by reflection–absorption infrared spectroscopy (RAIRS) and AFM.67 Oriented monolayers of this donor(D)–acceptor(A) system were formed by means of the LB technique. The study revealed an enhanced charge transfer between D–A systems in thin films via intermolecular effects, although an energy transfer process may coexist. Due to the different structures of the films, different properties were observed as a preferential intermolecular arrangement in LB films with respect to cast film.

Self-Assembly of Dendrimers in Layers

Figure 13.8

13.2.6

325

G1,5 fullerodendron for FET device fabrication

Other Examples

Among the various dendrons studied in the literature, Tsukruk and coworkers investigated the interfacial behavior of tree-like amphiphilic molecules incorporating three hydrophilic poly(ethylene oxide) branches attached to a hydrophobic octa-p-phenylene rod stem (Figure 13.9).68 The hydrophilic methyl-terminated dendron branches (a) assemble themselves in surface monolayers with the formation of (b) two-dimensional layered or (c) circular micellar structures examined by AFM. The formation of the planar ribbon-like structures with interdigitated layering within the loosely packed monolayers and circular, ring-like structures (two-dimensional circular aggregates) in the precollapsed state was suggested. Remarkably, such circular surface structures within planar monolayers had never been observed before. This is in contrast to the preferred three-dimensional spherical aggregates observed in solution for similar molecules when interfacial interactions do not contribute. Finally, Imae and coworkers69 illustrated how using the LB technique and an aza-C6PAMAM dendrimer derivative could led to the judicious fabrication of ordered metal nanoparticle monolayers (Figure 13.10). A 1.5th generation PAMAM dendrimer with an azacrown core, hexylene spacers, and octyl terminals was spread on a gold nanoparticle (Au-NP) suspension in water. The dendrimer L films on the Au-NP suspension were transferred to copper grids or on silicon substrate and examined by AFM, neutron and X-ray reflectivities. It was estimated that around 14 dendrimers bind to one Au-NP through their aza crown ring, and are localized on the upper half surface of Au-NP. The study highlights the fact that each unit of the dendrimer has a specific role for the film formation. The obtained films possess hexagonal lattice ordering of nanoparticles with half anchors on the dendrimer template and bare half surfaces as functional sites. It is noteworthy that, in these systems, the dendrimer shell could be functionalized for advanced applications.

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Dendrimers

Figure 13.9 (a) A tree-like amphiphilic molecule, (b) representation of its packing showing interdigitated layering, and (c) its circular planar structure

Figure 13.10 Formation of the dendrimer/Au-NP hybrid L film at the interface and transfer to the solid substrate

This last example illustrates how new objects can be produced using LB techniques and how new controlled and functionalized LB films can be developed as specific materials. However, the scope of this chapter does not focus on dendrimers or dendrons – for coating nanoparticles or as templates for the synthesis of nanoparticles (Chapter 6) – for modified electrodes as sensors (Chapter 14) – for the elaboration of DNA or biomicroarrays (Chapter 15) – or for elaboration of a modified surface obtained by spin-coating techniques.70,71 However, some examples of these subjects will now be provided in the following text.

13.3 Assemblies of Dendrons and Dendrimers on Solid Surfaces Self-assembled monolayers or SAMs are highly ordered two-dimensional structures formed spontaneously on a variety of surfaces. These chemisorbed monolayers can pas-

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sivate or modify the properties of the metal surfaces; however, as for LB layers, they can be used in surface patterning and bottom-up nanofabrication techniques (see Section 13.5). The most common SAMs (adsorbate/substrate) combinations are sulfur-containing molecules on gold72 and alkylsilanes on oxide surfaces.73 It is noteworthy that molecules of SAMs have a head group with a special affinity for the surface and can displace adsorbed materials from the substrate. The components of these molecules provide them with a number of useful properties and determine the atomic composition of the SAMs perpendicular to the surface. This latter interesting characteristic allows the use of organic synthesis to tailor organic or inorganic structures at the surface with positional control approaching ∼0.1 nm. The SAM thickness is typically 1–3 nm. In contrast to LB, their easy preparation does not require specialized equipment. They form on objects of all sizes as, for instance, nanowires or colloids, stabilizing them or adding them functions. They can also couple the external environment to the electronic and optical properties of metal structures. Moreover, microcontact printing (μCP), scanning probes, and beams of photons, electrons, or atoms may pattern SAMs in the plane of surfaces into forms having 10– 100 nm scale dimensions and phase-separated regions between constituent molecules having 100 nm2 scale dimensions.72,73 Although sulfur-containing molecules on gold have received the most attention, alkylsilanes on oxide surfaces as SiO2 are compatible with silicon technology and permit the use of optical techniques, such as fluorescence spectroscopy, as a read-out method. In the following section, we will illustrate by some examples the work done with dendrimers in this research field. The examples are classified according to the most common SAM (adsorbate/substrate) combinations, and also, when possible, by family of compounds.

13.3.1 Assembly of Dendrons and Dendrimers on Gold Surfaces In this field of research, the pioneering and comprehensive work of the group of R. M. Crooks has to be highlighted.74–82 This group focused its interest on producing, characterizing, and understanding the formation of self-assembling mono- and multilayers on the surface with PAMAM dendrimers. Two synthetic pathways establishing a covalent link between the dendrimer and the gold surface have been developed. The first one consists of the covalent link of the peripheral amino groups of the PAMAM dendrimer to the carboxylic acid functions of self-assembled monolayers (SAMs) of mercaptoundecanoic acid (MUA) on gold, leading to the formation of amide bonds.74 In the second case, PAMAM dendrimers were functionalized at the periphery with thiol groups and formed monolayers on gold.75 It is also noteworthy that the peripheric ramdom functionalization of dendrimers with thiol groups (around 20%) also led to monolayers in which nearly all the thiol functions are attached on the same side of the molecule to the surface. This fact evidences the flexibility of the molecule in order to minimize its free energy through interaction with the gold surface. When a gold (111) substrate was directly immersed in an ethanolic solution of PAMAM dendrimer, a stable monolayer was formed due to the chemisorption of terminal amines to the gold surfaces.76 These monolayers are more stable than those formed with primary n-alkylamine prepared in the same manner. Thus, the polydentate binding interactions realized between the amine functions of the dendrimers and the surface leads to a better

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stabilization of the monolayer. The chemical and physical properties of these amineterminated dendrimers were examined by a variety of analytical techniques and AFM was used to characterize the surface-bond conformations of the monolayers.77,78 The analyses showed that with different dendrimer generations (G1 to G8) terminated with amine or hydroxyl functions, stable and densely packed monolayers could be formed. For the dendrimers of higher generation the shape evolves from spheroidal in the bulk to a compressed, oblate configuration on the surface. The surface of the dendrimers is quite porous, but it produces slightly better diffusion barriers as it becomes more sterically crowded. Subsequent treatment of higher generation dendrimer monolayers with ethanolic solution of hexadecylthiol CH3(CH2)15SH (C16SH) results in dramatic compression and causes the dendrimers to reorient on the surface from an oblate to a prolate configuration. Thus, coadsorption of C16SH with a dendrimer monolayer induces a significant distortion of the structure. The primary driving force of this change seems to be terminal group solvation by suitable polar solvents. An important point is that the structure and stability of the monolayers are very sensitive to the conditions under which the single- and two-component monolayers are prepared. As illustrated by AFM, short-time preparation of the monolayer (<1 min) or low dendrimer concentrations [10−7 to 10−9 M] reduce the surface coverage and the film stability. Otherwise, interdigitation of dendrimer branches is a time-dependent aspect of the adsorption process, which may stabilize the monolayer and change its chemical and physical properties.77 A dynamic phase segregation process involving dendrimer/nalkylthiol mixed monolayers confined to Au(1,1,1) surfaces has been proposed, as indicated by Figure 13.11. The n-alkylthiol competes with the dendrimer to interact with the surface and causes the dendrimer to distort, phase-segregate, and finally to desorb. The same group also demonstrated that the nature of the peripheric functions of the dendrimers is of prime importance. Indeed, thiol-terminated PAMAM dendrimers do not phase-separate when exposed to ethanolic n-alkylthiol solutions. This suggests that one of the driving forces of this process is the difference in adsorption energies between the amine and the thiol groups and the Au substrate.78 Focusing on the properties of PAMAM surface-confined dendrimers, the group of Crooks has also shown that they can act as molecular gates in that they can be tailored to permit selective intradendrimer mass transfer such as redox probe through the interior of the dendrimer.79 New methods were also developed for surface immobilization and functionalization of PAMAM dendrimers on a gold surface, following the previous techniques. The idea was the development of dendrimer-based films as surface-confined chemical sensor arrays.80,81 In order to learn more about the rules governing organic chemistry at the vapor/solid interface for preparing functional films having technological applications,

Figure 13.11 n-alkylthiol

Proposed dynamic segregation process involving PAMAM dendrimer and

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the interfacial reactivity between the vapor or liquid-phase heptanoyl chloride and a hydroxyl-terminated fourth generation PAMAM dendrimer monolayer was examined and compared with other hydroxyl-terminated monolayers.82 Imae and coworkers examined the adsorption behavior of PAMAM dendrons with an aza crown core and long alkyl chain spacers toward gold and different SAMs83 by time-course attenuated total reflection-surface enhanced infrared adsorption and surface plasmon resonance spectroscopies. The adsorption of G2 amine-terminated dendrimer increased in the order dodecanethiol SAM < bare gold < 3-mercaptopropionic acid (MPA) SAM. On this latter SAM, it was concluded that the G2 dendrimer varied its conformation from the globular structures to the extended one perpendicular to the surface, while the G3 dendrimer quickly adsorbed with the perpendicular extended structure. This is explained by the fact that abundant terminal amine groups of the G3 dendrons led to stronger interactions with the carboxyl groups of MPA SAM than in the case of the G2 dendrons. For biological developments, fourth and fifth generations of poly(amidoamine) dendrimer monolayers were constructed on MUA SAMs on gold, and then the dendrimeric surface amine groups were functionalized with specific molecules.84,85 Functionalization with biotin analogs such as desthiobiotin produced a specific surface allowing association with avidin. Subsequent contact of this new surface with biotin induced avidin–biotin association and regenerated the specific surface. This process was employed for biospecific association/dissociation of biomolecules at the affinitysensing electrode surfaces.84 Functionalization with various ethylene glycol units (EGn, n = 3–5) also gave protein-resistant films.85 The EGn-modified dendrimer films resisted around 95% adsorption of fibrinogen. Remarkably, partially biotinylated-EG3 dendrimer films specifically bound avidin and gave rise to very good coverage of the surface by avidin (50 and 100%).84 Three dendrons constituted by polybenzyl ether moieties in the branches and at the periphery, and bearing a benzenethiol group at the focal point, were synthesized by C. B. Gorman and coworkers.86 Their self-assembled monolayers were prepared by immersing the polycrystalline gold substrate into a solution of organothiol dendrons. XPS measurements indicated that the dendrons were covalently bound to the surface as the aryl thiolate.87 Ellipsometry data showed that while the surface coverage was close to 100% for the G1 and G2 dendrons, the thickness of the G3 SAMs indicated incomplete surface coverage or flattening of the molecule. Capacitance and ferricyanide redox probe experiments evidenced a porous structure for the three adlayers. However, they showed different abilities to trap and hold a small molecule (trans-cyclohexanediol) within them. Carbosilane dendrons with a bromophenyl group (PhBr) at the focal point and three (for G0) or nine (for G1) thiol groups at the periphery formed SAMs on gold surfaces (Figure 13.12).88 For the G0 and G1 dendrons, respectively, about 20 and 28% of the S atoms were unbound to the surface. XPS and ellipsometry data revealed a flattening of the dendrons for maximizing the bonding of the SH groups with the surface. The spacing between the functional (–PhBr) groups can be controlled by the generation of the dendron and the thermal stability of the film was enhanced compared to octanethiolate SAMs on gold. C. Caï and coworkers showed that the PhBr groups could be used to anchor conjugated molecules on to the films under the Heck reaction. It was the first palladium-catalyzed coupling reaction performed on thiolate films.88 Recently, Reinhoudt and coworkers have developed a new concept for the production of peculiar SAMs of dendrimers based on the use of “molecular printboards”.89 These are

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Figure 13.12 Formula of G0 and G1 PhBr dendrons, and possible orientations of the G0 dendron on a gold surface

Figure 13.13

Schematization of the principe of a “molecular printboard”

β-cyclodextrin (β-CD) functionalized SAM adsorbates on a gold (or silicon oxide) surface, as schematized in Figure 13.13. Owing to their specific β-CD cavities, they are able to constitute a suitable host for different molecules, as for instance adamantyl (Ad) functionalized PPI dendrimers ranging from 4–64 Ad groups per molecule after their formation of water-soluble assemblies by cyclodextrin. The resulting host–guest supramolecular interactions led to well-ordered, densely packed monolayers on gold. In fact, the host surface can position multivalent guest molecules. The control of adsorption or desorption processes of the host by an environmental stimuli (electrochemistry) or by competition with another host in solution has been envisaged. It was elegantly demonstrated with ferrocenyl (Fc) and biferrocenyl (biFc) functionalized PPI dendrimer–cyclodextrin assemblies.90–92 The number of interactions, increasing with the dendrimer size, was determined by cyclic voltammetry (CV) and surface plasmon resonance (SPR).93 13.3.2 Assembly of Dendrons and Dendrimers on Silicon Substrates or Related Substrates J. M. J. Fréchet and coworkers modified silicon substrates using two main pathways. They designed PBzE dendrons protected at the periphery with either benzyl ether or tert-

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butyldiphenylsilyl ether groups and functionalized at the focal point with a long alkyl chain bearing a terminal chlorosilane coupling agent.94 To realize the covalent attachment to the silicon wafer surface, polished, n-type Si(000) wafers were cleaned and surface-oxidized prior to immersion in a piranha bath for 30 min at 120 °C. Then, the self-assembled monolayers were prepared by immersing the wafers in a solution of the desired silyl chloride dendrimer (5 mM) in distilled toluene. The film thickness was estimated between 35 and 45 Å. Owing to the hydrophilic silanol surface, the monolayer is constituted of dendrimers attached through Si–O bonds to the surface, and no multilayers could be formed. Alternatively, ionically bound dendrimers were prepared by the same team using an acid/ base self-assembly process.95 Several amphiphilic PBzE dendrons with carboxylic acids at either the focal point or the periphery have been prepared (see Section 13.5). Their respective monolayer could be assembled on a positively charged aminated silicon wafer surface prepared by pretreatment of the clean silicon surface with (3-aminopropyl)triethoxysilane (APTES). In each case, this leads to a stable film via formation of an ammonium salt of the functionalized dendrimer. The dendrimer bearing several carboxylic acid functions presents a higher affinity for the ammonium surface, which induces its slight flattening. Its film thickness and roughness are, respectively, 34 ± 2 Å and 5.8 Å. Under acidic conditions, removal of this latter film from the surface by protonation of the carboxylate moieties is harder than those of other dendrimers. All these Fréchet dendrimers were designed for use as resists for scanning probe lithography (SPL) (see Section 13.5). Tsukruk and coworkers also reported brilliant examples of self-assembled monolayers fabricated by an electrostatic deposition technique.96,97 This was done, for instance, by preparing first activated silicon substrates with a negative net charge induced by preliminary treatment at pH > 2. Then, these substrates were immersed in a 1% amine-terminated PAMAM dendrimer solution in Milli-Q water, rinsed with water and dried with a stream of nitrogen. The films are stable and the monolayer microroughness is close to that of the supporting substrates. The dendrimeric macromolecules are not only collapsed but are highly compressed along the surface normal and flattened. Thicknesses of the G4, G6, and G10 PAMAM monolayers are respectively 1.8, 2.8, and 5.6 nm. Electrostatic self-assembly of PAMAM dendrimers with terminal carboxylic negative groups was also performed with a positively charged surface of SAM of organic molecules (APTES) on a silicon wafer.97 To sum up, the general electrostatic self-assembly of dendrimers is presented Figure 13.14. Negatively charged native silicon or a positively charged surface of a self-assembled monolayer of organic molecules (for example APTES) are used for electrostatic adsorption of oppositely charged dendrimer molecules with ammonium (positive) or terminal carboxylate (negative) groups. The terminal groups of both substrate or adsorbate molecules are ionized by appropriate pH conditions. The adsorption behavior of some dendrimers on mica has also been investigated by several authors and information has been collected. H. Frey and coworkers98 showed that carbosilane dendrimers with mesogenic cholesteryl units on the periphery could lead to self-assembled ultrathin films (5–15 nm) on mica. Flat homogeneous films of two to four dendrimer layers were obtained when a high concentration of dendrimer solution was used. A single dendrimer monolayer exhibiting an irregular cellular pattern of holes was observed for low dendrimer concentrations. Annealing of the G3 dendrimer films, whose periphery is densely packed with mesogens, did not show dewetting or reorientation, contrary to the G1–G2 films (see Chapter 5 for other examples of liquid crystal dendrimers). It was

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Figure 13.14 General scheme of electrostatic self-assembly of dendrons and dendrimers on a silicon substrate

Figure 13.15

Chemical formula of the SiCl3-terminated G3 carbosilane dendron

attributed to the lower molecular mobility of G3 molecules. However, it has to be mentioned that in this latter case, spin coating was used to deposit the dendrimers. Caï and coworkers99 found evidence that SiCl3-terminated carbosilane dendrons (Figure 13.15) deposited on mica spontaneously adopted well-defined submicrometer ring structures across the surface (inner diameter of 450–550 nm). In this case, the terminal functions are hydrolyzed to Si(OH)3 groups by surface-bond and absorbed water, and intermolecular condensation may occur at room temperature. They cannot covalently bond to the mica surface, which does not contain OH groups, but undergo substantial condensation after curing to form a crosslinked network of Si–O–Si groups at elevated temperature. The results suggest that the dendrons fully cover the hydrophilic mica surface with all their SiOR (R = H or OSi), giving a hydrophobic film

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Figure 13.16 on mica

333

Schematic illustration of adsorption of PAMAM surface-block dendrimer G3

surface composed mostly of –CH2 groups. The ring structures are formed on this underlying layer of the dendrons physisorbed on mica (there is no ring structure for a monolayer coverage). The authors suggested that such ring structures could be used to isolate ensembles of macromolecules or nanoparticles for study by scanning probe microscopy.99 Previously, S. S. Sheiko and coworkers100 studied the wetting of a carbosilane dendrimer containing hydroxyl terminal groups on a mica surface by spin casting. The molecules segregated into microscopic droplets with a finite contact angle. It was established that, in the first layer, due to the preferential adsorption of the end –OH groups on the SiO2 surface, the hydrocarbon core was effectively also exposed to air, as in the case of dendrons studied by Caï and coworkers.99 Drops were formed due to the autophobic spreading of the carbosilane dendrimers on mica. This interpretation was consistent with scanning force microscopy (SFM) studies and molecular dynamic simulation. To investigate the formation of organized adlayers on solid substrates, Imae and coworkers compared the adsorption behavior of PAMAM dendrimer with those of amphiphilic AB-type surface-block dendrimers (Gn, n = 3 and 4) with hydroxyl group/n-hexyl group terminals on mica (Figure 13.16).101 The adsorption films prepared from an aqueous PAMAM dendrimer/HCl solution of 0.01 wt% were examined by AFM. The surface was uniformly flat and no ordering of molecules was observed, whatever the adsorption time. On the other hand, when freshly cleaved mica substrate was dipped into aqueous amphiphilic surface-block dendrimers, bilayers with a thickness of 6.0 ± 0.5 nm and 7.35 ± 0.15 nm, respectively, for G3 and G4 were formed. There was accumulation of bilayers due to their amphiphilic nature. In layers, dendrimers take a “pancake structure” formed by pairing between hydrophobic blocks bearing hexyl terminal functions. The adsorption film surface has a hydrophilic character. The adsorption proceeds more for the G3 than for the other dendrimers in relation to their hydrophobicity. Other AB-type surface-block dendrimers of different generations with amine/n-hexyl terminal groups and glucosamine/n-hexyl terminal groups were also examined.102 Whereas the latter displayed a rather flat structure, the others again formed dimer-unit layers. The whole adlayer thickness and the orientation of the molecules in the adlayers depended on the hydrophilic surface block and the generation. It was evident that the adsorption did not obey the Langmuir adsorption kinetics but did fit the two-step mechanism: fast and slow adsorption steps. Various silicon-related substrates were also tested for the deposition of dendrimers. Recently, M. Borkovec and coworkers studied the adsorption of PAMAM dendrimers to silica substrates by optical reflectometry and AFM.103 They showed that the initial

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adsorption rate is a first-order one with respect to the dendrimer concentration. This could be expected for an adsorption process driven by attractive forces between the dendrimers and the surface. It was also demonstrated that, for later stages, the maximum adsorbed amount increases strongly with the ionic strength and pH. Other SiO2-related substrates have been used in order to control the attachment of a monolayer to solid surfaces by the covalent approach. Plasma polymerization of maleic anhydride produced a well-adhered layer on to glass slides and J. P. S. Badyal and coworkers succeeded in immobilizing amine-terminated PAMAM dendrimers on to functionalized pulsed plasma polymer surfaces via amide linkage formation.104 The G4 PAMAM dendrimers are slightly flattened out on the maleic anhydride plasma polymer surface in order to maximize bond formation. Their width was about 5.30 ± 0.04 nm instead of 4.5 nm for a spherical shape. Interestingly, the packing density of the dendrimers at the surface could be controlled either by diluting the dendrimer solution or by varying the level of anhydride group incorporation during plasma polymer film deposition. The external amine groups associated with the fixed dendrimers were available for further chemical reaction as fluorination or imidization. Following the immobilizing process, when the dendrimer was sandwiched between two plasma polymer-coated polypropylene films and heated, adhesion was obtained. The new material formed also revealed an interesting improvement in the O2 gas barrier behavior. The group of A.-M. Caminade and J.-P. Majoral was interested in creating new materials based on the phosphorus dendrimers PPH, which are dendrimers possessing a phosphorus atom at each branching point (see Chapter 1).105 In this context, they have covalently grafted aldehyde-terminated phosphorus dendrimers to quartz plates previously modified by aminosilanes.106 Each dendrimer is strongly bound to the surface by several aldehyde groups, and the modification of the surface induces a noticeable lowering of the wettability of the plates when compared to the untreated plates. This latter property reveals the hydrophobic character of these dendrimers.107 Interestingly, the remaining available aldehyde functions of the dendrimers may be involved either in the grafting of a second layer of dendrimers bearing terminal NH2 functions (PAMAM) or for the immobilization of proteins, as shown in the case of human serum albumin.106 This team also succeeded in generating densely packed monolayers on various substrates such as silicon, when using a four-generation dendrimer with 96 thiol functions at its periphery and a special experimental setup.108

13.4

Several Routes for the Formation of Dendron or Dendrimer Multilayers

The formation of multilayers provides new composite or hybrid films devoted to the development of innovative and efficient materials in a wide range of applications, also covering nanomaterial science as the realization of bioarrays or dendrichips. As previously evoked, multilayers can be prepared by assembling monolayers using the LB technique or SAM techniques. However, different routes have been developed and some of them are illustrated in this section.

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Figure 13.17 Schematic drawing showing how to build a Gantrez multilayer of PAMAM dendrimer G4 on an amino-functionalized silica/silicon wafer

Although the use of polymers for the formation of composite films is not an objective of this chapter, the approach of D. E. Bergbreiter, R. M. Crooks, and coworkers has to be mentioned as they have created remarkable PAMAM dendrimer–polyanhydride composite films on a variety of substrates.109–111 To achieve this goal, an amino-functionalized surface is first prepared and treated with a solution of poly[maleic anhydride-co-(methyl vinyl ether)] (Gantrez™), which reacts with the surface through an amide bound formation with the maleic anhydride monomer units. This modified surface is treated with PAMAM solution, which creates new amide bonds with the remaining anhydrides of the Gantrez polymer. A multilayer of the two components is built by their alternating deposition (Figure 13.17). These composite films function as pH-sensitive membranes. Indeed, they were coated on a gold electrode and, depending on the pH used, they are permeable only to cations (or anions). At neutral pH, both species can diffuse through the electrode. When these robust composite films are heated at 120 °C, they produce new films highly impermeable to ionic species whatever the studied pH, thus showing their potential use as a coating material for the prevention of corrosion. Later, Crooks and coworkers combined the microcontact technique (see Section 13.5) with this kind of sequential deposition to

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fabricate PAMAM–Gantrez composite multilayer films.112 This method could provide a convenient approach to pattern ultrathin films for specific applications such as the patterning of biological molecules. Alternative methods for dendrimer multilayer formation were also rapidly developed. They are characterized by the specific use of charged species. In the literature, the work of S. L. Regen and S. Watanabe is considered to be the earliest known study involving the assembly of dendrimers on to solid surfaces based on the formation of dendrimer composite multilayers.113 Interestingly, a coordination chemistry approach has been used to produce the thin films. An aminated surface was prepared by treating an oxidized silicon surface with APDMES. Adsorption of K2PtCl4 from solution generated new surfaces that subsequently reacted with amine-terminated groups of absorbed PAMAM dendrimers. A multilayer of dendrimers with thicknesses of ca. 100 nm was formed when repeating this process many times. The group of Tsukruk, inspired by the methods developed by R. K. Iler114 and G. Decher and coworkers,115,116 explored the alternating electrostatic layer-bylayer deposition of oppositely charged PAMAM dendrimers in the combination Gn/Gn-1/2.117 The building units are surface amine groups for generations Gn and carboxylic groups for generations Gn-1/2. Practically, activated silicon substrate with a negative net charge induced by preliminary treatment at pH > 2 is immersed in a 1% dendrimer solution in Milli-Q water. The films are then rinsed with water, dried with nitrogen, and used for a subsequent cycle of deposition. Deposition of the first layer of amine-terminated dendrimers is performed at pH < 3 to favor adsorption of the positively charged ammonium salts to the silicon surface. The deposition of the subsequent layer of carboxylic acid-terminated dendrimer occurs at pH > 6 to favor the assembly of the carboxylate salt on to the positively charged ammonium salt layer. Thus, composite molecular films of (Gn/Gn-1/2)x type, where x is the number of monolayers, are fabricated by electrostatic self-assembly of dendritic molecules of adjacent generations. Taking into account the results obtained for the thickness measurements of the mono- and multilayers (up to 20 layers), the charged PAMAM dendrimers assume a highly compressed or flattened conformation on the surface. This is attributed to the high interaction strength of the sticky groups of adjacent dendrimeric molecular layers. Other multilayer self-assembled films could be obtained from layer-by-layer deposition of dendrimers and low-mass ions.96 D. A. Tomalia and coworkers were interested in preparing nanoscale uniform PAMAM multilayers of gold-dendrimer nanoclusters.118 The fabrication procedure is the following: a negatively charged support is prepared and a poly(dimethyl diallylammonium chloride) poly(sodium 4-styrenesulfonate) (PDAC/PSS) bilayer is deposited on its surface. This bilayer is built by subsequent immersion in cationic PDAC and anionic PPS solutions (2 mg mL−1). After appropriate rinsing and drying treatment, the modified substrate is immersed in a gold-PAMAM dendrimer solution (0.58 g L−1, pH 5 for gold) for 5 min. This process can be repeated until the desired number of bilayers of PSS/gold-dendrimer complex is obtained. X. Jia and coworkers119 described the preparation of an original photosensitive multilayer ultrathin film fabricated from the G1.5 PAMAM dendrimer (carboxylate salts) as polyanions and nitrocontaining diazoresin (NDR) as polycations via sequential deposition on mica. UV irradiation changed the linkage between the adjacent layers from ionic to covalent and decreased the layer thikness from 3.5 to 3.3 nm. In contrast to the unirradiated film, the new irradiated film showed no etching for 30 min in DMF, revealing its better stability toward the polar solvent under these conditions. Using the same LBL technique, J. A. Cox and coworkers fabricated

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organic–inorganic multilayer films based on the electrostatic attraction between polyoxometalate (POM: PMo12O403− or P2W18O626−) negatively charged layers and G4 PAMAM positively charged layers on treated quartz or gold surfaces.120 A three-dimensional distribution with a controlled population of catalytic centers favorable to the process of electrocatalyzation was researched. Well-defined self-assemblies with supramolecular structures were successfully obtained and mediated the reduction of iodate or nitride. The electrocatalytic properties of these films were accrued from the POM center. It is noteworthy that PAMAM dendrimers bearing NH2 terminal groups have also been assembled into LBL thin films through an electrostatic force of attraction with anionic polymers121–124 and studied for applications to drug delivery,122 electrochemical devices,123 and catalysis.124 While PAMAM-COOH has a lower toxicity than amine-terminated PAMAM, its use for constructing LBL films is limited.117,125 However, J.-I. Anzaï and coworkers recently reported the preparation of PAMAM-COOH and poly(methacrylic acid) PMA LBL thin films at precise acidic pH through electrostatic and hydrogen bondings. These sensitive films were successfully used for the pH-controlled release of dyes such as Rose Bengal.126 Important efforts have been done by the group of Caminade and Majoral in order to obtain multilayers of phosphorus dendrimers, eventually mixed with other components. These multilayers were prepared by the step-by-step superimposition of monolayers on a surface, either covalently, as explained above (Section 13.2), or by ionic interactions when dendrimers with peripheral charged groups are used.105 An important objective of this work was the formation of hybrid layered assemblies with a control of their internal supramolecular structure at the nanometer level. For example, a buildup of multilayers composed of polycationic phosphorus dendrimers and polystyrenesulfonic acid (PPS) in an alternative way was realized. The same process was used with polycationic dendrimers and glucose oxidase to generate multilayers (Figure 13.18). In another method, the luminescent properties of phosphorus dendrimers with a phthalocyanine core integrated in multilayer assemblies was monitored by surface plasmon fieldenhanced fluorescence spectroscopy.127 More recently, the covalent multilayer approach also led the group to the remarkable elaboration of biochips for the immobilization of biomolecules such as oligonucleotides on Si wafers.128,129 However, these results will be developed in Chapter 15. Caminade, Majoral, W. Knoll, and coworkers have also designed water-soluble phosphorus bisdendrons (surface-block or Janus dendrimers) for the construction of new LBL formed multilayers. In these bisdendrons, one of the two dendrons bears anionic groups (such as CO2−) in order to ensure solubility in water and easy surface modification (glass, quartz, etc.) via electrostatic interactions, while the other one easily bears quaternizable

Figure 13.18 Multilayers composed of monolayers of polycationic phosphorus dendrimer G4 and polystyrene sulfonic acid or glucose oxidase

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amino end groups.130 This type of bisdendron could be advantageously used for LBL deposition instead of alternating between polycationic and polyanionic dendrimers. Indeed, after deposition of the first layer of bisdendrons on a positively charged silica surface, the neutral NEt2 surface created by the bisdendron was quaternized using methyl iodide as the alkylating reagent. The resulting positive surface was then coated with the same bisdendron, and the reiteration of quaternization and adsorption sequences up to deposition of four layers produced the bisdendron thin film. This work constitutes a new strategy for various functionalizations of nanomaterials. These authors, in collaboration with D. H. Kim and coworkers, have also prepared hybrid organic–inorganic nanostructures containing metals and fabricated by LBL self-assembly.131,132 In the first case, the multilayer was formed by positively charged phosphorus dendrimers of the fourth generation with 96 NH+Et2Cl− terminal functions: G4(NH+Et2Cl−)96 and negatively charged hyperbranched polyglycerols PG50(COONa+)44, where 50 is the average number degree of polymerization and 44 the number of COOH groups per polymer molecule. Exploiting a binary reaction mechanism between water molecules trapped inside the film and TiCl4 precursors brought by chemical vapor deposition, they succeeded in generating TiO2 moieties inside the multilayers built on a 3-mercaptopropionic acid (3-MPA) gold surface.131 The amounts of TiO2 could be controlled by adding small amounts of salts in the dendrimer solution, which increased the porosity of the multilayers. The resulting hybrid film exhibited interesting photoluminescence properties. In the second case, multilayer films composed of Au nanoparticles (Au-NP) and cationic phosphorus dendrimers G4(NH+Et2Cl−)96 were also fabricated by an electrostatic LBL method.132 Interestingly, the localized surface plasmon resonance (LSPR) band of the hybrid films can be tuned either by adding NaCl to the dendrimer solution, which increases the distance between two neighboring anionic gold nanoparticles layers, or by removing the organic matrix (dendrimer layers) by UV irradiation (Figure 13.19). In this latter case, Au mesoporous films show LSPR sensing properties for alcohols with different refractive indices in the range 1.33–1.41. These two last examples show how dendrimeric architectures may serve as the template or scaffold for functional hybrid nanostructured materials.

Figure 13.19 Schematic diagram of the processes involved in the fabrication of the immobilized colloidal Au-NP and dendrimer multilayers on a substrate

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Figure 13.20 (a) Chemical structure of the N,N′-disubstituted hydrazine phosphoruscontaining dendrimers of the fourth generation (G4 polyelectrolyte) bearing six R identical branches and used in the LBL experiments

Another originality of Caminade, Majoral, Knoll, and coworkers was to examine the formation and behavior of their charged multilayers films, not only on planar surfaces but within preformed inorganic templates, to produce new objects. As an illustrative example, the ionic interactions between oppositively charged entities has been remarkably exploited for the template elaboration of nanotubes made of dendrimers.133 The used dendrimers have the specificity to possess one phosphorus atom at each branching point. They are water soluble, and bear negatively charged carboxylates or positively charged end groups as tertiary ammonium, as shown in Figure 13.20. To elaborate the nanotubes of dendrimers, a multistep procedure is followed. First, porous alumina templates are coated with APDMES, thus providing a positively charged surface inside the pores. Then, a negatively charged monolayer was deposited by immersing the template in a water solution of appropriate dendrimers. The positively charged G4 monolayer was subsequently deposited in this way. Twenty bilayers were deposited by alternately immersing the template in the appropriate solutions. Finally, an array of nanotubes was obtained by removal of the inorganic template. This array was the replica of the pores (Figure 13.21, top). SEM analysis of these open tubes indicated a length of 80 μm, an outer diameter of around 400 nm, and a thickness of the wall of 40 nm. These data reveal an important flattening of the dendrimer, whose expanded diameter is about 7 nm.134 More recently, the LBL deposition of polyelectrolyte dendrimers within cylindrical nanopores of anodic aluminum oxide (AAO) membranes was experimentally studied in situ by optical waveguide spectroscopy (OWS) and compared with regular deposition on a planar surface characterized by SPR (Figure 13.21, bottom).135 The effect of pore size and ionic strength of the dendrimer solutions were examined. The globular G4 polyelectrolyte was used as a model species for the deposition. The study quantifies in particular three interesting points. First, the deposition on top of the AAO on surfaces between the pore openings followed the behavior of the linear LBL deposition on a regular planar surface. Second, after an initial deposition regime, when the pores are significantly larger

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Figure 13.21 Schematic of the preparation of the phosphorus dendrimer nanotubes (top) and scheme illustrating the geometry of the polyelectrolyte multilayer experiments carried out within cylindrical nanopores of different diameters (D0), involving the interaction of charged dendrimers G4 with a positively charged surface obtained by silanization with APDMES (bottom)

than the diameter of the G4 polyelectrolyte (7 nm), LBL deposition within the pores is inhibited. Third, by adjusting the ionic strength of the deposition solution via the NaCl concentration, it is possible to deposit an LBL multilayer selectively. At low concentrations of NaCl, the deposition occurs on top of a nanoporous substrate, whatever the pore diameter (30–116 nm). Conversely, increasing the solution ionic strength, much greater than

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for experiments on flat surfaces with high NaCl concentrations, efficiently loads the polyelectrolytes within the nanopores. This study will aid in the template preparation of polyelectrolyte multilayer nanotubes and may be useful for investigating theories regarding the partitioning of nano-objects within nanopores where electrostatic interactions are dominant. At present, these latter studies are all the more remarkable by the fact that numerous applications, including separation and controlled drug release, gene delivery, analyte trapping, chemical catalysis within cavities, as well as sensor devices, have been suggested for LBL multilayered nanotubes.136 Caminade, Majoral, together with O. I. Vinogradova and coworkers, also focused on polyelectrolyte multilayer microcapsules incorporating dendrimers.137–139 The nanoshell of these capsules with a well-defined thickness structure represents an interesting freestanding multilayer film. In contrast to previous microcapsules made of oppositively charged linear flexible polyelectrolytes and of types of polyelectrolyte/DNA or inorganic nanoparticle or dye pairs, these new particles could allow two types of encapsulation, one in the microcapsule interior and the other in the dendrimer localized in the interior of the multilayer. Moreover, due to the composition of the multilayers presenting different types of interactions between components, new types of physical properties (elasticity, permeability, and stability) could be expected. The various microcapsules were first prepared as follows.137 A suspension of monodispersed weakly crosslinked melamine formaldehyde particles (MF particles) with a radius of around 2.0 μm was used as a template. This positively charged MF particles were then coated by the shell composed either of an alternating negatively charged layer, for instance poly(styrenesulfonate) (PSS), and a positively charged phosphorus dendrimer G4(+), or by alternating poly(allylamine hydrochloride) (PAH) and a negatively charged dendrimer G4(−). (PPS/G4(+))4, (PSS/G4(+))4(PSS/PAH), (PAH/G4(−))4, and (PAH/G4(−))4(PSS/PAH) coated MF particles were obtained. Exposing these systems to a pH of 1.1–1.6 HCl solution resulted in dissolution of the templates. Indeed, MF is expelled from the core via permeation through the multilayers upon appropriate dissolution and washing. According to the shell nature, there is a certain percentage of broken microcapsules. The same kind of problem had been observed previously by A, Khopade and F. Caruso preparing PSS/G4 PAMAM coated MF particles to test their drug delivery potential.122,140 However, coating the (PPS/G4(+))4 microcapsules by a final stabilizing PSS/PAH pair led to more than 80% ideal sphere-shaped microcapsules being obtained. Moreover, the (PAH/G4(−))4 coated MF particles led to unbroken microcapsules and represents the first successful attemps to prepare dendrimerbased capsules without a protective polyelectrolyte bilayer coating. The preparation of original DNA/phosphorus dendrimer multilayer microcapsules (DNA/G1–4(+))4 was also reported following the same concept.138 For each type of microcapsule, the corresponding type of multilayers were constructed on a planar support, which allows a linear growth of the multilayer film to be found by SPR after the first dendrimer layer. All of these phosphorus microcapsules are softer than those assembled from linear flexible polyelectrolyte of type PPS/PAH, as suggested by measuring force–deformation curves with AFM. It was also recently demonstrated that mechanical properties of these new nanometric objects could be tuned.139 Indeed, the addition of small amounts of THF (up to a volume of 7%) to the G3(+) dendrimer adsorption solution results in stiffening of the (PSS)/phosphorus dendrimer microcapsules without altering the multilayer thickness.

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Nanoimprinting of Dendrons and Dendrimers on Solid Surfaces

The generation of small structures (microfabrication) is very important for modern science and technology, in particular in microelectronics and optoelectronics.72,73 To control the properties of the surface regions, chemists have to create “chemically well-defined” surfaces. That implies the control of the placement, patterning, orientation, and packing of chemical functional groups on a surface. Therefore, the previous Langmuir–Blodgett, SAM, and LBL techniques have been developed. Then, to pattern (or write on) these surfaces, especially those using SAMs, two main strategies have been imagined, and will be considered successively in this section. First is the lithographic method,141 a negative printing technique, which relies on using scanning probe instruments, electron beams, or molecular beams to remove materials (SAMs or other resist layers) for subsequent processing or adsorptions steps. Second, soft lithography as a positive printing mode allows one to directly transport molecules to the substrate. For example, dip-pen lithography (DPN)142–144 uses an AFM tip as a “nib”, a solid Au substrate as paper, and molecules with a good affinity for the substrate as ink. There is a capillarity transport from the tip to the substrate and patterns of small collection molecules in submicrometer dimensions are formed. Entire patterns or series of patterns may also be deposited on the substrate in one step by using an elastomer stamp. This latter microcontact printing (μCp)145 technique constitutes another example of a complementary and simple soft lithography process. 13.5.1

Dendrimer-Based Self-Assembled Monolayers as Resists for Scanning Probe Lithography

In order to obtain faster and smaller semiconductor devices, both new materials and lithographic processes for nanofabrication have been developed. To create patterns with the nanometer-scale resolution, a lithographic process should manipulate materials made from molecules with dimensions no larger than the individual pixel that composes the image. In this context, Fréchet and coworkers have explored the use of PBzE dendrimers as passivation resists in scanning probe lithography (Figure 13.22(a)).94 This concept stems from several dendrimer properties. First, they have uniform size (several nm in diameter) and globular shape, which could serve as the ideal macromolecular template for a pixel-based approach to lithographic imaging. Second, ultrathin films prepared from dendrimers have a thickness much less than that of ordinary linear polymers obtained by spin-coating. Finally, the dendrimeric monolayers are more stable than the analogous alkylsilane monolayers of low molecular weight. Both types of Fréchet dendrimers described in Section 13.3.294,95 were tested on Si wafer to see if they could act in protecting or passivating the surface against a wet etching process. During the experiments, the conducting silicon tip of the scanning probe microscope is the exposure source brought into contact with the monolayer surface. A voltage is applied between the tip and the surface, inducing an intense electric field that decomposes the monolayer by oxidation in air. At a higher field strength, the silicon wafer may also be oxidized, as evidenced by raised sections of oxide relief on the surface. The etching process consists, for example, in immersing the wafer in aqueous fluoride, thus revealing the pat-

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Figure 13.22 (a) Structure of a representative monolayer obtained by covalent attachment of chlorosilane dendron to the silanol groups of the silicon surface and tested as a passivation resist in scanning probe lithography; (b) chemical formula of an amphiphilic PBzE dendron with a carboxylic acid function at the focal point

terns formed with the beam.94 Indeed, while oxidized materials are removed from the surface, the unexposed regions of the monolayer resist the etching process. Patterns created without optimization had features with dimensions below 60 nm. They were produced at a variety of scan speeds and voltages, and were imaged by AFM in contact mode. This process is useful for lithography, since the remaining unexposed regions of the film may serve as an etch mask, allowing for pattern transfer into the underlying silicon substrate. Under these conditions, pattern transfer may be accomplished by choosing an etchant that is either selective against the silicon oxide or the organic film. Other dendrimers have been designed by this team and were formed by amphiphilic PBzE dendrimers with carboxylic acid function(s) at either the focal point, as described in Figure 13.22(b), or at the periphery.95 In this case the dendrimers were ionically bound to the surface after self-assembly on APDMES wafers. The ultrathin films of monolayers may serve as either positive or negative tone resists for SPL. Patterning a single charged dendrimer monolayer resulted in the formation of a positive tone hole ∼35 nm in width, while patterning the multicharged dendrimer monolayer could result in the formation of negative tone oxide features ∼80 nm in width. This group also used G2 and G3 t-Boc-terminated PBzE dendrimers to generate films by spin-casting from propylene glycol methyl ether acetate.146 The resin formed was very sensitive to deep UV and electron beam exposure. Lines in the 50–100 nm range were routinely patterned in the resist using an electron beam at 50 keV, as shown by SEM images. This is the first example of a chemically amplified resist based on dendrimeric polymer resin. Moreover, a self-assembled dendrimer monolayer on thin Ti films were prepared and could be used as both positive and negative tone resists. For example, ca. 50 nm wide gaps in a thin Ti film and formation of TiO2 features ca. 25 nm wide and 12 nm tall on silicon oxide can easily be achieved using the drawn dendron (Figure 13.23).147 The covalent attachment of the dendron was realized by reaction of its triethoxysilane group and the surface hydroxyl groups on the native oxide of the Ti film.

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Figure 13.23 Schematic representation of the dendrimer-coated Ti films with two alternative routes for imaging positive or negative patterns

13.5.2

Microprinting, Transfer Printing, and Dip-Pen Nanolithography with Dendrimers

To transfer functional molecules on to surfaces on the nanometer scale, templates as patterns of self-assembled monolayers can be used to direct and control the selective deposition of molecules from solution. However, active deposition on to surfaces by means of a patterning element, for example as a stamp or a probe, is an alternative strategy. This type of transfer does not rely on expensive photolithographic procedures or does not require processing conditions incompatible with different interesting types of functions (biomolecules). It also avoids cross-contamination by nonspecific binding. Therefore, direct-patterning strategies, such as soft lithography and scanning-probe lithography (SPL),148 are widely used for immobilizing functional molecules on surfaces. Among these techniques, microcontact printing (μCP) of molecules on reactive SAMs on gold and dippen nanolithography (DPN) on gold are representative examples (Figure 13.24). The process of contact printing consists of three main steps: (1) replication of the nanoscale master structures in an elastomeric stamp; (2) inking the stamp with a molecule capable of forming a SAM on the substrate; (3) forming a conformal contact with a solid substrate.149 Printing patterns on gold with a stamp and alkenethiol “ink” followed by chemical etching were the first demonstration of μCP.150 However, a disadvantage of a long alkyl chain ink is the obvious diffusion during printing, which obscures the structure and limits the resolution. Taking that point into account, “heavyweight” molecules can be used as low-diffusion inks.151 N. T. S. Huck and coworkers have tested a new type of ink: dendrimers for high-resolution contact printing on silicon substrates.152 Nanocontact print-

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Figure 13.24 Schemes illustrating the principles of supramolecular μCP (left) and supramolecular DPN (right) on a CD SAM on an Au/silicon substrate: (a) inking with the dendrimer solution and (b) contact with the printboard surface

ing with modified poly(dimethylsiloxane) (PDMS) stamps on silicon with amine-terminated PAMAM G4 dendrimer as the ink was carried out. Periodic dendrimer lines could be printed with widths of 140 nm and 70 nm without noticeable diffusion. AFM measurements show that a single layer of dendrimer molecules can be transferred. The printed pattern is only determined by the conformal contact area, which is determined by the mechanical properties of the used stamp. A. M. Bittner and coworkers were interested by electroless deposition (ELD) of metal on dendrimer micropatterns.153 They showed that different submicrometric metallic patterns can be formed with high spatial selectivity on nonconducting surfaces, based on very simple wet chemical processes. Hydroxyl PAMAM dendrimers were microcontact-printed on silicon wafers and absorbed Pd2+ guest ions in the layers. These ions acted as nucleation centers for electroless cobalt plating. This team has also imagined a multistep metallization process.154 The microcontact printing of a passivation layer on Au or oxidized silicon wafer is followed by adsorption of functionalized PAMAM dendrimers on the bare areas. Then, Pd2+ guest ions are complexed by the amines, amides, or carboxylate functions of the dendrimers. After reduction, the formation of clusters provides chemically well-defined nuclei for the ELD of metals such as Cu or Pd. These examples of adsorption of metal ions into micropatterned dendrimer layers constitute a simple and interesting access to micro- and nanostructures on surfaces that are of relevance to microelectronics. In contrast with microcontact printing techniques, microtransfer molding (μTM)145 presents the advantage to produce thick layers. Thibault and coworkers have used this

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technique to deposit nanostructured pattern multilayers of G4 aldehyde hydrophobic phosphorus containing dendrimer on silicon wafers.155 PDMS stamps were used, and the process enabled good control of the thickness in the range of 45–85 nm via the dendrimer concentration. Features from 250 nm down to 40 nm could be transferred because of the low diffusivity of the dendrimer ink, revealing it as an ideal candidate for three-dimensional soft lithography. The group of Reinhoudt has successfully used microprinting and dip-pen nanolithography for writing patterns of guest-functionalized calixarene molecules, dendrimeric wedges labeled with fluorescent groups, and dendrimers on “β-CD-terminated printboards”.156–159 β-CD printboards were also developed on silicon oxide as SiO2 which permits fluorescence detection of the assemblies, whereas quenching occurs for SAMs on gold. The favored studied dendrimer of this team is the PPI dendrimer. As a selected example, directed immobilization of a third-generation PPI dendrimer − (β-CD) assembly: G3-PPI−(Fc)16−(βCD)16 – at the printboard was realized by microcontact printing.156,159 The new printed surfaces were visualized by AFM. In this case, scanning electrochemical microscopy (SECM) can electrochemically induce the desorption of the Fc dendrimers from a molecular printboard. Indeed, Fc moieties of the neutral dendrimers are able to form inclusion complexes with (β-CD) of the printboard, while cationic Fc+ dendrimers generated by local oxidation resulting from SECM use cannot. The combination of supramolecular and electrochemical control of dendrimer adsorption appears here as a promising tool in the integration of “bottom-up” and “top-down” nanofabrication schemes. The local desorption of guest molecules by ultramicroelectrodes or smaller conductive AFM tips may give small template patterns exposing the molecular printboard to which other guest molecules may bind. Otherwise, the transfer of a series of guests with different valencies on to (β-CD)terminated SAMs and on to reference hydroxy-terminated SAMs was performed.157 Physical contact was sufficient to generate the corresponding patterns in each case. However, only molecular patterns of multivalent guests transferred on to (β-CD-) SAMs were stable under the rinsing conditions that caused the removal of the same guests from the reference SAMs. This fact reveals the originality of this strategy based on specific, multivalent supramolecular interactions. To write local patterns of molecules on the created printboard, supramolecular DPN was also employed.156,157 Silicon nitride AFM tips were dipped into an aqueous solution of the guest molecule ink for 15 min and scanned in contact mode along a line on (β-CD-) as well as OH-SAMs for a certain period of time.157 For instance, with the fifth generation dendrimer G5-PPI-(Ad)64 multivalent guest, an array of lines 3 μm long with average widths of approximatively 60 nm ± 20 nm was drawn over a (β-CD-) printboard. It was verified that scanning with an uninked AFM tip under the same conditions did not form any pattern as no molecule transfer occurred from the tip. A readout of the patterns was done with the same tip by increasing the scan size and velocity (around 15 times the writing speed). Interestingly, electroless deposition of metal patterns on the molecular printboards was also demonstrated. The same group also tried to write more elaborated patterns on to CD SAMs that are patterned layer-by-layer (LBL) assemblies.158 These LBL assemblies are formed by alternating layers of adamantyl PPI dendrimers and CD-terminated Au nanoparticles (CD Au-NPs) linked by the same multiple supramolecular interactions as those mentioned previously. Various patterning strategies have been developed. However, a lack of specifi-

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Figure 13.25 Nanotransfer printing on CD SAMs: preparation of patterned LBL assemblies: (a) oxidation of the PDMS surface, (b) LBL assembly on the PDMS stamp, (c) contact of the stamp with the CD SAMs

city of the adsorption of the dendrimer prevented the use of LBL assembly on chemically patterned SAMs prepared either by microcontact printing or nanoimprint lithography (NIL). Nanotransfer printing (nTP) solved that problem and was achieved by LBL assembly on a PDMS stamp followed by transfer on to a full CD SAM by contact, as schematized in Figure 13.25. Practically, the stamp with 10 μm lines and dots was oxidized by a UV/ozone treatment, resulting in a negatively charged surface. It was first immersed in an aqueous solution of the dendrimer to allow electrostatic adsorption of this monolayer; then alternating adsorption of CD Au-NPs and dendrimer with rinsing steps led to a complete multilayer on the stamp surface. The patterned PDMS stamp was put into contact with the CD substrate for 5 min. After removal of the stamp, rinsing, and drying, the patterns were observed by AFM. The above-mentioned electrostatic interactions between the stamps and the first dendrimer layer are apparently weaker than the host–guest interaction between the last dendrimer layer and the CD SAM. Thus, hybrid organic/metal-NPs nanostructures have been developed with control over three dimensions: x and y by the top-down methods and z by the LBL method (bottom assembly). Following the same transfer printing approach, Reinhoudt’s group was interested by a new method to replicate DNA and RNA microarrays,160 which is a fundamental tool for high-throughput genetic analysis. In this case, oxidized PDMS stamps, named “dendri-stamps”, were first modified with (G5-PPI) dendrimers inducing a high-density positive charge on their surface that can attract negatively charged nucleotides in an LBL arrangement. Thus, DNA and RNA can be transfer-printed from the stamps to the target surfaces. A robust connection between the aminopolynucleotide strand and the aldehyde-terminated support (glass) was then established

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Figure 13.26 Schematic drawing showing the multiple supramolecular β-CD host–guest interactions between β-CD PPI dendrimer functionalized with ferrocene and the molecular printboard in a [metal-CD SAM-dendrimer-CD SAM-metal] junction

via a covalent bond. AFM and confocal analysis showed that the nucleotides were distributed homogeneously within the patterned area and available for further hybridization. Finally, using a robotic spotting system, an array of hundreds of spots of oligonucleotide labeled with fluorescein could be deposited on the surface of a flat dendrimer-modified stamp. This was subsequently used for repeated replication of the entire microarray by microcontact printing. Homogeneous probe density and regular spot morphology characterized these printed microarrays. This easy and rapid method should facilitate microarray-fabricated substrates. Recently, Reinhoudt’s group also prepared [metal-CD SAM-dendrimer-CD SAMmetal] junctions using a new type of metal transfer printing (mTP) (Figure 13.26).161 The formation of this junction is based on the use of multiple β-CD host–guest interactions between a metal-coated stamp bearing a monolayer of host β-CD molecules and a substrate functionalized by the same host molecules. Supramolecular metal transfer printing (mTP) was realized by adsorption of multivalent guest molecules that act as supramolecular “glue” at either the stamp or the substrate (Figure 13.27). Fc-, biFc-, and Ad-functionalized PPI dendrimers were used as glue. For example, various metal patterns could be faithfully transferred with dimensions varying from 5 to 50 μM. Moreover, using electrostatic interactions between positively charged dendrimers and SiO2 substrates allowed the transfer of metal on SiO2 surfaces. This approach of nanofabrication will potentially lead to modular assembly protocols of nanoscale devices by self-organization. The transfer-printing concept with stamps was recently used by the group of J. Huskens and Reinhoudt to transfer sophisticated nanostructures as three-dimensional supramolecular particle structures162 or freestanding three-dimensional supramolecular particle bridges

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Figure 13.27

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Schematic illustration of supramolecular mTP on substrates (three routes)

or structures163,164 on to various CD-SAM functionalized surfaces. These structures were successfully built combining self-assembly of particles and LBL assembly of host- and guest-functionalized glues within the particles. Interestingly, the shape and geometry of these superstructures including β-CD-functionalized polystyrene nanoparticles could be tuned by the nature of the PDMS stamps and their properties, for instance, by the nature of the supramolecular dendrimer glue. This kind of ordered and stable supramolecular structure has been announced as potential materials for future sensing or photonic devices. Independently, B. J. Ravoo, Reinhoudt, and coworkers also used microcontact printing to immobilize oligonucleotides on glass substrates in well-defined micropatterns using dendrimer-modified stamps. In this special case, under the confinement induced by the PPI-dendrimer-modified stamp, acetylene-modified oligonucleotides reacted with an azide-terminated glass slide. The “click” reaction, realized without the toxic Cu(I) catalyst, led to the covalent and efficient immobilization of the oligonucleotides.165 After binding with fluorescent molecules, the substrates were imaged by using a laser-scanning fluorescent confocol microscope and analyzed by AFM. Otherwise, different three-dimensional bionanocomposites patterns containing G4 PAMAM dendrimers, two proteins, and polyelectrolytes multilayers have been successfully obtained by I. Lee and coworkers combining LBL and transfer printing (μCP) techniques.166 Such nanostructures have potential applications in drug screening devices, biocatalysis, and optoelectronic and other devices. Finally, microcontact printing with dendrimers was recently investigated using different

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stamps as, for the first time, porous stamps acting as ink reservoirs167 or elastomeric stamps structured by plasma treatment for patterning PAMAM dendrimers.168 Considering more specifically DPN using AFM tip as a “nanopen”, R. McKendry and coworkers focused on how the writing resolution is affected by surface chemistry and molecular weight of dendrimer inks on Si/SiOx surfaces.169 Patterns with 100 nm features were generated (∼20 dendrimer molecules) and it was demonstrated that increasing the molecular weight led to narrower lines when using heavier dendrimers with similar surface chemistry. H. Schönherr, G. J. Vancso, and coworkers used DPN to link PAMAM dendrimers covalently to terminated N-hydrosuccinimide derivative SAMs on gold surfaces.170–171 High-definition patterns of dendrimers down to 30 nm length scales were prepared with G5 PAMAM. The remaining amino groups of the deposited dendrimers could potentially anchor biomolecules to these new platforms allowing applications in the life sciences. H. Zhang and coworkers also created PAMAM dendrimer nanopatterns on Si/SiOx substrates by using DPN. Using them as anchoring scaffolds, the authors succeeded in controlling growth of peptide nanoarrays, which is of fundamental importance for biological assays.172 The easily obtained peptide nanostructures with various surface composition and feature sizes could find potential applications in, for example, cell-behavior studies.

13.6

Conclusion

Dendrons and dendrimers, aesthetical and appealing molecules, are, first of all, fascinating, adaptable, and “intelligent” building blocks, not only for the construction of complex innovative highly organized thin films or nanopatterns “nano-building” on various solid substrates but also for the construction of new nanometric objects with predeterminated shape and function such as nanotubes and microcapsules. This is the result of several combined factors. First, there is the intrinsic controlled nano-sized constitution and functionalization of dendrimers developed in Chapter 1, presenting numerous advantages over less elaborated smaller molecules or bigger ones with “less controlled” shape. Second, a “how to build knowledge” has been developed through the Langmuir-Blodgett, SAM, and LBL techniques. In parallel, the recent explosion of characterization techniques such as electronic microscopies contributes to a better visualization and better understanding of the produced dendrimeric constructions. Third, simple or sophisticated “how to write” techniques on this construction allowed their efficient and modern “customization” for desired and various uses. It is noteworthy that these latter techniques have been inspired by old lithography techniques or are issued from recent development of modern technology such as use of the AFM tip. The mixing adaptability and compatibility of dendrimeric objects with numerous different molecules belonging to the inorganic or biological world has to be highlighted. It increases the possible richness of the constitution of the thin films, nanobuilding on surfaces or nanometric objects,173 creating variety and tunability of their chemical and physical properties. Several routes are often possible to create these different materials. For instance, considering nanocomposite patterns, the combination of dendrimers with other chemical species can be realized via chemical pathways to create first a nanobuilding before its transfer to the surface or by reaction (or interaction) of a dendrimer monolayer with a predeterminated elaborated surface. However, self-assembly processes,

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electrostatic interactions, and varied supramolecular interactions can be used to create the nanocomposite structures. It is noteworthy that the “how to build” tools help in controlling the growth and ordering of these new dendrimeric materials in a more or less precise manner, and with more or less technical constraints. However, the numerous possible constraints (for example imposed by the LB technique) are also a chance in deeply controlling and reproducing an elaborate assembly of dendrimers by imposing a well-chosen simple parameter (temperature, pressure, concentration, solvent, etc.). Clearly, if efforts have still to be done for improving the characterization and for following the growth of the various produced dendrimeric materials on surfaces, the “how to write technology” is already powerful, especially when combined with the known construction tools and possibilities of dendrimer chemistry. Naturally, one can envisage to also employ other concepts or technologies to make this already important “how to do” with dendrimers on surfaces flourish. A promising chance is now open in this research field for the construction of tunable, innovative, and perfectly controlled materials with potential applications in all domains from nanoelectronic to biology. The necessary and key condition of its success seems to be the collaboration of talented chemists, physicists, and biologists and the limit is probably their imagination.

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(113) S. Watanabe and S. L. Regen (1994) Dendrimers as building blocks for multilayer construction. J. Am. Chem. Soc., 116, 8855–8856. (114) R. K. Iler (1966) Multilayers of colloidal particules. J. Colloid. Interface Sci., 21, 569–594. (115) G. Decher, Y. Lvov, and J. Schmitt (1994) Proof of multilayer structural organization in selfassembled polycation–polyanion molecular films. Thin Solid Films, 244, 772–777. (116) G. Decher (1997) Fuzzy nanoassemblies: toward layered polymeric multicomposites. Science, 277, 1232–1237. (117) V. V. Tsukruk, F. Rinderspacher, and V. N. Bliznyuk (1997) Self-assembled multilayer films from dendrimers. Langmuir, 13, 2171–2176. (118) J.-A. He, R. Valluzzi, K. Yang, T. Dolukhanyan, C. Sung, J. Kumar, S. K. Tripathy, L. Samuelson, L. Balogh, and D. A. Tomalia (1999) Electrostatic multilayer deposition of a gold–dendrimer nanocomposite. Chem. Mater, 11, 3268–3274. (119) J. Wang, J. Chen, X. Jia, W. Cao, and M. Li (2000) Self-assembly ultrathin films based on dendrimers. Chem. Commun., 511–512. (120) L. Cheng and J. A. Cox (2001) Preparation of multilayered nanocomposites of polyoxometalates and poly(amidoamine) dendrimers. Electrochem. Commun., 3, 285–289. (121) A. J. Khopade and F. Caruso (2002) Investigation of the factors influencing the formation of dendrimer/polyanion multilayer films. Langmuir, 18, 7669–7676. (122) A. J. Khopade and F. Caruso (2002) Stepwise self-assembled poly(amidoamine) dendrimer and poly(styrenesulfonate) microcapsules as sustained delivery vehicles. Biomacromolecules, 3, 1154–1162. (123) F. N. Crespilho, M. E. Ghica, M. Florescu, F. C. Nart, O. N. Oliveira, and C. M. A. Brett (2006) A strategy for enzyme immobilization on layer-by-layer dendrimer–gold nanoparticle electrocatalytic membrane incorporating redox mediator. Electrochem. Commun., 8, 1665–1670. (124) Z. Liu, X. Wang, H. Wu, and C. Li (2005) Silver nanocomposite layer-by-layer films based on assembled polyelectrolyte/dendrimer. J. Colloid. Interface Sci., 287, 604–611. (125) J. Yuan, D. Han, Y. Zhang, Y. F. Shen, Z. Wang, Q. Zhang, and L. Niu (2007) Electrostatic assembly of polyaniline and platinum–poly(amidoamine) dendrimers hybrid nanocomposite multilayer, and its electrocatalysis towards CO and O2. J. Electroanal. Chem., 599, 127–135. (126) S. Tomita, K. Sato, and J.-I. Anzaï (2008) Layer-by-layer assembled thin films composed of carboxyl-terminated poly(amidoamine) dendrimer as a pH-sensitive nano-device. J. Colloid. Interface Sci., 326, 35–40. (127) J. L. Hernandez-Lopez, R. E. Bauer, W.-S. Chang, G. Glasser, D. Grebel-Koehler, M. Klapper, M. Kreiter, J. Leclaire, J.-P. Majoral, S. Mittler, K. Müllen, K. Vaisilev, T. Weil, J. Wu, T. Zhu, and W. Knoll (2003) Functional polymers as nanoscopic building blocks. Mater. Sci. Engng, C23, 267–274. (128) E. Trévisiol, V. Leberre-Anton, J. Leclaire, G. Pratviel, A.-M. Caminade, J.-P. Majoral, J. M. François, and B. Meunier (2003) Dendrislides, dendrichips: a simple chemical functionalization of glass slides with phosphorus dendrimers as an effective mean for the preparation of biochips. New J. Chem., 27, 1713–1719. (129) V. Leberre, E. Trévisiol, A. Dagkessamanskaia, S. Sokol, A.-M. Caminade, J.-P. Majoral, B. Meunier, and J. M. François (2003) Dendrimeric coating of glass slides for sensitive DNA microarrays analysis. Nucleic Acid Res., 31, e88/1–e88/8. (130) V. Maraval, A. Maraval, G. Spataro, A.-M. Caminade, J.-P. Majoral, D. H. Kim, and W. Knoll (2006) Design of tailored multi-charged phosphorus surface-block dendrimers. New J. Chem., 30, 1731–1736. (131) D. H. Kim, O.-J. Lee, E. Barriau, X. Li, A.-M. Caminade, J.-P. Majoral, H. Frey, and W. Knoll (2006) Hybrid organic–inorganic nanostructures fabricated from layer-by-layer self-assembled multilayers of hyperbranched polyglycerols and phosphorus dendrimers. J. Nanosci. Nanotechnol, 6, 3871–3875. (132) W. B. Zhao, J. Park, A.-M. Caminade, S.-J. Jeong, Y. H. Jang, S. O. Kim, J.-P. Majoral, J. Cho, and D. H. Kim (2006) Localized surface plasmon resonance coupling in Au nanoparticles/ phosphorus dendrimer multilayer thin films fabricated by layer-by-layer self-assembly method. J. Mater. Chem., 19, 2006–2012.

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(133) D.-H. Kim, P. Karan, P. Göring, J. Leclaire, A.-M. Caminade, J.-P. Majoral, U. Gösele, M. Steinhart, and W. Knoll (2005) Formation of dendrimer nanotubes by layer-by-layer deposition. Small, 1, 99–102. (134) M. Slany, M. Bardaji, M. J. Casanove, A.-M. Caminade, J. P. Majoral, and B. Chaudret (1995) Dendrimer surface chemistry. Facile route to polyphosphines and their gold complexes. J. Am. Chem. Soc., 117, 9764–9765. (135) T. D. Lazzara, K. H. A. Lau, A. I. Abou-Kandil, A.-M. Caminade, J.-P. Majoral, and W. Knoll (2010) Polyelectrolyte layer-by-layer deposition in cylindrical nanopores. ACS Nano, 4, 3909–3920. (136) S. Hou, C. C. Harrell, L. Troffin, P. Kohli, and C. R. Martin (2004) Layer-by-layer nanotube template synthesis. J. Am. Chem. Soc., 126, 5674–5675. (137) B.-S. Kim, O. V. Lebedeva, D. H. Kim, A.-M. Caminade, J.-P. Majoral, W. Knoll, and O. I. Vinogradova (2005) Assembly and mechanical properties of phosphorus dendrimer/ polyelectrolyte multilayer microcapsules. Langmuir, 21, 7200–7206. (138) B.-S. Kim, O. V. Lebedeva, K. Koynov, H. Gong, A.-M. Caminade, J.-P. Majoral, and O. I. Vinogradova (2006) Effect of dendrimer generation on the assembly and mechanical properties of DNA/phosphorus dendrimer multilayer microcapsules. Macromolecules, 39, 5479–5483. (139) B.-S. Kim, O. V. Lebedeva, M.-K. Park, W. Knoll, A.-M. Caminade, J.-P. Majoral, and O. I. Vinogradova (2010) THF-induced stiffening of polyelectrolyte dendrimer multilayer microcapsules. Polymer, 51, 4525–4529. (140) A. Khopade and F. Caruso (2002) Electrostatically assembled polyelectrolyte/dendrimer multilayer films as ultrathin nanoreservoirs. Nano Lett., 2, 415–418. (141) B. Michel, A. Bernard, A. Bietsch, E. Delamarche, M. Geissler, D. Juncker, H. Kind, J. P. Renault, H. Rothuizen, H. Schmid, P Schmid-Winkel, R. Stutz, and H. Wolf (2001) Printing meets lithography: soft approaches to high resolution printing. IBM J. Res. Dev., 45, 697–719. (142) M. Jaschke and H.-J. Butt (1995) Deposition of organic materials by the tip of a scanning force microscope. Langmuir, 11, 1061–1064. (143) R. D. Pinner, J. Zhu, F. Xu, S. Hong, and C. A. Mirkin (1999) “Dip-pen” nanolithography. Science, 283, 661–663. (144) C. A. Mirkin, S. Hong, and R. D. Levine (2001) Dip-pen nanolithography: controlling surface architecture on the sub-100 nanometer length scale. Chem. Phys. Chem., 2, 37–39. (145) Y. Xia and G. M. Whitesides (1998) Soft lithography. Angew. Chem., Int. Ed., 37, 550–575. (146) D. C. Tully, A. R. Trimble, and J. M. Fréchet (2000) Dendrimers with thermally labile end groups: an alternative approach to chemically amplified resist materials designed for sub100 nm lithography. Adv. Mater., 12, 1118–1122. (147) M. Rolandi, I. Suez, H. Dai, and J. M. J. Fréchet (2004) Dendrimer monolayers as negative and positive tone resists for scanning probe lithography. Nano Lett., 4, 889–893. (148) S. Krämer, R. R. Fuierer, and C. B. Gorman (2003) Scanning probe lithography using selfassembled monolayers. Chem. Rev., 103, 4367–4418. (149) Y. Xia, M. Mrksich, E. Kim, and G. M. Whitesides (1995) Microcontact printing of octadecylsiloxane on the surface of silicon dioxide and its application in microfabrication. J. Am. Chem. Soc., 117, 9576–9577. (150) A. Kumar and G. M. Whitesides (1993) Features of gold having micrometer to centimeter dimensions can be formed through a combination of stamping with an elastomeric stamp and an alkanethiol “ink” followed by chemical etching. Appl. Phys. Lett., 63, 2002–2004. (151) M. Liebau, J. Huskens, and D. N. Reinhoudt (2001) Microcontact printing with heavy weight inks. Adv. Funct. Mater., 11, 147–150. (152) H. Li, D.-J. Kang, M. G. Blamire, and W. T. S. Huck (2002) High-resolution contact printing with dendrimer. Nano. Lett., 2, 347–349. (153) X. C. Wu, A. M. Bittner, and K. Kern (2002) Spatially selective electroless deposition of cobalt on oxide surfaces directed by microcontact printing of dendrimers. Langmuir, 18, 4984–4988. (154) A. M. Bittner, X. C. Wu, and K. Kern (2002) Electroless metallization of dendrimer-coated micropatterns. Adv. Funct. Mat., 12, 432–436.

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(155) C. Thibault, C. Severac, E. Trévisiol, and C. Vieu (2006) Microtransfer molding of hydrophobic dendrimer. Microelectronic Engng, 83, 1513–1516. (156) T. Auletta, B. Dordi, A. Mulder, A. Sartori, S. Onclin, C. M. Bruinink, M. Peter, C. A. Nijhuis, H. Beijleveld, H. Schönherr, G. J. Vancso, A. Castani, R. Ungaro, B. J. Ravoo, J. Huskens, and D. N. Reinhoudt (2004) Writing patterns of molecules on molecular printboards. Angew. Chem., Int. Ed., 43, 369–373. (157) C. M. Bruinink, C. A. Nijhuis, M. Peter, B. Dordi, O. Crespo-Biel, T. Auletta, A. Mulder, H. Schönherr, G. J. Vancso, J. Huskens, and D. N. Reinhoudt (2005) Supramolecular microcontact printing and dip-pen nanolithography on molecular printboards. Chem. Eur. J., 11, 3988–3996. (158) O. Crespo-Biel, B. Dordi, P. Maury, M. Peter, D. N. Reinhoudt, and J. Huskens (2006) Patterned, hybrid, multilayer nanostructures based on multivalent supramolecular interactions. Chem. Mater., 18, 2545–2551. (159) C. A. Nijhuis, J. K. Sinha, G. Wittstock, J. Huskens, B. J. Ravoo, and D. N. Reinhoudt (2006) Controlling the supramolecular assembly of redox-active dendrimers at molecular printboards by scanning electrochemical microscopy. Langmuir, 22, 9770–9775. (160) D. I. Roskiewicz, W. Brugman, R. M. Kerkhoven, B. J. Ravoo, and D. N. Reinhoudt (2007) Dendrimer-mediated transfer printing of DNA and RNA microarrays. J. Am. Chem. Soc., 129, 11593–11599. (161) C. A. Nijhuis, J. ter Maat, S. Z. Bisri, M. H. H. Weusthof, C. Salm, J. Schmitz, B. J. Ravoo, J. Huskens, and D. N. Reinhoudt (2008) Preparation of metal–SAM–dendrimer–SAM–metal junctions by supramolecular metal transfer printing. New J. Chem., 32, 652–661. (162) X. Y Ling, I. Y. Phang, D. N. Reinhoudt, G. J. Vancso, and J. Huskens (2009) Transfer-printing and host–guest properties of 3D supramolecular particles structures. ACS Applied Materials and Interfaces, 1, 960-968. (163) X. Y Ling, I. Y. Phang, H. Schoenherr, D. N. Reinhoudt, G. J. Vancso, and J. Huskens (2009) Freestanding 3D supramolecular particle bridges and mechanical behavior. Small, 5, 1428–1435. (164) X. Y Ling, I. Y. Phang, W. Maijehburg, H. Schönherr, D. N. Reinhoudt, G. J. Vancso, and J. Huskens (2009) Free-standing 3D supramolecular hybrid particle structures. Angew. Chem., Int. Ed., 48, 983–987. (165) D. I. Rozkiewicz, J. Gierlich, G. A. Burley, K. Gutsmiedl, T. Carell, B. J. Ravoo, and D. N. Reinhoudt (2007) Transfer printing of DNA by “click” chemistry. Chem. Bio. Chem., 8, 1997–2002. (166) N. Kohli, R. M. Worden, and I. Lee (2007) Direct transfer of preformed patterned bionanocomposite films on polyelectrolyte multilayer templates. Macromol. Biosci., 7, 789–797. (167) H. Xu, X. Y Ling, J. van Bennekom, X. Duan, M. J. W. Ludden, D. N. Reinhoudt, M. Wessling, R. G. H. Lammertink, and J. Huskens (2009) Microcontact printing of dendrimers, proteins, and nanoparticles by porous stamps. J. Am. Chem. Soc., 131, 797–803. (168) H. Lalo and C. Vieu (2009) Nanoscale patterns of dendrimers obtained by soft lithography using elastomeric stamps spontaneously structured by plasma treatment. Langmuir, 25, 7752–7758. (169) R. McKendry, W. T. S. Huck, B. Weeks, M. Fiorini, C. Abell, and T. Rayment (2002) Creating nanoscale patterns of dendrimers on silicon surfaces with dip-pen nanolithography. Nano Lett., 2, 713–716. (170) G. H. Degenhart, B. Dordi, H. Schönherr, and G. J. Vancso (2004) Micro- and nanofabrication of robust reactive arrays based on the covalent coupling of dendrimers to activated monolayers. Langmuir, 20, 6216–6224. (171) R. B. Salazar, A. Shovsky, H. Schönherr, and G. J. Vancso (2006) Dip-pen nanolithography on (bio) reactive monolayer and block-copolymer platforms: deposition of lines of single macromolecules. Small, 2, 1274–1282. (172) X. Zhou, Y. Chen, B. Li, G. Lu, F. Y. C. Boey, J. Ma, and H. Zhang (2008) Controlled growth of peptide nanoarrays on Si/SiOx substrates. Small, 4, 1324–1328. (173) A.-M. Caminade and J.-P. Majoral (2010) Dendrimers and nanotubes: a fruitful association. Chem. Soc. Rev., 39, 2034–2047.

14 Dendrimers as Chemical Sensors Anne-Marie Caminade

14.1

Introduction

The development of a safer environment and life, which is one of the present aims of our societies, increases the demand for efficient equipments able to detect, for instance, traces of dangerous chemicals or pathogens. The desired properties of such sensors include high sensitivity, reliability, reproducibility, specificity, stability with time, temperature and humidity, and rapidity of detection. The present state of the art has already produced relatively efficient systems, but improvements are still needed, in particular in terms of sensitivity, specificity, and reproducibility. The use of dendrimers to improve the properties of sensors has been recognized relatively early,1 taking account of two main structural properties of dendrimers: their multiple terminal functions and their three-dimensional structure. In this chapter and the next, the word “sensor” should be taken in a wide sense, meaning something that converts an event into a signal that can be read by an observer or an instrument.2 The results about the use of dendrimers as sensors will be divided into two chapters; this one will concern chemical sensors, whereas the next one will concern biological sensors. This chapter about chemical sensors will be divided into three main parts. The first part will concern detection using dendrimers in solution; the multivalency of dendrimers is one of the important criteria for such a purpose. The second part will concern the modification of electrodes by electroactive dendrimers and their sensing properties. The third part will concern detection using dendrimers in the solid state; in this case, the threedimensional structure of dendrimers is the most important criteria, even if the dendrimers are generally flattened when deposited on a surface, compared to their shape in solution.3 Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Dendrimers as Chemical Sensors in Solution

Two main types of dendrimeric structures have been used as sensors in solution: either the probe is located at the core (this is in particular the case for porphyrins) or the probes are linked as terminal groups of the dendrimers. 14.2.1

Porphyrins and Other Macrocyclic Derivatives as the Core or Branches of Dendrimeric Sensors

It is well known that significant changes in absorption and emission spectra of free-base porphyrins can be observed when varying the pH of the solution. Using a free porphyrin as the core of polyglutamic dendrimers ended by carboxylates afforded sensitive pH indicators. Indeed, the fluorescence intensity was very low at acidic pH and increased with pH up to pH 4.1–4.6 (depending on the generation of the dendrimer). Higher pH values induced aggregation of the dendrimers and a decrease of the fluorescence intensity.4 The same type of compound was recently used for the acute measurement of proton concentration gradients in large unilamelar vesicles.5 An octa-substituted phthalocyanine as the core of phosphorus (PPH) dendrimers was also used as a pH-sensitive sensor. Furthermore, it was also an efficient probe for detecting the influence of the polarity of the dendrimeric branches upon the core.6 Some porphyrin dendrimers were also used as sensors for oxygen, which is known to be a quencher for the phosphorescence of porphyrins. This is, for instance, observed for a polyglutamic Pd-porphyrin. The intensity of the quenching depends both on the nature of the solvent and on the generation of the dendrimers, which can act as a barrier preventing the access of O2 to the core.7 These compounds were recently modified at the level of the core (symmetrically π-extended Pd and Pt porphyrins for tuning of the spectral parameters) and of the terminal groups (polyethyleneglycol for increasing the solubility in water and preventing interaction of the probe with its environment). This compound was used under physiological conditions, including for in vivo microscopy of the vascular pO2 in the rat brain.8 With the aim of using such properties for imaging oxygen in three dimensions, the phosphorescence quenching technique should be combined with two-photon laser scanning microscopy, but Pd and Pt porphyrin-based sensors have extremely low two-photon absorption (TPA) properties. Thus, the structure of the dendrimeric porphyrin was modified to incorporate an array of TPA chromophores, acting as an antenna for the porphyrin core but not directly linked to it, to prevent internal quenching.9 A series of Zn dendrimeric porphyrins in which the porphyrin(s) is not at the core but constitutes one layer of branches was synthesized and used for the chiroptical sensing of asymmetric ligating molecules. The ligation was detected by circular dichroism. The capability of chiroptical sensing is highly dependent on the generation number of the dendrimeric scaffold and a clear cooperative effect between the Zn-porphyrin units was demonstrated. An example of such dendrimers and guests is given in Figure 14.1.10 Besides porphyrins, other examples of macrocyclic dendrimeric derivatives used as sensors concern cyclam and bicyclam cores. When surrounded by naphthyl units, these compounds were used as fluorescence sensors for metal ions such as Zn2+ and Cu2+.11 Calix dendrimers (dendrimers incorporating calixarenes as constituents of their branches) were also found to be suitable as fluorescent probes for detecting the presence of metal cations.

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Figure 14.1 Example of a dendrimer having one layer of porphyrins, used as a sensor for chiral guests

A particular selectivity for the complexation (and hence the detection) of Al3+ and Ln3+ was observed.12 Another example in which the active center is located at the core (but is not a macrocycle) concerns a phenyleneethynylene dendron having an optically active BINOL as the core. This compound was used for the enantioselective recognition of amino alcohols. The rigid branches induced a dramatic enhancement in fluorescence intensity of the BINOL part, but interaction of its OH functions with amino alcohols led to fluorescence quenching.13 14.2.2 Terminal Groups of Dendrimers as Sensors in Solution Several examples of dendrimers having particular functions as terminal groups were used as sensors in solution. One of the first examples concerns a PPI dendrimer (G3) decorated

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with dansyl units at the periphery. This dendrimer is brightly fluorescent, but addition of Co2+ caused a strong quenching of the fluorescence intensity. It was shown that one Co2+ equivalent quenched 32 dansyl units (all the dansyl units of one molecule of dendrimer), which corresponds to an important signal amplification.14 Development of this work with larger generation fluorescent dendrimers also indicated that one Co2+ per dendrimer is sufficient to induce an almost total quenching of the fluorescence.15 PPI dendrimers were also used as sensitive pH sensors when functionalized by Methyl Orange (an azobenzene derivative) as terminal groups.16 Some examples of detection in solution were obtained by molecular recognition. Incorporation of 2,6-diamidopyridine units as branches of a small dendrimer allowed the molecular recognition of glutarimide through hydrogen bonds. The association was detected by 1H NMR titration experiments.17 A second generation adamantylurea-terminated PPI dendrimer was used for the binding of a guest having urea (for interaction through H-bonding) and a carboxylic, phosphonic, or sulfonic acid (for electrostatic interaction). The selectivity and strength of the interaction was assessed by mass spectrometry.18 Watersoluble aryl ether dendrimers having benzoate tethers were used for the detection of three cations of medical interest (acetylcholine, benzyltriethylammonium, and dopamine). The assembly by ion-pairing interaction with the terminal groups of dendrimers was investigated by 1H NMR spectroscopy.19 Metallic dendrimers ended by Pt(II) metal centers were used as gas sensors for the detection of SO2, which reversibly binds to Pt(II). The binding induces drastic color changes and allowed the detection of milligram quantities of toxic SO2 gas (Figure 14.2,

Figure 14.2

Structure of dendrimers for sensing toxic SO2 gas (left) and explosives (right)

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left).20 It was shown in particular that the selectivity toward SO2 is high and that the binding is fully reversible with air, allowing repeated absorption/desorption cycles,21 and also quantitative detection.22 Later on, these properties were used for assessing the permeability of nanofiltration membranes at ambient pressure.23 Besides toxic gas, other dendrimers were recently used for the detection of explosives in solution, in particular for 2,4,6-trinitrotoluene (TNT) derivatives. A dendrimer containing bisfluorene chromophores as branches (Figure 14.2, right) is brightly fluorescent (photoluminescence quantum yield close to 90%). Nitroaromatic compounds such as 1,4-dinitrobenzene, 2,4-dinitrotoluene, and 4-nitrotoluene, which are structurally similar to TNT, induce the quenching of the fluorescence intensity of the dendrimers.24 Dendrimers built with thiophene units as arms and triphenylamine centers were also used for sensing the same analytes.25 Very special examples of dendrimeric sensors in solution were obtained by crosslinking the olefinic terminal groups of dendrimers using Grubb’s catalyst. If the dendrimers have a core that can be cleaved and removed after the polymerization of the terminal groups, the internal void created by the removal of the core can be filled in by a host having a structure resembling that of the initial core. Such a type of monomolecular imprinting was used for the spectrophotometric detection of porphyrins26 and of diamines.27,28

14.3

Dendrimers as Electrochemical Sensors

Electrochemistry is a valuable technique for the design of sensor devices devoted to the recognition of cations, anions, or even neutral molecules, but it necessitates the selective binding of guest ions to a receptor having an electrochemical response, modified upon binding, or the guest ions should themselves have an electrochemical response.29 In particular, it is known that ferrocene/ferrocenium is a redox mediator to fabricate electrochemical glucose sensors.30 Indeed, ferrocene is a robust and versatile building block, which displays a reversible redox reaction and for which the electrochemical response is highly sensitive to its environment, particularly in the case of ferrocenyl dendrimers.31 Grafting ferrocenes as terminal groups of dendrimers should enhance the detection properties by strengthening the interaction between the ferrocenyl dendrimers and the electrode. Several reviews have emphasized the growing importance of this field,32 in particular those emanating from the group of D. Astruc, who has carried out the most important work related to the use of ferrocene dendrimers, such as electrochemical sensors.33,34 In their earlier examples, they demonstrated a dendritic effect when using a series of ferrocene dendrimers (Figure 14.3, left) as supramolecular redox sensors for the recognition of small anions, in particular H2PO4−, HSO4−, Cl−, and NO3−.35 Other examples reported the use of supramolecular assemblies, based on PPI G1 dendrimer as the core and ferrocene terminal dendrons for the detection of H2PO4−36 or based on gold nanoparticles covered by ferrocene dendrons for the detection of H2PO4−, HSO4−, and adenosine-5′-triphosphate (ATP2−) anions.37 Other series of ferrocene dendrimers were built with one or several layers of 1,2,3-triazoles as branches (Figure 14.3, right). As in the previous cases, these compounds were used for the detection of H2PO4− and ATP2−. Furthermore, due to the presence of the triazole rings, these ferrocene dendrimers were also able to detect Pd2+, Pt2+, and Cu+ or

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Figure 14.3

Two examples of ferrocene dendrimers usable for the detection of anions

Cu2+.38 The recognition becomes easier with increasing size of the dendrimer, the one having 243 ferrocenyl groups being the best.39 Another series of dendrimers having long alkyl chains terminated by ferrocenyl or pentamethyl ferrocenyl groups as surface functions were synthesized and used for the sensing of ATP2− anions.40 Other long alkyl chains terminated by ferrocenyl groups were grafted on to the surface of PPI dendrimers; selective recognition of H2PO4− over other anions was observed.41 PPI dendrimers were also used as scaffolds for the grafting of redox center [{CpFe(μ3-CO)}4] clusters, which were found useful for the sensing of H2PO4−, HSO4−, and ATP2− anions.42 Besides ferrocenes, some purely organic dendrimers enabled the elaboration of electrochemical sensors. Phosphorus-containing dendrimers (PPH) ended by tetrathiafulvalene (TTF) macrocyclic derivatives were used for elaborating modified electrodes by electrodeposition. These dendrimer films have the unique capability to detect the complexation/ expulsion of Ba2+. Indeed, the progressive addition of Ba2+ led to a positive shift of the first oxidation potential, corresponding to its complexation.43 Gold electrodes modified by a monolayer of G4 PAMAM dendrimers (NH2 terminal groups) enabled the voltametric detection of Cu2+ at picomolar concentrations.44 A gold electrode was also modified with 3-mercaptopropionic acid and with G4 PAMAM dendrimers, for which the unbound NH2 terminal groups were converted to 4-(trifluoromethylbenzamido) groups. These surfaces were used for the sensing of ions having an electrochemical response, such as [Ru(NH3)6]3+ and [Fe(CN)6]3−. It was shown that only the negatively charged ions can penetrate the two-component monolayer.45 Analogous experiments with 3-mercaptopropionic acid, G4 PAMAM dendrimers, and finally with gold nanoparticles, gave modified electrodes on which Prussian Blue was electrochemically deposited. This device has an excellent electrochemical response, usable for the detection of H2O2.46 Another example of an electrode modified by several layers concerns a glass carbon electrode first covered by multiwall

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carbon nanotubes, then covered by a layer of PAMAM–Au nanoparticle composite, and finally by acetylcholinesterase. This modified electrode is a biosensor with high sensitivity, good stability, and reproducibility for the detection of pesticides, in particular of carbofuran.47 The enzymatic activity of choline oxidase deposited with PAMAM G4 dendrimers on to an electrode was substantially depressed in the presence of organophosphate pesticides, affording a promising chip for the detection of environmental pollutants.48

14.4

Dendrimers on Modified Surfaces as Chemical Sensors

The elaboration of chemical sensor arrays are particularly useful for many analytical and detection applications.49 When using dendrimers for the elaboration of such devices, the dendrimers are linked/deposited on a solid surface and the analyte is in another phase, in contact with the solid phase. This second phase can be a liquid containing the analyte or the analyte can be in a gas phase. 14.4.1

Dendrimers on Surfaces at the Interface with a Solution

Using dendrimers on a solid surface gives access to new detection methods, when compared to the detection in solution. In particular, optical sensors based on surface plasmon resonance (SPR) allow real-time monitoring processes to occur at solid surfaces. This method was applied for monitoring the interaction between G5 PPI dendrimers immobilized on the SPR sensor and seven dye molecules in aqueous solutions. It was shown in particular that Rose Bengal has a high affinity for the interior of these dendrimers.50 The SPR technique was also used for sensing chemical nerve agent derivatives. A modified PAMAM carbazole dendrimer loaded with Cu2+ at the periphery was electropolymerized. The carbazole was used for the polymerization and the Cu2+ for the interaction with the analytes in acetate buffer. The analytes are pinacolyl methyl phosphate (PMP) and methyl phosphonic acid (MPA), which are hydrolysis products of toxic nerve agents, and other phosphorylated derivatives. Selectivity toward PMP was observed; it was detected with a sensitivity at the nanomolar concentration level.51 Competitive inhibition immunoassay procedures were used for the detection of explosive TNT by surface plasmon resonance. This sensor chip technology was based on PAMAM G4 dendrimer deposited on a gold chip interacting with an antigen, itself recognized by an antibody. This modified surface has shown a detection limit of 110 ppt for the TNT molecule and was found to be regenerable.52 Other classical detection methods have also been used, in particular fluorescence. For instance, a small Janus dendrimer bearing two phosphonate groups on one side for the grafting to a nanocrystalline mesoporous TiO2 thin film (both on the surface and inside the pores) and five fluorescent groups on the other side was used for the detection of hazardous phenols, including mono-, di-, and trinitrophenols. Indeed, solutions containing these phenols induced the quenching of the fluorescence of the film dendrimer–TiO2. The quenching response was much more efficient when the dendrimer was linked to the TiO2 film than in solution, demonstrating the efficiency of this new hybrid optical sensor.53

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Figure 14.4 Structure of the Janus dendrimer used for the detection of phenols and the efficiency of detection, depending on the structure of the phenols

Figure 14.4 displays the efficiency of detection of this device toward various phenols and also towards alcohol (pentanol) and water. PAMAM dendrimers partly functionalized with dansyl fluorophores and crosslinked with a siloxane were cast on to glass slides and cured into robust nanostructured coatings. This device was tested against various analytes, including the chemical warfare agent simulating dimethyl methylphosphonate.54 Xerogel sensing films were obtained by mixing small poly(amido-organosilicon) dendrimers, Mn(III) porphyrin derivatives, and methyltrimethoxysilane. The Mn(III) porphyrin allowed the selective detection of HNO in solution. The presence of the dendrimer enhanced the sensitivity of the device by increasing the nitroxyl penetration in the sensor film.55 Several examples of chemical sensors associate dendrimers and various types of nanoparticles (NPs). For instance, PAMAM dendrimers were coupled to gold NPs via a heterobifunctional dithiocarbamate reagent, forming crosslinked nanocomposite films. These films deposited on aminofunctionalized substrates were used for the detection of acids, bases, water, and organic solvents, which all induced reversible optical responses.56 PPI dendrimers–CdS quantum dot (QD) nanocomposites were used for sensing mercury(II), which induced the quenching of the fluorescence of the QDs.57 Adamantyl-terminated PPI dendrimers linked to a glass slide, in combination with QDs functionalized at the periphery with β-cyclodextrin, afforded luminescent surface patterns. Complex formation between these devices and ferrocene-functionalized molecules led to the partial quenching of the luminescence of the QDs.58 14.4.2

Dendrimers on Surfaces at the Interface with a Vapor

The use of dendrimers for such a purpose was proposed early. The first example concerned the grafting of G8 PAMAM dendrimers to a mercaptoundecanoic acid self-assembled

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monolayer, via amide bond formation. The resulting monolayer film of dendrimer is a chemically sensitive interface for sensing various types of vapors, detected by surface acoustic wave mass balance. The response of this sensor to volatile organic compounds decreased in the order acids > alcohols > hydrophobic compounds.1 It was shown that the sorption of organic vapors causes a large increase in the conductivity of polyamido dendrimers modified peripherally with oligothiophene groups.59 Analogous experiments were conducted with PPI dendrimers having various types of terminal groups. With amine terminal groups, the highest loading was for alcohols, via hydrogen bonding; with phenylamide terminal groups, an enhanced loading was observed for aromatic compounds, via π-stacking interactions.60 A polybenzyl ether was coated on to the surface of a quartz microbalance and used for the sensing of carbonyl compounds in the vapor phase. A selectivity of binding was observed for electron-rich arene derivatives.61 Polyphenylene dendrimers have a rigid framework, even in the solid phase, and this property should afford sensors with increased sensitivity. They were also coated on the surface of a quartz microbalance, and then exposed to different volatile organic compounds (VOCs). These devices were very selective to polar aromatic VOCs such as acetophenone, aniline, benzaldehyde, etc. Neither chlorinated nor unsubstituted aliphatic hydrocarbons, alcohols, amines, or carbonyl compounds were included in the layers of dendrimers, showing a high selectivity, attributed to the favored interactions with the exclusively aromatic skeleton.62 Modified polyphenylene dendrimers, in which some phenyl groups were replaced by pyridine groups, were also recently deposited on a quartz microbalance. These compounds display a high sensitivity for the detection of the explosive triacetone triperoxide.63 Very recently, several generations of phosphorus (PPH) dendrimers (G1 to G8) ended by aldehyde functions were also deposited on a quartz microbalance and used for the sensing of 29 vapor solvents. The distinctions in the binding selectivity of the studied dendrimers were found sufficient to construct a sensor array for the molecular recognition of organic vapors.64 Several examples of associations of dendrimers with nanoparticles were used for vapor sensing. In most cases these associations concern gold nanoparticles, because their physical properties can be utilized for signal transduction. Furthermore, the association of NPs and dendrimers can give highly porous materials that allow the diffusion of the analyte. Polyphenylene dendrimers ended by thioctic acid and reacted with gold NPs were used for the layer-by-layer fabrication of gold NP/dendrimer composite films, which were used as chemical sensor devices having a high sensitivity to vapors of toluene and tetrachloroethylene, which induced changes of resistance.65,66 The sensing properties of these films were also measured by a quartz microbalance.67 The same process was applied to other dendrimers (PPI and PAMAM). It was shown that the chemical selectivity of the film was largely controlled by the solubility properties of the dendrimers. The sensitivity to toluene vapor decreased in the order polyphenylene > PPI > PAMAM, whereas the relative response to 1-propanol and water vapor increased. Single-wall carbon nanotubes first decorated by PAMAM dendrons and then by Pd NPs were heated at 200 °C to induce the pyrolysis of the dendrimers. These modified nanotubes were used for hydrogen sensing experiments. The measurements were done by real-time electrical resistance responses, with an ultralow detection limit of 10 ppm. It was also shown that the nanotubes modified with dendrimers have a much faster response time and better recovery than those prepared without dendrimers.68 Carbon black dendrimers (PPI

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Figure 14.5 Modulation of the adsorption of volatile organic compounds (VOCs) using layers of dendrimers and polymers

or PAMAM) composites were used for the detection, classification, and quantification of vapors. Fifteen analytes chosen from primary amines, branched amines, anilines, and other organic analyte vapors were discriminated from each other by their different responses.69 Nanoporous alumina coatings prepared on a surface acoustic wave mass balance were modified by an organic film composed of PAMAM G6 dendrimers and a polymer. This organic thin film modulated adsorption of VOCs on to the pore wall. A 3-nm-thick monolayer of the dendrimers reduced permeability of the VOCs by ∼17%, whereas the 12-nmthick G6-NH2/ polymer composite reduced permeability by 100%.70

14.5

Conclusion

The use of dendrimers as chemical sensors has given birth to a diversity of examples in solution and in the solid state. The earliest examples in solution concerned the measurement of pH and the detection of the presence of metallic cations by fluorescence; by electrochemistry, most examples concerned the detection of anions, whereas in the solid state most examples concerned the detection of volatile organic compounds, in particular solvents, frequently measured by a quartz crystal microbalance. These earliest examples can be considered as the elaboration of protocols in view of the detection of more dangerous chemical compounds. Indeed, several recent examples reported the detection of explosives and also of toxic nerve agents, which could be detected at the nanomolar concentration level. These recent examples are the most promising ones, and will probably be developed in the future. We will see in the next chapter that this evolution toward more practical uses is also one of the key points concerning the elaboration of biosensors with dendrimers.

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15 Dendrimers as Biological Sensors Anne-Marie Caminade

15.1

Introduction

Several examples of uses of dendrimers as biological sensors resemble those already shown in the previous chapter concerning chemical sensors; thus this chapter will be roughly organized as the previous one. The first parts will concern properties in solution and the second parts will concern properties in the solid state, in particular for the elaboration of DNA microarrays (“DNA chips”). Indeed, such a type of biosensor is gaining an increasing importance in gene expression studies, for genotyping of individuals, in forensic applications, and also for the preservation of food safety and environment quality. This method of detection necessitates two parts: a probe and a target. The probe is often constituted of nucleic acids immobilized at discrete positions on surface activated slides; the target is generally part of a complex biological sample of fluorescently labeled nucleic acids. The supramolecular interaction between the probe and the target (hybridization) is generally quantified by fluorescence. The degree of sophistication of such devices increases continuously and the use of dendrimers allows an improvement of their sensitivity and reliability.

15.2

Dendrimers as Sensors in Solutions of Biological Media

The use of dendrimers as sensors in biological media necessitates first to have watersoluble compounds. They were used for various purposes, such as for measuring the pH values and for the recognition of biomolecules (including DNA) or of cell components. Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 15.1 Functionalized PAMAM dendrimer for the detection of the botulinum toxoid

In most cases, fluorescence is the most convenient tool for the detection; this is in particular the case for pH sensors. Pentaerythritol was chosen as the core of small aliphatic polyester dendrimers terminated by eight PEG chains and linked to cypate fluorescent probes by hydrolyzable bonds at acidic pH. In neutral pH found in healthy tissues the near-infrared (NIR) fluorescence intensity of this dendrimer is silent; at acidic pH found in disease tissues, the NIR fluorescence intensity increases as the cypate dyes are released. This dendrimer can be considered as a safe and nontoxic tool to detect and analyze acidic diseased tissues.1 A pH-sensitive dye (carboxyfluorescein) and a pH-insensitive rhodamine dye were both conjugated to PAMAM dendrimers. This fluorescent biosensor was introduced by electroporation in HeLa cells. They display specific subcellular localizations depending on the generation and the surface charges, allowing selective pH measurements in different organelles in living cells.2 Other examples of biosensors in solution concern specific recognition, using dendrimercoupled antibody reagents. Other examples displayed the use of PAMAM dendrimers for immunoassays. An enhanced sensitivity for creatine kinase MB isoenzyme, thyrotropin, and myoglobine was observed.3 Analogous experiments allowed the detection of biological warfare agents (anthrax)4 and also of botulinum toxoid. This latter case is shown in Figure 15.1; PAMAM dendrimers were conjugated to the antibody and to a fluorescent tag (FITC). Recognition of the botulinum toxoid by the antibody induced the immediate precipitation of highly crosslinked and fluorescent clusters, which are easily detectable.5 Other examples of specific recognition occur between lectins (sugar-binding proteins) and carbohydrates. The interaction between glycodendrimers bearing carbohydrates as terminal groups and a fluorescent organometallic core with Concavalin A (Con A) lectin resulted in the formation of colloidal aggregates when the carbohydrates are αmannopyranosides. It was shown that the agglutination is specific and detectable by turbidity analyses and that high sugar density was essential for lectin binding.6 Analogous experiments were carried out with a dendron having a closely related structure.7 It has been recently shown that when the metallic core is based on Ru(II), the relative change in fluorescence quantum yield of the Ru complex upon interaction of the carbohydrate with the lectin may serve as the output, together with the optical behavior.8 The presence of Ru(II) at the core also allowed the detection of the interaction by electrochemistry.9 PAMAM dendrimers terminated by mannose derivatives were also used to interact with

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Figure 15.2 Competitive binding assay for glucose from glycosylated PAMAM dendrimers with fluorescent labels and fluorescent Con A tetramer

lectin Con A. The aggregation of proteins orchestrated by binding to the glycodendrimer framework was monitored by an intrinsic fluorescence lifetime of Con A.10 Competitive binding assay for glucose from glycosylated PAMAM dendrimers with fluorescent labels and Con A tetramer with fluorescent labels were carried out, both fluorophores being able to induce FRET experiments. The principle is shown in Figure 15.2; the glycosylated PAMAM dendrimer was used for the aggregation of Con A tetramer and the addition of glucose induced the complete dissociation, eliciting a large optical response (disappearance of the FRET phenomenon).11 The FRET phenomenon was also useful in assessing the interaction between fluorescently labeled DNA (single-stranded, ss-DNA, or double-stranded, ds-DNA) and phenylene–fluorene-functionalized PAMAM dendrimers. It was shown that FRET from the fluorescent dendrimer to ds-DNA becomes more effective as the generation of the dendrimer increased, relative to ss-DNA.12 Hybridization inside microcapsules constituted of layers of polycationic phosphorus dendrimers (PPH) and polystyrene sulfonate was also detected by fluorescence. Cy-5 labeled ss-DNA was encapsulated in these microcapsules. When adding the complementary target, the fluorescence profile of the microcapsule indicated that the fluorescence is mainly detectable inside the capsule, When adding a total mismatch target, no hybridization can occur; thus leakage of the Cy-5 labeled ss-DNA was observed and the fluorescence was not detected in the microcapsule but in its wall.13,14 Binding interactions between fluorophore-cored polyarylether dendrons terminated by carboxylic acid with metalloproteins were detected by quenching the fluorescence. Different responses were obtained depending on the size of the dendrons and the type of metalloproteins.15 Fluorescence dendrimers were also used for studying the penetration inside cells and the detection of compartments in cells. These applications are somewhat related to medical imaging, which will be the topic of Chapter 16. Here we will focus on the sensor properties. Phosphorus dendrimers (PPH) decorated with azabisphosphonic derivatives and labeled by a fluorescent group were shown to bind to human monocytes and to become internalized within a few seconds, following the phagolysosomial route. When labeled with fluorescein, this dendrimer allowed FRET experiments with the typical innate toll-like receptor (TLR)-2 labeled with a phycoerythrin-coupled antibody, indicating that this

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receptor is somewhat involved in the mechanism (see Chapter 20 for the biological properties of this dendrimer), but is certainly not alone.16 Small Janus dendrimers constituted on one side of phenylene-vinylene fluorescent units and L-lysine on the other side were shown to localize within the cytosol in a discrete spherical compartment of two types of mammalian cells, mouse embryo fibroblasts and primary bovine chondrocytes.17 PAMAM G2 dendrimers decorated by Ru(bipy)3 luminescent derivatives were shown to accumulate in colon carcinoma cells, first in the lipid membranes and then to be internalized via passive endocytosis, and to accumulate in the lysosomes.18 PAMAM G5 dendrimer having six two-photon absorbing fluorophores and folic acid as terminal groups were used to label KB cell tumors in vivo. Xenograft tumors developed in mice expressing the green fluorescent protein (GFP) were detected by fluorescence, with a fourfold increase in animals that received the targeted dendrimers.19

15.3

Detection by Electrochemical Methods

Early attempts in this field concerned the use of PAMAM dendrimers linked to a gold electrode, then suitably modified to interact with the analyte. For instance, functionalization with biotin allowed the detection of avidin,20 whereas deposition of glucose oxidase allowed the detection of glucose.21 To try to improve the sensitivity, the dendrimers were crosslinked with glutaraldehyde,22 or the experiments were carried out in the presence of ferrocene methanol as the diffusional electron-transferring mediator.23 Then some ferrocenyl dendrimers were used for the detection of biomolecules. Mixed ferrocene–cobaltocenium PPI dendrimers were used for modifying the electrode surface and then for the immobilization of glucose oxidase. These modified electrodes were used for the detection of glucose by measuring the amperometric response, due to the mediation of the enzymatic reaction.24 The dendrimer generation plays a significant role; the smaller dendrimers exhibit a much higher electrocatalytic activity.25 Several examples concern the use of partially ferrocenyl-tethered PAMAM dendrimers. Alternate layer-by-layer deposition on to an Au electrode of these dendrimers and of oxidized glucose oxidase afforded a sensitive biosensor for the detection of glucose, significantly amplified by multilayer growth.26 An affinity biosensor system based on the same dendrimer, then biotinylated, was constructed on a gold electrode. An electrochemical signal was generated by the interaction with free glucose oxidase.27 The same ferrocene dendrimer was used as an electrocatalyst to enhance the electronic signals of DNA detection. Immobilization of the dendrimer on to an Au electrode, then of thiolate capture probe (ss-DNA), partial hybridization with the target, then with a biotinylated detection probe, followed by the association with avidin-alkaline phosphatase, allowed the generation of p-aminophenol (an electroactive label), which diffuses into the layers and is electrocatalytically oxidized by the electronic mediation of the immobilized ferrocene dendrimer.28 Other examples of partially ferrocenyl-tethered PAMAM dendrimers associated with gold NPs were reported. In particular, an ITO (indium titanium oxide) electrode was functionalized as shown in Figure 15.3 for the detection of a mouse target protein. The Au NPs generate aminophenol by catalytic reduction of nitrophenol; aminophenol is then electrochemically oxidized to quinine-imine via the electron mediation of ferrocenes and is

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Figure 15.3

379

Example of elaboration of an electrochemical biosensor

reduced back to aminophenol by NaBH4. This redox cycling increases the anodic current.29 An analogous principle was used for the sensing of DNA.30 Crosslinked PAMAM dendrimers prepared on a gold electrode were used for DNA hybridization analysis, detected in particular by electrochemical impedance spectroscopy (EIS), using the K3[Fe(CN)6]/ K4[Fe(CN)6] mixture as a redox probe.31 Besides ferrocene, a conducting polymer was used to enhance the detection of biomolecules. The device constituted an Au electrode covered by functionalized poly(terthiophene) covalently linked to PAMAM dendrimers interacting with gold nanoparticles (Au NPs). Biotin-functionalized DNA32 or biotin-functionalized IgG antibody33 was grafted to the NPs and finally avidin functionalized by hydrazine was adsorbed. The electrochemical detection was obtained by the electrocatalytic reduction of hydrogen peroxide by labeled hydrazine on the probe immobilized surface. Replacing the Au NPs by CdS NPs allowed the detection of chloramphenicol (CAP), an antibacterial agent recognized by antichloramphenicol acetyl transferase antibody. When using hydrazine-labeled CAP, the detection was done as in the previous case.34 Gold NPs entrapped in the dendrimers (not on their surface as previously) allowed the electrochemical properties to increase. Laccase (a protein) linked to the dendrimers was used for the sensing of catechin, which is an effective anticancer agent (its oxidation is catalyzed by laccase).35 A glassy carbon electrode was covered by Au NPs, functionalized poly(terthiophene), linked to PAMAM dendrimers and then to an antibody and hydrazine sulfate. This electrochemical device was used in particular for the detection of Annexin II, which is an antigen found only in lung cancer

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patients.36 Polypyrrole is another type of conducting polymer that was used in connection with DNA dendrimers (dendrimers constituted of short DNA sequences) to form the interface with an electrochemical sensor. This device was used for the detection of two salivary protein markers. A limit of detection of proteins of 100–200 fg mL−1 was achieved, which is 3 orders of magnitude better than without DNA dendrimers.37 Other examples of electrodes covered by PAMAM dendrimers were reported recently. Gold NPs-decorated amine-terminated PAMAM dendrimers deposited on to a gold electrode were used to immobilize a brevetoxin B-bovin serum albumin conjugate. A low detection limit of 0.01 ng mL−1 of brevetoxin B (a cyclic polyether causing the illness described as neurological shellfish poisoning) was obtained.38 A functionalized gold electrode covered by PAMAM dendrimers and then with single-stranded 3′-biotin end-labeled oligonucleotide was used as a recognition layer through a biotin–avidin combination to detect complementary targets, using Au NPs and [Ru(NH3)6]3+ as redox electroactive indicators.39 Association of single-wall carbon nanotubes (SWCNT) with PAMAM dendrimers was used for the generation of biosensing devices based on the detection using electrochemistry. The analysis of redox processes associated with biological macromolecules by the potentiometric biosensor obtained when adding a layer of enzyme penicillinase allowed the detection of penicillin by potentiometry40 and by capacitance–voltage.41 PAMAM dendrimers were also grafted to the inner surface of a nanopipette functionalized by aldehydes. After reduction, the nanopipette was filled with an electrolyte solution and an Ag/ AgCl electrode was inserted. Electrostatic adsorption of ss-DNA on the dendrimers was monitored by measuring the current–voltage response of the nanopipette. The probe DNA modified nanopipette was then exposed to complementary or noncomplementary DNA sequences. Only the complementary ones induced a dramatic increase in rectification of the current–voltage curve.42

15.4

Dendrimers or Dendrons for DNA Microarrays

DNA microarrays/DNA microchips are gaining growing importance connected to the demand for genetic information. Typical devices consist of two parts: first a nucleic acid (oligonucleotide or PCR (polymerase chain reaction) products) immobilized at discrete positions on surface-activated slides and constituting the probe and, second, a sample constituting a complex mixture of fluorescently labeled nucleic acids, which contains the target. Glass and silica are typical materials for optical sensors. They have several advantages such as a good chemical resistance and a low intrinsic fluorescence. The use of dendrimers or dendrons for improving the sensitivity and reliability of such devices has already been reviewed,43 and recently updated.44 Two main types of uses of dendrimers for bioarrays can be distinguished: either the dendrimeric compound is connected to the slide and is used as a support for the probe, ensuring the movement of the probe away from the solid surface (for improving hybridization) or the dendrimer is used to multiply labeled entities connected to the target for easier detection. Several types of dendrimeric structures were used for the elaboration of sensitive microarrays. In the case of dendrons, they can be linked to the array in two different ways: the core or their terminal groups (Figure 15.4, cases b and c, respectively).

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Figure 15.4 Different types of DNA arrays elaborated with dendrimeric structures: (a) dendrimer; (b) dendron linked by its core; (c) dendron linked by its terminal groups; (d) dendrimeric structure constituted of DNA

The first use of a dendrimer for DNA microarrays was proposed by R. Benters, C. M. Niemeyer, D. Wöhrle and coworkers,45 who grafted the fourth generation PAMAM dendrimer on to glass surfaces pretreated by 3-aminopropyltriethoxysilane and disuccinimidyl glutarate (DSG) or PDITC (1,4-phenylene diisothiocyanate). After grafting PAMAM dendrimers on to the surface, the homobifunctional reagents DSG and PDITC were used both to intermolecularly crosslink the dendrimers and to generate reactive groups suitable for reaction with amino-derivatized oligonucleotides. In the case of PDITC, high homogeneity of the spots was observed, as well as a remarkable stability. The intensity of the signal remained constant for more than 110 simulated regeneration cycles, showing that these slides are fully reusable. However, these arrays have a drawback, concerning the loading in oligonucleotides. Only an approximate twofold higher loading is achieved with the dendrimeric surface compared to classical surfaces, presumably indicating that many functional groups of the PAMAM dendrimers are consumed to form the polymeric network.45 Thus, it appeared interesting to test the same type of methodology, but avoiding crosslinking.46 Hybridization with a complementary Cy5-labeled oligonucleotide probe afforded an intensity of fluorescence approximately tenfold higher for the dendrimeric linker system than for classical systems. Furthermore, up to 10 regeneration and rehybridization procedures were carried out without loss of signal intensity. Single nucleotide polymorphism (SNP), which is particularly important for location of disease-causing genes, is also clearly detectable in hybridization assays. In particular, one mismatch in Cy5-labeled 212mer single-stranded DNA obtained by PCR leads to a decrease in signal intensity of 60–92%, depending on the position of the mismatch. Other types of dendrimers were used for obtaining DNA microarrays. The experiment was carried out with the third generation PPI dendrimer, reacted on an epoxide-modified solid surface. Oligonucleotides and cDNA were noncovalently immobilized on this dendrimeric surface. However, the results obtained for hybridization and fluorescence with these dendrimer-modified slides are no better than the results obtained for nondendrimeric arrays.47 Phosphorus-containing (PPH) dendrimers terminated by aldehydes allow both the direct grafting to the NH2 groups of the solid surface of the slide and also the direct reaction of the remaining aldehydes with amino-modified oligonucleotides, without any additional linker for both reactions – contrary to all the previously reported examples. Generations 1 to 7 of PPH dendrimers were tested for the elaboration of DNA microarrays; the best results concerning the signal-to-noise ratio were obtained with generations 4 to 7, and thus

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generation 4 was chosen (it is easier to synthesize than higher generations).48 To quantify the target/probe hybridization sensitivity, “dendrislides” and 12 commercially available glass slides were functionalized by a 35mer oligonucleotide, spotted at 10 μM in solution and then hybridized with increasing concentrations of a Cy5-labeled 15mer oligonucleotide complementary to the probe, from 0.001 nM to 100 nM. At 0.001 nM of DNA target a fluorescence signal was still quantifiable only using the dendrislides. Thus, the detection sensitivity of dendrislides is ten- to hundredfold higher than for arrays made with most other functionalized glass slides. This high hybridization sensitivity is particularly interesting for studies involving very low amounts of biological materials. The reusability of the dendrislides was also tested and was found to be excellent, even after 10 hybridization/ stripping cycles in the case of oligonucleotides,49 but the stripping process was found less effective using dendrimeric arrays bearing the whole yeast genome spotted as PCR products.48 Interestingly, single nucleotide polymorphism (SNP) can be detected with the dendrislides. The hybridization of four 15mer oligonucleotides having a single base mutation in the middle with a 35mer oligonucleotide probe grafted on the dendrislide is only effective when the oligonucleotide sequence is strictly complementary.49 The properties (in particular the sensitivity) of these dendrislides based on PPH dendrimers are so promising that a startup (Dendris) has been launched recently, and proposes a diagnosis solution for analytical laboratories in health, agrofood, and the environment. These DNA chips elaborated from the PPH G4 dendrimer can be converted to nanocapsule arrays by grafting on liposomes and oligonucleotides complementary to the oligonucleotides bound to the array. Two series of liposomes were synthesized, each series bearing one type of oligonucleotide. A fluorescent dye derived from rhodamine was used for labeling the liposome membrane of one series and a fluorescent dye derived from Cy5 was encapsulated in the liposome internal volume of the other series. Both series of liposomes were then mixed and deposited on a glass slide spotted with three different oligonucleotides; the first one is complementary to one series of liposomes, the second one is complementary to the other series of liposomes, and the third one is not complementary. Following hybridization, detection of fluorescence on the chip revealed colored spots corresponding to the fluorescent dyes used. Such a process is potentially usable for the encapsulation and spotting of proteins, keeping their conformation and activity within the liposomes.50 The nature of the support of the array can be varied in order to use other methods of detection than fluorescence. The fourth generation phosphorus (PPH) dendrimer was linked as previously, but to a piezoelectric membrane. The complementary oligonucleotide hybridized in this case does not bear a fluorescent label but a biotin label, for the selective recognition by streptavidin. This functionalized piezoelectric membrane was integrated in a flow injection analysis system, and its resonant frequencies were measured using the optical beam deflection technique. Measurements were carried out on the biotinylated DNA hybridized membrane after injection of a solution of streptavidin-conjugated gold nanoparticles. The mass loading induced by the supramolecular recognition is detected by a modification of the resonant frequency of the membrane. The mass sensitivity has been estimated to be −3.6 Hz pg−1, which was a factor of several hundred times better than stateof-art values for piezoelectric mass-sensing devices.51 Phosphorus (PPH) dendrimers (fourth generation) ended by ammonium or carboxylate groups were used for the layer-by-layer alternate deposition on to a gold-coated glass

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substrate. Up to eight bilayers of positively and negatively charged dendrimers were deposited and then the outermost layer with carboxylic groups was activated to allow the immobilization of probe DNA. DNA hybridization with target DNA was measured by surface plasmon field enhanced fluorescence spectroscopy (SPFS). The detection limit for this device was 30 pM.52 Besides “classical” dendrimers, DNA dendrimers (case d in Figure 15.4) were also used for the elaboration of DNA biosensors. About 18 layers of the fourth generation of such DNA dendrimers, possessing as end groups about 30 single-stranded arms specific to the water-borne pathogen Cryptosporidium parvum, were immobilized on to a quartz-crystal microbalance. The numerous probes on the outermost layer accessible to the Cryptosporidium DNA target yielded a three-dimensional surface hybridization and consequently a large resonant-frequency response.53 Cone-shaped dendrimeric molecules (dendrons) have also been used for the elaboration of DNA microarrays. Dendrons linked to a solid substrate by their surface groups (case c in Figure 15.4) generate mesospacing on the solid.54 Coupling of amino-modified oligonucleotides with the NH2 core function of the immobilized dendrons, using di(Nsuccinimidyl)carbonate (DSC) as the linker, affords DNA microarrays. Such processes provide each probe DNA with ample space for hybridization with incoming DNAs, resulting in high hybridization yields (80–100%). These particular arrays have been used to detect a successful discrimination ratio of 100 : <1 between a complementary pair and three internal single-base mismatched pairs.55 Single nucleotide variations in the exons 5–8 of the p53 gene in genomic DNAs from cancer cell lines were also detected with a high selectivity and sensitivity.56 A wide range of temperatures (37–50 °C) is usable and in general the hybridization behavior on these arrays is similar to the solution one.57 Sensitivity enhancement was obtained by using streptavidin–fluorophore conjugate.58 Very recently, such a type of device was used for on-chip DNA polymerization, which allows elongation of surface-bound primers with DNA polymerase and enhancement of the signal in the detection of target DNA.59

15.5

Dendrimers for Other Types of Biomicroarrays

The principles applied for the elaboration of DNA microarrays with dendrimers can be applied to other types of bioarrays, in particular for the detection of proteins. In most cases these experiments were carried out with PAMAM dendrimers (generally G4) for enhancing the performances of the devices. A glass surface was coated with carboxyl-terminated PAMAM dendrimers and then antibodies were immobilized, affording a protein microarray for high-sensitivity detection of antigens in complex biological samples. The detection limit was estimated to be about 1 pM for pure analytes.60 A polystyrene assay plate covered by PEG-maleimide was reacted with thiol-PAMAM dendrimers, which were then reacted with an antibody. Such a device was used as a solid phase for developing a sandwich-type enzyme-linked immuno absorbent assay (ELISA) to detect IL-6 and IL-7β (interleukins), which are important biomarkers.61 Thiol-PAMAM dendrimers were also used in lightinduced thiol-ene reactions suitable for the oriented and covalent immobilization of farnesylated proteins. The resulting functionalized slides were incubated with Cy3-labeled

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antibodies, which allowed the detection by fluorescence.62 The same principle was applied for the immobilization of glycopeptides, useful to probe antibodies in mouse serum.63 Besides PAMAMs, a few other types of dendrimeric structures were used for the detection/immobilization of proteins. PPH dendrimers were used for grafting to aminosilanized quartz plates, and then for the immobilization of human serum albumin (HAS), as detected by AFM.64 A fluorescent dendrimer having a Zn-porphyrin as the core, poly(benzyl ether) branches, and carboxylate terminal functions was used for the coating of positively charged silicon surfaces and then for protein immobilization, as detected by AFM and fluorescence microscopy. This device was used to detect glucose oxidase, which, using oxidation, quenched the fluorescence emission.65 The same dendrimer was used as the terminal layer of an LBL self-assembly of poly(ethyleneimine) and poly(styrenesulfonate); it allowed the immobilization of proteins (mouse IgG) at specific spots. Immunoassays were preformed with fluorescence-labeled antimouse IgG; it was shown that anti-IgG bound specifically to IgG-immobilized micropatterns.66 Glycodendrons grafted by their core to a microarray slide were used as multivalent inhibitors of carbohydrate binding proteins. In the first attempts, the binding of FITC-labeled lectins concanavalin A was tested;67 then series of fluorescent lectins were evaluated, showing the specificity of the lectins for a certain sugar.68 Beside DNA and proteins, a few other examples of detection of biological entities are known, generally based on PAMAM dendrimers. For instance, insulin was detected by a surface plasmon resonance biosensor elaborated from bifunctionalized PAMAM dendrimers linked to a gold surface and interacting with gold NPs. This device was used for analyzing insulin in human serum samples from healthy and diabetic patients, with a detection limit of 0.5 pm.69 PAMAM dendrimers immobilized on glass and modified with an Ni chelator was used for the sensing of histidine, via indicator displacement assays.70 A sensing film containing hydroxyl-terminated G4 PAMAM dendrimers and SYTOX Green fluorescent nucleic acid stain configured on disposable plastic coupons or optical fibers was used for the detection of live bacteria (Pseudomonas aeruginosa) in water. In the presence of PAMAMs the bacterial cell becomes permeable to SYTOX dye (it is not permeable without PAMAM) and the fluorescence is significantly enhanced; the intensity is 350% higher than without PAMAM at 5.4 × 107 cells mL−1.71 Analogous experiments were carried out with ammonium-PAMAM dendrimers linked to silanized glass slides, and embedding through host–guest interactions a lipophilic membrane dye (FAST DIA). Detection and quantitation of bacteria in water were obtained with a detection limit of 104 cells mL−1.72

15.6

Dendrimers on Other Types of Support

Besides flat surfaces of materials classically used as supports for the elaboration of chips, a few less conventional supports have been proposed for the elaboration of biosensors based on dendrimers. The use of dendrimers for such devices can be indirect, as already shown in Chapter 13. The dendrimers can be used as a mediator for the transfer printing of DNA and RNA microarrays; the positively charged dendrimers are deposited on the stamp surface for attracting the negatively charged oligonucleotides.73 Other examples concern the functionalization of AFM probes by dendrons linked by their terminal groups and having a complementary DNA oligonucleotide at the core, able to interact with oli-

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gonucleotides linked to the bioarray.74 Analogous experiments were recently carried out with antibody on the AFM probe and prostate-specific antigen on the microarray.75 Suspension microarrays are generally constituted of polystyrene microspheres (beads) to which the DNA probes are attached. Then 3 μm beads covered by G4 PAMAM dendrimers were reacted with dinitrophenol (DNP). Coordination with anti-DNP antibody labeled by fluorescein was observed by fluorescence microscopy. The same process was applied to beads–PAMAM covered by biotin, interacting with streptavidin labeled by phycoerythrin.76 Still less conventional supports for biosensors consist of nanotubes. Small dendrons, having pyrene as the core and alkyl chains as terminal groups, spontaneously form vesicles, which rearrange into nanotubes when cyclodextrin is added. Covering these nanotubes by biotin afforded a biosensing platform, using the specific binding with receptor proteins such as streptavidin and avidin, fluorescein-labeled for visualization by confocal laser scanning microscopy.77 Other types of nanotubes were obtained by layer-by-layer deposition of positively and negatively charged PPH dendrimers on the pore walls of an ordered porous alumina membrane. At some specific layers, negatively charged quantum dots (ZnCdSe alloys) were deposited instead of negatively charged dendrimers, in order to obtain graded-bandgap structures. In the last step, probe oligonucleotides were immobilized in the most inner part and then hybridized with target fluorescent-labeled oligonuclotides. An efficient excitation energy transfer occurs by FRET from the outer to the inner surface of the nanotube, allowing the detection of hybridization with a high sensitivity (Figure 15.5).78,79

15.7

Dendrimers as Multiply Labeled Entities Connected to the Target

Besides the sensitivity of the slides, which can be improved by using dendrimers as shown above, amplification of the signal resulting from detection events can also be enhanced using dendrimers or dendrons, bearing particular multiple fluorescent labels. In the case

Figure 15.5 Nanotube of PPH dendrimers and quantum dots used for the detection of hybridization. Only some layers are shown (in reality, three bilayers of positively and negatively charged dendrimers are first deposited, then five bilayers of positively charged dendrimers and quantum dots, repeated for each type of quantum dot). Only one side of the nanotube is represented

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of fluorescent dendrons, an oligonucleotide or a PCR product can be connected to their core. Such a strategy has been applied to various sizes of polyether-type dendrons bearing Cy3 dyes as end groups and PCR amplicons of different human herpes viruses (herpes simplex virus (HSV-1 and HSV-2), varicella zoster virus, Epstein–Barr virus, cytomegalovirus, and HHV-6). The fluorescence signal enhancement via the dendrons of the microarrays specifically hybridized to these fluorophore-labeled pathogenic DNAs was up to 30 times compared with a single fluorophore.80 Besides fluorescence, radioactivity is also a main tool in biology, especially γ -32P. The principle was the same as that for fluorescent dendrons; it was applied to oligonucleotide dendrons containing bunches of nine oligonucleotides labeled with [γ -32P]ATP and one specific oligonucleotide linked to the core. These multiply labeled structures showed much higher sensitivity than nondendrimeric (monomeric) labels when used as probes to arrays bearing oligonucleotides complementary to that of the core of the dendron. The large dendrimeric structure does not significantly affect the hybridization yield.81 Some DNA dendrimers have been especially designed to be used as highly fluorescent labels. In fact, the single-stranded arms on the surface of these dendrimers are used to attach two types of functionalities: one type is the label (mainly Cy3, Cy5, Alexa Fluor 546, or Alexa Fluor 647) and the other type of functionality will enable the attachment to the desired probe; both are attached by hybridization with oligonucleotides. These types of compounds are called 3DNA® dendrimer and are generally used for an indirect detection. Indeed, first a 3DNA capture sequence must be linked to the oligonucleotide or PCR products to be analyzed (the target), second the product must be hybridized to the microarray printed with the complementary oligonucleotide or PCR product, and third the fluorescent 3DNA is hybridized with the capture sequence.82 This indirect method has been found more efficient than a classical direct method for the labeling of the partial genome of the methylotrophic yeast Hansenula polymorpha and its detection on DNA arrays83 and for the detection of rare transcripts available in small quantities, such as hair cells in cochean tissues of mouse ear.84 These 3DNA dendrimers have been used as highly fluorescent, sensitive, and versatile labels for a number of purposes. In particular, they have been used in comparison with more classical techniques for the detection of predetermined ratio values from target external mRNA standards (spikes of Arabidopsis thaliana) in the background of total RNA,85 for studying the influence of multiple scanning on the accuracy of detection,86 for designing a microassay array that quantifies the measurement of hybridization stoichiometry in molar units,87 and also for protein detection88 and for the detection of genetically modified organisms (GMOs).89 DNA dendrimers were also used as fluorescent probes when linked to phycoerythrin for high-throughput subtyping of Listeria monocytogenes from genomic DNA, using suspension microarrays (polystyrene microspheres) as supports.90 Luminescent quantum dots (CdS/CdSe) covered by PPI dendrons were used for labeling antibodies specific to the same pathogen, captured on a membrane.91

15.8

Conclusion

Undoubtedly, the use of dendrimers for improving the efficiency of biosensors is a field that is presently in large expansion, as can be seen by the number of references published

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within the last two years, in particular concerning biomicroarrays for DNA or proteins. One of the most important properties concerning the use of dendrimers is the remoteness that they provide between the solid surface of the sensor and the biological entity to be detected. This is due to the branched structure of dendrimers, which remains threedimensional, even when it is “flopped” on to a surface. This property allows in particular the hybridization to occur, as in solution in the case of DNA chips, and preserves the structure of proteins, in the case of protein chips. Furthermore, in many cases the systems created by using dendrimers are very robust, can be stored for long periods of time, and can be reused for dozens or hundreds of experiments. It must be emphasized that one of the very first practical uses of dendrimers was in this field. The Stratus CS instrument (Dade Behring) detects certain protein biomarkers that are released in the blood stream as a result of heart muscle damage induced by a heart attack, and has been used in standard hospitals in the USA since 1998. The technology of this instrument is based on a G5 PAMAM dendrimer, which is used as “glue” between the glass surface of the device and the antibodies that are part of the biomarker ’s detection system.92

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Part 4 Applications in Biology/Medicine

16 Dendrimers for Imaging Cédric-Olivier Turrin* and Anne-Marie Caminade

16.1

Introduction

Molecular imaging slowly moved from tissue staining to antigen visualization by light microscopy; it now includes many imaging techniques like optical imaging and nonmicroscopical imaging techniques like positron emission tomography (PET), ultrasound imaging, photoacoustic imaging, computed tomography (CT), magnetic resonance imaging (MRI), etc. These techniques usually require the accumulation of contrast agents to enhance the imaging quality. Nano-objects have become suitable candidates for these purposes,1,2 for a set of reasons that includes adequate intrinsic properties, a range size that can allow a certain control over biodistribution, and the possibility to engineer the surface of these nano-objects to make them as smart as necessary. Dendrimers, nanoobjects of special interest due to their peculiar architectures, have been early assayed in this regard,3 and there are many instances where much effort has been made to develop dendrimer-based MRI agents incorporating gadolinium chelates as an alternative to other macromolecular systems or nanomaterials.4,5 Current studies on dendrimer-enhanced molecular imaging encompasses MRI, optical microscopy, nuclear imaging with radionuclides, CT, and multimodal systems that combine different types of tracers6,7 (Figure 16.1).

16.2

Magnetic Resonance Imaging with Dendrimers

Magnetic resonance imaging (MRI) was conceived in the 1970s,8 and is now widely used as a noninvasive imaging method to construct images of internal structures of the body. * Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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λex

λem

CT imaging

X-ray

image plane

MR imaging

PET/SPECT imaging

B

radio wave image plane

Figure 16.1

Molecular imaging with dendrimers

It is based on the mapping of proton density in tissues and measuring relaxation time gradients, which are responsible for contrasts in the pictures.9 Most of these protons originate from water located in tissues, but the variations in concentration of water between neighboring regions in the same tissue are often too weak to give enough contrast. This problem is solved by the use of contrast agents, which modify the relaxation rates of protons upon coordination with water (T1 is the spin–lattice relaxation rate, T2 the spin– spin relaxation rate, and T2* the transverse relaxation rate). Reduction of the T1 relaxation rate (by positive contrast agents) results in a signal increase and image brightening while reduced T2 relaxation times (by negative contrast agents) are responsible for image darkening. Generally, paramagnetic contrast agents used at low concentrations are positive MRI contrast agents because of the important T1 lowering effect; they are negative MRI contrast agents at higher concentrations where their T2 lowering effect dominates. On the contrary, ferromagnetic and superparamagnetic contrast agents are negative MRI contrast agents, which enhance image contrast by modifying the magnetic field gradient in their surroundings. Alternatively, the contrast can be modified by altering the proton density or total water signal detected by the MRI scanner by magnetization transfer. These techniques, known as chemical exchange saturation transfer and paramagnetic chemical exchange saturation transfer (CEST and PARACEST),10 are opening new perspectives in the field of “metabolic” imaging, that is the spatial resolution of subtle changes of pH, redox states, or p(O2) that traduce metabolic changes. Dendrimers offer several advantages to design contrast agents. Dendrimeric scaffolds can be used for incorporation of many contrast agents while remaining soluble, and multifunctionalization can be performed for targeting or for enhancing the biocompatibility. In addition, their size allows the accumulation in cancerous structures, taking advantage of the enhanced permeability and retention effect (EPR). Consequently, visualization of the related tumors can be possible, which is not the case with low molecular weight contrast agents.11 Actually, a high porosity is typically found in inflammation tissues or tumors: the cut-off size of a vascular pore in normal vasculature is between 2 to 4 nm, while it is

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between 380 to 780 nm12 in a solid tumor. It was observed that proteins and macromolecules accumulate more specifically at tumor sites than low molecular weight therapeutic agents.13,14 The EPR effect is related to the size and the molecular weight of the injected compounds,15,16 and is widely used in passive targeting of large nanodevices as an alternative to active targeting mediated by RGD peptides, folic acid (FA), or monoclonal antibodies, to name but a few. The use of dendrimers as chelating agents for MRI contrast agents has been early explored by the group of Wiener with gadolinium-based dendrimeric complexes,3 and the multifunctionalization offered by dendrimeric scaffolds was rapidly exploited to produce targeted dendrimer contrast agents.17 Since then many efforts have been made to optimize dendrimer-based MRI contrast agents, and a promising candidate developed by Schering™ named Gadomer 17 (Figure 16.2) even entered phase I clinical trials at the very beginning of this century. Despite the fact that this compound was not further commercialized, dendrimer-based MRI contrast agents still appear as attractive model systems: they generally increase the biocompatibility of the contrast agents, allow a significant control of their

Figure 16.2

Gadomer 17™

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clearance rates, and increase the image quality. They have been generating a growing number of publications that have been recently reviewed by several authors.4,9,18–24 This section will be limited to recent advances in the field of paramagnetic dendrimeric contrast agents as well and the emergence of alternative techniques based on T2 superparamagnetic contrast agents, CEST and PARACEST agents, 19F MRI, or hyperpolarized xenon. 16.2.1

Paramagnetic Dendrimer-Based Contrast Agents

Most used paramagnetic contrast agents are based on gadolinium ion Gd3+, typically for visualization of blood vessels. Because of its toxicity as a free ion, gadolinium is systematically bonded to chelating agents, usually from the diethylenetriamine pentaacetic acid (EDTA) family including, mainly, diethylenetriamine pentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and 1,4,7-tris[carboxymethyl]-10-[2′-hydroxypropyl]-1,4,7,10-tetraazacyclododecane (DO3A). Commercial low molecular weight contrast agents based on these ligands, like Magnevist® [Gd(DTPA)], Dotarem® [Gd(DOTA)], or Prohance® [Gd(DO3A)], present good biocompatibility of the chelating ligand, high stability, good solubility, and high relaxivity, but they suffer from high clearance rates, which necessitate high doses and injection rates (Figure 16.3).25 Attempts to solve this problem first involved grafting of gadolinium complexes to high molecular weight macromolecules such as human serum albumin (HSA)26 or polymers like dextran27 or polylysine.28 Along with an increase in the retention time, an increase in the relaxivity, related to proton relaxation enhancement,29,30 was observed, due to the fact that large molecules rotate more slowly than small molecules, decreasing the water exchange rate and causing longer T2 relaxation times. Imaging being also dependent on local Gd(II) concentration, dendrimers naturally appeared as a valuable alternative to these strategies, which were somehow limited because of synthetic and purification difficulties (polydispersity), and toxicity issues related to bad renal elimination. As mentioned above, the group of Wiener17,29–31 paved the way for the development of a dendrimer-based contrast agent for MRI, and most of the work devoted today to Gd-

Figure 16.3

Low molecular weight Gd contrast agents

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based dendrimeric contrast agents for MRI is centered on PAMAM dendrimers. The commercially available cystamine-cored PAMAM dendrimers offer a valuable possibility to design-targeted MRI contrast agents. In this regard, Gd(III)–DTPA complexes have been grafted on the surface of the generation 2 cystamine-cored PAMAM dendrimer, and after redox conversion of the disulfide core into a reactive thiol, biotin could be efficiently bonded by a maleimide–thiol coupling reaction. Interestingly, the Gd(II) complexes could be formed after or before the core modification.32 The resulting contrast agent was coupled to unlabeled avidin or rhodamine green-labeled avidin, because this tetrameric glycoprotein can bind to lectins that are differentially expressed on the surface of cancerous cells such as ovarian cancer cells. This dual imaging targeted MRI contrast agent was successfully assayed in mice bearing ovarian cancer tumors. The advantage of targeted dualprobed imaging systems involving a fluorescent label is the possibility to visualize during surgery the effectiveness and completeness of tumor debulking. Multifunctionalization of dendrimeric MRI contrast agents can also be achieved by a stochastic approach,33 as demonstrated by the group of H. Kobayashi, who randomly grafted on the 256 theoretical free amines of a PAMAM dendrimer an average of 140 to 191 Gd(III)–DTPA units and two near-infrared (NIR) Cy5.5 fluorescent probes in a stepwise manner.34 This agent was designed for MR lymphangiography (MRL), an alternative technique used to localize preoperatively (by MRI) and intraoperatively (by NIR optical imaging) the presence of sentinel lymph nodes (SLN), which are the hypothetical first group of nodes reached by metastastic cancer cells from a primary tumor. Conventional imaging of SLN comprises 99m Tc–sulfur colloid radioscintigraphy and optical imaging with isosulfan blue dye, which are used during biopsies to localize SLN. Both techniques, based on the assumption that these high molecular weight agents will be drained by the lymphatic channels and accumulate in the SLN after injection, are impaired by a low intrinsic spatial resolution and poor visibility respectively, which might be responsible for misdiagnosing. The duallabeled dendrimer-based contrast agents proved to be efficient to visualize the lymphatic drainage by MRI and to perform NIR image-guided surgery on small animals. These promising candidates for SLN localization are nevertheless impaired by the absence of MRI units and the almost absence of NIR cameras inside operating rooms, as well as the nonpredictable toxicity profile of the randomly functionalized dendrimeric contrast agents. In addition, the imaging performances of such macromolecular contrast agents for MRI at 1.5T and 3.0T have not been rationalized to date.35 Chemical transformations underlying the synthesis of these DTPA-based dendrimeric contrast agents are continuously improved by alternative approaches that encompass nonaqueous techniques36,37 with improved yields and easier purification steps as well as the use of preformed DTPA complexes of Gd(III), which can be efficiently grafted on amine-terminated dendrimers.38 The influence of chelate charge on rotational dynamics, which is related to free coordination sites and consequently to the number of bonds that allow rotation (or local motion), can affect the water exchange rate and thus relaxivity. In this regard, recent studies37 on uncharged PAMAM conjugates of pyridine-N-oxide DOTA complexes have shown that the high flexibility of PAMAM scaffolds is detrimental to relaxivity of uncharged Gd(III)–DOTA complexes, which exhibit a fast water-exchange in the monomeric form, the global rotational correlation times of dendrimers reflecting the rotational motion of portions of dendrimers rather than that of the entire dendrimer. In an attempt to increase the relaxivity, PAMAM dendrimers were crosslinked with short

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Figure 16.4

PEG-crosslinked multifunctional imaging dendrimers

oligoethyleneglycol (OEG) linkers and further equipped with Gd(III)–DTPA complexes, along with folic acid (FA) for tumor-targeting and a fluorescent probe. The resulting nanoclusters (Figure 16.4) were found to exhibit a marginal increase in the relaxivity values despite an increase in size and an expected reduction of internal motion due to crosslinking. In fact, the OEG linkers were assumed to allow deleterious internal motion.39 The authors also pointed out the difficulties in assessing the pharmacokinetics and other relevant toxicological data for such polydisperse samples. The prolonged blood circulation of the dendrimeric MRI contrast agent is beneficial to efficacy, along with the ability to accumulate into solid tumors thanks to the enhanced permeability and retention (EPR) effect, related to hyperpermeable vasculature,15 but it can be balanced by their slow excretion rates and long-term possible accumulation of free gadolinium. To overcome this drawback, a generation 6 dendrimer–DO3A conjugate was prepared with a biodegradable cystamine linkage. The strategy was validated by significant contrast enhancement, in particular in the tumor periphery, and rapid excretion by renal filtration compared to the control conjugate lacking the biodegradable linkage that accumulated in the tissues and liver.40 Nonetheless, mice treated with the biodegradable dendrimeric contrast agent died within one day after injection, contrary to mice treated with the nondegradable linker. This observation was related to severe hemolysis observed in the liver and intestines of dead animals related to the release of free PAMAM, confirming the intrinsic non-negligible hemotoxicity of PAMAM dendrimers.41,42 Despite these major drawbacks for further in vivo exploration of PAMAM-based MRI contrast agents, these commercially available dendrimers have permitted the validation of a number of key points related to the development of dendrimeric MRI contrast agents. For instance, the effectiveness of targeting in vivo xenograft tumor cells overexpressing an FA receptor with Gd(III) dendrimeric contrast agents bearing FA residues has been proven by different research groups by comparing the signal enhancement with analogous

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Gd(III) dendrimeric contrast agents lacking FA residues.9,39,43 In a pretargeting attempt with biotin/avidin systems based on a biotinylated antibody targeting a specific tumor site and a biotinylated Gd(III)DTPA dendrimeric MRI contrast, the presaturation of avidin with the biotinylated antibody discarded the pretargeting approach strategy, but the dendrimeric contrast agents were found to accumulate in the tumor tissues through an EPR effect. This EPR effect is directly related to the pore size in the blood tumor barrier of solid tumor microvasculature. The transvascular extravasation of generation 5 to generation 8 PAMAM dendrimers equipped with Gd(III)–DTPA complexes have been measured by MRI experiments and the upper limit of these pore sizes for malignant gliomas grown inside the brain of rats was found to be 12 nm in diameter.44 Other competitive related polymers45 recently used for the design of the gadoliniumbased T1 contrast agent include polypropylene imine (PPI) and poly(L-lysine) dendrimers, polyethyleneimine (PEI), and polyglycerol (PG) hyperbranched polymers. Generation 4 PAMAM and PG bearing DO3A and Gd(III)–DOTA complexes have been compared in vitro and in vivo with regard to MRI contrast agent application, and no significant difference could be observed between polymers and dendrimers, even in the case of PEGylated PAMAM dendrimer scaffolds.46 A series of PEG bisamines was suitably used to design PEG-cored poly(L-lysine) dendrimers of various sizes according to the PEG length and the dendrimer generation, ending with Gd(III)–DTPA complexes.47 These systems presented increased T1 relaxivities compared to free Gd(III)–DTPA, and the pharmacokinetics (blood clearance) could be adjusted by the molecular size. This parameter along with the Gd loading and the thermodynamic stability of all systems needed refinement. L-Lysine has also been used to build very compact dendrimers based on a cubic octasilsesquioxane core; when equipped with Gd(III)–DOTA complexes, these rigid systems were found to be promising candidates as contrast agents for MRI with size-dependent contrast enhancement at concentrations reduced by a factor of tenfold compared to clinically used contrast agents for blood vessels and microvasculature, a rapid excretion via renal filtration, and no significant liver uptake. PPI dendrimers terminated with Gd(III)–DTPA complexes were also described as good candidates for MRI purposes,48 showing also a size-dependent increase of relaxivities and very low operating concentrations when compared to Gd(III)– DTPA for the visualization of tiny blood vessels. Remarkably, all of the above-mentioned systems based on non-PAMAM structures were not affected by deleterious interactions with blood plasma proteins. Examples of non-Gd-based T1 dendrimeric contrast agents are scarce. Dendrimer-linked nitroxides49–51 have been assayed in vitro as an MRI contrast agent for immature bovine articular cartilage assessment, which is negatively charged due to the presence of glycosaminoglycan chains of proteoglycans. Dendrimer-linked nitroxides, being positively charged at physiological pH, allowed imaging in vitro of cartilage, possibly because of a concentration gradient from cartilage to fluids surrounding bone junctions, except for large dendrimers, which were probably excluded because of poor cartilage permeation. These preliminary studies should be completed by toxicological investigations and visualization of cartilage abnormality in vivo, which is the final goal. A dendrimeric manganese(II) chelate by D. Felder-Flesch and coworkers was recently reported to exhibit in vivo and in vitro higher relaxivities than commercially available Gd-based and Mn-based contrast agents. Contrary to studies reported above, the system contains a single chelate located at the focal point of a small Fréchet-type dendron suitably equipped with peripheral OEG.

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This small chelate was successfully assayed to image rat brains without significant toxicity.52 16.2.2

PARACEST Dendrimer-Based Contrast Agents

The modification of proton density or total water signal is also responsible for contrast enhancement. The chemical exchange saturation transfer (CEST) agents used in MRI provide contrast by tuning the water signal intensity through selective saturation of the resonance frequency of their exchangeable protons. CEST agents are exogenous or endogenous compounds that exchange protons with solvent water and PARACEST agents are exogenous paramagnetic complexes that exchange proton or water with solvent water.53 They are generally sensitive to tissue characteristics such as pH,54 temperature, and concentration of the exchangeable protons and can be useful to monitor metabolic modifications,10 like pH gradient modifications in cancerous cells.55 Paramagnetic lanthanide ion complexes display unusual slow water exchange kinetics, which can be used to alter image contrast by a selective presaturation pulse in the imaging pulse sequence that leads to CEST from the lanthanide-bound water to bulk water. Lanthanide-based PARACEST contrast agents also provide a very high sensitivity related to the chemical shift differences for protons located in their vicinity.56 Dendrimer-based PARACEST contrast agents can offer significant improvements related to the local density of exchangeable protons they can provide and represent an attractive alternative to dendrimer-based pH responsive MRI T1 contrast agents.57 A series of generation 1 to 3 PPI dendrimers capped with up to 16 Yb(III)–DOTAM (DOTA monoamide) complexes were efficiently prepared and assayed in vitro for MRI imaging. The lowest detectable concentration was linearly dependent on the number of exchangeable amide protons of the surface groups and the pH sensitivity was also dependent on the generation.58 The in vivo pharmacokinetics of generation 2 and generation 5 PAMAM dendrimers conjugated to Yb(III)–DOTAM-gly or Eu(III)–DOTAMgly have been studied in a mouse model of a mammary carcinoma. The largest dendrimers showed a lower tissue permeability and a lower elimination rate.59 16.2.3

Superparamagnetic Dendrimer-Based Contrast Agents

Superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO) contrast agents consist of suspended colloids of iron oxide nanoparticles that reduce the T2 signals of absorbing tissues such as the liver, spleen, or gastrointestinal tract.60 Recently, the group of J. R. Baker has developed series of dendrimer-functionalized shell-crosslinked iron oxide nanoparticles (Figure 16.5; see also Chapter 6) for tumor

Figure 16.5

Dendrimer-functionalized shell-crosslinked iron oxide nanoparticles

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MRI.61–63 The optimized systems combine layer-by-layer (LBL) deposition of poly(Llysine) (PLL) and poly(glutamic acid) (PGA) polymers on to superparamagnetic Fe3O4 nanoparticles, with a subsequent covalent crosslinking that provides a high stability to the coating, and a final layer consisting of a PAMAM dendrimer bearing fluorescent probes (FI) and folic acid (FA) moieties for tumor targeting. These nanoparticles were found to be stable, water soluble, and biocompatible, and allowed in vivo imaging of a folic acid receptor expressing a tumor model. The group of E. R. Gillies also reported recently USPIO protected by a dextran coating having pendant azide groups that were functionalized efficiently by a conjugated rhodamine derivative and by polypropionic acid-based dendrimers having peripheral guanidines. These dual tracers were successfully transfected to mouse glioma cells and significantly increased MRI signal intensity upon cellular uptake.64 16.2.4

Dendrimer-Based 129Xe HYPER-CEST MRI Contrast Agents

Hyperpolarized xenon MRI65 is foreseen as an emerging imaging technique thanks to its high detectability, its high solubility, and diffusion from the lung alveolae to capillary beds and subsequent transport into the body by the blood pool, and also to sensitivity of 129Xe chemical shifts that traduce its environment. In this pioneering context, PPI dendrimers and PAMAM dendrimers have been recently used to encapsulate 129Xe cages and amplify its signal by a factor of eightfold by preventing deleterious interferences between diastereoisomers of the biosensor.66 16.2.5

19

F Dendrimer-Based MRI Contrast Agents

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F MRI was discovered in the same decade as proton MRI, and it is still in its infancy, despite the sensitivity associated with 19F signals, mainly because associated imaging agents are instable, heterogeneous, or accumulate in the body for long periods of time. Nevertheless, this technique could be useful to trace the pharmacokinetics of biologically relevant compounds through efficient tagging. Little attention has been devoted to dendrimeric fluorous tracers, although they present attractive properties in terms of retention time, stability, and signal quality due to their symmetry, in comparison with perfluorocarbon emulsions. Recent examples include the preparation of a bisdendron-based platform equipped with a bunch of nine CF3 groups and four positions available for the grafting of the traced target,67 as well as PAMAM dendrimers partially fluorinated with perfluoroalkyl acids that self-assemble into aggregates according to a pH- and temperature-dependent process.68

16.3 16.3.1

Other Types of Imaging with Dendrimers Dendrimers for Optical Imaging

Optical imaging relies on following a luminescent emitter that may be targeted to an organ or a cell population of interest, and its mapping in the body. In vivo fluorescence or

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phosphorescence imaging usually generates two-dimensional images of integrated light emitted from the surface of the irradiated body or organ. The reconstruction of volumetric images associated with a better spatial and temporal resolution is among the most recent advances in this field. The advent of two-photon excited fluorescence (TPEF) microscopy has provided great opportunities in this regard by combining an intrinsic high spatial resolution and the possibility to operate with near-infrared (NIR) excitation radiation, which allows a deeper imaging of tissues with reduced photodamage. Dendrimers can be equipped with luminescent tracers in very sophisticated ways in order to confine the emitters in a controlled environment, provide them with biocompatibility, and/or increase their local density.69 One of the most straightforward approaches is the grafting of commercially available dyes on to dendrimeric architectures in order to follow their cellular trafficking,70,71 their interactions with key targets72,73 or their fate in animal models.74 Related strategies resemble the stochastic functionalization of dendrimers developed by the group of J. R. Baker33 to produce dendrimer-based systems randomly equipped with a range of functions (drug or pro-drug, solubilizing group, targeting agent, tracing emitter), albeit with a serious drawback related to the lack of homogeneity of studied samples. Alternatively, the precise grafting of the dye can be achieved at well-defined positions of dendrimers (core, branch, surface) or complex dendrimeric architectures.75 For example, the benefits of capping biodegradable polyester dendrimers with PEG could be assessed in vivo by tracing an FDA-approved NIR dye located at the core of such compounds74 over a few days, which is impossible with radioactive tracers. The group of A. M. Caminade and J. P. Majoral, together with the group of M. BlanchardDesce, also reported in vivo the imaging of the vascular network of a rat olfactive bulb (a region of the brain) with water-soluble bisdendrimers having at the core a TPA tracer.76 Recent development of these organic dots (Figure 16.6), which exhibit high fluorescence quantum yields and TPA cross-sections, should open new perspectives for in vivo optical imaging.77,78 Oxygen-dependent quenching of phosphorescence is another emerging field of applications for luminescent dendrimers related to planar two-dimensional imaging, highresolution microscopy, or NIR three-dimensional tomography.79 The most active group in this field has developed a series of phosphorescent probes (Oxyphors)80 based on a porphyrine core protected by polyglutamic81 or poly(arylglycine)79 dendrimer coatings that can be modified with PEG tails. Such systems can be improved by the grafting of TPA

Figure 16.6

TPA tracers incorporated into polyphosphorhydrazone (PPH) dendrimers

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Figure 16.7 Schematic representation of a dendrimeric two-photon enhanced oxygen sensor for oxygen microscopy (adapted from Finikova et al., 200883)

antennae82 that allow Förster-type resonance energy transfer (FRET) to the porphyrine core81,83 (see Figure 16.7) and enhance imaging quality in oxygen microscopy. 16.3.2

Dendrimers for Nuclear Medicine (NM) Imaging and Computed Tomography X-Ray Imaging (CT)

NM and CT imaging are based on tomography, which involves cross-sectional data acquisition and computed volumetric reconstruction. Nuclear medicine imaging (or radionuclide scanning) includes functional and structural imaging techniques like positron emission tomography (PET) or single positron emission computed tomography (SPECT) and the use of positive electron emitters and gamma emitters as contrast agents, respectively. Computed tomography X-ray imaging (CT) or computerized axial tomography (CAT) scanning uses X-rays to show cross-sectional images of the body, which are computerized to produce three-dimensional images or two-dimensional slices of a target area. The use of contrast agents that are opaque to X-rays allows CT imaging of blood vessels (iodinated contrast agents) or gastrointestinal tract (barium containing contrast agents). Iodinated dendrimeric systems represent a suitable source of contrast agents for CT applied to angiography, where extravasation from normal blood vessels can be reduced according to simple size-related properties. The partial grafting of triiodobenzene moieties on the surface of a generation 4 PAMAM dendrimer afforded an inhomogeneously functionalized material.84,85 An improved candidate consisting of a series of PEG-cored poly(L-lysine) dendrimers having triiodobenzene contrast agents on their surface was described and one candidate was successfully assayed in a preliminary in vivo CT experiment.86 Another type

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of contrast agent for CT using dendrimers consists of dendrimer-encapsulated gold nanoparticles, which were found to be stable and biocompatible enough to be visualized in mice, with a better contrast than state-of-the-art iodine-based contrast agents for the same concentration of gold and iodine.87 Emitting dendrimers for NM have been early developed by grafting gamma emitters (111In, 153Gd, 88Y) on targeting dendrimeric scaffolds having monoclonal antibodies88,89 toward specific tumors, although with a high kidney, liver, and spleen uptake. Recently, the group of J. M. J. Fréchet has developed a biodegradable positron emitting dendrimer based on a bifunctional polyester structure having PEG residues ended by targeting RDG peptides surrounding internal radiohalogens. The strategy was validated by increased stability of the radiomarkers, enhancement of the binding affinity of the RGD peptides, and in vivo selective imaging of angiogenesis.90 In another example, PAMAM dendrimers have been surface-modified with succinamic moieties and conjugated with multiple copies of phosphorodiamidate morpholino (MORF) oligomers to obtain a pretargeting amplified scaffold that could effectively host complementary MORF labeled with 99mTc and a complementary MORF equipped with a monoclonal antibody to target cancerous cells.91 The strategy was validated in vitro and the use of the pretargeting dendrimer scaffold amplified the signal by a factor of 6 to 14 times. Another example of radiolabeled dendrimeric tracers for SPECT is composed of biodegradable dendrons with a polyol-containing surface that can eventually be engineered and a 99mTc complex at the focal point. These compounds were successfully used in a dual CT/SPECT imaging experiment in vivo (Figure 16.8) and

Figure 16.8

99m

Tc-cored polyglutamic dendrimer

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were found to be excreted rapidly from animals. This study provided accurate quantitative information on the biodistribution of these tracers.92

16.4

Conclusion and Perspectives

Despite the fact that the Gadomer 17 stayed in the pipe, studies conducted over the last few years have opened up new perspectives for dendrimer-based molecular imaging. In particular, the multifunctionalization, performed either in a stochastic way or in a more sophisticated and topologically controlled manner, has led to the development of efficient dendrimer-based “nanotools”, which have exciting features for the development of the so-called “nanomedicine”. Among the main advances authorized by the use of multifunctional dendrimeric architectures, site isolation and biocompatibility have been made possible thanks to the use of PEG entities, allowing a precise control over excretion rates. The development of multimodal dendrimeric systems incorporating MRI contrast agents and fluorescent tracers32,34,93 for optical imaging is very promising for future applications requiring an imaging compound able to diagnose before surgery and to help the surgeon to localize cancerous areas accurately during surgery. In this respect, the group of R. Y. Tsien has reported on PAMAM-based multifunctional fluorescent tracers having fluorescent probes, Gd complexes or both, and activable cell penetrating peptides (ACPPs) for in vivo visualization of matrix metalloproteinase activities by MRI and fluorescence.94 Tumor uptake was 4 to 15 times higher than for unconjugated ACPPs, and these nanodevices allowed the detection of very small residual tumor and metastases (200 μm), which were resected under fluorescence guidance, leading to a dramatic increase in animal survival.95 Other innovative dual tracers include CT/MRI dual tracers for the intracerebral delivery of therapeutic agents.96 Finally, it is important to note that all progress made in molecular imaging with dendrimers is of crucial interest for future developments of dendrimer-based therapeutics and pro-drug agents, because they contribute considerably to a better knowledge of the pharmacokinetics of dendrimers, which is still a blocking point in the long way toward industrial development of any dendrimeric drug candidate.

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(29) E. C. Wiener, F. P. Auteri, J. W. Chen, M. W. Brechbiel, O. A. Gansow, D. S. Schneider, R. L. Belford, R. B. Clarkson, and P. C. Lauterbur (1996) Molecular-dynamics of ion–chelate complexes attached to dendrimers. J. Am. Chem. Soc., 118, 7774–7782. (30) E. C. Wiener, M. W. Brechbiel, H. Brothers, R. L. Magin, O. A. Gansow, D. A. Tomalia, and P. C. Lauterbur (1994) Dendrimer-based metal-chelates – a new class of magnetic-resonanceimaging contrast agents. Magn. Reson. Med., 31, 1–8. (31) E. C. Wiener, S. Konda, A. Shadron, M. Brechbiel, and O. Gansow (1997) Targeting dendrimerchelates to tumors and tumor-cells expressing the high-affinity folate receptor. Invest. Radiol., 32, 748–754. (32) H. Xu, C. A. S. Regino, Y. Koyama, Y. Hama, A. J. Gunn, M. Bernardo, H. Kobayashi, P. L. Choyke, and M. W. Brechbiel (2007) Preparation and preliminary evaluation of a biotintargeted, lectin-targeted dendrimer-based probe for dual-modality magnetic resonance and fluorescence imaging. Bioconjugate Chem., 18, 1474–1482. (33) D. G. Mullen, A. M. Desai, J. N. Waddell, X. M. Cheng, C. V. Kelly, D. Q. McNerny, I. J. Majoros, J. R. Baker, L. M. Sander, B. G. Orr, and M. M. B. Holl (2008) The implications of stochastic synthesis for the conjugation of functional groups to nanoparticles. Bioconjugate Chem., 19, 1748–1752. (34) Y. Koyama, V. S. Talanov, M. Bernardo, Y. Hama, C. A. S. Regino, M. W. Brechbiel, P. L. Choyke, and H. Kobayashi (2007) A dendrimer-based nanosized contrast agent, dual-labeled for magnetic resonance and optical fluorescence imaging to localize the sentinel lymph node in mice. J. Mag. Res. Imaging, 25, 866–871. (35) Y. Hama, M. Bernardo, C. A. S. Regino, Y. Koyama, M. W. Brechbiel, M. C. Krishna, P. L. Choyke, and H. Kobayashi (2007) MR lymphangiography using dendrimer-based contrast agents: a comparison at 1.5T and 3.0T. Magn. Reson. Med., 57, 431–436. (36) H. Xu, C. A. S. Regino, M. Bernardo, Y. Koyama, H. Kobayashi, P. L. Choyke, and M. W. Brechbiel (2007) Toward improved syntheses of dendrimer-based magnetic resonance imaging contrast agents: new bifunctional diethylenetriamine pentaacetic acid ligands and nonaqueous conjugation chemistry. J. Med. Chem., 50, 3185–3193. (37) M. Polášek, P. Hermann, J. A. Peters, C. F. G. C. Geraldes, and I. Lukes (2009) PAMAM dendrimers conjugated with an uncharged gadolinium(III) chelate with a fast water exchange: the influence of chelate charge on rotational dynamics. Bioconjugate Chem., 20, 2142–2153. (38) K. Nwe, H. Xu, C. A. S. Regino, M. Bernardo, L. Ileva, L. Riffle, K. J. Wong, and M. W. Brechbiel (2009) A new approach in the preparation of dendrimer-based bifunctional diethylenetriaminepentaacetic acid MR contrast agent derivatives. Bioconjugate Chem., 20, 1412–1418. (39) Z. Cheng, D. L. J. Thorek, and A. Tsourkas (2010) Gadolinium-conjugated dendrimer nanoclusters as a tumor-targeted T1 magnetic resonance imaging contrast agent. Angew. Chem. Int. Ed., 49, 346–350. (40) R. Z. Xu, Y. L. Wang, X. L. Wang, E. K. Jeong, D. L. Parker, and Z. R. Lu (2007) In vivo evaluation of a PAMAM-cystamine-(Gd-DO3A) conjugate as a biodegradable macromolecular MRI contrast agent. Expl Biol. Med., 232, 1081–1089. (41) N. Malik, R. Wiwattanapatapee, R. Klopsch, K. Lorenz, H. Frey, J. W. Weener, E. W. Meijer, W. Paulus, and R. Duncan (2000) Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of I-125-labelled polyamidoamine dendrimers in vivo. J. Controlled Release, 65, 133–148. (42) D. M. Domanski, B. Klajnert, and M. Bryszewska (2004) Influence of PAMAM dendrimers on human red blood cells. Bioelectrochemistry, 63, 189–191. (43) S. D. Swanson, J. F. Kukowska-Latallo, A. K. Patri, C. Y. Chen, S. Ge, Z. Y. Cao, A. Kotlyar, A. T. East, and J. R. Baker (2008) Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement. Int. J. Nanomed., 3, 201–210. (44) H. Sarin, A. S. Kanevsky, H. T. Wu, A. A. Sousa, C. M. Wilson, M. A. Aronova, G. L. Griffiths, R. D. Leapman, and H. Q. Vo (2009) Physiologic upper limit of pore size in the blood–tumor barrier of malignant solid tumors. J. Trans. Med., 7. (45) M. A. Quadir, M. R. Radowski, F. Kratz, K. Licha, P. Hauff, and R. Haag (2008) Dendritic multishell architectures for drug and dye transport. J. Controlled Release, 132, 289–294.

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(46) Z. Jaszberenyi, L. Moriggi, P. Schmidt, C. Weidensteiner, R. Kneuer, A. E. Merbach, L. Helm, and E. Toth (2007) Physicochemical and MRI characterization of Gd3+-loaded polyamidoamine and hyperbranched dendrimers. J. Biol. Inorg. Chem., 12, 406–420. (47) Y. J. Fu, H. J. Raatschen, D. E. Nitecki, M. F. Wendland, V. Novikov, L. S. Fournier, C. Cyran, V. Rogut, D. M. Shames, and R. C. Brasch (2007) Cascade polymeric MRI contrast media derived from poly(ethylene glycol) cores: initial syntheses and characterizations. Biomacromolecules, 8, 1519–1529. (48) S. Langereis, Q. G. de Lussanet, M. H. P. van Genderen, E. W. Meijer, R. G. H. Beets-Tan, A. W. Griffioen, J. M. A. van Engelshoven, and W. H. Backes (2006) Evaluation of Gd(III) DTPA-terminated poly(propylene imine) dendrimers as contrast agents for MR imaging. NMR in Biomedicine, 19, 133–141. (49) C. S. Winalski, S. Shortkroff, E. Schneider, H. Yoshioka, R. V. Mulkern, and G. M. Rosen (2008) Targeted dendrimer-based contrast agents for articular cartilage assessment by MR imaging. Osteoarthritis and Cartilage, 16, 815–822. (50) C. S. Winalski, S. Shortkroff, E. Schneider, R. V. Mulkern, A. Chatha, and G. M. Rosen. Effect of molecular properties of dendrimer-linked nitroxide MR contrast agents on cartilage enhancement. Radiology, 225, 329–329. (51) C. S. Winalski, S. Shortkroff, R. V. Mulkern, E. Schneider, and G. M. Rosen (2002) Magnetic resonance relaxivity of dendrimer-linked nitroxides. Magn. Reson. Med., 48, 965–972. (52) A. Bertin, A. I. Michou-Gallani,, J. Steibel, J. L. Gallani, and D. Felder-Flesch (2010) Synthesis and characterization of a highly stable dendritic catechol-tripod bearing technetium-99m. New J. Chem., 34, 267–275. (53) K. M. Ward, A. H. Aletras, and R. S. Balaban (2000) A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J. Magn. Reson., 143, 79–87. (54) K. M. Ward and R. S. Balaban (2000) Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn. Reson. Med., 44, 799–802. (55) L. E. Gerweck and K. Seetharaman (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res., 56, 1194–1198. (56) S. R. Zhang, M. Merritt, D. E. Woessner, R. E. Lenkinski, and A. D. Sherry (2003) PARACEST agents: modulating MRI contrast via water proton exchange. Acc. Chem. Res., 36, 783–790. (57) M. M. Ali, M. Woods, P. Caravan, A. C. L. Opina, M. Spiller, J. C. Fettinger, and A. D. Sherry (2008) Synthesis and relaxometric studies of a dendrimer-based pH-responsive MRI contrast agent. Chem.-Eur. J., 14, 7250–7258. (58) J. A. Pikkemaat, R. T. Wegh, R. Lamerichs, R. A. van de Molengraaf, S. Langereis, D. Burdinski, A. Y. F. Raymond, H. M. Janssen, B. F. M. de Waal, N. P. Willard, E. W. Meijer, and H. Grull (2007) Dendritic PARACEST contrast agents for magnetic resonance imaging. Contrast Media Mol. Imaging, 2, 229–239. (59) M. M. Ali, B. Yoo, and M. D. Pagel (2009) Tracking the relative in vivo pharmacokinetics of nanoparticles with PARACEST MRI. Molec. Pharm., 6, 1409–1416. (60) S. Laurent, D. Forge, M. Port, A. Roch, C. Robic, L. V. Elst, and R. N. Muller (2008) Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev., 108, 2064–2110. (61) X. Y. Shi, S. H. Wang, S. D. Swanson, S. Ge, Z. Y. Cao, M. E. Van Antwerp, K. J. Landmark, and J. R. Baker (2008) Dendrimer-functionalized shell-crosslinked iron oxide nanoparticles for in-vivo magnetic resonance imaging of tumors. Adv. Mater., 20, 1671–1678. (62) K. J. Landmark, S. DiMaggio, J. Ward, C. V. Kelly, S. Vogt, S. Hong, A. Kotlyar, A. Myc, T. P. Thomas, J. E. Penner-Hahn, J. R. Baker, M. M. B. Holl, and B. G. Orr (2008) Synthesis, characterization, and in vitro testing of superparamagnetic iron oxide nanoparticles targeted using folic acid-conjugated dendrimers. ACS Nano, 2, 773–783. (63) S. H. Wang, X. Y. Shi, M. Van Antwerp, Z. Y. Cao, S. D. Swanson, X. D. Bi, and J. R. Baker (2007) Dendrimer-functionalized iron oxide nanoparticles for specific targeting and imaging of cancer cells. Adv. Funct. Mater., 17, 3043–3050.

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(64) A. L. Martin, L. M. Bernas, B. K. Rutt, P. J. Foster, and E. R. Gillies (2008) Enhanced cell uptake of superparamagnetic iron oxide nanoparticles functionalized with dendritic guanidines. Bioconjugate Chem., 19, 2375–2384. (65) M. S. Albert, G. D. Cates, B. Driehuys, W. Happer, B. Saam, C. S. Springer, and A. Wishnia (1994) Biological magnetic-resonance-imaging using laser polarized Xe-129. Nature, 370, 199–201. (66) J. L. Mynar, T. J. Lowery, D. E. Wemmer, A. Pines, and J. M. J. Fréchet (2006) Xenon biosensor amplification via dendrimer-cage supramolecular constructs. J. Am. Chem. Soc., 128, 6334–6335. (67) Z. X. Jiang, X. Liu, E. K. Jeong, and Y. B. Yu (2009) Symmetry-guided design and fluorous synthesis of a stable and rapidly excreted imaging tracer for F-19 MRI. Angew. Chem. Int. Ed., 48, 4755–4758. (68) J. M. Criscione, B. L. Le, E. Stern, M. Brennan, C. Rahner, X. Papademetris, and T. M. Fahmy (2009) Self-assembly of pH-responsive fluorinated dendrimer-based particulates for drug delivery and noninvasive imaging. Biomaterials, 30, 3946–3955. (69) A. M. Caminade, A. Hameau, and J. P. Majoral (2009) Multicharged and/or water-soluble fluorescent dendrimers: properties and uses. Chem. Eur. J., 15, 9270–9285. (70) M. El-Sayed, M. F. Kiani, M. D. Naimark, A. H. Hikal, and H. Ghandehari (2001) Extravasation of poly(amidoamine) (PAMAM) dendrimers across microvascular network endothelium. Pharm. Res., 18, 23–28. (71) L. E. Samuelson, M. J. Dukes, C. R. Hunt, J. D. Casey, and D. J. Bornhop (2009) TSPO targeted dendrimer imaging agent: synthesis, characterization, and cellular internalization. Bioconjugate Chem., 20, 2082–2089. (72) M. Berna, D. Dalzoppo, G. Pasut, M. Manunta, L. Izzo, A. T. Jones, R. Duncan, and F. M. Veronese (2006) Novel monodisperse PEG-dendrons as new tools for targeted drug delivery: synthesis, characterization and cellular uptake. Biomacromolecules, 7, 146–153. (73) A. K. Galande, S. A. Hilderbrand, R. Weissleder, and C. H. Tung (2006) Enzyme-targeted fluorescent imaging probes on a multiple antigenic peptide core. J. Med. Chem., 49, 4715–4720. (74) A. Almutairi, W. J. Akers, M. Y. Berezin, S. Achilefu, and J. M. J. Fréchet (2008) Monitoring the biodegradation of dendritic near-infrared nanoprobes by in vivo fluorescence imaging. Molec. Pharm., 5, 1103–1110. (75) S. Fuchs, A. Pla-Quintana, S. Mazeres, A. M. Caminade, and J. P. Majoral (2008) Cationic and fluorescent “Janus” dendrimers. Org. Lett., 10, 4751–4754. (76) T. R. Krishna, M. Parent, M. H. V. Werts, L. Moreaux, S. Gmouh, S. Charpak, A. M. Caminade, J. P. Majoral, and M. Blanchard-Desce (2006) Water-soluble dendrimeric two-photon tracers for in vivo imaging. Angew. Chem. Int. Ed., 45, 4645–4648. (77) O. Mongin, T. R. Krishna, M. H. V. Werts, A. M. Caminade, J. P. Majoral, and M. BlanchardDesce (2006) A modular approach to two-photon absorbing organic nanodots: brilliant dendrimers as an alternative to semiconductor quantum dots? Chem. Commun., 915–917. (78) F. Terenziani, V. Parthasarathy, A. Pla-Quintana, T. Maishal, A. M. Caminade, J. P. Majoral, and M. Blanchard-Desce (2009) Cooperative two-photon absorption enhancement by throughspace interactions in multichromophoric compounds. Angew. Chem. Int. Ed., 48, 8691–8694. (79) A. Y. Lebedev, A. V. Cheprakov, S. Sakadzic, D. A. Boas, D. F. Wilson, and S. A. Vinogradov (2009) Dendritic phosphorescent probes for oxygen imaging in biological systems. ACS App. Mater. Interf., 1, 1292–1304. (80) D. F. Wilson, W. M. F. Lee, S. Makonnen, O. Finikova, S. Apreleva, and S. A. Vinogradov (2006) Oxygen pressures in the interstitial space and their relationship to those in the blood plasma in resting skeletal muscle. J. Appl. Physiol., 101, 1648–1656. (81) I. Dunphy, S. A. Vinogradov, and D. F. Wilson (2002) Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence. Anal. Biochem., 310, 191–198. (82) R. P. Brinas, T. Troxler, R. M. Hochstrasser, and S. A. Vinogradov (2005) Phosphorescent oxygen sensor with dendritic protection and two-photon absorbing antenna. J. Am. Chem. Soc., 127, 11851–11862.

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17 Dendrimers as Transfection Agents Cédric-Olivier Turrin* and Anne-Marie Caminade

17.1

Introduction

Gene transfection,1 an acronym for transmission infection, refers to the modification of eukaryotic cells by introduction of exogenous DNA in their own genetic material. This method was introduced in the late 1960s with the use of diethylamino ethanol (DEAE) modified dextran.2 Since then, the design of new transfection agents has led to the development of commercially available transfection kits for in vitro and in vivo gene transfection. In vitro gene transfection is generally motivated by comprehension of a chemical response (protein coding) related to a sequence of DNA, whereas in vivo gene delivery is more likely to be dedicated to the repairing of genetic deficiencies and related diseases by direct transfection of nucleic acids in a target cell population. Alternatively to in vivo gene transfection, the ex vivo approach involves the treatment of cells or transplants taken from a patient and their infusion or grafting after efficient gene delivery and successful metabolic modification. As bare DNA is very unstable in biological media, living bodies have developed many strategies to prevent the modification of their genetic patrimony by exogenous or endogenous species that may escape the immune system vigilance, like the physical barriers of the cell membrane and the nucleus membrane. Consequently, gene transfection faces two major difficulties, which are the need to compact and protect the transfected gene from the immune system and to make possible the penetration of cell and nucleus membranes. Despite its instability, bare DNA can be transfected with specific physical methods like gene guns or electroporation, but these methods are often deleterious to cell viability and so alternative gene delivery techniques based on the use of gene vectors have been developed. * Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 17.1

Possible mechanism of gene transfection with dendriplexes

As viruses are naturally equipped with specific machinery to enter cells, they have been successfully used to compact, protect, and deliver nucleic acids with unrivalled transfection efficiencies.3 The downside of viral vectors is related to biosafety issues4,5 and high costs of production. The so-called “chemical” alternative approach is based on the use of nonviral vectors,6 which are generally cationic molecules that are able to interact with nucleic acids by electrostatic interactions.7 When cationic lipids8 are used the resulting systems are called lipoplexes. This versatile technology is facilitated by the increasing number of commercially available cationic lipids rationally designed for this purpose and the possibility to enhance their transfection efficiency by formulating them with other lipids. Polyplexes result from the interaction of DNA with cationic polymers9 from linear structures to hyperbranched ones like polyethyleneimine (PEI), which can be chemically engineered to increase their transfecting performance. The cell transfection mechanism described in Figure 17.1 is still rather unclear, in view of the number of contradictory reports related to this issue.6 In particular, the first step has been described as a nonspecific, actin powered, adsorptive endocytosis of the positively charged lipoplex or polyplex on the cell surface via interactions with negatively charged glycans.10 Alternative approaches to rationalize this step comprise a lipid raft mediated mechanism proposed for PAMAM/DNA polyplexes,11 which was recently invalidated,12 or a clathrin-dependent endocytosis or a macropinocytosis.13,14 Independently from these hypotheses, cell specificity can be obtained with increased DNA uptake when a targeting moiety is attached to the DNA complex. Once internalized, the complex is retained in endosomes/lysosomes and must escape its vehicle to reach the cytoplasm. The disruption of the endosomal membrane is supposed to be achieved by swelling of the endosome due to protonation of the transfection agent upon acidification of the lysosome and subsequent osmotic equilibration, as conceptualized by J. P. Behr.15 In the case of nonprotonable systems like lipoplexes the disruption of the endosomes is provoked by fusogenic lipids that disrupt their membrane. Nucleic acids generally penetrate the nucleus passively after disassembly of the complex, although vector unpacking

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is not mandatory. In the case of targeted gene delivery systems, the very first step is driven by host–guest interactions between the targeting moieties of the dendriplex and a specific cellular receptor. The advent of dendrimers over the last decades has been accompanied by early results in the field of gene transfection, and the term dendriplex was rapidly created to describe DNA compacted with dendrimers. The rational design of engineered dendrimeric scaffolds for gene delivery has to comply with specific requirements associated with this purpose. An ideal synthetic transfecting agent should compact DNA in a discrete and stable manner, with a low toxicity profile and a long circulation time. Dendriplexes should also minimize interactions with serum proteins, like opsonins, to escape the immune system, and be selective toward a target cell population. Most of these challenging requirements have been successfully explored over the last decade by several groups.16–26

17.2 17.2.1

Gene Transfection with PAMAM Dendrimers Pioneering Results

PAMAM dendrimers are the most popular dendrimeric vectors for gene delivery, probably because they have been commercially available early. The first studies on dendriplexes were performed by the group of F. C. Szoka on PAMAM dendrimers.27 This seminal work highlighted the fact that the gene delivery performance of dendrimeric scaffolds was much superior to polylysine ones, and correlated these properties to several parameters like dendrimer generation, which affects their size and shape, and the proton sponge character of these macromolecules, which allows pH buffering in the endosomal compartment. A clear dendrimer effect was reported with a maximum efficacy for generation 6. The need for dendrimer surface engineering was also pointed out in this first report as the grafting of a water-soluble membrane-destabilizing peptide proved to enhance the gene delivery properties of the native dendrimer. This study initiated the development of this new field of research for PAMAM dendrimers,28–32 albeit with contradictory results. Actually, Szoka and coworkers could not reproduce the high levels of transfection initially observed. They reported later on the thermolysis of dendrimers in solvolytic solvents, which produced “fractured” dendrimers, the latter being more efficient for transfection than native PAMAM, mainly by increasing the flexibility of the system and its ability to compact DNA,33 as recently confirmed by in vitro and in vivo studies with thermally activated PAMAM.34 The high molecular fraction of these fractured dendrimers has led to a reference gene vector commercialized by Qiagen under the branded name SuperFect™. The group of J. R. Baker has shown that the transfection efficiency of native PAMAM dendrimers was strongly dependent on cell lines and on the dendrimer generation, high generations being more effective than small ones. This observation was also contradictory to the first observations made by Szoka and coworkers, who reported a decrease in transfection efficiency beyond generation 6, and it was correlated to the absence of pure dendrimeric species in the commercial samples used in the very first study.31 The size of dendriplexes was also related to the dendrimer generation and DEAE–dextran was used to reduce the size of the aggregates obtained with the highest generation by one order of magnitude to increase

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their transfecting efficiency, which was latter correlated to the dendrimer/DNA charge ratio.35 Further studies have been published on the influence of this ratio on DNA conformation and its compaction according to the size of the dendrimers.36 It has been shown that low-generation PAMAM dendrimers lead to relatively stable and well-defined aggregates while high-generation PAMAM dendrimers lead to globular and less defined aggregates.37,38 Additional findings highlighted the fact that condensation of DNA by PAMAM dendrimers is a cooperative self-assembly process that produces high-density aggregates in which DNA is too compacted to induce gene expression and low-density aggregates that behave almost like bared DNA and are responsible for gene expression.39

17.2.2

Gene Transfection with Surface-Modified PAMAM

Since the seminal work of Szoka,27 progress has been made to improve the transfecting performance of PAMAM dendrimers and reduce their toxicity by chemical engineering of their surface, while the mechanistic uncertainties evoked in the introduction of this chapter are still debated, despite a systematic and exhaustive review by D. Shcharbin and coworkers19,20 on the techniques and tools employed to characterize dendriplexes. The intrinsic cytotoxicity of positively charged PAMAM dendrimers40–46 and related SuperFect™ 47 is somehow shielded when they are complexed with DNA.31 Nevertheless, dendriplexes can present a non-negligible cytotoxicity according to cell lines, concentration, or charge ratio, and these nanomaterials are thus concerned with the general outcome of their toxic potential.48 Actually, a recent study by Baker and coworkers highlighted the fact that the putatively beneficial lysosomal swelling due to the pH increase during endocytosis of polyamines containing lipoplexes could also result in cell death through a lysosomal apoptotic pathway.41 These results offer an alternative hypothesis to rationalize the toxicity of amino-terminated PAMAM dendrimers, which is commonly related to membrane perturbation and/or hole formation42,49 caused by generation-dependent and concentrationdependent interactions with lipid bilayers.50 Efforts have been made to overcome the tricky issue of toxicity of polycations; they imply the masking of cationic charges, which are responsible for toxicity but are also necessary to compact DNA and interact with negatively charged cell surfaces. The outcome of these studies is generally difficult to predict because the toxicity of polycations is size dependent and toxicological studies are generally performed on dendrimers (a few to ten nanometers), which are much smaller than the resulting dendriplexes (tens or hundreds of nm). A strategy based on the quaternization of amines located inside the structure of PAMAM dendrimers terminated with hydroxyl groups significantly reduced, both their toxicity and their transfection ability,51 while the modification of dendriplexes with poly(ethyleneglycol) PEG tails grafted on to a PAMAM scaffold can reduce their toxicity and increase the solubility of the resulting dendriplexes without affecting their transfection ability.52 An in vivo study by R. Qi and coworkers involving partially pegylated native PAMAM dendrimers confirmed the beneficial effects of PEG on transfection efficiency and cytotoxicity.53 Generation 5 and generation 6 PAMAM conjugated with a 5000 Da PEG residue with an 8% molar ratio were found to transfect pEGFP efficiently, a plasmid encoding for enhanced green fluorescent protein, in neonatal mice by intramuscular injection, with decreased in vivo and in vitro cytotoxity. It is noteworthy that the gene transfer

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selectivity and efficiency of pEGFP with Superfect™ can be favored by targeting specific cell populations or tissues ex vivo via the conjugation of a monoclonal antibody.54 This strategy is of particular interest to target the vascular endothelium, a key target for the treatment of vascular diseases by gene therapy.55 The stochastic approach to multifunctional dendrimers conceptualized by Baker and coworkers56 has been appropriately applied to take the most of both tissue or cell targeting and pegylation for in vivo brain delivery of p-EGFP model plasmid. A generation 5 PAMAM dendrimer was conjugated with a bifunctionnal PEG (4300 Da) having an N-hydrosuccinidyl ester prone reacts with the aminated surface of PAMAM and a maleimide function for the subsequent grafting of a thiolated lactoferrin (Lf), a promising iron-binding protein that allows the crossing of the blood–brain barrier (BBB) by endocytosis with specific receptors.57,58 Cellular uptake on primary brain capillary endothelial cells (BCECs) was studied with BODIPY-labeled PAMAM conjugates. Biodistribution in small animals was determined with 125I-labeled conjugates, showing an increase of the BCEC uptake due to pegylation and an increase of the brain uptake after intravenous administration for PAMAM gene carriers conjugated to the Lf ligand (PAMAM-PEG-Lf) (Figure 17.2). The expression of exogenous GFP was also enhanced both on cell lines and in vivo throughout the brain in the presence of Lf. Other recent advances in the chemical engineering of the surface of PAMAM dendrimers for gene delivery purposes include the use of glucocorticoids like Dexamethasone59 or Triamcinolone acetonide60 as nucleus targeting agents, RGD targeting peptides,61 αcyclodextrins to reduce cytoxicity and increase transfection and dendriplexes stability,62–67 biodegradable esters containing arginine or lysine moieties, which can be hydrolyzed after

Figure 17.2 Schematic representation of a generation 4 PAMAM with PEG chains and targeting ligand

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DNA release,68,69 or phorphyrin conjugates that trigger cell internalization by photochemically perturbating the membrane where they are localized.70 17.2.3

Gene Transfection with Core-Modified PAMAM

As previously mentioned, the local density of amine functions on the outer shell of dendrimers, along with other parameters like size, generation,71 and charge density,72 have a dramatic influence on DNA compaction, on the characteristics of the resulting dendriplexes, and in general on gene transfection efficiency. In this regard, the modification of the PAMAM topology is being explored by replacing the cores of commercially available PAMAM dendrimers with highly functional molecules like trimesyl, pentaerythritol, or inositol moieties.73 For instance, a pentaerythritol-based hypercore having 12 reactive amine end groups was used to synthesize PAMAM-like dendrimers up to generation 5, which possess 384 surface amino groups, while a commercially available generation 5 PAMAM dendrimer with an ethylenediamine core possesses 128 surface amino groups.74 This generation 5 hypercored PAMAM dendrimer was found to be less toxic and more efficient to transfect in vitro p-EGFP than commercially available generation 5 and 7 PAMAM dendrimers, emphasizing the importance of the core for such purposes. In another example by J. S. Park and coworkers, a PEG chain equipped with two PAMAM substructures has also been reported as an efficient transfecting system with a reduced toxicity due to the presence of the PEG residue.52 Modification of the core of dendrimers is also pivotal for the design of the so-called dendrons, which are wedge-shaped dendrimers with multiple surface groups and a single reactive function at the focal point. Such modification can lead to giant amphiphilic molecules provided that the dendron branches and the function of the focal point have opposite affinity toward aqueous and organic phases. The group of K. Kono has been synthesizing a series of such dendronized surfactants based on lipophilic dialkyl cored PAMAM dendrons, which are macromolecular analogs of long-time assayed cationic lipids involved in the formation of lipoplexes75 (Figure 17.3).

Figure 17.3

Dendronized cationic lipids as described by Kono and coworkers

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Such dendronized cationic lipids show a high transfection activity which increases with the size of the PAMAM head.75 The length of the dialkyl chains was found dramatically to influence the size of the resulting dendriplexes, or lipoplexes, with plasmid DNA. Longer alkyl chains gave rise to smaller aggregates, and although both systems had the same transfection ability in vitro in the absence of serum, the long chained dendronized cationic lipids were more efficient in the presence of serum.76 These original systems have been optimized by the attachment of PEG chains on the surface of the PAMAM heads to increase their stability in the presence of serum.77 The same group also reported on linear poly(L)lysine dendronized with PAMAM heads, and the transfecting efficiency of these systems was correlated to a subtle balance between PAMAM dendrimeric head size, which affords pH buffering properties, and the poly(L)lysine chain length, which is responsible for DNA compaction.78,79 17.2.4

Gene Transfection with PAMAM-Functionalized Nanoparticles

Inorganic nanoparticles80 or polymer-based nanoparticles are nondendrimer-based gene vectors, which have been extensively studied.6 In some cases, the transfection efficiency of these systems can be enhanced by modification of their surface with PAMAM dendrimers or dendrons that can offer DNA compaction properties and biocompatible and/or targeting features provided that they are suitably functionalized. For instance, PAMAM dendrimers have been extensively used to stabilize and functionalize metal and metal oxide nanoparticles (see Chapter 6), and some of these systems, including silica nanoparticles81 and superparamagnetic nanoparticles,82,83 have been successfully assayed for transfection thanks to dendrimer functionalization. Carbon nanotubes, which have been suspected to be cancerous nanoparticles,84 have also been surface-modified with PAMAM dendrons to find applications as gene delivery systems.85–87 The supramolecular assembly of oppositely charged polymers can lead to the formation of multifunctional nanocomplexes; this route has been explored to obtain targeted and pH-responsive nucleic acids delivery systems. Such polyion complex micelles88 (PICMs; see Figure 17.4) comprising small interfering RNA (siRNA are double-stranded RNA

Figure 17.4 siRNA

Dendrimer-based core–shell PICMs for the targeted delivery of ODNs or

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Dendrimers

molecules involved in RNA interference and gene silencing) or antisense oligonucleotides, a linear and negatively charged PEG-modified block copolymer and PAMAM dendrimers were successfully assayed in vitro with a reduced cytoxicity and a good stability against enzymatic degradation.89,90 Similarly, biodegradable microparticles made of PAMAMplasmid DNA dendriplexes and biodegradable poly(D,L-lactide-co-glycolide) in which the genetic material can be trapped inside the capsules or complexed on their surfaces have been prepared and successfully assayed for nonviral gene delivery.91–93 Alternatively, substrate-mediated gene delivery has been performed with dendrimer/DNA complexes encapsulated into water-soluble polymers.94,95 All these strategies have led to an increased stability of the vectors in the presence of serum and a significant increase of the transfecting activity of the native capsules or systems lacking the PAMAM component.96–98 17.2.5

Gene Transfection with PAMAM-Like Hyperbranched Polymers

The commercial success of SuperFect™, a hyperbranched PAMAM polymer resulting from the degradation of PAMAM dendrimers, has inspired scarce examples of hyperbranched PAMAM polymers (hPAMAM or HyPAMAM) for nucleic acid delivery purposes (see Figure 17.5).99–102 These rather recent systems have shown superior transfecting properties compared to branched PEI, but their activity has not been compared to commercial Superfect™ or native PAMAM dendrimers.

Figure 17.5 Bioreducible hyperbranched PAMAM101 (top) and phenylalanine modified hyperbranched PAMAM102 (bottom)

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Gene Transfection with Other Dendrimers Gene Transfection with PPI Dendrimers

Due to comparable acid–base properties to those of PAMAM dendrimers, with basic amine terminal groups (pKa 9–11) and acidic internal tertiary amines (pKa 5–8),103 PPI dendrimers have been early assayed by V. A. Kabanov and coworkers as a potential transfection agent, the terminal functions exclusively interacting with the transported gene while the internal amines possibly act as a proton sponge to favor lysosome escape.104,105 Unlike PAMAM dendrimers, structure activity relationships have shown that only lower generation (typically generation 2) unmodified PPI dendrimers/DNA dendriplexes are suitable for in vitro gene delivery, complexes with higher generations being cytotoxic;106 these findings have been applied by I. F. Uchegbu and coworkers for the in vitro transfection of antisense oligonucleotides targeting the epidermal growth factor receptor protein.107 In vivo studies on mice were later performed with an N-methylated generation 2 PPI dendrimer.108 This candidate exhibited better compacting properties, lowered toxicity in vitro and in vivo, and a high hepatic uptake in comparison with a linear PEI, probably because of a reduced circulation time. The same authors also reported on the good performance and lack of toxicity of nonmodified PPI dendrimers in vivo for the transfection of TNF alpha expression plasmid in murine models. The third generation PPI dendrimer surpassed other commercial polycationic vectors and the authors observed the regression of remote xenograft murine tumors and long-term survival of up to 100% of the animals.109 Gene transfection is known to be very sensitive to subtle changes in the chemical nature of the vector, type of transfected material, operating condition, and the transfected cell.110 In addition, it has been shown that PPI dendrimers intrinsically alter gene expression during siRNA transfection assays on human epithelial cells.111,112 These findings confirm the sensitivity of gene delivery with dendrimers and open new perspectives related to the intrinsic activity of the vectors and their effects on cellular functions. Surface engineering is widely employed to alter the biological response of dendrimers; for example, it has been shown that surface functionalization of PPI dendrimers can drastically reduce their cytotoxicty.113 For instance, it has been demonstrated that interactions with DNA can be strengthened by the grafting of arginine114 or guanidine115,116 end groups, resulting in a lowered toxicity and increased gene delivery efficiency. This strategy has also been applied for the grafting of PEG-like groups and combined with quaternization of internal amines, allowing the use of fourth generation PPI dendrimers in vivo and in vitro with a low toxicity and good transfection efficiency in the presence of serum.117–119 Ternary complexes of diamino butane-terminated PPI dendrimers, cucurbituril (a macrocyclic molecule with glycoluril repeat units), and DNA have also been proposed to reduce cytotoxicity and allow the use of higher generation PPI dendrimers.120,121 Further efforts to address the cytotoxicity issue related to the use of higher generation PPI dendrimers include internal amine quaternization and/or surface modification with sugars,122 oligoethyleneimine moieties,123 and acid-cleavable alkyl chains.124

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Gene Transfection with Peptide-Based Dendrimers

Dendrimeric poly(L-lysine) PLL structures have been early used for gene transfection to overcome the toxic issue of linear PLL structures. In their pioneering studies, A. T. Florence and coworkers explored the possibilities offered by a series of small PLL-based dendrons having an alkyl chain at the focal point, different branch lengths, and various surface functions (sugars, nucleus-targeting peptide) to transfect fibroblasts.125,126 These systems inspired by lipid-cored peptides (LCP), described by I. Toth,127 exhibited good transfection properties. The versatility of these small lipidic peptide dendrimers was then assessed as they were found to transfect in vitro ODNs and siRNA efficiently and to transport proteins in the cytosol with minimum toxicity;128,129 they have also been used for encapsulation in PGLA nanoparticles.98 Symmetrical PLL dendrimers of higher generation, in particular a generation 6 dubbed as KG6, also offer good transfection rates, even in the presence of serum.130 However, these promising good results have not been confirmed in vivo, as shown by the absence of gene expression in major organs or in the subcutaneous injected tumors, and despite a long circulation time and tumor accumulation of KG6 by the enhanced permeability and retention effect.131,132 This failure, putatively attributed to strong binding of DNA to PLL dendrimer, illustrates the fact that transfection efficiency is hardly predictable. For instance, in vitro transfection efficiency of KG6 has been shown to increase with increasing dendriplex size,133 whereas in vivo transfection efficiency cannot be directly linked to the cellular uptake. Actually, KG6 PLL dendrimer induced a gene expression which was 100 times the one observed with linear PLL, although the latter led to a better cellular uptake.134 The delivery of siRNA has also been reported with KG6, and transfection efficiency was satisfactory only in the presence of additional commercial cationic lipid.135 Despite these uncertainties, surface modification of PLL scaffolds and other peptide-based dendrimers136 have been studied in view of increasing dendriplex stability, cellular uptake, and eventually gene expression after lysosome escape. Some of these modifications comprise the replacement of terminal lysines with arginines and histidines on a generation 6 PLL dendrimer.137 The DNA binding ability of the histidine-terminated dendrimer was lowered in comparison with the native generation 6 PLL, and no transfection was observed, whereas the arginine-terminated dendrimer exhibited slightly enhanced transfection properties. As in the case of other dendrimeric compounds, core modifications have been performed in view of increasing transfection efficiency by modifying physicochemical parameters of the dendrimeric vectors. These modifications include the use of a peptide core containing up to eight lysine entities,138 a PEG core,139 or a highly functional macromolecule.140 Lysine has also been grafted on the surface of peptide-based bisdendrons, and the resulting species were found to have DNA delivery abilities comparable or better than SuperFect™.141 In a recent example, a series of PLL dendrimers (generations 1 to 4) with a silsesquioxane cubic core has been synthesized by solution phase peptide chemistry. The generationdependent cytoxicity of this series was lower than that of linear PLL, and in vitro luciferase gene transfection in serum-free conditions was more efficient than SuperFect™.140 The generation 3 of this series has been surface functionalized in a random manner with doxorubicin (DOX) and difunctional PEG residues bearing RGD peptides for targeting. This nanoglobular carrier has been successfully assayed for in vitro codelivery of siRNA and

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DOX chemotherapeutic agent, although cytotoxity was somehow increased by the presence of RGD targeting peptide.142 Recent advances on the development of a dendrimeric PLL architecture include the synthesis of small lysine-based dendrons with a cleavable spermine surface having a low in vitro cytotoxic profile, strong DNA binding abilities, and exhibiting chemically induced DNA release.143 17.3.3

Gene Transfection with Phosphorus-Based Dendrimers

In 1999, the group of A. M. Caminade and J. P. Majoral reported on the use of poly(phosphorhydrazone) (PPH) dendrimers equipped with terminal diethylamine. The hydrochloride salts of these PPH dendrimers (generations 1 to 5) have been tested for the transfection of luciferase plasmid in eukaryotic cells. Generations 3 to 5 had roughly comparable efficiencies to standard PEI, even in the presence of 10% serum.144 The toxicity of these dendrimers was lower than that of lipofectin, and dependent on the cell line.145 Quaternization of the terminal amines with methyl iodide and subsequent counteranion exchange drastically reduced the transfecting properties,144 whereas the use of polyanionic compounds like oligonucleotides or dextran sulfate in the delivery mixture can increase the reporter gene expression, by reducing the compaction of the dendriplexes.146 Alternatively, other amines, including pyrrolidine, morpholine, methyl piperazine, and phenyl piperazine, have been grafted on to the surface of PPH dendrimers. The cytotoxicity and ability to transfect single- and double-stranded DNA into three cell lines was strongly affected by the type of surface function, and the fourth generation dendrimer having pyrrolidinium end groups was found to be the most efficient in dendriplex formation and transfection efficiency (Figure 17.6).147 Strategies involving polyanionic dendrimers for gene transfection are scarce, mainly because dendriplexes can obviously not be formed and biolabile conjugation of the genetic material must be taken into consideration. Nevertheless, this unexploited route can escape toxic issues related to polycations. In this regards, anionic phosphonate-based dendrimers have been designed through a solid phase divergent process involving pentaerythritol derivatives148 and conjugated to ODNs. The resulting structures (Figure 17.7) are highly biocompatible due to the presence of oligoethyleneglycol moieties, present enhanced biological stability, and improved cellular uptake.149 These conjugates remained in the cytosol and efficiently inhibited cancer cells growth by target protein expression knockdown.

Figure 17.6

Series of PPH dendrimers for transfection purposes (after reaction with HCl)

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Figure 17.7

17.3.4

Pentaerythritol-based phosphate dendron bioconjugated to ODNs149

Gene Transfection with Silane-Based Dendrimers

The group of R. Gomez and F. J. de la Mata in Madrid has reported recently on the functionalization of chlorosilane-terminated carbosilane dendrimers (described by P. W. N. M. van Leewen and coworkers150) with N,N-dimethylethanolamine and subsequent quaternization.151 Generation 2 dendrimers with 8 or 16 surface functions were found to be reason-

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ably biocompatible, as demonstrated by MTT test and cultures of peripheral blood mononuclear cells, which are sensitive primary cells, despite their rapid degradation in protic solvent by transalcoholysis of the terminal Si–O bonds, a well-established mechanism in sol-gel chemistry for instance. This rapid solvolysis precluded the testing of generation 0 dendrimers, which were too rapidly degraded, while the third generation dendrimers were too insoluble in water solution to perform biocompatibility assays. The hydrolysis of these dendrimers was found to liberate the surface ethanolamine and insoluble Si–OH-terminated dendrimers. Modification of the surface functions of these second generation dendrimers with other hydroxyl-functionalized amines was found to affect the haemolytic properties of these transfecting agents,152 but all candidates were found to be less toxic than SuperFect™ on PBMCs and formed stable dendriplexes with ODN and plasmids, which could be efficiently transferred to PBMCs. The protection against serum protein binding was demonstrated, and this new family of dendrimers increased at a 25% rate the inhibition of HIV replication in PBMCs by transfecting potentially HIV-inhibiting ODNs (TAR, GEM91, REV).153 Further studies on the dendriplex stability against serum proteins allowed dendrimers having two N-donor units per surface function to be identified as the best candidates (Figure 17.8).154 These dendrimers were assayed to deliver an siRNA that targets GADPH expression, an enzyme involved in glucose breakdown for energy production, to HIV-infected lymphocytes.155 No significant improvement in gene delivery was observed, as compared to siRNA alone or in the presence of Lipofectin®. HIV inhibition could be raised by up to 40% in the presence of the dendrimers, while alternative transfection by electroporation led to 80% HIV inhibition. The proof of the concept for the potential in vivo use of such vectors has been recently completed by ex vivo experiments, which demonstrated the efficiency of these dendrimers to transfect rat cortical postmitotic neurons. Transfection efficiency was found to surpass that of a generation 4 PAMAM dendrimer with arginine end groups or cationic lipids, and the authors reported on transfection efficiency equivalent to that of a model viral vector.156

Figure 17.8

Carbosilane dendrimers for gene delivery

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17.4

Dendrimers

Conclusion and Perspectives

Gene transfection is a very sensitive technique to initial conditions, and is obviously bound to butterfly effects. As mentioned in this chapter, the nature of the dendrimeric vectors (surface function, size, generation, etc.), the dendrimer/DNA ratios, the type of target cell, the presence of a codelivery system, or subtle changes in the preparation of the dendriplexes, can dramatically modify the transfection efficiency.157 The work of F. Diederich and coworkers to optimize amphiphilic dendrimers illustrates this complex issue, which has been rationalized in this case by a systematic correlation between molecular structure, self-assembling properties, and gene transfection efficiency,18,158,159 while recent theoretical studies by A. Danani and E. E. Simanek160 have highlighted the importance of dendrimer flexibility on the binding affinity and in vivo or in vitro siRNA transfection efficacy.161 Despite these difficulties, an important amount of knowledge has been produced over the last decade in this field, and some candidates have been finely optimized to afford good transfection efficiency with reasonable cytotoxicity profiles and good stability. Another aspect is the recent advent of siRNA-based strategies,162,163 which have also generated new perspectives for dendrimers as RNA delivery agents.164,165 In particular, the stability of siRNA against serum binding proteins can be efficiently increased, but, here again, small modifications can produce big changes in the transfection efficiency.110 The development of a new dendrimeric scaffold apart from the standard PAMAM, PPI, and PLL based structure also illustrates the recent progress made in this field. In addition to carbosilane and PPH structures, which have been evoked above, triazine dendrimers developed by the group of E. E. Simanek,166,167 dendrimers with internal PEG,168 biodegradable polyester-based dendrimers, and hyperbranched polymers169 show good promise. Recent advances also include efforts to accumulate pharmacokinetic information170 and in vivo data171 and to screen the cell subpopulations that may be alerted by the presence of dendrimeric exogenous vectors, such as macrophages.172,173

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(122) B. Klajnert, D. Appelhans, H. Komber, N. Morgner, S. Schwarz, S. Richter, B. Brutschy, M. Ionov, A. K. Tonkikh, M. Bryszewska, and B. Voit (2008) The influence of densely organized maltose shells on the biological properties of poly(propylene imine) dendrimers: new effects dependent on hydrogen bonding. Chem. Eur. J., 14, 7030–7041. (123) V. Russ, M. Gunther, A. Halama, M. Ogris, and E. Wagner (2008) Oligoethylenimine-grafted polypropylenimine dendrimers as degradable and biocompatible synthetic vectors for gene delivery. J. Controlled Release, 132, 131–140. (124) T. W. J. Steele and W. T. Shier (2010) Dendrimeric alkylated polyethylenimine nano-carriers with acid-cleavable outer cationic shells mediate improved transfection efficiency without increasing toxicity. Pharm. Res., 27, 683–698. (125) I. Toth, T. Sakthivel, A. F. Wilderspin, H. Bayele, M. O’Donnell, D. J. Perry, K. J. Pasi, C. A. Lee, and A. T. Florence (1999) Novel cationic lipid peptide dendrimer vectors. In vitro gene delivery. S.T.P. Pharma Sci., 9, 93–99. (126) D. S. Shah, T. Sakthivel, I. Toth, A. T. Florence, and A. F. Wilderspin (2000) DNA transfection and transfected cell viability using amphipathic asymmetric dendrimers. Int. J. Pharm., 208, 41–48. (127) I. Toth (1994) A novel chemical approach to drug-delivery – lipidic amino-acid conjugates. J. Drug Targeting, 2, 217–239. (128) H. K. Bayele, C. Ramaswamy, A. F. Wilderspin, K. S. Srai, I. Toth, and A. T. Florence (2006) Protein transduction by lipidic peptide dendrimers. J. Pharm. Sci., 95, 1227–1237. (129) H. K. Bayele, T. Sakthivel, M. O’Donell, K. J. Pasi, A. F. Wilderspin, C. A. Lee, I. Toth, and A. T. Florence (2005) Versatile peptide dendrimers for nucleic acid delivery. J. Pharm. Sci., 94, 446–457. (130) M. Ohsaki, T. Okuda, A. Wada, T. Hirayama, T. Niidome, and H. Aoyagi (2002) In vitro gene transfection using dendritic poly(L-lysine). Bioconjugate Chem., 13, 510–517. (131) T. Kawano, T. Okuda, H. Aoyagi, and T. Niidome (2004) Long circulation of intravenously administered plasmid DNA delivered with dendritic poly(L-lysine) in the blood flow. J. Controlled Release, 99, 329–337. (132) T. Kawano, T. Okuda, and T. Niidome (2004) Biodistribution of DNA-complex of dendritic poly(L-lysine) after intravenous injection. Molec. Ther., 9, S315–S315. (133) T. Okuda, S. Kidoaki, M. Ohsaki, Y. Koyama, K. Yoshikawa, T. Niidome, and H. Aoyagi (2003) Time-dependent complex formation of dendritic poly(L-lysine) with plasmid DNA and correlation with in vitro transfection efficiencies. Org. Biomol. Chem., 1, 1270–1273. (134) M. Yamagata, T. Kawano, K. Shiba, T. Mori, Y. Katayama, and T. Niidome (2007) Structural advantage of dendritic poly(L-lysine) for gene delivery into cells. Bioorg. Med. Chem., 15, 526–532. (135) Y. Inoue, R. Kurihara, A. Tsuchida, M. Hasegawa, T. Nagashima, T. Mori, T. Niidome, Y. Katayama, and O. Okitsu (2008) Efficient delivery of siRNA using dendritic poly(L-lysine) for loss-of-function analysis. J. Controlled Release, 126, 59–66. (136) D. J. Coles and I. Toth (2009) Dendritic peptide-based carriers for gene delivery. Curr. Drug Delivery, 6, 338–342. (137) T. Okuda, A. Sugiyama, T. Niidome, and H. Aoyagi (2004) Characters of dendritic poly((L)lysine) analogues with the terminal lysines replaced with arginines and histidines as gene carriers in vitro. Biomaterials, 25, 537–544. (138) K. D. Eom, S. M. Park, H. D. Tran, M. S. Kim, R. N. Yu, and H. Yoo (2007) Dendritic alpha,epsilon-poly(L-lysine)s as delivery agents for antisense oligonucleotides. Pharm. Res., 24, 1581–1589. (139) P. Agrawal, U. Gupta, and N. K. Jain (2007) Glycoconjugated peptide dendrimers-based nanoparticulate system for the delivery of chloroquine phosphate. Biomaterials, 28, 3349–3359. (140) T. L. Kaneshiro, X. Wang, and Z. R. Lu (2007) Synthesis, characterization, and gene delivery of poly-L-lysine octa(3-aminopropyl)silsesquioxane dendrimers: nanoglobular drug carriers with precisely defined molecular architectures. Molec. Pharm., 4, 759–768. (141) S. E. How, A. Unciti-Broceta, R. M. Sanchez-Martin, and M. Bradley (2008) Solid-phase synthesis of a lysine-capped bis-dendron with remarkable DNA delivery abilities. Org. Biomolec. Chem., 6, 2266–2269.

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(142) T. L. Kaneshiro and Z. R. Lu (2009) Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier. Biomaterials, 30, 5660–5666. (143) M. A. Kostiainen and H. Rosilo (2009) Low-molecular-weight dendrons for DNA binding and release by reduction-triggered degradation of multivalent interactions. Chem. Eur. J., 15, 5656–5660. (144) C. Loup, M. A. Zanta, A. M. Caminade, J. P. Majoral, and B. Meunier (1999) Preparation of water-soluble cationic phosphorus-containing dendrimers as DNA transfecting agents. Chem. Eur. J., 5, 3644–3650. (145) M. Maszewska, J. Leclaire, M. Cieslak, B. Nawrot, A. Okruszek, A. M. Caminade, and J. P. Majoral (2003) Water-soluble polycationic dendrimers with a phosphoramidothioate backbone: preliminary studies of cytotoxicity and oligonucleotide/plasmid delivery in human cell culture. Oligonucleotides, 13, 193–205. (146) A. V. Maksimenko, V. Mandrouguine, M. B. Gottikh, J. R. Bertrand, J. P. Majoral, and C. Malvy (2003) Optimisation of dendrimer-mediated gene transfer by anionic oligomers. J. Gene Med., 5, 61–71. (147) C. Padié, M. Maszewska, K. Majchrzak, B. Nawrot, A. M. Caminade, and J. P. Majoral (2009) Polycationic phosphorus dendrimers: synthesis, characterization, study of cytotoxicity, complexation of DNA, and transfection experiments. New J. Chem., 33, 318–326. (148) M. S. Shchepinov, K. U. Mir, J. K. Elder, M. D. Frank-Kamenetskii, and E. M. Southern (1999) Oligonucleotide dendrimers: stable nano-structures. Nucleic Acids Res., 27, 3035–3041. (149) M. Hussain, M. S. Shchepinov, M. Sohail, I. F. Benter, A. J. Hollins, E. M. Southern, and S. Akhtar (2004) A novel anionic dendrimer for improved cellular delivery of antisense oligonucleotides. J. Controlled Release, 99, 139–155. (150) A. W. Van der Made and P. W. N. M. Van Leeuwen (1992) Silane dendrimers. J. Chem. Soc. Chem. Commun., 1400–1401. (151) P. Ortega, J. F. Bermejo, L. Chonco, E. de Jesus, F. J. de la Mata, G. Fernandez, J. C. Flores, R. Gomez, M. J. Serramia, and M. A. Munoz-Fernandez (2006) Novel water-soluble carbosilane dendrimers: synthesis and biocompatibility. Eur. J. Inorg. Chem., 1388–1396. (152) J. F. Bermejo, P. Ortega, L. Chonco, R. Eritja, R. Samaniego, M. Mullner, E. de Jesus, F. J. de la Mata, J. C. Flores, R. Gomez, and A. Munoz-Fernandez (2007) Water-soluble carbosilane dendrimers: synthesis biocompatibility and complexation with oligonucleotides; evaluation for medical applications. Chem. Eur. J., 13, 483–495. (153) L. Chonco, J. F. Bermejo-Martin, P. Ortega, D. Shcharbin, E. Pedziwiatr, B. Klajnert, F. J. de la Mata, R. Eritja, R. Gomez, M. Bryszewska, and M. A. Munoz-Fernandez (2007) Watersoluble carbosilane dendrimers protect phosphorothioate oligonucleotides from binding to serum proteins. Org. Biomolec. Chem., 5, 1886–1893. (154) D. Shcharbin, E. Pedziwiatr, L. Chonco, J. F. Bermejo-Martin, P. Ortega, F. J. de la Mata, R. Eritja, R. Gomez, B. Klajnert, M. Bryszewska, and M. A. Munoz-Fernandez (2007) Analysis of interaction between dendriplexes and bovine serum albumin. Biomacromolecules, 8, 2059–2062. (155) N. Weber, P. Ortega, M. I. Clemente, D. Shcharbin, M. Bryszewska, F. J. de la Mata, R. Gomez, and M. A. Munoz-Fernandez (2008) Characterization of carbosilane dendrimers as effective carriers of siRNA to HIV-infected lymphocytes. J. Controlled Release, 132, 55–64. (156) I. Posadas, B. Lopez-Hernandez, M. I. Clemente, J. L. Jimenez, P. Ortega, J. de la Mata, R. Gomez, M. A. Munoz-Fernandez, and V. Cena (2009) Highly efficient transfection of rat cortical neurons using carbosilane dendrimers unveils a neuroprotective role for HIF-1 alpha in early chemical hypoxia-mediated neurotoxicity. Pharm. Res., 26, 1181–1191. (157) S. M. Grayson and W. T. Godbey (2008) The role of macromolecular architecture in passively targeted polymeric carriers for drug and gene delivery. J. Drug Targeting, 16, 329–356. (158) M. Guillot, S. Eisler, K. Weller, H. P. Merkle, J. L. Gallani, and F. Diederich (2006) Effects of structural modification on gene transfection and self-assembling properties of amphiphilic dendrimers. Org. Biomolec. Chem., 4, 766–769.

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(159) M. Guillot-Nieckowski, D. Joester, M. Stohr, M. Losson, M. Adrian, B. Wagner, M. Kansy, H. Heinzelmann, R. Pugin, F. Diederich, and J. L. Gallani (2007) Self-assembly, DNA complexation, and pH response of amphiphilic dendrimers for gene transfection. Langmuir, 23, 737–746. (160) G. M. Pavan, M. A. Mintzer, E. E. Simanek, O. M. Merkel, T. Kissel, and A. Danani (2010) Computational insights into the interactions between DNA and siRNA with “rigid” and “flexible” triazine dendrimers. Biomacromolecules, 11, 721–730. (161) O. M. Merkel, M. A. Mintzer, D. Librizzi, O. Samsonova, T. Dicke, B. Sproat, H. Garn, P. J. Barth, E. E. Simanek, and T. Kissel (2010) Triazine dendrimers as nonviral vectors for in vitro and in vivo RNAi: the effects of peripheral groups and core structure on biological activity. Molec. Pharm., doi: 10.1021/mp100101s. (162) A. J. Hamilton and D. C. Baulcombe (1999) A species of small antisense RNA in posttranscriptional gene silencing in plants. Science, 286, 950–952. (163) S. M. Elbashir, J. Harborth, W. Lendeckel, A. Yalcin, K. Weber, and T. Tuschl (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature, 411, 494–498. (164) J. H. Zhou, J. Y. Wu, N. Hafdi, J. P. Behr, P. Erbacher, and L. Peng (2006) PAMAM dendrimers for efficient siRNA delivery and potent gene silencing. Chem. Commun., 2362–2364. (165) J. H. Zhou, J. Y. Wu, X. X. Liu, F. Q. Qu, M. Xiao, Y. Zhang, L. Charles, C. C. Zhang, and L. Peng (2006) Cooperative binding and self-assembling behavior of cationic low molecularweight dendrons with RNA molecules. Org. Biomol. Chem., 4, 581–585. (166) M. A. Mintzer, O. M. Merkel, T. Kissel, and E. E. Simanek (2009) Polycationic triazine-based dendrimers: effect of peripheral groups on transfection efficiency. New J. Chem., 33, 1918–1925. (167) O. M. Merkel, M. A. Mintzer, J. Sitterberg, U. Bakowsky, E. E. Simanek, and T. Kissel (2009) Triazine dendrimers as nonviral gene delivery systems: effects of molecular structure on biological activity. Bioconjugate Chem., 20, 1799–1806. (168) E. Fernandez-Megia, J. Correa, and R. Riguera (2006) “Clickable” PEG–dendritic block copolymers. Biomacromolecules, 7, 3104–3111. (169) R. Reul, J. Nguyen, and T. Kissel (2009) Amine-modified hyperbranched polyesters as nontoxic, biodegradable gene delivery systems. Biomaterials, 30, 5815–5824. (170) B. J. Boyd, L. M. Kaminskas, P. Karellas, G. Krippner, R. Lessene, and C. J. H. Porter (2006) Cationic poly-L-lysine dendrimers: pharmacokinetics, biodistribution, and evidence for metabolism and bioresorption after intravenous administration to rats. Molec. Pharm., 3, 614–627. (171) E. J. Chisholm, G. Vassaux, P. Martin-Duque, R. Chevre, O. Lambert, B. Pitard, A. Merron, M. Weeks, J. Burnet, I. Peerlinck, M. S. Dai, G. Alusi, S. J. Mather, K. Bolton, I. F. Uchegbu, A. G. Schatzlein, and P. Baril (2009) Cancer-specific transgene expression mediated by systemic injection of nanoparticles. Cancer Res., 69, 2655–2662. (172) J. H. S. Kuo, M. S. Jan, and Y. L. Lin (2007) Interactions between U-937 human macrophages and poly(propyleneimine) dendrimers. J. Controlled Release, 120, 51–59. (173) R. Gras, L. Almonacid, P. Ortega, M. J. Serramia, R. Gomez, F. Javier de la Mata, L. A. Lopez-Fernandez, and M. Angeles Munoz-Fernandez (2009) Changes in gene expression pattern of human primary macrophages induced by carbosilane dendrimer 2G-NN16. Pharm. Res., 26, 577–586.

18 Dendrimer Conjugates for Drug Delivery Cédric-Olivier Turrin* and Anne-Marie Caminade

18.1

Introduction

Only a tiny portion of drugs reaches their targets (cells, organs). Actually, most of the injected materials stay in the body of the patient, may accumulate in nontargeted areas, and be responsible for adverse side-effects. This fact is often related to poor solubility and selectivity of active ingredients (AIs) in the body and is responsible for the withdrawal of a high percentage of drug candidates prior to phase I clinical trials. Drug delivery, or drug formulation technologies, is believed to overcome these challenges by allowing control over drug distribution, metabolism, and excretion, and by improving drug safety and efficacy.1 A wide collection of polymer-based nanosystems have been devoted to such purposes, along with colloidal soft matter,2,3 which encompasses supramolecular objects resulting from the self-assembly of amphiphilic molecules like microemulsions, organogels, vesicles, liposomes, etc. In this regard, dendrimers and dendrimeric polymers have been considered early as valuable candidates for drug delivery thanks to their size, porous structure, and ease of functionalization. As a matter of fact, a rapid survey of the literature shows that among the twelve thousand or so publications related to dendrimeric structures, almost one out of five deals with drug delivery. The interaction of dendrimers and dendrimeric polymers can be roughly subdivided into three main types: simple encapsulation, electrostatic interactions, and covalent conjugation (Figure 18.1). This chapter is solely dedicated to covalently bonded drugs, or dendrimer-based prodrugs, while noncovalent * Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 18.1

Drug delivery with dendrimeric structures

cargo systems are explored in Chapter 19. The rather specific application of drug delivery applied to genes was featured in Chapter 17. Among the impressive number of recent reviews dedicated to this field,3–23 selected emerging areas of interest are detailed hereafter, including oncology, which is the most intensively explored field of research, photodynamic therapy (PDT), and boron neutron capture therapy (BNCT). In the first section of this chapter, basic improvements ascribed to dendrimers, like solubility enhancement and bioavailability improvement, will be presented. Two other sections are presented according to the way chemotherapeutic agents can be delivered to cells, tissues, or organs: by passive targeting, thanks to a process known as the enhanced permeability and retention (EPR) effect, or by active targeting with the help of cell-targeting moieties. The issues of targeting, solubilization, and monitoring are also addressed thanks to multifunctional approaches, and, depending on the target application, concerns like drug release and scaffold advent are evoked.

18.2

Improving Bioavailability with Dendrimers

As recently pointed out by S. Svensson,23 the chemical bonding of AIs to dendrimers is a worthwhile challenging strategy in comparison with physical encapsulation, because it allows a higher loading and relative control over pharmacokinetics and pharmacodynamics, which are partly related to the size and nature of the scaffold and the nature of the chemical linkage. The dendrimer prodrug approach is actually a valuable approach to increase the water solubility of lipophilic drugs.24 For instance, naproxen, a nonsteroidal anti-inflammatory drug (NSAID) dedicated to oral administration has been conjugated to a polyester dendrimeric scaffold25 or to a generation 0 PAMAM26,27 by amide or ester bonds with L-lactic acid or diethylene glycol as a linker. The conjugates were found to be more water soluble than the parent AI and chemically stable for two days in buffer solutions (pH = 1.2 to 8.5), and ester conjugates could be enzymatically cleaved in human serum, although slowly in the case of the L-lactic acid linker. In addition, the grafting of a lauroyl chain increased the enzymatic cleavage rate and permeability across Caco-2 (human epithelial colorectal adenocarcinoma) cell monolayers. These features were found promising in view of enhancing the stability of NSAIDs in the gastrointestinal tract without precluding their controlled release after transepithelial adsorption. In comparison, Ibuprofen, another NSAID, has been conjugated with a small drug payload to a generation 4 PAMAM

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Figure 18.2

439

Conjugation of Ibuprofen on a generation 4 PAMAM dendrimer

dendrimer with amide and ester linkages, including a tetrapeptide sequence, and compared to a PEG (5 kDa) conjugate with ester linkage, resulting in a comparable drug payload (Figure 18.2). Amide conjugates were hydrolytically stable while the ester conjugates showed a pHdependent release profile. Enzymatic release in plasma was accelerated by the presence of the tetrapeptide linker, which allowed a reduction of the steric hindrance of the enzymesensitive ester sites.28 In a different approach, polyester dendrimers based on salicylic acid, glycerol, and succinic acid have also been described up to generation 3 containing sixty salicylate moieties, but no data on hydrolysis has been disclosed.29 The cellular release of the AI can be controlled with other parameters apart from pH modification. For instance, N-acetyl-cysteine (NAC) is an antioxidant and antiinflammatory drug which suffers from high plasma binding upon intravenous administration and requires the use of high doses to reach the target microglia cells for the treatment of neuroinflammation. These cells have high glutathione levels and the release of the AI can be controlled by means of a glutathione-sensitive disulfide linkage.30,31 This strategy has been applied to a generation 4 PAMAM drug conjugate and allowed the release of 60 to 70% of the payload and a significant increase of the antioxidant properties compared to free NAC. Dendrimers have also been found to be efficient transmembrane enhancers, in particular across epithelial cells through paracellular and transcellular pathways,32,33 for several purposes. In this regard, permeability-glycoprotein (P-gp) is involved in multidrug resistance and bioavailability decrease. Generation 3 PAMAM dendrimers have been conjugated to two to six molecules of propranolol,34 a beta-blocker used as a model P-gp substrate, in order to improve its water solubility. The resulting conjugates were found to bypass the P-gp efflux transporters through an epithelial endocytosis mechanism, which was enhanced in the case of lauroyl-modified PAMAM scaffolds. A specific study of the mechanism of internalization of these conjugates in HT-29 cells confirmed the increase of prodrug uptake in the case of lauroyl-modified dendrimers and a reduced lysosomal accumulation.35 Analogously, terfenadine, another P-gp substrate, was grafted on to a generation 1 PAMAM through a succinidyl-diethylene glycol linkage that allows good chemical stability in buffers and controlled release in plasma. Again, the transport of dendrimer

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Dendrimers

prodrugs across Caco-2 cell monolayers showed an increased permeability, in particular in the case of lauroyl-modified PAMAM.36 The blood–brain barrier (BBB), another obstacle to AIs, is composed of tightly arranged cells that restrict passage of substances from the bloodstream to cerebrospinal fluid in the central nervous system. 3,4-Hydroxy-L-phenylalanine (L-DOPA), a prodrug used in the treatment of Parkinson’s disease, is able to cross the BBB and has been used in conjunction with ethylene glycol and succidinic anhydride to synthesize L-DOPA-based polyester dendrimers having up to 30 prodrug residues on generation 3.37 The dendrimeric L-DOPA was found to be more water soluble and more UV stable than the parent prodrug, but no biological data has been published to validate this concept, although the polyester structure is expected to follow a sequential hydrolysis.

18.3 18.3.1

Passive Targeting in Tumors with Dendrimer–Drug Conjugates Dendrimer–Drug Bioconjugates and the EPR Effect

The tumoritropism of macromolecules is associated with the unique characteristics of tumor vasculature and tissues, including (i) hypervasculature, (ii) enhanced vasculature permeability, and (iii) little recovery of macromolecules via blood and the lymphatic system.38 Passive targeting of drugs with macromolecular scaffolds is based on this enhanced permeability and retention (EPR) effect (Figure 18.3), which is obviously related to the size and molecular weight of the carrier.39 The dendrimer–drug conjugate approach

solid tumor

tumor vasculature

altered endothelium

blood vessel

normal endothelium

Figure 18.3

EPR effect in a solid tumor

Dendrimer Conjugates for Drug Delivery

441

allows perfect control of these parameters. Other features like surface charge or lipophilicity that may affect the biodistribution, circulation time, and ability to cross endothelial barriers of macromolecular prodrugs can also be addressed by a suitable surface modification. The influence of the hydrodynamic volume of dendrimers on their ability to cross the microvascular endothelium has been demonstrated by several groups on native amineterminated PAMAM dendrimers, which exhibit an increasing ability to cross epithelial and endothelial barriers on going from generation 0 to 4.40–42 Gadolinium-functionalized PAMAMs used as MRI contrast agents (see Chapter 16) have also been successfully used to image these properties. The conjugation of highly cytotoxic anticancer drugs to dendrimers generally results in an increased water-solubility, a higher accumulation in solid tumors, and consequently a decreased systemic toxicity thanks to this EPR effect compared to the pure AI. This important point has early been reported in the case of cis-platine43 terminated dendrimers, which accumulate fiftyfold more in solid tumors, but are 3 to 15 times less toxic than pure cis-platine, probably because of an inappropriate conjugation strategy and bad release profile. More recently, 40 diaquo(1,2-diaminocyclohexane) platinum(II) units have been coordinated on a generation 4.5 PAMAM, and UV–vis titration of buffered solutions suggest a sustained delivery of active platinate species over 24 hours.44 5-Fluorouracil (5 FU) has also been grafted on PAMAM scaffolds having a cyclic core,45 but despite a good release profile and water-solubility, no biological study has been performed. The issue of the release of the AI is centered on the chemical nature of the linkage. Recent efforts in this field of research are centered on the conjugation strategy in order to provide a stable linkage at the physiological pH of 7.4, yet able to undergo hydrolysis under more acidic conditions. These acidic conditions can be found in late lysosomes (pH∼5.5) in which dendrimers are found following endocytosis and inside tumors (pH∼6.5).46 Actually, hypoxic microenvironments of solid cancers in regions distant from an efficient blood system are affected by increased anaerobic glycolysis known as the Pasteur effect, which is responsible for more acidic pH conditions.47 Additionally, this pH modification can also be increased by external stimuli like hyperthermia48 or mitochondrial inhibition. Other release pathways include enzymatic triggered degradations, and in this regard ester linkages offer a good compromise between chemical stability and enzymatic sensitivity, provided that the ester bond remains accessible to the active site of the esterase.28 The grafting strategy can also affect other physicochemical parameters of the conjugate. For instance, methotrexate (MTX)–PAMAM conjugates have been prepared from amineterminated and carboxylic acid-terminated dendrimers (Figure 18.4), resulting in different grafting positions on the MTX moiety, which possesses reactive amine and carboxylic

Figure 18.4

Ester and amide linked MTX–PAMAM conjugates

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Dendrimers

groups, and opposite surface charge due to partial surface loading (22.4 and 2.8%, respectively, estimated by the proton integration method). In the case of amide linkages on amine-terminated PAMAM, the MTX acid function involved in the ester bond was not clearly identified, but was supposed to be the γ position in view of previous reports.49 The negatively charged conjugate, although less drug-loaded, exhibited a higher activity against MTX-sensitive and -resistant cell lines than the positively charged conjugate and than the equivalent amount of free MTX, traducing the fact that the net surface charge of the carriers and the grafting options have dramatic influences on the cellular uptake and the intracellular release. The issue of the drug linkage has also been studied in the case of hyperbranched polymers. Chlorambucil, a mustard model drug, was conjugated to poly(amine ester) hyperbranched polymers by an ester linkage.50 The toxicity of the hydroxyl-terminated polyester was relatively low by MTT assay (100% cell viability at 1 mg mL−1), while the IC50 of the chlorambucil conjugated polyester was found to be 120 μg mL−1, which is almost twofold less than the free drug. Despite these promising results and the maintained activity of the drug, probably thanks to an efficient drug release in the endosomes/lysosomes, no accurate comparison with the free drug could be drawn due to lack of information on the equivalent number of chlorambucil loaded on the polymer. In another example, doxorubicin (DOX) has been grafted on a PAMAM-based star-like copolymer via a small peptidic sequence.51 DOX was efficiently released in vitro in the presence of cathepsin B, a lysosomal cysteine protease, and the release profile was strongly influenced by the presence of a dendrimeric core, due to differences in the rates of cell internalization related to the overall topology of the conjugates. 18.3.2

PEGylated Dendrimeric Scaffolds

PEGylation of dendrimeric scaffolds can be achieved by surface engineering or core functionalization.8,52,53 In many cases the main goal of PEGylation is to overcome shortcomings related to surface interaction: opsonization and uptake by the reticuloendothelial system (RES) immunogenicity, hemolytic issues, or poor water-solubility. This strategy has been successfully applied to produce PEGylated anticancer drugs (not dendrimeric) that are in clinical use or under clinical trials.54 PEGylated dendrimeric platforms offer a strong advantage in terms of drug loading and are suitable candidates for passive targeting of tumors by EPR effect thanks to their stealth and tunable size, although one should note that the grafting of short PEG tails can still be compatible with active targeting.55 PEGylation, like the final size of the conjugate or its overall charge,56 also affect transepithelial transport of dendrimer conjugates, a key concern related to oral bioavailability. 18.3.2.1

“Bow-tie” PEGylated Dendrimers and Related Dendrons

The group of J. M. J. Fréchet early reported on the core modification of dendrimeric polyethers with PEG entities;57 the technology was rapidly extended to the uncomplete grafting of PEG chains on the surface of polyether dendrimers with free remaining sites for drug attachments.58 These pioneering results have paved the way for the elaboration of PEGylated dendrimeric drug carriers, like bow-tie dendrimers consisting of two polyester dendrons, with one dendron equipped with PEG groups and one dendron available for grafting

Dendrimer Conjugates for Drug Delivery

Figure 18.5

Figure 18.6

443

DOX-containing PEGylated bow-tie dendrimers

Octafunctionalized aminoadipate dendrimer built from a PEG core

AIs.59–61 These systems are nontoxic, degraded to lower molecular weight species at physiological and lysosomal pH, and exhibit long circulation times and high tumoral uptake by the EPR effect. For instance, doxorubicin (DOX) has been grafted through an acidsensitive hydrazone linkage on to a polyester bisdendron scaffold having a PEGylated side and was found to efficiently cure mice bearing colon carcinomas after a single injection (Figure 18.5), contrary to the free drug at its maximum tolerated dose.62 The PEG chains were responsible for increased water-solubility, long half-lives in serum, increased tumoral uptake, and lack of aggregation. The hydrazone linkage was stable enough (less than 10% release) at physiological pH and afforded 100% release within two days at pH = 5. At a concentration of 20 mg·kg−1 (DOX), this system was found to be slightly more efficient and less toxic than Doxil, a commercially available PEGylatedliposomal formulation of DOX. In another approach, the PEG chain can be used as a mono- or difunctional dendrimer core (Figure 18.6). This strategy has been used to graft eight cytosine arabinose (ara-C) moities, a potent antileukemic drug, via an extended diethylene glycol amine spacer on

444

Dendrimers

the acid terminations of a telechelic PEG equipped with divergently grown aspartate-based dendrons. The results show an increased efficacy in comparison with the free drug and the simple difunctional ara-C PEG.63,64 Aminoadipic was also used instead of aspartic acid as a dendrimeric unit in order to reduce steric hindrance and overcome ara-C grafting difficulties in the absence of the extended spacer.65 As previously, the PEG–dendrimer conjugates were more efficient in vitro and in vivo than the free drug. In a similar approach, epirubicin (EPI) anticancer drug has been grafted on dendronized-PEG based on amino adipic acid or beta-glutamic acid, as a branching molecule. A hydrophilic peptide linker between the drug and the dendrimer surface was added to reach acceptable hydrophilicity. The conjugates showed better stability than free EPI in different pH buffers and in plasma as well as a prolonged residence time in blood.66 The same authors have recently reported on the use of hetero-difunctional PEG for grafting of a single EPI on one side and the growth of an aminoadipic acid-based dendron on the other side for grafting up to eight nitric oxide (NO) releasing molecules.67

18.3.2.2

Surface-PEGylated Dendrimers

The statistical grafting of different entities on the surface of dendrimers68 is very attractive to produce multifunctionalized platforms, mainly because this strategy is easy to carry out. This option has been widely used for several biomedical application purposes, despite the fact that it raises an accute issue related to the consistancy of results and statistical responses, in particular for the grafting of PEG chains. For example, partly PEGylated polyamidoamine dendrimers (generation 4) have been designed for tumor-selective targeting of doxorubicin by the EPR effect to investigate the effects of PEGylation degree and drug conjugation style.69 This study confirmed the fact that acid-sensitive (cis-aconityl) linkers are more efficient than acid-insensitive (succinic acid) linkers, and that higher degrees of PEGylation are responsible for prolonged circulation time, more tumor accumulation, and reduced liver and splenic accumulation, as demonstrated by pharmacokinetic and biodistribution studies. In a similar approach, generation 4 PAMAM dendrimers have been conjugated to adriamicyn through an amide (acid-insensitive) or hydrazone (acid-sensitive) linkage.70 The amide-linked conjugate showed a small release at pH 7.4 and 5.5, contrarily to the hydrazone linked conjugate, which showed a negligible release at pH 7.4 and efficient release at pH 5.5 (late lysosomal pH), and also a better efficacy in vitro. As mentioned earlier, the stochastic approach to multifunctional dendrimers may alter result consistency. This simple and cost-effective approach is nevertheless commonly used to circumvent multistep multipluri-functionalization earlier developed by A. M. Caminade and J. P. Majoral and coworkers,71 which permits the selective grafting of up to four different surface groups on PPH dendrimers. Similarly, the group of Fréchet has also developed an alternative approach to the stochastic functionalization of dendrimers. Heterobifunctional biodegradable polyester dendrimers based on 2,2-bis(hydroxymethyl) propanoic acid (bis-HMPA) and having carbonate surface functions can be sequentially functionalized by a ring-opening reaction with amines and oxime formation on the remaining hydroxyl groups (Figure 18.7).72 The synthetic strategy has been refined with the help of amino acid surface chemistry in order to allow the grafting of eight PEG chains and

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Figure 18.7

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Heterobifunctional biodegradable dendrimers developed by Fréchet

four DOX moieties through carbamate and hydrazone linkages, respectively (Figure 18.7).73 The advantages of these systems over clinically used PEGylated liposomal formulation Doxil or bow-tie PEGylated dendrimers reported by the group of Fréchet are longer circulation half-lives and absence of accumulation in normal tissue, as demonstrated in vivo with a radioiodinated tyrosine functionalized analog. The strategy can be applied to amine-terminated PEGylated dendrimers, as illustrated by the modification of aspartic acid-terminated PLL dendrimers74 or PAMAM dendrimers75 with PEG chains and anticancer drugs or bioimaging molecules. The resulting dendrimers exhibited an improved efficacy in vivo74 or in vitro75 compared to a linear PEG conjugate or the free drugs. Several candidates originating from this strategy have been described,76 involving the heterobifunctionalization of amine-terminated dendrimers capped with various amino acids, which provide a BOC-protected amine and a benzyl-protected carboxylic acid, which can be orthogonally deprotected and selectively functionalized. C. J. Porter and coworkers described a less-versatile strategy to modify a series of PLL dendrimers, generations 3 to 5, with small dendrons based on succinimyldipropyldiamine that contain 50% of PEG (570–2300 Da) and 50% of amide-linked MTX.77 The release properties were not detailed, but tritium-labeled analogs allowed the pharmacokinetics and tumor uptake of these systems to be studied. As already observed with analogous dendrimeric systems, larger dendrimers or dendrimers with larger PEG chains presented an increased metabolic stability and decreased renal elimination, although small dendrimers with small PEG (570 Da) were extensively retained in liver because of specific folate–MTX interactions. These observations are in agreement with previous reports on partly PEGylated PLL dendrimers78,79 and PEGylated amine-free dendrimer surfaces,80 which show increased stability and tumor uptake.

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The group of E. E. Simanek has also reported on an efficient alternative to synthesize heterobifunctionalized melamine-based dendrimers, and similar conclusions have been drawn regarding the effect of size on biodistribution81 and the need for a chemical linkage to anticancer drugs like paclitaxel82 or camptothecin83 that can bear physiological plasmatic conditions and can be cleaved enzymatically or hydrolytically during the endosome/ lysosome uptake for optimal activity.

18.4 Active Targeting with Site-Specific Dendrimer–Drug Conjugates Despite the advantages related to the use of PEG residues to produce stealthy systems able to take most of the EPR effect for passive targeting, the use of specific targeting agents is extensively developed to produce more specific dendrimer–drug conjugates,84 as demonstrated by the recent efforts by the group of J. R. Baker.85 Most strategies involve the use of small endogenous molecules, peptides, or monoclonal antibodies that target receptors, which are overexpressed at the tumor site (cell surface, angiogenic vessels). These techniques have been successfully applied to address dendrimer–drug conjugates mainly to cancer cells, although the strategy can be applied for other cells or tissues. 18.4.1 Addressing with Folic Acid (FA) Folic acid (FA) or vitamine B9 is essential to cell division processes and FA receptors (FARs) are overexpressed in many epithelial tumor cells, making this molecule a suitable targeting agent for selective delivery of anticancer AIs.86 FA acid targeting is often associated with high liver uptake due to the overexpression of FARs in hepatic cells.87,88 The group of E. C. Wiener was the first to graft FA on a Gd-containing PAMAM dendrimeric scaffold to target cancer cells for MRI purposes.89 Following the work of Fréchet and coworkers who described the statistical grafting of FA on a generation 2 polyarylether dendrimer by means of a hardly cleavable bishydrazide linkage,90 the group of Baker has developed a series of generation 5 multifunctional PAMAM dendrimers equipped with FA targeting moieties, fluorescent tags, and anticancer drug conjugates, the remaining amine surface groups of scaffold being acetylated91 (Figure 18.8). In a first report, the proof of concept was confirmed by an increased in vitro uptake of FA-functionalized MTX– dendrimer conjugates and increased efficiency on KB cells having an active multidrug resistance channel, and these preliminary results highlighted the need for biologically cleavable linkers between the drug and the dendrimer.91 The in vivo efficacy of this conjugate was tenfold higher compared with free methotrexate (MTX)92–94 and the four functions of the dendrimer (fluorescence, targeting, radiolabeling, and cytotoxicity) were found to operate independently.95 The proof of the concept of the stochastic approach by covalent grafting was also assessed by their superior efficacy over competitive dendrimerencapsulated drug delivery devices, like the ones based on analogous FA-modified PAMAM cargo-loaded with MTX.96 It is noteworthy that the folate targeting strategy with dendrimers presenting multiple copies of FA was clearly demonstrated to involve multivalent interactions that resulted in dramatically enhanced Kd (up to 170 000 times) through

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Figure 18.8

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Optimization of multifunctional dendrimeric platforms93

the multivalent effect.97 The combined results accumulated by the group of Baker have paved the way for developing analogous nanodevices incorporating other anticancer drugs like Taxol,98 5-FU,99 proapoptotic peptides,100 or other targeting moieties (see the following sections) or other dendrimeric scaffolds.101 Complementary information was provided by the grafting of a caspase-specific FRETbased apoptosis-detecting agent on the dendrimeric platform to measure in real-time the apoptotic effect of the delivered drug.102 Recent reports on this approach were devoted to implement preclinical studies. The batch-to-batch consistency and specificity were assessed in vitro on four different batches103 and the cytotoxic potential and specificity of a large

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scale batch were evaluated in vitro and in vivo.94 Preliminary information on the pharmacodynamics of these nanodevices was independently provided by L. van Haandel and J. F. Stobaugh,104 who developed an analytical method to measure the plasma concentration of MTX metabolites in rats, and following subcutaneous or IV administration, it was found that less than 0.1% of the MTX mass was released from the nanodevice in the plasma. The strategy was recently improved by a simpler synthetic approach involving a one pot synthesis of nanodevices showing the same profiles105 as the one obtained in a stepwise fashion. It is noteworthy that this approach devoted to new anticancer strategies should also be attractive for antiarthritis purposes, as MTX is one of the reference treatments for rheumatoid arthritis.86 In this regard, FA-functionalized PAMAM conjugated to indomethacin, another anti-inflammatory drug used in the treatment of arthritis, showed encouraging in vitro active targeting properties.106

18.4.2 Addressing with Tumor-Homing Peptides Some receptors for endogenous regulatory peptides are overexpressed in human cancer cells and can be targeted for peptide-mediated tumor-selective therapy, but this option requires an efficient protection of the peptides which generally have short half-lives in vivo. In this regard, peptides containing the Arg–Gly–Asp(RGD) motif that binds to the α(v)β(3) integrin have shown potential as therapeutics,107 in particular to target angiogenic tumor vasculature,108 and they have also been used to address dendrimers109 or dendrimercoated nanoparticles to angiogenic tissues110 or endothelial tissues that are concerned with dense microvascularization, like predentin in tooth organ cultures.111 Multivalency effects are expected with multiple presentation of RGD copies on the surface of branched structures,112 and several evidences of efficient tumor targeting have been obtained with dendrimeric nanodevices designed to image angiogenesis.113–115 A generation 5 PAMAM conjugated with approximately 4 cRGD peptide residues through the amino group of the lysine side chain was found to be nontoxic at physiologic concentration ranges and to bind specifically to the α(v)β(3) integrins stronger than the free cyclic cRGD peptide.116 Generation 3 PLL dendrimers built from a silsesquioxane cubic core have been decorated with DOX through a cleavable disulfide spacer and PEG chains having terminal cRGD for the codelivery of anticancer drug and siRNA. The nanodevice showed higher cytotoxicity than free DOX in vitro in glioblastoma U87 cells and the siRNA transfection resulted in higher gene silencing efficiency in these cells than those of control conjugates lacking siRNA.117 Dendrimers offer a clear advantage over alternative nanostructures to control the spatial arrangement of RGD clusters, which can be crucial to control both integrin binding and cell response.118 Additionally, it has been shown that RGD-adorned generation 3.5 PAMAM polyanionic dendrimers do not present toxicity on zebrafish at 20 μM, in contrast to the polycationic generation 4, proving again the importance of the overall charge of the dendrimer when dealing with toxicological issues.119 The neuropeptide neurotensin is another endogenous targeting peptide of which the receptor is overexpressed in colon, pancreatic, prostate, and small-cell carcinomas. A small lysine-based dendron presenting four functional fragments of this peptide and MTX or chlorin e6 (an anticancer drug used in photodynamic therapy) showed efficient targeting

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properties in vitro and ex vivo, and a sixtyfold tumor growth reduction compared to free MTX in vivo in mice bearing human cancer xenografts.120 18.4.3 Addressing with Monoclonal Antibodies Growth factors are endogenous proteins or steroids capable of stimulating cellular growth or proliferation and cellular differentiation. Fibroblast growth factors (FGF) and vascular endothelial growth factors (VEGF) stimulate blood vessel differentiation, and their receptors are overexpressed in angiogenic blood vessels. These receptors can be targeted with monoclonal antibodies (MoAb), and the latter can be grafted on dendrimers by suitable chemical bonding that does not alter the MoAb. The dendrimer surface has actually been demonstrated to be a suitable platform for the grafting of monoclonal antibodies (MoAbs), tracing fluorescent probes, and drugs. For instance, Herceptin,121 which targets an epidermal growth factor receptor (EGFR), or recombinant FGF-1122 have been successfully assayed to internalize PAMAM dendrimers into cells expressing these receptors after a specific binding step in vivo and in vitro. Other MoAbs, like J591, which targets a glycolipid overexpressed by prostate-cancer cells, and 60 bca, an anti-CD4 MoAb,123,124 have also been grafted efficiently on to dendrimers without loss of their targeting properties. Clinically approved anti-EGFR cetuximab (or C225) was covalently linked to a generation 5 PAMAM dendrimer containing approximately 12 MTX units. The 125I-labeled bioconjugates showed a favorable specific molecular targeting of tumor expressing EGFR in rats bearing glioma xenografts. However, median survival times of animals having received the dendrimer conjugates or free MTX were not statistically different, showing that accurate molecular targeting is not the only requirement that must be fulfilled to achieve therapeutic usefulness.125 The group of Baker has shown that a generation 5 PAMAM dendrimer equipped with MTX, an anti-EGFR MoAb, and a fluorescent probe selectively targeted EGFR overexpressing a cancer cell line and maintained their antifolate activity,126 while their cytoxicity was reduced fairly well compared to the free drug because of an unusually long residence time of the conjugates in the lysosomes. The same group also reported on the superagonist activity of EGFR targeting a dendrimer drug conjugate127 and the resulting cell growth stimulation that could lead to tumor development. Although this activity can be completely overcome by the presence of chemotherapeutic drugs on the dendrimer conjugate, this point should be taken into consideration for other applications like imaging, as recommended by the authors.

18.5

Dendrimers for Photodynamic Therapy (PDT)

PDT128 involves the systemic administration of photosensibilizing drugs and subsequent laser irradiation of tumoral tissues, which allow the local formation of highly toxic reactive oxygen species (ROS). One of the current issues of this technique are the poor water solubility and self-aggregation behavior of π-conjugated photosensitizers and the possibility to concentrate the latter in tumors with site-specific targeting agents. The first report in the field aimed at the delivery of 5-aminolevulinic acid (ALA), a poorly water-soluble natural precursor of endogenous protoporphyrin IX (PpIX) by means

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Dendrimers

of dendrimers covered with ALA residues. These systems containing up to 18 ALA residues were found to induce PpIX formation in vitro, with a good cellular phototoxicity following light exposure and minimal dark toxicity.129 The design of dendrons with modified ALA linkers showed that the lipophilicity and steric hindrance within the dendrimeric structure could restrict access to intracellular esterase responsible for efficient ALA release and subsequent PpIX formation,130 while in vivo experiments revealed that all systems were less efficient than free ALA by topical and systemic administration.131 A second generation candidate (Figure 18.9) was found to be more efficient than free ALA in vitro,132 but in vivo efficacy was impaired by nonspecific accumulation in healthy tissues, as indicated by sustained PpIX levels.133 Dendrimers having a porphyrin core have also been used as photosensitizers for PDT purposes with the aim to reduce the aggregation of the porphyrin core responsible for a decreased PDT activity. The strategy has been developed with porphyrin cores surrounded by Fréchet-type wedges terminated with amine or carboxylic acid end groups, which are able to self-assemble in phosphate buffered saline (PBS) solution with surfactant molecules of opposite charge to form supramolecular assemblies following the concept of polyion complex (PIC) micelles.134 In the case of ionic porphyrin-cored dendrimers, a PEG–PLL linear block copolymer is used to produce stable supramolecular objects con-

Figure 18.9

ALA capped dendrimers for PDT

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taining the porphyrin-cored dendrimers that are translocated from the endosomes/lysosomes to the cytoplasm during photoirradiation.135,136 The PIC micelle strategy137 increases the protection of the photosensitizers and is responsible for higher tumor uptake by the EPR effect. These systems have been found to be more efficient and induced less skin phototoxicity than clinically used Photofrin®,135 and also proved to treat corneal neovascularization efficiently.138 Further developments in this field should include targeted systems to increase the site-specificity and reduce skin phototoxicity.

18.6

Dendrimers for Boron Neutron Capture Therapy (BNCT)

BNCT relies on the irradiation of 10B with low energy thermal neutrons and subsequent ejection of lethal particles, namely highly energetic helium (4He) nuclei (alpha particles) and recoiling lithium (7Li) ions. Due to the short pathlength of these particles in tissues (less than 10 μm), their toxicity is limited to cells that have internalized 10B. BNCT efficiency is related to specific tumor accumulation to afford high boron content in the treated cells, a challenge that can be addressed with dendrimeric scaffolds, as commented by R. F. Barth and coworkers.139 This point can be illustrated by a multifunctional, and yet perfectly defined (Figure 18.10), dendrimeric PLL scaffold equipped with decaborane,

Figure 18.10

Early model for a multifunctional dendrimeric platform applied to BNCT

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Dendrimers

PEG solubilizing groups, an accessible thiol for antibody grafting, and an imaging fluorescent probe.140 This system, described by B. Qualmann and Kessels,140 is one of the earliest examples of accurate and rational molecular engineering with dendrimers, although its efficacy for BNCT purposes was not demonstrated. A pioneering assay by the group of Barth showed that PAMAM dendrimers grafted with an isocyanato polyhedral borane and monoclonal antibodies (MoAb) targeting murine melanoma141 accumulated in the spleen and the liver as a possible consequence of remaining free amine surface groups. Despite the grafting of EGF,142 whose receptor is overexpressed in high-grade gliomas, acceptable tumor accumulation could be obtained only by intracerebral administration.143 The use of the anti-EGF receptor MoAbs was alternatively used for targeting purposes,144 with encouraging in vivo results for biodistribution.145,146 Other receptors overexpressed at tumoral sites like VEGFR and FAR are currently being assayed on boronated dendrimeric platforms for BNCT purposes. For instance, a generation 5 PAMAM dendrimer equipped with 102 to 110 decaboranes, a fluorescent tag, and VEGF was found to accumulate in vitro in VEGFR expressing cells via a VEGFR-2 mechanism.147 A series of generation 3 PAMAM dendrimers were statistically surfacemodified with 12–15 decaboranes and PEG chains bearing a telechelic FA. Despite favorable FAR-mediated uptake of optimized structures in vitro, in vivo studies revealed a specific tumor uptake with high hepatic and renal uptake.148 In the same regard, in vivo studies by the group of Barth on heavily boronated PAMAM dendrimers equipped with different MoAbs targeting glioma cells resulted in a significant increase in the long-term survival time, and highlighted the need for a specific targeting strategy.146,149

18.7

Conclusion and Perspectives

The development of a dendrimer-based drug delivery system in which the drug is covalently linked to the dendrimeric scaffold has scaled several milestones, in particular regarding anticancer therapies. Passive targeting with stealth dendrimeric devices has been made possible and tunable with the help of PEG residues, and this progress should find further developments in conjugation with receptor targeting strategies. Actually, a study on G protein coupled receptor targeting dendrimers having PEG residues proved that sitespecific targeting was compatible with the presence of short PEG chains,55 so targeting stealthy devices could soon appear as an attractive approach. Among the targeting strategies that have been proposed to utilize the dendrimer platform, two approaches are being developed, one involving the accurate synthesis of single molecular objects with a rational and well-defined topological repartition of functional groups, another involving the stochastic surface functional derivatization with multiplurifunctional purposes. Both approaches, despite their almost opposite pros and cons, which have been discussed in this chapter, have paved the way for future developments and preclinical studies for drug candidates derived from both methods. These breakthroughs related to the unique structure of dendrimers have encouraged the gathering of information related to the biodistribution, toxicity, and pharmacodynamics of dendrimer–drug conjugates, which were somehow missing from the literature data, and take on a pivotal importance when dealing with pharmaceutical development. These studies should actually provide further data on the

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metabolism of dendrimers and, in this respect, some groups have already anticipated the issue of dendrimer degradation and have proposed self-immolative150 or cleavable dendrimers that can be remotely disassembled;151 the latter are attractive but still in their infancy. Alternatively, some groups have been developing biodegradable structures that offer less fancy but more synthetic possibilities. In this regard, the polyester route152,153 seems to be the most promising option in terms of synthetic versatility, allowing a variety of hyperbranched structures ranging from stepwise-grown dendrimers72 to hyperbranched polymers. Finally, on the fringe of this topic, another flourishing area is the formulation of dendrimer–drug conjugates with surfactant molecules or polymers to afford polyion complex (PIC) micelles or liposome locked-in dendrimers,154,155 which permits the stability of the drug and the size of the conjugate to increase for a better passive tumor targeting by the EPR effect.

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(133) A. Casas, S. Battah, G. Di Venosa, P. Dobbin, L. Rodriguez, H. Fukuda, A. Batlle, and A. J. MacRobert (2009) Sustained and efficient porphyrin generation in vivo using dendrimer conjugates of 5-ALA for photodynamic therapy. J. Controlled Release, 135, 136–143. (134) G. D. Zhang, N. Nishiyama, A. Harada, D. L. Jiang, T. Aida, and K. Kataoka (2003) PHsensitive assembly of light-harvesting dendrimer zinc porphyrin bearing peripheral groups of primary amine with poly(ethylene glycol)-b-poly(aspartic acid) in aqueous solution. Macromolecules, 36, 1304–1309. (135) N. Nishiyama, Y. Morimoto, W. D. Jang, and K. Kataoka (2009) Design and development of dendrimer photosensitizer-incorporated polymeric micelles for enhanced photodynamic therapy. Adv. Drug Delivery Rev., 61, 327–338. (136) N. Nishiyama, Y. Nakagishi, Y. Morimoto, P. S. Lai, K. Miyazaki, K. Urano, S. Horie, M. Kumagai, S. Fukushima, Y. Cheng, W. D. Jang, M. Kikuchi, and K. Kataoka (2009) Enhanced photodynamic cancer treatment by supramolecular nanocarriers charged with dendrimer phthalocyanine. J. Controlled Release, 133, 245–251. (137) A. Sousa-Herves, E. Fernandez-Megia, and R. Riguera (2008) Synthesis and supramolecular assembly of clicked anionic dendritic polymers into polyion complex micelles. Chem. Commun., 3136–3138. (138) K. Sugisaki, T. Usui, N. Nishiyama, W. D. Jang, Y. Yanagi, S. Yamagami, S. Amano, and K. Kataoka (2008) Photodynamic therapy for corneal neovascularization using polymeric micelles encapsulating dendrimer porphyrins. Investigative Ophthalmology and Visual Science, 49, 894–899. (139) G. Wu, R. F. Barth, W. Yang, R. J. Lee, W. Tjark, M. V. Backer, and J. M. Backer (2006) Boron containing macromolecules and nanovehicles as delivery agents for neutron capture therapy. Anti-Cancer Agents Med. Chem., 6, 167–184. (140) B. Qualmann, M. M. Kessels, H. J. Musiol, W. D. Sierralta, P. W. Jungblut, and L. Moroder (1996) Synthesis of boron-rich lysine dendrimers as protein labels in electron microscopy. Angew. Chem. Int. Ed. Engl., 35, 909–911. (141) R. F. Barth, D. M. Adams, A. H. Soloway, F. Alam, and M. V. Darby (1994) Boronated starburst dendrimer–monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture therapy. Bioconjugate Chem., 5, 58–66. (142) J. Capala, R. F. Barth, M. Bendayan, M. Lauzon, D. M. Adams, A. H. Soloway, R. A. Fenstermaker, and J. Carlsson (1996) Boronated epidermal growth factor as a potential targeting agent for boron neutron capture therapy of brain tumors. Bioconjugate Chem., 7, 7–15. (143) W. L. Yang, R. F. Barth, D. M. Adams, and A. H. Soloway (1997) Intratumoral delivery of boronated epidermal growth factor for neutron capture therapy of brain tumors. Cancer Res., 57, 4333–4339. (144) G. Wu, W. L. Yang, R. F. Barth, S. Kawabata, M. Swindall, A. K. Bandyopadhyaya, W. Tjarks, B. Khorsandi, T. E. Blue, A. K. Ferketich, M. Yang, G. A. Christoforidis, T. J. Sferra, P. J. Binns, K. J. Riley, M. J. Ciesielski, and R. A. Fenstermaker (2007) Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab. Clinical Cancer Res., 13, 1260–1268. (145) G. Wu, R. F. Barth, W. L. Yang, M. Chatterjee, W. Tjarks, M. J. Ciesielski, and R. A. Fenstermaker (2004) Site-specific conjugation of boron-containing dendrimers to anti-EGF receptor monoclonal antibody cetuximab (IMC-C225) and its evaluation as a potential delivery agent for neutron capture therapy. Bioconjugate Chem., 15, 185–194. (146) W. L. Yang, G. Wu, R. F. Barth, M. R. Swindall, A. K. Bandyopadhyaya, W. Tjarks, K. Tordoff, M. Moeschberger, T. J. Sferra, P. J. Binns, K. J. Riley, M. J. Ciesielski, R. A. Fenstermaker, and C. J. Wikstrand (2008) Molecular targeting and treatment of composite EGFR and EGFRvIII-positive gliomas using boronated monoclonal antibodies. Clin. Cancer Res., 14, 883–891. (147) M. V. Backer, T. I. Gaynutdinov, V. Patel, A. K. Bandyopadhyaya, B. T. S. Thirumamagal, W. Tjarks, R. F. Barth, K. Claffey, and J. M. Backer (2005) Vascular endothelial growth factor selectively targets boronated dendrimers to tumor vasculature. Molec. Cancer Ther., 4, 1423–1429.

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(148) S. Shukla, G. Wu, M. Chatterjee, W. L. Yang, M. Sekido, L. A. Diop, R. Muller, J. J. Sudimack, R. J. Lee, R. F. Barth, and W. Tjarks (2003) Synthesis and biological evaluation of folate receptor-targeted boronated PAMAM dendrimers as potential agents for neutron capture therapy. Bioconjugate Chem., 14, 158–167. (149) W. L. Yang, R. F. Barth, G. Wu, S. Kawabata, T. J. Sferra, A. K. Bandyopadhyaya, W. Tjarks, A. K. Ferketich, M. L. Moeschberger, P. J. Binns, K. J. Riley, J. A. Coderre, M. J. Ciesielski, R. A. Fenstermaker, and C. J. Wikstrand (2006) Molecular targeting and treatment of EGFRvIII-positive gliomas using boronated monoclonal antibody L8A4. Clin. Cancer Res., 12, 3792–3802. (150) M. A. Azagarsamy, P. Sokkalingam, and S. Thayumanavan (2009) Enzyme-triggered disassembly of dendrimer-based amphiphilic nanocontainers. J. Am. Chem. Soc., 131, 14184–14185. (151) M. Gingras, J. M. Raimundo, and Y. M. Chabre (2007) Cleavable dendrimers. Angew. Chem. Int. Ed., 46, 1010–1017. (152) C. C. Lee, J. A. MacKay, J. M. J. Fréchet, and F. C. Szoka (2005) Designing dendrimers for biological applications. Nat. Biotechnol., 23, 1517–1526. (153) S. Nummelin, M. Skrifvars, and K. Rissanen (2000) Polyester and ester functionalized dendrimers, in Dendrimers II. Architecture, Nanostructure and Supramolecular Chemistry (ed. F. Vögtle), vol. 210, Springer-Verlag, Berlin, Heidelberg. (154) A. Papagiannaros, C. Demetzos, K. Dimas, and G. T. Papaioannou (2004) In vitro cytotoxic activity of doxorubicin–PAMAM dendrimer complex incorporated into HEPC liposomes against cancer cell lines. Anticancer Res., 24, 3593–3594. (155) A. Papagiannaros, K. Dimas, G. T. Papaioannou, and C. Demetzos (2005) Doxorubicin– PAMAM dendrimer complex attached to liposomes: cytotoxic studies against human cancer cell lines. Int. J. Pharm., 302, 29–38.

19 Encapsulation of Drugs inside Dendrimers Cédric-Olivier Turrin* and Anne-Marie Caminade

19.1

Introduction

The physical entrapment of active ingredients (AIs) inside dendrimers for drug delivery purposes, by lipophilic or electrostatic interactions, is mainly based on solubility enhancement,1,2 as an alternative approach to the prodrug strategy surveyed in Chapter 18. Both options offer pros and cons that generally do not overlap. In terms of efficacy, which can be related to bioavailability, selectivity, half-life, or bioactivity, these opposite strategies often present contradictory advantages and are often reviewed in parallel for comparison purposes.3–9 Briefly, the literature survey shows that prodrugs based on covalent attachment of AIs on to the dendrimer result in a better control over drug release despite a lower water-solubility, whereas the encapsulation or complexation of AIs within dendrimers gives rise to systems that may release their content prematurely9 (Figure 19.1). The surface of dendrimer-based delivering devices can be engineered to make them as stealthy as possible, for instance with the use of PEG units, or to render them more selective by means of receptor targeting moieties. These possibilities, which have been explored with several dendrimer backbones or hyperbranched polymers, are overviewed in this chapter after short reminders on the general aspects related to dendrimer-based formulations. * Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 19.1

19.2

Drug delivery with dendrimeric structures

From Dendritic Boxes to Dendrimer-Based Formulations

The possibilities for encapsulating guest molecules in the interior of dendrimers was early proved by the solubilization of lipophilic molecules like aspirin10 or pyrene11 in water with the help of water-soluble dendrimers. In these examples based on dynamic processes, the guests can diffuse in and out of the dendrimer interior to a certain extent. The tedious control over the loading/release processes was achieved by the group of Meijer and the so-called “dendritic box”. Guest molecules are trapped into the structure of a generation 5 PPI dendrimer during the final step of the synthesis, which consists of the grafting of bulky Boc-protected phenylalanine groups to form a size-dependent permeable shell. The two-step surface deprotection by acidolysis at high temperature (Boc removal and amide bond cleavage) allows control of the sequential release of small molecules like pnitrobenzoic acid and then larger guests like Bengal Rose.12,13 These results have paved the way for the use of dendrimers to solubilize lipophilic AIs inside dendrimers, taking the most subtle structural modifications that can influence the loading and release processes. In spite of the expected dynamic behavior of guests trapped inside dendrimers, the cargo-loading strategy has proved its efficacy beyond expectations when applied to dendrimeric structures with surface functions that can be tailored to improve drug loading, stealth, and/or targeting. Additionally it should be noted that the stability of the host/guest complex can be favored by a combination of lipophilic effect, hydrogen bonding, and ionic interactions. In some cases, it has even been shown that drug–dendrimer formulations can be considered as well-defined supramolecular objects.14,15

19.3

Improving Bioavailability with Dendrimers?

The strict definition of bioavailability refers to the portion of unchanged AI that reaches the bloodstream following a nonintravenous administration. A common misnomer extends this definition to the effective portion of unchanged AI that can reach its site of action (tissue, organ, cell population). An attractive feature of drug formulation with dendrimers is that the surface of the latter remains available for chemical modifications that improve

Encapsulation of Drugs inside Dendrimers

Figure 19.2

465

Internalization of nonmodified PAMAM dendrimers depending on their size

the bioavailability of the encapsulated drug by active or passive targeting, the stability of the complex being maintained by interactions with the inner structure in the absence of a densely packed surface. In this regard, the use of dendrimers for drug delivery raises the question of their final destination and the different obstacles in the human organism, like the endothelial, mucosal, or epithelial barriers, or the reticuloendothelial system (RES).16 In vivo studies have shown that generation 1 to 4 PAMAM dendrimers can cross the microvascular endothelium, with an extravasion time increasing with the generation number.17 Studies on the transepithelial transport across Caco-2 cell monolayers (intestinal model cell) distinguished different pathways according to their size (Figure 19.2). Low generation (1 and 2) dendrimers follow a paracellular pathway whereas higher generation (3 to 5) dendrimers follow a transcellular one (via endocytosis).16 Further results suggest that adjusting the size and the surface functions of PAMAM dendrimers allows control of their residence time and their transepithelial transport17–23 in the digestive tract, or their transport across other epithelial24–30 or cellular barriers.31–34 Anionic modified PAMAM dendrimers show lower permeability compared to the unmodified amine-terminated PAMAM dendrimers at high generation, whereas medium anionic generation dendrimers can cross rapidly the epithelium using the paracellular pathway.21 In vitro studies using the everted rat intestinal sac system showed that they rapidly cross into the intestine of adult rats, with an even faster transfer rate than cationic analogues.35 Interestingly, it has also been shown that the toxicity of polycationic PAMAM dendrimers (see the next section) can be lowered by partial acetylation of the surface amine group.36 PEGylation is becoming a widespread strategy to reduce dendrimer toxicity and uptake by the RES, and it is also an appreciable strategy regarding transport across epithelial barriers, compared to linear PEGylated polymers.22

19.4 Toxicological Issues Dendrimers are often considered as better scaffolds than other polymers for drug delivery thanks to their well-defined structure and homogeneously functionalized outer shell.

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Dendrimers

Nevertheless, as with any other nanomaterial,37–39 some of them suffer from intrinsic toxicity, which is mainly due both to their size and to their surface functions.40 Actually, the nonspecific cellular uptake of PAMAM dendrimers was early related to the formation of holes on supported lipid bilayers and different cell lines, which can eventually cause cellular death at submicromolar concentrations (0.5 μM) for high-generation PAMAM dendrimers (generation 7),41 like other polycationic polymers (polyetheyleneimine, polyL-lysine, etc.),42 these concentrations being critical in several studies.43 On the contrary, acetylated generation 5 PAMAM or neutral polymers do not induce hole formation and are less internalized in the absence of a targeting moiety.44–46 This phenomenon can be related to the insertion of dendrimers deep inside zwitterionic lipid bilayers and tiny interactions between the amphipathic dendrimers and the lipids, as highlighted by solid-state NMR.47 The toxicity of high generation cationic PAMAM dendrimers at therapeutically relevant concentrations has also recently been correlated to other pathways, including lysosomal alkalinization and induction of mitochondria-mediated apoptosis,48, 49 deregulation of serine/threonine protein kinase, and subsequent autophagic cell-death after lung exposure of rodent animal models,50 while the influence of the surface function has also been clearly demonstrated by developmental studies on zebrafish embryos.51 Importantly, it should be noted that despite the non-negligible cytotoxic effects mentioned above, the use of cationic dendrimers as drug carriers is not precluded, as highlighted by the significant reduction of these effects upon complexation with a guest molecule, such as indomethacin.52

19.5 19.5.1

Dendrimer-Based Formulations for Drug Delivery Nontargeted Formulations

The encapsulation of drugs inside the voids of dendrimers is an efficient strategy for relatively small AIs provided that electrostatic interaction, lipophilic effect, or hydrogen bonding can maintain the drug inside the dendrimer until the device reaches its site of action; otherwise the dendrimer is considered as a simple solubility enhancer. These features can be significantly improved by surface PEGylation, despite slightly reduced transepithelial transport properties,22 and the optimal size for the PEG residue has to be optimized for each delivery system, short PEGs being less efficient to maintain the guest molecules inside the structure whereas longer PEG chains significantly reduce the rate of encapsulation.53 In addition, PEGylation offers a clear protection against opsonization and uptake by the RES and allows a fine control over the carrier size, which is beneficial for accumulation at tumor sites by the enhanced permeability and retention (EPR) effect (see Figure 18.3, Chapter 18).54 Alternative approaches are also being studied to incorporate PEG inside the dendrimer structure and provide the interior with polar and hydrophilic properties.55 19.5.1.1 Anticancer Drugs Anticancer drugs having a carboxylic acid function like methotrexate (MTX) or doxorubicin (DOX) can favorably interact with the basic interior of PPI or PAMAM dendrimers,56

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and their encapsulation rate consequently increases with growing generation, for instance up to 26 MTX molecules can enter a generation 4 PAMAM fully capped with 2 kDa PEG chains.57 Nevertheless, these devices present an unfavorable fast release of the cargo in isotonic conditions, despite good stability in low ionic strength water solutions7 and independence from the degree of PEG capping.56 MTX molecules encapsulated inside PAMAM–PEG conjugates were found to carry bound water molecules, as demonstrated by broadband dielectric spectroscopy, but this observation was not related to early drug escape in saline conditions,58 which can be significantly reduced by the encapsulation of the PAMAM–DOX59 or PAMAM–MTX60 complex into liposomes. Another approach consists in encapsulating the AI in polymersomes, which are liposomes resulting from the micellar assembly of polymers, or dendrimeric micelles.61 Actually, worm-like micelles constituted by dendronized triblock copolymers62 can significantly slow down the release kinetics of encapsulated MTX. Alternatively, dendritic core multishell architectures composed of hyperbranched PEI cores functionalized with an internal layer of alkyl chains and a terminal layer of PEG tails have been designed to increase the stability of AIs (MTX, DOX).63 These systems (Figure 19.3) mimic the structure of liposomes with a hydrophilic core, a nonpolar middle layer, and hydrophilic outershell and their drug transport ability is related to the size of the hydrophilic PEI core and the size of the nonpolar middle layer, indicating that encapsulation of drugs like MTX or DOX requires both a nonpolar environment and/or a basic confined environment. Such systems self-assemble into supramolecular aggregates above a well-defined critical aggregation concentration (CAC) that can accommodate polar and nonpolar environments.64 The PEI core can be replaced by a polyglycerol (PG) core, and such nanotransporters were found to penetrate efficiently human keratinocytes in vivo and pig skin ex vivo.65 Comparable results were obtained with

Figure 19.3

Vesicle-inspired dendrimeric multishell architectures for drug delivery

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Dendrimers

hyperbranched polyglycerols capped with oligoethyleneglycol (OEG) and fatty chains, which show increased ability to bind paclitaxel (PTX) in the presence of alkyl chainmodified PG and sustained released of the drug in phosphate buffered saline solutions.66 When favorable ionic interactions cannot be expected between the host and the guest, dendrimeric structures can still be useful to increase the solubility of poorly water-soluble drugs by encapsulation, like camptothecin derivatives encapsulated in polyglycerol succinic acid dendrimers, but the stability of the complex in isotonic solutions generally leads to analogous in vitro cytotoxicity of the free drug and its dendrimer formulated form.67,68 Stability increase can be achieved by surface locking, or other strategies to increase the affinity between the AI and the dendrimer, like bilayered systems evoked above. An alternative surface-locking strategy has been developed on the surface of hyperbranched polyglycerols by ring-closing methatesis.69 The transport ability, related to the surface blocking efficacy, is related to the nature of the crosslinker and its possible interactions with the AI,70 and raises the question of the delivery, which eventually can be achieved through photo-triggered degradation of the nanotransporter71 or pH-responsive structures with acid-sensitive linkers.72 Other ways to enhance host–guest complex stability that have been investigated concern structural modifications that may affect the internal density of the dendrimeric backbone, incorporation of aromatic moieties or PEG residues within the structure of dendrimers, this latter option being rationalized a priori by the fact that PEG polymers are clinically used to formulate anticancer drugs, e.g. Doxil, which is a PEGcontaining liposomal formulation of DOX. This strategy has been explored on biodegradable polyether-co-polyester (PEPE) dendrimers (Figure 19.4), which show increasing MTX encapsulation capabilities, with increasing number and size of branches composed mainly of OEG moieties and increasing number of aromatic rings within the structure.55,73 The release of MTX in phosphate buffer solutions (pH = 7.4) was initiated by a burst release and followed by a slow release. The initial burst release could be sterically reduced

Figure 19.4

Biodegradable PEPE dendrimers for MTX encapsulation

Encapsulation of Drugs inside Dendrimers

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by increasing the density of PEGs in the outer shell and increasing the size and lipophilic character of internal hydrophobic pockets.55,73 These results are in agreement with previous comparative studies on the solubilization and release of paclitaxel (PTX) with PEG-based grafts, star-shaped polymers, and polyglycerol dendrimers74 that highlighted the beneficial effect of amphiphilic hyperbranched structures and also the fact that solubilization/release processes are not necessarily connected to encapsulation or physical entrapment of the AI within these structures.75 These conclusions are also supported by studies on cholesterolmodified PG dendrimers that self-assemble into aggregates that can solubilize PTX according to analogous hydrotropic process.76 In a simpler approach, it should be noted that PTX formulated with nonmodified PAMAM dendrimers shows improved solubility and efficacy, even in the absence of control on the release profile.77 The formulation of anticancer drugs with dendrimer or dendrimer-like structures is a flourishing field of research, and many other examples can be found in the literature involving other drugs or model drug compounds and other dendrimeric architectures. For instance, the dendrimer-mediated delivery of different camptothecins, a family of potent antitumor drugs that suffer from poor water-solubility and bioavailability (less than 8%) and severe adverse effects like gastrointestinal toxicity, have been formulated with nonmodified PAMAM dendrimers,78,79 poly(glycerol-succinic acid) (PGLSA) dendrimers,80 or triazine dendrimers.81,82 As mentioned in previous examples, the issue of early release under stomach-like acidic conditions or in isotonic aqueous solutions is a major concern, despite encouraging in vitro studies that generally disclose increased cellular uptake and increased drug retention.80 19.5.1.2 Antimicrobial Drugs Formulation of antimicrobial agents with dendrimers is an emerging field of research that may target the increase of bioavailability, the reduction of side effects, or the deposition of the drug on to surfaces. It mainly concerns antimalarial and antibacterial and, to a lesser extent, antiviral drugs. Prolonged antimalarial chemotherapies induce several side-effects, which are responsible for new formulations of antimalarial drugs. The group of N. K. Jain has explored the possibility to formulate chloroquine phosphate with PEG-cored poly-Llysine dendrimers.83 Artemether (Figure 19.5), another potent antimalarial drug, is a lipid soluble methyl ether derivative of artemisin, active in vitro in the nanomolar range. Its

Figure 19.5

Antimicrobial drugs formulated with dendrimers

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Dendrimers

short half-life in vivo (3–5 hours) could be enhanced by suitable formulation to prevent uptake by the RES and opsonization. The same group proposed the use of dendrimeric micelles originating from the self assembly of small Fmoc-protected lysine dendrons with a PEG core for this purpose.84 Formulations of these drugs with the corresponding dendrimers or dendrimer-based micelles were found to significantly increase the watersolubility of the antimalarial drugs with a good stability and sustained release in water. The in vivo and in vitro cytotoxicity and efficiency were also found suitable for intravenous administration in the case of chloroquine phosphate formulations, although no stability study in a saline condition could comfort this idea.84 Triclosan (Figure 19.5) is an antibacterial antifungal agent widely used in oral care, cosmetics, and for surface treatment. ABA triblock copolymers consisting of PAMAM dendrimers (generation 1 to 6) as A blocks and a poly(propylene oxide) (PPO) as B blocks can form stable micelles that can encapsulate triclosan under microemulsion conditions more efficiently than nonmodified PAMAM dendrimers85 or a difunctional block copolymer having roughly the same critical micellar concentration (CMC) as the ABA triblock copolymers.86 The CMC was found to be pH dependent at high PAMAM generation (5 and 6) and low ionic strength. Accordingly, the release profile of the PAMAM–PPO– PAMAM generation 3 copolymer showed a sustained release of the drug, independently of the pH (7.4 or 5). These systems were used in combination with poly(acrylic acid) PAA for electrostatic LBL deposition of thin film incorporating triclosan.87 The half-life release at 37 °C in phosphate buffered solutions was approximately 3 days and complete release was achieved in more than 20 days, while the film was not affected by the diffusion-guided release process, making the approach potentially applicable for the coating of biomedical devices. The antibacterial activity of clinically used antibiotics can be increased by suitable formulation with dendrimers. For instance, nonmodified, amine-terminated PAMAM dendrimers have been evaluated as drug carriers of sulfamethoxazole (Figure 19.5).88 The results show a fair increase in the solubility and antimicrobial activity (4 to 8 times) against Escherichia coli. Analogous studies on the delivery of quinolones89 (nadifloxacine and prulifloxacin; see Figure 19.5) gave comparable results, with a pH-dependent solubility increase and a small activity increase (12 times) upon formulation with dendrimers. The marked pH dependence of the solubility properties led the authors to investigate the ionic interactions between the PAMAM scaffold and model drug compounds having negative charges by NMR, and the results clearly demonstrated that external electrostatic interactions contribute more than internal encapsulation to the solubility enhancement.90 These results rationalize the poor efficacy of this strategy for the oral administration route, which leads to degradation of the complex in the stomach where pH values range from 1.5 to 5. The same observations were made on water-soluble niclosamide–dendrimer complexes involving strong interactions between niclosamide and primary amines on the surface of the dendrimer.91 Conversely, the encapsulation of metal salts (silver, copper) within PAMAM dendrimers clearly involves interaction with the internal amines, and surface functions depending on their nature; the same observations were made for dendrimer-encapsulated copper nanoparticles (see Chapter 6). Dendrimer–silver complexes and the resulting nanocomposites obtained with amine-terminated or hydroxy-terminated PAMAM dendrimers have shown antimicrobial activity against different strains of pathogens, but the discrepancy of activity

Encapsulation of Drugs inside Dendrimers

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could not be clearly rationalized in terms of structural parameters such as dendrimer generation, surface function, or possible leakage of cytotoxic silver ions.92 These first insights were completed by a more systematic study on PAMAM-encapsulated silver nanoparticles showing that the biological properties of these composites was mainly due to the chemical nature of the surface functions of the dendrimers, indicating that silver is tightly encapsulated in these systems and may hardly escape.93 However, nanocomposite systems where the silver ions or nanoparticles are less tightly buried within dendrimers continue to be attractive for antimicrobial purposes. For instance, polyester-urethane polymers dendronized with PAMAM wedges have been used as stabilizers for the reduction of silver salts.94,95 These systems show good antibacterial in vitro activity against E. coli only in the presence of silver, proving the key role of the metal and suggesting its possible contact with the bacteria in view of previous results evoked above. PAMAM-like hyperbranched polymers have also been used in this respect.96 The bactericidal activity of systems increased with decreasing silver nanoparticle diameter, suggesting that direct contact between the pathogen and the colloids is required for microbicidal effect. Formulations of PAMAM dendrimers with subnanometer-sized silver colloids have also been assayed to treat textile fabrics,97 but the bactericidal effect could not be clearly attributed to the presence of silver as the PAMAM dendrimer alone showed a better activity, due to its ammonium terminations. 19.5.1.3 Anti-Inflammatory Drugs Most dendrimer-based anti-inflammatory formulations concern nonsteroidal antiinflammatory (NSAI) drugs (see Figure 19.8 later) and amine-terminated dendrimers. These delivery systems involve surface ionic interactions, as demonstrated by experimental98,99 and theoretical100 studies, and are treated in Section 19.5.2 of this chapter. In the case of nonacidic AIs like phenylbutazone, one of the oldest NSAI drugs, both lipophilic encapsulation and surface electrostatic interactions are responsible for watersolubility enhancement, as demonstrated by two-dimensional NOESY experiments and calorimetry studies.101 The surface ionic interactions result from the equilibrium between neutral phenylbutazone and enol forms in water solution (see Figure 19.6).

Figure 19.6

Possible interactions of phenylbutazone with PAMAM architecture

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Dendrimers

Citric acid, a biocompatible building block, has been used to synthesize PEG-cored bisdendrons that were found to encapsulate mefenamic acid and diclofenac efficiently (see Figure 19.8 later). The dendrimer–drug complexes were considered as hydrogels by the authors, who presented acceptable release profiles in various pH conditions. Aceclofenac (Figure 19.8), a diclofenac prodrug, has been formulated with PPI dendrimers partially capped with PEG chains.102 The PEGylation of surface amine functions increased the loading capacity of the dendrimeric structures, indicating the internal encapsulation of the drug. In vivo studies on the reduction of paw edema showed an increased efficiency of the drug–dendrimer complex in comparison with the plain drug. 19.5.1.4

Other Drugs

The formulation of famotidine, an antiulcera drug that inhibits stomach acid production, with a generation 5 pegylated PPI dendrimer has been evaluated in vitro and in vivo.103 The dendrimeric transporter was partially pegylated with the N-hydroxy succinimide ester of dicarboxylic acid PEG 2000 in the presence of N,N-dicyclohexyl carbodiimide, but no dendrimer interconnection was suspected by the authors.104 The pegylated dendrimer encapsulated twice the quantity of drug in comparison with the native dendrimer, indicating that encapsulation takes place both within the dendrimer structure and the PEG shell, and was found more biocompatible in vitro. In vivo, the ulceration score of animals treated intravenously with the PEG–dendrimer–famotidine complex was much lower than that of animals treated with the plain drug, and the serum half-life of famotidine was almost tripled upon formulation with the dendrimer.103 Ocular delivery is another challenging purpose that requires high penetrating capabilities, the corneal surface epithelium being almost impermeable and continuously drained by lachrymal fluid. Dendrimers, like other formulating agents, have been assayed to increase the residence time of antiglaucoma drugs dedicated to topical ocular instillation. Pilocarpine and tropicamide (Figure 19.7) have been formulated with carboxylic acid, hydroxyl, and amine-terminated PAMAM dendrimers, and the resulting ocular dosage formulations were found to significantly improve the corneal residence time of the drugs in vivo, thanks to the bioadhesive properties of the dendrimer, without detectable eye irritation.24 Analogous in vivo results have been obtained with formulation of carteolol in the presence of phosphorhydrazone-containing dendrons having an ammonium core and carboxylate surface functions, even if the residence time was modestly increased in this case, mainly because formulations obtained with medium generation dendrons were poorly water-soluble.25

Figure 19.7

Series of nonacidic drugs formulated with dendrimers

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Nifedipine is a calcium channel blocking agent mainly used to treat hypertension where water-solubility is more increased with ester-terminated PAMAM dendrimers than with amine-terminated ones, presumably because they offer less unprotonated amines than the former.105 These systems have been embedded in hydroxypropylmethyl cellulose hydrogels,106 and the release of nifepidine was proportional to the dendrimer-encapsulation rate. Dendrimers were less efficient than isopropanol, a reference formulating agent, in promoting the loading and the release of the drug, but they protected it more efficiently toward its recrystallization. 19.5.2 Supramolecular Assemblies Involving Surface Ionic Interactions The complexation of drugs by ionic interactions on the surface of positively charged dendrimers generally leads to a significant reduction of cytotoxic effects related to polycationic macromolecules.52 This strategy has been developed to formulate acidic NSAI drugs (Figure 19.8) and other drugs, although the nature of interactions between the drugs and the dendrimer architecture remains an issue under active investigation.90,100,107 Actually, besides surface ionic forces that are responsible for high cargo loading observed with amine-terminated dendrimers, physical encapsulation driven by lipophilic interactions also participates in drug transport (see Section 19.5.1.3). The solubility of ibuprofen in the presence of PAMAM dendrimers was early found to depend on pH, suggesting the presence of ionic interaction between the acidic part of ibuprofen and the terminal amine functions.108 Actually, at basic and neutral pH, the solubility of the drug is significantly increased while at lower pH values, the solubility of the drug drops to a nonformulated value. Combinations of UV–vis, FTIR, and NMR spectroscopies later confirmed the ionic interactions,99 and comparative studies on hyperbranched polyols showed that encapsulation of ibuprofen inside a dendrimeric structure is also possible, but less efficient to enhance its solubility.99 These systems facilitate cellular entry in epithelial cell lines.99,109 These preliminary studies have inspired comparable studies on ibuprofen-like NSAI drugs (Figure 19.8), ketoprofen, naproxen, diflunisal,110–112 or flurbiprofen.113 As previously observed with ibuprofen, ionization of these NSAI drugs in the presence of PAMAM dendrimers (generation 4 or 5) significantly increased their water-solubility

Figure 19.8

NSAI drugs formulated with dendrimers

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Dendrimers

Figure 19.9

Metal-based DNA intercalating drugs formulated with dendrimers

and reduced the hemolytic cytotoxicity of the polycationic carrier by charge-masking. In vivo studies on carrageenan-induced paw inflammation have shown a significant increase in the mean residence time and half-life of the dendrimer formulation in comparison with the plain drug after intravenous administration, with a rapid burst release followed by a slower release.113 Despite the known sensitivity of such ionic associations at low pH, in vivo studies on mice114 (stomach pH between 3 and 5) following oral absorption revealed a higher plasma drug concentration in animals treated with the dendrimer–ketoprofen formulations.112 Metal-based DNA intercalating drugs based on cationic Pt or Ru complexes (Figure 19.9) have been identified to interact with the surface of anionic PAMAM dendrimers by NMR.115 Remarkably, the binding constants were not dependent on the dendrimer generation, between 104 and 105 M-1 for Pt and Ru complexes, respectively, but their low value traduces insufficient binding strength to make these systems viable for drug delivery purposes (submicromolar constants are required). Alternatively, a strict molar ratio of drug can be used to afford well-defined supramolecular assemblies where each surface function of the dendrimeric platform is engaged with one drug unit. Depending on the stability of the ion pair, the system can be considered as a simple stoichiometric mixture of oppositely charged species25 or a well-defined supramolecular assembly. In the first case, the formulation is a dynamic system and the complexed drug may be separated from its dendrimeric host upon dilution in ionic media; in the second case, the assembly can form a rather stable supramolecular architecture that can even self-assemble into bigger supersupramolecular objects.15 These uncommon dendrimeric species are generally composed of an ionizable amphipathic dendrimer complexed with oppositely charged surfactants of biologogical interest. Ion-paired surfactants designated as catanionic surfactants116 have inspired the development of such catanionic dendrimers. The stability of the ion pair results both from lipophilic interactions between the drug having surfactant properties and the skeleton of the dendrimer, and a suitable solvation area surrounding the ion pair. The strategy has been applied to acid-terminated polyphosphorhydrazone (PPH) dendrimers,117 which can form multivalent catanionic analogs of galactosylceramide (galcer) upon complexation with N-hexadecylamino-1deoxylactitol (Figure 19.10). These systems are multivalent chimera of galcer, a cellular receptor involved in the early step of HIV infection, and have shown in vitro anti-HIV-1 inhibition activity in the submicromolar range and a cytotoxicity that is related to the stability of the ion pair.14,118

Encapsulation of Drugs inside Dendrimers

Figure 19.10

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Multivalent catanionic galcer analogs

19.5.3 Targeted Formulations Despite the fact that dendrimer formulation offers a significant advantage over other drug delivery techniques to address the issue of targeting, mainly thanks to the unlimited surface functionalization possibilities, the number of studies dedicated to dendrimer-based targeted formulations is relatively scarce in comparison with those dealing with nontargeted devices. The phosphate salt of the antimalarial drug primaquine has been formulated with a galactose-coated generation 5 PPI dendrimer.119 The latter was obtained by an amino reductive addition of galactose units to the terminal amines of the dendrimers. In vivo studies on albino rats showed a significant decrease of primaquine systemic toxicity related to its hemolytic properties upon dendrimer formulation along with a sustained released. In addition, the galactose coating was found to increase hepatic uptake, the target organ of the drug. Analogous results were obtained with chloroquine phosphate formulated with

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Dendrimers

Figure 19.11

Figure 19.12

Glycosylated PLL–PEG–PLL bisdendron

PEGylated folate residue for dendrimer derivatization

a galactose-terminated PLL core-modified dendrimer (Figure 19.11) obtained according to the same procedure.120 Anticancer drugs are also favorably addressed towards key organs upon formulation with dendrimers equipped with suitable targeting moieties. For example, PAMAM dendrimers have been surface-functionalized with folate-ended PEG tails (5 kDa) and loaded with 5FU (Figure 19.12).121 In vitro and in vivo studies proved the importance of both key surface functions in the improvement of the efficacy of 5FU. In particular, hemolytic toxicity was significantly reduced and tumor accumulation was favored in the presence of both surface functions, as compared to the PAMAM dendrimer bearing only the PEG residue122 or only the folate moieties.121 Additionally, this study proves that the beneficial effects related to the use of PEG residues (water solubility, stealth, size control for the optimal EPR effect) are compatible with active targeting moieties. Polyester-co-polyether (PEPE) dendrimers, which are highly water-soluble and biocompatible,55 have been used to deliver MTX to glioma cells.34 Partial glycosylation of hydroxyl surface groups was performed with D-glucosylamine in order to enhance delivery properties across the blood–brain barrier (BBB). In vitro studies on glioma cells, glioma tumor spheroids, and the BBB model show the beneficial effect of glucosylation on MTX cellular uptake, penetration and diffusion in avascular tumor regions, and reduction of tumor spheroid size.

Encapsulation of Drugs inside Dendrimers

19.6

477

Conclusion and Perspectives

Undoubtedly, the specific design of novel dendrimer species with biocompatible linkages and the advent of accurate surface chemistry have contributed to ascertain the idea that dendrimeric platforms offer incomparable opportunities to design drug delivery devices with adaptable loading capacities, specific targeting moieties, and tunable physicochemical properties. In this context, it should be noted that tumor-specific targeting minimizes the differences that may be observed between different nanocarriers, mainly by reducing their adverse site effect:123 the versatility of dendrimers toward surface function engineering should then increase their potential in this field. Despite these advantages and the encouraging results obtained with a large variety of AIs formulated with dendrimeric macromolecules, some issues still demand further effort, in particular to complement knowledge on systemic toxicity of dendrimers124 and drug–dendrimer complexes, taking into account that each device requires a specific study. The fast release under acidic or isotonic conditions7,57,99,125 of drugs from dendrimer formulations comprising protonable amines in their structure is also a serious concern regarding oral absorption or transdermal topical use, as the pH of the stomach is between 2 and 5 and the pH of the skin is around 5.5. Actually, tertiary amines in the internal voids or primary amines located on the surface are generally involved in the electrostatic stabilization of a drug–dendrimer complex. Upon a pH drop, their protonation leads to a burst release of the drug that can take place in a couple of hours, but one should note that even in these unfavorable cases, the dendrimer-based formulation still affords benefits in terms of cellular uptake, bioavailability, or/and efficacy. In addition, this property can also be beneficial to promote the release of the cargo in areas where the pH is lower, for example in tumor sites. Despite undesirable pH-triggered release problems, the use of dendrimer formulations for topical application purposes is also an expanding field of research, probably because regulatory obstacles are expected to be less blocking than in the case of projects targeting oral or parenteral administration of dendrimercontaining formulations. In this regard, hydrogels made of dendrimers (and other components) can encapsulate a large variety of active compounds,126,127 making the most of a combination of chemical/sterical complexation inside dendrimer voids and physical stabilization of the formulation related to the rheological properties of the gel. In addition, some of these gels can respond to controllable external stimuli and trigger suitable release profiles,106 for instance by small temperature shifts.128

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(82) W. Zhang, J. Jiang, C. H. Qin, L. M. Perez, A. R. Parrish, S. H. Safe, and E. E. Simanek (2003) Triazine dendrimers for drug delivery: evaluation of solubilization properties, activity in cell culture, and in vivo toxicity of a candidate vehicle. Supramol. Chem., 15, 607–616. (83) D. Bhadra, S. Bhadra, and N. K. Jain (2006) PEGylated peptide dendrimeric carriers for the delivery of antimalarial drug chloroquine phosphate. Pharm. Res., 23, 623–633. (84) D. Bhadra, S. Bhadra, and N. K. Jain (2005) PEGylated peptide-based dendritic nanoparticulate systems for delivery of artemether. J. Drug Delivery Sci. Technol., 15, 65–73. (85) J. Gardiner, S. Freeman, M. Leach, A. Green, J. Alcock, and A. D’Emanuele (2008) PAMAM dendrimers for the delivery of the antibacterial Triclosan. J. Enzyme Inhib. Med. Chem., 23, 623–628. (86) P. M. Nguyen and P. T. Hammond (2006) Amphiphilic linear–dendritic triblock copolymers composed of poly(amidoamine) and poly(propylene oxide) and their micellar-phase and encapsulation properties. Langmuir, 22, 7825–7832. (87) P. M. Nguyen, N. S. Zacharia, E. Verploegen, and P. T. Hammond (2007) Extended release antibacterial layer-by-layer films incorporating linear–dendritic block copolymer micelles. Chem. Mater., 19, 5524–5530. (88) M. L. Ma, Y. Y. Cheng, Z. H. Xu, P. Xu, H. Qu, Y. J. Fang, T. W. Xu, and L. P. Wen (2007) Evaluation of polyamidoamine (PAMAM) dendrimers as drug carriers of anti-bacterial drugs using sulfamethoxazole (SMZ) as a model drug. Eur. J. Med. Chem., 42, 93–98. (89) Y. Y. Cheng, H. Qu, M. L. Ma, Z. H. Xu, P. Xu, Y. J. Fang, and T. W. Xu (2007) Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study. Eur. J. Med. Chem., 42, 1032–1038. (90) Y. Y. Cheng, Q. L. Wu, Y. W. Li, and T. W. Xu (2008) External electrostatic interaction versus internal encapsulation between cationic dendrimers and negatively charged drugs: Which contributes more to solubility enhancement of the drugs? J. Phys. Chem. B, 112, 8884–8890. (91) B. Devarakonda, R. A. Hill, W. Liebenberg, M. Brits, and M. M. de Villiers (2005) Comparison of the aqueous solubilization of practically insoluble niclosamide by polyamidoamine (PAMAM) dendrimers and cyclodextrins. Int. J. Pharm., 304, 193–209. (92) L. Balogh, D. R. Swanson, D. A. Tomalia, G. L. Hagnauer, and A. T. McManus (2001) Dendrimer–silver complexes and nanocomposites as antimicrobial agents. Nano Lett., 1, 18–21. (93) W. Lesniak, A. U. Bielinska, K. Sun, K. W. Janczak, X. Y. Shi, J. R. Baker, and L. P. Balogh (2005) Silver/dendrimer nanocomposites as biomarkers: fabrication, characterization, in vitro toxicity, and intracellular detection. Nano Lett., 5, 2123–2130. (94) S. Ghosh (2005) Antibacterial effects of silver doped polyethyleneglycol based polyamidoamine side chain dendritic polyurethane. J. Macromol. Sci., Part A: Pure Appl. Chem., A42, 765–770. (95) S. Ghosh and A. K. Banthia (2007) Silver doped antibacterial polyamidoamine side chain dendritic polyesterurethane (SCDPEU) architectures. J. Mater. Sci., 42, 118–121. (96) Y. W. Zhang, H. S. Peng, W. Huang, Y. F. Zhou, and D. Y. Yan (2008) Facile preparation and characterization of highly antimicrobial colloid Ag or Au nanoparticles. J. Colloid Interface Sci., 325, 371–376. (97) S. Ghosh, S. Yadav, N. Vasanthan, and G. Sekosan (2010) A study of antimicrobial property of textile fabric treated with modified dendrimers. J. Appl. Polym. Sci., 115, 716–722. (98) O. M. Milhem, C. Myles, N. B. McKeown, D. Attwood, and A. D’Emanuele (2000) Polyamidoamine Starburst (R) dendrimers as solubility enhancers. Int. J. Pharm., 197, 239–241. (99) P. Kolhe, E. Misra, R. M. Kannan, S. Kannan, and M. Lieh-Lai (2003) Drug complexation, in vitro release and cellular entry of dendrimers and hyperbranched polymers. Int. J. Pharm., 259, 143–160. (100) I. Tanis and K. Karatasos (2009) Association of a weakly acidic anti-inflammatory drug (ibuprofen) with a poly(amidoamine) dendrimer as studied by molecular dynamics simulations. J. Phys. Chem. B, 113, 10984–10993.

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(101) W. J. Yang, Y. W. Li, Y. Y. Cheng, Q. L. Wu, L. P. Wen, and T. W. Xu (2009) Evaluation of phenylbutazone and poly(amidoamine) dendrimers interactions by a combination of solubility, 2D-NOESY NMR, and isothermal titration calorimetry studies. J. Pharm. Sci., 98, 1075–1085. (102) V. Gajbhiye, P. V. Kumar, A. Sharma, and N. K. Jain (2008) Novel PEGylated PPI dendritic nanostructures for sustained delivery of anti-inflammatory agent. Current Nanosci., 4, 267–277. (103) V. Gajbhiye, P. Vijayaraj Kumar, R. K. Tekade, and N. K. Jain (2009) PEGylated PPI dendritic architectures for sustained delivery of H2 receptor antagonist. Eur. J. Med. Chem., 44, 1155–1166. (104) H. Namazi and M. Adell (2005) Dendrimers of citric acid and poly (ethylene glycol) as the new drug-delivery agents. Biomaterials, 26, 1175–1183. (105) B. Devarakonda, R. A. Hill, and M. M. de Villiers (2004) The effect of PAMAM dendrimer generation size and surface functional group on the aqueous solubility of nifedipine. Int. J. Pharm., 284, 133–140. (106) B. Devarakonda, N. Li, and M. M. de Villiers (2005) Effect of polyamidoamine (PAMAM) dendrimers on the in vitro release of water-insoluble nifedipine from aqueous gels. AAPS PharmSciTech, 6, E504–E512. (107) Y. Y. Cheng, Y. W. Li, Q. L. Wu, H. H. Zhang, and T. W. Xu (2009) Generation-dependent encapsulation/electrostatic attachment of phenobarbital molecules by poly(amidoamine) dendrimers: evidence from 2D-NOESY investigations. Eur. J. Med. Chem., 44, 2219–2223. (108) O. M. Milhem, C. Myles, N. B. McKeown, D. Attwood, and A. D’Emanuele (2000) Polyamidoamine Starburst dendrimers as solubility enhancers. Int. J. Pharm., 197, 239–241. (109) S. Kannan, P. Kolhe, V. Raykova, M. Glibatec, R. M. Kannan, M. Lieh-Lai, and D. Bassett (2004) Dynamics of cellular entry and drug delivery by dendritic polymers into human lung epithelial carcinoma cells. J. Biomater. Sci., Polym. Ed., 15, 311–330. (110) Y. Y. Cheng and T. W. Xu (2005) Dendrimers as potential drug carriers. Part I. Solubilization of non-steroidal anti-inflammatory drugs in the presence of polyamidoamine dendrimers. Eur. J. Med. Chem., 40, 1188–1192. (111) Y. Y. Cheng, T. W. Xu, and R. Q. Fu (2005) Polyamidoamine dendrimers used as solubility enhancers of ketoprofen. Eur. J. Med. Chem., 40, 1390–1393. (112) N. Man, Y. Y. Cheng, T. W. Xu, Y. Ding, X. M. Wang, Z. W. Li, Z. C. Chen, G. Y. Huang, Y. Y. Shi, and W. Longping (2006) Dendrimers as potential drug carriers. Part II. Prolonged delivery of ketoprofen by in vitro and in vivo studies. Eur. J. Med. Chem., 41, 670–674. (113) A. Asthana, A. S. Chauhan, P. V. Diwan, and N. K. Jain (2005) Poly(amidoamine) (PAMAM) dendritic nanostructures for controlled site-specific delivery of acidic anti-inflammatory active ingredient. AAPS PharmSciTech, 6, E536–E542. (114) T. T. Kararli (1995) Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug Dispos., 16, 351–380. (115) M. J. Pisani, N. J. Wheate, F. R. Keene, J. R. Aldrich-Wright, and J. G. Collins (2009) Anionic PAMAM dendrimers as drug delivery vehicles for transition metal-based anticancer drugs. J. Inorg. Biochem., 103, 373–380. (116) E. Soussan, S. Cassel, M. Blanzat, and I. Rico-Lattes (2009) Drug delivery by soft matter: matrix and vesicular carriers. Angew. Chem. Int. Ed., 48, 274–288. (117) A. Pérez-Anes, G. Spataro, Y. Coppel, C. Moog, M. Blanzat, C. O. Turrin, A. M. Caminade, I. Rico-Lattes, and J. P. Majoral (2009) Phosphonate terminated PPH dendrimers: influence of pendant alkyl chains on the in vitro anti-HIV-1 properties. Org. Biomol. Chem., 7, 3491–3498. (118) A. Pérez-Anes, C. Stefaniu-Bololoï, C. Moog, J. P. Majoral, M. Blanzat, C. O. Turrin, A. M. Caminade, and I. Rico-Lattes (2009) Multivalent catanionic GalCer analogs derived from first generation dendrimeric phosphonic acids. Bioorg. Med. Chem., 18, 242–248. (119) D. Bhadra, A. K. Yadav, S. Bhadra, and N. K. Jain (2005) Glycodendrimeric nanoparticulate carriers of primaquine phosphate for liver targeting. Int. J. Pharm., 295, 221–233.

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20 Unexpected Biological Applications of Dendrimers and Specific Multivalency Activities Cédric-Olivier Turrin* and Anne-Marie Caminade

20.1

Introduction

Despite the fact that research is being continuously secured by national research agencies and formatted proposals that follow call for project guidelines, academic research still leads to unexpected properties or unpredictable theories, as a result of serendipity. Concerning biological applications, the field of dendrimer science is not an exception and some recent findings related to the properties of dendrimers were hardly foreseeable in the light of identified properties of any of their substructural building blocks. The most striking examples concern the unexpected gene regulation of human primary macrophages by carbosilane dendrimers1 and the natural killer (NK) cell amplification properties of a series of poly(phosphorhydrazone) (PPH) dendrimers,2 which were recently connected to immunomodulation and anti-inflammatory properties.3,4 In addition to these examples, which will be treated at the end of this chapter, a selection of biological applications related to the unique features of dendrimers will be presented, with a special emphasis on properties related to the multivalent character of dendrimers. This point will be illustrated by several examples ranging from glycodendrimers, which often provide unexpected dendritic effects to enhance ligand/receptor affinity, to charged dendrimers that behave like polyelectrolytes or unimolecular micelles for specific antibacterial strategies.5,6

* Corresponding author for this chapter.

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Figure 20.1 receptors13

20.2

Multivalent ligands involved in multiple interactions with cell-surface

Dendrimers and Multivalency

Multivalent effects,7–9 identified and conceptualized almost forty years ago,10–12 are found widely in nature, like the adhesion of bacteria or viruses to cell surfaces or the cell-to-cell adhesion processes. The attachment of polyvalent molecules via multiple interactions and the subsequent signal transduction cascades that may result are related to the fact that weak ligand–receptor interactions can be strongly reinforced by the simultaneous bonding of these ligands to these multiple receptors. In this regard, multivalent ligands interact with receptors located at cell surfaces according to different mechanisms (Figure 20.1).13 When multivalent ligands bind oligomeric receptors, the first binding event can favor the second and further bindings (Figure 20.1, A) according to a thermodynamic “chelate” effect.10 They are able to recruit receptors and make them cluster (Figure 20.1, B), they can bind primary and secondary binding sites (Figure 20.1, C), and finally the high local concentration of the ligand can also be responsible for a high affinity toward a single receptor (Figure 20.1, D). All parameters influencing these interactions have been thoroughly reviewed over the last decade.13–15 20.2.1

Multivalent Effects and Dendrimeric Effects

Dendrimers offer a unique versatility for the rational design of multiple ligands in comparison with other natural or synthetic scaffolds such as polymers, proteins, and liposomes. Actually, all structural parameters of a dendrimer, which have a dramatic influence on the final surface arrangement, can be precisely defined in terms of shape, orientation of recognition elements, flexibility, size, and valency.16 When a functional group is grafted on to the surface of a dendrimer, its properties, if quantifiable, may be modified in a nonproportional relationship to the number of surface functions. This modification of a functional group’s property after its grafting on a den-

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drimer ’s surface is often referred to as the dendritic effect or dendrimer effect.17 Nevertheless, the term multivalent effect is more appropriate to describe such amplification effects, which can be obtained with any multivalent scaffold.18 Conversely, a dendritic effect or dendrimer effect should be related to the nonlinear variation of a property with the generation of the dendrimer scaffold. Such dendrimer effects can be positive or negative, and many examples can be found in cell–receptor interactions, catalysis, or drug encapsulation. Multivalent effects are often at the center of interactions between receptors and natural or synthetic ligands. For instance, in the field of antiangiogenic tumor therapies aim to control the development of new capillary blood vessels, which facilitate the growth of tumors.19 Heparin, a highly-sulfated glycosaminoglycan, has been recognized to potentiate the activity of angiogenic growth factors.20 Hence, the competitive binding of polycationic species with endogenous angiogenic factors for heparin may result in reduced angiogenic activity. In this regard, a polycationic arginine capped dendrimer21 that mimicks endostatin, an endogenous antiangiogenic heparin binder, was found to exhibit antiangiogenic activity in the chicken embryo chorioallantoic membrane (CAM) assay. In another example, a generation 4.5 PAMAM dendrimer partially capped with glucosamine also exhibited antiangiogenic properties in vitro,22 but this moderate effect was not rationalized, in contrast with its anti-inflammatory properties, which were clearly related to immunomodulations (see Section 20.4.1.2). Recently, a generation 6 cationic PLL dendrimer was found to exhibit systemic antiangiogenic activity in vivo in a murine model submitted to daily intravenous injections at 50 mg·kg-1.23 This concentration was nontoxic in vitro on HUVEC cell lines, and biodistribution studies revealed a rapid blood clearance and preferential accumulation in the liver, kidneys, and spleen. Of the injected dendrimer, 4% reached the tumor site after 30 minutes, and the antiangiogenic effect was accompanied by a significant tumor growth reduction.23

20.2.2

Glycodendrimers

Glycodendrimers24–32 have emerged as a new class of glycoconjugates that can feature a precise distribution of relevant sugar moieties in a controlled microenvironment.32,33 In this respect, such carbohydrate–dendrimer conjugates32 are able to interact selectively with several cell receptors, like lectins,34–37 related to infection,38,39 cancer,40,41 immunology,42 or inflammation.22 The number of examples in the literature is large, ranging from sugarcoated dendrimers to dendrimeric wedges composed exclusively of carbohydrates, as detailed in recent reviews.24–32 A striking example has been reported by S. André and coworkers, who reported on the synthesis of lactose-capped wedge-like glycodendrimers40 based on 3,5-di-(2-aminoethoxy)benzoic acid (Figure 20.2). These dendrimers were tested in solid-phase and cell competition binding assays with lactose clusters for different galectins, which are mammalian lactose binding proteins involved in inflammation and tumor metastasis. Potent inhibition and clustering effects were observed for several galectins; for instance each lactose unit of the tetraglycosylated dendron showed up to 1167 times the inhibitory potency of free lactose. These results also confirm the fact that such multivalent interactions depend on interbinding distances and are very sensitive to a spatial arrangement, which results from the branching pattern of the dendrimeric structure.

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Figure 20.2

Lactose-capped dendrons for galectin binding assays

20.3 Antimicrobial Dendrimers Antimicrobial properties refer to compounds that are able to kill or inhibit the development of pathogenic microorganisms. Four main classes of antimicrobial agents are generally considered: antibacterials (antibiotics), antivirals, antiparasitics, and antifungals. These properties may result from detergent properties. This is the case of disinfectants used for topical use or surface treatment, whose action is related to cell-membrane destabilization by insertion of surfactant molecules. As dendrimers have early been considered as unimolecular micelles, charged dendrimers have naturally been assayed as antimicrobial agents. These dendrimers are often polycationic species at physiological pH, and the isolated charged entities generally lack the biological property of the whole structure. The same remark is applicable for polyanionic dendrimers having antiviral properties, which generally act as inhibitors targeting cation-rich viral receptors in a rather nonspecific way. In these cases, the overall structure is responsible for the biological effect and the dendrimer is used as a charged multivalent presenting agent, according to strategies inspired by nature and former observations on polymeric species.43,44 The use of polycationic and polyanionic dendrimers for antimicrobial applications is detailed hereafter, but dendrimeric systems comprising surface functions for which antimicrobial activity has been unambiguously identified, like quaternary ammonium,45,46 boron complexes,47 carbohydrates,33,48 or peptides,49–51 have been omitted. In addition and despite the fact that prions are disease-causing peptides that are neither bacterial nor fungal nor viral and contain no genetic material, we have deliberately chosen for simplification purposes to include in this section cationic dendrimers having antiprion activity.

Unexpected Biological Applications and Specific Multivalency Activities

20.3.1 20.3.1.1

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Polycationic Dendrimers Microbicidal Dendrimers

Polycationic dendrimers are usually and deservedly compared to unimolecular micelles, with a rather lipophilic core and a charged polar surface, and their cytotoxic properties have been rationalized in terms of size and number of positive charges,46,52–54 like other polycationic nanoparticles.55,56 Recently, it has been confirmed that high generation amine-terminated dendrimers (PLL and PEI, generations 5 and 7) can penetrate tissues via the formation of nanoholes in living cell plasma membranes, even at noncytotoxic concentrations.57 Amine-terminated PAMAM dendrimers (generation 3 and 5) exhibited antimicrobial activity against gram negative (Escherichia coli, Pseudomonas aeruginosa) and gram positive (Staphylococcus aureus) bacteria with minimum inhibitory concentrations in the micromolar to submicromolar range.58,59 Interestingly, partial PEGylation of the surface decreased both the antibacterial activity and the cytotoxicity toward human corneal epithelial cells, although it was possible to limit the loss of antibacterial activity with low PEG surface capping. The antimicrobial properties of PAMAM-like hyperbranched polymers can also be transferred to cotton fabrics, as demonstrated recently.60 Samples of cotton fabric and cotton yarns treated with aqueous solutions of PAMAM-like hyperbranched polymers showed good antimicrobial activity against E. coli and S. aureus, even after 20 laundering cycles. Among other improvements, this treatment allowed the dyeing of cotton with anionic dyes in the absence of additional salt, which are used in large amounts to overcome the static repulsions between the anionic dyes and the cotton fibers.60 Recently, the group of S. and R. M. Kannan explored the in vivo antibacterial potential of generation 4 PAMAM dendrimers by topical cervical application in a guinea pig model of chorioamnionitis, an intrauterine infection induced by E. coli.61 As expected from previous reports, an amine-terminated PAMAM dendrimer showed good antibacterial activity (IC50 = 0.27 μM) and a high cytotoxicity toward a human cervical epithelial cell line at concentrations above 0.7 μM, precluding its use for topical application. Unexpected antibacterial properties were observed with hydroxyl-terminated generation 4 (IC50 = 0.38 mM) and COOH-terminated generation 3.5 PAMAM dendrimers (IC50 = 1.7 mM), with reduced cytotoxicity toward the human cervical epithelial cell line, although the cytotoxic properties were assayed at concentrations that were 5 to 20 times lower than the measured IC50. Nevertheless, the hydroxy-terminated PAMAM dendrimer was considered as a good candidate for antibacterial purposes, and the antibacterial mechanism was putatively attributed to polyanionic lipopolysaccharide (LPS) binding in the case of amine-terminated dendrimer, hydrogen bonding with the hydrophilic O-antigens in E. coli membrane in the case of hydroxyl-terminated dendrimer, and divalent ion chelating in the outer-cell membrane of E. coli in the case of acid-terminated dendrimer.61 20.3.1.2 Antiprion Dendrimers The group of S. B. Prusiner first reported on the elimination of prions by branched polyamines in acidic conditions.62,63 Generation 4 PAMAM and PEI dendrimers (Figure 20.3) exhibited in vitro IC50 in the nanomolar range, comparable to those obtained with high molecular weight PEI polymers (MW ∼80 000 Da). This generation-dependent

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Figure 20.3

Reported generation 4 dendrimers with antiprion activity

property was assigned a high surface density of primary amine, and the dendrimermediated PrPSc clearance was supposed to occur in acidic lysosomes of infected neuroblastoma cells.63 Later, the groups of A. M. Caminade and J. P. Majoral and S. Lehmann reported strong antiprion activity in vitro and in vivo on a murine model of a generation 4 PPH dendrimer capped with tertiary amine (Figure 20.3) at noncytotoxic concentrations; this compound even showed a protective effect in vivo against prion infection.64 The group of U. Boas and P. M. H. Heegaard showed that a generation 2 PPI dendrimer capped with guanidinium could perturb peptide fibrillation whereas the same dendrimer lacking the guanidinium groups was found to support fibril formation.65 The implication of positive charges on the dendrimer surface62,63 in the protein destabilization by electrostatic interactions66 was also confirmed on a generation 4 PPI dendrimer terminated with guanidinium groups (Figure 20.3) and compared with urea-terminated PPI dendrimer (generation 4), which was found to be almost not active.67 Spectrofluorimetric and FTIR analysis of the interactions between the PPH dendrimer and prion peptide PrP 185-208 showed that the dendrimer clearly interferes with aggregation processes and fibril formation during the nucleation phase.68 This direct interaction between cationic dendrimers and amyloïd peptides69,70 and the subsequent disruption of existing aggregates was found to be more important with PAMAM dendrimer than with PPI or PPH dendrimers, as demonstrated by an EPR study.71 Additionally, it has been shown that these dendrimers interact with heparin, which is involved in the triggering of

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the amyloïdogenesis.72,73 This interaction could indirectly prevent the formation of fibrils at low dendrimer concentration, in addition to their direct antiaggregation properties. These results suggest that cationic dendrimers could play a significant role in the early stages of infection, thanks to their strong protein denaturing properties66 and their high specificity toward brain-localized fibrils in the nanomolar concentration range,64 as well as their ability to cross the blood–brain barrier (BBB).74 In this regard, a step forward could be realized with the help of glycosylated dendrimers, which offer an attractive alternative to cationic dendrimers. Actually, the group of D. Appelhans has shown that PPI dendrimers capped with a densely packed maltose shell (Figure 20.3) retain their antiprion activity in vitro,75 thanks to nonspecific hydrogen bonding with peptides,76 which is of significant interest considering the reduced toxicity of sugared dendrimers and their enhanced ability to cross the BBB.

20.3.2

Polyanionic Dendrimers

Antimicrobial strategies based on polyanionic dendrimers may originate from two distinct findings. First, anionic disinfectants are micellar systems that can be mimicked by unimolecular, pseudo-micellar, polyanionic dendrimers. This analogy has recently led to the evaluation of bactericidal properties of polyanionic dendrimers and polyanionic amphipathic dendrons that can potentially form giant micellar structures. Second, the study of polyanionic polymers with potential antiviral activity has been a subject of growing interest for forty years,44,77,78 mostly because viral receptors often present cation-rich regions. Several polyanionic antiviral candidates have reached clinical trials, in particular antiHIV1 microbicides,79 whose efficacy is based on the inhibition of gp120 viral glycoprotein.80 Nevertheless, the polyanionic topical microbicide fancy has been recently hampered by several failures during phase III clinical trials, related to the absence of efficacy (sulfonated polysaccharides, PRO-2000, Carraguard), dangerous side-effects at high doses (PRO-2000), or even enhanced HIV1 transmission rates (Ushercell, Nonoxynol-9, Savvy).81 However, the appraisal of these recent shortfalls could open a new perspective for the development of second generation microbicides in a polytherapeutical approach.81,82 In this highly versatile context, polyanionic dendrimers have been early assayed as potential antiviral candidates for the development of topical microbicides, and a leading compound is currently under phase II clinical trials under the trade name VivaGel, whose active ingredient has entry-inhibition and antiretroviral activities.83,84

20.3.2.1

Polyanionic Antibacterial Dendrimers

Despite the fact that several negatively charged amphiphiles are commonly used as disinfectants, by perturbation and disruption of prokaryotic membranes, examples of polyanionic bactericidal dendrimers are scarce. The group of M. W. Grinstaff has developed biodegradable amphiphilic dendrimers based on glycerol and succinic acid, with four carboxylic acids on the surface and one or two alkyl chains at the focal point (Figure 20.4). These compounds have critical aggregation concentrations (CAC) in the submicromolar range and show a better cytotoxic effect against a gram positive bacterium than triton X-100 and SDS (Figure 20.4) used as positive controls. The bactericidal effect was

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Figure 20.4

Biocompatible dendrimer with antibacterial properties

correlated to the formation of supramolecular assemblies and is more selective toward eukaryotic cells (versus prokaryotic cells) than the positive controls.85 Alternatively, dendrimers (generations 1 to 3) based on methylacrylate and ethylenediamine and with a poly(propylenoxide) triamine core (Figure 20.5) have also been assayed toward 13 microorganisms (bacteria, fungi) and show moderate activity. Actually, the starting poly(propylenoxide) triamine is generally more active than the related dendrimers. These results correlate with the loss of antibacterial properties of PAMAM structures when turning from amine end groups to carboxylic acid end groups.61 They also suggest that one of the basic requirements for nonspecific antimicrobial strategies based on polyanionic dendrimers relies on the amphipathic character of the structure that should exhibit tensioactive properties. Nevertheless, the case of SPL7013, a PLL dendrimer capped with sodium-1-(carboxymethoxy)naphthalene-3,6-disulfonate groups with HIV1 inhibition properties, evoked in the next subsection is contradictory with this assessment as it is currently entering phase II clinical trials for bacterial vaginosis,86 one of the most common vaginal infections, which may cause serious complications, such as increased susceptibility to sexually transmitted infections including HIV, and may present other complications for pregnant women. The scarce number of contradictory results reveals a need of further studies as polyanionic dendrimers may propose alternative approaches to circumvent the issue of resistance among bacteria. 20.3.2.2

Polyanionic Antiviral Dendrimers

Dendrimer-based antiviral strategies generally involve dendrimeric structures that inhibit or reduce viral infection by specific or nonspecific interactions with viral components or cell receptors targeted by the viruses.38 In the case of polyanionic dendrimers, most of the work has been devoted to the exploration of anti-HIV1 entry inhibitors, which interact with the V3 loop region of the viral glycoprotein gp120.87 The constant efforts of the Australian company Starpharma to bring to market the first pharmaceutical preparation

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Figure 20.5

493

Poly(propylenoxyde) triamine cored dendrimer (generations 1 and 2)

containing a dendrimer active ingredient have focused most of the attention in this field. The corresponding active dendrimer (SPL7013) is a generation 3 PLL dendrimer with a benzylhydrylamine core and 32 sodium 1-(carboxymethoxy)naphthalene-3,6-disulfonate groups are attached to terminal amino groups through amide bonds (Figure 20.6). This compound has been formulated with a water-based FDA approved gel. The resulting topical microbicide, trademarked Vivagel, has entered phase II clinical trials, 10 years after M. Witvrouw and coworkers had reported the inhibition of HIV replication using sulfonated PAMAM dendrimers, evidenced that gp120 glycoprotein was located at the HIV surface, and proved that the subsequent internalization of the dendrimer was also responsible for dose dependent antiretroviral properties.84 In parallel, N. Bourne and coworkers studied the in vitro activity of a series of PAMAM and PLL dendrimers capped with naphthyl disodium disulfonate or phenyl disodium dicarboxylate via thiourea linkages.88 These compounds were found to be active against herpes simplex virus (HSV) infection. The authors proposed their use as topical microbicides in vivo while their antiviral properties were extended to anti-HIV1 inhibition properties.89 All dendrimers prevented HSV adhesion in vitro but in vivo studies against genital HSV infection in mice highlighted superior activity of a generation 3 PLL dendrimer bearing naphthyl disodium disulfonate. Similarly to its PAMAM analogue, this antiviral PLL dendrimer not only inhibits HSV cell adhesion90 but also later stages of HSV replications.91 Its structure was optimized by replacing the initial thiourea bond by a more stable amide bond,92 and competitive PAMAM

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Dendrimers

Figure 20.6

Structure of SPL7013

and PEI candidates were rejected upon synthetic scaling-up considerations, despite their comparable activities.93 This compound, named SPL7013, has been evaluated in preclinical studies94 to assess its safety in vitro and in model animals, and it entered phase I clinical trials in 2005. An accurate literature survey on the ongoing story of Vivagel can be found in recent reviews, which detail all safety and efficacy studies that have been done to date.83,95,96 Vivagel is now expected to enter expanded safety trials (phase I/II) but the therapeutic issue has shifted to bacterial vaginosis as the main application, along with the prevention of HIV and HSV infection and possibly the prevention of human papillomavirus.86 In parallel to the development of Vivagel, other groups have developed new polyanionic dendrimers that were found to exhibit fairly good anti-HIV1 inhibition in vitro. These examples include generation 5 PPI dendrimers coated with partially sulfated galactose residues97 and PPH dendrimers terminated with various carboxylic and phosphonic acids.98

20.4

From Immunomodulation to Regenerative Medicine

In contrast with the foregoing example inspired by biomimetism or analogy with dynamic supramolecular systems, some dendrimers have revealed peculiar biological applications by chance, in the course of complementary analyses, or simply thanks to tireless curiosity and serendipity. 20.4.1 20.4.1.1

Immunomodulation and Anti-Inflammation Gene Expression Modifications with Carbosilane Dendrimers

Carbosilane dendrimers capped with ethylenediammonium salts have been evaluated for the delivery of antisense oligonucleotides and small interference RNA. Their toxicity was

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evaluated indirectly, and yet in a very sensitive manner, by the global gene expression profiling method, and they were found to induce gene expression modifications in human primary macrophages.1 The altered functions were related to immune response, proliferation, and transcription regulation pathways. In particular, the expression of cytokines involved in autoimmune diseases, like interleukine (IL) 17F, IL23R, and IL23 A, was significantly downregulated, which can be of interest for new therapeutic strategies in this field. 20.4.1.2

Immunosuppressive, Anti-Inflammatory PPH Dendrimers

PPH dendrimers capped with phosphonic acid derivatives is another emerging class of macromolecules with immunomodulatory and anti-inflammatory properties, for which the isolated surface functions totally lack biological activities.99–103 Actually, the group of J. P. Majoral and A. M. Caminade in collaboration with the group of J. J. Fournié and R. Poupot, studied the action of several dendrimers on human peripheral blood mononuclear cells (PBMCs) ex vivo. This systematic survey led to the identification of G1-TamBP, a first generation PPH dendrimer (Figure 20.7) terminated with 12 amino-bis(methylene phosphonic acids) as a natural killer (NK) cell amplifier.2 Complementary analysis of the PBMC subpopulations that could be affected by the dendrimer and eventually play a determinant role in this NK cell amplification revealed that monocytes were activated by the same dendrimer after a short contact time.100 NK cells and monocytes play a key role in the primary steps of an immune response. NK cells are among the first line of defence against all nonself pathogens as part of the innate immune system, and are able to kill foreign organisms like viruses, bacteria, fungi, and parasites, as well as tumor cells. Monocytes are phagocytic cells of the innate immune system, precursors of macrophages that can diffuse into the tissues and organs. They play a pivotal role in the initiation and the control of the response against infection before cells of the adaptative immune system take over. Activation of monocytes by G1-TamBP results in the downregulation of two surface proteins, CD14 and HLA-DR, longer lifetimes in cultures, along with size and granulosity increase, resulting in increased phagocytic activity. Toll-like receptor 2 (TLR2), a typical innate receptor on the surface of monocytes, was identified as one of the mediating receptors100 by Förster resonance energy transfer (FRET) experiments with a fluorescent analog of the hit dendrimer G1-TamBP. Elucidation of the monocyte activation pathway by genomic and proteomic analysis showed that dendrimer G1-TamBP activates human monocytes according to an alternative-like pathway, leading to anti-inflammatory and immunosuppressive dendrimer-activated monocytes.3 These findings open new perspectives for the treatment of uncontrolled inflammatory events in autoimmune diseases. Actually, the ex vivo expansion of NK cells from PBMCs2 induced by this monocyte-activating dendrimer was later correlated to a specific inhibition of the CD4+ lymphocyte compartment, which are prominently proinflammatory monocytes.4 Recent findings of this consortium involving dendrimer chemists and immunobiologists are opening new therapeutic perspectives in the field of inflammatory and autoimmune diseases.104 As exposed above, the action of dendrimer G1-TamBP on monocytes and NK cells results from several direct and indirect interactions with several subpopulations of PBMCs. Such events are regulated by a subtle balance between dendrimer-induced activating and

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Dendrimers

Figure 20.7 G1-TamBP

Tyramine-derived aminobis(methylenephosphonic acid) PPH dendrimer

deactivating signals among these subpopulations. Moreover, all biological tests to assess the effect of dendrimer candidates are performed ex vivo on PBMC aliquots that exhibit significant response variability from one donor to another. In this context, a quantitative structure–activity relationship can hardly be predicted as there is no well-defined process to describe the biological activities; the structure optimization was thus based on a dendrimer structure analysis. Key structural parameters of the hit dendrimer G1-TamBP, i.e. the chemical nature of surface functions, size and generation, the chemical nature of the dendritic skeleton, and the density of the functional outer shell, were varied and optimized independently and sequentially. A large variety of surface functions was assayed, including neutral surfaces, cationic entities, and acids100 such as functionalized phosphonic acids, amino-phosphonic acids, amino-bisphosphonic acids,103 and isosters of the surface function of the dendrimer hit.102 The generation was optimized in preliminary studies and set to generation 1.100 The influence of the chemical nature of the dendrimer ’s skeleton was analyzed by comparing the activities of PAMAM, PEI, PLL, carbosilane, thiophosphate,

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Figure 20.8 Evaluating the effects of PPH dendrimers on PBMCs

and several PPH-like dendrimers having roughly the same size and the same number of identical surface functions.105 Finally, optimization of the local density of the outer shell was performed independently on PPH structures having the same size and a controlled number of surface functions by selective locking reactions on the hexafunctionnal core of PPH dendrimers.101 The integrated project aiming at the evaluation of the effects of PPH dendrimers on PBMCs ex vivo (Figure 20.8) has led to new strategies for autoimmune diseases and clinically relevant NK-based cell therapies based on the outgrowth of NK cells, as described in Section 20.4.2.1. 20.4.1.3 Anti-Inflammatory PAMAM Dendrimers While studying the drug delivery of indomethacin, the groups of N. K. Jain and D. A. Tomalia have shown that PAMAM dendrimers have unexpected anti-inflammatory properties in the absence of the indomethacin anti-inflammatory drug.106 Series of generation 4 and generation 4.5 PAMAM dendrimers capped with unsophisticated surface functions (Figure 20.9) were assayed in three in vivo anti-inflammatory assay methods: (i) the carrageenan-induced paw edema model, (ii) the cotton pellet test, and (iii) the adjuvantinduced arthritis assay in rats.

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Dendrimers

Figure 20.9

PAMAM dendrimers assayed for their intrinsic anti-inflammatory properties

Hydroxy and amine-capped PAMAM dendrimers were more efficient than carboxylic acid-capped PAMAM to reduce inflammation. Amine-terminated dendrimers even surpassed free indomethacin.106 Even in the absence of rationale, these observations could lead to new strategies to fight inflammatory processes. These results actually corroborate previous studies by S. Shaunak and coworkers, who reported on the anti-inflammation properties of a generation 4.5 PAMAM partially coated with glucosamine (ca. 9 glucosamine conjugates out of 64 carboxylic acids).22 These properties were clearly associated to immunomodulatory properties, as indicated by the inhibition of the synthesis of proinflammatory cytokines and chemokines following LPS activation of human dendritic cells and macrophages, and the upregulation of membrane receptors or coreceptors associated with an anti-inflammatory response. These anti-inflammatory properties, conjugated to the antiangiogenic properties evoked above (see Section 20.2.1), were responsible for efficient prevention of scar tissue formation following glaucoma filtration surgery in a clinically relevant rabbit model. 20.4.2

Dendrimers and Regenerative Medicine

Regenerative medicine encompasses the use of ex vivo cultured cells and the creation of living and functional tissues, possibly with these cultured cells, to repair damaged tissues or organs. This relatively new field of research at the frontier of medicine and biotechnology is now counted with the multivalency-associated properties that dendrimers can add, as pointed out by pioneering results obtained by the group of Grinstaff107 and by the increasing number of publications related to this issue.108,109 Actually, recent strategies for tissue-engineering scaffolds are gradually shifting from hydrolytically degradable biomaterials to nano-organized biomaterials that mimic the extracellular matrix (ECM), which is now considered as a multifunctional nanocomposite,110 essentially composed of collagen and proteoglycans. 20.4.2.1

From Dendrimer-Based Scaffolds for Cell Culture to Corneal Sealants

Strategies currently developed to prepare dendrimer-based scaffolds or media for cell culture include: (i) dendronization of surfaces, (ii) modification of surfaces by layer-by-

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Figure 20.10

499

Dendrimer-based scaffolds for cell culture

layer (LBL) deposition of dendrimers, and (iii) biocompatible dendrimer-containing hydrogels (Figure 20.10). These studies generally aim at developing substrates or adjuvant components that may promote the proliferation of cells involved in tissue reconstruction (corneal, dental, epithelial, neuronal cells, etc.). Glutaraldehyde and tris(2-aminoethyl)amine have been used to grow hyperbranched polyazomethines from activated polystyrene cell culture plates in a stepwise fashion. Surface modification of the multivalent surface was achieved with the tripeptide growth factor, glycyl-L-histidyl-L-lysine (GHK),111 or fructose112 for the culture of rat hepatoma cells as a model substrate for a bioartificial liver support system. Viable and proliferative cells were found to adhere to amine-terminated hyperbranched polymers and cells cultivated on the higher generation fructose-modified hyperbranched polymers produced more urea, which traduces a better metabolic condition and reduced apoptosis.113 Alternatively, surface modification of these polyazomethines with D-glucose allowed the enhancement of adhesion properties of epithelial cells, in particular at high generations. The authors also observed morphological changes that were related to the roughness of the glycosylated surface.114 This stepwise surface modification is hardly compatible with a complete characterization of the dendrimeric structure which is grown, and undesired crosslinking and bridging reaction are expected with the use of nonorthogonal reactants such as glutaraldehyde and tris(2-aminoethyl)amine. In contrast, dendronized surfaces have been prepared by modification of gold-coated silicon wafers with hydroxy-terminated dendrons having a thiol function at the focal point, which were later modified with PEG chains on the surface.115 The surface dendronization enhanced the adhesion of human corneal epithelial cells and mouse 3T3 fibroblasts in comparison with naked gold surfaces or gold surfaces treated with linear PEG chains, although cell adhesion and proliferation were significantly reduced with PEG-terminated dendrons. Multilayer structures stabilized by multiple electrostatic interactions are an attractive alternative for surface coating.116 In this regard, oppositely charged PPH dendrimers have been used alone or in combination with oppositely charged linear polymers to coat silicon wafers covalently modified with 3-aminopropyltriethoxysilane. Cation-terminated coatings were slightly more efficient than anion-terminated films to promote adhesion and maturation of fetal cortical rat neurons.117 Alternatively, the group of Grinstaff developed dendrimer-based hydrogels as scaffolds for the culture of chondrocytes, which are the only cells present in cartilage and which are responsible for its production and maintenance. The strategy is based on photocrosslinkable macromomers consisting of a PEG chain terminated at each extremity with

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Dendrimers

Figure 20.11

Photocurable PEG–PGLSA bisdendron for ostechondral and corneal repair

small biodegradable poly(glycerol succinic acid) (PGLSA) dendrimers ended with methacrylate functions (Figure 20.11).118 Crosslinking reactions were performed in PBS solution containing 7.5 to 20% (w/w) of these macromonomers, triethanolamine (40%), and an eosine-based photoinitiator under visible light. This allowed the encapsulation of condrocytes, which were found to accumulate an abundant ECM containing collagen and proteoglycans, which spread abundantly in gels formed with low percentages of macromonomers. The mimicking of nanostructured collagen-rich ECM with hydrogels based on crosslinked dendrimers is closely related to the advances of these multivalent structures in the field of corneal sealing.119,120 Actually, corneal tissue is mainly composed of collagen, and the biocompatible dendrimeric systems described above have been used to seal corneal lacerations ex vivo by in situ photopolymerization.121,122 The same systems were also successfully tested in vivo for osteochondral repair, as demonstrated by good biocompatibility, good attachment to osteaochondral defects, and the presence of proteoglycans and collagen, which traduced the metabolic activity of chondrocytes that infused into the implanted gels.123 In a modified approach, dendrons have been used as in situ cogelators to secure corneal incisions.124 The gelating system comprises PEG dialdehydes and small lysine-based dendrons terminated with cysteine residues. Reticulation of saline solutions containing up to 50% (w/w) of gelators is obtained in three minutes at room temperature by peptide ligation and formation of thiazolidine linkages. Interaction with corneal tissue may involve cysteine groups of endogenous peptides, resulting in enhanced mechanical resistance of corneal incisions sealed with these gels and fastened corneal transplant healing.125 Alternative crosslinking systems based on amine-terminated PLL bisdendrons with a PEG core and a PEG diactivated ester have also proved to be efficient corneal sealants.126 The interface between dendrimer-based sealing hydrogels and collagen of the corneal ECM has also been studied by the group of H. Sheardown. In early model systems, collagen has been crosslinked with small amine-terminated PPI dendrimers by activation of the glutaric and aspartic acid residues of collagen and subsequent peptide formation with 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (EDC).127 The resulting crosslinked biomaterial exhibited suitable mechanical properties and was used as a substrate for adhesion and proliferation of human epithelial cell. It was found to be less toxic than glutaraldehyde-crosslinked collagen, used as a reference substrate. The system was later refined with carboxylic acid-

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terminated PPI dendrimers in order to graft laminine-based cell-adhering peptides, which promoted the adhesion of corneal epithelial and neuronal cells.128 Finally, the multivalency of dendrimers has been used efficiently to crosslink cells. Intercellular linking is currently being studied to generate cell aggregates that may be used as tissue precursors or building blocks for organ engineering, which require denser networks of cells than soft tissue engineering. In this context, PEI dendrimers capped with hydrazides129 or oleyl-functionalized PEG chains130 have been used for cell aggregation through covalent linkages or by insertion of alkyl chains in the cell membrane respectively. 20.4.2.2

Dendrimer-Boosted Cell Cultures for Cell-Based Therapies

The dendrimer G1-TamBP (Figure 20.5) mentioned in Section 20.4.1.2 was early identified as a specific NK cell amplifier.2 Actually, the addition of G1-TamBP to cultures of PBMCs supplemented with interleukin-2 (IL2) growth factor led to a dramatic increase in the percentage and number of NK cells, reaching a mean multiplication of 105 times in PBMC medium supplemented with G1-TamBP and IL2, whereas a mean multiplication of 7.5 times was achieved in medium supplemented only with IL2. These experiments conducted ex vivo are significantly blood-donor dependent and multiplications of 500 times were obtained with some donors. Importantly, the bioactivity of mature NK cells generated with the phosphonic acid-modified PPH dendrimer is not modified, contrarily to NK cells activated with specific ligands like NKG2D triggering ligands.131 This normal functionality has been evaluated by measuring the activity of dendrimer-expanded NK cells toward cancerous target cells and the absence of autologous cytotoxicity. In parallel with the structure optimization studies conducted for both monocyte activation (see Section 20.4.1.2) and NK cell amplification, the mechanism of action of the lead compound has recently been partially uncovered. Actually, it has been shown that the NK cell amplification results indirectly from the specific inhibition of T-CD4+ lymphocytes in PBMC cultures4 and that the activation of monocytes may participate in the triggering of the amplification of NK cells, as monocyte-free PBMCs or isolated NK cells cultivated with IL2 and G1-TamBP did not result in cell expansion.

20.5

Conclusion and Perspectives

The unique topological and chemical features of dendrimers have led to the development of dendrimer-based strategies based on the rational use of these versatile architectures for the design of multitask nanodevices. Beside this rationalized and predictable scaffold approach, which is concerned with multivalency mainly through multifunctionalization and additive effects, some dendrimeric structures have revealed unexpected properties, which cannot be uniquely related to the pivotal concept of multivalent effect but rather result from the unique size and structures of the corresponding dendrimers. Obviously, the question of multivalent effects has been addressed elegantly and efficiently with dendrimers, and in many cases dendrimer effects unexpectedly overwhelmed predicted multivalent effects. All these observations, resulting both from the rational design of multivalent

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Dendrimers

ligands inspired by known metabolic events and from serendipity, are opening up new perspectives for critical therapeutic issues. For instance, anticancer treatments could benefit from the recently disclosed antiangiogenic properties of a native PLL dendrimer or from the cell-boosting properties of a phosphonic acid-capped PPH dendrimer. The field of inflammation is also strongly concerned with possible breakthroughs by the discovery of unexpected anti-inflammatory and immunomodulation properties of several PAMAM dendrimers and phosphonic acid-capped PPH dendrimers.132 The mechanisms responsible for these properties remain unclear, despite accurate proteomic and genomic analysis in some cases, and the identification of receptors is expected to accelerate the examination of dendrimers as drug candidates and possibly to reveal new insights into biological properties associated with the targeted diseases.

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(106) A. S. Chauhan, P. V. Diwan, N. K. Jain, and D. A. Tomalia (2009) Unexpected in vivo antiinflammatory activity observed for simple, surface functionalized poly(amidoamine) dendrimers. Biomacromolecules, 10, 1195–1202. (107) M. W. Grinstaff (2002) Biodendrimers: new polymeric biomaterials for tissues engineering. Chem. Eur. J., 8, 2838–2846. (108) J. M. Oliveira, A. J. Salgado, N. Sousa, J. F. Mano, and R. L. Reis (2010) Dendrimers and derivatives as potential therapeutic tool in regenerative medicine strategies – a review. Prog. Polym. Sci., 35, 1163–1194. (109) N. Joshi and M. Grinstaff (2008) Applications of dendrimers in tissue engineering. Curr. Top. Med. Chem., 8, 1225–1236. (110) M. Goldberg, R. Langer, and X. Q. Jia (2007) Nanostructured materials for applications in drug delivery and tissue engineering. J. Biomater. Sci. – Polym. Ed., 18, 241–268. (111) M. Kawase, N. Kurikawa, S. Higashiyama, N. Miura, T. Shiomi, C. Ozawa, T. Mizoguchi, and K. Yagi (1999) Effectiveness of polyamidoamine dendrimers modified with tripeptide growth factor, glycyl-L-histidyl-L-lysine, for enhancement of function of hepatoma cells. J. Biosci. Bioengng, 88, 433–437. (112) M. Kawase, N. Kurikawa, N. Miura, T. Shiomi, C. Ozawa, S. Higashiyama, T. Mizoguchi, and K. Yagi (2000) Immobilization of ligand-modified polyamidoamine dendrimer for cultivation of hepatoma cells. Artificial Organs, 24, 18–22. (113) M. Kawase, T. Shiomi, H. Matsui, Y. Ouji, S. Higashiyama, T. Tsutsui, and K. Yagi (2001) Suppression of apoptosis in hepatocytes by fructose-modified dendrimers. J. Biomed. Mater. Res., 54, 519–524. (114) M. H. Kim, M. Kino-Oka, M. Kawase, K. Yagi, and M. Taya (2007) Response of human epithelial cells to culture surfaces with varied roughnesses prepared by immobilizing dendrimers with/without D-glucose display. J. Biosci. Bioengng, 103, 192–199. (115) S. R. Benhabbour, H. Sheardown, and A. Adronov (2008) Cell adhesion and proliferation on hydrophilic dendritically modified surfaces. Biomaterials, 29, 4177–4186. (116) G. Decher (1997) Fuzzy nanoassemblies: toward layered polymeric multicomposites. Science, 277, 1232–1237. (117) J. L. Hernandez-Lopez, H. L. Khor, A. M. Caminade, J. P. Majoral, S. Mittler, W. Knoll, and D. H. Kim (2008) Bioactive multilayer thin films of charged N,N-disubstituted hydrazine phosphorus dendrimers fabricated by layer-by-layer self-assembly. Thin Solid Films, 516, 1256–1264. (118) S. H. M. Sontjens, D. L. Nettles, M. A. Carnahan, L. A. Setton, and M. W. Grinstaff (2006) Biodendrimer-based hydrogel scaffolds for cartilage tissue repair. Biomacromolecules, 7, 310–316. (119) M. W. Grinstaff (2007) Designing hydrogel adhesives for corneal wound repair. Biomaterials, 28, 5205–5214. (120) M. C. Wathier, M. A. Carnahan, P. J. Jung, T. Kim, and M. W. Grinstaff (2005) Dendrimer hydrogels as new alternative for the repair of clear corneal incisions. Investigative Ophthalmology and Visual Science, 46, abstract 4993. (121) M. A. Carnahan, C. Middleton, J. Kim, T. Kim, and M. W. Grinstaff (2002) Hybrid dendritic– linear polyester-ethers for in situ photopolymerization. J. Am. Chem. Soc., 124, 5291–5293. (122) L. Degoricija, C. S. Johnson, M. Wathier, T. Kim, and M. W. Grinstaff (2007) Photo crosslinkable biodendrimers as ophthalmic adhesives for central lacerations and penetrating keratoplasties. Investigative Ophthalmology and Visual Science, 48, 2037–2042. (123) L. Degoricija, P. N. Bansal, S. H. M. Sontjens, N. S. Joshi, M. Takahashi, B. Snyder, and M. W. Grinstaff (2008) Hydrogels for osteochondral repair based on photocrosslinkable carbamate dendrimers. Biomacromolecules, 9, 2863–2872. (124) M. Wathier, P. J. Jung, M. A. Camahan, T. Kim, and M. W. Grinstaff (2004) Dendritic macromers as in situ polymerizing biomaterials for securing cataract incisions. J. Am. Chem. Soc., 126, 12744–12745. (125) M. Wathier, C. S. Johnson, T. Kim, and M. W. Grinstaff (2006) Hydrogels formed by multiple peptide ligation reactions to fasten corneal transplants. Bioconjugate Chem., 17, 873–876.

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(126) M. Wathier, M. S. Johnson, M. A. Carnahan, C. Baer, B. W. McCuen, T. Kim, and M. W. Grinstaff (2006) In situ polymerized hydrogels for repairing scleral incisions used in pars plana vitrectomy procedures. ChemMedChem, 1, 821–825. (127) X. Duan and H. Sheardown (2006) Dendrimer crosslinked collagen as a corneal tissue engineering scaffold: mechanical properties and corneal epithelial cell interactions. Biomaterials, 27, 4608–4617. (128) X. D. Duan, C. McLaughlin, M. Griffith, and H. Sheardown (2007) Biofunctionalization of collagen for improved biological response: scaffolds for corneal tissue engineering. Biomaterials, 28, 78–88. (129) D. Q. Zhao, S. M. Ong, Z. L. Yue, Z. Y. Jiang, Y. C. Toh, M. Khan, J. H. Shi, C. H. Tan, J. P. Chen, and H. R. Yu (2008) Dendrimer hydrazides as multivalent transient inter-cellular linkers. Biomaterials, 29, 3693–3702. (130) X. Mo, Q. Li, L. W. Yi Lui, B. Zheng, C. H. Kang, B. Nugraha, Z. Yue, R. R. Jia, H. X. Fu, D. Choudhury, T. Arooz, J. Yan, C. T. Lim, S. Shen, C. Hong Tan, and H. Yu (2010) Rapid construction of mechanically-confined multi-cellular structures using dendrimeric intercellular linker. Biomaterials, 31, 7455–7467. (131) A. Moretta, C. Bottino, M. Vitale, D. Pende, C. Cantoni, M. C. Mingari, R. Biassoni and L. Moretta (2001) Activating receptors and coreceptors involved in human natural killer cellmediated cytolysis. Ann. Rev. Immunol., 19, 197–223. (132) M. Hayder, M. Poupot, M. Baron, D. Nigon, C. O. Turrin, A. M. Caminade, J. P. Majoral, R. A. Eisenberg, J. J. Fournié, A. Cantagrel, R. Poupot, and J. L. Davignon (2001) A phosphorus-based dendrimer targets inflammation and osteoclastogenesis in experimental arthritis. Science Trans. Med., 3, 81ra35.

21 General Conclusions and Perspectives Anne-Marie Caminade

Treasures of imagination have been developed for years for the synthesis of dendrimers and of highly sophisticated dendrimeric structures. The field of synthesis is now mature, but there is still room for searching for improved methods, in particular for diminishing the time needed at the bench. Indeed, the main problem associated with dendrimers, which hampers part of their practical uses, is their cost due to their step-by-step synthesis. Nevertheless, the step-by-step synthesis is also an advantage over all other types of polymers, which ensures the purity and the reproducibility of the samples of dendrimers. Most early studies of dendrimers dealt with the discovery and understanding of their intrinsic physicochemical properties, which in some cases has evolved towards practical applications. This is, for instance, the case of fluorescent dendrimers, which were first synthesized for photophysical studies and for sensing their internal structure, but which have later found more practical uses such as the elaboration of light-emitting diodes (OLEDs) but also for imaging biological media or organisms. As the years went by, three main applications of dendrimers have emerged, concerning the fields of catalysis, materials, and biology. Most examples of uses of dendrimers as catalysts have emphasized properties that resemble those of homogeneous catalysis (dendrimers are generally soluble in the reaction media), together with those of heterogeneous catalysis (the dendrimers are often easy to recover and reuse, due to their large size). In addition to these expected properties, a positive “dendrimer effect” (nonlinear increased efficiency or selectivity of the catalysis when the generation of the dendrimer increases) has been observed from time to time. This effect presumably arises from a high local concentration of catalytic entities, either on the surface of the dendrimer or inside its structure. Several approaches have also been developed to prepare supported dendrimeric catalysts, with the aim of mimicking homogeneous

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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catalysis, but with insoluble supports. In these cases, the dendrimer acts as a spacer to take the catalytic sites away from the solid surface. A lot of work is currently being devoted to catalysis with dendrimers; some practical uses in academic laboratories can be foreseen, but industrial uses of such compounds have still to be found. It must be emphasized that changing industrial processes is highly costly, thus only major improvements in cost/ efficiency/energy/wastes can lead to changes of the processes. Substantial progress has still to be made with catalytically active dendrimers to fulfill these criteria. In the field of materials, incorporation of dendrimers inside materials has produced results for obtaining hydrogels or organogels, and also for the elaboration of OLEDs (frequently named DLEDs, for dendrimer light-emitting diodes). Some devices have shown interesting properties, but these do not encompass those of more classical OLEDs. A large amount of work has been devoted to the modification of the surface of materials at the nanometric scale by a monolayer (or multimonolayers) of dendrimers, either covalently linked or deposited by electrostatic interactions. Such devices were often elaborated with the aim of using them as chemical or biological sensors. In both cases, the presence of the dendrimers increases the sensitivity of the device, generally for the same reasons as those evoked for heterogeneous catalysis: the dendrimers avoid contact of the analyte with the solid surface, thus ensuring that the interaction probe/target can occur as well as in solution. In the case of chemical sensors, the detection of volatile organic compounds (such as solvents) was in particular carried out, as well as the detection of explosives (such a TNT) or of chemical warfare agents (toxic nerve agents), which have been detected at the nanomolar concentration level. These devices are promising and should be developed. The elaboration of biosensors concerns essentially biomicroarrays, in particular for the detection of DNA or of proteins. In the first case, the dendrimers allow the hybridization to occur as in solution and, in the second case, the dendrimers isolate the protein from the solid surface, preventing its denaturation. It is important to note that microarrays elaborated with PAMAM dendrimers are used for the detection of certain protein biomarkers that are generated by a heart attack, and have been used in USA hospitals since 1998. Very recently, biochips elaborated with phosphorus (PPH) dendrimers have led to the creation of a start-up that proposes diagnosis solutions for analytical laboratories in health, agrofood and the environment. Such properties are connected to the field of biology/medicine, which is certainly the most promising one to date. This may appear surprising for these non-natural compounds, which have no structural equivalent among biomolecules. Results recently obtained for imaging of cells, tumors, or blood vessels with (fluorescent) dendrimers have led in some cases to a dramatic increase in animal survival, particularly in the case of surgery of tumors stained with a fluorescent dendrimer. Another biological property, which has been recognized very early, concerns gene transfection with positively charged dendrimers. An important amount of knowledge has been generated for understanding the criteria that positively influence the transfection efficiency, the cytotoxicity, and the stability. First attempts concerned DNA and plasmids, while more recent attempts concerned siRNA. Even if the efficiency is by several orders of magnitude lower than that of inactivated viruses, dendrimers are among the most efficient chemical agents for transfection, including “fractured” dendrimers, which are commercially available under the name SuperFect™.

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Transfection experiments constitute the beginning of the use of dendrimers for drug delivery. Numerous attempts have been done in particular for anticancer therapies. Such strategies necessitate a targeting agent, in addition to the drug to be delivered. Two different strategies were proposed based on dendrimeric platforms. A well-defined dendrimer can be synthesized, often of type Janus, which is with two different terminal functions located in two different areas of the surface of the dendrimeric species, in particular a drug and targeting entity. Such compounds are generally lengthy and difficult to synthesize, but the advantage is a perfectly defined and highly reproducible structure. A more straightforward approach consists in the statistical grafting of different types of functions on a dendrimer platform. This approach is less time-consuming, allows several types of combinations to be produced rapidly, including a drug, a targeting function, a marker (generally fluorescent), and eventually stealth entities such as PEG chains. Obviously, the main inconvenience of this approach is the polydispersity inside each batch and the average reproducibility between batches. A way to manage to combine both approaches will consist in synthesizing well-defined dendrimers for which the structure will have been identified as a lead through the screening done with statistically functionalized dendrimers. However, the question of the release of the drug is important, because the grafting to the dendrimer may decrease or annihilate the efficacy of the drug. Both in the case of transfection and drug delivery, the biodistribution, the toxicity, and the pharmacodynamics of the dendrimers have to be studied. In an attempt to avoid problems eventually associated with these issues, self-immolative/cleavable/biodegradable dendrimers have been proposed. Another type of drug delivery consists in the noncovalent encapsulation of drugs inside dendrimers. The advantage is that the drug is nonmodified, but the problem is to keep it inside the dendrimer before the “vehicle” dendrimer + drug has attained the target and then to deliver it; such properties are generally triggered by pH. Topical applications of such systems are less constraining and should be developed. A final type of biological properties of dendrimers is those discovered by serendipity, which emphasize the role played by the multivalency of dendrimers. Indeed, some examples are known in which a monomeric function has no particular properties, whereas it becomes very active when linked (and multiplied) on the surface of a dendrimer. This effect is reminiscent to the dendrimer effect observed from time to time for catalysis with dendrimers. In biology, it has been observed essentially up to now in interaction with the human immune system, with the discovery of immunomodulation properties and antiinflammatory properties, observed in some cases of PAMAM dendrimers and PPH dendrimers. The state of the art about dendrimers and dendrimeric species demonstrates that many recent and important properties are observed at the frontier between several scientific disciplines, by association of chemists with physicists, with theoreticians, with biologists, and even with medicine doctors. However, all the applications of dendrimers, at least in the next forthcoming years, should necessitate only small quantities of dendrimers, due to their cost. That is the reason why properties of dendrimers for catalysis, in particular with recycling experiments for sensors obtained by the modification of solid surfaces of materials at the nanometric scale and for drug delivery or as drugs by themselves for which the cost is less important, should be mainly developed. For applications in bulk, for instance in the field of materials in which highly defined compounds are not necessary,

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hyperbranched polymers generally synthesized in one step appear to be more suitable than dendrimers. Dendrimers pertaining to the “nanoworld”, by virtue of their size, the present concerns/ warnings associated to nanoparticles, and the forthcoming regulatory directives concerning their use and dissemination, may have to be taken into account. However, there are several fundamental differences between dendrimers and “classical” nanoparticles (NPs). (i) The dendrimers are constituted of soft matter, whereas the NPs are generally constituted of hard matter, often metallic (or carbon nanotubes). (ii) The second difference concerns the purity and reproducibility of the samples. A sample of dendrimers contains only one type of molecule, which is well defined. In the case of NPs, a mean diameter can be given, but there are differences in the number of metallic atoms associated with each NP. (iii) The third difference concerns the modification of size and shape. Dendrimers, being constituted of soft matter, are sensitive to the media in which they exist, and, for instance, are generally flattened when interacting with a solid surface; such a phenomenon does not occur with NPs. (iv) The fourth difference concerns the stability. In “normal” conditions, a dendrimer has a stable chemical composition; in the same conditions, nanoparticles may suffer from an exchange of metallic atoms, which occurs in particular when weak ligands stabilize the NPs. For all these reasons, I strongly believe that despite their nanometric size, dendrimers should not be considered as nanoparticles, but as molecules. This means that any toxicity issue that may arise should never be associated with dendrimers in general, but only with the one or with those that were tested.

Index

α-hydrazination reactions 199–200 AAO see anodic aluminum oxide accelerated syntheses 26–9 aceclofenac 473 activatable cell penetrating peptides (ACPP) 407 adamantylurea-terminated dendrimers 364 addition reactions C=C double bonds 192 C=X double bonds 175–7, 186, 204–9 diethylzinc 201–3 adenosine triphosphate (ATP) 365–6 adriamycin 110 AFM see atomic force microscopy AIBN see azobisisobutyronitrile ALA see 5-aminolevulinic acid aldolizations 199, 209 aliphatic poly(ester) dendrimers 12 alkylsilanes 327 alkylthiols 327–30 allylic alkylations 198 allylic aminations 170–1, 191–2, 198, 217–18 alumina nanoparticles 247–8 aluminosilicates 129 ambidextrous gelators 271 AMINAP ligands 208 amino acids encapsulation into materials 278–9 liquid crystalline dendrimers 129 stimuli-responsive dendrimers 110

aminoadipate dendrimers 443–4 aminobenzamide linkages 85–6 aminobis(methylenephosphonic acid) dendrimers 495–6 5-aminolevulinic acid (ALA) 449–50 (3-aminopropyl)dimethoxysilane (APDMES) 336, 339–40, 343 (3-aminopropyl)triethoxysilane (APTES) 331 1,2-aminosulfonamidecyclohexane core ligands 230–1 amphiphilic dendrimers encapsulation into materials 279 liquid crystalline 129 self-assembly dendrimers 320–1, 323, 333, 343 stimuli-responsive dendrimers 112 ANBB see assembly of nano building blocks anionic polymers see polyanionic dendrimers anodic aluminum oxide (AAO) membranes 339–40 anti-Stokes Raman spectroscopy 42–3 antibacterial dendrimers 491–2 anticancer drugs 440–9, 466–9, 476 anti-inflammatory dendrimers 485, 487, 494–8, 513 anti-inflammatory drugs 438–9, 471–2

Dendrimers: Towards Catalytic, Material and Biomedical Uses, First Edition. Anne-Marie Caminade, Cédric-Olivier Turrin, Régis Laurent, Armelle Ouali and Béatrice Delavaux-Nicot. © 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.

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Index

antimicrobial dendrimers 488–94 antimicrobial drugs 469–71, 475–6 antimicrobial nanoparticles 154 antiprion dendrimers 489–91 antisense oligonucleotides 420 antiviral dendrimers 492–4 APDMES see (3-aminopropyl) dimethoxysilane apoptosis 447–8 APTES see (3-aminopropyl) triethoxysilane aqueous catalytic media 221–34 ara-C see cytosine arabinose arborols 7–8 artemether 469–70 assembly of nano building blocks (ANBB) 285 atomic force microscopy (AFM) 45, 49–50 biological sensors 384–5 nanoparticles 145 self-assembly dendrimers 317–20, 324–6, 328, 333–4, 342–3, 345–50 ATP see adenosine triphosphate avidin–biotin association 329, 401 Aza–Morita–Baylis–Hillmann reactions 209–10 azobenzene-containing dendrimers characterization methods 39, 43 photoresponsivity 99, 100, 101–8 self-assembly dendrimers 320–1 azobisisobutyronitrile (AIBN) 188 β-cyclodextrin 330, 346–8 11 B NMR 38–9 background fluorescence 86 bacterial growth 154 Baeyer–Villiger reaction 250 BAM see Brewster angle microscopy base pairing 24–5 Baylis–Hillman reaction 188, 217–18, 253 BBB see blood-brain barrier BCEC see brain capillary endothelial cells benzene linkages 84–5 benzoylations 198–9 beta-blockers 439–40

betamethasone valerate 114–15 bimetallic dendrimer-encapsulated nanoparticles 153–4 BINAP see 2,2'-bis(diphenylphosphino)-1, 1-binaphthylene binaphthol (BINOL) 201–3, 257–8, 363 bioavailability 438–40, 464–5 biological sensors 375–92, 512 applications 383, 386–7 DNA microarrays 375, 380–3 electrochemical detection 378–80 multiply labeled dendrimers 385–6 non-DNA microarrays 383–4 solutions of biological media 375–8 support types 384–5 biological warfare agents 376 biomedical applications anti-inflammatory dendrimers 485, 487, 494–8 antimicrobial dendrimers 488–94 catalysis 215 encapsulation of dendrimers 272, 274 glycodendrimers 487–8 immunomodulation 485, 494–8 luminescent dendrimers 70–2, 88, 90 multivalent effects 486–8 nanoparticles 146–7, 154–5 novel applications 485–509 polyanionic dendrimers 488, 491–4 polycationic dendrimers 489–91 regenerative medicine 498–501 stimuli-responsive dendrimers 111–12 see also contrast agents; drug delivery; transfection agents biomimics 166, 190, 224–5, 234 biosensors 323 biotin–avidin association 329, 401 biphasic catalytic media 216–19 bis(diphenylphosphine)-core dendrimers 184, 186 bis(diphenylphosphine)-terminated dendrimers 170–1 2,2’-bis(diphenylphosphino)-1, 1-binaphthylene (BINAP) ligands 204–6, 208, 218–19

Index

3,4-bis(diphenylphosphino)pyrrolidine ligands 205–7 2,2’-bis(diphenylphosphinoxy)biphenyl ligands 204–5 bis-HMPA see 2,2-bis(hydroxymethyl) propanoic acid 2,2-bis(hydroxymethyl) propanoic acid (bis-HMPA) 444–5 bis(oxazoline) ligands 200, 204–5, 232, 258 bithiophenesilane dendrons 322 blood–brain barrier (BBB) 417, 439, 476, 491 BNCT see boron neutron capture therapy BODIPY-labeled conjugates 417 bola-amphiphiles 270 bonded active ingredients 437–8 boranes 208 boron-containing dendrimers 38–9 boron neutron capture therapy (BNCT) 438, 451–2 botulinum toxoid 376 bow-tie dendrimers 442–4, 445 box nanocrystals 144–5 brain capillary endothelial cells (BCEC) 417 branching units catalytic applications 183, 191–2 liquid crystalline dendrimers 126–8, 134–5 brevotoxin B 380 Brewster angle microscopy (BAM) 318, 323 13

C NMR 36–7, 40 C–C bond formation 197, 209–10 C=C double bond addition reactions 192 C–X bond formation 167–77, 184–6, 188–90, 191–2, 197, 198–203, 209 C=X double bond addition reactions 175–7, 186, 204–9 CAC see critical aggregation concentrations cadmium sulfide/selenide nanoparticles biological sensors 385–6 chemical sensors 368

517

dendrimer coated 143–5, 149 encapsulation of dendrimers 280, 285, 287–8 calix[4]arenes, stimuli-responsive dendrimers 107 CAM see chorioallantoic membrane camptothecin 116 capillary electrophoresis 53 carbazole-containing dendrimers 291, 294, 297, 317 carbenes 173 carbohydrate–dendrimer conjugates 487–8 carbon-based dendrimers 17–19 carbon dioxide, supercritical 220–1 carbon nanotubes (CNT) 369–70, 380 carbosilane dendrimers see poly(carbosilane) dendrimers carbosilazane dendrimers 131 carteolol 472 cascade structures 5 cascading destruction 116 caspase 447–8 CAT see computerized axial tomography catalytic applications 511 addition reactions on C=C double bonds 192 addition reactions on C=X double bonds 175–7, 186, 204–9 aqueous media 221–34 branching units 183, 191–2 C–C bond formation 197, 209–10 C–X bond formation 167–75, 184–6, 188–90, 191–2, 197, 198–203, 209 characterization methods 39 core-functionalized dendrimers 183, 184–90 cross-coupling reactions 167–72 dendrimer effect 165–6 dendrons synthesized from solid material 240–54 dendrons/dendrimers grafted onto solid surfaces 254–7 enantioselectivity 197–213, 216–17, 219, 233–4 heterogeneous catalysis 239–65 insoluble dendrimers 257–60

518

Index

catalytic applications (Cont’d) internal functionalization 183–95 ionic liquids 219–20 metathesis 172–3 miscellaneous reactions 174–5, 188 nanoparticles 149, 152, 153–4 oligomerizations and polymerizations 173–4 organocatalysts 178–9, 188–90, 209–10, 233–4 organometallic sites 167–77, 198–209 oxidation reactions 177, 186–8 peptide dendrimers 222–4 polycationic dendrimers 221–2 polymer and resin organic supports 248–54 reaction media 215–38 redox processes 190 silica as an inorganic support 240–8 steric effects 165–6 stimuli-responsive dendrimers 111 supercritical media 220–1 terminal group selection 165–82 transition-metal-based core complexes 184–8 two-phase (liquid–liquid) media 216–19 see also recycling of catalysts cationic polymers see polycationic dendrimers CD see circular dichroism cell-based therapies 501 cell culture 498–501 cerium alkoxide 269 CEST see chemical exchange saturation transfer characterization methods 35–66 atomic force microscopy 45, 49–50 chemical composition 36–47 chirality 45 dielectric spectroscopy 51 differential scanning calorimetry 50–1 dipole moments 51–2 electrochemistry 46 electron paramagnetic resonance 45–6 electrophoresis 53

fluorescence 44–5 host guest interactions 39 infrared and Raman spectroscopy 42–3 intrinsic viscosity 50–1 laser light scattering 47 magnetometry 46 mass spectrometry 40–1 microscopy 44–5, 48–50 morphological properties 39 Mössbauer spectroscopy 46–7 nuclear magnetic resonance 36–40 polarizing optical microscopy 50 rheological and physical properties 50–2 scattering techniques 47–8 separation techniques 52–3 size exclusion chromatography 52–3 size and structure 39–40, 47–50 transmission electron microscopy 49 ultraviolet–visible spectroscopy 43–4 X-ray diffraction 41–2 X-ray spectroscopic methods 47 yield and conversion percentages 35–6 chelating agents 398–401 chemical exchange saturation transfer (CEST) 396, 398, 402–3 chemical ionization (CI) mass spectrometry 40 chemical sensors 361–74, 512 electrochemical sensors 361, 365–7 multivalency of dendrimers 361, 362–5 porphyrins 362–3 self-assembly dendrimers 328–9 solid state chemistry 361, 367–70 solution chemistry 361, 362–5 surface/solution interfaces 367–8 surface/vapor interfaces 368–70 terminal group functionalization 363–5 chiral mesophases 126 chlorambucil 442 chloroquine 469 chorioallantoic membrane (CAM) assays 487 chromophores see luminescent dendrimers CI see chemical ionization circular dichroism (CD) 45, 111–12

Index

cis/trans isomerizations 99, 101–3, 105–6, 108–9 click chemistry catalytic applications 227, 232 encapsulation of dendrimers 276, 280 nitrogen heterocycle-based dendrimers 20–1 self-assembly dendrimers 349 CNT see carbon nanotubes cobalt complexes catalytic applications 187–8, 200–1 heterogeneous catalysis 249–50, 252 stimuli-responsive dendrimers 111 collagen gels 272, 275 collagen mimetic dendrimers 111–12 column chromatography 167, 172–3 columnar phases 125–6, 132, 135 comb polymers 4 competitive binding assays 377 complexed active ingredients 437–8, 463–4 computed tomography (CT) X-ray imaging 405–7 computerized axial tomography (CAT) 405 Concavalin A (Con A) 376–7, 384 concentrator effect 166 cone-shaped multiporphyrin dendrons 79–81 confocal microscopy 44–5, 150 continuous-flow membrane reactors 170 contrast agents 395–412 applications 407 CEST/PARACEST agents 396, 398, 402–3 computed tomography X-ray imaging 405–7 19 F MRI 398, 403 hyperpolarized xenon MRI 403 luminescent dendrimers 72, 74 magnetic resonance imaging 395–403, 407 nanoparticles 154 nuclear medicine imaging 405–7 optical imaging 403–5 paramagnetic 396, 398–402

519

stimuli-responsive dendrimers 115 superparamagnetic 398, 402–3 cooperative effects 249, 252–4, 261 copolymerizations 173–4 copper complexes catalytic applications 171–2, 198–9, 232 chemical sensors 362–3, 365–6 luminescent dendrimers 78 core group functionalization catalytic applications 183, 184–90 drug delivery 442–4 liquid crystalline dendrimers 126–8 stimuli-responsive dendrimers 103–5, 107–8 transfection agents 418–19 core group luminescence 74–9 core–shell nanoparticles 143–5, 285, 419–20 corneal sealants 498–501 correlation spectroscopy (COSY) 37 coumarines 75, 78–9, 88 coupling reactions 171–2 covalent conjugation 437–53, 463–4 critical aggregation concentrations (CAC) 467, 491–2 cross-coupling reactions catalytic applications 167–72, 184–5, 221, 227–30, 232 heterogeneous catalysis 243, 249–52, 258–9 crown macrocycle-based dendrimers stimuli-responsive 114–15 synthetic methods 20, 22, 26 CT see computed tomography CV see cyclic voltammetry cyanobiphenyls 131–2 cyclams 78 cyclic voltammetry (CV) 148, 330 cyclization reactions 109 cyclodextrins 75 cytosine arabinose (ara-C) 443–4 cytotoxicity drug delivery 441–2, 448, 465–6, 471 transfection agents 416–17, 420, 423, 426

520

Index

DAB see diaminobutane dansyl core groups 75 dansyl terminal groups 68–9 Davisil silica 245–6 DEAE see diethylamino ethanol defects 3, 36–7 DEN see dendrimer-encapsulated nanoparticles dendrimer-based drug delivery formulations 464, 465–76 dendrimer-based prodrugs 437–53, 463–4 dendrimer-based scaffolds 498–501 dendrimer bridging strategy 145 dendrimer coated nanoparticles 149–51 dendrimer-encapsulated nanoparticles (DEN) 142, 152–4 catalytic applications 216, 232–4 heterogeneous catalysis 254–7 dendrimer-stabilized nanoparticles (DS NP) 141–2 Dendriphos ligands 184–5 dendriplexes see transfection agents dendrislides 382–4 dendri-stamps 314, 345–9 dendritic boxes 464 dendronized nanoparticles see nanoparticle-cored dendrimers dendronized polymers 112–14, 129 dendrons biological sensors 380–3 catalytic applications 185–6 characterization methods 35–6, 40, 50 drug delivery 442–4 heterogeneous catalysis 240–57 Langmuir–Blodgett films 314–26 liquid crystalline dendrimers 126–31 luminescent dendrimers 74–5, 78–81 mesogenic terminal functions 126–31 nanoimprinting on solid surfaces 342–50 nanoparticles 142–9 novel biomedical applications 487–8 self-assembled monolayers 326–34

stimuli-responsive dendrimers 100, 103–4, 112–14, 116–17 synthetic methods 4, 10–14, 20–3, 26–8 deuterated dendrimers 40 2,6-diamidopyridine units 364 diaminobutane (DAB) dendrimers 5 diarylphosphine cores 149 diclofenac 473 dielectric spectroscopy (DS) 51 Diels–Alder reactions carbon-based dendrimers 18–19 catalytic applications 185, 200 heterogeneous catalysis 258–9 luminescent dendrimers 69 stimuli-responsive dendrimers 117 diethylamino ethanol (DEAE) 413, 415 diethylzinc 201–3 differential scanning calorimetry (DSC) 50–1, 320 diflusinal 473 dinitrophenol (DNP) 385 dip-pen nanolithography (DPN) 314, 342, 344–50 1,2-diphenylethylenediamine (DPEN) 207–8 diphenylphosphine-terminated dendrimers 168–71 diphenylphosphinoferrocene (dppf) dendrimers 184, 186 diphosphine ligands 240–1, 245, 248–9, 252 1,3-dipolar cycloadditions 131 dipole moments 51–2 direct synthesis 147–9 disassembly 99, 115–18 diselenide dendrimers 190 disulfide cores 148 dithiophene (DTP) 293 DMAP see 4-(N,N-dimethylamino) pyridine 3DNA dendrimers 24–5 DNA elaboration 326 DNA microarrays 375, 380–3 DNA transfection see transfection agents double exponential growth 27–8 double-stage convergent approach 26–7 doxorubicin (DOX) 116–17, 422, 442–3, 444–5, 467–8

Index

DPEN see 1,2-diphenylethylenediamine DPN see dip-pen nanolithography dppf see diphenylphosphinoferrocene drug delivery 437–61, 513–14 active ingredients 437–8 active targeting 446–9 bioavailability 438–40, 464–5 boron neutron capture therapy 438, 451–2 classification of techniques 437–8 core group functionalization 442–4 covalent conjugation 437–53, 463–4 cytotoxicity 441–2, 448, 465–6, 471 dendrimer-based formulations 464, 465–76 dendritic boxes 464 encapsulated active ingredients 272, 437–8, 463–84 EPR effect 438, 440–2, 444, 446, 451 folic acid 446–8 luminescent dendrimers 72–4, 90 monoclonal antibodies 449, 452 nontargeted formulations 466–73 passive targeting in tumors 440–6 PEGylated dendrimer scaffolds 463, 465–70, 472, 476 PEGylated dendrimeric scaffolds 442–6, 450–2 photodynamic therapy 438, 449–51 stimuli-responsive dendrimers 99, 110, 112–15 supramolecular assemblies 473–5 surface ionic interactions 473–5 targeted 72–4, 90, 440–9, 475–6 terminal group functionalization 442, 444–6 tumor-homing peptides 448–9 DS see dielectric spectroscopy DSC see differential scanning calorimetry DS NP see dendrimer-stabilized nanoparticles DTP see dithiophene ECM see extracellular matrix ED see electron diffraction

521

EDC see 1-ethyl-3-(3dimethylaminopropyl)carbodiimide EGFR see epidermal growth factor receptor EIS see electrochemical impedance spectroscopy elaboration of gels see gel elaboration electroactivity 280 electrochemical impedance spectroscopy (EIS) 379 electrochemical sensors 361, 365–7, 378–80 electrochemistry 46 electroluminescence 75–7, 294–8 electron diffraction (ED) 318 electron paramagnetic resonance (EPR) 45–6 electrophoresis 53 electrospray ionization (ESI) mass spectrometry 40 electrostatic self-assembly 331–2 ELISA see enzyme-linked immuno assay enantioselectivity catalytic applications 197–213, 216–17, 219, 233–4 heterogeneous catalysis 243–5, 252–3, 255, 258 encapsulated active ingredients 272, 437–8, 463–84 encapsulation into materials 269–311 engineering applications 275 fluorescent dendrimers 276, 279, 285–6, 290–5 functional nanoarchitectures 285–8 gel elaboration 269, 270–85 hybrid materials 269, 282–4, 285–6, 299 hydrogels 270–6 organic light-emitting diodes 269, 288–99 organogels 276–80 phosphorescent dendrimers 295–8 polymer-type hydrogels 273–6 silica gels 269, 280–5 supramolecular gels 270–3 endocytosis 70

522

Index

endosome 414–15 enhanced permeability and retention (EPR) effect contrast agents 396–7, 400–1 drug delivery 438, 440–2, 444, 446, 451, 466 environmental applications 366, 368–70 environmental scanning electron microscopy (ESEM) 319 enzymatic degradation 116 enzyme-linked immuno assay (ELISA) 147 epidermal growth factor receptor (EGFR) 449, 452 epirubicin (EPI) 444 epoxidation reactions 186–7, 243–4, 258 EPR see electron paramagnetic resonance; enhanced permeability and retention Escherichia coli 471, 489 ESEM see environmental scanning electron microscopy ESI see electrospray ionization ester hydrolysis reactions 222–3 esterification reactions 220 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) 500–1 europium-based contrast agents 402 exchange spectroscopy (EXSY) 37 explosives sensors 364–5, 367, 512 EXSY see exchange spectroscopy extracellular matrix (ECM) 498, 500–1 FA see folic acid 19 F MRI 398, 403 19 F NMR 38–40 FAB see fast atom bombardment fac-tris(2-phenylpyridine) iridium-cored dendrimers 295–8 famotidine 472 fast atom bombardment (FAB) 40 ferrimagnetic properties 146–7 ferrocene-based dendrimers biological sensors 378 catalytic applications 184, 206 characterization methods 37–8, 40, 46–7

chemical sensors 365–6, 368 liquid crystalline dendrimers 131 nanoparticles 148 self-assembly dendrimers 330, 348 ferroelectric phases 131–2 FET see field-effect transistors fibroblast growth factors (FGF) 449 field-effect transistors (FET) 324–5 fipronil 117 first generation dendrimers 3–4 FITC see fluoresceine isothiocyanate flexibility see rigidity flow cytometry 150 fluorene dendrimers 291 fluoresceine isothiocyanate (FITC) 70–4 fluorescence sensors 362–3 fluorescent dendrimers 44–5, 67–90, 511 biological sensors 377–8 chemical sensors 365 encapsulation into materials 276, 279, 285–6, 290–5 liquid crystalline dendrimers 132 stimuli-responsive dendrimers 109, 116–17 fluoro-functionalized dendrimers 38, 220–1, 230–1 5-fluorouracil (5FU) 441, 447, 476 flurbiprofen 473 focal points 126–8 folic acid (FA) 149–50, 446–8, 476 Förster resonance energy transfer (FRET) biological sensors 377–8, 385 contrast agents 405 drug delivery 447–8 luminescent dendrimers 74–5, 88 novel biomedical applications 495 Fourier transform infrared (FTIR) 145, 490–1 Fourier transform ion cyclotron resonance (FT-ICR) 40 fractured dendrimers 415 FRET see Förster resonance energy transfer Friedel–Crafts reactions 259–60 FT-ICR see Fourier transform ion cyclotron resonance

Index

523

5FU see 5-fluorouracil fullerenes liquid crystalline dendrimers 130–2 luminescent dendrimers 78 self-assembly dendrimers 322–5 functional nanoarchitectures 285–8 functionalization chemical sensors 363–5, 368 drug delivery 442 internal 12–13, 22, 105–8, 183–95 liquid crystalline dendrimers 126–34 luminescent dendrimers 72–3 nanoparticles 149–51, 154 self-assembly dendrimers 329 stimuli-responsive dendrimers 100, 101–8, 113 transfection agents 416–19 see also catalytic applications functionalized hydrogels 499–500

glycerol-type pseudo dendrimers 9–10 glycodendrimers 487–8 GMO see genetically modified organisms GNP see gold nanoparticles gold catalysts 228–9 gold nanoparticles (GNP) 142–3, 148–51, 154 biological sensors 378–80 chemical sensors 365–9 encapsulation of dendrimers 280 heterogeneous catalysis 256 self-assembly dendrimers 325–6, 336, 338, 346 stimuli-responsive dendrimers 111 gold surface assemblies 317–18, 327–30 gradient hydrogen–nitrogen multiplequantum coherence (GHNMQC) 38 green chemistry 215, 233–4 Grignard reagents 16

G1-TamBP 495–6, 501 gadolinium-based dendrimers contrast agents 397–402, 407 drug delivery 441, 446 stimuli-responsive dendrimers 115 galactose-coated dendrimers 475–6 galactosylceramide 474–5 galectin binding assays 487–8 Gantrez multilayers 335–6 gel elaboration 269, 270–85 hydrogels 270–2 organogels 276–80 polymer-type hydrogels 273–6 silica gels 269, 280–5 supramolecular gels 270–3 gel electrophoresis 53, 143 gene delivery 420 gene expression modifications 494–5 gene transfection see transfection agents genetically modified organisms (GMO) 386 germanium-containing dendrimers 38 GHNMQC see gradient hydrogen– nitrogen multiple-quantum coherence glucocorticoids 417–18 glutaraldehyde 499–501

1

H NMR 36–7, 39 H NMR 40 Heck reaction 168–70, 221, 243, 249, 251–2 Henry reaction 188, 199–200 heparin 487 herpes simplex virus (HSV) 386, 493–4 heterobifunctional biodegradable polyester dendrimers 444–5 heterogeneous catalysis 239–65, 511 cooperative effects 249, 252–4, 261 dendrons synthesized from solid material 240–54 dendrons/dendrimers grafted onto solid surfaces 254–7 enantioselectivity 243–5, 252–3, 255, 258 insoluble dendrimers 257–60 organocatalysts 252–3 polymer and resin organic supports 248–54 recycling of catalysts 244, 247–50, 252, 258, 261 silica as an inorganic support 240–8 heterometallic dendrimers 19–20 2

524

Index

heteronuclear multiple-quantum coherence (HMQC) 37 heteronuclear Overhauser effect spectroscopy (HOESY) 39 high-power decoupling (HPDEC) NMR 40 high-resolution transmission electron microscopy (HRTEM) 148 highly branched homogeneous compounds 14–15 highly oriented pyrolytic graphite (HOPG) 256 HIV see human immunodeficiency virus HMQC see heteronuclear multiplequantum coherence HOESY see heteronuclear Overhauser effect spectroscopy hole transporting properties 296 homogeneous catalysis 511 addition reactions on C=C double bonds 192 addition reactions on C=X double bonds 175–7, 186, 204–9 branching units 183, 191–2 C–X bond formation 167–75, 184–6, 188–90, 191–2 core-functionalized dendrimers 183, 184–90 cross-coupling reactions 167–72 dendrimer effect 165–6 enantioselectivity 197–213 internal functionalization 183–95 metathesis 172–3 miscellaneous reactions 174–5, 188 oligomerizations and polymerizations 173–4 organocatalysts 178–9, 188–90, 209–10 organometallic sites 167–77, 198–209 oxidation reactions 177, 186–8 recycling of catalysts 166–7, 172–3 redox processes 190 terminal group selection 165–82 transition-metal-based core complexes 184–8 homometallic dendrimers 19–20 HOPG see highly oriented pyrolytic graphite

host–guest interactions 39, 54 HPAMAM see hyperbranched PAMAMlike polymers HPDEC see high-power decoupling HPG see hyperbranched polyglycerols HRTEM see high-resolution transmission electron microscopy HSV see herpes simplex virus human immunodeficiency virus (HIV) 425, 474, 491–4 HUVEC cell lines 487 hybrid materials 269, 282–4, 285–6, 299 hydrazine-labeled avidin 379–80 hydride-terminated carbosilane dendrimers 38 hydroesterification reactions 241 hydroformylation reactions heterogeneous catalysis 240–2, 245–6, 248 homogeneous catalysis 176, 225–6 hydrogels 270–6, 499–500 hydrogen bonding characterization methods 42 chemical sensors 364 encapsulation into materials 271, 279 liquid crystalline dendrimers 128–9 hydrogen peroxide activation 224–5 hydrogenation reactions enantioselectivity 197, 204–8 heterogeneous catalysis 247, 255 homogeneous catalysis 175–6, 192, 197, 204–8, 218, 230–3 hydrolytic kinetic resolution 200–1 hydrosilylation reactions 186–7, 208 hydrovinylation reactions 208–9 3,4-hydroxy-L-phenylalanine (L-DOPA) 440 hyperbranched polyamidoamines (HPAMAM/HYPAM) 151, 154, 420 hyperbranched poly(ethyleneimine) 285 hyperbranched poly(glycerol) (HPG) catalytic applications 227–8 encapsulation into materials 283–4 nanoparticles 151 hyperbranched polymers 4

Index

catalytic applications 218, 219, 227–8, 232–3 characterization methods 48 drug delivery 442, 453, 463, 468 encapsulation into materials 275, 280, 283–5, 295, 299 nanoparticles 151, 154 novel biomedical applications 499 synthetic methods 9–10, 12 transfection agents 420 hypercore 26–7 hypermonomers 27, 29 hyperpolarizability 321 hyperpolarized xenon MRI 403 hypervasculature 440–2 125

I-labeled conjugates 417, 445, 449 IBAM see isobutyramide ibuprofen 438–9, 473 IL see interleukins; ionic liquids imaging see contrast agents; individual techniques imino-pyridine terminated dendrimers 171–2 immunoassays 384 immunomodulation 485, 494–8, 513 immunosuppressive dendrimers 495–7 INADEQUATE see incredible natural abundance double-quantum transfer experiment inclusion of dendrimers see encapsulation into materials incredible natural abundance doublequantum transfer experiment (INADEQUATE) 37–8 indium titanium oxide (ITO) 145, 378 indomethacin 473 infrared (IR) spectroscopy 42–3, 147 insecticide delivery 117 insoluble dendrimers 257–60 intercalating drugs 474 interdendrimeric nanocomposites 141–2, 151–2, 153 interleukins (IL) 501 internal functionalization

525

catalytic applications 183–95 stimuli-responsive dendrimers 105–8 synthetic methods 12–13, 22 intramolecular hydroesterification reactions 241 intrinsic viscosity 50–1 intrinsically fluorescent dendrimers 81–6 ionic liquid crystalline dendrimers 134 ionic liquids (IL) 219–20 IR see infrared iridium-cored dendrimers 205–6, 295–8 iron complexes catalytic applications 174, 187–8 characterization methods 47 chemical sensors 366 luminescent dendrimers 78 iron oxide nanoparticles 147, 149 contrast agents 402–3 heterogeneous catalysis 247 isobutyramide (IBAM) 112 isomerization processes catalytic applications 226–7 encapsulation of dendrimers 278 stimuli-responsive dendrimers 99, 101–3, 105–6, 108–9 ITO see indium titanium oxide Jablonski diagrams 67, 68 Janus-type dendrimers 131, 132, 378 ketoprofen 115, 473 Kharasch reactions 176–7 kinetic resolution 200–1 Knoevenagel reactions 175, 234, 246, 253–4 L-DOPA see 3,4-hydroxy-L-phenylalanine lactoferrin (Lf) 417 lactose-capped dendrimers 487–8 lamellar mesophases 129, 131, 134–5 Langmuir isotherms 315 Langmuir–Blodgett (LB) films self-assembly 313, 314–26, 342, 350–1 stimuli-responsive dendrimers 103, 105 lanthanides 69, 78–9 laser assisted in situ keratomileusis (LASIK) 273

526

Index

laser light scattering (LLS) 47 LASIK see laser assisted in situ keratomileusis layer-by-layer (LBL) method contrast agents 403 drug delivery 470 novel biomedical applications 498–9 self-assembly 149–50, 315–16, 336–42, 346–7, 349–50 layered dendrimers 17, 29, 42, 47 layered double hydroxides (LDH) 286 LB see Langmuir–Blodgett LBL see layer-by-layer LCP see lipid-cored peptides LCST see lower critical solution temperature LDH see layered double hydroxides Lf see lactoferrin ligand exchange 142–7, 151 light harvesting properties 67, 69, 74–9 linear polymers 4 lipid-cored peptides (LCP) 422 lipoplexes 414 lipopolysaccharides (LPS) 489 liquid crystalline dendrimers 125–40 branching units 126–8, 134–5 characterization methods 40, 49–51 classification of mesophases 125–6 mesogenic groups 126–35 optical properties 125 self-assembly 126, 128–9, 134–5 synthetic methods 22, 24 terminal functions of dendrimers 131–4 terminal functions of dendrons 126–31 liquid–liquid catalytic media 216–19 lithographic methods 314 LLS see laser light scattering localized surface plasmon resonance (LSPR) 338 lower critical solution temperature (LCST) 110, 112–14 LPS see lipopolysaccharides LSPR see localized surface plasmon resonance

luminescent dendrimers 67–98 background fluorescence 86 characterization methods 43 chemical sensors 368 core group luminescence 74–9 fluorescent dendrimers 67, 68–90 fluorescent groups inside the dendrimer structure 79–81 fully substituted dendrimers 68–9 intrinsically fluorescent dendrimers 81–6 light harvesting properties 67, 69, 74–9 metallic cores 78–9 nanoparticles 144–5 organic fluorophore cores 74–9 partially substituted dendrimers 69–74 porphyrins and phthalocyanins 69, 71–2, 77–8, 79–83, 88 self-assembly 321–2 terminal group fluorescence 68–74, 88–9 two-photon absorption 67, 86–9 lysosomes 414–15, 416, 449 MAb see monoclonal antibodies macrocycle-based dendrimers chemical sensors 362–3, 368 luminescent dendrimers 78 nanoparticles 152 synthetic methods 20, 22, 25–6 macromolecule-based dendrimers 166, 440–1 macrophages 485 magic angle spinning (MAS) NMR 39–40 magnetic resonance imaging (MRI) contrast agents 395–403, 407 luminescent dendrimers 72, 74 nanoparticles 150 stimuli-responsive dendrimers 115 magnetometry 46 main-chain liquid crystalline dendrimers 135 MALDI-ToF see matrix-assisted laser desorption ionization time of flight manganese complexes catalytic applications 177, 187 chemical sensors 368

Index

contrast agents 401 heterogeneous catalysis 243–4 luminescent dendrimers 78 Mannich-type reactions 229–30, 234 MAO see methylaluminoxane MAS see magic angle spinning mass spectrometry 40–1 materials applications see biological sensors; chemical sensors; encapsulation into materials; selfassembly dendrimers matrix-assisted laser desorption ionization time of flight (MALDI-ToF) 40–1 Maxwell displacement current 321 MCM-41 silica 245–6, 283 mefenamic acid 473 melamine formaldehyde (MF) particles 341 3-mercaptopropionic acid (MPA) 329, 338 mercaptoundecanoic acid (MUA) 327, 329 mesogenic groups 126–35 branches of dendrimers 134–5 terminal functions of dendrimers 131–4 terminal functions of dendrons 126–31 mesostructured hybrid materials 285–6 metal-based intercalating drugs 474 metal transfer printing (mTP) 348–9 metallic cores, luminescent dendrimers 78–9 metallocene-based dendrimers biological sensors 378 catalytic applications 174 characterization methods 46 metallodendrimers catalytic applications 174, 221, 223–4 characterization methods 39 metathesis 172–3 methanofullerenes 130–1 methotrexate (MTX) 72–4, 441–2, 445, 446–9, 466–9, 476 methoxycarbonylation reactions 241–2 methylaluminoxane (MAO) 173–4 MF see melamine formaldehyde Michael-type additions

527

catalytic applications 175, 185–6, 200, 233–4 poly(amidoamine) dendrimers 7 poly(propyleneimine) dendrimers 5 microarrays 512 DNA microarrays 375, 380–3 non-DNA microarrays 383–4 self-assembly dendrimers 314, 326 microbicidal dendrimers 489 microcontact printing 314, 327, 335–6, 344–50 microtransfer molding 345–6 mixed aliphatic polyether/polyester dendrimers 12–13 molecular imaging 396 molecular printboards 329–30, 346 molecular sensors 314 molecular tweezers 174–5 monoclonal antibodies (MAb) 73, 449, 452 monocyte-activating dendrimers 495 MORF see phosphorodiamidate morpholino morphological properties 39 Mössbauer spectroscopy 46–7 MPA see 3-mercaptopropionic acid MRI see magnetic resonance imaging mTP see metal transfer printing MTX see methotrexate MUA see mercaptoundecanoic acid Mukaiyama aldolization 189 multifunctional dendrimers 3–4, 446–7, 451–2 multiporphyrin arrays 79–81 multivalent effects 486–8, 513 N-acetyl-cysteine (NAC) 439 (S,S)-N-arenesulfonyl-1,2diphenylethylenediamine (TsDPEN) 207–8, 231–2 N-heterocyclic carbenes (NHC) 186–7, 227–8 N–Si–C frameworks 37–8 NAC see N-acetyl-cysteine nadifloxacine 469, 470 nanofiltration 167

528

Index

nanoimprint lithography (NIL) 347 nanoimprinting on solid surfaces 342–50 nanoparticle-cored dendrimers (NCD) 141–9 direct synthesis 147–9 ligand exchange 142–7 nanoparticles (NP) 141–62, 514 biological sensors 378–80, 386–7 catalytic activity 149, 152, 153–4 catalytic applications 216, 232–4 chemical sensors 365–9 contrast agents 395, 402–3 dendrimer coated nanoparticles 149–51 dendrimer-encapsulated nanoparticles 142, 152–4, 216, 232–4, 254–7 dendrimer-stabilized nanoparticles 141–2 dendrimeric architectures 141–2 direct synthesis 147–9 drug delivery 470–1 encapsulation of dendrimers 280–1, 284–8 future perspectives 154–5 heterogeneous catalysis 247–8, 254–7 interdendrimeric nanocomposites 141–2, 151–2, 153 ligand exchange 142–7, 151 nanoparticle-cored dendrimers 141–9 self-assembly dendrimers 325–6, 336, 338–40, 346 template synthesis 152–4 transfection agents 419–20 nanotransfer printing (nTP) 347 nanotubes 75 naproxen 438, 473 natural killer (NK) cells 485, 495–7, 501 NCD see nanoparticle-cored dendrimers NDR see nitrocontaining diazoresin near-field scanning optical microscopy (NSOM) 45 near-infrared (NIR) spectroscopy 376, 399, 404 negative dendrimer effect 177, 209 nematic phases 125–6, 131, 135 neurotensin 448–9 neutron spin-echo (NSE) 48 NHC see N-heterocyclic carbenes

nickel-containing dendrimers 78, 176–7 niclosamide 469 nifedipine 115, 472–3 NIL see nanoimprint lithography NIR see near-infrared nitric oxide (NO) releasing molecules 444 nitroaldol reactions 188 nitrobenzylcinnamate-based dendrimers 110 nitrocontaining diazoresin (NDR) 336–7 nitrogen heterocycle-based dendrimers 19–21 NK see natural killer NM see nuclear medicine 4-(N,N-dimethylamino)pyridine (DMAP) 188–9 NOESY see nuclear Overhauser effect spectroscopy nonsteroidal anti-inflammatory drugs (NSAID) 438, 471–3 NP see nanoparticles NSAID see nonsteroidal anti-inflammatory drugs NSE see neutron spin-echo NSOM see near-field scanning optical microscopy nTP see nanotransfer printing nuclear magnetic resonance (NMR) spectroscopy 36–40, 364 nuclear medicine (NM) imaging 405–7 nuclear Overhauser effect spectroscopy (NOESY) 37, 39, 471 nucleic acid-based dendrimers biological sensors 380–3 synthetic methods 24–5 transfection agents 414–15, 419, 426 octaammonium core dendrimers 39 ocular delivery 472 ODN see oligodeoxyribonucleotides OEG see oligo(ethyleneglycol) OLED see organic light emitting diodes oligodeoxyribonucleotides (ODN) 423–5 oligo(ethyleneglycol) (OEG) units contrast agents 400, 401 drug delivery 468 self-assembly dendrimers 317

Index

stimuli-responsive dendrimers 113 transfection agents 423–4 oligomerization reactions catalytic applications 173–4, 186 stimuli-responsive dendrimers 109 oligonucleotide-based dendrimers biological sensors 380–4, 386 luminescent dendrimers 73 synthetic methods 24–5 transfection agents 420, 423–5 oligo(phenylenevinylene) (OPV) dendrons 145–6 liquid crystalline dendrimers 131 self-assembly dendrimers 317, 319–20 oligothiophene dendrons 112, 145–6 OMS see ordered mesoporous silica optical imaging contrast agents 403–5 optical microscopy 44–5 optical reflectometry 333–4 optical rotation 45 optical waveguide spectroscopy (OWS) 339–40 OPV see oligo(phenylenevinylene) ordered mesoporous silica (OMS) 245–6 organic fluorophore cores 74–9 organic–inorganic hybrid materials 269, 282–4, 285–6, 299 organic light-emitting diodes (OLED) 511–12 encapsulation of dendrimers 269, 288–99 fluorescent dendrimers 290–5 luminescent dendrimers 67, 69, 75, 79, 90 phosphorescent dendrimers 295–8 self-assembly dendrimers 321 organocatalysts aqueous media 233–4 core-group functionalization 188–90 enantioselectivity 209–10 heterogeneous catalysis 252–3 terminal group selection 178–9 organogels 276–80 organometallic catalysts 167–77, 198–209 orthogonal coupling strategy 28–9 osmium complexes 81, 83, 219

529

OWS see optical waveguide spectroscopy oxidation reactions 177, 186–8, 224–5 oxo process 225–6 oxygen microscopy 405 P-gp see permeability-glycoprotein 31 P NMR 37–8 PAAE see poly(aryl alkyl ether) paclitaxel (PTX) 468–9 PAGE see gel electrophoresis PAH see poly(allylamine hydrochloride) palladium complexes catalytic applications 167–72, 174–6, 184–5, 191–2, 198, 216–17, 221, 227–30, 232 characterization methods 39 chemical sensors 362, 365–6 heterogeneous catalysis 241–3, 246–7, 249–51, 255–9 luminescent dendrimers 78 nanoparticles 149, 152 PAMAM see poly(amidoamine) PAMAMOS see poly(amidoamine-organosilicon) paramagnetic chemical exchange saturation transfer (PARACEST) 396, 398, 402 paramagnetic contrast agents 396, 398–402 passive targeting in tumors 440–6 Pausond–Khand reaction 249–50 PBMC see peripheral blood mononuclear cell Pbpp see poly(bispyridyl) pyrazine PBzE see poly(benzyl ether) PCSi see poly(carbosilane) PDAC/PSS see poly(dimethyl diallylammonium chloride) poly(sodium 4-styrenesulfonate) PDMS see poly(dimethylsiloxane) PDT see photodynamic therapy PEA see poly(ether amide) PEGylated dendrimer scaffolds drug delivery 442–6, 450–2, 463, 465–70, 472, 476 novel biomedical applications 489, 499–501

530

Index

PEI see poly(ethyleneimine) pentaerythritol dendrons 423–4 pentathiophene (PTP) 293 PEPE see polyether-co-polyester peptide-containing dendrimers aqueous media 222–4 contrast agents 406 drug delivery 448–9 encapsulation into materials 276–8, 280 ligation 273–5 novel biomedical applications 489–91 perfluorinated polyphenylene dendrimers 38 perfluoro-functionalized dendrimers 220–1, 230–1 periodic mesoporous silica (PMS) 245, 284 peripheral blood mononuclear cells (PBMC) 425, 495–7, 501 permeability-glycoprotein (P-gp) 439–40 perylene dendrimers 293 perylene imide dendrimers 69, 84–5 PET see positron emission tomography PETIM see poly(propyl ether imine) PFGSE see pulse field-gradient spin echo PGA see poly(glutamic acid) PGLSA see poly(glycerol-succinic acid) PGly see poly(glycerol) PGSE see pulse field-gradient spin echo pH-responsive dendrimers 99, 114–15 pharmacological applications contrast agents 407 luminescent dendrimers 69, 72–4, 90 nanoparticles 155 see also drug delivery phenol sensors 368 phenylazomethine dendrimers 43 phenylbutazone 471 phosphine core ligands 217, 221, 226, 228–30 phosphorescent dendrimers 67, 78–9, 295–8 phosphorodiamidate morpholino (MORF) oligomers 406

phosphorus-containing dendrimers biological sensors 377–8, 381–5 catalytic applications 168–72, 175–6, 184–6, 198–9, 204–5 characterization methods 37–40, 43, 52–3 chemical sensors 366–7, 369 elaboration of materials 337–41 encapsulation into materials 271, 283–4, 285–6 luminescent dendrimers 69, 88–9 nanoparticles 145–6 novel biomedical applications 495–7, 502 self-assembly dendrimers 334, 337–9 stimuli-responsive dendrimers 107 synthetic methods 16–17, 18, 27–9 transfection agents 423–4, 426 photo-crosslinking 273–4 photochemical properties 132 photodynamic therapy (PDT) 438, 449–51 photoisomerization 278 photoluminescence 145, 322 photopolymerization 277 photoresponsive dendrimers 99, 100–10 photosensitivity 320–1 phthalocyanine complexes 187–8 phthalocyanine-based dendrimers characterization methods 43–4 luminescent dendrimers 77–8 stimuli-responsive dendrimers 114 PICM see polyion complex micelles piezoelectric mass-sensing devices 382 pilocarpine 472 pinacolyl methyl phosphate (PMP) 367 pincer nickel complexes 176–7 pincer palladium complexes 174–5, 192 plasma polymerization 334 platinum complexes catalytic applications 218, 232–3 characterization methods 39 chemical sensors 362, 364–6 drug delivery 474 heterogeneous catalysis 255–6 luminescent dendrimers 69 nanoparticles 152, 154

Index

PLL see poly(l-lysine) PLys see poly(lysine) PMel see poly(melamine) PMP see pinacolyl methyl phosphate PMS see periodic mesoporous silica PNIPAAm see poly(N-isopropylacrylamide) polarizing optical microscopy (POM) 50 poly(acrylic acid) (PAA) 470 poly(alkyl aryl ether) dendrimers 102–3 poly(alkyl ether amide) dendrimers 8 poly(alkyl ether) dendrimers 144 poly(allylamine hydrochloride) (PAH) 341 poly(amide) dendrimers 103, 107, 277–9 poly(amidoamine) (PAMAM) dendrimers biological sensors 376–81, 512 catalytic applications 170, 177, 189–90, 198, 200, 203, 207–8, 210, 219–20, 223–6, 232–4 characterization methods 36–41, 46, 48–51, 53 chemical sensors 366–70 contrast agents 399–401, 403, 405–7 drug delivery 438–42, 444–9, 452, 465–76 encapsulation into materials 272, 274–6, 278, 281–2, 284–7 heterogeneous catalysis 240–59 liquid crystalline dendrimers 132 luminescent dendrimers 69–74, 86 nanoparticles 143–4, 147–51, 154, 419–20 novel biomedical applications 487, 489–90, 493–4, 497–8, 502, 513 self-assembly dendrimers 319–20, 325–9, 331–7, 345, 350 stimuli-responsive dendrimers 102, 109–10, 111–17 synthetic methods 5–7 transfection agents 414, 415–20, 426 poly(amidoamine-organosilicon) (PAMAMOS) dendrimers 282 poly(amine) dendrimers 439, 441–2 polyanionic dendrimers drug delivery 448, 465 novel biomedical applications 488, 491–4 self-assembly 336–7

531

poly(aryl alkyl ether) (PAAE) dendrimers 10, 11 poly(aryl alkyne) dendrimers 104 poly(aryl amide) dendrimers 105 poly(aryl ester) dendrimers 13, 14 poly(aryl ether) dendrimers biological sensors 377 catalytic applications 189–90, 206 characterization methods 51–2 liquid crystalline dendrimers 132 synthetic methods 13–14 poly(benzyl) dendrimers 88 poly(benzyl ether) (PBzE) dendrimers characterization methods 39–40, 43–5, 47–8, 50, 53 chemical sensors 369 encapsulation into materials 276–7 luminescent dendrimers 75 self-assembly dendrimers 316–19, 329, 330–1, 342–3 stimuli-responsive dendrimers 102–4, 108, 113 synthetic methods 10, 11, 22 poly(bispyridyl) pyrazine (Pbpp) dendrimers 19–20 poly(carbazole) dendrimers 82–3 poly(carbosilane) (PCSi) dendrimers catalytic applications 170, 173–7, 186, 203, 208–9, 221 characterization methods 37–40, 50 hydride-terminated 38 liquid crystalline dendrimers 131 novel biomedical applications 485, 494–5 self-assembly dendrimers 321–2, 329–30, 332 stimuli-responsive dendrimers 102–3 synthetic methods 16 transfection agents 424–5 polycationic dendrimers 221–2 biological sensors 377–8, 381–5 drug delivery 448, 465, 474–5 encapsulation into materials 283–4 novel biomedical applications 489–91 self-assembly 336–7 transfection agents 414, 416

532

Index

poly(dimethyl diallylammonium chloride) poly(sodium 4-styrenesulfonate) (PDAC/PSS) bilayers 336–7 poly(dimethylsiloxane) (PDMS) 345, 347, 349 polyelectrolyte dendrimers 339–41 poly(ester) dendrimers drug delivery 439, 441–5 stimuli-responsive dendrimers 107 synthetic methods 10–14 poly(ether amide) (PEA) dendrimers 8, 77–8 poly(ether amine) dendrimers 168 poly(ether) dendrimers encapsulation into materials 288 liquid crystalline 129 synthetic methods 7–10, 12–13 polyether-co-polyester (PEPE) 468–9, 476 poly(ethylene glycol) (PEG) dendrimers catalytic applications 218, 227–8 drug delivery 442–6, 450–2, 463, 465–70, 472, 476 encapsulation into materials 273–6 novel biomedical applications 489, 499–501 poly(ethyleneimine) (PEI) dendrimers catalytic applications 219, 220 contrast agents 401 drug delivery 467–8 encapsulation into materials 275–6, 286–7 novel biomedical applications 489–90, 494, 501 transfection agents 414, 420, 423 poly(glutamic acid) (PGA) 403 poly(glycerol) (PGly) dendrimers catalytic applications 218 drug delivery 467–9 synthetic methods 9–10 poly(glycerol-succinic acid) (PGLSA) dendrimers characterization methods 39 drug delivery 439, 469 encapsulation into materials 273–4 novel biomedical applications 500

polyhedral silsesquioxane (POSS) 176 polyion complex micelles (PICM) 419–20, 450–1, 453 poly(l-lysine) (PLL) contrast agents 403, 405–6 drug delivery 445, 448, 450–2, 476 novel biomedical applications 487, 489, 492–4, 500–2 transfection agents 422–3, 426 poly(lysine) (PLys) dendrimers luminescent dendrimers 68–9, 86 synthetic methods 14–15 poly(melamine) (PMel) dendrimers 20–1, 23 polymer-supported heterogeneous catalysis 248–54 polymer-type hydrogels 273–6 polymerization reactions 4, 173–4 poly(N-isopropylacrylamide) (PNIPAAm) dendrimers 110–12, 276 polyoxometalate (POM) catalysts 177, 230–1, 337 poly(p-xylylene) (PPX) nanotubes 256–7 poly(phenyl acetylene) dendrimers characterization methods 50 enantioselectivity 202 encapsulation into materials 290–1 luminescent dendrimers 75–7 synthetic methods 18 poly(phenyl azomethine) (PPA) dendrimers 28 poly(phenyl melamine) dendrimers 23 poly(phenylene) (PPhen) dendrimers characterization methods 40 chemical sensors 369 encapsulation into materials 293 liquid crystalline dendrimers 132 luminescent dendrimers 75–9, 81, 83–4 stimuli-responsive dendrimers 104–5, 108–9, 113 synthetic methods 18–19 poly(phenylene sulfide) dendrimers 225 poly(phenylene vinylene) dendrimers 291–2, 295 poly(phosphorhydrazone) (PPH) dendrimers

Index

biological sensors 377–8, 381–5, 512 catalytic applications 226–7 characterization methods 37–47, 50–2 chemical sensors 366–7, 369 contrast agents 404 drug delivery 444, 474 nanoparticles 149, 152 novel biomedical applications 485, 490–1, 494–7, 499, 502, 513 self-assembly dendrimers 334 synthetic methods 17 transfection agents 423, 426 polyplexes 414 poly(propyl ether imine) (PETIM) dendrimers 5, 6, 86 poly(propylene amine) (POPAM) dendrimers 5 poly(propylene imine) (PPI) dendrimers biological sensors 378, 386–7 characterization methods 36–40, 42–8, 50, 53 chemical sensors 363–4, 366–9 contrast agents 401, 403 drug delivery 464, 466–7, 472, 475–6 encapsulation into materials 275, 281, 284–7 heterogeneous catalysis 256 homogeneous catalysis 168–75, 178, 189–92, 198, 206–9, 217–24, 230–2 liquid crystalline dendrimers 132, 134 luminescent dendrimers 68–9, 79, 86 nanoparticles 145, 151 novel biomedical applications 490–1, 500–1 self-assembly dendrimers 319–20, 330, 346–8 stimuli-responsive dendrimers 101–2, 109, 112, 114–15, 117 synthetic methods 5, 6 transfection agents 421, 426 poly(propylene oxide) (PPO) dendrimers 470 poly(propylene oxide) triamine-cored dendrimers 492–3 poly(pyrelene) dendrimers 69, 75

533

poly(pyrenyl) dendrimers 69, 75, 84–5 poly(pyrrole) dendrimers 380 poly(siloxane) dendrimers characterization methods 37–8 stimuli-responsive dendrimers 102–3 synthetic methods 15 poly(styrenesulfonic acid) (PSS) 337, 341 poly(tetrahydrofuran) (polyTHF) dendrimers 287 poly(thiophene) dendrimers 84–8 poly(triphenylene) dendrimers 293 poly(truxene) dendrimers 84–5 poly(vinyl alcohol) (PVA) 276 POM see polarizing optical microscopy; polyoxometalates POPAM see polypropylene amine porphyrin-based dendrimers biological sensors 384 catalytic applications 186–8 characterization methods 43–5 chemical sensors 362–3, 368 contrast agents 405 drug delivery 449–51 liquid crystalline dendrimers 132 luminescent dendrimers 69, 71–2, 77–8, 79–83, 88 stimuli-responsive dendrimers 114 transfection agents 418 positron emission tomography (PET) 405 POSS see polyhedral silsesquioxane PPA see poly(phenyl azomethine) PPH see poly(phosphorhydrazone) PPhen see poly(phenylene) PPI see poly(propylene imine) PpIX see protoporphyrin IX PPO see poly(propylene oxide) PPX see poly(p-xylylene) precipation techniques 167 primaquine 475–6 prodrugs, dendrimer-based 437–53, 463–4 propanolol 439–40 proteins 386 protoporphyrin IX (PpIX) 449–50 prulifloxacin 469, 470 pseudo-dendrimers 9–10 pseudo-rotaxanes 25–6, 115

534

Index

PSS see poly(styrenesulfonic acid) PTA see 1,3,5-triaza-7-phosphaadamantane 195 Pt NMR 39 PTP see pentathiophene PTX see paclitaxel pulse field-gradient NMR 23 pulse field-gradient spin echo (PFGSE) NMR 39 quantum dots (QD) 143–5, 368, 385–6 quenching effects 74, 79–81 radial complexation 43 radical initiators 190 radioactively-labeled dendrimers 386 RAFT see reversible additionfragmentation chain transfer RAIRS see reflection–absorption infrared microscopy Raman spectroscopy 42–3 RB see Rose Bengal RCM see ring closing metathesis reaction monitoring 43 reactive oxygen species (ROS) 449 recycling of catalysts heterogeneous catalysis 244, 247–50, 252, 258, 261 homogeneous catalysis 166–7, 172–3, 215, 219, 227, 229, 233–4 REDOR see rotational-echo double-resonance redox processes 190 reflection–absorption infrared microscopy (RAIRS) 324 regenerative medicine 498–501 RES see reticuloendothelial system resin-supported heterogeneous catalysis 248–54 reticulated polymers 4 reticuloendothelial system (RES) 442, 465, 466, 470 reversible addition-fragmentation chain transfer (RAFT) polymerization 111

rhodium complexes catalytic applications 175–6, 186–7, 192, 204–7, 219–20, 225–6, 230 heterogeneous catalysis 240–2, 245–9 nanoparticles 147 rigidity carbon-based dendrimers 17–18 liquid crystalline dendrimers 131–5 luminescent dendrimers 75 self-assembly 22 stimuli-responsive dendrimers 104–5 ring closing metathesis (RCM) 288 ROS see reactive oxygen species Rose Bengal (RB) 112, 337, 464 rotational-echo double-resonance (REDOR) NMR 40 rotaxanes 132 Ruhrchemie/Rhône–Poulenc oxo process 225–6 ruthenium complexes biological sensors 376–7 catalytic applications 172–3, 175, 187, 207–8, 218–19, 226–7, 230–1 characterization methods 39 chemical sensors 366 drug delivery 474 luminescent dendrimers 78–9, 81, 83, 87–8 salicylic acid 110, 439 SAM see self-assembled monolayers SANS see small-angle neutron scattering SAXS see small-angle X-ray scattering SBA-15 silica 246–8, 254–6 scandium-containing dendrimers 259–60 scanning electrochemical microscopy (SECM) 346 scanning electron microscopy (SEM) 339, 343 scanning force microscopy (SFM) 333 scanning probe lithography (SPL) 331, 342–4 scanning probe microscopy 333 SEC see size exclusion chromatography SECM see scanning electrochemical microscopy

Index

second harmonic generation (SHG) 321 selenium-containing dendrimers 18, 178, 190, 224–5 seleno-phosphate dendrimers 18 self-assembled monolayers (SAM) 313–14, 320, 326–34, 342–50 self-assembly dendrimers 313–59 applications 315, 323, 342–4 azobenzene-containing dendrimers 320–1 characterization methods 48, 50–1 dip-pen nanolithography 314, 342, 344–50 drug delivery 467 encapsulation into materials 269, 270–2, 276–7, 279–80, 299 fullerene-based dendrons 322–5 gold surface assemblies 317–18, 327–30 Langmuir–Blodgett films 313, 314–26, 342, 350–1 layer-by-layer method 334–41, 342, 346–7, 349–50 liquid crystalline dendrimers 126, 128–9, 134–5 lithographic methods 314 microcontact printing 314, 327, 335–6, 344–50 multilayers 313–59 nanoimprinting on solid surfaces 342–50 nanoparticles 149–50, 151, 325–6, 336 poly(amidoamine) dendrimers 319–20, 325–6 poly(benzyl ether) dendrimers 316–19 poly(carbosilane) dendrimers 321–2, 329–30, 332 poly(propyleneimine) dendrimers 319–20 scanning probe lithography 331, 342–4 self-assembled monolayers 313–14, 320, 326–34, 342–50 silicon substrate assemblies 330–4, 343 synthetic methods 21–6 transfer printing 344–50 self-condensation 28

535

SEM see scanning electron microscopy sensors see biological sensors; chemical sensors sentinel lymph nodes (SLN) 399 shape-persistence 39–40 SHG see second harmonic generation 29 Si NMR 37–8 silica gels 269, 280–5 silica-supported heterogeneous catalysis 240–8, 254–6, 258–9 silicon-containing dendrimers catalytic applications 170, 173–6, 186, 203, 208–9, 221, 232 characterization methods 37–40 encapsulation into materials 272 novel biomedical applications 485, 494–5 self-assembly dendrimers 321–2, 327, 329–30, 332, 342–5 stimuli-responsive dendrimers 102–3 synthetic methods 15–16 transfection agents 424–6 silicon substrate assemblies 330–4, 343 siloxanes see poly(siloxane) dendrimers silver complexes 470–1 single nucleotide polymorphisms (SNP) 382 single positron emission computed tomography (SPECT) 405–7 single/superconducting quantum interface device (SQUID) 46 single-wall carbon nanotubes (SWCNT) 369–70, 380 siRNA see small interfering RNA size exclusion chromatography (SEC) 52–3 SLN see sentinel lymph nodes small interfering RNA (siRNA) 426, 448, 494–5, 512 small-angle neutron scattering (SANS) 47–8 small-angle X-ray scattering (SAXS) 48 smectic phases 125–6, 130–2, 134–5 119 Sn NMR 38 SNP see single nucleotide polymorphisms sol-gel process 259, 269, 281, 299

536

Index

solid gels 285–6 solid-state NMR 40 solution media changes 99, 114–18 Sonogashira reaction 167–8 SPECT see single positron emission computed tomography SPFS see surface plasmon field-enhanced fluorescence spectroscopy SPIO see superparamagnetic iron oxide SPL see scanning probe lithography SPR see surface plasmon resonance SQUID see single/superconducting quantum interface device stabilizing agents 149, 154 star polymers 4, 110–11 Starburst dendrimers see poly(amidoamine) dendrimers statistical grafting 72–4 stepwise radial complexation 43 steric effects 4, 165–6 stilbene-containing dendrimers 100, 108–9 Stille reaction 168, 170 stimuli-responsive dendrimers 99–124 azobenzene-containing dendrimers 99, 100, 101–8 core group functionalization 103–5, 107–8 definition 99 dendrons 100, 103–4, 112–14, 116–17 disassembly 99, 115–18 internal functionalization 105–8 isomerization processes 99, 101–3, 105–6, 108–9 pH-responsivity 99, 114–15 photoresponsivity 99, 100–10 solution media changes 99, 114–18 stilbene-containing dendrimers 100, 108–9 terminal group functionalization 101–3 thermoresponsivity 99, 110–14 streptavidin 384–5 structural defects 3, 36–7 sulfamethoxazole 469, 470 sulfide oxidations 187–8 sulfur dioxide sensors 364–5

supercritical catalytic media 220–1 superparamagnetic contrast agents 398, 402–3 superparamagnetic iron oxide (SPIO) 146–7, 402–3 supramolecular assemblies 23–5, 473–5 supramolecular gels 270–3 surface functionalization see terminal group functionalization surface ionic interactions 473–5 surface plasmon field-enhanced fluorescence spectroscopy (SPFS) 337, 383 surface plasmon resonance (SPR) biological sensors 384 chemical sensors 367 self-assembly dendrimers 330, 338–40 Suzuki reaction 168–9, 249, 251, 256, 258–9 Suzuki–Miyaura reaction 184–5, 227–30, 232 SWCNT see single-wall carbon nanotubes synthetic methods 3–33 accelerated syntheses 26–9 carbon-based dendrimers 17–19 convergent versus divergent processes 3–4 dendrons 4, 10–14, 20–3, 26–8 hyperbranched polymers 9–10, 12 multifunctional cores 3–4 nitrogen heterocycle-based dendrimers 19–21 phosphorus-containing dendrimers 16–17, 18, 27–9 poly(amidoamine) dendrimers 5–7 poly(ester) dendrimers 10–14 poly(ether) dendrimers 7–10, 12–13 poly(lysine) dendrimers 14–15 poly(propyleneimine) dendrimers 5, 6 self-assembly dendrimers 21–6 silicon-containing dendrimers 15–16 TADDOL ligands 201, 203, 257 targeted drug delivery 72–4, 90, 440–9, 475–6 technetium labeling 406–7

Index

TEG see tetraethylene glycol; tri(ethylene glycol) tellurium-containing dendrimers 178, 224–5 TEM see transmission electron microscopy temperature modulated calorimetry (TMC) 50 template dendrisilica nanocomposites 284 template synthesis 152–4 TEMPO radical initiator 190 Tentagel resins 254 TEOS see tetraethyl-ortho-silicate terminal group characterization 36–40 terminal group functionalization catalytic applications 206–7, 220–1 chemical sensors 363–5 drug delivery 442, 444–6 fluorescence 68–74, 88–9 liquid crystalline dendrimers 126–34 nanoparticles 149–51, 154 stimuli-responsive dendrimers 101–3, 117 synthetic methods 4 transfection agents 416–18 tetraethyl-ortho-silicate (TEOS) 281–3 tetraethylene glycol (TEG) units 184–5 tetrafunctional dendrimers 72–3 tetrathiafulvalene (TTF) 366 TGA see thermogravimetric analysis thermal degradation 115–16 thermogravimetric analysis (TGA) 146–7 thermoresponsive dendrimers 99, 110–14 thienylethynylene linkages 84–5 thiol-PAMAM dendrimers 383–4 thiolated lactoferrin 417 thio-phosphate dendrimers 18 thiourea terminal groups 39 tin-containing dendrimers 38 titania films 343–4, 367–8 titanium alkoxide 269 titanium complexes 203, 257, 285–6 TMC see temperature modulated calorimetry TNT see 2,4,6-trinitrotoluene TOCSY see total correlation spectroscopy

537

tosyl-1,2-diphenylethylenediamine (TsDPEN) 207–8, 231–2 total correlation spectroscopy (TOCSY) 37 TPA see two-photon absorption TPEF see two-photon excited fluorescence trans/cis isomerizations 99, 101–3, 105–6, 108–9 transamination reactions 210 transfection agents 413–35, 512–13 core group functionalization 418–19 cytotoxicity 416–17, 420, 423, 426 definition and concepts 413–15 hyperbranched polymers 420 mechanism 414–15 nanoparticles 419–20 PAMAM dendrimers 414, 415–20 phosphorus-containing dendrimers 423–4, 426 pioneering work 415–16 PPI dendrimers 421 silicon-containing dendrimers 424–6 terminal group functionalization 416–18 transfer hydrogenation reactions 207–8, 230–1 transfer printing 344–50 transmembrane enhancement 439 transmission electron microscopy (TEM) 49 nanoparticles 148, 150 self-assembly dendrimers 318 stimuli-responsive dendrimers 105–6 triarylamine end-capped dendrimers 294–7 triarylethene dendrimers 84 1,3,5-triaza-7-phosphaadamantane (PTA) dendrimers 226 triazole-containing dendrimers 20–1 triclosan 469, 470 tri(ethylene glycol) (TEG) 228–9 2,4,6-trinitrotoluene (TNT) 365, 367, 512 triolefinic azamacrocycles 152 triphenylene dendrimers 84 tris(distyrylbenzyl)amine-centered dendrimers 291–3

538

Index

tris(oxazoline) ligands 200 tropicamide 472 TsDPEN see tosyl-1,2-diphenylethylenediamine TTF see tetrathiafulvalene tumor-targeted drug delivery 440–9, 466–9, 476 two branched monomer strategy 28–9 two-dimensional INADEQUATE 37–8 two-phase catalytic media 216–19 two-photon absorption (TPA) 67, 86–9, 362 two-photon excited fluorescence (TPEF) microscopy 404–5 tyramine-based dendrimers 495–6 ultrafiltration 153–4 ultrasmall superparamagnetic iron oxide (USPIO) 402–3 ultraviolet–visible (UV–Vis) spectroscopy 43–4, 323 USPIO see ultrasmall superparamagnetic iron oxide UV–Vis see ultraviolet–visible vascular endothelial growth factors (VEGF) 449, 452 vasculature 440–2 VEGF see vascular endothelial growth factors

viscosity, intrinsic 50–1 volatile organic compounds (VOC) 369–70 Wang resin 249, 252 wide-angle X-ray scattering (WAXS) 48 Wilkinson’s catalyst 246–8 Williamson ether synthesis 9 X-ray diffraction (XRD) 41–2, 323 X-ray fluorescence 47 X-ray photoelectron spectroscopy (XPS) 47, 329 X-ray reflectivity 317, 323–4, 325 xenon HYPER-CREST 403 xerogel sensing films 368 XPS see X-ray photoelectron spectroscopy XRD see X-ray diffraction ytterbium-based contrast agents 402 zeta potentials 149–50 zinc complexes biological sensors 384 catalytic applications 223–4 chemical sensors 362–3 heterogeneous catalysis 254–5, 257–8 zinc porphyrins 69, 79–83, 88 zinc sulfide nanoparticles 285