Single-Chain Polymer Nanoparticles

Single-Chain Polymer Nanoparticles

Synthesis, Characterization, Simulations, and Applications

Edited by José A. Pomposo

Editor

Prof. José A. PomposoUPV/EHU –IKERBASQUEMaterials Physics CenterPaseo Manuel de Lardizabal 520018 Donostia-San SebastiánSpain

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v

Contents

List of Contributors xiPreface xv

1 Synthetic Methods Toward Single-Chain PolymerNanoparticles 1Ozcan Altintas, Tobias S. Fischer, and Christopher Barner-Kowollik

1.1 Introduction 11.2 Single-Chain Rings via Irreversible and Reversible Bonds 21.3 Single-Chain Nanoparticles via Irreversible Bonds 81.4 Single-Chain Nanoparticles via Supramolecular Chemistry 171.5 Single-Chain Nanoparticles Based on Dynamic Covalent

Chemistry 321.6 Conclusions and Outlook 33

Acknowledgments 34References 34

2 Computer Simulations of Single-Chain Nanoparticles 47Angel J. Moreno and Federica Lo Verso

2.1 Computer Simulations in Soft Matter Science 472.2 Simulation of Single-Chain Nanoparticles: Antecedents 492.3 A Bead–Spring Model for Single-Chain Nanoparticles 502.4 Conventional Routes in Good Solvent: Sparse Single-Chain

Nanoparticles 532.4.1 The Simple Case: SCNPs from Homofunctional Precursors 542.4.2 SCNPs Synthesis via Orthogonal and Multi-orthogonal

Protocols 572.5 Routes to Globular Single-Chain Nanoparticles 612.5.1 Bonding Mediated by Long Linkers 632.5.2 Solvent-Assisted Routes 642.6 Sparse SCNPs: Analogies with Intrinsically Disordered Proteins 702.7 Globular SCNPs: A New Class of Soft Colloids 752.8 Conclusions and Outlook 792.8.1 SCNPs as Nanofillers in All-Polymer Nanocomposites 802.8.2 Nonlinear Rheology of SCNPs 81

vi Contents

2.8.3 SCNPs under Pulling Forces 81Acknowledgments 82References 82

3 Characterization of Single-Chain Polymer Nanoparticles:Analytical Techniques 91Ashley M. Hanlon, Kyle J. Rodriguez, Ruiwen Chen, Elizabeth Bright, andErik B. Berda

3.1 Introduction 913.2 Single-Chain Polymer Nanoparticle Characterization via Size

Exclusion Chromatography (SEC) 923.2.1 Standard Calibration SEC 923.2.2 Measuring Single-Chain Polymer Nanoparticle Formation via

SEC-MALS 983.2.3 Measuring Single-Chain Polymer Nanoparticle Formation via SEC

and Viscometry 1003.3 Spectroscopic Characterization of Single-Chain Polymer

Nanoparticles 1023.3.1 Single-Chain Polymer Nanoparticle Characterization via Standard 1D

1H NMR 1033.3.2 Single-Chain Polymer Nanoparticle Characterization via Other

Nuclei 1D NMR 1033.3.3 Single-Chain Polymer Nanoparticle Structural and Conformational

Characterization via NMR 1043.3.4 Single-Chain Polymer Nanoparticle Characterization via IR, UV–vis,

CD, and Fluorescence Spectroscopy 1103.4 Characterization of Single-Chain Polymer Nanoparticle

Morphology 1123.4.1 Morphological Characterization via TEM 1123.4.2 Morphological Characterization via AFM 1143.4.3 Morphological Characterization via Scattering 1203.5 Conclusions and Outlook 122

References 123

4 Structure and Dynamics of Systems Based on Single-ChainPolymer Nano-Particles Investigated by ScatteringTechniques 129Arantxa Arbe and Juan Colmenero

4.1 Introduction 1294.2 Scattering Experiments 1304.3 Sources and Instrumentation 1364.3.1 Sources 1364.3.2 Diffraction 1364.3.3 Quasielastic Neutron Scattering 1384.4 Application of Scattering Techniques to Polymeric Systems 1404.4.1 Polymer Melts 140

Contents vii

4.4.2 Polymer Solutions 1464.5 SCNPs in Dilute Solution 1484.5.1 How Globular Are SCNPs in Good Solvent? 1494.5.2 Chain Dynamics 1524.6 SCNPs in Bulk 1584.7 All-Polymer Nano-Composites: SCNPs Dispersed in a Linear

Polymer Matrix 1594.7.1 Interpenetration of the Components 1604.7.2 Dynamic Asymmetry 1624.7.3 Selecting Component Contributions by Deuterium Labeling 1634.7.4 Dynamics of SCNPs Observed by QENS 1654.7.5 Linear Polymer Matrix Dynamics 1654.8 SCNPs as Confining Medium of Linear Chains 1724.9 Conclusions 173

Acknowledgments 174References 174

5 Dynamically Folded Single-Chain PolymericNanoparticles 183Yiliu Liu and Anja R.A. Palmans

5.1 Introduction 1835.2 Single-Chain Polymeric Nanoparticles versus Conventional

Nanoparticles 1845.3 Preparation of Dynamically Folded Single-Chain Polymeric

Nanoparticles 1865.4 Characterization of Dynamically Folded Single-Chain Polymer

Nanoparticles 2005.5 Conclusions and Future Outlook 207

References 209

6 Metal Containing Single-Chain Nanoparticles 217Inbal Berkovich, Victoria Kobernik, Stefano Guidone and Norberto GabrielLemcoff

6.1 Introduction 2176.2 Palladium 2186.3 Iron 2226.4 Copper 2286.5 Other Metals 2396.5.1 Rhodium, Iridium, and Nickel 2396.5.2 Ruthenium 2426.5.3 Zinc 2466.5.4 Gold 2476.5.5 Gadolinium 2506.5.6 Gallium 2516.6 Conclusions and Outlook 253

References 253

viii Contents

7 Colloidal Unimolecular Polymer Particles: CUP 259Michael R. Van DeMark, Ashish Zore, Peng Geng, and Fei Zheng

7.1 Introduction 2597.2 Synthesis 2607.2.1 Monomers and Ratio, Molecular Weight, Glass Transition, Cup Size,

and Functionality 2647.2.2 Reduction and CUP Formation 2647.2.3 Collapse Point 2657.2.4 CUP Size and Distribution Correlation to Molecular Weight 2667.3 Theory of the Formation of CUP Particles 2677.3.1 Entropy Effect/SoapTheory 2677.3.2 Hydrophilic/Lipophilic Balance (HLB) 2697.3.3 Flory–Huggins Theory 2707.4 Conformation of the CUP Particles 2717.5 Electrokinetic Behavior in CUPs 2717.5.1 Zeta Potential, Debye–Hückel Parameter and Electrophoretic

Mobility 2727.5.2 Determining the Effective Nuclear Charge 2727.5.2.1 Nernst–Einstein Model 2727.5.2.2 Hessingers Model 2737.5.2.3 Charge Renormalization 2737.5.3 Electrokinetic Behavior in COO− CUPs 2737.6 Electroviscous Effect in CUPs 2747.6.1 Electroviscous Effect: Theory 2757.6.1.1 Primary Electroviscous Effect 2757.6.1.2 Secondary Electroviscous Effect 2767.6.1.3 Tertiary Electroviscous Effect 2777.6.2 Intrinsic Viscosity Determination 2777.6.3 Surface Water Determination 2777.6.4 Electroviscous Effect in CUPs 2787.6.4.1 Electroviscous Effect in COO− CUPs 2787.6.4.2 Electroviscous Effect in SO3−CUPs 2787.6.4.3 Electroviscous Effect in QUAT CUPs 2797.6.5 Effect of Salts on Rheology 2797.7 Gel Point Behavior 2807.7.1 Packing in CUPs 2807.7.2 Gel Point Study 2817.7.2.1 Determination of Gel Point 2817.7.2.2 Viscosity Measurements 2817.7.2.3 Maximum Packing Volume Fraction, Density, andThickness of

Surface Water 2827.7.3 Comparison with Commercial Resins like Latex and Polyurethane

Dispersions 2847.8 Surface Tension Behavior 2857.8.1 Equilibrium Surface Tension Behavior 2867.8.1.1 Effect of Concentration on Equilibrium Surface Tension 2867.8.1.2 Effect of Molecular Weight on Equilibrium Surface Tension 287

Contents ix

7.8.1.3 Effect of Surface Active Groups on Equilibrium Surface Tension 2887.8.2 Dynamic Surface Tension Behavior 2887.8.2.1 Effect of Molecular Weight on Kinetic Relaxation Time 2897.8.2.2 Effect of Concentration on Kinetic Relaxation Time 2907.8.2.3 Effect of Molecular Weight on Dynamic Surface Tension 2907.8.2.4 Effect of Concentration on Dynamic Surface Tension 2907.9 Cup Surface Water 2917.9.1 Electroviscous Effect and Gel Point 2917.9.2 Differential Scanning Calorimetry 2917.9.3 NMR Relaxation Study 2937.9.3.1 Proton NMR Spin–Lattice Relaxation Time Constant versus CUP

Concentration 2937.9.3.2 Proton NMR Spin–Lattice Relaxation Time Constant versus

Temperature 2947.9.3.3 Calculation of Bound Water Amount 2957.10 Study of Core Environment of CUPs 2977.10.1 F19 NMR T2 Relaxation Experiment 2977.11 Applications: Use of CUPs in Coatings 2987.11.1 Acrylic CUP Coating Lacquers 2987.11.2 Aziridine-Cured Acrylic CUPs Resin 2997.11.3 Use of CUPs with Melamine Resin Cross-Linking 3007.11.4 Use of Sulfonate CUPs as Catalyst for Melamine Cure Systems 3017.11.5 Epoxy 3027.11.6 Use of CUPs as Additive for Freeze–Thaw Stability and Wet Edge

Retention 305References 306

8 Single-Chain Nanoparticles via Self-Folding AmphiphilicCopolymers in Water 313Takaya Terashima andMitsuo Sawamoto

8.1 Introduction 3138.2 Single-Chain Folding Amphiphilic Random Copolymers 3158.2.1 Hydrophobic Alkyl Pendants 3168.2.2 Hydrophobic/Hydrogen-Bonding Pendants 3218.2.3 Fluorous Perfluorinated Pendants 3268.3 Precision Self-Assembly and Self-Sorting of Amphiphilic Random

Copolymers 3298.4 Single-Chain Crosslinked Star Polymers 3328.5 Conclusions and Future Directions 335

References 335

9 Applications of Single-Chain Polymer Nanoparticles 341Jon Rubio-Cervilla and Edurne González and José A. Pomposo

9.1 Introduction 3419.1.1 Single-Chain Soft Nano-Objects 3419.1.2 Reversible versus Irreversible Single-Chain Polymer

Nanoparticles 345

x Contents

9.1.3 Main Applications of Single-Chain Polymer Nanoparticles 3469.2 Nanomedicine 3479.2.1 Controlled Drug Delivery Systems 3499.2.1.1 Single-Chain Polymer Nanoparticles for Controlled Delivery of

Chiral Amino Acid Derivatives 3499.2.1.2 Single-Chain Polymer Nanoparticles for Controlled Delivery of

Peptides 3509.2.1.3 Single-Chain Polymer Nanoparticles for Controlled Delivery of

Vitamins 3519.2.1.4 Single-Chain Polymer Nanoparticles for Controlled Delivery of

Drugs 3539.2.2 Image Contrast Agents 3559.2.2.1 Single-Chain Polymer Nanoparticles for Magnetic Resonance

Imaging 3559.2.2.2 Single-Chain Polymer Nanoparticles for Single Photon Emission

Computerized Tomography 3569.2.2.3 Single-Chain Polymer Nanoparticles for Fluorescence Imaging 3569.3 Catalysis 3609.3.1 Single-Chain Polymer Nanoparticles as Nanoreactors for the

Synthesis of Chemical Compounds 3619.3.2 Single-Chain Polymer Nanoparticles as Nanoreactors for the

Synthesis of Polymers 3659.3.2.1 Ring-Opening Polymerization 3659.3.2.2 Controlled Radical Polymerization 3669.3.3 Single-Chain Polymer Nanoparticles as Nanoreactors for the

Synthesis of Nanomaterials 3679.3.3.1 Gold Nanoparticles 3679.3.3.2 Quantum Dots 3679.3.3.3 Carbon Nanodots 3689.4 Sensing 3699.4.1 Single-Chain Polymer Nanoparticles as Sensors of Metal Ions 3699.4.2 Single-Chain Polymer Nanoparticles as Sensors of Proteins 3699.5 Other Uses 3719.5.1 Porogens for Microelectronic Applications 3719.5.2 Functional Nanoparticles for Bioscience 3729.5.3 Reversible Hydrogels 3739.5.4 Supramolecular Films 3739.5.5 Rheology Modifiers 3749.5.6 All-Polymer Nanocomposites 3749.5.7 Surfactants 3759.6 Conclusions and Outlook 376

Acknowledgments 378References 378

Index 389

xi

List of Contributors

Ozcan AltintasUniversity of MinnesotaDepartment of ChemistryMinneapolisMN 55455-0431United States

Arantxa ArbeCentro de Física de Materiales (CFM)(CSIC-UPV/EHU)Materials Physics Center (MPC)Paseo Manuel de Lardizábal 520018 San SebastiánSpain

Christopher Barner-KowollikPreparative MacromolecularChemistryInstitut für Technische Chemie undPolymerchemieKarlsruhe Institute of TechnologyEngesserstraße 1876128 KarlsruheGermany

and

School of ChemistryQueensland University of Technology(QUT)Physics and Mechanical Engineering2 George StreetQLD 4000BrisbaneAustralia

Erik B. BerdaUniversity of New HampshireDepartment of Chemistry andMaterials Science ProgramDurhamNH 03824United States

Inbal BerkovichBen-Gurion University of the NegevDepartment of ChemistryBeer Sheva-84105Israel

Elizabeth BrightUniversity of New HampshireDepartment of ChemistryDurhamNH 03824United States

Ruiwen ChenUniversity of New HampshireDepartment of ChemistryDurhamNH 03824United States

Juan ColmeneroCentro de Física de Materiales (CFM)(CSIC - UPV/EHU)Materials Physics Center (MPC)Paseo Manuel de Lardizábal 520018 San SebastiánSpain

xii List of Contributors

and

Departamento de Física de Materiales(UPV/EHU)Apartado 107220080 SebastiánSpain

and

Donostia International Physics Center(DIPC)Paseo Manuel de Lardizábal 420018 SebastiánSpain

Tobias S. FischerPreparative MacromolecularChemistryInstitut für Technische Chemie undPolymerchemieKarlsruhe Institute of TechnologyEngesserstraße 1876128 KarlsruheGermany

Peng GengMissouri University of Science &TechnologyDepartment of ChemistryMissouri S&T Coatings InstituteRollaMO 65409United States

Edurne GonzálezCentro de Física de Materiales (CFM)(CSIC-UPV/EHU)Materials Physics Center (MPC)Paseo Manuel de Lardizábal 520018 San SebastiánSpain

Stefano GuidoneBen-Gurion University of the NegevDepartment of ChemistryBeer Sheva-84105Israel

Ashley M. HanlonUniversity of New HampshireDepartment of ChemistryDurhamNH 03824United States

Victoria KobernikBen-Gurion University of the NegevDepartment of ChemistryBeer Sheva-84105Israel

Norberto Gabriel LemcoffBen-Gurion University of the NegevDepartment of ChemistryBeer Sheva-84105Israel

Yiliu LiuLaboratory of Macromolecular andOrganic ChemistryInstitute for Complex MolecularSystemsTU EindhovenPO Box 5135600 MB EindhovenThe Netherlands

Federica Lo VersoCentro de Física de Materiales (CFM)(CSIC-UPV/EHU)Materials Physics Center (MPC)Paseo Manuel de Lardizábal 520018 San SebastiánSpain

List of Contributors xiii

Angel J. MorenoCentro de Física de Materiales (CFM)(CSIC-UPV/EHU)Materials Physics Center (MPC)Paseo Manuel de Lardizábal 520018 San SebastiánSpain

and

Donostia International Physics Center(DIPC)Paseo Manuel de Lardizábal 420018 SebastiánSpain

Anja R. A. PalmansLaboratory of Macromolecular andOrganic ChemistryInstitute for Complex MolecularSystemsTU EindhovenPO Box 5135600 MB EindhovenThe Netherlands

José A. PomposoCentro de Física de Materiales (CFM)(CSIC - UPV/EHU)Materials Physics Center (MPC)Paseo Manuel de Lardizábal 520018 San SebastiánSpain

and

Departamento de Física de Materiales(UPV/EHU)Apartado 107220080 SebastiánSpain

and

IKERBASQUE – Basque Foundationfor ScienceMaría Díaz de Haro 348013 BilbaoSpain

Kyle J. RodriguezUniversity of New HampshireDepartment of ChemistryDurhamNH 03824United States

Jon Rubio-CervillaCentro de Física de Materiales (CFM)(CSIC-UPV/EHU)Materials Physics Center (MPC)Paseo Manuel de Lardizábal 520018 San SebastiánSpain

Mitsuo SawamotoKyoto UniversityDepartment of Polymer ChemistryGraduate School of EngineeringKatsuraNishikyo-kuKyoto 615-8510Japan

Takaya TerashimaKyoto UniversityDepartment of Polymer ChemistryGraduate School of EngineeringKatsuraNishikyo-kuKyoto 615-8510Japan

Michael R. Van De MarkMissouri University of Science &TechnologyDepartment of ChemistryMissouri S&T Coatings InstituteRollaMO 65409United States

xiv List of Contributors

Fei ZhengMissouri University of Science &TechnologyDepartment of ChemistryMissouri S&T Coatings InstituteRollaMO 65409United States

Ashish ZoreMissouri University of Science &TechnologyDepartment of ChemistryMissouri S&T Coatings InstituteRollaMO 65409United States

xv

Preface

In the Nanotechnology era, many methods for synthesis of materials withwell-defined nanoscale dimensions (1 nm = 10−9 m) have been developed. As aremarkable example, excellent size and shape control has been achieved for thesynthesis of hard nanoparticles, such as quantumdots, gold nanoclusters ormetaloxide nanoparticles. Similar control to produce soft nanoparticles based on poly-mers with dimensions below 10 nmhas not been possible until just the beginningof the 21st Century. Advances in the synthesis of well-defined functional poly-mers through living radical polymerization processes, post-functionalizationtechniques, as well as development of highly-efficient intra-chain couplingreactions have paved the way to the reliable production of single-chain polymernanoparticles.Since 2001, this new topic has grown so rapidly and to such an extent, that it

was time to summarize, condense and comprehensively present all this new gen-erated knowledge. That is precisely the reason of this book, the first one specif-ically devoted to the synthesis, characterization, simulations and applications ofsingle-chain polymer nanoparticles as versatile soft nano-objects with potentialapplications in many fields, from catalysis to nanomedicine. The book aims toprovide an essential overview of this evolving field, and the current challengesone is faced to reach ultra-small unimolecular soft nano-objects endowed withuseful, autonomous and smart functions.Obviously, this book would not have been possible without the contribution of

the main players involved in research & development around “single-chain poly-mer nanoparticles”, so I am extremely grateful to all of them. Finally I would like tothank the editorial staff atWiley for their assistance in realizing this book project,and to IKERBASQUE - Basque Foundation for Science for continuous support.

José A. PomposoDonostia-San Sebastián

1

1

Synthetic Methods Toward Single-Chain PolymerNanoparticlesOzcan Altintas1, Tobias S. Fischer2, and Christopher Barner-Kowollik2,3

1University of Minnesota, Department of Chemistry, 207 Pleasant St SE, Minneapolis, MN 55455-0431, USA2Institut für Technische Chemie und Polymerchemie Karlsruhe Institute of Technology (KIT), PreparativeMacromolecular Chemistry, Engesserstraße 18, 76128 Karlsruhe, Germany3Queensland University of Technology (QUT), School of Chemistry, Physics andMechanical Engineering, 2George Street, QLD 4000, Brisbane, Australia

1.1 Introduction

Natural macromolecules such as enzymes effectively function due to a precise aswell as dynamic three-dimensional (3D) architecture. One of the most importantdriving forces for synthetic macromolecular design is the emulation of naturalprocesses and the design of chemical reaction sequences that are inspired bynature [1–3]. Nature’s degree of controlling the synthesis remains unreached bysynthetic chemists. Nevertheless, well-defined compact 3D synthetic functionalstructures can be prepared, reducing the conformational freedom of single poly-mer chains by connecting pendant subunits at predefined positions [4–6].Scientists have been interested in intramolecular cross-linking reactions

since the mid-twentieth century where cross-linking processes have beeninvestigated between variable molecules at very low concentrations of polymersin solution [7–9]. Reversible deactivation radical polymerization (RDRP) tech-niques such as atom transfer radical polymerization (ATRP) [10, 11], reversibleaddition–fragmentation chain transfer (RAFT) polymerization [12, 13], andnitroxide-mediated polymerization (NMP) [14] are employed to synthesizewell-defined polymers by controlling the dispersity, molecular weight, andarchitecture of the macromolecules. In addition, exploiting the combination ofRDRP techniques with modular and orthogonal ligation protocols [15–17], theintramolecular cross-linking of a single polymer chain leading to single-chainnanoparticles (SCNPs), has rapidly emerged as an alternative approach to gen-erate well-defined compact 3D synthetic functional structures with diametersof below 20 nm [18–27]. Supramolecular chemistry affords a high degree ofcontrol over naturally occurring molecules and macromolecules [28]. Typically,the formed natural biopolymers and their structure are controlled by reversibleself-folding processes induced by supramolecular interactions [29]. Hydrogenbonds, van der Waals interactions, and electrostatic or hydrophobic interactionsforce biomolecules such as proteins into their 3D folded analog. Folding of

Single-Chain Polymer Nanoparticles: Synthesis, Characterization, Simulations, and Applications,First Edition. Edited by José A. Pomposo.© 2017Wiley-VCH Verlag GmbH & Co. KGaA. Published 2017 byWiley-VCH Verlag GmbH & Co. KGaA.

2 1 Synthetic Methods Toward Single-Chain Polymer Nanoparticles

proteins, for instance, leads to complex secondary, tertiary, and quaternarystructures, which determine their properties and functions [30].Single-chain folding of synthetic macromolecules has been a fast moving and

innovative field in macromolecular chemistry, constituting a promising pathwaytoward artificial, adaptative, and smart single-chain polymer nanodevices. Thefolding and unfolding of well-defined single linear polymer chains has been stud-ied bymeans of single-chain technology [23] through intramolecular bonds fromthe viewpoint of synthetic macromolecular chemistry [25]. Generally, SCNPscan be generated by two approaches [26]. In one approach, individual – andoften mutually orthogonal – recognition motifs are attached to preselectedand defined points along the polymer chain, leading to well-defined SCNPs, aprocess that has been termed “selective-point folding”. A second pathway toform SCNPs is the so-called “repeat-unit approach.” For repeat-unit folding,block copolymers with specific complementary yet statistically scattered motifsalong the polymer backbone are designed. The resulting structures are lessdefined due to a chaotic and statistical collapse compared with selective-pointfolding. Single-chain folding technology makes intensive use of supramolecularnon-covalent interactions to generate SCNPs. We here focus on the applicationof irreversible bonds, non-covalent bonds, and dynamic covalent bonds to foldone single polymer chain into a SCNP. The current understanding of how tosynthesize well-defined precursor polymers as well as the corresponding SCNPswill be discussed in detail. Our exploration into SCNP synthetic technologycommences with a foray into the simplest of all folding systems, that is, rings.Throughout the current chapter, we do not attempt to provide a complete reviewof the field but will rather focus on critically selected examples.

1.2 Single-Chain Rings via Irreversible and ReversibleBonds

In nature, ring formation is employed to equip polypeptides with specificproperties, such as improved stability against enzymatic degradation. In recentyears, polymers possessing various topologies have been prepared via advancedmodular ligation reactions. Cyclic polymers with an endless molecular topologyhave gained interest from polymer and material scientists due to their uniquephysical properties [31, 32]. Cyclic polymers have significantly different char-acteristics with regard to intrinsic viscosity, glass transition temperature, andorder–disorder transition compared with their linear counterparts [33]. A widevariety of cyclization methods has been reported. We submit that the provisionof cyclic polymer systems is a key step preceding the preparation of single-chainpolymeric nanoparticles. There exist important similarities between the prepa-ration of cyclic polymers and single-chain polymeric nanoparticles in terms ofreaction conditions as well as characterization methods. However, the cyclicpolymer field is immense, and therefore, we highlight here selected examplesonly, where the same or similar chemistries were used for the preparation of theSCNPs.Grayson and coworkers first reported the preparation of single-chain rings

based on the combination of ATRP and the copper-catalyzed azide–alkyne

1.2 Single-Chain Rings via Irreversible and Reversible Bonds 3

O O

n Br

O OO O

NN

N

n nN3

iii

Figure 1.1 Synthetic route for the preparation of well-defined cyclic polystyrene via thecombination of ATRP and CuAAC reaction. (i) NaN3, DMF, room temperature (r.t.). (ii) CuBr/Bipy,in degassed DMF, 120 ∘C. (Laurent and Grayson 2006 [34]. Reproduced with permission of theAmerican Chemical Society.)

cycloaddition (CuAAC) reaction coupling azide and alkyne-functional endgroups (Figure 1.1) [34]. A linear poly(styrene) (PS) precursor was preparedvia the ATRP technique, using propargyl 2-bromoisobutyrate as the initiator.Subsequent azidation of the end group was carried out. The cyclization reactionwas successfully conducted on α-alkyne- and ω-azide-functionalized linearpolymers using a syringe pump system, allowing for very low concentrations(<0.01mM). The single-chain folding was followed by size-exclusion chromato-graphy (SEC), 1H nuclear magnetic resonance (NMR) spectrometry, and Fouriertransform infrared (FT-IR) analysis. The CuAAC reaction has received substan-tial attention in the field of cyclic polymers [35, 36] due to its often quantitativeyields, mild reaction condition, tolerance to a wide range of functional groups,and harmony with the RDRP techniques for the preparation of various cyclictopologies [37, 38].As an alternative to CuAAC processes, Diels–Alder (DA) cycloadditions

involve the reaction of a conjugated diene (4π) with a dieneophile (2π) toyield a 6-membered ring, where the [4+ 2] denotes the number of π-electronsthat are taking part in the cycloaddition process. Especially light-triggeredDA reactions ensure near quantitative coupling within short reaction times atambient temperature without a catalyst and are a highly promising avenue for thepreparation of cyclic polymers and SCNPs alike. Barner-Kowollik and cowork-ers introduced a facile method for the preparation of macrocyclic aliphaticpolyesters based on the catalyst-free and ambient-temperature intramolecularDA coupling of highly functional photosensitive α-o-methylbenzaldehyde andω-acrylate polyester chains (Figure 1.2) [39, 40]. Polycaprolactone (PCL) andpolylactide (PLA) were synthesized via ring-opening polymerization (ROP)using 2-((11-hydroxyundecyl)oxy)-6-methyl-benzaldehyde as an initiator in thepresence of triazabicyclodecene (TBD) or 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) functioning as organocatalysts. The hydroxyl functionality of the linearpolymers was reacted with acryloyl chloride to afford a terminal dienophilegroup. The completion of the end-group transformation was confirmed by1H NMR and electrospray ionization mass spectrometry (ESI-MS), and thesubsequent DA reactions were performed by irradiation of the linear pre-cursor solutions in acetonitrile at ambient temperature at concentrations of25mgL−1 for 12 h under ultraviolet (UV) light (𝜆max = 320 nm). The cyclicproducts were collected by evaporation of the solvent without the need foradditional purification steps and confirmed by SEC, 1H NMR, and ESI-MS. Inthe same context, Zhang and coworkers developed a method for the formation

4 1 Synthetic Methods Toward Single-Chain Polymer Nanoparticles

O

H

OOH O

O

H

O OO

O

O O

OH O

O

O

OH

O

O O5

O

On

H

OH

n

O

O

O

n

O

O

O

n

5

O

O5

O

O5

ii

iii

i

+5

Figure 1.2 Synthetic route for the preparation of cyclic poly(𝜀-caprolactone). (i) 1,5,7Triazabicyclo[4.4.0]dec-5-ene (TBD), CH2Cl2, r.t. (ii) Acryloyl chloride, triethylamine,tetrahydrofuran (THF), r.t. (iii) h𝜈 (𝜆max = 320 nm), acetonitrile, r.t. (Josse et al. 2013 [39].Reproduced with permission of the Royal Society of Chemistry.)

of various types of cyclic homopolymers and block polymers by a combinationof RAFT polymerization and a light-induced DA click reaction [41], basedon synthetic technology we introduced (light-induced hetero-DA chemistry)[42]. In following work by the same research group, an efficient and practicalway was investigated to produce cyclic polystyrenes on a large scale by thecombination of continuous flow techniques and UV-induced DA reactions[43]. In an alternative light-triggered approach, Yamamoto and colleagues [44]successfully demonstrated the intramolecular dimerization reactions of theanthryl and coumarinyl end-group-functionalized polymers both in water andorganic solvents.Thiol–ene reactions have recently been used for a variety of synthetic pro-

cesses including single-chain ring formation [45, 46]. For example, Zhang andcoworkers reported a straightforward approach for the one-pot synthesis ofcyclic polymers via thiol-Michael addition [47]. Linear precursor polymerswere prepared via RAFT polymerization using a chain transfer agent (CTA)with furan-protected maleimides at the R group. A highly diluted solution(0.014mM) of polymethyl methacrylate (PMMA) was prepared, and subse-quently the maleimide was deprotected at 110 ∘C followed by aminolyzing thethiocarbonylthio to a thiol group at ambient temperature. Upon the release ofthe thiol, the cyclic PMMA was obtained through intramolecular ring closurevia thiol–maleimide Michael addition. The cyclic PMMA was subjected toSEC, NMR, and matrix assisted laser desorption ionization-time of flight(MALDI-TOF) MS, which provided convincing evidence for the successfulpreparation of the cyclic structures.

1.2 Single-Chain Rings via Irreversible and Reversible Bonds 5

In related work, Monteiro and coworkers demonstrated a versatile strategyfor the cyclization of RAFT-based polymers in a one-pot synthesis using thethiol–ene or thio–bromo reaction [45]. The heterodifunctional trithiocarbonateRAFT agent featuring an alkyne functionality was designed tomediate the RAFTpolymerization of various monomers, and subsequently either activated acrylateor bromine functionalities were installed at the chain end of the polymer via anesterification reaction. Hexylamine was used to convert the RAFT end group toa free thiol moiety, which reacted with the acrylate on the other chain termi-nus to afford the cyclic polymer. The overall results indicate that the thiol–enecyclization reaction was more successful than the thio–bromo reaction.Reversible self-folding processes are nature’s way to control the conformation

of biological polymers, and specifically the disulfide bridges employed withinby natural proteins provide a robust system for dynamic single-chain systemsadaptable by external stimuli. In an interesting approach, Du Prez and cowork-ers developed an efficient synthetic pathway toward cyclic polymers basedon the combination of thiolactone and disulfide chemistry (Figure 1.3) [48].An α-thiolactone and an ω-dithiobenzoate functional linear polystyrene wasprepared via RAFT polymerization using a newly designed CTA and subsequentconversion of the dithioester end groups to thiols through aminolysis. Thesingle cyclic PS-featuring disulfide linkage was constructed under highly dilutedconditions, allowing for the one-step preparation of functionalized cyclic

OCN

S

S S

O O

S

S

ii

iii

CN

NH

R

N

O O

S

S

CN

CNSH

H NH

HS

R

N

O O

H NH

HS

R

N

O OCN

H NH

S

S

i

O

SNH

Figure 1.3 Combined RAFT and thiolactone approach toward functionalized cyclic polymers.(i) RAFT polymerization. (ii) Propylamine or ethanolamine, dichloromethane (DCM). (iii) DCM, 2days. (Stamenovic et al. 2012 [48]. Reproduced with permission of the Royal Society ofChemistry.)

6 1 Synthetic Methods Toward Single-Chain Polymer Nanoparticles

polymers with high yields. The cyclic PS disulfide ring formation was evidencedby SEC, MALDI-TOF MS, and 1H NMR characterization. Furthermore, thetopological transformation (folding/unfolding) was demonstrated by eitherdisulfide reduction or thiol–disulfide exchange reactions.Many proteins undergo folding in solution to yield delicate molecular

assemblies stabilized by non-covalent interactions such as hydrogen bonds.Barner-Kowollik and coworkers reported the first examples for single-chainfolding of α,ω-complementary hydrogen bonding motif functional polymerstrands prepared by a combination of ATRP and the CuAAC reaction in thecontext of macromolecular mimicry of naturally occurring proteins (Figure 1.4)[49]. While a cyanuric acid (CA) functional ATRP initiator provides for theα-end of the macromolecules, the Hamilton wedge (HW) was inserted intothe ω-end of the polymer strands via CuAAC. Single-chain self-folding of themacromolecules at concentrations of below <1mM was supported by 1H NMRand dynamic light scattering (DLS) analyses. A further related example waspresented by our team utilizing thymine (Thy) and diaminopyridine (DAP) as thehydrogen bonding complementary motifs [50]. A well-defined heterotelechelicpolystyrene was prepared by ATRP as well as CuAAC, where the Thy and theDAP recognition units were attached to the macromolecules in the α,ω-position,respectively, and subsequently single-chain folding of the polymer was studiedin detail using the same methods as in the previous publication. In related workby Barner-Kowollik and coworkers, the preparation of a well-defined triblockhomopolymer featuring two pairs of mutually orthogonal hydrogen bondingmotifs (CA–HW and thy–DAP) at well-defined points within the polymer chainwas first described [51]. Initially, the orthogonality of the motifs (CA, HW, Thy,DAP) was confirmed by 1H NMR spectroscopy between small molecules. Inour study, the CA functionality was located at the α-position of the polystyrenechain by virtue of a functional ATRP initiator, while the Thy and the DAPfunctionalities were inserted at preselected positions on the polymer backbone.The HW functionality was attached at the ω-position of the linear polymerchain with a combination of ATRP and the CuAAC reaction. The single-chainfolding/unfolding processes of the linear triblock homopolymers were followedby 1H NMR spectroscopy in tetrachloroethane at variable temperatures andlow concentrations, evidencing the hydrogen bonding interactions betweenthe Thy–DAP and CA–HW units. DLS as well as static light scattering (SLS)analyses of the macromolecular self-assembly systems in diluted solution furtherevidenced the formation of single-chain self-folded structures.In another example, Barner-Kowollik and coworkers reported the preparation

of well-defined 8-shaped cyclic diblock copolymers via single-chain hydrogenbonding-driven selective-point folding [52]. The well-defined linear polystyreneand poly(n-butyl acrylate) carrying complementary recognition units were syn-thesized via activators regenerated by electron transfer (ARGET) ATRP utiliz-ing functional initiators. The orthogonal hydrogen bonding recognition motifswere incorporated into the polymer chain ends of the respective building blocks.Diblock copolymer formation was successfully carried out via a CuAAC reac-tion. The concentration regime <10mgmL−1 for the single-chain formation was

O

O

O

O

O

O

NN

N

N

HH

H

H HH

N

N

NN

N

O

O

O

O

O

Br OO

O

Brii

iv

iii

i

O

O NHN

HN

O

O

NHN

HN

O

O

O

O

N O

O

O

ONH

NHN H

N

NHN

O

N N

O

NHN

HN

O

O

O

O

N3

O

NHN

HN

Figure 1.4 General strategy for preparing 𝛼,𝜔 hydrogen donor/acceptor functional polymers and their subsequent single-chain self-assembly. (i) CuBr,PMDETA, styrene, anisole, 90 ∘C. (ii) NaN3, DMF, r.t. (iii) CuSO4 × 5 H2O, sodium ascorbate, DMF, alkyne functional HW. (iv) High dilution in DCM. (Altintas et al.2010 [49]. Reproduced with permission of the Royal Society of Chemistry.)

8 1 Synthetic Methods Toward Single-Chain Polymer Nanoparticles

determined by diffusion-ordered spectroscopy (DOSY)NMRat ambient temper-ature indicating the concentration limit for single-chain folding.A second and versatile class of supramolecular motifs that are used for

single-chain folding are host–guest systems. Harada and coworkers were thefirst to perform the reversible folding of a polymer in aqueous conditions withthe CD-azobenzene (AB) host–guest motif [53]. We investigated the reversiblefolding behavior of well-defined polymers carrying the CD and adamantyl (AD)motif at the chain ends in aqueous media [54]. An α-CD, ω-AD-functionalizedpoly(N ,N-dimethyl acrylamide) (PDMAa) was initially synthesized by acombination of RAFT polymerization and CuAAC reactions with a novelbifunctional RAFT agent. The single-chain folding through the CD–ADhost–guest complexation occurs at concentrations lower than 0.6mM, whereashigher concentrations led to chain opening and intermolecular aggregation.Barner-Kowollik and coworkers published the first study on the selective-point

folding of a single polymer chain induced by metal–ligand complexation usingpalladium and triphenylphosphine as a ligand [55]. Dibromo functionalpolystyrene was synthesized via ARGET ATRP, and subsequently the chainends of the linear polymer were functionalized with alkyne triphenylphosphinesto obtain polymeric macroligands. The addition of palladium (II) ions via asyringe pump leads to the controlled folding of the polymer chain. 31P NMRspectroscopy revealed the success of the Pd complexation, which results ina significant shift of the macroligand resonance from −4.99 to 23.53 ppm.Additionally, the single-chain ring formation was characterized by DLS and SEC.The preparation of cyclic polymers can be considered the simplest form of

SCNP preparation, and thus the two fields are strongly intertwined. Herein,selected examples of single-chain ring formation have been highlighted. Impor-tantly, the highlighted modular ligation reactions, which have been used forthe preparation of cyclic polymers, can be readily adopted as an orthogonalapproach for the preparation of true SCNPs.

1.3 Single-Chain Nanoparticles via Irreversible Bonds

Several modular ligation chemistries have been applied to generate SCNPsfrom linear precursors possessing cross-linkable functionalities. The follow-ing reactions have been extensively employed as cross-linking processes toconstruct SCNPs, that is, dimerization of benzocyclobutene (BCB), CuAAC,Glaser–Hay coupling, thiol–ene/thiol–yne chemistry, modification of reactivegroups by reaction with amines/alcohols/thiols, thiol–disulfide exchange, DAreactions, Michael-type addition, modification of ketones and aldehydes withamines/alkoxyamines/hydrazines, and intramolecular polymerizations. In thefollowing section, the preparation of SCNPs by modular ligation reactions isexplored in detail as only few of these reactions have been introduced in theprevious section.The initial examples of intramolecular cross-linking of macromolecules

were studied in the 1950s in very diluted solutions where terephthalaldehyde

1.3 Single-Chain Nanoparticles via Irreversible Bonds 9

was added to an aqueous solution of polyvinyl alcohol. Intermolecular andintramolecular reactions were investigated by following the viscosity of the solu-tion. Intramolecular cross-linking reactions were observed in diluted solutions,whereas the intermolecular cross-linking predominated in concentrated systems[7–9, 56]. However, herein we focus on recent examples of intramolecularcross-linking reactions based on functional precursor polymers prepared viaadvanced polymerization methods. In early studies in the field, the BCB moietywas intensively used for the preparation of SCNPs. Several approaches for thecontrolled intramolecular folding of linear polymer chains to afford well-definedsingle-molecule nanoparticles were developed by Hawker and colleagues (referto Figure 1.5) using BCB motifs as intramolecular cross-linking agents formingbenzoquinone dimethanes [57–59]. In early studies, linear precursor polymerscontaining numerous latent coupling groups along the backbone were preparedby copolymerization of styrene and BCB functional monomer. A solution ofthe BCB-functionalized linear polymer was added to a benzyl ether solutionwithout any intermolecular cross-linking reaction by continuous addition ofthe precursor polymer solution to hot benzyl ether at 250 ∘C, thus achieving alow concentration of the linear precursor in the solution. The resulting SCNPswere readily characterized by standard techniques such as SEC, DLS, 1H NMRspectroscopy, and differential scanning calorimetry (DSC). For example, thestarting linear polymer features a number average molecular weight, Mn, of84.8 kDa; however, upon intramolecular reaction, the hydrodynamic volumeof the macromolecule decreases to an apparent Mn of 59 kDa to yield theSCNP. Subsequently, Harth and coworkers suggested alternative benzoquinonedimethane cross-linking precursors for intramolecular chain collapse nanopar-ticles inspired by BCB chemistry employing a novel vinylbenzosulfone (VBS)cross-linking unit for the preparation of well-defined nanoparticles [60]. Thecross-linking unit was synthesized by a five-step pathway, which requiresonly two purification steps. Random copolymers of styrene and the VBS unitwere synthesized via the NMP method with excellent control over molecularweight and with low polydispersity in the presence of R-hydrido alkoxyamine.After successful incorporation of the novel o-chinodimethane precursor intothe polystyrene, the intramolecular chain collapse process was carried out in

ON

+ + x

x

yO

N

y

xy

ON

NO

iii

Figure 1.5 Synthesis of benzocyclobutene-functionalized linear polystyrene and schematicrepresentation of the intramolecular collapse of the linear polymer. (i) 120 ∘C. (ii) 250 ∘C. (Harthet al. 2002 [57]. Reproduced with permission of the American Chemical Society.)

10 1 Synthetic Methods Toward Single-Chain Polymer Nanoparticles

dibenzyl ether to form o-quinodimethane intermediates, leading to well-definedmonodisperse nanoparticles of 5–10 nm size dimensions at temperatures closeto 250 ∘C. SCNPs formation was applied to the field of conducting copolymers,for example, the synthesis of polymeric nanoparticles from single ABA-typeblock copolymers in an intramolecular chain process was presented by Harthand coworkers [61]. ABA triblock copolymers were prepared from conductingpolymers such as fluorene homopolymers and fluorene/thiophene copolymersdesigned as telechelic macroinitiators to facilitate NMP methods. The poly-merization with styrene and VBS cross-linking units led to the desired ABAtriblock copolymers with various ratios of the polymer copolymer blocks. Inan intramolecular chain collapse process, the ABA triblock copolymers formedwell-defined SCNPs with the confined semiconducting polymer block B ascore unit via a controlled cross-linking of the benzosulfone unit within the Ablock copolymer. Photoluminescence measurements illustrate the influenceof the molecular weight of the A block to be crucial for the site isolation ofthe embedded conducting polymer block in the resulting nanoparticles withquantum efficiencies of 6%. The quantum efficiency of the formed polymericnanoparticles (6%) was three times higher in comparison to the linear precursor(2%). Most recently, a new synthetic pathway was presented by Hart and cowork-ers for the preparation of polyacrylate nanoparticles through an intramolecularchain collapse reaction at relatively low temperatures [62]. Poly(acrylic acid) wassynthesized by RAFT, and subsequently an amine functional BCB was graftedto the polymer through chloroformate activation chemistry. The BCB-basedcross-linking unit permits the reduction of the temperature to close to 100 ∘Cfor the formation of the polymeric nanoparticles.Due of their often quantitative conversions, mild reaction condition as well

as tolerance to several functional units, copper-catalyzed reactions are oftenemployed within the field of SCNPs [63–65]. For example, Loinaz and coworkersdescribed a new synthetic route and highly efficient ambient temperaturesynthetic method based on single-chain intramolecular CuAAC reactions[66]. Introduction of coupling precursors into the PMMA chains was simplyperformed by polymerization of methyl methacrylate (MMA) in the presenceof small stoichiometric amounts of azide- and protected alkyne-containingmethacrylate comonomers at three concentrations (4, 7, and 10mol%) usingthe RAFT polymerization technique. One-pot deprotection of the propargylmonomer units in the terpolymer was performed followed by a single-chainintramolecular CuAAC reaction at ambient temperature using a CuI salt and acontinuous addition technique. The CuAAC reaction induces an intramolecularcollapse of the linear chains to individual polymeric nanoparticles resulting ina significant reduction of the hydrodynamic volume and no significant changein polydispersity as observed by SEC. In addition, the terpolymers containingan excess of azide moieties (over-stoichiometric protected alkyne moieties)were prepared by RAFT polymerization, and subsequently the polymericnanoparticles with an excess of azide groups reacted with propargyl glycine.This versatile and general method opens a way for the synthesis of other kinds ofpolymeric and bioconjugated nanoparticles. Furthermore, SCNPs were prepared

1.3 Single-Chain Nanoparticles via Irreversible Bonds 11

OO

O

O

O O

O

i ii+

O

Figure 1.6 Single-chain nanoparticle construction at 25 ∘C under normal air atmosphere fromnaked P(MMA-co-PgA) precursor copolymers via the Glaser–Hay alkyne coupling reaction.(i) CPDB, BPO/NNDMANIL, THF, 25 ∘C. (ii) CuI, TMEDA, Et3N, THF, air, 25 ∘C. (Sanchez-Sanchezet al. 2012 [67]. Reproduced with permission of John Wiley and Sons.)

by Pomposo and coworkers using the copper-catalyzed Glaser–Hay alkyne cou-pling reaction as well as redox-initiated RAFT polymerization (Figure 1.6) [67].Redox-initiated RAFT polymerization of MMA and propargyl acrylate (PgA)at ambient temperature by the benzoyl peroxide (BPO)/N ,N-dimethylaniline(NNDMANIL) redox pair using 2-cyanoprop-2-yl-dithiobenzoate (CPDB) aschain transfer agent allows for the synthesis of a variety of precursor polymers(-D= 1.12–1.37 up to Mw = 100 kDa). Importantly, linear precursor polymerscontaining unprotected acetylenic functional groups were readily prepared byredox-initiated RAFT polymerization. After careful screening of the reactionconditions based on copper-catalyzed carbon–carbon coupling (Glaser–Haycoupling) of low-molecular-weight model compounds, nanoparticle synthesiswas performed in THF under air atmosphere at 25 ∘C in the presence of Et3N,using catalytic amounts of CuI and N ,N ,N ,N-tetramethylethylenediamine(TMEDA).Thiol–ene or thiol–yne radical addition reactions can be carried out under UV

irradiation in the presence of a photoinitiator (without using transition metalcatalysts) between a thiol and an alkene or an alkyne, resulting in thioetherproducts with a high degree of anti-Markovnikov selectivity [68]. For example,Pomposo and colleagues reported a strategy for the rapid, efficient synthesisof SCNPs (Figure 1.7) [69]. Precursors were prepared via ambient-temperatureredox-initiated RAFT polymerization in THF of MMA and allyl methacrylate(AMA) or PgA in the presence of CPBD as CTA and a nearly equimolar ratioof NNDMANIL/BPO as redox initiator system. The SCNPs were prepared fromthe precursor polymers by photoactivated radical-mediated thiol–ene coupling(TEC) and thiol–yne coupling (TYC) using 3,6-dioxa-1,8-octane-dithiol (DODT)as homobifunctional cross-linker and 2,2-dimethoxy-2-phenylacetophenone(DMPA) as photoinitiator. The reactions were carried out in THF in highdilution at ambient temperature for 90min. Confirmation of SCNP formationwas carried out by means of SEC/multi-angle light scattering (MALLS), 1HNMR, and transmission electron microscopy (TEM) measurements. SCNPs canbe prepared at concentrations≤ 0.5mgmL−1 based on the SEC/MALLS analysis.UV light-induced cycloadditions often constitute an alternative, convenient,

atom-efficient reaction class for single-chain folding that can be carried outquantitatively at ambient temperature without the need for any metal cata-lyst. A number of photo-induced reactions have been examined for SCNP

12 1 Synthetic Methods Toward Single-Chain Polymer Nanoparticles

O

OO O

OO O

nii

k

O O

S

O O

nki

+

O

O

O

O

HO

O O

O

m

O O

S

S

O Om np

i ii+

O

Figure 1.7 Synthetic strategy for the preparation of SCNPs through photoactivated thiol–eneand thiol–yne reactions. (i) THF, BPO/NNDMANIL, CPBD, r.t., 17 h. (ii)3,6-dioxa-1,8-octane-dithiol, DMPA, THF, UV light irradiation at 300–400 nm, r.t., 90 min.(Perez-Baena et al. 2014 [69]. Reproduced with permission of the American Chemical Society.)

formation including light-induced DA reactions [70], photo-induced Bergmancyclizations [71], photo-induced nitrile–imine-mediated tetrazole–ene cycload-ditions [72, 73], photo-cross-linking of azide functional polymers [74], andphoto-dimerizations of anthracene [75], coumarin [76, 77], and cinnamoyl [78,79]. For example, Hu and coworkers demonstrated the fusion of photo-Bergmancyclization and intramolecular chain collapse toward polymeric nanoparticles.Employing enediynes as cross-linking precursors, namely, photo-triggeredBergman cyclization, was integrated with an intramolecular chain collapse togenerate polymeric nanoparticles within the size regime below 20 nm. Theenediyne motif was designed judiciously to possess a high photoreactivity,with the double bond locked in a methyl benzoate ring with the triple bondssubstituted with phenyl moieties. Single-electron transfer living radical poly-merization (SET-LRP) was conducted to provide linear acrylate copolymers withcontrolled molecular weights and narrow polydispersities. The polymer bearingan enediyne cross-linker underwent a UV-induced Bergman cyclization, result-ing in well-defined polymeric nanoparticles. A series of other acrylate-basednanoparticles were investigated to confirm the applicability of such a uniquestrategy for thermally sensitive species, but UV-stable polymeric structures,making photo-Bergman cyclization a promising tool toward polymeric nanopar-ticles. In a study exploiting a unique photochemically induced cycloaddition,Barner-Kowollik and coworkers introduced a new ambient-temperature syn-thetic approach for the preparation of the SCNPs under mild conditions usinga UV light-triggered DA reaction for the intramolecular cross-linking of singlepolymer chains (Figure 1.8) [70]. Well-defined random copolymers with varyingcontents of styrene (S) and 4-chloromethylstyrene (CMS) were synthesizedemploying an NMP initiator, functionalized with a terminal alkyne moiety.Post-modification of the polymers with 4-hydroxy-2,5-dimethylbenzophenone