Springer ThesesRecognizing Outstanding Ph.D. Research

Novel Macromolecular Architectures via a Combination of Cyclodextrin Host/Guest Complexation and RAFT Polymerization

Bernhard V. K. J. Schmidt

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Bernhard V. K. J. Schmidt

Novel MacromolecularArchitectures via aCombination of CyclodextrinHost/Guest Complexationand RAFT Polymerization

Doctoral Thesis accepted byKarlsruhe Institute of Technology, Germany

123

AuthorDr. Bernhard V. K. J. SchmidtMaterials Research LaboratoryUniversity of CaliforniaSanta Barbara, CAUSA

SupervisorProf. Christopher Barner-KowollikDepartment of Preparative

Macromolecular ChemistryInstitute for Technical Chemistry

and Polymer ChemistryKarlsruhe Institute of Technology (KIT)KarlsruheGermany

ISSN 2190-5053 ISSN 2190-5061 (electronic)ISBN 978-3-319-06076-7 ISBN 978-3-319-06077-4 (eBook)DOI 10.1007/978-3-319-06077-4Springer Cham Heidelberg New York Dordrecht London

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Parts of this thesis have been published in the following journal articles:

1. Cyclodextrin-Complexed RAFT Agents for the Ambient Temperature AqueousLiving/Controlled Radical Polymerization of Acrylamido-MonomersSchmidt, B. V. K. J.; Hetzer, M.; Ritter, H.; Barner-Kowollik, C. Macromol-ecules 2011, 44 (18), 7220–7232.

2. Miktoarm Star Polymers via Cyclodextrin-Driven Supramolecular Self-AssemblySchmidt, B. V. K. J.; Hetzer, M.; Ritter, H.; Barner-Kowollik, C. Polym. Chem.2012, 3, 3064–3067.

3. Supramolecular Three-Armed Star Polymers via Cyclodextrin Host/Guest Self-AssemblySchmidt, B. V. K. J.; Rudolph, T.; Hetzer, M.; Ritter, H.; Schacher, F. H.;Barner-Kowollik, C. Polym. Chem. 2012, 3, 3139–3154.

4. UV-Light and Temperature Supramolecular ABA Triblock Copolymers viaReversible Cyclodextrin ComplexationSchmidt, B. V. K. J.; Hetzer, M.; Ritter, H.; Barner-Kowollik, C. Macromol-ecules 2013, 46 (3), 1054–1065.

5. Modulation of the Thermoresponsive Behavior of Poly(N,N-diethylacrylamide)via Cyclodextrin Host/Guest InteractionsSchmidt, B. V. K. J.; Hetzer, M.; Ritter, H.; Barner-Kowollik, C. Macromol.Rapid Commun. 2013, 34 (16), 1306–1311.

6. Complex Macromolecular Architecture Design via Cyclodextrin Host/GuestComplexesSchmidt, B. V. K. J.; Hetzer, M.; Ritter, H.; Barner-Kowollik, C. Prog. Polym.Sci 2014, 39, 235–249.

The true measure of a man is how he treatssomeone who can do him absolutely no good.

Samuel Johnson

I don’t mind your thinking slowly; I mindyour publishing faster than you think.

Wolfgang Ernst Pauli

Supervisor’s Foreword

Since its introduction in the 1970s, supramolecular chemistry has had a significantimpact on the chemical sciences. With nature as inspiration, opportunities togenerate new materials employing supramolecular concepts appear to be infinite.Cyclodextrins belong to a group of compounds that are capable of engaging instrong supramolecular interactions—host/guest complexes with hydrophobicmolecules. In a parallel development, the advent of living/controlled radicalpolymerization technologies, specifically the discovery of the RAFT/MADIXprocess in the late 1990s, had a significant impact on polymer chemistry and ourability to generate complex macromolecular architectures in a facile fashion.A myriad of new polymeric materials were suddenly accessible.

In the present thesis, the formation of novel macromolecular architectures via acombination of cyclodextrin-based host/guest chemistry and RAFT polymeriza-tions is pioneered, which was a rather unexplored area at the start of the project.A systematic approach is taken: Commencing with the synthesis of guestend-functionalized polymers and the complexation of chain ends with cyclodex-trins, the study progresses to establish the combination of cyclodextrin and guestcontaining macromolecular building blocks for the formation of complex dynamicmacromolecular architectures. The key features of RAFT polymerization wereutilized to achieve the research goal, i.e., its ability to provide macromolecules ofpredefined length and narrow size distribution. In addition, these key featuresinclude the ability to control the polymerization of functional monomers, e.g.,water-soluble monomers, with fine control over polymer functionality, specificallythe chain termini.

Initially, a method was developed to dissolve water-insoluble chain transferagents in aqueous solution via host/guest complexation in order to synthesizewater soluble polymers in a controlled fashion (Chap. 3). This method affordswater-soluble polymers with hydrophobic end groups in one step at ambienttemperature. These structures were subsequently utilized to modulate theself-assembly of a well-known thermoresponsive polymer via cyclodextrin host/guest interactions (Chap. 7). The supramolecular nature of the observed effectmade it possible to reverse the thermoresponsive modulation via the addition ofcompeting supramolecular guest molecules or by enzymatic degradation of thecyclodextrins. For the first time, a supramolecular ABA triblock copolymer for-mation via cyclodextrin-based interactions is described (Chap. 4). The pioneered

ix

system has the outstanding feature of switchable connections between the differentbuilding blocks, which can be addressed by light or temperature. Thus, the blockcopolymers can be reversibly disassembled via external stimuli, a key requirementfor their use as drug release systems. Furthermore, advanced and novel supra-molecular star (Chap. 5) and miktoarm star (Chap. 6) polymers are described thatcan be disassembled via external stimuli or form nanoscopic aggregates uponheating. In summary, the present thesis demonstrates that cyclodextrin-based host/guest chemistry and RAFT polymerization are a perfect combination for the for-mation of complex and stimuli-responsive polymer architectures.

The thesis—combining two disciplines of chemistry—is of substantial value forchemists in the areas of polymer chemistry, supramolecular chemistry, materialsscience, colloidal science, and biomedical sciences. Several original researchpublications are based on it as well as a detailed review covering the field ofcyclodextrin-mediated macromolecular architecture design. In addition, the thesisresults have inspired further work by our group, e.g., the formation of X- andH-shaped star block copolymers, single-chain self-folding in water or the forma-tion of supramolecular brushes.

On the basis of the results presented in this thesis, the formation of even morecomplex architectures is certainly possible. Furthermore, the combination ofvariable stimuli-responsive polymers will open new opportunities for advancedmaterial design, while the utilization of supramolecular chemistry and cyclodex-trin host/guest interactions appears to be an ideal tool for release system design.Importantly, cyclodextrin host/guest chemistry enables the implementation of self-assembly processes in aqueous environments.

Karlsruhe, February 2014 Prof. Christopher Barner-Kowollik

x Supervisor’s Foreword

Abstract

The design of complex macromolecular architectures constitutes an important fieldin modern polymer chemistry and provides the opportunity to generate a broadrange of materials with tuneable properties. The introduction of supramolecularchemistry had a significant impact on the synthesis of macromoleculararchitectures with a wide range of useful material properties ranging from self-healing to stimuli response. In particular, cyclodextrins (CDs) have proven to beversatile building blocks due to their ability to act as hosts in supramolecularinclusion complexes with hydrophobic molecules. In the course of the currentthesis, the possibilities of the combination of CD-based supramolecular chemistryand reversible addition-fragmentation chain transfer (RAFT) polymerization withregard to the preparation of new macromolecular architectures were investigated.With the synthesis of variable macromolecular building blocks, a broad range ofmacromolecular architectures are accessible via CD host/guest chemistry.

A new method was developed to solubilize hydrophobic RAFT reagents inwater and to utilize them in aqueous RAFT polymerizations of severalacrylamides, i.e., N,N-dimethylacrylamide (DMAAm), N,N-diethylacrylamide(DEAAm), and N-isopropylacrylamide (NIPAAm). The polymerization kineticswere investigated showing control similar to fully water-soluble systems.Furthermore, high end-group fidelities were found and efficient chain extensionswere performed. Thus, for the first time, water-soluble polymers with hydrophobicend groups were prepared in aqueous solution in one step with good control overmolecular weight and molar mass dispersity (Ðm).

After the preparation of end-functionalized polymers, the complexity of thearchitectures was increased via the utilization of several building blocks.Supramolecular three-arm star polymers were accessible via a threefold CD-functional core molecule and guest-functionalized polymers. The formation ofsupramolecular three-armed star polymers was shown to be temperatureresponsive leading to the disassembly of the star polymers after heating. Thisprocess proceeds in a reversible fashion as the supramolecular star polymersre-form after cooling to ambient temperature.

A further increase in complexity was achieved in the synthesis of AB2

miktoarm star polymers. In this case, a mid-chain guest functionalized PDMAAmwas synthesized as well as a b-CD-end functionalized PDEAAm. Complexation inwater leads to the formation of the desired miktoarm star polymers. The PDEAAm

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block was utilized to investigate the temperature-induced aggregation behavior.Significant differences between supramolecular miktoarm stars and nonstar-shapedpolymers were found that can be attributed to different architectures in solution.

Furthermore, supramolecular-bound ABA block copolymers were prepared viathe combination of CD end-functionalized poly(hydroxypropyl methacrylamide)(PHPMA) and doubly guest-functionalized PDMAAm or PDEAAm. Adamantyl-and azobenzene-guests were utilized allowing the disassembly of the blockcopolymers at elevated temperature (in the case of adamantyl- and azobenzene-guests) or via irradiation of UV-light (in the case of azobenzene-guests). Theutilization of thermoresponsive PDEAAm, which loses water solubility at elevatedtemperatures, and PHPMA, which is water soluble in the complete temperaturerange, enables the study of temperature-induced aggregation of the system.

In addition, the thermoresponsive behavior of PDEAAm was modulated via theformation of supramolecular host/guest complexes with hydrophobic polymer endgroups and CD. This effect could be reversed via the addition of competing guestmolecules or via enzymatic degradation of the CD moieties.

xii Abstract

Acknowledgments

First, and foremost, I am indebted to Prof. Christopher Barner-Kowollik foroffering me the opportunity to undergo my doctoral studies under his supervision.I am thankful for his trust in my abilities, his enthusiasm for my project, thediscussions that pushed the projects forward, and his support throughout mydoctoral studies.

Furthermore, I would like to thank Prof. Helmut Ritter and Dipl. WiChem.Martin Hetzer for the support and fruitful discussions in our collaborative project.

I am thankful for the great cooperation with Prof. Felix Schacher and Dipl.Chem. Tobias Rudolph. It was a pleasure to work with you. Furthermore, I thankProf. Mathias Rehahn and Dr. Markus Gallei for a great collaboration as well.Especially Markus has to be mentioned, as he had a significant impact on mylab-skills and on my development as a scientist.

Thanks go to Dr. Eva Blasco and Dr. Cesar Rodriguez-Emmenegger for fruitfulcollaborations during their stay in our group as visitor. I would also like to thankDipl. Chem. Tanja Claus, Dipl. Chem. Doris Abt, and B.Sc. Janin Offenloch whomI supervised in their advanced lab course, diploma thesis, or bachelor thesis,respectively. It was a pleasure to work with you, to teach you, and to follow howyou develop into good scientists.

Many thanks go to all present and former members of the macroarc researchteam. It was a pleasure to work and laugh with you. Furthermore, I thank the ACcrew for the nice atmosphere and company, especially Dr. Anna-Marie Zorn,Dr. Dominik Voll, Dipl. Chem. Johannes Willenbacher, and Peter Gerstel. Addi-tional thanks go to Dipl. Chem. Christiane Lang, Dr. Dominik Voll, Dipl. Chem.Johannes Willenbacher, and Dipl. Chem. Michael Kaupp for proof reading of thisthesis.

Many thanks to Gabriele Herrmann and Evelyn Stüring for the support inadministrative matters, as well as Dr. Maria Schneider and Peter Gerstel forordering every item that was used in the course of this thesis. Furthermore, I wouldlike to thank Dr. Maria Schneider for the great teamwork in the supervision of theSEC instruments and I am thankful to Pia Lang and Tanja Ohmer for performingNMR measurements at the Institute of Organic Chemistry.

Special thanks go to Anna-Marie Zorn, Astrid Hirschbiel, Azize Ünal, CesarRodriguez-Emmenegger, Christiane Lang, Christoph Dürr, Dominik Voll, DorisAbt, Jan Müller, Johannes Willenbacher, Kim Öhlenschläger, and Pieter Derboven

xiii

for their friendship during my time in Karlsruhe. I appreciate your support and carefor me. I will never forget you and hope to see you again.

I thank my chemistry teacher Hubert Giar for infecting me with his enthusiasmfor science, and chemistry in particular. Furthermore, I thank Peter Gerstel forsupporting me in scientific matters as well as the more important things in life.If I only had half of the spirit of you two I would be a great man.

Thanks go out to my friends, especially (in chronological order) Youssef Afkir,Martin Krauß, Jan Paul Marschollek, Ali Hartwig, Jan-Eric Teves, and Tobi Rudi.I am very proud to call you my friends.

I thank Anna-Elisabeth Kreuder for her support. She has an essential share inthe success of this thesis. Although many things come to an end, some thingsremain forever and are beyond this thesis.

Most notably, I thank Lisa Cielen for her support before the doctor examinationand the time afterwards. I hope to have many more exciting years with you.

Finally, I thank my parents and my sister for their support throughout my life’sjourney.

xiv Acknowledgments

Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 Motivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Thesis Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2 Theoretical Background and Literature Overview. . . . . . . . . . . . . 72.1 Reversible Addition-Fragmentation Chain

Transfer Polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.1.1 Living Polymerization . . . . . . . . . . . . . . . . . . . . . . . . 72.1.2 Mechanism and Kinetics. . . . . . . . . . . . . . . . . . . . . . . 82.1.3 Applicability of the Method and Reaction

Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.1.4 Preparation of Water-Soluble Polymers

via RAFT Polymerization . . . . . . . . . . . . . . . . . . . . . . 132.1.5 Complex Macromolecular Architectures

via RAFT Polymerization . . . . . . . . . . . . . . . . . . . . . . 142.2 Cyclodextrins and Their Complexes. . . . . . . . . . . . . . . . . . . . . 17

2.2.1 Supramolecular Chemistry . . . . . . . . . . . . . . . . . . . . . 172.2.2 Structure and Properties of CDs . . . . . . . . . . . . . . . . . 182.2.3 Thermodynamics and Theory of CD Inclusion

Complexation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192.2.4 Complex Types, Common Host/Guest Pairs

and Their Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.3 Complex Macromolecular Architectures Governed

by CD Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.3.1 Common CD Containing Building Blocks . . . . . . . . . . 232.3.2 Block Copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . 252.3.3 Brush Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272.3.4 Star Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282.3.5 Branched Polymers and Gels . . . . . . . . . . . . . . . . . . . 312.3.6 Other Architectures . . . . . . . . . . . . . . . . . . . . . . . . . . 33

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

xv

3 CD-Complexed RAFT Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453.2 Results and Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

3.2.1 Design and Synthesis of the Chain Transfer Agents . . . . 473.2.2 Complexation of Chain Transfer Agents

with Me-b-CD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473.2.3 Polymerization with Complexed Chain

Transfer Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623.4 Experimental Part . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

3.4.1 Synthesis of 4-(tert-butyl)phenyl 2-(((ethylthio)carbonothioyl)thio)-2-methylpropanoate (1). . . . . . . . . . 63

3.4.2 Synthesis of bis(4-(tert-butyl)benzyl)carbonotrithioate (2). . . . . . . . . . . . . . . . . . . . . . . . . . 64

3.4.3 Synthesis of 3-bromo-N-(4-(tert-butyl)phenyl)propanamide (4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

3.4.4 Synthesis of benzyl (3-((4-(tert-butyl)phenyl)amino)-3-oxopropyl) carbonotrithioate (3) . . . . . . . . . . . . . . . . 65

3.4.5 Exemplary Procedure for the Polymerizationof DMAAm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

3.4.6 Exemplary Procedure for the Chain Extensionof PDMAAm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

3.4.7 Exemplary Procedure for Kinetic Measurementsof DMAAm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

3.4.8 Exemplary Procedure for the Polymerizationof DEAAm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

3.4.9 Exemplary Procedure for Kinetic Measurementsof the Polymerization of DEAAm . . . . . . . . . . . . . . . . 68

3.4.10 Exemplary Procedure for the Polymerizationof NIPAAm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

3.4.11 Exemplary Procedure for the Chain Extensionof PNIPAAm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

3.4.12 Exemplary Procedure for Kinetic Measurementsof the Polymerization of NIPAAm. . . . . . . . . . . . . . . . 69

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

4 Supramolecular ABA Triblock Copolymers . . . . . . . . . . . . . . . . . 734.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734.2 Results and Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

4.2.1 Synthesis of the Building Blocks . . . . . . . . . . . . . . . . . 754.2.2 Formation of ABA Triblock Copolymers

via Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . 804.2.3 Investigations of the Stimuli-Responsive Behavior. . . . . 83

xvi Contents

4.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884.4 Experimental Part . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

4.4.1 Synthesis of 6-(adamantan-1-ylamino)-6-oxohexyl 2-((((3-((6-(-adamantan-1-ylamino)-6-oxohexyl)oxy)-3-oxopropyl)thio)carbonothioyl)thio)-2-methylpropanoate (5) . . . . . . . . . . . . . . . . . . . . . . . . . 89

4.4.2 Synthesis of bis(6-(4-(phenyldiazenyl)phenoxy)hexyl) 2;20-(thiocarbonylbis(sulfanediyl))bis(2-methylpropanoate) (6) . . . . . . . . . . . . . . . . . . . . . . 90

4.4.3 Synthesis of prop-2-yn-1-yl 4-cyano-4-(((ethylthio)carbonothioyl)thio)pentanoate (7) . . . . . . . . . . . . . . . . 90

4.4.4 Exemplary Procedure for the RAFT Polymerizationof DEAAm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

4.4.5 Exemplary Procedure for the RAFT Polymerizationof HPMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

4.4.6 Exemplary Click-Reaction of Alkyne-FunctionalizedPHPMA with b-CD-N3. . . . . . . . . . . . . . . . . . . . . . . . 92

4.4.7 Exemplary Supramolecular ABA BlockCopolymer-Formation via CD/Guest Interaction . . . . . . 92

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

5 Supramolecular Three Armed Star Polymers . . . . . . . . . . . . . . . . 955.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955.2 Results and Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

5.2.1 Synthesis and Characterizationof the Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . 97

5.2.2 Star Polymer Formation: Investigations UsingLight Scattering. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

5.2.3 Investigations of the Self-Assembly via ROESY . . . . . . 1055.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055.4 Experimental Part . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

5.4.1 Synthesis of 6-(Adamantan-1-ylamino)-6-oxohexyl 2-(((ethylthio)carbonothioyl)thio)-2-methylpropanoate (10) . . . . . . . . . . . . . . . . . . . . . . . . 106

5.4.2 Synthesis of N,N,N-(Tris-1-(mono-(6-desoxy)-b-CD)-1H-1,2,3-triazol-4-yl)methanamine (b-CD3) . . . . . . . . . . 106

5.4.3 Exemplary Procedure for the RAFT Polymerization. . . . 1075.4.4 Exemplary Procedure for the Self-Assembly

of the Adamantyl-Functionalized PDMAAmwith b-CD3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

5.4.5 Preparation for Dynamic Light ScatteringExperiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Contents xvii

6. AB2 Miktoarm Star Polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1116.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1116.2 Results and Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

6.2.1 Synthesis of the Building Blocks . . . . . . . . . . . . . . . . . 1126.2.2 Characterization of the Supramolecular

Miktoarm Star Polymer . . . . . . . . . . . . . . . . . . . . . . . 1166.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226.4 Experimental Part . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

6.4.1 Synthesis of 6-(Adamantan-1-ylamino)-6-oxohexyl-2,2,5-trimethyl-1,3-dioxane-5-carboxylate (14) . . . . . . . 122

6.4.2 Synthesis of 6-(Adamantan-1-ylamino)-6-oxohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (15) . . . . . . . . . . . . . . . . . . . . . . . . 123

6.4.3 Synthesis of 2-(((6-(Adamantan-1-ylamino)-6-oxohexyl)oxy)carbonyl)-2-methylpropane-1,3-diyl bis(2-(((ethylthio)carbonothioyl)thio)-2-methylpropanoate (11) . . . . . . . . . . . . . . . . . . . . . . . . 123

6.4.4 Synthesis of prop-2-yn-1-yl 2-(((ethylthio)carbonothioyl)thio)-2-methylpropanoate (12) . . . . . . . . . 124

6.4.5 Exemplary Synthesis of Mid-Chain Adamantyl-Functionalized PDMAAm. . . . . . . . . . . . . . . . . . . . . . 124

6.4.6 Exemplary Synthesis of Alkyne-FunctionalizedPDEAAm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

6.4.7 Exemplary Click-Reaction of Alkyne-FunctionalizedPDEAAm with b-CD-N3 . . . . . . . . . . . . . . . . . . . . . . 125

6.4.8 Exemplary Supramolecular Miktoarm StarPolymer-Formation via CD/Guest Interaction . . . . . . . . 125

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

7 Modulation of the Thermoresponsitivity of PDEAAmvia CD Addition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297.2 Results and Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

7.2.1 Synthesis of Guest Endfunctionalized PDEAAm . . . . . . 1307.2.2 Turbidimetric Measurements: Influence of Guest

Groups, Chain Length and CD/Endgroup Ratio . . . . . . . 1327.2.3 Reversal of the Effect via External Stimuli . . . . . . . . . . 136

7.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1387.4 Experimental Part . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

7.4.1 Synthesis of 6-(4-(phenyldiazenyl)phenoxy)hexyl2-(((ethylthio)carbonothioyl)thio)-2-methylpropanoate (16) . . . . . . . . . . . . . . . . . . . . . . . . 139

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

xviii Contents

8 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

9 Experimental Part . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1479.1 Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1479.2 Additional Experimental Procedures . . . . . . . . . . . . . . . . . . . . 148

9.2.1 Synthesis of Mono-(6-O-(p-toluenesulfonyl))-b-CD (18). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

9.2.2 Synthesis of Mono-(6-azido-6-desoxy)-b-CD(b-CD-N3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

9.2.3 Synthesis of 2-(((Ethylthio)carbonothioyl)thio)-2-methylpropanoic Acid (EMP) . . . . . . . . . . . . . . . . . . 149

9.2.4 Synthesis of 2-((((2-Carboxyethyl)thio)carbonothioyl)thio)-2-methylpropanoic Acid (CEMP) . . . . . . . . . . . . . 150

9.2.5 Synthesis of 2-(1-Carboxy-1-methylethylsulfanylthio-carbonylsulfanyl)-2-methylpropionic Acid (CMP) . . . . . 150

9.2.6 Synthesis of 4-Cyano-4-(((ethylthio)carbonothioyl)thio)pentanoate (CEP) . . . . . . . . . . . . . . . . . . . . . . . . 151

9.2.7 Synthesis of N-(Adamantan-1-yl)-6-hydroxyhexanamide (8) . . . . . . . . . . . . . . . . . . . . . . . 151

9.2.8 Synthesis of N-(2-Hydroxypropyl)methacrylamide(HPMA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

9.2.9 Synthesis of 6-(4-(Phenyldiazenyl)phenoxy)hexan-1-ol (9) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

9.3 Characterization and Methods . . . . . . . . . . . . . . . . . . . . . . . . . 153References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Appendix A: CD-Complexed RAFT Agents(Appendix to Chapter 3) . . . . . . . . . . . . . . . . . . . . . . . . 157

Appendix B: Supramolecular ABA Triblock Copolymers(Appendix to Chapter 4) . . . . . . . . . . . . . . . . . . . . . . . . 167

Appendix C: Supramolecular Three Armed Star Polymers(Appendix to Chapter 5) . . . . . . . . . . . . . . . . . . . . . . . . 181

Appendix D: AB2 Miktoarm Star Polymers(Appendix to Chapter 6) . . . . . . . . . . . . . . . . . . . . . . . . 187

Appendix E: Modulation of the Thermoresponsitivity of PDEAAmvia CD Addition (Appendix to Chapter 7) . . . . . . . . . . . 193

Curriculum Vitae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Publications and Conference Contributions . . . . . . . . . . . . . . . . . . . . 199

Contents xix

Abbreviations

2VP 2-Vinylpyridine4VP 4-VinylpyridineAA Acrylic acidAAm AcrylamideAd AdamantylAFM Atomic force microscopyAIBN 2;20-Azobis(2-methylpropionitrile)AMPS 2-Acrylamido-2-methylpropanesulfonic acidarom AromaticATRP Atomtransfer radical polymerizationbmn Overall association constantb-CD-N3 Mono azido functionalized b-CDCBMAA-3 3-(Methacryloylamino-propyl)-(2-carboxy-ethyl)-dimethylammo-

nium carboxybetaine methacrylamideCD CyclodextrinCL �-caprolactoneCMP 2-(1-Carboxy-1-methylethylsulfanylthiocarbonylsulfanyl)-2-

methylpropionic acidConA Concanavalin ACPDB 2-Cyano-2-propyl benzodithioateCTA Chain transfer agentCtr Chain transfer constantCTP 4-Cyano-4-(phenylcarbonothioylthio)pentanoic acidCuAAC Copper (I) catalyzed azide-alkyne cycloadditiond Average number of chains formed in a termination reactionDh Hydrodynamic diameterÐm Molar mass dispersityDp Degree of polymerizationDCC N;N 0-dicyclohexylcarbodiimideDCM DichloromethaneDEAAm N,N-diethylacrylamideDIAD DiisopropylazodicarboxylateDLS Dynamic light scatteringDMF N,N-dimethylformamide

xxi

DMAAm N,N-dimethylacrylamideDMAc N,N-dimethylacetamideDMAEMA N,N-dimethylaminoethyl methacrylateDMAP 4-DimethylaminopyridineDMAPS 3-Dimethyl(methacryloyloxyethyl) ammonium propane sulfonateDMP 2-(Dodecylthiocarbonothioylthio)-2-methylpropionic acidDMSO DimethylsulfoxideDNA Desoxyribonucleic acidDopat 2-((Dodecylsulfanyl)carbonothioyl)sulfanyl propionic acidDOSY Diffusion-ordered NMR spectroscopyDox DoxorubicinDPTS 4-(Dimethylamino)-pyridinium p-toluenesulfonateECD PEG-b-PCL-b-PDMAEMAEDTA Ethylenediaminetetraacetic acid disodium saltEMP 2-(((Ethylthio)carbonothioyl)thio)-2-methylpropanoic acidEPX Ethyl 2-((ethoxycarbonothioyl)thio)propanoateeq EquivalentsESI-MS Electrospray ionization mass spectrometryf Initiator efficiencyFT-IR Fourier transform infraredGAPDH Glyceraldehyde 3-phosphate dehydrogenaseDHcomplex Complex association enthalpyHEA Hydroxyethyl acrylateHPMA N-(2-hydroxypropyl)methacrylamideITC Isothermal titration calorimetryJ Coupling constantKij Association constant of i and jkadd Rate coefficient of additionkb Rate coefficient of fragmentationkde Rate coefficient of initiator decaykini Rate coefficient of initiationkp Rate coefficient of propagationktrec Rate coefficient of termination by recombinationktd Rate coefficient of termination by disproportionationk WavelengthLCST Lower critical solution temperatureMADIX Macromolecular design via the interchange of xanthatesMe-b-CD Randomly methylated b-cyclodextrinmCTA Molar mass of CTAmM Molar mass of monomerMn Number-average molecular weightMPEG Methoxy poly(ethylene glycol)MS Mass spectrometryMWCO Molecular weight cut offNAS N-acryloxysuccinimide

xxii Abbreviations

NCCM Noncovalently connected micelleNIPAAm N-isopropylacrylamideNMP Nitroxide-mediated polymerizationNMR Nuclear magnetic resonanceNOESY Nuclear Overhauser enhancement spectroscopyOEGMA Oligo ethylene glycol methacrylatePAA Poly(acrylic acid)PCL Poly(�-caprolactone)PDEAAm Poly(N,N-diethylacrylamide)PDMAAm Poly(N,N-dimethylacrylamide)PDMAEMA Poly(2-(dimethylamino)ethyl methacrylate)pDNA Plasmid DNAPEG Poly(ethylene glycol)PHEA Poly(hydroxyethyl acrylate)PHPMA Poly(N-(2-hydroxypropyl)methacrylamide)PLA Poly(lactic acid)PMDETA N;N;N 0;N 00;N 00-pentamethyldiethyltriaminePMMA Poly(methyl methacrylate)PNIPAAm Poly(N-isopropylacrylamide)PPG Poly(propylene glycol)PSty Poly(styrene)Rh Hydrodynamic radiusRAFT Reversible addition-fragmentation chain transferRI Refractive indexROESY Rotating frame nuclear Overhauser enhancement spectroscopyROP Ring opening polymerizationDScomplex Complex association entropySEC Size exclusion chromatographySEM Scanning electron microscopysiRNA Small interfering ribonucleic acidSLS Static light scatteringTEM Transmission electron microscopyTFA Trifluoroacetic acidTGA Thermo gravimetric analysisTHF TetrahydrofuranUV Ultra-violetUV/Vis Ultra-violet/visibleV-501 4;40-Azobis(4-cyanovaleric acid)VA-044 2;20-Azobis[2-(2-imidazolin-2-yl)propane]dihydrochlorideXPS X-ray photoelectron spectroscopy

Abbreviations xxiii

Chapter 1Introduction

1.1 Motivation

Polymeric materials play a significant role in contemporary society, e.g. asconsumables, as high performance materials or in high-tech applications. Theprogress in these fields depends to a significant amount on the achievements ofpolymer science. Especially the development of novel complex macromoleculararchitectures have driven polymer scientists in recent years [1–3]. The ability tocontrol macromolecular architectures gives rise to the fabrication of materials withnovel or improved properties and thus enables the development of new products ina broad range of applications, e.g. microelectronic materials [4], drug/gene delivery[5], biomedical materials [6], supersoft elastomers [7] or hybrid materials [8].

The development of reversible-deactivation radical polymerization techniques,e.g. nitroxide-mediated radical polymerization (NMP) [9, 10], atom transfer radicalpolymerization (ATRP) [11, 12], and reversible addition-fragmentation chain trans-fer (RAFT) polymerization [13–15], has provided very suitable and convenient toolsfor the preparation of complex macromolecular architectures in a controlled fash-ion. The introduction of click chemistry had a further impact on the preparation ofcomplex macromolecular architectures [16–19]. The utilization of complex buildingblockswith a largediversity, basedon thehigh toleranceof functional groups obtainedfrom reversible-deactivation radical polymerization techniques in highly efficientmild and fast coupling reactions enables the synthesis of complex macromoleculararchitectures in amodular fashion, e.g. via copper(I)-catalyzed azide-alkyne cycload-dition (CuAAc) [20], thiol-ene [21, 22] or Diels-Alder reactions [23].

Apart from reversible-deactivation radical polymerization techniques and clickchemistry, supramolecular chemistry had a significant impact on polymer science.Supramolecular interactions provide a set of new properties that can be utilized inmaterials design and especially in the formation of complex macromolecular archi-tectures, e.g. reversibility or stimuli-response. Several supramolecular systems havebeen utilized in polymer chemistry, e.g. hydrogen bonding [24, 25], metal complexes[26] as well as inclusion complexes [27–29]. One of the frequently utilized inclusion

B. V. K. J. Schmidt, Novel Macromolecular Architectures via a Combination of 1Cyclodextrin Host/Guest Complexation and RAFT Polymerization, Springer Theses,DOI: 10.1007/978-3-319-06077-4_1, © Springer International Publishing Switzerland 2014