OPTIMIZATION OF THE STRUCTURE OF BENZOCYCLOBUTENE CONTAINING METHACRYLATE MONOMER FOR CONTROLLED RADICAL POLYMERIZATION

Transcription

1 OPTIMIZATION OF THE STRUCTURE OF BENZOCYCLOBUTENE CONTAINING METHACRYLATE MONOMER FOR CONTROLLED RADICAL POLYMERIZATION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirement for the Degree Master of Science Isamu Ono August, 2016

2 OPTIMIZATION OF THE STRUCTURE OF BENZOCYCLOBUTENE CONTAINING METHACRYLATE MONOMER FOR CONTROLLED RADICAL POLYMERIZATION Isamu Ono Thesis Approved: Accepted: Advisor Dr. Coleen Pugh Dean of the College Dr. Eric Amis Faculty Reader Dr. Li Jia Dean of the Graduate School Dr. Chand Midha Department Chair Dr. Coleen Pugh Date ii

3 ABSTRACT Synthetic routes to benzocyclobutene (BCB)-containing methacrylate monomers were developed, and their (co) polymerization kinetics with methyl methacrylate (MMA) were investigated. Precursor 1-subsituted BCB compounds were generated via [2+2]- cycloaddition between benzyne and vinyl-substituted compounds. 1-Substituted benzocyclobutene alcohols that had 0- or 1-carbon spacers between the 1-position carbon of BCB and the hydroxyl group were subsequently synthesized through hydrolysis or reduction. Each alcohol product was esterified with methacryloyl chloride to produce a BCB-containing methacrylate monomer bearing no spacer or a one carbon spacer. The synthetic pathway to the monomer bearing a two-carbon spacer was explored and newly established. The 1-substituted BCB alcohol that had a two-carbon spacer was synthesized through a malonic ester synthesis and reduction starting from 1-bromoBCB. The alcohol product was esterified with methacryloyl chloride to yield the monomer. Each of these monomers was copolymerized with MMA by atom transfer radical polymerization (ATRP) and their kinetics was studied to investigate the controllability of the copolymerization. The copolymerizations were performed with a comonomer feed ratio (mol%) of 80/20 = MMA/BCB-monomer; there was no strong evidence of side reactions such as irreversible termination and degradative chain transfer during any of the copolymerizations. Therefore, the feed composition of BCB-monomer was increased to 50, 80, and 100 mol%. In the case of the BCB-monomer without a carbon spacer, the number iii

4 average molecular weight (Mn) decrease remarkably compared to the theoretical Mn and the molecular weight dispersity (Ð) increased to around 1.40 after 12 hours-reaction with increasing BCB-monomer in the feed composition of the monomer was increased. In contrast, the other two monomers with one- or two-carbon spacer(s) were (co)polymerized in a well-controlled manner even at high BCB content in the feed. These results show that the monomers with one- or two-carbon spacer(s) enable us to synthesize BCB-containing methacrylate copolymers with well-controlled molecular weight and narrow Ð. DSC analysis was performed for the obtained copolymers (50/50). Broad exothermic peak ranging from 170 C to 300 C (peak maximum: around 270 C) was observed only in the first heating scan for each copolymer, which shows BCB moieties in the copolymers underwent cross-link reaction when heated. iv

5 ACKNOWLEDGEMENTS Firstly, I would like to thank my parents for their supports to date. I would also like to thank my wife, Yumi Ono for her patience, support, and taking care of our son, Yutaka, in Japan while I lived in the United States alone and completed the Master s program. I would like to thank my advisor, Dr. Coleen Pugh, for allowing me to join her research group and providing an interesting project. She always encouraged me to research and provided many great suggestions that sharpened my scientific mind. I cannot thank her enough. I would like to thank the other members of Dr. Pugh s research group for their great help and encouragement. Especially, Ajay Amrutkar, my mentor, for providing a lot of help, suggestions and exiting discussions; Abby Freedman, Carolyn Scherger and Tyler Tommey for their proofreading of my thesis and a lot of suggestions. I would also like to thank Dr. Li Jia for being a faculty reader of my thesis and attending my seminar and providing a lot of suggestions. Finally, I would like to thank Nippon Paper Industries for providing me with the great opportunity to study at The University of Akron, the top institute of polymer science. v

6 TABLE OF CONTENTS Page LIST OF TABLES... xi LIST OF FIGURES... xii LIST OF SCHEMES... xvi CHAPTER I. INTRODUCTION...1 II. LITERATURE REVIEW Benzocyclobutene and its chemistry Preparation of BCB and derivatives 8, BCB in polymer synthesis BCB as a cross-linker Overview of polymeric nanoparticles Preparation of polymeric nanoparticles Poly(methyl methacrylate) Atom transfer radical polymerization (ATRP) 38, III. EXPERIMENTAL METHOD Materials Techniques Synthesis of 1-Acetoxy Benzocyclobutene (BCB-Ac) vi

7 3.4. Synthesis of 1-hydroxylbenzocyclobutene (BCB-OH) Synthesis of Benzocyclobutyl Methacrylate (BCB-MA) Synthesis of 1-Cyanobenzocyclobutene (BCB-CN) Synthesis of Benzocyclobutyl Carboxylic Acid (BCB-COOH) Synthesis of 1-Hydroxymethylbenzocyclobutene (BCB-CH2OH) Synthesis of (benzocyclobutyl)methyl methacrylate (BCB-CH2MA) Synthesis of 1-Bromobenzocyclobutene (BCB-Br) Synthesis of 3-phenyl-1-propanol Generation of Grignard Reagent Reaction with Ethylene Carbonate at Room Temperature Reaction with Ethylene Carbonate at 110 C Synthesis of Benzocyclobutyldimethyl Malonate Synthesis of (benzocyclobutyl)methylcarboxylic acid (BCB-CH2COOH) Synthesis of 1-Hydroxyethylbenzocyclobutene Synthesis of 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) Polymerization of MMA by ATRP Kinetic Study of MMA by ATRP Kinetic Study on the Copolymerization of BCB-MA with MMA by ATRP Kinetic study on copolymerization of BCB-CH2MA with MMA by ATRP Kinetic study on copolymerization of BCB-CH2CH2MA with MMA by ATRP vii

8 3.21. Copolymerization of BCB-MA with MMA by ATRP (feed ratio: MMA/BCB- MA = 50/50) Copolymerization of BCB-CH2MA with MMA by ATRP (feed ratio: MMA/BCB-CH2MA = 50/50) Copolymerization of BCB-CH2CH2MA with MMA by ATRP (feed ratio: MMA/ BCB-CH2CH2MA = 50/50) Copolymerization of BCB-MA with MMA by ATRP (feed ratio: MMA/BCB- MA = 20/80) Copolymerization of BCB-CH2MA with MMA by ATRP (feed ratio: MMA/BCB-CH2MA = 20/80) Copolymerization of BCB-CH2CH2MA with MMA by ATRP (feed ratio: MMA/ BCB-CH2CH2MA = 20/80) Polymerization of BCB-MA by ATRP Polymerization of BCB-CH2MA by ATRP Polymerization of BCB-CH2CH2MA by ATRP IV. MONOMER SYNTHESIS Introduction Synthesis of benzocyclobutyl methacrylate (BCB-MA) Synthesis of 1-acetoxybenzocyclobutene (BCB-Ac) Synthesis of 1-hydroxybenozcyclobutene (BCB-OH) Synthesis of benzocyclobutyl methacrylate (BCB-MA) Synthesis of (benzocyclobutyl)methyl methacrylate (BCB- CH2MA) Synthesis of 1-cyanobenzocyclotutene (BCB-CN) Synthesis of benzocyclobutylcarboxylic acid (BCB-COOH) viii

9 Synthesis of 1-Hydroxymethyl benzocyclobutene (BCB-CH2OH) Synthesis of (benzocyclobutyl)methyl methacrylate (BCB- CH2MA) Synthesis of 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) Synthesis of 1-bromobenzocyclobutene (BCB-Br) Model reaction of synthesis of 1-hydroxyethylbenzocyclobutene (BCB- CH2CH2OH) Generation of Grignard reagent Reaction of the Grignard reagent with ethylene carbonate Malonic ester synthesis Synthesis of benzocyclobutyldimethyl malonate Synthesis of (benzocyclobutyl)methylcarboxylic acid (BCB-CH2COOH) 62, Synthesis of 1-hydroxyethylbenzocyclobutene (BCB-CH2CH2OH) Synthesis of 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) Conclusion V. POLYMERIZATION OF BCB-MONOMERS Introduction Copolymerization of BCB-monomers with methyl methacrylate and kinetic studies Kinetic study of the polymerization of Methyl methacrylate by ATRP Kinetic study of the ATPR copolymerization of BCB-MA with methyl methacrylate ix

10 Kinetic study of the ATRP copolymerization of BCB-CH2MA with methyl methacrylate Kinetic study of the ATRPcopolymerization of BCB-CH2CH2MA with methyl methacrylate Summary of the kinetic studies (Co)polymerization of BCB-monomers with methyl methacrylate with various feed ratios Conclusion VI. SUMMARY REFERENCES x

11 LIST OF TABLES Table Page 2.1 Ring-opening temperatures of 1-substituted BCBs Basic physical and mechanical properties of pmma Comparison of the physical properties of ethylene carbonate and ethylene oxide Results of Grignard reagent formation Chain transfer constants (Cx) for various compounds in the free radical polymerization of styrene at 60 ºC, including 1-ethoxybenzocyclobutene (1- EtOBCB). 5, The original data of the kinetic studies on the polymerization of MMA. The experiment was performed in duplicate (entry 1 and entry 2), and the average and standard deviation of the two experiments are listed The original data of the kinetic studies on the copolymerization of BCB-MA with MMA: the experiments were repeated twice (entry 1 and entry 2) and the average and standard deviation of the two experiments are listed The original data of the kinetic studies on the copolymerization of BCB-CH2MA with MMA. The experiments were repeated twice (entry 1 and entry 2), and the average and standard deviation of the two experiments are listed The original data of the kinetic studies on the copolymerization of BCB-CH2CH2MA with MMA. The experiments were repeated twice (entry 1 and entry 2), and the average and standard deviation of the two experiments are listed The results of copolymerization varying the feed ratio of MMA to BCB-monomers xi

12 LIST OF FIGURES Figure Page 1.1 (A) Chain transfer to 1-EtOVBCB by hydrogen abstraction at the 1-positton to generate a radical stabilized by heteroatom and resonance. 4 (B) Expected chain transfer to BCB-containing methacrylate monomer. (C) Proposed BCB-containing methacrylate monomers to suppress the side reaction. (D) General scheme of the copolymerization of BCB-monomers with MMA by ATRP Deprotection of protected ureidopyrimidinone (UPy) urethane moieties by irradiating with UV light and subsequent intramolecular chain collapse via hydrogen bonds Synthesis of precursor polymer with BCB moieties and preparation of nanoparticles thorough intramolecular chain collapse Preparation of nanoparticles by utilizing click chemistry Synthesis of tadpole like amphiphilic polymeric nanoparticle using BCB chemistry Schematic illustration of examples of self-assembly of amphiphilic nanoparticles Intramolecular cross-linking reaction at lowered cross-linking temperature by 1- substituted BCB moieties The structure of methyl methacrylate and poly(methyl methacrylate) Examples of nitrogen-based ligands and their ATRP equilibrium constants (KATRP) in a reaction of the corresponding Cu I Br complexes with ethyl 2-bromoisobutyrate in MeCN at 22 C BCB-containing methacrylate monomers synthesized for this project H-NMR spectrum of 1-acetoxybenzocyclobutene (BCB-Ac) H-NMR spectrum of 1-hydroxybenzocyclobutene (BCB-OH) H-NMR spectrum of benzocyclobutyl methacrylate (BCB-MA) C-NMR spectrum of benzocyclobutyl methacrylate (BCB-MA) xii

13 4.6 1 H-NMR spectrum of 1-cyanobenzocyclotutene (BCB-CN) H-NMR spectrum of benzocyclobutylcarboxylic acid (BCB-COOH) H-NMR spectrum of 1-hydroxymethyl benzocyclobutene (BCB-CH2OH) H-NMR spectrum of (benzocyclobutyl)methyl methacrylate (MA) C-NMR spectrum of (benzocyclobutyl)methyl methacrylate (BCB-CH2MA) H-NMR spectrum of 1-bromobenzocyclobutene (A) 1 H-NMR spectrum of an isolated compound of the reaction mixture. (B) An assigned compound to the spectrum 57 and assumed mechanism based on a literature example H-NMR spectrum of BCB dimethyl malonate H-NMR spectrum of BCB-CH2COOH H-NMR spectrum of BCB-CH2CH2OH H-NMR spectrum of BCB-CH2CH2MA C-NMR spectrum of BCB-CH2CH2MA Synthetically available BCB-containing methacrylate monomers H-NMR spectrum of an aliquot taken at 6 hours during the polymerization of MMA by ATRP using CuCl, as the catalyst and PMDETA as the ligand in toluene at 90 C; [M]:[I]:[CuCl]:[PMDETA] = 100:1:1: GPC traces of aliquots taken from the reaction mixture of polymerization of MMA at various intervals (Entry 2 in Table 5.2) Plots of conversion vs time (left y-axis) and first order monomer conversion plots of ln([m]0/[m]) vs time (right y-axis) for polymerization of MMA by ATRP (A) Typical first order monomer conversion plots of ln([m]0/[m]) vs time and meanings of deviations from linearity. (B) Typical plots of number-average molecular weight (Mn) as a function of conversion and meaning of deviation from linearity. 38, General concept of PRE. (A) Scheme (1) shows activation of dormant species and generation of transient radicals (R ) and persistent radicals (Y ). Scheme (2) shows bimolecular termination reaction between transient radicals. (B) Concentrations of transient and persistent radicals and dormant chains vs. time in a doublelogarithmic plot xiii

14 5.6 Plots of first order conversion vs time 2/3 for polymerization of MMA by ATRP Number average molecular weight (Mn) (A), or Ð (B) on monomer as a function of conversion H-NMR spectrum of an aliquot taken at 6 hours during the copolymerization of BCB-MA with MMA by ATRP using CuCl, as the catalyst and PMDETA as the ligand in toluene at 90 C; [M]:[I]:[CuCl]:[PMDETA] = 100:1:1: GPC traces of aliquots taken from the copolymerization of BCB-MA at various intervals (Entry1 in Table 5.3) Kinetic experiments for copolymerization of BCB-MA at a feed ratio of 80/20 (MMA/BCB-MA) by ATRP. (A) Plots of conversion vs time (left y-axis) and first order monomer conversion plots of ln([m]0/[m]) vs time (right y-axis); (B) Plots of first order conversion vs time 2/3 ; Number average molecular weight (Mn) (C), or Ð (D) on monomer as a function of conversion H-NMR spectrum of an aliquot taken at 6 hours during the copolymerization of BCB-CH2MA with MMA by ATRP GPC traces of aliquots taken from the copolymerization of BCB-CH2MA at various intervals (Entry 1 in Table 5.4) Kinetic experiments for copolymerization of BCB-CH2MA at a feed ratio of 80/20 (MMA/BCB-CH2MA) by ATRP. (A) Plots of conversion vs time (left y-axis) and first order monomer conversion plots of ln([m]0/[m]) vs time (right y-axis); (B) Plots of first order conversion vs time 2/3 ; Number average molecular weight (Mn) (C), or PDI (D) on monomer as a function of conversion H-NMR spectrum of an aliquot taken at 6 hours during the copolymerization of BCB-CH2CH2MA with MMA by ATRP GPC traces of aliquots taken from the copolymerization of BCB-CH2CH2MA at various intervals (Entry 1 in Table 5.5) Kinetic experiments for copolymerization of BCB-CH2CH2MA at a feed ratio of 80/20 (MMA/ BCB-CH2CH2MA) by ATRP. (A) Plots of conversion vs time (left y-axis) and first order monomer conversion plots of ln([m]0/[m]) vs time (right y- axis); (B) Plots of first order conversion vs time 2/3 ; Number average molecular weight (Mn) (C), or Ð (D) on monomer as a function of conversion Summary of the kinetic experiments for copolymerization of BCB-monomers at a feed ratio of 80/20 (MMA/BCB). (A) Averages of conversion vs time; Averages of first order monomer conversion plots of ln([m]0/[m]) vs time (B) or vs time 2/3 (C) xiv

15 H-NMR spectrum of poly(bcb-ma) prepared by ATRP using CuCl, as the catalyst and PMDETA as the ligand in toluene at 90 C; [M]:[I]:[CuCl]:[PMDETA] = 100:1:1:1; reaction time = 12 h H-NMR spectrum of poly(bcb-ch2ma). prepared by ATRP using CuCl, as the catalyst and PMDETA as the ligand in toluene at 90 C; [M]:[I]:[CuCl]:[PMDETA] = 100:1:1:1; reaction time = 12 h H-NMR spectrum of poly(bcb-ch2ch2ma) prepared by ATRP using CuCl, as the catalyst and PMDETA as the ligand in toluene at 90 C; [M]:[I]:[CuCl]:[PMDETA] = 100:1:1:1; reaction time = 12 h GPC chromatogram of each copolymerization at feed ratio of 50/50 (MMA/BCB) by ATRP using CuCl, as the catalyst and PMDETA as the ligand in toluene at 90 C; [M]:[I]:[CuCl]:[PMDETA] = 100:1:1:1; reaction time = 12 h GPC chromatogram of each copolymerization at feed ratio of 20/80 (MMA/BCB) by ATRP using CuCl, as the catalyst and PMDETA as the ligand in toluene at 90 C; [M]:[I]:[CuCl]:[PMDETA] = 100:1:1:1; reaction time = 12 h GPC chromatogram of each homopolymerization of BCB-monomer by ATRP using CuCl, as the catalyst and PMDETA as the ligand in toluene at 90 C; [M]:[I]:[CuCl]:[PMDETA] = 100:1:1:1; reaction time = 12 h DSC thermogram showing the solid state curing of the 50/50 MMA-BCB-MA copolymer. Ramp rate = 10 C / min DSC thermogram showing the solid state curing of 50/50MMA-BCB-CH2MA copolymer. Ramp rate = 10 C/min DSC thermogram showing the solid state curing of 50/50MMA- BCB-CH2CH2MA copolymer. Ramp rate = 10 C/min Synthetically available BCB-containing methacrylate monomers General scheme of the copolymerization of BCB-monomers with MMA by ATRP xv

16 LIST OF SCHEMES Scheme Page 2.1 The first reported synthesis of benzocyclobutene derivatives and benzocyclobutene Preparation of a polymer via ring-opening dimerization of BCB moieties in the monomers Ring-opening and reaction of benzocyclobutene in the presence and absence of dienophile Synthetic route to BCB via Wolff rearrangement Synthetic route to BCB via carbene reaction Synthetic route to BCB through reactions of benzyne with olefins. 13, Synthetic route to BCB through homocyclic ring closure Polymerization of 1-methoxy BCB in the presence of radical initiator Preparation of poly(o-phenylenevinylene) Polymerization of α-methylenebenzocyclobutene (MB). The MB polymer did not react with dienophiles when heated Polymerization of p-(vinyltolyl)benzocyclobutene monomer Polymerization of AB type BCB monomer bearing a BCB moiety and a maleimide moiety AA+BB type polymerization of bis(bcb)s and bismaleimides General scheme of cross-link formation between BCB moieties Polymerization of bisbenzocyclobutene monomers to form cross-linked structure xvi

17 2.16 Synthesis of poly(ary1ene ether ketone)s containing BCB moieties Polymerization of 4-vinylbenzocyclobutene by conventional radical polymerization Polymerization of 4-vinylbenzocyclobutene by living anionic polymerization Cationic polymerization of 1-benzyocyclobutenyl vinyl ether and subsequent Diel- Alder reaction with maleic anhydride Typical scheme of Cu catalyzed ATRP The synthetic route to 1-acetoxybenzocyclobutene (BCB-Ac) The synthetic route to 1-hydroxybenozcyclobutene (BCB-OH) The synthetic route to benzocyclobutyl methacrylate (BCB-MA) The synthetic route to 1-cyanobenzocyclotutene (BCB-CN) The synthetic route to benzocyclobutylcarboxylic acid (BCB-COOH) The synthetic route to 1-hydroxymethylbenzocyclobutene (OH) The synthetic route to (benzocyclobutyl)methyl methacrylate (BCB-CH2MA) Bonan Yu s synthetic route for BCB-CH2CH2MA The initially proposed synthetic route to 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) using ethylene carbonate Literature examples of ethylene carbonate reacting with heteroatom nucleophilic sites for 2-hydroxyethyl functionalization The synthetic route to 1-bromobenzocyclobutene (BCB-Br) Scheme of the synthesis of 3-phenyl-1-propanol The formation of Grignard reagent using benzyl bromide and the reaction with DMF Undesirable side reaction in the Grignard reagent formation (Wurtz coupling reaction) Desired mechanism to form 3-phenyl-1-propanol based on a literature xvii

18 4.16 Overview of malonic ester synthesis to form the carboxylic acid and subsequent reactions to yield final monomer Synthetic route of BCB dimethyl malonate Synthetic route of BCB-CH2COOH Synthetic route to BCB-CH2CH2OH Synthetic route of BCB-CH2CH2MA Expected hydrogen abstraction from the monomer. The resulting radical would be stabilized by the resonance and the oxygen atom (red-colored) Chain transfer to 1-ethoxyvinylbenzocyclobutene (1-EtOVBCB) by hydrogen abstraction at the 1-positton to generate a radical stabilized by heteroatom and resonance BCB-containing monomers synthesized for this project which vary the length of methylene methylene carbon spacers between BCB-unit and methacrylate unit General concept of ATRP Expected side reaction for the monomer xviii

19 CHAPTER I 1. INTRODUCTION INTRODUCTION The goal of this project is to optimize the structure of benzocyclobutene (BCB)- containing methacrylate monomer to obtain well-defined methyl methacrylate copolymer with BCB functionality. The strained four-membered ring of an unsubstituted BCB can transform into an o- quinodimethane (oqdm) when heated at around 200 C. 1 This highly reactive species promptly undergoes Diels-Alder reactions with various dienophiles, including another oqdm intermediate, which generates dimers and oligomers of BCB. Through these reactions, BCBs can crosslink without any added catalyst and without the release of small molecule condensation byproducts. 1 For these desirable features of BCBs as cross-linking units, BCB-containing polymers have been used as precursors of nanoparticles since Hawker et al. first reported the synthesis of single-chain polymeric nanoparticles by intramolecular chain collapse using BCB chemistry. 2 It is important for these precursor polymer chains to have narrow dispersity (Ð) to obtain nanoparticles of uniform size. Therefore, these precursor polymers have been commonly synthesized by controlled polymerizations such as atom transfer radical polymerization (ATRP), to achieve well-controlled molecular weight and narrow Ð. 1

20 Recently, we synthesized a new BCB-containing vinyl monomer, 1- ethoxyvinylbenzocyclobutene (1-EtOVBCB), 3 and Dr. William Storms-Miller copolymerized this monomer with other vinyl monomers in his Ph.D. project and found that the Ð was broader than expected. 4 He assumed that the hydrogen at the 1-position on the BCB ring was readily abstracted because the resulting radical is stabilized by the adjacent hetero-atom (oxygen atom) and it is resonance due to the benzylic structure as shown in Figure 1.1 (A). Dr. James Baker, in his Ph.D. project, determined that the chain transfer constant of 1-ethoxybenzocyclobutene (1-EtOBCB), an analogue of 1-EtOVBCB, in the free radical polymerization of styrene at 60 ºC is as high as that of benzyl ether. 5 Poly(methyl methacrylate) (pmma) is one of the most important polymers in both academic and industrial fields because of its advantageous characteristics, such as high transparency, good mechanical properties, high biocompatibility, and low cost. 6 For these features, pmma has been applied to nanoparticles for biomedical applications such as drug delivery. 6 While these pmma nanoparticles have been commonly prepared by emulsion polymerizations, it is still challenging to prepare particles with sizes below 50 nm and narrow size distribution. 7 To my best knowledge, BCB chemistry has not been applied into pmma system to prepare nanoparticles, so far. One of our motivations is therefore synthesize a BCB-containing methacrylate monomer that can be used to eventually prepare well-defined pmma that has BCB functionality for applications in nanoparticles. However, abstraction of the hydrogen at the 1-position of the BCB-containing methacrylate remains a problem, as it can lead to less controlled copolymerizations. We expect this abstraction mechanism (Figure 1.1 (B)) to be similar to that of 1-EtOVBCB mechanism. 2

21 To suppress this expected side reaction and to obtain well-defined BCB-containing methacrylate copolymers, our strategy was to insert carbon spacer between BCB unit and the oxygen atom to weaken the effect of heteroatom stabilization on the resulting radical. To test our hypothesis, three monomers with 0, 1, or 2 carbon spacer(s) between the BCB unit and the oxygen atom were newly synthesized (Figure 1.1 (C)) and copolymerized with MMA by ATRP to investigate the controllability of the copolymerization as shown in Figure 1.1 (D). A B C D Figure 1.1: (A) Chain transfer to 1-EtOVBCB by hydrogen abstraction at the 1-positton to generate a radical stabilized by heteroatom and resonance. 4 (B) Expected chain transfer to BCB-containing methacrylate monomer. (C) Proposed BCB-containing methacrylate monomers to suppress the side reaction. (D) General scheme of the copolymerization of BCB-monomers with MMA by ATRP. 3

22 CHAPTER II 2. LITERATURE REVIEW LITERATURE REVIEW 2.1. Benzocyclobutene and its chemistry Benzocyclobutene (BCB, also known as bicyclo[4.2.0]octa-1,3,5-triene) and its derivatives have a long history and have been widely used in polymer science due to their unique chemical structure and properties as reactive molecules. 1 In 1909, Finkelstein first reported the preparation of 1,2,-dibromobenzocyclobutene through an elimination reaction of α,α,α,α -tetrabromo-o-xylene with sodium iodide. 8 After decades without further research in BCB chemistry, Cava and Napier in 1956, confirmed Finkelstein s earlier work and synthesized benzocyclobutene (Scheme 2.1). 9 Scheme 2.1: The first reported synthesis of benzocyclobutene derivatives and benzocyclobutene. 9 Since then, the chemistry of BCB and its applications have been vigorously studied by many researchers. For example, the Dow Chemical company started to research the synthesis and modification of polymers containing BCB in the late 1970s, and published the first patent reporting the synthesis of polymers through ring-opening polymerization of 4

23 BCB containing monomers (Scheme 2.2). 10 They reported that the polymers were thermally stable and had a good modulus and low water pickup. To this day, the research fields of BCB have continued to expand. Scheme 2.2: Preparation of a polymer via ring-opening dimerization of BCB moieties in the monomers. 10 Benzocyclobutene has a benzene ring and a highly strained four-member ring. Although BCB is stable at ambient temperature, the four-member ring undergoes ringopening isomerization when heated up to generate a highly reactive ortho-quinodimethane (oqdm) (Scheme 2.3). 11 This intermediate promptly undergoes a Diels-Alder [4+2] cycloaddition with dienophiles, or in the absence of dienophiles, reacts with another oqdms to produce dimers and oligomers (Scheme 2.3). 11 Therefore, BCBs are a useful precursor of dienes that can be deprotected thermally. Scheme 2.3: Ring-opening and reaction of benzocyclobutene in the presence and absence of dienophile. 11 5

24 There are several other pathways to generate oqdm intermediate, such as reverse Diels-Alder reaction using benzo-fused heterocyclic compounds, 1,4-elimination of α,α - substituted o-xylenes, photo-enolization using o-methylbenzaldehydes, and photorearrangement using o-methylstyrenes or o-xylene-metal complexes. 11 The advantages of BCB as an oqdm precursor over other methods are that BCB reactions do not require any catalysts, do not eliminate any byproducts, and have variable reaction temperatures based on the nature of the substituent on its cyclobutene ring. 1,11 The half-life for BCB conversion to oqdm at room temperature is years, which means that BCB is stable at room temperature. 1 However, the half-life for the ringopening fall to 8 days, 1.4 hours, and 1.5 minutes at 150 C, 200 C, and 250 C, respectively. While the ring-opening isomerization temperature of unsubstituted BCB is 220 C, it can be lowered by attaching a substituent on the cyclobutene ring. The extent to which the temperature can be lowered varies widely based on the nature of the substituent (Table 2.1). 11 Both electron-donating and electron-withdrawing substituents lower the isomerization temperature with different mechanism; electron-donating substituents raise the ground state energy to lower the temperature, and electron-withdrawing substituents lower the transition state energy. Table 2.1: Ring-opening temperatures of 1-substituted BCBs. 11 6

25 2.2. Preparation of BCB and derivatives 8,12 Since Finkelstein first reported the synthesis of BCB in 1909, several methods for the preparation of BCB have been developed, for example, o-quinomethane ring closure, Wolff rearrangement, carbene reactions, addition of benzyne to olefins, and ring-closure reactions. 8,12 Each of these methods has advantages and disadvantages, and are chosen in terms of availability of starting compounds, ease of synthesis, and adaptability of functionalization. 8 o-quinomethane ring closure is the original Finkelstein method in which α,α,α,α,α -tetrabromo-o-xylene is reacted with sodium iodide at ~78 C in ethanol to generate 1,2-dibromobenzocyclobutene, which is subsequently converted into BCB via a Pd-catalyzed hydrogenation (Scheme 2.1). Wolff rearrangement is a method in which α-diazoindanones are rearranged to generate substituted benzocyclobutenecarboxylic acids (Scheme 2.4). 12 Scheme 2.4: Synthetic route to BCB via Wolff rearrangement Chlorobenzocyclobutene was synthesized from carbene through the mono dichlorocarbene adduct (Scheme 2.5). 12 Scheme 2.5: Synthetic route to BCB via carbene reaction. 12 7

26 Benzyne generated from benzenediazonium-2-carboxylate was reacted with olefins such as vinyl acetate and ethyl vinyl ether to yield 1-acetoxy benzocyclobutene and ethyl benzocyclobutyl ether, respectively (Scheme 2.6). 13 Similar examples were provided by Matsuda et al. in The benzyne generated from benzenediazonium-2-carboxylate was reacted with acetonitrile and ethyl acrylate to yield 1-cyanobenzocyclobutene and ethyl benzocyclobutene-1-carboxylate, respectively (Scheme 2.6). 14 This is a useful synthetic route to BCB because a substituent is produced on the cyclobutene ring in one step. However, a disadvantage of this method is that it is difficult to perform these reactions on a large scale because of the explosive nature of benzenediazonium-2-carboxylate. 40% yield 13 45% yield 13 20% yield 14 8% yield 14 Scheme 2.6: Synthetic route to BCB through reactions of benzyne with olefins. 13,14 BCB derivatives can be prepared by homocyclic ring closure. In this method, versatile 1-substitueted BCB such as cyano-, sulfonyl-, carboethoxy-, or acyl-bcb can be prepared (Scheme 2.7). 15 Scheme 2.7: Synthetic route to BCB through homocyclic ring closure. 15 8

27 2.3. BCB in polymer synthesis BCBs have been widely utilized to prepare a variety of polymers. 1 Polymerization mechanisms are loosely categorized into two types; chain-growth polymerization and stepgrowth polymerization. Endo et al. polymerized methoxy-substituted BCB monomer by free radical chaingrowth polymerization (Scheme 2.8). 16 Scheme 2.8: Polymerization of 1-methoxy BCB in the presence of radical initiator. 16 They heated 1-methoxy BCB above 90 C with a radical initiator, such as 1,1 - azobis(cyclohexane-1-carbonitrile) (ABCN), di-tert-butyl peroxide and benzoyl peroxide, in bulk, and obtained poly(1-methoxy-o-quinodimethane). The reaction temperature was varied from 80 C to 140 C, and the highest yield was observed at 110 C, whereas, no polymer was obtained at 80 C even in the presence of the radical initiator. This temperature dependence of the polymerization shows that the monomer was polymerized via a monomer isomerization polymerization. As discussed in the previous section, the ring-opening isomerization temperature of methoxy-substituted BCB is around 120 C. Methoxy-substituted BCB isomerizes to form oqdm upon heating to 90 C or above and 9

28 the oqdm subsequently undergoes radical polymerization. In contrast, the BCB monomer does not isomerize below 80 C and therefore polymerization does not occur. If the BCB monomer was heated to more than 90 C without a radical initiator, polymer was not obtained but instead oligomers and dimers were formed as a result of a Diels-Alder dimerization (Scheme 2.8). Therefore, enough initiator should be added such that sufficient radical species attack oqdm intermediates before Diels-Alder dimerization occurs. Poly(1-methoxy-o-quinodimethane) was also treated with a catalytic amount of p- toluenesulfonic acid to yield poly(o-phenylenevinylene), which can be utilized for the synthesis of conjugated polymers (Scheme 2.9). 17 Scheme 2.9 Preparation of poly(o-phenylenevinylene). 17 This group also carried out the free radical polymerization of α- methylenebenzocyclobutene (MB) (Scheme 2.10). 18 Although they tried thermal ringopening and Diels-Alder reaction with dienophiles, they found that no Diels-Alder adduct formed but instead the MB polymer decomposed at elevated temperature. Scheme 2.10: Polymerization of α-methylenebenzocyclobutene (MB). The MB polymer did not react with dienophiles when heated

29 BCB monomers can also be polymerized via step-growth polymerization. In this case, there are AB type and AA+BB type polymerization. In the former case, monomer has a dienophile moiety at one end and a BCB moiety at the other end. In the latter case, one monomer has BCBs at both ends, and the other monomer has dienophiles at both ends. Upon heating above the ring-opening temperature of BCB, the generated oqdms react with dienophiles on other monomers. Therefore, these polymerizations are called Diels- Alder polymerizations. One example of an AB type monomer is a vinyl-containing BCB monomer. Hahn et al. polymerized p-(vinyltolyl)benzocyclobutene monomer and observed the formation of tetrahydronaphthalene repeat units that were formed via the Diels-Alder reaction as shown in Scheme Similarly, monomers containing both a BCB moiety and a maleimide moiety were synthesized as AB type monomers for Diels-Alder polymerization (Scheme 2.12). 20 Scheme 2.11: Polymerization of p-(vinyltolyl)benzocyclobutene monomer. 19 Scheme 2.12: Polymerization of AB type BCB monomer bearing a BCB moiety and a maleimide moiety

30 Tan et al. performed AA+BB type Diels-Alder polymerization using a bis(benzocyclobutene)-terminated monomer and a bismaleimide to yield a polyimide-type copolymer (Scheme 2.13). 21 They found that the copolymer had higher thermal stability than the polybismaleimide homopolymer; the copolymer retained most of its weight after 200 hours at 343 C, whereas the pure polybismaleimide rapidly lost its weight during the TGA experiment. 21 These kind of bisbenzocyclobutene polymers have been widely used in a various electronics applications, such as microelectronics, because of their low dielectric constant and their high thermal stability. 1 Scheme 2.13: AA+BB type polymerization of bis(bcb)s and bismaleimides BCB as a cross-linker Monomers bearing BCB moieties produce a cross-linked polymers when they are homopolymerized under heat or are heated after polymerization. When the BCB units in the monomers or polymers are heated to above 200 C, oqdms are generated and react together to form intra- and/or intermolecular cross-links (Scheme 2.14). The advantages of BCB as a cross-linking unit over many other cross-linking systems are that it does not require any catalyst for the reaction and does not release any volatile chemicals. 1,22 12

31 Scheme 2.14: General scheme of cross-link formation between BCB moieties. For instance, Kirchhoff et al. polymerized bisbenzocyclobutene monomers that do not have unsaturated reactive sites. Thermally induced ring-opening of the cyclobutene ring generates oqdm, which subsequently reacts with other oqdms to form a polymer with a cross-linked three dimensional network (Scheme 2.15). 1,22 Scheme 2.15: Polymerization of bisbenzocyclobutene monomers to form cross-linked structure. 1 The next example is cross-linkable engineering polymers. Poly(arylene ether ketone)s are widely used as engineering polymers under extreme conditions on account of their high thermal and chemical stability and low flammability. 23 However, semicrystalline poly(arylene ether ketone)s are generally only soluble in concentrated H2SO4 at ambient temperature, and are therefore difficult to process. Walker et al. synthesized amorphous poly(arylene ether ketone)s by incorporating BCB structures within the polymer backbone (Scheme 2.15). 23 The polymers were soluble in many chlorinated organic solvents, had low glass transition temperatures ( C) in contrast to the high melting temperatures of 13

32 semicristalline poly(arylene ether ketone)s ( C), and were therefore processable from solution or the bulk. DSC analysis showed an exothermic transition in the range of 300 to 370 C, which corresponded to the reaction of oqdm. The temperature range was remarkably higher than that of other BCB-containing polymers. Although the authors did not discuss this reaction temperature further, it might be attributed to the low chain mobility of this polymer. The cross-linked polymer was not soluble in all solvents, including concentrated H2SO4, at room temperature. These results demonstrate that both high processability and thermal and chemical stabilities can be achieved by utilizing BCB chemistry. Scheme 2.16: Synthesis of poly(ary1ene ether ketone)s containing BCB moieties. 23 BCB moieties have also been introduced into polymers as cross-linkable pendant functional groups. 4-Vinylbenzocyclobutene was polymerized by conventional radical polymerization 24 and by living anionic polymerization. 25 In the former case, Endo and Chino polymerized 4-vinylbenzocyclobutene in benzene for 24 hours at 60 C using AIBN as an initiator, and Mn of resulting polymer was 7.60 kda (Ð = 2.21) (Scheme 2.17). 24 In the latter case, Sakellariou et al. performed living anionic polymerization of 4- vinylbenzocyclobutene in benzene at 25 C with sec-buli as the initiator. The controlled behavior of the polymerization was observed by kinetic experiments, and Mn of resulting polymer was 2.70 x 10 4 Da (Ð = 1.02) (Scheme 2.18)

33 Scheme 2.17: Polymerization of 4-vinylbenzocyclobutene by conventional radical polymerization. 24 Scheme 2.18: Polymerization of 4-vinylbenzocyclobutene by living anionic polymerization. 25 Chino et al. synthesized 1-benzyocyclobutenyl vinyl ether and polymerized it by cationic polymerization as shown in Scheme The goal of this work was to decrease the ring-opening isomerization temperature of the BCB moieties in the polymer by using 1-ether substituted BCB. Diels-Alder reaction of the resulting polymer (Mn = 5.00 x 10 4 Da, Ð = 2.56) with maleic anhydride was performed at various temperatures (Scheme 2.19). The degree of maleic anhydride incorporation reached 100 % when the reaction temperature was above 100 C, which demonstrated that the ring-opening temperature of the pendant BCB moieties was lower compared to that of unsubstituted BCBs due to the 1-ether substituents. Scheme 2.19: Cationic polymerization of 1-benzyocyclobutenyl vinyl ether and subsequent Diel-Alder reaction with maleic anhydride

34 2.5. Overview of polymeric nanoparticles Nanoparticles are particles with diameter of nm and have significantly different chemical and physical properties from those of the corresponding bulk materials because of their high specific surface area. 27 Among various types of nanoparticles, polymeric nanoparticles have attracted great attention recently because they can be prepared with precisely controlled chemical composition, size, and arrangement of functional groups. 28,29 For these advantageous features over inorganic nanoparticles, polymeric nanoparticles have been applied to new areas such as drug delivery, 30,31 polymer blends, 32 rheology control agents, 27 image contrast agents, 34 catalysis, 35 and sensors for metal ions Preparation of polymeric nanoparticles Polymeric nanoparticles have been conventionally prepared by dispersion of preformed polymers or directly synthesized from monomers by emulsion polymerizations. 7 However, the particle size of polymeric nanoparticles prepared by these methods is greater than 100 nm even in the case of emulsion polymerizations. 7 Recently as an alternative approach to prepare polymeric nanoparticles with dimensions of less than 20 nm, intramolecular single-chain collapse has been developed. 2,28,29 Although polymeric nanoparticles with diameters of around 20 nm can be prepared from spherical polymers such as dendrimers and star polymers, the intramolecular chain collapse strategy, in which precursor linear polymer chain are synthesized followed by intramolecular cross-linking reaction in dilute condition to form globular folded chains, offers an easier procedure to prepare nanoparticles with diameters ranging from 1.5 to 20 16

35 nm. 28 The intramolecular cross-linking reaction must be preformed in an ultra-high dilute condition (concentration of cross-linker: M); otherwise intermolecular crosslinking reaction is favored. 2 In order to use polymeric nanoparticles in the new application fields mentioned in the previous section, nanoparticles with well-defined structure in terms of narrow size distribution are required, which means that the precursor polymer chains should have precisely controlled chemical composition, molecular weight and narrow molecular weight distribution (Ð). Therefore, the precursor polymer chains are commonly synthesized by controlled / living polymerization techniques such as atom transfer radical polymerization (ATRP), nitroxide-mediated polymerization (NMP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. 37,38 To generate nanoparticles from the precursor polymer chains, there are several chain folding strategies, which are classified into two major categories: non-covalent interactions (hydrogen bonding) and covalent bonds. 28,29,37 As an example of non-covalent interactions (hydrogen bond), Meijer et al. prepared linear poly(methacrylate) (pmma) chains with alkyne functionality by single electron transfer-living radical polymerization (SET-LRP) and subsequently functionalized them with protected ureidopyrimidinone (UPy) urethane moieties. 39 Upon irradiating with 350 nm UV light, UPy urethane moieties were deprotected and then the single polymer chain collapsed to form nanoparticles by intramolecular interactions via hydrogen bonding of the UPy urethane pendant groups (Figure 2.1). AFM study demonstrated that the diameters of the particles were nm. 17

36 Figure 2.1: Deprotection of protected ureidopyrimidinone (UPy) urethane moieties by irradiating with UV light and subsequent intramolecular chain collapse via hydrogen bonds. 39 For the covalent bonding approach, various types of chemistry have been utilized to form nanoparticles from single chains. In 2002, pioneering work was reported by Hawker s group. 2 They copolymerized styrene with 4-vinylBCB by nitroxide-mediated polymerization (NMP) and obtained precursor polymer chains with BCB pendant functionalities (Mn = kda, Ð = ). The polymer solution (BCB concentration of 0.2 M) was continuously added to dibenzyl ether heated at 250 C at a rate of addition that was much slower than the rate of the cross-link reaction, which provides pseudo high dilution conditions (Figure 2.2). Formation of unimolecular nanoparticles was confirmed by 1 H-NMR spectroscopy, showing the disappearance of resonances from BCB moieties, and GPC showing a shift to higher retention time (indicating a decrease of hydrodynamic volume). 18

37 Figure 2.2: Synthesis of precursor polymer with BCB moieties and preparation of nanoparticles thorough intramolecular chain collapse. 2 For another example of cross-linking chemistry, Pomposo et al. utilized click chemistry for intramolecular chain cross-linking reaction to form nanoparticles. 40 They copolymerized methyl methacrylate with azidopropyl methacrylate and trimethylsilylpropyn-1-yl methacrylate by RAFT polymerization and obtained a terpolymer with narrow Ð. After deprotection, Cu I -catalyzed azide alkyne cycloaddition reaction was performed at room temperature with a continuous addition technique (Figure 2.3). The formation of unimolecular collapsed nanoparticles was confirmed by 1 H-NMR spectra showing the presence of triazole units and GPC showing a decrease of the apparent Mn without a significant change in Ð. 19

38 Figure 2.3: Preparation of nanoparticles by utilizing click chemistry. 40 Cross-linkers for intramolecular chain collapse should meet some requirements: be selectively activated, promptly undergo cross-linking reaction and form a stable cross-link structure. Because BCB not only fulfills these conditions but also requires no catalyst and produce no byproducts, BCB has been used as a prominent cross-linker for preparation of nanoparticles. In addition to the spherical polymeric nanoparticles, Hawker s group also reported the synthesis of a tadpole-like copolymer by selective intramolecular cross-linking of the AB block copolymer having poly(ethylene glycol) block and poly(styrene-co-vinylbcb) block (Figure 2.4)

39 Figure 2.4: Synthesis of tadpole like amphiphilic polymeric nanoparticle using BCB chemistry. 41 These kind of amphiphilic nanoparticles have attracted great attention because they can form self-assembled ordered structures (Figure 2.5) Figure 2.5: Schematic illustration of examples of self-assembly of amphiphilic nanoparticles. 42 The same authors also prepared nanoparticles at lower temperature using 1- substituted BCB. 45 They synthesized poly(acrylic acid) grafted 1-ether substituted BCB 21

40 and synthesized nanoparticles at 150 C by intramolecular chain collapse. Although initially copolymerization of acrylates with 1-ether substituted BCB vinyl monomers were attempted, the synthetic route was altered to grafting the BCB unit onto a linear acrylate polymer backbone due to lack of control of molecular weight of the copolymer (Figure 2.6). DMF, 150 C Figure 2.6: Intramolecular cross-linking reaction at lowered cross-linking temperature by 1-substituted BCB moieties

41 2.7. Poly(methyl methacrylate) Figure 2.7: The structure of methyl methacrylate and poly(methyl methacrylate). Poly(methyl methacrylate) (pmma) is one of the most important thermoplastic amorphous polymers in industry because of its desirable features, such as high transparency, low cost, good mechanical properties, and high biocompatibility. 6 Table 2.2: Basic physical and mechanical properties of pmma. 6 Property Color Colorless Refractive index Density (g / cm 3 ) 1.18 Grass Transition Temperature (Tg, C) Tensile Strength (MPa) 72 Tensile Modulus (GPa) 3.10 Elongation at Break (%) 5 Because of these advantageous properties, pmma has been applied to many areas such as optics, molecular separations, nanotechnology, and biomedical applications. 6 Recently, pmma nanoparticles have attracted great attention in the biomedical fields because of its biocompatibility and mechanical properties and have been applied to drug delivery and protein separation. 6,46 So far, pmma nanoparticles have been commonly 23

42 synthesized by emulsion polymerizations, incruding miniemulsion polymerization and microemulsion polymerization. However, a problem with these methods is that the surfactants used in the polymerization have negative effects on the final products and are difficult to remove. Achieving particle size of less than 50 nm with narrow size distribution is also still challenging. 7 Intramolecular chain collapse strategies using BCB chemistry would be a solution to this problem Atom transfer radical polymerization (ATRP) 38,47 49 A number of controlled radical polymerization (CRP) methods, such as NMP, ATRP, and RAFT have been developed. 48 CRPs take advantages of free radical polymerizations (e.g. tolerance toward many kinds of functional groups, solvents, and additives of impurities). 48 Therefore, CRPs enable the preparation of well-defined polymers, specifically, polymers with predetermined molecular weight (Mn) and narrow Ð in a variety of systems. In conventional radical polymerizations, bimolecular termination and chain transfer cannot be suppressed and limit the control of Mn and Ð. A common strategy of CRP is to decrease the instantaneous concentration of a growing radical species by establishing an equilibrium between covalent dormant species and the active radical species by either reversible termination or reversible transfer. This equilibrium minimizes the probability of radical bimolecular termination and also assures all polymer chains of growing at the same rate. 38,49 Fast and quantitative initiation also enables all of the polymer chains to start growing simultaneously. 38 These features enable almost uniform chain length (molecular weight), which is determined by the molar ratio of monomer(s) to the initiator. 24

43 ATRP is one of the most successful methods of a reversible termination process. It was developed in the 1990 s. Scheme 2.20 shows the general mechanism for ATRP. k a k da k p k t X: Br or Cl Scheme 2.20: Typical scheme of Cu catalyzed ATRP. 47 ATRP is composed of an alkyl halide as the initiator, the monomer, and a transition metal redox complex (Cu I -X/Ligand in Scheme 2.20) as a catalyst. Whereas several transition metal atoms such as Fe, Mo, Rh, Re, and Ru have been examined for ATRP, the most used transition metal in conventional ATRP is Cu. 49 The active species are generated in a reversible redox process in which the metal catalyst undergoes a one-electron oxidation via abstraction of the halogen from a dormant species (P-X) to the metal, simultaneously with a one-electron reduction of the halogen. Monomers are added to this active species in a similar way to conventional radical polymerization, and polymer chains propagate a rate constant of propagation, kp. 38,47,49 Although termination reactions also occur in ATRP, they are negligible in a well-controlled ATRP. For a well-controlled ATRP, not only the components mentioned above but also other factors, for instance, temperature and solvent, should be carefully considered. For example, side reactions such as chain transfer become more significant at elevated temperatures. A variety of vinyl monomers such as styrenes, acrylates, methacrylates, acrylonitrile, and acrylamides have been polymerized in a well-controlled manner so far. Each monomer 25

44 has its own reactivity, and therefore reaction conditions (e.g. the amount and the reactivity of the catalyst system) should be carefully chosen to adjust the concentration of active species and the rate of deactivation during the polymerization. 47 The initiator is chosen to provide fast and quantitative initiation. Alkyl halides are typically used as the initiators in ATRP, and either bromine or chlorine provide the best control of the polymerization. 47 Although, any alkyl halide that has activating substituents on the α-carbon can be potentially used as initiators, an initiator with a structure similar to that of the propagating species is usually used because the activity of the C-X bond in the initiator should be similar to that of the dormant species chain end. Most of conventional ATRPs are performed using a mixture of a copper(i) bromide or chloride as the transition-metal catalyst and a nitrogen-based compound as the ligand because of their versatility and reasonable cost. 49 The main role of the ligand is to form a complex with the transition-metal salt to solubilize it in the reaction mixture and also to lower the redox potential of the metal center so that appropriate reactivity and dynamics for the halogen transfer can be achieved. For Cu-based ATRP, the coordination of the ligand to CuX salt significantly affects the catalyst activity. Bidentate ligands, for example 2,2 - bipyridyl (bpy) and its derivatives (e.g. 4,4 -dinonyl-2,2 -dipyridyl (dnbpy)) form relatively low-active Cu-ligand complexes. In tridentate and tetradentate aliphatic aminetype ligands, the distance between the nitrogen atoms influence the activity of the corresponding Cu complex; the number of carbon atoms between any two adjacent nitrogen atoms determines the coordination angle and strain in each chelate ring. For example, while a tetradentate aliphatic amine (N4[2,3,2], in Figure 2.8) has ATRP equilibrium constants (KATRP) of 4.2 x 10-10, KATRP of another tetradentate aliphatic amine 26

45 (N4[2,2,3], in Figure 2.8) increases to 1.5 x 10-7, almost 1000 times higher, with only a slight change of the number of carbon atoms between nitrogen atoms. Branched ligands form very active Cu complexes. For example, tris[2-(dimethylamino)ethyl]amine (Me- 6TREN) has KATRP of 1.5 x 10-4 which is 4 orders higher and 5 orders higher than that of N,N,N,N,N -pentamethyldiethylenetriamine (PMDETA, KATRP = 7.5 x 10-8 ) and bpy (KATRP = 3.9 x 10-9 ), respectively. The most active Cu-based catalysts are derived from the cyclam, tetradentate cyclic ligand, particularly from the dimethyl-cross-bridged cyclam, DMCBCy (KATRP = 4.7 x 10-5 ). Figure 2.8: Examples of nitrogen-based ligands and their ATRP equilibrium constants (KATRP) in a reaction of the corresponding Cu I Br complexes with ethyl 2-bromoisobutyrate in MeCN at 22 C

46 CHAPTER III 3. EXPERIMENTAL METHOD EXPERIMENTAL METHOD 3.1. Materials Acrylonitrile (Acros Organics, 99%), anthranilic acid (Sigma Aldrich, 98%), benzyl bromide (Alfa Aesar, 99%), bromine (Acros Organics, 99%), 1,2-dibromoethane (Eastman Organic Chemicals, reagent grade), dichloromethane (Sigma Aldrich, 99.5%), diethyl ether (EDM, 99%), N,N-dimethylformamide (EMD, 99.8%), dimethyl malonate (Sigma Aldrich, 98%), ethyl acetate (Fisher Scientific, 99.9 %), ethyl 2-bromoisobutyrate (Sigma Aldrich, 98%), ethylene carbonate (Acros Organics, 99%), isoamyl nitrite (Alfa Aesar, 97%), lithium aluminum hydride (Stream Chemicals, 95%), methacryloyl chloride (Sigma Aldrich, 96%), methanol (Sigma Aldrich, 99.8%), potassium hydroxide (Fisher Scientific, 86%), sodium hydroxide (VWR, 97%), sodium methoxide solution (Sigma Aldrich, 25 weight % in methanol), tetrahydrofurane (THF, Fisher Scientific, 99%, contains less than 0.025% of butylated hydroxytoluene as a stabilizer), toluene (Sigma Aldrich, 99.5%), p- toluenesulfonic acid (Fisher Scientific, 99%), trichloroacetic acid (Fisher Scientific, 95%), triphenyl phosphine (Sigma Aldrich, 99%), and vinyl acetate (Alfa Aecar, 99%) were used as received. Solvents were used as received unless noted otherwise. Dichloromethane (CH2Cl2) was dried by washing sequentially with concentrated H2SO4, saturated aqueous NaHCO3 and deionized water (DI); storing over CaCl2, and 28

47 distilling from CaH2 under N2. Diethyl ether was dried by distillation from sodium and benzophenone ketal under N2. THF was dried by distillation from sodium benzophenone ketal under N2. Toluene was dried by distillation from sodium benzophenone ketal under N2. Cuprous chloride (94%, Fisher Scientific) was purified by stirring over glacial acetic acid overnight, washing with ethanol and diethyl ether, and drying under vacuum overnight. Hydrochloric acid (HCl, EMD, %) was diluted by DI water to an appropriate concentration before use. Magnesium powder (Fisher Scientific, 99%) was freshly opened and stored in the drybox. Methyl methacrylate (MMA, Acros Organics, 99%) was passed through basic activated alumina to remove inhibitor right before use. N,N,N',N,''N''- pentamethyldiethylenetriamine (PMDETA Sigma Aldrich, 99%) was stored over potassium hydroxide. Triethylamine (TEA, Sigma Aldrich, 99%) was distilled from potassium hydroxide under N2 and stored over potassium hydroxide Techniques All reactions (under N2 atmosphere) and (co)polymerizations were performed on a Schlenk line, unless otherwise noted. 1 H (300 MHz) / 13 C (75 MHz) NMR spectra (δ, ppm) were recorded on a Varian Mercury 300 spectrometer. Unless otherwise noted, all spectra were recorded in CDCl3, and tetramethylsilane was used as an internal standard (0.00 ppm). Melting points were determined using a MEL-TEMPII apparatus. Number-average molecular weights (Mn), weight-average molecular weights (Mw) and dispersities (Ð = Mw / Mn) were determined by gel permeation chromatography (GPC) relative to linear poly(methyl methacrylate) from calibration curves of log Mn vs. elution volume at 35 ºC using THF as solvent (1.0 ml/min), a guard column, an AM GPC linear 5 μm column, a 29

48 set of 100, 500, and 10 4 Å Styragel 5 μm columns, a 50 Å Phenogel 5 um column, a Waters 410 differential refractometer, and Millennium Empower 3 software. Thermal analysis was conducted using a Perkin Elmer 8500 differential scanning calorimeter (DSC). Glass transition temperatures (Tg) were determined as the middle of the heat capacity change. Heating and cooling rates were 10 ºC/min. Transition temperatures were calibrated using indium and tin standards, and enthalpy was calibrated using an indium standard Synthesis of 1-Acetoxy Benzocyclobutene (BCB-Ac) 50 In a 400 ml beaker, with a stir-bar and cooled in an ice bath, anthranilic acid (10.05 g, 73 mmol) and trichloroacetic acid (116 mg, 0.72 mmol) were dissolved in 100 ml of THF and stirred for 25 minutes (min). Isoamyl nitrite (10.0 g, mmol) was added dropwise over 10 min. The color of the mixture changed from yellow to dark reddish brown. The mixture was stirred for 30 min in an ice bath, followed by 2 hours at room temperature. The resulting tan-colored suspension was mainly benzenediazonium-2-carboxylate, which is highly explosive and cannot be dry at any time. The reaction was filtered through a glass frit and rinsed with CH2Cl2 until the filtrate became almost colorless and then transferred into a Parr reactor with vinyl acetate (36.1 g, 419 mmol). The reaction was carried out at 90 C for 45 min. The maximum pressure was 100 psi. After the reaction was cooled to room temperature, it was removed from the Parr reactor, and excess vinyl acetate and dichloromethane were removed using rotovap. The remaining liquid and 10 g of silica gel were added into 100 ml of hexanes and stirred at 60 C for 20 min. The solution was filtered through a glass frit. The filtrate was yellow solution and the solvent was removed using rotovap. The remaining reddish brown liquid was distilled under vacuum (1 mm Hg), and 30

49 the product was collected at 70 to 75 C. The weight of the fraction was 2.50 g (yield: 21 %). The product was further purified by column chromatography using 30 g of silica gel and hexanes and ether (90/10) as the eluent. The pure 1-acetoxybenzocyclobutene obtained was a pale yellow oil (2.108 g, yield: 18 %). 1 H NMR: (m, 3H, aromatic H s), 7.15 (d, J=7.0 Hz, 1H, aromatic H), 5.92 (dd, 3 J=4.5 Hz, 3 J=1.8 Hz, 1H, PhCHOAC), 3.66 (dd, 2 J=14.5 Hz, 3 J=4.5 Hz, 1H, PhCHH), 3.23 (dd, 2 J=14.5 Hz, 3 J=1.0 Hz, 1H, PhCHH), 2.11 (s, 3H, O=C-CH3) Synthesis of 1-hydroxylbenzocyclobutene (BCB-OH) 50 In a 2-neck 50 ml round bottom flask equipped with a stir-bar, a N2 inlet, and a glass stopper, 1-acetoxybenzocyclobutene (3.00 g, mmol) and p-toluenesulfonic acid (1.01 g 5.56 mmol) were dissolved in 30 ml of methanol and stirred for 25 h under N2 at room temperature. The mixture was poured into 50 ml of water to quench the reaction and then extracted with diethyl ether (50 ml 3). The ether phases were combined and dried over magnesium sulfate (MgSO4), and solvent was removed using rotovap. The crude product was a pale yellow solid (1.81 g, crude yield: 82%). The crude product was recrystallized from 20 ml of hexanes. Solvent was removed using rotovap, and a white solid was obtained (1.68 g, yield: 75%), and had a melting point of C. 1 H NMR: (m, 3H, aromatic H s), (m, 1H, aromatic H), 5.29 (dd, 3 J=4.4 Hz, 3 J=1.8 Hz, 1H, PhCH- OH), 3.62 (dd, 2 J=14.3 Hz, 3 J=4.4 Hz, 1H, PhCHH), 3.04 (d, 2 J=14.3 Hz, 1H, PhCHH), 2.16 (s, 1H, PHCH-OH). 31

50 3.5. Synthesis of Benzocyclobutyl Methacrylate (BCB-MA) 50 A 250 ml 3-neck round bottom flask equipped with a stir-bar, an addition funnel, and a N2 inlet were dried in an oven at 150 C overnight. 1-Hydroxybenzocyclobutene (BCB- OH, 5.00 g, 41.6 mmol) and TEA (5.72 g, 56.2 mmol) were dissolved in 40 ml of dry THF and added into the flask cooled in an ice bath and stirred. Methacryloyl chloride (6.00 g, 57.4 mmol) was dissolved in 50 ml of dry THF was added into the flask dropwise through the addition funnel over 90 min. After 30 min, the flask was removed from the ice bath and the reaction mixture was stirred for 22 h at room temperature. The mixture was filtered through a glass frit. The filtrate was poured into 100 ml of water and extracted with diethyl ether (50 ml 3). The ether phases were combined and dried over magnesium sulfate, and most of the solvent was removed using rotovap. The remaining liquid was passed through a plug of basic activated alumina, and then solvent was removed using rotovap. A yellow oil was obtained (7.32 g, crude yield: 94 %). The crude product was purified by column chromatography using 180 g of silica gel and hexanes and ether (90/10) as the eluent. Benzocyclbutyl methacrylate (BCB-MA) (3.04 g) was obtained as color-less oil (yield: 39%). The product was further purified by passing through plug of basic activated alumina. Pure BCB-MA (2.70 g) was obtained (yield: 35 %). 1 H NMR: (m, 3H, aromatic H s), 7.15 (d, J=7.0 Hz, 1H, aromatic H), 6.15 (s, 1H, -C=CHH), 5.97 (dd, 3 J=4.5 Hz, 3 J=1.9 Hz, 1H, PhCH-OMA), (t, 4 J=1.5 Hz, 1H, -C=CHH), 3.68 (dd, 2 J=14.5 Hz, 3 J=4.5 Hz, 1H, 1H, PhCHH), 3.27 (d, 2 J=14.5 Hz, 1H, PhCHH), 1.97 (s, 3H, -CH3). 13 C NMR: (-CH3), (PhCH2), (PhCH), (aromatic C7), (CH2=C-), (aromatic C6), (aromatic C5), (aromatic C4), (CH2=C-), (aromatic C8), (aromatic C7), (O-C=O). 32

51 3.6. Synthesis of 1-Cyanobenzocyclobutene (BCB-CN) 50 In a 400 ml beaker with a stir-bar cooled in an ice bath, anthranilic acid (10.06 g, 73 mmol) and trichloroacetic acid (116mg, 0.72 mmol) were dissolved in 100 ml of THF and stirred for 30 min. Isoamyl nitrite (10.01g, mmol) was added into this solution dropwise over 10 min. The color of the mixture changed from yellow to dark reddish brown. The mixture was stirred for 30 min in an ice bath followed by 2 hours stirring at room temperature. The resulting tan-colored suspension was mainly benzenediazonium-2- carboxylate, which is highly explosive and cannot be dry at any time. The mixture was filtered through a glass frit and rinsed with CH2Cl2, and then transferred into a Parr reactor with acrylonitrile (11.70 g, mmol). The reaction was carried out at 90 C for 2 hours. The maximum pressure was 115 psi. After the mixture was cooled to room temperature, it was removed from the Parr reactor and excess vinyl acetate and dichloromethane were removed using rotovap. The remaining liquid and 10 g of silica gel were added into 150 ml of hexanes and stirred at 60 C for 30 min. The solution was filtered through a glass frit. The filtrate was yellow solution, and solvent was removed using rotovap. The remaining reddish brown liquid was distilled under vacuum (1 mm Hg), and the fraction that contained the product was collected at 95 to 105 C. Crude product (1.62 g) was obtained as a yellow oil (crude yield: 17 %). The crude product was purified by column chromatography using 48 g of silica gel and hexanes and dichloromethane (90/10) as the eluent. The pure 1-cyanobenzocyclobutene was obtained as pale yellow oil (0.87 g, yield: 9.5 %). 1 H NMR: (m, 3H, aromatic H s), (m, 1H, aromatic H), 4.25 (dd, 3 J=5.4 Hz, 3 J=2.8 Hz, 1H, PhCHCN), (dd, 2 J=14.5 Hz, 3 J=5.5 Hz,1H, PhCHH), (dd, 2 J=14.5 Hz, 3 J=2.8 Hz, 1H, PhCHH). 33

52 3.7. Synthesis of Benzocyclobutyl Carboxylic Acid (BCB-COOH) 50 In a 100 ml round bottom flask equipped with a stir-bar and a water-cooled condenser with N2 inlet, 1-cyanobenzocyclobutene (BCB-CN, 4.17g, 32.3 mmol) was dissolved in 30 ml of saturated sodium hydroxide solution in ethanol, and the solution was stirred under N2 for 24 hours at room temperature. The resulting orange-colored solution was diluted with 8 ml of DI water and then refluxed for 2 hours at 90 C. The mixture became a reddish brown solution and was poured into 40 ml of water in a separatory funnel to quench the reaction, and extracted with 40 ml of diethyl ether. The aqueous phase was acidified with 10 ml of 12 M hydrochloric acid to ph = 1 and the solution became turbid. This aqueous phase was extracted with diethyl ether (50 ml 3), and the organic phase was dried over magnesium sulfate. The solvent was removed using rotovap. A yellow solid was obtained (4.27 g, crude yield: 89%). The crude product was recrystallized from hexanes. Pure benzocyclobutylcarboxylic acid (3.53 g) was obtained as a pale yellow solid (yield: 74 %). 1 H NMR: (m, 2H, aromatic H s), (m, 2H, aromatic H s), 4.34 (t, 3 J=4.0 Hz, 1H, PhCH-COOH), 3.49 (d, 3 J=4.0 Hz, 2H, PhCH2) Synthesis of 1-Hydroxymethylbenzocyclobutene (BCB-CH2OH) 50 In a 200 ml 3-neck round bottom flask equipped with a stir-bar, an addition funnel, N2 inlet, and a glass stopper were dried in an oven at 150 C overnight, and assembled in the drybox. Lithium aluminum hydride (1.81 g, 47.7 mmol) was added into the flask, and then the flask was removed from the drybox. 25 ml of dry diethyl ether was added into the flask under positive N2 pressure. A solution of benzocyclobutylcarboxylic Acid (BCB- COOH, 3.53 g, 28.9 mmol) in 25 ml of dry diethyl ether was added dropwise over 15 min 34

53 through the addition funnel into the flask cooled in an ice bath. After the addition, the flask was removed from the ice bath and stirred for 30 hours at room temperature. The mixture was a gray suspension. The reaction was quenched by slowly adding aqueous saturated MgSO4 solution until the generation of hydrogen gas stopped. A white precipitate was generated. The mixture was filtered through a glass frit and extracted with diethyl ether. The filtrate was dried over MgSO4 and the solvent was removed using rotovap. The liquid was passed through a plug of basic activated alumina and solvent was removed using rotovap. 1-Hydroxymethylbenzocyclobutene was obtained as yellow oil (2.44g, yield: 64 %). 1 H NMR; (m, 2H, aromatic H s), (m, 2H, aromatic H s), 3.89 (dd, 2 J=19.1 Hz, 3 J=10.8 Hz, 1H, PhCH-CH2OH), (ddd, 3 J=10.8 Hz, 3 J=5.3 Hz, 3 J=1.6 Hz, 1H, PhCHCH2OH), 3.30 (dd, 2 J=14.2 Hz, 3 J=5.3 Hz, 1H, PhCHH), 2.92 (dd, 2 J=14.2 Hz, 3 J=1.6 Hz, 1H, PhCHH), 1.73 (br. s., 1H, CH2-OH) Synthesis of (benzocyclobutyl)methyl methacrylate (BCB-CH2MA) 50 A 100 ml 3-neck round bottom flask equipped with a stir-bar, an addition funnel, a N2 inlet and a glass stopper were dried in an oven at 150 C overnight. A solution of 1- hydroxymethylbenzocyclobutene (4.20 g, 31.3 mmol) and TEA (4.81 g, 47.5 mmol) in 40 ml of dry THF were added into the flask in an ice bath and stirred. A solution of methacryloyl chloride (5.12 g, 48.9 mmol) in 40 ml of dry THF was added into the flask dropwise through the addition funnel over 1 h and 40 min. After 40 min, the flask was removed from the ice bath and stirred for 21 hours at room temperature. A white precipitate was observed after 21 hours. The mixture was filtered through a glass frit into 30 ml of water and extracted with diethyl ether (75 ml 3). The ether phases were combined and 35

54 dried over magnesium sulfate, and the solvent was removed using rotovap. The remaining liquid was passed through a plug of basic activated alumina and the solvent was removed using rotovap. A yellow oil was obtained (5.72 g, crude yield: 91%). The product was further purified by column chromatography using 183 g silica gel and hexanes and diethyl ether (90/10) as the eluent and then passed through a plug of basic activated alumina. Pure (benzocyclobutyl)methyl methacrylate (BCB-CH2MA) (2.69 g) was obtained as a colorless oil (yield: 43%). 1 H NMR: (m, 3H, aromatic H s), (m, 1H, aromatic H), 6.11 (s, 1H, -C=CHH), 5.56 (s, 1H, -C=CHH), (m, 1H, PhCHCHHCH2O-), (m, 1H, PhCH-CHHCH2O-), (m, 1H, PhCH- CH2), 3.36 (dd, J=14.3, 5.3 Hz, 1H, PhCHH), 2.93 (dd, J=14.2, 2.2 Hz, 1H, PhCHH), 1.95 (s, 3H, -CH3). 13 C NMR: (-CH3), (PhCH2), (PhCH), (PhCH-CH2- O), (aromatic C4), (aromatic C7), (CH2=C-), (aromatic C6), (aromatic C5), (CH2=C-), (aromatic C3), (aromatic C8), (O-C=O) Synthesis of 1-Bromobenzocyclobutene (BCB-Br) 50 A 25 ml 2-neck round bottom flask equipped with a stir-bar, an addition funnel, and a condenser with a N2 inlet was dried in an oven (150 C) overnight. Triphenylphosphine (1.65 g, 6.29 mmol), dissolved in 3 ml of dry CH2Cl2, was placed in the flask cooled in an ice bath. Bromine (320 μl, 6.21 mmol), dissolved in 3 ml of dry dichloromethane, was added dropwise through the addition funnel to this yellow solution over 15 min. The resulting orange suspension was stirred for 3 hours at room temperature. Solvent and excess bromine were removed using trap-to-trap distillation. A solution of 1-Hydroxy 36

55 benzocyclobutene (0.22 g, 1.83 mmol) in 20 ml of dry dichloromethane was added dropwise through the addition funnel to the resulting yellow powder, cooled in an ice-bath, over 15 min. After removed from the ice-bath, the yellow suspension was stirred for 19 hours at room temperature. Solvent was removed from the yellow suspension by a rotavapor. The remaining orange colored solid was extracted with 15 ml of hexanes. Solvent was removed from the combined hexanes phase using rotovap. An orange oil remained (0.26 g, crude yield: 77 %). The crude product was purified by column chromatography using 7.5 g of silica gel with hexanes. Pure 1-bromobenzocyclobutene was obtained as colorless oil (0.22 g, yield: 67%). 1 H NMR: (m, 2H, aromatic H s), (m, 2H, aromatic H s), 5.43 (dd, 3 J=4.7 Hz, 3 J=1.8 Hz, 1H, PhCH-Br), 3.88 (dd, 2 J=14.6 Hz, 3 J=4.5 Hz, 1H, PhCHH), 3.48 (d, 2 J=14.6 Hz, 1H, PhCHH) Synthesis of 3-phenyl-1-propanol To establish the conditions for the reaction to yield 1-hydroxyethylbenzocyclobutene (BCB-CH2CH2OH), benzyl bromide was used as model compound for BCB-Br to yield 3- phenyl-1-propanol because its structure, and thus reactivity, is similar to that of BCB-Br Generation of Grignard Reagent 51 A 25 ml 3-neck round bottom flask equipped with a stir-bar, an addition funnel, and a water-cooled condenser with N2 inlet was dried in an oven (150 C) overnight. In a drybox, Magnesium powder (0.16 g, 6.7 mmol) was placed in the flask, and the flask was taken out of the drybox to the hood and connected to the Schlenk line with N2. Dry diethyl 37

56 ether (1 ml) and a few drops of 1,2-dibromoethane were added into the flask under a positive flow of N2. After a few min, an exothermic reaction took place and small bubbles evolved from the surface of the magnesium. Before the exothermic reaction was complete, 0.5 ml of benzyl bromide solution in dry ether (benzyl bromide (0.361 g, 2.10 mmol) in 6 ml of dry ether) was added under a positive flow of N2. The flask was immersed into an ice-bath and the remaining benzyl bromide solution was added over 3.5 hours using a syringe pump. The mixture was pale yellow with a white fine precipitate and unreacted magnesium. An aliquot was taken under a positive flow of N2, quenched with a few drops of DMF, acidified with few drops of 5 M aq HCl, and analyzed by 1 H-NMR spectroscopy. The mixture contained 3 mol% of unreacted benzyl bromide, 15 mol% of bibenzyl (side product), 3 mol % of toluene (side product generated by reaction of Grignard reagent with H2O, and 79 mol% of phenylacetaldehyde (desired product) Reaction with Ethylene Carbonate at Room Temperature A solution of ethylene carbonate (0.376 g, 4.27 mmol) in 5 ml of dry THF was added into the flask containing the Grignard reagent, generated in the previous section, through the addition funnel over 10 min. The flask was removed from the ice-bath and the reaction mixture was stirred at room temperature for 72 hours. 1 H-NMR spectroscopy showed that there were no resonances from 3-phenyl-1-propanol but many unknown peaks. 38

57 Reaction with Ethylene Carbonate at 110 C Solvent was removed via trap-to-trap distillation from the Grignard reagent prepared in the same way as the previous section (3.11.2), and then a solution of ethylene carbonate (0.375 g, 4.26 mmol) in 4 ml of dry toluene was added dropwise over 5 min through the addition funnel. The flask was immersed into an oil bath (110 C) and stirred for 1 hour. The reaction mixture was quenched with 1 M aq HCl aqueous solution, extracted with ether (15 ml x 2), dried over MgSO4, and solvent was removed in under rotovap. An orange colored oil (0.135 g, crude yield 47 %) was obtained. The crude product was isolated by column chromatography using 4.3 g of silica gel and hexanes and diethyl ether (50/50) as the eluent. Two fractions were obtained and analyzed by 1 H-NMR spectroscopy. One fraction contained no 3-phenyl-1-propanol but many unknown peaks. The other fraction contained no 3-phenyl-1-propanol but 2-hydroxyethyl-2-phenylacetate Synthesis of Benzocyclobutyldimethyl Malonate A 250 ml 3-neck round bottom flask equipped with a stir-bar, addition funnel, and a water-cooled condenser with a N2 inlet was dried in an oven (150 C) overnight. Sodium methoxide solution in methanol (34.0 ml, 148 mmol) was placed in the flask. A solution of dimethyl malonate (36.62g, 277 mmol) in 40 ml of methanol was added dropwise over 15 min. The flask was immersed into an oil bath (65 C), and the mixture was stirred at reflux for 2 hours. A solution of 1-bromo benzocyclobutene (BCB-Br, g, 88.5 mmol) in 40 ml of methanol was added dropwise through the addition funnel to this refluxing colorless solution over 2 hours and the mixture was stirred at reflux in an oil bath (65 C) for 18 39

58 hours. The mixture became yellow. Solvent was removed using rotovap, and the remaining solid and oil was dissolved in 100 ml of 5 M hydrochloric acid aqueous solution and 50 ml of diethyl ether. The aqueous phase was extracted with ether (100 ml x 3), and the combined organic phases were dried over magnesium sulfate. After solvent was removed using rotovap, a yellow oil remained (39.9 g). Column chromatography was performed to purify the crude product using 215 g of silica gel and hexanes and ether (70/30) as the eluent. A colorless oil was obtained (17.5 g, yield: 85 %). 1 H NMR: (m, 3H, aromatic H s), (m, 1H, aromatic H s), 4.06 (ddd, 3 J=10.8 Hz, 3 J=5.3 Hz, 3 J=2.2 Hz, 1H, PhCH-malonate), 3.78 (d, J=9.4 Hz, 6H, CH3-OCO), 3.59 (d, 3 J=10.8 Hz, 1H, PhCH-CH- (COOCH3)), 3.46 (dd, 2 J=14.5 Hz, 3 J=5.3 Hz, 1H, Ph-CHH), 2.97 (dd, 2 J=14.5 Hz, 3 J=2.2 Hz, 1H, Ph-CHH) Synthesis of (benzocyclobutyl)methylcarboxylic acid (BCB-CH2COOH) In a 500 ml 1-neck round bottom flask equipped with a stir-bar and a water-cooled condenser, potassium hydroxide (17.28 g, 308 mmol) was dissolved in 80 ml of water. A solution of benzocyclobutyl dimethyl malonate (17.50 g, mmol) in 160 ml of methanol was added and the mixture was stirred at reflux in an oil bath (100 C) for 5 hours. The solution was yellow and homogeneous. The reaction was cooled to room temperature, the solvent was removed using rotovap, and extracted with 150 ml of ether. The aqueous phase was diluted with 300 ml of water, acidified to ph = 1 using 12 M aq HCl, and a white precipitate of benzocyclobutyl diacid formed. The suspension was extracted with ethyl acetate (150 ml x 3), the combined organic phase was dried over magnesium sulfate, and solvent was removed using rotovap and the Schlenk line. A white solid remained (14.4 g, 40

59 yield: 93.4 %). The product was used without further purification and placed in a 500 ml round bottom flask equipped with an air-cooled condenser with N2 inlet. The flask was purged with N2 and immersed into an oil bath (150 C). The flask was removed from the oil bath after 2 hours, when the evolution of carbon dioxide stopped, and yellow liquid remained (11.20 g, yield: 92.5 %). 1 H NMR: (m, 2H, aromatic H s), (m, 2H, aromatic H s), 3.81 (m, 1H, PhCH-CH2), 3.41 (dd, 2 J=14.3 Hz, 3 J=5.3 Hz, 1H, PhCHH), 2.83 (dd, 2 J=14.32 Hz, 3 J=1.9 Hz, 1H, PhCHH), (m, 2H, PhCH-CH2- COOH) Synthesis of 1-Hydroxyethylbenzocyclobutene In a 50 ml 3-neck round bottom flask equipped with a stir-bar, an addition funnel, N2 inlet, and a glass stopper were dried in an oven at 150 C overnight, and assembled in the drybox. Lithium aluminum hydride (0.27 g, 7.0 mmol) was added into the flask, and then the flask was removed from the drybox. Dry THF (5 ml) was added into the flask under a positive flow of N2. A solution of (Benzocyclobutyl)methylcarboxylic acid (BCB- CH2COOH, g, 2.69 mmol) in 7 ml of dry THF was added dropwise through the addition funnel into the flask cooled in an ice bath, and then the flask was removed from the ice bath and stirred for 24 hours at room temperature. The mixture was a gray suspension, and the reaction was quenched by slowly adding aqueous saturated MgSO4 solution until the generation of hydrogen gas stopped. A white precipitate was generated. The mixture was filtered through a glass frit and washed with dichloromethane. The filtrate was dried over magnesium sulfate, and most of the solvent was removed using rotovap. The liquid was passed through a plug of basic activated alumina, and then solvent was 41

60 completely removed using rotovap and under vacuum. 1-Hydroxyethylbenzocyclobutene was obtained as a yellow oil (0.24g, yield: 61 %). 1 H NMR: (m, 2H, aromatic H s), (m, 2H, aromatic H s), 3.84 (t, J=6.6 Hz, 2H, PhCH-CH2CH2-OH), (m, 1H, PhCH), 3.38 (dd, 2 J=14.1 Hz, 3 J=5.3 Hz, 1H, PhCH-CHH), 2.82 (dd, 2 J=14.1 Hz, 3 J=1.9 Hz, 1H, PhCH-CHH), 2.00 (q, 3 J=7.0 Hz, 2H, PhCH-CH2CH2-OH) Synthesis of 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) A 250 ml 3-neck round bottom flask equipped with a stir-bar, an addition funnel, and a N2 inlet were dried in an oven at 150 C overnight. A solution of 1- hydroxyethylbenzocyclobutene (BCB-CH2CH2OH, 7.62 g, 51.5 mmol) and TEA (6.94 g, 68.5 mmol) in 70 ml of dry THF was added into the flask cooled in an ice bath and stirred. A solution of methacryloyl chloride (6.34 g, 60.6 mmol) in 50 ml of dry THF was added into the flask dropwise through the addition funnel over 90 min. After 30 min, the flask was removed from the ice bath and stirred for 22 hours at room temperature. A white precipitate was observed immediately. The mixture was filtered through a glass frit. The filtrate was poured into 100 ml of water and extracted with diethyl ether (100 ml 3). The ether phases were combined and dried over magnesium sulfate and then most of the solvent was removed using rotovap. The remaining liquid was passed through a plug of basic activated alumina and the solvent was completely removed. A yellow oil was obtained (9.51 g, crude yield: 86%). The crude product was purified by column chromatography using 93 g of silica gel and hexanes and diethyl ether (90/10) as the eluent. The fraction containing the product was passed through a plug of basic activated alumina and solvent was completely removed using rotovap and the Schlenk line. Pure 2-42

61 (benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) (3.70 g) was obtained as a colorless oil (yield: 33%). 1 H NMR: (s, 1H, CO2H), (m, 2H, aromatic H s), (m, 2H, aromatic H s), 6.12 (s, 1H, -C=CHH), (t, 4 J=1.5 Hz, 1H, - C=CHH), 4.33 (dt, 3 J=6.5 Hz, 4 J=2.0 Hz, 2H, PhCHCH2-CH2-O), (ddt, 3 J=6.5 Hz, 3 J=6.5 Hz, 3 J=2.0 Hz, 1H, PhCH-CH2-), 3.38 (dd, 2 J=14.2 Hz, 3 J=5.4 Hz, 1H, PhCH- CHH), 2.83 (dd, 2 J=14.2 Hz, 3 J=2.0 Hz, 1H, PhCH-CHH), 2.10 (q, 3 J=6.5 Hz, 2H, PhCH- CH2CH2), 1.96 (s, 3H, -CH3). 13 C NMR (CH3Cl-d,300MHz): δ (ppm) (-CH3), (PhCH), (PhCH2), (PhCH-CH2-CH2-O), (PhCH-CH2-CH2-O), (aromatic C4), (CH2=C-), (aromatic C7), (aromatic C5), (aromatic C6), (CH2=C-), (aromatic C8), (aromatic C3), (O- C=O) Polymerization of MMA by ATRP A typical polymerization by ATRP was carried out as follows: In a 15 ml Schlenk tube equipped with a stir-bar and a glass stopper, CuCl (6.1 mg, mmol) was placed, and the tube was evacuated and then backfilled with N2. A solution of PMDETA (11.5 mg, mmol) in 1.2 ml of toluene was added into the tube under a positive flow of N2, and stirred for 10 min at room temperature. The mixture became light blue solution with undissolved dark blue chunk of CuCl clinging to the wall of the tube. Ethyl 2- bromoisobutyrate (12.0 mg, mmol) and methyl methacrylate (0.616 g, 6.15 mmol) were mixed in a small vial and added into the tube under a positive flow of N2. After the mixture was stirred for 2 min, it was degassed by seven freeze-pump-thaw ( min) cycles. The tube was backfilled with N2 after the last cycle, and stirred for 2 min. The tube 43

62 was immersed into an oil bath (90 C) to start the reaction. After 12 hours, the reaction was quenched by immersing into liquid N2 and exposing to the air. The mixture was thawed and an aliquot was taken for 1 H-NMR spectroscopy to determine conversion (97.4 %). The green viscous liquid was dissolved in 2 ml of THF and passed through a plug of basic activated alumina to remove CuCl, and the filtrate was directly dropped into 30 ml of methanol. White precipitation formed was collected on a grass frit and dried under vacuum. A white powder was obtained (0.536 g, Yield: 87 %). The polymer was analyzed by GPC: Mn pmma = 1.20 x 10 4 Da, Ð = Kinetic Study of MMA by ATRP A typical kinetic study was performed as follows: In a 15 ml Schlenk tube, equipped with a stir-bar and a glass stopper, CuCl (6.3 mg, mmol) was added, and the tube was evacuated and then backfilled with N2. A solution of PMDETA (11.5 mg, mmol) in 1.2 ml of toluene was added into the tube under a positive flow of N2 and stirred for 10 min at room temperature. The mixture became light blue with undissolved dark blue CuCl clinging to the wall of the tube. Ethyl 2-bromoisobutyrate (12.0 mg, mmol), dissolved in MMA (0.624 g, 6.23 mmol), was added into the mixture under a positive flow of N2 and stirred for 2 min. The reaction mixture was degassed by five freeze-pump-thaw ( min) cycles. After the last cycle, the tube was backfilled with N2, and stirred for 1 minute. An aliquot (about 0.1 ml) was taken under a positive flow of N2 using a syringe with a needle purged with N2 and the tube was immersed into an oil bath (90 C) to start the reaction. Aliquots were taken at intervals (30 min, 1, 2, 4, 6, 8, 10, and 12 hours after reaction was started, 0.1 ml each) under a positive flow of N2 using a syringe with a needle 44

63 purged with N2. Each aliquot was dissolved in CDCl3 and analyzed by 1 H-NMR spectroscopy to calculate conversion (30 min: 9.2 %, 1 h: 45.6 %, 2 h: 68.3 %, 4 h: 84.0 %, 6 h: 90.3 %, 8 h: 93.8 %, 10 h: 96.0 %, and 12 h: 97.4 %). The same aliquot used to obtain the NMR spectrum would then be used for GPC analysis. To prepare the sample, it was passed through a basic activated alumina plug, to remove CuCl and the solvent was removed using rotovap. After 12 hours, the reaction was quenched by immersing into liquid N2 and exposing to air. The mixture was allowed to thaw. The green viscous liquid was dissolved in 1 ml of THF and passed through basic activated alumina plug to remove CuCl and then precipitated into 30 ml of methanol. A white precipitate was collected on a grass frit and dried under vacuum Kinetic Study on the Copolymerization of BCB-MA with MMA by ATRP The Kinetic Study on the Copolymerization of BCB-MA with MMA by ATRP was performed in the same procedure as the section 3.17 using CuCl (6.3 mg, mmol), PMDETA (11.5 mg, mmol), ethyl 2-bromoisobutyrate (12.0 mg, mmol), MMA (0.490 g, 4.89 mmol), BCB-MA (0.230 g, 1.22 mmol), and 1.2 ml of toluene Kinetic study on copolymerization of BCB-CH2MA with MMA by ATRP The Kinetic Study on the Copolymerization of BCB-CH2MA with MMA by ATRP was performed in the same procedure as the section 3.17 using CuCl (6.2 mg, mmol), PMDETA (11.3 mg, mmol), ethyl 2-bromoisobutyrate (12.1 mg, mmol), methyl methacrylate (0.493 g, 4.92 mmol), BCB-CH2MA (0.250 g, 1.24 mmol), and 1.2 ml of toluene. A white powder was obtained (0.244 g). 45

64 3.20. Kinetic study on copolymerization of BCB-CH2CH2MA with MMA by ATRP The Kinetic Study on the Copolymerization of BCB-CH2CH2MA with MMA by ATRP was performed in the same procedure as the section 3.17 using CuCl (6.1 mg, mmol), PMDETA (11.5 mg, mmol), ethyl 2-bromoisobutyrate (12.1 mg, mmol), methyl methacrylate (0.490 g, 4.89 mmol), BCB-CH2CH2MA (0.265 g, 1.23 mmol), and 1.2 ml of toluene Copolymerization of BCB-MA with MMA by ATRP (feed ratio: MMA/BCB-MA = 50/50) The copolymerization was performed in the same procedure as the section 3.16 using CuCl (3.0 mg, mmol), PMDETA (5.3 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), methyl methacrylate (0.154 g, 1.54 mmol), BCB-MA (0.289 g, 1.54 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.302 g, Yield: 68 %). The copolymer was analyzed by GPC: Mn pmma = 1.30 x 10 4 Da, Ð = Copolymerization of BCB-CH2MA with MMA by ATRP (feed ratio: MMA/BCB- CH2MA = 50/50) The copolymerization was performed in the same procedure as the section 3.16 using CuCl (3.1 mg, mmol), PMDETA (5.3 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), methyl methacrylate (0.154 g, 1.54 mmol), BCB-CH2MA (0.311 g, 1.54 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.450 g, Yield: 97 %). Mn pmma = 1.43 x 10 4 Da, Ð =

65 3.23. Copolymerization of BCB-CH2CH2MA with MMA by ATRP (feed ratio: MMA/ BCB-CH2CH2MA = 50/50) The copolymerization was performed in the same procedure as the section 3.16 using CuCl (3.0 mg, mmol), PMDETA (5.3 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), methyl methacrylate (0.154 g, 1.54 mmol), BCB-CH2CH2MA (0.332 g, 1.54 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.369 g, Yield: 76 %). The copolymer was analyzed by GPC: Mn pmma = 1.41 x 10 4 Da, Ð = Copolymerization of BCB-MA with MMA by ATRP (feed ratio: MMA/BCB-MA = 20/80) The copolymerization was performed in the same procedure as the section 3.16 using CuCl (3.0 mg, mmol), PMDETA (5.6 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), methyl methacrylate (0.062 g, 0.62 mmol), BCB-MA (0.464 g, 2.46 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.463 g, Yield: 88 %). The copolymer was analyzed by GPC: Mn pmma = 8.61 kda, Ð = Copolymerization of BCB-CH2MA with MMA by ATRP (feed ratio: MMA/BCB- CH2MA = 20/80) The copolymerization was performed in the same procedure as the section 3.16 using CuCl (3.0 mg, mmol), PMDETA (5.6 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), methyl methacrylate (0.061 g, 0.61 mmol), BCB-CH2MA (0.497 g, 2.46 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.538 g, Yield: 96 %). The copolymer was analyzed by GPC: Mn pmma = 1.55 x 10 4 Da, Ð =

66 3.26. Copolymerization of BCB-CH2CH2MA with MMA by ATRP (feed ratio: MMA/ BCB-CH2CH2MA = 20/80) The copolymerization was performed in the same procedure as the section 3.16 using CuCl (3.0 mg, mmol), PMDETA (5.3 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), methyl methacrylate (0.062 g, 0.61 mmol), BCB- BCB-CH2CH2MA (0.532 g, 2.46 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.555 g, Yield: 93 %). The copolymer was analyzed by GPC: Mn pmma = 1.45 x 10 4 Da, Ð = Polymerization of BCB-MA by ATRP The polymerization was performed in the same procedure as the section 3.16 using CuCl (3.1 mg, mmol), PMDETA (5.6 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), BCB-MA (0.578 g, 3.07 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.502 g, Yield: 87 %). The copolymer was analyzed by GPC: Mn pmma = 8.40 kda, Ð = Polymerization of BCB-CH2MA by ATRP The polymerization was performed in the same procedure as the section 3.16 using CuCl (3.0 mg, mmol), PMDETA (5.5 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), BCB-CH2MA (0.621 g, 3.07 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.605 g, Yield: 97 %). The copolymer was analyzed by GPC: Mn pmma = 1.43 x 10 4 Da, Ð =

67 3.29. Polymerization of BCB-CH2CH2MA by ATRP The polymerization was performed in the same procedure as the section 3.16 using CuCl (3.3 mg, mmol), PMDETA (5.5 mg, mmol), ethyl 2-bromoisobutyrate (6.0 mg, mmol), BCB-CH2CH2MA (0.669 g, 3.10 mmol), and 0.6 ml of toluene. A white powder was obtained after precipitation (0.594 g, Yield: 89 %). The copolymer was analyzed by GPC: Mn pmma = 1.51 x 10 4 Da, Ð =

68 CHAPTER IV 4. MONOMER SYNTHESIS MONOMER SYNTHESIS 4.1. Introduction The goal of this project is to optimize the structure of a BCB-containing methacrylate monomer to obtain well-defined methyl methacrylate copolymer with BCB functionality. Optimization is necessary because hydrogen abstraction is likely from the 1-position of the BCB-containing methacrylate monomer during radical copolymerization, which would make the resulting copolymerization less-controlled, is similar to that of 1- ethoxyvinylbenzocyclobutene (1-EtOVBCB). 4,5 Therefore, to suppress this expected side reaction, and to obtain well-controlled BCB-containing methacrylate copolymer, our strategy was to insert methylene carbon spacer(s) between the BCB unit and the oxygen to weaken the stabilization of the resulting radical. This was investigated using three recently synthesized monomers with 0, 1, or 2 methylene carbon spacer(s) (Figure 4.1). The synthetic routes for the monomers with 0 and 1 methylene carbon spacers were already established by Bonan Yu, who previously worked on this project. 50 Therefore, I synthesized these monomers following his procedures and focused on establishing a synthetic route for the monomer with 2 methylene carbon spacers. 50

69 BCB-MA BCB-CH2MA BCB-CH2CH2MA Figure 4.1: BCB-containing methacrylate monomers synthesized for this project Synthesis of benzocyclobutyl methacrylate (BCB-MA) 50 Benzocyclobutyl methacrylate (BCB-MA) that has no methylene carbon spacer between BCB unit and the oxygen atom was synthesized according to procedures of a previous group member Synthesis of 1-acetoxybenzocyclobutene (BCB-Ac) First, 1-acetoxybenzocyclobutene (BCB-Ac) was synthesized in % yield through a benzyne cycloaddition reaction. The benzyne intermediate generated from anthranilic acid was reacted with vinyl acetate (Scheme 4.1). Scheme 4.1: The synthetic route to 1-acetoxybenzocyclobutene (BCB-Ac). 51

70 The 1 H-NMR spectrum of 1-acetoxybenzocyclobutene is shown in Figure 4.2. The proton at the 1-position resonates at 5.92 ppm as a doublet of doublets with coupling constants 3 J=4.5 and 3 J=1.8 Hz. Each of the two benzylic methylene protons appears as a doublet of doublets where one resonates at 3.23 ppm and the other resonates at 3.66 ppm with coupling constants 2 J=14.5 and 3 J=1.8 Hz, and 2 J=14.5 and 3 J=4.5 Hz, respectively. The methyl unit resonates as a singlet at 2.11 ppm. The resonances from four aromatic protons are packed together in a complex multiplet spanning ppm *: CHCl3 4,5,6 * Chemical Shift (ppm) Figure 4.2: 1 H-NMR spectrum of 1-acetoxybenzocyclobutene (BCB-Ac) Synthesis of 1-hydroxybenozcyclobutene (BCB-OH) 1-Acetoxybenzocyclobutene was hydrolyzed to obtain 1-hydroxybenozcyclobutene in % yield (Scheme 4.2). 52

71 Scheme 4.2: The synthetic route to 1-hydroxybenozcyclobutene (BCB-OH). The 1 H-NMR spectrum of BCB-OH is shown in Figure 4.3. The proton at the 1- position resonates at 5.29 ppm as a doublet of doublets with coupling constants 3 J=4.4 and 3 J=1.8 Hz. One of the 2-position protons resonates at 3.62 ppm as a doublet of doublets with coupling constants 2 J=14.3 and 3 J=4.4 Hz, and the other resonates at 3.04 ppm as doublet with the coupling constant 2 J=14.3 Hz. The four aromatic resonances are packed together in a complex multiplet spanning ppm TMS ,5,6 * 3 *: CHCl OH Chemical Shift (ppm) Figure 4.3: 1 H-NMR spectrum of 1-hydroxybenzocyclobutene (BCB-OH) Synthesis of benzocyclobutyl methacrylate (BCB-MA) Benzocyclobutyl methacrylate was synthesized by the esterification of 1- hydroxybenozcyclobutene with methacryloyl chloride (Scheme 4.3). 53

72 Scheme 4.3: The synthetic route to benzocyclobutyl methacrylate (BCB-MA). The 1 H-NMR spectrum of BCB-MA is shown in Figure 4.4. The proton at the 1- position resonates at 5.97 ppm as a doublet of doublets with coupling constants of 3 J=4.5 and 3 J=1.9 Hz. One of the 2-position protons resonates at 3.68 ppm as a doublet of doublets with coupling constats 2 J=14.5 and 3 J=4.5 Hz, and the other resonates at 3.27 ppm as a doublet with a coupling constant 2 J=14.5 Hz. The two vinyl protons are inequivalent: one resonates at 6.15 ppm as a singlet and the other resonates at ppm as a triplet with a coupling constant 4 J = 1.5 Hz. The methyl protons resonate at 1.97 ppm as a singlet. The four aromatic resonances are packed together in a complex multiplet spanning ppm. The 13 C-NMR spectrum of BCB-MA is shown in Figure 4.5. The methyl carbon resonates at ppm. The 2-position methylene carbon resonates at ppm. The 1- position carbon resonates at ppm. The vinyl carbons (C10 and C11) resonate at ppm and ppm, respectively. The 9-position carbon resonates at ppm. The aromatic carbons (C3, C4, C5, C6, C7, and C8) resonate at , , , , , and ppm, respectively. 54

73 * CHCl ,5, TMS Chemical Shift (ppm) Figure 4.4: 1 H-NMR spectrum of benzocyclobutyl methacrylate (BCB-MA) CDCl Chemical Shift (ppm) Figure 4.5: 13 C-NMR spectrum of benzocyclobutyl methacrylate (BCB-MA). 55

74 4.3. Synthesis of (benzocyclobutyl)methyl methacrylate (BCB- CH2MA) 50 (Benzocyclobutyl)methyl methacrylate (BCB- CH2MA) that has a methylene carbon spacer between the BCB unit and the oxygen atom was also synthesized according to procedures of a previous group member Synthesis of 1-cyanobenzocyclotutene (BCB-CN) 1-Cyanobenzocyclobutene (BCB-CN) was synthesized through benzyne cycloaddition reaction in % yield. The benzyne intermediate generated from anthranilic acid was reacted with acrylonitrile (Scheme 4.4). Scheme 4.4: The synthetic route to 1-cyanobenzocyclotutene (BCB-CN). The 1 H-NMR spectrum of BCB-CN is shown in Figure 4.6. The proton at the 1- position resonates at 4.25 ppm as a doublet of doublets with coupling constats 3 J=5.4 and 3 J=2.8 Hz. The 2-position protons resonate at 3.56 and 3.69 ppm as doublet of doublets coupled to the other 2-position protons and to the proton at the 1-position. The four aromatic resonances are packed together in a complex multiplet spanning ppm. 56

75 4,5,6 * CHCl Chemical Shift (ppm) Figure 4.6: 1 H-NMR spectrum of 1-cyanobenzocyclotutene (BCB-CN) Synthesis of benzocyclobutylcarboxylic acid (BCB-COOH) 1-Cyanobenzocyclobutene was hydrolyzed to obtain benzocyclobutyl carboxylic acid in % yield (Scheme 4.5). Scheme 4.5: The synthetic route to benzocyclobutylcarboxylic acid (BCB-COOH). The 1 H-NMR spectrum of BCB-COOH is shown in Figure 4.7. The proton at the 1- position resonates at 4.34 ppm as a triplet with a coupling constat 3 J=4.0 Hz. The 2-position protons resonate at 3.49 ppm as a doublet with a coupling constant 3 J=4.0. The two aromatic resonances resonate at ppm and the other two resonate at ppm as multiplets. 57

76 * CHCl3 2 5, * TMS Chemical Shift (ppm) Figure 4.7: 1 H-NMR spectrum of benzocyclobutylcarboxylic acid (BCB-COOH) Synthesis of 1-Hydroxymethyl benzocyclobutene (BCB-CH2OH) 1-hydroxymethylbenzocyclobutene was synthesized via reduction of benzocyclobutylcarboxylic acid by lithium aluminum hydride (LiAlH4) (Scheme 4.6). Scheme 4.6: The synthetic route to 1-hydroxymethylbenzocyclobutene (BCB-CH2OH). The 1 H-NMR spectrum of BCB-CH2OH is shown in Figure 4.8. The proton at the 1- position resonates at ppm as a doublet of doublet of doublets with coupling constants 3 J=10.8, 3 J=5.3 Hz and 3 J=1.6 Hz coupled to the 2-position protons and the 7- position methylene protons. One of the 2-position protons resonates at 2.92 ppm as a doublet of doublets with coupling constants 2 J=14.2 and 3 J=1.6 Hz, and the other resonates 58

77 at 3.30 ppm as a doublet of doublets with coupling constants 2 J=14.2 and 3 J=5.3 Hz. The methylene protons resonate at 3.89 as a doublet of doublets with coupling constants 2 J=19.1 and 3 J=10.8 Hz. The two aromatic resonances appear at ppm and the other two appear at ppm as a multiplet TMS , , OH Chemical Shift (ppm) Figure 4.8: 1 H-NMR spectrum of 1-hydroxymethyl benzocyclobutene (BCB-CH2OH) Synthesis of (benzocyclobutyl)methyl methacrylate (BCB- CH2MA) 1-Hydroxymethylbenzocyclobutene (BCB-CH2OH) was esterified with methacryloyl chloride to yield (benzocyclobutyl)methyl methacrylate (Scheme 4.7). Scheme 4.7: The synthetic route to (benzocyclobutyl)methyl methacrylate (BCB- CH2MA). 59

78 The 1 H-NMR spectrum of BCB-MA is shown in Figure 4.9. The proton at the 1- position resonates at ppm as a multipulet. One of the 2-position protons resonates at 2.93 ppm as a doublet of doublets with coupling constats 2 J=14.2 and 3 J=2.2 Hz, and the other resonates at 3.36 ppm as a doublet of doublets with coupling constants 2 J=14.3 and 3 J=5.3 Hz. One of the vinyl protons resonates at 5.56 ppm as a singlet and the other resonates at 6.11 as a singlet. The methylene protons resonate at 1.95 as a singlet. The methyl protons (9-position) resonates at 4.47 and 4.34 ppm as doublet and doublets with coupling constants 2 J=10.8 Hz and 3 J=7.0 Hz. The two aromatic resonances appear at ppm and the other two appear at ppm as multiplets. The 13 C-NMR spectrum of BCB- CH2MA is shown in Figure The methyl carbon resonates at ppm. The 2-position methylene carbon resonates at ppm. The 1-position carbon resonates at ppm. The methylene carbon (C9) resonates at ppm. Vinyl carbons (C11 and C12) resonate at ppm and ppm, respectively. The 10-position carbon resonates at ppm. The aromatic carbons (C3, C4, C5, C6, C7, and C8) resonate at , , , , , and ppm, respectively. 60

79 , * *: CHCl , TMS Chemical Shift (ppm) Figure 4.9: 1 H-NMR spectrum of (benzocyclobutyl)methyl methacrylate (BCB-CH2MA) CDCl Chemical Shift (ppm) Figure 4.10: 13 C-NMR spectrum of (benzocyclobutyl)methyl methacrylate (BCB- CH2MA). 61

80 4.4. Synthesis of 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) Bonan Yu previously worked on this project and attempted to synthesize the monomer, 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA), that has two methylene carbon spacers between the BCB unit and the oxygen. 50 His planned synthetic route is shown in Scheme 4.8. Scheme 4.8: Bonan Yu s synthetic route for BCB-CH2CH2MA. 50 He planned to generate a Grignard reagent from 1-bromoBCB (BCB-Br) and then react it with ethylene oxide to yield 1-hydroxyethylbenzocyclobutene (BCB-CH2CH2OH), and then esterify it with methacryloyl chloride to obtain BCB-CH2CH2MA. Although he successfully synthesized BCB-Br, he could not synthesize BCB-CH2CH2MA. One of the reasons for the failure may have been because handling ethylene oxide was extremely difficult, as it is a gas at room temperature and had to be condensed when setting up the reaction. Therefore, in my first attempt at synthesizing this monomer, I used ethylene carbonate as an electrophile instead of ethylene oxide in the nucleophilic addition reaction of the Grignard reagent (Scheme 4.9), as ethylene carbonate is a solid at room temperature and easy to handle. There are many literature examples in which ethylene carbonate was used as an electrophile reacting with heteroatom nucleophilic site to obtain 2-hydroxyethyl functionalized compounds in good yield (Scheme 4.10) However, to the best of my knowledge, there are no examples of reactions of ethylene carbonate with Grignard reagents. 62

81 Scheme 4.9: The initially proposed synthetic route to 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) using ethylene carbonate. Table 4.1: Comparison of the physical properties of ethylene carbonate and ethylene oxide. Ethylene carbonate Ethylene oxide Mw. (g/mol) mp ( C) bp ( C) Scheme 4.10: Literature examples of ethylene carbonate reacting with heteroatom nucleophilic sites for 2-hydroxyethyl functionalization

82 Synthesis of 1-bromobenzocyclobutene (BCB-Br) 1-hydroxylbenzocyclobutene was converted to BCB-Br using triphenylphosphine bromide (Scheme 4.11). Scheme 4.11: The synthetic route to 1-bromobenzocyclobutene (BCB-Br). The 1 H-NMR spectrum of BCB-Br is shown in Figure The proton at the 1- position resonates at 5.43 ppm as a doublet of doublets with coupling constats 3 J=4.7 and 3 J=1.8 Hz. One of the 2-position protons resonates at 3.48 ppm as a doublet with a coupling constant 2 J=14.6 Hz. The other 2-position protons resonate at 3.88 ppm as a doublet of doublets with coupling constants 2 J=14.6 and 3 J=4.5 Hz. The two aromatic resonances appear at ppm and the other two appear at ppm as multiplets. 64

83 , , TMS Chemical Shift (ppm) Figure 4.11: 1 H-NMR spectrum of 1-bromobenzocyclobutene Model reaction of synthesis of 1-hydroxyethylbenzocyclobutene (BCB- CH2CH2OH) To establish the conditions for the reaction shown in Scheme 4.9, benzyl bromide was used as model compound for BCB-Br because its structure, and thus reactivity, is similar to that of BCB-Br. Scheme 4.12: Scheme of the synthesis of 3-phenyl-1-propanol. 65

84 Generation of Grignard reagent Formation of a Grignard reagent is one of the most basic reactions in organic chemistry to form a carbon-carbon bond. I tried to establish the conditions for the Grignard reagent formation using benzyl bromide. After the Grignard reagent formation reaction, I reacted it with N,N-dimethylformamide (DMF) to form phenylacetaldehyde to check if the Grignard reagent had been generated successfully because the Grignard reagent is too moisture sensitive to detect directly (Scheme 4.13). I used 1,2-dibromoethane to activate magnesium, as it is a popular magnesium activator and because it was easy to tell the completion of activation by observing generation of small bubbles of ethane from the surface of magnesium. Scheme 4.13: The formation of Grignard reagent using benzyl bromide and the reaction with DMF. Unfortunately this reaction suffers from a side reaction: a coupling reaction called the Wurtz coupling reaction, which occurs between benzyl bromide and the generated Grignard reagent to form bibenzyl (Scheme 4.14). This occurs because benzyl bromide is a very reactive electrophile. 51 Scheme 4.14: Undesirable side reaction in the Grignard reagent formation (Wurtz coupling reaction). 66

85 Choosing the right solvent is important to prevent the undesired coupling reaction. Zhang et al. reported that when they used diethyl ether as solvent, they obtained 80 % of the desired product and 20 % of the side product. However, when they used THF, there was a significant decrease in the desired product to 30 % and an increase of the side product to 70 %. 51 This effect of solvents on the yields can be attributed to the difference of solvating ability of the solvent to the magnesium compounds. Magnesium compounds can be more strongly solvated by THF than by diethyl ether 55 and thus have higher reactivity in THF than in diethyl ether, which would result in increasing side reaction. They also mentioned that the reaction should be performed at around 0 C. Therefore, after using their reaction conditions, I was able to suppress the side reaction to 15 % (summarized in Table 4.2.). Table 4.2: Results of Grignard reagent formation. solvent THF ether Molecular distribution of the crude products (mol%) * conditions Temp. ( C) 25 0 addition rate of benzyl bromide (hours) Unreacted reactant benzyl bromide 2 3 Side product bibenzyl Side product generated by reaction with H2O toluene 0 3 Desired product phenylacetaldehyde * Composition of the reaction mixture calculated by 1 H-NMR spectroscopy Reaction of the Grignard reagent with ethylene carbonate I subsequently reacted the Grignard reagent with ethylene carbonate. Scheme 4.15 shows the desired reaction mechanism to generate 3-phenyl-1-propanol. The carbanion of the Grignard reagent may attack a methylene carbon of ethylene carbonate and form 3- phenyl-1-propanol and release carbon dioxide

86 Scheme 4.15: Desired mechanism to form 3-phenyl-1-propanol based on a literature. 56 However, the desired product was not observed after 72 hours when the reaction was carried out at room temperature or when increased to 110 C. However, 1 H NMR spectroscopy indicated that an alternate reaction was occurring. To identify this compound, column chromatography using silica gel was performed to separate all products. Two fractions were obtained. One fraction contained several compounds, whereas the other fraction contained only one compound. The latter fraction was analyzed by 1 H-NMR spectroscopy (Figure 4.12); the resonances were assigned to the compound (2- hydroxyethyl-2-phenylacetate) shown in Figure (B) (A) Figure 4.12: (A) 1 H-NMR spectrum of an isolated compound of the reaction mixture. (B) An assigned compound to the spectrum 57 and assumed mechanism based on a literature example

87 The formation of this compound indicated that the reaction with ethylene carbonate proceeded by the mechanism shown in Figure 4.12, 58 not by the mechanism shown in Scheme The reason that the Grignard reagent attacked carbonyl carbon was provably that the Grignard reagent was hard nucleophile and attacked preferably hard electrophile, in this case carbonyl carbon of ethylene carbonate. To make the Grignard reagent selectively attack the methylene carbon that is softer electrophile than the carbonyl carbon, the Grignard reagent should be made softer. Lithium organocuprate(i) reagents (R2CuLi) are used to soften the hardness and to increase selectivity of alkyl lithium reagents and Grignard reagents However, optimizing the selectivity seemed to be difficult and time consuming. I decided to suspend examination of this synthetic route and to explore an alternative pathway Malonic ester synthesis Malonic ester synthesis was chosen as an alternative way to synthesize the monomer. This route is a common method to synthesize substituted acetic acid. It is simple and easy to perform, and there are few side reactions. The steps of the malonic ester synthesis and subsequent reactions to yield the monomer are as follows: deprotonation and alkylation of dimethyl malonate with alkyl halide (BCB-Br), hydrolysis and decarboxylation of the resulting alkylated malonic acid to form a carboxylic acid compound, reduction of the acid to form alcohol product, and then esterification with methacryloyl chloride (Scheme 4.16). 69

88 Alkylation Hydrolysis Decarboxylation Scheme 4.16: Overview of malonic ester synthesis to form the carboxylic acid and subsequent reactions to yield final monomer Synthesis of benzocyclobutyldimethyl malonate The first step of malonic ester synthesis is alkylation. Dimethyl malonate is easily deprotonated by a base and generates a resonance-stabilized carbanion. The carbanion promptly reacts with the electrophile, in this case BCB-Br, to yield benzocyclobutyldimethyl malonate (BCB dimethyl malonate) (Scheme 4.17). While dimethyl malonate was used in this work, diethyl malonate would work in the same way. Scheme 4.17: Synthetic route of BCB dimethyl malonate. The 1 H-NMR spectrum of BCB dimethylmalonate is shown in Figure The proton at the 1-position resonates at 4.06 ppm as a doublet of a doublet of doublets with 70

89 coupling constants 3 J=10.8, 3 J=5.3, and 3 J=2.2 Hz. One of the 2-position proton resonates at 2.97 ppm as a doublet of doublets with coupling constats 2 J=14.5 and 3 J=2.2 Hz, and the other resonates at 3.46 ppm as a doublet of doublets with coupling constants 2 J=14.5 and 3 J=5.3 Hz. The 7-postion proton resonates at 3.59 ppm as a doublet with a coupling constant 3 J=10.8 Hz. Contrary to expectation, the methyl protons (8-position) are not equivalent and resonate at 3.78 ppm as a doublet with a coupling constant J=9.4 Hz. The two aromatic resonances appear at ppm and the other two appear at ppm as multiplets. * *: CHCl3 5, , TMS Chemical Shift (ppm) Figure 4.13: 1 H-NMR spectrum of BCB dimethyl malonate Synthesis of (benzocyclobutyl)methylcarboxylic acid (BCB-CH2COOH) 62,63 BCB dimethyl malonate was hydrolyzed under basic conditions to yield (benzocyclobutyl)methylcarboxylic acid. Upon acidifying the reaction mixture, dicarboxylic acid formed as a white precipitate. The dicarboxylic acid was subsequently heated under N2 to generate (benzocyclobutyl)methylcarboxylic acid accompanied by the 71

90 evolution of carbon dioxide (Scheme 4.18). After some moments, some of the dicarboxylic acid solid turned to liquid and the generation of carbon dioxide started. Scheme 4.18: Synthetic route of BCB-CH2COOH. The 1 H-NMR spectrum of BCB-CH2COOH is shown in Figure The proton at the 1-position resonates at 3.81 ppm as a multiplet. One of the 2-position protons resonates at 2.83 ppm as a doublet of doublets with coupling constats 2 J=14.3 and 3 J=1.9 Hz and the other resonates at 3.41 ppm as a doublet of doublets with coupling constants 2 J=14.3 and 3 J=5.3 Hz. The 7-postion methylene protons resonate at ppm as a multiplet. The two aromatic resonances appear at ppm and the other two appear at ppm as multiplets. 72

91 10.09 OH , 6 3, 4 * *: CHCl Chemical Shift (ppm) Figure 4.14: 1 H-NMR spectrum of BCB-CH2COOH Synthesis of 1-hydroxyethylbenzocyclobutene (BCB-CH2CH2OH) (benzocyclobutyl)methylcarboxylic acid (BCB-CH2COOH) was reduced to 1- hydroxyethylbenzocyclobutene using LiAlH4. Scheme 4.19: Synthetic route to BCB-CH2CH2OH. The 1 H-NMR spectrum of BCB-CH2CH2OH is shown in Figure The proton at the 1-position resonates at ppm as a multiplet. One of the 2-position protons resonates at 2.82 ppm as a doublet of doublets with coupling constats 2 J=14.1 and 3 J=1.9 Hz and the other resonates at 3.38 ppm as a doublet of doublets with coupling constants 2 J=14.1 and 3 J=5.3 Hz. The 7-postion methylene protons resonates at 2.00 ppm as a quartet 73

92 with a coupling constat 3 J=7.0 Hz. The 8-postion methylene protons resonates at 3.84 ppm as a triplet with a coupling constat 3 J=6.6 Hz. The two aromatic resonances appear at ppm and the other two appear at ppm as multiplets , 6 * , 4 *: CHCl Chemical Shift (ppm) Figure 4.15: 1 H-NMR spectrum of BCB-CH2CH2OH Synthesis of 2-(benzocyclobutyl)ethyl methacrylate (BCB-CH2CH2MA) 1-Hydroxyethylbenzocyclobutene was esterified with methacryloyl chloride to yield 2-(benzocyclobutyl)ethyl methacrylate (Scheme 4.20). Scheme 4.20: Synthetic route of BCB-CH2CH2MA. The 1 H-NMR spectrum of BCB-MA is shown in Figure The proton at the 1- position resonates at 3.57 ppm as a doublet of doublet of triplets with coupling constant 3 J=6.5 Hz, 3 J=6.5 Hz, and 3 J=2.0 Hz. One of the 2-position protons resonates at 2.83 ppm as a doublet of doublets with coupling constats 2 J=14.2 and 3 J=2.0 Hz and the other resonates at 3.38 ppm as a doublet of doublets with coupling constants 2 J=14.2 and 3 J=5.6 74

93 Hz. One of the vinyl protons resonates at 5.57 ppm as a triplet with coupling constant 4 J=1.5 Hz, and the other resonates at 6.12 as a singlet. The methyl protons resonate at 1.96 as a singlet. The methylene protons (9-position) resonates at 2.10 ppm as a quartet with a coupling constant 3 J=6.5. The methylene protons (10-position) resonates at 4.33 ppm as a doublet of triplets with coupling constants 3 J=6.5 and 4 J=2.0 Hz. The two aromatic resonances appear at ppm and the other two appear at ppm as multiplets. The 13 C-NMR spectrum of BCB-CH2CH2MA is shown in Figure The methyl carbon resonates at ppm. The 1-position methylene carbon resonates at ppm. The 2-position carbon resonates at ppm. The methylene carbons (C9 and C10) resonate at and ppm, respectively. The vinyl carbons (C12 and C13) resonate at ppm and ppm, respectively. The 11-position carbon resonates at ppm. The aromatic carbons (C3, C4, C5, C6, C7, and C8) resonate at , , , , , and ppm, respectively , , TMS Chemical Shift (ppm) Figure 4.16: 1 H-NMR spectrum of BCB-CH2CH2MA. 75

94 CDCl Chemical Shift (ppm) Figure 4.17: 13 C-NMR spectrum of BCB-CH2CH2MA Conclusion BCB-containing methacrylate monomers with 0 or 1 methylene carbon spacers between the BCB unit and the oxygen atom were successfully synthesized following the procedures established by Bonan Yu. 50 A 7-step synthetic route to the BCB-containing methacrylate monomer with a 2 methylene carbon spacer between the BCB unit and the oxygen atom was established and successfully synthesized starting from anthranilic acid and using a malonic ester synthesis. 76

95 BCB-MA BCB-CH2MA BCB-CH2CH2MA Figure 4.18: Synthetically available BCB-containing methacrylate monomers. 77

96 CHAPTER V 5. POLYMERIZATION OF BCB-MONOMERS POLYMERIZATION OF BCB-MONOMERS 5.1. Introduction The goal of my project was to optimize the structure of BCB-containing methacrylate monomer so that we can obtain poly(methyl methacrylate) containing BCBfunctionality with controlled molecular weight and narrow molecular weight distribution. We expected that the monomer in which the BCB unit directly attach to methacrylate unit would be subject to hydrogen abstraction at the 1-position, because the resulting radical would be highly stabilized by the benzylic structure and the hetero atom, in this case the oxygen atom (Scheme 5.1). This side reaction would cause a less-controlled molecular weight and potentially broaden copolymer s polydispersity (Ð). Scheme 5.1: Expected hydrogen abstraction from the monomer. The resulting radical would be stabilized by the resonance and the oxygen atom (red-colored). This undesirable side reaction was highly anticipated, because Dr. Bill Storms-Miller observed a large Ð when he synthesized precursor copolymer for nanoparticles using 1-78

97 ethoxy-4-vinyl BCB (1-EtOVBCB) in his Ph.D. project. 4 He presumed that the hydrogen at the 1-position of 1-EtOVBCB was readily abstracted, which caused a degradative chain transfer reaction and thus a broad Ð. Scheme 5.2: Chain transfer to 1-ethoxyvinylbenzocyclobutene (1-EtOVBCB) by hydrogen abstraction at the 1-positton to generate a radical stabilized by heteroatom and resonance. 4 A similar problem was reported by Dobish and Harth; 45 they tried to prepare copolymers of acrylates with 1-ethoxy substituted BCB vinyl monomers by RAFT or NMP, and they found that the resulting copolymers had less-controlled molecular weights. They changed synthetic strategies to a grafting-on method as an alternative in which 1-ethoxy substituted BCBs with amine functionality were grafted onto a linear acrylate polymer backbone. Although they did not provide further discussion about the reason of lesscontrolled copolymerization with 1-ethoxy BCB monomer, a side reaction (chain transfer to the monomer) cause was assumed similarly to Dr. Storms-Miller s case. Dr. James Baker investigated the chain transfer constant of 1- ethoxybenzocyclobutene (1-EtOBCB), an analogue of 1-EtOVBCB, in free radical polymerization of styrene at 60 C. 5 The chain transfer constant of 1-EtOVBCB was relatively high (0.006) and similar to that of benzyl ether (0.0062) (Table 5.1). 79

98 Table 5.1: Chain transfer constants (Cx) for various compounds in the free radical polymerization of styrene at 60 ºC, including 1-ethoxybenzocyclobutene (1-EtOBCB). 5,65 Since the BCB-containing methacrylate monomer has similar structure to that of 1- EtOVBCB and 1-EtOBCB, radical chain transfer to this monomer and a resulting large Ð was expected. To optimize the structure of the BCB-containing methacrylate monomer, to prevent hydrogen abstraction from this monomer, our strategy was to insert methylene spacers between the BCB unit and the oxygen atom to weaken the effect of the oxygen atom on the stabilization of the resulting radical (Scheme 5.3). These monomers were successfully synthesized as described in the previous chapter. BCB-MA BCB-CH2MA BCB-CH2CH2MA Scheme 5.3: BCB-containing monomers synthesized for this project which vary the length of methylene methylene carbon spacers between BCB-unit and methacrylate unit. 80