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<p>This work focused on grafting water-soluble polymers with well-controlled properties such as tuneable polymer chain length and high graft density to improve the biocompatibility of polymer surfaces via surface-initiated atom transfer radical polymerization (s-ATRP); and on gaining improved fundamental understanding of the mechanisms and factors (e.g., graft chain length and surface density of monomer units) in protein resistance of the water-soluble grafts.</p><p>Protein-resistant polyurethane (PU) surfaces were prepared by grafting watersoluble polymers including poly(oligo(ethylene glycol) methacrylate) (poly(OEGMA)) and poly(l-methacryloyloxyethyl phosphorylcholine) (poly(MPC)) via s-ATRP. A typical three-step procedure was used in the ATRP grafting. First, the substrate surface was treated in an oxygen plasma and reactive sites (-OH and -OOH) were formed upon exposure to air. Second, the substrate surface was immersed in 2-bromoisobutyryl bromide (BffiB)-toluene solution to form a layer of ATRP initiator. Finally, target polymer was grafted from the initiator-immobilized surface by s-ATRP with Cu(I)Br/2bpy complex as catalyst. The graft chain length was adjusted by varying the molar ratio of monomer to sacrificial initiator in solution. The modified PU surfaces were characterized by water contact angle, X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM).</p><p>Protein adsorption experiments were carried out to evaluate the protein resistance of the surfaces. Adsorption from single and binary protein solutions as well as from plasma decreased significantly after poly(OEGMA) grafting, and decreased with increasing poly(OEGMA) main chain length. Fibrinogen (Fg) adsorption on the most resistant surfaces (chain length 200 units) was in the range of 3-33 ng/cm^2, representing a reduction of more than 96% compared to the control surfaces.</p><p>OEGMA monomers with three different molecular weights (MW 300, 475, 1100 g/mol) were used to achieve different side chain lengths of poly(OEGMA). Fibrinogen (Fg) and lysozyme (Lys) were used as model proteins in adsorption experiments. The effects of side chain length as well as main chain length were then investigated. It was found that adsorption to the poly(OEGMA)-grafted PU (PU/PO) surfaces was protein size dependent. Resistance was greater for the larger protein. For grafts of a given side chain length, the adsorption of both proteins decreased with increasing polymer main chain length. For a given main chain length, the adsorption of Fg, the larger protein, was independent of side chain length. Surprisingly, however, Lys (the smaller protein) adsorption increased with increasing side chain length. A reasonable explanation is that graft main chain density decreased as monomer size and footprint on the surface increased. Protein size-based discrimination suggests that the chain density was lower than required to form layers in the "brush" regime in which protein size is expected to have little effect on protein adsorption.</p><p>In order to achieve high surface densities of ethylene oxide (EO) units, we used a sequential double grafting approach whereby the surface was grafted first with poly(2-hydroxyethyl methacrylate) (HEMA) by s-ATRP. OEGMA grafts were then grown from the hydroxyl groups on HEMA chains by a second ATRP. The effect of EO density on protein-resistant properties was then investigated. Protein adsorption on the sequentiallygrafted poly(HEMA)-poly(OEGMA) surfaces (PU/PH/PO) was not only significantly lower than on the unmodified PU as expected, but also much lower than on the PU/PO surfaces with the same poly(OEGMA) chain length. Moreover, protein adsorption decreased with increasing EO density for these grafts. On the PU/PH/PO surface with a poly(OEGMA) chain length of 100, the adsorption of Ls and Fg were reduced by ~98% and >99%, respectively, compared to the unmodified PU. Binary protein adsorption experiments showed that suppression of protein adsorption on the PU/PH/PO surfaces was essentially independent of protein size. The double-grafted OEG layers resisted both proteins equally.</p><p>The general applicability of this approach which combines oxygen plasma treatment and ATRP grafting was also studied. Various kinds of polymers such as PU, silicone hydrogel, and polydimethylsiloxane (PDMS) were chosen as substrates. Poly(MPC) grafts with different chain lengths were achieved by the three-step ATRPgrafting procedure. It was found that protein adsorption levels on the poly(MPC) grafts were significantly lower than on the respective unmodified surfaces. Protein adsorption decreased with increasing poly(MPC) chain length. Among the surfaces investigated, PU/MPC showed the highest protein resistance for a given chain length.</p> / Thesis / Doctor of Philosophy (PhD)

<p>  </p> <p>Alkyl radicals are powerful intermediates for the generation of carbon-carbon bonds, which play an indispensable role in the synthesis of natural products, pharmaceuticals, and pesticides. Traditionally, there are two main methods for the generation of alkyl radicals. The first is C-H bond functionalization via hydrogen-atom-transfer (HAT). HAT processes have been used as an effective approach for selectively activating C-H bonds via radical pathways. The other strategy to explore the generation of alkyl radicals is C-X bond functionalization via halogen-atom-transfer (XAT). Alkyl halides are one of the largest classes of building blocks in synthesis and they can be obtained from the corresponding alcohols. The most straightforward and effective way to form such alkyl radicals is the direct homolytic cleavage of C-X bonds. In past decades, photoredox catalysis has emerged as a powerful and greener tool for the synthesis of radicals under mild reaction conditions, which has brought tremendous attention. Although remarkable success has been made in this field, some methods still require costly transition metal catalysts or toxic reagents. Herein, we display a series of visible light-induced approaches under transition-metal free conditions or using earth-abundant metals. These novel photo-induced transformations and corresponding mechanistic work will be discussed in the following order:</p> <p>We will first present our work on metal-free visible-light-promoted C(sp3)-H functionalization of aliphatic cyclic ethers using trace O2.  This reaction uses a trace amount of aerobic oxygen as the sole green oxidant under blue light at room temperature to achieve the synthesis of sulfone and phosphate derivatives in good to excellent yields using cyclic ethers and vinyl sulfones. Then, we report on a photo-induced C(sp3)-H chalcogenation of amide derivatives and ethers via a ligand-to-metal charge-transfer. This reaction converts secondary and tertiary amides, sulfonamides, and carbamates into the corresponding amido-<em>N,S</em>-acetal derivatives in good yields, using an earth abundant metal catalyst under mild conditions.</p> <p>Finally, we present a photoredox polyfluoroarylation of alkyl halides via halogen atom transfer. This method converts primary, secondary, and tertiary unactivated abundant alkyl halides into the corresponding polyfluoroaryl compounds in good yields and has good functional group compatibility.</p>

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京都大学 / 新制・課程博士 / 博士(工学) / 甲第23925号 / 工博第5012号 / 新制||工||1782(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 村上 正浩, 教授 杉野目 道紀, 教授 中尾 佳亮 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

<p> Poly(N-isopropylacrylamide) (PNIPAM) has attracted much attention as a thermo-responsive polymer. However, the molecular weight (MW) dependence of its phase transition temperature is still controversial. This situation is largely due to the difficulty in synthesizing narrow-disperse PNIPAM. We have addressed the challenge and developed an atom transfer radical polymerization (ATRP) method to prepare narrow-disperse PNIPAM with moderate to high conversions, using branched alcohols as solvents. Aqueous solutions of these narrow-disperse PNIPAMs showed a dramatic decrease of the phase transition temperature with increasing molecular weight, as measured by turbidimetry and differential scanning calorimetry. Four other series of narrow-disperse PNIPAM with well-controlled molecular weights and with end groups of varying hydrophobicity were also synthesized by ATRP using the corresponding initiators, which enabled us to resolve the MW and end group effects. All the four series of samples showed an inverse molecular weight (MW) dependence of their phase transition temperature. The magnitude of the MW dependence decreased when using more hydrophobic end groups. The end groups were observed to have effects on the cloud point temperature, on the shape of the cloud point curves, and on the enthalpy of the phase transition.</p> / Thesis / Master of Science (MSc)

When a biomaterial is inserted into the body, the interaction of the surface with the surrounding biological environment is crucial. Given the importance of the surface, the ability to alter the surface properties to support a compatible environment is therefore desirable. Silicone hydrogel contact lenses (CL) allow for improved oxygen permeability through the incorporation of siloxane functional groups. These groups however are extremely surface active and upon rotation, can impart hydrophobicity to the lens surface, decreasing lens wettability and increasing protein and lipid deposition. Lens biofouling may be problematic and therefore surface modification of these materials to increase compatibility is exceedingly recognized for importance in both industry and research. The current work focuses on the creation of a novel anti-fouling polymer surface by the incorporation of 2-methacryoyloxyethyl phosphorylcholine (MPC), well known for its biomimetic and anti-fouling properties. A controlled polymerization method was used to generate a unique double-grafted architecture to explore the effect of increasing surface density of polyMPC chains on corresponding anti-fouling properties. The novel free polymer was synthesized by a 3-step atom transfer radical polymerization (ATRP). First, poly(2-hydroxyethyl methacrylate) (polyHEMA) was polymerized by ATRP, where the hydroxyl (OH) groups of the polymer then underwent an esterification to create macroinitiating sites. From these sites, a second ATRP of poly(MPC) varying in length occurred, yielding the double-grafted polymer poly(2(2-bromoisobutyryloxy-ethyl methacrylate)-graft-poly(2-methacryloyloxyethyl phosphorylcholine (pBIBEM-g-pMPC). The polymer was designed for resistance to protein adsorption through a possible synergistic effect between the surface induced hydration layer by surrounding PC groups coupled with steric repulsion of the densely grafted chains. To test its potential as a surface modifier, the polymer was grafted from model silicone hydrogel CL through a 4-step surface initiated ATRP (SI-ATRP) in a similar manner to the free polymer. First, the ATRP initiator was immobilized from the HEMA OH groups of the unmodified CL, generating Intermedate-1. A polyHEMA brush was grafted from the initiating sites yielding pHEMA-50, followed by the generation of a second initiator layer (Intermediate- 2). A sequential ATRP of poly(MPC) then generated the target pMPC-50/pMPC-100 surfaces. For the free pBIBEM-g-pMPC polymer analysis, 1H-NMR and GPC determined polymers formed with a predictable MW and low polydispersity (PDI). For surface grafting, using a sacrificial initiator, 1H-NMR and GPC indicated that the pHEMA-50 and pMPC-50/pMPC-100 polymers were well-controlled, with a MW close to the theoretical and a low PDI. For surface chemical composition, ATR-FTIR showed the presence of the ATRP initiator (Intermediate-1 and 2) by the appearance of a C-Br peak and disappearance of the OH peak. XPS confirmed the chemical composition of the 4-step synthesis by a change in the fraction of expected surface elements. Both the surface wettability and EWC of the materials increased upon pMPC modification, further improving upon increasing pMPC chain length. The contact angle was as low as 16.04 ± 2.37º for pMPC-50 surfaces and complete wetting for pMPC-100. Finally, the single protein adsorption using lysozyme and bovine serum albumin (BSA) showed significantly decreased protein levels for pMPC-50/100 lenses, as much as 83% (p 0.00036) for lysozyme and 73% (p 0.0076) for BSA, with no significant difference upon chain length variation. The aforementioned data demonstrates that the novel polymer has potential in providing an anti-fouling and extremely wettable surface, specifically regarding silicone hydrogel CL surfaces. / Thesis / Master of Applied Science (MASc)

The recent upsurge of degenerative diseases believed to be the result of oxidative stress has sparked an increased interest in utilizing the fundamental principles of physical organic chemistry to understand biological problems. Enzyme pathways can pose several experimental complications due to their complexity, therefore the small molecule probe approach can be utilized in an attempt understand the more complex enzyme mechanisms. The work described in this dissertation focuses on the use of N-cyclopropyl amines that have been used as probes to study the mechanism of monoamine oxidase (MAO) and cytochrome P-450 (cP-450). A photochemical model study of benzophenone triplet (3BP) with the MAO-B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and two of its derivatives, 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)-[trans-2-phenylcyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine is presented in Chapter 2. The barrier for ring opening of aminyl radical cations derived from N-cyclopropyl derivatives of tertiary amines (such as MPTP) is expected to be low. Reactions of 3BP with all three compounds are very similar. The results suggest that the reaction between benzophenone triplet and tertiary aliphatic amines proceed via a simple hydrogen atom transfer reaction. Additionally these model examinations provide evidence that oxidations of N-cyclopropyl derivatives of MPTP catalyzed by MAO-B may not be consistent with a pure SET pathway. The chemistry of N-cyclopropyl amines has been used to study the mechanism of amine oxidations by cP-450. Until recently, the rate constant for these ring opening reactions has not been reported. Direct electrochemical examinations of N-cyclopropyl-N-methylaniline showed that the radical cation undergoes a unimolecular rearrangement consistent with a cyclopropyl ring opening reaction. Examination of both the direct and indirect electrochemical data showed that the oxidation potential N-cyclopropyl-N-methylaniline to be +0.528 V (0.1 M Ag⁺/Ag), and rate constant for ring opening of 4.1 x 10⁴ s⁻¹. These results are best explained by two phenomena: (i) a resonance effect in which the spin and charge of the radical cation in the ring closed form is delocalized into the benzene ring hindering the overall rate of the ring opening reaction, and/or (ii) the lowest energy conformation of the molecule does not meet the stereoelectronic requirements for a ring opening pathway. Therefore a new series of spiro cyclopropanes were designed to lock the cyclopropyl group into the appropriate bisected conformation. The electrochemical results reported herein show that the rate constant for ring opening of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] are 3.5 x 10² s⁻¹ and 4.1 x 10² s⁻¹ with redox potentials of 0.3 V and 0.366 V respectively. In order to examine a potential resonance effect a derivative of N-methyl-N-cyclopropylaniline was synthesized to provide a driving force for the ring opening reaction thereby accelerating the overall rate of the ring opening pathway. The electrochemical results show that the rate constant for ring opening of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline to be 1.7 x 10⁸ s⁻¹ . The formal oxidation potential (E°OX) of this substrate was determined to be 0.53 V. The lowered redox potentials of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] can be directly attributed to the electron donating character of the ortho alkyl group of the quinoline base structure of these spiro derivatives, and therefore the relative energy of the ring closed radical cations directly affects the rate of ring opening reactions. The relief of ring strain coupled with the formation of the highly resonance stabilized benzylic radical explains the rate increase for the ring opening reaction of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline. / Ph. D.

Oxidative processes are linked to a number of major disease states as well as the breakdown of many materials. Of particular importance are reactive oxygen species (ROS), as they are known to be endogenously produced in biological systems as well as exogenously produced through a variety of different means. In hopes of better understanding what controls the behavior of ROS, researchers have studied radical chemistry on a fundamental level. Fundamental knowledge of what contributes to oxidative processes can be extrapolated to more complex biological or macromolecular systems. Fundamental concepts and applied data (i.e. interaction of ROS with polymers, biomolecules, etc.) are critical to understanding the reactivity of ROS. A detailed review of the literature, focusing primarily on the hydroxyl radical (HO•) and hydrogen atom (H•) abstraction reactions, is presented in Chapter 1. Also reviewed herein is the literature concerning high density polyethylene (HDPE) degradation. Exposure to treated water systems is known to greatly reduce the lifetime of HDPE pipe. While there is no consensus on what leads to HDPE breakdown, evidence suggests oxidative processes are at play. The research which follows in Chapter 2 focuses on the reactivity of the hydroxyl radical and how it is controlled by its environment. The HO• has been thought to react instantaneously, approaching the diffusion controlled rate and showing little to no selectivity. Both experimental and calculational evidence suggest that some of the previous assumptions regarding hydroxyl radical reactivity are wrong and that it is decidedly less reactive in an aprotic polar solvent than in aqueous solution. These findings are explained on the basis of a polarized transition state that can be stabilized via the hydrogen bonding afforded by water. Experimental and calculational evidence also suggest that the degree of polarization in the transition state will determine the magnitude of this solvent effect. Chapter 3 discusses the results of HDPE degradation studies. While HDPE is an extremely stable polymer, exposure to chlorinated aqueous conditions severely reduces the lifetime of HDPE pipes. While much research exists detailing the mechanical breakdown and failure of these pipes under said conditions, a gap still exists in defining the species responsible or mechanism for this degradation. Experimental evidence put forth in this dissertation suggests that this is due to an auto-oxidative process initiated by free radicals in the chlorinated aqueous solution and propagated through singlet oxygen from the environment. A mechanism for HDPE degradation is proposed and discussed. Additionally two small molecules, 2,3-dichloro-2-methylbutane and 3-chloro-1,1-di-methylpropanol, have been suggested as HDPE byproducts. While the mechanism of formation for these products is still elusive, evidence concerning their identification and production in HDPE and PE oligomers is discussed. Finally, Chapter 4 deals with concluding remarks of the aforementioned work. Future work needed to enhance and further the results published herein is also addressed. / Ph. D.

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