Functional degradable polymers via RAFT/MADIX mediated polymerization of cyclic ketene acetals and vinyl monomers

This thesis explores the synthesis of functional degradable polymers via the radical ringopening polymerization (rROP) of cyclic ketene acetal (CKA) monomers and their copolymerization with vinyl ester monomers using the reversible addition-fragmentation chain transfer (RAFT/MADIX) polymerization. Chapter 1 introduces the polymerization technique used in this thesis (namely RAFT polymerization) and gives a summary of the conventional and new approaches to synthesize poly(esters) for use as degradable materials, with a focus on the arising use of rROP of CKA monomers. In Chapter 2 the copolymerization of the CKA 2-methylene-1,3-dioxepane (MDO) and vinyl acetate (VAc) is investigated using RAFT/MADIX polymerization with a view towards the formation of degradable copolymers with controlled molecular weights and narrow dispersities. Chapter 3 discusses the use of the palladium vinyl exchange reaction to create a novel functional bromine derivative monomer of VAc, vinyl bromobutanoate (VBr). The homopolymerization of VBr and copolymerization with MDO using the RAFT/MADIX polymerization is further reported to produce homopolymers and degradable copolymers with functional pendent groups able to be further modified post-polymerization to introduce different properties to the polymer materials. In Chapter 4 further investigation into the RAFT/MADIX copolymerization of VAc and MDO, as well as its homopolymerization, is explored using a different chain transfer agent (CTA) in order to understand the cause of the lower degree of control observed for some of the copolymerizations in Chapter 2. Chapter 5 describes the formation of degradable hydrophilic copolymers showing tunable thermoresponsive properties via the copolymerization of MDO and novel oligo(ethyleneglycol) methyl ether vinyl acetate monomers. In Chapter 6 the copolymerization of MDO with vinyl ester monomers is presented using a macro-CTA of poly(N-vinylpyrrolidone) to create amphiphilic block copolymers of poly(NVP)-b-poly(MDO-co-vinyl esters) able to self-assemble in water to form degradable nanoparticles. Chapter 7 provides a summary of the work reported in Chapters 2-6 and potential perspectives for the methodology designed in this thesis

Functional degradable polymers by radical ring-opening copolymerization of MDO and vinyl bromobutanoate : synthesis, degradability and post-polymerization modification

The synthesis of vinyl bromobutanoate (VBr), a new vinyl acetate monomer derivative obtained by the palladium-catalyzed vinyl exchange reaction between vinyl acetate (VAc) and 4-bromobutyric acid is reported. The homopolymerization of this new monomer using the RAFT/MADIX polymerization technique leads to the formation of novel well-defined and controlled polymers containing pendent bromine functional groups able to be modified via postpolymerization modification. Furthermore, the copolymerization of vinyl bromobutanoate with 2-methylene-1,3-dioxepane (MDO) was also performed to deliver a range of novel functional degradable copolymers, poly(MDO-co-VBr). The copolymer composition was shown to be able to be tuned to vary the amount of ester repeat units in the polymer backbone, and hence determine the degradability, while maintaining a control of the final copolymers’ molar masses. The addition of functionalities via simple postpolymerization modifications such as azidation and the 1,3-dipolar cycloaddition of a PEG alkyne to an azide is also reported and proven by 1H NMR spectroscopy, FTIR spectroscopy, and SEC analyses. These studies enable the formation of a novel class of hydrophilic functional degradable copolymers using versatile radical polymerization methods

Controlling the synthesis of degradable vinyl polymers by xanthate-mediated polymerization

The copolymerization of vinyl acetate (VAc) and 2-methylene-1,3-dioxepane (MDO), as well as the homopolymerization of MDO in the presence of a p-methoxyphenyl xanthate chain transfer agent (CTA) is reported and comparison of the homopolymerization of MDO with other known xanthates was also investigated. In depth investigation showed loss of the xanthate functionality was a result of Z-group fragmentation leading to the formation of carbonodithioate groups, as confirmed by 13C NMR spectroscopy. The use of the xanthate with a substituted phenyl Z-group drastically reduces fragmentation through the Z-group and hence significantly increases chain-end retention during the polymerization using the RAFT/MADIX technique. Post-polymerization modification of the chain-end of poly(MDO) was achieved by in situ aminolysis and base-catalyzed Michael addition of propargyl methacrylate onto the terminal thiol to form alkyne functional poly(MDO)

Synthesis of degradable poly(vinyl alcohol) by radical ring-opening copolymerization and ice recrystallization inhibition activity

Poly(vinyl alcohol), PVA, is the most active synthetic mimic of antifreeze proteins and has extremely high ice recrystallization inhibition, IRI, activity. Addition of PVA to cellular cryopreservation solutions increases the number of recovered viable cells due to its potent IRI, but it is intrinsically non-degradable in vivo. Here we report the synthesis, characterization and IRI activity of PVA-containing degradable ester linkages. Vinyl chloroacetate, VClAc, was copolymerized with 2-methylene-1,3-dioxepane (MDO) which undergoes radical ring-opening polymerization to install main-chain ester units. The use of the chloroacetate monomer enabled selective deacetylation with retention of esters within the polymer backbone. Quantitative IRI assays revealed that the MDO content had to be finely tuned to retain IRI activity, with higher loadings (24 mol%) resulting in complete loss of IRI activity. These degradable materials will help translate PVA, which is non-toxic and biocompatible into a range of biomedical applications

Controlling the synthesis of degradable vinyl polymers by xanthate-mediated polymerization

The copolymerization of vinyl acetate (VAc) and 2-methylene-1,3-dioxepane (MDO), as well as the homo-polymerization of MDO in the presence of a p-methoxyphenyl xanthate chain transfer agent (CTA) is reported and comparison of the homopolymerization of MDO with other known xanthates was also investigated. In depth investigation showed loss of the xanthate functionality was a result of Z-group fragmentation leading to the formation of carbonodithioate groups, as confirmed by C-13 NMR spectroscopy. The use of the xanthate with a substituted phenyl Z-group drastically reduces fragmentation through the Z-group and hence significantly increases chain-end retention during the polymerization using the RAFT/MADIX technique. Post-polymerization modification of the chain-end of poly(MDO) was achieved by in situ aminolysis and base-catalyzed Michael addition of propargyl methacrylate onto the terminal thiol to form alkyne functional poly(MDO)

Amphiphilic block copolymer self-assemblies of poly(NVP)-b-poly(MDO-co-vinyl esters) : tunable dimensions and functionalities

Functional, degradable polymers were synthesized via the copolymerization of vinyl acetate (VAc) and 2-methylene-1,3-dioxepane (MDO) using a macro-xanthate CTA, poly(N-vinylpyrrolidone), resulting in the formation of amphiphilic block copolymers of poly(NVP)-b-poly(MDO-co-VAc). The behavior of the block copolymers in water was investigated and resulted in the formation of self-assembled nanoparticles containing a hydrophobic core and a hydrophilic corona. The size of the resultant nanoparticles was able to be tuned with variation of the hydrophilic and hydrophobic segments of the core and corona by changing the incorporation of the macro-CTA as well as the monomer composition in the copolymers, as observed by Dynamic Light Scattering, Static Light Scattering, and Transmission Electron Microscopy analyses. The concept was further applied to a VAc derivative monomer, vinyl bromobutanoate, to incorporate further functionalities such as fluorescent dithiomaleimide groups throughout the polymer backbone using azidation and “click” chemistry as postpolymerization tools to create fluorescently labeled nanoparticles

Functional Degradable Polymers by Xanthate-Mediated Polymerization

Herein we report the first example of the controlled synthesis of linear and hyperbranched copolymers of 2-methylene-1,3-dioxepane (MDO) with functional vinyl monomers to deliver a range of functional, degradable polymers by reversible deactivation radical polymerization. The copolymerization was able to be tuned to vary the incorporation of degradable segments to create degradable materials with predictable molar mass, low dispersity values while also featuring side-chain functionality. The formation of nanoparticles by the addition of divinyladipate to form degradable hyperbranched copolymers was proven by DLS and TEM analyses

Functional Degradable Polymers by Xanthate-Mediated Polymerization

Herein we report the first example of the controlled synthesis of linear and hyperbranched copolymers of 2-methylene-1,3-dioxepane (MDO) with functional vinyl monomers to deliver a range of functional, degradable polymers by reversible deactivation radical polymerization. The copolymerization was able to be tuned to vary the incorporation of degradable segments to create degradable materials with predictable molar mass, low dispersity values while also featuring side-chain functionality. The formation of nanoparticles by the addition of divinyladipate to form degradable hyperbranched copolymers was proven by DLS and TEM analyses