Date of Award

Spring 5-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Polymers and High Performance Materials

Committee Chair

Charles L. McCormick

Committee Chair Department

Polymers and High Performance Materials

Committee Member 2

Robson F. Storey

Committee Member 2 Department

Polymers and High Performance Materials

Committee Member 3

Daniel A. Savin

Committee Member 4

Derek L. Patton

Committee Member 4 Department

Polymers and High Performance Materials

Committee Member 5

Sarah E. Morgan

Committee Member 5 Department

Polymers and High Performance Materials

Abstract

The work described in this dissertation focuses on the development of synthetic approaches toward novel polymer architectures that specifically address the issues of in vivo drug delivery. Successful implementation of the synthetic methodologies described herein required fundamental investigations into the underlying chemistries in ways that now provide greater insights into the nature of the these chemical reactions.

In Section I, the synthesis of tunable pH- and CO2-responsive sulfonamide-containing polymers using reversible addition-fragmentation chain transfer (RAFT) polymerization is described. Initially, poor polymerization control of methacryloyl sulfonamide (MSA) monomers was observed using traditional RAFT polymerization conditions. Ultimately, reducing the polymerization temperature to 30 °C afforded polymers of controlled molecular weights and low dispersities. A library of sulfonamide-containing polymers was subsequently synthesized and their tunable pH-responsive and reversible CO2-responsive aqueous solution properties investigated.

The work in Section II provides mechanistic understanding of the limited molecular weight control observed during the RAFT polymerization of MSAs at 70 °C (from Section I). This work demonstrates the unique influence of N-arylmethacrylamide substitution on trithiocarbonate chain-end degradation during RAFT polymerization at elevated temperatures. Detailed kinetic and structural analysis of RAFT polymer small molecule analogs showed trithiocarbonate chain-end degradation occurs by N-5 nucleophilic attack on the terminal thiocarbonyl by the ultimate methacrylamide unit. On-going work regarding the development of a mechanistic and kinetic theory aimed at explaining the unique influence of N-arylsubstitution on amide nucleophilicity is further discussed in Appendix B.

In section III we investigate deleterious side reactions that occur during “one-pot” aminolysis/thiol-maleimide end group modification of RAFT polymers. Commonly employed thiol-ene Michael catalysts including amines, amidines, and phosphines were demonstrated to initiate the anionic polymerization of maleimide in a range of organic solvents, resulting in reduced RAFT polymer end group functionalization efficiency. Additionally, thiols and thiol-maleimide adducts were shown to initiate maleimide polymerization in polar solvents in the presence of triethylamine (TEA). Reaction conditions which favor rapid and quantitative end group functionalization of RAFT polymers using “one-pot” aminolysis/thiol-maleimide chemistry were ultimately identified.

Section IV details a new “grafting through” synthetic route towards molecular brushes capable of intracellular-induced disassembly. RAFT polymer-derived macromonomers were synthesized using “one-pot” aminolysis/thiol reactions with maleimide- or methanethiosulfonate-functional oxanorbornenes. Subsequent ring opening metathesis polymerization (ROMP) of the resulting macromonomers afforded molecular brushes with RAFT polymer side chains attached to a polyoxanorbornene backbone via either permanent thioether linkages or reversible disulfide linkages. Molecular brushes comprised of disulfide linkages were shown to undergo reduction-induced disassembly and show promise as a new class of stimuli-responsive polymer therapeutics.

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