The Thiol-Michael Reaction: From First Principles to Applications in Macromolecular Synthesis

Abstract

Click chemistry has emerged as a powerful approach to mimic nature’s unparalleled ability to perform combinatorial chemistry with remarkable modularity and diversity. The rapid reaction kinetics and high efficiency of the thiol-Michael click reaction fit well within the click paradigm, however, this reactivity has hindered the orthogonal application of these reactions in some cases. The research presented herein was undertaken to i) develop a deeper mechanistic understanding of the thiol-maleimide reaction to provide insight into the design of selective thiol-maleimide reactions (Chapter 2), ii) develop comprehensive selectivity charts to explore the design of selective, quaternary and greater mixtures (Chapter 3), iii) address concerns surrounding the formation of byproducts along the nucleophile initiated thiol-Michael reaction (Chapter 4), and iv) explore the application of orthogonal click chemistries to the synthesis of previously inaccessible dendritic architectures. With the goal of learning to control, or in essence hide, the high potential reactivity of thiols in a given environment in order to design selective, orthogonal thiol-Michael reactions, we discovered mechanistic insights that led to the design of selective ternary thiol-maleimide reactions (Chapter 2), developed selectivity charts that enabled the selective sequential and one-pot reactions of quaternary and greater mixtures of thiol-Michael reactions (Chapter 3), learned byproduct formation along the amine and phosphine initiated pathways is not as large of a concern as previously thought, and proposed a mechanistic explanation for difference in byproduct formation observed along the amine and phosphine paths (Chapter 4), and applied our newfound understanding of the thiol-Michael reaction to synthesis of novel dendritic architectures (Chapter 5).