Over the past 50 years the thiol-Michael addition reaction has become an increasingly popular tool for organic and materials scientists for synthesizing macromolecules with a high degree of control. The thiol-Michael reaction has been utilized in a myriad of applications ranging from bimolecular synthesis to surface modification to engineering adhesives and laminates to dendrimer synthesis and block polymer conjugation. Despite decades of fundamental investigations the thiol-Michael reaction remains not as well understood as is generally thought. In particular, it is unclear whether a variety of nucleophiles act as initiators or catalysts during thiol-Michael reactions. A more complete mechanistic understanding of the thiol-Michael reaction has implications in reaction efficiencies, propensity for side reactions and selectivity among reactants. We are currently studying the competing mechanisms of various nucleophiles along the thiol-Michael reaction pathway computationally and experimentally. Insight gained from a more detailed understanding of thiol-Michael reactions can applied to more efficient macromolecule synthesis. For example, our computational efforts provide a platform from which to develop routes toward the highly efficient and selective growth of monodisperse dendrimers. Specifically, electron-poor maleimides react irreversibly with thiols in a kinetically driven ‘click’ reaction, and reversibly with furan in a thermodynamically driven process. The thiol-maleimide click reactions initiate dendrimer growth, and equally efficient furan-maleimide protection/deprotection reactions guarantees controlled and monodisperse growth with near quantitative yields. Combining the computationally idealized thiol-Michael conditions and orthogonal maleimide reactivity, we synthesized a new class of rationally designed dendrimers with precise control over the chemical composition of each generation, up to G4.

Computational and experimental investigations of the thiol-Michael click reaction and its applications in dendrimer synthesis

253rd National Meeting (2017)

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