Toward an Understanding of Hydrogen-Bonding Bifunctional Organocatalyst Conformations and Their Activity in Asymmetric Mannich Reactions

Small molecule catalysts capable of simultaneously activating and coordinating reactive substrates through weak interactions, in a highly selective fashion, typically suffer from a lack of generality. Moreover, the interplay of several weak interactions in catalyst-substrate complexes is often not well understood. The aim of this thesis is to explain the factors governing the complexation and the activation of hydrogen bonding substrates with conformationally flexible bifunctional thiourea-tertiary amine organocatalysts during the catalytic cycle. Enantioselective Mannich reactions were used as model reactions. The catalyst family discovered in a prior study was further screened and developed to improve selectivity, reactivity and to expand the catalyst utility in related reactions. Computational and kinetic studies were conducted to establish a model explaining the observed selectivity and reactivity patterns. Additionally, conformational preference of the catalyst upon anion binding was studied with an array of anions in the solid state and in the solution to correlate the anion size and shape with observed catalyst folding. The thesis is based on three peer-reviewed publications. Keywords: bifunctional organocatalysis, organic synthesis, anion binding, hydrogen bonding, kinetic experiments