Reactivity and Enantioselectivity in NHC Organocatalysis Provide Evidence for the Complex Role of Modifications at the Secondary Sphere.

Secondary-sphere interactions are often harnessed to control reactivity and selectivity in organometallic and enzymatic catalysis. Yet, such strategies have only recently been explicitly applied in the context of organocatalytic systems. Although increased stability, reproducibility, and selectivity were obtained in previous work using this approach, the precise mechanistic pathway promoted by secondary-sphere modification in organocatalysis remained unclear. Herein, we report a comprehensive mechanistic study on the origin of the unique reactivity patterns and stereocontrol observed with boronic acids (s) as secondary-sphere modifiers of N-heterocyclic carbene () organocatalysts. Kinetic experiments revealed partial order in catalyst upon the addition of and unusual preactivation behavior, indicating the presence of stable off-cycle catalyst aggregation and -base adducts. These hypotheses were supported both by computations and by a series of NMR and nonlinear effect experiments. Furthermore, computations indicated a rate-limiting, water-assisted hydrogen atom transfer mechanism. This finding led to a considerable enhancement in the experimental reaction rate while maintaining excellent enantioselectivity by adding catalytic amounts of water. Finally, computations and racemization experiments uncovered an uncommon Curtin-Hammett-controlled enantioselectivity in the presence of secondary-sphere modifiers.