On- and Off-Cycle Catalyst Cooperativity in Anion-Binding Catalysis

Chiral, neutral H-bond donors have found widespread use as catalysts in enantio­selective reactions involving ion-pair intermediates. Herein, a systematic mechanistic study of a proto­typical anion-binding reaction, the thiourea-catalyzed enantio­selective alkylation of α-chloro­ethers, is detailed. This study reveals that the catalyst resting state is an inactive dimeric aggregate that must dissociate and then reassemble to form a 2:1 catalyst–substrate complex in the rate-determining transition structure. Insight into this mode of catalyst cooperativity sheds light on the practical limitations that have plagued many of the H-bond donor-catalyzed reactions developed to date and suggests design strategies for new, highly efficient catalyst structures.