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.