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.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
David D
DD
Ford
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Dan
D
Lehnherr
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
C Rose
CR
Kennedy
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Eric N
EN
Jacobsen
D000838:Anions; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods*; D018360:Crystallography, X-Ray; D004986:Ether / Q000737:chemistry; D006860:Hydrogen Bonding; D007700:Kinetics; D013890:Thiourea / Q000737:chemistry
D000838:Anions; D004986:Ether; D013890:Thiourea