Dual hydrogen-bond donor (DHBD) organocatalysts, such as chiral urea and thiourea complexes, are becoming increasingly popular catalysts for enantioselective organic reactions. Recent studies suggest that DHBDs form a stereodifferentiated environment to control selectivity of nucleophilic addition. However, the structural details of how two catalytic units deliver stereoselectivity and efficiency is not well understood. We report on the possible low energy DHBD conformations and configurations of the catalyst used for the thiourea-catalyzed alkylation of α-chloroethers through anion-abstraction. QM computations using Stewart’s PM7 semi-empirical method and Truhlar’s M06-2X functional with Dunning’s jul-CC-pvDZ basis set were performed to scan soft dihedral angles. A QM/MM hybrid methodology was also implemented to sample conformations and configurations, including the development of AMBER parameters for the DHBD catalysts of interest. We specifically compared our structures with the previously reported structures and found significant differences. Energy comparisons and root-mean-square deviation analysis revealed three distinct conformations of the catalyst, which deliver distorted anion complexes. The key intermolecular interactions and proposed origin of the stereodifferentiated environment are presented. Our hybrid QM/MM calculations provide a foundation for understanding how organocatalyst conformation develops a stereodifferentiated environment to control stereoselectivity of alkylation of α-chloroethers.

Conformational and configurational analysis of a thiourea chiral hydrogen-bond donor organocatalyst

2019 Spring National Meeting

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