title: Insights into the Competing Mechanisms and Origin of Enantioselectivity for N-Heterocyclic Carbene-Catalyzed Reaction of Aldehyde with Enamide.
abstract: Hydroacylation reactions and aza-benzoin reactions have attracted considerable attention from experimental chemists. Recently, Wang et al. reported an interesting reaction of N-heterocyclic carbene (NHC)-catalyzed addition of aldehyde to enamide, in which both hydroacylation and aza-benzoin reactions may be involved. Thus, understanding the competing relationship between them is of great interest. Now, density functional theory (DFT) investigation was performed to elucidate this issue. Our results reveal that enamide can tautomerize to its imine isomer with the assistance of HCO3-. The addition of NHC to aldehydes formed Breslow intermediate, which can go through cross-coupling with enamide via hydroacylation reaction or its imine isomer via aza-benzoin reaction. The aza-benzoin reaction requires relatively lower free energy barrier than the hydroacylation reaction. The more polar characteristic of C=N group in the imine isomers, and the more advantageous stereoelectronic effect in the carbon-carbon bond forming transition states in aza-benzoin pathway were identified to determine that the imine isomer can react with the Breslow intermediate more easily. Furthermore, the origin of enantioselectivities for the reaction was explored and reasonably explained by structural analyses on key transition states. The work should provide valuable insights for rational design of switchable NHC-catalyzed hydroacylation and aza-benzoin reactions with high stereoselectivity.
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences.|Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou 450001, Henan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences.|Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou 450001, Henan, China.
authors.forename: Xinhuan
authors.initials: X
authors.lastname: Chen
authors.affiliation: The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, Henan, China.
authors.forename: Donghui
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences.|Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou 450001, Henan, China.
authors.forename: Junbiao
authors.initials: J
authors.lastname: Chang