Mechanistic Insight into Palladium-Catalyzed Enantioselective Remote meta-C-H Arylation and Alkylation by Using Density Functional Theory (DFT) Calculations

摘要

Steric hindrance is usually the only determining factor in controlling the enantioselectivity of a reaction. Here, we disclose a different way in which steric hindrance and electronic properties cooperate to control the transformation enantioselectivity. In this study, palladium-catalyzed enantioselective remote meta-C-H arylation and alkylation via a chiral transient mediator was investigated to elucidate the mechanistic details and essence of the excellent enantioselectivity by using density functional theory methods. The calculations indicate that the deprotonation process is the rate-determining step of the reaction, whereas norbornene insertion is most likely the enantioselectivity-determining step. Although transition state structure analysis indicates that steric hindrance indeed contributes to this enantioselectivity, its individual action is insufficient to account for the excellent S-configuration selectivity. The electronic nature of substituents on the C=C double bond of norbornene as a chiral transient mediator plays a crucial role in this enantioselective conversion. A weak electron-withdrawing group is favorable for enantioselectivity, whereas strong electron-withdrawing and electron-donating groups are exactly the opposite. Computations reveal that a weak electron-withdrawing group slightly lowers the charge density of the chiral norbornene C=C double bond, resulting in a decrease in reactivity. Especially, for the R-configuration, the insertion reaction energy barrier increases to approximately 29.3 kcal/mol. Such a high barrier is commensurate with that of the S-configuration rate-determining step (28.2 kcal/mol), thereby preventing the formation of R-configuration products and ultimately determining the enantioselectivity of the protocol.