Understanding the Structure-Activity Relationship of Ni-Catalyzed Amide C-N Bond Activation using Distortion/Interaction Analysis

Transition metal-catalyzed amide C-N bond activation has emerged as a powerful strategy to utilize amides in synthetic transformations. The key mechanistic basis for the rational design of amide reagents is the structure-activity relationship of amide C-N bond activation. In this work, the controlling factors of Ni/PCy3-catalyzed amide C-N bond activation barrier are elucidated with density functional theory (DFT) calculations and distortion/interaction analysis. We found that the substrate distortion is the key factor that differentiates the amide reactivity in the C-N bond activation. The substrate distortion of amide is associated with two distinctive structure-activity relationships. The general planar amides undergo a classic three-membered ring oxidative addition to cleave the C-N bond, in which the C-N heterolytic bond dissociation energy has a linear relationship with the activation barrier. The twisted amides have a chelation-assisted transition state for the amide C-N bond cleavage, and the twisted angle tau can serve as a predictive parameter for the reactivity of the twisted amides. The understanding of the structure-activity relationship of amide C-N bond activation provides a rational and predictive basis for future reaction designs involving transition metal-catalyzed amide C-N bond activation.

Automated summary

This study elucidates the controlling factors of Ni/PCy3-catalyzed amide C-N bond activation barrier using density functional theory calculations and distortion/interaction analysis. It is found that substrate distortion is the key factor that differentiates amide reactivity, leading to two distinctive structure-activity relationships for planar and twisted amides. Moreover, the understanding of the structure-activity relationship provides a rational and predictive basis for future reaction designs involving transition metal-catalyzed amide C-N bond activation.