Towards the activity of twisted acyclic amides.

,-Boc amides have emerged as the most common class of acyclic twisted amides that have been engaged in a range of C-N activation and cross-coupling processes of ubiquitous amide bonds. These amides are readily synthesized from primary amides through a site-selective -butoxycarbonylation. Due to the steric bulk of di--butoxy groups, these amides exhibit significant C[double bond, length as m-dash]N bond twisting, which promotes N-C bond cleavage, facilitating their use in cross-coupling reactions. Herein, we present a computational blueprint for the C[double bond, length as m-dash]N bond rotation in ,-Boc amides, revealing that the rotational barrier and twist angle () are influenced by the nature of the substituents at the sp carbon position. Sterically hindered substituents exhibit the highest distortions, leading to lower rotation barriers. Rotation along the C[double bond, length as m-dash]N bond is accompanied by phenyl ring rotation to minimize steric clashes. A strong correlation between the rotational barriers and the HOMO energies is observed. These findings provide key insights into the fundamental role of amide bond distortion in C-N activation processes.