Towards the activity of twisted acyclic amides

<i>N</i>,<i>N</i>-Boc₂ 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 <i>tert</i>-butoxycarbonylation. Due to the steric bulk of di-<i>tert</i>-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 <i>N</i>,<i>N</i>-Boc₂ amides, revealing that the rotational barrier and twist angle (<i>τ</i>) are influenced by the nature of the substituents at the sp² 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.