Cis/Trans Isomerization in Secondary Amides: Reaction Paths, Nitrogen Inversion, and Relevance to Peptidic Systems.

Cis/trans isomerization of 2°-amide bonds is a key step in a wide range of important processes. Here we present a theoretical assessment of cis/trans isomerization of 2°-amide bonds using B3LYP density functional methods, describing two reaction paths and corresponding geometry changes during isomerization of N-methylacetamide (NMA) and glycylglycine methyl ester (GGMe). The isomerization begins via a common path, as the extended π-bonding of the amide bond maintains approximate planarity of the O-C-N-H dihedral angle, with only gradually increasing pyramidalization of the nitrogen atom, until a bifurcation point is reached. Both subsequent paths comprise two phases, an "ω phase" (characterized by a major change in C-C-N-C dihedral) and a "θ phase" (characterized by major change in O-C-N-H dihedral), with two distinct transition states. The θ phase involves inversion of the pyramidal amide-nitrogen geometry. Both reaction paths converge at another bifurcation point near the opposite geometry. Studies on the larger GGMe show in addition that the multiple additional rotamers do not change the qualitative properties of the isomerization, but do affect the energies of the differing transition states. These detailed results provide significant new insights into cis/trans isomerization paths in 2°-amides, and serve as a basis for theoretical studies on larger peptidic systems.