A self-assembled coordination cage enhances the reactivity of confined amides via mechanical bond-twisting.

Self-assembled coordination cages composed of metal cations and ligands can enhance the hydrolysis of non-covalently trapped amides in mild conditions as demonstrated in recent experiments. Here, we reveal the mechanism that accelerates base-catalyzed amide hydrolysis inside the octahedral coordination cage, by means of a quantum mechanics/molecular mechanics/polarizable continuum model. The calculated activation barrier of the nucleophilic OH - addition to a planar diaryl amide drastically decreases in the cage because of mechanical bond-twisting due to host-guest π-stacking. By contrast, the OH - addition to an N -acylindole, which possesses a twisted amide bond in bulk water, is not enhanced in the cage. Even though the cage hinders OH - collisions with the confined amide, the cage can twist the dihedral angle of the planar amide so as to mimic the transition state of OH - addition.