Inhibited Hydrolysis of 4‑(N,N‑Dimethylamino)aryl Imines in a Weak Acid by Supramolecular Encapsulation inside Cucurbit[7]uril

Schiff bases are imines formed by condensing primary amines with aldehydes (aldimines) or ketones (ketimines), and they are common functional groups in nature. This current study prepared 10 different aldimine and ketimine derivatives, based on the 4-(N,N-dimethylamino)aryl imine scaffold, and measured hydrolysis rate constants at pH 6.0, where the mole fraction of protonated imine was very high. The hydrolysis rate constants for the free protonated imines exhibited a logarithmic correlation with the calculated electrophilicity index (ω). Imine hydrolysis was reduced by 15–97-fold by the presence of cucurbit[7]uril (CB7), which forms a protective inclusion complex. Quantum chemical calculations and molecular dynamics simulations of the supramolecular complex indicate that the protonated imine guest is “clamped” inside the host cavity by a combination of attractive van der Waals interactions with the CB7 interior and directional N–H···O and C–H···O hydrogen bonds to the CB7 oxygens at the opposite portals. From a practical perspective, the enhanced imine stability provided by CB7 encapsulation can be used to protect imine derivatives of drug molecules for diverse applications such as drug authentication, formulation, and controlled release.