Computational DFT investigation of vicinal amide group anchimeric assistance in ether cleavage

Density functional theory (DFT) computations in solvent have been used to investigate the mechanism of anchimeric assistance (by a vicinal amide group) in the acid-induced ether cleavage. The calculations were carried out at the B3LYP/6-31G* level of theory via full geometry optimizations within the IEF-PCM continuum solvent model. Two different mechanisms have been investigated here that were previously hypothesized for the rate-determining step of this process: the first (mechanism A1) involves a protonated amide and an ethereal oxygen as the nucleophile, while the second (mechanism A2) involves protonation of the ethereal oxygen followed by a nucleophilic attack of the amide. Computations clearly show that the second (involving protonation of the less basic site) is the most favorite route and leads to the formation of an oxazolidinic intermediate that triggers ether hydrolysis. Results are produced that are in excellent agreement with the experiments, and a rationale for them is provided, which represents a general interpretative basis for similar anchimerically assisted processes, such as the ones characterizing the glycosidic activity of two very important classes of enzymes: beta-hexosaminidases and O-GlcNAcases.