Coordination among Bond Formation/Cleavage in a Bifunctional-Catalyzed Fast Amide Hydrolysis: Evidence for an Optimized Intramolecular N‑Protonation Event

• Published in: Journal of organic chemistry Vol. 85; no. 7; pp. 4663 - 4671
• Main Authors: Scorsin, Leandro, Affeldt, Ricardo F, Oliveira, Bruno S, Silveira, Eduardo V, Ferraz, Matheus S, de Souza, Fábio P. S, Caramori, Giovanni F, Menger, Fredric M, Souza, Bruno S, Nome, Faruk
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03.04.2020
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.9b03383

A density functional theory (DFT) computational analysis, using the ωB97X-D functional, of a rapid amide cleavage in 2-carboxyphthalanilic acid (2CPA), where the amide group is flanked by two catalytic carboxyls, reveals key mechanistic information: (a) General base catalysis by a carboxylate coupled to general acid catalysis by a carboxyl is not operative. (b) Nucleophilic attack by a carboxylate on the amide carbonyl coupled to general acid catalysis at the amide oxygen can also be ruled out. (c) A mechanistic pathway that remains viable involves general acid proton delivery to the amide nitrogen by a carboxyl, while the other carboxylate engages in nucleophilic attack upon the amide carbonyl; a substantially unchanged amide carbonyl in the transition state; two concurrent bond-forming events; and a spatiotemporal-base rate acceleration. This mechanism is supported by molecular dynamic simulations which confirm a persistent key intramolecular hydrogen bonding. These theoretical conclusions, although not easily verified by experiment, are consistent with a bell-shaped pH/rate profile but are at odds with hydrolysis mechanisms in the classic literature.