Chiral phosphoric acid (CPA)-catalyzed transformation reaction of ketene: Competing mechanisms and origin of regio- and stereoselectivities

DFT calculations have been carried out to explore the competing mechanisms and origin of selectivities of chiral phosphoric acid (CPA)-catalyzed Friedel-Crafts-like reaction of ketene and pyrrole. Two kinds of pathways including O-protonation pathway and C-protonation pathway have been investigated and compared in theory for the first time. The O-protonation pathway is confirmed as the most favorable pathway, and contains several stages: (1) combination of CPA and ketene, (2) complexation with pyrrole, (3) O-protonation, (4) stepwise CPA-assisted [1,3]-proton transfer, and (5) dissociation of CPA. Frontier molecular orbital (FMO) analysis indicates the CPA can promote the reaction by lowering the energy gap of FMOs, which is remarkably different from the role of Lewis acid/Lewis base catalysts by changing the FMO overlap modes. Local nucleophilic activity indexes have been computed to explore the origin of regioselectivity. Furthermore, atoms-in-molecules (AIM) analysis on the stereoselectivity-determining CPA-assisted [1,3]-proton transfer process demonstrates that the stronger C–H⋯O interaction and more C–H⋯π interactions are key for controlling the stereoselectivity. The obtained insights should be helpful for recognizing the general nature and regio-/stereo-selectivities of the CPA-catalyzed activation and transformation reactions of ketenes.