Insights into chemoselective fluorination reaction of alkynals via N-heterocyclic carbene and Brønsted base cooperative catalysis

A systematically theoretical study has been carried out to understand the mechanism and chemoselectivity of N-heterocyclic carbene (NHC)-catalyzed fluorination reaction of alkynals using density functional theory calculations. The calculated results reveal that the reaction contains several steps, i.e., formation of the actual catalyst NHC, the nucleophilic attack of NHC on the carbonyl carbon atom of a formyl group, the formation of Breslow intermediate, the removal of methyl carbonate group to afford cumulative allenol intermediate, C–F bond formation coupled with generation of (SO2Ph)2N− anion, esterification accompanied with formation of (SO2Ph)2NH, and dissociation of NHC from product. For the formation of Breslow intermediate via the [1,2]-proton transfer process, apart from the direct proton transfer mechanism, the H2O- and EtOH-mediated proton transfer mechanisms were also investigated, and the free energy barriers for the crucial proton transfer steps can be significantly lowered by explicit inclusion of the protic media EtOH. Furthermore, multiple analyses have also been performed to explore the roles of catalysts and origin of chemoselectivity. Noteworthily, the in situ formed Bronsted base (BB) (SO2Ph)2N− anion was found to play an indispensable role in the esterification process, indicating that the reaction undergoes NHC-BB cooperatively catalytic mechanism, which is remarkably different from the direct esterification pathway proposed in the experimental references. This theoretical work provides a case on the exploration of the dual catalysis in NHC chemistry, which is valuable for rational design on newly cooperative organocatalysis in future.