Mechanistic study of NHC-catalyzed oxidative N vs. O chemoselective acylation of aldehydes with alkanolamines

The possible catalytic mechanism was proposed and studied comprehensively at the M062X/6-31G(d,p) level of theory for a reported chemoselective intermolecular S(N)2 nucleophilic substitution of aldehydes with alkanolamine. The calculated results show that the catalytic cycle occurs through six stages, namely, the nucleophilic attack of active N-heterocyclic carbene (NHC) on the substrate, generation of the Breslow intermediate, oxidative addition of NBS and alkanolamine, S(N)2 nucleophilic substitution, Et3N-assisted debromination, and finally regeneration of the NHC along with the release of the product. The results show that TSs of the C-N or C-O bond formation is the key transition state that determines the chemoselectivity of the title reaction. Moreover, our results demonstrated that the N-bromoamine intermediate is more favorable both thermodynamically and kinetically than hypobromite by 14.2 kcal mol(-1), which is consistent with the fact that only the N-acylation product was observed in the experiment. In addition, we found that alkanolamine not only acts as a reactant but also as a proton-shuttle and stabilizer to stabilize the structure of the favored chemoselective transition state by multiple N-H & ctdot;N, N-H & ctdot;O and C-H & ctdot;Br- noncovalent interactions. Et3N firstly acts as a base to promote the formation of the active catalyst NHC, then the protonated Et3N acts as a proton-shuttle to accelerate the Breslow intermediate formation and decrease the activation barrier. The Parr functions and frontier molecular orbital analyses of key species indicate that NHC remarkably enhances the nucleophilicity of the substrate aldehyde, leading to a significant increase of the HOMO energy and a moderate increase of the LUMO energy. We hope this work could provide deeper insights into the fundamental mechanisms of the Et3N-assisted NHC-catalyzed S(N)2 substitution reactions.