Insight into [3+2]-dehydration Cycloaddition Reaction Catalyzed by Brønsted Acid: A Theoretical Study

Donor-acceptor cyclopropanes (DACs) serve as significant substrates for the synthesis of natural products, with Lewis acids commonly employed as catalysts to facilitate the activation of DACs. This study investigates the [3 + 2]-cycloaddition reaction of DAC catalyzed by the Brønsted acid TfOH, using the M06-2X/SMD/6-311 + G(d, p)//M06-2X/6-31G(d, p) computational level. The theoretical analysis reveals that the reaction mechanism comprises four critical steps: C-C bond polarization, cycloaddition, dehydration, and deprotonation, with the cycloaddition step identified as the rate-limiting step. The DAC is initiated through the polarization of the C-C bond, which enhances the electrophilicity of the carbon atom substituted by the donor group. This study elucidates the mechanisms of C-C bond polarization utilizing analytical techniques such as LBO and dual descriptors analysis. Furthermore, the computational analysis delineates the distinctions in the C-C polarization process when catalyzed by Lewis acids compared to Brønsted acids, indicating a greater efficacy of Lewis acids in this context. Additionally, the influence of Brønsted acid catalysts is predominantly observed during the dehydration phase, where the energy barrier of the transition state exhibits a direct correlation with the E _HB , achieving a fitting coefficient of 0.9946 across various Brønsted acids. Thus, this molecular-level investigation offers valuable insights into the DACs facilitated by Brønsted acid catalysts.