Computational Assessment of the Mechanistic Journey in Chan-Lam-Based Arylation of Imidazoles

Cu(II)-catalyzed C-N bond formation reactions remain one of most widely practiced and powerful protocols for the synthesis of value-added chemicals, bioactive molecules, and materials. Despite numerous experimental contributions, the overall mechanistic understanding of the C-N coupling reaction based on the Chan-Lam (CL) reaction methodology is still limited and underdeveloped, particularly with respect to the use of different substrates and catalytic species. Herein, we report an in-depth DFT-based study on the mechanism of N-arylation of imidazoles following Collman's experimental setup. Our findings unfold for the first time the ligand-based CL coupling catalyzed by the [Cu(II)(OH)TMEDA]₂Cl₂ complex. The transmetalation step with an energy span of 26.2 kcal mol^-1 is rate-determining, while the subsequent disproportionation and reductive elimination are relatively facile (δE = 16.4 kcal mol^-1) in comparison to the CL amination of secondary amines. The final oxidative catalyst regeneration results in the presence of O₂, accompanying an energy span of 12.8 kcal mol^-1, where hydrogen transfer from the coordinated water allows the reduction of superoxo linkage. Couplings performed in the presence of a combination of bidentate sp³-N ligands with single and double -(CH₂)- spacer units afford a kinetically facile transformation (24.5 kcal mol^-1). Furthermore, our results agree with the experimental outcomes of regioselective couplings of substituted imidazoles.