Mechanistic and thermodynamic studies on directing group-assisted copper-catalyzed α-C(sp2)−H amination of aryl amines with alkylamines

In mechanistic, three possible pathways of α-C(sp[2])−H functionalization amination of picolinamide with morpholine catalyzed by Cu(OAc)₂/O₂ in p-xylene were studied. Through theoretical calculations, it was found that the pathway involving the radical-cation intermediates produced by the subsequent single electron transfer (SET) was proved to be the most favorable. Then, we also discussed the solvation and substituent effects of three key steps, including N − H bond deprotonation, C − N bond formation rate-determining step and C − H bond deprotonation step, so as to fully understand the mechanism of directing group-assisted copper-catalyzed α-C − H functionalization of aniline and the screening of substrates and solvents. In thermodynamic, the SET process plays a crucial role in the entire catalytic cycle. Therefore, we further studied the reduction potential (E_red) values of Cu(II) radical-cation intermediates involved in the SET process, reflecting the occurrence trend of SET from the thermodynamic point of view, and studied the substituent effects and structure-activity relationships on E_red values of Cu(II) complexes derivatives formed by different Cu(Ⅱ) catalysts, different directing groups, different alkylamines and aromatic amines substrates. It is also found that there are many quantitative structure-activity relationships between E_red and the singly occupied molecular orbital (SOMO) energy, Hammett substituent constant σ⁺ and other structural parameters.