Mechanistic and thermodynamic studies on the CuBr/TBHP-catalyzed cross-dehydrogenative coupling reaction of SF4-alkyne with amines

This study elucidates the mechanistic and thermodynamic aspects of the CuBr/TBHP-catalyzed cross-dehydrogenative coupling reaction between SF 4 -alkynes and tetrahydroisoquinolines using Density Functional Theory calculations. We first systematically evaluated four candidate mechanisms proposed by organic chemists and identified the energetically most favorable pathway. The origin of the barrier differences was then quantified by distortion/interaction–activation-strain analyses, and our conclusion was further corroborated with wave-function analyses as well as solvation and substituent-effect calculations. In the thermodynamic section, first, the M06-2X functional was found to best reproduce experimental oxidation potentials values, providing a reliable tool for predicting substrate reactivity in single-electron transfer step. Then, thermodynamic analysis focused on the oxidation potential of various kinds of amine substrates, including thiazolidinone, benzylamine, tetrahydroquinoline, β-lactam and piperidine-fused aromatic compounds, revealing strong linear structure-activity relationships between oxidation potential and singly occupied molecular orbitals energies. This work offers the in-depth theoretical analysis of SF 4 -alkyne cross-dehydrogenative coupling reactions, guiding the rational design of more efficient substrates and catalytic systems. It also provides a foundation for expanding the synthetic utility of -SF 4 -containing compounds in medicinal chemistry and fluorinated drug development.