Mechanistic origin of halogen-dependent reactivity in metal-free C-3 halogenation of pyridine N-oxides: a DFT study.

CONTEXT: Metal-free halogenation of pyridine N-oxides represents an important strategy for the functionalization of heteroaromatic compounds; however, the mechanistic origin of halogen-dependent reactivity remains incompletely understood. In this study, density functional theory calculations were employed to investigate the C-3 halogenation of pyridine N-oxide using N-fluorosuccinimide (NFSu), N-chlorosuccinimide (NCS), and N-bromosuccinimide (NBS). The computed free-energy profiles support a common stepwise ionic mechanism involving σ -complex intermediates and two transition states. Solvent effects significantly influence the reaction energetics and alter the rate-determining step across the halogen series. In the gas phase, the calculated activation barriers follow the order F > Cl > Br , whereas the solution-phase rate-determining barriers follow the order Cl > F > Br with activation free energies of 59.94, 51.27, and 42.13 kcal mol - 1 , respectively. This difference highlights the significant influence of differential solvation on the relative stabilization of the transition states. Frontier molecular orbital, conceptual DFT, and natural bond orbital analyses further indicate that variations in N-X bond cleavage, halogen-dependent electronic interactions, and stabilization within the pyridine N-oxide framework contribute to the observed energetic differences.

METHODS: All calculations were performed using density functional theory as implemented in Gaussian 16. Geometry optimizations, frequency calculations, and intrinsic reaction coordinate analyses were carried out at the B3LYP/6-31+G(d,p) level of theory. Solvent effects were included using the SMD implicit solvation model with acetonitrile as the solvent. Frontier molecular orbital analysis, global reactivity descriptor calculations, and natural bond orbital analysis were performed to investigate electronic structure, donor-acceptor interactions, and the mechanistic origin of halogen-dependent reactivity.