Revealing the Oxidative Defluorination Mechanism of Fluorine‐Containing Benzylphthalazine Derivatives Towards Quinone: Insights From DFT Analysis

ABSTRACT Fluorine is commonly incorporated into pharmaceuticals to enhance properties such as metabolic site blocking. However, the Smoothened receptor (SMO) inhibitor, 2,4‐Difluoro‐benzylphthalazine derivative, undergoes metabolism by CYP450 to generate toxic quinone species. A combination of reactivity and accessibility is employed to demonstrate that the quinone production involves hydrogen abstraction from benzyl instead of the phenyl epoxidation mechanism. The main metabolite of fluorine‐containing benzylphthalazine derivatives is benzyl hydroxylation derivatives, which corroborates well with experimental observations. The rate‐determining step in the epoxidation process is a CO bond formation, leading to the production of a radical species instead of a carbocation intermediate. The substitution of F with groups such as CF 3 or CN can increase the energy barrier associated with CO bond formation, thereby augmenting the difficulty in producing quinones. The present study provides a theoretical foundation for the drug metabolism and drug design of pharmaceuticals containing fluorine atoms.