Density functional theory study of metabolic derivatives of the oxidation of paracetamol

The hypothetical oxidation mechanism of paracetamol (PAR) has been investigated using quantum chemical calculations at the density functional theory (DFT)/B3LYP theory level with the 6‐31G* basis set. The calculations using Cpd I for the cytochrome P‐450 model showed that, for PAR oxidation, an initial hydrogen atom abstraction from the phenolic hydroxyl group is thermodynamically more favored by 12.04 kcal mol−1 than from the acetylamine nitrogen atom. Spin density calculations were performed for the radical formed by the hydrogen abstraction from the phenolic hydroxyl group and showed that the unpaired electron remains predominantly localized on the O7 phenolic oxygen (39%), C3 and C5 carbon atoms at ortho positions (27% and 26%, respectively) and C1 at para position (33%). The results also show that the formations of dimer and trimer radicals are energetically more favored than the formation of NAPSQI, which is in agreement with observed experimental results.