Mechanistic insights into the bioactivation of phenacetin to reactive metabolites: A DFT study

► DFT/B3LYP study of O-dealkylation, N-hydroxylation, N-deacetylation of phenacetin. ► O-dealkylation pathway to acetaminophen is energetically most favorable. ► Activation barrier for O-dealkylation of phenacetin is the lowest (41.54 kcal/mol). ► O-Et-NAPQI is the electrophilic metabolite (ω = 19.43 eV) leading to carcinogenicity. ► Understanding crucial Phase I and II metabolic reactions of phenacetin.