Advanced oxidation chemistry of paracetamol. UV/H2O2-induced hydroxylation/degradation pathways and 15N aided inventory of nitrogenous breakdown products

The advanced oxidation chemistry of the antipyretic drug paracetamol (1) with the LTV/H2O2 system was investigated by an integrated methodology based on N-15-labeling and GC-MS, HPLC, and 2D H-1, C-13, and N-15 NMR analysis. Main degradation pathways derived from three hydroxylation steps, leading to 1,4-hydroquinone/1,4-benzoquinone, 4-acetylaminocatechol and, to a much lesser extent, 4-acetylaminoresorcine. Oxidation of the primary aromatic intermediates, viz. 4-acetylaminocatechol, 1,4-hydroquinone, 1,4-benzoquinone, and 1,2,4-benzenetriol, resulted in a series of nitrogenous and non-nitrogenous degradation products. The former included N-acetylglyoxylamide, acetylaminomalonic acid, acetylaminohydroxymalonic acid, acetylaminomaleic acid, diastereoisomeric 2-acetylamino-3-hydroxybutanedioic acids, 2-acetylaminobutenedioic acid, 3-acetylamino-4-hydroxy-2-pentenedioic acid, and 2,4-dihydroxy-3-acetylamino-2-pentenedioic acid, as well as two muconic and hydroxymuconic acid derivatives. N-15 NMR spectra revealed the accumulation since the early stages of substantial amounts of acetamide and oxalic acid monoamide. These results provide the first insight into the advanced oxidation chemistry of a 4-aminophenol derivative by the UV/H2O2 system, and highlight the investigative potential of integrated GC-MS/NMR methodologies based on N-15-labeling to track degradation pathways of nitrogenous species.