Mechanistic pathways of the photolysis of paracetamol in aqueous solution: An example of photo-Fries rearrangement

Abstract

The mechanism of the photolysis of N-(4-hydroxyphenyl)ethanamide (paracetamol, PA), a widely prescribed analgesic and antipyretic drug, has been investigated in the absence and in the presence of oxygen. Identification of products and kinetic analyses were performed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and by ultra-performance liquid chromatography with a diode array detector (UPLC-PDA). The results show that, under irradiation at 254 nm and independently of the presence of oxygen, the predominant reaction pathway is a photo-Fries rearrangement (PFR), yielding the PA isomer 2′-amino-5′-hydroxyacetophenone (PAI). This reaction occurs from the singlet excited state of the molecule and involves the migration of the acetyl group onto the aromatic ring in the ortho-position to the amine moiety. The formation of 4-aminophenol (4-AP) was observed as a minor competitive pathway. The quantum yield of PA consumption (Φ-PA) was determined to be 1.0(±0.1) × 10-3 by chemical actinometry. As its concentration increases, the PFR product (PAI) competes with PA for light absorption and undergoes, in the presence of oxygen, a photooxygenation process leading to the formation of a peroxyester. © 2013 The Royal Society of Chemistry and Owner Societies.