Kinetic and Mechanistic Investigations of the Oxidation of Tramadol by Ferrate and Ozone
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Abstract
The kinetics and oxidation products (OPs) of tramadol (TRA), an opioid, were investigated for its oxidation with ferrate (Fe(VI)) and ozone (O<sub>3</sub>). The kinetics could be explained by the speciation of the tertiary amine moiety of TRA, with apparent second-order rate constants of 7.4 (±0.4) M<sup>–1</sup> s<sup>–1</sup> (Fe(VI)) and 4.2 (±0.3) × 10<sup>4</sup> M<sup>–1</sup> s<sup>–1</sup> (O<sub>3</sub>) at pH 8.0, respectively. In total, six OPs of TRA were identified for both oxidants using Qq-LIT-MS, LTQ-FT-MS, GC-MS, and moiety-specific chemical reactions. In excess of oxidants, these OPs can be further transformed to unidentified OPs. Kinetics and OP identification confirmed that the lone electron pair of the amine-N is the predominant site of oxidant attack. An oxygen transfer mechanism can explain the formation of <i>N</i>-oxide-TRA, while a one-electron transfer may result in the formation of N-centered radical cation intermediates, which could lead to the observed <i>N</i>-dealkylation, and to the identified formamide and aldehyde derivatives via several intermediate steps. The proposed radical intermediate mechanism is favored for Fe(VI) leading predominantly to <i>N</i>-desmethyl-TRA (ca. 40%), whereas the proposed oxygen transfer prevails for O<sub>3</sub> attack resulting in <i>N</i>-oxide-TRA as the main OP (ca. 90%)