Kinetic and Mechanistic Investigations of the Oxidation of Tramadol by Ferrate and Ozone

The kinetics and oxidation products (OPs) of tramadol (TRA), an opioid, were investigated for its oxidation with ferrate (Fe(VI)) and ozone (O-3). The kinetics could be explained by the speciation of the tertiary amine moiety of TRA, with apparent second-order rate constants of 7.4 (+/- 04) M-1 s(-1) (Fe(VI)) and 4.2 (+/- 0.3) x 10(4) M-1 s(-1) (O-3) at pH 8.0, respectively. In total, six OPs of TRA were identified for both oxidants using Qq-LIT-MS, LTQFT-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 N-oxide-TRA, while a one-electron transfer may result in the formation of N-centered radical cation intermediates, which could lead to the observed N-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 N-desmethyl-TRA (ca. 40%), whereas the proposed oxygen transfer prevails for O-3 attack resulting in N-oxide-TRA as the main OP (ca. 90%).