Chlorination of tramadol: Reaction kinetics, mechanism and genotoxicity evaluation

Tramadol (TRA) is one of the most detected analgesics in environmental matrices, and it is of high significance to study the reactivity of TRA during chlorination considering its potential toxicity to the environment. The chlorine/TRA reaction is first order with respect to the TRA concentration, and a combination of first-order and second-order with respect to chlorine concentration. The pH dependence of the observed rate constants (k(obs)) showed that the TRA oxidation reactivity increased with increasing pH. /cobs can be quantitatively described by considering all active species including C-12, CL2O and HOCI, and the individual rate constants of HOCl/TRA(0), HOCl/TRAH(+), Cl-2/TRA and Cl2O/TRA reactions were calculated to be (2.61 +/- 0.29) x 10(3) M-1 s(-1), 14.73 +/- 4.17 M-1 s(-1), (3.93 +/- 0.34) x 10(5) M-1 s(-1) and (5.66 +/- 1.83) x 10(6) M(-1)s(-1), respectively. Eleven degradation products were detected with UPLC-Q-TOF-MS, and the corresponding structures of eight products found under various pH conditions were proposed. The amine group was proposed to be the initial attack site under alkaline pH conditions, where reaction of the deprotonated amine group with HOCI is favorable. Under acidic and neutral pH conditions, however, two possible reaction pathways were proposed. One is an electrophilic substitution on the aromatic ring, and another is an electrophilic substitution on the nitrogen, leading to an N-chlorinated intermediate, which can be further oxidized. Finally, the SOS/umu test showed that the genotoxicity of TRA chlorination products increased with increasing dosage of chlorine, which was mostly attributed to the formation of some chlorine substitution products. (C) 2015 Elsevier Ltd. All rights reserved.