Chemical fate of antidepressant paroxetine. Computational study of radical-mediated rearrangements and base-induced elimination reactions of chlorinated metabolites.

Quantum chemical calculations have been used to model reactions which are important for understanding the chemical fate of paroxetine-derived metabolites in the environment. To explain the experimental observation that the loss of water and/or formation of imines occurs along the degradation pathway of paroxetine, four different mechanisms of radical-induced dehydrations, and two different base-catalyzed reactions of chlorinated 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine derivative have been considered. The elimination of water from the N-centered radical cation, which results in the formation of an imine intermediate, has been theoretically evaluated as the most feasible process. Dehydrochlorination with subsequent formation of imine or intramolecular addition to double bond/nitrogen atom has been investigated in basic solution1. The predicted energy barriers are within the barrier limits set by experimental measurements. Several new structures, which comply with the available experimental data, have been proposed as conceivable products relevant for the chemical and environmental fate of antidepressant paroxetine, but also for biologically related substrates. The interplay between theory and experiment shows the way in which quantum chemical methods can be used to supplement experimental studies.