Ozonation of piperidine, piperazine and morpholine: Kinetics, stoichiometry, product formation and mechanistic considerations

Piperidine, piperazine and morpholine as archetypes for secondary heterocyclic amines, a structural unit that is often present in pharmaceuticals (e.g., ritalin, cetirizine, timolol, ciprofloxacin) were investigated in their reaction with ozone. In principle the investigated compounds can be degraded with ozone in a reasonable time, based on their high reaction rate constants with respect to ozone (1.9 x 10(4) -2.4 x 10(5) M-1 s(-1)). However, transformation is insufficient (13-16%), most likely due to a chain reaction, which decomposes ozone. This conclusion is based on (OH)-O-center dot scavenging experiments, leading to increased compound transformation (18-27%). The investigated target compounds are similar in their kinetic and stoichiometric characteristics. However, the mechanistic considerations based on product formation indicate various reaction pathways. Piperidine reacts with ozone via a nonradical addition reaction to N-hydroxypiperidine (yield: 92% with and 94% without scavenging, with respect to compound transformation). However, piperazine degradation with ozone does not lead to N-hydroxypiperazine. In the morpholine/ozone reaction, N-hydroxymorpholine was identified. Additional oxidation pathways in all cases involved the formation of (OH)-O-center dot with high yields. One important pathway of piperazine and morpholine by zonation could be the formation of C-centered radicals after ozone or OH radical attack. Subsequently, O-2 addition forms unstable peroxyl radicals, which in one pathway loose superoxide radicals by generating a carbon-centered cation. Subsequent hydrolysis of the carbon-centered cation leads to formaldehyde, whereby ozonation of the N-hydroxy products can proceed in the same way and in addition give rise to hydroxylamine. A second pathway of the short-lived peroxyl radicals could be a dimerization to form short-lived tetraoxides, which cleave by forming hydrogen peroxide. All three products have been found. (C) 2015 Published by Elsevier Ltd.