Reaction of O2 with α-Aminoalkyl Radicals Derived from Tetrahydropyridines

Tetrahydropyridines, such as the Parkinsonian-symptom-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its derivatives are unique in that they are the only known tertiary amines that are monoamine oxidase (MAO) substrates or inhibitors. These compounds all possess an exceptionally weak C–H bond at C-6, which is alpha both to a nitrogen lone pair and a C═C. Radicals (R^•) derived from hydrogen abstraction at this position are exceptionally stable. Similar to other α-aminoalkyl radicals, these radicals react with oxygen at a nearly diffusion-controlled rate and are readily oxidized. Evidence suggests that while the initial product of this reaction is likely a peroxyl radical resulting from radical trapping (ROO^•), a dihydropyridinium species (DHP⁺) is produced through what can be described as an overall inner-sphere electron transfer process. These results imply another role for O₂ in the MAO catalytic cycle. In addition to regenerating the flavin moiety in MAO, O₂ may also be directly involved in oxidizing the substrate radical.