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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 -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. 

Abstract Results pertaining to the mechanism of the oxidation of the tertiary amine 1‐methyl‐4‐(1‐methyl‐1‐H‐pyrrol‐2‐yl)‐1,2,3,6‐tetrahydropyridine (MMTP, a close analog of the Parkinsonism inducing compound MPTP) by 3‐methyllumiflavin (3MLF), a chemical model for the FAD cofactor of monoamine oxidase, are reported. MMTP and related compounds are among the few tertiary amines that are monoamine oxidase B (MAO−B) substrates. The MMTP/3MLF reaction is catalytic in the presence of O₂and the results under anaerobic conditions strongly suggest the involvement of radical intermediates, consistent with a single electron transfer mechanism. These observations support a new hypothesis to explain the MAO‐catalyzed oxidations of amines. In general, electron transfer is thermodynamically unfavorable, and as a result, most 1° and 2° amines react via one of the currently accepted polar pathways. Steric constraints prevent 3° amines from reacting via a polar pathway. Those select 3° amines that are MAO substrates possess certain structural features (e. g., a C−H bond that is α‐ both to nitrogen and a C=C) that dramatically lower the pK_aof the corresponding radical cation. Consequently, the thermodynamically unfavorable electron transfer equilibrium is driven towards products by an extremely favorable deprotonation step in the context of Le Chatelier's principle.