Phenoxazine: A Privileged Scaffold for Radical-Trapping Antioxidants

Diphenylamines are widely used to protect petroleum-derived products from autoxidation. Their efficacy as radical-trapping antioxidants (RTAs) relies on a balance of fast H-atom transfer kinetics and stability to one-electron oxidation by peroxidic species. Both H-atom transfer and one-electron oxidation are enhanced by substitution with electron-donating substituents, such as the S-atom in phenothiazines, another important class of RTA. Herein we report the results of our investigations of the RTA activity of the structurally related, but essentially ignored, phenoxazines. We find that the H-atom transfer reactivity of substituted phenoxazines follows an excellent Evans–Polanyi correlation spanning kᵢₙₕ = 4.5 × 10⁶ M–¹ s–¹ and N–H BDE = 77.4 kcal mol–¹ for 3-CN,7-NO₂-phenoxazine to kᵢₙₕ = 6.6 × 10⁸ M–¹ s–¹ and N–H BDE = 71.8 kcal mol–¹ for 3,7-(OMe)₂-phenoxazine (37 °C). The reactivity of the latter compound is the greatest of any RTA ever reported and is likely to represent a reaction without an enthalpic barrier since log A for this reaction is likely ∼8.5. The very high reactivity of most of the phenoxazines studied required the determination of their kinetic parameters by inhibited autoxidations in the presence of a very strong H-bonding cosolvent (DMSO), which slowed the observed rates by up to 2 orders of magnitude by dynamically reducing the equilibrium concentration of (free) phenoxazine as an H-atom donor. Despite their remarkably high reactivity toward peroxyl radicals, the phenoxazines were found to be comparatively stable to one-electron oxidation relative to diphenylamines and phenothiazines (E° ranging from 0.59 to 1.38 V vs NHE). Thus, phenoxazines with comparable oxidative stability to commonly used diphenylamine and phenothiazine RTAs had significantly greater reactivity (by up to 2 orders of magnitude). Computations suggest that this remarkable balance in H-atom transfer kinetics and stability to one-electron oxidation results from the ability of the bridging oxygen atom in phenoxazine to serve as both a π-electron donor to stabilize the aminyl radical and σ-electron acceptor to destabilize the aminyl radical cation. Perhaps most excitingly, phenoxazines have “non-classical” RTA activity, where they trap >2 peroxyl radicals each, at ambient temperatures.