Autoxidation of biological molecules. 1. Antioxidant activity of vitamin E and related chain-breaking phenolic antioxidants in vitro

The rate constants, k5, for abstraction by peroxyl radicals of the phenolic hydrogens from a number of phenols have been measured at 30°C. Values of k5 for α-, β-, γ-, and δ-tocopherols are 23.5, 16.6, 15.9, and 6.5 × 105 M-1 s-1, respectively. Like most other phenols these tocopherols react with two peroxyls per molecule and the reaction with peroxyls exhibits a substantial deuterium kinetic isotope effect. α-Tocopherol is the most reactive chain-breaking, phenolic antioxidant known. The simple model compound 4-methoxy-2,3,5,6-tetramethylphenol (TMMP) is much less reactive, with a k5 value of only 2.1 × 105 M-1 s-1. A better model compound is 2,2,5,7,8-pentamethyl-6-hydroxychroman (PMHC) which has a k5 value of 21.4 × 105 M-1 s-1. The low reactivity of TMMP compared with α-tocopherol and PMHC is attributed to stereoelectronic factors. In TMMP the methoxy group is twisted out of the plane of the aromatic ring by steric forces and, in consequence, the p-type lone pair on the methoxyl oxygen cannot help stabilize the phenoxyl formed upon abstraction of the phenolic hydrogen. However, in the tocopherols and in PMHC the chroman ring system holds the ethereal oxygen's p-type lone pair nearly perpendicular to the aromatic ring, thereby providing additional stabilization for the resultant phenoxyls. This hypothesis has been confirmed by X-ray analysis of TMMP and PMHC and of 4-methoxyphenol and 2,6-di-tert-butyl-4-methoxyphenol. © 1981 American Chemical Society.