Autoxidation of biological molecules. 4. Maximizing the antioxidant activity of phenols

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Abstract

Rate constants, k1, for H-atom abstraction by peroxyl radicals from α-tocopherol and 35 structurally related phenols have been measured at 30°C by the inhibited autoxidation of styrene (IAS) method. An independent laser-flash kinetic EPR method was used with ten of these phenols which gave k1 values at 24°C that were in satisfactory agreement with the values found by the IAS method. The structures of several phenols were determined by X-ray analysis. The EPR spectral parameters for the phenoxyl radicals derived from many of these phenols were also measured. The relative magnitudes of k1 values for phenols that are structurally closely related and have an oxy substituent para to the hydroxyl group can be correlated with the degree of stabilization of the phenoxyl radical. Stabilization depends on two factors: (i) the extent of orbital overlap between the 2p type lone pair on the para oxygen atom and the aromatic π electron system and (ii) the electron-donating or withdrawing character of the group bonded to the para oxygen atom. Orbital overlap depends on the dihedral angle, θ, between the direction of the 2p orbital on the para oxygen and a line perpendicular to the aromatic plane. It can be estimated from the X-ray structures. Along the series 4-methoxytetramethylphenol (VIc), 6-hydroxy-2,2,5,7,8-pentamethylchromene, 6-hydroxy-2,2,5,7,8-pentamethylchroman, and 2,3-dihydro-5-hydroxy-2,2,4,6,7-pentamethylbenzofuran (IIIb), k1 increases from 3.9 × 105, 2.5 × 106, 3.8 × 106, to 5.7 × 106 M-1 s-1, as θ decreases from 89, 38, 17, to 6°. Compound IIIb is the most active antioxidant being 1.8 times more active than α-tocopherol. For 2-substituted 6-hydroxy-2,5,7,8-tetramethylchromans log (k1/M-1 s-1) can be correlated with the σI constant of the 2-substituent, ρI = -1.25. For these compounds and for some 2,6-dimethylphenols log (k1/M-1 s-1) can also be correlated with the extent of stabilization of the corresponding phenoxyl radicals as measured by the unpaired spin density at the two ortho methyl groups. Some additional kinetic and spectroscopic data are presented. It is also shown that the perpendicular methoxy group in VIc is not deactivating relative to a hydrogen atom but is, instead, about as activating as a methyl group.

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