Chromanol methide radical

The occurrence of a 5a-C-centered tocopherol-derived radical 10, often called chromanol methide radical or chromanol methyl radical, had been postulated in literature dating back to the early days of vitamin E research,12 19 which have been cited or supposedly reconfirmed later (Fig. 6.5).8,20-22 In some accounts, radical structure 10 has been described in the literature as being a resonance form (canonic structure) of the tocopheroxyl radical, which of course is inaccurate. If indeed existing, radical 10 represents a tautomer of tocopheroxyl radical 2, being formed by achemical reaction, namely, a 1,4-shift of one 5a-proton to the 6-oxygen, but not just by a shift of electrons as in the case of resonance structures (Fig. 6.5). In all accounts mentioning... 

FIGURE 6.5 The hypothetical chromanol methide radical 10 as a tautomer of a-tocopher-oxyl radical 2. 

The third fact that seemed to argue in favor of the occurrence of radicals 10 was the observation that reactions of a-tocopherol under typical radical conditions, that is, at the presence of radical initiators in inert solvents or under irradiation, provided also large amounts of two-electron oxidation products such as o-QM 3 and its spiro dimerization product 9 (Fig. 6.8).16,25,26 This was taken as support of a disproportionation reaction involving a-tocopheroxyl radical 2 and its hypothetical tautomeric chromanol methide radical 10, affording one molecule of o-QM 3 (oxidation) and regenerating one molecule of 1 (reduction). The term disproportionation was used here to describe a one-electron redox process with concomitant transfer of a proton, that is, basically a H-atom transfer from hypothetical 10 to radical 2. 

By a combination of synthetic approaches, isotopic labeling, using tocopherols with 13C-labeling at C-5a and C-7a, EPR spectroscopy, and high-level DFT computations, it was shown that there is no radical formation at either C-5a or C-7a and that chromanol methide radical 10 does not occur in tocopherol.11 EPR failed to detect... 

To conclusively disprove the involvement of the chromanol methide radical, the reaction of a-tocopherol with dibenzoyl peroxide was conducted in the presence of a large excess of ethyl vinyl ether used as a solvent component. If 5a-a-tocopheryl benzoate (11) was formed homolytically according to Fig. 6.6, the presence of ethyl vinyl ether should have no large influence on the product distribution. However, if (11) was formed heterolytically according to Fig. 6.9, the intermediate o-QM 3 would be readily trapped by ethyl vinyl ether in a hetero-Diels-Alder process with inverse electron demand,27 thus drastically reducing the amount of 11 formed. Exactly the latter outcome was observed experimentally. In fact, using a 10-fold excess of ethyl vinyl ether relative to a-tocopherol and azobis(isobutyronitrile) (AIBN) as radical... 

Also for the reaction that was described as dimerization of the chromanol methide radicals 10 to the ethano-dimer of a-tocopherol 12, the involvement of the C-centered radicals has been disproven and these intermediates lost their role as key intermediates in favor of the o-QM 3. It was experimentally shown that ethano-dimer 12 in hydroperoxide reaction mixtures of a-tocopherol was formed according to a more complex pathway involving the reduction of the spiro dimer 9 by a-tocopheroxy 1 radicals 2, which can also be replaced by other phenoxyl radicals (Fig. 6.10).11 Neither the hydroperoxides themselves, nor radical initiators such as AIBN, nor tocopherol alone were able to perform this reaction, but combinations of tocopherol with radical initiators generating a high flux of tocopheroxyl radicals 2 afforded high yields of the ethano-dimer 12 from the spiro dimer 9. 

The above-described experiments, calculations, and theroretical considerations showed that there is no theoretical or experimental evidence whatsoever for the 5a-C-centered radical 10. All relevant reactions can be traced back to occurrence and reactions of o-QM 3 as the central intermediate. The three reactions commonly cited to support the occurrence of the chromanol methide radical 10 in vitamin E chemistry (Figs 6.6-6.8) are actually typical processes of the o-QM intermediate (Figs 6.9-6.11). 

Rosenau, T. Kloser, E. Gille, L. Mazzini, F. Netscher, T. Vitamin E. Chemistry studies into initial oxidation intermediates of a-tocopherol disproving the involvement of 5a-C-centered Chromanol Methide radicals.. /. Org. Chem. 2007, 72(9), 3268-3281. 

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