A-Tocopherol dimer

Tocopherols behave as chain breaking antioxidants by competing with the substrate (RH) for the chain peroxyl radicals (ROO ) that are normally present in the highest concentration in the system. Tocopherols donate hydrogen to a peroxyl radical resulting in an a-tocopherol semiquinone radical (reaction 1). This may further donate hydrogen to produce methyl tocopherol quinone or react with another a-tocopheryl semiquinone radical (reactions 2 and 3) to produce an a-tocopherol dimer which also possesses antioxidant activity. ... 

Phenols are important antioxidants, with vitamin E being the most important endogenous phenolic membrane-bound antioxidant. Membrane levels of vitamin E are maintained through recycling of the vitamin E radical with ascorbate and thiol reductants. Vitamin E is a mixture of four lipid-soluble tocopherols, a-tocopherol being the most efiective radical quencher. The reaction of a-tocopherol with alkyl and alkylperoxyl radicals of methyl linoleate was recently reported. These are facile reactions that result in mixed dimer adducts (Yamauchi etal., 1993). 

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. 

FIGURE 6.7 Formation of a-tocopherol ethano-dimer (12) as the result of a hypothetical radical recombination of two radicals 10. 

FIGURE 6.8 Hypothetical disproportionation of two a-tocopherol-derived radicals 2 and 10 in the absence of other coreactants to account for the formation of typical two-electron oxidation products (o-QM 3, a-tocopherol spiro dimer 9). 

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 last reaction commonly evoked to support the involvement of radical species 10 in tocopherol chemistry is the disproportionation of two molecules into the phenol a-tocopherol and the ort/zo-quinone methide 3 (Fig. 6.8), the latter immediately dimerizing into spiro dimer 9. This dimerization is actually a hetero-Diels-Alder process with inverse electron demand. It is largely favored, which is also reflected by the fact that spiro dimer 9 is an almost ubiquitous product and byproduct in vitamin E chemistry.28,29 The disproportionation mechanism was proposed to account for the fact that in reactions of tocopheroxyl radical 2 generated without chemical coreactants, that is, by irradiation, the spiro dimer 9 was the only major product found. 

FIGURE 6.11 Confirmed pathway for the observed disproportionation of tocopheroxyl radical 2 into a-tocopherol (1) and o-QM 3, the latter immediately dimerizing into a-tocopherol spiro dimer (9). 5a-C-centered radicals 10 are not involved in this process. 

The first indication27 3 that a verification of its occurrence might be indeed possible was provided with the observation that oxidation of a-tocopherol by excess Ag20 at —78 °C caused immediate formation of the spiro dimer via the o-QM 3 within less than... 

FIGURE 6.17 Oxidation of a-tocopherol (1) conventionally leads to its spiro dimer (9) via ortho-quinone methide 3 (path A). The zwitterionic o-QM precursor 3a is stabilized by NMMO in complex 17, which upon rapid heating produces small amounts of new dioxocine dimer 18 (path B). Acid treatment of 18 causes quantitative conversion into spiro dimer 9, via o-QM 3 (path C). 

It was shown that complexes 19 of the zwitterionic precursors of ortho-quinone methides and a bis(sulfonium ylide) derived from 2,5-di hydroxyl 1,4 benzoquinone46 were even more stable than those with amine N-oxides. The bis(sulfonium ylide) complexes were formed in a strict 2 1 ratio (o-QM/ylide) and were unaltered at —78 °C for 10 h and stable at room temperature under inert conditions for as long as 15—30 min (Fig. 6.18).47 The o-QM precursor was produced from a-tocopherol (1), its truncated model compound (la), or a respective ortho-methylphenol in general by Ag20 oxidation in a solution containing 0.50-0.55 equivalents of bis(sulfonium ylide) at —78 °C. Although the species interacting with the ylide was actually the zwitterionic oxidation intermediate 3a and not the o-QM itself, the term stabilized o-QM was introduced for the complexes, since these reacted similar to the o-QMs themselves but in a well defined way without dimerization reactions. 

The oxidation of a-tocopherol (1) to dimers29,50 and trimers15,51 has been reported already in the early days of vitamin E chemistry, including standard procedures for near-quantitative preparation of these compounds. The formation generally proceeds via orf/zo-quinone methide 3 as the key intermediate. The dimerization of 3 into spiro dimer 9 is one of the most frequently occurring reactions in tocopherol chemistry, being almost ubiquitous as side reaction as soon as the o-QM 3 occurs as reaction intermediate. Early accounts proposed numerous incorrect structures,52 which found entry into review articles and thus survived in the literature until today.22 Also several different proposals as to the formation mechanisms of these compounds existed. Only recently, a consistent model of their formation pathways and interconversions as well as a complete NMR assignment of the different diastereomers was achieved.28... 

The spiro dimer of a-tocopherol (9, see also Fig. 6.4) is formed as mixture of two diastereomers by dimerization of the o-QM 3 in a hetero-Diels-Alder reaction with inverse electron demand. Both isomers are linked by a fluxion process (Fig. 6.22), which was proven by NMR spectroscopy.53 The detailed mechanism of the interconversion, which is catalyzed by acids, was proposed to be either stepwise or concerted.53-55... 

Formation of the ethano-dimer of a-tocopherol (12) by reduction of spiro dimer (9) proceeds readily almost independently of the reductant used. This reduction step can also be performed by tocopheroxyl radicals as occurring upon treatment of tocopherol with high concentrations of radical initiators (see Fig. 6.10). The ready reduction can be explained by the energy gain upon rearomatization of the cyclohexadienone system. Since the reverse process, oxidation from 12 to 9 by various oxidants, proceeds also quantitatively, spiro dimer 9 and ethano-dimer 12 can be regarded as a reversible redox system (Fig. 6.22). 

The methano-dimer of a-tocopherol (28)50 was formed by the reaction of o-QM 3 as an alkylating agent toward excess y-tocopherol. It is also the reduction product of the furano-spiro dimer 29, which by analogy to spiro dimer 9 occurred as two interconvertible diastereomers,28 see Fig. 6.23. However, the interconversion rate was found to be slower than in the case of spiro dimer 9. While the reduction of furano-spiro dimer 29 to methano-dimer 28 proceeded largely quantitatively and independently of the reductant, the products of the reverse reaction, oxidation of 28 to 29, depended on oxidant and reaction conditions, so that those two compounds do not constitute a reversible redox pair in contrast to 9 and 12. 

FIGURE 6.22 Spiro dimer of a-tocopherol (9) formation, redox reactions, and fluxional nature. 

FIGURE 6.23 Methano-dimer of a-tocopherol (28) formation and redox reactions, including oxidation to the two fluxationally interconvertible diastereomers of furano-spiro dimer 29. 

FIGURE 6.24 Redox behavior of the methano-dimer of a-tocopherol (bis(5-tocopheryl) methane, 28) temperature dependence of the oxidation with bromine. 

Treatment of methano-dimer 28 with elemental bromine revealed a remarkable reactivity at low temperatures it proceeded quantitatively to the furano-spiro dimer 29, by analogy with the ethano-dimer 12 giving spiro dimer 9 upon oxidation. With increasing temperatures, the reaction mechanism changed, however, now affording a mixture of 5-bromo-y-tocopherol (30) and spiro dimer 9 (Fig. 6.24). Thus, the methano-dimer 28 fragmented into an a-tocopherol part, in the form of o-QM 3 that dimerized into 9, and a /-tocopherol part, which was present as the 5-bromo derivative 30 after the reaction. Thus, the overall reaction can be regarded as oxidative dealkylation. 

FIGURE 6.25 Spiro trimers of a-tocopherol (31, 32) formed by reaction of o-QM 3 with the two diastereomers of spiro dimer 9. 

A particularly interesting case was the oxidative spiro dimerization of a,CO-bis (tocopheryl)alkanes (36), which basically present two a-tocopherol units linked at C-5a by an alkyl bridge.59 The reaction of other a,0)-bis(hydroxyphenyl)-alkanes, such as 37—40, proceeded similarly (Fig. 6.30). 

The spiro polymerization is a novel reaction type that uses the spiro dimerization of o-QMs to build up linear oligomers and polymers. The basic properties of the spiro dimer of a-tocopherol, that is, its fluxional structure and its ready reduction to the ethano-dimer, remain also active when such structural units are bound in the polymer. The products of the reaction, both in its poly(spiro dimeric) form (41) and in the form of the reduced polytocopherols (42), are interesting materials for application as high-capacity antioxidants, polyradical precursors, or organic metals, to name but a few. 

Treatment of a-tocopherol (1) with elemental bromine provided quantitative yields of 5a-bromo-a-tocopherol (46). The reaction was assumed to proceed according to a radical mechanism, but later a nonradical oxidation-addition mechanism was proven (Fig. 6.33). Bromine oxidized a-tocopherol (1) to the intermediate ortho-qainone methide (3), which in turn added the HBr produced in the oxidation step.60 If the HBr was removed by flushing with nitrogen, the spiro dimer (9) became the main product, and if it was purged by HC1 gas, mainly 5a-chloro-a-tocopherol was produced. 

Patel A. Mazzini F. Netscher T. Rosenau T. On a novel dimer of a-tocopherol. Research letters in Organic Chemistry 2008, article ID 742590, doi 10.1155/2008/742590. 

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