Tocopheroxyl radical

Another approach to safer stabilization is to use a biological antioxidant such as vitamin E (a-tocopherol is the active form of vitamin E, AO-9, Table la). It is essentially a hindered phenol which acts as an effective chain breaking donor antioxidant, donating a hydrogen to ROO to yield a very stable tocopheroxyl radical, a-Tocopherol is a very effective melt stabilizer in polyolefins that offers high protection to the polymer at very low concentration [41], (Table 2). 

The main function of vitamin E is as a chain-breaking, free radical trapping antioxidant in cell membranes and plasma lipoproteins. It reacts with the lipid peroxide radicals formed by peroxidation of polyunsaturated fatty acids before they can establish a chain reaction. The tocopheroxyl free radical product is relatively unreactive and ultimately forms nonradical compounds. Commonly, the tocopheroxyl radical is... 

MORTENSEN A, SKIBSTED L H (1997) Relative stability of carotenoid radical cations and homologue tocopheroxyl radicals. A real time kinetic study of antioxidant hierarchy. FFBS Letters, 417, 261-6. 

It has been proposed that the a-tocopheroxyl radical can be recycled back to tocopherol by ascorbate producing the ascorbyl radical (Packer etal., 1979 Scarpa et al., 1984). The location of a-tocopherol, with its phytyl tail in the membrane parallel to the fatty acyl chains of the phospholipids and its phenolic hydroxyl group at the memisrane-water interface near the polar headgroups of the phospholipid bilayer, enables ascorbate to donate hydrogen atoms to the tocopheroxyl radical. The suitability for ascorbate and tocopherol as chain-breaking antioxidants is exemplified (Buettner,... 

The spin density of tocopheroxyl radical 2, a classical phenoxyl radical, is mainly concentrated at oxygen 0-6, which is the major position for coupling with other C-centered radicals, leading to chromanyl ethers 5. These products are found in the typical lipid peroxidation scenarios. Also at ortho- and para-positions of the aromatic ring, the spin density is increased. At these carbon atoms, coupling with other radicals, especially O-centered ones, proceeds. Mainly the para-position (C-8a) is involved (Fig. 6.3), leading to differently 8a-substituted chromanones 6. 

FIGURE 6.4 Reactions and products of the primary oxidation intermediates of a-tocopherol (1), the tocopheroxyl radical 2, ortho-quinone methide 3, and chromanoxylium cation 4. 

In contrast to the a-tocopheroxyl radical (2) and chromanoxylium cation 4 for which the oxidation allows only one structure to form, generation of an o-QM from a-tocopherol could proceed, theoretically, involving either of the two methyl groups C-5a or C-7a. The reason for the large selectivity of o-QM formation, that is, the nearly exclusive involvement of position 5a, will be discussed in more detail in Section 6.3.1. The overall formation of the o-QM from the parent phenol a-tocopherol means a loss of H2, or more detailed, of two electrons and two protons. In which order and as which species those are released, for example, as protons, H-atoms, or hydride ions, will have major implications on o-QM formation and chemistry, which is discussed in Section 6.3.2. 

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... 

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. 

The initiator-derived radical products generate a-tocopheroxyl radicals (2) from a-tocopherol (1). The radicals 2 are further oxidized to ort/io-quinone methide 3 in a formal H-atom abstraction, thereby converting benzoyloxy radicals to benzoic acid and phenyl radicals to benzene. The generated o-QM 3 adds benzoic acid in a [ 1,4] -addition process, whereas it cannot add benzene in such a fashion. This pathway accounts for the observed occurrence of benzoate 11 and simultaneous absence of a 5 a-phenyl derivative and readily explains the observed products without having to involve the hypothetical C-centered radical 10. 

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. 

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). 

Bisby, R.H. and Parker, A.W. 1995. Reaction of ascorbate with the a-tocopheroxyl radical in micellar and bilayer membrane systems. Arch. Biochem. Biophys. 317 170-178. 

However, it has been suggested that in contrast to traditional view about the inactivity of tocopheroxyl radical, a-Toc is capable of participating in chain propagation. This mechanism was discussed in detail [121-124], It has been proposed that at low free radical fluxes and in the absence of ascorbate or ubihydroquinone (both antioxidants are supposedly able to regenerate a-tocopherol) tocopheroxyl radical abstracts a hydrogen atom from the bisallylic position of unsaturated compounds ... 

Low-density lipoprotein oxidation. A detailed EPR study of LDL oxidation by HRP has been reported by Pietraforte and colleagues, who reported the direct observation of the a-tocopheroxyl radical and a protein radical (g = 2.003), assigned tentatively to a tyrosyl radical and also trapped with MNP.295 Another study reported the observation of the probucol phenoxyl radical in LDL undergoing oxidation by lipoxygenase. This finding supports the assertion... 

Similarly, the antioxidant activity of vitamin E is centreed on its chainbreaking donor activity in-vitro rate studies on a-tocopherol have shown that it is one of the most efficient alkylperoxyl radical traps, far better than commercial hindered phenols such as BHT, 2,6-di- ferf.butyl-4-methylphe-nol. Its efficiency was attributed [30, 31] to the highly stabilised structure of tocopheroxyl radical (which is formed during the rate-limiting step, reaction 3) because of favourable overlap between the p-orbitals on the two oxygen atoms. 

Based on the evidence obtained from the amount and nature of transformation products formed, a mechanism of melt stabilising action of tocopherol in PP and PE has been proposed, see Scheme 6 [34]. It is well known that, like other hindered phenols, a-tocopherol is rapidly oxidised by alkylperoxyl radicals to the corresponding tocopheroxyl radical (a-Toe, Scheme 6a). Further oxidation of the tocopheroxyl radical in the polymers leads to the formation of coupled and quinonoid-type products, e.g. SPD, TRI, DHD (see Figs. 8 and 9). Dimerisation of the intermediate o-quinone methide (QM) leads to the formation of the quinonoid-type dimeric coupled product, SPD (Scheme 6 reaction d). 

The interaction of y-tocopherol (6) with radicals generates the relatively stable y-tocopheroxyl radical (7). While the O-centered form of the y-tocopheroxyl radical has a lower affinity towards other radicals and forms relatively labile tocopheryl ether products, its C-centered resonance structure 7a, with the radical being located at C-5, readily recombines with other radicals present in the mixture to give stable compounds. This way, trapping products of all three radicals 3, 4, and 5 were isolated and fully analytically characterized (Scheme 2) [17]. 

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