Reactions of Tocopherols

The in vitro oxidation products from tocopherol have been studied in detail although less is known about its in vivo metabolism. The oxidation of a-tocopherol is light-catalysed and accelerated by unsaturated fatty acids, metal salts and alkali. The structure of many of the products from chemical oxidation has been established (ref. 98). It is used in the form of the unnatural acetate in which form it may well be more chemically stable although the manifestation of antioxidancy requires the presence of the free phenol since its radical is stabilised by resonance and by steric effects with the participation of several contributory structures. It has been suggested, as mentioned earlier, that the activity of vitamins E and C are related synergistically and evidence from pulse radiolysis has supported this augmenting interaction on the effect of vitamin E (ref.130), depicted in the equation. 

Enzymic conditions by an NADH system could reform vitamin C. Although the biological activity, presumably its antioxidancy, is said to be preserved in the acetate this is almost lost in its ethers and thus the phenolic group is a vital functional group. 

In recent quantitative work by HPLC related to the oxidation of a-tocopherol (ref. 131) the model compound 6-hydroxy-2,2,5,7,8-pentamethylchroman was found to result in new compounds, during attempts to synthesise the model oxidation analogue of tocored, 2,2,7,8-tetramethylchroman-5,6-dione and of tocopurple, 2,2,7-trimethyl-6-hydroxychroman-5,8-dione, 

Reference has been made to an 8-hydroxymethyl product arising from oxidation studies and from this an 8-formyl compound might well be expected to arise. The 5-formyl compound has been synthesised by the oxidation of a-tocopherol with dioxane dibromide by way of a bromoquinone intermediate (ref. 134). 

The susceptibility of tocopherol towards deterioration suggests that this might be circumvented or overcome by synthetic means to improve on the slight deficiencies of a natural product. Although the whole area of vitamins remains somewhat sacrosanct and molecular tinkering might be frowned on, a 

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Weinbeig, E.D. (1992). Iron depletion - a defense against intracellular infection and neoplasia. LifeSci. 50, 1289-1297. Yamauchi, R, Miyake, N., Kato, K., and Ueno, Y. (1993). Reaction of tocopherol with alkyl and alkylpcroxyl radicals of methyl linoleate. Lipids 8, 201-206. 

Figure 4.3. Reaction of tocopherol with lipid peroxides the tocopheroxyl radical can he reduced to tocopherol or undergo irreversible onward oxidation to tocopherol qninone.

Kapoor S, Mukherjee T, Kagiya TV, Nair CKK. (2002) Redox reactions of tocopherol monoglucoside in aqueous solutions A pulse radiolysis study. JRadiat Res A3 99-106. 

Vitamins that have a role as antioxidants (vitamin E, ascorbic acid and provitamins A) are easily oxidisable substances that react with free radicals or act as singlet oxygen scavengers. The reaction of tocopherols (T-OH) with hydroperoxyl radicals (ROO ) is also a part of the protective mechanisms in biomembranes of living tissues ... 

The mechanism of the antioxidant effect of vitamin E is similar to the effect of other lipophilic antioxidants. Tocopherols react with a number of free radicals including active oxygen species. One tocopherol molecule can react with two hydroperoxyl radicals. Autoxi-dation of lipids is inhibited by reaction of tocopherols (abbreviated as T-OH) with hydroperoxyl lipid radicals (R-O-O ) with the formation of hydroperoxides (R O-OH) and radicals of tocopherols (tocopheroxyl radicals, T O ). This reaction interrupts the radical chain autoxidation reaction of Hpids during the propagation phase ... 

Tocotrienols differ from tocopherols by the presence of three isolated double bonds in the branched alkyl side chain. Oxidation of tocopherol leads to ring opening and the formation of tocoquinones that show an intense red color. This species is a significant contributor to color quaUty problems in oils that have been abused. Tocopherols function as natural antioxidants (qv). An important factor in their activity is their slow reaction rate with oxygen relative to combination with other free radicals (11). 

X5lenol is an important starting material for insecticides, xylenol—formaldehyde resins, disinfectants, wood preservatives, and for synthesis of a-tocopherol (vitamin E) (258) and i7/-a-tocopherol acetate (USP 34-50/kg, October 1994). The Bayer insecticide Methiocarb is manufactured by reaction of 3,5-x5lenol with methylsulfenyl chloride to yield 4-methylmercapto-3,5-xylenol, followed by reaction with methyl isocyanate (257). Disinfectants and preservatives are produced by chlorination to 4-chloro- and 2,4-dich1oro-3,5-dimethylpheno1 (251). 

Although all four tocopherols have been synthesized as their all-rac forms, the commercially significant form of tocopherol is i7//-n7i a-tocopheryl acetate. The commercial processes ia use are based on the work reported by several groups ia 1938 (15—17). These processes utilize a Friedel-Crafts-type condensation of 2,3,5-trimethylhydroquinone with either phytol (16), a phytyl haUde (7,16,17), or phytadiene (7). The principal synthesis (Fig. 3) ia current commercial use iavolves condensation of 2,3,5-trimethylhydroquiQone (13) with synthetic isophytol (14) ia an iaert solvent, such as benzene or hexane, with an acid catalyst, such as ziac chloride, boron trifluoride, or orthoboric acid/oxaUc acid (7,8,18) to give the all-rac-acetate ester (15b) by reaction with acetic anhydride. Purification of tocopheryl acetate is readily accompHshed by high vacuum molecular distillation and rectification (<1 mm Hg) to achieve the required USP standard. 

Demailly and coworkers195 found that the asymmetric induction increased markedly when optically active methyl pyridyl sulfoxide was treated with an aldehyde. They also synthesized (S)-chroman-2-carboxylaldehyde 152, which is the cyclic ring part of a-tocopherol, by aldol-type condensation of the optically active lithium salt of a,/3-unsaturated sulfoxide. Although the diastereomeric ratio of allylic alcohol 151 formed from lithium salt 149 and 150 was not determined, the reaction of 149 with salicylaldehyde gave the diastereomeric alcohol in a ratio of 28 72196. 

The strong Bronstedt acid nature of some hexacoordinated phosphorus derivatives, [7",H ] (Et20)4 in particular, was recently used within the context of an industrial application [36]. The conjugated acid of tris(oxalato)phosphate anion 7 was found to effectively catalyze the ring-forming reaction of trimethyl-hydroquinone 63 with isophytol 64 to give (all rac)-a-tocopherol 65 (ethylene-carbonate/heptane 1 1,100 °C, 90%, Scheme 19). This process is particularly... 

The reaction of eq. 16.9 will regenerate the antioxidant Arj-OH at the expense of the antioxidant At2-OH. Despite the fact that such regeneration reactions are not simple electron transfer reactions, the rate of reactions like that of eq. 16.9 has been correlated with the E values for the respective Ar-0. Thermodynamic and kinetic effects have not been clearly separated for such hierarchies, but for a number of flavonoids the following pecking order was established in dimethyl formamid (DMF) by a combination of electrolysis for generating the a-tocopherol and the flavonoid phenoxyl radicals and electron spin resonance (ESR) spectroscopy for detection of these radicals (Jorgensen et al, 1999) ... 

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). 

Chromanoxylium cation 4 preferably adds nucleophiles in 8a-position producing 8a-substituted tocopherones 6, similar in structure to those obtained by radical recombination between C-8a of chromanoxyl 2 and coreacting radicals (Fig. 6.4). Addition of a hydroxyl ion to 4, for instance, results in a 8a-hydroxy-tocopherone, which in a subsequent step gives the /zara-tocopherylquinone (7), the main (and in most cases, the only) product of two-electron oxidation of tocopherol in aqueous media. A second interesting reaction of chromanoxylium cation 4 is the loss of aproton at C-5a, producing the o-QM 3. This reaction is mostly carried out starting from tocopherones 6 or /zora-tocopherylquinone (7) under acidic catalysis, so that chromanoxylium 4 is produced in the first step, followed by proton elimination from C-5a. In the overall reaction of a tocopherone 6, a [ 1,4] -elimination has occurred. The central species in the oxidation chemistry of a-tocopherol is the o-QM 3, which is discussed in detail subsequently. 

FIGURE 6.6 Hypothetical radical mechanism for the formation of 5a-a-tocopheryl henzoate (11) hy reaction of a-tocopherol (1) with dibenzoyl peroxide. 

Basically, three reactions were evoked to support the occurrence of 5a-C-centered radicals 10 in tocopherol chemistry. The first one is the formation of 5a-substituted derivatives (8) in the reaction of a-tocopherol (1) with radicals and radical initiators. The most prominent example here is the reaction of 1 with dibenzoyl peroxide leading to 5a-a-tocopheryl benzoate (11) in fair yields,12 so that a typical radical recombination mechanism was postulated (Fig. 6.6). Similarly, low yields of 5a-alkoxy-a-tocopherols were obtained by oxidation of a-tocopherol with tert-butyl hydroperoxide or other peroxides in inert solvents containing various alcohols,23 24 although the involvement of 5 a-C-centered radicals in the formation mechanism was not evoked for explanation in these cases. 

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 formation of 5a-a-tocopheryl benzoate (11) upon reaction of a-tocopherol (1) with dibenzoyl peroxide, which has usually been taken as solid proof of the involvement of 5a-C-centered radicals in tocopherol chemistry (see Fig. 6.6), was shown to proceed according to a nonradical, heterolytic mechanism involving o-QM 3 (Fig. 6.9). 

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 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. 

REACTIONS OF THE COMMON TOCOPHEROL-DERIVED OR77/0-QUINONE... 

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