C-centered radicals

The oxidative dimerization of the anion of methyl phenyl sulfone (from a Grignard reagent) in ethereal solution in the presence of cupric chloride in 5% yield has been reported47. Despite the reported48 poor stability of the a-sulfonyl C-centered radicals, Julia and coworkers49 provoked the dimerization (in 13 to 56% yields) of the lithiated carbanion of alkyl phenyl sulfones using cupric salts as oxidants. The best results are obtained with cupric triflates in THF-isobutyronitrile medium (56% yield for R = H). For allyl phenyl sulfones the coupling in the 3-3 mode is predominant. 

The C-centered radical is thought initially to rearrange to a S-centered radical via a 1,3-hydrogen shift, followed by a radical translocation from sulfur to the silicon surface on the neighboring row. The abstraction of a H-atom from... 

The reactivity shown in Scheme 3 results from the low bond dissociation energy (BDE) of the P-H bond [11] k=l.2 10 M s for the H-transfer from R02P(0)H to a primary C-centered radical) and the fast halogen-atom transfer from a C-halogen bond to a phosphonyl radical [9,12] (fc=4 10 M s for f-Bu-Br and k=83 10 M s for Cl3C-Br). Piettre et al. [13] pointed out that these chain reactions were even more efficient when dialkylthiophosphites and the corresponding dialkylphosphinothioyl radicals were involved. 

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. 

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 second observation cited as evidence for aradical mechanism involving radical 5 is the frequent occurrence of ethano-dimer 12, proposed to proceed by recombination of two 5a-C-centered radicals 10 (Fig. 6.7).21 25 26... 

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). 

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. 

FIGURE 6.10 Confirmed formation pathway of ethano-dimer 12 by reduction of spiro dimer 9 in different reaction systems. 5a-C-centered radicals 10 are not involved in this process. 

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). 

The questions whether 5a-C-centered radicals exist in oxidation chemistry of a-tocopherol and whether mechanisms proposed in early days of vitamin E research are correct might appear academic at a first glance, but as soon as one recalls the immense medical, physiological, and economic importance of a-tocopherol and its... 

The addition of C-centered radicals to the C=N bond giving rise to radicals B (Scheme 3.98) can be used for organization of radical C-alkylation of primary nitro compounds containing the sulfo group at the a-position (315). 

Scheme 35 Barton carbonate PTOC-OMe, a radical chain transfer reagent able to convert a C-centered radical into an O-centered radical (Eq. 35.1) and a radical initiator (Eq. 35.2)...

Any substituent on a trivalent C-centered radical is stabilizing. This phenomenon is a result of interactions resulting from mixing the SOMO containing the odd... 

It is generally accepted that the endoperoxide moiety of artemisinin 1 and its analogues undergo a reaction with Fe(ll) to yield O- and C-centered radicals (Scheme 1). 

Reid DL, Shustov GV, Armstrong DA, Rauk A, Schuchmann MN, Akhlaq MS, von Sonntag C (2002) Fl-Atom abstraction from thiols by C-centered radicals. An experimental and theoretical study. Phys Chem Chem Phys 4 2965-2974... 

Reid DL, Armstrong DA, Rauk A, Nese C, Schuchmann MN, Westhoff U, von Sonntag C (2003) H-atom abstraction by C-centered radicals from cyclic and acyclic dipeptides. A theoretical and experimental study of reaction rates. Phys Chem Chem Phys 5 3278-3288 Roberts BP (1996) Understanding the rates of hydrogen abstraction reactions empirical, semi-em-pirical and ab initio approaches. J Chem Soc Perkin Trans 2 2719-2725 Russell GA (1973) Reactivity, selectivity, and polar effects in hydrogen atom transfer reactions. In Kochi JK (ed) Free radicals. Wiley, New York, pp 275-331 Russo-Caia C, Steenken S (2002) Photo- and radiation-chemical production of radical cations of methylbenzenes and benzyl alcohols and their reactivity in aqueous solution. Phys Chem Chem Phys 4 1478-1485... 

With GSH carbon-centered besides thiyl radical are formed upon OH attack, notably at pH > 7 (Sjoberg et al. 1982 Eriksen and Fransson 1988). It has been shown subsequently that this is due to an intramolecular H-transfer [reaction (35) Grierson et al. 1992], When the a-NH2 group is no longer protonated as in neutral solution the C-H is only weakly bound and equilibrium (35) is shifted to the side of the C-centered radical. 

Simic MG, Hunter EPL (1986) Reaction mechanisms of peroxyl and C-centered radicals with sulphy-dryls. J Free Rad Biol Med 2 227-230... 

Examples for frequently encountered intermediates in organic reactions are carbocations (carbenium ions, carbonium ions), carbanions, C-centered radicals, carbenes, O-centered radicals (hydroxyl, alkoxyl, peroxyl, superoxide anion radical etc.), nitrenes, N-centered radicals (aminium, iminium), arynes, to name but a few. Generally, with the exception of so-called persistent radicals which are stabilized by special steric or resonance effects, most radicals belong to the class of reactive intermediates. 

Scheme5 Radical recombinations with C-C bond formation, involving the NMMO-derived C-centered radicals 4 and 5...

Under our standard conditions [5], with reflux under N2 (Hg conditions), Hg is the reactive species which attacks the substrate. C-H bond scission produces C-centered radicals and H atoms. The H atoms do not recombine but tend to... 

There are isolated reports of Sh2 reactions involving attack by C-centered radicals. These are typically gas-phase reactions using the photolysis of acetone (sometimes the per-deutero or per-fluoro analog) as a source of Me, which gives CD3 with Hg(CD3)2 examples involving B and Sn have also been reported. 

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