Reactions with Alkyl and Thiyl Radicals

A case in point is the combination of a Thy -OH-adduct with a tyrosine-derived phenoxyl radical [reaction (186) Simic and Dizdaroglu 1985], 

Apparently, the phenoxyl radical reacts also at carbon [reaction (187) the typical site for self-termination Jin et al. 1993,1995]. The resulting product undergoes an H-shift and eliminates water [reactions (188) and (189)]. The first step is certainly very fast and is expected to occur on the sub-ms time scale (cf. Capponi 

These reactions are only trivial as far as their chemistry is concerned (recombination of radicals and subsequent water elimination). This does not mean, however, that these reactions are of little importance in cellular-DNA free-radical chemistry. 

It will be shown below that alkyl radicals add predominantly at the C(6)-positions of the pyrimidines and, when products as shown above are found after OH-attack in very complex systems such as nucleohistones (e.g., Gajewski et al. 1988 Dizdaroglu and Gajewski 1989 Dizdaroglu et al. 1989 Gajewski and Dizd-aroglu 1990) or Thy dimers in polydeoxythymidylic acid (Karam et al. 1986), it cannot be fully excluded that they are formed via the trivial two-radical recombination mechanism. 

One of the first OH-induced purine damage detected was in the 5, 8-cyclonucleotides. This lesion was later also observed in DNA (Chap. 12.5). In the following, the non-trivial case, the reactions of organic radicals with pyrimidines and purines will be discussed, and a special section will devoted to 5, 8-cyclonucleosides and nucleotides whose mechanism of formation has been found to be very complex. 

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The propagation steps of these chain reactions are given in Scheme 12, which represents a plausible mechanistic rationalization of the results. That is, Bu Sn radical, initially generated by photolysis of ditin, reacts with alkyl halide to form an alkyl radical that attacks the allyl sulfide (Sh2 process) to give the desired product and thiyl radical. The displacement reaction from ditin gives the Bu Sn radical, thus completing the cycle of this chain reaction. An intramolecular version of this process (equation (43)) has been introduced by Ueno et ai [89a] and later applied by Boger and Wysocki as a key step in multistep synthesis of some natural products [89b]. 

Thiols react more rapidly with nucleophilic radicals than with electrophilic radicals. They have very large Ctr with S and VAc, but near ideal transfer constants (C - 1.0) with acrylic monomers (Table 6.2). Aromatic thiols have higher C,r than aliphatic thiols but also give more retardation. This is a consequence of the poor reinitiation efficiency shown by the phenylthiyl radical. The substitution pattern of the alkanethiol appears to have only a small (<2-fokl) effect on the transfer constant. Studies on the reactions of small alkyl radicals with thiols indicate that the rate of the transfer reaction is accelerated in polar solvents and, in particular, water.5 Similar trends arc observed for transfer to 1 in S polymerization with Clr = 1.4 in benzene 3.6 in CUT and 6.1 in 5% aqueous CifiCN.1 In copolymerizations, the thiyl radicals react preferentially with electron-rich monomers (Section 3.4.3.2). 

The reaction of thiyl radicals with silicon hydrides (Reaction 8) is the key step of the so-called polariiy-reversal catalysis in the radical chain reduction. The reaction is strongly endothermic and reversible with alkyl-substituted silanes (Reaction 8). For example, the rate constants fcsH arid fcgiH for the couple triethylsilane/ 1-adamantanethiol are 3.2 x 10 and 5.2xlO M s respectively. 

The low reactivity of alkyl and/or phenyl substituted organosilanes in reduction processes can be ameliorated in the presence of a catalytic amount of alkanethiols. The reaction mechanism is reported in Scheme 5 and shows that alkyl radicals abstract hydrogen from thiols and the resulting thiyl radical abstracts hydrogen from the silane. This procedure, which was coined polarity-reversal catalysis, has been applied to dehalogenation, deoxygenation, and desulfurization reactions.For example, 1-bromoadamantane is quantitatively reduced with 2 equiv of triethylsilane in the presence of a catalytic amount of ferf-dodecanethiol. 

RSOO are generated by the hydrogen abstraction from thiols by OH radicals, alcohol radicals, etc., producing thiyl radicals (RS ) which on reaction with oxygen produce RSOO [Eqs. (34) and (35)]. Alternatively, reaction of alkylsulfonyl chloride with e q produces alkyl sulfonyl peroxyl radicals [Eq. (36)]. 

Reactions with other radicals, namely, photochemically generated a-keto radicals and alkyl thiyl radicals exhibit results similar to those of PhS. 

Silverman and Zieske have rationalized how a protein nucleophile other than flavin is involved in MAO inactivation reactions, and why different inactivator compounds specifically react with flavin, protein amino acids, or both (100). Hydrogen atom donation from a cysteine residue to the flavin semiquinone radical would produce a thiyl radical, which could then capture the primary or secondary alkyl radical generated on cyclopropyl ring opening from the amine radical cation of the inactivator. The hydrogen atom abstraction reaction between the flavin and active site amino acid may be an equilibrium process such that either species could be present at any turnover. Hence, a combination of steric constraints and proximity to either the flavin semiquinone radical or the thiol radical will determine the site of adduct formation for a particular inactivator structure. A two-dimensional representation is shown in Scheme 23 (compounds 40-42), which illustrates the proposed equilibrium between the flavin semiquinone radical and amino acid as well as the proposed intermediates for the inactivation of MAO by A-(l-methylcyclopropyl)benzylamine 40 (104), rrradical center relative to the particular protein radical is consistent with proposed site of attachment of inactivator to protein 40 is near the flavin radical, such that exclusive flavin attachment occurs, 41 is positioned closer to the amino... 

The complex photochemistry of cysteine derivatives sensitized by 4-carboxy-benzophenone 15 has been unravelled by CIDNP. The initially formed sulphur-centred (see. Figure 19) radical decarboxylates rapidly to give an a-amino alkyl radical, which in turn cleaves into a thiyl radical R-S and a vinylamine in competition with being oxidized to an imine by surplus sensitizer all these resulting species are unstable themselves and undergo further reactions. The rates of the radical fragmentations and the radical oxidation were obtained from the CIDNP experiments. 

If one of the reactions in a radical chain sequence is too slow to compete effectively with radical-radical reactions, the chain will collapse. Slow reactions of simple silanes such as Et3SiH with alkyl radicals precludes their use in the tin hydride method. Although quite reactive with alkyl radicals, thiols and selenols fail in the tin hydride method because the thiyl and selenyl radicals do not react rapidly with organic halide precursors. Nonetheless, it is possible to use thiols and selenols in tin hydride sequences when a Group 14 hydride is used as a sacrificial reducing agent. The thiyl or selenyl radical reacts with the silane or stannane rapidly, and the silicon- or tin-centered radical thus formed reacts rapidly with the organic halide [8], In practice, benzeneselenol in catalytic amounts has been used in radical clock studies where BusSnH served as the sacrificial reductant [9]. 

Kropp and coworkers have been concerned with systems in which homolysis is followed by rapid electron transfer, such as the photolysis of certain alkyl halides [55]. Photolysis of the norbomyl phenyl sulfoxide 110 was examined. The notion was that sulfide photolysis is usually homolytic, but the sulfinyl radical is more electronegative than the sulfenyl (thiyl) radical, which might assist in electron transfer reactions. Thus, it was thought, ionic reactivity might be observed. In addition to inversion of the sulfur center and deoxygenation (yide infra), norbomane 111 and norbomene 112, both presumed to... 

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