Thiyl radical reactions with

Nauser T, Felling J, Schoneich C. (2004) Thiyl radical reaction with amino acid side chains Rate constants for hydrogen transfer and relevance for posttransla-tional protein modification. Chem Res Toxicol 17 1323-1328. 

The investigation into thiyl-catalyzed isomerization of olefins eventually resulted in the measurement of relative rate coefficients for several CH3S + olefin reactions. These early relative rate studies relied on the interpretation of complex chemical systems to arrive at rate coefficients for the elementary reactions involving CH3S attack on the olefin double bond. More recently, the characterization of the CH3S laser induced fluorescence (LIF) spectrum [90,91] has led to direct measurements of rate coefficients for methyl thiyl radical reactions with unsaturated hydrocarbons. Reported relative rate coefficients are tabulated along with the recent direct measurements of Balia et al. [92] (see Table 6). This has been done to allow for observation of any reactivity trends that may be present and to facilitate qualitative discussion of proposed CH3S+olefin reaction mechanisms. 

The self-reactions of thiyl radicals and the reactions of thiyl radicals with other organosulfur radicals and organic radicals proceed predominantly via combination, with disproportionation being of minor importance (see Table 7). Little information is available regarding the kinetics and mechanisms of thiyl radical reactions with organic radicals. The ensuing discussion focuses primarily on thiyl radical self-reactions. The reader is referred to Tables 7 and 8 and the relevant references for information regarding reactions other than thiyl radical selfreactions. 

THIYL RADICAL REACTIONS WITH SULFIDES AND DISULFIDES... 

The reaction of H atoms with bovine pancreatic ribonuclease A (RNAse A) has been studied by steady-state /-radiolysis of lipid vesicle suspensions containing RNAse A. The inactivation of RNAse A caused by interaction of H atoms with protein involved selective attack on methionine residues and was connected with release of diffusible thiyl radicals [reaction (36)] ... 

Figure 6. Mechanism of cysteine-fatty acid adduct formation from the reaction of 13-hydroperoxylinoleic acid and cysteine in the absence of O2. The epoxyallylic radical at the top originates from the oxydiene radical of 13-hydroperoxylinoleic acid abbreviated structure) and RS is the cysteine thiyl radical. Reproduced with permission from Ref. 28.)...

The reaction is absolutely dependent on the formation of a thiyl radical (located on Cys-461) on the p face of the ribonucleotide. The model postulates that the enzyme catalyzes the homolysis of the cobalt-carbon bond of AdoCbl to generate, in a concerted fashion, this thiyl radical together with 5 -deoxyadenosine and cob(II)alamin. The radical initiates the reaction by abstraction of Ha the hydrogen atom at the 3 position of the substrate ribose, to give a 3 -radical. The... 

No direct studies of CH3S reactions with HO2 or organic peroxy radicals have been reported. However, because the atmospheric concentrations of peroxy radicals are much smaller than typical concentrations of O3, peroxy radicals will generally be unimportant as CH3S reaction partners. Indirect experimental evidence suggests that the methyl thiyl radical reacts with both HO2 and CH3O2 via O atom transfer [63, 64] (see Table 3). 

Misleading conclusions can be drawn if only the reduction potentials of, for example, the GS, HVGSH and PhO, H /PhOH couples are considered and the law of mass action is ignored. Rate constants for repair of phenoxyl radicals by GSH, producing thiyl radicals, of < 10 dm moP s have been estimated in the cases of 1-naphthol [67] or acetaminophen [68]. The latter phenol was oxidized by thiyl radicals (cysteine) with 5 ca. 7x10 dm moP s at pH 7, an estimate of the reduction potential of the acetaminophen phenoxyl radical, (PhO, H /PhOH) = 0.71 V confirming that reaction (5), as an equilibrium, is well over to the left [69]. In spite of this, thiyl radicals are undoubtedly formed during peroxidase catalysed oxidation of acetaminophen in the presence of thiols [64,70]. Similar results were obtained with 4-ethoxyaniline (p-pheneti-dine) [71]. 

These results suggests that the Bpq group effectively suppresses the reaction of the initially formed thiyl radical 40 with a second molecule of S-nitrosothiol 37 to afford 39, which enabled the slow reaction to afford 38 and 36 to take place. As described in Section 11.4.3, BmtSNO (29) was converted to the synunetrical disulfide 30 upon heating under similar conditions. The framework of the Bpq group is apparently more effective for suppressing the bimolecular decomposition of reactive species than that of the Bmt group. In spite of such high thermal stability, 5-nitrosothiol 37... 

Traditionally thiols or mercaptans are perhaps the most commonly used transfer agents in radical polymerization. They undergo facile reaction with propagating (and other) radicals with transfer of a hydrogen atom and form a saturated chain end and a thiyl radical (Scheme 6.6). Some typical transfer constants are presented in Table 6.2. The values of the transfer constants depend markedly on the particular monomer and can depend on reaction conditions.4"1 44... 

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 results were interpreted on the basis of a mechanism that starts with the photolytic formation of a radical cage consisting of an aryldiazenyl and and arylthiyl (Ar - S ) radical, followed by diffusion of both radicals out of the cage. Three reactions of the aryldiazenyl radical are assumed to occur bimolecular formation of the azoarene and N2, or of biphenyl and N2 (Scheme 8-37), the monomolecular dediazoniation (Scheme 8-38), and recombination with the thiyl radical accompanied by dediazoniation (Scheme 8-39). In addition, two radicals can react to form a di-phenyldisulfide (Scheme 8-40). 

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. 

In an analogous process, the reactions of unsubstituted and 2-substituted allyl phenyl sulfides with (TMSlsSiH give a facile entry to allyl fns(trimethylsilyl) silanes in high yields (Reaction 26). In this case, the addition of (TMSlsSi radical to the double bond is followed by the S-scission with ejection of a thiyl radical, thus affording the transposed double bond. Hydrogen abstraction from (TMSlsSiH by PhS radical completes the cycle of these chain reactions. ... 

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. 

We suggest that the ejected thiyl radical undergoes a fast 1,2-migration of silyl group from silicon to sulfur (Reaction 85), affording a new silyl radical that either reacts with (TMSlsSiH (Reaction 86) which completes the reaction cycle, or replaces the (TMSlsSi radical in the above described reaction sequence. 

The degradation of tetrachloromethane by a strain of Pseudomonas sp. presents a number of exceptional features. Although was a major product from the metabolism of CCI4, a substantial part of the label was retained in nonvolatile water-soluble residues (Lewis and Crawford 1995). The nature of these was revealed by the isolation of adducts with cysteine and A,A -dimethylethylenediamine, when the intermediates that are formally equivalent to COClj and CSClj were trapped—presumably formed by reaction of the substrate with water and a thiol, respectively. Further examination of this strain classified as Pseudomonas stutzeri strain KC has illuminated novel details of the mechanism. The metabolite pyridine-2,6-dithiocarboxylic acid (Lee et al. 1999) plays a key role in the degradation. Its copper complex produces trichloromethyl and thiyl radicals, and thence the formation of CO2, CS2, and COS (Figure 7.64) (Lewis et al. 2001). 

The reaction of P-CAR with thiyl (RS ) and thiyl sulfonyl (RS()2 ) radicals have both been reported using pulse radiolysis (Everett et al. 1995, 1996). It was found that radical addition to P-CAR occurred and that p-CAR scavenges the thiyl radical, including that derived from glutathione, only via this mechanism, whereas it reacts with thiyl sulfonyl radicals by electron transfer as well. 

The radicals (14) formed may be trapped with, for example, (10) above. Simple alkyl thiyl radicals such as MeS have been detected as reaction intermediates they are highly reactive. Relatively stable oxygen-containing radicals are also known. Thus the phenoxy radical (15),... 

The half-order of the rate with respect to [02] and the two-term rate law were taken as evidence for a chain mechanism which involves one-electron transfer steps and proceeds via two different reaction paths. The formation of the dimer f(RS)2Cu(p-O2)Cu(RS)2] complex in the initiation phase is the core of the model, as asymmetric dissociation of this species produces two chain carriers. Earlier literature results were contested by rejecting the feasibility of a free-radical mechanism which would imply a redox shuttle between Cu(II) and Cu(I). It was assumed that the substrate remains bonded to the metal center throughout the whole process and the free thiyl radical, RS, does not form during the reaction. It was argued that if free RS radicals formed they would certainly be involved in an almost diffusion-controlled reaction with dioxygen, and the intermediate peroxo species would open alternative reaction paths to generate products other than cystine. This would clearly contradict the noted high selectivity of the autoxidation reaction. 

The product cystine is presumably formed in the recombination of two thiyl radicals. This free-radical model is suitable for formal treatment of the kinetic data however, it does not account for all possible reactions of the RS radical (68). The rate constants for the reactions of this species with RS-, 02 and Cu L, (n = 2, 3) are comparable, and on the order of 109-10loM-1s-1 (70-72). Because all of these reaction partners are present in relatively high and competitive concentrations, the recombination of the thiyl radical must be a relatively minor reaction compared to the other reaction paths even though it has a diffusion controlled rate constant. It follows that the RS radical is most likely involved in a series of side reactions producing various intermediates. In order to comply with the noted chemoselectivity, at some point these transient species should produce a common intermediate leading to the formation of cystine. 

Other postulated routes (Jourd heuil et al., 2003) to RSNO formation include the reaction between NO and 02 to yield N02 via a second-order reaction. NO and thiolate anion, RS, react giving rise to thiyl radical, (RS ) [e]. RS then reacts with NO to yield RSNO [f]. The reaction between RS and RS- can also be the source of non-enzymatic generation of superoxide anion (02 ) [g], [h]. 02 reacts with NO to produce peroxynitrite (ONOO ) [i] (Szabo, 2003). Thiols react with ONOOH to form RSNOs [k] (van der Vliet et al.,1998). 

The implication of these observations was that these reactions take place in isolation within an oxyHb-SOD encounter complex channeling the released NO directly to the P C93-thiyl radical. In this manner, NO will not be consumed by reacting with oxyHb and producing N03- (Eq. (2)). 

The attack by the thiolate anion on the N-oxide oxygen of 62 produces the intermediate sulfenic acid derivative 65, which, in the presence of thiols, further reacts with the thiolate anion, to give the oxime 66, which has been isolated among the reaction products. By contrast, spontaneous loss of the halide anion from 65 affords the ni-troso intermediate 67 that, by losing NO and the thiyl radical directly, or through 68, produces the a-nitrosoolefm 69. By a Michael type reaction with water this last product immediately yields the final oxime 70, which has been isolated among the reaction products. 

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