Thiols and Thiyl Radicals

Volume 251. Biothiols (Part A Monothiols and Dithiols, Protein Thiols, and Thiyl Radicals)... 

Since thiols and thiyl radicals are known to readily undergo addition reactions at unsaturated carbon centers (199, 202, 204), a possible mechanism for this inactivation reaction is shown in Scheme 43. Addition of the active site nucleophilic or radical species followed by protonation or electron transfer, respectively, would yield the thioacrylate derivative and inactive enzyme. Of course, addition to C-2 of propargylic acid is also possible, forming a 2-substituted acrylate derivative instead. 

MODEL STUDIES Early in this study it appeared that [2.2.1]bicyclic olefin resins added conventional crosslinking thiols in a rapid, exothermic, manner. These results appear to contradict earlier reports that internal olefins and cyclic olefins such as cyclohexene and cydopentene react only slowly with thiols. In reality, [2.2.1]bicydic olefins represent a separate dass of reactive olefins. These results are also consistent with reports (16-19) that bicyclic olefins such as norbomadiene are quite reactive to the addition of monofunctional thiols and thiyl radicals. In order to quantify the relative reactivity of norbornene resins with other "standard" ene components, a model study of the addition reaction was undertaken. A "typical" thiol (ethyl mercaptoacetate) was examined in a series of competitive reactions in which there was a defidency of olefin (Figure 4). Olefin substrates that were compared were norbornene, styrene, butyl vinyl ether, [2.2.2]bicydooctene and phenyl allyl ether. The results of that study are listed below in Table I. 

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). 

This reaction is based on a stoichiometric reaction of multifunctional olefins (enes) with thiols. The addition reaction can be initiated thermally, pho-tochemically, and by electron beam and radical or ionic mechanism. Thiyl radicals can be generated by the reaction of an excited carbonyl compound (usually in its triplet state) with a thiol or via radicals, such as benzoyl radicals from a type I photoinitiator, reacting with the thiol. The thiyl radicals add to olefins, and this is the basis of the polymerization process. The addition of a dithiol to a diolefin yields linear polymer, higher-functionality thiols and alkenes form cross-linked systems. 

Hermann R, Dey GR, Naumov S, Brede O. (2000) Thiol radical cations and thiyl radicals as direct products of the free electron transfer from aromatic thiols to -butyl chloride radical cations. Phys Chem Chem Phys 2 1213-1220. 

For thiols, the expected other product, H atoms, is produced, and in the gas phase they are hot as initially formed (2, 3, 4). Simple thiols give H2 with a quantum yield of near unity (2, 5). The photolysis of sulfides and disulfides in the liquid phase has been studied also, and thiyl radicals are primary products in these reactions as well (6). A detailed study of the photodiemistry of liquid thiols is underway in these laboratories (7), and preliminary results indicate that thiyl radicals and hydrogen atoms are the main products of photolysis. 

Ramsbottom, Pintar and Forbes have studied the radical recombination in irradiated polycrystalline cysteine HCl monohydrate at temperatures 340-390 K. Above 333 K a second phase, glassy in nature, was found to form and it was presumed that this was caused by free water molecules around lattice imperfections because irradiated samples had a greater percentage of this new phase. This phase which was absent in anhydrous samples would contain no radicals, and the observed decay was of radicals in the crystalline phase. The decay exhibited second-order kinetics over 4-5 half-lives and an activation energy of 50kJmol" (12 kcalmol" ). They concluded that the decay mechanism involved dimerization of thiyl radicals and that H atom transfer between the thiol group and thiyl radicals could occur above 378 K. The half-life at 375 K was approximately 200 min, and these results would seem to throw doubt on Omerod s observation that radicals decayed at 200 K. 

The second special case is the case of thiyl radicals interacting with another RSH molecule. A predominant type of interaction in this case is believed not to be hydrogen but three-electron S-S bonding [31, 39]. This situation typically occurs in solutions of thiols in hydrocarbons with a low glass transition temperature (Tg) like 3-methylpentane (3-MP) [6, 9, 27]. Non-polar media and low values of Tg assist aggregation of the thiol and as a result the thiyl radical is produced in thiol environment. Thiyl radicals complexed with another RSH molecule typically display almost axial g anisotropy with the gy much smaller that for thiyl radicals in single crystals [6, 9, 27]. The ESR characteristics of some species identified as the RSS(H)R or RSSR2 adducts are presented in Table 2. 

The most important source of RSO radicals in the condensed phase is the reaction of thiyl peroxyl radicals RSOO vide infra) with thiols RSH [4-6]. Thiol peroxyl radicals needed for this reaction are easily produced from molecular oxygen and thiyl radicals which are common intermediates in free radical processes involving thiols [5-13]. All known examples of this reaction include aliphatic derivatives. The reaction proceeds easily even in low temperature glasses [5, 6, 12] and appears to be controlled by diffusion of the reactants into each other. For this reason the RSO radical was once taken for an RSOO species in early low temperature studies of y-radiolysis of cysteamine in frozen oxygenated solution [14]. Thus the activation energy for RSO formation from RSOO appears to be small. Despite this, the reaction is slow with respect to diffusion at room temperature in aqueous solution where its rate constant has been reported to be 2 x 10 M" s [4]. 

The interaction of thiols (including cysteine and GSH) with metals, especially Fe (II), enhances the reduction ability of thiols considerably superoxide and thiyl radicals can be formed, as well as hydroxyl radicals [88]. Xenobiotic thiols such the antihypertensive agent, captopril (l-(3-mercapto-2-methyl-l-oxo-propyl)-L-proline) can also similarly form thiyl radicals [89]. 

The reaction of arenethiols with a stable prototype nitroxide (2,2,6,6-tetram-ethylpiperidine-l-oxyl, TEMPO) has been the subject of a detailed study [31]. The spontaneous reaction of nitroxide with thiols leads to the formation of 2,2,6,6-tetramethyIpiperidine as well as the corresponding piperidinium arylsul-finates and arylsulfonates in 70-80% yields (Scheme 4). Four other minor products containing sulfur were identified and allowed for a rationalization of the reaction mechanism. The key steps are discussed in terms of nitroxide and thiyl radical combination to form an intermediate which decomposes homolytically to piperidinyl and sulfinyl radicals followed by known chemistry. The PhSH/RjNO ... 

As illustrated in Scheme 6, there are two general methods which imply thiyl radicals in multistep radical reactions. In the first approach (thiol as a coreactant) the thiyl radicals add to the substrate to form an initial radical which undergoes a radical cyclization to give the final radical. Hydrogen abstraction from the thiol gives the desired product and thiyl radical, thus completing the cycle of this chain reaction. In the second approach (thiyl radical as a catalyst) the initial thiyl radical adduct proceeds through a multistep reaction and the final radical terminates via ejection of the thiyl radical. The prototype of this approach is the Z)-(E) interconversion of olefins mentioned above. 

The addition of aromatic and aUphatic thiols, RSH and ArSH, and a thioacetic acid to isoprene yields mainly the trans-l,4-adduct (56). The aromatic thiyl radicals, ArS , add almost entirely to the first carbon atom however, aUphatic thiyl radicals, RS, also add to the fourth C atom in significant amounts. 

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). 

Thiol-ene polymerization was first reported in 1938.220 In this process, a polymer chain is built up by a sequence of thiyl radical addition and chain transfer steps (Scheme 7.17). The thiol-ene process is unique amongst radical polymerizations in that, while it is a radical chain process, the rate of molecular weight increase is more typical of a step-growth polymerization. Polymers ideally consist of alternating residues derived from the diene and the dithiol. However, when dienes with high kp and relatively low A-, monomers (e.g. acrylates) are used, short sequences of units derived from the diene are sometimes formed. 

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. 

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 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. 

The reaction of thiyl radicals with silicon hydrides (Reaction 3.18) is the key step of the so called polarity-reversal catalysis in the radical-chain reduction of alkyl halides as well as in the hydrosilylation of olefins using silane-thiol couple (see Sections 4.5 and 5.1) [33]. The reaction is strongly endothermic and reversible (Reaction —3.18). 

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