Reactions of Thiols

Although thiols are weak acids, they are far stronger acids than alcohols. The sulfur atom of a thiol is sp -hybridized, and orbital overlap between this orbital and the Is orbital of hydrogen is poor. As a result, the S—H bond is nonpolar, and it is much weaker than the short, polar, O—H bond of alcohols. 

The sulfhydryl group reacts with hydroxide ions to form thiolate ions, which are excellent nucleophiles. 

The oxidation of alcohols occurs at the carbon bound to oxygen atom and gives compounds with a carbon-carbon double bond. The oxidation reactions of thiols are very different. Although sulfur analogs of aldehydes, ketones, and carboxylic acids exist, they are not obtained by the direct oxidation of thiols. 

Thiols are easily oxidized, but oxidation occurs at the sulfur atom rather than the carbon atom. Mild oxidation agents such as bromine and iodine convert thiols into disulfides. In the foUow-ing equation, the symbol [O] represents an unspecified oxidizing agent that removes hydrogen atoms. 

This reaction is of great biochemical importance because many proteins contain the amino acid cysteine. Oxidation of the sulfhydryl group gives a disulfide bond in an amino acid called cystine. 

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Mixed sulfides are prepared in the flavor industry by the reaction of thiols, 2inc oxide, and a bromoalkane (39). Some of these mixed sulfides are constituents of allium, asafetida, coffee, and meat flavors. A representative reaction is represented in equation 24. 

Metal Ion-Promoted Reactions of Thiols. Metal ion-promoted reactions of thiols have been reviewed (53). The bulk of the coverage concerns metal ion promoted aspects of sulfur chemistry. The main topics of interest are the formation of sulfenamides, sulfides, and disulfides using metal-mediated reactions. 

Although the oxidation of thiols with chlorine or bromine in the presence of water gives sulfonyl halides or sulfonic acids, the reaction of thiols with a stoichiometric amount of BTMA Br3 and sodium hydroxide in dichloromethane-water at room temperature gives disulfides in good yields (Fig. 29) (ref. 37). 

Thiol is acting as a co-catalyst in this transformation. In 1997, Alper et al. reported the reaction of thiols, propargyl alcohol, and CO catalyzed by Pd(PPli3)4 (Eq. 7.20)... 

The recent work by Winterbourn and Metodiewa [211] demonstrated that the above values for the rate constant of reaction of DHLA with superoxide might be overestimated. These authors studied the reactions of superoxide with several thiols, glutathione, cysteine, cysteamine, penicillamine, /V-acetylcysteine, dithiothreitol, and captopril and found that thiols reacted with superoxide by a chain mechanism with the regeneration of superoxide. They suggested that the rate constants for the reactions of thiols with superoxide could not be more than 103 ImoN1 s-1. 

These findings may or may not be applied to DHLA. The chain mechanism of reaction of thiols with superoxide suggests that the first step of this reaction is the oxidation of thiols ... 

S-Nucleophiles are very reactive in 1,3-addition reactions with nitrile oxides. A series of a-glucosinolates 27 (R = CR1=NOH R1 =Ph, CH2PI1, CH2CH2PI1, ( )-CH=CHPh, 3-indolylmethyl) was prepared by addition reactions of thiol 27 (R = H) with nitrile oxides (123). The indolyl-substituted glucosinolate was then converted to a-glucobrassicin 28. 

The chemical reactivity of crown-ether complexes with neutral molecules has received little attention. Nakabayashi et al. (1976) have reported crown-ether catalysis in the reaction of thiols with l-chloro-2,4-dinitrobenzene. The catalytic activity was attributed to deprotonation of thiols by dicyclohexyl-18-crown-6 in acetonitrile solution. Blackmer et al. (1978) found that the rate of aquation of the cobalt(III) complex [333] increases on addition of... 

MICHAEL-TYPE REACTIONS OF THIOLS WITH ELECTRON-DEFICIENT C-C AND C=C BONDS... 

Michael-type reactions of thiols with a,p-unsaturated carbonyl compounds R R C=CHCOR ... 

The reduction of disulfides is a reverse reaction of thiol oxidation and, under protic... 

The reaction of thiols with aldehydes and ketones parallels that of alcohols. However, the reactions are more favourable because sulfur is a better nucleophile than oxygen (see Section 6.1.2). Electrons in larger atoms are more easily polarizable and it becomes easier for them to be donated to an electrophile. 

Structures of this type were generated in the reaction of Af-acyloxy-Af-alkoxyamides with thiols. Treatment of Ai-acetoxy-iV-butoxybenzamide (145, R = Bu, = Me) and a series of Ai-benzoyloxy-Ai-benzyloxybenzamides (139) with cysteine derivatives generated disulfides and hydroxamic esters (Section IV.C.3.b, Scheme 24). The intermediate Ai-alkoxy-Ai-thioalkylamides were unstable under the reaction conditions, reacting with a second thiol molecule at sulfur. The reaction of thiols at the anomeric nitrogen of Af-acyloxy-Ai-alkoxyamides has been modelled theoretically and is predicted to be favourable energetically, leading to a stable substitution product ... 

Silver ion also catalyzes nucleophilic reactions of thiol esters, including reactions of acetylhomocysteine thiolactone (12) and diethylethylphosphonothiolate (52). In the first reaction, an insoluble complex of silver ion and the substrate was first produced at pH 7.5, which then reacted with the nucleophile, in this case an amino group of a protein. In the second reaction silver ion complexes of the substrate were also postulated, on the basis that silver ion complexes with sulfur are much more stable than those with oxygen (I). The complexes postulated were 1 1 and 2 1 silver ion-substrate complexes. These complexes were suggested to react with the nucleophiles, water and fluoride ion, giving as products phos-phonic acid and phosphonyl fluoride, respectively, and silver mercaptide. It is evident that the last reaction at least must involve only the direct interaction of a silver ion with the sulfur atom of the thiol ester without chelate formation. Therefore it appears the metal ion-catalyzed reactions of thiol esters are unique, in that they involve complex formation, but not chelate formation in their catalytic mechanism. 

Alkylsulfenyl chlorides.2 Sulfenyl chlorides are usually prepared by reaction of thiols with chlorine or sulfuryl chloride. NCS can also be used. NBS can be used to obtain sulfenyl bromides, but these substances are extremely sensitive to heat. 

Chalcogenolato complexes of mercury can be prepared by a variety of methods. Early preparations involve the reactions of thiols with mercury cyanide,1 the reaction of mercury salts with alkali chalcogenolates, electrochemical methods,2 and the oxidative addition of dichalcogenides to metallic mercury.3 The last method is very convenient for the preparation of complexes with sterically undemanding ligands, but becomes less facile as the... 

Another versatile chemoselective ligation method for the efficient synthesis of TASP[98] molecules is based on the rapid and selective reaction of thiols with activated double bonds, e.g. in a maleimide group (Scheme 17).[106-108] For this purpose, the cyclic decameric template is functionalized with four maleimide residues, which allow reaction with thiol-containing peptide fragments in aqueous solution. 

The reactions of vinyl sulfones with various nucleophiles are usually stereoselective. Substituted vinyl sulfones are less reactive toward nucleophiles than the analogous vinyl ketones or esters 10 and are quite inert toward thiols. Peptide vinyl sulfones do not react with thiols such as glutathione under enzyme assay conditions. The reaction of thiols with aryl vinyl sulfones has been reported, however, it is performed in the presence of base. 11 ... 

The thiylation of conjugated dienes and allenes proceeds as expected. Thus, the acid-catalyzed reaction of thiols with 1,3-dienes affords the 1,4-addition product,552 whereas the nucleophilic addition to allene provides the product arising from sulfur attack at the central carbon (equations 303 and 304).553... 

Cyclization of either of the thiols (24) with acid provided the saturated thia-PGIi analogs (26) as a 2.7 1 mixture of the exo and endo isomers.271 Although many addition reactions of thiols to alkenes are radical reactions catalyzed by light, oxygen, or other radical initiators, conversion to (26) was not effected under photolytic conditions or with AIBN. A radical chain mechanism for selenothiolactonization has also been reported recently.275... 

Thioacetals and -ketals. A1C13 is an effective catalyst for the condensation of aldehydes and ketones with thiols or dithiols. The reaction of thiols with carbonyl groups with an a-proton results in low yields but the reaction with dithiols proceeds in high yield.8... 

The (oxidizing) a-carboxyalkyl radicals do not react readily with thiols (Table 6.4). They are, however, rapidly reduced by thiolate ions [reaction (20)]. The reactions of thiols with DNA radicals play a very important role in the chemical repair of DNA radicals in cells (Chaps 12.10 and 12.11). The reversibility of the H-donation of thiols, that is, H-abstraction by thiyl radicals, is discussed in Chapter 7.4. 

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