Oxidation of thiols to disulfides

The conversion of thiols into disulfides (oxidative S—S coupling) is an important reaction in synthetic organic chemistry and many stoichiometric and catalytic metal reagents have been reported as oxidants for this transformation. However, there are only few reports on the oxidation of thiols using iron-based systems. 

J oshi and coworkers reported the first catalytic oxidation of thiols using an iron(III) complex (Table 3.4) [153]. Fem-EDTA proved to be an excellent catalyst for the oxidation of a variety of aromatic, aliphatic and heterocyclic thiols under alkaline conditions using molecular oxygen as the primary oxidant. Aromatic thiols were found to be more reactive than aliphatic thiols, for which the reactivity was strongly dependent upon the pH of the medium. 

The oxidative dimerization of thiols was catalyzed by anhydrous FeCl3 and sodium iodide under air at room temperature in acetonitrile (Table 3.5) [154]. The corresponding disulfides were formed in excellent yields (96-99%). 

Remarkably, although oxidation of thiols has been more intensively studied, reports on the selective coupling of dithiols are rare due to facile competitive polymerization reactions [155]. 

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Disulfides. As shown in Figure 4, the and h-chains of insulin are connected by two disulfide bridges and there is an intrachain cycHc disulfide link on the -chain (see Insulin and other antidiabetic drugs). Vasopressin [9034-50-8] and oxytocin [50-56-6] also contain disulfide links (48). Oxidation of thiols to disulfides and reduction of the latter back to thiols are quite common and important in biological systems, eg, cysteine to cystine or reduced Hpoic acid to oxidized Hpoic acid. Many enzymes depend on free SH groups for activation—deactivation reactions. The oxidation—reduction of glutathione (Glu-Cys-Gly) depends on the sulfhydryl group from cysteine. 

Oxidation of sulfides to sulfoxides and oxidation of thiols to disulfides... 

Selenoxides and telluroxides also function as mild oxidants for the conversion of thiols to disulfides as shown in equations (16) and (17) for the reaction of thiophenol with diphenylselenoxide (47) and diphenyltelluroxide (48). Mechanistically, the oxidation of thiols to disulfides with selenoxides and telluroxides is a multi-step process, which takes advantage of the ease with which tellurium(IV) and selenium(IV) species form trigonal bipryamidal... 

Fig. 21 General mechanism for the oxidation of thiols to disulfides with selenoxides or telluroxides.

A reasonable mechanism for the iodine oxidation of 5-Trt cysteine peptides is given in Scheme 6. 45 Reaction of iodine with the divalent sulfur atom leads to the iodosulfonium ion 5 which is then transformed to the sulfenyl iodide 6 and the trityl cation. Sulfenyl iodides are also postulated as intermediates in the iodine oxidation of thiols to disulfides. The disulfide bond is then formed by disproportionation of two sulfenyl iodides or by reaction between the electrophilic sulfur atom of R -S-I and the nucleophilic S-atom of a second R -S-Trt molecule. The proposed mechanism suggests that any sulfur substitution (i.e., thiol protecting group) capable of forming a stabilized species on cleavage, such as the trityl cation, can be oxidatively cleaved by iodine. 

Although the oxidation of thiols to disulfides in the presence of a catalyst is a reaction of commercial interest, it is only comparatively recently that the marked effects of impurities on the system has been realized. Wallace and co-workers (13, 14) have studied the metal-catalyzed oxidation of some thiols in the presence of a few metal ions and complexes under comparable conditions, and they have suggested a general mechanism for the reaction, based on Reactions 1, 4, 5, 6, and 7. The rate of reaction was found to depend on the chemical nature and the physical state of the catalyst. The reaction was suggested to involve metal complexes in the solid state (13). 

In summary, the oxidation of thiols to disulfides is quantitative in aqueous alkaline solution and may best be effected at high oxygen pressures in the presence of a catalyst. The catalyst should dissolve in the alkaline solutions, and of the simple metal salts, the addition of copper, cobalt, and nickel results in the most effective catalysis. 

Oxidations of hydrocarbons (cycloalkanes, cycloalkenes, aromatics) photo-catalyzed by metallotetrapyrroles lead to the formation of epoxides, aldehydes, ketones, alcohols, and carboxylic acids both in solutions and polymer matrices. These processes frequently occur as selective (one-product formation) reactions. Irradiation with visible light has a pronounced accelerating effect on such important industrial processes as the oxidation of thiols to disulfides (Merox process [265]) in a treatment of petroleum distillates or waste water cleaning. 

The role of Coball-dioxygen complexes in autooxidations other than phenol oxidation is less certain, and ostensibly similar reactions appear to follow radically different pathways. Thus, in the oxidation of thiols to disulfide catalyzed by Co11 species catalysis by the phthalocyanine complex [Con(TSPc)]4 apparently proceeds via a Co1 intermediate and without participation of Co—02 species,680 whereas catalysis by [CoH(TPP)] appears to involve initial formation of an >/ cobalt-dioxygen complex from which Of is displaced by thiolate.681 Several reviews giving extensive coverage to oxidations catalyzed by cobalt(II) complexes are available.649,650,682 683... 

Oxidation of Thiols to Disulfides by Molecular Oxygen and Chemical Reagents... 

The oxidation of thiols to disulfides is a very facile process and many reagents function as oxidants. Ease of oxidation usually decreases in the following order ArSH > n-RSH > s-RSH > t-RSH. The use of vigorous conditions such as strong oxidants, excess oxidants, higher temperatures and longer reaction times etc. usually results in further oxidation of initially produced disulfides to give a mixture of several... 

The oxidation of thiols to disulfides by molecular oxygen or air is believed to proceed via two routes as shown in Scheme 3. Thus, the reaction may be enhanced under basic conditions but more stable anions react at a slower rate, while aliphatic thiols are oxidized faster than aromatic ones. 7... 

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