Thiol-sulfonic acid oxidation

Oxidation of Thiols and Other Sulfur Compounds to Sulfonic Acids Thiol-sulfonic acid oxidation... 

A major difference between alcohols and thiols concerns their oxidation We have seen earlier m this chapter that oxidation of alcohols gives compounds having carbonyl groups Analogous oxidation of thiols to compounds with C=S functions does not occur Only sulfur is oxidized not carbon and compounds containing sulfur m various oxida tion states are possible These include a series of acids classified as sulfemc sulfimc and sulfonic according to the number of oxygens attached to sulfur... 

Of these the most important are the sulfonic acids In general however sulfonic acids are not prepared by oxidation of thiols Arenesulfomc acids (ArS03H) for example are prepared by sulfonation of arenes (Section 12 4)... 

Section 15 13 Thiols are compounds of the type RSH They are more acidic than alco hols and are readily deprotonated by reaction with aqueous base Thiols can be oxidized to sulfemc acids (RSOH) sulfimc acids (RSO2H) and sulfonic acids (RSO3H) The redox relationship between thiols and disul tides IS important m certain biochemical processes... 

General Reaction Chemistry of Sulfonic Acids. Sulfonic acids may be used to produce sulfonic acid esters, which are derived from epoxides, olefins, alkynes, aHenes, and ketenes, as shown in Figure 1 (10). Sulfonic acids may be converted to sulfonamides via reaction with an amine in the presence of phosphoms oxychloride [10025-87-3] POCl (H)- Because sulfonic acids are generally not converted directiy to sulfonamides, the reaction most likely involves a sulfonyl chloride intermediate. Phosphoms pentachlotide [10026-13-8] and phosphoms pentabromide [7789-69-7] can be used to convert sulfonic acids to the corresponding sulfonyl haUdes (12,13). The conversion may also be accompHshed by continuous electrolysis of thiols or disulfides in the presence of aqueous HCl [7647-01-0] (14) or by direct sulfonation with chlorosulfuric acid. Sulfonyl fluorides are typically prepared by direct sulfonation with fluorosulfutic acid [7789-21-17, or by reaction of the sulfonic acid or sulfonate with fluorosulfutic acid. Halogenation of sulfonic acids, which avoids production of a sulfonyl haUde, can be achieved under oxidative halogenation conditions (15). 

Alkyl sulfonic acids are prepared by the oxidation of thiols (36,37). This reaction is not quite as simple as would initially appear, because the reaction does not readily go to completion. The use of strong oxidants can result in the complete oxidation of the thiol to carbon dioxide, water, and sulfur dioxide. 

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). 

Oxidation of alkanethiols to alkanesulfonic acids with excess cone, acid as usually described is potentially hazardous, the exotherm often causing ignition of the thiol. A modified method involving oxidation under nitrogen and at temperatures 1-2 C above the m.p. of the thiol is safer and gives purer products [1]. Technical butanethiol (containing 28% of propane- and 7% of pentane-thiols) is hypergolic with 96% acid [2], Oxidation of several thiols to the sulfonic acids by addition to stirred cone, acid had been effected normally, but when 2 new... 

Oxidize thiol to form sulfonic acid, RSO3H, (HNO3)... 

The l3C chemical shifts of methyl derivatives with sulfur substituents [e.g., SH, -S, -SCH3, -SSCH3, -SSSCHj, -S(0)CH3, -S02CH3, -S(CH3)2+, -SC(0)CH3, -SC(S)CH3, and -SC(S)SCH3] (130,131) and of vicinal and gem-inal bis-sulfides (290) have been reported. Freeman and co-workers have published similar studies on thiols, sulfides, disulfides, and sulfinic and sulfonic acid derivatives (131,132,433) and Tseng and Bowler (434), on thiocarbamates, their S-oxides and S,5-dioxides [R-X-C(0)-NR 2 with X = S, SO, S02]. 

An important drug in the present context is the mineralocorticoid receptor antagonist spironolactone (7.74, Fig. 7.12). Among its many metabolic reactions, spironolactone is readily hydrolyzed at the thioester bond (Fig. 7.12, Reaction a) to form deacetyl-spironolactone (7.75, Fig. 7.12), a metabolite found in a variety of tissues [155 -157]. This thiol compound, which is also a potent mineralocorticoid antagonist, promotes the mechanism-based inactivation of hepatic, adrenal, and testicular cytochrome P450 isozymes. There is now good evidence to indicate that this behavior is the result of microsomal 5-oxidation (see Chapt. 7 in [7]). When spironolactone was incubated with liver microsomes from rats pretreated with dexamethasone (an inducer of CYP3A), the sulfinic and sulfonic acid derivatives were characterized [158]. Perhaps the importance of the 5-deacetylation of spironolactone... 

The development of sulfone linkers, the exploration of sulfone based chemical transformations and cleavage strategies are an important objective in soHd-phase organic synthesis. This kind of Hnker (Tab. 3.7) has been used with thioethers [108], sulfoxides [109], sulfones [110], sulfonic acids and their corresponding derivatives [111]. Because carbon-sulfur bonds can be cleaved under very mild conditions, some Hnkers have been based on this effect. They can be cleaved under reductive conditions ]112, 113], photolytic conditions [114, 115] or with strong bases [116]. Various safety catch Hnkers have been developed based on the fact that thiols can be oxidized to sulfoxides and sulfones [112, 113]. 

Compound 264 is unexpectedly stable against light, but can easily be oxidized to the sulfoxide 265 and the sulfone 266. Sulfoxide 265 can be isolated and a-activated by reaction with acetic anhydride (Scheme 4.46). a-Acetoxylated tetrahydrothio-phene 267 has 0,S-acetal-like reactivity and can be functionalized with various alcohols or thiols under acid catalysis with camphorsulfonic acid (CSA) (268). 

Sulfur compounds with divalent sulfur functionalities are much more prone to dioxirane oxidation on account of their higher nucleophilicity compared to the above-presented oxygen-type nucleophiles. Examples of this type of dioxirane oxidation abound in the literature. Such a case is the oxidation of thiols, which may be quite complex and afford a complex mixture of oxidation products, e.g. sulfinic acids, sulfonic acids, disulfides, thiosulfonates and aldehydes , and is, therefore, hardly useful in synthesis. Nevertheless, the oxidation of some 9i/-purine-6-thiols in the presence of an amine nucleophile produces n >( -nucleoside analogs in useful yields (equation 19). This reaction also displays the general chemoselectivity trend that divalent sulfur functionalities are more reactive than trivalent sp -hybridized nitrogen compounds P. 

Substituents attached to a heterocyclic ring through a sulfur atom exist in wider variety than those through oxygen. Besides the simple thio analogues—the thiols (mercaptans), thioethers, thioesters and the like—they include compounds of various higher oxidation states of sulfur, including sulfoxides, sulfones, sulfinic and sulfonic acids and their derivatives. 

The alkyl sulfonic acid is made by oxidizing the thiol, which in turn comes from the halide. 

Thiols, sulfoxides, sulfones, disulfides,407 and other sulfur compounds can be oxidized to sulfonic acids with many oxidizing agents, though for synthetic purposes the reaction is most important for thiols.408 Among oxidizing agents used are boiling nitric acid and barium... 

For a general review of Ihe oxidation of thiols, see Capozzi Modena, in Patai The Chemistry of the Thiol Group. pt. 2 Wiley New York, 1974, pp. 785-839. For a review specifically on the oxidation to sulfonic acids, sec Gilbert Sulfonation and Related Reactions Wiley New York. 1965, pp. 217-239. 

De Vos et al. have recently published details of supported sulfonic acids prepared by cocondensation of thiol-containing silanes with TEOS[l 1]. The oxidation of these materials was achieved by treatment with hydrogen peroxide, followed by washing with dilute sulphuric... 

Sulfonic acids are prepared on a commercial scale by the sulfonalion of organic substrates using a variety of sulfonating agents, including sulfur trioxidc (diluted in air), sulfur trioxide (in sulfur dioxide), sulfuric acid, oleum (fuming sulfuric acid), chlorosulfuric acid, sulfamic add, trialkylamine-sulfur trioxide complexes, and sulfite ions. Other methods of sulfonic acid production, practiced on an industrial scale, include the oxidation of thiols, sulfide, disulfides, sulfoxides, sulfones, and sulfinic acids. See also Sulfonalion and Sulfation. 

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