Oxidation of Thioethers and Disulfides

Various sulfur-containing compounds, including thioamides, thioureas, thiols, thioethers and disulfides, are oxidized by this enzyme system. However, unlike cytochromes P-450, it cannot catalyze hydroxylation reactions at carbon atoms. It is clear that this enzyme system has an important role in the metabolism of xenobiotics, and examples will appear in the following pages. Just as with the cytochromes P-450 system, there appear to be a number of isoenzymes, which exist in different tissues, which have overlapping substrate specificities. 

The catalytic oxidation of sulfur-containing compounds has been studied mostly on the examples of thioethers and thiols, which are most often encountered in petrochemical industry. Elimination of the foul odor arising from thiols (mercaptans) contained in some oils ("sweetening") is mostly carried out by oxidation of thiols to disulfides. The oxidation of sulfur salts is also of practical importance in the processing of sulfide ores and handling the... 

The equilibrium formulated in reaction (14) will respond sensitively not only to the structure of the disulfide but also to the nature of the substituents R. This will become apparent in some more detail later (see Section 3.1 on the oxidation of thioethers). Because of the involvement of the thiolate, the equilibrium depends on the concentration of RS" and thus to a critical extent also on the pH of the solution. As [RS"j is raised, (RSASR)" species become increasingly stabilized and may attain halflives of up to milliseconds at sufficiently high pH and thiol concentrations. 

Pyrrolethiols, readily obtained from the corresponding thiocyanates by reduction or treatment with alkali, rapidly oxidize to the corresponding disulfides. They are converted into thioethers by reaction with alkyl halides in the presence of base. Both furan- and thiophene-thiols exist predominantly as such rather than in tautomeric thione forms. 

Cysteine sulfhydryls and cystine disulfides may undergo a variety of reactions, including alkylation to form stable thioether derivatives, acylation to form relatively unstable thioesters, and a number of oxidation and reduction processes (Figure 1.10). Derivatization of the side chain sulfhydryl of cysteine is one of the most important reactions of modification and conjugation techniques for proteins. 

Example The oxidative addition of dimethyl disulfide (DMDS) transforms the double bond to its 1,2-bis-thiomethyl derivative (a). Induced by charge localization at either sulfur atom, the molecular ions of DMDS adducts are prone to a-cleavage at the former double bond position (b). This gives rise to sulfonium ions that are readily identified from the mass spectrum (Chap. 6.2.5). The method can be extended to dienes, trienes, and alkynes. [70,71] (For the mass spectral fragmentation of thioethers cf. Chap. 6.12.4). 

In an earlier experiment, Jori et al. (14) reported that methionyl residues are important in maintaining the tertiary structure of lysozyme. The introduction of a polar center into the aliphatic side chain of methionine, as a consequence of the conversion of the thioether function to the sulfoxide, may bring about a structural change of the lysozyme molecule which, in turn, reduces the catalytic efficiency. When ozonized lysozyme was treated with 2-mercaptoethanol in an aqueous solution according to the procedure of Jori e al. (14), the enzyme did not show any increase in its activity. This may be explained in two ways. In one, such reactions are complicated by many side reactions, e.g. sulfhydryl-disulfide interchange, aggregation and precipitation of the modified enzyme (24-26). In the other, the failure to recover the activity of the enzyme may by associated with the extensive oxidation of other residues. 

Phenolic derivatives were prepared and then converted into thioether analogs using ethanedithol followed by oxidation of this intermediate to the disulfide. Phenolic resins were prepared by electrophilic substitution of allyl phenol derivatives with formaldehyde and then flee radically copolymerizing with ethanedithol. Epoxidation was performed using epichlarohydrine. 

Figure 27.18 Common configuration for postcolumn reactors with electrochemical analysis. (A) LC-chemical reaction-EC. Postcolumn addition of a chemical reagent (for example, Cu2+ or an enzyme). (B) LC-enzyme-LC. Electrochemical detection following postcolumn reaction with an immobilized enzyme or other catalyst (for example, dehydrogenase or choline esterase). (C) LC-EC-EC. Electrochemical generation of a derivatizing reagent. The response at the second electrode is proportional to analyte concentration (for example, production of Br2 for detection of thioethers). (D) LC-EC-EC. Electrochemical derivatization of an analyte. In this case a compound of a more favorable redox potential is produced and detected at the second electrode (for example, detection of reduced disulfides by the catalytic oxidation of Hg). (E) LC-hv-EC. Photochemical reaction of an analyte to produce a species that is electrochemically active (for example, detection of nitro compounds and phenylalanine). Various combinations of these five arrangements have also been used. [Reprinted with permission from Bioanalytical Systems, Inc.]...

Since the oxidative polymerization of diphenyl disulfide catalyzed by VO(acac)2 results in selective formation of thioether bonds without any oxygenated compounds such as sulfoxides and/or sulfones, it should be noted that H20 should be produced predominantly by the reduction of 02 catalyzed by the vanadium complex without the formation of partially reduced side products such as H202. 

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