Oxidations of sulfides

Sulfides are easily oxidi2ed by hydrogen peroxide at room temperature to form sulfoxides. Continued oxidation to form sulfones occurs with excess reagent, but usually requires a peroxy acid such as peroxyacetic acid. Sodium periodate (Nal04) oxidi2es sulfides to sulfoxides, but not to sulfones. 

Dimethyl sulfoxide (DMSO) has a high dielectric constant and is an excellent aptotic solvent for nucleophilic substimtion reactions. DMSO readily penetrates the skin, and any compound dissolved in DMSO is carried with it across the skin. Hence, great caution is required when this compound is used as a solvent. 

Write the product of the base-catalyzed reaction of CH3CH2SH and ethyloxirane. Explain why only a catalytic amount of base is required. 

Preparation of sulfoxides can be achieved by use of various oxidants diphenyl,898 dibenzyl,596 bis-(4-acetylaminophenyl),596 and diethyl sulf- 

Benzyl phenyl sulfoxide 600 Benzyl phenyl sulfide (52 g) is dissolved in acetone (250 ml), filtered, and treated with 30 % hydrogen peroxide (40 g), then thoroughly shaken and set aside for 72 h. The acetone is evaporated and the residue is caused to crystallize by moderate cooling and then recrystallized (yield 40 g m.p. 122-123°) from 60% ethanol. 

Dicydopentyl sulfoxide 601 Dicyclopentyl sulfide (3.4 g) is dissolved in glacial acetic acid (30 ml), treated with 100% hydrogen peroxide (2.5 g), and heated on a water-bath for 3 h, then the acetic acid is removed in a vacuum. Recrystallization of the crystalline residue affords the sulfoxide, m.p. 71.5°. 

The more important of the other oxidizing agents reported for the preparation of sulfoxides are peracids602,603 (in equivalent amounts), sodium metaperiodate,604 chromic acid in glacial acetic acid,605 and nitric acid.606 

General directions for oxidation of sulfides to sulfoxides 604 A mixture of a 0.5M-solution (210 ml, 0.105 mole) of sodium metaperiodate in water and of the sulfide (0.1 mole) is stirred at 0° for 12 h. The precipitated sodium iodate is filtered off and the solution is extracted with chloroform. The chloroform is removed in a vacuum and the residual product is purified by distillation, crystallization, or sublimation. Yields of sulfoxide are about 90%. 

Many chemical reagents are reported to selectively oxidize sulfides, but none seems to be suitable for synthesis on a large scale. 

A protocol that sometimes is amenable to scale-up uses as oxidant oxone in aqueous acetone, buffered to pH 7.8-8.0 with sodium bicarbonate [49]. The procedure is mild, cheap and environment-friendly and the oxidation produces sulfoxides or sulfones depending on the equivalents of oxone, temperature and reaction time. When the oxidation is carried out in water only buffered with phosphate to pH 6-7, the reaction is very fast and high conversions of sulfoxides and sulfones are obtained [15]. 

SPB is another cheap and large-scale industrial chemical that in aqueous methanolic sodium hydroxide smoothly oxidizes sulfides into sulfones with excellent yield [50]. 

Oxidation of sulfides with commercial 70% aqueous TBHP in water only occurs in the heterogeneous phase at 20-70°C and affords sulfoxides selectively with very good yields [51], Some examples are reported in Table 6.6. The reaction works better in water than in dichloroethane (DCE) and the oxidation rate is markedly increased when the reaction is executed in aqueous H2SO4. The higher reactivity of sulfides in aqueous medium can be explained considering that water facilitates 0-0 bond fission, which promotes hydrogen transfer in the transition state of the rate-determining step  

In acid medium, protonated TBHP is the oxidizing agent. 

This asymmetric oxidation of sulfides has been achieved successfully using bio-transformations. However, a detailed discussion of these reactions is beyond the scope of the present book. A number of enatiomerically pure transition metal complexes in combination with terminal oxidants have been used to effect the asymmetric oxidations of sulfides to sulfoxides.  

Kagan and Pitchen ° and Modena and coworkers independently reported the oxidation of sulfides to sulfoxides using modified Sharpless epoxidation catalyst (titanium/diethyl tartrate). By 1987, Kagan had already reported a catalytic variation of the reaction and an improved catalytic system allows for the use of lower (10 mol%) loading of catalyst. For example, sulfide (5.143) undergoes sulfoxidation with good enantioselectivity. An alternative catalyst based on Ti(0 Pr)4 and BINOL is also effective for sulfoxidation, providing up to 96% ee.  

Jacobsen and Katsuki have both reported the use ofmanganese(III) (salen) catalysts for sulfide oxidation. These catalysts can be effective for the enantiose-lective oxidation of several aryhnethylsulfides using iodosylbenzene as the stoichiometric oxidant. Additionally, titanium(salen) complexes function as efficient catalysts in this procedure, providing up to 94% ee in the oxidation of methyl phenyl sulfide using the more economical urea hydrogen peroxide as oxidant.  

Sulfides can usually be selectively oxidised to sulfoxides without (too much) over-oxidation to the corresponding sulfones. However, the conversion of sulfoxides into sulfones can be achieved under relatively mild catalytic conditions, if required. Uemura has demonstrated a kinetic resolution of sulfoxides by catalysed oxidation. For example, the oxidation of racemic phenyhnethylsulfoxide (5.152) 

10 mol% (RyBINOL 5mol%ri(0 Prli 1 equiv. BuOOH 1 equiv. H2O 6 h, 25 C. CCI4 

Sulfoxides are easily obtained by oxidation of sulfides. They can be further oxidized to sulfones. Many reagents have been used, and the possibility to synthesize selectively sulfoxides and sulfones, often in the presence of other sensitive functionalities, is an important feature for synthetic applications. The reaction is well documented [75], and only a few notable aspects are mentioned here. 

With peroxides and peroxycarboxylic acids the oxidation of sulfides to sulfoxides proceeds much more rapidly than that of sulfoxides to sulfones. The oxidation occurs by electrophilic attack of the peroxide on sulfur and, as the nucleophilicity of the sulfur atom is reduced in the sulfoxide compared to that of the sulfide, the sulfoxides are normally easily isolable (generally 1 mol of oxidant is used). Over-oxidation of sulfoxides can also be avoided with specific reagents sodium metaperiodate has been usually used. Sulfoxides are also obtained exclusively by oxidation of sulfides with the couple Mn02/Me3SiCl in methanol [76]. 

With oxidative reagents of a nucleophilic nature such as sodium and potassium permanganate, sulfoxides react faster than sulfides and a chemoselective oxidation of a sulfoxide in preference to that of a sulfide is available [77-79]. 

The following experimental procedures illustrate the use of these reagents for the synthesis of the monosulfoxide (2) and monosulfone (3) derived from the useful 1,3-dithiane (1) of Corey and Seebach (they can and have been used in a similar fashion). 

Oxidised sulfides, such as sulfones and sulfoxides, are important intermediates in chemical reactions for biological molecules and are used in metal separations. Syntheses of these compounds are typically achieved using stoichiometric oxidants, such as peracids and dioxiranes however, these chemicals are not atom efficient. Thus, the use of environmentally benign oxidants such as hydrogen peroxide is being explored for sulfide 

Sulfoxides can be considered as oxidized sulfides and are interesting molecules in organic chemistry. The sulfur atom in sulfoxides presents a lone pair of electrons, 

Non-asymmetric Oxidations Suarez and coworkers described the oxidation of sulfides using FeBr3 or (FeBr3)2(DMSO)3 (10mol%) and nitric acid as oxidant (Table 3.6) [157]. Both iron catalysts are able to provide sulfoxides in good yields (65-99%). 

Oxidation of sulfides to sulfoxides and sulfones was achieved in moderate to high yields with good selectivity by using 1 mol% of Fe203 as catalyst with molecular oxygen in the presence of isovaleraldehyde (Table 3.7) [145]. 

Another successful iron-catalyzed reaction is sulfoxidation, consisting of the use of the binary catalyst Fe(N03)3 -9H20-FeBr3.This system was able to catalyze efficiently the oxidation of sulfides at room temperature in MeCN under air (Table 3.8) [159]. 

Asymmetric Oxidations Catalytic asymmetric oxidation of sulfides has attracted great interest in recent decades. The field is dominated by use of titanium, manganese and vanadium complexes, and examples of the use of iron catalysts are less common. The challenging asymmetric oxidation of sulfides with non-heme iron catalysts has been achieved with success in a few cases. 

Dialkyl sulfides, alkyl aryl sulfides, diaryl sulfides, and cyclic sulfides are oxidized to the corresponding sulfoxides or sulfones. Often, both products can be obtained on oxidation with the same oxidant, depending on 

Dibutyl sulfide is converted into dibutyl sulfoxide with one equivalent of peroxytrifluoroacetic add and into dibutyl sulfone with two equivalents of peroxytrifluoroacetic acid [279]. On the other hand, with manganese dioxide, dibutyl sulfide yields dibutyl sulfoxide exclusively 541], and with chromic acid, it yields dibutyl sulfoxide, even when an excess of the oxidant is used and even when the reaction is carried out at 100 °C 541] (equation 552). 

Organic peroxy acids, especially at low temperatures, oxidize sulfides to sulfoxides 163, S24], whereas tetrabutylammonium persulfate 209] at room temperature and hydrogen peroxide at higher temperatures yield sulfones 163, 324], However, hydrogen peroxide in acetic anhydride at room temperature yields sulfoxides 166], Under these conditions, double bonds resist epoxidation 163, 166, 324] (equation 553). 

The oxidation reagents used most frequently for the conversion of sulfides into sulfoxides and sulfones are hydrogen peroxide, peroxy acids, and periodates. Periodates usually do not oxidize sulfoxides to sulfones [770 771, 772, 776, 775], In addition, many other, even rather exotic, oxidants have been used especially for chemoselective oxidations of sulfides containing functional groups vulnerable to attack by peroxy compounds, such as double bonds and carbonyl groups. 

Many examples with references are quoted in equations 554-557 to show various reaction conditions. 

Sulfones are valuable intermediates for the synthesis of chemically and biologically useful molecules. Traditionally, they are prepared by oxidation of sulfides with nitric acid, KMnO, MnO, NaClO, m-chloroperbenzoic acid, sodium metaperiodate, bromine, dinitrogen tetraoxide, oxaziri-dine, benzeneseleninic peracid, tert-butyl hydroperoxide, sulfinyl peroxy compounds, iodosobenzene diacetate and 4-methylmorpholine N-oxide/ osmium tetroxide. 

Costa et al. have prepared a chiral molybdenum alkoxide complex, 67, and used it for the sulfoxidation (reaction 7.8) of sulfide, 68, at low temperature with t-butylhydroperoxide (TBHP) in CHCl [55]. They successfully controlled the production of sulfones, 69, or sulfoxides, 70, by the variation of oxidant mol% and reaction temperature in reaction of methyl phenyl sulfide, 71, but enantioselectivity did not gain by their catalytic system. 

Bearing these considerations in mind, Reddy and Verkade prepared a titanium alkoxide complex, 72, with good stability toward moisture for the selective oxidation of sulfides to sulfones and sulfoxides with hydrogen peroxide in recyclable ionic liquid solvents at room temperature [56]. They optimized reaction conditions and recovering procedure for thioanisole 71, and used their obtained results for oxidation of different aliphatic, aromatic and xmsaturated sulfides. Their results proved the chemoselectivity 

Vanadium(IV) Schiffsbase complexes derived from P-aminoalcohols 7.62 and vanadyl acetylacetonate have been used to oxidize different substrates to chiral sulfoxides. 

The intermediate formed in this oxidation is 2 1 complex of SchifPs base ligand 7.62 and vanadium. This intermediate then reacts with hydrogen peroxide, eliminating one of the ligands to give a vanadium hydroperoxide complex, which then oxidizes the sulfide to sulfoxide. 

Environmentally benign oxidation of sulfides to sulfoxides was reported by Kita and co-workers by using iodine(III) reagents such as iodosobenzene (PhIO) or phenyliodine diacetate (PIDA) with KBr in water. 

However, when recyclable poly(diacetoxyiodo)styrene in water was used for the oxidation of sulfides, the corresponding sulfoxides were obtained in excellent yields without the formation of sulfones .  

12 Oxidation of aiiphatic side chains attached to aromatic ring 

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Section 16 16 Oxidation of sulfides yields sulfoxides then sulfones Sodium metaper lodate IS specific for the oxidation of sulfides to sulfoxides and no fur ther Hydrogen peroxide or peroxy acids can yield sulfoxides (1 mole of oxidant per mole of sulfide) or sulfone (2 moles of oxidant per mole of sulfide)... 

Manufacture. Sodium thiosulfate has been produced commercially by the air oxidation of sulfides, hydrosulfides, and polysulfides. 

Oxidation of sulfides results both in sulfoxides and sulfones, as well as starting material. 

The earliest attempts to obtain optically active sulfoxides by the oxidation of sulfides using oxidants such as chiral peracids did not fare well. The enantiomeric purities obtained were very low. Biological oxidants offered great improvement in a few cases, but not in others. Lately, some very encouraging progress has been made using chiral oxaziridines and peroxometal complexes as oxidants. Newer developments in the use of both chemical oxidants and biological oxidants are described below. 

A number of studies describing the oxidation of sulfides to sulfoxides by biological oxidizing agents have been published over the years2 9,13,107- Microbial systems are often... 

A useful comparison of the 13C shifts for acyclic and cyclic five- and six-membered sulfur compounds has been made86,220, but data on cyclic sulfur compounds of other ring sizes are rather limited. Typically, oxidation of sulfide to a sulfone results in 20-25 ppm... 

Davis and coworkers40 have developed use of diastereomerically pure 2-sulfonyl and 2-sulfamyloxaziridines for asymmetric oxidation of sulfides into sulfoxides (equation 7). The best results (using the sulfamyloxaziridines) range from 38 to 68% enantiomeric purity of the resultant sulfoxides. The structural diversity of such substituted oxaziridines, their... 

Several alkyl aryl sulfides were electrochemically oxidized into the corresponding chiral sulfoxides using poly(amino acid)-coated electrodes448. Although the levels of enan-tioselection were quite variable, the best result involved t-butyl phenyl sulfoxide which was formed in 93% e.e. on a platinum electrode doubly coated with polypyrrole and poly(L-valine). Cyclodextrin-mediated m-chloroperbenzoic acid oxidation of sulfides proceeds with modest enantioselectivity44b. 

Modena and colleagues47 have developed use of some chiral, non-racemic terpene alcohols as directing groups for highly diastereoselective m-chloroperbenzoic oxidation of sulfides into sulfoxides. Specifically the isobornyl vinylic sulfides 8 undergo hydroxyl-directed oxidation to give a 9 1 ratio of diastereomeric sulfoxides (equation 11). 

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

The oxidation of sulfides to sulfoxides are occasionally found to be unsatisfactory, since the resulting sulfoxides are easily oxidized to sulfones. In order to avoid the further oxidation of sulfoxides into sulfones, several oxidizing agents have been selected. Recently, we found that BTMA Bt3 is the most effective and satisfactory oxidizing agent for this purpose. That is, the reaction of sulfides with a calculated amount of BTMA Br3 and aq. sodium hydroxide in dichloromethane at room temperature, or in 1,2-dichloroethane under reflux, gave sulfoxides in good yields (Fig. 28) (ref. 36). 

Encapsulation in Y zeohte was also the method chosen to immobihze Mn complexes of C2-symmetric tetradentate hgands (Fig. 24) [75]. These materials were used as catalysts for the enantioselective oxidation of sulfides to sulfoxides with NaOCl. The lack of activity when the larger io-dosylbenzene was used as an oxidant was interpreted as an indication that the reaction took place inside the zeolite microporous system. Both the chemo- and enantioselectivity were dependent on the structure of the sulfide. (2-Ethylbutyl)phenylsulfide led to better results than methylphenylsulfide, although in all cases the enantioselectivity was low (up to 21% ee). 

The various oxidation states of sulfur have been determined by polarography. The electrochemical oxidation of sulfide ions in aqueous solution may lead to the production of elementary sulfur, polysulfides, sulfate, dithionate, and thiosulfate, depending on the experimental conditions. Disulfides, sulfoxides, and sulfones are typical polarographically active organic compounds. It is also found that thiols (mer-captans), thioureas, and thiobarbiturates facilitate oxidation of Hg resulting thus in anodic waves. 

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