Disulfides Unsymmetrical

Unsymmetrical disulfides. Unsymmetrical disulfides can be prepared in 70-95% yield by the procedure shown in equation I. Only traces of symmetrical disulfides are obtained. 

Preparation of Disulfides. Unsymmetrical alkyl and aryl P3nidyl disulfide-A oxides are prepared by the reaction of 2,2 -dipyridyl disulfide-A,)V-dioxide with various thiols in good yields (eq 2). 7V hydroxypyridine-2-thione is a by-product of this reaction. 

Unsymmetrical Disulfides. Unsymmetrical aryl and alkyl disulfides are prepared from silyl sulfides and MeSS02Me in CHCI3 at 60 °CP Methyl 2- and 4-pyridyl disulfide are prepared conveniently from 2- and 4-thiopyridone and MeSS02Me in the presence of NaOH in H2O in excellent yields. ... 

Various oxidation reagents have been used iodine (148, 149). ammonium persulfate (149). and HIO4 (149). Unsymmetrical disulfides... 

Oxidation. Disulfides are prepared commercially by two types of reactions. The first is an oxidation reaction uti1i2ing the thiol and a suitable oxidant as in equation 18 for 2,2,5,5-tetramethyl-3,4-dithiahexane. The most common oxidants are chlorine, oxygen (29), elemental sulfur, or hydrogen peroxide. Carbon tetrachloride (30) has also been used. This type of reaction is extremely exothermic. Some thiols, notably tertiary thiols and long-chain thiols, are resistant to oxidation, primarily because of steric hindrance or poor solubiUty of the oxidant in the thiol. This type of process is used in the preparation of symmetric disulfides, RSSR. The second type of reaction is the reaction of a sulfenyl haUde with a thiol (eq. 19). This process is used to prepare unsymmetric disulfides, RSSR such as 4,4-dimethyl-2,3-dithiahexane. Other methods may be found in the Hterature (28). 

Three substituted 5-phenyl unsymmetrical disulfides have been prepared, i, ii, and iii —compounds i and ii by reaction of a thiol with a sulfenyl halide, compound iii from a thiol and an aiyl thiosulfonate (ArS02SAr). The disulfides are cleaved by reduction (NaBH4) or by treatment with excess thiol (HSCH2CH2OH). 

A thiol can be protected by oxidation (with O2 H2O2 I2 ) to the corresponding symmetrical disulfide, which subsequently can be cleaved by reduction [Sn/HCl Na/xylene, Et20, or NH3 LiAlH4 NaBH4 or thiols such as H0(CH2)2SH]. Unsymmetrical disulfides have also been prepared and are discussed. 

A 1 1 mixture of thiols (7 and 2), on treatment with oxygen in the presence of a catalytic amount of Et3N, gives one unsymmetrical (4) and two symmetrical disulfides (3 and 5) (Eq. 4). As a measure of the degree of the recognition between 7 and 2 in the oxidation, the selectivity (r) is employed which is represented by the logarithmic ratio of the yield of 4 to twice that of 3 (Eq. 5). The r is so defined as to become zero when oxidation yields the three disulfides in a 1 2 1 ratio. In the present case, the recognition process is followed by covalent bond formation. 

A similar approach has been used to prepare dithiocarbamates, xanlhates and unsymmetrical trithiocarbonates.478 Thus, unsymmetrical primary and secondary trithiocarbonates arc readily prepared in a one pot reaction by treating a thiol with carbon disulfide in the presence of triethylamine to form a carbotrilhioale salt and then adding the appropriate alkylating agent.457 47 The process is shown in Scheme 9.40 for 231.46j... 

When thionyl chloride is used, diaryl sulfoxides are usually the main products. Unsymmetrical diaryl sulfides can be obtained by treatment of an aromatic compound with an aryl sulfenyl chloride (ArSCl) in the presence of a trace amount of iron powder.Aromatic amines and phenols can be alkylthiolated (giving mostly ortho product) by treatment with an alkyl disulfide and a Lewis acid catalyst. With certain substrates (primary amines with a chloro group, or a group not replaceable by chloro, in the para position), treatment with S2CI2 and NaOH gives thiophenolate salts ... 

Unsymmetrical disulfides can be prepared by treatment of a thiol RSH with diethyl azodicarboxylate (EtOOCN=NCOOEt) to give an adduct, to which another thiol R SH is then added, producing the disulfide RSSR. ... 

FIGURE 6.22 Disulfide interchange.92 (A) Discovered in synthesis when hydrazinolysis of an unsymmetrical derivative of cystine gave two symmetrical products instead of the expected monohydrazide at the urethane-protected cysteine moiety of the derivative.95 (B) Mechanism for interchange catalyzed by strong acid,94 which is suppressed by thiols. (C) Mechanism for interchange catalyzed by weak alkali, which is enhanced by thiols. 

L Zervas, L Benoiton, E Weiss, M Winitz, JP Greenstein. Preparation and disulfide interchange reactions of unsymmetrical open-chain derivatives of cystine. J Am Chem Soc 81, 1729, 1959. 

At the time of the earlier review (66HC1155), it was already known that combinations of arenes with sulfur, or with sulfur mono- or dichlorides in the presence of Lewis acids (IV,B,1), or of aryl thiols, diaryl sulfides, or disulfides (IV,B,2 and 3) again heated with Lewis acid catalysts, generate thianthrenes, sometimes in acceptable preparative yields. A complimentary method is the treatment of aryl thiols with c. H2SO4. Routes from arenes and aryl thiols almost certainly involve the initial formation of diaryl sulfides. All these methods inevitably give symmetrical thianthrenes carrying identical substituents on each benzene ring (Scheme 9), unless the second sulfur is introduced in a controlled fashion into a preformed, unsymmetrical diphenyl sulfide. 

The metalation chemistry of the imidazoline system has received attention only recently, with the lithiation of l-benzyl-2-imidazoline being found to occur at the 2-position (90TL1767). Although the reactivity of the lithi-ated species with alkyl halides was poor, better results were achieved with disulfide and carbonyl electrophiles (90TL1767,90TL1771). The products formed by reaction with ketones were found to be unstable with respect to fragmentation, and this result was utilized to provide a new route for the synthesis of unsymmetric ketones (Scheme 138). 

The two most used reversible covalent reactions are disulfide exchange and palladium-catalyzed olefin metathesis. We first probed the incorporation of olefin units into the H bonded duplexes by subjecting the modified duplexes to a Pd (Gmbb s) catalyst. Based on a duplex template with the same unsymmetrical H bonding sequence used for directing the formation of the /3-sheet structures, we prepared two groups (strands 17 and 18) of five olefins covalently linked to the two template strands (Fig. 9.13). Mixing each one of components 17 with each one of components 18 in a 1 1 fashion results in a small library of 25 (5 x 5) members. 

Dimethylhydrazine, N,N Unsymmetrical Dimethylhydrazine under Hydrazine Derivatives Dimethyl Sulfide under Sulfides, Disulfides Dinitrotoluene under Simple Aromatic Nitro Compounds... 

For the synthesis of double-stranded symmetrical and unsymmetrical monocystine peptides the formation of an intermolecular disulfide bridge is required. For homodimerization of cysteine peptides all the methods discussed in Section 6.1.1 can be applied taking into account the reactivity of the different oxidative agents toward sensitive amino acid residues present in the peptide sequences. Synthetic approaches based on the direct use of suitable cystine derivatives can be envisaged, at least for small-size peptides since disproportionation would in all cases retain the homodimeric structure 241... 

In order to obtain heterodimers a cysteine residue of one peptide has to be specifically activated for subsequent reaction with the cysteine residue of the second peptide. Thiols are activated by introducing an electron-withdrawing substituent that increases the responsiveness of the sulfur to nucleophilic substitution. This topic has been reviewed 41311 Of the various older methods known in sulfur chemistry for the preparation of unsymmetrical disulfides, i.e. thiosulfates,11321 S-alkylthiosulfonates,11331 5-alkylthiosulfinates,11341 sulfanyl-amines,11351 sulfanylimides,11361 sulfanyl thiocyanates and sulfenyl chlorides,1137,1381 sulfan-... 

These early studies clearly revealed the inherent problems of the chemistry for site-directed formation of unsymmetrical disulfides that has to avoid formation of homodimers. These can result from (i) slow rates of activation of the cysteine peptide, (ii) disproportionation of the activated cysteine species, (in) weak activation and thus slow thiolysis by the second cysteine component and thus its oxidation to the homodimer as well as thiol/ disulfide exchange reactions on the unsymmetrical disulfide present in the reaction media. The latter side reactions are partly controlled by operating in degassed argon-saturated buffers or in organic solvents and preferably under acidic conditions where thiol/disulfide exchange reactions on the nonactivated disulfides, i.e. on the target unsymmetrical cystine peptide occurs at slow rates. 

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