Sulfenyl halides

Sulfenyl halides have been found to be specific, mild reagents for modification of tryptophan containing peptides and proteins 123, 124). By reaction with a sulfenyl halide like 2-nitrophenylsulfenyl chloride 

In principle, any member of the large class of sulfenyl halides could be used for labelling of tryptophan in proteins. However, these reagents are highly unstable in aqueous solvent with the notable exception of 2-nitrophenyl compounds 123, 354). In the case of the easily hydrolyzable sulfenyl halides, an aqueous medium can still be employed, provided that an excess of reagent dissolved in an organic solvent is used and is added dropwise under stirring to an aqueous solution of the protein. 

At the present time the most widely used sulfenyl halide is 2-nitrophenylsulfenyl chloride 124). Other compounds tested are 4-nitro-phenyl- 354), 2,4-dinitrophenyl- 354), 2-nitro-4-carboxyphenyl- 416) and 2,4-dinitrophenyl-1,5-disulfenyl chloride 417). The bifunctional reagent has been used to introduce selectively intramolecular crosslinks between tryptophan units (140). 

Quantitative modification of tryptophan in proteins can be achieved readily by using a low molar ratio of reagent to protein. The tryptophan residues of lysozyme, trypsin, and chymotrypsin were fully modified by reacting the protein with 20 equivalents of a freshly prepared solution of 2-nitrophenylsulfenyl chloride in 50% acetic acid (354). Acetate buffer pH 4-5 has been used in the modification of human growth hormone (60), lysozyme (341) and a-lactalabumin (357). 

Sulfenyl halides possess several particularly valuable features for protein modification studies. Their high selectively for tryptophan in proteins lacking SH-groups is especially remarkable. Furthermore, even if cysteine residues are present, selectivity for tryptophan can still be achieved since the disulphides formed by reaction of the halide with cysteine SH-groups can be easily reconverted to cysteine by subsequent reduction with mercaptoethanol. Other techniques for tryptophan modification are less specific and in several cases the reaction products are undefined. 

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Sulfenylation of indoles can be carried out with sulfenyl halides[7], disulfides[7-9] or with A -methylthiomorpholine[10]. With disulfides the indoles are converted to lithium[8] or zinc[9] salts prior to sulfenylation. Thiophenols and iodine convert indoles to 3-(arylthio)indoles[l 1]. 

MO calculations for the gas phase indicate that sulfurane intermediate (17) is more stable than the ion (18) by about 380 kJ moP, which suggests that sulfuranes may be important in the reaction of sulfenyl halides with alkenes in non-polar solvents (77JCS(P2)1019). 

Chloroethyldisulfides are obtained by electrophilic attack on the sulfur atom of thiiranes by sulfenyl halides (Scheme 39). Sulfur dichloride and disulfur dichloride react similarly to give more sulfur-rich derivatives di- and tri-sulfenyl halides, and tri- and tetra-sulfides (Scheme 42). A 1 1 ratio of sulfur halide to thiirane gives the di- or tri-sulfenyl halide a 2 1 ratio the tri- or tetra-sulfide. Thiirane 1-oxides are cleaved by sulfenyl halides to thiolsulfinates (Scheme 43) (74JAP7440461). 

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). 

Sulfenamides, R2NSR, prepared from an amine and a sulfenyl halide, " are readily cleaved by acid hydrolysis and have been used in syntheses of peptides, penicillins, and nucleosides. They are also cleaved by nucleophiles, and by Raney nickel desulfurization. ... 

In earlier days it was fairly common to suggest that sulfenium ions, RS+, were involved as intermediates in a number of these substitutions, particularly those in which sulfenyl halides RSX reacted with very weak nucleophiles, or those where electrophilic catalysis of the substitution was observed (Parker and Kharasch, 1959). However, it has since become evident (Owsley and Helmkamp, 1967 Helmkamp et al., 1968 Capozzi et al., 1975) that sulfenium ions are almost impossible to generate as intermediates. For example, Capozzi et al., (1975) showed that although treatment of a sulfenyl chloride RSC1 with the powerful Lewis acid antimony pentafluoride led to the complete conversion of the sulfenyl chloride to a cation, what was formed was, not the sulfenium ion RS+, but rather the cation [59] in reaction (172). These results, and others... 

The addition of sulfenyl halides to both alkenes and alkynes had been the subject of extensive mechanistic study. The salient results up to about 1969 have been reviewed by Mueller (1969) and Modena and Scorrano (1968). Considerable additional work on various aspects of the detailed mechanisms has been done since that time by Schmid and his co-workers (Schmid and Csizmadia, 1972 Schmid et al., 1972 Schmid and Nowlan, 1976 Schmid et al., 1976b Cerksus et al., 1978). A recent short review by Smit et al. (1979) criticizes some aspects of earlier interpretations of mechanism. 

V. ELECTROPHILIC SULFUR AND SELENIUM A. Sulfenyl Halides and Related Compounds... 

Electrophilic addition of sulfenyl compounds at carbon-carbon double bonds, extensively studied and reviewed2,4 715 106, finds numerous synthetic applications owing to the regio- and stereoselectivity of the addition26. The most common types of agents for the electrophilic addition of sulfur to double and triple bonds are sulfenyl halides (RSX,... 

In agreement with the mechanism reported in equation 90, the reaction generally follows a second-order rate law (equation 92), first order in the sulfenyl halide and in the alkene, respectively. 

Generally, the addition of sulfenyl halides to conjugated dienes occurs, under kinetic control, at either double bond with anti stereospecificity to give 1,2-adducts with either... 

Simple 1,2-additions to this compound have been observed123131132 also in other sulfenylation reactions, and in other electrophilic additions involving strongly bridged intermediates. Although these results have been interpreted as evidence that additions of sulfenyl halides to symmetrical alkenes do not involve open carbenium ions before the product-determining step, the different behavior observed in the case of 49 suggests123 that close proximity is necessary to have transannular participation of 7r-bonds, at least in additions of sulfenyl derivatives and of some other electrophiles carried out in the presence of efficient nucleophiles. 

Further, the metal fluorides SbFs (with admixture of small quantities of SbCls), HgF2, and AgF are also found suitable for the fluorination of sulfenyl halides, e.g.. 

Chlorination of thiols serves for the preparation of temperature-sensitive sulfenyl halides, since the main reaction products are easily separated from the side products by fractional condensation, e.g.,... 

Addition of halogens or interhalogens to perfluorohalogenothio-ketones, as already described, represents an important method for the preparation of complex sulfenyl halides. 

In an attempt to add sulfenyl halides to the C=S double bond, only the unsymmetrical disulfanes are formed, instead of mercapto-substi-tuted sulfenyl halides (54, 56, 72), e.g.,... 

Sulfenyl halides do not react with thiocarbonyls unless irradiated with UV light. 

Other disulfanes can be prepared similarly, as summarized in Table IV. The yields are substantially higher when sulfenyl halides of the formula CFnCls-jjSX (X = Cl, Br) are reacted. Within a homologous series the... 

The introduction of the perfluorohalogenosulfenyl group into aromatic compounds was accomplished long before the preparation of sulfenyl halides. The CFgS-subBtituted compounds have been synthesized largely by chlorination of the side chain in arylmethylthioethers followed by chlorine-fluorine exchange. This method was applied for the first time in the synthesis of trifluoromethylmercaptobenzene 92, 140, 172) ... 

Indole and carbazole, which can be regarded theoretically as derivatives of pyrrole through its anellation with one or two benzene rings, show variable behavior toward sulfenyl halides ... 

Electrophilic substitutions on thiophene, like those on benzene, can be carried out only in the presence of catalysts. In reactions with sulfenyl halides, SnCl4 proved to be particularly suitable in the case of the less reactive sulfenyl halides, Grignard reactions lead to the desired products ... 

With CFsSCl and in the presence of pyridine as HCl acceptor, a reaction takes place to give 5-trifluoromethylmercaptouracil. Under identical reaction conditions the sulfenyl halides CFnCl3 SCl ( = 0, 1) afford dinitrogen-substituted products ... 

A theoretical interpretation of this different behavior is not yet available. In any case, the most obvious possibility that all sulfenyl halides attack initially at the nitrogen as the most electron abundant site 160), and that the CF3S compound is then converted to the more stable 5-substi-tuted product, is to be disregarded, since 1,3-dimethyluracil, with both nitrogen atoms blocked, gives with CF3SCI the 5-substituted compounds in high yield. 

Mononitrogen-substituted derivatives are obtained from sodium uracil and sulfenyl halides CF Cl3 SCl (w = 0, 1, 2) 49, 96) ... 

The yield decreases with increasing degree of fluorination of the reactant sulfenyl halides. In the reaction with CF3SCI, no appreciable quantity of the desired product could be isolated. Although in the mass spectrum of the reaction mixture a peak was observed corresponding to the molecular ion M = 212, the position of the substituent could not be unequivocally determined. 

Perhalogenated sulfanes can be obtained by condensation of 5-mercapto-uracil with sulfenyl halides, CFMCl8 nSCl ( = 1, 2, 3) ... 

Mechanistic studies have been most thorough with the sulfenyl halides.63 The reactions show moderate sensitivity to alkene structure, with electron-releasing groups on the alkene accelerating the reaction. The addition can occur in either the Markownikoff or anti-Markownikoff sense.64 The variation in regioselectivity can be understood by... 

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