Zincke disulfide cleavage

What is Zincke disulfide cleavage?

The first attempt at the reaction using diphenyl disulfide and bromine in the absence of a diluting solvent was made by Otto in 1868, which resulted in the formation of only 4-bromophenyl disulfide. The Zincke disulfide cleavage method, which involves the oxidation of corresponding disulfides with halogens, was first used by Zincke in 1911 to prepare arylsulfenyl halides from aryl disulfides.

Zincke disulfide cleavage - general reaction scheme
Zincke disulfide cleavage
  • Ar = aryl
  • X = Cl, Br (see list of acronyms)

Zincke and his team also developed two other methods involving the action of chlorine or bromine on thiophenols or arylbenzyl sulfides to form sulfenyl halides, which are often mentioned together with the Zincke disulfide cleavage.

Zincke disulfide cleavage - general reaction scheme
Zincke disulfide cleavage
  • Ar = aryl
  • X = Cl, Br (see list of acronyms)

The arylsulfenyl halides can be easily prepared from aryldisulfides, with decreasing reactivity from chlorine to iodine.

Zincke disulfide cleavage - general reaction scheme
Zincke disulfide cleavage
  • Ar = aryl
  • X = Cl, Br (see list of acronyms)

However, bromine fails to react with some anthraquinonyl disulfides to form the corresponding sulfenyl bromide, and only one sulfenyl iodide, 2-benzothiazolesulfenyl iodide, has been reported so far.

Stoichiometric amounts of halogen and disulfide must be used in this reaction, as an excess amount of halogen may form a tetrahalogen derivative that will hydrolyze to thiosulfonic esters. The resulting sulfenyl halide can further react with substrates with active hydrogens (e.g., NH2), unless it is protected. The formation of sulfenyl halide is competed by the halogenation of the aromatic nucleus and the aliphatic moiety of disulfide. However, in the presence of an electron-withdrawing group, such as NO2, the electrophilic substitution by halogen on the aromatic nucleus is impeded, and the corresponding sulfenyl halide can be properly formed.

To minimize possible aromatic halogenation, the Zincke disulfide cleavage is usually performed at low temperature without light and in an anhydrous solvent that will dissolve both reactants. Suitable solvents include carbon tetrachloride, chloroform, ethylene chloride, and occasionally benzene, pentane, or other hydrocarbon solvents. In the presence of a hydroxylic solvent (e.g., acetic acid) or moisture, sulfonyl chloride rather than sulfenyl chloride forms.

Aryldisulfides can also react with phenols and cyclic esters of phosphoramidous acid (i.e., phosphoramidite). Under basic conditions, aryldisulfide is cleaved in the reaction with phenols to form thiophenol and 4-arylthiophenols, and the yields are greatly influenced by the steric hindrance from ortho substituents on the original phenols. The reaction between phosphoramidite and disulfides proceeds by two routes, either a Michaelis-Arbuzov rearrangement to form phosphoramidothioic ester or desulfurization to give sulfide and cyclic phosphoramidothionate.

Applications

The Zincke disulfide cleavage is highly advantageous in the preparation of thioethers that contain an adjacent halogen. This is because sulfenyl halide can readily add to olefins, such as in the reaction that occurs with bicyclo[2.2.1]hepta-2,5-diene.

Additionally, arylsulfenyl chloride is widely used in the quantification of tryptophan and cysteine residues in proteins. These residues are difficult to measure using traditional hydrolysis methods. When this test is performed, the protein is labeled with 2-thioether derivatives or mixed disulfides resulting from the reaction between 4-nitrophenylsulfenyl chloride and tryptophan or cysteine residues, respectively.

The amount of cysteine can be determined by measuring the absorbance of the cleaved 4-nitrothiophenol at 450 nm using 0.1 N NaOH. Tryptophan, on the other hand, can be evaluated at 365 or 328 nm for sulfenylated proteins.

References

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