Recent advances in S–S bond formation

Abstract

Organic compounds possessing S–S bonds, often called disulfides or more specifically disulfanes, have been widely applied in various fields ranging from biochemistry to different industrially important polymers, used as synthetic intermediates in other fine chemicals such as catenanes, rotaxanes, micelles, and also in areas like peptidomimetics, self-assembled monolayers (SAMs) etc. Such versatile applications have steered the development of several new methods for the preparation of organic disulfides. The present review has attempted to comprehensively summarize recent advances in the process of S–S bond formation, highlighting plausible mechanistic considerations, scope and limitations.

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Bablee Mandal

Bablee Mandal obtained an M.Sc. degree in chemistry from the University of Burdwan, India in 2004. She earned National Eligibility Test (NET) with a scholarship and joined with Professor B. Basu at North Bengal University, Darjeeling in 2005. She worked on the solid surface-promoted organic reactions and heterogeneous nanocatalysis, and was awarded a Ph.D. in 2009. From 2008, she has been working as an Assistant Professor at Surya Sen College, Siliguri, India and been engaged in writing review articles in areas of synthetic organic chemistry.

Basudeb Basu

Basudeb Basu did his Ph.D. work from the Indian Association for the Cultivation of Science, Kolkata, working on the synthesis of fused and bridged carbocyclic frameworks related to natural products. He joined North Bengal University as an Assistant Professor in 1986. He did his post-doctoral works with Prof. R. G. Salomon at Case Western Reserve University, Ohio, USA (1987–89) on the total synthesis of optically active marine natural products, and again with Prof. T. Frejd at Lund University, Sweden (1994–96), on the asymmetric synthesis of non-natural amino acids. He has been working as a Professor of Chemistry in North Bengal University since 2004. He was Visiting Professor in Sweden, Denmark, France and Taiwan. His current research interests include new reactions and methodology, new heterogeneous nanocatalysts and green chemistry.

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1. Introduction

Organic compounds bearing S–S bonds, often called disulfides or more specifically disulfanes, are biochemically unique. Disulfanes and polysufanes are covalently joined compounds of the type R–S_n–R (n = 2, 3…) and are IUPAC recommended nomenclature.¹ Large disulfide-linked aggregates are prevalent in proteins and many other bioactive naturally occurring molecules.² Disulfide- and polysulfide-containing metabolites from marine sources represent an important class of natural products, which often exhibit promising bioactivities including antitumor, antibiotic and enzyme-inhibitory activities.^2b,c The formation of S–S bond is an essential step in the folding and assembly of the extracellular domains of many membranes and secreted proteins. Failure to form the correct disulfide bonds leads to protein aggregation and subsequent degradation by cellular proteases.³ The role of disulfides in the in vitro folding of proteins (Fig. 1) has been studied in great detail for a number of eukaryotic model proteins, including ribonuclease A (RNaseA) and bovine pancreatic trypsin inhibitor (BPTI).⁴ It is generally believed that disulfides typically function to stabilize the tertiary structure of a protein. A protein whose cysteines are linked via disulfide bonds can take on many fewer conformations than a protein whose cysteines remain free. The generally accepted theory is that the disulfide bonds stabilize the native conformation of the protein by destabilizing the denatured form. In other words, they decrease the entropy of the unfolded form of the protein, making it less favorable compared to the folded form. Consequently, disulfide heterodimers find applications in the synthesis of a variety of bioconjugates of peptides,⁵ oligonucleotides,⁶ and peptide nucleic acids.^7a In biological systems, glutathione (GSH), a thiol-containing molecule present at micromolar levels in common fluids outside cells, undergoes a reversible redox reaction to glutathione disulfide (GS–SG) (Fig. 2).^7b The disulfide, 5,5′-dithiobis(2-nitrobenzoic acid), also called Ellman's reagent, is popularly used for the estimation of free thiol groups on proteins (Fig. 2).^7c In recent times, disulfides have been actively investigated as potential drug delivery systems.^7d

Fig. 1 Role of disulfide in protein folding – a schematic presentation.

Fig. 2 Redox reaction of glutathione and glutathione disulfide; Ellman reagent – a disulfide used for estimating free or covalently modified thiol groups on proteins.

Industrially, disulfides find wide applications as vulcanizing agents⁸ for rubbers and elastomers, by bestowing excellent tensile strength to them. Moreover, polysulfides bearing the S–S bonds have been proved to be useful in the design of rechargeable lithium batteries.⁹ Unsymmetrical disulfides have fungicidal properties.¹⁰ In a recent study, it is revealed that oxidized species of disulfides, such as thiosulfinate or thiosulfonate may operate as a first line of the body's defense against cyanide intoxication.¹¹ Moreover, disulfides find vast applications in agro-chemicals, as shown by large varieties of new sulfur-based crop protection chemicals around the world.¹² Disulfides are also valuable synthetic intermediates for various organic transformations,¹³ and pharmacological chemistry.¹⁴ Thiols are often protected through the formation of S–S bonds, since it can be easily regenerated by cleavage or reduction with CN⁻, OH⁻ or hydrazines. Because of versatile importance of organic disulfides, the search for efficient, mild and inexpensive methods for the S–S bond formation (i.e. the synthesis of disulfides) is an important area of modern research. Various aspects of the S–S bond formation are available in some books on organic functional group transformations, while one review article has been published in the year 2008 highlighting recent developments of disulfide bond formation using a variety of reagents.¹⁵ However, investigations on new methods are being regularly reported and new types of disulfides are synthesized. This review is aimed at compiling advances in the formation of S–S bond of disulfides highlighting the novelty and other notable facets with a major focus since 2008. The present article primarily views various approaches towards the formation of S–S bonds based on starting materials and reagents with plausible mechanistic consideration, wherever available, as well as the scope and limitations.

2. Methods of synthesis

2.1. From thiols

2.1.1. Thiolysis-based methods. To prepare organic disulfides, thiols are used as the starting materials in most cases. So far, two major reactions have been utilized for the preparation of disulfides: (i) thioalkylation or thiolysis of S-containing compounds via nucleophilic displacement of a suitable leaving group by either a thiol or thiolate anion, and (ii) the oxidative coupling of thiols and their derivatives in the presence of different oxidizing agents. Some of these conditions are accompanied by certain disadvantages. The main disadvantages are long reaction times, harsh reaction conditions, difficult work-up, over-oxidation, and the use of expensive reagents. Moreover, while the oxidation of thiols results in the formation of an S–S bond in a symmetrical disulfide, the synthesis of unsymmetrical disulfide is indeed a subtle methodological challenge. Nevertheless ceaseless experimentations are going on to prepare the target disulfides, both symmetrical and unsymmetrical disulfides, in high yields, by using both thioalkylation as well as oxidative coupling of thiols.
2.1.1.1. Using sulfonyl chloride. A very mild and effective protocol for disulfide synthesis in an aqueous medium at room temperature has been reported by Wu et al.¹⁶ In their process, thiols are treated with phenyl sulfonyl chloride under basic medium to form a thiosulfonate intermediate, which is actually the S-transfer agent, reacts with another molecule of thiol to form the disulfide. Aryl thiols bearing different functional groups responded to the reaction conditions effectively and corresponding diaryl disulfides are formed within a very short time (Scheme 1).

Scheme 1 Diaryl disulfide synthesis from aryl thiols using phenyl sulfonyl chloride.

The reaction mechanism is proposed involving two steps (Scheme 2). The initially formed thiolsulfonate is more reactive with thiophenol than the benzene sulfonyl chloride (i.e. K₂ ≫ K₁). The role of the base is to eliminate the acid by-product.

Scheme 2 Proposed mechanistic steps involving aryl thiol and sulfonyl chloride.

2.1.1.2. Using arene sulfenamide. Searching for ambient reaction conditions to prepare unsymmetrical disulfides, Bao and Shimizu hit upon N-trifluoroacetyl arenesulfenamides as effective precursors for the synthesis of unsymmetrical disulfides (Scheme 3).¹⁷ Most reactions are completed within 5 min. with excellent yields, though aliphatic dodecanethiol gave a poor yield even after 1 h. The precursor 1, a solid crystalline compound, was prepared via a chlorine-free procedure.¹⁸ Compound 1 undergoes a nucleophilic substitution reaction with thiols and the electron-withdrawing nature of R¹ suppresses its reactivity. The reaction proceeds under neutral conditions in a short time thereby avoiding any thiol–disulfide exchange during the course of the reaction. The yields of the unsymmetrical disulfides are good to excellent. The only limitation is that the procedure consists of two-steps and requires expensive reagents.

Scheme 3 Disulfide synthesis using arenesulfenamide and thiol.

2.1.1.3. Using thiourea. Ayodele et al. carried out the synthesis of unsymmetrical disulfides from thiol, thiourea and thioacetic acid.¹⁰ The method involved the reaction of thiol and thiourea, the latter acts as the S-transfer agent, to form an intermediate S–benzylthioisothiouronium chloride 2 that finally reacts with thioacetic acid (Scheme 4).

Scheme 4 Disulfide synthesis using thiourea and thiol via thiouronium salt.

Mechanistically, it is proposed that the intermediate S–benzylthioisothiouronium chloride 2 in the presence of base produces the disulfide anion (RS-S⁻), which then reacts with thioacetic acid to produce compound 3, as depicted in Scheme 5.

Scheme 5 Mechanism defining disulfide formation from thiourea and thiol.

2.1.1.4. Using DEAD and related derivatives. Diethylazo dicarboxylate (DEAD),¹⁹ and other related compounds bearing properly activated N–N double bonds have been employed for the oxidation of thiols to disulfides. The reaction proceeds through activation of one thiol molecule, which then reacts with another thiol to produce the disulfide. The reaction is usually carried out at room temperature or under reflux in anhydrous solvent. Other DEAD analogues such as diisopropylazo dicarboxylate (DIAD),^19a tetramethylazodicarboxamide (TMAD),^19b diazenecarboxamide,^19c and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD),^19d have also been used for this reaction.

Morais and Falconer demonstrated one-pot synthesis of glycosyl disulfides from the reaction between thiosugar and thiol in the presence of diethylazo dicarboxylate (DEAD) under mild, neutral conditions and with excellent yields (Scheme 6).²⁰ A closer analysis of these reactions revealed that the thiosugar reacts very quickly with DEAD to form intermediate 4. The reacting thiol then acts as a nucleophile, forming the disulfide and leaving the saturated DEAD by-product (and conversely the thiosugar reacted with the thiol–DEAD complex in the reverse order of addition). A two-fold excess of DEAD was required to prevent the thiosugar reacting with the rapidly formed sugar–DEAD intermediate (which also occurs rapidly) in place of the reacting thiol.

Scheme 6 Synthesis of unsymmetrical disulfides from thiosugar and thiol mediated by DEAD.

The DEAD-promoted method has also been employed in the unsymmetrical sugar-based disulfide linked with vancomycin,²¹ which exhibited an improved ADME (Absorption, Distribution, Metabolism and Excretion) profile in vivo studies.

2.1.1.5. Using benzothiazole disulfanyl compound. Attempts to prepare diallyl disulfide analogues were successful in the following synthesis of benzyl 4-halobenzyl and allyl benzyl disulfide (Scheme 7).²² Since diallyl disulfide, found in garlic, has been known to inhibit the growth of various human cancer cells, analogues of diallyl disulfide were tested and found to be active on the growth inhibition of MCF-7 and SNU C5 cells, indicating that the disulfide functional group might be responsible for the tumor growth inhibitory effects. Radio-iodine-labeled unsymmetrical disulfides, [¹²³I/¹²⁵I] 6 & 7, were synthesized for use as the radiotracer and to facilitate tumor imaging.

Scheme 7 Synthesis of allyl benzyl disulfides bearing radioactive iodine.

2.1.1.6. Using 1-chlorobenzotriazole. Hunter et al.²³ reported the synthesis of unsymmetrical disulfides using thiol (R¹SH) and 1-chlorobenzotriazole (BtCl) at −78 °C in DCM to initially form an intermediate (R¹SBt), which further reacts with a different thiol (R²SH) to form the unsymmetrical disulfide in a one-pot sequence (Scheme 8). The ratio of BtCl : BtH : R¹SH : R²SH was maintained as 3 : 2 : 2 : 3 to optimize the formation of BtSR¹ and minimize the formation of the homo-dimer R¹S–SR¹.

Scheme 8 Unsymmetrical disulfide synthesis using BtCl as the reagent.

One major facet of this procedure is that no significant amount of the symmetrical disulfide is detected and the hetero-dimer (unsymmetrical disulfide) is obtained in appreciable yield via the formation of 8a (Scheme 9). The procedure practically involves successive double S_N2-type reactions giving the possibility for the preparation of unsymmetrical disulfanes.

Scheme 9 Mechanism defining the role of BtCl.

Thus the authors were successful in synthesizing aryl alkyl disulfides in excellent yields. An interesting observation regarding the order of thiol addition came out of this study. The addition of aliphatic thiol first resulted in a significant amount of the aliphatic homodimer, whereas the reverse addition gave the unsymmetrical disulfide in significant yield. This indicates the greater nucleophilicity of the aliphatic thiol towards the intermediate sulfenyl chloride. Again, the yield is significantly improved with aromatic thiols bearing electron-withdrawing groups. Another interesting observation is that the sterically bulkier and more acidic thiol, if added second in order, can afford a better yield of the unsymmetrical disulfide.

Designing an effective protocol for the synthesis of unsymmetrical aliphatic–aliphatic disulfide was a task that the authors found most challenging. Eventually they came up with a condition where aliphatic R¹SH was added to a two-fold excess of BtCl to ensure complete conversion to the desired BtRS¹ intermediate (TLC corroboration). While decomposing excess BtCl by adding thiourea (3 equiv.), the intermediate BtSR¹ presumably reacts with the thiourea to form an isothiouronium salt, the latter then reacts with the other thiol (R²SH) to ensure complete conversion to the desired unsymmetrical disulfide without significant interference from homodimer formation (NMR analysis). The overall process takes place at −78 °C to room temperature and the yields of unsymmetrical aliphatic disulfides are reported to be good to excellent (Scheme 10). The mechanistic cycle, as postulated by the authors, is depicted in Scheme 11. The benzotriazole (BtH) is converted to BtCl in reaction with NaOCl.

Scheme 10 Synthesis of unsymmetrical aliphatic disulfides using excess BtCl and urea.

Scheme 11 Possible role of BtCl.

The methodology offers an attractive environmentally friendly and cost-effective protocol where the BtCl is uniquely employed as the oxidant with a carrier (BtH) having recyclable properties. In continuation, the authors further reported its scope for differentially protecting cysteine thiols to afford unsymmetrical cysteine derivatives as a model reaction for intermolecular peptide disulfide heterodimer synthesis.²⁴ The reaction conditions were very simple. R¹SH (1 equiv.) was added to BtCl (1.5 equiv.) and BtH (1 equiv.) at −78 °C in CH₂Cl₂ and left for an hour. Then cysteine derivative R²SH (1 equiv.) was added at the same temperature and left to stir for four hours followed by quenching with aq. Na₂S₂O₃/NaHCO₃. The result was the formation of the desired unsymmetrical cystine derivatives as new compounds in high yields of around 90%. It is notable that the yield of the unsymmetrical disulfides was independent of either the choice of protecting group or the order of the cysteine thiol addition sequence (Scheme 12).

Scheme 12 Synthesis of new cystine derivatives bearing different protective groups using BtCl.

2.1.1.7. Using dialkoxylthiophosphoranesulfenyl halides. A versatile synthetic route to functionalized unsymmetrical disulfides was reported from thiols with the aid of (5,5-dimethyl-2-thiono-1,3,2-dioxophosphorinanyl)sulfenyl bromide 10, derived from bis-(5,5-dimethyl-2-thiono-1,3,2-dioxaphosphorinanyl)disulfide 9. The adduct 11 obtained from thiol and 10 can undergo thiol–thiol coupling at room temperature in the presence of NEt₃, as outlined in Scheme 13.²⁵ The method can be applied to thiols possessing neutral, aromatic, basic or acidic functionalities with variable carbon chains.²⁶

Scheme 13 Synthesis of unsymmetrical disulfides bearing variable lengths of carbon chains.

As an extension of this versatile procedure, functionalized disulfides of cysteine derivatives have also been prepared (Scheme 14).²⁷

Scheme 14 Functionalization of cysteine derivatives by unsymmetrical disulfide bond formation.

2.1.1.8. Using S-nitrosothiols. Xian et al. reported a reductive ligation mediated disulfide formation from S-nitrosothiols and o-phosphine substituted arylthioester (Scheme 15).²⁸ Studies were conducted with a series of phosphine thioester substrates and S-niroso-cysteine derivatives. The solvent used was a (3 : 1) THF/PBS buffer having pH 7.4. Disulfide formations at room temperature were usually completed within an hour. Initially sulfenamide and thiolate intermediates are formed, which then undergo fast intermolecular disulfide formation.

Scheme 15 Reductive ligation mediated disulfide formation.

The same group reported another one-step disulfide synthesis from S-nitrosothiols.²⁹ The reaction mediated by phosphine is effective in converting unstable S-nitrosothiols to stable disulfides via sulfenamide intermediates at room temperature using a 3 : 1 mixture of THF/PBS buffer as a solvent (Scheme 16).

Scheme 16 Disulfide synthesis from S-nitrosothiol.

The authors performed a cross-over experiment to establish that the reaction is specific to S-nitrosothiols and doesn't affect the disulfide (Scheme 17).

Scheme 17 A cross-over experiment.

2.1.1.9. Using thiosaccharine/thioamide. Thiosachharine in aqueous solution exists in tautomeric equilibrium between the thiol and the thione forms. On oxidation with any conventional reagent, the thiol form produces the corresponding disulfide. Ferullo et al.³⁰ carried out the synthesis by oxidizing 10 ml aq. thiosaccharine solution with KMnO₄ solution (H₂O₂ or HNO₃ can also be used) in the molar ratio 5 : 1 and obtained the desired product in 75% yield (Scheme 18). The product was purified by simple filtration followed by washing with water.

Scheme 18 Disulfide formation from thiosachharine by using KMnO₄ or H₂O₂.

A mild and efficient synthesis of disulfide from arylthioformanilides in the presence of DDQ as the oxidant has been reported (Scheme 19).³¹ Other oxidizing agents such as Ceric ammonium nitrate (CAN), Dess-Martin periodinane (DMP), phenyliodine(III) bis(trifluorocaetate) or K₃Fe(CN)₆ did not work as efficiently as done by DDQ. The authors suggested the formation of a thiyl radical intermediate, which can either dimerize or can form benothiazole, as outlined in Scheme 20. The stability of the thiyl radical in the presence of substituents on the aromatic ring dictates the formation of disulfide or the cyclic benzothiazole as the product.

Scheme 19 Disulfide formation from arylthioformanilide by oxidation using DDQ.

Scheme 20 Plausible mechanism with the formation of a thiyl radical.

2.1.1.10. Using cyclodextrine-tethered thiol. Cyclodextrins (CDs), the cyclic oligosaccharides consisting of six or more D-(+)-glucopyranose units, are well known to accommodate various guest molecules into their condensed cone-shaped hydrophobic cavity in aqueous solution. This fascinating property enables them to be successfully used as drug carriers,³² separation reagents,³³ enzyme mimics,³⁴ photochemical sensors,³⁵ catalysts³⁶ etc. A linker or a spacer, when attached to the CD, improves its association abilities and molecular selectivities. The synthesis of cyclodextrin dimers tethered by a disulfide linker was successfully acheived by Tang et al.³⁷ Compound 13 (6-OTs-β-CD) was prepared by the reaction of p-tosyl chloride with β-CD in dry pyridine. It was converted to 6-deoxy-6-mercapto-β-CD 14. It was dissolved in 10% H₂O₂ by heating followed by stirring for 5 hour yielding the desired product 15 (Scheme 21).

Scheme 21 Synthesis of disulfide from cyclodextrine-tethered thiol.

2.1.1.11. Using sulfenyl chloride. Sulfenyl chlorides react with alkylthiotrimethylsilanes giving unsymmetrical disulfides with an average yield of more than 80% (Scheme 22).³⁸

Scheme 22 Disulfides from sulfenyl chloride and alkylthiotrimethylsilanes.

There was no trace of any symmetrical disulfides except in aralkyl and dialkyl cases where traces of the symmetrical disulfides were formed. Since sulfenyl chlorides are generally unstable compounds, the reaction is carried out via in-situ generated sulfenyl chloride at a low-temperature chlorination of thiol acetate or disulfide in acetic anhydride and DCM.

2.1.2. Oxidative coupling of thiols.
2.1.2.1. Oxidation using metals. The use of Cu(NO₃)₂·3H₂O as an oxidant was reported to be an efficient catalyst for the conversion of thiols to their corresponding disulfides.³⁹ Since the salt, Cu(NO₃)₂·3H₂O, is a cheap and easily available compound in laboratories and the reaction is carried out in acetone at room temperature (Scheme 23) using catalytic amounts (0.2 equimolar), the procedure is convenient for large-scale operations.

Scheme 23 Cu nitrate-catalyzed conversion of thiols to disulfides.

The reaction is believed to occur through the formation of a thionitrite intermediate, which was detected by UV-spectral analysis in the reactions. The catalytic effects of Cu(II) and Cu(I) on the decomposition of the thionitrite being quite established,⁴⁰ a mechanism was suggested by the authors explaining the catalytic role of Cu(NO₃)₂·3H₂O (Scheme 24).

Scheme 24 Mechanistic role of copper in disulfide formation.

Rhodium complex, [Rh(cod)₂]BF₄ in the presence of phosphine ligands (PPh₃) was found to be a very effective catalytic system for the dehydrogenation of thiols to symmetrical disulfides (Scheme 25).⁴¹ The same group⁴² reported that this cationic phosphine-free Rh(I) complex can also act as an effective catalyst for the disulfide exchange reaction of symmetrical disulfides leading to the formation of unsymmetrical disulfides. The reaction proceeds under air without the addition of any phosphine ligands (Scheme 26).

Scheme 25 Rh-catalyzed synthesis of symmetrical disulfide.

Scheme 26 Rh-catalyzed synthesis of unsymmetrical disulfide.

Ni-nanoparticles are found to act as a green, recyclable catalysts that selectively catalyze the oxidative coupling of thiols to disulfides without producing any over-oxidized products (Scheme 27).^43a The reaction conducted with 15 mol% Ni-nanoparticles in air gives high TON and TOF values. The reaction is completed within 15 min with 90% yield.

Scheme 27 Disulfide synthesis catalyzed by Ni-nanoparticles.

Laser-generated copper nanoparticles (Cu NPs) prepared from CuO in 2-propanol were used for the oxidation of long chain aliphatic thiols (C₁₀SH, C₁₂SH, C₁₄SH, C₁₆SH C₁₈SH).^43b The deep wine-red colloidal solution of the Cu NPs turned brown after adding thiol and standing overnight, with the formation needle like crystals of disulfides for some disulfides (Scheme 28).

Scheme 28 Oxidation of thiols by laser-prepared copper nanoparticles.

Copper deposited by reduction using borohydride exchange resins (BER) has also been employed for the disproportionation of thiols resulting in the formation of disulfides.^43c The authors observed that copper catalysts prepared by using NaBH₄, either with or without silica gel, or Cu powder were much less effective than the BER-CuSO₄ catalyst. Disproportionation of hexanethiol using the catalyst in the presence of styrene gave the corresponding disulfide exclusively (Scheme 29), while the same reaction in the presence of AIBN produced 2-phenethyl hexyl sulfide without contamination of dihexyl disulfide. This strongly suggests non-involvement of a radical pathway for the BER-CuSO₄ catalyzed thiol to disulfide transformation.

Scheme 29 Disulfide synthesis by copper-catalyzed disproportion of thiols using BER-CuSO₄.

Metal-organic frameworks (MOFs) have appeared in recent years as promising heterogeneous catalysts for the oxidation of thiols.⁴⁴ Commercially available Fe(BTC) (BTC: 1,3,5-benzenetricarboxylate) was exploited as a suitable and reusable redox catalyst for the aerobic oxidation of thiols to disulfides (Scheme 30).⁴⁵

Scheme 30 Oxidation of thiols to disulfides using Fe-MOFs.

Heterogeneous acidic catalyst consisting of aluminum nitrate [Al(NO₃)₃·9H₂O] and silica sulfuric acid (SiO₂–OSO₃H) (1 : 1.1) has been shown to be effective for the oxidative coupling of thiols (Scheme 31).⁴⁶ Notable facets of this method include high yields (∼99%) of the corresponding disulfides and the absence of silica–sulfuric acid doesn't give any coupled product. Silica–sulfuric acid (SSA) is prepared by treating silica with chlorosulfonic acid and catalyst was prepared by stirring aluminum nitrate with SSA (1 : 1.1) in DCM.

Scheme 31 Oxidative coupling of thiols under heterogeneous conditions.

The plausible mechanism, suggested by the authors, involves the generation of nitric acid from aluminum nitrate on treatment of SSA followed by the decomposition of nitric acid into nitronium cations, which react with the thiol. The resulting intermediate RSNO₂ finally gives rise to the formation of the S–S bond of the disulfide (Scheme 32).

Scheme 32 Mechanism for the coupling of thiols by heterogeneous acid catalyst.

2.1.2.2. Oxidation using (NH₄)₂Cr₂O₇/silica chloride/wet silica. The oxidation of different thiols by ammonium dichromate in the presence of silica chloride and wet SiO₂ was investigated in the presence as well as absence of solvent with good results (Scheme 33).⁴⁷ The authors suggest the in situ generation of H₂CrO₄ in a low concentration at the surface of wet SiO₂ by silica chloride and ammonium dichromate. In most cases, the reaction is very fast and completed within 5 min.

Scheme 33 Coupling of thiols using (NH₄)₂Cr₂O₇/silica chloride/wet silica.

2.1.2.3. Oxidation in ionic liquids. Ionic liquids are used to catalyze or mediate various organic reactions. The selenium containing ionic liquid, [bmim][SeO₂(OCH₃)], was found to promote the S–S bond formation from thiols both under thermal and microwave conditions.⁴⁸ Aromatic, heteroaromatic and aliphatic thiols gave satisfactory results producing corresponding symmetrical disulfides (Scheme 34). The reactions were found to be accelerated by microwaves and the desired disulfides were obtained in good to excellent yields. The Se–ionic liquid presumably acts both as the solvent as well as the catalyst. The ionic liquid can be easily recovered and dried under vacuum and utilized for further oxidation reactions.

Scheme 34 Disulfides from thiols in ionic liquid media.

Cobalt(II) phthalocyanines (CoPc) and cobalt(II) tetranitrophthalocyanine (CoTNPc) immobilized in ionic liquid were used as efficient catalysts in the oxidation of thiols to disulfides using molecular oxygen (Scheme 35).⁴⁹ The catalysts were freely dissolved in [bmim][BF₄] by simple mixing and the oxidation was carried out in the homogeneous medium under an oxygen atmosphere. The recovered ionic liquid could be recycled up to 5–6 times with almost comparable yields.

Scheme 35 Disulfide synthesis catalyzed by Co-containing [bmim][BF₄].

2.1.2.4. Oxidation using halogens. Iodine has been efficiently used as the oxidant for the synthesis of long-chain n-alkyl disulfanes. For example, the Na salt of thiosulfuric acid S-alkyl ester (Bunte salt) produces dihexadecyl disulfane upon treatment with iodine.^50a The unsymmetrical disulfane, 11-(12-iododecyldisylfanyl)-undeca-1-ol, has also been synthesized using iodine in ethanol from a mixture of 12-iodo-dodecane-1-thiol and 11-mercapto-1-undecanol (Scheme 36).^50b

Scheme 36 Synthesis of long-chain n-alkyl disulfanes using I₂.

Zong et al.⁵¹ reported a simple synthetic method of monomer terminated dialkyl disulfides, namely the di-11,11′-N-pyrroylundecano-1,1′-disulfane (Scheme 37). The method can also be used towards a general synthetic protocol for the preparation of ω-functionalized dialkyl disulfanes.

Scheme 37 Synthesis of di-11,11′-N-pyrroylundecano-1,1′-disulfane.

Oae et al.⁵² reported the oxidation of thiols to disulfides in almost quantitative yields using a catalytic amount of iodine or aq. HI solution in the presence of excess DMSO (Scheme 38). The reaction is carried out in benzene at room temperature. Simple alkyl and aryl thiols react easily giving excellent yields but the yield was substantially lower when the R is sterically hindered.

Scheme 38 I₂/HI-catalyzed disulfide synthesis.

HBr mediated disulfide formation could be achieved in long-chain thiols with terminal bromides, which is then protected with uracil for subsequent transformations. (Scheme 39)⁵³

Scheme 39 Synthesis of long-chain disulfanes with terminal bromides for further functionalization.

2.1.2.5. Oxidation using HNO₃. Nitric acid mediated oxidation of thiols was reported by Misra and Agnihotri (Scheme 40).⁵⁴ The reaction was carried out in DCM to avoid further oxidation or aromatic nitration. The authors suggest that the reaction probably proceeds via a radical mechanism. The reaction is carried out at 0 °C and most of the reactions are fast and completed within an hour.

Scheme 40 Synthesis of disulfides using nitric acid as the oxidant.

2.1.2.6. Oxidation using 2,6-DCPCC. 2,6-Dicarboxypyridinium chlorochromate (2,6-DCPCC) was reported as an oxidizing agent for the oxidation of thiols to disulfides at room temperature in acetonitrile in less than 30 min (Scheme 41).⁵⁵ Aliphatic, aromatic and heteroaromatic thiols are oxidized irrespective of the presence of sulfides along with minimal quantities of the over-oxidized thiones.

Scheme 41 Coupling of thiols using 2,6-DCPCC.

2.1.2.7. Oxidation using DDQ. Vandavasi et al.⁵⁶ exploited 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, commonly known as DDQ (0.5 equiv.) as the oxidizing agent for converting thiols to both symmetrical (Scheme 42) as well as unsymmetrical disulfides (Scheme 43). The reaction was carried out in DCM at 0 °C for 5 min only to give the resultant disulfides. The reaction, though successful for secondary thiols, was found to be unsuccessful for tertiary thiols, probably due to steric resistance. Amino thiols when used were found to be decomposed.

Scheme 42 Preparation of symmetrical disulfides using DDQ as oxidant.

Scheme 43 Unsymmetrical disulfides using DDQ as oxidant.

The process is also quite successful for the synthesis of unsymmetrical disulfides though a mixture of two aromatic thiols gives a better yield as compared to a mixture of aromatic and aliphatic thiols (Scheme 43). Moreover, aliphatic thiols with increasing chain-length afforded relatively poor yields.

2.1.2.8. Electrochemical oxidation. Electrochemical oxidation represents another common procedure that has been employed for the preparation of unsymmetrical disulfides.⁵⁷ Electrophilic species like 16 or 17 in Scheme 44, prepared by the anodic oxidation of symmetrical disulfides, were reacted with thiols or other disulfides to afford the unsymmetrical disulfides. The formation of the transient electrophilic cation 17 (R¹S⁺) is supported by UV spectral analysis. In acetonitrile the dicationic species 16 was found to be prevalent but can evolve towards the monocation 17. In DCM, the formation of the sulfenium cation 17 takes place if a higher potential is applied. The sulfenium cation can then be made to react with thiols or symmetrical disulfides resulting in the formation of unsymmetrical disulfides.

Scheme 44 Unsymmetrical disulfide synthesis by electrochemical oxidation.

As the unsymmetrical disulfides are oxidizable in the same range of potential as that of the symmetrical one, they are generally prepared in a two-step process. Hence, the method has certain disadvantages along with the electrochemical oxidation set up, including long reaction time, cumbersome work up and moderate yields.

2.1.2.9. Intramolecular oxidative coupling resulting in cyclic disulfanes. The synthesis of cyclic disulfides through an unusual cyclization has been reported by Eisner and Krishnamurthy.⁵⁸ Hydrogen sulfide reacts with acetylene dicarboxylate 18 in the presence of an aromatic aldehyde and BF₃ etherate producing the cyclic disulfide 20 via the formation of 1,3-dithiin 19 and subsequent rearrangement on heating at 185 °C (Scheme 45).

Scheme 45 Synthesis of cyclic disulfides from aldehydes via dithiols and rearrangement.

2.1.3. Other methodologies. Thiyl or thiol radicals (R–S˙) can be generated by different routes, viz. by abstraction of hydrogen from thiols or by other methods of homolysis. Dimerization of highly active thiyl radicals results in the formation S–S bonds of disulfides. Thiyl radicals are common in biological systems and also as intermediates in vulcanization processes. This section covers preparation of disulfides involving thiyl radicals and subsequent dimerization.
2.1.3.1. Using air. Sasson et al.⁵⁹ reported a very mild procedure using air as the oxidant in the presence of a mild base, anhydrous K₃PO₄. The reaction was carried out in acetonitrile at room temperature (Scheme 46). GC analysis of the mixture indicated complete conversion within 1–2 h. The oxidation reaction was efficient with alkyl, cycloalkyl, aryl and benzyl thiols. Heteroaromatic thiols were also effectively transformed to their corresponding disulfides.

Scheme 46 Potassium phosphate-mediated disulfide synthesis.

A mechanism (Scheme 47) was proposed by the authors where, in the presence of the phosphate base, a mercaptide anion is generated. The latter reacts with oxygen to yield a thiyl radical and peroxide (or superoxide) anion. The thiyl radical thus generated dimerizes to give the disulfide. The base is regenerated and therefore the ratio of base to the substrate (1 : 2) sufficed to complete the process. The authors claimed that the regenerated base can be recovered by filtration and after drying it could be reused.

Scheme 47 Plausible mechanistic pathway explaining the role of the base.

Shah et al.⁶⁰ reported the use of CsF–Celite as a solid base for the easy conversion of alkyl, aryl and heterocyclic thiols to disulfides (Scheme 48). Coupling of dithiols is also possible resulting in the formation of cyclic tetrasulfide products in approximately 80% yield. The fluoride ion activates the thiol group whose ionic character is increased owing to the low charge/surface area ratio of the Cs⁺ cation. The CsF–Celite may also activate the alkyl group by a Lewis acid type effect.^61a,b Heterogeneous solid base KF/Al₂O₃ (40%) has also been used under solvent-free and microwave-irradiated conditions for the conversion of thiols to disulfides.^61c,d

Scheme 48 CsF–Celite mediated disulfide synthesis.

An ultrasonicator has also been employed for the preparation of disulfide from thiols by usual oxidative coupling. Aryl, alkyl and heteroaryl disulfides were obtained in very good yields by the sonication of thiols at room temperature in DMF using Et₃N as a base (Scheme 49).⁶² The major advantage of this process is the significant acceleration by ultrasound (few minutes at room temperature). A reaction requiring 40 min at room temperature takes only 5 min for completion when the temperature is raised to 40 °C. Effective yields are also obtained from aminothiols and L-cysteine.

Scheme 49 Disulfide synthesis under sonication.

Conversion of thiols to disulfides using an activated carbon/molecular oxygen system was reported by Hayashi et al.⁶³ (Scheme 50). There is no reaction observed in the absence of activated charcoal even at 140 °C.

Scheme 50 Oxidation of aromatic/aliphatic thiols to disulfides using activated charcoal/molecular oxygen.

The method is not only applicable to aliphatic and aromatic thiols but also for 3,4-dihydropyrimidin-2(1H)-thiones and N-Boc-L-cysteine. The mechanism is outlined in Scheme 51. It was proposed that the thione undergoes oxidation and subsequent tautomerization results in the formation of thiol, and the latter finally oxidatively couples to produce the disulfide.

Scheme 51 Oxidation of functionalized 3,4-dihydropyrimidin-2(1H)-thiones.

The method is also extended to N-Boc-L-cysteine, which was converted to the corresponding disulfide in 75% yield (Scheme 52).

Scheme 52 Oxidation of N-Boc-L-cysteine.

We should also mention another example of cyclization which has been reported by Nakhmanovich et al.⁶⁴ During the reaction of α-acetylenic ketones 21 with a two-fold excess of sodium hydrosulfide in dry alcohol, apart from a minor amount of desaurines 22, 2,5-bis(β-acylmethylene)-1,3,4-trithiolane 23 was obtained. A mechanism has been suggested where the substituted trithiolanes 23 are proposed to form via the dithiol 24, which reacts with the intermediate 25 to give dithiols 26. When oxidized with aerial oxygen, the dithiols 26 form the corresponding trithiolanes 23 (Scheme 53).

Scheme 53 Synthesis of trithiolanes from α-bromoacetylene.

2.1.3.2. Using ascorbyl radical (in the absence of O₂). In a recent report, Kumar et al.⁶⁵ reported the oxidation of thiols to disulfides catalyzed by ascorbic acid (Scheme 54). The procedure finds applicability for a wide range of aliphatic and substituted aromatic thiols. The reaction was carried in water and under a N₂ atmosphere. The oxidation occurs cleanly at room temperature in a short reaction time and with high yields.

Scheme 54 Ascorbic acid-catalyzed disulfide synthesis.

The authors proposed that ascorbic acid after deprotonation forms the ascorbyl radical, which produces a thiyl radical from thiol, and finally two thiyl radicals undergo dimerization to generate the S–S bond (Scheme 55).

Scheme 55 Proposed mechanism involving ascorbyl free radicals.

2.1.3.3. Using metals. One of the simple methods for the oxidative coupling of alkyl and aryl thiols has been reported by Hosseinpoor and Golchoubian using urea–hydrogen peroxide (UHP) as the oxidant in the presence of a catalyst based on Mn(III) Schiff–base complex 27 (Scheme 56).⁶⁶

Scheme 56 Disulfide formation catalyzed by a Mn(III)-complex.

The Mn(III)-initiated free radical mechanism substantiated by experimental results has been proposed by the authors (Scheme 57). UHP is an odorless solid, which is safe, non-toxic, easy to use and releases hydrogen peroxide locally and water is the only expected by-product. At the end of the reaction, simple filtration yielded the product with adequate purity. The reaction has an appreciable functional group tolerance (Scheme 56). The catalyst was shown to possess stability and reusability. It was recycled four times without loss of activity. UV and IR spectroscopy of the recycled catalyst revealed no detectable change.

Scheme 57 Mn(III)-initiated free radical formation and subsequent dimerization.

Bis(2-hydroxybenzene)phthaldiimine (BHBPDI), a new quadridentate Schiff base ligand was used for complexing with Mn(III). The resulting manganese-based complex [Mn(III)(BHBPDI)Cl] was used for catalyzing the aerobic oxidation of thiols at room temperature (Scheme 58).⁶⁷

Scheme 58 Oxidation of thiols using Mn(III) complex.

A probable mechanism has been suggested by the authors, again through the formation of thiyl radical and subsequent dimerization. The reduced manganese species is further oxidized to Mn(III) under an acidic medium (Scheme 59). It was observed that electron-withdrawing substituents at the 2-position of aromatic moiety slow down the reaction, probably due to the instability of the thionyl radicals as well as steric effects. The thiols with heterocyclic rings are oxidized as the next preference, which is related to thiol–thione equilibriums of them in solution that make them difficult to be oxidized.

Scheme 59 Probable mechanism of Mn(III) complex catalyzed oxidation of thiols.

Co-Salophen is a Schiff–metal complex, whose catalytic and oxygen carrying capacities are widely recognized. A method of preparation of disulfides from thiols under air oxidation using this Co-Salophen as the catalyst (1 mol%) at 60 °C has been recently reported (Scheme 60).⁶⁸

Scheme 60 Oxidation of thiols to disulfides using Co-Salophen Schiff–metal complex.

The catalyst was recovered and can be reused for four runs. A probable mechanism was suggested by the authors involving oxygen free radicals, as outlined in Scheme 61.

Scheme 61 Mechanism of oxidation of thiols to disulfides using Co-Salophen.

Aerobic oxidation of thiols to disulfides catalyzed by diaryl tellurides such as bis(4-methoxyphenyl) telluride (An₂Te) (1 mol%) under photosensitized conditions has been reported by Oba et al.⁶⁹ The reaction does not proceed in the dark or in the absence of a photosensitizer. The sensitizer (0.1 mM) used was tetraphenylporphyrin (TPP) or Rose Bengal (RB). In this catalytic system, the active species is the tellurone oligomer, produced by the reaction of a telluride with singlet oxygen, which is capable of oxidizing thiols (Scheme 62). Alkyl, aryl, heteroaryl thiols as well as cysteine give excellent yields under the reaction conditions, but dithiols afforded the cyclic disulfides in comparatively low yields. The high toxicity of tellurides, however, limits its use.

Scheme 62 Plausible catalytic cycle for An₂Te-catalyzed oxidation of thiols to disulfides.

2.1.3.4. From thiocarboxylic acid. Aromatic thiocarboxylic acids have also been exploited for disulfane synthesis.⁷⁰ The method involves the Ag⁺-catalyzed oxidation of thiobenzoic and thiophene-2-carboxylic acids into the corresponding dibenzoyl disulfane under basic medium (Scheme 63).

Scheme 63 Ag⁺-catalyzed synthesis of disulfane from thiocarboxylic acid.

The mechanism is proposed to be analogous to the transition metal-catalyzed oxidation of thiols. In the catalytic cycle, thiobenzoate ions undergo Ag⁺-catalyzed radical formation, which is then dimerized to form the dibenzoyl disulfane. The reduced metallic silver is oxidized by oxygen and participates in the catalytic process. One molecule of water and half a molecule of dioxygen are also consumed in each cycle (Scheme 64).

Scheme 64 Ag⁺-catalyzed catalytic cycle for conversion of thiobenzoic acid to dibenzoyl disulfane.

2.2. From thiocyanates

Apart from thiol as the primary source for the preparation of disulfide, other S-containing starting materials have also been employed for their synthesis. Reductive dimerization of organyl thiocyanates constitutes another practical procedure for the preparation of symmetrical disulfides. Organic thiocyanates are easily available from the reaction between alkyl halides and potassium thiocyanate in refluxing ethanol. Other simple processes are also known for the preparation of organyl thiocyanates. Formation of disulfides via reductive dimerization of thiocyanates has been reported both under base-promoted and metal-catalyzed conditions.

2.2.1. Base-promoted reductive dimerization. Organic thiocyanates are considered as important compounds for the synthesis of heterocycles and have traditionally been used as pesticides.⁷¹ The treatment of a base (e.g. NaOH, NH₃) with organyl thiocyanates is known to generate symmetrical disulfides in moderate to good yields.⁷² The reaction is believed to occur via a simple nucleophilic displacement of the cyanide anion and subsequent attack of the thiolate anion to another thiocyanate molecule resulting in the formation of S–S bond. Since the use of bases could be harmful to the thiocyanates bearing base-sensitive functionality (for example, ester or keto-methyl), Burns et al.^72b developed a method (Scheme 65) where organyl thiocyanates undergo disulfide formation in the presence of excess of tetrabutylammonium fluoride (TBAF). The conditions do not however give good yields for cyclic disulfide formation, though intermolecular S–S bond formation is afforded in high yield.

Scheme 65 Formation of disulfides from thiocyanates.

Towards using heterogeneous bases, conversion of acid chlorides to acyl disulfides was studied in the presence of excess of elemental sulfur.⁷³ An efficient, mild and metal-free approach has been developed for the preparation of organic disulfides from alkyl/aryl and acyl methyl thiocyanates in the presence of poly-ionic resin hydroxide in aqueous medium (Scheme 66).⁷⁴ Organic disulfides were efficiently prepared in the presence of commercially available inexpensive ion-exchange resins, Amberlyst A-26 (OH). The poly-ionic resins are recovered by simple filtration, washed, and can be recycled with appreciable conversions of thiocyanates to corresponding disulfides. A comparison with other homogeneous bases (NaOH, NH₃, K₂CO₃) clearly establishes the advantage of using a poly-ionic resin hydroxide. The reaction occurs smoothly for aromatic thiocyanates (80–90%) except the nitro-substituted aryl thiocyanate (no conversion). This may be attributed to the strong electron-withdrawing nature of –NO₂, which possibly reduces the electron density on the S-atom. But benzoyl methyl thiocyanates undergo smooth conversion with 80% yield. Aliphatic thiocyanates or allyl thiocyanates also gave excellent yields. An attempt to synthesize unsymmetrical disulfides under the reaction conditions also gave positive results. The unsymmetrical disulfides were always formed in larger quantities as compared with the homo-coupled products.

Scheme 66 Disulfide synthesis from organyl thiocyanates promoted by a heterogeneous resin hydroxide base.

Towards mechanism of the reaction, it was proposed that in the presence of the heterogeneous base, the nucleophilic thiolate anion is formed initially, which displaces the cyanide ion of another organyl thiocyanate resulting in the formation of the disulfide. The ion-exchange resins possibly scavenge the liberated cyanide ion so as to free the product from toxic cyanide contamination. Formation of the cross-coupled products suggests the formation of the disulfides in a step-wise manner (Scheme 67).

Scheme 67 Plausible mechanism for disulfide synthesis using a heterogeneous poly-ionic resin hydroxide.

2.2.2. Metal-catalyzed dimerization. Samarium diiodide (SmI₂) mediated reduction of thiocyanates was reported by Zhang et al.⁷⁵ The thiocyanates reacted with an equivalent amount of SmI₂ in THF for 10–15 min. The desired disulfides were obtained in 75–85% yields (Scheme 68). It is speculated that SmI₂ might transfer one electron to thiocyanate to form the radical anion (R-S-CN)˙⁻, which was cleaved into RS˙ and CN⁻. The coupling of the thiyl radical (RS˙) gives the disulfide.

Scheme 68 Disulfide synthesis from long-chain alkyl thiocyanates promoted by SmI₂.

Chandrasekaran et al.⁷⁶ reported use of benzyltriethylammonium tetrathiomolybdate [(PhCH₂NEt₃)₂MoS₄] for the synthesis of disulfides from thiocyanates. Both acyclic and cyclic thiocyanates are capable of forming corresponding disulfides at room temperature. The tetrathiomolybdate anion 28 is not involved in the S-transfer, instead it mediates the reductive dimerization of the thiocyanate (Scheme 69).

Scheme 69 Synthesis of disulfide from thiocyanate using tetrathiomolybdate salt.

Zhang et al.⁷⁷ studied the oxidative dimerization of organyl thiocyanates using a combination of TiCl₄/Sm systems, the method is functional for both alkyl and aryl thiocyanates (Scheme 70).

Scheme 70 Disulfide from thiocyanate using a combination of TiCl₄/Sm.

2.3. From alkyl halides

2.3.1. Using metal catalysts. The most common reagent for the conversion of alkyl halides to disulfides has been a mixture of Na₂S and elemental sulfur, which gives moderate yields.⁷⁸ Dhar and Chandrasekaran,⁷⁹ with a view to exploit alkylations of tetrathiometalates of molybdenum and tungsten, reported disulfide synthesis from alkyl halides. The reaction of alkyl halides with pyridinuim tetrathiomolybdate 30 or pyridinium tetrathiotungstate 31 was carried out at room temperature in DMF for 0.5 to 1 h giving the desired disulfides in excellent yields (Scheme 71). They observed that benzyl chloride underwent reaction with the partial formation of benzyl thiol (20%), though benzyl bromide and iodide gave dibenzyl disulfide as the exclusive product.

Scheme 71 Transition metal-catalyzed disulfide synthesis from alkyl halides.

A tentative mechanism has been proposed for the reaction (Scheme 72). The first step involves either an alkylation across the M–S bond to facilitate the departure of RS⁻ or protonation of WS₄²⁻ (from the piperidinium cation) to help the departure of SH⁻ concomitant with dimerization to form the intermediate M₂S₇²⁻ ion 32. It is likely that the alkyl chlorides tend to yield thiols as a minor product as a consequence of the first step of the mechanism envisaged.

Scheme 72 Mechanistic pathway explaining transition metal-catalyzed disulfide synthesis.

The method is equally applicable to intramolecular reactions leading to cyclic disulfides. Reaction of 31 with α,α′-dibromo-o-xylene afforded the corresponding disulfide as the sole product in excellent yield. 1,3- and 1,4-dibromobutane also undergo reaction to give their corresponding cyclic disulfides in moderate yields (Scheme 73). Even a dibromocarboxylic acid [3-bromo-2-(bromomethyl)-propanoic acid] undergoes smooth reaction giving asparagusic acid (a naturally occurring 1,2-dithiolane) in good yield.

Scheme 73 Cyclic disulfides from dibromo compounds.

Chandrasekaran et al. have introduced benzyltriethylammonium tetrathiomolybdate as an efficient S-transfer reagent for the synthesis of disulfides from alkyl halides.⁸⁰ Several sugar halides,^80a and long chain halides,^80b and also in the cleavage of N-tosyl aziridine,^80c epoxides,^80d and alcohols,^80e have been converted to corresponding disulfides (Scheme 74).

Scheme 74 Synthesis of disulfides using benzyltriethylammonium tetrathiomolybdate.

A new S-transfer reagent, benzyltriethylammonium tetracosathioheptamolybdate [(C₆H₅CH₂N(Et)₃)₆Mo₇S₂₄], has been discovered by Kaushik et al.⁸¹ for converting alkyl halides to disulfides. The reaction was carried out at room temperature affording excellent yields (Scheme 75). The reaction was successful only for primary or secondary alkyl halides but fails for aryl halides. Even for tertiary butyl halide the yield is reported to be less than 20%.

Scheme 75 Disulfide from alkyl halide using a new Mo-complex as S-transfer agent.

Taniguchi reported the synthesis of diorganyl disulfides by the reaction of alkyl iodides with elemental sulfur, catalyzed by Cu-bpy, aluminum and sodium carbonate.⁸² Braga et al. improved upon the methodology using CuO nanopowder and a microwave-assisted procedure in the presence of a base but absence of any inert atmosphere (Scheme 76).⁸³

Scheme 76 CuO nanopowder-catalyzed disulfide synthesis from alkyl iodide.

A copper catalyst was also used in conjunction with potassium 5-methyl-1,3,4-oxadiazole-2-thiolate 33 that is proposed to be multifunctional, acting as the base, ligand, and sulfur-transfer reagent (Scheme 77).⁸⁴ Symmetrical disulfides were produced in DMF, although a temperature as high as 130 °C had to be employed to eliminate the sulfide by-product.

Scheme 77 Disulfide synthesis using CuCl and oxadiazole-thiolate.

2.3.2. Resin-embedded reagents. A convenient and rapid method for the synthesis of symmetrical disulfides from alkyl or aryl halides using sulfurated borohydride exchange resin (SBER) was reported by Bandgar et al.⁸⁵ The reaction takes place in dry methanol at room temperature and is completed in less than 5 min to give the corresponding disulfides in good to excellent yield (Scheme 78).

Scheme 78 SBER-promoted disulfide synthesis.

2.3.3. Using phase transfer catalysts (PTC). In pursuit of a simpler and rapid conversion of alkyl halides to disulfides, Sasson et al. reported the use of a phase transfer catalyst didecyldimethylammonium bromide (DDAB).⁸⁶ The method is based on the reaction of sulfur with sodium sulfide using DDAB as the catalyst. The process affords symmetrical disulfides at room temperature. Alkyl bromides were stirred with sulfur and aqueous sodium sulfide (in the ratio 1 : 2) in the presence of DDAB (4 mol%) at room temperature in a chloroform–water mixture for 2–9 h affording the desired disulfides in excellent yields (Scheme 79). Factors such as halide and the structure of the alkyl group were found to have a profound influence on the course of the reaction. Iodides reacted quickly, whereas chlorides were rather slow. The reactivity order for various alkyl/aryl groups was found to be: benzyl halide > primary alkyl halide > secondary alkyl halide > tertiary alkyl halide > aryl halide.

Scheme 79 Disulfide synthesis using PTC and sulfur.

They proposed a mechanism where aqueous sodium sulfide in the presence of sulfur forms Na₂S₂. This reacts with the phase transfer catalyst to form the ion pair Q₂S₂, which is transferred to the organic phase to react with the substrate and yield the product and regenerate the catalyst (Scheme 80).

Scheme 80 Proposed mechanism defining the role of PTC.

2.4. From alcohols

Iranpoor et al. described a method of synthesis of symmetrical disulfides from alcohols using heteroaromatic diazenes, ammonium thiocyanate and triphenylphosphine via the Mitsunobu reaction (Scheme 81).⁸⁷ Both primary and secondary acyclic as well as cyclic aliphatic alcohols gave a clean conversion under the reaction conditions. But the yield of the disulfide was found to be decreased with an increasing length of the carbon chain.

Scheme 81 Disulfide synthesis catalyzed by heteroaromatic diazenes.

The authors postulated that their reagent system first induces thiocyanation of the alcohol to generate the alkyl thiocyanate intermediate 37, which is attacked by 36 to generate the desired disulfide (Scheme 82). They have corroborated their presumed mechanism by performing NMR, mass & IR spectroscopy of the compound 38 that was isolated as a yellow precipitate.

Scheme 82 Mechanistic pathway involving heteroaromatic azo-compound via alkyl thiocyanate.

2.5. From acid chlorides

Disulfides have been synthesized by reacting elemental sulfur with acid chlorides in the presence of a resin (Amberlyst A-26 OH⁻ form) in benzene (Scheme 83).^73a The authors presume the formation of S₂²⁻ species from sulfur in the presence of the hydroxide resins, since diacyl disulfides were the sole products of the reaction in high yields. The use of an excess amount of elemental sulfur and high reactivity of acyl chloride remain major limitations for this methodology.

Scheme 83 Disulfides from acid chloride using elemental sulfur in the presence of a heterogeneous base.

2.6. From sulfonyl chloride

Aryl sulphonyl chloride has been employed as a starting material for the synthesis of symmetrical disulfide using PPh₃ in anhydrous THF (Scheme 84).⁸⁸ Excess use of PPh₃, maintaining strictly dry conditions and recovery of the disulfide product from excess PPh₃ and the oxidized phosphine (Ph₃PO) restrain this method from broader applications. The procedure is mostly limited to aromatic thiols.

Scheme 84 Formation of diaryl disulfide from aryl sulfonyl chloride.

The mechanism of the reaction is not well-defined and two possibilities are suggested. Isolation of Ph₃PO indicates that the reaction might proceed through the reduced intermediate (ArSCl). On the other hand, formation of the cross-coupling product 4-bromophenyl-4-tolyl disulfide, as detected by GC–MS from the reaction of an equimolar mixture of para-toluenesulfonyl chloride and para-bromosulfonyl chloride, suggests the possibility of radical intermediates in the process.

2.7. From disulfides

A completely new class of polymers, functionalized with the S–S bond, poly(disulfidediamines), was synthesized in high yield from a diamine monomer in the presence of imide-based disulfide transfer reagent 39.⁸⁹ Disulfide transfer agents based on succinimide and phthalimide are well-known in the literature and are prepared by the reaction of the imide with S₂Cl₂ (Scheme 85).⁹⁰

Scheme 85 Preparation of imide-based disulfide transfer agent.

In the polymerization reaction, the secondary amine undergoes a transamination reaction with the disulfide diamine functional group along the backbone of the polymer 40 (Scheme 86). This leads to a broadening of the polydispersity of the polymer and affects its final stability if an amine is the end group of the polymer. These polymers are characterized by high stabilities, they are easy to handle, and they possess no noticeable odor. They do, however, decompose at high temperature (175 °C), presumably by the homolytic cleavage of the S–S bond in these polymers, to yield highly reactive sulfur-based radicals. On the other hand, studies with similar small molecules revealed that the disulfidediamine functional group undergoes rapid decomposition in methanol/water systems in the presence of a carboxylic acid, which is an important degradative pathway for polymers used in drug and gene delivery.

Scheme 86 Synthesis of diaminedisulfide-functionalized polymer 40.

Thayumanavan and coworkers reported the synthesis of a disulfide-linked block copolymer.⁹¹ The diblock copolymer, PS–ss–PEO, was synthesized by the RAFT (reversible addition fragmentation chain transfer) polymerization of styrene with a PEO-based macroinitiator containing a disulfide bond. Reaction of monomethylated PEO with thioglycolic acid produces 41, which was then attached to the RAFT initiator through the thiol functionality to get the macroinitiator 42 (Scheme 87).

Scheme 87 Synthesis of PS–ss–PEO block copolymer via a thiol–disulfide exchange process.

3. Disulfides of importance in nano- & bio-science

3.1. As nano materials

Over the last decade, self-assembled monolayers (SAMs) of disulfides on gold and other metals have found vast applications as surface coatings, in micro- and nano-fabrication, in molecular electronics, in sensory applications, as molecular lubricants etc., and more new applications are likely to be developed. Because of the vast applications of ω-functionalized long-chain disulfides as potential building block of SAMs, several methods have been developed for their synthesis.⁹² Assessing the vast repertoire of these methods is a review in itself, so only a few representative examples has been included in this section.

The development of a procedure for the immobilization of monolayers of highly reactive thiopyridyl groups on oxidized Si <100> surfaces has been reported by Ledung et al.^93a The method has been optimized with respect to reaction times both for the evaporation of (3-mercaptopropyl)triethoxysilane (MPTS) on the wafers and for the concomitant solvent-dependent reaction for the formation of monolayers of reactive disulfides (Scheme 88). In their approach, the (3-mercaptopropyl)triethoxysilane (MPTS) was treated with 2,2′-dithiopyridine and 2-thiopyridone at pH < 7.5 to afford the silica-immobilized unsymmetrical disulfide.

Scheme 88 Reactions Involved during funtionalization of mercaptopropyl-derivatized silicon wafers.

In a recent approach, Lin and his coworkers demonstrated the synthesis of mesoporous silica nanoparticle (MSN)-based cysteine disulfide (MSN–S–Cys) via 2-pyridinyldisulfanylpropyl-functionalized MSN (Scheme 89).^93b

Scheme 89 Synthesis of mesoporous silica nanoparticle-linked cysteine disulfide via 2-pyridyl disulfanyl derivative.

3.2. Disulfides in biology

It has long been known that the formation of disulfide bonds between pairs of cysteine residues is essential for the folding and stability of many proteins. Enzymatic redox catalysts are believed to effect in vitro thiol–disulfide exchange reactions. The search for enzymatic catalysts revealed the discovery of the enzyme protein disulfide isomerase (PDI), which can catalyze the S–S bond formation, reduction and isomerization depending upon the redox conditions. The core pathway for the disulfide bond formation in the endoplasmic reticulum (ER) of eukaryotic cells has been identified as the ER membrane flavoprotein, Ero1 generated disulfide bond transfer to secretory proteins via PDI.⁹⁴ In a recent study, Cumming and coworkers isolated disulfide-bonded proteins (DSBP) in mammalian neuronal cell line (HT22) and exposed to various oxidative insults. Their studies revealed that the disulfide bond formation within families of cytoplasmic proteins is dependent on the nature of the oxidative insults.⁹⁵

Naturally occurring water-soluble thiols such as cysteine and glutathione can be converted to corresponding disulfides in the presence of a Mn(CO)₅Br catalyst with the evolution of hydrogen.⁹⁶ This has demonstrated that biological thiol–disulfide exchange reactions in the presence of corresponding enzymes effectively convert protons into hydrogen without sacrificing any thiols.

3.2.1. Enzyme-catalyzed disulfide formation. Laccases are easily available multi-copper oxidases produced by fungi, plants and prokaryotes. These enzymes catalyze the oxidation of organic molecules using molecular oxygen under mild conditions. Beifuss et al. exploited laccases from Trametes versicolor and Agaricus bisporus for the oxidative coupling of heterocyclic thiols (Scheme 90).⁹⁷ The reactions however require an appreciably long time (72 hours) for complete conversion. The method A yields disulfides ranging from 5–47% whereas method B yields 18–50%. To improve the yields, method A was modified taking 200 U laccase and 2.5 mol% 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) as the mediator, the other conditions being kept the same. The modification created a huge improvement in the yields, which now ranged from 50–95%.

Scheme 90 Laccase-catalyzed oxidative coupling of heterocyclic thiols.

The authors proposed that the laccase oxidizes ABTS to the corresponding ABTS radical accompanied by the reduction of O₂ to H₂O. This is followed by the dimerization of thiols to disulfides. The cycle is completed with the reduction of the ABTS radical to ABTS (Scheme 91).

Scheme 91 Proposed catalytic cycle for the laccase–ABTS-catalyzed oxidation of heterocyclic thiols to corresponding disulfides.

3.2.2. Disulfides from biomolecules. The naturally occurring opium alkaloid thebaine 43 is a suitable starting material in the synthesis of several 2-substituted dopaminergic aporphines. Berényi et al.⁹⁸ reported a synthesis of S–S linked bis-aporphine from thebaine. Hydrolysis of thebaine 43 with methane sulfonic acid at 90 °C gave a low-yield product 44 instead of the expected thiol. The multicomponent reaction takes place in the presence of potassium thiocyanate. This was shown to be a disulfide type bis-aporphine. Interestingly, reduction of the thiocyanato derivative 46 with sodium borohydride in ethanol also afforded the disulfide 44 (Scheme 92). The product 44 is a disulfide and not a thiol, as was confirmed by Welsh acylation,⁹⁹ as the product did not give the 11-o-acetyl derivative of the expected of the thiol.

Scheme 92 Synthesis of S–S linked bis-aporphines from naturally occurring thebaine.

Chemical modifications of naturally occurring nucleosides and nucleotides have led to a large number of analogues used for their therapeutic properties, especially owing to their antiviral and antitumoral activities.¹⁰⁰ Among these, many S-containing molecules show interesting biological activities.¹⁰¹ 2-(Trimethylsilyl)-ethyl sulfides are versatile intermediates that can be selectively converted into their corresponding methyl disulfides.¹⁰² Using this chemistry an interesting reaction of 2′-uridine sulphide 47 in dichloromethane was reported by Décout et al.¹⁰³ The reaction was carried out with cyanogen bromide under reflux conditions. A white precipitate was obtained, which after purification by column chromatography gave 70% yield. It was characterized as the symmetric uridine disulfide 48 by comparison with a prepared authentic sample (Scheme 93).

Scheme 93 Synthesis of uridine disulfide mediated by BrCN.

Reverse transcriptase (RT) is a key enzyme in the HIV replication cycle and is one of the main targets in the development of drugs for treating HIV infection and AIDS.¹⁰⁴ Non-nucleoside RT inhibitors (NNRTIs) bind to an allosteric hydrophobic pocket located at about 10 Å away from the polymerase active site and lock the enzyme into an inactive form by affecting the geometry of the polymerase active site aspartyl residues.¹⁰⁵ A new synthetic method to prepare symmetric formimidoester disulfides from thiocarbamates (Scheme 94) was reported, which is shown to function as a NNRTI.¹⁰⁶

Scheme 94 Symmetric formimidoester disulfide from thiocarbamates.

An eight-membered ring consisting of a vicinal disulfide ring (VDR) is a rare motif in protein structures and is functionally important to those few proteins that posses it. Hondal et al.¹⁰⁷ have reported the synthesis of various strained and unstrained VDR mimics (49, 50) (Scheme 95).

Scheme 95 Synthesis of VDR mimics.

Peptides represent a class of therapeutic candidates that often suffer from cellular uptake problems. Covalent attachment of cell permeable moieties (CPMs) to bioactive peptides is essential for the cellular transport of the latter. Reversible conjugation of CPMs via a disulfide linkage is a strategy for peptides targeted for an intracellular milieu, where the highly reducing environment within a cell reduces the intermolecular disulfide bridge to liberate the bioactive peptide.¹⁰⁸

Zoller et al. suggested that for the peptidomimetic synthesis,¹⁰⁹ where the risk of racemisation is different, it might be interesting to attach the molecule with the resin directly through the thiol, which increases the flexibility of chain elongation. Accordingly, they set out a reaction strategy with Wang resin to prepare a macrocyclic disulfide involving two cysteines and a β-alanine in the presence of NCS (Scheme 96). The complex NCS/DMS is a very mild reagent, compatible with a large number of protective groups, which promotes the formation of a macrocyclic disulfide from a sulfide and a thiol in the solid phase.

Scheme 96 Resin-supported approach for the synthesis of macrocyclic disulfide.

Galande et al.¹¹⁰ reported the synthesis of an orthogonal disulfide template 51 and its use to synthesize unsymmetrical intermolecular disulfide bond peptides on a solid support. Template 51 was constructed from Boc–Cys(Npys)–OH, Fmoc–Cys(Mmt)–OH, and 4-methylbenzhydrylamine (MBHA) resin. A mixture of these protected amino acids in a molar ratio of 1 : 1.3 was loaded onto MBHA resin (substitution level of 1.2 mmol g⁻¹) using DCC and HOBt as coupling reagents to achieve equimolar loading. The Mmt side chain protecting group was selectively cleaved from the Fmoc-protected cysteine by treating the resin with 1% TFA in DCM by a continuous flow method. This rendered the thiol free to attach on the adjacent Npys protecting group of the Boc-protected cysteine to form intermolecular and unsymmetrical disulfide bonds while maintaining the orthogonal Boc and Fmoc protection of the amines (Scheme 97). This modified MBHA support with a built-in intermolecular disulfide bridge finds use as an orthogonal template for the synthesis of disulfide heterodimers of peptides or other organic molecules. Cystine and β-substituted cystine derivatives which are incorporated in many peptide sequences are known to possess diverse biological activities. The introduction of an appropriate β-substituted cystine into a peptide sequence preserves the side chain orientation and restricts the C–S–S–C dihedral angle. Hence, there is a need for an efficient approach for the synthesis of β-substituted cystine and its diastereomers in an enantiomerically pure form. Another on-resin disulfide formation in solid-phase peptide synthesis using N-chlorosuccinimide has been reported very recently by Postma and Albericio.^110c Another recent example describes the synthesis of cyclic peptides containing vicinal disulfide linkages. The constrained cyclic disulfide scaffold improves both the chemical and biological stability while maintaining full potency.^110d

Scheme 97 Synthesis of dilsulfide heterodimers of peptides.

Chandrasekaran et al.¹¹¹ investigated the chemistry of benzyltriethylammonium tetrathiomolybdate [BnNEt₃]₂MoS₄ 52 for the synthesis of 3,3′-dimethylcystine and its diastereomers from L-threonine in an enantiomerically pure form. The reaction of tosylate 53a with KSCN in acetonitrile and the resulting thiocyanate was treated with tetrathiomolybdate 52 (1.2 equiv., CH₃CN, 28 °C, 10 h), and underwent reductive dimerization to give the allo-3,3′-dimethylcystine derivative 54a in 92% yield without loss of enantiomeric purity (Scheme 98). This methodology could be extended to the synthesis of Boc- and Fmoc-protected 3,3′-dimethylcystine derivatives 54b and 54c with the same efficiency.

Scheme 98 Synthesis of an allo-3,3′-dimethylcystine derivative.

The next target was the synthesis of threo-3,3′-dimethylcystine derivatives. Compound 55a was treated with an excess of KSCN followed by reductive dimerization with tetrathiomolybdate 52 (1.2 equiv., CH₃CN, 28 °C, 10 h) resulting in the threo-3,3′-dimethylcystine derivative 52a in excellent yield (Scheme 99). This methodology was extended further for the synthesis of Boc and Fmoc-protected threo-3,3′-dimethylcystine derivatives 56b–c.

Scheme 99 Synthesis of threo-3,3′-dimethylcystine derivatives.

4. Summary and outlook

It is evident from the above discussion that thiols, which are commercially available or easily synthesizable, remain the major choice as the starting materials for the synthesis of disulfides. The formation of the S–S bond in disulfide generally involves thiolysis or occurs via radical formation and subsequent dimerization. A fair overview is that the formation of the S–S bond in disulfide is more common with aromatic thiols than alkyl thiols. Moreover, the synthesis of cyclic disulfanes and methods for the selective preparation of unsymmetrical disulfides are limited, and for the latter, the thiol–disulfide exchange reactions remain the most popular method. Organic compounds bearing other functional groups have been less commonly utilized, possibly because of their high reactivity and sometimes limited accessibility. Although the S–S bond plays an essential role in many in vivo biochemical processes, enzyme-catalyzed in vitro processes have also been much less explored. The applications of organic disulfides are incredibly vast, ranging from biochemical processes to industrial and pharmaceutical chemistry, and also to other emerging areas of bioconjugates, peptidomimetics, self-assembled monolayers (SAMs) etc. It is therefore imperative that more general, improved and eco-friendly methodologies should be developed for the synthesis of both symmetrical and unsymmetrical disulfides.

Acknowledgements

We are pleased to acknowledge financial support from the Department of Science and Technology (DST) and the Council for Scientific and Industrial Research (CSIR), New Delhi, India for our research. The authors are thankful to reviewers for comments, which were useful to improve the article.

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