Rapid and efficient synthesis of symmetrical alkyl disulfides under phase transfer conditions

Article abstract of DOI:10.1016/j.tetlet.2007.06.074

A one-pot, rapid and general method for the synthesis of symmetrical disulfides based on reaction of sulfur with sodium sulfide in the presence of didecyldimethylammonium bromide (DDAB) as a phase transfer catalyst is reported. Reaction with a variety of alkyl halides, at room temperature, afforded the disulfides in good to excellent isolated yields in a short time.

Full text of DOI:10.1016/j.tetlet.2007.06.074

Tetrahedron Letters 48 (2007) 6048–6050
Rapid and efficient synthesis of symmetrical alkyl disulfides
under phase transfer conditions
Sachin U. Sonavane, Mandan Chidambaram, Joseph Almog and Yoel Sasson*
Casali Institute of Applied Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
Received 6 May 2007; revised 5 June 2007; accepted 14 June 2007
Available online 20 June 2007
Abstract—A one-pot, rapid and general method for the synthesis of symmetrical disulfides based on reaction of sulfur with sodium
sulfide in the presence of didecyldimethylammonium bromide (DDAB) as a phase transfer catalyst is reported. Reaction with a vari-
ety of alkyl halides, at room temperature, afforded the disulfides in good to excellent isolated yields in a short time.
Ó 2007 Elsevier Ltd. All rights reserved.
Disulfides are important compounds possessing unique
and diverse chemistry in the synthetic and biochemical
areas. Large disulfide-linked aggregates are prevalent
in proteins and many other bioactive molecules.1 Indus-
trially, disulfides find wide applications as vulcanizing
agents for rubbers and elastomers, giving them excellent
tensile strength. Several methods for the preparation of
organic disulfides have been described.2 Numerous
reagents and catalysts have been applied to oxidize
thiols to disulfides under controlled conditions.3 Disul-
fides can be easily prepared by electrochemical oxidation
of the corresponding thiols in methanol/sodium meth-
oxide solution under conditions of constant current.4
The catalytic couplings of thiols using Fe(III) and NaI
have been reported.5 Disulfides were also synthesized
from thiol acetate with clayfen in the absence of sol-
vent,6 and via oxidative cleavage of aryl or alkyl tert-
butyl sulfides.7 Recently, we reported the synthesis of
disulfides through the oxidative coupling of thiols using
oxygen in the presence of potassium phosphate as cata-
lyst.8 Phase transfer catalysis (PTC) has been applied for
the solid–liquid or liquid–liquid reactions of sulfide salts
with alkyl halides. Landini and Rolla used Na2S for the
synthesis of symmetrical thioethers.9 This process was
further studied by Sharma and Pradhan10 and by Wang
and Tseng.11 Aliphatic polysulfides were prepared by
PTC reaction of Na2S with dibromoalkanes.12 Na2S
was also widely used for the reduction of nitroarenes
to anilines under PTC conditions.13
Disulfide and other polysulfide anions are easily ob-
tained by mixing aqueous solutions of S2ꢀ with sulfur.
Several analytical methods were recently developed to
assess the polysulfide distribution in various sulfur/sul-
fide mixtures.14
A mixture of Na2S with sulfur was used by Aizenshtat in
a Michael type reaction with unsaturated ketones to
yield disulfides.15 Hase used Li2S2 for the preparation
of dialkyldisulfides.16 The same reagent was later used
for the synthesis of cyclic disulfides.17 The conversion
of aryl/acyl halides to disulfides has also been carried
out using Na2S2, which requires a long reaction time,
and presented difficulties in isolation and required high-
er temperatures.18a,b
Despite the plethora of methods available in the litera-
ture for the synthesis of disulfides, the search for a sim-
ple and rapid conversion of alkyl halides to disulfides is
still a challenge and an interesting area of research. In
continuation of our ongoing research on exploring
DDAB as a phase transfer catalyst19 here we report
the synthesis of disulfides from alkyl halides using
DDAB as catalyst. The process affords symmetrical
disulfides in good to excellent isolated yields. The reac-
tion is fast, and is carried out at room temperature
(Scheme 1).
In a generalized procedure benzyl bromide (in an organ-
ic solvent) was stirred with aqueous sodium sulfide and
sulfur in the presence of various phase transfer catalysts
at room temperature. We investigated the effect of differ-
ent PTCs on the reaction rate and selectivity. When
*
Corresponding author. Tel./fax: +972
ysasson@huji.ac.il
2 6528 250; e-mail:
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.074

S. U. Sonavane et al. / Tetrahedron Letters 48 (2007) 6048–6050
6049
Table 1. Effect of various phase transfer catalysts on the synthesis of
dibenzyl disulfide
S
Entry
PTCa used
Conversionb (%)
Yieldc (%)
Br
S
PTC, Na2S, S, H2O
2 h, 25 ˚C
1
2
3
4
TBAB
95
91
100
83
88
80
96
68
TBMAB
DDAB
PEG-300
Scheme 1.
Reaction conditions: A mixture of sulfur powder (0.32 g, 10 mmol),
sodium sulfide (1.56 g, 20 mmol), and water (5 ml) was stirred at 50 °C
for 30 min. The solution was cooled to rt, PTC (4 mol %) was added,
followed by substrate (20 mmol) and chloroform (5 ml) and stirring
continued at 25 °C for 2 h.
DDAB was used, the yield of the dibenzyl disulfide was
high (96%) with complete conversion. The efficiency of
the PTCs studied decreased in the order DDAB >
TBAB > TBMAB > PEG-300. The results are summa-
rized in Table 1.
a TBAB—Tetrabutylammonium bromide; TBMAB—Tributylmethyl-
ammonium bromide; DDAB—Didecyldimethyl-ammonium bro-
mide; PEG—Polyethylene glycol.
b Conversion based on gas-chromatography analysis with area
minimization.
c Isolated yields.
The potential of various solvent systems such as tolu-
ene–water, methylene chloride–water, chloroform–water
and ethyl acetate–water were examined in the synthesis
of dibenzyl disulfide. The chloroform–water mixture
was found to be the superior solvent system for the
reaction.
alkyl halide > aryl halide. While benzyl halides reacted
rapidly because of the stabilization of the incipient posi-
tive charge, the lack of reactivity of tertiary halides is
ascribed to steric hindrance. The reactions of aryl halides
did not occur favourably under these conditions.
Amongst alkyl halides, bromides were more reactive
than the corresponding chlorides, which made it possible
to carry out the selective synthesis of the disulfide of
1-bromo-3-chloropropane. Thus, in this study we have
been able to demonstrate the utility and efficiency of
DDAB as a phase transfer catalyst.
To explore further the utility of this catalytic system,
several alkyl halides were reacted under the above con-
ditions (Table 2). All were converted into the corre-
sponding disulfides in excellent yields. Disulfides were
found to be the only products under the optimized reac-
tion conditions.
Factors such as halide and the structure of the alkyl
group profoundly influenced the course of the reaction.
For example, iodides reacted quickly, whereas chlorides
were rather slow. Studies were carried out to understand
the influence of structural variations on the alkyl moiety.
The reactivity order was found to be: benzyl halide >
primary alkyl halide > secondary alkyl halide > tertiary
We propose a putative reaction mechanism where, in the
presence of sulfur, aqueous sodium sulfide forms
Na2S2.10 The latter reacts with the phase transfer cata-
lyst to form the ion pair Q2S2, which is transferred to
Table 2. Synthesis of various disulfides using didecyldimethylammonium bromide as phase transfer catalysta
Entry
Reactant
Time (h)
Product
Conversionb (%)
Yieldc/(mp/bp) (%)
S
S
Br
Cl
S
S
1
2
100
96 (67 °C)
2
4
96
88 (65 °C)
S
3
4
2
6
100
98
91 (80 °C)
80 (44 °C)
I
S
S
Cl
Cl
Br
Cl
S
5
6
CH3(CH2)8Br
CH3–CH2–I
4
2
CH3(CH2)8–S–S–(CH2)8CH3
CH3–CH2–S–S–CH2–CH3
79
85 (oil)
100
95 (152 °C)
7
9
71
90
62 (70 °C)
Br
S
S
S
Cl
Br
S
8
5
80 (62 °C)
Cl
Cl
a Reaction conditions: A mixture of sulfur powder (0.32 g, 10 mmol), sodium sulfide (1.56 g, 20 mmol), and water (5 ml) was stirred at 50 °C for
30 min. The solution was cooled to rt, DDAB (4 mol %) was added, followed by substrate (20 mmol) and chloroform (5 ml) and stirring continued
at 25 °C.
b Conversion based on gas-chromatography analysis with area minimization.
c Isolated yields.

6050
S. U. Sonavane et al. / Tetrahedron Letters 48 (2007) 6048–6050
2. (a) Karchmer, J. H. The Analytical chemistry of Sulfur and
its Compounds; Wiley: New York, 1972; (b) Kuhle, E. The
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the organic phase to react with the substrate to yield the
dialkyl disulfide and the catalyst as follows:
Na2SðaqÞ þ S
! Na2S2ðaqÞ
ðaqÞ
Na2S2ðaqÞ þ 2QX
! Q S2ðorgÞ þ 2NaX
ðaqÞ
ðorgÞ
2
2PhCH2Br þ Q2S2ðorgÞ ! ðPhCH2SÞ2 þ 2QBr
Since it is known that the nature of the polysulfide anion
in water ðS2xꢀ where x ¼ 2; 3; 4; 5Þ can be determined by
controlling the sulfide/sulfur ratio,20 we believe that tri,
tetra and higher dialkyl polysulfides can be synthesized
using the method described above.
In conclusion, a simple, efficient and practical method
has been developed for the synthesis of symmetrical
alkyl disulfides using DDAB as a phase transfer catalyst.
General procedure: A mixture of sulfur powder (0.32 g,
10 mmol), sodium sulfide (1.56 g, 20 mmol) and water
(5 ml) was stirred vigorously for 30 min at 50 °C. After
dissolution, the reaction mixture was cooled to room
temperature and DDAB (4 mol %) was added. A
mixture of substrate (20 mmol) and chloroform (5 ml)
was added and the mixture was stirred for an appro-
priate period at 25 °C. The progress of the reaction
was monitored by GC. After completion of the reac-
tion, the product was extracted with two consecutive
portions of diethyl ether; the combined organic layers
were washed well with water and dried over sodium sul-
fate. The organic layer was concentrated under reduced
pressure to afford a crystalline (or liquid) dialkyl
disulfide.
Pure solid products were obtained by purification on a
short silica gel column using petroleum ether as the
eluent and recrystallization from ethanol. All the prod-
13. Pradhan, N. C.; Sharma, M. M. Ind. Eng. Chem. Res.
1992, 31, 1606.
14. Kamyshny, A.; Ekeltchlk, I.; Gun, J.; Lev, O. Anal. Chem.
2006, 78, 2631.
1
ucts had satisfactory H NMR, IR and elemental ana-
15. Krein, E. B.; Aizenshtat, Z. J. Org. Chem. 1993, 58,
6103.
lysis data and were compared with authentic samples.
16. Hase, T. A.; Perakyla, H. Synth. Commun. 1982, 12,
947.
Acknowledgement
17. Weyerstahl, P.; Oldenburg, T. Flavour Fragr. J. 1998, 13,
177.
18. (a) Toru, T.; Kenjiro, I.; Kawanobe, T. Japan Patent, JP
2001039947, 2001; Chem. Abstr. 2001, 134, 162815; (b)
Gopalan, A. S.; Jacobs, H. K. J. Chem. Soc., Perkin
Trans. 1 1990, 1897.
M.C. is grateful to the Pikovski-Valazzy Fund for their
support.
References and notes
19. Chidambaram, M.; Sonavane, S.U.; Zerda, J.; Sasson, Y.
Tetrahedron, in press. (doi:10.1016/j.tet.2007.05.017).
20. Jaroudi, O. E.; Picquenard, E.; Gobeltz, N.; Demortier,
A.; Corset, J. Inorg. Chem. 1999, 38, 2917.
1. Bodzansky, M. Principles of Peptide Synthesis; Springer:
Berlin, 1984, Chapter 4.