A rapid and efficient synthesis of symmetrical disulfides under microwave irradiation conditions

Article abstract of DOI:10.1081/SCC-120003143

A rapid and general method for the synthesis of symmetrical disulfides involves reaction of sulfur with sodium hydroxide under PTC-microwave irradiation condition to give sodium disulfide, which reacts with alkyl halides to afford the disulfides in good to excellent isolated yields.

Full text of DOI:10.1081/SCC-120003143

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A RAPID AND EFFICIENT SYNTHESIS OF SYMMETRICAL
DISULFIDES UNDER MICROWAVE IRRADIATION
CONDITIONS
Jin-Xian Wang a , Lijuan Gao b & Danfeng Huang a
a Department of Chemistry, Institute of Chemistry, Northwest Normal University, 95 An Ning
Road (E.), Lanzhou, 730070, China
b Department of Chemistry, Ningxia University, Yinchuan, 75000, China
Published online: 21 Aug 2006.
To cite this article: Jin-Xian Wang , Lijuan Gao & Danfeng Huang (2002): A RAPID AND EFFICIENT SYNTHESIS OF SYMMETRICAL
DISULFIDES UNDER MICROWAVE IRRADIATION CONDITIONS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:7, 963-969
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SYNTHETIC COMMUNICATIONS, 32(7), 963–969 (2002)
A RAPID AND EFFICIENT SYNTHESIS OF
SYMMETRICAL DISULFIDES UNDER
MICROWAVE IRRADIATION
CONDITIONS
Jin-Xian Wang,1, Lijuan Gao,2 and Danfeng Huang1
*
1Institute of Chemistry, Department of Chemistry,
Northwest Normal University, 95 An Ning Road (E.),
Lanzhou, 730070 China
2Department of Chemistry, Ningxia University,
Yinchuan, 75000 China
ABSTRACT
A rapid and general method for the synthesis of symmetrical
disulfides involves reaction of sulfur with sodium hydroxide
under PTC-microwave irradiation condition to give sodium
disulfide, which reacts with alkyl halides to afford the disul-
fides in good to excellent isolated yields.
Disulfides are important organic sulfur compounds possessing a unique
and rich chemistry in the synthetic and biochemical area. For example, large
disulfide-linked aggregates are prevalent in proteins and many other bioactive
molecules.1 Industrially, disulfides find wide applications as vulcanizing
agents for rubbers and elastomers, giving them excellent tensile strength.
*Corresponding author.
963
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

964
WANG, GAO, AND HUANG
Several methods for the preparation of organic disulfide have been
described.2–6 Many reagents and catalysts have been introduced to oxidize
thiols to disulfides under controlled conditions.7–23 Disulfides can be easily
prepared by electrochemical oxidation of the corresponding thiols in
methanol/sodium methoxide solution under conditions of constant cur-
rent,24 thiol acetate with clayfen in the absence of solvent,25 and oxidative
cleavage of aryl or alkyl tertbutyl sulfides.26 Recently, the catalytic coupling
of thiols and new methods have been reported.27 Although there are a
number of methods available in the literature for the synthesis of disulfides,
the most commonly employed method for the direct conversion of benzyl
halides to disulfides has been using Na2S2 or Na2S/S.28 However, these
methods suffer from severe disadvantages, such as long reaction times and
operational complications.
In recent years, microwave-induced rate acceleration technology has
become a powerful tool in organic synthesis, because of milder reaction
conditions, reduction of reaction times, enhanced selectivity, and associated
ease of manipulation. Microwave irradiation has also been applied to
several organic reactions. It has been used for a great variety of organic
reactions, such as Reformatsky, Knoevenagel, Bischler–Napieralski, ether-
ification, esterification, oxidation, hydrolysis, Diels–Alder reactions and
solid-phase peptide synthesis. Some important reviews have been pub-
lished.29 We have reported the synthesis of substituted glycerol selenide
ether and chiral glycerol sulfide ethers under sulfur in base under PTC-
microwave irradiation to afford the symmetrica disulfides in good to excel-
lent isolated yields. The results are summarized in Table 1.
These results show that the phase transfer catalyst is not only involved
in the formation of the disulfide ion in solution, but also catalyses the
substitution reaction on the alkyl chlorides.
Using the reaction of benzyl chloride with sulfur as an example, we
investigated the effect of phase transfer catalysts (PTC) on the reaction.
When PEG-400 was used as a phase transfer catalyst, the yield of
the dibenzyl disulfide was high (91%). The efficiency of several PTCs
studied is in the order PEG-400 ffi PEG-600 > n-C16H33NMe3Br >
Bu4NBr > Me4NI: The results are summarized in Table 2.
The effects of various solvents used in the formation of dibenzyl
disulfide were studied and DMF was found to be the best solvent for
the reaction. Because DMF is a polar solvent and its boiling point is
high, it can efficiently absorb microwave energy. Other solvents were studied
for these reactions and their suitability are in the order DMF>
EtOH>butanol>acetone>benzene.
We have also investigated the effects of irradiation power and time on
the reactions. It was found that the highest yield of compound 3 is obtained

SYMMETRICAL DISULFIDES
965
NaOH, PEG-400
2RX þ 2S ÀÀÀÀÀÀÀÀÀÀÀ! RSSR
DMF, MW, 6À7 min
Table 1. Synthesis of Disulfides 3a- Under PTC-Microwave Irradiationa
Irradiation
Condition
Power (W)/ Yieldb
Entry
R
X
Product
Time (min)
(%)
1
2
3
4
5
6
7
8
9
t-C4H9
n-C5H11
Cl (t-C4H9S)2
Cl (n-C5H11S)2
(3a)
(3b)
(3c)
(3d)
(3e)
(3f)
375/6
375/6
375/6
375/6
375/6
375/6
375/7
375/7
375/6
90
88
90
91
85
81
67
65
90
CH2 ¼ CH-CH2 Cl (CH2¼CH-CH2S)2
C6H5CH2
4-ClC6H4CH2
2-BrC6H4CH2
Cl (C6H5CH2S)2
Cl (4-ClC6H4CH2S)2
Br (2-BrC6H4CH2S)2
4-O2NC6H4CH2 Br (4-O2NC6H4CH2S)2 (3g)
2-O2NC6H4CH2 Br (2-O2NC6H4CH2S)2 (3h)
2-C10H7CH2
Br (2-C10H7CH2S)2
(3i)
aThe reactions were carried out in the presence of NaOH using PEG-400 as catalyst
b
in DMF under microwave irradiation condition; Isolated yield.
Table 2. Effect of Phase Transfer Catalyst on the Formation of (3d)a
Catalyst
(C4H9)4NBr
76.2
n-C16H33N(CH3)3Br
PEG-600
89.3
PEG-400
91
Yieldb (%)
82
aThe reaction was carried out in DMF at a power level of 375 W for 6 min; bIsolated
yield.
at a power level of 375 W for 6–7 min continuous irradiation. The results we
summarized in Tables 3 and 4.
The impact of the PTC-microwave irradiation and PTC for the
synthesis of compounds 3a–i has been compared and results are summarized
in Table 5. The results show that the synthesis of compounds 3a–i under
PTC-microwave irradiation are 34–40 times faster than under phase
transfer conditions. This ratio between the reaction time using PTC and
PTC-microwave irradiation (tp/tp-mw), under the same condition, quantifies
the PTC-MW effect.

966
WANG, GAO, AND HUANG
Table 3. The Effect of Microwave Irradiation Powera
Irradiation Power (W)
Yieldb (%)
75
150
80.6
225
88.4
375
91
450
91
74.5
aThe reaction was carried out in the presence of NaOH using PEG-400 as catalyst in
b
DMF for 6 min; Isolated yield.
Table 4. The Effect of Microwave Irradiation Timea
Irradiation Time (min)
Yieldb (%)
3
4
5
6
7
64.2
75
85
88
88.4
aThe reaction was carried out in the presence of NaOH using PEG-400 as catalyst in
DMF at power level of 375 W under continuous irradiation conditions; bIsolated
yield.
Table 5. Comparison of Time and Yields in Synthesis of Compounds 3a–i Using
PTC-Microwave Irradiation and Phase Transfer Catalysis
Phase Transfer Catalysisa
PTC-Microwave Irradiation
Product
t (h)
Yield (%)
Power (W)
t (min)
Yieldb (%)
tp/tp-mw
3a
3b
3c
3d
3e
3f
3g
3h
3i
4
4
4
4
4
4
4
4
4
50
76
80
95
97
70
80
75
90
375
375
375
375
375
375
375
375
375
6
6
6
6
6
6
7
7
6
90
88
90
91
85
81
67
65
90
34
34
34
34
34
34
40
40
34
aThe reaction was carried out in the presence of NaOH using PEG-400 as catalyst at
65–70ꢀC; Isolated yield.
b
EXPERIMENTAL
IR spectra were measured for KBr discs using an Alpha centauri
1
FT-IR spectrophotometer. H-NMR spectra (80 MHz) were recorded in
CDCl3 or [(CD3)2CO] using an FT-80 spectrometer. Microanalyses were

SYMMETRICAL DISULFIDES
967
measured using a Carlo Erba 1106 microelemental analyzer. Microwave
irradiations were carried out with a modified Galanz WP 750B commercial
microwave oven at 2450 MHz.
General procedure: Sulfur powder 0.4 g (12.5 mmol) was added to a
mixture of PEG-400 0.2 g (0.005 mmol), sodium hydroxide 2 g (50 mmol)
and DMF (20 ml) after which the reaction mixture was irradiated at
375 W for 3 min. The solution changed from colorless to blue. Then the
alkyl halides (10 mmol) were added and the reaction mixture was irradiated
for 3–4 min under the same irradiation power. When the blue color disap-
peared in the solution, the reaction was completed. The solid inorganic salt
was separated by filtration and solvent was removed by evaporation under
reduced pressure to afford a crystalline (or liquid) dialkyl disulfide. The pure
solid products were obtained by recrystallization from ethanol, and pure
liquid products were obtained by a short silica gel column using petroleum
ether as the eluent.
Bis(t-Butyl)disulfide 3a: oil; b.p.: 66–68ꢀC/5 mmHg (Lit.31 88ꢀC/
12 mmHg). 1H-NMR (CDCl3): d 1.32 (s, 18H, 2 ꢁ CH2)3. IR n (KBr):
2959, 2862, 697, 615, 466.
Bis(n-Pentyl)disulfide 3b: oil; b.p.: 118–119/7 mmHg (Lit.31
119ꢀC/7 mmHg). H-NMR (CDCl3): d 2.64 (t, 4H, 2 ꢁ CH2S), 1.21–1.62
1
(m, 12H, 2 ꢁ (CH2)3), 1.20 (t, 6H, 2 ꢁ CH3). IR n (KBr): 2957, 2870, 507, 419.
Bis(Allyl)disulfide 3c: oil; b.p.: 88–90ꢀC/22 mmHg (Lit.31 78–80ꢀC/
16 mmHg). 1H-NMR (CDCl3): d 5.8 (q, 2H, 2 ꢁ ¼CH-), 5.01 (q, 4H,
2 ꢁ CH2¼C-), 2.82 (d, 4H, 2 ꢁ -Ch2S). IR n (KBr): 3082, 2987, 579, 429.
Dibenzyldisulfide 3d: m.p.: 71–72ꢀC (Lit.31 71–72ꢀC). 1H-NMR
(CDCl3): d 7.20–7.79 (m, 10H, 2 ꢁ ArH), 3.80 (s, 4H, 2 ꢁ CH2S). IR n (KBr):
3051, 2964, 2909, 708, 564, 465. Anal. calcd for C11H14S2: C, 68.29; H, 5.73.
Found: C, 68.58; H, 5.82.
Bis(4-Chlorobenzyl)disulfide 3e: m.p. 59–60ꢀC (Lit.32 60–66ꢀC);
1H-NMR (CDCl3): d 7.36–7.60 (q, 8H, 2 ꢁ ArH), 3.81 (s, 4H, 2 ꢁ CH2S).
IR n (KBr): 3080, 2980, 2879, 679, 519, 464. Anal. calcd for C14H12C12S2: C,
53.23; H, 3.81. Found: C, 52.98; H, 3.74.
Bis(2-Bromobenzyl)disulfide 3f: m.p. 87–88ꢀC (Lit.32 87–88ꢀC);
1H-NMR (CDCl3): d 7.37–7.89 (m, 8H, 2 ꢁ ArH), 3.94 (s, 4H, 2 ꢁ CH2S).
IR n (KBr): 3079, 2879, 699, 666 528, 486. Anal. calcd for C14H12Br2S2: C,
41.60; H, 2.97. Found: C, 41.50; H, 2.99.
Bis(4-Nitrobenzyl)disulfide 3g: m.p. 109–111ꢀC (Lit.32 111–113ꢀC);
1H-NMR (CDCl3): d 7.34–8.01 (m, 8H, 2 ꢁ ArH), 4.06 (s, 4H, 2 ꢁ CH2S).
IR n (KBr): 3080, 2872, 622, 539, 473. Anal. calcd for C14H12N2O4S2: C,
50.00; H, 3.57; N, 8.33. Found: C, 50.25; H, 3.50; N, 8.21.
Bis(2-Nitrobenzyl)disulfide 3h: m.p. 105–106ꢀC (Lit.32 106–107ꢀC);
1H-NMR (CDCl3): d 7.28–7.59 (m, 8H, 2 ꢁ ArH), 3.94 (s, 4H, 2 ꢁ CH2S).

968
WANG, GAO, AND HUANG
IR n (KBr): 3075, 2940, 2872, 657, 572, 439. Anal. calcd for C14H12N2O4S2:
C, 50.00; H, 3.5 N, 8.33. Found: C, 50.09; H, 3.56; N, 8.31.
Bis(2-Naphthylmethylene)disulfide 3i: m.p. 116–117ꢀC (Lit.32
116–117ꢀC). H-NMR (CDCl3): d 7.22–7.81 (m, 14H, 2 ꢁ C10H7), 3.92 (s,
1
4H, 2 ꢁ CH2S). IR n (KBr): 3080, 2980, 2879, 645, 579, 479. Anal. calcd for
C22H18S2: C, 76.30; H, 5.20. Found: C, 76.04; H, 5.20.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation
of China and the Northwest Normal University Science and Technology
Development Foundation of China.
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Received in the USA April 5, 2001