A simple and practical method for the oxidation of thiols to disulfides at mild conditions without solvents

Article abstract of DOI:10.1080/10426507.2012.674585

A green, straightforward, and novel method for the oxidation of thiols to the corresponding disulfides is reported using hydrogen peroxide catalyzed by tetrabutylammonium iodide (TBAI) without solvents at room temperature. The corresponding disulfides were obtained with excellent yields and short reaction times. Copyright

Full text of DOI:10.1080/10426507.2012.674585

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Phosphorus, Sulfur, and Silicon and the
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A Simple and Practical Method for the
Oxidation of Thiols to Disulfides at Mild
Conditions Without Solvents
Ying He a , Dongliang Hang a & Ming Lu a
a School of Chemical Engineering, Nan Jing University of Science and
Technology, Nanjing, P.R. China
Accepted author version posted online: 27 Mar 2012.Version of
record first published: 19 Jun 2012.
To cite this article: Ying He , Dongliang Hang & Ming Lu (2012): A Simple and Practical Method for the
Oxidation of Thiols to Disulfides at Mild Conditions Without Solvents, Phosphorus, Sulfur, and Silicon
and the Related Elements, 187:9, 1118-1124
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Phosphorus, Sulfur, and Silicon, 187:1118–1124, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.674585
A SIMPLE AND PRACTICAL METHOD FOR THE
OXIDATION OF THIOLS TO DISULFIDES AT MILD
CONDITIONS WITHOUT SOLVENTS
Ying He, Dongliang Hang, and Ming Lu
School of Chemical Engineering, Nan Jing University of Science and Technology,
Nanjing, P.R. China
GRAPHICAL ABSTRACT
Abstract A green, straightforward, and novel method for the oxidation of thiols to the cor-
responding disulfides is reported using hydrogen peroxide catalyzed by tetrabutylammonium
iodide (TBAI) without solvents at room temperature. The corresponding disulfides were ob-
tained with excellent yields and short reaction times.
Keywords Thiols; disulfides; oxidation; hydrogen peroxide; tetrabutylammonium iodide
INTRODUCTION
Disulfides are useful reagents in organic synthesis.1,2 They have been utilized exten-
sively in carbon–carbon bond-forming reactions, molecular rearrangements, and functional
group transformations.3 Oxidation of thiols is the most common way to obtain the cor-
responding disulfides. Thus, various reagents have been used, e.g., molecular oxygen,4
trichloroisocyanuric acid,5 ion exchange catalysis in the presence of potassium perman-
ganate,6 ammonium persulfate,7 tetrathiomolybdate,8 benzyltriphenylphosphonium per-
oxymonosulfate,9 I2/HI,10 Br2,11 KMnO4/CuSO4,12 HMDS/DMSO,13 hydrogen peroxide
in fluoroalcohols,14 NaI/H2O2 in ethyl acetate15 nitric acid,16 DMSO,17 NaBrO3/SiO2-
OSO3H,18 bromodimethylsulfonium bromide,19 N-chlorosuccinimide,20 (n-Bu4N)2S2O8,21
SO2Cl2,22 K2S2O8.23
Although these reagents afford the disulfides in good yield, there are still some
problems such as expensive reagents, longer reaction times, large quantity of solvents,
and difficult isolation. Therefore, there is still an interest in developing a clean, mild, and
efficient method to synthesize disulfide.
Received 4 January 2012; accepted 3 March 2012.
We thank the National Basic Research Program (973) of China (No. 613740101) and Natural Science
Foundation of Jiangsu Province for support of this research.
Address correspondence to Ming Lu, School of Chemical Engineering, Nan Jing University of Science and
Technology, Nanjing 210094, P.R. China. E-mail: orienthawk@163.com
1118

METHOD FOR THE OXIDATION OF THIOLS TO DISULFIDES AT MILD CONDITIONS 1119
Hydrogen peroxide is also a very attractive and clean oxidant for liquid-phase oxi-
dations. Besides water as the sole byproduct, it provides a high content of active oxygen
species and is much cheaper and safer than organic peroxides or peracids.24 Thus, the
catalytic oxidation of thiols using hydrogen peroxide has received much attention from the
viewpoint of green chemistry.
In this article, we report the oxidation of thiols with 1% hydrogen peroxide catalyzed
tetrabutylammonium iodide (TBAI) (Scheme 1). This is a new, mild, and practical oxidation
method for the oxidation of thiols to the corresponding disulfides under neutral conditions
without solvents. The green chemistry, straightforward workup, mild reaction conditions,
high yields of the products, and short reaction times make this a useful method for the
oxidation of thiols to disulfides.
Scheme 1
RESULTS AND DISCUSSION
Effect of Various Catalysts
First, we were interested to examine various catalysts at room temperature under
solvent-free conditions. Oxidation of benzyl mercaptan to dibenzyl disulfide was selected
as a model reaction. Test reactions were carried out by mixing benzyl mercaptan (1 mmol)
and 1% hydrogen peroxide (1 mmol) in the absence or presence of various catalysts
(0.01 mmol) at room temperature (Table 1).
As indicated in Table 1, the reaction in the absence of a catalyst was found to be
very slow and the product yield of the reaction was only a trace in water after 24 h (Table
1, entry 1). In the cases of KI, it took a longer time to complete the reaction (24 h) for
reasonable yields (94%) because of the solubility problem (Table 1, entry 3). The reactivity
of quaternary ammonium salts is more effective than KI. TBAI was a good catalyst for the
reaction and provided the dibenzyl disulfide in excellent yields with a shorter reaction time
(10 min) (Table 1, entry 5). In this study, the order of the catalytic efficiencies of various
catalysts was found to be: TBAI > TBAB > KI > KBr. The results show that quaternary
ammonium salts work effectively to enhance the reaction rate by increasing the reagent
solubility.
Table 1 Comparative study between various catalysts under solvent-free conditions
Entry
Catalyst
Time min/(h)
Yield (%)a
1
2
3
4
5
–
KBr
KI
TBABb
TBAIc
(24)
(24)
(24)
(2)
trace
35
94
92
98
10
aIsolated yield.
bTBAB: tetrabutylammonium bromide.
cTBAI: tetrabutylammonium iodide.

1120
Y. HE ET AL.
Effect of the Amount of PTC
Having established the importance of the PTC, we switched our attention to the
amount of TBAI. The oxidative transformation was performed with a varied quantity of the
TBAI, from a 0.001 to a 0.1 molar ratio. Using a 0.001 molar ratio of TBAI, the reaction
became slow and did not reach completion in half an hour. After some experimentation
with respect to the molar ratio of TBAI, we found that the use of 0.01 moles TBAI per
mole of the substrate in water consistently produced good to excellent yields of disulfides.
However, further increasing the amount of TBAI under the same conditions did not enhance
the formation of the dibenzyl disulfide significantly.
Effect of Different Concentration of H2O2
Selective oxidation reactions inherently suffer from overoxidation, as the desired
partially oxidized product is generally easily oxidized to the corresponding sulfinothioic,
sulfonothioic, and disulfone derivatives. During the oxidation of benzyl mercaptan to
dibenzyl disulfide, formation of the corresponding overoxidized polar impurities (detected
by TLC) may reduce the dibenzyl disulfide yield. The yield of dibenzyl disulfide depends
on the concentration of oxidant. The results of studying the effect of different concentration
of hydrogen peroxide on the yield of dibenzyl disulfide are shown in Table 2.
From the above data, we can clearly recognize that the yield rises gradually with
decreasing concentration of hydrogen peroxide at room temperature. When 30% hydrogen
peroxide was used, the yield of dibenzyl disulfide decreased to 62%, which was lower
than the others yields due to overoxidation of dibenzyl disulfide. Lower concentrations of
hydrogen peroxide were preferred to reduce the oxidative capacity and further oxidation.
To explain to this evidence and other reported mechanisms10, 11, 15, a possible catalytic
cycle for the biphasic oxidation is shown in Scheme 2.
Scheme 2 Proposed catalytic cycle TBAI = tetrabutylammonium iodide.
Table 2 Effects of different concentration of H2O2 on the oxidation of benzyl mercaptan to dibenzyl disulfide
under solvent-free conditionsa
b
Entry
Concentration of H2O2
Time (min)
Yield (%)d
1
2
3
30%
15%
1%
c
c
10
62
81
98
Unless otherwise noted, the reactions were carried out with benzyl mercaptan (1 mmol), H2O2 (1 mmol), TBAI
(0.01 mmol) in water at room temperature.
aMonitored by TLC analysis.
bH2O2 was consumed completely via an inspection with potassium iodide-starch test paper.
cReactions were completed immediately.
dIsolated yield.

METHOD FOR THE OXIDATION OF THIOLS TO DISULFIDES AT MILD CONDITIONS 1121
Table 3 Oxidation of various thiols using TBAI in water at room temperature
Yield
(%)b
Time
(min)
Bp/mp (◦C) found
(reported) refs.
Entry
1
Substrate
Producta
98
97
95
93
10c
10c
10
69–70 (69–70)23
126–128 (124–129)23
59–60 (59–61)23
47–48 (47–48)23
2
3
4
15c
5
6
95
96
5
139–140 (139–141)23d
5c
99–100/10 torr
(94–96/6 torr)23
7
93
50
53–54 (52–53)23
8
9
94
95
10
15
128–130/10 torr
(117–119/6 torr)23
73–74 (72–75)25
de
10
11
95
94
5
–
40
202–204 (202–204)26
12
13
14
95
96
94
65
60
15
93–94 (93–94)27
71–73 (72–73)20
54–55 (55–56)28
aIdentified by comparison with those reported in the literature.
bIsolated yield.
cReaction time was shortened greatly from 24 h to 10 min compared with KI in water.15
dAfter the completion of reaction, the water was evaporated under reduced pressure to obtain the crude product,
then washed with ethanol
and dried at reduced pressure.
eIdentified by comparison with authentic sample which was purchased from BASF company.

1122
Y. HE ET AL.
Table 4 Comparison of TBAI/H2O2 with some of the other reagents for oxidation of thiols
Substrate
Condition
Time min/(h)
10
Yield (%)
98
Reagent
TBAI/H2O2
References
–
Solvent free
CH3CN/CH2Cl2
CH2Cl2
(1)
(2.3)
(1.5)
(24)
30
76
96
97
94
82
98
trichloroisocyanuric acid
KMnO4/IER
5
6
DMSO
HMDS
13
15
16
22
Solvent free
CH2Cl2
KI/H2O2
Excessive HNO3
Excessive SO2Cl2
Neat
30
A thiol reacts with TBAI readily to form the iodide ion and quaternary ammonium
sulfide salts (TBA+RS−) which facilitate the migration of a thiol from the organic phase
into the aqueous phase. The iodide ion is oxidized to molecular iodine by hydrogen per-
oxide which reacts with the quaternary ammonium sulfide salts (TBA+RS−) to afford an
intermediate sulfenyl iodide RSI. Then, it couples with the quaternary ammonium sulfide
salt (TBA+RS−) to yield the disulfide.
In order to further assess the catalytic capabilities of this reagent, we also decided to
perform oxidation reactions of different thiols under the same reaction conditions. As can
be seen from Table 3, alkyl, phenyl, and benzyl thiols are converted into the corresponding
disulfides with good yields under very mild reaction conditions without solvents in shorter
reaction times.
The comparison of the present method with respect to the amount of the thiols,
reaction time, and yields with those reported in literature reveals that this developed method
is superior to many reported procedures. In order to show the advantage and drawbacks of
the TBAI/H2O2 oxidation system, we have compared some of our results with results from
the literature in Table 4.
CONCLUSIONS
In conclusion, we have developed a simple, mild, and environmentally benign method
for the synthesis of disulfides by the oxidation of thiols in water. This method offers the
advantage of shorter reaction time, high yield, and easy workup.

METHOD FOR THE OXIDATION OF THIOLS TO DISULFIDES AT MILD CONDITIONS 1123
EXPERIMENTAL
All thiols were commercially available and used without further purification. TBAI
was obtained from sinopharm chemical reagent company. NMR spectra were recorded with
a Bruker DRX-500 spectrometer (1H: 500 MHz, 13C: 125 MHz), chemical shifts δ (ppm)
are related to TMS as internal standard.
General Oxidation of Thiols to Disulfides without Solvents
A round bottom flask was charged with 1% H2O2 (1 mmol) and TBAI (0.01 mmol).
The thiol (1 mmol) was added to the solution at room temperature with vigorous stirring.
The reaction was monitored by TLC (n-hexane:ethyl acetate 15:3). After the completion
of the reaction, the products were filtered off and dried or extracted with ethyl acetate (3 ×
5 mL). Then the combined organic phases were washed with water (2 × 4 mL), separated,
and dried with anhydrous Na2SO4. The solvent was evaporated under reduced pressure to
obtain the corresponding disulfides.
Selected Spectroscopic Data
Dibenzyl disulfide. 22 (Table 4, entry 1). 1H NMR (CDCl3): 3.6 (s, 4H), 7.22–7.25
(m, 4H), 7.27–7.32 (m, 6H). 13C NMR (DMSO): 41.78, 127.26, 128.38, 129.19, 137.24.
Diphenyl disulfide. 22 (Table 4, entry 3). 1H NMR (CDCl3): 7.20–7.23 (m, 2H),
7.28–7.31 (m, 4H), 7.48–7.50 (m, 4H). 13C NMR (DMSO): 127.12, 127.63, 129.56, 135.78.
Dioctyl disulfide. 29 (Table 4, entry 9). 1H NMR (CDCl3): 2.59–2.61 (t, J = 8 Hz,
4H), 1.51–1.53 (m, 4H), 1.22–1.28 (m, 18H), 0.92–0.95 (t, J = 8 Hz, 6H); 13C NMR
(CDCl3) 33.56, 32.57, 31.43, 31.38, 31.28, 27.03, 23.49, 15.08.
Bis(3-sodiumsulfopropyl) disulfide. (Table 4, entry 10). 1H NMR (D2O): 2.08
–2.11 (m, 4H), 2.79–2.82 (m, 4H), 2.97–2.99 (t, 4H).
REFERENCES
1. Ogawa, A.; Nishiyama, Y.; Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett. 1987, 28, 3271-
3274.
2. Antebi, S.; Apler, H. Tetrehedron Lett. 1985, 26, 2609-2612.
3. (a) Hajipour, A. R.; Hantehzadeh, M. Phosphorus Sulfur Silicon Relat. Elem. 2000, 161, 181-189
(b) Hajipour, A. R. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1997, 36, 329-332
(c) Hajipour, A. R. Synth. Commun. 1996, 26, 3627-3632 (d) Hajipour, A. R.; Pyne, S. G. J.
Chem. Res. Synop. 1995, 360 (e) Zahouily, M.; Journet, M.; Malacria, M. Synlett 1994, 366-368
(f) Pyne, S. G.; Hajipour, A. R.; Prabakaran, K. Tetrahedron Lett. 1994, 35, 645-648 (g) Pyne, S.
G.; Hajipour, A. R. Tetrahedron 1992, 48, 9385-9390 (h) Posner, G. H.; Weitzberg, M.; Hamill,
T. G.; Asirvatham, E.; He, C. H.; Clardy, J. Tetrahedron 1986, 42, 2919-2929 (i) Block, E.
Reactions of Organosulfur Compounds; Academic Press, New York, 1978.
4. Liu, K. T.; Tong, Y. C. Synthesis 1978, 669-670.
5. Zhong, P.; Guo, M. P. Synth. Commun. 2001, 31, 1825-1828.
6. Shaabani, A.; Teimouri, F.; Lee, D. G. Synth. Commun. 2003, 33, 1057-1065.
7. Varma, R. S.; Mesharam, H. M.; Dahiya, R. Synth. Commun. 2000, 30, 1249-1255.
8. Sinha, S.; Ilankumaran, P.; Chandrasekaran, S. Tetrahedron 1999, 55, 14769-14776.
9. Hajipour, A. R.; Mallakpour, S. E.; Adibi, H. J. Org. Chem. 2002, 67, 8666-8668.
10. Aida, T.; Akasaka, T.; Furukawa, N.; Oae, S. Bull. Chem. Soc. Jpn. 1976, 49, 1441-1442.

1124
Y. HE ET AL.
11. Wu, X.; Rieke, R. D.; Zhu, L. Synth. Commun. 1996, 26, 191-196.
12. Noureldin, N. A.; Caldwell, M.; Hendry, J.; Lee, D. G. Synthesis 1998, 1587-1589.
13. Karimi, B.; Zareyee, D. Synlett 2002, 346-348.
14. Kesavan, V.; Bonnet-Delpon, D.; Begue, J. P. Synthesis 2000, 223-225.
15. Kirihara, M.; Asai, Y.; Ogawa, S.; Noguchi, T. Synthesis 2007, 3286-3289.
16. Misra, A. K.; Agnihotri, G. Synth. Commun. 2004, 34, 1079-1085.
17. Tam, J. P.; Wu, C. R.; Liu, W.; Zhang, J. W. J. Am. Chem. Soc. 1991, 113, 6657-6662.
18. Shaabani, A. Synth. Commun. 2004, 34, 3303-3315.
19. Olah, G. A. Synthesis 1979, 721.
20. Hajipour, A. R. J. Sulfur Chem. 2006, 27, 441-444.
21. Chen, F. E. Synth. Commun. 2002, 32, 3487-3492.
22. Leino, R.; Lonnqvist, J. E. Tetrahedron Lett. 2004, 45, 8489-8491.
23. Hajipour, A. R.; Mostafavi, M.; Ruoho, A. Phosphorus Sulfur Silicon Relat. Elem. 2009, 184,
1920-1923.
24. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press,
1998.
25. Shaabani, A. Phosphorus Sulfur Silicon Relat. Elem. 2010, 185, 463-468.
26. Sharma, S. P. Catal. Commun. 2009, 10, 905-912.
27. Field, L. J. Am. Chem. Soc. 1952, 74, 394-398.
28. Kodama, S.; Saito, K.; Tanaka, S.; Horikawa, C.; Saito, A. Bull. Chem. Soc. Jpn. 2010, 83,
335-344.
29. Mohammadi, M. K.; Shahriare, G. Chin. J. Chem. 2010, 28, 2199-2203.