Urea- Hydrogen Peroxide (UHP) oxidation of thiols to the corresponding disulfides promoted by maleic anhydride as mediator

Article abstract of DOI:10.3390/10101385

Urea-hydrogen peroxide (UHP) was used in the presence of maleic anhydride as mediator in a simple and convenient method for the oxidation in high yield of some thiols to the corresponding disulfides. Peroxymaleic acid formed in situ from the reaction of U

Full text of DOI:10.3390/10101385

Molecules 2005, 10, 1358-1363
molecules
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Urea- Hydrogen Peroxide (UHP) Oxidation of Thiols to the
Corresponding Disulfides Promoted by Maleic Anhydride as
Mediator
1
,
1
2
Bahador Karami *, M. Montazerozohori and M. H. Habibi
1
Department of Chemistry, Yasouj University, Yasouj 75914-353, Iran
Department of Chemistry, Isfahan University, Isfahan 81745-117, Iran
2
*
Author to whom correspondence should be addressed. E-mail: karami@mail.yu.ac.ir
Received: 12 July 2005; in revised form: 21 July 2005 / Accepted: 22 July 2005 / Published: 31
October 2005
Abstract: Urea-hydrogen peroxide (UHP) was used in the presence of maleic anhydride
as mediator in a simple and convenient method for the oxidation in high yield of some
thiols to the corresponding disulfides. Peroxymaleic acid formed in situ from the reaction
of UHP with maleic anhydride has a key role in this oxidation. Performance of the
o
reaction in various solvents showed that methanol was the solvent of choice at 0 C. The
products were isolated by simple filtration on silica gel.
Keywords: UHP; thiols; disulfides; oxidation.
Introduction
Conversion of thiols to the related disulfides is of interest both from a biological and chemical
point of view [1, 2]. Disulfides, especially diaryl disulfides, are very commonly used as electrophiles
in the sulfenylation of enolates and other anions [3-4]. Oxidative S-S coupling of thiols can be done
under biological conditions in the presence of oxidants such as flavins and cytochromes [5]. In the
laboratory thiols can be oxidized to corresponding disulfides by several oxidants such as: redox dyes
[
5], nitro compounds [6], diazocompounds [7], sulfoxides [8], halogens [9], 2-polyvinyl-
pyridine/bromine complex [10], H [11], KMnO /CuSO [12], DMSO/I [1a,13], sodium perborate
14] and by electrochemical methods [15]. Due to the synthetic importance of disulfides, there has
been an ongoing interest in new chemical and biotic methods [16-18]. Some of the methods mentioned
2
O
2
4
4
2
[

Molecules 2005, 10
1359
suffer from a variety of disadvantages such as long reaction times, unavailability and/or toxicity of the
reagents and difficult isolation of products. As a result the introduction of readily available, safe and
stable reagents for the oxidation of thiols to disulfides is still a necessity. Over the past few years,
several reports have appeared on the use of urea-hydrogen peroxide (UHP) in oxidations, namely for
the conversion of amines to nitroalkanes [19], Baeyer-Villiger oxidations of ketones to lactones [20],
oxidations of sulfides to sulfones [21], oxidation of aromatic aldehydes [22], aromatization of 1,4-
dihydro-pyridines [23], epoxidation of alkenes and conversion of pyridine to pyridine N-oxides [24].
2 2 ,
In continuation of our studies on applications of UHP as a replacement for H O [25] we were
interested in using the UHP/maleic anhydride system for the conversion of thiols to disulfides.
Results and Discussion
Hydrogen peroxide is the most common reagent for oxidation of organic compounds, especially
thiols, but it has several problems such as instability of the reagent itself and overoxidation of thiols to
sulfonic acids as well as the desired disulfides. The use of hydrogen peroxide adducts is a convenient
2 2
strategy to control H O oxidation reactions. In general, hydrogen peroxide adducts are not able to
oxidize organic compounds by themselves, therefore introduction of an inorganic catalyst or organic
mediator for active oxygen transfer of these adducts is a necessity in oxidation systems where they are
used. Among these adducts urea-hydrogen peroxide is an inexpensive, stable, mild and easy to handle
2 2 .
source of pure H O [25] Considering this fact the potential use of a UHP containing system for the
oxidation of thiols was investigated. We found that 4-methylthiophenol was oxidized to 4,4’-dimethyl-
diphenyldisulfide by UHP under mild conditions in the presence of maleic anhydride as mediator. A
control reaction for the oxidation of 4-methylthiophenol in the absence of maleic anhydride was
performed and the results showed that the reaction did not take place to any significant extent,
therefore we conclude that maleic anhydride was need for efficient progress of the reaction.
To examine the effect of the solvent, the oxidation of 4-methylthiophenol was performed in different
solvents. As shown in Table 1, methanol was the best solvent under the reaction conditions, apparently
because of good solubility of starting materials, although the reaction was also completed in
acetonitrile but in longer period.
Table 1. Solvent effects on oxidative coupling of 4-methylthiophenol with
o
UHP/maleic anhydride at 0 C
Completion time of reaction [min]
Solvent
o
0
120
140
C
RT
120
140
a
a
a
a
CH
CHCl
CH OH
CH CN
2
Cl
2
3
b
b
a
3
10
30
20
40
a
3
a
The reaction was not completed within the mentioned period
The reaction was completed in the mentioned time
b

Molecules 2005, 10
1360
o
UHP has already been used at different temperatures (0 C, room temperature and reflux) in
previous reports [24-25]. The temperature effect in our experiments showed that the oxidation reaction
o
was completed faster at 0 C than at other temperatures, due to the high efficiency and stability of UHP
o
at lower temperatures (Table 1). Hence, oxidation of other thiols was carried out in methanol at 0 C.
The results are summarized in Scheme 1 and Table 2.
Scheme 1
UHP/Maleic anhydride
2
RSH
RSSR
Methanol, RT
R= Aryl, UHP= H NCONH .....H O
2
2
2
2
o
Table 2. Oxidative coupling of thiols using UHP/Maleic anhydride system in methanol at 0 C
Rea
ctio
n
Tim
e
M.P.
a,b
o
Yield
M.P. ( C)
o
Run
Thiols
Disulfides
( C)
(
%)
Literature
Found
(mi
n.)
SH
S
S
1
2
3
10
90
91
90
144-146
43-44
142-145 [16]
44-45 [16]
70-71[16]
CH3
SH
SH
CH
3
S
S
CH
3
10
30
Cl
Cl
S
S
Cl
72-73
CH SH
CH
2
S
S
SCH
2
2
4
5
20
10
90
95
69-71
90-92
69-70 [16]
91-93 [16]
Br
SH
Br
S
Br
SH
SH
S
S
S
S
6
7
N
40
60
78
76
55-56
55-57 [16]
N
N
N
N
N
133-135
134-136 [26]
N
N
N
N
S
N
S
N
S
SH
SH
S
S
S
S
8
9
30
65
177-179
177-180[27]
202-204 [28]
N
N
N
N
H
N
H
N
H
60
18
63
94
202-204
Oil [28]
CH
CH
3
(CH
(CH
2
)
2
CH
CH
2
SH
SH
1
1
0
1
(CH
3
(CH
(CH
2
)
2
CH
CH
2
S)
S)
2
3
2
)
6
2
20
93
Oil [28]
(CH
3
2
)
6
2
2
1
1
2
3
n-BuSH
(n-BuS)
2
20
20
92
94
Oil [16]
Oil [16]
c-C
6
H11SH
(c-C H11S)
6 2
a
b
1
Refers to isolated yields; Identified by MS and H- NMR.

Molecules 2005, 10
1361
We suggest that oxidation of thiols with urea-hydrogen peroxide proceeds according to Scheme 2.
Based on literature precedents, peroxymaleic acid, formed in situ from the reaction of hydrogen
peroxide with maleic anhydride (eq.1) is the active oxidant [24-25]. The active oxygen of the
peroxymaleic acid oxidizes RSH to RSOH (eq.2) via I, that reacts with another RSH molecules to
produce the disulfide. This is consistent with the fact, as shown in Table 2, that thiols bearing more
electron withdrawing substituents, which lead to potentially unstable transition states I as proposed,
are oxidized with more difficulty.
Scheme 2
O
O
O
1)
+ H N-CO-NH . H O
O
OH
2
2
2
2
+
HN -CO-NH
2 2
COOH
O
O
H
O
O
H
-δ
+δ
..... SR
.
.
COOH
COOH
O
O...O
2)
RSH
+
..
RSOH +
COOH
COOH
H
I
RSOH +RSH
RSSR + H O
2
3)
Conclusions
We have described a facile, mild and efficient method for the synthesis of symmetric disulfides with
UHP using maleic anhydride as an oxygen transfer agent. Several advantages of this method include
high yields of products, relatively short reaction times, low cost, ease of isolation of products, safety
and use of a non-toxic oxidant which make this reaction convenient and efficient.
Acknowledgements
Financial support for this work by Yasouj University is acknowledged. We are also thankful to
1
Mahshahr Petrochemical Company and Mina Varzande for recording H-NMR spectra.
Experimental
General
Thiols and maleic anhydride were purchased from Aldrich, Fluka and Merck. UHP was
synthesized according to previous report [25]. The reactions were monitored by TLC. The products
were isolated and identified by comparison of their physical and spectroscopic data with authentic
samples that prepared according to previous methods [16]. IR spectra were recorded on a Jasco-680
1
FT-IR and the H-NMR spectra were obtained on a Brucker 300 MHz instrument. Mass spectra were
recorded on an AMD 604 spectrometer, in EI-mode at 70 eV and FT-mode at 0.005 V.

Molecules 2005, 10
1362
Typical procedure for oxidation of 4-methylthiophenol
To a solution of 4-methylthiophenol (0.1242 g, 1 mmol) in methanol (10 mL) at 0°C, UHP (0.0941
g, 1 mmol) and maleic anhydride (0.0980 g, 1 mmol) were added. The progress of the oxidation was
followed by TLC (n-hexane-ethyl acetate, 7:3). After completion of the reaction, the solvent was
evaporated under vacuum at room temperature and then n-hexane/chloroform (9:1, 10 mL) was added
and the mixture was filtered on silica gel. The solvent was removed under vacuum and 4,4-dimethyl-
diphenyl disulfide was obtained as white crystals (0.2217 g, 90% yield); m.p. 45-47°C (Ref. [16] 44-
1
4
5°C); H-NMR (CDCl
3
): δ/ppm: 7.50 (d, 4H), 7.20 (d, 4H), 2.46 (S, 6H, 2CH
3
); MS (70 eV): m/z:
+
2
46 (M ).
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Sample Availability: Available from the authors.
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