Metal-free oxidative coupling of thiols to disulfides using guanidinium nitrate or nitro urea in the presence of silica sulfuric acid

Article abstract of DOI:10.1007/s12039-011-0094-3

Efficient combination of nitro urea or guanidinium nitrate and silica sulfuric acid (SiO₂OSO₃H) as a new oxidizing system is able to oxidize a variety of aliphatic or aromatic thiols to the corresponding disulfides. The process reported here is operationally simple, environmentally benign and reactions have been mildly and heterogeneously performed in dichloromethane at room temperature. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-011-0094-3

c
J. Chem. Sci. Vol. 123, No. 4, July 2011, pp. 453–457. ꢀ Indian Academy of Sciences.
Metal-free oxidative coupling of thiols to disulfides using guanidinium
nitrate or nitro urea in the presence of silica sulfuric acid
ARASH GHORBANI-CHOGHAMARANI∗, MOHSEN NIKOORAZM,
HAMID GOUDARZIAFSHAR, ALIREZA SHOKR and HOSEIN ALMASI
Department of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
e-mail: arashghch58@yahoo.com
MS received 8 April 2010; revised 9 January 2011; accepted 28 February 2011
Abstract. Efficient combination of nitro urea or guanidinium nitrate and silica sulfuric acid (SiO2OSO3H) as
a new oxidizing system is able to oxidize a variety of aliphatic or aromatic thiols to the corresponding disulfides.
The process reported here is operationally simple, environmentally benign and reactions have been mildly and
heterogeneously performed in dichloromethane at room temperature.
Keywords. Thiols; disulfides; guanidinium nitrate; nitro urea; silica sulfuric acid; oxidation; coupling.
1. Introduction
work-up of products, low yields, heavy metal con-
tamination, toxicity, and cost effective reagents or
catalysts.
The controlled oxidative coupling of thiols to disulfides
is important in organic synthesis.1 The conversion of
thiols to the corresponding disulfides is an important
reaction in chemical and biological process such as
vulcanization,2 synthesis of 4H-1,4-benzothiazines,3
carbon–carbon bond forming,4 protein thiol oxidation
in tumor cells,5 and cysteinyl thiol oxidation in vas-
cular smooth muscle cells.6 Oxidation of thiols is the
most exploited method for disulfide synthesis mainly
because a large number of thiols are commercially
available and are easily synthesized.7 Thiols and disul-
fides are important in living cells being a structural
feature of many biomolecules including proteins. In
many biochemical redox reactions they are intercon-
verted.8 In recent years, several reagents or reagent
systems have presented ability of thiols coupling into
disulfides such as molybdate sulfuric acid/sodium
nitrite,9 monochloro poly(styrenehydantoin),10 tetram-
ethylammonium fluorochromate,11 O2/manganese(III)
Schiff-base complex,12 I2/CeCl3.7H2O/graphite,13
ethylenebis(N-methylimidazolium) chlorochromate,14
tripropylammonium fluorochromate,15 N-tert-Butyl-
N-chlorocyanamide,16 and iron(III) trifluoroac-
etate/air;17 but some of these procedures are not
satisfactory because of several reasons such as overox-
idation to sulfoxides and other by-products, tedious
2. Experimental
The chemicals and solvents were purchased from Fluka,
Merck and Aldrich chemical companies and used with-
out further purifications. All products are known and
were characterized by comparison of their spectral (IR,
1H NMR, or 13C NMR) and physical data with authentic
samples.
2.1 Preparation of nitro urea (NH2CONHNO2.xH2O)
In a 50 mL round-bottomed flask, 4 mL of HNO3
(65%) and 3.46 g of urea was stirred at room
temperature for 2 h, and a white crystalline solid
(NH2CONHNO2.xH2O) was obtained quantitatively.
M.p. 156–158.4◦C (Ref.28 157–159◦C); MS (70 eV):
m/z = 105 (M+), 91, 69, 63, 60, 46 (base peak, NO+2 ),
44.
2.1a Oxidative coupling of 2-mercaptobenzothiazole
into 1,2-bis(benzo[d]thiazol-2-yl) disulfane by nitro
urea and silica sulfuric acid: As a typical procedure:
Nitro urea (NH2CONHNO2.xH2O), (0.40 g) and sil-
ica sulfuric acid (0.60 g) was added to a solution of
2-mercaptobenzoxazole (0.167 g, 1 mmol) in CH2Cl2
∗For correspondence
453

454
Arash Ghorbani-Choghamarani et al.
Table 1. Oxidative coupling of thiols to the corresponding disulfides using combination of guanidinium nitrate I or nitro
urea II in the presence of silica sulfuric acid III in dichloromethane at room temperature.
Entry Substrate Product
Substrate/Reagents (mmol)a
Time
Yield
(%)b
Mp (◦C)
found
Mp (◦C)
reported
Reference
I
II
III
(Min)
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
2.5
—
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.4
—
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
—
20
15
17
40
10
22
8
15
17
28
10
26
22
51
10
7
5 h
5 h
19
10
39
78
21
40
22
16
12
52
86
88
90
87
88
84
92
138–139
139–141
89–91
89–91
oil
144–146
90–92
oil
(9)
(9)
(27)
(9)
oil
41–41.5
39–41
43–44
41–43
283–285
283–286
89–91
77–84
77.6–79
75–78
—
43–44
42–43
278–280
78–92
77.5–79
—
92
9
92d
95d
95
(13)
(24)
(27)
(24)
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1f
2f
93
96
97
90
1g
1g
1h
1h
1h
1h
1i
1i
1j
1j
1k
1k
1l
1l
1m
1m
2g
2g
2h
2h
2h
2h
2i
2i
2j
2j
2k
2k
2l
2l
2m
2m
96
No Reac.
No Reac.
86
—
—
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
177.5–178 177–179
177–179
68–70
68–70
166.5–168 167–169
165–167
oil
oil
oil
oil
(9)
80
92
88
91
92
62
61
63
70–71
(8)
(13)
(24)
(8)
oil
oil
0.4
64
aI refers to mmol of guanidinium nitrate and II and III refer to grams of nitro urea and silica sulfuric acid, respectively.
bIsolated yield. cIn the absence of silica sulfuric acid. dProduct purified by column chromatography
(10 mL). The resulting mixture was stirred at room tem- or nitro urea, (2.5 mmol or 0.4 g, respectively) and
perature for 10 min (the reaction progress was mon- silica sulfuric acid (0.6 g) in CH2Cl2 (10 mL) one of
itored by TLC) and then filtered. The residue was the thiols 1f, 1l or 1m (1 mmol) was added, and the
washed with CH2Cl2 (4 × 5 mL). Finally, CH2Cl2 mixture was stirred at room temperature for the speci-
was removed and 1,2-bis(2-benzoxazol)disulfane was fied time (table 1) the reaction progress was monitored
obtained in 80% yield (0.258 g) as crystalline white by TLC. After reaction completion CH2Cl2 was evap-
solid; mp 177–179◦C; H NMR (400 MHz, CDCl3): δ = orated and ethanol (10 mL) was added to the residue,
7.96–7.94 (d, J = 8 Hz, 1H), 7.80–7.78 (d, J = 8 Hz, this mixture was stirred for 5 minutes then filtered.
1H), 7.50–7.46 (t, J = 7.6 Hz, 1H), 7.39–7.35 (t, J = The residue was washed with CH3CH2OH (4 × 5 mL).
7.2 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ =
167.9, 154.6, 136.2, 126.6, 125.3, 122.7, 121.3 ppm. All
the thiols converted into disulfides via same procedure
except compounds f, l and m.
+
NH2
O
H2N
NH2
H2N
NHNO2
-
NO3
2.1b General procedure for the oxidative coupling of
thiols 1f, 1l and 1m into disulfides 2f, 2l and 2m using
guanidinium nitrate or nitro urea in the presence of sil-
ica sulfuric acid: To a mixture of guanidinium nitrate
nitro urea
Guanidinium nitrate
Figure 1. Chemical structures of guanidinium nitrate and
nitro urea.

Metal-free oxidative coupling of thiols to disulfides
455
OH+NO3
-
O
-H2O
Neat
rt
H2NCONHNO2.XH2O
X=1-2.5
H2N
NH2 + HNO3 (65%)
H2N
NH2
Scheme 1. Preparation of nitro urea.
Finally, CH3CH2OH was removed by rotary evapora- 3. Results and discussion
tor and resulting sediment was washed with H2O (4 ×
Recently we have introduced several heterogeneous
procedures for the in situ generation of nitronium ion
(NO+2 ) and nitrosonium ion (NO+) for different organic
functional group transformations.18–26 In continuation
of our investigation we became interested to delineate a
new protocol to convert different types of thiols to the
corresponding disulfides by guanidinium nitrate or nitro
urea (figure 1) in the presence of silica sulfuric acid.
Guanidinium nitrate as commercially available
reagent is a natural source of nitronium ion. While
nitro urea could be easily prepared by the reaction of
urea with nitric acid to produce urea nitrate, which
immediately dehydrated to nitro urea (scheme 1).27,28
Consequently, we decided to use guanidinium nitrate
and nitro urea in the presence of silica sulfuric acid for
the oxidative coupling of aliphatic and aromatic thiols
to prepare corresponding disulfide derivatives. There-
fore, a variety of aliphatic and aromatic thiols 1 con-
verted into corresponding disulfides 2 by combination
of guanidinium nitrate I or nitro urea II and silica sul-
furic acid III in dichloromethane as solvent at room
temperature (scheme 2 and table 1).
20 mL) and dried under vacuum to give pure disulfides
2f, 2l or 2m.
2.2 Representative NMR Data
2.2a 1,2-Bis(4-bromophenyl)disulfane 2b: 1H NMR
(500 MHz, CDCl3): δ = 7.43 (d, J = 8.4 Hz, 4H), 7.36
(d, J = 7.9 Hz, 4H) ppm; 13C NMR (125 MHz, CDCl3):
δ = 135.8, 132.3, 129.5, 121.6 ppm.
2.2b 1,2-Dip-tolyldisulfane 2d: 1H NMR (500 MHz,
CDCl3): δ = 7.42 (d, J = 7.9 Hz, 4 H), 7.42 (d, J =
7.9 Hz, 4 H), 2.35 (s, 6H) ppm; 13C NMR (125 MHz,
CDCl3): δ = 137.5, 134.0, 129.8, 128.6, 21.1 ppm.
2.2c 1,2-Bis((4,6-dimethylpyrimidin-2-
yl)methyl)disulfane 2k: 1H NMR (500 MHz, CDCl3):
δ = 6.76 (s, 2H), 2.39 (s, 12H) ppm; 13C NMR
(125 MHz, CDCl3): δ = 169.0, 167.6, 117.1, 23.8 ppm.
SiO2 OSO3H
Guanidinium nitrate
or nitro urea
RS SR
SH
R
CH2Cl2, rt
1
2
R= Alkyl or Aryl
SH
Br
SH
MeO
SH
F
SH
H3C
SH
a
f
b
c
d
e
Cl
COOH
SH
S
O
N
h
CH2SH
SH
SH
SH
N
Cl
g
i
j
N
N
CH2SH
HSCH2COOH
HSCH2CH2OH
k
l
m
Scheme 2. Oxidative coupling of thiols by guanidinium nitrate or nitro urea in the presence of silica sulfuric acid.

456
Arash Ghorbani-Choghamarani et al.
Silica sulfuric acid
Guanidinium nitrate
or nitro urea
O
R SH
R S S R
R S S R
+
CH2Cl2, rt
100%
0%
Scheme 3. Chemoselectivity in the oxidative coupling of thiols.
+
NH2
O
H2N
NH2
-
NO3
H2N
NHNO2
SiO2-OSO3H
HNO3
SiO2-OSO3H
+
NO2
RSH
RSNO2 + H+
RSSR + N2O4
Scheme 4. Mechanism of oxidative coupling of thiols.
All the coupling reactions were performed easily by of disulfides under mild, metal-free and heterogeneous
mixing of a thiol, guanidinium nitrate or nitro urea conditions. Furthermore, this method exhibits substrate
and silica sulfuric acid in dichloromethane and stir- versatility, non-toxic conditions, cost effective reagents,
ring this mixture for appropriate time at room temper- easy and clean work-up of products.
ature. Finally, pure product readily obtained by simple
filtration, washing by appropriate solvent (CH2Cl2 or
CH3CH2OH) and evaporation of the solvent. Because of
Acknowledgements
mild properties of these heterogeneous systems, there is
no overoxidation to sulfone was observed (scheme 3).
Silica sulfuric acid has a critical role in the
coupling reaction by described reagents. Entries
17 and 18 from table 1 show that the cou-
pling of 2-mercaptobenzoxazole into 1,2-bis(2-
benzoxazol)disulfane using guanidinium nitrate and
nitro urea, as a standard reaction, in the absence of
silica sulfuric acid does not occur after 5 h.
This work was supported by the research facilities of
Ilam University, Ilam, Iran.
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