Simple and efficient oxidative transformation of thiols to disulfides using Cu(NO3)2·3H2O in H2O/AcOEt

Article abstract of DOI:10.1007/s00706-014-1178-9

A simple and efficient methodology is described for the preparation of symmetric disulfides from corresponding thiols in the presence of Cu(NO ₃)₂ and in H₂O/AcOEt (1:2). This process is environmentally friendly and economical because it does not use toxic or expensive reagents.

Full text of DOI:10.1007/s00706-014-1178-9

Monatsh Chem (2014) 145:1151–1154
DOI 10.1007/s00706-014-1178-9
ORIGINAL PAPER
Simple and efficient oxidative transformation of thiols to disulfides
using Cu(NO3)2Á3H2O in H2O/AcOEt
•
Mohammad Soleiman-Beigi Zahra Taherinia
Received: 10 November 2013 / Accepted: 11 February 2014 / Published online: 11 March 2014
Ó Springer-Verlag Wien 2014
Abstract A simple and efficient methodology is descri-
bed for the preparation of symmetric disulfides from
corresponding thiols in the presence of Cu(NO3)2 and in
H2O/AcOEt (1:2). This process is environmentally friendly
and economical because it does not use toxic or expensive
reagents.
generate undesirable waste materials, overoxidation,
tedious work-up of products, and a need for a large excess
of the reagents and catalysts. Therefore, there is still
interest in developing green, economical, and mild meth-
ods to produce the desirable disulfides in high yields and
short reaction times. In accordance with these aims and in
continuation of our previous reports on the synthesis of
disulfides [22, 27, 34, 35], we searched for a novel meth-
odology for the preparation of disulfides for use as
intermediates in organic synthesis with a view to mini-
mizing one or more of the aforementioned drawbacks by
using Cu(NO3)2Á3H2O under aqueous conditions.
Keywords Disulfide Á Oxidative transformation Á
Copper nitrate Á Aqueous media
Introduction
Disulfides are beneficial building blocks for the synthesis
of organosulfur compounds [1–3], which have important
roles in biological and chemical processes [4–6]. A rela-
tively broad range of methods for their preparation are
reported in the literature [7–14]. However, the most com-
monly exploited method is oxidative conversion of thiols to
the corresponding disulfides [15–33]. This approach ben-
efits from the wide range of thiols that are commercially
available.
Results and discussions
Initially, to investigate the oxidative conversion of thiols to
disulfides in homogenous aqueous conditions, various cat-
alysts were examined with 4-bromothiophenol as the model
substrate at room temperature (Scheme 1; Tables 1 and 2).
Cu(NO3)2Á3H2O, Al(NO2)3, Fe(NO2)3Á9H2O, (NH4)2
Ce(NO3)6, and Bi(NO2)3 facilitated this transformations
successfully with good to excellent yields (75–98 % yield;
Table 1, entries 1–5), whereas the reaction was not suc-
cessful with K3Fe(CN)6Á3H2O, Ce(SO4)4Á4H2O, CuCl2,
CuCl, NaNO3, and NH4NO3 (Table 1, entries 6–11).
Reaction in the presence of other salts of iron and copper
was also ineffective. We concluded that cations as well as
the nitrate anion (NO3-) are important for the reactions.
A series of different solvents were examined, among
which AcOEt/H2O (2:1) was the most effective
(Table 2, entry 3). Gratifyingly, the use of AcOEt/H2O
(2:1), an inexpensive and environmentally benign sol-
vent, resulted in disulfide in nearly quantitative yields
(98 %). In the absence of ethyl acetate no reaction was
Additionally, numerous reagents and catalysts have been
applied to oxidize thiols to disulfides under a range of
experimental conditions [17–36]. However, these reagents
suffer from disadvantages, such as long reaction times, low
yields, low selectivity, toxicity, difficulty of preparation,
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-014-1178-9) contains supplementary
material, which is available to authorized users.
M. Soleiman-Beigi (&) Á Z. Taherinia
Department of Chemistry, Ilam University,
P.O. Box 69315-516, Ilam, Iran
e-mail: SoleimanBeigi@yahoo.com
123

1152
M. Soleiman-Beigi, Z. Taherinia
Scheme 1
Scheme 2
Br
Cu(NO3)2
RS-SR
AcOEt/H2O
SH
RSH
Catalyst
S
S
r. t.
Solvent, r. t.
Br
1a-1n
2a-2n
Br
Table 1 Optimization study: catalyst screening
Investigation of the optimization of reaction conditions
mentioned in Tables 1 and 2 clearly indicated that
Cu(NO3)2Á3H2O in H2O/AcOEt is a versatile reagent for
the synthesis of disulfides from the corresponding thiols. A
broad range of symmetric disulfides were synthesized
cleanly and smoothly under optimized reactions conditions
(Scheme 2; Table 3).
Entry
Catalyst
Time/min
Yield/%a
1
Cu(NO3)2Á3H2O
Al(NO2)3
18
40
100
50
35
50
50
50
50
60
60
98
2
80
3
Fe(NO2)3Á9H2O
(NH4)2Ce(NO3)6
Bi(NO2)3
75
4
92
5
87
The reaction was tolerant of various substituents, such as
CO2H, Br, NH2, and CH3. As shown in Table 3, the position
of the substituent on the aromatic ring does not play a vital
role in the yield of the product. However, excellent yields of
disulfides were obtained with thiols containing electron-
withdrawing groups (Table 3, entries 8–10). 2-Amino-,
4-aminobenzenethiols, and 2-mercaptopyridine were also
converted into the corresponding disulfides more rapidly
than other thiols (6–10 min; Table 3, entries 6, 7, and 9). As
can be seen, these functionalities remain intact during the
formation of the product disulfides. This protocol was also
satisfactory with some heteroaryl thiols furnishing the
desired products with somewhat longer reaction times and
lower yields in comparison with aliphatic and aromatic
thiols (Table 3, entries 11–14).
6
K3Fe(CN)6Á3H2O
Ce(SO4)4Á4H2O
CuCl2
NR
NR
NR
NR
NR
NR
7
8
9
CuCl
10
11
NaNO3
NH4NO3
Model reaction conditions: 1 mmol 4-bromothiophenol and 1 mmol
catalyst in 3 cm3 AcOEt/H2O (2:1) at room temperature
NR no reaction observed
a
Yield refers to isolated product
Table 2 Optimization study: screening of solvent of reactions
Entry
Solvent (v/v)
Time/min
Yield/%a
1
2
3
4
5
6
7
8
9
AcOEt
50
50
18
50
50
50
50
50
50
55
AcOEt/H2O (1:1)
AcOEt/H2O (2:1)
H2O
80
Conclusions
98
We developed a simple and efficient methodology for the
preparation of symmetric disulfides from the corresponding
thiols in the presence of Cu(NO3)2Á3H2O as an inexpensive
and commercially available catalyst. The present method is
of general applicability to aromatic, aliphatic, and hetero-
aryl thiols. This method is characterized by simple work-
up, short reaction times, mild reaction conditions, high
chemoselectivity, and excellent yields. In addition, this
process is environmentally friendly and economical
because it uses AcOEt/H2O as the solvent and
Cu(NO3)2Á3H2O as the reagent, low consumption of sol-
vent, and does not use toxic or expensive reagents.
NR
NR
NR
NR
NR
NR
EtOH/H2O (1:1)
EtOH/H2O (2:1)
CH3CN
CH3CN/H2O (2:1)
CH2Cl2/H2O (2:1)
Model reaction conditions: 1.0 mmol 4-bromothiophenol and
1.0 mmol Cu(NO3)2Á3H2O in 3 cm3 solvent under air and at room
temperature
NR no reaction observed
a
Yield refers to isolated product
observed (Table 2, entry 4). Importantly, product work-
up could be carried out without using additional organic
solvents, but simply separating the organic layer and
evaporating it after drying. We believe that this feature
renders the process practical, economical, and environ-
mentally friendly.
Experimental
Chemicals were purchased from commercial suppliers
and were used without further purification. Yields refer
123

Simple and efficient oxidative transformation of thiols
1153
Table 3 Oxidation of thiols to
Entry
Thiol
Product
Time/
min
Yield/
a
M.p.
(lit. m.p.)/°C
References
disulfides with copper(II) nitrate
at room temperature in AcOEt/
H2O
%
1
PhSH
2a
2b
2c
2d
2e
2f
20
60
30
23
18
10
2
88
85
80
80
98
87
82
95
92
92
75
71
70
60–61(59–61)
[17, 37]
[17, 37]
[31]
2
PhCH2SH
66–67 (66–68)
142–145 (143–145)
43–45 (43–44)
89–92 (90–92)
75–78 (76–78)
88–89 (89–91)
277–280 (278–280)
54–55 (55–56)
166–169 (167–169)
90–94 (92–94)
177–179 (178–179)
69–72
3
Naphthyl-2-SH
4-Me-PhSH
4
[22]
5
4-Br-PhSH
[37]
6
4-NH2-PhSH
2-NH2-PhSH
2-CO2H-PhSH
2-Pyridyl-SH
4,6-Me2-pyrimidyl-2-SH
Benzoxazolyl-2-SH
Benzthiazolyl-2-SH
[31]
7
2g
2h
2i
[37]
8
45
4
[27]
9
[17, 36]
[24]
10
11
12
13
2j
25
100
120
120
2k
2l
[37]
[37]
5-(4-Me-Ph)-1,3,
4-oxadiazolyl-2-SH
2m
–
14
CH3(CH2)3-SH
2n
65
83
Oil
[26]
a
Isolated yield
J = 8.4 Hz, 4H, Ar–H), 7.99 (d, J = 8.4 Hz, 4H, Ar–H)
ppm; 13C NMR (100 MHz, CDCl3): d = 21.68 (CH3),
120.72, 127.07, 129.84, 142.62, 152.44 (OC=N), 164.93
(OC=N) ppm; MS (EI, 70 eV): m/z (%) = 57.2 (72), 64.0
(100), 69.2 (28), 85.2 (32), 85.2 (31), 96.1 (37), 97.2 (38),
128.0 (64), 160.0 (37), 192.0 (12), 255.9 (26), 258.0 (17),
280.5 (10), 337.6 (5), 382.0 (3).
to isolated products. Melting points were determined on
an Electrothermal 9,100 apparatus. The 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Bruker Avance NMR spectrometer in
CDCl3 solution. Mass spectra were recorded on an Ag-
ilent Technology (HP) 5,973 instrument (ionizing voltage
70 eV). Elemental analyses were done on a Carlo-Erba
EA1110 CHNO-S analyzer. The progress of the reaction
was monitored by TLC using silica-gel SILG/UV 254
plates.
Acknowledgment We gratefully acknowledge the financial support
from the Ilam University Research Council.
General experimental procedure for the preparation
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