Mild and highly efficient preparation of symmetrical disulfides and diselenides using bipyridinum hydrobromide perbromide as a new oxidative reagent

Article abstract of DOI:10.1080/104265090507966

A rapid and efficient method for the large-scale synthesis of symmetrical disulfides and diselenides is developed involving oxidative coupling of corresponding thiols and selenols using bipyridinium hydrobromide perbromide (BPHP). Copyright Taylor & Francis Inc.

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Mild and Highly Efficient
Preparation of Symmetrical
Disulfides and Diselenides
Using Bipyridinum
Hydrobromide Perbromide as a
New Oxidative Reagent
a
a
a
M. Joshaghani , A. R. Khosropour , H. Jafary
&
a
I. Mohammadpoor-Baltork
a
Chemistry Department, Faculty of Science, Razi
University, Kermanshah, Iran
b
Chemistry Department, Faculty of Science, Isfahan
University, Isfahan, Iran
Version of record first published: 01 Feb 2007.
To cite this article: M. Joshaghani , A. R. Khosropour , H. Jafary & I. Mohammadpoor-
Baltork (2005): Mild and Highly Efficient Preparation of Symmetrical Disulfides and
Diselenides Using Bipyridinum Hydrobromide Perbromide as a New Oxidative Reagent,
Phosphorus, Sulfur, and Silicon and the Related Elements, 180:1, 117-123
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Phosphorus, Sulfur, and Silicon, 180:117–123, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090507966
Mild and Highly Efficient Preparation of Symmetrical
Disulfides and Diselenides Using Bipyridinum
Hydrobromide Perbromide as a New Oxidative Reagent
∗
M. Joshaghani
A. R. Khosropour
H. Jafary
Chemistry Department, Faculty of Science, Razi University,
Kermanshah, Iran
I. Mohammadpoor-Baltork
Chemistry Department, Faculty of Science, Isfahan University,
Isfahan, Iran
A rapid and efficient method for the large-scale synthesis of symmetrical disulfides
and diselenides is developed involving oxidative coupling of corresponding thiols
and selenols using bipyridinium hydrobromide perbromide (BPHP).
Keywords Diselenide; disulfide; oxidative coupling; selenols; thiols
INTRODUCTION
Oxidative coupling of thiols and selenols to the corresponding disulfides
1
–3
4–13
and diselenides is very important in biology,
organic synthesis,
1
4–16
and industries. Due to ease of preparation, disulfides are usually
used as sulfenylating agent for carbonyl compounds.
1
7–20
There are var-
ious methods for the oxidative coupling of thiols, but most of them suffer
from one or more disadvantages such as unavailability of reagents, un-
favorable conditions for preparation of the reagent, toxicity, high cost,
long reaction and/or monitoring period, over-oxidation, and cumber-
some work-up procedures. Most reagents are metallic and are toxic for
the environment,21 while, others such as Br2 are non-metallic and
encounter the difficulty in handling and isolation.
22
Received March 18, 2004; accepted June 16, 2004.
Address correspondence to M. Joshaghani, Chemistry Department, Faculty of
Science, Razi University, Tagh-E-Bostan, Kermanshah, Iran. E-mail: Joshaghanim@
yahoo.com
117

1
18
M. Joshaghani et al.
Herein, we introduce a new reagent, bipyridinium hydrobromide per-
bromide (BPHP), for selective oxidative coupling of thiols and selenols
to their corresponding disulfides and diselenides (Scheme 1, Table I). In
some cases (Table I, entries 3–4 and 16–17) the activity of the reagent
in large-scale synthesis was investigated.
SCHEME 1
The utility of the BPHP in the oxidation of aromatic, aliphatic, ben-
zylic, heterocyclic thiols, and aromatic selenols was tested. The results
are shown in Table I. Aromatic thiols, independent of electronic and
steric effects of the substituents, react well to afford the corresponding
disulfides in high yields (Table I, entries 1–7). It is important to note
that no oxidation of an amino group was observed (Table I, entry 4).
Therefore, the high selectivity, in addition to the ease of oxidation com-
pared to the previously reported reagents,23 is a remarkable advantage
of this reagent.
In the case of aliphatic thiols, it seems that the reaction depends
on the electronic properties of the thiols.24 Comparison of the results
obtained with entries 9–11 reveals that the reactivity decreased with
increasing the electron withdrawing property of the substituents which
follows the order Pr > CH2OH ꢀ COOH.
One of the most important advantages of our study comes from the
oxidative coupling of the two benzimidazoles, 2-mercaptobenzimidazole
and 2-mercaptothiobenzimidazole (entries 14 and 15, respectively).
They were oxidized to their corresponding disulfides in acetonitrile for
only 5 minutes at room temperature by BPHP. The disulfides were iso-
lated in high yields (85 and 90%, respectively).
In order to investigate the potential of BPHP in large-scale synthesis
of disulfides and diselenides, the reactions were carried out using about
5
0 mmol of each entry 3, 4, 16, and 17. The yields were high to excellent
(
80, 83, 85, and 85%, respectively). So, it is concluded that BPHP is very
effective for large-scale synthesis of these compounds.
It also should be emphasized that the reactions could be performed
cleanly and controlled to stop at the disulfide and diselenide stage. Over-
oxidation has not been observed, even when the reactions were carried
out in different conditions (entries 1 and 8).

Symmetrical Disulfides and Diselenides
119
TABLE I Oxidative Coupling of Thiols and Selenols by BPHPa
Time (min) RE-ER yield (%)b
M.P. ( C)
◦
Lit. M.P. ( C)
◦
Entry
RE-H
1c
60–6110,22
10
88
61
2
3
10
15
85
90
72
70–7128
—
198
4
15
95
92
91–9228
5
6
20
5
88
95
70
45
71–7128
43–448
7
5
95
144
143–14429
8
9
0
nC8H17SH
nC4H9S
30
15
35
75
92
70
Oil
Oil
Oil
Oil33
d
21,22
Oil
Oil
2
2
1
OH
|
H2C CH2SH
O
1
1
40
65
106
10736
|
|
HOC CH2SH
1
2
3
15
30
90
70
126
Oil
124–12930
Oil9
1
1
1
4
5
5
5
85
90
201
180
20031
180–18232
1
1
6
7
5
5
95
95
56
92
5626
91–9334
aAll reactions were carried out at room temperature using oxidant to substrate molar
ratio 1:2 in acetonitrile except indicated. All products were identified by their IR and
NMR spectral data and comparison of their mp with published data.
b
Isolated yields.
c
Reaction was performed under solvent-free condition.
d
CH2Cl2 was used as solvent.

1
20
M. Joshaghani et al.
TABLE II Competitive Oxidative Coupling of Thiols with BPHPa
Entry
Substrates (1:1)
Products
Time (min)
Yield (%)b
89
1
10
100
90
2
3
10
20
1
1
00
80
00
92
4
10
100
1
1
00
00
5
5
a
Oxidant to substrate molar ratio is 1:2.
Isolated yield.
b
In order to evaluate the intermolecular chemoselectivity of the
reagent, the competitive reactions were carried out and the results are
summarized in Table II. It is interesting to note that cross-coupling
reaction was not achieved under the reaction conditions (Table II,
entries 1–3). Furthermore, in this competitive reaction, sensitive
groups to oxidation, like anilines or aldehydes, are stable and remained
intact in the reaction mixture (Table II, entries 1, 4). Such selectivity
has not been reported previously and could be considered a useful prac-
tical achievement in disulfide synthesis.

Symmetrical Disulfides and Diselenides
121
Recently a convenient procedure for the synthesis of organic sulfide
3
5
from alkyl halides and aryl disufides has been reported. The authors
have suggested a SN2 type mechanism is responsible for these reac-
tions. We encouraged to examine the possibility of one pot conversion
of thiols to the coressponding sulfide using methyliodide as a strong
nucleophile suitable for such mechanism (Table II, entry 5). The result
shows that the nucleophile remained intact and the reaction performed
and controlled to stop at the disulfide stage.
EXPERIMENTAL
Melting points were recorded on Electrothermal apparatus and were
uncorrected. All chemicals are commercially available and used with-
1
13
out further purification. H and C NMR spectra were recorded on a
Bruker Avance 200 MHz NMR Spectrometer. Elemental analyses were
performed using CHN Herause rapid model. Thin layer chromatogra-
phy was performed on precoated silica gel Fluorescent 254 nm (0.2 mm)
on aluminum plates. All yields referred to isolated pure products.
Preparation of Bipyridinium Hydrobromide
Perbromide (BPHP)
To a flask containing bipyridine (7.8 g, 50 mmol) cooled in an ice-salt
bath hydrobromic acid (5.0 ml, 107 mmol) was added slowly. The reac-
tion was stirred for about 5 min, and then bromine (5.5 ml, 107 mmol)
◦
was added dropwise. The temperature was maintained at about −5 C.
A bulky orange solid was formed immediately which was dried in vacuo.
◦
Mp 140–143 C (decomp). Yield 16.7 g (72%). Anal calc. For C10H9N2Br3:
C, 30.26%; H, 2.29%; N, 7.06%. Found: C, 30.47%; H, 2.35%; N, 7.03%
(
mean value of two analyses).
Reaction of 4-Chlorothiophenol with BPHP—A Typical
Procedure
To a stirred solution of 4-chlorothiophenol (0.29 g, 2 mmol) in ace-
tonitrile (5 ml) BPHP (0.60 g, 1.5 mmol) was added, and the mix-
ture was stirred at room temperature for 10 min. A yellowish solid
was formed and was treated with a 1:1 mixture of ether and water
(
2 ml). The reaction mixture was extracted with ether (3 × 10 ml).
The organic layers were combined together and dried over anhydrous
MgSO4. The solvent was removed by a rotary evaporator to afford
◦
25
the corresponding disulfide in 85% (0.22 g) yield, mp 72 C (Lit. mp
◦
74 C).

1
22
M. Joshaghani et al.
Reaction of Selenophenol with BPHP—A Typical Procedure
for Large-Scale Synthesis
To a stirred solution of selenophenol (5.0 ml, 47.2 mmol) in acetonitrile
(
30 ml) BPHP (14.0 g, 35.4 mmol) was added, and the mixture was
stirred at room temperature for 10 min. The solid was treated with a 1:1
mixture of ether and water (40 ml). The reaction mixture was extracted
with ether (5 × 20 ml). The organic layers were combined and dried over
anhydrous MgSO4. The solvent was removed by a rotary evaporator
to afford a white solid in 85% (6.25 g) yield, mp 64–65 C (Lit. m.p.
6
◦
26
◦
5 C).
ACKNOWLEDGMENT
The authors are grateful to the Razi University Research Council
and Kermanshah Refinery Company for the support of this work and
Mr. M. Irandoost for running the NMR spectra.
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