Efficient and convenient oxidation of thiols to symmetrical disulfide with silica-PCl5/NaNO2 in water

Article abstract of DOI:10.1080/00397910802697442

A very simple, environmentally benign, cost-effective, and efficient synthesis of disulfides from thiols using silica-PCl5/NaNO2 in aqueous medium has been described. The reaction was found to occur rapidly under mild conditions, and disulfides were obtained easily through a simple workup.

Full text of DOI:10.1080/00397910802697442

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Efficient and Convenient
Oxidation of Thiols to
Symmetrical Disulfide with
Silica–PCl /NaNO in Water
5
2
a
a
Uma Pathak , Lokesh Kumar Pandey & Sweta
a
Mathur
a
Synthetic Chemistry Division , Defense Research
and Development Establishment , Gwalior, India
Published online: 14 Jul 2009.
To cite this article: Uma Pathak , Lokesh Kumar Pandey & Sweta Mathur (2009)
Efficient and Convenient Oxidation of Thiols to Symmetrical Disulfide with
Silica–PCl /NaNO in Water, Synthetic Communications: An International Journal
5
2
for Rapid Communication of Synthetic Organic Chemistry, 39:16, 2923-2927, DOI:
0.1080/00397910802697442
1
To link to this article: http://dx.doi.org/10.1080/00397910802697442
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Synthetic Communications , 39: 2923–2927, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802697442
Efficient and Convenient Oxidation
of Thiols to Symmetrical Disulfide
with Silica–PCl /NaNO in Water
5
2
Uma Pathak, Lokesh Kumar Pandey, and Sweta Mathur
Synthetic Chemistry Division, Defense Research and Development
Establishment, Gwalior, India
Abstract: A very simple, environmentally benign, cost-effective, and efficient
synthesis of disulfides from thiols using silica–PCl =NaNO in aqueous medium
5
2
has been described. The reaction was found to occur rapidly under mild condi-
tions, and disulfides were obtained easily through a simple workup.
5
Keywords: Aqueous medium, disulfide, oxidation, silica-PCl , thiols
[
1]
Disulfides are important from synthetic and biological points of view.
Oxidative coupling of thiols to disulfide through thionitrite formation
[2]
is a potential method. This is usually performed by a reagent combina-
tion of inorganic acid–sodium nitrite in appropriate solvent. Generally,
chlorinated solvents such as dichloromethane or water–alcohol are used
as solvent. Use of strong acid and chlorinated solvents often limits the
utility of this protocol. Hence, there is a scope for further improvement
by avoiding the use of strong=hazardous acids and chlorinated solvents.
Recently, we have developed a novel heterogenized solid acid, silica–
[
3]
PCl5. Silica–PCl can be prepared conveniently from silica and PCl ,
5
5
which is inexpensive and available commercially. Ease in handling, low
cost, simple preparation, and formation of non toxic phosphate
Received July 23, 2008.
Address correspondence to Uma Pathak, Synthetic Chemistry Division,
Defense Research and Development Establishment, Jhansi Road, Gwalior
4
74002, MP, India. E-mail: sc_drde@rediffmail.com
2
923

2924
U. Pathak, L. K. Pandey, and S. Mathur
Table 1. Synthesis of disulfides
a
c
Yield (%)
Entry
1
Substrate
Product
Time (min)
3
95
92
2
5
3
4
5
6
95
92
5
6
4
89
82
b
3
b
7
8
2
81
90
4
b
9
2
78
81
b
3
1
1
1
0
1
2
5
4
92
91
1
1
3
4
5
4
93
90
15
4
89
a
All products were identified by comparison of their physical and spectral data
with those reported in literature.
b
After extraction, the contents were stirred until decolorization of the solution.
Isolated yield.
c

Oxidative Coupling of Thiols to Disulfides
2925
Scheme 1. Oxidation of thiols.
by-products allows this reagent to perform simple, safe, and environmen-
tally benign oxidative coupling of thiols to disulfides.
To investigate the potential of this reagent for performing oxidative
coupling of thiols to disulfides, we selected thiophenol as model substrate.
Initially, the reaction was carried out by stirring a reaction mixture of
silica–PCl , NaNO , and thiophenol in dichloromethane (DCM) containing
5
2
a catalytic amount of water at room temperature. Immediate green colora-
tion was observed, which disappeared after a few minutes. On analysis by
gas chromatography–mass spectrometry (GC-MS), clean and complete con-
version of thiophenol into disulfide was found. Next, we were interested to
know whether this reaction can be done in aqueous medium. We reasoned
that even though some of the P–Cl bonds get hydrolyzed, the resulting
P–OH moiety may still show activity. To illustrate this, the same reaction
was carried out in water in place of organic solvent at room temperature.
Indeed, the reaction occurred in a similar manner without any differ-
ence. After having studied the feasibility of oxidative coupling of thiols to
disulfides in aqueous medium, different kinds of thiols were then exam-
ined (Scheme 1). Reaction was investigated with a variety of thiols as
shown in Table 1. Aromatic and heterocyclic thiols underwent excellent
disulfide formation. With primary and secondary aliphatic thiols, some
side products were also formed. With tertiary mercaptans, which are
otherwise difficult substrates, conversion took place easily with no side
product formation. In all cases, isolation of disulfide was extremely facile
because the phosphate by-product remained bound to the silica and disul-
fide, being water insoluble, was easily separated. In those instances when
disulfides are liquid, isolation can be done by simple phase separation.
In conclusion, we have demonstrated a simple, cost-effective, and
practical method for oxidative coupling of thiols to disulfides. Reaction
in aqueous medium, easy isolation, and generation of nontoxic phosphate
by-products makes this reaction environmentally benign and convenient.
EXPERIMENTAL
Preparation of Silica–PCl5
Dry silica (15 g) was mixed with 10 g of PCl . To this, 50 ml of dry DCM
5
were added dropwise, and the mixture was stirred at room temperature

2926
U. Pathak, L. K. Pandey, and S. Mathur
ꢀ
for 1 h. The solvent was evaporated, and the contents were heated at 70 C
for 3 h with stirring. HCl was removed with a slow stream of nitrogen.
Contents were then washed with 100 ml of DCM, filtered under vacuum,
ꢀ
and dried at 100 C for 3 h. The free-flowing, white silica–PCl thus
5
obtained was stored in a tightly caped bottle. Infrared spectra of both
silica and silica–PCl were similar, and both showed strong adsorption
5
ꢁ
1
at 1098 cm and 800 cm . Acid–base titration of the reagent gave a
ꢁ1
total acid content of 54 mg KOH=g of silica-PCl5.
General Procedure
Silica–PCl (2.1 g, 2 mmol) and NaNO (0.14 g, 2 mmol) were taken in a
5
2
round-bottom flask. To this, 2 mL of water were added immediately,
followed by addition of the thiol. A green or red color was produced.
The reaction mixture was stirred vigorously. The color disappears within
2
appears, reaction contents were neutralized with NaHCO , extracted
–6 min, indicating completion of the reaction. As soon as the color dis-
3
with appropriate solvent, and dried over anhyd. Na SO . Removal of
2
4
the solvent in vacuo gave the pure product. In the case of aliphatic pri-
mary and secondary thiols, the moment color starts disappearing, the
reaction was neutralized with sodium bicarbonate and extracted with
an appropriate solvent. The extract was further stirred untill the color
completely disappears and then eluted through a short column of silica.
Spectral Data for Selected Compounds
0
4
,4 -Dimethyl Phenyl Disulfide (3)
ꢀ
ꢀ
1
White solid; mp 44–45 C (lit., 43–46 C). H NMR (CDCl =TMS
3
4
EIMS m=z: 246 (M ), 213, 198, 182, 123, 108, 79, 77, 45.
00 MHz): d 2.25 (s, 6H), 7.03 (d, J ¼ 8 Hz, 4H), 7.30–7.35 (m, 4H).
þ
0
2
,2 -Dipyrimidyl Disulfide (8)
ꢀ
1
Light yellow solid; mp 134–136 C, H NMR (DMSO-d =TMS 400 MHz):
6
þ
d 7.21 (t, 2H), 8.65 (m, 4H). EIMS m=z: 222 (M ), 158, 80, 79, 53.
ACKNOWLEDGMENTS
We are thankful to Mr. Basant Lal for recording the NMR spectra. We also
thank Dr. R. Vijayaraghavan, director, Defense Research and Develop-
ment Establishment, Gwalior, for his keen interest and encouragement.

Oxidative Coupling of Thiols to Disulfides
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2927
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