A convenient method for the aerobic oxidation of thiols to disulfides

Article abstract of DOI:10.1080/10426500802418628

Thiols are oxidized to the corresponding disulfides using K ⁺/CH₃CN system under ambient conditions in the presence of air. This system provides a convenient, rapid, and efficient aerobic oxidative for the syntheses of symmetrical disulfides.

Full text of DOI:10.1080/10426500802418628

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A Convenient Method for the
Aerobic Oxidation of Thiols to
Disulfides
Wei-Li Dong a , Guang-Ying Huang a , Zheng-Ming Li a
& Wei-Guang Zhao a
a National Pesticide Engineering Research Center
(Tianjin), State Key Laboratory of Elemento-
Organic Chemistry , Nankai University, Tianjin Key
Laboratory of Pesticide Science , Tianjin, P. R. China
Published online: 22 Jul 2009.
To cite this article: Wei-Li Dong , Guang-Ying Huang , Zheng-Ming Li & Wei-Guang
Zhao (2009) A Convenient Method for the Aerobic Oxidation of Thiols to Disulfides,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:8, 2058-2065, DOI:
10.1080/10426500802418628
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Phosphorus, Sulfur, and Silicon, 184:2058–2065, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802418628
A Convenient Method for the Aerobic Oxidation of Thiols
to Disulfides
Wei-Li Dong, Guang-Ying Huang, Zheng-Ming Li, and
Wei-Guang Zhao
National Pesticide Engineering Research Center (Tianjin), State Key
Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin
Key Laboratory of Pesticide Science, Tianjin, P. R. China
Thiols are oxidized to the corresponding disulfides using K+/CH CN system under
3
ambient conditions in the presence of air. This system provides a convenient, rapid,
and efficient aerobic oxidative for the syntheses of symmetrical disulfides.
Keywords Aerobic oxidative; disulfide; K+/CH3CN; thiol
INTRODUCTION
Transformation of thiols to disulfides is important from both synthetic
and biochemical points of view.1−3 Disulfides have found industrial ap-
plications as vulcanizing agents,4 flavours,5,6 and drugs.7 They are also
important synthetic intermediates with many applications in organic
synthesis.8 Recently, they have been frequently used in dynamic com-
binatorial synthesis.9−12 Many procedures and methods have been de-
vised for this transformation.13−31 However, there is still an interest in
developing a clean, mild and efficient oxidative methods that would pro-
duce the target disulfides in high yields without complicated work-up
procedures.
Generally molecular oxygen is considered as an ideal “green” oxidant
due to its strength and lack of toxic byproducts. Consequently, oxida-
tion of thiols with air or oxygen in the presence of basic alumina,32
Received 3 May 2008; accepted 12 August 2008.
We gratefully thank the China 973 Program (grant No. 2003CB114406) and the
National Natural Science Foundation of China (grant No. 20772069) for financial support
of this research.
Address correspondence to Wei-Guang Zhao, National Pesticide Engineering Research
Center (Tianjin), State Key Laboratory of Elemento-Organic Chemistry, Nankai Univer-
sity, Tianjin Key Laboratory of Pesticide Science, Tianjin 300071, P. R. China. Email:
zhaoweiguang@foxmail.com
2058

A Convenient Method for Aerobic Oxidation
2059
CsF-Celite,33 rhodium complex,34 anhydrous potassium phosphate35
and a manganese(III) Schiff-base complex36 have also been studied.
In our laboratory, we have prepared a series of sulfides by the re-
action of thiols with chlorides in the K2CO3/CH3CN system.37 In this
procedure, we found, in the system, disulfides can be synthesized in ex-
cellent yields by oxidation of the corresponding thiols. In this paper, we
report a simple aerobic oxidative coupling of thiols to disulfides using
K+/CH3CN system at room temperature with good to excellent yields,
and examined the effect of the solvent and base on the oxidation of
thiols in detail.
RESULTS AND DISCUSSION
4-Methylthiophenol (1a) was selected as a model substrate for op-
timization studies. In a typical reaction, a mixture of 1 mmol 4-
methylbenzenethiol (1a), 1 mmol base and 5 mL of solvent were stirred
at room temperature in a round bottom flask without an air bubbler.
Initially, various solvents and bases were examined to facilitate this
transformation. As results showed that acetonitrile was most effective
solvent and itself had some catalytic activity for the oxidation in pres-
ence of air (Table I, entry 6). The examination of base effect showed
that the catalytic activity of K2CO3 was the highest in acetonitrile (Ta-
ble I, entries 1 and 6–8). Even the reaction was completed in 40 min
with catalytic amount of K2CO3 to give the correspounding disulfides
in quantitative yield (Table I, entry 10). To prove the significance of O2
TABLE I The Effects of the Solvent and Base
on the Oxidation of Thiols
Entry
Base
Solvent
Time
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
Et3N
Pyridine
Na2CO3
K2CO3 (Cat.)
K2CO3 (oxygen-free)
CH3CN
CH2Cl2
CH3Cl
30 mina
ꢀ3 hb
ꢀ3 hb
3 ha
CH3OH
benzene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
3 h (trace)
>7d
6 ha
>6 hb
4 ha
10
11
40 mina
1hb (trace)
aThe reaction was completed in the mentioned time.
bThe reaction was not completed in the mentioned time.

2060
W.-L. Dong et al.
TABLE II Synthesis of Disulfides 2a Using Various
K+/CH3CN System at Room Temperature
Entry
Base
Time
Yield of 2a (%)
1
KF
1 h
99b (99.7)e
8.79d
2
3
4
5
6
7
KCl
KBr
KI
24 h
24 h
48 h
1 h
1 h
30 min
91a (98.9)e
trace
KI + Et3N
KI (Cat.) + Et3N
K2CO3
99a (99.4)e
95a (99.9)e
quant.b (99.7)c
aIsolated yield by silica-gel column chromatography.
bIsolated yield by direct filtration, evaporation.
cPurity assessed by HPLC.
dYield by GC.
ePurity assessed by GC.
in the reactions, we conducted a oxygen-free operation, in which a mix-
ture of thiophenol and K2CO3 in acetonitrile without O2 were stirred.
The oxidation hardly occur in the absence of O2, which indicated that
O2 acted as the oxidant in the oxidation process.
Next, the coupling of 4-methylbenzenethiol (1a) using a series of
potassium halides in a neutral or near-neutral medium was carried
out to expand the reaction conditions. The results indicated that potas-
sium salts indeed promoted the reaction, and the order of the catalytic
activity of potassium salts was KFꢀKBrꢀKCl>KI (Table II, entries
1–4). Aromatic thiol 1a was converted to the corresponding disulfide
in 1 h in the presence of KF and in 24 h in the presence of KBr at
room temperature. In the presence of KI, 1a was not converted into
corresponding disulfide completely even after 48 h because of the weak
acidity of the reaction solution. However, the addition of Et3N was
found to be effective to promote the reaction. With 1 mmol 1a and 1
mmol KI in acetonitrile, when the reaction system was adjusted to pH
= 8∼9 using Et3N (2 drops), the reactions were completed within 1 h,
and the disulfide 2a was obtained in excellent yield after chromato-
graphic purification (Table II, entry 5). In the case of the reaction with
1 mmol 1a, catalytic amount of KI (0.1 mmol) and Et3N (2 drops) was
sufficient, and the disulfide 2a was obtained in excellent yield after
chromatographic purification (Table II, entry 6). From these results it
was concluded that, in the K+/CH3CN system, weak alkaline medium
could increased the oxidation rate greatly. Furthermore, highly pure
disulfides were also obtained without tedious column chromatographic
purification, the reaction mixture was filtered, the resulting residue

A Convenient Method for Aerobic Oxidation
2061
TABLE III Reaction of Thiol 1a in K2CO3/CH3CN/H2O System at
Room Temperature
Entry
VH2O/VCH3CN (%) Time
Yield of 2a (%)
1
2
3
4
5
5
5
20
40
40
1 h
6h
6h
6h
24 h
45a (99.7)b
quanta(99.6)b
quanta(99.7)b
22a (99.8)b
60a (98.1)b
aIsolated yield by direct filtration after adding water.
bPurity assessed by GC.
was washed with petroleum ether (2 × 5 mL), then evaporation of the
filtrate under reduced pressure to obtain highly pure disulfides in good
yields (Table II, entries 1 and 7). Additionally, the yields of disulfides
were not affected by the reaction temperature.
Further, we examined the reaction in a mixture solvent of acetoni-
trile and water, these results are summarized in Table III. In these
cases, it took longer time to complete the reaction (Table III, entries 2
and 3), still affording the desired disulfides in high yields. In the case
of entries 4 and 5, the reactions could not reach completion and only
about 60% yield of the disulfide was obtained even with a prolonged re-
action time. However, in these cases, after the reaction completed, the
disulfide could precipitated out from the reaction mixture completely
by adding a certain volume water, then highly pure disulfides were
isolated by simple filtration.
The results above showed that the K2CO3/CH3CN system was the
most suitable for the aerobic oxidative coupling of thiols to disulfides.
Finally, the oxidative coupling of other thiols were carried out according
to established methods. As shown in Table IV, the desired disulfides 2
were obtained in 90–99% yields after silica-gel column chromatography
purification (Table IV, entries 1–6). And the results showed that the re-
actions of aromatic thiols bearing electron-donating groups were faster,
and the reactions of thiophenols were faster than that of benzyl mer-
captan. Regrettably, when aliphatic thiol 1g was used, the reactivity
was significantly decreased, and the reaction could not reach comple-
tion under the conditions described above (Table IV, entry 7), which
was on the contrary to the general notion that the oxidation reaction of
aliphatic thiols is faster than that of aromatic thiols.

2062
W.-L. Dong et al.
TABLE IV Oxidative Coupling of Thiols 1 to the Corresponding
Disulfides 2 in K2CO3/CH3CN System at Room Temperature
air oxidatio, r.t.
R–SH −−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ R–S–S–R
K2CO3(1 mmol)/CH3CN (5 mL)
1
2
(1 mmol)
Entry
Thiols 1
Time
Disulfide 2
Yield (%)a
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
p-Tolylthiol
Phenylthiol
30 min
30 min
20 min
7 h
24 h
2.5 h
24 h
2a
2b
2c
2d
2e
2f
96
94
95
90
90
p-methoxyphenylthiol
3,4-difluorophenylthiol
4-Chlorobenzyl mercaptan
4-tert-butylbenzyl mercaptan
n-C12H25SH
91
1g
2g
16.4b
aIsolated yield by silica-gel column chromatography.
bYield by GC.
CONCLUSION
In conclusion, we have introduced a simple, mild, clean and efficient
aerobic oxidative coupling of thiols to disulfides using K+/CH3CN sys-
tem. Compared with the previously reported the aerobic oxidation of
thiols, the procedure have have the following advantages: (1) potas-
sium salts as catalysts is more available; (2) simplicity of the reaction
conditions without an air bubbler; (3) neutral or weak alkaline of the
reaction medium; (4) the reaction is insensitive to water. So the oxida-
tion method meets the needs of contemporary green chemistry and is
suitable for practical synthesis.
EXPERIMENTAL
Melting points were conducted on a Yanaco MP-500 micro melting-
1
point apparatus. H NMR spectra were recorded in CDCl3 as solvent
on Bruker AC-300 and Bruker AC-400 instrument using TMS as an in-
ternal standard. Elemental analysis was performed on a Yanaco CHN
Corder MF-3 automatic elemental analyzer. GC analyses of the com-
pounds were performed on an Agilent Technologies 6890 N Network
GC System (with a TCZWAX capillary 30m column).

A Convenient Method for Aerobic Oxidation
2063
General Procedure for the Oxidation of Thiols
A mixture of thiol (1.0 mmol), potassium carbonate (1.0 mmol) in
acetonnitrile (5 mL) is strirred at room temperature and access to
atmosphere in a glass reactor equipped without an air purge. The
completion of reaction is monitored by TLC. The reaction mixture is
filtered, and evaporation of the filtrate under reduced pressure fol-
lowed by preparative thin layer chromatography on silica gel afforded
the pure products.
1
2a. Yield: 96% Mp 40–43◦C (Lit.38 mp 42–43◦C). H NMR (300 MHz,
CDCl3): δ 2.340 (s, 6H, CH3), 7.127 (d, 4H, Ph, J = 6.0 Hz), 7.406 (d,
4H, Ph, J = 6.3 Hz).
1
2b. Yield: 94% Mp 64–66◦C (Lit.39 mp 61–62◦C). H NMR (300 MHz,
CDCl3): δ 7.198–7.510 (m, 8H, Ph).
1
2c. Yield: 95% Mp 35–36◦C (Lit.40 mp 40–42◦C). H NMR (400 MHz,
CDCl3): δ 3.795 (s, 6H, OCH3), 6.830 (d, 4H, Ph, J = 8.4 Hz), 7.381–
7.403 (m, 4H, Ph).
2d. Yield: 90% oil liquid, 1H NMR (400 MHz, CDCl3): δ 6.822–6.887 (m,
4H, Ph), 7.467–7.525 (m, 2H, Ph).
1
2e. Yield: 90% Mp 56–58◦C (Lit.41 mp 59–60◦C). H NMR (400 MHz,
CDCl3): δ 3.569 (s, 4H, CH2), 7.414–7.161 (m, 4H, Ph), 7.282–7.303
(m, 4H, Ph).
2f. Yield: 91% Mp 65–66◦C. 1H NMR (400 MHz, CDCl3): δ 1.310 (s, 18H,
CH3), 3.593 (s, 4H, CH2), 7.173 (d, 4H, Ph, J = 8.0 Hz), 7.340(d, 4H,
Ph, J = 8.4 Hz). Anal. calcd. for C22H30S2: C, 73.68; H, 8.43. Found:
C, 73.38; H, 8.33.
2g. Yield: 16.4% Mp 28–29◦C (Lit.42 mp 29–31◦C).1H NMR (300 MHz,
CDCl3): δ 0.881, (t, 6H, CH3, J = 6.3), 1.262–1.398 (m, 36H, CH2),
1.620–1.717 (M, 4H, CH2), 2.655, 2.680, 2.704 (t, 3H, CH2, J = 7.2).
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