Synthesis of disulfides by laccase-catalyzed oxidative coupling of heterocyclic thiols

Article abstract of DOI:10.1039/c3gc40106e

A new method employing a laccase-mediator system as the catalyst and aerial oxygen as the oxidant has been developed for the oxidative coupling of heterocyclic thiols to the corresponding disulfides with yields up to 95% under mild reaction conditions.

Full text of DOI:10.1039/c3gc40106e

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Synthesis of disulfides by laccase-catalyzed oxidative
coupling of heterocyclic thiols†
Cite this: Green Chem., 2013, 15, 1490
Received 15th January 2013,
Accepted 16th April 2013
Heba T. Abdel-Mohsen, Kavitha Sudheendran, Jürgen Conrad and Uwe Beifuss*
DOI: 10.1039/c3gc40106e
www.rsc.org/greenchem
A new method employing a laccase–mediator system as the cata- aromatizations, like the transformation of 1,4-dihydropyri-
lyst and aerial oxygen as the oxidant has been developed for the dines to pyridines and the synthesis of 2-aryl-1H-benzimid-
oxidative coupling of heterocyclic thiols to the corresponding dis- azoles.7 Laccases have also been used for the in situ generation
ulfides with yields up to 95% under mild reaction conditions.
of o- and p-quinones followed by Diels–Alder reactions8 or
nucleophilic additions of C-, N- and S-nucleophiles.4c,9
Another interesting field is the laccase-catalyzed oxidative
coupling of electron rich phenols10 like sesamol type com-
pounds,10a,b vanillidene derivatives,10c coniferyl alcohol,10d,e
totarol,10f and hydroxystilbene derivatives.10g
Disulfides play a vital role in living systems with respect to
the folding, stability and activity of numerous proteins11 as
well as their DNA-cleaving properties.12 They are also of great
interest as cleavable linkages for the design of drug delivery
systems.13 In organic chemistry, disulfides are used as inter-
mediates for the synthesis of sulfinyl and sulfenyl com-
pounds.14 In industry, they are of great importance as
vulcanizing agents.15 In addition, it is known that different
heterocyclic disulfides have interesting cytotoxic activity.16
Therefore, the oxidation of thiols to the corresponding disul-
fides is of great interest both from a biological and a chemical
point of view.
One of the most important methods for the preparation of
symmetrical disulfides is the oxidative dimerization of the
corresponding thiols (Scheme 1). Most procedures are based
on the use of at least stoichiometric amounts of an inorganic
oxidant, such as 2,6-dicarboxypyridinium chlorochromate,17a
(NH4)2Cr2O7/silica chloride/50 wt% wet SiO2,17b KMnO4/
CuSO4,17c MnO2,17d Br2,17e HNO3,17f I2/DMSO17g and Al(NO3)3·
9H2O/silica sulfuric acid.17h
Recently, a number of methods using O2 as the oxidant
have been developed for the oxidative dimerization. Typical
examples include the oxidation of thiols with O2 in the pres-
ence of 100 wt% of activated carbon,18a an excess of Al2O3,18b
1.5 equiv. of CsF on Celite18c and 38 mol% of a MOF [Fe(BTC)].18d
Over the last few decades, the use of enzymes as catalysts in
organic synthesis has received steadily increasing attention
due to its economical and ecological advantages.1 This holds
particularly true for enzyme-catalyzed oxidations. Here,
enzymes are being employed for the development of green oxi-
dations, which are characterized by the use of nontoxic oxi-
dants such as O2 or H2O2, nontoxic solvents like H2O, mild
reaction conditions such as room temperature and atmos-
pheric pressure and the formation of nontoxic side products
like H2O.2
Laccases (benzenediol: O2 oxidoreductase; E.C. 1.10.3.2.)
are easily available multicopper oxidases produced by fungi,
plants and prokaryotes.3 They catalyze the oxidation of organic
molecules using molecular oxygen as the oxidant under mild
conditions, i.e. in aqueous solvent systems at room tempera-
ture and at atmospheric pressure. As aerial oxygen is not only
one of the cheapest oxidants available, but also regarded as an
environmentally benign, sustainable oxidant, its application
has become very popular over the last few years. In laccases,
the substrate oxidation is accompanied by a reduction of
oxygen to completely safe and nontoxic water.4 The substrate
range of laccases can be extended considerably by employing
laccase–mediator systems which allow the oxidation of sub-
strates with higher redox potentials.5
Meanwhile, laccases and laccase–mediator systems have
been used for the oxidation of a number of functional groups,
including activated methyl groups, alcohols, ethers and
amines.6 Other interesting transformations rely on oxidative
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstr. 30,
Stuttgart, D-70599, Germany. E-mail: ubeifuss@uni-hohenheim.de;
Fax: (+49) 711 459 22951; Tel: (+49) 711 459 22171
†Electronic supplementary information (ESI) available: Experimental data and
copies of the 1H NMR and 13C NMR spectra. See DOI: 10.1039/c3gc40106e
Scheme 1 Oxidative dimerization of thiols to disulfides.
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In addition, the oxidative coupling of thiols with O2 has been
also achieved using a number of catalysts including 1 mol%
diaryl tellurides under photosensitized conditions,18e 1 mol%
Table 1 Laccase-catalyzed oxidative coupling of heterocyclic thiols 1 to dis-
ulfides 2 using different laccasesa
Co(II)-Schiff base (Co-salophen),18f 10 mol% Mn(III)-Schiff
18h
base,18g 20 mol% NaI/10 mol% FeCl3
and 15 mol% Ni-
nanoparticles.18i The oxidative dimerization of thiols with O2
was also possible in several ionic liquids18j–l or under soni-
cation with Et3N in DMF.18m Despite some progress, most of
these methods suffer from a number of disadvantages, includ-
ing the use of toxic and/or expensive oxidants or catalysts.
Some of the reagents employed are commercially unavailable
and their preparation is tedious. Also, some catalysts suffer Entry
Method A
Yield 2 (%)
Method B
Yield 2 (%)
1
Product
from low catalytic efficiency. In addition, many of the methods
reported require the use of volatile organic solvents. Another
problem is that some reactions need to be run at high reaction
1
1a
5
—
—
temperatures. Against this background, it is a surprise that
only little is known about the enzyme-catalyzed coupling of
thiols using O2 as the oxidant. So far, only horseradish peroxi-
dase, mushroom tyrosinase19a and baker’s yeast19b have been
used for the oxidative dimerization of thiols.
Here, we report on the laccase-catalyzed oxidative coupling
of heterocyclic thiols (Fig. 1) to the corresponding disulfides at
room temperature using aerial oxygen at atmospheric pressure
as the oxidant.
It is known that laccases differ with respect to their oxi-
dation potentials and their optimal reaction conditions.20 Lac-
cases from Trametes versicolor (20 U mg−1)‡ and Agaricus
bisporus (6 U mg−1)§ were chosen for this investigation. It has
been reported that the optimum pH for the laccase from
T. versicolor is around 4.4,21a while the optimum pH for the
laccase from A. bisporus is around 6.0.21b,c
2
3
4
1c
1f
15
26
47
25
45
1g
5
6
1i
1j
27
10
18
27
7
1m
11
50
After some preliminary experiments with the laccases from
T. versicolor and A. bisporus with regard to the amount of
laccase, organic cosolvents and reaction time, selected thiols
a 1 mmol substrate was reacted.
were reacted under the conditions given in Table 1 (Method A
and Method B).
Using laccase from T. versicolor (Method A), the disulfides 2
were formed exclusively with yields ranging from 5 to 47%. With
the laccase from A. bisporus (Method B) the yields were in the
range between 18 and 50%. However, with 1a and 1c as the sub-
strates no product formation was observed with the A. bisporus
laccase as the catalyst (Table 1, Method B, entries 1 and 2).
We wondered whether it is possible to improve the yields of
the laccase-catalyzed oxidative dimerization by employing a
laccase–mediator system. The oxidative coupling of 1a to 2a
was chosen as a model reaction for the laccase-catalyzed oxi-
dative coupling in the presence of different mediators
(Table 2). 2-Mercaptobenzoxazole (1a) was oxidized with aerial
O2 in the presence of a combination of 300 U laccase from
T. versicolor or A. bisporus and 5 mol% of a mediator (vs. sub-
strate), such as ABTS, HOBT, TEMPO and violuric acid. The
reactions with T. versicolor were performed at pH 4.4 while the
transformations with A. bisporus were run at pH 6.0. It turned
Fig. 1 Heterocyclic thiols employed as substrates.
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out that ABTS was the most suitable mediator to serve this
purpose. With T. versicolor as the enzyme and 5 mol% ABTS as
the mediator, 2a was isolated in 58% yield (Table 2, entry 1).
Using a combination of laccase from A. bisporus and ABTS, the
yield of 2a amounted to 53% (Table 2, entry 2). With HOBT,
TEMPO and violuric acid the yields of 2a were considerably
lower (Table 2, entries 3–8). In the absence of any mediator,
the yield of 2a dropped to 5% or traces (Table 2, entries 9 and
10 resp., see also Table 1, entry 1). As the yields with the
laccase from T. versicolor were higher and because this enzyme
is cheaper than the laccase from A. bisporus, all further experi-
ments focused on the transformations with the combination
T. versicolor–ABTS.
Table 3 Optimization of the laccase–ABTS-catalyzed oxidation of 1a to
disulfide 2aa
Laccase
(U)
ABTS
(mol%)
Yield of
2a (%)
Entry
T (°C)
Time (h)
1
2
3
4
5
6
7
300
300
200
200
200
150
—
5
10
5
2.5
1.25
2.5
2.5
50
rt
rt
rt
rt
rt
rt
24
24
28
30
30
30
20
56
57
59
59
40
48
—
It is assumed that the reaction starts with the laccase-cata-
lyzed oxidation of ABTS to the corresponding ABTS radicals,
which is accompanied by the reduction of O2 to water. This is a 1 mmol 1a was reacted.
followed by the oxidative dimerization of thiols 1 to give the
corresponding disulfides 2. This process is coupled with the
reduction of ABTS radicals to ABTS (Scheme 2).
from T. versicolor and 2.5 mol% ABTS (Table 3, entry 4). A
further reduction of the amount of laccase or ABTS did not pay
off (Table 3, entries 5 and 6). When the reaction with 2.5 mol%
ABTS was performed in the absence of any laccase, no for-
mation of 2a took place (Table 3, entry 7).
When the oxidation of 1a to 2a was repeated under the con-
ditions given in Table 2, entry 1, but at 50 °C, the yield of 2a
was 56% (Table 3, entry 1). In order to increase the yield of 2a
and/or reduce the amounts of laccase and ABTS needed, the
laccase-catalyzed transformation was run under the conditions
given in Table 3. The best result was obtained when the trans-
formation of 1a to 2a was run in the presence of 200 U laccase
We also tried to replace the laccase–ABTS system by CuSO4
as a simulation of laccase enzyme without protein backbone
under the same experimental conditions. However, when the
transformation of 1a was run in the presence of 4 mol%
CuSO4, the yield of disulfide 2a was very low (2%) (Scheme 3).
With the optimized conditions in hand (Table 3, entry 4),¶
the oxidative dimerization of a number of heterocyclic thiols
including 2-mercaptobenzoxazoles 1a,b, 2-mercaptobenzothi-
azoles 1c–e, 2-mercaptothiazoles 1f–h, 2-mercaptopyridine (1i)
and 2-mercaptopyrimidines 1j–m was studied. It was observed
that all thiols could be oxidized smoothly. In all cases the dis-
ulfides 2a–m were formed exclusively with yields ranging
between 50 and 95% (Table 4). Noteworthy to mention is that
no side products from overoxidation could be isolated.
Table 2 Laccase-catalyzed oxidation of 2-mercaptobenzoxazole (1a) to
disulfide 2a using different laccases and different mediatorsa
Time Yield of
Entry Laccase
Buffer (pH)
Mediator
ABTS
(h)
2a (%)
The laccase-catalyzed oxidative coupling of thiols to disul-
fides presented here is in accordance with the principles of
1
2
3
4
5
6
7
8
9
10
T. versicolor Acetate (4.4)
A. bisporus
T. versicolor Acetate (4.4)
A. bisporus
T. versicolor Acetate (4.4)
A. bisporus
T. versicolor Acetate (4.4)
A. bisporus
T. versicolor Acetate (4.4)
A. bisporus Phosphate (6.0)
24
24
48
72
48
48
58
53
33
5
13
4
17
Phosphate (6.0) ABTS
HOBT
Phosphate (6.0) HOBT
TEMPO
Phosphate (6.0) TEMPO
Violuric acid 48
Phosphate (6.0) Violuric acid 72
Traces
5
Traces
—
—
24
24
a 1 mmol 1a was reacted.
Scheme 3 Coupling of 1a to 2a with 4 mol% CuSO4/air.
Scheme 2 Proposed mechanism of the laccase–ABTS catalyzed oxidation of heterocyclic thiols 1 to disulfides 2.
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oxidant is converted into nontoxic water as the only byproduct
of the conversion. Using the oxidative coupling of 1m to 2mk
as an example, the E-factor (kg waste per kg product)22c,d,23 of
the overall process amounts to 8.08 kg kg−1. This value com-
pares well with the E-factors of other synthetic methods for the
synthesis of disulfides.17–19 The atom economy22c,24 of the oxi-
dative coupling of thiols to disulfides is very high; it amounts
to 94%. The laccase-catalyzed process employs aerial oxygen as
an oxidant and avoids the use of any toxic reagents like hazar-
dous heavy metal catalysts/oxidants as well as other toxic
reagents. The reactions were run in a mixture of acetate buffer
(pH 4.4) and up to 17 vol% methanol, which is a safe and
environmentally preferred solvent25 as the reaction medium.
Ethyl acetate, a preferred green solvent, was the solvent used
in most cases for extraction. In contrast to other processes, the
laccase-catalyzed oxidative dimerization can be carried out
under mild reaction conditions, i.e. at room temperature,
under air at atmospheric pressure, in an aqueous system at pH
4.4. The laccase-catalyzed disulfide synthesis is characterized
by high turnover numbers. Using the dimerization of 1m to
2m as an example, it amounts to 9024. This value confirms the
high catalytic efficiency of the process. The turnover frequen-
cies of the process are also high; in the above mentioned
example the TOF is 1128 h−1. These values compare well with
TONs and TOFs of other synthetic methods for the synthesis
of disulfides. Unfortunately, the STY of the process is only
0.005 mol × h−1 × L−1. However, it is expected that it could be
improved by immobilization of laccase as CLEAs.26 And last
but not least, the laccase catalyst is isolated from renewable
feedstock and is completely biodegradable. The same holds
true for the acetic acid of the acetate buffer used.
Table 4 Scope of the laccase–ABTS catalyzed oxidation of 1 to 2
Time
(h)
Yield 2
(%)
Entry
1a
1
Product
1a
30
59
50
2b
3a
4b
1b
1c
1d
24
24
24
78
91
5a
1e
12
89
6a
7a
1f
8
8
81
66
1g
8a
1h
8
92
The structures of all disulfides 2a–m were either confirmed
by comparing their physical and spectral data with their refer-
ence data or unambiguously elucidated by NMR spectroscopy
9a
1i
1j
5
5
82
90
1
and mass spectrometry.** Full assignment of the H and 13C
10a
chemical shifts were achieved by evaluating their gCOSY,
gHSQC and gHMBC spectra.
For example, compound 2c contains a coupled 1H spin
system consisting of aromatic protons 4-H, 5-H, 6-H and 7-H
(Fig. 2). The sequence of the protons in the spin systems was
determined by an analysis of the gCOSY spectrum. Determi-
nation of the chemical shifts of the quaternary carbons C-3a
and C-7a was not unambiguous by 3J-HMBC. Therefore, 13C
NMR chemical shifts were computed by quantum mechanical
DFT calculations at the DFT GIAO mPW1PW91/6-311+G(2d,p)//
mPW1PW91/6-31G(d) level of theory.27 On the basis of the
computationally calculated 13C chemical shifts, the quaternary
11a
1k
5
87
12a
13a
1l
6
8
85
95
1m
a 1 mmol substrate was reacted. b 0.5 mmol substrate was reacted.
green chemistry22 for the following reasons: The reaction is a
highly selective enzyme-catalyzed process that allows for a sub-
stantial reduction of waste. The oxidative dimerization of
thiols 1 delivers analytically pure disulfides 2 in up to 95%
yield. No toxic byproducts are formed. Aerial oxygen as the
Fig. 2 Important HMBC correlations of 2c.
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carbons C-3a and C-7a were assigned at δ = 154.54 ppm
(δ calcd = 152.58 ppm) and δ = 136.13 ppm (δ calcd = 140.04.
ppm), resp. The remaining chemical shift at δ = 167.83 ppm
was assigned at C-2 (δ calcd = 168.58 ppm).
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To summarize,
a laccase–mediator system has been
employed to catalyze the oxidative coupling of heterocyclic
thiols to the corresponding disulfides. The reactions make use
of aerial oxygen at atmospheric pressure as the oxidant,
proceed at room temperature in an aqueous solvent system at
pH 4.4 and deliver the disulfides in good to excellent yields.
Acknowledgements
We thank Ms S. Mika for recording NMR spectra and
Dr A. Baskakova as well as Dipl.-Ing. J. Trinkner (Institut für
Organische Chemie, Universität Stuttgart) for recording mass
spectra. H. T. A.-M. is grateful to Deutscher Akademischer
Austauschdienst (DAAD) for financial support.
Notes and references
‡Determination of the activity of laccase from T. versicolor according to ref. 28. A
0.1 M solution of ABTS (0.3 mL) in 0.2 M acetate buffer (pH 4.4) was diluted
with 0.2 M acetate buffer (2.6 mL, pH 4.4) and treated with a solution of laccase
in the same buffer (0.1 mL). The change in absorption was followed via UV-Vis
spectroscopy (λ = 414 nm). One unit was defined as the amount of laccase that
converts 1 μmol of ABTS per minute at pH 4.4 at rt.
§The activity of laccase from A. bisporus was taken as given by the supplier (6 U
mg−1).
¶General procedure for the laccase-catalyzed oxidation of heterocyclic thiols 1a–m
to the corresponding disulfides 2a–m: A 50 or 100 mL round bottomed flask
with a magnetic stirrer bar was charged with a solution or suspension of the
heterocyclic thiol 1 (1 mmol) in methanol (3–6 mL). Acetate buffer (0.2 M, pH
4.4, 20–30 mL), laccase from T. versicolor (200 U, 10 mg) and ABTS diammonium
salt (13.7 mg, 0.025 mmol) were added and the reaction mixture was stirred at rt
for the time given. After extraction with EtOAc (3 × 30 mL) or CH2Cl2 (3 ×
30 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered
and evaporated in vacuo. The crude product was purified by flash chromato-
graphy on SiO2.
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kReaction was run using 1m (1 mmol), methanol (1 mL), acetate buffer (0.2 M,
pH 4.4, 10 mL), T. versicolor (200 U, 10 mg) and ABTS diammonium salt
(13.7 mg, 0.025 mmol). After completion of the reaction, the crude product was
extracted with EtOAc (3 × 3 mL) and purified by flash chromatography on SiO2 to
deliver 2m in 131 mg, 94% yield.
**Selected analytical data of bis(2-benzothiazolyl)disulfide (2c): white powder
(129 mg, 78%); mp 176–178 °C (lit.,29 178–179 °C); Rf = 0.61 (petroleum ether–
3
EtOAc = 5 : 1); δH (300 MHz; CDCl3) 7.36 (2H, ddd, J5-H,6-H 7.5 Hz or 8.3 Hz,
4
3
3J6-H,7-H 7.5 Hz or 8.3 Hz, J4-H,6-H 1.2 Hz, 6-H), 7.47 (2H, ddd, J4-H,5-H 7.2 Hz or
3
4
3
8.4 Hz, J5-H,6-H 7.2 Hz or 8.4 Hz, J5-H,7-H 1.2 Hz, 5-H), 7.78 (2H, dd, J4-H,5-H
4
3
4
8.0 Hz, J4-H,6-H 1.2 Hz, 4-H) and 7.94 (2H, dd, J6-H,7-H 7.9 Hz, J5-H,7-H 1.2 Hz,
7-H); δC (75 MHz; CDCl3) 121.29 (C-4), 122.68 (C-7), 125.28 (C-6), 126.57 (C-5),
136.13 (C-7a), 154.54 (C-3a) and 167.83 (C-2).
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