Use of base control to provide high selectivity between diaryl thioether and diaryl disulfide for C-S coupling reactions of aryl halides and sulfur and a mechanistic study

Article abstract of DOI:10.1021/om400784w

Previous studies have reported that S-arylation produces diaryl disulfide when the precursors include sulfur powder and aryl halide using CuI as the catalyst. However, our research has revealed that the use of different bases in the above S-arylation process results in the coproduction of diarylsulfane and diaryldisulfane. In addition, we have demonstrated that the ratio of the two products can be controlled by selecting the alkalinity of the bases. ¹H NMR spectra showed that diaryldisulfane was the first product, which became the reagent in a reaction with aryl halide to form diarylsulfane through CuI catalysis. Various aryl halides were tested to enhance the selectivity between diarylsulfane and diaryldisulfane using various different bases, leading to the following principles. A weak base, such as metal carbonate or acetate, results in the production of only diaryldisulfane; a strong base, such as metal hydroxide, results in the production of both diaryldisulfane and diarylsulfane. According to DFT calculations, hydroxide ions, which were exchanged for iodide and bonded with Cu, affected Cu electrons more strongly to reduce diaryl disulfide.

Full text of DOI:10.1021/om400784w

Article
pubs.acs.org/Organometallics
Use of Base Control To Provide High Selectivity between Diaryl
Thioether and Diaryl Disulfide for C−S Coupling Reactions of Aryl
Halides and Sulfur and a Mechanistic Study
Hsing-Ying Chen, Wei-Te Peng, Ying-Hsien Lee, Yu-Lun Chang, Yen-Jen Chen, Yi-Chun Lai,
Nai-Yuan Jheng, and Hsuan-Ying Chen*
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China
S
* Supporting Information
ABSTRACT: Previous studies have reported that S-arylation produces
diaryl disulfide when the precursors include sulfur powder and aryl halide
using CuI as the catalyst. However, our research has revealed that the use
of different bases in the above S-arylation process results in the coproduc-
tion of diarylsulfane and diaryldisulfane. In addition, we have demonstrated
that the ratio of the two products can be controlled by selecting the
1
alkalinity of the bases. H NMR spectra showed that diaryldisulfane was
the first product, which became the reagent in a reaction with aryl halide
to form diarylsulfane through CuI catalysis. Various aryl halides were
tested to enhance the selectivity between diarylsulfane and diaryldisulfane
using various different bases, leading to the following principles. A weak
base, such as metal carbonate or acetate, results in the production of only diaryldisulfane; a strong base, such as metal hydroxide,
results in the production of both diaryldisulfane and diarylsulfane. According to DFT calculations, hydroxide ions, which were
exchanged for iodide and bonded with Cu, affected Cu electrons more strongly to reduce diaryl disulfide.
ligand for the coupling of aryl chloride and triflates with thiols.
Palladium-catalyzed coupling is a powerful method for forming
aromatic carbon−sulfur bonds. Considering the current costs of
Pd ($600−700/ounce) and phosphine ligands, the search for
less costly alternatives has led to the application of other tran-
sition metals such as nickel,7 iron,8 indium,9 cobalt,10 and copper11−14
for S-arylation. Copper salts in particular provide higher cat-
alytic activity at a lower price than most of the other candidate
materials. A variety of methods have been reported for the
study of copper-catalyzed S-arylation, including (1) Cu-nano-
particle systems,11 (2) ligand-free systems,12 (3) ligand-based
systems,13 and (4) systems using various sulfur reagents;14
method 4 deals mainly with the application of new reagents for
S-arylation. Figure 1 outlines the fourth method using various
sulfur reagents.
Among these methods, S-arylation from sulfur powder shows
particular promise, due to its low coat and only faint odor. Jiang
and Ma14k reported several polysulfanes with various numbers
of sulfur molecules as byproducts of S-arylation from sulfur
powder (Figure 2a). Xu and Feng14j reported that arenethiols
could be synthesized after treating the coupling products with
Zn and HCl (Figure 2b). We recently determined that the
product of the above coupling reaction is diaryldisulfane, as
identified by GC-MS using Na2CO3 as a base. Li14l and Srogl14n
respectively reported that unsymmetrical sulfides were
INTRODUCTION
■
Recently, C−N, C−S, and C−O coupling reactions have been
performed using transition metals as catalysts. Such applications
have been studied extensively because the resulting derivatives,
such as phenol, aniline, and thiophenol, are important for
synthesizing natural products, pharmaceuticals, and polymeric
materials. Among them, scientists have paid particular attention
to C−S coupling reactions because the derivatives exhibit bio-
logical activity. Liu and Huth1a reported a series of p-(arylthio)-
cinnamide-based antagonists of the LFA-1/ICAM-1 interaction,
represented by 1 (Chart1). This series of compounds was
identified by screening for the inhibition of the LFA-1/ICAM-1
interaction with full length proteins. Silvestri1b reported a series
of arylthioindoles (ATIs) (Chart 1) that were effective inhibitors
of the tubulin assembly and MCF-7 cell growth at nanomolar
concentrations. In addition, aryl sulfides and their derivatives
are important for their biological, pharmaceutical, and material
interest.2
Conservative methods used in the formation of C−S bonds
often require severe reaction conditions.3 To overcome this,
attention has been focused on the evolution of catalytic systems
for the S-arylation of thiols using aryl halides. Transition-metal-
catalyzed cross-coupling reactions of aryl halides with arenethiol or
alkanethiol are effective methods for forming carbon−sulfur
bonds. Migita4 reported the first palladium-catalyzed coupling
reaction of iodo- and bromoarenes with thiols, and various
ligands5 have been tested for this reaction. Hartwig6 reported a
highly efficient palladium-catalyzed system using the Josiphos
Received: August 4, 2013
© XXXX American Chemical Society
A
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Chart 1. Examples of Sulfur-Containing Molecules with Biological Importance for Pharmaceuticals, Biologically Active
Molecules, and Polymeric Materials
Table 1. Optimization of Cu Salts and Bases for C−S Coupling Reactions of 4-Iodotoluene and Sulfur Powder
d
conversn, %
entry
Cu salt
none
base
ditolylsulfane
ditolyldisulfane
iodotoluene
a
1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
0
<1
<1
<1
<1
<1
0
0
56
58
52
23
63
0
100
44
a
a
a
a
a
a
a
a
a
c
2
CuI
3
CuBr
CuCl
Cu2O
Cu2S
CuO
CuS
42
4
48
5
73
6
37
7
100
100
100
100
43
8
0
0
9
Pd(OAc)2
PdCl2
CuI
0
0
10
11
12
13
14
15
16
17
18
19
0
0
32
34
<1
7
25
38
48
54
57
22
43
48
18
ab
,
CuI
28
CuI
52
CuI
39
CuI
KOH
5
38
CuI
NaOH
40
44
<1
38
CuI
LiOH·H2O
CH3COOK
12
CuI
52
CuI
CH3COONa
0
82
a
b
c
d
1
Alfa reagent. A drop of water was added. Acros reagent. Detection from H NMR spectra. For example, 63% in entry 6 means that 63% of
4-iodotoluene transformed to ditolyldisulfane.
produced from aryl halide and diaryl disulfane. On the basis of
this approach, this study sought to synthesize a symmetrical
diaryldisulfane (from aryl halide and sulfur power using Cu salt
and Na2CO3), which was then coupled with another aryl halide
to obtain an unsymmetrical diarylsulfane. Jiang and Ma also
described the production of arenethiol through the reaction of
diarylpolysulfane with NaBH4. This study investigated the use
of NaBH4 as the base in the coupling reaction to obtain a
symmetrical diarylsulfane. These results imply that there should
be two products in the coupling reaction of aryl halide and
sulfur powder: diarylsulfane and diaryldisulfane. In the coupling
reaction of aryl halide with sulfur powder, diaryldisulfane was
B
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Figure 2. S-arylation from sulfur powder and aryl iodide.
Pd(OAc)2 or PdCl2 (entries 9 and 10) was ineffective. With
Cs2CO3 (99.5%) (entry 11) from Acros as the base, the
production of ditolylsulfane (conversion 32%) and ditolyl-
disulfane (conversion 25%) was observed. It is believed that
this was due to the deliquescence of the Cs2CO3 from Acros,
and a comparison reaction was devised to provide entry 12.
Cs2CO3 from Alfa was used with a drop of water for the C−S
coupling reaction of 4-iodotoluene and sulfur powder, resulting
in the production of ditolylsulfane (conversion 34%) and
ditolyldisulfane (38%) with a slight increase in catalytic activity.
One explanation may be that the water promoted the
dissolution of Cs2CO3 in DMF, CsOH was produced from
water and Cs2CO3 at 100 °C, and metal hydroxide helped the
Cu salt to generate ditolylsulfane. To validate this assumption,
KOH, NaOH, and LiOH·H2O were tested for the C−S
coupling reaction of 4-iodotoluene and sulfur powder (entries
15−17), all of which produced ditolylsulfane and ditolyldi-
sulfane. Other weak bases, such as K2CO3, CH3COOK, and
CH3COONa (entries 13, 18, and 19), were also used; only
ditolyldisulfane was observed in the C−S coupling reaction of
4-iodotoluene and sulfur powder.
To reveal the reaction mechanism, we monitored the processes
involved in the C−S coupling reaction of 4-iodotoluene and
sulfur powder with Cs2CO3 (Acros) as the base using 1H NMR
spectra, as shown in Figures 3 and 4. When the reaction started,
only 4-iodotoluene was observed (peaks 7.56 and 6.92 ppm,
Figure 3a). After 30 min (Figure 3b), ditolyldisulfane was
observed at 7.38 and 7.11 ppm. After 1 h, ditolylsulfane was
observed at 7.22 and 7.09 ppm. The ratios of iodotoluene, diaryl-
sulfane, and diaryldisulfane are shown in Figure 4. Ditolylsul-
fane was produced during 0.5−1 h, and ditolyldisulfane showed
signs of decreasing after 1 h, suggesting that the first product
was ditolyldisulfane, which was consumed to produce ditolyl-
sulfane. To demonstrate this, diaryldisulfane and 4-iodotoluene
were used as the precursors with various bases to produce
ditolylsulfane, as shown in Table 2.
Figure 1. C−S coupling reactions using various sulfur reagents: (a)
S-arylation of arylboronic acid with alkanethiols,14b N-thiol(alkyl, aryl,
heteroaryl) imides,14a or TMSCF3,14c (b) C−H activation and C−S
cross-coupling of heterocycles with thiols,14d (c) synthesis of
unsymmetrical sulfides using ethyl potassium xanthogenate,14e,f (d)
methylthiolation of aryl C−H nonds with DMSO,14g (e) synthesis of
aryl methyl sulfones from aryl halides and DMSO,14h (f) synthesis of
arenethiols from aryl iodide and thiourea,14i (g) synthesis of
arenethiols from aryl iodide, sulfur powder, and reductants,14j−l,t and
(h) synthesis of unsymmetrical sulfides from aryl iodides and
diaryldisulfanes.14m−p
completely investigated14s but the control of the ratio between
products (diaryldisulfane and diarylsulfane) by the different bases
and the mechanism were not studied. Thus, this study applied
various bases in coupling reactions to determine the influence
of the base on the coupling reaction and underlying
mechanism.
Entries 1−3 in Table 2 reveal that 4-iodotoluene, a base, and
CuI were necessary for the formation of ditolylsulfane. Surprisingly,
Cs2CO3 and K2CO3 influenced Cu catalysis in the synthesis of
ditolylsulfane. Thus, Cs2CO3 and K2CO3 are both able to synthesize
ditolyldisulfane and ditolylsulfane; however, the coupling
reaction of ditolyldisulfane from S8 and iodotoluene is more
effective than that of ditolylsulfane frpm ditolyldisulfane and
iodotoluene. Other metal carbonates and weak bases, such as
CH3COONa, did not promote the synthesis of ditolylsulfane
from CuI (entries 7, 8, and 12). In contrast, all of the metal
hydroxides, such as LiOH, NaOH, and KOH, broke the S−S
bond by CuI and produced ditolylsulfane. This means that
hydroxide is a strong base and offers more electrons to Cu in
RESULTS AND DISCUSSION
■
We first performed the optimization of Cu salts and bases for
the C−S coupling reaction of 4-iodotoluene and sulfur powder
(Table 1). Using Cs2CO3 (Alfa reagent, 99%) as the base with
various Cu salts resulted in the production of only ditolyldisulfane.
The catalytic rates in decreasing order were Cu2S (63%) >
CuBr (58%) > CuI (56%) > CuCl (52%) > Cu2O (23%) ≫
CuO, CuS (0%). Cu2S was the most effective Cu salt; however,
the underlying mechanism remained unclear. We selected CuI
for subsequent C−S coupling reactions due to its powerful
catalytic activity and stability in air. Changing the catalyst to
−
comparison with CO3 . CuOH with higher electron density is
capable of facilitating the breaking of the S−S bond. All
reactions can be described as shown by eq 1. In addition, the
C
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Figure 3. 1H NMR spectra of tracking the C−S coupling reaction of 4-iodotoluene and sulfur powder with Cs2CO3 (Acros) as the base: (a) 0 min;
(b) 30 min; (c) 4 h; (d) 8 h; (e) 12 h.
Table 2. C−S Coupling Reaction of 4-Iodotoluene and
Ditolylsulfane Catalyzed by CuI with Various Bases
entry
1
base
conversn to ditolylsulfane, %
none
Cs2CO3 (Acros)
Cs2CO3 (Acros)
Cs2CO3 (Acros)
Cs2CO3 (Alfa)
K2CO3
0
0
a
2
◆
▲
Figure 4. Ratios of iodotoluene (black ), ditolylsulfane (blue ),
b
1
3
0
■
and ditolyldisulfane (pink ) monitored by H NMR during time
4
5
54
43
31
0
tracking of the C−S coupling reaction of 4-iodotoluene and sulfur
powder using Cs2CO3 as the base.
6
Table 3. C−S Coupling Reaction of 4-Iodotoluene with a
Range of S8 Amounts Catalyzed by CuI and Base (LiOH·
H2O or CH3COONa) in DMF at 100 °C for 24 h
7
Na2CO3
8
Li2CO3
0
9
KOH
54
93
64
0
10
11
12
NaOH
a
conversn, %
LiOH·H2O
CH3COONa
b
entry I-toluene:S ditolyldisulfane ditolylsulfane I-toluene ratio, %
c
a
b
1
2
3
4
5
6
7
8
3:1
0
25
0
30
0
70
75
42
58
17
45
0
45
25
42
16
37
18
36
27
Without CuI. Without 4-iodotoluene.
d
c
3:1
3:1.5
3:1.5
3:2
58
0
d
c
42
0
Ar−I
Ar−I + S8 ⎯⎯⎯⎯⎯⎯⎯⎯⎯→ Ar−SS−Ar ⎯⎯⎯⎯⎯⎯⎯⎯⎯→ Ar−S−Ar
83
0
pathway A
pathway B
(1)
d
c
3:2
55
29
73
3:3
71
0
d
Li14m and Srogl14n groups showed that this reaction needs
reductants, such as Fe and ascorbate, to reduce Cu
intermediates, but our result showed that it worked well
without reductants. This means that there is something which
serves as the reductant, such as S8 or I−. To figure out the real
reductants, a range of S8 amounts was tested for coupling with
3:3
27
a
b
1
Detection from H NMR spectra. The ratio of S8 was used as the
c
d
reductant. LiOH·H2O. CH3COONa.
iodotoluene, shown in Table 3. In Table 3, S8 was the limiting
reagent and the quantity of S8 was not equal to that of the
D
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Figure 5. DFT calculations of the reaction between CuX (X = OH, CH3COO) and diphenyldisulfane. The values in parentheses are charges on S,
Cu, and X.
coupling products. This mean that parts of S8 may be the
reductant and the ratio of S8 used as the reductant is 36−46%
using LiOH·H2O as the base (entries 1, 3, 5, and 7) and
16−27% using CH3COONa as the base (entries 2, 4, 6, and 8).
This means that 16−27% of S8 was the reductant in pathway
A of eq 1 and 9−26% in pathway B. In addition, the
concentration of S8 is low, which made the production rate of
Ar−SS−Ar (pathway A) lower than that of Ar−S−Ar (B);
hence, there is no ditolyldisulfane obtained and CH3COONa
could not break the S−S bond by activating Cu to produce Ar−
S−Ar. However, the results of Table 2 showed that the catalytic
reaction still proceeded without S8. There must be another
reductant in this reaction. Therefore, the CuI in DMF was
heated at 100 °C for 5 h and I3− was detected by LC-MS. This
means that I− also can reduce CuI to form I2 and Cu and then
the S−S distance increases from 2.12 Å in free disulfane to 3.43
and 3.25 Å in Cu complexes with hydroxide and acetate,
respectively. The test of wavefunction stability indicated that
the stable electronic state of Ia is a singlet biradical rather than a
closed-shell singlet, reflecting the fact that the S−S bond is
basically broken in these Cu complexes. In the Ia state, the Cu
complex with hydroxide showed an unsymmetrical geometry
with the Cu−S bond lengths being 2.22 and 2.31 Å. In contrast,
the analogous complex with acetate displayed a symmetric
structure with the Cu−S bond length being 2.28 Å. It is worth
noting that one of the Cu−S bonds in the hydroxide-containing
complex Ia (2.31 Å) is longer than that in the acetate-
containing complex Ia (2.28 Å). This difference in geometry
was expected to cause the former to more easily dissociate to
form the monomer Ib, which was assumed to be the active
intermediate that subsequently undergoes the oxidative
addition with aryl iodide, in comparison to the latter. This
inference was supported by the computational results of
reaction free energy (ΔrxnG) for Ia → 2Ib; the ΔrxnG value for
the hydroxide-containing system was calculated to be 17.1 kcal/mol,
which is smaller than 19.4 kcal/mol for the acetate-containing
system. The hydroxide-containing Ib might be further
coordinated by a DMF solvent to form Ic; the free energy of
this process was estimated to be −3.6 kcal/mol. However, the
−
react with another I− to become I3 .
To understand the influence of the base on the C−S coupl-
ing reaction of 4-iodotoluene and sulfur powder, we employed
DFT calculations to investigate the different reaction behaviors
of metal hydroxide and metal acetate. We propose that two
equal Cu salts will interact with the S−S bond of diphenyl-
disulfane to form the cyclic intermediate Ia (Figure 5). The
DFT optimized geometries of intermediate Ia revealed that
the S−S bond is ruptured upon coordination with the Cu salts;
E
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Figure 6. Proposed mechanism of the C−S coupling reaction of aryl halide and sulfur.
corresponding process for the acetate-containing system was
energetically unfavorable, with a free energy of 2.8 kcal/mol. In
addition, the charge on the Cu atom of Ib with hydroxide ion
(+0.609) is less positive than that of Ib with acetate ion
(+0.676). In other words, hydroxide ion donates more negative
charge to Cu and makes it more electron rich in comparison
with acetate ion. The Cu center with a higher electron density is
expected to more effectively facilitate the oxidative addition of aryl
iodide. These computational results explain why metal hydroxide
is capable of producing ditolylsulfane but metal acetate is not.
Kinetic experiments were performed to reveal the reaction
mechanism. The reaction can be divided into two stages: the
formation of ditolyldisulfane from iodotoluene followed by the
formation of ditolylsulfane from ditolyldisulfane and iodoto-
luene. During the C−S coupling reaction of 4-iodotoluene and
sulfur powder with Na2CO3 as the base, the concentration of
reaction time indicates that rate = kobs[iodotoluene].2 This
reveals that the rate-determining step of this reaction is the
oxidative addition of aryl iodide, in which two iodotoluenes are
consumed in each catalytic cycle. The C−S coupling reaction of
4-iodotoluene and ditolyldisulfane with LiOH·H2O as the base
was then performed, and the concentrations of iodotoluene and
ditolyldisulfane were monitored by 1H NMR spectra, as shown
in Table S2 and Figures S2 and S3 (Supporting Information).
In Figure S2, the linear relationship of [ditolyldisulfane] versus
reaction time indicates that the reaction rate is irrelevant to the
concentration of ditolyldisulfane. In Figure S3, the linear
relationship of ln[iodotoluene]0 − ln[iodotoluene] versus
reaction time indicates that the reaction rate is irrelevant to
the concentration of ditolyldisulfane. Plots of ln[iodotoluene]0
− ln[iodotoluene] vs time are linear, indicating that the
coupling reaction proceeded with a first-order dependence on
the concentration of iodotoluene. The rate of the C−S coupling
reaction of 4-iodotoluene and ditolyldisulfane can be written as
−d[iodotoluene]/dt = kobs[ditolyl disulfane]0[iodotoluene]1.
1
iodotoluene was monitored by H NMR spectra, as shown in
Table S1 and Figure S1 (Supporting Information). The linear
relationship of 1/[iodotoluene] − 1/[iodotoluene]0 versus
F
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Table 4. C−S Coupling Reaction of Various Aryl Halides and Sulfur Powder Catalyzed by CuI with Various Bases
entry
ArX
2-iodotoluene
base
time, h
Ar2S:Ar2S2
total conversn, %
a
1
LiOH·H2O
NaOAc
36
72
1:0
100
100
100
100
100
75
a
2
0:1
a
3
3-iodotoluene
LiOH·H2O
NaOAc
36
1:0
a
4
72
0:1
b
5
4-iodotoluene
Cs2CO3
10
9:1
c
6
NaOAc
10
0:1
d
7
4-nitrobromobezene
4-bromobenzonitrile
4-iodobenzotrifluoride
3-iodopyridine
Cs2CO3
10
1:0
100
62
e
8
NaOAc
10
1:3.4
1:0
f
9
Cs2CO3
10
100
51
g
10
NaOAc
15
1:7.5
1:0
b
11
Cs2CO3
10
100
96
c
12
NaOAc
40
1:15
1:0
d
13
LiOH·H2O
NaOAc
72
100
100
97
h
14
72
1:1.6
3.6:1
1: 3
1:0
15
16
2-bromopyridine
4-fluoroiodobenzene
4-chloroiodobenzene
4-bromoiodobenzene
4-iodophenol
LiOH·H2O
NaOAc
168
168
24
93
d
17
LiOH·H2O
NaOAc
100
94
d
18
24
1:2.3
15.6:1
0:1
d
19
LiOH·H2O
NaOAc
24
100
92
d
20
24
21
22
LiOH·H2O
NaOAc
24
1:0
100
82
24
1:1.2
8.1:1
0:1
i
23
i
LiOH·H2O
NaOAc
168
168
168
168
168
100
100
98
24
25
26
27
28
4-iodoanisole
LiOH·H2O
NaOAc
2.0:1
0: 1
4.9:1
0:1
37
1,3,5-trimethyliodobenzene
LiOH·H2O
NaOAc
100
56
168
a
b
Detection by GC-MS; the spectrum showed only one product without the precursor. Detection by 1H NMR spectrum; the spectrum is given in
c
d
1
1
ref 15a. Detection by H NMR spectrum; the spectrum is given in ref 15c. Detection by H NMR spectrum the spectrum is given in ref 15b.
e
f
g
Detection by 1H NMR spectrum; the spectrum is given in ref 15g. Detection by 1H NMR spectrum; the spectrum is given in ref 15e. Detection by
h
i
1H NMR spectrum; the spectrum is given in ref 15d. Detection by H NMR spectrum; the spectrum is given in ref 15f. Detection by H NMR
1
1
spectrum; the spectrum is given in ref 15j.
This reveals that the rate-determining step of this reaction is
also the oxidative addition of aryl iodide; however, only one
iodotoluene is consumed in every catalytic cycle. The reaction
mechanism is outlined in Figure 6. Initially, sulfur powder
reacted with the base to become metal sulfide. The exchange of
anions between CuI and metal sulfide produced copper sulfide
and metal iodide. Our kinetic study revealed that two iodo-
toluenes were consumed in every catalytic cycle; therefore, the
two iodotoluenes caused the oxidative addition of copper sulfide
to become A. Reductive elimination then occurred to form B,
and ditolyldisulfane disscoiated to generate the original CuI.
Ditolyldisulfane may return to associate with CuI to form B
because this is a reversible reaction. The hydroxide of the base
exchanged with B to become C, and CuI quickly reduced the
S−S bond to become the CuII dimer form D. The dimer then
transformed into a monomer form and reduced to CuI complex
E by reductants, such as I− and sulfur powder. The oxidative
addition of iodotoluene occurred with complex E to become
CuIII complex F, another rate-determining step. Finally, a
reductive elimination occurred, resulting in the production of
ditolylsulfane and CuI.
To determine whether the selectivity of the base control is
suitable for the C−S coupling reaction of sulfur powder with
other aryl iodides, we tested a variety of aryl halides in this
coupling reaction, as shown in Table 4. Most coupling products
from aryl halides and sulfur powder are controlled by the base.
Aryl halides with electron-withdrawing groups had greater
activity than electron-donating groups. However, aryl halides
with electron-withdrawing groups using a weak base, such as
CH3COONa, also produced a trace of diarylsulfane. 3-Iodo-
pyridine and 2-bromopyridine presented poor selectivity
between diaryldisulfane and diarylsulfane. It may be that the
potential energy of the transition state from C to D (Figure 6)
is low for aryl halides with electron-withdrawing groups because
electron-withdrawing groups let Cu reduce the S−S bond
easily.
CONCLUSION
■
This study demonstrated that the base is a key in controlling
the ratio of diaryldisulfane and diarylsulfane from the C−S
coupling reaction of aryl halide and sulfur powder. A weak base,
such as metal carbonate or acetate, produced only diaryldisulfane.
G
dx.doi.org/10.1021/om400784w | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
and spin density distributions were obtained by natural population
analysis.
A strong base, such as metal hydroxide, first produced diaryl-
disulfane, which then pushed the Cu center to catalyze diaryl-
disulfane and aryl halide to become diarylsulfane. This can be
explained by DFT calculations which show that hydroxides
form a monomer (ArS−Cu−OH) from a dimer more easily
than acetate ions. Controlling the base is an effective method to
obtain the single product of diaryldisulfane and diarylsulfane.
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables and figures giving compound characterization data,
including NMR spectra, and details of the kinetic study and
DFT atom coordinates and absolute energies for all relevant
computationally studied species. This material is available free
of charge via the Internet at http://pubs.acs.org.
EXPERIMENTAL SECTION
■
2-Iodotoluene, 4-iodotoluene, 4-nitrobromobezene, cesium carbonate,
and 4-iodobenzotrifluoride were purchased from Acros. 3-Iodotoluene,
potassium carbonate, sodium carbonate, lithium carbonate, 4-bromo-
benzonitrile, and 3-iodopyridine were purchased from Alfa. Sulfur
powder was purchased from Shimakyo’s Pure Chemicals. Potassium
hydroxide, sodium hydroxide, and lithium hydroxide were purchased
from Nihon Shiyaku. Potassium phosphate, sodium acetate, copper(I)
oxide, copper(II) sulfide, and copper chloride were purchased from
Showa. Copper iodide, copper bromide, copper chloride, copper(I)
oxide, copper(II) oxide, copper(I) sulfide, copper(II) sulfide were
purchased from Aldrich. Copper bromide, copper(I) sulfide, were
purchased from Strem Chemicals. Copper(II) oxide was purchased
from Merck. Palladium(II) acetate was purchased from Seedchem Co.
Palladium(II) chloride was purchased from Catalyst Co. 1H and
13C NMR spectra were recorded on Varian Gemini 2000-200 (200
AUTHOR INFORMATION
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was obtained from the National Science
Council (Grant NSC 101-2113-M-037-009) and the Funda-
mental Research Funds from Kaohsiung Medical University
(KMU-Q100011). We thank the Center for Research
Resources and Development at Kaohsiung Medical University
for the instrumentation and equipment support. We also thank
the National Center for High-performance Computing for
computer time and facilities.
1
MHz for H and 50 MHz for 13C) and Mercury plus-400 (400 MHz
for 1H and 100 MHz for 13C) spectrometers with chemical shifts given
in ppm from internal TMS or the center line of CDCl3.
General Procedure for Coupling Reactions of S8 and Aryl
Halide. A typical coupling reaction was exemplified by the synthesis of
entry 2 (Table 1); iodotoluene (1.5 mmol), sulfur powder (1.5 mmol),
CuI (0.1 mmol), and Cs2CO3 (3.0 mmol) were stirred at 100 °C in
DMF (2 mL). After 5 h, the solution was cooled to room temperature,
diluted with CH2Cl2, and filtered through silica gel with copious
washing (CH2Cl2). The yield was determined by a 1H NMR spectrum.
General Procedure for the Kinetic Study of the C−S
Coupling Reaction of 4-Iodotoluene and Sulfur Powder. In a
flame-dried test tube containing a magnetic stirring bar were placed
CuI, Na2CO3, sulfur powder, and iodotoluene in DMF under N2. The
mixture was heated to 100 °C. At appropriate time intervals, 0.1 mL
aliquots were removed and quenched with CDCl3 (1 mL). The CDCl3
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1
solution was analyzed by a H NMR spectrum.
Dipyridin-2-ylsulfane. 1H NMR (CDCl3, 400 MHz): δ 8.53 (d, 2H,
J = 5.2 Hz), 7.62 (t, 2H, J = 7.6 Hz), 7.44 (d, 2H, J = 7.6 Hz), 7.10
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J = 4.8 Hz), 7.61 (b, 2H), 7.11 (m, 2H), 6.58 (m, 2H).
Bis(4-bromophenyl)disulfane. 1H NMR (CDCl3, 200 MHz): δ
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Bis(4-methoxyphenyl)sulfane. 1H NMR (CDCl3, 400 MHz): δ
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1
Bis(4-methoxyphenyl)disulfane. H NMR (CDCl3, 400 MHz): δ
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1
Dimesityldisulfane. H NMR (CDCl3, 400 MHz): δ 6.83 (s, 4H),
2.24 (s, 6H), 2.20 (s, 12H).
1
Dimesitylsulfane. H NMR (CDCl3, 400 MHz): δ 6.82 (s, 4H),
2.42 (s, 6H), 2.20 (s, 12H).
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