Cu(I)-PNF, an organic-based nanocatalyst, catalyzed C-O and C-S cross-coupling reactions

Article abstract of DOI:10.1139/cjc-2017-0733

Peptide nanofiber has been prepared via a self-assembly protocol and decorated with Cu(I) to prepare a nanostructural catalyst. The catalytic activity of this prepared nanomaterial (Cu(I)-PNF) was examined in C-O and C-S cross-coupling reactions. Compared with conventional copper-ligand catalytic systems, CuNP-PNF has unique advantages such as water solubility, high efficiency, and low cost, which makes it a highly efficient and beneficial catalyst to reuse in cross-coupling reactions.

Full text of DOI:10.1139/cjc-2017-0733

Canadian Journal of Chemistry
Cu(I)-PNF, an organic-based nanocatalyst, catalyzed C–O and C–S cross-
coupling reactions
Zahra Taherinia and Arash Ghorbani-Choghamarani*
Z. Taherinia. Department of Chemistry, Faculty of Science, Ilam University, P. O. Box 69315516,
Ilam, Iran. E-mail: Zahra.taheriniya@yahoo.com
Corresponding author: A. Ghorbani-Choghamarani. Department of Chemistry, Faculty of Science, Ilam University,
P. O. Box 69315516,
Ilam, Iran E-mail: arashghch58@yahoo.com; a.ghorbani@ilam.ac.ir; Fax: +98841 2227022; Tel: +98 841 2227022
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Abstract: Peptide nanofiber has been prepared via a self-assembly protocol and decorated with Cu (I) to prepare a nanostructural
catalyst. The catalytic activity of this prepared nano material (Cu (I)-PNF) was examined in C–O and C–S cross-coupling
reactions. Compared with conventional copper-ligand catalytic systems, CuNP-PNF has unique advantages such as water
solubility, high efficiency and low cost, which makes it a highly efficient and beneficial catalyst to reuse in cross coupling
reactions.
Key words: catalyst recyclability, copper, peptide nanofiber, sulfide asymmetry, benzoic acid and ether
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Introduction
Supported metallic nanoparticles and their catalytic applications in organic reactions and drug delivery have
attracted extensive interest in recent years. Ullmann type C-S and C-O bond formation reactions are very
important and powerful tools for numerous applications in the pharmaceutical, agrochemical and polymer
industries. Due to the high costs associated with palladium-based catalyst systems, the past decade has seen
the development of a multitude of copper catalysts for heteroatom bond formations. The effectiveness of the
previously reported catalytic systems for the synthesis of C-heteroatom bonds required harsh reaction
conditions, stoichiometric amounts of promoters, use of strong bases, and bipyridine or phosphine-type
ligands [1-3]. Hence, it is necessary to find an efficient procedure to overcome these drawbacks. A shift
toward copper nanoparticles has been apparent in the past decade because they offer advantages specific to
both heterogeneous and homogeneous catalysts and for this reason they are sometimes called “semi-
heterogeneous” catalysts [4]. Metal nanoparticles easily agglomerate and oxidize due to high surface energy
in aqueous solutions, hence, immobilized on a support that acts as a stabilizing agent. Recently, polymeric
and composite materials [5], boehmite[6], zeolites [7], dendrimers [8], MCM-41[9], activated carbon[10],
carbon nanotube[11] and nanofiber [12] have been used as supports because the support acts as a stabilizing
agent to prevent aggregation of the nanoparticles. Among these supports, nanofibers ranging from micron to
nanometer scales have created interest due to their unique high surface areas to volume ratio, film thinness,
lighter weight and super
thermal stability, and they could be easily recycled due to their one-dimensional structure. Nanofibers
can be generated by numerous techniques such as drawing [13], template synthesis [14], self-assembly [15],
electro spinning [16]. Self-assembly is the most popular fabrication strategy. Self-assembly is a process in
which individual molecules organize and arrange themselves into patterns or structures due to structural
complementarities with hydrogen bonding, electrostatic interactions, hydrophobic affinity, etc. Factors such
as concentration of peptide molecules, pH, solvent polarity, sonication, ionic strength, interaction with
anions such as phosphate are also expected to affect the self-assembly. Self-assembling peptides are
relatively scarce and particularly interesting due to wide application in tissue engineering [17], drug
delivery [18] and use as platforms for presenting antigen epitopes[19]. However, to achieve an efficient
simple fabrication, we demonstrate the self-assembly of a peptide with arginine as the building block. After
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the peptides self-assemble into nanofibers copper nanoparticles were immobilized on the surface of this
nanostructural compound and we studied the catalytic ability for C-O, and C-S coupling reactions. The
2
formation of a bond between sp -carbon and sulfur atoms has received less attention, despite the fact that
sulfides have wide application as potent drugs for HIV [20], Alzheimer [21], and Parkinsons diseases [22]
and are important intermediates in organic synthesis [23]. These sulfides were traditionally prepared via the
reduction of sulfones or sulfoxides involves strong reducing agents, such as DIBAL-H or LiAlH
and the cross-coupling reactions of aryl halides with thiols in the presence of copper [28-29], palladium
30], nickel [31], cobalt [32], iron [33], and indium [34] catalysts. However, arenethiols are susceptible to
oxidative homo coupling to give disulfides as by-products. Decarboxylation of carboxylic acids by loss of
carbon dioxide (CO ) has recently emerged as efficient and new methods for the construction of C–C and
4
[24-27]
[
2
C-Se bonds [35] but the formation of carbon-sulfur bonds was only very recently reported via the copper-
catalyzed, 2-substituted arene carboxylic acid and a thiol or disulfide in the presence of arenecarboxylic
acid containing an electron-withdrawing group [36] (Scheme 1). It is particularly noteworthy that for the
first time we have demonstrated the preparation of aryl sulfides from direct decarboxylative C-S coupling
of aryl halides and aryl carboxylic acids (without the need of an electron-withdrawing group on the
8
arenecarboxylic acid) in the presence of S as a sulfur source and an efficient catalyst (Scheme 1). In
addition this catalyst exhibits high catalytic activity in C–O bond forming reactions.
Scheme 1
Results and Discussion
In our newly published work we investigate the activity of peptide nanofiber decorated with copper as an effective
catalyst for the decarboxylative N-arylation of substituted benzoic acids as well as synthesis of 5-substituted 1H-
tetrazoles (Figure1) [37]. Peptide nanofiber decorated with Cu features led us to further study the scope of peptide
nanofibers for the catalysis of C-O, C-S cross-coupling reactions.
Catalytic studies
After characterization of Cu (I)-PNF, the catalytic activity of this nanostructural compound has been investigated for
C-hetroatom coupling reactions (including C-O and C-S bond formation). Initially, we examined coupling reactions
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of 4-iodoanisole with 4-bromobenzoic acid and S
8
in the presence of catalytic amounts of Cu(I)-PNF, and various
parameters were optimized to achieve the best coupling conditions Table 1. It was found that the base and solvent
significantly affected the yield of the desired product. Among organic and inorganic bases, the most favorable one
was found to be KOH. Also among tested solvents, DMSO and DMF both gave the best yields compared with other
solvents (Chart 1, entries 3, 5). The amount of Cu (I)-PNF was optimized to reveal that the best results were
-1
obtained in the presence of 1.28 g.L of catalyst. The results also show that this coupling reaction is strongly
dependent on reaction temperature. When the reaction was conducted at 100 °C, the observed yield was very low
(table1, entries 14), however, the ideal temperature for coupling reaction was found to be 130 °C. Also, other sulfur
sources such as thiourea and thioacetamide were examined for the model reaction but their observed yields were
very low. It should be mentioned when the reaction conducted in the presence of CuCl in the similar conditions
(
Table1, entry 19), the yields observed were low. We proposed that this reaction occurred via reaction iodoobenzene
with S for the synthesis of symmetrical aryl sulfides, because decarboxylation happens very slowly. Eventually the
best results were obtained with 4-iodoanisole (1 mmol), 4-bromobenzoic acid (1.2 mmol), S (1.5 mmol) and KOH
4 mmol) in the presence catalytic amounts of Cu (I) immobilized on woven nanofiber (200 µl) in DMSO as solvent
8
8
(
at 130 °C (Table 1). The generality of this nanoparticles Cu (I)-PNF was investigated on the substrate scope for the
C-S cross-coupling reaction under the optimized reaction conditions (Chart 1,1a-3g).
Scheme 2
Table 1
3 2
Experimental results show that halide derivatives with different functional groups, such as OCH , NO , Cl,
Br and I provide good to excellent yields of the corresponding sulfides. Meanwhile, in some cases the
coupling reaction of aryl halides containing electron withdrawing substituent's reacted in shorter reaction
time than aryl halides with electron-donating groups.
Scheme 3
Table 2
Chart 1(3a-3g)
The proposed mechanism for the C-S cross-coupling reaction based on previous reports is depicted in Scheme 4
[
38]. Initially S
8
reacts with KOH to give potassium disulfide. Then the peptide nanofiber decorated with Cu
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nanoparticles reacts with potassium disulfide to give copper disulfide, which adds to benzoic acid via an oxidative
addition reaction to produce intermediate 1. This subsequently forms intermediate 2. Aryl halide reacts with
intermediate 2 by oxidative addition to generate 3, which can undergo reductive elimination to afford diaryl sulfide.
Scheme 4.
The reactivity of Cu (I) supported on woven peptide nanofiber was also examined for the cross-coupling reaction
between aryl halides with 4-bromophenol and 4-chlorophenol. In order to optimize reaction conditions, the coupling
reaction between iodobenzene and 4-chlorophenol was selected as the model reaction and various parameters were
optimized (Table 3). All the reactions were carried out under standard conditions and manipulated without any
special precaution. According to results in Table 3, it was found that among organic and inorganic bases, KOH was
found to be the most effective base for this reaction. The effect of solvents was also investigated and it was observed
that the desired product was obtained in DMSO and the coupling reaction in other solvents (such as DMF, PEG and
2
H O) didn’t give satisfactory result. Basis on these results, the optimal conditions involved the following
parameters: iodobenzene (1 mmol), 4-chlorophenol (1 mmol), Cu (I)-PNF (200µl), KOH (1.5 mmol), DMSO (2 mL)
and 130 °C as reaction temperature. Under optimized reaction conditions, a series of structurally various aryl halides
was subjected to the reaction with 4-bromophenol and 4-chlorophenol. The results are summarized in Chart 2(4a-6i),
3 3 2
the results showed that the aryl halide derivatives with different functional groups, such as CH , OCH and NO ,
provide desired products in good to excellent yields (Table 4).
Scheme 5
Table 3
Scheme 6
Table 4
The proposed mechanism for the C-O cross-coupling reaction on the basis of previous reports [39] is illustrated in
Scheme 7. Initially aryl halide reacts with Cu by oxidative addition to form intermediate (a), then the intermediate
(a) reacts with 4-chlorophenol in the presence of the base KOH to provide intermediate (b), then intermediate (b) via
reductive elimination afford ether and releases the copper nanoparticle.
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Scheme 7
Catalyst recyclability
The reusability of a catalyst is one of the most important aspects in industrial point of view. The recyclability of
described catalyst (Cu (I)-PNF) was examined by the cross-coupling reaction of benzoic acid with iodobenzene as a
model reaction. Upon completion of the reaction, the mixture was cooled to room temperature. 20 mL of ethyl
acetate was added to the reaction mixture, which led to the precipitation of Cu (I)-PNF. The resulting precipitate was
washed twice with ethyl acetate (2 x 10 mL), dried and applied for the next run. It was found that Cu (I)-PNF could
be reused at least four times without a significant loss of its catalytic activity (Fig 2). Also hot filtration technique
was done for the synthesis of diphenyl sulfide when the reaction had preceded to nearly50% completion, by adding
ethyl acetate to the reaction mixture, this led to the precipitation of Cu (I)-PNF. The resulting precipitate was
washed twice with ethyl acetate (2 x 10 mL), and then filtered. The filtrate was evaporated under vacuum; DMSO (2
mL) was added and allowed the filtrate to react further. We found that no further reaction occurred after the
separation of catalyst; this means that the Cu (I) catalyst remains on the support at elevated temperatures during the
reaction.
Figure 2
In summary, a novel copper-based peptide nanofiber catalyst was successfully prepared by a simple self-assembly
method and used as a catalyst with excellent activity for C–O and C–S bond formation. In this research for the first
time we demonstrate application of peptide nanofiber decorated with inexpensive copper (I) instead of palladium
and toxic phosphane-containing ligands for C–S bond formation by decarboxylative C-S cross-couplings
Experimental
Chemicals and solvents used in this work were obtained from Sigma-Aldrich, Fluka or Merck chemical companies
and used without further purification.
Preparation of peptide nanofiber (PNF)
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Canadian Journal of Chemistry
Peptide nanofiber has been prepared by our newly published procedure [10].
Synthesis of Cu nanoparticle supported on the peptide nanofiber (CuNP-PNF)
For the synthesis of CuNP-PNF catalyst, 30.14 mg of peptide was dissolved in 0.2 mL of doubly distilled water and
0
.8 mL phosphate buffer solution (pH 8) and the solution was sonicated for a few minutes, then stirred at 80°C
overnight. In the next step CuCl (2.2 mg, 0.02 mmol) was added to the reaction mixture and heated to 80°C for 12 h.
Upon stirring, solution suspension of Cu nanoparticle supported on the peptide nanofiber was formed [37].
General procedure for C-S cross-coupling reaction
8
S (1.5 mmol), benzoic acid (1.2 mmol), aryl halide (1 mmol), 200μL of the solution containing Cu nanoparticle
decorated on nanofibers and KOH (4 mmol) were stirred at 130 °C in DMSO (2 mL). The progress of the reaction
was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the reaction mixture extracted
2 4
with ethyl acetate (3 x 20 mL). The organic layer was washed twice with water and dried with Na SO . Finally,
evaporation of the solvent then purification by column chromatography on silica gel (n-hexane/EtOAc) achieves
corresponding sulfide.
General procedure for C-O cross-coupling reaction
Phenol (1 mmol), aryl halid (1 mmol), Cu nanoparticle supported on the peptide nanofiber (Cu (I)-PNF), (200 µl)
and KOH (1.5 mmol) were stirred at 130 °C in DMSO (2 mL). The progress of the reaction was monitored by TLC
using ethyl acetate and n-hexane as eluent. After completion, the reaction mixture was extracted with ethyl acetate
2 4
(3 x 20 mL). The organic extract was washed twice with water and dried with Na SO then evaporated. The products
purified by thin layer chromatography.
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Captions
Scheme 1. Approaches to C–S bond formation
Scheme 2. Preparation of C–S bond formation
Scheme 3. Synthesis of C–S bond formation
Scheme 4. Proposed mechanism for the synthesis of unsymmetrical sulfides
Scheme 5. Preparation of C–O bond formation
Scheme 6. Synthesis of C–O bond formation
Scheme 7. Proposed mechanism for C-O cross-coupling
Fig 1. SEM images of (a,b and c) immobilised Cu nanoparticles on the surface of the woven nanofibers
Fig. 2 Catalyst recycling studies
Table 1 Optimization of the reaction conditions for the C-S bond forming
Table 2 Synthesis of unsymmetrical sulfides via reaction of benzoicacid and aryl halides/S catalyzed by
8
peptide nanofibers decorated with Cu nanoparticles (CuNP-PNF) in DMSO.
Table 3. Optimization of the reaction conditions for the C-O cross-coupling between iodobenzene and
4
-chlorophenol.
Table 4. Cu(I)-PNF catalyzed C-O cross-coupling of Substituted phenols with aryl halides.
Chart 1(1a-3g). A series of several unsymmetrical sulfides
Chart 2(4a-6i). A series of several unsymmetrical ethers
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I
CO H
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a
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I
I
Br
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4
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4b
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Previous works
NH2
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NMP ,1 60 °C
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This work
S
X
Cu (I)-PNF (Cat.)
CO H
2
DMSO, KOH CO2
R
R'
R
R
130 °C
, S8
Scheme 1
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Page 15 of 25
Canadian Journal of Chemistry
S
X
Cu (I)-PNF (Cat.)
DMSO, KOH
CO H
2
Br
Br
130 °C,
CO2
OMe
MeO
S8
X= Cl, Br and I
Scheme 2
CO H
S
2
X
Cu (I)-PNF (Cat.)
R'
DMSO,S8
CO2
KOH,130 °C
R
R
R
X= Cl, Br and I
Scheme 3
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Canadian Journal of Chemistry
Page 16 of 25
S
Ar
Ar
S S
HO S S
HO S S
S S
S S
K
K
S
S
2KOH
S S
S
S
S
S
reductive-
elimination Cu
X
Cu
Cu
Ar
S
S S
1
Cu Ar
S S
Ar
Ar-COOH
Cu
Cu
Cu
Cu
3
-
CO2
Ar
oxidative-
addition
Ar-X
Ar
2
S
Cu
Cl
S S
Ar
Cu
Cu
1
Ar
Cu
Cu
PNF
nanofibers decorated with Cu
Scheme 4
OH
I
CuNP-PNF (Cat.)
O
+
Base, Solvent ,
Cl
Cl
Scheme 5
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Page 17 of 25
Canadian Journal of Chemistry
OH
X
O
CuNP-PNF (Cat.)
+
X
KOH, DMSO
X
1
30 °C
X= Br, Cl
X= I, Br
12-20 h
Scheme 6
X
Ph- Cu
KOH
PhOH
PhOH
KX+H O
2
(b)
OPh
Ph- Cu
-X
(c)
(a)
reductive elimination
oxidative addition
Cu
PhOPh
Ph-X
Cu
Cu
PNF
Scheme 7
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Canadian Journal of Chemistry
Page 18 of 25
Table 1
Entry
S source
thiourea
Cat. Solvent Temp.
Base
Base
(mmol)
4
Yield
a
b
(µl)
(ºC)
1
2
3
4
5
6
7
8
9
200
DMSO
DMSO
DMSO
PEG
130
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
N.R
30
thioacetamide 200
130
130
130
130
100
80
4
4
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
S
8
200
200
200
200
200
82
4
N.R
43
DMF
4
H
2
O
4
N.R
N.R
N.R
N.R
N.R
63
EtOH
CN
4
200 CH
3
80
4
200
200
200
200
200
100
200
200
200
200
200
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
130
130
130
130
130
130
100
130
130
130
130
Et
3
N
4
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
KF
4
NaOH
4
K
2
CO
3
4
N.R
N.R
28
Na
2
CO
3
4
KOH
KOH
-
4
4
43
-
N.R
trace
37
KOH
KOH
KOH
1.5
2.5
4
C1
9
43
aReaction conditions:4-iodoanisole (1 mmol), 4-bromobenzoic acid (1.2 mmol), base, Cu (I)-PNF (µl), S
(1.5 mmol) and solvent (2 mL). Isolated yield. C
b
8
in the presence of CuCl
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Page 19 of 25
Canadian Journal of Chemistry
Table 2
Time
m.p
Entrya
Acid
Ar-X
product
Yield b
(h)
1
2
3
1a
1a
2a
2b
2c
3a
3a
3b
11
13
8
oil[40]
oil[40]
92
72
75
1
1
a
a
54-56[41]
4
5
6
2d
2e
2c
3c
3d
3e
20
18
11
85
82
65
oik[42]
oil[43]
1
a
1
1
b
b
9
2-95[44]
7
8
9
2d
2f
3f
3e
3f
24
14
24
8
55-57[45]
92-95[44]
63-65[46]
80-83[44]
82
61
90
1
b
1
1
c
c
2d
2c
1
0
3g
80
a
Reaction conditions:4-iodoanisole (1 mmol), 4-bromobenzoic acid (1.2 mmol), base (4 mmol), Cu (I)-PNF (200µl), S
Isolated yield.
8
(1.5 mmol) and solvent (2 mL).
b
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Canadian Journal of Chemistry
Page 20 of 25
Table 3
Entry Cat solvent Temp.
base
mmol of Yield
a
b
(µl)
(ºC)
base
(%)
1
2
200 DMSO
130
KOH
KOH
1.5mmol
78
200
200
200
DMF
PEG
130
130
130
130
130
130
130
1.5mmol N.R
1.5mmol N.R
1.5mmol N.R
1.5mmol N.R
1.5mmol N.R
1.5mmol N.R
3
4
5
6
7
KOH
KOH
2
H O
200 DMSO
200 DMSO
200 DMSO
200 DMSO
Et
KF
CO
CO
3
N
K
2
3
8
9
Na
2
3
1.5mmol N.R
1.5mmol trace
200 DMSO
200 DMSO
100 DMSO
200 DMSO
200 DMSO
80
KOH
KOH
KOH
-
1
0
1
2
3
100
130
130
130
1.5mmol
1.5mmol
-
43
17
1
1
1
N.R
55
KOH
3mmol
a
b
Reaction conditions: Iodobenzene (1 mmol), 4-chlorophenol (1 mmol), base, solvent (2 mL) and Cu(I)- PNF (µl). Isolated yield.
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Page 21 of 25
Canadian Journal of Chemistry
Table 4
Product
Phenol
m.p
Entry a
Ar-X
4a
Yield b
%)
(
6
a
55-57[47]
65-68[48]
65-68[48]
81-83[48]
90-94[49]
1
2
3
4
5a
5a
5a
5a
85
75
70
80
6
6
6
b
b
d
4b
4c
4d
6
e
C5
4e
5a
82
6
f
oil[50]
6
7
8
9
4a
4b
4c
4d
4e
5b
5b
5b
5b
5b
78
65
53
70
75
6
6
6
g
g
h
53-56[51]
53-56[51]
52-54[52]
6i
7
0-73[51]
d1
0
a
b
c and d
Reaction conditions: iodobenzene (1 mmol), phenol (1mmol), KOH (1.5mmol), Cu(I)-PNF (200µl) and solvent (2 mL). Isolated yield.
8h)
time
(
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Canadian Journal of Chemistry
Page 22 of 25
9
9x31mm (600 x 600 DPI)
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Page 23 of 25
Canadian Journal of Chemistry
9
9
8
8
7
7
5
0
5
0
5
0
92
9
0
90
8
8
1
2
3
4
Run
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Canadian Journal of Chemistry
Page 24 of 25
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