Palladium supported on bis(indolyl)methane functionalized magnetite nanoparticles as an efficient catalyst for copper-free Sonogashira-Hagihara reaction

Article abstract of DOI:10.1016/j.apcata.2016.06.041

A novel heterogeneous catalyst based on palladium nanoparticles supported on 3,3′-bisindolyl(4-hydroxyphenyl)methane functionalized magnetite (Fe₃O₄) nanoparticles was synthesized, characterized and used as catalyst for Sonogashira-Hagihara reaction. The alkynylation of a variety of aryl iodides and aryl bromides with terminal alkynes was carried out at 60?°C under copper and phosphane-free conditions using N,N-dimethyl acetamide as solvent, DABCO as base and low Pd loadings (0.18 mol%) under air. In the case of aryl chlorides, the reaction was carried out at 120?°C in the presence of tetra-n-butylammonium bromide (TBAB) and 0.36 mol% of Pd catalyst. The heterogeneous palladium catalyst introduced in this study is recoverable by an external magnet and it can be used for seven consecutive runs without a significant loss in catalytic activity.

Full text of DOI:10.1016/j.apcata.2016.06.041

Accepted Manuscript
Title: Palladium Supported on Bis(indolyl)methane
Functionalized Magnetite Nanoparticles as an Efficient
Catalyst for Copper-Free Sonogashira-Hagihara Reaction
Author: Mohammad Gholinejad Abdollah Neshat Fatemeh
Zareh Carmen N a´ jera Mehran Razeghi Abbas Khoshnood
PII:
S0926-860X(16)30355-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2016.06.041
APCATA 15937
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
11-12-2015
25-6-2016
30-6-2016
Please cite this article as: Mohammad Gholinejad, Abdollah Neshat, Fatemeh
Zareh, Carmen N a´ jera, Mehran Razeghi, Abbas Khoshnood, Palladium Supported on
Bis(indolyl)methane Functionalized Magnetite Nanoparticles as an Efficient Catalyst
for Copper-Free Sonogashira-Hagihara Reaction, Applied Catalysis A, General
http://dx.doi.org/10.1016/j.apcata.2016.06.041
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Palladium Supported on Bis(indolyl)methane Functionalized Magnetite Nanoparticles as
an Efficient Catalyst for Copper-Free Sonogashira-Hagihara Reaction
a
a
a
b
Mohammad Gholinejad,* Abdollah Neshat,* Fatemeh Zareh, Carmen Nájera , Mehran
a
b
Razeghi, Abbas Khoshnood
a
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), P. O. Box
5195-1159, Gava zang, Zanjan 45137-6731, Iran.
4
Email: gholinejad@iasbs.ac.ir; a.neshat@iasbs.ac.ir
b
Departamento de Química Orgánica and Centro de Innovación en Química Avanzada (ORFEO-
CINQA). Universidad de Alicante, Apdo. 99, E-03080-Alicante, Spain

Graphical abstract
ArX + R
Ar
R
X= Cl, Br, I
26 examples
Recycled for 7 runs
HN
HN
SiO2
Pd NPs
Fe O NPs
3
4

Highlights
A novel catalyst using Pd supported on bisindolyl functionalized Fe O is synthesized.
3
4
The catalyst was characterized using different analytical methods.
The catalyst was applied for Sonogashira reactions of aryl halides (Cl, Br, I) under air.
The Sonogashira reaction was performed under Copper and Phosphane free conditions.
The catalyst was successfully recycled for seven consecutive runs by an external magnet.

Abstract
A novel heterogeneous catalyst based on palladium nanoparticles supported on 3,3’-bisindolyl(4-
hydroxyphenyl)methane functionalized magnetite (Fe O ) nanoparticles was synthesized,
3
4
characterized and used as catalyst for Sonogashira-Hagihara reaction. The alkynylation of a
variety of aryl iodides and aryl bromides with terminal alkynes was carried out at 60 °C under
copper and phosphane-free conditions using N,N-dimethyl acetamide as solvent, DABCO as
base and low Pd loadings (0.18 mol%) under air. In the case of aryl chlorides, the reaction was
carried out at 120 ºC in the presence of tetra-n-butylammonium bromide (TBAB) and 0.36 mol%
of Pd catalyst. The heterogeneous palladium catalyst introduced in this study is recoverable by
an external magnet and it can be used for seven consecutive runs without a significant loss in
catalytic activity.
Keywords: Magnetic, Palladium, Nanoparticles, Sonogashira, Copper-free
1
. Introduction
The palladium catalyzed carbon-carbon bond forming reactions are of great importance in
modern synthetic organic chemistry [1]. Among well-known carbon-carbon coupling
reactions, the Sonogashira-Hagihara cross-coupling stands out as a unique method enabling
2
the coupling between (sp) carbon and (sp ) carbon atoms [2-9]. The reaction products
containing such bonds have found applications in a wide range of synthetic reactions such as
biologically active compounds and pharmaceuticals [10-12]. Palladium catalyzed
Sonogashira-Hagihara alkynylation reaction can be performed either in the presence of
copper as co-catalyst or under copper-free conditions. The presence of copper increases the
reactivity of the acetylene by the formation of a copper acetylide. However, the formation of

undesired homo-coupling byproducts is usually observed (Glaser coupling reaction) [13-14].
Thus, the design and synthesis of active palladium catalysts for Sonogashira-Hagihara
reaction under copper free and mild reaction conditions are highly desirable [15-24].
Due to difficulties in the removal of metal contaminants of coupling reaction products under
homogeneous conditions, many heterogeneous palladium catalysts for Sonogashira-Hagihara
reaction have also been developed in recent years [2, 25-29]. However, despite great
developments in this field, heterogeneous catalysts are also difficult to separate from the
reaction mixture by standard laboratory methods such as filtration and centrifugation. In this
regard, magnetic nanoparticles with large ratio of surface area to volume, superparamagnetic
behavior and low toxicity have proven to be an excellent supports for the stabilization of
palladium nanoparticles (NPs) [30-36]. Variety of ligands such as those containing
phosphane or nitrogen functional groups have been used for the modification of Fe O
3
4
nanoparticles. However, phosphane-based ligands are air and/or moisture sensitive,
poisonous, unrecoverable and degradable at elevated temperatures which limits their large
scale application in industrial level chemistry [37-39]. We have recently introduced two
novel and efficient phosphane-free magnetic nanoparticles which supported palladium
catalysts for Suzuki-Miyaura coupling reaction in water [40-41]. However, to date, a few
magnetite nanoparticles supported palladium catalysts have been prepared and successfully
used in the Sonogashira-Hagihara coupling reaction [42-50].
We envisaged that supporting a 3,3’-bisindolyl(4-hydroxyphenyl)methane ligand to
magnetite nanoparticles coated with silica gel would be an adequate and simple way to
coordinate and stablize Pd nanoparticles. Herein, we report the synthesis of a new and highly

active palladium catalyst supported on functionalized magnetite nanoparticles for
Sonogashira-Hagihara reaction under copper and phosphane-free conditions.
2
. Experimental Section
2
.1. General
All chemicals were purchased from Sigma-Aldrich, Acros and Merck companies and were
used without further purification. Magnetite (Fe O ) nanoparticles were prepared according to
3
4
a previously reported method in the literature [51-52]. Synthesis of 3,3’-Bisindolyl(4-
hydroxyphenyl)methane was carried out by the modification of the published literature
1
13
procedure [53]. H and C NMR spectra were recorded in DMSO-d and CDCl at room
6
3
temperature on a Bruker 400 MHz spectrometer and referenced internally using TMS as
internal standard. Thermogravimetric analysis (TGA) was conducted from room temperature
to 700 °C in an oxygen, sure flow using a NETZSCH STA 409 PC/PG instrument.
Transmission Electron Microscopy was carried out by JEOL model JEM-1400 Plus working
at 120 kV with a LaB6 filament. Magnetic measurements were performed using vibration
sample magnetometry (VSM, (MDK Co. Kashan, Iran) analysis. FT-IR spectra were recorded
on a Bruker Vector 22 instrument. Energy dispersive X-ray analysis (EDX) results were
obtained using Carl Zeiss Sigma instrument. Adsorption-desorption analyses were recorded
using BELsSORP-max instrument. The content of copper and palladium in the catalyst was
determined using Varian atomic absorption spectrometry.
2
.2. Synthesis of silica-coated Fe O nanoparticles (SMNP):
3 4
Fe O (1.0 g) was sonicated in ethanol (200 mL) for 30 min. at room temperature. Then, to
3
4
the resulting suspension were added tetraethyl orthosilicate (TEOS, 2.0 mL) and aqueous
ammonia (25%) (6.0 mL) and the mixture was stirred for 24 h at room temperature. The

obtained silica-coated Fe O nanoparticles were separated by an external magnet and washed
3
4
with distilled water (3×10 mL) and ethanol (3×10 mL) and dried under vacuum.
2
.3. Procedure for the preparation of Cl@SiO @Fe O (1):
2 3 4
Dry SMNP powder (1.0 g) was mixed with dry toluene (50 mL) to produce a homogeneously
mixed solution. This mixture was sonicated for 30 min. prior to the addition of (3-
chloropropyl) trimethoxysilane (7.0 mmol, 1.27 mL). The resulting mixture was refluxed for
2
4 h under argon atmosphere. Then, the reaction mixture was subjected to magnetic
separation and the resulting powder was washed sequentially with distilled water (3×10 mL)
and ethanol (3×10 mL) and finally dried under vacuum.
2
.4. Procedure for the preparation of compound (2):
Compound 1 (500 mg) was sonicated and dispersed separately in dry toluene (20 mL) for 30
min. In a separate experiment, sodium hydride (1.2 mmol, 27 mg) was added to prepared 3,3’
bisindolyl(4-hydroxyphenyl)methane (1 mmol, 330 mg) under argon and the resulting
mixture was added to the flask containing compound 1. The reaction mixture was stirred at
1
00 °C for 24 h under argon atmosphere. Then, the reaction mixture was cooled to room
temperature and bis indole functionalized magnetic nanoparticles (2) were subjected to
magnetic separation. The isolated product was washed sequentially with ethanol (2×10 mL)
and dried under vacuum for 24 h.
2
.5. Procedure for the preparation of Pd@bisindole@SiO @Fe O :
2 3 4
Compound 2 (400 mg) was sonicated in dichloromethane (10.0 mL) for 30 min. at room
temperature. Then, Pd(OAc) (0.09 mmol, 20 mg) was added and the mixture was stirred for
2

2
4 h at room temperature under argon atmosphere. Then, the reaction mixture was subjected
to magnetic separation and the isolated material was washed sequentially with distilled water
3×10 mL) and ethanol (3×10 mL). Drying under vacuum for 24 h provided compound
Pd@bisindole@SiO @Fe O as a black powder.
(
2
3
4
2
.6. General procedure for the Sonogashira-Hagihara reaction:
Aryl halide and a terminal alkyne, with an equivalent molar ratio of 1.0 to 1.5, were added to
a mixture of Pd@bisindole@SiO @Fe O (0.18 mmol, 20 mg) and DABCO (2.0 mmol, 224
2
3
4
mg) in a flask and 2 mL DMA was added. The reaction mixture was stirred at 60 °C for aryl
iodides and aryl bromides. The reaction temperature was set to 120 °C for aryl chlorides and 1
mmol TBAB was also added. The progress of the reaction was monitored by gas
chromatography. After completion of the reaction, distilled water (2 mL) was added to the
reaction mixture and the crude product was extracted with ethyl acetate (3×5.0 mL). The
crude product was further purified by column chromatography using n-hexane and ethyl
acetate as eluents.
3
. Results and Discussion
The catalyst preparation steps are summarized in Scheme 1. Briefly, Fe O nanoparticles were
3
4
prepared in a co-precipitation step based on the procedure of Massart et al. using FeCl .6H O
3
2
and FeCl .4H O salts [51]. The obtained Fe O NPs were coated with a thin layer of silica
2
2
3
4
using tetraethyl orthosilicate to produce core/shell Fe O NPs (SMNP) [52]. The presence of a
3
4
-1
sharp peak in the IR spectrum around 1091 cm (Figure 1, supporting information) confirmed
the formation of Si-O-Fe bonds. SiO @Fe O core/shell nanospheres were allowed to react
2
3
4
with 3-chloropropyltrimethoxysilane to afford chloro-functionalized magnetic NPs

(
Cl@SiO @Fe O ). In the next step, NaH was used as base to deprotonate the hydroxyl group
2 3 4
of the prepared 3,3’-bisindolyl(4-hydroxyphenyl)methane. Then, Cl@SiO @Fe O was added
2
3
4
to
afford
3,3’-bisindolyl(4-hydroxyphenyl)methane
functionalized
Fe O4
NPs
3
(
bisindole@SiO @Fe O NPs). In the final step, the desired palladium-supported catalyst (3)
2 3 4
was obtained by treating bisindole@SiO @Fe O NPs with Pd(OAc) in dichloromethane at
2
3
4
2
room temperature. The obtained material which is used as catalyst in this work is referred to
as Pd@bisindole@SiO @Fe O throughout the text of this article.
2
3
4
Our initial goal was to test the reactivity of the bisindole@SiO @Fe O NPs with Pd(OAc)
2
2
3
4
to examine whether the bisindole unit of the nanoparticle can bind to palladium as a
monodentate or bidentate ligand via the elimination of one or two acetic acid (AcOH)
molecules. However, we were surprised by the formation of palladium nanoparticles even in
the absence of reducing agent such as NaBH , which usually is a requirement for the
4
reduction of Pd(II) species to Pd(0) prior to the formation of the metal nanoparticles.
Therefore, understanding the mechanism of the formation of Pd@bisindole@SiO @Fe O
4
2
3
NPs (Scheme 1) in this study requires further analyses. We speculated that the presence of N-
H groups in the indole ring can stabilize palladium NPs, similar to ionic liquids with amide
end-groups [54].

O
O Si
O
Si(OEt)4
dry Toluene
reflux, 24h
Fe O
Cl
Fe O
Fe O
(MeO) Si
Cl
3
4
3
4
3
4
+
3
SiO2
SiO2
1
NH
NH
HO
NaH,
NH
NH
O
O Si
O
Fe O
3
4
O
Toluene, reflux, 24h
SiO2
2
NH
NH
Pd(OAc) , CH Cl
2
2
2
O
O Si
O
Fe O
O
PdNPs
3
4
r.t. 24 h
SiO2
3
Scheme 1. Pd@bisindole@SiO @Fe O preparation steps.
2
3
4
Thermogravimetric analysis was confirmed the formation of compound 1 showing two-step
weight loss (Figure 1). First weight loss is related to water and physically adsorbed solvents and
the second one is related to the organic residues attached to the surface of the support.
Figure 1. Thermogravimetric diagram of Cl@SiO @Fe O .
2
3
4

Moreover, thermogravimetric analysis of compound 2 showed an increase in loading
which is probably related to the attaching of 3,3’-bisindolyl(4-hydroxyphenyl)methane to
surface of compound 1 (Figure 2).
Figure 2. Thermogravimetric diagram of bisindole@SiO @Fe O nanoparticles.
2
3
4
Scanning electron microscopy (SEM) image of final Pd@bisindole@SiO @Fe O shows highly
2
3
4
uniform particles (Figure 3). Furthermore, energy-dispersive X-ray spectroscopy (EDX) obtained
from SEM shows the presence of Pd atoms as well as N, Fe, and Si atoms in the structure of
compound Pd@bisindole@SiO @Fe O (Figure 4).
2
3
4

Figure 3. SEM image of Pd@bisindole@SiO @Fe O
4
2
3
Figure 4. EDX diagram of Pd@bisindole@SiO @Fe O .
2
3
4
X-ray photoelectron spectrum (XPS) of these palladium nanoparticles confirmed the presence of
both Pd(0) and Pd(II) species in equal ratios by the appearance of two intensive doublets at 335
eV and 340 eV related to Pd(0) and peaks at 337 eV and 342 eV related to Pd(II) corresponding
to Pd 3d and Pd 3d , respectively (Figure 5) [41,55].
5/2
3/2
Figure 5. XPS spectrum of the Pd@bisindole@SiO @Fe O .
2
3
4
High resolution transmission electron microscopy (HTEM) images show the presence of highly
uniform and small size palladium nanoparticles in average size of 2 nm supported by 3,3’-

bisindolyl(4-hydroxyphenyl)methane functionalized Fe O NPs (Figure 6). TEM images also
3
4
show the average shell size of about 5 nm and Fe O NPs with an average size of 15 nm.
3
4
Figure 6. HTEM images of Pd@bisindole@SiO @Fe O .
2
3
4
We have also studied magnetization curves for Fe O NPs, SiO @Fe O NPs, and
3
4
2
3
4
Pd@bisindole@SiO @Fe O at room temperature (Figure 7). Results indicate that in all samples
2
3
4
no hysteresis loop is observed, with both remanence and coercivity being zero, suggesting the
superparamagnetic nature of the samples. It is worth mentioning that a decrease in the
-1
-1
magnetization value of the SiO @Fe O (39 emug ) in comparison with Fe O NPs (61 emug )
2
3
4
3
4
confirms the silica coating and formation of core/shell nanoparticles. Furthermore, a decreases in
-1
the magnetization value of the Pd@bisindole@SiO @Fe O (3) (33.3 emug ), confirms the
2
3
4
immobilization of organic groups on the surface.

Figure 7. Magnetization curves of Fe O , SiO @Fe O , and Pd@bisindole@SiO @Fe O
4
3
4
2
3
4
2
3
(catalyst).
The N2 adsorption–desorption isotherms for bisindole@SiO @Fe O
NPs and
Pd@bisindole@SiO @Fe O are presented in Figure 8 and the physical parameters measured
2
3
4
2
3
4
with N sorption are summarized in Table 1. The results indicated that both isotherms are of type
2
IV according to IUPAC classification and exhibiting H3 hysteresis loop. The surface areas were
2
calculated by Brunauer–Emmet–Teller (BET) method and are in the range of 31-39 m /g. Also,
the pore size and pore volume were calculated by Barrett–Joyner–Halenda (BJH) method, the
3
pore diameter were in between 25 and 31.5 nm with total pore volume in the range of 7-9 cm /g.
These results indicated that surface area and pore volume increased after introducing palladium
nanoparticles (Table 1). This may be related to palladium complex formation which caused an
increase in the surface area and porosity of the catalyst.
Table 1. The BET surface area, BJH pore volume and pore size for bisindole@SiO @Fe O NPs
2
3
4
and Pd@bisindole@SiO @Fe O
4
2
3

2
-1
3 -1
Sample
SBET(m g )
V (cm g ) DBJH (nm)
t
bisindole@SiO @Fe O NPs 31
7.3
9.0
31.14
25.75
2
3
4
Pd@bisindole@SiO @Fe O 39
2
3
4
Figure 8. N2 adsorption/desorption isotherms of bisindole@SiO @Fe O
4
and
2
3
Pd@bisindole@SiO @Fe O (catalyst).
2
3
4
The catalytic activity of Pd@bisindole@SiO @Fe O was evaluated in Sonogashira-Hagihara
2
3
4
reaction. Initial experiments with using iodobenzene and phenyl acetylene were performed to
optimize the reaction conditions such as solvent type, temperature, and quantities of the base and
catalyst (Table 2). As shown in Table 2, the reaction in distilled water in the presence of different
bases resulted in low yields and only moderate yields were obtained using Et N, 1,4-diazabicyclo
3
i
[
2.2.2] octane (DABCO), and Pr N (Table 2, entries 2, 3 and 8). The use of inorganic salts as
3
base did not improve reaction yields (Table 2, entries 1, 5-7). Reaction condition was also
studied using organic bases in other solvents such as CH CN, DMF, THF, EtOH, toluene, DMA,
3

PEG 200, and H O-CH CN mixture. The best yields were obtained using DABCO as base and
2
3
DMA as solvent at 60 °C (Table 2, entry 19). It is noticeable that when the reaction was carried
out at room temperature, 18% drop in reaction yield was observed (Table 2, entry 20).
Table 2. Optimization of reaction condition for the coupling of iodobenzene and phenyl
a
acetylene
I
Catalyst (0.18 mol %)
+
Base, solvent, 24 h
b
c
Entry
Base
Solvent
Temperature (˚C) Yield (%)
RSD
1
2
3
4
5
6
7
8
9
K PO
H O
60
60
60
60
60
60
60
60
60
2
52
32
17
4
0.41
0.03
0.05
0.06
0.21
0.26
0.52
0.05
0.02
3
4
2
NEt3
H O
2
DABCO
Pipyridine
K CO
H O
2
H O
2
H O
2
2
3
t-BuOK
NaOAc
N(i-Pr)3
NEt3
H O
2
7
H O
2
2
H O
2
31
82
CH CN
3

1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
NEt3
NEt3
DMF
THF
60
60
60
60
60
60
60
60
60
60
30
7
0.2
26
31
4
0.06
0.04
0.21
0.35
0.02
0.02
0.02
0.04
0.01
0.01
NEt3
EtOH
NEt3
Toluene
DMA
NEt3
5
NEt3
CH CN/H O
53
90
68
42
98
80
3
2
DABCO
DABCO
NEt3
CH CN
3
PEG200
PEG200
DMA
DABCO
DABCO
DMA
a
Reaction conditions: iodobenzene (1.0 mmol), phenylacetylene (1.5 mmol), base (2.0 mmol),
b
solvent (1.5 mL), catalyst (4.0 mg, containing 0.18 mol % Pd). Yield determined by GC
c
analysis. The relative standard deviation (error bars) was obtained from three independent
reactions.
With the optimized reaction conditions in hand, the substrate scope of the Sonogashira-Hagihara
reaction was evaluated for the reaction of structurally diverse aryl halides and acetylenes in the
presence of Pd@bisindole@SiO @Fe O (Table 3). The reaction of both electron-rich and
2
3
4
electron-poor aryl iodides with phenylacetylene gave the corresponding products in high to

excellent yields (Table 3, entries 1-8). The reaction of 2-iodothiophene as a heterocyclic aryl
iodide with 4-ethynyltoluene afforded the desired product in 99% yield (Table 3, entry 3). The
catalytic scope of Pd@bisindole@SiO @Fe O was also investigated for the reaction of various
2
3
4
aryl bromides with terminal alkynes. As expected, aryl iodides were more reactive than aryl
bromides, and the substituent effects in aryl iodides appeared to be less significant than in aryl
bromides. Results showed that both activated aryl bromides such as 1-bromo-4-nitrobenzene, 4-
bromobenzaldehyde, 4-bromobenzonitrile, 4-bromoacetophenon, 1-bromo-, 4-fluorobenzene and
unactivated aryl bromides such as bromobenzene, 4-bromoanisole, 1-bromonaphtalene reacted
well and the corresponding internal alkynes were obtained in high yields. Reaction of 1-bromo-
4
-chlorobenzene and 4-bromonitrobenzene with propargyl alcohol also provided desired
coupling products in excellent yields (Table 3, entries 21 and 22). However, less reactive 4-
chloronitrobenzene under optimized reaction conditions resulted in 39% of the desired product.
However, the same reaction as well as the reaction of 4-chlorobenzaldehyde, 4-
chlorobenzonitrile with phenylacetylene at elevated temperature (120 °C) in the presence of
TBAB and 0.36 mol% of palladium catalyst gave corresponding products in high to excellent
yields (Table 3, entries 23-26). Based on the coupling results represented in Table 3, the Pd
catalyst developed in this study, efficiently catalyzed the reaction of different aryl halides with
alkynes under air with reproducible, high turnover and frequency numbers, and copper-free
conditions. It is worth mentioning that obtained standard deviation (error bars) from four
independent replicate experiments were less than 0.4.
Table 3. Copper-free and phosphane-free Sonogashira-Hagihara reactions of terminal alkynes
a
with aryl halides

Catalys (0.18-0.36 mol%)
Ar
R
ArX + R
DABCO, 60-120 °C
DMA
d
Yield TON/TOF RSD
Entry
Ar
R
t(h)
Product
b
-1 c
(%)
(h )
5
22/74.1 0.012
1
C H
24
24
12
24
12
94
6
5
Me
511/72.2 0.015
4
-
2
3
4
5
92
95
93
MeC H
6
4
Me
550/77.7
0.01
4
-
MeC H
6
4
S
5
5
50/69.4 0.013
C H
6
5
Me
55/61.3 0.011
e
C H
100
6
5
MeO

5
5
5
3
4
5
44/72.2 0.015
44/71.4 0.015
27/83.1 0.013
94/42.1 0.014
6
7
8
9
C H
12
12
6
98
98
6
5
5
5
5
5
5
F
C H
6
Cl
C H
6
95
O N
2
C H
6
24
24
24
71
MeO
38/53.8
0.38
1
0
1
C H
6
79
55/61.1 0.011
e
1
C H
6
100
N
N

5
5
5
5
5
55/60.3 0.013
e
1
1
1
1
2
3
4
5
C H
24
24
24
24
100
98
6
5
5
5
5
N
44/40.6 0.021
C H
6
NC
22/64.8
0.3
C H
6
94
OHC
50/66.7 0.012
e
C H
6
99
OHC
Me
16/67.9 0.039
4
-
1
1
6
7
24
24
93
98
MeC H
6
4
OHC
5
44/75.9 0.013
C H
6
5
O N
2

5
5
22/72.3 0.017
1
1
8
9
C H
24
24
94
95
6
5
F
27/66.5 0.019
C H
6
5
O
C
Me
4
83/50.4 0.021
2
0
C H
24
87
6
5
5
5
33/57.4
0.02
OH
OH
2
2
1
2
HOCH2- 24
HOCH2- 24
96
96
Cl
33/62.3 0.018
O N
2
1
72.2/10.9 0.029
e,f
2
3
C H
48
62
6
5

2
2
2
52/18.5 0.018
47/16.2 0.015
36/14.4 0.013
f
f
f
2
2
2
4
5
C H
48
48
48
91
89
85
6
5
5
5
OHC
C H
6
O N
2
6
C H
6
NC
a
Reaction conditions: ArX (1 mmol), alkyne (1.5 mmol), DABCO (1.5 mmol), catalyst (0.18
b
c
d
mol%), DMA (2 mL); Isolated yields; TOF are after 6 h from starting of the reactions; The
e
relative standard deviation (error bars) was obtained from four independent reactions; GC
f
yields; Using 1.0 mmol TBAB.
In order to demonstrate the practical application of Pd@bisindole@SiO @Fe O , reaction of
2
3
4
iodobenzene with phenylacetylene was scaled up to 10 mmol under optimized reaction
conditions. Results showed that reaction proceed efficiently and produced desired product in
8
9% isolated yield after 24 h.
In order to assess the catalytic system changes, we made careful kinetic monitoring of the
reaction of 5-bromopyrimidine with phenylacetylene under different reaction conditions. Under
optimized reaction condition, it proceeded smoothly without induction period and was completed

during 24 h period (Figure 9, a). Lower amounts of catalyst loading (0.02 and 0.01) caused a
decrease in the reaction yield compared to standard reaction under optimized conditions (Figure
9
, b,c). However, an increase in the catalyst amount to 0.36 caused an increase in reaction rate
and completion of the reaction faster (Figure 9, d).
To confirm the heterogeneous nature of the active catalyst introduced in this study, some
catalytic reactions were performed in the presence of excess Hg(0) as catalyst poison (molar ratio
to [Pd] ~ 400). As shown in Figure (9, e), reaction rate was strongly suppressed. It is well known
that Hg(0) can poison heterogeneous catalysts by amalgamating the metal or adsorbing on the
metal surface. On the other hand, Hg(0) has no poisoning effect on molecular homogeneous
(ligand-protected) Pd species. Poly(vinylpyridine)(PVPy) is another catalyst poising agent and
scavenger for soluble molecular Pd and soluble Pd(0) nanoparticles. The catalytic reactions were
conducted in the presence of an excess amount of PVPy (molar ratio to [Pd] ~ 400) and the
results showed no change in reaction rate and it proceeded similar to standard optimized
conditions, confirming heterogeneous nature of the catalyst (Figure 9, f) [56,57].
Figure 9. Kinetic monitoring of the reaction of 5-bromopyrimidine with phenylacetylene under
different reaction conditions: (a) reaction under optimized reaction conditions, (b) using 0.02

mol% Pd catalyst, (c) using 0.01 mol% Pd catalyst, (d) using 0.36 mol% Pd catalyst, (e) reaction
in the presence of an excess Hg(0), (f) reaction in the presence of an excess amount of PVPy
Further information about homogeneous or heterogeneous nature of the catalyst was obtained by
hot filtration test for the reaction of iodobenzene and phenylacetylene. After 5 h with 54%
conversion to desired product, the reaction mixture was filtered and filtrate was allowed to react
for 24 h. GC analysis after 24 h showed 65% conversion to desired coupling product. This result
also confirms that using this catalyst reaction proceeds mostly under heterogeneous conditions.
One of the main factors sought in designing any catalyst system, especially for practical
industrial scale reactions is the recyclability of the catalyst. This factor was measured for our
palladium catalyst, Pd@bisindole@SiO @Fe O , in the Sonogashira-Hagihara reaction of
2
3
4
iodobenzene and phenylacetylene. After completion of the reaction, the magnetic catalyst was
easily recovered from the reaction mixture by an external magnet and after water/diethyl ether
wash, it was reused in another coupling reaction. Results indicated that the catalyst can be
effectively used at least during seven consecutive runs without a significant loss of activity,
confirming reproducibility of results (Figure 10). It is notable that leaching of Pd into the
reaction mixture after first run was determined to be 1% (ICP analysis), confirming the obtained
results from poisoning and hot filtration tests.

Figure 10. Successive reaction runs and GC yields for the reaction of iodobenzene with
phenylacetylene with Pd@bisindole@SiO @Fe O (Error bars show standard deviation from
2
3
4
four separate experiments).
TEM image of the catalyst after three runs, shown in Figure 11, reveals that
Pd@bisindole@SiO @Fe O preserves its original structure after each reaction.
2
3
4

Figure 11. TEM image of the recovered Pd@bisindole@SiO @Fe O after three runs.
2
3
4
rd
Superparamagnetic property of the catalyst and recovered catalyst after 3 run was also
measured and results indicate that magnetization of the catalyst is decreased slightly after each
reaction run (Figure 12).
rd
Figure 12. Magnetization curves for Pd@bisindole@SiO @Fe O and its recycled form after 3
2
3
4
run.
Furthermore, XPS analysis of Pd@bisindole@SiO @Fe O after three run showed the presence
2
3
4
of the related peaks for both Pd(0) and Pd(II) at 335-340 and 337-342 eV, respectively (Figure
3).
1
rd
Figure 13. XPS spectrum of the recycled Pd@bisindole@SiO @Fe O after 3 run
2
3
4

4
. Conclusion
In conclusion, palladium supported on Bis(indolyl)methane functionalized magnetite
nanoparticles, a new magnetically separable catalyst, has been prepared, characterized and
successfully applied as catalyst in Sonogashira-Hagihara reaction. Aryl iodides and bromides
were reacted efficiently under air and copper-free conditions with different alkynes by using 0.18
mol % of this catalyst at 60 °C. These reactions afforded desired products in high to excellent
yields with high TON and the error bars were less than 0.4. Aryl chlorides were also reacted at
1
20 °C using TBAB additive. Negiligilibe leaching of Pd and hot filteation tests showed the
heterogeneous nature of the catalyst under reaction conditions. Kinetic monitoring of the reaction
of 2-bromopipyridine with phenylacetylene under different reaction conditions showed important
effects of catalyst quantity in reaction rate. Also, the application of two general poisoning agents
(Hg(0), PVPy) confirmed heterogeneous nature of catalyst during catalytic reactions. Main
advantages of this new catalyst system are its simple recoverability by use of an external magnet
and its effecgtive recyclability. The results show that a four layer heterogenous system
introduced in this work can be used as catalyst in seven consecutive catalytic reaction runs with
negligible decrease in its activity. This was carried out through 4 times repetition of each of
seven runs, emphasizing its reproducibility. Besides, TEM, XPS and VSM analyses of the
recovered catalyst suggest that the catalyst’s originl shape is maintained during reaction. Results
from coupling reaction of a series of selected aryl halides and alkynes show comparatively
improved yields of Sonogashira-Hagihara cross-coupling in air and at lower temperatures in the
presence of a recoverable catalyst system introduced in this study.

Acknowledgment
The authors thank Institute for Advanced Studies in Basic Sciences (IASBS) Research Council
and Iran National Science Foundation (INSF-Grant number: 94010666) for financial support of
this work. C. Nájera is also thankful to The Spanish Ministerio de Economia y Competitividad
(MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), FEDER, the Generalitat
Valenciana (PROMETEOII/2014/017) and the University of Alicante for financial support.
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