Synthesis of N-aryl imidazoles catalyzed by copper nanoparticles on nanosized silica-coated maghemite

Article abstract of DOI:10.1016/j.tet.2014.04.003

A magnetically recoverable catalyst consisting of copper nanoparticles (CuNPs) on nanosized silica-coated maghemite is presented. The catalyst has been prepared under mild conditions by mixing the magnetic support with a freshly prepared suspension of CuN

Full text of DOI:10.1016/j.tet.2014.04.003

Accepted Manuscript
Synthesis of N-aryl imidazoles catalysed by copper nanoparticles on nanosized silica-
coated maghemite
Fabiana Nador, María Alicia Volpe, Francisco Alonso, Gabriel Radivoy
PII:
S0040-4020(14)00474-8
10.1016/j.tet.2014.04.003
TET 25453
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 December 2013
Revised Date: 27 March 2014
Accepted Date: 1 April 2014
Please cite this article as: Nador F, Volpe MA, Alonso F, Radivoy G, Synthesis of N-aryl imidazoles
catalysed by copper nanoparticles on nanosized silica- coated maghemite, Tetrahedron (2014), doi:
10.1016/j.tet.2014.04.003.
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Synthesis of N-aryl imidazoles catalysed by
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coated maghemite
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Fabiana Nador, María Alicia Volpe, Francisco Alonso*, and Gabriel Radivoy* �
Instituto de Química del Sur, INQUISUR (CONICET-UNS), Departamento de Química, Universidad Nacional
del Sur, Av. Alem 1253, 8000 Bahía Blanca, Argentina

1
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Tetrahedron
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Synthesis of N-aryl imidazoles catalysed by copper nanoparticles on nanosized silica-
coated maghemite
a
b
c,
a,
Fabiana Nador , María Alicia Volpe , Francisco Alonso ∗ , and Gabriel Radivoy ∗
a
Instituto de Química del Sur, INQUISUR (CONICET-UNS), Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, 8000 Bahía Blanca,
Argentina
b
Planta Piloto de Ingeniería Química, PLAPIQUI (CONICET-UNS), Camino La Carrindanga Km 7, CC 717, 8000 Bahía Blanca Argentina
Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, E-03080, Alicante,
c
Spain
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A magnetically recoverable catalyst consisting of copper nanoparticles (CuNPs) on nanosized
silica- coated maghemite is presented. The catalyst has been prepared under mild conditions by
mixing the magnetic support with a freshly prepared suspension of CuNPs obtained by fast
2
reduction of anhydrous CuCl with lithium sand and a catalytic amount of DTBB (4,4'-di-tert-
Available online
butylbiphenyl) as electron carrier. This copper-based catalyst has shown to be very efficient in
the N-(hetero)arylation of imidazole using (hetero)aryl bromides and iodides as arylating agents
under ligand-free conditions. The catalyst is easily recovered by means of an external magnet
and can be reutilized in three N-arylation cycles without apparent loss of catalytic activity.
Keywords:
Copper nanoparticles
Magnetic catalyst
Maghemite
2
014 Elsevier Ltd. All rights reserved.
C-N cross-coupling
N-arylation
Imidazole
1
. Introduction
to the development of copper-based catalysts to perform these C-
N bond forming reactions. Significant contributions to this
renaissance of Ullmann-type arylations have been made by the
The development of new methodologies for C(aryl)-
N(heterocycle) bond formation is of high interest in synthetic
organic chemistry, mainly because nitrogen containing
heterocyclic moieties are extensively found in natural and
synthetic bioactive compounds. In addition, many of these N-
heterocyclic substructures are used as ligands for transition metal
catalysis, and also in the synthesis of ionic liquids. Among the
N-aryl derivatives, N-aryl imidazoles are often considered as
privileged motifs which play a pivotal role in the synthesis of a
broad range of pharmaceutical and agrochemical products;
among other properties, they allow soluble salts formation which
is essential for drug bioavailability.
7
8
9
10
groups of Buchwald, Taillefer, and Ma, among others.
Although many of these new methodologies helped to overcome
some of the main drawbacks of traditional copper-promoted N-
arylation procedures (i.e. harsh conditions, over-stoichiometric
amount of copper reagents), most of them involve the use of
homogeneous copper catalysts, and even though copper is
inexpensive and low metal loading is often sufficient to achieve
reasonable conversions, the difficulty in the recovery and reuse
of these homogeneous catalysts limit their use, mainly in the
synthesis of drug molecules which must be free of residual metal.
1
2
3
There are few examples in the literature about the use of
Transition-metal catalysed cross-coupling between aryl
halides and N-heterocyclic compounds is arguably the most
powerful and broadly accepted tool for the synthesis of N-aryl
11
heterogeneous copper-based catalysts for imidazole N-arylation,
and in about half of them aryl boronic acids are employed as aryl
11d-f
donors (Lam-Chan reaction).
Although these boronic reagents
4
5
6
heterocycles. Although palladium and nickel catalysts have
proven to be highly efficient in promoting these coupling
reactions, in the last decade, economical and environmental
considerations have drawn the attention of many research groups
allow mild reaction conditions, their application is limited by the
availability and cost of functionalized boron compounds, and in
addition, the atom efficiency of the process is low. On the other
hand, copper nanoparticles (CuNPs) as copper source in
—
——
∗
∗
Corresponding author. Tel.: +54-291-459-5100; fax: +54-291-459-5187; e-mail: gradivoy@criba.edu.ar
Corresponding author. Tel.: +34-965-903-548; fax: +34-965-903-549; e-mail: falonso@ua.es

2
Tetrahedron
heterogeneous catalysts for C-N bond forma
A
tio
C
n
C
ha
E
s
P
sc
T
arce
E
D
ly MAat
NU
omic
S
e
C
mi
R
ss
I
ion spectroscopy (ICP-AES). The copper loading
P
T
12
been reported. It is known that, due to their large surface-to-
volume ratio, nanosized metal particles often exhibit remarkable
catalytic properties, showing both higher activities and
selectivities compared to that of the bulk metal. These metal
nanoparticles have been considered to be on the frontier between
the homogeneous and heterogeneous catalysis, preserving the
fixed to the magnetic support was 6.8 wt% as determined by ICP-
AES. The TPR profile of the catalyst showed only one peak,
which was assigned to the reduction of copper oxidized species
(CuO). The presence of this species indicates that CuNPs have
been oxidized during handling of the catalyst under air. Besides,
no peaks attributable to the support reduction were detected. The
lack of iron species available for reduction strongly suggests that
13
main advantages of both methodologies.
However, the
separation and recovery of these nanocatalysts from the reaction
medium is not always easy due to the nanometric size of the
particles that hinders the use of standard separation methods
the magnetic core is fully coated by the SiO shell. Energy
2
dispersive X-ray analysis on various regions confirmed the
presence of copper, with energy bands of 8.04, 8.90 (K lines) and
0.92 keV (L line). The XRD diffractogram showed the support
diffraction pattern, but no diffraction peaks owing to copper
species were detected, this could be attributed to the amorphous
character of the CuNPs deposited on the support and/or to the
existence of crystal domains below 10 nm in size. Analysis by
TEM showed the presence of well dispersed spherical
nanoparticles on the magnetic support, with a narrow size
distribution and an average particle size of 3.0 ± 0.8 nm (Figure
1).
(filtration, centrifugation), thus dispersion of metal nanoparticles
over organic or inorganic supports is mandatory to overcome this
drawback. In this context, in the last decade nanotechnology has
significantly contributed to the development of new magnetic
materials for their use as supports in the preparation of magnetic
nanocatalysts that can be easily separated from the reaction
14
medium by means of an external magnet. These magnetic
nanomaterials used as supports usually consist of core-shell
structures in which iron oxides (Fe O ) are commonly used as the
x
y
magnetic core. Coating of this magnetic core with organic or
inorganic polymers prevents undesired agglomeration processes,
for this purpose, silica coating is widely used as it improves both
chemical and thermal stability of the magnetic nanomaterials and
also because it can be easily functionalized for diverse
SiO
2
x y
Fe O
SiO
2
15
applications. To the best of our knowledge, the only example in
the literature about the use of a copper-based magnetic catalyst
for the N-arylation of heterocycles is a recent work by Panda et
x y
Fe O
CuNPs
16
al. who reported on the use of copper ferrite (CuFe O )
2
4
nanoparticles for the N-arylation of diverse N-heterocycles,
although only three imidazoles using bromobezene as arylating
agent were tested, and metal leaching (copper and iron) from the
catalyst was detected.
2
0 nm
18%
On the other hand, in the last years, we have actively been
working on the use of nanosized copper-based catalysts for their
16%
14%
17
12%
use in a variety of coupling and cycloaddition reactions. Very
recently, we have reported on the preparation of a new magnetic
nanocatalyst consisting in copper nanoparticles dispersed on
10%
8%
6%
18
silica-coated maghemite (MagSilica®), which demonstrated to
be a very efficient, versatile and reusable catalyst for three
important transformations involving terminal alkynes, i.e. the
synthesis of 1,3-diynes, the three-component coupling of alkynes3,
aldehydes and amines for the synthesis of propargyl amines (A
coupling), and the 1,3-dipolar cycloaddition reaction of terminal
alkynes with in situ generated organic azides for the synthesis of
4%
2%
0%
0,0
1,5
3,0
4,5
diameter (nm)
Figure 1. TEM micrograph of the magnetic support (up left); TEM
micrograph of CuNPs/MagSilica catalyst (up right); size distribution
graphic of supported CuNPs (bottom). The sizes were determined for
1
,2,3-triazoles. Encouraged by the remarkable performance of
this new copper based nanocatalyst, and prompted by our interest
in broadening its synthetic applications, we set out to evaluate its
catalytic efficiency in the synthesis of N-aryl imidazoles.
1
00 nanoparticles selected at random.
2
.2 Synthesis of N-aryl imidazoles
A series of N-aryl imidazoles were synthesized under mild
2
2
. Results and discussion
conditions by reacting a variety of aryl- or heteroaryl halides with
imidazole in the presence of the CuNPs/MagSilica nanocatalyst,
under air. For the optimisation of the reaction conditions,
bromobenzene (1a) was chosen as model arylating agent
.1 Catalyst preparation and characterisation
The CuNPs-based magnetic-catalyst was prepared as
18
previously reported by us (see Experimental section for details).
Briefly, CuNPs were prepared by fast reduction of anhydrous
(
Scheme 1).
CuCl with an excess of lithium sand and a catalytic amount of
2
N
CuNPs/MagSilica
reaction conditions
N
4
,4'-di-tert-butylbiphenyl in THF at room temperature. Then, the
Br + HN
N
magnetic support (MagSilica) was added and after stirring the
resulting suspension for 1 h, the catalyst was filtered, washed and
dried under vacuum for 2 hours.
1a
2a
Scheme 1. Optimization of reaction conditions.
The catalyst was characterised by means of transmission
electron microscopy (TEM), energy dispersive X-ray (EDX)
analysis, powder X-ray diffraction (XRD), temperature
programmed reduction (TPR), and inductively coupled plasma
We started the optimisation of the N-arylation process by
reacting bromobenzene (1.0 mmol) with imidazole (1.0 mmol) in
the presence of the CuNPs/MagSilica catalyst (100 mg, 11 mol%

3
Cu), in DMF as the solvent and using K CO (2
A
.0
C
m
C
m
E
ol)
P
a
T
s b
E
a
D
se. MAsh
N
ow
U
n
S
in
C
T
R
ab
I
le
P
1 (entries 6 to 9), aprotic polar solvents such as
T
2
3
Under these conditions, 1-phenyl-1H-imidazole (2a) was
obtained in 52% yield after 24 h of reaction time at the reflux
temperature of DMF (Table 1, entry 1). When the reaction was
performed in the absence of any added base the yield decreased
to 4% (Table 1, entry 2), thus demonstrating the necessity of the
presence of a base for the reaction to take place. In view of this
observation, we decided to test bases of different nature, where
K CO proved to be the most effective one (compare entry 1 with
DMF and DMSO gave better results than protic polar ones (H O)
2
or those with lower dipolar moment (toluene, THF). After that,
we analyzed the influence of the imidazole/PhBr ratio on the
reaction yield, and we observed that a twofold increase in this
ratio resulted in a significantly higher yield of the desired N-
arylated product (Table 1, entry 10). Finally, the optimal amount
of catalyst was found to be 100 mg under the reaction conditions
(see Table 1, footnotes d and e).
2
3
entries 3, 4 and 5). Then, the effect of the solvent was studied. As
a
Table 1. Optimisation of the reaction conditions for the N-arylation of imidazole.
N
CuNPs/MagSilica
reaction conditions
N
Br + HN
N
1
a
2a
b
Entry
Solvent
DMF
DMF
DMF
DMF
DMF
Toluene
THF
Temp. (ºC)
152
Base
Time (h)
24
2a Yield %
1
2
3
4
5
6
7
8
K
2
CO
3
52
4
152
–
30
152
tert-BuOK
DBU
24
11
2
152
24
152
TBAH
24
15
–
111
K
2
CO
CO
CO
CO
3
3
3
3
20
66
K
2
22
12
–
H
2
O
100
K
2
20
9
DMSO
189
K
2
24
42
c
d
e
f
1
0
DMF
152
K
2
CO
3
24
85 (60) (71) (86)
a
b
c
d
e
f
Bromobenzene (1.0 mmol), imidazole (1.0 mmol), base (2.0 mmol), 100 mg of catalyst, in 6 mL of solvent and under air atmosphere, unless otherwise stated.
GLC yield based on the starting bromobenzene.
Reaction performed using 2.0 mmol of imidazole.
Reaction performed using 50 mg of catalyst.
Reaction performed using 75 mg of catalyst.
Reaction performed using 150 mg of catalyst.
With the optimized reaction conditions in hand, the scope of
the catalyst in the N-arylation of imidazole using different
arylating agents was evaluated (Scheme 2).
led us to further explore the influence of the electronic properties
of the aromatic ring of the arylating agent on the course of the C-
N coupling reaction. Thus, we tested different aryl bromides and
iodides substituted with electron-withdrawing or electron-
donating groups. As shown in Table 2, aryl iodides 1g and 1h
gave the corresponding N-arylated products in good yields
irrespective of the electronic properties of the substituents
attached to the aromatic ring (Table 2, entries 7 and 8). On the
contrary, electron poor aryl bromide 1i showed to be much less
reactive than that bearing a strong electron-donating group on the
aromatic ring (compare entries 9 and 10 in Table 2). On the other
hand, p-bromostyrene (1k) and 4-bromo-1,1'-biphenyl (1l)
showed to be as reactive as p-bromotoluene (1b), leading to the
corresponding N-arylated imidazoles 2g and 2h in good yield
N
CuNPs/MagSilica
N
Ar
X
+
HN
Ar N
K CO DMF, 152ºC
2
3,
1
2
Scheme 2. Synthesis of N-aryl imidazoles.
In order to study the effect of the nature of the halide on the
reaction course, we first tested different p-halotoluenes. As
expected, the reactivity followed the order aryl iodide > aryl
bromide >> aryl chloride. As shown in Table 2 (entries 2 to 4), p-
chlorotoluene (1d) was found to be almost unreactive, whereas
both p-bromotoluene (1b) and p-iodotoluene (1c) gave the
corresponding N-arylated imidazole 2b in good yield, 1c being
converted into 2b at a considerably shorter reaction time. With
the aim to take advantage of the lack of reactivity showed by the
aryl chlorides, we decided to explore the selectivity of the
arylation process by using dihalogenated arylating agents. For
(
Table 2, entries 11 and 12). Unfortunately, the catalyst showed
to be less efficient in the coupling of sterically-demanding
arylating agents such as 1-bromonaphthalene (1m), which was
converted into 1-(naphthalen-1-yl)-1H-imidazole (2i) in 55%
yield after 60 h of reaction time. In an attempt to extend the
scope of our methodology to the use of boronic acids as arylating
agents (Lam-Chan reaction), phenyl boronic acid was reacted
with imidazole under the optimized conditions leading to 1-
phenyl-1H-imidazole 2a in moderate yield (Table 2, entry 14).
this
purpose,
p-chloroiodobenzene
(1e)
and
p-
bromochlorobenzene (1f) were reacted with imidazole under the
optimized conditions, and we found that 1e was efficiently
converted into the expected chlorinated product 2c (Table 2,
entry 5) whereas 1f also gave 2c as the major reaction product
but in a markedly lower yield (Table 2, entry 6). This observation

4
Tetrahedron
ACCEPTED MANUSCRIPT
a
Table 2. Synthesis of N-aryl imidazoles catalysed by CuNPs/MagSilica
N
CuNPs/MagSilica
K CO DMF, 152ºC
N
Ar
X
+
HN
Ar N
2
3,
1
2
b
Entry
Aryl halide 1
Reaction
Time (h)
Product 2
Yield %
80
1
2
3
4
5
6
7
8
24
22
14
30
18
32
12
18
83
91
10
88
c
45
93
87
9
26
67
1
1
0
1
21
20
90
80
1
1
2
3
22
60
85
64
1
1
4
5
30
24
58
92
a
The reactions were conducted under the optimized conditions.
b
c
Isolated yield after column chromatography (hexane/ethyl acetate), based on the starting aryl halide.
Together with 10% of the corresponding bis-imidazole product.
On the other hand, we were pleased to find that the N-arylation
reaction also proceeded with 2-bromothiophene (1o) as arylating
agent leading to 1-(thien-2-yl)-1H-imidazole (2j) in excellent
yield as the only reaction product (Table 2, entry 15).
Unfortunately, when we applied the same N-arylation process to
other N-heterocycles such as pyrrole, indole, pyrazole or
benzotriazole, using bromobenzene as arylating agent, the
unreacted starting materials were recovered after 24 h of reaction
time.
the reaction flask, thus minimizing the loss of catalyst which
usually occurs in filtration processes. Figure 2 shows the
recovery process of the catalyst by means of an external magnet,
and the catalyst performance for the synthesis of 2a after three
consecutive cycles without significant loss of catalytic activity.
On the other hand, since no copper leaching has been
detected by atomic absorption spectrometry in the crude reaction
mixture after removal of the catalyst, the N-arylation process is
suggested to be heterogeneous in nature. Although, an alternative
catalytic process in which the copper supported nanocatalyst
could be acting as a reservoir of copper species that leach into the
2
.3 Recovery and reuse of the catalyst
We selected bromobenzene as model arylating agent for the
19
solution and re-adsorb, should not be discarded.
study of the catalyst performance after various cycles of recovery
and reuse. The catalyst could be separated from the reaction
medium, washed with solvent and reused very easily, simply
with the aid of a permanent magnet placed on the outer wall of

5
ACCEPTED MApe
N
rfo
U
rmSCth
R
e pIPar
T
ticle size distribution. Copper content in the
supported catalyst was determined by Inductively Coupled
Plasma Atomic Emission Spectroscopy (ICP-AES), in a Spectro
Arcos instrument. The catalyst specific surface area was
measured by BET method, from a N isotherm at 77K in NOVA
2
1
200e apparatus. The reducibility of the supported catalysts was
analyzed by Temperature Programmed Reduction (TPR) in a in-
house-made equipment. Before reduction, the samples were
treated with flowing Ar at 300 ºC. Then, a flowing mixture (20
mL/min) of 10 % H /Ar was introduced, raising the temperature
2
at 8 ºC/min from room temperature up to 550 ºC. The TPR
profile was obtained following the H consumption with a TCD
2
detector. X-ray diffraction (XRD) analyses were performed using
a Bruker AXS D8 Advance diffractometer, equipped with a Cu-
Kα1,2 radiation source. Atomic absorption spectroscopy was
carried out in a Perkin Elmer AA700 spectrometer.
Figure 2. Recovery of the magnetic catalyst (left), and performance of
the catalyst in the synthesis of 1-phenyl-1H-imidazole (2a) after three
consecutive cycles (right).
4
.3. CuNPs/MagSilica catalyst preparation.
3
. Conclusions
A mixture of lithium sand (21 mg, 3.0 mmol) and 4,4'-di-tert-
butylbiphenyl (DTBB, 26 mg, 0.1 mmol) in THF (3 mL), was
stirred at room temperature under nitrogen atmosphere. When the
reaction mixture turned dark green (15 min), indicating the
We have successfully developed a new methodology for the
copper-catalyzed N-(hetero)arylation of imidazoles with
hetero)aryl bromides and iodides under ligand-free conditions,
(
formation of the corresponding lithium arenide, anhydrous CuCl2
using a magnetically recoverable nanocatalyst consisting of
copper nanoparticles on nanosized silica-coated maghemite. The
catalyst is very stable under the reaction conditions and allow the
N-arylation reaction to be conducted under air. The simplicity of
the methodology, together with the high atom economy of the
process and the easy of recovery and reuse of the catalyst, makes
this copper-based magnetic nanocatalyst a very attractive
alternative for the synthesis of N-(hetero)aryl imidazoles. We are
actively exploring other applications of this copper nanocatalyst
in synthetic transformations of high interest for the fine chemical
industry.
was added (134 mg, 1.0 mmol). The resulting suspension was
stirred until it turned black (15-30 min), indicating the formation
of copper(0) nanoparticles. Then, it was diluted with THF (10
mL) and MagSilica (500 mg) was added. The resulting
suspension was stirred for 1 h, and then bidistilled water (2 mL)
was added for eliminating the excess of lithium. The resulting
solid was filtered under vacuum in a Buchner funnel and washed
successively with water (10 mL) and acetone (10 mL). Finally,
the solid was dried under vacuum (5 Torr) for 2 hours.
4
.4. General procedure for imidazole N-arylation reaction
4
4
. Experimental section
To a vigorously stirred suspension of the CuNPs/MagSilica
catalyst (100 mg) in DMF (6 mL) under air, K CO (276 mg, 2.0
2
3
.1. General
mmol) and imidazole (136 mg, 2.0 mmol) were added. The
reaction mixture was stirred for 30 min and then the
corresponding aryl halide (1.0 mmol) was added and the reaction
flask was immersed in an oil bath at the reflux temperature of
DMF (152 ºC). The reaction mixture was stirred at this
temperature until no further conversion of the starting aryl halide
was observed (TLC, GC). The catalyst was immobilized by
means of a permanent magnet placed on the outer wall of the
All moisture sensitive reactions were carried out under a
nitrogen atmosphere. Anhydrous tetrahydrofuran was freshly
distilled from sodium/benzophenone ketyl. Other solvents were
20
treated prior to use by standard methods. All starting materials
were of the best available grade (Aldrich, Fluka, Merck) and
were used without further purification. Commercially available
copper(II) chloride dihydrate was dehydrated upon heating in
oven (150 ºC, 45 min) prior to use for the preparation of CuNPs.
MagSilica® was provided by Evonik Industries AG (Essen,
Germany). Column chromatography was performed with Merck
silica gel 60 (0.040–0.063 µm, 240–400 mesh). Thin layer
chromatography (TLC) was performed on precoated silica gel
plates (Merck 60, F254, 0.25 mm).
reaction flask, and washed twice with Et O (10 mL each).
2
Finally, the catalyst was dried under vacuum (5 Torr) for its
recovery and reuse. The crude reaction mixture was evaporated
under vacuum (15 Torr) and the resulting residue was purified by
flash column chromatography (silica gel, hexane/AcOEt) to
afford the corresponding N-aryl imidazoles (2a-j). All known
compounds included in Table
comparison of their chromatographic and spectroscopic data ( H,
1 were characterised by
4
.2. Instrumentation and analysis
1
13
C NMR, and MS) either with those of the corresponding
commercially available pure samples (2g) or with those described
Nuclear magnetic resonance (NMR) spectra were recorded on
a Bruker ARX-300 spectrometer using CDCl as the solvent and
3
21
21
22
21
23
23
24
25
26
in the literature (2a, 2b, 2c, 2d, 2e, 2f, 2h, 2i, 2j ).
tetramethylsilane (TMS) as internal reference. Mass spectra (EI)
were obtained at 70 eV on a Hewlett Packard HP-5890 GC/MS
instrument equipped with a HP-5972 selective mass detector.
Infrared (FT-IR) spectra were obtained on a Nicolet-Nexus
spectrophotometer. The purity of volatile compounds and the
Acknowledgments
This work was generously supported by the Consejo Nacional
de Investigaciones Científicas y Técnicas (CONICET), Agencia
Nacional de Promoción Científica y Tecnológica (ANPCyT) and
Universidad Nacional del Sur (UNS).
chromatographic analyses (GC) were determined with
a
Shimadzu GC-14B instrument equipped with a flame-ionisation
detector and a 30 m column (HP-5MS, 0.25mm, 0.25µm), using
nitrogen as carrier gas. The freshly prepared catalyst was
characterized by Transmission Electron Microscopy (TEM) in a
JEOL JEM-2100F-UHR instrument, operated at an acceleration
voltage of 200 kV. One hundred metal particles were measured to

6
Tetrahedron
ACCEPTED MANUSCRIPT
2
008, 49, 4386–4389. (f) Kelkar, A. A.; Patil, N. M.; Chaudhari,
Supplementary data
R. V. Tetrahedron Lett. 2002, 43, 7143–7146. (g) Liu, L.; Frohn,
M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J. J. Org.
Chem. 2005, 70, 10135–10138. (h) Feng, Y. S.; Man, Q. S.; Pan,
P.; Pan, Z. Q.; Xu, H. J. Tetrahedron Lett. 2009, 50, 2585–2588.
Supplementary data associated with this article can be found
in the online version, at
(
i) Yang, C. T.; Fu, Y.; Huang, Y. B.; Yi, J.; Guo, Q. X.; Liu, L.
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Supporting Information
Synthesis of N-aryl imidazoles catalysed by copper nanoparticles on nanosized
silica- coated maghemite
a
b
c,
a,
Fabiana Nador , María Alicia Volpe , Francisco Alonso ∗ , and Gabriel Radivoy ∗
a
c
Instituto de Química del Sur, INQUISUR (CONICET-UNS), Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, 8000 Bahía
Blanca, Argentina
Planta Piloto de Ingeniería Química, PLAPIQUI (CONICET-UNS), Camino La Carrindanga Km 7, CC 717, 8000 Bahía Blanca Argentina
Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, E-03080,
Alicante, Spain
b
Index
1
2
3
4
5
6
. Representative TEM images of the catalyst
2
3
3
4
4
5
. EDX spectrum of the catalyst
. TPR profile of the catalyst
. XRD diffractogram of the catalyst
. ICP-AES analysis of the crude reaction mixture after catalyst recovery
. Catalyst leaching test
∗
∗
Corresponding author. Tel.: +54-291-459-5100; fax: +54-291-459-5187; e-mail: gradivoy@criba.edu.ar
Corresponding author. Tel.: +34-965-903-548; fax: +34-965-903-549; e-mail: falonso@ua.es

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1. Representative TEM images of the catalyst
Fig. S1. Representative TEM images of the catalyst

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ACCEPTED MANUSCRIPT
2. EDX spectrum of the catalyst
Fig. S2. EDX spectrum of the catalyst
3. TPR profile of the catalyst
Fig. S3. TPR profile of the catalyst. The amount of hydrogen consumed corresponds to the
reduction of the whole CuO present in the catalyst. No peaks attributable to the support reduction
are observed.

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4. XRD diffractogram of the catalyst
Fig. S4. XRD pattern of the catalyst. Only diffraction peaks owing to the support are observed.
5. ICP-AES analysis of the crude reaction mixture after catalyst recovery
Experimental procedure: after the reaction of 1a with imidazole under the optimized conditions, the
catalyst was removed from the reaction mixture by means of a permanent magnet. The solvent was
evaporated under vacuum. The digestion of the residue was done by using a microwave digestor
(MARS-5, CEM Corporation, USA), utilizing nitric acid pro-analysis (Merck), according to
standard SRM 1577a. Nitric acid was ultrapurified by distillation prior to use (Berghof Distillacid
BSB-939-IR, GmbH, Germany). Quantification of the metal content of the samples was carried out
by external calibration using certified standards (Chem-Lab, Zedelgem B-8210, Belgium).
The ICP-AES analysis gave <60 ppb of copper (iron was not detected at ppb levels). The
corresponding spectrum is shown below.
Cu 327.396
Cond 1x
1150
1100
1050
1000
950
900
850
800
750
700
650
Fig. S5. ICP-AES profile of the sample around 327.4 nm

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6. Catalyst leaching test
In addition to the ICP-AES analysis, a catalyst leaching test was carried out as follows.
Bromobenzene (1a) and imidazole were allowed to react under the optimized conditions for 8 h,
affording 53% conversion into 2a (GC-MS). The catalyst was removed and, after stirring the
reaction mixture overnight at the reflux temperature of DMF (152 ºC), no further conversion into 2a
was observed.