Cu(II) immobilized on guanidinated epibromohydrin-functionalized γ-Fe2O3@TiO2 (γ-Fe2O3@TiO2-EG-Cu(II)): A highly efficient magnetically separable heterogeneous nanocatalyst for one-pot synthesis of highly substituted imidazoles

Article abstract of DOI:10.1002/aoc.4095

A simple, efficient and eco-friendly procedure has been developed using Cu(II) immobilized on guanidinated epibromohydrin-functionalized γ-Fe₂O₃@TiO₂ (γ-Fe₂O₃@TiO₂-EG-Cu(II)) for the synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles, via the condensation reactions of various aldehydes with benzil and ammonium acetate or ammonium acetate and amines, under solvent-free conditions. High-resolution transmission electron microscopy analysis of this catalyst clearly affirmed the formation of a γ-Fe₂O₃ core and a TiO₂ shell, with mean sizes of about 10–20 and 5–10?nm, respectively. These data were in very good agreement with X-ray crystallographic measurements (13 and 7?nm). Moreover, magnetization measurements revealed that both γ-Fe₂O₃@TiO₂ and γ-Fe₂O₃@TiO₂-EG-Cu(II) had superparamagnetic behaviour with saturation magnetization of 23.79 and 22.12?emu g^?1, respectively. γ-Fe₂O₃@TiO₂-EG-Cu(II) was found to be a green and highly efficient nanocatalyst, which could be easily handled, recovered and reused several times without significant loss of its activity. The scope of the presented methodology is quite broad; a variety of aldehydes as well as amines have been shown to be viable substrates. A mechanism for the cyclocondensation reaction has also been proposed.

Full text of DOI:10.1002/aoc.4095

Received: 4 May 2017
DOI: 10.1002/aoc.4095
Revised: 14 August 2017
Accepted: 15 August 2017
F U L L P A P E R
Cu(II) immobilized on guanidinated epibromohydrin‐
functionalized γ‐Fe2O3@TiO2 (γ‐Fe2O3@TiO2‐EG‐Cu(II)):
A highly efficient magnetically separable heterogeneous
nanocatalyst for one‐pot synthesis of highly substituted
imidazoles
Mahdi Nejatianfar | Batool Akhlaghinia
| Roya Jahanshahi
Department of Chemistry, Faculty of
A simple, efficient and eco‐friendly procedure has been developed using Cu(II)
immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe2O3@TiO2
(γ‐Fe2O3@TiO2‐EG‐Cu(II)) for the synthesis of 2,4,5‐trisubstituted and 1,2,4,5‐
tetrasubstituted imidazoles, via the condensation reactions of various aldehydes
with benzil and ammonium acetate or ammonium acetate and amines, under sol-
vent‐free conditions. High‐resolution transmission electron microscopy analysis
of this catalyst clearly affirmed the formation of a γ‐Fe2O3 core and a TiO2 shell,
with mean sizes of about 10–20 and 5–10 nm, respectively. These data were in
very good agreement with X‐ray crystallographic measurements (13 and 7 nm).
Moreover, magnetization measurements revealed that both γ‐Fe2O3@TiO2 and
γ‐Fe2O3@TiO2‐EG‐Cu(II) had superparamagnetic behaviour with saturation
magnetization of 23.79 and 22.12 emu g−1, respectively. γ‐Fe2O3@TiO2‐EG‐
Cu(II) was found to be a green and highly efficient nanocatalyst, which could
be easily handled, recovered and reused several times without significant loss of
its activity. The scope of the presented methodology is quite broad; a variety of
aldehydes as well as amines have been shown to be viable substrates. A mecha-
nism for the cyclocondensation reaction has also been proposed.
Sciences, Ferdowsi University of Mashhad,
Mashhad 9177948974, Iran
Correspondence
Batool Akhlaghinia, Department of
Chemistry, Faculty of Sciences, Ferdowsi
University of Mashhad, Mashhad
9177948974, Iran.
Email: akhlaghinia@um.ac.ir
KEYWORDS
Cu(II) immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe2O3@TiO2 (γ‐Fe2O3@TiO2‐
EG‐Cu(II)), heterogeneous nanocatalyst, solvent‐free, substituted imidazoles
1 | INTRODUCTION
antagonists,[4] glucagon receptor antagonists[5] and inhib-
itors of interleukin‐1 and 5‐lipoxygenase.[6] Using imidaz-
Imidazole ring‐containing compounds, which are a subset
of nitrogen‐containing heterocyclic compounds, exhibit
wide ranges of biological and pharmacological activities
that make them very attractive compounds for organic
chemists.[1,2] Many substituted imidazoles are known as
biocides (in particular, herbicides, fungicides and
growth 2regulators),[3] potent angiotensin II receptor
oles in ionic liquids[7] and in N‐heterocyclic carbenes[8]
has given a new dimension to the area of organometallics
and ‘green chemistry’. Also, imidazole derivatives have
been used in photography as photosensitive compounds[9]
and also as useful building blocks for the synthesis of
other classes of compounds. Therefore, the development
of novel synthetic methods towards the preparation of
Appl Organometal Chem. 2017;e4095.
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Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4095

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NEJATIANFAR ET AL.
substituted imidazoles has become an important target in
recent years.
determinations of the products and the progress of
the reactions were accomplished by TLC on silica gel
polygram STL G/UV 254 plates. Melting points of the
products were determined with an Electrothermal Type
9100 melting point apparatus. Fourier transform infra-
red (FT‐IR) spectra were recorded with pressed KBr
pellets using an AVATAR 370 FT‐IR spectrometer
(Thermo Nicolet, USA) at room temperature in the
The traditional approaches for the preparation of both
2,4,5‐trisubstituted and 1,2,4,5‐tetrasubstituted imidazoles
are mainly based on the cyclocondensation reaction of a
1,2‐diketone with an aldehyde and a nitrogen source
(ammonium acetate or ammonium acetate and amine).[10]
Literature survey reveals that a great variety of catalysts,
promoters and solvents have been developed for the syn-
thesis of both 2,4,5‐trisubstituted and 1,2,4,5‐
tetrasubstituted imidazoles, including the use of n‐
PeFBA,[11] HClO4–SiO2,[12] zeolite HY,[13] WD/SiO2,[14]
RFOH/SBA‐15‐Pr‐SO3H,[15] SZ,[16] Fe3O4,[17] Fe3O4–
range 400–4000 cm−1, with a resolution of 4 cm−1
,
and each spectrum was the average of 32 scans. NMR
spectra were obtained with a Bruker Avance NMR
spectrometer at 300 MHz, using CDCl3 and DMSO‐d6
solvents in the presence of tetramethylsilane as the
internal standard. Elemental analyses were performed
using a Thermo Finnigan Flash EA 1112 Series instru-
ment (furnace: 900 °C; oven: 65 °C; flow carrier:
140 ml min−1; flow reference: 100 ml min−1). Mass
PEG–Cu,[18]
InCl3⋅3H2O,[19]
NiCl2⋅6H2O,[20]
K5CoW12O40⋅3H2O,[21] silica gel/NaHSO4,[22] molecular
iodine,[23] heteropolyacids,[24] MW/Al2O3,[25] trichloroi
socyanuric acid,[26] benzotriazole,[27] ZrCl4,[28] acetic
acid,[29] silica‐supported sulfuric acid,[30] CAN,[31]
Cu(TFA)2,[32] Yb(OTf)3,[33] GO–chitosan,[34] DABCO,[35]
FeCl3⋅6H2O,[36] mercaptopropylsilica,[37] L‐proline,[38]
MCM‐41 or p‐TsOH,[39] and 1‐butyl‐3‐methylimidazolium
bromide.[40] Despite the many methods available for
the synthesis of 2,4,5‐trisubstituted and 1,2,4,5‐
tetrasubstituted imidazoles, most of these procedures suf-
fer from one or more serious drawbacks such as use of
expensive and hazardous acid catalysts, using toxic metal
catalysts, harsh reaction conditions, occurrence of side
reactions, laborious and complex work‐up and purifica-
tion, high temperature, long reaction time, low yields and
using expensive and excess reagents. Therefore, the devel-
opment of a new, green, high‐yielding, mild and efficient
catalytic system to overcome these shortcomings along
with introducing a mild, efficient and environmentally
benign protocol for the synthesis of highly substituted
imidazoles is an important task in the planning of
substituted imidazole synthesis.
spectra were recorded with
a
CH7A Varianmat
Bremem instrument at 70 eV with electron impact
ionization. Thermogravimetric analysis (TGA) and dif-
ferential thermogravimetry (DTG) were carried out
using a Shimadzu TG‐50 thermogravimetric analyser
in the temperature range 25–900 °C at a heating rate
of 10 °C min−1, under air atmosphere. High‐resolution
transmission electron microscopy (HRTEM) was per-
formed using a Philips CM30 microscope. Inductively
coupled plasma (ICP) analysis was conducted with a
VISTA‐PRO, CCD (Varian, Australia). Elemental com-
positions were determined using energy‐dispersive spec-
troscopy (EDS; SC7620) with a 133 eV resolution at
20 kV. Room temperature magnetization isotherms
were obtained using vibrating sample magnetometry
(VSM; LakeShore 7400). Powder X‐ray diffraction
(XRD) was performed using an X'Pert Pro MPD diffrac-
tometer with Cu Kα (λ = 0.154 nm) radiation. All
yields refer to isolated products after purification by
recrystallization. γ‐Fe2O3@TiO2‐EG‐Cu(II) nanoparticles
were prepared using a method previously reported in
the literature.[41a]
In continuation of our efforts to explore the catalytic
activity of heterogeneous Lewis and Brønsted acids[41] for
various organic transformations, we report herein
a simple, mild and expeditious synthesis of 2,4,5‐trisubsti-
tuted and 1,2,4,5‐tetrasubstituted imidazoles in high
yields, using Cu(II) immobilized on guanidinated
2.2 | Typical procedure for preparation of
2,4,5‐Triphenyl‐1H‐imidazole (3a)
epibromohydrin‐functionalized
γ‐Fe2O3@TiO2
(γ‐
Fe2O3@TiO2‐EG‐Cu(II)) as an effectual catalyst.
γ‐Fe2O3@TiO2‐EG‐Cu(II) nanoparticles (2.5 mol%,
0.030 g) were added to a mixture of benzil (1 mmol,
0.210 g), benzaldehyde (1 mmol, 0.106 g) and NH4OAc
(2.5 mmol, 0.192 g). The resulting mixture was stirred
at 100 °C under neat conditions, until the reaction was
judged to be complete by TLC (eluent = n‐hexane–ethyl
acetate, 7:3). After cooling to room temperature, hot
ethanol (5 ml) was added to the reaction mixture and
the catalyst was separated from the solution using an
2 | EXPERIMENTAL
2.1 | General
All chemical reagents and solvents were purchased
from Merck and Sigma‐Aldrich and were used as
received without further purification. The purity

NEJATIANFAR ET AL.
3 of 12
external magnet, washed with ethanol (2 × 10 ml) and
air‐dried to be ready for the next run. Thereafter, the
resultant mixture was concentrated under rotary
vacuum evaporation and the obtained crude product
was recrystallized from ethanol to afford the pure
2,4,5‐triphenyl‐1H‐imidazole (0.290 g, 98%).
obtained crude product was recrystallized from ethanol
to afford pure 1,2,4,5‐tetraphenylimidazole (0.364 g, 98%).
3 | RESULTS AND DISCUSSION
Nanomagnetic catalysts have received a great deal of
attention in organic chemistry due to their easy
separation from reaction mixtures using an external
magnet (which is not time‐consuming in comparison
with the standard methods), clean forward reactions,
and their having remarkable physical and chemical
properties by controlling particle size and surface area.
Recently, we successfully synthesized γ‐Fe2O3@TiO2‐
EG‐Cu(II) as a novel and magnetically recyclable
heterogeneous nanocatalyst[41a] (Scheme 1). The cata-
lytic activity of the synthesized nanocatalyst was
initially investigated in the one‐pot synthesis of 1,4‐
disubstituted 1,2,3‐triazoles, through alkyne–azide
cycloaddition reactions, in water.[41a]
2.3 | Typical procedure for preparation of
1,2,4,5‐Tetraphenylimidazole (3 t)
γ‐Fe2O3@TiO2‐EG‐Cu(II) nanoparticles (2.5 mol%,
0.030 g,) were added to a mixture of benzil (1 mmol,
0.210 g), benzaldehyde (1 mmol, 0.106 g), NH4OAc
(1.5 mmol, 0.115 g) and aniline (1 mmol, 0.093 g). The
resulting mixture was stirred at 100 °C under neat
conditions, until the reaction was judged to be complete
by TLC (eluent = n‐hexane–ethyl acetate, 7:3). After
cooling to room temperature, hot ethanol (5 ml) was
added to the reaction mixture and the catalyst was
separated from the solution using an external magnet,
washed with ethanol (2 × 10 ml) and air‐dried to be ready
for the next run. Afterwards, the resultant mixture was
concentrated under rotary vacuum evaporation and the
In the present study we decided to extend the
application of γ‐Fe2O3@TiO2‐EG‐Cu(II) as a reusable
solid acid nanomagnetic catalyst towards the efficient
synthesis
of
2,4,5‐trisubstituted
and
1,2,4,5‐
SCHEME 1 Overview of γ‐Fe2O3@TiO2‐EG‐Cu(II) preparation

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NEJATIANFAR ET AL.
SCHEME 2 Synthesis of 2,4,5‐
trisubstituted and 1,2,4,5‐tetrasubstituted
imidazoles via one‐pot condensation
reactions of aldehydes with benzil and
ammonium acetate or ammonium acetate
and amines in the presence of γ‐
Fe2O3@TiO2‐EG‐Cu(II)
tetrasubstituted imidazoles via one‐pot condensation
reactions of aldehydes with benzil and ammonium
acetate or ammonium acetate and amines (Scheme 2).
diagnostic absorption bands corresponding to Cu─N and
Cu─O vibrations were observed at 428 and 450 cm−1
,
respectively.[41b] The respective bands were covered by
stretching vibration modes of Fe─O and Ti─O bonds.
Furthermore, ─NH2 and probably ─OH stretching
3.1 | Characterization of γ‐Fe2O3@TiO2‐
EG‐Cu(II)
The γ‐Fe2O3@TiO2‐EG‐Cu(II) catalyst synthesized
based on the pathway described in Scheme 1 was then
fully characterized using various techniques including
FT‐IR spectroscopy, powder XRD, HRTEM, TGA/
DTG, EDS, VSM, ICP analysis and elemental analysis
(CHNS).
FT‐IR spectroscopy was engaged to compare the
synthesized γ‐Fe2O3@TiO2, epibromohydrin‐functional-
ized γ‐Fe2O3@TiO2, guanidinated epibromohydrin‐func-
tionalized γ‐Fe2O3@TiO2 and γ‐Fe2O3@TiO2‐EG‐Cu(II)
(Figure 1). The characteristic absorption band related to
the stretching vibration of Fe─O bond in γ‐Fe2O3 was
FIGURE 1 FT‐IR spectra of (a) γ‐Fe2O3@TiO2 nanoparticles,
(b) epibromohydrin‐functionalized γ‐Fe2O3@TiO2‐E, (c) guanidinated
epibromohydrin‐functionalized γ‐Fe2O3@TiO2‐EG, (d) γ‐Fe2O3@TiO2‐
EG‐Cu(II)) and (e) γ‐Fe2O3@TiO2‐EG‐Cu(II) recovered after sixth run
present at about 571–698 cm−1 [42]
the broad absorption band of Ti─O in the TiO2 lattice
at 500–850 cm−1 [43]
Also, the absorption band at
,
which was covered by
.
1619 cm−1 and the broad band appearing at
3100–3500 cm−1 were in turn associated with bending
and stretching vibrations of the adsorbed water molecules
and the surface‐attached hydroxyl groups (Figure 1a).[44]
Immobilization of the epoxy ring to γ‐Fe2O3@TiO2 frame-
work was identified by the methylene C─H stretching
and bending vibration bands appearing at around
2872–2923 and 1454 cm−1, respectively (Figure 1b).[45]
Moreover, C─O─C vibrational stretching modes were
visualized at 1112 cm−1. These findings indicated the
successful grafting of epoxy rings to the γ‐Fe2O3@TiO2
surface. Evidence for the ring opening of epoxy with gua-
nidine groups was the appearance of indicative bands at
around 3378 and 1454 cm−1, which were related to
N─H and C─N stretching vibrations, respectively
(Figure 1c).[44c] After coordination with Cu(II), the
FIGURE 2 XRD pattern of γ‐Fe2O3@TiO2

NEJATIANFAR ET AL.
5 of 12
frequencies (at around 3162–3378 cm−1) were shifted to
lower wavenumber as a result of the metallation process.
In addition, NH and probably OH bending vibrations
(positioned at 1617 and 1619 cm−1, respectively) were also
shifted to lower frequencies after coordination with
Cu(II). Likewise, C─N and C═N stretching vibrations
(positioned at 1454 and 1662 cm−1) were shifted to lower
wavenumbers due to the metallation process (Figure 1d).
On the other hand, bands at 1634 and 1401 cm−1 in the
spectrum of γ‐Fe2O3@TiO2‐EG‐Cu(II) were related to
COO (in acetate),[42] which proved the presence of Cu in
the catalyst. The mentioned absorption bands were cov-
ered by broad stretching vibration frequencies related to
C─N bond. Accordingly, potent metal–ligand interaction
was confirmed.
no. 04–0755), were readily recognized from the XRD pat-
tern. Moreover, the existence of weak diffraction peaks
relating to (0 1 1), (0 0 4) and (0 2 0) crystallographic faces
could be assigned to anatase XRD diffraction peaks.
Accordingly, the average crystallite sizes of γ‐Fe2O3
and TiO2 (anatase) which were calculated using the
Debye–Scherrer equation were approximately 13 and
7 nm, respectively.
According to the HRTEM images of the catalyst
(Figure 3), a relatively good monodispersity was obvious
for the γ‐Fe2O3@TiO2‐EG‐Cu(II) structure. Interestingly,
it is evident that a dark γ‐Fe2O3 core with an average size
of about 10–20 nm was surrounded by a grey titania shell
with a thickness of about 5–10 nm in the catalyst
structure (Figure 3).
Powder XRD measurement was accomplished to
identify the crystalline structure of γ‐Fe2O3@TiO2.
As shown in Figure 2, the reflection planes of (2 2 0),
(3 1 1), (4 0 0), (4 2 2), (5 1 1) and (4 4 0), which are
ascribed to the cubic structure of γ‐Fe2O3 (JCPDS file
TGA/DTG study of γ‐Fe2O3@TiO2‐EG‐Cu(II) was
conducted to investigate the thermal stability of the
catalyst, as well as the amount of immobilized organic
functional groups on the support (Figure 4). As can be
seen in the TGA thermogram, the observed weight loss
FIGURE 3 HRTEM images of γ‐
Fe2O3@TiO2‐EG‐Cu(II)
FIGURE 4 TGA/DTG thermograms of
γ‐Fe2O3@TiO2‐EG‐Cu(II)

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NEJATIANFAR ET AL.
FIGURE 5 EDS analysis of γ‐
Fe2O3@TiO2‐EG‐Cu(II)
Fe2O3@TiO2‐EG‐Cu(II) have superparamagnetism at
room temperature. A slight decrease in the saturation
magnetization of γ‐Fe2O3@TiO2 after the surface grafting
could be attributed to the contribution of the
non‐magnetic materials.
3.2 | Catalytic synthesis of 2,4,5‐
Trisubstituted and 1,2,4,5‐Tetrasubstituted
Imidazoles in presence of γ‐Fe2O3@TiO2‐
EG‐Cu(II)
To evaluate and optimize the catalytic behaviour of γ‐
Fe2O3@TiO2‐EG‐Cu(II) in the synthesis of imidazoles,
initially a multicomponent condensation reaction for the
preparation of 2,4,5‐triphenyl‐1H‐imidazole was studied
under various conditions (including different solvents,
temperatures, amounts of catalyst and molar ratios of
reactants). The results are summarized in Table 1. As a
first step, to monitor whether the use of γ‐Fe2O3@TiO2‐
EG‐Cu(II) is crucial for this transformation, the multi-
component condensation reaction of benzil (1 mmol),
benzaldehyde (1 mmol) and ammonium acetate
(2.5 mmol) at 100 °C was conducted under solvent‐free
condition in the absence of γ‐Fe2O3@TiO2‐EG‐Cu(II)
and also in the presence of γ‐Fe2O3@TiO2, γ‐
Fe2O3@TiO2‐E and γ‐Fe2O3@TiO2‐EG (Table 1, entries
1–4). The obtained results clearly indicate that
Fe2O3@TiO2‐EG‐Cu(II) is a vital catalyst for this conden-
sation reaction (compare entry 5 with entries 1–4). It is
interesting to note that temperature plays an important
role in the catalytic synthesis of 2,4,5‐triphenyl‐1H‐imid-
azole. To get more insight into the temperature effect,
the model reaction was performed in the temperature
range 90–120 °C. At 90 °C the reaction was completed
in a prolonged time, while further increasing the reaction
temperature (110 and 120 °C) had no great influence on
the reaction rate (Table 1, entries 6–8). Hence, 100 °C
was selected as the optimum temperature to accomplish
FIGURE
6
Magnetization curves of (a) γ‐Fe2O3@TiO2
nanoparticles and (b) γ‐Fe2O3@TiO2‐EG‐Cu(II)
at temperatures below 200 °C was related to the adsorbed
water molecules on the support. Then, the decomposition
of organic motifs occurred at temperatures ranging from
200 to 670 °C (17.23 wt%). Based on the TGA results, the
amount of organic backbone supported on γ‐Fe2O3@TiO2
is estimated to be 0.70 mmol g−1. These results were in a
good agreement with the elemental analysis data
(N = 3.01% and C = 7.02%) and ICP analysis. The ICP
analysis indicated that 0.74 mmol of copper was anchored
on 1.00 g of the catalyst.
EDS analysis disclosed the existence of C, O, Fe, Ti
and Cu elements (Figure 5). This analysis well demon-
strated that Cu(II) is immobilized on the guanidinated
epibromohydrin‐functionalized γ‐Fe2O3@TiO2.
The magnetic properties of γ‐Fe2O3@TiO2 and γ‐
Fe2O3@TiO2‐EG‐Cu(II) were measured at ambient
temperature using VSM. As indicated in Figure 6, the
saturation magnetization values for γ‐Fe2O3@TiO2 and
γ‐Fe2O3@TiO2‐EG‐Cu(II) were 23.79 and 22.12 emu g−1
,
respectively. Indeed, the absence of hysteresis phenome-
non indicated that both γ‐Fe2O3@TiO2 and γ‐

NEJATIANFAR ET AL.
7 of 12
TABLE 1 Optimization of various reaction parameters for one‐pot synthesis of 2,4,5‐triphenyl‐1H‐imidazole
Molar ratio of benzaldehyde:benzil:
ammonium acetate
Catalyst
(mol%)
Temperature
(°C)
Time
(min)
Isolated
yield (%)
Entry
Solvent
1
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2.5
1:1:2
—
100
100
—
60/24 (h)
60
0/0
2a
3b
4c
5
0.03 (g)
0.03 (g)
0.03 (g)
2.5
—
Trace
Trace
Trace
98
100
—
60
100
—
60
100
—
20
6
2.5
110
—
20
98
7
2.5
120
—
20
98
8
2.5
90
—
30
98
9
1.6
100
—
25
90
10
11
12
13
14
15
16
17
3.2
100
—
20
98
4
100
—
20
98
2.5
100
—
30
96
1:1:3
2.5
100
—
20
98
1:1:3.5
1:1:2.5
1:1:2.5
1:1:2.5
2.5
100
—
20
98
2.5
Reflux
Reflux
Reflux
H2O
EtOH
CH3CN
60
70
2.5
60
78
2.5
60
73
aReaction performed in the presence of γ‐Fe2O3@TiO2.
bReaction performed in the presence of γ‐Fe2O3@TiO2‐E.
cReaction performed in the presence of γ‐Fe2O3@TiO2‐EG.
the reaction. To further develop the progress of reaction in
terms of efficiency and time, the model reaction was car-
ried out in the presence of various amounts of the catalyst.
By applying lower catalytic amount (1.6 mol%), the prod-
uct yield was found to be 90% in longer reaction time
(Table 1, entry 9), whereas using higher amounts of cata-
lyst (3.2 and 4 mol%) did not have any substantial effect
on the reaction progress (Table 1, entries 10 and 11). To
explore the effect of molar ratio of reactants on the reac-
tion rate, we also implemented three separate experi-
ments by applying 1:1:2, 1:1:3 and 1:1:3.5 molar ratios of
benzaldehyde:benzil:ammonium acetate at 100 °C, under
solvent‐free condition (Table 1, entries 12–14). By using
1:1:2 molar ratio, the reaction rate was not so satisfactory.
However, additional amounts of ammonium acetate did
not have any noticeable influence on the reaction prog-
ress. Accordingly, the optimal molar ratio of benzalde-
hyde:benzil:ammonium acetate was selected as 1:1:2.5.
To investigate the effect of solvent, the model reaction
was carried out in H2O, EtOH and CH3CN (Table 1,
entries 15–17). It was found that conducting the reaction
under solvent‐free condition generates the desired prod-
uct in excellent yield within a short reaction time, in
comparison with the use of solvent (compare entry 5 with
entries 15–17).
After optimizing the reaction conditions, to show the
general applicability of the present method, the reaction
of benzil with a wide variety of aldehydes (aromatic,
heteroaromatic and aliphatic) and ammonium acetate
was investigated under the optimized conditions
(Table 2). A broad range of aromatic aldehydes bearing
both electron‐donating and electron‐withdrawing substit-
uents underwent the successful one‐pot, multicomponent
cyclocondensation reactions to provide 2,4,5‐trisubsti-
tuted imidazoles in excellent yields (Table 2, entries 1–
15). Interestingly, heteroaromatic aldehydes as well as
aliphatic aldehydes also afforded the corresponding imid-
azoles in high yields (Table 2, entries 16–19). In general,
the aspect of this protocol is broad, since various
functional groups were found to be compatible under
such reaction conditions.
To widen the applicability of the present protocol, syn-
thesis of 1,2,4,5‐tetrasubstituted imidazoles was also
investigated via the one‐pot, multicomponent condensa-
tion reactions of benzil, aromatic aldehydes, ammonium
acetate and a selection of primary aromatic amines, under
the optimized conditions established for the preparation
of 2,4,5‐trisubstituted imidazoles (Table 3). As can be
seen, electron‐withdrawing substituents on aromatic ring
of aldehyde and electron‐donating substituents on

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NEJATIANFAR ET AL.
TABLE 2 Synthesis of various 2,4,5‐trisubstituted imidazoles in presence of γ‐Fe2O3@TiO2‐EG‐Cu(II) under solvent‐free condition
Entry
R
Product
3a
Time (min)
Isolated yield (%)
1
C6H5
20
98
2
4‐NO2C6H4
4‐CNC6H4
4‐FC6H4
3b
3c
25
25
25
20
30
30
30
25
20
20
30
25
30
30
37
20
25
28
95
95
90
95
95
95
90
96
95
98
90
92
91
85
92
90
95
93
3
4
3d
3e
5
4‐ClC6H4
2‐ClC6H4
3‐BrC6H4
4‐MeOC6H4
2‐MeOC6H4
4‐MeC6H4
2‐MeC6H4
4‐OHC6H4
2‐OHC6H4
4‐iprC6H4
4‐(CH3)2NC6H4
C4H4N
6
3f
7
3 g
3 h
3i
8
9
10
11
12
13
14
15
16
17
18
19
3j
3 k
3 l
3 m
3n
3o
3p
3q
3r
2‐C4H3S
C5H11
C6H13
3 s
TABLE 3 Synthesis of various 1,2,4,5‐tetrasubstituted imidazoles in presence of γ‐Fe2O3@TiO2‐EG‐Cu(II) under solvent‐free condition
Entry
R
R′
Product
3 t
Time (min)
Isolated yield (%)
1
C6H5
C6H5
25
98
2
3
4
5
6
7
4‐ClC6H4
2‐CH3OC6H4
C6H5
C6H5
3u
3v
3w
3x
3y
3z
20
27
18
15
28
23
92
94
90
90
90
92
C6H5
4‐CH3C6H4
4‐CH3OC6H4
4‐ClC6H4
C6H5CH2
C6H5
C6H5
C6H5
aromatic ring of primary amines could almost equally
accelerate the corresponding condensation reactions.
Generally, the reactions were clean and no side products
were detected. In all cases, the reactions proceeded
efficiently and gave the corresponding products in good
to excellent yields within short reaction times.
In our experiments, the completion of the reaction is
confirmed by the disappearance of aldehydes determined

NEJATIANFAR ET AL.
9 of 12
using TLC, followed by the appearance of a strong sharp
absorption band in the FT‐IR spectra of the products at
around 3338 or 1540 cm−1 and a medium absorption band
at 1666 cm−1, which are assigned to N─H or C─N and
C═N stretching vibrations of 2,4,5‐trisubstituted imidaz-
oles or 1,2,4,5‐tetrasubstituted imidazoles, respectively.
All of the obtained products were known and their phys-
ical data (colour, melting points) and spectral data (mass
spectrometry) were found to be identical with those of
authentic compounds. Selected compounds were further
aldimine I. Subsequently, the catalyst facilitates the for-
mation of intermediate II, by increasing the electrophilic-
ity of the C═N on the aryl aldimine I towards the
nucleophilic attack of ammonia or amine. There is no ten-
dency between benzil and ammonia to produce α‐imino
ketone I′. To understand which component (aldehyde or
benzil) is more reactive toward ammonia, in two separate
flasks, NH4OAc was treated in turn with aldehyde and
benzil under optimized reaction conditions, using stoi-
chiometric amounts of the reactants. The rapid reaction
of aldehyde with NH4OAc produced aryl aldimine I,
which next led to facile formation of intermediate II when
treated with NH4OAc or amine. On the other hand, a
trace amount of α‐imino ketone I′ was produced from
the reaction of benzil with NH4OAc or amine after a
prolonged time. When the progress of the reaction mix-
ture was followed precisely, α‐imino ketone I′ was not
detected. So, according to the above results, we can
deduce that in the presence of aldehyde, nucleophilic
attack of NH4OAc or amine on benzil is not successful.
Intermediate II, in the presence of γ‐Fe2O3@TiO2‐EG‐
Cu(II), condenses with benzil to form intermediate III
or III′ which in turn rearranges to 2,4,5‐trisubstituted
imidazole or 1,2,4,5‐tetrasubstituted imidazole by a [1,5]
hydrogen shift or dehydration, respectively, and then the
re‐generated catalyst re‐enters the catalytic cycle.
1
identified using FT‐IR, H NMR and 13C NMR spectros-
copies, the results of which were compared with literature
data. A diagnostic 1H NMR signal at around 12.70–
11.20 ppm is assigned to the NH of 2,4,5‐trisubstituted
imidazoles. In 13C NMR spectra, a signal at around
157.33–144.04 or 150.71–137.54 ppm is allocated to C‐2
of
2,4,5‐trisubstituted
imidazoles
or
1,2,4,5‐
tetrasubstituted imidazoles, respectively. See the
supporting information for details.
A postulated mechanism for this reaction is shown in
Scheme 3. The crucial catalytic role of γ‐Fe2O3@TiO2‐EG‐
Cu(II) in this condensation reaction was established by
performing the reaction in the absence of γ‐
Fe2O3@TiO2‐EG‐Cu(II). In this context, even after a long
reaction time, no product was obtained (Table 1, entry 1).
It is speculated that the nucleophilic attack of the ammo-
nia nitrogen (obtained from NH4OAc) on the activated
carbonyl group of aldehyde results in formation of aryl
The recovery and reusability of the catalyst were
examined in the synthesis of 2,4,5‐triphenyl‐1H‐
SCHEME 3 Proposed mechanism for
formation of 2,4,5‐trisubstituted and
1,2,4,5‐tetrasubstituted imidazoles in the
presence of γ‐Fe2O3@TiO2‐EG‐Cu(II)

10 of 12
NEJATIANFAR ET AL.
imidazole. In this regard, after completion of the reaction,
the reaction mixture was dissolved in hot ethanol and the
catalyst was separated using an external magnet. Then the
catalyst was washed with ethanol, air‐dried and stored for
subsequent reaction runs. The product was obtained in
98, 98, 97, 95, 92 and 89% isolated yields in six consecutive
runs, which evidently indicated that the catalyst could be
reused for at least six runs without loss of its activity
(Figure 7).
It is important to note that the FT‐IR spectrum of the
nanocatalyst recovered after the sixth run (Figure 1e)
indicated the entire preservation of the position, shape
and relative intensity of the indicative absorption bands.
These data verified that no substantial changes happened
to the chemical structure of the functional groups and
hydrogen bonding network of the nanocatalyst.
Also, it is noteworthy that the copper content of the
freshly prepared catalyst which was obtained using ICP
FIGURE 7 Synthesis of 2,4,5‐triphenyl‐
1H‐imidazole in the presence of reused γ‐
Fe2O3@TiO2‐EG‐Cu(II). (*data refer to
conversion of benzaldehyde)
TABLE 4 Comparison of catalytic activity of present catalyst with that of some other reported methods in preparation of 2,4,5‐triphenyl‐1H‐
imidazole and 1,2,4,5‐tetraphenylimidazole
Entrya
Catalyst (loading)
Reaction conditions
Time (min)
Yield (%)
1
ZrO2‐β‐CDb (40 mol%)
Solvent‐free/100 °C
24
96[46]
95[33]
94[47]
90[38]
96[48]
93[49]
82[19]
73[30]
99[23]
2
Yb (OTf)3 (5 mol%)
HOAc/70 °C
120
70
3
Zinc(II) [tetra(4‐methylphenyl)] (2 μmol%)
L‐Proline (15 mol%)
EtOH/ultrasound/r.t.
MeOH/reflux
4
540
240
150
480
240
15
5
Polymer–ZnCl2 (0.102 g)
Alumc (0.3 g)
EtOH/reflux
6
EtOH/70 °C
7
InCl3.3H2O (10 mol%)
Silica sulfuric acid (0.5 g)
I2 (5 mol%)
MeOH/r.t.
8
H2O/reflux
9
EtOH/75 °C
10
11
12
13
14
15
16
17
γ‐Fe2O3@TiO2‐EG‐Cu(II) (2.5 mol%)
TiCl4.SiO2 (50 mol%)
BF3.SiO2 (0.32 g)
Solvent‐free/100 °C
Solvent‐free /110 °C
Solvent‐free/140 °C
EtOH/75 °C
15
98 (present study)
190
120
50
75[50]
92[51]
I2 (10 mol%)
96[52]
SBPPSAd (0.25 g)
Solvent‐free/140 °C
PEG‐400/110 °C
t‐BuOH/60 °C
Solvent‐free/100 °C
60
90[53]
PEG‐400 (1.5 g)
360
720–900
20
86[54]
92[35]
DABCO (0.7 mol%)
γ‐Fe2O3@TiO2‐EG‐Cu(II) (2.5 mol%)
98 (present study)
aEntries 1–10 refer to synthesis of 2,4,5‐triphenyl‐1H‐imidazole. Entries 11–16 refer to synthesis of 1,2,4,5‐tetraphenylimidazole.
bZrO2‐supported‐β‐cyclodextrin.
cPotassium aluminium sulfate.
dSilica‐bonded propylpiperazine‐N‐sulfamic acid.

NEJATIANFAR ET AL.
11 of 12
analysis was 0.74 mmol of Cu per gram of the catalyst,
while ICP analysis indicates that the catalyst after the
sixth run comprises 0.68 mmol of Cu per gram. Fascinat-
ingly, the amount of copper leached from the surface of
the catalyst is very low.
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SUPPORTING INFORMATION
Additional Supporting Information may be found online
in the supporting information tab for this article.
How to cite this article: Nejatianfar M,
Akhlaghinia B, Jahanshahi R. Cu(II) immobilized
on guanidinated epibromohydrin‐functionalized γ‐
Fe2O3@TiO2 (γ‐Fe2O3@TiO2‐EG‐Cu(II)): A highly
efficient magnetically separable heterogeneous
nanocatalyst for one‐pot synthesis of highly
substituted imidazoles. Appl Organometal Chem.
2017;e4095. https://doi.org/10.1002/aoc.4095