Hantzsch reaction on free nano-Fe2O3 catalyst: Excellent reactivity combined with facile catalyst recovery and recyclability

Article abstract of DOI:10.1039/c1cc12693h

A magnetic nanoparticle catalyst was readily prepared from inexpensive starting materials which catalyzed the Hantzsch reaction. High catalytic activity and ease of recovery from the reaction mixture using an external magnet, and several reuse times without significant losses in performance are additional eco-friendly attributes of this catalytic system.

Full text of DOI:10.1039/c1cc12693h

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COMMUNICATION
Hantzsch reaction on free nano-Fe2O3 catalyst: excellent reactivity
combined with facile catalyst recovery and recyclabilityw
Nadiya Koukabi,a Eskandar Kolvari,*b Ardeshir Khazaei,*a Mohammad Ali Zolfigol,*a
Behzad Shirmardi-Shaghasemic and Hamid Reza Khavasid
Received 7th May 2011, Accepted 27th June 2011
DOI: 10.1039/c1cc12693h
A magnetic nanoparticle catalyst was readily prepared from
inexpensive starting materials which catalyzed the Hantzsch
reaction. High catalytic activity and ease of recovery from the
reaction mixture using an external magnet, and several reuse
times without significant losses in performance are additional
eco-friendly attributes of this catalytic system.
a route that has attracted wide research interest for its unique
physical properties.6 They possess advantage of being
magnetically recoverable, thereby eliminating the requirement
for either solvent swelling before or catalyst filtration after
the reaction.7–9 In comparison with other transition metals
extensively used, iron-based catalysts are cheap, non-toxic,
environmentally friendly and abundant. In the past decades,
various iron salts have been applied as Lewis acids (Fe3+) in
homogeneous catalysis and different catalytically active iron
complexes were also reported.10 In heterogeneous catalysis,
iron oxides have been frequently used as catalysts and
supports in bulk industrial processes, usually at high temperature
(4300 1C) and pressure.11,12 At the onset of this study, no
example of the iron oxide nanoparticle had been reported for
the multicomponent reaction. Multicomponent reactions13
allow the creation of several bonds in a single operation and
are attracting increasing attention as one of the most powerful
emerging synthetic tools for the creation of molecular diversity
and complexity.14 In recent years, much attention has been
focused on the synthesis of 1,4-dihydropyridine compounds,
due to their significant biological activity.15–18 We were, thus,
intrigued by the possibility of applying nanotechnology to the
design of a novel, active, recyclable, and magnetically recoverable
‘‘free’’ nano-iron oxide as a Lewis-acid catalyst for the synthesis
of 1,4-dihydropyridine compounds under mild reaction conditions
for the first time.
Transition-metal catalyzed organic reactions are often con-
sidered to follow the principles of ‘‘Green Chemistry’’;
i.e. these catalyzed reactions consume a minimum of energy
and reagents or auxiliaries and minimize waste. Nanocatalysts
are considered to be a bridge between homogeneous and hetero-
geneous catalysis.1 With the development of nanochemistry it
has been possible to prepare ‘‘soluble’’ analogous of hetero-
geneous catalysts, materials that might have properties inter-
mediate between those of bulk and single particles due to high
surface areas and high densities of active sites.2 Unfortunately,
unsupported nanoparticles are usually unstable and the
coagulation of the nanoparticles during reaction is frequently
unavoidable.3 Thus, till now, the investigation of ‘‘free’’
nanoparticles as catalysts has been rare, although it is
an important tool to gain a fundamental understanding of
catalysis.4,5 Clearly, the development of ‘‘free’’ nanoparticles
with tunable catalytic activity is of great significance for both
academia and industry. However, the recycle problem must be
addressed before nanocatalytic processes can be scaled-up, due
to the fact that nanoparticles, which include nano-scaled metal
catalysts and supports, are difficult to separate from the
reaction mixture, which can lead to the blocking of filters
and valves by the nanoparticle catalyst. Currently, a method used
to address this problem is the use of magnetic nanoparticles,
For initial optimization of the reaction conditions and the
identification of the best iron source, temperature, and amount
of the catalyst, benzaldehyde 1, ethyl acetoacetate 2a and
ammonium acetate 3 were chosen as model substrates (Scheme 1).
By screening a wide range of iron sources, we found that the
product 4a could be obtained in yields ranging from 51 to 95% in
any oxidation state of iron salt (0, II, III; Table 1). As expected,
bulk Fe2O3 displayed only low activity (Table 1, entry 2). Next, we
a Faculty of Chemistry, Bu-Ali Sina University,
Hamedan 6517838683, Iran. E-mail: zolfi@basu.ac.ir,
Khzaei_1326@yahoo.com; Fax: +988118257407
b Department of Chemistry, Faculty of Science Semnan University,
Semnan, Iran. E-mail: kolvari@semnan.ac.ir; Fax: +982313354082
c Department of Chemistry, Payam Noor University, Hamedan, Iran
d Department of Chemistry, Shahid Beheshti University, Tehran, Iran
w Electronic supplementary information (ESI) available: General
experimental details for starting materials and instruments, catalysis
measurement: XRD pattern, and XPS spectra and also elemental
analysis, spectral data of all compounds and literature references for
known compounds. CCDC 823102. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c1cc12693h
Scheme 1 Synthesis of Hantzsch 1,4-dihydropyridines catalyzed by
‘‘free’’ nano-g-Fe2O3.
c
9230 Chem. Commun., 2011, 47, 9230–9232
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Table 1 Screening of iron sources for the Hantzsch synthesis of
1,4-dihydropyridinea
Entry
Catalyst (0.15 mmol)
t/min
Yieldb (%)
1
2
3
4
5
Fe
25
40
60
35
25
51
70
63
80
95
Bulk-Fe2O3
FeCl2Á4H2O
FeCl3Á6H2O
Nano-g-Fe2O3
a
Benzaldehyde–ethyl acetoacetate–NH4OAc = 1 : 2 : 1.5, solvent-free,
b
80 1C. Yields refer to isolated products.
19
studied nanoparticle-sized Fe2O3 because of its super-
paramagnetic property,20 hence recovery and recycling of the
catalyst could be easily achieved. In the presence of nano-
Fe2O3, in which the majority of the particles is 14 nm in size
(Fig. 1a) the conversion reached 95% (Table 1, entry 5). The
corresponding catalytic activity is higher than the corresponding
bulk Fe2O3.
The crystal structure of the iron oxide g-Fe2O3 is reported as an
inverse spinel structure (Scheme 2),19,21,22 in which all the iron
cations are in the trivalent state, and the charge neutrality of the
cell is guaranteed by the presence of cation vacancies. The unit cell
Scheme 2 Proposed mechanism for ‘‘free’’ nano-g-Fe2O3 catalyzed
Hantzsch synthesis.
of maghemite can be represented as (Fe3+)8[Fe3+
&1/6]16O32,
5/6
where the brackets (), [] and & designate tetrahedral, octahedral
and vacant sites, respectively.23
combination of nano-Fe2O3 (0.15 mmol), benzaldehyde 1a
(1 mmol), ethyl acetoacetate 2a (2 mmol), ammonium acetate
3 (1.5 mmol) at 90 1C under solvent-free conditions. In view
of these results, we then selected the optimized reaction
conditions to determine the scope of this ‘‘free’’ nano-Fe2O3
catalyzed reaction. A wide range of aromatic, aliphatic and
heteroaromatic aldehydes were subjected to react with 2a, 2b
in the presence of ammonium acetate 3 and 0.15 mmol of
nano-Fe2O3 to generate 4, 528 (Scheme 1) and the results are
summarized in Table 2. The aryl group substituted with
different groups and same groups located at different positions
of the aromatic ring does not show much effect on the
formation of the final product and afford the expected
products 4, 5 in good to high yields. The products were
characterized by IR, 1H NMR and 13CNMR spectroscopy,
and also by comparison with authentic samples. Product 4g
was structurally determined by X-ray single crystal diffraction
(see ESIw). This superparamagnetic property of nano-Fe2O3
made the isolation and reuse of this catalyst very easy. After
completion of the reaction, the mixture was triturated
with ethyl acetate. In the presence of a magnetic stirrer bar,
nano-Fe2O3 moved onto the stirrer bar steadily and the
reaction mixture turned clear within 10 s. The catalyst can
be isolated by simple decantation (see ESIw). After being
washed with acetone and dried in air, the nano-Fe2O3 can be
directly reused without any deactivation even after five rounds
of synthesis of product 4a (Table 3).
X-Ray diffraction (XRD) powder patterns confirm that
bulk and nano-Fe2O3 have the same crystal strucure.24 From
the binding energies derived from X-ray photoelectron spectro-
scopy (XPS), it is clear that the surface iron ions are trivalent in
both samples.25
The reason for the improved activity of nano-iron oxide
most probably originates from the nanometre size of the bulk
iron oxide. In general, nanoscale heterogeneous catalysts
should offer higher surface areas, low-coordinated sites, and
surface vacancies, which are responsible for the higher catalytic
activity.26 Theoretically, it can be assumed that with a decrease
of the particle size down to a ‘‘molecular’’ level, the nanocatalyst
behaves as a homogeneous system in which the catalytic
activity is not controlled by the surface area of the catalyst
but rather governed by the concentration.27 The most important
significance of these results is that ‘‘free’’ nano-Fe2O3, but not
immobilized nano-Fe2O3, is highly active, selective, and stable
by merely controlling the particle size. Variation of the
amount of catalyst (0.15 mmol) and temperature (90 1C)
revealed an increased conversion of reactants and a product
yield of 98%. In summary, the optimal conditions for the
‘‘free’’ nano-Fe2O3 catalyzed Hantzsch reaction involved a
The characterization of the nano-Fe2O3 before and after
reuse five times showed the same particle size by transmission
electron microscopy (TEM; Fig. 1b) and the same crystal
structure by XRD. The only difference is visible from XPS,
which showed lower peak intensity after the fifth use (see
ESIw). This is due to the increased carbon content of
the surface. The C/Fe ratio rose from 1.51 atom% in fresh
nano-Fe2O3 to 2.10 atom% after the fifth use in the synthesis
Fig. 1 TEM images of nano-g-Fe2O3 before use (a) and after reuse
five times (b).
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9230–9232 9231

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Table
2
‘‘Free’’ nano-g-Fe2O3 catalyzed Hantzsch synthesis of
of its simple recyclability. From a scientific point, our results
1,4-dihydropyridinesa
expand the application of ‘‘free’’ nanoparticles. They should
be helpful to understand the advantageous combination of the
properties of homogeneous and heterogeneous catalysis and
the development of new catalytic systems.
Entry R1
R2
Product t/min Yieldb (%)
1
2
3
4
5
6
7
8
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
4a
4b
4c
4d
4e
4f
4g
4h
4i
15
25
15
20
32
25
40
30
15
15
20
20
12
15
10
20
25
12
10
20
35
40
15
19
15
25
30
98
90
92
81
94
93
90
88
90
91
87
92
89
95
94
96
93
90
88
85
91
94
96
89
80
86
91
p-MeC6H4
p-ClC6H4
p-HOC6H4
p-O2NC6H4
p-FC6H4
p-CNC6H4
p-BrC6H4
o-MeOC6H4
m-ClC6H4
Notes and references
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Ed., 2010, 49, 3428–3459.
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9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4j
4k
4l
4-HO-3-MeOC6H3 OEt
n-Pr
2-Furyl
Ph
OEt
OEt
4m
OMe 5a
OMe 5b
OMe 5c
OMe 5d
OMe 5e
OMe 5f
OMe 5g
OMe 5h
OMe 5i
OMe 5j
o-MeOC6H4
p-O2NC6H4
p-MeC6H4
p-ClC6H4
p-HOC6H4
p-FC6H4
p-NCC6H4
p-BrC6H4
o-ClC6H4
4-HO-3-MeOC6H3 OMe 5k
n-Pr
2-Furyl
m-O2NC6H4
OMe 5l
OMe 5m
OMe 5n
12 T. Riedel, H. Schulz, G. Schaub, J. Jun and K. Lee, Top. Catal.,
2003, 26, 41–51.
13 B. Jiang, T. Rajale, W. Wever, S. J. Tu and G. Li, Chem.–Asian J.,
2010, 5, 2318–2335.
a
All products were characterized by IR, 1H NMR and 13C NMR
b
spectroscopic data, and melting points. Yields refer to isolated
products.
14 Some
reviews
on
diversity-oriented
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15 P. P. Mager, R. A. Coburn, A. J. Solo, D. J. Triggle and H. Rothe,
Drug Design Disc., 1992, 8, 273–289.
Table 3 Reuse of ‘‘free’’ nano-g-Fe2O3 in the synthesis of
1,4-dihydropyridinesa
Run
1
2
3
4
5
16 R. Miri, K. Javidnia, H. Sarkarzadeh and B. Hemmateenejad,
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153–156.
Yieldb (%)
98
98
96
96
92
a
Benzaldehyde–ethyl acetoacetate–NH4OAc = 1 : 2 : 1.5, solvent-free,
90 1C, 0.15 mmol ‘‘free’’ nano-g-Fe2O3; the weight loss of catalyst after
5 runs was 9 wt%. Isolated yields.
19 Y. K. Sun, M. Ma, Y. Zhang and N. Gu, Colloids Surf., A, 2004,
245, 15–19.
b
20 Z. Xu, C. Shen, Y. Tian, X. Shi and H. J. Gao, Nanoscale, 2010, 2,
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28 General procedure for the synthesis of 1,4-dihydropyridine
compounds: All reactions were carried out in an oil-bath (oil-bath
temperature 90 1C). The aldehyde (1 mmol), b-keto compound
(2 mmol), ammonium acetate (1.5 mmol) and nano-Fe2O3
(0.15 mmol) were added to a glass reactor (ca. 25 mL). The
reaction mixture was vigorously stirred. After completion of the
reaction (monitored by TLC), the mixture was cooled to room
temperature and triturated with ethyl acetate (10 mL). In the
presence of a magnetic stirrer bar, nano-Fe2O3 moved onto the
stirrer bar steadily and the reaction mixture turned clear within
10 s. The catalyst can be isolated by simple decantation.
The reaction mixture was treated with brine, extracted with
ethyl acetate (2Â20 mL). After evaporation of the solvent, the
crude product was recrystallized from EtOH–H2O to give a pure
solid.
of product 4a. We believe that this is also the possible reason
for the high stability of the nano-Fe2O3 presented herein. A
thin layer of carbon is formed during the reaction which prevents
significant coagulation of the nano-Fe2O3. Obviously, carbon-
containing deposits cover the iron oxide particles partly during
reaction which, however, seems not to be detrimental to the
activity. The proposed mechanism for the synthesis of
1,4-dihydropyridines involves Lewis-acid catalyzed cyclo-
condensation of intermediates A and B, generated respectively
by Knoevenagel condensation of one equivalent of ethyl
acetoacetate with aldehyde and reaction of a second equivalent
of ethyl acetate with ammonia generated from ammonium
acetate (Scheme 2).
In conclusion, unsupported ‘‘free’’ nano-Fe2O3 has been
shown to be a stable yet highly active catalyst for preparing a
variety of 4-substituted-1,4-dihydropyridines from the one-pot
three-component condensation reaction. The catalytic research on
novel approaches toward nanomaterials should be improved
to enhance organic synthesis. For that purpose, magnetic
catalyst provides a new way for continuous processes, because
c
9232 Chem. Commun., 2011, 47, 9230–9232
This journal is The Royal Society of Chemistry 2011