Anchored sulfonic acid on silica-layered NiFe2O4: A magnetically reusable nanocatalyst for Hantzsch synthesis of 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.poly.2019.04.035

In this study, the immobilization of sulfonic acid on silica-layered nickel ferrite, NiFe₂O₄@SiO₂@SO₃H, was investigated. The sulfonated Ni-nanocatalyst was then characterized using FT-IR, SEM, EDX, XRD and VSM analyses. Catalytic activity of the Ni-nanocomposite was also studied towards Hantzsch synthesis of 1,4-dihydropyridines via one-pot condensation reaction of 1,3-diketones (ethyl acetoacetate or 4-hydroxycoumarin), aromatic aldehydes and aqueous ammonia in H₂O (70 °C)as a green solvent. All reactions were carried out within 10–100 min to afford the products in high to excellent yields. The green aspect of this synthetic protocol was more studied by examining the reusability of NiFe₂O₄@SiO₂@SO₃H MNPs for seven consecutive cycles without the significant loss of catalytic activity. The current method represents remarkable advantages in terms of mild reaction conditions, using H₂O as an environmental-friendly solvent, stability and easy separation of the magnetic nanocatalyst, high yield of products, wide tolerance of starting materials and the perfect reusability of the applied Ni-nanocatalyst.

Full text of DOI:10.1016/j.poly.2019.04.035

Accepted Manuscript
Anchored sulfonic acid on silica-layered NiFe2O4: a magnetically reusable
nanocatalyst for Hantzsch synthesis of 1,4-dihydropyridines
Behzad Zeynizadeh, Soleiman Rahmani, Elham Eghbali
PII:
S0277-5387(19)30282-7
https://doi.org/10.1016/j.poly.2019.04.035
POLY 13895
DOI:
Reference:
Polyhedron
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 January 2019
2 April 2019
22 April 2019
Please cite this article as: B. Zeynizadeh, S. Rahmani, E. Eghbali, Anchored sulfonic acid on silica-layered
NiFe2O4: a magnetically reusable nanocatalyst for Hantzsch synthesis of 1,4-dihydropyridines, Polyhedron (2019),
doi: https://doi.org/10.1016/j.poly.2019.04.035
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Anchored sulfonic acid on silica-layered NiFe2O4: a magnetically reusable nanocatalyst for
Hantzsch synthesis of 1,4-dihydropyridines
Behzad Zeynizadeh*, Soleiman Rahmani and Elham Eghbali
Faculty of Chemistry, Urmia University, Urmia 5756151818, Iran,
E-mail: bzeynizadeh@gmail.com
Abstract: In this study, the immobilization of sulfonic acid on silica-layered nickel ferrite, NiFe2O4@SiO2@SO3H, was
investigated. The sulfonated Ni-nanocatalyst was then characterized using FT-IR, SEM, EDX, XRD and VSM analyses.
Catalytic activity of the Ni-nanocomposite was also studied towards Hantzsch synthesis of 1,4-dihydropyridines via
one-pot condensation reaction of 1,3-diketones (ethyl acetoacetate or 4-hydroxycoumarin), aromatic aldehydes and
aqueous ammonia in H2O (70 °C) as a green solvent. All reactions were carried out within 10‒100 min to afford the
products in high to excellent yields. The green aspect of this synthetic protocol was more studied by examining the
reusability of NiFe2O4@SiO2@SO3H MNPs for seven consecutive cycles without the significant loss of catalytic activity.
The current method represents remarkable advantages in terms of mild reaction conditions, using H2O as an
environmental-friendly solvent, stability and easy separation of the magnetic nanocatalyst, high yield of products,
wide tolerance of starting materials and the perfect reusability of the applied Ni-nanocatalyst.
Keywords: Ethyl acetoacetate; Hantzsch 1,4-dihydropyridines; 4-hydroxycoumarin; NiFe2O4; sulfonic acid
1. Introduction
Catalysis is one of the essential aspects of chemical reactions which is offering selectivity and high yield of
the products as well as faster reaction rates. In this context, acids are used frequently as catalysts in various
laboratory and industrial reactions [1‒4]. Strong acids such as sulfuric, phosphoric and hydrochloric acids
are used as homogeneous acid catalysts in various organic reactions, such as alkylation, hydration,
dehydration, rearrangement, carbonyl and condensation reactions. Nevertheless, sulfuric acid is not
considered as a reusable and benign catalyst. It has several drawbacks in terms of corrosiveness,
insufficient isolation and tedious workup procedure. In spite of these, the need for sulfuric acid in chemical
reactions is crucial [5]. The literature review shows that numerous efforts have been realized for modifying
homogeneous catalysts to heterogeneous one. In this area, the immobilization of homogeneous catalysts
on the surface of solid supports such as metal oxide [6‒8], polymer matrix [9‒12], carbon materials [13‒
17], porous silica [5, 18‒21] and zeolites [22‒24] has gained the considerable interest.
Nowadays, the application of magnetic nanoparticles (MNPs) of transition metal oxides as solid supports
has been frequently studied. They are easily prepared and because of the extreme surface area of
nanoparticles, stability, magnetic property and the inherent electronic influence of transition metal
constituents are the suitable candidates to immobilize various homogeneous catalysts. In this area, the
application of cubic spinel nickel ferrite (NiFe2O4) has been more investigated. This magnetic material has
high thermal stability (up to 900 °C) and super paramagnetic property for easy separation from the reaction
mixture [25‒30]. In spite of the great capabilities of nano ferrites, however, they have a strong tendency for
agglomeration. Encapsulation of nano ferrites nucleus with silica layer is an easy way to overcome the
mentioned shortcoming. It is also reported that the suitable deposition of silica layer on the surface of
magnetic nucleus improves their chemical stability [31‒34].
Recently, a considerable impact has been paid to the synthesis of acidic functional groups anchored on the
surface of magnetic nanoparticles towards the promotion of various organic reactions. As well, they have
good the magnetic property, high stability and clean reaction products without possessing disadvantages of
homogeneous acid-catalysts [35‒42].
Among N-containing heterocycles, 1,4-dihydropyridines (1,4-DHPs) are too important materials and
received much attention due widespread biological activities such as anti-cancer, vasodilator, cytotoxic,
antidiabetic, antitumor, antimicrobial, antialzheimer and hepatoprotective agents [43‒50]. 1,4-DHPs are

also served as L-type Ca2+ channel blockers to treat hypertension and angina diseases [51‒54]. These
characteristics clearly represent the considerable impact of 1,4-DHPs as the source of valuable drugs. The
literature review shows that using alginic acid [55], AlCl3·6H2O [56], MgAl2-hydrotalcite [57], MgO NPs [58],
TiO2 NPs [59], montmorillonite K10 [60], chitosan supported copper sulfate [61], cellulose sulfuric acid [62],
CeO2 [63], acidic ionic liquid on polymer [PS-IM(CH2)4SO3H][HSO4] [64], PPh3 [65], Fe3O4 NPs [66], trifluro-
ethanol [67] and tetra-n-butylammonium bromide/microwave [68] for synthesis of diester 1,4-DHPs as well
Fe3O4@SiO2 [69], guanidinium-based sulfonic acid [70], silica gel or acidic alumina/microwave [71] and
lactic acid [72] for synthesis of coumarin-based 1,4-DHPs has been successfully reported. Although the
reported method have the own merits and shortcomings, however, the development of simple, efficient
and environmental benign protocols for synthesis of 1,4-DHPs using reusable heterogeneous solid acid
catalyst is highly demanded. Figure 1 shows the structure of some pharmacological active 1,4-DHPs.
Figure 1. Drugs containing 1,4-DHP structure
In line with the outlined strategies and continuation of our research program towards synthetic usefulness
of magnetically nanocatalyst systems [73‒76], herein, we wish to introduce sulfonic acid immobilized on
silica-layered nickel ferrite, NiFe2O4@SiO2@SO3H as an efficient magnetic and reusable solid acid catalyst
for the one-pot and three-component condensation reaction of aromatic aldehydes (1), ethyl acetoacetate
(2)/4-hydroxycoumarin (3) and ammonia (4) in H2O giving 1,4-dihydropyridines 5(a-l) and 6(a-l) in high
yields (Figure 2).

Figure 2. Synthesis of 1,4-DHPs catalyzed by NiFe2O4@SiO2@SO3H MNPs
2. Experimental
2.1. Instruments and reagents
All chemicals were purchased from chemical companies with the best quality and they were used without
1
further purification. H, 13C NMR and FT-IR spectra were recorded on 300 MHz Bruker Avance and Thermo
Nicolet Nexus 670 spectrometers. X-ray diffraction (XRD) measurements were carried out on a X'PertPro
Panalytical, Holland diffractometer in 40 kV and 30 mA with a CuKα radiation (λ=1.5418 Å). Signal data
were recorded in 2θ = 10°‒80° with a step interval of 0.05o. Morphology and size distribution of
nanoparticles were examined by scanning electron microscopy (SEM) using FESEM-TESCAN MIRA3
instrument. The chemical composition of the prepared nanocomposites was determined by energy-
dispersive X-ray (EDX) spectroscopy. Magnetic property of the nanocatalysts was measured using vibration
sample magnetometer (VSM, Meghnatis Daghigh Kavir Co., Iran) analysis under an external magnetic field
up to 20 kOe. Melting points were recorded on Electrothermal 9100 melting point apparatus and
uncorrected. TLC was applied for monitoring of the reactions over silica gel 60 F254 aluminum sheet.
Spectral data for compounds 5(a-l) and 6(a-l) were added in supplementary information.
2.2. Synthesis of NiFe2O4 MNPs
A desired amount of Ni(OAc)2·4H2O, Fe(NO3)3·9H2O, NaOH and NaCl in a molar ratio of 1:2:8:2, respectively,
were mixed in a mortar and grinded for 50 min at room temperature. After that, the mixture was washed
with deionized water for several times and dried at 80 °C for 10 h. The resulting product was calcinated at
700 or 900 °C for 2 h to afford magnetically nanoparticles of NiFe2O4 [76].
2.3. Synthesis of NiFe2O4@SiO2 MNPs
A mixture of NiFe2O4 (1.5 g) MNPs in i-PrOH (200 mL) and deionized water (20 mL) was prepared. The
resulting mixture was then irradiated by ultrasound for 30 min. PEG-400 (5.36 g), deionized water (20 mL),
aqueous ammonia 28% (10 mL) and tetraethyl orthosilicate (TEOS, 2 mL) was then added and the resulting
mixture was stirred at room temperature for 28 h. After that, magnetically nanoparticles of NiFe2O4@SiO2
were separated by an external magnetic field. The nanoparticles were then washed with ethanol and

deionized water followed by drying under air atmosphere for 12 h.
2.4. Synthesis of NiFe2O4@SiO2@SO3H MNPs
A suspension of NiFe2O4@SiO2 (2 g) MNPs in CHCl3 (15 mL) and under ice-bath condition (0‒5 °C) was
prepared. While the mixture was stirred, ClSO3H (0.5 g, 9 mmol) was added within 50 min in drop wise
manner. The resulting mixture was continued to stirring for 2 h at room temperature for the complete
releasing of HCl from the mixture. The mixture was then filtered and the solid residue was washed with
MeOH (20 mL) and dried at room temperature for 12 h giving NiFe2O4@SiO2@SO3H as the black powder.
Through the acid-base titration, the amount of sulfonic acid moiety (H+ sites) in the nanocatalyst was
determined 0.33 mmol·g‒1.
2.5. A general procedure for Hantzsch synthesis of 1,4-DHPs catalyzed by NiFe2O4@SiO2@SO3H MNPs
In a round-bottom flask (10 mL) equipped with a magnetic stirrer, a mixture of aromatic aldehyde (1 mmol),
ethyl acetoacetate or 4-hydroxycoumarin (2 mmol) and aqueous ammonia 28% (2 mmol) in H2O (2 mL) was
prepared. NiFe2O4@SiO2@SO3H MNPs (20 mg) was then added and the resulting mixture was stirred at 70
°C for an appropriate time (Table 2 and 3). Progress of the reaction was monitored by TLC (eluent, n-hexane
/EtOAc: 10/4). After completion of the reaction, EtOAc (3 mL) was added and the mixture was stirred for 5
min followed by magnetic separation of the Ni-nanocatalyst. At the next, the organic layer was separated
from the aqueous solution and dried over anhydrous sodium sulfate. Evaporation of the solvent under
reduced pressure gave the corresponding 1,4-DHP product in high yield. Further purification could be
carried out by recrystallization from hot EtOH.
3. Results and Discussion
3.1. Synthesis and characterization of NiFe2O4@SiO2@SO3H MNPs
The synthesis of sulfonated silica-layered NiFe2O4 (NiFe2O4@SiO2@SO3H) MNPs was carried out in a three-
step procedure: i) synthesis of NiFe2O4 MNPs by solid state grinding of Ni(OAc)2·4H2O and Fe(NO3)3·9H2O in
the presence of NaOH followed by calcination at 700 or 900 °C, ii) layering of SiO2 by tetraethyl orthosilicate
(TEOS) on nano nucleus of NiFe2O4 and iii) immobilization of sulfonic acid moiety on the surface of
NiFe2O4@ SiO2 MNPs via the simple reaction of silica-layered nickel ferrite with ClSO3H at 0‒5 °C (Figure 3).
Figure 3. Preparation of NiFe2O4@SiO2@SO3H MNPs

3.2. Characterization of NiFe2O4@SiO2@SO3H MNPs
After the successful synthesis of sulfonated silica-layered nickel ferrite, the structure of nanocatalyst was
elucidated using FT-IR, SEM, EDX, and VSM analyses.
3.2.1. FT-IR analysis
Fourier transform Infrared spectroscopy is a straightforward method for elucidation of structure as well as
functional groups in a material. In this context, FT-IR spectra of NiFe2O4, NiFe2O4@SiO2 and NiFe2O4@SiO2
@SO3H MNPs are illustrated in Figure 4. In the case of NiFe2O4 (Figure 4a), two main metal-oxygen bands at
598 and 432 cm‒1 are attributed to the tetrahedral and octahedral frameworks of iron or nickel ions [77‒
80]. The band around 3700 cm‒1 is also attributed to hydroxyl groups bonded to metal ions, and the
absorption bands at 3437 and 1640 cm‒1 to H-O-H stretching and bending vibrations of physically adsorbed
water, respectively. FT-IR spectrum of silica-layered nickel ferrite (Figure 4b) shows the stretching
absorption bands corresponding to Si-O-Si at the range of 1000–1200 cm‒1. In the case of NiFe2O4@
SiO2@SO3H (Figure 4c) and due overlapping of Si-O-Si, Fe-O-Si and O-S-O stretching bands at 1086 cm‒1, the
presence of SO3H groups on the surface of NiFe2O4@SiO2 MNPs is demonstrated. As well, the absorption
band at 3431 cm‒1 is attributed to stretching vibration band of OH in sulfonic acid moiety on the surface of
silica-layered nickel ferrite. These results successfully confirm the synthesis of NiFe2O4@SiO2@SO3H MNPs.
Figure 4. FT-IR spectra of a) NiFe2O4, b) NiFe2O4@SiO2 and c) NiFe2O4@SiO2@SO3H MNPs
3.2.2. SEM and EDX analysis
The morphology and elemental composition of the prepared NiFe2O4 and NiFe2O4@SiO2@SO3H MNPs were
determined by SEM and EDX analyses. SEM images of the prepared samples of NiFe2O4 at 700 °C (Figure 5a
and b) and 900 °C (Figure 5c and d) show that the prepared one at 700 °C was agglomerated and
constructed from roughly particles. Accordingly, the prepared NiFe2O4 at 900 °C was constructed from
regular-shape particles with the uniform distribution. These results represent that the influence of
calcination-temperature on morphology and size distribution of nanoparticles is noteworthy. Therefore, it
is concluded that calcination of NiFe2O4 at 900 °C gives the best crystallinity structure with size distribution
of nanoparticles in the range of 55‒72 nm. In this context, SEM images of NiFe2O4@SiO2@SO3H MNPs
(Figure 6a-c) show that the sulfonated nanocomposite was constructed from regular and spherical

nanoparticles with uniform distribution. It’s seen that due layering of SiO2@SO3H moiety on the surface of
NiFe2O4, the size of nanoparticles in NiFe2O4@SiO2@SO3H MNPs is bigger than that of NiFe2O4. As well, the
nanoparticles are distributed in the range of 148‒240 nm. In continuation, the existence of Ni, Fe and O in
NiFe2O4 as well Ni, Fe, O, Si and S elements in NiFe2O4@SiO2@SO3H MNPs was clearly demonstrated by EDX
analyses (Figures 5e and 6d). These analyses exhibited that the nucleus of NiFe2O4 were successfully
encapsulated by sulfonated silica-layer moiety.

Figure 5. SEM images of NiFe2O4 [calcinated at 700 °C (a, b) and 900 °C (c, d)] and its EDX spectrum (e)

Figure 6. SEM images (a-c) and EDX spectrum (d) of NiFe2O4@SiO2@SO3H MNPs
3.2.3. XRD analysis
X-ray diffraction analysis is a useful technique to elucidate the phase purity and crystallinity structure of
materials. In this context, the issue was investigated through the depicted X-ray diffractograms of NiFe2O4
and NiFe2O4@SiO2@SO3H MNPs in Figure 7. According to XRD pattern of Figure 7a, the diffraction peaks at
2Ɵ = 30.51°, 35.9°, 37.49°, 43.58°, 54.02°, 57.58° and 63.20° are corresponded to reflection planes of (220),
(311), (222), (400), (422), (511) and (440) in NiFe2O4. This pattern represent that the prepared NiFe2O4 has a
good phase purity and crystallinity in cubic spinel structure. The pattern is in an exact agreement with the
standard one of NiFe2O4 (JCPDS 54-0964). Subsequently, Figure 7b represents XRD diffractogram of
NiFe2O4@SiO2@SO3H MNPs. Comparing the XRD patterns of NiFe2O4 and NiFe2O4@SiO2@SO3H MNPs
shows that the sulfonated nanocatalyst has the phase purity and characteristic peaks of NiFe2O4. Because
of high [noise/signal] ratio in the pattern, it is also demonstrated that SiO2@SO3H moiety was successfully
immobilized on the surface of nano nucleus of NiFe2O4 [81].

Figure 7. XRD patterns of NiFe2O4 and NiFe2O4@SiO2@SO3H MNPs
3.2.4. VSM analysis
In continuation, the magnetic behavior of NiFe2O4 and NiFe2O4@SiO2@SO3H MNPs was studied by vibrating
sample magnetometer (VSM) analysis. In this context, the magnetization curve for both of samples (Figure
8) reveals a nonlinear and reversible behavior with small hysteresis loop describing NiFe2O4 and NiFe2O4@
SiO2@SO3H have the property of soft ferromagnetic materials. As well, the magnetization (Ms) values of
NiFe2O4 and NiFe2O4@SiO2@SO3H are 28.15 and 20.24 emu·g‒1, respectively. Decreasing in magnetization
value of NiFe2O4@SiO2@SO3H is attributed to the presence of sulfonated silica-layer moiety on the surface
of NiFe2O4 nucleus. This level of magnetization (20.24 emu·g‒1) is enough for any magnetic separation.
Figure 8. Magnetization curves of NiFe2O4 and NiFe2O4@SiO2@SO3H MNPs

3.3. Hantzsch synthesis of 1,4-dihydropyridines catalyzed by NiFe2O4@SiO2@SO3H MNPs
At the next, catalytic activity of NiFe2O4@SiO2@SO3H MNPs was studied towards Hantzsch synthesis of 1,4-
dihydropyridines. In this context, the one-pot and three-component condensation reaction of 4-chloro-
benzaldehyd (1 mmol), ethyl acetoacetate (2 mmol) and ammonia (2 mmol) was selected as a model
reaction and progress of the condensation reaction was studied through the change of reaction-solvent and
temperature as well the amount of nanocatalyst. The results of this investigation are summarized in Table
1. Entry 11 shows that using H2O (at 70 °C), aqueous ammonia as the source of amine and 20 mg of NiFe2O4
@SiO2@SO3H was the requirement to afford high yield of the product.
Table 1. Optimization experiments for the reaction of 4-chlorobenzaldehyde (1 mmol), ethyl acetoacetate
(2 mmol) and an amine source (2 mmol) catalyzed by NiFe2O4@SiO2@SO3H MNPs
Ni-Catalyst
(mg)
Amine source
(2 mmol)
Entry
Solvent (2 mL)
Temp. (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
‒
‒
EtOH
H2O
EtOH
50
50
50
50
50
50
50
50
50
25
00
00
00
00
aq. NH3
aq. NH3
aq. NH3
aq. NH3
aq. NH3
aq. NH3
aq. NH3
aq. NH3
aq. NH3
aq. NH3
aq. NH3
aq. NH3
NH4OAc
NH4Cl
300
300
45
30
30
200
200
120
60
120
20
20
120
120
5
5
20
20
20
20
20
20
20
20
20
10
20
20
60
85
00
45
50
50
50
60
95
60
70
60
H2O
EtOH-H2O (1:1)
EtOAc
CH3CN
DMF
Solvent-free
H2O
H2O
H2O
H2O
H2O
The capability of NiFe2O4@SiO2@SO3H MNPs for Hantzsch synthesis of 1,4-dihydropyridines was further
studied by one-pot condensation reaction of structurally diverse aromatic aldehydes, ethyl acetoacetate
and ammonia at the optimized reaction conditions. The results of this investigation are illustrated in Table
2. The Table shows that various aryl aldehydes including electron releasing or withdrawing functionalities
were efficiently participated in the condensation reaction within 20‒100 min to give the corresponding
diester 1,4-DHPs in high o excellent yields.
Table 2. Preparation of diester 1,4-dihydropyridines catalyzed by NiFe2O4@SiO2-SO3H MNPsa
M.p. (oC) [65‒68]
Entry
Ar-
Product
Time (min)
Yield (%)b
Found
Reported
156‒158
146‒147
150‒152
152‒155
240‒242
1
2
3
4
5
C6H4
5a
5b
5c
5d
5e
40
30
20
40
45
85
95
95
97
75
156‒157
144‒145
150‒152
151‒153
242‒245
2-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
3-OH,4-MeOC6H3

6
7
4-MeOC6H4
3-MeOC6H4
4-MeC6H3
5f
5g
5h
5i
40
35
75
70
153‒155
151‒153
135‒137
234‒236
131‒132
164‒165
230‒232
154‒156
153‒155
135‒137
233‒235
130‒132
163‒164
231‒233
8
80
05
9
4-OHC6H4
00
70
10
11
12
4-O2NC6H4
3-O2NC6H4
3-NO2,4-ClC6H3
5j
80
100
95
5k
5l
100
90
90
a All reactions were carried out with the molar ratio of aryl aldehyde/ethyl acetoacetate/aq. Ammonia (1:2:2) in
the presence of 20 mg nanocatalyst in H2O (2 mL, 70 °C). b Yield refers to isolated pure product.
The possibility of this synthetic protocol was also examined by the one-pot condensation reaction of 4-
hydroxycoumarin as another source of 1,3-dicarbonyl compounds with aromatic aldehydes and aqueous
ammonia. The experiments resulted that the mentioned conditions for Hantzsch synthesis of 1,4-DHPs with
ethyl acetoacetate was also efficient for Hantzsch synthesis with 4-hydroxycoumarin. Therefore structurally
diverse aromatic aldehydes (1 mmol), 4-hydroxycoumarin (2 mmol) and aqueous ammonia (2 mmol) were
reacted in the one-pot manner with 20 mg of NiFe2O4@SiO2@SO3H MNPs. The results of this investigation
are illustrated in Table 3. The Table shows that all reactions were carried out successfully within 10‒45 min
to afford dichromeno-1,4-DHPs in high to excellent yields. As well, electron-withdrawing functionalities on
aromatic rings prolonged the reaction times. In contrast, electron-releasing groups accelerated the rate of
condensation reaction.
Table 3. Hantzsch synthesis of dichromeno-1,4-DHPs catalyzed by NiFe2O4@SiO2@SO3H MNPsa
M.p. (oC) [69‒72]
Entry
Ar-
Product
Time (min)
Yield (%)b
Found
Reported
185‒187
217‒220
222‒225
210‒215
209‒214
178‒182
195‒198
191‒194
173‒178
210‒212
209‒213
201‒205
1
2
C6H4
6a
6b
6c
6d
6e
6f
20
25
20
10
10
15
10
15
20
45
30
40
95
90
98
85
90
90
85
90
85
80
75
80
186‒188
216‒218
222‒224
212‒216
208‒213
179‒183
194‒197
190‒193
174‒177
211‒213
208‒210
200‒203
2-ClC6H4
3
4-ClC6H4
4
3-OH,4-MeOC6H3
4-OH,3-MeOC6H3
3-MeOC6H4
2-MeOC6H3
4-MeC6H4
5
6
7
6g
6h
6i
8
9
4-OHC6H4
10
11
12
4-O2NC6H4
6j
3-O2NC6H4
6k
6l
3-O2N,4-ClC6H3
a All reactions were carried out with the molar ratio of aryl aldehyde/4-hydroxycoumarin/aq. ammonia (1:2:2) in
the presence of 20 mg nanocatalyst in H2O (2 mL, 70 °C). b Yield refers to isolated pure product.
Although the exact mechanism of this synthetic protocol is not clear, however, a depicted mechanism
(Figure 9) could be outlined for the role of nanocatalyst catalyzing the synthesis of 1,4-DHPs. Sulfonated
silica-layered nickel ferrite primarily activates the carbonyl moiety of aromatic aldehyde. Then, enol-form of
β-dicarbonyls reacts with activated aldehyde to form Knoevenagel intermediate II. At the next, through the

acid activation of intermediate II and its Michael addition with enol-form of β-ketoester, intermediate IV is
produced. Finally, by the reaction of intermediate IV with ammonia and ring closing of intermediate VI,
formation of 1,4-DHP is taken place.
Figure 9. A proposed mechanism for Hantzsch synthesis of 1,4-DHPs catalyzed by NiFe2O4@SiO2@SO3H MNPs
The usefulness and capability of NiFe2O4@SiO2@SO3H MNPs in Hantzsch synthesis of 1,4-DHPs 5c [diethyl
4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] and 6c [7-(4-chlorophenyl)-7,14-
dihydro-6H,8H-dichromeno[4,3-b:3',4'-e]pyridine-6,8-dione] was also highlighted by a comparison with the
previously reported promoters (Tables 4 and 5). A case study shows that in terms of reaction times,
reusability of the nanocatalyst and yield of the products, the present work exhibited the perfect efficiency
than the other promoters.
Table 4. Synthesis of diester 1,4-DHP 5c by NiFe2O4@SiO2@SO3H and other reported promoters
Entry
Catalyst
Time (min)
Yield (%)
Condition
Temp (°C) Reusability Ref.
1
2
3
4
5
6
NiFe2O4@SiO2@SO3H
Alginic acid
AlCl3·6H2O
MgAl2-hydrotalcite
MgO NPs
TiO2 NPs
20
60
130
360
165
160
95
92
76
65
90
90
H2O
EtOH
Solvent-free
CH3CN
EtOH
70
reflux
60
r.t.
reflux
80
7
6
‒
‒
3
5
*
55
56
57
58
59
EtOH

7
8
9
10
11
10
Montmorillonite K10
Chitosan-CuSO4
Cellulose sulfuric acid
CeO2
[PS-IM(CH2)4SO3H][HSO4]
PPh3
30
65
120
60
140
120
91
95
78
74
90
81
EtOH
EtOH
Solvent-free
Solvent-free
EtOH
80
reflux
80
80
reflux
reflux
3
5
‒
5
4
‒
60
61
62
63
64
65
EtOH
* Present work
Table 5. Synthesis of coumarin-based 1,4-DHP 6c by NiFe2O4@SiO2@SO3H and other reported promoters
Entry
Catalyst
Time (min)
Yield (%)
Condition
Reusability Ref.
1
2
3
4
5
6
NiFe2O4@SiO2@SO3H
Fe3O4@SiO2
Guanidinium-sulfonic acid
Silica gel
Acidic alumina
Lactic acid
20
20
120
25
14
150
95
88
86
65
75
79
H2O (70 °C)
H2O (reflux)
H2O (reflux)
Microwave
Microwave
7
4
4
‒
‒
‒
*
69
70
71
71
72
ethyl-L-lactate (100 °C)
*Present work
3.4. Recycling of NiFe2O4@SiO2@SO3H MNPs
The green and economic aspect of this synthetic protocol was further studied by examining the possibility
of sulfonated Ni-nanocatalyst for reusing at the next runs of the condensation reaction. To do this, progress
of the model reaction (4-chlorobenzaldehyde, ethyl acetoacetate and ammonia) in the presence of NiFe2O4
@SiO2@SO3H MNPs was investigated. When the reaction was completed, the nanocatalyst was magne-
tically separated from the reaction mixture and then washed with EtOAc followed by drying at 80 °C. The
model reaction was again charged with the freshly components of the condensation reaction and the
recovered Ni-nanocatalyst. The summarized results in Figure 10 show that the sulfonated Ni-nanocatalyst
was reused for 7 consecutive cycles without the significant loss of catalytic activity.
98
97.5
97
96.5
96
95.5
95
94.5
94
93.5
1
2
3
4
5
6
7
Run
Figure 10. Reusability of NiFe2O4@SiO2@SO3H MNPs in the synthesis of 1,4-DHP 5c
4. Conclusions
In this study, the synthesis of sulfonic acid anchored on silica-layered nickel ferrite, NiFe2O4@SiO2@SO3H,
was investigated. The prepared nanocatalyst was then characterized using FT-IR, SEM, EDX, XRD and VSM
analyses. The sulfonated Ni-nanocatalyst showed the perfect catalytic activity towards Hantzsch synthesis
of 1,4-DHPs using ethyl acetoacetate/4-hydroxycoumarin, aromatic aldehydes and ammonia. All reactions

were carried out in H2O (at 70 °C) within 10‒100 min to afford the products in high to excellent yields. The
current protocol represents remarkable advantages in terms of easy preparation and the magnetic
property of the sulfonated Ni-nanocatalyst, high yield of the products, short reaction times, wide tolerance
of starting materials, benefits of using water as a green and economic solvent as well as the perfect
reusability of the magnetic nanocatalyst.
Acknowledgments
The authors gratefully acknowledged the financial support of this work by the research council of Urmia
University.
References
[1] M.B. Smith, March's advanced organic chemistry: reactions, mechanisms, and structure, 7th ed., Wiley,
New Jersey, 2013.
[2] H. Yamamoto, K. Ishihara, Acid Catalysis in Modern Organic Synthesis, Wiley-VCH, Wienheim, 2008.
[3] G. Busca, Chem. Rev. 107 (2007) 5366–5410.
[4] M. Rueping, D. Parmar, E. Sugiono, Asymmetric Brønsted Acid Catalysis, Wiley-VCH, Wienheim, 2016.
[5] A. Corma, H. Garcia, Adv. Synth. Catal. 348 (2006) 1391‒1412.
[6] A. Amoozadeh, S. Golian, S. Rahmani, RSC Adv. 5 (2015) 45904‒45982.
[0] E. Tabriziana, A. Amoozadeh, RSC Adv. 6 (2016) 96606‒96615.
[8] C.S. Gill, B.A. Price, C.W. Jones, J. Catal. 251 (2000) 145‒152.
[9] S.A. Dergunov, A.T. Khabiyev, S.N. Shmakov, M.D. Kim, N. Ehterami, M.C. Weiss, V.B. Birman, E.
Pinkhassik, ACS Nano 10 (2016) 11397–11406.
[10] P. Hodge, Ind. Eng. Chem. Res. 44 (2005) 8542–8553.
[11] Q. Sun, Z. Dai, X. Meng, F.S. Xiao, Chem. Soc. Rev. 44 (2015) 6018–6034.
[12] Z. Xie, Z. Liu, Y. Wang, Q. Yang, L. Xu, W. Ding, Int. J. Mol. Sci. 11 (2010) 2152–2187.
[13] P. Serp, J.L. Figueiredo, Carbon Materials for Catalysis, Wiley, New Jersey, 2009.
[14] S.L. Suib, New and Future Developments in Catalysis: Hybrid Materials, Composites, and
Organocatalysts, Elsevier B.V., Chapter 3, Pages 55–78, 2013.
[15] A. Schaetz, M. Zeltner, W.J. Stark, ACS Catal. 2 (2012) 1267–1284.
[16] F. Rodríguez-Reinoso, Carbon 36 (1998) 159–175.
[17] E. Pérez-Mayoral, V. Calvino-Casildaa, E. Soriano, Catal. Sci. Technol. 6 (2016) 1265–1291.
[18] J. Liang, Z. Liang, R. Zou, Y. Zhao, Adv. Mater. 29 (2017) 1701139.
[19] N. Linares, A.E. Sepúlveda, M.C. Pacheco, J.R. Berenguer, E. Lalinde, C. Nájerac, J. Garcia-Martinez, New
J. Chem. 35 (2011) 225–234.
[20] N. Pal, A. Bhaumik, RSC Adv. 5 (2015) 24363–24391.
[21] Y. Ren, B. Yue, M. Gu, H. He, Materials 3 (2010) 764–785.
[22] S. Chassaing, V. Beneteau, B. Louis, P. Pale, Curr. Org. Chem. 21 (2017) 779–793.
[23] Y.I. Isakov, K.M. Minachev, Russ. Chem. Rev. 51 (1982) 1188–1204.
[24] S. Chassaing, A. Alixa, A. Olmos, M. Keller, J. Sommer, P. Pale, Z. Naturforsch. 65b (2010) 783–790.
[25] L. Yang, Y. Xie, H. Zhao, X. Wu, Y. Wang, Solid-State Electron. 49 (2005) 1029–1033.
[26] M. Salavati-Niasari, F. Davar, T. Mahmoudi, Polyhedron 28 (2009) 1455–1458.
[27] A.M. Abu‐Dief, I.F. Nassar, W.H. Elsayed, Appl. Organomet. Chem. 30 (2016) 917–923.
[28] S. Payra, A. Saha, S. Banerjee, RSC Adv. 6 (2016) 52495–52499.
[29] S. Moradi, S. T. Fardood, A. Ramazani, J Mater. Sci. Mater. El. 29 (2018) 14151–14160.
[30] Y. Zhang, G. Rimal, J. Tang, Q. Dai, Mater. Res. Express 5 (2018) 025023.
[31] A.H. Lu, E.L. Salabas, F. Schüth, Angew. Chem. Int. Ed. 46 (2000) 1222‒1244.
[32] B. Dam, S. Nandi, A. Kumar Pal, Tetrahedron Lett. 55 (2014) 5236‒5240.
[33] L. Zhang, H.P. Shao, H. Zheng, T. Lin, Z.M. Guo, Int. J. Min. Met. Mater. 23 (2016) 1112–1118.
[34] F. Tajfirooz, A. Davoodnia, M. Pordel, M. Ebrahimi, A. Khojastehnezhad, Appl. Organomet. Chem.
32 (2018) e3930.
[35] F. Nemati, S. Sabaqian, J. Saudi Chem. Soc. 21 (2010) S383‒S393.
[36] M. Beyki, M. Fallah-Mehrjardi, Iran. Chem. Commun. 5 (2010) 364‒493.

[37] K. Rajkumari, J. Kalita, D. Das, L. Rokhum, RSC Adv. 7 (2017) 56559–56565.
[38] J. Li, H. Zhao, X. Hou, W. Fa, J. Cai, Micro Nano Lett. 12 (2017) 53–57.
[39] F. Alemi-Tameh, J. Safaei-Ghomi, M. Mahmoudi-Hashemi, R. Teymuri, Res. Chem. Intermed. 42 (2016)
6391–6406.
[40] M.M. Dutta, K.K. Rajbongshi, P. Phukan, Synth. Commun. 47 (2017) 2330–2341.
[41] N.G. Salunkhe, C.A. Ladole, N.V. Thakare, A.S. Aswar, Res. Chem. Intermed. 44 (2018) 355–372.
[42] S. Swami, A. Agarwala, R. Shrivastava, New J. Chem. 40 (2016) 9788–9794.
[43] V.K. Sharma, S.K. Singh, RSC Adv. 7 (2017) 2682–2732.
[44] M. George, L. Joseph, C. Joseph, Pharma Innov. 6 (2017) 165–170.
[45] G.W. Zamponi, Nat. Rev. Drug Discov. 15 (2016) 19–34.
[46] P.A. Datar, P.B. Auti, J. Saudi Chem. Soc. 20 (2016) 510–516.
[47] S.A. Khedkar, P.B. Auti, Mini-Rev. Med. Chem. 14 (2014) 282–290.
[48] R.S. Kumar, A. Idhayadulla, A.J.A. Nasser, J. Selvin, J. Serb. Chem. Soc. 76 (2011) 1–11.
[49] R.S. Kumar, A. Idhayadulla, A.J.A. Nasser, K. Murali, Indian J. Chem. 50B (2011) 1140–1144.
[50] G. Swarnalatha, G. Prasanthi, N. Sirisha, C. Madhusudhana Chetty, Int. J. ChemTech Res. 3 (2011) 75–
89.
[51] C. Bladen, V.M. Gadotti, M.G. Gündüz, N.D. Berger, R. Şimşek, C. Şafak, G.W. Zamponi, Pflug. Arch.
Eur. J. Phy. 467 (2014) 1237–1247.
[52] N. Edraki, A.R. Mehdipour, M. Khoshneviszadeh, R. Miri, Drug Discov. Today 14 (2009) 1058–1066.
[53] D.J. Triggle, Curr. Pharm. Des. 12 (2006) 443–457.
[54] R. Peri, S. Padmanabhan, A. Rutledge, S. Singh, D.J. Triggle, J. Med. Chem. 43 (2000) 2906–2914.
[55] M.G. Dekamin, S. Ilkhanizadeh, Z. Latifidoost, H. Daemi, Z. Karimi, M. Barikani, RSC Adv. 4 (2014)
56658‒56664.
[56] S.D. Sharma, P. Hazarika, D. Konwar, Catal. Commun. 9 (2008) 009‒014.
[57] C.A. Antonyraj, S. Kannan, Appl. Catal. A: Gen. 338 (2008) 121‒129.
[58] H. Mirzaei, A. Davoodnia, Chin. J. Catal. 33 (2012) 1502‒1500.
[59] M. Tajbakhsh, E. Alaee, H. Alinezhad, M. Khanian, F. Jahani, S. Khaksar, P. Rezaee, M. Tajbakhsh, Chin.
J. Catal. 33 (2012) 1510‒1522.
[60] G. Song, B. Wang, X. Wu, Y. Kang, L. Yang, Synth. Commun. 35 (2005) 2805‒2880.
[61] M.G. Dekamin, E. Kazemi, Z. Karimi, M. Mohammadalipoor, M.R. Naimi-Jamal, Int. J. Biol. Macromol.
93 (2016) 060‒004.
[62] Y.L.N. Murthy, A. Rajack, M.T. Ramji, J.J. Babu, C. Praveen, K.A. Lakshmi, Bioorg. Med. Chem. Lett. 22
(2012) 6016‒6023.
[63] O. D'alessandro, Á.G. Sathicq, J.E. Sambeth, H.J. Thomas, G.P. Romanelli, Catal. Commun. 60 (2015)
65‒69.
[64] B. Jahanbin, A. Davoodnia, H. Behmadi, N. Tavakoli-Hoseini, Bull. Korean Chem. Soc. 33 (2012) 2140‒
2144.
[65] A. Debache, W. Ghalem, R. Boulcina, A. Belfaitah, S. Rhouati, B. Carboni, Tetrahedron Lett. 50 (2009)
5248‒5250.
[66] M. Nasr-Esfahani, S.J. Hoseini, M. Montazerozohori, R. Mehrabi, H. Nasrabadi, J. Mol. Catal. A: Chem.
382 (2014) 99‒105.
[67] A. Heydari, S. Khaksar, M. Tajbakhsh, H.R. Bijanzadeh, J. Fluorine Chem. 130 (2009) 609‒614.
[68] H. Salehi, Q. X. Guo, Synth. Commun. 34 (2004) 4349‒4350.
[69] B. Dam, S. Nandi, A. Kumar Pal, Tetrahedron Lett. 55 (2014) 5236–5240.
[70] A. Shaabani, S. Shaabani, M. Seyyedhamzeh, M. H. Sangachin, and F. Hajishaabanha, Res. Chem.
Intermed. 42 (2016) 7247–7256.
[71] M. Kidwai, S. Rastogi, R. Mohan, Bull. Korean Chem. Soc. 25 (2004) 119–121.
[72] S. Paul, A. R. Das, Tetrahedron Lett. 53 (2012) 2206–2210.
[73] M. Gilanizadeh, B. Zeynizadeh, J. Iran. Chem. Soc. 15 (2018) 2821‒2830.
[74] S. Rostamnia, B. Zeynizadeh, E. Doustkhah, A. Baghban, K.O. Aghbash, Catal. Commun. 68 (2015) 00‒
83.

[75] B. Zeynizadeh, S. Rahmani, RSC Adv. 9 (2019) 8002–8015.
[76] B. Zeynizadeh, I. Mohammadzadeh, Z. Shokri, S.A. Hosseini, J. Colloid Interface Sci. 500 (2010) 285‒
293.
[77] S. Sagadevan, Z.Z. Chowdhury, R.F. Rafique, Mater. Res. 21 (2018) e20160533.
[78] M. De, A. Mukherjee, H.S. Tewari, Process. Appl. Ceram. 9 (2015) 193–197.
[79] P. Sivakumar, R. Ramesh, A. Ramanand, S. Ponnusamy, C. Muthamizhchelvan, Mater. Res. Bull. 46
(2011) 2208–2211.
[80] K. Maaz, S. Karim, A. Mumtaz, S.K. Hasanain, J. Liu, J.L. Duan, J. Magn. Magn. Mater. 321 (2009) 1838‒
1842.
[81] A. Phukan, J.N. Ganguli, D.K. Dutta, J. Mol. Catal. A: Chem. 202 (2003) 209‒280.

Anchored sulfonic acid on silica-layered NiFe2O4: a magnetic solid acid nanocatalyst for
Hantzsch synthesis of 1,4-dihydropyridines
Behzad Zeynizadeh*, Soleiman Rahmani and Elham Eghbali
In this study, the immobilization of sulfonic acid on silica-layered nickel ferrite, NiFe2O4@SiO2@SO3H,
was investigated. The prepared sulfonated Ni-nanocatalyst exhibited the perfect catalytic activity
towards Hantzsch synthesis of 1,4-dihydropyridines via the one-pot condensation reaction of ethyl
acetoacetate/4-hydroxycoumarin, aromatic aldehydes and ammonia in H2O within 10‒100 min.