Effective fabrication of poly(anilin-formaldehyde)-supported hybrid nanomaterial and catalytic synthesis of dihydropyridines

Document Type : Research Paper


1 Department of Chemistry, Faculty of Science, Arak University, Iran

2 Institute of Nanosciences and Nanotechnology, Arak University, Arak, Iran


In this study, Fe3O4@SiO2-PAF-SO3H nanocomposite was successfully fabricated by immobilization of sulfonic acid groups on the surface of poly(anilin-formaldehyde)-supported on magnetic Fe3O4@SiO2 nanoparticles through layer-by-layer assembly. Fe3O4@SiO2-PAF-SO3H composite nanostructure has been fully characterized using various techniques including the Fourier-transform infrared spectroscopy (FT-IR), X-ray powder diffraction patterns (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and vibrating sample magnetometry (VSM). The one-pot synthesis of mono and bis 1,4-dihydropyridine derivatives, as pharmaceutically interesting compounds, have been achieved in high yields via three-component and pseudo five component condensation of an aromatic aldehyde, ammonium acetate and ethyl acetoacetate in the presence of Fe3O4@SiO2-PAF-SO3H as a novel retrievable hybrid nanocatalyst under solvent-free conditions. This protocol has advantages in terms of short reaction time, solvent-free condition, high yield and purity, easy work-up and eco-friendly process as well as recyclability of the nanocatalyst (at least 6 times) with no decrease in catalytic activity.



Magnetic nanoparticles (MNPs) attract great attention of worldwide scientist and researchers because of their ripsnorting distinguished properties such as high surface area, low cost, low toxicity, high stability, simple separation, easy synthesis and functionalization [1-3]. Due to the unique and valuable properties of MNPs, several applications and potential activities have been reported for MNPs in the field of electronic, biology, pharmacology, drug delivery and catalysis area [3-5]. The heterogenization of homogeneous acidic and basic groups in catalytic reactions (such as covalently bound acidic or basic catalysts) allows for the facile separation and reuse of catalysts. The inorganic-supported catalysts especially hybrid magnetic nanomaterials, inorganic-polymer hybrid nanocomposites have been widely used in recent years that could be applied in diverse applications such as drug delivery system, catalysis and biological diagnostics [3, 6-8].

In multicomponent reactions (MCRs), several available compounds (three or more starting materials) react simultaneously in one container to result a desired product. MCRs produce complex and diverse combinations of products and follow many principles of green chemistry, such as solvent-free or aqueous condition, atom economy, energy saving with short reaction times, waste diminish, high yields and selectivity [9-12]. The ١,٤-dihydropyridine derivatives are known as an important group of heterocyclic compounds having a special place in organic chemistry due to their extensive pharmaceutical activities [١٣,١٤]. These compounds have many therapeutic treatments as sedative, anti-hypertensive [١٥,١٦], anticonvulsant [١٧], calcium channel blockers [١٨-٢١] and anti-clot treatment [٢٢,٢٣]. Many reported synthetic methods for ١,٤-dihydropyridine suffer from limitations such as low efficiency, long reaction time, the use of toxic solvents, the use of expensive catalysts, difficult reaction conditions and boring purification procedures. To overcome some of these obstacles, we have synthesized a novel magnetic hybrid nanocatalyst, namely Fe3O4@SiO2-PAF-SO3H, and investigated its role as an efficient catalyst for synthesize of 1,4-dihydropyridine derivatives via the one-pot three-component and pseudo five component condensation of an aromatic aldehyde, ammonium acetate and ethyl acetate under solvent-free condition (Scheme 1).


Materials and methods

The chemicals were purchased from reputable chemical companies (Merck, Aldrich, and Fluka) or were synthesized and purified in the laboratory. The FT-IR spectra were recorded using a Galaxy-series FT-IR 5030 spectrophotometer in the region 4000–400 cm-1 using pressed KBr Discs. The 1H and 13C-NMR spectra were recorded on a Brucker Avance spectrometer operating at 300 MHz for 1H and 75 MHz for 13C-NMR in DMSO-d6 with TMS as an internal standard. Powder X-ray diffraction (XRD) was carried out using a Philips XPert (Cu-Kα radiation,  = 0.15405 nm) over the range 2q = 20–80using ٠.٠٤o as the step length. Thermal gravimetric analysis (TGA) and differential thermal gravimetric (DTG) data for Fe٣O٤@SiO٢-PAF-SO٣H MNPs were recorded on a Mettler TA٤٠٠٠ System under an atmosphere of N٢ at a heating rate of ١٠ °C min. The magnetization and hysteresis loop were measured at room temperature using a Vibrating Sample Magnetometer (Model ٧٣٠٠ VSM system, Lake Shore Cryotronic, Inc., Westerville, OH, USA). The scanning electron microscope measurement was carried out using a Hitachi S-٤٧٠٠ field emission-scanning electron microscope (FE-SEM). The transmission electron microscopy (TEM) measurements were performed on a Philips CM10 analyzer operating at 150 kV.

Synthesis of Fe3O4@SiO2-PAF-SO3H hybrid nano-material

Fe3O4 nanoparticles were prepared by chemical co-precipitation method described in the literature [24]. The synthesized Fe3O4 MNPs were used for coating with a silica shell according to the Stober method [25]. Aminopropyl-modified silica-coated MNPs were prepared according to a reported procedure [26] .In a typical procedure, 1.0 g of Fe3O4@SiO2 MNPs was dispersed in 40 mL of dry toluene using an ultrasonic bath for 30 minutes to produce a uniform suspension. Then, 0.6 mL of 3-aminopropyltriethoxysilane (APTES) was added using a syringe. The reaction mixture was refluxed under N2 atmosphere at 110 °C for 12 h. Finally, the aminopropyl-functionalized solid (Fe3O4@SiO2–PrNH2 MNPs) was washed with toluene for several times, separated using a magnet, and dried under vacuum. To synthesize Fe3O4@SiO2-PAF-NH2, a mixture of 1 g of formaldehyde, 0.5 g of aniline and 1 g of Fe3O4@SiO2–PrNH2 in 50 mL of DMF at 100 ml round-bottomed flask was stirred under sonication. Then, the mixture was stirred with a magnetic stirrer for 24 h at 100 °C. After the reaction was completed, the precipitate was washed several times with hot ethanol and dried in an oven. In the last step, 1 g of Fe3O4@SiO2-PAF-NH2 in 40 mL dichloromethane was stirred for 10 minutes, then by placing the reaction mixture under aqueous vacuum 1 g of chlorosulfonic acid was added slowly and the reaction mixture was stirred at room temperature for 2 h. The resulting precipitate was washed with ethanol and dried in the vacuum oven to result in the final hybrid acidic nanomaterial (Fe3O4@SiO2-PAF-SO3H).

General procedure for the synthesis of 1,4-dihydropyridines

A mixture of an aromatic aldehyde (1 mmol), ammonium acetate (3 mmol, 60 mg) (in an excess amount), ethyl acetoacetate (2 mmol, 0.254 ml), and Fe3O4@SiO2-PAF-SO3H (0.02 g) was magnetically stirred under the thermal solvent-free condition on a preheated oil bath at 50 °C for an appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, the resulting solidified mixture was diluted with hot ethanol (10 mL) and the catalyst was easily separated by an external magnet and reused for the subsequent runs. Water was added to the remaining clear solution, after which the precipitate was appeared and separated. The pure, crystalline 1,4-dihydropyridine was achieved by crystallization in a mixture of ethanol : water (1:1).

Selected spectroscopic data

4a: IR (KBr) (nmax, cm‐1): 3344, 3063, 2982, 1689, 1653, 1489, 1375, 1213, 1091. 1H NMR (DMSO-d 6, 300 MHz) dH: 1.47 (6H, t, CH(OCH2CH3), J= 5.4 Hz), 2.27 (6H, s, CH3), 4.02 (4H, q, CH(OCH2CH3J=5.4 Hz), 4.92 (1H, s, CH), 5.48 (1H, s, NH), 7.01-7.24 (4H, m, Harom).

4b: IR (KBr) (nmax, cm‐1): 3358, 2989, 1697, 1653, 1487, 1371, 1215, 1093. 1H NMR (DMSO-d 6, 300 MHz) dH: 1.13 (6H, t, CH(OCH2CH3), J= 5.4 Hz), 2.20 (6H, s, CH3), 4.02 (4H, q, CH(OCH2CH3J=5.4 Hz), 4.92 (1H, s, CH), 6.30 (1H, s, NH), 7.05-7.16(4H, m, Harom).

4c: IR (KBr) (nmax, cm‐1): 3352, 3090, 2980, 1653, 1595, 1477, 1373, 1217, 1081. 1H NMR (DMSO-d 6, 300 MHz) dH: 1.15 (6H, t, CH(OCH2CH3), J= 5.1 Hz), 2.21 (6H, s, CH3), 4.01 (4H, q, CH(OCH2CH3J=5.1 Hz), 4.89 (1H, s, CH), 6.23 (1H, br, NH), 7.04-7.15 (4H, m, Harom).

4e: IR (KBr) (nmax, cm‐1): 3348, 3094, 2984, 1693, 1566, 1500, 1373, 1213, 1099. 1H NMR (DMSO-d 6, 400 MHz) dH: 1.15 (6H, t, CH(OCH2CH3), J= 5.1 Hz), 2.23 (6H, s, CH3), 3.95 (4H, q, CH(OCH2CH3J=5.1 Hz), 4.86 (1H, s, CH), 6.58-7.05 (4H, m, Harom), 7.99(1H, s, OH and NH).

4g: IR (KBr) (nmax, cm‐1): 3346, 2991, 1647, 1527, 1487, 1348, 1213, 1118. 1H NMR (DMSO-d 6, 400 MHz) dH: 1.24 (6H, t, CH(OCH2CH3), J= 5.1 Hz), 2.37 (6H, s, CH3), 4.08 (4H, q, CH(OCH2CH3J=5.4Hz), 5.10 (1H, s, CH), 5.63 (1H, s, NH), 7.44- 8.09 (4H, m, Harom).

4j: IR (KBr) (nmax, cm‐1): 3340, 3095, 2984, 2837, 1689, 1614, 1491, 1373, 1303, 1028. 1H NMR (DMSO-d 6, 300 MHz) dH: 1.23 (6H, t, CH(OCH2CH3), J= 5.1 Hz), 2.33 (6H, s, CH3), 3.76 (3H, s, OCH3), 4.10 (4H, q, CH(OCH2CH3J=5.1 Hz), 4.93 (1H, s,CH), 5.54 (1H, s, NH), 6.74-7.22 (4H, m, Harom).

4l: IR (KBr) (nmax, cm‐1): 3354, 2976, 2841, 1693, 1604, 1570, 1504, 1371, 1275, 1207, 1124. 1H NMR (DMSO-d 6, 300 MHz) dH: 1.19 (6H, t, CH(OCH2CH3), J= 5.4 Hz), 2.31 (6H, s, CH3), 3.82 (3H, s, OCH3), 4.06 (4H, q, CH(OCH2CH3J=5.4 Hz), 4.97 (1H, s, CH), 6.28 (1H, s, NH and OH), 6.43-6.91 (4H, m, Harom).

4n: IR (KBr) (nmax, cm‐1): 3364, 3092, 2986, 2841, 1682, 1620, 1491, 1371, 1305, 1222, 1030. 1H NMR (DMSO-d 6, 300 MHz) dH: 1.11 (12H, t, CH(OCH2CH3), J= 5.1 Hz), 2.23 (12H, s, CH3), 3.95 (8H, q, CH(OCH2CH3J=5.1 Hz), 4.76 (2H, s, CH), 6.95 (4H, s, Harom), 8.75 (2H, s, NH).

4o: IR (KBr) (nmax, cm‐1): 3340, 3163, 2984, 1691, 1491, 1371, 1303, 1211, 1114. 1H NMR (DMSO-d 6, 300 MHz) dH: 1.09 (12H, t, CH(OCH2CH3), J= 5.4 Hz), 2.23 (12H, s, CH3), 3.95 (8H, q, CH(OCH2CH3J=5.4 Hz), 4.79 (2H, s, CH), 6.85- 6.99 (4H, m, Harom), 8.75 (2H, s, NH).


Characterization of novel Fe3O4@SiO2-PAF-SO3H catalyst

The Fe3O4@SiO2-PAF-SO3H catalyst was prepared as shown in Scheme 2. Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA) and vibrating sample magnetometry (VSM) were used to identify and characterize the prepared catalyst.

The FT-IR spectra of Fe3O4, Fe3O4@SiO2, Fe3O4@SiO2-NH2, Fe3O4@SiO2-PAF-NH2 and Fe3O4@SiO2-PAF-SO3H are shown in Fig. 1. The FT-IR spectrum of magnetic Fe3O4 MNPs shows the characteristic Fe–O absorption band around 580 cm-1 (Fig. 1a). Fe3O4@SiO2 shows characteristic FT-IR bands at around 1100 cm-1 , 950 cm-1, 820 cm-1 and 460 cm-1 which are attributed to the asymmetric stretching, symmetric stretching, in plane bending and rocking mode of the Si–O–Si group, respectively, that confirm the formation of SiO2 shell. The broad peak observed in the range of 3200 - 3500 cm-1 was related to the stretching vibration mode of Si-OH and H-O-H. The weak peak located in 1630 cm-1 was due to the O–H stretching vibration mode of Si–OH. The weak bands at 2920 cm-1 and 2960 cm-1 were related to the C-H symmetric and asymmetric stretching modes of the attached alkyl groups (Fig 1c-e). Thus, the obtained results indicate that the functional groups were successfully grafted onto the surface of the magnetic nanoparticles.

The XRD analysis result confirmed the presence as well as the degree of crystallinity of magnetic Fe3O4 and the Fe3O4@SiO2-PAF-SO3H catalyst (Fig. 2). The same peaks were observed in both of the Fe3O4 and Fe3O4@SiO2-PAF-SO3H patterns, demonstrating retention of the crystalline spinel ferrite core structure during the coating process. The XRD patterns of the synthesized MNPs exhibit diffraction peaks at 2θ = 30°, 35.7°, 43.3°, 53.9°, 57°, 63.5° and 74.5° which can be referred to the (220), (311), (400), (422), (511), (440) and (533) planes of Fe3O4, respectively. These results indicate that the Fe3O4 particles in the nanoparticles are pure Fe3O4 with a cubic spinel structure and matched well with the standard Fe3O4 sample (JCPDS card no. 85-1436). The broad peak from 2θ = 22° to 28° is consistent with an amorphous silica phase of Fe3O4@SiO2-PAF-SO3H (Fig. 4b). The average crystallite size of MNPs by Scherrer’s formula (D=0.9λ/β cos θ) was estimated from the (311) XRD peak. The crystallite size of MNPs calculated from the width of the peak at 2θ = 35.7° (311) is 57 nm, which is in the range determined using FE-SEM analysis (Fig. 4).

The stability of the Fe3O4@SiO2-PAF-SO3H nanocomposite was determined by thermogravimetric analysis (TGA) (Fig. 6). The magnetic catalyst shows two weight loss steps over the temperature range of TGA. (Fig. 3). The first stage, including a low amount of weight loss at T < 300 °C, was due to the removal of physically adsorbed solvent, water and surface hydroxyl groups. The second step at about 300 °C to nearly 600 °C is attributed to the decomposition of the organic layer in the nanocomposite. Therefore, the weight loss between 300 and 600 °C gives the organic moiety ratios grafted on the prepared nanomaterial. The organic moiety grafted on the Fe3O4@SiO2-PAF-SO3H was approximately 10 wt.%.

FE-SEM was used to investigate the size and morphology of the Fe3O4@SiO2-PAF-SO3H particles (Fig. 4). As can be seen from Fig. 2(a), Fe3O4@SiO2-PAF-SO3H nanoparticles have a mean diameter of about 51 nm and a nearly spherical shape. The EDS analysis obviously shows the presence of N and C in the Fe3O4@SiO2-PAF-SO3H nanoparticles (Fig. 5). Furthermore, the presence of Si, O and Fe signals indicates that the iron oxide particles were loaded into silica, and the higher intensity of the Si peak compared to the Fe peak exhibits that the Fe3O4 nanoparticles have been trapped by the SiO2 layer. So, based on the results, the Fe3O4@SiO2-PAF-SO3H nanocomposite has been fabricated successfully.

The magnetic properties of the nanoparticles was distinguished using a vibrating sample magnetometer (VSM). Fig. 6 shows the plots of room temperature magnetization (M) versus magnetic field (H) (M–H curves or hysteresis loops) of Fe3O4 and Fe3O4@SiO2-PAF-SO3H nanoparticles. The hysteresis curve allows determination of the saturation magnetization (Ms), remanent magnetization (Mr) and coercivity (Hc). The magnetization of samples could be completely saturated at high fields up to ±8000.0 Oe and, due to the formation of a silica shell around the Fe3O4 core, the Ms of samples changes from 57.8 to 33.4 emu g-1 The hysteresis loops exhibit the super-paramagnetic behavior of the Fe3O4 and Fe3O4@SiO2-PAF-SO3H particles in which the Mr and Hc are close to zero (Mr = 0.85 and 0.45 emu per g, and Hc = 4.90 and 4.0 Oe, respectively) [27].

Synthesis of 1,4-dihydropyridines catalyzed by Fe3O4@SiO2-PAF-SO3H

The 4-chlorobenzaldehyde, ammonium acetate and ethyl acetoacetate were selected as model substrates and the reaction was carried out in various conditions to obtain the optimized condition. The different solvents as well as solvent-free medium, temperatures and catalyst amounts were examined on model reaction and the results are shown in Table 1. Under the solvent free condition, and use of 20 mg of Fe3O4@SiO2-PAF-SO3H as a catalyst at 50 °C, serves as the best condition with respect to the green nature and clean workup procedure for this synthesis (Table 1, entry 10). To define the role of Fe3O4@SiO2-PAF-SO3H as a catalyst for the preparation of 1,4-dihydropyridines, the model reaction was performed under the same conditions with Fe3O4, Fe3O4@SiO2, Fe3O4@SiO2-PAF-NH2, Fe3O4@SiO2-PAF-SO3H and without any catalyst. With respect to the reaction time and yield of product, the best results are achieved using Fe3O4@SiO2-PAF-SO3H as the catalyst (Table 1, entry 10, 14-17). In order to determine the generality and efficacy of the catalyst, various aldehydes carrying either electron-donating or electron-withdrawing groups were reacted under the optimized reaction condition. It was found that the reactions for all of the various substrates proceed efficiently to produce corresponding 1,4 dihydropyridine in good to excellent yields without formation of side products (Table 2). A possible mechanism for the construction of 1,4-dihydropyridine is shown in Scheme 3. Fe3O4@SiO2-PAF-SO3H as an acidic catalyst activates the carbonyl group and facilitates the condensation reactions. Firstly, Knoevenagel condensation of aldehyde and β-ketoester takes place to form intermediate I. Then, intermediate II is produced by the condensation of the second equivalent of β-ketoester. Finally, condensation of these two fragments results in intermediate III, which subsequently is cyclized (intramolecular) to the target product in the presence of the catalyst and with elimination of H2O molecule (Scheme 3).

Catalyst recovery and reuse

The recovery and reusability of the catalyst are very important for commercial and industrial applications as well as green process aspects. Thus, the recovery and reusability of Fe3O4@SiO2-PAF-SO3H was investigated in the model reaction. After completion of the reaction, the resulting solidified mixture was diluted with hot EtOH (15 mL). Then, the catalyst was easily separated, washed with hot EtOH, dried under vacuum and reused in a subsequent reaction. Nearly, quantitative recovery of catalyst (up to 97%) could be obtained from each run. As seen in Fig. 7, the recycled catalyst could be reused six times without any additional treatment or appreciable reduction in catalytic activity. The consistent structure and activity of recovered and reused Fe3O4@SiO2-PAF-SO3H catalyst confirms its stability, recyclability and performance for the synthesis of desired heterocycles.


In summary, a layer of poly aniline-formaldehyde was fabricated on magnetic nanoparticles surfaces and functionalized by sulfonic acid groups successfully. The novel magnetic inorganic-polymer hybrid nanostructure (Fe3O4@SiO2-PAF-SO3H) was characterized and successfully applied as an acidic retrievable nanocatalyst for preparation of mono and bis 1,4-dihydropyridine derivatives in high yields via three-component and pseudo-five-component condensation reaction. This protocol has advantages in terms of short reaction time, solvent-free condition, high yield and purity, easy work-up and eco-friendly process as well as the recyclability of the nanocatalyst with no notable diminish in catalytic performance.


We gratefully acknowledge financial support from the Research Council of Arak University.


The authors declare that they have no conflict of interest.


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