Introducing a new magnetic nanocomposite based on the chitosan modified by sulfonic acid-containing moieties for synthesis of 1,4-dihydropyridines and polyhydroquinolines

Due to environmental concerns, the development of bio-inspired nanocatalysts is growing increasingly. Hence, in this study an acidic magnetic nanocomposite was prepared through a simple and efficient method. In this regard, chitosan (CS) was anchored by 4-amino-3-hydroxy-naphthalen-1-sulfonic acid (SA) and then magnetized by Fe3O4. Successful synthesis of magnetic CS–SA nanocomposites was confirmed with the help of FTIR, XRD, FESEM, EDX, VSM, TGA and BET techniques. The as-synthesized magnetic CS–SA nanocomposites exhibited a very good activity for the multicomponent synthesis of 1,4-dihydropyridine and polyhydroquinoline compounds in the ethanol at 50 °C. The synergistic effect of –SO3H groups and Fe3O4 nanoparticles justified the remarkable activity of magnetic CS–SA nanocomposites. The catalyst was reusable 5 times and remained stable based on the hot filtration test. Some of the salient features of this method are easy catalyst separation, short reaction times, high to excellent efficiencies, safe and green solvent.


Introduction
The widespread application of mineral acids such as H 2 SO 4 , HNO 3 , HCl, and HF poses many environmental problems because they are corrosive and require further purification.In this regard, the development of supported solid acid catalysts has increased significantly by using various organic and inorganic supports [1][2][3][4].Solid acids offer many advantages over homogeneous acids in industry and the laboratory.
Although most solid acid catalysts are based on silica and zeolite, the use of more environmentally friendly support materials is in high demand.
Polysaccharides are being considered by academic communities because of their biodegradability, low manufacturing and disposal costs, low toxicity and renewability.Researchers are also focusing today on modifying magnetic nanoparticles with polysaccharides.One of them, chitosan (CS), is a natural polysaccharide obtained from the alkaline distillation of chitin (Scheme 1) [5].Nowadays, the application of Fe 3 O 4 nanoparticles in catalysts has attracted much attention.Iron nanoparticles not only have unique properties such as high reactivity, high dispersion and easy separation from the reaction medium due to their magnetic properties and particle size, but also possess the properties of homogeneous and heterogeneous nanocatalysts [6].
Multicomponent reactions (MCRs) are one of the most powerful tools for the synthesis of heterocyclic compounds.Less chemical waste, time saving, higher efficiency, saving of pots /atoms, and easy isolation and purification of the product are some of the unique features of MCRs that have attracted the attention of chemists to these reactions [7][8][9].

Scheme 1 Chemical structure of chitosan
Introducing a new magnetic nanocomposite based on the chitosan… that are still challenging.Another important class of heterocyclic compounds is the polyhydroquinolines, which include a wide range of important biomedical compounds.To date, several biological properties have been reported for polyhydroquinoline derivatives.These compounds display anti-tumour [22,23], antihypertensive [24], anti-atherosclerosis, anti-diabetes [25,26], and vasodilation activities [27].
Based on the above facts and in line with green chemistry, we present sulfonic acid-modified magnetic chitosan (Magnetic-CS-SA) as a new, renewable and biocompatible nanocomposite for the preparation of 1,4-dihydropyridine and polyhydroquinoline compounds.

Materials and methods
All the chemicals, solvents, and reagents were obtained from Aldrich and Merck and used without any purification.Shimadzu IRPrestige-21 spectrophotometer was applied for recording FT-IR spectra based on KBr pellets.Melting points of products were recorded with Barnstead Electrothermal IA9200 apparatus and mentioned without rectification.The Bruker DRX-301 Avance spectrometer ( 1 H NMR: 301 MHz and 13 C NMR 76 MHz) was used to record the 1 H and 13  C NMR in DMSO-d 6 or CDCl 3 as a solvent.The PANalytical X'Pert Pro diffractometer with Cu radiation source (λ = 1.54050Å) was applied to analyse the crystalline structure of the nanocomposite.The magnetic properties of magnetic-CS-SA nanocomposite were evaluated at room temperature by VSM, BHV-55, Riken, Japan.The structure and morphology of the magnetic-CS-SA were investigated by FESEM, MIRA III, TESCAN, Czech Republic, which is equipped with an energy dispersive X-ray analysis (EDX) to detect chemical elements in the structure of the nanocatalyst.The thermal stability of the nanocomposite was evaluated using SDT Q600 V20.9 Build 20 apparatus in the air atmosphere at 25-800 °C.Brunauer-Emmet-Teller (BET) analysis is performed by Micromeritics TriStar II plus.

Modification of chitosan using 1-3-di bromopropane (CS-Pr-Br)
Ethanol (15 mL) was added to CS (1 g) and exposed to ultrasonic for 30 min. 1, 3-Di bromopropane (5 mmol, 0.5 mL) was added to it and then stirred vigorously at room temperature for 24 h.The catalyst was then removed and washed thoroughly with ethanol.Finally, it was dried in an oven at 50 °C for drying.
Preparation of 4-amino-3-hydroxy-naphthalen-1-sulfonic acid-chitosan (CS-SA) CS-Br (1 g) was added to dry ethanol (20 mL) and subjected to ultrasonic for 30 min.Next, SA (4 mmol, 0.95 g) was added slowly and the resulting mixture was refluxed at 80 °C for 24 h.The synthesized CS-SA was then removed by filtration, washed several times with ethanol and dried at 50 °C for 4 h.

Preparation of Fe3O4 nanoparticles
FeCl 3 •6H 2 O (6 g) and FeCl 2 •4H 2 O (2 g) were mixed in deionized water (120 mL) and stirred until the salts were completely dissolved.Then, NH 4 OH 25% (24 mL) was slowly added to the stirred solution until the pH reached 11.The solution was then stirred at 80 °C for 1 h.The black magnetic Fe 3 O 4 precipitates were separated using a magnet, dried after washing with ethanol and water at ambient temperature.

Synthesis of magnetic CS-SA nanocomposites
First, a mixture of CS-SA (1 g) in ethanol (10 mL) was ultrasonically treated for 15 min.Then, 0.5 g of Fe 3 O 4 •NPs (0.5 g) were added to the above mixture and sonicated again for 0.5 h.Next, the mixture was stirred at room temperature for 24 h.The resulting nanoparticles were then isolated by a magnet and dried at 60 °C to obtain magnetic-CS-SA nanoparticles.
Introducing a new magnetic nanocomposite based on the chitosan…

Determination of acid capacity
The acidity of magnetic CS-SA nanocomposites can be evaluated by an acid-base method [18].Typically, 0.2 g of CS-SA magnetic nanocomposites was dispersed in 20 mL of 1.0 M NaCl solution (1.0 M, 20 mL) and stirred at room temperature for 18 h.The CS-SA magnetic nanocomposites were magnetically removed.Then, the remaining solution was titrated with 0.017 M NaOH standard solution (0.017 M) in the presence of phenolphthalein.The amount of conjugate acid (H 3 O + ) was calculated by Eq. ( 1), where D: acid exchange capacity (mmol/g), C: concentration of NaOH solution, V 1 and V 0 : volume of consumed NaOH, and m catalyst : the mass of catalyst.The amount of conjugate H 3 O + was found to be 0.97 mmol/g.

Catalyst identification
The synthesis steps of magnetic CS-SA nanocomposite are illustrated in Scheme 2. After the synthesis of the magnetic-CS-SA nanocomposites, FT-IR, (1) Scheme 2 Synthesis steps for the preparation of magnetic-CS-SA nanocomposite XRD, EDX, FESEM, TGA, VSM, etc. techniques were used to confirm its synthesis and structure.The FTIR technique was applied to show the main functional groups in the structure of the nanocomposite.FTIR spectra were taken from all nanocomposite synthesis steps (Fig. 2).
As FTIR spectrum of CS (Fig. 2a) shows, bands in 3414.4 cm −1 and 3474.3 cm −1 are related to N-H stretching, and O-H adsorption appears at 3550.5 cm −1 .The aliphatic C-H stretching vibration appeared at 2927.1 cm −1 .The bending frequencies of N-H and O-H are appeared at 1521.1 cm −1 and 1616.9 cm −1 .The emerging frequencies at 1155.9 cm −1 and 1083.7 cm −1 belong to the C-N, C-O [28].The CS-Pr-Br (Fig. 2b) shows almost identical spectrum to CS with a slight shift of C-C vibration at 665.4 to 657.7 cm −1 due to appearance of C-Br adsorption band at 657.7 cm −1 [29].As can be seen from the IR spectrum of CS-SA (Fig. 2c), three new peaks are visible in the spectrum, the first at 755.9 cm −1 (belonging to the S-O tensile frequency) [30], the second at 1617.6 cm −1 belonging to the C=C aromatic and the third adsorption at 1388.2 cm −1 relating to the S=O stretching frequency.The adsorption peaks of stretching amino groups and their bending adsorption peaks were appeared in the range of 3300-3500 cm −1 and 1526 cm −1 , respectively.In the IR spectrum of magnetic-CS-SA nanocomposite, Fe-O at 612.1 cm −1 is emerged (Fig. 2d).The IR spectrum was taken again from the catalyst after the fifth thigh, based on the spectrum; the structure of the nanocatalyst is preserved.
The crystalline structure of CS (a) Fe 3 O 4 (b) and magnetic-CS-SA nanocomposites (c) was investigated using XRD analysis (Fig. 3).In the XRD pattern of CS, only one peak is seen in 2θ = 20.21°,which is related to amorphous structure of chitosan.As it is obvious, the peaks appearing in the 2θ = 30.57°(220), 35 Introducing a new magnetic nanocomposite based on the chitosan… of CS in the structure [31,32].Also, the presence of chitosan did not change the crystalline phase of iron nanoparticles (Fig. 3).
FESEM analysis was also used to study the structure of nanocomposite.According to the FESEM images (Fig. 4a, b), nanoparticles have a spherical structure with a unique distribution.Energy dispersive X-ray analysis (EDS) was also used to confirm the presence of the main elements in the nanocomposite structure (Fig. 4c).According to the EDS pattern, iron (20.26%), carbon (44.20%), oxygen (32.35%), sulfur (1.71%), and nitrogen (1.69%) are present in the structure of magnetic-CS-SA nanocomposites.Another practical technique to confirm the synthesis of the nanocatalyst is elemental mapping.As Fig. 5 shows, all the key elements are well and evenly distributed in the nanocomposite texture.
The magnetic behavior of the (a) Fe 3 O 4 nanoparticles, (b) magnetic-CS-SA nanocomposites and (c) reused magnetic-CS-SA nanocomposites was evaluated by VSM technique (Fig. 6).These nanoparticles showed 52.85 emu g −1 , 38.57emu g −1 and 34.4 emu g −1 , respectively.According to the results, both samples showed superparamagnetic properties.The decrease in magnetic property of magnetic-CS-SA indicates the binding of iron nanoparticles to CS-SA and its successful synthesis.
Thermal stability evaluation of magnetic-CS-SA nanocomposites was evaluated using TGA analysis (Fig. 7).The weight loss observed before 200 °C is consistent with the evaporation of organic solvents and adsorbed water.The next weight losing happens in 200-400 °C, which is due to the separation and disintegration of organic groups such as 4-amino-3-hydroxy naphthalen-1-sulfonic acid and chitosan from the nanocomposite surface.Also, due to the presence of chitosan and organic groups, the nanocomposite is stable up to about 250 °C, which can be easily used in organic reactions and at high temperatures [33].Iron nanoparticles can be attached to chitosan through Fe +3 ions and also attached to chitosan through transverse bridging.The weight loss observed at 400 to 700 °C is probably related to the detachment of the chitosan connected by the bridge [27].
Textural properties of magnetic-CS-SA nanocomposites were studied by N 2 adsorption-desorption analysis.In addition, the surface area of the catalyst was calculated with the Brunauer-Emmet-Teller (BET) method.The N 2 adsorption-desorption isotherm of the catalyst (Fig. 8) can be categorized as type II, indicative of nonporous materials.BET surface area of the catalyst was 8.5 m 2 /g and total pore volume was found to be 0.03 cm 3 /g.

Catalytic studies
Catalytic performance of magnetic-CS-SA nanocomposites in the one-pot reaction between benzaldehyde (1 mmol), ammonium acetate (1 mmol) and ethyl acetoacetate (2 mmol) was evaluated as the selected reaction for the formation of 1,4-DHPs (Table 1).Also for the preparation of polyhydroquinolines, we used 1 mmol of  2).First, both of these model reactions were carefully investigated with different solvents like water, ethanol, solvent-free conditions, tetrahydrofuran, methanol, and toluene.The results show that the highest yield was obtained when ethanol solvent was used.In the next step to optimize the amount of composite loading Introducing a new magnetic nanocomposite based on the chitosan… (0.02, 0.03, 0.035, 0.04 g), both model reactions were evaluated (Tables 1, 2, entries 8-13).Based on the attained evidence, 0.035 g of catalyst has the best performance.Also, as shown in Tables 1 and 2, entry13, the increase in the amount of product did not improve when the catalyst loading or temperature were increased.In addition, no improvement in the reaction yield was observed with longer reaction time (30 min) (Tables 1, 2, entry 14).The 0.035 g Fe 3 O 4 , CS, SA and CS-SA were also tested (Tables 1, 2, entries [15][16][17][18] in which CS-SA gave the best results.However, using the magnetic CS-SA leads to better performance and reusability.After obtaining the appropriate amount of catalyst (0.035 g), temperature was investigated as another effective parameter.With elevation of the reaction temperature to 50 °C the yield increased by about 12-13%.(Tables 1, 2, entries 10, 12).Based on the results,  3).Also, the best time and the highest efficiency were obtained in the presence of benzaldehyde (entries 5 and 14).As Table 3 displays, the electronic effects have little influence on reaction rate and yield.Moreover, thiophene-2-carbaldehyde was also converted to its relative 1,4-DHP and polyhydroquinoline compounds with high yields in short times in the presence of the magnetic composite (Table 3, entries 9, 18).The possible mechanism for the preparation of 1,4-DHPs and polyhydroquinolines has been summarized in Scheme 3. As presented, the SO 3 H groups on the surface of the catalyst play the role of the Brønsted acid and the Fe 3 O 4 nanoparticles groups act as Lewis acid.First, the catalyst activates aldehyde and the Introducing a new magnetic nanocomposite based on the chitosan… 1,3-di-carbonyl compounds (step 1).Then, the Knoevenagel condensation reaction occurs between the aldehyde and dimedone or ethyl acetoacetate, which forms the intermediates (I) and (III).The reaction of ammonium acetate with ethyl acetoacetate (step 2) also produces the intermediate (II).Then, magnetic-CS-SA accelerates the Michael addition between intermediates (I) and (II) in order to create 5a-5i products.Also, to create products 6a-6i, intermediates (II) and (III) react together in the presence of nanocomposites (Scheme 3).
Scheme 3 Probable mechanism for the formation of 1,4-DHPs and polyhidroquinolines using magnetic-CS-SA nanocomposites In order to evaluate the efficiency of the synthesized nanocomposite, its catalytic activity was compared with other catalysts.As can be seen from Table 4, magnetic-CS-SA nanocomposite performs better in a shorter time than most previously reported nanocatalysts under mild and safe reaction conditions.

Reusability of the magnetic-CS-SA nanocomposites
In the last decade, the issue of recycling heterogeneous nanocatalysts has been one of the most serious issues for researchers, because recyclable catalysts are not only economically viable but also environmentally friendly.For this reason, the recoverability of magnetic-CS-SA nanocomposites was surveyed in model reactions (Tables 2, 3, entry 12) under optimized conditions.After completion of the reaction and separation of the catalyst with a magnet, the nanocatalyst was rinsed with ethanol, dried and used for five consecutive runs.Despite five consecutive uses of the nanocomposite, less than 10% yield reduction was observed for two reactions (Fig. 9).The percentage of Fe 3 O 4 nanoparticles leached after 5th run was found to be 1.5% for synthesis of 5e and 1.8% for 6e based on the AAS.

Hot filtration study
In the hot filtration test, the model reactions of 1,4-dihydropyridine and polyhydroquinoline derivatives were investigated under optimal conditions (Tables 2, 3, entry 12) in the presence of magnetic nanocomposite CS-SA.After half the reaction time (8 min), the catalyst was removed with the help of an external magnet and the reaction was continued without catalyst-with filtrate under similar conditions.It is noteworthy that after removal of the nanocomposite, the reaction did not show any improvement, so no remarkable leaching of acidic groups or Fe 3 O 4 from the Introducing a new magnetic nanocomposite based on the chitosan… nanocomposite surface was occurred.Based on hot filtration experiments, the asymmetric and symmetric Hantzsch reactions are catalyzed by heterogeneous magnetic-CS-SA nanocomposite (Fig. 10).

Conclusion
In this study, we successfully synthesized a magnetic nanocomposite based on chitosan with acidic properties.Briefly, the surface of chitosan was modified by 1,3-di-bromopropane and then 4-amino-3-hydroxy-1-naphthalen-1-sulfonic acid was attached to the brominated chitosan.Finally, for the synthesis of the final

Table 1
Optimization of model reaction in the synthesis of 1,4-DHPs a

Table 2
Optimization of model reaction for the synthesis of polyhidroquinolines a

Table 3
Formation of diverse derivatives of 1,4-dihydropyridine and polyhydroquinoline. a

Table 4
Comparison of magnetic-CS-SA with some other systems in the synthesis of 1,4-DHP and polyhidroquinolines a Amine functionalized graphene oxide nano sheet