Molybdic Acid-Functionalized Nano-Fe3O4@TiO2 as a Novel and Magnetically Separable Catalyst for the Synthesis of Coumarin-Containing Sulfonamide Derivatives

Supported molybdic acid on nano-Fe3O4@TiO2 (Fe3O4@TiO2@(CH2)3OMoO3H) has been successfully prepared, characterized and applied as a catalyst for the synthesis of sulfonamide containing coumarin moieties. The prepared Fe3O4 nanoparticles by coprecipitation of Fe2+ and Fe3+ ions were treated with tetraethyl orthotitanate to obtain Fe3O4@TiO2. By anchoring 3-chloropropyltriethoxysilan on Fe3O4@TiO2 followed by reacting with molybdic acid, the desired catalyst was produced. The synthesized catalyst was characterized using XRD, SEM, EDS, FT-IR and VSM analysis. Fe3O4@TiO2@ (CH2)3OMoO3H was used as a catalyst for the synthesis of sulfonamide containing coumarin moieties via a three-component reaction of aryl aldehydes, para-toluenesulfonamide and 4-hydroxycoumarin or 5,7-dihydroxy-4-methylcoumarin. The catalyst recovery test showed the catalyst is highly reusable without losing its activity.


Introduction
Nanochemistry is becoming increasingly significant which involves the synthesis and application of nanoparticles of different sizes and shapes. [1][2][3][4][5][6][7][8][9] Nanoparticles are different from their bulk counterparts and show special properties. A considerable amount of attention to nanoparticles is due to their unique properties such as ease of availability, chemical inertness, high surface area to volume ratio, high activity and selectivity, thermal stability and low toxicity. 10,11 Nanomaterials have been widely utilized as solid support material for the design of environmentally benign heterogeneous catalysts to address various economic and green chemistry issues. [12][13][14][15] Among them, magnetic nanoparticles (MNPs), especially nano-Fe 3 O 4 , have been more desirable because of their remarkable advantages. Nano-Fe 3 O 4 has been intensively used as catalytic supports owing to the capability of separation from the reaction mixture via an external magnet which achieves a simple separation without filtration. 16,17 Supported catalysts on nano-Fe 3 O 4 show not only high catalytic activity but also a high degree of chemical stability and they do not swell in organic solvents.
Nano-TiO 2 owing to its nontoxicity, long-term photostability, and high effectiveness has broadly been applied as catalyst in many organic transformations. 18,19 It has good mechanical resistance and stability in acidic and oxidative environments. Nano-TiO 2 is broadly utilized in fuel processing because of its tunable porous surface and distribution, high thermal stability and mechanical strength. 20 Despite the several mentioned advantages of TiO 2 nanoparticles, they are difficult to separate from the reaction media beacause of their small size. To simplify the separation and in order to increase the surface area, TiO 2 can be immobilized on magnetic nanoparticles to produce magnetically recoverable heterogeneous catalysts. [21][22][23] In recent years, there has been an increased interest on the utilization of sulfonamide derivatives as basic constituents of numerous drugs include anticancer, anti-inflammatory, antiviral agents and HIV-protease inhibitors. [24][25][26] Antibacterial agents with sulfonamide structure, e.g. sulfadiazine have been therapeutically used for many decades. 27 They have also been applied as azo dyes for achieving improved light stability, water solubility, and fixation of fibers. Sulfonamides are also known as inhibitors of the activity of the enzymes, such as dihydropteroate synthase (DHPS), matrix metalloproteinase, and carbonic anhydrase (CA). 28 Coumarins as a class of lactones are important heterocycles that not only have many biological activities, but are also found in the structure of a large number of natural compounds. 29 With an entirely looking at medicinally important heterocycles, we find numerous drugs containing coumarin moiety. [30][31][32] Their easy synthetic modifications cause the design and synthesis of various coumarin-based derivatives with diverse activities against cancer. 33 Also, coumarins are widely employed as cosmetics, pigments and agrochemicals. They can be fused with different classes of heterocycles to obtain novel useful compounds. The unique properties and wide applications of coumarins have promoted extensive studies for the synthesis of these heterocycles.
Due to these benefits and as a continuation of our studies on the preparation of new heterogeneous catalysts, 34-36 herein we have developed synthesis and characterization of Fe 3 O 4 @TiO 2 @(CH 2 ) 3 OMoO 3 H as a novel recoverable nanocatalyst. Then, its application was investigated for the synthesis of sulfonamide containing coumarin moieties.

Results and Discussion
Because of reasonable needs for clean and green heterogeneous catalysts, Fe 3 O 4 @TiO 2 @(CH 2 ) 3 OMoO 3 H was synthesized following the procedure shown in Scheme 1. In the first step, the magnetic Fe 3 O 4 nanoparticles were synthesized by coprecipitation of iron(II) and iron(III) ions. 17 Consequently,the TiO 2 shell was prepared by the hydrolysis of tetraethyl orthotitanate (TEOT) in an absolute ethanol/ acetonitrile mixture in the presence of the well-dispersed Fe 3 O 4 nanocrystals. 37 In continuation, the OH groups on the titanium coating magnetic nanoparticles (Fe 3 O 4 @ TiO 2 ) can be functionalized with 3-chloropropyltriethoxysilan molecule. 38 Next, the new catalyst 1 was obtained by replacing chloride group using molybdic acid. The structure of the nanocatalyst 1 was studied and fully characterized using SEM, EDX, VSM, XRD, and FT-IR.  tensity (311, 2θ = 35.522) was picked out to evaluate the particle diameter of the nanoparticles. Furthermore, in Figure 1b a broad diffraction peak appeared at 2θ = 20-30 nm that can be indexed to amorphous TiO 2 . 39 The main peaks for the Fe 3 O 4 @TiO 2 are similar to the standard Fe 3 O 4 particles, which reveals that the crystal structure of Fe 3 O 4 @TiO 2 is well coated. No obvious diffraction peak for the TiO 2 is observed, suggesting amorphous TiO 2 coating is formed by the hydrolysis of tetraethyl titanate (TEOT) in the presence of the well-dispersed Fe 3 O 4 nanocrystals by a sol-gel process. 40 In Figure 1c, the confirming peak showing the presence of molybdate group has appeared in the range of 2θ = 20-30° which is covered by the broad peak of TiO 2 . 39,41 The FT-IR spectra of Fe 3 O 4 , Fe 3 O 4 @TiO 2 , Fe 3 O 4 @ TiO 2 @(CH 2 ) 3 Cl and Fe 3 O 4 @TiO 2 @(CH 2 ) 3 OMoO 3 H were compared to analyze the progress of catalyst synthesis (Fig.  2). The observed characteristic peaks due to Fe-O stretching vibration at 583 cm -1 in all compared spectra is a confirmation of which nanostructure of Fe 3 O 4 is preserved during the process. The appeared peaks at 1118 and 1400 cm -1 in Fig. 2b could be associated with stretching vibration modes of Ti-O and Fe-O-Ti bonds, respectively. 35 In Fig. 2c, the CH 2 bending as broadband and symmetric CH 2 and asymmetric CH 2 of the alkyl chains appear at 1480 cm -1 and 2860-2923 cm -1 , respectively. Fig. 2d shows new bands at 1623 and 3297-3436 cm -1 attributable to stretching vibration of Mo-O and OH. 43,44 The vibrating sample magnetometer (VSM) was applied to evaluate the magnetic measurement of the prepared catalyst (Fig. 3). Based on the results, the saturation magnetization for Fe 3 O 4 @TiO 2 @(CH 2 ) 3 OMoO 3 H and Fe 3 O 4 @TiO 2 are 22.98 and 77.85 emu g -1 , respectively. The decrease of the saturation magnetization of Fe 3 O 4 @TiO 2 after surface coating with molybdic acid was ascribed to the increase of particle size of Fe 3 O 4 @TiO 2 . This evidence indicates that molybdic acid immobilized on modified TiO 2 -coated Fe 3 O 4 has been successfully obtained.
The surface morphology of Fe 3 O 4 @TiO 2 @(CH 2 ) 3 O-MoO 3 H was observed via a scanning electron microscopy (Fig. 4). The result demonstrates that nearly spherical nanoparticles with a narrow distribution were obtained with an average diameter of about 43.25 nm. Energy-dispersive X-ray spectroscopy (EDS) analysis of Fe 3 O 4 @ TiO 2 @(CH 2 ) 3 OMoO 3 H (Fig. 5) contains all expected elemental cases including Fe, Ti, Mo, C, Si and O. The EDS spectra of the catalyst confirmed the existence of molybdate and hence indicated that molybdic acid grafted successfully on the catalyst surface.      In a preliminary study, the reaction of benzaldehyde, para-toluenesulfonamide and 4-hydroxycoumarin was selected as a model reaction to determine suitable conditions. To illustrate the need of Fe 3 O 4 @TiO 2 @(CH 2 ) 3 O-MoO 3 H for this condensation, we examined the model reaction in the absence of this catalyst at various conditions. The results show clearly that Fe 3 O 4 @TiO 2 @ (CH 2 ) 3 OMoO 3 H is an effective catalyst for this reaction and in the absence of this catalyst the reaction did not take place, even after 24 h. Next, the model reaction was conducted in the presence of several amounts of catalyst 1 at different conditions (Table 1). Through screening we found that this reaction was efficiently completed in the presence of 0.003 g of Fe 3 O 4 @TiO 2 @(CH 2 ) 3 OMoO 3 H at 90 o C under solvent-free conditions.
To investigate the generality of this protocol, the reaction of different aryl aldehydes, containing both electron-donating and electron-withdrawing groups were employed in the reaction. In general, the reaction proceeded smoothly to afford the desired products 6 in good to excellent yields. Furthermore, under similar conditions, aryl aldehydes and para-toluenesulfonamide were reacted with 5,7-dihydroxy-4-methylcoumarin in the presence of the catalyst 1 (Table 2). According to the reported procedure in the literature, 45   external magnet, washed with MeOH and reused in the next run. As outlined in Fig. 6, Fe 3 O 4 @TiO 2 @(CH 2 ) 3 O-MoO 3 H exhibited no considerable decrease in activity after six cycles. This advantage besides the recoverability of the biodegradable and green catalyst makes this research highly favorable for large-scale synthesis. A plausible mechanism for the synthesis of product 6 is outlined in Scheme 3. It is reasonable to assume that para-toluenesulfonamide attacks the activated arylaldehyde by the acid catalyst to give sulfonyl aldimines 4. Then, intermediate 7 or 8 is generated from the condensation of 5 (5,7-dihydroxy-4-methylcoumarin or 4-hydroxycoumarin) with 4 which rearranges into the desired product.
The filtration test was performed to show the heterogeneity of the catalyst. For this purpose, after the development of about 40% of the model reaction (synthesis of 6a), the catalyst was removed and the progress of the residual mixture was monitored. Interestingly, no further conversion was observed in this case. Therefore, we found that the catalyst operates in a heterogeneous manner and no leaching of molybdic acid as active species occurs under the applied conditions.

Experimental
All chemicals used in this research were purchased from Fluka and Merck chemical companies. The monitoring of the reaction progress and the purity of the compounds were accomplished using TLC performed with silica gel SIL G/UV254 plates. Melting points were determined by an electrothermal KSB1N apparatus and are uncorrected. 1 H NMR spectra were recorded in DMSO-d 6 on a Bruker Avance Ultra Shield 400 MHz instrument spectrometers and 13 C NMR spectra were recorded at 100 MHz. X-ray powder diffraction (XRD) patterns were recorded using a Bruker AXS (D8 Advance) X-ray diffractometer with Cu Kα radiation (λ = 0.15418 nm). The measurement was made in 2θ ranging from 10° to 80° at the speed of 0.05° min -1 . For the preparation of the sample for XRD, after synthesis, the sample was powder, which was clumpy, and then XRD was measured. Analysis conditions includes: voltage: 40 kV and current: 30 mA. Energy dispersive spectroscopy (EDS) was performed using a TES-CAN Vega model instrument. The morphology of the particles was observed by scanning electron microscopy (SEM) under an acceleration voltage of 26 kV. Before SEM characterization, the sample was powdered and then coated with gold. The magnetic measurement was carried out in a vibrating sample magnetometer (VSM) at Kashan University (Kashan, Iran) at room temperature.

Synthesis of Fe 3 O 4 MNPs
A solution of FeCl 3 •6H 2 O (1.35 g, 5 mmol) and FeCl 2 • 4H 2 O (0.5 g, 2.5 mmol) (dissolved in 22 mL double distilled water) stirred under argon atmosphere at 80 °C for 30 min. Next the sodium hydroxide solution (2.5 mL, 10 M) was added dropwise to the reaction mixture with stirring for 1 h under argon atmosphere. Finally, the formed nanoparticles were collected using an external magnet. The nano particles were washed with distilled water repeatedly and then dried at 60 °C. 47

Synthesis of nano-Fe 3 O 4 @TiO 2
Fe 3 O 4 nanoparticles were added to a mixture of ethanol and acetonitrile (250:90 mL) and sonicated for 25 min. Next an aqueous ammonia solution (1.5 mL, 25 W%) was added and the resulting mixture was stirred at 25 °C for 30 min. Then, tetraethyl orthotitanate (3 mL) dissolved in absolute ethanol (20 mL) was added. After stirring for 2 h the obtained mixture was washed completely with absolute ethanol and was collected with an external magnet. 37

Preparation of Fe 3 O 4 @TiO 2 @(CH 2 ) 3 OMoO 3 H
A mixture of Fe 3 O 4 @TiO 2 @(CH 2 ) 3 Cl (1 g) and Na-2 MoO 4 •2H 2 O (0.5 g) in DMSO (10 mL) was stirred at reflux under argon atmosphere for 12 h. The resulting product was decanted and washed twice with DMSO, once with distilled water and was dried at 50 ºC for 18 h. Then, it was added to the flask containing HCl (60 mL, 0.1 N) and stirred for 2 h at room temperature. The resulting catalyst was decanted, washed with DMSO and water, afterwards dried at room temperature.

General Procedure for the Synthesis of 6
Catalyst 1 (0.003 g) was added to the mixture of para-toluenesulfonamide (1 mmol), aldehyde (1 mmol) and 4-hydroxycoumarin (1 mmol) or 5,7-dihydroxy-4-methylcoumarin (1 mmol). The resulting mixture was stirred in an oil bath (90 °C) under solvent-free conditions. The reaction progress was monitored by TLC (n-hexane/EtOAc, 2:1). After completion of the reaction, boiling methanol (10 mL) was added, and the catalyst was separated by an external magnet. The obtained powder was recrystallized from hot EtOH.

Conclusion
In summary, we have introduced Fe 3 O 4 @TiO 2 @ (CH 2 ) 3 OMoO 3 H as a novel modified Fe 3 O 4 MNPs. It was fully characterized by XRD, SEM, EDS, FT-IR and VSM analysis. Furthermore, the first application of this reusable nanocatalyst for the synthesis of sulfonamide containing coumarin derivatives was successfully examined. The use of Fe 3 O 4 @TiO 2 @(CH 2 ) 3 OMoO 3 H as a green and safe catalyst under solvent-free conditions, high yield of pure products, short reaction times and a simple recovery procedure are the main promising points of this work.