Journal of Nanostructures

Journal of Nanostructures

Design, Characterization, and Use of Nano Fe3O4@Cellulose/Ti(IV) as an Efficient and Magnetically Recoverable Nano-Catalyst for the Synthesis of Highly Functionalized Tetrahydropyridines and DFT Calculations

Document Type : Research Paper

Authors
Bi Bi Fatemeh Mirjalili 1
Hadi Basharnavaz 1
Hamid Bamoniri 2
Sara Azad 1
1 Department of Chemistry, College of Science, Yazd University, Yazd, P.O.Box 89195-741, I.R.Iran
2 Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, I.R.Iran
10.22052/JNS.2026.01.096
Abstract
The facile two-step process for the preparation of nano Fe3O4@cellulose/Ti(IV) as a novel magnetic nano-solid acid catalyst is described, which includes the synthesis of nano Fe3O4@cellulose/Ti(IV) as a magnetic core-shell structure, followed by supporting titanium tetrachloride on the cellulosic shell. The structure, morphology, and magnetic properties of nano Fe3O4@cellulose/Ti(IV) were studied with some different techniques, such as Fourier transform infrared (FT-IR) spectroscopy, field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray fluorescence (XRF), vibrating sample magnetometry (VSM) and thermo-gravimetric analysis (TGA). The catalytic performance of this nano-catalyst has been studied in the synthesis of asymmetric highly functionalized tetrahydropyridines via a five-component condensation reaction of p-substituted anilines, aldehydes, and ethyl acetoacetate under thermal conditions. This procedure offers the advantages of mild reaction conditions, easy work-up, excellent yields, simple magnetic separation of the catalyst, and its recyclability for up to seven cycles without any considerable loss of efficiency, which is consistent with the results of DFT computation.
Keywords
Highly functionalized tetrahydro pyridines
Magnetic catalyst
Nano-cellulose
Nano Fe3O4@cellulose/Ti(IV)
Supported Lewis acid

INTRODUCTION
In recent decades, magnetic nanoparticles (MNPs) have appeared as an excellent type of catalyst support because of their good stability, easy synthesis and functionalization, high surface area and facile separation by magnetic forces, as well as low toxicity and price [1,2]. Other important features of these magnetic catalysts are high catalytic activity, high degree of chemical stability in various organic and inorganic solvents, reusability, and benign character in the context of green chemistry. Among the various MNPs, magnetite (Fe3O4) is mostly used as a core magnetic support [3-5]. Fe3O4 nanoparticles have been prepared by precipitation [6], co-precipitation [7], and hydrothermal [8] methods. However, pure Fe3O4 nanoparticles are likely to form a large aggregation with fewer activating groups and are easily oxidized or dissolved in an acid medium [9]. To overcome these problems, Fe3O4 nanoparticles are coated with various materials such as surfactants [10], polymers [11,12], silica [13], and carbon [14] to form a core–shell structure. It is noteworthy that in many cases the protecting shells not only stabilize the nanoparticles but can also be used for further functionalization, for instance with other nanoparticles or various ligands, depending on the desired application [15].
Recently, polysaccharides as natural polymers have been used to prevent magnetite nanoparticles from aggregating, and represent an attractive choice for the preparation of functional materials [16-19]. Among polysaccharides, cellulose is one of the most abundant and renewable polymers in the world and has been widely studied in both academic and industrial research [20]. This biopolymer exhibits some excellent properties, including mechanical robustness, biodegradability, hydrophilicity, and biocompatibility [21]. Owing to these fascinating properties, cellulose has found a wide application in a variety of areas such as pharmacy, agriculture, medical science, industries and so many other related branches [22-27]. Specifically, the hydroxyl groups in cellulose provide active sites for numerous attractive chemical modifications. Thus, Cellulose can be used as an efficient support for bonding several functional groups to produce impressive biopolymer-based catalysts [28,29].
Within the family of cellulose derivatives, the nano-structure of the cellulose is a particularly appealing duo to combining important properties of cellulose with amazing features of nano-scale materials. Hence, one of the main goals of the present work is the preparation of nano-cellulose (NCs) by sulfuric acid hydrolysis of cotton and using it for the synthesis of nano Fe3O4@cellulose/Ti(IV) (Fe3O4@NCs/Ti(IV)) as a new, biodegradable, effective and reusable magnetic nano-catalyst.
Tetrahydropyridines (THPs) and their derivatives have potent pharmaceutical properties as antiemetic and antipsychotic agents [30,31], anticancer [32] and antimalarial [33]. THPs have been used as drugs in the treatment of diseases such as Alzheimer (GTS-21) [34] and central nervous system (CNS) disorders (RO-10-5824) [35-37]. Alkyl-1-aryl-4-(arylamino)-2, 6-di-aryl-1, 2, 5, 6-tetrahydro-pyridine-3-carboxylates are some important densely substituted tetrahydro pyridines. These compounds are synthesized via one-pot reaction of p-substituted anilines, p-substituted aldehydes, and alkyl acetoacetate. Recently, these compounds have been synthesized in the presence of catalysts such as InCl3 [37,38], BDMS [39], L-proline/TFA [33], TBATB [40], I2 [41], CAN [42], ZrOCl2·8H2O [43], ZrCl4 [32], p-TsOH·H2O [44], Fe(NO3)3·9H2O [45], FeCl3/SiO2 [46], amberlite IRA400-Cl resin/I2/KI [47], HOAc [48], BF3.SiO2 [49], nano-silica sulfuric acid [50], and NiFe2O4@SiO2 [51]. Some of these catalysts suffer from drawbacks such as long reaction times and low yield. Therefore, the development of new solid acid catalysts with numerous advantages such as cost-effectiveness, environmentally benign, easy workup, and good stability for the synthesis of highly functionalized tetrahydropyridines is of prime importance. 
Herein we wish to report nano Fe3O4@cellulose/Ti(IV) as a bio-based, magnetic, and effective heterogeneous nano-catalyst for the synthesis of Alkyl-1-aryl-4-(arylamino)-2, 6-di-aryl-1, 2, 5, 6-tetrahydro- pyridine-3-carboxylates via multi-component reaction of p-substituted anilines, p-substituted aldehydes and ethyl acetoacetate.  

 

MATERIALS AND METHODS
General
All compounds were purchased from Merck, Aldrich, and Fluka chemical companies and used without additional purification. A refrigerated centrifuge (Appendorf Centrifuge 5417R) was used to prepare nano-cellulose. FT-IR spectra were run on a Bruker, Equinox 55 spectrometer. A Bruker (DRX-400 Avance) NMR was used to record the 1H-NMR and 13C-NMR spectra. Melting points were determined by a Buchi melting point B-540 B.V.CHI apparatus and were uncorrected. The X-ray diffraction (XRD) pattern was obtained by a Philips Xpert MPD diffractometer equipped with a Cu Ka anode (k=1.54 A°) in the 2θ range from 10 to 80°. Field Emission Scanning Electron Microscopy (FESEM) was obtained on a Mira 3-XMU. Transmission electron microscopy (TEM) was obtained using a Philips CM120 with a LaB6 cathode and an accelerating voltage of 120 kV. XRF analysis was done with Bruker, S4 Explorer instrument. The VSM measurements were performed using a vibrating sample magnetometer (Meghnatis Daghigh Kavir Co. Kashan Kavir, Iran). 


Preparation of nano-cellulose from cotton
Cotton fibers were washed with distilled water several times and dried in an air-circulated oven at 100±2 oC until constant weight. Then they were chopped to an approximate length of 5-10 mm. The fibers were then treated with a 17.5 w/v NaOH solution at 100 °C for 12 hours under mechanical stirring. This treatment allowed purifying cellulose by removing other constituents like lignin, hemicellulose, wax, organic acids, and so on present in the fibers. Subsequently, fibers were filtered and washed with distilled water until the alkali was completely eliminated. It was then bleached with 100 ml of 1:1 aqueous dilution of 3.5% w/v sodium hypochlorite at 80 °C for 3 hours under mechanical stirring. The resulting alpha-cellulose was hydrolyzed partially using a 65% sulfuric acid aqueous solution with a cotton-to-acid weight ratio of 1–10 at 45 °C. After 1 hour, the obtained suspension was diluted with water five-fold to stop the hydrolysis reaction. The suspension was centrifuged at 12,000 rpm to separate the nano-cellulose from the acid solution. The washing with water and centrifuging was repeated four to five times to remove any remaining free acid.

 

Preparation of Fe3O4@NCs
1 g of nano-cellulose is dissolved in 100 mL of 0.05 M acetic acid solution; to which FeCl3·6H2O (3.51 g, 0.013 mol) and FeCl2·4H2O (1.29 g, 0.0065 mol) are added. The resulting solution is mechanically stirred for 4 h at 80 °C. Consequently, 6 mL of 25% NH4OH is injected drop wise into the reaction mixture with constant stirring. After 30 min, the mixture is cooled to room temperature, and nano-cellulose coated over magnetic nanoparticles is separated by an external magnet, first washed with distilled water, then ethanol, and finally dried under vacuum at room temperature.

 

Preparation of nano Fe3O4@cellulose/Ti(IV)
In a well-ventilated system, TiCl4 (5 mL) was added drop wise to the mixture of Fe3O4@NCs (5 g) in chloroform (20 mL). The mixture was stirred for one hour at room temperature. The resulting suspension was filtered, washed with chloroform, and dried at room temperature.

 

General procedure for synthesis of THPs
To a stirring solution of para-substituted anilines (2 mmol), ethyl acetoacetate (1 mmol), and nano Fe3O4@cellulose/Ti(IV) (0.03 g) in 5 mL EtOH, para-substituted benzaldehydes (2 mmol) was added, and the reaction mixture was refluxed for an appropriate time as indicated in Table 4. After completion of the reaction (monitored by TLC), the catalyst was separated by using an external magnet, and the reaction mixture was decanted. Subsequently, by adding water to the decanted solution, the product appeared as a pure solid in high yields. The recovered catalyst was washed 3 times with ethanol, dried, and reused for subsequent runs under the same reaction conditions.

 

RESULT AND DISCUSSION
Nano Fe3O4@cellulose/Ti(IV) was generally prepared in a two-step process. First, we synthesized Fe3O4@NCs by co-precipitation of Fe3+ and Fe2+ ions in the presence of nano-cellulose, and then we used it as magnetic support for bonding TiCl4 (Fig. 1).
The magnetically heterogeneous catalyst, nano Fe3O4@cellulose/Ti(IV), is characterized by Fourier transform infrared (FT-IR) spectroscopy, FESEM, TEM, XRD, X-ray fluorescence (XRF), vibrating sample magnetometer (VSM), and thermo gravimetric analysis (TGA).
The FT-IR spectra of (a) nano-cellulose, (b) Fe3O4@NCs, and (c) nano Fe3O4@cellulose/ Ti(IV) are shown in Fig. 2. The FT-IR spectrum of nano-cellulose shows a broad band at 3337 cm-1 which corresponds to the stretching vibrations of OH groups. The absorption bands around 1055 and 1108 cm-1 display the stretching vibrations of the C-O bonds. For Fe3O4@NCs, cellulose absorptions appear in addition to the stretching vibrations of Fe-O groups at 586 and 634 cm-1; indicating that the magnetic Fe3O4 NPs are coated by nano-cellulose. The FT-IR spectrum of nano Fe3O4@cellulose/Ti(IV) shows a characteristic peak at 794 cm-1 corresponding to C-O-Ti stretching according to the IR spectrum of Ti(OBu)4 [52,53]. The peak at 406 cm-1 corresponds to the O-Ti-O bending vibrations [54]. The stretching vibrations of O–H bonds are observed at 3376 cm-1. The 1585 cm-1 band might be due to the H-O-H bending vibration of adsorbed water [55]. In comparison with Fe3O4@NCs, bonding Ti to the cellulosic shell shifts Fe-O stretching vibrations to lower wavenumber (from 586 and 634 cm-1 to 558 and 606 cm-1, respectively). 
The particle size of nano-cellulose and nano Fe3O4@cellulose/Ti(IV) were investigated by field emission scanning electron microscopy (FESEM) and TEM in which the dimensions of them were achieved below 50 nm (Fig. 3). 
The structure and phase purity of Fe3O4, Fe3O4@NCs, and nano Fe3O4@cellulose/Ti(IV) are studied using high angle XRD (Fig. 4). The bare Fe3O4 shows diffraction peaks at 2θ=30.4358°, 35.8507°, 43.4470°, 53.9461°, 57.4597°, and 63.0368° with FWHM equal to 0.4723, 0.4723, 0.4723, 0.7872, 0.6298, and 0.6298 respectively, which are quite matched with the cubic spinel structure of pure Fe3O4 described in the literature (Fig. 4a) [56]. The same peaks were also observed in the Fe3O4@NCs XRD pattern, indicating retention of the crystalline spinel ferrite core structure during the cellulose-coating process. Moreover, a diffraction peak at 2θ =23.0444 appeared in the Fe3O4@NCs MNPs, which could be related to the cellulose coating of Fe3O4 NPs (Fig. 4b). The XRD pattern of nano Fe3O4@cellulose/Ti(IV) shows an amorphous structure (Fig. 4c). The weak diffraction peaks at 2θ=29.9870°, 35.6108°, 46.5512°, and 56.0212° correspond to Fe3O4 cores (Fig. 4c). Other peaks at around 2θ=21°-23° reveal the existence of cellulose and bonding of Ti to cellulosic shell.
The chemical composition of the catalyst has been measured using XRF analysis (Table 1, Fig. 5). In order to obtain the Ti:Cl ratio in nano Fe3O4@cellulose/Ti(IV) by XRF analysis, Killo Counts Per Seconds (KCPS) values of elements in the catalyst were compared with KCPS values of the same elements in pure samples, NaCl and TiO2. By this comparison, the amount of Ti and Cl were obtained 4.51 g (0.1 mol) and 5.1 g (0.14 mol), respectively. Thus, the ratio of Ti:Cl in the catalyst is approximately 1:1.
To investigate the magnetic property of the catalyst, magnetic measurements were carried out using a vibrating sample magnetometer (VSM) in an applied magnetic field at 300 K. As shown in Fig. 6, no hysteresis loop and no remanence was detected, and also the coercivity value is zero for all samples, suggesting typical super paramagnetic property at room temperature. The saturation magnetization (Ms) values of Fe3O4, Fe3O4@NCs, and nano Fe3O4@cellulose/ Ti(IV) are 49.177, 33.057, and 6.062 emu/g, respectively. These results indicate that the magnetization of Fe3O4 decreased considerably by coating it with nano-cellulose and bonding TiCl4 to OH groups of nano-cellulose. Even with this reduction in the saturation magnetization, the catalyst can still be efficiently separated from the solution with a permanent magnet (as shown in the inset of Figure 5). 
The thermal stability of nano Fe3O4@cellulose/Ti(IV) was investigated by TGA in the temperature range of 50-372 °C (Fig. 7). The TGA curve illustrates four mass-loss steps. Firstly, a very small weight loss (2.14%) from 50 to 100 °C is corresponded to the remove of catalyst moisture. Subsequently, there are two weight loss steps in the temperature ranges 100-135 and 150-180 °C (12.62 and 7.72%, respectively). Finally, the main weight loss (17.35 %), observed in the range of 180-372 °C, is attributed to the decomposition of cellulose units through the formation of levoglucosan and other volatile compounds [57]. The char yield of the catalyst at 372 °C is 58.62%.
The catalytic activity of nano Fe3O4@cellulose/Ti(IV) was investigated for the synthesis of highly functionalized tetrahydropyridines via a five-component condensation reaction of p-substituted anilines, aldehydes and ethyl acetoacetate.
In order to optimize the reaction conditions, including solvent, temperature, and catalyst loading, the model reaction of 4-ethylaniline, 4-chlorobenzaldehyde, and ethyl acetoacetate was initially carried out under different conditions in the presence of a catalytic amount of nano Fe3O4@cellulose/Ti(IV). The results have been summarized in Table 2. Different solvents including THF, H2O, CH3CN, EtOH, MeOH, and CHCl3 were screened (Table 2, Entries 4-10); the model reaction was easier and gave the highest yield in EtOH as solvent under reflux condition (Table 2, Entry 5). To optimize the catalyst amount, the model reaction was performed in the presence of various amounts of the catalyst and according to the obtained results (Table 2, Entries 11-13), 0.03 g of the catalyst was chosen as the best catalyst amount (Table 2, Entry 15). In conclusion, the best reaction condition for this transformation is the use of 0.03 g of the catalyst in EtOH as solvent under reflux condition (Table 2, Entry 12). 
The reusability of the catalyst was also investigated in the model reaction. The magnetic nature of the catalyst allowed its facile separation by magnetic decantation, washing with ethanol and drying at room temperature to provide an opportunity for recycling experiments. The separated nano-catalyst was reused in the mentioned reaction seven times without considerable loss of its catalytic activity (Fig. 8). Partial loss of activity may be due to blockage of some active sites of the catalyst and/or partial leaching of titanium from the catalyst.
Comparison of the results of the nano Fe3O4@cellulose/Ti(IV)-catalyzed reaction of para-substituted aniline (2 mmol), para-substituted benzaldehyde (2 mmol), and ethyl acetoacetate (1 mmol) with previously reported methods shows the merit of the present protocol (Table 3). 
Based on the optimized reaction conditions, a range of THP derivatives were synthesized by the reaction of various para-substituted anilines (2 mmol), para-substituted benzaldehydes (2 mmol) and ethyl acetoacetate (1 mmol) (Table 4). All compounds were identified by physical and spectroscopic data (mp, FT-IR, and 1H NMR). Moreover, the new products were specified using the aforementioned methods as well as 13C NMR spectroscopy and CHN analysis. In the FTIR spectra, the ester C=O stretching frequency appeared around 1650 cm-1 due to conjugation and hydrogen bonding with N-H. In the 1H NMR spectra, the distinct peak near δ=10.5 ppm is assigned to N-H of secondary amine-containing hydrogen bonding with the ester C=O group. 
A suggestion mechanism for this multi-component reaction was shown in Fig. 9. Titanium in Fe3O4@NCs/TiCl activates the C=O group in β-ketoester and aldehyde to promote the β-enaminone (4) or imine (5) formation. The intermolecular Mannich addition of the β-enaminone (4) to the imine (5) affords the intermediate (6). Subsequently, the reaction of activated aldehyde with the intermediate (6) proceeds to afford the intermediate (7) by the elimination of H2O. Then, tautomerization of (7) generates intermediate (8), which immediately undergoes an intramolecular Mannich-type reaction to give intermediate (9). Finally, the intermediate (9) tautomerizes to generate the desired THP derivative containing a conjugated ester group which bonds to NH with hydrogen bonding.

 

COMPUTATIONAL DETAILS
Becke’s 3-parameter hybrid (B3) exchange functional and the Lee–Yang–Parr correlation functional with 6–311G (d, p) basis sets [58-67] were used to determine the most stable compounds of functionalized tetrahydropyridines (IVa-n). All computations were carried out using Density Functional Theory (DFT) [68-71] as implemented in the Gaussian 09 package [72-77]. The total energy and band gap (Eg=EHOMO-ELUMO) calculations for highly functionalized tetrahydropyridines (IVa-n) are given in Table 5. The stability of IVe compound is higher than that of the other reported compounds, according to total energy and stability statistics.
Additionally, the relaxed structures of functionalized tetrahydropyridines IVe, IVh, IVf and IVk with the total energy of -7523.27167, -6836.27649, -6608.48436, and -6608.48399 a.u, respectively, are displayed in Fig. 10. 
The obtained results illustrated that the functionalized tetrahydropyridines IVe is more stable than that of the other reported compounds, which is in good agreement with the experimentally reported data.

 

CONCLUSION
In summary, to make a good contribution to the innovation of green chemistry, we have demonstrated the preparation and characterization of nano Fe3O4@cellulose/Ti(IV) as a highly efficient, magnetically recyclable, cheap and novel bio-based heterogeneous catalyst. The catalytic activity of the prepared catalyst was investigated in the synthesis of highly functionalized tetrahydropyridines through one-pot five-component condensation reaction of p-substituted anilines, aldehydes, and ethyl acetoacetate under reflux conditions in EtOH. This procedure offers the advantages of mild reaction conditions, easy work-up, excellent yields, simple magnetic separation of the catalyst, and its recyclability for up to seven cycles without any considerable loss of efficiency. The computation outcomes revealed that the DFT calculation results validated the experimentally reported data.

 

ACKNOWLEDGEMENTS 
The Research Council of Yazd University gratefully acknowledged for the financial support for this work.

 

CONFLICT OF INTEREST
The authors declare that there is no conflict of interests regarding the publication of this manuscript.

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Journal of Nanostructures
Volume 16, Issue 1
Winter 2026
Pages 1076-1090