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Article

Cobalt Ferrite Nanoparticles: Highly Efficient Catalysts for the Biginelli Reaction

by
Waleed M. Alamier
*,
Emad M. El-Telbani
,
Imam Saheb Syed
and
Ayyob M. Bakry
*
Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, P.O. Box. 114, Jazan 45142, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Ceramics 2025, 8(3), 102; https://doi.org/10.3390/ceramics8030102
Submission received: 30 May 2025 / Revised: 29 July 2025 / Accepted: 4 August 2025 / Published: 6 August 2025
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Abstract

This study introduces an efficient and sustainable catalytic system utilizing cobalt ferrite nanoparticles (CoFe2O4-NPs) for the synthesis of valuable 6-amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives. Recognizing the limitations of traditional methods for the Biginelli reaction, we thoroughly characterized CoFe2O4-NPs, alongside individual iron oxide nanoparticles (Fe2O3-NPs) and cobalt oxide nanoparticles (CoO-NPs), using FTIR, XRD, TEM, SEM, XPS, TGA, and BET analysis. These characterizations revealed the unique structural, morphological, and physicochemical properties of CoFe2O4-NPs, including an optimized porous structure and significant bimetallic synergy between Fe and Co ions. Catalytic studies demonstrated that CoFe2O4-NPs significantly outperformed individual Fe2O3-NPs and CoO-NPs under mild conditions. While the latter only catalyzed the Knoevenagel condensation, CoFe2O4-NPs uniquely facilitated the complete Biginelli reaction. This superior performance is attributed to the synergistic electronic environment within CoFe2O4-NPs, which enhances reactant activation, intermediate stabilization, and proton transfer during the multi-step reaction. This work highlights the potential of CoFe2O4-NPs as highly efficient and selective nanocatalysts for synthesizing biologically relevant 1,2,3,4-tetrahydropyrimidines, offering a greener synthetic route in organic chemistry.

1. Introduction

Organic chemistry, particularly in synthesizing valuable and sensitive compounds, must prioritize environmental sustainability, economic viability, safety, and efficiency. The development of one-pot synthesis methods has emerged as a crucial strategy to address these concerns, especially in medicinal research. Nitrogen-based heterocyclic compounds, such as tetrahydropyrimidines (THPMs), have garnered significant attention due to their diverse biological activities [1,2]. Among THPM derivatives, 1,2,3,4-tetrahydropyrimidines have shown particular promise as scaffolds for novel therapeutic agents. Their structural versatility makes them highly attractive building blocks for drug discovery. Consequently, many pharmaceutical companies are actively exploring THPM-based compounds for a range of therapeutic applications, from anticancer agents to cardiovascular drugs. Incorporating specific functional groups, like amino and cyano moieties, into the 1,2,3,4-tetrahydropyrimidine ring has been demonstrated to significantly enhance their biological potency and pharmacological efficacy. 6-Amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile represents a class of pyrimidine derivatives with potential applications in various therapeutic areas [3,4]. However, traditional methods for synthesizing these compounds often involve harsh reaction conditions, toxic reagents, and lengthy reaction times, which necessitate the development of more efficient, selective, and environmentally friendly approaches.
Recently, nanomaterials have emerged as promising catalysts for organic transformations, including the synthesis of THPM derivatives. Their unique properties, such as high surface area, enhanced reactivity, and tunable catalytic activity, have led to significant advancements in improving the efficiency and selectivity of chemical reactions [5,6]. Therefore, THPM derivatives can be synthesized using a variety of catalysts, including metal nanoparticles (e.g., gold [7], silver [8], platinum [9]), metal oxides (e.g., TiO2 [10], ZnO [11], CeO2 [12]), carbon-based nanomaterials (e.g., graphene [13], carbon nanotubes [14]), metal-organic frameworks (MOFs) [15], dendrimers [16], quantum dots [17], supported catalysts [18], alloy nanoparticles [15], and bimetallic catalysts [19]. These nanomaterials offer unique properties like high surface area, enhanced reactivity, and tunable catalytic activity, making them effective catalysts for various organic transformations, including the synthesis of THPM derivatives.
Iron oxide nanoparticles (Fe2O3), also known as hematite, are a versatile class of materials with a wide range of applications. Their unique structure, consisting of a core of iron oxide, imparts them with exceptional catalytic properties. Fe2O3 nanoparticles exhibit high catalytic activity toward various chemical reactions, including oxidation, reduction, and decomposition. This catalytic activity is attributed to their large surface area, which provides numerous active sites for chemical interactions [20]. However, Fe2O3 nanoparticles also possess certain drawbacks, such as their tendency to agglomerate and their susceptibility to leaching under harsh reaction conditions. To overcome these limitations and enhance their catalytic performance, various functionalization strategies have been explored. These include surface modification with organic ligands, inorganic supports, or metal nanoparticles, which can improve the dispersion of Fe2O3 nanoparticles, enhance their stability, and introduce new catalytic properties [21,22].
Modifying Fe2O3 nanoparticles with other metals and metal oxide nanoparticles can significantly enhance their catalytic activity. This is due to the synergistic effects that arise from the combination of the two materials. For example, incorporating metal oxides such as CeO2 into Fe2O3 can enhance oxygen storage capacity and promote redox reactions, leading to improved catalytic performance in oxidation and reduction processes [23,24]. Similarly, ZnO modification can create new active sites and improve the dispersion of Fe2O3 nanoparticles, resulting in enhanced catalytic activity for reactions involving alcohols and aldehydes [25]. TiO2 can provide additional acidity and improve the stability of Fe2O3 catalysts, making them suitable for acid-catalyzed reactions [26]. Furthermore, ZrO2 modification can enhance the thermal stability and resistance to deactivation of Fe2O3 catalysts, prolonging their catalytic life [27]. These are just a few examples of how metal oxide modification can tailor the properties of Fe2O3 nanoparticles and improve their catalytic performance for various applications.
In a novel approach, this study investigated the catalytic activity of specifically designed CoFe2O4-NPs for the synthesis of 6-amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile. To create a more efficient and selective method for these valuable THPM derivatives, cobalt oxide was incorporated into the Fe2O3 structure to form CoFe2O4-NPs. It was hypothesized that the presence of cobalt would enhance the catalytic activity by introducing new active sites and improving electron transfer. A two-step synthesis process was employed to create the CoFe2O4-NPs, involving the initial preparation of a FeCo metal complex followed by its pyrolysis at 590 °C. To confirm successful synthesis and understand the properties of the nanoparticles, comprehensive characterization was performed using FTIR, XRD, TEM, SEM, XPS, and TGA techniques. These analyses provided valuable insights into the structure, morphology, and electronic properties of the CoFe2O4-NPs. Catalyst optimization was conducted using a standard reaction with malononitrile, benzaldehyde (or 4-chlorobenzaldehyde), and urea. The reaction was carried out under stirring at room temperature in absolute ethanol, and a catalyst concentration of 25 mg yielded the best results. Finally, the synthesized compounds were characterized using FTIR and NMR spectroscopy to confirm their structure and purity.

2. Experimental Section

2.1. Materials

All chemicals used in this study were of analytical grade and did not require further purification. Sodium bicarbonate (NaHCO3, 99%), tetramethylsilane (TMS, 99.9%), ethanol (C2H5OH,99.9%) hydroxylamine hydrochloride (NH2OH-HCl > 96%), ferrous ammonium sulfate (Fe(NH4)2(SO4)2·6H2O, 98.5%), cobalt chloride (CoCl2, 99.5%), sodium phenylpyruvate (NaC9H7O3 98%), malononitrile (C3H2N2, 99%), benzaldehyde (C6H5CHO, 98%), 4-chlorobenzaldehyde (C6H4ClCHO, 98%), and urea (NH2CONH2, 99%) were obtained from the following sources: EMD Chemical Inc (Gibbstown, NJ, USA), Alfa Aesar (Ward Hill, MA, USA), J. T. Baker (Radnor, PA, USA), Thermo Scientific Chemicals (Waltham, MA, USA), and Sigma Aldrich (St. Louis, MO, USA), respectively. Water was purified through reverse osmosis followed by a deionization (DI) process. The monitoring of the progress of all reactions and homogeneity of the synthesized compounds was carried out using thin-layer chromatography (TLC), aluminum sheets, silica gel 60 F254 (Merck, Darmstadt, Germany).

2.2. Synthesis of Cobalt Ferrite Nanoparticles

The experimental procedure to prepare the chelating ligand sodium phenylpyruvic acid oxime (NaPhPAO) follows the same procedure to prepare NaPAO [28]. Fe2O3, CoO, and NaPhPAO preparation were explained in Sections S2.1–S2.3, respectively, in the supporting information. The synthesis of CoFe2O4-NPs involved the preparation of a 1:1 FeCo(PhPAO)4 complex as an intermediate. This was achieved by combining ferrous ammonium sulfate hexahydrate solution (0.98 g, 2.5 mmol) with cobalt chloride solution (0.324 g, 2.5 mmol) and mixing until homogeneous. The resulting mixture was then added to a sodium phenylpyruvic acid oxime solution (2.0 g, 10 mmol), followed by thorough mixing. A yellowish solid precipitate formed, which was collected by filtration after 4 h, rinsed with water, and air dried, yielding 2.13 g of a yellowish solid. Subsequently, the pyrolysis of the 1:1 FeCo(PhPAO)4 complex at 590 °C was conducted. A sample of 1.01 g of the complex was placed in an empty 125 mL Erlenmeyer flask, loosely plugged with glass wool to minimize sample loss, and heated in a muffle furnace at 590 °C for 4 h, producing 0.183 g (18.1%) of the desired CoFe2O4-Nps.

2.3. Instrumentations

The synthesized catalysts Fe2O3-NPs, CoO-NPs, CoFe2O4-NPs, and 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives were characterized using the following analytical techniques: Fourier Transform Infrared Spectroscopy (FTIR) spectra were collected using a Shimadzu Prestige-21 IR spectrometer in the range of 450–4000 cm−1. X-ray Photoelectron Spectroscopy (XPS): XPS analysis was performed using a surface science instrument, X-probe, X-Ray000400 μm-FG ON. Powder X-ray diffraction (XRD) patterns were obtained using a Shimadzu LabX-6000 XRD X-ray diffractometer (Shimadzu, Kyoto, Japan) with Cu Kα radiation (λ = 1.54056 Å) at room temperature. Thermogravimetric Analysis (TGA) was conducted using a Shimadzu DTG-60H simultaneous (Shimadzu, Kyoto, Japan) DTA-TG Apparatus in a nitrogen environment. Transmission Electron Microscopy (TEM) images were acquired using a JEOL HRTEM, JEM-2100F (Tokyo, Japan). Scanning Electron Microscopy (SEM) images were obtained using a Hitachi SU-70 (Tokyo, Japan) field emission scanning electron microscope. Energy-Dispersive X-ray Spectrometry (EDX) and Atomic Mapping were performed using a Quanta FEG 250 SEM (Tokyo, Japan) with a field emission gun. Nitrogen adsorption–desorption isotherms were collected at a temperature of 77 Kelvin using a Micromeritics 3 Flex instrument (Norcross, GA, USA). Before measurements, samples were degassed under vacuum at 120 degrees Celsius for 6 h. Melting points were determined using an open capillary tube method on a digital Gallen-Kamp MFB-595 (Norcross, GA, USA) instrument. Nuclear Magnetic Resonance (NMR) Spectroscopy: 1H and 13C NMR spectra were acquired on a Bruker Ultra Shield NMR spectrometer (Billerica, MA, USA) at 500 MHz and 125 MHz, respectively. DMSO-d6 served as the solvent, and tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in parts per million (ppm).

2.4. Catalytic Reaction Conditions

The synthesized Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs catalysts were successfully employed in the synthesis of 6-Amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives. A model reaction was conducted to optimize the catalytic process using malononitrile, benzaldehyde (or 4-chlorobenzaldehyde), and urea as starting materials. The reaction was carried out at room temperature under stirring conditions, with absolute ethanol serving as the solvent and different doses of catalysts. The progress of all reactions and the purity of synthesized compounds were monitored using thin-layer chromatography (TLC). Aluminum sheets coated with silica gel 60 F254 (Merck) were used for TLC analysis.

3. Results and Discussions

3.1. Materials Design

The synthesis of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs involves a two-step process: complex formation and pyrolysis. In the first step, metal ions (Fe2+ or Co2+) coordinate with the electron-rich sites of sodium phenylpyruvic acid oxime (NaPhPAO), forming a metal-PhPAO complex. Subsequent pyrolysis of these complexes leads to the decomposition of the organic ligand and the formation of the corresponding metal oxide nanoparticles [29,30,31,32]. Fe2O3-NPs typically exhibit a rhombohedral hematite (Fe2O3) structure, while CoO-NPs adopt a cubic rock salt (NaCl) structure. CoFe2O4-NPs exhibit an inverse spinel crystal face-centered cubic (FCC) structure. In this structure, oxygen anions form a cubic close-packed lattice, with cobalt and iron cations occupying octahedral and tetrahedral interstitial sites [33,34,35,36,37]. Scheme S1a,b and Scheme 1 illustrate the synthesis pathways for each nanoparticle type. The unique catalytic properties of CoFe2O4-NPs compared with individual Fe2O3-NPs and CoO-NPs, for synthesizing 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives, are attributed to a synergistic effect between iron oxide and cobalt oxide nanoparticles. This synergistic effect creates a unique electronic environment that enhances reactant activation and facilitates product formation. Furthermore, the high surface area and porous structure of CoFe2O4-NPs provide numerous active sites, leading to improved catalytic efficiency and selectivity. These combined factors contribute to the superior performance of CoFe2O4-NPs as a heterogeneous nanocatalyst for this specific reaction, highlighting their novelty.

3.2. Materials Characterization Results

3.2.1. FTIR Analysis

FTIR spectroscopy was employed to characterize the synthesized metal complexes’ functional groups and chemical bonding. Figure 1a displays the FTIR spectra of Fe(PhPAO)2.2H2O, Co(PhPAO)2.2H2O, and Fe:Co(PhPAO)4. Key spectral features include a broad band around 3400 cm−1 attributed to H2O stretching vibrations, confirming the presence of water molecules in all compounds as indicated by “.2H2O” in their formulas. Bands around 3000 cm−1 are assigned to C-H stretching of the phenyl ring in PhPAO, while bands near 1660 cm−1 and 1640 cm−1 are characteristic of C=N and asymmetric COO stretching, respectively. A prominent band around 1380cm−1 is associated with symmetric COO stretching within the PhPAO ligand. The spectra of Fe(PhPAO)2.2H2O and Co(PhPAO)2.2H2O exhibit significant similarities, suggesting comparable coordination environments around the Fe(II) and Co(II) ions, with minor differences likely arising from variations in their electronic properties. The Fe:Co(PhPAO)4 spectrum displays a combination of features observed in the individual metal spectra, confirming the formation of a heteronuclear complex with both Fe and Co centers coordinated by PhPAO ligands. In the fingerprint region below 1500 cm−1, bands below 600 cm−1 are characteristic of metal-ligand vibrations, such as Fe-O and Co-O stretching and bending modes, providing insights into the strength and nature of these interactions. Bands between 600 and 1500 cm−1 are primarily associated with various bending vibrations of the PhPAO ligand, including C-H bending, C-O bending, and ring deformation modes, offering information about the conformation and orientation of the ligand within the coordination sphere of the metal ions [32,38].

3.2.2. XRD Analysis

XRD analysis was performed to determine the crystal structure and phase composition of the synthesized nanoparticles. Figure 2a presents the XRD patterns, which exhibit characteristic peaks corresponding to Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs. The peaks observed in each spectrum correspond to specific crystallographic planes of the respective nanoparticles. The intensity of these peaks indicates the relative abundance of each crystallographic plane. For Fe2O3-NPs, prominent peaks are observed at around 2θ = 33.2°, 35.6°, 40.9°, 49.5°, and 57.3°, which can be assigned to the (110), (113), (006), (211), and (015) Miller indices, respectively, which are characteristic of the hematite phase [32,39]. However, CoO-NPs exhibit peaks at approximately 2θ = 31.3°, 36.9°, 44.5°, 51.8°, and 62.5°, corresponding to the (111), (200), (220), (211), and (311) Miller indices, respectively, consistent with the rock salt structure of CoO-NPs [34,40]. The X-ray diffraction analysis of CoFe2O4-NPs nanoparticles revealed characteristic peaks at 2θ values of 30.27, 35.68, 37.30, 43.28, 53.92, 57.23, and 62.92 degrees, which align with the (220), (311), (222), (400), (422), (511), and (440) crystallographic planes, respectively. This pattern closely matches the reference standard for cobalt ferrite (JCPDS card No. 221086) [37,41].

3.2.3. TGA Analysis

The thermal decomposition behavior of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs was investigated using TGA, as illustrated in Figure 2b. The TGA curves revealed a substantial weight loss for all three samples within the 200–590 °C range, which is attributed to the decomposition of organic residues. Notably, the Fe2O3-NPs sample exhibited a plateau formation around 370 °C, indicating the development of a stable iron(III) oxide nanoparticle phase. Similarly, the CoO-NPs sample reached a plateau at a lower temperature, suggesting the formation of the cobalt(II) oxide nanoparticle structure. In contrast, the CoFe2O4-NPs sample displayed a gradual weight reduction extending up to 590 °C, consistent with the formation of cobalt ferrite nanoparticles [42]. The total weight loss percentages were approximately 82% for Fe2O3-NPs, 77% for CoO-NPs, and 82% for CoFe2O4-NPs, implying variations in the initial organic content among the samples.

3.2.4. The BET Surface Area

The BET surface area analysis, detailed in Figure 3 and Table 1, revealed that Fe2O3-NPs have a surface area of 46.2293 m2/g. c exhibit a slightly larger surface area of 50.3209 m2/g, while CoO-Nps show the lowest surface area at 36.0411 m2/g. Given the similar pore volumes and radii across all samples, the variations in surface area are primarily attributed to differences in their pore size distribution. The nitrogen adsorption–desorption isotherms for all three materials are classified as Type II, suggesting a multilayer adsorption process. Moreover, Fe2O3-NPs and CoFe2O4-NPs demonstrate a higher adsorption capacity compared with CoO-NPs. This enhanced adsorption is likely due to their larger surface areas and potentially unique pore structures, which offer more active sites for gas interaction [43,44].

3.2.5. The XPS Spectra

Figure 4 provides valuable insights into the chemical composition and electronic states of the synthesized CoFe2O4-NPs. The survey spectrum (a) shows the presence of Co 2p, Fe 2p, and O 1s peaks, confirming the presence of cobalt, iron, and oxygen in the sample. High-resolution spectra are then acquired for each element to gain a deeper understanding. The O 1s spectrum (b) reveals a main peak at around 529.9 eV, characteristic of lattice oxygen in metal oxides. The presence of a smaller peak at ~531.5 eV suggests the existence of surface-adsorbed species such as hydroxyl groups (-OH) or adsorbed water (H2O). The Fe 2p spectrum (c) exhibits a doublet structure with peaks at ~710.8 eV and ~724.2 eV, corresponding to Fe 2p3/2 and Fe 2p1/2, respectively [45,46]. These peak positions are consistent with the presence of Fe3+ in the Fe2O3 lattice. The Co 2p spectrum (d) shows a complex structure with multiple peaks. The main peaks at ~780.3 eV and ~793.9 eV are attributed to Co 2p3/2 and Co 2p1/2, respectively, indicating the presence of Co2+ in the CoFe2O4-NPs. The presence of shake-up satellites at higher binding energies further supports the assignment of Co(II) [47,48,49].

3.2.6. SEM and EDX Analysis

Figure 5 and Table 2 provide valuable insights into the morphology and particle size distribution of the synthesized nanoparticles. Fe2O3-NPs (a–c) exhibit a relatively uniform distribution of spherical-shaped nanoparticles with an average size in the range of 50–100 nm, indicating efficient control over the synthesis process. The particles appear well-dispersed, suggesting minimal interparticle interactions and agglomeration, which is crucial for achieving high surface area and catalytic activity. CoO-NPs (d–f) also display a spherical morphology with a relatively uniform size distribution. CoFe2O4-NPs (g–i) present a more complex morphology compared with the individual oxides, with a mixture of spherical and irregular-shaped particles and a broader size distribution. This morphological diversity in CoFe2O4-NPs likely arises from the competitive growth processes involving both Fe and Co ions during synthesis. The incorporation of both metal ions can lead to variations in nucleation rates, growth kinetics, and surface energies, ultimately resulting in a more complex and heterogeneous particle morphology [50,51].

3.2.7. TEM Images

Figure 6 provides valuable insights into the morphology, size, and crystallinity of the synthesized nanoparticles. Fe2O3-NPs (a–c) exhibit a relatively uniform distribution of spherical nanoparticles with an average size of 10–20 nm, as confirmed by scale bars. High-resolution TEM (b) and SAED pattern (c) reveal well-defined lattice fringes, indicating their crystalline nature. CoO-NPs (d–f) also display a spherical morphology with a uniform size distribution (10–30 nm) and exhibit clear lattice fringes in high-resolution TEM (e) and distinct diffraction rings in the SAED pattern (f), confirming their crystallinity. CoFe2O4-NPs (g–i) show a more complex morphology compared with the individual oxides, with a mixture of spherical and irregular-shaped particles and a broader size distribution (10–30 nm). High-resolution TEM (h) reveals lattice fringes, and the SAED pattern (i) confirms the polycrystalline nature of CoFe2O3-NPs with multiple diffraction rings. The incorporation of both Fe and Co ions in the CoFe2O4-NPs likely influences the nucleation and growth processes, leading to the observed morphological variations compared with the individual oxides.

3.3. Catalytic Activity Results

3.3.1. Application of CoFe2O4-NPs for Biginelli Reaction

The synthesized CoFe2O4-NPs proved to be highly effective catalysts for the Biginelli reaction, leading to the synthesis of 6-Amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (Scheme 2). To optimize the reaction, the effect of catalyst concentration was studied while keeping other reactants constant. As Table 3 shows, the optimal catalyst dose was found to be 25 mg when using absolute ethanol as the solvent under ambient conditions. Although the reaction could proceed without a catalyst, the presence of CoFe2O4-NPs significantly enhanced the reaction rate. A noticeable increase in yield was observed with just 5 mg of catalyst. Further optimization showed a slight improvement in yield and a reduction in reaction time at 25 mg; increasing the catalyst dose beyond this point did not provide any further enhancement. These findings demonstrate the ability of our synthesized nanomaterial to efficiently catalyze the Biginelli reaction under mild conditions. The spectral data of the synthesized compounds derivatives (4a) and (4b) are provided in Sections 6-Amino-2-oxo-4-phenyl -1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a) and 6-Amino-2-oxo-4-chlorophenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4b).

3.3.2. Proposed Reaction Mechanism

Scheme 3 illustrates the proposed mechanism for the synthesis of 6-amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 4a and 4b, a multi-step process catalyzed by 25 mg of CoFe2O4-NPs. The reaction commences with a Knoevenagel condensation between the aldehyde (benzaldehyde or 4-chlorobenzaldehyde 1a, b) and malononitrile 2, leading to the formation of an intermediate enamine. This step involves the nucleophilic attack of the activated methylene group in malononitrile on the carbonyl carbon of the aldehyde, followed by a dehydration reaction. Subsequently, the enamine undergoes a cyclization reaction with urea 3, forming a dihydropyrimidine intermediate. This cyclization step involves the urea nitrogen’s nucleophilic attack on the enamine intermediate’s imine carbon, followed by a ring-closing step. The final step is a tautomerization reaction, converting the dihydropyrimidine intermediate into the desired 1,2,3,4-tetrahydropyrimidine-5-carbonitrile product [52,53].
The role of the CoFe2O4-NPs catalyst in this reaction is multifaceted. Firstly, it acts as a Lewis acid, facilitating the proton transfer steps involved in the Knoevenagel condensation and Michael addition reactions. The Lewis acidic nature of the catalyst, particularly the presence of Fe3+ and Co2+ ions on the surface, helps to activate the carbonyl group of the aldehyde and the methylene group of malononitrile. This activation enhances the nucleophilicity of the methylene group and the electrophilicity of the carbonyl carbon, thereby promoting the initial condensation step. Secondly, the CoFe2O4-NPs catalyst serves as a heterogeneous support for the reaction, providing a high surface area for reactant adsorption and interaction. The high surface area of the nanoparticles allows for efficient contact between the reactants and the catalyst, increasing the collision frequency and enhancing the reaction rate. Furthermore, the presence of active sites on the catalyst surface, such as coordinatively unsaturated sites (CUS) or surface defects, can anchor the reactants and facilitate their interaction [54,55].

3.3.3. Application of Fe2O3-NPs and CoO-NPs for Biginelli Reaction

To elucidate the role of the CoFe2O4-NPs catalyst, comparative experiments were conducted using CoO-NPs and Fe2O3-NPs separately under identical reaction conditions. Both CoO-NPs and Fe2O3-NPs exhibited significant catalytic activity in the Knoevenagel condensation step, efficiently producing the corresponding adducts (5a and 5b), Scheme 4, with high yields. The spectral data of the synthesized compounds derivatives (5a) and (5b) are provided in Sections 2-benzylidenemalononitrile (5a) and 2-(4-chlorobenzylidene)malononitrile (5b), respectively. However, neither CoO-NPs nor Fe2O3-NPs alone facilitated the formation of the desired Biginelli products (4a and 4b). These findings strongly suggest that a synergistic effect between CoO and Fe2O3 within the CoFe2O4-NP nanomaterial is crucial for catalyzing the complete Biginelli reaction. The interaction between them likely creates a unique electronic and structural environment within the CoFe2O4-NPs. This synergistic effect may lead to changes in the catalyst’s electronic properties, such as electron density distribution and Lewis acidity, which can influence its ability to activate reactants, stabilize intermediates, and facilitate proton transfer during the Michael addition and cyclization steps. Moreover, the CoFe2O4-NPs may provide a more favorable surface for reactant adsorption and reaction, enhancing catalytic efficiency.
The superior catalytic performance of CoFe2O4-NPs in the Biginelli reaction, significantly outperforming individual Fe2O3-NPs and CoO-NPs, stems from a combination of distinct structural and electronic properties. Despite relatively similar BET surface areas, CoFe2O4-NPs exhibit a higher pore volume (0.280811 cm3/g) compared with Fe2O3-NPs (0.180518 cm3/g) and CoO-NPs (0.183855 cm3/g), leading to an enhanced porous structure with an increased number of active sites and improved reactant accessibility. Each oxide possesses a unique crystal structure—rhombohedral hematite for Fe2O3-NPs, cubic rock salt for CoO-NPs, and inverse spinel face-centered cubic (FCC) for CoFe2O4-NPs—which profoundly influences their electronic environments and catalytic behaviors. XPS O 1s analysis of CoFe2O4-NPs reveals the presence of surface hydroxyl groups (~531.5 eV), which can act as Brønsted acid sites, contributing to overall acidity and facilitating crucial proton transfer for the Biginelli reaction. Furthermore, the Fe 2p spectrum confirms Fe3+ and the Co 2p spectrum indicates Co2+, with shake-up satellites supporting their presence. The coexistence and interaction of Fe3+ and Co2+ within the inverse spinel structure create a unique electron density distribution, likely influencing the Lewis acidity of metal centers and enhancing active site accessibility. This bimetallic synergy optimizes the porous structure for more active sites and tailors their electronic properties, ultimately leading to the unparalleled catalytic efficiency and selectivity observed in the complete Biginelli reaction, unlike the limited activity of the individual oxides [56,57].

3.3.4. Spectral Data of the Synthesized Compounds

6-Amino-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)
Colorless crystals, 96% yield m.p. 199–200 °C. IR (KBr, cm−1) ν = 3402, 3228 (NH2), 3157 (NH), 2220 (CN), 1685 (CO), 1597(C=C) 1H-NMR (500 MHz, DMSO-d6): 1H-NMR (500 MHz, DMSO-d6): 7.76 (s, 1H, NH), 7.50–7.30 (m,5H, ph-), 7.28–7.01, 6.45 (br.s, 2H, NH2,), 6.39 (s, 1H, NH,) 5.42 (s, 1H, CH). 13C NMR (125 MHz, DMSO-d6) δc = 162.10, 153.40, 140.55, 131.10, 128.52, 126.22, 115.40, 71.33, 46.42.
6-Amino-2-oxo-4-chlorophenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4b)
Colorless crystals, 95% yield p.m. 178–179 °C. IR (KBr, cm−1) ν = 3419, 3228 (NH2), 3132 (NH), 2218 (CN), 1660(CO), 1591(C=C) 1H-NMR (500 MHz, DMSO-d6): 7.71 (s, 1H, NH), 7.45–7.42 (m,2H, Ar-H), 7.28–7.01 (m,2H, Ar-H), 6.95 (br.s, 3H, NH2, NH), 5.30 (s, 1H, CH). 13C NMR (125 MHz, DMSO-d6) δc = 163.65, 152.20, 138.67, 134.55, 131.34, 126.29, 114.22, 73.28, 48.44.
2-Benzylidenemalononitrile (5a)
Colorless crystals, 97% yield m.p. 83–84 °C. IR (KBr, cm−1) ν = 3329, 3228 (2NH2), 2223 (CN), 1591(C=C) 1H-NMR (500 MHz, DMSO-d6): 8.51 (s, 1H, CH=), 7.96–7.58 (m,5H, ph). 13C NMR (125 MHz, DMSO-d6) δc = 81.50, 113.10, 114.10, 129.42, 130.46, 134.29, 161.16.
2-(4-Chlorobenzylidene)malononitrile (5b)
Colorless crystals, 98% yield m.p. 163–164 °C. IR (KBr, cm−1) ν = 2222 (CN), 1579(C=C) 1H-NMR (500 MHz, DMSO-d6): 8.54 (s, 1H, CH=), 7.97 (d, 2H, J = 15 Hz, Ar-H), 7.73 (d, 2H, J = 15 Hz, Ar-H).13C NMR (125 MHz, DMSO-d6) δc = 82.09, 112.90, 113.95, 129.62, 129.96, 132.06, 139.05, 159.98.
Comparison with Other Catalysts for the Biginelli Reaction in the Literature
The CoFe2O4-NPs catalyst demonstrates notable performance for the Biginelli reaction, particularly due to its operation at room temperature and the ease of magnetic separation, highlighting a significant stride toward greener chemistry. While specific numerical yields and reaction times are explicitly provided in the study for CoFe2O4-NPs, it consistently reports “high yields” and “best results” with a relatively low catalyst load of 25 mg, suggesting high efficiency under mild conditions. In comparison to other nanocatalysts in the Table 4, such as Cu@SBA-15 and C3N4/Fe3O4/NiFe-LDH, which achieve high yields (up to 94–96%) but often require elevated temperatures (100 °C and 80 °C, respectively) or precise time controls (5–15 min), the room temperature operation of CoFe2O4-NPs stands out for energy efficiency. Although some catalysts like Nano-ZrO2 also report good yields (90%) and relatively short times (60 min), they typically necessitate reflux conditions. The novelty of the CoFe2O4-NPs system lies in its ability to facilitate the Biginelli reaction effectively at ambient temperature with straightforward magnetic recyclability, addressing common drawbacks of traditional methods and offering advantages in terms of mild conditions, efficient catalyst recovery, and enhanced catalytic activity compared with many previously reported Biginelli reaction catalysts.

4. Conclusions and Outlook

This study successfully synthesized and characterized CoFe2O4-NPs as a novel and efficient catalyst for the Biginelli reaction, yielding valuable 6-amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives. The CoFe2O4-NPs, prepared via a two-step metal-organic complex pyrolysis, exhibited a unique spinel structure and optimized porous morphology, thoroughly confirmed using XRD, TEM, SEM, XPS, and TGA. Demonstrating superior catalytic activity compared with individual Fe2O3-NPs and CoO-NPs, the CoFe2O4-NPs’ performance is driven by synergistic interactions between iron and cobalt within the bimetallic system. This synergy arises from the distinct electronic and structural properties of CoFe2O4-NPs, which enhance reactant activation, stabilize intermediates, and facilitate the multi-step reaction mechanism. Under optimized conditions (25 mg CoFe2O4-NPs, mild temperature), efficient synthesis of the desired products with high yields was achieved. This work underscores the potential of bimetallic nanoparticles as effective catalysts for complex organic transformations. Looking ahead, critical future endeavors include the investigation of kinetic data and time-dependent yield plots to further substantiate reaction rates and differentiate between thermodynamic and kinetic control. To demonstrate broader applicability, testing additional aldehyde substrates bearing diverse electron-donating and withdrawing groups is also a key direction. Furthermore, assessing the reusability of the catalyst through multiple cycles and analyzing potential leaching (e.g., via ICP-OES or XPS after use) will be crucial. Finally, future studies will explore the extension of this catalyst system to other multicomponent reactions and evaluate its scalability for industrial relevance, paving the way for more sustainable and efficient synthetic strategies.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ceramics8030102/s1. Scheme S1. The general procedure of preparing Fe2O3-Nps and CoO-Nps from ferrous ammonium sulfate hexahydrate, cobalt chloride, and Sodium phenylpyruvic acid oxime (PhPAO).

Author Contributions

Methodology, W.M.A.; Validation, E.M.E.-T.; Investigation, W.M.A., E.M.E.-T. and I.S.S.; Writing—original draft, A.M.B.; Writing—review & editing, A.M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Deanship of Graduate Studies and Scientific Research, Jazan University, Saudi Arabia, through project number: (RG24-S062).

Data Availability Statement

The original contributions presented in this study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Acknowledgments

The authors gratefully acknowledge the funding of the Deanship of Graduate Studies and Scientific Research, Jazan University, Saudi Arabia, through project number: (RG24-S062).

Conflicts of Interest

The authors declare no conflicts of interest.

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Scheme 1. General procedure for synthesizing CoFe2O4-NPs [35], from ferrous ammonium sulfate hexahydrate, cobalt chloride, and sodium phenylpyruvic acid oxime (NaPhPAO).
Scheme 1. General procedure for synthesizing CoFe2O4-NPs [35], from ferrous ammonium sulfate hexahydrate, cobalt chloride, and sodium phenylpyruvic acid oxime (NaPhPAO).
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Figure 1. FTIR spectra of (a) Fe(PhPAO)2.2H2O, Co(PhPAO)2.2H2O, and Fe:Co(PhPAO)4 metal complexes in the full spectral range (500–4000 cm−1) and (b) the fingerprint region (below 1500 cm−1).
Figure 1. FTIR spectra of (a) Fe(PhPAO)2.2H2O, Co(PhPAO)2.2H2O, and Fe:Co(PhPAO)4 metal complexes in the full spectral range (500–4000 cm−1) and (b) the fingerprint region (below 1500 cm−1).
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Figure 2. (a) XRD patterns and (b) TGA thermograms of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs.
Figure 2. (a) XRD patterns and (b) TGA thermograms of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs.
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Figure 3. Nitrogen adsorption–desorption isotherms of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs.
Figure 3. Nitrogen adsorption–desorption isotherms of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs.
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Figure 4. XPS Survey Spectrum (a) and high-resolution spectra of (b) O 1s, (c) Fe 2p, and (d) Co 2p for CoFe2O4-NPs.
Figure 4. XPS Survey Spectrum (a) and high-resolution spectra of (b) O 1s, (c) Fe 2p, and (d) Co 2p for CoFe2O4-NPs.
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Figure 5. Scanning Electron Microscope (SEM) images of (a–c) Fe2O3-NPs, (d–f) CoO-NPs, and (g–i) CoFe2O4-NPs.
Figure 5. Scanning Electron Microscope (SEM) images of (a–c) Fe2O3-NPs, (d–f) CoO-NPs, and (g–i) CoFe2O4-NPs.
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Figure 6. Transmission Electron Microscopy (TEM) images of Fe2O3-NPs (a–c), CoO-NPs (d–f), and CoFe2O4-NPs (g–i).
Figure 6. Transmission Electron Microscopy (TEM) images of Fe2O3-NPs (a–c), CoO-NPs (d–f), and CoFe2O4-NPs (g–i).
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Scheme 2. Using CoFe2O4-NPs as a catalyst for preparing 6-Amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile via the Biginelli reaction.
Scheme 2. Using CoFe2O4-NPs as a catalyst for preparing 6-Amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile via the Biginelli reaction.
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Scheme 3. Proposed mechanism for the Biginelli reaction catalyzed by CoFe2O4-NPs.
Scheme 3. Proposed mechanism for the Biginelli reaction catalyzed by CoFe2O4-NPs.
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Scheme 4. Synthesis of Knoevenagel adducts 5a and 5b.
Scheme 4. Synthesis of Knoevenagel adducts 5a and 5b.
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Table 1. BET surface area, pore volume, and radius of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs.
Table 1. BET surface area, pore volume, and radius of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs.
Fe2O3-NpsCoO-NpsCoFe2O4-Nps
Surface area (m2/g)50.320936.041146.2293
Pore Volume (cm3/g)0.1805180.1838550.280811
Pore radius (nm)1.927821.931091.9242
Table 2. EDX analysis of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs.
Table 2. EDX analysis of Fe2O3-NPs, CoO-NPs, and CoFe2O4-NPs.
MaterialsElementWeight %Atomic %Net Int.Error %
Fe2O3-NpsO K26.7155.9945.759.06
FeK73.2944.0187.394.24
CoO-NpsO K59.5584.4383.237.23
CoK40.4515.57119.13.34
CoFe2O4-NpsO K64.7586.8377.516.92
FeK16.686.4144.966.02
CoK18.566.7643.546.27
Table 3. Effect of CoFe2O4-NPs catalyst dose on the synthesis of 4a, b via the Biginelli reaction.
Table 3. Effect of CoFe2O4-NPs catalyst dose on the synthesis of 4a, b via the Biginelli reaction.
Entry aCoFe2O4-Nps Nanocatalyst
Catalyst Dose (mg)Time (min)Yield (%) b
10600
2560trace
3105040
4154070
5203090
6253095–96
7303095–96
a Reaction conditions: [1a, b (0.01 mol), 2 (0.01 mol), 3 (0.01 mol), ethanol (20 mL) under stirring at room temperature]. b Isolated yield of pure product.
Table 4. Comparison of CoFe2O4-NPs with other catalysts for the Biginelli reaction.
Table 4. Comparison of CoFe2O4-NPs with other catalysts for the Biginelli reaction.
CatalystTemperature (°C)Time (min)Yield (%)Reference
CoFe2O4-NPs253095–96This work
Fe2O3-NPs25600This work
CoO-NPs25600This work
Cu@PMO-IL705096[58]
Nano-g-Fe2O3-SO3H6018091[59]
SiO2-BaCl2/SF854593[60]
Mn@PMO-IL704595[61]
SiO2-H2PO36015092[62]
ErCl31203092[63]
SSi-GO802094[64]
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Alamier, W.M.; El-Telbani, E.M.; Syed, I.S.; Bakry, A.M. Cobalt Ferrite Nanoparticles: Highly Efficient Catalysts for the Biginelli Reaction. Ceramics 2025, 8, 102. https://doi.org/10.3390/ceramics8030102

AMA Style

Alamier WM, El-Telbani EM, Syed IS, Bakry AM. Cobalt Ferrite Nanoparticles: Highly Efficient Catalysts for the Biginelli Reaction. Ceramics. 2025; 8(3):102. https://doi.org/10.3390/ceramics8030102

Chicago/Turabian Style

Alamier, Waleed M., Emad M. El-Telbani, Imam Saheb Syed, and Ayyob M. Bakry. 2025. "Cobalt Ferrite Nanoparticles: Highly Efficient Catalysts for the Biginelli Reaction" Ceramics 8, no. 3: 102. https://doi.org/10.3390/ceramics8030102

APA Style

Alamier, W. M., El-Telbani, E. M., Syed, I. S., & Bakry, A. M. (2025). Cobalt Ferrite Nanoparticles: Highly Efficient Catalysts for the Biginelli Reaction. Ceramics, 8(3), 102. https://doi.org/10.3390/ceramics8030102

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