High-Power and High-Performance Catalyst for Suzuki Coupling Reaction

Abstract

In this project, the aim was to carry out the Suzuki reaction using a new and unique catalyst with a base of Fe₃O₄ magnetic nanoparticles coated using a new ligand. In fact, this magnetic catalyst has an inhomogeneous surface to create a connection between the organic and aqueous phases so that the carbon–carbon coupling reaction is completely performed on its large surface. The structure of this catalyst uses two metals, nickel and cobalt, which are coated on a bed of amino linkers and propel the Suzuki coupling reaction at high speed on the catalyst surface. The products obtained are from ideal and optimal conditions with an efficiency of over 98%. The catalyst has a recovery power of over 96% and has enough power to perform several coupling reactions several times. Lastly, the magnetic nanocatalyst is easily separated from the reaction medium by an external field and has 100% power when performing other reactions.

1. Introduction

For many years, in the field of nanotechnology, special attention has been paid to nanoparticles and its applications, among which magnetic nanoparticles have many practical advantages. Their several advantages include a large catalytic surface to create a heterogeneous surface to accelerate a variety of chemical reactions, easy synthesis of inexpensive materials such as iron salts, and easy separation from the reaction solution by an external magnetic field with high loading of various ligands (organic and metal) [1].

These nanoparticles have many applications in the chemical and medical industries as nanocatalysts in the reactions of atoms pairing with each other, as well as for separating and purifying medical enzymes and biomolecules in vitro. One of the reactions that has been considered by researchers for many years is the carbon–carbon coupling reaction, which is obtained from the reaction of two aryl halide reactants with phenyl boronic acid, following Akira Suzuki’s efforts to expand this coupling for which he won the Nobel Prize in 2010 [2,3,4,5,6].

The importance of this type of coupling both in the chemical industry and in the medical industry is due to the synthesis of important and vital structures that allow the production of useful and biologically active compounds for the production of drug biomolecules, attracting the attention of many scientists [7,8,9,10,11,12].

To evaluate the performance of magnetic nanocatalysts, special attention should be paid to the surface of nanoparticles because their surface may be slightly oxidized in the presence of air, and their efficiency may be reduced. For this purpose, the surface can be covered with insulating and very useful materials such as silica (SiO₂) to prevent excess oxidation of their surface and to prevent clumping or loss of their reactivity surfaces, which is also a biodegradation advantage. Coating also confers plasticity to nanoparticles in targeted drug transfers so that they can be easily separated from the reaction medium by an external field without causing toxicity at the transport site. Applications of targeted drug delivery, adsorption, and release, as well as the antibacterial properties of magnetic nanocatalysts, have been presented in previous reports [13,14,15,16,17].

In the Suzuki reaction, carbon–carbon coupling has been used to create di-aryl products that contain very important ligands with many applications in the medical industry, such as creating pharmaceutical products with anti-inflammatory, antiplatelet, and antiviral properties [18,19,20,21].

Today, all efforts to create structures with amino groups and oxygen positioned in catalytic structures are made using ligands to create a suitable space for loading a variety of intermediate metals (which have the catalytic power to accelerate the Suzuki coupling reaction on the magnetic nanoparticle substrate). The existence of such functional groups has greatly helped to accelerate the Suzuki coupling reaction with the loaded metal to synthesize the resulting compounds with a high percentage of efficiency in the development of drugs or biological compounds [22,23].

In this project, the main goal was to introduce a potential catalyst of the Suzuki reaction with much better reaction conditions than other catalysts and a much higher percentage of products obtained by the material. This nanocatalyst is made of magnetic nanoparticles that have magnetic properties (controlled by an external field), very good particle size, and a very large catalyst surface to advance the carbon–carbon coupling reaction. Nanoparticles ideally have a size of about 100 nm, and the efficiency of the products obtained at a temperature of 70 °C is more than 98%. The bulk ligand tested on a magnetic nanoparticle substrate by IR, NMR, and EDX analysis is a new ligand used in the construction of catalysts. Due to the optimal conditions and higher efficiency, this nanocatalyst has a better performance than other catalysts, with an estimated 25% higher power. An overview of the Suzuki reaction is shown in this project, which, in addition to showing the conversion of reagents into a product (coupling), provides ¹H-NMR analysis to identify and confirm the resulting product along with the reaction conditions (Scheme 1).

2. Results and Discussion

2.1. General Overview of Nanocatalysts

The aim of this project was to design a unique catalyst with very successful performance in most possible reactions that is able to successfully undergo IR analyses after synthesis. The main structure of the catalyst is based on a shell/core structure with a core of magnetite nanoparticles and a shell of a bulky ligand that is eventually attached to the silicate structure. The important thing about these magnetic nanoparticles is the coordination of the particles that make up their structure, in which are in the range of 0 to 100 nm, typically less than 20 nm in medical applications (as widely used in previous projects). Another important point to consider is the very large catalytic surface suitable for a variety of chemical and even biological reactions, as well as their unique property of being easily separated from the reaction medium by an external magnetic field.

2.2. Analysis Tools of Detection

2.2.1. SEM and TEM Analyses

Synthetic nanocatalysts should be identified using a series of devices including SEM and TEM analyses to determine nanoparticle morphology and nanoparticle diameter, as well as produce images of their inner and outer surface for evidence of the surface crystalline order. These analyses are performed within the dimensions of 50–500 nm, and the shape information of the nanoparticles is shown schematically, allowing the presence of the coated metal and ligands on the surface of the nanoparticles to be identified (Figure 1).

2.2.2. FTIR Analysis

FTIR analysis is important for identifying the functional groups in a compound, revealing the presence of functional groups and their links. This analysis is typically reported between 400 and 4000 cm⁻¹. In the nanocatalyst synthesized in this project, the iron–oxygen bond in the range of 500 cm⁻¹ revealed the core structure, i.e., magnetic nanoparticle, presenting a very large peak that gradually became more regular and sharper with the coating of the nanocatalyst and ligand. The loose structure or shell can subsequently be identified, consisting of a silicate in the form of a silyl–oxygen–silyl bond with a strong peak around 1000 cm⁻¹. The presence of the silica coating prevents excessive oxidation of the nanocatalyst surface and grants it good biocompatibility and biodegradability. The C₂₀H₁₉N₃O ligand to be placed on the silica coating, resulted in a bulge next to the silicate peak, thus generating a bifurcation. Peaks related to nitrogen were located in the area of oxygen peaks, but could also be independently identified around 3300 cm⁻¹. Hydrogen–carbon bonds of ring structures generated a peak around 3100 cm⁻¹. If we compare the spectra, we can come to the conclusion that the peaks became more regular and the structure of the nanocatalyst became more complete, when considering the presence of carbon–hydrogen, carbon–carbon, and free amine bonds (Figure 2).

2.2.3. EDX Analysis

EDX analysis allows characterizing the nanoparticles as a function of the percentage of elements contained. This is also a valuable tool for identifying links between elements, whereby overlapping peaks indicate that two elements are related, regardless of their size. Indistinguishable peaks indicate the presence of a covalent or van der Waals bond (such as a hydrogen or electrostatic bond). Results are expressed as the percentage of an element in units of keV (Figure 3).

2.2.4. The XRD spectrum of Fe₃O₄@L/Co/Ni

X-ray diffraction allows analyzing the number of electron transmissions using X-rays in terms of the energy levels in orbital layers and their electron capacities. Fe₃O₄ presented peaks at 2θ = 30.1°, 35.4°, 43.2°, 53.7°, 56.9°, and 62.9° with bands visible at 220, 311, 422, 511, and 440 cm⁻¹ (Figure 3), indicating that Fe₃O₄ was successfully synthesized without an effect on its crystalline structure. However, two new peaks were observed at 2θ = 44° and 56°, corresponding to bands at 111 and 200 cm⁻¹, which confirmed the complexation of Co to the surface of the Fe@L/Co/Ni magnetic nanoparticles with a silica substrate. Furthermore, peaks at 2θ = 44° and 56° for Co and 34° and 57° for Ni, according to the Scherrer equation, suggested that the crystalline nanoparticles of Co/Ni (0) were about 9 nm in size (Figure 3).

2.2.5. VSM Analysis

VSM is used to measure the amount of magnetometer saturation according to the type of magnetic nanoparticle (para-, dia-, or ferromagnetic), as well as the amount of magnetism in the magnetic field. Therefore, for this purpose, analysis was performed in terms of emu/g in the units of the magnetic field (kOe). The magnetic nanoparticles (Fe₃O₄) presented results of 57 emu/g at 25–100 °C and pH = 8–12, in contrast to 21 emu/g for silica/(C₂₀H₁₉N₃O) groups and 13 emu/g for Co/Ni fixed to magnetic nanoparticles. Lastly, after synthesis of the Fe₃O₄/L/Co/Ni nanocomposite, the degree of magnetization was 31 emu/g. This decrease was due to the magnetic nanoparticles becoming superparamagnetic, indicating their excellent quality for the Suzuki coupling reaction, with a 27% improvement compared to previous studies (Figure 3).

2.3. General Overview of Suzuki Reaction

In this section, an attempt was made to apply the synthesized nanocatalysts (analyzed by SEM, TEM, FTIR, etc.) in the Suzuki coupling reaction (Scheme 2), i.e., carbon–carbon bonding. This reaction was performed under optimal conditions, i.e., using the minimum amount of catalyst sample, at the right temperature, with adequate levels of salt and cheap base, resulting in products with an efficiency of over 98%. The purpose of this study was to optimize the reaction conditions and synthesize products with suitable efficiency compared to the literature.

2.4. The Amount of Nanocatalyst

According to previous studies, most nanocatalysts used in this coupling reaction are typically above 0.02 g, which is not ideal for the standardization of a reaction. Thus, in order to increase the efficiency of the catalyst and prevent wasting of the sample, the least amount of catalyst should be used. Therefore, the amount of catalyst used in this reaction was 0.2.% mol, i.e., an extraordinarily low amount of ~0.002 g. As shown in the table, this amount of catalyst was enough to complete the reaction (

Table 1. Suzuki coupling reaction results.

Entry	Salt	Solvent	Base	Cat. (mg)	Temperature (°C)	Time (min)	Yield (%) a	TON	TOF (h−1)
1	NaSCN	CH3CN	DABCO	10	70	90	80	68	6.8
2	Cs2CO3	THF	KF	10	110	100	85	74	13.5
3	K2CO3	DMSO	KF	5	100	80	92	54	27
4	NaHCO3	DMF/H2O	NaOH	5	70	70	90	59	8.9
5	K2CO3	DMF/H2O	KI	0.75	50	60	96	82	41
6	K2CO3	DMF/H2O	KI	0.5	70	55	96	86	43
7	K2CO3	DMF/H2O	KI	1	80	45	98	92	47
8	K2CO3	DMF/H2O	KI	1.5	100	35	99	94	49.5
9	K2CO3	DMF/H2O	KI	2	70	60	99	97	48.5
10	-	Not cat.	-	-	100	120	-	89	44.5
11	K2CO3	Fe3O4	KI	20	100	22 h	trace	90	45
12	K2CO3	Fe/L	KI	20	100	20	20	87	43.5
13	-	Co/Ni (OAc)2·H2O	-	20	70	14	65	82	41
14	K2CO3	Fe/L/Co/Ni	KI	2	70	60	99	48	24

^a Yield refer isolated products.

). By examining the Suzuki reaction using magnetite nanoparticles (without ligand), as well as with ligand and cobalt/nickel nanoparticles (alone), the efficiency of the obtained products was much lower over time (even with a sample size of 20 mg) compared to when the nanocatalyst was used.

2.5. Solvent Type

Although solvents are not always needed for reactions, some organic reactants only dissolve in organic solvents. However, since the tendency of two reactants to react with each other in different solvents (whether organic or inorganic) should be tested, the best conditions involve the use of a harmless green solvent. Therefore, the role of the solvent is very effective in bringing the two phases closer, providing the exchange of functional groups and the creation of a covalent bond between the two organic reactants. On the other hand, because a strong base is needed to help remove the boronic group from both sides of the reactants in this reaction, a compound with a new covalent bond is formed as a coupling. As shown in Table 1, the solvent used was 1 cc of DMF/H₂O for C–C (single bond) with 0.2 mL of KI. Water was selected as a green solvent with optimal results at 70 °C, with a high ability to combine the reactants.

2.6. Salt

Salts are used as a substrate to adjust the pH of the reaction medium and mediate the ion exchange between two reactants. Potassium carbonate salt (0.02 g) was found to be ideal as it did not ionize itself or cause a series of unwanted reactions (Table 1).

2.7. Time

The reaction involving the magnetic nanoparticles, salt, and solvent creates a level of inhomogeneity between the catalyst and the reactants, which decreases with increasing temperature. Although some reactions could proceed at room temperature, a substantial amount of catalyst was required; thus, the ideal temperature for this reaction was 70 °C (Table 1). According Table 1, the nanocatalyst presented a high efficiency of 98% in a reaction time of (0.5–1) h.

2.8. Correct Identification of the Obtained Products

In order to identify the products, a TLC solution was taken, after 5 min, and hexane, ethanol, and ethyl acetate were used as solvents to elute nonpolar and polar products. As the product composition percentage was 100%, the organic product could be easily separated from the aqueous phase by an organic solvent using a decanter funnel (i.e., ethyl acetate). Then, for further studies, a tablet was generated using potassium bromide and analyzed in an IR device. It can be concluded that the proposed nanocatalyst (last row) was ideal compared to other catalysts in the literature (

Table 2. Comparison of Fe@L/Co/Ni nanocatalyst with other catalysts.

Entry	Catalyst	Conditions	Time (h)	Yield (%) a	References
1	Cu2–β-CD (0.01 mmol), K2CO3 (3 equiv.)	DMF (1 mL), 90 °C	48	90	[24]
2	Cu(OAc)2 (5–20 mol %), myristic acid (10–40 mol%)	Toluene (2 mL), r.t.	24	92	[25]
3	CuFAP (100 mg)	Methanol (4 mL), r.t.	3	90	[26]
4	Cu-BIA-Si-Fe3O4 (1.5 mol%), KF (0.2 mmol)	DMSO (4 mL), 100 °C	2.5	96	[27]
5	Cu-BIA-Si- Fe3O4 (1.5 mol%) K2CO3 (1 mmol)	DMSO, 80 °C	2	95	[28]
6	Palladium N-heterocyclic carbene (0.02 mmol), K2CO3 (1.2 eq)	i-PrOH (4 mL), r.t.	6	98	[29]
7	Pd(OAc)2/LHX (15 mol%)	DMF/H2O (2 mmol), 50 °C	3	93	[30]
8	Aminomethyldiphosphine–Pd(II) (1.2 mmol)	DMF/H2O (3/3 mL), 80 °C	7	95	[31]
9	Pd (1.0 mol) K3PO4·3H2O (1.5 mmol)	H2O/ethanol (2 mL), 80 °C	3	98	[32]
10	Cross-linked poly(ITC-HPTPy)-Pd (0.23 mol%) K2CO3 (1.5 mmol)	H2O/ethanol (3 mL), 80 °C	2	98	[33]
11	CuCl2 (10 mol%), 4,40-di-tert-butyl-2,20-bipyridine (10 mol%), DCM (1.0 mL)	Cs2CO3 (2.0 equiv), r.t.	24	78	[34]
12	Hercynite@L-methionine-Pd (0.1 mol%) K2CO3 (3 mmol)	ethanol (3 mL), 80 °C	1.5	80	[35]
13	GO/Fe3O4/Pd nanocomposite (0.36 mol) K2CO3 (3 mmol)	H2O/ethanol (3 mL), 80 °C	10	80	[36]
14	Cu(II)–β-cyclodextrin (0.1 eq)	DMF, 90 °C	10	80	[37]
15	Cu-PAR (0.05 g, 0.0129 mmol) KOH (1 mmol)	DMSO, 120 °C	14	94	[38]
16	Fe@L/Co/Ni (0.2 mol%)	DMF/KI, 70 °C	0.5–1	99	present

^a Yield refer isolated products, ref. [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38].

and

Table 3. Derivatives provided of Suzuki coupling reaction.

Entry	Arylhalide + Phenyl Boronic Acid	Product	Time (min)	Yield (%) a	TON	TOF (h−1)	Found	Reported Melting Point °C
1	Ortho-NO2PhI		45	100	87	43.5	102–104	102.8
2	Para-NO2PhI		50	99	86	43	102–104	103.2
3	NO2PhI		60	98	95	47.5	Oil	Oil
4	2,4,6-tri-NO2PhI		60	99	71	35.5	345.68	345.7
5	2,4-di-NO2PhF		55	98	68	34	201.9	202
6	Para-NH2PhCl		1.5 h	97	58	29	100.12	100.2
7	2,6-di-NO2PhF		60	98	67	33.5	201.8	201.9
8	Para-CO2HPhCl		60	98	61	30.5	134.77	134.8
9	2-CH2OHPhI		55	97	101	50.5	88.95	89
10	3-CH2OHPhBr		60	97	114	57	88.98	89.2
11	4-CH2OHPhI		70	96	121	60.5	89.1	89.5

^a Yield refer isolated products.

) [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38].

2.9. Coupling Reaction Process

This coupling reaction process involved a one-step reaction with two metals: one coupled to the boronic group of the phenylboronic compound (nucleophile) and the other coupled to the iodide of the arylphenyl compound (electrophile), thereby yielding a Suzuki carbon–carbon bonding product. This reaction was performed under 1 mmol of potassium iodide, using water as the solvent, at a temperature 70 °C; the final product of this reaction can be used in the medical industry as an organic bio-compound. Scheme 3 provides an overview of the process.

2.10. Comparison of Mechanism, Recovery, and Reuse of Nanocatalysts

A mechanism showing the general process of the reaction is proposed in Scheme 4. In this design, the reaction mechanism is divided into two parts, as explained previously. The magnetic nanocatalyst features two metals, cobalt and nickel, on its catalytic substrate. Both cobalt and nickel acetate have two electron capacities (through oxidation, the two empty orbitals to bond to the two reactants, i.e., a nucleophile or an electrophile). Cobalt/nickel(II) attack the reactants separately before being coupled in the final transformation of two aryl carbon sp² via a sigma bond (sp³). The metals can be separated from the reaction by reducing their acetate group, and the Suzuki coupling product along with its various derivatives can be separated and purified. This reaction is continuously repeated to synthesize a product with high efficiency and optimal quality. In the previous section, this nanocatalyst was shown to be superior to others in the literature. Furthermore, the current nanocatalyst had almost maximum power after being reused 10 times, showing only a 5% reduction, as revealed by SEM, TEM, and IR analyses. Figure 4 also shows that the structural and functional quality of the catalyst was maintained.

3. Materials and Methods

All reagents used met the necessary standards, and the solvent used was deionized water at 18 MΩ/cm. C₂₀H₁₉N₃O₂ (molecular weight 333.89 g/mol, 99.999% purity), C₄H₆NiO₄ (molecular weight 176.8 g/mol, 99% purity), C₄H₆CoO₄, (cobalt(II) acetate, molecular weight 177.02124 g/mol, 99% purity), and CPTES (molecular weight 198.72, 97% purity) were purchased from Sigma Aldrich (St. Louis, MO, USA). FeCl₂·4H₂O, Fe(Cl)₃·6H₂O, deionized water, argon gas, NaOH (34% aqueous solution), TEOS, HCl, and methanol were purchased from Sinopharm Chemical Reagent Co. (Shanghai, China).

Powder XRD of the prepared catalyst was performed using a Philips PW 1830 X-ray diffractometer with a Cu Kα source (λ = 1.5418 Å) in the Bragg angle range 10–80° at 25 °C. FTIR spectra were obtained using an FTIR spectrometer (Vector 22, Bruker) in the range 400–4000 cm⁻¹ at room temperature. SEM analysis was conducted using a VEGA//TESCAN KYKY-EM 3200 microscope (acceleration voltage of 26 kV). TEM experiments were conducted using a Philips EM 208 electron microscope. EDX analysis of the catalyst was conducted using a VEGA3 XUM/TESCAN. TGA was performed using a Stanton Red Craft STA-780 (London, UK). NMR spectra were obtained using a Bruker DRX-400 instrument (300.1 MHz for ¹H-NMR, 75.4 MHz for ¹³C-NMR). The spectra were obtained using CHCL₃-d1 as a solvent. Magnetic measurements were carried out using a VSM instrument (MDK, model 7400). Melting points were evaluated using an Electrothermal 9100 apparatus.

3.1. Nanoparticle Synthesis Method

The chemical coprecipitation method [13,14,15,16,17,18] was used due to its simplicity and the high yield of synthetic products. This study was based on the creation of a heterogeneous catalyst in the aqueous phase, initiating phase transfer of the organic phase (reactors). Magnetic nanoparticles were obtained in the form of iron oxide, which was achieved by combining two iron salts (II) and (III) in a ratio of 1:2.

$${\mathrm{M}}^{2+}+8{\mathrm{OH}}^{-}+{\mathrm{Fe}}^{3+}\to {\mathrm{MFe}}_2{\mathrm{O}}_4+4{\mathrm{H}}_2\mathrm{O}$$

$${\mathrm{MFe}}_2{\mathrm{O}}_4\stackrel{\mathrm{M}=\mathrm{Fe},\mathrm{L}}{\to }{\mathrm{Fe}}_3{\mathrm{O}}_4@\mathrm{L}\stackrel{+\mathrm{Co}/\mathrm{Ni}}{\to }{\mathrm{Fe}}_3{\mathrm{O}}_4@\frac{\mathrm{L}}{\mathrm{Co}}/\mathrm{Ni}$$

3.2. Synthesis of Fe₃O₄ Magnetic Nanoparticles

The synthesis of magnetite magnetic nanoparticles was based on a core/shell nuclear structure consisting of iron oxide composed of iron(II) (0.9 g, 0.2 mol.%) and iron(III) (1.7 g, 0.5 mol.%) salts in 300 cc of water, which was stirred for 2 h. This reaction was scaled from room temperature to 65 °C than 2 h, at which point 20 mol.% of sodium hydroxide was added, and the reaction was continued for another 2 h. continued. The reaction solution was separated from the nanoparticles using an external magnetic field and repeatedly rinsed with ethanol and distilled water several times, before being placed in an oven at 70 °C. After drying completely, the resulting powder (burnt brown color) was collected.

3.3. Nanoparticle Core/Shell Structure with Metal Coating

After the synthesis of the magnetic nanoparticles, the surface was coated with silicate nanoparticles. To do this, 0.25 g of the synthesized catalyst was first weighed in 50 mL of distilled water on a sonication device for 1.5 h. Then, in a separate reaction vessel, 4 cc of tetraorthosilicate was combined with 5 cc of ethanol and added to the previous solution. During this reaction, 5 cc of 10% sodium hydroxide solution was added to the reaction solution, and the sonication step was continued for 2 h. The reaction was further continued for another 2.5 h at room temperature, i.e., 25 °C, thus yielding the core/shell product containing silica nanoparticles. However, in this reaction, magnetite nanoparticles were synthesized first before adding the desired ligand (via electrostatic bonding with the silicate). The reaction is performed sequentially, whereby the first 0.25 g of the core/shell nanocatalyst was dissolved in 50 cc of distilled water, before dissolving another 1 mmol. Then, 25 cc of ethanol was added to the previous solution, and the whole solution is refluxed at 75 °C for 24 h. After 1 day, the product was washed and dried several times with ethanol and distilled water and collected after oven drying at 65 °C. In another step, 0.25 g of the core/shell catalyst was added to 25 cc of distilled water before being combined with 0.002 g of cobalt(II) acetate and nickel(II) acetate nanoparticles dissolved in 25 cc of ethanol. Finally, the whole solution was refluxed together at 75 °C for 1.5 days. The synthesized nanocatalysts were repeatedly washed with ethanol and double-distilled water and dried in an oven at 55 °C. Scheme 5 shows complete reaction process.

4. Conclusions

The main purpose of this project was to design a new nanocatalyst to optimize the carbon–carbon coupling reaction. For this purpose, a magnetic nanocatalyst was used, characterized by external field control properties, a wide catalyst surface for the coupling reaction, easy separation from the reaction medium, a low fabrication cost, and the inclusion of two metals, which accelerated the reaction process. Synthetic catalysts show great promise for application in the chemical and medical industries.