Magnetic nanocatalyst for the synthesis of maleimide and phthalimide derivatives

Abstract

An efficient and green protocol for the synthesis of N-aryl maleimide and phthalimide derivatives has been developed. The high efficiency of the catalyst was observed due to the homogeneous distribution of the nanoparticles. The catalyst was fully characterised by physicochemical methods such as IR spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction, dynamic light scattering (DLS), energy dispersive X-ray spectrum and zeta potential measurement techniques. The ease of separation of the catalyst from the reaction mixture and its high activity are eco-friendly attributes of this system.

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Introduction

Nanoparticles have emerged as an important tool in catalysis,^1,2 and they act as a bridge between homogeneous and heterogeneous catalysis. Nanoparticles can get homogenised in a reaction mixture during organic synthesis to increase the catalytic efficiency and can be easily separated by means of centrifugation or an external magnetic field.³ Since the past few years, catalysts supported over magnetic nanoparticles have gained considerable attention in C–X coupling and other organic reactions.^4–8 Hazardous mineral acids are usually in demand for numerous acid catalysed reactions due to their excellent catalytic performance.⁹ However, their separation from reaction mixtures exhibits limitation on their use due to environmental concerns. Such mineral acids upon being supported over magnetic nanoparticles, can be easily separated from reaction mixtures without hampering their catalytic activity, which makes the protocol more cost effective and environmentally benign. N-substituted imide derivatives find wide application in medicinal chemistry,^10,11 biology,^12,13 material science and polymer chemistry.¹⁴ Maleimides are the backbone of peptide–conjugate haptens, immune conjugates, and enzyme inhibitors.¹⁵ In organic synthesis, imide derivatives play a vital role for the protection of the amino group.¹⁶ Despite their wide application, availability of environmentally benign, inexpensive synthetic protocols for the preparation of imides is limited.

The conventional methods for the synthesis of imide derivatives are the dehydrative condensation of anhydride and amine in the presence of sulfuric acid¹⁷ and N-alkylation of imides promoted by PPh₃ in the presence of alcoholic media.¹⁸ These conventional protocols suffer drawbacks such as high temperature and longer reaction time. Several attempts to improve these protocols using ionic liquids^19,20 have also been reported. Unfortunately, they also suffer from longer reaction time and tedious product isolation methods. Hence, there is a need for the development of a protocol for the synthesis of imide derivatives with a shorter reaction time and easy separation of products from the reaction mass. In the current protocol, we have introduced sulphuric acid functionalised silica supported over magnetite nanoparticles. It provides an easy separation of catalyst from the reaction mass, and its recyclability induces cost effectiveness to the system (Scheme 1).

Scheme 1

Results and discussion

In the present work, we have reported a simple, efficient and practical approach for the synthesis of N-aryl imide derivatives. We have used phthalic anhydride and aniline as standard substrates to screen for a suitable solvent for the reaction. Among the tested solvents, ethanol was the most effective reaction medium for the N-insertion reaction (Table 1, Entry 6). Low yield of the target product was obtained when EDC, DMF, toluene, and acetone were used as solvents. When the reaction was carried out on bare magnetite nanoparticle Fe₃O₄ (Table 1, Entry 4), as well as on bare silica coated nanoparticle Fe₃O₄@SiO₂ (Table 1, Entry 5), it resulted in a poor yield. However, it gave a good yield with sulfonic acid functionalized silica coated magnetite nanocatalyst. To determine the catalyst loading, a model reaction of phthalic anhydride and aniline in ethanol was performed. The reaction occurred smoothly in the presence of 20 wt% of Fe₃O₄@SiO₂–SO₃H, affording a single product (Table 2, entry 4) in 89% yield. Increasing the amount of catalyst to more than 20 wt% showed no substantial improvement in the yield. It is worthy to mention that we examined the model reaction without any catalyst in ethanol at reflux temperature and the product yield did not increased beyond 29% even after prolonged heating (Table 1, Entry 1). The optimized reaction conditions include 3.37 mmol of phthalic anhydride, 3.37 mmol of aniline and 20 wt% of Fe₃O₄@SiO₂–SO₃H in ethanol at 80 °C. Furthermore, for comparison, the model reaction was carried out using amberlyst 15 and silica sulfuric acid under similar conditions, which gave the desired product in 81% and 77% yield, respectively (Table 1, Entries 2 and 3) after 8 h of heating. This suggests that catalyst plays a major role in the reaction. The reaction was faster in the case of Fe₃O₄@SiO₂–SO₃H catalyst because of acid active sites and higher surface area of the catalyst, as a result of its nano form. To investigate the effect of electron donating and withdrawing groups on the rate of reaction, we have studied different anhydrides with various aromatic primary amines (Table 3). In the case of electron donating substituents, the reaction was faster and gave better yields, whereas the reaction afforded moderate to good yields when an electron withdrawing substituent was present on the aromatic amine. The proposed reaction mechanism of the reaction using catalyst is depicted in Fig. 1.

Table 1 Effect of solvent and catalyst on the synthesis of N-phenyl phthalimide^b

Entry	Catalyst	Wt%	Solvent/temp	Time (h)	Yield^a (%)
a Isolated yields.b Reaction condition: phthalic anhydride: 3.37 mmol; aniline: 3.37 mmol; solvent: 5 ml.
1	—	—	Ethanol/80 °C	4	29%
2	Amberlyst 15	20%	Ethanol/80 °C	8	81%
3	Silica sulfuric acid	20%	Ethanol/80 °C	8	77%
4	Fe3O4	20%	Ethanol/80 °C	1	Traces
5	Fe3O4@SiO2	20%	Ethanol/80 °C	1	Traces
6	Fe3O4@SiO2–SO3H	20%	Ethanol/80 °C	1	89%
7	Fe3O4@SiO2–SO3H	20%	Toluene/80 °C	1	72%
8	Fe3O4@SiO2–SO3H	20%	DMF/80 °C	1	70%
9	Fe3O4@SiO2–SO3H	20%	EDC/80 °C	1	30%
10	Fe3O4@SiO2–SO3H	20%	Acetone/55 °C	1	32%

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Table 2 Effect of catalyst loading (wt%) on the synthesis of N-phenyl phthalimide^b

Entry	Catalyst wt%	Time (h)	Yield^a (%)
a Isolated yield.b Reaction condition: phthalic anhydride: 3.37 mmol; aniline: 3.37 mmol; solvent: ethanol: 5 ml; temp = 80 °C.
1	5%	5.0	60%
2	10%	3.0	67%
3	15%	2.5	74%
4	20%	1.0	89%
5	25%	1.0	89%

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Table 3 The synthesis of N-aryl imide derivatives in the presence of Fe₃O₄@SiO₂–SO₃H^d

Entry	Product	Time	Yield (%)^a	TON^b	TOF^c (min^−1)
a Isolated yield.b TON = turn over number.c TOF = turn over frequency.d Reaction condition = Temp: 80 °C; catalyst loading: 20 wt%; reaction medium: 5 ml ethanol.
A		2 h	84%	41.96	0.34
B		2 h	86%	42.96	0.35
C		1 h 30 min	88%	43.96	0.32
D		2 h 15 min	81%	40.46	0.29
E		2 h 45 min	77%	38.46	0.23
F		2 h 15 min	80%	39.96	0.29
G		4 h	76%	37.96	0.15
H		1 h	89%	75.11	1.25
I		1 h	90%	75.95	1.26
J		45 min	91%	76.80	1.70
K		1 h 30 min	81%	68.36	0.75
L		1 h 45 min	80%	67.51	0.64
M		1 h 30 min	78%	65.83	0.73
N		2 h 30 min	77%	64.98	0.43

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Fig. 1 Proposed reaction mechanism.

The catalyst was easily separated from the reaction mixture by magnetic separation method. It was successfully recycled up to six runs. The catalyst performs well with a high turnover number (TON) and turn over frequency (TOF), which indicates that the catalyst is highly stable and efficient. The concentration of acid sites determined on the catalyst is 0.4 mmol g⁻¹.

Characterisation of the catalyst

The TEM image of the catalyst displays a dark Fe₃O₄ core surrounded by a lighter amorphous silica shell as shown in Fig. 2b, which confirms that the catalyst has been encapsulated by a thin layer of silica particles and it has an average particle size of 30 nm. The energy dispersive spectrum indicated the presence of Fe, Si and S (Fig. 12 ESI†). The SEM image of Fe₃O₄@SiO₂–SO₃H nanoparticles is shown in Fig. 2a, which shows a spherical morphology and a marked tendency to form large aggregates. The clustering tendency was observed because of the weak hydrogen bonding forces between Fe₃O₄@SiO₂–SO₃H and the magnetic characteristic of nanoparticles.

Fig. 2 (a) SEM and (b) TEM images of Fe₃O₄@SiO₂–SO₃H catalyst.

The XRD analysis of Fe₃O₄, Fe₃O₄@SiO₂, and Fe₃O₄@SiO₂–SO₃H has been performed, and its comparative spectra is depicted in Fig. 3. The XRD spectrum of Fe₃O₄ clearly matches with those of the literature reports.²¹ The XRD pattern of Fe₃O₄@SiO₂ and Fe₃O₄@SiO₂–SO₃H shows a broad band at 2θ = 20–24°, which is due to the presence of an amorphous silane shell formed around the magnetic core. There is no other appreciable shift in the peak positions, which indicates the structural stability of magnetite nanoparticles. The measurement of zeta potentials of the Fe₃O₄, Fe₃O₄@SiO₂ and Fe₃O₄@SiO₂–SO₃H samples has been performed to determine the surface modification of the nanoparticle. The observed zeta potential of the Fe₃O₄ and Fe₃O₄@SiO₂ were about −45 mV and −120 mV (Fig. 8 and 9 ESI†), respectively, which explains that the surface modification of the nano Fe₃O₄ has occurred and is in good agreement with the literature data.²² The zeta potential distribution for Fe₃O₄@SiO₂–SO₃H is positively charged at 25.3 mV (82%) and 95.5 mV (18%). It is because of the presence of H⁺ ion on the surface of the catalyst, as shown in Fig. 4. To determine percentage average particle present in the sample, dynamic light scattering measurements were carried out as shown in Fig. 5, and the observed results were similar to the literature reports.²³ For this reason, an aqueous stock solution (1 mg ml⁻¹ of water) was prepared in an ultrasonic bath for 30 min.

Fig. 3 XRD spectra of (a) Fe₃O₄, (b) Fe₃O₄@SiO₂ and (c) Fe₃O₄@SiO₂–SO₃H.

Fig. 4 Zeta potential of Fe₃O₄@SiO₂–SO₃H.

Fig. 5 DLS measurement of (1) Fe₃O₄ (2) Fe₃O₄@SiO₂ and (3) Fe₃O₄@SiO₂–SO₃H.

The IR spectrum shows a band between 637–410 cm⁻¹, which corresponds to the stretching vibration of the Fe–O bond.²⁴ The band at 1080 cm⁻¹ corresponds to the Si–O stretching vibration (Fig. 6b). The weak band at 814 cm⁻¹ is observed for the Si–O–Fe bond (Fig. 6b), which indicates the immobilisation of silica on the surface of Fe₃O₄ nanoparticles.²⁵ This band is shifted to 807 cm⁻¹ in the case of Fe₃O₄@SiO₂–SO₃H (Fig. 6c). Fig. 6a and b show a broad peak between 3000–3400 cm⁻¹ and a sharp peak around 1630 cm⁻¹ for the presence of adsorbed water. The absorption band at 1128 cm⁻¹ corresponds to the stretching of the S–O bond (Fig. 6c), which justify the presence of the sulfonic acid group on its surface. The broad absorption at 3453 cm⁻¹ and sharp peak at 1624 cm⁻¹ correspond to the stretching vibrations of the OH group in SO₃H (Fig. 6c).

Fig. 6 FT-IR spectra of (a) Fe₃O₄, (b) Fe₃O₄@SiO₂ and (c) Fe₃O₄@SiO₂–SO₃H.

Recyclability study

The catalyst recyclability study was carried out on phthalic anhydride 3.37 mmol, aniline 3.37 mmol and catalyst (20 wt%) in 5 ml ethanol at 80 °C. The results are summarised in Fig. 7. After completion of the reaction, catalyst was separated by an external magnet, washed with acetone and dried at 60 °C for 1 h. The recovered catalyst was then used for the next batch. It was observed that the catalyst could be recycled efficiently up to six runs. SEM and TEM images of the recycled catalyst were taken (Fig. 8a and b), which show that the structural and morphological properties of the catalyst remain unaltered even after the 6^th recycle. The comparative IR spectra of fresh and reused catalyst shows that there is no change in functional group values (Fig. 7 ESI†)

Fig. 7 Recyclability study of Fe₃O₄@SiO₂–SO₃H in the synthesis of N-phenyl phthalimide.

Fig. 8 (a) SEM and (b) TEM images of recovered catalyst after six successive runs of reaction.

Determination of acidic sites

The surface-bound acidic protons were ion exchanged with a brine solution by sonicating the Fe₃O₄@SiO₂–SO₃H catalyst for 24 h. The catalyst was separated magnetically, the brine solution was decanted and titrated with 0.1 N NaOH solution to determine the loading of acid sites on the catalyst. The H⁺ ion loading was found to be 0.40 mmol g⁻¹.

Experimental

Materials and methods

TEM studies of the nanocatalyst were carried out with a JEOL JEM-2100 instrument. SEM micrographs and EDXS data were obtained on a JEOL JSM 6380LA instrument. The XRD study was performed on a Bruker AXS powder diffractometer D8 with Cu-kα (1.54 Å). The FT-IR spectra of the catalyst were measured with KBr pellets using a Bruker-VERTEX 80v vacuum FTIR spectrometer, and the IR spectra of the synthesized compounds were recorded on a Jasco FT-IR ATR-PRO/4100 spectrophotometer. ¹H NMR spectra were recorded on a Bruker 400 MHz spectrometer and Agilent 500 MHz spectrometer in CDCl₃ solvent. Mass spectral data were obtained with a Finnigan LCQ Advantage max spectrometer.

Iron(III) chloride hexahydrate (98%), Iron(II) chloride tetrahydrate (99%), chlorosulfonic acid, and other chemical materials were purchased from S.D. Fine Chemical Ltd., India, and tetraethylorthosilicate were purchased from Sigma Aldrich. Anhydride and aniline were also purchased from S.D. Fine Chemical Ltd., India.

General procedure for the preparation of catalyst

Fe₃O₄@SiO₂ nanoparticles were prepared by the literature reported method.^26,27 Under a nitrogen atmosphere, a mixture of 5.0 g of ferric chloride and 1.85 g of ferrous chloride salts were dissolved in distilled water and heated to 90 °C. Then, an aqueous ammonia solution (25%) was added, from which a precipitate of Fe₃O₄ was obtained. The supernatant was decanted, and the precipitate was isolated by magnetic separation. The obtained black powder (Fe₃O₄) was washed with acetone and dried under vacuum. The coating of silica on the surface of Fe₃O₄ nanoparticles was achieved by diluting 2.0 g of Fe₃O₄ nanoparticles in water (40 ml), ethanol (120 ml) and aqueous ammonia solution (3.0 ml, 25%). The resultant dispersion was homogenised by sonicating for 1 h at 40 °C. Then subsequently, tetraethyl orthosilicate diluted in ethanol was charged slowly under continuous mechanical stirring, and the mixture was further stirred for 12 h. The resultant brown powder was separated magnetically and washed three times with acetone, and then dried.

The immobilization of the sulfonic acid group on Fe₃O₄@SiO₂ was done by the literature reported method.²⁸ For the preparation of sulfonic acid coated nanocatalyst, mixture of silica coated magnetite (2.0 g) and 10 ml of n-hexane was cooled. Chlorosulfonic acid (1.0 g) was added slowly to the abovementioned mixture over a period of 30 min at room temperature. The resulted sulfonic acid coated magnetic nanoparticles were separated and washed repeatedly with ethanol and dried in the oven at 60 °C.

General procedure for the synthesis of imide derivatives

In a general procedure, a mixture of phthalic anhydride (0.5 g, 3.37 mmol), aniline (0.31 g, 3.37 mmol) and Fe₃O₄@SiO₂–SO₃H (0.1 g, 20 wt%) in ethanol (5 ml) was stirred for 60 min at 80 °C. After completion of the reaction (monitored by TLC), the catalyst was separated from the reaction mass by use of an external magnet. The organic layer was concentrated under reduced pressure to give the desired product, which was subsequently purified in ethanol. The recovered catalyst was washed with acetone and dried at 60 °C to give recyclable Fe₃O₄@SiO₂–SO₃H. Yield 89%, 0.67 g, m.p. 208 °C. All compounds were analysed by melting point, mass, IR and ¹H-NMR techniques.

Conclusion

In conclusion, we have developed an efficient protocol for the synthesis of N-aryl phthalimide and biphenyl maleimide derivatives using sulphonic acid functionalised silica over magnetite Fe₃O₄ nanoparticles. These reactions were optimised for various parameters and have been employed for wide substrates. The advantages offered by this protocol include high TON values, easy separation method and recyclability of the catalyst up to six runs. This simple, efficient protocol can be explored for other organic synthesis methods in future as well.

Acknowledgements

Authors are thankful to UGC-SAP, Technical Education Quality Improvement Programme, for providing financial assistance and the Institute of Intensive Research for Basic Sciences for recording ¹H NMR.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra09008j

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