Nanostructured oxytyramine catalyst for the facile one-pot synthesis of cyclohexanecarbonitrile derivatives

Abstract

The magnetic, recyclable heterogeneous organocatalyst OT@Si@SPIONs has been developed in this report, with the aim of synthesizing cyclohexanecarbonitriles. The prepared nanocatalyst was fully characterized by various techniques and its catalytic activity has been tested in a one pot reaction which involves the in situ formation of imines from cyclohexanones and amines, which further undergo nucleophilic addition with TMSCN. Moreover, although this Strecker reaction is centuries old, its applicability to ketones is still a less explored subject, and our investigation provides an insight into the efficient synthesis of cyclohexanecarbonitrile derivatives using a ketone i.e. cyclohexanone. When compared with other catalytic systems reported in the literature, ours showed superior catalytic activity at a remarkably low catalyst loading i.e. 5 mg.

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1. Introduction

The combination of nanotechnology with green chemistry has proven to be a boon for industry.¹ The chemical and pharmaceutical industries are keen to look for economical and environmentally benign measures for recycling catalysts,² as although homogeneous catalysts are endowed with chemo, regio and enantioselectivity, they introduce the difficulty of catalyst separation from the final product.³ In such respect, nano-magnetic catalysis plays a major role in heterogeneous catalysis as it provides easy magnetic recovery of the catalyst from the reaction mixture with the help of a permanent magnet,⁴ hence removing the need for conventional techniques like filtration, centrifugation etc. Nanocatalysts, either metallic nanoparticles or supported magnetic nanoparticles, have high catalytic activity, a high degree of chemical stability, and act as simple, robust, and readily available high surface area heterogeneous catalysts.⁵ Among the different magnetic nanocatalysts known to date, Fe₃O₄ nanoparticles have had the greatest impact in this field as they can efficiently reinforce the functionality of different moieties by acting as a support to them⁶ and they produce heterogeneous and magnetically separable catalysts due to their superparamagnetic character. Although bare iron oxide nanoparticles are hard to handle due to their extremely reactive nature towards oxidation, this extreme reactivity can be mitigated by tailoring the surface of the nanoparticles. Along with high reactivity, many other pitfalls of bare nanoparticles like the formation of large aggregates to minimize surface energy, loss of dispersibility, low thermal stability and high chemical activity can also be lessened by applying some protection strategies which include grafting or coating with an inert material.⁷ The most studied inert material for protecting iron oxide nanoparticles is silica, which can be further used to anchor the catalytic molecules into its pores to generate catalytic centres.⁸ Many organic ligands have also been reported to stabilize the magnetic nanoparticles and also aid their particular application.⁹ Magnetic iron nanoparticles and their functionalized counterparts have numerous applications in various fields such as data storage,¹⁰ catalysis,^6,11 drug-targeting,¹² cancer therapy,¹³ lymph node imaging or hyperthermia,¹⁴ magnetic resonance imaging,¹⁵ sensors¹⁶ and many more.

Ample attention has been paid to bifunctional entities in organic synthesis because of their vast applications in drug design. Amino nitriles are potent examples of bifunctional compounds. Both amino and nitrile moieties can easily undergo a diversity of modifications allowing rapid advances towards synthetically important organic products. Transformation of the nitrile group in α-aminonitriles to a carboxylic acid by hydrolysis leads to the formation of α-amino acids, and this transformation was first carried out by Adolph Strecker in 1850,¹⁷ thereafter termed the Strecker synthesis. Since then a vast amount of research has been carried out on this reaction with various catalysts like Yb(OTf)₃-pybox,¹⁸ lanthanum(III)-binaphthyl disulfonate,¹⁹ Jacobsen’s thiourea catalyst,²⁰ mesoporous aluminosilicate (Al-MCM-41),²¹ Fe(Cp)₂PF₆,²² N-heterocyclic carbene (NHC)-amidate palladium(II) complex,²³ BINOL-phosphoric acid,²⁴ K₂PdCl₄,²⁵ gallium(III) triflate,²⁶ IBX/TBAB,²⁷ nanocrystalline magnesium oxide,²⁸ superparamagnetic iron oxide²⁹ and Lewis bases³⁰ e.g. N,N-dimethylcyclohexylamine etc., and various sources of amino and cyano groups like HCN, KCN, (EtO)₂P(O)CN, Et₂AlCN, Bu₃SnCN and TMSCN.^31,32 The Strecker reaction is the simplest and most economical method for the synthesis of α-aminonitriles, which are versatile synthons of various amino acids and many other bioactive compounds including natural products. Recently, various pharmacologically useful compounds like phthalascidin 622,³³ hepatitis C virus NS3 serine protease inhibitors³⁴ and boron containing retinoids³⁵ have been synthesized following this strategy. The Strecker reaction with ketones has been rarely studied due to the very slow reaction rates, as ketones are challenging substrates due to their steric demands during the formation of the C–C bond.³⁶ Often ketone Strecker reactions are carried out stepwise using premade imines or high pressure conditions. Although some one pot procedures have been reported, most of them involve the use of expensive reagents, harsh conditions, tedious work ups and long reaction times. So we herein report the Strecker reaction involving ketones i.e. cyclohexanone as the substrate with good results at ambient temperature and under solvent free conditions. The advantage of this methodology is the simplicity of the procedure, which avoids the use of tedious chromatographic purification of the products and does not use harsh organic solvents, thus supporting the central issue of today’s research i.e. green chemistry.

So, in a continuation of our previous work,^37,38 we describe here an environmentally sound protocol for the facile synthesis of cyclohexanecarbonitrile derivatives using cyclohexanone. Herein, we also report the preparation and structural determination of a new organocatalyst, the oxytyramine immobilized silica@Fe₃O₄ nanocatalyst. Oxytyramine is a naturally occurring catecholamine which acts as an inotropic agent. It is an essential part of the human body as it has many important functions, like controlling motor abilities, motivation, concentration, sleep, mood, memory, learning etc.³⁹ It can improve the functioning of the heart and is also used for the treatment of Parkinson’s disease. Therefore, the oxytyramine anchored Si-SPIONs can be used in a variety of applications. The utilization of magnetic nanoparticles as catalysts for this reaction is just one approach, and is green, inexpensive, facile and widely applicable.

2. Results and discussion

2.1 Synthesis of OT-Si-SPIONs

The core of the oxytyramine grafted, silica coated superparamagnetic iron oxide nanoparticles (OT-Si-SPIONs) has been synthesized by a co-precipitation⁴⁰ method combined with low power sonication. A modified Stöber method⁴¹ in addition to ultrasonication has been used to prepare the OT-Si-SPIONs, which has an advantageous effect in that this method does not require a high temperature treatment to obtain crystalline nanoparticles, as the ultrasonic waves generate some localized hot spots which induce in situ calcination.⁴² The oxytyramine moiety has been coated on the Si-SPIONs as the former is a high affinity binding molecule and thus stabilizes the SPIONs. The –NH₂ group on this moiety could be used as the reaction site. The synthesis of the magnetite nanoparticles and their functionalization is represented in Scheme 1.

Scheme 1 Schematic representation of coating magnetite nanoparticles with silica and oxytyramine.

2.2 Characterization of prepared OT-Si-SPIONs

2.2.1 FT-IR. In order to depict the surface modification of the SPIONs with TEOS and oxytyramine, the FT-IR spectra of the SPIONs, Si-SPIONs and OT-Si-SPIONs are shown in Fig. 1A in which Fig. 1A(a) displays the FT-IR spectrum of the SPIONs. The absorbance bands at 590 and 633 cm⁻¹ are ascribed to Fe–O vibrations and are consistent with the reported IR spectrum for spinel Fe₃O₄.⁴³ The IR bands at 3393 and 1625 cm⁻¹ are due to the stretching and deformation vibrations of –OH groups of adsorbed water on the surface of the magnetite nanoparticles. The FT-IR spectrum of the Si-SPIONs is shown in Fig. 1A(b). The absorption band at 1097 cm⁻¹, characteristic of Si–O groups, indicates covalent bonds between the nanoparticle surface and the silane. The bands at 957 cm⁻¹ and 801 cm⁻¹ are due to the vibrations of Si–O–Si groups. These results indicate the successful immobilization of SiO₂ on the surface of the Fe₃O₄ nanoparticles. Fig. 1A(c) depicts the FT-IR spectrum of the prepared OT-Si-SPIONs. Several new peaks at 1281, 1488 and 1614 cm⁻¹, characteristic of C–O vibrations, benzene ring C–C vibrations and N–H stretching, respectively, confirm the successful coating of oxytyramine over the silica coated magnetite nanoparticles.

Fig. 1 (A) FT-IR spectra of (a) SPIONs; (b) Si-SPIONs; (c) OT-Si-SPIONs. (B) XRD spectra of (a) SPIONs; (b) Si-SPIONs; (c) OT-Si-SPIONs.

2.2.2 XRD. As presented in Fig. 1B, the SPIONs show characteristic diffraction peaks at different values of 2θ i.e. 30.12, 35.54, 43.13, 53.56, 57.17, and 62.78 with the corresponding diffraction planes 220, 311, 400, 422, 511 and 440 which are totally consistent with spinel cubic Fe₃O₄ diffraction peaks (JCPDS 19-0629).⁴⁴ Fig. 1B(b) shows the XRD pattern of the Si-SPIONs, showing exactly the same peaks as that of the Fe₃O₄ nanoparticles in addition to a broad hump at 2θ = 20–25°, which is characteristic of amorphous silica. The repetition of the same peaks depicts that the crystallinity of the nanoparticles has been restored even after their functionalization. The XRD pattern of the OT-Si-SPIONs is shown in Fig. 1B(c). The broad peak at 2θ = 20–25° in the Si-SPIONs has been shifted to lower values due to the synergistic effect of amorphous silica. Also the intensity of the characteristic peaks of the SPIONs further decreases because of the surface coating of shell layers, which confirms the cover-up of subsequent layers. The average size of the SPIONs, as calculated by the Debye–Scherrer formula is found to be ∼13 nm.

2.2.3 Morphology. Fig. 2 displays the TEM (a–c) images of the SPIONs, Si-SPIONs and OT-Si-SPIONs which reveal that the iron oxide nanoparticles are spherical in nature with a size ranging from 12–15 nm which is consistent with the size calculated from the XRD data, and they are present in a non-aggregate form. Fig. 2b shows the core–shell structure of the silica coated iron oxide nanoparticles and Fig. 2c portrays the mosaic type structure of the OT-Si-SPIONs in which the organic moiety, oxytyramine, has been coated over multiple Si-SPIONs. Fig. 2e shows the SEM image of the OT-Si-SPIONs confirming their spherical shape.

Fig. 2 TEM images of (a) SPIONs; (b) Si-SPIONs; inset shows its core–shell structure (c) OT-Si-SPIONs; (d) recovered OT-Si-SPIONs after the 5^th cycle; (e) SEM image of OT-Si-SPIONs.

2.2.4 Magnetic properties. A vibrating sample magnetometer was used to examine the magnetic properties of the synthesized nanoparticles i.e. OT-Si-SPIONs at room temperature. Fig. 3 shows the VSM plot of the oxytyramine anchored Si-SPIONs, which depicts the superparamagnetic nature of the nanoparticles in which the saturation magnetization value comes out at 2.413 emu g⁻¹ which is very small compared to the bulk value of uncoated SPIONs i.e. approximately 90 emu g⁻¹.⁴⁵ This decrease in saturation magnetization is because of the very small size of the synthesized nanoparticles as there is a linear correlation between particle size and saturation magnetization and also due to the non-magnetic layer on the surface of the nanoparticles, which further decreases the value. The zero coercivity and small remanence value also proves the superparamagnetic properties of the synthesized functionalized nanoparticles.

Fig. 3 VSM image of the OT-Si-SPIONs.

2.2.5 Surface properties. Fig. 4 shows the N₂ adsorption–desorption isotherm of the OT-Si-SPIONs. The BET surface area of the particles was found to be 5.9115 m² g⁻¹, as calculated from the linear part of the BET plot. The total pore volume at P/P₀ = 0.98 is 0.0106 cm³ g⁻¹ and the average pore diameter is 26.00626 nm. This pore size indicates that the particles are mesoporous in nature.⁴⁶ The BET isotherm is characteristic of a type IV porous material with a pore size in the range of 1.5–100 nm.⁴⁷

Fig. 4 (a) BET plot of the OT-Si-SPIONs; (b) type IV isotherm plot of the OT-Si-SPIONs.

2.2.6 UV-Vis. UV-Vis spectral analysis (Fig. 5) has been used to confirm the formation and stability of the magnetic nanoparticles in an ethanolic colloidal solution. Pure Fe₃O₄ nanoparticles absorbed light with wavelengths mainly below 750 nm (Fig. 5a); in comparison to the Fe₃O₄ nanoparticles, a shift of the absorption band towards lower wavelengths i.e. blue shift was noticed with silica as well as oxytyramine coating over the Fe₃O₄ nanoparticles. The UV-Vis spectra of the synthesized nanoparticles were also obtained after 10 days, and showed no significant change in the absorption peaks, which confirms the stability of the nanocatalysts.

Fig. 5 UV-Vis spectra of (a) SPIONs; (b) Si-SPIONs; (c) OT-Si-SPIONs.

2.2.7 TGA. To investigate the stability of the synthesized nanoparticles, thermogravimetric analysis of the SPIONs, Si-SPIONs and OT-Si-SPIONs has been performed from 40–750 °C at a heating rate of 10 °C min⁻¹ under a nitrogen atmosphere, as shown in Fig. 6. In the case of the SPIONs, an initial weight loss of 1.9% was observed in the temperature range of 100–350 °C due to the loss of moisture and after 350 °C only 0.9% weight loss was seen up to 700 °C. In the case of the Si-SPIONs, two stages of weight loss are observed in the temperature ranges of 40–100 °C and 100–600 °C. The initial weight loss of 3.8% at the first stage corresponds to the loss of adsorbed water and ethanol. The second stage weight loss of 4% could be attributed to the removal of residual TEOS as well as structural water. In OT-Si-SPIONs, an initial 14.6% weight loss was observed until 193.8 °C which is due to the loss of moisture and volatile components. Furthermore, from 194–424 °C a weight loss of 11.9% occurred due to the loss of structural water or entrapped hydroxyl groups on the surface of the nanoparticles and also may be because of degradation of the oxytyramine. After that, no significant loss was seen up to 750 °C which showed the superior thermal stability of the OT-Si-SPIONs. Also, a very low percentage of weight loss was observed at around 100 °C which confirms the stability of the catalyst in our reaction protocol.

Fig. 6 TGA plots of (a) SPIONs; (b) Si-SPIONs; (c) OT-Si-SPIONs.

2.3 Catalytic activity of OT-Si-SPIONs

The catalytic activity of OT-Si-SPIONs was tested by using it as a heterogeneous catalyst under various conditions (Table 1), by choosing the reaction of cyclohexanone (1), aniline (2a) and trimethylsilylcyanide (3) as a model reaction. Initially the influence of the catalyst on the model reaction was explored at room temperature by performing the reaction without a catalyst and with a catalyst (OT-Si-SPIONs), giving a 67.59% yield of the product in 94 minutes and a 94.48% yield of the product in 7 minutes, respectively (Table 1, entry 1 and 2). These results encouraged us to optimize the reaction conditions. Hence further study of the loading of the catalyst was examined. As shown in Table 1, it was found that the catalyst loading affected the reaction greatly. The use of 2.5 mg of the OT-Si-SPIONs catalyst gave 4a in only 81.72% yield (Table 1, entry 3). With 5 mg of the catalyst, the yield was increased to 94.48% taking a time of 7 minutes to complete the reaction (Table 1, entry 2). Further increasing the amount of catalyst led to a decrease in yield of 4a to 86.43% (Table 1, entry 6). Thus 5 mg of the catalyst was the best choice.

Table 1 Optimization of different loadings of the OT-Si-SPIONs nanocatalyst along with solvents and temperature for the synthesis of 4a

Entry	Catalyst amount (in mg)	Solvent	Temperature (°C)	Yield/time (%)/(min)
a Reaction conditions: cyclohexanone (1, 1 mmol), aniline (2a, 1 mmol), trimethylsilylcyanide (TMSCN, 3, 1.3 mmol), OT-Si-SPIONs (5 mg).b Reaction conditions: Fe3O4 (SPIONs) as catalyst.c Reaction conditions: Si–Fe3O4 (Si-SPIONs) as catalyst.d Reaction conditions: oxytyramine (OT) as bulk catalyst.
1	—	—	R.T.	67.59/94
2	5^a	—	R.T.	94.48/7
3	2.5^a	—	R.T.	81.72/—
4	7.5^a	—	R.T.	91.62/18
5	10^a	—	R.T.	87.26/4
6	15^a	—	R.T.	86.43/10
7	5^a	CH3OH	R.T.	58.61/24
8	5^a	C2H5OH	R.T.	74.31/23
9	5^a	H2O	R.T.	51.05/—
10	5^a	CH3CN	R.T.	83.43/18
11	5^a	THF	R.T.	77.83/21
12	5^a	Toluene	R.T.	79.25/20
13	5^a	1 : 1 (C2H5OH : H2O)	R.T.	52.59/—
14	5^a	—	60 °C	65.67/29
15	5^a	—	120 °C	60.58/28
16	5^b	—	R.T.	79.94/1 day
17	5^c	—	R.T.	82.19/1 day
18	5^d	—	R.T.	76.05/28

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In a subsequent study the reaction was conducted with various solvents to find out the most appropriate solvent. Various solvents such as H₂O, CH₃OH, C₂H₅OH, THF, toluene, CH₃CN and a H₂O : C₂H₅OH (1 : 1) mixture were tried in the model reaction (Table 1, entries 7–13). Among all of these solvents the reaction with CH₃CN gave the best results with an 83.43% yield in 18 minutes (Table 1, entry 10). Furthermore the model reaction was also carried out in the absence of solvent which gave the best yield of 4a i.e. 94.48% in 7 minutes (Table 1, entry 2).

The effect of temperature was studied by carrying out the model reaction at different reaction temperatures (R.T., under refluxing on water bath [≈60 °C], under refluxing on oil bath at 120 °C) (Table 1, entries 2, 14, and 15) under the optimized conditions and the best results were obtained at R.T. (Table 1, entry 2).

Using all the optimized reaction conditions, the model reaction was carried out to investigate the reaction time which was found to be 7 minutes at room temperature for compound 4a.

Furthermore to examine the significance of supporting the catalyst and the efficiency of the protocol, bare Fe₃O₄ nanoparticles (Table 1, entry 16), silica coated Fe₃O₄ nanoparticles (Table 1, entry 17), and bulk oxytyramine (Table 1, entry 18) were also studied. To our delight, the best results were obtained with the catalyst being reported in this paper. These results confirm that the catalytic activity is derived from the oxytyramine species present on the nanocatalyst surface, as well as being increased significantly due to the increase in surface area of the catalyst, which is a result of supporting the active phase i.e. oxytyramine on a nanosized material.

Additionally, the versatility of this protocol was examined by the reaction of cyclohexanone and TMSCN with different amines under the optimized reaction conditions and the results are summarized in Table 2. The reactions were carried out using 1 mmol of cyclohexanone, 1 mmol of amine, 1.3 mmol of TMSCN and a low catalyst loading (5 mg) under solvent free conditions. The reaction mixture was stirred using a magnetic stirring bar at room temperature. Various substituted amines like amines containing both electron donating as well as electron withdrawing groups (Table 2) were investigated. Amines containing both electron withdrawing and electron donating groups showed a similar trend in reactivity. The completion of the reaction was indicated by solidification of the reaction medium and TLC. After completion, 5 ml of methanol was added to dissolve the product completely and the catalyst was separated magnetically. The formation of no byproduct was observed. The product was then recrystallized with methanol and characterized with melting point and ¹H-NMR spectroscopic techniques.

Table 2 OT-Si-SPIONs catalyzed reaction with different substituted amines to synthesize cyclohexanecarbonitriles^a

Entry	Ar (amine)	Product	Time (min)	Yield (%)
a Reaction conditions: cyclohexanone (1, 1 mmol), amine (2a–z, 1 mmol), TMSCN (3, 1.3 mmol), OT-Si-SPIONs (5 mg).
2a	C6H5		7	94.48
2b	2-ClC6H4		17	48.33
2c	4-ClC6H4		23	97.44
2d	4-FC6H4		4	94.60
2e	2-BrC6H4		12	45.50
2f	2-OCH3C6H4		66	52.69
2g	2-CH3C6H4		45	78.96
2h	3-BrC6H4		11	89.76
2i	4-BrC6H4		7	91.60
2j	2-OCH2CH3C6H4		62	29.82
2k	3-CH3C6H4		42	92.06
2l	3-ClC6H4		16	54.29
2m	2-FC6H4		19	68.24

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The present protocol as compared to previously reported methods is more environmentally compatible, economical and green (Table 3).

Table 3 Comparison of the synthesis of α-aminonitrile derivatives by reported protocols for compound 4a^a

Entry	Catalyst used	Conditions/solvent	Catalyst loading	Time (min)	Yield (%)
a * For 1 mmol of 1, 1 mmol of 2a and 1.2 mmol of 3, ⁁ for 3 mmol of 1, 3 mmol of 2a and 3.6 mmol of 3, # for 1 eq. of 1, 1 eq. of 2a and 1.1 eq. of 3, ¤ for 1 eq. of 1, 1 eq. of 2a and 1 eq. of 3, ^Δ for 1 mmol of 1, 1 mmol of 2a and 1.3 mmol of 3.
1	B-MCM-41 (ref. 48)	*R.T./EtOH	50 mg	404	89
2	MCM-41-SO3H^49	*R.T./EtOH	5 mg	180	91
3	SBA-15-Ph-Pr-SO3H^50	⁁50 °C/—	5 mol%	480	95
4	LiBF4 (ref. 51)	#R.T./—	0.1 eq.	25	88
5	Sulfated tungstate	¤R.T./—	10 wt%	360	88
6	OT-Si-SPIONs	^ΔR.T./—	5 mg	7	94.48 (present work)

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2.4 Recyclability of catalyst

The ability of the OT-Si-SPIONs particles to act as a heterogeneous recyclable catalyst has been examined by carrying out repeated runs on the same batch of the used 5 mg magnetic catalyst in the reaction of cyclohexanone (1, 1 mmol), aniline (2a, 1 mmol) and TMSCN (3, 1.3 mmol) (Fig. 7). The catalyst was separated from the reaction mixture magnetically after the completion of the reaction and was washed with methanol and acetone successively before being dried at 50 °C for 30 minutes. The catalytic activity of the nanoparticles did not decrease significantly even after five catalytic cycles. TEM analysis (Fig. 2d) of the used catalyst revealed that the morphology of the recovered nanoparticles remained almost unaltered.

Fig. 7 Recyclability of OT-Si-SPIONs up to 5 cycles.

Scheme 2 represents the proposed mechanism for the synthesis of the cyclohexanecarbonitriles. The catalytic NH₂ group forms an H-bond with the O of cyclohexanone thus facilitating the rate determining step of the Strecker reaction i.e. formation of an imine intermediate, which further reacts with TMSCN to form the product.

Scheme 2 Proposed mechanism for the synthesis of cyclohexanecarbonitriles.

3. Experimental section

3.1 Materials

All chemicals were purchased from local suppliers and were used without any further purification.

3.2 Instrumentation

Fourier transform infrared spectra (FT-IR) were recorded using a Perkin Elmer spectrum RX-I Fourier transform infrared spectrophotometer using KBr pellets over a scan range of 4000–400 cm⁻¹. The crystalline phase of the nanoparticles was characterized by means of X-ray diffraction (XRD) measurements using Cu Kα radiation (λ = 0.154 nm) on a Panlytical XPERTPRO (NDP) X-ray diffractometer in a 2θ range of 15–80°. The morphology, nanostructure and particle size of the functionalized nanoparticles was studied by transmission electron microscopy (TEM) on a Hitachi S7500 instrument. The sample was prepared by dispersing a small amount of the solid nanoparticles in ethanol and then depositing it over carbon coated Cu grids by dropcasting, followed by drying. Magnetic measurements were carried out on the dried sample to evaluate the magnetic properties of the multifunctional nanoparticles at room temperature. For this, vibrating sample magnetometry was carried out on a Princeton applied research model 155. Scanning electron microscope images were obtained using a JEOL JSM-6610LV instrument. The thermogravimetric analysis (TGA), differential thermal analysis (DTA) and differential thermal gravimetry (DTA) curves were recorded using an EXSTAR6000TG/DTA 6300 instrument at a heating rate of 10 °C min⁻¹ under a nitrogen atmosphere. The surface area, pore volume and pore diameter of the nanoparticles were obtained using a micromeritics ASAP 2010 model of accelerated surface area and porosimetry system. The UV spectra were obtained using an Agilent Technologies Cary series UV-Vis spectrophotometer. The organic products were characterized by ¹H nuclear magnetic resonance spectroscopy at 400 MHz with the aid of an Advance 400 spectrometer using tetramethylsilane as the internal standard and DMSO-d₆ as the solvent.

3.3 Synthesis of OT-Si-SPIONs

3.3.1 Synthesis of SPIONs (Fe₃O₄ nanoparticles). Superparamagnetic iron oxide nanoparticles were synthesized by a modified co-precipitation method without using any surfactants at room temperature in an ambient atmosphere. Ferrous sulphate (FeSO₄·7H₂O) and ferric sulphate (Fe₂(SO₄)₃·nH₂O) were used as the iron salts in their respective stoichiometric ratio of Fe²⁺ : Fe³⁺ = 1 : 2. At first, 10 ml of aqueous solutions of both iron salts [Fe²⁺(7.19 mmol, 2.0 g)] and [Fe³⁺(13.0 mmol, 5.2 g)] were made separately and ultrasonicated for 15 minutes at room temperature. The solutions were mixed and again ultrasonicated for 30 minutes. Then NH₄OH (25%) was added dropwise to the above mixed solution to reach a pH value of approximately 10 along with sonication and constant stirring to attain a homogeneous mixture. After complete addition, the mixture was stirred at 60 °C for 1 hour. The precipitates were isolated in the magnetic field and the supernatant was discarded by centrifugation (5000 rpm, 15 min). Successive washings with deionized water were done to attain pH ≈ 7. Then the precipitates were dried in an oven at 50 °C for 24 hours.

3.3.2 Preparation of silica coated magnetite nanoparticles (Si-SPIONs). The Stöber method⁴¹ with some alteration in combination with sonochemistry was used to prepare silica layer encapsulated SPIONs. 0.5 g of the as prepared Fe₃O₄ nanoparticles was dispersed in 50 ml of deionized water by sonication for 30 minutes. The precipitates were isolated magnetically and redispersed in 25 ml of water and 90 ml of ethanol by sonication for 30 minutes. The solution was turned basic by adding 5 ml (25%) of ammonia solution. After thorough mixing by a mechanical stirrer, 7 ml of TEOS was added dropwise. Then, the mixture was stirred for 5.5 hours at room temperature. The as prepared nanoparticles were washed several times, magnetically separated, centrifuged (3500 rpm, 15 min) and dried in an oven at 50 °C. These obtained nanoparticles were abbreviated as Si-SPIONs.

3.3.3 Functionalization of Si-SPIONs with oxytyramine (OT). Si-SPIONs (0.1 g) were added to a mixture of 5 ml of water and 1 ml of ethanol and sonicated for 30 minutes. Meanwhile, 0.1 g (0.55 mmol) oxytyramine solution in 2 ml of water was also sonicated for 30 minutes. The solutions were mixed, sonicated for 15 minutes and stirred overnight at 50 °C. Then the particles were washed with water, centrifuged (5000 rpm, 15 min) and dried in an oven at 50 °C.

3.3.4 General procedure for the synthesis of cyclohexanecarbonitriles. To a mixture of cyclohexanone (1 mmol, 103.64 μl), amine (1 mmol) and TMSCN (1.3 mmol, 162 μl) in a round-bottom flask, OT-Si-SPIONs (5 mg) was added and it was stirred at room temperature for the desired time. The reaction progress was followed by the solidification of the product as well as thin layer chromatography (TLC) in 30% ethylacetate : hexane solution. After completion of the reaction, the solid was dissolved completely in 5 ml of methanol and the catalyst was separated by an external magnet, washed with CH₃OH and CH₃COCH₃ and dried for further use. The product was recrystallized with methanol and further characterized by its melting point and ¹H-NMR.

3.3.5 Spectral data for all compounds.
4a: 1-(phenylamino)cyclohexanecarbonitrile. M.p. 71–72 °C; ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.27–1.33 (m, 1H), 1.57–1.77 (m, 6H), 1.79–1.8 (m, 1H), 2.31–2.34 (t, 2H), 3.62 (s, 1H, NH), 6.88–6.92 (t, 3H), 7.22–7.26 (t, 2H).
4b: 1-(2-chlorophenylamino)cyclohexanecarbonitrile. M.p. 89 °C; ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.37–1.42 (m, 1H), 1.68–1.78 (s, 7H), 2.37–2.39 (t, 2H), 4.38 (s, 1H, NH), 6.75–6.80 (m, 1H), 7.19–7.21 (d, 2H), 7.29–7.31 (d, 1H).
4c: 1-(4-chlorophenylamino)cyclohexanecarbonitrile. M.p. 98–100 °C; ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.23–1.36 (m, 1H), 1.68–1.81 (m, 7H), 2.28–2.32 (m, 2H), 3.63 (s, 1H, NH), 6.82–6.86 (m, 2H), 7.17–7.21 (m, 2H).
4d: 1-(4-fluorophenylamino)cyclohexanecarbonitrile. M.p. 104–106 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.26–1.35 (m, 1H), 1.58–1.74 (m, 6H), 1.78–1.81 (m, 1H), 2.21–2.27 (m, 2H), 3.48 (s, 1H, NH), 6.90–6.98 (m, 4H).
4e: 1-(2-bromophenylamino)cyclohexanecarbonitrile. M.p. 82–84 °C; ¹H-NMR (400 Hz, CDCl₃) δ (ppm): 1.65–1.80 (m, 8H), 2.34–2.37 (t, 2H), 4.40 (s, 1H, NH), 6.69–6.73 (t, 1H), 7.10–7.26 (q, 2H), 7.46–7.48 (dd, 1H).
4f: 1-(2-methoxyphenylamino)cyclohexanecarbonitrile. M.p. 82–84 °C; ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.25–1.36 (m, 1H), 1.67–1.79 (m, 7H), 2.37–2.39 (t, 2H), 3.84 (s, 3H), 4.35 (bs, 1H, NH), 6.81–6.83 (q, 2H), 6.87–6.91 (m, 1H), 7.08–7.10 (dd, 1H).
4g: 1-(2-tolylphenylamino)cyclohexanecarbonitrile. M.p. 68–70 °C; ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.33–1.38 (m, 1H), 1.69–1.79 (m, 7H), 2.17 (s, 3H), 2.37–2.40 (t, 2H), 3.49 (s, 1H, NH), 6.78–6.82 (t, 1H), 7.10–7.18 (m, 3H).
4h: 1-(3-bromophenylamino)cyclohexanecarbonitrile. M.p. 94–98 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.25–1.37 (m, 1H), 1.67–1.81 (m, 7H), 2.31–2.35 (t, 2H), 3.71 (s, 1H, NH), 6.82–6.85 (d, 1H), 6.90–7.01 (d, 2H), 7.0–7.11 (t, 1H).
4i: 1-(4-bromophenylamino)cyclohexanecarbonitrile. M.p. 116–120 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.29–1.35 (m, 1H), 1.64–1.81 (m, 7H), 2.29–2.33 (q, 2H), 3.65 (s, 1H, NH), 6.77–6.80 (m, 2H), 7.31–7.34 (m, 2H).
4j: 1-(2-ethoxyphenylamino)cyclohexanecarbonitrile. M.p. 92–94 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.34–1.36 (m, 1H), 1.40–1.44 (t, 3H), 1.67–1.77 (m, 7H), 2.35–2.38 (d, 2H), 4.04–4.09 (q, 2H), 4.40 (bs, 1H, NH), 6.77–6.82 (m, 2H), 6.86–6.9 (m, 1H), 7.09–7.11 (d, 1H).
4k: 1-(3-tolylphenylamino)cyclohexanecarbonitrile. M.p. 88–90 °C; ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.28–1.36 (m, 1H), 1.56–1.72 (m, 6H), 1.76–1.80 (m, 1H), 2.30–2.34 (q, 5H), 3.56 (s, 1H, NH), 6.71–6.74 (d, 3H), 7.10–7.14 (t, 1H).
4l: 1-(3-chlorophenylamino)cyclohexanecarbonitrile. M.p. 80 °C; ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.32 (s, 1H), 1.67 (s, 7H), 2.33 (s, 2H), 3.70 (s, 1H), 6.23–6.25 (t, 1H), 6.8 (s, 2H), 7.1 (s, 1H).
4m: 1-(2-fluorophenylamino)cyclohexanecarbonitrile. M.p. °C; ¹H-NMR (400 Hz, CDCl₃) δ (ppm): 1.64–1.78 (m, 8H), 2.31–2.34 (t, 2H), 4.19 (s, 1H, NH), 6.45–6.89 (t, 1H), 7.0–7.26 (q, 2H), 7.41–7.48 (dd, 1H).

4. Conclusions

In summary, a new type of versatile and efficient heterogeneous magnetic nanocatalyst (OT-Si-SPIONs) has been developed using a combined sonochemical and co-precipitation process; furthermore this recyclable catalyst has been successfully applied to the synthesis of various new cyclohexanecarbonitriles. The reaction was carried out under stirring at room temperature, which gave excellent results and renders this protocol economical. The synthesis of cyclohexanecarbonitriles is rarely discussed because of the slow reaction rate but in our protocol the products have been synthesized efficiently. The simple procedure for catalyst preparation, easy recovery of the catalyst and recyclability of the catalyst without any significant loss in its activity even after 5 cycles makes it an ideal catalytic system. The excellent features of this protocol are its short reaction time and simple work up process, and it is a green synthesis, column-free process and environmentally benign.

Acknowledgements

We are thankful to SAIF, Panjab University Chandigarh for FT-IR, TEM and ¹H-NMR, IIT Ropar for SEM and XRD, CSMCRI Bhavnagar for BET. Two of the authors (P. A. and H. S.) are thankful to MHRD, UGC and NIT Jalandhar for providing the research fellowship.

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