Introduction

Benzylidene malononitriles (BMNs), the main products of the Knoevenagel condensation of various substituted aldehydes with active methylene compound malononitrile, have vast applications in the field of chemistry. They were reported to be effective anti-fouling agents, fungicides, insecticides and also used as cytotoxic agents against tumors or as riot control agents [1–3]. Their derivatives which incorporate bis(2-chloroethyl) amino groups, a bis(chloromethyl) pyrrolidine substituent, or phenylazopyrimidine residue have been used for chemotherapeutic treatment of cancer. Among various BMNs compounds, (2-chlorobenzylidene)malononitrile (CS) was largely used as a riot control agent because it causes irritation of eyes, nose, and respiratory tract with the consequent production of profuse tears and mucus. It is, therefore, also termed as an irritant or tear gas compound [4].

Various BMNs like 2-(3-methoxybenzylidene)malononitrile, 2-(2-methylbenzylidene)malononitrile, etc., have shown good-to-excellent anti-bacterial activities against pathogenic organisms like Bacillus cereus, Staphylococcus aureus, Vibrio cholerae, Shigella dysenteriae, Salmonella typhi, Klebsialla pneumoniae, Escherichia coli, and Pseudomonas aeruginosa and anti-fungal activities against Aspergillus flavus and Saccharomyces cerevisiae [5, 6]. They have also found applications in industry, agriculture, medicine, biological science, and in the elegant synthesis of fine chemicals. Due to the unique biological properties of benzylidene malononitrile, the development of new synthetic routes to these compounds has stimulated constant interest and has been the focus of many research groups. Most of the traditional methods for synthesis of benzylidene malononitrile involve the use of dipolar aprotic solvents such as dimethylformamide (DMF) or dimethylsulfoxide (DMSO) that are toxic, teratogenic and suspected carcinogens and weak bases such as secondary or primary amines, pyridine, or suitable combinations of amines and Lewis acids under homogeneous conditions were employed as catalysts in these procedures, difficult to recover and often entail severe environmental pollution during the process of waste disposal [7]. Knoevenagel condensation catalyzed by organic bases such as aliphatic amines, ethylenediamine, and piperidine or their corresponding ammonium salts employs hazardous solvents like benzene and requires prolonged heating with continuous water removal. In comparison to the large number of bases as catalysts, limited Lewis acid (LA) catalysts are also known for Knoevenagel condensation such as Mg(ClO4)2 [8], LaCl3 [9], NbCl5 [10], TiCl4 [11, 12], ZnCl2 [13], and MgBr2 [14]. Some of these Lewis acids need to be used in more than stoichiometric quantity. Many other catalysts such as clays [15], layered double hydroxides (LDHs) [16], piperidine [17], aminopropylated fly ash [18], various homogeneous and heterogeneous catalysts such as CeCl3·7H2O/NaI [19], HClO4–SiO2 [20], Ni–SiO2 [21], etc., and organocatalysts like chitosan hydrogel [22] were also employed for catalyzing Knoevenagel condensation.

Recently amine functionalized K10 montmorillonite [23], P4VP/Al2O3–SiO2 [24], Ti-PCS [25], aminated poly(vinyl chloride) [26], CuBTC (metal–organic framework) [27], aminated ordered mesoporous carbons [28], lipase [29], piperidine [30], aqueous DABCO [31], ionic liquids [32], etc., were emerged as new types of catalysts which catalyzes the Knoevenagel condensation reaction.

But, the use of these bases, solvents, and Lewis acids leads to generation of pollutants during the course of the reaction and some of these Lewis acids degraded in the reaction which renders it non-reusable catalysts. l-proline, a versatile amino acid, is non-toxic, inexpensive, and available in very pure form [33]. Due to these features of l-proline, it has gained importance as organocatalyst for various organic transformations [34] such as asymmetric aldol addition [35], halolactonization, Michael and Mannich reactions, reduction of C=O, C=N, and C=C bonds, alkylation and allylation, and synthesis of optically active phosphorous compounds [36] and various other compounds such as (E)-ethyl 2-cyano-3-(1H-indol-3-yl)acrylates and (E)-3-(1H-indol-3-yl)acrylonitriles [37]. l-proline was also utilized for providing chiral enhancement in the diethyl malonate addition reaction [38] and inversion of enantioselectivity was also observed in the asymmetric aldol addition catalyzed by polystyrene-supported proline di- and tripeptides [39].

Nowadays, heterogenation of homogeneous catalysts has made a remarkable change in the field of catalysis. Therefore, the immobilization of l-proline on inorganic supports like silica [40, 41], HAP, clays, etc., further increases the activity, selectivity, reusability, and easy handling of l-proline. Based on the various factors discussed above, we have chosen SiO2-l-proline as catalyst for condensation reaction of various aldehydes and malononitrile as reaction substrates. Therefore, we have developed benzylidene malononitrile derivatives by the selective condensation of various aromatic and heteroaromatic aldehydes with malononitrile in the presence of SiO2-l-proline as heterogeneous catalyst by stirring in acetonitrile at 80 °C (Scheme 1).

scheme 1

Results and discussion

Characterization of SiO2-l-proline

SiO2-l-proline was characterized by FT-IR, thermal gravimetric analysis (TGA), SEM and TEM analysis.

FT-IR

The FT-IR spectrum of catalyst showed strong absorption peaks at 473 and 803 cm−1 which is attributed to Si–OH bending and stretching vibrations. The characteristic band derived from the stretching vibration mode of C=O in the FT-IR spectrum of catalyst at around 1,636 cm−1 provides direct evidence of l-proline in the catalyst. The absorption peak at 1,097 and 565 cm−1 corresponds to stretching and bending mode of vibrations of l-proline ring. The peak at 972 and 3,457 cm−1 corresponds to bending of OH and stretching NH, respectively, as shown in Fig. 1.

Fig. 1
figure 1

FT-IR spectra of silica-l-proline

Full size image

Thermal gravimetric analysis

The stability of the SiO2-l-proline was determined by thermal gravimetric analysis (Fig. 2). The curve showed an initial weight loss up to 131 °C which may be due to the loss of residual water trapped onto the surface of silica and then slight weight loss occurs up to 377 °C which may be due to the decomposition of l-proline followed by continuous weight loss up to 484 °C. This indicates that catalyst is stable up to 377 °C and hence it is safe to carry out the reaction at 80 °C.

Fig. 2
figure 2

Thermal gravimetric analysis of silica-l-proline

Full size image

Transmission electron microscope

The TEM micrographs of the catalyst provide a direct observation of the morphology and distribution of the l-proline in SiO2-l-proline. The TEM micrographs indicated that l-proline is uniformly distributed onto the surface of silica (Fig. 3) and further infer that SiO2 forms a mesh-like network in which the l-proline molecules get entrapped. The mean diameter was found to be 5.40 nm.

Fig. 3
figure 3

TEM images of SiO2-l-proline

Full size image

Scanning electron microscope

The microstructure and morphology of SiO2-l-proline were studied using a scanning electron microscope (SEM). The surface of SiO2-l-proline was found to be fine homogeneous powder with porous structure and it was observed that l-proline particles are adsorbed onto the surface of silica as shown in Fig. 4.

Fig. 4
figure 4

SEM images of SiO2-l-proline: a ×100,000 and b ×600

Full size image

Optimization of reaction conditions

To select the appropriate reaction conditions, 3,4-dimethoxybenzaldehyde and malononitrile were selected as test substrates and the reaction was carried out under different set of conditions with respect to different catalysts, quantities of SiO2-l-proline, solvents, and temperatures. Firstly, we have carried out the reaction of test substrates with different catalysts and we have found that out of all different catalysts which we have tried, SiO2-l-proline has showed better results with respect to short reaction time and better yield of product. The results are shown in Table 1. The reaction was also carried out in different quantities of SiO2-l-proline as shown in Table 2. After carrying out series of reactions, 0.1 g of SiO2-l-proline was found to be sufficient to carry out the reaction selectively with excellent yield of products. To test the reactivity of various nucleophiles like ethylcyanoacetate, diethyl malonate and malononitrile for Knoevenagel condensation in presence of SiO2-l-proline, the reaction of 4-nitrobenzaldehyde with various nucleophiles has been carried out as shown in Table 3.

Table 1 Effect of different catalysts on Knoevenagel condensation reaction
Full size table
Table 2 Effect of different quantities of silica-l-proline on Knoevenagel condensation reaction
Full size table
Table 3 Reaction between 4-nitrobenzaldehyde and various nucleophiles
Full size table

From Table 3, it has been concluded that malononitrile was more reactive than ethylcyanoacetate and diethyl malonate. This may be attributed to the fact that the electron-withdrawing ability of the substituent CN group in malononitrile is stronger than that of the carbonyl group in ethylcyanoacetate and diethyl malonate which makes the methylene group of malononitrile more reactive than others and reacted more readily with aromatic/heteroaromatic aldehydes.

To further optimize the reaction conditions, the test reaction of 3,4-dimethoxybenzaldehyde with malononitrile was also carried out using polar and non-polar solvents like acetonitrile, toluene, and water. The reaction was also carried out under solvent-free conditions. After examining the reactions under these conditions, we have found that acetonitrile gave the best results in terms of yield, selectivity, and reaction times. The results are shown in Table 4.

Table 4 Effect of solvents on Knoevenagel condensation reaction
Full size table

To make the reaction conditions milder and effective, the test reaction was also attempted at different temperatures as shown in Table 5. It was found that the rate of reaction at room temperature and 50 °C was very slow. Thus, 80 °C was selected as the optimum reaction temperature at which the reaction proceeded smoothly and gave better yields of products with good selectivity.

Table 5 Effect of temperature on Knoevenagel condensation reaction
Full size table

To study the generality of the newly developed protocol, different aromatic and heteroaromatic aldehydes substituted with electron-donating and electron-withdrawing substituents were selected that gave good-to-excellent results. The results are summarized in Table 6. The structure-activity relationship has been drawn from Table 6 and it was inferred that in case of aromatic aldehydes substituted with electron-withdrawing groups undergo faster reactions than aromatic aldehydes substituted with electron-donating groups and heteroaromatic aldehydes.

Table 6 Knoevenagel condensation reaction between aromatic/heteroaromatic aldehydes and malononitrile catalyzed by SiO2-l-proline in acetonitrile at 80 °C (Scheme 1)
Full size table

The Knoevenagel reaction was also carried out between aliphatic aldehydes and malononitrile in the presence of SiO2-l-proline as catalyst. The results are shown in Table 7. From this table, it has been concluded that aliphatic aldehydes did not undergo Knoevenagel condensation with malononitrile in the presence of SiO2-l-roline as catalyst and after 8 h, in case of formaldehyde, only 20 % reaction occurs whereas in case of acetaldehyde and butyraldehyde, no reaction occurs and we just recovered starting materials.

Table 7 Reaction between aliphatic aldehydes and malononitrile
Full size table

To study the effect of SiO2-l-proline as catalyst, the reaction of the test substrates was also carried out in the absence of catalyst and it was found that without catalyst, the reaction did not take place even after 8 h of stirring at 80 °C in acetonitrile. Thus, it became quite clear that the condensation of aromatic/heteroaromatic aldehydes and malononitrile was catalyzed by SiO2-l-proline in acetonitrile at 80 °C. The reaction of 3,4-dimethoxybenzaldehyde with malononitrile using SiO2-l-proline was also tried under microwave conditions for about 3 h, but the reaction did not proceed to completion.

Recyclability and heterogeneity of SiO2-l-proline

To classify the catalyst as heterogeneous catalyst, recyclability of the catalyst required to be examined. A series of five consecutive runs were carried out in case of 4-nitrobenzaldehyde and malononitrile (Table 6, entry 3). It was found that a little drop in the activity of the catalyst was observed. The results are shown in Table 8 and Fig. 5. The hot filtration test has also been performed for testing the heterogeneity of the catalyst using 4-nitrobenzaldehyde and malononitrile as test substrates. Firstly, in this test, the reaction has been carried out in the presence of SiO2-l-proline in acetonitrile at 80 °C. After 4 h, catalyst was filtered off from the reaction mixture and the rest of the reaction mixture was further monitored for 3 h and it was found that the reaction has not been proceeded with further in the absence of the catalyst. Therefore, it may be concluded that there is no leaking of the l-proline from the SiO2-l-proline catalyst.

Table 8 Recyclability of SiO2-l-proline in case of 4-nitrobenzaldehyde and malononitrile
Full size table
Fig. 5
figure 5

Recyclability of SiO2-l-proline in case of 4-nitrobenzaldehyde and malononitrile

Full size image

Conclusion

In conclusion, we have developed a mild and convenient methodology for the synthesis of various substituted benzylidene malononitrile using amino acid functionalized silica composites as heterogeneous catalyst. This method has several advantages including good isolated yields of the products and easy workup. The catalyst also showed good activity and could be recovered and recycled up to fourth run with little drop in activity after every run.

Experimental

All the chemicals and solvents were purchased from Sigma-Aldrich and Merck and were used without further purification. IR spectra were recorded on Perkin Elmer FT-IR spectrophotometer. The mass spectra were recorded on Esquire 3000 Bruker Daltonics spectrometer (ESI). 1H and 13C NMR spectra were recorded in CDCl3 and DMSO-d 6 on a Bruker Avance III 400 MHz spectrometer using TMS as an internal standard. TGA was recorded on Linesis Thermal Analyser with heating rate of 10 °C/min. FT-IR was recorded on Perkin Elmer-Spectrum RX-IFTIR spectrophotometer. SEM images were recorded on JSM-7600F scanning electron microscope. TEM images were recorded on CM200 PHILIPS transmission electron microscope. All physical and spectroscopic data of products were compared with those reported in the literature.

Synthesis of silica-supported l-proline

Preparation of activated silica

Silica gel (15 g, K 100) was added to a solution of 1:1 HCl (150 ml) and H2O (150 ml) in a 500 mL round-bottom flask and the reaction mixture was stirred at 120 °C for 12 h. The activated silica was filtered at pump, washed with water until washings were neutral and dried in oven at 110 °C for 5 h.

Preparation of silica-supported l-proline (SiO2-l-proline)

In a round-bottom flask, l-proline (0.15 mmol) was dissolved in 0.9 cm3 methanol. To this solution, 500 mg activated silica gel was added. The mixture was shaken for few minutes and then evaporated under reduced pressure of 333 mbar for 25 h to give free flowing powder. The complete preparation procedure for silica-supported l-proline is represented in Scheme 2.

scheme 2

General procedure

To the mixture of aldehyde (1 mmol), malononitrile (1 mmol), and 0.1 g SiO2-l-proline (10 mol %) in a 100 cm3 round-bottom flask, 3 cm3 acetonitrile was added and the reaction mixture was stirred at 80 °C in an oil bath. On completion (monitored by TLC), the reaction mixture was diluted with 10 cm3 EtOAc and filtered to separate SiO2-l-proline from the reaction mixture. The filterate was washed with distilled water and dried over anhydrous Na2SO4. Finally, the product was obtained after removal of solvent under reduced pressure followed by crystallization from EtOAc: petroleum ether or by passing through column of silica gel and elution with EtOAc: petroleum ether. The catalyst was washed with EtOAc (2 × 5 cm3) followed by double distilled water (2 × 10 cm3). It was dried for 2 h and then reused for subsequent reactions. The structures of the products were confirmed by IR, 1H NMR, 13C NMR, mass spectral data, and comparison with authentic samples available commercially or prepared according to the literature methods.