Introduction: In the realm of green chemistry, there is a continuous demand for the development of chemical processes that are environmentally friendly, highly atom-economical, and capable of delivering high yields. The increasing threat of environmental pollution and its adverse impact on living systems has driven researchers to design chemical reactions that utilize safer reagents, benign solvents, non-toxic catalysts, atom-efficient procedures, and innovative energy inputs. One of the key focuses in this area is the reduction or elimination of transition metals in chemical processes, as these metals are often toxic, challenging to dispose of safely in large quantities, and can contaminate final products. The presence of residual transition metals in chemical products complicates purification and poses significant health risks, making their avoidance highly desirable.
Recent experimental and theoretical studies have highlighted the remarkable catalytic potential of triethanolamine (TEOA) in various reactions, including the carboxylative cyclization of propargylic amines with carbon dioxide. TEOA is an inexpensive, water-soluble, biodegradable, commercially available, and recyclable organocatalyst. Its solubility in water, basic nature, non-toxic profile, low cost, and environmental compatibility make it an attractive candidate for green chemical processes. These characteristics motivated us to explore TEOA as a novel, metal-free, basic organocatalyst for the Knoevenagel condensation. Employing metal-free catalysts not only reduces costs but also mitigates environmental pollution, aligning perfectly with the principles of green chemistry.
Knoevenagel condensation is a pivotal reaction in organic synthesis, widely used to generate intermediates for pharmaceutical precursors and other fine chemicals. Consequently, it has been extensively studied, and researchers continue to develop novel catalysts and methodologies to enhance its efficiency. The reaction produces α,β-unsaturated compounds, which serve as intermediates or final products in the synthesis of pharmaceuticals, natural products, agrochemicals, and other fine chemicals.
Over the years, various methods have been reported for synthesizing these compounds, employing catalysts such as Ni(NO₃)₃, Pb(II)-MOFs, ammonium acetate, copper salts, zirconium oxide, calcium ferrite, and choline chloride/urea. While these methods have proven effective in some cases, they often suffer from significant limitations, including long reaction times, laborious catalyst preparation, tedious workup procedures, low product yields, hazardous waste generation, use of toxic catalysts, and the extensive application of harmful organic solvents. These drawbacks highlight the urgent need for alternative methods that are both highly efficient and environmentally sustainable.
Developing organocatalytic processes that operate under mild conditions—such as room temperature, low pressure, and metal-free environments—is therefore a priority in green chemistry. Alkanolamines, as a class of low-cost, biodegradable bases, have found broad industrial applications, including in adhesives, natural gas processing, acid neutralization, surfactants, paint stripping, and pharmaceutical derivatives. Among them, TEOA has demonstrated high catalytic efficiency, along with the added advantage of being easily recoverable and reusable without significant loss of activity.
Given the significance of the Knoevenagel condensation in organic synthesis, the development of simple, efficient, and versatile methodologies for this reaction remains an active area of research. Despite numerous reported methods, there is still a need to establish protocols that adhere strictly to green chemistry principles while providing milder reaction conditions and higher product yields.
As a continuation of our ongoing research on green chemistry and one-pot synthesis of various heterocyclic compounds, we herein report a rapid and environmentally friendly procedure for the Knoevenagel condensation. This method involves the one-pot reaction of substituted aromatic aldehydes with malononitrile in the presence of TEOA as a catalyst, using ethanol as a solvent at room temperature (Scheme 1). The process exemplifies a green, metal-free approach with high efficiency, operational simplicity, and potential applicability in the synthesis of fine chemicals and pharmaceuticals.
Scheme 1. Knovengeal condensation of aromatic aldehydes with malononitriles
MATERIAL AND METHODS
Experimental
Triethanolamine (Spectrochem), aromatic aldehydes (Spectrochem and Thomas Baker), and malononitrile (Thomas Baker) were used as received without further purification. All reactions were performed under an open atmosphere using dried glassware. The melting points of the synthesized compounds were determined with a hot paraffin bath and are reported as uncorrected. NMR spectra were recorded on a Bruker Avance spectrometer (400 MHz for ¹H NMR and 100 MHz for ¹³C NMR) using CDCl₃ as the solvent and tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are expressed in parts per million (ppm) relative to TMS, and coupling constants (J) are reported in hertz (Hz).
General Procedure for the Knoevenagel Condensation
A solution of an aromatic aldehyde (1 mmol) and malononitrile (1 mmol) in ethanol (5 mL) was stirred, and triethanolamine (TEOA, 20 mol%) was added. The reaction mixture was stirred at room temperature for 10–30 minutes, and product formation was monitored by thin-layer chromatography (TLC). Upon completion, the reaction mixture often solidified in the flask. The resulting solid was filtered, washed with cold water to remove the catalyst, and dried to obtain the product. Typically, no further purification was required for the solid products. All products were previously reported and characterized using melting point determination, ¹H NMR, and ¹³C NMR spectroscopy.
Spectral Data of Representative Compounds
2-(4-Methoxyphenylmethylene)malononitrile (Table 3, 4d)
¹H NMR (400 MHz, CDCl₃): δ 7.02 (d, 2H, Ar H), 7.93 (d, 2H, Ar H), 7.68 (s, 1H), 3.94 (s, 3H)
¹³C NMR (100 MHz, CDCl₃): δ 55.83, 78.54, 113.37, 114.46, 115.16, 124.04, 133.48, 158.90, 164.85
2-(2-Furylphenylmethylene)malononitrile (Table 3, 4l)
¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, 1H, Ar H), 7.32 (d, 1H, Ar H), 6.84 (t, 1H, Ar H), 7.53 (s, 1H)
¹³C NMR (100 MHz, CDCl₃): δ 112.67, 113.89, 114.47, 123.80, 143.22, 148.07, 149.69
RESULT AND DISCUSSION
The metal-free organocatalyzed Knovengeal condensation by the reaction of aryl aldehyde and malononitrile is one of the effective green catalytic synthetic protocols.In a first step, in order to find the best optimal reaction conditions, condensation of 4-methoxybenzaldehyde (1mmol) and malononitrile (1mmol) was chosenas the model reaction (Scheme 2).
Scheme 2. Knovengeal condensation of 4-methoxybenzaldehyde with malononitrile catalyzed by TEOA
To optimize the reaction conditions, we have studied the effect of different solvents and
amount of the incorporated catalyst and the reaction temperature on the model reaction of 4-methoxy benzaldehyde and malononitrile. Initially, a model reaction of 4-methoxy benzaldehyde and malononitrile, was carried out at room temperature in the presence of TEOA (30 mol%) as a catalyst to obtain the corresponding product , using different solvents.Moreover, we have tested the effects of various solvents for Knovengeal condensation. Among the screened solvent systems, ethanol was found to be the solvent of choice for the Knovengeal condensation. The comparative result using different solvents are summarized in Table 1and it was found that a brief screening of solvent showed that chloroform, methanol, acetonitrile were less effective than ethanol. Ethanol is a greener, economical non-toxic, relatively less expensive solvent and efficient solvent for the present protocol.
Table 1: Optimization of the reaction conditions using different solvents.a
| Entry | Solvent | Catalyst | Yield (%)b |
| 1 | Chloroform | TEOA | 50 |
| 2 | Acetonitrile | TEOA | 68 |
| 3 | Methanol | TEOA | 78 |
| 4 | Ethanol | TEOA | 92 |
aReaction conditions : 4-methoxybenzaldehyde (1 mmol), malononitrile, and TEOA (30 mol%) in solvent (5 mL) at given temperature,b Isolated yield.
After we came to know that the reaction performed in ethanol at room temperarture, is the best reaction condition. Next, we optimized the quantity of catalyst required for the reaction. There is only trace amount of product when the reaction is proceed in the absence of catalyst. Then we started from 5 mol% of TEOA catalyst, when the reaction could be completed in 30 min with 60% yield. In this way catalyst amount was increased up to 30 mol%, with increment of each reaction. It was observed that with an increase in the amount of catalyst loading,a gradual increase in the yield of the desired poduct was noticed. No improvement in yield was observed even by increasing the amount of catalyst. It was also observed that higher amount of catalyst did not improve the results. The optimum amount of catalyst was found to be 20 mol% at room temperature condition. The comparative result using different amount of catalyst are summarized in Table 2.
Table 2: Effect of the amount of TEOA on the yield of model reaction.a
| Entry | Catalyst (mol%) | Time (min.) | Yield (%)b |
| 1 | No catalyst | 20 | Trace |
| 1 | 05 | 20 | 60 |
| 2 | 10 | 20 | 72 |
| 3 | 15 | 20 | 80 |
| 4 | 20 | 20 | 92 |
| 5 | 30 | 20 | 92 |
aReaction conditions: 4-methoxy benzaldehyde (1 mmol), malononitrile, and TEOA (20 mol%) in ethanol(5 mL) at room temperature,b Isolated yield.
The generality of this process was demonstrated by the wide range of substituted and structurally diverse aryl aldehydes carrying either electron-withdrawing or electrondonating groups, which were used for Knovengeal condensation of aryl aldehydes and malanonitrile using a TEOA as an organocatalyst and environmentally benign solvent.The scope and efficiency of the process were explored under the optimized conditions. We have examined the reaction by various aromatic aldehydes containing electron-withdrawing or electron-donating groups as reactants gave the expected results with good to excellent yields .The results are listed in Table 3.
Table 3 TEOA catalyzed synthesis of 3a-l a
| Entries | Aryl aldehyde | Product | Time (min) | Yieldb % | Mp (°C) (Reported) | Ref. |
| 1 | 4a | 10 | 98 | 81-82 (83-84) | 20 | |
| 2 | 4b | 10 | 94 | 160-162 (159-160) | 23 | |
| 3 | 4c | 15 | 98 | 100-102 (100-101) | 21 | |
| 4 | 4d | 20 | 94 | 112-113 (114-115) | 23 | |
| 5 | 4e | 15 | 90 | 95-97 (96-98) | 22 | |
| 6 | 4f | 15 | 92 | 153-155 (153-154) | 22 | |
| 7 | 4g | 30 | 90 | 184-185 (183-184) | 21 | |
| 8 | 4h | 30 | 94 | 135-136 (133-134) | 20 | |
| 9 | 4i | 25 | 94 | 158-160 (159-160) | 21 | |
| 10 | 4j | 25 | 92 | 180-181 (180-82) | 22 | |
| 11 | 4k | 30 | 90 | 98-100 (101-103) | 22 | |
| 12 | 4l | 20 | 94 | 70-72 (68-69) | 20 |
aReaction conditions: arylaldehyde (1 mmol), malononitrile, and TEOA (20 mol%) in ethanol(5 mL) at reflux temperature,b Isolated yield
From Table 3, we observed that the condensation of aldehydes with electron-withdrawing groups such as –Cl and –NO2 in the aromatic ring, with active methylene compounds, could be carried out in relatively shorter times and higher yields than electron-donating groups such as – N(CH3)2,− OH and – OCH3.The advantage of the procedure are milder reaction condition, better yield, shorter reaction time, and easier workup.
A plausible mechanism for the Knovengeal condensation using TEOA in ethanol is outlined in Scheme 3. Based on this mechanism; TEOA is an effective catalyst for the formation of olefin I, readily prepared by Knoevenagel condensation of aryl aldehyde and active methylene compound 24,25.Due to the strong basicity of TEOA and hydrogen bond formed between the hydroxyl group of the side chain of TEOA and carboxyl moiety of aldehydes, the dual activation of methylene ingredients and aldehydes facilitate the formation of a Knoevenagel condensation product I.
Scheme 3. A Plausible mechanism forKnovengeal condensation of 4-methoxybenzaldehyde with malononitrile catalyzed by TEOA
The possibility of recycling the catalyst was examined using the reaction of p-methoxybenzaldehyde and malononitrile under the optimized conditions, after establishing a general protocol for the knovengeal condensation.In this context ,we summarized that, catalyst recovery for possible reuse would be tedious, as well as expensive,because catalyst is completely soluble in the reaction medium, hence we checked reusability of the reaction medium. After the isolation of product by filtration, the filtrate obtained was reused for next reaction. Aryl aldehyde and malononitrile was directly added into the filtrate without adding further catalyst and solvent, resulted in the formation of an expected product with slight loss of catalytic activity at least up to fifth run. Only a slight decrease in the yields of the expected product was observed (94% – 85%). The reaction medium was reused five times in the Knovengeal condensation reaction of 4-methoxybenzaldehyde and malononitrile with slight loss of catalytic activity was noticed from the 5th time of reuse.Therefore catalyst can be reused for at least five consecutive runs for the developed protocol as shown in Table 4.
Table 4: Reusability of TEOA for the yield of model reaction.a
| No. of Cycle | Time (min) | Yield (%)b |
| 1 | 20 | 94 |
| 2 | 20 | 92 |
| 3 | 20 | 90 |
| 4 | 20 | 88 |
| 5 | 20 | 85 |
aReaction conditions: p-nitrobenzaldehyde (1 mmol), malanonitrile, and TEOA (20 mol%) in ethanol(5 mL) at room temperature.b Isolated yield
CONCLUSION
In summary, we have developed an environmentally friendlygreen procedure for the Knovengeal condensation by the reaction of substituted aromatic aldehydes with malononitrile using TEOA as an organocatalyst, in an environmentally benign solvent ethanol at room temperature. The current strategy offers several advantages such as high yields, purity of products, low amount of catalyst, safe, cheap, shorter reaction time, environmentally benign solvent, an easy experimental workup procedure,fully green procedure and clean reaction profile. The reactions using ethanol as solvent, at room temperature conditions and metal-free environment allowed Knoevenagel condensation reactions to be performed in a very simple, clean and green manner.
Conflict of interest
The authors declares no conflict of interest.
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