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Ultrasound Promoted Synthesis of Arylmethylenemalonitriles Catalyzed by Melamine.

Byline: Qing Liu and Hong Mei Ai

Summary: Arylmethylenemalonitriles were synthesized in the presence of melamine through the Knoevenagel condensation of aldehydes with malononitrile in ethanol. Two strategies such as the conventional stirring and ultrasound-assisted method were performed in this work, and improvements were observed by carrying out the reactions under ultrasound irradiation. The effect of frequency and power of ultrasound on the yields was investigated, and the optimum frequency and power was 45 kHz and 240 W, respectively. The Knoevenagel reaction was carried out smoothly under the optimum conditions with the yields of 80-99% within short time. The melamine catalyst showed high activity and reusability, and exhibited no substantial loss of activity over up to four reaction cycles. This work demonstrated that short reaction times and high yields of arylmethylenemalonitriles can be obtained with the facile operation in the presence of the low-toxic, cheap and reusable melamine catalyst.

Keywords: Arylmethylenemalonitriles, Melamine, Ultrasound, Catalysis

Introduction

Melamine (MM), also known as cyanuramide or traminotriazine, has been widely used in industry such as plastics, resins, flame retardants, fertilizer and insecticide [1]. Recently, much attention has been paid to melamine since the scandal of high levels of melamine in different foods, especially milk products [2]. However, previous toxicological study has demonstrated that melamine is generally considered as a low toxicity to mammals [3], with a large oral LD50 of 3161 mg/kg in rats, and 90% of ingested melamine could be excreted by kidneys within 24 h. So the new applications of melamine in other fields should be unceasingly studied. Melamine has never been reported as a catalyst to our knowledge; its catalysis ability has been neglected for a long time. Therefore, the study of melamine as an efficient catalyst is in demand.

Knoevenagel condensation is a widely used reaction for a, b-unsaturated carbonyl compounds in both laboratory and industry, and has been of importance for pharmaceuticals, cosmetics, perfumes and agrochemicals [4, 5]. Various homogeneous and heterogeneous catalysts have been investigated in Knoevenagel condensation reactions, such as organo-bases, Lewis acids, heteropolyacids, molecular sieves functionalized with amino groups, metal organic framework based materials, and nitrogen-containing carbon [6-8]. In spite of the high separation and recycling of the heterogeneous catalysts, the heterogeneous catalysts suffer from limitations, such as the low catalytic activity and the harsh reaction conditions as well as the deactivation by leaching of the active sites. For this reason, the highly active homogeneous catalysts which can be easily recycled and reused are highly attractive in this reaction.

Ultrasound has been widely used in many different fields such as detection, location, medicine, cleaning, welding as well as organic synthesis [9]. Compared with traditional methods, it is more convenient and easily controlled with a higher yield, shorter reaction time or milder conditions under ultrasonic irradiation [9]. Continuing our work on sonocatalysis organic transformations [10-12], we report here an efficient synthesis of arylmethylenemalonitrile through Knoevenagel condensation between malononitrile and various aromatic aldehydes catalyzed by melamine through ultrasound irradiation method.

Experimental

All reagents were purchased and used without further purication (analytical grade). Melting points were determined by using XT-4 micromelting point apparatus. Infrared spectra were recorded on a Nicolet Avatar 360 fourier transform instrument in KBr with absorption in cm-1. 1H NMR spectra were recorded on a Bruker ARX-300 spectrometer using CDCl3 as solvent and TMS as the internal standard. Ultrasonication was performed in a KQ-300VDE ultrasound cleaner with a frequency of 45, 80 and 100 kHz and an output rated power from 0 to 300 W.

General procedure for Knoevenagel condensation through the conventional stirring method (method A) (with the synthesis of 3a as an example)

Benzaldehyde (25 mmol), malononitrile (25 mmol) and ethanol (2.5 mL) were mixed thoroughly, and then 0.25 mmol of melamine was added to a 50 mL round-bottomed flask. The reaction mixture was stirred at room temperature. After complete solidification, the reaction mixture was treated with cold 5% aqueous alcohol (30 mL) and distilled water (3x50 mL). The product was filtered, dried, and, in general, no further purication method was required to afford the product 3a. The product 3a was previously reported and characterized by comparing Mp, IR and 1H NMR with those reported in the literatures [10, 12].

2-(Phenylmethylene)malononitrile (3a)

White solid, 95% yield, Mp 93-94 C, 1H NMR ( CDCl3 ) d: 7.57 ( t, J = 8.0 Hz, 2H, Ar-H ), 7.67 ( t, J = 7.6 Hz, 1H, Ar-H ), 7.81 ( s, 1H, CH = ), 7.93 ( d, J = 7.6 Hz, 2H, Ar-H ); IR (KBr) (cm-1): 3050, 2222, 1595, 1563, 1439, 1217.

General procedure for Knoevenagel condensation through the ultrasound irradiation method (method B) (with the synthesis of 3i as an example)

Furfural (25 mmol), malononitrile (25 mmol) and ethanol (2.5 mL) were mixed thoroughly, and then 0.25 mmol of melamine was added to a 50 mL round-bottomed flask. The flask was located at the maximum energy area in the ultrasonic cleaner and addition or removal of water was used to control the temperature of the water bath at room temperature (25-30 C). After completion of the reaction, the product 3i could be obtained with the same treatments as in method A.

2-(2-Furylmethylene)malononitrile (3i)

Yellow solid, 87% yield, Mp 65-66 C, 1H NMR (CDCl3, 300 MHz) d: 6.74 (q, J = 1.7 Hz, 1H, 2-furyl-H), 7.39 (d, J = 3.5Hz, 1H, 2-furyl-H), 7.54 (s, 1H, CH = ), 7.84 (d, J = 1.5 Hz, 1H, 2-furyl-H); IR (KBr) (cm-1): 3047, 2235, 1609, 1531, 1455, 1295, 1020.

Results and Discussion

At the beginning, in order to evaluate effect of amount of catalyst on Knoevenagel condensation, a model reaction between benzaldehyde and malononitrile through method A was carried out. It was seen that the yield was 95% with 1 mol% melamine (Table-1, entry 3). Although the reaction time was shortened a little while more catalyst was added, the yields also decreased, so the optimum amount of catalyst was 1 mol%. As we all know, melamine is an organic base, and the decline in reactivity with the decrease in the amount of melamine also shows that the Knoevenagel condensation is a base-catalyzed reaction in the procedure described in this study.

Table-1: Effect of catalyst amount on Knoevenagel condensation of benzaldehyde with malononitrile through the conventional stirring method.

Entry###Amount (mol %)###Time (min)###Yield (%)a

###1###0.25###35###92

###2###0.5###24###93

###3###1###20###95

###4###2###20###92

###5###5###17###92

In order to investigate the influence of the solvents, the model reaction between benzaldehyde and malononitrile was carried out through method A in various solvents as well as under solvent-free condition. As shown in Table-2, the reaction proceeded well in ethanol (Table-2, entry 1) and water (Table-2, entry 6), whereas in the other solvents or under solvent-free condition the reaction proceeded difficultly. Although the yield was 92% when water was used, the reaction time was much longer (Table-2, entry 6). Thus, the remainder of reactions through both method A and method B were carried out in ethanol.

Table-2: Effect of solvents on Knoevenagel condensation catalyzed by melamine through the conventional stirring method.

Entry###Solventa###Time (min)###Yield (%)b

1###C2H5OH###20###95

2###CH3CN###120###0

3###CH2Cl2###120###0

4###1, 4-Dioxane###120###0

5###Acetone###120###0

6###H2O###120###92

7###Solvent-free###90###Trace

As we all know, frequency and power are two of the important parameters of ultrasound. Hence, the effect of frequency and power of ultrasound irradiation was also investigated on the model reaction in this work. Frequency can control the behavior of cavitation which strongly changes the efficiency of sonochemical reaction [13]. Meanwhile, we have observed that the effect of frequency of ultrasound on the reaction was significant in the literature [10], and so was the Knoevenagel condensation catalyzed by melamine. Three different frequencies 45, 80 and 100 kHz were used in this reaction with the same output power of 300 W. The yield was 96% only after 8 minutes under ultrasound at 45 kHz (Table-3, entry 1), which was more active compared to the reaction without ultrasound irradiation (Table-2, entry 1), indicating that the significant improvement was obtained under ultrasound.

However, experiments carried out with higher frequency (80 and 100 kHz) showed the different trend, whose yields were lower than the one without ultrasound irradiation. This may because that the ultrasound activation can be weak only at an unsuitable frequency, and the higher frequency may be adverse. The driving energy of ultrasound is provided by cavitations. In other words, the formation and collapse of bubbles can liberate considerable energy in short time. While the critical size and lifetime of the cavitations bubbles depend on the liquid property and the ultrasound frequency [10]. The implosion time and the size of the cavitation bubbles and the mechanical mixing effects in the liquid increase with decreasing frequencies, which is favorable for the reaction, so lower frequencies are preferred for the condensation. The similar frequency effect was observed for several other reactions [14]. As a result, further experiments were carried out with the frequency of 45 kHz.

The reaction rate was also compared with different output power from 120 to 300 W at 45 kHz. As shown in Table-3, firstly, the reaction time prolonged as the decrease of ultrasound power (Table-3, entry 1 and 4); And there was no obvious prolongation of the reaction time while the power of ultrasound continued to decreased. On the other hand, the yields reached a maximum (Table-3, entry 5) and then decreased as the power of ultrasound decreased from 300 W to 120 W. The intense cavitation was induced close to the probe tip for high acoustic power and might absorb a great part of the acoustic wave energy, resulting in preventing the sound from penetrating deeply in the liquid. These facts meant that there was an optimum ultrasound power of 240 W in this work, and the effect of ultrasound power on the yields was smaller than that of ultrasound frequency. As a result, further experiments were carried out with power of 240 W.

Table-3: Effects of frequency and power of ultrasound on Knoevenagel condensation catalyzed by melamine.

Entry Frequency (kHz)###Power (W) a###Time (min)###Yield (%)b

1###45###300###8###96

2###80###300###12###91

3###100###300###14###90

4###45###270###10###96

5###45###240###11###99

6###45###210###11###97

7###45###180###12###97

8###45###150###12###97

9###45###120###12###95

After optimizing the reaction conditions, aromatic aldehydes were treated with malononitrile in the presence of melamine under ultrasound irradiation or through the conventional stirring method, and the results are listed in Table-4. By the conventional stirring method at room temperature, the corresponding products were obtained in good to excellent yields (method A). Meanwhile, by the ultrasound-assisted method (method B), the reaction times were largely reduced and all the yields were significantly improved. Aromatic aldehydes with an electron-withdrawing group were converted to their corresponding arylmethylenemalonitriles under these conditions in excellent yields after a short time (Table-4, entries 2-3). On the other hand, the aromatic aldehydes with electron-donating group afforded the corresponding acylal in excellent yield and purity (Table-4, entry 4) [15].

The hydroxyl is strong electron-donating group, which decreases the activity of aldehydes and the yields were inferior (Table-4, entry 5-7). Furthermore, the sensitive cinnamaldehyde and heteroaromatic furfural were converted to the corresponding arylmethylenemalonitriles successfully (Table-4, entries 8-9).

The miscibility of melamine with water made the catalyst separation process quite easy. The melamine could be removed from the product simply by washing the product with 5% cold aqueous alcohol and distilled water. The catalyst in the aqueous phase could be recovered by removing water under the vacuum, then washed with acetone and dried. Catalyst reusability was assessed in the reaction of benzaldehyde with malononitrile under ultrasound irradiation. It was seen in Table-5 that the catalyst can be reused for 4 times without significant decrease of the reactivity, indicating the high reusability of melamine in this work.

Table-4: Knoevenagel condensation catalyzed by melamine through ultrasound-assisted or conventional stirring method

###Time (min)###Yield (%)

Entry###R###Compd.###Aa###Bb###Aa###Bb

###1###C6H5###3a###20###11###95###99

###2###2-ClC6H4###3b###7###4###95###97

###3###2, 4-Cl2C6H3###3c###15###7###94###96

###4###4-CH3OC6H4###3d###47###20###95###96

###5###2-OHC6H4###3e###11###5###78###81

###6###4-OHC6H4###3f###99###30###66###80

###7###Vanillin###3g###120###65###78###93

###8###Cinnamaldehyde###3h###140###58###95###96

###9###2-Furyl###3i###198###60###81###87

Table-5: The reuse of melanine for Knoevenagel condensation of benzaldehyde and malononitrile

###Cycle###1###2###3###4

###Yield/%a###99###99###98###96

In order to show the merit of melamine in comparison with the other catalysts used for the same reaction, we have tabulated some of the results in Table-6. As it is evident from the results, the required amount for the most catalysts used for this purpose is more than 1 mol% and also the required reaction time is longer. Mention must be made here that some catalysts are expensive, complex or unavailable.

Table-6: Comparison of different catalysts for Knoevenagel condensation of benzaldehyde with malononitrile

###Amount###Time###Yield

Entry###Catalyst and conditions###Ref.

###(mol%)###(min)###(%)a

###1###Melamine/EtOH/Ultrasound###1###11###99###-b

###Potassium

###2###sorbate/Solvent-free###1###3###95###[10]

###/Ultrasound

###3###I2/K2CO3/EtOH###30###12###80###[16]

###4###[2-aemin][PF6]/H2O###0.8###20###92###[17]

###5###HEAPs/H2O###10###10###95###[18]

###6###[C4dabco][BF4]/H2O###15###less than 1###100###[19]

Conclusion

A facile and efficient method for the Knoevenagel condensation of aromatic aldehydes with malononitrile catalyzed by melamine under ultrasound irradiation was reported in this work. Improvements in reaction rates and yields were observed under ultrasound irradiation. The optimum frequency and power of ultrasound were achieved. The attractive features of this procedure were the facile and mild reaction conditions, high yields, short reaction times and reusability of the catalyst. All of which made it a useful and attractive strategy for the preparation of arylmethylenemalonitriles.

Supplementary Material

Supplementary material relating to analytical data as well as characterization of the samples using 1H-NMR and FT-IR is available on the publishers Web site along with the published article.

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Author:Liu, Qing; Ai, Hong Mei
Publication:Journal of the Chemical Society of Pakistan
Article Type:Report
Geographic Code:9PAKI
Date:Jun 30, 2016
Words:3119
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