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Amines and amino acids as catalysts in Knoevenagel condensation reaction of benzaldehyde with malononitrile.

Introduction

The Knoevenagel Condensation Reaction (KCR) is one of the most well known reactions in organic chemistry which was introduced by Emil Knoevenagel [1]. It is one of the most useful and widely employed reaction for carbon-carbon double bond formation in a broad spectrum of substituted olefins [2]. Furthermore, KCR was of particular interest because of its application in industry [3]. It is simply a condensation reaction between an aldehyde or a ketone and a compound containing an active methylene group. It is promoted by various catalysts to generate chemical compounds which are used in pharmaceutical and food industries [4,5]. The use of amines and amino acids as catalysts in Knoevenagel condensation of benzaldehyde with malononitrile can be highlighted in the following reported research work: Sun et al. [6] used urea as a catalyst; to a mixture of benzaldehyde and malononitrile, urea was added and the resultant mixture was heated to 100[degrees]C and kept for 20 minutes with constant stirring. The reaction yield was 98%. Cai et al. [7] used 1-aminoethyl-3-methylimidazolium hexaflurophosphate [2-aemim][[PF.sub.6]] as a catalyst; a solution of benzaldehyde, malononitrile and [2-aemim][[PF.sub.6]] in water was stirred at room temperature for 20 minutes. The reaction yield was 92%. Yi and Cai [8] used perfluoroalkylated pyridine as a catalyst; benzaldehyde was slowly added into a mixture of malononitrile, n-octane and the catalyst and was stirred for 1.5 hours at 80[degrees]C. The reaction yield was 99%. Forbes et al. [9] used glycine in 1-hexyl-3methylimidazolium hexafluorophosphate [hmimi][[PF.sub.6]] ionic liquid as a catalyst; to a 5 mL reaction conical vial containing a magnetic spin vane, were added in the following order: [hmimi][[PF.sub.6]], malononitrile, benzaldehyde and glycine. The reaction mixture was allowed to stir at 50[degrees]C for 22 hours. The reaction yield was 77%. Balalaie et al. [10] used proline in water as a catalyst; a solution of benzaldehyde, malonitrile, 5,5-dimethyl-1,3-cyclohexanedione and proline in water was stirred at room temperature for 30 minutes. The reaction yield was 82%.

When examining the above reported procedures for the use of amines and amino acids as catalysts in the condensation of benzaldehyde with malononitrile, the following observations are important:

1. Urea, [2-aemim][[PF.sub.6]] and perfluoroalkylated pyridine were used in different molar quantities: 1 mmole urea, 8 mmole [2-aemim][[PF.sub.6]] and 0.25 mmole perfluoroalkylated pyridine. Amino acids such as glycine and proline were also used with different molar quantities: 0.12 mmole glycine and 5 mole% proline. On the other hand, the quantities of reactants, benzaldehyde and malononitrile used in the various techniques reported were very small, ranging from 0.61 mmole to 10 mmole. It is quite clear that all reported research works on the reaction of benzaldehyde and malononitrile were carried out using very small quantities of reactants.

2. Heating of the solution mixture in the presence of the catalyst such as urea and perfluoroalkylated pyridine at elevated temperatures (80-100[degrees]C) is necessary for reaction completion to give a 98-99% yield. On the other hand, when [2-aemim][[PF.sub.6]] catalyst was used at room temperature, the reaction yield was 92%. This might be due to the type of reaction catalysis; heterogeneous catalysis and homogeneous catalysis.

3. Water and n-octane were used as solvents for [2-aemim][[PF.sub.6]] and perfluoroalkylated pyridine respectively. In case of amino acids, water was used with proline.

In general and from the above observations, the use of a catalyst and a solvent in the condensation of benzaldehyde with malononitrile is important. However, Deb and Bhuyan [11] have developed a technique for the condensation of benzaldehyde with malononitrile at room temperature without catalyst and using water as a solvent. Briefly, to a stirred solution of malononitrile in water, benzaldehyde was added all at once. After five minutes, the solid product was isolated by simple filtration and dried, and the reaction yield was 95%. Their experiments were carried out with small quantities of reactants: 0.212 gram benzandehyde with 0.132 gram malononitrile in 8 mL water. They suggest that their technique may displace all other methods which use various organic solvents, catalysts and are performed at high temperatures. The reaction of benzaldehyde with malononitrile in water at room temperature without the use of a catalyst raises the following questions: can we apply this technique to other condensation reactions of aldehydes and ketones with active methylene compounds? what is the reaction mechanism? what is the role of water in the reactions?.

Table 1 gives a summary of the data collected from reported research works on amines and amino acids. In case of amines, the reaction yield was 92-99% and the reaction time was 20 minutes to 90 minutes. While in case of amino acids, the reaction yield was 77-82% and the reaction time was 30 minutes for proline and 22 hours for glycine.

From the above analysis presented in Table 1, it is clear that none of the reported techniques can be considered an industrial technique due to the fact that the industry cannot accept results of experiments in which the quantity of reactants is in "mmole" range. However, there are a few reported research works which can be considered as a good example for the industrial application of KCR [12].

In this paper we would like to demonstrate an effective technique for the condensation of benzaldehyde with malononitrile using an amino acid catalyst. This technique can be carried out at room temperature with a high yield and we believe that it can be used for the condensation of other aldehydes and ketones with active methylene compounds.

Experimental

All of the chemicals used in this study were purchased from Across Organics and were used without any further purification. The reactions were carried out at room temperature.

An equimolar amount of 0.1 mole of benzaldehyde and malononitrile were mixed in a 100 mL conical flask. A solution of an amino acid in glacial acetic acid (4 grams in 10 mL) was prepared. A small quantity of the prepared solution (0.66 mL, 2 mmole) was added dropwise to the reactants mixture at room temperature. Upon the addition of the catalyst under the fume hood and with slight shaking, the solution turned into reddish color and within a minute it turned into a pale yellow solution. The reaction was complete in about four minutes. The reaction product was then recrystallized using an organic solvent such as ethanol to obtain a white crystalline product. The identity and purity of the product were checked using melting point (MEL-TEMP 3.0) and [sup.1]H NMR (Bruker 400-MHz spectrometer) (melting point = 83-84[degrees]C, [sup.1]H NMR (CD[Cl.sub.3], [delta], ppm): 7.91 (d, J= 7.6 Hz, 2H, Ar), 7.78 (s, [sup.1]H, C=CH), 7.64 (t, J= 7.6 Hz, [sup.1]H, Ar), 7.55 (t, J= 8 Hz, 2H, Ar)). A large scale experiment with a high reaction yield was carried out using an equimolar amount of one mole of benzaldehyde and malononitrile..

Results and discussion

Three amino acids were used in this study: 3-aminopropionic acid ([beta]-alanine) and 4-aminobutyric acid and 6-aminocaproic acid. The purpose of this experiment is to compare and observe the effect of chain length which corresponds to the number of methylene group units on the effectiveness of the catalyst in the reaction of benzaldehyde with malononitrile. The results are presented in Table 2.

The above results in Table 2 suggest that the number of methylene group units could help the catalyst to effectively handle the reactants; benzaldehyde and malononitrile. This could mean that 6-aminocaproic acid has more flexibility in making the reactants quickly interact with each other within 4 minutes to give the product. We believe that the catalyst acts through its dipolar ion properties of the amino acid [[sup.+][H.sub.3]N-[(C[H.sub.2]).sub.n]-CO[O.sup.-]]. Therefore, the mechanism of catalysis is a concerted mechanism (acid-base catalysis) as illustrated in Figure 1:

[FIGURE 1 OMITTED]

The effect of solvent on the condensation of benzaldehyde with malononitrile was also tested. The use of water, instead of glacial acetic acid, as a solvent for 6-aminocaproic acid proved that the type of solvent is important and it has a direct influence on the catalyst behavior towards the reactants. The 6-aminocaproic acid dissolved in water took 15 minutes to complete the reaction, while it was significantly faster (4 minutes) when glacial acetic acid was used as a solvent.

Conclusion

The 6-aminocaproic acid in glacial acetic acid proved to be an effective catalyst for the Knoevenagel condensation of benzaldehyde with malononitrile. Further work is undergoing to investigate the effectiveness of this technique in other Knoevenagel Condensation Reactions.

Acknowledgement

I would like to thank Dr. Mamoun AbuKhader for his fruitful discussion and comments. I also would like to acknowledge the support from Applied Science University.

References

[1] Knoevenagel, E., 1894, Chem. Ber., 27, pp. 2345.

[2] Jones, G., 1967, The Knoevenagel condensation reaction, in Organic Reaction, Wiley, New York, Vol. 15.

[3] Tietze, L. F., Beifuss, U., 1991, The Knoevenagel Condensation, in Comprehensive Organic Synthesis, ed. by B.M. Trost, Fleming, I., Heathcock, C. H., Pergamon Press, Oxford, pp. 341.

[4] Freeman, F., 1980, Chem. Rev. 80, pp. 329.

[5] Tietze, L. F., 1996, Chem. Rev. 96, pp. 115.

[6] Sun, Q., Shi, L.-X., Ge, Z.-M., Cheng, T.-M., Li, R.-T., 2005, Chinese J. Chem. 23, pp. 745.

[7] Cai, Y., Peng, Y., Song, G., 2006, Catal. Lett. 109, pp. 61.

[8] Yi, W.-B., Cai, C., 2008, Catal. Commun. 9, pp. 1291.

[9] Forbes, D., Law, A., Morrison, D., 2006, Tetrahedron Lett. 47, pp. 1699.

[10] Balalaie, S., Bararjanian, M., Amani, A., Movassagh, B., 2006, Synlett. 2, pp. 263.

[11] Deb, M., and Bhuyan, P., 2005, Tetrahedron Lett. 46, pp. 6453.

[12] Pande, A., Ganesan, K., Jain, A., Gupta, P., Malhotra, R., 2005, Org. Process Res. 9, pp. 133.

Majed M. AbuKhader

Faculty of Pharmacy, Applied Science University, 11931, Amman, Jordan

Corresponding Author E-mail: m_abukhader@asu.edu.jo
Table 1: Amines and amino acids which are used as catalysts for
the condensation of benzaldehyde with malononitrile.

Amines

Catalyst Quantities Reactants Reaction
 Quantities Temperature

Urea 1 mmole 10 mmole 100[degrees]C
 Benzaldehyde
 10 mmole
 Malononitrile

1-aminoethyl-3 8 mmole 5 mmole Room
-methylimidazolium Benzaldehyde temperature
hexafluorophosphate 5 mmole
[2-emim] [[PF.sub.6]] Malononitrile

Perfluoroalkylated 0.25 5 mmole 80[degrees]C
Pyridine mmole Benzaldehyde
 5 mmole
 Malononitrile

Amino acids

Catalyst Quantities Reactants Reaction
 Quantities Temperature

Glycine 0.12 0.61 mmole 50[degrees]C
 mmole Benzaldehyde
 0.61 mmole
 Malononitrile

Proline 5 mole% 1 mmole Room
 Benzaldehyde temperature
 1.2 mmole
 Malononitrile

Amines

Catalyst Reaction Yield Solvent
 Time

Urea 20 98% Solvent-free
 minutes

1-aminoethyl-3 20 92% Water
-methylimidazolium minutes
hexafluorophosphate
[2-emim] [[PF.sub.6]]

Perfluoroalkylated 1.5 hours 99% n-octane and
Pyridine perfluorodecaline

Amino acids

Catalyst Reaction Yield Solvent
 Time

Glycine 22 hours 77% Ionic liquid

Proline 30 82% Water
 minutes

Table 2: The reaction time and yield for different amino acid
catalysts used in the condensation of benzaldehyde
with malononitirle.

[FORMULA NOT REPRODUCIBLE IN ASCII]

Catalyst Structure Fraction Reaction
 time yield
 (minutes) (%)

3-Ammopropionic acid [FORMULA NOT 8 99%
([beta]-alanine) REPRODUCIBLE
 IN ASCII]

4-Ammobutync acid [FORMULA NOT 6 99%
 REPRODUCIBLE
 IN ASCII]

6-Ammocaproic acid [FORMULA NOT 4 99%
 REPRODUCIBLE
 IN ASCII]
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Author:AbuKhader, Majed M.
Publication:International Journal of Applied Chemistry
Date:Jan 1, 2011
Words:1903
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