Malononitrile: A Versatile Active Methylene Group

: The title role of malononitrile in the development of Knoevenagel condensation of organic synthesis and their new findings are explored in this review. The active methylene group of malononitriles is very important attacking part in the heterocyclic conversions and also having a great potency towards several microbial and biological systems.


INTRODUCTION:
In the earlier periods, the nitrile derivative differs and proved their multiple practices in the heterocyclic synthesis. Furthermore they performed as an intermediary part in a number of reaction conversions. The malononitrile derivatives exhibits the synergistic toxicity in the toxic-dynamic and toxic-kinetic interactions with aldehyde components [1] . Some of the malononitrile derivatives shows the significant antimicrobial [2] such as antibacterial [3] and antifungal [4] [5] , anti-proliferative activities on human breast adenocarcinoma, ovarian adenocarcinoma and lymphoblastic leukemia cell [6] . They also acts as anticancer [7] , mollucicidal [8] , anti-inflammatory [9] and anti-oxidant [10] agents. Besides these the definite complex molecules of malononitrile derivatives by copper metal confers the virtuous anticancer activities [11] and similarly acts as G protein-coupled receptor 35 (GPR 35 ) agonists [12] .

CONCEPT OF ACTIVE METHYLENE GROUP IN MALONONITRILE:
Active methylene group of malononitrile 1 analogs plays a vital and attacking role in the heterocyclic synthesis. Malononitrile innumerate the unique interest in the organic synthesis due to the conversion of different functional groups such as ketones, aldehydes, esters, Oxo and amines corresponding carbanions of malononitrile molecule causes very essential for structural and spectral changes [13] . The Knoevenagel condensation reaction offers most of the conversion between carbonyl carbons with active methylene group of the nitrile analogs. Their molecular crystal acts as phase transfer in the specific heat capacity at low temperature [14] . In the photochemical study of malononitrile 1 measured by the photo absorption and fluorescence excitation in vacuum UV region by Rydberg states. It was proved that CN (B 2 ∑ + ) and CN (A 2 II) photo fragments increases by decreasing the wavelength excitation in fluorescence spectrum [15] . 3.1 Synthesis using ketones: Wang G. and Cheng B. [16] have synthesized the arylidene 3(a-c) malononitrile analogs by uniform mixture of substituted ketones 2 (a-c) and dicyanomethane 1 catalyzed by ammonium acetate or silica gel under the microwave assisted solvent free synthesis. (Scheme-01)

3(a-c)
Gupta R. et al [17] have buildup the simple and efficient silica supported method of Knoevenagel condensation method. Identical molar mixture of different substituted ketones 4(a-f) and malononitrile 5(a-b) were reacted in presence of silica supported ammonium acetate catalyst refluxed on 60ºC temperature in methylene dichloride solvent; furnished compound 6(a-l) gave high quality and yields. (Scheme -02)  [19] synthesized arylidene malononitrile derivatives 11(a-k) by parallel mixture of substituted aromatic aldehydes 10(a-k) and malononitrile 1 using catalytic amount of ammonium acetate under microwave irradiation. (Scheme -05) Sheibani H. and Saljoog A. S. [20] have reported the ecofriendly high speed Knoevenagel condensation synthesis. In the reaction condition, counterpart mixture of the substituted aldehydes 12(a-v) and nitrile groups 13(a-b) were carried out under ethanol-aqueous media in presence of KOH or NaOH catalyst at 50-60ºC temperature afforded the productive 14(a-t) derivatives.   13 14(a-t) Rajendran A. et al [21] have reported the simple efficient and rapid Knoevenagel condensation synthesis by using ionic liquid media. The mixture of aromatic aldehyde 15(a-f) and dicyanomethane 1 were evenly carried out in pyridinium salicylate ionic liquid refluxed on 40ºC for few minutes occupied the malononitrile 16(a-f) derivatives.

ArCHO
Pal R. [22]  Lin Q. et al [25] have designed a novel chemosensor of cyanide analogous 26 by the condensation between napthaldehyde 25 with mlononitrile 1 heated at 90°C fro 2 hrs in aqueous media via green synthesis. (Scheme -11) Basude M. et al. [26] have prepared the methylene-dinitrile derivatives 29(a-i) under water. An experimental section, substituted aryl aldehydes 27(a-i) reacts with malononitrile or ethyl cyanoacetate 28(a-b) in presence of ZnO catalyst in an aqueous condition at ambient temperature that gives end products

32(a-t)
Gutch P. K. et al [28] have formulated and reported the biologically active riot control agent benzylidene malononitrile 34 groups. These are synthesized by the mixture of substituted aromatic aldehydes 33 and malononitrile 1 in presence of highly alkaline catalyst like piperidine refluxed in cyclohexane solvent. They are bio-significant riot-control agents. (Scheme -14) Scheme -14 33 1 Gauda M. A. and Abu-Hasan A. [29] have intended the eco-friendly synthesis of malononitrile derivatives 36, 38 in an aqueous media. In the Knoevenagel condensation synthesis of aromatic aldehydes 35, 37 and malononitrile 1 were equally mixed by using lithium hydroxide monohydrate catalyst which acts as dual-activator nature. (

130
ILCPA Volume 57 [31] have reported the Knoevenagel condensation of isatins 44(a-h) in an aqueous condition. These products were synthesized by the parallel mixture of indoles 42(a-d) and nitriles 43(a-b) refluxed in presence of silica based sulphonic acid (SBA-Pr-SO 3 H) catalyst under water.

CONCLUSION
This review has attempted to summarize the synthetic methods and reactions of malononitrile groups. Many biologically active heterocyclic compounds have been synthesized from that group. These reactions greatly extended synthetic possibilities in organic chemistry.