A novel eco-friendly process for the synthesis of 2- chlorobenzylidenemalononitrile and its analogues using water as a solvent

Article abstract of DOI:10.1021/op0498262

A simple and novel eco-friendly process for the synthesis of 2-chlorobenzylidene malononitrile (CS) and their analogues in water using 1-methyl imidazole (catalyst) has been developed. The reaction conditions for the preparation of CS are optimized for la

Full text of DOI:10.1021/op0498262

Organic Process Research & Development 2005, 9, 133−136
Full Papers
A Novel Eco-Friendly Process for the Synthesis of
2-Chlorobenzylidenemalononitrile and ITS Analogues Using Water As a Solvent
Ambuja Pande, Kumaran Ganesan, Asheesh Kumar Jain, Pradeep Kumar Gupta, and Ramesh Chandra Malhotra*
Synthetic Chemistry DiVision, Defence Research and DeVelopment Establishment, Jhansi Road,
Gwalior - 474 002 (M.P.), India
Abstract:
environmental friendly solid bases7 such as AlPO4-Al2O3,
alkylamine-functionalized silica gel, ZnO or MgO, xonolite,
KF/Al2O3, zeolite CsX, etc. as alternative catalysts to organic
bases. Microwave, infrared radiation, and ultrasound-
promoted Knoevenagel condensations were also reported.8,9
In addition, condensations by ball-milling/grinding under
solvent-free conditions were also studied.10 In the case of
solvent-free, microwave, or IR heating reactions, the yield
and the purity were less7,11 and these methods were pertinent
to preparative scale8 only. Morrison et al. reported Knoev-
enagel reactions in ionic liquid solvents as an environmen-
tally benign approach.12 Condensation of benzaldehyde and
malononitrile in ionic solvents occurred in 22 h, the yield
was 77%, and recycling of ionic liquid resulted in 39% yield
only.12 Thus the drawbacks of the known methods for the
production of benzylidenemalononitriles include more reac-
tion time, low yield, less purity, use of hazardous inflam-
mable organic solvents, and more cost.
A simple and novel eco-friendly process for the synthesis of
2-chlorobenzylidene malononitrile (CS) and their analogues in
water using 1-methyl imidazole (catalyst) has been developed.
The reaction conditions for the preparation of CS are optimized
for large scale applications.
Introduction
Benzylidene malanonitriles have received much attention
as cytotoxic agents against tumours, and some of the
derivatives have also been used as rodent control agents.1,2
2-Chlorobenzylidene malononitrile (CS) is one of the most
potent lachrymator skin irritants and is a well-known riot
control agent3 used by law enforcing agencies during civil
disturbances. Various methods4 have been reported for the
synthesis and process development of 2-chlorobenzylidene
malononitrile/analogues and were prepared by Knoevenagel
condensation of the corresponding substituted benzaldehydes
with malononitrile in the presence of different bases as
catalyst in organic solvents, such as cyclohexane, methanol,
or ethanol. In recent years, environmentally benign synthetic
methods have received considerable attention due to world-
wide concerns over chemical wastes and future resources.
Thus, green chemistry approaches have been developed for
various existing processes.5
Herein we report a simple, clean, efficient, environment
and eco-friendly process for the synthesis 2-chloroben-
zylidenemalononitrile (CS) in water, and the conditions were
optimized for upscaling to the manufacturing process. The
water used was recycled for further runs to reduce the
effluent load. In addition, few analogues of CS were also
synthesized in water by following the same process.
Results and Discussion
The Knoevenagel condensation has been an important tool
for constructing the R,â-unsaturated structure unit from a
carbonyl and an active methylene compound.6 In recent
years, this reaction was exploited with various inorganic
1. Preparation of CS in Water Using Different Cata-
lysts. Knoevenagel condensation is a base-catalyzed reaction.
To investigate the effect of base on the reactivity, condensa-
tion reactions of 2-chlorobenzaldehyde with malononitrile
were carried out at preparative scale with different catalysts
in water at 35 °C. The effect of catalyst on reaction time
* Corresponding Author. E-mail: rcmalhotra@hotmail.com. Fax: 00-91-751-
2341148.
(1) Rose, S. P.; Smith, R. New Sci. 1969, 43, 468.
(2) Tigner, J. R.; Besser, J. F. J. Agric. Food Chem. 1962, 10, 484.
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(7) Peng, Y.; Song, G. Indian J. Chem. 2003, 42B, 924-26 and refs 3 to 18
therein.
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Synth. Commun. 1998, 28, 4649-63. McNulty, J.; Steere, J. A.; Wolf, S.
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A. S.; Texier-Boullet, F.; Hamelin, J. Synthesis 1994, 258.
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Tetrahedron Lett. 2002, 43, 3117-3120.
(4) Corson, B. B.; Stoughton, R. W. J. Am. Chem. Soc. 1928, 50, 2825-2837.
Knapp, J. S. U.S. Patent 3,963,770, 1976 (CA 1976, 85, 77925t). Shulgin,
A. T.; Calif, L. U.S. Patent 3,250,798, 1966. Rosin, J. Maplewood, N. J.
U.S. Patent 3,549,683, 1970. Berry, W. L.; Yardley, Pa., Jr.; Nisonger, D.
P.; Craig, P. S. U.S. Patent 3,715,379, 1973.
(5) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100, 1025. Cave, G. W. V.; Raston,
C. L.; Scott, J. L. J. Chem. Soc., Chem. Commun. 2001, 2159-2169.
Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practie; Oxford
Science Publications: New York, 1998.
(6) Jones, G. Organic Reactions; Wiley: New York, 1967; pp 15, 204-599.
Tietze, L. Beifuss, U. In ComprehensiVe Organic Synthesis; Heathcock,
C., Ed.; Oxford, Pergamon Press: 1991; pp 2, 341-394.
(12) Morrison, D. W.; Forbes, D. C.; Davis, J. H., Jr. Tetrahedron Lett. 2001,
42, 6053-55.
10.1021/op0498262 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/21/2005
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Table 1. Synthesis of 2-chlorobenzylidenemalononitrile in
water using various catalysts
electron availability on the nitrogen atom but also by the
extent to which the cation, formed by uptake of a proton,
can undergo hydration and so become stabilised. The more
hydrogen atoms attached to nitrogen in the cation, the greater
the possibilities of powerful hydration via bonding between
these and water. Therefore the reaction time was high for
aliphatic bases even though pKa values (11-14) of these
bases in water are very high; i.e., the catalyst activity of these
bases is less.13 It was observed that the reaction time using
diethylamine was 2-fold greater than that using triethylamine
as catalyst. Among three imidazoles used, i.e., imidazole,
1-methyl imidazole, and 2-methyl imidazole, 1-methyl imi-
dazole showed maximum activity due to a +I effect of CH3
directly attached to nitrogen atom. The exceptionally less
reaction time with high yield of CS (quantitative) was
obtained using 1-methyl imidazole as catalyst.
Overall, among the various catalysts investigated for the
preparation of CS, 1-methyl imidazole proved to be efficient
in terms of reaction time, product yield, and purity. Therefore
this catalyst was selected for further studies.
2. Effect of Catalyst (1-Methyl Imidazole) Concentra-
tion in the Preparation of CS in Water. To find out the
optimum quantity of catalyst required for the synthesis of
CS, experiments were carried out with different quantities
of 1-methyl imidazole (0.0025 M to 0.1 M of catalyst per 1
mol of 2-chlorobenzaldehyde/malononitrile, Figure 1). The
reaction occurred at all concentrations of the catalyst used.
It was observed that the reaction time was inversely
proportional to the amount of catalyst. However, when the
reactions were carried out with higher concentrations of
1-methyl imidazole, the reactions took place rapidly and solid
CS formed in lumps containing aldehyde/malononitrile
trapped in it. This in turn affected the purity and yield of
CS isolated by filtration. The product was slightly coloured
with increasing concentrations of the catalyst. Keeping into
consideration the reaction time and purity/yield of CS, we
chose as the optimum concentration of catalyst 0.01 M for
1 mol of either of the reactants.
3. Effect of Quantity of Water in the Preparation of
CS. The next critical part was determining the minimum
volume of water with which the reaction could be run. To
find the optimum requirement of water required for the
reaction, experiments were carried out with different mole
ratios of water. The product formation occurred rapidly in
all these reactions; when the quantity of water used was less,
product was obtained in lumps containing unreacted alde-
hyde/malononitrile in its cavity. This resulted in the reduction
in both yield and purity of the isolated product. When an
adequate quantity of water was used, the reactants as well
as product were homogeneously dispersed in the reaction
medium, leading to pure fine particles of CS in high yield.
It was observed that, at optimised conditions, the molar ratio
of malononitrile/water required was found to be 1:30. The
excess of water was uneconomical considering the increase
in reaction time and reaction vessel and wastage of water.
required for the formation of 2-chlorobenzylidenemalono-
nitrile is given in Table 1. It was observed that there was a
direct relationship between the electron-donating potential
of nitrogen atom of the base in water and the reaction time.
It is evident that, in the case of methyl pyridines, the
inductive effect of methyl group decreased the reaction time.
In 4-hydroxypyridine, the availability of the lone pair of
electrons of a nitrogen atom is reduced due to resonance;
therefore the reaction time enhanced drastically. The reactiv-
ity of quinoline was similar to that of methyl pyridines, but
indole showed poor activity due to increased delocalization
of the lone pair and its exceedingly low basicity (pKa -2).
In the case of aliphatic bases, the reactivity or the basic
strength of these bases in water is determined not only by
(13) Sykes, P. A guide book to mechanism in organic chemistry; Orient
Longman: New Delhi, 1986; pp 66-74.
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Figure 1. Effect of catalyst amount on reaction time for the preparation of CS in water medium.
4. Optimized Conditions for the Preparation of CS in
Water. From the above experiments, it is concluded that
the molar ratio 1:1:0.01:30 of 2-chlorobenzaldehyde/mal-
ononitrile/1-methylimidazole (catalyst)/water was required
to obtain CS in high yield and high purity.
Table 2. Synthesis of benzylidenemalononitriles in water
medium
5. Upscaling of Preparation of CS in Water. Synthesis
of 2-chlorobenzylidenemalononitrile in water was performed
at a preparative scale of 0.01 mol of CS to a bench scale of
10 mol of CS (1.88 kg) using 1-methyl imidazole as catalyst
under the above optimized reaction conditions for large scale
applications. It was observed that the purity and yield of CS
remained same in all the batches. An preparative scale, the
temperature of the reaction was kept at 35 °C to maintain
homogeneous malononitrile suspension in water (since
melting point of malononitrile is 32-34 °C). The reaction
was exothermic, and it was maintained below 50 °C in the
bench scale experiments by either external cooling of the
reaction vessel with ambient temperature water or controlled
addition of 2-chlorobenzaldehyde. If the temperature was not
maintained below 50 °C, reaction was so rapid that CS was
obtained in lumps instead of fine particles.
6. Recycling of Mother Liquor. The filtrate water from
the above experiments was reused continuously in the
repeated runs by the same procedure for the preparation of
CS. It was found that there was no change either in yield or
in purity of the product. However, it may be mentioned that
recycled water after 10 repeated runs leads to slight colouring
of the product. By conventional methods4 for the production
of CS, volatile organic solvents such as cyclohexane,
methanol, and ethanol were used. Since CS is soluble in these
solvents, they were removed by distillation to isolate CS.
The product thus obtained was recrystallized from organic
solvent; therefore the actual yield of the product was less
than the required yield. Moreover, high inflammability and
high volatility of these solvents pose fire and environmental
hazards. The effluent containing used solvent was either
disposed as such or destroyed by incineration.
reaction
mpa
no.
R1
R2
R3
time/min
(°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
H
OH
H
H
H
OH
H
H
H
H
H
H
H
OCH3
H
OCH3
H
NO2
H
H
H
H
19.6
1.66
0.75
1.75
3.1
50
3.16
2.0
2.0
22
2
3.16
11
2.5
5.5
2.0
1.5
7.0
1.0
83
166
153
187
94
H
OH
H
Cl
Br
F
H
H
OCH3
H
H
H
NO2
H
H
H
Cl
Br
H
H
90
119
163
91
84
104
114
134
138
98
160
150
178
188
OCH3
OH
H
H
H
Cl
H
NO2
Cl
N(CH3)2
COOH
H
H
H
H
a Mp’s are uncorrected and are in agreement with the reported values.
to 10 mmHg while heating was rapidly increased to at least
120 °C. In this reaction, yields depended on mixing of the
reactants, and the overall yield was <80% only after the
water produced in the reaction and base catalyst used were
removed by heating under a vacuum at 120 °C. This lead to
loss of CS by vaporisation; heating of CS to 120 °C lead to
colouration to the product. The process is also not cost-
effective.
The other solvent-free reaction for the production of CS
involved three steps: (i) the mixture of the reactants viz
2-chlorobenzaldehyde, malononitrile, and piperidine as base
catalysts was allowed to react at 35-60 °C; (ii) reaction
mixture was heated at 60-105 °C under a partial vacuum
gave 80% yield; and (iii) the vacuum was decreased further
7. Synthesis of CS Analogues in Water. The feasibility
of extending above reaction for the preparation of various
other benzylidenemalononitriles was attempted at laboratory
scale. Thus the optimum conditions observed for the prepara-
tion of CS were used for the synthesis of various other
benzylidenemalononitriles as shown in (Table 2). The CS
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analogues were synthesised at laboratory scale by the mixing
of an equimolar quantity of corresponding aldehyde and
malononitrile suspension in water at 35 °C using 1-methyl
imidazole as catalyst (1/100 mol of malononitrile). In general,
the reactions were very fast (1-20 min) and gave nearly
quantitative yield of the products. The solid products were
separated simply by filtration and dried under a vacuum. The
yield and purity were >97%. The physical and spectral data
of the synthesized compounds were in agreement with the
reported data.
Preparation of CS and Its Analogues (General Pro-
cedure): To a mixture of malononitrile (2.64 g, 0.04 mol)
and 1-methyl imidazole (0.03 g, 0.0004 mol) in water (21.6
mL) at 35 °C, corresponding aldehyde (0.04 mol) was added
with constant stirring. For example, in the case of 2-chlo-
robenzaldehyde, 5.62 g (0.04 mol) were used. The crystalline
solid was obtained, separated by filtration and dried under a
vacuum (∼25 mm) at room temperature. The yields were
97-99%, and purity (by GC) was >99%.
Scalable Process for 2-Chlorobezylidenemalononitile
(CS): In a 10 L three neck-round-bottom flask equipped with
thermometer, pressure equalising funnel, and magnetic stirrer,
water (5400 mL) was taken. To this malononitrile (660.6 g,
10 mol) and then 1-methyl imidazole (10 mL, 0.1 mol) were
added with constant stirring at 35 °C. To this 2-chloroben-
zaldehyde (1405 g, 10 mol) was added slowly in 30 min
with continuous stirring through the pressure equalising
funnel. The reaction was exothermic, and the temperature
of the reaction mixture was maintained below 50 °C during
addition of 2-chlorobenzaldehyde by cooling of the reaction
flask with water. (Alternatively, when the same quantity of
2-chlorobenzaldehyde was added in 90 min, the temperature
was below 50 °C without any requirement of cooling of the
reaction flask.) After the complete addition, the reaction
mixture was stirred for 15 min. The white crystalline solid
CS thus obtained was filtered and then dried under vacuum
(25 mm Hg) at room temperature.
Conclusions
In summary, a simple, efficient, economical, and eco-
friendly process for the synthesis and upscaling of 2-chlo-
robenzylidenemalononitrile in water medium using 1-methyl
imidazole as catalyst was developed. The main advantages
of the present developed method are as follows: (i) no
organic solvent is required; (ii) the condensation reaction is
carried out very efficiently at 35 °C, at which homogeneous
dispersion of malononitrile in water medium occurred; (iii)
CS is insoluble in water, and thus the product is isolated by
simple filtration and yields are also high (99%); (iv) water
used in the reaction media is recycled which enhances the
green perspective; and (v) since all the operations of the
reaction such as addition of reactant, separation, and drying
are carried out in ambient temperature, overall, this is an
energy-saving process.
Mother liquor obtained after filtration of white solid was
reused for further runs (10 times) for the preparation of CS
by the same procedure. The yield and purity of the product
in all the runs remained same.
Experimental Section
General. 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 in
ordinary water without distilling it. The melting points are
uncorrected. Infrared spectra were recorded as KBr pellet
using a Perkin-Elmer FT-IR spectrophotometer. Nuclear
magnetic resonance (1H NMR) spectra were recorded on a
Bruker Avance 400 NMR, with tetramethylsilane (TMS)
used as an internal standard. Chemical shifts (δ) were
recorded in parts per million (ppm) from the internal standard
(TMS ) 0.00).
Gas chromatography-mass spectrometry (GC-MS) was
performed using a Hewlett-Packard 6890 gas chromatograph
equipped with a split/splitless injector and a capillary column
(30 m × 0.32 mm i.d., 0.25 µm film thickness, BP-5
stationary phase, SGE) directly coupled to a Hewlett-Packard
5973 quadrupole mass spectral detector and integral data
system. Ionization was done by electron impact at 70 eV
and 230 °C. The carrier gas was helium.
Yield 99%; Purity 99%. mp 93-94 °C.
IR (KBr): 3051 (CsH aromatic), 2230 (CtN), 1585,
1443, 1378 (CdC).
H1 NMR (CDCl3): δ 7.2-7.9 (m, 3H, φ), 8.2 (d, 1H, φ),
8.3 (s, 1H dCHs).
MS (m/z): 153 (M+ - Cl, 100), 188 (M+), 126, 75, 99,
63, 51, 137.
Acknowledgment
We sincerely thank Mr. K. Sekhar, Director, Defence
Research and Development Establishment, Gwalior for his
keen interest and encouragement in this work.
Received for review September 21, 2004.
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