Choline chloride and urea based eutectic solvents: Effective catalytic systems for the Knoevenagel condensation reactions of substituted acetonitriles

Article abstract of DOI:10.3184/174751914X13926483381319

The Knoevenagel condensation of aromatic aldehydes with active methylene compounds such as malononitrile, ethyl cyanoacetate, benzimidazole-2- acetonitrile and benzothiazole-2-acetonitrile proceeded very smoothly, in a reusable and cheap choline chloride and urea based deep eutectic solvents. Both reaction time and yield are satisfactory. The advantages of this catalyst are that it is readily available, biodegradable, non-toxic, low cost and is recyclable.

Full text of DOI:10.3184/174751914X13926483381319

186 RESEARCH PAPER
VOL. 38 MARCH, 186–188
JOURNAL OF CHEMICAL RESEARCH 2014
Choline chloride and urea based eutectic solvents: effective catalytic
systems for the Knoevenagel condensation reactions of substituted
acetonitriles
Shuo Liub, Yuxiang Nib, Wenjing Weia, Fangli Qiua, Songlin Xub* and Anguo Yinga
aSchool of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, P.R. China
bSchool of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
The Knoevenagel condensation of aromatic aldehydes with active methylene compounds such as malononitrile, ethyl
cyanoacetate, benzimidazole-2-acetonitrile and benzothiazole-2-acetonitrile proceeded very smoothly, in a reusable and cheap
choline chloride and urea based deep eutectic solvents. Both reaction time and yield are satisfactory. The advantages of this
catalyst are that it is readily available, biodegradable, non-toxic, low cost and is recyclable.
Keywords: Knoevenagel condensation, deep eutectic solvents, choline chloride, urea
The Knoevenagel condensation reaction is an important
reaction for the formation of carbon–carbon bonds.1–3 It has
been used for the synthesis of important intermediates or
products for cosmetics, perfumes, pharmaceuticals, calcium
antagonists and polymers.4–8 Traditionally, the Knoevenagel
condensation is performed in organic solvents in the presence
of bases or acids.9–12 Recently, heterogeneous catalysts have
been used such as nitrogen-doped carbon materials,13 Ni–SiO2-
supported catalysts14 and modified polyacrylamide containing
amino functional groups.15 However, many of these procedures
have drawbacks such as long reaction time, harsh reaction
conditions, the use of hazardous organic solvent or catalysts,
and, in some reactions, the catalysts are not efficient and cannot
be reused.
With the introduction of the concept of green chemistry in
the early 1990s, various ionic liquids have been used as solvents
and catalysts for the Knoevenagel condensation16–22 due to
their unique chemical and physical properties of nonvolatility,
nonflammability, thermal stability, and controlled miscibility.23
Our group have used 2-hydroxyethylammonium formate24 and
several DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) based ionic
liquids to catalyse the Knoevenagel condensation reaction with
great success.25–27 However, many ionic liquids have drawbacks
such as high price, toxicity, and poor biodegradability.28,29
Deep eutectic solvents (DESs) emerged at the beginning of
this century to overcome the high cost and toxicity of ionic
liquids, DESs are generally composed of two or three cheap and
safe components which are capable of associating with each
other through hydrogen bond interaction, to form a eutectic
mixture.30–32 They have the advantage of low melting point
and are not hazardous. We report a Knoevenagel condensation
reaction of substituted acetonitriles and aromatic aldehydes
using a DES prepared from choline chloride (ChCl) and urea.
two components’ molecular weight. Thus the molecular weight
of the DES (ChCl:urea=1:2) is 259.74. Through changing the
amount of DES, it was found that 20% (molar) DES was the
most effective (entry 3, Table 1). Attempts to combine DES
with methanol as the solvent, led to no significant change of
yield (entry 4, Table 1). Thus 20% DES is the most effective
condition.
With the optimum catalytic system in hand, we investigated
the Knoevenagel reaction of various aromatic aldehydes with
malononitrile and ethyl cyanoacetate (Table 2). It can be seen
that the two active methylene compounds reacted with various
aromatic aldehydes. The effects of substituents on the aromatic
ring in the Knoevenagel reaction were studied. Aromatic
aldehydes substituted with electron-withdrawing groups
reacted smoothly with active methylene compounds to give the
corresponding products in high yields (entries 3–8, Table 2).
Aromatic aldehydes substituted with electron-donating groups
also underwent a Knoevenagel condensation with malononitrile
smoothly and gave good yield (entries 11 and 13, Table 2).
However, ethyl cyanacetate gave only low yields (entries 10,
12 and 14, Table 2). The Knoevenagel condensation of hetero-
aromatic aldehydes such as 2-thiophenecarboxaldehyde with
active methylene compounds also proceeded satisfactorily at
Table 1 Optimisation of catalyst/organic solvent in Knoevenagel
condensation reactiona
CN
CHO
CN
CN
r. .
t
+
H2O
+
CN
Sample no.
1
Solvent
Methanol
Toluene
DES
–
–
Yield/%b
–
–
Results and discussion
DMF
–
–
ChCl:Urea=1:1c
ChCl:Urea=1:2c
ChCl:Urea=1:3c
10% DESd
54
86
72
84
86
92
91
88
The reaction of benzaldehyde with malononitrile was used as
the model to optimise the reaction conditions (Table 1). The
reaction did not proceed at all in absence of DES (entry 1,
Table 1). However, reaction was observed soon after addition
of DES. We used different DES prepared from different molar
ratios of ChCl and urea to catalyse the reaction without any
solvent (entry 2, Table 1). It was found that the best molar ratio
was 1:2.
–
–
–
–
–
–
–
2
15% DESd
3
4
20% DESd
25% DESd
20% DES
Methanol
Then we studied the effect of the amount of the DES. We
defined the molecular weight of the DES as the addition of the
aReaction conditions: benzaldehyde (1.0 equiv.) and malononitrile
(1.0 equiv.), 20% DES, room temperature, reaction time = 20 min.
bIsolated yields.
cMolar ratio.
* Correspondent. E-mail: slxu@tju.edu.cn
dChCl: Urea =1:2 (molar ratio).
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JOURNAL OF CHEMICAL RESEARCH 2014 187
Table 2 Knoevenagel condensation reaction of active methylene
Table 4 Knoevenagel condensation reaction of other active methylene
compounds with functionalised aromatic aldehydes in DESa
compounds with functionalised aromatic aldehydes in DESa
E2
+
E1
CHO
20%DES
r. t.
CN
CHO
X
Y
+
R
20%DES
r. t.
H2O
X
Y
R
R
E1
+
N
C
E2
R
Reaction
time
Entry
R
E1
E2
Yield/%
Reaction
time
/min
Entry
R
X
Y
Yield/%
/min
1
2
3
4
5
6
7
8
9
10b
11
12
13
14c
15
16
H
H
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
20
60
20
30
20
120
20
90
120
120
30
120
10
92
89
97
96
95
85
94
90
20
0
92
30
96
Trace
88
79
60
90
20
30
120
10
60
180
120
1
2
3
4
5
6
7
8
9
H
N
N
N
N
N
N
N
N
H
S
S
S
NH
NH
NH
NH
NH
NH
94
92
91
93
90
92
82
84
trace
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
4-OMe
2-Cl
3-NO2
3-NO2
2-Cl
2-Cl
4-Cl
4-Cl
4-Me
4-Me
2-OMe
2-OMe
3-OMe
3-OMe
2-thienyl
2-thienyl
H
2-Cl
4-OMe
4-N(Me)2
2-thienyl
H
aReaction conditions: aldehyde (1.0 mmol) and active methylene compound
(1.0 mmol), 0.5 mL DES, room temperature.
120
15
150
In order to demonstrate the industrial potential of this
methodology, the reaction of ethyl cyanoacetate and
benzaldehyde was scaled-up. The reaction was completed in
1 h. A good yield of 89% was achieved. On the same scale, the
recyclability of the catalytic system was investigated using the
same reaction as the model reaction. The DES was recovered
by removing the aqueous layer using a rotary evaporator. The
recovered DES was reused in subsequent reactions. As shown
in Fig. 1, no significant decrease in yields was observed even
after four runs.
aReaction conditions: aldehyde (1.0 mmol) and active methylene compound
(1.0 mmol), 20% DES, room temperature. If the aldehyde was solid, then
0.5 mL DES was added.
bProlonged reaction time (12 h), no product appeared.
cProlonged reaction time (12 h), only trace product appeared.
room temperature (entries 15 and 16, Table 2).
Encouraged by these results, we studied the reaction of
aromatic aldehydes with other active methylene compounds,
such as benzimidazole-2-acetonitrile, benzothiazole-2-
acetonitrile, phenylacetonitrile, 3-chlorophenylacetonitrile
and indole-2-acetonitrile. The reaction proceeded smoothly
to afford the corresponding products in moderate to good
yield except for the reaction of indole-2-acetonitrile with
benzaldehyde (entry 9, Table 4). From these results we consider
that the acidity of the proton of the methylene group was
the key factor influencing the reaction rate (entries 1 and 2,
Table 2; entry 3, Table 3; entries 1, 4 and 9, Table 4). Especially,
noteworthy was malononitrile, for which the acidity of the
proton of the methylene was greater than the other compounds
leading to comparatively rapid reaction rates (entries 1, 3, 5, 7,
11, 13 and 15, Table 2).
Conclusions
The use of DES (choline chloride/urea) as a solvent without
any additional catalyst permits an efficient Knoevenagel
condensation of aromatic aldehydes with active methylene
compounds. Compared to the reported methods, this method
offers marked improvements in terms of simplicity, decreased
reaction time, chemoselectivity, general applicability, low
cost and no need for a hazardous organic solvents and toxic
catalysts. Thus it provides a better and practical alternative to
existing procedures.
Table 3 Knoevenagel condensation reaction of phenylacetonitriles with
functionalised aromatic aldehydes in DESa
R1
CHO
20%DES
r. t.
CN
+
R1
R
R
NC
Reaction
time
Entry
R
R1
Yield/%
/min
1
2
3
4
4-OMe
4-OH
H
H
H
3-Cl
3-Cl
60
60
45
45
83
85
90
92
4-OMe
Fig. 1 Reuse of catalyst for Knoevenagel condensation between
benzaldehyde (100 mmol) and ethyl cyanoacetate (100 mmol) in 20 mmol
DES at room temperature for 2 h.
aReaction conditions: aldehyde (1.0 mmol) and active methylene compound
(1.0 mmol), 0.5 mL DES, room temperature.
JCR1302250_FINAL.indd 187
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188 JOURNAL OF CHEMICAL RESEARCH 2014
We are grateful for the financial support of this research by
the National Natural Science Foundation of China (Grant No.
21106090)andPostdoctoralFoundationofChina(2012M511352)
and Foundation of Low Carbon Fatty Amine Engineering
Research Center of Zhejiang Province (2012E10033).
Experimental
All chemicals were used as supplied without further purification
unless otherwise specified. Melting points were taken on a Gallen-
kamp melting point apparatus and were uncorrected. 1H and 13C NMR
spectra were recorded on a Bruker AM-400 MHz spectrometer.
HRMS values were measured by a JEOL JMS-SX or JEOL JMS-SX
102A spectrometer. Flash column chromatography was performed on
silica gel (200–300 mesh) (Qingdao Haiyang Chemical Co. Ltd, China)
and TLC measurements were performed on silica gel GF254 plates
(Qingdao Haiyang Chemical Co. Ltd, P.R. China).
Received 25 October 2013; accepted 27 January 2014
Paper 1302250 doi: 10.3184/174751914X13926483381319
Published online: 7 March 2014
Synthesis of DES; general procedure
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Knoevenagel condensation reactions without any purification.
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