A simple, efficient, and green protocol for Knoevenagel condensation in a cost-effective ionic liquid 2-hydroxyethlammonium formate without a catalyst

Article abstract of DOI:10.1007/s11164-011-0300-4

Knoevenagel condensation of aromatic aldehydes with active methylene compounds such as malononitrile, ethylcyanoacetate, and cyanoacetamide proceeded very smoothly in reusable and cheap ionic liquid 2-hydroxyethylammonium formate at room temperature in the absence of a catalyst. Compared to other reported ionic liquids, the ionic liquid 2-hydroxyethylammonium formate shows better potential in the applications on the industrial scale with its low cost and viscosity.

Full text of DOI:10.1007/s11164-011-0300-4

Res Chem Intermed (2011) 37:579–585
DOI 10.1007/s11164-011-0300-4
A simple, efficient, and green protocol for Knoevenagel
condensation in a cost-effective ionic liquid
2-hydroxyethlammonium formate without a catalyst
•
Anguo Ying Huading Liang Renhua Zheng
•
•
•
Changhua Ge Huajiang Jiang Chenglin Wu
•
Received: 17 November 2010 / Accepted: 13 December 2010 / Published online: 22 March 2011
Ó Springer Science+Business Media B.V. 2011
Abstract Knoevenagel condensation of aromatic aldehydes with active methylene
compounds such as malononitrile, ethylcyanoacetate, and cyanoacetamide pro-
ceeded very smoothly in reusable and cheap ionic liquid 2-hydroxyethylammonium
formate at room temperature in the absence of a catalyst. Compared to other
reported ionic liquids, the ionic liquid 2-hydroxyethylammonium formate shows
better potential in the applications on the industrial scale with its low cost and
viscosity.
Keywords Knoevenagel condensation Á Ionic liquid Á Recyclability Á
Cost-effectiveness
Introduction
Knoevenagel condensation plays an important role in the formation of C=C bond
reactions in of organic synthesis [1]. It has been used for the preparation of natural
products [2], cosmetics, perfumes, several therapeutic drugs [3], and fine chemicals
[4]. In general, Knoevenagel condensation is performed in organic solvents in the
presence of the bases or acids, mainly including DMAP [5], N-methylpiperazine [6],
potassium fluoride mixture [7], guanidines [8], ZnCl2 [9], and LaCl3 [10]. Recently,
some novel heterogeneous catalysts, basic Si-MCM-41 [11], nitrogen-doped carbon
materials [12], Ni-SiO2-supported catalysts [13], and modified SBA-1 materials [14]
have been exploited as catalysts for the Knoevenagel reaction. However, many of
the above procedures have some or one of the drawbacks such as a long reaction
time, harsh reaction conditions, stoichiometric amount of catalysts, or a large
amount of organic solvent as the reaction medium.
A. Ying (&) Á H. Liang Á R. Zheng Á C. Ge Á H. Jiang Á C. Wu
School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 317000, China
e-mail: agying@tzc.edu.cn; yinganguo@163.com
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A. Ying et al.
On the other hand, ionic liquids (ILs), possessing advantages such as
undetectable vapor pressure and excellent reusability, have been investigated
extensively in organic transformations as solvents or catalysts [15–17]. Thus,
various ILs have been used as reaction solvents as well as catalysts for Knoevenagel
condensation [18–21]. While considering the applications of ILs in industrial
processes, one major concern is cost. Almost all reported ILs used in the
Knoevenagel reaction are imidazolium ILs, which are relatively expensive. Thus,
the need to explore simple and cost-effective ILs for Knoevenagel condensation still
exists.
Ionic liquid 2-hydroxyethylammonium formate was simply prepared by
neutralization reaction of 2-hydroxyethylamine and formic acid (Scheme 1) [22].
Compared to traditional imidazolium ILs, 2-hydroxyethylammonium formate has
much lower cost, melting points, and viscosity [22]. Considering these advantages
of the IL 2-hydroxyethylammonium formate, Degani and Sharma [23] utilized
2-hydroxyethylammonium formate as a reaction solvent as well as the catalyst in
hetero-Michael addition, and satisfactory results were observed. With our contin-
uous research in organic transformations using ILs as both catalyst and green
solvent [24–27], herein we first reported a simple and environmentally benign
methodology for the Knoevenagel condensation of aromatic aldehydes with active
methylene compounds using 2-hydroxyethylammonium formate as reaction solvent
without any catalyst.
Results and discussion
The reaction of benzaldehyde with ethyl cyanoacetate without any catalyst was
selected as the model to establish the rational reaction conditions. As shown in
Table 1, the reaction in organic solvents, acetonitrile, methanol, and toluene
proceeded very slowly (entries 1–3). We then investigated the efficiency of IL
2-hydroxyethylammonium formate compared to the most commonly used ILs,
[Bmim]BF4 and [Bmim]PF6 by the model condensation (entries 4–6). The results
showed that the reaction in the absence of catalyst with the two imidazolium ILs
as reaction solvents proceeded very slowly and the reaction could react smoothly
in the presence of the novel IL 2-hydroxyethylammonium formate. The results
summarized in Table 1 show that the IL 2-hydroxyethylammonium formate plays a
dual role as both a catalyst and a solvent in the reaction. The volume of the IL was
also tested with the same reaction as model (Table 1, entries 7–9). The suitable
solvent amount is 2 mL. As a result, we adopted the optimal reaction conditions
+
HO
-
rt, 24h
COO
HO
NH3
+
HCOOH
NH2
2-Hydroxyethylammoniumformate
Scheme 1 Preparation of ionic liquid 2-hydroxyethylammonium formate
123

A simple, efficient, and green protocol for Knoevenagel condensation
581
(aldehydes:1 mmol, active methylene compounds: 1 mmol, 2 mL 2-hydroxyethy-
lammonium formate, rt) for further examinations.
With the optimal reaction system in hand, we then investigated the Knoevenagel
condensation of various aromatic aldehydes with malononitrile, ethyl cyanoacetate,
and cyanoacetamide. It can be observed from Table 2 that three active methylene
ingredients could successfully react with various aromatic aldehydes and all
products (3a–3o) obtained were E-geometry exclusively and no subsequent Michael
adduct was detected. The effects of substituents at the aromatic ring on the
Knoevenagel reaction were also studied, and the reaction time of electron-
withdrawing group (such as nitro group) substituted aromatic aldehydes was shorter
than that of electron-donating group (such as methoxyl, methyl, or 4-(N,N)-dimethyl
group) substituted aromatic aldehydes (Table 2, entries 2–5, 14, 15). The hindrance
of substituents such as chloro could retard the reaction and decreased the product
yields (Table 2, entries 11–13). In addition, Knoevenagel condensation of hetero
aromatic aldehydes such as 2-furaldehyde and 3-pyridinecarboxaldehyde with
active methylene compounds also underwent smoothly at room temperature
(Table 2, entries 7, 8).
Finally, in order to demonstrate the industrial applicability of this methodology,
the Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate was carried
out on a larger scale (Table 3). The reaction was completed in 3 h. An excellent
yield of 92% for the condensational product was achieved. On the same scale, the
recyclability of the catalytic system was investigated using the same reaction as
model reaction. Upon the completion of the reaction, the product was isolated via
filtration, washed with water, and then dried under vacuum without further
separation, while the filtrate IL 2-hydroxyethylammonium formate was dried to
Table 1 Effects of various reaction solvents and their quantities on the Knoevenagel condensation of
benzaldehyde and ethyl cyanoacetate at room temperature
CN
CN
rt
H2O
+
Ph
+
PhCHO
C
H
Solvent
CO2Et
CO2Et
Entry
Solvents (mL)
Yieldsa (%)
1
2
3
4
6
7
8
9
Acetonitrile (2)
Methanol (2)
Toluene (2)
33
29
22
9
[Bmim]BF4 (2)
[Bmim]PF6 (2)
16
90
91
58
2-hydroxyethylammonium formate (2)
2-hydroxyethylammonium formate (5)
2-hydroxyethylammonium formate (1)
Reaction conditions: benzaldehyde (1.0 mmol), ethyl cyanoacetate (1.0 mmol), reaction time (3 h), rt
a
Isolated yields of products
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A. Ying et al.
Table 2 Results of Knoevenagel condensation between various aromatic aldehydes and methylene
active compounds at room temperature in ionic liquid 2-hydroxyethylammonium formate
HO
R
E1
E2
E1
R
COO
NH3
H O
+
2
C
H
+
CHO
rt
E2
3
1
2
Entry
R
E1
E2
Time (h)
Product
Yieldsa (%)
1
2
3
4
5
6
7
H
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
5
6
5
7
2
8
4
3a
3b
3c
3d
3e
3f
88
94
94
90
88
96
93
4-Me
4-MeO
2-MeO
4-NO2
4-(N,N)-dimethyl
3g
CHO
O
N
8
CN
CN
4
3h
92
CHO
9
4-Me
CN
CN
CN
CN
CN
CN
CN
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CONH2
CONH2
8
4
6
8
6
5
8
3i
98
92
82
75
95
90
91
10
11
12
13
14
15
4-NO2
3j
3,4-Dichloro
2,4-Dichloro
4-Chloro
4-NO2
3k
3l
3m
3n
3o
4-MeO
Reaction conditions: aromatic aldehydes (1 mmol), active methylene compounds (1 mmol) stirred in
ionic liquid (2 mL) 2-hydroxyethylammonium formate without a catalyst at room temperature
a
Isolated yields of desired products
remove water at 60 °C under vacuum. The recovered IL was reused in subsequent
reactions. As shown in Table 3, the IL 2-hydroxyethylammonium formate can be
recycled five times without a considerable decrease of activity.
Table 3 Reuse of catalyst for Knoevenagel condensation between benzaldehyde (100 mmol) and ethyl
cyanoacetate (100 mmol) in 200 mL ionic liquid 2-hydroxyethylammonium formate in the absence of a
catalyst at room temperature within 3 h
Cycles
1
2
3
4
5
Producta (%)
92
89
92
89
86
a
Isolated yields
123

A simple, efficient, and green protocol for Knoevenagel condensation
583
Conclusions
The use of IL 2-hydroxyethylammonium formate as a solvent without a catalyst
allows Knoevenagel condensation of aromatic aldehydes with active methylene
compounds to be performed both simply and highly efficiently. Compared to the
reported methods, the present protocol has many obvious advantages, including low
cost of IL, no need for the use of a catalyst, ease of work-up, high product yields, as
well as good recyclability of IL 2-hydroxyethylammonium formate.
Experimental section
1
All chemicals used were purchased from Aldrich or Fluka. H and 13C NMR were
recorded on a Bruker Avance DPX 400 spectrometer at 400 MHz and 100 MHz in
CDCl3 and D2O, respectively. Chemical shifts were reported in parts per million (d),
relative to the internal standard of tetramethylsilane (TMS). Melting points were
determined using a YRT-3 apparatus and were not corrected. Elemental analysis
was carried out on a Carlo Erba 1160. All reactions were monitored by thin-layer
chromatography (TLC). All condensation products were characterized by NMR
analysis and measurement of melting points.
A typical experimental procedure for Knoevenagel condensation
Benzaldehyde (1 mmol) and ethyl cyanoacetate (1 mmol) were mixed together in
the presence of 2 mL IL 2-hydroxyethylammonium formate, and then stirred at
room temperature. Upon the completion of the reaction (monitored by TLC), the
mixture was filtrated and the solid dried in vacuo at 60 °C for 10 h, was the
condensational product with high purity, which did not need further purification.
The filtrate (including IL and water) was dried to remove water at 60 °C under
vacuum, and the recovered IL was reused for subsequent reactions. The product was
1
analyzed by melting point, H NMR and 13C NMR.
Data for representative products
2-(Phenylmethylene)-malononitrile (product 3a)
1
White solid; mp 79–80 °C (Ref. [28]: 80–81 °C); H NMR (400 MHz, CDCl3)
(ppm): 7.91 (d, 2H, J = 7.6 Hz, ArH), 7.79 (s, 1H, C=CH), 7.64 (t, 1H, J = 7.6 Hz,
ArH), 7.27 (t, 2H, J = 7.6 Hz, ArH), 7.27 (t, 2H, J = 7.6 Hz, ArH); 13C NMR
(100 MHz, CDCl3) (ppm): 160.0, 134.6, 130.9, 130.7, 129.6, 113.7, 112.5, 82.7.
2-(4-Methyoxyphenylmethylene)malononitrile (product 3c)
Yellow solid; mp 110–112 °C (Ref. [28]: 110–111 °C); 1H NMR (400 MHz,
CDCl3) (ppm): 7.91 (d, 2H, J = 8.8 Hz, ArH), 7.66 (s, 1H, C=CH), 7.01 (d, 2H,
123

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A. Ying et al.
J = 8.8 Hz, ArH), 3.92 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) (ppm): 164.8,
158.9, 133.4, 123.9, 115.1, 114.4, 113.3, 78.4, 55.8.
2-(2-Furylmethylene)malononitrile (product 3g)
Pale yellow solid; mp 68–69 °C Ref. [28]: 68–69 °C); 1H NMR (400 MHz, CDCl3)
(ppm): 7.81 (d, 1H, J = 1.6 Hz, furyl), 7.52 (s, 1H, C=CH), 7.37 (d, 1H,
J = 3.6 Hz, furyl), 6.73–6.71 (m, 1H, furyl); 13C NMR (100 MHz, CDCl3) (ppm):
149.6, 147.9, 143.0, 123.6, 114.4, 113.8, 112.6.
2-(3-Pyridylmethylene)malononitrile (product 3h)
1
White solid; mp 80–83 °C (Ref. [29]: 78–80 °C); H NMR (400 MHz, CDCl3)
(ppm): 8.89 (d, 1H, J = 2 Hz, pyridyl), 8.83 (d, 1H, J = 3.6 Hz, pyridyl), 8.49-8.47
(m 1H, pyridyl), 7.55–7.52 (m, 1H, pyridyl); 13C NMR (100 MHz, CDCl3) (ppm):
158.5, 154.6, 152.3, 135.6, 126.9, 124.2, 112.9, 111.9, 85.5.
Ethyl (E)-2-cyano-3-(4-nitrophenyl)-2-propenoate (product 3j)
1
Pale yellow solid; mp 168–171 °C (Ref. [28]: 169–170 °C); H NMR (400 MHz,
CDCl3) (ppm): 8.35 (d, 2H, J = 8.4 Hz, ArH), 8.31 (s,1H, C=CH), 8.14 (d, 2H,
J = 8.4 Hz, ArH), 4.43 (q, 2H, J = 7.2 Hz, CH2), 1.42 (t, 3H, J = 7.2 Hz, CH3);
13C NMR (100 MHz, CDCl3) (ppm): 161.4, 151.7, 149.6, 136.9, 131.1, 124.3,
114.5, 107.3, 63.3, 14.1.
Ethyl (E)-2-cyano-3-(4-chlorophenyl)-2-propenoate (product 3m)
1
White solid; mp 89–90 °C (Ref. [28]: 91–92 °C); H NMR (400 MHz, CDCl3)
(ppm): 8.20 (s, 1H, C = CH), 7.94 (d, 2H, J = 8.8 Hz, ArH), 7.48 (d, 2H,
J = 8.8 Hz, ArH), 4.39 (q, 2H, J = 7.2 Hz, CH2), 1.40 (t, 3H, J = 7.2 Hz, CH3);
13C NMR (100 MHz, CDCl3) (ppm): 162.2, 153.4, 139.5, 132.2, 129.8, 129.6,
115.2, 103.4, 62.8, 14.1.
Ethyl (E)-2-cyano-3-(4-methoxyphenyl)-2-acrylamide (product 3o)
White solid; mp 213–214 °C (Ref. [28]: 214–215 °C); 1H NMR (400 MHz, CDCl3)
(ppm): 8.10 (s, 1H, C=CH), 7.96 (d, 2H, J = 8.4 Hz, ArH), 7.56 (br, s, 2H, NH2),
7.16 (d, 2H, J = 8.4 Hz, ArH), 4.02(S, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
(ppm): 162.3, 151.4, 137.5, 136.8, 131.2, 129.5, 127.6, 115.2, 103.4, 61.8.
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