2-pyrrolidinecarboxylic acid ionic liquid catalyzed knoevenagel condensation

Article abstract of DOI:10.1016/S1872-2067(11)60364-1

The pyrrolidinecarboxylic functionalized ionic liquid, 1-butyl-3- methylimidazolium-(S)-2-pyrrolidinecarboxylic acid salt ([bmim][Pro]), was prepared using an improved procedure. α,β-Unsaturated carbonyl compounds were selectively synthesized and high yie

Full text of DOI:10.1016/S1872-2067(11)60364-1

CHINESE JOURNAL OF CATALYSIS
Volume 33, Issue 4, 2012
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2012, 33: 666–669.
ARTICLE
2
-Pyrrolidinecarboxylic Acid Ionic Liquid Catalyzed
Knoevenagel Condensation
SONG Hongbing, YU Yinghao, CHEN Xuewei, LI Xuehui*, XI Hongxia
School of Chemistry and Chemical Engineering, Pulp and Paper Engineering State Key Laboratory of China, South China University
of Technology, Guangzhou 510640, Guangdong, China
Abstract: The pyrrolidinecarboxylic functionalized ionic liquid, 1-butyl-3-methylimidazolium-(S)-2-pyrrolidinecarboxylic acid salt
([bmim][Pro]), was prepared using an improved procedure. ꢀ,ꢁ-Unsaturated carbonyl compounds were selectively synthesized and high
yields (88%–97%) were obtained at room temperature in aqueous media when [bmim][Pro] was used as the catalyst for the Knoevenagel
reaction between a methylene compound and an aldehyde or ketone. [bmim][Pro] was reused six times without loss of catalytic activity.
The catalytic mechanism is briefly discussed.
Key words: proline; ionic liquid; catalysis; Knoevenagel condensation
The Knoevenagel condensation reaction is one of the most
important reactions in organic synthesis for carbon-carbon
bond formation [1]. In recent years, there has been growing
interest in it for the synthesis of important intermediates or
products for perfumes, pharmaceuticals, calcium antagonists,
and polymers [2–4]. This reaction is catalyzed by bases [5,6],
acids [7], and catalysts containing acidic or basic sites [8].
Basic microporous titanosilicate ETS-10 [9], modified poly-
acrylamide containing amino functional groups [10], and rare
earth exchanged NaY zeolite [11] have been employed in
solution and under solvent-free conditions with variable yields.
However, the use of hazardous and carcinogenic solvents and
difficulty in catalyst recovery are incompatible with green
chemistry. Therefore, an environmental benign process for this
reaction is desired.
reaction [17], Diels-Alder reaction [18], and Aldol reaction
[19]. Proline is a common amino acid without a hydrogen on
the amide group. It cannot act as a hydrogen bond donor, but is
a hydrogen bond acceptor. Therefore, proline and its deriva-
tives are often used as asymmetric catalysts in organic reac-
tions. For example, chiral pyrrolidines derived from L-proline
and its derivates were successfully used as highly enantiose-
lective organocatalysts [20–22]. In this work, a new route for
the synthesis of 1-butyl-3-methylimidazolium-(S)-2-pyr-
rolidinecarboxylic acid ionic liquid ([bmim][Pro]) was devel-
oped and its catalytic properties for the Knoevenagel conden-
sation reaction of a methylene compound with aldehyde in
water were investigated. It gave high yields (88%–97%) and
selectivity (100%), and was recyclable.
Ionic liquids (ILs), especially for those derived from natural
products [12], are catalysts and potential alternatives to vola-
tile and hazardous organic solvents for a variety of important
reactions [13,14]. Amino acids are good candidates for the
development of novel functional ILs due to the varied struc-
tures and functionalities of their groups [15,16]. Chiral ILs
derived from natural amino acids or amino acid esters have
been used as catalysts in the asymmetric Michael addition
1 Experimental
1.1 Reagents
N-methylimidazole and n-butyl chloride (purity ˚99%)
were purchased from Acros Organics. L-proline and other
reagents (AR grade) were purchased from Guangdong
Guanghua Chemical Factory Co., Ltd. All reagents were used
Received 29 October 2011. Accepted 20 December 2011.
*
Corresponding author. Tel/Fax: +86-20-87114707; E-mail: cexhli@scut.edu.cn
This work was supported by the National Natural Science Foundation of China (20876055 and 20906029), the Natural Science Foundation of Guangdong Province
S2011020001472), and the Fundamental Research Funds for the Central Universities.
(
Copyright © 2012, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(11)60364-1

SONG Hongbing et al. / Chinese Journal of Catalysis, 2012, 33: 666–669
O
O
O
NaOH/CH OH
[Bmim]Cl
3
N
N
O
ONa
O
CH OH
NH2
NH
3
HN
Scheme 1. Synthesis of [bmim][Pro] ionic liquid.
as received without further purification.
.2 Preparation and characterization of [bmim][Pro]
then neutralized by the natural amino acid L-proline. However,
the preparation of onium hydroxide is time consuming and it is
difficult to purify onium hydroxide because of the strong hy-
drogen bonds between water and onium hydroxide, which is
1
[
bmim]Cl was synthesized by a reported procedure [23].
also sensitive to the CO in air [25]. Thus, we developed here a
2
[
bmim][Pro] was prepared in two steps (Scheme 1). First, the
simple and efficient method for the preparation of the required
task-specific ionic liquid from L-proline. In our procedure, the
neutralization of L-proline with sodium hydroxide takes place
quickly and the subsequent anion exchange avoids the use of
neutralization reaction between L-proline (50 mmol, 5.76 g)
and sodium hydroxide (50 mmol, 2.00 g) was carried out in 10
ml methanol under mild stirring at 25 C for 4 h, after which the
o
water and methanol were evaporated to get the L-proline so-
dium salt (Na[Pro]). Second, anion exchange between
the unstable CO -sensitive hydroxide intermediate. The ad-
vantages of this approach include high yield, good controlla-
bility, short reaction time, and simple operation.
2
[
bmim]Cl (50 mmol, 8.74 g) and Na[Pro] (50 mmol, 6.85 g)
o
was carried out in methanol at 25 C for 4 h, after which the
precipitate (NaCl) was removed by filtration and the resulting
solution was evaporated to give the colorless and transparent
oily liquid [bmim][Pro] (11.53 g, 91%).
2.2 Knoevenagel condensation catalyzed by [bmim][Pro]
The [bmim][Pro] ionic liquid was then tested as the catalyst
for the Knoevenagel condensation reaction of aromatic alde-
hydes with malononitrile or ethyl cyanoacetate under different
reaction conditions (Scheme 2). Excellent product yields were
obtained in a short time using water at room temperature as the
medium. The results are summarized in Table 1.
The structure of the [bmim][Pro] ionic liquid was charac-
1
13
1
terized by IR, H NMR and C NMR as follows. H NMR
400 MHz, DMSO) ꢀ 0.85 (t, J = 7.2 Hz, 3H), 1.21 (q, 2H),
.37 (m, 1H), 1.45 (m, 1H), 1.57 (m, 1H), 1.72 (m, 3H), 2.87
m, 1H), 3.01 (s, 1H), 3.12 (s, 1H), 3.60 (s, 1H), 3.83 (s, 3H),
(
1
(
4
.14 (t, J = 7.2 Hz, 2H), 7.71 (s, 1H), 7.79 (s, 1H), 9.54 (s, 1H).
C NMR (400 MHz, DMSO) ꢀ 13.7, 19.2, 26.5, 31.6, 31.9,
6.1, 47.5, 48.9, 63.1, 122.7, 124.0, 137.6, 177.0. IR (KBr):
The reaction between benzaldehyde and malononitrile in
aqueous medium gave the product 3a with 95% yield in 20 min,
and benzaldehyde reacted with ethyl cyanoacetate to give the
product 3b with 88% yield in 40 min (Table 1). 3c (97%) and
1
3
3
3
ꢀ
1
406, 2962, 2220, 1579, 1390, 1169, 623 cm .
3
d (93%) were obtained in 20 min when furfuraldehyde was
1
.3 Procedure for Knoevenagel condensation
In a typical experiment, benzaldehyde (10 mmol, 1.06 g) and
reacted with malononitrile and ethyl cyanoacetate, respec-
tively. The condensation product (3e) was obtained with
moderate yield (90%) in 20 min. Moreover, it was clear that the
reactions between furfuraldehyde and malononitrile/ethyl
malononitrile (10 mmol, 0.66 g) were simultaneously trans-
ferred into a 25 ml round-bottomed flask equipped with a
magnetic stirrer, and then the ionic liquid catalyst [bmim][Pro]
CN
[
bmim][Pro]
H O, r.t.
CN
Ar CHO +
Ar
2
(
10 mol% of benzaldehyde, 0.253 g) and water (10 ml) were
R
2
R
1
3
added. The reaction mixture was stirred at room temperature
for 20 min, and then the solid product was filtrated and
washed with water (10 ml × 3). After drying, 1.47 g
Scheme 2. Knoevenagel condensation catalyzed by [bmim][Pro].
Table 1 Yields from Knoevenagel condensation with different sub-
strates
2-benzylidene malononitrile was obtained with 95% of yield.
1
13
This was also characterized by H NMR, C NMR, and IR.
The reaction is highly stereo-selective and gave only the
E-isomer.
a
Time
Yield
(%)
95
Product
Aldehyde
R
(
min)
20
3
a
benzaldehyde
benzaldehyde
furfural
CN
COOEt
CN
3
b
40
88
2
Results and discussion
3
c
20
97
3
3
d
e
furfural
4-hydroxybenzaldehyde
COOEt
COOEt
20
20
93
90
2
.1 The advantages of the new synthesis route of
[
bmim][Pro] ionic liquid
Reaction conditions: 10 mmol reactants, 1 mmol [bmim][Pro], 10 ml
O, 25 C.
Refer to the pure isolated products characterized by IR, H NMR and
NMR spectroscopic data.
o
H
2
a
1
13
The synthesis of [bmim][Pro] has been described previously
24]. In that procedure, onium hydroxide was first prepared and
C
[

SONG Hongbing et al. / Chinese Journal of Catalysis, 2012, 33: 666–669
cyanoacetate achieved much higher yield than those of the
Table 2 Effect of recycling on the reaction
reactions between benzaldehyde and malononitrile/ethyl
cyanoacetate. In addition, malononitrile was more reactive than
ethyl cyanoacetate with the same aromatic aldehyde because
the electron withdrawing ability of the substituent CN group is
stronger than that of the carbonyl group, that is, the methylene
group of malononitrile was more reactive than that of ethyl
cyanoacetate and reacted more readily with aromatic alde-
hydes, which is consistent with a precious report [26].
a
Recycle time
Isolated yield (%)
1
2
3
4
5
6
95
94
92
89
87
84
Reaction conditions: 10 mmol furfural, 10 mmol ethyl cyanoacetate, 1
1
o
The isolated products were also characterized by H NMR,
mmol [bmim][Pro], 10 ml H
Refer to isolated pure product 3a, unless stated otherwise.
2
O, 25 C, 20 min.
1
3
a
C NMR, and IR as follows.
1
3
a (Table 1) H NMR (400 MHz, CDCl ) ꢀ 1.40 (t, J = 7.2
3
1
3
Hz, 3H), 4.39 (q, 2H), 7.51 (t, J = 7.2 Hz, 2H), 7.56 (t, J = 7.2
Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 8.16 (s, 1H). C NMR (400
MHz, CDCl ) ꢀ 14.09, 62.51, 98.92, 116.37, 123.97, 133.93,
154.77, 161.33, 163.21. IR (KBr): 3325, 3024, 2226, 1714,
1
3
Hz, 1H), 7.99 (d, J = 7.6 Hz, 2H), 8.26 (s, 1H). C NMR (400
3
MHz, CDCl ) ꢀ 14.19, 62.73, 103.03, 129.26, 131.05, 133.28,
3
ꢀ
1
1
1
55.00, 162.48. IR (KBr): 2980, 2220, 1730, 1600, 1440,
1587, 1443, 1284, 1205, 1171, 843, 515 cm .
ꢀ
1
300, 1260, 1200, 1090, 1010, 768, 683, 582, 482 cm .
1
3
b (Table 1) H NMR (400 MHz, CDCl ) ꢀ 7.55 (t, J = 8.0
2.3 Recycle of [bmim][Pro]
3
Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.91 (d, J = 7.6
1
3
Hz, 2H). C NMR (400 MHz, CDCl ) ꢀ 14.20, 62.68, 102.96,
It is well known that a notable advantage of an IL as a
catalyst is its recyclability. After product filtration and water
evaporation, the catalyst was reused for the reaction.
[bmim][Pro] IL was successfully recycled six times without a
decrease in activity. All the reactions were completed in 20
min and yields of 84%–95% were obtained (Table 2).
3
1
1
29.21, 131.00, 133.28, 155.13, 163.25. IR (KBr): 3032, 2222,
ꢀ
1
591, 1448, 1215, 957, 756, 677, 617, 517 cm .
1
3
c (Table 1) H NMR (400 MHz, CDCl ) ꢀ 1.38 (t, J = 7.2
3
Hz, 3H), 4.35(q, 2H), 6.66(q, 1H), 7.39 (d, J = 4.0 Hz, 1H),
1
3
7
.75(d, J = 1.6 Hz, 1H), 8.01 (s, 1H). C NMR (400 MHz,
CDCl ) ꢀ 14.14, 62.89, 98.82, 113.84, 115.31, 121.71, 139.46,
3
1
2
5
48.52, 149.04, 162.57. IR (KBr): 3420, 3130, 3040, 2990,
220, 1920, 1720, 1620, 1540, 1460, 1370, 1260, 1020, 760,
2.4 Mechanism of Knoevenagel condensation catalyzed
by [bmim][Pro]
ꢀ
1
88 cm .
d (Table 1) H NMR (400 MHz, CDCl ) ꢀ 6.71 (q, 1H),
1
3
An IL derived from natural L-proline can behave as an anion
and it has been proposed that the L-proline functional group
acts as a “microaldolase” that facilitates the reaction steps
including the formation of the imine intermediate and the
carbon-carbon bond [27]. Hence, a mechanism (Fig. 1) can be
proposed where the L-proline anion acts as an organocatalyst
with the acceptor role of the corresponding iminium interme-
3
7
.37 (d, J = 3.6 Hz, 1H), 7.51 (s, 1H), 7.80 (d, J = 1.6 Hz, 1H).
1
3
C NMR (400 MHz, CDCl
3
) ꢀ 30.85, 112.50, 113.69, 114.36,
1
1
23.20, 142.98, 148.09, 149.41. IR (KBr): 3043, 2226, 1606,
ꢀ
1
455, 1294, 1149, 1020, 937, 766, 582 cm .
1
3
e (Table 1) H NMR (400 MHz, CDCl ) ꢀ 1.38 (t, J = 7.2
3
Hz, 3H), 4.35 (q, 2H), 6.95 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 1.6
Fig. 1. Mechanism for Knoevenagel condensation catalyzed by [bmim][Pro].

SONG Hongbing et al. / Chinese Journal of Catalysis, 2012, 33: 666–669
diate. When the L-proline anion reacts with a methylene group,
7
8
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an intermediate is formed that can react with the aldehyde, and
the resulting aldol undergoes a subsequent base-induced
elimination.
1
9
0
1
2
3
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The synthesis of [bmim][Pro] developed is simple and effi-
3
85
cient. [bmim][Pro] is an environmentally friendly catalyst for
the Knoevenagel condensation reaction in aqueous solution at
room temperature, in which aldehydes were reacted with me-
thylene compounds. It gave 88%–97% isolated product yields
under mild conditions. The significant features of this process
include high yields, mild reaction conditions, short reaction
time, high yields, and ease of product isolation. [bmim][Pro]
was recycled six times without loss of activity. A reaction
mechanism was proposed.
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