Sevelamer as an efficient and reusable heterogeneous catalyst for the Knoevenagel reaction in water

Article abstract of DOI:10.1016/j.cclet.2014.03.002

A catalyst system of Sevelamer, a phosphate-binding drug, has been prepared and used in the Knoevenagel reaction of aromatic aldehydes in water to produce substituted electrophilic alkenes. The products were obtained in excellent yields. Several novel, re

Full text of DOI:10.1016/j.cclet.2014.03.002

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CCLET-2886; No. of Pages 4
Chinese Chemical Letters xxx (2014) xxx–xxx
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Chinese Chemical Letters
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Original article
Sevelamer as an efficient and reusable heterogeneous catalyst for the
Knoevenagel reaction in water
b,
a
a
b
Xian-Liang Zhao a, , Ke-Fang Yang , Yan-Ping Zhang , Ju Zhu , Li-Wen Xu
*
*
a School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
b Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A catalyst system of Sevelamer, a phosphate-binding drug, has been prepared and used in the
Knoevenagel reaction of aromatic aldehydes in water to produce substituted electrophilic alkenes. The
products were obtained in excellent yields. Several novel, related catalytic systems showed promising
catalytic properties for aromatic and heterocyclic aldehydes. The Sevelamer catalyst can be recovered
using simple filtration and reused numerous times (up to 15 times) in the aqueous Knoevenagel reaction
without any significant lowering of activity.
Received 22 December 2013
Received in revised form 21 January 2014
Accepted 20 February 2014
Available online xxx
Keywords:
ß 2014 Xian-Liang Zhao and Ke-Fang Yang. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Knoevenagel reaction
Sevelamer
Recycle
Heterogeneous
1. Introduction
reaction [23–26], but most of these catalysts also suffer from long
reaction time, complex preparation, and low-loading functional
Functional polymeric catalysts have recently attracted signifi-
cantattention for organicsynthesis because oftheir easeofrecovery,
reuse, and simplified product isolation and purification [1,2]. Using
polymeric catalysts is an efficient way to achieve economically
advantageous and environmentally friendly processes.
groups. Therefore, the study of
a
catalyst for Knoevenagel
condensation based on
challenging.
a functional polymeric catalyst is
Sevelamer, a phosphate-binding drug used to prevent hyper-
phosphatemia, is a copolymer of epichlorohydrin and allylamine.
Sevelamer is an environmentally friendly solid material with
excellent mechanical strength and stability. This compound
contains abundant amine groups which can be easily transformed
into various functions and can also be used as a catalyst.
Recently, we have focused our attention on the use of polymeric
bases as recyclable catalysts in organic synthesis [27]. In this paper,
we demonstrate that Sevelamer can be used for malononitrile
reactions with various aromatic aldehydes in water to provide
Knoevenagel condensation products with excellent yields. Water
can considerably accelerate this reaction even though the reaction
was conducted in a heterogeneous system. The Sevelamer catalyst
(S) can be easily recovered and still retains catalytic activity.
The Knoevenagel condensation is
a powerful method to
construct a carbon–carbon bond and has been widely used in
the production of fine chemicals, such as cosmetics, drugs, and
other substances [3–5]. Numerous reaction systems have been
developed for this reaction, but several disadvantages remain
regarding to the use of these catalysts, such as difficulties in
catalyst recovery and reuse, longer reaction time, or hash reaction
conditions [6–13].
A wide range of heterogeneous catalysts have recently been
used in the Knoevenagel condensation [14–22]. However, few of
these catalysts are based on functional polymeric catalysts. The
polystyrene, polyacrylonitrile and polyacrylonitrile were linked or
transformed to catalytically active bases for the Knoevenagel
2. Experimental
General procedure for Knoevenagel condensation: A 10 mL
round-bottomed flask was charged with the carbonyl compound
(1 mmol), active methylene compound (1 mmol), S-4 catalyst
*
Corresponding authors.
E-mail addresses: xlzhao@iccas.ac.cn (X.-L. Zhao), kfyang@hznu.edu.cn (K.-F.
Yang).
http://dx.doi.org/10.1016/j.cclet.2014.03.002
1001-8417/ß 2014 Xian-Liang Zhao and Ke-Fang Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: X.-L. Zhao, et al., Sevelamer as an efficient and reusable heterogeneous catalyst for the Knoevenagel
reaction in water, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.002

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Table 1
The phosphate-binding capacity and acid exchange capacity of Sevelamer-type catalysts.
Cat (S)
Allylamine:epichloro-hydrin
Yield (%)
Phosphate-binding capacity
(meq/g)
Acid exchange capacity (mmol/g)
pH 3.0
pH 7.0
S-1
S-2
S-3
S-4
S-5
S-6
1:0.08
1:0.11
1:0.08
1:0.11
1:0.15
1:0.20
94
98
92
94
96
98
1.3
1.8
3.1
5.8
3.6
2.8
1.0
1.2
2.1
4.7
2.4
1.7
3.5
3.4
4.4
4.6
4.3
3.2
Table 2
Table 3
Effects of catalysts Sevelamer on the reaction of 1a with 2a.a
The solvent effects on the reaction of 1a with 2a using S-4 catalyst.a
Entry
S
Cat. Loading
(mol%)
Time (min)
Yield
of 3a (%)b
1
2
3
4
5
6
7
8
9
S-1
S-2
S-3
S-4
S-4
S-4
S-4
S-5
S-6
20
20
20
30
20
10
5
60
90
92
90
91
90
91
90
89
92
90
50
30
Entry
Solvent
Time (h)
Yield (%)b
30
120
480
50
1
2
3
4
5
6
7
8
CH2Cl2
CH3OH
CHCl3
THF
2
85
90
86
89
90
92
89
91
1
20
20
2
60
2
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), H2O (3 mL), room temperature.
CH3CN
DMF
–
2
b
Isolated yield.
1
8
H2O
0.5
a
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), catalyst
(20 mol%), solvent (3 mL), r.t.
b
Isolated yield.
Based on the highest acid exchange capacity among all
catalysts, we selected S-4 as the catalyst to examine the effects
of the solvent. Various solvents were employed in the reaction of
1a with 2a in the presence of catalyst S-4 (20 mol%) at room
temperature (Table 2). The reaction was found to proceed
smoothly to completion in the organic solvents (Table 2, entries
1–6). The reaction rate was faster in polar organic solvents, such as
CH3OH, DMF and CH3CN, than non-polar solvents, such as CH2Cl2,
CHCl3 and THF. As noted, the reaction time was prolonged to 8 h
under solvent-free conditions (Table 2, entry 7). Interestingly, this
reaction was finished in water in 0.5 h, and 3a was found to have a
yield of 91% (Table 2, entry 8). The reaction rate was faster in water
than in organic solvent or solvent-free conditions.
system (12 mg and 20 mol% of the substrates), and water (3 mL).
The resulting reaction suspension was stirred at room tempera-
ture. The reaction progress was monitored by thin layer
chromatography using n-hexane–EtOAc (5:1, v/v) as eluent. Upon
completion, the reaction mixture solidified in the round-bottomed
flask. The solids were then dissolved in hot ethanol (30 mL). The
catalyst was removed by filtration and washed with ethanol. The
solid product was obtained after the ethanol was concentrated in
vacuo.
We further investigated the catalytic activity of the S-1 to S-5
catalysts in the reaction of benzaldehyde (1a) with malononitrile
(2a) in water (Table 3). The reaction was completed in 1 h and 1.5 h
when catalyzed by S-1 and S-2, respectively, with the yields
afforded above 90% (Table 3, entries 1 and 2). From Table 3, using
catalyst S-3 the reaction was faster than S-1, although they all used
8 mol% epichlorohydrin as cross-linking agent (Table 3, entry 3).
This result confirms that the catalysts prepared by Method B are
better than those from Method A. Also S-4 was found to be the best
catalyst among S-3 to S-6. With an increased ratio of epichlorohy-
drin, the catalytic activity of Sevelamer decreased because the
amine, as a functional group, is difficult to act as catalyst in the
reactions with increased cross-linking agent. The effects of the
molar ratio of S-4 on the Knoevenagel reaction were also
investigated. Although the product 3a was formed in high yields,
longer reaction times were needed at catalyst loadings of 10 mol%
and 5 mol% (Table 3, entries 6 and 7).
3. Results and discussion
Sevelamer-type catalysts (S-1 and S-2) were synthesized
according to Method A (see Supporting information, Scheme 1).
The yield of Sevelamer-type catalyst, S-1, was 40% with 8 mol% of
epichlorohydrin as cross-linking agent. The phosphate-binding
capacity of S-1 was determined to be 1.3 meq/g and 1.0 meq/g at
pH 3.0 and 7.0, respectively (Table 1) [28,29]. The corresponding
acid exchange capacity of S-1 was determined to be 3.5 mmol/g.
The yield of catalyst S-2 was 98% with 11 mol% epichlorohydrin as
cross-linking agent. The phosphate-binding capacity and the
corresponding acid exchange capacity of S-2 were lower than S-1.
Sevelamer-type catalysts (S-3 to S-6) were synthesized
according to Method B. The phosphate-binding capacity of S-3
was determined to be 3.1 meq/g and 2.1 meq/g at pH 3.0 and 7.0,
respectively. The corresponding acid exchange capacity of S-3 was
determined to be 4.4 mmol/g. Compared with S-1, these two main
parameters of S-3 were greatly improved. The acid exchange
capacity of S-3 to S-5 did not show any apparent difference,
although the amounts of cross-linking agent were different.
However, the acid exchange capacity of S-6 was lower than S-4.
Based on the optimal reaction conditions, various aldehydes
were reacted with malononitrile in the presence of S-4 (20 mol%)
in water (Table 4). Both electron-rich and electron-deficient
aromatic aldehydes worked well and produced high product
yields. Electron-deficient aldehydes, however, needed less time
Please cite this article in press as: X.-L. Zhao, et al., Sevelamer as an efficient and reusable heterogeneous catalyst for the Knoevenagel
reaction in water, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.002

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3
Table 4
Reaction of aldehydes (1a-h) with 2a-b in water catalyzed by S-4.a
Entry
Ar
2
Time (min)
Product
Yield (%)b
1
2
1a Ph
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
30
30
40
20
60
60
30
30
50
50
50
40
90
90
50
50
3a
3b
3c
3d
3e
3f
91
94
90
91
91
92
92
94
90
91
90
93
90
91
93
92
1b p-ClPh
3
1c o-ClPh
4
1d p-NO2Ph
1e p-MeOPh
1f p-OHPh
5
6
7
1g 2-furaldehyde
1h 2-thienaldehyde
1a Ph
3g
3h
3i
8
9
10
11
12
14
14
15
16
1b p-ClPh
3j
1c o-ClPh
3k
3l
1d p-NO2Ph
1e p-MeOPh
1f p-OHPh
3m
3n
3o
3p
1g 2-furaldehyde
1h 2-thienaldehyde
a
Reaction conditions: aldehyde (1 mmol), 2 (1 mmol), S-4 (20 mol%) in H2O (3 mL), room temperature.
b
Isolated yield.
100
and produced relatively higher yields than their electron-rich
counterparts (entries 1–6, Table 4). Heterocyclic aldehydes also
afforded high yields (entries 7 and 8, Table 4). The treatment of
aldehydes with methyl cyanoacetate also produced Knoevenagel
products with high yields under similar reaction conditions.
Compared with malononitrile, the reactions of methyl cyanoace-
tate with the same aromatic aldehydes required more time (entries
9–16, Table 4).
Finally, the recovery and reuse of the catalytic systems has
been investigated (Fig. 1). Once product 3a was dissolved in hot
ethanol and filtered from the reaction mixture, S-4 was directly
used for another cycle. As shown in Fig. 1, the catalyst S-4
substantially demonstrated the ability to retain its catalytic
activity even after fifteen cycles and all reactions were completed
in 0.5 h.
95
90
85
80
75
70
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
Run (No.)
Fig. 1. Recycling of catalyst S-4 in the aqueous reaction of 1a with 2a. Reaction
conditions are same as in Table 2.
Scheme 1. Synthesis of Sevelamer-type catalysts S-1 to S-6.
Please cite this article in press as: X.-L. Zhao, et al., Sevelamer as an efficient and reusable heterogeneous catalyst for the Knoevenagel
reaction in water, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.002

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In conclusion, a catalyst system of Sevelamer as phoshate-
binding drug was prepared and employed as an effective catalyst
for the Knoevenagel condensation of aromatic aldehydes in water.
Water was not only employed as a reaction medium, but also
played a role in accelerating the Knoevenagel condensation. The
green and mild reaction conditions, short to medium reaction
times, excellent yields, and operational simplicity are among the
attractive features of this catalytic system. The catalysts can be
easily recovered by simple filtration and display no loss of activity
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We gratefully acknowledge financial support by the National
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Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.03.
002.
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Please cite this article in press as: X.-L. Zhao, et al., Sevelamer as an efficient and reusable heterogeneous catalyst for the Knoevenagel
reaction in water, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.002