Polystyrene-immobilized DABCO as a highly efficient and recyclable organocatalyst for the Knoevenagel condensation reaction

Article abstract of DOI:10.1039/c3ra43921f

Polystyrene-immobilized DABCO was used for the first time as a basic organocatalyst for carbon-carbon bond formation reactions. The supported catalyst could be used as a reusable catalyst in the Knoevenagel condensation of a wide range of aromatic/heterocyclic/α,β-unsaturated aldehydes and ketones with active methylene compounds. The reaction conditions are mild and the method is operationally simple. The reactions proceed in a short time period and with 100% selectivity. The catalyst could be easily separated from the reaction by filtration and recycled ten times without activity loss. Based on the catalyst, a continuous flow process was also developed.

Full text of DOI:10.1039/c3ra43921f

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Polystyrene-immobilized DABCO as a highly efficient
and recyclable organocatalyst for the Knoevenagel
condensation reaction †
Cite this: RSC Adv., 2013, 3, 23075
a
a
Da-Zhen Xu,ab Sen Shi and Yongmei Wang
*
Polystyrene-immobilized DABCO was used for the first time as a basic organocatalyst for carbon–carbon
bond formation reactions. The supported catalyst could be used as a reusable catalyst in the
Knoevenagel condensation of a wide range of aromatic/heterocyclic/a,b-unsaturated aldehydes and
ketones with active methylene compounds. The reaction conditions are mild and the method is
operationally simple. The reactions proceed in a short time period and with 100% selectivity. The
catalyst could be easily separated from the reaction by filtration and recycled ten times without activity
loss. Based on the catalyst, a continuous flow process was also developed.
Received 29th July 2013
Accepted 11th September 2013
DOI: 10.1039/c3ra43921f
www.rsc.org/advances
as a polystyrene-supported organic base14 or Lewis acid,15 or
magnetic nanoparticle-supported basic ionic liquids,16 have
Introduction
The Knoevenagel condensation, the nucleophilic addition of a
carbanion to an electrophilic carbonyl group in the presence of
a relatively weak base followed by dehydration, is one of the
most important reactions in organic synthesis for carbon–
carbon bond formation. It is oen employed in the synthesis of
therapeutic drugs,1 natural products,2 ne chemicals3 and
carbocyclic as well as heterocyclic4 compounds of biological
signicance. In recent years, a wide array of catalysts have been
employed to catalyze this reaction,5 each one affording variable
yields of Knoevenagel condensation compounds in solution or
under solvent-free conditions. However, there are still a lot of
disadvantages associated with these catalysts. For example, the
reaction conditions should be free from water,6 the reaction
time is too long7 and the reaction requires heating or other
also been employed in the Knoevenagel condensation.
However, these immobilized catalysts oen needed several
steps to be obtained, and nearly all of them can only be reused
ve times. Therefore, the development of a simple and efficient
catalyst, which can be recovered and reused for more turns, and
even applied to continuous ow operations, remains a big
challenge.
In our previous work, we have reported an efficient and green
procedure for the Knoevenagel condensation of various alde-
hydes with active methylene compounds catalyzed by DABCO-
base ionic liquid catalysts using water as a solvent at room
temperature.17a As part of our continuing efforts to develop a
highly efficient and environmental friendly catalytic system for
carbon–carbon bond formation reactions,17 we report here the
Knoevenagel condensation catalyzed by a polystyrene-sup-
ported DABCO catalyst, which can be easily recovered from
products with solvent, and reused more than ten times. In
addition, this catalytic system can even be applied to contin-
uous ow operations.
8
special conditions, such as microwave irradiation.
From both industrial and environmental viewpoints, catalyst
immoblization9 onto solid supports, such as mesoporous silica
or polymers, has many advantages in organic synthesis over
liquid bases.10,11 For instance, aer the reaction is completed,
the working catalyst can be easily recovered from products and
solvents by ltration or centrifugation, and further used for the
next run. Up to now, many polystyrene-immobilized catalysts
have been synthesized and utilized as reusable catalysts for
different reactions.12,13 Some of the immobilized catalysts, such
Results and discussion
Firstly, the polystyrene-supported DABCO catalyst
3 was
synthesized according to the synthetic route shown in Scheme
aDepartment of Chemistry, State Key Laboratory and Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin, 300071, People's Republic of China. E-mail:
ymw@nankai.edu.cn; Fax: +86 22 2350 2654
bNational Pesticide Engineering Research Center (Tianjin), Nankai University, Tianjin,
300071, People's Republic of China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra43921f
Scheme 1 Synthesis of the catalyst.
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Table 1 The Knoevenagel condensation of benzaldehyde with malononitrilea
Table 2 Knoevenagel condensations catalyzed by the Merrifield resin poly-
strene-supported catalysta
Time [min] Yieldb [%]
Entry
Cat. [mol%]
Solvent
Time [min]
Yieldb [%]
Entry Product
1
E
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
5
3
1
0
H2O
AcOEt
10
99
65
99
>99
80
>99
>99
>99
>99
<5
12 h
18 h
27
300
15
25
30
38
24 h
1
2
6a
6b
CN
CN
15
30
>99
99
CH2Cl2
CH3CN
C2H5OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
3
6c
CN
25
99
10
a
Reaction conditions: benzaldehyde (1.0 mmol), malononitrile
(1.0 mmol), catalyst (44 mg, 10 mol%), solvent (1.0 mL), room
temperature (25 ꢁC). b Isolated yield of product.
4
5
6
7
6d
6e
6f
CN
CN
CN
CN
21
12
45
10
99
99
98
99
1. The supporting process could be performed in a single
step from commercial chloromethyl polystyrene (PS-1% DVB,
100–200 mesh, nominal loading: 2.5 mmol gꢀ1) and the corre-
sponding 1,4-diazabicyclo[2.2.2]octane (DABCO) in toluene at
100 ꢁC for 48 h. Aer the organic compounds were ltered, the
resin was washed several times with DCM and acetone, and
polystyrene-supported DABCO was obtained. According to the
elemental analysis of nitrogen, the loading of catalyst 3 was
6g
8
6h
6i
CN
CN
CN
48
48
60
99
99
2.31 mmol gꢀ1
.
With the supported DABCO catalyst 3 in hand, its activity was
tested on the Knoevenagel condensation of benzaldehyde (4a)
with malononitrile (5a) in different solvents under room
temperature. When the reaction was performed in water, a 99%
yield was obtained in only 10 minutes (Table 1, entry 1), but the
products were stuck on the catalyst, which made it difficult to
recover the catalyst from the products. Organic solvents were
then used instead of water to avoid this difficult separation step.
However, the reaction time was too long when both ethyl acetate
and CH2Cl2 were used as solvents (Table 1, entries 2 and 3).
When the reaction was performed in CH3CN, 6a was obtained in
9
10
6j
>99
11
12
6k
6l
CN
CN
10
20
>99
>99
>99% yield in 27 minutes (Table 1, entry 4). The most polar 13
solvents, such as C2H5OH and CH3OH were also employed in
the reaction, but C2H5OH needed ve hours to give a yield of
6m
CO2Et 360
>99
14c
6n
6o
6p
CO2Et
35
99
97
99
80% (Table 1, entry 5). The best result was observed when
CH3OH was used as the solvent, as the reaction could be
completed in 15 minutes with >99% yield (Table 1, entry 6).
When we reduced the amount of the catalyst, polystyrene-sup-
15c
CO2Et 100
ported DABCO, the reactions required more time to complete,
16c
CO2Et
90
but the yields were also very high (Table 1, entries 7–9). Even
when only 1 mol% of the catalyst was used, the product 6a could
be obtained with >99% yield in 38 minutes. The product was
obtained in a very low yield aer 24 hours when no catalyst at all
was added (Table 1, entry 10).
Next, the Knoevenagel condensation reactions of various
aldehydes, including aromatic/heterocyclic/a,b-unsaturated
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Table 2 (Contd. )
Ketones, including aliphatic and aromatic ketones, which
were oen recognized as inactive carbonyl compounds in the
Knoevenagel condensation reaction, were also examined in the
reaction catalyzed by catalyst 3. The reaction of the ketones with
ethyl cyanoacetate were oen carried out under heating condi-
tions, and afforded the products 8a–d in good to excellent yields
(Scheme 2, 8a–d). When malononitrile was used in the same
reaction at room temperature, product 8e was obtained in an
excellent yield of 99%, with a reaction time of only 15 min
(Scheme 2, 8e).
Next, we investigated the possibility of recycling and reusing
the resin catalyst. The catalyst 3, which was ltered from the
mixture, was directly reused for the same reaction in the next
catalytic cycle. The crude product 6a was obtained aer vacuum-
evaporation of CH3OH. The recycled solvent could also be
directly reused for the next catalytic cycle. Very gratifyingly, the
yield was preserved at >99% throughout the ten-cycle experi-
ment, but consecutive cycles required more time to complete.
The result of recycling is shown in Table 3. The supported
catalyst is very stable under the reaction conditions, but stirring
provokes some etching in the beads of the immobilized catalyst
leading to a decrease in the effective catalyst loading as the
series of experiments progresses. With sufficiently active
immobilized catalysts, this phenomenon can be suppressed by
performing the reactions in a continuous ow mode.
Entry Product
1
E
Time [min] Yieldb [%]
17c
6q
6r
CO2Et 300
CO2Et 300
99
99
18c
a
Reaction conditions: 4 (1.0 mmol), 5 (1.0 mmol), catalyst (44 mg,
b
10 mol%), CH3OH (1.0 mL), room temperature (25 ꢁC). Isolated
c
yield of product. Reaction temperature of 45 ꢁC.
aldehydes, with active methylene compounds, were examined
in the presence of polystyrene-supported DABCO catalyst 3
(10 mol%) in CH3OH. The results are summarized in Table 2.
The reaction between malononitrile and the aldehydes pro-
ceeded well at room temperature, with CH3OH as the reaction
solvent. All of the reactions were completed in 60 minutes,
resulting in near quantitative yields of the products (Table 2,
entries 1–12). Compared to the Knoevenagel reactions of
malononitrile with aromatic aldehydes, the reactions of ethyl
cyanoacetate with the same aromatic aldehydes needed more
time because of the decreased activity. However, when the
reactions were carried out at a higher temperature, such as
45 ꢁC, the products could be obtained with high yields in a
shorter reaction time (Table 2 entry 13 vs. entry 14). Under these
heating conditions, all of the products were obtained in near
quantitative yields (Table 2, entries 15–18). The reaction is
highly stereoselective, with only an E-geometry.
To prove the efficiency of our approach, we have also per-
formed the Knoevenagel condensation reaction of benzalde-
hyde (4a) and malononitrile (5a) on a large-scale setting in a very
simple continuous ow reactor we designed. The schematic
representation of the reactor is illustrated in Scheme 3. The
glass column was charged with the polystyrene-supported
DABCO catalyst (2.2 g) swollen with CH3OH. A mixture of
benzaldehyde (0.5 M) and malononitrile (0.5 M) in CH3OH was
Table 3 Recycling of the catalyst in the Knoevenagel condensation reaction
between benzaldehyde and malononitrilea
Cycle
Time [min]
Yieldb [%]
1
2
3
4
5
6
7
8
9
10
15
18
20
23
27
31
35
40
43
45
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
Scheme 2 Knoevenagel condensation of ketones catalyzed by the supported
catalyst 3. The reaction was carried out with ketones (7, 1.0 mmol), ethyl cya-
noacetate or malononitrile (5, 1.0 mmol), and catalyst 3 (44 mg, 10 mol%) in
CH3OH (1.0 mL). The reactions forming 8a–d occurred at 65 ꢁC. The reaction
forming 8e occurred at room temperature.
a
Reaction conditions: benzaldehyde 4a (1.0 mmol), malononitrile 5a
(1.0 mmol), catalyst (44 mg, 10 mol%), CH3OH (1.0 mL), room
temperature (25 ꢁC). b Isolated yield of product.
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electrophilic alkenes without producing any waste. We have
also designed a very simple continuous ow reactor to improve
the efficiency of the approach. This has allowed a long-standing
continuous ow operation with a short residence time (10 min).
Experimental section
Synthesis of the polystyrene-supported DABCO catalyst
Merrield resin 1 (2.5 mmol gꢀ1, 100–200 mesh, 1% DVB, 4.0 g),
1,4-diazabicyclo[2.2.2]octane 2 (2.24 g, 20 mmol) and toluene
(50 mL) were added to a round bottom ask equipped with a
magnetic stirrer. The mixture was heated to 100 ꢁC and this
temperature was maintained while stirring for 48 h. Aer cooling
to room temperature, the suspension was ltered and the poly-
mer was washed with DCM and acetone several times. The solid
was dried under reduced pressure to give polystyrene-supported
DABCO 3 as a pale yellow powder (4.49 g). Elemental analysis: C,
Scheme 3 Preparation of 6a using a cyclic continuous flow reactor.
67.15; H, 8.67; N, 6.47%. Catalyst loading: 2.31 mmol gꢀ1
.
Table 4 The continuous flow Knoevenagel condensation reaction catalyzed by
the supported catalyst 3a
General procedure for the Knoevenagel condensation reaction
Entry
Time [h]
Conversionb [%]
A 5 mL round bottomed ask was charged with the carbonyl
compound (1.0 mmol), the active methylene compound
(1.0 mmol), the polystyrene-supported DABCO catalyst (44 mg,
0.1 mmol, loading 2.31 mmol gꢀ1) and CH3OH (1.0 mL). The
reaction mixture was stirred at room temperature. The formation
of the products was monitored by TLC. Aer completion of the
reaction, the catalyst was ltered off and washed with CH3OH
(2 ꢂ 2 mL). The catalyst was directly used in the next recycling
run. The methanol was removed under vacuum and the residue
was puried by simple crystallization (cyclohexane–ethyl acetate
¼ 2 : 1) to give the pure products. The supported catalyst could be
recovered and reused in the reaction at least ten times.
1
2
3
4
5
6
7
8
0.5
1
2
3
4
5
6
7
8
>95
>95
>95
>95
>95
>95
>95
>95
>95
92
9
10
11
9
10
90
a
Conditions: benzaldehyde 4a (0.5 M) and malononitrile 5a (0.ꢀ51M) in
b
CH3OH, room temperature (25 ꢁC), outow rate of 0.2 mL min
.
By
1H NMR.
Continuous ow operation
The glass column was charged with the polystyrene-supported
DABCO catalyst 3 (2.2 g) swollen with CH3OH. A mixture of
benzaldehyde (0.5 M) and malononitrile (0.5 M) in CH3OH was
added. The outow rate was controlled at 0.2 mL minꢀ1 to
promote the condensation reaction. The product was collected
in a ask at room temperature. Analytic samples (0.5 mL) were
collected at each given time point and the solvent CH3OH was
removed under reduced pressure. The crude product was
then added. The outow rate of 0.2 mL minꢀ1 was controlled to
promote the condensation reaction.
The simple device was kept in operation for 10 h, the product
being collected in a ask at room temperature. As shown in
Table 4, the conversion did not decrease during the rst 8 h of
operation with residence times of 10 min. A slight decrease in
conversion was observed aer 8 h of operation, but remained in
all cases higher than 90%. Aer 10 h of continuous ow oper-
ation, 56.1 mmol of 6a could be isolated.
1
directly analysed by H NMR spectroscopy.
Acknowledgements
This work was nancially supported by the National Natural
Science Foundation of China (Grant No. 21302101), the
National Basic Research Program of China (973 Program:
2010CB833300), and the Fundamental Research Funds for the
Central Universities. We also thank the Nankai University State
Key Laboratory of Elemento-Organic Chemistry for support.
Conclusion
In summary, it was demonstrated that readily available and
economic polystyrene-immobilized DABCO could behave as a
recyclable catalyst for the Knoevenagel condensation reactions
of a broad range of aldehydes and ketones with active methy-
lene compounds, offering excellent yields in a short reaction
time. The catalyst and the solvent were easily recovered, and the
polystyrene-immobilized DABCO catalyst can be recycled at
least ten times without activity loss. This simple process could
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