Knoevenagel condensation catalyzed by chemo-selective Ni-nanoparticles in neutral medium

Article abstract of DOI:10.1016/j.catcom.2010.01.017

Recyclable Ni-nanoparticles provides an efficient, economic and rapid method for catalyzing Knoevenagel condensation of aldehydes with an active methylene compound at room temperature. The method offers high yield preferably in case of aromatic aldehydes and proceed well in neutral medium. This method provides a wide range of substrate applicability and simple workup procedure. The products need no further purification and the process is environmentally benign.

Full text of DOI:10.1016/j.catcom.2010.01.017

Catalysis Communications 11 (2010) 679–683
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Knoevenagel condensation catalyzed by chemo-selective Ni-nanoparticles
in neutral medium
Ajeet Kumar a, Manika Dewan a, Amit Saxena a, Arnab De b,1, Subho Mozumdar a,
*
a Department of Chemistry, University of Delhi, Delhi-7, India
b Indiana University, Bloomington, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Recyclable Ni-nanoparticles provides an efficient, economic and rapid method for catalyzing Knoevenagel
condensation of aldehydes with an active methylene compound at room temperature. The method offers
high yield preferably in case of aromatic aldehydes and proceed well in neutral medium. This method
provides a wide range of substrate applicability and simple workup procedure. The products need no fur-
ther purification and the process is environmentally benign.
Received 12 November 2009
Received in revised form 20 January 2010
Accepted 25 January 2010
Available online 1 February 2010
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Knoevenagel condensation
Ni-nanoparticles
Neutral medium
Active methylene compounds
1. Introduction
well documented elsewhere by our research group [21–23]. The
process is cost-effective and eco-friendly as it does not require ele-
The Knoevenagel condensation is a useful carbon–carbon bond
forming reaction [1,2] with numerous applications in the synthesis
of fine chemicals [3], hetero-Diels–Alder reactions [4] and in the
synthesis of carbocyclic as well as hetero cyclic [5] compounds.
The reaction has been utilized in the preparation of coumarin
derivatives [6], cosmetics [7], perfumes [8] and pharmaceutical
chemicals [9]. Traditionally, this condensation has been carried
out between a carbonyl compound and an active methylene com-
pound in the presence of bases such as ethylenediamine [10],
piperidine [11] or corresponding ammonium salts [12], amino
acids [13], dimethylaminopyridine [14] and potassium fluoride
mixture [15]. Recently, many efforts have been made to prepare
electrophilic alkenes by conducting this reaction under heteroge-
neous conditions [16] using inorganic salts like Al2O3 [17], zeolite
[18] and calcite [19]. Ionic liquids [20] have also played a vital role
as a reaction media for this condensation. However, some of these
processes require harsh conditions and suffer from a lack of gener-
ality. Hence, there is an existing need for the development of
milder methods for obtaining these products under conditions tol-
erated by sensitive functional groups from both synthetic and envi-
ronmental points of view. The synthetic challenge is to carry out
this reaction in a neutral medium thus avoiding the use of bases.
The role of Ni-nanoparticles in dehydration chemistry has been
vated temperatures, harsh bases and is an excellent methodology
for carrying out the reaction in a neutral medium. Moreover, it is
a one pot synthesis and has an easy work up and product isolation
procedure. Finally, the use of Nickel-nanoparticles owing to their
recyclability makes the procedure eco-friendly, as in typical cases
where metal salts and other complexes are used as catalysts, an
excessive amount of catalysts (usually in grams) is needed and this
is eliminated as a ‘waste product/contaminant’ generating un-
wanted toxicity and pollution. The quantity of catalyst that we
use here is in microgram scales, thereby reducing the level of toxic
waste. It may be additionally noted that in the recent past Ni-nano-
particles have been used for various applications including in vivo
and in vitro treatment of living cells/organisms and no evidence of
toxicity has been reported for low dosages [24–26]. Therefore, we
can claim that our method is eco-friendly and environmentally be-
nign. Furthermore, recycling/reusability of Ni-nanoparticles can
decrease the generation of toxic waste and thereby minimizing
contamination. It has been observed that the Nickel-nanoparticles
prepared as per our procedure [21–23] could be stored easily in
absolute ethanol for long duration (>2 months) retaining their cat-
alytic activity.
2. Results and discussion
In this communication, we wish to highlight our findings on the
Ni-nanoparticles catalysed condensation of active methylene com-
pounds, such as malonic acid, ethyl cynoacetate, malononitrile and
* Corresponding author. Fax: +91 11766 6593.
E-mail address: subhoscom@yahoo.co.in (S. Mozumdar).
1
Present address.
1566-7367/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2010.01.017

680
A. Kumar et al. / Catalysis Communications 11 (2010) 679–683
Table 1
Ni-nanoparticles catalysed Knoevenagel condensation of aldehydes with active methylene compounds.a
b,c
Entry
1
Carbonyl compound
Active methylene compounds
Products
Time (h)
0.30
Yield (%)
98
COOH
O
O
CHO
COOH
CN
HO
OH
2
3
0.58
0.33
97
98
CHO
CHO
COOC2H5
CN
N
N
CN
4
COOH
0.50
92
O
O
Cl
Cl
Cl
CHO
COOH
CN
HO
OH
5
6
7
0.75
0.25
1.00
95
97
81
Cl
Cl
Cl
CHO
CHO
CHO
COOC2H5
CN
CN
N
N
Cl
O
O
Cl
O
H
O
8
9
1.16
1.41
92
97
COOH
O
O
H3CO
CHO
H3CO
H3CO
H3CO
COOH
CN
HO
OH
H3CO
H3CO
CHO
CHO
COOC2H5
10
11
CN
CN
0.83
0.41
94
85
N
N
N
N
OH
OH
CN
CHO
CN
CN
12
13
0.75
0.83
89
91
HO
HO
CHO
COOC2H5
NO2
NO2
CN
CHO
COOC2H5
CN
14
15
1.33
1.25
72
80
C2H5
C2H5
CHO
OCH3
COOC2H5
H3CO
OCH3
H3CO
CN
COOC2H5
CHO
H3CO
HO
16
0.41
83
H3CO
HO
CN
COOC2H5
CHO
17
18
4.16
5
–
CN
COOC2H5
H3C CHO
H3C
C
H
–
12.00
O
H3C
C CH3
a
b
c
Reaction condition: 5 mmol of aldehydes, 6 mmol of active methylene compound, 10 mol% Ni-nanoparticles (15–20 nm); Ethanol; 25 °C 1 atm.
Confirmed by comparison with authentic samples (FT-IR, 1HNMR, 13CNMR, TLC, MP/BP).
Isolated and unoptimised yields.
dimedone with aldehydes at room temperature in a neutral med-
ium. It may be postulated that the nanoparticles play a complex re-
dox role in accelerating the condensation reaction [27] and thus
may promote the formation of Knoevenagel products. Moreover,
because of their higher surface-to-volume ratio, nanoparticles
can provide increased surface area which in turn can enhance
the rate of the reaction. In general, substituents at the ortho-posi-
tion of the aromatic aldehydes (Table 1:11, 13 and 15) seemed to

A. Kumar et al. / Catalysis Communications 11 (2010) 679–683
681
Table 2
be 45%, 85%, 98%, 32%, and 98%, respectively. Hence, out of ethanol
and DMSO, ethanol was used as solvent through out the reaction
course as the removal of DMSO from the reaction mixture is quite
difficult.
The effect of Ni-nanoparticles concentration on the Knoevenagel condensation at
room temperature under air atmosphere (Table 1, Entry 3)a.
Catalyst concentration (Ni-np) (mol%) Time (h) Yield (%)b,c TOF (sÀ1
)
No catalyst
2
5
10
20
24
1
1
1
1
–
52
85
98
98
–
7.2 Â 10À3
4.2 Â 10À3
2.7 Â 10À3
1.3 Â 10À3
5. Recyclability of catalyst
Further, the use of Ni-nanoparticles as a recyclable catalyst was
tested by carrying out repeated runs of the reaction on the same
batch of the catalyst system (Table 3). The data shows a gradual
loss of the activity of the catalyst used in the experiment with
the increasing number of cycles. It was found from QELS, TEM
and XRD data (see supporting information for details) that the
Ni-nanoparticles underwent aggregation as well as oxidation
(Nickel to Nickel oxide) during the course of reaction and recycling
of catalytic Ni-nanoparticles. Hence, it may be proposed that both
the factors together were responsible for the decrease in catalytic
activity of Ni-nanoparticles.
a
Reaction condition: 5 mmol of aldehydes, 6 mmol of active methylene com-
pound, Ni-nanoparticles (15–20 nm); Ethanol; 25 °C 1 atm.
b
13
Confirmed by comparison with authentic samples (FT-IR, 1HNMR,
C-NMR,
TLC, M.P/B.P).
c
Isolated and unoptimised yields.
Table 3
Reuse of Ni-nanoparticles for the formation of Knoevenagel productsa.
Run
Table 1, Entry 1
Time (h)
Table 1, Entry 3
Time (h)
Yield (%)b,c
Yield (%)
b,c
6. Experimental
1
2
3
4
5
1
1
1
1
1
96
91
82
78
42
1
1
1
1
1
98
97
89
70
51
6.1. General remarks
The materials were purchased from Sigma–Aldrich and Merck
and were used without any additional purification. All reactions
were monitored by thin layer chromatography (TLC) on gel F254
plates. The silica gel (250–400 meshes) for column chromatography
was purchased from Spectrochem Pvt. Ltd., India. 1HNMR
(400 MHz) and 13CNMR spectra were recorded in CDCl3 on a AMX
400 spectrometer (with TMS for 1H and CDCl3 for 13CNMR as inter-
nal references); software IRIX 6.5/XWINNMR. MS were recorded on
ESI-Mass spectrometer Model-Esquire 3000 Plus (Bruker Daltonics
Data analysis 3.1). Melting points were recorded on Buchi melting
point 540 instruments. The size and morphology of Ni-nanoparti-
cles were characterized with the help of transmission electron
microscope (TEM, FEI Philips Morgani 268D model Acc. volt-
age:70 kV with magnification:upto 80,000Â) and Quasi Elastic
Light Scattering instrument (QELS, Photocor-FC, model-1135 P)
and the metallic nature of the particles was confirmed with UV-
spectrophotometer (Hitachi AU-2700).
a
Reaction condition: 5 mmol of aldehydes, 6 mmol of active methylene com-
pound, 10 mol% Ni-nanoparticles (15–20 nm); Ethanol; 25 °C;1 atm.
b
Confirmed by comparison with authentic samples (FT-IR, 1HNMR, 13CNMR, TLC,
M.P/B.P).
c
Isolated and unoptimised Yields.
decrease the rate of the reaction together with the overall yield and
this may be because of steric constraints offered to the incoming
nucleophile. Ketones showed no reactivity at all under the same
conditions (Table 1:18).
3. Catalyst concentration
Catalyst concentration was found to be another influencing
parameter that plays a major role in optimizing the product yield.
The yield generally increased with the increasing concentration of
the catalyst; however increasing the molar concentration of the
Ni-nanoparticles (15–20 nm) from 10 to 20 mol% did not substan-
tially increase the yield of the product (Table 2). Hence, a concentra-
tion of 10 mol% of Ni-nanoparticles was considered as a suitable
choice for the optimum yield of Knoevenagel products. It has been
observed that per mole of catalyst could convert 23.43 Â 1015 moles
of substrate into products before getting deactivated i.e. a TON value
of 23.43 Â 1015 could be achieved using Ni-nanoparticles as catalyst.
6.2. Preparation of nickel-nanoparticles
A chemical method involving reduction of Ni2+ ions to Ni (0) in a
reverse micellar system was employed to prepare the Nickel-nano-
particles. Triton X-100 (TX-100) was used as the surfactant, cyclo-
hexane as the solvent (continuous phase), hexanol as co-
surfactant and aq. solution of salts as dispersed phase. The reverse
micelles were prepared by dissolving TX-100 in cyclohexane (usu-
ally 0.08–0.15 M of TX-100 solution). A typical preparative method
is as follows: to a set volume of 100 ml (0.1 M TX-100 solutions in
4. Solvent effects
cyclohexane) 900 ll of Ni(NO3)2 aq. solution (2% w/v) and hexanol
The solvent used have a strong effect in deciding the reaction
path and the nature of the product. Usually, the increase in polarity
leads to increase in reaction rate. This behavior is attributed to the
influence of the solvent on the transition state and to a change in
the capacity of the catalyst for proton transfer:when polar reagents
are involved, the transition-state complex is better solvated by po-
lar solvents and the partition of the reactants at the solid–liquid
interface is higher, decreasing the activation free enthalpy and
enhancing the reaction rate [28,29]. The Knoevenagel condensation
between benzaldehyde and malanonitrile was also investigated in
various solvents such as CH3CN, DMF, DMSO, CHCl3 and Ethanol
with all the other parameters kept constant and the progress of
the reaction was checked through TLC. The yields were found to
(quantity sufficient, q.s.) was added to prepare an optically clear re-
verse micellar solution (RM-1). To another 100 ml (0.1 M TX-100
solution in cyclohexane) alk. solution of NaBH4 (5% w/v in 2% NaOH
w/v aq. solution) and hexanol (q.s.) was added to obtain RM-2. To
the prepared reverse micellar solution of Ni(NO3)2 aq. solution
(2% w/v) (RM-1) another reverse micellar, alk Solution of NaBH4
(5% w/v in 2% NaOH w/v aq. solution) (RM-2) was added drop wise
with constant stirring maintaining the nitrogen atmosphere. In the
presence of nitrogen atmosphere the resulting solution was kept on
further stirring for 3 h to allow complete Ostwald Ripening (particle
growth). The Ni-nanoparticles were extracted by adding absolute
ethanol to the resulting reverse micellar solution followed by cen-
trifugation at 3000–4000 rpm for 10 min. By varying the water con-

682
A. Kumar et al. / Catalysis Communications 11 (2010) 679–683
Fig. 1. (a) QELS data of Ni-nanoparticles: plot of population distribution in percentile versus size distribution in nanometre, (b) TEM image of Ni-nanoparticles. The scale bar
corresponds to 50 nm in the TEM image.
tent parameter Wo (defined as the molar ratio of water to surfac-
tant concentration, Wo = [H2O]/[surfactant]) the size of the nano-
particles could be controlled. The sizes of the Ni-nanoparticles
prepared at Wo value of 5 were confirmed as 15–20 nm through
Quasi Elastic Light Scattering (QELS) (Fig. 1a) and transmission elec-
tron microscopy (TEM) technique (Fig. 1b). The Ni-nanoparticles
prepared were round in shape and black in color (in colloidal state).
ucts (Table 1). The analysis of complete spectral and compositional
data revealed the formation of Knoevenagel products with excel-
lent purity.
6.4. Typical procedure for the recycling of the Ni-nanoparticles
(catalyst)
After completion of the reaction (as confirmed by TLC), the reac-
tion mixture was centrifuged at 4000–6000 rpm for 10 min, which
precipitated the Ni-nanoparticles as solid pellet at the bottom of
the centrifuge tube. The nanoparticles were washed with Ethanol
4–5 times to confirm the complete removal of any residual mate-
rial. The particles were then redispersed in the Ethanol for further
catalytic reaction cycles. The same process was repeated after each
reaction cycle to isolate and reuse the Ni-nanoparticles as catalyst.
6.3. Typical procedure for the Ni-nanoparticles catalysed Knoevenagel
product
To a mixture of aldehydes (5.0 mmol), active methylene com-
pound (6.0 mmol) in Ethanol (10 ml) Ni-nanoparticles were added
as catalyst (15–20 nm, 10 mol%). The resulting reaction mixture
was stirred at room temperature for a specified period (Table 1).
The progress of the reaction was monitored by thin layer chroma-
tography (TLC), after complete conversion, as indicated by TLC; the
reaction mixture was diluted by adding Ethyl acetate (50 ml) and
washed with water thrice followed by brine. The organic layer
was dried over anhydrous sodium sulphate (Na2SO4) followed by
evaporation of solvent using a rotary evaporator under reduced
pressure and concentrated to dryness gave the desired product,
which after re-crystallisation afforded the pure Knoevenagel prod-
Acknowledgements
Dr. S. Mozumdar and Ajeet Kumar gratefully acknowledges
financial support from the Department Biotechnology, Govt. of IN-
DIA (BT/PR8918/NNT/28/05/2007) and the help of Professor P. Bal-
ram, Director, Indian Institute of Science, Bangalore for his help in
the Mass and NMR characterization done in this work.

A. Kumar et al. / Catalysis Communications 11 (2010) 679–683
683
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