Microwave-assisted and efficient solvent-free Knoevenagel condensation. A sustainable protocol using porous calcium hydroxyapatite as catalyst

Article abstract of DOI:10.3390/molecules15020813

A sustainable Knoevenagel condensation of a series of aldehydes with malononitrile and ethyl cyanoacetate is described. The process is based on the combination of microwave activation and hydroxyapatite catalysis under solvent-free conditions. Products ar

Full text of DOI:10.3390/molecules15020813

Molecules 2010, 15, 813-823; doi:10.3390/molecules15020813
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Microwave-Assisted and Efficient Solvent-free Knoevenagel
Condensation. A Sustainable Protocol Using Porous Calcium
Hydroxyapatite as Catalyst
Siham Mallouk 1, Khalid Bougrin 1,*, Abdelaziz Laghzizil 2 and Rachid Benhida 3,*
1
Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, Université
Mohammed V-Agdal, Faculté des Sciences, B.P. 1014 R.P, Rabat, Maroc
2
Laboratoire de Chimie Physique Générale, Université Mohammed V-Agdal, Faculté des Sciences,
B.P. 1014 R.P, Rabat, Maroc
3
Laboratoire de Chimie des Molécules Bioactives et des Arômes, UMR 6001 CNRS, Institut de
Chimie de Nice, Université de Nice-Sophia Antipolis, 28 avenue de Valrose, 06108 Nice Cedex 2,
France
* Authors to whom correspondence should be addressed; E-Mails: benhida@unice.fr (R.B.);
kbougrin@yahoo.fr (K.B.).
Received: 8 December 2009; in revised form: 21 January 2010 / Accepted: 21 January 2010 /
Published: 4 February 2010
Abstract: A sustainable Knoevenagel condensation of a series of aldehydes with
malononitrile and ethyl cyanoacetate is described. The process is based on the combination
of microwave activation and hydroxyapatite catalysis under solvent-free conditions.
Products are obtained in and high yields after short reaction times. The effects of the
specific surface of porous calcium hydroxyapatite and microwave activation are discussed.
Keywords: solvent-free; sustainable procedure; microwave; Knoevenagel; catalysis
1. Introduction
The Knoevenagel condensation is one of the most important, useful and widely employed methods
for the formation of carbon-carbon bonds [1,2]. It has been used for the preparation of a range of
substituted alkenes and bioactive molecules, and as a key step in natural product synthesis. In general,
the Knoevenagel condensation is carried out using organic bases such as aliphatic amines, urea,
ethylenediamine and piperidine or their corresponding ammonium salts, and the amino acids glycine

Molecules 2010, 15
814
or β-alanine [3,4]. Much work has shown that this condensation is strongly solvent-dependent and
benzene, ethanol and DMF are commonly used. Other Lewis bases and acids have also been reported
as catalysts in the Knoevenagel condensation, including ZnCl2 [5], CdI2 [6], TiCl4 [7], Al2O3 [8], Ni-
SiO2 [9], MgO and ZnO [10], AlPO4–Al2O3 [11], KF–Al2O3 [12], natural phosphate [(NP)/KF or
NP/NaNO3] [13] and synthetic phosphate (Na2CaP2O7 [14], Ca2P2O7 [14] and K2NiP2O7 [15]).
However, the use of such bases/acids and solvents in large scale Knoevenagel reactions has led to
environmental problems, i.e. the necessity to dispose of huge amounts of organic waste due to the
formation of undesirable side products resulting from polymerisation, bis-addition and self-
condensation; in addition to the total dissolved salts formed during the neutralisation of the base or
acid catalysts. As a result other modified inorganic solids [16–18], resins [19], phase-transfer agents
[20], ionic liquid [21,22], LDH-F hydrotalcite [23], cation-exchanged zeolites [16], or mesoporous
materials [24], and MCM-41 [25] have been introduced as new catalysts. Electrochemical, microwave
and ultrasound activation methods have also been reported [26–31]. Nevertheless, most of these
known methods suffer from significant limitations, which include toxic reagents, harsh reaction
conditions, low yields or long reaction times. Only a few sustainable procedures and particularly with
basic heterogeneous catalyst were reported [32–35].
The application of MW irradiation as a non-conventional energy source for the activation of
reactions has now become a very popular and useful technology in organic chemistry [36–39].
Moreover, the combination of MW activation and solvent-free conditions leads to enhanced
conversion rates, higher yields, easier work-up and in general cleaner reactions confirming
therefore the real advantages of this approach in the framework of green chemistry.
In continuation of our studies directed at the development of practical and efficient chemical
processes [40–43], we report herein a sustainable Knoevenagel condensation protocol using a
cooperative effect of MW activation and natural hydroxyapatite catalysis [Ca10(PO4)6(OH)2] (p-
HAP) under solvent-free conditions. This strategy was applied for the condensation of malonitrile
and ethyl cyanoacetate with different aldehydes (Table 1). The effect of MW and specific surface
area of the catalyst on the rate enhancement are also dicussed.
Table 1. Knoevenagel condensation of aldehydes with ethyl cyanoacetate 2a and
malonitrile 2b catalyzed by p-hydroxyapatite under solvent-free and microwave irradiation
(Power = 1250 W, irradiation time = 2 min).
R1
R1
CN
CN
Catalyst / MW / 5 min
see table
+
O
H
R2
H
R2
3
1
2a (R2 = CO2Et)
2b (R2 = CN)

Molecules 2010, 15
815
Table 1. Cont.
Entry Product
R1
R2
Catalyst
p-HAP300
p-HAP300/N2
p-HAP300/
hydroquinone
p-HAP300
p-HAP100
p-HAP800
KF/Al2O3
T(°C) Yield %
Mp (°C)[Lit.]
1
3a
3a
3a
C6H5
C6H5
C6H5
CO2Et
CO2Et
CO2Et
85
80
88
46
89
88
52-54 (50) [21]
2 a
3 b
4
5
3b
3b
3b
3b
3c
3d
3e
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
CO2Et
CO2Et
CO2Et
CO2Et
CN
76
62
50
88
57
78
54
96 (10)d 170-172 (172-173) [28]
82
15
80
6
7
8
p-HAP300
p-HAP300
p-HAP300
93
92
91
162-164 (162) [21]
115-117 (116) [21]
125-127 (129) [21]
9
4-CH3OC6H4
4-CH3C6H4
CN
10
CN
11
3f
2-furyl
C6H5
CN
CN
p-HAP300
p-HAP300/
hydroquinone
p-HAP300
p-HAP300
p-HAP300
p-HAP300
p-HAP300
p-HAP300
p-HAP300
p-HAP300
p-HAP300
p-HAP300
p-HAP300
92
81
89
87
87-89 (91-92) [14]
12b
3g
13
14
15
16
17
18
19
20
21
22
23
3h
3i
4-NO2C6H4
4-ClC6H4
CN
56
70
96 (36)d 160-162 (161-162) [29]
95 (28)d
94
CO2Et
92-94 (91) [21]
86-88 (83-84) [28]
90-92 (94-95) [28]
68-70 (72) [14]
125-127 (126-127) [28]
170-172 (171-172) [28]
Liquid [21]
3j
4-CH3OC6H4 CO2Et
64
3k
3l
4-CH3C6H4
2-furyl
CO2Et
CO2Et
81
96
105
89
90
3m
3n
3oe
3pe
3qe
3re
4-(CH3)2NC6H4 CO2Et
87
4-HOC6H4
propyl
CO2Et
CO2Et
CO2Et
CN
101
87
80
89
methyl
propyl
87
91
Liquid [21]
89
88
Liquid [21]
methyl
CN
89
b
98
Liquid [21]
a Air is excluded by purging the reaction vessel with nitrogen. 20% molar of hydroquinone was
added. c Yields of pure products obtained under MW irradiation. d Yields of pure products obtained
e
under conventional heating. Liquid products 3o-r were purified by chromatography on silica gel
(hexane/ethyl acetate: 9/1).
2. Results and Discussion
First, to survey of the reaction conditions we chose malonitrile, ethyl cyanoacetate and aromatic
aldehyde as model reaction partners (Table 1). The porous calcium hydroxyapatites used in our
work—p-HAP100, p-HAP300 and p-HAP800—were prepared by a chemical wet method and heated
at different temperatures (100, 300 and 800 °C, respectively) as reported in our previous work [44].
The mineral reagent thus obtained was impregnated with a 1:2 molar mixture of aldehyde 1 and ethyl
cyanoacetate (2a) or malonitrile (2b), respectively. The reaction vessel was placed and irradiated in
microwave reactor for 2 min.
Several parameters were surveyed to achieve optimum conditions, including stoichiometry of the
reagents, irradiation time and microwave power levels. The best result was obtained when using
1 mmol of 1, 1.2 mmol of 2a or 2b and 0.1 g/mmol of the p-HAP catalyst. For example, treatment of

Molecules 2010, 15
816
4-nitrobenzaldehyde (1b) with 1.2 mmol of ethyl cyanoacetate (2a) in the presence of 0.1 g of p-
HAP300 afforded alkene 3b in almost quantitative yield (Table 1, entry 4). Under MW activation and
p-HAP300 catalysis, all reactions proceeded efficiently, within short reaction times (Table 1). Products
3a-r were isolated by simple filtration and were identified as the corresponding E-isomers. Their
spectral data were identical to those reported in the literature (see references in Table 1). Both
electron-rich and electron-poor benzaldehydes were converted to their corresponding alkenes in good
to excellent yields, which indicated that the electronic effect did not significantly affect the reactivity
(Table 1, entries 1–10, 12, 13–16, 18–19). Furancarboxaldehyde also undergoes clean condensation
(Table 1, entries 11, 17). Moreover, aliphatic aldehydes showed good reactivity with 2a and 2b and led
to products 3o-3r in 89–98% yields (Table 1, entries 20–23). However, in the first condensation
reaction, benzaldehyde gave only 46% yield of product 3a (Table 1, entry 1). This result was clearly
ascribed to the high sensitivity of benzaldehyde to air oxidation during the reaction. Indeed, when the
reaction was carried out under nitrogen (Table 1, entry 2) or in the presence of hydroquinone as
antioxidant (Table 1, entry 3) it provided 3a in ca. 89% yield.
The use of microwave heating was critical to the success of the reaction. Indeed, control
experiments conducted on 4-nitro- and 4-chlorobenzaldehyde (Table 1, entries 13, 14) showed that
when the condensation was carried out under microwave irradiation, compounds 3h and 3i were
obtained in ca. 95% yield, whereas only low yields (36% and 28% respectively, Table 1, entries 13,
14) were obtained under conventional heating due to the formation of side non-identified products as
attested by TLC. The worst results obtained under conventional heating could be ascribed to the low
thermal conductivity of p-HAP300 [40].
The specific microwave effects in this Knoevenagel condensation were then investigated in all
reactions. For example, in Table 1 entry 4, a control experiment was conducted under the same
reaction conditions: 4-nitrobenzaldehyde (1a) and p-HAP300 was reacted in a preheated oil bath at
76 °C for 1 h to 24 h, without solvent. Under these conditions the yield of product 3b did not exceed
10% (GC-MS analysis), whereas under MW irradiation the same reaction led to a 96% yield. This
result clearly attested to a significant specific non-thermal microwave effect, which gave rise to
dramatic enhancement of the reactivity [45].
Figure 1. Catalytic activity of p-HAP100, p-HAP300, p-HAP800 and KF/Al2O3 in the
Knoevenagel condensation of 4-nitrobenzaldehyde (1b) with ethyl cyanoacetate (2a).
100
80
60
40
20
0
p-HAP300
KF/γ-Al2O3
p-HAP100
p-HAP800
0
40
80
120
Ti m e ( s )
We also compared the effect of the catalyst and used p-HAP100, p-HAP300 and p-HAP800 apatites
and the known KF/Al2O3 hyperbase [28]. In a model reaction involving 4-nitrobenzaldehyde (1b) and

Molecules 2010, 15
817
ethyl cyanoacetate (2a), p-HAP100, p-HAP300 and KF-Al2O3 showed similar catalytic activity and
efficiency after 2 h, with the best results being obtained with p-HAP300 (Figure 1). In contrast, p-
HAP800 was found to be less effective. In line with this result, we observed that the yield of the
reaction and the activity of the catalyst were affected by two major factors, i.e., the effect of specific
surface area and the chemical nature of the solid surface, as shown in Table 2.
Table 2. The specific surface area effect of supports on Knoevenagel condensation
involving 4 nitrobenzaldehyde (1b) and 2a under microwave irradiation.
Specific surface area
Support
Time (min) T (°C)
Yield (%)a
(m2.g-1)
253
p-HAP100
p-HAP300
p-HAP800
KF/Al2O3
2
2
2
2
62
76
50
88
82
96
15
80
159
89
High
a
Isolated yield of pure 3b obtained in the condensation of 4-nitrobenzaldehyde (1 mmol),
malonitrile (1.2 mmol) and catalyst (100 mg) under solvent-free microwave irradiation.
Furthermore, the use of p-HAP300 is particularly convenient since this catalyst is efficiently
recycled by simple heating at 300 °C under reduced pressure during 20 min. Excellent preservation of
basic capacity of the p-HAP300 catalyst was observed. The good yields obtained during ten cycles
(see Plots P1 to P4 in Figure 2) clearly attested for the preservation of the basicity and the high
recyclability of this catalyst. The best yields were obtained with the optimum molar ratio of
1b:2a = 1:1.2. The increase of this ratio decreased the yield (Figure 2, P5 and P6), which is probably
due to the accumulation of the reactants on p-HAP300 surface. The use of an increased amount of p-
HAP300 did not have a significant effect on the reaction yield (Figure 2, P7). In the case of KF-Al2O3
we found that the catalytic activity dramatically decreased after only one cycle (Figure 2, P8). In line
with this result, previous work reported that in the absence of chemisorbed water and under microwave
heating KF/Al2O3 did not catalyze the basic reaction after one cycle [46].
Figure 2. Recycling of the p-HAP300 catalyst for ten successive cycles and effect of molar
ratio n(1b):n(2a) on the yield of Knoevenagel condensation affording 3b, under microwave
irradiation.
MW (2.45 GHz, Pmax=1250W, time=2min/cycle)
100
80
60
40
20
0
P1 (1:1.2 / 100mg p-HAP300)
P2 (2:2.4 / 100mg p-HAP300)
P3 (3:3.6 / 100mg p-HAP300)
P4 (4:4.8 / 100mg p-HAP300)
P5 (5:6 / 100mg p-HAP300)
P6 (6:7.2 / 100mg p-HAP300)
P7 (6:7.2 / 200mg p-HAP300)
P8 (1:1.2 / 100mg KF-Al2O3)
1
2
3
4
5
6
7
8
9
10
Cycles

Molecules 2010, 15
818
All together these results indicate that p-HAP300 is an excellent catalyst for the Knoevenagel
condensation. By applying our procedure, the separation of the catalyst from the product only required
simple filtration and the recyclability of the catalyst was higher compared to the conventional heating
method. The high catalytic activity of p-HAP300 could be ascribed to the Ca2+–O2− acid-base pair sites
on the apatite surface that participate efficiently in the catalysis of deprotonation-aldol-dehydration
steps, as proposed in Scheme 2.
Scheme 2. Plausible catalytic pathway for the p-HAP300-mediated Knoevenagel
condensation under MW activation.
1
R2
R1
H
R2
CN
CN
2a, 2b
_
O
H
O
H
O
deprotonation
O
O
P O
O
O
O
P O
O
+
O P
O
O
Ca
O P
O
O
Ca
Aldol
R1
NC
R2
H
NC
R2
R1
O
_
H
O
H
O
dehydration
- H2O
R1
H
O
O
P O
O
CN
R2
O
O
O
O
O P
O
+
O P OH
O
O
Ca
P
Ca
O
+
H
3
3. Experimental
3.1. General
All reactions were run in dried glassware. Solvents were dried and distilled by standard procedures.
Reagents were purchased (Alfa Aesar or Sigma-Aldrich) and used without further purification. All
reactions were monitored by thin layer chromatography (TLC) plates (0.2 mm, silica gel 60). Flash
1
13
chromatography was performed using silica gel (60, 0.040–0.063 mm). H NMR and C NMR were
1
13
recorded on 200 and 500 instruments (200 and 500 MHz for H, 50 and 125 MHz for C). Chemical
shifts (δ) were reported in parts per million and the coupling constants were reported in hertz (Hz).
Reactions were irradiated in a multimode microwave oven (frequency: 2.45 GHz; maximal power:
1.250 kW).
3.2. Preparation of p-HAP100/300 and 800
The porous hydroxyapatite (denoted as p-HAp) was synthesized following a modified chemical
wet method reported elsewhere [44]. At 25 °C, Ca(OH)2 (0.5M) was first dissolved in an ethanol-
water mixture (1:1 volume ratio) and stirred for 3 hours. Aqueous solution of NH4H2PO4 (0.6M)
was then added to the Ca(OH)2 solution over a period of 24 h. The amount of reagents in the
solution were calculated to obtain a Ca/P molar ratio equals to 1.67, corresponding to a

Molecules 2010, 15
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stoichiometric hydroxyapatite. The pH of the slurry was measured during the precipitation reaction
at 25 °C, reaching a final value of ca. pH = 11. The precipitated crystals was aged for 24 h, filtered
and dried at 100 °C overnight. The obtained powder is calcined at 300 and 800 °C for 3 hours. The
data of these solids are described in our previous work [26].
The resulting p-HAP solids were characterized using X-ray powder diffraction (Philips PW131
diffractometer). The averge crystallite size of the precipitates was estimated by using the simple
Scherrer Equation D = Kλ/(β1/2 cosθ) where D is the size (in Ǻ), K the shape factor equals to 0.9, λ the
wavelength of X-rays equals to 1.5418 Ǻ, θ the diffraction angle for each reflexion and β1/2 is defined
as the the diffraction peak width at half height (in radian). The particule size of the powders was
analyzed by Dynamic Light Scattering on a Zetaplus (Broohaven Instruments) apparatus by
suspending the powder in water by sonication. Infrared spectra were recorded at a 2 cm-1 resolution
from 4000 to 400 cm-1 on a Bruker IFS 66v Fourier transform spectrometer using KBr pellets. The
phosphorus content was assayed by absorption photometry after formation of the yellow phosphato-
molybdic complex (λmax = 460 nm). The calcium content was determined by complexometric titration
with EDTA. Nitrogen adsorption isotherms were recorded at 77 K using a Micromeritics ASAP 2010
instrument. The specific surface areas (SSA) were calculated according to the Brunauer–Emmett–
Teller (BET) method using adsorption data in the relative pressure range from 0.05 to 0.25 whereas the
pore size and volume were estimated using the Barret-Joyner-Halenda (BJH) approximation.
3.3. Typical procedure for the Knoevenagel condensation
A mixture of malonitrile (2b, 79.3 mg; 1.2 mmol) and 4-nitrobenzaldehyde (1a, 151.1 mg,
1 mmol) was added to p-HAP300 (100 mg) in dichloromethane (5 mL). The solvent was
evaporated under reduced pressure at moderate temperature (28 °C) and then the mixture was
irradiated in a multimode microwave oven (frequency: 2.45 GHz; maximal power: 1.250 kW) for a
determined period of time and temperature (see Table 1). The reaction progress was followed by
TLC using n-hexane/ ethyl acetate (8:2) as eluent. After 2 min, the reaction vessel was cooled and
the product was washed with dichloromethane or ethyl acetate (2 × 10 mL). The extract was
filtered on a thin Celite bed and evaporated under reduced pressure to leave a pale yellow solid,
which was recrystallized from ethanol to give pure 4-nitrobenzylidenemalonitrile (3h, 192 mg,
1
96%) as pale yellow crystals, mp = 160–162 °C (Lit. [15a] 160 °C) H-NMR (CDCl3): δ 7.78 (s,
1H, CH=), 8.09 (d, 2H, J = 8.9 Hz, ArH), 8.38 (d, 2H, J = 8.9 Hz, ArH); IR (KBr): ν 3035, 2228,
1579, 1522 cm-1; EI-MS: m/z (%):199 (M+), 142; Anal. Calcd for C12H10N2O4: C, 58.54, H, 4.09;
Found: C, 58.65, H, 4.21.
4. Conclusions
In summary, we have reported an efficient and sustainable solvent-free Knoevenagel
condensation using a cooperative effect of MW activation and p-HAP300 catalysis. The procedure
is convenient and highly efficient since the title compounds are produced in good to excellent
yields after short reaction times. Moreover, p-HAP300 showed high thermal stability and can be
recovered by simple filtration and reused for at least ten reaction cycles without loss of activity.

Molecules 2010, 15
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Efforts to extend this green procedure to other functionnalised substrats including heteroaromatic
aldehydes and ketones are under way.
Acknowledgements
Financial support from Ministry of Education - Morocco (PROTARS III, D13/57), CNRST-
Morocco, CNRS, UNS, Conseil Régional PACA, MAE (PAI Volubilis and ARCUS-CERES) are
gratefully acknowledged.
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Sample Availability: Samples of all compounds are available from the authors.
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