Applied Catalysis A: General 228 (2002) 155–159

Hydroxyapatite as a new solid support for the Knoevenagel

reaction in heterogeneous media without solvent
Saı̈d Sebti∗ , Rachid Tahir, Rachid Nazih, Ahmed Saber, Saı̈d Boulaajaj
Laboratoire de Chimie Organique Appliquée et Catalyse, Faculté des Sciences Ben M’Sik,
Université Hassan II, BP 7955 Casablanca, Morocco
Received 24 July 2001; received in revised form 13 November 2001; accepted 14 November 2001

Abstract
The Knoevenagel condensation is easily carried out without a solvent at room temperature using hydroxyapatite (HAP).
Activation by water and benzyltriethylammonium chloride (BTEAC) has also been investigated. When used with water and
ammonium salt, hydroxyapatite is an excellent solid support for the Knoevenagel condensation, leading to excellent yields
in a few minutes. Taking into account environmental and economical considerations, the handling of hydroxyapatite used
here presents many advantages such as easier separation and recovery from the reaction mixture and thus, enhanced recycling
possibilities, which are now well established in fine organic synthesis. © 2002 Elsevier Science B.V. All rights reserved.
Keywords: Hydroxyapatite; Activation by ammonium; Activation by water; Solid support; Heterogeneous catalysis; Knoevenagel reaction

1. Introduction product plays the role of catalyst and solid support to

Heterogeneous catalysis is an important applica-
tion of porous solids possessing acid and base Lewis
sites. The reactions can be carried out with or with-
out a solvent. The appellation solid/liquid can even
be applied in absence of solvent. Indeed, the organic
substrates constitute the liquid phase and the mineral
reagent represents the solid phase. The reaction takes
place at the solid/liquid interface. In absence of sol-
vent, it is necessary to use a relatively large mass of
the mineral solid in order to adsorb completely the
organic substrates. A deficit of the solid slows down
the reaction rate and the reproducibility becomes
bad. An excess of the solid can adsorb strongly the
organics, leading to a reduction of yields. The mineral
∗ Corresponding author. Tel.: +212-61-46-48-19;
fax: +212-22-24-96-72.
E-mail address: saidsebti@yahoo.fr (S. Sebti).
organic substrates by behaving as a “solid solvent”.
When the mineral solid is not transformed during the
reaction, it can be considered as being a “catalyst”.
Usually, this word is used when a product is not either
transformed or regenerated after the reaction and in
this case, it is used in a small quantity.
In recent years, the Knoevenagel reaction in het-
erogeneous media has been carried out in presence of
alumina [1,2], silica [3], zinc and magnesium oxides
[4], resins [5] and other catalysts [6–18].
Recently, we have shown that natural phosphate,
trisodium phosphate and fluorapatite are excellent
catalysts of the Knoevenagel condensation [19,20].
These new phosphates catalysts have been used also
for the controlled hydration of nitriles to amides [21]
and the synthesis of ␣-hydroxyphosphonates [22].
Previously, we have shown that hydroxyapatite
(HAP) can be used as an acidic catalyst for the Friedel–
Crafts alkylation [23]. In this paper, we present the

0926-860X/02/$ – see front matter © 2002 Elsevier Science B.V. All rights reserved.
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156 S. Sebti et al. / Applied Catalysis A: General 228 (2002) 155–159
Scheme 1.
use of basic proprieties of HAP in the Knoevenagel
condensation. We describe also its activation by wa-
ter, benzyltriethylammonium chloride (BTEAC) and
both. The reaction is carried out without a solvent
between an aldehyde 1 and an activated methylene 2
(Scheme 1). Indeed, a series of hydroxyapatite cata-
lysts of varying Ca/P ratios were prepared and char-
acterised by a number of physical methods [24]. The
HAP has recently received much attention [25,26] in
view of its potential usefulness as adsorbent and most
importantly as catalyst in solid/gas reactions [27,28].
2. Experimental
2.1. Preparation and characterisation of HAP
The synthesis of hydroxyapatite [29,30] is carried
out by reaction between diammonium phosphate and
calcium nitrate in presence of ammonia (Scheme 2).
An amount of 250 ml of a solution containing 7.92 g of
diammonium hydrogen phosphate, maintained at a pH
greater than 12 by addition of ammonium hydroxide
(60–70 ml), were dropped under constant stirring into
150 ml of a solution containing 23.6 g calcium nitrate
[Ca(NO3 )2 ·4H2 O]. The suspension was refluxed for
4 h. Doubly distilled water (DDW) was used to prepare
the solutions. The hydroxyapatite crystallites were fil-
tered, washed with DDW, dried overnight at 80 ◦ C and
calcined in air at 700 ◦ C for 30 min before use.
Scheme 2.
The structure of obtained apatite was confirmed by
X-ray diffraction, infrared spectra and chemical anal-
ysis. The hydroxyapatite crystallises in the hexagonal
system with the space group P63 /m. The lattice param-
eters of the prepared HAP are in excellent agreement
with standard data: a = 6.883 Å and c = 9.422 Å.
Surface area of calcined HAP was determined by the
BET method from the adsorption–desorption isotherm
of nitrogen at its liquid temperature (77 K), and was
found to be S = 38.26 m2 g−1 . The total pore volume
was calculated by the BJH method at P/P0 = 0.98
(V T = 0.157 cm3 g−1 ). The basic properties of HAP
have been determined by the adsorption of phenol on
the HAP at 25 ◦ C as: 137 ␮mol g−1 (2 h).
2.2. General procedure for the Knoevenagel
condensation
To a flask containing an equimolar mixture
(1.5 mmol) of aldehyde 1 and nucleophile 2, the hy-
droxyapatite (1.25 g) was added and the mixture was
vigorously stirred at room temperature (20–25 ◦ C).
Workup included extraction with CH2 Cl2 , filtration
and evaporation. Products were subsequently purified
by distillation under vacuum or recrystallisation and
identified by 1 H, 13 C NMR and IR spectroscopy (all
the products 3 are known). The same procedure was
used for the reactions carried out with HAP (1.25 g)
activated with water (0.05 ml) and/or BTEAC (0.03 g).
Water was always added in the last place. The results
obtained are grouped in Table 1.
3. Results and discussion
The hydroxyapatite alone promotes the Knoeve-
nagel condensation but the reaction rates are relatively
slow. The yields exceed 80% when the reaction times
are prolonged, case of 3a–3c and 3h. For the other
cases, yields seem to be limited even if the time of the
reaction is prolonged. These results show that HAP
possesses a basic character and can be used in hetero-
geneous synthesis solid/liquid.
The solid support is particularly interesting when it
can be regenerated. In this case, HAP was regenerated,
by calcination at 700 ◦ C during 15 min, and after nine
successive recuperation, alkenes 3 are obtained with
the same yields.
 S. Sebti et al. / Applied Catalysis A: General 228 (2002) 155–159 157

Table 1
Synthesis of alkenes 3 by Knoevenagel condensation with HAP, HAP/water, HAP/BTEAC and HAP/BTEAC/water
Alkenes Yield in percent (time) (min)a,b

R1 R2 HAP HAP/water HAP/BTEAC HAP/BTEAC/water

3a Ph– –CN 24 (15) 83 (10) 87 (3) 96 (3)

80 (90) 95 (7)

3b –CN 23 (5) 80 (5) 82 (1) 98 (1)

83 (30) 90 (30) 97 (2)

3c –CN 59 (30) 89 (30) 74 (10) 93 (10)

86 (90)
3d Ph– CO2 Me 20 (30) 22 (30) 37 (20) 64 (20)
90 (60)c

3e CO2 Me 34 (30) 60 (30) 60 (5) 98 (5)

94 (7)

3f CO2 Me 50 (30) 53 (30) 69 (5) 81 (5)

97 (10)
3g Ph– CO2 Et 10 (30) 20 (30) 44 (20) 66 (20)
90 (60)c

3h CO2 Et 53 (30) 67 (30) 35 (5) 91 (5)

82 (90) 90 (7)

3i CO2 Et 26 (30) 36 (30) 59 (15) 76 (5)

94 (60)c
a Yields in products isolated by distillation under vacuum and identified by 1 H, 13 C NMR and IR spectroscopy.
b Reaction carried out at room temperature with 1.25 g HAP, 30 mg BTEAC and water (0.05 ml) per 1.5 mmol of reagents.
c HAP (1.5 g); BTEAC (60 mg) and water (0.05 ml).

We have shown that natural phosphate [31] and

fluorapatite [20] can be activated by water and/or
BTEAC. In the same conditions, we have carried out
the Knoevenagel condensation over the hydroxyap-
atite in presence of water, BTEAC or both.
Indeed, we have carried out the synthesis of alkene
3a (1.5 mmol substrates), without solvent and dur-
ing 15 min, in presence of hydroxyapatite (1.25 g).
Various quantities of water were used (Fig. 1). In
all cases, the yields are increased. The addition of
0.05 ml of water is the optimum. This activation is
probably due to the interaction between water and the
solid surface. A large amount of water becomes an
obstacle between the organic reagents and phosphate.
This system is three phase catalyst, the HAP as solid,
organics reagents and water. Its active site can be the
oxygen of PO4 and/or − OH. As fast as the Knoeve-
nagel condensation progress, the water formation can Fig. 1. Influence of water in the synthesis of alkene 3a.
158 S. Sebti et al. / Applied Catalysis A: General 228 (2002) 155–159

help to activate the catalytic system and the reaction

can be performed without adding of water. However,
the addition of small quantity of water as starting
material provokes an enhancement of reaction rate.
In the same conditions, we have synthesised the
other alkenes 3. A notable improvement of rate and/or
yields in alkenes 3 was observed except for 3d and 3f.
For alkenes, 3a–3c, the reaction rates are considerably
increased by addition of water. So, yields in percent
(time (min)) pass from 80 (90) to 83 (10); 83 (30) to
80 (5) and 86 (90) to 89 (30), respectively. For alkenes,
3e, 3g–3i, yields are increased, in 30 min reaction,
from 34 to 60%, 10 to 20%, 53 to 67% and 26 to 36%,
respectively. Nevertheless, yields cannot be increased
further, reactions seem to be blocked.
The addition of BTEAC provokes a very signifi-
Fig. 2. Synthesis of alkene 3g by HAP, water and various quantities
cant activation of hydroxyapatite in the synthesis of all of BTEAC.
alkenes 3. The yields and reaction rates are dramati-
cally improved. The yields exceed 90% in a few min-
utes for the synthesis of alkenes 3a, 3b, 3e and 3h. The
In presence of BTEAC, the activating role of water
activating role of ammonium salt is higher than water.
is observed (Table 1). For example, for alkenes 3a, 3c,
The simultaneous addition of water and ammonium
3e and 3h, the yields in percent (time) pass from 87
salt shows a clear superiority in the activation of the
(3) to 96 (3); 74 (10) to 93 (10); 60 (5) to 98 (5) and 35
hydroxyapatite. The reactions rates are improved and
(5) to 91 (5), respectively. These results may be due
the yields are very high for all alkenes and exceed
to the fact that water dissolves the ammonium salt and
90%. For the synthesis of alkenes 3d, 3g and 3i, the
facilitates its interaction with HAP, what can provoke
yields can be further improved when we increase the
the activation of this last. The role of water is observed
quantities of BTEAC. Indeed, we have carried out the
as well in presence as in absence of ammonium. In
synthesis of alkene 3g (1.5 mmol substrates), with-
all case, only E isomer of alkenes 3 was formed. The
out solvent and during 20 min, in presence of hy-
effect of water and ammonium salt is similar to that
droxyapatite (1.5 g), the water (0.05 ml) and various
quantities of BTEAC (Fig. 2). We observe that ad-
dition of BTEAC improves the yields in all case. A
weight of 0.06 g of ammonium is the optimum. When
the reaction was carried out only with water, BTEAC
or both without hydroxyapatite, reagents were recu-
perated. The catalytic activity of HAP/BTEAC and
HAP/BTEAC/water is not permanent. Indeed, the am-
monium salt can be easily lost by washing these sys-
tems with water. The calcinations at 700 ◦ C is neces-
sary to obtain a recoverable original catalyst (HAP),
which can easily promote this reaction after adding a
novel quantity of BTEAC.
The comparison of the activity of HAP, HAP/water,
HAP/BTEAC and HAP/BTEAC/water, in the syn-
thesis of alkene 3b is illustrated in the Fig. 3. The
activation of HAP with ammonium salt and water is Fig. 3. Synthesis of alkene 3b with HAP, HAP/water, HAP/BTEAC
higher than ammonium or water alone. and HAP/BTEAC/water.
 S. Sebti et al. / Applied Catalysis A: General 228 (2002) 155–159
observed in phase transfer catalyst (PTC) with very
large concentrations of surfactant [32,33] or in sup-
ported aqueous phase (SAP) catalysis used for hydro-
formylation [34,35], hydrogenation [36] and allylic
alkylation [37]. That suggests an great assistance effect
provided by ammonium cation contained in the water
film, to activate the carbonyl group of the aldehyde.
In the synthesis of alkene 3a, the yield (time)
obtained with HAP/BTEAC/water are equivalent
to that of natural phosphate [19] (90 (7)), fluorap-
atite/BTEAC/water [20] (98 (4)), MgO [4] (94 (5)),
Al2 O3 [1] (96 (3)) or Na2 CO3 /zeolite [18] (98 (15))
and greater to that of KF/Al2 O3 [2] (86 (150)),
AlPO4 /Al2 O3 [14] (80 (15)), resin [5] (92 (300)) and
zeolite [15] (78 (720)).
In summary, the activity of hydroxyapatite has been
improved by the addition of water or BTEAC. The
good conditions to promote the Knoevenagel conden-
sation are obtained by simultaneous addition of water
and BTEAC. The yields obtained are very high. The
hydroxyapatite is a new solid support of the Knoeve-
nagel condensation in heterogeneous media without
solvent, which can contribute to the development of
cleaner catalytic processes.
Acknowledgements
Financial assistance of the Ministry of Education,
Government of Morocco (PROTARS, P2T3/59) is
gratefully acknowledged. We thank also the “Office
Chérifien des Phosphates (OCP)” and the “Cen-
tre d’Etudes et de Recherches sur les Phosphates
Minéraux (CERPHOS)” for their support.
References
[1] F. Texier-Boullet, A. Foucaud, Tetrahedron Lett. 23 (1982)
4927.
[2] J. Yamawaki, T. Kawate, T. Ando, T. Hanafusa, Bull. Chem.
Soc., Jpn. 56 (1983) 1885.
[3] E. Angeletti, C. Canepa, G. Martinetti, P. Venturello,
Tetrahedron Lett. 29 (1988) 2261.
[4] H. Moison, F. Texier-Boullet, A. Foucaud, Tetrahedron 43
(1987) 537.
[5] T. Saito, H. Goto, K. Honda, T. Fujii, Tetrahedron Lett. 33
(1992) 7535.
[6] E. Kim, D.L. Gin, Polym. Mater. Sci. Eng. 79 (1998) 64.
[7] I. Rodriguez, H. Cambon, D. Brunel, M. Lasperas, J. Mol.
Catal. A: Chem. 130 (1998) 195.
159
[8] M. Lasperas, T. Llorett, L. Chaves, I. Rodriguez, A. Cauvel,
D. Brunel, Stud. Surf. Sci. Catal. 108 (1997) 75.
[9] M. Lakshmi Kantam, B.M. Choudary, C.V. Reddy, K.
Koteswara Rao, F. Figueras, Chem. Commun. (1998) 1033.
[10] D.J. Macquarrie, J.H. Clark, D.B. Jackson, A. Lambert, J.E.G.
Mdoe, A. Priest, Spec. Publ.: R. Soc. Chem. 216 (1998) 174.
[11] D.J. Macquarrie, J.H. Clark, A. Lambert, J.E.G. Mdoe, A.
Priest, React. Funct. Polym. 35 (1997) 153.
[12] K. Borszeky, T. Mallat, A. Baiker, Tetrahedron: Asymmetry
8 (1997) 3745.
[13] P. De la Cruz, E. Diez-Barra, A. Loupy, F. Langa, Tetrahedron
Lett. 37 (1996) 1113.
[14] J.A. Cabello, J.M. Campelo, A. Garcia, D. Luna, J.M.
Marinas, J. Org. Chem. 49 (1984) 5195.
[15] T.I. Reddy, R.S. Varma, Tetrahedron Lett. 38 (1997) 1721.
[16] I. Rodriguez, S. Iborna, A. Corma, F. Rey, J.L. Jorda, Chem.
Commun. (1999) 593.
[17] H.M. Wiame, C.M. Cellier, P. Grange, J. Phys. Chem. B 104
(2000) 591.
[18] B. Siebenhaar, B. Casagrande, M. Studer, H.-U. Blaser, Can.
J. Chem. 79 (2001) 566.
[19] S. Sebti, A. Saber, A. Rhihil, Tetrahedron Lett. 35 (1994)
9399.
[20] S. Sebti, R. Nazih, R. Tahir, L. Salhi, A. Saber, Appl. Catal.
A 197 (2000) L 187.
[21] S. Sebti, A. Rhihil, A. Saber, N. Hanafi, Tetrahedron Lett.
37 (1996) 6555.
[22] S. Sebti, A. Rhihil, A. Saber, M. Laghrissi, S. Boulaajaj,
Tetrahedron Lett. 37 (1996) 3999.
[23] S. Sebti, R. Tahir, R. Nazih, S. Boulaajaj, Appl. Catal. A 218
(2001) 25.
[24] J.A.S. Bett, L.G. Christner, W.K. Hall, J. Am. Chem. Soc.
89 (1967) 5535.
[25] M.E. Fleet, X. Liu, J. Solid State Chem. 149 (2000) 391.
[26] K. Kandori, A. Fudo, T. Ishikawa, Phys. Chem. Chem. Phys.
2 (2000) 2015.
[27] S. Sugiyama, T. Minami, T. Moriga, H. Hayashi, K. Koto,
M. Tamka, J.B. Moffat, J. Mater. Chem. 6 (1996) 459.
[28] S. Sugiyama, K. Abe, H. Hayashi, Y. Matsumura, J.B. Moffat,
J. Mol. Catal. A: Chem. 144 (1999) 347.
[29] T.S.B. Narasaraju, D.E. Phebe, J. Mater. Sci. 31 (1996) 1 and
references cited therein.
[30] K. Ishikawa, M. Kon, S. Tenshin, N. Kuwayama, Dent. Mater.
J. 9 (1990) 58.
[31] S. Sebti, A. Saber, A. Rhihil, R. Nazih, R. Tahir, Appl. Catal.
A 206 (2001) 217.
[32] D.H. Wang, H.S. Weng, Chem. Eng. Sci. 43 (1988) 2019.
[33] D. Mason, S. Magdassi, Y. Sasson, J. Org. Chem. 56 (1991)
7229.
[34] J.P. Arhancet, M.E. Davis, J.S. Merola, B.E. Hanson, J. Catal.
121 (1990) 327.
[35] G. Fremy, E. Monflier, J.F. Carpentier, Y. Castanet, A.
Mortreux, Angew. Chem. Ind. Ed. Engl. 34 (1995) 1474.
[36] E. Fache, C. Mercier, N. Pagnier, B. Despeyroux, P. Panster,
J. Mol. Catal. 79 (1993) 117.
[37] S. dos Santos, Y. Tong, F. Quignard, A. Choplin, D. Sinou,
J.P. Dutasta, Organometallics 17 (1998) 78.