Activated hydrotalcites as catalysts for the synthesis of chalcones of pharmaceutical interest

Article abstract of DOI:10.1016/j.jcat.2003.09.012

The Claisen-Schmidt condensation between benzaldehyde and acetophenone has been carried out in the presence of calcined-rehydrated hydrotalcites as solid-base catalysts. The rehydration method and the effect of the water content as well as the chemical composition of the rehydrated Al-Mg mixed oxides have been studied. The results showed that an Al-Mg mixed oxide with an Al/(Al+Mg) molar ratio of 0.25 with a water content of 35 wt% was the optimum catalyst which gives excellent activity for this type of condensation. This optimized catalyst has been applied to the synthesis of several chalcones with antiinflammatory, antineoplasic, and diuretic pharmacological activities achieving in all cases excellent activity and selectivity to the corresponding chalcones. A comparative study in the homogeneous phase using KOH as base catalyst showed that the rehydrated Al-Mg mixed oxides can compete with the conventional KOH when the reaction is performed at higher reaction temperatures. This behavior is not attributed to a lower intrinsic activity of the active sites on the solid, but to the small concentration of accessible active sites existing on the rehydrated sample.

Full text of DOI:10.1016/j.jcat.2003.09.012

Journal of Catalysis 221 (2004) 474–482
www.elsevier.com/locate/jcat
Activated hydrotalcites as catalysts for the synthesis of chalcones
of pharmaceutical interest
∗
M.J. Climent, A. Corma, S. Iborra, and A. Velty
Instituto de Tecnología Química, UPV-CSIC, Universidad Politécnica de Valencia, Avda. de los Naranjos s/n, 46022 Valencia, Spain
Received 7 May 2003; revised 7 August 2003; accepted 5 September 2003
Abstract
The Claisen–Schmidt condensation between benzaldehyde and acetophenone has been carried out in the presence of calcined-rehydrated
hydrotalcites as solid-base catalysts. The rehydration method and the effect of the water content as well as the chemical composition of the
rehydrated Al–Mg mixed oxides have been studied. The results showed that an Al–Mg mixed oxide with an Al/(Al+Mg) molar ratio of 0.25
with a water content of 35 wt% was the optimum catalyst which gives excellent activity for this type of condensation. This optimized catalyst
has been applied to the synthesis of several chalcones with antiinflammatory, antineoplasic, and diuretic pharmacological activities achieving
in all cases excellent activity and selectivity to the corresponding chalcones. A comparative study in the homogeneous phase using KOH
as base catalyst showed that the rehydrated Al–Mg mixed oxides can compete with the conventional KOH when the reaction is performed
at higher reaction temperatures. This behavior is not attributed to a lower intrinsic activity of the active sites on the solid, but to the small
concentration of accessible active sites existing on the rehydrated sample.

2003 Elsevier Inc. All rights reserved.
Keywords: Chalcone synthesis; Hydrotalcites as catalysts; Hydrotalcites for fine chemicals; Brönsted basic solid catalysts
1
. Introduction
eration of wastes can be avoided. The generation of wastes
can be important in the synthesis of fine chemicals and phar-
maceuticals, and they consist primarily of inorganic salts
such as sodium chloride, sodium sulfate, and ammonium
sulfate formed in the reaction or in subsequent neutralization
steps. The replacement of liquid by solid-base catalysts for
the production of fine chemicals not only allows easy separa-
tion and recycling of the catalyst from the reaction mixture,
but for many bimolecular reactions heterogeneous catalysts
can give better selectivity than homogeneous catalysts.
The use of basic solids, such as potassium carbonates [7],
barium hydroxides [8–10], alumina [11], MgO [12], cal-
cined hydrotalcites [13,14], and natural phosphates modi-
fied with sodium nitrate [15] or with KF [16], has received
much attention over the last years as potential catalysts for
Claisen–Schmidt condensations.
The Claisen–Schmidt (CS) condensation between ace-
tophenone and benzaldehyde derivatives is a valuable C–C
bond-forming reaction which allows α, β-unsaturated ke-
tones called chalcones to be obtained. Chalcones belong to
the flavonoid family which are synthesized in plants per-
forming diverse physiological functions such as attractants
of pollinators, UV protectors, and insect repellents. They
have found numerous applications as pesticides, photopro-
tectors in plastic, solar creams, food additives, and a plethora
of interesting biological activities (antimalarial [1], anti-
inflammatory [2], cytotoxic [3], anticancer [4], diuretic, and
choleretic [5,6]) have been reported.
Traditionally, the Claisen–Schmidt condensation is car-
ried out at 323 K using 10–60% of alkaline hydroxides or
sodium ethoxide over a period of 12–15 h [6]. It is widely ac-
cepted that there is a need to develop clean and economical
processes, where the use of noxious substances and the gen-
Solid-base catalysts, such as alkali-exchanged zeo-
lites [17], sepiolites [18], organic resins [19], magnesium
aluminum mixed oxides derived from hydrotalcites [20], and
more recently, aluminophosphatesoxinitrides (ALPON) [21]
which can cover a wide range of basic strengths, have been
used at the laboratory scale for different organic reactions.
*
Corresponding author.
E-mail address: acorma@itq.upv.es (A. Corma).
0021-9517/$ – see front matter  2003 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2003.09.012

M.J. Climent et al. / Journal of Catalysis 221 (2004) 474–482
475
Among them, calcined hydrotalcites are the most promising
2. Experimental
candidates for performing aldol condensations [22].
Hydrotalcites, Mg6Al2(OH)16CO34H2O, are hydrated
aluminum–magnesium hydroxides of lamelar structure, in
which the excess of positive charge, originating from the
2.1. Catalysts
Al–Mg hydrotalcites were prepared from gels produced
by mixing two solutions: solution A containing 3 − x mol of
Mg(NO ) · 6H O and x moles of Al(NO ) · 9H O in the
2
+
3+
Mg –Al substitution, is compensated by interlayer an-
ions such as carbonate anions. Its structure resembles that of
brucite, Mg(OH)2, where the magnesium cation is octahe-
drally coordinated by hydroxyl ions. Calcination over 800 K
decomposes reversibly the hydrotalcite into a high surface
area mixed magnesium–aluminum oxide which presents ba-
sic sites that are associated to structural hydroxyl groups
3
2
2
3 3
2
(Al + Mg) concentration of 1.5 mol/L for a ratio x/3:0.25
and 0.33, solution B containing of 6 + x mol of NaOH and
2 mol of Na CO dissolved in the same volume of the so-
2
3
lution A. Both solutions are coadded at a rate of 1 mL/min
under a vigorous mechanical stirring at room temperature.
The product was left at 333 K for 12 h. The hydrotalcite
formed was filtered and washed until the pH of the filtrate
was 7. The resultant solid was dried at 333 K for 12 h. The
hydrotalcite was activated by calcination at 723 K in a dry ni-
as well as strong Lewis basic sites associated to O2 Mn
−
+
acid–base pairs [23–25]. Calcined hydrotalcites are able to
catalyze aldol condensations such as the self-condensation
of acetone [26], acetaldehyde [27], the condensation of
formaldehyde and benzaldehyde with acetone [14,28], and
the Claisen–Schmidt condensation to obtain chalcones and
flavanones [13,14]. However, it has been reported recently
that the catalytic activity of calcined hydrotalcites can be
enhanced by rehydration at room temperature under exclu-
sion of CO2 [29]. This treatment results in the restoration
of the original layered structure where the compensating an-
◦
trogen flow. The temperature was raised at a rate of 2 C/min
to reach 723 K and was maintained at this temperature for
6 h. The solid was then cooled until room temperature and
used.
Rehydration of calcined hydrotalcites (HTc) was carried
out by two different methods: rehydration at room temper-
ature under a flow of nitrogen gas (40 mL/min) saturated
with water vapor for different times (HTc-R series) and by
directly adding different amounts of water on the calcined
hydrotalcite just before reaction (HTc-A series).
−
ions in the interlayer are OH . Although little is known up
to now about the nature and number of active Brönsted ba-
sic sites and the mechanism involved, this material is able to
catalyze aldol condensations such as the self-condensation
of acetone [30], benzaldehyde with acetone [14,29], citral
with acetone or methyl ethyl ketone [31], Knoevenagel con-
densations [32], and Michael additions [33].
The KF/Al2O3 sample with a 40 wt% of KF was pur-
chased from Aldrich.
X-ray diffraction measurements were recorded with a
Philips X’PERT (PN 3719) diffractometer (Cu-Kα radiation
provided by a graphite monochromator) equipped with an
automatic variable divergence slit and working in the con-
stant irradiated area mode.
Chemical analyses of the samples were performed by
atomic absorption after disintegration of the solids. N2 and
Ar adsorption/desorption isotherms were performed at 77
and 87.3 K, respectively, in an ASAP 2010 apparatus from
Micromeritics, after pretreating the samples under vacuum
at 673 K overnight (for the calcined hydrotalcites) and at
Concerning the Claisen–Schmidt condensation between
acetophenone and benzaldehyde, only one example of the
use of calcined-rehydrated hydrotalcites as basic catalyst
has been reported in the literature. The condensation was
carried using dimethylformamide as a solvent, at 273 K
and in the presence of a calcined hydrotalcite sample that
was rehydrated with a flow of nitrogen saturated with wa-
ter for 6 h. Under these reaction conditions it was possible
to achieve about 80% yield of chalcone after 3 h of reac-
tion time [34]. However, a “green” process would tend to
avoid the use of organic solvents. Along this line we have
shown that it is possible to prepare flavonoids using cal-
cined hydrotalcites as base catalysts in the absence of sol-
vent at temperatures between 423 and 443 K [13]. In the
present work we have attempted to optimize the activation
of double-layered materials as basic catalysts using the con-
densation between benzaldehyde and acetophenone as a re-
action test. The knowledge acquired from this study has been
used for the synthesis of chalcones with different chemical
structures, which exhibit anticancer and anti-inflammatory
activity [35,36]. Finally, the synthesis a commercial product
3
93 K (for the calcined-rehydrated hydrotalcites). The BET
surfaces were obtained using the BET methodology. The
physicochemical characteristics of the samples are summa-
rized in Table 1.
Table 1
Main physicochemical characteristics of the catalysts
Catalyst
Al/
Al + Mg)
0.25
0.33
0.25
0.25
Surface area
BET (m /g)
Average pore
diameter (Å)
2
(
HTc(0.25)
HTc(0.33)
HTc-R(0.25)
245
220
46
103
103
266
277
a
b
HTc-A(0.25)
a
30
ꢀ
ꢀ
called Vesidryl (2 ,4,4 -trimethoxychalcone) using the opti-
mized solid-base catalysts has been carried out successfully.
This product is of pharmacological interests because of its
diuretic and choleretic properties [5].
Rehydrated for 18 h at room temperature under a flow of nitrogen sat-
urated with water vapor (40 mL/min) (35 wt% of water content).
b
Rehydrated by directly adding 35 wt% of water on the calcined hydro-
talcite.

476
M.J. Climent et al. / Journal of Catalysis 221 (2004) 474–482
2
.2. Reaction procedure
Typically, a mixture of benzaldehyde (17.76 mmol), ace-
tophenone (14.8 mmol), and the catalyst was added in a
three-necked-bottom flask equipped with a condenser sys-
tem. The resultant suspension was heated up to the required
temperature under vigorous stirring in an oil bath equipped
with an automatic temperature control system. Samples were
taken at regular time periods and analyzed by gas chro-
matography (GC) using a FID detector and a Tracer-wax
column (15 m × 0.32 mm × 0.25 µm).The response fac-
tors were calculated for each reactive agent from pure sam-
ples. Reaction products were identified by GC-MS (Hewlett-
1
Packard 5988 A) and by H NMR spectroscopy (Varian
VXR-400S, 400 MHz).
Fig. 1. Yield of chalcone 3 versus reaction time obtained in the condensa-
tion between acetophenone and benzaldehyde at 423 K in the presence of
24-h rehydrated hydrotalcite (HTc-R(0.25)) (!) and calcined hydrotalcite
(HTc(0.25)) (1).
2
.3. Synthesis of Vesidryl in the homogeneous phase
As can be observed in Fig. 1, there is a clear improve-
Typically 2.36 mmol of KOH in 2 mL of hydroalco-
holic solution (50%) was added to a mixture of anisaldehyde
10.5 mmol) and 2,4-dimethoxyacetophenone (10.5 mmol),
ment in the catalytic activity when the calcined hydrotalcite
is rehydrated, while the selectivity to chalcone is the same
on the two catalysts. This increase in activity due to rehy-
(
and the mixture was stirred at 298 K. Samples were taken at
regular time periods and analyzed by gas chromatography.
After a 6-h reaction time, the catalyst was neutralized with
an aqueous solution of hydrogen chloride, and the aqueous
layer was extracted two times with dichloromethane. The or-
ganic layer was dried with anhydrous sodium sulfate. After
solvent evaporation, the organic residue was weighed and
−
dration has been attributed to the presence of OH anions
which present Brönsted basicity and therefore high activity
in aldol-type reactions [29].
The high activity exhibited by the calcined-rehydrated
hydrotalcite allows a decrease of the reaction temperature
and, in order to select the most appropriate, the condensation
between acetophenone and benzaldehyde was carried out at
1
analyzed by GC and H RMN.
3
03, 323, 343, and 373 K, using 15% of HTc(0.25) sample
which was rehydrated for 24 h.
In Fig. 2, yields of chalcone (3) versus time at different
reaction temperatures are presented. These results show that
using a rehydrated hydrotalcite it is possible to reduce the
reaction temperature to 323 K, achieving under these condi-
tions practically total conversion after a 2-h reaction time.
From this study it was possible to calculate the apparent
activation energy of 39.80 kJ/mol which is very similar to
that reported previously in the literature using solid-base ca-
3
. Results and discussion
The Claisen–Schmidt condensation between acetophe-
none (1) and benzaldehyde (2) (Scheme 1) was first carried
out at 423 K, in the absence of solvent and in the presence
of 10 wt% of either a calcined hydrotalcite (HTc(0.25)) or
the corresponding rehydrated sample (HTc-R(0.25) for 24 h.
With this last catalyst the reaction gives trans-chalcone (3),
and the mechanism generally accepted involves the forma-
tion of the anion of acetophenone followed by its attack to
the carbonyl group of benzaldehyde. The yield of chalcone
versus time obtained is displayed in Fig. 1 and compared
with that obtained using the calcined hydrotalcite precur-
sor as catalyst. Neither benzyl alcohol nor benzoic acid were
observed in the reaction products with either of the two cat-
alysts, indicating that the Cannizaro reaction does not take
place under these conditions.
Fig. 2. Influence of the temperature on the yield of chalcone 3 in the pres-
ence of 24-h rehydrated hydrotalcite (HTc-R(0.25)), at 303 (1), 323 (!),
343 (E), and 373 (×).
Scheme 1.

M.J. Climent et al. / Journal of Catalysis 221 (2004) 474–482
477
Table 2
Claisen–Schmidt condensation between benzaldehyde (18.5 mmol) and
acetophenone (14.8 mmol) using calcined HTc(0.25) (15 wt%) with dif-
ferent amounts of water content at 323 K
Rehydration
time (h)
Water content
(wt%)
r
Yield (%)
to 3 (1 h)
0
4
×10 (mol/(min g))
0
6
0
20
25
35
47
82
0.28
1.9
2.7
5.2
4.0
3.1
4
47
64
82
73
50
12
18
24
48
stroyed during calcination at 723 K, and it is converted in
a mixed oxide of the Mg(Al)O type. The original layered
structure is restored to a large extent by rehydration of the
calcined solid, giving a meixnerite-like structure where the
weak base carbonate anions have been replaced by the strong
−
Brönsted OH sites. Moreover, a strong decrease in sur-
2
2
face area from 245 m /g after calcinations to 46 m /g after
8 h of rehydration is observed, as a consequence of the
1
closure of micropores and mesopores by agglomeration of
platelets [38]. These different rehydrated hydrotalcites were
tested at 323 K using a benzaldehyde/acetophenone ratio of
1.2. In Table 2 the initial rate of formation of chalcone per
gram of HTc(0.25) as a function of the water content and the
yield of chalcone after 1 h of reaction time are reported. As
we can observe, the activity of the calcined sample (mixed
oxide) is very low, but activity and yield of chalcone increase
when increasing the amount of water added until reaching a
maximum for 35 wt% of water (18 h of rehydration), after
which the activity decreases progressively when increasing
the water added. After this maximum we can suppose that
there is an excess of water on the catalyst surface that nega-
tively affects the active sites and the reaction equilibrium.
Fig. 3. Powder X-ray diffraction patterns of hydrotalcite after synthesis,
calcination, and rehydration for different periods of time.
talysts [9,14], as well as for other condensations of this type
in the homogeneous phase [37], indicating that the reaction
was not limited by either external or internal diffusion on the
solid catalyst.
3
.1. Influence of the water content of calcined-rehydrated
hydrotalcites
Since water is also a product in the Claisen–Schmidt
condensation it is of interest to study the influence of the
water content in the rehydrated sample on the rate of reac-
tion. Thus, we have studied the influence of the rehydration
time, and consequently the influence of the amount of water
content over the calcined hydrotalcite, on activity and selec-
tivity. Owing to the fact that water reacts with the catalyst
surface activating the basic sites and that water is also a re-
action product, a maximum in activity for an optimum water
content of the catalyst should be expected. Indeed an excess
of water on the catalyst surface could cause, besides the poi-
soning of the active basic sites, the shifting of the reaction
equilibrium toward the formation of reagents.
3
.2. Influence of the rehydration methodology
At this point it is seen that the most active HTc-R sam-
ple has 35% of water content. However in order to achieve
this level of catalyst activation a lengthy (18 h) rehydration
treatment was needed when following the reported proce-
dure [29]. With the aim of finding a faster and easy workup
rehydration procedure we have studied the possibility of ac-
tivating the HTc samples by a simple water addition on
the freshly calcined hydrotalcite. Then, in a given amount
(15 wt%) of HTc(0.25) sample, different amounts of water
were dropped just before the addition of reagents (HTc-
A(0.25) series).
The study was carried out starting from the HTc(0.25)
sample. Equivalent amounts of this catalyst were rehydrated
at room temperature in the absence of any CO2 for 6, 12, 18,
The results of initial rate versus water content of the
samples are displayed in Fig. 4. As one can observe, when
the percentage of water content is low (20 and 25%) there
is a difference in the initial activity between the samples
rehydrated with a stream of nitrogen saturated with water
(HTc-R(0.25)) and the samples rehydrated by directly drop-
ping the water on them (HTc-A(0.25)) that are more active.
This result could indicate that by treating at short times the
2
4, and 48 h in a stream of nitrogen saturated with water va-
por at 295 K. The X-ray diffraction patterns of hydrotalcites
after synthesis, calcination, and rehydration for different pe-
riods of time are presented in Fig. 3. It can be observed
that the layered crystalline structure of hydrotalcite is de-

478
M.J. Climent et al. / Journal of Catalysis 221 (2004) 474–482
ethanol and dried under an argon flow at room temperature.
After this treatment, the solid (called as HTc-I(0.25) sample)
had a water content of 40 wt%. The results of activity ob-
tained with the HTc-I(0.25) sample for the Claisen–Schmidt
condensation were compared with those obtained using a
HTc-A(0.25) sample prepared by adding 40 wt% of water,
and we found that after 2 h of reaction time the HTc-A
sample gives 92% of chalcone, whereas the HTc-I sample
achieves 72%.
From these results we can conclude that the hydrotalcite
activation method by in situ dropping the water to the mixed
oxide allows us to achieve a high yield and selectivity of
chalcone at very reasonable reaction times and temperatures,
showing that this is an interesting alternative to the use of
other rehydration methods reported previously for the acti-
vation of hydrotalcites.
Fig. 4. Influence of water content (wt%) of the calcined hydrotalcite
HTc(0.25)) on the initial rate of formation of chalcone 3 at 323 K in the
presence of HTc-R series (") and HTc-A series (!).
(
calcined hydrotalcite with nitrogen saturated with water va-
por, a low reconstruction degree of the hydrotalcite could be
3
.3. Influence of the chemical composition of the
−
achieved, which means a low density of available OH sites
rehydrated hydrotalcite catalyst
and therefore lower catalytic activity. On the other hand, the
water directly dropped on the catalyst reacts instantly with
the most accessible oxygen anions at the surface, generat-
ing Brönsted basic sites that could be easily accessible to
acetophenone reagent. However, for values of water con-
tent equal or higher than 35%, both series (HTc-R(0.25) and
HTc-A(0.25)) exhibit similar behavior, achieving the max-
imum activity for the same value of water content which
corresponds to 35 wt%. In fact, when the kinetic behavior
of the two most active samples rehydrated following both
methods are compared (Fig. 5) we can see that they display
the same activity, achieving a 98% yield of chalcone after 4 h
of reaction time. These results are in good agreement with
the X-ray diffraction patterns of both samples that show the
same reconstruction level.
In order to study the influence of the chemical compo-
sition of hydrotalcite catalyst on the activity and selectivity
to chalcone, we prepared a second hydrotalcite sample with
an Al/(Al + Mg) ratio of 0.33 (HTc(0.33)), and after calci-
nation and rehydration, its activity for the Claisen–Schmidt
condensation between acetophenone and benzaldehyde was
compared with that obtained with the rehydrated HTc(0.25)
sample. The reaction was carried out with 7 wt% of catalyst,
at 323 K and both catalyst samples were activated by adding
3
5 wt% of water just before reaction. In Fig. 6 it is possible
to see that for the same amount of water content, the hydro-
talcite sample with a lower Al/(Al + Mg) ratio displays a
superior activity.
Owing to the fact that the number of compensating hy-
droxyl groups increases when increasing the Al/Mg ratio
in the meixnerite-like form, it could be expected in prin-
ciple, that with the sample with a higher Al/Mg ratio, the
amount of water content giving the maximum catalytic activ-
For comparison purposes, another rehydration methodol-
ogy of hydrotalcites which has been previously reported [38]
was carried out. Thus, the HTc(0.25) sample was immersed
in CO2-free water (100 mL/g) and stirred under an argon at-
mosphere for 1 h at room temperature. After filtration under
inert atmosphere, the catalyst was thoroughly washed with
Fig. 5. Yield of chalcone versus reaction time when Claisen–Schmidt con-
densation was carried out at 323 K in the presence of 18-h rehydrated
hydrotalcite (35 wt%) (HTc-R(0.25)) ("), and calcined hydrotalcite with
Fig. 6. Influence of the Al/(Al + Mg) ratio on the yield of chalcone 3 when
the condensation was carried out using HTc(0.25) (!) and HTc(0.33) (1)
with 35% water added, respectively.
35 wt% water added (HTc-A(0.25)) (!).

M.J. Climent et al. / Journal of Catalysis 221 (2004) 474–482
479
isophorone isomerization [40], where the authors found a
maximum activity for a calcined-rehydrated hydrotalcite
with an Al/(Al + Mg) ratio of 0.25.
3
.4. Preparation of chalcones with biological activity using
calcined-rehydrated hydrotalcites
Recently, chalcone derivatives are attracting important at-
tention due to the numerous pharmacological studies con-
cerning their anti-AIDS, anti-inflammatory, anticancer, and
antibacterial activity. Moreover, they are important interme-
diates in much pharmaceutical synthesis. Thus, the knowl-
edge acquired in the previous part of the work was extrapo-
lated here to prepare a variety of recently reported chalcones
that present anticancer [35] and anti-inflammatory [36] ac-
tivity (see Table 3).
Fig. 7. Influence of water added (wt%) to HTc(0.33) on yield of chalcone 3;
!) 34 wt%; (×) 43 wt%; (1) 60 wt%; (E) 77 wt%.
(
ity should be shifted toward higher values than those found
for the sample with lower Al/Mg ratios. Indeed, when the
influence of water content of the HTc(0.33) on the catalytic
activity was studied, we found (Fig. 7) that for this sam-
ple 60 wt% of water was necessary to be added in order
to achieve the best catalytic activity. In any case, the cata-
lytic activity is lower than that of the HTc-A(0.25) with
the optimum level of rehydration (35 wt% of water). These
results indicate that, as in the case of calcined hydrotal-
The condensations were carried out at different reaction
temperatures using a HTc-A(0.25) with a 35 wt% of wa-
ter content and, when it was possible, in the absence of
solvent (Table 3). No by-products coming from ketone self-
condensation or Cannizaro’s reaction were detected, achiev-
ing maximum selectivity in all cases. The activity shown
by the basic catalyst for these condensations, as well as the
yield of chalcone derivative obtained for each substrate, is
well correlated with the acidity of the α-hydrogen of the
corresponding alkyl aryl ketone (Fig. 8) and/or with the pos-
itive charge density bearing on the carbon in the carbonyl
group of the aromatic aldehyde. Thus, the β-diketone (en-
try 4) gives the bests results, achieving a 93% yield of chal-
−
cites, the basicity of the regenerated OH hydrotalcites
strongly depends on their chemical composition. These re-
sults are in good agreement with those previously reported
for the condensation of benzaldehyde and acetone [39] and
Table 3
a
Synthesis of chalcone derivatives using a regenerated hydrotalcite by the addition of water
Entry
1
Aldehyde
Alkyl aryl ketone
Chalcone derivative
T (K)
Yield (%)
87 (2 h)
Selectivity (%)
99
333
2
3
333
68 (2 h)
99
99
99
99
99
333
26 (7 h)
60 (7 h)
88 (7 h)
373
393
b
b
2
3
98
33
95 (7 h)
93 (1 h)
99
99
4
3
3
33
73
45 (7 h)
75 (4 h)
99
99
5
a
Reaction conditions: ketone (10 mmol); aldehyde (10 mmol), using HTc(0.25), (10 wt%) with 35 wt% of water ((HTc-A(0.25) sample). Reactions were
carried out in absence of solvent except for entry 4.
b
1
0 mL of CH Cl as a solvent.
2 2

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M.J. Climent et al. / Journal of Catalysis 221 (2004) 474–482
Fig. 8. Positive charge density of the α-hydrogen of different alkyl aryl
ketones versus their corresponding initial rates of condensation with ben-
zaldehyde; tetralone ("); acetophenone (2), and 1,3-indandione (Q).
Fig. 9. Yield of Claisen–Schmidt condensation between benzaldehyde with
acetophenone (Q) and acetonaphthone (×) versus reaction time using
(KOH) as homogeneous catalyst. Reaction conditions: 10 mmol aldehyde,
−
1
0 mmol aryl ketone in 5 × 10 4 mol of KOH in 2 mL of ethanol at 298 K.
cone at 333 K after a 1-h reaction time, whereas in order
to achieve a good yield for the condensation of benzalde-
hyde with the tetralone (entry 3) it was necessary to increase
the temperature to 393 K. When benzaldehyde was substi-
tuted by 2-pyridil carboxyaldehyde (entry 5) a decrease in
activity was observed. This behavior must be correlated with
the lower positive charge density bearing on the carbon of
the carbonyl group in the 2-pyridil derivative (+0.30) with
respect to benzaldehyde (+0.33). Finally, it is interesting
to note the different yield obtained for acetophenone and
acetonaphthone (entries 1 and 2) despite the fact that the
acidity of the α-hydrogens at the methyl group should be
the same for both reactants. In fact, an additional experi-
ment carried out in the homogeneous phase using KOH as
catalyst showed that both molecules have the same reactiv-
ity (Fig. 9). Therefore, we must conclude that the differences
in conversion obtained with these two reactants on the solid
catalyst are not related to differences of intrinsic reactivity
of the molecules, but should be related to geometrical con-
straints for adsorption on the catalyst surface. Perhaps the
most bulky acetonaphthone has lesser accessibility to the ac-
tive sites than acetophenone, for this reason decreasing the
final yield to the corresponding chalcone derivative.
applying the catalyst optimized in this work for the synthe-
sis of Vesidryl, the reaction between 4 and 5 was carried
out using a HTc(0.25) sample, which was activated in situ
by the addition of 35 wt% of water. The reaction was per-
formed in the absence of solvent, using 12 wt% of catalyst
and 353 K.
In Table 4 the results obtained with this calcined-rehydra-
ted hydrotalcite are compared with those obtained with a
homogeneous base and other heterogeneous catalysts such
as KF/alumina, and the calcined hydrotalcite precursor.
Results in Table 4 show that KF/alumina and rehydrated
hydrotalcite are the most active solid-base catalysts. How-
ever, rehydrated hydrotalcite exhibiting Brönsted basic sites
gives higher selectivity to Vesidryl (99%) than the former
(
62%) and is much more active than the calcined sample.
The high activity of KF-alumina was expected considering
the high activity shown by this material in Michael addi-
tions or aldol condensations [41] that require strong basic-
ities. In fact, with this catalyst it was possible to achieve
9
0% conversion of dimethoxyacetophenone (4) within 1 h
Table 4
Synthesis of Vesidryl on different catalysts
Finally, we have tested the activity of the rehydrated hy-
drotalcite for preparing Vesidryl. As we said above, Vesidryl
Entry
Catalyst
Catalyst Time
T
Yield of 6 Selectivity
(wt%)
(h)
(K)
(%)
to 6 (%)
ꢀ ꢀ
(
2 ,4,4 -trimethoxychalcone) (6) (Scheme 2) is a chalcone
1
2
3
4
5
6
HTc-A(0.25)
HTc(0.25)
KF/Al O
12
12
12
4
0.2
57
2
4
1
2
6
4
353
393
353
353
393
298
57
20
56
77
6
99
99
62
99
100
98
with a pharmaceutical interest owing to its choleretic and
diuretic properties. This compound is obtained by Claisen–
Schmidt condensation between 2,4-dimethoxyacetophenone
2
3
KOH
KOH
KOH
(
4) and 4-methoxybenzaldehyde(5) under base catalysis and
90
more specifically using KOH as catalyst. With the aim of
Scheme 2.

M.J. Climent et al. / Journal of Catalysis 221 (2004) 474–482
481
4
. Conclusions
We have seen that partially regenerated hydrotalcites pre-
pared by fast rehydration of the calcined mixed oxides are
active and selective catalysts for CS condensations. Opti-
mized rehydrated catalysts required an optimum amount of
water added, which is a function of the chemical composi-
tion Al/(Al + Mg) ratio of the precursor.
The optimized hydrotalcite catalysts can successfully be
applied to the synthesis of chalcones with anti-inflammatory,
anticancer, and diuretic pharmacological activities. These
solid catalysts can only compete with the conventionally
used KOH when the former are used at higher reaction tem-
peratures. This is not due to a lower intrinsic activity of the
active sites in the rehydrated hydrotalcite, but to the small
amount of the active sites accessible to the reactants in the
solid catalyst. It becomes evident to us that delaminated hy-
drotalcites or hydrotalcites with smaller crystallites should
be prepared in which the number of accessible active sites
would be larger.
Fig. 10. Yield of Vesidryl versus reaction time when the condensation was
performed using a HTc-R(0.25) sample with 35 wt% water content at 373 K
(!) and 408 K (1).
of reaction time. However, the presence of strong basic sites
should be responsible for its low selectivity to Vesidryl (6),
due to the consecutive Michael addition of the acetophe-
none derivative of the Vesidryl. The results from Fig. 10
show that it is possible to achieve more than 90% yield of
Vesidryl with 99% selectivity within 4 h, on the rehydrated
hydrotalcite when the reaction temperature is increased to
Acknowledgment
The authors thank the Spanish CICYT for financial sup-
port (Projects MAT2000-1392).
4
08 K.
For comparison purposes, the reaction was also per-
formed in the homogeneous phase using a strong conven-
tional base (KOH). In this case, the amount of base used was
the equivalent in moles to the amount of Al content in the
rehydrated hydrotalcite, and at 353 K, a good conversion to
Vesidryl was observed (Table 4, entry 4). However, when the
amount of KOH was decreased 20-fold, which corresponds
to the theoretical 5% accessible Brönsted basic sites exist-
ing in the rehydrated hydrotalcite [42], the Claisen–Schmidt
condensation did not occur at 353 K in the time periods stud-
ied, and only when the temperature was increased to 393 K,
References
[1] R. Li, G.L. Kenyon, F.E. Cohen, X. Chen, B. Gong, J.N. Dominguez,
E. Davison, G. Kurzban, R.E. Miller, E.O. Nuzman, J. Med. Chem. 38
(1995) 5031.
[2] J.F. Ballesteros, M.J. Sanz, A. Ubeda, M.A. Miranda, S. Iborra, M.
Paya, M.J. Alcaraz, J. Med. Chem. 38 (1995) 2794.
[3] (a) C.C. Yit, N.P. Das, Cancer Lett. 82 (1994) 65;
(b) Y. Satomi, Int. J. Cancer 55 (1993) 506;
(c) J.R. Dimmock, N.M. Kandepu, M. Hetherington, J.W. Quail, U.
Pugazhenthi, A.M. Sudom, M. Chamankhah, P. Rose, E. Pass, T.M.
Alle, S. Halleran, J. Szydlowski, B. Mutus, M. Tannous, E.K. Mana-
vathu, T.G. Myers, E.D. Clercq, J. Balzani, J. Med. Chem. 41 (1998)
6
% of chalcone was detected after a 6-h reaction time (en-
1014.
try 5). These results agree with those recently reported by
Roelofs et al. for the self-condensation of acetone using re-
generated hydrotalcites as catalysts, where they concluded
that the activation of calcined hydrotalcites by rehydration
[4] (a) L.W. Wattenberg, J.B. Coccia, A.R. Galhaith, Cancer Lett. 83
(1994) 165;
(b) A.T. Dinkova-Kostova, C. Abeygunawardana, P. Talalay, J. Med.
Chem. 41 (1998) 5287.
−
[5] B. Chabannes, M. Grandgeorge, B. Duperray, H. Pacheco, Fr. Chim.
Ther. 8 (1973) 621.
implies not only the incorporation of OH as an interlayer
anion, but the calcination-rehydration process of the layered
double hydroxide precursor gives rise the formation of an
irregular structure which leads to an increase of the basic
[6] (a) D.N. Dhar, Chemistry of Chalcones and Related Compounds, Wi-
ley, New York, 1981;
(b) J.B. Harbone, T.J. Mabry, The Flavonoids: Advances in Research,
Chapman & Hall, New York, 1982.
−
strength of the OH near the edges of HT platelets. This is
[7] W. Rochus, N. Kickuth, German patent 1,095,832, 1957.
[8] S. Sathyanarayana, A.G. Krishnamurty, Curr. Sci. 57 (1988) 1114.
[9] A. Aguilera, A. Alcantara, J.M. Marinas, J.V. Sinisterra, Can. J. Chem.
responsible of the high activity exhibited by the materials
in aldol condensation reactions [43]. Finally, from Table 4,
we can see that working with KOH as catalyst it is possible
to obtain a good yield of Vesidryl working at room temper-
ature (entry 6). However in this case a high concentration
of base should be used, with the corresponding negative ef-
fects on product separation and catalyst neutralization and
disposal.
6
5 (1987) 1165.
[10] A. Fuentes, J.M. Marinas, J.V. Sinisterra, Tetrahedron Lett. 28 (1987)
541.
11] R.S. Varma, G.W. Kabalka, L.T. Evans, R.M. Pagni, Synth. Commun.
5 (1985) 279.
12] M.T. Drexler, M.D. Amiridis, Catal. Lett. 79 (2002) 175.
4
[
[
1
[13] M.J. Climent, A. Corma, S. Iborra, J. Primo, J. Catal. 151 (1995) 60.

482
M.J. Climent et al. / Journal of Catalysis 221 (2004) 474–482
[
14] A. Guida, M.H. Lhouty, D. Tichit, F. Figueras, P. Geneste, Appl. Catal.
A 164 (1997) 251.
[30] R. Teissier, D. Tichit, F. Figueras, J. Kervennal, FP 2729137, 1995.
[31] (a) M.J. Climent, A. Corma, S. Iborra, A. Velty, Green Chem. 4 (2002)
474;
(b) M.J. Climent, A. Corma, S. Iborra, A. Velty, Catal. Lett. 79 (2002)
157.
[32] M.L. Kantam, B.M. Choudary, C.V. Reddy, K.K. Rao, F. Figueras,
Chem. Commun. (1998) 1033.
[15] (a) S. Sebti, A. Solhy, R. Tahir, S. Boulaajaj, J.A. Mayoral, J.M. Fraile,
A. Kossir, H. Oumimoun, Tetrahedron Lett. 42 (2001) 795;
(
b) S. Sebti, A. Solhy, R. Tahir, S. Abdelatif, S. Boulaajaj, J.A. May-
oral, J.I. García, J.M. Fraile, A. Kossir, H. Oumimoun, J. Catal. 213
2003) 1.
(
[
[
16] D.J. Macquarrie, R. Nazih, S. Sebti, Green Chem. 4 (2002) 56.
17] A. Corma, V. Fornés, R.M. Martín-Aranda, H. García, J. Primo, Appl.
Catal. 59 (1990) 237.
[33] B.M. Choudary, M.L. Kantam, C.V. Reddy, K.K. Rao, F. Figueras,
J. Mol. Catal. A 146 (1999) 279.
[34] J. Lopez, R. Jacquot, F. Figueras, Stud. Surf. Sci. Catal. 130 (2000)
491.
[35] P.J. Bowen, T.P. Robinson, T. Ehlers, D. Goldsmit, J. Arbiser, WO
0146110, 2001.
[
[
18] A. Corma, R.M. Martín-Aranda, J. Catal. 130 (1991) 130.
19] K. Tanabe, in: B. Imelik, et al. (Eds.), Catalysis by Acids and Bases,
Elsevier, Amsterdam, 1985, p. 1.
[
20] (a) A. Corma, V. Fornés, R.M. Martín-Aranda, F. Rey, J. Catal. 134
[36] D.G. Batt, R. Goodman, D.G. Jones, J.S. Kerr, L.R. Mantegna, C.R.
Mcallister, C. Newton, S. Nurnberg, P.K. Welch, M.B. Covington,
J. Med. Chem. 36 (1993) 1434.
(1992) 58;
(b) A. Corma, V. Fornés, F. Rey, J. Catal. 148 (1994) 205.
[
21] M.J. Climent, A. Corma, A. Frau, V. Fornés, R. Guil, S. Iborra, J. Pri-
mo, J. Catal. 163 (1996) 392.
[37] J.D. Gettler, L.P. Hammett, J. Am. Chem. Soc. 65 (1943) 1824.
[38] J.C.A.A. Roelofs, A.J. van Dillen, K.P. de Jong, Catal. Lett. 74 (2001)
91.
[22] W.T. Reichle, J. Catal. 94 (1985) 547.
[
23] D. Tichit, M.N. Bennani, F. Figueras, J.R. Ruiz, Langmuir 14 (1998)
[39] J. Lopez, J. Sanchez-Valente, J.M. Clacens, F. Figueras, J. Catal. 208
(2002) 30.
2086.
[
[
[
[
[
[
24] A.L. McKenzie, C.T. Fishel, R.J. Davis, J. Catal. 138 (1992) 547.
25] V. Constantino, T. Pinnavaia, Catal. Lett. 23 (1994) 361.
26] W.T. Reichle, S.Y. Kang, D.S. Everhardt, J. Catal. 101 (1986) 352.
27] W. Kagunya, W. Jones, Appl. Clay Sci. 10 (1995) 95.
28] E. Suzuki, Y. Ono, Bull. Chem. Soc. Jpn. 61 (1988) 1008.
29] K.K. Rao, M. Gravelle, J. Valente, F. Figueras, J. Catal. 173 (1998)
[40] F. Figueras, J. Lopez, J. Sanchez-Valente, T.T.H. Vu, J.M. Clacens,
J. Palomeque, J. Catal. 211 (2002) 144.
[41] J.H. Clark, Chem. Rev. 80 (1980) 429.
[42] J.C.A.A. Roelofs, A.J. van Dillen, K.P. de Jong, Catal. Today 60
(2000) 297.
[43] J.A.A. Roelofs, D.J. Lensveld, A.J. van Dillen, K.P. de Jong, J. Ca-
tal. 203 (2001) 184.
115.