A green approach to the synthesis of chalcones via Claisen-Schmidt condensation reaction using cesium salts of 12-tungstophosphoric acid as a reusable nanocatalyst

Article abstract of DOI:10.1007/s00706-012-0814-5

The catalytic efficacy of different cesium salts of 12-tungstophosphoric acid as nanocatalysts was checked in Claisen-Schmidt condensation of aldehydes and ketones under solvent-free conditions to produce chalcones. The reaction is fast and environmentally benign with excellent selectivity for the synthesis of chalcones. Results of potentiometric titration and catalytic reactivity of the catalysts indicated that the catalytic reactivity should be directly proportional to the strength and number of the surface acid sites, which are the ones accessible to the reactants. Reusability of the catalysts and acidic properties of reused catalysts were investigated. Coking could cause a loss in catalyst acidity, leading to a decrease in the product yield. But the amount of coke remains constant in successive runs. Furthermore, the use of this catalyst is feasible because of its easy preparation and handling, and stability. Large-scale synthesis is also beneficial in this method. Two new compounds are synthesized and fully characterized. .

Full text of DOI:10.1007/s00706-012-0814-5

Monatsh Chem (2013) 144:361–367
DOI 10.1007/s00706-012-0814-5
ORIGINAL PAPER
A green approach to the synthesis of chalcones via Claisen-Schmidt
condensation reaction using cesium salts of 12-tungstophosphoric
acid as a reusable nanocatalyst
•
Ezzat Rafiee Farzaneh Rahimi
Received: 20 October 2011 / Accepted: 1 July 2012 / Published online: 9 August 2012
Ó Springer-Verlag 2012
Abstract The catalytic efficacy of different cesium salts
of 12-tungstophosphoric acid as nanocatalysts was checked
in Claisen-Schmidt condensation of aldehydes and ketones
under solvent-free conditions to produce chalcones. The
reaction is fast and environmentally benign with excellent
selectivity for the synthesis of chalcones. Results of
potentiometric titration and catalytic reactivity of the cat-
alysts indicated that the catalytic reactivity should be
directly proportional to the strength and number of the
surface acid sites, which are the ones accessible to the
reactants. Reusability of the catalysts and acidic properties
of reused catalysts were investigated. Coking could cause a
loss in catalyst acidity, leading to a decrease in the product
yield. But the amount of coke remains constant in suc-
cessive runs. Furthermore, the use of this catalyst is
feasible because of its easy preparation and handling, and
stability. Large-scale synthesis is also beneficial in this
method. Two new compounds are synthesized and fully
characterized.
inflammatory [3], anti-malarial [4], and anti-hyperglycemic
agents [5]. Chalcones could be obtained via Claisen-
Schmidt condensation carried out in basic or acidic media
under homogenous conditions [6]. Claisen-Schmidt con-
densation is one of the multicomponent reactions (MCRs)
that are the most important protocols in organic synthesis
and medicinal chemistry. These processes consist of two or
more synthetic steps, which are performed without isola-
tion of any intermediates, thus reducing time and saving
both energy and raw material [7–10]. The heterogeneous
catalysts have also been used for the Claisen-Schmidt
condensation, including Lewis acids [11, 12], Brønsted
acid [13], solid acid [14], solid bases [15, 16], and other
catalysts with more or less success [17, 18]. The recent
concern about the environment includes the chemical
industry and the development of environmentally benign
products and processes that are based on the principle of
so-called ‘‘green chemistry’’ or ‘‘sustainable chemistry’’.
Solvent-free reactions are of great importance in organic
synthesis as they reduce environmental pollution and
reduce handling costs by simplifying the workup tech-
niques. The pKA of 12-tungstophosphoric acid (PW) is
lower than that of the conventional solid acid catalysts
[19]. Therefore, it is generally an active catalyst that allows
efficient operation under mild conditions. Owing to the
inherent advantages of PW, heterogeneous acid catalysis
by this compound has the potential to be of great economic
reward and green benefits. In order to achieve this goal, one
method is to exchange their protons with large alkali metal
cations such as Cs? to form insoluble salts. It was dem-
onstrated that CsxH3–xPW12O40 possesses superacidity.
Cesium salts as nanocatalyst have a high surface area; thus,
many more acidic sites are available for catalytic reactivity
[20, 21]. This high surface area makes it a more active
catalyst than the parent acid and also other known solid
Keywords Acidity Á Claisen-Schmidt condensation Á
Heteropoly acid Á Heterogeneous catalysis Á Nanostructure Á
Solvent-free
Introduction
Chalcones, which are the main precursors for the synthesis
of flavonoids, are attracting increased attention because of
numerous pharmacological applications. They exhibit
various biological activities such as anti-cancer [1, 2], anti-
E. Rafiee (&) Á F. Rahimi
Faculty of Chemistry, Razi University, 67149 Kermanshah, Iran
e-mail: ezzat_rafiee@yahoo.com; e.rafiei@razi.ac.ir
123

362
E. Rafiee, F. Rahimi
O
O
CHO
Table 1 Efficacies of different CsxH3-xPW12O40 catalysts in a model
reaction
Catalyst
+
Solvent free,10 min
Entry
Catalyst
Amount/mol%
Yield/%
1
2
PW
8
8
65
Scheme 1
Cs2CO3
11
3
Cs3PW12O40
Cs2.5H0.5PW12O40
Cs2H1PW12O40
Cs1H2PW12O40
Cs1H2PW12O40
Cs1H2PW12O40
Cs1H2PW12O40
Cs1H2PW12O40
Cs2.5H0.5PW12O40
8
40
71 (96)a
acids such as zeolites. Here, we try to eliminate toxic and
dangerous solvents in the Claisen-Schmidt condensation
and report a simple, efficient, and green protocol for syn-
thesis of chalcones using CsxH3–xPW12O40 as nanocatalyst.
4
8
5
8
66
6
8
95
7
4
51
8
6
64
9
10
8
93
Results and discussion
10
11
96b
74b
8
To optimize the reaction conditions at first, cyclohexanone
and benzaldehyde were chosen as model substrates
(Scheme 1).
Reaction conditions: benzaldehyde (1.0 mmol) and cyclohexanone
(0.5 mmol) at 50 °C and solvent-free conditions after 10 min
a
To establish optimal conditions, a set of experiments
varying the amount of catalyst and temperature was car-
ried out in solvent-free conditions using various types of
CsxH3–xPW12O40 and also Cs2CO3. The result showed
that when the reaction was carried out at 50 °C, the
corresponding product was obtained with high selectivity
in comparison with room temperature. Then various types
of CsxH3–xPW12O40 (x = 0, 1, 2, 2.5, and 3) were
examined to find the best catalyst. It is obvious that
Cs1H2PW12O40 (Cs1) is the best catalyst among the
others, as shown in Table 1. The next step in our inves-
tigation was the optimization of the catalyst amount. The
best result in terms of economy and reaction time was
obtained when 8 mol% of catalyst was used (Table 1,
entries 6–9). No improvement in catalytic activity was
obtained when the catalysts were dried at 120 °C for 1 h
(Table 1, entries 10, 11).
Results in parentheses after 25 min
b
Catalyst was dried at 120 °C for 1 h
Acidity measurements of the catalysts by means of
potentiometric titration with n-butylamine were carried out
to determine if there is any relationship between acidic
properties and catalytic reactivity (Fig. 1). This method
enables determining the distribution and total number of
acid sites and their acid strength. As a criterion to interpret
the obtained results, it was suggested that the initial elec-
trode potentional (Ei) indicates the maximum acid strength
of the sites. The value of mmol amine/g solid, where the
plateau is reached, indicates the total number of acid sites
(n). The acidic strength of the acid sites can be classified
according to the following ranges: Ei [ 100 mV (very
strong acid), 0 \ Ei \ 100 mV (strong acid), -100 mV
\ Ei \ 0 (weak sites), and Ei \ -100 mV (very weak
sites) [22]. According to the mentioned scale, it was
observed that Cs1 is a very strong acid and also more acidic
than the other salts. As expected, the acidity decreases with
increasing cesium content. However, the number of acidic
sites in Cs2.5H0.5PW12O40 (Cs2.5) is higher than in other
Fig. 1 Potentiometric titration curves of CsxH3–xPW12O40
cesium salts (about 2 mmol amine/g catalyst) and close to
Cs1. So it seems that the higher reactivity of Cs1 is related
to both factors, highly functional acid sites dispersed on the
surface of the solid catalyst and acidic strength.
To establish the generality of this condition, the reaction
of various substituted aldehydes 1 and ketones 2a, 2b was
investigated. In most cases, the reaction proceeded
smoothly to produce the corresponding chalcones in
63–98 % yields (Table 2). A variety of aromatic aldehydes
were condensed with different cyclic and acyclic ketones to
provide the corresponding products in good to excellent
yields. In most cases the reaction was found to be clean,
and the products were obtained in excellent yields without
the formation of any side product.
123

Synthesis of chalcones via Claisen-Schmidt condensation
363
Table 2 Synthesis of chalcones in the presence of Cs1 or Cs2.5
O
O
O
R1
R1
R2
R1
R2
R4 R5
R4 R5
+
R4 R5
CHO
R2
2a, 2b
R1
R2
R3
R3
R3
3a-3f
3g, 3h
R3
O
O
R1
R2
R4
CH3
R4
1
2a
O
O
:
:
1
2
3
1a
1b
1c
: R =R =R =H
2c-2e
1
2
3
2b
: R =R =H; R =CH3
1
2
3
R3
4
: R =R =H; R =Cl
2c
3i-3n
: R =Ph
1
2
3
2d: R4=4-Cl-Ph
1d
: R =R =H; R =OH
1e: R1=H; (R2,R3)=C4H4
4
2e
: R =4-OH-Ph
Entry Aldehyde Ketone Product
Cs1
Cs2.5
M.p./°C
Time/min Yield/%a Time/min Yield/%a Found
10 (15)b 98 (94)b 20 (30)b 95 (89)b 116–117 116–117 [25]
Reported
1
2
3
4
1a
1b
1c
1d
2a
2a
2a
2a
15
95
25
93
168–170 170–171 [25]
144–146 147–148 [25]
288–290 288–290 [26]
15
98
25
97
25
93
40
90
15
96
60
46
281–282
–
123

364
E. Rafiee, F. Rahimi
Table 2 continued
Entry Aldehyde Ketone Product
Cs1
Cs2.5
M.p./°C
Time/min Yield/%a Time/min Yield/%a Found
Reported
5
1e
2a
–
–
60
50
35
93
50
52
288–290
–
6
1e
2b
–
–
50
45
7
8
1a
1c
2c
2c
25 (30)b
95 (90)b 30 (45)b
90 (84)b 54–56
54–57 [27]
15 (30)b
97 (91)b 30 (45)b
91 (87)b 111–112 111–114 [27]
9
1b
1d
2c
2c
15
10
71
93
25
30
98
90
97–98
97–98 [28]
10
178–180 181–184 [29]
11
1a
2d
60
72
40
98
98–100
100–101 [29]
123

Synthesis of chalcones via Claisen-Schmidt condensation
365
Table 2 continued
Entry Aldehyde Ketone Product
Cs1
Cs2.5
M.p./°C
Time/min Yield/%a Time/min Yield/%a Found
Reported
12
1a
2e
10
63
30
98
172–174 173–174 [29]
Reaction conditions: Cs1 or Cs2.5 (8 mol%), 50 °C, solvent free
a
Isolated yield
b
Results in parentheses are for large-scale synthesis
The proposed mechanism of the reaction may proceed
through the enolate intermediate (compound II) generated
via the initial addition of H? to the carbonyl function
of ketone (compound I) and abstraction of proton from the
a-carbon of the ketone. This intermediate further coordi-
nates to the aldehyde, so the electrophilicity of the carbonyl
group is increased. Nucleophilic attack of the enolate ion
followed by a dehydration process generates the resultant
product (compound III) (Scheme 2).
The stability of the active species has been of concern
for solid acids. The reusability of the catalyst was studied
by employing it in a model reaction. In the present cases,
the quantity of the catalyst used was too low to recollect
and be reused after the first run. Hence, the higher quantity
of the catalyst was taken to investigate its reusability. The
model reaction was carried out by using 1 g of Cs1, and
the experiments were properly scaled up. After each run,
the catalyst was washed with EtOAc/hexane as solvent and
dried as described in the experimental section. As shown in
Fig. 2, Cs1 was not a good reusable catalyst. It should be
mentioned that the yield of the products in the model
reaction was 70 % after 45 min in the second run, so not
only the yield of the product decreased, but also the reac-
tion time increased compared to the first run. Thus, the
Fig. 2 Reusability of the catalysts in a model reaction after 45 min
for Cs1 and Cs2.5
reusability of Cs2.5 was investigated as the second choice
(this catalyst showed excellent reactivity at a longer reac-
tion time in comparison with Cs1; Table 1, entry 5). As
shown in Fig. 2, Cs2.5 was found to be better for reuse
compared to Cs1. Potentiometric titration of reused cata-
lysts (Cs1 and Cs2.5 after the fifth run) was investigated to
understand what happens to the surface acidity of the cat-
alysts after recovery. As shown in Fig. 3, Ei of Cs1 comes
down to about 250 mV in reused compared to fresh Cs1
(Ei = 548 mV in fresh Cs1). However, the Ei of Cs2.5
shows less reducing compared to fresh Cs2.5 (E = 199 mV
in reused Cs2.5 compared to 270 mV in fresh Cs2.5).
However, there were no significant differences in ‘‘n’’
values between fresh and reused catalysts. Also, a portion
of the catalysts was taken for analyzing the carbon content.
Coke deposited on the catalysts during the reaction built 4
and 10 wt% carbon for Cs2.5 and Cs1, respectively, after
the first run. In successive runs, the amount of coke
depended on the workup, ranging from 4 to 11 wt%. Thus,
the amount of coke remains constant in successive runs.
Coking could cause a loss in catalytic acidity, leading to a
decrease in the yield of the products.
O
H
H
H
C
O
Ph
O
H
O
2
Ph
Ph
Ph
CH2
H
H
O
H
(II)
H
O
Ph
CH3
(I)
O
Ph
H
H
Ph
O
O
H
Ph
(III)
Ph
Ph
H2O
H
Scheme 2
123

366
E. Rafiee, F. Rahimi
friendly procedures, low cost, and easy preparation and
handling of the catalyst are some of the salient advantages
of this method. Large-scale synthesis is also beneficial in
this method. Cs2.5 is a reusable catalyst. Further applica-
tions of this catalyst to other transformations are currently
under investigation.
Experimental
All organic materials were purchased from Fluka and
Merck Cos. and were used without further purification.
Cs2CO3 from Merck and H3PW12O40 (PW) from Aldrich
were used. Nuclear magnetic resonance spectra were
recorded on a Bruker Avance 200 MHz NMR spectrometer
with CDCl3 as the solvent and TMS as the internal stan-
dard. CHN compositions were measured by the Hekatech
elemental analysis model Euro EA 3000, and the results
agreed favorably with calculated values. Mass spectra were
determined on an Agilent 6890N GC–MS. Melting points
were determined using a digital Gallenkamp apparatus.
Fig. 3 Potentiometric titration curves of reused catalysts after the
fifth run
The reaction of various substituted aldehydes 1 and
ketones 2a, 2b was investigated in the presence of the Cs2.5
as a reusable catalyst. Good to excellent yields were
obtained with excellent selectivity. But in the case of
naphthaldehyde, 45 and 50 % of product 3 g and 3 h were
obtained, respectively (entries 5 and 6).
Preparation of the catalysts CsxH3–xPW12O40
In the cases of entries 7–12, 1H NMR spectral data
clearly indicated that the compounds were geometrically
pure and were configured trans (JHa–Hb = 15–16 Hz). In
other reactions, we obtained only the E, E isomer. In the
spectra of compounds, the signals for the protons of the
CH = group appear at d = 7.41–7.81 ppm. It is known
[23, 24] that the Z isomers are characterized by the
chemical shifts at d * 6.8 ppm, whereas the signals for the
E isomers should appear at a higher field than 7.2 ppm.
The acidic salts of CsxH3–xPW12O40 were prepared by
adding the required amount of aqueous solution of cesium
carbonate to aqueous solution of PW with stirring. An
appropriate amount of the aqueous solution of Cs2CO3
(0.10 M) was added dropwise to the aqueous solution of
PW (0.08 M) at room temperature with vigorous stirring.
The Cs content was adjusted by the amount of Cs2CO3
solution added. As an example of the synthesis of Cs2.5, the
appropriate amounts of solution of Cs2CO3 and PW are 8.3
and 8.4 cm3, respectively. From the beginning of the
addition of Cs2CO3, very fine particles (precipitates) were
formed to make the solution milky. After this, the solution
was aged at room temperature overnight. The precipitate
obtained was dried at 40 °C in a rotary evaporator.
Large-scale synthesis
Three entries in Table 2 (entries 1, 7, and 8) were selected
for large-scale synthesis. The reactions of 1 (20.0 mmol)
with 2a (10.0 mmol, entry 1) or 2b (20 mmol, entries 7 and
8) in the presence of Cs1 (8 mol%) were carried out at
50 °C in solvent-free conditions. As can be seen, Cs1 is a
good candidate for the large scale, and the yield of the
reactions was in the range of 90–94 % in larger reaction
times compared to on the small scale. Large-scale synthesis
in the presence of the Cs2.5 was better than in Cs1 because
it could be reusable; results of these tests are presented in
Table 2, entries 1, 7, and 8.
Acidity measurement
For the potentiometric titration, 0.05 g of solid catalyst was
suspended in 90 cm3 acetonitrile and stirred for 3 h. The
suspension was titrated with a 0.05 N solution of n-butyl-
amine in acetonitrile. The potential variation was measured
with a Hanna 302 pH meter using a double junction
electrode.
In conclusion, this procedure reveals a simple approach
to the synthesis of chalcones via Claisen-Schmidt con-
densation. Results of Ei, n, and the catalytic reactivity of
Cs1 and Cs2.5 salts indicated that the catalytic reactivity
should be directly proportional to the strength and number
of the surface acid sites, which are the ones accessible to
the reactants. Excellent yields, selectivity, environmentally
Typical procedure for Claisen-Schmidt condensation
To a mixture of ketone (1 mmol) and aldehyde (2 mmol
for entries 1–6, 1 mmol for entries 7–12), Cs2.5H0.5PW12
O40 (0.8 mol%) was added and stirred at 50 °C for an
123

Synthesis of chalcones via Claisen-Schmidt condensation
367
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reaction was monitored by TLC, using n-hexane/ethyl-
acetate (10:4) as eluent. After completion of the reaction,
2 9 10 cm3 of acetonitrile was added to the mixture and
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Spectroscopic data of the known products matched well
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2,6-Bis(naphthalen-2-ylmethylene)cyclohexanone
(3e, C28H22O)
Yellow solid; m.p.: 281–282 °C; 1H NMR (200 MHz,
CDCl3): d = 7.61 (s, 2H), 7.28–7.58 (m, 12H), 2.78 (t, 4H,
J = 5.6 Hz), 1.45 (m, 2H) ppm; 13C NMR (200 MHz,
CDCl3): d = 190.2, 149.3, 143.4, 133.8, 132.3, 133.0,
129.2, 127.4, 126.2, 125.5, 122.6, 28.1, 24.4 ppm; IR
(KBr): m = 1,660 (C = O), 1,622 (C = C) cm-1; MS:
ꢀ
m/z = 374.16.
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4-Methyl-2,6-bis(naphthalen-2-ylmethylene)cyclohexanone
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Yellow solid; m.p.: 288–290 °C; 1H NMR (200 MHz,
CDCl3): d = 7.69 (s, 2H), 7.29–7.56 (m, 12H), 2.81 (m,
4H), 1.63 (m, 1H), 1.51 (d, 3H, J = 6.2 Hz) ppm; 13C
NMR (200 MHz, CDCl3): d = 190.2, 148.1, 142.8, 135.6,
132.7, 131.2, 128.3, 127.4, 126.2, 125.4, 122.0, 35.2,
ꢀ
28.3, 21.5 ppm; IR (KBr): m = 1,660 (C = O), 1,620
(C = C) cm-1; MS: m/z = 388.16.
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