Microwave-assisted synthesis of calix[4]resorcinarenes

Article abstract of DOI:10.1016/j.tet.2006.03.095

Microwave-assisted synthesis of calix[4]resorcinarenes by cyclocondensation of various aldehydes and resorcinol catalysed by 12-tungstophosphoric acid type Keggin (H₃PW₁₂O₄₀·13H₂O) or concentrated HCl is describ

Full text of DOI:10.1016/j.tet.2006.03.095

Tetrahedron 62 (2006) 5652–5655
Microwave-assisted synthesis of calix[4]resorcinarenes
c
a
c
Madani Hedidi,a Safouane M. Hamdi,b, Tassadit Mazari, Baya Boutemeur, Cherifa Rabia,
*
Farid Chematd, and Maamar Hamdi
a
*
ˆ
a
´
´ ´
´
´
Laboratoire de chimie organique appliquee (Equipe Heterocycles), Faculte de chimie, Universite des Sciences et de la Technologie
`
Houari Boumediene, BP 32, El-Alia, 16111 Bab-Ezzouar, Alger, Algeria
ˆ
b
Laboratoire de Biochimie, Hopital La Grave, Place Lange, 31052 Toulouse, France
c
´
´
`
Laboratoire de chimie du gaz naturel, Faculte de chimie, Universite des Sciences et de la Technologie Houari Boumediene, BP 32,
El-Alia, 16111 Bab-Ezzouar Alger, Algeria
Laboratoire de Chimie des Substances Naturelles et des Sciences des Aliments, Faculte des Sciences et Technologies,
d
´
Universite de La Reunion, F-97715 Saint Denis, Reunion
´
´
´
Received 20 January 2006; revised 22 March 2006; accepted 27 March 2006
Available online 27 April 2006
Abstract—Microwave-assisted synthesis of calix[4]resorcinarenes by cyclocondensation of various aldehydes and resorcinol catalysed by
12-tungstophosphoric acid type Keggin (H3PW12O40$13H2O) or concentrated HCl is described. Excellent isolated yields (up to 90%)
were attained within short reaction times (typically, 3–5 min) when the reaction was performed under microwaves irradiation.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
principles and that is efficient for both aromatic and aliphatic
aldehydes.
Interest in the chemistry of calixarenes has increased in re-
cent years. Of particular significance has been the prepara-
tion of a range of calix[4]resorcinarene derivatives in high
yields.1 Self-assembled monolayers of resorcinarene deriv-
atives on gold surfaces provide an important starting point
for fabricating and operating nanoscale devices for ad-
vanced information technologies. Resorcinarene derivatives
have also been used as stationary phase in achiral capillary
gas chromatography for the separation of positional isomers
of substituted benzenes.2
Tungstophosphoric acid (TPA), an effectivecatalyst in the se-
ries of Keggin-structure HPAs, is believed to have extensive
prospects of application in synthesis chemistry, analysis
chemistry, biology, medicine, catalysis and materials sci-
ence. Especially,itsutilityandversatilityincatalysisandvari-
ous medical applications would thereby be increased. Their
significantly higher Brønsted acidity, compared with the
acidity of traditional mineral acid catalysts, is of great impor-
tance for catalysis because HPA-based catalysts have higher
activity than known traditional catalysts. Using HPA-based
catalysts, it is frequently possible to obtain higher selectivity
and successfully solve ecological problems.3
Recently, Robertetal.1 andCaveetal.1 obtainedtheC-methyl-
calix[4]resorcinarene and five arylcalix[4]resorcinarenes by
simply grinding together resorcinol and aldehydes in the
presence of catalytic quantities of p-toluenesulfonic acid.
The final product partition was carried out either at room tem-
perature (for aromatic aldehydes) or at ꢀ78 ꢁC (for acetalde-
hyde). These ‘green’ approaches to synthetize resorcinarenes
were convincing and efficient but it seems that their applica-
tion to both aromatic and aliphatic aldehydes was not claimed
by the authors. The use of aliphatic aldehydes as starting
material in these approaches was unsuccessful since the
longer the alkyl chain of aldehydes, the lower the reaction
yield. For this purpose, we searched for a simple and rapid
synthesis pathway that applies most of the green chemistry
In recent decades microwave technology has taken an
undeniable place in chemical laboratory practise as a very
effective and non-polluting method for activating reactions.
Examples of this technology in organic synthesis and to
organo-metallic chemistry are numerous. The greater suc-
cesses achieved have been to perform reactions very effi-
ciently in closed vessels or in the reduction or absence of
organic solvents. The uses of microwaves provide fast volu-
metric heating of the chemicals thus enhancing reaction
rates and dramatically shortening preparation times.4
Herein, we report the first synthesis of calix[4]resorcin-
arenes using aldehydes and resorcinol catalysed by 12-
tungstophosphoric acid type Keggin (H3PW12O40$13H2O)
* Corresponding authors. Tel.: +33 5 61 77 94 03; fax: +33 5 61 77 94 01;
e-mail: sahamdi@toulouse.inserm.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.095

M. Hedidi et al. / Tetrahedron 62 (2006) 5652–5655
5653
HO
HO
OH
OH
or concentrated HCl under microwave irradiations. The re-
action takes place in excellent yield (>90%) with short reac-
tion times (<3–5 min) and does not require harsh conditions.
The reaction allows the presence of some functional groups
thanks to the rather mild acidic conditions.
HO
HO
OH
OH
R
R
R
HO
OH
R
CHO
+
R
2. Results and discussion
1
2
3
Scheme 1 represents the general procedure for the formation
of calix[4]resorcinarenes 3 by acid-catalysed cycloconden-
sation of resorcinol 1 and aldehydes 2. Selected reaction
data obtained from model compounds 2a–i were illustrated in
Table 1 according to different experimental procedures. The
process involves microwave irradiation (modified domestic
microwave oven) of a mixture containing the resorcinol 1
and aldehydes 2 with a catalytic amount of TPA (procedure
D) for 5 minor HCl (procedure B)for 3 min. The correspond-
ing thermal reaction takes 5 h with TPA catalyst (procedure
C) and 10 h with concentrated HCl (procedure A).
Scheme 1. Synthesis of calix[4]resorcinarenes by cyclocondensation of
resorcinol and aldehydes.
1
purity. We carefully analyzed H NMR spectra of 3a, 3i
(aromatic) and 3c, 3d, 3f, 3g (aliphatic). All of them
exhibited an equivalent single resonance for the four ortho
protons of resorcinol rings. It was also the case for the four
meta protons. These NMR data were consistent with those
previously reported for the C4v isomer.1 Thus, using our
procedure, we obtained the 3a–i products with high yield,
purity and stereoselectivity. This synthesis route can fruit-
fully used to expand possibilities of molecular recognition
in solution of resorcinarenes.1
Products (3a–i) were dried at 70 ꢁC under vacuum. Micro-
1
analyses, H and 13C NMR spectra confirmed their good
Table 1. Microwave-assisted cyclocondensation of resorcinol 1 and aldehydes 2a–i
Product
R–
Procedures
Conditions
Time (min)
Yield (%)
Mp (ꢁC)
Power (W)
T (ꢁC)
3a
p-But-O-C6H4
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
86
96
78
91
>300
300
3b
3c
3d
3e
3f
CH3
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
60
88
67
89
>300
>300
>300
>300
280
300
CH3(CH2)3
CH3(CH2)4
CH3(CH2)6
CH3(CH2)7
CH3(CH2)8
CH3(CH2)10
C6H5
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
69
82
91
88
300
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
87
95
88
91
300
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
79
93
84
91
300
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
82
96
91
90
300
3g
3h
3i
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
84
93
87
89
295
300
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
85
93
—
90
285
300
A
B
C
D
—
100
—
600
3
300
5
80
80
80
108
88
94
78
95
300
300

5654
M. Hedidi et al. / Tetrahedron 62 (2006) 5652–5655
Analysis of selected reaction data (see Table 1) obtained
from model compounds 2a–i shows the following outstand-
ing facts:
and less reaction time, which means less energy consumed
for heating. This ‘green’ procedure for cycloaddition reac-
tion may set the basis for its application assisted by micro-
waves in a near future.
(a) Comparison between conventional heating and micro-
wave irradiation (same temperature, same reagents) re-
vealed a strong specific effect of microwaves because,
under conventional heating, the reaction occurred in
a very limited extension. After 30 min, thermal reaction
did not allow to produce any calix[4]resorcinarenes
using 2-ethoxyethanol as solvent with procedures B or
C. A possible explanation for the favourable effect of
microwaves is that they enhance dipole–dipole interac-
tion in the transition state (Scheme 2).
4. Experimental
Procedure A: to a solution of resorcinol 1 (10 mmol) and
aldehydes 2 (10 mmol) was added a solution of ethyl alcohol
(25 mL, 95%) and concentrated HCl (7 mL). This mixture
was heated by conventional heated jacket for 10 h. The reac-
tion mixture was cooled in an ice bath and the solid material
formed was filtered off and washed by water to eliminate acid
trace. The filtrate was dried at 70 ꢁC and analysed by 1H and
13C NMR spectra recorded in CDCl3 or acetone-d6 solutions,
on a VARIAN spectrometer operating at 300 MHz. Melting
points were determined on a Stuart scientific SPM3 apparatus
fitted with a microscope. Procedure B: to a solution of resor-
cinol 1 (10 mmol) and aldehydes 2 (10 mmol) was added a
solution of 2-ethoxyethanol (2 mL) and concentrated HCl
(2 mL). This mixture was heated by microwaves for 3 min
with a fixed power of 100 W. Procedure C: to a solution of
resorcinol 1 (10 mmol) and aldehydes 2 (10 mmol) was
added a solution of ethyl alcohol (12 mL, 95%) and TPA
(0.31 g, 1% molar). This mixture was heated by conventional
heated jacket for 5 h. Procedure D: to a solution of resorcinol
1 (10 mmol) and aldehydes 2 (10 mmol)was added asolution
of 2-ethoxyethanol (2 mL) and TPA (0.31 g; 1% molar). This
mixture was heated by microwaves for 5 min with affixed
power of 300 W.
R
‡
R
Ar
Ar
O
O
C=O
O
H
H
H
H
Scheme 2. Dipolar transition state.
However, a crucial role for the acid during the dehydra-
tation step cannot be excluded since we obtained very
low yields in all reactions carried without acid.
(b) Calix[4]resorcinarenes 3 have been synthesised after 5–
10 h by conventional heating with fairly moderate yields
between 60 and 90%. Under microwave irradiation, ex-
cellent yields (between 80 and 99%) were obtained after
3–5 min.
(c) The power range was set to 100 W for HCl catalyst and
300 W for TPA catalyst, since an excessive power could
cause the degradation of the product.
(d) When microwave irradiation is applied, less solvent
is necessary for conducting cyclocondensation acid-
catalysed by HCl or TPA. One of the goals of the ‘green
chemistry’ is to avoid or to reduce the use of solvents in
organic chemistry.
1H and 13C NMR spectroscopic data example of calix[4]-
resorcinarene (300 MHz): 2,8,14,20-tetra(p-butoxyphenyl)-
pentacyclo[19,3,1,1,1]octacosa-1(25),3,5,7,(28),9,11,13(27)
15,17,19(26),21,23, dodecanene-4,6,10,12,16,22,24-octol
(3a); 1H NMR (acetone-d6) dH (ppm): 0.98 (12H, t,
J¼6.72 Hz,CH3), 1.50 (8H, m, CH2), 1.75 (8H, m, CH2),
4.00 (8H, t, J¼7.8 Hz, OCH2), 5.75 (4H, s, CH), 6.30 (4H,
s, ArH meta of OH), 6.34 (4H, s, ArH ortho OH), 6.69 (8H,
m, ArH meta of O-alkyl), 6.78 (8H, m, ArH ortho of O-alkyl),
7.51 (8H, s, ArOH); 13C NMR (acetone-d6) dC (ppm): 14.26,
20.00, 32.38, 42.00, 67.87, 102.00, 114.00, 122.26, 130.39,
132.06, 137.30, 153.70, 157.42.
(e) In general, the cyclocondensation worked well with alkyl
or aryl aldehydes with or without functional groups.
Microwaves are used as a useful tool for preparative organic
synthesis: reactions can be carried with less solvent under
monitored temperature. There is a fundamental difference
between microwave irradiation and conventional heating;
conventional heating is an inward heat transfer (from the
heatingdevice, e.g., thewallsofthereactorforjacketedtanks,
to the medium); in microwave irradiation, thermal energy is
generated in situ due to the interaction of polar molecules or
ionic species with the electric field. Physical acceleration
(higher temperature) or chemical activation (enhancement
in dipole moment) could be happened using microwaves,
which reduce reaction times and enhance yields in compari-
son with conventional reflux reaction conditions.
The multimode microwave reactor (a modified microwave
oven candy mga20m) has a single magnetron (2450 MHz)
with a maximum delivered power of 800 W. It was directly
graduated in W (from 100 to 800 W). Experiments were car-
ried out in a Pyrex reactor fitted with a condenser. During ex-
periments, time, temperature and power were monitored.
Temperature was monitored with the aid of an external infra-
red IR thermometer (Flashpoint FZ400).
Resorcinol, aldehydes, ethyl alcohol, 2-ethoxyethanol and
HCl, were purchased from Aldrich and TPA synthesized
by authors following literature procedures.5
3. Conclusion
An extremely simple method for the preparation of calix[4]-
resorcinarenes 3 by acid-catalysed cyclocondensation of
aldehydes 2 and resorcinol 1 has been perfected using micro-
wave technology. The reaction can be carried out in environ-
mentally friendly conditions: less solvent, less added acid
Acknowledgements
The present Work was supported by ANDRS (Project: 05/
05/01/01/019).

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