Synthesis of calix[4]arene alkylamine derivatives as new phase-transfer catalysts for esterification reaction

Article abstract of DOI:10.1016/j.tet.2011.06.050

This study reports the synthesis of calix[4]arene-based phase-transfer catalysts derived from the reaction of 5,17-di-tert-butyl-25,27,26,28- tetrahydroxycalix[4]arene with N-ethylpiperazine, diallylamine or 4-benzylpiperidine. The catalytic efficiency of

Full text of DOI:10.1016/j.tet.2011.06.050

Tetrahedron 67 (2011) 6240e6245
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Tetrahedron
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Synthesis of calix[4]arene alkylamine derivatives as new phase-transfer catalysts
for esterification reaction
*
Ezgi Akceylan, Mustafa Yilmaz
Selcuk University, Department of Chemistry, 42031 Konya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
This study reports the synthesis of calix[4]arene-based phase-transfer catalysts derived from the reaction
of 5,17-di-tert-butyl-25,27,26,28-tetrahydroxycalix[4]arene with N-ethylpiperazine, diallylamine or 4-
benzylpiperidine. The catalytic efficiency of the calix[4]arenes alkylamine derivatives was evaluated by
carrying out the ester-forming reaction of alkali metal carboxylates (sodium butyrate or sodium cap-
rylate) with p-nitrobenzyl bromide. It has been observed that the ester-forming reaction of alkali metal
carboxylates with p-nitrobenzyl bromide, using the N-ethylpiperazine amine derivative of calix[4]arene
as a phase-transfer catalyst in dichloromethane at 25 ꢀC, provided the best yields.
Received 23 February 2011
Received in revised form 9 May 2011
Accepted 16 June 2011
Available online 22 June 2011
Keywords:
Calix[4]arene
Phase transfer
Catalysis
Ó 2011 Elsevier Ltd. All rights reserved.
Esterification
1. Introduction
catalyst and used the aldol type condensation and Michael addition
reactions, alkylation reactions of active methylene compounds with
Reaction between two substances located in different phases of
a mixture is often inhibited because of the inability of the reagents
to come together. An alternative solution to the heterogeneity
problem, phase-transfer catalysis (PTC), is introduced here.1,2
Nowadays, phase-transfer catalysis has become a favored tech-
nique in organic synthesis and is widely used to manufacture
pharmaceuticals, agricultural chemicals, perfumes, flavors, dyes,
and specialty polymers. Moreover, the applications of phase-
transfer catalysis in industry have been extended to the pollution
and environmental control processes.3e7
alkyl halides in aqueous NaOH solution.
In this paper, the main focus of this work is the design of new
calixarenes bearing alkyl amino groups on their upper rim, and use
of the calixarenes as phase-transfer agents in the esterification
reaction with p-nitrobenzyl bromide and sodium butyrate or so-
dium caprylate.
2. Results and discussion
2.1. Synthetic routes
Calixarenes can be easily modified and tailored for many ap-
plications, such as ionophores in catalysis, heavy metal adsorption
agents, alkali metal complexation agents, and chemical sensors.8e12
Among the functional groups that have been appended are ethers,
esters, amides, ketones, alkenes, ammonium species, phosphines,
and heterocycles.13e23 The aromatic-rich nature of calixarenes
makes them essentially insoluble in water, which enhances their
utility as phase-transfer reagents.
During the past 15 years, calixarenes have received increasing
attention due to their utilization in supramolecular chemistry.24
Some functionalized calixarenes have been developed as new
phase-transfer agents for PTC reactions. Shimizu et al.25,26 prepared
p-(trimethylammoniomethyl)calix[n]arene methyl ethers as
The main focus of this work was the design of new calixarene
based ionophores that are easily accessible, have effective binding
characteristics for a particular set of cations/anions and molecules,
and could be useful for multiple applications, such as laboratory,
clinical, environmental, and industrial process analyses. To achieve
the desired goal, p-tert-butylcalix[4]arene (1) has been chosen as
the precursor. A synthesis strategy has been developed to enable its
derivatization. Such a synthesis route is depicted in Scheme 1. The
syntheses for compounds 1e4 are based on previously published
procedures.27,28 The substitution of 5,17-di-tert-butyl-25,26,27,28-
tetrahydroxycalix[4]arene (4) at its upper rim (Mannich reac-
tion)29e31 was conducted in the presence of AcOH in THF with
secondary amines (N-ethylpiperazine, diallylamine or 4-
benzylpiperidine) and formaldehyde to afford the cone conformer
5e7 at high yields. The conformational characteristics of calix[4]
arenes were conveniently estimated by the splitting pattern of the
* Corresponding author. Tel.: þ90 332 2233873; fax: þ90 332 2410520; e-mail
address: myilmaz42@yahoo.com (M. Yilmaz).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.050

E. Akceylan, M. Yilmaz / Tetrahedron 67 (2011) 6240e6245
6241
Scheme 1. A schematic representation of the synthesis of calix[4]arene derivatives bearing amino groups on their upper rim (5e7).
ArCH2Ar methylene protons in the 1H NMR spectrum.24,32 1H NMR
spectroscopic data showed that compounds 5e7 were in the cone
(J¼12.5 Hz) for 7 in 1H NMR. The high field doublets at
d
3.51 ppm
for 5 and d 3.50 ppm for 6 and 7 were assigned to the equatorial
conformation. A typical AB pattern was observed for the methylene
protons of methylene groups, whereas the low field signals at
4.22 ppm for 5, 4.24 ppm for 6, and 4.25 ppm for 7 were
assigned to the axial protons in the 1H NMR.
bridge ArCH2Ar protons at
d
3.51 and 4.22 ppm (J¼12.5 Hz) for 5,
d
d
d
d
3.50 and 4.24 ppm (J¼12.3 Hz) for 6, and
d
3.50 and 4.25 ppm

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E. Akceylan, M. Yilmaz / Tetrahedron 67 (2011) 6240e6245
2.2. Ester-forming reactions
butyrate, experiments were carried out at 25 ꢀC and 60 ꢀC. It was
found that the reaction rate increased with an increase in
temperature.
The temperature dependence of the p-nitrobenzyl butyrate
yield percentage and of the esterification reaction set in motion by
catalyst 7 were studied at 60 ꢀC and the results are shown in Figs. 3
and 4.
The main effect on the rate can be attributed to the nature of the
anion paired with the quaternary ammonium cation in the organic
phase. It has been known that the calixarenes11 are considerably
stronger acids than their monomeric phenolic analogous. The un-
usual ease with which the first dissociation of the calix[4]arenes
occurs is attributed to stabilization of the monoanion relative to the
parent species.31 Semi-empirical calculations32 indicate that the
monoanion is strongly hydrogen bonded to its flanking OH groups
which, in turn, are stabilized by a bifurcated hydrogen bond with
the fourth OH group. The dissociation of the second proton of the
calix[4]arenes, on the other hand, is slightly less facile than that of
the corresponding monomeric phenolic analogous. Although cal-
culations indicate that hydrogen bonding still contributes to the
Various phase-transfer catalysts were used to compare their
catalytic activity. The catalytic activity of calix[4]arenes based alkyl
amino groups on their upper rim (5, 6, and 7) were examined for
esterification of p-nitrobenzyl bromide and sodium butyrate or so-
dium caprylate. This synthesis route is depicted in Schemes 2 and 3.
Mixtures containing an aqueous solution (5 mL) of sodium butyrate,
or sodium caprylate (9a or 9b) solution at a concentration of 0.8 M
and 4 mL of a 0.5 M solution of p-nitrobenzyl bromide (8), and 1 mL
of a 5ꢁ10ꢂ2 M solution of calixarene 5, 6 or 7 in CH2Cl2 were vigor-
ouslyagitated in a stoppered glass tube at 25 ꢀC and 60 ꢀC for a given
period of time, usually for 30 h. The results are shown in Table 1. A
workup of the resulting mixtures yielded p-nitrobenzyl butyrate
(10a) or p-nitrobenzyl caprylate (10b) (Scheme 2). The progress of
the reaction was followed by monitoring the production of p-
nitrobenzyl butyrate and p-nitrobenzyl caprylate, using HPLC. In the
absence of calixarene derivatives, the reaction did not occur ap-
preciably, indicating that 5, 6, and 7 serve as catalysts for these es-
terification reactions. The results are shown in Figs. 1 and 2.
O
cat
COONa
O2N
O2N
Br
OC
+
n
n
8
9a,b
10a,b
a: n=1
b: n=5
a: n=1
b: n=5
Scheme 2. Synthesis of p-nitrobenzyl butyrate and p-nitrobenzyl caprylate.
Scheme 3. The proposed mechanism of esterification reaction.
From the data in Table 1, a smaller acceleration effect was ob-
served when calix[4]arene derivative 6 was added to the reaction
mixture as a phase-transfer catalyst. In contrast, the addition of the
calix[4]arene derivative 5 resulted in an excellent yield of the es-
terification product, p-nitrobenzyl caprylate. It is observed that the
catalyst 5 afforded relatively better results than the other catalysts.
The percentage of p-nitrobenzyl caprylate yield was 80% for catalyst
5, 47% for 7 and 10% for 6 when the sodium caprylate was used
(Fig. 2).
stabilization of the dianion, unfavorable electrostatic repulsions
appear to be the dominant factor. Thus, a tert-amino group of cal-
ixarene is protonated with the phenolic group at the interface of
two phases in order to yield the ammonium form of calixarene,
which remains at the interface due to its highly polar character. The
protonated calixarene is complexed with carboxylate anion as an
ion pair. In literature Atwood et al.31 synthesized p-[4-(2-
hydroxyethyl)-piperidinomethyl]calix[4]arene and single-crystal
X-ray diffraction study revealed the presence of a ethyl acetate
guest in the cavity. In this complex the arms are directed up from
the rim of the calix[4]arene to produce a cavity so deep that the
In order to examine the effect of the temperature on the course
of the reaction between p-nitrobenzyl bromide and sodium

E. Akceylan, M. Yilmaz / Tetrahedron 67 (2011) 6240e6245
6243
Table 1
Reaction of alkali metal carboxylates with p-nitrobenzyl bromide
Entry
Catalyst
Substrate
Nucleophile
T/ꢀC
t/h
Yield (%)
1
2
3
4
5
6
7
8
None
5
6
7
None
5
6
7
None
5
6
7
None
5
7
None
5
7
None
5
7
None
5
6
7
None
5
6
7
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
p-NitroBnBr
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)2COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
CH3(CH2)6COONa
25
25
25
25
25
25
25
25
25
25
25
25
60
60
60
60
60
60
60
60
60
25
25
25
25
25
25
25
25
25
25
25
25
10
10
10
10
20
20
20
20
30
30
30
30
10
10
10
20
20
20
30
30
30
10
10
10
10
20
20
20
20
30
30
30
30
0
33
Trace
3
0
53
2
23
0
75
32
55
0
84
61
Trace
94
65
Trace
99
90
Trace
28
2
8
2
54
3
18
3
80
9
47
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Fig. 3. Effect of reaction temperature on the esterification of p-nitrobenzyl bromide
with sodium butyrate with catalyst 5.
None
Fig. 4. Effect of reaction temperature on the esterification of p-nitrobenzyl bromide
with sodium butyrate with catalyst 7.
5
6
7
To clarify the phenomena, similar experiments were performed
on compound 11 (Scheme 4). From the results, it has been observed
that the diester derivative of calix[4]arene (11), which has a cone
conformation, is a good extractant for Naþ ion, but a poor catalyst
for the reaction. On the other hand, Et3N was used as phase-transfer
agent in the ester-forming reaction, however, the results showed
that Et3N was poor catalyst. In literature Shimizu et al.26 synthe-
sized noncyclic monomeric analog of macrocyclic calixarene (12)
(Scheme 4) to understand the effective role of the macrocyclic
scaffold of calixarenes as a phase-transfer catalyst. The results
showed that no acceleration effect is observed when the noncyclic
monomeric analog is added to the reaction mixture. It has been
concluded that the protonated form of calixarene and the guest
inclusion in the calixarene cavity plays a key role in the catalytic
process.
100
5
6
7
80
60
40
20
0
no catalyst
0
5
10
15
20
25
30
35
Time (h)
Fig. 1. Effect of PTC type on the formation of p-nitrobenzyl butyrate. Aqueous phase
(5.0 mL) contains sodium butyrate (0.8 M), whereas organic phase (CH2Cl2, 5.0 mL)
contains p-nitrobenzyl bromide (0.50 M) and catalyst (0.050 M). Temperature 25 ꢀC.
N+Me3Cl-
ethyl acetate guest molecule is completely enshrouded. The suffi-
ciently lipophilic Q then moves into the organic phase to react with
p-nitrobenzyl bromide and thus yield the ester. After the reaction,
calixarene is regenerated and enters the next catalytic cycle.
O
O
OH
HO
Na+
100
80
60
40
20
0
5
O
O
OMe
12
6
OCH3
H3CO
7
11
no catalyst
Scheme 4. Proposed interactions of the compound 11 with Naþ and previously syn-
thesized compound 12.
3. Conclusions
0
5
10
15
20
25
30
35
In summary, we have synthesized three new upper rim-
substituted calix[4]arene alkylamine derivatives, and have used
calixarenes as phase-transfer agents in the esterification reaction
with p-nitrobenzyl bromide and sodium butyrate or sodium cap-
rylate. In the absence of calixarene derivatives, the reaction did not
Time (h)
Fig. 2. Effect of PTC type on the formation of p-nitrobenzyl caprylate. Aqueous phase
(5.0 mL) contains sodium caprylate (0.8 M) whereas organic phase (CH2Cl2, 5.0 mL)
contains p-nitrobenzyl bromide (0.50 M) and catalyst (0.050 M). Temperature 25 ꢀC.

6244
E. Akceylan, M. Yilmaz / Tetrahedron 67 (2011) 6240e6245
occur appreciably, indicating that 5, 6, and 7 serve as catalysts for
these esterification reactions. It is observed that catalyst 5 afforded
relatively better results than the other catalysts.
removed by suction filtration. The product was dried in vacuo and
recrystallized from chloroform.
4.3.3. 5,17,Di-tert-butyl-11,23-bis[(N-ethylpiperazine)methyl]-
25,26,27,28-tetrahydroxycalix[4]arene. Compound 5 was obtained
in 85% yield as a pink solid; mp 140 ꢀC; IR (KBr disk): 3168, 2951,
4. Experimental
4.1. General
2806, 1662, 1481, 1163, 872, 790 cmꢂ1; 1H NMR (CHCl3):
d
¼1.02 (t,
t
6H, CH2CH3), 1.18 (s, 18H, Bu), 2.35 (m, 20H, NCH2), 3.24 (s, 4H,
ArCH2N), 3.51 (d, 4H, J¼12.5 Hz, ArCH2Ar), 4.22 (d, 4H, J¼12.5 Hz,
1H NMR spectra were recorded with a Varian 400 MHz spec-
trometer in CDCl3. FT-IR spectra was recorded with a PerkineElmer
spectrum 100. Elemental analyses were performed on a Leco CHNS-
932 analyzer. High-performance liquid chromatography (HPLC)
Agilent 1200 Series were carried out using a 1200 model quater-
nary pump, a G1315B model Diode Array and Multiple Wavelength
UVevis detector, a 1200 model Standard and preparative auto-
sampler, a G1316A model thermostated column compartment,
a 1200 model vacuum degasser, and an Agilent Chemstation
B.02.01-SR2 Tatch data processor. All analytes used in this study
were of analytical grade and were obtained from SigmaeAldrich
and Merck. All aqueous solutions were prepared with deionized
water that had been passed through a Millipore milli Q Plus water
purification system. The yield of product was determined by HPLC
(Agilent 1200 Series) analysis by using Zorbax SIL (4.6ꢁ250 mm)
column at the temperature of 25 ꢀC. Column Zorbax SIL was pur-
chased from Agilent technology. In the analysis, hexane/chloroform
(2:8 v/v) was used as the mobile phase at the flow rate of 1 mL/min;
and UV detection was done at 254 nm. HPLC grade n-hexane and
chloroform were purchased from Merck.
ArCH2Ar), 6.92 (s, 4H, Ar), 7.08 (s, 4H, Ar). 13C NMR (CDCl3):
d (ppm):
12.17, 31.71, 32.42, 34.29, 52.52, 53.02, 53.31, 62.83, 126.12, 127.80,
128.40,129.92,131.65. Anal. Calcd for C50H68O4N4: C, 75.94; H, 8.86;
N, 7.08%. Found: C, 75.89; H, 8.89; N, 7.15%.
4.3.4. 5,17,Di-tert-butyl-11,23-bis[(diallyl) methyl]-25,26,27,28-
tetrahydroxycalix[4]arene. Compound 6 was obtained in 70% yield
as white solid; mp 170 ꢀC; IR (KBr disk): 3172, 2954,1657,1482,1199,
1091, 816, 782 cmꢂ1; 1H NMR (CHCl3):
8H, NCH2CH]), 3.34 (s, 4H, ArCH2N), 3.50 (d, 4H, J¼12.3 Hz,
ArCH2Ar), 4.24 (d, 4H, J¼12.3 Hz, ArCH2Ar), 5.13 (m, 8H, CH2]), 5.82
(m, 4H, CH]CH2), 6.99 (s, 4H, Ar), 7.06 (s, 4H, Ar). 13C NMR (CDCl3):
d
¼1.22 (s, 18H, tBu), 3.02 (d,
d
(ppm): 31.9, 32.5, 34.54, 56.52, 57.55,117.58,126.16,127.78,128.37,
129.78, 136.17, 144.78, 146.96, 147.77. Anal. Calcd for C50H62O4N2: C,
79.57; H, 8.22; N, 3.71%. Found: C, 79.83; H, 8.35; N, 3.93%.
4.3.5. 5,17,Di-tert-butyl-11,23-bis[(4-benzylpiperidine)
methyl]-
25,26,27,28-tetrahydroxycalix[4]arene. Compound 7 was obtained in
80% yield as white solid; mp 135 ꢀC; IR (KBr disk): 3242, 2921, 1659,
1453,1301, 745, 699 cmꢂ1; 1H NMR (CHCl3):
d
¼1.23 (s,18H, tBu),1.36
(m, 4H, NCH2CH2), 1.51 (m, 2H, CH), 1.6 (m, 4H, NCH2CH2), 1.85 (m,
4H, NCH2CH2), 2.54 (d, 4H, CHCH2Ar), 2.87 (m, 4H, NCH2CH2), 3.3 (s,
4H, ArCH2N), 3.50 (d, 4H, J¼12.5 Hz, ArCH2Ar), 4.25 (d, 4H,
J¼12.5 Hz, ArCH2Ar), 6.97 (s, 4H, Ar), 7.07 (s, 4H, Ar), 7.13e7.3 (m,
4.2. Catalytic application
The phase-transfer catalysis was carried out between water
(5 mL, [sodium butyrate and sodium caprylate]¼0.8 M) and
dichloromethane (5 mL, [catalyst]¼5.0ꢁ10ꢂ2 M, [p-nitrobenzyl
bromide]¼0.50 M). We here tested compounds 5, 6, and 7 as phase-
transfer catalysts. The aliquot was withdrawn from the organic
phase and subjected to HPLC analysis (column Zorbax SIL, mobile
phase hexane/chloroform¼2:8 v/v). The concentration of yielded p-
nitrobenzyl butyrate and caprylate was determined from the cali-
bration curve made separately using the authentic sample.
10H, Ar). 13C NMR (CDCl3):
d (ppm): 31.7, 32.15, 32.46, 34.27, 37.9,
43.01, 53.08, 62.8,125.99,126.1,127.87,128.36,128.50,129.39,130.01,
140.8, 144.58, 147.14, 148.39. Anal. Calcd for C62H74O4N2: C, 81.75; H,
8.13; N, 3.07%. Found: C, 81.49; H, 8.3; N, 3.13%.
Acknowledgements
We thank the Scientific Research Projects Foundation of Selcuk
University (SUBAP-Grant Number 2008-08101023) for financial
support of this work produced from a part of E.A.’s Ph.D. Thesis.
4.3. Synthesis
4.3.1. Calix[4]arene derivatives. Calixarenes have been widely used
as three-dimensional building blocks for the construction of arti-
ficial molecular receptors capable of recognizing neutral molecules,
cations, and more recently anions.33 Thus, having chosen the p-tert-
butylcalix[4]arene as the basis for derivatives, a synthetic scheme
had to be developed to enable the derivatization of the molecule.
Such a synthetic route is shown in Scheme 1.
The syntheses of compounds 1e4 (Scheme 1) were based on the
previously published procedures.27,28 The following general
procedure29e31 was adopted to transform calix[4]arene (4) into the
corresponding alkylamine derivatives 5, 6, and 7.
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4.3.2. General procedure (Mannich reactions). To a solution of
compound 4 (10 mmol) in 90 mL of THF/DMF were added 11 mL of
acetic acid, the secondary amine (N-Ethylpiperazine, diallylamine
or 4-benzylpiperidine) (50 mmol), and 37% aqueous formaldehyde
(50 mmol) and the reaction mixture was stirred for 24 h at room
temperature. The solvent was removed in vacuo and the residue
was dissolved in 75 mL of water. The aqueous solution was
extracted twice with 50 mL of diethyl ether and then neutralized
with 10% aqueous K2CO3 solution. The precipitate that formed was

E. Akceylan, M. Yilmaz / Tetrahedron 67 (2011) 6240e6245
6245
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