Calorimetric investigation of nano-basket's binding

Article abstract of DOI:10.14233/ajchem.2013.12058a

Eleven scaffolds of di-ionizable calix[4]arene conformers bearing two pendant groups of N-phenyl-sulfonyl carboxamides were synthesized and examined using isothermal titration calorimetry. The binding mechanisms of those conformers towards alkali metal ca

Full text of DOI:10.14233/ajchem.2013.12058a

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Asian Journal of Chemistry; Vol. 25, No. 1 (2013), 13-18
http://dx.doi.org/10.14233/ajchem.2013.12058
Calorimetric Investigation of Nano-Basket’s Binding
*
BAHRAM MOKHTARI and KOBRA POURABDOLLAH
Razi Chemistry Research Center, Shahreza Branch, Islamic Azad University, Shahreza, Iran
*Corresponding author: Fax: +98 321 3213103; Tel: +98 912 5143351; E-mail: pourabdollah@iaush.ac.ir
(Received: 27 May 2011;
Accepted: 2 July 2012)
AJC-11811
Eleven scaffolds of di-ionizable calix[4]arene conformers bearing two pendant groups of N-phenyl-sulfonyl carboxamides were synthesized
and examined using isothermal titration calorimetry. The binding mechanisms of those conformers towards alkali metal cations were
evaluated and two main interactions were assessed including cation-π interaction between alkali metal cation and the aromatic unit of
conformer as well as the strong binding ion-dipole interaction between nitrogen atoms in the pendant groups and alkali cation. The
isothermal titration calorimetry data revealed that the bindings of cone and partial-cone conformers towards alkali metal cations exhibited
one-step mechanism, while both 1,2-alternate and 1,3-alternate conformers bound the alkali metal cations in a two-steps mechanism.
Key Words: Nano-basket, Calixarene, Calorimetry, Binding.
determined. Fig. 1 shows the hierarchical structures of comp-
lexes were studied.As depicted in Fig. 1, eleven scaffolds were
used to assess the binding constants of isoconformations using
isothermal titration calorimetry experiments.
INTRODUCTION
Isothermal titration calorimetry (ITC) as an analytical tool
directly determines the binding heat of two species1 and are
used to characterize the binding thermodynamics in the
chemical and the biological systems such as complexation of
isoleucine by phosphorylated calix[4]arene2, solvation changes
in cyclodextrin complexes3, complexation of glyco- and tauro-
conjugated bile salts with modified β-cyclodextrins4, associa-
tion of surfactants with β-cyclodextrin5 and proteins6. The other
hosts:guests interactions of cations and anions7 using isothermal
titration calorimetry has been reported in the literatures. Not
only isothermal titration calorimetry determines the binding
stoichiometry and affinity as well as the binding entropy and
enthalpy, but also it used to characterize the self-association
of some polymers8 and the binding constant of water-soluble
calix[4,6]arene sulfonates towards acetylcholine9. Mun et al.10
used isothermal titration calorimetry to investigate interactions
between cycloamylose and three surfactants with C12 non-polar
tail groups and charged or non-charged head-groups.
EXPERIMENTAL
Synthesis procedure: Methylation of p-tert-butylcalix[4]-
arenes (1) with 1 equivalent of K2CO3 in MeCN and methyl
tosylate at reflux for 40 h yielded 88 % dimethoxycalix[4]arene
(2). Initially, more than 2 equivalents of BrCH2CO2Et was
added to the reaction mixture, then another one equivalent
was added after 4 h. The reaction was terminated after another
3 h. Owing to the low electrophilic reactivities of BrCH2CO2Et
and ICH2CO2Et, highly polar DMF was used as the slvent,
which greatly facilitate the nucleophilic reaction comparing
to MeCN. Diester 3 was obtained in 80 % yield. To avoid
trapping of metal cations, diester 3 was hydrolyzed with
tetramethylammonium hydroxide in aqueous THF at reflux
to provide 95 % yields of calix[4]arene dicarboxylic acid (4).
This derivative was refluxed with oxalyl chloride in benzene
to give the corresponding di(acid chloride), which were used
without further purification for reactions with the sodium salt
form of appropriate sulfonamide to give 6 in 80 % yield. Other
isoconformers were synthesized using the first scafold of 1,2-
alternate and partial-cone. Fig. 2 illustrated the synthesis
procedure of calix[4]arenes bearing two N-(X) sulfonyl
carboxamides pendant groups.
Nano-baskets of calixarenes have been subjected to exten-
sive researches in development of transporters, extractants,
stationary phases, electrode ionophores and optical sensors
over the past decades11-28. Therefore, the aim of this study is to
highlight the role of isothermal titration calorimetry in
calixarene-base researches, in which the interactions of
calixarenic hosts and cationic guests are assessed. Moreover,
the binding constants of di-ionizable p-tert-butylcalix[4]arene
conformers towards dissolved alkali metal cations were
All of the experiments carried out using nine confor-
mations of di-ionizable p-tert-calix[4]arene di-[N-(phenyl)-

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14 Mokhtari et al.
Asian J. Chem.
sulfonyl carboxamide]. According to the synthesis procedure
that is shown in Fig. 2, two cone conformers (7 and 8), two
1,3-alternate conformers (9 and 10), three 1,2-alternate
conformers (11-13) and four partial-cone conformers (14-17)
were synthesized to extract alkali metals. The cis/trans symbols
refer to the direction of two di-ionizable moieties and the ortho/
para depict the relative situation of two di-ionizable moieties.
Fig. 3 shows the chemical structure of those nine conformations
7-17 (R group is defined as: -OCH2CONHSO2Ph. Fig. 3 shows
the chemical structure of selected di-ionizable calix[4]arene
conformers.
Ring
Conformation
Orientation
Isomerisation
Posinional
Isomerisation
ortho-
para-
cis-
Cone
ortho-
cis-
Calix[4] arene
1,2- alternate
ortho-
para-
trans-
para-
para-
cis-
1,3- alternate
Partial Cone
trans-
ortho-
para-
cis-
ortho-
para-
trans-
Fig. 1. Hierarchical structure of complexes were investigated using isothermal titration calorimetry experiments
Fig. 2. Synthesis procedure of calix[4]arenes with elongated N-(X)sulfonyl carboxamides

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Vol. 25, No. 1 (2013)
Calorimetric Investigation of Nano-Basket’s Binding 15
Fig. 3. Structures of di-ionizable p-tert-butylcalix[4]arene conformers 7-17
Calorimetric setup and procedure: The micro-calorimetry
system (MCS) was manufactured by MicroCal Inc. (Northampton,
MA) including an isothermal titration calorimetry unit. The
isothermal titration calorimetry unit was combined with an
external water bath (Isothemp Model 3016 D) and the hosts:
guests interactions were recorded using the MCS Observer
software. Using a basic solvent, the proton-ionizable calix[4]-
arene conformers were de-protonated in methanol. 5 mM
tetrabutylammonium hydroxide in dried methanol was used
as the solvent for both the alkali metal chloride solutions and
the di-ionized calix[4]arene conformers. Solutions of
calix[4]arene conformers and alkali metal chloride were
prepared in a concentration range of 1 mM and 8-20 mM,
respectively. A 2.5 mL glass syringe with a long needle was
used to inject the sample and the reference solutions into the
isothermal titration calorimetry cells. The reference cell was
filled with ca. 1.7 mL of methanol and the calixarenic solution
was injected into the sample cell after rinsing it. The solution
of alkali metals was loaded into a 250 µL injection syringe
through a holder assembly.
RESULTS AND DISCUSSION
Thermodynamics of conformer's binding: Solvent
extraction results showed that sodium, potassium and rubidium
cations were selectively extracted by the cone di-ionizable
p-tert-butylcalix[4]arene derivatives (7, 8), conformers (9-11)
and 1,2-alternate conformers (12, 13), respectively. The
extractions using partial-cone conformers (14, 15) were un-

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16 Mokhtari et al.
Asian J. Chem.
selective, while derivatives (16, 17) showed a high selectivity
towards potassium. For conformers (16, 17) no extraction
tendency was found for cesium and rubidium cations. However,
for all conformers one or two-step bindings for sodium cations
were obtained as shown in Table-1. For ligands with two-step
bindings at the same binding site or two binding sites, the first
binding is often stronger than the second by at least two orders
of magnitude in the K values. The exceptions are symmetric
conformers (10, 12, 13), in which the K values are same. The
comparison of log K for the first binding is more significant.
The interaction of alkali metal cations with two nitrogen donors
of the N-phenyl-sulfonyl carboxamides substituents is not
favourable due to the steric repulsion. The proposed binding
sites may be contributed by ion-dipole interaction of one
alkali metal cation with one nitrogen donor of the N-phenyl-
sulfonyl carboxamides substituent. According to Table-1, the
conformers 7, 8 exhibited one-step binding and slightly weaker
binding affinity towards sodium cations than 9, 10. Fig. 6 (C1)
depicted a proposed model for binding of cone calix[4]arene
conformer 7 towards sodium cations. In similar way, the
conformer 8 binds to the sodium cations.
TABLE-1
STOICHIOMETRIES AND BINDING CONSTANTS FOR
INTERACTION OF SODIUM WITH CONFORMERS 7-17
The bindings of 9-13 with alkali metal cations exhibited
two-steps mechanisms. In the first step, one metal cation is
bonded with one or two nitrogen atoms at the lower rim. The
second step is proposed when another metal cation is bonded
to the other side of calixarenic scaffold. As show in Table-1,
in conformer 9 the first step of binding is stronger than the
second with 3.2 orders of magnitude difference in K values
towards sodium cations. On the other hand, owing to the steric
symmetry of conformers 10, 12, 13 there were not any signi-
ficant differences in the K values towards sodium cations.
Fig. 6 (C2 and C3) illustrated the schematic of the first step as
well as the second step for 1,3 alternate conformer 10 (also 9).
According to Table-1, in conformers 11-13 there are two
steps for binding to sodium cations, in which both of them are
presented schematically in Fig. 6 (C4 and C5). Among three
conformers in form of 1,2 alternate, derivatives 12, 13 are
symmetric and there are not any difference in K values towards
sodium cations, as presented in Table-1. While in conformer
11, the first step binding is stronger than the second step
because of a two-way interaction between cation and the
calixarene scaffold including the cation-π interaction between
alkali metal cation and the inverted aromatic units in confor-
mers as well as the ion-dipole interaction with the nitrogen
atoms on the lower rim. Fig. 6 (C4 and C5) shows the schematic
of the first and the second steps for 1,2 alternate conformer 11
(also conformers 12, 13).
Binding
stages
Conformers
n1
log K1
n2
log K2
7
1
1
2
2
2
2
2
1
1
1
1
0.58
0.62
0.92
0.80
0.42
0.50
0.50
0.26
0.24
0.12
0.18
6.36 0.08
6.54 0.06
-
-
-
-
8
9
7.87 0.08 0.72
7.70 0.10 0.80
4.31 0.02 0.53
3.12 0.04 0.50
3.11 0.03 0.50
4.64 0.02
10
11
12
13
14
15
16
17
7.68 0.08
3.48 0.05
3.13 0.04
3.13 0.03
1.11 0.02
1.00 0.01
0.64 0.01
0.68 0.01
-
-
-
-
-
-
-
-
Calix[4]arene derivatives (7,8) in cone conformation
showed clear one-step binding. Derivatives (9-13) depicted
two-step binding towards with log K differences of 1 to 3
between the first and second binding constants. Conformers
(14-17) in partial-cone conformer showed one-site binding.
The raw data from isothermal titration calorimetry experiments
using conformers (8-11) is showed in Fig. 4, respectively.
Influence of the conformation variation: Conforma-
tional variation had an important influence on cation binding
affinity for conformers (7-17). As shown in Table-1, the log K
values for sodium binding decreased from the 1,2-alternate
conformation to the partial-cone conformers. In this case, the
isothermal titration calorimetry results were consistent with
the solvent extraction results, which are illustrated in Fig. 5.
In the solvent extraction results, the 2-alternate conformers
(14, 15) did not show outstanding extraction selectivity.
Sodium cations could have an ion-dipole interaction with
the nitrogen atoms on the lower rim of cone conformers 7, 8.
However, the binding is not contributed to the π interaction
between alkali metal cation and the aromatic units in confor-
mers due to opposite situation of them. The bindings of 7, 8
with alkali metal cations both exhibited one-step mechanism.
Base upon the data in Table-1, in conformers 14-17 an
one-step binding to sodium cations was distinguished.An ion-
dipole interaction between sodium and nitrogen atom(s) as
well as a weak π interaction between cation and the inverted
aromatic unit in conformers is responsible for complex forma-
tion. A second stage binding towards sodium cations was not
distinguished and it shows that the steric affect in the upper
rim of partial-cone conformers 14-17 constraints the binding
mechanism to one-step. Such steric affect was related to three
t-butyl moieties on the upper rim. Fig. 6 (C6) depicted the
binding schematic for conformer 16 as well as 14, 15, 17.
60
60
60
58
58
58
58
56
56
56
56
54
52
50
48
46
54
52
50
48
54
54
52
52
50
50
0
50
100
150
0
50
100
150
0
50
100
150
0
50
100
150
Time (min)
Time (min)
Time (min)
Time (min)
Fig. 4. Raw data from isothermal titration calorimetry titrations present one-step binding for 8-11 scaffolds towards Rb+