Synthesis of biscalix[4]arene with enhanced binding ability to a cationic guest

Article abstract of DOI:10.1016/S0040-4039(01)01577-5

The biscalix[4]arene showed remarkably enhanced inclusion ability for the N-methylpyridinium ion due to the increasing π-basicity of the benzene rings, which interact with the guest in an edge-to-face manner, in calix[4]arene skeletons.

Full text of DOI:10.1016/S0040-4039(01)01577-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7465–7468
Synthesis of biscalix[4]arene with enhanced binding ability to a
cationic guest
Koji Araki,a,* Tomokazu Watanabe,a Monoru Oda,a Hiromi Hayashida,a Mikio Yasutakeb and
Teruo Shinmyozub
aDepartment of Applied Chemistry, Kyushu Institute of Technology, 1-1 Sensui-cho, Tobata-ku, Kitakyushu 804-8550, Japan
bInstitute for Fundamental Research of Organic Chemistry, Kyushu University, 6-10-1 Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
Received 11 June 2001; revised 6 August 2001; accepted 24 August 2001
Abstract—The biscalix[4]arene showed remarkably enhanced inclusion ability for the N-methylpyridinium ion due to the
increasing p-basicity of the benzene rings, which interact with the guest in an edge-to-face manner, in calix[4]arene skeletons.
© 2001 Elsevier Science Ltd. All rights reserved.
Calixarenes, a new class of synthetic macrocycles having
phenolic units linked by methylene groups, have received
considerable attention for host guest chemistry in the last
decade.1 The architecture of the calixarene can provide
a p-basic cavity. Hence, they are useful for designing a
globular p-basic cavity by connecting the upper rims of
two calixarenes.2–10 We previously demonstrated that
conformational isomers derived from calix[4]arenes are
very useful for estimating the contribution of the cation-p
interaction11 to the host–guest complexation process,12
and biscalix[4]arene 1 prepared by connecting two con-
formationally immobile calix[4]arenes with two spacers
at the upper rims has significant inclusion ability for
positively charged aromatic guests with a disk shape.13
The rigid conformation of the biscalix[4]arene skeleton
permits prediction of the complex structure as shown in
Fig. 1. Two possible orientation modes of cation-p
interaction can be seen in the complex. One is the
edge-to-face type interaction between the flattened ben-
zene rings in the biscalix[4]arene and the guest protons
that are vertically in contact with them. The other is the
face-to-face interaction between the benzene rings, which
are connected with the spacers at the p-positions and
stand in parallel, in the biscalix[4]arene and the guest
p-system sandwiched with them (Fig. 2). To clarify the
contribution of these two interactions to the binding
R
R
O
R
face-to-face type interaction
R
O O
O
π
π
+
O
N
H
H
H
H
RO
RO
OR
OR
N+
O
O
R
O
R
O
R
R
π
π
Figure 1. Schematic representation for the proposed complex
structure.
edge-to-face type interaction
Keywords: calixarenes; cation-p interaction; host–guest complexation.
* Corresponding author. Fax: +81 93 884 3318; e-mail: araki@
che.kyutech.ac.jp
Figure 2. The edge-to-face and face-to-face type interaction in
the biscalix[4]arene complex.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01577-5

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K. Araki et al. / Tetrahedron Letters 42 (2001) 7465–7468
1
force on the complexation of the biscalix[4]arene, we
designed a new biscalix[4]arene 2 with four phenol units
that will interact with the peripheral protons of a
disk-shaped guest in an edge-to-face manner. If the
edge-to-face type interaction is the predominant inter-
action as the intermolecular attractive force for the
complexation with the cationic guests, 2 would show
enhanced inclusion ability for the cationic guests
because the phenol units in 2 provide increasing p-
basicity compared with the propoxybenzene units in 1.
We now report the synthesis and the inclusion proper-
ties of the biscalix[4]arene 2.
spectral evidence and elemental analysis. The H NMR
spectrum of 2 shows two sets of doublets for the
ArCH2Ar methylene protons, indicating that both of
the two calix[4]arene skeletons adopt the cone
conformation.
The inclusion properties of 2 to N-methylpyridinium
(4) iodide were examined using 1H NMR measure-
ments. It is reported that the chemical shifts for the
protons in the quaternary ammonium ions are only
slightly shifted to a higher magnetic field in the pres-
ence of calix[4]arenes, and the cation-p interaction
between the calix[4]arenes and the cationic guests is
quite weak.12 The H NMR spectrum of 4 iodide (10.0
1
Pr
Pr
mM) in the presence of 2 (5.0 mM), on the other hand,
gave two separated peaks for each proton at 25°C in
CDCl3, which are assigned to the complexed and
uncomplexed 4. These peaks did not coalesce into an
average peak even at 130°C in 1,1,2,2-tetra-
chloroethane-d2. This remarkably high coalescence tem-
perature, Tc, reveals that the dynamic process during
the complexation and the decomplexation is much
slower than the NMR time scale, suggesting that 4 is
tightly encapsulated in the inner sphere of 2 and the
complex is quite stable.
O
O
O
RO
OR
O
OR
Pr
RO
O
O
Pr
1: R = n-Pr
2: R = H
The peaks for all the protons in 4 were shifted to the
upper magnetic field upon complexation, i.e. the chemi-
cal shifts of the a-, b-, g- and N-methyl protons in the
complexed 4 were 3.82, 4.08, 4.91 and 1.61 ppm and
those in the free 4 were 9.38, 8.12, 8.48 and 4.73 ppm,
respectively. These significant upfield shifts rationalized
by the shielding effect of the benzene rings in 2 imply
that 4 is included in the inner sphere of 2. Indeed, these
upfield shifts caused by the complexation were not
observed for nonionic guests such as pyridine, picoline,
benzene or toluene. The essential cationic charge in the
guests establishes the significant contribution of the
cation-p interaction to the formation of the complex in
2.
The biscalix[4]arene 2 was synthesized from cone-25,27-
dibenzyloxycalix[4]arene14 3a according to Scheme 1.
The products were identified by IR, H NMR and mass
1
OR1
OR2
CH2
CH2
2
X
3a: R1 = Bn, R2 = H, X = H
3b:
3c:
3d:
3e:
R1 = Bn, R2 = H, X = Br
R1 = Bn, R2 = Pr, X = Br
R1 = Bn, R2 = Pr, X = OH
R1 = H, R2 = Pr, X = OH
The association constants Ka of 1 and 2 for 4 picrate
were estimated using UV–vis spectroscopy. For exam-
ple, the UV–vis spectra of 4 gave an absorbance maxi-
mum at 361 nm in the absence of 2 in CHCl3. With the
addition of 2, the absorbance at 361 nm decreased and
that at 378 nm assigned to the complex increased. This
bathochromic shift indicates that 4 and the picrate
anion form a separated ion pair and the picrate is left
outside of 2. This behavior of 2 as a molecular capsule
is characterized by the steric shielding of 4 from contact
to the picrate. The plot of the absorbance versus [2]/
[guest] gave a gradual curve indicating the 1:1 stoi-
chiometry of the host and guest for the complex. The
Ka values were determined by the curve fit method for
these plots using the computer-assisted nonlinear least-
square procedure. The Ka for the complex of 1 with 4
was 1.55×104 dm3 mol−1, whereas that of 2 was 5.13×
106 dm3 mol−1, which is greater by 330-fold than that of
1. Obviously, this significant enhancement in Ka is
attributed to the increasing p-basicity of the flattened
3f: R1 = Bn, R2 = Pr, X = COOH
3g:
3h:
R1 = Bn, R2 = Pr, X = CH2OH
R1 = H, R2 = Pr, X = CH2Br
iii, iv, v
i
ii
vi
3a
3b
3c
3d
3e
85 %
97 %
95 %
80 %
iii, vii
97 %
viii
vi
3f
3g
3h
91 %
82 %
ix
3e + 3h
2
38 %
Scheme 1. Synthesis of 2. Reagents and conditions: (i) Br2,
CHCl3, 0°C; (ii) n-PrBr, NaH, DMF, 0°C; (iii) n-BuLi, THF,
−78°C, 1 h; (iv) B(OCH3)3; (v) AcOH, H2O2; (vi) TMSBr,
CHCl3, rt, 1 h; (vii) CO2; (viii) LiAlH4, THF, reflux, 24 h; (ix)
Cs2CO3, THF, reflux, 2 days.

K. Araki et al. / Tetrahedron Letters 42 (2001) 7465–7468
7467
benzene rings, which interact with the guest protons in
an edge-to-face manner.
adopt the pinched cone conformation with C2v symme-
try, i.e. the two benzene rings connected with the
spacers at the p-positions stand almost parallel and the
other two phenol units are flattened in each
calix[4]arene skeleton. When 2 forms the complex with
a disk-shaped guest, the guest is probably sandwiched
between the perpendicular benzene units, and conse-
quently the highly directional CꢀH bond in the guest
will be in contact with the phenol units in 2 in an
edge-to-face manner.
Computational studies using molecular mechanics and
semiempirical molecular orbital calculations with PM3
approximation predicted the pinched cone conforma-
tion for both calix[4]arene skeletons in 2. The signifi-
cant enhancement in Ka for the complex of 2 cannot be
explained by a similar structure predicted for 1. The
plane canting angle, which is defined as a dihedral angle
between the phenyl plane and the mean plane of the
bridging methylene carbons, for 2 is larger than that for
1. However, the CPK model and computer-assisted
calculation examination revealed that 1 possessed a
suitable room of the inner cavity to form the tightly fit
complex with N-methylpyridinium whereas the cavity
of 2 was somewhat large to suitably include it. In spite
of this disagreement on the size of 2 and the guest, the
fact that the Ka for 2 is larger than that for 1 will
support the explanation by not the steric factor but by
an electrostatic factor.
The UV–vis spectra of 4 iodide (0.5 mM) gave an
absorbance maximum at 371 nm in the absence of 2 in
CHCl3 which is assigned to the charge-transfer (CT)
band from the iodide anion to the pyridinium cation.
By the addition of 2 (0.5 mM), the absorbance at 371
nm disappeared and no other band assigned to the CT
band appeared. Although the CT band for the complex
of 2 with a stronger acceptor molecule, 1,1%-dimethyl-
4,4%-bipyridinium, was observed as a shoulder at longer
wavelengths than 400 nm, the chemical shift changes in
1
the H NMR spectra were not observed for the 1,1%-
The most definitive proof for the structure of 2 came
from an X-ray crystallographic analysis.15 The single
crystal was obtained as a 2·3CHCl3 complex from the
CHCl3 solution. One CHCl3 molecule occupies the
inner sphere of 2 and the others are in the crystal
lattice. As shown in Fig. 3, both calix[4]arenes in 2
dimethyl-4,4%-bipyridinium upon the complexation,
indicating that 2 formed the exo-complex with the guest
molecule and it was located outside of 2. The p–p
interaction of the face-to-face type in the complex of 2
can be reasonably regarded as the CT interaction,
because it is the p–p stacking between the acceptor
aromatic molecule with a positive charge and dialkoxy-
benzene. However, the UV–vis data obviously support
the extremely weak possibility that the main driving
force for the complexation of 2 with the N-methylpyri-
dinium is the CT interaction of the face-to-face type.
The CꢀH bonds have been considered to weakly inter-
act with a molecular fragment bearing a partial nega-
tive charge or polarized electron cloud, because they
generally have a small dipole moment with a positively
charged hydrogen atom. The positive charge signifi-
cantly enhances the polarity of the CꢀH bonds and the
acidity of the hydrogen atom in the guests. Therefore,
the positive charge in the guests is essential for the
host–guest systems of the biscalix[4]arenes. The preor-
ganized phenol units in 2 behave as a p-base. The
property of the hydroxy group as an electron-donating
substitution is not much different from that of the
propoxy group; Hammett constant |p=−0.37 and |m=
0.12 for OH, |p=−0.27 and |m=0.12 for OMe. How-
ever, the hydroxy groups in 2 form the hydrogen
bonding to the neighboring propoxy groups and the
hydrogen bonding must enhance their polarization.
In conclusion, the present study showed that the bis-
calix[4]arene involving the phenol units has improved
inclusion ability for the N-methylpyridinium ion due to
the cation-p interaction, and the contribution of the
CH-p interaction with the edge-to-face contact to the
cation-p interaction is important. An appropriate
molecular design for the calixarene host proved that the
edge-to-face interaction was useful as an intermolecular
attractive force for molecular recognition.
Figure 3. X-Ray crystal structure of 2. The hydrogen atoms
are omitted for clarity.

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K. Araki et al. / Tetrahedron Letters 42 (2001) 7465–7468
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