Calix[4]arene-based ditopic receptor for dicarboxylates

Article abstract of DOI:10.1016/j.tetlet.2004.01.118

Shape-selective recognition for the dicarboxylates in DMSO can be attained by a new calix[4]arene-based receptor 1 having two urea groups. Biologically active chorismate selectively bound in 1 over its dehydrated derivative. Molecular mechanics calculations gave a plausible explanation for the selective binding.

Full text of DOI:10.1016/j.tetlet.2004.01.118

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2281–2284
Calix[4]arene-based ditopic receptor for dicarboxylates
Takeharu Haino, Masaki Nakamura, Nobuki Kato, Miki Hiraoka
and Yoshimasa Fukazawa*
Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Hiroshima,
Higashi 739-8526, Japan
Received 23 October 2003; revised 22 January 2004; accepted 26 January 2004
Abstract—Shape-selective recognition for the dicarboxylates in DMSO can be attained by a new calix[4]arene-based receptor 1
having two urea groups. Biologically active chorismate selectively bound in 1 over its dehydrated derivative. Molecular mechanics
calculations gave a plausible explanation for the selective binding.
Ó 2004 Elsevier Ltd. All rights reserved.
Carboxylates are involved in many biological recognition
events, and some of them play a key role in the regulation
of biological process. The selective recognition of carb-
oxylates by synthetic receptors becomes a topic of current
interest in supramolecular chemistry. Carboxylate rec-
ognition has been widely investigated with many artificial
receptors,1 including several calix[4]arene-based ones
employing fluoro alcohol,2 amide3 and (thio)urea4 on
their upper rim. These calix[4]arene-based receptors can
bind to mono- and dicarboxylates; however, the shape-
selective recognition for dicarboxylates is limited so far.
This is probably due to the limited binding environment
in the pinched cone conformation of the O-alkylated
calix[4]arenes.3d;e;5 We envisioned to construct the pre-
organized guest-binding space on the calix[4]arene upper
rim in which dicarboxylates can accommodate selec-
tively. During the last decade, our group has investigated
the upper rim functionalized calixarene hosts for neutral
guests.6 In this paper we report the shape-selective rec-
ognition of dicarboxylates with calix[4]arene-based syn-
thetic receptor 1 in DMSO.
groups away from each other. This provides the large
guest-binding space in which the urea groups will act
simultaneously in grasping a proper bifunctional anion
with hydrogen bonds.
Bn
H
H
OBn
O
O
O
H
N
H
H
H
N
N
O
1
N
O
The synthesis of 1 started from dibromocalix[4]arene 27
according to Scheme 1. Compound 2 was subjected to
react with sodiumhydride. The resulted diphenolate was
treated with methoxymethylchloride to give dibromo-
calix[4]arene 3 only in the cone conformation. Palladium
catalyzed coupling between 3 and organozinc reagent 4
proceeded smoothly, and subsequent treatment of
TBAF gave diol 5. Mitsunobu reaction of 5 with
phthalimide, triphenyl phosphine, and DEAD in THF,
followed by treatment with hydrazine gave diamino-
calix[4]arene 6.
Placing hydrogen-bonding groups on the calix[4]arene
platform should be an effective strategy for a receptor of
carboxylates. Two urea groups are attached with the
aromatic linkages on the upper rim. The para-xylylene
spacer and the lower rim intramolecular hydrogen
bonding of phenolic hydroxyl groups keep the urea
Keywords: Calix[4]arene; Supramolecular chemistry; Host–guest chem-
istry; Hydrogen bonding; Molecular mechanics.
The cyclization reaction of 6 with isocyanate equivalent
7 smoothly proceeded to give the diurea derivative,
* Corresponding author. Tel.: +81-824-24-7427; fax: +81-824-24-0724;
e-mail: fukazawa@sci.hiroshima-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.118

2282
T. Haino et al. / Tetrahedron Letters 45 (2004) 2281–2284
CH2
OBn
CH2
OBn
OH
Br
OH
Br
OBn
OMOM
Br
OMOM OBn
Br
a
2
3
CH2
OMOM OBn
OMOM OBn
d, e
b, c
5
OH
OH
CH2
OMOM OBn
OMOM OBn
f, g
1
6
NH2
NH2
ZnCl
Scheme 1. Reagents and conditions: (a) MOMCl, NaH/DMF 70%; (b) Pd(PPh3)4,
4/THF; (c) TBAF/THF 72%; (d) phthalimide, DEAD,
OTBS
O
N
O
N
N
N
PPh3/THF 83%; (e) H2NNH2/EtOH 93%; (f)
7/DMF 29%; (g) 6 N HCl/EtOH 97%.
H
H
N
N
which was treated with acidic ethanol. The desired
receptor was given in reasonable yield.
1:1 complex formation between the host and the guest.
A nonlinear least square curve-fitting analysis9 gave an
association constant, 1100 200 Mꢀ1
.
Receptor 1 showed good solubility in DMSO, known as
a highly competitive solvent to hydrogen bonding. The
ditopic binding sites of 1 are solvated in DMSO and
hence, multipoint hydrogen bonds between 1 and a
guest are required for the effective complexation.
Dicarboxylates 8–15 are selected as guests because of the
complementary multipoint hydrogen bonds to the urea
group8 (Fig. 1).
The binding abilities of guests 9–16 toward 1 were
evaluated in DMSO. In all cases, the characteristic
down-field shift of the urea N–H resonance was
observed. From the titration experiment, the association
constants were estimated (Table 1).
All the ditopic guests 8–15 bind more strongly than
benzoate 16. Previously reported bisureido calix[4]arene
selectively bound monocarboxylates over dicarboxy-
lates.4f The different binding manners suggest that the p-
xylylene spacer plays a crucial role in the dicarboxylate
recognition. However, the p-xylylenebisurea unit itself
hosts dicarboxylates.10 The binding behavior of N,N00-
(p-xylylene)bis(N0-benzylurea) 1711 was evaluated for the
carboxylates (9: Ka ¼ 130 10M ꢀ1, 16: Ka ¼ 43 3 Mꢀ1).
Dicarboxylate 9 complexes with 1 ca. four times as
strongly as with 17 while monocarboxylate 16 does not
shows any selective binding. This clearly indicated that
1H NMR spectrum of 1 in DMSO-d6 gave the sharp N–
H resonances. When bis(tetrabutylammonium)-4-tert-
butylisopthalate 8 was added to the solution of 1, the N–
H resonances shifted down field. This indicative shifts
provide the evidence for the formation of the hydrogen-
bonded complex even in DMSO (Fig. 2).
The stoichiometry of the host–guest complex was stud-
ied by Jobꢀs plot. The amount of the host–guest complex
reached a peak at the mole fraction of 0.5. This confirms
(ppm)
0.2
X
-
CO2
-
-
CO2
-
O2C
O2C
-
-
CO2
O2C
8: X= t-Bu
11
12
9:
10:
H
OMe
-
CO2
0.1
0.0
∆δ
CH2
CO2
-
-
CO2
4
O2C
-
O
OH
13
14
-
CO2
CH2
CO2
-
-
O
0.0
0.5
1.0
CO2
Mole fraction of 1
15
16
Figure 1. The carboxylates for the binding studies of 1.
Figure 2. Jobs plot for guest 8 with 1.

T. Haino et al. / Tetrahedron Letters 45 (2004) 2281–2284
Table 1. Binding constants (Mꢀ1) of 1 with various carboxylates 8–16
in DMSO-d6 at 298 K
2283
Guest
Ka
Guest
Ka
8
1100 200
490 30
170 10
180 10
370 30
13
14
15
16
650 100
600 50
150 30
9
10
11
12
43
2
the combination of the calix[4]arene and the p-xylyl-
enebisurea produced the selective recognition toward
the dicarboxylates.
As expected, the shape selectivity of 1 toward the guests
9, 11, and 12 is very substantial, reflecting the directional
interaction of the hydrogen bonding. It is known that in
the case of hydrogen-bonding interaction between car-
boxylate anion and urea group, two linear hydrogen-
bond pair is more stable than two bent pair (Fig. 3).12
Comparison of the binding constants for guests 8–10
suggested the importance of the electronic effect on the
hydrogen-bonding interaction. A simple model building
consideration suggested that the host is not large enough
to accommodate the guests thoroughly within its cavity
when two-bent hydrogen bonds between the carboxylate
and urea groups were applied twice. Actually, the
molecular mechanics calculation by MacroModel V.6.5
using MMFF force field13 gave the most stable structure
(Fig. 4a) in which the benzene ring of the guest stays
outside from the host cavity. This implies that the
nondirectional forces (van der Waals, CH/p, p–p
stacking etc.) between the guest and the host cavity do
not play an important role in the complex formation.
Hence, Hammett plot of the binding strengths DG ver-
sus substituents constants rm (–t-Bu: )0.1, –OCH3:
0.12)14 gave a good correlation ðR2 ¼ 0:99Þ, suggesting
that the basicity of the dicarboxylate regulates the guest
selectivity.
Figure 4. Stereo drawings of the complexes of 1 (a) with 9, (b) with 13,
(c) with 14, and (d) with 15, obtained by MacroModel calculation.
In a series of flexible guests 13–15, a sizable difference of
the binding constant was observed. Although the num-
ber of the rotable bond in 14 and 15 is identical to each
other, the binding constant of 14 is much larger than
that of 15. Compound 13 is the most flexible among the
three, but its binding constant is rather similar to that of
14.
double two linear hydrogen-bond pairs can explain the
large binding constant of 13, which can be attained due
to the flexibility of the side chain of 13. However, an
entropic cost for adjusting to the favorable guest con-
formation prevented to have much larger binding con-
stant. Because of the smaller number of the rotable bond
in 14 and 15, bent hydrogen-bond pair was seen in both
complexes 1Æ14 and 1Æ15. This is a reasonable explana-
tion of the small binding constant of the latter. Extra
stabilization of the former complex might be the further
reduction of the flexibility of the guest. It deduces the
entropic cost for the complex formation (Fig. 4c). The
intramolecular hydrogen-bonding interaction between
the C4 hydroxyl group and the side chain carboxylate is
well known even in polar solvents15 and it reduces the
conformational flexibility of the guest. Nondirectional
forces between the host cavity wall and the guest might
be the favorable interaction in the complex formation in
these cases.
Two types of hydrogen bonding are seen in the most
stable structure of these complexes (Fig. 4). Favorable
O
H
N
N
O
H
N
N
O
O-
O
O-
H
H
(a)
(b)
Figure 3. Two different types of the hydrogen-bonding interactions (a)
linear, and (b) bent hydrogen bonding between carboxylate and urea
groups.

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T. Haino et al. / Tetrahedron Letters 45 (2004) 2281–2284
Lett. 1999, 40, 6301–6304; (c) Haino, T.; Matsumura, K.;
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In conclusion, we developed the upper rim functional-
ized calix[4]arene receptor having two urea groups,
capable of binding selectively to the dicarboxylates over
the monocarboxylate. The shape selective recognition
among the dicarboxylates were achieved. Molecular
mechanics calculation gave a helpful information for the
rational explanation of the selectivity.
7. Shimizu, S.; Shirakawa, S.; Sasaki, Y.; Hirai, C. Angew.
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