Crowned dendron: Ion-responsive flexibility of macromolecules induced by integrated crown ether moieties

Article abstract of DOI:10.1016/j.tet.2005.06.037

Polybenzyl ether type dendrons bearing the crown ether moieties at the periphery, namely, crowned dendrons were synthesized, and the effect of complex formation on their flexibility with metal-ion binding properties was examined. Upon addition of Na⁺, ¹H NMR spectra of the crowned dendrons in CD₃CN were significantly broadened, reflecting the flexibility restriction of the crowned dendrons by the complex formation with Na⁺. Such a significant flexibility restriction was observed only with Na⁺, although ESI-MS studies revealed that the crowned dendrons formed 1:2 complexes (a metal ion:the crown ether moiety) regardless of the kind of metal ions. The flexibility restriction became significant with increasing dendron generation on the basis of ¹H NMR spectra and spin-lattice relaxation time (T₁) measurements. Binding constants of the crowned dendrons with metal ions in CD₃CN decreased with the increase of the dendron generation, reflecting an influence of the charge repulsion as well as a dendrimer effect to cause the steric hindrance. The examination of UV-vis absorption spectra for complexes of the crowned dendron with metal picrates in THF displayed the formation of a loose ion-pair complex with Na⁺, namely, a typical sandwich type complex. However, in CH₃CN, all metal picrates were solvated to be in a loose ion-pair even without complex formation. These results suggested that the control of macromolecular flexibility with metal ions is feasible by the integration of crown ether moieties with a dendritic structure.

Full text of DOI:10.1016/j.tet.2005.06.037

Tetrahedron 61 (2005) 8159–8166
Crowned dendron: ion-responsive flexibility of macromolecules
induced by integrated crown ether moieties
b
c
c
a,†
Mutsuo Tanaka,a, Yoshihiro Higuchi, Naoki Adachi, Yasuhiko Shibutani, Saleh A. Ahmed,
*
Shinpei Kado,b Makoto Nakamurab and Keiichi Kimurab,
*
aInstitute for Biological Resources and Functions, AIST, Central 5, 1-1-1, Higashi, Tsukuba, Ibaraki 305-8565, Japan
bDepartment of Applied Chemistry, Faculty of Systems Engineering, Wakayama University, 930, Sakae-dani, Wakayama,
Wakayama 640-8510, Japan
cDepartment of Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1, Ohmiya, Asahi-ku, Osaka 535-8585, Japan
Received 23 May 2005; revised 14 June 2005; accepted 14 June 2005
Available online 11 July 2005
Abstract—Polybenzyl ether type dendrons bearing the crown ether moieties at the periphery, namely, crowned dendrons were synthesized,
and the effect of complex formation on their flexibility with metal-ion binding properties was examined. Upon addition of NaC, 1H NMR
spectra of the crowned dendrons in CD3CN were significantly broadened, reflecting the flexibility restriction of the crowned dendrons by the
complex formation with NaC. Such a significant flexibility restriction was observed only with NaC, although ESI-MS studies revealed that
the crowned dendrons formed 1:2 complexes (a metal ion:the crown ether moiety) regardless of the kind of metal ions. The flexibility
1
restriction became significant with increasing dendron generation on the basis of H NMR spectra and spin-lattice relaxation time (T1)
measurements. Binding constants of the crowned dendrons with metal ions in CD3CN decreased with the increase of the dendron generation,
reflecting an influence of the charge repulsion as well as a dendrimer effect to cause the steric hindrance. The examination of UV–vis
absorption spectra for complexes of the crowned dendron with metal picrates in THF displayed the formation of a loose ion-pair complex
with NaC, namely, a typical sandwich type complex. However, in CH3CN, all metal picrates were solvated to be in a loose ion-pair even
without complex formation. These results suggested that the control of macromolecular flexibility with metal ions is feasible by the
integration of crown ether moieties with a dendritic structure.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
photochromic molecule afforded ion-responsive photo-
chromic materials.1 These contexts prompted us to study
flexibility behavior of macromolecules induced by complex
formation of integrated crown ether moieties. Recently,
dendrimer is one of the attractive macromolecules to
produce various function because of its ordered structure,
dendritic structure,2 and some dendrimers, which have
several molecular recognition sites have been reported.3
Therefore, we set out to synthesize a dendrimer bearing
crown ether moieties at the periphery, namely, crowned
dendrimer. In this macromolecule, the crown ether moieties
are integrated with a dendritic structure, and ion-responsive
flexibility induced by the complex formation of the
integrated crown ether moieties is expected.
In biological systems, the stimulation, recognition, and
response are a series of events to produce biological
functions, in which specific flexibility and shape persistence
of macromolecules are essential factors. The molecular
recognition to induce an allosterism through flexibility
control of macromolecules has been considered as one of
factors to produce biological functions such as non-linear
response, switching, self-restoration, and so on. To under-
stand such a biological system and to realize it artificially
have been a fascinating work in chemistry.
Our interest is in the manipulation of molecular functions
with metal ions in view of the molecular recognition. For
example, the combination of a crown ether moiety with a
Several crowned dendrimers have already been reported.4–7
In the case of dendrimers bearing crown ether moieties at
the periphery,4,5 however, any flexibility change by the
formation of metal ion complex in solution have not been
found.5 Among dendrimers bearing crown ether moieties at
the core,6,7 the first example of ion-responsive morphology
was reported in a mesophase.7 To the best of our knowledge,
Keywords: Dendron; Ion-responsive flexibility; Crown ether.
*
Corresponding authors. Tel.: C81 72 751 9209; fax: C81 72 751 9629;
e-mail: mutsuo-tanaka@aist.go.jp
† Present address: Chemistry Department, Faculty of Science, Assiut
University, 71516 Assiut, Egypt
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.037

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M. Tanaka et al. / Tetrahedron 61 (2005) 8159–8166
ion-responsive flexibility of crowned dendrimers in solution
has not been reported yet, although there is a report on a
dendrimer showing pH-responsive flexibility due to the
charge repulsion in solution.8
In this paper, we report the synthesis of a new macro-
molecule bearing crown ether moieties with a dendritic
structure, and its ion-responsive flexibility induced by its
metal ion binding.
2. Results and discussion
2.1. Synthesis
Crowned dendrons, Gn-X (nZ0–3, XZOH, Cl, or Br)
listed in Scheme 1 were synthesized according to a
convergent approach.9 We chose 12-crown-4 as a building
block for our crowned dendrimer because assembling
12-crown-4 moieties shows marked differences from the
single 12-crown-4 moiety not only in the metal-ion binding
ability but also in the complex structure; the 12-crown-4
moiety forms 2:1 complexes with NaC and 1:1 complexes
with LiC, respectively.10
Scheme 2. Synthesis outline. BnO18C6 represents benzyloxymethyl-18-
crown-6.
The adopted synthetic procedures for the crowned dendrons
are summarized in Scheme 2. At the first step, 12-crown-4
moiety was introduced at the para position of benzyl
alcohol to afford G0-OH. And the generation of the
crowned dendron was then increased according to
´
the synthetic procedures for Frechet type dendrimer in the
presence of benzyloxymethyl-18-crown-6 (BnO18C6) as a
phase transfer catalyst.11 The reactivity of benzyl hydroxyl
group at the focal position decreased with increasing
dendron generation, and finally, attempts to synthesize the
fourth generation dendron and the dendrimer with G3-OH
dendron were not successful. Therefore, we examined the
flexibility of maclomolecules with a dendron structure. The
structure of G3-OH did not seem to be too crowded to
hamper the reaction on the basis of the result of molecular
mechanics calculation. Some interaction of the crown ether
moieties with the reactant may disturb the subsequent
reaction.
2.2. Flexibility of G3-OH depending on metal ions
In order to investigate the influence of complex formation
on the flexibility of G3-OH, 1H NMR spectra were
measured in the presence of various alkali and alkaline-
earth metal ions in CD3CN at room temperature. Upon
addition of alkali metal perchlorates, a drastic down-field
shift in the spectra for protons of the crown ether moieties
was observed, which indicated complex formation of the
crown ether moieties with metal ions. The spectra of the
G3-OH protons of the crown ether moieties in the presence
of LiC and NaC are shown in Figure 1. In the case of NaC,
a significant broadening of spectra was induced. This
broadening obviously suggests that the flexibility of the
crowned dendron was restricted by the NaC complex
formation in 1H NMR time-scale. On the other hand, such a
significant broadening was not observed with other alkali
metal ions, although the down-field shift for the protons of
the crown ether moieties appeared with all the metal ions.
Scheme 1. Synthesized crowned dendrons.

M. Tanaka et al. / Tetrahedron 61 (2005) 8159–8166
8161
Furthermore, any spectral change was hardly observed in
the presence of RbC and CsC except for the down-field shift
of the crown ether protons. In the cases of alkaline-earth
metal ions, although a significant down-field shift was
observed for the protons of the crown ether moieties, any
spectral broadening could not be detected because of the
low solubility of the complexes. Those results suggest that
the complex formation affects the flexibility of G3-OH
depending on the kind of metal ions.
In order to investigate the influence of anion on the
flexibility of G3-OH, lithium and sodium picrates, the
picrate anion, of which is known as a large counteranion,
1
were added to G3-OH in CD3CN, and H NMR spectra
were examined. In the case of sodium picrate, some
1
broadening of H NMR spectra was observed in a similar
Figure 1. 1H NMR spectra for crown ether protons of G3-OH in the
presence or absence of metal ions in CD3CN at room temperature. The
concentrations of G3-OH and MClO4 were 1!10K3 and 1!10K2
mol dmK3, respectively.
way to the case of NaClO4. With lithium picrate, a down-
field shift indicating the complex formation was discernible,
but no broadening was detected. This result suggests that the
difference of the metal ion size controls the flexibility of
G3-OH rather than the difference of the anion size.
The spectral change induced by the complex formation was
found not only at the protons of the crown ether moieties but
also at all the protons of G3-OH. Especially, the peaks of
the G3-OH aromatic protons at the periphery (the protons of
the aromatic ring moiety adjacent to the crown ether moiety)
showed a very intriguing behavior depending on the kind of
metal ions, as depicted in Figure 2. In the presence of LiC,
the shape of the peaks were sharp with a down-field shift
indicating the complex formation with LiC, and such a
down-field shift was observed for all the protons in G3-OH.
To the contrary, the addition of NaC induced an up-field
shift with a significant broadening in the spectrum, and the
up-field shift was observed for all the protons except for the
protons of the crown ether moieties. At a higher
temperature, 70 8C, the spectrum with NaC became sharp
with a smaller up-field shift. Therefore, the up-field shift
induced by the NaC complex formation seemed to reflect
diamagnetic anisotropy of aromatic rings12 caused by the
flexibility restriction. In the case of KC, a slight up-field
shift was observed except for the crown ether protons. The
behavior of the KC complexation is similar to that of the
NaC complexation, but any broadening was not discernible.
ESI-MS measurements were carried out to determine how
many metal ions were captured by G3-OH in CH3CN. The
ESI-MS spectra showed that each G3-OH molecule holds
four metal ions, where the peaks at m/z of 842 with LiC and
at m/z of 858 with NaC were observed. Even in the presence
of 100-fold excess amount of LiC and NaC, each G3-OH
molecule was found to hold four metal ions at most. The
ESI-MS spectrum with NaC is shown in Figure 3.
1
Additionally, the Job plots for H NMR titration data gave
a maximum close to 0.8 in the molar fraction of LiC, which
is consistent with the ESI-MS result. Therefore, the crown
ether moieties tend to form 1:2 complexes (a metal ion:the
crown ether moiety) regardless of the kind of metal ions.
This result means that the difference between LiC and NaC
1
complexes of G3-OH in H NMR spectra was induced by
the difference in the metal ion size (LiCZ0.60 and NaCZ
˚
0.98 A) but not in the number of the captured metal ions.
´
In Frechet type dendrimer, a metal ion could be attached to
1
the benzyl ether oxygens. Upon addition of LiC, the H
NMR spectra for G3-OH showed a down-field shift induced
Figure 2. 1H NMR spectra for aromatic protons of G3-OH in the presence
or absence of metal ions in CD3CN at room temperature. The
concentrations of G3-OH and MClO4 were 1!10K3 and 1!10K2
mol dmK3, respectively.
Figure 3. ESI-MS spectra of G3-OH in the presence of NaClO4 in CH3CN.
The concentrations of G3-OH and NaClO4 were 1!10K5 and 1!10K3
mol dmK3, respectively.

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M. Tanaka et al. / Tetrahedron 61 (2005) 8159–8166
by complex formation with LiC for all protons. The down-
field shift for the crown ether protons was about 0.15 ppm
but that for the benzyl protons was much smaller being
between 0.05 and 0.07 ppm. Furthermore, in the case of
NaC, the down-field shift was observed only for the crown
ether protons, and ESI-MS measurements revealed that the
G3-OH can capture a maximum of four metal ions.
Therefore, the metal ion captured by G3-OH seems to be
located at the crown ether moieties.
induce any peak broadening in spectra for all the crowned
dendrons. However, in the case of NaC, the 1H NMR
spectral peaks became drastically broad with increasing
dendron generation (Fig. 5). This result indicates that the
flexibility restriction of the crowned dendron by NaC
complex formation depends strongly on the dendron
generation, that is, a dendrimer effect.
In Figure 4, the down-field shift induced by the LiC
complexation is increased with increasing the dendron
generation from DdZ0.01 for G0-OH to DdZ0.04 for
G3-OH. On the other hand, the up-field shift caused by the
NaC complexation showed an opposite tendency. The up-
filed shift induced by NaC is the most significant for
G1-OH (DdZK0.12) and is decreased with the increase
of dendron generation, being DdZK0.09 and K0.06 for
G2-OH and G3-OH, respectively. As anticipated, such an
up-field shift was not observed for G0-OH. This result again
implies that the difference in the metal ion size caused a
significant difference in the dendron flexibility.
Unfortunately, attempts to visualize the difference in
flexibility between LiC and NaC complexes of G3-OH
by atomic force microscopy (AFM) failed.
2.3. Dendrimer effect on flexibility
1
In order to evaluate the dendrimer effect, H NMR spectra
were examined for G0-OH, G1-OH, and G2-OH in the
presence of various alkali metal ions in a similar way to
G3-OH. The 1H NMR spectra of the aromatic protons at the
periphery in the presence of LiC and NaC are shown in
Figures 4 and 5, respectively. In Figure 4, LiC did not
In order to express the flexibility restriction of the dendron
numerically, the spin-lattice relaxation time (T1) in CD3CN
at room temperature was measured as an indicator for the
flexibility restriction of the crowned dendron, where the
decrease of intramolecular motion results in the T1 reduc-
tion. It is known that the complex formation of crown ethers
with metal ions reduces their T1 value in the NMR spectra
through the reduction of intramolecular motion.13 The T1
values of the aromatic protons at the periphery (protons of
the aromatic ring moiety adjacent to the crown ether moiety)
for G0w3-OH in the absence of metal ions were 3.5, 1.9,
1.5, and 1.3 s, respectively, which indicated the enhance-
ment of flexibility restriction with increasing the dendron
generation. When LiClO4 and NaClO4 were added to the
G3-OH solution, the T1 value decreased to 1.1 and 0.72 s,
respectively. This result clearly indicates that the metal
complex formation of G3-OH reduces the intramolecular
motion, namely, the flexibility, and that NaC is more
effective in the flexibility restriction than LiC. This
significant flexibility restriction induced by the complex
formation of G3-OH with NaC, as shown in the T1
measurements, is consistent with the result of the 1H NMR
studies.
Figure 4. 1H NMR spectra for aromatic protons of G0w3-OH in the
presence of LiClO4 in CD3CN at room temperature. The concentrations of
G0w3-OH and LiClO4 were 8, 4, 2, 1!10K3, and 1!10K2 mol dmK3
respectively.
,
2.4. Metal-ion binding properties
The binding constants for complexes with metal perchlor-
ates in CD3CN at room temperature were evaluated through
the binding isotherms by non-linear least-square regres-
sion14 using the 1H NMR titration data. The tertiary proton
of the crown ether moiety was used as an indicator. The
binding constants for G1w3-OH were determined as the
average value for the binding sites, in which two crown
ether moieties captured one metal ion. The obtained data are
summarized in Table 1. Although the binding constants for
G0-OH showed LiC, Ca2C, and Sr2C selectivity, the
selectivity was not remarkable. On the other hand, the
binding constants for G1w3-OH indicated a clear
selectivity to NaC and Ca2C. While the metal-ion binding
ability of 12-crown-4 towards LiC is well known to form
1:1 complex,15 bis(12-crown-4) derivatives generally show
a high binding ability towards NaC by the formation of
Figure 5. 1H NMRspectra foraromaticprotonsof G0w3-OHinthepresence
of NaClO4 in CD3CN at room temperature. The concentrations of G0w3-OH
and NaClO4 were 8, 4, 2, 1!10K3 and 1!10K2 mol dmK3, respectively.

M. Tanaka et al. / Tetrahedron 61 (2005) 8159–8166
Table 1. Binding constants with metal perchlorates in CD3CNa
8163
LiC
NaC
KC
RbC
CsC
Mg2C
Ca2C
Sr2C
Ba2C
24
G0-OH
G1-OH
G2-OH
G3-OH
14
1.3
0.84
0.78
7.7
110
96
2.3
3.0
1.0
0.96
0.66
1.8
0.74
(9.8)c
0.28
0.79
0.64
(19)c
0.34
0.28
2.2
73
110
6.5
5.7
(52)c
b
460
330
170
—
b
—
b
90
2.1
—
a The unit is 103 molK1 dm3.
b The values could not be determined.
c The values did not reflect conceivable binding constants because of charge repulsion and steric hindrance.
sandwich-type complexes, namely, 1:2 (a metal ion:the
crown ether moiety) complex.16 In the case of polymers
carrying a 12-crown-4 moiety at the side chain, high binding
abilities towards NaC are also attained by the formation of
similar sandwich-type complexes.17 Therefore, this binding
ability of G1w3-OH to NaC is derived from the formation
of sandwich-type complexes. However, the binding con-
stants for G1w3-OH generally decreased with the increase
of dendron generation. The degree of decrease in the
binding constants with increasing dendron generation was
more significant with Ca2C than with NaC. This implies
that the charge repulsion of divalent Ca2C became more
serious than that of monovalent NaC with increasing the
UV–vis absorption spectra depending on the nature of ion-
pair. The formation of a sandwich type complex with crown
ethers to afford a loose ion-pair complex induces a red-shift
in the UV–vis absorption spectra in THF.18 Therefore,
UV–vis absorption spectra with alkali metal picrates were
measured in the presence or absence of G3-OH to evaluate
its complexing behavior. The UV–vis absorption spectra of
lithium and sodium picrates are shown in Figure 6. Upon the
addition of G3-OH, while lithium picrate did not show any
meaningful change in the spectrum, sodium picrate
indicated a significant spectral change with 7 nm red-shift
at the maximal absorption (shift from 352 to 359 nm). It is
obvious that this red shift in the spectrum indicates the
formation of a sandwich type complex, in which a metal ion
is captured by two crown ether moieties effectively, and
therefore the formation of a loose ion-pair.18 Such a
significant red-shift was only observed with sodium picrate,
and other metal picrates showed only a slight red shift of
less than 3 nm.
C
˚
dendron generation, since the radius of Na (0.98 A) is as
large as that of Ca2C(0.99 A). Thus, the dendrimer effect
˚
was also observed in the binding constants reflecting the
charge repulsion.8
In the cases of RbC, CsC, and Sr2C, the binding constants
for G3-OH shown in parenthesis in Table 1 were extra-
ordinary large. To determine the binding constants, G3-OH
was regarded as a tetradentate ligand, tentatively. However,
because of the charge repulsion and steric hindrance with
the dendrimer effect, it is likely that G3-OH could not act as
a tetradentate ligand with those metal ions to yield
extraordinarily large binding constants.
In CH3CN, however, such a spectral change was hardly
observed by addition of G3-OH, and all the picrates showed
the maximal absorption at 375 nm. This tendency shows
that all the metal picrates are in a loose ion-pair by solvation
with CH3CN even without complex formation, as the
wavelength of the maximal absorption (375 nm) for the
metal picrates in CH3CN was much longer than that
(359 nm) for sodium picrate in THF in the presence of
G3-OH. These observations again support that the metal ion
captured by the crown ether moieties is a crucial factor to
induce the flexibility restriction of the crowned dendron.
2.5. Complexing behavior of G3-OH with metal picrates
Metal picrates are known to show significant changes in the
3. Conclusions
The manipulation of macromolecular flexibility by recog-
nition of metal ions was examined with dendrons bearing
crown ether moieties at the periphery, crowned dendron,
where the crown ether moieties were integrated with their
dendronstructure. Thesignificantinfluencesofmetalcomplex
formation on the flexibility demonstrate that the manipulation
of macromolecular flexibility by recognition of metal ions is
possible by integration of the crown ether moieties in
macromolecules. A studyonapplicationofthis ion-responsive
flexibility of macromolecules for molecular function control
to materials chemistry is in progress in due course.
4. Experimental
4.1. General
Figure 6. UV–vis absorption spectra of metal picrates in the presence of
G3-OH in THF at room temperature. The concentrations of G3-OH and
metal picrates were 5!10K5 mol dmK3. PicLi and PicNa represent lithium
and sodium picrates, respectively.
All chemicals and metal perchlorates were of available

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M. Tanaka et al. / Tetrahedron 61 (2005) 8159–8166
purity and used without further purification. For the UV–vis
absorption spectra measurements, THF and CH3CN of
spectroscopic grade were used. Metal picrates were
prepared by the reaction of equimolar amounts of aqueous
picric acid and metal hydroxide, or carbonate. To avoid the
explosion of metal picrates during drying, only a small
amount of metal picrates was prepared each time. Gel
permeation chromatography (GPC) using chloroform as an
eluent was used for purification of the dendrons.
of phosphorus tribromide (813 mg, 3 mmol) was added
dropwise, and the reaction mixture was stirred for 1 h. The
reaction mixture was poured into water, and the organic
layer was separated. The crude product obtained by solvent
evaporation was purified by GPC to give a colorless liquid
product (77%); 1H NMR (CDCl3, 400 MHz) d 3.4–3.9
(17H, m, OCH2, OCH]), 4.49 (2H, s, PhCH2), 4.54 (2H, s,
PhCH2), 7.30 (2H, d, JZ8.0 Hz, ArH), 7.37 (2H, d, JZ
8.0 Hz, ArH).
4.2. Synthesis of dendrons
4.2.5. Compound G1-OH. Under a nitrogen atmosphere,
G0-Br (778 mg, 2 mmol), 3,5-dihydroxybenzyl alcohol
(133 mg, 0.95 mmol), benzyloxymethyl-18-crown-6
(BnO18C6, 77 mg, 0.2 mmol), potassium carbonate
(556 mg, 4 mmol) and acetone (50 mL) were put in a
three-necked flask, and the mixture was refluxed for 3 days
under nitrogen atmosphere. The solvent was evaporated,
and aqueous hydrochloric acid (5 wt%) was poured to
acidify the obtained residue. The product was extracted with
chloroform, and the organic layer was separated. The crude
product obtained by solvent evaporation was purified by
4.2.1. 4-Chloromethylbenzoic acid methyl ester. Methanol
(1.60 g, 50 mmol), triethylamine (1.52 g, 15 mmol), and
chloroform (100 mL) were put into a three-necked flask at
0 8C. A chloroform solution (20 mL) of 4-chloromethyl-
benzoyl chloride (1.89 g, 10 mmol) was added dropwise to
the mixture. The reaction mixture was allowed to warm at
room temperature and stirred for 12 h. The reaction mixture
was poured into water, and the organic layer was separated.
The crude product (quantitative) obtained as a colorless
liquid by solvent evaporation was used for the subsequent
synthesis after drying.
1
GPC to yield a colorless liquid (94%); H NMR (CDCl3,
400 MHz) d 3.4–3.9 (34H, m, OCH2, OCH]), 4.54 (4H, s,
PhCH2), 4.60 (2H, s, PhCH2OH), 5.01 (4H, s, PhCH2), 6.52
(1H, s, ArH), 6.61 (2H, s, ArH), 7.33 (4H, d, JZ7.6 Hz,
ArH), 7.38 (4H, d, JZ7.6 Hz, ArH); IR (neat, cmK1): 3020
(CH2), 1215 (OCH2); m/z 756 (MC NaC). Anal. Calcd for
C41H56O13: C, 65.06; H, 7.46. Found: C, 65.18; H, 7.43.
4.2.2. 4-(12-Crown-4-methoxymethyl)benzoic acid methyl
ester. Hydroxymethyl-12-crown-4 (2.27 g, 11 mmol),
sodium hydride (720 mg, 30 mmol), and dioxane (100 mL)
were put in a three-necked flask, and the mixture was refluxed.
A dioxane solution (20 mL) of crude 4-chloromethylbenzoic
acid methyl ester (1.85 g, 10 mmol) was added dropwise
and the reaction mixture was then refluxed for 5 h. Methanol
was added to the cooled reaction mixture to quench the
excess sodium hydride, and the solvent was then evapor-
ated. Aqueous hydrochloric acid (5 wt%) was added to
acidify the residue, and the product was extracted with
chloroform. The organic layer was separated, and the crude
product (quantitative) obtained as a brownish liquid by
solvent evaporation was used for the subsequent synthesis
after drying.
4.2.6. Compound G1-Cl. Compound G1-OH (724 mg,
1 mmol), pyridine (474 mg, 6 mmol), and benzene (100 mL)
were put in a three-necked flask at room temperature. A
benzene solution (20 mL) of thionyl chloride (714 mg,
6 mmol) was added dropwise, and the reaction mixture was
refluxed for 4 h. Concentrated aqueous hydrochloric acid
was added dropwise to the cooled reaction mixture. The
reaction mixture was poured into water, and the benzene
layer was separated. The crude product obtained by solvent
evaporation was purified by GPC to give a colorless liquid
product (67%); 1H NMR (CDCl3, 400 MHz) d 3.4–3.9
(34H, m, OCH2, OCH]), 4.50 (2H, s, PhCH2Cl), 4.55 (4H,
s, PhCH2), 5.02 (4H, s, PhCH2), 6.55 (1H, s, ArH), 6.63 (2H,
s, ArH), 7.34 (4H, d, JZ7.6 Hz, ArH), 7.39 (4H, d, JZ
7.6 Hz, ArH).
4.2.3. Compound G0-OH. Lithium aluminum hydride
(760 mg, 20 mol) and THF (100 mL) were put in a three-
necked flask. A THF solution (20 mL) of crude 4-(12-
crown-4-methoxymethyl)benzoic acid methyl ester (3.54 g,
10 mmol) was added dropwise at room temperature, and the
reaction mixture was refluxed for 20 h. Concentrated
aqueous hydrochloric acid was added dropwise to the
cooled reaction mixture to quench the excess lithium
aluminum hydride. The solvent was evaporated, and water
was poured into the obtained residue. The product was
extracted with chloroform twice, and the organic layer was
separated. The crude product obtained by solvent evapora-
tion was purified by GPC to afford a colorless liquid product
4.2.7. Compound G2-OH. Under a nitrogen atmosphere,
G1-Cl (1.485 g, 2 mmol), 3,5-dihydroxybenzyl alcohol
(133 mg, 0.95 mmol), benzyloxymethyl-18-crown-6
(BnO18C6, 77 mg, 0.2 mmol), potassium carbonate
(2.76 g, 20 mmol), catalytic amount of sodium iodide, and
acetone (50 mL) were put in a three-necked flask, and the
mixture was refluxed for 3 days under nitrogen atmosphere.
The solvent was evaporated, and aqueous hydrochloric acid
(5 wt%) was poured to acidify the obtained residue. The
product was extracted with chloroform, and the organic
layer was separated. The crude product obtained by solvent
evaporation was purified by GPC to afford a pale-yellow
liquid (39%); 1H NMR (CDCl3, 400 MHz) d 3.4–3.9 (68H,
m, OCH2, OCH]), 4.54 (8H, s, PhCH2), 4.60 (2H, s,
PhCH2OH), 4.96 (4H, s, PhCH2), 5.02 (8H, s, PhCH2), 6.51
(1H, s, ArH), 6.55 (2H, s, ArH), 6.58 (2H, s, ArH), 6.66 (4H,
s, ArH), 7.33 (8H, d, JZ8.0 Hz, ArH), 7.38 (8H, d, JZ
8.4 Hz, ArH); IR (neat, cmK1): 3017 (CH2), 1217 (OCH2);
1
(63%); H NMR (CDCl3, 400 MHz) d 3.4–3.9 (17H, m,
OCH2, OCH]), 4.54 (2H, s, PhCH2), 4.68 (2H, s, PhCH2),
7.31 (2H, d, JZ8.4 Hz, ArH), 7.34 (2H, d, JZ8.4 Hz, ArH);
IR (neat, cmK1): 3019 (CH2), 1219 (OCH2); m/z 349 (MC
NaC). Anal. Calcd for C17H26O6: C 62.56, H 8.03, found: C
62.65, H 8.07.
4.2.4. Compound G0-Br. Compound G0-OH (652 mg,
2 mmol) and chloroform (50 mL) were put in a three-necked
flask at room temperature. A chloroform solution (20 mL)

M. Tanaka et al. / Tetrahedron 61 (2005) 8159–8166
8165
m/z 1640 (MC NaC). Anal. Calcd for C89H116O27: C 66.07,
H 7.23, found: C 66.00, H 7.13.
concentrations of G0w3-OH were 8!10K3, 4!10K3, 2!
10K3, and 1!10K3 mol dmK3, respectively, for LiC and
NaC. On the other hand, in the cases of KC, RbC, and CsC,
the concentrations of G0w3-OH were 4!10K5, 2!10K3
1!10K3, and 5!10K4 mol dmK3, respectively.
,
4.2.8. Compound G2-Cl. Compound G2-OH (1.55 g,
1 mmol), pyridine (474 mg, 6 mmol), and benzene
(100 mL) were put in a three-necked flask at room
temperature. A benzene solution (20 mL) of thionyl
chloride (714 mg, 6 mmol) was added dropwise, and the
reaction mixture was refluxed for 4 h. Concentrated aqueous
hydrochloric acid was added dropwise to the cooled reaction
mixture. The reaction mixture was poured into water, and
the benzene layer was separated. The crude product
obtained by solvent evaporation was purified by GPC to
afford a pale-yellow liquid product (74%); 1H NMR
(CDCl3, 400 MHz) d 3.4–3.9 (68H, m, OCH2, OCH]),
4.51 (2H, s, PhCH2Cl), 4.55 (8H, s, PhCH2), 4.97 (4H, s,
PhCH2), 5.02 (8H, s, PhCH2), 6.5 (3H, m, ArH), 6.62 (2H, s,
ArH), 6.67 (4H, s, ArH), 7.34 (8H, d, JZ8.0 Hz, ArH), 7.39
(8H, d, JZ8.4 Hz, ArH).
The sum of the concentrations for G3-OH and LiClO4 was
1!10K2 mol dmK3 for Job plots.
For the T1 measurement, the concentrations of G0w3-OH
solutions were 8!10K3, 4!10K3, 2!10K3, and 1!
10K3 mol dmK3, respectively. On the other hand, the
concentration of metal ions was 1!10K2 mol dmK3. A
weighted average was adopted as the T1 value of coupling
peaks.
4.4. ESI-MS spectra measurements
ESI-MS measurement was carried out using acetonitrile
as the solvent. The concentration of G3-OH was 1!
10K5 mol dmK3, and that of metal perchlorate was 1!
4.2.9. Compound G3-OH. Under a nitrogen atmosphere,
G2-Cl (3.14 g, 2 mmol), 3,5-dihydroxybenzyl alcohol
(133 mg, 0.95 mmol), benzyloxymethyl-18-crown-6
(BnO18C6, 77 mg, 0.2 mmol), potassium carbonate (2.76 g,
20 mmol), a catalytic amount of sodium iodide, and acetone
(50 mL) were put in a three-necked flask, and the mixture
was then refluxed for 3 days under nitrogen atmosphere. The
solvent was evaporated, and aqueous hydrochloric acid
(5 wt%) was poured to acidify the obtained residue. The
product was extracted with chloroform, and the organic
layer was separated. The crude product obtained by solvent
evaporation was purified by GPC to give a pale-yellow
liquid (47%); 1H NMR (CDCl3, 400 MHz) d 3.4–3.9 (136H,
m, OCH2, OCH]), 4.4–4.6 (18H, m, PhCH2, PhCH2OH),
4.8–5.0 (28H, m, PhCH2) 6.5–6.7 (21H, m, ArH), 7.32
(16H, d, JZ6.4 Hz, ArH), 7.38 (16H, d, JZ8.4 Hz, ArH);
IR (neat, cmK1): 3015 (CH2), 1215 (OCH2); m/z 858.6
((MC4NaC)/4). Anal. Calcd for C185H236O55: C, 66.53; H,
7.12. Found: C, 66.63; H, 7.11.
10K4 or 1!10K3 mol dmK3
.
4.5. UV–vis spectra measurements
The concentrations for metal picrates and G3-OH were 5!
10K5 mol dmK3, and THF and CH3CN of spectroscopic
grade were used. For measurements, a quarts cell which has
a 10 mm light path length was used.
4.6. AFM measurements
A CH3CN solution of G3-OH whose concentration was 1!
10K4 mol dmK3 was put on graphite plate, and the sample
was dried for several hours. Without metal ion, thickness of
the G3-OH layer was less than 20 nm. In the presence of an
equal amount of NaClO4 (1!10K4 mol dmK3), however,
G3-OH formed a particle, the radius, of which was several
hundreds nm. The reason for why the addition of NaClO4 to
G3-OH caused such a significant morphology change of
G3-OH under dry conditions is not understood yet.
4.3. NMR spectra measurements
NMR measurement was carried out in the presence or
absence of various metal perchlorates or picrates in
acetonitrile-d3 at room temperature. The concentrations of
LiClO4 and NaClO4 were 1!10K2 mol dmK3, and that of
G3-OH was 1!10K3 mol dmK3. Because of the low
solubility, the concentrations of KClO4, RbClO4, and
CsClO4 were 5!10K3 mol dmK3 and the concentration of
G3-OH was 5!10K4 mol dmK3. In the cases of alkaline-
earth metal perchlorates, a precipitation was formed with
G3-OH solution (1!10K3 mol dmK3), when the concen-
tration of metal ions was more than 1!10K4 mol dmK3. For
metal picrates, the concentration of G3-OH was 5!
10K4 mol dmK3, and that of lithium and sodium picrates
Acknowledgements
We are very much indebted to Japan Society for Promotion
of Science (JSPS) for the financial support of this work by a
Grant-in-Aid for JSPS fellows. We also thank Ms. Eiko
Muro and Ms. Sachiko Namba for their experimental
assistance.
References and notes
was 2.5!10K3 mol dmK3
.
1. (a) Sasaki, H.; Ueno, A.; Anzai, J.; Osa, T. Bull. Chem. Soc.
Jpn. 1986, 59, 1953–1956. (b) Inouye, M.; Akamatsu, K.;
Nakazumi, H. J. Am. Chem. Soc. 1997, 119, 9160–9165. (c)
Kimura, K.; Yamashita, T.; Yokoyama, M. J. Phys. Chem.
1992, 96, 5614–5617. (d) Ahmed, S. A.; Tanaka, M.; Ando,
H.; Iwamoto, H.; Kimura, K. Tetrahedron 2004, 60,
3211–3220. (e) Tanaka, M.; Ikeda, T.; Xu, Q.; Ando, H.;
In order to examine the dendrimer effect, the concentrations
of G0w3-OH were 8!10K3, 4!10K3, 2!10K3, and 1!
10K3 mol dmK3, respectively, and the concentration of
lithium and sodium perchlorates was 1!10K2 mol dmK3
.
In the case of the binding constants determination, the

8166
M. Tanaka et al. / Tetrahedron 61 (2005) 8159–8166
8. Young, J. K.; Baker, G. R.; Newkome, G. R.; Morris, K. F.;
Shibutani, Y.; Nakamura, M.; Sakamoto, H.; Yajima, S.;
Kimura, K. J. Org. Chem. 2002, 67, 2223–2227. (f) Salhin, A.
M. A.; Tanaka, M.; Kamada, K.; Ando, H.; Ikeda, T.;
Shibutani, Y.; Yajima, S.; Nakamura, M.; Kimura, K. Eur.
J. Org. Chem. 2002, 655–662. (g) Tanaka, M.; Nakamura, M.;
Salhin, A. M. A.; Ikeda, T.; Kamada, K.; Ando, H.; Shibutani,
Y.; Kimura, K. J. Org. Chem. 2001, 66, 1533–1537.
Johnson, C. S., Jr. Macromolecules 1994, 27, 3464–3471.
9. Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. Rev.
1999, 99, 1665–1688.
10. (a) Maeda, T.; Ouchi, M.; Kimura, K.; Shono, T. Chem. Lett.
1981, 1573–1574. (b) Flink, S.; Boukamp, B. A.; Berg, A.v. d.;
Veggel, F.C.J.M. v.; Reinhoudt, D. N. J. Am. Chem. Soc. 1998,
120, 4652–4657.
2. Dendric Molecules: Concepts, Synthesis, Perspectives;
¨
Newkome, G. R., Moorefield, C. N.F, Vogtle, F., Eds.;
11. (a) Sadamoto, R.; Tomioka, N.; Aida, T. J. Am. Chem. Soc.
1996, 118, 3978–3979. (b) Jiang, D.; Aida, T. J. Am. Chem.
Soc. 1998, 120, 10895–10901. (c) Enomoto, M.; Aida, T. J.
Am. Chem. Soc. 1999, 121, 874–875.
VCH: Weinheim, 1996.
3. (a) Marchion, F.; Venturi, M.; Credi, A.; Balzani, V.;
Belohradski, M.; Elizarov, A. M.; Tseng, H.; Stoddart, J. F.
J. Am. Chem. Soc. 2004, 126, 568–573. (b) Paulo, P. M. R.;
Gronheid, R.; Schryver, F. C. D.; Costa, S. M. B.
Macromolecules 2003, 36, 9135–9144. (c) Dirksen, A.;
Hahn, U.; Schwanke, F.; Nieger, M.; Reek, J. N. H.;
12. (a) Inouye, M.; Hyodo, Y.; Nakazumi, H. J. Org. Chem. 1999,
64, 2704–2710. (b) Wall, S. L. D.; Meadows, E. S.; Barbour,
L.; Gokel, G. W. J. Am. Chem. Soc. 1999, 121, 5613–5614. (c)
Bartoli, S.; Roelens, S. J. Am. Chem. Soc. 1999, 121,
11908–11909.
¨
Vogtle, F.; Cola, L. D. Chem. Eur. J. 2004, 10, 2036–2047. (d)
13. (a) Kleinpeter, E.; Grotjahn, E.; Klika, K. D.; Drexler, H.;
Holdt, H. J. Chem. Soc., Perkin Trans. 2 2001, 988–993. (b)
Mizugaki, T.; Murata, M.; Ooe, M.; Ebitani, K.; Kaneda, K.
Chem. Commun. 2002, 52–53.
Langereis, S.; Lussanet, Q. G. d.; Genderen, M. H. P. v.;
Backes, W. H.; Meijer, E. W. Macromolecules 2004, 37,
3084–3091.
4. (a) Launay, N.; Slany, M.; Caminade, A.; Majoral, J. P. J. Org.
Chem. 1996, 61, 3799–3805. (b) Larre, C.; Bressolles, D.;
Turrin, C.; Donnadieu, B.; Caminade, A.; Majoral, J. J. Am.
Chem. Soc. 1998, 120, 13070–13082.
14. Binding Constants; Connors, K. A., Ed.; Wiley: New York,
1987.
15. (a) Pedersen, C. J.; Frensdorff, H. K. Angew. Chem. 1972, 84,
16–26. (b) Popov, A. I.; Lehn, J. M. In Coordination
Chemistry of Macrocyclic Compounds; Nelson, G. A., Ed.;
5. (a) Nagasaki, T.; Kimura, O.; Ukon, M.; Arimori, S.; Hamachi,
I.; Shinkai, S. J. Chem. Soc., Perkin Trans. 1 1994, 75–81. (b)
Stephan, H.; Spies, H.; Johannsen, B.; Gloe, K.; Gorka, M.;
¨
Plenum: New York, 1979. (c) Weber, E.; Vogtle, F. In
¨
Host-Guest Complex Chemistry: Macrocycles; Vogtle, F.,
Weber, E., Eds.; Springer: Berlin, 1995.
¨
Vogtle, F. Eur. J. Inorg. Chem. 2001, 2957–2963. (c) Beer, P.
D.; Gao, D. Chem. Commun. 2000, 443–444. (d) Fulton, D. A.;
Cantrill, S. J.; Stoddart, J. F. J. Org. Chem. 2002, 67,
7968–7981. (e) Jones, J. W.; Bryant, W. S.; Bosman, A. W.;
Janssen, R. A. J.; Meijer, E. W.; Gibson, H. W. J. Org. Chem.
2003, 68, 2385–2389.
16. (a) Pedersen, C. J. J. Am. Chem. Soc. 1970, 92, 386–391. (b)
Frensdorff, H. K. J. Am. Chem. Soc. 1971, 93, 600–606. (c)
Bourgoin, M.; Wong, K. H.; Hui, J. Y.; Smid, J. J. Am. Chem.
Soc. 1975, 97, 3462–3467. (d) Kimura, K.; Tsuchida, T.;
Maeda, T.; Shono, T. Talanta 1980, 27, 801–805.
17. Allcock, H. R.; Olmeijer, D. L.; O’Connor, S. J. M.
Macromolecules 1998, 31, 753–759.
6. Gitsov, I.; Ivanova, P. T. Chem. Commun. 2000, 269–270.
7. (a) Percec, V.; Johansson, G.; Ungar, G.; Zhou, J. J. Am. Chem.
Soc. 1996, 118, 9855–9866. (b) Percec, V.; Cho, W.; Ungar,
G.; Yeardley, D. J. P. Chem. Eur. J. 2002, 8, 2011–2025.
18. Bourgoin, M.; Wong, K. H.; Hui, J. Y.; Smid, J. J. Am. Chem.
Soc. 1975, 97, 3462–3467.