Formation and characterization of water-soluble hetero capsules derived from multiple ionic interactions

Article abstract of DOI:10.1016/j.tet.2011.12.015

We now report the formation and characterization of water-soluble hetero-capsules 12 resulting from the ionic interactions between positively charged flexible aniline hydrochloride 1 and negatively charged phosphonate 2 having rigid homooxacalix[3]arene u

Full text of DOI:10.1016/j.tet.2011.12.015

Tetrahedron 68 (2012) 1492e1501
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formation and characterization of water-soluble hetero capsules derived from
multiple ionic interactions
*
Takahiro Kusukawa , Chikako Katano, Chizuru Kim
Department of Chemistry and Materials Technology, Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku Kyoto 606-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We now report the formation and characterization of water-soluble hetero-capsules 1$2 resulting from
the ionic interactions between positively charged flexible aniline hydrochloride 1 and negatively charged
phosphonate 2 having rigid homooxacalix[3]arene units. The formation of the molecular capsules was
studied by NOESY, DOSY NMR spectroscopy and ESI-Mass spectrometry. The water solubility of the
capsules is improved by the introduction of mono- or triethylene glycol substituents in the homooxacalix
[3]arene-based phosphonate units 2.
Received 7 November 2011
Received in revised form 5 December 2011
Accepted 6 December 2011
Available online 13 December 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Water-soluble capsule
Electrostatic interaction
Hetero-capsule
1. Introduction
most accessible building blocks, such as calixarene and resorci-
narene have C4v symmetry (i.e., calix[4]arene, resorcin[4]arene),
The synthesis of molecular capsules using noncovalent in-
teractions is a very attractive area in hosteguest chemistry.1 The
resulting molecular capsules have found applications in sensing,2a
catalysis,2b selective recognition, and molecular storage.1 One of
the most challenging objectives of hosteguest chemistry is the
synthesis of water-soluble capsules for biological applications, such
as drug encapsulation, transport through cell membranes, and drug
delivery systems.3 Recently, metal-coordination is mostly applied
for the formation of water-soluble capsules, and many studies of
the chemical reactions in these hydrophobic cavities have been
reported by Fujita4 and Raymond.5 On the other hand, electrostatic
interactions are also known as a useful attractive force for the
formation of molecular capsules. Recently, Reinhoudt6 and co-
workers reported the formation of capsule-like structures based
on electrostatic interactions in water as a heme-protein active site
model (Fig. 1, type a). Reinhoudt,7aec Schrader,7d,e and Verboom7f
reported the formation of capsules based on electrostatic in-
teractions in polar solvents (Fig. 1, type b). In these cases, to achieve
the formation of capsules using electrostatic forces, rigid compo-
nents, such as calix[4]arene, resorcin[4]arene and porphyrin units
having C4v (or D4h) symmetry are essential to control the capsule
formation. Due to this limitation, the water solubility of capsules
becomes low, and consequently the formation of water-soluble
capsules using electrostatic interactions is generally difficult. The
and there is a big limitation on structure modification. Recently,
Reek and co-workers reported the formation of a hetero capsule
using a calix[4]arene tetraanion and bisphosphine tetraaminium
units in MeOH solution.8 On the other hand, the molecules having
C3 (C3v) symmetry are easily accessible and a variety of structure
Fig. 1. Molecular capsules and capsule-like structures derived from (a) calix[4]arenes
and porphyrins, (b) oppositely charged calix[4]arenes or resorcin[4]arenes, (c) oxacalix
[3]arenes and a capping unit having C3v (D3h) symmetry.
* Corresponding author. Tel./fax: þ81 75 724 7506; e-mail address: kusu@ki-
t.ac.jp (T. Kusukawa).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.015

T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
1493
modifications are possible in contrast to a compound having C4
(C4v) symmetry.9
chromatography, the cone-isomers 6 were converted to the dieth-
ylphosphonate derivatives 8 by the Ni-catalyzed coupling re-
In this paper, we report the formation and characterization of
new water-soluble capsules 1$2 having C3v symmetry that consist
of a cationic flexible aniline unit 1 and anionic lithium phosphonate
unit 2. The water solubility of the capsules is improved by the in-
troduction of mono- or triethylene glycol substituents in the
homooxacalix[3]arene-based phosphonate units 2 (Fig. 1, type c).
actions. The desired diethylphosphonate compounds 8 were
treated with LiBr in 2-hexanone for the selective mono-lithiation;
the lithium phosphonates 2 were precipitated and then collected
by centrifugation. All these lithium phosphonates were readily
soluble in water and methanol. The phosphonate 2c having the
triethylene glycol unit, which was introduced to improve its water
solubility, had a higher hygroscopic property.
2. Results and discussion
2.3. Formation of capsules 1$2
2.1. Synthesis of anilinium unit 1
The formation of capsule 1$2a (0.25 mM) was achieved by
mixing equimolar solutions (0.5 mM) of 1 and 2a in D2O at room
temperature (Scheme 3). The 1H NMR spectrum of the desired
solution shows the characteristic upfield and downfield shifts with
respect to those of 1 and 2a (Fig. 2). Interestingly, the characteristic
upfield-shifts (DdCH2¼0.37 ppm, DdCH3¼0.47 ppm) for the protons
of the phosphonate substituents (P-OEt) of 2a were observed due to
encapsulation of the substituents in the interior of the 1$2a cavity
(Scheme 4).
The molecular modeling study shows that the cavity size of 1$2a
is not big enough to encapsulate three ethyl phosphonate groups
(P-OEt). One or two of the ethyl phosphonate groups (P-OEt) might
be encapsulated in the cavity of 1$2a (Fig. 3). A single set of proton
resonances for the free and bonded building blocks was observed in
The anilinium unit (aniline hydrochloride) 1 was synthesized by
the cyclotrimerization of aryl ethynyl ketone, followed by the
WolffeKishner reduction (Scheme 1). The triaroyl benzene 3 was
synthesized by the trimerization of 4-nitrophenyl ethynyl ketone in
refluxing DMF.10 The obtained triaroyl benzene 3 was converted to
the corresponding aniline derivative 4 under the WolffeKishner
condition (KOH/H2NNH2$H2O). In this step, three carbonyl groups
and three nitro groups were reduced, and 1,3,5-tris(4-
aminobenzyl)benzene 4 was then obtained. The obtained aniline
derivative 4 was treated with concd HCl in MeOH, and after evap-
oration of the solvent, the corresponding aniline hydrochloride 1
was obtained in quantitative yield. The obtained aniline hydro-
chloride 1 was readily soluble in methanol and water.
Scheme 1. Synthesis of anilinium unit 1.
2.2. Synthesis of phosphonate units 2aec
the temperature range of 5e25 ꢀC, indicating a fast exchange pro-
cess on the NMR time scale. The capsule 1$2a was also prepared by
mixing methanol solutions of 1 and 2a in a 1:1 ratio. However, in
the methanol solution, a smaller upfield shift of the ethyl phos-
phonate substituents (P-OEt) corresponding to the D2O solution
The phosphonate units 2aec were synthesized using a modified
literature procedure for preparation of the calix[4]arene-based
phosphonate compounds7e (Scheme 2). Tribromohexahomotriox-
acalix[3]arene 5 was treated with tert-BuOK and the corresponding
bromoacetate (R-Br) or tosylate (TsOR) in THF under reflux condi-
tions to give the corresponding cone-isomers 6 and partial-cone
isomers 7 in an almost 1:1 ratio. After separation by column
was observed in the 1H NMR spectra
(DdCH2¼0.17 ppm,
DdCH3¼0.19 ppm for P-OEt, Fig. S1). This observation shows that the
formation of capsule 1$2a is driven by hydrophobic interactions
due to encapsulation of the phosphonate substituents (P-OEt) into

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T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
Scheme 2. Synthesis of phosphonate units 2aec.
Scheme 3. Formation of capsules 1$2.
the cavity of 1$2a. For the formation of capsules 1$2b and 1$2c in
D2O, also shows similar characteristic upfield-shifts
DdCH2¼0.46 ppm, DdCH3¼0.35 ppm for 0.25 mM 1$2b,
analysis of 1$2b and 1$2c also showed a similar 1:1 stoichiometry
(Figs. S6 and S7).
a
(
The binding constants for capsule formation were determined
by 1H NMR titrations in CD3OD solution. The experimental data
were fitted to a 1:1 binding model giving K1$2a¼3.0ꢁ0.7ꢂ103 Mꢃ1
for capsule 1$2a, K1$2b¼2.5ꢁ0.6ꢂ103 Mꢃ1 for capsule 1$2b, and
DdCH2¼0.32 ppm, DdCH3¼0.48 ppm for 0.25 mM 1$2c) for the pro-
tons of the phosphonate substituents (P-OEt) of 2, and smaller
chemical shift change corresponding to the D2O solution was ob-
served in CD3OD (Figs. S2eS5). However, big difference was not
observed about 1H NMR chemical shift change between the cap-
sules 1$2a, 1$2b and 1$2c, although the hydrophilic substituents
were introduced in phosphonate unit 2b and 2c.
K1$2c¼1.5ꢁ0.3ꢂ103
M
ꢃ1 for capsule 1$2c (Figs. S8eS10). According
to the binding constants of the capsules 1$2 in CD3OD
(K1$2¼w103 Mꢃ1), these capsules may exist in equilibrium with free
building blocks in CD3OD solutions.
Further proof of the stoichiometry of the complexes was ob-
tained from a Job’s plot analysis of the titration experiments. For
solubility reasons, the titrations were performed in CD3OD instead
of D2O. A Job’s plot analysis of 1$2a definitely proved the 1:1 stoi-
chiometry in the CD3OD solution (Fig. 4). Additionally, a Job’s plot
The NOESY spectrum of the capsule 1$2a in CD3ODeD2O (1:9) at
283 K displays significant negative intermolecular NOE contacts
between the aromatic protons of 1 and P(OEt) protons of 2a (Fig. 5).
For solubility reasons,
a mixed solvent (CD3ODeD2O) was
employed for the NOESY measurement of 1$2a. The rather water-

T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
1495
Fig. 2. 1H NMR spectra (0.25 mM, D2O, 298 K) of (a) 2a, (b) capsule 1$2a obtained by mixing equimolar solutions of 1 and 2a, and (c) 1. Asterisks indicate signals from the external
standard (TMS/CDCl3 in glass capillary).
soluble capsules 1$2b and 1$2c showed similar NOEs in D2O at
room temperature (Figs. S11eS13).
Additional evidence for the formation of capsule 1$2a was ob-
tained by electrospray ionization mass spectrometry (ESI-MS). The
positive-mode ESI-MS spectrum of 1$2a in H2OeCH3OH shows
a prominent monoisotopic ion peak of the capsule at m/z 1384.5
corresponding to [1$2aþH]þ. All the capsule’s ion peaks correspond
Scheme 4. Schematic representation of the formation of capsule 1$2 and encapsula-
tion of ethyl phosphonate substituents (P-OEt).
to 1:1 complexes, while no ion peaks for higher aggregates were
detected (Fig. 6). The ESI-MS spectrum of capsules 1$2b and 1$2c
also shows a similar spectroscopic character (Figs. S14 and S15).
Moreover, diffusion-ordered NMR spectroscopy (DOSY) was
performed for the solutions of 1, 2a, and capsule 1$2a in D2O
(Fig. 7). The DOSY spectra showed that the diffusion coefficient of
capsule 1$2a is lower than those of the corresponding free building
blocks (1, 2a), confirming the formation of the larger sized capsule
1$2a (Fig. 7). The observed diffusion coefficients and calculated
molecular volumes derived by the MM2 optimized structures
(Fig. 8) for the capsules and building blocks are summarized in
Table 1. The molecular volumes derived from the DOSYexperiments
are nearly consistent with the calculated molecular volumes de-
rived from the optimized structures (Table 1). These findings sug-
gest the formation of capsules 1$2ae1$2c in water. However, in the
DOSY spectrum of capsule 1$2c, the diffusion signals derived from
the anilinium unit 1 and the phosphonate unit 2c were separately
observed under the diffusion time (D) of 100e400 ms (Table 1, Figs.
S17, S18). The separately observed DOSY signal for capsule 1$2c
shows that the capsules exist in equilibrium with free building
blocks even in D2O solution.
2.4. Water solubility of capsules 1$2ae1$2c
To compare the solubility of capsules 1$2ae1$2c, we measured
the 1H NMR spectrum of the capsules (1$2ae1$2c) at different
concentrations (0.125e3.0 mM) in D2O. At a higher concentration,
the capsules precipitated in the D2O solutions after mixing the
solutions of 1 and 2. We estimated the concentration of the cap-
sules in D2O by comparison of the 1H NMR integration of 1$2ae1$2c
with the internal standard (TMS/CDCl3 in glass capillary) at differ-
ent concentrations. The 1H NMR integration of the clear solutions
(0.125 mM for 1$2a or 0.25 mM for 1$2b, 1$2c) were selected for the
standard solutions, and the calculated changes in the NMR in-
tegration depended on the increasing concentration (Fig. 9). For
capsule 1$2a, a linear relationship of the prepared and estimated
concentrations of the capsule was observed up to a 0.25 mM
Fig. 3. Molecular structure of 1$2a obtained by PM6 calculation in water.

1496
T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
Fig. 4. Job’s plot for the capsule formation between anilinium unit 1 and phosphonate unit 2a at a total concentration of 4 mM in CD3OD at 298 K, (a) for the anilinium protons (HA,
HB, HC), (b) for the phosphonate protons (Ha, Hb).
Fig. 5. NOESY spectrum of 1$2a in CD3ODeD2O (1:9) at 283 K (mixing time: 0.5 s).
concentration. However, for the capsules 1$2b and 1$2c having
ethylene glycol substituents, they had a linear relationship up to
a 1 mM concentration. A remarkable increase in the water solubility
was observed for capsules 1$2b and 1$2c. Although the water
solubility was increased, we have to remember that the capsules
exist in equilibrium with free building blocks.
2.5. Guest binding study in 1$2a and 1$2c
To investigate the guest binding properties of capsules 1$2a and
1$2c, we carried out NMR measurements before and after the ad-
ditions of the guest molecules. The ethoxy group (P-OEt) of the
phosphonate unit 2 of capsule 1$2 was used as a probe to detect any
guest encapsulation (Scheme 5).
The formation of capsule 1$2a was achieved by mixing equi-
molar D2O solutions of 1 and 2a. The addition of an excess
(0e50 equiv) of either 1-methylpyrazinium iodide 9 or 1,4-
dimethylpyridinium iodide 10 to the capsule 1$2a in D2O
(0.25 mM) causes a downfield shift of the proton signals of the ethyl
phosphonate group P-OEt (Figs. S18 and S19). The guest resonance
itself hardly shifts upon complexation, because it is an averaged
signal for the free and complexed guest molecule. Additionally,
similar guest binding properties are observed for the capsule 1$2c
with 9 (Fig. S20). The capsules 1$2 exist in equilibrium with free
building blocks; the quantitative analysis of guest binding is diffi-
cult in this system. However, fitting of the 1H NMR titration data for
the 1-methylpyrazinium iodide 9 and 1,4-dimethylpyridinium io-
dide 10 to a 1:1 binding model gave Ka¼w102 Mꢃ1 in D2O for
capsule 1$2a (Figs. S21 and S22).
Fig. 6. ESI-MS spectrum of 1$2a in H2O/MeOH.

T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
1497
Fig. 7. DOSY spectra (0.25 mM in D2O, 25 ꢀC,
D¼100 ms) of (a) capsule 1$2a, (b) phosphonate 2a, and (c) aniline hydrochloride 1.
Fig. 8. Molecular model and measured dimensions of aniline hydrochloride 1, phosphonates 2, and capsules 1$2.
To investigate the ability of the water-soluble capsule 1$2 to
include guest molecules, we carried out numerous preliminary
experiments (such as with C3 symmetry neutral guest molecules,
neutral aromatic molecules). However, no binding was observed for
the neutral guest molecules (toluene, benzene, and 1,3,5-
trimethoxybenzene) in the 1H NMR measurement. During the
course of the investigations, a weak guest binding was observed for
iso-propyl benzene (cumen) 11 (DdCH3¼ꢃ0.01 ppm for cumene 11,
DdP-OCH2CH3¼0.01 ppm for 0.25 mM 1$2a) and dimethylphenylsi-
lane (Me2SiHPh) 12 (DdCH3¼0.02 ppm for Me2SiHPh 12, DdP-
Table 1
Comparison of diffusion coefficients, molecular radii, and volumesa
Compound Concn (mM) D (m2 sꢃ1
)
rH (A) V (A ) Vcalcd (A )
3
c
3
ꢀ
ꢀ
ꢀ
1
2a
2b
2c
1$2a
1$2b
1$2cb
0.25
0.25
1.0
1.0
0.25
1.0
3.81ꢁ0.01ꢂ10ꢃ10
2.97ꢁ0.07ꢂ10ꢃ10
2.62ꢁ0.02ꢂ10ꢃ10
2.53ꢁ0.02ꢂ10
6.43 1114
8.26 2361
9.36 3435
9.70 3823
9.47 3557
9.73 3859
9.66 3776
1600
2800
3000
3600
3700
4000
4500
2.59ꢁ0.20ꢂ10ꢃ10
2.52ꢁ0.07ꢂ10ꢃ10
2.54ꢁ0.02ꢂ10ꢃ10 (N)
1.0
2.30ꢁ0.05ꢂ10ꢃ10 (P) 10.7
5131
¼0.01 ppm for 0.25 mM 1$2a) in the D2O solution of capsule
OCH2CH3
a
Diffusion coefficients were recorded at 25 ꢀC (diffusion time
D
¼100 ms), and
1$2a (Figs. S23 and S24). The binding constant of neutral guest
molecules could not determined due to the less water solubility of
these guest molecules.
molecular radii were calculated using the StokeseEinstein equation.
b
Diffusion time
D¼300 ms was employed.
c
Calculations of molecular volumes were performed using HyperChem 7.52.

1498
T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
calix[3]arene-25,26,27-triol (5),11 7,15,23-tribromo-25,26,27-tris
[(ethoxycarbonyl)methoxy]-2,3,10,11,18,19-hexahomo-3,11,19-trioxa-
calix[3]arene (6a),11 1,3,5-tris(4-nitrobenzoyl)benzene (3),10 tri-
ethylene glycol monomethyl ether monotosylate,12 and 2-
methoxyethyl bromoacetate13 were prepared by the published
procedure.
4.1.1. 7,15,23-Tribromo-25,26,27-tris[(3-oxabutoxycarbonyl)me-
thoxy]-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]arene (6b, 7b).
A
mixture of 7,15,23-tribromo-2,3,10,11,18,19-hexahomo-3,11,19-
trioxacalix[3]arene-25,26,27-triol 5 (302 mg, 0.468 mmol) and tert-
BuOK (941 mg, 4.78mmol) inTHF (45 mL) wasstirred at 50 ꢀC for 0.5 h
under an argon atmosphere, and then 2-methoxyethyl bromoacetate
(941 mg, 4.78 mmol) was added via a syringe during 15 min, and the
mixture was stirred at reflux temperature for 3 h. After cooling, the
reaction was stopped by the addition of ethanol (5 mL) and the so-
lution was evaporated to dryness. After the addition of 1 N HCl
(50 mL), the mixture was extracted with chloroform, dried over an-
hydrous Na2SO4 and the solvent was evaporated. The products 6b
(cone-isomer,151 mg, 32%) and 7b (partial-cone isomer,197 mg, 42%)
were isolated after gel permeation chromatography (CHCl3) followed
by column chromatography (SiO2, CHCl3/AcOEt¼3:1). Compound 6b
(cone-isomer): colorless oil; 1H NMR (500 MHz, CDCl3)
4.78 (d, J¼13.0 Hz, 6H), 4.49 (s, 6H), 4.42 (d, J¼13.0 Hz, 6H), 4.34 (m,
d
¼7.04 (s, 6H),
Fig. 9. Comparison of prepared and estimated concentrations of capsules 1$2ae1$2c in
D2O.
Scheme 5. Schematic representation of guest binding for the capsule 1$2 and structure of guest molecules.
3. Conclusions
6H), 3.63 (m, 6H), 3.39 (s, 9H).13C NMR(125MHz, CDCl3)
154.1 (Cq),133.8 (Cq),132.8 (CH),117.3 (Cq), 71.0 (CH2), 70.2 (CH2), 68.7
(CH2), 63.9 (CH2), 58.8 (CH3). HRMS (FAB, NBAþNaI) m/z¼1017.0182
(calculated for C39H45Br3O15Na: 1017.0175). Compound 7b (partial-
d
¼169.0 (Cq),
We have synthesized a new family of water-soluble hetero-
capsules 1$2 having a homooxacalix[3]arene-based phosphonate
unit and a flexible anilinium unit. The water solubility of the cap-
sules was improved by the introduction of an ethylene glycol
substituent in the phosphonate units. The formation of the mo-
lecular capsules was studied by NOESY, DOSY NMR spectroscopy
and ESI-Mass spectrometry. This approach to building a water-
soluble capsule by using C3v symmetry building blocks opens up
a new opportunity to synthesize a variety of water-soluble capsules
by electrostatic interactions. The synthesis of larger water-soluble
capsules is under investigation.
cone isomer): colorless oil; 1H NMR (500 MHz, CDCl3)
d¼7.46 (s, 2H),
7.39(d, J¼2.5 Hz, 2H), 7.35 (d, J¼2.5 Hz, 2H), 4.97 (d, J¼9.5 Hz, 2H), 4.93
(d, J¼12.5 Hz, 2H), 4.73 (d, J¼16.3 Hz, 2H), 4.56 (d, J¼12.0 Hz, 2H),
4.28e4.11 (m, 12H), 4.07 (d, J¼16.3 Hz, 2H), 3.55 (m, 6H), 3.40 (s, 3H),
3.38 (s, 2H), 3.35 (s, 6H). 13C NMR (125 MHz, CDCl3)
d
¼169.4 (Cq),168.5
(Cq),155.4 (Cq),154.0 (Cq),134.2 (CH),133.9 (Cq),133.6 (CH),133.3 (Cq),
132.9 (CH), 132.3 (Cq), 116.9 (Cq), 116.2 (Cq), 70.7 (CH2), 70.12 (CH2),
70.06 (CH2), 69.8 (CH2), 68.7 (CH2), 66.6 (CH2), 64.4 (CH2), 63.77 (CH2),
63.75 (CH2), 58.9 (CH3), 58.7 (CH3). HRMS (FAB, NBAþNaI) m/
z¼1017.0234 (calculated for C39H45Br3O15Na: 1017.0175).
4. Experimental section
4.1. General
4.1.2. 7,15,23-Tribromo-25,26,27-tris(3,6,9-trioxadecyloxy)-
2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]arene (6c, 7c). A mixture
of 7,15,23-tribromo-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]
arene-25,26,27-triol 5 (1.00 g, 1.56 mmol) and tert-BuOK (1.72 g,
15.4 mmol) in THF (150 mL) was refluxed for 0.5 h under argon
atmosphere, and then triethylene glycol monomethyl ether mon-
otosylate (4.78 g, 15.0 mmol) was added during 15 min and the
mixture was stirred at reflux temperature for 22 h. The products 6c
(cone-isomer, 487 mg, 29%) and 7c (partial-cone isomer, 494 mg,
29%) were isolated after gel permeation chromatography (CHCl3)
followed by column chromatography (SiO2, AcOEt). Compound 6c
Melting points were determined on a Yanaco micro melting point
apparatus and are uncorrected. 1H NMR, 13C NMR, and 31P NMR were
recorded on a Bruker DRX-500 (500,125, and 202 MHz) spectrometer.
FAB-mass spectra were recorded on a JEOL JMS-700 mass spectrom-
eter. ESI-mass spectra were recorded on a Bruker micrOTOF mass
spectrometer. Elemental analyses were obtained on a Yanaco MT-5
CHN recorder. Gel permeation chromatography (GPC) was per-
formed on an LC 908 instrument (Japan Analytical Industry Co., Ltd.).
All solvents and reagents were purified according to standard pro-
cedures. 7,15,23-Tribromo-2,3,10,11,18,19-hexahomo-3,11,19-trioxa-
(cone-isomer): colorless oil; 1H NMR (500 MHz, CDCl3)
6H), 4.60 (d, J¼13.5 Hz, 6H), 4.52 (d, J¼13.5 Hz, 6H), 3.86 (m, 6H),
d¼7.09 (s,

T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
1499
3.72 (m, 6H), 3.69 (s, 12H), 3.66 (m, 6H), 3.56 (m, 6H), 3.37 (s, 9H).
13C NMR (125 MHz, CDCl3)
117.1 (Cq), 73.8 (CH2), 71.9 (CH2), 70.70 (CH2), 70.66 (CH2), 70.61
(CH2), 70.2 (CH2), 67.8 (CH2) 59.0 (CH3). HRMS (FAB, NBAþNaI) m/
z¼1107.1571 (calculated for C45H63Br3O15Na: 1107.1586). Com-
pound 7c (partial-cone isomer): colorless oil; 1H NMR (500 MHz,
arene 6c (0.14 g, 0.11 mmol, cone-isomer) and NiCl2 (9.7 mg,
0.075 mmol) in benzonitrile (1.5 mL) was added dropwise P(OEt)3
(0.10 mL, 0.63 mmol) during 15 min under argon at 160 ꢀC and
stirring was continued for 4 h. The product 8c (73 mg, 55% yield)
was isolated after gel permeation chromatography (toluene) fol-
lowed by column chromatography (SiO2, AcOEt/MeOH¼3:1).
d¼153.3 (Cq), 133.8 (d, Cq), 131.9 (CH),
CDCl3)
d
¼7.44 (s, 2H), 7.38 (d, J¼2.5 Hz, 2H), 7.29 (d, J¼2.5 Hz, 2H),
Compound 8c: colorless oil; 1H NMR (500 MHz, CD2Cl2)
d¼7.38 (d,
4.75 (d, J¼11.5 Hz, 2H), 4.63 (d, J¼12.5 Hz, 2H), 4.48 (d, J¼11.5 Hz,
2H), 4.37 (d, J¼12.5 Hz, 2H), 4.21 (d, J¼11.5 Hz, 2H), 4.19 (d,
J¼12.5 Hz, 2H), 3.81 (m, 2H), 3.68e3.47 (m, 32H), 3.38 (s, 3H), 3.37
JPeH¼13.0 Hz, 6H), 4.82 (d, J¼13.0 Hz, 6H), 4.56 (d, J¼13.0 Hz, 6H),
3.98 (m, 6H), 3.89e3.80 (m, 12H), 3.79 (m, 6H), 3.69e3.64 (m, 12H),
3.60 (m, 6H), 3.50 (m, 6H), 3.31 (s, 9H), 1.26 (t, J¼7.0 Hz, 18H). 13C
(s, 6H), 3.08e3.01 (m, 4H). 13C NMR (125 MHz, CDCl3)
d¼155.9 (Cq),
NMR (125 MHz, CD2Cl2)
d
¼158.8 (d, JCeP¼3.8 Hz, Cq), 133.3 (d,
155.5 (Cq), 134.3 (Cq), 133.4 (Cq), 133.3 (CH), 133.1 (CH), 133.0 (CH),
132.9 (Cq), 116.3 (Cq), 116.1 (Cq), 74.0 (CH2), 73.6 (CH2), 71.9 (CH2),
70.63 (CH2), 70.53 (CH2), 70.48 (CH2), 70.36 (CH2), 70.1 (CH2), 69.7
(CH2), 67.7 (CH2), 64.9 (CH2), 64.4 (CH2), 59.0 (CH3). HRMS (FAB,
NBAþNaI) m/z¼1107.1561 (calculated for C45H63Br3O15Na:
1107.1586).
JCeP¼11.3 Hz, Cq), 132.9 (d, JCeP¼15.1 Hz, CH), 123.7 (d,
JCeP¼188.7 Hz, Cq), 74.2 (CH2), 72.3 (CH2), 70.9 (CH2, 2C), 70.8 (CH2),
70.6 (CH2), 69.1 (CH2), 62.3 (d, JCeP¼5.0 Hz, CH2), 58.9 (CH3), 16.5 (d,
JCeP¼6.3 Hz, CH3). 31P NMR (202 MHz, CD2Cl2, H3PO4 in D2O as
external standard)
(calculated for C57H93O24P3Na: 1277.5167).
d
¼18.0. HRMS (FAB, NBAþNaI) m/z¼1277.5184
4.1.3. 25,26,27-Tris[(ethoxycarbonyl)methoxy]-7,15,23-tris(diethoxy-
phosphoryl)-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]arene
(8a). Toa solutionof 7,15,23-tribromo-25,26,27-tris[(ethoxycarbonyl)
methoxy]-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]arene cone-
6a (0.40 g, 0.44 mmol) and NiCl2 (77 mg, 0.59 mmol) in benzonitrile
(3 mL) was added dropwise P(OEt)3 (0.56 mL, 3.2 mmol)during 15 min
under argon at 160 ꢀC and stirring was continued for 1 h. The reaction
mixture was poured into toluene (50 mL), the organic layer was
washed four times with 5% aqueous NH3, dried over Na2SO4 and the
solvent was evaporated. The remaining benzonitrile was removed
under reduced pressure at 60 ꢀC. The product 8a (332 mg, 70% yield)
was isolated after chromatography (SiO2, CHCl3/MeOH¼20:1) as
4.1.6. 25,26,27-Tris[(ethoxycarbonyl)methoxy]-7,15,23-tris(hydroxye-
thylphosphoryl)-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]arene,
trilithium salt (2a). 25,26,27-Tris[(ethoxycarbonyl)methoxy]-7,15,23-
tris(diethoxyphosphoryl)-2,3,10,11,18,19-hexahomo-3,11,19-trioxa-
calix[3]arene 8a (100 mg, 0.093 mmol) and LiBr (26.7 mg, 0.31 mmol)
were refluxed in 2-hexanone (10 mL) under an argon atmosphere.
After 1.5 h, the white precipitate was collected by centrifugation and
washed five times with Et2O. The collected precipitate was dried over
under vacuum to give trilithium salt 2a as a white powder. Yield:
82.8 mg (88%); mp: >300 ꢀC. 1H NMR (500 MHz, D2O, TMS in CDCl3 as
external standard)
d
¼7.50 (d, JPeH¼12.3 Hz, 6H), 5.12 (d, J¼11.2 Hz, 6H),
4.95 (s, 6H), 4.58 (d, J¼11.2 Hz, 6H), 4.32 (q, J¼7.2 Hz, 6H), 3.63 (m, 6H),
a colorless solid. Mp: 34e35 ꢀC; 1H NMR (500 MHz, CD2Cl2)
d¼7.40 (d,
1.37 (t, J¼7.2 Hz, 9H), 1.13 (t, J¼7.0 Hz, 9H). 13C NMR (125 MHz, D2O,
JPeH¼13.0 Hz, 6H), 5.03 (d, J¼12.0 Hz, 6H), 4.70 (s, 6H), 4.45 (d,
J¼12.0 Hz, 6H), 4.25 (q, J¼7.2 Hz, 6H), 4.0e3.8 (m,12H),1.32 (t, J¼7.1 Hz,
TMS in CDCl3 as external standard)
d¼171.7(Cq), 158.2 (d, JCeP¼3.5 Hz,
Cq), 134.3 (d, JCeP¼10.1 Hz, CH), 130.8 (d, JCeP¼14.4 Hz, Cq), 129.1 (d,
JCeP¼178.5 Hz, Cq), 71.1 (CH2), 69.6 (CH2), 62.4 (CH2), 61.2 (d,
JCeP¼4.8 Hz, CH2), 15.7 (d, JCeP¼6.8 Hz, CH3), 13.4 (CH3). 31P NMR
9H), 1.27 (t, J¼7.1 Hz, 18H). 13C NMR (125 MHz, CD2Cl2)
¼169.3 (Cq),
d
159.5 (d, JCeP¼3.5 Hz, Cq), 134.2 (d, JCeP¼10.7 Hz, CH), 132.1 (d,
JCeP¼15.3 Hz, Cq), 124.0 (d, JCeP¼189.5 Hz, Cq), 70.9 (CH2), 70.0 (CH2),
62.1 (d, JCeP¼5.2 Hz, CH2), 61.2 (CH2), 16.3 (d, JCeP¼6.4 Hz, CH3), 14.2
(CH3). 31P NMR (202 MHz, CD2Cl2, H3PO4 in D2O as external standard)
(202 MHz, D2O, H3PO4 in D2O as external standard)
d¼14.3. MS (ESI
negative, MeOH/H2O) m/z¼989 (M-3Liþ2H)ꢃ, 995 (M-2LiþH)ꢃ, 1001
(MꢃLi)ꢃ. Anal. Calcd for C42H54Li3O21P3$2H2O: C, 48.29; H, 5.60.
Found: C, 47.92; H, 5.26.
d
¼17.6. MS (FAB, NBAþNaI) m/z 1098 (MþNaþ). Anal. Calcd for
C48H69O21P3$2H2O: C, 51.89; H, 6.62. Found: C, 51.51; H, 6.35.
4.1.7. 7,15,23-Tris(hydroxyethylphosphoryl)-25,26,27-tris[(3-
oxabutoxycarbonyl)methoxy]-2,3,10,11,18,19-hexahomo-3,11,19-
trioxacalix[3]arene, trilithium salt (2b). Yield 85%; mp: >300 ꢀC. 1H
4.1.4. 7,15,23-Tris(diethoxyphosphoryl)-25,26,27-tris[(3-oxabutoxy-
carbonyl)methoxy]-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]
arene (8b). To a solution of 7,15,23-tribromo-25,26,27-tris[(3-
oxabutoxycarbonyl)methoxy]-2,3,10,11,18,19-hexahomo-3,11,19-
trioxacalix[3]arene cone-6b (132 mg, 0.133 mmol) and NiCl2
(12.3 mg, 0.0949 mmol) in benzonitrile (1.5 mL) was added drop-
NMR (500 MHz, D2O, TMS in CDCl3 as external standard)
d
¼7.48 (d,
JPeH¼12.0 Hz, 6H), 5.08 (d, J¼11.0 Hz, 6H), 4.94 (s, 6H), 4.57 (d,
J¼11.0 Hz, 6H), 4.39 (t, J¼4.3 Hz, 6H), 3.76 (t, J¼4.3 Hz, 6H), 3.60 (m,
6H), 3.42 (s, 9H), 1.11 (t, J¼7.0 Hz, 9H). 13C NMR (125 MHz, D2O, TMS
wise P(OEt)3 (120
m
L, 0.692 mmol) during 5 min under argon at
in CDCl3 as external standard)
d
¼171.5 (Cq), 158.2 (d, JCeP¼3.8 Hz,
160 ꢀC and stirring was continued for 2 h. The product 8b (101 mg,
65%) was isolated after gel permeation chromatography (toluene)
followed by column chromatography (SiO2, AcOEt/MeOH¼6:1) as
Cq), 134.3 (d, JCeP¼10.1 Hz, CH), 130.8 (d, JCeP¼15.1 Hz, Cq), 129.1 (d,
JCeP¼179.8 Hz, Cq), 70.9 (CH2), 69.9 (CH2), 69.7 (CH2), 64.3 (CH2),
61.2 (d, JCeP¼5.0 Hz, CH2), 58.2 (CH3), 15.8 (d, JCeP¼6.3 Hz, CH3). 31
P
a colorless oil. 1H NMR (500 MHz, CD2Cl2)
d¼7.39 (d, JPeH¼13.0Hz,
NMR (202 MHz, D2O, H3PO4 in D2O as external standard)
d
¼14.2.
6H), 5.02 (d, J¼12.1 Hz, 6H), 4.73 (s, 6H), 4.44 (d, J¼12.1 Hz, 6H),
MS (ESI negative, MeOH/H2O) m/z¼1079 (M-3Liþ2H)ꢃ, 1085 (M-
2LiþH)ꢃ, 1091 (MꢃLi)ꢃ. Anal. Calcd for C45H60Li3O24P3$5H2O: C,
45.47; H, 5.94. Found: C, 45.26; H, 5.43.
4.32 (m, 6H), 4.0e3.8 (m, 12H), 3.62 (m, 6H), 3.36 (s, 9H), 1.27
(t, J¼7.1 Hz, 18H). 13C NMR (125 MHz, CD2Cl2)
¼169.9 (Cq), 159.8
d
(d, JCeP¼3.9 Hz, Cq), 134.6 (d, JCeP¼10.8 Hz, CH), 132.6 (d,
JCeP¼15.3 Hz, Cq), 124.3 (d, JCeP¼189.6 Hz, Cq), 71.3 (CH2), 70.7
(CH2), 70.4 (CH2), 64.6 (CH2), 62.6 (d, JCeP¼5.1 Hz, CH2), 59.1 (CH3),
16.7 (d, JCeP¼6.5 Hz, CH3). 31P NMR (202 MHz, CD2Cl2, H3PO4 in D2O
4.1.8. 7,15,23-Tris(hydroxyethylphosphoryl)-25,26,27-tris(3,6,9-
trioxadecyloxy)- 2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]arene,
trilithium salt 2c. Yield 90%, mp: >300 ꢀC. 1H NMR (500 MHz, D2O,
as external standard)
(calculated for C51H75O24 P3Na: 1187.3759).
d¼17.5. HRMS (FAB, NBAþNaI) m/z¼1187.3751
TMS in CDCl3 as external standard)
d
¼7.42 (d, JPeH¼12.0 Hz, 6H),
4.91 (d, J¼12.0 Hz, 6H), 4.64 (d, J¼12.0 Hz, 6H), 4.15 (br t, 6H), 3.91
(br t, 6H), 3.76e3.72 (m, 12H), 3.71 (m, 6H), 3.62 (m, 6H), 3.50 (m,
6H), 3.37 (s, 9H), 1.07 (t, J¼7.0 Hz, 9H). 13C NMR (125 MHz, D2O, TMS
4.1.5. 7,15,23-Tris(diethoxyphosphoryl)-25,26,27-tris(3,6,9-
trioxadecyloxy)-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]arene
in CDCl3 as external standard)
d
¼157.8 (Cq), 133.3 (d, JCeP¼10.1 Hz,
(8c). To
a
solution of 7,15,27-tribromo-25,26,27-tris(3,6,9-
Cq), 131.1 (d, JCeP¼13.8 Hz, CH), 128.8 (d, JCeP¼178.6 Hz, Cq), 73.6
trioxadecyloxy)-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]
(CH2), 71.2 (CH2), 70.3 (CH2), 69.9 (CH2), 69.8 (CH2), 69.7 (CH2), 68.7

1500
T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
(CH2), 61.1 (d, JCeP¼5.0 Hz, CH2), 58.1 (CH3), 15.8 (d, JCeP¼6.3 Hz,
6H), 3.95 (br s, 6H), 3.75 (s, 6H), 3.70e3.59 (m, 24H), 3.35 (s, 9H),
3.13 (m, 6H), 0.50 (t, J¼7.0 Hz, 9H). 13C NMR (125 MHz, D2O, TMS in
CH3). 31P NMR (202 MHz, D2O, H3PO4 in D2O as external standard)
d
¼14.4. MS (ESI negative, MeOH/H2O) m/z 1169 (M-3Liþ2H)ꢃ, 1175
CDCl3 as external standard):
d¼158.7 (Cq), 142.3 (Cq), 141.7 (Cq),
(M-2LiþH)ꢃ, 1181 (MꢃLi)ꢃ. Anal. Calcd for C51H78Li3O24P3$9H2O: C,
135.6 (d, JPeC¼10.1 Hz, CH), 130.6 (d, JPeC¼13.8 Hz, Cq), 130.0 (CH),
129.7 (d, JPeC¼178.6 Hz, Cq), 127.7 (Cq), 127.0 (CH), 122.4 (CH), 73.1
(CH2), 71.2 (CH2), 70.8 (CH2), 70.1 (CH2), 69.9 (CH2), 69.7 (CH2), 69.6
(CH2), 60.8 (d, JPeC¼5.0 Hz, CH2), 58.1 (CH3), 40.4 (CH2), 15.3 (d,
JPeC¼6.3 Hz, CH3). 31P NMR (202 MHz, D2O, H3PO4 in D2O as ex-
45.34; H, 7.16. Found: C, 45.40; H, 6.41.
4.1.9. 1,3,5-Tris(4-aminobenzyl)benzene (4). A mixture of 1,3,5-
tris(4-nitrobenzoyl)benzene 3 (1.00 g, 1.64 mmol, including one
molecule of CH2Cl2 in the crystal, see Ref. 10), hydrazine mono-
hydrate (3.0 mL) and potassium hydroxide (1.0 g) in dieth-
yleneglycol (30 mL) was heated at 180 ꢀC for 40 h. The reaction
mixture was poured onto ice and extracted with CH2Cl2, dried over
Na2SO4, and evaporated in vacuo. The product 4 was isolated after
chromatography (SiO2, CHCl3/MeOH¼4:1) as a pale yellow solid.
Yield 0.410 g (64%); mp: 117e118 ꢀC. 1H NMR (500 MHz, CD2Cl2):
ternal standard):
(500 MHz, CD3OD, TMS in CDCl3 as external standard):
J¼12.3 Hz, 6H), 7.77 (br s, 6H), 7.50 (s, 3H), 7.5 (br, 6H), 5.89 (d,
J¼10.0 Hz, 6H), 5.22 (d, J¼10.6 Hz, 6H), 5.22 (br s, 6H), 4.59 (m, 6H),
4.53 (br s, 6H), 4.44 (m, 12H), 4.39 (m, 6H), 4.29 (m, 6H), 4.17 (m,
6H), 4.05 (s, 9H), 1.58 (t, J¼6.7 Hz, 9H).
d
¼13.2. Capsule 1$2c (2 mM in CD3OD): 1H NMR
d
¼8.26 (d,
d
¼6.92 (d, J¼8.3 Hz, 6H), 6.83 (s, 3H), 6.59 (d, J¼8.3 Hz, 6H), 3.75 (s,
4.3. 1H NMR titrations
6H), 3.6 (br s, 6H). 13C NMR (125 MHz, CD2Cl2):
d
¼145.0 (Cq), 142.4
(Cq), 131.3 (Cq), 129.6 (CH), 127.0 (CH), 115.1 (CH), 41.1 (CH2). MS (EI)
m/z¼393 Mþ. Anal. Calcd for C27H27N3$0.7H2O: C, 79.85; H, 7.05; N,
10.35. Found: C, 79.75; H, 6.90; N, 10.06.
The 1H NMR titrations of 1 with 2a, 2b, and 2c were measured in
CD3OD at 298 K for solubility reasons in D2O. The concentration of 1
was kept constant (2.0 mM) and the concentrations of 2a, 2b, and
2c were varied from 0 to 10.0 mM. The chemical shifts of 1$2a, 1$2b,
and 1$2c, relative to the chemical shifts of 2aec, respectively, were
calculated and fitted to a 1:1 binding model using a least-squares
fitting procedure. The association constant found for capsule 1$2a
is K1$2a¼3.0ꢁ0.7ꢂ103 Mꢃ1, for 1$2b is K1$2b¼2.5ꢁ0.6ꢂ103 Mꢃ1, and
4.1.10. 1,3,5-Tris(4-aminobenzyl)benzene trihydrochloride salt (1).
To
a solution of 1,3,5-tris(4-aminobenzyl)benzene 4 (0.41 g,
1.04 mmol) in MeOH (10 mL), 1 mL of concd HCl was added. The
solvent was evaporated in vacuo and the product 1 was obtained as
awhite solid.Yield0.51g (98%). Mp:>300ꢀC.1HNMR (500MHz,D2O,
for 1$2c is K1$2c¼1.5ꢁ0.3ꢂ103 Mꢃ1
.
TMS in CDCl3 as external standard)
d
¼7.36 (d, J¼8.5 Hz, 6H), 7.31 (d,
J¼8.5 Hz, 6H), 7.03 (s, 3H), 3.92 (s, 6H). 13C NMR (125 MHz, D2O, TMS
4.4. Jobs plot
in CDCl3 as external standard):
d¼142.7 (Cq), 142.2 (Cq), 130.3 (CH),
127.9 (Cq),127.2 (CH),123.1 (CH), 40.4 (CH2). MS (ESI positive, MeOH/
H2O) m/z¼394 (M-3Clꢃꢃ2Hþ)þ. Anal. Calcd for C27H30Cl3N3$0.5H2O:
C, 63.35; H, 6.10; N, 8.21. Found: C, 62.97; H, 5.96; N, 8.28.
Equimolar solutions (10 mM) of 1 and 2 in CD3OD were pre-
pared and mixed in various ratios. The total concentration of 1 and
2 was kept constant at 4 mM and only the 1/2 ratio was varied. 1H
NMR spectra of the mixture were recorded, and the chemical shifts
of 1 and 2 were analyzed by Job’s method.14
4.2. Formation of capsules 1$2a, 1$2b, and 1$2c
Capsules 1$2ae1$2c were prepared in situ by mixing equimolar
solutions of 1 and 2aec in D2O. Capsule 1$2a (0.25 mM in D2O): 1H
4.5. DOSY measurements
NMR (500 MHz, D2O, TMS in CDCl3 as external standard):
d
¼7.54 (d,
In the DOSY experiments with the free building blocks (1, 2aec)
as well as the capsules (1$2ae1$2c), the concentrations of 1, 2bec,
and 1$2be1$2c were kept constant at 1.0 mM (the concentrations
of 2a and 1$2a were kept at 0.25 mM due to lower solubility). 1H
DOSY experiments were carried out at 298 K on a Bruker DRX 500
spectrometer equipped with a GREAT 1/10 gradient generator and
a 5-mm BBO probe with a z-axis gradient coil. Data were acquired
and processed using the Bruker software XWINNMR 3.5. A series of
diffusion-ordered spectra were collected on samples using the
LEDbp pulse sequence.15 Pulse-fields were incremented in 50 steps
from 2% up to 95% of the maximum gradient strength in a linear
ramp. Gradient length was selected between 2.0 and 3.0 ms, with
a diffusion time of 100 ms, and an eddy current delay of 5 ms.
J¼12.0 Hz, 6H), 7.14 (d, J¼8.0 Hz, 6H), 6.88 (s, 3H), 6.72 (br s, 6H),
5.31 (d, J¼10.0 Hz, 6H), 5.08 (s, 6H), 4.55 (d, J¼10.0 Hz, 6H), 4.33 (d,
J¼7.0 Hz, 6H), 3.83 (s, 6H), 3.25 (m, 6H), 1.36 (t, J¼7.0 Hz, 9H), 0.66
(t, J¼7.0 Hz, 9H). 31P NMR (202 MHz, D2O, H3PO4 in D2O as external
standard):
d
¼13.5. Capsule 1$2a (2 mM in CD3OD): 1H NMR
(500 MHz, CD3OD, TMS in CDCl3 as external standard):
d
¼8.25 (d,
J¼12.2 Hz, 6H), 7.76 (d, J¼8.0 Hz, 6H), 7.51 (s, 3H), 7.5 (br, 6H), 5.95
(d, J¼10.9 Hz, 6H), 5.64 (s, 6H), 5.21 (d, J¼10.9 Hz, 6H), 5.51 (q,
J¼7.2 Hz, 6H), 4.53 (s, 6H), 4.21 (m, 6H), 2.07 (t, J¼7.2 Hz, 9H),1.63 (t,
J¼7.0 Hz, 9H). Capsule 1$2b (2 mM in D2O): 1H NMR (500 MHz, D2O,
TMS in CDCl3 as external standard):
d
¼7.55 (d, JPeH¼12.0 Hz, 6H),
7.12 (d, J¼8.0 Hz, 6H), 6.86 (s, 3H), 6.72 (br s, 6H), 5.32 (d, J¼10.0 Hz,
6H), 5.13 (s, 6H), 4.54 (d, J¼10.0 Hz, 6H), 4.42 (br s, 6H), 3.79 (s, 6H),
3.78 (br s, 6H), 3.43 (s, 9H), 3.20 (m, 6H), 0.58 (t, J¼7.0 Hz, 9H). 13C
4.6. Computional methods
NMR (125 MHz, D2O, TMS in CDCl3 as external standard):
d
¼170.8
(Cq), 158.5 (Cq), 142.2 (Cq), 141.7 (Cq), 135.7 (d, JPeC¼10.0 Hz, CH),
130.19 (Cq), 130.18 (d, JPeC¼179.9 Hz, Cq), 130.05 (CH), 128.0 (Cq),
127.1 (CH), 122.3 (CH), 70.6 (CH, 2C), 69.8 (CH2), 64.4 (CH2), 60.9 (d,
JPeC¼5.0 Hz, CH2), 58.2 (CH3), 40.4 (CH2), 15.4 (d, JPeC¼6.3 Hz, CH3).
31P NMR (202 MHz, D2O, H3PO4 in D2O as external standard):
Optimization of 1$2a: starting geometry was constructed via the
CAChe WorkSystem Pro Version 5.02 and optimized using the PM6
16
Hamiltonian Ref.
in water (COSMO method) via the semi-
empirical MOPAC2009 software (Stewart Computational Chemis-
try). Optimization for DOSY analysis: the structures of capsules
(1$2ae1$2c) and free building blocks (1, 2aec) were optimized by
the MM2 force field via the CAChe WorkSystem Pro Version 5.02
and the molecular volumes were estimated using HyperChem 7.52.
d
¼13.2. Capsule 1$2b (2 mM in CD3OD): 1H NMR (500 MHz, CD3OD,
TMS in CDCl3 as external standard):
d
¼8.26 (d, J¼12.2 Hz, 6H), 7.76
(d, J¼8.2 Hz, 6H), 7.51 (s, 3H), 7.48 (br, 6H), 5.97 (d, J¼10.8 Hz, 6H),
5.68 (s, 6H), 5.20 (d, J¼10.8 Hz, 6H), 5.11 (m, 6H), 4.40 (s, 6H), 4.19
(m, 6H), 4.13 (s, 9H), 1.62 (t, J¼7.0 Hz, 9H). Capsule 1$2c (3 mM in
D2O): 1H NMR (500 MHz, D2O, TMS in CDCl3 as external standard):
Acknowledgements
d
¼7.54 (d, J¼12.2 Hz, 6H), 7.08 (d, J¼7.0 Hz, 6H), 6.81 (s, 3H), 6.68
This work was supported by a Grant-in-Aid for Young Scientists
(B) (No.17750127) from MEXT of Japan and by the Kyoto Institute of
(br s, 6H), 5.21 (d, J¼9.6 Hz, 6H), 4.62 (br s, 6H), 4.51 (d, J¼9.6 Hz,

T. Kusukawa et al. / Tetrahedron 68 (2012) 1492e1501
1501
6. MeOH-soluble capsule-like structure; (a) Fiammengo, R.; Timmerman, P.;
Huskens, J.; Versluis, K.; Heck, A. J. R.; Reinhoudt, D. N. Tetrahedron 2002, 58,
757 water-soluble capsule-like structure;; (b) Fiammengo, R.; Wojciechowski,
K.; Crego-Calama, M.; Timmerman, P.; Figoli, A.; Wessling, M.; Reinhoudt, D. N.
Org. Lett. 2003, 5, 3367.
Technology Research Fund. We thank Prof. T. Harada (Kyoto In-
stitute of Technology) for helpful discussions.
Supplementary data
7. Water-soluble capsules; (a) Corbellini, F.; Costanzo, L. D.; Crego-Calama, M.; Ger-
emia, S.; Reinhoudt, D. N. J. Am. Chem. Soc. 2003,125, 9946; (b) Corbellini, F.; Knegtel,
R.M.A.; Grootenhuis, P. D.J.;Crego-Calama, M.;Reinhoudt,D.N.Chem.dEur. J. 2005,
11, 298 MeOH-soluble capsules (insoluble in 100% water); (c) Corbellini, F.; Fiam-
mengo, R.; Timmerman, P.; Crego-Calama, M.; Versluis, K.; Heck, A. J. R.; Luyten, I.;
Reinhoudt, D. N. J. Am. Chem. Soc. 2002, 124, 6569; (d) Zadmard, R.; Junkers, M.;
Schrader, T.; Grawe, T.; Kraft, A. J. Org. Chem. 2003, 68, 6511; (e) Zadmard, R.;
Schrader, T.; Grawe, T.; Kraft, A. Org. Lett. 2002, 4, 1687; (f) Oshovsky, G. V.; Rein-
houdt, D. N.; Verboom, W. J. Am. Chem. Soc. 2006, 128, 5270.
8. (a) Koblenz, T. S.; Dekker, H. L.; De Koster, C. G.; Van Leeuwen, P. W. N. M.;
Reek, J. N. H. Chem. Commun. 2006, 1700; (b) Koblenz, T. S.; Dekker, H. L.;
de Koster, C. G.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem.dAsian J. 2011, 6,
2431; (c) Koblenz, T. S.; Dekker, H. L.; de Koster, C. G.; van Leeuwen, P. W. N. M.;
Reek, J. N. H. Chem.dAsian J. 2011, 6, 2444.
9. Gibson, S. E.; Castaldi, M. P. Angew. Chem., Int. Ed. 2006, 45, 4718.
10. Pigge, F. C.; Ghasedi, F.; Zheng, Z.; Rath, N. P.; Nichols, G.; Chickos, J. S. J. Chem.
Soc., Perkin Trans. 2 2000, 2458.
11. Ikeda, A.; Suzuki, Y.; Yoshimura, M.; Shinkai, S. Tetrahedron 1998, 54, 2497.
12. Lottner, C.; Bart, K.-C.; Bernhardt, G.; Brunner, H. J. Med. Chem. 2002, 45, 2079.
13. Bonnans-Plaisance, C.; Retif, P.; Levesque, G. Polymer Bull. 1995, 34, 141.
14. Blanda, M. T.; Horner, J. H.; Newcomb, M. J. Org. Chem. 1989, 54, 4626.
15. Wu, D.; Chen, A.; Johnson, C. S., Jr. J. Magn. Reson., Ser. A 1995, 115, 260.
16. Stewart, J. J. P. J. Mol. Model. 2007, 13, 1173e1213.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.015.
References and notes
1. Rudkevich, D. M. In Functional Synthetic Receptors: Molecular Containers in Ac-
tion; Schrader, T., Hamilton, A. D., Eds.; Wiley-VCH: Weinheim, Germany, 2005;
pp 257e298.
2. (a) Castellano, R. K.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. J. Am. Chem. Soc. 2000,
122, 7876; (b) Ballester, P.; Vidal-Ferran, A. In Supramolecular Catalysis: In-
troduction to Supramolecular Catalysis; van Leeuwen, P. W. N. M., Ed.; Wiley-
VCH: Weinheim, Germany, 2008; pp 1e27.
3. Biros, S. M.; Rebek, J., Jr. Chem. Soc. Rev. 2007, 36, 93.
4. (a) Fujita, M.; Tominaga, M.; Hori, A.; Therrien, B. Acc. Chem. Res. 2005, 38, 369;
(b) Yoshizawa, M.; Klosterman, K. J.; Fujita, M. Angew. Chem., Int. Ed. 2009, 48,
3418; (c) Fujita, M.; Umemoto, K.; Yoshizawa, M.; Fujita, N.; Kusukawa, T.;
Biradha, K. Chem. Commun. 2001, 509.
5. (a) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Acc. Chem. Res. 2009, 42, 1650;
(b) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Science 2007, 316, 85; (c) Fiedler,
D.; Leung, D. H.; Bergman, R. G.; Raymond, K. N. Acc. Chem. Res. 2005, 38, 351.