Guest encapsulation and self-assembly of a cavitand-based coordination capsule

Article abstract of DOI:10.1002/chem.200500976

The synthesis and spectroscopic characterization of a cavitand-based coordination capsule 1·4 BF₄ of nanometer dimensions is described. Encapsulation studies of large aromatic guests as well as aliphatic guests were performed by using ¹

Full text of DOI:10.1002/chem.200500976

DOI: 10.1002/chem.200500976
Guest Encapsulation and Self-Assembly of a Cavitand-Based Coordination
Capsule
Takeharu Haino,* Mutsumi Kobayashi, and Yoshimasa Fukazawa*[a]
Abstract: The synthesis and spectro-
scopic characterization of a cavitand-
based coordination capsule 1·4BF4 of
nanometer dimensions is described.
Encapsulation studies of large aromatic
guests as well as aliphatic guests were
space in which molecules with lengths
of approximately 14 Š can be selective-
ly accommodated. The rigid cavity dis-
tinguished slight structural differences
in the flexible alkyl-chain guests as
well as the rigid aromatic guests. The
detailed thermodynamic studies re-
vealed that not only CH–p interactions
between the methyl groups on the
guest termini and the aromatic cavity
walls, but also desolvation of the inner
cavity play a key role in the guest en-
capsulation. The cavity preferentially
selected the hydrogen-bonded hetero-
dimers of a mixture of two or three
carboxylic acids 18–20. The chiral cap-
sule encapsulated a chiral guest to
show diastereoselection.
1
performed by using H NMR spectros-
copy in [D1]chloroform. In addition to
the computational analysis of the shape
and geometry of the capsule, an experi-
mental approach to estimate the interi-
or size of the cavity is discussed. The
cavity provides a highly rigid binding
Keywords: cavitands
· metal co-
ordination · molecular recognition ·
self-assembly
chemistry
·
supramolecular
Introduction
within the interior, to control and change the reaction rates
and regiochemistry, and to amplify and catalyze reactions.
Metal-coordination-driven self-assembly has become an-
other tool for creating a variety of multicomponent self-as-
semblies because a large number of combinations of coordi-
nation motifs and ligands are available. Thus, metal-directed
self-assembly is intensely developed as a promising ap-
proach to generate supramolecular architectures possessing
nanometric cavities.[5] Such structures may find use in many
potential applications: as reaction vessels, catalysts, drug
containers, molecular switches, memory storage devices, and
others. In particular, cavitand-based coordination capsules
and cages have received a great deal of attention due to
their unique guest-binding properties, arising from their dis-
crete cavities. Introduction of four ligation sites (pyridyl, ni-
trile, dithiocarbamate, and others) on the upper rim of the
cavitands provides the tetradentate ligands, which can as-
semble to form a capsule or a cage by means of metal liga-
tion.[6] We previously reported the synthesis and the binding
properties of a new self-assembling capsule in which two oc-
tadentate cavitands possessing four bipyridyl groups com-
plex with four silver cations in a tetrahedral fashion.[7] In
this paper, we describe the experimental details of the syn-
thesis and characterization of a nanosized self-assembling
capsule 1·4BF4, and introduce probes that reveal the behav-
ior of sizeable organic guests inside the cavity—their dimen-
Cavitand-based molecular containers provide enforced cavi-
ties surrounded by aromatic hemispheres, showing unique
guest-encapsulation properties.[1] Cram and co-workers have
developed molecular containers consisting of two cavitands
with covalent linkages, so-called “carcerands”and “hemicar-
cerands”, which provide the confined inner cavities.[2]
A
wide variety of guests of different size, shape, charge, and
stability were entrapped within their interiors. The recent
strategy to construct confined inner cavities surrounded by
hemispheres is based on self-assembly by hydrogen-bonding
interactions. Resorcinarene-based self-assembling cylindrical
dimers and hexameric assemblies have been developed.[3,4]
Their nanometric cavities are large enough to bind sizable
guests or even more than one guest molecule. Particularly
impressive features of the cavities are their ability to stabi-
lize reactive intermediates and unusual molecular species
[a] Prof. Dr. T. Haino, M. Kobayashi, Prof. Dr. Y. Fukazawa
Department of Chemistry, Graduate School of Science
Hiroshima University
1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526 (Japan)
Fax : (+81)82-424-0724
E-mail: haino@sci.hiroshima-u.ac.jp
fukazawa@sci.hiroshima-u.ac.jp
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FULL PAPER
sions and stability. Thereafter we discuss the thermodynamic
study of guest encapsulation by the capsule. The pairwise in-
teractions of small guest dimers and the diastereoselective
binding of a chiral guest within the capsule are presented.
Results and Discussion
Design, synthesis, and characterization of self-assembled
capsule 1: A methylene-bridged cavitand has a small cavity
in which small guests can be accommodated.[1c] Octadentate
cavitand 2 has a large cavity, expanded by the introduction
of four aromatic spacers on its upper rim. Self-assembly of
two of the expanded cavities by silver coordination in a tet-
rahedral fashion offers the easy construction of an extremely
large guest binding space (Scheme 1). According to molecu-
lar modelling by MacroModel V.6.5 with the amber* force
field,[8] the calculated structure of 1 has a large cavity, with
Scheme 2. Reagents and conditions: a) [Pd(PPh3)4], Na2CO3, dioxane,
H2O, 49%; b) nBuLi, I2, THF, 79%; c) [PdCl2(PPh3)2], Ph3As, Cs2CO3, 5,
dioxane, 80%.
3
the volume estimated to be ꢀ580 Š by the Grasp pro-
began with tetrabromocavitand 6 prepared as described ear-
lier by Reinhoudt.[12] Cavitand 6 was treated with nBuLi and
subsequent addition of iodine to give tetraiodocavitand 7. A
Suzuki coupling reaction[13] of 5 and 7 proceeded smoothly
to give the desired octadentate cavitand 2.
Capsule 1·4BF4 was formed as a colorless solid by the ad-
dition of two equivalents of silver tetrafluoroborate to a so-
lution of 2 in nitromethane. The elementary composition of
1·4BF4 was confirmed by using combustion analysis. Be-
cause the versatility of electrospray ionization (ESI) mass
spectrometry in determining the molecular weight and the
isotopic distribution pattern of highly charged systems is
well established, the ESI mass measurement of 1·4BF4 was
carried out (Figure 1). The mass spectrum shows several
gram.[9] This large cavity can show highly selective binding
of small guest pairs as well as large guests. Cavitand-based
chiral assembly has been limited so far. Chiral, assembled
capsule 1 exhibits D4 symmetry. Encapsulation of a chiral
guest should give rise to diastereomeric complexes.
The synthesis of cavitand 2 was performed according to
Scheme 2. The phenyl spacer was attached to bipyridine 3[10]
by Suzuki coupling with diboronate 4,[11] which afforded bi-
pyridine 5 in a good yield. The synthesis of the new cavitand
Figure 1. ESI MASS spectra of complex 1·4BF4. The inset shows the cal-
culated (straight line) and the experimental isotopic pattern (curve) of
[1·BF4]3+
.
characteristic peaks, which were assigned to the dimeric
structure of 1. The four observed peaks (av m/z=4840
(calcd 4841) [1·3BF4]+; av m/z=2378 (calcd 2377)
[1·2BF4]2+; av m/z=1556 (calcd 1556) [1·BF4]3+; av m/z=
1145 (calcd 1145) [1]4+) belonged to species resulting from a
consecutive loss of four tetrafluoroborate counterions from
the +1 charged state to the +4 charged state. The experi-
mental isotopic pattern of [1·BF4]3+ matched the calculated
pattern very well. These results excluded the formation of
tri- and tetrameric assemblies.
Scheme 1. Self-assembled capsule 1·4BF4 and cavitand 2. In the energy-
minimized structures, the long alkyl chains are omitted for viewing clari-
ty. Van der Waals surfaces are shown in each structure. Left: Top view of
the cavitand. Right: Side view of the capsule. Some atoms have been re-
moved to show the inner surface of the cavity.
Chem. Eur. J. 2006, 12, 3310 – 3319
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3311

T. Haino, Y. Fukazawa, and M. Kobayashi
Figure 2. 1H NMR spectra in [D1]chloroform of a) 2 and b) 1·4BF4.
1
The H NMR spectrum of the capsule gives detailed struc-
tural information (Figure 2). Self-assembly of two octaden-
tate cavitands 2 with four silver cations might be expected
to form many diastereomeric forms of the capsule; however,
1
the H NMR spectrum in CDCl3 showed the selective for-
mation of the D4 symmetric form in which the eight bipyrid-
yl groups are magnetically equivalent. Pyridyl protons Ha
and Hg showed upfield shifts whereas downfield shifts were
À
observed for Hb to Hf as a consequence of the Ag N bond
formation. In general, metal complexation to pyridine
causes downfield shifts of the pyridyl protons. The irregular
upfield shifts of protons Ha and Hg rationalizes the idea that
a silver cation complexes to two bipyridine groups in a tetra-
hedral fashion; protons Ha and Hg stay in the shielding
region of the other bipyridyl group and experience their
shielding effect. Although the precise reason for the selec-
tive formation of the D4 form remains to be determined,
molecular modelling of 1·4BF4 suggests that the D4 symmet-
ric form is more stable than the others.
~
*
( ) and 2 ( ) at 297 K in
Figure 3. Stejskal–Tanner plot of 1·4BF4
[D1]chloroform.
spectively).[17] The resulting ratio Ddim/Dmono =0.76 is in rea-
sonable agreement with the theoretical ratio of 0.72–0.75 ex-
pected for a dimer and confirms the dimeric nature of the
complex 1·4BF4.[18]
The diffusion coefficient of a molecule depends on its size
and shape. The Stoke–Einstein equation (D=kT/6phr)
shows that the diffusion coefficient (D) is inversely propor-
tional to the hydrodynamic radius (r). Hence, by determin-
ing the ratio of the diffusion coefficients for two different
molecules, the ratio of their radii is provided.[14] Diffusion
NMR spectroscopy is an emerging technique in supramolec-
ular chemistry. In recent years, this technique has been used
to investigate issues of structure and mechanism in molecu-
lar assembly.[15,16] A number of theoretical studies have pre-
dicted that a dimer should have a diffusion coefficient (D)
that is 72–75% of its corresponding monomerꢁs value.[17]
To gain further evidence of the capsule formation in solu-
tion, we set out to determine diffusion coefficients for
1·4BF4 and 2 by pulsed field gradient NMR using a bipolar
pulse pairs stimulated echo (BPPSTE) pulse sequence. The
influence of increasing magnetic field gradient strength (g)
on the intensity of the terminal methyl proton signal of the
alkyl chains for both 1·4BF4 and 2 was monitored. The
signal intensities of the protons for both molecules decayed
as a function of the gradient strengths. The given data were
fitted using the Stejskal–Tanner equation (Àln(I/I0)=g2g2d2-
(DÀd/3)D, Figure 3) to give the diffusion coefficients (3.66Æ
0.05”10À10 and 4.79Æ0.04”10À10 m2 sÀ1 for 1·4BF4 and 2, re-
Complex 1·4BF4 is very stable in [D1]chloroform. Howev-
er, the kinetic stability of the complex in organic solution
was not assessed. When
a
solution of 1·4BF4 in
[D1]chloroform was added to that of 2, their sharp signals
appeared independently; this observation supports the exis-
tence of sizable energetic barriers between free and com-
plexed states. To gain an insight into the dynamic behavior
between the complexed and the free states, 2D EXSY spec-
tra of the mixture was measured (Figure 4).[19] Exchange
cross peaks were observed in the spectrum, revealing that
dynamic exchange between them still exists, but that the
rate is slower than the NMR timescale. In common Ag–bi-
pyridine complexes, the energy barrier for the exchange be-
tween the free and the complexed states is small.[20] This
high kinetic stability of capsule 1·4BF4 would be a result of
the cooperative complexation of the bipyridine units.
Encapsulation of guests by capsule 1·4BF4: In molecular
recognition the dimension and shape of an internal cavity of
cavitands, carcerands, and capsules can usually be estimated
by using molecular modelling, or more precisely, by using
X-ray crystallography. Molecular modelling of the capsule
based on MacroModel V.6.5 presented the extremely large
dimension of its cavity: the distance from the bottom of the
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Cavitand-Based Capsule
FULL PAPER
The large upfield shifts of the
terminal methyl groups of
guests 8–10 (Dd=3.7 ppm)
place them near the ends of
capsule 1·4BF4. Intense inter-
molecular nuclear Overhauser
effect (NOE) contacts were ob-
served between the cavitand
protons (Hj, Hl, and Hm shown
in Figure 2) of 1·4BF4 and the
methyl groups of encapsulated
9, thus indicating that its
methyl groups are positioned
deep inside the cavitand termini
of the capsule (Figure 6). The
calculated structures of the cap-
sule with 8–10 help to explain
the observed upfield shifts of
the terminal methyl groups and
the NOE contacts.
In contrast, shorter aromatic
acetates 11–14 were found to
be bound within the capsule,
however, the time-averaged
1H NMR spectra of these com-
Figure 4. 2D EXSY spectrum of a mixture of 1·4BF4 (0.40 mmolLÀ1) and 2 (1.00 mmolLÀ1). The signals of 2
are marked with *.
one cavitand to the other is about 16 Š, and the volume of
the cavity is calculated to be ꢀ580 Š3; however, cavitand 2
itself has a narrow cavity at the bottom end, complementary
to only a methyl group. Accordingly, the selected guests
have a methyl group on either one or both ends of their
structure. The binding properties for guests 8–14 to capsule
plexes carried out at room temperature, with the upfield
shifts of their methyl protons less than 0.2 ppm, suggests
that their molecular lengths are too short to fit within the
cavity of capsule 1·4BF4. The exchange processes of these
shorter guests probably occur through the opened spaces
among the side arms of the capsule, and the dimensions of
the cavity permit these guests to move freely within the
cavity.
The binding abilities of guests 8–10 were much higher
than those of the other aromatic acetates. Guests 8 and 9
are especially distinctive in terms of their binding abilities.
The structures obtained by molecular modelling suggest that
guests 8, 9, and 10 can be accommodated in the cavity. The
methyl groups are placed near the end of the cavity, with
close contact to the aromatic side walls, thus creating CH–p
interactions (Figure 6).[21] Accordingly, more acidic methyl
groups create more effective CH–p interactions to the aro-
matic walls of the capsule (Table 1).
Flexible alkyl diacetates 15–17 were accommodated
1
within capsule 1·4BF4. Their H NMR signals broadened in
the presence of the capsule at room temperature; however,
the protons of the encapsulated guests appeared as sharp
signals at 218 K (Figure 7). At 218 K, the association con-
stants of the guests with the capsule were determined. Sur-
prisingly, the binding ability of 16 is about 150 times higher
than those of 15 and 17. This remarkably strict molecular
recognition of the capsule is obviously based on the rigid
and closed binding environment provided by the self-assem-
bled capsule.
1
1·4BF4 were assessed by using H NMR spectroscopy. The
reasonably rigid guests 8–10, possessing lengths of 14.1–
14.6 Š, were shown to be excellent guests for capsule
1·4BF4. They are also complementary in shape and function-
ality and long enough to occupy a sizable part of the inter-
nal cavity. In the resulting complexes, the signals of the
bound and unbound guests did not overlap at room temper-
ature, indicating that a sizable kinetic barrier exists between
the exchange process of the guests in and out of the capsule
at room temperature (Figure 5).
The signals of methyl groups of 15–17 were shifted higher
than 0.0 ppm (Dd=3.5 ppm), indicating that the methyl
groups are situated near the ends of the capsule, as found
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3313

T. Haino, Y. Fukazawa, and M. Kobayashi
Molecular modelling clearly
shows that diacetates 15 and 16
can be encapsulated in the
cavity in their fully extended
conformation, but 17 is too long
to be incorporated in its ex-
tended form: their calculated
molecular lengths are 14.5, 15.8,
and 17.0 Š for 16, 17, and 18,
respectively. Yet, all of them
are encapsulated as shown by
the 1H NMR spectra. The calcu-
lated structures of their com-
plexes with the capsule gave in-
sight into their binding confor-
mations (Figure 8). Molecular
modelling confirmed that diace-
tates 15 and 16 are lying in an
Figure 5. 1H NMR of the supramolecular complexes of capsule 1·4BF4 with a) 8, b) 9, c) 10 in CDCl3 at 298 K.
elongated manner within the
cavity, with the methyl groups
positioned close to the ends.
This is consistent with the
1H NMR spectra of the com-
plexes.
The bound guests are marked with *.
Coiling into a helix is one of
the ways for an alkyl chain to
decrease its length in a restrict-
ed space. Rebek and co-work-
ers have recently reported that
long alkyl chains show helical
folding within cylindrical cap-
sules.[22] The calculated struc-
ture of bound diacetate 17 sug-
Figure 6. Computer-generated structures of the host–guest complexes of 1·4BF4 with a) 8, b) 9, or c) 10.
Table 1. Association constants (Ka) and free energy (DG) of guests 8–14
with the capsule in [D1]chloroform at 298 K.
Guest
Ka [mÀ1]
]
ÀDG [kcalmolÀ1
]
8
9
170000Æ20000
82000Æ2000
410Æ10
7.13
6.70
3.56
2.82
2.59
2.42
2.80
10
11
12
13
14
15
16
17
118Æ5
80Æ10
60Æ8
113Æ6
33Æ1[a]
1.51[a]
3.68[a]
1.86[a]
4900Æ500[a]
73Æ1[a]
Figure 7. 1H NMR spectra of the host–guest complexes of 1·4BF4 with
a) 15, b) 16, or c) 17 in [D1]chloroform at 218 K. The methyl protons of
the bound guests are marked with *.
[a] Association constants were determined at 218 K in [D1]chloroform.
for guests 8–10, even though guests 15–17 are conformation-
ally more flexible than the others. The methylene protons
adjacent to the acetoxyl group commonly display a sharp
triplet resonance due to unrestricted rotation around the
single bonds; however, they are already magnetically non-
equivalent in the bound states in all cases due to the chiral
nature of the capsule.
gests that it can adopt a helical conformation to fit within
the cavity. The signals for the methylene group next to the
acetoxyl group of diacetate 17 were well split and of AB
type, which supports the suggestion that 17 adopted a helical
conformation within the cavity (Figure 8c).
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Cavitand-Based Capsule
FULL PAPER
Complexes of 1·4BF4 with 9,
10, or 16 have large favorable
entropic components. As associ-
ations of two or more molecu-
lar components are commonly
entropically unfavorable, the
trends for 1·4BF4 are unexpect-
ed. One plausible explanation
can be given in terms of the
desolvation of the cavity.[23] The
self-assembled capsule 1·4BF4
has an extremely large cavity
whose interior can be occupied
Figure 8. The calculated structures of the complexes of 1·4BF4 with a) 15, b) 16, or c) 17.
Thermodynamic studies of the complexation: Vanꢁt Hoff
analysis of the guest encapsulations provides further insights
into the role of the huge cavity of capsule 1·4BF4 (Figure 9).
by several chloroform molecules. Encapsulation of the
guests within the cavity forces the solvents out of the cavity.
The positive entropic changes of the guest encapsulations
are rationalized in terms of the desolvation of the solvated
interior of the cavity.
The compensation relationship[24] between the enthalpic
and entropic changes was observed here with the supra-
molecular complexations (Table 2). It shows that the stron-
ger the attractive interaction between the host and guest,
the more reduced the freedom of the guest movement in the
supramolecular complex, which results in an entropic loss.
Indeed, 8 receives the largest enthalpic gain during the com-
plexation, but has to pay the largest entropic cost, the con-
tribution of which is larger than that of the desolvation. The
enthalpic gain of 16 with complexation is the smallest, which
suggests that the guest still has some freedom of movement
in the cavity, which is of course smaller than the available
space on the outside of the cavity. In this case, the contribu-
tion of the desolvation overcomes the entropic loss due to
the restriction of the freedom of the guestꢁs movement in
the complex. Accordingly, both the solvation–desolvation
and change of the freedom of the guestꢁs movement play an
important role in the complex formation in organic media.
~
*
^
Figure 9. Vanꢁt Hoff plots for guests 8 ( ), 9 ( ), 10 (&), and 16 ( ).
The association constants of guests 8, 9, 10, and 16 were de-
termined at four different temperatures for each guest. The
plots gave good linear correlations and so provided thermo-
dynamic parameters for their encapsulation (Table 2). Com-
Table 2. Thermodynamic parameters for the encapsulation of guests 8, 9,
10, and 16 in [D1]chloroform.
Co-encapsulation of carboxylic acids: Rebek and co-workers
have shown that a cylindrical capsule encapsulated benzoic
acids and pyridone as hydrogen-bonded homodimeric
forms.[25] The different carboxylic acids form statistical mix-
tures of the homo and the hetero hydrogen-bonded dimers
in organic solution. If one of them is complementary to the
interior of the capsule, the capsule enhances this dimeriza-
tion within the cavity (Scheme 3).
Guest
DH [kcalmolÀ1
]
DS [calmolÀ1 KÀ1
]
8
9
10
16
À7.8Æ0.2
À2.4Æ0.8
4.2Æ0.2
6.8Æ0.5
5.9Æ0.6
À5.61Æ0.06
À1.55Æ0.08
À2.4Æ0.1
parison of the relative enthalpic and entropic components of
the four complexes of 1·4BF4 with 8, 9, 10, or 16 provides a
more detailed picture of the driving forces for their encapsu-
lation. The enthalpic component of the stabilities of the
complexes is undoubtedly composed of a variety of nonco-
valent interactions: van der Waals, electrostatic, CH–p, and
others.
Encapsulation of guests 8, 9, and 10 are enthalpically fa-
vored, most likely because of their size and shape. The large
enthalpic difference (DDH=4.06 kcalmolÀ1) for encapsula-
tion between 9 and 10 most likely comes from CH–p inter-
actions of the more acidic methyl protons of 9.
Scheme 3. Schematic representation of the selective encapsulation of the
hydrogen-bonded heterodimer.
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3315

T. Haino, Y. Fukazawa, and M. Kobayashi
The molecular lengths of the dimers formed among car-
boxylic acids 18, 19, and 20 were calculated by using molec-
ular mechanics calculations (Table 3). Molecular modelling
The relative stability of the heterodimers was studied by a
competition experiment. When 18, 19, and 20 were added in
a 1:1:1 ratio into a solution of 1·4BF4 in chloroform, the
heterodimer 18·19 formed exclusively. The molecular mod-
elling of the complexes provided plausible structures of the
dimers within the cavity. Figure 11 shows that both hetero-
Table 3. Calculated molecular lengths of the hydrogen-bonded dimers
formed by the combination of carboxylic acids 18, 19, and 20.
Dimer
Molecular length [Š]
19·19
19·20
20·20
18·19
18·20
18·18
6.84
7.54
8.46
13.19
13.92
19.59
Figure 11. Calculated structures of the host–guest complexes of 1·4BF4
with a) 18·19 or b) 18·20.
suggested that only heterodimers 18·19 and 18·20 have mo-
lecular lengths complementary to the cavity; those of the
other dimers differ from the complementary length by
about 14 Š.
When a 1:1 mixture of 18 and 19 was added to the solu-
tion of 1·4BF4, an asymmetrically filled capsule was exclu-
sively observed at 218 K (Figure 10a). Two singlets appeared
dimers fit well inside the cavity, and that the methyl groups
of 18, 19, and 20 point down to the ends of the cavity, creat-
ing CH–p interactions. The more acidic methyl group of 19
shows a more attractive CH–p interaction with the aromatic
cavity. Accordingly, the CH–p interaction between the
methyl groups and the aromatic interior of the cavity could
account for the highly selective encapsulation of dimer
18·19.
Capsule 1·4BF4 is D4 symmetric, meaning that the capsule
exists as a racemic mixture, P and M forms, which equili-
brates slowly on an NMR timescale. When a chiral guest is
encapsulated, the guest-encapsulated capsule is diastereo-
meric, and the population of the two diastereomers can be
determined by using spectroscopic methods.[26] 4,4’-Diacet-
oxybiphenyl 9 is shown to be a good guest. When capsule
1·4BF4 was added to the solution of racemic 21, the para-
acetylmethyl groups appeared higher than d=0 ppm with
two sharp signals of unequal intensities, which indicates that
the chiral capsule gives a diastereomeric selection of 26%
(Figure 12).
Figure 10. 1H NMR spectra of the host–guest complexes of 1·4BF4 with
a) a 1:1 mixture of 18 and 19, b) a 1:1 mixture of 18 and 20, and c) a 1:1:1
mixture of 18, 19, and 20 in [D1]chloroform at 218 K.
in the clear window higher than d=0 ppm, assigned to the
methyl groups of 18 and 19 (d=À1.43 ppm, Dd=À3.8 ppm
for 18; d=À1.54 ppm, Dd=À3.7 ppm for 19) by a 2D-
EXSY experiment. These characteristic upfield shifts of the
methyl groups and the integrations confirmed the formation
of the hydrogen-bonded heterodimer 18·19 in the capsule.
Propionic acid 20 also forms a hydrogen-bonded heterodi-
mer with 18 in the capsule. The characteristic upfield shifts
À
À
À
were observed for the CH3 and CH2 of 20 (Dd=À3.1
À
À
À
Figure 12. 1H NMR spectrum of the complex of 1·4BF4 with 21. The inset
shows the enlargement of the upfield signals.
and À2.0 ppm for CH3 and CH2 , respectively), placing
À
both CH3 groups near the ends of the cavity (Figure 10b).
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Cavitand-Based Capsule
FULL PAPER
The complexation-induced shifts (CIS) for the protons of the guests are
listed. The CIS values of the methyl protons for guests 11, 12, and 13
were derived by means of nonlinear curve fitting analyses. 8: DdÀ3.66
Conclusion
We have presented the synthesis and encapsulation proper-
ties of the metal-coordination-driven self-assembling capsule
1·4BF4 based on cavitand 2. The capsule is an excellent
model for studying the noncovalent interactions for guest se-
lection as well as the desolvation of the interior of the large
cavity. Encapsulation of the guests, as individual and as
pairs, is unique to the capsule; in particular, pair-wise encap-
sulation of two different guests suggests the possibility that
the capsule acts as a supramolecular catalyst. Diastereo-
meric-selective encapsulation of the capsule is just one of
the interesting properties displayed. We will report on these
properties in due course.
À
(COCH3), À0.60 ppm (CHOAc); 9: DdÀ3.70 (COCH3), À0.67 (Ar Ho),
À
À
À0.32 ppm (Ar Hm); 10: DdÀ3.53 (OCH3), À0.48 (Ar Ho), À0.29 ppm
À
(Ar Hm); 11: DdÀ0.03 ppm (COCH3); 12: DdÀ0.10 ppm (COCH3); 13:
DdÀ0.08 ppm (COCH3); 15: DdÀ3.65 (COCH3), À0.62 ppm (CH2OAc);
16: DdÀ3.92 (COCH3), À0.58 ppm (CH2OAc); 17: DdÀ3.86 (COCH3),
À0.47 ppm (CH2OAc).
5-(4-Pinacolborylphenyl)-2,2’-bipyridine (5): [Pd(PPh3)4] (15 mol%) and
Na2CO3 (2m, 67 mL) were added to a solution of 5-bromobipyridine 3
(6.1 g, 26 mmol) and 4 (22 g, 66 mmol) in dioxane (100 mL) and ethanol
(67 mL). After stirring for 4 h at 808C in the dark, the reaction mixture
was poured into aqueous NH4Cl and extracted with chloroform. The or-
ganic layer was dried over Na2SO4 and concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel to give the de-
sired compound 5 (4.6 g, 49%). M.p. 167–1698C; 1H NMR (300 MHz,
CDCl3): d=8.93 (d, J=2.4 Hz, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.47 (d, J=
8.2 Hz, 1H), 8.44 (d, J=7.6 Hz, 1H), 8.04 (dd, J=8.2, 2.4 Hz, 1H), 7.93
(d, J=8.2 Hz, 2H), 7.83 (dt, J=7.6, 1.6 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H),
7.32 (ddd, J=7.6, 5.1, 1.1 Hz, 1H), 1.37 ppm (s, 12H); 13C NMR
(75 MHz, CDCl3): d=155.8, 155.1, 149.2, 147.7, 140.2, 136.9, 136.2, 135.5,
135.2, 126.3, 123.7, 121.0, 120.9, 83.9, 24.8 ppm; elemental analysis calcd
(%) for C22H23BN2O2: C 73.76, H 6.47, N 7.82; found: C 73.66, H 6.43, N
7.99.
Experimental Section
General: 1H NMR spectra were measured with a JEOL ECA 600, a
JEOL Lambda 500, or a Varian Mercury 300 spectrometer using a resid-
ual solvent signal as internal standard. 13C NMR spectra were taken with
a JEOL Lambda 500 or a Varian Mercury 300 spectrometer. 13C NMR
chemical shifts (d) were with reference to internal [D1]chloroform (d=
77.0 ppm) and carbon disulfide (d=192.8 ppm). All NMR spectra were
recorded in CDCl3 unless otherwise indicated. IR spectra were measured
on a JASCO FT/IR-420S spectrometer. Mass spectra were recorded with
a JEOL JMX-SX 102 mass spectrometer. Elemental analyses were per-
formed on a Perkin Elmer 2400CHN elemental analyzer. Melting points
were measured with a Yanagimoto micro melting point apparatus and
are uncorrected. UV spectra were measured on a JASCO V-560 spec-
trometer.
Tetraiodo cavitand 7: A butyllithium solution (1.8 mL of a 1.59m solu-
tion) was slowly added to a solution of cavitand 6 (1.0 g 0.70 mmol) in
anhydrous THF (56 mL) at À788C under an argon atmosphere. The reac-
tion mixture was stirred for 1 h, and I2 (2.0 g, 7.8 mmol) in THF (5 mL)
was added at À788C. The reaction mixture was poured into aqueous
NH4Cl and extracted with ethyl acetate. The organic layer was washed
with aqueous Na2S2O3 and aqueous NaHCO3, and dried over Na2SO4.
The organic layer was concentrated in vacuo. The residue was purified by
column chromatography on silica gel to give desired cavitand 7 (921 mg,
79%). M.p. 112–1138C; 1H NMR (300 MHz, CDCl3): d=7.05 (s, 4H),
5.96 (d, J=7.4 Hz, 4H), 4.84 (t, J=8.2 Hz, 4H), 4.31 (d, J=7.4 Hz, 4H),
2.15–2.22 (m, 8H), 1.26–1.39 (m, 72H), 0.88 ppm (t, J=6.3 Hz, 12H);
13C NMR (75 MHz, CDCl3): d=154.8, 138.7, 120.6, 98.7, 93.0, 37.9, 31.9,
30.0, 29.6, 29.3, 27.7, 22.6, 14.1; elemental analysis calcd (%) for
All reactions were carried out under an argon atmosphere unless other-
wise noted. THF, Et2O, toluene, and dioxane were freshly distilled from
sodium benzophenone. Dichloromethane and pyridine were freshly dis-
tilled from CaH2. MeOH and EtOH were freshly distilled from activated
magnesium. Column chromatography was performed using Merck silica
gel (70–230 mesh).
C76H108O8I4·1= C6H14: C 55.80, H 6.82; found: C 55.54, H 7.04.
2
Octadentate cavitand 2: H2O (12 mL), bipyridine 5 (5.0 g, 14 mmol), and
AsPh3 (1.7 g, 5.5 mmol) in dioxane (200 mL) were added to a mixture of
7 (2.3 g, 1.4 mmol), [PdCl2(PPh3)2] (500 mg, 50 mol%), and Cs2CO3 (14 g,
42 mmol) in dioxane (300 mL). After stirring for 5 h at 1208C in the
dark, the reaction mixture was filtered on a celite pad and the solution
was concentrated in vacuo. The residue was purified by GPC and column
chromatography on Al2O3 to give 2 (2.3 g, 80%). M.p. 2958C; 1H NMR
(500 MHz, CDCl3) d=8.91 (d, J=2.4 Hz, 4H), 8.66 (d, J=4.9 Hz, 4H),
8.44 (d, J=8.2 Hz, 4H), 8.41 (d, J=7.9 Hz, 4H), 8.01 (dd, J=8.2, 2.4 Hz,
4H), 7.81 (dt, J=7.9, 1.8 Hz, 4H), 7.64 (d, J=8.2 Hz, 8H), 7.39 (s, 4H),
7.29 (dd, J=7.9, 4.9 Hz, 4H), 7.22 (d, J=8.2 Hz, 8H), 5.41 (d, J=7.0 Hz,
4H), 4.92 (t, J=8.2 Hz, 4H), 4.39 (d, J=7.0 Hz, 4H), 2.37–2.41 (m, 8H),
1.29–1.52 (m, 72H), 0.89 ppm (t, J=6.7 Hz, 12H); 13C NMR (75 MHz,
CDCl3): d=155.8, 155.0, 152.7, 149.2, 147.5, 138.5, 136.9, 136.3, 135.7,
135.0, 133.9, 130.7, 128.7, 126.5, 123.6, 121.0, 120.9, 120.1, 100.6, 37.1,
31.9, 30.5, 29.8, 29.7, 29.4, 28.0, 22.7, 14.1 ppm; elemental analysis calcd
(%) for C140H152N8O8: C 81.05, H 7.38, N 5.40; found: C 80.81, H 7.35, N
5.32.
Molecular mechanics calculations were performed with the MacroModel
V6.5 program package running on a SGI O2. A low-mode search option
was used for the initial geometry generation, and the given geometries
were optimized by a conjugate gradient energy minimization using the
amber* force field.
Determination of the association constants for guests 8–17 was carried
out by means of a 1H NMR titration technique in [D1]chloroform. The
complexes of 8–10 and 15–17 with 1·4BF4 were in slow exchange on the
NMR timescale and displayed well-resolved signals for the free and
bound guests. In these cases the relative intensity of the protons of the
free and bound guests, along with the known concentrations of the guests
and 1·4BF4, were used to determine the association constants. In con-
trast, the complexes of the other guests with 1·4BF4 were in fast ex-
change on the NMR timescale and showed only one set of resonances for
the guest protons. In these cases, the association constants were deter-
mined by nonlinear-curve fitting analysis of the complexation-induced
upfield-shifted data of the methyl protons upon the addition of 1·4BF4.
Self-assembled capsule 1·4BF4: AgBF4 (83.0 mg, 0.43 mmol) in nitrome-
thane (5 mL) was added to a solution of 2 (440 mg, 0.21 mmol) in chloro-
form (20 mL). The reaction mixture was stirred for several hours and the
solvent was removed in vacuo. The crude compound was recrystallized
from chloroform and hexane (7:3) to give desired compound 1·4BF4
(498 mg, 95%). M.p. >3008C; 1H NMR (500 MHz, CDCl3): d=8.88 (d,
J=8.5 Hz, 8H), 8.85 (d, J=7.9 Hz, 8H), 8.55 (d, J=5.2 Hz, 8H), 8.49 (s,
8H), 8.26 (dd, J=8.5, 2.0 Hz, 8H), 8.17 (t, J=7.9 Hz, 8H), 7.45 (dd, J=
7.9, 5.2 Hz, 8H), 7.36 (d, J=8.2 Hz, 16H), 7.29 (s, 8H), 7.06 (d, J=
8.2 Hz, 16H), 5.28 (d, J=6.7 Hz, 8H), 4.82 (t, J=7.9 Hz, 8H), 4.21 (d,
Thermodynamic parameters were determined by vanꢁt Hoff analyses
using the association constants determined at different temperatures. 8:
Ka =57000Æ2000 (323 K), 111000Æ7000 (308 K), 170000Æ20000
(296 K), 320000Æ10000 mÀ1 (283 K); 9: Ka =54000Æ5000 (323 K),
82000Æ7000 (308 K), 110000Æ10000 (296 K), 183000Æ8000 (283 K),
320000Æ40000 mÀ1 (268 K); 10: Ka =340Æ10 (323 K), 400Æ10 (308 K),
450Æ10 (296 K), 500Æ20 (283 K), 570Æ10 mÀ1 (268 K); 16: Ka =1600Æ
200 (273 K), 3000Æ200 (243 K), 4000Æ600 (228 K), 4900Æ500 mÀ1
(218 K).
Chem. Eur. J. 2006, 12, 3310 – 3319
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3317

T. Haino, Y. Fukazawa, and M. Kobayashi
J=6.7 Hz, 8H), 2.28–2.34 (m, 16H), 1.27–1.47 (m, 144H), 0.88 ppm (t,
J=6.7 Hz, 24H); 13C NMR (75 MHz, CDCl3): d=152.6, 152.3, 151.9,
150.4, 150.3, 148.7, 139.7, 138.6, 138.3, 137.9, 135.5, 133.8, 131.0, 128.0,
126.7, 125.3, 124.2, 120.1, 100.6, 37.1, 31.9, 30.5, 29.8, 29.7, 29.4, 27.9, 22.7,
14.1 ppm; elemental analysis calcd (%) for C280H304Ag4B4F16N16O16: C
68.24, H 6.22, N 4.55; found: C 68.00, H 6.31, N 4.49.
Angew. Chem. Int. Ed. 1998, 37, 1840–1843; h) T. N. Parac, D. L.
Caulder, K. E. Raymond, J. Am. Chem. Soc. 1998, 120, 8003–8004;
i) D. W. Johnson, J. Xu, R. W. Saalfrank, K. E. Raymond, Angew.
Chem. 1999, 111, 3058–3061; Angew. Chem. Int. Ed. 1999, 38, 2882–
2885; j) D. L. Caulder, K. E. Raymond, J. Chem. Soc. Dalton Trans.
1999, 1185–1200; k) D. K. Chand, K. Biradha, M. Fujita, Chem.
Commun. 2001, 1652–1653; l) N. Takeda, K. Umemoto, K. Yamagu-
chi, M. Fujita, Nature 1999, 398, 794–796; m) T. Kusukawa, M.
Fujita, Angew. Chem. 1998, 110, 3327–3329; Angew. Chem. Int. Ed.
1998, 37, 3142–3144; n) T. Kusukawa, M. Fujita, J. Am. Chem. Soc.
1999, 121, 1397–1398; o) M. Fujita, D. Oguro, M. Miyazawa, H.
Oka, K. Yamaguchi, K. Ogura, Nature 1995, 378, 469–471; p) P.
Baxter, J.-M. Lehn, A. DeCian, J. Fisher, Angew. Chem. 1993, 105,
92–95; Angew. Chem. Int. Ed. Engl. 1993, 32, 69; q) E. Leiz, A. V.
Dorsselaer, R. Krämer, J.-M. Lehn, J. Chem. Soc. Chem. Commun.
1993, 990; r) H. Sleiman, P. N. W. Baxter, J.-M. Lehn, K. Rissanen, J.
Chem. Soc. Chem. Commun. 1995, 715–716; s) G. S. Hanan, C. R.
Arana, J.-M. Lehn, D. Fenske, Angew. Chem. 1995, 107, 1191;
Angew. Chem. Int. Ed. Engl. 1995, 34, 1122–1124; t) A. Ikeda, Y.
Yoshimura, H. Udzu, C. Fukuhara, S. Shinkai, J. Am. Chem. Soc.
1999, 121, 4296–4297.
[1] For reviews on large cavities, see: a) D. M. Rudkevich, J. Rebek, Jr.,
Eur. J. Org. Chem. 1999, 1991–2005; b) D. M. Rudkevich, Chem.
Eur. J. 2000, 6, 2679–2689; c) D. J. Cram, Science 1983, 219, 1177–
1183; d) C. D. Gutsche, Calixarenes Revisited, The Royal Society of
Chemistry, Cambridge, 1998; e) D. M. Rudkevich in FunctionalSyn-
thetic Receptors (Eds.: T. Schrader, A. D. Hamilton), Wiley, Wein-
heim, 2005, pp. 257–298.
[2] For reviews on carceplexes and hemicarceplexes, see: a) E. Maver-
ick, D. J. Cram, Compr. Supramol. Chem. 1996, 2, 367–418; b) D. J.
Cram, Nature 1992, 356, 29–36; c) J. C. Sherman, Tetrahedron 1995,
51, 3395–3422; d) R. G. Chapman, J. C. Sherman, Tetrahedron 1997,
53, 15911–15945; e) A. Jasat, J. C. Sherman, Chem. Rev. 1999, 99,
931–967; f) H.-J. Choi, D. J. Cram, C. B. Knobler, E. F. Marverick,
Pure Appl. Chem. 1993, 65, 539–543.
[3] For reviews on self-assembling capsules and cages, see: a) J. Re-
bek, Jr., Angew. Chem. 2005, 11, 2104–2115; Angew. Chem. Int. Ed.
2005, 44, 2068–2078; b) J. Rebek, Jr., Chem. Soc. Rev. 1996, 255–
264; c) M. M. Conn, J. Rebek, Jr., Chem. Rev. 1997, 97, 1647–1668;
d) F. Hof, J. Rebek, Jr., Proc. Natl. Acad. Sci. USA 2002, 99, 4775–
4777; e) F. Hof, S. L. Craig, C. Nuckolls, J. Rebek, Jr., Angew. Chem.
2002, 114, 1556–1578; Angew. Chem. Int. Ed. 2002, 41, 1488–1508;
f) L. J. Prins, D. N. Reinhoudt, P. Timmerman, Angew. Chem. 2001,
113, 2446–2492; Angew. Chem. Int. Ed. 2001, 40, 2382–2426.
[6] a) P. Jacopozzi, E. Dalcanale, Angew. Chem. 1997, 109, 665–667;
Angew. Chem. Int. Ed. Engl. 1997, 36, 613–615; b) B. Bibal, B.
Tinant, J.-P. Declercq, J.-P. Dutasta, Chem. Commun. 2002, 432–
433; c) S. J. Park, J.-I. Hong, Chem. Commun. 2001, 1554–1555;
d) K. Kobayashi, Y. Yamada, M. Yamanaka, Y. Sei, K. Yamaguchi,
J. Am. Chem. Soc. 2004, 126, 13896–13897; e) O. D. Fox, J. F.-Y.
Leung, J. M. Hunter, N. K. Dalley, R. G. Harrison, Inorg. Chem.
2000, 39, 783–790; f) O. D. Fox, E. J. S. Wilkinson, P. D. Beer,
M. G. B. Drew, Chem. Commun. 2000, 391–392.
[7] T. Haino, M. Kobayashi, M. Chikaraishi, Y. Fukazawa, Chem.
Commun. 2005, 2321–2323.
[4] a) T. Heinz, D. M. Rudkevich, J. Rebek, Jr., Nature 1999, 37, 3410–
3413; b) F. C. Tucci, D. M. Rudkevich, J. Rebek, Jr., J. Am. Chem.
Soc. 1999, 121, 4928–4929; c) R. S. Meissner, J. Rebek, Jr., J. D.
Mendoza, Science 1995, 270, 1485–1488; d) K. D. Shimizu, J. Re-
bek, Jr., Proc. Natl. Acad. Sci. USA 1995, 92, 12403–12407; e) B. C.
Hamann, K. D. Shimizu, J. Rebek, Jr., Angew. Chem. 1996, 108,
1425–1427; Angew. Chem. Int. Ed. Engl. 1996, 35, 1326–1329;
f) R. K. Castellano, D. M. Rudkevich, J. Rebek, Jr., J. Am. Chem.
Soc. 1996, 118, 10002–10003; g) N. Branda, R. M. Grotzfeld, C.
ValdØs, J. Rebek, Jr., J. Am. Chem. Soc. 1995, 117, 85–88; h) B. M.
OꢁLeary, R. M. Grotzfeld, J. Rebek, Jr., J. Am. Chem. Soc. 1997,
119, 11701–11702; i) J. M. Rivera, T. Martín, J. Rebek, Jr., J. Am.
Chem. Soc. 1998, 120, 819–820; j) B. M. OꢁLeary, T. Szabo, N.
Svenstrup, C. A. Schalley, A. Lützen, M. Schäfer, J. Rebek, Jr., J.
Am. Chem. Soc. 2001, 123, 11519–11533; k) D. W. Johnson, F. Hof,
P. M. Iovine, C. Nuckolls, J. Rebek, Jr., Angew. Chem. 2002, 114,
3947–3950; Angew. Chem. Int. Ed. 2002, 41, 3793–3796; l) L. R.
MacGillivray, J. L. Atwood, Nature 1997, 389, 469–472; m) A. Shi-
vanyuk, J. Rebek, Jr., Proc. Natl. Acad. Sci. USA 2001, 98, 7662–
7665; n) R. E. Brewster, S. B. Shuker, J. Am. Chem. Soc. 2002, 124,
7902–7903; o) L. R. MacGillivray, P. R. Diamente, J. L. Reid, J. A.
Ripmeester, Chem. Commun. 2000, 359–360; p) C. M. Drain, R.
Fischer, E. G. Nolen, J.-M. Lehn, J. Chem. Soc. Chem. Commun.
1993, 243–245; q) K. Kobayashi, T. Shirasaka, K. Yamaguchi, S. Sa-
kamoto, E. Horn, N. Furukawa, Chem. Commun. 2000, 41–42; r) K.
Kobayashi, K. Ishii, S. Sakamoto, T. Shirasaka, K. Yamaguchi, J.
Am. Chem. Soc. 2003, 125, 10615–10624.
[5] a) S. R. Seidel, P. J. Stang, Acc. Chem. Res. 2002, 35, 972–983;
b) Y. K. Kryschenko, S. R. Seidel, D. C. Muddiman, A. I. Nepomuce-
no, P. J. Stang, J. Am. Chem. Soc. 2003, 125, 9647–9652; c) K.-W.
Chi, C. Addicott, Y. K. Kryschenko, P. J. Stang, J. Org. Chem. 2004,
69, 964–966; d) P. S. Mukherjee, N. Das, P. J. Stang, J. Org. Chem.
2004, 69, 3526–3529; e) D. L. Caulder, C. Brückner, R. E. Powers, S.
Kçnig, T. N. Parac, J. A. Leary, K. E. Raymond, J. Am. Chem. Soc.
2001, 123, 8923–8938; f) M. Scherer, D. L. Caulder, D. W. Johnson,
K. E. Raymond, Angew. Chem. 1999, 111, 1689–1694; Angew.
Chem. Int. Ed. 1999, 38, 1588–1592; g) D. L. Caulder, R. E. Powers,
T. N. Parac, K. E. Raymond, Angew. Chem. 1998, 110, 1940–1943;
[8] F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp, M.
Lipton, C. Caufield, G. Chang, T. Hendrickson, W. C. Still, J.
Comput. Chem. 1990, 11, 440–467.
[9] A. Nicholls, K. A. Sharp, B. Honig, Proteins 1991, 11, 281.
[10] F. M. Romero, R. Ziessel, Tetrahedron Lett. 1995, 36, 6471–6474.
[11] M. H. Todd, S. Balasubramanian, C. Abell, Tetrahedron Lett. 1997,
38, 6781–6784.
[12] P. Timmerman, H. Boerrigter, W. Verboom, G. J. Van Hummel, S.
Harkema, D. N. Reinhoudt, J. Inclusion Phenom. Mol. Recognit.
Chem. 1994, 19, 167–191.
[13] L. Sebo, F. Diederich, V. Gramlich, Helv. Chim. Acta 2000, 83, 93–
113.
[14] D. C. Teller, E. Swanson, C. DeHaen, Methods in Enzymology Vol.
61, Academic Press, New York, 1979, pp. 103–124.
[15] Y. Cohen, L. Avram, L. Frish, Angew. Chem. 2005, 117, 524–560;
Angew. Chem. Int. Ed. 2005, 44, 520–554.
[16] a) M. S. Kaucher, Y.-F. Lam, S. Pieraccini, G. Bottarelli, J. T. Davis,
Chem. Eur. J. 2005, 11, 164–173; b) L. Avram, Y. Cohen, Org. Lett.
2003, 5, 1099–1102.
[17] E. O. Stejskal, J. E. Tanner, J. Chem. Phys. 1965, 42, 288–292.
[18] a) A. S. Altieri, D. P. Hinton, R. A. Byrd, J. Am. Chem. Soc. 1995,
117, 7566–7567; b) V. V. Krishnan, J. Magn. Reson. 1997, 124, 468–
473.
[19] a) L. C. Palmer, J. Rebek, Jr., Org. Biomol. Chem. 2004, 2, 3051–
3059; b) C. L. Perrin, T. J. Dwyer, Chem. Rev. 1990, 90, 935–967.
[20] T. Haino, H. Araki, Y. Yamanaka, Y. Fukazawa, Tetrahedron Lett.
2001, 42, 3203–3206.
[21] a) K. Kobayashi, Y. Asakawa, Y. Kikuchi, H. Toi, Y. Aoyama, J.
Am. Chem. Soc. 1993, 115, 2648–2654; b) D. Falꢂbu, A. Shivanyuk,
M. Nissinen, K. Rissanen, Org. Lett. 2002, 4, 3019–3022.
[22] A. Scarso, L. Trembleau, J. Rebek, Jr., J. Am. Chem. Soc. 2004, 126,
13512–13518.
[23] a) J. Kang, J. Rebek, Jr., Nature 1996, 382, 239–241; b) R. M. Grotz-
feld, N. Branda, J. Rebek, Jr., Science 1996, 271, 487–489.
[24] a) Y. Inoue, T. Hakushi, J. Chem. Soc. Perkin Trans. 2 1985, 935–
946; b) Y. Inoue, F. Amano, N. Okada, H. Inada, M. Ouchi, A. Tai,
T. Hakushi, Y. Lu, L.-H. Tong, J. Chem. Soc. Perkin Trans. 2 1990,
3318
www.chemeurj.org
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Cavitand-Based Capsule
FULL PAPER
1239–1246; c) D. B. Smithrud, T. B. Wyman, F. Diederich, J. Am.
Chem. Soc. 1991, 113, 5420–5426.
[25] Benzoic acids and methylpyridone formed homodimers in the self-
assembled cylindrical capsule. See: T. Heinz, D. M. Rudkevich, J.
Rebek, Jr., Angew. Chem. 1999, 111, 1206–1209; Angew. Chem. Int.
Ed. 1999, 38, 1136–1139.
2001, 123, 5213–5220; c) R. K. Castellano, B. H. Kim, J. Rebek, Jr.,
J. Am. Chem. Soc. 1997, 119, 12671–12672; d) R. K. Castellano, C.
Nuckolls, J. Rebek, Jr., J. Am. Chem. Soc. 1999, 121, 11156–11163.
Received: August 11, 2005
Revised: October 12, 2005
Published online: February 15, 2006
[26] a) J. M. Rivera, T. Martín, J. Rebek, Jr., Science 1998, 279, 1021–
1023; b) J. M. Rivera, T. Martín, J. Rebek, Jr., J. Am. Chem. Soc.
Chem. Eur. J. 2006, 12, 3310 – 3319
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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