Self-assembled octameric cage constructed by the potassium salt of p-tert-butylcalix[6]arene p-bromophenylalanine derivative in the solid state

Article abstract of DOI:10.1039/b605555a

Potassium salts of p-tert-butylcalix[6]arene p-bromophenylalanine derivative formed sizable octameric cages in the solid state that were revealed by X-ray crystallographic analysis. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605555a

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Self-assembled octameric cage constructed by the potassium salt of
p-tert-butylcalix[6]arene p-bromophenylalanine derivative in the solid
state{
Koji Tsukamoto,a Hirofumi Ohishi,*b Yoichi Hiyama,c Naoyoshi Maezaki,*a Tetsuaki Tanaka*a and
Toshimasa Ishidab
Received (in Cambridge, UK) 19th April 2006, Accepted 12th July 2006
First published as an Advance Article on the web 26th July 2006
DOI: 10.1039/b605555a
they formed very similar octamers regardless of the amount of
potassium ions. However, the mode of their self-assembly was
different. In the crystal of 1a rich in potassium ions, the driving
force of the self-organization was the coordinate bonds and the
ionic bonds between the amino acid moieties and the potassium
ions. In the crystal of 1b containing fewer potassium ions, the
hydrogen bonding between the carboxyl groups of the amino acids
compensated for the lack of ions. While the inner spaces of the
preceding molecular capsules were hydrophobic,1,6 the insides of
the cages of 1a and 1b were hydrophilic since the carboxyl groups
of the amino acids were directed inside. To the best of our
knowledge, this is the first report describing X-ray structures of a
calix[6]arene amino acid derivative as well as those of rare
octamers.
Potassium salts of p-tert-butylcalix[6]arene p-bromophenyl-
alanine derivative formed sizable octameric cages in the solid
state that were revealed by X-ray crystallographic analysis.
Investigation of self-assembled molecular capsules and molecular
cages has attracted much interest in supramolecular chemistry.1
They can serve as molecular containers for inclusion of guest
molecules, and have been applied to isolation of unstable
intermediates,2 selective recognition of guest molecules,3 promo-
tion of chemical reactions,4 and regio- and stereoselective
reactions.5 In the self-assembly process, hydrogen bonding and
metal coordination play an important role in building unique cage
structures, which have a larger size than single molecules can
create.1a,6 Many self-assembled cage structures have been reported
so far.1–6 However, more progress is required to elaborate their
functions and to enable them to accommodate a wide variety of
guest molecules.
p-tert-Butylcalix[6]arene p-bromophenylalanine derivative 2 was
synthesized in good yield from the known tricarboxylic acid 313
(Scheme 1). Potassium salts 1a and 1b were prepared by treatment
of 2 with 1.5 and 0.5 equiv. of potassium carbonate, respectively.
In the mass spectral data of 1a, molecular ion peaks corresponding
to the mono-, di-, and tripotassium salts were observed. For 1b,
the peaks corresponding to the monopotassium salt and the free
acid 2 were observed. These results suggest that compounds 1a and
1b are an equilibrium mixture of these molecules.{
Crystals of 1a and 1b were obtained from aqueous methanol.
Because their total molecular weights were large and the collected
data with the X-ray source in a laboratory were low resolution due
to containing many disordered solvent molecules in the structure,
direct methods for phase calculations were unsuccessful in the
X-ray crystallographic analysis. Thus, the X-ray diffraction data
sets were measured by synchrotron radiation at four wavelengths,
and the phases were calculated with the multiwavelength
anomalous diffraction method,14 using the anomalous scattering
Calixarenes have been extensively studied as excellent host
molecules in host–guest chemistry.7 Calixarenes and their con-
geners are known to form molecular capsules and molecular cages
by self-assembly. In particular, there are many examples of dimeric
molecular capsules, e.g., calixresorcinarene derivatives,8a ureidoca-
lixarenes,8b,c and calixarenes connected with amino acids or
peptides.9,10 However, there are few examples for further poly-
merization. Chiral calix[4]arene dimelamines form an asymmetric
trimer box with barbiturates,11 and C-methylcalix[4]resorcinarenes
form a hexameric cage.12
Here, we show that the potassium salts of p-tert-butylcalix[6]-
arene p-bromophenylalanine derivative construct novel octameric
cage structures in the solid state that were revealed by X-ray
crystallographic analysis using synchrotron radiation. To investi-
gate the structural difference due to variation of the amount of
potassium ions, two kinds of potassium salts, 1a and 1b, were
prepared by neutralization of the calix[6]arene derivative 2 with 1.5
and 0.5 equiv. of potassium carbonate, respectively. We found that
aGraduate School of Pharmaceutical Sciences, Osaka University, 1-6
Yamadaoka, Suita, Osaka, 565-0871, Japan.
E-mail: t-tanaka@phs.osaka-u.ac.jp; Fax: +81 6 6879 8214;
Tel: +81 6 6879 8210
bOsaka University of Pharmaceutical Sciences, 4-20-1 Nasahara,
Takatsuki, Osaka, 569-1094, Japan. E-mail: ohishi@gly.oups.ac.jp;
Fax: +81 72 690 1090; Tel: +81 72 690 1090
cGenomic Science Laboratories Group III, Dainippon Sumitomo Pharma
Co., Ltd., 33-94 Enoki, Suita, Osaka, 564-0053, Japan
{ Electronic supplementary information (ESI) available: Crystallographic
data, experimental section for synthesis, Fig. S1, Table S1 and Table S2.
See DOI: 10.1039/b605555a
Scheme 1 Synthesis of 1a and 1b. PyBroP1 = bromotripyrrolidinopho-
sphonium hexafluorophosphate.
3606 | Chem. Commun., 2006, 3606–3608
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was filled with methanol and water molecules, although some were
not assigned because of their great disorder. Inside the cage of 1a,
fifteen methanol molecules and forty-two water molecules were
assigned (Fig. 1c). In the cage of 1b, only twenty-four waters and
six methanols were assigned because of their severer disorder than
3
˚
1a. The volumes of the solvent regions inside the cages are 890 A
3
15
˚
and 1160 A in 1a and 1b, respectively. p-Bromophenyl groups
were inserted between adjoining calixarene moieties, though there
was no stacking among the p-bromophenyl groups and aromatic
rings of the calixarenes. Near the center of all the cube surfaces,
four p-bromophenylalanine residues were aggregated around two
potassium ions in 1a and one potassium ion in 1b. The space group
of both crystals was R3. The octamers of 1a and 1b were
constructed with two complete C3 symmetric molecules and six
pseudo C3 symmetric molecules (see Fig. S1 in ESI{).
In each octamer, there were two modes of potassium ion
uptake, which is crystallographically asymmetric. Fig. 2a shows
two kinds of aggregation sites of the amino acid moieties in the
crystal of 1a. These structures resembled each other. In both sites,
two potassium ions were included by ionic or coordinate bonds
with the carboxyl groups and the amide carbonyl groups in the
p-bromophenylalanine residues. The upper potassium ion was
bound to the four carboxyl groups and water molecule(s). Two
carboxyls, three amide carbonyls, and water(s) interacted with the
lower potassium ion.
In contrast, only one potassium ion existed in the aggregation
sites of 1b (Fig. 2b). The highly disordered potassium ion was
apart from the carboxyl anion and occupied almost the same
position as the lower potassium ion in 1a. The carboxyl groups of
the p-bromophenylalanine residues formed hydrogen bonds with
each other. That is, the hydrogen bonding between the carboxyl
groups compensated for the lack of potassium ion.
In conclusion, we have elucidated the X-ray structure of the
p-tert-butylcalix[6]arene p-bromophenylalanine derivatives 1a and
1b. In the crystal 1a with high ion content, eight calixarenes were
assembled by the aid of twelve potassium ions, thereby making up
into a unique cube-like cage structure. The octameric cage has a
hydrophilic hole at each center of the six surfaces and two
potassium ions were included in each hole. It is noteworthy that a
Fig. 1 (a) Crystal packing of 1a (green: carbons; white: hydrogens; red:
oxygens; blue: nitrogens; purple: potassiums). The four cube-like octamers
are displayed and solvents are omitted for clarity. (b) The octameric cage
of 1a viewed along the c crystal axis. (c) Solvent molecules inside
the octameric cage of 1a shown by space-filling model. (d) Inside of the
octameric cage 1a. Four calixarenes and two potassium ions of the
octamer have been omitted for clarity. Hydrogens and solvents are also
omitted. The selected interatomic distances in the left space-filling model
t
are as follows. l1 (between the Bu groups) = 25.5 A, l2 (between the
˚
˚
˚
˚
oxygens of the methoxy groups) = 23.5 A, l3 = 10.1 A, l4 = 8.2 A. The right
stick model displays coordination and ionic bonds by blue dotted lines. (e)
Inside of the octameric cage 1b. Each potassium ion is disordered and
occupies two positions. In the right stick model, hydrogen bonds are
represented by orange dotted lines.
effect of bromines.§ The obtained crystal structures are shown in
Fig. 1.
The crystals of the potassium salts 1a and 1b formed a cube-like
supramolecular cage consisting of eight p-tert-butylcalix[6]arene
p-bromophenylalanine molecules. Each calixarene moiety was
located at a corner of the cube, and the hydrophilic carboxyl
groups of the p-bromophenylalanine residues were directed to the
inside of the octameric cage. The inner hydrophilic area in the cage
Fig. 2 Two kinds of the aggregation sites of 1a (a) and 1b (b). Only
p-bromophenylalanine moieties, potassium ions, and solvents without
hydrogens are shown for clarity. Occupancies of the disordered potassium
ions in 1b are indicated.
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3
˚
˚
rhombohedral, a = 43.22(4), c = 43.40(4) A, V = 70187(121) A , space
group R3, Z = 3, m = 0.532 mm21, 97012 reflections measured, 36570
unique which were used in all calculations (Friedel pairs were not merged),
3123 parameters, 4280 restraints. The final R1 (I . 2s(I)) = 0.1437, and
wR2 = 0.4079 for all data. CCDC 268806.
similar cube-like octameric structure was constructed even in the
crystal 1b with lower ion content. In sharp contrast to 1a, the
hydrogen bond network between the carboxyl groups compen-
sated for the loss of interaction with the potassium ion in the
crystal 1b. These results show that coordination of amides to
potassium ion is preferred over that of carboxylic acids despite the
attractive ion–ion interaction. The self-assembled nano-cages
stimulate our imagination for the design of new supramolecules
as well as their application. Further study is in progress.
The synchrotron radiation experiments were performed at the
BL38B1 in the SPring-8 with the approval of the Japan
Synchrotron Radiation Research Institute (JASRI) (Proposal
No. 2005A0258-NL1-np).
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{ Preparation of 1a and 1b: potassium carbonate (2.2 mg, 16.1 mmol) was
added to a solution of 2 (20 mg, 10.7 mmol) in MeOH (5 mL). After the
solution was refluxed for 40 min, the solvent was evaporated to give 1a as a
colorless powder. 1b was also prepared using 2 (30 mg, 16.1 mmol) and
0.5 equiv. of potassium carbonate (1.1 mg, 8.0 mmol) by the same
procedure as that described for 1a. Crystals for X-ray analysis were
obtained from aqueous MeOH. The mass spectroscopic data showed that
1a exists as a mixture of monopotassium (A), dipotassium (B), and
tripotassium (C) salts: MS (FAB): m/z 1907 ([A + H]+, calcd 1907), 1944
([B + H]+, calcd 1945), 1983 ([C + H]+, calcd 1983). 1b also exists as a
mixture of the neutral molecule (2) and the monopotassium salt: MS
(FAB): m/z 1891 ([2 + Na]+, calcd 1891), 1907 ([A + H]+, calcd 1907).
§ X-Ray crystallographic analysis of 1a and 1b: diffraction data sets of the
crystal of 1a were collected on a beamline BL38B1 at SPring-8 (Hyogo,
Japan), and those of 1b were collected on a beamline BL-6A at the Photon
Factory (Tsukuba, Japan) using a Quantum 4R CCD X-ray detector (Area
Detector Systems Corporation, California, USA). The crystals were
cryoprotected with glycerol in a nitrogen stream at 95 K. Four X-ray
wavelengths—peak (a peak of the K edge of bromine), inflection (an
inflection point of the K edge), low-energy remote (a remote point from the
K edge to the low-energy wavelength side), and high-energy remote (a
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˚
˚
wavelengths were 0.7000 A in 1a and 0.9220 A in 1b. The positions of
hydrogen atoms, excepting those of the carboxyl groups and all solvent
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data of 1a: 8C102H118.5Br3N3O15?12K?33CH3OH?66H2O, Mr = 17645.6,
3
˚
˚
rhombohedral, a = 43.05(4), c = 44.17(4) A, V = 70897(123) A , space
group R3, Z = 3, m = 1.145 mm21, 60089 reflections measured, 20981
unique which were used in all calculations (Friedel pairs were not merged),
3205 parameters, 4522 restraints. The final R1 (I . 2s(I)) = 0.1347, wR2 =
0.3053 for all data. CCDC 290779. Crystal data of 1b:
8C102H119.25Br3N3O15?6K?21CH3OH?27H2O, Mr
= 16330.0,
3608 | Chem. Commun., 2006, 3606–3608
This journal is ß The Royal Society of Chemistry 2006