Hydrogen bonded calixarene capsules kinetically stable in DMSO

Article abstract of DOI:10.1039/b105613c

Half-life times up to 4 days in DMSO at room temperature are observed for the decomposition of dimeric capsules of urea substituted calix[4]arenes held together by a combination of hydrogen bonds, mechanical entanglement and cation-π interactions.

Full text of DOI:10.1039/b105613c

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Hydrogen bonded calixarene capsules kinetically stable in DMSO
Myroslav O. Vysotsky,a Iris Thondorfb and Volker Böhmer*a
a Johannes Gutenberg - Universität Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany.
E-mail: vboehmer@mail.uni-mainz.de
b Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 3, D-06099 Halle, Germany
Received (in Cambridge, UK) 25th April 2001, Accepted 31st July 2001
First published as an Advance Article on the web 5th September 2001
Half-life times up to 4 days in DMSO at room temperature
are observed for the decomposition of dimeric capsules of
urea substituted calix[4]arenes held together by a combina-
tion of hydrogen bonds, mechanical entanglement and
cation–p interactions.
Natural macromolecules like proteins, DNA and RNA possess
specific three-dimensional structures which determine their
biological activity in complex sequences of intracellular
transformations including recognition, catalysis and self-repli-
cation.1 Their stability in water is achieved by a combination of
numerous weak, noncovalent interactions such as hydrogen
bonding, cation–p, p–p, and hydrophobic interactions.
Fig. 1 Simulated structure of a dimer of 1 with Me4N+ as a guest.
between the cation and the extended p-basic cavity should
additionally stabilise the ternary complex.
Indeed, when the urea 1 is refluxed for 2–4 weeks in
dichloromethane in the presence of tetramethylammonium
iodide or chloride an additional spot appears in the TLC (Rf =
0, instead of Rf = 1 for 1 with ethyl acetate as eluant) indicating
the formation of charged species. A simple column separation
allowed isolation of the compounds 1·Me4N+·1 I2 and
Spatially well defined artificial hydrogen bonded assemblies
which are thermodynamically or at least kinetically stable in
highly competitive hydrogen bonding solvents such as water,
DMF or DMSO are rare.2,3 Recent examples are polymers
formed by cooperative stacking of hydrogen-bonded pairs in
water4 and dimeric glycoluril capsules formed by self-assembly
via hydrogen bonds in the presence of a hydrophobic guest in
DMF.5 In the latter case, the observation of signals of both the
dimer and the monomer in the 1H NMR spectra, indicated that
the dimers are stable on the NMR time-scale. To our
knowledge, this example is unique, although simpler systems
like hydrogen bonded complexes of anions in d6-DMSO which
are stable on the NMR time-scale have been described.6 In the
following we disclose our first results on self-assembled dimers
which possess high kinetic stability on a ‘human time-scale’ in
a hydrogen bond breaking solvent like d6-DMSO.
Calix[4]arenes bearing four urea functions at the wide rim,
form dimeric capsules in appropriate nonpolar solvents.7 These
capsules are held together by a hydrogen bonded belt formed
between the self-complementary urea units. A suitable guest,
often a solvent molecule, must be included inside. The dimers
are usually rapidly destroyed by small amounts (only up to 2%)
of DMSO added to the apolar solvent, while kinetically very
stable assemblies are available in the absence of competitive
hydrogen bonding solvents.8 We have demonstrated, for
instance, that the mechanical entanglement of bulky residues
like trityl (1) and p-tritylphenyl (2) attached to the urea
1·Me4N+·1 Cl22 in 33 and 13% yield, respectively. The H
1
NMR spectrum in CDCl3 shown in Fig. 2a clearly supports their
structures by the sharp, low field shifted NH signals and one of
two meta-coupled doublets characteristic for the aromatic
protons of the calixarene in dimeric urea complexes.† The
signal of the included tetramethylammonium cation is upfield
shifted to d 21.1 ppm due to shielding by the aromatic residues
of the calixarene. The MALDI-TOF spectrum shows a peak at
m/z 3886.8 (calc. for 1·Me4N+·1 3886.7).
Surprisingly, the spectrum of the 1·Me4N+·1 I2 recorded in
d6-DMSO shows the same set of signals, typical for a dimeric
structure, which slowly disappear while signals for the
monomeric 1 and for the uncomplexed tetramethylammonium
functions leads to dimers with kinetic stability on the ‘human
1
time-scale’ (t = 60 h for the heterodimer 1·2 in d6-benzene).
2
MD simulations performed for 2·2, 1·2 and 1·1 have shown8a
that the inner volume of the capsule decreases in this row, and
that the cavity size of the trityl urea dimer 1·1 would be too
small for the inclusion of benzene. As predicted 1 does not form
dimers in this solvent. However, we assumed that a small cation
like tetramethylammonium could be a good template for the
dimerisation of 1 (Fig. 1),9 since favourable interactions
Fig. 2 Section of the 1H NMR spectra (400 MHz) of 1·Me4N+·1 I2 recorded
in CDCl3 (a) and in d6-DMSO after 1 day (b). Calixarene, amide and guest
protons are indicated in (a), the disappearing signals of the dimer (5) and
the growing signals of the monomer 1 (2) are marked in (b).
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Chem. Commun., 2001, 1890–1891
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105613c

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cation appear (Fig. 2b). These spectral changes obey first-order
kinetics. Activation parameters (Table 1) for the reaction:
1·Me4N+·1 X2 ? 2 1 + Me4N+ X2 were derived from Eyring
plots (Fig. 3) in the 25–55 °C temperature range.
signals for the calixarene skeleton. Six signals of the trityl
groups are sufficiently resolved to distinguish clearly cross-
peaks corresponding to two different phenyl groups in the
gradient selected COSY spectrum. The pattern of the spectrum
proves the fast rotation of the phenyl groups.‡ Thus, the
splitting of the signals must be due to the slow rotation of the
entire trityl groups around the C–N bonds. Models suggest that
this rotation must occur in a concerted way for all of the eight
trityl groups.
Table 1 Activation parameters for the decomposition of the capsules in d6-
DMSO
1·Me4N+·1 Cl2 1·Me4N+·1 I2
In conclusion, we have described an unprecedented example
of a molecular capsule self-assembled via a belt of hydrogen
bonds, showing kinetic stability on ‘the human time-scale’ in
the hydrogen bond breaking solvent d6-DMSO. This kinetic
stability is caused, to a large extent, by the mechanical
entanglement of bulky, noncyclic residues (trityl groups)
attached to the urea functions which hinder the access of solvent
to the hydrogen bonded belt. We propose to call this type of
molecule ‘anchoranes’ since — in contrast to ‘rotaxanes’§ —
noncyclic structural elements or residues are mechanically
entangled similar to an anchor holding a ship due to its
interlocking with noncyclic structures on the bottom of the
sea.
DH≠ /kJ mol21
118.0 ( 6.5)
49.0 ( 21)
103.4
99.9 ( 2.6)
218.4 ( 8.2)
105.6
DS≠ /J K21 mol21
DG≠ /kJ mol21 at 25 °C
1
t /hours at 25 °C
40
93
2
We thank Professor J. Okuda for generous access to the
Bruker DRX 400 Avance instrument and Dr B. Mathiasch for
his technical assistance during the NMR experiments. The
financial support from the Deutsche Forschungsgemeinschaft
(Bo523/14-1, Th520/5-1) is gratefully acknowledged.
Notes and references
† In gradient selected-COSY spectra there are cross-peaks from this signal
to another meta-coupled doublet overlapped with signals of trityl groups.
‡ Only two cross-peaks between three signals of the rings a or b are
observed. If rotation about the C–C bond were slow on the NMR time-scale,
five signals would be expected for each phenyl group.
Fig. 3 Eyring plot for the decomposition of 1·Me4N+·1 I2 (5) and
1·Me4N+·1 Cl2 (») in d6-DMSO.
The half-life slightly depends on the counter anion and
reaches 93 hours at 25 °C in the case of iodide, which is
unprecedented for such a hydrogen bonded assembly to our
knowledge. This high kinetic stability of the capsules in d6-
DMSO suggests that the mechanical entanglement of the bulky
trityl residues protects the belt of 16 hydrogen bonds from
access by DMSO (cf., Fig. 1).10
§ Although ‘rotaxanes’ are topologically not exactly defined like catenanes,
the concept of (pseudo)rotaxanes has proved to be very fruitful.
1 L. Stryer, Biochemistry, W. H. Freeman and Company, New York,
1995, pp. 1–144.
2 For capsules formed in water due to mainly hydrophobic interactions
between host and guest see: T. Andersson, K. Nilsson, M. Sundahl, G.
Westman and O. Wennerstrom, J. Chem. Soc., Chem. Commun., 1992,
604; A. Ikeda, T. Hatano, M. Kawaguchi, H. Suenaga and S. Shinkai,
Chem. Commun., 1999, 1403; H. Dodziuk, A. Ejchart, O. Lukin and
M. O. Vysotsky, J. Org. Chem., 1999, 64, 1503.
3 H. Fenniri, P. Mathivanan, K. L. Vidale, D. M. Sherman, K. Hallenga,
K. V. Wood and J. G. Stowell, J. Am. Chem. Soc., 2001, 123, 3854.
4 J. H. K. K. Hirschberg, L. Brunsveld, A. Ramzi, J. A. J. M. Vekemans,
R. P. Sijbesma and E. W. Meijer, Nature, 2000, 407, 167.
5 N. Branda, R. M. Grotzfeld, C. Valdès and J. Rebek, Jr., J. Am. Chem.
Soc., 1995, 117, 85.
The signals of the trityl groups in the 1H NMR spectrum are
broad at 25 °C and split into several broad signals in the case of
1·Me4N+·1 Cl2 in CD2Cl2 at 250 °C (Fig. 4), in contrast to the
monomeric 1. The overall symmetry of the capsule remains S8
as deduced from the presence of only two NH and two ArH
6 See for example: K. Choi and A. D. Hamilton, J. Am. Chem. Soc., 2001,
123, 2456.
7 For a review see: J. Rebek, Jr., Chem. Commun., 2000, 641.
8 (a) M. O. Vysotsky, I. Thondorf and V. Böhmer, Angew. Chem., Int.
Ed., 2000, 39, 1264; (b) M. O. Vysotsky and V. Böhmer, Org. Lett.,
2000, 2, 3571.
9 An inclusion of tetraalkylammonium cations into calix[4]arene urea
dimeric capsules has been described: C. A. Schalley, R. K. Castellano,
M. S. Brody, D. M. Rudkevich, G. Siuzdak and J. Rebek, Jr., J. Am.
Chem. Soc., 1999, 121, 4568; M. O. Vysotsky, A. Pop, F. Broda, I.
Thondorf and V. Böhmer, Chem. Eur. J., in the press.
10 For a ‘rotaxane-like complex’ assembled from a crown-ether and a
dialkylammonium cation showing a half-life time of 11 minutes in
CD2Cl2–d6-DMSO (50+50), see: S.-H. Chiu, S. J. Rowan, S. J. Cantrill,
P. T. Glink, R. L. Garrell and J. F. Stoddart, Org. Lett., 2000, 2,
3631.
Fig. 4 Section of the 1H NMR (250 °C, CD2Cl2, 400 MHz) of 1·Me4N+·1
Cl2. Calixarene and amide protons are marked with NH and ArH
respectively. Two low-field shifted signals of the phenyl group (assigned
‘b’) overlap with signals of the third phenyl ring (‘g’).
Chem. Commun., 2001, 1890–1891
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