Water-stabilized cavitands

Article abstract of DOI:10.1021/ja012453p

Tetrabenzimidazole cavitands 4 were prepared by condensation of ortho esters with octaamino cavitand 3 in 70-80% yield. Molecular modeling predicted that no intramolecular hydrogen bonds are possible between the imidazole fragments in the vase conformation of 4. Instead, this conformation provides four perfect binding sites for hydroxyl-containing molecules through an N-H...O-H...N pattern. Such interactions provide the means for sealing the cavitand's cavity. Accordingly, dry compounds 4 are not soluble in dry CDCl₃ but readily dissolve upon addition of small amounts of alcohols or by saturation of the solution with water. ¹H NMR spectroscopy revealed that in these solutions molecules 4 adopt a vase conformation while 1D GOESY experiments revealed their monomeric nature. In water-saturated CDCl₃, these cavitands 4 form kinetically stable 1:1 inclusion complexes with tetramethylphosphonium bromide and triethylammonium chloride in which the cation is incorporated into the π-basic cavity. Thus, cavitands 4 are a novel class of open-ended molecular containers capable of the formation of highly kinetically stable complexes upon assistance by hydrogen-bonding water molecules. Copyright

Full text of DOI:10.1021/ja012453p

Published on Web 02/27/2002
Water-Stabilized Cavitands
Adel Rafai Far, Alexander Shivanyuk, and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, MB-26, 10550 North Torrey Pines Road,
La Jolla, California 92037
Received October 30, 2001
Cavitands are open-ended host molecules possessing enforced
cavities in which complementary guest molecules can be accom-
modated and detained.1 The inclusion complexes (caviplexes) of
the resorcinarene-based cavitands have typically been characterized
in the crystalline state by single-crystal X-ray analysis.2 At ambient
temperatures in solution the caviplexes are short-lived on the NMR
time scale.3 The upper rims of the cavitands can be extended through
synthesis, but such changes can also result in conformations that
no longer possess well-defined cavities.4 Additional features that
favor a vaselike shape must be incorporated, such as a cyclic array
of intramolecular hydrogen bonds.5 These constructs allow the
formation of kinetically stable caviplexes with sizable guests, such
as adamantane derivatives and ammonium cations. We report here
that the cyclic array of hydrogen bonds can be provided in an
intermolecular sense, from interacting water molecules.6 The result
is novel molecular containers of tetrabenzimidazoles that form
kinetically stable inclusion complexes on the NMR time scale.
Scheme 1
Figure 1. Energy-minimized structures of 4a (A) and 4a‚4H2O (B) and
self-folding cavitand 5 (C) in space-filling representations (AMBER force
field). Long pendant chains are replaced by methyls for clarity.
the NH and N atoms of the neighboring benzimidazole fragments
(Figure 1). On the other hand, structure A provides four excellent
binding sites for hydroxyl-containing molecules such as alcohols
and water, which would stabilize the vase shape to give structure
B. This prediction and the experimental results below strongly
suggest that cavitands 4 can exist in water-saturated CDCl3 in the
form of hydrogen-bonded complexe(s) resembling structure B.
Dry tetrabenzimidazoles 4 are not soluble in dry CDCl3 but form
gels upon heating. In commercial CDCl3, these compounds are
scarcely soluble, and the 1H NMR spectra of such solutions contain
incomprehensible sets of broad resonances, likely due to the
Alkylation of resorcinarene 1 with 4 equiv of 1,2-dinitro-4,5-
difluorobenzene resulted in octanitrocavitand 2. Complete reduction
of 2 by SnCl2 in EtOH/ HCl led to octaamine 3 in hydrochloride
form. The treatment of this amine salt with excess ortho esters7 in
1:3 DMF:CH2Cl2 at room temperature afforded the corresponding
benzimidazole derivatives 4 in 52-82% yield. Compounds 4 were
characterized by NMR and IR spectroscopy and mass spectrometry.
The energy-minimized8 structure of 4 in the vase conformation
shows that no intramolecular hydrogen bonds are possible between
formation of ill-defined aggregates. However, the addition of small
amounts of alcohols (ca. 5%)9 resulted in immediate solubilization
in CDCl3. The same was also observed upon saturation of the CDCl3
solutions with water. The 1H NMR spectrum of 4b in water-
saturated CDCl3 is sharp and contains one triplet for the methine
protons of the bridges at 5.68 ppm, two singlets for the protons of
the resorcinol rings, and one singlet for the protons of methyl groups
at the 2-position of the benzimidazole fragments of the cavitand
walls (Figure 2a). This pattern is characteristic for a hollow C4V-
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2854 VOL. 124, NO. 12, 2002 J. AM. CHEM. SOC.
10.1021/ja012453p CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
M-1). Tetraethylphosphonium and ammonium bromides 7(b-c)+-
Br-, as well as adamantane and 1-hydroxyadamantane did not
interact with cavitands 4 under the same conditions.
The octaamide 5 also forms a kinetically stable 1:1 complex with
7a+Br- either in dry or water-saturated CDCl3. The induced upfield
shifts for the 1H and 31P signals were considerably smaller (∆δ )
-3.4 and -5.8 ppm, respectively) than those for the complex with
4. An analogous trend was found also for the complexes with
triethylammonium chloride. Apparently the four imidazole rings
in 4 contribute to the shielding effect of the cavity. The addition
of 5% of methanol resulted in a complete destruction of the
inclusion complexes of cavitands 4. Whether this is due to better
solvation of the guest, host or both is not yet known.
In summary, readily available tetrabenzimidazole cavitands 4 are
new open-ended hosts with deep cavities. The crucial role of water
in the hydrogen bonding with 4 is, to the best of our knowledge,
the first example of such solvent effects on simple cavitands.6,13
Acknowledgment. We are grateful to the Skaggs Foundation
and the National Institute of Health for financial support. A.R.F.
and A. S. are Skaggs postdoctoral fellows.
Figure 2. The 1H NMR spectra in water-saturated CDCl3 (600 MHz, 295
K): (a) 4b; (b) 3 4b + 7a+ Br- water saturated CDCl3. (b) water; (*)
methine protons of the bridges; (1) methyl protons of benzimidazole
fragments.
Supporting Information Available: Synthetic procedures and
analytical data for compounds 4 (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
symmetrical vase conformation of cavitands. A signal for water
involved in hydrogen bonds to 4 was broad and centered at 2.70
ppm; free water molecules gave a broad signal at 1.6 ppm. The
pattern for the cavitand protons did not significantly change with
temperature between 233 and 323 K. The vase conformation is rigid.
The pattern of hydrogen bonds presented by the imidazoles is
self-complementary and raised the possibility that the compounds
exist as dimeric capsules, but the following experiments exclude
such structures. The 1H NMR spectra of 1:1 mixtures of 4a + 4b,
4a + 4c, and 4b + 4c in water-saturated CDCl3 were the
superimpositions of the spectra of the individual components and
showed no sign of kinetically stable heterodimers. Moreover,
cavitands 4 and monomeric self-folding cavitands 5 showed nearly
the same kinetics of NOEs (1D GOESY) upon irradiation of the
methine protons of the bridges, which reveals the comparable size
of both molecules. This is in contrast to the same experiments with
the tetraimide 6.10 This compound exists as a dimer and forms a
cylindrical capsule approximately twice as large as the monomers
4 and 5.11 The capsule’s negative NOEs are about 10 times stronger
than those of the monomers 4 and 5. The solubility and the NMR
spectra of 5 in CDCl3 show no dependence on the amount of water
present in the solution.
Structure B has nearly the same size of cavity as 5 (structure C,
Figure 2), and therefore similar inclusion properties were expected.
The addition of tetramethylphosphonium bromide 7a+Br- to the
solution of 4b in water-saturated CDCl3 resulted in a new set of
cavitand signals which grew at the expense of the original set upon
further addition of the salt (Figure 2b). A sharp doublet emerged
at -2.32 ppm, corresponding to the methyl protons of the
complexed cation. The large upfield shift for this resonance (∆δ
) -4.4 ppm) is consistent with the position of the cation 7a+ deep
in the cavity of the host. The broad signal for water was found at
3.0 ppm in the caviplex.12 Upon complexation, the 31P resonance
of 7a+ undergoes an upfield shift of 8.0 ppm. The complex has a
1:1 stoichiometry and is kinetically stable on the NMR time scale
at 295 K. The low solubility of 7a+Br- in CDCl3 and its strong
complexation in the cavitand hampered the reliable evaluation of
the stability constant.
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