Calix[4]pyrroles bearing proximally meso-meso linking straps: Synthesis and anion binding properties

Article abstract of DOI:10.1039/c2cc33537a

Calix[4]pyrroles bearing two proximally crossing straps on the same or the opposite sides have been synthesized for the first time. The doubly cis-strapped compound exhibited highly cooperative six-point hydrogen bonding interactions with the anion involv

Full text of DOI:10.1039/c2cc33537a

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COMMUNICATION
Calix[4]pyrroles bearing proximally meso–meso linking straps: synthesis
and anion binding propertiesw
Ja-Young Park,a Kamil Skonieczny,b Naoki Aratani,c Atsuhiro Osuka,c Daniel T. Gryko*b
and Chang-Hee Lee*a
Received 30th March 2012, Accepted 11th June 2012
DOI: 10.1039/c2cc33537a
Calix[4]pyrroles bearing two proximally crossing straps on the
same or the opposite sides have been synthesized for the first time.
The doubly cis-strapped compound exhibited highly cooperative
six-point hydrogen bonding interactions with the anion involving
both pyrrolic N–Hs and Ar–Hs.
groups engaged in research aimed at improving anion binding
affinity and selectivity.7 It is envisaged that calix[4]pyrroles
bearing pre-organized and flexible binding domains will exhibit
enhanced affinity and selectivity.
As part of our ongoing efforts to develop versatile receptors
based on the strapped calix[4]pyrroles, we herein report the first
example of a new class of calix[4]pyrroles, including compounds
1 and 2, bearing proximal double straps on either side of the
parent macrocycle (Scheme 1). The solid-state structures and
anion binding behaviors of these doubly strapped calix[4]pyrroles
are also reported. It was envisaged that the introduction of a
flexible strap enabling the isolation of the binding domain by
encapsulation would provide additional hydrogen bonding
donor sites and potentially allow for specific modulation of the
anion affinities. It was also anticipated that the incorporation of a
variety of functionalities with different chain-lengths into the
straps would enhance affinity and selectivity.8 Moreover, the use
of a hydrophobic cavity surrounded by the four alkyl groups
could enhance the selectivity for hydrophobic anions.z
The design and synthesis of neutral anion receptors with high
affinity and selectivity for a variety of targeted anions represents
a significant challenge in supramolecular chemistry. The use of
hydrogen bonding interactions as recognition motifs for specific
anions has been studied extensively because of the potential
applications of the technologies in biological and environmental
sciences.1 Applications that have received particular interest in
recent years include ion selective electrodes, fluorescence
chemosensors and electrochemical signaling devices.2 The
development of novel and more specifically functionalized
receptors showing enhanced selectivity requires fine tuning
of the interactions with targeted guest molecules. Although
hydrogen bonding interactions are weak non-covalent interactions
that are strongly affected by both pH and solvent, they are
commonly used as the driving force in anion recognition. Thus,
the effective design of anion receptors is more challenging than the
design of the corresponding cation receptors.3 Among the various
anion recognition motifs reported in the literature,4 calix[4]pyrroles,
which are readily accessible from the condensation of pyrrole
and ketones, have been identified as versatile hosts for anion
recognition and for halide anions especially.5 We have
reported several strapped calix[4]pyrroles as new homologues
for anion-binding and ion-pair recognition motifs.6 Three-
dimensional cyclic oligopyrroles have been reported by several
Our original intention was to synthesize desired receptor 3,
which bears diametrically crossing straps on the top and
bottom sides of the macrocycle, via direct condensation of
pyrrole and bis-ketone 4. However, the attempted condensa-
tion under various conditions failed to give desired product 3.
It was envisaged that compound 3 would display multiple
anion-binding properties with an especially high affinity for
sphere shape anions. Compound 4 was synthesized over three
steps (Scheme 2). The acid catalyzed condensation of bis-ketone
4 with pyrrole afforded bis-dipyrromethane 5 in 52% yield.
Subsequent BF3 mediated condensation of bis-dipyrromethane
a Department of Chemistry and Institute of Molecular Science &
Fusion technology, Kangwon National University,
Chun-Chon 200-701, Korea. E-mail: chhlee@kangwon.ac.kr
b Institute of Organic Chemistry Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland.
E-mail: danieltgryko@gmail.com
c Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
E-mail: osuka@kuchem.kyoto-u.ac.jp
w Electronic supplementary information (ESI) available: Synthetic
details of all the compounds, spectroscopic data and single crystal
X-ray data. CCDC 872113 (1) and 872114 (2). For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2cc33537a
Scheme 1 Calix[4]pyrroles bearing proximally meso–meso linking
straps (1 and 2) and distally meso–meso linking straps (3).
c
8060 Chem. Commun., 2012, 48, 8060–8062
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Scheme 2 Synthesis of compounds 1, 2 and 6.
5 with bis-ketone 4 unexpectedly afforded a mixture of products,
including 1, 2 and 6 in yields of 3%, 2% and 10%, respectively.
However, compound 3 which is expected to form was not isolated.
Mechanistically, it was envisaged that the formation of
compound 6 must be associated with an acid-catalyzed cleavage
of the pyrrole–carbon bond in bis-dipyrromethane 5 affording a
carbocationic intermediate, which underwent intramolecular
Fig. 2 300 MHz 1H NMR spectra of compounds 2 (top) and 1
(bottom) in CDCl3.
at 7.05 ppm (Fig. 2). The anion binding behavior of compounds 1
and 2 in acetonitrile was studied by 1H NMR spectroscopy. The
slow nature of the complexation–decomplexation equilibrium
enabled direct observation of the binding process. Quantitative
binding studies with fluoride and chloride anions revealed
distinctive changes in the chemical shifts of all the proton
signals (ESIw). Two singlets corresponding to the N–H resonances
in compound 1 that appeared at 6.99 and 6.82 ppm were shifted
to B13.24 ppm following the addition of fluoride anions and
subsequently appeared as a pair of doublets. This splitting of the
pyrrolic N–H resonances to two sets of doublets reflects the
anisochronic nature of the complex (Fig. 3).10 The b-pyrrolic
resonances that originally appeared as two singlets at 5.87 and
5.84 ppm were also shifted to 5.63 and 5.60 ppm, respectively,
upon addition of the fluoride anion. The resonance of the inner
Ar–H on the strap that originally appeared at 6.0 ppm was shifted
to 6.37 ppm upon addition of a fluoride anion, which was
consistent with the presence of a weak hydrogen bonding
interaction between the Ar–H bond and the fluoride anion.
A slight shift down-field of the methylene proton next to the
phenolic oxygen also indicated the presence of a weak hydrogen
bonding interaction.
nucleophilic attack by
a neighboring pyrrole. Subsequent
condensation of 6 with bis-ketone 4 with released pyrrole could
afford either compound 1 or 2. To the best of our knowledge,
compounds 1 and 2 are unprecedented in the literature. The
structures were confirmed by X-ray diffraction analysis, which
was performed on single crystals obtained by slow evaporation of
the compounds from a mixture of chloroform and hexanes.
Single crystal X-ray crystallographic analysis of compounds
1 and 2 revealed that the two compounds adopted completely
different geometries in the solid state.9 The conformation
of cis-doubly strapped compound 1 adopted a near perfect
1,3-alternate form, whereas the trans-doubly strapped compound
2 adopted a partial cone conformation (Fig. 1).
Consideration of the partial cone structure of compound 2
(Fig. 1(b)) revealed that two pyrrolic N–Hs were involved in
an intramolecular hydrogen bonding interaction with two of
the phenolic oxygens. The observed distance between N2 and
O2 was 3.125 A and N1 and O3 was 3.255 A. The scoop-like
solid state conformation of compound 2 was also reflected in
solution NMR.
In contrast, receptor 1 exhibited a fast complexation–
decomplexation equilibrium process with chloride anions
(Fig. 4). Anion-dependent shifts were observed in all of the
signals. The pyrrolic N–H resonances were shifted to 11.12 ppm
and appeared as a broad singlet. The inner Ar–H resonance on
the strap was shifted to 6.62 ppm upon saturation. The inner
Ar–H exhibited a slight down field shift following fluoride
binding. These results provide support for the contention that
the chloride anion forms stronger hydrogen bonding interactions
Intramolecular hydrogen bonding of the two pyrrolic N–Hs
appeared clearly at 8.69 ppm in the 1H NMR spectra, whereas
the other two non-hydrogen bonding pyrrolic N–Hs appeared
Fig. 1 Single crystal X-ray structures of receptors 1 (a) and 2 (b). The
hydrogen atoms have been removed for clarity. Two of the pyrrole
N–Hs and two of the phenolic oxygen atoms on the strap form
hydrogen bonding interactions (b). The displacement ellipsoids have
been scaled to the 50% probability level.
Fig. 3 Changes in the 1H NMR spectra of receptor 1 following the
addition of fluoride anions (as its tetrabutyl ammonium salt) in
CDCl3.
c
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Chem. Commun., 2012, 48, 8060–8062 8061

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acknowledge the Central Instrumentation Facility at KNU and
BK21 program for support. D.T.G. thanks the Polish Ministry
of Science and Higher Education (Contract N204 123837).
Notes and references
z X-ray summary for 1 and 2: crystals grew by slow evaporation from
acetonitrile and diethyl ether.
1 (a) P. Chakrabarti, J. Mol. Biol., 1993, 234, 463; (b) M. A. Van
Kuijck, R. A. M. H. Van Aubel, A. E. Busch, F. Lang,
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Deen, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 5401;
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A. D. Frankel, Science, 1991, 252, 1167.
2 (a) A. P. de Silva, H. Q. N. Guanarante, T. Gunnlaugson, A. J. M.
Huxley, C. P. McCoy, J. T. Rademacher and T. E. Rice, Chem.
Rev., 1997, 97, 1515; (b) J. L. Sessler, CHEMTECH, 1999, 29, 16.
3 (a) J. L. Sessler, A. Gebauer and P. A. Gale, Gazz. Chim. Ital.,
1997, 127, 723; (b) J. L. Sessler, P. Anzenbacher, Jr., K. Jursikova,
H. Miyaji, J. W. Genge, N. A. Tvermoes, W. E. Allen and
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4 (a) K. Kavallieratos, S. R. de Gala, D. J. Austin and R. H. Crabtree,
J. Am. Chem. Soc., 1997, 119, 2325; (b) K. Kavallieratos,
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2006, 47, 8217; (d) J. M. Mahoney, A. M. Beatty and B. D. Smith,
J. Am. Chem. Soc., 2001, 123, 5847; (e) M. J. Deetz, M. Shang and
B. D. Smith, J. Am. Chem. Soc., 2000, 122, 6201; (f) Z. Rodriguez-
Docampo, S. I. Pascu, S. Kubik and S. Otto, J. Am. Chem. Soc.,
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K. Bowman-James, Angew. Chem., Int. Ed., 2006, 45, 1921.
5 J. L. Sessler, D. E. Gross, W.-S. Cho, V. M. Lynch,
F. P. Schmidtchen, G. W. Bates, M. E. Light and P. A. Gale,
J. Am. Chem. Soc., 2006, 128, 12281.
6 (a) H. Miyaji, H.-K. Kim, E.-K. Sim, C.-K. Lee, W.-S. Cho,
J. L. Sessler and C.-H. Lee, J. Am. Chem. Soc., 2005, 127, 12510;
(b) C.-H. Lee, H. Miyaji, D.-W. Yoon and J. L. Sessler, Chem.
Commun., 2008, 24; (c) J. L. Sessler, S. K. Kim, D. E. Gross,
C.-H. Lee, J.-S. Kim and V. M. Lynch, J. Am. Chem. Soc., 2008,
130, 13162; (d) J. Yoo, M.-S. Kim, S.-J. Hong, J. L. Sessler and
C.-H. Lee, J. Org. Chem., 2009, 74, 1065; (e) S.-H. Kim,
S.-J. Hong, J. Yoo, S. K. Kim, J. L. Sessler and C.-H. Lee, Org.
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Fig. 4 Changes in the 1H NMR spectra of receptor 2 following the
addition of fluoride anions (as its tetrabutyl ammonium salt) in
CDCl3.
with the inner Ar–H than the fluoride anion. The larger size of
chloride anions provides a rational basis for this conclusion.
1H NMR spectral titration indicated that the smaller and more
electronegative fluoride anion formed tighter hydrogen bonding
interactions with the pyrrolic N–Hs and looser interactions with the
Ar–Hs. In contrast, the relatively larger and less electronegative
chloride anion formed loose hydrogen bonding interactions with
the pyrrolic N–Hs and stronger interactions with the Ar–Hs. No
appreciable binding interactions were observed with other anions
such as bromide, iodide, sulfate or dihydrogen phosphate. To
determine the energetics associated with the formation of the
receptor–anion complexes, isothermal titration calorimetry
(ITC) measurements were performed in acetonitrile. Unfortunately,
the calorimetric traces for the fluoride anions did not show
proper curve fitting. In contrast, traces for the chloride anions
revealed progressive changes in the heat pulse and showed
proper curve fitting.
The binding isotherm obtained for the binding of receptor 1
with Clꢀ revealed clean exothermic equimolar binding for the
formation of the corresponding complexes. Interestingly, the affinity
constant for the formation of [1ꢁClꢀ] (K = 2.65 ꢂ 105 Mꢀ1
)
was ten times larger than that for the formation of [2ꢁClꢀ]
(K = 2.31 ꢂ 104
M
ꢀ1), clearly indicating the cooperative
binding of the two Ar–Hs with the chloride anion in receptor 1
(ESIw). The highly selective binding of receptor 1 with fluoride
anions indicates that the double strapping of the calix[4]pyrrole
macrocycle induces high selectivity toward smaller anions such
as fluoride and chloride anions. The driving force for the
enhanced binding was considered to be a combination of
the C–H–Xꢀ and N–H–Xꢀ hydrogen bonding interactions. The
introduction of multiple straps also reduced the matrix–guest
interaction by isolation of the binding domain.
7 (a) S.-J. Hong, J. Yoo, D.-W. Yoon, J. Yoon, J. S. Kim and
C.-H. Lee, Chem.–Asian J., 2010, 5, 768; (b) C. Bucher,
R. S. Zimmerman, V. M. Lynch and J. L. Sessler, J. Am. Chem.
Soc., 2001, 123, 9716.
8 (a) C.-H. Lee, J.-S. Lee, H.-K. Na, D.-W. Yoon, H. Miyaji,
W.-S. Cho and J. L. Sessler, J. Org. Chem., 2005, 70, 2067;
(b) D. W. Yoon, H. Hwang and C. H. Lee, Angew. Chem., Int.
Ed., 2002, 41, 1757.
9 X-ray data of a crystal having dimension of 0.3 ꢂ 0.3 ꢂ 0.4 mm
were collected on a Nonius CAD4 mach 3 diffractometer equipped
with graphite-monochromated MoKa radiation (l = 0.71373 A)
at room temperature. The unit cell was determined to be mono-
clinic, P21/n (no. 14), jZ = 4, a = 10.335(2), b = 16.519(3), c =
20.329(3)A, b = 95.297(14)1, V = 3455.9(9)A3, rcalc = 1.243
gcmꢀ3 on the basis of 25 reflections. A total of 7467 reflections
were measured, 6990 unique (Rint = 0.0646). The structure refined
In conclusion, doubly strapped calix[4]pyrroles have been
successfully synthesized and characterized for the first time.
The current receptor systems support the concept of designer
anion receptors used for the recognition of smaller anions with
high affinity and selectivity. The approach detailed within this
report provides a novel and useful complementary tool to
other affinity modulation techniques currently being pursued
in the context of supramolecular calix[4]pyyrrole-based anion
binding chemistry.
data F2 to Rw = 0.3248, R = 0.1013 (3162 reflections with Fo
>
4sFo), and GoF = 1.125 for 433 refined parameters. The data were
collected by using the o-2y scan technique in the range 2.141 o
y o 26.291. No absorption corrections were applied. The structure
was solved by a direct method and refined by full matrix least
square calculation with SHELXL-97. Anisotropic thermal para-
meters were used for all non-hydrogen atoms.
We are grateful for support received from the Basic Science
Research Program through the NRF (2009-0087013). We also
10 W. Sato, H. Miyaji and J. L. Sessler, Tetrahedron Lett., 2000,
41, 6731.
c
8062 Chem. Commun., 2012, 48, 8060–8062
This journal is The Royal Society of Chemistry 2012