Calix[2]bispyrrolylarenes: New expanded calix[4]pyrroles for fluorometric sensing of anions via extended π-conjugation

Article abstract of DOI:10.1021/ol3032158

Two new expanded calix[4]pyrroles 3 and 4 were synthesized by '2 + 2' cyclocoupling of easily prepared diboryldipyrromethane 7 (by Ir-catalyzed CH-bond activation) with appropriate diiodoarenes using the Suzuki protocol. Owing to the unique design, both m

Full text of DOI:10.1021/ol3032158

ORGANIC
LETTERS
2013
Vol. 15, No. 2
306–309
Calix[2]bispyrrolylarenes: New Expanded
Calix[4]pyrroles for Fluorometric Sensing
of Anions via Extended π‑Conjugation
Brijesh Chandra,† Sanjeev P. Mahanta,† Narendra N. Pati,† Sambath Baskaran,‡
Ravi K. Kanaparthi,§ Chinnappan Sivasankar,‡ and Pradeepta K. Panda*,†
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India,
Department of Chemistry, School of Physical, Chemical and Applied Sciences,
Pondicherry University, Puducherry 605 014, India, and Inorganic and Physical
Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
pkpsc@uohyd.ernet.in; pradeepta.panda@gmail.com
Received November 21, 2012
ABSTRACT
Two new expanded calix[4]pyrroles 3 and 4 were synthesized by ‘2 þ 2’ cyclocoupling of easily prepared diboryldipyrromethane 7 (by Ir-catalyzed
CH-bond activation) with appropriate diiodoarenes using the Suzuki protocol. Owing to the unique design, both macrocycles exhibited extended
π-conjugation and enhanced fluorescence. Upon complexation with anions (fluoride and acetate), receptor 3 displayed turn-on sensing of
fluorescence, whereas 4 showed turn-off sensing.
Subsequent to the discovery of anion binding by calix-
[4]pyrrole, the challenge was to achieve needful manipula-
tions so as to enhance the affinity and selectivity toward
various anions to find potential applications of this tetra-
pyrrolic nonaromatic macrocycle.1 Toward this end, the
major emphasis has been on substitution at its periphery to
enhance the strength of H-bonding,2 attachment of a strap
to increase preorganization,3 and core expansion via either
increasing the number of pyrrolic moieties (and hence
number of H- bond donors)4 or utilizing various spacers
to increase the core size,5 and as a consequence increasing
the possibility to access larger anions. The latter strategy,
while increasing the core size, also increased the option to
† University of Hyderabad.
‡ Pondicherry University.
§ Indian Institute of Chemical Technology.
(1) (a) Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V. J. Am. Chem.
Soc. 1996, 118, 5140. (b) Sessler, J. L.; Gale, P. A.; Genge, J. W. Chem.;
Eur. J. 1998, 4, 1095.
(2) (a) Sessler, J. L.; Anzenbacher, P., Jr.; Jursikova, K.; Miyaji, H.;
Genge, J. W.; Tvermoes, N. A.; Allen, W. E.; Shriver, J. A. Pure. Appl.
Chem. 1998, 70, 2401. (b) Gale, P. A.; Sessler, J. L.; Allen, W. E.;
Tvermoes, N. A.; Lynch, V. Chem. Commun. 1997, 665. (c) Sessler, J. L.;
Cho, W.-S.; Gross, D. E.; Shriver, J. A.; Lynch, V. M.; Marquez, M.
J. Org. Chem. 2005, 70, 5982. (d) Mahanta, S. P.; Kumar, B. S.; Panda,
P. K. Chem. Commun. 2011, 47, 4496.
(4) (a) Sessler, J. L.; Anzenbacher, P., Jr.; Shriver, J. A.; Jurisikova,
K.; Miyaji, H.; Lynch, V.; Marquez, M. J. Am. Chem. Soc. 2000, 122,
12061. (b) Sessler, J. L.; An, D.; Cho, W.-S.; Lynch, V. Angew. Chem.,
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2002, 41, 1757. (b) Lee, C.-H.; Na, H.-K.; Yoon, D.-W.; Won, D.-H.;
Cho, W.-S.; Lynch, V. M.; Shevchuk, S. V.; Sessler, J. L. J. Am. Chem.
Soc. 2003, 125, 7301. (c) Lee, C.-H.; Lee, J.-S.; Na, H.-K.; Yoon, D.-W.;
Miyaji, H.; Cho, W.-S.; Sessler, J. L. J. Org. Chem. 2005, 70, 2067.
(5) (a) Cafeo, G.; Kohnke, F. H.; White, A. J. P.; Garozzo, D.;
Messina, A. Chem.;Eur. J. 2007, 13, 649. (b) Sessler, J. L.; An, D.; Cho,
W.-S.; Lynch, V.; Marquez, M. Chem.;Eur. J. 2005, 11, 2001. (c)
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r
10.1021/ol3032158
Published on Web 12/26/2012
2012 American Chemical Society

bring forth additional interactions such as aromatic
CH-anion (receptor 1) and intermolecular CH π inter-
3 3 3
actions to enhance binding affinity and/or selectivity.5 In
this direction, we have very recently demonstrated that
incorporation of simple ethene moieties as spacers between
two dipyrromethane units can lead to colorimetric sensing
of fluoride ion via anionꢀπ interactions (receptor 2a).6
We envisaged that incorporation of a fluorescent probe as
a spacer can further enhance the sensitivity of this type of
system toward anions. In this regard, herein we report the
synthesis of calix[2]bispyrrolylarenes 3 and 4, two new
expanded calix[4]pyrroles, and their anion binding proper-
ties in organic media. These macrocycles were synthesized
in two steps by following two routes (Scheme 1). In route
A, 2-borylpyrrole7 was coupled with 1,2-diiodobenzene by
the Suzuki protocol to obtain bispyrrolyl benzene 5 in 55%
yield. However, the reaction with 2,3-diiodonaphthalene
under the identical conditions gave 6 in only 11% yield
(removal of naphthalene, probably obtained via deiodina-
tion, caused a major hindrance and reduced the yield).8
Acid catalyzed condensation of 5 and 6 with acetone
afforded macrocycles 3 and 4 in 8% and 3% yield respec-
tively. However, isolation of the products (very closely
associated with another spot in TLC) required rigorous
chromatographic purification, reducing the yields, making
reaction scaleup difficult. This led us to explore alternate
synthetic routes. In this regard, the direct borylation of
pyrrole at the R-position (employed in route A) appeared
very attractive. Consequently, we redesigned our synthetic
strategy according to route B. Here, the Ir-catalyzed CꢀH
bond activation methodology7 yielded the 2,20-diboryldi-
pyrromethane 7 in a single step from the corresponding
dipyrromethane in very good yield (83%). Isolation of 7
was very easy as the product precipitated out from the
reaction mixture and hence the reaction could be easily
scaled up to make the desired precursor at gram scale.
Subsequent ‘2 þ 2’ cyclocoupling of 7 with 1,2-diiodoben-
zene or 2,3-diiodonaphthalene, using the Suzuki protocol,
led to formation of 3 and 4 as a single product in 16% and
6% yield respectively (route B).8 Interestingly, unlike in the
case of 1, we did not observe the formation of higher
macrocyclic analogues.5 While Osuka et al. have used this
borylation strategy extensively on porphyrins, to the best
of our knowledge there is no report utilizing this metho-
dology to prepare oligopyrrolic building blocks.9 In parti-
cular, this is very useful in designing hosts for anions,
Scheme 1. Synthetic Protocol of Calix[2]bispyrrolylarenes
where selective R-halogenation of pyrrole mostly leads to
polymerization in the absence of protecting groups or
electron-withdrawing substituents at their β-positions; in
contrast, the easily prepared alkylated derivatives drasti-
cally reduce their affinity for anions in the neutral state.10
To our knowledge, this is the first report where the Suzuki
protocol is utilized for the generation of macrocycles for
hostꢀguest chemistry (that are in general synthesized
following acid catalyzed methodologies) and there are very
few reports where this strategy is employed for porphyr-
inoidsynthesis.11 All thecompounds werecharacterized by
1H, 13C NMR spectroscopy and mass analysis. Further,
the solid state structure of 3 could also be elucidated by a
single crystal X-ray diffraction method. The macrocycle
adopts a 1,3-alternate conformation, and the alternate
NHs are directed in opposite directions with respect to
each other as in 2b6 and the two phenylene rings are
inclined away from the core forming an overall distorted
bowl-like structure (Figure 1). Interestingly, in receptor 3,
two alternate pyrrole units reside almost in the plane of the
adjacent phenylene moieties (dihedral angles 17.2° and
18.6°) while the remaining two pyrroles adopt an almost
orthogonal geometry with respect to the phenylene rings
(dihedral angles 80.5° and 76.2°). This near coplanarity,
owing to the fusion of benzene moieties at the calix-
[4]pyrrole periphery, resulted in an extended π-conjuga-
tion in 3, associated with fluorescence enhancement com-
pared to its constituents (Φ = 0.16, Figure 2), and this
effect could also be observed upon fusion of naphthalene
moieties, which resulted in large red-shifted absorption
and emission bands for4 comparedtonaphthalene(Stokes
shifts of 117 and 142 nm for 3 and 4 respectively). The
observed extended π-conjugation in both hosts is well
supported by the computationally obtained electrostatic
potential plots, which clearly display localization of the
electron density only on the two opposite pyrrole moieties
(6) Mahanta, S. P.; Kumar, B. S.; Baskaran, S.; Sivasankar, C.;
Panda, P. K. Org. Lett. 2012, 14, 548.
(7) (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.;
Smith, M. R., III. Science 2002, 295, 305. (b) Ishiyama, T.; Takagi, J.;
Yonekawa, Y.; Hartwig, J. F.; Miyaura, N. Adv. Synth. Catal. 2003, 345,
1103. (c) Ishiyama, T.; Takagi, J.; Nobuta, Y.; Miyaura, N. Org. Synth.
2009, Coll. Vol. 11, 1007. (d) Ishiyama, T.; Miyaura, N. Pure. Appl.
Chem. 2006, 78, 1369.
(10) (a) Algi, M. P.; Oztas, Z.; Algi, F. Chem. Commun. 2012, 48,
10219. (b) Gale, P. A.; Sessler, J. L.; Allen, W. E.; Tvermoes, N. A.;
Lynch, V. Chem. Commun. 1997, 665.
(11) (a) Arnold, L.; Norouzi-Arasi, H.; Wagner, M.; Enkelmann, V.;
Muellen, K. Chem. Commun. 2011, 47, 970. (b) Zhang, Z.; Lim, J. M.;
Ishida, M.; Roznyatovskiy, V. V.; Lynch, V. M.; Gong, H.-Y.; Yang, X.;
Kim, D.; Sessler, J. L. J. Am. Chem. Soc. 2012, 134, 4076. (c) Arnold, L.;
Baumgarten, M.; Muellen, K. Chem. Commun. 2012, 48, 9640.
(12) Piatek, P.; Lynch, V. M.; Sessler, J. L. J. Am. Chem. Soc. 2004,
126, 16073.
(8) Sestune, J.-I.; Toda, M.; Watanabe, K.; Panda, P. K.; Yoshida, T.
Tetrahedron Lett. 2006, 47, 7541.
(9) (a) Hata, H.; Shinokubo, H.; Osuka, A. J. Am. Chem. Soc. 2005, 127,
8264. (b) Yamaguchi, S.; Katoh, T.; Shinokubo, H.; Osuka, A. J. Am.
Chem. Soc. 2007, 129, 6392. (c) Ikeda, T.; Aratani, N.; Easwaramoorthi, S.;
Kim, D.; Osuka, A. Org. Lett. 2009, 11, 3080. (d) Nakamura, Y.; Jang,
S. Y.; Tanaka, T.; Aratani, N.; Lim, J. M.; Kim, K. S.; Kim, D.; Osuka, A.
Chem.;Eur. J. 2008, 14, 8279.
Org. Lett., Vol. 15, No. 2, 2013
307

Figure 1. Two views of the solid state structure of 3. Thermal
ellipsoids are scaled to the 35% probability level. All hydrogen
atoms bound to carbon atoms are omitted for clarity. Color
code: blue, N; gray, C; white, H.
Figure 2. Absorption spectra of 3 (black) and 4 (blue) and cor-
responding emission spectra (red and green) in CH3CN. λex
=
292 nm for 3 (1.06 ꢁ 10ꢀ6 M) and 304 nm for 4 (2.01 ꢁ 10ꢀ6 M).
(Figure 3). The former exhibits higher sensitivity than the
latter, with a detection limit of 80 and 300 nM for the
fluoride ion respectively (SI).13 These observations were
well supported by time-resolved fluorescence decay mea-
surements. The singlet-state lifetime of receptor 3 was
0.68 ns in the unbound state, which dramatically in-
creases to 5.68 ns upon fluoride ion binding. Yet, the
singlet-state lifetime of receptor 4 (5.38 ns) remains un-
changed even in the presence of a higher fluoride ion
concentration (SI).
(blueshadesaroundpyrrolicNs), disposedorthogonallyto
the adjacent arenes (Supporting Information (SI)). To our
knowledge, this type of extended conjugation had been
unreported for any nonaromatic receptors including the
isomer of 3 (i.e., receptor 1).5b Very recently, Sessler et al.
reported cyclo[m]pyridine[n]pyrroles which display extended
π-conjugation only upon protonation.11b While these macro-
cycles exhibit solid state fluorescence, their hostꢀguest chem-
istry is not reported.
As our attempts to obtain diffraction quality crystals
so far remain futile, to gain insight into the hostꢀguest
interactions, we performed density functional theory
(DFT) calculations. The optimized structures reveal the
approach of anions from the concave side of the bowl-like
structure attained by the host upon complexation, to
facilitate anionꢀπ interactions (Figure 4). Complexation
of anion led to the routine conformational change from the
1,3-alternate to the cone conformation of the four pyrrole
units to bind the fluoride ion through NꢀH...F H-bonds.
However, closer inspection revealed that the cone is no
longer a regular one as observed for simple calix[4]pyrrole
systems.1a,5b,12 Here two pyrrole moieties of one dipyrro-
methane unit are in a relatively more planar conformation
with the arenes (dihedral angles 41.76°, 41.77° for 3, and
Unlike 2a, 3 and 4 do not exhibit any colorimetric
response or appreciable change in their absorption spectra
upon anion addition. However, isothermal titration ca-
lorimetry (ITC) revealedonlymoderatebindingoffluoride
ions with 3 and 4 having Ka values on the order of 104 (SI).
This also indicates that increasing the distance between
the H-bonding sites (i.e., pyrrolic NHs) of calix[4]pyrrole
increases the selectivity toward the fluoride ion, while
reducing its affinity. However, exploration of their binding
behavior using fluorescence spectroscopy with tetra-
butylammonium (TBA) salts of various anions, viz. Fꢀꢀ,
Clꢀ, Brꢀ, Iꢀ, H2PO4ꢀ, HSO4ꢀ, ClO4ꢀ, CH3COOꢀ, NO3
,
CNꢀ, and PF6ꢀ, in acetonitrile revealed interesting results.
For example, the initial screening showed that only the
fluoride ion exhibits a strong interaction with the recep-
tors, whereas acetate interacts to a lesser degree (Figure 3).
Further, upon addition of these two anions, 3 displays
fluorescence enhancement (turn-on), hitherto not observed
for this class of macrocycles, accompanied by a bath-
ochromic shift (26 nm), whereas that led to only a decrease
in fluorescence intensity (turn-off) in the case of 4
Figure 3. Fluorescence spectra of (a) 3 (1.06 ꢁ 10ꢀ6 M) and (b) 4
(2.01 ꢁ 10ꢀ6 M) upon addition of various anions (as their
tetrabutylammonium salts) in CH3CN. λex = 292 nm for 3
and 304 nm for 4.
(13) Shortreed, M.; Kopelman, R.; Kuhn, M.; Hoyland, B. Anal.
Chem. 1996, 68, 1414.
308
Org. Lett., Vol. 15, No. 2, 2013

42.51°, 42.40° for 4) than the remaining two pyrroles
(dihedral angles 80.18°, 80.29° for 3, and 79.00°, 79.61°
for 4) of the other dipyrromethane moiety (SI). This again
confirms, albeit qualitatively, that the extended conjugation
observed in the calix[4]pyrrole derivatives still persists even
upon complexation, particularly in the case of 3, where
otherwise the complexation should have resulted in the
decrease of fluorescence, owing to the breakdown of the
extended π-conjugation (in a regular cone conformation).
Further, determination of HOMO and LUMO energies for
the hosts and their fluoride and acetate complexes in the gas
phase as well as in different solvents clearly indicate stabi-
lization of the complexes in the presence of solvents; how-
ever as the polarity of the solvents increases, the HOMOs
become relatively more stabilized compared to their corre-
sponding LUMOs (SI). As a result, the energy difference
between HOMO and LUMO increases; this is probably
reflected in the lack of colorimetric response noticed upon
complexation in these cases. However, the charge transfer
(CT) nature of the interaction between the receptors and the
fluoride ion could be confirmed by the observation of EPR
signals with g-values of 2.0052 for both 3 and 4 confirming
the formation of anion radicals (SI). The solvent dependent
emission spectra further suggested the CT nature in which
the emission spectra of 3 and 4 are red-shifted with increas-
ing polarity of the media. However, a complete under-
standing of the solvatochromic effect requires more
detailed study (SI). Few generalizations may be drawn from
this study. For example, the solvent effect is more pro-
nounced in the case of the polar aprotic solvents vs polar
protic or nonpolar solvents. While macrocycle 3 displays
only one broad emission band around 420 nm in acetoni-
trile, in other polar solvents it displays a more resolved
emission pattern with maxima between 350 and 360 nm and
a shoulder at a longer wavelength, which resolved into a
band in more polar solvents such as DMF and DMSO. The
fluorescence enhancement accompanied by a bathochromic
shift of the emission bands (in particular the shoulder or
the band at the lower energy) upon complexation with a
fluoride ion is more noticeable in the case of acetonitrile,
THF, and DMSO. Yet, macrocycle 4 displays only one
broad emission band with maxima around 450 nm which is
not much affected by the polarity of the solvents, and
complexation with a fluoride ion only led to quenching of
this fluorescence. From the above studies, we can conclude
that complexation of fluoride resulted in a weak charge
transfer from the anion to the macrocycles, probably
owing to the less planar conformation (compared to
2a).6 In contrast, the distorted cone structure adopted
by the hostꢀanion complexes helps them in retaining
the extended π-conjugation between the alternate pyr-
roles and the fused arenes of the receptors. Further, the
resultant CT state (upon complexation) is more fluor-
escent in 3•Fꢀ and less fluorescent in the 4•Fꢀ complex,
Figure 4. Space filling model of DFT-optimized structure of 3
and 4, along with their fluoride complexes. Color code: green, F;
blue, N; gray, C; white, H.
thereby displaying a turn-on and turn-off response
respectively.
In conclusion, we have designed and synthesized two
new expanded calix[4]pyrrole receptors following a new
strategy: Ir-catalyzed diborylation of dipyrromethane via
CꢀH activation, followed by ‘2 þ 2’ cyclocoupling using
the Suzuki protocol. This strategy will provide a new
direction for porphyrinoid synthesis in basic media in
general and receptors for anions in particular. Moreover,
this approach has a greater advantage over the commonly
used acid catalyzed one, where the formation of a large
number of products (and/or side products) occurs possibly
owing to acidolysis. Both receptors exhibit fluorescence
owing to extended π-conjugation with a large Stokes shift,
an attribute not observed in this class of receptors. Again,
the turn-on fluorescence observed in the case of calix-
[2]bispyrrolylbenzene upon binding of a fluoride and
acetate ion is unprecedented in this chemistry. Presently,
we are employing this new approach to develop new
porphyrinoids for better hostꢀguest selectivity.
Acknowledgment. This work is supported by D.S.T.,
India (Project no. SR/S1/IC-20/2007 and SR/FT/-055/2008)
and C.S.I.R., India (Project no. 01(2449)/10/EMR-II).
B.C., S.P.M. and N.N.P. thank C.S.I.R. for the financial
support. We thank Dr. L. Giribabu, I.I.C.T., Hyderabad
for help in the lifetime study. We thank S. A. M. Shamimul
Ahsan, University of Hyderabad for his contribution at
the initial stages, during his Master’s project.
Supporting Information Available. Synthetic procedure,
characterization data, and crystal data for 3 (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 2, 2013
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