A calix[2]phenol[2]pyrrole and a fused pyrrolidine-containing derivative

Article abstract of DOI:10.1039/c2cc17888e

The hybrid calix[2]phenol[2]pyrrole 4 and the fused pyrrolidine-containing macrocycle 9 were synthesized from two different isomeric starting materials, namely dimethyl 2-hydroxyisophthalate and 5-hydroxyisophthalate, respectively. The fused species 9 is

Full text of DOI:10.1039/c2cc17888e

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Porphyrins &
Phthalocyanines
web themed issue
Guest editors: Jonathan Sessler, Penny Brothers and
Chang-Hee Lee
All articles in this issue will be gathered together
online at
www.rsc.org/porphyrins

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 2495–2497
www.rsc.org/chemcomm
COMMUNICATION
A calix[2]phenol[2]pyrrole and a fused pyrrolidine-containing derivativewz
Kwang-Bok Jung,a Sung Kuk Kim,b Vincent M. Lynch,b Dong-Gyu Cho*a and
Jonathan L. Sessler*bc
Received 17th December 2011, Accepted 9th January 2012
DOI: 10.1039/c2cc17888e
The hybrid calix[2]phenol[2]pyrrole 4 and the fused pyrrolidine-
containing macrocycle 9 were synthesized from two different
isomeric starting materials, namely dimethyl 2-hydroxy-
isophthalate and 5-hydroxyisophthalate, respectively. The fused
species 9 is devoid of obvious substrate binding properties. In
contrast, the heterocalix system 4 displays the fluoride-induced
conformational changes characteristic of the parent system.
both pyrrolic and phenolic building blocks are unknown. Here, we
report the synthesis and characterization of a new chimera system,
specifically the calix[2]phenol[2]pyrrole 4, as well as a related
hybrid system (9) that incorporates a fused pyrrolidine subunit.
Two distinct calix[2]phenol[2]pyrroles of relatively high
symmetry with a basic phenol–pyrrole–phenol–pyrrole sequence
of subunits can be conceived depending on whether the phenolic
subunits are attached via the 2,6 or 3,5 positions. We thought that
these two putative products (4 and 8) could be synthesized from
the two isomeric intermediates 2 and 6 as shown in Scheme 1.
Starting from dimethyl 5-hydroxyisophthalate, compound 2 was
prepared in 73% yield via a Grignard reaction. Substitution with
pyrrole in acetonitrile then afforded compound 3 in 73% yield.
Reaction of 3 and 2 in the presence of p-TsOH then gave the
target calix[2]phenol[2]pyrrole (4) in 13% yield. Attempts to react
2 with pyrrole directly in the presence of acetone were not fruitful;
under these conditions, calix 4 was only obtained in 2% yield.
In an attempt to prepare isomer 8, a similar synthetic
protocol was employed. Interestingly, the same conditions
used to obtain the dipyrrole substituted phenol (3) failed to
Calixarenes, synthesized from phenol and formaldehyde, continue
to play a central role in supramolecular chemistry due to their
unique vessel-like structures and recognized ability to act as
receptors for a wide-range of ionic and small molecule neutral
substrates. The structural diversity embodied within this family of
compounds has made them of further interest for the construction
of self-assembled materials, as well as a wide range of functiona-
lized hosts.1 It has also inspired efforts to make new analogues
wherein one or more of the constituent phenols is replaced by a
different aromatic subunit. Among the most extensively studied of
these latter analogues are the calix[4]pyrroles, a class of
compounds first reported by Baeyer in 18862 that have recently
attracted attention as simple-to-prepare anion binding agents.
As in the case of calixarenes, efforts have been devoted to the
preparation of new calix[4]pyrrole derivatives, with modified
structure and function. To this end, the calix[4]pyrrole core has
been extensively modified by varying the b-pyrrolic substituents,3
incorporating meso carbon substituents other than CH3,4 or
expanding the size of the ring (calix[n]pyrroles; n 4 4).5 Work
has also been devoted to replacing the pyrroles by other hetero-
cyclic building blocks (e.g. pyridine).6 However, to the best of our
knowledge, calixarene–calixpyrrole hybrid systems that contain
a Department of Chemistry, Inha University, 253 Yonghyundong
Namgu, Inchon 402-751, Republic of Korea.
E-mail: dgcho@inha.ac.kr; Fax: +82 32 867 5664;
Tel: +82 32 860 7686
b Department of Chemistry and Biochemistry University of Texas at
Austin, Austin, TX 78712, USA. E-mail: sessler@mail.utexas.edu;
Fax: +1 512 471 7550; Tel: +1 512 471 5009
c Department of Chemistry, Yonsei University, Seoul 120-749,
Republic of Korea
w This article is part of the ChemComm ’Porphyrins and phthalocyanines’
web themed issue.
z Electronic supplementary information (ESI) available: Synthetic
procedures and characterization data for all new compounds, X-ray
data for 4, 4ꢀTBAF, and 9,10 and NMR spectra provided in support of
the results presented in the main text. CCDC 858002 (9), 858003 (4)
and 858004 (4ꢀTBAF). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc17888e
Scheme 1 Synthesis of macrocycles 4 and 9. Reagents and conditions:
(a) MeMgCl, ether, 73%; (b) pyrrole, p-TsOH, CH3CN, 43%; (c) p-TsOH,
2, CH3CN : DCM (7 : 10 v/v), 13%; (d) MeMgCl, ether, 62%; (e) pyrrole,
p-TsOH, CH3CN, 68%; (f) methane sulfonic acid, CH3CN, 10%.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2495–2497 2495

provide the expected disubstituted product. Rather, what was
obtained in 68% yield was the monopyrrole substituted
phenol 7. A subsequent acid catalyzed reaction afforded the
unexpected fused calix[2]phenol[2]pyrrole (fused calix 9) in
10% yield. The desired target, the putative calix 8 (and isomer
of 4), was thus not obtained.
The unique fused calix 9 was characterized by standard
spectroscopic techniques, as well as by single-crystal X-ray
diffraction analysis (Fig. 2a). In the solid state, there are two
molecules of the fused calix 9 in each asymmetric unit. One is
hydrogen bonded to a molecule of acetonitrile (Fig. S6, ESIz).
The second one is disordered by an approximately 1801
rotation about the mean plane through the two orientations
of the molecule (Fig. S7, ESIz).
Fig. 2 X-Ray crystal structures. (a) Top view of 9. (b) Top view of 4.
(c) Cone conformation of 4 stabilized in the presence of Fꢁ anions.
Thermal ellipsoids are scaled to the 50% probability level. Most
hydrogen atoms and the disordered solvent molecules have been
omitted for clarity.
opposite direction. Calix 4 thus exists in a unique alternate
form, and one that differs from what is typically seen for either
calixarenes or calix[4]pyrroles in the solid state.
The unusual fused nature of product 9, as well as the
disorder revealed in the solid state structure, led us to consider
whether this particular calix derivative might not have
fluxional character. Specifically, we speculated that it might
exist in the form of two identical tautomeric structures that
could interconvert via 8, as shown in Fig. 1. To test whether
interconversion between these proposed tautomers took place,
deuterium exchange studies were carried out in CD2Cl2 at
298 K.7 These studies involved adding CD3OD to an initial
solution of 9 and recording the changes in the 1H-NMR
spectrum as a function of time. It was found that the protons
on C14 and C15 underwent exchange and were replaced by
deuterium. In contrast, the protons on C2 and C3 did not
exchange (Fig. 1 and Fig. S2, ESIz). These results provide
support for the conclusion that, once formed, compound 9 is
stable; it exists in the fused form and is not a labile species that
is in effective equilibrium with the proposed calix intermediate
8 or the labeled tautomer of 9 shown in Fig. 1.
Within the crystal lattice, the calix[2]phenol[2]pyrrole
macrocycle acts to create a what can be considered to be a
rectangular container wherein the meso carbons are separated
by distances of 5.081 and 5.101 A, respectively (cf. Fig. 2b).
This container-like structure is presumably stabilized by six
hydrogen bonds per unit of calix 4. These hydrogen bonds
involve two phenolic oxygen centers and two pyrrole NH
protons per calix molecule (cf. Fig. S8 and S9, ESIz). These
interactions are thought to underlie the formation of molecular
columns in the solid state, as seen in the unit cell packing
diagram. They are also responsible, presumably, for the low
solubility of this prototypic calix[2]phenol[2]pyrrole observed in
solvents of low dielectric constant, such as CH2Cl2, CHCl3, and
CH3CN. Unfortunately, this low solubility precluded a detailed
analysis of the conformational properties in solution, at least
using standard 1H-NMR spectroscopic methods.
The addition of TBAF salts to a heterogeneous suspension of
4 in CH2Cl2 results in formation of a clear solution. Diffusion of
n-hexane into a solution produced in this way afforded single
crystals suitable for X-ray diffraction analysis. As can be seen
from an inspection of Fig. 2c, calix[2]phenol[2]pyrrole 4 adapts a
cone conformation in the solid state in the presence of fluoride
anions, a species that is bound in a 2 : 1 (receptor : anion)
stoichiometry in the solid state. The bound fluoride ion is
hydrogen bonded to two phenolic OH protons arising from
two different receptor molecules, as well as by two water
molecules (Fig. 2c). In marked contrast to what is seen in the
case of calix[4]pyrroles, the NH protons do not participate in
hydrogen bond interactions with the fluoride anion and play no
obvious role in stabilizing the overall complex or the observed
cone conformation.
Calix[4]arenes generally exist in the cone conformation as
long as strong intramolecular hydrogen bonds are maintained
between the phenolic OH subunits. In contrast, anion-free
calix[4]pyrroles are generally conformationally flexible and
exist predominantly in the 1,3-alternate conformation in the
absence of a bound anion. On the other hand, the addition of
suitable anionic guests generally serves to lock calix[4]pyrroles
into the corresponding cone conformation. Given this disparity
in conformational behavior for the two ‘‘parent’’ systems from
which it is formally derived, efforts were made to analyze the
conformational features of calix 4. These analyses were carried
out primarily in the solid state as detailed below.
Single crystals of 4 suitable for X-ray diffraction analysis
were grown by slow diffusion of n-hexane into an acetone
solution of 4. The resulting structure, shown in Fig. 2b, reveals
that one of the two phenolic OH and one of the pyrrolic NH
groups point in one direction, while the other set points in the
The bound fluoride ion resides on a crystallographic two-
fold rotation axis. Two TBA ions are seen per anion equivalent.
These cations are bound within the cavity produced by the
association of the two anion-tethered units of 4. The net result
is an apparent charge imbalance at the level of the co-bound
anions. This imbalance is accommodated by a negative charge
that arises from deprotonation of one of the phenolic OH
protons at O1 and O10.
Phenolic hydrogen bond donors8 have not been widely used
for the construction of synthetic anion receptors due to their
susceptibility to deprotonation in the presence of basic anions,
such as carboxylic and fluoride anions. On the other hand,
phenolic OH motifs are present in the naturally occurring,
Fig. 1 Summary of deuterium exchange experiments with 9 carried
out in CD2Cl2/CD3OD.
c
2496 Chem. Commun., 2012, 48, 2495–2497
This journal is The Royal Society of Chemistry 2012

structurally characterized chloride anion channel.9 Calix 4 is
thus of interest because it contains two phenol OH and two
pyrrole NH moieties that could act as hydrogen bonding
donors. The number of hydrogen bonding donors is thus the
same as present in the calix[4]pyrroles. However, the phenolic
OH proton (pKa ca. 10) is more acidic than the pyrrole
NH proton (pKa ca. 23 in DMSO), and a priori might be
considered to be the better anion recognition motif. Moreover,
the X-ray diffraction analyses described above revealed no
interaction between the pyrrole NH groups and the bound
fluoride anion in the solid state. We were thus curious to see
if this selectivity in favor of OH hydrogen bond donors over
NH donors was maintained in solution. In an effort to probe
this issue, preliminary 1H-NMR spectroscopic binding experi-
ments were carried out using the chloride anion (chosen in
preference to fluoride due to its lower basicity). These experi-
ments, conducted at room temperature in CD2Cl2/DMSO-d6
(20/1, v/v) using tetrabutylammonium chloride (TBACl) as the
chloride anion source, revealed an upfield shift in the pyrrolic
NH proton resonance and little change in the pyrrolic
CH signal (Fig. S3, ESIz). In contrast, downfield shifts were
observed for the ortho-CH proton of the phenolic ring.
A broadening of the OH proton signal was also seen as the
titration progressed (cf. Fig. S3 and S4, ESIz). Such changes
are consistent with the OH, rather than the NH, serving as the
primary donor group. The unusual upfield shifts seen for the
pyrrolic NH protons can be explained by the fact that in
the absence of a bound anion the pyrrolic NH protons are tied
up in hydrogen bonds, involving either the phenolic OH protons
or the DMSO solvent. These bonds become reduced in strength
upon conversion to the cone conformation and concomitant
formation of a more protected cavity-like structure.
approach to the creation of new hybrid receptor systems. It has
also permitted a direct comparison between two ostensibly related
hydrogen bond donor motifs (OH vs. NH) and has provided
evidence that OH hydrogen bonds can be used to support anion
recognition in suitably designed receptor systems.
This work was supported by Inha University Research
Grant, the Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by
the Ministry of Education, Science and Technology (grant no.
2010-0004206), the Robert A. Welch Foundation (F-1018 to
J.L.S.), and the National Science Foundation (grants no.
CHE-1057904 to J.L.S. and 0741973 for the X-ray diffracto-
meter). Support under the WCU (World Class University)
program (R32-2008-000-10217-0) is also acknowledged.
Notes and references
1 (a) W. Sliwa and C. Kozlowski, Calixarenes and Resorcinarenes:
Synthesis, Properties and Applications, Wiley-VCH Verlag GmbH
& Co. KGaA, Weinheim, 2009; (b) M. Z. Asfari, V. Bohmer,
¨
J. Harrowfield and J. Vicens, Calixarenes 2001, Kluwer Academic
Publishers, Dordrecht, Netherlands, 2000.
2 A. Baeyer, Ber. Dtsch. Chem. Ges., 1886, 19, 2184–2185.
3 (a) S. K. Kim, D. E. Gross, D.-G. Cho, V. M. Lynch and
J. L. Sessler, J. Org. Chem., 2011, 76, 1005–1012; (b) J. S. Park,
E. Karnas, K. Ohkubo, P. Chen, K. M. Kadish, S. Fukuzumi,
C. W. Bielawski, T. W. Hudnall, V. M. Lynch and J. L. Sessler,
Science, 2010, 329, 1324–1327; (c) J. L. Sessler, W.-S. Cho,
D. E. Gross, J. A. Shriver, V. M. Lynch and M. Marquez,
J. Org. Chem., 2005, 70, 5982–5986.
4 (a) C.-H. Lee, H. Miyaji, D.-W. Yoon and J. L. Sessler, Chem.
Commun., 2008, 24–34 and references cited therein; (b) D.-W. Yoon,
D. E. Gross, V. M. Lynch, J. L. Sessler, B. P. Hay and C.-H. Lee,
Angew. Chem., Int. Ed., 2008, 47, 5038–5042.
5 G. Cafeo, F. H. Kohnke, G. L. La Torre, A. J. P White and
D. Williams, Angew. Chem., Int. Ed., 2000, 39, 1496–1498.
6 (a) J. L. Sessler, D. An, W.-S. Cho and V. Lynch, J. Am. Chem. Soc.,
Finally, it was noted that the dimethyl protons of calix 4
appear as a singlet peak in the absence or presence of TBACl.
Such a finding is consistent with the rate of conformational
change being fast on the NMR time scale, as is true for
calix[4]pyrroles.
´
2003, 125, 13646; (b) V. Kral, P. A. Gale, P. Anzenbacher Jr.,
K. Jursıkova, V. Lynch and J. L. Sessler, Chem. Commun., 1998, 9–10.
´
´
7 H. A. Potts and G. F. Smith, J. Chem. Soc., 1957, 4018–4022.
8 (a) S. K. Berezin and J. T. Davis, J. Am. Chem. Soc., 2009, 131,
2458–2459; (b) S.-I. Kondo, T. Suzuki, T. Toyama and Y. Yano,
Bull. Chem. Soc. Jpn., 2005, 78, 1348–1350; (c) C. Lee, D.-H. Lee
and J.-I. Hong, Tetrahedron Lett., 2001, 42, 8665–8668.
The affinity constant for chloride ions (KCl = 46 ꢂ 3 Mꢁ1
)
deduced from the above titration is relatively low (Fig. S5, ESIz).
This result is rationalized in terms of the hydrogen bond donors
present in 4 not acting in a cooperative fashion, as is typically
the case for calix[4]pyrroles. Nevertheless, the fact that anion
recognition is achieved serves to underscore the role that OH,
rather than NH, hydrogen bond donor groups could have in the
design of future anion receptor systems.
9 R. Dutzler, E. B. Campbell, M. Cadene, B. T. Chait and
R. MacKinnon, Nature, 2002, 415, 287–294.
10 Crystal data for 9 (CCDC 858002): C66H79N5O4, M = 1005.61,
orthorhombic, a = 24.3554(10) A, b = 11.3368(3) A, c =
20.2929(4) A, a = 90.001, b = 90.001, g = 90.001, V =
5603.1(3) A3, T = 153(2) K, space group Pna21, Z = 4, 12 374
reflections measured, 6597 independent reflections (Rint = 0.0527).
The final R1 values were 0.0519 (I 4 2s(I)). The final wR(F2)
values were 0.1218 (I 4 2s(I)). The final R1 values were 0.0972 (all
data). The final wR(F2) values were 0.1394 (all data). Crystal data
for 4 (CCDC 858003): C32H38N2O2, M = 482.64, monoclinic, a =
7.3075(2) A, b = 17.5050(4) A, c = 9.9498(3) A, a = 90.001, b =
91.307(1)1, g = 90.001, V = 1272.43(6) A3, T = 153(2) K, space
group P21/n, Z = 2, 5334 reflections measured, 2892 independent
reflections (Rint = 0.0184). The final R1 values were 0.0417 (I 4
2s(I)). The final wR(F2) values were 0.1076 (I 4 2s(I)). The final
R1 values were 0.0555 (all data). The final wR(F2) values were
0.1164 (all data). Crystal data for 4ꢀTBAF (CCDC 858004):
C99H155Cl6FN6O5, M = 1740.99, monoclinic, a = 29.8044(8) A,
b = 10.3800(5) A, c = 31.855(2) A, a = 90.001, b = 95.290(2)1,
g = 90.001, V = 9813.1(8) A3, T = 153(2) K, space group I2/a,
Z = 4, 18 633 reflections measured, 10 914 independent reflections
(Rint = 0.0493). The final R1 values were 0.0831 (I 4 2s(I)). The
final wR(F2) values were 0.2221 (I 4 2s(I)). The final R1 values
were 0.1623 (all data). The final wR(F2) values were 0.2553.
In summary, two new hybrid calixarene–calixpyrrole
systems have been prepared. These consist of the bona fide
calix[2]phenol[2]pyrrole 4 and a fused derivative calix 9. These
two macrocyclic products were synthesized from two different
isomeric starting materials, namely dimethyl 2-hydroxy-
isophthalate and 5-hydroxyisophthalate, respectively. The
fused calix 9 was fully characterized in solution and in the
solid state. Deuterium exchange experiments disclosed that
fused calix 9 maintains its structural integrity in solution. The
calix 4 was also fully characterized in solution and in the solid
state. It was found to act as a weak anion receptor as the result
of OH, rather than NH, hydrogen bond donor-anion interactions.
The present study has thus demonstrated a possibly general
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2495–2497 2497