Cis- and trans-strapped calix[4]pyrroles bearing phthalamide linkers: Synthesis and anion-binding properties

Article abstract of DOI:10.1021/jo0487146

(Chemical Equation Presented) New cis-strapped calix[4] pyrrole derivatives 12, 13, and 19 and trans-strapped systems 14 and 15 bearing isophthalate-derived diamide spacers linked to the tetrapyrrolic core have been synthesized and characterized by spectr

Full text of DOI:10.1021/jo0487146

Cis- and Trans-Strapped Calix[4]pyrroles Bearing Phthalamide
Linkers: Synthesis and Anion-Binding Properties
Chang-Hee Lee,*,† Jin-Suk Lee,† Hee-Kyung Na,† Dae-Wi Yoon,† Hidekazu Miyaji,†
Won-Seob Cho,‡ and Jonathan L. Sessler*,‡
Department of Chemistry and Institute of Basic Science, Kangwon National University,
Chun-Chon 200-701 Korea, and Department of Chemistry and Biochemistry, University of Texas at
Austin, Austin, Texas 78712
chhlee@kangwon.ac.kr; sessler@mail.utexas.edu
Received July 27, 2004
New cis-strapped calix[4]pyrrole derivatives 12, 13, and 19 and trans-strapped systems 14 and 15
bearing isophthalate-derived diamide spacers linked to the tetrapyrrolic core have been synthesized
and characterized by spectroscopic means. The anion-binding behavior of these receptors was
investigated by proton NMR spectroscopy and isothermal titration calorimetry (ITC). A 2:1 binding
stoichiometry was observed under the conditions of NMR analysis but not at the lower concentration
regime used for ITC. As gauged from both sets of analyses, these new strapped systems display
affinities for halide anions that are enhanced compared to those of normal, unstrapped calix[4]-
pyrrole. However, contrary to expectations, no size-dependent selectivity for anions is observed as
the length of the bridging strap is varied. Such results are interpreted in terms of anion-binding
processes that occur outside the central pocket defined by the strap but that still favor strong
associations as the result of the increased number of hydrogen-bonding donors the amide groups
provide.
The design and synthesis of anion receptors possessing
high affinity and selectivity represents a challenge that
continues to attract considerable attention within the
molecular recognition and supramolecular chemistry
communities due to the important role anions play in
areas as diverse as the environment and medicine.1 Calix-
[4]pyrroles (e.g., 1) represent a set of readily accessible
receptors for various anions whose affinity toward fluo-
ride, chloride, and phosphate anion in organic media has
been well documented since their anion recognition
characteristics were first reported by Sessler and co-
workers in 1996.2 Recently, we reported that strapping
one face of a calix[4]pyrrole could significantly enhance
the affinity and selectivity for appropriately sized anions
and that the anion recognition specifics could be “fine-
tuned” by modifying the length and nature of the bridging
straps.3 As a general rule, greatly enhanced anion
affinities were seen, and in the best of cases, binding
† Kangwon National University.
‡ University of Texas at Austin.
(1) (a) Chakrabarti, P. J. Mol. Biol. 1993, 234, 463-482. (b) Van
Kuijck, M. A.; Van Aubel, R. A. M. H.; Busch, A. E.; Lang, F.; Russel,
G. M.; Bindels, R. J. M.; Van Os, C. H. and Deen, P. M. T. Proc. Natl.
Acad. Sci. U.S.A. 1996, 93, 5401. (c) Calnan, B. J.; Tidor, B.;
Biancalana, S.; Hudson, D. and Frankel, A. D. Science 1991, 252, 1167.
10.1021/jo0487146 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/18/2005
J. Org. Chem. 2005, 70, 2067-2074
2067

Lee et al.
SCHEME 1
constants for halide anions were obtained that far
surpassed those achieved using alternative modification
approaches, including those based on the introduction of
electron withdrawing substituents in the â-pyrrolic posi-
tions,4 the use of covalently linked dimers,5 functional-
ization with chromophores,6 or the synthesis of so-called
deep cavity systems.7
Accordingly, we are currently seeking to develop new
systems based on other types of bridging motifs and in
this paper wish to report the design, synthesis, and
anion-binding properties of a new set of strapped-calix-
[4]pyrroles that contain amide functionality within the
caplike strap. These systems stand in contrast to the
earlier ones in that they possess additional hydrogen-
bonding donor sites with the straps. They also differ from
the earlier ones in that they have been isolated, at least
in the case of the larger straps, in two different configu-
rations, the “cis” and “trans” isomeric forms.
In the design of the present generation of strapped
calix[4]pyrrole receptors, a flexible, m-phthalate-derived
strap containing two amide groups was chosen as the
strapping element. The presence of these amide groups
was expected to provide additional hydrogen bonding
sites for anion recognition, while, as in the past, the
choice of strap size was expected to impart a degree of
anion selective recognition. As it turned out, these
expectations were only partly met.
To date, we have relied on straps that contain either
ether or ester functionality. However, such systems
represent but a small subset of what might be possible
in the context of the generalized strapping paradigm.
(2) (a) Gale, P. A.; Sessler, J. L.; Kra`l, V. and Lynch, V. J. Am. Chem.
Soc. 1996, 118, 5140-5141. (b) Sessler, J. L.; Gale, P. A.; Genge, J. W.
Chem. Eur. J. 1998, 4, 1095-1099. (c) Sessler, J. L.; Gale, P. A.
Calixpyrroles: Novel Anion and Neutral Substrate Receptors. In The
Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.;
Academic Press: San Diego, CA, and Burlington, MA, 2000. (d) Sessler,
J. L.; Anzenbacher, P., Jr.; Miyaji, H.; Jursikova, K.; Bleasdale, E. R.;
Gale, P. A. Ind. Eng. Chem. Res. 2000, 39, 3471-3478. (e) Sessler, J.
L.; Genge, J. W.; Gale, P. A.; Kra`l, V. ACS Symp. Series. 2000, 757
(Calixarenes for Separations) 238-254. (f) Gale, P. A.; Anzenbacher,
P., Jr.; Sessler, J. L. Coord. Chem. Rev. 2001, 222, 57-102. (g) Bucher,
C.; Zimmerman, R. S.; Lynch, V.; Sessler, J. L. J. Am. Chem. Soc. 2001,
123, 9716-9717.
Results and Discussion
The synthesis of the larger strapped systems, com-
pounds 12-15, is shown in Scheme 1. Starting with
potassium phthalimide, reaction with 6-bromohexan-2-
one (2) or 7-bromoheptan-2-one (3)8 gives the correspond-
ing N-alkyl phthalimides 4 and 5. Acid-catalyzed hydrol-
ysis then afforded the aminoketone hydrochloride salts
6 and 7, respectively, in almost quantitative yields. These
amine salts were not isolated or subject to further
purification. Rather, they were converted directly into the
corresponding bis-ketones, 8 and 9, by reacting with
isophthaloyl chloride. Treatment of diketones 8 and 9
with pyrrole in the presence of trifluoroacetic acid (1.0
molar equiv) then afforded the corresponding bisdipyr-
romethanes 10 and 11, respectively.
(3) Yoon, D. W.; Hwang, H.; Lee, C. H. Angew. Chem., Int. Ed. 2002,
41, 1757-1759.
(4) (a) Gale, P. A.; Sessler, J. L.; Allen, W. E.; Tvermoes, N. A.;
Lynch, V. Chem. Commun. 1997, 665-666. (b) Anzenbacher, P., Jr.;
Try, A. C.; Miyaji, H.; Juris´ıkova´, K.; Lynch, V. M.; Marquez, M.;
Sessler, J. L. J. Am. Chem. Soc. 2000, 122, 10268-10272. (c) Miyaji,
H.; An, D.; Sessler, J. L. Supramol. Chem. 2001, 13, 661-669.
(5) Sato, W.; Miyaji, H.; Sessler, J. L. Tetrahedron Lett. 2000, 41,
6731-6736.
(6) (a) Miyaji, H.; Sato, W.; Sessler, J. L.; Lynch, V. M. Tetrahedron
Lett. 2000, 41, 1369-1373. (b) Miyaji, H.; Sato, W.; Sessler, J. L.
Angew. Chem., Int. Ed. 2000, 39, 1777-1779. (c) Anzenbacher, P., Jr.;
Jursikova, K.; Sessler, J. L. J. Am. Chem. Soc. 2000, 122, 9350-9351.
(7) (a) Anzenbacher, P., Jr.; Jursikova, K.; Lynch, V. M.; Gale, P.
A.; Sessler, J. L. J. Am. Chem. Soc. 1999, 121, 11020-11021. (b)
Camiolo, S.; Gale, P. A. Chem. Comm. 2000, 1129-1130.
Once intermediates10 or 11 were in hand, they were
condensed with acetone in the presence of a catalytic
amount of BF3 to produce the desired strapped calix[4]-
(8) Zhang, W.; Li, C. J. Org. Chem. 2000, 65, 5831-5833.
2068 J. Org. Chem., Vol. 70, No. 6, 2005

Cis- and Trans-Strapped Calix[4]pyrroles Bearing Phthalamide Linkers
SCHEME 2
pyrroles 12 and 13 in yields of 18% and 19%, respectively.
Interestingly, calix[4]pyrroles such as 14 and 15, which
represent configurational isomers of 12 and 13, were
unexpectedly isolated in relatively lower yield (∼6% for
14 and ∼17% for 15). Receptors 14 and 15 have a trans
junction for the diametrically positioned strap. The
identity of the two compounds was confirmed unambigu-
ously by proton NMR spectroscopy, while their isomeric
nature was supported by mass spectroscopic analyses.
Although the yields of these new strapped systems were
moderate, the synthesis, purification, and isolation of the
key bisdipyrromethane intermediates 10 and 11 proved
to be straightforward, requiring only simple column
chromatography over silica. As a result, systems 12-15
could be obtained in sufficient quantities so as to allow
for detailed anion-binding studies.
Analogue 19, bearing a shorter strap, could not be
obtained readily using the procedure of Scheme 1.
Therefore, it was synthesized using an alternative method
as shown in Scheme 2. Briefly, the known dipyr-
romethane intermediate 163 was converted into its ph-
thalimide derivative 17 in high yield (87%) in the
presence of P(Ph)3 and diisopropyl azodicarboxylate
(DIAD). After conversion to the corresponding amine by
treatment with hydrazine, immediate reaction with
isophthaloyl dichloride afforded the bis-dipyrromethane
18. Acid-catalyzed condensation of 18 with acetone in the
usual way then provided the desired product 19 in 16%
yield. In this case, no evidence for the formation of the
isomeric trans-strapped system was seen. Presumably,
this reflects the fact that the strap is too short to permit
the formation of such an inherently strained species.
As can be seen from an inspection of Figure 1,
dramatically different proton NMR spectroscopic behav-
ior was seen in the case of the “trans” systems 14 and
15. For example, the resonance of the amide NH protons
in 15 appeared at 6.37 and 6.13 ppm as two distinctive
singlets and those of the pyrrolic NHs were also observed
at 6.97 and 6.78 ppm in the form of two distinct singlets.
The two ArH protons at positions 4 and 6 of the phthaloyl
group were found to be split into two distinct doublets
appearing at 8.10 and 7.70 ppm. In addition, the shielded
resonance of the methylene protons next to the meso
position appeared at 0.47 ppm indicated that the com-
pound was unusually distorted compared to the corre-
sponding cis-strapped system, where the methylene
proton signals appeared at 1.26 ppm. In the 13C NMR
spectrum of compound 15, two sets of signals were
observed for all the carbon atoms, including those of the
carbonyl group. Unfortunately, the trans-strapped com-
pounds 14 and 15 proved rather unstable in organic
solvents and slow decomposition was observed, as evi-
denced by a general degradation of the NMR spectral
features.
The proton NMR spectra of the “cis” systems 12, 13,
and 19 in chloroform-d were found to be in accord with
the proposed structures. For example, in the case of 13,
the amide NH resonances appeared at 6.70 ppm in the
form of a triplet, while the signals for the pyrrolic NHs
were observed as a singlet at 7.84 ppm in a singlet. By
contrast, the amide NH signals in 12 appeared at 6.48
ppm, while the pyrrolic NH signal appeared as a singlet
at 7.92 ppm. These observations support the intuitively
appealing notion that the tetrapyrrolic core present in
the more tightly strapped system 12 is more distorted
than that present in 13.
FIGURE 1. Typical proton NMR spectra at cis-strapped (13)
(bottom trace) and trans-strapped (15) (top trace) calix[4]-
pyrroles in CDCl3 at 25 °C.
Initial studies of the anion-binding properties of sys-
tems 12, 13, and 19 were carried out in acetonitrile-d3
using proton NMR spectroscopy. Unfortunately, slow
J. Org. Chem, Vol. 70, No. 6, 2005 2069

Lee et al.
FIGURE 2. Titration of compound 12 with halide anions (as
their corresponding tetrabutylammonium (TBA) salts) in CD3-
CN (1.0 mM). In the case of fluoride anion, the saturation point
in the binding curve is seen after the addition of 1 stoichio-
metric equivalent of the anion; in the case of bromide anion,
saturation is seen after the addition of 0.5 molar equiv; in the
case of chloride it is seen after the addition of ∼0.7 molar equiv.
FIGURE 3. Job plot corresponding to the titration of com-
pound 12 with chloride anion (as TBACl) in CD3CN.
next to the amide subunits underwent a shift from 3.45
to 3.49 ppm. In all cases, an essentially complete disap-
pearance of the original signals, along with the appear-
ance of the new signals, was observed after the addition
of only ∼0.7 molar equiv of chloride anion. This is
reflected in the saturation point seen in the binding
profile curve for this anion-receptor pair (Figure 2).
In contrast to the above, saturation in the binding
profile curve was seen after the addition of 1 molar equiv
of anion in the case of fluoride anion (added as TBAF.-
3H2O) and after the addition of ca. 0.5 anion equiv in
the case of bromide anion. Such findings are consistent
with a single fluoride anion being bound by a single
strapped calix[4]pyrrole host but bromide being bound
by two such receptor species. They also provide a strong
“hint” that the binding stoichiometry in the case of
chloride is less “clean”. Further analyses involving this
anion were thus carried out as described below.
In accord with the finding that greater than 0.5 molar
equiv but fewer than one full stoichiometric equivalent
of TBACl was required to effect a considerable change
in the overall spectral features, the maximum of the Job
plot (Figure 3), corresponding to the binding of chloride
anion to 12, was observed when the Cl- mole fraction
was 0.4. Such a mole fraction value, which was found to
be entirely reproducible, is not completely consistent with
the formation of a 2:1 (receptor:anion) binding stoichi-
ometry (for which a maximum in the Job plot at a mole
fraction of 0.33 would be expected) under the relatively
high (e.g., 1.0 mM in 12) concentrations of the NMR
studies. Nor is it consistent with the formation of a 1:1
complex. However, it may indicate the existence of
equilibrium between a 1:1 (20) and 2:1 (receptor/anion)
complex (21) as shown in Scheme 3. In particular, it is
suggested that at high relative receptor concentrations
(i.e., after the addition of only a small amount of TBACl),
a species such as 21 forms that then dissociates to form
a 1:1 complex (20) as the relative concentration of the
anion substrate increases. In the case of fluoride, it is a
complex of 1:1 stoichiometry (e.g., 22) that is formed at
most receptor:anion ratios, whereas in the case of bro-
mide it is the 2:1 species, 23, that predominates.
complexation/decomplexation kinetics was observed for
all host systems, meaning no quantitative anion affinity
information could be deduced from these studies. On the
other hand, these 1H NMR spectroscopic studies did
provide good qualitative evidence for the proposed halide
anion binding. For example, when receptor 12 (containing
straps with four methylene units) was subjected to
titration with TBAF in acetonitrile-d3, dramatic changes
in the 1H NMR signals were observed. In particular, the
integrated intensity of the pyrrole NH proton signals,
originally observed at 8.37 ppm in the absence of any
anion, was seen to diminish as the titration progressed.
Meanwhile, a new signal was observed to appear at 11.84
ppm, with an integrated intensity that increased as the
titration was allowed to run its course. Complete disap-
pearance of the original signal at 8.37 ppm was observed
with the addition of 1.0 equiv of TBAF.
In the titration with chloride anion, the integrated
intensity of the pyrrole NH protons, again observed at
8.37 ppm in the absence of the added anion, was found
to decrease upon the addition of small quantities of
TBACl with noticeable changes being seen even after the
addition of ∼0.05 equiv. Concurrently, a new signal was
seen to grow in at 10.30 ppm. In the case of bromide
anion, a complete shift in the pyrrole NH signal, from
8.37 to 10.02 ppm, was observed upon the addition of only
0.5 equiv of TBABr. While these differences in shift
behavior have important implications in terms of assign-
ing binding stoichiometry under solution-phase condi-
tions, they also lead us to the intriguing proposal that
anion discrimination could be effected by analyzing
changes in the pyrrole NH signal.
Information about the anion-binding process can also
be inferred from the changes observed for several of the
1
other signals seen in the H NMR spectrum of 12, 13,
and 19. For instance, in the case of receptor 12, the amide
NH protons, initially appearing at 7.04 ppm, were seen
to shift to 8.22 ppm upon titration with TBACl. Moreover,
the signal for the aromatic CH proton at position 2 (i.e.,
between the two carbonyl groups) was found to shift from
8.23 to 8.44 ppm. The signals for the methylene protons
The low temperature (-50 °C; CD3CN) proton NMR
spectrum of free host 12 shows only a single peak for the
pyrrolic NH resonances at 8.84 ppm, while the compa-
2070 J. Org. Chem., Vol. 70, No. 6, 2005

Cis- and Trans-Strapped Calix[4]pyrroles Bearing Phthalamide Linkers
FIGURE 4. Low-temperature (-50 °C; CD3CN) proton NMR
spectrum of free receptor 12 (trace a). Notice the presence of
a single pyrrolic NH resonance. Trace b shows the spectrum
recorded at a 3:2 stoichiometric ratio of 12/TBACl (a ratio
corresponding to the saturation point seen in Figure 2) under
analogous conditions. Here, attention is drawn to the split
nature of the pyrrolic NH signal.
FIGURE 5. Plot showing the results of a reverse proton NMR
spectroscopic titration: The strapped calix[4]pyrrole 12 was
added to solutions of tetrabutylammonium bromide (TBABr)
and tetrabutylammonium chloride (TBACl) (1.0 mM in CD3-
CN), respectively. The 2:1 (receptor/anion) complex ratio was
maintained up to the point where roughly ∼2 molar equiva-
lents of the calixpyrrole had been added in the case of bromide.
In the case of chloride anion, a 2:1 (receptor/anion) complex
ratio was maintained up to the point where ∼1.3 molar equiv
of the host had been added.
SCHEME 3
at this stage. The nature of the spectral features, and
hence complex ratio, remained unchanged until ∼2 molar
equiv of host 12 had been added. Such an invariance is
consistent with the formation of a 2:1 (receptor/Br-)
complex in the solution under these conditions. After the
addition of >2 molar equiv of receptor 12, the complex
ratio started to decrease, as reflected in the appearance
of peaks ascribed to the uncomplexed free host (i.e., 12).
Taken in concert, these results provide important support
for the proposal that the receptor is binding with bromide
anion in a clean 2:1 (receptor to anion) fashion under
most solution phase conditions, including those of Figure
2. The results also indicate that receptors such as 12
might be useful systems for effecting the quantitative
analysis of anions under various “real life” scenarios.
Additional quantitative studies of the anion-binding
properties of 12, 13, and 19 were made using isothermal
titration calorimetry (ITC). An advantage of this method
is that it allows for the study of recognition events,
including those involving calix[4]pyrroles,9,10 at concen-
trations that are lower than those required for NMR
spectroscopic analyses. ITC also permits the determina-
tion of much higher binding affinities than do NMR-based
methods. Unfortunately, to date, we have been unable
to obtain reliable binding constant data for fluoride anion
for any receptor, including 1, by ITC. This anion was,
therefore, excluded from the present study.
Table 1 summarizes the equilibrium association con-
stants Ka, measured by ITC for the binding of various
halide anions to receptors 12, 13, and 19 as determined
in dry acetonitrile.11 The sum total of the data leads us
to propose that the binding mode observed with these
new systems may be different from that seen in the
rable spectrum recorded at the point where the stoichio-
metric ratio of 12 to TBACl was 3:2, revealed two
separate pyrrolic N-H resonances at 10.32 and 10.20
ppm (Figure 4). These distinct N-H signals are assigned
to the 1:1 and 2:1 complexes, respectively. This splitting
is not observed at room temperature, presumably as the
result of a rapid equilibrium between what is predomi-
nantly a mixture of the 1:1 and 2:1 (receptor:anion)
complexes (cf. Scheme 3).
To provide more support for the proposed binding
modes, a so-called reverse titration was performed with
bromide anion. This experiment was carried out by
adding small portions of host 12 to a solution of tetrabu-
tylammonium bromide (1.0 mM) in CD3CN (Figure 5).
At the beginning of this “titration” (i.e., when 0.1 molar
equiv of 12 had been added), the complex ratio (i.e.,
[complex]/([free calixpyrrole] + [complex]) determined
1
from integration of the H NMR spectrum showed that
(9) Schmidtchen F. P. Org. Lett. 2002, 4, 431-434.
(10) Lee, C. H.; Na, H. K.; Yoon, D. W.; Won, D. H.; Cho, W. S.;
Lynch, V. M.; Shevchuk, S. V.; Sessler, J. S. J. Am. Chem. Soc. 2003,
125, 7301-7306.
essentially every host molecule added to the solution was
bound to a bromide anion, as would perhaps be expected
given the relatively high excess of bromide anion present
J. Org. Chem, Vol. 70, No. 6, 2005 2071

Lee et al.
TABLE 1. Association Constants, Ka, and Thermodynamic Parameters for the Binding of Chloride, Bromide, and
Iodide Anions by Hosts 12, 13, and 19 As Measured by ITC (Isothermal Titration Calorimetry) at 30 °C Using the
Corresponding Alkylammonium Salts (TBA ) Tetrabutylammonium)
19 (C3)
12 (C4)
13 (C5)
anion
solventa
∆H
TBA-Cl
CH3CN
-9.75
TBA-Br
CH3CN
-7.11
TBA-I
TBA-Cl
CH3CN
-9.79
TBA-Br
CH3CN
-8.39
TBA-I
TBA-Cl
CH3CN
-10.00
-9.03
TBA-Br
CH3CN
-8.13
TBA-I
CH3CN
-4.85
CH3CN
CH3CN
-4.89
∆G
-9.14
-8.53
-9.75
-8.46
-4.65
-8.10
-4.83
T∆S
Ka
-0.61
1.42
-0.74
0.07
-0.24
-0.97
-0.03
-0.02
3.89 × 106
1.41 × 106
ND
3.35 × 106
1.25 × 106
2.30 × 103
3.24 × 106
7.0 × 105
3.0 × 103
a The CH3CN was rigorously dried by passage over two columns of activated molecular sieves using a solvent dispensing system ([H2O]
< 10 ppm).
previously reported strapped calix[4]pyrrole systems.10
Although a large increase in across-the-board anion
affinity, relative to the unstrapped “control” calix[4]-
pyrrole 1, is seen for all three of the test anions
considered, no size discrimination is observed. Rather,
in contrast to what was found in the case of the analogous
ether linked strapped systems,10 all three new receptors
give rise to more or less the same binding behavior and
thus do not show any kind of anion-to-receptor size
matched selectivity. Such a result was entirely unex-
pected and, in our view, is one that is most easily
rationalized in terms of a binding process that takes place
outside of the strap-derived binding pocket. On the other
hand, the dramatic increase in affinity observed relative
to 1 indicates that, in the case of 19, 12, and 13, anion
binding likely benefits from interactions involving both
the amide NH and pyrrolic NH protons.
Structures 20 and 21 show schematic representations
of the proposed binding modes of receptor 12 with
chloride anion and are designed to illustrate the equi-
librium between 1:1 and 2:1 (receptor/anion) complexes
that are formed from 12. The moderate size of chloride
anion does not permit it to fit into the cavity well and,
accordingly, interactions involving slight out-of-cavity
binding may be preferred. On the other hand, in the case
of fluoride anion it is the 1:1 complex (structure 22) that
is formed to near exclusion, while its larger congener,
bromide anion, forms a 2:1 complex (structure 23) almost
exclusively. The fact that the nature of the binding modes
for 12 and these three halide anions shifts from 1:1 to
2:1 in a monotonic fashion depending on the size of the
anion, means that both the size of the anion and the
tightness of the strap lay key roles in regulating the
recognition process and that the latter “variable” provides
a potentially versatile “tool” for fine-tuning the anion
affinities and selectivities of cis-configured calix[4]pyrrole
systems. On the other hand, this choice of spacer enforces
an orientation for the two amide-derived NH donor
groups that are necessarily oriented parallel to the
phenyl ring. As a consequence, a strap orientation where
the m-phthalamide “cap” is perpendicular to the calix-
[4]pyrrole cone leads to a pocket that is too small to
accommodate readily even the smallest of the test anions
considered in this study, i.e., chloride anion. By contrast,
opening up the cavity, to provide structures such as 20
allows for a full complement of anion-receptor binding
interactions while at the same defining avenues of
approach that permit dimerization, as per structure 21.
This latter form, which provides for multiple receptor-
anion hydrogen bonding interactions, is expected to be
particularly stable, especially at high receptor:anion
ratios. While no independent structural proof for this
model currently exists (e.g., from X-ray diffraction analy-
sis), it is very much in accord with the experimental
observations.
No substantial changes in the proton NMR spectrum
were observed when compound 8 (the calix[4]pyrrole-free,
bis-amide “strap” intermediate) was titrated with tet-
rabutylammonium chloride under conditions analogous
to those used in the study of 12, 13, and 19. This lack of
appreciable change is consistent with the proposal made
above, namely that receptor-anion interactions involving
both the two amide NHs and the pyrrolic NH protons
are responsible for the high anion binding affinities seen
in the case of this cis-configured receptor systems.
Further support for this generalized conclusion came
from studies of the trans-configured receptor 14. In this
case, evidence for fast complexation/decomplexation ki-
netics was observed, as evidenced by the gradual down-
field shifts of the two amides NH proton signals seen in
the 1H NMR spectrum of 14 upon the addition of
increasing quantities of TABCl (measurements made, as
above, in acetonitrile-d3). Interestingly, the chemical shift
of the pyrrolic NH protons remained almost unchanged
throughout the course of the titration. From this latter
observation, we infer that there is, at best, minimal
participation of the pyrrolic NHs in the binding event;
presumably, this reflects the high conformational rigidity
imposed by the trans configuration of the calixpyrrole-
strap junctions. Calix[4]pyrrole 14 and its congener 15,
are constrained to a rigid conformation as the result of
these strap-bearing junctions and are thus probably
unable to adopt the cone conformation that is known to
favor the binding of anions in receptors of this type.
(11) Isothermal titration calorimetery (ITC) measurements were
performed as follows: Solutions of the chosen receptor in rigorously
dry acetonitrile were made up so as to provide a receptor concentration
range of 0.1-1 mM. These solutions were then individually titrated
with the appropriate alkylammonium salts at 30 ( 0.01 °C. The
original heat pulses were normalized using reference titrations carried
out using the same salt solution but pure solvent, as opposed to a
solution containing the receptor. The values recorded in Table 1 are
the average result of at least three separate titrations carried out using
at least two different concentrations.
Conclusion
In summary, we have shown that strapping a calix[4]-
pyrrole core with amide-containing linkers increases the
binding affinity for halide anions in acetonitrile solution.
However, in contrast to what is true for the corresponding
ester or ether strapped systems, these newer m-phthal-
imide-derived systems failed to show an appreciable size-
2072 J. Org. Chem., Vol. 70, No. 6, 2005

Cis- and Trans-Strapped Calix[4]pyrroles Bearing Phthalamide Linkers
(m, 2H); 13C NMR (CDCl3) δ 209.2, 168.8, 134.3, 132.9, 123.6,
based selectivity among the three test anions studied,
namely chloride, bromide, and iodide. This is rationalized
in terms of a binding mode that does not involve com-
plexation of the anionic substrate within a well-defined
central pocket established by the bridging strap. Rather,
it is proposed that the strap tilts to one side so as to allow
both amide- and pyrrole NH-based hydrogen bonding
interactions. A consequence of this is the possibility of
facile dimerization to form 2:1 receptor/anion complexes,
something that is seen in the case of bromide anion in
acetonitrile-d3 and for chloride anion at high receptor/
anion ratios in this same solvent. To the extent such a
hypothesis is correct it leads to the suggestion that the
choice of strap could play a profound role not only in
increasing the intrinsic anion affinities of calix[4]pyrroles
but also in modulating the receptor:anion stoichiometry,
thereby modifying potentially the inherent anion binding
selectivity. Current work is focused on preparing other
strapped systems and extending this control paradigm
into the realm of other receptor systems. Particular
emphasis is being placed on the construction of systems
containing straps with built-in chromophores that could
act as new colorimetric anion sensors, as well as the
generation of new receptors with preorganized clefts that
might allow for the specific targeting of nonspherical
anions, such as oxalate anion or pyrophosphate anion,
that are of obvious biological importance.
43.8, 38.1, 30.3, 28.8, 26.7, 23.6; HRMS calcd for C15H17NO3
259.1208, found 259.1208.
N,N′-Bis(6-oxohexyl)isophthalamide (8). Compound 4
(1.19 g, 4.86 mmol) was subjected to hydrolysis using concen-
trated aqueous HCl (35%, 3.5 mL) affording 6 in essentially
quantitative yield. At this point, compound 6 (0.87 g, 5.25
mmol), NaOH (2.0 g, 50.0 mmol), tetrabutylammonium hy-
drogensulfate (0.165 g, 0.047 mmol), and isophthaloyl dichlo-
ride (0.494 g, 2.40 mmol) were subjected to reaction in a
manner analogous to that used to prepare 9. Purification was
effected by column chromatography over silica gel (THF/EtOAc
1
) 3:7, eluent): yield 0.339 g (39%); H NMR (CDCl3) δ 8.26
(bs, 1H), 7.99-7.97(m, 2H), 7.50 (t, 1H, J ) 7.7 Hz), 6.98-
6.92 (m, 2H), 3.45-3.40 (m, 4H), 2.51 (t, 4H, J ) 6.5 Hz), 1.68-
1.58 (m, 8H); 13C NMR (CDCl3) δ 209.7, 167.1, 135.2, 130.5,
129.3, 125.3, 43.4, 40.1, 30.8, 29.2, 20.9; HRMS calcd for
C20H28N2O4 360.209, found 360.2050.
N,N′-Bis(6-oxoheptyl)isophthalamide (9). A mixture of
N-(6-oxoheptyl)phthalimide (1.0 g, 3.86 mmol) and concen-
trated HCl (3 mL) was heated for 60 h at 100 °C. After the
mixture was allowed to cool to room temperature, water (20
mL) was added. The solid precipitate that formed was removed
by filtration and discarded, and the aqueous layer was washed
with diethyl ether twice, with these washings also being
discarded. The water was removed in vacuo, and the remaining
solid was dried. The resulting 6-amino-2-heptanone-HCl salt
was then used to the next step without further purification
due to its instability. Specifically, this salt (6-amino-2-hep-
tanone-HCl; 0.87 g, 5.25 mmol) was dissolved in aqueous
NaOH (0.527 M, 100 mL), and the resulting mixture was
combined with tetrabutylammonim hydrogen sulfate (0.179 g,
0.527 mmol) and CH2Cl2 (40 mL). It was then stirred for 1 h
before isophthaloyl dichloride (0.508 g, 2.50 mmol) dissolved
in CH2Cl2 (10 mL) was added dropwise over a period of 5 min.
The mixture produced in this way was stirred for 1 h and
extracted with CH2Cl2. The organic layer was dried (anhydrous
Na2SO4), and the solvent was removed in vacuo. The remaining
solid was purified by column chromatography over silica gel
(THF/EtOAc ) 3:7, eluent): yield 0.709 g (73%); 1H NMR
(CDCl3) δ 8.19-8.19 (m, 1H), 7.98 (dd, 2H, Ja-b ) 7.8 Hz, Ja-c
) 0.1 Hz), 7.53 (t, 1H, Ja-b ) 7.8 Hz), 6.60 (bs, 2H), 3.49 (q,
4H, J ) 6.6 Hz), 2.48 (t, 4H, J ) 7.1 Hz), 2.15 (s, 6H), 1.68-
1.58 (m, 8H), 1.43-1.37 (m, 4H); 13C NMR (CDCl3) δ 209.9,
167.0, 135.2, 130.6, 129.4, 125.1, 43.8, 40.0, 30.5, 29.4, 26.6,
23.3; HRMS calcd for C22H32N2O4 388.24, found 389.18 (MH+).
Isophthalic Acid Bis[5,5-bis(1H-pyrrol-2yl)hexyl]-
amide (10). Compound 8 (0.298 g, 0.827 mmol), pyrrole (5
mL, 72.07 mmol), and TFA (63.7 µL, 0.827 mmol) were
subjected to reaction under conditions identical to those used
for the synthesis of 11. Column chromatography over silica
gel (EtOAc/CH2Cl2 ) 3:7, eluent) was used to effect purifica-
tion: yield 0.384 g (78%); 1H NMR (CDCl3) δ 8.05 (bs, 1H),
7.92 (bs, 4H), 7.85-7.83 (m, 2H), 7.49 (t, 1H, J ) 7.7), 6.60-
6.58 (m, 4H), 6.19 (bs, 2H), 6.11-6.09 (m, 4H), 6.06-6.05 (m,
4H), 3.44-3.40 (m, 4H), 2.04-2.01 (m, 4H), 1.58-1.55 (m, 4H),
1.58 (s, 6H), 1.29-1.26 (m, 4H); 13C NMR (CDCl3) δ 167.3,
138.4, 135.3, 130.2, 129.3, 125.7, 117.4, 108.1, 104.9, 40.8, 39.9,
39.5, 30.2, 26.8, 21.8; HRMS calcd for C36H44N6O2 592.35,
found 592.40.
Experimental Section
Proton NMR spectra (400 MHz) were recorded using TMS
as the internal standard. High- and low-resolution FAB mass
spectra were obtained on a high-resolution mass spectrometer.
Column chromatography was performed over silica gel (230-
400 mesh). Pyrrole was distilled at atmospheric pressure from
CaH2. Both CH2Cl2 and CHCl3 (reagent grade) were distilled
from K2CO3 to eliminate traces of acid. All other reagents were
obtained from a commercial supplier and used as received
unless noted otherwise. Isothermal titration calorimetery (ITC)
measurements were performed as follows: Solutions of the
chosen receptor in rigorously dry acetonitrile were made up
so as to provide a receptor concentration range of 0.1∼1.0 mM.
These solutions were then individually titrated with the
appropriate alkylammonium salts at 30 ( 0.01 °C. The original
heat pulses were normalized using reference titrations carried
out using the same salt solution but pure solvent, as opposed
to a solution containing the receptor. The values recorded in
Table 1 represent the average of at least three separate
titrations carried out using at least two at different concentra-
tions.
N-(6-Oxohexyl)phthalimide (4). Phthalimide (1.55 g, 8.36
mmol) and 6-bromo-2-hexanone (1.14 g, 6.39 mmol) were
subjected to reaction as in the synthesis of 5: yield 1.47 g
1
(94%); H NMR (CDCl3) δ 7.85-7.82 (m, 2H), 7.73-7.70 (m,
2H), 3.71 (t, 2H, J ) 6.9), 2.51-2.48 (t, 2H, J ) 7.1 Hz), 172-
1.60 (m, 4H); 13C NMR (CDCl3) δ 208.3, 168.4, 133.9, 132.1,
123.2, 42.9, 37.5, 30.0, 27.9, 20.8; HRMS calcd for C14H15NO3
245.1052, found 245.1045.
Isophthalic Acid Bis[6,6-bis(1H-pyrrol-2yl)heptyl]-
amide (11). To a mixture of N,N′-bis(6-oxoheptyl)isophthala-
mide (0.56 g, 1.44 mmol) and pyrrole (10 mL, 141.25 mmol)
was added trifluoroacetic acid (111.4 µL, 1.44 mmol). The
mixture was then stirred for 1.5 h at 60 °C before being
quenched with aqueous NaOH (0.1 N, 20 mL) and extracted
with CH2Cl2. The organic layer was collected and dried
(anhydrous Na2SO4) before the solvent was removed in vacuo.
The resulting solid was purified by column chromatography
over silica gel (EtOAc/CH2Cl2 ) 3:7, eluent): yield 0.742 g
N-(6-Oxoheptyl)phthalimide (5). A mixture of phthal-
imide potassium salt (1.60 g, 8.72 mmol), 7-bromo-2-heptanone
(1.10 g, 5.70 mmol), and DMF (10 mL) was stirred for 4 h at
65 °C. The mixture was cooled to room temperature and
combined with water (50 mL). The mixture was then extracted
with CHCl3, and the organic layer was washed with aqueous
NaOH (∼40%) and water successively. The solvent was
removed in vacuo, and the resulting solid was recrystallized
in water: yield 1.34 g (91%); 1H NMR (CDCl3) δ 7.86-7.82
(m, 2H), 7.73-7.69 (m, 2H), 3.68 (t, 2H, J ) 7.22 Hz), 2.43 (t,
2H, J ) 7.4 Hz), 2.13 (s, 3H), 1.73-1.58 (m, 4H), 1.39-1.31
1
(83%); H NMR (CDCl3) δ 8.13 (bs, 1H), 8.00 (bs, 4H), 7.82-
7.80 (m, 2H), 7.38 (t, 1H, J ) 7.8 Hz), 6.66 (bs, 2H), 6.54-
J. Org. Chem, Vol. 70, No. 6, 2005 2073

Lee et al.
6.53 (m, 4H), 6.08-6.06 (m, 4H), 5.99 (bs, 4H), 3.30-3.23 (m,
4H), 1.90-1.86 (m, 4H), 1.52 (s, 6H), 1.49-1.42 (m, 4H), 1.25-
1.20 (m, 4H), 1.18-1.13 (m, 4H); 13C NMR (CDCl3) δ 167.4,
138.6, 135.2, 130.3, 129.3, 125.8, 117.4, 107.9, 104.9, 41.4, 40.5,
39.3, 29.8, 27.7, 26.5, 24.5; HRMS calcd for C38H48N6O2 620.38,
found 620.39.
column chromatography over silica gel (CH2Cl2/EtOAc ) 19:
1
1, eluent): yield 1.66 g (80%); H NMR (CDCl3) δ 7.82-7.80
(m, 2H), 7.72 (bs, 2H), 7.71-7.69 (m, 2H), 6.57 (m, 2H), 6.08
(m, 2H), 6.05 (m, 2H), 3.60 (t, J ) 7.2 Hz, 2H), 2.04-1.99 (m,
2H), 1.63-1.59 (m, 2H), 1.56 (s, 3H); 13C NMR (CDCl3) δ 168.4,
137.5, 133.9, 132.1, 123.2, 117.2, 107.8, 104.7, 38.8, 38.2, 38.1,
26.3, 23.9; EI MS calcd for C21H21N3O2 347.16, found 347.16.
N,N′-Bis[4,4-bis(1H-pyrrol-2-yl)pentyl]isophthala-
mide (18). Compound 17 (1.66 g, 4.77 mmol) was dissolved
in ethanol (50 mL), and then hydrazine monohydrate (0.93 mL,
19 mmol) was added. The resulting mixture was heated at
reflux for 24 h and then cooled to room temperature. The
mixture then was combined with aqueous NaOH (50 mL) and
extracted with CH2Cl2. The solvent was removed in vacuo, and
the resulting solid was used directly in the next step without
further purification. The meso-(3-aminopropyl, methyl)dipyr-
romethane (1.0 g, 3.94 mmol) obtained as the result of this
operation and isophthaloyl dichloride (0.374 g, 1.84 mmol)
were dissolved in CH2Cl2 (40 mL). Triethylamine (1.03 mL,
7.37 mmol) was then added, and the mixture was stirred for
12 h at room temperature. At this point, the mixture was
combined with water (50 mL) and extracted with CH2Cl2. The
organic layer was collected and taken to dryness in vacuo. The
resulting dark solid was purified by column chromatography
(C4)-Strapped Calix[4]pyrrole (12). Compound 10 (0.27
g, 0.46 mmol), acetone (300 mL), and BF3‚OEt2 (28.6 µL, 0.23
mmol) were reacted together in a manner identical to that used
in the synthesis of 13. Column chromatography over silica gel
(EtOAc/CH2Cl2 ) 3:7, eluent) gave two fractions identified as
12 and 14. For 12: yield 56 mg (18%); 1H NMR (CDCl3) δ
8.20-8.19 (m, 1H), 7.94-7.91 (m, 6H), 7.54 (t, 1H, J ) 7.7),
6.49-6.46 (m, 2H), 5.90-5.89 (m, 4H), 5.83-5.82 (m, 4H),
3.56-3.52 (m, 4H), 1.92-1.88 (m, 4H), 1.61-1.58 (m, 4H), 1.52
(s, 6H), 1.49 (s, 6H), 1.47 (s, 6H), 1.42-1.37 (m, 4H); 13C NMR
(CDCl3) δ 166.4, 138.9, 137.1, 134.6, 129.7, 128.9, 126.0, 103.4,
103.0, 40.3, 39.9, 39.4, 35.4, 30.6, 29.7, 28.9, 28.6, 23.6; HRMS
(FAB) calcd for C42H52N6O2 672.40, found 672.60. For 14: 1H
NMR (CDCl3) δ 8.26 (s, 1H), 7.99 (d, 1H), 7.72 (d, 1H), 7.51 (t,
1H, J ) 7.7 Hz), 7.00 (bs, 2H), 6.71 (bs, 2H), 6.02 (bs, 1H),
5.91-5.90 (m, 4H), 5.83-5.82 (m, 2H), 5.67-5.66 (m, 2H), 5.59
(bs, 1H), 3.68-3.67 (m, 2H), 3.17-3.15 (m, 2H), 1.84-0.80 (m,
30H); 13C NMR (CDCl3) δ 167.7, 139.2, 138.0, 136.3, 136.2,
135.2, 134.9, 130.8, 128.2, 127.9, 126.9, 104.8, 103.7, 102.9,
102.8, 43.5, 40.9, 40.1, 39.6, 38.6, 35.6, 35.5, 30.9, 30.8, 29.9,
28.9, 26.8, 24.4, 24.0, 21.4; FAB MS calcd for C42H52N6O2
672.40, found 672.64
1
over silica gel (CH2Cl2/EtOAc ) 1:1): yield 1.02 g (76%); H
NMR (CDCl3) δ 8.07 (bs, 4H), 7.98 (m, 1H), 7.76-7.74 (m, 2H),
7.38-7.34 (m, 1H), 6.53 (m, 4H), 6.50 (t, J ) 5.3 Hz, 2H), 6.06-
6.04 (m, 4H), 5.99 (m, 4H), 3.26-3.22 (m, 4H), 1.98-1.94 (m,
4H), 1.52 (s, 6H), 1.41-1.39 (m, 4H); 13C NMR (CDCl3) δ 166.9,
137.7, 134.7, 129.9, 128.8, 125.4, 117.2, 107.7, 104.7, 40.4, 38.9,
38.2, 26.2, 24.8; EI MS calcd for C34H40N6O2 564.32, found
564.32.
(C5)-Strapped Calix[4]pyrrole (13). To a solution of
isophthalic acid bis[6,6-bis(1H-pyrrol-2-yl)]heptylamide (0.266
g, 0.43 mmol) in acetone (200 mL) was added BF3‚OEt2 (27.2
µL, 0.215 mmol). The mixture was then stirred for 30 min at
room temperature before being quenched with aqueous K2CO3
(saturated, 20 mL) and extracted with CH2Cl2. The organic
layer was collected and dried, and the resulting solid was
purified by column chromatography over silica gel (EtOAc/CH2-
Cl2 ) 3:7, eluent) to afford two fractions that were identified
as 13 and its isomer 15. For 13: yield 0.058 g (19%); 1H NMR
(CDCl3) δ 8.30 (bs, 1H), 7.98-7.96 (m, 2H), 7.84 (bs, 4H), 7.57
(t, 1H, J ) 7.8 Hz), 6.71-6.68 (m, 2H), 5.78 (m, 8H), 3.44-
3.39 (m, 4H), 1.98-1.94 (m, 4H), 1.68-1.64 (m, 4H), 1.51 (s,
6H), 1.46 (s, 6H), 1.45(s, 6H), 1.45-1.40 (4H), 1.26-1.23 (m,
4H); 13C NMR (CDCl3) δ 166.9, 138.8, 138.3, 134.4, 129.6,
128.9, 126.7, 103.1, 102.8, 39.1, 38.9, 38.7, 35.3, 29.9, 29.1, 28.2,
27.2, 25.0, 22.2; HRMS calcd for C44H56N6O2 700.45, found
C3-Strapped Calix[4]pyrrole (19). Compound 18 (1.0 g,
1.77 mmol) was dissolved in acetone (200 mL), and BF3‚OEt2
(0.09 mL, 0.71 mmol) was added. The resulting mixture was
stirred for 30 min at room temperature and then combined
with aqueous NaOH (10%, 20 mL). The mixture produced in
this way was extracted with CH2Cl2. The organic extracts were
collected and taken to dryness in vacuo, and the resulting solid
was purified by column chromatography over silica gel (CH2-
Cl2/EtOAc ) 1:1, eluent): yield 0.12 g (11%); 1H NMR (CDCl3)
δ 8.17 (m, 1H), 8.07 (bs, 4H), 7.80-7.77 (m, 2H), 7.51-7.47
(m, 1H), 6.18 (t, J ) 5.7 Hz, 2H), 5.96-5.90 (m, 4H), 5.85-
5.83 (m, 4H), 3.52-3.48 (m, 4H), 2.17-2.11 (m, 4H), 1.54 (s,
6H), 1.48 (s, 6H), 1.45-1.40 (m, 4H), 1.18 (s, 6H); 13C NMR
(CDCl3) 168.2, 138.7, 137.7, 135.7, 129.5, 129.3, 126.6, 103.9,
103.1, 39.4, 38.7, 38.2, 34.9, 30.6, 27.6, 25.5, 24.9; HRMS calcd
for C40H48N6O2 644.3839, found 644.8918.
1
700.40. For 15: H NMR (CDCl3) δ 8.26 (s, 1H), 8.08 (d, 1H),
7.70 (d, 1H), 7.48 (t, 1H, J ) 7.7 Hz), 6.96 (bs, 2H), 6.78 (bs,
2H), 6.37 (bs, 1H), 6.13 (bs, 1H), 5.96-5.85 (m, 8H), 3.36 (m,
4H), 1.92 (m, 2H), 1.82 (m, 2H), 1.44-1.19 (m, 32H), 1.10 (m,
2H), 0.47 (m, 2H); 13C NMR (CDCl3) δ 167.0, 166.5, 138.9,
137.6, 137.2, 136.5, 135.3, 135.0, 131.5, 128.9, 128.0, 125.5,
104.6, 103.8, 102.5, 40.8, 39.3, 39.1, 38.8, 38.1, 30.8, 30.4, 29.4,
27.0, 25.9, 25.7, 25.3, 24.5, 23.7, 23.4; FAB MS calcd for
C44H56N6O2 700.45, found 700.60.
Acknowledgment. This work was supported by a
grant (R05-2003-000-11220-0) from the Basic Research
Program of the Korea Science and Engineering Founda-
tion (KOSEF) and by the National Institutes of Health
(Grant No. GM 589907 to J.L.S.). NMR and Mass
Spectra were recorded at the Central Instrumentation
Facility in KNU. The Vascular System Research Center
(VSRC) at KNU is also acknowledged for support.
2-[4,4-Bis(1H-pyrrol-2-yl)pentyl]isoindole-1,3-dione (17).
To a mixture of 4,4-bis(1H-pyrrol-2-yl)pentan-1-ol (16) (1.3 g,
6 mmol), phthalimide (2.63 g, 3 equiv, 17.9 mmol), PPh3 (4.7
g, 3 equiv, 17.9 mmol), and THF (100 mL) was added dropwise
diisopropyl azodicarboxylate (DIAD; 3.5 mL, 3 equiv, 17.8
mmol) over a period of 15 min. This reaction mixture was
stirred for 12 h at room temperature and then combined with
water (100 mL). It was then extracted with methylene chloride,
and the organic extracts were dried over Na2SO4. The solvent
was removed in vacuo, and the resulting solid was purified by
Supporting Information Available: Spectroscopic data
and ITC plots. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0487146
2074 J. Org. Chem., Vol. 70, No. 6, 2005