Anion binding behavior of heterocycle-strapped calix[4]pyrroles

Article abstract of DOI:10.1007/s10847-009-9645-3

A comparative study of the halide and benzoate anion binding properties of a series of phenyl, pyrrole, and furan-strapped calix[4]pyrroles has been carried out. These receptors, which have previously been shown to bind the chloride anion (Yoon et al., Angew. Chem., Int. Ed. 47(27):5038-5042, 2008), were found to bind bromide and benzoate anion (studied as the corresponding tetrabutylammonium salts) with near equal affinity in acetonitrile, albeit less well than chloride, as determined from ITC measurements or NMR spectroscopic titrations. This stands in marked contrast to the parent octamethylcalix[4]pyrrole, where the carboxylate anion affinities are substantially higher than those for bromide anion under identical conditions. This finding is rationalized in terms of tighter binding cavity present in the strapped systems. For all three anions for which quantitative data could be obtained (i.e., Cl^-, Br^-, PhCO₂^-), the pyrrole-strapped system displayed the highest affinity, although the relative enhancement was found to depend on the anion in question. In the specific case of fluoride anion binding to the pyrrole-strapped receptor, two modes of interaction are inferred, with the first consisting of binding to the calix[4]pyrrole via NH-anion hydrogen bonds, followed by a process that involves deprotonation of the strapped pyrrolic NH proton. A single crystal X-ray diffraction analysis provides support for the first of these modes and further reveals the presence of a methanol molecule bound to the fluoride anion. Springer Science+Business Media B.V. 2009.

Full text of DOI:10.1007/s10847-009-9645-3

J Incl Phenom Macrocycl Chem (2010) 66:81–85
DOI 10.1007/s10847-009-9645-3
ORIGINAL ARTICLE
Anion binding behavior of heterocycle-strapped calix[4]pyrroles
Dustin E. Gross Æ Dae-Wi Yoon Æ Vincent M. Lynch Æ
Chang-Hee Lee Æ Jonathan L. Sessler
Received: 28 June 2009 / Accepted: 8 July 2009 / Published online: 28 July 2009
Ó Springer Science+Business Media B.V. 2009
Abstract A comparative study of the halide and benzoate
anion binding properties of a series of phenyl, pyrrole, and
furan-strapped calix[4]pyrroles has been carried out. These
receptors, which have previously been shown to bind the
chloride anion (Yoon et al., Angew. Chem., Int. Ed.
47(27):5038–5042, 2008), were found to bind bromide and
benzoate anion (studied as the corresponding tetrabutyl-
ammonium salts) with near equal affinity in acetonitrile,
albeit less well than chloride, as determined from ITC
measurements or NMR spectroscopic titrations. This stands
in marked contrast to the parent octamethylcalix[4]pyrrole,
where the carboxylate anion affinities are substantially
higher than those for bromide anion under identical condi-
tions. This finding is rationalized in terms of tighter binding
cavity present in the strapped systems. For all three anions
for which quantitative data could be obtained (i.e., Cl-,
Br-, PhCO2-), the pyrrole-strapped system displayed the
highest affinity, although the relative enhancement was
found to depend on the anion in question. In the specific
case of fluoride anion binding to the pyrrole-strapped
receptor, two modes of interaction are inferred, with the first
consisting of binding to the calix[4]pyrrole via NH-anion
hydrogen bonds, followed by a process that involves
deprotonation of the strapped pyrrolic NH proton. A single
crystal X-ray diffraction analysis provides support for the
first of these modes and further reveals the presence of a
methanol molecule bound to the fluoride anion.
Keywords Supramolecular chemistry Á Anion
recognition Á Deprotonation Á Calixpyrrole Á Isothermal
titration calorimetry
Introduction
Tuning the selectivity and strength of anion–receptor
interactions is one of the major goals in the field of anion
recognition. In the case of oligopyrroles, a well-recognized
class of anion-binding agents, these features are thought to
be tunable on the basis of cavity size, number of H-bond
donors, NH proton acidity, receptor charge, conformational
flexibility, and the nature and directionality of ancillary
electron donor or acceptor groups. Calixpyrroles are now a
well-known class of anion receptors. In the specific case of
calix[4]pyrroles, recent efforts to enhance the anion binding
affinities, as well as to modulate the selectivity of this easy-
to-make class of uncharged receptors, have led inter alia to
the synthesis of strapped calix[4]pyrroles [1–3]. As detailed
in a recent review [4], several strapped calix[4]pyrroles
containing phenyl subunits within their respective straps
display enhanced halide anion affinities. In some cases,
these enhancements were as high as ca. 209 and 2,0009
relative to 1 for bromide and chloride, respectively, as
inferred from the corresponding Ka(Cl) and Ka(Br) values
derived from ITC measurements carried out in CH3CN [2].
More recently, it was shown that a pyrrole strapped
calix[4]pyrrole system could be used to determine the
concentration of anions in a commercial sports drink [5],
Electronic supplementary material The online version of this
article (doi:10.1007/s10847-009-9645-3) contains supplementary
material, which is available to authorized users.
D. E. Gross Á D.-W. Yoon Á V. M. Lynch Á J. L. Sessler (&)
Department of Chemistry and Biochemistry, Institute for
Cellular and Molecular Biology, The University of Texas,
1 University Station-A5300, Austin, TX 78712-0165, USA
e-mail: sessler@mail.utexas.edu
C.-H. Lee
Department of Chemistry, Kangwon National University,
Chun-Chon 200-701, Korea
123

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J Incl Phenom Macrocycl Chem (2010) 66:81–85
and that, separately, a triazole strapped system was capable
of affecting the transport of anions across lipid bilayer
membranes [6]. Strapped calix[4]pyrroles have also proved
instrumental in defining the importance of CHÁÁÁanion
interactions in supramolecular chemistry. With this latter
consideration in mind, we previously reported the synthesis
of the strapped calix[4]pyrroles 2–4 and their chloride anion
binding properties [7]. Here, we extend our studies to
include other anions, specifically fluoride, bromide and
benzoate, and on this basis are able to confirm further the
correlation between the size and shape of an anion with the
affinity and selectivity of calix[4]pyrroles 1–4. We also
show that in the particular case of the fluoride anion and the
pyrrole strapped receptor 3, initial anion binding to the four
NH protons of the calix[4]pyrrole core is followed by
deprotonation of the strapping pyrrole NH proton.
a slightly different binding mode compared to what was
seen in the case of halide anion binding. Specifically, when
a slight excess of benzoate anion (ca. 1.4 equiv.) was added
to a DMSO-d6 solution containing this receptor, the
calix[4]pyrrole NH signal originally present at 9.43 ppm
was split into two singlets, which were seen at 11.84 and
9.93 ppm, respectively. In the case of TBAOAc (ca. 4
equiv.), these same signals were seen at 11.54 and
11.32 ppm. While not a proof, these observations are con-
sistent with the intuitively reasonable notion that the bulky
benzoate anion binds asymmetrically to the calix[4]pyrrole
NH protons due to the limited size of the binding cavity.
In the course of studying the interaction of fluoride with
strapped calix[4]pyrrole 3 via NMR spectroscopy, a dis-
appearance of one set of signals (corresponding to free host,
3) was noted, along with the appearance of a new set of
signals (3ÁF- two doublets at 15.20 ppm (J = 50 Hz) and
12.20 ppm (J = 33 Hz) see Table 1) as up to one equiva-
lent of fluoride anion was added. These observations are
consistent with a strong 1:1 binding interaction and the
inclusion of fluoride within the cavity of the pyrrole strap-
ped calix[4]pyrrole 3. However, the subsequent addition of
excess fluoride anion produced a completely new set of
signals, including a doublet at 13.1 ppm (J = 43 Hz),
ascribed to the calix[4]pyrrole NH resonance, as well as a
triplet at 16.01 ppm (J = 120 Hz) diagnostic of the [F–H–
F]- anion [8]. We rationalize these findings in terms of
deprotonation of the strapping pyrrole subunit in the pres-
ence of excess fluoride anion. Such an interpretation is
consistent with the enhanced acidity expected for the pyr-
role within the strap due to the electron withdrawing esters
used to tether it to the rest of the receptor [9, 10].
O
O
N
H
O
O
NH
HN
H
N
H
H
N
N
N
H
N
H
1
2
O
O
O
O
O
N
H
O
O
O
O
Given the above findings, an attempt was then made to
quantify the binding of fluoride anion to strapped system 3
using ITC (isothermal titration calorimetry) in acetonitrile.
As expected, plots consistent with an exothermic, two-step
process were obtained (see Fig. 1). This result, which
unfortunately could not be interpreted to obtain quantitative
equilibrium values (i.e., Ka’s), nevertheless supports the
conclusion that anion binding to the calix[4]pyrrole core
takes place initially followed by deprotonation of the pyr-
rolic NH strap proton as proposed on the basis of the NMR
spectroscopic analyses (vide supra). Such aputative two-step
process was not evident in the case of the other calixpyrrole
receptors of this study (for any of the test anions) or when 3
was either treated with chloride, as shown in previous work,
or with benzoate and bromide, as detailed further below.
A single crystal suitable for X-ray diffraction analysis
was grown by treating receptor 3 with an excess of TBAF in
CH2Cl2 and layering with CH3OH. The resulting structural
analysis revealed the formation of the fluoride anion inclu-
sion complex 3ÁF-Á2CH3OH (see Fig. 2). In this 1:1 anion–
receptor complex, the calix[4]pyrrole was found to exist in
H
H
H
H
N
N
N
N
N
H
N
N
H
N
H
H
3
4
Results and discussion
Initially, NMR spectroscopy was used to study the binding
of fluoride, bromide and benzoate to receptors 3–4 (see
Table 1). Downfield shifts of the pyrrolic NH proton signals
were seen upon the addition of these anions (as the corre-
sponding tetra-n-butylammonium (TBA) salts in acetoni-
trile-d3 and dimethylsulfoxide-d6). Unfortunately, as with
the previous chloride studies [7], these anions displayed
slow association/dissociation kinetics with compound 3.
This precluded an accurate measurement of Ka values.
Nevertheless, structural insights could be inferred in the
case of the non-spherical, benzoate anion, which displayed
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J Incl Phenom Macrocycl Chem (2010) 66:81–85
83
Table 1 Selected proton chemical shifts (ppm) for strapped calix[4]pyrroles 3 and 4, and their respective anion complexes as recorded in
DMSO-d6
Strap NH
CP NH
Strap b-H
CP b-H
3a
11.58
9.43
6.93
5.76, 5.74
3ÁFb 3ÁF(-H)c
3ÁCld
3ÁBre
3ÁOBzf
3ÁOAcg
4h
15.20(16.09)
12.20(13.21)
10.92
6.93(6.48)
6.93
5.51, 5.49 (5.34, 5.31)
5.48, 5.45
12.87
12.81
10.48
6.89
5.48, 5.45
16.03
11.84, 9.93
11.54, 11.32
9.39
6.72
5.54, 5.49, 5.45, 5.39
5.50, 5.44, 5.40, 5.35
5.71, 5.69
15.97
6.80
–
–
–
–
–
7.42
4ÁFi
13.03
7.36
5.38, 5.36
4ÁClj
11.47
7.28
5.41, 5.39
4ÁBrk
4ÁOBzl
a
9.44
7.38
5.63
10.08
7.33
5.61, 5.59
Concentration of 3 = 9.0 mM; b 1.12 equiv. of TBAF; c 5.59 equiv. of TBAF; d 1.46 equiv. of TBACl; e 1.29 equiv. of TBABr; f 1.38 equiv.
g
of TBAOBz; 3.91 equiv. of TBAOAc; Concentration of 4 = 11.4 mM; 1.22 equiv. of TBAF; 1.12 equiv. of TBACl; 3.44 equiv. of
h
i
j
k
l
TBABr; 4.01 equiv. of TBAOBz
O–HMeOHÁÁÁF- = 1.679 A). Such a bridging interaction
˚
stands in marked contrast to what is seen in the case of the
chloride anion complex of 3, whose structure was reported
earlier [7] and which is reproduced in Fig. 3 for the sake of
comparison. Presumably, this difference reflects the smaller
and more highly solvated nature of the fluoride anion, which
makes it less able to bind fully within the pentaaza cavity of
3 without inducing an energetically unfavorable distortion
in the receptor structure, at least in the absence of an
ancillary donor group (methanol in the present instance).
Unfortunately, efforts to obtain diffraction grade crystals
under more forcing conditions, i.e., an excess of fluoride
anion that might favor deprotonation, proved unsuccessful.
Thus, we have no direct structural proof for the existence of
the species that we believe is produced at the end of the
NMR spectroscopic and ITC titrations.
As noted above, NMR spectroscopic titrations of 3 with
benzoate anion carried out in acetonitrile-d3 revealed slow
exchange kinetics. The same proved true for bromide anion
(both species were studied in the form of their respective
TBA salts). Thus, we turned to ITC as an alternative
method to determine the binding affinities of 3 for these
two species. We have previously shown that under appro-
priate conditions the Ka value for a 1:1 binding interaction
derived from NMR spectroscopy and ITC titration data is
Fig. 1 ITC plot of the interaction of 3 [1.08 mM] with TBAF
[0.094 mM] in acetonitrile
comparable [12]. In the case of 3, the ITC analyses in
acetonitrile were ‘‘clean’’ and the resulting data fit well to a
1:1 binding profile. This allowed Ka values of 4.5 9 105
M-1 and 7.9 9 105 M-1 to be derived for bromide and
benzoate, respectively (cf. Table 2).
the cone conformation with four NH hydrogen bonds
interacting with the fluoride anion (1.817, 1.932, 2.024,
˚
2.067 A). However, it also revealed that the strapped pyr-
rolic NH was neither deprotonated nor directly bound to the
fluoride anion. Rather, this particular donor site was found to
interact with a molecule of methanol, which in turn was
In the context of these studies, we were also able to
obtain the previously elusive affinity of 2 for bromide
(Ka = 2.1 9 103 M-1 in acetonitrile; Table 2) by
increasing the titration concentration. This bromide anion
˚
bound to the fluoride anion (N–HÁÁÁOMeOH = 1.990 A,
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J Incl Phenom Macrocycl Chem (2010) 66:81–85
Fig. 2 Front (left) and side
(right) views of the single
crystal X-ray structure of the
anion complex 3ÁF-Á2MeOH.
Displacement ellipsoids are
scaled to the 50% probability
level. Structure deposited to The
Cambridge Crystallographic
Data Centre (CCDC-737942).
These data can be obtained free
of charge via
www.ccdc.cam.ac.uk/
data_request/cif
Fig. 3 Front (left) and side
(right) views of the single
crystal X-ray structure of the
anion complex 3ÁCl- (right).
Displacement ellipsoids are
scaled to the 50% probability
level. This structure was
originally published in ref. [7]
affinity is notable in that it is more than 2 orders of mag-
nitude lower than that recorded for 3 under identical con-
ditions. Presumably, this reflects entropy and enthalpy
terms for 3 that are more favorable.1 This relative
enhancement in favor of 3 over 2 was extended to benzoate
anion as well, as can seen by an inspection of Table 2.
In contrast to what was seen in the case of 3, NMR
spectroscopic investigations of the anion binding behavior
of receptor 4 revealed that the system was under fast
exchange in the case of bromide and benzoate; therefore,
association constants could be determined by standard
curve fitting methods. Specifically, by following the shift in
the furanyl protons as a function of anion concentration and
using Wilcox’s 1:1 binding profile [11] (this reference first
appears in a footnote to Table 2) we determined the
binding constants for bromide (KBr = 54 M-1) and ben-
zoate (KOBz = 46 M-1; see Table 2) in acetonitrile.
Table 2 Thermodynamic data for the interaction of calix[4]pyrroles
1-4 with chloride, bromide, and benzoate anions
Guest
Cl-a
Host
TDS
DH
DG
Ka (M-1
)
Ka/Kdfuran
1
-2.9
-1.9
-1.4
-1.7
–
-10.2
-10.5
-11.3
-8.9
–
-7.3
-8.6
-9.9
-7.2
–
2.2 9 105
2.2 9 106
1.8 9 107
1.9 9 105
3.4 9 103
2.1 9 103
4.5 9 105
5.4 9 101
1.4 9 105
1.1 9 103
7.9 9 105
4.6 9 101
1.2
2
12
95
3
4
1b
1
Br-
63
2
-2.9
-7.4
-7.2
–
-4.5
-7.7
–
39
3
4c
0.48
8,333
1
–
BzO-
1
-4.4
-3.3
-4.5
–
-11.4
-7.4
-12.6
–
-7.0
-4.2
-8.0
–
3,043
24
2
3
4c
17,179
1
Units of TDS, DH, and DG are (kcal mol-1); titrations were run at
25 °C in acetonitrile, and the anions were used in the form of their
respective tetrabutylammonium (TBA) salts
With the binding data for 4 in hand, the selectivity ratios
for chloride/bromide and chloride/benzoate could be ana-
lyzed across the series of receptors 1–4. Specifically, from
the data included in Table 2, chloride/bromide selectiv-
ity ratios, KCl/KBr, of 64, 1048, 40, and 3518 could be
a
b
c
From reference [7]; From reference [2] at 30 °C; Derived from
NMR spectroscopic titrations using standard curve fitting procedures
[11]; d Ka/Kfuran is the affinity enhancement ratio relative to the furan-
strapped system 4
1
In fact, the interaction of calixpyrrole 3 with TBABr actually has a
calculated for compounds 1–4, respectively. All three
strapped systems 2–4 also proved selective for chloride over
benzoate, with this selectivity being especially apparent in
favorable TDS; while further analysis is required, this finding could
reflect a solvation energy for bromide anion that is relatively small as
compared to that of other anions considered in this study.
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J Incl Phenom Macrocycl Chem (2010) 66:81–85
85
Acknowledgements This work was supported by the National
Institutes of Health (grant GM 58907 to J.L.S.) and the Korea
Research Foundation (C00477).
the case of compounds 2 and 4. Interestingly, the preference
for chloride anion seen in the three strapped systems stands
in contrast to what is observed in the case of the parent
calixpyrrole 1, where the affinities for chloride and benzoate
are essentially the same, i.e., 1.4 and 2.2 9 105 M-1
,
respectively. We ascribe this difference between the parent
calix[4]pyrrole 1 and the modified systems 2–4 to the better
preorganization of the strapped calix[4]pyrroles. These lat-
ter are characterized by a less flexible binding pocket, which
allows them to able to accommodate better the small,
spherical chloride anion than the larger benzoate anion. The
detailed NMR spectroscopic studies carried out in the
case of 3 (vide supra) are fully consistent with such an
interpretation.
References
1. Yoon, D.-W., Hwang, H., Lee, C.-H.: Synthesis of a strapped
calix[4]pyrrole: structure and anion binding properties. Angew.
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2. Lee, C.-H., Na, H.-K., Yoon, D.-W., Won, D.-H., Cho, W.-S.,
Lynch, V.M., Shevchuk, S.V., Sessler, J.L.: Single side strapping:
a new approach to fine tuning the anion recognition properties of
calix[4]pyrroles. J. Am. Chem. Soc. 125, 7301–7306 (2003)
3. Lee, C.H., Lee, J.S., Na, H.K., Yoon, D.W., Miyaji, H., Cho,
W.S., Sessler, J.L.: Cis- and trans-Strapped calix[4]pyrroles
bearing phthalamide linkers: synthesis and anion-binding prop-
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4. Lee, C.-H., Miyaji, H., Yoon, D.-W., Sessler, J.L.: Strapped and
other topographically nonplanar calixpyrrole analogues.
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Conclusion
In previous studies, we were able to show that an order of
magnitude increase in the chloride affinity relative to that of
the unfunctionalized parent calix[4]pyrrole system 1 could
be attained by using strap that contained a putative CH
donor site (i.e., by switching to receptor 2). Conversely, we
were able to show that the furan equivalent 4, a ‘‘negative
control,’’ displayed a lower chloride anion affinity relative
to both the phenyl-strapped receptor 2 and its pyrrole-con-
taining congener 3 by ca. 1 and 2 orders of magnitude,
respectively. In the present work, we have extended these
studies to other representative anionic guests and have found
that the affinities of both bromide and benzoate anions are
enhanced in the phenyl- and pyrrole-strapped systems 2 and
3 relative to the furan-containing control 4, but not relative
to simple meso-octamethylcalix[4]pyrrole 1. Finally, in the
case of the pyrrole-strapped system 3, but not the phenyl or
furan analogues 2 and 4, the interaction with fluoride was
found to be a two-step process, as inferred from ITC and
NMR spectroscopic measurements. Based on an analysis of
the NMR spectroscopic data recorded in acetonitrile-d3, this
two-step process is ascribed to anion binding followed by
deprotonation. On the other hand, solid state structural data,
obtained using a single crystal grown in the absence of
excess fluoride anion, revealed ‘‘standard’’ binding of the
fluoride anion by the calix[4]pyrrole core (i.e., four
N–HÁÁÁF- hydrogen bonds) complemented by a bridging
solvent interaction involving the strapped pyrrole NH
proton.
12. Sessler, J.L., Gross, D.E., Cho, W.-S., Lynch, V.M., Schmidt-
chen, F.P., Bates, G.W., Light, M.E., Gale, P.A.: Calix[4]pyrrole
as a chloride anion receptor: solvent and countercation effects.
J. Am. Chem. Soc. 128, 12281–12288 (2006)
123