Small triiminopyrrolic molecular cage with high affinity and selectivity for fluoride

Article abstract of DOI:10.1039/c9cc05613k

A small molecular cage (4) with high affinity and complete selectivity for fluoride to the limit of detection over other competing small anions was synthesized. Cage 4 was also found to retain the encapsulated fluoride anion within its cavity even after o

Full text of DOI:10.1039/c9cc05613k

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Small triiminopyrrolic molecular cage with high affinity and
selectivity for fluoride
Hye Jin Han,a Ju Hyun Oh,a Jonathan L. Sessler*,b and Sung Kuk Kim*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
selectivity.12,13 In contrast, molecular cage
3, possessing both
A small molecular cage (4) with high affinity and complete
selectivity for fluoride to the limit of detection over other
competing small anions was synthesized. Cage 4 was also found to
retain the encapsulated fluoride anion within its cavity even after
one or two pyrrolic NH protons were subject to deprotonation.
hydrogen bonding donor and acceptor sites, was found to bind
tetrahedral oxyanions as well as spherical halide anions with
significantly enhanced affinity, albeit without appreciable
selectivity.14 Based on these prior advances, we designed and
synthesized the relatively small molecular cage (
contains three iminopyrrole groups and was designed to act as
a structurally contracted analogue of cage . As described in
4 4
).11 Cage
The fluoride anion plays important roles in a range of
environmental, biological, and chemical processes and is the
subject of policy debates involving public health and medicine.
Not surprisingly, therefore, this small, Lewis basic species has
become a special target for selective anion receptor design.1-3
Although numerous efforts have been devoted to the
development of anion receptors with high affinity and
selectivity for the fluoride anion,4-6 few anion receptors have
been reported that demonstrate exclusive selectivity,
especially, in the presence of other competing anions.7 The
design of such a receptor is particularly challenging because of
the small size, high charge density of fluoride, and exceptional
Lewis basicity of the fluoride anion. To achieve high affinity and
selectivity for the fluoride anion, we believe that good size
matching between the receptor and the anion, as well as a high
degree of spatial preorganization is essential. Structural rigidity
and an appropriate geometry of the receptor are likewise
expected to be critical design elements if better anion selectivity
is to be achieved.8 In this vein, cage-like molecules have
attracted increasing attention as supramolecular hosts; many
have proved effective in forming strong and selective complexes
with guests, presumably as the result of encapsulating them
within the essentially shielded cavities.9-11 For instance, tripodal
3
detail below, this new system was found to bind the fluoride
anion via hydrogen bonding interactions with high affinity and
complete selectivity in chloroform as well as in relatively polar
solvent, DMSO, as inferred from 1H NMR, and 19F NMR
spectroscopic analyses. A combination of 1H and 19F NMR
spectral data also provides support for the conclusion that the
mono- and doubly deprotonated forms of cage 4, obtained by
treatment with an excess of tetrabutylammonium fluoride (e.g.,
>1.66 equiv.), were able to bind the fluoride anion, presumably
as the result of residual NH-F– hydrogen bonding interactions.
The synthesis of cage
trispyrrolic benzene derivative
4
is shown in Scheme 1. Briefly, the
was synthesized by means of
5
an electrophilic substitution reaction involving pyrrole and
1,3,5-tribromomethyl-2,4,6-triethylbenzene carried out in the
presence of K2CO3 as a base.15 Subsequently, the pyrrole groups
receptors 1 and 2 were reported to recognize halide anions and
oxyanions, respectively, but with relatively low affinity and
of compound
using DMF and POCl3 to give compound
groups of were condensed with the 1,3,5-triaminomethyl-
2,4,6-triethylbenzene to give the [1 + 1] molecular cage in
essentially quantitative yield. The structure of cage was
confirmed by standard spectroscopic means, including H and
5
were subject to Vilsmeier-Haack formylation
6. Finally, the formyl
6
a. Department of Chemistry and Research Institute of Natural Science, Gyeongsang
National University, Jinju, 660-701, Korea. E-mail: sungkukkim@gnu.ac.kr
b. Department of Chemistry, The University of Texas at Austin, 105 E. 24th, Street-
Stop A5300, Austin, Texas 78712-1224. E-mail: sessler@cm.utexas.edu
†Electronic Supplementary Information (ESI) available: Synthetic details, 1H, 19F, and
13C NMR spectroscopic data, and UV/Vis spectroscopic data. See
DOI: 10.1039/x0xx00000x
4
4
1
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13C NMR spectroscopy and high resolution mass spectrometry proton signals were again visible for all observable protons in
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(HRMS).
the 1H NMR spectra recorded before satuDraOtIi:o1n0.w10a3s9/aCt9tCaiCn0e5d61(3aKt
ca. 1.01 equiv. of TBAF; Figure 1). Indeed, the spectral changes
matched those seen when
4 was titrated with TBAF in the
absence of any potential competing anions (Figure S3). The
binding constant (Ka) corresponding to the interaction of cage
4
1
with the fluoride anion was approximated from this H NMR
spectroscopic titration to be >10,000 M-1 even when the various
potentially competing anions were present in the solution.16
Scheme 1. Synthesis of cage 4
Initial studies involving the anion recognition features of cage
4
were carried out in CDCl3 and DMSO-d6 solution by means of
1H NMR spectroscopy. In CDCl3, the 1H NMR spectrum of cage
4
in its as-prepared form is characterized by one singlet at δ = 7.70
and a pair of doublets at δ = 6.61 ppm and 6.11 ppm
corresponding to the imine CH and the pyrrolic CH proton
resonances, respectively (Figures S1 and S2). In analogy to what
was seen with cage
3
, the proton signal of the pyrrolic NH
1
protons were not seen in the H NMR spectrum in CDCl3, a
finding attributed to peak broadening by intra- or inter-
molecular hydrogen bonding interactions (Figure S1). When
Figure 1. Partial 1H NMR spectra recorded during the titration of cage 4 (3 mM) with TBAF
(tetrabutylammonium fluoride) in the presence of TBACl, TBABr, TBAI, and (TBA)2SO4
(>10 equiv. each) in CDCl3.
cage
4
was exposed to a variety of anions including F–, Cl–, Br–,
I–, HCO3 , SO4
,
H2PO4 , and HP2O7
(as the
–
2–
–
3–
–
tetraethylammonium (TEA) salt for HCO3 and the
tetrabutylammonium (TBA+) salts for all other anions), only
fluoride produced an appreciable change in H NMR spectrum
(Figures S1). The F–-induced spectral changes (discussed in
1
In marked contrast to what was seen in CDCl3, the H NMR
spectrum of cage
this relatively polar solvent, sharp and split signals were seen for
all the protons of cage , even the NH protons (Figures 2 and
S4). This finding leads us to suggest that the DMSO solvent
interacts with cage so as to retard conformational motion of
the cage on the NMR time scale. As a result, ostensibly
equivalent protons are placed in different magnetic
environments giving rise to different chemical shifts. In
contrast, the addition of fluoride produces a simplified 1H NMR
spectrum analogous to that recorded in CDCl3 (cf. Figures 2 and
S1). We interpret this finding in terms of the fluoride anion
being bound within the middle of the cavity leading to a system
that is both symmetric and conformationally locked on the NMR
time scale. These changes occur in a concentration dependent
4 measured in DMSO-d6 proved complex. In
1
4
detail below) proved similar to those seen in the case of
3
. We
thus suggest that cage
4 binds fluoride with complete selectivity
4
over other test anions, at least to the limits of 1H NMR spectral
detection. This binding behaviour stands in sharp contrast to
what was seen with tripodal receptors
1 and 2 and cage 3 that
lacked selectivity for specific anions.12-14 We ascribe the evident
selectivity for fluoride to the increased rigidity and contracted
cavity size of cage
4 relative to 3.
1
When cage was subjected to an H NMR spectral titration
4
with TBAF in chloroform-d1, two sets of distinct resonances
were seen for proton signals of the pyrrolic CHs, the imine CHs,
and the methylene CHs bonded to the imine nitrogen atoms
before saturation was reached upon the addition of ≈1 equiv. of
fluoride (Figure S3). These peaks are derived from the anion-
fashion. Specifically, when cage
4 was titrated with TBAF in
DMSO, a new set of readily discernible proton signals begin to
appear in 1H NMR spectra while the original proton signals
free form and the fluoride complex of cage
4, respectively. Such
corresponding to anion-free cage
4 gradually disappear before
a
finding is consistent with the suggestion that the
saturation occurs upon the addition of ca. 1.20 equiv. of TBAF.
The presence of signals for both the anion-bound and free
binding/release equilibrium between cage 4 and fluoride is slow
on the 1H NMR time scale. Although not a proof, in our
experience such slow exchange kinetics are characteristic of
strong anion binding in the case of pyrrole-based receptors.
Further support for the proposed high affinity and selectivity
receptor forms of
4 seen at intermediate fluoride anion
concentrations is, as above, taken as evidence for a strong
binding interaction. Further support for the strong fluoride
binding by cage
4 came from the observations that the NH
for fluoride displayed by of cage 4
came from a 1H NMR spectral
titration experiment carried out in CDCl3 in the presence of an
excess of various other competitive anions (>10 equiv. for each
anion). Upon subjecting cage 4 to titration with TBAF in CDCl3 in
the presence of Cl–, Br–, I–, and SO42–, two separate sets of
proton signals appear to be downfield-shifted with splitting into
doublet (J = 54.6 Hz) as the result of coupling between the NH
protons and the bound fluoride anion (Figure 2).7,9 H-F coupling
was also seen in the corresponding 19F NMR spectrum (Figure
3). For example, in the presence of the fluoride anion, a fluoride
2 | J. Name., 2012, 00, 1-3
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resonance at δ = -97.52 ppm is seen. This signal appears in the
COMMUNICATION
After allowing a sample of cage
4
to stand overnight in the
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DOI: 10.1039/C9CC05613K
form of an apparent quartet (J = 55.6 ppm) as a result of the presence of 6.0 equiv of fluoride in DMSO-d6, a new triplet
coupling between the bound fluoride and the three pyrrolic NH signal at δ = -98.3 ppm was observed in the 19F NMR spectrum.
protons (Figure 3). This finding lends credence to the notion that This peak appears at slightly higher field (Δδ = 0.78 ppm) than
the fluoride anion sits in the middle of cage 4
and is bound with the original quartet seen in the presence of ca. 1 equiv of F–
a 1:1 stoichiometry, as would be inferred from the ca. 1.2 equiv. (Figure 4). Based on the inferred coupling to two protons (giving
1
needed to produce saturation in the H NMR spectral titration rise to the observed triplet) and the chemical shift value, this
discussed above.
new signal is ascribed to a cage complex wherein a fluoride
anion is bound within the cavity of a mono-deprotonated form
1
of cage
proton signals of [
downfield-shifted doublet. This signal is distinct from that
ascribed to the neutral fluoride-bound complex of cage
(Figures 2 and 4). Such findings lead us to suggest that, after
deprotonation, cage is still able to encapsulate the fluoride via
4
([
4
- H+]). In the H NMR spectrum, the pyrrolic NH
4
- H+]•F– appear in the form of slightly
4
4
strong hydrogen bonds as shown schematically in Figure 5.
Figure 2. 1H NMR spectra recorded during the titration of cage 4 (3 mM) with TBAF in
DMSO-d6.
Figure 4. Partial 1H (left) and 19F (right) NMR spectra of cage 4 (27 mM) recoreded (a)
with 1.0 equiv. of TBAF in DMSO-d6, (b) with 6.0 equiv. of TBAF in DMSO-d6, and (c) after
adding 10% water to (b). NMR spectra were recorded after the samples were allowed to
stand overnight at room temperature. Fluorobenzene was used as an internal reference.
Figure 5. Proposed binding interactions between various forms of cage 4 and the fluoride
anion as inferred from 1H and 19F NMR spectral studies.
Figure 3. Partial 19F NMR spectra recorded during the titration of 4 (27 mM) with TBAF
in DMSO-d6. Fluorobenzene (C6H5F, 16.2 mM) was used as an internal reference.
Further treatment with fluoride anion led to the production
of a new signal, a doublet at δ = -99.2 ppm, in the 19F NMR
spectrum that is distinct from the quartet and the triplet signals
ascribed to the fluoride anion complexes of the neutral and
Adding quantities of fluoride to cage 4 beyond those needed
to achieve saturation of the CH signals in the 1H NMR spectrum
recorded in DMSO-d6 (ca. 1.2 equiv.; vide supra) leads to the
appearance of a new signal in the range of 15.5-16.5 ppm. This
new resonance appears in the form of a triplet with a large
coupling constant (J = 121 Hz) and its relative integration
increases as a function of fluoride anion concentration (Figure
2). This triplet peak is attributable to the formation of the
mono-deprotonated forms of
is ascribed to the formation of a fluoride anion bound complex
involving a doubly deprotonated species ([
- 2H+]) as shown
schematically in Figure 5. To the extent this interpretation of the
19F-1H splitting is valid, it leads to the inference that cage
is
4 (Figure 4(b)). Again, this finding
4
4
able to bind the fluoride anion even after loss of two pyrrolic NH
protons and the formation of a formally dianionic cage species.
This, in turn, implies that the specific structure of cage 4, as well
–
bifluoride anion (HF2 ) as the result of pyrrole NH deprotonation
–
by the Lewis basic fluoride anion. A signal corresponding to HF2
at δ = -144 ppm is also seen in the 19F NMR spectrum (Figure 3).
as hydrogen bonding, plays a crucial role in fluoride anion
binding. In contrast, the addition of water (10%) to solutions of
1
[
4
- H+]•F– or [
4
- 2H+]•F– gave rise to similar H NMR and 19F
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NMR spectra as those of 4
•F– (Figure 4(c)). This is consistent
with the deprotonated pyrrolic subunits being re-protonated in
the presence of water.
2
3
(a) Kirk, L. K. Biochemistry of the Halogens and Inorganic
Halides; Plenom Press: New York, 1991. (b) KleeVrieewkoAprtieclre,OMnl.ine
DOI: 10.1039/C9CC05613K
Endocrinol. Metab. Clin. North Am. 1998, 27, 441-452. (c)
Briancon, D. Rev. Rhum. 1997, 64, 78-81.
The binding affinity of cage
quantified by UV/Vis spectroscopic analyses. Cage
free form exhibits two absorption peaks at 310 nm and 360 nm,
respectively (Figure S8). When cage was exposed to increasing
4
for fluoride in DMSO was
(a) Michigami, Y.; Kuroda, Y.; Ueda, K.; Yamamoto, Y. Anal.
Chim. Acta. 1993, 274, 299-302 (b) Grandjean, P.; Landrigan,
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S.; Kharb, S. Bio. Trace Elem. Res. 2011, 144, 1–5.
4
in its ion-
4
amounts of fluoride, the absorption band at 360 nm undergoes
a gradual hypochromic shift and then reaches saturation quickly
(Figure S8). By fitting the UV/Vis spectroscopic titration data to
a standard 1:1 binding profile, an association constant (Ka) of
1.01 × 107 M-1 could be derived.18 This value is significantly
higher than the corresponding values recorded for receptors 1-
3
(Ka < 5 M-1 for
1
and
).12-14 This marked difference is ascribed to the well-
, as well as a cavity
2 3
vs Ka = 1.57 × 106 M-1 for vs 1.01 × 107
4
5
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M-1 for
4
defined and preorganized structure of cage
4
size that is presumably nearly optimal for fluoride anion
encapsulation.
6
Conclusions
7
In conclusion, a molecular cage (4) possessing a small, rigid
cavity was synthesized in high yield via a [1 + 1] condensation
reaction involving 1,3,5-triaminomethyl benzene and an α-
formylated-1,3,5-tripyrrolyl benzene. 1H NMR and UV/Vis
spectroscopic analyses provided support for the conclusion that
cage 4 is capable of binding the fluoride anion with high affinity
and selectivity in chloroform and DMSO. 1H and 19F NMR
spectroscopic studies proved consistent with the suggestion
8
9
that cage 4 is able to encapsulate the fluoride anion not only in
its neutral form, but also after being subject to mono- and even
double deprotonation. The present work thus serves to
highlight the importance of structural design in the creation of
systems that are capable of capture specific anions with both
high affinity and selectivity.
Acknowledgment. This work was supported by the National
Research Foundation of Korea (NRF) grant funded by the Korea
10 Lopez, N.; Graham, D. J.; McGuire Jr. R.; Alliger, G. E.; Shao-
Horn, Y.; Cummins, C. C.; Nocera, D. G. Science 2012, 335,
450-453.
11 Liu, Y.; Zhao, W.; Chen, C.-H.; Flood, A. H. Science 2019, 365,
159-161.
12 Hong, S,-J,; Yoo, J.; Jeong, S.-D.; Lee, C.-H. J. Incl. Phenom.
Macrocycl. Chem. 2010, 66, 209-212.
13 Bill, N. L.; Kim, D.-S.; Kim, S. K.; Park, J. K.; Lynch, V. M.;
Young, N. J.; Hay, B. P.; Yang, Y.; Anslyn, E. V.; Sessler, J. L.
Supramol. Chem. 2012, 24, 72-76.
government
(MSIT)
(NRF-2019R1F1A1061780
and
2017R1A4A1014595 to S.K.K.). The work in Austin was
supported by the U.S. Department of Energy, Office of Basic
Energy Sciences (DE-FG02-01ER15186 to J.L.S.) and the Robert
A. Welch Foundation (F-0018 to J.L.S.).
14 Oh, J. H.; Kim, J. H.; Kim, D. S.; Han, H. J.; Lynch, V. M.;
Sessler, J. L.; Kim. S. K. Org. Lett. 2019, 21, 4336-4339.
15 Cacciarinim, M.; Nativi, C.; Norcini, M.; Staderini, S.;
Francesconi, O.; Roelens, S. Org. Biomol. Chem. 2011, 9,
1085-1091.
Conflicts of interest
There are no conflicts to declare.
16 Approximate binding constant from: Connors, K, A. Binding
Constants: The Measurement of Molecular Complex Stability;
Wiley-Interscience: New York, 1987.
17 Yin, Y.; Sarma, T.; Wang, F.; Yuan, M.; Duan, Z.; Sessler, J. L.;
Zhang, Z. Org. Lett. 2019, 21, 1849-1852.
18 The Ka value was approximated using BindFit v5.0 available
from URL: “http://app.supramolecular.org/bindfit/”.
Notes and references
1
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Elder, R. Can. Hist. Rev. 2008, 89, 345-371. (d) Connet, P.
Fluoride 2007, 40, 155-158. (e) Foulkes, R. G. Fluoride 2007,
40, 229-237. (f) Carton, R. J. Fluoride 2006, 39, 163-172.
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