Capture and displacement-based release of the bicarbonate anion by calix[4]pyrroles with small rigid straps

Abstract

Two-phenoxy walled calix[4]pyrroles 1 and 2 strapped with small rigid linkers containing pyridine and benzene, respectively, have been synthesized. ¹H NMR spectroscopic analyses carried out in CDCl₃ revealed that both of receptors 1 and 2 recognize only F⁻ and HCO₃⁻ among various test anions with high preference for HCO₃⁻ (as the tetraethylammonium, TEA⁺ salt) relative to F⁻ (as the TBA⁺ salt). The bound HCO₃⁻ anion was completely released out of the receptors upon the addition of F⁻ (as the tetrabutylammonium, TBA⁺ salt) as a result of significantly enhanced affinities and selectivities of the receptors for F⁻ once converted to the TEAHCO₃ complexes. Consequently, relatively stable TEAF complexes of receptors 1 and 2 were formed via anion metathesis occurring within the receptor cavities. By contrast, the direct addition of TEAF to receptors 1 and 2 produces different complexation products initially, although eventually the same TEAF complexes are produced as via sequential TEAHCO₃ and TBAF addition. These findings are rationalized in terms of the formation of different ion pair complexes involving interactions both inside and outside of the core receptor framework.

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Introduction

An increasing appreciation of the role played by anions in a variety of biological and environmental systems, as well as a number of industrial processes, has made a variety of anions specific targets for selective recognition.^1–3 Among such anions, small, basic anions such as the bicarbonate anion (HCO₃⁻) and the fluoride anion (F⁻) have recently drawn particular attention. For example, the bicarbonate anion plays a critical role in physiological pH buffering and signal transduction in the human central nerve system as well as in triggering certain intracellular events.^4,5 In addition, the bicarbonate anion is an essential element in the natural carbon cycle in which the bicarbonate anion largely generated from gaseous CO₂ from the atmosphere acts as a key component in regulating and maintaining the pH of aquatic environments; it is thus necessary for a wide range of living organisms to survive.⁶ On the other hand, the fluoride anion plays a role in public health and is key to a number of chemical processes.^7–9 In spite of their importance, only a handful of anion receptors capable of recognizing these basic anions with near-complete selectivity have been reported.^10–13 Moreover, to our knowledge no receptors are known whose selectivity and inherent affinity for these two specific anions, e.g., the bicarbonate and fluoride anion, can be reversed by ion pairing effects. Here we report the synthesis of bicarbonate-selective receptors and the reversal of their inherent selectivity through ion pairing. As detailed below, this allows the bicarbonate anion to be bound and then released by treating with an appropriately chosen fluoride anion salt.

The design of a receptor with high selectivity for relatively basic anions, such as the bicarbonate anion or the fluoride anion, is a recognized challenge in the anion binding community.^10–12 Good size matching between the receptor and the anion, as well as appropriate spatial preorganization and orientation of the anion binding motifs within the receptor are time-honoured approaches to achieving selectivity.^{1–3,10–13} Preorganized geometries and structural rigidity can also contribute to the preparation of receptors targeting specific anions.^{1–3,10–13} Finally, the presence of one or more auxiliary hydrogen bond donors or acceptors within the receptor framework can impart selectivity for oxoanions, such as bicarbonate, by supporting additional interactions with the anions.¹³ In aggregate, these design considerations lead us to suggest that calix[4]pyrrole, a tetrapyrrolic macrocyclic compound featuring sp³-hybridized meso-carbons, would be an attractive framework for preparing anion receptors selective for the bicarbonate anion or the fluoride anion. Calix[4]pyrroles are relatively easy to functionalize and modify synthetically.¹⁴ For instance, both the meso-carbon atoms and the β-pyrrolic carbon atoms of the calix[4]pyrrole skeleton can be substituted with various functional groups.¹⁴ A particularly appealing set of calix[4]pyrroles are the so-called strapped calix[4]pyrroles, wherein the two diagonally opposing meso carbons are linked by a tether that can be used to introduce functional groups or modulate the size and rigidity of the binding cavity.^14c,g For example, strapped calix[4]pyrroles bearing ancillary hydrogen bond donors on the strap show enhanced affinity for specific anions while those strapped with a small or rigid bridging element are selective for relatively small anions.^13–15 Taking this into consideration, we designed and synthesized the HCO₃⁻-selective anion receptors 1 and 2. These systems consist of a calix[4]pyrrole with small rigid straps that connect two diametrical phenol walls via pyridine and benzene linkers, respectively. As detailed below, receptors 1 and 2 in their ion free forms are able to recognize both the bicarbonate anion (as the TEA⁺ salt) and the fluoride anion (as the TBA⁺ salt) among various test anions in CDCl₃ with higher affinity being seen for the former anion. Counterintuitively, as compared with the ion-free forms of receptors 1 and 2, their HCO₃⁻ complexes were found to bind the fluoride anion (as the corresponding TBA⁺ salt) with remarkably enhanced affinity. As a result, the bound bicarbonate anion is released from receptors 1 and 2 upon the addition of the fluoride anion (as the TBA⁺ salt) via anion metathesis. In contrast, the direct addition of TEAF to receptors 1 and 2 produces different complexation products initially, although eventually the same TEAF complexes are produced as generated via sequential TEAHCO₃ and TBAF addition. These findings are explained in terms of ion pairing effects, which are operative both inside and outside of the receptor framework.

Results and discussion

Receptors 1 and 2 were prepared by following the synthetic procedure depicted in Scheme 1. In contrast to the general strategy adopted for the synthesis of a strapped calix[4]pyrrole, receptors 1 and 2 were synthesized by installing the strap units linking the diagonal meso carbons in the final step. Briefly, cis-diphenolic calix[4]pyrrole 3 was synthesized following a literature procedure via the [2 + 2] condensation reaction of a meso-phenol substituted dipyrromethane with acetone in the presence of BF₃·OEt₂ as a Lewis acid. It was separated from the reaction mixture, which also contains the corresponding trans-isomer, by column chromatography.¹⁶ Subsequently, compound 3 was subjected to reaction with 2,6-bis(bromomethyl)pyridine and 1,3-bis(bromomethyl)benzene in the presence of K₂CO₃ in acetonitrile to give the strapped calix[4]pyrroles 1 and 2, respectively. Receptors 1 and 2 were fully characterized by standard spectroscopic means, such as ¹H and ¹³C NMR spectroscopy and high resolution mass spectrometry (HRMS). The structure of receptor 1 was further confirmed by a single crystal X-ray diffraction analysis (Fig. 1). Single crystals of receptor 1 suitable for X-ray diffraction analysis were grown by subjecting a chloroform/methanol mixture containing receptor 1 to slow evaporation. The resulting crystal structure revealed that in the solid state the calix[4]pyrrole subunit of receptor 1 exists in the 1,3-alternate conformation with no solvent molecules found to interact with the receptor (Fig. 1).

Scheme 1 Synthesis of receptors 1 and 2.

Fig. 1 Two different views of the single X-ray crystal structure of receptor 1. Thermal ellipsoids are scaled to the 50% probability level. Most hydrogen atoms are omitted for clarity.

The ability of receptors 1 and 2 to bind certain anions was assessed initially by means of ¹H NMR spectroscopic studies carried out in CDCl₃. When the receptors were treated with various anions (>10 equiv.) including F⁻, Cl⁻, Br⁻, I⁻, HCO₃⁻, H₂PO₄⁻, HSO₄⁻, and SO₄²⁻, only the F⁻ and HCO₃⁻ anions caused the proton signals of receptors 1 and 2 to undergo chemical shift changes consistent with anion binding to the respective calix[4]pyrrole subunits (Fig. S1 and S2†). We thus infer that both receptors (1 and 2) bind F⁻ and HCO₃⁻ selectively over other anions (Fig. S1 and S2†). This presumed selectivity is attributed to the small cavity size and the rigidity of the straps within receptors 1 and 2. It is important to note that in these studies all anions other than bicarbonate were used in the form of their respective tetrabutylammonium (TBA⁺) salts. The TBA⁺ salt of bicarbonate is not commercially available and our attempts to prepare and purify it proved unsuccessful, perhaps as a consequence of facile Hofmann elimination. Thus, the tetraethylammonium (TEA⁺) salt of HCO₃⁻ was used in the present study.

In order to obtain further insights into the anion binding features of receptors 1 and 2, detailed ¹H NMR spectral titrations were performed with F⁻ (as its TBA⁺ salt) and HCO₃⁻ (as its TEA⁺ salt) in CDCl₃. For example, when receptor 1 was subjected to titration with F⁻ and HCO₃⁻, respectively, two sets of distinguishable signals were seen for the all observable protons in the ¹H NMR spectra before saturation was reached (at ca. 2.62 and ca. 2.06 equiv. for F⁻ and HCO₃⁻, respectively; Fig. S3 and S4†). These peaks are attributable to the anion-free and the anion-bound forms of receptor 1, respectively. This leads to the conclusion that the corresponding association/dissociation equilibria are slow on the ¹H NMR time scale, as typically seen for calix[4]pyrrole with high anion affinities. The presumed strong binding interactions between receptor 1 and F⁻ and HCO₃⁻ were further supported by the observation of anion-induced chemical shift changes in the proton signals of receptor 1. For instance, upon the exposure of receptor 1 to F⁻, the pyrrolic NH proton signal in the ¹H NMR spectrum initially appearing as a singlet at δ ≈ 6.83 ppm undergoes a remarkable downfield shift to δ ≈ 12.56 ppm (Δδ ≈ 5.73 ppm) and becomes split into a doublet (J = 44.6 Hz), as would be expected for a relatively symmetric system with ¹⁹F–¹H coupling (Fig. S3†). In contrast, addition of F⁻ causes the aromatic proton signals corresponding to the phenoxy walls (H_d) and β-pyrrolic protons (H_e) to move towards higher field (Δδ ≈ 0.13 ppm for H_d and Δδ ≈ 0.19 ppm for H_e, respectively) (Fig. S3†). Similar ¹H NMR spectral changes were seen when receptor 1 was titrated with HCO₃⁻, although a small quantity of HCO₃⁻ with respect to F⁻ was needed to achieve saturation (Fig. S4†). On the basis of these ¹H NMR spectral titrations, the binding constants (K_a) corresponding to the interaction of receptor 1 with F⁻ and HCO₃⁻ were calculated to be approximately 240 and 1440 M⁻¹, respectively (Table 1).¹⁷

Table 1 Binding constants (K_a, M⁻¹) corresponding to the interaction between receptors 1 and 2 and their TEAHCO₃ complexes and the fluoride and bicarbonate anions as determined in CDCl₃ at room temperature. The values were obtained by averaging K_a values calculated from ¹H NMR spectral titrations with the anion salts in question

Guest	Host
	1	2	1·TEAHCO3	2·TEAHCO3
TBAF	240	910	3330	5450
TEAF	380	980	340	430
TEAHCO3	1440	2300	—	—

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The relatively high selectivity of receptor 1 for HCO₃⁻ over F⁻ is attributed, in part, to the fact that the counter cation, TEA⁺, used in the case of HCO₃⁻ possesses a relatively high charge density with respect to the TBA⁺ cation employed in the case of F⁻. For the bicarbonate complex, the TEA⁺ cation was believed to be co-bound with the HCO₃⁻ anion and to reside in the cone-shaped electron rich calix[4]pyrrole pocket leading to formation a receptor-separated ion pair complex.¹⁸ This presumption was supported by the finding that the proton signals of the TEA⁺ counter cation underwent an appreciable upfield shift when receptor 1 was subject to titration with TEAHCO₃ (Fig. S4 and cf. Fig. S5†).

Further evidence for the proposed binding mode of receptor 1 with TEAHCO₃ came from a single crystal X-ray diffraction analysis (Fig. 2). Single crystals suitable for such analyses were grown by subjecting a chloroform/acetonitrile solution containing receptor 1 and an excess of TEAHCO₃ to slow evaporation. The resulting crystal structure revealed that one oxygen atom of the HCO₃⁻ anion forms hydrogen-bonds with all four NH protons of the calix[4]pyrrole unit at distances ranging from 2.74 and 2.95 Å (N⋯O interactions) (Fig. 2). As expected, the TEA⁺ cation is encapsulated by the electron rich calix[4]pyrrole cavity locked in the cone conformation presumably via electrostatic interactions (Fig. 2).

Fig. 2 Two different views of the single X-ray crystal structure of the TEAHCO₃ complex of receptor 1. Thermal ellipsoids are scaled to the 30% probability level. Most hydrogen atoms are omitted for clarity.

In analogy to what was seen with receptor 1, receptor 2 (capped with benzene in lieu of pyridine) is able to recognize F⁻ and HCO₃⁻via slow anion binding/release equilibria in CDCl₃ (Fig. 3 and S7†). The binding constants corresponding to the interaction of receptor 2 with F⁻ and HCO₃⁻ were estimated to be K_a = 910 M⁻¹ and K_a = 2300 M⁻¹, respectively (Table 1).¹⁷ These values were taken as an indication that receptor 2 is also selective for TEAHCO₃ over TBAF.

The relatively high K_a values seen for HCO₃⁻ and F⁻ in the case of receptor 2 as compared to receptor 1 are presumed to result from structural differences in the strap subunits. In the case of 1, electron repulsion between the bound anions and the nitrogen lone pair electrons of the pyridine strap would be expected. In contrast, in the case of receptor 2 and HCO₃⁻, an additional hydrogen bonding interaction between the anion and the aryl C–H proton (H_g) on the strap of receptor 2 should contribute to an enhancement in the binding affinity.¹⁹

In order to evaluate further the selectivity of receptors 1 and 2 for TEAHCO₃ relative to TBAF and vice versa, we also quantified their affinity for F⁻ in the presence of an excess quantity of HCO₃⁻ (as its TEA⁺ salt) by ¹H NMR spectroscopic titrations. For instance, when the TEAHCO₃ complex of receptor 2 (2·TEAHCO₃) was titrated with F⁻ (as its TBA⁺ salt) in CDCl₃, all proton signals corresponding to the complex of 2·TEAHCO₃ gradually disappeared in the ¹H NMR spectrum giving rise, at the same time, to a new set of proton resonances consistent with the F⁻ complex of receptor 2 (Fig. 4 and S8†). These findings lead us to suggest that under these conditions the bound HCO₃⁻ anion is released from receptor 2 and replaced by the added F⁻ anion via a slow exchange equilibrium to produce the corresponding 2·TEAF complex in quantitative yield. The K_a value corresponding to the binding of F⁻ to the preformed TEAHCO₃ complex of receptor 2 was enhanced by 6-fold and calculated to be ca. 5450 M⁻¹ in CDCl₃, which is remarkably high compared with what was seen when TBAF was added directly to 2 in its ion-free form (vide supra and Table 1).¹⁷ In a similar way, the HCO₃⁻ anion complexed with receptor 1 was also readily released from the receptor cavity upon the addition of the F⁻ anion with attendant formation of the corresponding TEAF complex (1·TEAF). Again, this finding leads us to suggest that the preformed TEAHCO₃ complex (1·TEAHCO₃) is able to bind the F⁻ anion with a 14-fold enhanced affinity relative to the corresponding ion free form (Fig. S9† and Table 1).

Fig. 3 Partial ¹H NMR spectra recorded during the titration of 2 (3 mM) with tetrabutylammonium fluoride (TBAF) in CDCl₃. *Denotes the residual CHCl₃ peak from the NMR solvent.

Fig. 4 Partial ¹H NMR spectra recorded during the titration of the TEAHCO₃ complex of receptor 2 (2·TEAHCO₃, 3 mM) with TBAF in CDCl₃. The spectra of the TEAF and TBAF complexes of receptor 2 measured in the absence of TEAHCO₃ are also shown. *Denotes peaks originating from the NMR solvent or NMR spinning sidebands.

The enhancement in the K_a value is rationalized in terms of F⁻ binding to receptors 1 and 2 being enhanced by strong ion pairing with the pre-bound TEA⁺ cation (i.e., the counter cation added with the initial HCO₃⁻ anion). The tetraethylammonium cation with its relatively high charge density is expected to form stronger receptor-separated ion pair complexes than its TBA⁺ congener thus enhancing the apparent fluoride anion affinity (for a discussion of the ion pairing between F⁻ and TEA⁺ and the receptors of this study, see Section S1 in the ESI†). The net result of this ion pairing is anion metathesis between the initially bound HCO₃⁻ anion and the added F⁻ anion within the strapped cavities of these two receptors. Also contributing to an increase in the K_a value is the fact that pre-complexation of TEAHCO₃ serves to lock the calix[4]pyrrole moiety into the cone conformation favourable for anion binding. (For a discussion of TEA⁺ cation interactions with the cavity formed when calix[4]pyrrole 2 is locked in its cone conformation, see Section S2 in the ESI†).

Further evidence that receptors 1 and 2 bind the fluoride anion via this proposed anion metathesis with remarkably improved efficiency came from ¹H NMR titration experiments with the fluoride anion involving the use of 1 : 1 mixtures of the TEAHCO₃ complexes and the anion free forms of receptors 1 and 2 (Fig. 5 and S10†). The mixtures were prepared by adding TEAHCO₃ (0.6 equiv.) to CDCl₃ solutions of receptors 1 and 2, respectively. In the resulting ¹H NMR spectra, all observable proton signals appeared as two separate sets in nearly 1 : 1 integral ratio. These peaks were assigned to the anion free and TEAHCO₃ complexed forms of receptors 1 and 2, respectively (Fig. 5 and S10†). When these mixtures were titrated with TBAF in CDCl₃, a new set of proton signals corresponding to the fluoride complex of receptor 2 appeared, while those of its ion-free form and the TEAHCO₃ complex gradually disappeared before saturation was observed upon the addition of ca. 1.2 equiv. of TBAF (Fig. 5). In this case, the TEAHCO₃ complex of receptor 2 reached saturation more quickly than its ion free form (Fig. 3 and 5). Again, this finding supports our suggestions that (1) fluoride binding to receptor 2 in its cone conformation is favoured as the result of anion metathesis involving the preformed TEAHCO₃ complexes and that (2) this complexation process is more favourable than the ostensibly similar, but chemically distinct, alternative of adding TBAF to the initial 1,3-alternate form of the ion-free receptor.

Fig. 5 Top: Proposed fluoride complexes formed when a mixture of receptor 2 in its ion-free form and its TEAHCO₃ complexed form are subject to titration with TBAF. Bottom: Partial ¹H NMR spectra recorded during the titration of a mixture of ion-free 2 and its TEAHCO₃ complex with TBAF in CDCl₃. ·Denotes proton signals corresponding to the TEAHCO₃ complex of receptor 2. *Denotes peaks originating from the NMR solvent.

TEA⁺ binding to the cone-shaped calix[4]pyrrole cavities of receptors 1 and 2via cation metathesis with TBA⁺ was also quantified by ¹H NMR spectral titrations of the TBAF complexes of receptors 1 and 2 with TEAHCO₃. For example, when the TBAF complexes of receptors 1 and 2 were titrated with TEAHCO₃ in CDCl₃, the signals corresponding to the N⁺CH₂ protons of the TBA⁺ cation gradually shift to lower field before saturation is observed upon the addition of ≈1 equiv. of TEAHCO₃ (Fig. S11 and S12†). By contrast, the CH₃ protons of the TEA⁺, which resonate at ca. 1.35 ppm in the absence of a receptor (cf. Fig. S5†), are seen to resonate between 0.5 and 0.7 ppm as increasing aliquots of TEAHCO₃ are added up to ≈1 equiv. Little or no changes were observed for any of the proton signals assigned to the receptors (Fig. S11 and S12†). Collectively, these findings are consistent with the TBA⁺ cation initially located within the calix[4]pyrrole cavity being replaced by TEA⁺ as it is added in the form of the counter cation to the TEAHCO₃ salt used in these titrations while the fluoride anion remains fully bound (i.e., not displaced by the added HCO₃⁻ anion). The K_a values corresponding to this cation metathesis were calculated to be ca. 23 960 M⁻¹ for receptor 1 and 15 150 M⁻¹ for receptor 2, respectively.²⁰ By contrast, when the ion free form of receptor 2 was treated with BF₄⁻ (as the TEA⁺ salt), no evidence of either anion or TEA⁺ cation binding was observed (Fig. S13†). This is consistent with cation binding being dependent on anion binding and conversion of the initial 1,3-alternate conformation to the corresponding cone form.

We also investigated the effect of the counter cation on the F⁻ binding by receptors 1 and 2, This was done by replacing the TBA⁺ cation with the TEA⁺ cation. Two sets of separate signals corresponding to the ion-free forms and TEAF complexed forms, respectively, of receptors 1 and 2 were seen in the ¹H NMR spectra upon titration with TEAF before saturation was reached upon of the addition of 2.18 equiv. and 1.72 equiv. of TEAF, respectively (Fig. S14 and S15†). Over the course of the titrations, the binding modes of the TEAF to ion pair receptors 1 and 2 were found to change from a receptor-bound contact ion pair to receptor-separated ion pair (for a discussion of the binding of the TEAF ion pair to receptors 1 and 2, see Section S3 in the ESI†). The binding constants (K_a) of receptors 1 and 2 for the F⁻ anion as the TEA⁺ salt, estimated from the ¹H NMR spectral titrations, were found to be 380 M⁻¹ and 980 M⁻¹, respectively. These values are somewhat higher than those for the corresponding TBA⁺ salt but are significantly reduced compared to those recorded when the preformed TEAHCO₃ complexes of receptors 1 and 2 are titrated with TBAF salt (see above discussion and Table 1).¹⁸ This observation leads us to suggest that strong ion pairing occurs within the added TEAF salt and that this prevents in whole or in part the TEA⁺ cation from binding to the calix[4]pyrrole cavity. This reflects the greater energetics needed to separate the TEAF ion pair vs. forming a TEAF complex via addition of fluoride to a preformed TEA⁺ cation–receptor complex. As a result, TEAF initially binds to these receptors in the form of internal, as opposed to receptor-separated, ion pair complex. This sequence of binding events, which leads to the formation of the thermodynamically most stable TEAF complex of 2 in CDCl₃, is summarised in Fig. 6.

Fig. 6 Hess diagram showing the binding modes and processes for the formation of the TEAF complex of receptor 2.

In order to obtain greater insight into the release of bicarbonate from receptors 1 and 2 upon treatment with a fluoride anion source, we carried out ¹H NMR spectral titrations with TEAF starting with the TEAHCO₃ complexes of 1 and 2 (Fig. S17 and S18†). For these titrations, greater quantities of TEAF were necessary to achieve saturation than was required in the case of titration of the ion-free receptors with TEAF. This leads us to suggest that the binding affinities for F⁻ (as its TEA⁺ salt) for the TEAHCO₃ complexes of receptors 1 and 2 are decreased with respect to those of their ion-free forms (K_a = 380 M⁻¹ for ion-free 1vs. K_a = 340 M⁻¹ for 1·TEAHCO₃ and K_a = 980 M⁻¹ for ion-free 2vs. K_a = 430 M⁻¹ for 2·TEAHCO₃; cf.Table 1). These findings stand in striking contrast to what was seen when the TEAHCO₃ complexes of receptors 1 and 2 was titrated with F⁻ as the corresponding TBA⁺ salt (vide supra). Taken together, these findings provide support for the suggestions that (1) inherently strong ion pairing between TEA⁺ and F⁻ outside the receptors impedes F⁻ binding to the receptors while (2) their tendency to ion pair within the receptors favours fluoride binding. To the best of our knowledge, receptors 1 and 2 are the first examples of rationally designed receptors capable of binding ion pairs with different binding modes and affinities depending on the specific ion pair complex being formed.

In order to support the notion that tight ion pairing between TEA⁺ and F⁻ could reduce the effective fluoride anion binding affinity in the case of receptors 1 and 2, we also performed ¹H NMR spectral titrations involving the treatment of receptor 2 with TEAF in 10% aqueous DMSO-d₆. Unfortunately, receptor 1 proved too insoluble in this medium to allow for its study. A mixture of 10% aqueous DMSO-d₆ has a higher dielectric constant (ε_r) than CDCl₃ (56.2 vs. 4.7)²¹ and was expected to favor dissociation of TEAF into its constituent ions. On the other hand, solvation of the individual ions was expected to increase. The balance between these competing effects was not known a priori. Flood and coworkers reported that the anion affinity of a given receptor is likely to be diminished in proportion to the solvent dielectric constant because of the solvation of the anion.²¹ However, when receptor 2 was subjected to titration with TEAF in 10% aqueous DMSO-d₆, chemical shift changes consistent with F⁻ anion binding were seen in the corresponding ¹H NMR spectra with saturation being reached upon the addition of only ≈1 equiv. of TEAF (Fig. 7). The binding constant for this equilibrium was calculated to be K_a = 10 160 M⁻¹,¹⁷ a value that is significantly higher than what is seen in CDCl₃ (K_a = 380 M⁻¹). On this basis we conclude that the extent to which the TEAF fluoride anion source separates into its constituent ions, TEA⁺ and F⁻, plays a crucial role in regulating the effective anion affinities of the present set of receptors. In 10% aqueous DMSO-d₆ no change in the chemical shift of the TEA⁺ resonances was seen as additional quantities of TEAF were added. This observation led us to suggest that in this solvent system the TEA⁺ cation remains solvated rather than being co-bound to the cone-shaped calix[4]pyrrole cavity (Fig. 7). We thus conclude that the effects of ion pairing both within and outside of receptors 1 and 2 play a critical role in regulating the observed overall anion binding affinities.

Fig. 7 ¹H NMR spectra recorded during the titration of 2 (3 mM) with TEAF in 10% D₂O in DMSO-d₆.

Conclusions

In conclusion, the strapped calix[4]pyrroles 1 and 2 wherein two diametrical meso-phenol walls are linked via a rigid benzene and pyridine spacer, respectively, were found to bind the HCO₃⁻ anion (as the TEA⁺ salt) and the F⁻ anion (as the TBA⁺ salt) with high selectivity over various other test anions in CDCl₃. A higher affinity for the bicarbonate anion is seen over the fluoride anion under these conditions. In contrast, upon the addition of TBAF to the preformed TEAHCO₃ complexes of receptors 1 and 2, the bound bicarbonate anion was released and replaced by the F⁻ anion. This anion metathesis gives rise to the corresponding TEAF complexes. As compared to what is seen when TBAF is added to receptors 1 and 2 in their ion free forms, the fluoride anion binding affinities are increased when starting with the preformed TEAHCO₃ complex, a result ascribed to the formation of a receptor separated F⁻–TEA⁺ ion pair complex. When receptors 1 and 2 in their ion free forms are titrated with TEA⁺ and F⁻ (in the form of TEAF) TEAF complexes are formed in which the binding mode of TEA⁺ varies depending on the relative quantity of TEAF present with the same complex formed via anion metathesis eventually being formed. However, the observed binding affinity was unexpectedly low, a result ascribed to the TEAF salt remaining ion paired in CDCl₃. The use of a more polar medium was found to increase the K_a values dramatically. The present findings provide support for the notion that ion pairing effects, occurring both inside and outside of the receptors, can play an important role in regulating the binding interactions between synthetic receptors and their targeted ions. In the present instance, these effects can be exploited to create systems that act as bicarbonate anion receptors from which HCO₃⁻ can be released via fluoride anion-mediated anion metathesis.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2020R1A4A2002831 to S. K. K.). The work in Austin was supported by the Office of Basic Energy Sciences, U.S. Department of Energy (DOE) (Grant DEFG02-01ER15186 to J. L. S.) and the Robert A. Welch Foundation (F-0018 to J. L. S.).

Notes and references

1. (a) J. L. Sessler, P. A. Gale and W.-S. Cho, Anion Receptor Chemistry, ed. J. F. Stoddart, Royal Society of Chemistry, Cambridge, 2006; (b) A. Bianchi, K. Bowman-James and E. García-España, Supramolecular Chemistry of Anions, Wiley-VCH, New York, 1997; (c) Anion Coordination Chemistry, ed. K. Bowman-James, A. Bianchi and E. García-España, Wiley-VCH, Weinheim, 2011.
2. (a) P. D. Beer and P. A. Gale, Angew. Chem., Int. Ed., 2001, 40, 486–516; (b) R. Martínez-Máñez and F. Sancenán, Chem. Rev., 2003, 103, 4419–4476; (c) P. A. Gale, N. Busschaert, C. J. E. Haynes, L. E. Karagiannidis and I. L. Kirby, Chem. Soc. Rev., 2014, 43, 205–241; (d) M. Wenzel, J. R. Hiscock and P. A. Gale, Chem. Soc. Rev., 2012, 41, 480–520; (e) P. A. Gale, Chem. Soc. Rev., 2010, 39, 3746–3771; (f) C. Caltagirone and P. A. Gale, Chem. Soc. Rev., 2009, 38, 520–563; (g) P. A. Gale and G. Caltagirone, Chem. Soc. Rev., 2015, 44, 4212–4227.
3. (a) S. O. Kang, R. A. Begum and K. Bowman-James, Angew. Chem., Int. Ed., 2006, 45, 7882–7894; (b) S. O. Kang, J. M. Llinares, V. W. Day and K. Bowman-James, Chem. Soc. Rev., 2010, 39, 3980–4003; (c) J. H. Oh, J. H. Kim, D. S. Kim, H. J. Han, V. M. Lynch, J. L. Sessler and S. K. Kim, Org. Lett., 2019, 21, 4336–4339.
4. (a) Y. Chen, M. J. Cann, T. N. Litvin, V. Iourgenko, M. L. Sinclair, L. R. Levin and J. Buck, Science, 2000, 289, 625–628; (b) B. J. Krieg, S. M. Taghavi, G. L. Amidon and G. E. Amidon, J. Pharm. Sci., 2014, 103, 3473–3490; (c) R. D. Vaughan-Jones and K. W. Spitzer, Biochem. Cell Biol., 2002, 80, 579–596; (d) A. Roos and W. F. Boron, Physiol. Rev., 1981, 61, 296–434; (e) J. H. Zippin, L. R. Levin and J. Buck, Trends Endocrinol. Metab., 2001, 12, 366–370.
5. (a) J. R. Casey, Biochem. Cell Biol., 2006, 84, 930–939; (b) Y. Liu, D.-Ke. Wang and L.-M. Chen, Biol. Reprod., 2012, 86, 1–13.
6. (a) D. M. Sigman and E. A. Boyle, Nature, 2000, 407, 859–869; (b) N. Zeng, Adv. Atmos. Sci., 2003, 20, 677–693; (c) C. Heinze, S. Meyer, N. Goris, L. Anderson, R. Steinfeldt, N. Chang, C. L. Quéré and D. C. E. Bakker, Earth System Dynamics, 2015, 6, 327–358.
7. (a) L. W. Ripa, Journal of Public Health Dentistry, 1993, 53, 17–44; (b) M. S. McDonagh, P. F. Whiting, P. M. Wilson, A. J. Sutton, I. Chestnutt, J. Cooper, K. Misso, M. Bradley, E. Treasure and J. Kleijnen, Br. Med. J., 2000, 321, 855–859; (c) C. Carstairs and R. Elder, Can. Hist. Rev., 2008, 89, 345–371; (d) P. Connet, Fluoride, 2007, 40, 155–158; (e) R. G. Foulkes, Fluoride, 2007, 40, 229–237; (f) R. J. Carton, Fluoride, 2006, 39, 163–172.
8. (a) L. K. Kirk, Biochemistry of the Halogens and Inorganic Halides, Plenom Press. New York, 1991; (b) M. Kleerekoper, Endocrinol. Metab. Clin. North Am., 1998, 27, 441–452; (c) D. Briancon, Revue du Rhumatisme, 1997, 64, 78–81.
9. (a) Y. Michigami, Y. Kuroda, K. Ueda and Y. Yamamoto, Anal. Chim. Acta, 1993, 274, 299–302; (b) P. Grandjean and P. J. Landrigan, Lancet, 2006, 368, 2167–2178; (c) M. C. Friesen, G. Benke, A. Del Monaco, M. Dennekamp, L. Fritschi, N. de Klerk, J. L. Hoving, E. MacFarlane and M. R. Sim, Cancer, Causes Control, Pap. Symp., 2009, 20, 905–916; (d) E. Gazzano, L. Bergandi, C. Riganti, E. Aldieri, S. Doublier, C. Costamagna, A. Bosia and D. Ghigo, Curr. Med. Chem., 2010, 17, 2431–2441; (e) O. Barbier, L. Arreola-Mendoza and L. M. Del Razo, Chem.-Biol. Interact., 2010, 188, 319–333; (f) B. Spittle, Fluoride, 2011, 44, 117–124; (g) R. Sandhu, H. Lal, Z. S. Kundu and S. Kharb, Biol. Trace Elem. Res., 2011, 144, 1–5.
10. J. T. Davis, P. A. Gale, O. A. Okunola, P. Prados, J. C. Iglesias-Sánchez, T. Tomás and R. Quesada, Nat. Chem., 2009, 1, 138–144.
11. I. Suzuki, M. Ui and A. Yamauchi, J. Am. Chem. Soc., 2006, 128, 4498–4499.
12. E. Mulugeta, Q. He, D. Sareen, S.-J. Hong, J. H. Oh, V. M. Lynch, J. L. Sessler, S. K. Kim and C.-H. Lee, Chem, 2017, 3, 1008–1020.
13. N. J. Heo, J. H. Oh, J. T. Lee, Q. He, J. L. Sessler and S. K. Kim, Org. Chem. Front., 2020, 7, 548–556.
14. (a) P. A. Gale, J. L. Sessler, V. Král and V. Lynch, J. Am. Chem. Soc., 1996, 118, 5140–5141; (b) P. A. Gale, J. L. Sessler and V. Král, Chem. Commun., 1998, 1–8; (c) C.-H. Lee, H. Miyaji, D.-W. Yoon and J. L. Sessler, Chem. Commun., 2008, 24–34 and references therein. (d) S. K. Kim and J. L. Sessler, Acc. Chem. Res., 2014, 47, 2525–2536 and references therein. (e) I. Saha, J. T. Lee and C.-H. Lee, Eur. J. Org. Chem., 2015, 18, 3859–3885; (f) S. Ko, S. K. Kim, A. Share, V. M. Lynch, J. Park, W. Namkung, W. V. Rossom, N. Busschaert, P. A. Gale, J. L. Sessler and I. Shin, Nat. Chem., 2014, 6, 885–892; (g) S. Peng, Q. He, G. I. Vargas-Zúñiga, L. Qin, I. Hwang, S. K. Kim, N. J. Heo, C.-H. Lee, R. Dutta and J. L. Sessler, Chem. Soc. Rev., 2020, 49, 865–907.
15. (a) S. K. Kim, V. M. Lynch and J. L. Sessler, Org. Lett., 2014, 16, 6128–6131; (b) R. Samanta, B. S. Kumar and P. K. Panda, Org. Lett., 2015, 17, 4140–4143.
16. J. Yoo, I.-W. Park, T.-Y. Kim and C.-H. Lee, Bull. Korean Chem. Soc., 2010, 31, 630–634.
17. Approximate binding constant calculated per, K. A. Connors, Binding Constants: The Measurement of Molecular Complex Stability, Wiley-Interscience, New York, 1987.
18. (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. L. Sessler, D. E. Gross, W.-S. Cho, V. M. Lynch, F. P. Schmidtchen, G. W. Bates, M. E. Light and P. A. Gale, J. Am. Chem. Soc., 2006, 128, 12281–12288.
19. This presumption was supported by the finding that the aryl proton signal (H_g) undergoes a noticeable downfield shift (up to Δδ ≈ 0.29 ppm) in the ¹H NMR spectra recorded as receptor 2 is titrated with HCO₃⁻ (Fig. S7†). In contrast to what was seen upon titration with TEAHCO₃, the addition of TBAF induces an upfield shift in the benzene proton signal (H_g) of 2. Presumably, this reflects the presence of increased electron density within the receptor cavity as the result of fluoride anion binding (Fig. 3). No evidence of a hydrogen bond interaction between the aryl CH proton of the strap and the bound F⁻ was observed.²² This latter absence is ascribed to the F⁻ anion being small and a lack of flexibility in the strap unit that might otherwise allow the strap in receptor 2 to interact with the bound fluoride anion.²².
20. Association constants (K_a) were evaluated using BindFit v5.0 available from URL http://app.supramolecular.org/bindfit/.
21. Y. Liu, A. Sengupta, K. Raghavachari and A. H. Flood, Chem, 2017, 3, 411–427.
22. 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.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2010538 and 2010539. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0sc03445b

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