Anion Receptor Chemistry

Abstract

Anion receptor chemistry concerns the design of molecules that recognize, respond to, or sense species that carry a negative charge. This area of supramolecular chemistry has a number of applications, including in organocatalysis (where metal-free molecules can catalyze reactions via hydrogen-bonding interactions), in separating mixtures of anions in industrial or radioactive waste, and in producing anion sensors that can be used under real-world conditions to sense trace quantities of anions such as fluoride. Anion receptor chemistry may also be useful in the future treatment of diseases, such as cystic fibrosis, caused by problems with chloride transport through faulty ion channels in epithelial cell membranes. One proposed approach to tackling this is “channel replacement therapy,” wherein small molecules facilitate the transport of chloride; significant effort is currently being devoted in this area. This review covers advances in anion complexation in 2013, 2014, and 2015. The review focuses on the applications of anion receptor chemistry, including sensing, self-assembly, extraction, transport, catalysis, and fundamental advances in the area. This review covers advances in anion complexation in 2013, 2014, and 2015. The review focuses on the applications of anion receptor chemistry, including sensing, self-assembly, extraction, transport, catalysis, and fundamental advances in the area. As the field of anion coordination chemistry continues to develop, we are seeing a shift away from systems that function only under laboratory conditions (e.g., hydrogen-bond-based anion receptors that function only in organic solvents) to new anion receptors that employ a variety of interactions to function under real-world conditions. In this review, we cover recent advances in the design of anion receptors and the increase in the proportion of systems involving non-classical non-covalent interactions, together with the latest developments in anion sensing and separation, as well as new self-assembling systems involving anions in 2013, 2014, and 2015. We also highlight advances in catalysis and anion-transport processes. These advances highlight the interdisciplinary nature of this area of supramolecular chemistry with advances at the borders of materials science and biology.1Gale P.A. Busschaert N. Haynes C.J.E. Karagiannidis L.E. Kirby I.L. Anion receptor chemistry: highlights from 2011 and 2012.Chem. Soc. Rev. 2014; 43: 205-241Crossref PubMed Google Scholar There is still much to learn about the behavior of receptors that use hydrogen-bond donors to interact with anions. In this section, we refer to anion receptors that use NH and OH groups as their main hydrogen-bond donors as classic hydrogen-bond-based receptors. In the last 3 years, new anion-binding motifs and scaffolds have continued to be developed. Arylboronic acids are well known for their ability to form covalent adducts with basic anions such as hydroxide and fluoride to the Lewis acidic boron center. Martínez-Aguirre and Yatsimirsky2Martínez-Aguirre M.A. Yatsimirsky A.K. Brønsted versus Lewis acid type anion recognition by arylboronic acids.J. Org. Chem. 2015; 80: 4985-4993Crossref PubMed Scopus (9) Google Scholar demonstrated that, in addition to Lewis-acid-type covalent binding, arylboronic acids can also interact with anions via hydrogen bonding with the B(OH)2 hydroxyl groups (Figure 1). In DMSO, the formation of tetrahedral covalent adducts was found to dominate over hydrogen-bonding adducts for fluoride and dihydrogenphosphate; however, less basic anions, including chloride, bromide, hydrogensulfate, and acetate, only formed hydrogen-bonding adducts with arylboronic acids, as revealed by 1H and 11B nuclear magnetic resonance (NMR) binding studies in DMSO-d6 and CD3CN. Compared with commonly used hydrogen-bond-based anion receptors such as phenylureas and isophthalamides, the phenylboronic acids showed a less pronounced decrease in anion-binding affinity on going from chloroform to the highly competitive solvent DMSO. Surprisingly, the affinity for chloride and acetate in DMSO-d6 was found to be higher than that of simple phenylureas and isophthalamides. By adding a nitro substituent, the authors achieved an anion-induced UV-visible (UV-Vis) spectroscopic response. Thus, this work illustrated the overlooked potential of phenylboronic acids as non-covalent anion receptors for possible sensing applications. Shokri et al.3Shokri A. Wang X.-B. Kass S.R. Electron-withdrawing trifluoromethyl groups in combination with hydrogen bonds in polyols: Brønsted acids, hydrogen-bond catalysts, and anion receptors.J. Am. Chem. Soc. 2013; 135: 9525-9530Crossref PubMed Scopus (23) Google Scholar examined the acidity, chloride binding, and catalytic properties of three polyols 1–3 (Figure 2). These compounds stabilize their deprotonated forms by intramolecular hydrogen bonds (Figure 2) and contain CF3 groups, leading to strong Brønsted acids. Negative-ion photoelectron spectroscopic measurements revealed that deprotonated anions in the gas phase of 1 and 2 were much more stable than those of 1,3-propanediol and 1,2-ethanediol. In solutions, 1–3 were found to be rather acidic in DMSO (pKa = 16.0, 4.8, and 7.1 for 1, 2, and 3, respectively) and water (pKa = 5.6 and 7.1 for 2 and 3, respectively). Notably, despite separation of the CF3 groups by three carbons in 3, 3 was more acidic than 1,1,1,3,3,3-hexafluoro-2-propanol by 2.2 pKa units in water. This demonstrated that the inductive effect can be transmitted via intramolecular hydrogen bonds even in an aqueous environment. Remarkably, 1 and 2 showed the highest chloride affinity in CD3CN (3,300 for 1 and 6,700 for 2 M−1) among reported aliphatic alcohols. Compounds 1–3 were found to act as hydrogen bond and Brønsted acid catalysts in a Friedel-Crafts reaction and a styrene oxide aminolysis reaction, respectively. Elmes et al.4Elmes R.B.P. Turner P. Jolliffe K.A. Colorimetric and luminescent sensors for chloride: hydrogen bonding vs deprotonation.Org. Lett. 2013; 15: 5638-5641Crossref PubMed Scopus (11) Google Scholar reported anion binding and spectroscopic sensing properties of squaramide-based anion receptors 4–6 (Figure 3), which showed the highly unusual behavior of deprotonation by the relatively weakly basic anion chloride in DMSO. Titration of 4–6 with chloride led to dramatic changes in the color of the solution and quenching of the excimer emission at 530 nm. On the basis of the disappearance of the NH 1H-NMR resonances and color changes induced by high concentrations of chloride, the authors proposed that 4–6 could be deprotonated by chloride at high concentrations, whereas hydrogen bonding to chloride occurred at low chloride concentrations. Deprotonation was not observed with less basic anions (bromide, iodide, and nitrate) or with the less acidic squaramide 7 in the presence of chloride. Calix[4]arene is an ideal scaffold for constructing multivalent anion receptors for high-affinity anion binding and sensing.5De Solis S. Elisei F. Gunnlaugsson T. Lower Rim Amide (1,3) functionalised calix[4]arene amido-thiourea derivatives as dimetallic Zn(II) coordination complexes for anion recognition/sensing.Supramol. Chem. 2015; 27: 697-705Crossref Google Scholar Gaeta et al.6Gaeta C. Talotta C. Della Sala P. Margarucci L. Casapullo A. Neri P. Anion-induced dimerization in p-squaramidocalix[4]arene derivatives.J. Org. Chem. 2014; 79: 3704-3708Crossref PubMed Scopus (8) Google Scholar developed two anion receptors, 8 and 9 (Figure 3), in which two squaramide moieties were attached to the upper rim of the calix[4]arene scaffold. Interestingly, spherical anions including chloride and bromide were found to induce dimerization of both 8 and 9, forming 2:1 calixarene-anion complexes as demonstrated by Job plots and electrospray ionization mass spectrometry (ESI-MS) data. Binding and dimerization with trigonal-planar anions, including benzoate and nitrate, however, was only observed for the proximal isomer 9, which was ascribed to an intramolecular hydrogen bond in 9 that favors binding with trigonal-planar anions via one squaramide moiety. Pinter et al.7Pinter T. Simhadri C. Hof F. Dissecting the complex recognition interfaces of potent tetrazole- and pyrrole-based anion binders.J. Org. Chem. 2013; 78: 4642-4648Crossref PubMed Scopus (4) Google Scholar reported anion-binding studies of a new class of anion receptors, 10–12, that are based on the tetrazole-pyrrole-amide framework (Figure 4). These compounds show a much stronger affinity for chloride (with binding constants in the order of 105 M−1 in CD3CN) than bis-amidopyrroles do. Surprisingly, ester 10 binds Cl− with an affinity similar to that of amides 11 and 12. Given the small chloride-induced shift of amide NH resonance of these compounds, the authors concluded that the amide groups in 11 and 12 do not donate strong hydrogen bonds to chloride. Instead, like the role of the ester group in 10, the amide groups in 11 and 12 influenced anion binding by inductive effects, causing increased acidity of the central pyrrole NH. The work demonstrated that incorporating tetrazole motifs can aid in the design of high-affinity anion receptors. The [n]polynorbornane framework has been used to preorganize anion-binding motifs to develop high-affinity anion receptors. Long and Pfeffer8Long B.M. Pfeffer F.M. The influence of the framework: an anion-binding study using fused [n]polynorbornanes.Chem. Asian J. 2014; 9: 1091-1098Crossref PubMed Scopus (5) Google Scholar investigated the influence of the [n]polynorbornane framework size on anion binding (using NMR) in a series of bis-thiourea-functionalized receptors, 13–18 (Figure 5). Job plot analysis revealed that all receptors formed 1:1 complexes with pyrophosphate, pimelate, and terephthalate in DMSO-d6, presumably with the anion bound cooperatively between the two thiourea moieties at the two-armed end. Surprisingly, whereas the larger receptors 16 and 17 bound acetate similarly in a 1:1 cooperative manner (with binding constants 102.6 for 16 and 102.7 for 17), compound 14 accommodated up to two acetate anions with K1 (103.9) > K2 (102.1). The authors proposed that solvation effects or stabilization of the acetate CH3 group by the larger hydrophobic framework could be the cause of the different acetate binding behaviors. The framework size, however, had no influence on the dihydrogenphosphate binding stoichiometry. Tris-thiourea 18 bound a single H2PO4−, whereas the stoichiometry was 1:2 (receptor:H2PO4−) for 13–17. Tröger's base is a rigid scaffold that contains two aryl rings almost perpendicular to each other. Boyle et al.9Boyle E.M. Comby S. Molloy J.K. Gunnlaugsson T. Thiourea derived Tröger’s bases as molecular cleft receptors and colorimetric sensors for anions.J. Org. Chem. 2013; 78: 8312-8319Crossref PubMed Scopus (25) Google Scholar used this scaffold to preorganize two thiourea groups for the binding and sensing of anions. Receptors 19 and 20 (Figure 5) were found to form 1:1 and 1:2 (receptor:anion) hydrogen-bond complexes with dihydrogenphosphate and acetate in DMSO, and interestingly neither of them bound sulfate. Notably, dihydrogenphosphate and acetate binding resulted in dramatic changes in the UV-Vis absorption spectra of 20 but only small changes in that of 19, allowing compound 20 to function as a colorimetric sensor for these anions. For both receptors, titration with F− led to the initial formation of hydrogen-bond complexes, followed by deprotonation at higher F− concentrations. In a very elegant study, Jia et al.10Jia C. Wang Q.-Q. Begum R.A. Day V.W. Bowman-James K. Chelate effects in sulfate binding by amide/urea-based ligands.Org. Biomol. Chem. 2015; 13: 6953-6957Crossref PubMed Google Scholar reported a detailed analysis of chelation effects on sulfate binding by six amide- or urea-based receptors, 21–26 (Figure 6). Job plot experiments indicated that all of the compounds formed 1:1 complexes with sulfate. The sulfate affinity in DMSO-d6 containing 0.5%–50% H2O was found to be in the order 21 < 22 < 23 < 24 < 25 < 26, which corresponds to increasing numbers of hydrogen-bond donors in the receptors, highlighting chelation-enhanced binding. The strong binders 24–26 could bind sulfate in a highly competitive medium of DMSO-d6/25% H2O, and binding constants were determined to be 68 M−1 (24), 294 M−1 (25), and 7,025 M−1 (26). Selectivity for sulfate over phosphate is an important attribute of bacterial sulfate binding proteins and facilitates selective transmembrane transport of sulfate ions. Schaly et al.11Schaly A. Belda R. García-España E. Kubik S. Selective recognition of sulfate anions by a cyclopeptide-derived receptor in aqueous phosphate buffer.Org. Lett. 2013; 15: 6238-6241Crossref PubMed Scopus (11) Google Scholar developed a cyclopeptide 27 (Figure 7) that binds sulfate selectively even in aqueous phosphate buffer. Compound 27 is based on the cyclic hexapeptide scaffold with amide NH hydrogen-bond donors. The three pendent ammonium-containing side chains serve as additional anion-binding sites via Coulombic attractions and hydrogen bonds. The structure of a 1:1 SO42−·27·3H+ complex was optimized, which showed that sulfate was bound by 27·3H+ by nine hydrogen bonds. The formation of the 1:1 SO42−·27·3H+ complex was demonstrated by ESI-MS measurements. Potentiometric titrations revealed the strong sulfate affinity of 27, and SO42− binding constants were determined to be 104.04, 103.44, and 103.08 for the tri-, di-, and mono-protonated 27, respectively. Control compounds 28 and 29 (Figure 7) were also investigated and showed decreased sulfate affinity in the order 27 > 28 > 29. Importantly, isothermal titration calorimetry (ITC) studies in water revealed that replacing the acetate buffering agent (40 mM, pH 4.8) with phosphate (40 mM, pH 4.6) only slightly decreased the sulfate binding constant of 27 from 104.20 to 103.62, demonstrating the high sulfate selectivity of 27. In a separate study, Sommer and Kubik12Sommer F. Kubik S. Anion binding of a neutral bis(cyclopeptide) in water-methanol mixtures containing up to 95% water.Org. Biomol. Chem. 2014; 12: 8851-8860Crossref PubMed Google Scholar studied solvent-dependent binding of sulfate and iodide by a neutral bis(cyclopeptide) 31 (Figure 7). Compared with the previously reported compound 30, the attachment of triethylene glycol chains allowed solubility of 31 in 95% water-methanol without compromising its anion-binding affinity. Using NaI and Na2SO4, ITC anion-binding studies of compound 31 were carried out in water-methanol mixtures with the water content ranging from 20% to 95%. Compound 31 was found to bind sulfate and iodide with binding constants in the order of 104 M−1 in 95% water-methanol; it showed a slight preference for iodide over sulfate in 95% water-methanol but a strong selectivity for sulfate in 30% water-methanol. Interestingly, although the Gibbs free energy for the formation of both sulfate and iodide complexes decreased with increasing water content, the complexation enthalpy and entropy for both anions showed U-shaped curves with minima at 50% water-methanol. Although the increasingly unfavorable binding enthalpy and favorable entropy with high water content can be explained by anion desolvation, the same trend observed with high methanol content was unexpected. The authors ruled out potential ion pairing to be responsible on the basis of no counterion dependence. Instead, the authors proposed that free 31 remained preferentially solvated by water molecules even under solvent conditions with high methanol content and that the release of solvated water molecules from 31 upon anion binding is enthalpically more penalizing but entropically more favorable with high methanol content. Receptors that show chiroptical properties induced by chiral substrate binding are potentially useful in sensing and developing electronic and optical materials. Maeda et al.13Maeda H. Shirai T. Uemura S. Anion-driven structures of radially arranged anion receptor oligomers.Chem. Commun. 2013; 49: 5310-5312Crossref PubMed Scopus (11) Google Scholar developed π-conjugated anion receptors 32–35 and studied their interactions with chiral anions (Figure 8). Binding of an l-phenylalanine anion (l-Phe) to 33–35 in CH2Cl2 led to the induction of circular dichroism (CD) signals from the π-conjugated chromophore. The signs of the CD signals indicate that l-Phe dictated the predominant formation of the M-helix configuration in the case of 33 and the P-type helix in the cases of 34 and 35. Furthermore, these helical complexes emitted circularly polarized luminescence (CPL) at −50°C, representing the first examples of chiral anion-induced CPL from π-conjugated molecules. Mixed-valence metal complexes that display reversible redox activities are attractive candidates for developing molecular-scale electronic devices. Zubi et al.14Zubi A. Wragg A. Turega S. Adams H. Costa P.J. Félix V. Thomas J.A. Modulating the electron-transfer properties of a mixed-valence system through host-guest chemistry.Chem. Sci. 2015; 6: 1334-1340Crossref Google Scholar demonstrated that the redox properties of a mixed-valence complex can be modulated by anion binding. The receptor under study was a kinetically locked trinuclear Ru(II) metallamacrocycle 363+ (Figure 9A ), which could be oxidized to mixed-valence states. Cationic 363+ was found to bind halide ions with affinities in the sequence Cl− > Br− > I− > F− (using tetrabutylammonium [TBA+] salts) in CD3CN. Theoretical studies showed that the cavity size matched chloride better than other halides, allowing chloride binding by three NH hydrogen bonds (Figure 9B). Cationic 363+ has three redox potentials, corresponding to oxidations to the 364+ (RuII2RuIII), 365+ (RuIIRuIII2), and 366+ (RuIII3) states. Square-wave voltammograms showed that fluoride and chloride induced anodic shifts of all three oxidation potentials, whereas bromide shifted the first two oxidation potentials anodically but the third potential cathodically. Iodide led to small perturbations of the potentials. The magnitude of the shifts revealed that the most charge-dense anion fluoride stabilized the highest oxidation state 366+ more than other halides, whereas chloride and bromide selected for the intermediate 365+ state. Finally, the authors demonstrated that, without a change in applied potential, the addition of fluoride could switch the receptor from the 364+ state to the 365+ state, leading to a large change in the intervalence charge-transfer absorption band as a result of increased electronic delocalization in the 365+ state. Chang et al.15Chang K.-C. Minami T. Koutnik P. Savechenkov P.Y. Liu Y. Anzenbacher P. Anion binding modes in meso-substituted hexapyrrolic calix[4]pyrrole isomers.J. Am. Chem. Soc. 2014; 136: 1520-1525Crossref PubMed Scopus (13) Google Scholar have reported hexapyrrolic calix[4]pyrrole isomers 37 and 38 (Figure 10), which interact with anions via different types of interactions, leading to different anion-binding affinities. Compounds 37 (trans-isomer) and 38 (cis-isomer) differ in the orientation of two pyrrole side arms with respect to the calixpyrrole macrocycle. On the basis of 1H-NMR, 2D NMR, and density functional theory (DFT) calculation studies, the authors deduced that 38 binds F− via four pyrrolic hydrogen bonds from the bottom calix[4]pyrrole macrocycle and, surprisingly, additional anion-π interactions with F− sandwiched between the electron-deficient side-arm pyrrole rings. Fluoride binding by 37, by contrast, involves binding of only one of the side-arm pyrroles via a hydrogen bond, in addition to the four hydrogen bonds provided by the calix[4]pyrrole macrocycle. Interestingly, UV-Vis binding studies in acetonitrile showed cross-reactivity of 38 toward different anions, whereas 37 was more selective toward F− over other anions such as Cl−, AcO−, BzO−, and H2PO4−. Although 37 and 38 are not interconvertible, it would be of interest to develop anion receptors that can switch between isomers that differ in anion-binding affinity. Such systems would be reminiscent of biological membrane transporters that change their substrate affinity by switching between different conformations, triggered by ligand binding or dissociation, or a change in pH or voltage. Wezenberg et al.16Wezenberg S.J. Vlatković M. Kistemaker J.C.M. Feringa B.L. Multi-state regulation of the dihydrogen phosphate binding affinity to a light- and heat-responsive bis-urea receptor.J. Am. Chem. Soc. 2014; 136: 16784-16787Crossref PubMed Scopus (12) Google Scholar reported a bis-urea receptor, 39, that upon irradiation or heating, isomerizes reversibly between three states with different H2PO4− affinities, namely a stable trans-isomer, a stable cis-isomer, and an unstable cis-isomer (Figure 11). Both cis-isomers show a much higher affinity for H2PO4− than the trans-isomer as a result of cooperative binding with four hydrogen bonds. In addition, the H2PO4− affinity differs significantly for the stable and unstable cis-isomers because of different torsion angles (Figure 11). 31P-NMR spectra demonstrated the ability of this system to reversibly control the fraction of bound phosphate in a 1:1 receptor-phosphate mixture by switching between the three photostationary states. Stereodynamic anion receptors that change conformations upon anion binding have attracted significant interest because they mimic the induced-fit binding model of naturally occurring enzymes. Gavette et al.17Gavette J.V. Mills N.S. Zakharov L.N. Johnson C.A. Johnson D.W. Haley M.M. An anion-modulated three-way supramolecular switch that selectively binds dihydrogen phosphate, H2PO4−.Angew. Chem. Int. Ed. Engl. 2013; 52: 10270-10274Crossref PubMed Scopus (18) Google Scholar reported an example of an anion-modulated molecular switch that adopted three distinct conformations depending on the anionic guest species. Molecular rotor 40 (Figure 12) featured two urea anion-binding moieties connected via a flexible rotor that consisted of two arylacetylene units and a bipyridine unit. Interestingly, halide ions (Cl−, Br−, and I−) and oxoanions (H2PO4−, HSO4−, OAc−, and NO3−) led to different binding conformations. It was concluded from 1H-NMR (in 10% DMSO-d6/CDCl3) and DFT studies that compound 40 binds halides via a Z conformation that involves both urea NH hydrogen bonds and an aryl CH hydrogen bond, whereas protic oxoanions do not form aryl CH hydrogen bonds and prefer U or S (at high anion concentrations) conformations presumably as a result of hydrogen-bond donation to the pyridine nitrogen lone pair. A follow-up study involving other model compounds provided more evidence for U conformation preference in the case of 1:1 40·HSO4− binding, but it also raised uncertainty for the originally assigned binding conformation of 40·Cl−.18Gavette J.V. Evoniuk C.J. Zakharov L.N. Carnes M.E. Haley M.M. Johnson D.W. Exploring anion-induced conformational flexibility and molecular switching in a series of heteroaryl-urea receptors.Chem. Sci. 2014; 5: 2899-2905Crossref PubMed Scopus (8) Google Scholar Proton NMR studies demonstrated the reversibility of the conformational switch modulated by changing the anionic guest from Cl− to HSO4−. Another interesting aspect of the chemistry of 40 is selective binding of H2PO4−, which probably results from hydrogen bonding or even proton transfer between the H2PO4− proton and the pyridine nitrogen. Anion binding utilizing aromatic or aliphatic CH⋯anion hydrogen bonds has gained increasing popularity in recent years. CH groups are generally less acidic than NH and OH groups, leading to weak binding energy with anions for an individual CH donor. Nevertheless, moderate-to-strong anion binding can be achieved by preorganization of a multivalent receptor. The weak acidity and relative hydrophobicity of CH groups have sometimes proved crucial to aqueous anion binding and preference for more hydrophobic (chaotropic) anions, as will be demonstrated in some of the following examples. Shi et al.19Shi G. Gadhe C.G. Park S.-W. Kim K.S. Kang J. Seema H. Singh N.J. Cho S.J. Novel ionophores with 2n-crown-n topology: anion sensing via pure aliphatic C–H⋯anion hydrogen bonding.Org. Lett. 2014; 16: 334-337Crossref PubMed Scopus (9) Google Scholar reported a new class of CH anion receptors, 41–45, based on the 6-crown-3 scaffold (Figure 13). The three axially positioned CH bonds, polarized by adjacent oxygen atoms, served as the anion-binding motif. Although the CH bond polarization in 41 and 42 was not sufficient for anion binding and 45 gradually decomposed in solutions, 43 and 44 showed observable interactions with anions, including NO2−, AcO−, and halides, with binding constants ranging from 2 M−1 to 15 M−1 in C6D6 or CD3CN. Lee et al.20Lee S. Chen C.-H. Flood A.H. A pentagonal cyanostar macrocycle with cyanostilbene CH donors binds anions and forms dialkylphosphate [3]rotaxanes.Nat. Chem. 2013; 5: 704-710Crossref PubMed Scopus (84) Google Scholar have continued their efforts to create new anion receptors based on CH hydrogen bonds. In addition to the well-known 1,2,3-triazole motif, they incorporated a new CH hydrogen-bond motif, cyanostilbene, into a macrocyclic receptor cyanostar, 46, that contains ten CH hydrogen-bond donors in its central cavity (Figure 14). Compound 46 was easily obtained via a Knoevenagel self-condensation reaction in high yield. In 40% methanol/CH2Cl2, 46 formed 2:1 (46:anion) sandwich complexes with large weakly coordinating anions, including PF6−, ClO4−, and BF4−, with unprecedented high affinity (β2 in the order of 1011–1012 M−2) and positive cooperativity (K12/K11 > 8). Compound 46 showed selectivity based on the size of anions; too large (e.g., PtCl6−) or too small (Cl−) anions showed weakened affinity and cooperativity. Another interesting property of 46 is its ability to form a [3]rotaxane with a dialkylphosphate ligand. The bifluoride ion (HF2−) has largely been overlooked in the area of anion receptor chemistry.21Kang S.O. Powell D. Day V.W. Bowman-James K. Trapped bifluoride.Angew. Chem. Int. Ed. Engl. 2006; 45: 1921-1925Crossref PubMed Scopus (107) Google Scholar Ramabhadran et al.22Ramabhadran R.O. Liu Y. Hua Y. Ciardi M. Flood A.H. Raghavachari K. An overlooked yet ubiquitous fluoride congenitor: binding bifluoride in triazolophanes using computer-aided design.J. Am. Chem. Soc. 2014; 136: 5078-5089Crossref PubMed Scopus (20) Google Scholar investigated bifluoride (HF2−) binding to a previously reported triazoloplane macrocycle, 47, and subsequently optimized the receptor structure by using computer-aided design to develop triazoloplane 48 (Figure 15), which showed enhanced affinity for HF2− (in relation to Cl− affinity). A combination of computational and experimental NMR binding studies indicated that, in the case of the 47·HF2− complex, the bound HF2− preferentially oriented along the north-south direction, with a tilting angle of 20° out of the macrocyclic plane. Although the calculated gas-phase binding energies for 47 with Cl− and HF2− were almost the same, experimental results showed that HF2− bound with an affinity 25 times weaker than that of Cl−, which was attributed to solvation of tilted HF2− in the complex that attenuated its hydrogen bonding with 47. The structure of 47 was then modified by extension of the cavity size and increase of CH bond polarization by adding electron-withdrawing groups or forming intramolecular hydrogen bonds. The new receptor 48 accommodated an untilted HF2− along its east-west axis. The elimination of tilting resulted in a bifluoride affinity of 48 (6.2 × 105 M−1) now of the same magnitude as its chloride affinity in CH2Cl2. Although examples of binding apolar guests in water on the basis of hydrophobic interactions are well known, Hua et al.23Hua Y. Liu Y. Chen C.-H. Flood A.H. Hydrophobic collapse of foldamer capsules drives picomolar-level chloride binding in aqueous acetonitrile solutions.J. Am. Chem. Soc. 2013; 135: 14401-14412Crossref PubMed Scopus (44) Google Scholar demonstrated in a seminal report that hydrophobic interactions can be exploited to drive the binding of hydrophilic anions in aqueous solutions. The two aryl-triazole foldamers 49 and 50 (Figure 16) were studied, in which the main chain could associate intramolecularly or intermolecularly via π-stacking, and the azobenzene unit further shielded the anion-binding site from solvents. Compounds 49 and 50 could bind chloride via the formation of single-helix 1:1 complexes or double-helix 2:1 complexes. Formation of single-helix 1:1 Cl− complexes of 49 and 50 were found to dominate in pure acetonitrile, with a negative cooperativity for forming the duplex. Remarkably in 50% CH3CN/H2O, chloride binding induced the formation of the double helix of 50, which has ∼80% of its π-surfaces buried. This led to a solvent-excluding microenvironment favorable for Cl− binding via CH hydrogen bonds. The effect of hydrophobic collapse was manifested in the surprisingly high chloride affinity (log β2 = 13.0) and high cooperativity (K2/K1 = 165) in 50% CH3CN/H2O, which compensated for the dehydration energetic cost of chloride. High-affinity anion binding by neutral, non-covalent receptors in pure water still represents a formidable challenge for supramolecular chemists. A promising solution is to use macrocycles with a hydrophobic cavity. The success of this approach was highlighted in the bambusuril macrocycle receptor 51 (Figure 17) reported by Yawer et al.24Yawer M.A. Havel V. Sindelar V. A bambusuril macrocycle that binds anions in water with high affinity and selectivity.Angew. Chem. Int. Ed. Engl. 2015; 54: 276-279Crossref PubMed Scopus (29) Google Scholar Compound 51 contains twelve CH hydrogen-bond donors (Ha) and negatively charged carboxylate groups ensuring its s