Anion Recognition Strategies Based on Combined Noncovalent

Review pubs.acs.org/CR

Anion Recognition Strategies Based on Combined Noncovalent Interactions Pedro Molina,* Fabiola Zapata,* and Antonio Caballero* Departamento de Química Orgánica, Universidad de Murcia, Campus de Espinardo, E-30100 Murcia, Spain ABSTRACT: This review highlights the most significant examples of an emerging field in the design of highly selective anion receptors. To date, there has been remarkable progress in the binding and sensing of anions. This has been driven in part by the discovery of ways to construct effective anion binding receptors using the dominant N− H functional groups and neutral and cationic C−H hydrogen bond donors, as well as underexplored strong directional noncovalent interactions such as halogen-bonding and anion−π interactions. In this review, we will describe a new and promising strategy for constructing anion binding receptors with distinct advantages arising from their elaborate design, incorporating multiple binding sites able to interact cooperatively with anions through these different kinds of noncovalent interactions. Comparisons with control species or solely hydrogen-bonding analogues reveal unique characteristics in terms of strength, selectivity, and interaction geometry, representing important advances in the rising field of supramolecular chemistry.

CONTENTS 1. Introduction 2. Use of Csp2−H and H−N Interactions 2.1. Alkene 2.2. Vinyl 2.3. Aromatic Systems 2.3.1. Phenyl 2.3.2. Naphthyl 2.3.3. Azulene 2.3.4. Pyridine 2.3.5. Isoquinoline 2.3.6. Triazole 2.3.7. Ferrocene 3. Use of Csp2−H and H−C′sp2 Interactions 4. Use of Csp2−H and Anion−π Interactions 5. Use of Csp2−H and XB Interactions 6. Use of Csp2−H and M+ Interactions 7. Use of Neutral Csp2 −H and Cationic H−C +sp2 Interactions 8. Use of C+sp2−H and H−N Interactions 8.1. Triazolium 8.2. Pyridinium and Quinolinium 8.3. Imidazolium 9. Use of C+sp2−H and Anion−π Interactions 10. Use of C+sp2−H and H−O Interactions 11. Use of C+sp2−H and H−Csp3 Interactions 12. Use of Csp3−H and H−N Interactions 13. Use of N−H and H−N′ Interactions 14. Use of N−H and π-Stacking Interactions 15. Use of N−H and H−O Interactions 16. Use of N−H and Anion−π Interactions 16.1. Pentafluorophenyl 16.2. Others 17. Use of N−H and XB Interactions © 2017 American Chemical Society

17.1. Rotaxanes 17.2. Catenanes 17.3. Urea 18. Use of XB+ and XB Interactions 19. Use of More than Two Noncovalent Interactions 20. Conclusions and Outlook Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments References

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1. INTRODUCTION The field of anion recognition and sensing by synthetic molecular receptors has become one of the most important areas of supramolecular chemistry due to the important role that anions play in numerous biological and environmental processes; several comprehensive reviews on this topic have been published.1−4 Despite the enormous progress achieved in this field, selective anion recognition continues to be a real challenge, especially in water5 and biological media due to the intrinsic characteristics of anions. Anions have more diffuse charge in comparison with the corresponding isoelectronic cations, a large variety of geometries, including spherical, linear, tetrahedral, trigonal planar, and octahedral, and a greater dependence on the pH, and they are heavily solvated by polar

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Received: December 5, 2016 Published: June 30, 2017 9907

DOI: 10.1021/acs.chemrev.6b00814 Chem. Rev. 2017, 117, 9907−9972

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bonding interactions are established between weakly polarized D−H bonds (e.g., aliphatic C−H) and mildly electron rich Hacceptor moieties (e.g., alkene π-electrons).29−31 While a single interaction is energetically insignificant, when several weak Hbonds coexist, they can stabilize protein structures.32−34 In addition to hydrogen, other atoms can also serve a similar function as a bridge between two molecules; this important and relatively unexplored group of noncovalent interactions has been classified as σ-hole bonding. Even a strongly electronegative halogen atom can interact attractively with an electron donor. The origin of this attraction is the anisotropy of the electron density on the halogen, where the negative charge is distributed around the equator of the halogen and the positive charge is located along the axis of the covalent bond with the halogen atom.35 To explain the formation mechanism of these noncovalent interactions, Polizter and co-workers proposed the concept of the “σ-hole”,36,37 a region with positive molecular electrostatic potentials (MEPs) on the outer end of the R−X bond axis, characteristic of halogen bonding (XB). Recently, these σ-hole-driven halogen bonds have attracted more attention, owing to their potential applications, similar to those of hydrogen bonds. This topic has been comprehensively reviewed.38−44 Work over the years has shown that this bonding mechanism is not limited to the halogen family but also extends to other atoms, some of which are less electronegative than others.45 One general conclusion arising from these studies is that the halogen bond is capable of being sufficiently strong to compete with the more traditional HBs. Accordingly, to date, it has not been possible to make any sweeping statements about the relative stability of these noncovalent interactions, such as the fact that the H-bond is stronger than a halogen bond, or even that an O−H···O HB is necessarily stronger than a C−H···O HB. A counterpart of a σ-hole is the important and relatively unexplored group of noncovalent interactions classified as πhole bonding. A positive π-hole is a region of positive electrostatic potential involving π-orbitals that are perpendicular to a portion of a molecular framework. In examples that include an aromatic π-system substituted with electronwithdrawing groups, the interaction is known as lone pair−π46 or anion−π,47−52 depending on the nature of the electron donor. The anion−π interactions have become more frequently utilized in the design of selective anion receptors.53−55 Although a number of solid-state examples and theoretical studies have revealed the potential of anion−π and halogenbonding interactions for anion recognition, only very recently have they been exploited in the solution phase. Although there are many anions of biological relevance, we specifically highlight a few of them. Adenosine 5′-triphosphate (ATP) is one of the most important anions present in the cell and is generally referred to as the universal molecular energy currency in living cells56−59 for intracellular energy transfer. It also plays an important role in the modulation of the ion channels.60 Another example is the pyrophosphate (PPi) anion, a byproduct of cellular hydrolysis of ATP. The specific detection of high levels of PPi in synovial fluid is indicative of calcium pyrophosphate dihydrate crystal deposition disease,61 whereas the general detection of pyrophosphate has also been considered a biomarker for cancer diagnosis.62 Fluoride is considered essential for healthy bone and teeth growth, and some countries add fluoride into public water supplies, despite some controversy arising from the fact that

solvents. To gain the desired selectivity, a number of important approaches have been reported in the literature. Motivated by the high interest in the recognition and detection of anions, many research groups have developed different approaches to reach this objective in the past two decades. In this context, noncovalent interactions have attracted much attention due to their extensive applications in chemistry, physics, and biology.6 The hydrogen bond (HB) has emerged as the most widely studied of noncovalent interactions. The hydrogen bonding between a donor (D) and acceptor (A) in the moiety D−H···A is a particularly well studied and established supramolecular interaction.7 The majority of hydrogen-bonding anion receptors use N−H groups as hydrogen bond donors integrated into the receptors. One of the first approaches to the design of anion receptors used positively charged ammonium-based receptors, and since the first example reported in the literature,8 ammonium-based receptors have been used extensively for anion recognition purposes.9−15 Due to their relatively facile synthesis, amides16 and ureas17 are probably the most widely used hydrogen bond donors in hydrogen-bonding receptors, although the presence of the CO hydrogen bond acceptor in these anion binding sites is sometimes an inconvenience due to aggregation effects. This inconvenience is avoided when the anion receptors use pyrrole18 or imidazole19 as anion binding sites in their structures, which is why the use of these groups has become increasingly common in recent years. More recently, structural motifs that support C−H···X (X = anion) hydrogen bonds20 have been actively used in various shape-persistent macrocycles, foldamers, and “molecular machines”. Specifically, the 1,2,3triazole ring has been used extensively as a binding site in the design of new anion receptors.21 The collective electronegativity of the three nitrogen atoms polarizes the C−H bond, which, in combination with the lone electron pairs on the nitrogen atoms, acts to establish a large 5D dipole oriented along the C−H bond, with its positive end directed almost in line with the C5−H bond. This combination of features makes them interesting candidates for amide bond surrogates. Since the C5−H···A− binding ability is greatly enhanced by converting the triazole unit into a triazolium cation, the latter is expected to be a more efficient anion captor.22 In this context, a number of supramolecular structures containing triazolium cations have been reported to exhibit strong anion binding affinities involving the formation of hydrogen bonds with oxoanions.23 Futhermore, imidazolium cations, formed either by protonation or by substitution at a nitrogen atom of imidazole, also exhibit high acidity (pKa = 21−23) at the C2−H hydrogen atom of the imidazolium ring. Consequently, the imidazolium cations have been used as anion receptors where the charge−charge electrostatic interaction dominates. This novel type of charged hydrogen bonding has the advantage of possessing both electrostatic and hydrogen-bonding interactions in the same binding site, allowing the possibility of pHindependent binding compared with other, more conventional N−H-based hydrogen bond donors.24,25 On the other hand, several experimental studies have extensively shown that weak interactions can be established between triple and double bonds, aromatic and cyclopropane rings, and X−H compounds (O−H, N−H, and C−H derivatives, etc.). These interactions, which possess the essential properties of hydrogen bonds, are usually called “X−H··· π hydrogen bonds”.26 These HB interactions range in strength from very weak (about 1 kcal/ mol)27 to very strong (about 40 kcal/mol).28 The weakest H9908


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fluoride has a benign effect up to 1 ppm concentration but is toxic at higher doses.63,64 The detection of high levels of chloride in extracellular fluid indicates a misregulation of chloride anion transport, which is linked to diseases such as cystic fibrosis.65 Other biologically significant anions include iodide, which has been found to be essential for biosynthesis of hormones by the thyroid gland,66 as well as the bicarbonate anion, which is responsible for regulating the pH in the body. Certain anions can cause serious environmental damage, so their detection and the control of their relative concentrations are very important. An example of an anion that can be harmful to the environment is sulfate, which can be a troublesome species as a prominent constituent of acid rain, as an interfering agent in the treatment of nuclear waste, and as the cause of permanent hardness in water.67 Selectivity of sulfate over phosphate is an important attribute of bacterial sulfate binding proteins and facilitates transmembrane transport of sulfate anions. Nitrate also produces acid rain and is a contaminant in groundwater as a consequence of its use in fertilizers for agriculture.68 Phosphates arising from agricultural and other industrial activities cause sprawls of toxic algal blooms and the eutrophication of waterways.69 Pertechnetate is a radioactive anion and a byproduct of nuclear fuel processing.70 Perchlorate, an anionic byproduct of rocket fuel and firework production, is also of concern given the uncertainty around its toxicity and potentially negative health effects and its ability to accumulate in vegetables. Cyanide is a very toxic anion which can bind to the enzyme cytochrome c oxidase, preventing the transport of electrons from cytochrome c to oxygen and disrupting the electron transport chain, in turn making it impossible for cells to produce ATP.71 The main objective of this review is to provide the most significant examples of an emerging field within the area of anion recognition. This is based on the use of elaborate, polybinding-site anion receptors able to simultaneously interact with anions through different kinds of noncovalent interactions, including binary or tertiary combinations of HB through N−H and C−H donor groups and halogen-bonding and anion−π interactions. This combination of noncovalent interactions gives rise to highly selective and sensitive receptors able to detect anions in aqueous and biological media. This topic, which is in its infancy, represents a new and promising approach in the field of anion recognition. Accordingly, this review will provide a point of view radicially different from those of pre-existing reviews devoted to anion recognition, which are generally compendiums of receptors classified by functional groups (urea, amide, pyrrole, etc.), different anions for recognition (F−, HSO4−, ...), the nature of the donor group (N−H, C−H, C−X, ...), or the output detected upon occurrence of the recognition event (chromogenic, fluorogenic, redox, ...).

binding of most hosts. In this section, we will highlight the importance of the Csp2−H hydrogen donor groups, not only because the hydrogen bond energy can be modulated by substitution with either electron-withdrawing or electrondonating substituents, but also because moderate-to-strong anion binding can be achieved by preorganization of multivalent receptors. Illustrative examples of anion recognition based on the combination of different Csp2−H donor groups with several types of N−H interactions are given. The relative hydrophobicity of the C−H donor groups has sometimes proved crucial to aqueous anion binding, and the preference for more hydrophobic (cheotropic), weakly hydrated anions will be demonstrated in some of the following examples. In several cases, the prevalence of the Csp2−H···A− interactions could however be more important than that of the classical N−H···A− interactions. From a sensing point of view, the combined action of Csp2−H and N−H interactions allows the selective sensing of CN− and Cl− anions in pure water and lipid bilayer transport. 2.1. Alkene

Maeda and co-workers72 have extensively explored the utilization of anion receptors based on hydrogen bonding involving a combination of pyrrole N−H···A− and alkene Csp2− H···A− interactions. In 2005, these authors reported dipyrrolyl diketones 1 and 2 and their respective difluoroboron complexes 3 and 4 (Figure 1) as anion receptors.

Figure 1. Molecular structures of the receptors 1−4.

The anion binding studies performed revealed the essential role of the alkene Csp2−H···A− interactions relative to other systems. 1H NMR studies in CD2Cl2 demonstrated the participation of both the pyrrolyl N−H and the alkene Csp2− H protons in the anion recognition process. The presence of F− or Cl− anions induced a significant downfield shift in the resonances attributed to the pyrrolyl N−H protons, Δδ = 5.30 ppm for F− and Δδ = 2.95 ppm for Cl− anions, and the alkene Csp2−H, Δδ = 0.44 ppm for F− and Δδ = 2.13 ppm for Cl− anions. From this finding, it is inferred that Csp2−H···X− interactions play an essential role and are responsible for the strong associations observed. This binding mode was also supported by theoretical studies (Figure 2). The geometries of the optimized structure indicated the presence of a “hemi” cavity suitable for anion binding. Consistent with experimental results, the pyrrole nitrogen atoms are twisted to the opposite side of the molecule due to intramolecular associations with the BF2-bound oxygen atoms. However, upon complexation of an anion, both pyrrole rings rotate “inward” to interact with the anion in a concerted fashion.

2. USE OF CSP2−H AND H−N INTERACTIONS Traditionally, the neutral or positively charged structural motifs used for anion recognition have been nitrogen-based receptors. These functionalities interact strongly with anions as the result of N−H···A− hydrogen bonds and electrostatic interactions. By comparison, individual C−H bond donors typically give rise to relatively weak binding energies with anions, given that they are generally less acidic than N−H and O−H groups. Thus, the phenyl Csp2−H (pKa ≈ 37) donor group has been relatively underappreciated in supramolecular chemistry. Despite their ubiquity, aryl protons have played only a small role in the anion 9909


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to the conclusion that the Csp2−H···A− interaction cannot behave as an association unit by itself, although it plays an important role in assisting the complexation between more polarized pyrrole N−H protons and anions. On the basis of the unique properties seen in a Csp2−H···A− interaction, this kind of hydrogen donor group promotes the fabrication of functional anion receptors based on this moiety. In this context, structural modifications of the receptor 3 by incorporation of an electron-withdrawing fluoride allowed the formation of the anion receptor 874 (Figure 4). Not only does Figure 2. Optimized structure of the complex 3·F− at the B3LYP/631G** level. Reprinted from ref 73. Copyright 2006 American Chemical Society.

Further investigations into the importance of alkene Csp2−H protons as anion binding sites in similar systems were reported in 2006, involving the synthesis and study of the pyrrole-based receptors73 5−7 (Figure 3).

Figure 4. Molecular structure of the receptor 8.

this exhibit a more polarized pyrrole N−H bond, resulting in an enhanced affinity for anions, it also allows the receptor to associate with biotic species such as amino acids in polar media. Receptor 8 selectively binds the AcO− anion in CH2Cl2 with an association constant of Ka = 9.6 × 105 M−1 over F−, Cl−, Br−, H2PO4−, and HSO4− anions. Interestingly, the association constants calculated for all the anions in the fluorine-substituted receptor 8 were considerably stronger than those calculated for the proton-substituted analogue 3 (Table 2). The UV−vis absorption and fluorescence changes of 8 elucidated the recognition of L-phenylalanine, which was also supported by the spectral changes. Density functional theory (DFT) calculations performed in the complexes of the receptor 8 with F−, Cl−, AcO− (Figure 5), and H2PO4− indicated the synergic action of both alkene Csp2− H···A− and pyrrole N−H···A− interactions.


The receptors 5 and 6, with only one pyrrole N−H bond, and the receptor 7, with an alkyl group at the bridging carbon atom, exhibit smaller affinities than the bispyrrole receptors 3 and 4 (Tables 1 and 2). The analysis of the titrations gave rise Table 1. Anion Binding Constants (Ka, M−1) of the Receptors 4−7 with Different Anions in CH2Cl2, As Obtained by UV−Vis Spectroscopy73 anion

4

−

F Cl− H2PO4−

5

1.0 × 10 2.0 × 103 1.3 × 104 5

6

4.2 × 10 2.4 × 102 1.4 × 103 4

7

2.5 × 10 1.6 × 102 3.2 × 103

3.4 × 104 NO3− > Br− ≫ I− observed for all hosts. Receptor 29 was the more efficient anion receptor given that it bears the electron-withdrawing NO2 group. By contrast, receptor 34, 9914


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showed that the Cl− anion is stabilized by a total of eight hydrogen bonds: six with indole N−H groups and two phenyl Csp2−H hydrogen bonds on the benzoate termini (Figure 24). The latter C−H···Cl− hydrogen bonds make both benzoate termini inclined toward the indolocarbazole surface, thus allowing for a tilted T-shaped stacking.

Table 5. Anion Binding Constants (Ka, M−1) of the Receptors 35−38 with Cl− Anion in Acetonitrile, As Obtained by Isothermal Titration Calorimetry85 receptor

Ka (M−1)

Ka/Ka(receptor 38)

35 36 37 38

× × × ×

1.2 12 95 1

2.2 2.2 1.8 1.9

5

10 106 107 105

Figure 24. Top (left) and side (right) views of an energy-minimized structure, 41b·Cl. The C−Ha hydrogen atoms, hydrogen bonded with the chloride ion, are marked by dotted arrows in the side view. Reprinted from ref 86. Copyright 2008 American Chemical Society.

The imidazole-based anion receptors87 42 and 43 (Figure 25) bearing the ruthenium bpy group as a signaling unit were Figure 22. X-ray structure of the complex 36·Cl− (CSD Refcode EFEREN). Distances are given in angstroms.

Jeong and co-workers86 prepared a series of indolocarbazoles, 39−41 (Figure 23), that can fold into a helical array to render an internal tubular cavity able to establish multiple indole N− H···A− interactions.

Figure 23. Molecular structure of the receptors 39−41.

The longest receptor 41b binds smaller halides by multiple hydrogen N−H···A− and phenyl Csp2−H ···A− bonds in the order Cl− (Ka = 65 M−1) > F− (Ka = 46 M−1) > Br− (Ka = 19 M−1) in water, different from the binding trend in organic media DMSO/MeOH: F− > Cl− > Br− > I−, where the calculated association constants were at least 2 orders of magnitude stronger, due to the competing solvation energy. 1H NMR studies demonstrated the participation of the phenyl Csp2−H···A− in the binding process. Three N−H signals of 41a were clearly resolved, and all appear at far downfield regions, as a result of hydrogen bonding with the Cl− anion. The aromatic Csp2−H signals were shifted upfield relative to the corresponding signals of 39a. The average chemical shifts for the aromatic signals of 39a, 40a, and 41a in the presence of Cl− become more upfield shifted as the chain length grows. In agreement with the 1H MNR data obtained, theoretical calculations

Figure 25. Molecular structures of the receptors 42 and 43.

successfully explored for CN− anion recognition via hydrogenbonding interactions in water through the formation of cooperative imidazole N−H···A− and phenyl Csp2−H···A− hydrogen-bonding interactions, with binding constants of Ka = 345 and Ka = 878, respectively, obtained by emission spectroscopy. Receptor 43 possesses an appropriate pKa value of a N−H proton and a C-shaped cavity structure with three hydrogen bond donors pointing toward the CN−, consisting of N−H and phenyl Csp2−H hydrogen bonds. The multipoint hydrogen bonding included the weak cooperative Csp2−H phenyl hydrogen bonding and a N−H proton of appropriate acidity, which were both important in enhancing the selectivity 9915


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and sensitivity of the receptor toward the CN− anion in water. For the first time, the phenyl C−H···CN− hydrogen-bonding interaction has been observed by the heteronuclear multiplebond correlation (HMBC) NMR technique. Theoretical calculations performed on complex 43·CN− showed that the anion was anchored at the C-shaped cavity, in which receptor 43 donates five-point hydrogen bonds to CN− in the energy-minimized structure. The two imidazole protons are indeed hydrogen-bonded to CN−. The Csp2−H proton of the bridged phenyl ring is hydrogen-bonded to CN− with distances of 3.41 and 3.61 Å, which is in agreement with the HMBC experiment (Figure 26).

Figure 28. 1H NMR spectra of the receptor 44 (a) with the addition of 0.5 (b), 1.0 (c), and 2.0 (d) equiv of chloride in DMSO. NHc and CHc represent complexed 44·Cl− signals, and NHf and CHf represent the signals of free 44. Reprinted from ref 88. Copyright 2016 American Chemical Society.

four N−H groups were found to point toward the center of the cavity to form a 1:1 complex. The guest Cl− anion was accommodated in the center of receptor 44, showing pseudoD2 symmetry. The N−H···Cl− distance indicated strong hydrogen bonds. Two 2,2′-binaphtyl moieties adopt a cisoid conformation, and the 1-C−H proton of the naphthyl groups made a small contribution through a weak hydrogen bond to the guest Cl− anion (Figure 29).

Figure 26. Optimized structure of the complex 43·CN− using the B3LYP method and the 6-31G* basis set for hydrogen, carbon, and nitrogen atoms and the SDD (Stuttgart−Dresden) energy-consistent pseudopotentials for ruthenium. Reprinted from ref 87. Copyright 2012 American Chemical Society.

2.3.2. Naphthyl. The macrocyclic bisurea receptor88 44 (Figure 27) binds the Cl− anion strongly in the competitive

Figure 27. Structure of the receptor 44. Figure 29. X-ray structure of the complex 44·Cl− (CSD Refcode IZIMUB). Distances are given in angstroms.

mixture MeCN/H2O (5%) with an association constant of Ka = 9.95 × 105 M−1 as determined by UV−vis spectroscopy, although with low selectivity toward AcO− (Ka = 5.43 × 103 M−1), F− (Ka = 2.34 × 104 M−1), and Br− (Ka = 3.61 × 104 M−1) anions. The 1H NMR titration of the receptor 44 with Cl− anions in DMSO revealed a slow equilibrium between the free receptor and the complex. The addition of increasing amounts of Cl− anions promoted the gradual disappearance of the signals attributed to the urea N−H and the inner naphthyl Csp2−H protons and the concomitant appearance of new signals downfield shifted by Δδ = 0.90 ppm and Δδ = 0.28 ppm, attributed to the resonances of the N−H and Csp2−H protons of the complex, respectively (Figure 28), indicating that the Cl− anion was bound by four urea N−H interactions and four naphthyl Csp2−H hydrogen-bonding interactions. The X-ray structure of the complex 44·Cl− showed that the two urea units adopt a trans−trans conformation. The two naphthyl groups of 2,2′-binaphthyl units were twisted, and all

2.3.3. Azulene. With the intention to extend the family of known aromatic building blocks in the field of anion recognition, in 2008, Jurczak and co-workers89 described the bisamides 45−50 based on an azulene moiety (Figure 30). Upon 1H NMR titration in DMSO/D2O (0.5%) with anions, the signals assigned to amide or thioamide N−H protons shifted downfield, indicating a direct hydrogen-bonding interaction with the anion. The authors also observed a downfield shift of the signal of the central azulene Csp2−H proton. The downfield shift observed for this proton was much more important for receptors 47−50 (Δδmax about 1 ppm), which used the five-membered ring as the binding site, than that observed for the receptors 45 and 46. The changes in chemical shift allowed the calculation of the binding constant values (Table 6), and the data gave a consistent fit with a 1:1 binding model, as confirmed by Job plots. 9916


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complexes in solution was reported by Gale, Loeb, and coworkers.90 The synthesis and sensing properties of a series of pyridine- and/or imidazole-based receptors, 51 and 52 (Figure 32), containing either no N−H hydrogen bond donors or a combination of N−H and Csp2−H donors have been studied to compare the affinity of these receptors toward anions.


Table 6. Anion Binding Constants (Ka, M−1) of the Receptors 45−50 with Different Anions in DMSO/D2O (0.5%), As Obtained by 1H NMR Spectroscopy89 anion −

Cl Br− PhCOO− H2PO4−

45

46

47

48

49

50

6.1 − 13 27

13 − 46 104

1.2 − 27 73

9.3 − 105 496

17 − 550 1400

2 − 17 82


The anion binding properties of the receptors 51 and 52 were investigated by 1H NMR in DMSO. Receptor 51, which has no N−H hydrogen bond donor groups, interacts with anions as evidenced by downfield shifts of up to 0.50 ppm for the proton in the 2-position of the pyridine ring. Titration data could be fitted to a 1:1 anion/receptor binding model, with the results shown in Table 7. The highest affinity for anions of the

Molecular modeling of the ligand complex 48·Cl− indicated that the Cl− anion was bound by two hydrogen bonds formed by amide N−H protons and that the anion is positioned in the azulene plane. The Csp2−H distances were in the C−H hydrogen bond range, whereas the Csp2−H···Cl− distance is in agreement with the bond formed by arenes with electronwithdrawing substituents, which may suggest the presence of a Csp2−H···A− interaction. The results supported the hypothesis that the complex 48·Cl− involved Csp2−H···A− hydrogen bond interactions; furthermore, there is also a close contact between Csp2−H of the phenyl side chain and the anion, which may indicate the presence of additional aromatic Csp2−H···A− interactions and explain the efficiency of the receptor (Figure 31). 2.3.4. Pyridine. An interesting investigation of the role that Csp2−H···A− hydrogen bonds play in stabilizing the anion

Table 7. Anion Binding Constants (Ka, M−1) of the Receptors 51 and 52 with Different Anions in DMSO, As Obtained by 1H NMR Spectroscopy90 anion

51

52a

52b

Cl− Br− I− AcO−

195 121 50 84

216 211 113 117

PhCOO− MeSO3− NO3− HSO4−

132 45 − C-linked phenylene. Thus, the triazolophane system appears to be well-suited for fundamental studies of Csp2−H hydrogen bonding, which clearly shows the importance of aromatic Csp2−H hydrogen bond donors in binding anions. A comparative study between the preorganized arylriazole receptor 70 and the nonpreorganized analogous receptor 71 (Figure 48) was reported by Flood and co-workers,100 showing that preorganizing the conformation of the receptor is crucial for obtaining high binding affinities. The preorganization of receptor 70 by intramolecular hydrogen bonds enhances Cl− binding in CH2Cl2 solution by the cooperative action of the triazole Csp2−H···Cl− and the phenyl Csp2−H···Cl− interactions (Ka = 4.68 × 104 M−1) in receptor 71a (Ka = 1.0 × 103 M−1). The presence of Cl− anions in a solution of the receptors 70 and 71a in CD2Cl2 promoted a noticeable downfield shift in the resonances assigned to the triazole Csp2−Hb and the inner phenyl Csp2−Ha protons (Figure 49). Following the same line of research and with the aim to incorporate additional phenyl Csp2−H···A− interactions, the same group reported101 the recognition properties of the


related 1,8-naphthalimide-based receptor 72 toward Cl− anions (Figure 50). The incorporation of the dipolar character of the naphthalimide units provided greater Cl− anion stabilization than the N-aryl-substituted analogue 71b used for comparison purposes (Table 9). 1H NMR titrations showed important downfield shifts in the signals for the triazole Csp2−Hb (Δδ = 2.48 ppm) and phenyl Csp2−Ha (Δδ = 3.04 ppm) protons involved in the recognition process. The participation of the 1,8-naphthalimide protons Hc and Hd in the Cl− recognition was also very important, whereby downfield shifts by Δδ = 2.56 ppm and Δδ = 3.49 ppm, respectively, were observed, consistent with the Csp2−H···Cl− interactions within the receptor cavity. 1H NMR studies also indicated the existence of a complex with 1:2 anion/receptor stoichiometry and the 9922


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Figure 51. Structure of the complex 72·Cl− obtained using B3LYP/631+G(d,p). Reprinted from ref 101. Copyright 2011 American Chemical Society.

Figure 49. Partial 1H NMR spectra of 70 upon titration with tetrabutylammonium chloride in CD2Cl2. Reprinted from ref 100. Copyright 2010 American Chemical Society.


Table 9. Anion Binding Constants (Ka, M−1) of the Receptors 71b and 72 with Different Anions in CH2Cl2, As Obtained by UV−Vis Spectroscopy101 anion −

Cl Br− I−

71b


stoichiometry and the association constants calculated by 1H NMR in acetone were 1:1 and Ka = 1.7 × 104 M−1, respectively. Salient features of this work were that 1:1 interactions between neutral triazoles and Cl− anions were directional and sufficiently strong to be observable by 1H NMR spectroscopy and that Csp2−H···anion contacts guide the folding of aryltriazole oligomers in solution and in the solid state. Taking into account the cavity formed in the oligomer 73 in the presence of the Cl− anion, one year later, the same group extended the binding studies of the receptor toward a variety of anions.103 The calculated association constants in acetone for several anions are shown in Table 10. Solvent effects are

72

4.2 × 10 1.1 × 104 108 M−1) and Br− (Ka > 107 M−1) anions in CH2Cl2 solvent.

Figure 61. Optimized structure of the complex 86·Cl− using a CAChe 7.5 PM5 semiempirical calculation. Reprinted with permission from ref 108. Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA.


Table 12. Anion Binding Constants (Ka, M−1) of the Receptor 86 with Various Guests and Solvents, As Obtained by UV−Vis Spectroscopy108 solvent

guest

CH2Cl2

Cl− Br− I− tert-butylpyridine Cl− Br− I− Cl− Br− I−

acetone

DMSO

a naphthalene spacer group is decorated with two arms containing benzimidazolium motifs as binding sites end-capped with a photoactive pyrene ring. UV−vis and fluorescence spectroscopic data, as well as 1H NMR anion titration studies, revealed that the receptor 87 showed a preferred association for SO42− and HP2O73− anions in the competitive DMSO/D2O (9:1, v/v) medium. 1 H NMR spectroscopy studies revealed important downfield shifts in the signals for both imidazolium C+sp2−Hd protons (up to Δδ = 1.75 ppm) and also the inner naphthalene Csp2−Hc protons (up to Δδ = 0.67 ppm), which clearly indicates their participation in the recognition event (Figure 63). The association constant for the SO42− anion calculated from 1 H NMR titrations in DMSO/D2O (9:1, v/v) was found to be Ka = 2.1 × 103 M−1, which was considerably stronger than that calculated for the HP2O73− anion (Ka = 351 M−1). Anion binding studies via emission spectroscopy in DMSO/ D2O (9:1, v/v) revealed that the presence of HP2O73− and SO42− anions induced a change in the ratio of the monomer and the excimer bands in the free receptor from 0.29 to 0.41 for HP2O73− and 0.43 for SO42−. A similar example of the synergic participation of the neutral aromatic Csp2−H and cationic C+sp2−H interactions to bind anions was reported by Schubert and co-workers.110 The triazolium-based receptors 88 and 89 were able to complex SO42− anions by the cooperative action of the C+sp2−H triazolium protons and the internal aromatic Csp2−H proton of the central phenyl ring used as a spacer. Interestingly, receptor 88 showed a 1:1 anion/receptor stoichiometry for the SO42− anion with an association constant of Ka = 2.4 × 104 M−1 in the

Ka (M−1) >108 1.79 × 1.84 × 1.08 × 3.53 × 1.92 × 3.21 × 2.22 × 4.09 × 12

107 105 104 106 105 103 104 102

Theoretical calculations also supported this binding mode as deduced from 1H NMR studies in solution (Figure 61). The results indicated that all Hf protons in triazole units are directed toward the center of the porphyrin unit and create an optimal cavity for the formation of hydrogen bonding with halides. Because the triazole Csp2−H group is directed toward the center of the porphyrin, all halides become very close to the metal, and the tilted conformation of the triazole groups means they are tilted in the same direction, resulting in the effective formation of Csp2−H···A− hydrogen bonds.

7. USE OF NEUTRAL CSP2−H AND CATIONIC H−C+SP2 INTERACTIONS In 2014, our research group109 described the synthesis of a novel fluorescent bisbenzimidazolium, 87 (Figure 62), wherein 9926


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Figure 65. Optimized structure of the complex [89]2·SO4 using B3LYP/SVP, with the substituents omitted for clarity. Reprinted from ref 110. Copyright 2010 American Chemical Society.

molecule were visible. In contrast, the 2:1 complex showed contacts to the central phenyl ring and the other end of the molecule, which was only possible if the two ligands arranged in the desired orthogonal fashion. Figure 63. Changes in the 1H NMR spectrum of the receptor 87 in DMSO with the addition of up to 1.2 equiv of SO42− anions. Reprinted with permission from ref 109. Copyright 2015 Royal Society of Chemistry.

8. USE OF C+SP2−H AND H−N INTERACTIONS The combination of cationic C+sp2−H donor groups provided by pyridinium, quinolinium, 1,2,3-triazolium, and imidazolium and N−H donor groups from amine, amide, or urea units offers interesting possibilities not only for sensing anions but also in anion-templated formation of rotaxanes. In one case, a more significant involvement of the cationic C+sp2−H···A− interactions is observed than that seen for the N−H···A − interactions.

solvent mixture CD3CN/CD3OD (4:1, v/v), as calculated by 1 H NMR, while the receptor 89 shows a 1:2 anion/receptor stoichiometry for SO42− anion with association constants of K1 = 5.4 × 103 M−1 and K2 = 1.3 × 103 M−1. The structures of the receptors 88 and 89, and the proposed binding mode deduced from 1H NMR titrations, are shown in Figure 64.

8.1. Triazolium

In 2009, Beer and co-workers111 reported the synthesis of the triazolium-based [2]rotaxane 90 (Figure 66). This was

Figure 66. Molecular structure of the rotaxane 90. Figure 64. Proposed binding modes of the receptors 88 and 89 with SO42− anions.

performed starting from the triazolium motif incorporated in the axle and able to act as a C+sp2−H donor group, with the neutral isophthalamide macrocycle as a N−H donor group, using Cl− and Br− as templating anions. 1 H NMR anion binding studies on rotaxane 90 demonstrated that the presence of halide anions caused a significant downfield shift of the signals for the triazolium C+sp2−H proton as well as the isophthalamide N−H protons of the macrocycle. Additionally, the inner phenyl Csp2−H proton of the macrocycle was shifted downfield. These downfield shifts confirmed that the

Theoretical calculations at the B3LYP/SVP level were realized to consolidate the proposed binding mode for the complex [89]2·SO42−. The obtained structure supported the presence of phenyl Csp2−H···A− and triazolium C+sp2−H···A− interactions (Figure 65). For the 1:1 complex, only a strong contact to the adjacent aromatic proton and moderately strong contacts to the triazolium protons on the same side of the 9927


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The anion recognition properties of rotaxane 92 were investigated by 1H NMR experiments in the competitive CDCl3/CD3OD (1:1, v/v) solvent mixture. Both Cl− and Br− anions were bound strongly by the rotaxane; the significant chemical shifts observed suggested the participation of both amide N−H···A− and triazolium Csp2−H···A− interactions in the anion binding event. The association constants calculated from the 1H NMR titrations showed the selectivity of the interlocked host for Br− and Cl− anions (Ka = 2.0 × 103 M−1) over the larger and more basic oxoanions AcO− and H2PO4−. Single-crystal X-ray structure analysis (Figure 69) revealed that the Br− anion is held within the interlocked cavity by

strength of the anion binding was enhanced greatly owing to the cooperative binding effects of both the triazolium axle and isophthalamide macrocycle within the unique highly preorganized three-dimensional cavity afforded by the interlocked rotaxane host structure. The rotaxane complexed Br− in the solvent mixture CDCl3/MeOD (1:1, v/v) with an association constant Ka = 970 M−1 calculated by 1H NMR, which was more than an order of magnitude stronger than that calculated for Cl− anions (Ka = 90 M−1). On the basis of a similar idea but using the naphthalimide triazolium moiety in the axle, the same research group reported112 the rotaxane 91 (Figure 67), which was synthesized

Figure 67. Molecular structure of the rotaxane 91.

by using Cl− anion templation. The rotaxane was demonstrated to exhibit selective binding for Cl− (Ka = 527 M−1) and Br− (Ka = 673 M−1) anions in the solvent mixture CDCl3/CD3OD (4:1, v/v) over the rest of the anions tested: I− (Ka = 173 M−1), H2PO4− (Ka = 83 M−1), and AcO− (Ka = 59 M−1). Addition of 1 equiv of Cl− anion to the rotaxane resulted in cooperative hydrogen bonding to the halide anion by the isophthalamide macrocycle and the triazolium thread as indicated by downfield shifts in the triazolium C+sp2−H proton and the isophthalamide N−H protons of the macrocycle. Importantly, the rotaxane also showed unidirectional shuttling behavior driven by anion binding and controlled by increasing the competitive nature of the solvent. Complete macrocycle translocation only occurred upon the recognition of the strongly bound smaller halide anions. The rotaxane 92 (Figure 68) was also reported by Beer and co-workers113 in which the anion binding site is composed by one triazolium C+sp2−H and one amide N−H donor group placed in the axle and two amide N−H donor groups at the isophthalamide macrocycle.

Figure 69. X-ray structure of the rotaxane 92+·Br− (CSD Refcode SOFFAW).

hydrogen bonds from triazolium, amide, and macrocycle phenylene protons. The hydrogen bonds from the axle triazolium C+sp2−H and amide N−H groups are of moderate strength, while the anion sits unsymmetrically within the macrocycle, forming one strong hydrogen bond and one weak hydrogen bond to amide donors from the macrocycle. Donor− acceptor interactions were observed between one of the macrocycle’s hydroquinone rings and the central phenylene of the axle component. 8.2. Pyridinium and Quinolinium

Gale, Loeb, and co-workers114 studied the anion complexation properties of the trans-functionalized platinum(II) isoquinoline pyridine complex 93 (Figure 70) in the competitive solvent DMSO. The receptor is capable of binding SO42− via N−H···O and C−H···O hydrogen-bonding interactions in a unique 3:2 receptor/SO42− stoichiometry. 1 H NMR titration demonstrated that the receptor 93 complexes anions by the cooperative action of the pyridinium C+sp2−H and the urea N−H protons present in their structure. Receptor 93 binds halides in a 1:2 receptor/halide stoichiometry with a K1 value higher than K2. The affinities of receptor 93 for halides were lower than those obtained for SO42− and H2PO4− anions (Table 13). Importantly, two different receptor-to-anion stoichiometries were observed for the complexes. The authors suggested that the receptors adopt an up−up conformation with 1:1 anion/ receptor stoichiometry when the concentration of the anion is below 1 equiv. The anion is bound by two urea groups oriented in the same direction on one face of the receptor. However, when the concentration of the anion is higher than 1 equiv, the receptor adopts an up−down conformation with the urea

Figure 68. Molecular structure of the rotaxane 92. 9928


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Csp2−H donor groups in the α-position of the heteroaromatic rings of the metal complexes form Csp2−H···O hydrogenbonding interactions with the anion. In all, there are 14 N−H and Csp2−H donor groups around each SO42− anion. This complex contains both the bonding modes proposed for anion binding in solution, the up−up conformation binding anions at low anion concentrations and the up−down conformation at higher anion concentrations. Tripodal trisurea cationic receptors 94 and 95, containing both urea and pyridinium functionalities (Figure 72), were synthesized, and their anion binding behavior was studied by 1 H NMR spectroscopy in DMSO and CD3CN by Steed and coworkers.115 Figure 70. Molecular structure of the receptor 93.

Table 13. Anion Binding Constants (Ka, M−1) of the Receptor 93 with Different Anions in DMSO, As Obtained by 1H NMR Spectroscopy114 anion Cl− Br−

receptor 93 K1 K2 K1 K2

= = = =

2350 450 942 131

anion I− SO42− H2PO4−

receptor 93 K1 K2 K1 K2 K1

= = > = >

161 16 104 7800 104


groups oriented on different faces of the receptor, with each urea binding two different halide anions. The X-ray structure of the complex 93·2Br− revealed that the receptor adopts an up−down conformation in the solid state. The Br− anion was bound by the receptor via four pyridine and isoquinoline C+sp2−H···Br− hydrogen bonds and a single urea N−H···Br− hydrogen bond (Figure 71). On the other hand, the structure of the complex of receptor 93 with the SO42− anion revealed a 3:2 binding model. The metal complex 93 adopts an up−down conformation with each urea group bound to a SO42− anion. Each SO42− anion is also bound to another metal complex 93 adopting an up−up conformation. In addition,

1 H NMR studies demonstrated that the two host species displayed significant affinity for both halides and AcO− anions (Tables 14 and 15). An interesting trend was observed for the

Table 14. Anion Binding Constants (Ka, M−1) of the Receptor 94 with Different Anions in DMSO, As Obtained by 1H NMR Spectroscopy115 anion

K11

K12

K13

Cl− Br− I− NO3− AcO− HSO4− H2PO4−

436 2884 41 347 1622 85 5011

151 977 4 166 5012 40 4786

25 16 11 5 − 36 −

Table 15. Anion Binding Constants (Ka, M−1) of the Receptor 95 with Different Anions in Acetonitrile, As Obtained by 1H NMR Spectroscopy115 Aanion

K11

K12

K13

Cl− Br− NO3− AcO−

7079 4169 2884 40738

91 174 457 200

851 91 78 4677

halide binding behavior of receptor 94. The strongest association constant was obtained for the Br− anion, with K11 being an order of magnitude larger than that obtained for the Cl− anion. However, this anion produced the greatest changes in the 1H NMR chemical shift values of the urea N−H protons during the titrations. It is thought that the Br− selectivity of 94 arises from the difference in size between Cl− and Br−. The results also revealed the presence of pyridinium C+sp2−H···A−

Figure 71. X-ray structure of the bromide complex of the receptor 93 (CSD Refcode XOLJEO). Distances are given in angstroms. 9929


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interactions, despite the presence of “stronger” N−H donor groups. As expected, the flexible nature of the receptors allowed multiple host−guest stoichiometries in solution. Computational studies suggested that the lowest energy conformation for the complex 94·Cl− was one in which the three ureidopyridinium arms were oriented upward, forming a cavity that was sealed by C−H···π interactions, effectively forming a unimolecular capsule (Figure 73), whereas for 95 a less symmetrical “two-up, one-down” geometry was favored.

Figure 75. Schematic representation of the two isomers of the complex 96·Cl− (top). Changes in the 1H NMR spectrum of the receptor 96 with the addition of 1 equiv of different anions in CD3CN (bottom). Reprinted from ref 116. Copyright 2010 American Chemical Society. Figure 73. DFT-minimized structure of the 94·Cl− complex. Reprinted from ref 115. Copyright 2006 American Chemical Society.

downfield shifts of the proton NMR signals of pyridinium C+sp2−H groups relative to those of N−H groups were larger for the cationic receptors, reflecting more significant involvement of C+sp2−H···Cl interactions. The 1H NMR signals of both H2 and H6 protons were shifted equally. These results were consistent with the involvement of aminopyridine C+sp2− H groups in the hydrogen bonding of anions and showed that the binding can occur with the receptor in two conformations. Thus, the authors postulated the existence of two isomeric complexes, as shown in Figure 75, top. Protons H2 and H6 are equivalent in the receptor 97, and their equivalence is conserved during the titration with anions, which indicates a fast equilibrium between each other. Interestingly, an upfield shift of the signal for the N+−Me protons was observed, resulting from the inductive effect of the negative charge of the anion. The receptors 96−98 strongly bind F−, Cl−, Br−, I−, H2PO4−, AcO−, and NO3− in CD3CN with a 1:1 stoichiometry (Ka in the range of 3.23 × 103 to 2.81 × 106 M−1). The highest association constants, as calculated by 1H NMR, were obtained for Cl− anions (Table 16). The selectivity and the high affinity of the dicationic pyridine-2,6-dicarboxamides for anions was

The synergic action of charge-assisted C+sp2−H and amide N−H interactions was also explored by Yatsimirsky and coworkers116 in the study of the sensing capability of the dicationic receptors 96−98 (Figure 74) bearing the pyridine2,6-dicarboxamide unit as the N−H donor group and Nmethylated pyridinium or quinolinium rings. 1 H NMR spectroscopic anion titrations of the receptors 96− 98 in CD3CN showed significant downfield shifts of the signals of the amide N−H protons and the pyridinium and quinolinium H2 and H6 protons (Figure 75, bottom). The

Table 16. Anion Binding Constants (Ka, M−1) of the Receptors 96−98 with Different Anions in DMSO, As Obtained by 1H NMR Spectroscopy116 anion −

F Cl− Br− I− H2PO4− AcO− NO3−

Figure 74. Molecular structures of the receptors 96−98. 9930

96 1.90 1.86 1.73 6.3 1.58 2.51 1.28

× × × × × × ×

97 5

10 105 105 103 104 104 104

2.29 4.46 1.94 3.71 1.51 2.39 2.18

× × × × × × ×

98 4

10 105 104 103 105 105 104

1.41 2.81 1.23 1.65 1.99 3.23 5.75

× × × × × × ×

105 106 104 104 104 105 103


Chemical Reviews

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attributed by the authors to the rigid preorganized structure of the receptors, the high acidity of the amide N−H protons, the presence of C+sp2−H donor groups, and the electrostatic charge effect. The highly preorganized receptor117 99 exhibits an excellent selective sensing for H2PO4− anions by fluorescence spectroscopy in CHCl3. 1H NMR in DMSO solution and emission in CHCl3 solution studies allowed the authors to propose two different binding modes for the receptor 99 with H2PO4− anions (Figure 76). In the first instance, the presence of up to 1


abundant sialic acid, by a combination of neutral/chargereinforced hydrogen bonds, ion pairs, and C−H−π and van der Waals interactions in highly competitive aqueous DMSO media. The global association constants (β) calculated for the complexes, which form 2:1 receptor/anion stoichiometries in all cases, were found to be around 107 M−2.

Figure 76. Proposed binding mode of the receptor 99 in the presence of 1 (top) or 2 (bottom) equiv of H2PO4− anions.

equiv of H2PO4− anions promoted the formation of a complex with a 1:1 receptor/anion stoichiometry, where the two amide N−H protons and two pyridinium ring C+sp2−H protons act as hydrogen bond donors to bind one anion, producing an observable enhancement of excimer emission by the anthracene moiety. The presence of more than 1 equiv of H2PO4− promoted a conformation change in the receptor to bind two anions with a 1:2 receptor/anion stoichiometry, and the enhancement was only observed in the monomer emission. The resulting association constants calculated from fluorescence titrations were K11 = 3.0 × 104 M−1 and K12 = 5.0 × 104 M−1. 1H NMR studies showed that the amide proton and the hydrogen proton of the pyridinium ring displayed a remarkable downfield shift with increasing addition of H2PO4−, indicating the presence of hydrogen-bonding interactions between the N−H proton together with the acidic 4-C−H or 2-C−H pyridinium proton and H2PO4− anions. On the other hand, the remaining hydrogen protons at the pyridinium ring shifted upfield, implying the participation of electrostatic interactions between the pyridinium ring and the anion. The combination of cationic pyridinium or quinolinium together with neutral aminopyridine groups has been shown to be a useful way to obtain building blocks for the construction of receptor molecules for anionic carbohydrates.118 The combination of C+sp2−H and neutral amine N−H recognition groups in the receptors 100−105 (Figure 77) was responsible for effective binding of N-acetylneuraminic acid, the most naturally

8.3. Imidazolium

In 2011, Kim and co-workers reported119 the fluorescent imidazolium-based cholestane receptor 106 (Figure 78). Anion binding studies on the receptor 106 using UV−vis and fluorescence spectroscopies revealed that the receptor 106 binds anions strongly in CH3CN and in the aqueous mixture CH3CN/H2O (9:1, v/v). The Job plot experiment revealed a 1:1 stoichiometry for all of the tested anions (H2PO4−,

Figure 78. Molecular structure of the receptor 106. 9931


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HP2O73−, HSO4−, F−, and CH3COO−). The highest association constants obtained from the emission titration data were found to be Ka = 1.6 × 105 M−1 for H2PO4− and Ka = 1.6 × 105 M−1 for HP2O73− anions in CH3CN, which were 2 orders of magnitude higher than those calculated in the aqueous solvent mixture CH3CN/H2O (9:1, v/v). The presence of all of these anions induced a decrease of the monomer emission bands of the receptor 106; thus, addition of 10 equiv of H2PO4− and HP2O73− caused 95% and 90% quenching, respectively, while the quenching of the other anions was around 20−40%. On the contrary, an increase in the fluorescence was observed after the addition of the different anions in the solvent mixture CH3CN/H2O (9:1, v/v). From a molecular mechanics calculation, it is evident from the optimized geometry that the guest was strongly bound in the cleft, involving a large number of hydrogen bond interactions with both the oxygens of the H2PO4− anion and the imidazolium protons. Both of the amines, as well as the imidazolium protons, form hydrogen bonds through C+sp2−H··· O− and N−H···O−H interactions. (Figure 79).

CD3OD (9:1, v/v) suggested that hydrogen bonding of one of the triazolium C+sp2−Ha protons (Δδ ≈ 0.7 ppm), and anion−π interaction with the other triazolium ring (Δδ ≈ − .1 ppm) of the receptor, occurred simultaneously during the recognition process of the HP2O73− anion with receptors 107 (Ka = 3000 M−1) and 109 (Ka = 4526 M−1) (Figure 81), whereas receptors

Figure 81. Changes in the 1H NMR chemical shift of the triazolium C+sp2−Ha proton of the receptor 107 during the addition of increasing amounts of HP2O73− in CD3CN/CD3OD (9:1, v/v). Reprinted with permission from ref 120. Copyright 2014 Royal Society of Chemistry.

108 and 110 bind the HP2O73− exclusively by anion−π interactions with Ka = 1310 M−1 and Ka = 1305 M−1, respectively. On the other hand, the H2PO4− anion was bound to the receptors by combined interactions of cationic C+sp2−H protons of the triazolium units and neutral Csp2−H protons of the central naphthalene unit. All receptors underwent a downfield shift of the triazolium protons as well as the inner naphthalene protons in the presence of this anion. Theoretical calculations provided a model for the unexpected unsymmetrical H−π interactions. The anion interacts on one side with the hydrogen atom of the triazolium C+sp2−H unit and on the other side with the triazolium ring by anion−π interaction. Besides two naphthalene Csp2−H groups pointing toward an oxygen atom, the O−H group points toward the naphthalene ring in an almost O−H··π interaction (Figure 82).

Figure 79. Optimized structure of the complex 106·H2PO4− at the Hartree−Fock 3-21G(*) level. Reprinted with permission from ref 119. Copyright 2011 Elsevier.

9. USE OF C+SP2−H AND ANION−π INTERACTIONS Recently, the bistriazolium-based receptors120,121 107−110 (Figure 80) were synthesized, and their capabilities as chemosensor molecules for anion recognition were studied by our research group. The anion recognition mechanism was found to be strongly dependent on the oxoanions used, as well as the electronic nature of the substituents at the 4-position of the triazolium rings. 1H NMR experiments in the solvent mixture CD3CN/

Figure 82. Optimized structure of the complex 1072+·HP2O73− using B97D/6-31+G(d). Reprinted with permission from ref 120. Copyright 2014 Royal Society of Chemistry.

Electrochemical studies to evaluate the electrochemical sensing properties of the receptor 110 were performed by Osteryoung square-wave voltammetry (OSWV) in CH3OH. The results revealed that only the addition of HP2O73− induced significant changes in the redox peak (ΔE = 63 mV) of the ferrocene/ferrocenium redox couple of the end-capped ferrocene units.



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The synergic action of both hydrogen bonding of the imidazolium C+sp2−H protons and the anion−-π interactions of the electron-rich triethylbenzene with F− anions was demonstrated by Yoon and co-workers122 in the receptor 111 (Figure 83). This receptor contains three imidazolium rings inserted

Figure 85. Optimized structure of complex 111·F− at the TPSS-D/ aVDZ level of theory in acetonitrile solvent. Reprinted with permission from ref 122. Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA.

from this work. First, clear evidence has been obtained for participation of anion−π interactions in anion recognition events in solution. Second, a relevant structural feature related to the nature of the anion−π interactions is that these interactions are possible even for electron-rich aromatic systems when the induction effect is large enough to compensate for the electrostatic repulsion.


between two substituted benzene rings with the three imidazolium C+sp2−H hydrogen atoms directed toward the cyclophane cavity. Selective complexation of the F− anion by combination of anion−π interactions and C+sp2−H···F−-type ionic hydrogen bonds takes place in the cyclophane cavity bridged with three naphthoimidazolium groups. 1 H NMR experiments in CD3CN showed that the addition of F− anions to a solution of the receptor 111 induced a dramatic downfield shift in the resonance of the imidazolium C+sp2−H protons (from δ = 6.43 ppm to δ = 12.60−12.81 ppm) and the splitting of the signal into a doublet (J = 84 Hz, spin− spin coupling between imidazolium C2−H and F−). The 19Fdecoupled 1H NMR spectrum of the complex 111·F− displayed a broad singlet at δ = 12.71 ppm (Figure 84). 19F NMR

10. USE OF C+SP2−H AND H−O INTERACTIONS A strategy based on the simultaneous use of these types of interactions has been successfully applied for the design of highly selective chemosensors for chiral recognition of α-amino acids and natural hydroxycarboxylates. The anion sensing properties of the chiral imidazoliumfunctionalized BINOL receptor (R)-112 (Figure 86), in which

Figure 86. Molecular structure of the receptor (R)-112.

the imidazolium groups are directly attached to the 3,3′ -positions of BINOL, were explored by Yu and co-workers123 in 2009 toward halide, AcO−, and HSO4− anions. Furthermore, the chiral recognition of the two enantiomers of α-aminocarboxylates was also studied, the receptor displaying a remarkable binding ability for the [(tert-butyloxy)carbonyl]alanine anion in CH3CN (obtained from emission studies) with a noteworthy enantioselectivity (KL/KD = 4.5). UV−vis and fluorescence experiments in CH3CN revealed that only F− and AcO− anions promoted significant changes in the absorption and emission spectra of the receptor (R)-112, which showed excellent selectivity for F− over AcO−. In addition, the colorless (R)-112 solution became markedly yellow after the addition of F−, while a pale yellow color was induced by the AcO− anion. An 1H NMR experiment showed that the most obvious changes were observed in the presence of the F− anion: the imidazolium C2−H unit displayed a large downfield shift, while several aromatic peaks split to multiplets. Two effects were responsible for the signal changes to the expected strong C+sp2−H···A− ionic hydrogen bonding between the C2−H of the imidazolium rings and the anion. An overall change to the electronic distribution and the strong high-field shift of the naphthyl proton signal were observed, giving

Figure 84. 1H NMR spectra of the receptor 111 in CD3CN (a) with the addition of 0.5 equiv of F− anion (b) and 1 equiv of F− anion (c). (d) shows the 19F coupling of the receptor 111 with 1 equiv of F− anions. Reprinted with permission from ref 122. Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA.

experiments also suggest the inclusion of the F− anion in the cavity, and a substantial upfield shift of the signal for the free fluoride from δ = −115.4 ppm to δ = −47 ppm and splitting of this signal into a quartet (J = 84 Hz) were observed in the presence of the receptor 111. The association constant (Ka = 6.8 × 10 −5 M −1 ), stoichiometry (1:1 F−/receptor), and all the thermodynamic parameters of the binding event were obtained by isothermal titration calorimetry. Theoretical calculations at the TPSS-D/ aVDZ level support the F− binding by the receptor 111 via hydrogen bonding of the imidazolium C+sp2−H protons and anion−π interactions (Figure 85). The F− anion is stabilized inside the cage with the formation of C+sp2−H···F− ionic hydrogen bonds, whereas the anion−π interaction, though small, is key for the selectivity of F−. Two trends have surfaced 9933


Chemical Reviews

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evidence for the deprotonation. Addition of the AcO− anion induced strong hydrogen bonding with the C2−H protons of the imidazolium ring and the synergic coordination with the phenolic hydroxyl O−H protons. The most stable conformers of host−guest complexes were theoretically investigated (Figure 87). The optimized geometry of the complex (R)-

Figure 87. Optimized structure of the complex (R)-112·AcO− carried out at the B3LYP/6-31G* level. Reprinted from ref 123. Copyright 2009 American Chemical Society. −

Figure 88. Molecular structures of the receptors (R)-113 to (R)-116.

imidazolium ring, provided nearly no enantioselectivity. In contrast, the Me-protected macrocycle 115 gave a moderate enantioselective recognition (KD/KL = 2.1), and the methoxymethyl (MOM)-protected macrocycle 114 showed enhanced enantioselectivety with a KD/KL value as high as 6.2. Interestingly, the KD/KL selectivities of 114 and 115 toward Trp are the inverse of those of 112 and 116 (Table 17).

−

112·AcO showed a strong C sp −H···A ionic hydrogen bond between the C2−H imidazolium ring and AcO−. Meanwhile, strong O−H···A− hydrogen bonds could also form between the phenolic hydroxyls and oxygen atoms of the AcO−. This example reveals clearly that, in the reviewed anion recognition strategy, synergistic coordinations play a critical role in the binding process. One year later, the same group extended its research124 and studied the effect of the rigidity and the importance of the presence of the imidazolium C+sp2−H···A− hydrogen bonding in the selective recognition of α-aminocarboxylates in aqueous solutions by receptors (R)-112 to (R)-116 (Figure 88). The anion binding studies on the imidazolium-functionalized BINOL receptors (R)-112 to (R)-116 were investigated by UV−vis and fluorescence experiments toward various natural αamino acids in aqueous solutions under the physiological pH value (pH 7.4). The experimental results revealed that the structurally open receptor (R)-112 exhibits the more significant selectivity and affinity toward L-tryptophan (L-Trp) over the other α-amino acids tested. The macrocyclic 114 exhibits a remarkable chiral recognition capability with a KD/KL of 6.2, ascribed to a reduced cavity size leading to a better fit, thus making the enantiodiscriminating compliment of interactions more effective. Despite the methylation at the C2 hydrogen of the imidazolium nucleus of 112, the imidazolium ring was identified as a strong hydrogen bond donor in the selective recognition process. Thus, small or negligible changes in the fluorescence spectrum of 113 were detected in the presence of α-amino acids. A similar experiment performed with the receptor (R)-115 demonstrated the selective sensing of this receptor for L-Trp α-amino acid. The analysis of the calculated association constant obtained by emission spectroscopy of the receptors (R)-112 to (R)-116 for Trp in aqueous solutions (10 mM HEPES buffer, pH 7.4) revealed that the acyclic 112 displayed a small KD/KL value for Trp, while the acyclic 113, lacking the C2 hydrogen of the +

2

Table 17. Anion Binding Constants (Ka, M−1) of the Receptors (R)-112 to (R)-116 with Tryptophan (Trp) in Aqueous Solution (10 mM HEPES Buffer, pH 7.4), As Obtained by Emission Spectroscopy124 receptor (R)-112 (R)-113 (R)-114 (R)-115 (R)-116

L-Trp

1.73 8.04 2.89 2.59 4.78

× × × × ×

104 10 103 103 103

D-Trp

KD‑Trp/KL‑Trp

× × × × ×

0.6 1.0 6.2 2.1 0.7

1.09 8.34 1.79 5.42 3.38

104 10 104 103 103

The optimized geometry of the (R)-112·L-Trp complex at the HF/STO-3G* level revealed a 1:1 stoichiometry for the multiply hydrogen-bonded complex between (R)-112 and LTrp, in which the strong interactions between the carboxyl group of L-Trp and the chiral ligand, including two C+sp2−H atoms of two imidazolium rings and one aryl hydroxyl group, were observed. Additional hydrogen bonds formed between the indole unit (N−H) and the other hydroxyl group stabilize the complex (Figure 89). The binding properties of receptors 117−120 (Figure 90) bearing chiral cyclohexanols and two or three imidazolium rings attached to a central phenyl ring125 were studied toward citrate, isocitrate, and the two enantiomers of malate. 1 H NMR experiments in CD3CN/CD3OD (9:1, v/v) revealed that receptor 117 binds the dianionic malate (Ka = 6.3 × 103 M−1) stronger than the trianionic citrate (Ka = 4.9 × 103 M−1) or isocitrate (Ka = 3.9 × 103 M−1). The calculated association constants obtained for receptors 119 and 120 were 9934


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Figure 89. Optimized geometry of the complex (R)-112·D-Trp at the HF/STO-3G* level. Reprinted with permission from ref 124. Copyright 2010 Royal Society of Chemistry.

Figure 91. Optimized structures of the complexes (a) 117·Cit, (b) 117·L-Mal, and (c) 117·D-Mal. Reprinted from ref 125. Copyright 2014 American Chemical Society.

11. USE OF C+SP2−H AND H−CSP3 INTERACTIONS This “hybrid” C−H interaction is found in systems in which the charged C+sp2−H donor group belongs to a 1,2,4-triazolium or imidazolium ring, whereas the neutral Csp3−H donor group is provided by methylene groups N-linked to these systems. This strategy has been used for the fluorescent sensing of organic phosphates. Cyclic and acyclic bile-acid-based 1,2,3-triazolium receptors showed a remarkable ability to recognize anions through C− H···X hydrogen bond interactions.126 The anion binding properties of the triazolium-based receptors 121−123 (Figure 92) were studied by monitoring the 1H NMR spectral changes after addition of several types of anions to a CDCl3 solution of the receptors. 1 H NMR titration binding studies of the receptors with halide, AcO−, and H2PO4− anions revealed important downfield shifts (δ = 1.3−0.9 ppm) for both triazolium C+sp2−H protons. Additionally, significant downfield shifts were also observed for the bridging methylene Csp3−H protons (Figure 93), which clearly indicate the participation of these protons in the recognition process, along with the C5 triazolium protons. The calculated anion/receptor stoichiometry for all of the anions was 1:1, and the highest association constant was found to be for the acyclic receptor 123 with H2PO4− anions (Ka = 1920 M−1) (Table 18). The binding mode proposed by the authors is shown in Figure 94. Interestingly, the acyclic receptor 123 showed much higher affinity and selectivity toward the H2PO4− ion as compared to the cyclic receptors 121 and 122, which may be attributed to the greater flexibility of the acyclic receptor than

Figure 90. Structures of the imidazolium-based receptors 117−120.

slightly lower than those observed for 117 and 118 due to a combination of a larger number of electrostatic and hydrogenbonding interactions and a more efficient preorganization in the cone-type conformation. The optimized geometries of the complexes of 117 with the two enantiomers of malate led to the conclusion that the selectivity was due to the cooperative action of the imidazolium C+sp2−H···A− and O−H···A− interactions and the lower geometrical distortion of the receptor from the cone conformation that occurred with the malate ion (Figure 91). A reasonable difference was observed in the disposition and interactions of the hydroxyl alcohol group of the malate. For the D-enantiomer, the corresponding O−H is pointing away, thus precluding any interaction with the host, whereas in the Lenantiomer, the malate hydroxyl group is pointing to the host, possibly establishing a C−H···O−H hydrogen bond. This could account for the moderate L-selectivity exhibited by the receptor 117. 9935


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the cyclic receptor for adopting the geometry required for the binding of a tetrahedral H2PO4− anion. Anion sensing studies by fluorescence spectroscopy were performed with ATP, GTP, CTP, TTP, UTP, ADP, and AMP (adenosine 5′-triphosphate, guanosine 5'-triphosphate, cytidine 5′-triphosphate, thymidine 5′-triphosphate, uridine 5'-triphosphate, adenosine 5'-diphosphate, and adenosine 5'-monophosphate) nucleotides. The receptors used were the twoarmed anthracene-derivative-based molecules127 124−126 (Figure 95) bearing two imidazolium C+sp2−H and Csp3−H bonds as hydrogen donor groups adjacent to two or four ammonium functionalities acting as hydrogen donors.


Figure 93. Partial 1H NMR spectrum of the receptor 123 (bottom) and after the addition of 2.5 equiv of Cl− anion (top) in CD3Cl. Reprinted from ref 126. Copyright 2009 American Chemical Society.

Table 18. Anion Binding Constants (Ka, M−1) of the Receptors 121−123 with Different Anions in CDCl3, As Obtained by 1H NMR126 anion

121

122

123

F− Cl− Br− I− AcO− H2PO4−

560 270 220 100 60 −

370 690 450 200 25 1100

360 390 200 110 30 1920


The anion binding studies of the receptors 124−126 by fluorescence techniques at pH 7.4 (10 nM HEPES) revealed that receptor 124 showed a large fluorescent quenching effect with GTP (Ka = 8.7 × 104 M−1) and a weaker fluorescent enhancement with ATP (Ka = 1.5 × 104 M−1). On the other hand, different fluorescent changes were observed in the 9,10isomer 125. The presence of TTP-, CTP-, and UTP-induced fluorescent enhancements was observed in the receptor 125, while GTP (Ka = 2.4 × 104 M−1) and ATP (Ka = 5.1 × 104 M−1) induced a significant fluorescent quenching effect; ADP and AMD also promoted fluorescent quenching effects but to a lesser extent. Compound 126 displayed a large fluorescent enhancement with ATP (Ka = 7.7 × 103 M−1) and CTP, while smaller fluorescent enhancements with ADP (Ka = 2.3 × 103 M−1) and AMP (Ka = 2.0 × 103 M−1) were also observed. In contrast, GTP (Ka = 4.1 × 103 M−1) induces significant fluorescence quenching. Theoretical calculations revealed that important hydrogenbonding interactions such as T-shaped H−π interactions between the base of ATP/GTP/AMP and the anthracene moiety can be clearly seen in the complexes. In addition to the H−π interaction, it is believed that the electrostatic interactions between the positively charged moieties of 125 and 126the

Figure 94. Proposed binding mode for the receptor 123 with the H2PO4− anion. 9936


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C+sp2−H unit of the imidazolium moiety, the Csp3−H hydrogen atoms of the alkyl chain, and the (N−H)+ groups of the protonated amine and phosphate moieties of the ATP/GTP have a significant contribution. In the same context, anthracene derivatives bearing two imidazolium groups at the 1,8- and 9,10-positions, as well as quaternary ammonium groups, display the ability to recognize nucleotides though C+sp2−H and N+−H hydrogen donor groups. In an effort to develop new and effective sensors for the biologically important ATP toward the other structurally related nucleoside triphosphates (GTP, CTP, UTP, and TTP) under physiological conditions (pH 7.4) or in aqueous solutions, in 2009, Yoon and co-workers128 reported the twoarmed tetraimidazolium-based receptor 127 (Figure 96), which

12. USE OF CSP3−H AND H−N INTERACTIONS Methylene groups linked to nitrogen functionalities (N− CH2−) connected to amines or urea groups have shown capability as donor groups through Csp3−H interactions, which together with the well-known ability of the N−H functionality to act as a donor group provides a simple structural motif for the design of anion receptors able to act by combination of these interactions. The cooperative action of Csp3−H···A− and amine N−H···A− interactions has been explored in thiophene-based macrocyclic receptors 128 and 129 in D2O and DMSO129 (Figure 98).

Figure 98. Molecular structures of the receptors 128 and 129. 1

H NMR experiments suggested that the macrocyclic receptors bind H2PO4− anions in DMSO with a 1:2 receptor/anion stoichiometry, and the reported association constants were found to be β = 1.77 × 105 M−2 for the receptor 128 and β = 1.58 × 104 M−2 for the receptor 129. The same studies performed in D2O with the receptor 128 showed moderate binding for H2PO4− (Ka = 200 M−1), providing a good fit to a 1:1 binding model. However, under identical conditions, no binding of the H2PO4− anion was detected in the receptor 129. X-ray structural analysis of the H2PO4− complex with the receptor 128 revealed that each macrocycle adopts the shape of a flat ellipsoid and binds two H2PO4− groups: one is HPO42−, and the other is H2PO4−, located above and below the elliptical plane. The complex is established through electrostatic interactions and multiple hydrogen bonds. The monohydrogen phosphate is held by two N−H···O and two Csp3−H···O bonds, while the dihydrogen phosphate interacts through two strong N−H···O bonds and one weak N−H···O bond. As a result, the monohydrogen phosphate is closer to the cavity than the dihydrogen phosphate. In conclusion, both N−H···O and Csp3− H ···O interactions play key roles in stabilizing the host−guest complex (Figure 99). The synergic action of Csp3−H···A− and amine N−H···A− interactions was also explored in the preorganized macrobicyclic azaphane 130 (Figure 100), which behaves as a selective chemosensor molecule for F− anions.130 Anion binding studies of the receptor 130 were made by potentiometric methods in DMSO in the presence of 0.01 M TsOH and 0.1 M TsONa as the supporting electrolyte. The calculated association constants revealed strong interactions of the receptor 130 with F− and Cl− anions (Table 19). Compound 130 in its hexaprotonated form displayed high selectivity for F− over Cl− (log KF/log KCl > 5), while no response was observed for Br− or NO3− anions. The weak binding of Br− in particular is surprising given that this anion (and I−) is included in the cavity in the solid state; however, it is likely that inclusion of larger halides introduces significant


was end-capped with a pyrene ring. The excimer emission band of the photoactive pyrene ring acts as a signal source, and the four imidazolium rings act as anion binding sites. The different fluorescent response of the receptor observed for ATP relative to the rest of the nucleotides tested could be explained by the formation of an additional π-stacking interaction between ATP and the pyrene units present in the receptor that is not observed with the other nucleosides. The presence of the ATP anion induced downfield shifts of the signals for the alkyl H4 proton (0.21 ppm) and the imidazolium H9 (0.58 ppm) and H10 (0.62 ppm) protons in the 1H NMR spectrum of the receptor. Theoretical calculations also supported the action of multiple C+sp2−H···A− and Csp3−H interactions between the receptor and ATP (Figure 97). Interestingly, receptor 127 was successfully applied to sense ATP in living HeLa cells.

Figure 97. Optimized structure of the complex 127·ATP at the B97D/TZV2P level. Reprinted from ref 128. Copyright 2009 American Chemical Society. 9937


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Figure 99. X-ray structure of the complex 128·2H2PO4− (CSD Refcode UNAXIS).

Figure 101. X-ray structure of the receptor 130 hosting the F− anion (CSD Refcode BIHQAL).


Table 19. Anion Binding Constants (Ka, M−1) of the Receptor 130 with Different Anions at Different States of Protonation in DMSO, As Obtained from Potentiometric Titrations130 anion

130·H6X

130·H5X

130·H4X

130·H3X

F− Cl− Br− NO3−

3.46 × 109 1.54 × 104 − −

6.91 × 107 7.58 × 103 − −

4.46 × 105 1.14 × 102 − −

7.24 × 104 − − −


through Csp3−H···F− interactions, forming a hexacoordinate complex (Figure 103).

strain and hence destabilizes solution binding, particularly involving unfavorable anion···π interactions. The X-ray structure of the F− complex clearly shows the formation of three simultaneous N−H···A− and three Csp3−H··· A− hydrogen-bonding interactions between the receptor and the F− anion (Figure 101). Anion binding studies on the urea-based molecular cleft131 131 (Figure 102) derived from a propylene-linked dipodal amine in DMSO showed that the receptor binds F−, HSO4−, H2PO4−, and AcO− anions in a 1:1 binding mode via a range of hydrogen-bonding interactions. The highest association constant, obtained from 1H NMR titrations in DMSO, was for the F− anion (Ka = 346 M−1), although the selectivity toward the rest of the anions tested was low for Cl− (Ka = 50 M−1), HSO4− (Ka = 148 M−1), H2PO4− (Ka = 162 M−1), and AcO− (Ka = 239 M−1). The interactions of receptor 131 with F− have also been evaluated on the basis of DFT. Theoretical calculations revealed that a strong electrostatic potential is created inside the cleft due to the presence of nitro groups on the aromatic spacers, making the host effective for anion recognition. In the complex, the F− anion is coordinated by all four N−H groups via N−H··· F− bonds and also forms two additional hydrogen bonds

Figure 103. Optimized structure of the complex 131·F−. Reprinted with permission from ref 131. Copyright 2015 Elsevier.

13. USE OF N−H AND H−N′ INTERACTIONS Due to large amounts of nitrogen functionalities bearing a N− H moiety able to act as an anion binding site through hydrogen bond interactions, there are a number of possibilities to design anion receptors containing different N−H groups. The nature of this group may be either acyclic (e.g., urea, amine, amide, and guanidine) or cyclic (pyrrole or fused pyrroles such as indole, carbazole, etc.). Consequently, this is the most popular strategy for the design of multibinding anion receptors. An advantage of this methodology is the fact that the acidity of the N−H group, and consequently its tendency toward deproto9938


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nation or complex formation, may be modulated by the electronic nature of the substituent present in the receptor skeleton. Bis(amidopyrrolyl)methanes 132 and 133 have been shown to exhibit selectivity for oxoanions from a variety of putative anionic guest species.132 1H NMR titrations in two different competitive mixtures (DMSO/D2O (5%) and DMSO/D2O (25%)) were used to determine the association constants of the receptors 132 and 133 (Figure 104) against F−, Cl−, Br−,


ppm in 134), which indicated that those protons were the most directly involved in the recognition process. The calculated association constants indicated that the appended pyrrole receptor 135 binds the anionic guest stronger than the receptor 134 (Table 21).


H2PO4−, HSO4−, and PhCOO− anions. The complexation of these anions takes place through four convergent hydrogen bonds, two amide N−H hydrogen bonds and two pyrrole N−H hydrogen bonds. This compound forms extended hydrogenbonded sheets in the solid state. Pyrrole N−H and amide N−H groups form a convergent hydrogen-bonding array coordinating a carbonyl group from an adjacent molecule. The association constants calculated from 1H NMR titrations in DMSO/D2O (5%) showed that receptors 132 and 133 bind F− and PhCOO− with a 1:1 stoichiometry and high association constant (Table 20), although unfortunately an adequate fit for

Table 21. Anion Binding Constants (Ka, M−1) of the Receptors 134 and 135 with Different Anions in Acetone/ D2O (5%, v/v), As Obtained by 1H NMR Spectroscopy133 anion −

AcO PhCOO− H2PO4− HP2O73−

Table 20. Anion Binding Constants (Ka, M−1) of the Receptors 132 and 133 with Different Anions in DMSO/ D2O (5%, v/v) (a) and DMSO/D2O (25%, v/v) (b), As Obtained by 1H NMR Spectroscopy132 anion F− Cl− Br− H2PO4− HSO4− PhCOO−

132

133

7560 (a) 11 (b) 23 (a) 13 (a) 20 (b) 44 (a) 354 (a)

8990 (a) 114 (b) 43 (a) 10 (a) 234 (b) 128 (a) 424 (a)

134

135

304 513 206 435

1036 889 831 9081

DFT-based quantum chemical calculations supported the hydrogen-bonding interactions observed by 1H NMR (Figure 106). Receptor 135 strongly binds the hydrogen pyrophos-

H2PO4− could not be obtained. Perhaps the most notable result from these studies was the fact that compound 133, a neutral hydrogen bond donor, was found to complex H2PO4− very strongly (Ka = 234 M−1) in the solvent mixture DMSO/D2O (25%, v/v); however, this anion was bound only weakly by the receptor 132 (Ka = 20 M−1). A comparative study between neutral amido-substituted benzodipyrrole-based receptors 134 and 135 (Figure 105) was reported by our research group in 2009.133 Anion binding studies carried out by 1H NMR spectroscopy in acetone/D2O (5%, v/v) mixtures revealed significant downfield shifts in the N−H proton signals of the benzodipyrrole (Δδ = 1.6−2.9 ppm in 134; Δδ = 2.7 ppm in 135), the N−H proton signals of the amide groups in the side arms (Δδ = 0.4−0.9 ppm in 134; Δδ = 0.6−1.6 in 135), and the end-capped pyrrolic N−H proton signals (Δδ = 0.4−1.7

Figure 106. Most stable calculated structure for the complex 135· HP2O73− using hybrid metafunctional mPW1B95. Reprinted with permission from ref 133. Copyright 2009 Royal Society of Chemistry.

phate anion due to the simultaneous action of a relatively preorganized benzodipyrrole diamide central scaffold together with the peripheral pyrrole substituent, yielding up to six strong hydrogen bonds. Gale and co-workers134 reported the synthesis and anion sensing capabilities of 2-amidopyrroles and 2,5-diamidopyrroles 136−139 (Figure 107). Due to solubility problems of receptors 9939


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137 and 139 in CD3CN, a comparative study of the anion binding capability was only possible with receptors 136 and 138.


H NMR titration demonstrated that receptor 138 showed a good selectivity for the PhCOO− anion toward the rest of the anions tested in CD3CN. Both receptors show selectivity for the benzoate anion, binding this anion with association constants of 202 and 2500 M−1, respectively. The H2PO4− anion is also complexed, albeit with a smaller association constant (Table 22). On the other hand, 1H NMR studies on Figure 108. Proposed binding modes of PhCOO− with receptors 136 and 138.

Table 22. Anion Binding Constants (Ka, M−1) of the Receptors 136 and 138 with Different Anions in CD3CN, As Obtained by 1H NMR Spectroscopy134 anion

136

138

F− Cl− Br− H2PO4− PhCOO−

134 28 104 (a) 1360 (b)

Cl−

104 >104

16 567 736 4790

Table 28. Anion Binding Constants (Ka, M−1) of the Receptor 161 with Different Anions in DMSO/D2O (0.5%), DMSO/D2O (10%), and DMSO/D2O (25%), As Obtained by 1H NMR Spectroscopy144 anion

DMSO/D2O (0.5%)

DMSO/D2O (10%)

DMSO/D2O (25%)

Cl− AcO− PhCOO− H2PO4−

128 >104 >104 >104

17 774 521 5170

− 20 precipitate 160

Table 29. Anion Binding Constants (Ka, M−1) of the Receptors 162 and 163 with Different Anions in DMSO/ D2O (0.5%), As Obtained by 1H NMR Spectroscopy144 anion −

Cl AcO− PhCOO− H2PO4−

Figure 123. X-ray structure of the protonated receptor 159·HCl (CSD Refcode POXPEY). Distances are given in angstroms. 9945

162

163

128 2830 514 3830

74 1620 477 1630 DOI: 10.1021/acs.chemrev.6b00814 Chem. Rev. 2017, 117, 9907−9972

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The obtained X-ray structures of the complexes showed that the receptors adopt almost planar conformations in the solid state and are able to bind the anions by four simultaneous hydrogen bonds, two from the urea/thiourea N−H protons and two from the indole N−H protons (Figure 125). To fill the

Figure 127. Chemical shifts of the indole N−H (left) and one of the urea N−H protons (right) of the receptor 165 in CD3OD during the addition of different anions. Reprinted from ref 145. Copyright 2010 American Chemical Society.

X-ray structures of the complexes also supported the formation of synergic hydrogen bonds between the receptors and the anion. All N−H groups form hydrogen bonds with oxygen atoms of the anion, and judging by the N−O distances, indole moieties bind the anion more strongly than urea groups. Receptor 166 was able to bind H2PO4− via eight complementary hydrogen bonds (Figure 128).

Figure 125. X-ray structure of the complex 163·Cl− (CSD Refcode WOLQEU). Distances are given in angstroms.

coordination sphere of CO32− or PO43−, two or three receptors bind to each anion in the solid state; thus, these oxoanions were stabilized by 8 or 12 hydrogen bonds. In closely related work, Jurczak and co-workers145 described the preferential binding of tetrahedral oxoanions by neutral acyclic ureidoindole-containing receptors 164−166 (Figure 126).

Figure 128. X-ray structure of the complex 166·HPO4− (CSD Refcode FACWIR). Distances are given in angstroms.

The tricationic (guanidiniocarbonyl)pyrrole receptor146 167 (Figure 129) is able to recognize citrate 169 and other tricarboxylates such as trimesic acid tricarboxylate 168 with unprecedentedly high association constants in aqueous solvent mixtures, as demonstrated by 1H NMR, UV−vis, and fluorescence spectroscopic studies. The association constants calculated by 1H NMR spectroscopy were higher than 105 M−1 in the solvent mixture DMSO/ D2O (10%). Molecular modeling calculations and nuclear Overhauser effect spectroscopy (NOESY) experiments suggested that the tricarboxylate anions 168−170 were bound by the guanidiniocarbonyl protons and pyrrole N−H protons within the cavity of receptor 167. Additionally, the ion pairing between the anions and the guanidinium group also increased the strength of the bond. Upon addition of trimeric acid 168 to a solution of receptor 167 in DMSO/H2O (10%), significant complexation-induced shift changes of the amide N−H and the pyrrole C−H proton NMR signals were observed, indicating a strong molecular interaction between 167 and 168. The signals for the ethyl groups attached to the central benzene ring did not show any shift changes, demonstrating that they do not participate in the binding process.


1

H NMR studies in CD3OD evidenced the simultaneous participation of both urea and indole protons in the anion recognition event (Figure 127). The highest association constants obtained for receptor 165 were Ka = 535 M−1 and Ka = 280 M −1 for H2PO4− and HSO4−, respectively. Surprisingly, the introduction of two additional indole units in 166 did not result in stronger anion binding than those observed in receptor 165. These results could be explained by the higher acidity of the urea protons. Values of Ka calculated for different N−H protons are generally in good agreement, showing that both urea and indolyl protons can equally participate in the anion binding event. It seems that the urea group interacts slightly more strongly with oxoanions and the indole moiety with halides. 9946


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A new class of binding motif for anions was reported by Hunt and co-workers147 in 2009. The skeleton of the binding site was composed by a combination of pyrrole and sulfonamide units, and its sensing capability was explored in the model receptors 171−174 (Figure 131).


Anion recognition studies conducted by 1H NMR spectroscopy with receptors 171−174 and Cl−, Br−, HSO4−, and NO3− anions in dry CDCl3 showed that both pyrrole and sulfonamide N−H proton signals experienced significant downfield shifts of Δδ = 0.5−1.2 ppm and Δδ = 1.5−2.3 ppm, respectively, in the presence of the anions, which clearly indicated the participation of both units in the anion recognition process (Figure 132).

Figure 129. Molecular structures of the receptor 167 and the tricarboxylates 168−170.

The obtained energy-minimized complex structure is shown in Figure 130. The substrate (yellow) lies atop the benzene ring

Figure 132. Changes in the 1H NMR chemical shifts of the pyrrole N−H and sulfonamide N−H proton signals of the receptor 173 during the addition of HSO4−, Br−, Cl−, and NO3− anions in CDCl3. Reprinted with permission from ref 147. Copyright 2009 Royal Society of Chemistry.

Figure 130. Optimized structure of the complex between the receptor 167 and the tricarboxylate 168 using Macromodel V 8.0, the Amber* force field, and generalized Born/surface area (GB/SA) water solvation treatment. Reprinted from ref 146. Copyright 2005 American Chemical Society.

The study of the obtained association constants revealed that the receptors 171 and 172, containing only a single pyrrole and sulfonamide, present lower association constants than those obtained for the bisanalogues 173 and 174. High association constants were obtained for the receptors 173 (Ka = 1768 M−1) and 174 (Ka = 867 M−1) for the HSO4− anion. The pyrrole N− H proton signals experienced a 0.5−1.2 ppm change in chemical shift upon addition of the exogenous guest, while the sulfonamide N−H protons generally experienced slightly larger changes in chemical shift, ca. 1.5−2.3 ppm. Computational studies predicted the structure of the disulfonamide 174· HSO4− complex to involve five hydrogen bonds. Each pyrrolesulfonammide moiety was in the syn conformation,

of the receptor (gray) within the van der Waals distance, probably allowing for an attractive π-stacking between the electron-rich benzene ring of 167 and the electron-poor trimeric acid tricarboxylate 168. Each carboxylate group is bound by one of the (guanidiniocarbonyl)pyrrole arms by ion pair formation with the guanidinium cation and additional hydrogen bonds from the pyrrole N−H and the amide N−H hydrogen atoms. The receptor 167 can be seen as a “molecular flytrap”, as in the absence of a substrate the three arms point away from each other and upon binding the three arms close up and completely surround the guest. 9947


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stacking interactions of the ATP with the receptors. The larger constant found for the interaction of the anthracene receptors with ATP may be due to the fact that the more hydrophobic local environment of anthracene will favor electrostatic interactions and hydrogen bonding. A greater π−π stacking contribution in the anthracene system could also be argued. Along the same line, the bisphenanthridinium−adeninebased receptor149 183 (Figure 135) displayed a high affinity

and both N−H protons are hydrogen bonded to the same oxygen atom of HSO4− (Figure 133).

Figure 133. Optimized structure of the complex 174·HSO4−. Reprinted with permission from ref 147. Copyright 2009 Royal Society of Chemistry.


toward the complementary nucleotide uridine 5′-monophosphate (UMP) with an association constant of Ka = 7.76 × 106 M−1 in water obtained from emission titrations. Theoretical calculation studies revealed that the selectivity found for 183 toward UMP compared to the other nucleotides tested was due to the formation of a number of intra- and intermolecular aromatic stacking interactions, i.e., between phenanthridinium subunits, covalently attached adenine, and added UMP, while the selectivity of adenine conjugates toward UMP with respect to the other nucleotides is most likely the consequence of additional hydrogen bonds between uracil UMP and adenine. This result was supported by UV−vis experiments wherein a hypochromic effect was observed. Hydrogen bonds between uracil and 183 were also responsible for the UMP recognition (Figure 136).

14. USE OF N−H AND π-STACKING INTERACTIONS Compounds 175−182 (Figure 134), open-chain polyamines linked at one or both ends to anthrylmethyl or naphthylmethyl


Figure 136. Optimized structure of the complex 183·UTP. Reprinted with permission from ref 149. Copyright 2010 Elsevier.

moieties, were tested as anion-based receptors for the recognition of adenosine 5′-triphosphate (ATP) in aqueous solution by potentiometric titration, 1H, 13C, and 31P NMR, and fluorescence spectroscopic measurements.148 The results revealed that the receptors bearing one anthracene moiety bind ATP stronger than the receptor containing one naphthalene moiety. The stabilities of the compounds with both ends N-substituted with naphthylmethyl groups were close to those containing just one anthrylmethyl unit. The strong binding found for the anthracene-based receptor with ATP was explained by both the amine N−H hydrogen-bonding interactions and additional formation of π-

15. USE OF N−H AND H−O INTERACTIONS A comparative study of the anion binding and sensing behavior of the receptors 184 and 185 (Figure 137), which incorporate two indole rings substituted with chromogenic azobenzene units and additional O−H hydrogen bond donor groups, was performed by Jeong and co-workers.150 An analysis of the calculated association constants (Table 30) and the chemical shift observed from 1H NMR titration experiments in the solvent mixture DMSO/CD3CN (1:9, v/v) allowed the authors to conclude that basic oxoanions bind more strongly to 184 and 185, as commonly seen in anion receptors 9948


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Table 30. Anion Binding Constants (Ka, M−1) of the Receptors 184 and 185 with Different Anions in DMSO/ CD3CN (1:9, v/v)150 anion

184

F− Cl− Br− I− N3 − AcO− H2PO4− NO3− HSO4−

deprotonation 57 1.0 × 106 1.9 × 103 2.0 × 105 4.3 × 103 7.7 × 103 −

Figure 154. Optimized structures of the complexes cis-212·Cl− and trans-212·Cl− at the B3LYP/6-31G* level. Reprinted from ref 158. Copyright 2014 American Chemical Society.

workers. 159 The bis(phenylcarbamoyl)-functionalized tetraoxacalix[2]arene[2]triazine receptor 213a (Figure 155)

Figure 155. Molecular structures of the receptors 213a and 213b.

exhibits a selective recognition of H2PO4− anions in CH3CN by the cooperative action of hydrogen-bonding and anion−π interactions. The association constant calculated on the basis of fluorescence titration curves for H2PO4− anions was found to be Ka = 7.98 × 103 M−1 for the receptor 213a, almost 10 times higher than that found for the receptor 213b (Ka = 8.14 × 102 M−1), where hydrogen-bonding interactions were not present. Single-crystal X-ray data of 213a solvated with CH3CN revealed a 1,3-alternate conformation in which two triazine rings form an electron-deficient V-shaped cleft. Acetonitrile was included in this cavity, and the two phenylcarbamoyl groups seem to self-adjust their orientations to create a cavity to accommodate CH3CN. In addition to the observation of noncovalent interactions, such as intramolecular hydrogen bonding between two amide moieties and lone-pair electron−π interactions between one amide oxygen atom and one of the triazine rings, the observation of multiple noncovalent interactions between the host and guest was noteworthy. In 2007, Mascal and co-workers reported the first practical solid-state application of anion−π bonding in a purpose-

Figure 153. 1H NMR titrations of (a) cis-212 and (b) trans-212 upon the addition of F− anions in CD3CN. Reprinted from ref 158. Copyright 2014 American Chemical Society.

isomer, featuring anion−π interactions, showed cross-reactivity toward anions, while the trans isomer displayed a more selective response to anions, namely, AcO−. Interestingly, the association constants obtained from the UV−vis titrations of cis-212 were higher than those of the receptor trans-212 (Table 35). The different binding modes were also supported by theoretical calculations (Figure 154). In the case of the cis212 isomer, the model revealed that the pyrrole side arms contribute to anion binding by 2-fold anion−π interactions. By contrast, the trans isomer 212 formed the receptor−anion complex solely on the basis of hydrogen bonding, without any contribution from anion−π interactions. A tailor-made macrocyclic host able to act as a multivariate receptor for anions through cooperative anion−π and hydrogen bond interactions has been described by Wang and co9954


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designed macrocyclic anion host.160 The cyanuric acid-based cylindrophane 214 (Figure 156a) can be easily triprotonated to

Figure 156. (a) Structure of the receptor 214. (b) X-ray structure of the complex [H3-214-F][BF4]2 (CSD Refcode KISDIA).

give the solid complex [H3-214]3+, which forms an inclusion complex with F− anions by a combination of anion−π interactions and ion-pair-reinforced hydrogen bonding. Cage 214 introduces a new class of anion binding, whereby anion−π interactions operate alongside conventional ion pairing, hydrogen bonding, and the classic “preorganization” effect. An X-ray crystal structure of the [H3-214-F]2+ sandwich complex (Figure 156b) shows the F− ion occupying the center of the cavity, the distance between the centroid of the trimethylcyanuric acid model and the F− ion being 2.68 Å and the hydrogen bond length between the trimethylammonium group and the F− ion being 2.79 Å. Receptor [H3-214]3+ shows no affinity for Cl− anions in the electrospray mass spectrum and indeed has been predicted by comparative binding energetics in models to be completely fluoride-selective. No solution-state study of this interaction has yet been reported.


17. USE OF N−H AND XB INTERACTIONS 17.1. Rotaxanes

The Beer group has extensively shown that three-dimensional interlocked anion host molecular frameworks display a high degree of selectivity for the templating anion.161,162 For example, rotaxane 215 (Figure 157) was synthesized via the Br− anion-templated, halogen-bonding iodotriazolium axle and an isophthalamide-based macrocycle as the N−H donor unit, allowing a comparative study between the rotaxane with a halogen atom in its cavity and the hydrogen-bonding analogue 163 by 1 H NMR in a CDCl 3 /CD 3 OD/D 2 O (45:45:10) solvent mixture. 1 H NMR experiments using the halide anions Cl−, Br−, and − I demonstrated that the rotaxane 215 showed a preference for the larger halide anion I− (Ka = 2228 M−1), in contrast to the protic triazolium analogue 90, which was Br−-selective. Additionally, the analogous protic rotaxane showed a lower association constant than that calculated for the halogenbonding 215. The preference of the rotaxane 215 for I− anions was attributed by the authors to the accessibility of the binding site to larger anions and weaker competition for the more lipophilic halide by the aqueous solvent medium. The obtained X-ray structure of the rotaxane 215+·Br− (Figure 158) clearly confirms the interlocked nature of the system and the key role

Figure 158. X-ray structure of the rotaxane 215+·Br− (CSD Refcode TACPUK). Distances are given in angstroms.

played by the halogen-bonded anion templation in its assembly. The Br− anion is coordinated by both the triazolium iodine atom C+sp2−I and the amide protons. The halogen bond is lengthened slightly, due to the competitive hydrogen bonding with the Br− anion. The assembly is further stabilized by charge-assisted π−π stacking and secondary hydrogen bonding between the triazolium methyl group and the polyether chain of the macrocycle. A slight variation of this strategy was based on the use of a carbazole as a spacer motif on which was appended halogenbonding iodotriazolium groups. The central core unit offers the possibility of acting as a fluorescent probe to sense binding events. The mixed halogen- and hydrogen-bonding rotaxane host 216 (Figure 159), containing a bis(iodotriazolium) carbazole axle and an isophthalamide-based macrocycle, showed good 9955


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selectivity for Br− anions (Ka > 104 M−1) compared to the other halide anions tested, including Cl− (Ka = 2.3 × 103 M−1) and I− (Ka = 7.5 × 102 M−1), and the oxoanions AcO− (Ka = 25 M−1) and H2PO4−, with very weak binding in a CDCl3/CD3OD/ D2O (45:45:10) mixture.164 The association constants were calculated by 1H NMR titrations, and the affinity of the rotaxane for Br− anions was explained on the basis of the complementary size and shape of the cavity in the rotaxane, in which the halide is located and complexed by the isophthalamide N−H protons of the two C+sp2−I groups of the triazolium axle. High-affinity anion binding by neutral noncovalent receptors in pure water still represents a formidable challenge for supramolecular chemists. In this context, Beer and co-workers have demonstrated the potential superiority of halogen bonding over hydrogen bonding in achieving anion binding in water. They reported the synthesis and anion binding studies in pure water of a mixed hydrogen- and halogen-bonding rotaxane,165 217. The association constant calculated by 1H NMR in D2O revealed that the rotaxane 217 binds I− strongly (Ka = 2.2 × 103 M−1), with an excellent selectivity toward Cl− (Ka = 55 M−1), Br− (Ka = 2.9 × 102 M−1), and SO42− (Ka = 30 M−1) anions. Thermodynamic studies indicated that the anion binding of the halogen-bonded rotaxane is driven exclusively by favorable enthalpic contributions arising from the halogenbonding interactions. By comparison, the anion binding by the hydrogen-bonded rotaxanes 218 and 219 was entropically driven. These observations demonstrate the unique nature of halogen bonding in water as a strong alternative interaction to the ubiquitous hydrogen bonding in molecular recognition and assembly (Figure 160). Throughout the molecular dynamics simulations, the three halide complexes exhibit an orthogonal arrangement of the axle and macrocyclic components in the interlocked structure. Receptor 217 tightly coordinates each halide anion via two independent linear halogen-bonding interactions, assisted by two intermittent N−H···X− hydrogen bonds. The anions are positioned slightly above the plane of the macrocycle with the N···X− and I···X− distances mirroring the increasing size of the halide anion (Figure 161). Rotaxane 220, featuring a halogen-bonding axle component, which is stoppered with water-solubilizing permethylated βcyclodextrin motifs and a luminescent tris(bipyridine)ruthenium(II)-based macrocycle component, allowed the same authors166 to optically sense the selective binding of I− in water (Figure 162). In this case, the association constant in D2O for I− anions calculated by 1H NMR spectroscopy (Ka = 6.3 × 103 M−1) was considerably higher than those found for

Figure 160. Molecular structures of the rotaxanes 217−219. Reprinted with permission from ref 165. Copyright 2014 Nature Publishing Group.

Figure 161. Molecular dynamics snapshot of the rotaxane 217+·I−. Reprinted with permission from ref 165. Copyright 2014 Nature Publishing Group.

Cl− (Ka = 1.9 × 102 M−1), Br− (Ka = 1.02 × 103 M−1), and SO42− (Ka = 4.5 × 102 M−1). The presence of the tris(bipyridine)ruthenium(II)-based luminescent signaling units within the I−-selective rotaxane 220 allowed the authors to study the anion sensing of this halide anion by means of the modulation of the metal-to-ligand charge transfer (MLCT) emission from the transition metal. The presence of an excess of I− and Br− anions (1 mM) in a solution of the rotaxane 220 in water (1 × 10−5 M) induced an enhancement (6% for I− anion and 3% for Br− anion) and 3 nm hypsochromic shift in its emission band. This behavior was 9956


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macrocycle and the C+sp2−X (X = I or H) units of the triazolium axle (Figure 164).

Figure 164. Molecular structure of the two-station rotaxane 223 and the schematic representation of the molecular motion of the isophthalamide-containing macrocycle wheel component.

Figure 162. Molecular structure of the rotaxane 220. Reprinted with permission from ref 166. Copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA.

17.2. Catenanes

explained by the authors as “the increased rigidity of the strong I− rotaxane complex compared to the free rotaxane, which reduces the available nonradiative vibrational relaxation pathways that contribute to quenching of the emissive excited state”. No changes in the emission spectrum of the rotaxane were observed in the presence of Cl− anions. The dynamic behavior of the anion complexes of halogen-bonded rotaxane 220 and the halide anions was investigated by means of molecular dynamics calculations. Rotaxane 220 binds each halide anion using two independent halogen-bonding interactions complemented by two N−H···A (A = Cl−, Br−, or I−) hydrogen bonds. The first example of using halogen-bonding anion recognition to control the molecular motion of an interlocked structure was reported by Beer and co-workers.167 The different binding affinities for Cl− and I− anions in CDCl3/CD3OD (1:1, v/v) exhibited by the hydrogen-bonded triazolium and halogenbonded iodotriazolium rotaxanes 221 and 222 (Figure 163),

An isophthalamide-containing macrocycle and bromo- or iodofunctionalized pyridinium threading components were used for the construction of the interlocked catenanes 224 and 225168 (Figure 165).

Figure 165. Molecular structures of the rotaxanes 224 and 225.

The anion recognition properties of the catenanes, obtained using 1H NMR spectroscopic experiments in the competitive solvent mixture CDCl3/CD3OD (1:1 v/v), demonstrated preferential recognition of the heavier halides I− and Br− over Cl− and AcO−. The iodopyridinium-containing catenane 225 showed higher association constants than those obtained with the bromopyridinium-functionalized catenane 224 (Table 36), which is in accordance with the greater halogen bond donor ability of the iodine atom relative to the bromine atom. Upon addition of halide anions to both catenane species, significant downfield shift perturbations of the o-isophthalamide proton and the β-pyridinium proton were observed with increasing anion concentration. Thus, through the combination of noncovalent halogen- and hydrogen-bonding interactions, Br− and I− anions were able to template the formation of


respectively, were used to demonstrate molecular motion of the isophthalamide-containing macrocycle wheel component. Given the halogen-bonding and hydrogen-bonding bistability of rotaxane 223, upon I− recognition, the macrocyclic wheel moved from the hydrogen-bonding triazolium station to the halogen-bonding triazolium station. The contrasting chemical shift perturbations of the two signals corresponding to the N−CH3 triazolium protons suggest that the macrocycle has moved from the hydrogenbonding triazolium station to the halogen-bonding triazolium station upon I− recognition. The halide recognition takes place by the synergic action of the two amide N−H protons of the

Table 36. Anion Binding Constants (Ka, M−1) of the Catenanes 224 and 225 with Different Anions in CDCl3/ CD3OD (1:1, v/v), As Obtained by 1H NMR Spectroscopy168 anion −

Cl Br− I− AcO− 9957

224

225

130 200 220 −

160 230 340 − DOI: 10.1021/acs.chemrev.6b00814 Chem. Rev. 2017, 117, 9907−9972

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binding cavity of the halogen-bonding catenane is of complementary size and shape for halides, whereas the oxoanions are too large and are of the wrong geometry for encapsulation. Single-crystal X-ray structural analysis indicates that the [2]catenane host framework 227 binds the halide anions within the cavity (Figure 168). By contrast, the AcO− and H2PO4−

interpenetrative macrocycle assemblies with halo-functionalized pyridinium threading components. The hetero[2]catenane169 226 (Figure 166), comprised of one hydrogen-bonding macrocycle and one halogen-bonding


macrocycle, was synthesized via an anion-templated Grubbs IIcatalyzed ring-closing metathesis (RCM) clipping, mechanical bond forming methodology. Anion binding studies using 1H NMR spectroscopy and fluorescence titration experiments in CH3CN revealed that the interlocked catenane 226 binds AcO− and H2PO4− via two N− H hydrogen bonds from the isophthalamide-containing macrocycle and one halogen bond from the iodotriazolium-containing macrocycle with high association constants (Ka = 1.5 × 105 M−1 and Ka = 4.5 × 105 M−1, respectively). Fluorescence anion titration experiments revealed that the addition of Cl−, Br−, I−, AcO−, and H2PO4− anions promoted important changes in the monomer/excimer ratio of the naphthalene units of the catenane 226. An enhancement of the monomer emission band was observed in all cases, but it was most significant for AcO− and H2PO4− anions. The authors postulated that the anion is bound between the two naphthalene groups, preventing the formation of the excimer emission band. An interesting contribution of the Beer group revealed the first evidence of intense pre-edge features characteristic of charge transfer between the halide donor and the halogenbonding receptor.170 The halogen-bonding bis(iodotriazole) pyridinium motif was shown to be a potent anion-coordinating motif in the competitive aqueous medium D2O/CDCl3/ CD3OD (10:45:45), especially when incorporated into a [2]catenane host structural framework, 227 (Figure 167). Halogen-bonding interactions were more covalent in character than comparable hydrogen-bonding interactions. The association constants calculated by 1H NMR in D2O/ CDCl3/CD3OD (10:45:45) were greater than 104 M−1 for I− and Br− anions, and the association constant for Cl− anion was Ka = 1850 M−1, while no binding was detected for AcO− and H2PO4− anions. This suggests that the unique interlocked host

Figure 168. X-ray structure of the rotaxane 227+·Cl− (CSD Refcode CUJTOS). Distances are given in angstroms.

oxoanions were found outside the three-dimensional binding pocket, which could explain the selectivity found in solution. While both hydrogen and halogen bonds are observed between the host and the anionic guest, the catenane adopts an open conformation rather than completely encapsulating the anion. Additional Cl and Br K-edge X-ray absorption spectroscopy studies clearly indicate an important degree of covalency in the halogen-bonding interaction, similar to that observed in transition-metal complexes. 17.3. Urea

In a seminal work, Taylor and co-workers171 studied an anion receptor equipped with both halogen bond and hydrogen bond donor functional groups, demonstrating that it is indeed possible to employ these interactions cooperatively in molecular recognition. To this end, a series of urea-based receptors bearing π-deficient arene groups, 228−238 (Figure 169), were prepared, and their sensing behavior was tested toward different kinds of anions. 1 H and 19F NMR spectroscopy and computational studies (Figure 170) indicated that both interactions are involved in the recognition process, which leads to unusual effects on receptor selectivity. The authors affirm that halogen- and hydrogen-bonding receptors display anion selectivity that represent a compromise between the distinct preferences of the two interactions, which could therefore represent an unconventional approach in the design of new anion receptors. The authors also estimated the contribution of the halogenbonding interaction to the free energy of anion binding whereby the contribution was dependent on the geometric features of the group linking the hydrogen bond and halogen bond donor groups and on the identity of the bound anion. The explanation for this was based on the high directionality of the halogen-bonding interaction and its preference for halides over oxoanions. The calculated association constants and the

Figure 167. Molecular structure of the rotaxane 227. 9958


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Table 37. Anion Binding Constants (Ka, M−1) of the Receptors 228−233 in CH3CH with Halide Anions and Free Energy Contributions of the Halogen-Bonding Interaction (ΔΔGXB), As Obtained by UV−vis171 receptor 228 229 228 229 228 229 230 231 230 231 230 231 232 233 232 233 232 233

anion −

Cl Cl− Br− Br− I− I− Cl− Cl− Br− Br− I− I− Cl− Cl− Br− Br− I− I−

Ka (M−1)

ΔΔGXB (kcal/mol)

× × × × × × × × × × ×

103 103 103 103 102 102 103 103 103 102 102

−0.2 ± 0.1

× × × × ×

103 103 103 103 103

−0.3 ± 0.1

8.5 6.5 1.7 1.4 1.3 1.0 8.0 1.7 2.4 3.7 2.2 55 4.9 3.1 9.4 5.0 1.1 61

−0.1 ± 0.1 −0.2 ± 0.1 −0.9 ± 0.1 −1.1 ± 0.1 −0.9 ± 0.1

−0.4 ± 0.1 −0.3 ± 0.1

bonding rotaxane, which cooperatively used two iodotriazole and two iodotriazolium halogen-bonding donor groups. The anion-templated all-halogen-bonding rotaxane 239 (Figure 171) combines the bis(iodotriazole)-based macrocycle


Figure 171. Molecular structure of the rotaxane 239. −

Figure 170. Optimized structure of the complex 237·Cl using B3LYP/6-31G(d,p)-LANL2DZdp. Reprinted from ref 171. Copyright 2011 American Chemical Society.

and the bis(iodotriazolium)-functionalized carbazole axle suitable for binding anions, in turn enabling the investigation of its anion binding capabilities. Receptor 239 also incorporates a photoactive rhenium(I) bipyridyl as a fluorescent signaling unit within the macrocycle component.172 Anion binding titrations performed by luminescence spectroscopy in CH3CN/H2O (10%) revealed that the presence of I− anions promotes the most notable optical response, with a significant quenching of the fluorescence of the rotaxane, whereas Cl− and Br− anions cause an initial increase of the fluorescence followed by a subsequent decrease in the intensity. No response was observed after addition of AcO− and H2PO4− anions, suggesting no binding. The calculated association constants indicated that the rotaxane 239 was able to bind and sense the halide anions Cl−, Br−, and I− through halogen-bonding C+sp2−I···A− and Csp2−I···A− interactions with high association constants in very competitive aqueous mixtures, up to 50% H2O in CH3CN. Interestingly, a closer analysis of the obtained association

free energy contributions of the halogen-bonding interactions (ΔΔGXB) are summarized in Table 37. These interesting results allowed the authors to conclude that cooperation between two distinct noncovalent interactions leads to unsusual effects on receptor selectivity as a result of fundamental differences in the interaction of halogen bond and hydrogen bond donor groups with anions.

18. USE OF XB+ AND XB INTERACTIONS As discussed above, the Beer group reported the first halogenbonding rotaxane, containing an iodotriazolium axle that selectively bound I− through a combination of halogen- and hydrogen-bonding interactions. In addition, a halogen-bonding catenane was shown to selectively bind Cl− and Br− through cooperative halogen-bonding bromoimidazolium donor groups. The same group reported the synthesis of the first all-halogen9959


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Table 38. Anion Binding Constants (Ka, M−1) of the Rotaxane 239 with Different Anions in a Range of H2O/CH3CN Mixtures, As Obtained by Emission Spectroscopy172 anion −

F Cl− Br− I−

K11 (M−1) (10% H2O)

K12 (M−1) (10% H2O)

K11 (M−1) (20% H2O)

K12 (M−1) (20% H2O)

K11 (M−1) (50% H2O)

− 1.09 × 104 1.05 × 105 1.38 × 105

− 6.45 × 102 2.63 × 103 5.49 × 103

− 3.09 × 103 3.09 × 104 8.91 × 104

− 4.27 × 102 7.41 × 102 4.07 × 104

− 5.13 × 102 5.75 × 103 2.40 × 104

constants concluded that the increase in the amount of water had practically no effect on the association constant values for halide anions, remaining in the same magnitude, especially for the heavier halides (Table 38). Interestingly, no binding was detected for a wide range of oxoanions.

19. USE OF MORE THAN TWO NONCOVALENT INTERACTIONS The neutral ferrocene−triazole-based receptor 240 (Figure 172) selectively recognizes H2PO4− and HP2O73− anions in Figure 173. Changes in the 1H NMR spectrum of the receptor 240 in CD2Cl2 with the addition of Cl−, H2PO4−, and HP2O73−. Reprinted from ref 173. Copyright 2011 American Chemical Society.


CH2Cl2 by using the cooperative action of the triazole Csp2−H, phenyl Csp2−H, and ferrocene Csp2−H hydrogen-bonding interactions.173 Electrochemical studies by cyclic voltammetry (CV) revealed that only H2PO4− and HP2O73− induced a remarkable cathodic shift of the ferrocene/ferrocinium redox couple. By contrast, Cl−, Br−, I−, PF6−, HSO4−, and AcO− anions did not promote any changes in the voltammogram. These facts were explained on the basis of the different binding modes deduced from the 1 H NMR spectroscopic experiments. They indicated that the Cl−, Br−, I−, PF6−, HSO4−, and AcO− anions are recognized by the receptor without the cooperation of the ferrocene units, and no downfield shifts of the ferrocene protons were observed, although the presence of H2PO4− or HP2O73− induced a downfield shift of the ferrocene protons Hc by Δδ = 0.17 and Δδ = 0.10 ppm, respectively (Figure 173). In addition, these anions promoted considerable changes in the triazolium Ha and aromatic Hb protons, demonstrating that these protons may also be involved in the binding event. Theoretical calculations support the binding modes deduced from the 1H NMR titrations (Figure 174). Receptor 240 selectively recognizes a H2PO4− anion in such a manner that all the triazole Csp2−H, inner benzene Csp2−H, and α-ferrocene Csp2−H bonds take part in the Csp2−H···O hydrogen bonding, which induced a large cathodic shift in the CV. By contrast, for Cl− anion binding, the α-ferrocene proton is excluded from the H-bonding, and consequently, no changes in CV were observed. A number of two-armed 2,4,5-trimethylimidazolium-based oxoanion receptors, 241−244, which incorporated two endcapped photoactive anthracene rings, with the central core

Figure 174. Optimized structures of the complexes 240·H2PO4− (left) and 240·Cl− (right) at the B3LYP/6-31G* level. Reprinted from ref 173. Copyright 2011 American Chemical Society.

being an aromatic or heteroaromatic ring (Figure 175), were recently reported by our research group.174 1 H NMR experiments in CD3CN/CD3OD (95:5, v/v) including several types of anions clearly indicated the simultaneous occurrence of several charge-assisted aliphatic Csp3−H and aromatic Csp2−H noncovalent interactions. Addition of HP2O73− anions to a solution of the receptor 241 in CD3CN/CD3OD (95:5, v/v) induced significant downfield shifts for the imidazolium C2−Csp3−H3 (Hm) protons, the methylene N−CH2 (Hj) protons, and the inner aromatic (Hh) proton (Figure 176). Receptors 241 and 244, bearing a meta-substituted phenyl ring and the analogous 2,6-disubstituted pyridyl moiety, respectively, exhibit remarkable binding affinities for SO42− ions, being almost 5 times higher than those calculated for HP2O73−. The utilization of naphthalene and m-phenyl units in receptors 242 and 243, respectively, caused an inversion in the selectivity, and HP2O73− was the preferred anion. The key role of the aromatic Csp2−H protons pointing into the cavity was manifested by the fact that the receptors 241 and 242 displayed moderate association constants for H2PO4− anions, whereas in receptors 243 and 244, where these protons are absent, no binding for H2PO4− anions was detected (Table 39). The emission binding studies showed that the presence of HP2O73−, 9960


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Figure 175. Structures of the 2,4,5-trimethylimidazolium-based receptors 241−244.

H2PO4−, and SO42− promoted a significant quenching in the monomer emission band of the receptor, whereas no important changes were observed after addition of HSO4−, NO3−, Cl−, Br−, I−, ClO4−, or BF4− anions. DFT calculations clearly showed short contacts between the oxygen atom of the anions and the hydrogen atoms of the receptor, mainly Hi and Hm. Moreover, complexes derived from 241 present an additional interaction involving the aromatic hydrogen Hh. In addition, the AIM method confirms the establishment of intermolecular O···H−Csp2 interactions between the anions and the trimethylimidazolium scaffolds (Figure 177). Using a skeleton similar to that of the previously described receptors 241 and 242, our research group reported175 a comparative study of charge-assisted hydrogen- and halogenbonding capabilities in solutions of the two-armed imidazolium receptors 245 and 246 toward oxoanions (Figure 178). The halogen-bonding receptor 245 acted as a selective fluorescent molecular sensor for H2PO4− anions in CH3CN, since only this anion promoted the appearance of the anthracene excimer emission band. 1H NMR titration experiments in CD3CN/MeOD (8:2, v/v) and theoretical calculations demonstrated the synergic action of the inner naphthalene Csp2−H and the methylene Csp3−H hydrogen bonds, together with the imidazolium C+sp2−Br halogenbonding interaction in the complexation of H2PO4− anions. A Jobs plot experiment revealed a 2:1 H 2PO4−/receptor stoichiometry. Receptor 245 also binds SO42− with a 1:1 stoichiometry. The calculated association constants for the halogen-bonding complexes in a competitive solvent mixture were higher than those found for the hydrogen-bonding counterpart. In contrast, the binding affinity for anions in the less competitive solvent was stronger in the hydrogen-bonding receptor 246 (Table 40). In addition, this halogen receptor behaves as a chemodosimeter toward HP2O73− anions. Receptor 245 was also successfully tested as an imaging agent in living cells in a wide range of emission wavelengths.

Figure 176. 1H NMR spectral changes observed for the receptor 241 in CD3CN/CD3OD (95:5, v/v) during the addition of HP2O73− ions. Reprinted from ref 174. Copyright 2016 American Chemical Society.

Table 39. Association Constants (Ka, M−1) Obtained by 1H NMR Spectroscopy for Receptors 241−244 with Different Anions in CD3CN/CD3OD (95:5, v/v)174 receptor

HP2O73−

241

1267

242

6542

243 244

2234 853

H2PO4− K11 K12 K11 K12 − −

= = = =

1828 656 4662 258

SO42− 5744 3840 868 3935

Recently, our research group has also reported176 the synthesis and anion binding studies of the racemic BINOL bistriazolium-based receptors 247−250 (Figure 179). 1 H NMR studies with several types of anions indicated the simultaneous occurrence of several charge-assisted aliphatic Csp3−H and heteroaromatic Csp2−H noncovalent interactions, and additional combinations of hydrogen- and halogen-bonding interactions in the binding process are also present (Figure 180). The receptors were able to selectively recognize HP2O73−, H2PO4−, and SO42− anions, and the value of the association 9961


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Figure 179. Structures of the triazolium-based receptors 247−250.

Figure 177. Optimized structures of the complexes (a) 241·SO42− and (b) 241·HP2O73− at the PCM(MeCN)-M06-2X/6-31+G(d,p) level. Reprinted from ref 174. Copyright 2016 American Chemical Society.

Figure 178. Structures of the imidazolium-based receptors 245 and 246.

Table 40. Association Constants Calculated for Receptors 245 and 246 with HP2O73−, SO42−, and H2PO4− Anions in CH3CN and CD3CN/MeOD (8:2, v/v)175 receptor

anion

stoichiometry

245 245

HP2O73− SO42−

− 1:1

245

H2PO4

246

HP2O7

246

SO42−

246

H2PO4

−

3−

1:2 1:2 1:1

−

1:2

CD3CN/MeOD (8:2, v/v)

CH3CN − Ka = 8.0 β= 5.0 β= 8.0 Ka = 1.4 β= 9.8

× 10 M 4

Figure 180. 1H NMR spectral changes observed in the receptor 250 in CD3CN/CD3OD (9:1, v/v) during the addition of up to 2.4 equiv of SO42−. Reprinted with permission from ref 176. Copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA.

−1

× 1011 M−2 × 1012 M−2 × 106 M−1 × 1011 M−2

− Ka = 5.3 β= 9.9 β= 3.3 Ka = 2.2 β= 5.6

× 103 M−1

Table 41. Association Constants for Receptors 247−250 with HP2O73−, SO42−, and H2PO4− Anions in CD3CN/ MeOD (9:1, v/v), As Obtained by 1H NMR Spectroscopy176

× 103 M−2 × 105 M−2 × 103 M−1 × 103 M−2

constant in CD3CN/CD3OD (9:1, v/v) follows the trend HP2O73− > SO42− > H2PO4− (Table 41). In the hydrogenbonding bistriazolium receptor 247, the triazolium protons were the most strongly affected signals, which were significantly shifted downfield. The presence of anions also promoted a remarkable splitting of the signals corresponding to the −O− CH2− and −CH2−N− protons. The doublet shown by the Hg proton attributed to the binaphthalene moiety was also shifted after the addition of anions. 9962

receptor

anion

K11 (M−1)

247 247 247 248 248 248 249 249 249 250 250 250

HP2O73− SO42− H2PO4− HP2O73− SO42− H2PO4− HP2O73− SO42− H2PO4− HP2O73− SO42− H2PO4−

× × × × × × × × × × × ×

7.9 5.5 3.2 3.6 2.5 1.3 5.2 2.5 1.0 3.7 2.9 1.1

3

10 103 103 103 103 103 103 103 103 103 103 103

K12 (M−1) − − 4.0 − − 1.2 − − 5.0 − − 7.0

× 102

× 103

× 102

× 102


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Anion binding studies by fluorescence spectroscopy in CH3CN showed that only the presence of H2PO4− anions promoted changes in the fluorescence spectrum of the receptors 247−249. A new band assigned to the formation of the eximer emission band was observed in the receptor 247, while only the increase in the intensity of the emission bands of the receptors 248 and 249 was observed during the addition of H2PO4−. In the structure of the complex 2472+·[H2P2O7]2−, the receptor is connected to the anion through its stronger hydrogen bond donor, the triazolyl Csp2−H, which acts as a hydrogen bond acceptor. In the crystal, every cation···anion unit was connected to another cation···anion unit. Thus, cation···anion···anion···cation complexes are formed through O−H···O(P) hydrogen bonds (Figure 181a). In the structure

The pyrrole-based triazolophane anion receptor177 251 (Figure 182), which incorporates three different binding sites


such as triazole Csp2−H, phenyl Csp2−H, and pyrrole N−H donor groups, showed selectivity for HP2O73− anions in CDCl3 solution with 1:1 stoichiometry, and the association constant was found to be Ka = 2.3 × 106 M−1, followed by those for HSO4− (Ka = 4.8 × 105 M−1), H2PO4− (Ka = 2.38 × 105 M−1), Cl− (Ka = 1.18 × 104 M−1), and Br− (Ka = 2.64 × 103 M−1). Host−guest interactions between macrocycle 251 and HP2O73− anions were studied by 1H NMR spectroscopy. Titration of the receptor 251 in CDCl3 clearly demonstrated the hydrogen-bonding interaction between the pyrrole N−H (Δδ = 5.09 ppm), triazole Csp2−H (Δδ = 1.96 ppm), and endocyclic hydrogen atom of the N′-linked phenyl ring Csp2−H (Δδ = 1.22 ppm) protons in the presence of HP2O73− anions (Figure 183). These changes followed the sequence of expected hydrogen acidity, namely, pyrrole N−H > triazole Csp2−H > benzene Csp2−H. The X-ray structure obtained of the complex with the HP2O73− anion indicated that both N−H and neutral Csp2−H interactions combine to effect HP2O73− anion recognition. In the complex, the macrocycle displayed a folded conformation; this provides a cliplike slot into which the HP2O73− anion

Figure 181. Crystal packing for compounds (a) 2472+·[H2P2O7]2− and (b) 2492+·SO42−. Reprinted with permission from ref 176. Copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA.

of 2492+·SO42−, every receptor molecule is connected by two different SO42− anions through C−I···OSO3 halogen bonds, with triazolyl Csp2−I bonds acting as halogen bond donors and one oxygen atom of each SO42− anion acting as a halogen bond acceptor. In the crystal structure, the receptor adopts a tubular supramolecular structure, in which all Csp2−I bonds point toward the inside of the molecular channel and all SO42− anions lie within the channels, thus forming supramolecular tubes (Figure 181b).

Figure 183. Changes in the 1H NMR spectrum of the receptor 251 during the addition of increasing amounts of HP2O73− anions in CDCl3. Reprinted from ref 177. Copyright 2010 American Chemical Society. 9963


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inserts. All the pyrrole N−H, triazole Csp2−H, and endocyclic benzene Csp2−H protons point toward the center of the ring and are involved in hydrogen bond interactions with the bound HP2O73− guest, as inferred from the bond distances (Figure 184).

calculations indicated that the amide N−H, triazole Csp2−H, and phenyl Csp2−H protons were involved in the guest recognition event (Figure 186).

Figure 184. X-ray structure of the complex 251·HP2O73− (CSD Refcode ARUQOU). Distances are given in angstroms.

The pyrrole-based triazolium-phane 252, related to receptor 251, with four additional triazolium rings, displayed a high selectivity for tetrahedral oxoanions in mixed polar organic− aqueous media.178 The selectivity was solvent dependent and was found to be less pronounced in CH3CN. The results serve to underscore the benefits of combining various hydrogen bond donor motifs within a single receptor to achieve the recognition of anions and also allowed for a direct comparison of the relative importance of N−H, Csp2−H, and C+sp2−H anion interactions in the receptor 252 (Figure 185). The results

Figure 186. Structure of the bis(triazole)−benzamide receptor 253 and the proposed binding modes with anions.

The zigzag “anti” conformation of the molecule generated two regions with complementary positive and negative potentials that favor the statistical complexation of two molecules of the neutral carboxylic acid. The amide group determined the complexation of both anionic and neutral species by primary acid−base interactions. The heterobimetallic ferrocene−imidazophenanthroline dyad 254 was described by our research group180 in 2008, and its anion recognition and sensing properties were investigated toward a variety of halides and oxoanions, using 1H NMR, electrochemical, and fluorescence techniques (Figure 187).


provided support for the counterintuitive conclusion that triazolium C+sp2−H···A− interactions are less important in an energetic sense than neutral aromatic Csp2−H···A− interactions. The bis(triazole)−benzamide receptor179 253 bound Cl− and Br− anions in CDCl3 with low association constants, Ka = 29 M−1 and Ka = 37 M−1, respectively, with a 1:1 stoichiometry. Additionally, receptor 253 was able to bind the neutral gallic acid derivative with a 1:2 host/guest stoichiometry, and the association constants were found to be K1 = 426 M−1 and K2 = 106 M−1. 1H NMR spectroscopic experiments and theoretical

Figure 187. Structure of the heterobimetallic receptor 254.

Receptor 254 exhibited high selectivity for Cl− anions (Ka = 4.5 × 104 M−1) over the other anions tested. The presence of Cl− anions induced an increase of the emission band of the receptor (43-fold) and a remarkable cathodic shift of the ferrocene/ferrocenium oxidation wave (ΔE1/2 = 80 mV) in CH3CN solution. 1H NMR experiments in acetone showed important downfield shifts not only for the imidazophenanthro9964


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complexation of anions in the presence of a semirigid m-xylene spacer (Figure 190).

line N−H protons (Δδ = 3.16 ppm, red signal) but also for the ferrocene Csp2−H (Δδ = 0.43 ppm, blue signal) and imidazophenanthroline Csp2−H (Δδ = 1.43 ppm, green signal) protons, indicating their participation in the Cl− recognition process (Figure 188).


Receptor 255 bound the H2PO4− anion strongly, with an association constant of Ka = 2.23 × 104 M−1, and exhibited a large emission ratiometric change in CH3CN. By comparison, F− (Ka = 8.88 × 103 M−1) anions caused significant quenching in the fluorescence of the receptor 255 with no ratiometric behavior. The presence of HSO4−, ClO4−, Br−, and Cl− anions did not cause significant changes in the emission spectrum. The presence of H2PO4− anions in a DMSO solution of the receptor induced a downfield shift of the resonances attributed to the benzimidazolium Csp2−H protons (Δδ = 0.41 ppm) and the methylene Csp3−H protons adjacent to the pyrene amide endcapped group (Δδ = 0.1 ppm). The amide protons became too broad to accurately identify on complexation. The optimized geometry of the receptor 255 with a H2PO4− anion showed that the anion is complexed into the cavity involving multiple imidazolium C+sp2−H···A−, aromatic Csp2−H···A−, aliphatic Csp3−H···A−, and amide N−H···A− interactions (Figure 191), which supported the observations made by the 1H NMR study.

1

Figure 188. H NMR spectral changes observed for 254 in acetone, after addition of increasing amounts of Cl− in CD3CN: (a) 0, (b) 0.25, (c) 0.50, (d) 0.75, and (e) 1 equiv. Reprinted from ref 180. Copyright 2008 American Chemical Society.

The optimized structure of the complex 254·Cl− at the B3LYP/aug-6-31G*/SDD-ecp level also indicated the cooperative action of three different hydrogen-bonding interactions in the formation of the complex (Figure 189). DFT calculations of

Figure 189. Optimized structure of the complex 254·Cl− at the B3LYP/aug-6-31G*/SDD-ecp level. Reprinted from ref 180. Copyright 2008 American Chemical Society.

the complex revealed that the structure was characterized by strong N−H···Cl− bridge bonding, with the pyrrolic hydrogen atom of the imidazole ring and the guest Cl− anion forming a complementary bridge bond with the phenanthroline 4-H as well as two other weak bonds with the ferrocenyl Hα and H− Cpb protons. 1H NMR spectroscopy also provided a variety of evidence clearly indicating that some of the protons in this structure participate in an authentic hydrogen-bonded complex: there was remarkable downfield shifting of the N−H proton signal, the signal of the 4-H protons of the phenanthroline was split into two signals, with one of them shifted downfield and the second one remaining in the same position, and finally, one of the cyclopentadienyl ring protons was shifted downfield. Pyrene-appended benzimidazolium-based receptor181 255, bearing amide hydrogen atoms, polar C−H bonds, and cationic charge, exhibits a number of weak interactions which allow

Figure 191. Optimized structure of the complex 255·H2PO4−. Reprinted with permission from ref 181. Copyright 2011 Elsevier.

Cooperative hydrogen-bonding interactions of the triazolium C+sp2−H···A− and aromatic Csp2−H···A− and also halogenbonding interactions with the iodotriazolium C+sp2−X···A− group were evidenced in receptor107 256 (Figure 192) during the selective recognition of HP2O73− anions by 1H NMR titrations in CD3CN/CD3OD (9:1, v/v) and theoretical calculations. The resulting association constant, Ka = 1734 M−1, was similar to that obtained for the hydrogen-bonding 9965


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interlocked cavity protons. In both rotaxanes, the internal pyridinium proton of the axle, the amide N−H proton, and the inner phenyl Csp2−H protons of the macrocycle were shifted significantly downfield, as well as the triazole Csp2−H proton of the receptor 258. These observations further highlight how the integration of halogen-bonding and hydrogen-bonding donor groups into the mechanically bonded cavity can dramatically affect the anion recognition properties of the interlocked host. Recently, Kang and co-workers reported the densely functionalized nitrogen-rich anion receptor 259 (Figure 194), with a photoactive anthracene group as the central spacer and two arms with acylhydrazone and pyrazole binding sites endcapped by a p-nitrophenyl group as a chromogenic unit.183


receptor 85 and lower than those observed for the halogenbinding receptors 83 and 84. Beer and co-workers have demonstrated that the binding properties of the halogen-bonding [2]rotaxane 257 are in stark contrast to those of the hydrogen-bonding [2]rotaxane host analogue 258 (Figure 193).182


Receptor 259 formed a stable 1:1 complex with a H2PO4− anion with an association constant value of Ka = 1.2 × 104 M−1 in DMSO. Receptor 259 also recognizes HSO4− (Ka = 1.1 × 103 M−1), Cl− (Ka = 8.0 × 102 M−1), and Br− (Ka = 5.3 × 102 M−1), but with smaller association constants. Hydrogen bond formation was also confirmed by 1H NMR titration, in which the amide N−H, pyrazole N−H, and vinylic Csp2−H signals showed intense broadening and downfield shifts. The optimized binding mode of the receptor 259 with the H2PO4− anion shows that the planarity of the receptor in the complex and the six hydrogen bonds with the anion (two pyrazole N−H···O, two OCN−H···O, and two Csp2−H··· O interactions) are responsible for the high binding energy of the receptor 259 with H2PO4− anions (Figure 195).


The synthesis was achieved by using the 5-iodo-1,2,3triazole- or 1,2,3-triazole-functionalized pyridinium motifs, respectively, within the axle component and an isophthalamide-containing macrocycle. 1 H NMR experiments using several kinds of anions in the solvent mixture CDCl3/CD3OD (1:1, v/v) indicated that the halogen-bonding rotaxane 257 binds halides over the more basic oxoanions. In contrast, the all-hydrogen-bonding proton triazole−rotaxane analogue 258 demonstrated a preference for H2PO4− over the halides (Table 42). The presence of the recognized anions promoted significant downfield shifts of the Table 42. Anion Binding Constants (Ka, M−1) of the Rotaxanes 257 and 258 with Different Anions in the Mixture CDCl3/CD3OD (1:1, v/v), As Obtained by 1H NMR182 anion

257

258

Cl− Br− I− H2PO4− AcO−

381 532 466 221 −

1831 1299 449 2399 543

Figure 195. Structure of the complex 259·H2PO4− obtained using B3LYP/6-31g(d) in DMSO solvent. Reprinted with permission from ref 183. Copyright 2015 Royal Society of Chemistry. 9966


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by the same physical principles. Historically, they have been used in supramolecular chemistry in solid-state and crystal engineering; however, the potential utility of the chalcogen bond in solution-phase anion receptor chemistry has recently been brought into the spotlight.196,197 The major drawback of existing chalcogen bond donation is this system’s limited stability in the presence of moisture and basic anions. Accordingly, further efforts to improve its stability are required before this system can find real-world applications, although this aspect seems to have been solved very recently.198 The use of these promising noncovalent interactions in anion recognition events is expected to give rise to a significantly greater variety of anion recognition probes. Consequently, new strategies will be developed for designing a wide variety of multi-bonding-site receptors able to detect anion species in competitive media in a selective and highly sensitive fashion, as well as for separation, self-assembly systems involving anions, catalysis, and anion-transport processes.

Theoretically, the calculated structure of the host−guest complex revealed that all the N−H protons acted as donors for the H2PO4− anion. Overall, four types of N−H···O hydrogen bonding were observed in the host−guest complex. Moreover, two additional weak types of Csp2−H···O hydrogen bonding were also observed. In total, six hydrogen bonds and the planarity of the host in the complex are responsible for the high binding energy.

20. CONCLUSIONS AND OUTLOOK In the past few years, a vast array of anion supramolecular chemistry has been demonstrated in a range of different fields spanning anion binding, changes in the electro-optical properties of anion receptors, anion sensing, and strategic templation. Furthermore, much research has been devoted to employing the lessons learned from pure anion binding studies in realworld applications, such as sensing, catalysis, and the medicinal use of transmembrane anion transports. We anticipate this field of research to continue to grow and produce exciting new applications in years to come. The contents of this review serve to illustrate and highlight that there is a bright future for supramolecular science, in particular the creation of systems with a combination of cooperative, noncovalent interactions. Studies of anion receptors equipped with two different donor functional groups demonstrated that it is indeed possible to employ these interactions cooperatively in molecular recognition, indicating that the two interactions occur simultaneously upon binding of ditopic receptor anions. Receptors composed of both donor groups display anion selectivities that represent a compromise between the distinct preferences of the two interactions. This represents an unconventional approach to modulate the receptor selectivity. We foresee exploitation and numerous applications of the strategy based on the cooperative combination of classical N− H hydrogen-bonding interactions, “unconventional” anion−π interactions, neutral and cationic C−H hydrogen bonding, and halogen bonding. This is viewed as an area with tremendous growth potential, and it is hoped that this review will expedite the intelligent synthesis of a multitude of poly-binding-site molecular host systems. By fine-tuning and carefully designing the topological features of organic systems, new bond donor motifs beyond those detailed in this review will hopefully be discovered and exploited for the purpose of binding biologically and environmentally relevant substrates, which will undoubtedly drive progress in the recognition of anions in competitive aqueous solvents and in cells. As explored in this review, recent investigations have used a strategy of combining distinctly noncovalent interactions to reveal the unique characteristics of anion recognition in terms of bond strength, selectivity, and interaction geometry. This serves to highlight the possibility of complementing, and in many cases outperforming, more traditional supramolecular interactions, such as independent hydrogen bonding or halogen bonding. It will be of particular interest to identify situations in which this strategy gives rise to unique behavior or properties in comparison to these traditional supramolecular interactions. An emerging group of so-called “unconventional” noncovalent interactions, such as chalcogen bonding,184−187 pnictogen bonding,188−191 and tetrel bonding,192−195 have also been explored by structural chemists in various inter- and intramolecular contexts. It has become clear that these bonds could be similar in strength to hydrogen bonds and governed

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Pedro Molina: 0000-0001-8568-9449 Notes

The authors declare no competing financial interest. Biographies Pedro Molina was born in Totana (Murcia), Spain. He graduated with honors in chemistry from the University of Murcia in 1968 and obtained his Ph.D. in 1973. During the period 1976−1978, he joined the group of Prof. A. R. Katriztky at the University of East Anglia (Norwich, U.K.). Since 1980, he has been a full professor in the Department of Organic Chemistry of the University of Murcia. He was awarded the 2007 Research Prize of the Division of Organic Chemistry of the Spanish Royal Society. His research has mainly been devoted to the area of heterocyclic chemistry. However, in the past few years, he has turned his interest toward the synthesis of new derivatives of ferrocene to be studied as molecular receptors. Fabiola Zapata was born in Murcia, Spain, in 1977. She graduated with a degree in chemistry from the University of Murcia in 2004, and she obtained her Ph.D. in 2009 under the supervision of Prof. Pedro Molina and Dr. Antonio Caballero. In 2009, she gained a postdoctoral grant from the Goverment of Spain to work under the supervision of Prof. Paul D. Beer at the University of Oxford (U.K.). In 2012, she obtained a Juan de la Cierva contract from the Government of Spain to work at the University of Murcia. Her research interests are focused on the development of new anion sensors by unconventional noncovalent interactions. Antonio Caballero was born in Murcia, Spain, in 1976. He graduated with a degree in chemistry from the University of Murcia in 2001, and he obtained his Ph.D. in 2007 under the supervision of Profs. Pedro Molina and Alberto Tárraga. In 2009, he moved to the University of Oxford (U.K.) as a Marie Curie Postdoctoral Fellow (2009−2011) and in 2011 worked as a postdoctoral research assistant under the supervision of Prof. Paul D. Beer. In 2012, he obtained a Ramon y Cajal contract from the Government of Spain to work at the University of Murcia. His research interests are focused on the 9967


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development of new anion sensors by unconventional noncovalent interactions.

ACKNOWLEDGMENTS We thank the European Commission (FP7-PEOPLE-2012CIG No. 321716), Government of Spain, Ministerio de Economiá y Competitividad, and European FEDER (Fonds Européen de Développement Régional) (Grant No. CTQ201346096-P), as well as the Comunidad Autónoma de la Región de Murcia, Fundación Séneca (Grant Nos. 18948/JLI/13 and 19337/PI/14). F.Z. and A.C. also acknowledge the Government of Spain for Juan de la Cierva and Ramon y Cajal contracts, respectively. We also thank Sam Bennett for proofreading the manuscript. REFERENCES (1) Evans, N. H.; Beer, P. D. Advances in Anion Supramolecular Chemistry: from Recognition to Chemical Applications. Angew. Chem., Int. Ed. 2014, 53, 11716−11754. (2) Gale, 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, 205−241. (3) Santos-Figueroa, L. E.; Moragues, M. E.; Climent, E.; Agostini, A.; Martinez-Mañez, R.; Sancenon, F. Chromogenic and Fluorogenic Chemosensors and Reagents for Anions: A Comprehensive Review of the Years 2010−2011. Chem. Soc. Rev. 2013, 42, 3489−3613. (4) Gale, P. A.; Howe, E. N. W.; Wu, X. Anion Receptor Chemistry. Chem. 2016, 1, 351−422. (5) Kubik, S. Anion Recognition in Water. Chem. Soc. Rev. 2010, 39, 3648−3663. (6) Scheiner, S. Hydrogen Bonding: A Theoretical Perspective; Oxford University Press: New York, 1997. (7) Desiraju, G. R. A Bond by any other Name. Angew. Chem., Int. Ed. 2011, 50, 52−59. (8) Park, C. H.; Simmons, H. E. Macrobicyclic Amines. III. Encapsulation of Halide Ions by in,in-1,(k + 2)-Diazabicyclo[k.l.m.]alkane Ammonium Ions. J. Am. Chem. Soc. 1968, 90, 2431−2432. (9) Llinares, J. M.; Powell, D.; Bowman-James, K. Ammonium Based Anion Receptors. Coord. Chem. Rev. 2003, 240, 57−75. (10) García-España, E.; Díaz, P.; Llinares, J. M.; Bianchi, A. Anion Coordination Chemistry in Aqueous Solution of Polyammonium Receptors. Coord. Chem. Rev. 2006, 250, 2952−2986. (11) Hosseini, M. W.; Lehn, J.-M. Anion Receptor Molecules. Chain Length Dependent Selective Binding of Organic and Biological Dicarboxylate Anions by Ditopic Polyammonium Macrocycles. J. Am. Chem. Soc. 1982, 104, 3525−3527. (12) Schmidtchen, F. P. Macrocyclic Quaternary Ammonium Salts. II. Formation of Inclusion Complexes with Anions in Solution. Chem. Ber. 1981, 114, 597−607. (13) Bazzicalupi, C.; Bencini, A.; Giorgi, C.; Valtancoli, B.; Lippolis, V.; Perra, A. Exploring the Binding Ability of Polyammonium Hosts for Anionic Substrates: Selective Size-Dependent Recognition of Different Phosphate Anions by Bis-macrocyclic Receptors. Inorg. Chem. 2011, 50, 7202−7216. (14) Bencini, A.; Coluccini, C.; Garau, A.; Giorgi, C.; Lippolis, V.; Messori, L.; Pasini, D.; Puccioni, S. A BINOL-Based Chiral Polyammonium Receptor for Highly Enantioselective Recognition and Fluorescence Sensing of (S,S)-Tartaric Acid in Aqueous Solution. Chem. Commun. 2012, 48, 10428−10430. (15) Hossain, M. A.; Kang, S. A.; Kut, J. A.; Day, V. W.; BowmanJames, K. Influence of Charge on Anion Receptivity in Amide-Based Macrocycles. Inorg. Chem. 2012, 51, 4833−4840. (16) Bondy, C. R.; Loeb, S. J. Amide Based Receptors for Anions. Coord. Chem. Rev. 2003, 240, 77−99. (17) Amendola, V.; Fabbrizzi, L.; Mosca, L. Anion Recognition by Hydrogen Bonding: Urea-Based Receptors. Chem. Soc. Rev. 2010, 39, 3889−3915. 9968


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