Macrocycles as Ion Pair Receptors - Chemical Reviews (ACS

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Macrocycles as Ion Pair Receptors Qing He,*,‡,∥ Gabriela I. Vargas-Zúñiga,*,‡ Seung Hyun Kim,§ Sung Kuk Kim,*,§ and Jonathan L. Sessler*,†,‡ †

Institute for Supramolecular Chemistry and Catalysis, Shanghai University, Shanghai 200444, P.R. China Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States § Department of Chemistry and Research Institute of Natural Science, Gyeongsang National University, Jinju, 660-701, Korea ∥ State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China Downloaded via BOSTON COLG on May 13, 2019 at 18:22:10 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

ABSTRACT: Cation and anion recognition have both played central roles in the development of supramolecular chemistry. Much of the associated research has focused on the development of receptors for individual cations or anions, as well as their applications in different areas. Rarely is complexation of the counterions considered. In contrast, ion pair recognition chemistry, emerging from cation and anion coordination chemistry, is a specific research field where co-complexation of both anions and cations, so-called ion pairs, is the center of focus. Systems used for the purpose, known as ion pair receptors, are typically di- or polytopic hosts that contain recognition sites for both cations and anions and which permit the concurrent binding of multiple ions. The field of ion pair recognition has blossomed during the past decades. Several smaller reviews on the topic were published roughly 5 years ago. They provided a summary of synthetic progress and detailed the various limiting ion recognition modes displayed by both acyclic and macrocyclic ion pair receptors known at the time. The present review is designed to provide a comprehensive and up-to-date overview of the chemistry of macrocycle-based ion pair receptors. We specifically focus on the relationship between structure and ion pair recognition, as well as applications of ion pair receptors in sensor development, cation and anion extraction, ion transport, and logic gate construction.

CONTENTS 1. Introduction 2. Recognition with Macrocyclic Ion Pair Receptors 2.1. Organic Cations and Inorganic Anions as Ion Pairs 2.2. Organic Cations and Organic Anions as Ion Pairs 2.3. Inorganic Cations and Organic Anions as Ion Pairs 2.4. Inorganic Cations and Inorganic Anions as Ion Pairs 2.5. Zwitterions 3. Applications of Macrocyclic Ion Pair Receptors 3.1. Ion Pair Sensors 3.1.1. Colorimetric Ion Pair Sensors 3.1.2. Fluorometric Ion Pair Sensors 3.1.3. Electrochemical Ion Pair Sensors 3.1.4. Multisignaling Ion Pair Sensors 3.2. Ion Pair Extraction and Separation 3.2.1. Solid−Liquid Extraction of Ion Pairs 3.2.2. Liquid−Liquid Extraction of Ion Pairs 3.3. Transmembrane Ion Pair Transport 3.3.1. Liposome Membrane Transport 3.3.2. Bulk Liquid Membrane Transport 3.3.3. Supported Liquid Membrane Transport © XXXX American Chemical Society

3.4. Ion Pair Recognition-Based Logic Gates 4. Conclusions and Outlook Author Information Corresponding Authors ORCID Author Contributions Notes Biographies Acknowledgments Abbreviations References

A C C G H K AD AK AK AK AN AS AU AY AY BC BI BI BK BN

BP BS BT BT BT BT BT BT BT BT BU

1. INTRODUCTION Ion recognition has been a subject of intense study due to the important role that charged species play in physiology, medicine, the environment, and industrial processes.1−4 Not surprisingly, considerable effort has been devoted to the development of receptors capable of recognizing and binding selectively individual cations and anions. This is chemistry that Special Issue: Macrocycles Received: December 4, 2018

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DOI: 10.1021/acs.chemrev.8b00734 Chem. Rev. XXXX, XXX, XXX−XXX

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has been comprehensively reviewed.5−12 In the case of simple, or so-called monotopic, cation and anion receptors, effective ion recognition normally requires the use of a lipophilic anion (for example, picrate and perchlorate) or cation (tetraalkylammonium). Absent these adjuvants, the energetic cost to separate the individual cation or anion from its counterion or solvation sphere can be prohibitively high. The selected counterions play an important role in regulating the binding behavior of monotopic receptor systems, something that has been referred to as the counterion effect.13−18 Although the beginnings of anion recognition chemistry can be traced back to the time where cation recognition chemistry was seeing explosive initial growth,19−21 it took almost 20 additional years before this subfield began to blossom. It soon became appreciated that receptors capable of complexing both anions and cations, i.e., ion pairs, could offer advantages in terms of both efficacy and selectivity. Historically, the 1991 report by Reetz and co-workers is recognized as one of the earliest, if not the first, examples of an ion pair receptor.22 Over the course of the ensuing 10 years, a limited number of ion pair receptors were described in the literature. Most were based on combinations of recognition motifs suitable for cation complexation, such as crown ethers and calixarenes, with Lewis acidic centers, pyrroles, amides, or urea groups known for their anion recognition ability. Several minireviews summarizing this early progress were published in the early 2000s.23−25 Since then, the ion pair recognition field has witnessed almost explosive growth and a number of systems capable of targeting specific ion pairs are now known. Broadly speaking, ion pair receptors are di- or multitopic hosts that contain recognition sites for both cations and anions and which are capable of binding concurrently both an anion and a cation (or more than one anion and cation).26−28 They are of interest in that they may allow complications associated with ion binding, such as variability in the binding constants due to the dielectric constant and ion pairing effects arising from the presence of ions in the medium, to be overcome.29−32 One motivation for developing ion pair receptors reflects an appreciation that, relative to stand-alone anion or cation recognition units, the ion binding affinities could be enhanced and the binding selectivies improved. This has inspired the design and synthesis of ion pair receptors that can simultaneously bind both cations and anions. Another incentive driving the field is the long-felt and still largely unmet need for new advanced separation technologies. Here, receptors capable of binding concurrently both an anion and a cation could offer advantages as extractants for salts of recognized or potential commercial interest such as LiCl. Related systems could prove useful as ion transporters and as potential treatments for disorders, such as cystic fibrosis, characterized by dysfunction in cellular ion transport systems. As a general rule, ion pair complexation can be achieved via cooperative interactions that serve to modulate the binding strength and selectivity of the charged species in question. In many cases, the recognition of a first ion (anion or cation) facilitates the subsequent co-binding of its counterion. This overall recognition process is often subject to conformationalor electrostatic-based allosteric effects. This is because, theoretically, the prebound ion may promote the binding of its counterion, leading to a positive allosteric effect. However, a first ion binding event can inhibit follow up recognition, which leads to negative allostery (Figure 1). To date, positive

allostery has been more commonly seen in the context of ion pair recognition, although there are also counter examples.

Figure 1. Allosteric effects on binding pairs of ions using ion pair receptors. PAE, positive allosteric effect; NAE, negative allosteric effect.

In addition to allostery, proximity effects also play a key role in regulating the complexation of ion pairs. In fact, as a general rule, receptors that serve to bring the targeted anions and cations close enough to one another (and thus favoring electrostatic interactions between the co-bound ions) have proved particularly effective. Independent of the underlying mechanism, the operational goal in creating ion pair receptors has been to achieve a high level of control over the ion recognition and, where relevant, release processes.25,26,33−35 One way to classify ion pair receptors is in terms of how the ion pair associates with the receptor. In this sense, three limiting binding modes can be defined: (a) contact ion pair, (b) solvent-separated ion pair, and (c) host−guest separated ion pair, as shown in Figure 2.26 To date, these three limiting

Figure 2. Schematic representation of the three limiting binding modes seen for an ion pair and a ditopic receptor used for concurrent cation and anion recognition: (a) contact ion pair, (b) solventseparated ion pair, and (c) host-separated ion pair. This figure was redrawn with permission from the original, which appeared in ref 26. Copyright 2010 Royal Society of Chemistry.

binding modes have been illustrated in a variety of systems based on calixpyrrole, calixarene, or crown ether scaffolds, many of which bear ancillary substituents that enhance the affinity and selectivity of one particular ion pair target over other potentially interfering cation and anion combinations. More sophisticated systems have been prepared and used in a variety of applications, including catalysis, transmembrane B


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higher affinity for the monoalkylammonium salt 2 over the tetraalkylammonium salts was ascribed to the narrow complexation site present in 1 that is thought to preclude the effective binding of bulkier cations. Calixarenes and crown ethers substituted with urea and thiourea groups have been used to prepare ditopic receptors. For instance, Dalla, Jabin, and co-workers prepared the calix[6]arene system 3 that bears three thiourea groups on the lower rim (Figure 4a).37 The ability of receptor 3 to bind

transport, salt extraction, sensors, and information processing. Many of the most promising systems are macrocyclic in nature. The aim of this review, therefore, is to describe through appropriate examples the use of macrocyclic receptors that illustrate the problems and promise associated with ion pair binding. Also discussed where appropriate is the associated applications chemistry. An effort has been made to be current with the literature through September of 2018.

2. RECOGNITION WITH MACROCYCLIC ION PAIR RECEPTORS The design of ion pair receptors usually involves the incorporation of structural motifs that function as hydrogenbond donors, Lewis acidic sites, or positively charged groups for anion recognition, while motifs such as Lewis basic sites and π-electron moieties are used for cation complexation.29−32 In particular, ditopic receptors capable of binding simultaneously both cations and anions often exhibit cooperative and allosteric effects that influence the binding properties of the receptor. Most efforts to date have been focused on exploiting these basic recognition motifs to maximize the selectivity and affinity for various ion pairs. In this context, much of the focus to date has been on inorganic salts and, in fact, relatively few examples of organic ion pair recognition have been reported. Mixed organic inorganic ion pairs have, however, been the frequent targets of receptor design. Our treatment below starts with this latter class of substrates. 2.1. Organic Cations and Inorganic Anions as Ion Pairs

In the context of anion recognition chemistry, lipophilic organic cations, such as tetraalkylammonium cations (e.g., tetrabutylammonium), are commonly employed. Since these cations normally remain unbound, as a general rule, such systems will not be discussed in this review. However, in some cases, relatively lipophilic organic cations, such as tetramethylammonium and tetraethylammonium, are found bound with a cation binding site present in an ion pair receptor, while an accompanying inorganic anion is found captured within an anion binding site present in the same ion pair receptor. Examples where this occurs will be detailed in this section. In 2005, Gibb and co-workers reported macrocycle 1, a system that contains three converging pyridine subunits linked

Figure 4. (a) Schematic representation of ion pair recognition as achieved by the ditopic receptor 3. (b) Binding of dibenzylammonium salts (e.g., 5) by the dibenzo-24-crown-8 receptor 4.

ion pairs in deuterated chloroform was analyzed via 1H NMR spectroscopy. These studies revealed that receptor 3 encapsulates propylammonium chloride such that the chloride anion interacts with the thiourea groups via hydrogen bonds while the alkylammonium group is bound within the calix[6]arene cavity. This recognition was ascribed to a highly cooperative two-step binding process. The recognition of organic salts, such as dibenzylammonium salts (e.g., 5), in acetonitrile/chloroform solution (2:3, v/v) was achieved by Huang and co-workers using the dibenzo-24-crown-8 derivative 4. In this case, anion binding to the urea group in 4 serves to enhance the formation of a threaded ion pair complex (Figure 4b).38 Later, Gattuso and co-workers prepared the ditopic receptors 6 and 7. These systems are based on calixarene cores substituted with urea-functionalized crown ether subunits (Figure 5).39 1H NMR spectroscopic analyses in CDCl3 revealed that the trisureido calix[5]arene-crown-3 6 bound 2-phenylethylammonium (as its chloride salt, PEAHCl) with a binding constant (Ka) of 1.89 × 105 M−1. On the basis of the chemical shifts of the NH and NH3+ resonances as well as semiempirical calculations (PM3) of the ion pair complex [6·PEAHCl], the authors concluded that the PEA guest was embedded within the calix[5]arene cavity, whereas the chloride anion was bound to the ureido substituents. As an extension of this study, the same group later reported the binding properties of receptor 7 (Figure 5). This system contains three pendant naphthalene moieties that allowed exposure to n-butylammo-

Figure 3. Structures of ion pair receptor 1 and L-phenylalanine methyl ester nitrate salt 2.

by two carbonyl groups and two amide subunits (Figure 3).36 1 H NMR spectroscopic analyses of receptor 1 in CDCl3 revealed the existence of two enantiomers capable of recognizing L-phenylalanine methyl ester 2 in the form of its NO3−, Cl−, CF3CO2−, Br−, or I− salt. Compared with the corresponding tetrabutylammonium (TBA) salts of these latter anions, a higher binding constant was seen for the amino acid nitrate salt than the corresponding TBA salt (e.g., Ka = 1.84 × 104 M−1 vs 70 M−1 for 2 and TBANO3, respectively).36 This C


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Figure 5. Structure of receptors 6 and 7 and the ion pair complex ([6· PEAHCl]) formed from 6 upon treatment with 2-phenylethylammonium hydrochloride.

Figure 7. Structure of the calix[4]arene diethyl ester-strapped calix[4]pyrrole 9 and the single crystal structure of the ion pair complex [9·TEAF·H2O]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 1026519).

nium salts (as the Cl− or PF6− salts in dichloromethane solution) to be monitored by fluorescent and UV spectroscopy. On this basis, conditional binding constants of 7.9 × 105 and 3.16 × 106 M−1 were derived for Cl− and PF6−, respectively.40 In 2010, Diederich, Dalcanale, and co-workers reported the cavitand 8. In this system, phosphate groups on the lower rim were designed to promote cation complexation, whereas the methylene bridges spanning the upper rim served to fix the resorcinarene conformation in a way that was expected to promote CH−anion interactions (Figure 6).41 The resulting

Figure 6. Structure of the cavitand 8 and a schematic representation of ion pair complexation by receptor 8.

presence of competing anions (i.e., Cl−, Br−, I−, AcO−, NO3−, SO42−, H2PO4−, and HP2O73−; all as their respective TBA salts). This led to the conclusion that 9 selectively binds the F− anion (as its tetrabutylammonium, TBA salt) with moderately high affinity (Ka ≥ 104 M−1).42 Single crystal X-ray diffraction analysis of the corresponding tetraethylammonium fluoride monohydrated complex ([9·TEAF·H2O] revealed that the F− anion is hydrogen-bonded to the four pyrrolic NH groups present in the calix[4]pyrrole along with a molecule of water. In contrast, the TEA cation was found to be bound within the electron-rich pocket of the calix[4]pyrrole (Figure 7).42 Cooperativity effects and preorganization of the macrocycle, provided by the calix[4]arene cap, were factors considered responsible for the relatively high fluoride anion selectivity displayed by 9. Ballester and co-workers reported the bis(calix[4]pyrrole) receptor 10 (Figure 8) that consists of two calix[4]pyrrole subunits linked by two diynyl moieties. Receptor 10 was found to exhibit a high affinity for the TBA salts of the chloride and cyanate anions (i.e., TBAOCN and TBACl).43 1H NMR spectroscopic and isothermal calorimetry titration (ITC)

synergistic combination of CH−anion and hydrogen-bonding interactions was found to promote the binding of primary ammonium halide ion pairs. For instance, an analysis of the 1H and 31P NMR spectroscopic titration data acquired in CDCl3 using various n-octylammonium (NOA) halide anion salts (e.g., Cl−, Br−, and I−) revealed formation of a complex with 1:1 stoichiometry wherein the PO groups functioned as cation binding subunits. ITC analyses of 8 and representative n-octylammonium halide anion salts revealed the highest affinity for the bromide and iodide salts (i.e., Ka = 1.8 × 104 and 4.7 × 104 M−1 for Br− and I−, respectively, vs Ka = 1.6 × 103 M−1 for Cl−).41 In this case, the complex formation was entropy driven, a finding ascribed to the preorganization of the anion pocket in 8 and the ability of the PO groups present on the lower rim of the receptor to engage in substrate recognition. Sessler and co-workers prepared a calix[4]pyrrole, 9, containing a calix[4]arene diethyl ester bearing two phenylbased bridges (Figure 7).42 The binding properties of receptor 9 in CDCl3 were analyzed via 1H NMR spectroscopy in the

Figure 8. Structure of the bis(calix[4]pyrrole) 10 and the single crystal structure of the complex [10·(TBAOCN)2]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 930892). Chloroform solvent molecules have been omitted for clarity. D


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analyses involving exposure of receptor 10 to first 1 equiv followed by 1.7 additional equiv of TBAOCN in CH(D)Cl3 led to the conclusion that 10 forms two ion pair complexes. One consists of a 1:1 host/guest complex ([10·TBAOCN]), wherein 50% of the receptor is bound to the TBAOCN salt. The second complex corresponds to a 1:2 host/guest complex ([10·(TBAOCN)2]), formed with an association constant of K2:1 > 108 M−2.43 An X-ray diffraction analysis of [10· (TBAOCN) 2] using single crystals grown from CDCl 3 revealed a cylindrical homoditopic structure wherein the two rigid spacers position the two calix[4]pyrrole units at an ideal distance and orientation for effective ion pair binding and formation of a five-component cascade (Figure 8). The resulting complex, [10·(TBAOCN)2], is characterized by two different binding arrangements. In one, the ion pair is bound as a close-contact complex, while, in the second, the ion pair is bound in a receptor-separated binding mode. Evidence for formation of an intermediate complex, [10·TBAOCN], was also seen, which was taken as an indication that TBAOCN binds to 10 in a stepwise fashion.43 The tripeptide (R)-2-(3-aminophenoxy)propionic acid 11 was synthesized by Akazome and co-workers. This system is characterized by a bowl-like structure with C3-symmetry and acts as a receptor for both acetylcholine chloride (AChCl) and benzylmethylammonium salts (Figure 9a).44 The cavity size

molecules, presumably from the crystallization medium, are found to bridge the complex. The hemicryptophane 12, shown in Figure 10, prepared by Dutasta, Martinez, and co-workers, was found to form ion pair

Figure 10. Structure of the hemicryptophane receptor 12.

complexes with the tetramethylammonium (TMA) salts of Br−, AcO−, F−, and Cl− in CDCl3 solution.45 In the solid state, the preorganized cyclotriveratrylene cavity was found to encapsulate these ammonium salts within the cavity in the form of a contact ion pair complex. Data from 1H NMR spectroscopic titrations carried out in CDCl3 revealed a relatively low affinity for tetraalkylammonium salts (e.g., Ka TBAF = 120 M−1).45 This low affinity was ascribed to the poor fitting of the large TBA cation into the receptor cavity. However, the exposure of 12 to the smaller tetraalkylammonium salt, such as TMA halide salts, produced complexes characterized by higher binding constants in the order Cl− > F− > Br−.45 The higher affinity observed for the smaller ammonium salts was attributed to a better cation size match, which in turn was thought to support efficient hydrogenbonding and CH−π/cation−π interactions, which serve to maximize the formation of the observed contact ion pair complexes. Ballester and co-workers reported the tetraphosphonate calix[4]pyrrole cavitand 15 prepared via the condensation of the tetrasubstituted calix[4]pyrrole 13 and phosphonate 14 (Figure 11).46 The resulting diastereomeric deep cavitand system was found to present three or four of the PO groups (i.e., 15a or 15b; Figure 11) away from the cavity. Both diasteroisomers were found to bind tetramethylphosphonium chloride (TMPCl) and octylammonium chloride (OAMCl) in a host-separated fashion and with 1:1 stoichiometry. Nevertheless, the complexation of OAMCl is dependent on the isomer. For instance, a host-separated complex is formed when OAMCl is bound to 15a, whereas a close-contact arrangement of the ions is observed in the case of 15b. Of interest was the finding, inferred from 1H NMR spectroscopic analyses carried out in CD2Cl2 solution, that the complexes formed between TMPCl and either diasteroisomer of receptor 15 were less stable than those formed from 13. This was attributed to repulsive interactions arising from the negative dipole moment of the PO moieties. The same research group reported the synthesis of a [2]rotaxane based on the bis(calix[4]pyrrole) 16 and a 3,5bisamidepyridyl-N-oxide derivative 17, which functions as an

Figure 9. (a) Structures of receptor 11 and acetylcholine chloride (AChCl). (b) Single crystal structure of the ion pair complex [11· AChCl]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 930852). The ethanol and water solvent molecules have been omitted for clarity.

and restricted conformation allow the ammonium cation to be accommodated via cation−π interactions. 1H NMR spectroscopic analyses led to the conclusion that, in CDCl3 solution, receptor 11 forms a 1:1 complex with AChCl with the ammonium cation bound into the cavity via cation−π interactions.44 A single crystal X-ray diffraction analysis led to the conclusion that in the ion pair complex [11·AChCl] cation−π interactions involving the trimethylammonium moiety and the three benzene rings of the receptor, as well as hydrogen bonds between the chloride anion and the amide groups at the bottom of the bowl-like receptor, serve to stabilize the complex (Figure 9b). Water and ethanol E


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supported by ITC analyses and led to the conclusion that the mixed complex 16·17 acts as a heteroditopic receptor and supports formation of 1:1 ion pair complexes. The binding is driven by an ion pair association process wherein hydrogenbonding interactions with two different moieties in the acceptor 16·17 stabilize the bound anion (e.g., the N-oxide moiety bound to one hemisphere of 16 interacts with the cyanate anion that is bound to the other hemisphere), while the TBA cation is constrained within the electron-rich cavity of the calix[4]pyrrole (Figure 12).47 The formation of the ion pair complex exhibited concentration dependence. This became evident when addition of more than 1 equiv of TBA salt was found to induce disassembly of [OCNTBA·16·17] to produce complexes with higher order stoichiometries. So-called click chemistry was used to attach the calix[4]azacrown 18 to modified silicon surfaces containing pendant azide groups (Figure 13a). The resulting constructs (repre-

Figure 11. (a) Synthesis of receptor 15 and the structures of tetramethylphosphonium chloride (TMPCl) and octylammonium chloride (OAMCl) salts used as guests in recognition studies. (b) Single crystal structure of the ion pair complex [15a·TMPCl]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 1053431).

axle. Treatment of the interlinked system, 16·17, with TBAX salts (X = Cl−, NO3−, OCN−) was found to result in the formation of four-particle aggregates [XTBA·16·17] that possess [2]pseudorotaxane-like structures, as shown in Figure 12.47 For instance, the addition of 1 equiv of TBAOCN to a mixture of 16 and 17 in CDCl3 (both at 1 mM) was found to give rise to the self-assembled system [OCNTBA·16·17] featuring a [2]pseudorotaxane topology (Ka ∼ 1011 M−2) in almost quantitative yield, as inferred from a diffusion ordered spectroscopic (DOSY) NMR analysis.47 This result was

Figure 13. (a) Synthesis of system 19 and the proposed interactions between 19 and [20·Cl]. (b) Wettability switching seen for 19 upon exposure to first [20·Cl] and then water, showing the reversibility between a surface form characterized by superhydrophobicity and high hydrophilicity. Reprinted with permission from ref 48. Copyright 2012 American Chemical Society.

sented by 19) were used to prepare switchable wettability sensors for ion pairs.48 The wettability of the system 19 was found to depend on the presence or absence of 1-butyl-3methylaimidazolium chloride [20·Cl]. In contrast, upon immersion into solutions containing [20·Br], [20·PF6−], or NaCl, the wettability of the surface remained unchanged. These results were taken as an indication that the modified surface 19 responded selectively to [20·Cl]. In fact, system 19 was found capable of switching from a highly hydrophilic form to one characterized by superhydrophobicity depending on whether [20·Cl] was present or absent, as shown in Figure 13b.48 UV−vis absorption and 1H NMR spectroscopic analysis led to the conclusion that a cooperative molecular mechanism is involved in the ion pair responsive wettability of the system.

Figure 12. Schematic representation showing the formation of the four-particle system [OCNTBA·16·17] produced upon treatment of the [2]rotaxane 16·17 with OCNTBA. F


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spectroscopy as well as single crystal X-ray diffraction analyses revealed that the ammonium ion is hydrogen-bonded to the oxygens in the crown ether moiety of 25, whereas the methoxy anion is linked to the borate moiety.22 Although receptor 25 exhibited affinity for the methylbenzylammonium and benzylammonium cations, competition experiments revealed that 25 displayed selectivity for methanol over larger alcohols, including ethanol. In 2001, Pochini and co-workers reported the recognition of organic ion pairs using the calix[4]arene-based receptors 26 and 27 (Figure 16).15 1H NMR spectroscopic titrations

It was found that the exposure to [20·Cl] produces silicon surfaces with hydrophilic character. In 2016, Yuan and co-workers reported the heteroditopic cyclo[6]aramide receptor 2148 (Figure 14) and showed that it

Figure 14. Structures of the cyclo[6]aramide 21 and the amidinium chloride salts 22, 23, and 24.

recognized amidinium salts in 10% methanolic chloroform.49,50 Density functional theory (DFT) calculations revealed that the bound chloride anion was stabilized by hydrogen-bonding interactions involving two of the amide NH protons and one of the aromatic hydrogen atoms present in the cavity of receptor 21. Binding analyses, carried out using 1H NMR spectroscopic studies in CDCl3, revealed that the acetamidinium chloride salt 22 is bound to receptor 21 as an ion pair complex within the central cavity, as predicted by DFT.50 However, the strength and the type of complex resulting from such an association was found to be dependent on the size of the ion pair. For instance, electrical conductivity (σ/μS) measurements and 1H NMR spectroscopic titrations carried out in CDCl3−CD3OH, 9:1 (v/v), revealed that the smaller formamidinium chloride salt 23 formed a contact ion pair complex with 21 (σ/μS(complex) = 50.3 cm−1; Ka = 5.98 × 104 M−1), whereas the larger bisamidinium salt 24 produced a loose ion pair complex (σ/ μS(complex) = 319.4 cm−1; Ka = 5.91 × 103 M−1).50

Figure 16. Structures of calix[4]arene-based receptors 26 and 27.

provided evidence that these two receptors would form complexes with various tetramethylammonium salts (TMAX, X = Cl−, tosylate (TsO−), acetate (AcO−), trifluoroacetate (TFA−), and picrate (Pic−)), albeit not with equal affinities. For instance, in CDCl3/CD3CN (8:2, v/v) solution, the affinities of receptor 26 were found to follow the order TsO− > Pic− > Cl− > AcO− > TFA−, which reflects, with the exception of Pic−, an effective reversal of what might be expected on the basis of classic Hofmeister effects.15 2D 1H NMR NOE and ROESY spectral analyses led to the conclusion that this binding order reflected the formation of a ligand-separated ion pair complex. In contrast, receptor 27 upon exposure of the same TMA salts in CDCl3 exhibited no discernible binding trend, i.e., Pic− ≅ TFA− > Cl− ≅ AcO− > TsO−.15 In this latter case, the affinity results were rationalized in terms of the formation of a loose ion pair complex. Höpfl and co-workers reported the diorganotin complexes 28 and 29 (Figure 17a and b), prepared from amino acid dithiocarbamates. The resulting metal-linked macrocyclic structures were found to bind TBAOAc in a 1:2 host:guest stoichiometry, as inferred from 1H NMR and UV−vis spectroscopic titrations carried out in chloroform.51 The authors proposed that the acetate anions bind to the receptor at the periphery (i.e., exo to the tin atoms; Figure 17c),51 while the cations would be accommodated within the cavity of the macrocycle to form what is formally an ion pair inclusion complex. The ion pair receptor 30 reported by Romański and coworkers contains two chiral amino acid units, used for anion binding, and two crown ether units for cation binding attached to a 1,8-diaminoanthracene scaffold (Figure 18). This system was found to recognize chiral carboxylate salts.52 UV−vis and 1 H NMR spectroscopic analyses of the binding properties in acetonitrile revealed that receptor 30 was able to recognize inorganic anions (i.e., Br−, NO2−, and Cl−) as their tetrabutylammonium (TBA) salts, even when the solution

2.2. Organic Cations and Organic Anions as Ion Pairs

In this section, macrocyclic ion pair receptors that are capable of binding concurrently organic cations, such as tetraalkylammonium cations, and organic anions, such as acetate, benzoate, phosphate esters, and amino acids, will be discussed. One of the first ion pair receptors capable of binding organic salts was the borate-containing macrocycle 25 reported by Reetz and co-workers in the early 1990s.22 Macrocycle 25 was found to form an ion pair complex [25·PhCH2NH3OCH3] in dichloromethane upon treatment with methanol and benzylamine (Figure 15). A combination of 11B, 1H, and 13C NMR

Figure 15. Schematic representation of the ion pair complex [25· PhCH2NH3OCH3] and its formation from receptor 25. G


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7.76 × 104 M−1, as TBA salts).52 The highest enantiodiscrimination was also observed in this case (KL/KD for Trp = 1.66),52 a finding ascribed to the presence of chiral amino acid units within the scaffold of receptor 30 that serve to enhance the affinity for L-tryptophan relative to its enantiomer. 2.3. Inorganic Cations and Organic Anions as Ion Pairs

Ion pairs containing organic anions with an inorganic countercation are common. This class of substrates includes, for example, sodium carboxylate salts, sodium salts of amino acids, and sodium phosphate ester salts. In this section, we discuss receptors that are capable of interacting with both inorganic cations, such as alkali metal ions, and organic anions. In 1993, Kilburn and co-workers53 prepared a simple receptor 31, featuring a bis(amidopyridine) unit that was known to serve as a binding site for carboxylic acid moieties54 and a diazacrown ether well documented to bind to metal cations (i.e., K+). In fact, 31 was found to serve as an ion pair receptor for the monopotassium salts of various dicarboxylic acids, as well as that of phenylphosphonate. This conclusion was supported by various extraction experiments monitored by 1 H NMR spectroscopy, intermolecular NOE (nuclear Ö verhausser effect), and FAB (fast atom bombardment) mass spectrometry. The authors proposed that the potassium cation is held in the crown ether and that an anionic carboxylate functionality or phenylphosphonate group associates with it, while, at the other end of the complex, the proton of the carboxylic acid or phosphonate is hydrogen-bonded to the amidopyridine unit (Figure 19).

Figure 17. (a) Structure of the diorganotin receptors 28 and 29. (b) Single crystal structure of receptor 29. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 686294). (c) Representation of the ion pair complexes formed between these receptors and TBAOAc.

Figure 18. Structures of receptor 30, L-TrpCOO−, and D-TrpCOO−.

contained sodium cations (added in the form of NaClO4). Moreover, the interactions with chiral carboxylate salts were not influenced appreciably by the presence of sodium cations. The ability of receptor 30 to recognize enantiomers was tested using various amino acids, including tryptophan (Trp), phenylalanine (Phe), and valine (Val). Receptor 30 displayed the highest affinity for Trp over the other amino acids, as summarized in Table 1. In addition, higher affinities were seen for L-TrpCOO− relative to D-TrpCOO− (Ka = 1.288 × 105 and

Figure 19. Proposed binding modes of receptor 31 with (a) monopotassium salts of dicarboxylic acids (shown in schematic form) and (b) the monopotassium salt of phenylphosphonate.

Table 1. Association Constants (Ka) for Interactions between Receptor 30 and Selected Chiral Anions in the Absence or Presence of 2 equiv of NaClO452 KL/KD or KR/KS carboxylates − L-ValCOO − D-ValCOO − L-PheCOO − D-PheCOO − L-TrpCOO − D-TrpCOO

R-PhCH(OH)COO− S-PhCH(OH)COO− R-C2H5CH(Ph)COO− S-C2H5CH(Ph)COO−

30

30 + Na+

KNa+/KTBA

TBA

Na+

33100 25700 34670 26300 128800 77620 4900 4260 100000 77620

27540 31380 33200 25100 97700 60250 7760 7250 52480 42660

0.83 0.83 0.96 0.95 0.76 0.78 1.58 1.70 0.52 0.55

1.29

1.29

1.32

1.32

1.66

1.62

1.15

1.07

1.29

1.23

H


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of a single crystal X-ray diffraction analysis. A 1:1 (host:acetate) stoichiometry in solution was inferred from Job plot analyses of the data from 1H NMR spectroscopic titration experiments carried out in CDCl3. The corresponding affinity constant for the acetate anion was calculated to be 35 M−1. Interestingly, a 4-fold increase in acetate binding affinity was observed if the crown ether loop of receptor 35 is precomplexed with the potassium cation (introduced as KBPh4), leading the authors to suggest that ion pair recognition benefits from a positive cooperative effect between the two binding sites. Similar positive cooperative or allosteric effects were also seen in a system where a regioselectively bis(thiourea)substituted dibenzo-diaza-30-crown-10 (36) serves as a multisite receptor. This particular system, reported by Kubo and co-workers, was found to capture simultaneously potassium cations and diphenylphosphate anions (Figure 22).64 Receptor 36 was prepared by functionalizing a highly

Calixarenes have been widely used as building blocks for constructing functionalized receptors for cations and neutral molecules.55,56 Appending thiourea or urea units, moieties that are powerful hydrogen-bond donors and are able to efficiently coordinate anions, to calixarenes allowed Ungaro and coworkers57 to prepare the ditopic calix[4]arene receptors 32− 34 (Figure 20). On the basis of 1H NMR spectroscopic

Figure 20. Molecular structures of receptors 32−34.

titration experiments carried out in DMSO-d6 solution, it was inferred that receptor 32 displays a lower affinity toward sodium carboxylate salts than does compound 33. This was rationalized in terms of the reduced hydrogen-bond donor ability of the urea group compared with thiourea.58 In contrast, receptor 34 bearing a thiourea subunit directly connected to the aromatic backbone proved more effective in recognizing sodium carboxylate salts than 33, a system that contains a CH2 spacer between the urea and calixarene subunits. To date, most calixarene-derived heteroditopic receptors have been constructed using calix[4]arenes in their cone conformation.59−62 In 2002, a heteroditopic receptor 35 containing a calix[4]arene backbone with the 1,3-alternate conformation was reported.63 This system bears a polyether loop on one side of the calix[4]arene macrocyclic ring and two pentafluoro benzamide groups as anion binding units on the other. Receptor 35 was found to be capable of binding potassium acetate as a host-separated ion pair, forming an unusual 2:2:2 (ligand:cation:anion) complex (Figure 21). The unexpected structure was confirmed in the solid state by means

Figure 22. (a) Molecular structure of the receptor 36 and (b) proposed structure of the complex [36·K+·(PhO)2P(O)O−].

flexible dibenzo-30-crown-10 macrocycle known to complex the potassium ion (K+) well with thiourea units as anion binding sites.65−67 1H NMR spectroscopic titration experiments carried out in CD3CN solution allowed for the quantitative assessment of the cooperative ion pair binding effects. It was found that changes in chemical shifts of the crown ether portion of 36 were observed upon the addition of K+ (in the form of the tetrakis(p-chlorophenyl)borate salt). For instance, the proximal proton resonances adjacent to the nitrogen atoms in the crown ether were found to shift upfield by 0.34 ppm in the case of the N−CH3 and 0.26 ppm for N− CH2CH2− resonances, respectively. This was taken as evidence that the K+ cation is complexed in the concave cavity formed by the crown ether. In contrast, the addition of (PhO)2P(O)O− (as its Et4N salt) to solutions of 36 or 36 + K+ in CD3CN caused appreciable chemical shifts of the Ar−NH− C(S) resonance. The effect was greater in the latter case, as would be expected for a situation where prebinding of a cation facilitates the subsequent binding of anions. The authors suggested that this feature could lead to the application of the

Figure 21. (a) Molecular structure of receptor 35 and (b) the selfassembled 2:2:2 ([35·K+·CH3COO−]) complex seen in the solid state (color code: C, black; O, red; N, blue; H, gray; K, purple). (b) This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 172977). I


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specific ion pairs, receptor 38 was found to prefer CH3COOCs, while 39 displayed selectivity toward CsNO3. In 2002, Beer and co-workers72 reported a set of heteroditopic nickel(II) and copper(II) transition metal dithiocarbamate ion pair receptors that contain amide groups for anion recognition and benzo-15-crown-5 moieties for cation complexation (Figure 25). Both receptors 41 and 42

system in the area of catalysis, specifically for the promoted hydrolysis of phosphate diesters. Due to ion pairing within salts,68 anion binding by neutral hosts in organic solvents can often be inhibited by the addition of (alkali metal) cations (i.e., Na+, K+, and Cs+). However, in principle, such putative inhibition can be reduced by using heteroditopic ion pair receptors that are able to bind concurrently both the cations and the anions, as shown schematically in Figure 23. A body of research has been devoted to testing this basic hypothesis.

Figure 23. Ion pairing vs ion pair recognition using heteroditopic saltbinding hosts.

In classic studies involving the recognition of either a single cation or a single anion, particularly in organic solvents, noncompeting counterions were commonly used in order to minimize the interference due to salt ion pairing. For example, anion binding studies are often carried out using tetrabutylammonium salts, while cation binding experiments often utilize picrate or perchlorate salts of the cation under study.1,69−71 However, as implied in Figure 23, the use of a ditopic receptor could obviate this need. Smith and coworkers14 were among the first to appreciate this. They reported a series of ditopic crown conjugates 38−40 (Figure 24) and used them to study the effect of competing cations on

Figure 25. (a) Molecular structures of the receptors 41 and 42 and (b) schematic of the ion pair binding seen in the case of 41.

exhibited positive cooperative complexation of cation−anion ion pairs, such as potassium acetate and potassium benzoate, as inferred from 1H NMR spectroscopic titration experiments carried out in DMSO-d6:CD2Cl2 (4:1) solution. A 6-fold enhancement in the value of the stability constant for the acetate anion was observed when a potassium cation was prebound within the benzo-15-crown-5 moieties of 41. This was taken as evidence of positive cooperativity and was thought to reflect favorable electrostatic and pseudomacrocyclic preorganization effects within the intramolecular sandwichlike complex. Due to the fact that squaramide-based receptors have been widely used for the molecular recognition of anions,73,74 Frontera, Morey, and co-workers75 attached crown ethers to an anthracene functionalized squaramide core to create the ion pair receptor 43 (Figure 26a). As deduced from a single crystal structural analysis of 43, a large variety of inter- and


the ability of a neutral host to complex anions. As a control, the neutral receptor 37 containing only an anion binding site was prepared; in this latter case, significant inhibition was seen in the presence of Na+ and K+, as inferred from 1H NMR spectroscopic titration experiments carried out in polar organic media (CD3CN or DMSO-d6). In contrast, receptors 38−40, bearing either an anion binding urea or 1,3-phthalamide moiety connected to a cation binding crown ether, were characterized by anion association constants that were enhanced in the presence of a small metal cation (i.e., Na+, K+, and Cs+). This was ascribed to the beneficial effects of complexing concurrently an anion and a cation. In terms of the

Figure 26. (a) Molecular structure of the ditopic receptor 43 and (b) PB86/SVP optimized structure of the complex [43·CH3COOK]. Selected distances are given in Å. This figure was reprinted with permission from ref 75. Copyright 2005 American Chemical Society. J


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NMR spectroscopic analyses carried out in CD2Cl2. This led to the conclusion that receptor 25 is capable of binding KF, KCN, and KOCH3 in an ion pair fashion but binds KI and KSCN in a monotopic fashion wherein the cation is bound to the crown moiety with the counteranions remaining “outside” of the receptor. Little affinity for KCl and KBr was seen; presumably, this reflects the weak nature of B−Cl and B−Br bonds as compared to B−F bonds. A single crystal X-ray diffraction analysis of complex [25·KF] revealed that the K+ is included within the crown ether while the F− anion is bound to the boron center with a B−F contact distance of 1.41 Å (Figure 29a). It is noteworthy that receptor 25 was also found

intramolecular nonbonded interactions, including C−H/π contacts, C−H···O and N−H···O hydrogen bonds, and π−π stacking between the squaramide rings, are possible within the free receptor. Nevertheless, receptor 43 proved capable of forming co-complexes with sodium acetate and potassium acetate, as inferred from DFT calculations carried out at the PB86/SVP level (Figure 26b). The resulting binding energies proved very similar for both complexes (−56.3 kcal/mol for AcONa vs −56.6 kcal/mol for AcOK). Experimentally, it was found that insoluble carboxylate salts, such as sodium benzoate and potassium acetate, could be solubilized in chloroform by means of receptor 43, as determined via 1 H NMR spectroscopic analyses carried out in CDCl3 (Figure 27).

Figure 29. X-ray structures of (a) the complex [25·KF] and (b) the complex [44·LiCl]. Color code: C, black; O, red; H, gray; Li, violet; B, light pink; F, chartreuse yellow; Al, rose brown; Cl, green; K, purple. These structures were reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 1286277 and 1292606).

Figure 27. 1H NMR spectra of 43 and 43 + AcOK recorded at 298 K in CDCl3. Reprinted with permission from ref 75. Copyright 2005 American Chemical Society.

capable of simultaneously and selectively binding methanol and amines in the form of the corresponding ammonium methoxide complex, as reported separately by the same group.76 Another example of a preorganized Lewis acid macrocyclic host, receptor 44, that could be used to bind both anions and cations was reported by the Reetz group in 1994.77 This system consists of an aluminum phenolate moiety surrounded by a crown ether. It proved capable of capturing LiCl as an ion pair via interactions involving the Lewis acidic aluminum center and the crown ether either moiety, as deduced from NMR spectroscopic experiments and an X-ray structure analysis (Figure 29b). In analogy to what was seen for 25, the ditopic receptor 44 proved capable of stabilizing ion pair complexes with LiBr and LiI (no interaction for LiF) as well as KX (X = F, Cl, Br, and I), as evidenced by 1H, 13C, and 27Al NMR spectroscopic studies. Interestingly, a significant kinetic effect was seen, where the lithium salts bind rapidly and essentially quantitatively within 2 h, whereas the corresponding potassium complexes require about 2 weeks to reach equilibrium. In 1994, Reinhoudt and co-workers described two ion pair receptors, 45 and 46 (Figure 30), that proved effective for the co-complexation of KH2PO4 and NaH2PO4, respectively.78,79 The design of these receptors was based on the fact that macrocyclic and acyclic ligands that contain Lewis-acidic binding sites, such as boron, silicon, tin, and mercury centers, complex anions.80−82 The same group had previously shown that neutral metalloclefts and metallomacrocycles containing both immobilized Lewis-acidic (UO22+) centers and amido subunits are excellent receptors for anions, displaying high selectivity for dihydrogen phosphate H2PO4−.83 In 45 and 46, a Lewis-acidic uranyl (UO22+) center is formally combined with two benzo[15]crown-5 units or a calix[4]arene

2.4. Inorganic Cations and Inorganic Anions as Ion Pairs

Many common salts, found in nature and in the laboratory, comprise both inorganic cations and inorganic anions. Perhaps not surprisingly, therefore, considerable effort within the ion pair recognition community has been devoted to creating receptors that can recognize efficiently simple inorganic salts. In fact, to date, the recognition of soft-anion/soft-cation pairs, soft-anion/hard-cation pairs, and hard-anion/soft-cation pairs has been achieved. A plethora of ion pair receptors have been reported in this regard. However, receptors, especially metalfree receptors, capable of recognizing hard-anion/hard-cation pairs, e.g., LiF and LiOH, are limited. Indeed, their design and synthesis remains a challenging task. The recognition of inorganic ion pairs dates back to at least 1991 when Reetz and co-workers reported a new class of heterotopic receptors containing a 21-membered crown ether bearing a Lewis-acidic borate ester center (25) (Figure 28).22 The crown ether was expected to serve as a binding site for cations, while the Lewis-acidic group was expected to provide for anion recognition. A series of potassium salts, KX (X = F, Cl, Br, I, SCN, CN, OCH3), were studied via 11B and 13C

Figure 28. Molecular structures of the receptors 25 and 44. K


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Figure 30. Molecular structures of the receptors 45 and 46.

Figure 32. X-ray structures of the complexes (a) [48·KCl], (b) [48· KF], (c) [48·NaF], (d) [48·CsCl], (e) [48·RbCl], and (f) [47·LiCl]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 1439190, 1439189, 1439185, 1439195, 1439194, and 1439180).

tetraethylester subunit, respectively. In fact, receptor 45 proved capable of binding KH2PO4 as an ion pair, while receptor 46 proved effective at capturing NaH2PO4, as inferred from 1H NMR spectroscopy, cyclic voltammetry, and fast atom bombardment mass spectrometry (FAB-MS). Recently, Rissanen and co-workers reported two ditopic uranyl salophen receptors (47 and 48, Figure 31) containing

Willem and co-workers prepared several organotin derivatives of [18]crown-6 and [15]crown-5-(benzo-4-carboxylate) ethers (i.e., receptors 49−52, Figure 33).89 Across the board, these

Figure 31. Molecular structures of receptors 47 and 48.

benzo-15-crown-5 and benzo-18-crown-6 subunits, respectively.84 Uranyl salophens were previously known to be effective anion receptors, an attribute ascribed to the strongly Lewis acidic nature of the uranyl cation (UO 2 2+ ). 85 Incorporation of uranyl salophen moieties into ditopic receptors could allow them to bind hard-to-capture ion pairs (i.e., NaF and KF). In-depth ion pair complexation studies in the solid state revealed that receptor 47 was capable of binding LiCl, NaBr, RbF, and CsF, while 48 was found effective at capturing NaF, NaBr, NaI, KF, KCl, KBr, KI, RbCl, CsCl, KAcO, and NH4Br (Figure 32). Both separated ion pair and contact ion pair complexes were observed in the solid state. Both the fluoride and chloride anions were found coordinated to the uranyl centers, presumably reflecting their strong Lewis basicity. In contrast, it was inferred that the bromide anion is bound in a more labile fashion, whereas no evidence of direct iodide−uranyl interactions was seen. Instead, the iodide anions serve only as weak hydrogen-bond acceptors within the crystal lattice. Organotin-based compounds, bearing Lewis acidic sites, have long been appreciated as being useful for the selective complexation of anions.86−88 Building off this foundation,

Figure 33. Molecular structures of the receptors 49−55.

systems were found to be capable of binding NaSCN and KSCN as ion pairs, as evidenced by solid state X-ray diffraction analyses and NMR spectroscopic studies carried out in acetone-d6 solution. Interestingly, 1H, 13C, 23Na, and 117Sn NMR spectroscopic studies performed over a range of temperatures revealed rather complex equilibria between several solution state species in the case of the tri-n-butyl tin analogues 50 and 52 and these two test ion pairs. To avoid elimination of the carboxylate moiety in the presence of the targeted SCN− anion, Jurkschat and coworkers developed two more stable carbon-bonded organotinfunctionalized ditopic receptors (53 and 54, Figure 33).90 These systems contain a Lewis acid center for anion recognition, as well as the macrocyclic crown ether for cation complexation. X-ray diffraction analyses of complex [54· NaSCN] revealed that the sodium cation is strongly coordinated by five oxygen atoms of the crown ether while the rhodanide anion is located close to the sodium cation with L


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an Na−N distance of 2.34 Å. The SCN− anion was seen to interact weakly with a tin atom present in an adjacent molecule with a large S−Sn contact of 4.63 Å. Support for the suggestion that 54 is an ion pair receptor capable of complexing simultaneously Na+ and SCN− came from 13C and 119Sn NMR spectroscopic studies carried out in CD2Cl2, as well as both electrospray mass spectrometric analyses (ESMS) and transport experiments. Later, several related ditopic organotinsubstituted receptors were reported by the same group.91−96 The complexation of so-called “hard” ion pairs (i.e., LiF, NaF, and LiOH) is a widely recognized challenge due to their relatively high lattice energies. To compensate for these lattice energies, strong ion-receptor binding is deemed advantageous. Recognizing that bis(organostannyl)methanes, such as Ph2XSnCH2SnXPh2 (X = halogen), are excellent fluoride ion acceptors,88 a robust ditopic receptor Ph2ISnCH2Sn(I)(Ph)− CH2−[16]crown-5 (55) was designed by Chaniotakis and coworkers (Figure 33). It was prepared by linking a bicentric organotin-based Lewis acid with a crown ether moiety.97 In accord with the authors’ design expectations, receptor 55 was found capable of overcoming the high lattice energy of NaF and solubilizing it in acetonitrile. Evidence for NaF binding came from a single crystal X-ray diffraction analysis, wherein a methanol molecule was observed to bridge the sodium cation and the fluoride anion with a Na−F distance of 4.51 Å (Figure 34).98

Figure 35. Molecular structure of the calix[4]arene-capped tetraphenylporphyrin−ZnII complex 56 and its proposed mode of interaction with appropriately selected ion pairs (i.e., NaI and KI).

Figure 36. Molecular structures of the hydrated forms of the zinc cyclen-based ion pair receptors 57 and 58.

cyclen were known to bind water,106 it was expected that receptors 57 and 58 would prove to be water-soluble ion pair receptors capable of binding Lewis-basic anionic guests, such as phosphate salts, after formation of the zinc(II) complex. Evidence in support of this suggestion came from binding studies carried out using 1H NMR spectroscopy, UV−vis spectroscopy, and ITC (isothermal titration calorimetry). The size of the crown ether in 57 favors K+ cation recognition over Na+ cation complexation. Consistent with this, receptor 57 was found to be selective for KH2PO4 over NaH2PO4. A similar preference (KH2PO4 > NaH2PO4 > LiH2PO4) was also seen under physiological conditions in the case of receptor 58. Positive cooperativity was seen for ion pair binding in the latter model system. This was attributed to a combination of complementarity between the host and the guest, as well as efficient desolvation. Parenthetically, it is worth noting that, in aqueous environments, it is often solvation effects (e.g., relative hydration energies) that determine the specifics of ion recognition. Generally, the determinants of ion binding in water are almost entirely entropic. The favorable entropy is associated with desolvation of both the phosphate guest and the crown ether cavity. The hydration properties of ions can significantly affect the desolvation, which, in turn, can influence the entropy contribution. It has long been appreciated that appropriately designed positively charged moieties, including those containing protonated ammonium cationic sites, may be used effectively to construct anion receptors.107 In 1992, Lockhart and coworkers exploited such subunits to create what is generally considered to be the first multitopic ion pair receptor (59) containing protonated ammonium groups that proved capable of binding concurrently both an anionic guest and its countercation (Figure 37).108 Receptor 59 contains crown ethers (as well as the protonated ammonium linker) and was found to form a sandwich-like structure wherein both the anion and cation are bound when treated with KCl, as inferred from NMR spectroscopic studies.

Figure 34. (a) Proposed binding mode for complex [55·NaF· CH3OH] and (b) X-ray structure of the ion pair complex [55·NaF· CH3OH]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 671304). Color code: C, black; O, red; H, gray; F, chartreuse yellow; I, dark violet.

Capped porphyrins have a time-honored role as receptors for small molecules.99−101 They have also seen use in the area of ion pair recognition. In 1995, Shinkai and co-workers designed and synthesized a C4-symmetrical hard−soft ditopic metal receptor by coupling a skirt-like calix[4]arene with a tetraphenylporphyrin.102 Subsequent insertion of ZnII yielded the calix[4]arene-capped tetraphenylporphyrin−ZnII complex 56. The calix[4]aryl amide moiety present in 56 is known to interact well with alkali metal cations, in particular Na+,103 while the zinc porphyrin can bind anion axial ligands. In fact, receptor 56 was found to bind KI with a log Ka = 5.23 and NaI with a log Ka = 3.91, as determined by absorption spectroscopy (CHCl3:CH3CN = 4:1, v/v) (Figure 35). In contrast, almost no binding of KClO4 by 56 was seen. A similar approach to ditopic ion pair receptor design was reported by Peacock and co-workers in 2004.104,105 These researchers described the synthesis and binding properties of modular hybrid receptor systems (i.e., 57 and 58, Figure 36) containing both an aza macrocycle 1,4,7,10-tetraazacyclododecane (cyclen) and crown ether. Since zinc(II) complexes of M


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ditopic receptor proved capable of binding Ba2+, K+, or HSO4− (but not Cl−) when studied in the form of salts containing weakly coordinating counterions, as deduced from 1H NMR spectroscopic studies carried out in CD3CN. Receptor 62 was also found to function as an ion pair receptor and capture concurrently various cation−anion combinations of Ba2+, K+, HSO4−, and Cl− and do so in a positive cooperative fashion. More importantly, the ferrocenecarboxamide moiety permitted voltammetric investigations of ion recognition; these studies revealed that receptor 62 could be used to recognize electrochemically pairwise combinations of these anions and cations.111 A similar example was reported by Ahn and coworkers.112 Here, potassium cyanide was found to be selectively bound by a heteroditopic ferrocene-based crown ether-trifluoroacetylcarboxanilide receptor, as inferred from NMR spectroscopic studies and ITC analyses carried out in acetonitrile. Beer and co-workers synthesized the heteroditopic RuII and ReI bipyridyl bis(benzo-15-crown-5) receptors 63 and 64 (Figure 39) and used them to investigate the cooperative and


Employing a similar principle, Tuntulani and co-workers designed and synthesized two tripodal aza crown ether calix[4]arenes, 60 and 61 (Figure 37), that contain both cation and anion binding sites.109 Detailed 1H NMR spectroscopic investigations revealed that receptors 60 and 61 both bind I− more strongly than Br− and that neither forms appreciably stable complexes with F−. Differences in the relative affinities were seen (Table 2) that are ascribed to the Table 2. Association Constants of 60 and 61 toward Br− and I− Determined in the Presence of Various Countercations109 Ka (M−1) metal

anion

60

61

none Na+ K+ none Na+ K+

Br− Br− Br− I− I− I−

84.2 58.6 120.1 108.9 77.2 103.3

76.5 53.0 34.9 137.9 57.3 66.3

differences in the two structures. Importantly, the presence of K+ was found to enhance the binding affinity of 60 toward Br−. In the presence of base (i.e., NaOH), both compounds 60 and 61 can be transformed into their neutral form, species that were found to bind transition metal ions such as Co2+, Ni2+, and Cu2+ in a 1:1 fashion.110 In addition to the Lewis acids and positive charged groups mentioned above, neutral hydrogen-bond donors, such as amide, (thio)urea, and pyrrolic NH, have also been widely used in the construction of ion pair receptors. As early as 1995, Beer and co-workers prepared a bis(ferrocenecarboxamide)substituted diaza l8-crown-6 receptor (62) that contains binding sites for both cations and anions, Figure 38.111 This


allosteric effects associated with ion pair recognition.113 Both receptors were found to possess affinity toward the Cl− and H2PO4− anions. As inferred from either 1H or 13C NMR spectroscopic titration experiments carried out in DMSO-d6 solution, the specific binding interactions were found to be dependent on changes in the receptor conformation, as well as electrostatic effects arising from co-binding of a K+ countercation in the form of a crown ether sandwich complex. Specifically, in the absence of K+, both 63 and 64 are selective for H2PO4− over Cl−. However, selectivity for Cl− over H2PO4− was seen in the presence of K+. The cooperative binding of potassium cations and chloride anions in the case of similar rhenium(I) bipyridyl amide crown ether receptors was reported by the same research group.113 It was also found that by extending formally the m-xylyl spacer of 64 (to give the heterotopic receptor 65) a marked increase in the acetate binding affinity was observed in the presence of the potassium cation.114 In this case, both KCl and KAcO were recognized in the form of ion pairs with significant cooperative interactions being observed between the co-bound anions and cations. Large positive allosteric effects on halide ion cesium salts were observed by Nabeshima and co-workers.115 These researchers prepared a heterotopic receptor (66) bearing

Figure 38. Molecular structure of 62 and proposed binding mode for cation−anion ion pair complexation. N


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design expectations, bicycles 69 and 70 were found to be versatile receptors for a range of salts (i.e., alkali metal chloride salts) and neutral molecule guests, including solvent molecules. For example, 70 proved to bind selectively NaCl, KCl, and CsCl with the enhanced chloride affinity per the following sequence: K+ (9-fold enhancement) > Na+ (8-fold enhancement) ≫ Cs+ (no enhancement), as determined from 1H spectroscopic analyses carried out in DMSO-d6/CD3CN (3:1, v/v) in the presence of 1 molar equiv of the metal cation under consideration. In the case of NaCl complexation, a chloroform molecule was found to bridge the Na+ cation and the Cl− anion, forming a solvent-separated complex with a Na···Cl distance of 7.31 Å, as inferred from the solid-state metric parameters. Receptor 70 proved capable of extracting an almost stoichiometric amount of KCl into DMSO. In addition, this receptor was found to bind dimethyl sulfoxide (DMSO) with an association constant of 160 M−1 in CDCl3. Operating under the assumption that the binding cooperativity would be improved if the salt were bound to the receptor as a contact ion pair complex, the Smith group designed a macrobicyclic receptor (71, Figure 41) with a smaller distance between the anion and cation binding sites than present in either 69 or 70.118 In accord with their design expectations, receptor 71 was found to bind alkali metal chloride salts (i.e., NaCl and KCl) as contact ion pairs, as demonstrated by single crystal X-ray diffraction analyses (Figure 42). It was found that K+ was able to enhance more

four amide groups and two crown ethers (Figure 40). The spacer between two 18-crown-6 rings in 66 is quite long and

Figure 40. Allosteric regulation and the formation of 68 (X = Cl or Br).

flexible, allowing a range of conformations to be sampled in solution. However, in the presence of more than 1 equiv of Cs+ (as its tetrakis[3,5-bis(trifluoromethyl)phenyl] borate (TFPB) salt), the benzo-18-crown-6 moieties form a 2:1 sandwich complex 67 that holds the cation in a tweezers-like manner, as deduced from 1H NMR spectroscopic studies carried out in a mixture of CDCl3 and CD3CN (4:1, v/v), as well as ESI-MS analyses. However, the addition of an excess (2 equiv) of Cs+ led to the formation of complex [66·2Cs+] (structure not shown). The cesium cation complexation constants determined by 1H NMR spectroscopic titrations carried out in CDCl3:CD3CN = 4:1 (v/v) were estimated to be K1 > 1.0 × 105 M−1 and K2 ≈ 1.0 × 104 M−1. In the presence of only 1 equiv of Cs+, the association constants corresponding to the binding of the chloride or bromide anions to 66 were calculated to be 9000 ± 700 and 3400 ± 200 M−1, respectively. In marked contrast, the corresponding values for the chloride or bromide anions (as their TBA salts) were estimated to be merely 210 ± 30 and 290 ± 60 M−1, respectively. These findings were taken as evidence that the Cs+ cation acts as a positive allosteric effector for the binding of halide anions in this system (68). In 2000, Smith and co-workers described the design and synthesis of two bicyclic heteroditopic receptors 69 and 70 (Figure 41).116 These systems contain two quite different binding sites, that is, a dibenzo-18-crown-6 and a bridging 1,3phenyldicarboxamide. It was known at the time of publication that N-methylanilides prefer to adopt a syn conformation, forming convergent or juxtaposed binding sites that allow for anion recognition,117 whereas the crown moieties were expected to promote cation complexation. In accord with the

Figure 42. X-ray crystal structures of (a) [71·NaCl] and (b) one of the two [71·KCl] structures found in the unit of the complex. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 166349 and 166348).

effectively the Cl− affinity of 71 than Na+ (1 molar equiv of each cation), a finding that was rationalized by the closer contact between the co-bound K+ cation and the Cl− anion within 71, as inferred from 1H NMR spectroscopic experiments performed in DMSO-d6 at 295 K. It was also found that receptor 71 is capable of dissolving 1 molar equiv of KCl in CHCl3 and that the resulting ion pair complex [71·KCl] proved sufficiently stable to survive column chromatography over silica gel using weakly polar solvents as the eluent. As reported by the same research group, receptor 71 could further be used to distinguish between various monoalkylammonium salts on the basis of differences in their binding behavior.119 A somewhat analogous ion pair receptor, the 2,5diamidopyrrole-strapped system 72 having an additional pyrrole-derived hydrogen-bond donor site, was reported by by Gale, Smith, and co-workers in 2001.120 Compared with receptor 71, the binding affinity of ditopic receptor 72 for Cl− proved 3 times larger, a finding ascribed to a cooperative interaction between the pyrrole NH proton with the bound Cl− anion, as revealed by 1H NMR spectroscopic titrations carried out in DMSO-d6. As above, the addition of 1 molar equiv of K+ to 72 was found to enhance substantially the

Figure 41. Molecular structures of receptors 69−71. O


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affinity for halide anions. In contrast, almost no appreciable enhancement in the Cl− affinity was seen upon addition of 1 equiv of Na+ cation. Unambiguous support for the fact that 72 could act as a heterotopic ion pair receptor capable of coordinating NaCl as a tight contact ion pair (producing [72· NaCl]) came from an X-ray crystallographic analysis (Figure 43). It was found that both ions are co-bound within the cavity


systems was easily prepared via a Rh(II)-catalyzed decomposition of an α-diazo-β-keto ester in 1,4-dioxane (up to 20 g in one batch).126 The desired ditopic polyamide receptors could then be obtained from the unsaturated crown ether via a two-step late-stage functionalization process. The affinity of 74−79 for small cations (i.e., Na+ and K+) and anions, such as Cl−, Br−, I−, N3−, NCO−, SCN−, NO3−, and H2PO4−, was examined by means of 1H NMR spectroscopy in a mixture of CDCl3 and DMSO-d6 (4:1, v/v). It was found that these heteroditopic receptors interacted well with small cations (Na+, K+) and linear triatomic anions (N3−, OCN−, SCN−), as well as the triangle-shaped NO3− anion, but not with the Cl−, Br−, or I− anions. Single crystal X-ray diffraction analysis revealed that both 74 and 75 were capable of binding NaN3, NaNO3, and NaOCN in the form of ion pair complexes (Figure 46). The larger thiocyanate (SCN−) anion did not appear to fit well within the cavity.

Figure 43. (a) Molecular structure of receptor 72; (b) crystal structure of the complex [72·NaCl]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 191389).

of the bicycle with a short Na···Cl distance of 2.65 Å being observed. The bound Cl− anion was found stabilized by hydrogen-bonding interactions involving the two amide NH protons, the single pyrrolic NH proton, and two aryl CHs protons. In contrast, the Na+ cation was bound, as expected, by the diaza-18-crown-6 ring. The indole scaffold has been widely utilized as a molecular building block to prepare anion receptors.121−123 Appreciating this, Jeong and co-workers prepared an ion pair receptor (73) by coupling a diaza-18-crown-6 ether to a rigid bis-indole scaffold bearing two indole NH hydrogen-bond donors (Figure 44).124 On the basis of 1H NMR spectroscopic studies carried

Figure 44. Molecular structure of 73 and the binding mode proposed for ion pair complexation.

Figure 46. Single crystal X-ray diffraction structures of the ion pair complexes (a) [75·KOCN], (b) [75·NaNO3], (c) [75·NaN3], and (d) [74·NaN3]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 1578258, 1578259, 1578264, and 1578260). The inorganic ion pairs are shown in space-filling form. Solvent molecules are omitted for clarity.

out in 10% (v/v) DMSO-d6/CD3CN, the association constants for chloride anion recognition were determined to be 120, 14,000, and 6200 M−1 in the presence of lithium, sodium, and potassium ions, respectively. In the absence of a coordinating metal countercation, the Cl− affinity was found to be 7 M−1. The cation effects proved relatively independent of the halide anion tested and generally followed the order Li+ < K+ < Na+. Additional support for the proposed contact ion pair binding mode came from an energy-minimized analysis of [73·NaCl] optimized using a MMFF force field (MacroModel 7.1). Recently, Lacour and co-workers reported efficient syntheses of several new polyamide−crown ether conjugates (74−79, Figure 45),125 which proved to be effective ditopic ion pair receptors. The unsaturated crown ether core present in these

Urea functionalities have been commonly incorporated into anion receptors due to their recognized capacity to act as hydrogen-bond donors.8,127−130 Ion pair receptors can be built by combining urea subunits with one or more cation complexation sites. The urea-functionalized macrocyclic crown ether system, 4-phenylurea-benzo-15-crown-5 (80, Figure 47), reported by Barboiu and co-workers provides an example of a heteroditopic receptor prepared in accord with such a generalized strategy. It was found capable of complexing P


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complexation of cations (Na+, K+, and Rb+) and halide anions (Cl−, Br−, and I−), a finding attributed to a combination of favorable electrostatic interactions and hydrogen bonding. Single crystal X-ray diffraction structures of 81 crystallized in the presence of KF, KCl, KBr, KI, RbCl, NH4Cl, NH4Br, KAcO, K2CO3, and K2SO4, respectively, were solved and used to analyze the binding motifs of 81 seen in complexes containing alkali or ammonium halide or oxyanion salts in the solid state (Figure 49). All cations were found to be complexed


the Ag+ cation and then further binding hydrophobic (BF4−, and PF6−) and oxoanions (NO3−, CF3SO3−).131 For example, the Ag+ complex of 80 was found to bind BF4−, PF6−, CF3SO3−, and NO3− with association constants of 140, 255, 660, and 980 M−1, respectively, as determined by 1H NMR spectroscopic titrations carried out in CD3CN. A single crystal X-ray diffraction structural analysis of [80·AgNO3] revealed the presence of two heteroditopic antiparallel dimers of [80· AgNO3]2 in the solid state (Figure 48). In this complex, the

Figure 49. CPK models of the X-ray structures of (a) [81·RbCl], (b) [81·KF]2, (c) [812·K2CO3], and (d) [812·K2SO4]2. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 1408388, 1408386, 1408384, and 1408385). Colors (green, red, yellow, and blue) are used to highlight different independent ligands. Solvent molecules are omitted for clarity.

by the crown ether moieties, while the anions were found bound by the urea groups present in either single or multiple molecules of 81. Receptor 81 was able to capture K2CO3 in the form of the dimeric complex [812·K2CO3] and bind K2SO4 in the form of a higher order complex [812·K2SO4]2. Electrospray ionization mass spectrometric (ESI-MS) studies provided support for the formation of ion pair complexes and the binding preferences observed in solution, namely, KCl > NaCl > KBr > KI. In order to study the nature of the ion pair complexes and uncover how the crown ether size affects the underlying ion pair recognition modes, Rissanen and co-workers created the ion pair receptors 82 and 83 that contain larger crown ethers and a greater number of urea groups than present in 81.133 It was found that receptor 82, containing a dibenzo[21]crown-7 subunit, adopts an open conformation due to the asymmetric crown ether scaffold, whereas receptor 83 adopts a compact, folded conformation upon complexing an alkali metal cation, as inferred from solid state structural analyses (Figure 50). In the case of receptor 82, the rubidium cation is coordinated to all seven crown ether oxygen atoms, which are relatively coplanar, while the anions (i.e., CO32−) were seen to interact with the multiple urea moieties of the hosts. However, in the crystal structures of the Rb+, Cs+, and Ba2+ complexes of 83, the crown ethers exist in twisted or folded conformations. This, in turn, allows the urea-bearing “arms” of the receptor arms to be oriented in the same direction, which creates a binding site suitable for the recognition of test anions, such as Cl−, Br−, I−, AcO−, and MeOCOO−. 1H NMR spectroscopic studies carried

Figure 48. Structure of the dimer of [80·AgNO3]2 seen in the solid state. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 949582).

Ag+ cations are equatorially coordinated by the dimensionally incompatible 15-crown-5 macrocycle and the co-bound NO3− anions. The latter are hydrogen-bonded to the urea groups. The presumed synergetic anion−cation recognition is likely affected by the self-dimerization of the silver complex as well as the specific choice of anions. Another example of such a system comes from the Rissanen research group, who reported the synthesis of a simple 18crown-6-based bis-urea ion pair receptor (81).132 The ion pair recognition characteristics of this receptor system were studied in solution using NMR spectroscopy, in the solid state via single crystal X-ray diffraction analysis, and in the gas phase using mass spectrometry. As inferred from 1H NMR spectroscopic investigations carried out in 4:1 (v/v) CDCl3/ DMSO solution, positive cooperativity was seen for the coQ


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case of the direct contact ion pair binding, the electrostatic cooperativity is dictated by the size of the ions. On this basis, it was suggested that trends involving electrostatic cooperativity could be predicted on the basis of Coulomb’s law. However, it was noted that the absolute value is overestimated due to the putative charge dilution that occurs when the individual ions bind to their respective anion and cation recognition sites. In order to prepare ion pair receptors suitable for complexing alkaline earth metal halide salts, Lüning and coworkers designed and synthesized a neutral tritopic macrocycle 85;135 this was done by incorporating two isophthalamide moieties into a cyclic glycol ether in symmetric fashion, Figure 52. Receptor 85 is formally a tritopic macrocycle and can

Figure 50. Crystal structures of (a) [83·RbCl], (b) [83·CsCl], (c) [822·Rb2CO3], and (d) [83·BaCl2]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 1478712, 1478715, 1478711, and 1478718). Different colors (green and yellow) are used to highlight the various independent ligands in [822·Rb2CO3]. Solvent molecules are omitted for clarity.

out in 4:1 (v/v) CDCl3/DMSO-d6 led to the suggestion that both 82 and 83 exhibit positive heterotropic cooperativity in the recognition of halide anion salts, with the halide affinity increasing in order I− < Br− < Cl− in the presence of Rb+ or Cs+. Compared with 82, receptor 83 shows a higher affinity for various Rb+ or Cs+ salts, binding representative ion pairs in the order CsI < CsBr < CsCl < RbCl. These inferences were further supported by mass spectrometric analyses, as well as computational studies. Understanding the cooperative interactions between anions and cations within the context of ion pair binding to receptors could provide a new means for manipulating salts. Recognizing this need, the Flood group designed and prepared a set of semiflexible monocyclic aryl-triazole-ether macrocycles (e.g., 84), which permit the binding of ion pairs (NaX, X = Cl, Br, I) (Figure 51).134 Using these receptors, these researchers were


provide three binding sites: two different isophthalamide residues for binding two anions136 and four oxygen atoms in the diethylene glycol part for complexing one cation. In fact, receptor 85 was found capable of binding selectively LiCl over NaCl and KCl or CaCl2 over MgCl2 or BaCl2, as determined by 1H NMR spectroscopic studies (Figure 53) carried out in

Figure 53. Chemical shift changes seen for the NH protons of 85 and 86 upon treating with saturated solutions of the indicated group 1 and 2 metal halides. The solvent used for these studies was 9:1 CDCl3:DMSO-d6. Reprinted with permission from ref 137. Copyright 2012 Royal Society of Chemistry. Figure 51. Molecular structure of 84 and its proposed complexation of NaX (X = Cl, Br, or I) salts.

CDCl3/DMSO-d6 (95:5, v/v) and mass spectrometric analyses. These researchers proposed that, in the case of the binding of CaCl2, two chloride anions were captured by two separate isophthalamide groups, while the calcium cation was coordinated by the two glycol chains, forming a contact ion pair complex. According to the authors, receptor 85 was at the time of publication the first neutral macrocycle capable of binding an alkaline earth metal dihalide (i.e., CaCl2) as a contact ion−triplet complex. In 2012, Georghiou and co-workers reported a closely related macrocyclic receptor, namely, 86.137 This system

able to quantify ion pair binding as well as the degree and origin of cooperativity via a combination of experimental and computational analyses. For instance, studies of the complexation of NaI and NaClO4 by 84 revealed the former salt is bound with a higher cooperativity than the latter (cooperativity factor (α): 1300 vs 400). Density functional theory calculations, used to examine separately conformational allostery and electrostatic cooperativity, revealed that, in the R


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was seen. However, precomplexation of Ca2+ cations to 87 served to switch on anion binding. Depending on the solvent system, Cl− anions were found to bind either in a noncooperative fashion or with strong positive cooperativity. In 2002, three near-contemporaneous theoretical studies were published by Alkorta et al.,139 Deyà et al.,140 and Mascal et al.141 detailing so-called anion−π interactions as favorable noncovalent contacts between an electron deficient (π-acidic) aromatic system and an anion.140 Since then, the underlying concepts have attracted a great deal of interest in terms of both theory and experiment. As an effective motif for probing anion−π interactions, the 1,3,5-triazine moiety has been incorporated into several anion receptors.142−144 For instance, Wang and co-workers145 synthesized the tritopic ion pair receptor 88 containing two preorganized triazine units for anion recognition and a pentaethylene glycol chain for cation complexation (Figure 55). In accord with the authors’ design

consists of a 34-membered macrocycle as opposed to the 30membered macrocycle present in 85. In analogy to what was observed in Lüning’s system, receptor 86 proved capable of binding both alkali metal and alkaline earth metal chloride salts. However, in contrast to 85, receptor 86 did not show appreciable selectivity toward LiCl over NaCl or KCl (Figure 53), as inferred from 1H NMR spectroscopic studies carried out in 9:1 CDCl3:DMSO-d6. However, in addition to CaCl2, receptor 86 was found to complex SrCl2 with a 1:1 binding stoichiometry with reasonable affinity, Ka = 285 ± 15 M−1 (vs 209 ± 17 M−1 for CaCl2), as determined by NMR spectroscopy in this solvent mixture. The proposed “ion triplet” binding feature was supported by the ESI-MS studies. Macrocycle 86 was also found to bind TBA salts with a 1:1 binding stoichiometry and to favor TBACl over the other TBA salts, including TBABr, TBAI, TBAPF6, and TBABF4. In 2014, Thordarson and co-workers reported the heterotopic receptor 87 that can be considered as a further expanded homologue of 85 and 86 in that the crown-4 of 86 is replaced by a crown-6.138 Receptor 87 was found to possess two isophthalamide anion recognition sites and two unusual “half-crown/bis-carbonyl” cation recognition sites. It thus functions as a tetratopic ion pair receptor, as inferred from single crystal X-ray diffraction analyses of the free host and the Ca(ClO4)2 complex, as well as two-dimensional NMR spectroscopic and computational studies. Interestingly, macrocycle 87 was found to function as a ditopic anion receptor capable of binding simultaneously two anions, such as Cl− and AcO−, in noncompetitive aprotic solvents (e.g., DMSO-d6/ acetone-d6 (1:9, v/v)). Complexation was subject to negative cooperativity, presumably as the result of the electrostatic repulsion between the two anions, which serves to inhibit the second binding event. A single crystal structure of the complex [87·Ca(ClO4)2] confirmed that 87 could support the concurrent complexation of two Ca2+ cations with both the carbonyl groups and the crown ether contributing to binding (Figure 54). The complexation of two Ca2+ leads to a change

Figure 55. (a) Molecular structures of receptors 88 and 89 and (b) electrostatic surface potentials (ESPs) for Cl− (left) and N,Ndimethyl-substituted triazine moieties (right). Reproduced with permission from ref 145. Copyright 2018 Royal Society of Chemistry.

expectations, receptor 88 proved capable of trapping divalent Ca2+ halide anion salts, such as CaBr2 and CaI2. As revealed by single crystal X-ray structural analyses of two complexes, namely, [88·CaBr2] and [88·CaI2], CaBr2 is bound as a tightcontact ion pair, whereas CaI2 is captured in the form of a solvent-separated ion pair. In both cases, relatively short contacts between the halide anions and the triazine rings were observed, which was taken as evidence of stabilizing anion−π interactions. More detailed support for the suggestion that anion−π interactions play a stabilizing role in ion pair binding came from the 1H NMR spectroscopic titration experiments carried out in CD3CN. It was also reported by the same group that the electronics of the triazine moieties could be modified by the introduction of a dialkylamino substituent.145 On the basis of simple polarity arguments, supported by electrostatic surface potential (ESP) calculations for Cl− and the N,N-dimethyl-substituted triazine moieties (Figure 55), receptor 89 was expected to be more electron rich than 88. Thus, although 89 displayed stronger binding toward Ca2+ (K = 8871 ± 1065 M−1 vs 2243 ± 21 M−1 for 88), the resulting complex displayed a lower propensity to bind Br− and I− than 88, lending credence to the conclusion that anion−π interactions play an important role in

Figure 54. Single crystal X-ray diffraction structure of the complex [87·Ca(ClO4)2]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 994171). The Ca2+ cation and NH H-bonded ClO4− anions are shown in space-filling form. The water molecules coordinated to the Ca2+ center and other solvent molecules are omitted for clarity.

from a folded-closed conformation (as seen in the free host 87) to an open form (in the calcium complex). The 1:2 (87:Ca 2+ ) stoichiometry was supported by 1 H NMR spectroscopic titrations carried out in different solvents of varying polarity. In the presence of competitive media (i.e., CDCl3/CD3OD (9:1, v/v)), no discernible anion recognition S


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groups.151 These ancillary functionalities were expected to abet cation and anion recognition, respectively. In fact, 92 was found to complex Na+ in close proximity to the calix[4]arene backbone, while the Br−, Cl−, and HSO4− counteranions were concurrently bound by the remote NH hydrogen-bond donors (Figure 57).

mediating the binding of the ion pairs in question. In addition, the same group exploited anion−π interactions to capture zinc salts, such as ZnCl2 and Zn(NO3)2.146 Taken together, this set of studies provides important experimental support for the notion that so-called “weak” anion−π interactions can be exploited successfully in the design of effective ion pair receptors. A number of ion pair receptors can trace their origin to early cation recognition efforts. Several di- and polytopic calix[4]arene-based systems fall into this category. The calix[4]arene platform is one of the more important stand-alone motifs in supramolecular chemistry. It provides near-unique possibilities in terms of providing a framework onto which binding motifs may be arranged in a manner complementary to potential guest species, in particular cations.147−149 As an early example, in 1995, Beer and co-workers prepared two new heteroditopic calix[4]arene-based receptors (90 and 91) (Figure 56),150

Figure 57. Molecular structure of receptor 92 and its proposed ion recognition modes.

Tomišić and co-workers reported the ion pair binding properties of a tetra-substituted lower-rim calix[4]arene tryptophan derivative 93.152 This system was found to act as an efficient ligand for several alkali metal cations and the Eu3+ cation, as inferred from spectrophotometric, spectrofluorimetric, conductometric, and potentiometric titrations carried out in acetonitrile.153 The amide groups and indole moieties present in 93 were expected to provide two independent anion binding sites. In fact, the tryptophan-based receptor 94 was found to capture F− anions selectively relative to other halide ions and to form complexes [93·F−] (1:1) and [93·2F−] (1:2) in acetonitrile, as inferred from spectrophotometric and NMR spectroscopic titrations carried out in protic or deuterated acetonitrile. Receptor 93 also proved capable of binding strongly the Na+ cation (log Ka = 8.25). The subsequent addition of F− (as its tetrabutylammonium salt) led to the formation of [93·NaF], a complex that is in fast exchange with [93·Na+] on the NMR time scale. However, this exchange is accompanied by dissociation of the complexes due to the strong ion pairing between Na+ and F− that occurs in acetonitrile.154 In fact, the deliberate addition of excess fluoride anion leads to the formation of [93·F−] and [93·2F−] species (Figure 58). In 2005, Nabeshima and co-workers reported the design and synthesis of a novel multiresponsive heterotopic ion pair receptor 94, as well as its binding behavior.155 Intentionally, three different types of ion binding sites, namely, two esters, two polyether moieties for binding hard cations, two urea sites for anion recognition, and two bipyridine units for binding soft cations, were appended onto a calix[4]arene skeleton to produce relatively sophisticated molecular systems that proved responsive to different external stimuli. In light of its design, receptor 94 was expected to allow for the effective and regulated multistep recognition of anions by exploiting two different cationic guests (Figure 59). In fact, receptor 94 proved capable of complexing the NO3− and CF3SO3− anions with association constants (log Ka) of 1.88 ± 0.03 and 1.4 ± 0.2, respectively, as inferred from 1H NMR spectroscopic analyses performed in CDCl3/CD3CN (9:1, v/v) (Table 3).


which at the lower rim contain amide-linked benzo-15-crown-5 (2,3,5,6,8,9,11,12-octahydro-1,4,7,10,13-benzopentaoxacyclopentadecine) units designed to capture cations at the crown ether recognition sites. At the same time, the amide NH protons were expected to favor anion binding. The close proximity between the co-bound anions and cations was expected to provide further stabilizing electrostatic interactions for bound ion pairs. In fact, receptor 90 was found to bind cations (i.e., K+, Ba2+, and NH4+) well and exclusively at the crown ether rings in a 1:1 intramolecular sandwich fashion, as inferred from 1H NMR spectroscopic studies carried out in deuterated acetonitrile and solid-state X-ray diffraction analyses. In contrast, receptor 91 proved able to bind five cations (either Na+ or K+), forming a super [91·5M+] (M+ = Na+, K+) complex, where an alkali metal cation binds within each of the four crown ether moieties while the tetraamide lower-rim cavity of the calix[4]arene is occupied by one metal cation, as inferred from 1H NMR spectroscopic analyses carried out in CD3CN. As prepared, neither 90 nor 91 proved effective as an anion receptor. However, in the presence of K+ or NH4+ cations, 1:1 stoichiometric binding of Cl−, NO3−, HSO4−, and H2PO4− anions was seen in the case of 90. The latter two anions were bound most strongly, possibly due to the complementarity between these tetrahedral anions and the unique pseudotetrahedral arrangement of the amide and hydroxyl hydrogen-bond donors present on the lower rim of this particular calix[4]arene. Stibor and co-workers reported the calix[4]arene-based ditopic ion pair receptor 92, which bears four amide moieties near the macrocyclic core, as well as four remote carbamate T


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Table 3. Association Constants log Ka (Ka in M−1) for the Indicated Hosts and Anionic Guestsa 155 host 94 [94·Ag+] [94·Na+] [94·Ag+·Na+]

NO3−

CF3SO3−

1.88 ± 0.03 3.31 ± 0.07 (30)c 3.82 ± 0.15 (90)c 5.07 ± 0.17 (1500)c

1.4 ± 0.2 3.40 ± 0.07 (100)c 3.32 ± 0.11 (80)c 4.7 ± 0.2 (2000)c

BF4− b b 3.46 ± 0.11 4.28 ± 0.11

a

Determined by 1H NMR spectroscopy (400 MHz, CDCl3/CD3CN (9:1, v/v), [host] = 2.0 × 10−3 M). bNot determined due to small chemical shift change. cValues in parentheses are relative anion affinities (Ka for [94·Ag+], [94·Na+], or [94·Ag+·Na+] over Ka for 94). These data are taken from ref 148.

thus what is formally a cation-promoted positive allosteric effect. In an effort to enhance the affinity and selectivity of ion pair receptors, the Beer group prepared two heteroditopic calix[4]arene bisesters, compounds 95 and 96 (Figure 60).156 In this

Figure 58. Molecular structure of receptor 93 and its proposed interactions with Na+ and F−.


case, a lower-rim ester-substituted calix[4]arene platform was employed mainly due to its unique selectivity toward Na+ cations.157,158 In fact, receptor 95 was found to bind the Na+ cation more effectively than Li+ (as their respective perchlorate salts) with association constants of 3500 and 470 M−1 being seen for these two cations, respectively, as determined by 1H NMR spectroscopic methods in acetone-d6. Almost no interactions were observed in the case of K+ and NH4+. Prebinding of certain cations (i.e., Na+ but not K+) was found to enhance halide recognition, as inferred from 1H NMR spectroscopic analyses carried out in CD3CN. Receptor 96 was found to mirror the features of 95, Figure 60. In fact, this system was found to coordinate the Li+ and Na+ cations in a 1:1 stoichiometry with association constants of 2840 and 3350 M−1, respectively. No binding was seen in the case of larger monovalent cations (e.g., K+, Rb+, and NH4+). Interestingly, the bromide anion was found to enhance the affinity of 96 toward the Li+ cation and vice versa. In contrast, the bromide anion exerts an anticooperative effect on Na+ binding. In order to develop redox active calixarene-based receptors for ion pair recognition, Yang and co-workers synthesized in

Figure 59. Anion recognition by receptor 94 is regulated by two different cationic effectors. Reprinted with permission from ref 155. Copyright 2005 American Chemical Society.

The anion affinities were further enhanced in the presence of Na+ or Ag+. For example, after precomplexation of Ag+, the binding constants (log Ka) corresponding to the interaction between 94 and NO3− and CF3SO3− were found to be 3.31 ± 0.07 and 3.40 ± 0.07, respectively. In the case of [94·Na+], the corresponding log Ka values were found to be 3.82 ± 0.15, 3.32 ± 0.11, and 3.46 ± 0.11 for NO3−, CF3SO3−, and BF4−, respectively. When Na+ and Ag+ were co-bound to 94 simultaneously, the corresponding log Ka values for the aforementioned anions increased to 5.07 ± 0.17, 4.7 ± 0.2, and 4.28 ± 0.11, respectively. This remarkable stepwise enhancement in the affinities is rationalized in terms of the electrostatic interactions between the anions and cations and U


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cooperative fashion in a mixture of 2% water/acetonitrile. Precomplexation of cations such as Na+ and K+ to the calix[4]diquinone oxygen atoms and triazole nitrogen donor groups was found to enhance the strength of halide complexation by up to 11-fold in the case of the NaCl. Conversely, prebinding of anions within the isophthalamide cavity of receptor 99 served to enhance cation recognition. Solid-state X-ray crystallographic structural analyses led to the suggestion that 99 is capable of encapsulating NaCl, KBr, and NH4Cl. These salts are bound in the form of water-separated ion pairs with the cations coordinated to the lower-rim cavity of the calix[4]diquinone and the anions captured by the isophthalamide sites. In the case of KCl, a dimeric complex [99·KCl]2 is produced wherein the chloride anion is directly coordinated to the K+ center (Figure 63).

high yield two calix[4]arene-based ditiopic receptors (97 and 98) bearing large conjugated ferrocene groups, Figure 61.159


Per the design expectation, both compounds exhibited excellent electrochemical reversible redox response properties, as revealed by electrochemical analyses carried out in dry CH2Cl2/MeCN (1:4, v/v). Detailed 1H NMR spectroscopic titrations revealed that 98 bound NaH2 PO 4 and the zwitterionic (neutral) form of glycine in a 1:1 fashion. The corresponding binding constants were calculated to be 3850 and 2460 M−1, respectively. An alternative strategy for modifying the calixarene framework involves oxidation. This strategy has been used to prepare a variety of calix[4]arene-based mono-, di-, tri-, and tetraquinone species, referred to as calix[4]quinones.160−162 As a class, these macrocycles are versatile redox-active ionophores for metal ions.163−165 Recognizing this, the Beer group166 prepared a heteroditopic calix[4]diquinone triazolebased ion pair receptor 99, which proved capable of binding alkali metal cation/halide anion ion pairs (Figure 62). A combination of 1H NMR and UV−vis spectroscopic titration studies revealed that 99 is able to bind halide−monovalent cation combinations (i.e., NaCl, KCl, NH4Cl, and KBr) in a Figure 63. Crystal structures of the complexes (a) [99·NaCl·H2O], (b) [99·KBr·H2O], (c) [99·KCl]2, and (d) [99·NH4Cl·H2O]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 863829, 863831, 863828, and 863830). The inorganic ion pairs and bridging H2O molecule are shown in space-filling form. Solvent molecules are omitted for clarity.

The upper rim of the basic calix[4]arene platform may also be used to create heterotopic binding domains. For example, in 2003, Beer and co-workers reported two upper-rim functionalized heteroditopic calix[4]arene receptors containing amide linked bis(benzo-15-crown-5)-bis(ferrocene) (100) and tetrakis(benzo-15-crown-5) ether groups (101), Figure 64.167 These systems were designed to bind simultaneously cations and anions. On the basis of 1H NMR spectroscopic titration studies carried out in CD3CN:DMSO-d6 (1:1, v/v), it was suggested that both receptors show a preference for the potassium cation over the sodium cation. However, in the case of K+, complexation-induced conformational effects were seen. This was ascribed to the fact that bis(benzo-15-crown-5) ether ligands are well-known to form sandwich complexes with

Figure 62. (a) Molecular structure of receptor 99 and (b) its possible solution state ion pair recognition mode. Part b was reproduced with permission from ref 166. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA. V


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On the basis of 1H NMR spectroscopic titrations carried out in CDCl3/CD3CN (10:1, v/v), these heterotopic ion pair receptors were capable of binding alkali metal cations (i.e., Li+ and Na+) and halide anions (i.e., Cl− and Br−) at the lower and upper rims, respectively. Interestingly, precomplexation of a Li+ cation to the lower rim was found to improve the binding affinity for both Cl− and Br− (Figure 66 and Table 4). In


potassium cations.168−170 Nevertheless, in the presence of 1 equiv of K+ (as its perchlorate salt), the affinities for the chloride, benzoate, and dihydrogen phosphate anions were increased. In contrast, when 100 was exposed to 2 equiv of Na+ or when 101 was treated with 4 equiv of Na+, a general decrease in the anion binding affinity was observed due to the fact that each crown ether contains a bound Na+ cation, which precludes the amide moieties being able to complex effectively an anionic guest. In accord with the design expectations, receptor 100, bearing electroactive bis(ferrocene) functional groups, was found to recognize anions, in particular benzoate, electrochemically in the presence of potassium. Using calix[4]arene as the functionalization platform, Tuntulani and co-workers designed and synthesized two new calix[4]arene derivatives, 102 and 103, Figure 65.171 These

Figure 66. Molecular receptors 104−107 and a schematic view of the ion pair binding that is expected for lithium halide salts.

Table 4. Association Constantsa for the Interaction of 104− 107 with Chloride and Bromide Anionsb 172 association constant Ka (M−1) host

Cl−

Cl− + Li+

Br−

Br− + Li+

104 105 106 107

31(±6) 50(±7) 150(±20) 396(±36)

1557(±140) 1082(±110) 2234(±200) 5123(±420)

50(±6) 24(±5) 95(±10) 168(±23)

1241(±130) 134(±12) 1449(±135) 3289(±330)

a

Measured in CDCl3/CD3CN (10:1, v/v) by means of 1H NMR spectroscopic titrations. bGuests studied: LiClO4, TBACl, and TBABr.

contrast, Na+ ion complexation to the same cation binding site led to no substantial enhancements in the anion binding affinities. This observation was rationalized in terms of allosteric effects. Specifically, the complexation of an alkali metal cation to the lower rim controls the cavity size and shape of the calixarene. Thus, when a Na+ cation (with a larger radius than Li+) is bound to the lower rim domain, the calix cavity changes from a flattened cone shape to a more upright form that may favor intramolecular hydrogen bonding between neighboring NH and CO groups, thus interfering with anion binding at the upper rim. It was also found that the presence of electron withdrawing groups on the upper rim leads to an increase in anion binding affinity, presumably as the result of increasing the acidity of the amide protons and their associated ability to act as hydrogen-bond donors. After the cone-like conformation of calix[4]arene, the 1,3alternate conformation is the one most commonly used to generate ion receptors. It can provide a multiplicity of excellent binding sites for ion pair recognition when proper functionalization can be achieved. For example, the Yamato group reported a heteroditopic 1,3-alternate thiacalix[4]arene receptor 108 that contains a crown ether moiety attached to the lower rim together with two urea linked pyrene moieties appended to the opposite side of the thiacalix[4]arene cavity.173 As inferred from fluorescence spectral studies and 1 H NMR spectroscopic titrations carried out in CD2Cl2− DMSO-d6 (10:1, v/v), receptor 108 proved able to bind K+ cation in a 1:1 stoichiometry with an association constant (Ka)


receptors contain urea and crown-urea moieties, intended to act as ion binding sites, on the upper rim and lower rim, respectively. Both 102 and 103 were found to complex Cl−, Br−, NO3−, and H2PO4− with the same selectivity order, namely, H2PO4− > Cl− > Br− > NO3−, as determined from 1H NMR spectroscopic titrations carried out in DMSO-d6. Compared to 102, receptor 103 bears an additional crown-5 unit on the lower rim. This was expected to lead to enhanced cation recognition and an increased anion affinity upon cation complexation. In fact, in the presence of Na+, an increase in the H2PO4− binding affinity was seen, with association constants of 1029 and 200 M−1 being recorded for 103 in the presence and absence of Na+. Yamato and co-workers introduced amide groups onto the upper rim and diethylacetamides onto the lower rim of a hexahomotrioxacalix[3]arene, yielding the ditopic ion pair receptors 104−107, which adopt cone-like conformations.172 W


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of 1.48 × 104 M−1. Conformational changes are thought to accompany ion recognition. Consistent with this hypothesis, the addition of Br− (as its TBA salt) to 108 leads to an enhancement in subsequent Br− anion binding, presumably because of a positive allosteric effect and a relatively dramatic conformational change. In contrast, the addition of Cl− ions gives rise to negative allosteric behavior, a finding attributed to receptor 108 binding the Cl− ion strongly via the two urea linked pyrene moieties, which induces a conformational change within the thiacalix[4]crown-5 and release of the K+ ion from this recognition site (Figure 67).


anions well with Ka values of up to 42,500 ± 2975 M−1 and that it is a more effective receptor than 114 and 115, Figure 68. The fluorescent features of receptor 116 were found to vary upon exposure to the Ag+ ion. This allowed the associated binding constant (Ka) to be determined as 61,975 ± 4336 M−1 via a fluorescence titration experiment carried out in CH2Cl2− DMSO (10:1, v/v). The Ksp for AgCl is 1.8 × 10−10 at room temperature, underscoring the difficulty associated with binding AgCl as a non-contact ion pair. However, in this case, Ag+ and Cl− were found to be co-bound by 116 probably as a host-separated ion pair, as inferred from 1H NMR spectroscopic studies performed in CDCl3−DMSO-d6− CD3CN (10:1:1, v/v/v) (Figure 69). The formation of the resulting ternary complex [Ag+·116·Cl−] was thought to benefit from a positive allosteric effect.

Figure 67. Molecular structure of receptor 108 and its proposed positive allosteric interactions with the Br− and K+ ions and the negative allosteric behavior seen with the Cl− and K+ ions.

By replacing the pyrene subunits with functionalized phenyl groups bearing electron donating or withdrawing groups at their m- or p-positions, the same group174 reported a series of 1,3-alternate thiacalix[4]arene-based ion pair receptors 109− 113 (Figure 68). Possessing an electron-withdrawing NO2 group at the p-position, 113 was found to bind selected anions, such as Cl−, with high affinity, as inferred from the 1H NMR spectroscopic and UV−vis titration experiments carried out in chloroform−DMSO (10:1, v/v). Again, depending on the choice of substrate, either positive or negative allosteric behavior could be observed in the case of receptor 113. Building also on the thiacalix[4]arene platform in its 1,3alternate conformation, the Yamato group synthesized a family of heteroditopic receptors 114−116 that rely on two pyreneappended triazole rings instead of the commonly employed crown ether as the cation-binding sites.175 1H NMR and UV− vis spectroscopic and fluorescence titration experiments provided support for the notion that 116 can bind chloride

Figure 69. Partial 1H NMR spectra of (a) free 116, (b) 116 + Bu4NCl, (c) 116·Cl− + AgSO3CF3, and (d) 116·Cl− + AgSO3CF3. H/ G = 1:1. Solvent: CDCl3−DMSO-d6−CD3CN (10:1:1, v/v/v). *Residual solvent peak. Reprinted with permission from ref 175. Copyright 2014 Elsevier.

Taking advantage of the 1,3-alternate conformer of calix[4]arene, the Nam group reported a new bifunctional receptor 117, Figure 70.176 This system contains urea and crown ether moieties linked to opposing sides of the lower rim of the calix[4]arene core. Receptor 117 was found to bind Cl−, Br−, I−, H2PO4−, HSO4−, and CH3COO− with association constants of 1054, 288, 208, 790, 840, and 2970 M−1, respectively, as determined by 1H NMR spectroscopic titrations carried out in CDCl3 (Table 5). Precomplexation of K+ at a 1:1 stoichiometry was found to enhance the ability of X


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Table 5. Stability Constants (Ka) of 117 in CDCl3176 Kab (M−1) none K+ a

Cl−

Br−

I−

H2PO4−

HSO4−

CH3COO−

1054 5240

288 1550

208 808

790 c

840 c

2970 c

a

Titrations were carried out in the presence of 1 equiv of potassium perchlorate. bErrors estimated to be 2.8 × 105 M−1 in CDCl3 and was even found to function as a receptor in protic environments. On the other hand, little interaction between receptor 174 and DOPE was seen even in the presence of a large excess (20 equiv) of DOPE.269 Receptor 174 proved selective for sn-DOPC (K a = 3.7 × 104 M −1) over dodecylphosphocholine (DPC) (Ka = 950 M−1) in CD3OD/ CDCl3 (1:50, v/v), a finding that was supported by theoretical calculations (Figure 106). Recently, the bis-calix[6]arene system 174 was reported to function as a heteroditopic receptor capable of binding biologically relevant quaternary ammonium ions (i.e., choline and acetylcholine) and zwitterions (e.g., β-alanine betaine and deoxycarnitine).270 Notably, a quaternary ammonium group in the guest was considered necessary to support efficient binding. AI


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Figure 108. DFT optimized structure of the [12·176] complex. Reprinted with permission from ref 274. Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA.

complementarity between the CTV-derived host and these specific guests. The three linkers in receptor 12 are made up from electronrich aromatic rings. This, it was postulated, might lead to electrostatic repulsions with an anion located within the cavity, destabilizing the host−guest complex. With such considerations in mind, Dutasta and co-workers synthesized a new CTV-derived hemicryptophane host 180 (Figure 109a) that

Figure 106. Energy minimized structures of (a) [174·DPC] and (b) [174·sn-DOPC]. Hydrogen bonds are indicated by dashed lines. Socalled binding tunnels were obtained by generating the Connolly molecular surface (radius: 1.4 Å) of the host 174 from the energy minimized structures of [174·DPC] and [174·sn-DOPC]. With the exception of the NH protons, all of the hydrogen atoms of receptor 174 are omitted for clarity. Reprinted with permission from ref 268. Copyright 2015 American Chemical Society.

Cyclotriveratrylenes (CTVs) are bowl-shape scaffolds that have proved useful for binding guest ammonium cations among other guests.271,272 Dutasta, Martinez, and collaborators273 reported that a ditopic C3-symmetrical hemicryptophane 12 containing tris(N-alkylcarbamoylmethyl)amine and CTV subunits could recognize not only tetramethylammonium halide salts with positive cooperativity45 but also zwitterionic species (Figure 107).274 In a Figure 109. (a) Molecular structure of receptor 180 and (b) DFT optimized structure of the [180·176] complex. Reprinted with permission from ref 276. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.

incorporates ethylenediamide linkers and a more electrondeficient benzene-1,3,5-tricarbonyl moiety, Figure 108a.276 Receptor 180 proved capable of binding zwitterionic β-alanine, 176, GABA, and 178 with the associations of (1.5 ± 0.1) × 104, (5.0 ± 0.4) × 105, (2.3 ± 0.1) × 105, and (1.1 ± 0.2) × 105 M−1, respectively, as determined via 1H NMR spectroscopic titrations carried out in CD3CN/D2O (80:20, v/v). In all cases, the cationic ammonium group is bound within the upper part of the cavity through multiple cation−π interactions involving the −NH3+ and three electron-rich aromatic rings of the CTV unit. Meanwhile, the anionic group is held within the lower portion of the cavity through a combination of presumed hydrogen binding interactions and anion−π interactions. Those inferences were consistent with the 1H NMR spectroscopic experiments and are supported by DFT calculations (Figure 109b). Recognizing that the CTV platform is inherently chiral, in 2013, Hutton and co-workers prepared a pair of diastereomeric hemicryptophane cages 181 that were obtained by attaching a CTV moiety to a functionalized chiral nonracemic cyclic peptide.277 The resulting receptors PL-181 and ML-181 (Figure 110) could be readily separated by column chromatography and their absolute configurations determined

Figure 107. Proposed interactions between receptor 12 and the zwitterionic substrates 176−179.

competitive solvent, e.g., acetonitrile/water, macrocycle 12 was no longer able to capture effectively ion pairs, such as NH4+, (Me)4N+, or (nBu)4N+ salts of CH3SO3−, CH3COO−, or H2PO4−. However, it remained effective as a receptor for zwitterionic guests,275 such as 176 (taurine, Figure 108), 177, 178 (homotaurine), 179, and glycine, as estimated by theoretical calculations for the [12·176] complex. In the case of the taurine guest, the association constant determined by DOSY NMR spectroscopy experiments in CD3CN/D2O (9:1, v/v) was estimated to be on the order of 14,000 M−1, whereas for 179 it was about 8500 M−1. The affinities displayed by 12 toward taurine (176) and 179 were attributed to the high AJ


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Figure 112. Molecular structures of 182−185. Figure 110. Molecular structures of hemicryptophanes PL-181 and ML-181.

bound through a combination of hydrogen-bonding, electrostatic, and possibly cation−π interactions with association constants in the range of 1.63−3.21 log units. The fully protonated receptor displays a preference for amino acids bearing a tetrahedral anionic group, such as 184, 185, and 176; presumably, this reflects complementarity between the tren subunit of the receptor 182 and the inherent 3-fold symmetry of these specific anionic guests.

by circular dichroism (CD) spectroscopy. They were then tested for their ability to recognize specific biological substrates, such as carnitine. While the unnatural antipode, D-carnitine, is devoid of a recognized biological role, the naturally occurring L-carnitine is involved in fatty acid transport through the formation of fatty acid-carnitine esters.278−281 PL-181 was found to bind L-carnitine with an association constant of (4.1 ± 0.3) × 103 M−1 and a 1:1 stoichiometry, as inferred from 1H NMR spectroscopic analyses carried out in CD3CN. Molecular modeling studies led to the suggestion that receptor PL-181 binds L-carnitine in a ditopic fashion with the carnitine carboxylate group stabilized by the cyclic peptide moiety via hydrogen-bonding interactions. In contrast, the carnitine quaternary ammonium group interacts with the CTV subunit through cation−π/CH−π interactions (Figure 111).

3. APPLICATIONS OF MACROCYCLIC ION PAIR RECEPTORS This section will focus on demonstrated and potential applications of ion pair receptors in a number of areas, including ion pair sensing, ion pair extraction and separation, cross-membrane transport, and logic gate construction. 3.1. Ion Pair Sensors

One important application of ion pair recognition has involved the creation of so-called ion pair sensors. Sensing of a particular pair of ions could have certain advantages over that associated with the detection of either the cationic or anionic constituents in that it could provide more accurate qualitative and quantitative data on the concentration of ions present in the analysis sample. For example, blood formally contains a number of ion pairs, including NaCl, KCl, NaHCO3, and KHCO3, to name a few. Among them, NaCl, but not KCl or NaHCO3, is known to elevate blood pressure and can lead to hypertension. Therefore, the measurement of the concentration of NaCl in blood could help in clinical diagnoses. In this case, the use of single ion selective sensors for either Na+ or Cl− would be unable to offer accurate quantitative data for NaCl because the counterions might not be fully determined; they could originate from salts other than NaCl. In contrast, ion pair sensors capable of detecting NaCl selectively should be free from this problem, permittng more accurate analyses of an ion pair of interest. In general, ion pair sensors contain a chromophore, a fluorophore, or an electroactive functional group as the signaling (or reporter) units linked ion pair receptor. Often the connection is at or near one of the ion recognition sites. Most ion pair sensors produce different readout signals depending on the specific ionic species being recognized. The associated information is in the form inter alia of a color change, difference in fluorescence intensity, or shifts in the redox potential. 3.1.1. Colorimetric Ion Pair Sensors. The earliest examples of colorimetric ion pair sensors were synthesized on the basis of chromogenic porphyrin−metal complexes linked to cation recognition sites, such as functionalized calix[4]arene and crown ethers. The Lewis acidic metal cores of the metal coordinated porphyrin moieties served as sites for

Figure 111. (a) Proposed binding mode and (b) energy-minimized structure of the [PL-181·L-carnitine] complex. Reprinted with permission from ref 277. Copyright 2013 Royal Society of Chemistry.

Delgado and co-workers prepared a polyoxapolyaza macrobicyclic receptor 182 for the recognition of zwitterions by coupling a tripodal tris(2-aminoethyl)amine (tren) with a tripodal trialdehyde intermediate derived from a 2,4,6triethylbenzene scaffold, Figure 111.282 Binding studies were carried out by means of potentiometry in a mixed H2O− MeOH (50:50, v/v) medium at 298.2 K containing 0.10 M NMe4TsO. At the resulting pH (≤6.2), it was expected that receptor 182 would mainly exist in its triprotonated form, while various targeted substrates, i.e., glycine, β-alanine, GABA, 184, 185, and 176, would all be present predominantly in their zwitterionic form (i.e., 185, Figure 112). These substrates were AK


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anion recognition. For example, in 1995, Shinkai and coworkers synthesized a porphyrinato zinc complex (56) connected to a calix[4]arene core via four bisamide linkers (Figure 113).102 Receptor 56 was found to bind the Li+ (log Ka

Figure 113. Ion pair sensor 56 based on tethered calix[4]arene and Zn-porphyrin subunits and its proposed binding mode with NaI and KI. Figure 114. Metalloporphyrin−crown ether constructs studied as ion pair receptors.

= 4.84) and Na+ (log Ka = 3.69) cations with high affinity in CHCl3/CH3CN (4/1, v/v) relative to K+ (log Ka < 2) when the noncoordinating ClO4− was used as a counteranion. By contrast, 56 showed significantly enhanced affinity for KI (log Ka = 5.23) over LiI (log Ka = n.d.) and NaI (log Ka = 3.91). 1H NMR and UV−vis spectroscopic analyses revealed that the cations were bound in a pocket created by the oxygen atoms of the calix[4]arene lower rim and the nearest amide groups. The iodide anion is also bound within the central cavity of 56; it was found to be both coordinated to the Zn center of the porphyrin and hydrogen-bonded to the amide NH protons closest to the porphyrin core. The direct interaction between the Zn center and the iodide anion was proposed to account for the bathochromic shift in the Soret-like absorption band of 56 and the accompanying color changes seen in solution upon exposure to these salts. For instance, upon exposure to KI, the absorption band of 56, originally appearing at 436 nm, was seen to shift to 446 nm with an isosbestic point at 440 nm. Crown ether metalloporphyrin constructs have also been studied as ion pair sensors (Figure 114). In these systems, the crown ether moieties serve the role as cation recognition sites, whereas the Lewis acidic porphyrin metal centers are expected to interact with basic anions, such as the cyanide anion and carboxylate anions. In 2002, the Hong group synthesized the ion pair receptors (186 and 187) comprised of a benzocrown5 subunit covalently linked to a zinc porphyrin and studied their ability to bind and detect various sodium salts.283 1H NMR and UV−vis spectroscopic analyses carried out in chloroform, dichloromethane, and DMSO provided support for the suggestion that both 186 and 187 would solubilize NaCN into organic solvents and do so with high selectively over other sodium salts. Exposure of 186 or 187 to NaCN in dichloromethane solution induced a bathochromic shift in the Soret-like absorption band of the zinc porphyrin centered at 420 nm and led to a color change from red to green. This color change was attributable to the coordination of the cyanide anion to the Zn center of the porphyrin subunit. In the presence of NaCN, upfield shifts in the proton signals corresponding to the crown ether subunit in 1H NMR spectra

were also observed. This was taken as evidence that the sodium cation is complexed within the crown ether moiety. It was thus concluded that receptors (186 and 187) bind NaCN in a heteroditopic fashion. Further evidence for the strong interaction between 186, 187, and NaCN came from two phase extraction experiments. In sharp contrast to what was seen from the porphyrin−Zn complex without a crown ether arm, receptors 186 and 187 proved capable of extracting NaCN from an aqueous phase into an organic phase, such as CH2Cl2, and of forming complexes that are kinetically stable on the NMR time scale. In 1999, Tsukube et al. reported the benzocrown-6 appending porphyrin−lanthanide acetylacetonate complexes (188−190, Figure 114) and examined their ability to extract and detect the chirality of amino acids using UV−vis and CD spectroscopy.284 The erbium porphyrin−crown ether conjugate 188 was found, for instance, to extract tryptophan (Trp) from an aqueous solution into CH2Cl2 solution with twice the efficiency (40%) compared to the corresponding crown etherfree erbium porphyrin (18%) or its equimolar mixture with the constituent crown ether (18%). The extraction ability of 188 proved highly dependent on the pH of the aqueous solution and was maximal at pH 5.7. This finding led to the suggestion that the Trp guest is extracted in its zwitterionic form. Receptors 188 and 189 containing gadolinium and ytterbium porphyrin complexes, respectively, were also found to act as extractants for Trp, albeit with slightly lower efficiency than 188. CD spectral measurements revealed that receptor 188 could be used to discriminate the chirality of various test amino acids. For example, the CH2Cl2 extracts obtained with LTrp, L-Phe, 3-(2-thienyl)-L-Ala, 3-(2-thienyl)-L-Gly, and L-Leu gave rise to reversed S-shaped CD bands near the porphyrin Soret maximum, whereas their D-isomers produced normal Sshaped CD bands. The bis-azacrown ether-strapped porphyrin−Zn complexes (191 and 192, Figure 114) were reported by Chen et al. in 2005.285 Their ability to recognize and detect various sodium AL


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the acetate and benzoate anions (as their TBA salts) in acetonitrile, a distinct red shift in the absorption band originally appearing at 344 nm was seen (i.e., to 377 nm). This was accompanied by a color change from colorless to yellow. These changes are ascribed to the formation of hydrogen bonds between the carboxylates and the thiourea NH protons that, in turn, modulate the electronics of the nitrophenyl group. The presence of Na+ and K+ exerts a significant influence on the binding affinity in the case of these two test anions. For example, in the presence of the K+ cation, the binding affinity of 194 is enhanced by 2.7-fold and 3.2-fold for the acetate and benzoate anions, respectively. As evidenced by 1H NMR spectral studies, the K+ cation is not only bound to the crown ether moiety but also coordinated to the sulfur atom of the thiourea moiety (Figure 115). The latter interaction is presumed to enhance the acidity of the thiourea NH protons, leading to the observed improvements in carboxylate anion affinities. In contrast, in the presence of the Na+ cation, the acetate anion affinity decreases. This is attributable to formation of an ion pair complex that is only weakly bound to the crown ether moiety outside the receptor (i.e., without participation of the thiourea protons). The fact that sensor 194 gives rise to different color changes depending on the cation in question allowed for the chromogenic detection of, and discrimination between, TBAOAc, NaOAc, and KOAc in acetonitrile. The calix[4]arene-based chromogenic heteroditopic sensor 195 was prepared by Chawla et al. in 2012 (Figure 116).288 In

and potassium salts was studied in methanol solution. UV−vis and 1H NMR spectroscopic analyses revealed that 191 and 192 are capable of binding NaCN and KCN in methanol with the specific selectivity depending on the size of the crown ether ring in question. Specifically, receptor 191, bearing the smaller crown ether ring, proved 56 times more selective for NaCN than KCN, whereas 192 was found to bind KCN 13 times more strongly than NaCN. It was suggested that these salts were bound in ditopic fashion as ion pairs with the Na+ or K+ cations bound to the crown ether moiety and the CN− ligated to the zinc porphyrin metal center. Again, this latter interaction was thought to be largely responsible for the color change observed in solution. A number of receptors containing crown ethers and thiourea groups linked to a chromophore have been developed for the purpose of ion pair recognition and sensing. For example, in 2008, Nam and co-workers synthesized the three-component system 193 (Figure 115) and studied its ability to bind various

Figure 115. Chromogenic ion pair sensors 193 and 194 and schematic representation of the proposed binding of KOAc by 194.

anions in the presence and absence of the Na+ cation.286 Sensor 193 is composed of a benzocrown-5 for cation recognition, a thiourea tether that was expected to serve as an anion binding domain, and a chromogenic nitrophenyl group. In fact, receptor 193 was found to undergo a change in color from colorless to yellow upon exposure to basic anions, such as the fluoride, acetate, benzoate, and dihydrogen phosphate, in acetonitrile (using the TBA salts). In the case of the fluoride anion, the yellow color produced upon initial exposure to the anion becomes colorless upon the addition of a sodium cation source. This finding is ascribed to the fluoride anion being bound preferentially in the form of a contact ion pair with the crown ether-bound sodium cation, rather than by the thiourea moiety. Thus, the sodium cation can be thought to be exerting a negative cooperative effect. In contrast, in the presence of a sodium cation source, the affinities of 193 for other anions (e.g., OAc−, Cl−, Br−, I−, and HSO4−) are improved in acetonitrile by 1.2−2.3-fold. In these instances, a combination of 1H NMR and UV−vis spectroscopic analyses led to the suggestion that the sodium cation is bound to the crown ether while the anions are hydrogen-bonded to the NH protons of the thiourea. In 2011, Piat̨ ek reported a heteroditopic chromogenic chemosensor (194) that also contains crown ether and thiourea subunits. The ability of this system to serve as a receptor for various anions was studied in the absence and presence of Na+ and K+.287 When receptor 194 was exposed to

Figure 116. A calix[4]arene-based chromogenic ion pair receptor (195) designed to effect the simultaneous binding of Co2+ and F−. Also shown is the proposed binding mode.

this system, two bipyridyl units designed to act as a cooperative cation binding site are connected to a calix[4]arene via two of the four phenolic oxygen atoms. Hydrazone units directly linked to 2,4-dinitrophenyl groups and tethered to the bipyridine units are further incorporated for anion recognition (Figure 116).288 The UV−vis spectrum of receptor 195 is characterized by the presence of two peaks at 287 and 388 nm that are attributable to the absorptions of the bipyridyl and hydrazone subunits, respectively. Upon treatment of receptor 195 with a F− source, the absorption peak centered at 388 nm undergoes a significant bathochromic shift to 483 nm. In DMSO/CH3CN (0.5/9.5, v/v), a color change from light yellow to dark purple is seen. Presumably, this reflects hydrogen-bonding interactions between the bound F− anion and the hydrazone NH protons. In contrast, the addition of Co2+ (as the perchlorate salt) to receptor 195 triggers a bathochromic shift in the absorption peak originally appearing AM


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Figure 117. Schematic representation of the formation of a CT complex between cyclo[6]aramide 196 and the Tr+ cation and its use for the colorimetric discrimination between tight ion pairs and loose ion pairs. Reproduced with permission from ref 289. Copyright 2015 American Chemical Society.

at 287 nm (to 308 nm; Δλ = 21 nm), while the peak at 388 nm remains effectively unchanged. This finding is interpreted in terms of the Co2+ cation being bound to the bipyridyl subunits of receptor 195. When receptor 195 is exposed to both Co2+ and F− in DMSO/CD3CN (1/9, v/v), the two absorption peaks experience bathochromic shifts and move to 308 and 483 nm, respectively. This change in the absorption spectra of 195 was taken as evidence that both Co2+ and F− are bound concurrently to receptor 195 (Figure 116). An approach to differentiating between loose and tightly bound dibutylammonium (DBuA+) ion pairs was reported by Yuan and co-workers in 2015.289 These researchers synthesized the shape-persistent iso-C16-cyclo[6]aramide 196 (Figure 117) and prepared its charge-transfer (CT) complex with the aromatic carbonium tropylium cation (Tr+). UV−vis and 1H NMR spectroscopic analyses carried out in CHCl3/CH3CN (1/1, v/v), supported by DFT (density functional theory) calculations, revealed that cyclo[6]aramide 196 forms a charge transfer complex with Tr+ as its BF4− salt. In this complex, the Tr+ cation is located above the shallow bowl-shaped cyclo[6]aramide lying parallel to the mean plane formed by the carbonyl oxygen atoms within the cavity of 196. The formation of this charge transfer complex is reflected in the appearance of a new CT band at longer wavelengths (i.e., ≥400 nm) and is accompanied by a color change. Upon exposure of this initial charge transfer complex [196⊃Tr+] to loose ion pairs of DBuA, such as its BF4− and PF6− salts, the CT band disappears and the color of the solution fades. This is consistent with the DBuA cation occupying the cavity of 196 and displacing the Tr+ cation to form a pseudorotaxane involving macrocycle 196. In contrast, when tight ion pairs of DBuA, such as DBuACl, DBuABr, and DBuAI, were added to the charge transfer complex [196⊃Tr+], little or no change in the UV−vis spectrum or color of the solution was observed. This lack of a discernible change is interpreted in terms of the DBuA cation in these salts being unable to expel and replace the Tr+ cation that makes up the CT complex. This inability, in turn, is attributed to tight ion pairing between the DBuA cation and these halide anions. Taken together, this CT system was proposed as being the first colorimetric sensor capable of discriminating between tight and loose ion pairs via a guestcompetitive complexation process (Figure 117). A selective colorimetric sensor (197) for specific ion pairs such as cesium salts (CsF, CsCl, and CsNO3) was reported r e c e n t l y b y S e s s l e r e t a l . 2 9 0 It con ta in s a 3(dicyanomethylidene)indan-1-one chromophore linked to one of the β-positions of a known calix[4]arene-calix[4]pyrrole

hybrid ion pair receptor (Figure 118). UV−vis and 1H NMR spectroscopic studies performed in 10% methanol in chloro-

Figure 118. Chemical structure of ion pair sensor 197 and its proposed ion binding behavior, which follows the rules of an AND logic gate.

form revealed that 197 proved, as expected, capable of binding only cesium ion pairs (e.g., CsF, CsCl, and CsNO3). It did not interact appreciably with the constituent ions, namely, the cesium cation (as its perchlorate salt) or the F−, Cl−, or NO3− anions (as their TBA salts). In the presence of CsF, CsCl, and CsNO3, the absorption peak of 197, originally appearing around 500 nm in the UV−vis absorption spectrum, is redshifted to 520 nm with a shoulder around 430 nm being seen in the case of CsCl and CsNO3 (Figure 119). A noticeable color change was also seen. These colorimetric differences, which mirror so-called AND logic behavior, were ascribed to the effect of anion binding to the calix[4]pyrrole moiety on the covalently linked chromophore (Figure 118). Receptor 197 was found to bind CsF with an association constant of 1.1 × 104 M−1, as determined by UV−vis spectral titrations carried out in 10% methanol−chloroform. Sensor 197 was also found to produce a selective colorimetric response to cesium ion pairs under the conditions of both solid−liquid extraction using nitrobenzene as the organic phase and liquid−liquid extraction using nitrobenzene-d5 and D2O. 3.1.2. Fluorometric Ion Pair Sensors. One of the earliest examples of a fluorescent ion pair receptor was synthesized by de Silva and co-workers on the basis of fluorescence on−off PET (photoinduced electron transfer) and CHEF (chelationenhanced fluorescence) effects.291 The system in question, fluorescent sensor 198, contains a monoaza-18-crown-6 ether for cation recognition connected to a guanidinium anion binding site via a fluorogenic anthracene subunit (Figure 120). The de Silva team used this system for sensing of γaminobutyric acid (GABA), a brain neurotransmitter, and AN


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Table 8. Parameters Derived from the Fluorescence Enhancement of 198 with Various Organic Guestsa 291 guest

binding constant (M−1)

fluorescence enhancement factor (FE)e

H3N+CH2CO2− H3N+(CH2)2CO2− H3N+(CH2)3CO2− H3N+(CH2)4CO2− H3N+(CH2)5CO2− H3N+(CH2)7CO2− H3N+CH(CO2−)(CH2)2CO2− Me(CH2)2NH3+ b MeCO2− c

d 17 36 84 54 44 d 79 d

1.2 1.9 2.2 3.5 3.1 3.1 1.1 2.3 1.1

10−5 M sensor 198 in MeOH/H2O (3/2, v/v) at pH 9.5 maintained with 10−3 M trimethylamine and adjusted with Me4NOH and HCl. 10−2 M Me4NCl was used to minimize ionic strength variations. b Counterion = Cl−. cCounterion = Me4N+. dThe fluorescence response proved too small to determine the binding constants. e [Guest] = 0.1 M. a

Figure 119. (a) UV−vis absorption spectra of receptor 197 in 10% methanol in chloroform recorded in the presence and absence of 5 equiv of various salts. (b) Colors of CHCl3/CH3OH (9/1, v/v) solutions of 197 seen in the presence of the indicated ion pairs (5 equiv). Reproduced with permission from ref 290. Copyright 2016 American Chemical Society.

cation binding site, a boronic acid group as an anion recognition site, and a pyrene as a fluorescent reporter (Figure 121). Addition of KF to receptors 200 and 201 in methanol

Figure 120. Chemical structures of fluorescent sensor 198 useful for the detection of zwitterionic amino acids. Also shown is the control compound 199.

related amino acids in their zwitterionic forms. Fluorescence spectra of 198 were measured at pH 9.5 in order to minimize interference from protons and maintain the test amino acids in their zwitterionic forms. Exposure of sensor 198 to amino acids including γ-aminobutyric acid in methanol/water (3/2, v/v) at pH 9.5 led to a 1.1−3.5-fold increase in its fluorescence intensity, allowing association constants (Ka) of 17−84 M−1 to be calculated (Table 8). This increase in the fluorescence intensity was ascribed to inhibition of PET resulting from the binding of amino acid ammonium moieties to the monoazacrown ether of 198. 1H NMR spectroscopic analyses led to the proposition that the ammonium groups of the amino acids are complexed to the crown ether of 198, while the carboxylate moieties are hydrogen-bonded to the guanidinium moiety. In contrast, the control compound 199, which lacks a guanidinium moiety, was not found to undergo a change in fluorescence when exposed to γ-aminobutyric acid. Such a finding is consistent with the guanidinium moiety playing a crucial role in sensing the amino acids, presumably via cooperative binding interactions involving the crown ether. An interesting approach to the construction of fluorescent ion pair sensors was reported by James et al. in 2005.292 Their approach involved the preparation of the multitopic receptors, 200 and 201, which contain benzocrown-5 or -6 ethers as a

Figure 121. KF-selective fluorescence ion pair sensors (200 and 201) and their proposed binding interactions with KF. Also shown are the chemical structures of control compounds 202, 203, and 204.

led to an enhancement in the fluorescence intensity, while no fluorescence change was seen in the case of KCl and KBr. This finding is consistent with the notion that both 200 and 201 are highly selective for KF over KCl or KBr. For KF (6 mM), the observed fluorescence enhancement factors were 1.77 for 200 and 1.60 for 201. In contrast, control compounds 202 (lacking a crown ether), 203, and 204 (without a boronic acid subunit) produced little fluorescence intensity change upon exposure to KF under otherwise analogous conditions. These findings led to the conclusion that both the crown ether and the boronic acid units of 200 and 201 are required for efficient KF recognition. A fluorogenic ion pair receptor 205 having an anion binding site closely linked to a cation binding site was reported by Frontera and co-workers in 2005.75 Receptor 205 consists of a squaramide moiety for anion binding connected to a 18-crown6 for cation recognition, as well as a fluorescent anthracene reporter group (Figure 122). On the basis of 1H NMR spectroscopic studies and DFT calculations, it was inferred that AO


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reflects binding of the F− anion to [206·Zn]2+ and [206·Pb]2+ to form ion pair complexes (Figures 123 and 124). The

Figure 122. Chemical structure of fluorogenic ion pair receptor 205 containing a squaramide and a [18]crown-6. Also shown is the predicted binding mode in the case of the corresponding NaOAc or KOAc ion pair complexes.

receptor 205 is able to complex concurrently either a K+ or Na+ cation and an OAc− anion. Chemical shift changes for the proton signals of 205 observed in the presence of KOAc and NaOAc led to the suggestion that the cations are bound to the crown ether and that the OAc− anion is hydrogen-bonded to the squaramide NH protons. Receptor 205 was also found to possess the ability to solubilize in chloroform otherwise insoluble carboxylate salts, such as sodium acetate and sodium benzoate. A different type of fluorogenic ion pair receptor (206) based on anion−π interactions was reported by Wang et al. in 2011 (Figure 123). The ability of this so-called oxacalix[2]arene[2]-

Figure 124. Left: Fluorescence titration of 206 (3.99 × 10−4 M in acetonitrile) with F− ((0−3.41) × 10−4 M) and Zn2+ ((0−9.65) × 10−4 M) (studied as their TBA+ and ClO4− salts, respectively). Right: Fluorescence titration of 206 (3.99 × 10−4 M in acetonitrile) with F− ((0−4.18) × 10−4 M as its TBA salt) in the presence of 1 equiv of Zn2+ added in the form of its ClO4− salt. Reproduced with permission from ref 146. Copyright 2011 The Royal Society of Chemistry.

association constants (Ka) for F− were determined to be 1.53 × 105 M−1 for [206·Zn]2+ and 3.71 × 103 M−1 for [206·Pb]2+ in acetonitrile. In particular, [206·Zn]2+ shows a 23× greater affinity for the fluoride anion than does the metal-free form 206. In sharp contrast to what was seen for the parent system 206, its Zn2+ complex, [206·Zn]2+, was found to interact with other anions, such as Cl−, Br−, and NO3−, with association constants of 7.39 × 103, 1.59 × 103, and 4.25 × 103 M−1, respectively. A ratiometric fluorescent ion pair receptor (207) for both Zn2+ and H2PO4− was reported by Yamato and co-workers in 2011.293 This system was synthesized on the basis of a homooxacalix[3]arene macrocyclic core functionalized with three ester groups linked to pyrene fluorophores via triazole units (Figure 125). When receptor 207 was titrated with Zn2+ in the

Figure 123. Chemical structure of the fluorogenic ion pair receptor 206 and its putative binding interactions with the Zn2+ cation and various anions (studied as their TBA salts).

triazine azacrown to recognize cations, anions, and ion pairs was examined using fluorescence and 1H NMR spectroscopies.146 It was found to bind selectively basic anions, such as F− (Ka = 6.59 × 103 M−1), CN− (Ka = 4.16 × 103 M−1), and OAc− (Ka = 4.52 × 103 M−1) in acetonitrile via anion−π interactions involving the anions and the two face-to-face electron deficient triazine subunits. This binding gives rise to an increase in the fluorescence emission band centered around 450 nm. It was also reported that receptor 206 is capable of recognizing transition metals. However, little evidence of alkali or alkaline earth metal cation complexation with the azacrown ether moiety was seen. This research team also investigated the ability of receptor 206 to bind ion pairs by means of 1H NMR and fluorescence spectroscopies. It was found that the addition of F− (as the TBA salt) to the complexes of 206 with Fe2+, Co2+, Cu2+, and Hg2+ led to a quenching of the fluorescence signal centered around 450 nm. This finding was ascribed to the decomplexation of the metal ions induced by the F− anion. In contrast, in the case of the Zn2+ and Pb2+ complexes ([206· Zn]2+ and [206·Pb]2+) prepared using the corresponding ClO4− salts, titration with F− led to an increase in the fluorescence feature appearing at 425 nm. Presumably this

Figure 125. Chemical structure of the homo-oxacalix[3]arene-based fluorescence ion pair sensor 207 and its presumed binding interactions with Zn2+ and H2PO4−.

form of its noncoordinating perchlorate salt in CH3CN/ CH2Cl2 (1000/1, v/v), the fluorescence intensity at 485 nm corresponding to the pyrene eximer emission gradually decreased with concomitant enhancement of the fluorescence emitted at 396 nm from the pyrene monomer (Figure 126). This finding was interpreted in terms of receptor 207 being AP


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Figure 126. Left: Fluorescent spectra of the ion pair sensor 207 (1.0 μM) recorded in the presence of increasing quantities of ZnClO4. Right: Fluorescent spectra of [207·Zn2+] in the presence of various anions as their tetrabutylammonium salts in CH3CN/CH2Cl2 (1000/ 1, v/v). Reproduced with permission from ref 293. Copyright 2011 American Chemical Society.

able to recognize Zn2+ and produce a ratiometric change in the fluorescent profile as a result. From the spectral changes, the binding constant for Zn2+ was calculated to be 9.51 × 104 M−1. On the basis of 1H NMR spectroscopic analyses, it was also suggested that the triazole nitrogen atoms and ester carbonyl groups of receptor 207 are coordinated to Zn2+ cation and that this precludes excimer formation (Figure 125). In contrast, little or no change in fluorescence intensity was seen when receptor 207 was treated with various test anions, including halides, NO3−, OAc−, and H2PO4− in the form of their TBA salts. This finding was interpreted in terms of there being no appreciable interaction between receptor 207 and these anions in the absence of Zn2+. In contrast, when the Zn2+ complex of 207 ([207·Zn]2+) was exposed to those anions, noticeable fluorescence changes were observed, in particular, for H2PO4−. In this latter case, the intensity of the pyrene monomer emission of [207·Zn]2+ was reduced, while its excimer emission was enhanced by 1.64-fold (Figure 126). On the basis of these fluorescence titration experiments, the binding constant of [207·Zn]2+ for H2PO4− was estimated to be 1.01 × 105 M−1 in CH3CN/CH2Cl2/H2O (1000/1/5, v/v). 1H NMR spectroscopic analyses led to the conclusion that in the ion pair complex ([207·Zn·H2PO4]+) only the triazole units are involved in Zn2+ cation coordination, whereas the carbonyl groups form hydrogen bonds with the H2PO4− (Figure 125). The H2PO4− anion was also proposed to be coordinated to the Zn2+ center. The authors thus concluded that receptor 207 could serve as a ratiometric fluorescence ion pair sensor for Zn2+ and H2PO4−. The limits of detection were given as 1.66 × 10−7 M for Zn2+ and 1.52 × 10−7 M for H2PO4−. The calix[6]arene-based fluorescent sensors (208 and 209) were developed for the recognition of organic contact ion pairs and reported by Jabin et al. in 2014.294 Ion pair sensors 208 and 209 were synthesized by functionalizing the ammoniumselective 1,3,5-trimethoxycalix[6]arene scaffold with fluorogenic pyrene groups via urea groups capable of acting as anion recognition sites (Figure 127). 1H NMR spectroscopic analyses carried out in DMSO-d6 served to confirm that 208 and 209 having a three-dimensional structure are able to bind alkylammonium salts of the SO42− dianion selectively relative to other test anions (i. e., Cl−, OAc−, and HSO4−). In the case of 208, binding constants of log Ka = 3.4 and >4 in DMSO and chloroform, respectively, were calculated for SO42− from 1H

Figure 127. Chemical structures of ion pair sensors 208 and 209 and proposed binding interactions between 208 and alkylammonium cation−sulfate dianion ion pairs.

NMR spectral titrations. The ability of receptors 208 and 209 to bind various alkylammonium sulfate ion pairs was also investigated in chloroform. Crucial support for a strong interaction between receptors 208 and 209 and alkylammonium sulfate ion pairs came from 1H NMR spectroscopic analyses. For example, in the presence of alkylammonium sulfates, both NH proton signals of the urea moieties undergo significant downfield shifts, presumably as a result of hydrogen bonds between the urea NH protons and the SO42− dianion. In contrast, the proton signals of alkylammonium cations were remarkedly upfield-shifted in these 1H NMR spectra. Specifically, for PrNH3+TBA+SO42−, the CH2 and CH3 proton signals of the propyl group were strongly upfield-shifted and found to resonate at δ = −1.90 and −1.23 ppm, respectively. These upfield shifts were ascribed to the inclusion of this alkylammonium cation within the calix[6]arene cavity of the receptors forming a contact ion pair with the co-bound SO42− (Figure 127). The complexation of alkylammonium sulfate ion pairs by receptors 208 and 209 also leads to discernible changes in their optical properties, including the UV−vis absorption and fluorescence spectra. For instance, when receptor 208 was exposed to PrNH3+TBA+SO42−, the fluorescence corresponding to the pyrene monomer emission significantly increased with a concomitant decrease of the pyrene excimer emission being observed (Figure 128). This finding was ascribed to the sulfate dianion binding to the urea group and thus inhibiting formation of a pyrene-based excimer. In the case of 208, the binding constant (log Ka) for the complexation PrNH3+TBA+SO42− was determined to be 4.8 on the basis of a fluorescence titration experiment carried out in chloroform. On the other hand, in a protic environment consisting of 1:11 CD3OD/CDCl3 (v/v), there was no evidence of an interaction between 208 and TBASO4 or PrNH3+ (as the picrate (Pic−) salt). However, in the presence AQ


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changes 210 were seen upon the addition of carboxylate anions. At pH 7.4 in methanol/water (1/1, v/v), these spectral titrations allowed binding constants (log Ka) of 3.95 for citrate, 2.33 for lactate, 2.71 for acetate, and 3.05 for bicarbonate to be derived, respectively. It was proposed that the Eu(III) complex 210 forms a 1:1 complex with Zn2+ via the iminodiacetate moiety that is coordinated with the Eu3+ center in the absence of Zn2+; this allows the added carboxylate anions to coordinate to the Eu3+ center. In 2015, Martinez et al. reported that the fluorescence sensor 211 could be used to achieve the selective detection of the biologically important zwitterion, choline phosphate (Figure 130).296 This fluorescent heteroditopic cage contains a

Figure 128. Fluorescence spectra recorded in chloroform for the titration of 208 (4.8 × 10−6 M) with increasing quantities of PrNH3+TBA+SO42− (0−19 equiv). Reproduced with permission from ref 294. Copyright 2014 American Chemical Society.

of both SO42− and PrNH3+, receptor 208 was converted quantitatively to the corresponding ion pair complex [208· PrNH3+·SO42−]. Differences between 208 and 209 were found. While 208, having six t-butyl groups on the calix[6]arene upper rim, displayed a strong affinity for small linear alkylammonium salts, 209 with three t-butyl groups was able to recognize effectively the sulfate salt of the 3,4-Odimethyldopammonium cation. These results highlight how subtle changes in the structure of ostensibly similar receptors can translate into readily discernible differences in binding selectivities. A different approach to the development of an ion pair sensor was reported by Parker and McMahon in 2014.295 Their system, complex 210, contains a 1,4,7-triazacyclononane-Eu(III) subunit that was expected to serve as both the anion binding motif and a luminescent signaling unit (Figure 129).295 The triazacyclononane ring was also functionalized

Figure 130. Chemical structure of the choline phosphate-selective ion pair sensor 211 and its predicted binding interactions with the choline phosphate.

cyclotriveratylene (CTV) unit for the recognition of the positively charged choline guest and a tren−Zn2+ complex for phosphate anion recognition, as well as three naphthalene units as fluorescent signaling subunits (Figure130). When receptor 211 was exposed to choline phosphate (212) in 2% water in DMSO, a drastic quenching of the fluorescence intensity was seen, presumably as a result of encapsulation of the zwitterion by receptor 211. 1H NMR spectroscopic studies carried out in DMSO-d6/D2O (4/1, v/v) and accompanying DFT calculations provided support for the conclusion that the ammonium portion of the guest is complexed within the electron-rich CTV, while the phosphate head is coordinated to the Zn2+ center. On the basis of a fluorescence spectral titration, the binding constant for choline phosphate was estimated to be 4.1 × 103 M−1. This value is 49.2 times larger than that for a choline derivative bearing a hydroxyl substituent instead of the normal phosphate group. This disparity was taken as evidence for the proposed synergistic anion and cation recognition achieved by 211 in the case of choline phosphate. In 2015, the Wang group designed and synthesized the trisubstituted benzene-based tripodal fluorescence ion pair sensor 213 and reported that it could be used to achieve the selective detection of Cu(ClO4)2 and Cu(NO3)2.297 This system was synthesized by incorporating three fluorogenic naphthalimide groups bearing piperazine units to a podandshaped core via imidazolium linkages (Figure 131).297 The Nalkylated piperazine units were designed to function as cation recognition sites, whereas the three imidazolium groups were

Figure 129. Chemical structure of the luminescent ion pair sensor 210, which allows for the concurrent binding of Zn2+ cations and carboxylate anions.

with the alkyliminodiacetate group which acts as a cation binding site at pH 7.4. No emission spectral changes were observed when either Zn2+ or carboxylate anions (as the corresponding chloride and sodium salts) were added separately to methanol/water (1/1, v/v) solutions of 210. This finding led to the suggestion that there is no interaction between the receptor and either the Zn2+ cation or the carboxylate anions. However, in the presence of ZnCl (10 mM), significant and ratiometric luminescence spectral AR


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recognition, the fluorescence spectra of 213 were measured in acetonitrile in the presence of various Cu(II) salts. Fluorescent changes similar to those produced by Cu(ClO4)2 were observed for Cu(NO3)2. This led to the conclusion that receptor 213 can be used to achieve the selective recognition of Cu(NO3)2 and Cu(ClO4)2 salts by means of fluorescence spectral changes. 3.1.3. Electrochemical Ion Pair Sensors. One of the earliest electrochemical ion pair sensors was reported by Tuntulani et al. in 2005. The system in question, receptor 214, was prepared by strapping a bisazacrown-6 with an electrochemically acitve amidoferrocene (Figure 132).298 On the

Figure 132. Electrochemical ion pair sensor 214.

basis of 1H NMR spectroscopic studies and cyclic voltammetric analyses, it was concluded that receptor 214 is unable to recognize the Br− anion (as its TBA salt) in 5% acetonitrile in chloroform. By contrast, the same analyses performed in the presence of Na+ revealed that receptor 214 is capable of interacting with the Br− anion with a reported binding constant (Ka) of 16,096 M−1. This finding was interpreted in terms of the Na+ cation bound to the crown ether playing a critical role in recognizing the Br− anion. Cyclic volatammetric analyses of receptor 214 revealed reversible redox behavior and E1/2 = 0.473 mV for the ferrocene/ferrocenium (Fe/Fe+) couple. Upon addition of Na+ or K+, the CV wave of receptor 214 undergoes a slight anodic shift. Conversely, the addition of Cl− results in a new oxidation wave appearing at a less positive potential and loss of the original Fc/Fc+ redox wave. In the presence of Na+ and K+, the addition of Cl− gives rise to a cathodic shift in the redox potential of 214. Also in 2005, Molina et al. synthesized the electrochemical ion pair sensor 215, which possesses similar cation and anion binding domains as present in receptor 214.299 Receptor 215 consists of two crown-6 ether units and two urea groups directly linked to an electroactive ferrocene (Figure 133).299 1 H NMR spectroscopic analyses revealed that receptor 215 is able to bind F− (Ka = 1.4 × 103 M−1) and H2PO4− (Ka = 1.5 × 104 M−1) selectively with 1:1 stoichiometries among a test panel of various anions (studied as their ClO4− salts) in chloroform. Receptor 215 was also found to bind K+ but with 1:2 (host:guest) stoichiometry. By contrast, in the presence of H2PO4−, presumably prebound to the urea groups, K+ is recognized well (Ka = 7.3 × 103 M−1) in the form of a 1:1 sandwich-like complex involving the crown ether moieties (Figure 133). Cyclic voltammetric studies of 215 in CH2Cl2 containing 0.1 M TBAClO4 as the supporting electrolyte revealed a reversible one-electron oxidation process at E1/2 = −0.31 V vs the Fe+/Fe couple. Electrochemical anion and cation sensing experiments were carried out using differential pulse voltammetry (DPV). Upon the addition of H2PO4− (2

Figure 131. Top: Chemical structure of the fluorescent ion pair sensor 213 and the binding modes proposed for its Cu(ClO4)2 and Cu(NO3)2 complexes. Bottom: Fluorescence spectral titration of 213 with Cu(ClO4)2 in acetonitrile. Inset: Plot of If vs [Cu(ClO4)2]. Reproduced with permission from ref 297. Copyright 2015 The Royal Society of Chemistry.

expected to bind anions in a cooperative manner. When receptor 213 was treated with various ClO4− salts of alkali, alkaline earth, and transition metals in acetonitrile, a change in fluorescence intensity with a concomitant small blue shift was seen only for Cu(ClO4)2. This finding led to the suggestion that receptor 213 is able to recognize Cu(ClO4)2 with high selectivity. Upon subjecting receptor 213 to a fluorescence spectroscopic titration using Cu(ClO4)2 as the guest, an increase in fluorescence intensity was seen through the addition of up to 10 equiv of Cu(ClO4)2. After that, the fluorescence intensity increased drastically with a commensurate color change from yellow green to light blue being seen. A plateau was reached up to the addition of ≥15 equiv of Cu(ClO4)2. This stepwise fluorescence change was interpreted in terms of a two-step binding event. Specifically, it was proposed that the slight enhancement in the fluorescence intensity seen in the presence of up to 10 equiv of Cu(ClO4)2 reflects an anion-induced conformational change that allows the imidazolium units to bind the perchlorate anion readily. The dramatic enhancement in fluorescence intensity, with a corresponding slight blue shift, seen upon adding more Cu(ClO4)2 was ascribed to complexation of Cu2+ by the piperazine group of 213, which inhibits PET and facilitates ICT (internal charge transfer) (Figure 131). In order to evaluate the anion selectivity within the context of copper(II) AS


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Figure 133. Electrochemical ion pair sensor 215 and its proposed binding interactions with K+ and H2PO4−.

equiv), the oxidation peak of receptor 215 experiences a marked cathodic shift from E1/2 = −0.31 V vs Fe+/Fe to E1/2 = −0.50 V vs Fe+/Fe, presumably reflecting the strong binding of H2PO4−. In contrast, treatment of receptor 215 with K+ causes no redox potential change, presumably because the crown ether subunits are located too far from the ferrocene redox active center to elicit a discernible change. However, addition of K+ (2 equiv) to test solutions of [215·H2PO4−] was found to elicit a slight anodic shift (+50 mV). This finding was interpreted in terms of receptor 215 being able to complex both K+ and H2PO4− concurrently (Figure 133). An ion pair receptor (216) based on the use of an otrifluoroacetylcarboxyanilide (TFACA) subunit as the anion binding motif was reported by Ahn and co-workers in 2008.112 TFACA is known to recognize the CN− anion with high selectivity by forming a dynamic covalent bond with the carbonyl carbon atom. Receptor 216 also includes an 18crown-6 ether for K+ cation recognition and an electroactive amidoferrocene to allow for electrochemical sensing. Evidence that receptor 216 is able to bind K+ and CN− separately and concurrently came from 1H and 19F NMR spectroscopic analyses as well as ITC (isothermal titration calorimetry) experiments. On this basis, it was concluded that the K+ cation is complexed by the crown-6 ether subunit present in receptor 216 while the CN− anion forms a reversible covalent bond with the electron-deficient carbonyl carbon atom by means of a nucleophilic addition process (Figure 134). The resulting alkoxide anion is stabilized by forming hydrogen bonds with the amide groups in the absence of K+ or by being coordinated to the complexed K+ in the presence of K+. The binding of KCN was thus found to be highly cooperative. The binding constants (Ka) for 216 as inferred from ITC studies were reported to be 4.2 × 103 M−1 for K+ (studied as the PF6− salt) and 1.9 × 105 M−1 for CN− (in the form of its TBA salt). However, the Ka values for K+ and CN− were improved by 2 orders of magnitude when studied in the form of the ion pair. The interactions between KCN and receptor 216 were also probed using electrochemical methods. For instance, when the cyclic voltammograms were recorded upon the sequential addition of K+ and CN− to receptor 216 (1.0 mM) in acetonitrile, the formal oxidation potential of receptor 216 [E° = +0.95 V (vs Ag/AgCl)] was found to undergo a positive shift (+14 mV) upon addition of K+ (1 equiv as its PF6− salt). The subsequent addition of CN− (1 equiv as the TBA salt) induced a negative shift in the oxidation potential from +14 to +3 mV.

Figure 134. Electrochemical ion pair receptor 216 and its putative binding interactions with K+ and CN−.

These findings were taken as evidence that KCN binds well to receptor 216. The calix[4]arene-based electroactive ion pair receptors (217 and 218) were reported by Tuntulani et al. in 2011.300 Receptors 217 and 218 are composed of a cone-calix[4]arene diametrically functionalized with ethyl esters designed to act as a cation recognition site and an amidoferrocene group as an anion binding motif and electrochemical reporter group (Figure 135).300 On the basis of 1H NMR spectroscopic

Figure 135. Electrochemical ion pair sensors 217 and 218.

analyses, it was concluded that receptors 217 and 218 are both selective for Na+ over other alkali metal cations in the absence of coordinating anions. The relevant binding constants for 217 and 218 were estimated to be 760 and 505 M−1, respectively, for the complexation of Na+ (studied as its ClO4− salt) in 5% CD3CN in CDCl3. In contrast, only weak interactions between receptors 217 and 218 and various test anions were found (Table 9). However, in the presence of Na+, the anion affinities were increased, presumably as the result of stabilizing interactions between the prebound Na+ and the added anions (Table 9). Complexation-induced changes in the redox potentials of receptors 217 and 218 in the presence of Na+ and various anions were studied using cyclic and square-wave voltammetries. The cyclic voltammograms revealed redox potentials of Epa = 0.493 V and Epc = 0.386 V for receptor 217 and Epa = 0.428 V and Epc = 0.321 V for receptor 218, AT


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Table 9. Binding Constants (Ka) for Receptors 217 and 218 Recorded for Various Anionic Guests in the Presence and Absence of Na+ in 5% CD3CN/CDCl3300 Ka (M−1) −

receptor

Cl

217 [217·Na+] 217 [218·Na+]

a b a b

Br

−

a 2096 a 1119

−

I

a 1187 25 b

BzO−

AcO−

H2PO4−

25 b 66 b

a b 64 b

a b 32 b

a

Values are very small; errors >10%. bValues could not be calculated due to ion pair formation.

respectively, in 40% acetonitrile−chloroform, where Epa and Epc indicate the anodic and cathodic potentials, respectively. When receptor 217 was exposed to a cation source Na+, a relatively large anodic shift (ΔE = +42 mV; ΔE = Epa(complex) − Epa(receptor)) in the Fc/Fc+ redox couple was observed for receptor 217 relative to what was seen for receptor 218 (ΔE = +7 mV). This finding was attributed to the larger distance between the cation binding site and the electroactive ferrocene group in the case of receptor 218. In the presence of anions, such as Cl− and OAc− (studied as the TBA salts), the Fc/Fc+ redox couples of 217 and 218 were seen to undergo relatively large cathodic shifts; presumably, this reflects hydrogen-bonding interactions between the anions and the amide NH protons which facilitate oxidation of the ferrocene subunit (Table 10). In the case of the Na+ complex

Figure 136. Top: LiCl-selective electrochemical ion pair sensor 219 and its binding interactions with LiCl as inferred from solid state structural analyses. Bottom: Single crystal X-ray diffraction structure of the LiCl complex of 219. The figure of the crystal structure was reproduced with permission from ref 94. Copyright 2013 American Chemical Society.

the changes seen in the 119Sn, 7Li, 1H, and 13C NMR spectra upon the addition of LiCl in CD3CN. For example, in the presence of LiCl, the 119Sn resonance signal, originally appearing at δ = 67 ppm, experiences an upfield shift to δ = −28 ppm. This finding was taken as evidence for Cl− binding to the Sn atom. In contrast, the chemical shift changes seen for the proton and carbon resonances of the crown ether and the lithium resonances seen in the 1H, 13C, and 7Li NMR spectra were taken as evidence that the Li+ is bound to the crown ether ring. The ability of receptor 219 to form a complex with LiCl as an ion pair was confirmed in the solid state by means of a single crystal X-ray diffraction analysis (Figure 136). The resulting structure (of [219·LiCl]) revealed that the LiCl guest is complexed as a host-separated ion pair with the Cl− anion being covalently bound to the Sn atom and the Li+ cation being complexed within the crown ether cavity (Figure 136). There are intermolecular interactions between the bound Li+ and Cl− ions (separation distance = 2.329 Å), which give rise to the formation of a one-dimensional polymeric chain structure. Receptor 219 in its ion-free form was found to have a standard oxidation potential E° (V vs a polypyrrole reference electrode) of 0.221 V. However, in the presence of LiCl (2 equiv), a cathodic shift to 0.154 V (ΔE° = −66 mV) was seen. A similar effect was noted upon the sequential addition of Li+ (as the ClO4− salt), followed by Cl− as its HexMe2(C16H33)N+ salt, where Hex and Me refer to n-hexyl and methyl, respectively. 3.1.4. Multisignaling Ion Pair Sensors. So-called dual ion pair sensors that rely on two distinct optical responses have been developed. For example, in 2010, Tuntulani et al. synthesized ion pair receptor 220 having two different chromoand fluorophores by connecting a rhodamine with naphthalene groups via an anion binding thiourea linkage.301 The rhodamine group is known to bind specific cations through ring opening of its spirolactam moiety, a transformation that gives rise to a significant color change and leads to an enhancement in the fluorescence intensity. When receptor 220 was exposed to various anions (F−, Cl−, Br−, I−, NO3−, ClO4−,

Table 10. Cathodic Shifts (ΔE) in the Ferrocene Redox Couples of Receptors 217 and 218 Seen upon the Addition of 4 equiv of Cl− and AcO− a (Studied as Their TBA Salts)300 ΔEb (mV) receptor

Cl−

AcO−

217 [217·Na+] 218 [218·Na+]

−70 −100 −80 −90

−80 −106 −180 −120

a

Experiments were carried out in 40% CH3CN/CH2Cl2 using at Pt working electrode, Ag/AgNO3 as the reference electrode, and TBAPF6 as the supporting electrolyte at a scan rate of 100 mV/s. b ΔE is defined as Epa(complex) − Epa(receptor), where Epa refers to the anodic potentials.

of receptor 217 ([217·Na+]), amplified electrochemical signals, including larger cathodic shifts, were seen when the preformed complex [217·Na+] was exposed to either the Cl− or OAc− anions (Table 10). In the case of the Na+ complex, [218·Na+], a smaller cathodic shift was seen upon exposure to OAc− than was seen for the cation-free form of the receptor (i.e., 218). In 2013, a different approach to the construction of an electrochemically active ion pair receptor was introduced by Jurkschat et al.94 These researchers synthesized the organotincontaining 13-crown-4 ether functionalized ferrocenophane 219 as a redox-active ion pair receptor for LiCl (Figure 136).94 This relatively small crown ether subunit was selected to favor Li+ complexation, while the Sn atom was incorporated into the design to serve as a recognition site for the Cl− as well as to provide an electrochemical signaling unit. Initial evidence that receptor 219 forms an ion pair complex with LiCl came from AU


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H2PO4−, OAc−, and BzO− as their TBA salts) in CD3CN, the thiourea NH proton resonances in the corresponding 1H NMR spectra were seen to undergo downfield shifts in the case of most of the test anions. These changes were ascribed to the presence of hydrogen-bonding interactions between the NH protons and the anions in question. The corresponding binding constants (log Ka) were found to range from 2.12 to 4.44. Receptor 220 was also found to produce a selective colorimetric and fluorometric response to Cu2+. Specifically, treatment of receptor 220 in acetonitrile with Cu2+ led to the appearance of a new band at 558 nm in the UV−vis absorption spectrum as well as a color change from colorless to pink. The fluorescence emission band at 490 nm was found to shift to 584 nm upon exposure to Cu2+ when irradiated at 300 nm; presumably, these changes reflect FRET (fluorescence resonance energy transfer) from the naphthalene-derived excimer to the ring-opened rhodamine moiety. The color change is attributed to the ring opening of the rhodamine spirolactam induced by Cu2+ complexation. When the acetate anion is added to this ring-opened complex, an immediate change in color from pink to colorless is seen. The fluorescence is also turned off, presumably because the ring recloses to regenerate the original spirolactam form of receptor 220 (Figure 137). Binding of Cu2+ to receptor 220 ([220·Cu2+])

Figure 138. Ion pair sensor 221 and its proposed binding interactions with K+ and HSO4−.

221 led to a color change from yellow to orange with associated UV−vis and fluorescence spectral changes (Figure 139). Likewise, addition of K+ to a solution of receptor 221

Figure 137. Dual colorimetric and fluorometric ion pair sensor 220. Also shown is the ring opening induced by Cu2+, the ring closure promoted by OAc−, and the base-induced removal of the bound ion pair.

Figure 139. UV−vis spectra for titration of [221·K+] with HSO4− in DMSO. Inset: Colors corresponding to the indicated species. Reproduced with permission from ref 302. Copyright 2012 Elsevier.

was also found to facilitate anion binding by 1.68-fold for F−, 1.91-fold for H2PO4−, and 1.65-fold for OAc− as compared with the ion free form. On this basis, it was concluded that receptor 220 acts as a colorimetric and fluorometric sensor for the Cu2+ cation and various test anions. Of note is that treatment of the resulting complex ([220·Cu2+·OAc−]) with NaOH, followed by silica gel column chromatography, affords ion-free 220, leading to the suggestion that ion binding to, and release from, receptor 220 can be reversed (Figure 137). In 2012, Bu and co-workers synthesized the dibenzo-18crown-6 ether fused to two diindolylquinoxaline moieties (221) and studied it as a colorimetric and fluorometric ion pair sensor (Figure 138).302 UV−vis and fluorescence spectral analyses revealed that receptor 221 is able to bind K+ (as its ClO4− salt) with a binding constant (Ka) of 776 M−1 in DMSO. No spectral changes in either the absorption or fluorescence bands were seen when receptor 221 was exposed to HSO4− (as its TBA salt). However, in the presence of K+ (presumably bound to the dibenzo crown ether moiety of receptor 221), the addition of HSO4− to a solution of receptor

containing HSO4− induced discernible spectral changes. The binding constant for HSO4− in the presence of K+ was calculated by fluorescence titration experiments to be Ka = 1.2 × 103 M−1 for receptor 221. During the course of the titration of complex [221·K+] with HSO4− (or of complex [221· HSO4−] with K+), the fluorescence intensity at λ = 490 nm gradually decreases with a concomitant increase in the fluorescence signal at λ = 565 nm. The ratiometric response obtained by comparing the emission intensity (I565/I490) at these two wavelengths led to the suggestion that receptor 221 could serve as a ratiometric fluorescent sensor for HSO4− and K+. A Hill coefficient value close to 2 was found, which was interpreted in terms of a 1:2 (host:guest) stoichiometry for the formation of [221·K+·(HSO4−)2] (Figure 138). Receptors 222 and 223, put forward for the purpose of multichannel ion pair sensing, were reported by Chailap and Tuntulani in 2012.303 Receptors 222 and 223 were synthesized on the basis of the cone- and 1,3-alternate-calix[4]arene crown-5 diametrically connected to anthraquinone units via AV


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amide linkages, respectively (Figure 140).304 The binding constants (Ka) of receptors 222 and 223 for K+ (as its PF6−

Figure 140. Ion pair sensors 222 and 223 and proposed binding of K+ and F− by receptor 222.

salt) in 5% CD3CN in CDCl3 were estimated by 1H NMR spectral titration experiments to be Ka = 2700 M−1 and 2650 M−1, respectively. UV−vis and fluorescence spectroscopic analyses revealed that receptor 222 is also able to bind F− (studied as its TBA+ salt) with 1:2 (host:guest) stoichiometry. A 1:1 stoichiometry for F− was seen in the case of receptor 223. The two sequential binding constants (log Ka) for receptor 222 interacting with F− were determined to be log Ka1 = 2.94 and log Ka2 = 4.50 and that of receptor 223 to be log Ka = 3.77. In the presence of K+, the F− affinity of receptor 222 was notably enhanced (log Ka1 = 3.39 and log Ka2 = 6.25), which led to the suggestion that the K+ and F− ions are cooperatively bound to the receptor via a positive allosteric effect presumably driven by an electrostatic interaction between the two ions. In contrast, the addition of F− to the preformed complex [223·K+] caused dissociation of K+ from the receptor 223. In the case of receptor 222, evidence of ion pair binding came from UV−vis and fluorescence spectral analyses as well as from cyclic voltammetry. For instance, in the presence of both K+ and F−, the fluorescence intensity of receptor 222 was enhanced by inhibition of ESPIT (excitedstate intramolecular proton transfer) as compared to what was seen in the presence of either K+ or F− (Figure 141). Electrochemical analyses carried out in CH3CN/CH2Cl2 (2/3, v/v) revealed two consecutive one-electron reversible waves for receptor 222 corresponding to two single-electron reduction processes that produce mono- and dianionic species, respectively. The half-wave potentials were observed at E1/2I = −1.21 V and E1/2II = −1.66 V (vs Ag/AgNO3). When receptor 222 was exposed to K+ (10 equiv), the redox waves were shifted by 60 and 95 mV for ΔE1/2I and ΔE1/2II, respectively. On the other hand, the addition of F− (10 equiv) to the preformed complex [222·K+] induced a further shift in the second wave (E1/2II) toward less negative potentials, presumably due to ion pair binding within receptor 222 (Figure 141). The BODIPY-based fluorometric and colorimetric ion pair receptor 224 was reported in 2014 by Rurack et al. Receptor

Figure 141. Fluorescence spectra (a) and cyclic voltammograms (b) of 222 recorded in CH3CN and CH3CN/CH2Cl2 (2/3, v/v), respectively, in the presence and absence of K+ and F−. Reproduced with permission from ref 303. Copyright 2012 The Royal Society of Chemistry.

224 contains a boron-dipyrromethane (BODIPY) conjugated via ethylene groups to both an 18-azacrown-6 for cation complexation and a calix[4]pyrrole for anion recognition (Figure 142).304 In acetonitrile solution, the UV−vis and

Figure 142. Ion pair sensor 224 and its proposed binding interactions with GABA (γ-aminobutyric acid).

fluorescence spectral features were found to depend on the presence or absence of both cations and anions. It was thus concluded that receptor 224 has the ability to bind a number of discrete anions, including F−, OAc−, Cl−, and Br− (studied as their TBA salts) and cations such as NH4+, Li+, Na+, and K+ (studied as their ClO4− salts). The hypsochromic shifts observed upon the addition of the cations were attributed to complexation within the azacrown moiety present in 224, while the bathochromic shifts induced by anions were proposed to originate from hydrogen-bonding interactions between the anions and the calix[4]pyrrole moiety. The ion pair binding ability of receptor 224 was tested using two-phase solid−liquid extraction experiments with various alkali metal halide salts that are largely insoluble in acetonitrile. In this case, AW


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the 1H NMR spectra recorded after subjecting mixtures of receptor 224 with the alkali metal halide salts to mechanical stirring for 24 h were consistent with the formation of ion pair complexes. This led to the suggestion that receptor 224 is able to bind and extract ion pairs into acetonitrile. Upon treatment of receptor 224 with sodium halide salts, the absorption peak originally appearing at λ = 685 nm undergoes an hypsochromic shift to λ = 618−632 nm. The extent of the shift was smaller than that seen upon treating with the Na+ cation in the absence of a halide anion. In addition, the intensity of the fluorescence signal for receptor 224 at λ = 743 nm was reduced and the band slightly shifted upon treatment with potassium halide ion pairs. The authors also evaluated the ability of receptor 224 to recognize zwitterionic amino acids, such as glycine, tyrosine, arginine, cysteine, aspartic acid, glutamic acid, and γ-aminobutyric acid (GABA), in acetonitrile. In analogy to what was seen for receptor 224 and alkali metal halide ion pairs, treatment with these guests led to a modest hypsochromic shift in the absorption band (from λ = 685 nm to λ = 677 nm). A drastic quenching of the fluorescence intensity was also seen (Figure 143). These findings were ascribed to interactions

Figure 144. Chemical structures of the dual ion pair sensors 225 and 226 and the control system 227 that lacks an azacrown ether cation binding subunit. Also shown is the proposed binding mode for the NaCl complex of receptor 225.

such as Cl−, Br−, NO2−, and NO3− as their noncoordinating TBA salts via hydrogen-bond interactions involving the thiourea NH protons and the anions. Basic anions, specifically OAc− and OBz−, were found to induce deprotonation of the thiourea NH protons. In the presence of Na+, the binding affinity of receptors 225 and 226 for anions was enhanced, while that of receptor 227 decreased. For example, the association constants (Ka) of receptors 225 (Ka = 10,000 M−1) and 226 (Ka = 11,500 M−1) for Cl− were enhanced in the presence of Na+, namely, to Ka = 30,900 M−1 (3.09-fold increase) in the case of receptor 225 and to Ka = 25,700 M−1 (2.23-fold increase) in the case of receptor 226. This increase in the binding affinities was rationalized in terms of the assumption that the Na+ cation bound to the azacrown ether of receptors 225 and 226 diminishes the electron density of the phenyl ring directly linked to the thiourea unit, resulting in an increase in acidity of the thiourea NH protons. The concurrent binding of both Na+ and Cl− to receptors 225 and 226 causes slight bathochromic shifts in the UV−vis spectral features, which, in turn, allows for the visual detection of NaCl. Electrochemical studies were also carried out using cyclic voltammetry (CV) to investigate ion pair binding features of receptors 225 and 226. Receptor 225 exhibits two consecutive one-electron reversible waves at E1/2I = −1.166 V and E1/2II = −1.473 V (vs Ag/AgCl) corresponding to two single-electron reductions of the anthraquinone to the corresponding monoand dianionic species. When titrated with the TBA+ salts of anions, such as Cl−, Br−, NO2−, and NO3−, receptor 225 gradual shifts in the reduction potential peaks toward more negative potentials were seen with the effect being more noticeable in the case of the first peak (Figure 145). In contrast, treatment with Na+ leads to an anodic shift in the first redox wave, a finding that is attributed to a decrease in the receptor as the result of Na+ complexation within the azacrown units. The addition of anions to complex [225·Na+] was found to produce greater cathodic shifts in the reduction potentials than those induced by the same anions in the absence of Na+. For example, the addition of 5 equiv of NO2− to the ion-free receptor 225 led to a cathodic shift of ΔE1/2 = 34 mV. A similar addition in the case of the Na+ complex [225·Na+] gave rise to ΔE1/2 = 56 mV (Figure 145). Similar reduction potential changes were observed for receptor 226. In contrast, with the control system 227, relatively small changes in the reduction potentials were observed upon the addition of anions in the presence of Na+. On this basis, it was concluded that receptors 225 and 226 are able to act as optical and electrochemical sensors for various sodium anion salts.

Figure 143. UV−vis (top) and fluorescence spectra (bottom) of 224 recorded in the absence and presence of Gly and GABA. Reproduced with permission from ref 304. Copyright 2014 Wiley-VCH Verlag GmbH & Co. KGaA.

between the azacrown and the ammonium groups of the amino acids. In particular, GABA induced similar changes in the absorption and fluorescence features of receptor 224, as caused by the ion pair complexation of the various sodium halide salts (Figure 143). This led to the suggestion that the carboxylate group of GABA is bound to the calix[4]pyrrole moiety while the ammonium group is complexed by the azacrown ether (Figure 142). In 2016, Romański and Karbarz reported the dual ion pair sensors 225 and 226, as well as the control compound 227 (Figure 144).305 Regioisomers 225 and 226 both contain an azacrown-6 designed to serve as a cation binding domain, along with a thiourea unit for anion recognition that is covalently linked to an electroactive anthraquinone. The control system 227 lacks a cation binding site (Figure 144).305 UV−vis spectroscopic analyses performed in acetonitrile revealed that receptors 225−227 are able to bind anions AX


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organic or inorganic ion pairs, as well as zwitterions, assisted by macrocyclic ion pair extractants. One of the very early examples involving the use of an ion pair receptor as an extractant in SLE came from the Reinhoudt group.309 They explored a series of bifunctional receptors 228−230 (cf. Figure 146) bearing four ester groups at the

Figure 145. Cyclic voltammograms of receptor 225 (0.5 mM in acetonitrile) recorded upon the addition of 0, 1, 3, and 5 equiv of TBANO2 as determined in the absence (a) and presence (b) of Na+. The concentration of the supporting electrolyte (TBAPF6) was 0.1 M, and the scan rate was 100 mV/s. The potentials are referenced relative to the Ag/AgCl couple. Reproduced with permission from ref 305. Copyright 2016 American Chemical Society.


lower rim of a calix[4]arene core and two or four urea groups at the upper rim. Appreciating the fact that calix[4]arenes tetrasubstituted with four ethyl ester groups at the lower rim display high selectivity for Na+ cations158 and that proper positioning of the urea moieties on the calix[n]arene (n = 4, 6) framework should provide for hydrogen-bonding-mediated halide anion recognition310,311 led to the consideration that 228−230 could function as NaX (X = halide) extractants. These ditopic receptors were found capable of binding “hard” ion pairs such as NaCl and NaBr, as inferred from 1H NMR spectroscopic studies carried out in CDCl3. Moreover, they proved capable of extracting alkali metal halide salts such as NaCl, NaBr, NaI, KCl, KBr, and KI (but not CsX (X = halide); Table 11) from their solid state forms into a chloroform phase,

3.2. Ion Pair Extraction and Separation

Extractions represent some of the most venerable and widely used separation processes. Their importance runs the gamut from the chemical laboratory to mining operations and largescale waste remediation and includes the limits of liquid−liquid and solid phase extractions. Typically, an initial feed solution or a solid mixture containing the desired solute is brought into contact with a solvent that is selected to have a greater affinity for the solute. Often the partition of the solute can be enhanced by adding a so-called extractant into the receiving phase. Not surprisingly, therefore, this puts a premium on new potential extractants that can be used to control the selectivity and efficiency of an extraction process. The state of the art with respect to liquid−liquid extraction (LLE) and solid−liquid extraction (SLE) has been summarized in a number of reviews and books from different perspectives.69,306,307 This review focuses on solid−liquid extraction and liquid−liquid extraction of ion pairs and zwitterions using macrocyclic receptors as the extractants. 3.2.1. Solid−Liquid Extraction of Ion Pairs. Solid− liquid extraction, sometimes referred to as leaching, involves the transfer of solutes from a solid matrix to a solvent normally containing specific extractants. Most effective extractants are efficient and selective receptors for the targeted solutes that can involve a range of chemical forms. In fact, SLE technology is extensively used in food engineering to recover many commercially important components, including sucrose from cane or beet sources and lipids from oilseeds.308 However, the current review will only cover the solid−liquid extraction of

Table 11. Percentage of MX Complex Formed with 228, 229, and 230 after Solid-Liquid Extractiona 308 228 Cl− Br− I− a

Na+

K+

100 100 100

16 100

229 Cs+

Na+

K+

100 100 100

29 62 100

230 Cs+

Na+

K+

100 100 100

30 75 100

Cs+

Receptor concentration = 5 mM in CDCl3.

as confirmed by both 1H NMR spectroscopic and FAB mass spectrometric analyses. A preference for sodium halide salts over test ion pairs was noted. Notably, 231 (a receptor expected to bind only anions) and 232 (designed for cation recognition) failed to effect the extraction of either NaCl(s) or NaBr(s) under the same solid−liquid extraction conditions. On AY


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this basis, it was concluded that both the cation binding and anion recognition sites must be incorporated within the same calix[4]arene skeleton to achieve effective SLE. The Beer group developed a ditopic receptor 233 that relies on a calix[4]semitube for cation recognition and urea functionality for anion complexation (Figure 147).312 As


solution. Appreciable positive cooperativity was seen in acetonitrile solution in that preformation of either the Li+ or Na+ complex led to significant increases in the bromide and iodide anion affinities. Interestingly, the degree of halide binding enhancement for the neutral rhenium(I) receptors 234−237 proved considerably larger than for the charged ruthenium(II) receptors 238−241, a finding attributed to unfavorable electrostatic effects. Solid−liquid extraction experiments using CD2Cl2 as the organic phase revealed that two of the receptors, that is, 235 and 240, were capable of serving as SLE extractants for NaCl and NaOAc. A heteroditopic calix[4]arene-based receptor 242, bearing an amide linked bis(benzo-15-crown-5) at the upper rim of a calix[4]arene scaffold, was reported by the Beer group in 2003. When exposed to Na+ cations, a 2:1 cation-to-receptor complex is formed that results in the amide moieties being unable to complex an anion cooperatively due to the electrostatic repulsion between the co-bound sodium cations, as inferred from 1H NMR spectroscopic studies and electrospray mass spectrometry (ESMS). In contrast, receptor 242 was found to bind the K+ cation in the form of a 1:1 intramolecular sandwich complex (Figure 149). Anions, such as OBz− and H2PO4− (as their TBA salts), could be bound to this K+ complex though hydrogen binding and electrostatic interactions. Solid−liquid extraction studies revealed that extractant 242 was capable of extracting solid KOAc into a chloroform phase with 100% efficiency. However, no effective extraction was observed in the case of KCl, KH2PO4, NaCl, NaOAc, or NaH2PO4 under the same extraction conditions, confirming the extraordinary selectivity of 242 toward KOAc under solid−liquid extraction conditions. In 2004, Beer and co-workers reported that the ditopic macrobicyclic receptor 71 can be used to achieve the selective solid−liquid extraction of lithium halide salts.314 As discussed previously, receptor 71 and its analogues (69 and 70, Figure 41) are versatile ion pair receptors for alkali halides and alkylammonium salts.116,118,119 Receptor 71 was found to bind and extract solid NaCl, KCl, NaBr, and KBr into CDCl3 in the form of contact ion pairs.315 LiCl and LiBr were extracted as water-separated ion pairs, as deduced from 1H NMR spectroscopic and single crystal X-ray diffraction analyses (Figure 150). Under conditions of SLE, a cation selectivity of Li+ > Na+ > K+ was seen. For instance, in the case of a threecomponent mixture consisting of solid LiCl, NaCl, and KCl, the ratio of salts extracted and complexed to the receptor in CDCl3 was found to be 94:4:2, respectively, while, in the case of a three-component mixture of solid LiBr, NaBr, and KBr, the ratio of the corresponding extracted salts was 92:5:3,

Figure 147. Molecular structure of receptor 233 and its proposed cocomplexation of anions and cations.

opposed to the pronounced sodium selectivity of the tetraester systems of Reinhoudt and co-workers discussed immediately above, receptor 233 displays a remarkable selectivity for the potassium cation over all other alkali metal cations, Ka > 105 M−1 for K+ (vs 30 M−1 for Na+, 80 M−1 for Rb+, and 0 M−1 for Cs+ as their perchlorate or hexafluorophosphate salts), as determined by 1H NMR spectroscopy in CDCl3:CD3OD (4:1, v/v). Although halide and acetate anions were bound very weakly to 233 in 2:1 CDCl3:CD3CN, their binding affinity could be appreciably enhanced by using the preformed sodium and potassium ion complexes of 233. Solid−liquid extraction experiments demonstrated that this receptor, serving as an ion pair extractant, is capable of solubilizing solid sodium and potassium salts in chloroform. As shown in Table 12, the percentage complex formed Table 12. Percentage of Alkali Halide and Acetate Salts Extracted into CDCl3 by 233312 complex (%) [lattice energy/kJ mol−1] −

Cl Br− I− OAc−

Na+

K+

0 [786] 3 [747] 27 [704] 0 [763]

0 [715] 13 [682] 95 [649] 13 [682]

approximately mirrors the lattice energy of the salt being extracted. Thus, halide salts with lower lattice energies (e.g., KI) are extracted from the solid state into this organic medium more effectively. In contrast to the host-separated ion pair binding achieved with receptors 228−233, the Beer group also developed a series of heteroditopic rhenium(I) and ruthenium(II) bipyridyl calix[4]arene receptors 234−241 (Figure 148)313 that simultaneously complex alkali metal cation−anion ion pairs at the calixarene lower rim. These ditopic receptors proved capable of binding “hard” alkali metal cations and “soft” halide anion combinations (i.e., LiI, LiBr, NaI, NaBr), as inferred from 1H NMR spectroscopic titrations carried out in CD3CN AZ


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Figure 149. Molecular structure of receptor 242 and its proposed 1:1 potassium cation sandwich complex, which favors anion recognition. Also shown is the sodium complex, which does not act to recognize anions in a cooperative fashion.

Figure 151. Single crystal structures of (a) [71·KNO3], (b) [71· NaNO3], (c) [71·LiNO3·H2O], and (d) [71·NaNO2]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 196910, 188060, 250320, and 250321). The ion pairs and bridging water are shown in space-filling form. Other solvent molecules are omitted for clarity.

2-Amido-8-aminoquinolines have been used as backbones for anion recognition.317−319 Recognizing this, Albrecht and co-workers designed a novel receptor 243 (Figure 152) that

Figure 150. Proposed binding mode present in complexes [71·MA] (where M = Na+ or K+, A = anion) and [71·H2O·LiA].

respectively. This extraordinary selectivity of 71 toward LiCl and LiBr over other alkali halide salts is thought to reflect in part the unusually high relative solubility of lithium salts in organic solvents. Later, Beer and co-workers noted that receptor 71 is also able to complex a range of trigonal oxyanions in the form of their alkali metal salts (e.g., KNO3, NaNO3, LiNO3, and NaNO 2 ), as inferred from solution phase 1 H NMR spectroscopic studies in CDCl3 and in the solid state via Xray crystallography (Figure 151).316 It is worth noting that LiNO3 was bound to 71 as a solvent-separated ion pair with one water molecule linking the Li+ cation and the NO3− anion. In contrast, KNO3, KOAc, NaNO3, and NaNO2 were trapped as contact ion pairs. Evidence of an anisotropic shielding surface around the nitrate and nitrite anions was inferred on the basis of the unprecedented upfield shift seen for the receptor amide NH signal upon anion complexation. Receptor 71 also proved effective at extracting the solid forms of these monovalent salts (i.e., KNO3, KOAc, NaNO3, LiNO3, KNO2, and NaNO2) into chloroform solution.


was created by joining a quinoline moiety to an 18-crown-6 ether.320 Receptor 243 was found to bind halides (as their TBA salts) in CDCl3 solution per the following affinity sequence: I− < Br− < Cl−. In the presence of K+ cations, a slight enhancement in chloride and bromide anion affinities was observed. The low cooperativity factors were attributed to the rigidity of the spacer phenyl group between the anion binding site and the cation complexation site. Under conditions of solid−liquid extraction, this receptor was found to promote the solubilization of the solid salt forms of KCl, NaCl, and NH4Cl in chloroform and DMSO, as confirmed by 1 H NMR spectroscopy and ESI mass spectrometry. Receptor 243 could be easy recycled (Figure 153), which was thought to augur well for possible applications of 243 in separation science and catalysis. BA


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Cl− (Ka = 1288 M−1) or NO3− (Ka = 324 M−1) in the presence of the K+ cation. Recently, our group reported the selective solid−liquid extraction (SLE) and liquid−liquid extraction (LLE) of LiCl by means of the ditopic-strapped calix[4]pyrroles 245 and 246 (Figure 155).322 Both ion pair receptors proved capable of

Figure 153. Extraction-release studies involving receptor 243. Figure 155. Structures of receptors 245 and 246.

In 2015, the Ghosh group described the selective solid− liquid extraction of KBr utilizing a crown ether-based pentafluorophenyl urea functionalized ditopic receptor 244.321 This system was tested as a possible extractant of solid Na+ and K+ salts of F−, Cl−, Br−, I−, NO3−, HSO4−, H2PO4−, and AcO− into CD3CN solution as monitored by 1H NMR spectroscopy. On this basis, it was determined that receptor 244 was unable to extract any of the Na+ salts into the organic phase. In contrast, with KCl, KBr, KI, and KNO3, changes consistent with extraction were seen in the 1H NMR spectra of the CD3CN solutions (Figure 154). The underlying

selectively binding LiCl, as inferred from 1 H NMR spectroscopic and single crystal X-ray diffraction analyses (Figure 156). Under solid−liquid conditions, receptor 245

Figure 156. Single crystal structures of (a) [245·LiCl] and (b) [246· LiCl]. The Li+ and Cl− ions are shown in space-filling form. Ellipsoids are set to the 50% probability level. Solvent molecules are omitted for clarity. Reprinted with permission from ref 322. Copyright 2018 Wiley-VCH Verlag GmbH & Co. KGaA.

proved capable of extracting solid LiCl, NaCl, and KCl into nitrobenzene efficiently over the course of 48 h. Receptor 245 exhibited selectivity (∼100%) toward LiCl when tested using a mixture of salts (NaCl and KCl; 1:1, w/w) containing either 10% or only 1% of LiCl by mass, as determined by 1H NMR spectroscopy, qualitative flame tests, and quantitative inductively coupled mass spectrometric (ICP-MS) analyses (Figure 157). Under similar SLE conditions but using chloroform as the organic phase, receptor 246 with a smaller inner cavity was found to extract LiCl but not NaCl or KCl. High LiCl selectivity (∼100%) was observed when a solution of 246 in CDCl3 was layered over a solid mixture of NaCl and KCl (1:1, by mass) containing only 200 ppm LiCl and subjected to sonication for 1 h. These receptors were also tested under conditions of liquid−liquid extraction. Here, receptor 245 proved capable of extracting LiCl, NaCl, and KCl from an aqueous source phase into nitrobenzene according to the selectivity sequence KCl > NaCl > LiCl. In contrast, even

Figure 154. Changes in the chemical shifts of the urea NH signal of 244 under conditions of solid−liquid extraction using different K+ salts; Receptor 244 was dissolved in CD3CN (∼2 mM), whereas the K+ salts were studied as solids present in excess (5 equiv with respect to 244). Reprinted with permission from ref 321. Copyright 2015 Royal Society of Chemistry.

extraction was also confirmed by ESI-MS studies. No evidence of receptor 244 serving to promote the extraction of KF, KHSO4, KH2PO4, or KOAc was seen, a result ascribed to the relatively high lattice energy of these salts. When the SLE studies were carried out with mixtures of KCl, KBr, and KNO3, KBr was found to be extracted preferentially, as supported by ESI-MS and 1H NMR spectral studies. This preference for KBr was rationalized in terms of the stronger binding affinity displayed by receptor 244 for Br− (Ka = 2455 M−1) relative to BB


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group and the higher relative acidity it imparts. Receptor 251 proved less effective as an extractant for 4-aminobutanoic acid (GABA) than either 247 or 248 probably due to poor size complementarity. 3.2.2. Liquid−Liquid Extraction of Ion Pairs. Liquid− liquid extraction, also known as solvent extraction, is a versatile technique for separating a solute between two immiscible liquids. It involves the transfer of a target species from one liquid phase to another liquid phase (usually from an aqueous phase to an organic phase). Applications of this process include removal of a specific species, i.e., neutral molecules, anions, cations, or ion pairs, from aqueous media. This review only focuses on the use of macrocyclic ion pair receptors as extractants. The reader is referred to several other reviews and books that detail progress in the area of LLE for anions or cations.5,12,324−330 It is also to be appreciated that, in the literature, the so-called dual-host approach, wherein separate anion and cation receptors are used to extract ion pairs, is well documented.331−335 Since dual-host strategies do not involve macrocyclic ion pair receptors per se, they are not included in this review. One of the very early examples where an ion pair receptor was used to promote the liquid−liquid extraction of targeted salts was reported by Beer and co-workers in 1999.336 These researchers found that the tripodal tris(amido benzo-15-crown5) receptor 252 (Figure 159) could capture in a cooperative

Figure 157. Results of ICP-MS analyses showing the percent receptor loading for the indicated alkali metal chloride salts after extraction into nitrobenzene or chloroform from a mixture of solid salt forms consisting of (A) LiCl, NaCl, and KCl (100:100:100, molar ratio), (B) NaCl and KCl containing 10% of LiCl (mass content), and (C) experiments analogous to part B in which the LiCl content was 1% by mass. The concentration of receptor 245 was 4 mM in nitrobenzene in all three studies. (D) Analogous studies involving a solid mixture of NaCl and KCl containing 200 ppm of LiCl (by mass) using receptor 246 (3 mM in chloroform). Reprinted with permission from ref 322. Copyright 2018 Wiley-VCH Verlag GmbH & Co. KGaA.

under LLE conditions, receptor 246 displayed a near 100% selectivity toward LiCl over NaCl and KCl. Common amino acids in their zwitterionic form are known to be practically insoluble in common organic solvents. However, they may be easily transferred into organic media with the assistance of ditopic ion pair receptors. For example, Costero and co-workers prepared five heteroditopic ion pair receptors 247−251 (Figure 158) containing crown ether


fashion the chloride, iodide, and perrhenate anions when a sodium cation was co-bound within the crown ether portion of the scaffold. At low concentrations of Na+, a 1:1 sandwich complex was seen, while, at high concentrations of sodium cation (i.e., ≥3 equiv), one sodium cation is found bound in each benzo-15-crown-5 moiety, as inferred from UV−vis and 1 H NMR spectroscopic titrations carried out in CDCl3. The extraction preference was Na+ > K+ > Cs+ in the case of LLE extraction studies involving various alkali metal cations (studied as their picrate salts). The precomplexation of Na+ was found to enhance the binding of the tetrahedral pertechnetate anion (ReO4−), presumably due to the favorable cation-complexation-induced preorganization. Receptor 252 proved capable of extracting the ReO4− anion from an aqueous source phase into chloroform. In fact, the pertechnetate sodium salt (NaTcO4) could be extracted into a CH2Cl2 receiving phase from simulated nuclear waste streams containing NH4TcO4 and NaNO3 with a ca. 70% extraction efficiency. In contrast, the tripodal receptors 253 and 254, lacking crown ether moieties and studied as control compounds, proved capable of extracting less than 10 and roughly 0% of the TcO4−, respectively, even after 24 h, as determined by IP-MS and 99Tc NMR spectroscopy. Preliminary U-tube membrane transport studies revealed that 252


moieties for cation complexation and amide or thiourea groups as anion binding sites.323 Due to the instability of 249 and 250 in DMSO solution, only 247, 248, and 251 were tested as extractants in SLE experiments using DMSO-d6 as the organic phase. It was found that these three systems could act as heteroditopic receptors and were capable of extracting solid zwitterionic amino acids with different chain lengths (i.e., 4aminobutanoic acid, 5-aminopentanoic acid, and 6-aminohexanoic acid) into DMSO with high efficiency compared to mixtures of the corresponding monotopic receptor subunits. Compared with 247, receptor 248 was found to accelerate the extraction process, presumably due to the presence of the nitro BC


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could enhance the rate of transport of TcO4− (flux = 6.3 × 10−8 mol h−1) relative to benzo-15-crown-5 (flux = 1.0 × 10−8 mol h−1). To design effective heteroditopic molecular receptors for the concurrent binding of anions and cations, the Romański and Piat̨ ek groups developed a simple heteroditopic salt receptor 255 (Figure 160) on the basis of an L-ornithine molecular

Figure 161. Molecular structures of free-standing and supported receptors 258−261.

sequence Br− < NO2− < Cl− < PhCOO− < AcO−, as determined from UV−vis spectroscopic titrations using the TBA salts. In the presence of Na+ cations, receptors 258 and 259 displayed enhanced affinities for all anions tested with the exception of acetate. The enhancement in the sodium salt affinity proved even more pronounced in the case of the urea supported receptor 258. This finding was rationalized in terms of the spatial demands of the binding sites, as well as in terms of hard−soft acid−base theory.340 After 258 and 259 were incorporated into copolymers (260 and 261), no appreciable enhancement of extraction efficiency was observed. For example, in the case of solid−liquid extraction, receptor 258 and its copolymer 260 were found to extract solid sodium nitrite similarly well, with extraction efficiencies of 19 and 21% being seen, respectively. In the case of the liquid−liquid extraction, receptor 258 and copolymer 260 were found to extract sodium nitrite from an aqueous source phase into a chloroform phase only weakly (3.5 and 3.4% efficiencies, respectively), as determined using UV colorimetric assays. Presumably, the lack of improvement seen for the supported system reflects the relatively low molecular weight of the copolymers as well as the relatively low ion binding site loadings.338 It was suggested that the methacrylamide group located on the side arm of receptor 255 provides an additional binding domain for anion recognition, which enhances the salt binding. In order to increase further the anion affinity and consequently the thermodynamic driving force for salt association, several Lornithine-based salt receptors 262−265 (Figure 162) were synthesized; this was done by introducing stronger H-bond donor groups onto the L-ornithine side arms.341 The resulting receptors were found to display anion binding behavior that was similar to the original systems when tested using salts containing the noncoordinating TBA cation. However, in the presence of Na+ cations, a significant enhancement in the NO2− anion binding affinity was observed. This proved particularly true for receptor 263, where an ∼13-fold enhancement was seen. This increase was ascribed to the fact that a single bound anion could interact with the incorporated hydrogen-bond donors without perturbing the complexation of the sodium cation by the crown ether subunit. In the event, receptor 263 was found to be highly selective for NaNO2 over sodium bromide or sodium nitrate. This system also proved capable of extracting solid NaNO2, NaNO3, NaBr, and NaCl into chloroform solution with a high selectivity for NaNO2. A similar extraction preference was observed in the case of the liquid−liquid extraction studies, where NaNO2 was found to be effectively transported by 263 from the aqueous phase into the organic phase.


scaffold.337 This system was found to associate with sodium nitrite effectively and selectively, where the urea CO group binds to a sodium cation complexed within the crown ether and the methacrylamide group located at the side arm of receptor 255 serves to reinforce the ion pair binding as judged from 1H NMR spectroscopic titration experiments carried out in CDCl3, as well as molecular modeling studies. A similar heteroditopic ion pair receptor (256, Figure 160) was also prepared.338 It consists of an aza-18-crown-6, nitrophenylthiourea, and an additional methacrylamide group appended to the carboxylic, α-amine, and δ-amino groups of Lornithine, respectively. Receptor 256 proved capable of binding sodium salts of chloride, acetate, and nitrate. Under conditions of LLE with CHCl3 as the organic phase, the extraction efficiency of receptor 256 toward NaNO3 and NaCl was almost negligible (2.9 and 2.2% extraction efficiencies, respectively), as determined by atomic emission spectroscopy and a colorimetric nitrite−nitrate method (Table 13). Table 13. Summary of Extraction Dataa 338 extracted ion

AIb

NO3− Cl−

0.487 0.219

NO3− Cl−

0.032 0.025

c (mg L−1)(%) Polymer 257 12.63 5.60 Receptor 256 0.832 0.637

extraction efficiency 44 19 2.9 2.2

32c

1.3c

Little discernible extraction of Cl− or NO3− into pure chloroform is observed. bAbsorption intensity. cDetermined by the NO2−/NO3− colorimetric test after back-extraction into H2O. a

However, copolymer 257 containing ditopic receptor 256 as a pendant group was found to enhance significantly the extraction efficiency and the selectivity of NaNO3 from an aqueous source phase to a CHCl3 receiving phase. It was suggested that a proper combination of an ion pair receptor and a polymeric matrix is needed to achieve effective salt extraction. Similarly, Romański and co-workers reported the synthesis and binding properties of the L-tyrosine-based ion pair receptors 258 and 259 (Figure 161).339 Both receptors were found to complex various anions according to the affinity BD


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acetate (∼5 M) from an aqueous source phase into organic media (CDCl3) with ∼100% efficiency. Very recently, the Romański group described the synthesis and recognition properties of an ion pair receptor 271 (Figure 163) consisting of a crown ether domain for cation binding


and a squaramide moiety for anion recognition.345 This receptor was found to bind a series of sodium salts, including NaCl, NaBr, NaNO 3 , and NaNO 2 , as inferred from spectrophotometric and spectroscopic measurements carried out in acetonitrile and in acetonitrile/water mixtures, as well as single crystal X-ray diffraction analyses. Receptor 271 proved capable of extracting sodium chloride from aqueous media into an organic receiving phase (PhNO2-d5), as determined through a combination of 1H NMR spectroscopic studies, mass spectrometric measurements, and atomic absorption analyses. In contrast, the urea-based ion pair receptor 272 and the monotopic receptor 273 lacking a crown ether unit failed to extract NaCl under identical extraction conditions (Figure 164).


Receptors 266 and 267, containing either a urea or thiourea group, respectively, at the δ-position of the L-ornithine molecular scaffold, were reported by the same group.342 Again, the rationale was to complement the contributions of the amino acid side arm to anion recognition by providing ancillary H-bond donor groups. In fact, both receptors were found to bind anions (e.g., Br−, Cl−, NO3−, OAc−, and PhCOO− in CH3CN in the form of their TBA salts), as determined through spectrophotometric and 1H NMR spectral titrations. In an effort to study in greater detail the influence of the cation recognition site on ion recognition and extraction, two additional heteroditopic receptors based on the L-ornithine scaffold that differ only in their cation binding domains, namely, 268 and 269, were prepared.343 Compared with 268, which bears an electron withdrawing group adjacent to the cation binding site, receptor 269 proved to be a more effective receptor for cations such as Na+, K+, and NH4+. Not surprisingly, therefore, receptor 269 proved to be an effective extractant for KCl and NH4Cl (but ineffective for NaCl). Under liquid−liquid extraction conditions, extraction efficiencies (i.e., the fraction of receptor molecules occupied by the complex in the organic phase) of 97 and 93%, respectively, were recorded for these two salts. Under identical LLE experimental conditions, receptor 268 was completely inactive as an extractant. These observations led to the suggestion that the combined presence of both strong cation and relatively strong anion binding sites is critical to achieving effective and highly synergistic ion pair binding and extraction. Recently, Piat̨ ek and co-workers prepared a non-multimacrocyclic heteroditopic receptor 270 in three synthetic steps.344 This structurally simple receptor was able to associate with most ion pair combinations comprised of the Na+, K+, and NH4+ cations and the Cl−, Br−, I−, AcO−, PhCOO−, and LBocPhe− anions. A preference for KOAc was observed, as inferred from UV−vis and 1H NMR spectroscopic titrations carried out in acetonitrile solution. Under liquid−liquid extraction conditions, receptor 270 was found to function as an ion pair receptor/extractant capable of extracting potassium

Figure 164. Schematic illustration of liquid−liquid extraction of NaCl mediated by the ditopic receptor 271. Reprinted with permission from ref 345. Copyright 2018 American Chemical Society.

Another example involving the liquid−liquid extraction of ammonium nitrate came from the same group.346 They prepared a heteroditopic macrotricyclic molecular receptor 274, which consists of a 4,10,16-triaza-18-crown-6 cation binding domain and a tripodal anion binding motif (Figure 165). This receptor displays selectivity for the nitrite and nitrate anions over the Cl−, Br−, AcO−, and H2PO4− anions in the presence of a noncoordinating TBA cation, as determined from 1H NMR spectroscopic titrations carried out in DMSOd6. Enhancements in both the association constants and relative selectivity for nitrite and nitrate, particularly the latter, BE


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Figure 165. (a) Molecular structure of receptor 274 and (b) DFT optimized structure of its ammonium nitrate complex [274· NH4NO3]. Reprinted with permission from ref 346. Copyright 2013 American Chemical Society.

Figure 167. Proposed steps in the liquid−liquid extraction of cesium salts effected by meso-octamethylcalix[4]pyrrole 124. Adapted with permission from ref 347. Copyright 2008 American Chemical Society.

were observed when NH4+ was used as the countercation. In the presence of NH4+, the binding constants were found to be 980 and 1050 M−1 for NO2− and NO3−, respectively. The selectivity of receptor 274 toward NH4NO3 was supported by means of density functional theory (DFT) calculations (Figure 165). Under conditions of solid−liquid extraction, receptor 274 was found to act as an ion pair extractant and to extract solid NH4+ salts of AcO−, Cl−, Br−, and NO3− into CDCl3 solution. In contrast, extraction of solid Na+ and K+ salts of AcO−, Cl−, Br−, and NO3− proved less effective. Receptor 274 was also able to extract NH4NO3 (1.7 M) from water into CDCl3 with an ∼65% extraction efficiency, as determined by means of both 1H NMR spectroscopic analyses (Figure 166) and nitrate anion colorimetric assays.

offer practical advantages in terms of the stripping or removal of the extracted ions, after extraction.348 In contrast, in the case of CsNO3, under the identical LLE conditions, the calix[4]pyrrole does not act as an ion pair receptor, a finding that was rationalized in terms of the nitrate anion being only weakly bound to the calix[4]pyrrole in organic media.185 The calix[4]pyrrole unit has been incorporated into methyl methacrylate (MMA) polymers. A first generation system was found to be effective at extracting tetrabutylammonium chloride and fluoride from aqueous media into a dichloromethane phase.349 In an effort to extract “hard” ion pairs, such as KF or KCl, from aqueous media, Sessler and co-workers developed a modified calixpyrrole-containing polymer 276.350 This was done by including benzo-15-crown-5 moieties for cation recognition as well as calix[4]pyrrole moieties.351 The nonpolymeric ditopic receptor 275 and polymers 277 and 278, containing only one type of ion recognition moiety, were also prepared as control systems (Figure 168). Parallel extraction

Figure 166. Partial 1H NMR (200 MHz) spectra of receptor 274 recorded as (a) a 11.8 mM solution in wet CDCl3; (b) after extracting NH4NO3 from an aqueous phase; (c) after back-extraction into a distilled water receiving phase. Reprinted with permission from ref 346. Copyright 2013 American Chemical Society.

Figure 168. Molecular structures of receptor 275 and polymers 276− 278.

studies revealed that the polymer-free receptor 275 and polymer 278 proved almost ineffective as extractants for either KF or KCl. However, polymers 276 and 277, particularly polymer 276, were found to promote the liquid−liquid extraction of KF and KCl, as inferred from 19F NMR spectroscopy and flame emission spectroscopy (FES). These findings were rationalized in terms of polymer 276 containing an appropriate combination of both anion and cation binding sites within the same matrix, thus being able to overcome the relatively high hydration energies of KF and KCl.352 The multitopic ion pair receptor 279 (Figure 169), which contains a calix[4]pyrrole anion binding motif and a calix[4]arene crown-5 subunit for cation recognition, was

As discussed above, the easy-to-prepare system mesooctamethylcalix[4]pyrrole 124 is known to be a versatile anion receptor as well as an ion pair receptor for certain cation salts. It was also found to promote the liquid−liquid extraction of cesium chloride and cesium bromide.347 Under conditions of extraction from water to nitrobenzene, the formation of an ion paired 1:1:1 cesium:calix[4]pyrrole:halide complex (Figure 167) was observed in the case of several cesium halide salts, as inferred from plots of the cesium distribution ratios vs cesium salt and receptor concentration. This receptor thus favors the concurrent, paired extraction of both anions and cations (i.e., formation of an overall neutral ensemble). This is thought to BF


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Receptor 279 also proved capable of capturing CsCl and CsNO3 in 10% methanol-d4 in CDCl3, as inferred from 1H NMR spectroscopic analyses and single crystal X-ray diffraction studies.355 Normally, receptor 279 binds the CsNO3 ion pair with the Cs+ cation and the NO3− anion bound concurrently to the receptor, being stabilized by the ethylene glycol spacers and the calix[4]pyrrole moiety, respectively. Upon addition of KClO4 to these cesium complexes, a novel type of cation metathesis is seen, wherein the “exchanged” cations occupy different binding sites; namely, the incoming K+ is bound by the crown ether, whereas the departing Cs+ leaves from the ethylene glycol spacers. Under liquid−liquid extraction conditions, receptor 279 proved capable of extracting CsNO3 and CsCl from a D2O source phase into nitrobenzene-d5, as determined from 1H NMR spectroscopic analyses and radiotracer measurements (Figure 171). Upon exposing to an aqueous KClO4 solution, the


also designed as an extractant for the “hard” ion pair KF.351 It proved effective for this task and for CsF recognition. In the case of KF, the calix[4]arene crown-5 moiety binds the K+ cation first and, subsequently, the calix[4]pyrrole subunit complexes the F− anion to provide an overall 1:1:1 receptor− cation−anion complex. In the case of CsF, two binding modes are seen in 10% CD3OD in CDCl3, as inferred from solution state 1H NMR spectroscopic analyses and single crystal X-ray crystal structural data (Figure 170). In the first mode, the CsF

Figure 171. Schematic representation of the two-phase extraction and recovery of CsNO3 achieved using the ion pair receptor 279. The stages include initial Cs+ complexation and K+ for Cs+ cation exchange, followed by regeneration of the free receptor by contact with chloroform and water. Reprinted with permission from ref 355. Copyright 2012 American Chemical Society.

extracted CsNO3 complex in the nitrobenzene phase was found to release the Cs+ into the aqueous phase with the receptor forming a KNO3 complex. Further washing allowed for regeneration of the receptor. In 2015, Sundararajan carried out DFT calculations in an effort to shed light on the cooperative binding features displayed by 279.356 The Cs+ salts were found bound to the receptor mainly through electrostatic interactions with small contributions from covalent interactions in the case of the complexes involving anions with large ionic radii. Moreover, this receptor was predicted through DFT calculations to extract Sr2+ selectively over Ca2+ in nitrate-rich media.357 Recently, considerable effort within our research group has been devoted to the extraction and possible recycling of lithium salts through use of hemispherand-strapped calix[4]pyrroles. Because of the “hard” nature of Li+, as reflected in its high hydration energy (−475 kJ mol−1 for Li+), its selective recognition relative to other alkali metal cations is a challenge.352 In a first contribution within this problem area, our group prepared the hemispherand-strapped calix[4]pyrrole 281.358 This putative ion pair receptor contains a hemispherand unit for cation binding and a calix[4]pyrrole moiety

Figure 170. Single crystal structures of complexes [279·CH3OH·KF] and [279·CH3OH·CsF]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 826579 and 826578). The ion pairs and bridging solvent molecules are shown as space-filling models. Other solvent molecules are omitted for clarity.

ion pair interacts with receptor 279 with the Cs+ cation bound to the calix[4]arene crown-5 ring weakly and the counteranion not co-bound; in the second, the Cs+ and F− ions bind simultaneously to the receptor through the ethylene glycol spacers and the calix[4]pyrrole moiety, Importantly, however, receptor 279 displays ion pair selectivity toward KF over CsF. Moreover, it acts as a viable ion pair extractant capable of extracting KF from an aqueous phase into nitrobenzene, thus overcoming the relatively high hydration energies of both the K + and F − ions. Neither the anion receptor, mesooctamethylcalix[4]pyrrole, nor the cation receptor, 280, is able to extract appreciable quantities of KF under identical liquid−liquid extraction conditions.353,354 BG


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for anion recognition.232,359,360 Receptor 281 proved capable of stabilizing 1:1 ion pair complexes with several lithium salts (e.g., LiCl, LiBr, LiI, LiNO2, and LiNO3). Good selectivity over the corresponding sodium and potassium salts was seen both in the solid state, as confirmed by single crystal X-ray diffraction analyses (Figure 172), and in organic solutions, as

Figure 174. (a) Single crystal structure of complex [281·Cs2CO3]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 1549914). (b) DFT optimized structure of complex [281·CsOH]. This figure was reproduced with permission from ref 358. Copyright 2016 ACS Publications.

Figure 172. (a) Molecular structure of receptor 281 and (b) single crystal structure of [281·LiNO2]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC No. 1483283). The LiNO2 is shown in space-filling form. Other solvent molecules are omitted for clarity.

Cs2CO3 and CsOH from highly basic aqueous media under conditions of liquid−liquid extraction, as inferred from 1H NMR spectroscopic studies carried out using CDCl3 as the organic phase. An extraction efficiency of ca. 50% was calculated, and selectivity toward CsOH and Cs2CO3 over CsF, CsCl, and CsBr was observed (Figure 175). Support for

inferred from standard spectroscopic protocols. Receptor 281, when dissolved in CDCl3, was able to act as a LiNO2 extractant under both solid−liquid extraction and liquid−liquid extraction conditions (Figure 173). Good selectivity for lithium nitrite over sodium nitrite and potassium nitrite was observed.

Figure 175. (a) Bar graph showing the concentrations of cesium salts extracted from aqueous solutions using 281 (20 mM CHCl3) as an extractant and (b) illustration of the general U-tube setup used to test the ability of 281 to function as an extractant for CsOH under liquid− liquid conditions. Adapted with permission from ref 361. Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA. Figure 173. Cartoon illustration of the solid−liquid extraction and liquid−liquid extraction of LiNO2 effected by receptor 281. Adapted with permission from ref 358. Copyright 2016 American Chemical Society.

these findings came from U-tube experiments involving the transport of CsOH through an intervening chloroform layer. It was found that in the presence of receptor 281 the pH of the receiving phase increases, while that of the source phase decreases. These findings are noteworthy in light of the high hydration energy of the carbonate anion (−1315 kJ mol−1)352 and the potential benefits of being able to control pH through extraction-based methods. Complexation-induced supramolecular assembly has been reported to be effective for enhancing liquid−liquid extraction of both metal ions and sulfate anions.362,363 Our group has recently reported that molecular recognition and ion pair extraction can be effected under interfacial conditions by means of calix[4]pyrrole-based cross-linkable micelles.364 A first system reported in this context is the anthracenefunctionalized calix[4]pyrrole 282 (Figure 176), which bears a cation binding domain and an anion recognition site. Calix[4]pyrrole 282 was found to complex FeF2 and to selfassemble into multimicelles in aqueous media, a finding

Analysis of the cavity present in 281 led to the consideration that a lithium cation would be coordinated in a nonsymmetrical fashion in the solid state or shuttle rapidly between the two subcavities defined by the central methoxy group in solution.358 Similar analyses led to the expectation that relatively large cations, e.g., Cs+, would fit well within the full hemispherand cavity. In fact, the strapped calix[4]pyrrole 281 was found to capture well various cesium salts, including CsF, CsCl, and CsBr. It also proved capable of recognizing CsOH and M2X-type ion pairs (i.e., Cs2CO3), as supported by a single crystal structure of the latter complex, DFT calculations (Figure 174), and 1H NMR spectroscopic analyses.361 Under conditions of solid−liquid and liquid−liquid extraction, receptor 281 could be used to extract CsCl selectively over LiCl, NaCl, KCl, and RbCl. It also proved capable of extracting BH


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Figure 178. Illustration of the self-assembly process for diblock copolymer 284 that can give rise to multiaggregated reversed micelles. Reprinted with permission from ref 365. Copyright 2018 ACS Publications.

ascribed to an ion pair complexation-induced change in receptor polarity. The resulting FeF2-containing micelles could be further stabilized by cross-linking the anthracene units under photoirradiation conditions. Receptor 282 was found to be ca. 3× more effective than 283 when tested as an FeF2 ion pair extractant under LLE conditions. Very recently, our group reported a diblock copolymer 284 containing a strapped calix[4]pyrrole-based ion pair receptor.365 This polymer is devoid of any particular morphological form in dichloromethane. However, it is able to self-assemble into reversed micelles (characterized by transmission electron microscopy (TEM), energy-dispersive X-ray analysis (EDX), and dynamic light scattering (DLS)) that remain within an organic phase when dissolved in dichloromethane and exposed to simple ion pairs (e.g., CsCl or CsF) at an organic−aqueous interface (Figure 177). This copolymer-derived system proved

They might also impart useful selectivities. In living systems, the controlled transport of ions through cellular membranes by natural ion carriers or specialized proteins embedded in the membrane is essential to maintain optimal physiological function. Defective ion transport, on the other hand. is thought to underlie a number of diseases, such as cystic fibrosis. Rationally designed ion pair carriers that overcome these transport deficiencies could have a role to play in the treatment of ion-transport-related diseases. Thus far, a small number of ion pair receptors have been tested as transmembrane ion pair transporters using liposomal model membranes. Ion pair receptors have also found use in effecting the separation of specific ions or ion pairs by means of socalled bulk liquid membrane models (i.e., multiphase U-tube systems) as well as supported liquid membranes (SLMs) involving porous polymeric supports. In this section, we summarize studies of ion pair receptors as ion transporters. 3.3.1. Liposome Membrane Transport. The earliest example of ion pair receptors used to effect transmembrane ion transport was reported by Smith et al. in 2003.366 These researchers found that the ion pair receptor 71 (discussed in section 2.4 above) could be used to transport NaCl and KCl in model membrane transport experiments involving vesicles made from unilamellar 1-palmitoyl-2-oleoylphosphatidylcholine (POPC). Cl− efflux from POPC vesicles was monitored by a Cl− selective electrode. The resulting Cl− efflux profiles revealed that receptor 71 acts as a highly efficient transporter (Figure 179). For instance, at a phospholipid-to-receptor ratio of 2500:1, roughly half of the initial Cl− content within the vesicle was removed within about 300 s. By contrast, a binary mixture of bis-azacrown-6 286 and isophthalamide 287, monomers corresponding to the two ion binding constituents


capable of extracting simple inorganic ion pairs from aqueous solution into an organic receiving phase more effectively than a control calix[4]pyrrole-based ion pair receptor 285 (Figure 178). 3.3. Transmembrane Ion Pair Transport

Ion pair receptors are of interest as transmembrane ion transporters. Because of their superior ability to recognize ions, they could offer advantages in this particular application area.

Figure 179. Chemical structures of ion pair transporter 71 as well as two control compounds 286 and 287. BI


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of receptor 71, failed to induce Cl− efflux under otherwise identical conditions (Figure 180). Mechanistic studies

Figure 182. Cl− efflux promoted upon addition of 124 (molar carrier to lipid ratio: 2% on a per mole basis) to unilamellar POPC vesicles loaded with 488 mM CsCl (■), RbCl (○), KCl (▲), or NaCl (□), 5 mM phosphate buffer, pH 7.2, dispersed in 488 mM NaNO3, 5 mM phosphate buffer, pH 7.2, and unilamellar POPC vesicles loaded with 488 mM CsCl (●), 5 mM phosphate buffer, pH 7.2, dispersed in 162 mM Na2SO4. Reproduced with permission from ref 367. Copyright 2008 Royal Chemical Society.

Figure 180. Cl− efflux seen upon addition of receptor 71 (0.4 μM, green ○; 4.0 μM, red ▽; 40.0 μM, blue □) or a 1:1 molar mixture of 286 and 287 (40 μM each, blue ■) to unilamellar POPC vesicles (200 nm mean diameter, 1 mM phospholipid) containing 500 mM NaCl dispersed in 500 mM NaHCO3. Reproduced with permission from ref 366. Copyright 2003 Royal Society of Chemistry.

provided support for the hypothesis that the facilitated efflux of ion pairs is made possible because transporter 71 passes through the vesicle as a neutral species, as does its ion pair complexes. Support for the notion that transporter 71 enhances ion fluxes came from 35Cl and 23Na NMR spectral studies. Using these latter spectroscopic techniques, the signal of the Na+ (or Cl−) within the vesicles could be distinguished from that of bulk Na+ (or Cl−). Calix[4]pyrrole 124 (discussed in section 2.4 above) and the oligoether-strapped calix[4]pyrrole 288 were studied as ion pair transporters by Sessler and co-workers (Figure 181).367,368

It was also inferred from 1H NMR spectroscopic analyses that the crown ether-strapped calix[4]pyrrole 288 is capable of binding several alkali metal fluoride and chloride salts.368 In these latter instances, the cesium cation is bound to the cuplike calix[4]pyrrole cavity that is stabilized in the cone conformation. However, other alkali metal cations are complexed by the crown ring moiety. Transmembrane ion transport experiments using unilamellar POPC vesicles with external solutions of NaNO3 and Na2SO4 revealed that receptor 288 is able to transport chloride salts of Na+, K+, Rb+, and Cs+ with greater transport efficiency being observed for the more lipophilic cations (Na+ < K+ < Rb+ < Cs+) (Figure 183). Bulk membrane transport experiments were carried out to elucidate the transport mechanisms. Here, a U-tube setup

Figure 181. Chemical structures of ion pair receptors 124 and 288.

As discussed above, the unfunctionalized calix[4]pyrrole was found to bind cesium halide salts in the solid state as well as in solution.367 Transmembrane transport experiments revealed that receptor 124 is also able to transport CsCl effectively across phospholipid bilayers and do so selectively over other alkali metal chloride salts (Figure 182). For this study, unilamellar POPC vesicles, loaded with alkaline chloride ion pairs, were prepared and suspended in an external Na2SO4 or NaNO3 solution. A DMSO solution of receptor 124 (2% molar carrier to lipid) was added, and the changes in external chloride anion concentration were monitored using a chloride selective electrode. The vesicle was lysed via the addition of detergent 5 min after adding receptor 124. The resulting electrode reading was used to determine the 100% release value.

Figure 183. Cl− efflux promoted by receptor 288 (4 mol % with respect to lipid) from unilamellar POPC vesicles loaded with 489 mM MCl buffered to pH 7.2 with sodium phosphate salts (M = Na, K, Rb, or Cs). The vesicles were dispersed in 167 mM Na2SO4 buffered to pH 7.2 with 5 mM sodium phosphate salts. Each point represents the average of three trials. Reproduced with permission from ref 368. Copyright 2012 Wiley-VCH Verlag GMbH & Co. KGaA. BJ


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was used in which two aqueous phases containing 0.5 M MCl (M = Na, K, and Cs) and either 0.5 M NaNO3 or Na2SO4 in 20 mM phosphate buffer (pH 7), respectively, were separated by a dichloromethane layer containing receptor 288. On the basis of these studies, it was concluded that receptor 288 transports KCl and CsCl through a cation−anion cotransport (or symport) mechanism and NaCl with a Cl−/NO3− antiport (or exchange) mechanism. In 2014, Jeong and co-workers synthesized the ion pair receptors 289 and 290 that consist of two heteroditopic binding domains, an azacrown-5 or -6 ether for binding of an alkali metal cation and a cavity bearing three hydrogen-bond donors for anion recognition (Figure 184).369 The association Figure 185. Cl− efflux facilitated by symporter 289 and control compound 291 (2 mol % relative to lipid). The studies were carried out using vesicles loaded with sodium chloride (500 mM in 5 mM phosphate buffer at pH 7.2) and either a NaNO3 or a Na2SO4 solution as the external phase. Reproduced with permission from ref 369. Copyright 2014 American Chemical Society.

Figure 184. Ion pair transporters 289 and 290 and the control compound 291.

constants (Ka) for Cl− were evaluated via 1H NMR spectral titrations carried out in 10% CD3OD in CDCl3 and found to be 72 and 57 M−1 for receptors 289 and 290, respectively. In the presence of either Na+ (as the ClO4− salt) or K+ (as the PF6− salt), the association constants for Cl− were increased by an order of magnitude, presumably as the result of additional electrostatic interactions between the co-bound ion pairs. The binding affinities of receptors 289 and 290 for Na+ (as the ClO4− salt) and K+ (as the PF6− salt) were quantified by means of 1H NMR spectral titrations carried out in CD3OD/CD3CN (1/1, v/v). The results revealed that receptor 289 has a slightly higher affinity for Na+ (Ka = 630 M−1) than K+ (Ka = 200 M−1). In contrast, receptor 290, containing a larger crown ether, was more selective for K+ (Ka > 20,000 M−1) over Na+ (Ka = 2900 M−1). A single crystal X-ray diffraction structure of the NaCl complex of receptor 289 revealed that the Na+ cation is bound to the crown ether moiety and that the Cl− anion is hydrogen-bonded to NH protons of the urea group as well as to the OH group. The co-bound Na+ and Cl− ions exist in the form of a contact ion pair held within the receptor. Transmembrane ion transport experiments were performed using unilamellar POPC vesicles. In sharp contrast to what was seen for the crown-free control compound 291, known to be an effective Cl−/NO3− antiporter,369 receptor 289 proved capable of transporting Cl− from within the vesicles to an external Na2SO4 solution, as shown in Figure 185. The highly hydrophilic SO42− ion is thought to resist in large measure transport across a POPC membrane. In light of these observations, it was concluded that the Cl− transport facilitated by receptor 289 occurs mostly via Na+/Cl− symport. The authors also examined the transport selectivity for ion pairs using a series of POPC vesicles containing alkali metal chloride salts suspended in aqueous Na2SO4 solutions. The resulting Cl− efflux data revealed that receptor 289 is capable of transporting NaCl with high transport efficiency. In contrast, receptor 290 was found to transport KCl with greater efficiency under the same conditions (Figure 186a). In this

Figure 186. (a) Cl− efflux facilitated by symporter 290 (2 mol % relative to lipid) from unilamellar POPC vesicles loaded with the indicated salts (500 mM in 5 mM phosphate buffer at pH 7.2). (b) K+ and Cl− efflux studied in the presence of symporter 290 using unilamellar POPC vesicles loaded with KCl into a Na2SO4(aq) receiving phase. Reproduced with permission from ref 369. Copyright 2014 American Chemical Society.

case, it was considered that membrane transport of KCl takes place via K+/Cl− symport, K+/Na+ antiport, or Cl−/SO42− antiport. In order to elucidate the contribution of each transport mechanism, the efflux rates of both K+ and Cl− were monitored by K+-selective and Cl−-selective electrodes, respectively (Figure 186b). The Cl− efflux rate was very similar to, but slightly lower than, that of K+. These findings led to the suggestion that K+/Cl−symport is highly favored but that K+/Na+ antiport could well be occurring. 3.3.2. Bulk Liquid Membrane Transport. Several ion pair receptors have been reported that are able to transport ion pairs or zwitterionic amino acids across a liquid bulk membrane. For example, in 1996, Sessler and Andrievsky synthesized the sapphyrin−lasalocid conjugate 292 (Figure 187) and investigated its ability to transport zwitterionic aromatic amino acids through a model membrane.370 In this case, the sapphyrin moiety is involved in recognition of the carboxylate while the lasalocid moiety is responsible for the binding of the ammonium components. The transport experiments were conducted using a U-tube model membrane system in which a CH2Cl2 layer containing receptor 292 was used to separate two aqueous phases. Initial amino acid transport rates (kt in units of 10−5 mol cm−2 h−1) facilitated by receptor 292 were measured to be 20 for L-Phe, 12.7 for D-Phe, BK


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Table 14. Tryptophan Flux Values for Transporters 293 and 294−297 (Based on 24 h Measurements)371

a

transporter

fluxa

293 294 295 296 297 298

2.04 32.5 54.9 109 9.92 62.5

The unit for influx is (mol/second/mol carrier/m2) × 10−4.

phenylalanine.372 Tests were carried out using a U-tube setup wherein the source and receiving aqueous solutions were separated by a 1,2-dichloroethane or dichloromethane organic phase containing the putative transporters. Receptors 299− 304 contain a bicyclic chiral guanidinium framework designed to recognize the carboxylate component. The guanidinium moiety is functionalized via ester or amide linkages with crown ethers or lasalocid A moieties designed to act as ammonium binding domains. These receptors also contain aromatic or hydrophobic subunits that were expected to provide additional interactions with the aromatic groups of various amino acids (Figure 189). Experiments carried out using a U-tube model

Figure 187. Chemical structure of conjugate 292, a ditopic receptor developed as a transporter for aromatic amino acids.

5.0 for L-Trp, and 4.2 for D-Trp, respectively, at neutral pH. On the basis of these findings, it was suggested that receptor 292 is able to act as a selective transporter for phenylalanine, particularly in its D-form. In 2001, Coucouvanis et al. synthesized 4,5-bis(3,5-di-tertbutylsalicylideneimine)benzo-18-crown-6 (293) and reported that it formed stable Mn3+ complexes. These complexes, in turn, could interact with anions via Mn3+−X− coordination (X− = Cl−, I−, CH3COO−, (CH3)3CCOO−, and BPh4−) to form complexes of general structure [2932−·Mn3+·X−]. These species (294−298) were found to facilitate the transport of zwitterionic tryptophan across a CH3Cl bulk membrane separating two aqueous phases (Figure 188).371 Mechanistic

Figure 188. Receptor 293 and its complexes 294−298 used for the transport of tryptophan across a bulk liquid membrane.

studies provided support for the conclusion that both the crown ether moiety and the metal center of transporters 294− 298 play important roles in mediating the transport of tryptophan by binding the ammonium cation and the carboxylate anion, respectively. An analysis of the flux promoted by these transporters revealed that transporter 296, a system containing a relatively weakly bound anion, transports tryptophan with the greatest efficiency, while complex 297, containing an anion that is relatively tightly bound, was the least effective transporter (Table 14). Receptor 293 in its ion free form was not effective as a transporter for tryptophan. A number of guanidinium-based heteroditopic carriers, including receptors 299−304, were synthesized by de Mendoza and co-workers and tested as transporters for zwitterionic aromatic amino acids, such as tryptophan and

Figure 189. Guanidinium-based receptors 299−304 designed to act as enantioselective amino acid carriers. BL


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membrane system revealed initial transport rate constants (k in units of mol cm−2 h−1) of k = 6.8 × 10−6 for 299, k = 8.3 × 10−6 for 300, k = 2.0 × 10−6 for 303, k = 1.7 × 10−6 for 301, and k = 0.8 × 10−6 for 304, respectively, in the case of L-Trp. These transport experiments demonstrated that the carriers bearing an azacrown ether are superior to those based on a lasalocid subunit (Table 14). In addition, carrier 300 with an amide group was found to transport Trp most efficiently, presumably because the amide NH provides an additional hydrogen-bond donor for carboxylate anion recognition (Table 14). Analogous U-tube experiments were used to evaluate the ability of these carriers to transport chiral amino acids enantioselectivity. In these studies, saturated solutions containing racemic Trp or Phe were used in the source phase and the enantiomeric excess in the receiving phase was monitored by chiral HPLC (with a UV detector) until ca. 10% of the initial substrate had been transported. It was concluded that the ester-based carrier 299 was more effective than its amide-based congener 300 in spite of the fact that the former is an overall slower carrier (Table 15). A similar effect was seen

Figure 190. Structure of ion pair receptor 305 used to transport sodium anion salts across a bulk liquid membrane.

For example, receptor 305 proved capable of transporting highly hydrophilic anions, such as SO42− and OAc− (as the Na+ salts), more efficiently than other Na+ salts (Figure 191). This apparent ability to overcome the Hofmeister bias is noteworthy.

Table 15. Enantioselective Transport Results for Carriers 299−304372 receptor

time (h)

% Trp

% ee

time (h)

% Phe

% ee

299

2 3 6 2 3.5 20 1 2.5 4 2 4 9 13 15 20 15 17

1 2.5 10 1 8 44 0.5 6 12 1 1.5 7.4 1 2 3.5 0.5 1

28 34 22 0 0 0 32 26 26 12 12 10 14 14 10 2 0

3 4 5 2 6 21 2 3 6 2 4 5 3 4 6 4 5 7

3 4.5 5.2 8 10 50 4 5 12 1.5 3 4 1.5 2 4 1.5 3.5 5

20 24 24 2 0 0 20 18 14 6 8 6 14 12 16 8 4 4

300

301

302

303

304

Figure 191. Normalized initial fluxes (J* = J0/N0, J0 = initial flux and N0 = initial moles of salt in the source phase) promoted by receptor 305 as a function of the gas−water transfer Gibbs energy for different transported anions. Reproduced with permission from ref 373. Copyright 2003 American Chemical Society.

In 2014, Romański and co-workers reported the synthesis and ion binding properties of the ion pair receptor 306. This system contains an L-ornithine azacrown-6 moiety, a nitrophenyl urea, and trifluoroacetamide (Figure 192).341 1H NMR

for receptors 301 and 302. It was also found that the extent of the enantioselective transport by receptor 299 is highly dependent on the concentration of the carrier. Namely, lower concentrations of receptor 299 serve to transport Trp with higher enantioselectivity. For example, receptor 299 in 0.125 mM transports Trp with 79% ee after 3 h, while a 1.0 mM solution produced an ee of 16% under otherwise identical conditions. A receptor consisting of a benzocrown-5 subunit linked to urea (305) was synthesized as a Na+-selective ion pair receptor by Barboiu et al. in 2003 (Figure 190).373 A combination of 1H NMR spectroscopic analyses and single crystal X-ray diffraction studies revealed that receptor 305 is able to bind and solubilize sodium salts such as NaF, NaCl, NaNO3, and NaCF3SO3 in CDCl3. Bulk liquid membrane transport experiments using a U-tube system and a chloroform organic phase provided support for the proposition that in the case of receptor 305 synergetic sodium anion salt (NaX) recognition is closely related to its ability to act as a carrier for NaX salts.

Figure 192. L-Ornithine-based ion pair receptor 306 and its proposed binding mode for NaNO2.

spectroscopic analyses revealed that precomplexation with Na+ improves the ability of receptor 306 to bind anions, such as Br−, NO2−, and NO3−. For example, the association constant for NO2−, Ka = 1450 M−1 for the ion-free receptor 306 in CDCN3, was enhanced to Ka = 19,000 M−1 (a 13.1-fold increase) in the presence of Na+. In this case, the NO2− anion is hydrogen-bonded to the urea NH protons as well as to the trifluoroacetamide NH proton (Figure 192). Transport experiments using a bulk liquid membrane (chloroform) and an aqueous source phase containing 1 M aqueous NaNO2 BM


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revealed an initial flux of 2.26 × 10−6 mol m−2 s−1, leading to the conclusion that receptor 306 is capable of transporting NaNO2 across a bulk liquid membrane. In 2017, Jurkschat and co-workers synthesized the organotin-based heteroditopic receptor 307 and evaluated its ability to transport KF across a bulk liquid membrane.374 Receptor 307 is composed of a Ph2FSnCH2SnFPh subunit and a 19crown-6 ether covalently linked to one another via a methylene tether (Figure 193).374 119Sn, 19F, and 1H NMR and ESI-MS

the receiving phase, the quantity of the KF transported by receptor 307 (0.37 M) was estimated to be 15.3% while the corresponding value for the mixed receptor (or so-called dual host) system consisting of 308 + 309 was only 2.8%. These findings underscore the benefits associated with using an ion pair receptor, at least in this instance. 3.3.3. Supported Liquid Membrane Transport. Several ion pair receptors were developed for transport of specific ion pairs through supported liquid membranes. For example, in 1995, Reinhoudt et al. reported the ion pair receptor 310 consisting of a 1,3-alternate calix[4]arene crown-6 as a Cs+selective binding site and a Lewis acidic uranyl (UO2)2+ group for anion recognition (Figure 195).375 For comparison, these

Figure 193. Chemical structures of the organotin-based ion pair receptor 307 and its control compounds 308 and 309. A proposed binding mode for receptor 307 interacting with KF is also shown.

spectroscopic analyses provided evidence that receptor 307 forms a strong and selective complex with KF in acetonitrile, wherein the K+ cation is bound to the crown ether moiety while the F− anion is coordinated to the Lewis acidic Sn atom. U-Tube-type transport experiments involving a 0.37 M aqueous KF source phase and a chloroform liquid membrane containing receptor 307 revealed that after 14 days the conductivity in the receiving phase was 3450 μS cm−1 and that the conductivity increased on the order of 8.9 μS cm−1 h−1. This latter value is 5.6 times higher than that obtained for an equimolecular mixture of control compounds 308 and 309 (1.6 μS cm−1 h−1) (Figure 194). By comparing the initial conductivity of the source phase with the final conductivity of

Figure 195. Ion receptor 310 and its control compounds 311 and 312.

researchers also prepared the control compounds 311 and 312 lacking a calix[4]arene crown-6 and a uranyl group, respectively. The ability of these putative receptors to transport CsCl and CsNO3 was evaluated using a supported liquid membrane (or SLM). The SLM used consisted of a porous polymeric support (Accurel) impregnated with o-nitrophenyl n-octyl ether (NPOE) designed to act as a hydrophobic barrier. A higher rate of flux through the hydrophobic membrane containing receptor 310 was observed for CsCl (1.20 × 10−7 mol m−2 s−1) than for CsNO3 (0.89 × 10−7 mol m−2 s−1). The value for CsCl with receptor 310 is significantly higher than those recorded when compounds 311 (0.07 × 10−7 mol m−2 s−1) or 312 (0.42 × 10−7 mol m−2 s−1) were tested. Receptor 312, a system lacking an anion binding site, displayed a higher selectivity for CsNO3 over CsCl. Taken in concert, these results provide support for the conclusion that the presence of both anion and cation recognition sites is necessary to achieve efficient CsCl binding and transport. The same research group also reported the ion pair receptors 313 and 314 based on calix[4]arene crown ethers and evaluated their ability to transport KCl and CsCl through a SLM.376 The SLM used in this study consisted of a polymeric Accurel 1E-PP film in which the receptors dissolved in NPOE were immobilized. Receptors 313 and 314 contain 1,3alternate calix[4]arene crown-5 and -6 as the cation binding domains and two parallel thiourea groups for anion recognition. In contrast, control compounds 315, 316, and 317 lack the cation binding site or anion recognition site (Figure 196). Transport experiments revealed that an equimolecular mixture of 315 and 317 transports CsCl more efficiently than the monotopic receptor 317. This finding

Figure 194. Plot of the conductivity vs time showing the KF transport activity of the ion pair receptor 307 and the dual host system consisting of an equimolar mixture of 308 and 309. The concentration of KF in the source phase was 0.37 M. Reproduced with permission from ref 374. Copyright 2017 Royal Chemical Society. BN


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Figure 197. Structures of heteroditopic ion pair receptor 71 and control monotopic receptors 318 and 319.

mM) and a source phase containing a mixture of LiCl, NaCl, and KCl (1 M each). After 3 h of transport, the salt ratio in the receiving phase was observed to be 81% KCl, 19% NaCl, and 0% LiCl. KCl transport fluxes were also evaluated and compared using SLMs containing ion pair receptor 71 (50 mM), cation receptor 318 (50 mM), anion receptor 319 (50 mM), and an equimolecular mixture of 318 (50 mM) and 319 (50 mM), respectively. A 1 M aqueous KCl solution was used as the source phase. As summarized in Table 17, the ditopic receptor

Figure 196. Chemical structures of heteroditopic ion pair, anion, and cation receptors 313−317 tested as ion and ion pair transporters using SLMs.

provided support for the notion that the cooperative recognition of CsCl by 315 and 317 could promote efficient CsCl transport. In addition, it was demonstrated that the heteroditopic receptors 313 and 314 were able to transport KCl (J0 (flux rate) = 3.9 × 10−7 mol m−2 s−1) and CsCl (J0 = 4.1 × 10−7 mol m−2 s−1), respectively. Presumably, this reflects an ability to complex concurrently both the cation and the anion. It was also noted that, at low salt concentration ([CsCl] < 0.1 M), the ion pair receptor 314 is able to transport CsCl much more efficiently than either the anion receptor 315 or the cation receptor 317. However, at high concentrations of KCl ([KCl] > 0.3 M), the ion pair receptor 313 was found to be less effective than the cation receptor 316. This seemingly nonintuitive result was ascribed to an unexpectedly low diffusion rate for the KCl complex of the bifunctional carrier (317). Smith and co-workers also carried out transport experiments using SLMs and assessed the ability of receptor 71 to transport alkali metal halide salts through SLMs.315,366 In these studies, the receptors were dissolved in NPOE and the resulting organic liquid was immobilized in a thin, flat sheet of porous polypropylene. The resulting SLM transport studies revealed that heteroditopic receptor 71 can transport alkali metal halide salts up to 10-fold more rapidly than does the monotopic cation receptor 318 (Table 16). Both transport systems (Figure 197) involving carriers 71 and 318, respectively, showed the same qualitative order of ion selectivity, namely, K+ > Na+ > Li+ for a constant counteranion and I− > Br− > Cl− where the cation was held invariant. A competitive transport experiment was also performed using a SLM containing 71 (50

Table 17. Initial KCl Transport Flux Values for SLMs Containing Different Receptorsa 376 flux (×10−8 mol m−2 s−1)

LiCl NaCl KCl LiBr NaBr KBr LiI NaI KI

71 6 37 90 10 32 111 7 43 160

± ± ± ± ± ± ± ± ±

6 5 12 6 3 20 7 27 40

± ± ± ± ± ± ± ± ±

319

71 + 319

18 ± 1

50 ± 2

Source phase, 1 M KCl; membrane, 50 mM receptor in NOPE; receiving phase, water. T = 25 °C.

71 was found to transport KCl twice as quickly as did an equimolecular mixture of 318 and 319. This outcome stands in contrast to what was observed for receptors 313−317 as reported by Reinhoudt and co-workers.376 There are likely two contributing factors underlying this seeming contradiction. First, because the KCl complex of receptor 71 ([71·KCl]) is smaller than that of the binary mixture of [319·K+] and [319· Cl−], the diffusion constant of the [71·KCl] complex is expected to be higher. Second, the polarity of the [71·KCl] complex is likely relatively low because the ion pair is encapsulated within the receptor as a contact ion pair. With the goal in mind of transporting Na2CrO7 and Na2SO4 through a SLM, Morzherin et al. prepared the calix[4]arenebased heteroditopic ion pair receptor 320 as well as control compounds 321 and 322 (Figure 198).377 Ion pair receptor 320 contains a calix[4]arene functionalized via the lower rim with four ethyl esters designed to function as a Na+-selective binding domain. The upper rim also bears tetrakis-sulfamide groups for an anion recognition. The SLM employed consisted of a porous polytetrafluoroethylene support impregnated with a NPOE solution containing the test receptors. Transport of

318 1 2 3 1 2 3 1 2 5

318 12 ± 1

a

Table 16. Initial Transport Fluxes (×10−8 mol m−2 s−1)a 315 carrier

71 90 ± 3

1 1 1 1 1 1 1 2 2

a

Source phase, 1 M salt; membrane, 50 mM receptor in NOPE (onitrophenyl n-octyl ether); receiving phase, water. T = 25 °C.

Figure 198. Structures of heteroditopic ion pair receptor 320 and monotopic 321 and 322. BO


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Na+ salts across the SLM was monitored by measuring the conductivity of the receiving phase. The ditopic receptor 320 was found to transport Na2CrO7 and Na2SO4 much more efficiently than the monotopic receptors 321 and 322 (Table 18). For example, the initial flux of Na2SO4 with receptor 320 proved to be 65 and 92 times higher, respectively, than the corresponding values with receptors 321 and 322 (Table 18). Table 18. Initial Flux Values for Various Salts Promoted as Inferred from SLM Studies377

Figure 199. Chemical structure of the NaH2PO4 receptor 323 that displays AND logic features.

flux (mol m−2 s−1) carrier blank 320 321 322

Na2CrO7 7.50 1.23 9.60 5.66

× × × ×

10−10 10−6 10−8 10−8

Na2SO4 7.35 4.37 6.72 4.72

× × × ×

10−10 10−5 10−7 10−7

sodium and phosphate ions (as NaH2PO4 at 0.1 M), the fluorescence output increases significantly even under alkaline conditions (pH ≤ 8.5).3 This difference in fluorescence compared with the free receptor at the same pH values was ascribed to perturbations in the otherwise operative PET process. Consistent with this proposed mechanism, the fluorescent output was low when only one of the inputs (A or B) was present (e.g., treating 323 with NaCl or TBAH2PO4, where Cl− and TBA+ function as innocent counterions). Hence, receptor 323 behaved as a photoionic AND logic gate system, where the presence of both the sodium and phosphate ions were required as inputs to obtain a strong fluorescent response. Beer and co-workers reported the heteroditopic calix[4]diquinone receptors 324−326 (Figure 200a) and showed that

3.4. Ion Pair Recognition-Based Logic Gates

Molecules capable of performing logic operations have been actively explored since the 1990s.378 In their simplest embodiment, these operations rely on the chemical bonding of a guest (the “input”) that induces a photonic response or a redox change in the receptor (the “output”).378,379 More complex arrangements are now known, and a variety of observable outputs, such as changes in absorption, fluorescence, or redox potentials, have been exploited in the context of chemical logic device design. A range of logic functions, including AND, NOR, XOR, NAND, INHIBIT, YES, and NOT, have been demonstrated using molecular systems that react to a particular ion or ion pair.379 Many of the possibilities are shown in Table 19. However, we Table 19. Truth Table for Logic Gates Involving Two Inputs379

encourage the reader to consult the review by Szacilowski to obtain further insights into the basic concepts underlying these logic functions.379 Here, we discuss briefly molecular logic gates based on ion pair recognition by macrocyclic hosts. In 2003, Pagliari, de Silva, and co-workers reported the detection of NaH2PO4 in a methanol/water mixture (1:1, v/v) by the heteroditopic receptor 323. This system contains a benzo-15-crown-5 ether as well as anthrylpolyamine moieties and was found to exhibit AND logic gate behavior (Figure 199).380 In the absence of any of the two inputs (i.e., Na+ (“A”) and H2PO4− (“B”)), the fluorescence output of receptor 323 is low. This inherent fluorescence was found to be pH dependent. For instance, under basic conditions, the fluorescence is largely quenched via a process ascribed to photoinduced electron transfer (PET) from the benzylic amine lone pair to the excited state of the anthracene moiety. However, in the presence of a high concentration of both

Figure 200. (a) Structure of calix[4]diquinone receptors 324−326. (b) Single crystal structure of receptor 324 and its ion pair complex [324·NH4Cl]. This figure was reproduced using data downloaded from the Cambridge Crystallographic Data Centre (CCDC Nos. 289857 and 683885). The acetonitrile solvent molecules have been removed for the sake of clarity. BP


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observed. In this case, the input defined as “B” is followed by “A” to give an “OFF” response. With monitoring carried out at 370 nm, this was considered analogous to a “BAOFF” logic signal or an incorrect entry into a keypad-type lock (Figure 201b). Chung and co-workers prepared the triazole-containing calix[4]arene receptor 328 (Figure 202), which was designed

they acted as a Boolean AND logic gate.381−383 Anion binding analyses carried out via 1H NMR spectroscopy in CD3CN revealed that 324 displayed no appreciable affinity for chloride anion (as the TBA salt).381 However, in the presence of cationic species, such as Na+, K+, and NH4+, a 1:1 complex was seen to form with stability constants >104 M−1.381 The dramatic enhancement in affinity for the chloride anion was recapitulated in the case of the bromide anion. UV−vis spectroscopic analyses of the quinone n−π* absorption band led to the conclusion that the binding of Na+, K+, and NH4+ was enhanced in the presence of a chloride anion source.381 In the specific case of Na+ and NH4+, little appreciable cation affinity was seen when the corresponding hexafluorophosphate salts were tested. This lack of affinity was ascribed to strong intramolecular hydrogen-bonding interactions between the quinone and the isophthalamide moieties that are only effectively disrupted upon binding a suitable ion pair. A single crystal X-ray structure of the ion pair complex [324·NH4Cl] (Figure 200b) was obtained. It revealed the expected contact ion pair binding with the chloride anion being coordinated through two amide NH protons and one isophthalamide proton via hydrogen bonding.382 In contrast, a solid state structure of the free receptor revealed interactions between a quinone oxygen atom and the isophthalamide amide protons.381 The increase in cation affinity seen in the presence of a chloride anion source is fully consistent with AND logic gate behavior.381,382 In 2009, Kumar, Bhalla, and co-workers reported the thiacalix[4]arene chemosensor 327 (Figure 201a). This system

Figure 202. Structure of the triazole-containing calix[4]arene receptor 328.

to produce an output when exposed to Ca2+ and F− ions as inputs.385 The triazole moieties in 328 were found to coordinate efficiently with Ca2+, Pb2+, and Ba2+ ions (studied as their perchlorate salts in MeCN/CHCl3 (v/v = 1000:4)) over other double charged metal cations, including Hg2+, Mn2+, Mg2+, Zn2+, and Ni2+, or single charged metals, such as Li+, Na+, K+, and Ag+. In particular, it was observed that, upon addition of 10 equiv of Ca2+,385 the absorption spectrum of 328 underwent a bathochromic shift from 390 to 496 nm with the Pb2+ and Ba2+ ions also producing a shift. The maximum absorption change and affinity trend seen for 328 was Ca2+ > Pb2+ > Ba2+.385 In the same solvent mixture, the anion binding properties of 328 toward single charged anions (i.e., F−, Cl−, Br−, HSO4−, AcO−, and H2PO4−, as their TBA salts) were likewise studied. It was found that the F−, AcO−, and H2PO4− anions led to a bathochromic shift in the λmax per the following intensity trend: F− > AcO− > H2PO4−. The fluoride anion produced the highest bathochromic shift (from λmax = 390 to 626 nm; Δλmax = 236 nm), with substantial but smaller shifts being seen for the AcO− and H2PO4− anions.385 When up to 10 equiv of fluoride anion was added to the [328·Ca2+] complex, no red absorption band at 626 nm was obtained.385 Very different optical responses were displayed by 328 in the presence and absence of the Ca2+ and F− ions used. The authors noted that formation of [328·Ca2+] produced a color change from green to bright yellow. This color remained unchanged upon the addition of F− ions. This response function mimics a YES logic gate, where a single input device delivers an output signal dictated by a single input. In the case of 328, exposure to 10 equiv of the inputs Ca2+ (A) or F− (B), or an equimolar mix of both ions, produced a color change (from green to bright yellow) that reflects formation of the [328·Ca2+] complex, as per the logic truth table in Table 20. However, the addition of 10 equiv of F− (input B) produced a color change from green to bluish, corresponding to an INHIBIT logic gate, as shown in Table 20. Although

Figure 201. (a) Structure of the ion pair chemosensor 327 and (b) schematic representation of the key pad lock based on the receptor 327 response to Cu2+ or F−.

exhibited a fluorescence response in tetrahydrofuran (THF) solution that mimics that of a keypad lock.384 Specifically, a low fluorescence signal is observed in dry THF when compound 327 is treated with a Cu2+ ion source, as its perchlorate salt (to form a 1:1 complex, [327·Cu2+]). Other metal cations, such as Li+, Na+, K+, Zn2+, Cd2+, Ni2+, Pb2+, and Ag+ (as their perchlorate salts) at 100 μM, produced little change in the fluorescence. The quenched fluorescence seen with Cu2+ was recovered when F− ions (as the TBA salt) were added to the solution. This restoration in the fluorescence signal was ascribed to the binding of the F− to the Cu2+ center and a redistribution in the energy levels in the [327·Cu2+] complex that are responsible for the emission quenching. In the event, the Cu2+ ion could be considered as an input that produces state “A”. Treatment with F− (as input “B”) then produced an “ON” emission at 370 nm, as shown in Figure 201b. In contrast, when Cu2+ ions were added to a solution containing [327·F−], a fluorescence quenching response was BQ


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In 2013, Park, Sessler, and co-workers exploited a selfassembly approach to produce a NAND-logic gate.386 To achieve this, the electron-rich tetrathiafulvalene (TTF)substituted calix[4]pyrrole 329 was used in conjunction with an electron deficient trans-bis(methylpyridinium)-meso-substituted calix[4]pyrrole 330 (as its iodide salt) to create selfassembled materials (Figure 204a). Three limiting equilibrium

Table 20. Truth Table for the Receptor 328 in the Presence of the Inputs A and B385 output

output

input

input

(A) YES

(B) INHIBIT

(A) Ca2+

(B) F−

496 nm

626 nm

0 1 0 1

0 0 1 1

0 1 0 1

0 0 1 0

compound 328 does not function as a ditopic receptor for CaF2 per se, this system represents an example of a molecular switch where both anion and cation inputs play a critical role. In 2010, Sessler, Lee, Kim, Delmau, Hay, and co-workers reported a calix[4]arene-strapped calix[4]pyrrole ion pair receptor 120 (previously mentioned in section 2.4) that mimics a cooperative AND logic gate (Figure 203).180

Figure 204. (a) Structure of the TTF-calix[4]pyrrole 329 and the bispyridinium calix[4]pyrrole 330. (b) Schematic representation of the self-assembled NAND logic gate [329·330]n and ion pair complex [329·TEAI]. This latter figure was reproduced in part with permission from ref 386. Copyright 2013 American Chemical Society.

states (i.e., monomer, capsule, and oligomer) could be accessed. The oligomeric form, [329·330]n, characterized by a lower energy charge-transfer (CT) band, was obtained by simply mixing 329 and 330 in chloroform. Exposure of [329· 330]n to the iodide anion (I−) and the tetraethylammonium (TEA+) cation gave rise to the near-complete dissociation of the oligomer and production of “monomers” (i.e., 329 and 330). This disassembly resulted in the loss of the CT band due to sequestration of the TEA within the bowl-like cavity found for the cone conformation of 330 (Ka(TEAI) = 1.5 × 105 M−1).386 Use of TBA salts led to stabilization of a capsulelike form, again chracterized by a CT band. Structural support for the states in question was obtained. This three-state switchable behavior corresponds to a NAND logic gate (Figure 204b) wherein a false response is produced only if all needed inputs are present.386 A heteroditopic boron dipyrromethane (BODIPY) dye 224 (previously mentioned in section 3.1.4) was reported by Costero, Rurak, and co-workers.387 This system bears alkali metal ion and anion binding sites and was found to exhibit multiple logic gate operations controlled by ion pair recognition (Figure 205). The K+ and F− ions (expected to be bound to the aza-oxa crown and the calix[4]pyrrole moieties, respectively) were used as chemical inputs, while light was used as an output. In this case, the intramolecular charge transfer (ICT) features were found to depend on ion binding. Moreover, emission spectroscopic analyses at 680 nm in acetonitrile revealed that receptor 224 functioned as an XOR logic gate.387 This conclusion was based on the fact that receptor 224 in both its ion-free form (0,0 state) and as an ion pair complex, e.g., [K+·224·F−] (1,1 state), gives rise to a weak emission signal, whereas exposure to only a single input (K+ cation or F− anion but not both) resulted in a high emission signal as long as noncompeting counterions were employed. This system could be converted into an OR gate by adjusting the “on” threshold limit from 25 to 10% of the transmittance. Moreover, the system behaved as an AND gate when an

Figure 203. Proposed CsF ion pair complex formed from receptor 120. Also shown is its AND logic gate behavior.

Receptor 120 contains a strong anion-binding site with a weak cation recognition site. 1H NMR spectroscopic titrations and ITC studies of 120 with CsF in methanol/chloroform solution (1:9 v/v) provided data consistent with the formation of an ion pair complex. In this complex, it was proposed that the phenoxy groups stabilize Cs+ cation complexation with the pyrrolic NH protons interacting with the co-bound F− anions through hydrogen bonds. A Ka of 1.3 × 104 M−1 was calculated.180 Exposure of receptor 120 to perchlorate salts of other metal ions, such as those of Li+, Na+, K+, and Rb+, led to no discernible spectral changes. Likewise, no evidence of binding was seen when TBAF was added to receptor 120. This finding provides support for the notion that the F− anion binds to 120 effectively only in the presence of Cs+. Single crystal Xray diffraction studies revealed that receptor 120 forms a stable 1:1 CsF complex with a solvent molecule serving to bridge the ions. BR


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system as an AND logic gate. Treating complex [Na·331· HSO4] with water restored the fluorescence and led to the consideration that receptor 331 could function as a reversible system suitable for extraction studies. Solid−liquid extraction experiments were carried out and led to the conclusion that receptor 331 could be used to extract NaHSO4 salts into dichloromethane solution. No discernible emission quenching was obtained in the presence of other salts, such as Na2SO4, NaF, NaCl, and NaH2PO4, exposure to which maintained the system in the “ON” state (cf. Figure 206b).

4. CONCLUSIONS AND OUTLOOK Over the last 30 years or so, ion pair recognition chemistry has emerged as a fast growing subdiscipline of research with roots in seminal studies involving cation complexation and anion binding chemistry. It has blossomed because of the fundamental properties of the receptors in question involving the concurrent recognition of both cations and anions. This differs in concept from more classic cation and anion recognition chemistry, where the focus is typically placed on complexing a single ion. This review has attempted to highlight efforts to achieve ion pair recognition using macrocycles as the ion pair receptors. Where appropriate, applications of the resulting systems in sensing, extraction, specific salt separations, and transport have been noted, as well as the use of such systems as the starting point for logic gates construction. Considerable attention has been paid to the rational designs and syntheses of ion pair receptors for specific ion pairs, such as alkali metal halide salts.25−27,389−391 However, longer term, a broader set of ion pairs will need to be considered. On a mechanistic level, it is noteworthy that cooperativity in ion pair recognition is generally seen, underscoring the benefits associated with the co-binding of positive and negative ionic targets.173,392,393 Areas that have witnessed particular growth in recent years include the development of extractants for LiCl, NaCl, KCl, CsOH, and Cs2CO3, which may have important practical and commercial implications.322,361,364 We foresee a challenging but bright future for ion pair recognition chemistry. We predict that steady progress will lead to a further blooming of this field. Nevertheless, there is much to do to realize this promise. Current challenges facing researchers in the area include the following: (1) Recognition of so-called “hard” ion pairs, such as LiF, NaOH, and LiOH, as well as salts of various oxoanion species (e.g., sulfate and carbonate). These “hard” ion pairs contain anions and cations that both have high hydration energies. This disfavors host− guest interactions in aqueous media. Moreover, these ion pairs are characterized by strong electrostatic interactions between the constituent ionic species, something that makes the task of effective receptor-based recognition particularly challenging from an energetic perspective. To overcome these barriers, new powerful ion pair receptors with exceptional binding affinities are needed. (2) Improving ion pair recognition efficiency and specificity. Relative to what is seen in natural ion recognition systems, the efficiency and specificity achieved with synthetic constructs remains less than ideal. (3) Using ion pair receptors more effectively in various real-world applications. Ultimately, one would like to see ion pair receptors used to achieve state-of-the-art separations in a technologically and economically viable manner. This could allow a specific component to be separated out from the bulk contents of a mixture. One example where such an ability might prove transformative involves lithium purification. Current methods

Figure 205. (a) Structure of the heteroditopic BODIPY-based receptor 224. (b) Inputs and outputs used to produce the logic functions: XOR and OR, (c) INHIBIT and (d) AND. This picture was reproduced in part with permission from ref 387. Copyright 2013 Royal Society of Chemistry.

output absorption signal at λ = 395 nm was selected.387 Monitoring the absorbance signal at 650 nm, where the highest single input response (produced by K+ or F−) was seen, yielded an INHIBIT gate. Finally, an IMPLICATION gate could be achieved by negation of the INHIBIT gate. In 2017, Cho and co-workers reported a diphenylacetylene (tolan) derivative 331 that functioned as an ion pair receptor and which exhibited AND logic gate function when allowed to interact with the Na+ or Li+ cations and the HSO4− anion (Figure 206a).388 This receptor contains an aza-crown-5

Figure 206. (a) Structure of the ditopic tolan-based receptor 331. (b) Fluorescent signal changes from an ON to an OFF state as seen after the solid−liquid extraction of NaHSO4. This picture was reproduced in part with permission from ref 388. Copyright 2017 Royal Society of Chemistry.

subunit for cation recognition and a urea motif for anion complexation connected to a tolan dye. The net result is a system that was expected to produce an optical response depending on the ionic inputs. Fluorescence titrations in CH3CN revealed that receptor 331 was poorly emissive (“OFF” state) when exposed to Na+ or Li+ (added as the (Ph)3B and ClO4− salts, respectively) in the presence of 1 equiv of HSO4− ions (as its TBA salt). It was emissive in the absence of both inputs. It was proposed that cooperative binding of the HSO4− anion contributes to an enhancement in the binding constants (Ka Na/LiHSO4 = 2.3 × 104 M−1 for Na+ and Li+ vs Ka Na(Ph)3B/LiClO4 = 5.0 × 103 M−1).388 The selectivity of 331 for Na/LiHSO4 salts and the emission quenching seen upon the formation of complexes of general structure [M·331· HSO4] (where M = Na or Li) allowed the authors to use the BS


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for recovering lithium from common brine sources require that over 99% of the brine be discarded. This renders the process economically nonviable. Lithium salt-specific ion pair extractants might allow lithium salts to be captured directly from the brine source. New ion pair receptors might allow this and other desirable separations to be achieved, including those associated with the recycling of economically important materials from postconsumer sources, the modulation of pH, or the remediation of pollutants found in nature or in spent nuclear wastes. Last but not least, new receptors that allow for the recognition of complicated guest species, such as those containing complex multiatom ions or those important in catalysis, would likely help drive the field forward. It is hoped that the present review has provided the groundwork for addressing these and other ion-recognition-related challenges.

Kim. He is currently a graduate student pursuing a Ph.D. degree at the same university and working in the group of Prof. Sung Kuk Kim. His research interests are in the development of cation and ion pair receptors using calix[4]arene and calix[4]pyrrole frameworks. Sung Kuk Kim earned his Ph.D. degree from the University of Texas at Austin in 2011 under the supervision of Prof. Jonathan L. Sessler. After working as a postdoctoral researcher in the same research group, he joined the faculty in 2005 at Gyeongsang National University where he is currently an associate professor. His research interests include the development of synthetic receptors for anions, cations, and ion pairs as well as neutral molecules. Jonathan L. Sessler received a B.Sc. degree in Chemistry in 1977 from the University of California, Berkeley. He obtained his Ph.D. from Stanford University in 1982. He was an NSF-NATO and NSF-CNRS Postdoctoral Fellow at the Université Louis Pasteur de Strasbourg (1982−1983). In 1984, he accepted a position as an Assistant Professor of Chemistry at The University of Texas at Austin, where he is currently the Doherty-Welch Chair. Prof. Sessler is Director of the Institute for Supramolecular Chemistry and Catalysis of Shanghai University. He is working in the areas of supramolecular chemistry and expanded porphyrin chemistry. Home page: http://sessler.cm. utexas.edu.

AUTHOR INFORMATION Corresponding Authors

*E-mail: *E-mail: *E-mail: *E-mail:

[email protected]. [email protected]. [email protected]. [email protected].

ORCID

ACKNOWLEDGMENTS Work on this review was supported by the Center for Supramolecular Chemistry and Catalysis, Shanghai University, the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, Separation Science program under Award Number (DE-FG02-01ER15186 to J.L.S.), the National Institutes of Health (R01 GM 103790 to J.L.S.), and the Robert A. Welch Foundation (F-0018 to J.L.S.); this funding is acknowledged with gratitude. Further support for this work was provided by the Basic Science Research Program (2017R1A4A1014595 to S.K.K.) funded by the National Research Foundation (NRF) under the Ministry of Science, ICT & Future Planning of Korea. This work was also supported by the Fundamental Research Funds for the Central Universities (Startup funding for Q.H.)

Qing He: 0000-0003-3117-9587 Sung Kuk Kim: 0000-0001-6995-1144 Jonathan L. Sessler: 0000-0002-9576-1325 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest. Biographies Qing He was born and grew up in the small village of Chenzhou, located in the south of Hunan province, China. He completed his B.Eng. degree in pharmaceutical engineering in 2010 at Hunan Normal University and obtained his Ph.D. degree in chemistry in 2015 at the Institute of Chemistry, Chinese Academy of Sciences (ICCAS), under the supervision of Acad. Prof. Zhi-Tang Huang and Prof. De-Xian Wang. He then moved to The University of Texas at Austin to work in the laboratory of Prof. Jonathan L. Sessler as a postdoctoral fellow. In November of 2018, he joined the College of Chemistry and Chemical Engineering at Hunan University, where he is currently a full professor. His research interests focus on the development of new functional macrocycles and supercycles for molecular recognition, sensing, mass transport, extraction, assembly, catalysis, and ion manipulation, as well as their applications in the areas of critical material development, energy, environment, and biology.

ABBREVIATIONS TMA tetramethylammonium TEA tetraethylammonium TBA tetrabutylammonium NMR nuclear magnetic resonance NOE nuclear Overhausser effect FAB fast atom bombardment MS mass spectrometry DMSO dimethyl sulfoxide CCDC Cambridge Crystallographic Database Centre DFT density functional theory TFPB tetrakis[3,5-bis(trifluoromethyl)phenyl] borate Cycle 1,4,7,10-tetraazacyclododecane ITC isothermal titration calorimetry ESMS electrospray mass spectrometry ESI-MS electrospray ionization mass spectrometry ESP electrostatic surface potential MP2 second order Møller−Plesset perturbation theory CuAAC copper-catalyzed azide−alkyne cycloaddition GABA γ-aminobutyric acid Phe phenylalanine Gly glycine Trp tryptophan

Gabriela I. Vargas-Zúñiga received her B.Sc. and M.Sc. in Chemistry from the National Autonomous University of Mexico, Mexico City. She earned her Ph.D. degree from the University of Texas at Austin in 2013 under the supervision of Prof. Jonathan L. Sessler. She is currently a research associate in the same group. Her research interests include synthetic anion and ion pair receptors that can be used for sensing, for extraction, and as building blocks for supramolecular polymers. Seung Hyun Kim received his M.S. degree from Gyeongsang National University in South Korea under the supervision of Prof. Sung Kuk BT


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valine high performance liquid chromatography leucine tyrosine isoleucine alanine arginine aspartic acid proline histidine asparagine photoinduced electron transfer o-(carboxamido)trifluoroacetophenone gold nanoparticles diffusion ordered spectroscopy X-ray diffraction dioctanoyl-L-α-phosphatidylcholine phosphatidylcholines phosphatidylethanolamines 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine dodecylphosphocholine cyclotriveratrylene circular dichroism tris(2-aminoethyl)amine solid−liquid extraction liquid−liquid extraction inductively coupled plasma mass spectrometry flame emission spectroscopy atomic absorption spectroscopy transmission electron microscopy dynamic light scattering energy-dispersive X-ray analysis o-nitrophenyl n-octyl ether

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