AnionâÏ Interactions with Fluoroarenes - Chemical Reviews (ACS

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Anion−π Interactions with Fluoroarenes Michael Giese,*,† Markus Albrecht,*,‡ and Kari Rissanen*,§ †

Institut für Organische Chemie, Universität Duisburg Essen, Universitätsstraße 7, 45141 Essen, Germany Institut für Organische Chemie, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany § Department of Chemistry, Nanoscience Center, University of Jyvaskyla, P.O. Box. 35, FI-40014 Jyvaskylan yliopisto, Finland mentary subunits to form functional aggregates is a powerful tool to obtain new materials and nanoscaled devices.2 Therefore, a thorough understanding of noncovalent interactions is essential. In numerous chemical processes, noncovalent interactions involving arenes are of crucial relevance.3,4 A large number of crystal structures reveal the role of aromatic interactions in drug recognition, protein folding, and crystal engineering.5 An undisputable example for these interactions is π−π stacking of aromatic units in the side chains of amino acids6 or in DNA and RNA.7 In addition to π−π stacking, other noncovalent interactions such as CH−π,8−11 lone-pair−π12−14 or cation−π bonding15 have been found to be important in biochemical recognition processes and in the stabilization of secondary, CONTENTS tertiary, or quaternary structures of biological macromolecules. Complementing the biological relevance of aromatic inter1. Introduction A actions, a large number of studies and reports manifest their 2. Computational Investigations B relevance in organic synthesis and reaction control.16−19 2.1. Origin of Anion−π Interactions B Unlike cation−π interaction, the anion−π interaction 2.2. Fluoroarenes As Electron-Deficient Aroremained unnoticed for many years, due to its intuitively matics C repulsive nature. The first experimental evidence for this 2.3. Influence of the Anion D 2.4. Hapticity of Anion−π Interactions D interaction was given by Schneider et al.20 Computational 2.5. Additivity of Anion−π Interactions E studies by Mascal, Alkorta, Deyà, and co-workers finally 2.6. Interplay of Anion−π with Other Nonrevealed the attractive nature of the interaction between anions covalent Interactions F and electron-deficient arenes, and thus the term anion−π 2.6.1. Anion−π, Cation−π, and π−π Interacinteraction was introduced.21 Some fundamental work was tions F published in 2002 that brought the anion−π interaction into 2.6.2. Anion−π Interactions and Halogen the focus of computational as well as experimental invesBonding F tigations.22−27 The aim of recent studies has been to investigate 3. Experimental Evidence for Anion−π Interactions G the complex interplay of anion−π interactions with other 3.1. Investigations in the Gas Phase G similar noncovalent interactions and to demonstrate their 3.2. Solid State Investigations G relevance for anion recognition as well as their role in 3.2.1. Analysis of Structural Databases H biochemical processes.28−31 3.2.2. Crystallographic Studies J Another field of intense research activity is the utilization of 3.2.3. Anion−π Interactions in Solution O anion−π interactions in the design of superior anion receptors 4. Conclusion and Outlook X and transport channels.32,33 The interest in the design and Author Information X synthesis of highly selective anion receptors follows from the Corresponding Authors X ubiquity and vital role of anions in both biological systems and Author Contributions X synthetic chemistry.34−38 In general, a plethora of concepts is Funding X available to design anion receptors employing various nonNotes X covalent interactions ranging from strong Coulombic attracBiographies X tions (ion pairing) and Lewis acid−base pairing (metal Acknowledgments Y coordination), through moderate interactions by dipole− References Y anion interactions and hydrogen and halogen bonding, to relatively weak anion−π interactions39 or nonclassical hydrogen bonding (Figure 1).40 1. INTRODUCTION ‡

Well-orchestrated noncovalent interactions are fundamental in chemical processes.1 For example, the assembly of comple© XXXX American Chemical Society

Received: March 17, 2015

A

DOI: 10.1021/acs.chemrev.5b00156 Chem. Rev. XXXX, XXX, XXX−XXX

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same time to provide an overview of the recent work in anion recognition using anion−π interactions. Because competing halogen bonding has recently been thoroughly investigated71 and gained a growing interest in anion recognition, selected examples of iodoperfluoroarenes that are related to corresponding anion−π receptors will be discussed as well.72−75

2. COMPUTATIONAL INVESTIGATIONS While ion pairing, metal coordination, and interactions with dipoles (including hydrogen bonding) of anions are wellknown and understood, the interactions with arenes are the focus of intense studies and controversial discussions. The binding mode of the interaction of anions with electrondeficient arenes is versatile. Negatively charged ions can bind via CH hydrogen bonding (A/B) and halogen bonding (C) “side-on” to the periphery of arenes, or they might interact directly with the electron-deficient π-system (D). A covalent species between anion and arene, the Meisenheimer76 complex (E) is also possible (Figure 3).

Figure 1. Representation of different interactions found in anion sensing and recognition.

Early investigations of anion−π interactions were based on derivatives of heterocyclic aromatics23−25 such as pyridine, pyrazine,41,42 1,4,5,8,9,12-hexaazatriphenylene hexacarbonitrile (HAT),43−46 triazines,25,47−55 cyanuric acids,47,56,57 or tetrazine41,58 derivatives (Figure 2). Many of these systems bear

Figure 3. Schematic representation of the noncovalent interactions of anions with electron-deficient arenes by nonclassical hydrogen bonding via CH···anion (A/B), halogen bonding (C), anion−π interaction (D), and the covalent Meisenheimer complex (E).

During the past two decades, several research teams performed computational studies on the interaction of anions with fluoroarenes. Fundamental work has been contributed by Dougherty,77 Besnard,78 Alkorta79 and co-workers, who investigated the interaction between hexafluorobenzene and the lone pairs of HF, HCN (HX), and H2O (Figure 4). The

Figure 2. Overview of various neutral aromatic systems used in anion−π studies as well as selected quadrupole moments Qzz.

positive charges at the aromatic moiety or the heterocycle is directly coordinated to a metal cation. In those cases, the mode of interaction cannot be unambiguously determined, whether the attraction observed is based significantly on anion−π interaction or if the electrostatic attraction between cation and anion overrules the inherent repulsion between the π-system and the anion. Charge-neutral systems based on cyanobenzene, 42,59,60 nitrobenzene, 42,61−63 or naphthalene diimide32,33,64−70 with various substitution patterns are also employed in anion−π studies. Although those systems show strongly positive quadrupole moments, making the interactions with anions possible, they offer additional binding sites via nonclassical hydrogen bonding. In contrast, perfluorinated arenes are excellent systems for the systematic study of anion−π interactions because they are charge-neutral and do not offer CH···anion interactions at the arene. In addition, they possess an opposite quadrupole moment to benzene, which makes them Lewis acidic with πacceptor properties. The purpose of the present review is to summarize theoretical as well as experimental studies that show the relevance of interactions of anions with fluoroarenes and at the

Figure 4. Computationally investigated complexes of HF, HCN, or water with C6F6.77−79

theoretically calculated binding constants were found to be similar in strength compared to weak hydrogen bonds. Simultaneously the groups of Deyà, Mascal, and Alkorta revealed in their seminal works the existence of attractive interactions between electron-deficient arenes and anions by computational methods.21,80,81 2.1. Origin of Anion−π Interactions

Detailed computational studies80−85 show that anion−π interactions mainly rely on electrostatic forces and anioninduced polarization effects.86,87 The electrostatic term can be correlated with the quadrupole moment Qzz of the aromatic B


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inverse order is found for the corresponding nonfluorinated compounds (Table 1).

unit, which describes the charge distribution of a molecule relative to a particular axis (z axis: perpendicular to the arene plane and through its center). The quadrupole moment of benzene is negative with Qzz = −8.5 B, while it becomes positive if strong electron-withdrawing substituents are present at the arene. Thus, hexafluorobenzene has a large positive quadrupole moment of Qzz = +9.5 B. A visual representation of the quadrupole moment is given by charge density calculations for the aromatic moieties88 (Figure 5). Accordingly, electron-

Table 1. Corrected Interaction Energies (kcal/mol) and Distances (in Å) at the MP2/6-31++G** Level of Theory for Some Fluoroarene Chloride Complexes81,87 complex

E

Re

C6F6·Cl− C6H3F3·Cl− C10F8·Cl− C5NF5·Cl− C3N3F3·Cl− C4OF4·Cl− C4SF4·Cl−

−12.6 −4.8 −17.3 −14.1 −15.0 −9.0 −8.1

3.15 3.32 3.06 3.09 3.01 3.11 3.25

In 2007, Hermida-Ramón and Estévez91 reported the interaction of a series of fluorinated analogues of Klärner’s tweezers92 (Figure 7) with iodide. The complexes were

Figure 5. Structures and electron-density surfaces of selected arenes showing low electron density (blue region) in the aromatic core of C6F6 and C3N3F3 (left). In addition the concept of “anion-induced dipole moment” is illustrated (right).88

rich benzene can interact attractively with cations while anions form stable complexes with hexafluorobenzene. Arenes with moderate quadrupole moments such as trifluorotriazine (Qzz = +8.2 B) are able to interact attractively with both anions and cations. The second term, the ion-induced polarization, can be correlated with the molecular polarizability α∥ of the aromatic compound. For molecules with high molecular polarizability such as s-tetrazine (α∥ = 58.7 au89,90), α∥ contributes significantly to the anion−π interaction. 2.2. Fluoroarenes As Electron-Deficient Aromatics

Figure 7. Klärner’s tweezer compounds 1−3 as studied by HermidaRamón et al.91

Alkorta et al. investigated anion−π complexes of various anions with different perfluoroarenes on B3LYP/6-31++G**, MP2/631++G**, and MP2/6-311++G** levels of theory.81 The results indicate that the B3LYP/6-31++G** basis set provides smaller interaction energies as well as longer distances, and therefore it only affords a qualitative description of anion−π interaction. The authors visualized the interaction between the investigated anions and the fluoroarenes by molecular electrostatic potential maps and found positively charged regions above the plane of the perfluoro compounds. Additionally, the same study revealed a correlation between the aromaticity of the compound and the calculated energy value in the order pentafluoropyridine > octafluoronaphthalene > trifluorotriazine > pentafluoropyridine > hexafluorobenzene ≫ tetrafluorofuran > tetrafluorothiophene > trifluorobenzene (Figure 6). An

analyzed by symmetry-adapted perturbation theory (SAPT) and association constants were calculated on the MP2 level of theory for complex geometries optimized using density functional theory (DFT) and the B3LYP functional/basis set. The molecular electrostatic potential (MEP) values in the center of the cavities are −10.25 (1), −5.79 (2), and −0.64 (3) kcal/mol. It should be noticed that a large binding constant is calculated for 3·I− even though the obtained electrostatic potential is slightly negative. The described results (Table 2) clearly show that an increase in fluorine substitution at the tweezers stabilizes the complex with iodine, caused by the depletion of the electrostatic repulsion between the negative charge and the π-system. A

Figure 6. Octafluoronaphthalene, trifluorotetrazine, pentafluoropyridine, hexafluorobenzene, tetrafluorofuran, and tetrafluorothiophene.80 C


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anion−π complex (Figure 8, D), and the donor π-acceptor complex between the anion and just one carbon atom of the aromatic moiety (Figure 8, F). In 2008 this series was extended by a crystallographic study performed by us.96 X-ray structures reveal two additional binding motifs for spatially different interactions of anions and electron-deficient π-systems, viz. interaction with two (G) or three carbon atoms (H), respectively (Figure 8). To describe those different structures, the hapticity concept of organometallic complexes has been adapted for anion−π contacts. The structural versatility of anion−π interactions raises the question for rational criteria for how to classify/categorize the anion−π contacts. Indeed most electron-deficient aromatic systems exhibit anisotropy in their charge distribution due to substituents at the arene. Therefore, the C6-symmetric interaction with the anion directly above the center of the arene moiety is rarely found in crystal structures. Recently, Estarellas et al. investigated the directionality of anion−π interactions by calculating the interaction energy for selected positions of the chloride anion above the plane of hexafluorobenzene. They compared it to the corresponding cation−π complex of benzene and sodium.97 Their results revealed significant differences between the energies calculated for anion−π and cation−π interactions. For the anion−π interactions, only a slight energy change through moving of the anion in the xy-plane is found (Figure 9), which supports the

Table 2. Interaction Energies (kcal/mol) Calculated for the Iodide Complexes of Tweezers 1−391

a b

complex

ΔEcomplexa

ΔEinterb

1·I− 2·I− 3·I−

5.20 −0.28 −5.95

−4.06 −9.72 −15.82

Obtained by using B3LYP functional ΔEcomplex = ΔEinter + ΔEdeform. Obtained by single-point MP2 calculations on optimized geometries.

simulated continuum model93 of the solvent shows that none of the complexes is stable in the presence of water. 2.3. Influence of the Anion

The nature of the anions involved in an anion−π complex plays a significant role because the electrostatic term as well as the polarization term of the interaction energy strongly depends on the distance between anion and arene.83,87,89 Small anions such as fluoride and chloride have a strong polarizing effect and a shorter distance to the π-system. Accordingly, the resulting association energies are found to be more negative (Table 3). Some anions such as CO32− or NO3− are even able to interact by π−π stacking and therefore can form very stable complexes with electron-deficient arenes.83,84 Table 3. Corrected Interaction Energies (kcal/mol) and Distances (in Å) at the MP2/6-31++G** Level of Theory for Anion Hexafluorobenzene Complexes83,87,89 complex

E

Re

C6F6·H− C6F6·F− C6F6·Cl− C6F6·Br− C6F6·NO3− C6F6·CO32−

−12.1 −18.2 −12.6 −11.6 −12.2 −34.7

2.69 2.57 3.15 3.20 2.92 2.72

2.4. Hapticity of Anion−π Interactions

As already mentioned in the Introduction, anions can occupy very different positions with respect to the electron-deficient arenes. In contrast to the geometrically more defined “side on” hydrogen and halogen bonding, the “on top” interaction of a negative species with a π-system is spatially versatile. The highly symmetrical (η6) C6−π-complex D (Figure 8) represents an

Figure 9. Energy profile (kcal/mol) of C6F6 and C6H6 for the interaction with chloride in different positions of the xy-plane calculated at the RI-MP2(full)/aug-cc-p VDZ level of theory. Adapted with permission from refs 22 and 97. Copyright 2011 John Wiley and Sons and 2011 Royal Society of Chemistry, respectively.

previously observed geometrical versatility of this interaction in the solid state. In contrast, the cation−π complexes show a significant decrease of binding energy caused by the displacement of the cation in the xy-plane. This is also in agreement with crystallographic findings. For the elongation of the interaction distance along the z-axis, a significant reduction of binding energy is found for both anion−π and cation−π interactions (Figure 10). According to their results the authors suggested more general criteria for the evaluation of anion−π interactions, viz. the distance between the anion and the bonded carbon atoms has to be below the sum of the van der Waals radii of the involved atoms plus a tolerance of 0.8 Å. More recently the spatial variations of anion−π interactions have been studied computationally,98 and the interaction energy of bromide with fluoroarenes possessing various substitution patterns and degrees of fluorination has been

Figure 8. Anion−π binding motifs as described by the groups of Hay60 (D and F) and Albrecht96 (G and H).

exceptional, very rarely observed structure in the solid state.94 The main reason for this is the competition with nonclassical CH···anion hydrogen bonds as well as the formation of weak charge transfer (CT) complexes with only one of the carbon atoms of the arene leading to an offset from the center.94,95 Hay and co-workers discussed in their 2007 study “Structural Criteria for the Design of Anion Receptors” three types of anion−π interactions.60 These are the covalently bonded Meisenheimer complex (Figure 3, E), the C6-symmetrical D


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Figure 12. Schematic representation of the anion−π complexes of an anion with one, two, or three trifluoro-1,3,5-triazine units.99

Table 4. Binding Energies (kcal/mol) with (EBSSE) and without (E) the Basis Set Superposition Error (BSSE) Correction and the Corresponding Equilibrium Distances (Re, in Å) on RI-MP′′ Level of Theory99

Figure 10. Energy profile (kcal/mol) of C6F6 and C6H6 for the interaction with chloride in different distances between the anion and the arene calculated at the RI-MP2(full)/aug-cc-p VDZ level of theory. Adapted with permission from refs 22 and 97. Copyright 2011 John Wiley and Sons and 2011 Royal Society of Chemistry, respectively.

calculated. By moving the anion in the xy-plane within the equilibrium distance above the fluoroarenes, 2200 data sets were obtained for each investigated system to create an energy map of the anion−π interactions. In the case of hexafluorobenzene, the resulting energy maps show a clear energetic minimum for the position of the anion above the center of the arene (η6, Figure 8, D). For less-fluorinated systems the energy map is flatter and becomes less symmetric. In addition, asymmetry in substitution is reflected in the energy maps for the corresponding systems (Figure 11). These results help us to understand the wide variety in the geometry of anion−π contacts as observed in solid state studies (vide infra).

a

complex

E

EBSSE

Re

Cl−···(C3N3F3) Br−···(C3N3F3) Cl−···(C3N3F3)2 Br−···(C3N3F3)2 Cl−···(C3N3F3)3 Br−···(C3N3F3)3

−20.3 −18.8 −38.2 −36.4 −64.2 −60.7

−15.1 −14.2 −28.6 −26.8 −41.0 −38.6

3.008 3.176 3.006 3.170 3.019a 3.172a

Mean distances.

that the charge density of the π-systems as well as the strength of the individual anion−π interactions do not change, even in the presence of two or three arenes. In 2011, Garau et al. performed computational studies on π− anion−π′ complexes on a RI-MP2 and MPWB1K level (Figure 13 and Table 5).102 The authors concluded that the MPWB1K functional is appropriate to describe anion−π interactions and might be a better alternative to the widely used B3LYP functional. The obtained interaction energies suggest a close to additive behavior for the π−anion−π′ complexes. A deep understanding of the interplay of different noncovalent bonds is of high importance because several different noncovalent interactions occur concerted in molecular assembly processes. A detailed review focusing on theoretical results of the interplay of noncovalent interactions, including a brief discussion of anion−π interactions, is given by Alkorta et al.103 For reasons of integrity, the key aspects concerning the interplay of anion−π interactions with other weak noncovalent bonds are discussed in the following, including some very recent studies.

2.5. Additivity of Anion−π Interactions

In 2005, Garau et al. reported the additivity of anion−π interactions in trifluoro-1,3,5-triazine (TFA) anion complexes.99 The binding energies for the 1:1 (X·C3N3F3), 1:2 (X·(C3N3F3)2) and 1:3 (X·(C3N3F3)3) complexes of TFA (Figure 12) with chloride and bromide have been calculated on the MP2/6-31++G** level of theory (Table 4). While the distances between the central anion and the center of the arene remain almost constant, the interaction energies are found to be approximately 2 and 3 times higher in respect to the 1:1 complex. This trend is maintained even by involvement of solvents (chloroform and water) by the polarized continuum solvent model using RI-MP2(full)/6-31++G** basis set/level of theory. The atoms in molecules (AIM)100,101 analysis reveals

Figure 11. Selected energy (kcal/mol) maps for anion−π complexes of C6F6 and C6H3F3 with bromide at the MP2/6-311++G** level of theory. Reproduced with permission from ref 98. Copyright 2014 Verlag der Zeitschrift für Naturforschung. E


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Interestingly the nature of the participating arene is circumstantial, and attractive interactions are found for a broad range of derivatives with different quadrupole moments (Table 6). Table 6. Interaction Energies (kcal/mol) for the Investigated Anion−π, Cation−π, and Anion−π−Cation Complexes on MP2/6-31++G** Level of Theory and Corresponding Equilibrium Distances (Re, in Å)104,105 complex

E

Na ···C6H6 Na+···C6F3H3 Na+···C6F6 C6H6···F− C6H6···Cl− C6H6···Br− Na+···C6H6···F− Na+···C6H6···Cl− Na+···C6H6···Br− Na+···C6F3H3···F− Na+···C6F3H3···Cl− Na+···C6F3H3···Br− Na+···C6F6···F− Na+···C6F6···Cl− Na+···C6F6···Br−

−21.0 −8.2 +3.5 +2.8 +2.4 +1.9 −93.1 −85.1 −84.3 −90.9 −80.4 −78.9 −88.4 −75.6 −74.0

+

Figure 13. Representative structures of π−anion−π′ complexes as studied by Garau et al.102

Table 5. Interaction Energies (kcal/mol) with BSSE Correction for the Investigated π−Anion−π′ Complexes at RI-MP2(full)/6-31++G** Level of Theory and Corresponding Equilibrium Distances (R, in Å)102 complex

EBSSE

Rπ−anion

Ranion−π′

C6F6···F−···C6H3F3 C6F6···Cl−···C6H3F3 C6F6···Br−···C6H3F3 C6F6···NO3−···C6H3F3 C6F6···CO32−···C6H3F3 C6F6···F−···C3N3F3 C6F6···Cl−··· C3N3F3 C6F6···Br−··· C3N3F3 C6F6···NO3−··· C3N3F3 C6F6···CO32−··· C3N3F3 C6H3F3···F−···C3N3F3 C6H3F3···Cl−··· C3N3F3 C6H3F3···Br−··· C3N3F3 C6H3F3···NO3−··· C3N3F3 C6H3F3···CO32−··· C3N3F3

−25.01 −17.68 −17.28 −17.77 −47.42 −39.94 −26.65 −25.61 −24.07 −63.53 −30.41 −19.56 −18.72 −18.07 −50.55

2.539 3.132 3.273 2.917 2.742 2.374 2.974 3.182 2.815 2.567 2.724 3.312 3.462 3.023 2.888

2.704 3.330 3.446 3.020 2.886 2.617 3.103 3.277 2.919 2.765 2.378 3.014 3.183 2.803 2.541

Eint

Re (cation−π)

Re (anion−π)

2.429 2.552 2.652

−22.4 −21.9 −22.1 −19.5 −17.1 −16.0 −17.1 −12.1 −11.2

2.280 2.304 2.313 2.353 2.389 2.399 2.437 2.488 2.495

3.162 3.731 3.840 2.482 3.049 3.157 2.368 2.925 3.006 2.286 2.835 2.913

Furthermore, the interaction energies as well as equilibrium distances of several anion− and cation−π−π-stacked assemblies have been calculated and compared to the cation− and anion−π complexes (Figure 15 and Table 7). The more favorable binding constants and shorter distances of the πstacked complexes prove the synergistic effect of the cooperating intermolecular forces.

2.6. Interplay of Anion−π with Other Noncovalent Interactions

2.6.1. Anion−π, Cation−π, and π−π Interactions. Anion−π interactions are usually observed for arenes with strong positive quadrupole moments. Theoretical investigations by Quiñonero and Frontera et al. revealed that stable anion−π complexes also can be obtained with electron-rich arenes such as benzene by simultaneous interaction with cations from the opposite side of the π-system (Figure 14).104,105 This synergistic effect of both interactions with ions is expressed by large negative binding energies and short distances.

Figure 15. Structures of the investigated anion− and cation−π−πstacked assemblies.104,105

2.6.2. Anion−π Interactions and Halogen Bonding. A recent report by Lu et al. describes the synergistic effect of halogen bonding71 and anion−π interaction by ab initio MP2 calculations.106 While the simultaneous interaction of anions with halogen-bonded pyrazine exhibits a stabilization of the anion−π complex, the interaction of tetrafluoro-1,4-diiodobenzene (TFIB) halide complex shows a mutual attenuation of both interactions (Figure 16 and Table 8). From the theoretical/computational point of view, the anion−π interactions are well understood and their additivity (Figure 17a) as well as their interplay with other cooperative or competitive interactions such as cation−π (Figure 17b), π−πstacking (Figure 17c), or halogen bonding (Figure 17d) as well as subtle steric or electronic interfering effects can be modeled. Figure 17 summarizes intermolecular interactions influencing the strength of anion−π interactions as proven by computational studies. In addition, an interesting different kind of

Figure 14. Structures of the investigated anion−π, cation−π, and anion−π−cation complexes.104,105 F


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Table 7. Binding (EBSSE) and Synergic Energies (Esyn) (kcal/ mol) with BSSE Correction As Well As the Corresponding Equilibrium Distances (Re, in Å) at RI-MP2/6-31++G** Level of Theory104,105 complex

E

EBSSE

Esyn

Re

Li+··· C6F3H3 Na+···C6F3H3 K+··· C6F3H3 C6F3H3···F− C6F3H3···Cl− C6F3H3···Br− C6F3H3··· C6F3H3 Li+···C6F3H3···C6F3H3 Na+···C6F3H3···C6F3H3 K+···C6F3H3···C6F3H3 F−···C6F3H3···C6F3H3 Cl−···C6F3H3···C6F3H3 Br−···C6F3H3···C6F3H3 Li+···C6F3H3··· C6F3H3···F− Na+···C6F3H3··· C6F3H3···Cl−

−20.3 −11.9 −7.6 −10.2 −9.0 −8.9 −9.6 −32.8 −24.2 −19.0 −21.4 −20.4 −20.0 −97.4

−16.1 −8.0 −4.6 −7.7 −4.8 −4.9 −3.5 −20.0 −12.2 −8.8 −12.4 −9.2 −9.4 −80.2

−3.0 −2.7 −1.8 −1.2 −0.9 −0.9 −52.9

2.02 2.50 3.04 2.75 3.34 3.47 3.42 1.98 2.46 3.00 2.73 3.28 3.41 1.89, 2.50

Rs

3.30 3.32 3.35 3.43 3.41 3.43 3.17

−80.0

−60.7

−44.4

2.38, 3.08

3.21

Figure 17. Schematic representation of competive and cooperative intermolecular forces influencing the strength of anion−π bonding.

solution. The huge number and complex interplay of other weak noncovalent interactions, e.g., in a solution, make the structural prediction of anion−π-acceptor complexes difficult if not impossible.

3. EXPERIMENTAL EVIDENCE FOR ANION−π INTERACTIONS 3.1. Investigations in the Gas Phase

Gas-phase experiments on anion−π complexes offer the advantage that the results can be directly compared with computational studies, because both methods focus on nonsolvated complexes without disturbing effects due to packing (like in the crystal) or solvent interaction. So far only a few gas-phase investigations are described in the literature.32,43 Hiraoka et al. investigated C6F6···F− complexes in the gas phase by pulsed electron-beam high-pressure mass spectrometry in 1986.108 The experimentally determined association constant gives evidence for covalent bonding between hexafluorobenzene and the fluoride anion and can be described as Meisenheimer-type complex (E) (Figure 18). Another

Figure 16. Structure of the investigated halogen-bonded anion−π complexes as investigated by Lu et al.106

Table 8. Binding Energies (kcal/mol) and Halogen Bond As Well As Anion−π Distances (Re, in Å) in the Investigated Complexes at MP2/6-31++G** Level of Theory106 complex

E

C6F4I2···Cl− C6F4I2···Br− C6F4I2···I− C6F4I2···NF3 C6F4I2···NH3 F3N···C6F4I2···NF3 H3N···C6F4I2···NH3 C6F4I2···NF3·Cl− C6F4I2···NF3·Br− C6F4I2···NF3·I− C6F4I2···NH3·Cl− C6F4I2···NH3·Br− C6F4I2···NH3·I− F3N···C6F4I2···NF3·Cl− F3N···C6F4I2···NF3·Br− F3N···C6F4I2···NF3·I− H3N···C6F4I2···NH3·Cl− H3N···C6F4I2···NH3·Br− H3N···C6F4I2···NH3·I−

−11.18 −10.06 −8.69 −0.67 −5.07 −1.35 −9.68 −11.94 −10.81 −9.46 −12.51 −11.52 −10.41 −12.69 −11.57 −10.20 −13.52 −12.74 −11.93

Re (XB)

Re (anion−π) 3.088 3.248 3.501

3.227 2.970 3.227 2.993 3.287 3.284 3.277 3.158 3.134 3.114 3.289 3.285 3.285 3.160 3.146 3.138

Figure 18. Anion−π complexes investigated by Hiraoka et al. in the gas phase.108,109

extended study shows noncovalent interactions in gas-phase clusters of hexafluorobenzene and various halides (C6F6···X−; X = Cl, Br, and I).109 The authors suggest a C6-symmetric anion−π complex with an anion located on top of the electrondeficient arene (D). In 2007, Weber and co-workers studied mass-selected complexes of anions with fluoroarenes (C6FnH6−n···X−; X− = Cl, I, and SF6) by infrared photodissociation spectroscopy assisted by computational methods.110 It has been possible to show that perfluorination of the aromatic unit is needed to observe anion−π complexes (Figure 19, D) in the gas phase. In the case of less-fluorinated molecules, the anion is bound by CH−anion hydrogen bonds (Figure 19, A and B). Additionally, it has been found that bifurcated CH−anion interactions of adjacent CH groups (B) are preferred over the interactions with a single CH group (A).

3.093 3.250 3.503 3.124 3.285 3.536 3.089 3.249 3.501 3.152 3.315 3.567

anion−π binding is the recently described interaction of aromatics with salt bridges. In such examples the π-system is simultaneously interacting with an anionic and a cationic unit that are bound to each other (Figure 17).107 However, the computational results are obtained for pairs or small clusters of interacting molecules and therefore cannot directly be correlated with systems in the solid state or in

3.2. Solid State Investigations

A number of crystallographic data-mining studies revealed thousands of contacts between various anions and fluoroarenes in the crystal. The majority of these solid state studies do not recognize or report the noncovalent interactions between G


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in the periphery of a phenyl group, while for pentafluorophenyl groups the anions are mostly found above (or below) the electron-deficient arene (Figure 20e−h). Applying the same criteria for anion−π and lone-pair−π interactions between N-, O-, and S- atoms and F−, Cl−, Br−, and I− anions led to comparable results (Figure 21). More recently, Mooibroek and Gamez reported on the directional and predictable character of anion−pentafluorophenyl interactions based on the CSD analysis.111 Because only BF4− and PF6− achieve a statistically significant number of hits in the CSD, the authors focused their study on the interactions of these anions with phenyl and pentafluorophenyl groups. For phenyl groups the anions are mainly observed in the periphery exhibiting CH···anion interactions with the arene whereas for pentafluorobenzene the anions prefer the position above or below the π-system. They observe 150 contacts between the anion and any carbon atom of the C6F5 unit for BF4− with an average distance of 3.05 Å and 36 hits for PF6− with an interaction distance of 3.06 Å. These results are in agreement with earlier findings by Frontera et al.22 By analyzing the exact position of the anions relative to the arene (taking the fraction of hits in a certain volume Pn* as a measure), the authors are able to support their findings statistically. While the number of hits decreases with longer distance from the center of the arene for pentafluorophenyl, the number of hits for phenyl increases (Figure 22). A very detailed and systematic analysis of crystal structures of pentafluorophenyl derivatives and anions has been recently published by us.112 Anion−π interactions in the crystal structures of 80 different pentafluorophenyl−anion complexes are analyzed. In many of these structures, more than one anion−π interaction is found, and therefore, the positions of 101 anions (8 chloride, 58 bromide, 17 iodide, and 17 others such as tetrafluoroborate, hexafluorophosphate, or nitrate) with respect to the fluoroarene are determined and plotted against a normalized C6F5 unit with the xy-plane centered in the origin. The graphical analysis (Figure 23) of the data shows that the majority of the observed anions are located above or below the π-system (91 hits, 89%) while only 11 hits are found in the periphery of the arene. Limiting the observed hits to structures with a rigid and symmetric DABCO-based backbone

Figure 19. Arene−anion complexes as described by Weber’s group.110

anions and electron-deficient arenes. In the following section, several structural database analyses will be compared and a series of examples for anion−π interactions in crystal structures will be presented. The described examples are taken from experimental studies that focused on the investigation of anion−π interactions. 3.2.1. Analysis of Structural Databases. Data-mining studies of crystallographic databases are a common method to support the experimental evidence for theoretical investigations on weak noncovalent bonds. The seminal computational studies of Quiñonero et al. were accompanied by a detailed analysis of the Cambridge Structural Database (CSD) to underline their computational results on anion−π interactions.21 Since 2002, many such combined studies have been published. Interestingly, the initially unambiguous evidence for anion−π bonds extracted from a huge number of crystal structures21,87,97 has been put on trial by changing the search criteria applied in the data-mining studies from the CSD.94 Quiñonero et al. found 1944 hits for anion−π and lonepair−π interactions between perfluorobenzene and F, Cl, Br, O, S, and N. Using only slightly different criteria, Hay and coworkers observed only a couple of hundred contacts in 200760 and finally with even tougher criteria in 200994 they did not find any structure to manifest anion−π interactions. Because of this, recently Frontera et al. reported a new CSDbased study of anion−π interactions between pentafluorophenyl and several strongly and weakly coordinating anions.22 This approach resulted in a three-dimensional image of the surrounding of the aromatic unit with a huge number of anion positions extracted from the 3-D coordinates in the CSD. The IsoStar plots (Figure 20a,b,e,f) reveal that weakly coordinating anions such as BF4− or ClO4− prefer the position

Figure 20. IsoStar plots showing anion contacts between C6H5 and BF4− (a and b) and ClO4− (e and f) as well as anion−π interactions between C6F5 and BF4− (c and d) and ClO4− (g and h). Reproduced and adapted with permission from ref 22. Copyright 2011 John Wiley and Sons. H


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Figure 21. Anion−π contacts between C6F5 units and heteroatoms (N-, O-, and S- atoms and F−, Cl−, Br−, and I− anions). Reproduced and adapted with permission from ref 22. Copyright 2011 John Wiley and Sons.

Figure 23. Distribution of the anion positions in respect to a normalized fluoroarene (Cl−, green; Br−, red; I−, pink; other anions (BF4−, PF6−, NO3−, I3−, BrIBr−, I42−), blue): (a) top view and (b) side view. Reproduced with permission from ref 112. Copyright 2015 Royal Society of Chemistry.

Figure 22. Fraction of hits (Pn*) versus r charts for molecule pairs involving the F atoms of BF4− (a)/PF6− (b) and a phenyl (gray) or pentafluorophenyl (black) unit within a 5 Å high and wide hemisphere. Reproduced with permission from ref 111. Copyright 2012 Royal Society of Chemistry.

(DABCO = diazobicyclo[2.2.2]octane) as well as excluding disturbance by cocrystallized solvent molecules shows exclusively anions above the center of the arene (Figure 24a− b). In contrast, structures without disturbing solvents but more flexible and/or less symmetric backbones reveal a broader positional distribution of the anions (Figure 24c−d). According to the described findings, the following criteria for the definition of the anion−π contacts/interactions were developed: • The anion has to be placed above the π-system: The angle between centroid, any carbon atom of the ring, and the anion has to be below 90° (±10° tolerance). • The distance between anion and the plane of the ring has to be shorter than ΣvdW + 0.4 Å. • The hapticity is given by any carbon anion contact shorter than ΣvdW + 0.4 Å.

Figure 24. Comparative, graphical analysis for structures of πacceptors with a symmetrical, rigid scaffold without cocrystallized solvent molecules ((a) top and (b) side view) as well as for less rigid and symmetric scaffolded acceptors ((c) top and (d) side view). Reproduced with permission from ref 112. Copyright 2015 Royal Society of Chemistry.

I


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study shows that the attractive interaction between bromide and fluorophenyl DABCO derivatives (5−8) turns into repulsive interaction when 3.51 Å), although the study raises the question for intramolecular anion−π interactions in pentafluorophenyl betaines.135 Therefore, a series of carboxylate 28a,b and sulfonate betaines 29 (Figure 44) with pentafluorobenzyl substituents has been prepared and crystallized. Surprisingly, the investigated systems show exclusively intermolecular interactions between the negatively charged carboxylate (28a, η3-type; C··· OCO−R = 3.06, 3.25, 3.27 Å; centroid···OCO−R = 3.15 Å) or

Figure 39. Representative views of the crystal structure of the BrIBr− salt showing the anion encapsulated in a channel formed by C6F5 units.124

By crystallization of pentafluorobenzyl quinolinium hydrobromide in the presence of air, the simple bromide as well as the tribromide structure 23 is obtained (Figure 40). While the bromide shows anion−π contacts with only one carbon atom of the C6F5 unit (η1-type; C···Br = 3.88 Å), the slightly asymmetric tribromide salt (Br1−Br2 = 2.64 Å, Br2−Br3 = 2.47 Å) exhibits an interesting porous structure, where the linear polyhalide is paneled by C6F5 at the ends (η3-type, C···

Figure 40. Representative part of the crystal structure of the tribromide salt showing the porous structure of 23.126 N


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Figure 44. Intermolecular anion−π contacts as observed in the crystal structures of the betaines 28a and 29.135

However, it should be noted that crystal structures are the result of the interplay of a variety of intermolecular forces− attractive and repulsive. In all structures presented so far, a positive charge is located in close proximity to the electrondeficient arene, which might lead to an overestimation of anion−π interactions. Nevertheless, we think that systematic studies on, e.g., the influence of the electronic nature of the arene114 as well as important key structures96,113,115,120 reported here give persuasive arguments for the attractive nature and functional relevance126 of anion−π interactions in crystals. 3.2.3. Anion−π Interactions in Solution. This chapter will summarize the observation of interactions between anions and perfluorinated arenes in solution. The search for anion−π interactions in solution is a story with many failures but also some success.136 Because halogen bonding has recently gained a growing interest in anion-binding studies and frequently occurs in anion−π studies as a competing interaction, selected examples for the recognition of anions by iodoperfluoroarenes will be briefly presented. A more general account on experimental anion−π studies in solution has recently been published by Ballester.137 3.2.3.1. Charged Receptors. In 2007, a study by Ghosh and co-workers described the tris(pentafluorobenzylaminoethyl)amine 30 (Figure 45).117 By protonation with p-toluene sulfonic and hydrofluoroboric acid, the corresponding salts (H330)(TsO)3 and (H330)(BF4)3 were obtained. Titration with tetrabutylammonium chloride (TBACl) and bromide (TBABr) revealed 1:1 complexes for the receptor/anion pairs in dimethyl sulfoxide (DMSO-d6). Both fluorinated salts show a

Figure 42. Crystal structures of 25 and 26 showing the stabilization of I42− under participation of anion−π interactions.126

Figure 43. Side and top views of a betaine pair as observed in the solid-state structure of 27.124

sulfonate group (29, C···OSO2−R = 2.98−4.29 Å) and the electron-deficient arene. A reason might be that the intramolecular interactions prevent a close packing of the molecules, and therefore it is suppressed. In addition, the close packing leads to short contacts between the adjacent betaine pairs and thus supports the intermolecular interaction. The presented examples of anion−π interactions discussed here show the geometrical versatility of this weak noncovalent bond in the solid state. In addition factors like the electrondeficiency at the arene and the structure of anions, spherical and nonspherical, in anion−π interactions are discussed, and the relevance of this intermolecular interaction by encapsulation of anions in electron-deficient cavities as well as for the stabilization of rather unstable anionic species has been demonstrated.124,126,127,129−135

Figure 45. Structures of the protonated anion−receptor complexes H330X2+ and H331X2+ as reported by Ghosh and co-workers.117 O


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tetrabutylammonium halides (Cl, Br, and I), which induce a shifting of the benzylic protons. While the crystal structures of the pentafluorobenzyl phosphonium salts (Figures 47 and 48) show various anion−π contacts as well as interactions with CH groups, the NMR titration experiments do not show any preference of a specific anion either for the fluorinated or the corresponding nonfluorinated cation (Figure 49). A related study on anion−π interactions of pentafluorobenzyl-4-tert-butylpyridinium tetrafluoroborate 34a has been performed recently (Figure 50).128 The crystal structures of the corresponding pyridinium salts 34b−c show anion−π contacts to the C6F5 as well as to the pyridinium moiety. Differential binding constants were determined in chloroform by successive addition of tetrabutylammonium halides following different signals in the 1H/19F NMR spectra. No distinct evidence for anion−π interactions in solution was found. 3.2.3.2. Charge-Neutral Receptors. In 2004, Furuta and coworkers reported on the ability of metalated (M(II) = Ni, Pd, and Cu) N-confused porphyrins (NCPs) to bind anions in dichloromethane.140,141 The UV−vis titration data for the pentafluorophenyl derivative 35a as well as for the phenylsubstituted analogue 35b (Figure 51) in dichloromethane obtained by successive addition of TBA halides show the formation of a 1:1 complex. The binding affinity for 35a increases in the order Cl− > Br− > I− for all metal complexes. The corresponding phenyl derivative 35b shows a significantly weaker binding, which the authors ascribed to dependence on the enhancement of acidity of the NH group by the electronwithdrawing effect of the pentafluorophenyl moiety and in addition to anion−π interactions (based on the observation of shifting in the 19F NMR spectra). In subsequent studies, Maeda et al. reported anion−π interactions in NCP derivatives 36−38 bearing three pentafluorophenyl units in different positions (Figure 52).142 The binding constants of the nickel(II) complexes with chloride are determined and are slightly smaller than for the tetrasubstituted porphyrin 35a. Surprisingly, the binding affinity of 36 without the C6F5 unit neighboring the N-confused unit shows the anion−π interaction to be nearly the same as for 35a and is the biggest within this series. The weakest binding was found for 38 (Table 12). In conclusion, the relevance of anion−π interaction in the observed binding constants, if present, is small. The shifting 19F NMR signals for the C6F5 unit adjacent to the NH group is more an effect of shielding of the negative charge than an indicator of the presence of anion−π interactions. A similar concept using a combination of hydrogen bonding next to an electron-deficient aromatic moiety for anion−π studies in solution has been presented by Johnson and coworkers.143 The 1H NMR titration data for 39a and 39b (Figure 53) in chloroform upon addition of TBA halides (Cl−, Br−, I−) were analyzed for 1:1 complexes. The solution data clearly show an enhanced binding affinity of the halide anions to the receptor 39a. For 39b no binding is observed. The authors related the enhanced binding affinity to the presence of anion−π interactions. The reported crystal structures of 39a exhibit no anion−π interactions in the solid state. A ditopic pentafluorophenyl salicylamine receptor 40a (Figure 54) has been synthesized to bind anions via both hydrogen bonding as well as anion−π interactions.144 The corresponding dichlorophenyl derivative 40b has been synthesized as reference.

higher binding affinity for chloride and bromide than the corresponding nonfluorinated salt (H331)(TsO)3 (Figure 45 and Table 11) .138 Table 11. Binding Constants for (H330)(TsO)3, (H330)(BF4)3, and (H331)(TsO)3 with Chloride and Bromide (Added as n-Bu4N+) Determined in DMSOd6117,138 log Ka (M−1) anion

(H330)(TsO)3

(H330)(BF4)3

(H331)(TsO)3a

2.56 2.04

2.68 2.15

1.80 1.70

−

Cl Br− a

From ref 138.

In addition to the results obtained in solution, it has been possible to crystallize the chloride (H330)Cl3 and bromide (H330)Br3 salts (Figure 46). Both complexes are isostructural

Figure 46. Representative part of the crystal structure of (H330)Cl3 showing the encapsulated chloride anion surrounded by dominant NH···anion as well as weak anion−π interactions.117

and show the encapsulation of the anion inside the receptor’s cavity. Two additional halide ions are bound to the outside of the receptor. The encapsulated anion shows strong interactions with one of the ammonium hydrogens of each arm and two weak anion−π contacts (η1). The authors described the encapsulation of the anions in combination with the solution studies as an indication for the pivotal role of anion−π interactions in the recognition of anions in such systems. In 2010, the interaction of anions with pentafluorobenzyl phosphonium salts was reported in solution accompanied by a detailed crystallographic study.139 The NMR titration experiments with hexafluorophosphate 32a and tetrafluoroborate 32b salts and the analogous benzyl-substituted compounds 33a and 33b (Figure 47) were performed in chloroform. Binding constants were determined upon successive addition of

Figure 47. Anion-exchange equilibrium as investigated by Albrecht and co-workers.139 P


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Figure 48. Representative examples of the crystallographic findings by Albrecht and co-workers. Top (a) and side views (b) of the solid-state structure of pentafluorobenzyltriphenyl phosphonium iodide as well as top views of the corresponding tetrafluoroborate (c) and the hexafluorophosphate (d). For all structures anion−π interactions are observed in the solid state.123,139

bonding. Because anion−π interactions are weak, they can be easily overruled by other noncovalent interactions (Figure 55). The cooperativity of hydrogen bonding and anion−π interactions in pentafluorobenzamide receptors 41a and a corresponding nonfluorinated receptor 41b (Figure 56) represent an interesting case.145 Job plots show a 1:1 ratio for all investigated anion/receptor pairs in chloroform. The NMR data result in a slightly higher binding constant for 41a than for 41b with a binding order of Cl− > Br− > I− for both receptors (Table 13). Because the differences between the binding constants for 41a and 41b are quite small, there is no clear trend in the binding. However, the related ditopic receptor 42 (Figure 56) has been investigated by NMR titration in CD3CN. The binding constants for the 1:1 complex were determined by following different signals in the 1H NMR and 19F NMR spectra. The differences in the binding affinities are significantly higher than for 41a and decrease in the order Cl− > Br− > I− (Table 14). For receptor−anion complex 42·X−, two different structures are possible (I and II, Figure 56). The performed computational studies on MP2HF/6-311++G** level of theory show that the ditopic anion−π complex II should be the preferred binding mode for 42. The described NMR studies were complemented by the solid-state structures of the complex of pentafluorobenzamide and tetraethylammonium bromide 43·TEABr (Figure 57). The crystal structure reveals close contacts between the C6F5 unit and the bromide anion (C···Br = 3.65−4.16 Å) with a distance of only 3.67 Å to the centroid. The crystal structure of 43· TEABr is the first example of short anion−π contacts between an uncharged pentafluorophenyl derivative and an anion. Computational studies as well as the crystal structure of the model complex 43·TEABr support the existence of anion−π interactions of 42 in solution. Following the concept of simultaneous NH···anion and anion−π interactions, Meyer, Mata, and co-workers reported 1,3-bis(pentafluorophenylimino)isoindoline (44) (Figure 58) and a 3,6-di-tert-butyl-1,8-bis(pentafluorophenyl)-9H-carbazole (45) as receptors for capturing halide anions (chloride and

Figure 49. Representative view of the ion pair as observed in the crystal structure of pentafluorobenzyltriphenyl phosphonium iodide showing the anion−π interaction, which in solution is overruled by the competing nonclassical CH···anion hydrogen bond.123,139

Figure 50. Investigated anion-exchange equilibrium for tert-butylpentafluorobenzylpyridinium salts 34a−e and pyridinium salts studied in the crystal.128

Job plots of the receptors in CDCl3 upon addition of TBA halide solutions prove the 1:1 ratio of the receptor/anion complexes. The binding affinities for both receptors 40a and 40b decrease in the order Cl− > Br− > I−. The presented NMR studies did not provide any evidence for anion−π interactions in solution for 40a. In contrast to the expectations, the nonfluorinated receptor 40b shows a significantly higher affinity for chloride than 40a, which can be explained by competing HQ


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Figure 51. Anion complexation in solution by N-confused porphyrins as investigated by Furuta and co-workers.140,141

Figure 52. N-confused porphyrin derivatives 36−38 as reported by Maeda et al.142

Figure 54. Salicylamine-based anion−receptor systems.144

Table 12. Binding Constants of Complexes 35−38 with Chloride, Bromide, and Iodide (Added as n-Bu4N+ Salts) in CH2Cl2140−142 Ka (104 M−1) receptor

anion

M = Ni(II)

M = Pd(II)

M = Cu(II)

35·M

Cl− Br− I− Cl− Cl− Cl− Cl−

5.7 ± 0.4 0.8 ± 0.04 0.1 ± 0.002 Br− > I− for both 51a and 51b ranging from 3.94 to 2.96 for 51a and from 3.35 to 1.36 for 51b, respectively. Very convincing studies on anion−π interactions in solution have been performed since 2008 by Wang and co-workers when investigating the anion binding ability of tetraoxacalix[2]arene[2]-triazine macrocycles.52,53,148 They were able to observe binding constants up to 4000 M−1 in acetonitrile. Crystallographic studies revealed the interaction of the anions with the electron-deficient triazine moiety, and more recently amphiphiles based on the tetraoxacalix[2]arene[2]-triazine scaffold show size-selective self-assembly into vesicles controlled by the presence of anions in the order F− < SCN− < BF4− < Br− < Cl− < NO3−.55,149 In 2012, Wang and co-workers decorated the tetraoxacalix[2]arene[2]triazine macrocycles with pentafluorophenyl groups (52a and 52b) (Figure 63) for anion−π interactions in solution.54The UV−vis and fluorescence titration experiments are performed in acetonitrile with addition of TBAF and TBAN3 salts to provide binding constants ranging from 3.52 × 103 to 1.33 × 103 M−1. The addition of other TBA salts shows no change in the UV−vis spectra. It should be noted that the addition of any TBA salt, even TBAF or TBAN3, did not show shifts in the proton NMR spectra, which is in agreement with earlier findings of Wang and co-workers.52,53,148 Related macrocycles have been studied by Ballester and coworkers, namely, calix[4]pyrroles 53 with two attached arenes (phenyl 53b, methoxyphenyl 53c, pyridyl 53d, pentafluor-

Figure 61. Molecular structure of 50 and two representative views of the crystal structure of 50·Cl− showing the anion encapsulated in between four electron-deficient arenes (TBA cation omitted for clarity).119

titration (ITC) experiments in acetonitrile.119 The solution studies are supported by electrospray ionization MS (ESI-MS) as well as by crystal structures. The binding constants for 50 determined by ITC decrease in the order of CH3COO− > C6H5COO− > Cl− > Br− (Table 15). Comparable results were found by NMR titrations. The authors were able to crystallize the corresponding fluoride and chloride complex of 50, which both reveal the encapsulation of the anions inside the tripodal receptor. For both anions strong interactions with the amide protons were observed. The contact of the anions to the C6F5 units seems to be weak, if present at all, while the anion−π T


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kcal mol−1). This enhanced iodide binding was assigned to the increased size and polarizability of the iodine. Of particular interest is the interaction of nitrate with the calix[4]pyrrole receptors.61 The authors observed a strong binding of the nitrate anion in the cleft between the two electron-deficient arenes, whereby one of the oxygen atoms interacts via four NH−anion interactions with the calix[4]pyrrole backbone and the other two oxygens interact with the arenes. These results were supported by X-ray analysis studies of 53f·NO3−. Furthermore, the authors give first evidence for the relevance of anion−π interactions in active ion transport through biological membranes. To understand the binding events in detail, Ballester and coworkers executed a thorough investigation of the thermodynamic contributions of the anion binding.150 In acetonitrile the enthalpy term remains almost constant for all investigated receptor−anion complexes. The differences in the Gibbs free energy were exclusively assigned to changes of the entropy due to the strong solvation of the anions in the polar solvent. In chloroform solutions the solvation effect is significantly reduced and the change in Gibbs free energy is mainly driven by enthalpy. In summary, the study revealed the weakly attractive nature of anion−π interaction in polar and nonpolar solvents (−0.7 to −1.0 kcal mol−1) to be driven by enthalpy.136 It should be noticed that the determined free binding energies do most likely slightly underestimate the anion−π interactions, since they are obtained by comparison with an octamethyl calix[4]pyrrole possessing CH···anion interactions. Thus, the values obtained for the free binding energies connot be taken as absolute estimates of the anion−π interaction in solution, but it is at least more favorable than the CH···anion octamethyl calix[4]pyrrole system.26,150,151 3.2.3.3. Anion−π Interaction versus Halogen Bonding. As already mentioned before, halogen bonding, XB,131,152has gained growing interest in anion recognition.72−75,153−157 Because many of the studies use compounds analogues to anion−π receptors, this section will summarize some of the recent investigations with fluoroaryl halogen binders. Resnati, Metrangolo, and co-workers described a concept for ion-pair recognition by ditopic receptors 54a and 54b (Figure 65).158 Both hosts offer a chelating unit for the coordination of cations, thus preorganizing a binding site for anions. While 54a provides anion−π interactions with the pentafluorophenyl units, 54b binds an anion by halogen bonding of the iodotetrafluorophenyl group. The binding constants for 54a

Figure 63. Molecular structure of 52a and 52b as investigated by Wang and co-workers.54

ophenyl 53e, and dinitrophenyl 53f) (Figure 64).61,150 The anions are captured by NH groups in the center of the pyrrole

Figure 64. Molecular structure of the investigated calix[4]pyrrole receptors 53a−f and the crystal structure of the “two-walled” 53e·Cl receptor−anion complex.61,150

in close proximity to the electron-deficient arenes. This is shown by the crystal structure of the pentafluorophenyl derivative 53e. The anion−π complexes of 53e with chloride, bromide, and iodide were obtained by cocrystallization of 53e with the corresponding tetramethylammonium halide. In all three crystal structures, the halide anions are bound between the two parallel orientated C6F5 units with distances of 3.90− 4.12 Å to their centers. The binding behaviors of the calix[4]pyrrole receptors 53a−f were studied in solution via 1H NMR spectroscopy. The receptor design forces the anions to interact with a variety of electronically different aromatic units either attractively or repulsively. The authors observed an increasing attraction of the anion parallel to an increasing electron-withdrawing character of the substituents on the aromatic unit. To get an estimation of the strength of the anion−π interactions, the binding energies of calix[4]pyrrole 53a are determined and are compared to the “two-walled” systems 53b−f. Thereby, very similar binding strength for chloride and bromide (−0.6 to −0.8 kcal mol−1) with the electron-deficient arenes were observed while iodide shows slightly stronger binding (−1.0

Figure 65. Molecular structure of receptors 54a and 54b as well as a representative part of the crystal structure of the 54b−sodium iodide complex. The anion is exclusively bound to halogen atoms.158 U


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and 54b with NaI were determined by calibrated competitive 1 H NMR studies in CDCl3 with the Na+ and [18]crown-6 complex as reference. The comparison of the binding constants were found to be ∼20 times higher for NaI to 54b due to halogen bonding. The complexation of NaI by receptor 54b was supported by ESI-MS as well as by crystallography. In 2010, Taylor and co-workers reported a series of pentafluorophenyl 55a and iodofluorophenyl receptors 55c and 55i (Figure 66) for anion recognition in solution.159,160 19F

Figure 67. Urea receptors 56a−58a as reported by Taylor and coworkers.161

anions to receptors providing halogen-bonding sites was found to be clearly higher. This supports the role of halogen binding in the receptor anion interaction. Remarkable differences in the binding constants of 57a,b and 58a,b with iodide (Table 17) were observed. Table 17. Association Constants (Ka in CD3CN) of Receptors 56−58 with Chloride, Bromide, and Iodide (Added As n-Bu4N-salts) As Well As the Free Energy Contributions of the Halogen Bond Interaction (ΔΔGXB)161

Figure 66. Pentafluorophenyl 55a and iodofluorophenyl receptors 55c and 55i, which were investigated by Taylor et al.160

receptor

NMR studies in acetone revealed that the fluorine atom has to be ortho to the iodine in order to obtain significant binding affinities between the receptors and chloride (as TBACl). The perfluorinated derivative 55a shows 1000 times weaker binding affinity to chloride than the corresponding halogen bond receptor 55b. Extended NMR studies on the receptors were performed with tetrabutylammonium halides and revealed the expected order Cl− > Br− > I− (Table 16).

56a 56b 56a 56b 56a 56b 57a 57b 57a 57b 57a 57b 58a 58b 58a 58b 58a 58b

Table 16. Association Constants (Ka in Acetone) of Receptors 55a−i with Various Anions (Added as n-Bu4Nsalts)160 receptor 55a 55b 55c 55d 55e 55f 55g 55g 55g 55g 55g 55h 55i

anion −

Cl Cl− Cl− Cl− Cl− Cl− Cl− Br− I− PhCO2− H2PO4− Cl− Cl−

Ka (M−1)

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