CationâÏ Interaction: Its Role and Relevance in Chemistry, Biology

Review pubs.acs.org/CR

Cation−π Interaction: Its Role and Relevance in Chemistry, Biology, and Material Science A. Subha Mahadevi and G. Narahari Sastry* Molecular Modeling Group, CSIR-Indian Institute of Chemical Technology Tarnaka, Hyderabad 500 607, Andhra Pradesh, India 10. Conclusions Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Emergence of Cation−π Interactions 3. Cation−π Interactions 3.1. Host−Guest Complexes 3.2. Material Science 3.3. Catalysis and Reaction Mechanisms 4. Cation−π Interactions in Biological Systems 4.1. Peptides 4.2. Adenine- and Arginine-Containing Biomolecules and Ade−Arginine Interaction 4.3. Nucleic Acids, mRNA Cap Binding Proteins, Histones, and Telomeres 4.4. Enzymes 4.5. Protein Structure 4.6. Viruses and Extremophiles 4.7. Antibody-Binding Interactions 4.8. Betaine-Containing Systems 4.9. Cu-Containing Proteins 4.10. Cyclases 4.11. Factor Xa Protein 4.12. Small Molecule Recognition 4.13. Biomembranes 4.14. Drug Design and Scoring Functions 5. Databases 5.1. Cation Aromatic Interaction Database (CAD) 5.2. CaPTURE 5.3. Protein Explorer 6. Computational Methods 7. Modulation of Cation−π Interactions 7.1. Nature of Cation and π-System 7.2. Size and Curvature of π System 7.3. Substitution 7.4. Cation−π versus Cation−σ Interaction 7.5. Cation−π versus Proton Affinity 7.6. Solvation 7.7. Counterion 8. Cooperativity Induced by Cation−π Interactions 8.1. Cation−π and Hydrogen Bonding 8.2. Cation−π and π−π Stacking Interaction 9. Energy Decomposition Analysis

© XXXX American Chemical Society

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1. INTRODUCTION Noncovalent interactions are essential for the existence of solid and liquid phases.1,2 Traditionally touted as weak forces, quantification of these interactions, which govern the molecular aggregation and determine the supramolecular assembly, is of fundamental interest.3,4 Hydrogen bonding has been extremely well studied and recognized as the most important of all noncovalent interactions.5,6 In recent years a great deal of attention is given to understand various kinds of weak interactions such as hydrophobic interaction, dispersion interaction, halogen bonding, anion-π interaction, salt bridge interaction, intercalation and CH−π, NH−π, OH−π, and SH−π interactions, etc.7,8 Several studies are directed toward understanding the nature, type, extent, and relevance of hydrogen bonding in chemical and biological systems.9−11 Apart from hydrogen bond, two major interactions, namely, π−π stacking and cation−π interaction, have emerged as the forces of outstanding importance in controlling the structure and function of macromolecules in recent years.12−15 In general, stacking interactions are weaker compared to hydrogen bonding while cation−π interactions tend to be stronger.12,13 Cation−π interactions are ubiquitous and are of prime importance in several fields of contemporary interest, such as chemistry, material science, biology, and allied areas.16−20 Although these interactions were noticed about three decades ago, their significance and importance has been firmly established in recent years. Cation−π interaction is essentially of electrostatic origin because a positively charged cation interacts with negatively charged electron cloud of π systems, and thus, it is arguably the strongest among the noncovalent interactions.21−23 Such strong interactions, obviously, are expected to have a profound influence in controlling the neighboring structural environment. Under certain circumstances, cation−π interactions may also be relatively weak depending on the nature of cation, whether it is coordinately saturated or not and also on the nature of the π acceptor and hence the range that is spanned by them is quite vast.15 In the current era of nanotechnology, understanding the nature, range

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dx.doi.org/10.1021/cr300222d | Chem. Rev. XXXX, XXX, XXX−XXX

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foregoing studies are important to get a quantitative picture on the strength of cation−π interaction. Dougherty and coworkers made seminal contributions in identifying cation−π interactions in a variety of host−guest model systems including macro cyclic receptors, which explore the phenomenon of molecular recognition.33−41 Besides, ab initio studies on interaction between complexes of benzene with ammonium cations report binding energies for the NH−aromatic interaction to be significant, around 18.0 kcal/mol.42,43 The free energy of binding between tetramethylammonium ion (TMA+) and benzene in an aqueous environment was determined along with prediction of its binding association constant.44 Schwabacher et al. underscored the importance of directionality in cation−π effects, while studying the interaction of charges with the edge of a bound aromatic ring.45 By employing vibrational spectroscopy, Lisy and co-workers explored the competition between K+ interaction with benzene and water.46 These studies led to important observations on the preferential binding of K+ to benzene, the dehydration of K+ by benzene and the ability of water to act as a double proton donor with π-hydrogen bonds to two benzenes. It has been observed that K+ displays higher selectivity to interact with an aromatic complex in an aqueous environment compared to Na+.47 This led to a proposal of a size-specific mechanism for interaction of alkali metal ions with aromatic side chains in some K+ channel proteins. The competition between ion− molecule and molecule−molecule interactions in M+(phenol)2 cluster ions (M+ = Li+, Na+, K+, and Cs+) revealed that intermolecular hydrogen bond in the phenol dimer is stretched and weakened with increasing strength of associated cation−π interaction.48 Variations in cation binding abilities among a series of prototypical aromatic systems were rationalized by Dougherty and co-workers using a simple electrostatic model.37,49 Consideration of the EES (electrostatic energy) component of the total energy alone was shown to be enough to get a quantitative understanding of the trend seen across a series of prototypical aromatic systems. Cubero et al. have shown significant variation in contribution of the polarization component in case of cation−π interactions for systems, where the aromatic cores are different.50 The polarization component was demonstrated to be governed by the size of the aromatic system with little dependence on the nature of substitution in it. The importance of the induction component was further elucidated by Tsuzuki et al. on the basis of ab initio studies in M+−π (M+ = Li+, Na+, and K+; π = benzene, toluene, ethylbenzene, and tert-butylbenzene) complexes.51 The contribution of dispersion was found to be negligible here. A subsequent study on Mg2+ and Ca2+ complexes with benzene also established the major contributions of long-range induction and electrostatic interactions besides indicating the minimal impact of short-range, covalent interactions in these systems.52 Studies employing the symmetry adapted perturbation theory (SAPT) framework to complexes of alkali and alkaline earth metals and benzene have further established the role of induction in defining geometrical and energetic properties leading to the formation of cation−π complex.53 In the past decade, mounting experimental evidence for cation−π interaction has been forthcoming.54−56 Some of these studies use NMR to detect cation−π interactions. Binding energies of cation−π interactions between aminoacid side chains of selected aminoacid derivatives were estimated by employing 1H NMR spectroscopic titrations in aqueous and

and relevance of cation−π interaction is of outstanding importance in designing molecules and materials. In this Review, we present the relevance and role of cation−π interactions in chemistry, biology, material science, and nanosystems. Particular attention is paid to understand the factors responsible in modulating the cation−π interaction along with their structural and functional significance. The review summarizes the significant experimental, computational, and database studies24 involving cation−π interactions because an effective interplay among these fields is warranted for obtaining deeper insights.

Figure 1. Important factors modulating cation−π interactions.

2. EMERGENCE OF CATION−π INTERACTIONS The interaction between ion and neutral molecule tends to be electrostatically stronger when compared to that between two neutral molecules, especially when the neutral molecule is easily polarizable.25−27 A noncovalent cation−π interaction results when a closed shell cation interacts with a neutral π system. Kebarle and co-workers made the first measurement of K+ ion interaction with benzene and have convincingly shown that K+ ion has a slight preference to bind to benzene compared to water molecule.28 The mass spectrometric results were further validated by ab initio computations, which unambiguously establish that K+ ion is disposed on C6 axis symmetrically above the molecular plane of benzene. Subsequent to this study on metal ion−π interactions, Moetner and co-workers established the interaction of NH4+ and MeNH3+ with C2H4 and benzene derivatives and evaluated their interaction energies, which are stronger than typical hydrogen bonds.29 Later Burley and Petsko reported a geometric analysis of 33 refined highresolution protein crystal structures. According to this study, positively charged aminoacids, such as Lys, Arg, Asn, Gln, and His, are preferentially located within 6 Å of the ring centroids of aromatic aminoacids Phe, Tyr, and Trp. The interaction between them was inferred to be electrostatic in origin.30,31 Guo et al. employed high-pressure mass spectrometry to analyze the equilibrium of the interaction between Na+ and Pb+ ions and benzene.32 Similar to the results obtained by Kebarle and co-workers28 they report binding energies for Na+− benzene (−28.0 kcal/mol) and Pb+−benzene (−26.2 kcal/ mol), which are higher in value compared to the interaction between Na+−H2O (−24.0 kcal/mol) and Pb+−H2O (−22.4 kcal/mol), respectively. The observations made by the B


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organic solvents.57 The results obtained in these experiments show that the strength of cation−π interactions was comparable to that of salt bridge interactions and hydrogen bonds. An NMR signature of cation−π interactions has been established based on multinuclear solid-state NMR study of tetraphenylborate salts.58,59 Alkali metal ions in these compounds, exhibit highly negative 23Na, 39K, 87Rb, and 133Cs chemical shifts which correspond to a highly shielded environment at the metal center, thus this feature can be used as an NMR spectral signature for detecting cation−π interactions. NMR results from a study on imidazolium-based ionic liquids and benzene, revealed the presence of an imidazolium ring sandwiched between two benzene molecules showing a cation−π interaction.60 Solid-state 23Na NMR study of sodium lariat ether complexes in which a sodium cation interacts with an indolyl group also generated quadrupolar coupling constants which are characteristic of a cation−π interaction.61 133Cs pulsed diffusion NMR spectroscopy serves as an another approach to recognize existence of an inclusion complex of calix[4]arenes particularly when such an association is driven by cation−π interactions.62 Strong cation−π interactions in complexes formed by cyclooctatetraene and alkaline earth metals were validated by their 13C NMR data.63 Thus, NMR spectra has been extensively employed to identify and characterize cation−π interactions in several classes of compounds. Mass spectrometry has emerged as an ideal tool to understand the intrinsic modes of binding in different cation−π complexes.64−85 Ag+ interaction with phenylalanine has been investigated using collision-induced dissociation (CID) experiments to understand the mechanism involved in their dissociation reaction.68 Dunbar and co-workers have focused on understanding formation of metal ion−π complexes using the Fourier-transform ion cyclotron resonance (FT-ICR) ion trapping mass spectrometer.69−72 They have employed mass spectrometry to analyze monomer and dimer complexes of different atomic ions with coronene,69 complexes of Na+ interacting with Ala and Phe aminoacids71 and encapsulation of metal cations by Phe−Phe ligand.72 A stronger Na+ binding to Phe, Tyr, and Trp aminoacids compared to K+ was demonstrated using the kinetic method.70 Armentrout et al. determined the sequential bond dissociation energies of monoand bis-benzene complexes with alkali metal cations using CID technique.73 The trend observed in the binding energies for these complexes depends on the varying magnitudes of electrostatic interactions and ligand−ligand repulsions. Rodgers and co-workers performed number of experiments on metal ion−π complexes using the threshold CID technique along with computational studies.74−81 The strength of cation−π interaction for alkali metal ions complexed with a vast variety of π systems including azines, nitrogen heterocycles, halobenzenes, toluene, aromatic aminoacids Phe, Tyr, and Trp is shown to depend both on nature of π-group and the kind of substituent present in it. Electrospray ionization Fouriertransform mass spectrometry (ESI-MS) studies on interactions between hydrated divalent alkaline earth metal ions and benzene show that cation−π interaction between Mg2+ and benzene is partially screened by H2O molecules.82 ESI-MS studies on interaction between phosphorylated peptides and compounds containing quaternary amines indicate that presence of one quaternary amine in a compound is enough to form a noncovalent complex with a phosphorylated residue.83 In case of presence of two quaternary amines in

one molecule the electrostatic interactions of the quaternary amines with the phosphate produces a covalent-like stability. Cation−π interactions have been shown to enhance the formation of sandwich benzo-crown ether-alkali metal cation complexes for Na+, K+, and Cs+ ions.84 Infrared predissociation (IRPD) spectroscopic studies of argon-tagged alkali metal ion−crown ether complexes reveal how neutral vibrations for each crown ether shift to higher frequency when complexed to an alkali metal ion.85 Infrared multiple photon dissociation (IRMPD) spectroscopy has been employed by Dunbar et al. to characterize behavior of small and large alkali ions interacting with different di-, tripeptides and Phe ligands via a cation−π interaction.72,86,87 Presence of a strong intramolecular cation−π interaction was shown to control the peptide conformation in protonated GlyGlyPhe.88 IRMPD spectroscopy results of protonated serotonin reveal that the lowest energy conformer for these structures is one where one of the three protons of the ammonium group points toward the indole subunit maximizing the intramolecular electrostatic cation−π interaction (NH+−π).89 A combined strategy of using CD spectra analysis along with quantum chemical investigations was employed to study the differences in solid and solution phases of neutral and cationic nicotinamide derivatives.90 Dramatic changes in CD spectra between neutral and cation−π containing nicotinamide derivative were shown through this study. Microcalorimetry has also been employed to demonstrate formation of weak inclusion complexes mediated by cation−π interactions for monovalent monatomic cations interacting with the psulfonatocalix[4]arene in water.91 The selectivity of the calixarene for the binding to alkali-metal cations is mainly due to differences in cation dehydration. Selective enhancement of Raman bands of aromatic ring vibrations with UV excitation has led to an understanding of interactions in aromatic aminoacid residues.92 Schlamadinger et al. have detected systematic shifts in relative intensity in the 760−780 cm−1 region upon the formation of cation−π interaction between Na+ or K+ and the pyrrole groups of indole moieties of diaza crown ether using UV resonance Raman (UVRR) spectroscopy.93 Tryptophan fluorescence intensity has been employed to gauge the cation−π interaction between Trp and Arg residues in switch II of Gαi family proteins that mediates an observed red shift in its emission maxima.94 Ultraviolet second-derivative absorbance spectroscopy has been exploited to provide useful information on eight different protein structures that have cation−π interactions. This technique tries to consider not only the Trp residues as is the case with fluorescence studies of proteins but seeks to incorporate information from all the aromatic aminoacid residues.95 Thus different spectroscopy techniques have emerged as reliable sources of information on the cation−π interaction. Several solid state structures have been investigated in recent times to throw light on cation−π interactions.96−98 Gokel and co-workers have effectively employed the lariat ether model systems as definitive solid-state evidence for cation−π interactions in case of family of synthetic receptors that incorporate the aromatic side chains of Phe, Tyr, and Trp.22,23,61,99−105 In some part, this has been attributed to the presence of flexible side arms which can compete with the counteranion. The diaza-18-crown-6 scaffold in the synthetic receptor model systems act as the primary binding site of metals in these systems, and various adaptations made to this scaffold by modifying/removing its side arms have led to C


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differences in their ability to bind to the cation. Besides they have also demonstrated the importance of cation−π interactions in obtaining a stable, active conformation for cation transport using hydraphile channels made of compounds containing side arms with varying degrees of π density.106 M+−π interaction strengths are in the order Cs+ ≈ Rb+ > K+ > Na+, which is notably different from that observed in the gas phase, in case of X-ray crystallographic analysis of the 1:1 complexes of Na+, K+, Rb+, and Cs+ with hexakis-(methoxymethyl) benzene.107 Favorable steric conditions make it possible for the capture of alkali-metal cations via a pair of ether tentacles, loosely positioning them over the benzene ring. X-ray crystallographic analysis of noncyclic system of N-[3,5bis(α,α-dimethylbenzyl-2-hydroxybenzyl)] iminodiaceticacid ligands in which a potassium ion is bound by aromatic groups reveal a strong effect of cation−π interactions of metal ion with α,α-dimethylbenzyl groups in their coordination complexes.108 Studies on screening of Cambridge Structural Database (CSD) for metal ligand aromatic cation−π interactions and also on cationic metal complexes with aromatic rings of tetraphenylborate anion have been reported.109−111 Several sandwich complexes containing cation−π interactions involving cyclopentadienyl ligand have been isolated and examined in solid state.112,113 Crystal structure determination and FT-IR spectroscopy of tris(2,6-diisopropylphenoxy)-silanethiol has yielded evidence of intramolecular interaction of π-system of the arene with sodium cation in the presence of sodium salts as against an S−H···π interaction in solid state.114 In the current section we provide the details on the occurrence and characterization of cation−π interaction. The relevance of cation−π interaction in different fields is given in the following section.

Figure 2. Synthetic host−guest complexes stabilized by cation−π interactions: (a) ref 140, (b) ref 150, (c) ref 134, (d) ref 156, (e) ref 165, (f) ref 649, (g) ref 130, (h) ref 153, and (i) ref 115.

Several cagelike structures, in addition to modified cryptophanes,129,130 have been probed and display great ability to hold cations in their cavities.131−133 Tran et al. reported the synthesis of zorbarene, which has a calixarene-like structure, and showed how the tetramethylammonium cation has relatively strong association constants suggesting stronger cation−π mediated interactions with these hosts.131 Synthesis of cage-type molecules composed of phenyl walls and caps as hosts for the binding of ammonium and alkali metal cations through cation−π interactions has also been reported.132 This study suggests a gate-selective binding process in case of binding with Li+ and NH4 + ions and not the cavity size of the cage type molecules as a guiding factor. Studies on host molecules in which one diethylene glycol chain is incorporated along with two phenolic aromatic rings linked by a xylene spacer into a macrocycle reveal how this design serves to enhance any potential cation−π, N+−H···π and N+C−H···π interactions between the dibenzylammonium ion and the phenolic rings of the macrocycle.133 C3-symmetric macrotricycles built from π electron-rich resorcinol show a preferential recognition of NH4+ over K+, along with a poor response to the larger t-BuNH3+ cation, suggesting that NH4+ binds intramolecularly via cation−π interactions.134 Molecular structure of spontaneously assembled supramolecular clusters containing different metals, for example, GaIII, FeIII, TiIV, and six bis-bidentate ligands, encapsulated with different guests showed cation−π interactions on the exterior of the assembly along with π−π or CH−π interactions.135 As mentioned earlier with reference to several studies on solid state structures, Gokel and co-workers have employed the lariat ether model systems particularly in organometallic complexes having flexible side arms that can augment the complexation of a ring bound cation.22,23,61,99−105 A few studies have enumerated properties of modified crown ether model systems and emphasized their ability to bind cationic species.136−138 Rathore and co-workers report the design and synthesis of a hexaaryl benzene based receptor that contains a bipolar receptor site, which allows efficient binding of a single potassium cation by way of a synergistic interaction with a polar ethereal fence and with the central benzene ring through a

3. CATION−π INTERACTIONS 3.1. Host−Guest Complexes

Host guest complexes have served as extremely useful tools for studying molecular recognition between artificial/synthetic receptors and small guest molecules mediated by cation−π interactions.115−118 Design, synthesis and characterization of a large number of derivatives of cyclophane hosts enabled Dougherty et al. to provide insights into host guest binding both in aqueous and in organic solvents.33,35,36,39,119−121 Competition between binding to cavities of the synthetic receptors or aqueous solvation and the prominent role of the hydrophobic interaction in an aqueous environment were important factors reflected upon by them in these studies. Studies by Lehn and co-workers122,123 and Schneider et al.124,125 using modified cyclophane receptors as host systems with different guest species have also contributed to evaluate the strength of host guest interactions. Inokuchi et al. reported the selective recognition of alkali metal cations through cation−π interactions in cyclophanes on the basis of mass spectrometry even when the concentration of such complexes was very low in solution.126 The cyclophane receptor has been used as a model to demonstrate the dramatic dependence of binding energy of cation−π interaction on the counterion that is present alongside.127 Molecular dynamics (MD) simulation of cryptophane with guest tetramethyl ammonium ions suggest how the presence of TMA+ imparts rigidity in cryptophane molecules and hinders the fluctuations necessary for their release, leading to longer lifetimes of the host−guest complex.128 D


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cation−π interaction.139,140 Kim and co-workers have designed molecular systems with circular arrangement of benzene units ([n]collarenes) and also with ethene groups linked by −CH2 linkages ([n]beltenes) capable of acting as ionophores with high selectivity for specific cations.141,142 In addition, they have worked on the rational design of several receptor systems having high affinity to ammonium cations.143−145 Rebek Jr. and co-workers have reported synthetic receptors containing deep cavity for binding choline and carnitine molecules through an interaction between positively charged guest molecules and electron-rich aromatic surfaces of the host molecules.146 Catalysis by a synthetic receptor sealed at one end and salen functionalized at the other along with its zinc complex was shown to accelerate reactions of choline derivatives.147 Presence of cation−π interactions and a CO···Zn coordination bond simultaneously were revealed in these complexes. Uranyl−salophen complexes endowed with aromatic side arms have been shown to behave as very efficient receptors toward the tetralkylammonium halides by a combination of Lewis acid−base and cation−π interactions.148−150 Solid-state structures of complexes formed by the two armed uranyl− salophen complex receptor with CsF and with chlorides of K+, Rb+, and Cs+ reveal assembly of receptor into capsules fully enclosing ion quartets.151 It has also been suggested that cation−π interactions exist between ions and side arms of the receptor. Further studies on the functionalization of uranyl− salophen unit with conformationally flexible side arms bearing phenyl or naphthyl substituents promoting cation−π interaction152 and those forming elaborate architectures150 have also been reported. Pyrogallarenes153 and resorcinarenes154 have been exploited for their ability to bind to cations K+, Rb+, and Cs+. NMR and X-ray crystallograpic analysis in case of resorcinarene−metal complexes show the importance of complementarity and preorganization in establishing complexation affinity.154 Calixarenes, which are cyclic oligomers obtained from condensation of formaldehyde with para-alkylphenols under alkaline conditions, form a class of host molecules explored in a large number of studies because of their ability to form inclusion complexes governed by cation−π interactions.91,155−168 Chiral calixarene analogues, constructed by changing the methylene moiety to a chiral unit provide the possibility of enantiomeric selectivity toward chiral guests.158 A specific instance of cation−π-mediated interaction was shown in case of aminoacid moieties introduced into the cyclic array to verify their binding abilities to quaternary ammonium salts. Density functional theory (DFT) studies have demonstrated the role of contribution of multiple weak nonoptimal cation−π interactions (where cation does not approach in a path perpendicular to the aromatic ring center) to the overall binding strength of dehydroxylated calix[4]arene with alkali metal cations while underscoring the importance of neighboring aromatic faces.157 On the basis of binding studies of Nmethylpyridinium ion pairs with a series of monotopic and heteroditopic calix[4]arene-based receptors pairs, Secchi and co-workers have shown stabilization of these complexes through the cooperation of weak (CH−π and cation−π interactions) and strong (hydrogen bonding) intramolecular interactions.165 Studies on complexation between calix[4]areneN-azacrown-5 and metal cations K+ and Ag+ have resulted in novel molecular architecture resembling a molecular syringe.166 Cations in these systems are bound to one of two ionophoric binding sites composed of two oxygenic ligands and two

benzene rings through electrostatic interactions, as well as cation−π interactions. Thus a large number of systems where the interaction between the host and guest is mediated either in part or fully through cation−π interaction have been described. 3.2. Material Science

Experimental evidence for the presence of cation−π interactions in nanosystems including nanotubes, nanocapsules, nanospheres, nanogel-composites, etc., has been gradually forthcoming over the past decade.16,169−176 Several examples of synthesis of these materials with a predominant role for cation−π interactions in their structure or function are reviewed here.

Figure 3. Examples of cation π interactions in nanosystems: (a) ref 198 (b) ref 174 (c) ref 172, and (d) ref 16.

Kim and co-workers reported the synthesis of singlecrystalline silver nanowires of atomic dimensions inside pores of nanotubes composed of calix[4]hydroquinones (CHQs).16 The rich electron density of hydroquinone moieties in these nanotubes enables them to capture metal ions in their pores with high affinity through cation−π interactions. Since then several studies have reinforced the role of cation−π mediated interactions at a nanoscale. Park et al. have designed a methodology for constructing nanoscale self-assembled molecular capsules from resorcin[4]arene derivatives composed of rigid pendent pyridine groups and square planar metal complexes.169 Positively charged derivatives of N-alkylpyridinium are encapsulated inside these capsules via strong cation−π mediated interactions. Synthesis of multi 1,3 alternate calixcrowns of nanoscale dimensions which form ligand− metal complexes in different ratios have also been reported.170,171 1,3-alternate calix-thiacalix[4]crown trimers interact with encapsulated Ag+ cations by a cation−π mediated interaction at a nanoscale.171 Rissanen and co-workers have reported the synthesis and characterization of packing motifs of different shapes and sizes on interacting C-methyl resorcinarene with alkyl ammonium salts of several sizes.149 Nanotubular structures held together by well-ordered intratubular π−π or hydrogen bonding interactions hosting alkyl ammonium guests via cation−π interactions have also been reported. 172 Rudkevich and co-workers worked extensively on synthesis of structural analogues of single wall nanotubes (SWNT) to generate covalently linked calixarene based nanotubes.173−176 E


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electronic states of Li+ along the diffusion path on C60 were analyzed.197 Highly reliable DFT calculations on linear and branched polycyclic aromatic hydrocarbon (PAH) systems to quantify impact of increasing the size of π system on noncovalent interaction have been reported.198 The considered π systems serve as a mimic for graphene nanoflakes. Interaction energies observed lead to concluding the existence of a chemisorptive mode of interaction between metal ions and PAH surface. A differential preference for peripheral binding in case of branched PAHs compared to central aromatic rings in linear PAHs was shown for Li+ and Mg2+. In a follow up to this study, the effect of chirality and curvature of carbon nanotubes (CNT) on their interaction with mono and dicationic ions was explored. Interestingly with the exception of Be2+ contrasting preferences of monocationic ions to bind to the zigzag CNTs and of dicationic ions to armchair CNTs because of HOMO energy stabilization have emerged.199 Valencia et al. employed DFT calculations to understand the adsorption of Li, Na, and K on graphite surface.200 On the basis of analysis of the electronic charge distribution and density difference distribution they suggest that one valence electron is entirely transferred from the atom to the surface, giving rise to a strong interaction between the resulting lithium ion and the cloud of π electrons in the substrate. Ab initio and molecular mechanics studies on Li+, Na+, and K+ ions interacting with CNTs on their outer side show a cation−π-like interaction independent of its curvature.201 Selective adsorption of NO2+ cation on SWNT revealed adsorption to be dependent on concentration of cations along with diameter and the electronic structure of SWNTs.202 Moradi et al. performed DFT calculations to investigate cation−π interactions between alkali cations (Li+, Na+, and K+) and pristine C24 or corresponding doped fullerenes with either a single boron or nitrogen atom.203 A preferential adsorption site is found to be atop the center of a six-membered ring on the exterior surface of fullerene molecule, and there is an increase in the interaction energy for boron doped fullerenes, while for nitrogen-doped fullerenes it decreases. Hilder et al. report the design of synthetic nanotubes, which show selectivity to specific ions reminiscent of biological ion channels.204 Performing MD simulations on CNTs reveal an interesting finding that they selectively allow monovalent cations to move across while rejecting all anions.205 Further cation movement across a narrow pore chaperoned by the resident counterion is demonstrated. Several recent studies highlighted the effectiveness of cation−π interactions in dealing with organic pollutants present in the soil and other environments.206−210 Zhu and co-workers have explored the potential of cation−π interactions in adsorption of different kinds of molecules including antibiotics, organic pollutants, smectites, etc.207,208 These studies suggest the presence of strong adsorptive interactions between tetracycline and graphene surface mediated through van der Waals forces and cation−π bonding. A putative role for cation−π interactions between aromatic ring structures and environmental sorbents as an adsorption mechanism that affects fate and transport of organic contaminants has also been revealed recently.209 Graphene oxide has emerged as a potential effective absorbent for tetracycline antibiotics to remove them from aqueous solution.210 Spectrophotometry results implicated that π−π interaction and cation−π bonding were involved in effecting the absorption. A host of novel

These synthetic nanotubes were shown to be adept at entrapment and conversion of NO2/N2O4 gases. NO+ cations are strongly encapsulated within the π-electron rich calix[4]arene tunnel through cation−π interactions. Some examples of cation−π interactions involved in systems containing ionic liquids in combination with SWNTs/graphene have emerged recently.177−180 Fukushima et al. focused on imidazolium ion-based room-temperature ionic liquids which in combination with SWNTs form physical gels.181 Investigating the phase transition and rheological properties of the ensuing gel product, which contains untangled finer nanotube bundles, they suggest the system to be likely ruled by a large number of weak physical cross-links among the SWNT bundles for which molecular ordering of ionic liquids is responsible. This ordering is made feasible by way of a possible cation−π interaction between SWNTs and imidazolium ions on their π-electronic surfaces. A three-dimensional graphene−ionic liquid nanocomposite used to detect the presence of nitric oxide is also shown to be formed by a good interaction of graphene with the ionic liquid through cation−π interaction.182 Zhang et al. suggest a role for an imidazolium containing ionic liquid mediated cation−π interaction between surface of gold/ platinum nanosphere and multiwalled carbon nanotubes in the process of their assembly.183 Ramamurthy and co-workers have shown the aggregation of aromatic molecules within cation exchanged Y zeolites. This aggregation was traced to the presence of cation-aromatic π-interaction.184 In addition, they have expounded elaborately on the presence of alkali ions within zeolitic cages suggesting a major role for them through cation−π interactions.185 Avinash et al. have shown the synthesis of tryptophanappended naphthalene diimides, which can be self-assembled as H-type aggregates by the addition of sodium hydroxide.186 1H NMR spectra was used to establish evidence of sodium mediated cation−π interactions leading to structural variations in these molecules. In a study on pseudoisocyanine iodide (PIC) self-assembly on supported lipid bilayers, zwitterionic phospholipids were shown to mediate J-aggregate formation through specific cation−π interactions between PIC and the lipid head groups.187 Some instances of studies on cation−π interactions in surfactant behavior have also been shown.188−191 Wang et al. have provided evidence for a strong cation−π mediated macroscopic adhesion between synthetic polymers using XPS surface analysis and Raman spectroscopy.192 A highly cross-linked epoxy polymer working as a solid adherent and three polymer substrates were chosen as systems in which the sole contribution to direct adhesion was from noncovalent interactions. A large number of studies emphasize the interaction between neutral metals and graphene or carbon nanotubes. However, computational studies on cation−π interactions in nanosystems are comparatively limited.193−195 Tachikawa et al. have studied the diffusion dynamics of Li+ on a model surface of amorphous carbon composed of C96H24.196 Following the analysis of the diffusion processes of Li+ on the model surface by semiempirical MO theory and direct MO dynamics method they were able to illustrate the preference of binding of Li+ at the edges of the cluster. Significant charge transfer from Li+ to the cluster surface along with clear temperature dependence for transport of Li+ on the same was also made in this study. More recently they also showed the mode of diffusion of the Li+ on C60 surface. Two stable binding sites were indicated and F


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and pyridinium salts with significant contributions from induction and electrostatic energies show the importance of cation−π interaction in these systems.228 Pyridinium−π interactions were shown to have a remarkable effect on stereoselectivity during the photodimerization of the transstyrylpyridines.229 X-ray crystallographic analysis supported the existence of such a pyridinium−π interaction. More recent studies reveal the role of cation−π interactions in controlling molecular conformation and in crystals including formation of molecular dimers.230−234 Fossey and co-workers elucidated the presence of an intramolecular cation−π interaction in Nmethyl-pyridinium iodides formed from conversion of conformationally flexible pyridines.235 An associated large change in fluorescence response was used by them as a tool to sense the presence of low concentrations of alkylating agents in solution.236 Jacobsen and co-workers reported the development of a thiourea catalyst for the enantioselective bicyclization of hydroxylactams, wherein stabilizing cation−π interactions play a principal role in asymmetric induction.237 Stabilization of a dominant transition state for achieving high levels of enantioselectivity was suggested. The concept of small molecule catalysts promoting enantioselective reactions solely through cooperativity of noncovalent interactions including cation−π interactions was put forward.238 Ishihara et al. have designed a small-molecule catalyst which uses an intramolecular cation−π interaction for guiding enantioselective Diels−Alder and Mukaiyama−Michael reactions.239,240 Shibasaki’s M3(THF)n(BINOLate)3Ln complexes are examples of asymmetric Lewis acid catalysts, which readily bind substrates when the metal is Li and not Na or K. This was attributed to structural evidence for the absence of cation−π interactions involving Li and three carbons of BINOLate naphthyl rings unlike the case of Na and K complexes.241 Monje et al. explored the development of new synthetic uses for α-oxy-organolithium compounds and demonstrated quantitatively the stabilizing effect of cation−π interactions in Sn−Li exchange equilibria.242 Cation−π interactions are shown to contribute alongside CH-π interactions, steric repulsion and lowering of torsional strain in the transition state in case of additions of aryl-substituted silyl enol ethers to a chiral oxazolinium ion.243 Schneider et al. suggest a role for cation−π interaction between a phenyl ring and protonated nitrogen centers of the polymer backbone in chitosan while studying translation of chiral recognition into mechanical motion.244 While exploring the scope of cationic polycyclization methodology to produce a wide range of interesting structures, Shenvi et al. showed the relationship between substrate structure and π-facial selectivity revealing subtle differences in π-facial selectivity at the double bond involved in closure of the ring.245 Recently a series of alkali metal cation functionalized titanosilicate molecular sieves were reported in which cyclohexene epoxidation with H2O2 as a test reaction was shown and a distinct relationship between catalytic activities, intermolecular interaction energies along with a predominant presence of cation−π interactions were reported.246 Heavier alkali cations are capable of improving the diffusion properties of olefin molecules acting as reversible adsorption sites via a weak cation−π interaction, exhibited enhanced catalytic activity.

applications employing cation−π interactions have come into light in the field of nano and material sciences. 3.3. Catalysis and Reaction Mechanisms

Another aspect in which cation−π interactions have found rapid application is the field of catalysis and organic synthesis.211 Dougherty et al. explored the role of cation−π interaction and high polarizability of positively charged transition states in catalysts for alkylation reactions operating in cyclophane hosts.38,41 Cation−π interactions have been invoked as one of the important controlling features in stereoselective reactions.212−234 There are a few reactions which provide evidence for cation−π interactions influencing reaction selectivities. Neda et al. demonstrated the application of cation−π interactions to synthetic reactions in the case of stereoselective β-galactosylation in the presence of calixarene.212 The photooxygenation of alkenes adsorbed on dyesupported zeolites is one such instance which has been exploited due to the significant enhancement of product regioselectivity. In this regard, Ramamurthy and co-workers have elucidated the preferential binding of alkali metal cations to ideally placed phenyl rings via a cation−π interaction as a strategy for unidirectional photoisomerization in diarylcyclopropanes.213 Synergism of steric effects and cation−π interactions in the diastereoselectivity trends in the photooxygenation of chiral alkenes bearing a phenyl and an alkyl group at the stereogenic center has also been reported.214−216 Aubé and co-workers showed that Lewis acid-promoted reactions of hydroxyalkyl azides with substituted cyclohexanones proceed with high levels of diastereotopic groupselectivity on modulation by through-space cation−π stabilization.217 Studies on bridged bicyclic lactam synthesis where regiochemistry is controlled by a through-space interaction of an aryl group with a cationic leaving group in a key reaction intermediate have been undertaken.218,219 A series of 1,3hydroxyalkyl azides bearing electronically tuned aromatic groups were shown to react with ketones to conformationally restrict the rotational orientation of the aromatic substituent.220 Cation−π interaction between an aryl moiety and an N2+ leaving group serves as a key determining factor. These studies were able to demonstrate that maximization of attractive nonbonded interactions plays a vital role in determining the stereoselectivity of reactions. The decreasing ability of cation−π interactions to act as a controlling element when Lewis acids coordinate to substituents on the aromatic ring at the αposition adjacent to the ketone was shown to establish tunability of the interaction.221 The role of cation−π interactions in a host of chiral amine catalyzed reactions that proceed via nitrogen-containing cationic intermediates particularly iminium, pyridinium, imidazolium, and thiazolium intermediates have been studied extensively by Yamada and co-workers.222−225 Pyridinium cation−π interactions are useful to bias the conformation of amide derivatives in asymmetric synthesis. An example in this regard is the study on synthesis of chiral 1,4-dihydropyridines with excellent stereoselectivity using the presence of an intramolecular cation−π interaction.226 Employing a simple 1 H NMR based pH-dependent titration profile, evidence for intramolecular aromatic interaction between pyridinium and neighboring phenyl groups mediated through a weak cation−π interaction in protonated nicotinamide derivatives was established.227 Attractive interactions between a thiocarbonyl group and a pyridinium nucleus in selected nicotinic amides G


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Figure 4. (a) Examples of cation−π interactions in systems containing arginine and adenine−arginine interactions along with their PDB IDs. (b) Examples of cation−π interactions in nucleic acids, mRNA cap binding proteins, histones, and telomeres along with their PDB IDs. (c) Examples of cation−π interactions in enzymes along with their PDB IDs. (d) Examples of cation−π interactions important in structure of biological molecules along with their PDB IDs. (e) Examples of cation−π interactions in other classes of biomolecules along with their PDB IDs.

4. CATION−π INTERACTIONS IN BIOLOGICAL SYSTEMS Dougherty’s group is one of the first groups to systematically analyze the different biological systems where cation−π interactions were predominant and functionally important.15 However the last 15 years has shown an exponential increase in the different kinds of biomolecules where cation−π interactions find a role and are operative. The number of structures in Protein Data Bank (PDB) where cation interacts with an aromatic π system are continuously increasing and metal ions are implicated in a number of important biological functions.24 Several of these studies on different classes of biomolecules where these interactions prevail have been detailed below.

on their structure. This has been explored by application of a variety of techniques on different model systems.247−251 Pletneva et al. reported energies of cation−π interactions based on 1H NMR spectroscopic titrations between aminoacid side chains in model systems.57 Analyses of dynamic complexes of several pentapeptides lead to the design of novel peptides with enhanced cation−π interactions. Preorientation of the cationic and aromatic side chains by multiple forces was deemed to be crucial for producing a stable cation−π interaction. Kallenbach and co-workers showed how single Trp/Arg interaction on the surface of a peptide can make a significant net favorable free energy contribution to helix stability if the two residues are positioned with appropriate spacing and orientation.252 This was in contrast to Phe/Arg (i, i + 4) cation−π interaction, which does not contribute to helix stability in terms of net free energy.253 A simple interaction

4.1. Peptides

The stabilizing nature of the cation−π interaction between different aminoacids in peptide chains has a substantial impact H


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proteins are involved in effecting control in this process. Methylation of histone lysine, followed by recognition of such a methylated group by an aromatic cage, has been shown to be vital in the gene expression control. Several important studies have emerged in this context in the recent years.280 The structural elucidation of complex between the Drosophila HP1 chromodomain and the histone H3 tail with a methyllysine at residue 9 revealed a methylammonium group caged by three aromatic side chains.281 Further, a comparison of different extent of methylation suggested a role for cation−π and van der Waals interactions, with trimethylation slightly improving the binding affnity. Nielson et al. show how dimethylated nitrogen of Lys9 in the mouse histone H3 is flanked by a binding pocket provided by three aromatic side chains, Tyr21, Trp42, and Phe45 of the heterochromatin protein 1 (HP1).282 Waters and co-workers compared the interaction of trimethyl lysine and its neutral analogue (tert-butylnorleucine) with tryptophan, in a βhairpin peptide model system based on evidence found for presence of cation−π interactions between the methylated lysine and the aromatic pocket in chromodomains.283 Comparing the near-identical size, shape, and polarizabilities of the two side chains that however differ in their charges, they were able to demonstrate the necessity of a cation−π interaction to binding with the chromodomain. Structural studies on polycomb protein EED important for maintenance of repressive chromatin states show how aromatic cage containing carboxy-terminal domain of EED specifically binds to histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks.284,285 Li et al. demonstrated the molecular basis for specific recognition of residues 1−15 of histone H3 trimethylated at Lys4 by a plant homeodomain (PHD) finger of human BPTF (bromodomain and PHD domain transcription factor).286 The long side chains of an arginine and K4Me3 fit snugly in adjacent preformed surface pockets, providing a molecular explanation for H3K4Me3 site specificity. Cation−π interaction was also implicated for its contribution in the process of recognition of 5′ mRNA cap with its partner cap binding protein during protein translation.287−294 Quiocho and co-workers have determined crystal structures of ten complexes of cap nucleosides and nucleotides and methylated bases of the vaccinia virus VP39 in cap-specific RNA 2′-Omethyltransferase to understand the atomic basis of cap binding.288 Using fluorescence stopped-flow technique, they later also revealed how the fast and precise tight insertion of the 7-methylguanine moiety in between two stacked aromatic side chains mediated by cation−π interaction was operative.289 Stolarski and co-workers have employed biophysical methods, thermodynamic studies, and X-ray crystallographic analysis to understand the interaction between 7-methylguanine of mRNA 5′ cap and eukaryotic translation initiation factor (eIF4E).290,291 Cation−π stacking of 7-methylguanine with two tryptophan residues is shown to be a precondition to form three more hydrogen bonds with other aminoacids. Studies on mutants in which each tyrosine was replaced by phenylalanine or alanine suggest a crucial role for cation−π stacking in specific cap recognition by comparing experimentally derived Gibbs free binding energy with the stacking energy calculated by ab initio methods.292 Recently Zou et al. addressed an important question on how methyl-CpG binding domain proteins are capable of recognizing methylated DNA. MD simulations coupled with quantum chemical investigations show that there is an increased hydrophobic interfacial contact area, as the

between a phenyl ring and ammonium cation was shown to be similar in magnitude to a salt bridge in an α-helix thus lending stability to the peptide in aqueous solution.254 Waters and coworkers have then investigated the effects of methylation and acetylation of Lys and Arg and variation of chain length on stability of β-hairpin peptides by conducting several studies.255−261 Modifications of Lys and Arg groups resulted in design of peptides, where cation−π mediation plays a vital role in enhancing stability of structure. Studies by Slutsky et al.262 however could not find convincing evidence for stabilization by cation−π interactions even though they report an (i, i + 4) Arg−Phe pairing, which appears to specifically stabilize both two-stranded and three-stranded coils. They infer that it is hydrophobic packing, rather than the cation−π effect, which is more likely to be responsible for the stability of peptide in their model system. 4.2. Adenine- and Arginine-Containing Biomolecules and Ade−Arginine Interaction

Tripsianes et al. have reported the structure of symmetric and asymmetric dimethylated arginine bound SMN and SPF30 Tudor domains in ribonuclear protein complexes.263 Dimethylarginine recognition by electrostatic stabilization through cation−π interactions was reported in this aromatic cage of the Tudor domain. The role of arginine solutions on suppression of protein aggregation in the context of their ability to form cation−π interactions is also being recognized recently.264,265 Cumpstey et al. have reported molecular modeling study of aromatic lactose 2-O esters in complex with galectins, confirming their inhibitory efficiency because of the formation of strong interactions between the aromatic ester moieties and the arginine guanidinium groups of galectin-1.266 Using mass spectrometry as an analytical tool Woods has explored interpeptide interactions, in peptides epitopes containing adjacent aromatic residues and Arg as a model to delineate role of cation−π complexes in protein−protein interaction.267 Crystal structures of the NADP+-dependent aldehyde dehydrogenase and tropinone reductase show interactions of an arginine residue with an adenine moiety via a cation−π interaction.268,269 The ability of adenine and guanine groups of different adenophostin A and guanophostin A analogues to interact with arginine in the active site of inositol 1,4,5-trisphosphate receptor is also mediated through a cation−π interaction.270−272 4.3. Nucleic Acids, mRNA Cap Binding Proteins, Histones, and Telomeres

Williams and co-workers reported a potential role for magnesium and other biological inorganic ions to unstack bases of DNA and RNA through cation−π interactions requiring access to cations or their first hydration shells to faces of nucleic acid bases.273,274 A putative role for cation−π interactions along with H-bonds and stacking between loop residues and the outer G-quartets has been suggested in the formation and stability of dimeric DNA G-quadruplexes.275−278 Studies by Horvath et al. on the crystal structure of telomere end binding protein in complex with ssDNA show how Arg140 is uniquely situated to recognize the single stranded DNA based on its ability to form a cation−π interaction with a G10 nucleabase, while simultaneously participating in hydrogen bond networks that lock the base in its position.279 Regulation of gene expression is done by complex protein− protein and protein−DNA interactions with chromatin. More often than not post translational modifications of histone I


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Arabidopsis thaliana displays an extensive network of intramolecular cation−π interactions surrounding Trp 285 and Arg 286 in one of its blades.348 This study put forth a molecular mechanism for UVR8-mediated ultraviolet-B perception, which results in the destabilization of intramolecular cation−π interactions, thereby leading to disruption of several critical intermolecular hydrogen bonds mediated by Arg286 and Arg338 and yields subsequent dissociation of the UVR8 homodimer. Gasymov et al. reveal how the interloop cation−π interaction in the pair Phe28−Lys108 contributes significantly to stabilize the conformation of the loop in the case of tear lipocalin present at the ocular surface.349 Horng and co-workers provide experimental results indicating the importance of cation−π interactions in promoting the self-assembly of collagen triple helices into a higher-order structure in a headto-tail manner.350,351 Kenoth et al. suggest a role for cation−π interactions along with salt bridge formation between different side chains to contribute to HET-C2 glycolipid transfer protein fold stability.352 Recent studies on integrins which are cell adhesion molecules revealed a role for a highly conserved aromatic residue in β7subunit (Phe185) linking the specificity-determining loop and the synergistic metal ion-binding site through cation−π interaction.353 This study neatly elucidated how disruption of the above-mentioned cation−π interaction caused impaired α4β7-mediated signaling. Another study on small heat shock protein αβ-crystallin suggests a possible role for an intermolecular cation−π interaction between Phe118 and Arg116 of two different monomers to contribute to dimer stability.354 Systematically substituting the tyrosine with fluorinated phenylalanine in yeast cells for the interaction involving Tyr13 and Arg58 of a peptide α factor in a GPCR lead to evidence for cation−π mediated trigger for signal transduction in these systems.321 Contestabile and co-workers suggest a vital need for presence of Tyr55 bound through a cation−π interaction with Arg235 in the enzyme serine hydroxymethyltransferase, for correct positioning of the cofactor and for the maintenance of the structure of several loops involved in substrate and cofactor binding.355 Hoette et al. have shown the contribution of both cation−π and charge− charge interaction in case of binding of siderocalins to ferric siderophores.356 By using a series of isosteric enterobactin analogues coupled with small molecule crystallography and fluorescence based binding assay the contribution from the cation−π interaction was found to be more important to binding than the Coulombic attraction between the anionic substrate and the cationic calyx. Experimental and computational studies involving all atom dynamics simulations and double mutant analysis in the villin headpiece HP36 demonstrated the role played by interaction between Phe47 and Arg55 in stabilizing the native state through a cation−π interaction.357 Prajapati et al. however report in case of four different proteins where Lys interaction with aromatic aminoacids is measured, that at room temperature cation−π interactions are at best weakly stabilizing and in some cases destabilizing, while at elevated temperatures, they are generally stabilizing.358 Studies on inhalation of drugs and inhibition of NMDA receptors show that their potencies are correlated strongly with their abilities to engage in cation−π interactions.359 X-ray crystallographic studies of ligand complexed to human phosphatidylcholine transfer protein show how positively charged headgroup of choline interacts with a cage formed from three π faces of aromatic rings.360

cation−π interaction of the 5-methyl group lead to enhanced binding affinity.293 While exploring the potential of small molecule carriers along with siRNA as transporting agents, MD and NMR analysis reveal stabilization of carrier guanidines by cation−π interactions involving a biphenyl system.294 4.4. Enzymes

Many studies have focused on the possible role of cation−π interactions in enzymatic function and activity.295−320 A synergistic combination of X-ray structural elucidation, experimental site-directed mutagenesis along with molecular modeling validation has been employed to explore the molecular basis for the unique enzymatic ability.299,300 Goldstein et al. have determined the crystal structure of the enzyme phosphatidylinositol-specific phospholipase C in Staphylococcus aureus.301 They suggest that an intramolecular cation−π interaction in the enzyme’s structure provides an explanation for the activity of the enzyme at acidic pH. This titratable intramolecular cation−π interaction between His258 and Phe249 also effects rim loop displacement while undergoing a pH change. Reductive and oxidative half-reactions of the wild-type fructosamine oxidase enzyme from Aspergillus f umigatus was analyzed by employing transient kinetic studies.302 A specific cation−π interaction involving Lys53 aminoacid and flavin moiety of FAD redox cofactor was found to be critical for flavin reduction. However, this interaction does not effect a subsequent reaction with molecular oxygen. Several examples of cation−π interactions in enzyme activity reveal formation of cation−π stabilized carbocation intermediates.303,304 Allemann and co-workers have provided experimental evidence lending strong support for cation−π interactions in establishing energetically demanding stabilization of transition states and reaction intermediates in sesquiterpene synthase chemistry.304 In the specific instance of Penicillium roqueforti aristolochene synthase using X-ray structural analysis of different mutant and recombinant enzymes, they propose that cation−π interaction between indole ring of the active site residue Trp334 and farnesyl diphosphate could be responsible for stabilization of eudesmane cation intermediate in the aristolochene biosynthetic pathway. X-ray structure determination and stopped-flow kinetic experiments on inhibition of a key enzyme Sadenosylmethionine decarboxylase in the polyamine biosynthetic pathway by ligands, such as 5′-deoxy-5′-dimethylthioadenosine and 5′-deoxy-5′-(N-dimethyl)amino-8-methyladenosine revealed how a favorable cation−π interaction between the ligand and the aromatic side chains of Phe7 and Phe223 are vital.305 Zhang et al. have recently reported studies on rabeprazole and its various analogues for the inhibition of small C-terminal domain phosphatase enzymes and their role in human neuronal silencing.306 Mutation studies reveal a cation−π interaction involving a sulfoxide group of rabeprazole and Tyr158 side chain to be significant. Presenting crystallographic evidence for peptide deformylase family enzymes over a range of pH values Zhou et al. highlight two pairs of Arg109 mediated cation−π interactions, as well as hydrogen bonds as important to stabilize the different loop conformations of the enzyme.307 4.5. Protein Structure

A large number of protein structures have now been characterized wherein a structurally important role for cation−π interaction is shown.321−360 A few recent and salient examples are detailed below. The photoreceptor protein UVR8 in J


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4.6. Viruses and Extremophiles

of ligand in the protein environment was suggested as a simple indicator of cation−π interactions.382

A few examples from different studies on viruses where a significant role for cation−π interactions has been ascribed is given below.361−366 Takeuchi and co-workers described a key role for a specific cation−π interaction between a protonated His and a Trp aminoacid in Influenza A virus in the case of the protonated ion channel M2.362,363 Besides they also investigated the structure and mechanism of BM2 proton channel in the Influenza B virus using a 31-mer peptide to represent the transmembrane domain of the protein.364 Using fluorescence and Raman spectra for the wild and mutant BM2-TMP, they show how a cation−π interaction with Trp23, His19, and His27 imidazole rings promotes channel opening and enhanced channel activity. Studies on the Norwalk virus specifically on histo-blood group antigens (HBGA) reveal how precisely juxtaposed polar side chains engage the sugar hydroxyls in cooperative hydrogen bonding and a His−Trp pair involved in a cation−π interaction contribute to selective and specific recognition of A and H-type HBGAs.365 Rosen et al. suggest that interstrand cation−π interactions between positively charged and aromatic residues induce a phenotypic conversion involving a switch from R5 virus to the X4 conformation as a result of the S306R mutation in the HIV-1 coreceptor.366 Several studies focus on cation−π interactions in the context of understanding thermo or psychro stabilizing interactions.367−372 While studying the features responsible for enhanced stability of proteins in thermophiles Chakravarty et al. undertook a genomics based study.370 Analysis of a data set of models of 900 mesophilic and 300 thermophilic protein single chains revealed contribution of cation−π interactions along with surface salt bridges to protein rigidity, and increased thermal stability owing to stabilization of secondary structure. Matsumara et al. reveal presence of a unique Na+−π interaction with Phe16 in the wild type T1 lipase of Geobacillus zalihae strain based on crystal structure analysis.371 MD simulations on the same molecule in the presence and absence of accurate Na+−π interaction energy have shown how a large enthalpy gain stabilizes the catalytic site. Further the cation−π interaction in this lipase establishes a stable core structure by combining a hydrophobic aromatic ring and hydrophilic residues.372

4.8. Betaine-Containing Systems

Numerous studies have elucidated the nature of interaction in betaine-specific binding proteins.383−388 High resolution structure of periplasmic binding protein ProX in complex with its ligands, glycine betaine and proline betaine, revealed cation−π interactions between the positive charge of the quaternary amine of the ligands and three tryptophan residues as key determinants of the high affinity binding of compatible solutes by ProX.384,385 Ressl et al. have reported the X-ray structure of Na+-coupled symporter BetP from Corynebacterium glutamicum, in a highly effective osmoregulated uptake system for glycine betaine.386 Glycine betaine molecule is typically bound in a tryptophan box occluded from both sides of the membrane with aromatic side chains lining the transport pathway by a combination of cation−π and van der Waals interaction. Focusing on the interactions of glycine betaine as an osmolyte in terms of its interactions with molecular surfaces in water, it was shown that glycine betaine competes effectively with water to interact with amide and cationic nitrogens via hydrogen bonding and especially with aromatic hydrocarbon through cation−π interactions.387 Structural and site-directed mutagenesis evidence coming from plant ALDH10 enzymes have also proved the involvement of box like aromatic residues in binding of the trimethylammonium group of betaine aldehyde.388 4.9. Cu-Containing Proteins

CusF protein is a copper trafficking factor, in which strong cation−π interaction with a tryptophan residue and thioether ligation stabilize metal binding.389−391 Spectroscopic studies in this protein reveal a wavelength-dependent inversion of Raman intensities along with the reported tryptophan mode frequency shifts implying a strong cation−tryptophan π-interaction for both the Cu(I) and Ag(I) forms of the protein.389 Chakravorty et al. have used QM calculations and MD simulations for the CusF chaperone molecule in both apo and bound states emphasizing the importance of the Cu+−Trp 44 interactions in protecting Cu+ from water oxidation.392 The measurement of the CD spectrum of a 10-mer bioactive peptide, neuromedin C associated with presence of an analogous band pair lead to the discovery of the Cu2+−Trp interaction in the peptide.393 MD simulations performed to gauge the structural effects of copper coordination in the octapeptide region of the human prion protein indicate a significant role for cation−π interaction between tryptophan indole ring and Cu(II) without any water mediation.394

4.7. Antibody-Binding Interactions

Studies on binding of several antibodies to the corresponding protein moieties is also mediated partly via cation−π interactions.373−382 Ringe and co-workers have analyzed the crystal structures of an antimorphine antibody 9B1 and its complex with morphine to reveal a double cation−π mediated interaction with two Trp residues.379 A similar study on cocaine bound to anticocaine antibody M82G2 revaled how the antibody utilizes water-mediated hydrogen bonding, cation−π and (π−π) stacking interactions to provide specificity.380 A more recent example is of the cockroach allergen Blag2 where cation−π interactions between Lys65, Arg83, and Lys132 with tyrosines 53, 92, and 33 from the mAb 7C11, as well as electrostatic and hydrophobic interactions, were important for monoclonal antibody and IgE antibody binding.381 Laserinduced fluorescence spectroscopy in low and high resolution modes was employed to explore the interaction between pyrene of benzopyrene and its derivatives and anti-PAH monoclonal antibody complex. Narrowing of the fluorescence origin band

4.10. Cyclases

A large number of studies on terpenoid metabolites and associated terpenoid cyclases show a significant role for stabilization of carbocation intermediates in the cyclization cascade through cation−π interactions.395−413 Christianson and co-workers used catalytic antibody technology to show how each cyclase contains numerous aromatic residues which not only form a template to bind the productive conformation of a flexible polyene substrate but also stabilize carbocation intermediates by electrostatic interactions with their π electron clouds.404,405 Mutagenesis of aromatic residues Phe95, Phe96, and Phe198, which are well-oriented to stabilize the carbocation intermediates in the cyclization cascade through cation−π interactions results in the production of alternative sesquiterK


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method to incorporate a series of increasingly fluorinated phenylalanine side chains at position 449 supported a strong cation−π component to the TEA block. Following this, several studies now seek to establish the role played by cation−π interactions in the K+ and Na+ ion channels.419−426 While studying the physical determinants for strong voltage sensitivity in case of inward-rectifier K+ (Kir) channels, Xu et al. have shown the presence of cage-like arrangement of four Phe255 side chains in the isolated cytoplasmic pore which may possibly form cation−π interactions.423 Ahern and co-workers have demonstrated how the cation−π interaction between Lys374 and Trp290 in Shaker potassium channels is mechanistically insightful considering the strong en face geometric preference of cation−π interaction.424 Dougherty et al. studied the incorporation of fluorinated derivatives of phenylalanine into a voltage-gated sodium channel to demonstrate how presence of an aromatic residue in a specific location in the external vestibule of the ion-conducting pore is mandatory for tetrodotoxin sensitive sodium channels.425 In contrast, there exist varying opinions on extent of contribution from cation−π interaction between NH4+ ions and aromatic residues belonging to the ammonia transporter AmtB protein.427−429 Several examples of biological receptors which include members of Cys-loop receptor family, mediate rapid chemical transmission of signals.430−434 Most of these case studies have shown a role for the cation−π interaction mediated molecular recognition. A crucial role for cation−π interaction between agonist and Tyr and Arg residues of the GABA receptor has been explored using unnatural aminoacid mutagenesis, patch clamp electrophysiology experiments and MD simulations.435−440 Another classic example is of acetylcholine binding protein where binding of the quaternary ammonium group of the agonist, acetylcholine to the nicotinic acetylcholine receptor has been extensively studied.441−463

pene product arrays because of corresponding altered modes of stabilization of carbocation intermediates.406 Hoshino and coworkers experimentally validated the involvement of cation−πmediated stabilization of intermediates in triterpene biosynthesis.407−409 The catalytic sites of Phe365 and Phe605 in squalene hopene cyclase were substituted with O-methyltyrosine, tyrosine, tryptophan, and different fluorinated phenylalanines to gauge their effect on the cation−π binding energies. Besides they also investigated the role of conserved phenylalanine residues both in squalene-hopene cyclases and in hopene synthase enzyme for facilitating the ring expansion and for stabilizing the intermediate carbocation.410,411 In the context of understanding the dichotomy between accurate and multifunctional cyclases Lodeiro et al. do not find a major role for cation−π based stabilization of carbocation intermediates specifically with regard to baruol synthase, a cyclase from Arabidopsis thaliana and the structural and mechanistic diversity of its product profile.412 Wu et al. conducted sitesaturated mutagenesis experiments on the His234 residue of Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase and reviewed the enzyme conformation, the cation−π interactions between the carbocationic intermediate and the side chain functional group, besides the product profile.413 Although not ruling out the possibility of an alternative cyclization pathway they conclude that a mutant compromises the cation−π interaction between the intermediate carbocation and Phe699, resulting in destabilization of the tertiary cation created during the C-ring formation. 4.11. Factor Xa Protein

Johnson and co-workers proposed a cation−π binding mechanism for synthetic inhibitors of Factor Xa, a vital serine protease in the blood coagulation cascade.414,415 They suggested that a cavity-like S4 subsite formed by the three π faces of aromatic residues (Tyr99, Phe174, and Trp215) serves not only as a hydrophobic pocket, but also forms a cation recognition site. Diederich and co-workers have investigated the S4-pocket of Factor Xa based on X-ray crystallography and the aromatic box formed by the side chains of Phe 174, Tyr99, and Trp215 as an effective onium binding site.416 They established the free enthalpy increment for cation−π interactions in this box as 2.8 kcal/mol. While examining the mechanism of inhibitor action against this protein, stepwise Nmethylation, from the primary ammonium ion to quaternary onium ion was shown to result in the binding affinity increasing by a factor of 1000.417 Design of a series of high affinity ligands (nonpeptidic small molecule inhibitors) with inhibitory constants in nanomolar range ensued from this understanding of cation−π-mediated interaction.418

4.13. Biomembranes

MD simulations have been used to indicate the role of cation−π interactions in membrane environments not only in a scenario of exploring the binding, partitioning, and folding of proteins but also to know their role in antimicrobial functioning of peptides.464−469 Khandelia et al. report a persistent cation−π interaction between Trp11 and Arg13 in a 13-residue antimicrobial peptide indolicidin near the interface in dodecylphosphocholine micelles as responsible for its welldefined boat-shaped structure.464 Studies on specificity of antimicrobial peptide cateslytin to fungal membranes show mediation by attractive dipole−dipole interactions between basic arginine residues and negatively charged lipid head groups and cation−π interactions between arginine and the conjugated π electrons of the ergosterol fused-ring system.465 Simulation studies on a pentapeptide have shown how the conformations of the peptide are restricted by their presence at the aqueous−organic interface and can be assigned to a few major conformational clusters.466 A cation−π interaction between the Arg and the Trp side chains in these pentapeptide conformations was shown to be stable in the lipid bilayer for about 15 ns before breaking. In the case of integral membrane proteins having a preference for aromatic residues at the interface between the lipid bilayer core and the aqueous phase, Petersen et al. report cation−π mediation for several tryptophan residues via the indole group interaction with nitrogen of headgroup of lipid moiety.468 Studies on helix− helix interactions in transmembrane segment of membranous

4.12. Small Molecule Recognition

Dougherty et al. provided examples of different ion channels where a putative role for cation−π mediated selectivity has been suggested.15 In the subsequent years several studies on ion channels have come forth particularly in the case of K+ ion channels.419−424 Following the structural elucidation of the shaker ion channel in Drosophila, the X-ray crystal structure of KcsA K+ channel in Streptomyces lividans was determined in two different orientations of Tyr 82.419 The positioning of the aromatic rings in one of the two orientations does not permit formation of a cation−π interaction. Dougherty et al. subsequently investigated whether a cation−π interaction is operative between a tetraethyl ammonium channel blocker and such an aromatic ring.420 The in vivo nonsense suppression L


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proteins show cation−π interactions particularly between the aminoacids Lys and Trp, Tyr, or Phe, along with weakly polar interactions between pairs of aromatic residues to enhance the strength of oligomerization of hydrophobic helices significantly.469 Besides studies on kinases, including choline kinase and p38 MAP kinase, which are important targets in treatment of diseases such as cancer, have also helped to reinforce the role and relevance of cation−π interactions in the active site of enzymes.309−316 The foregoing discussion forms strong evidence for relevance of cation−π interactions in biology and importantly for their ubiquitous presence. It is but the tip of the iceberg with a vast number of large biological molecules yet to be explored by rigorous application of synthetic, spectroscopic and computational procedures revealing the contribution of cation−π interactions to full extent.

Table 1. List of Online Server/Tools That Predict Cation−π Interactions in a Protein S. no. 1.

name

2.

Cation Aromatic Interaction Database (CAD) CaPTURE

3.

Protein explorer

web site http://203.199.182. 73/gnsmmg/ databases/cad/ http://capture. caltech.edu/ http://molvis.sdsc. edu/pe1.982/ protexpl/cationpi. htm

ref

criteria

24

geometry based

PDB

471

energy based geometry based

PDB

472

source

PDB

While all of them essentially check for presence of a cation and aromatic group in close proximity, they differ in the criteria employed to define and evaluate these interactions. Typically a cationic side chain of either Lys or Arg and an aromatic sidechain of Phe, Tyr, or Trp are considered. Depending on its protonation state, His can participate in cation−π interactions either as a cation or as a π-system and is thus considered as both in some cases or not at all in others. The search criterion in a majority of these database searches is primarily structural in nature, with an emphasis on a specific cutoff geometric parameters involved between cation side-chain and center of π ring. Three of the most commonly used applications in considering cation−π interactions from the PDB are elaborated below.

4.14. Drug Design and Scoring Functions

Quantitative understanding of drug receptor interaction with biological receptors is of prime importance in pharmacy. While there are plenty of docking protocols most of them rely on scoring functions for hydrogen bonding and van der Waals interactions. However in many instances the interactions, such as cation−π, π−π, and anion−π interactions, seem to be playing an important role. Due to the unavailability of proper scoring functions for cation−π interactions the current docking protocols appear to be largely inadequate. Cation−π interactions become important especially when the ligand is charged, as noticed in the case of bis-pyridonium ligands developed toward the choline kinase inhibition.309−311 However in other cases, like that of p38 MAP kinase enzyme the cation−π interactions are responsible in triggering conformational changes.312−316 The presence of cation−π interactions in key positions in the active site of proteins, provides scope to control the processes, which they regulate and helps in modification or design of new ligand molecules. The studies on inhibition of Factor Xa,416,417 ion channels422 and cation−π mediated side effects of inhaled drugs359 constitute examples of systems where the presence of cation−π interactions have been exploited. In this context cooperativity between different nonbonded interactions plays a key role. Hangauer and co-workers designed a series of thrombin inhibitors which exploited the cooperativity between the hydrophobic interaction and the hydrogen bond at the active site to dispel the common notion that ligand binding affinity contributions of noncovalent interactions are additive.470 As mentioned earlier ability of adenine and guanine groups of different adenophostin A and guanophostin A analogues to interact with arginine in the active site of inositol 1,4,5trisphosphate receptor through a cation−π interaction has been explored by Potter at al. to design potent inhibitors for this target.270−272 Although there are now several examples of studies for design of new compounds against specific drug targets the improvement of different scoring functions to give a correct representation of cation−π interactions still remains a challenging task.

5.1. Cation Aromatic Interaction Database (CAD)

An understanding of the metal ion interaction with aromatic groups in the PDB is rather scarce. This lacuna becomes significant while modeling various processes in metalloproteins. With this objective an exhaustive database of metal-aromatic motifs present in the PDB was constructed employing geometrical criteria, to screen and develop new methods for identifying and ranking these interactions.24 This public domain database developed by Sastry and co-workers includes metalaromatic motifs where the metal ion interaction with the aromatic group can be along the axis or perpendicular to it, giving cation−σ and cation−π motifs respectively. To designate the nature of interaction, aromatic motifs of all Phe, Tyr, and Trp aminoacids were taken as rings, and a sphere with a specific radius and a cylinder were generated. If the cationic motif is within the cylinder it was designated as cation−π. However if it is within the sphere and outside the cylinder it is designated as cation−σ interaction(Figure 5). A statistical analysis of this database reveals that the aromatic side of the histidine moiety prefers to bind in a σ fashion, while the other aromatic residues show a propensity to bind in π-fashion. The predominance of σ-type interaction in His moiety may be traced to the presence of electron deficient nitrogen atom. Even though most of the cation-aromatic interactions are contributed by basic aminoacid residues Lys, Arg, and His, metal ions too have significant number of cation-aromatic interactions (cation−σ and cation−π). Coming to cations of basic aminoacid residues, Arg cation forms interactions within typical cation−π interaction distance range. Zn followed by Fe show more cation-aromatic interactions. An online tool has been incorporated in the database, which furnishes all the cation−π interactions for any new protein.

5. DATABASES Databases and informatics have become extremely useful in getting general insights about bonding patterns in chemistry and biology. Several online tools are now available, which help to enumerate and quantify cation−π interactions present in the PDB.

5.2. CaPTURE

Gallivan et al. provide a gallery of energetically significant cation−π interactions in a server that lists text results from their M


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5.3. Protein Explorer

Protein explorer is a web tool developed by Martz which also explores presence of cation−π interactions.472 It shows more cation−π pairs than the number of energetically significant cation−π interactions reported by CaPTURE. The method built into Protein Explorer locates all Lys and Arg within 6.0 Å of three alternate carbons in a six-carbon ring of Trp, Tyr, or Phe. It allows the customization of cationic and aromatic atoms considered and also the distance. Although PDB has been the database of choice for most studies, several other data sets have also been considered to identify the occurrence of cation−π interactions. Different classes of protein−protein interfaces were surveyed for cation−π interactions by Crowley et al.473 They employed the CaPTURE program to identify interactions between the cationic group of Lys or Arg and the aromatic rings of Phe, Tyr, and Trp. This study demonstrated the importance of arginine via cation−π interaction in the interfaces of protein complexes and homodimers. About half of the protein complexes and onethird of the homodimers analyzed showed at least one intermolecular cation−π interaction pair. Using a distance based search they showed that fifty percent of the guanidinium:aromatic pairs pack together in a coplanar arrangement. Knowledge of cation−π interactions in protein− protein interfaces is important as it is potentially useful for protein docking studies. Cation−π interactions between adenine base and positively charged residues of (Lys and Arg) and π−π stacking interactions between adenine base and surrounding aromatic residues (Phe, Tyr, Trp) are found to be crucial for adenine binding in proteins. Hu et al. made the discovery of multiple modes of intermolecular interactions between positively charged residues (Lys and Arg) and the adenine moiety of the ATP molecule in data mining study of PDB carried out using RELIBASE+ program474 to identify proteins that contain bound ATP, ADP, AMP, and ANP proteins.475 Later, they employed large-scale data mining along with quantum chemical analysis of PDB to analyze molecular determinants for recognition of the adenine moiety of ATP by proteins.476 The study revealed that an average of 2.7 hydrogen bonding, 1.0 π−π stacking, and 0.8 cation−π interactions were present in each adenylate-binding protein complex, implying the significance of the three major interactions.

Figure 5. Schematic representation of the position of the cation with respect to the aromatic ring. Two distances (r1, r2) are provided. r1= the cation to the plane of the aromatic ring, r2 = the cation to the principal axis (depicted as dotted line) of the aromatic ring.

program CaPTURE.471 On the basis of a strategy where cation−π interactions with binding energies that are above a certain threshold are retained, they documented some significant preferences for certain aminoacid pairs as partners in a cation−π interaction. For a smaller data set of 68 proteins used as a test case, binding energy of each interaction (which meets a geometric cutoff) was evaluated with ab initio calculations. On a larger data set of 593 proteins using force field-based method, OPLS electrostatic energies were evaluated to reproduce the trends in the ab initio data. Their study clearly showed that the geometry in the protein data set analyzed is biased toward experiencing a favorable cation−π interaction. The side chain of Arg is more likely than that of Lys to be in a cation−π interaction. Among the aromatics Trp motif shows an overwhelming bias, such that over one-fourth of all tryptophans in the PDB form part of an energetically significant cation−π interaction. Zacharias et al. later reviewed cation−π interactions for small molecule recognition in specific cases of ligand binding protein molecules such as neuroreceptors, GPCR’s, transporter and also enzymes.430

Table 2. List of Studies Exploring Presence of Cation−π Interactions in a Database of Biomolecules S. no. 1. 2. 3. 4. 5. 6. 7. 8. 9.

molecule

ref

X-ray structures of proteins bound to ligand molecules containing a nucleic acid base protein−DNA complexes from PDB

481

geometric

criteria

482

high-resolution structures of protein−DNA complexes protein−DNA interaction motifs high-resolution crystal structures of adenylate-binding proteins in PDB Macromolecular Structure Database (MSD) for protein−protein interfaces and guanidinium aromatic residue pairs positively charged residues with adenine in ATPBinding proteins from PDB association of phenylalanine, tyrosine, and tryptophan with arginine and lysine representative protein structures from PDB 3D domain swapping in proteins

479 480 476

distribution of atoms 5 and 6-member rings of DNA bases around the positive charged atoms of Lys and Arg and, energetic contribution of contacting atoms from electrostatic and van der Waals interactions. presence of stair motifs graph spectral algorithm large-scale data mining and MP2 calculations on structures

473

using the CaPTURE tool

475

RELIBASE+ program

484

geometric

337

database-derived potentials employing geometric criteria N


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Table 3. Experimental and Computational Estimates of Metal Cation Interaction (Li+, Na+, K+) with Benzene (in kcal/mol) Edited and Reprinted with Permission from Ref 21. Copyright 2005 American Chemical Society. method

Li+

Na+

Exp CID-GIBMSd CCSD(T)/CBSj,e BP86/TZ94Pj,f MP2(full)/6-311+G**//MP2(full)/6-31G*d MP2/6-311+G*j,f MP2/6-31+G*g B3LYP/6-31++G**h MP2/6-31++G**h B3LYP/6-311++G**i MP2/6-311++G**i B3LYP/6-31G**i MP2/6-31G**i CCSD(T)/6-31G**i CCSD(T)/6-311++G(2d,2p)l

−37.90 −38.50 ± 3.23 −36.80 ± 0.20 −33.60 −34.30 −35.00 −34.60 −35.35 −31.66 −36.12 −33.76 −38.10 −36.94 −41.56 −35.80

−28.00 ± 1.50 −22.13 ± 1.39 −24.70 ± 0.30 −21.00 −21.37 −21.00 −22.14 −23.16 −20.07 −22.24 −20.42 −25.39 −24.39 −28.06 −22.20

S. no. 1 2 3 4 5k 6k 7k 8k 9k 10k 11k 12k 13k 14k 15k

j

a

K+ b

−19.20c −17.52 ± 0.91 −20.10 ± 0.40 −13.00 −17.09 −16.00 −15.47 −14.90 −16.17 −15.20 −16.31 −15.52 −16.36 −19.09 −16.50

a

Ref 526. bRef 32. cRef 28. dRef 73. Bond dissociation energies at 0 K. eRef 495. fRef 536. gRef 726. hRef 528. iRef 21. jEnthalpies calculated at 298 K. kEntries 5−15 are values corrected for BSSE. lRef 525.

these different studies indicated in Table 3 are obtained by employing a range of theoretical methods to model alkali metal ion−π interaction.21 The studies performed with HF, B3LYP, and MP2 and CCSD (T) levels of theory using different basis sets incorporating polarization and diffuse functions clearly reiterate that the trends obtained at various levels of theory are essentially similar, albeit with minor quantitative differences. Besides the reported interaction energies are also in good agreement with the experimental results and consistent with other theoretical studies. A few benchmarking studies have appeared that attempt to test the accuracy of theoretical methods for estimation of the cation−π interactions.488−502 Feller et al. evaluated the complete basis set estimate of cation−π bond strengths for Na+−ethylene and Na+−benzene systems495,503 Neves et al. have investigated the accuracy of density functionals currently available for the description of Na+−benzene and Na+−water model systems.496 A systematic application of 46 density functionals compared to the results from MP2 to extrapolated CCSD(T)/CBS methods showed that the 6-311++G(2d,2p) basis set, which is of triple-ζ quality with added polarization and diffuse functions represented the best compromise between accuracy and computational time. Friesner and co-workers have developed a diverse data set of noncovalent interaction energies including for cation−π interaction obtained at the counterpoise corrected CCSD(T) level of theory and then used them to train a novel, B3LYP specific, empirical correction scheme for these interactions and basis set superposition error.494 Du et al. have suggested that amino acid based empirical equations and parameters provide simple and useful tools for evaluations of cation−π interaction energies in protein interactions.490 They have developed two types of empirical equations one a modified distance and orientation dependent Lennard-Jones equation and the second a polynomial function of distance and angle variables based on accurate interaction energies of aromatic amino acids (Phe, Tyr, and Try) with protonated amino acids (Arg and Lys) and metallic cations calculated using B3LYP/6-311+G(d,p) method as the benchmark for the empirical formulization and parametrization. Bayly and coworkers have derived a dielectric-adapted least-squares-fit procedure called DRESP to generate atomic partial charges

Cohen et al. explored a high resolution, nonredundant, protein−protein interaction database of 1374 homodimer and 572 heterodimer complexes, to compare the properties of different interactions between protein interfaces and monomers in them.477 Using two geometric criteria, (a) the distance between the aromatic center of mass and the cation and (b) the angle between the center of mass and the cation vector to the normal to the aromatic plane, they illustrate the sharp distribution of cation−π interactions. The analysis revealed a most preferred angle of 5° placing the cation just above aromatic center of mass with a preferred distance of 3.2 Å. Biot et al. systematically searched for cation−π interactions in proteins bound to ligand molecules containing a nucleic acid base.478 Using geometric criteria, cation−π interactions between the base and a positively charged or partially charged side chain group located above it were screened for. This study highlights an overwhelming involvement of Ade base in a majority of cation−π contacts. In another study on 52 protein− DNA complexes, 37 were reported to form cation−π stair motif interactions with the DNA bases.479 Sathyapriya et al. report that the interaction of proteins with DNA in the same data set of 52 protein−DNA complexes is operative through clusters in about half of the proteins and through individual residues in the remaining half.480 In addition, several other studies have screened protein DNA complexes,479,481−483 domain swapping proteins,337 and other specific classes of proteins484−487 for the presence of cation−π interactions.

6. COMPUTATIONAL METHODS An important aspect regarding computational approaches used to analyze cation−π interactions concerns the reliability and quality of the theoretical data that is employed. Cation−π interactions studied employing theoretical methods are often not as sensitive to different levels of theory unlike other noncovalent interactions such as π−π stacking. While quantitative differences persist when comparing a series of complexes, qualitative results are virtually identical in most cases. This is made obvious by a brief glance at the experimental and computational estimates of selected metal ions interacting (Li+, Na+, K+) with benzene (interaction energy values in kcal/mol) from different studies. The results from O


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based on a fit to a QM ab initio electrostatic potential. This is followed by application of electronic polarization from internal continuum to a cation−π binding system formed by an atomic cation and benzene to accurately account for the induction energy.489 Several theoretical studies on cation−π interactions have employed Bader’s analysis504−506 of electron density to examine the topological changes in electron density originating from the interaction between cation and the π-electron system.507−518 The nature of bonding between different atoms may be characterized by the value of electron density (ρ) and the sign of the Laplacian of electron density (∇2ρ) at the bond critical point. Lower ρ values along with the positive ∇2ρ values are indicative of interactions involving noncovalent complexes.

7. MODULATION OF CATION−π INTERACTIONS 7.1. Nature of Cation and π-System

Various model systems have been considered to understand the underlying nature of interaction in the case of cation−π interaction. The cationic groups chosen include alkali and alkaline earth metal ions,503,507−510,519−540onium ions including ammonium and alkyl ammonium ions,42,43,144,145,541−549 carbocations,550,551 and transition metal ions.109−111,552−557 Thus there is a marked diversity in the type of ions involved in cation−π interaction.558 While onium ions and carbocations show competitive binding with hydrogen bond, often the transition metal cations bind almost as strongly as covalent bonds. The strength of cation−π interactions involving the alkali and alkaline earth metal ions, is in general, between the cationic motifs and transition metal ions. To gauge the impact of different cations and preferential site of binding to aromatic group a systematic analysis of cations (M+ = H+, Li+, Na+, K+, Mg2+, Ca2+, NH4+, NMe4+) binding with different aromatic side chains was undertaken by Sastry and co-workers.21 Figure 6 gives a representation of all the model systems considered for the study. The regioselectivity aspect of cation binding to aromatic side chain motifs and protons has been investigated. The regioisomers of protonated complexes assess the relative propensity of various sites for proton attachment. The covalent binding of proton to the aromatic ring carbon atoms is contrastingly different to the other metal cations, as well as ammonium ions which are found to form cation−π and cation-heteroatom interactions. The NH4+ and NMe4+ ions have shown NH−π interaction and CH−π interaction with the aromatic motifs. The interaction energies of NH−π and CH−π complexes are higher than hydrogen bonding interactions; thus, the orientation of aromatic side chains in protein is effected in the presence of ammonium ions. However, the regioselectivity of metal ion complexation is controlled by the affinity of the site of attack. In the imidazole unit of histidine the ring nitrogen has much higher metal ion (as well as proton) affinity when compared to the π-face, facilitating the in-plane complexation of the metal ions. The interaction energies increase in the order of benzene−M < toluene−M < para-hydroxy benzene−M < methyl indole−M < methyl imidazole−M. Similarly, the interaction energies with the model systems decrease in the following order: Mg2+ > Ca2+ > Li+ > Na+ > K+ = NH4+ > NMe4+. It has been observed that in the presence of an alternative basic group, the preference for covalent interaction appears to overtake the cation−π interaction. Thus, the proton and metal ion complexation in biological systems with aromatic

Figure 6. (a) Schematic representation of model systems considered for studying cation−π interactions. (b) Interaction energy profiles of the various cation-aromatic complexes at MP2/6-311++G** level of theory. Reprinted with permission from ref 21. Copyright 2005 American Chemical Society.

motifs are very different and need to be viewed as two different types of interactions.While considering the nature of the π system involved in the cation−π interaction the size of the π acceptor and the nature of substitution, if any on the π moiety become important factors. Benzene is used as a prototypical representative for π group in a majority of the studies. Impact of presence of different sized π systems, as well as heteroaromatic groups has been discussed in the following subsection on modulating factors. Indeed there is substantial variety in the nature of π systems considered in understanding the cation−π interaction.107,511,512,534,559−591 7.2. Size and Curvature of π System

The question of how varying the size of the aromatic system and its curvature modulates the cation−π interaction has been addressed by employing both experimental and theoretical studies. These studies seek to understand how increasing π system size gradually, effects cation−π complexation. Dunbar et al. studied the complexation of twenty five atomic ions including alkali, alkaline earth and transition metal ions, with coronene, while contrasting the binding with its isomeric molecule tribenzocyclyne.69 This study was done using a combination of (FT-ICR) ion trapping mass spectrometry and ab initio calculations and showed formation of π and in selective cases, sandwich complexes with coronene of sufficient strength readily observable under radiative association conditions. Sastry and co-workers through computational studies have addressed the issue of evaluating size effect of π system on cation−π interactions. The first mode was to systematically increase the number of double bonds in the π conjugated P


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flexibility to reorient their structure upon metal ion complexation, exhibit higher stabilization energy especially in those cases in which greater distortion is observed from the idealized planar form. A further study by Sastry’s group evaluated the significance of increasing the alkyl portion size in several model systems and its dependence on various metal ions (Li+, Na+, K+, Ca2+, Mg2+, Cu+, and Zn2+) in cation−π complexes (Figure 7b).508 In general, the complexation energy increases significantly when a hydrogen is replaced by a methyl group or by ring expansion in ethylene. However as the cycloalkene ring size increases from four to eight, the difference in complexation energy decreases gradually, showing that the methyl group substitution becomes less effective when ring size increases. The correlation between increasing alkene size and increasing complexation energy was associated with a corresponding rise in the polarizability of alkene. Energy decomposition analysis (EDA) suggests that the polarization component significantly contributes to the increase in complexation energy when alkene size increases. While probing the effect of increasing the number of fused rings in Li+−π complexes of aromatic systems Yáñez and coworkers employed a combination of (FT-ICR) ion trapping mass spectrometry and DFT calculations and elucidated that strength of the binding to a given aromatic cycle decreases as the number of cycles directly fused to it increases.65 This study also showed how the stability of the outer π-complex, wherein Li+ is attached to the peripheral rings is systematically higher than that of the complex in which the metal is attached to the inner rings. Rodgers and co-workers used the threshold CID technique to ascertain the bond dissociation energies of different cation bound naphthalene complexes in order to examine the influence of extended π networks on binding, when compared to cations bound to aniline, anisole, benzene, flourobenzene, phenol, and toluene systems.592 An increase in the strength of the cation−π interaction for extended π network of naphthalene in their mono and di complexes of all alkali metal cations was shown. Electrostatic nature of the bonding explains the trends in observed bond dissociation energies. The enhanced binding observed compared to that for benzene, is attributed to the increased polarizability of the ligand where there is no significant change in the quadrupole moment in the extended π network. Recently Lee et al. studied binding of Li+ in its complexes with naphthalene, pyrene, perylene and coronene, and reported a preference for Li+ binding to a ring with a higher π-electron content and aromaticity.593 They also show that the metal−ligand bond energies increase with the extension of the π-electron network up to perylene and then decrease from perylene to coronene. Leszczynski and co-workers explored the role of ring annelation to benzene and its consequent effect on cation−π interactions using computational approaches.594 The change of Li+-benzene interaction energy by annelation of three benzene rings to the alternate sides of benzene was examined along with interaction energy variation by sequential replacement of annelated benzene from triphenylene using bicyclo[2.1.1]hexene.595 The study reveals a consequent gradual increase in the binding strength of Li+ with the central benzene ring. Binding affinity to alkali metal cations (Li+, Na+, and K+) by a scheme of sequential ring annelation of six-membered aromatic ring or highly strained bicyclo[2.1.1] hexene moieties was also studied.596 Dinadayalane et al. further looked into alkali metal ion (Li+, Na+, K+) complexation with cup-shaped systems trindene and benzotripyrrole and compared the results with

systems both cyclic and acyclic,522 then, the effect of increasing size of alkyl portion attached to the π-system containing a double bond with regard to its complexation with different cations was studied.508 The first study analyzed the binding energies of cation−π complexes by taking representative mono and dicationic metal ions, Li+ and Mg2+ respectively with the πface of linear and cyclic unsaturated hydrocarbons.522 A wide range of sizes for aromatic systems were covered (Figure 7a).

Figure 7. Model systems considered in refs (a) 522, (b) 508, and (c) 198 to gauge impact of increasing size of aromatic system on cation−π interaction.

The study has most convincingly demonstrated that the complexes with larger π acceptor molecule exhibit a dramatic enhancement of complexation energy. This increase is uniform both in cyclic and acyclic systems and hence the number of double bonds in conjugation may be taken as a general signature, to estimate the cation−π binding at least in the gas phase.The increase in interaction energy correlated with the strain induced in the system upon metal ion complexation and on charge transfer. Acyclic systems, which demonstrate higher Q


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benzene−metal ion complexes to note the effect of ring addition to benzene.597 The study indicates a preference of metal ions to bind with the top face over bottom face of the cup-shaped molecules with the exception of a single case. The selectivity of the top face is explained on the basis of a strong interaction of the cation with the π cloud not only from the central six-membered ring but also from the π electrons of rim CC bonds. Theoretical studies were employed to gauge whether the strength of binding of the lithium cation to a given aromatic ring in a molecule was related to its aromatic character or to any change in its aromaticity on complexation using different probes for aromaticity.598 The study revealed the preferential interaction of Li+ with π electron richer rings of the PAHs and a small reduction in the aromaticity of the ring directly interacting with the Li+. Yuan et al. worked on interaction of annulated benzene model system with alkali and alkaline earth metal cations to establish that the annulated benzene is a stronger ligand to bind cations compared to benzene.599 DFT studies on preferential chemisorbtion of metal ions for various linear and branched polycyclic aromatic hydrocarbons by Sastry and co-workers have indicated a definite effect of ring size on the interaction energy values in different metal ion-π complexes (Figure 7c).198 Cation−π complexes of PAHs in which the benzene rings (n = 1−10) are linearly fused show a corresponding linear increase in the complexation energy as a function of the size effect. However such a behavior is not seen in branched PAH complexes. Polarizability of PAHs was used to explain these different trends. The study also showed a preference for peripheral binding of metal ions in branched systems while in contrast a preference for central ring binding was noticed in linear PAHs. To know how inclusion complexes of fullerenes or nanotubes operate and how the surface activation and the functionalization of fullerenes and nanotubes proceeds, knowledge of the controlled positioning of metal centers either on the inside or outside of the bowls is essential.97 Expectedly studies comparing the binding preferences of Li+ and H+ to neutral corannulene established a preferential attachment of proton to one carbon atom forming a σ-complex, whereas lithium cation positions itself preferentially over a ring.600 A small energetic preference was noted for binding with the six membered ring over the five membered ring (by ∼2 kcal/mol) and for binding the convex face over the concave face (by ∼3−5 kcal/mol). Dunbar et al. reported preferential convex binding of transition metals in complexes with corannulene and its derivatives using DFT method.601 Sastry and co-workers have systematically studied the interaction of a large series of aromatic hydrocarbons and their hetero analogs in complex with Li+ and Na+ ion while assessing the impact of curvature of polycyclic systems on cation−π interaction (Figure 8).559,560 The interaction energies observed in these systems exhibited a wide range from 25 to 59 and 15−43 kcal/mol for Li+ and Na+ ions, respectively.559 While the metal ions bind to both the faces of the buckybowls, a distinct convex face binding is preferred over concave binding in all the cases by about 1−4 kcal/mol.560 Similar binding energies for bowl and planar forms of cation−π complexes suggest that the curvature of the buckybowls seems to have only a minor effect on the complexation energies. Even upon metal ion complexation the curvature and flexibility of the curved surfaces was virtually undisturbed. While the strength of cation−π binding is controlled by electronic factors, the bowlto-bowl inversion barrier is exclusively controlled by the size of

Figure 8. Illustration of preferential binding of smaller cations on convex side of bowl as against the concave side, along with distinct rim vs hub binding preference in case of sumanene and corannulene as seen in refs507, 559, and 560.

the heteroatom. The binding possibilities of Li+, Na+, K+, and Cu+ cations to the concave and convex sides of the hub and rim rings of sumanene and corannulene have also been systematically studied.507 A definite preference for cation binding to the convex surface rim 6-membered ring for both buckybowls emerged, which corroborated with X-ray data available for complexes of bowls. Besides, it is to be noted that increasing the size of the cation enabled hub complexation substantially in case the metal ion was present on the concave surface. Correlating the effect of complexation and bowl depth suggested that bowls flatten when a cation is complexed to the convex surface and deepen when complexed to the concave surface of bowls. Ansems et al. reported the preferential binding of both tetramethyl ammonium ion and Ag+ in the concave pocket of circumtrindene forming cation−π interactions.602 Hirao’s group has performed several studies on the complexation preferences of cations to large buckybowls providing valuable insights.603,604 A key contribution to establishing concave binding preference of cyclopentadienyl iron complex to sumanene and alkyl substituted sumanene was shown through NMR characterization and X-ray crystal structure analysis of these complexes. Petrukhina and co-workers have explored the binding preferences of a range of metal ions, in particular transition metal ions, in extended organometallic networks built on metalπ-arene interactions.97 While reporting the first structural characterization of the C20H10 bowl and their cesium and rubidium salts they explain the dependence on the ion size for the site of alkali metal binding to corannulene.98 Their studies focus on (a) how reactivity of buckybowls relates to that of fullerenes and of other planar PAHs, (b) whether the properties of buckybowls vary with increasing size and curvature, and (c) if reactive sites can be fine-tuned and controlled in terms of reactivity. An interesting exception to typical rim binding of transition metal ions to bowl shaped polyarenes was demonstrated in case of rhodium ion binding to a hub carbon of a corannulene framework, but on the convex side.605 In the specific case of rhodium-based complexes of buckybowls, a qualitative trend of greater curvature of the aromatic surface R


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resulting in stronger π-bonding was observed, for the compounds studied by them.606 A study by the same group on interactions of Rh2+ centers with a number of differently sized π-ligands including acetylene, ethylene, delocalized planar π-systems (such as benzene, naphthalene, acenaphthylene, and pyrene) and curved surfaces (such as corannulene, C3hemifullerene, and C60-fullerene) shows how the trends for binding depend on the ligand coordination site and the nature of metal.607 Two major components are deemed to contribute to the overall interaction. First, coulomb interaction between the positively charged rhodium center and an induced dipole moment of axially bound hydrocarbons and second donor− acceptor interactions between dimetal core and π-type MOs of ligands where a dominant contribution ensues from ligand to metal. There has been a growing interest in recent times in understanding how different kinds of metal ions behave when they are encapsulated. Keeping the concept of chemical microencapsulation in mind Dunbar et al. employed three prototypical surfaces of increasing curvature to estimate presence of favorable cation binding sites and explored factors responsible for the same using DFT calculations.608 An analysis of binding of several classes of cations including small and large monocations and cations with multiple charges revealed a distinct preference to binding inside in case of large sized and charged ions. A vital role was ascribed to both polarization and short-range interactions in determining the preferred binding sites inside and outside these buckybowls. Cabaleiro-Lago and co-workers have suggested an important role for inductive and steric effects besides the dominant electrostatic term to explain the relative binding preferences of alkaline metal ions with deep bowls derived from fullerenes.609 An asymmetry in electrostatic potential is generated as a consequence of curvature of these π systems leading to more negative molecular electrostatic potential on the convex face of the buckybowls. Correspondingly although formation of metal ion bowl complexes were shown to be feasible both for convex and concave binding, metal ions bound to convex side of the bowls were found to be more stable. Thus the size and curvature of π systems have emerged as one of the more crucial factors to modulate the interaction operative between different cationic and π systems.

acetylcholine receptors and aided in gaining an insight into these systems. The contribution of inductive effect of a substituent over resonance-based intuitions was also emphasized on the basis of these studies.37 Role of electrostatics in the cation−π interaction was also evaluated by studies on fluorinated derivative of cyclophane host and cationic guests demonstrating a measurable drop in cation binding post fluorination.39

Figure 9. How does substituent effect operate in cation−π interactions?

In a quest to understand the nature of weak noncovalent interactions, Hunter et al. employed an approach of using chemical double mutant cycles to get a quantitative measurement of noncovalent functional group interactions.612 Considering the specific case of interaction of a pyridinium cation with the π-face of functionalized aromatic rings in chloroform they established how an electron rich π-system gave rise to a very attractive interaction in chloroform. An electron-poor π-system leads to an unfavorable repulsive interaction. The high sensitivity of magnitude of the cation−π interaction to the electron density on the face of an aromatic ring, which in turn depends on the substituent, was established to be vital in determining either the repulsive or attractive character of the interaction. The substituent effects in cation−π interactions have been attributed to the polarization of the aryl−π system. Rodgers and co-workers employed the threshold CID technique along with theoretical studies for a large number of substituted π systems interacting with alkali metal cations to gauge the influence of substituents on cation−π interactions.75,76,79−81,592,613−615 These include alkali metal cations in complex with toluene, flouro, and other halobenzenes, phenol, aniline, N-methyl aniline, NN-dimethyl aniline, anisole, and aromatic aminoacids. In all these cases, the influence of the substituents on the strength of the cation−π interaction could be explained by considering its effect on the quadrupole moment and polarizability of the aromatic ligand. The electrostatic nature of cation−π interaction, arising from ion− dipole, ion-induced dipole, and ion−quadrupole interactions but, being dominated by the ion−quadrupole interaction, was used to explain the differences in effect of substituent. More recently Rodger’s group evaluated the nature and strength of binding in copper-substituted π complexes and compared them with the corresponding Na+−π complexes to show multiple low energy π-binding conformers for the Cu+ complexes.79 An alternative line of thought has been established more recently with regard to the substituent effect.515,616−618 Houk

7.3. Substitution

Another factor modulating the strength of a cation−π interaction is the presence and nature of substituent groups in the π system. Majority of experimental and theoretical studies conducted compare the binding affinities of substituted π complexes with those of prototypical cation-benzene interaction.610−624 Substituent effects in cation−π interactions are typically explained using simple electrostatic models. As mentioned earlier in the historical perspective the electrostatic nature of substituent effects in cation−π interactions involving the interaction of the cation with the large, permanent quadrupole-moment of the aromatic ring were established by Dougherty’s group.37,39,49 On the basis of an analysis of electrostatic potential maps for a series of 11 substituted benzene molecules interacting with Na+, it was shown that essentially 100% of the variation in binding energy was due to the electrostatic term, where the electrostatic potential at the sodium position was taken as a measure of the electrostatic contribution to the binding energy.49 Consistent with the electrostatic model, substituent effects in cation−π interactions were utilized to characterize binding sites of nicotinic S


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and co-workers616 have suggested that the electrostatic potential (ESP) value evaluated at a single point above the center of a substituted aryl ring arises primarily from throughspace effects of the substituents and not as a result of polarization as suggested earlier by Hunter et al.612 Employing a truncated model of the aryl−π system and using an additive model for a series of twenty five substituted benzene systems showed that π polarization has no appreciable net effect on the ESPs above the centers of substituted benzenes, except in limiting cases of strong π-electron acceptors and donors where donation or withdrawal from the π system possibly plays a role. This establishes a relatively constant backdrop via which the through-space electrostatic effects of the substituents are operative. Emphasizing the impact of through-space effect of substituent on strength of cation−π interaction in substituted [n.n]-paracyclophanes (n = 2, 3) with Li+ and Na+, Frontera et al. have shown that substitution at the aromatic ring that is not interacting with the cation has a strong influence upon the binding energy.515 The differences found in the total interaction energy on substitution of the lower ring were traced to electrostatic effects as the polarization term was reported to be approximately constant in all complexes considered. In a study on the tunability of cation−π interactions mediated by absence/presence of triple bonds between the substituent and the aromatic ring, the ethynyl group was shown to reduce the effect of the electron withdrawing substituent hence improving the cation−π interaction.617 Cormier et al. suggest a chargetransfer model in line with through-space interactions of substituent to understand Li+ and Na+ binding to substituted cyclopentadienyl (Cp) anions where ring centroid−metal distances and the binding energies of the Cp-metal complexes correlate well with the summed Hammet constant (Σσm) of the substituted Cp ring.618 The molecular electrostatic potential minimum (Vmin) values located for the arene π system of several substituted benzene systems give a good measure of the electron donating/ withdrawing power of a substituent on the arene ring, as it exhibits a linear relationship with the substituent constant. This approach based on molecular electrostatic potential (MESP) topography was used to quantify substituent effect in the cation−π interaction in the complexes of mono, di, tri, and hexasubstituted benzenes with Li+, Na+, K+, and NH4+.619 A suggestion for largely additive behavior of substituent effect in multisubstituted complexes is given by these studies.620−622 Exploring the substituent effect on the cation−π interaction between Na+ and substituted CC or CC bond systems, Yang et al. showed that an electron-donating substituent increases electron density of the CC multiple bond by means of the n−π, π−π conjugative, or σ−π hyperconjugative effects, resulting in the increased cation−π interaction compared with that of the unsubstituted HCCH−Na+ interaction.623 Correspondingly, the presence of electron-withdrawing substituent decreases the cation−π interaction. Studies on alkyl derivatives of benzene, n-butylbenzene and n-heptylbenzene interacting with Li+, indicate that the most stable complexes formed correspond to those complexes in which the alkyl chain coils up toward the aromatic ring to favor its interaction with the metal.624 The extra stabilization provided by the flexible alkyl chain polarized by the charge on Li+ is effected by a “scorpion effect” showing cation−π complexes can be stabilized in the gas phase by alkyl chains with ≥3 carbon atoms as substituents in aromatic systems.

7.4. Cation−π versus Cation−σ Interaction

The competition between σ and π binding in case of cation−π interaction depends on nature of heteroaromatic groups present in the π system.

Figure 10. Schematic representation of nitrogen and phosphorus substituted model systems taken (ref 523) to examine contrasting π and σ binding preferences of metal ions.

A marked difference in the preference for σ versus π binding with different cations is observed depending on presence of either nitrogen or phosphorus in the π system. Sastry and coworkers have extensively analyzed the binding modes of alkali and alkaline earth metal cations to heterocyclic systems including mono-, di-, and trisubstituted azoles, phospholes, azines, and phosphinines using theoretical calculations.523 The choice of considering cation−π complexes of phosphorus containing heteroaromatics was essentially motivated by the presence of several crystal structures which have Li+ and Na+ bound to phosphorus in CSD and PDB. The following criteria were then considered when evaluating metal ion binding to heteroaromatics (a) the relative strength of σ and π binding modes, (b) the regioselectivity of metal ion binding, and (c) all possible minima of metal ion and ring complexes. Azoles and azines form strong σ complexes in marked contrast to the phospholes and phosphinines which show a higher preference for forming π complexes with the metal ions Li+, Mg2+, and Ca2+. With Na+ and K+ there is little difference between the σ and π complexation energies for phosphorus heteroaromatics. The σ and π complexation energy of azoles and azines is found to decrease as the heteroatom substitution increases in the ring. In contrast, the complexation energies of both phosphole and phosphinines show little dependence on the number of phosphorus atoms in the ring. For both azoles and phospholes, the metal binds away from the electrondeficient heteroatom. Thus, a strikingly important contrast between nitrogen and phosphorus containing heteroaromatics is revealed. A further study on Li+ and Mg2+ interacting with a series of homo/hetero substituted nitrogen and phosphorus analogues of benzene also reveal distinct contrasting σ and π binding preferences in these systems.586 EDA using DFT-SAPT and HF-SAPT schemes for these systems have shown that for the cation−π complexes it is the induction term which dominates the total interaction energy. T


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biomolecules proton affinity and pKa values were found to be very important measures which aid in understanding catalytic activity and function. Theoretical studies toward measurement of accurate proton affinity values of naturally occurring aminoacids572 and that of five membered heterocyclic amines573 have been performed. The number of intramolecular hydrogen bonds and their relative strength play a vital part in the proton affinity of aminoacids.572 The regioselectivity in case of proton binding to heterocyclic amines revealed a preference to the in-plane lone pair of the nitrogen in most cases. In the absence of such a possibility as in case of pyrrole it binds to a ring carbon.573 Wu et al. obtained a good correlation between NH4+ binding energies and proton affinities considering the cation−π interaction enhancement obtained from such an interaction in case of aromatic aminoacid residues.625 The nature and mode of binding of proton to a π system is quite different to cationic metal ions such as Li+ and Na+. In contrast to the strongly bound cation−π complexes with the metal and the ammonium ions, the proton prefers to bind covalently to one of the ring carbons of π system.21 Using a combined approach of electrospray ionization mass spectrometry studies along with QM calculations the relative gas phase affinity of lithium ion was compared with the proton affinities, on seven α,ω-diamines.577 The complexation energy from acyclic to cyclic structures increases by ∼10% for proton binding, and by more than 80% for Li+ ion. Although metal ions have much smaller magnitudes of affinity to diamines, their gain in energies going to bidentate ligation is substantial. Interestingly, the proton which binds in an unsymmetrical fashion induces higher strain in the diamine skeleton upon complexation. The larger size of Li+ ion as well as noncovalent nature of interaction is shown to be responsible for a highly flexible complexation. Cation−π interactions are competitive with cation−σ interactions within the same molecules and this plays an important role in stabilizing the chelating conformations. Three binding preferences, namely, monodentate binding in π and σ fashion to aromatic and amine groups and the bidentate mode of binding of Li+, Na+, and Mg2+ ions with aromatic amines (Ph-(CH2)n-NH2, n = 2−5) were considered while studying regioselectivity and preferential binding of the cation in the same molecule.571 The model systems devised to examine the binding strength of the interactions where the aromatic and amine motifs are not interconnected are shown in Figure 11. The main question addressed was regarding the relative preference of Li+ and Mg2+ to bind to an aromatic ring in a π fashion and of amines to bind in a σ fashion. The results obtained in this study reveal how Li+ and Na+ have displayed a consistently higher propensity to bind with the amine group compared to the aromatic group. In contrast, Mg2+ binds more strongly to the π systems compared to the amine group. From the mono to bidentate, the chelation gain in the binding energy for Mg2+ is about three to four times greater than that of Li+ and Na+. Cation−π interactions seem to show a higher dependence on the charge of the metal ion compared to cation interaction with lone-pair-bearing molecules. Thus, the divalent metal ion complexation leads to a significant variation in the macromolecular structure and the function. Regioselectivity and the nature of cation involved thus play a vital role in determining the effective strength of cation−π interactions. Methyl cation affinity (MCA) appears to be an even better measure for the nucleophilic affinity compared to H + affinities.574−576 Studies on selected commonly used nitrogen

Rodgers and co-workers have used threshold CID technique supported by theoretical studies in the case of azines including pyridine, pyridazine, pyrimidine, pyrazine, and 1,3,5-triazine and their complexes with Li+, Na+, and K+ revealing how most of the complexes are nearly planar while π complexes are significantly less stable.74 The nature and strength of copper-π interactions were also extensively studied upon. Comparing them with their earlier results they demonstrated that the number, size, position, and electron negativity of substituents are key factors.79 The N heteroatom of the C 4H5N, C4H4NCH3, and C8H7N π-ligands was shown to delocalize electron density into the aromatic ring along the direction of the dipole moment leading to an enhancement of electrostatic and specific orbital interactions with Cu+. Smith identified complexes of five electrophiles (Cl2, Br2, NO+, SiH3+, and CH3+) with benzene exhibiting a full range of complexation from true π complexes to full σ complexes.590 Interaction of tetramethylammonium with pyrrole, furan, and imidazole systems have revealed that a large part of the binding energies in these systems is contributed by typical cation−π interaction along with a significant contribution from dispersion terms.512,587 Jiang and co-workers also explored the possibility of inducing an aromatic N6 ring via a cation−π interaction and showed that the planar structure of the N6 ring is stable only in the case of Ca2N6 complex.581 A DFT study on interaction involving nucleobases (adenine, cytosine, guanine, thymine, and uracil) and alkali and alkaline earth metals revealed the formation of two kinds of complexes, one where ion is located above the nucleobase ring (only in case of Li+ and alkaline earth metal ions) and another where the ion directly interacts with the heteroatoms of a nucleobase (possible for all cations considered).588 The ring structures of the nucleobases in some cation−π complexes were also found to be deformed. Siu et al. have indicated the competitive nature of cation−π binding modes with non-π-binding modes in Phe−M+ (M+ = Li+, Na+, and K+) complexes in the gas phase. The energetically preferred binding site in phenylalanine was suggested to be the carbonyl oxygen.580 Tsuzuki et al. suggest that the interactions in pyridinium and N-methylpyridinium complexes with benzene be categorized into cation−π interactions on account of the dominant contribution of electrostatic and induction components to attraction in these systems.582 On the other hand, interaction in the corresponding pyridine complex is a π−π interaction owing to the predominant presence of dispersion interaction in this complex. Watt et al. compared the relative strengths of cation−π and cation-dipole complexes. They compared Na+ binding with monosubstituted aromatics either through binding to the π cloud or to the negative end of the aromatic dipole moment.589 Aromatic complexes of the nature C6H5X (X = F, Cl, Br, I, CN, NO2, BH2, CH3, SiH3, NH2, PH2, OH, and SH) were used. Cation−dipole complexes of fluorobenzene, aniline, and phenol were determined to be more stable than the cation−π complexes. Cation−π complexes are revealed to be more stable than their corresponding cation−dipole complex in case of the remaining aromatics including phenylborane, phenylphosphine, phenylthiol, (by ∼1−3 kcal/mol) and chlorobenzene, bromobenzene, iodobenzene, toluene, and phenylsilane (by ∼8−21 kcal/mol). 7.5. Cation−π versus Proton Affinity

Proton affinity has been an important measure of nucleophilicity of molecules and their regioselectivity. Particularly in U


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attributed to sufficiently strong interaction between benzene and K+ resulting in partial dehydration of the ion. Na+ is unable to have such an interaction due to higher hydration energies.47 Competitive binding studies of divalent alkaline earth metal cations with water and benzene provide information about both the structure of the hydrated cations as well as the relative importance of hydration in aromatic π interactions.82 Initial experimental efforts were geared to establish the presence of the cation−π interaction in different solvents. The existence of complexes between phenol and tetramethylammonium ion in aqueous solution was reported by Gaberšcě k et al. using impedance spectroscopy.626 IR spectra data of hydrated metal ion clusters, such as those of Na+ and K+ ions, in complex with phenol have shown to be dominated by ion phenol configurations in σ configurations although with a minor presence of π isomers.627 Several examples of experimental determination of cation−π interaction have indeed evaluated them in presence of solvent54,62,63,91 Hanusa and co-workers present evidence that π-bonded structures may exist in the solution for magnesium.628 They report the first crystallographic evidence for a polyhapto allylmagnesium species where a cation−π description fits the bonding of the magnesium centers to allyl ligands in solvent THF. However they opine that this π type bonding is energetically feasible, only in the absence of perturbing forces. Studies investigating the simultaneous presence of an aromatic ring at the 5′-position of an inosine derivative and a positively charged imidazolium ring in a purine base reveal how an intramolecular cation−π interaction drives the conformation of the nucleoside toward a very major conformer in solution.629 Figure 11. Model systems considered to examine the binding strength of the interactions when aromatic and amine motifs are not interconnected are shown in panels a and b. Edited and reprinted with permission from ref 571. Copyright 2009 American Chemical Society.

and phosphorus nucleophile organocatalysts, with focus on a comparison of their methyl cation affinities and their proton affinities as measures reflecting their catalytic activity, suggest that the poorer predictive ability of proton affinity values is indeed a reflection of steric effects between organocatalysts and reactant electrophiles, and the inability to model this reaction with a proton.575 Systematic differences in bond strengths between second- and third-row elements is also a key point making MCA values superior descriptors of the catalytic activity of phosphanes than proton affinity or pKa data. Thus the nature of cationic interactions is quite characteristic and a quantitative estimation of its affinity is of outstanding importance to correlate cation binding strengths to various properties such as catalytic activity.

Figure 12. Schematic representation of (a) sequential addition of (H2O)n to alkali and alkaline earth metal cations (Li+, Na+, K+, Mg2+, and Ca2+) interacting with benzene considered in ref 529 and (b) sequential addition of (H2O)n to alkali and alkaline earth metal cations (Li+, K+, and Mg2+) interacting with benzene, both on metal side, as well as the side opposite to the metal binding face of aromatic group as seen in ref 509.

7.6. Solvation

A major factor modulating the expression of cation−π interaction in terms of its effective strength is the presence of surrounding solvent. Studies on impact of aqueous and organic media in the process of regulating molecular recognition for a large and diverse series of synthetic macrocylic host systems with their cationic guests were undertaken by Dougherty and co-workers.33−41 Frequent instances of presence of energetically significant cation−π interactions on the surfaces of proteins, exposed to aqueous environment have been reported.40 Preferential ion selectivity in aqueous environment for potassium ions over other ions in K+ ion channels is shown to be mediated by cation−π interaction.34 This selectivity is

Several theoretical studies have established the importance of solvent to cation−π interactions.630−644 Interest in Sastry’s group on impact of solvation on cation−π interaction stemmed from an analysis performed on PDB and CSD crystal structures. While structural parameters obtained by X-ray analysis are normally in excellent agreement with computations on single molecules in the gas phase, the role of the environment on the geometric parameters appears to be rather critical for cation−π interactions. CAD, a cation−aromatic interaction database,24 V


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complex as radicals in gas phase and as ions in aqueous phase emerged. While considering different virtual screening filters for the design of novel type II p38 MAP kinase inhibitors we find the side-chain of Phe 169 of this kinase shows a tendency to form cation−π interactions with positively charged residues. Moreover these interactions increase the potential of the Phe169 aromatic ring to be solvated.313,314 These observations indicate the biological relevance of solvent assisted enhancement of cation−π interaction. Biot et al. performed free energy calculations spanning from vacuum to protein-like environments and observed the behavior of these interactions.631 Solvation free energies of a modified ensemble of cation−π interactions between an Ade moiety included in a protein ligand and an aminoacid side chain carrying a positive charge on its amino group was noted. For cation−π complexes in a solvent, the electrostatic contributions to the interaction free energy were drastically screened, whereas the electron correlation contributions were not. The interaction free energies of cation−π systems in protein-like solvents CCl4, THF, and acetone were found to follow their normalized frequencies of occurrences similar to what is observed in protein−ligand structures. Both implicit and explicit addition of water molecules to complexes of TMA cation with benzene, phenol and indole revealed a reduction of about three-quarters of their calculated binding energies compared to the corresponding gas-phase results.632 Xu et al. showed the influence of introducing water molecules into a cation−π complex by employing ab initio calculations.633 Sequential addition of water molecules showed a continual decrease in the interaction between the cation and π system which is correlated to increasing distances and reduced charge transfer between the two moieties. The weakening of cation−π interaction on hydration was demonstrated to be on account of electrostatic and induction interactions. Berry et al. characterized a system that more closely mimics the properties of naturally occurring cation−π interactions in terms of a true representation of solvent exposed and buried residues for peptide model systems.634 They suggested that interaction energy values derived from highly solvent exposed peptide model systems represent the lower limit estimates for the free energy contribution in case of cation−π interactions. Recently Caricato et al. put forth the implementation of PCM studies to take into account the solvent effects on cation−π interaction between a benzene ring and two cations, NH4+ and K+.635 Studies pursuing microhydration of interaction of guanidinium cation with benzene reveal how inclusion of water molecules promotes a change in the structure of the cation−π contact although these stability changes are reflective of the structure of the hydrating water molecules rather than to a modulation of the cation−π interaction.636 Explicit addition of water molecules to the interaction between Li+, Na+, and K+ and indole molecule show that the strength of cation−π interactions get substantially reduced when the metal ion is solvated or the size of metal cation increases.637 Studies on Phe−M, Tyr−M, and Trp−M (M = Li+, Na+, or K+) complexes and their microsolvation demonstrated the existence of a strong cation−π interaction between the alkali metals and the aromatic aminoacids, which make about 8% of all known protein sequences.638 Polarizable potential models investigating cation−π interactions in aqueous solution were developed to calculate the potential of mean force between four cations (Li+, Na+, K+, and NH4+) and a benzene molecule.639 Binding of K+ and NH4+ ions to benzene was revealed besides mutually

built earlier reveals that the frequency of cation−π interactions is relatively high in cation−π distances around 3.5−4.5 Å. These bond lengths are well over 1−2 Å longer than corresponding optimized geometries obtained for smaller model systems using reliable QM methods. In order to identify plausible reasons for this disparity between bond distances noted from X-ray crystal structures and those from theoretical studies, the effect of explicit solvation of the cation−π system where the first solvation shell of cations is saturated with water was considered.529 This serves to provide a realistic description of the first solvation shell, not only in a manner relevant for its role in biomolecules, but also to mimic the saturation of metal ion coordination. Quantum chemical studies on hydrated metal ion (Li+, Na+, K+, Mg2+, and Ca2+) complexes with benzene as model systems were reported. In the case of fully solvated metal ion the cation−π interaction strength was nearly halved in gasphase considering solvated K+ benzene interaction, while it reduces to almost one-fifth for the divalent Mg2+ ion. A stepwise decrease in the strength of cation−π interaction was noticed as the metal ion was incrementally solvated. Even though cation−π strength is actually much smaller in the condensed phase compared to gas phase, all energies are still substantially higher than the interaction energy of the waterbenzene complex. Expectedly, coordination of metal ions with water molecules results in lengthening the cation−π distance. This is precisely why a large span of cation−π distances are indeed observed in protein databases. A subsequent analysis of sequential attachment of water molecules via the explicit solvation mode to Li+, K+, and Mg2+ complexes with benzene reveals how cation−π interaction energy is extremely sensitive to the site of solvation of cation−π systems, and also the size and charge of the metal ion.509 K+−π interaction energies were indeed shown to be more competitive with metal-water interaction energies compared to Mg2+ and Li+. Strength of the cation−π interaction is attenuated when water molecules selectively surround the metal ion, while it is enhanced upon selectively solvating the π system. Although the qualitative observation is virtually similar in Li+, K+, and Mg2+, the solvent-assisted augmentation and attenuation of the cation−π strength depending on the face of metal ion attack is more dramatic in the case of K+ ion. Systematic computational studies on impact of solvation on cation−aromatic interaction involving the binding of hydrated Li+, Na+, K+, Mg2+, Cu+, and Zn2+ metal ions with biologically relevant heteroaromatics such as imidazole and methylimidazole have also been reported.530 Alkali and alkaline earth metal and transition metal ions binding to imidazole and methyl imidazole motifs have shown a strong preference to bind to the lone pair of nitrogen. The metal ions show higher propensity to bind to the imidazole motif compared to water or benzene. The presence of solvent molecules near one nitrogen of imidazole or methylimidazole enhances the metal ion binding at the second nitrogen position. The binding of metal ion at the second nitrogen position strengthens the hydrogen bonding at the N(1) position. The study further demonstrates a higher cooperative effect in the hydrogen bonding due to transition metal ions compared to alkali and alkaline earth metals. Another study directed toward impact of solvation, focuses on the dissociation preference of metal−cycopentadienyl cation−π complexes into either radicals or ions in presence and absence of solvent.510 In this study, two plausible dissociation pathways of half sandwich complex of selected main group metallocenes were considered and a clear preference for dissociation of the W


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enhanced cation−π and π−π affinities as compared to the pairwise affinities in the presence of two benzene molecules, thus confirming their cooperativity even in aqueous solution. In the early 1990s, using the Monte Carlo approach, Jorgenson and co-workers showed interaction between TMA+ and benzene in water where TMA+ is bound to benzene more favorably compared to Cl−.640 Several molecular mechanics studies try to circumvent the inability of standard force fields to represent the energetics of cation−π interactions accurately. This has resulted in interesting studies where new parameters have been incorporated to improve the existing force fields. While establishing a favorable association in a polar aqueous medium between NH4+ and toluene with an association constant of 6.5 M−1 consistent with experimental data on related π−cation systems, the role of solvent in reducing the attraction compared to that observed in vacuum was noted.542 This was done using a simple “short range” attractive term in a modified potential energy function. The magnitude and the directionality of cation−π interactions in conjecture with the presence of solvent were revealed to impact the overall strength of cation−π interaction. Costanzo et al. investigated the stability of the Na+−Phe complex in aqueous solution while demonstrating how the free energy barrier opposing dissociation of the complex is sizable, considering the competition between cation−π interaction and aqueous solvation for the Na+ ion.641 Car−Parrinello molecular dynamics studies also showed the stability of the cation−π interaction between ammonium and benzene in aqueous solution. Interestingly the geometry of the complex in aqueous solution changes frequently, with the ammonium ion interacting with benzene mostly through three of its hydrogen atoms unlike two hydrogens in gaseous phase.642 Considering the competitive solvation of M+ by benzene and argon atoms, the preference of Ar atoms to solvate M+ better than benzene has been observed by increasing the number of solvent atoms.643 This however did not preclude the fact that the benzene molecule is always placed in the first layer of solvation around the cation for all M+−benzene−Arn clusters. Studies on polarizable potential models parametrized based on ab intio calculations indicate that in aqueous solution, while Li+ and Na+ do not bind to benzene, K+ and NH4 + bind with free energies of −1.2 and −1.4 kcal/mol, respectively.639 The most stable arrangement of K+−(benzene)2 or NH4+−(benzene)2 in water, corresponds to a “triangle” geometry in which two benzene molecules are both directly coordinated to the cation, preserving the benzene− benzene hydrophobic interaction, while also minimizing ion dehydration. Thus several aspects of solvation in terms of how they affect the cation−π interaction have been explored. Therefore, the strength of cation−π interaction can be substantially attenuated or enhanced by selective solvation of the cation or π faces. Subtle variations in solvation seem to have a significant alteration in the manifestation of the interaction.

primary alkylammonium guest and a neutral crown ether host.646 Almost two decades later Roelens and co-workers studied the role of a noncompetitive counterion and demonstrated its importance when measuring the cation−π interaction in different solvated systems.127,647 Experimental evidence established the adverse contribution of counterion to overall interaction, to an extent where on occasion it completely suppresses the cation binding. Studies on the binding of ACh and TMA to cyclophane host systems employing 1H NMR titrations in CDCl3 along with a significant range of commonly used anions emphasized that in the case of an unfavorable choice of the counterion, the interaction can even fall below the detectable limit.647 Furthermore, correlation was found between the “goodness” of anions as binding partners and the solubility of their salts.127 Charge dispersion serves as a major factor in determining the influence of the anion on the cation−π interaction, and the study showed that anions with a diffuse charge (i.e., picrate) do not impact interaction strength as dramatically as anions with localized charge (i.e., acetate). Roelens and co-workers thus established the transmission of electrostatic effects from the ion pair to the cation−π interaction. Further studies by their group revealed that the contribution of counterion to inhibit cation−π binding appeared to be a characteristic constant of each anion, the value of which could be expressed by the calculated electrostatic potential of the ion pair.648,649 Cheng et al. employed reliable ab initio calculations on [C6H6···MX]+ complexes (M = Be2+, Mg2+, Ca2+ and X = H−, F−, Cl−, OH−, SH−, CN−, NH2−, CH3−) showing the range of modulation effected by the counterions on [C6H6···MX]+ interaction.650 Many properties were close to those for the prototypical benzene−alkali cation complexes unlike the much stronger cation−π interaction between benzene and a naked alkaline earth cation. Similarly ab initio calculations on the cation−π interaction between pyrrole and a naked alkaline earth cation (M = Be2+, Mg2+, and Ca2+) is shown to be much stronger than the pyrrole-alkali cation interaction.651 But when a counterion is introduced into the [pyrrole···M]2+ complex, the [pyrrole···MX]+ interaction was found to be very similar to the pyrrole−alkali cation interaction in many aspects. Hunter et al. employed a double mutant cycle experiment for quantification of the interaction of the edge of a pyridinium cation with the face of an aromatic ring. In this process they reveal that although the binding constants for the complexes depend strongly on the anion, the cation−π interaction energy is almost constant at 2.5 ± 0.4 kJ/mol.652 The effect of anion on the stabilities of the complexes is due to anion competing for some of the other binding sites in the complex. Exploring the relative strength of cation−π vs salt-bridge interactions in the Gtα(340−350) peptide/rhodopsin system Marshall and coworkers considered the contribution of counter-anionic carboxylate of Phe350 to reducing the energy contribution of the cation−π interaction.653 Absence of a correlation between the experimental binding affinity and variation in the electronic density of the aromatic ring at position 350 involved in cation−π interactions for a series of peptides was explained by counteranion effect. Stoddart and co-workers have recently reviewed the solution phase counterion effects in supramolecular and mechanostereochemical systems.654 Counterions were shown to operate in myriad ways for example through steric effects, charge polarization, competition, and stability of the separated ion-pair in supramolecular systems etc. The interaction of anions with cation−π complexes between

7.7. Counterion

Among the different factors which modulate cation−π interactions the effect of counterion presence is fairly less explored.645−655 The consequences of the presence of extra salts in different experimentally employed buffers are often overlooked. Very early studies on a series of substituted macrocyclic polyether systems as hosts and cationic guests came from Cram and co-workers who noted that the counterion affected the association constant (Ka) between a X


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Review

guanidinium cation and benzene demonstrate an anticooperative three-body interaction when the cation and the anion are on the same side of the π system. But when the anion and the cation are on opposite sides of the π system, the three-body interaction show a cooperative manifestation.655 The foregoing discussion delineates major factors tuning cation−π interactions, and obviously the subtle mode of their operation provides vast scope for the implementation in material design.

8. COOPERATIVITY INDUCED BY CATION−π INTERACTIONS A phenomenon of high current interest is the manifestation of cooperativity among noncovalent interactions, more so between cation−π and neighboring nonbonded interactions. The preceding sections clearly demonstrate that the structure, energy, site and binding preference of cation−π interactions could be dramatically modulated by a range of factors. It then becomes imperative to ask how nonbonded interactions mutually influence each other. A cursory glance at the current literature reveals that cooperativity is indeed a widely used term, especially in a biological context.656−662 Cooperative behavior has served as the first clue toward understanding conformational transition and allosteric interactions in proteins. Allosteric oxygenation of the hemoglobin molecule is a benchmark example from biology for such a display of cooperativity.663−665 Cooperativity however is not limited only to ligand binding processes and allosteric proteins. In 1957, Frank et al. discussed the importance of many-body effects in water while trying to describe the cooperativity of hydrogen bonds.666 They postulate that the formation of hydrogen bonds in water is predominantly a cooperative phenomenon, accordingly formation of one bond triggers the formation of associate bonds. Simultaneously, when one bond breaks typically a whole cluster gets affected. Hyskens considered factors which govern the influence of a first hydrogen bond on the formation of a second one.667 Suhai reported an enhancement in binding energy per hydrogen bond by 47% for an infinite water polymer compared to water dimer.668 This study employed first principles calculations to explore the cooperative effects in hydrogen bonding based on the structural and electronic properties of ice and hydrogen-bonded periodic infinite chains of water molecules. Dannenberg et al. explored the behavior of several hydrogen bonded model systems including chains of formamide, acetic acid, nitroanilines, urea etc.669−672 These studies show that the electrostatic model for pair wise interactions to be inadequate to describe the major component of cooperativity in case of long chains. There are indeed, quite a large number of studies which have focused on cooperativity observed in hydrogen bonded systems.671−701 Thus cooperativity is a well studied phenomenon in hydrogen bonded clusters. In contrast the number of studies which provide a quantitative estimate of cooperativity or anticooperativity in systems containing cation−π interactions are rather limited.519−521,541,702−715 Sastry’s group has addressed the fundamental question of how a pair of noncovalent interactions mutually impact each other, especially when one of them is a cation−π interaction. In the first case cooperativity between cation−π interaction and hydrogen bonding521 is dealt with and in the second between cation−π and π−π interactions.541 The common coexistence of M−π and π−π interactions in biology and chemistry has been explored to garner a better understanding of how one kind of noncovalent interaction

Figure 13. Illustration of metal cation−π−π interactions in selected PDB structures and representation of model systems taken to consider cooperativity of cation−π interactions with (a) hydrogen bonding, ref 521, and (b) π−π interactions, ref 541.

affects the strength of another.519,520 This influence is typically described in terms of cooperativity and anti cooperativity in bonding. The occurrence of M−π−π (M = Li+, K+, Na+, Mg2+, and Ca2+) interactions in the CSD and PDB databases have been studied and compared with the number of exclusive M−π motifs. Different forms of benzene dimers (PD-parallel displaced, S-stacked and T shaped) were also subjected to ab initio calculations as part of this study, to establish the relative preference of differently oriented aromatic moieties to bind to each other. The PDB was then searched for metal ion containing structures having less than 3 Å resolution and Rvalue

CationâÏ Interaction: Its Role and Relevance in Chemistry, Biology

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