Accurate prediction of cation-π interaction energy using substituent effects

Substituent effects on cation-π interactions have been quantified using a variety of Φ-X···M(+) complexes where Φ, X, and M(+) are the π-system, substituent, and cation, respectively. The cation-π interaction energy, E(M(+)), showed a strong linear correlation with the molecular electrostatic potential (MESP) based measure of the substituent effect, ΔV(min) (the difference between the MESP minimum (V(min)) on the π-region of a substituted system and the corresponding unsubstituted system). This linear relationship is E(M(+)) = C(M(+))(ΔV(min)) + E(M(+))' where C(M(+)) is the reaction constant and E(M(+))' is the cation-π interaction energy of the unsubstituted complex. This relationship is similar to the Hammett equation and its first term yields the substituent contribution of the cation-π interaction energy. Further, a linear correlation between C(M(+))() and E(M(+))()' has been established, which facilitates the prediction of C(M(+)) for unknown cations. Thus, a prediction of E(M(+)) for any Φ-X···M(+) complex is achieved by knowing the values of E(M(+))' and ΔV(min). The generality of the equation is tested for a variety of cations (Li(+), Na(+), K(+), Mg(+), BeCl(+), MgCl(+), CaCl(+), TiCl(3)(+), CrCl(2)(+), NiCl(+), Cu(+), ZnCl(+), NH(4)(+), CH(3)NH(3)(+), N(CH(3))(4)(+), C(NH(2))(3)(+)), substituents (N(CH(3))(2), NH(2), OCH(3), CH(3), OH, H, SCH(3), SH, CCH, F, Cl, COOH, CHO, CF(3), CN, NO(2)), and a large number of π-systems. The tested systems also include multiple substituted π-systems, viz. ethylene, acetylene, hexa-1,3,5-triene, benzene, naphthalene, indole, pyrrole, phenylalanine, tryptophan, tyrosine, azulene, pyrene, [6]-cyclacene, and corannulene and found that E(M)(+) follows the additivity of substituent effects. Further, the substituent effects on cationic sandwich complexes of the type C(6)H(6)···M(+)···C(6)H(5)X have been assessed and found that E(M(+)) can be predicted with 97.7% accuracy using the values of E(M(+))' and ΔV(min). All the Φ-X···M(+) systems showed good agreement between the calculated and predicted E(M(+))() values, suggesting that the ΔV(min) approach to substituent effect is accurate and useful for predicting the interactive behavior of substituted π-systems with cations.     

Enhanced catalytic activity on titanosilicate molecular sieves controlled by cation-π interactions

A new class of heterogeneous catalytic systems utilizing cation-guest interactions was designed based on microporous titanosilicate molecular sieves. Introducing heavier alkali metal cations on ion-exchange sites of the framework resulted in a significant enhancement of the catalytic activity for oxidation of cyclohexene and styrene, whereas such an enhancement was not observed in oxidation of cyclohexane without π systems. Distinct relationships between the catalytic activities and intermolecular interaction energies which were determined by IR spectroscopic and computational approaches clearly evidenced the predominance of the cation-π interaction in this catalytic system.     

Contribution of cation-π interactions in iminium catalysis

Ab initio calculations were carried out for a benzyl-substituted iminium cation derived from (E)-crotonaldehyde and a chiral imidazolidinone that was developed as an organocatalyst by MacMillan et al. At the MP2 level of theory it is predicted that the phenyl group is close to the iminium moiety in the most stable conformer, suggesting that the cation-π interaction contributes to the stabilization of this conformer. Energy decomposition analyses on model systems indicate that the electrostatic and polarization terms make significant contribution to the attractive interactions between the benzene ring and the iminium cation.     

A simple chiral recognition system to investigate substituent effects on π-π interactions

We have used a simple molecular recognition system to study substituent effects in aromatic interactions. A series of substituted benzoylleucine diethyl amides with aromatic rings of varying electronic character were crystallized. All of the substituted dimers organized into homochiral dimers in the solid state but with pronounced differences in regard to the orientation of the aromatic rings with respect to each other. However, no homochiral dimerization was observed in the unsubstituted case.     

Relative substituent position on the strength of π-π stacking interactions

It was observed that the relative position of the arene substituents has a profound influence on the strength of π-π stacking in the 9-benzyl-substituted triptycene system. A new series of model compounds (3a-i) capable of revealing quantitatively π-π stacking interactions was studied. This series of compounds (3a-i) has an ortho-substituted methyl group in one of the two interacting arenes and the syn/anti ratios were determined and compared to a series previously studied compounds (4a-i) that have a para methyl group on the corresponding arene. A greater than 50% increase in the strength of π-π stacking interactions was observed with the methyl group in the ortho position comparing to that in the para position. No difference in π-π stacking interactions was observed when the other aromatic ring was a pentafluorobenzoate group.     

Empirical formulation and parameterization of cation-π interactions for protein modeling

Cation-π interaction is comparable and as important as other main molecular interaction types, such as hydrogen bond, electrostatic interaction, van der Waals interaction, and hydrophobic interaction. Cation-π interactions frequently occur in protein structures, because six (Phe, Tyr, Trp, Arg, Lys, and His) of 20 natural amino acids and all metallic cations could be involved in cation-π interaction. Cation-π interactions arise from complex physicochemical nature and possess unique interaction behaviors, which cannot be modeled and evaluated by existing empirical equations and force field parameters that are widely used in the molecular dynamics. In this study, the authors present an empirical approach for cation-π interaction energy calculations in protein interactions. The accurate cation-π interaction energies of aromatic amino acids (Phe, Tyr, and Try) with protonated amino acids (Arg and Lys) and metallic cations (Li(+), Na(+), K(+), and Ca(2+)) are calculated using B3LYP/6-311+G(d,p) method as the benchmark for the empirical formulization and parameterization. Then, the empirical equations are built and the parameters are optimized based on the benchmark calculations. The cation-π interactions are distance and orientation dependent. Correspondingly, the empirical equations of cation-π interactions are functions of two variables, the distance r and the orientation angle θ. Two types of empirical equations of cation-π interactions are proposed. One is a modified distance and orientation dependent Lennard-Jones equation. The second is a polynomial function of two variables r and θ. The amino acid-based empirical equations and parameters provide simple and useful tools for evaluations of cation-π interaction energies in protein interactions.     

Two significantly different conformations in crystal: formation of a molecular dimer governed by cation-π interactions

Two significantly different conformations were observed in crystal of 1, which form an unsymmetrical molecular dimer governed by cation-π interactions between a pyridinium cation and a phenyl ring, whereas compound 2 forms a head-to-tail type of dimer.     

Geometric effects in olefinic cation-π interactions with alkali metals: a computational study

Although cation-π interactions commonly involve aromatic or heteroaromatic rings as the source of π-electrons, isolated and nonconjugated olefins are equally effective donors of π-electron density. Previous comparisons of these π-electron sources have indicated that the net energy of the binding interactions is not a simple additive function of the number of π-bonds involved. For instance, the enthalpy of binding (ΔH°) of Li(+), Na(+), or K(+) cations to two ethylene molecules or to one benzene molecule is approximately the same, despite the 4:6 ratio of π-electrons involved. This present density functional theory study indicates that geometric factors can partially account for the proportionally greater interaction energies of olefins, but whether they are symmetrically placed around the cation or grouped on one hemisphere has little effect on the binding energy. Instead, flexible ligands that permit olefinic π-electrons to be oriented more favorably toward the metal than those in rigid aromatic rings can be correlated with greater bonding. For Li(+) complexes, this appears to be an appreciable factor, although it is less significant with Na(+) and K(+) complexes. For all three cations, stronger polarization interactions with olefins compared to arenes contribute to the strength of cation-π interactions involving olefinic π-bonds.     

Substituent effects in cation-π interactions: a unified view from inductive, resonance, and through-space effects

The quantification of inductive (I), resonance (R), and through-space (TS) effects of a variety of substituents (X) in cation-π interactions of the type C?H?X···Na? is achieved by modeling C?H?-(Φ?)(n)-X···Na? (1), C?H?-(Φ?)(n)-X···Na? (2), C?H?-(Φ(2perpendicular))(n)-X···Na? (2'), and C?H? ···HX···Na? (3), where Φ? = -CH?CH?-, Φ? = -CHCH-, Φ(2perpendicular) indicates that Φ? is perpendicular to the plane of C?H?, and n = 1-5. The cation-π interaction energies of 1, 2, 2', and 3, relative to X = H and fitted to polynomial equations in n have been used to extract the substituent effect E?1, E?2, E?(2'), and E?3 for n = 0, the C?H?X···Na? systems. E?1 is made up of inductive (E(I)) and through-space (E(TS)) effects while the difference (E?2 - E?(2')) is purely resonance (E(R)) and E?3 is attributed to the TS contribution (E(TS)) of the X. The total interaction energy of C?H?X···Na? is nearly equal to the sum of E(I), E(R), and E(TS), which brings out the unified view of cation-π interaction in terms of I, R, and TS effects. The electron-withdrawing substituents contribute largely by TS effect, whereas the electron-donating substituents contribute mainly by resonance effect to the total cation-π interaction energy.     

Calculations of heat of solvation by a simple electrostatic approach to molecular interactions

An extremely simple formula to estimate the heat of formation of complexes between anion and a polar molecule or between highly polar systems is presented.The formula is entirelyelectrostatic and the expression used is verified by means of perturbation theory.This formula is test-ed for several ion-molecule and molecule-molecule pairs.It is also applied to estimate the heat ofhydration of simple salts.     

Selective stabilization of self-assembled hydrogen-bonded molecular capsules through π-π interactions

Subtle noncovalent forces such as π-π interactions play an import role in the folding of biological macromolecules such as DNA and proteins. We describe here a system where such interactions on the outside of a molecular capsule trigger a selective change of its structure as a self-assembled receptor.     

A computational study of cation-π interactions in polycyclic systems: exploring the dependence on the curvature and electronic factors

Density functional theory (B3LYP) calculations with double and triple-ζ quality basis sets were performed on the Li⁺ and Na⁺ π-complexes of corannulene 2, sumanene 3CH₂, heterosumanenes 3X, triphenylene 4 and heterotrindenes 5X. The metal ions bind to both convex and concave faces of buckybowls, with a consistent preference to bind to the convex surface by about 1-4 kcal/mol. The metal ion complexation with the π-framework of the central six-membered ring span wider range compared to benzene, indicating the control of size, curvature and electronic perturbations over the strength of cation-π interactions. Computations show that the bowl-to-bowl inversion barriers are only slightly altered upon metal complexation, indicating the continuity of bowl-to-bowl inversion despite metal complexation. We have calculated the binding energies of model systems, triphenylene (4) and heterotrindenes (5X), which indicate that the interaction energies are controlled by electronic factors. While the inversion barrier is dependent mainly on the size of the heteroatom, the extent of binding is independent of the size of the atom or the bowl depth.     

Complexation of monosubstituted benzenes and methanes by cyclotetrachromotropylene in aqueous solution: Substituent effects on π-π and Ch-π interactions

The stability constantsK of 11 complexes formed in aqueous solution between several monosubstituted benzenes (C₆H₅X) and methanes (CH₃X) as guests and cyclotetrachromotropylene as host were determined by proton NMR spectroscopy. Variations ofK with the substituent X are attributed to the electronic effect of X and the presence of C–H or aromatic bonds, if any, interacting with the host bonds.     

Preference of intra- and intermolecular cation-π interaction: cis-trans geometrical effects of amide bond on the interaction mode

An intermolecular cation-π interaction is observed in trans-amide 3, whereas an intramolecular interaction is observed in cis-amide 4, suggesting that cis-trans conformational difference plays a critical role in the preference of the interaction modes.     

4 + 4] photodimerization of azaanthracenes in both solution and solid phase controlled by cation-π interactions

Regio- and stereoselective [4 + 4] photodimerization reactions of 1- and 2-azaanthracenes were performed in both methanol solution and solid phases to give anti-HT dimers in high yields. In these reactions, intermolecular cation-π interactions between the pyridinium cation and the benzene ring play a key role in preorientation prior to the photodimerization reactions.     

Molecular recognition at the active site of factor Xa: cation-π interactions, stacking on planar peptide surfaces, and replacement of structural water

Factor Xa, a serine protease from the blood coagulation cascade, is an ideal enzyme for molecular recognition studies, as its active site is highly shape-persistent and features distinct, concave sub-pockets. We developed a family of non-peptidic, small-molecule inhibitors with a central tricyclic core orienting a neutral heterocyclic substituent into the S1 pocket and a quaternary ammonium ion into the aromatic box in the S4 pocket. The substituents were systematically varied to investigate cation-π interactions in the S4 pocket, optimal heterocyclic stacking on the flat peptide walls lining the S1 pocket, and potential water replacements in both the S1 and the S4 pockets. Structure-activity relationships were established to reveal and quantify contributions to the binding free enthalpy, resulting from single-atom replacements or positional changes in the ligands. A series of high-affinity ligands with inhibitory constants down to K(i)=2 nM were obtained and their proposed binding geometries confirmed by X-ray co-crystal structures of protein-ligand complexes.     

Theoretical studies on cation-π interactions (I)——Density-functional theory investigation on the configurations and interaction for ammonium cation-benzene complex

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Substituent effects in synthetic lectins--exploring the role of CH-π interactions in carbohydrate recognition

Contacts between aromatic surfaces and saccharide CH groups are common motifs in natural carbohydrate recognition. These CH-π interactions are modeled in "synthetic lectins" which employ oligophenyl units as apolar surfaces. Here we report the synthesis and study of new synthetic lectins with fluoro- and hydroxy-substituted biphenyl units, designed to explore the role of π-electron density in carbohydrate CH-π interactions. We find evidence that recognition can be moderated through electronic effects but that other factors such as cavity hydration are also important and sometimes predominant in determining binding strengths.     

Ratiometric electrochemical detection of Pd•••π interactions: application towards electrochemical molecular logic gates

Abstract

The widespread and large scale use of platinum group metals, especially palladium, in a wide variety of industrial applications has seen their levels in wastewater streams, roadside dust and even pharmaceuticals significantly rise over recent years. Due to the possible environmental damage and potential health risk this may cause, there is now substantial demand for inexpensive, efficient and robust methods for the detection of palladium. Based upon self-immolative linker technologies, we have designed and synthesised a number of allyl ether-functionalised electrochemical probes to determine the optimum probe structure required to deliver a ratiometric electrochemical detection method capable of achieving a limit of detection of <1 mg/mL within 20 min through the use of disposable screen-printed carbon electrodes. Combined with an enzymatic assay, this method was then used to achieve a proof-of-principle ratiometric electrochemical molecular logic gate.     

Influence of anion on the quadratic nonlinearity and depolarization ratios of scattered second harmonic light from cation-π complexes

We have investigated quadratic nonlinearity (β(HRS)) and linear and circular depolarization ratios (D and D('), respectively) of a series of 1:1 complexes of tropyliumtetrafluoroborate as a cation and methyl-substituted benzenes as π-donors by making polarization resolved hyper-Rayleigh scattering measurements in solution. The measured D and D(') values are much lower than the values expected from a typical sandwich or a T-shaped geometry of a complex. In the cation-π complexes studied here, the D value varies from 1.36 to 1.46 and D(') from 1.62 to 1.72 depending on the number of methyl substitutions on the benzene ring. In order to probe it further, β, D and D(') were computed using the Zerner intermediate neglect of differential overlap-correction vector self-consistent reaction field technique including single and double configuration interactions in the absence and presence of BF(4) (-) anion. In the absence of the anion, the calculated value of D varies from 4.20 to 4.60 and that of D(') from 2.45 to 2.72 which disagree with experimental values. However, by arranging three cation-π BF(4)(-) complexes in a trigonal symmetry, the computed values are brought to agreement with experiments. When such an arrangement was not considered, the calculated β values were lower than the experimental values by more than a factor of two. This unprecedented influence of the otherwise "unimportant" anion in solution on the β value and depolarization ratios of these cation-π complexes is highlighted and emphasized in this paper.