Cation–π interaction


Cation–π interaction is a noncovalent molecular interaction between the face of an electron-rich π system and an adjacent cation. This interaction is an example of noncovalent bonding between a monopole and a quadrupole. Bonding energies are significant, with solution-phase values falling within the same order of magnitude as hydrogen bonds and salt bridges. Similar to these other non-covalent bonds, cation–π interactions play an important role in nature, particularly in protein structure, molecular recognition and enzyme catalysis. The effect has also been observed and put to use in synthetic systems.

Origin of the effect

, the model π system, has no permanent dipole moment, as the contributions of the weakly polar carbon–hydrogen bonds cancel due to molecular symmetry. However, the electron-rich π system above and below the benzene ring hosts a partial negative charge. A counterbalancing positive charge is associated with the plane of the benzene atoms, resulting in an electric quadrupole. The negatively charged region of the quadrupole can then interact favorably with positively charged species; a particularly strong effect is observed with cations of high charge density.

Nature of the cation–π interaction

The most studied cation–π interactions involve binding between an aromatic π system and an alkali metal or nitrogenous cation. The optimal interaction geometry places the cation in van der Waals contact with the aromatic ring, centered on top of the π face along the 6-fold axis. Studies have shown that electrostatics dominate interactions in simple systems, and relative binding energies correlate well with electrostatic potential energy.
The Electrostatic Model developed by Dougherty and coworkers describes trends in binding energy based on differences in electrostatic attraction. It was found that interaction energies of cation–π pairs correlate well with electrostatic potential above the π face of arenes: for eleven Na+-aromatic adducts, the variation in binding energy between the different adducts could be completely rationalized by electrostatic differences. Practically, this allows trends to be predicted qualitatively based on visual representations of for a series of arenes. Electrostatic attraction is not the only component of cation–π bonding. For example, 1,3,5-trifluorobenzene interacts with cations despite having a negligible quadrupole moment. While non-electrostatic forces are present, these components remain similar over a wide variety of arenes, making the electrostatic model a useful tool in predicting relative binding energies. The other "effects" contributing to binding are not well understood. Polarization, and charge-transfer interactions have been implicated; however, energetic trends do not track well with the ability of arenes and cations to take advantage of these effects. For example, if induced dipole was a controlling effect, aliphatic compounds such as cyclohexane should be good cation–π partners.
The cation–π interaction is noncovalent and is therefore fundamentally different than bonding between transition metals and π systems. Transition metals have the ability to share electron density with π-systems through d-orbitals, creating bonds that are highly covalent in character and cannot be modeled as a cation–π interaction.

Factors influencing the cation–π bond strength

Several criteria influence the strength of the bonding: the nature of the cation, solvation effects, the nature of the π system, and the geometry of the interaction.

Nature of the cation

From electrostatics, smaller and more positively charged cations lead to larger electrostatic attraction. Since cation–π interactions are predicted by electrostatics, it follows that cations with larger charge density interact more strongly with π systems.
The following table shows a series of Gibbs free energy of binding between benzene and several cations in the gas phase. For a singly charged species, the gas-phase interaction energy correlates with the ionic radius, .

M+Li+Na+K+NH4+Rb+NMe4+
−ΔG 38271919169
0.761.021.381.431.522.45


This trend supports the idea that coulombic forces play a central role in interaction strength, since for other types of bonding one would expect the larger and more polarizable ions to have greater binding energies.

Solvation effects

The nature of the solvent also determines the absolute and relative strength of the bonding. Most data on cation–π interaction is acquired in the gas phase, as the attraction is most pronounced in that case. Any intermediating solvent molecule will attenuate the effect, because the energy gained by the cation–π interaction is partially offset by the loss of solvation energy.
For a given cation–π adduct, the interaction energy decreases with increasing solvent polarity. This can be seen by the following calculated interaction energies of methylammonium and benzene in a variety of solvents.
Additionally, the trade-off between solvation and the cation–π effect results in a rearrangement of the order of interaction strength for a series of cations. While in the gas phase the most densely charged cations have the strongest cation–π interaction, these ions also have a high desolvation penalty.
This is demonstrated by the relative cation–π bond strengths in water for alkali metals:

Nature of the π system

Quadrupole moment

Comparing the quadrupole moment of different arenes is a useful qualitative tool to predict trends in cation–π binding, since it roughly correlates with interaction strength. Arenes with larger quadrupole moments are generally better at binding cations.
However, a quadrupole-ion model system cannot be used to quantitatively model cation–π interactions. Such models assume point charges, and are therefore not valid given the short cation–π bond distance. In order to use electrostatics to predict energies, the full electrostatic potential surface must be considered, rather than just the quadrupole moment as a point charge.

Substituents on the aromatic ring

The electronic properties of the substituents also influence the strength of the attraction. Electron withdrawing groups weaken the interaction, while electron donating substituents strengthen the cation–π binding. This relationship is illustrated quantitatively in the margin for several substituents.
The electronic trends in cation–π binding energy are not quite analogous to trends in aryl reactivity. Indeed, the effect of resonance participation by a substituent does not contribute substantively to cation–π binding, despite being very important in many chemical reactions with arenes. This was shown by the observation that cation–π interaction strength for a variety of substituted arenes correlates with the Hammett parameter. This parameter is meant to illustrate the inductive effects of functional groups on an aryl ring.
The origin of substituent effects in cation–π interactions has often been attributed to polarization from electron donation or withdrawal into or out of the π system. This explanation makes intuitive sense, but subsequent studies have indicated that it is flawed. Recent computational work by Wheeler and Houk strongly indicate that the effect is primarily due to direct through-space interaction between the cation and the substituent dipole. In this study, calculations that modeled unsubstituted benzene plus interaction with a molecule of "H-X" situated where a substituent would be accounted for almost all of the cation–π binding trend. For very strong pi donors or acceptors, this model was not quite able account for the whole interaction; in these cases polarization may be a more significant factor.

Binding with heteroaromatic systems

Heterocycles are often activated towards cation–π binding when the lone pair on the heteroatom is in incorporated into the aromatic system. Conversely, when the lone pair does not contribute to aromaticity, the electronegativity of the heteroatom wins out and weakens the cation–π binding ability.
Since several classically "electron rich" heterocycles are poor donors when it comes to cation–π binding, one cannot predict cation–π trends based on heterocycle reactivity trends. Fortunately, the aforementioned subtleties are manifested in the electrostatic potential surfaces of relevant heterocycles.
Cation–heterocycle interaction is not always a cation–π interaction; in some cases it is more favorable for the ion to be bound directly to a lone pair. For example, this is thought to be the case in pyridine-Na+ complexes.

Geometry

Cation–π interactions have an approximate distance dependence of 1/rn where n<2. The interaction is less sensitive to distance than a simple ion-quadrupole interaction which has 1/r3 dependence.
A study by Sherrill and coworkers probed the geometry of the interaction further, confirming that cation–π interactions are strongest when the cation is situated perpendicular to the plane of atoms. Variations from this geometry still exhibit a significant interaction which weakens as θ angle approaches 90 degrees. For off-axis interactions the preferred ϕ places the cation between two H atoms. Equilibrium bond distances also increase with off-axis angle. Energies where the cation is coplanar with the carbon ring are saddle points on the potential energy surface, which is consistent with the idea that interaction between a cation and the positive region of the quadrupole is not ideal.

Relative interaction strength

Theoretical calculations suggest the cation–π interaction is comparable to ammonium-carboxylate salt bridges in aqueous media. Computed values below show that as solvent polarity increases, the strength of the cation–π complex decreases less dramatically. This trend can be rationalized by desolvation effects: salt bridge formation has a high desolvation penalty for both charged species whereas the cation–π complex would only pay a significant penalty for the cation.