Cation–π interaction

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.

[1][2] Benzene, the model π system, has no permanent dipole moment, as the contributions of the weakly polar carbon–hydrogen bonds cancel due to molecular symmetry.

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.

Practically, this allows trends to be predicted qualitatively based on visual representations of electrostatic potential maps for a series of arenes.

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.

Polarization, donor-acceptor[permanent dead link‍] 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.

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.

[7][8] 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.

While in the gas phase the most densely charged cations have the strongest cation–π interaction, these ions also have a high desolvation penalty.

[4] 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.

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 (corrected for extra hydrogen atoms) accounted for almost all of the cation–π binding trend.

Conversely, when the lone pair does not contribute to aromaticity (e.g. pyridine), the electronegativity of the heteroatom wins out and weakens the cation–π binding ability.

[14] Theoretical calculations suggest the cation–π interaction is comparable to (and potentially stronger than) ammonium-carboxylate salt bridges in aqueous media.

In fact, macromolecular binding sites that were hypothesized to include anionic groups (based on affinity for cations) have been found to consist of aromatic residues instead in multiple cases.

Cation–π interactions can tune the pKa of nitrogenous side-chains, increasing the abundance of the protonated form; this has implications for protein structure and function.

A study published in 1986 by Burley and Petsko looked at a diverse set of proteins and found that ~ 50% of aromatic residues Phe, Tyr, and Trp were within 6Å of amino groups.

[18] Studies on larger data sets found similar trends, including some dramatic arrays of alternating stacks of cationic and aromatic side chains.

The guanidinium moiety of Arg in particular has a high propensity to be stacked on top of aromatic residues while also hydrogen-bonding with nearby oxygen atoms.

Cation–π binding is also thought to be important in cell-surface recognition[2][26] Cation–π interactions can catalyze chemical reactions by stabilizing buildup of positive charge in transition states.

Since proton-triggered polycyclizations of squalene proceed through a (potentially concerted) cationic cascade, cation–π interactions are ideal for stabilizing this dispersed positive charge.

For example, Aoki and coworkers compared the solid state structures of Indole-3-acetic acid choline ester and an uncharged analogue.

It was found that even when anionic solubilizing groups were appended to aromatic host capsules, cationic guests preferred to associate with the π-system in many cases.

[29] More recently, cation–π centered substrate binding and catalysis has been implicated in supramolecular metal-ligand cluster catalyst systems developed by Raymond and Bergman.

Stoddart and co-workers developed a series of systems utilizing the strong π-π interactions between electron-rich benzene derivatives and electron-poor pyridinium rings.

The π-π interaction between A and B directed the formation of an interlocked template intermediate that was further cyclized by substitution reaction with compound C to generate the [2]catenane product.