title: The cation-π interaction.
abstract: The chemistry community now recognizes the cation-π interaction as a major force for molecular recognition, joining the hydrophobic effect, the hydrogen bond, and the ion pair in determining macromolecular structure and drug-receptor interactions. This Account provides the author's perspective on the intellectual origins and fundamental nature of the cation-π interaction. Early studies on cyclophanes established that water-soluble, cationic molecules would forego aqueous solvation to enter a hydrophobic cavity if that cavity was lined with π systems. Important gas phase studies established the fundamental nature of the cation-π interaction. The strength of the cation-π interaction (Li(+) binds to benzene with 38 kcal/mol of binding energy; NH4(+) with 19 kcal/mol) distinguishes it from the weaker polar-π interactions observed in the benzene dimer or water-benzene complexes. In addition to the substantial intrinsic strength of the cation-π interaction in gas phase studies, the cation-π interaction remains energetically significant in aqueous media and under biological conditions. Many studies have shown that cation-π interactions can enhance binding energies by 2-5 kcal/mol, making them competitive with hydrogen bonds and ion pairs in drug-receptor and protein-protein interactions. As with other noncovalent interactions involving aromatic systems, the cation-π interaction includes a substantial electrostatic component. The six (four) C(δ-)-H(δ+) bond dipoles of a molecule like benzene (ethylene) combine to produce a region of negative electrostatic potential on the face of the π system. Simple electrostatics facilitate a natural attraction of cations to the surface. The trend for (gas phase) binding energies is Li(+) > Na(+) > K(+) > Rb(+): as the ion gets larger the charge is dispersed over a larger sphere and binding interactions weaken, a classical electrostatic effect. On other hand, polarizability does not define these interactions. Cyclohexane is more polarizable than benzene but a decidedly poorer cation binder. Many studies have documented cation-π interactions in protein structures, where lysine or arginine side chains interact with phenylalanine, tyrosine, or tryptophan. In addition, countless studies have established the importance of the cation-π interaction in a range of biological processes. Our work has focused on molecular neurobiology, and we have shown that neurotransmitters generally use a cation-π interaction to bind to their receptors. We have also shown that many drug-receptor interactions involve cation-π interactions. A cation-π interaction plays a critical role in the binding of nicotine to ACh receptors in the brain, an especially significant case. Other researchers have established important cation-π interactions in the recognition of the "histone code," in terpene biosynthesis, in chemical catalysis, and in many other systems.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
mesh_terms: D000838:Anions; D001554:Benzene / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002412:Cations / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D010649:Phenylalanine / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D055672:Static Electricity; D014364:Tryptophan / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D000838:Anions; D002412:Cations; D011506:Proteins; D014867:Water; D010649:Phenylalanine; D002244:Carbon; D006859:Hydrogen; D014364:Tryptophan; D001554:Benzene