Electrostatic Forces in Aqueous Media and the Nature of the Cation-π Interaction

Author: Mecozzi, Sandro

Year: 1997

Degree: Dissertation (Ph.D.)

Advisors: Dougherty, Dennis A.; Goldreich, Peter Martin

Committee Members: Imperiali, Barbara; Gray, Harry B.; Carreira, Erick Moran; Dougherty, Dennis A.

Option: Chemistry

DOI: 10.7907/vpy4-bb38

Abstract

The forces responsible for the molecular recognition of organic compounds in aqueous media are mainly hydrophobic and electrostatic forces. It has been known for some time that water-solvated positively charged organic compounds, such as N-methylquinolinium and adamantyl trimethylammonium, are bound by cyclophane receptors, in aqueous media, more strongly than neutral organic molecules. The origin of this interaction can be found in the attraction between the cation and the electron-rich face of the aromatics in the host. This intermolecular force has been called the cation-1t interaction. We report our findings on the nature of this interaction. We performed a series of high level ab initio computational studies on the binding of the sodium cation to the π face of eleven aromatic molecules. Binding energies were evaluated at the 6- 31G**//6-31G** level. We then replaced the sodium cation in the optimized complex with a dummy probe atom and evaluated the electrostatic potential at that point. This procedure allowed us to calculate the electrostatic contribution to the binding. A plot of the electrostatic potentials vs. the binding energies showed that the electrostatic component of the cation-1t interaction is highly variable. However, across the series of examined molecules, essentially 100% of the variation in binding energy is reflected in the electrostatic term. All other factors, including induced dipole interactions, charge transfer, and dispersion forces, are absorbed in a constant term worth ca. 12 kcal/mol in the prototype aromatics considered in this study. These results prompted us to use electrostatic potential surfaces of aromatics as a qualitative and semi-quantitative guide for cation-π interactions. We report the electrostatic potential surfaces for seventeen different π systems. We found that the trend found in the binding of sodium cation to the π surface of the aromatic can be easily reproduced by simple visual inspection of these surfaces. We evaluated the electrostatic potential surfaces with ab initio and semi-empirical calculations and we found that AM1 surfaces can reproduce the trends found in the ab initio surfaces. We then report a series of AM1 electrostatic potential surfaces for a larger series of aromatic systems, and show their relevance to medicinal and biological issues.

The synthesis of a neutral water-soluble cyclophane receptor is then reported. This molecule originated from previous studies on a similar receptor bearing four peripheral carboxylates. The uncertain importance of these carboxylates on the binding of cations inspired us to make its neutral water-soluble analog. We report the binding affinities of this host for some neutral and positively charged guests. The absence of the external negative charges results in a decrease of approximately 1.5 kcal/mol in selected guests.

Finally, synthetic approaches to the synthesis of two new cyclophane receptors are reported. In one case we added four more peripheral negative charges to the host, and in the other case we made a water-soluble cyclophane with only one carboxylate adjacent to the binding cavity. The former receptor was designed to study long-range electrostatic interactions in aqueous media, while the latter host was designed to study short-range electrostatic interactions.

Files