Penetration of Negatively Charged Lipid Interfaces by the Doubly Deprotonated Dipicolinate

The possibility that a negatively charged organic molecule penetrates the lipid interface in a reverse micellar system is examined using UV-vis absorption and NMR spectroscopy. The hypothesis that deprotonated forms of dipicolinic acid, H(2)dipic, such as Hdipic(-) and dipic(2-), can penetrate the lipid interface in a microemulsion is based on our previous finding that the insulin-enhancing anionic [VO(2)dipic](-) complex was found to reside in the hydrophobic layer of the reverse micelle (Crans et al. J. Am. Chem. Soc. 2006, 128, 4437-4445). Penetration of a polar and charged compound, namely Hdipic(-) or dipic(2-). into a hydrophobic environment is perhaps unexpected given the established rules regarding the fundamental properties of compound solubility. As such, this work has broad implications in organic chemistry and other disciplines of science. These studies required a comprehensive investigation of the different dipic species and their association in aqueous solutions at varying pH values. Combining the aqueous studies using absorption and NMR spectroscopy with those in microemulsions defines the differences observed in the heterogeneous environment. Despite the expected repulsion between the surfactant head groups and the dianionic probe molecule, these studies demonstrate that dipic resides deep in the hydrophobic portion of the reverse micellar interface. In summary, these results provide evidence that ionic molecules can reside in nonpolar locations in microheterogeneous environments. This suggests that additional factors such as solvation are important to molecule location. Documented ability to penetrate lipid surfaces of similar charge provides a rationale for why specific drugs with less than optimal hydrophobicity are successful even though they violate Lipinski's rules.