When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

• Published in: International journal of quantum chemistry 2002, Vol.89 (4), p.419-427
• Main Authors: Hoffmann, Marcin, Rychlewski, Jacek
• Format: Article
• Language: English
• Subjects: computational chemistry; deoxyfluoroglucose; drug design; fluorine-containing compounds; tartaric acid derivatives
• ISSN: 0020-7608; 1097-461X
• DOI: 10.1002/qua.10277

In this article, we deal with the question of whether a fluorine atom can substitute a hydroxyl group in such a way that will lead to a compound showing a desired biologic activity, that is, a potential new drug. It is obvious that a fluorine atom differs from a hydroxyl group, as it cannot donate hydrogen bonds. However, it can accept them. Moreover, both fluorine and oxygen are of similar size and are the most electronegative elements. Therefore, a fluorine atom is thought to be a good substitute for a hydroxyl group. However, it was shown that for conformationally labile aliphatic compounds a replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorine‐containing aliphatic molecules are present in equilibrium at room temperature as a mixture of several different conformers. In contrast, for cyclic compounds the substitution of an OH group by an F atom does not much change shape and electrostatic potential around corresponding conformers. Moreover, these compounds are present in equilibrium at room temperature in aqueous solution as a mixture of the same most favored structures. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002