Stephen G. DiMagno and Haoran Sun Pages 1473 - 1482 ( 10 )
Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-π...X and C-F...X interaction energies are possible. Existing studies show that fluorinationimpact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F...X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity.
fluorination, C-C framework, Fluorobenzenes, intermolecular interaction, arene-arenen interactions, carbonic anhydrase inhibitors
University of Nebraska,Department of Chemistry, Hamilton Hall, Lincoln, NE 68588-0304.