An ab initio study of the alpha-fluorination effects on phosphatase inhibitors

Ab initio methods were used to investigate the α-fluorination of simple phosphonic acid molecules. We found that fluorine atoms are not strong hydrogen bond acceptors, and the substitution marginally enhances the hydrogen bonds between the phosphonic group (-PO(OH)2) and its surrounding polar groups. However, profound effects are observed in the stability of ionic species due to the substitution of fluorine atom(s). The proton transfer from phosphonic acids to proton-accepting groups such as water or ammonia molecules is energetically plausible in water solution to generate anions, and the α-fluorination significantly stabilizes the anions. This result explains the established correlation between bioactivities and the pKa values and sheds light on the significant enhancement in the bioactivity of phosphatase inhibitors due to their fluoro-substitution.