The steric and electronic effects of aliphatic fluoroalkyl groups

Ab initio calculations were performed on 18 fluorinated and unfluorinated alcohols at the B3LYP and HF levels with the 6-311G'* basis set. Molar volumes of the alcohols were computed at each level and averaged to produce a scale of relative size. From this, various isosteric replacements of potential use in drug design were suggested: ethyl by FCH2CH2 or HCF2CH2, propyl by CF3CH2, isopropyl by CF3(CH3)CH or (FCH2)(2)CH, isobutyl or t-butyl by (CF3)(2)CH, and 3-methyl-2-butyl by CF3(CH3)(2)C. Calculation of the charge on oxygen and the Wiberg index of the C-O bond allowed an electronegativity scale to be constructed for the fluoroalkyl groups. Electronegativity decreased in the order: (CF3)(3)C > (CF3)(2)CH > C2F5CH2 > CF3CH2 > CH3(CF3)(2)C > HCF2CH2 > CF3(CH3)CH > (FCH2)(2)CH > FCH2CH2 > CF3 (CH3)(2)C. This ranking agreed with literature acid dissociation data for the alcohols studied. (C) 2003 Elsevier B.V. All rights reserved.