The steric and electronic effects of aliphatic fluoroalkyl groups |
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| Authors: | Christopher M Timperley William E White |
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| Institution: | a Chemical and Biological Defence Sector, Defence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, Wiltshire, UK
b Edgewood Chemical and Biological Centre, Aberdeen Proving Ground, MD 21010, USA |
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| Abstract: | 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)2CH, isobutyl or t-butyl by (CF3)2CH, and 3-methyl-2-butyl by CF3(CH3)2C. Calculation of the charge on oxygen and the Wiberg index of the CO bond allowed an electronegativity scale to be constructed for the fluoroalkyl groups. Electronegativity decreased in the order: (CF3)3C>(CF3)2CH>C2F5CH2>CF3CH2>CH3(CF3)2C>HCF2CH2>CF3(CH3)CH>(FCH2)2CH>FCH2CH2>CF3(CH3)2C. This ranking agreed with literature acid dissociation data for the alcohols studied. |
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| Keywords: | Ab initio calculations Electronic effect Fluoroalcohol Fluoroalkyl Steric effect |
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