Partially fluorinated alkoxy groups − Conformational adaptors to changing environments

Abstract

Lipophilicities of partially fluorinated n-propyloxy indole derivatives and their rates of oxidative metabolic degradation are presented. Comparison of the lipophilicity data with those of compounds containing the same partially fluorinated propyl groups attached to carbon or nitrogen reveals remarkable similarities and some distinct differences. A further striking difference in lipophilicity pattern is noted between terminally fluorinated n-propyloxy and corresponding methoxy derivatives. The lipophilicity patterns are rationalized in a consistent way by application of a simple rule-of-thumb based on polar-bond vector superposition, taking into account conformational aspects deduced from X-ray crystal structures and quantum chemical calculations. Several of these groups can switch between polar and non-polar conformations of comparable energies and may thus be regarded as potentially effective conformational adaptors to changing chemical environments. All compounds exhibit relatively high rates of metabolic degradation with a moderate correlation between degradation rate and lipophilicity.