Fluoro, Trifluoromethyl, and Trifluoroacetyl Substituent Effects on Cycloaddition Reactivities: Computations and Analysis.

The importance of fluoro and trifluoromethyl substituents in drug effectiveness prompted the computational exploration of fluorine-containing substituents in valuable synthetic cycloadditions. Diels-Alder or 1,3-dipolar cycloaddition reactions of typical reactants, cyclopentadiene, -phenyldiazoacetamide, tetrazine, and -phenylsydnone involving fluorine-containing substituents (F, CF, and COCF) were studied with M06-2X density functional theory. Inductive and conjugative effects influence normal and inverse electron-demand reactions differently. These results provide a guide to the design and use of cycloadditions for the introduction of fluoro and trifluoromethyl substituents in synthetic processes.