Can we predict reactivity for aromatic nucleophilic substitution with [18F]fluoride ion?

The correlation between the 13C-NMR chemical shift of the aromatic ring carbon bearing the leaving group and the yield of nucleophilic aromatic displacement with no-carrier-added [18F]fluoride ion was evaluated. In comparison of structurally analogous compounds (fluoro, nitro and trimethylammonium substituted benzaldehydes, benzophenones and benzonitriles), the 13C-NMR chemical shift of the reactive aryl ring carbon correlated quite well with the [18F]fluorination yield (r2=0.87) for most but not all ring structures. Compounds with trimethylammonium leaving groups or methyl ring substituents were found to not fit the proposed correlation. Kinetic studies indicated clearly different rates of reaction for these compounds, with much higher than expected reactivity for the compounds with the cationic leaving group. Competition experiments suggest that low reactivity of methyl-substituted rings may be due to conversion of [18F]fluoride to an unreactive form. Our results indicate that the correlation between [18F]fluorination yields for nucleophilic aromatic substitution reactions and the 13C NMR chemical shift of the aryl ring carbon bearing the leaving group is applicable to numerous structurally analogous compounds, but cannot be simply generalized to aromatic rings with different leaving groups or ring substituents. (author)