Organic soluble anhydrous fluoride sources are sought after reagents to introduce fluorine into arenes through nucleophilic aromatic substitution (S<sub>N</sub>Ar). Two commonly used reagents are tetrabutylammonium fluoride (TBAF) and tetramethylammonium fluoride (TMAF), which have their advantages and disadvantages. Anhydrous TBAF binds weakly to fluoride causing it to be a very strong nucleophile, however this quaternary ammonium salt is relatively unstable in its anhydrous form due to its propensity to undergo Hofmann elimination in reduced polarity solvents or in polar aprotic solvents at elevated temperatures. An additional complication is that anhydrous TBAF cannot be formed directly from its readily available hydrate. In contrast, anhydrous TMAF is stable when heated and can be prepared from its hydrate, but the TMA cation binds fluorine significantly more avidly than the TBA cation, making the fluoride less nucleophilic. To simultaneously balance practical and reactivity concerns, we designed a reagent, trineopentylmethylammonium fluoride (TNPMAF), which can be heated without significant decomposition and which binds fluoride comparably to TBAF. This anhydrous reagent can be prepared easily by heating the hydrated salt under vacuum. The fluoride ion nucleophilicity of TNPMAF is slightly below that of TBAF at room temperature, but it is significantly greater than that of TMAF. The thermal stability of TNPMAF allows it to be heated in various polar aprotic solvents, thereby increasing its reactivity above that observed for TBAF at its stability limit. Halogen exchange of aryl chlorides to aryl fluorides using anhydrous TNPMAF were carried out in good to excellent yields with short reaction times. Results contrasting TMAF, TBAF, and TNPMAF show that TNPMAF is a readily prepared, highly nucleophilic fluoride source suitable for S<sub>N</sub>Ar reactions.

Novel counterion for soluble anhydrous fluoride

253rd National Meeting (2017)

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