Homogeneous nucleophilic radiofluorination and fluorination with phosphazene hydrofluorides

Article abstract of DOI:10.1002/chem.201100458

A series of phosphazenium hydrofluorides, P₁ ^tBu·[^18/19F]HF, P₁ ^tOct·[^18/19F]HF, P₂^Et· [^18/19F]HF, and P₄^tBu·[ ^18/19F]HF, was synthesized. The radioactive phosphazenium [ ¹⁸F]hydrofluorides were obtained by the one-step formation and trapping of gaseous [¹⁸F]HF with the respective phosphazene bases. The [¹⁹F] isotopomers were prepared from the corresponding phosphazene bases and Et₃N·3HF. Under the design of experiment (DoE)-optimized conditions, P₂^Et·HF and P ₄^tBu·HF fluorinated alkyl chlorides, bromides, and pseudohalides in 76-98 % yield, but gave lower yields with iodides and electron-deficient arenes. DoE models showed that fluorination can be performed in glass vessels, and that the reactivity of P₂^Et· HF and P₄^tBu·HF is dominated by solvent polarity but is insensitive to water to at least 2 equiv. In contrast, P₁ ^tBu·HF and P₁^tOct·HF were unstable towards autofluorolysis. DFT calculations were performed to rationalize this finding in terms of diminished steric bulk, higher Parr's electrophilicity, and chemical hardness of P₁^RH ⁺. The corresponding radiofluorination reaction gave no valid DoE model but displayed similar substrate scope. High specific activity and excellent radiochemical yields with various pseudohalides (81-91 %) suggest that the proposed radiofluorination methodology can complement the current [ ¹⁸F]KF/Kryptofix methods, particularly in the areas for which nonpolar reaction conditions are required. A tale of fluoride: Up to 82 % of [¹⁸F]fluoride can be recovered from aqueous solution as [ ¹⁸F]HF gas in just one step (see scheme; Tf: trifluoromethanesulfonyl, Ms: methanesulfonyl, Ts=p-toluenesulfonyl). Trapped as phosphazenium hydrofluorides, ¹⁸F^- and ¹⁹F^- isotopomers attain high nucleophilicity and solubility in nonpolar solvents. Excelling in fluorination and radiofluorination of various pseudohalides, their substrate scope also extends to halides and nitroarenes. Copyright