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Homogeneous Nucleophilic Radiofluorination and Fluorination with Phosphazene Hydrofluorides
Author(s) -
Mathiessen Bente,
Jensen Andreas T. I.,
Zhuravlev Fedor
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201100458
Subject(s) - phosphazene , chemistry , nucleophile , reactivity (psychology) , steric effects , electrophile , yield (engineering) , medicinal chemistry , stereochemistry , organic chemistry , catalysis , materials science , medicine , polymer , alternative medicine , pathology , metallurgy
A series of phosphazenium hydrofluorides, P 1 t Bu ⋅ [ 18/19 F]HF, P 1 t Oct ⋅ [ 18/19 F]HF, P 2 Et ⋅ [ 18/19 F]HF, and P 4 t Bu ⋅ [ 18/19 F]HF, was synthesized. The radioactive phosphazenium [ 18 F]hydrofluorides were obtained by the one‐step formation and trapping of gaseous [ 18 F]HF with the respective phosphazene bases. The [ 19 F] isotopomers were prepared from the corresponding phosphazene bases and Et 3 N ⋅ 3HF. Under the design of experiment (DoE)‐optimized conditions, P 2 Et ⋅ HF and P 4 t Bu ⋅ 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 P 2 Et ⋅ HF and P 4 t Bu ⋅ HF is dominated by solvent polarity but is insensitive to water to at least 2 equiv. In contrast, P 1 t Bu ⋅ HF and P 1 t Oct ⋅ 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 P 1 R H + . 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 [ 18 F]KF/Kryptofix methods, particularly in the areas for which nonpolar reaction conditions are required.