Fast and High-Yield Microreactor Syntheses of ortho-Substituted [18F]Fluoroarenes from Reactions of [18F]Fluoride Ion with Diaryliodonium Salts

A microreactor was applied to produce ortho-substituted [F-18]fluoroarenes from the reactions of cyclotron-produced [F-18]fluoride ion (t(1/2) = 109.7 min) with diaryliodonium salts. The microreactor provided a very convenient means for running sequential reactions rapidly with small amounts of reagents under well-controlled conditions, thereby allowing reaction kinetics to be followed and Arrhenius activation energies (E-a) to be measured. Prepared symmetrical iodonium chlorides (Ar2I+Cl-) rapidly ( < 4 min) gave moderate (Ar = 2-MeOC6H4, 51%) to high (Ar = Ph or 2-MeC6H4, 85%) decay-corrected radiochemical yields (RCYs) of a single radioactive product ((ArF)-F-18). Reaction velocity with respect to Ar group was 2-MeOC6H4 < Ph < 2-MeC6H4. Activation energies were in the range 18-28 kcal/mol. Prepared unsymmetrical salts (e.g., 2-RC(6)H(4)I(+)2'-R'C6H4X-; X = Cl or OTs) also rapidly gave two products (2-(RC6H4F)-F-18 and 2-R'(C6H4F)-F-18) in generally high total RCYs (79-93%). Selectivity for product [F-18]fluoroarene was controlled by the nature of the ortho substituents. The power of ortho substituents to impart an ortho-effect was in the following order:, 2,6-di-Me > 2,4,6-tri-Me > Br > Me > Et approximate to Pr-i >> H > OMe. For (2-methyphenyl)(phenyl)iodonium chloride, the time-course of reaction product selectivity was constant and consistent with the operation of the Curtin-Hammett principle. These results will aid in the design of diaryliodonium salt precursors to F-18-labeled tracers for molecular imaging.