title: Fast and high-yield microreactor syntheses of ortho-substituted [(18)F]fluoroarenes from reactions of [(18)F]fluoride ion with diaryliodonium salts.
abstract: A microreactor was applied to produce ortho-substituted [(18)F]fluoroarenes from the reactions of cyclotron-produced [(18)F]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 (Ar(2)I(+)Cl(-)) rapidly (<4 min) gave moderate (Ar = 2-MeOC(6)H(4), 51%) to high (Ar = Ph or 2-MeC(6)H(4), 85%) decay-corrected radiochemical yields (RCYs) of a single radioactive product (Ar(18)F). Reaction velocity with respect to Ar group was 2-MeOC(6)H(4) < Ph < 2-MeC(6)H(4). Activation energies were in the range 18-28 kcal/mol. Prepared unsymmetrical salts (e.g., 2-RC(6)H(4)I(+)2'-R'C(6)H(4)X(-); X = Cl or OTs) also rapidly gave two products (2-RC(6)H(4)(18)F and 2-R'C(6)H(4)(18)F) in generally high total RCYs (79-93%). Selectivity for product [(18)F]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 approximately (i)Pr >> 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 (18)F-labeled tracers for molecular imaging.
authors.affiliation: PET Radiopharmaceutical Sciences Section, Molecular Imaging Branch, National Institute of Mental Health, Rm. B3 C346A, Building 10, 10 Center Drive, Bethesda, Maryland 20892-1003, USA.
authors.forename: Joong-Hyun
authors.initials: JH
authors.lastname: Chun
authors.forename: Shuiyu
authors.initials: S
authors.lastname: Lu
authors.forename: Yong-Sok
authors.initials: YS
authors.lastname: Lee
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D019149:Bioreactors; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D005464:Fluorobenzenes / Q000138:chemical synthesis* / Q000737:chemistry; D006847:Hydrocarbons, Iodinated / Q000737:chemistry*; D007477:Ions / Q000737:chemistry; D046210:Microfluidic Analytical Techniques; D015394:Molecular Structure; D012492:Salts / Q000737:chemistry
chemical_list: D005462:Fluorine Radioisotopes; D005464:Fluorobenzenes; D006847:Hydrocarbons, Iodinated; D007477:Ions; D012492:Salts