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.

Figure 1

Time-course of [¹⁸F]fluorobenzene RCY from reactions of [¹⁸F]fluoride ion with diphenyliodonium chloride (5 mM) in DMF-0.25% water in the presence of 0.5 mM KF-K 2.2.2 at 90, 105 and 110 °C (CA), or in DMF in the presence of K₂CO₃-K 2.2.2 at 90 °C (NCA).

Figure 2

Kinetics of the radiofluorination of bis-(o-methylphenyl)iodonium chloride in DMF-0.25% H₂O to give [¹⁸F]2-fluorotoluene at different temperatures.

Figure 3

Arrhenius plot for the reaction of [¹⁸F]fluoride ion with bis-(2-methylphenyl)iodonium chloride (data derived from that in Figure 2). The solid line is the best fit determined by linear regression and the dotted lines are the 90% confidence limits (see Experimental).

Figure 4

Time-course of the decay-corrected radiochemical yield (RCY) of [¹⁸F]2-fluorotoluene (△) and [¹⁸F]fluorobenzene (▼), and of the product selectivity (●), from the reaction of CA [¹⁸F]fluoride ion with (2-methylphenyl)(phenyl)iodonium chloride at 110 °C in DMF-0.25% H₂O, in the presence of K⁺-K 2.2.2. Reagents and K⁺-K 2.2.2 were each initially at 2.5 mM. The dashed line is the line of linear regression for the product selectivity data.

Scheme 1

Reactions of diaryliodonium salts with [¹⁸F]fluoride Ion

Scheme 2

Routes used for the syntheses of diaryliodonium salts in this study

Scheme 3

Set-up of microfluidic apparatus for the study of radiofluorination reactions

Scheme 4

Suggested outline mechanism for the radiofluorination of an unsymmetrical diaryliodonium salt, through transition states TS₁ and TS₂ to give products P₁ and P₂, respectively.