Computational studies on hypervalent iodonium(III) compounds as activated precursors for 18F radiofluorination of electron-rich arenes

Abstract

Fluorination of deactivated and non-activated electron-rich arenes via nucleophilic aromatic substitution (SNAr) reactions represents a major challenge in medicinal and radiochemistry. In efforts to activate electron-rich arenes for facile synthesis of fluoroarenes, a wide range of reagents have been developed. In particular, aryliodonium(III) species (salts and ylides) show promise as reagents for synthesising 18F-radiolabelled molecules for use in positron emission tomography (PET). However, in fluorination reactions involving a reductive elimination mechanism, aryliodonium(III) reagents present two competing pathways that lead to product (via transition state 1 (TS1)) or by-product (TS2) formation. Here, we present detailed computational studies using Density Functional Theory (DFT) methods on the relatively stability of these competing transition states and present an analysis based on transition state theory that allows prediction of chemoselectivity in aryliodonium(III) fluorination reactions. The methods developed indicate that the calculated difference in free energy (ΔΔG‡) and the calculated equilibrium constant (lnK‡) between the two transition states are chemically accurate molecular descriptors of chemoselectivity in aryliodonium(III) fluorination. It is anticipated that the tools developed here will aid design of the next generation of reagents with increased chemoselectivity for fluorination and radiofluorination of electron-rich arenes.