Abstract
We review recent works for nucleophilic fluorination of organic compounds in which the Coulombic interactions between ionic species and/or hydrogen bonding affect the outcome of the reaction. SN2 fluorination of aliphatic compounds promoted by ionic liquids is first discussed, focusing on the mechanistic features for reaction using alkali metal fluorides. The influence of the interplay of ionic liquid cation, anion, nucleophile and counter-cation is treated in detail. The role of ionic liquid as bifunctional (both electrophilic and nucleophilic) activator is envisaged. We also review the SNAr fluorination of diaryliodonium salts from the same perspective. Nucleophilic fluorination of guanidine-containing of diaryliodonium salts, which are capable of forming hydrogen bonds with the nucleophile, is exemplified as an excellent case where ionic interactions and hydrogen bonding significantly affect the efficiency of reaction. The origin of experimental observation for the strong dependence of fluorination yields on the positions of -Boc protection is understood in terms of the location of the nucleophile with respect to the reaction center, being either close to far from it. Recent advances in the synthesis of [18F]F-dopa are also cited in relation to SNAr fluorination of diaryliodonium salts. Discussions are made with a focus on tailor-making promoters and solvent engineering based on ionic interactions and hydrogen bonding.
Highlights
Nucleophilic fluorination [1,2,3,4] using various sources of F fluoride exhibits several advantages over the electrophilic [5,6] counterpart, especially for introducing the isotopic F-fluorine onto organic compounds: First, it does not need to use the carrier added [18 F]F2 gas that are very cumbersome to handle
In the second part of this brief review, we show that nucleophilic fluorinations of diaryliodonium salts using alkali metal fluoride are significantly affected by these electrostatic interactions
Nucleophilic fluorination, and especially [18 F]Fluorination, is usually very difficult due to unfavorable solvent effects on the small-sized F fluoride when the reaction is attempted in organic solvent
Summary
Nucleophilic fluorination [1,2,3,4] using various sources of F fluoride exhibits several advantages over the electrophilic [5,6] counterpart, especially for introducing the isotopic F-fluorine onto organic compounds: First, it does not need to use the carrier added [18 F]F2 gas that are very cumbersome to handle. We show that the rates and yields of nucleophilic fluorination may be improved by monitoring and controlling the Coulombic forces and weak interactions (hydrogen bonding, π-interactions, etc.) between IL cation, anion and substrates (especially, the leaving group). These interactions determine the efficiency of SN Ar fluorination of diaryliodonium salts that are gaining much importance as a useful path to incorporating 18 F and 19 F to aromatic compounds. In order to scrutinize the configuration of the reacting system (diaryliodonium cation, counter-anion, leaving group, metal cation and F− ) in pre-reaction complex and transition state to analyze the experimentally observed efficiency of reaction, quantum chemical calculations are indispensable, and we discuss the relevant recent works
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