Ionic Liquids as Organocatalysts for Nucleophilic Fluorination: Concepts and Perspectives

Abstract

Besides their extremely useful properties as solvent, ionic liquids (ILs) are now considered to be highly instructive tools for enhancing the rates of chemical reactions. The ionic nature of the IL anion and cation seems to be the origin of this fascinating function of ILs as organocatalyst/promoter through their strong Coulombic forces on other ionic species in the reaction and also through the formation of hydrogen bonds with various functional groups in substrates. It is now possible to tailor-make ILs for specific purposes as solvent/promoters in a variety of situations by carefully monitoring these interactions. Despite the enormous potentiality, it seems that the application of ILs as organocatalysts/promoters for chemical reactions have not been fully achieved so far. Herein, we review recent developments of ILs for promoting the nucleophilic reactions, focusing on fluorination. Various aspects of the processes, such as organocatalytic capability, reaction mechanisms and salt effects, are discussed.

Keywords: ionic liquids; nucleophilic fluorination; organocatalysis.

Scheme 1

Two examples of nucleophilic fluorination (a) solvent free nucleophilic introduction of fluorine with [bmim][F], Ref. [35] (b) nucleophilic fluorination with KF catalyzed by 18-Crown-6 and bulky diols, Ref. [40].

Scheme 2

Fluorination of mesylates with KF or CsF in ionic liquids.

Scheme 3

Using PS[hmim][BF₄] and PS[hmim][OTf] (A) in tert-amyl alcohol (B) for S_N2 fluorination.

Figure 1

Calculated transition state for S_N2 fluorination using CsF facilitated by [bmim][OMs].

Figure 2

Calculated structures of pre-reaction complex, transition state and post-reaction complex of S_N2 fluorination for IL:substrate ratio = 2:1. Distances in Å.

Figure 3

S_N2 fluorination of trichlorotoluene by KF in ILs.

Figure 4

Calculated transition state of S_N2 fluorination in [bmim][PF₆] (a) activated by KPF₆ with substrate:KF:KPF₆ = 1:1:1 and (b) with substrate:KF = 1:2.

Figure 5

S_N2 fluorination [Cs⁺F⁻ + C₃H₇OMs → C₃H₇F + Cs⁺OMs⁻] in [hexaEGmim][X] ionic liquids.

Scheme 4

(a) Cold fluorination using CsF in CH₃CN; (b) hot fluorination of diarylio donium salts using (i) [¹⁸F] K⁺-APE 2.2.2 under N₂ at 85 °C 40 min and (ii) [¹⁸F]F⁻ Cs⁺, in CH₃CN under N₂ at 85 °C, 40 min.

Scheme 5

Multistep synthesis to [¹⁸F]6-fluoro-3,4-dihydroxy-L-phenylalanine ([¹⁸F]F-dopa) using chiral phase-transfer catalysts.

Scheme 6

Preparation of [¹⁸F]F-dopa from tert-butyl ester precursor. (a) [¹⁸F]F-, toluene, 105–110 °C, 10 min; (b) aq. HCl conc., 120 °C, 7 min.

Scheme 7

One-pot synthetic procedure for 6-[18F]fluorodopamine ([¹⁸F]F-DA).

Figure 6

Cluster–continuum solvation of KF and CsF with four tert-butanol molecules.

Figure 7

Molecular environment for the S_N2-[Bmim][Br] system at different kinetic states: (a) reactant, (b) transition state, and (c) product.

Figure 8

First-solvation shell [Bmim][BF₄] encapsulation of the (a) addition transition state and (b) the Meisenheimer intermediate, for the S_NAr reaction between piperidine and 2-methoxy-5-nitrothiophene. Ref. [71].