Selective electrochemical fluorination of organic molecules and macromolecules in ionic liquids

This article provides an outline of recent studies on selective electrochemical fluorination in ionic liquid fluoride salts toward green sustainable chemistry. First, a brief historical background of electrochemical fluorination in organic solvents is provided, and some particular problems and unique solvent effects associated with this technique are briefly mentioned. Second, recent progress in selective fluorination and fluorodesulfurization of organic molecules and macromolecules in ionic liquids using direct and indirect electrolysis with recyclable mediators is reviewed.     

Selective fluorination of an aryl triazolinone herbicide intermediate

Fluoroaryl 1,2,4-triazolin-5-ones are an important class of herbicidal compounds useful in a variety of crop protection applications, primarily for the control of grassy and broad-leaf plant species. While a number of different synthetic strategies can be used for the step-wise preparation of these complex molecules, it is generally preferred to introduce fluorine later in the synthetic pathway, since the presence of fluorine and other halogens has a dominant effect on all subsequent synthetic steps. We have investigated the reactions that occur between aryl triazolinones and a variety of fluorination agents, including F₂/N₂, XeF₂, (CF₃SO₂)₂NF, Selectfluor^®, CF₂(OF)₂, CF₃OF, CH₃COOF, and CF₃COOF, and have used this knowledge to develop several alternative high-yielding routes to fluoroaryl 1,2,4-triazolin-5-ones. The fluorine introduction strategy and experimental results for a representative example of this important class of compounds are discussed herein.     

电化学氟化的新进展

电化学氟化是利用电极反应将氟直接引入有机或无机物的一种重要方法。有机物的电化学氟化方法有两种: 一是Simons于1941年发明的, 用镍作阳极, 在无水氟化氢溶液中, 电解制备全氟化合物的方法。此方法在近年来有不少改进。另一是1970年Rozhkov提出的, 以有机溶剂(如含Et3N.3HF的MeCN)为介质, 在铂阳极上,氧化得到单氟化产物的方法。本文全面地综述了这两种方法, 并着重于最新民发展。     

The electrochemical fluorination of acetyl fluoride

The electrochemical fluorination of acetyl fluoride in anhydrous hydrogen fluoride to produce trifluoroacetyl fluoride was investigated in a microprocessor-aided modified Simons' reactor. The product was recovered in acetic acid as trifluoroacetic acid. The experiments were carried out at a controlled anodic potential using a Cu/CuF₂ reference electrode. Product yields of 36 - 45%, current efficiencies of 30 to 50% and energy efficiencies of 11 – 23% were obtained.Experimental results of this investigation are presented and discussed.     

Selective aliphatic fluorination by halogen exchange in mild conditions

HF-Base media, in particular (HF)₁₀-pyridine or (HF)₃-triethylamine, allow aliphatic chlorine-fluorine exchanges on acid-sensitive molecules. Depending on the nature (pyridine or triethylamine), stoichiometry of the base and temperature, selective mono-, di-, or tri-chlorine-fluorine exchanges on trichloromethyl groups alpha to sulfur, oxygen and carbon atoms can be obtained.     

Selective direct fluorination of quinoline derivatives

Direct fluorination of various quinoline derivatives in acidic reaction media gives fluorinated quinoline products arising from selective, efficient electrophilic substitution processes.     

Selective anodic fluorination of electrophilic alkenes

Anodic fluorination of some electrophilic alkenes (conjugated with electron-withdrawn groups), ethyl cinnamates, RC₆H₄CHCHCO₂Et (R = H, CH₃, CH₃O, F and CF₃), cinnamonitrile, C₆H₄CHCHCN, phenyl stryryl ketone, and t-butyl styryl ketone using ammonium fluorides as the fluorine source and supporting electrolyte, in CH₂Cl₂ as electrolytic solvent yields the expected vicinal difluoro compounds, as mixture of erythro and threo isomers. The anodic fluorination of phenyl 3,5-di-t-butyl-4-hydroxystyryl ketone yields two monofluoro compounds. A possible reaction mechanism is discussed.     

Detection of free radicals in electrochemical fluorination

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 255–256, January, 1991.     

Microwave assisted fluorination: an improved method for side chain fluorination of substituted 1-arylethanones

A two-step, one-pot microwave (MW) assisted fluorination of 1-arylethanones to their corresponding 1-aryl-2-fluoroethanones has been developed. The first step utilises Selectfluor™ as a fluorinating agent in methanol forming 1-aryl-2-fluoroethanones and their corresponding dimethyl acetals. In the second step, water is added and Selectfluor™ acts as a Lewis acid in the hydrolytic cleavage of the dimethyl acetals. Compared to the thermal synthesis, the MW assisted method leads to a reduction in reaction time both in the fluorination and for the dimethyl acetal cleavage. Moreover, the one-pot procedure reduces reagent and solvent consumption. The method is best suited for the preparation of 1-aryl-2-fluoroethanones containing substituents that deactivates electrophilic aromatic substitution, however highly electron deficient ketones such as 1-(3,5-dinitrophenyl)ethanone reacts more slowly. Reactions using electron rich aromatic ketones had a low regioselectivity, and also produced fluoroaromatic products.     

Products of electrochemical fluorination of tripropylamine and triallylamine

Products of electrochemical fluorination of tripropylamine and triallylamine were studied by gas chromatography-mass spectrometry and high-resolution ¹⁹F NMR spectroscopy. The use of these methods allowed identification of the structures and isomeric composition of components of the electrolysis products.     

Selective fluorination of 1-hydroxyisoquinolines using Selectfluor™

The highly regioselective fluorination of 1-hydroxyisoquinoline is described using Selectfluor™ (F-TEDA-BF₄) under a variety of conditions.     

Selective electrochemical glycosylation by reactivity tuning

Electrochemical glycosylation of a selenoglycoside donor proceeds efficiently in an undivided cell in acetonitrile to yield beta-glycosides. Measurement of cyclic voltammograms for a selection of seleno-, thio-, and O-glycosides indicates the dependence of oxidation potential on the anomeric substituent allowing the possibility for the rapid construction of oligosaccharides by selective electrochemical activation utilising variable cell potentials in combination with reactivity tuning of the glycosyl donor. A variety of disaccharides are readily synthesised in high yield, but limitations of the use of selenoglycosides as glycosyl donors for selective glycosylation of thioglycoside acceptors are exposed. The first electrochemical trisaccharide synthesis is described.     

Selective fluorination of bile acids using elemental fluorine

Specific direct mono fluorinations on various sites of the steroidal skeleton of bile acids were achieved by introduction of electronegative groups at selected points.     

Selective fluorination of m-tyrosine by OF2

Fluorine-18 labeled aromatic amino acids are routinely used as tracers in positron emission tomography (PET) to study in vivo metabolic processes. The most versatile method for the production of such radiotracers is electrophilic fluorination of the aromatic amino acid with [¹⁸F]F₂, which is most commonly produced by the gas-phase nuclear reaction ¹⁸O(p, n)¹⁸F. Although [¹⁸F]F₂ is the major product, considerable amounts of [¹⁸F]OF₂ (up to 20%) are also produced. Electrophilic fluorination reactions of l-phenylalanine, 3-nitro-l-tyrosine, 4-nitro-dl-phenylalanine, 3,4-dihydroxyphenyl-l-alanine (l-DOPA), 3-O-methyl-l-DOPA, 3,4-dimethoxy-l-phenylalanine, p-tyrosine and o-tyrosine in H₂O and of m-tyrosine in anhydrous HF (aHF), CF₃SO₃H, CF₃COOH, CH₃COOH, HCOOH and H₂O using OF₂ were investigated. Although F₂ is an efficient fluorinating agent in aHF, electrophilic fluorination reactions using OF₂ were shown to be most efficient in less acidic media such as H₂O. In addition, and contrary to reports that OF₂ and F₂ have similar reactivities, m-tyrosine was the only aromatic system studied that was fluorinated by OF₂ and this was optimum in H₂O for the fluorinated m-tyrosine isomers (total yield, 4.35 ± 0.04%). The presence of [¹⁸F]OF₂ byproduct has no significant impact on the fluorination of aromatic amino acids investigated in this study and the subsequent production of their corresponding ¹⁸F-labeled radiotracers for patient use.     

Selective fluorination by C19XeF6

Selective fluorination by C₁₉XeF₆ of β-diketones and β-ketoesters is described. The ease of handling of this fluorinating reagent and high yields of mono fluorinated products obtained, show promise in organic synthesis.     

The electrochemical fluorination of octanoyl fluoride with electrolyte circulation

A modification to the standard method of electrochemical fluorination is described which embodies a forced flow of electrolyte through the electrode pack. A preliminary study of flow characteristics through an electrode pack was carried out.Good yields of perfluorooctanoyl fluoride and associated perfluorinated products are reported. The nature of the anode surface was studied before and after fluorination by scanning electron microscopy.     

Selective and sensitive determination of hydroxyl radicals generated from living cells through an electrochemical impedance method

An efficient protocol for selective and sensitive detection of generated hydroxyl radicals was first developed in the photocatalytic system through an electrochemical impedance method and further successfully applied to monitor hydroxyl radicals in the LPS-mediated cellular ROS/RNS burst process.     

Highly selective electrochemical fluorination of organic compounds in ionic liquids

Recent studies on electrochemical partial fluorination in ionic liquid fluoride salts are reviewed. At first, historical background and some problems of electrochemical fluorination in organic solvents are briefly mentioned. Solvent-free electrochemical fluorinations in ionic liquids are explained as follows. Ultrasonication was found to improve both the yield and current efficiency for electrochemical fluorination of α-phenylthioacetate, which is mainly attributable to marked mass transport promotion of the substrate and the suppression of anode passivation. Highly regioselective and efficient fluorination of cyclic ethers, lactones, and cyclic carbonate was achieved in Et₄NF·4HF and Et₃N·5HF. Selective fluorination of hardly oxidizable phthalide was realized using a combination of imidazolium and fluoride ionic liquids. The unique effect of imidazolium ionic liquids on electrochemical fluorodesulfurization of 3-phenylthiophthalide was explained. Reuse of ionic liquids for electrochemical fluorination is also possible.     

Selective cleavage of polycyclic cyclopropanes by electrochemical oxidation

Anodic oxidation in acetic acid of polycyclic cyclopropanes, namely tricyclene, cyclofenchene, and longicyclene, followed by hydrolysis brought about stereo- and regioselective formation of the corresponding homoallylic alcohols as the main product in good yields.     

Unique solvent effects on selective electrochemical fluorination of organic compounds

Recent studies on solvent effects on electrochemical partial fluorination are reviewed. At first, the historical background and some problems of electrochemical fluorination in organic solvents like acetonitrile (MeCN) are briefly mentioned. Ethereal solvents like dimethoxyethane (DME) and a mixture of DME and MeCN were found to improve both the yield and current efficiency for electrochemical fluorination since these solvent systems effectively suppress anode passivation and overoxidation of fluorinated products once formed during the electrolysis. It was also found that DME stabilizes radical cationic intermediates of 4-arylthio-1,3-dioxolan-2-ones and 3-phenylthiophthalide leading to α-fluorination while dichloromethane (CH₂Cl₂) destabilizes them leading to fluorodesulfurization. On the other hand, imidazolium ionic liquids and liquid fluoride salts like Et₄NF·4HF and Et₃N·5HF exhibited similar effects to CH₂Cl₂. Selective fluorination of hardly oxidizable phthalide was also achieved using a combination of two kinds of ionic liquids (imidazolium triflate and liquid fluoride salts).