Fluorination

Living Edition
| Editors: Jinbo Hu, Teruo Umemoto

Electrochemical Fluorination for Preparation of Alkyl Fluorides

  • Toshio FuchigamiEmail author
  • Shinsuke Inagi
Living reference work entry
DOI: https://doi.org/10.1007/978-981-10-1855-8_7-1

Introduction

Electrochemical fluorinations of organic compounds are classified into three processes: Simons’ process, Philips’ process, and partial (selective) fluorination process.

The Simons’ process is the oldest technique, which is a highly useful route to many perfluorinated organic compounds [1, 2]. A solution or dispersion of organic substrate is electrolyzed at a Ni anode in anhydrous hydrogen fluoride (AHF). The products are mostly perfluorinated, and they are commercially significant materials like perfluoroalkanes, perfluoroacyl fluorides, perfluoroalkanesulfonyl fluorides, perfluorotrialkylamines, and perfluoroalkyl esters. The mechanism of the Simons’ process seems to involve the generation of cationic intermediates and high-valence nickel fluorides.

The Phillips’ process utilizes a porous carbon anode in a molten KF-2HF electrolyte [2].

The substrate, typically a gas or volatile liquid particularly insoluble in the electrolyte, is introduced through the porous anode and undergoes statistical replacement of hydrogen with fluorine. The products range from monofluoro to perfluoro compounds and include alkane, chloroalkane, carbonyl fluoride, and ester derivatives. The mechanism is believed to involve the generation of elementary fluorine followed by in situ reaction with the organic substrate via a free radical. Thus, this process can be classified as an indirect anodic substitution reaction.

Partial electrochemical fluorination is a rather new method and it is generally carried out in an aprotic solvent containing an organic substrate and a fluoride salt as a supporting electrolyte and a fluorine source [3, 4, 5]. The products are mono- and/or difluorinated compounds, which are formed through the generation of a cationic intermediate followed by reaction with fluoride ions. Therefore, the mechanism is quite similar to other anodic substitution processes.

Electrochemical Perfluorination

Electrochemical perfluorination is a process in which all the hydrogen atoms in a starting organic molecule are substituted with fluorine atoms without elementary fluorine generation during electrolysis.

The Simons’ Process

J. H. Simons developed the electrochemical perfluorination of organic compounds in anhydrous liquid HF using nickel electrodes to provide perfluorinated products in the late 1930s, and first published the details in 1949 [6]. He is a pioneer of electrochemical perfluorination and this method is called Simons’ process. The process uses an undivided cell at low temperature to keep HF as a liquid (the boiling point of HF is 19.5 °C).

Although highly pure AHF has no electric conductivity, organic compounds containing oxygen, nitrogen, or sulfur have relatively high solubility in liquid hydrogen fluoride and form an electrically conducting solution. On the other hand, hydrocarbons are not very soluble and do not form conducting solutions, but the addition of KF and NaF which imparts conductivity enables the process to be used even with hydrocarbon starting materials. AHF boils at 19.5 °C, thus electrolysis is typically performed at −10 °C up to slightly above the boiling temperature of AHF. From carboxylic acids (its chlorides), sulfonic acids (its chlorides) and trialkylamines, the perfluorinated products are obtained in good yields, as shown in Schemes 13 [7, 8, 9]. However, in many cases the yield for electrochemical perfluorination is rather low because of carbon–carbon bond cleavage during electrolysis. The products, perfluoroalkyl carboxylic acids and sulfonic acids, are useful as detergents and lubricants.
Scheme 1

Electrochemical perfluorination of methanesulfonyl chloride

Scheme 2

Electrochemical perfluorination of n-octanoyl halide

Scheme 3

Electrochemical perfluorination of tripropylamine

The reaction mechanism has been discussed for many years [9, 10, 11, 12]. One mechanism involves anodically generated fluorine radical as the vital reagent for perfluorination. For example, the fluorination of CH3(CH2) n SO2F and CH3(CH2) n COF to CF3(CF2) n SO2F and CF3(CF2) n COF, which are surface-active agent precursors produced by 3 M Company in USA, is as follows:
$$ {\mathrm{F}}^{-}\to \bullet \mathrm{F}+{\mathrm{e}}^{-} $$
(1)
In the case of C m H2m+1SO2F, fluorination takes place according to Reactions (2) and (3).
$$ {\mathrm{C}}_m{\mathrm{H}}_{2m+1}{\mathrm{SO}}_2\mathrm{F}+\bullet \mathrm{F}\to \bullet {\mathrm{C}}_m{\mathrm{H}}_{2m}{\mathrm{SO}}_2\mathrm{F}+\mathrm{HF} $$
(2)
$$ \bullet {\mathrm{C}}_m{\mathrm{H}}_{2m}{\mathrm{SO}}_2\mathrm{F}+\bullet \mathrm{F}\to {\mathrm{C}}_m{\mathrm{H}}_{2m}{\mathrm{FSO}}_2\mathrm{F} $$
(3)
Total reaction for fluorination of C m H2m+1SO2F is written as Reaction (4)
$$ {\mathrm{C}}_m{\mathrm{H}}_{2m+1}{\mathrm{SO}}_2\mathrm{F}+2\bullet \mathrm{F}\to {\mathrm{C}}_m{\mathrm{H}}_{2m}{\mathrm{FSO}}_2\mathrm{F}+\mathrm{HF} $$
(4)
In the case of fluorinating C m H2m+1COF, similar reactions take place. The total reactions for electrolytic production of these surfactant precursors are written as Reactions (5) and (6).
$$ {\mathrm{CH}}_3{\left({\mathrm{CH}}_2\right)}_n{\mathrm{SO}}_2\mathrm{F}+\left(6+4n\right)\mathrm{HF}-\left(6+4n\right){\mathrm{e}}^{-}\to {\mathrm{CF}}_3{\left({\mathrm{CF}}_2\right)}_n{\mathrm{SO}}_2\mathrm{F}+\left(3+2n\right)\mathrm{HF}+\left(3+2n\right){\mathrm{H}}_2 $$
(5)
$$ {\mathrm{CH}}_3{\left({\mathrm{CH}}_2\right)}_n\mathrm{COF}+\left(6+4n\right)\mathrm{HF}-\left(6+4n\right){\mathrm{e}}^{-}\to {\mathrm{CF}}_3{\left({\mathrm{CF}}_2\right)}_n\mathrm{COF}+\left(3+2n\right)\mathrm{HF}+\left(3+2n\right){\mathrm{H}}_2 $$
(6)

Another mechanism involves electrogenerated highly oxidized nickel fluorides such as Ni2F5, NiF3 and NiF4 on a nickel anode surface and fluoro complex such as NiF6 2− electrochemically regenerated at the nickel anode. During the electrolysis, partially fluorinated products have polarity and they stay in the electrolyte to be subjected to further electrolysis. The final perfluorinated products are non-polar and their specific density is very high, therefore they precipitate from liquid HF onto the cell bottom as a liquid.

Characteristics of electrochemical perfluorination (Simons’ process) are as follows:
  1. 1.

    Liquid hydrogen fluoride (anhydrous hydrofluoric acid), which is industrially produced on a large scale, can be used as a fluorine source.

     
  2. 2.

    Perfluorinated compounds can be obtained in one step process.

     
  3. 3.

    Although the cleavage of carbon-carbon bond in a fluorinating organic compound often takes place in a certain degree during electrochemical fluorination, functional groups in starting materials such as COF, SO2F retain in perfluorinated products.

     
  4. 4.

    The yield of perfluorinated organic compounds using Simons’ process is generally low. However, the yield of perfluorinated organic compounds using chemical fluorination reaction is much lower than that using electrochemical fluorination.

     
  5. 5.

    Any partially fluorinated compound can be hardly obtained by this process.

     
  6. 6.

    A nickel or nickel alloy anode is effective for this process.

     

Synthetic Aspects of the Simons’ Process

As already mentioned, the yield of perfluorinated products is low since they are usually accompanied by bond cleavage, dimerization, and cyclization. The yield of the desired product generally decreases with increasing carbon chain length.

Formation of cyclic ethers during electrolyses of acid fluorides or esters in the Simons’ process is well documented. In the case of aliphatic ether, similar trend is observed [13, 14, 15]. Abe and his coworkers reported many papers dealing with electrochemical perfluorination of aliphatic alcohols, esters, amines, cyclic amines like piperidine and morphorine as shown in Schemes 410. In most cases, however, the yield of perfluorinated products is very low because of various side reactions.
Scheme 4

Electrochemical perfluorination of 2-methylpentanol

Scheme 5

Electrochemical perfluorination of methyl 2-(2-cyclohexenyl)butylate

Scheme 6

Electrochemical perfluorination of diethylamine

Scheme 7

Electrochemical perfluorination of 2-diethylaminoethanol

Scheme 8

Electrochemical perfluorination of methyl 3-dimethylaminopropionate

Scheme 9

Electrochemical perfluorination of N,N’-bis(2-hydroxyethyl)piperidine

Scheme 10

Electrochemical perfluorination of 3,5-dimethylmorpholine

As shown in Scheme 1, electrochemical perfluorination of CH3SO2Cl is the key step in the production of triflic acid, CF3SO3H. In the case of C2H5SO2Cl, the conversion of sulfonyl chloride into sulfonyl fluoride prior to the electrochemical fluorination is required to preserve high yield of perfluorinated substance, C2F5SO2F [16]. Ignat’ev and his co-workers reported the electrolytic perfluorination of pyridine and sulfonamides as shown in Schemes 1113 [17, 18, 19, 20, 21]. (CF3)2NSO2CF3 is a useful starting material for the generation of various compounds containing (CF3)2N group [22]. Electrochemical perfluorination of trialkylphosphines, R3P affords tris(perfluoroalkyl)difluorophosphoranes, (RF)3PF2, in high yield as 49–74% [23].
Scheme 11

Electrochemical perfluorination of pyridine

Scheme 12

Electrochemical perfluorination of diethylaminosulfonyl fluoride

Scheme 13

Electrochemical perfluorination of N,N-dimethyltrifluoromethanesulfonamide

The Phillips’ Process

This process was developed at Phillips Petroleum Company in Germany [2, 24]. Suitable substrates are at least moderately volatile and not particularly soluble in the molten KF-2HF electrolyte, e.g., alkanes, cycloalkanes, chloroalkanes, acyl fluorides, and esters. It is thought that elementary fluorine is generated as the anode reaction. The anode is porous carbon (not graphite), and the process is thought to involve the electrolytic generation of elementary fluorine and reaction of that fluorine with substrates within the porous carbon anode.

The products appear to be formed by the statistical replacement of substrate hydride with fluoride and range from monofluoro to perfluoro compounds. The electrolysis is run at 90–100 °C. Mechanism of fluorination in this process is “In situ” reaction with fluorine generation, that is, a hydrocarbon substrate reacts with free radicals of fluorine and so this process is classified as indirect fluorination.

The process is efficient for many fluorinations. Different from the Simons’ process, the structure of substrate is retained mostly. For example, ethane is frequently run as a model substrate and various fluoroethanes are formed. Other easily run substrates are 1,2-dichloroethanes (80% retention of 1,2-dichloro structure), acetyl fluoride (85% yield of fluorinated acetyl fluorides), and tetrafluorocyclobutane (90% retention of structure). Current efficiencies are generally rather good (80 ~ 100%). This process is a useful complement to the Simons’ process for many volatile substrates and products.

Process for Perfluorotrimethylamine[(CF3)3N] Production

Perfluorotrimethylamine, (CF3)3N, easily decomposes to release trifluoromethyl radicals, •CF3 which react with organic compounds and promote lipophilicity of the resulting products. It is therefore considered that (CF3)3N is an important fluorine source for synthesis of many useful organofluoro compounds. (CF3)3N is a potential fire extinguish gas, and it is also expected as an etching gas for SiO2 film on Si wafer instead of hexafluoroethane, C2F6, in semi-conductor industry.

Recently, Tasaka and his coworkers developed a new process for electrosynthesis of (CF3)3N at room temperature using a nickel anode and a mixed melt of (CH3)4NF•mHF and CsF-2.0HF as an electrolyte [25, 26, 27]. In this process, electrochemical fluorination of (CH3)4N+ cation takes place according to Reaction (7).
$$ {\left({\mathrm{CH}}_3\right)}_4{\mathrm{N}}^{+}+25{\mathrm{F}}^{-}\to {\left({\mathrm{CF}}_3\right)}_3\mathrm{N}+{\mathrm{CF}}_4+12\mathrm{HF}+24\mathrm{e} $$
(7)

Mechanism on fluorination of (CH3)4N+ and (CH3)3N is similar to that in Simons’ process. In the mixed melt of (CH3)3N•mHF and CsF-2.3HF, the highly oxidized nickel fluoride of CsNi2F6 is formed on a nickel anode and it also fluorinates (CH3)3N to form (CF3)3N.

Electrochemical Partial Fluorination

Electrochemical partial fluorination can be commonly achieved in aprotic solvents such as acetonitrile (MeCN), dichloromethane, dimethoxyethane (DME), nitromethane, and sulfolane containing fluoride ions to provide mostly mono- and/or difuorinated products [1, 2, 3, 4, 5]. Electrolyses are conducted at constant potentials slightly higher than the first oxidation potential of a substrate by using a platinum or graphite anode. Constant current electrolysis is also effective for partial fluorination in many cases. Choice of the combination of a supporting fluoride salt and an electrolytic solvent is most important to accomplish efficient selective fluorination because competitive anode passivation (the formation of a nonconducting polymer film on the anode surface that suppresses faradaic current) takes place very often during the electrolysis. Pulse electrolysis is in many cases effective in order to avoid such passivation. Therefore, difficult-to-oxidize fluoride salts, which do not cause the passivation of the anode and have strongly nucleophilic F, are generally recommended as the supporting fluoride salts. Thus, room temperature-molten salts such as R3N-nHF (n = 3–5), R4NF-nHF (n = 3–5), and pyridine poly(hydrogen fluoride) salt (Py-nHF) are most often used and even R4NBF4 and R4NPF6 salts are effective in some cases [1, 2, 3, 4, 5]. Particularly when a HF supporting salt and a low hydrogen overvoltage cathode such as platinum are used, the reduction of protons (hydrogen evolution) occurs predominantly at the cathode during the electrolysis. Therefore, a divided cell is not always necessary for the fluorination under such conditions.

In an aprotic solvent, F becomes more nucleophilic; however, the reactivity of F is quite sensitive to a water-content of the electrolysis system because a hydrated F is a weak nucleophile. Drying of both the solvent and electrolyte is therefore necessary to optimize the formation of fluorinated products.

Since the discharge potential of fluoride ions is extremely high (> + 2.9 V vs. SCE at Pt anode in MeCN), the fluorination proceeds via a (radical) cation intermediate as shown in Scheme 14, which is the general pathway for anodic nucleophilic substitutions.
Scheme 14

Mechanism for electrochemical monofluorination of organic compounds

Fluorination of Olefins

Electrochemical fluorination of olefins provides mono- and/or difluorinated products (Scheme 15) [28, 29, 30, 31].
Scheme 15

Electrochemical mon- and /or difluorination of olefins

Anodic fluorination of vinyl sulfides such as 2-(phenylthio)styrene provides vicinal difluorides [32]. 1-Phenylhexene undergoes stereoselective difluorination and fluoroacetamidation upon anodic oxidation in MeCN while the difluorination predominates in the less nucleophilic solvent, dichloromethane (CH2Cl2).

Styrene gives a vic-difluoro product in moderate yield (Scheme 16) [33], while α-acetylstyrene and 1-acetoxy-3,4-dihydronaphthalene provide the corresponding α-fluoroketones as shown in Scheme 17 [34, 35, 36].
Scheme 16

Electrochemical difluorination of styrene

Scheme 17

Electrochemical monofluorination of α-acetoxystyrenes

Benzylic Fluorination

Generally, anodic benzylic substitution reactions take place readily. However, anodic benzylic fluorination does not always occur. The major competitive reaction is acetamidation when MeCN is used as a solvent. Laurent et al. found that anodic benzylic mono- and difluorination proceeds selectively when the benzylic position is substituted by electron-withdrawing groups (EWG) (Scheme 18) [37]. In these cases, p-methoxy or p-chloro substituents on the benzene are necessary for the operation of efficient fluorination. In their absence, benzylic acetamidation becomes a major reaction (Scheme 19).
Scheme 18

Electrochemical benzylic mono-and difluorination

Scheme 19

Substituent effects on electrochemical benzylic fluorination

In the case of anodic α-fluorination of toluene, ethylbenzene, and cumene in MeCN, the effciency of the fluorination is in the following order: cumene > ethylbenzene > toluene [38]. On the other hand, the efficiency of acetamidation is reverse. Moreover, triphenylmethane is selectively monofluorinated to provide fluorotriphenylmethane in high yield (80%) even in MeCN [39]. These facts suggest that the more stable benzylic cation intermediate reacts with fluoride ion more efficiently.

Fluorination of Organosulfur Compounds

Anodic fluorination of sulfides having α-electron-withdrawing groups proceeds quite well to provide the corresponding α-fluorinated products in good yields as shown in Scheme 20 [40, 41]. The electron-withdrawing ability of the fluoroalkyl group does not affect the efficiency of anodic monofluorination of sulfides. Even simple alkyl phenyl sulfides devoid of an electron-withdrawing group undergo fluorination in ethereal solvents such as tetrahydrofuran (THF) and dimethoxyethane (DME) to provide monofluorinated products in moderate yields [42].
Scheme 20

Electrochemical monofluorination of sulfides having various α-substituents

The fluorination proceeded by way of a Pummerer-type mechanism via the fluorosulfonium cation (A), as shown in Scheme 21 [37]. Thus, when R is an electron-withdrawing group, the deprotonation of A is significantly facilitated, and consequently, the fluorination proceeds efficiently.
Scheme 21

Pummerer type mechanism for electrochemical fluorination via fluorosulfonium ion

Regioselective electrochemical fluorination of alkyl ary sulfides having an electron-withdrawing group on the aromatic ring can be also achieved in Et3N-3HF/MeCN [43].

Regioselective electrochemical fluorination at the side chain of various heterocyclic compounds has been systematically studied [44, 45]. The active methylenethio group attached to heterocycles is selectively fluorinated to give the corresponding α-fluorinated products (Scheme 22). Notably, the use of MeCN prevented the formation of fluorinated products, while the use of DME markedly increased their yields [45, 46]. The pronounced solvent effect of DME could be explained in terms of the significantly enhanced nucleophilicity of fluoride ions, as well as the suppression of anode passivation and overoxidation of fluorinated products [46].
Scheme 22

Marked solvent effects on electrochemical fluorination of heterocyclic sulfide

Various heterocyclic propargyl sulfides are also anodically fluorinated to give the α-fluoro products (Scheme 23) [47].
Scheme 23

Electrochemical monofluorination of heterocyclic propargyl sulfides

Diastereoselective electrochemical fluorination of heterocyclic sulfides has been reported, as depicted in Scheme 24 [48].
Scheme 24

Diastereoselective electrochemical fluorination of heterocyclic sulfide

Fluorination of Other Chalcogeno Compounds

Anodic α-monofluorination of selenides bearing α-electron-withdrawing cyano and ester groups can be performed in Et3N-3HF/MeCN using an undivided cell, while the fluorination of α-selenoamide requires an anion-exchange membrane diaphragm (Scheme 25) [49].
Scheme 25

Electrochemical monofluorination of selenides

In contrast, anodic oxidation of organotellurium compounds in the presence of fluoride ions results in difluorination at the tellurium atom predominantly in excellent yields and with high current efficiencies (Scheme 26) [50]. In this case, α-fluorination does not occur.
Scheme 26

Electrochemical difluorination of organotellurium compounds

Fluorination of Organic Oxygen, Nitrogen and Halogen Compounds

Selective anodic formyl hydrogen-exchange fluorination of aliphatic aldehydes in Et3N-5HF/MeCN provides the corresponding acyl fluorides in good yields (Scheme 27) [51]. In these reactions, Et3N-3HF is not suitable because of its discharge prior to oxidation of the carbonyl group. In the case of aromatic aldehydes, the aromatic ring is also fluorinated simultaneously.
Scheme 27

Electrochemical monofluorination of aliphatic aldehydes

Selective and indirect introduction of a fluorine atom into the α-position of the β-dicarbonyl compounds was achieved electrolytically using iodotoluene difluoride as a mediator (Scheme 28) [52].
Scheme 28

Electrochemical monofluorination of β-dicarbonyl compounds

Anodic fluorination of ethers such as DME and diethyleneglycol dimethylether, results in monofluorination at the terminal carbon selectively, while that of crown ethers undergoes carbon-carbon bond cleavage preferentially on fluorination to provide the α,ω-difluorinated products in good yields (Scheme 29) [53].
Scheme 29

Electrochemical difluorination of crown ethers

Anodic fluorination accompanied by carbon-carbon bond formation is useful for the preparation of fluorinated tetrahydropyranes by using silyl, stannyl or thio groups as electroauxiliaries as shown in Scheme 30 [54, 55, 56]. In this case, BF4 anion is a fluorine source.
Scheme 30

Electrochemical monofluorination accompanied by carbon-carbon bond formation

Anodic deiodofluorination of alkyl iodides provides the corresponding alkyl fluorides chemoselectively (Scheme 31) [57].
Scheme 31

Electrochemical deiodofluorination of alkyl iodides

Anodic oxidation of benzophenone hydrazone in Et3N-3HF/CH2Cl2 gives mainly diphenylmonofluoromethane (Scheme 32) [58].
Scheme 32

Electrochemical fluorination of benzophenone hydrazine

Fluorination of Other Heteroatom Compounds

Anodic oxidation of tetraalkylsilanes in the presence of fluoride ions provides the corresponding fluorosilanes derived from cleavage of the C–Si bond [59]. In the case of cyclic oligo(dialkylsilane)s, α,ω-difluoroligosilanes are formed through Si-Si bond cleavage (Scheme 33) [60].
Scheme 33

Electrochemical fluorination of cyclic oligo(dipropylsilane)

Anodic oxidation of organic compounds containing group 15 elements in the presence of fluoride ions provides the corresponding fluorinated products (Scheme 34) [61]. Fluorination occurs at the heteroatoms selectively.
Scheme 34

Electrochemical difluorination of triphenylphosphine and triphenylstibine

Fluorination of Heterocyclic Rings

Heterocyclic compounds having a phenylthio group as an electroauxiliary are selectively oxidized to result in regioselective α-fluorination. Thus, various α-phenylthio lactones and lactams including β-lactams can be anodically fluorinated efficiently (Schemes 35 and 36) [62, 63].
Scheme 35

Electrochemical fluorination of lactone and lactams

Scheme 36

Electrochemical fluorination of β-lactams

The lactams having no sulfenyl group in their rings were electrochemically fluorinated using Et3N·5HF [64]. In this work, fluorine atom was selectively inserted at the α position to the lactam nitrogen as outlined in Scheme 37. Fluorination of heterocyclic compounds fused with a heterocyclic ring as shown in Scheme 38 was achieved by using anodically stable supporting fluoride salt [65]. A fluorine atom was introduced to at the α-position to oxygen exclusively.
Scheme 37

Electrochemical fluorination of N-acetyllactams

Scheme 38

Electrochemical fluorination of 1,4-oxadinones fused with a pyridine ring

Cyclic phosphonate can be also similarly fluorinated as shown in (Scheme 39) [66].
Scheme 39

Electrochemical fluorination of cyclic phosphonates

Highly regioselective, anodic monofluorination of oxindole and 3-oxo-1,2,3,4-tetrahydroisoquinoline can be achieved by using Et4NF-mHF (m = 3, 4) (Scheme 40) [67].
Scheme 40

Regioselective electrochemical fluorination of oxindole and tetrahydroisoquinolone derivatives

Various sulfur-containing heterocyclic compounds can be easily fluorinated regioselectively as follows. Highly regioselective anodic monofluorination of 2-aryl-4-thiazolidinones can be performed by using pulse electrolysis in Et3N-3HF/MeCN (Scheme 41) [68]. However, this electrolytic system is not suitable for anodic monofluorination of 2-substituted 1,3-dithiolan-4-ones and 1,3-oxathiolan-4-ones owing to severe passivation of the anode. In contrast, Et4NF-4HF provides monofluorinated products selectively (Scheme 41) [69, 70]. In these cases, benzylic fluorination does not take place at all although anodic benzylic substitution easily takes place in general.
Scheme 41

Regioselective electrochemical fluorination of 4-thiazolidinone, 1,3-dithiolanone, and 1,3-oxathiolanone derivatives

Diastereoselective electrochemical fluorination of various heterocyclic compounds has been reported, as depicted in Scheme 42 [71, 72, 73].
Scheme 42

Regio- and diastereoselective electrochemical fluorination of thiazolidine and 1,3-oxazolidine

Potentiostatic anodic fluorination of the s-triazolo[3,4-b]thiadiazine derivative in DME containing Et4NF-4HF using an undivided cell afforded the corresponding 7-monofluorinated product. The 7,7-difluorinated derivative could be obtained by direct anodic fluorination of the monofluoro derivative, as shown in Scheme 43 [74].
Scheme 43

Electrochemical mono- and gem-difluorination of fused type thiadiazine derivative

Electrochemical fluorination of N-substituted pyrroles and its application to the synthesis of gem-difluorinated fused heterocyclic compounds has also been reported (Scheme 44)] [75].
Scheme 44

Electrochemical difluorination of 1-methyl-2-cyanopyrrole followed by Diels-Alder reaction with diene

Interestingly, electrochemical fluorination of dehydrodimers readily derived from benzothiazines provides gem-difuorinated benzothiazine derivatives (Scheme 45) [76].
Scheme 45

Electrochemical gem-difluorination of benzothiazine dehydrodimers

Electrochemical Dethiofluorination

Dethiofluorination of dithioacetals and thiocarbonyl compounds using chemical oxidising reagents like NBS is a well-established method for the preparation of gem-difluoro compounds. However, this process requires a large amount of oxidizing reagents particularly in a large scale. In sharp contrast, electrochemical dethiofluorination does not require any oxidants.

Electrolytic dethiofluorination of dithioacetals and dithioketals has been reported [77]. Electrolysis of the dithioacetals in the presence of Et3N·3HF provided the corresponding gem-difluoro compounds (Scheme 46). Dithioacetals of the aromatic aldehyde; however, afforded the gem-difluorothioether through C (Scheme 47) while aliphatic aldehyde gave the monofluorothioether, as shown in Scheme 48.
Scheme 46

Electrochemical dethiofluorination of dithioketals

Scheme 47

Electrochemical dethiofluorination of aromatic dithioacetal

Scheme 48

Electrochemical dethiofluorination of aliphatic dithioacetal

Dethiofluorination of β-lactam derivatives is also achieved by using a triarylamine mediator as shown in Scheme 49 [78]. Without mediators, severe anode passivation takes place to result in poor yield.
Scheme 49

Electrochemical dethiofluorination of β-lactams using a triarylamine mediator

Electrolytic solvents played a significant role in the product selectivity during the fluorination of 4-phenylthio-1,3-dioxolan-2-one [79, 80]. As shown in Scheme 50, dethiofluorination in CH2Cl2 or MeCN occurred to give 4-fluoro-1,3-dioxolan-2-one (2) selectively, however, α-fluorination took place in dimethoxyethane (DME) to give 1 preferentially in addition to 2. Further electrolytic fluorination of 1 in CH2Cl2 afforded 4,4-difluoro-1,3-dioxolan-2-one (3) (Scheme 50) [79, 80].
Scheme 50

Solvent effects on electrochemical dethiofluorination

A thiocarbonyl group can be converted electrochemically to gem-difluoromethylene group. Electrochemical dethiofluorination of O-ethyl benzothioate in Et4NF-3HF containing poly(ethylene glycol) (PEG) as an additive was achieved (Scheme 51) [81, 82].
Scheme 51

Effects of PEG additive on electrochemical dethiodifluorination O-ethyl benzothioate in Et4 NF-3HF

Solvent-Free Electrochemical Fluorination

Solvent-free electrochemical fluorination is an alternative method for preventing anode passivation and acetoamidation [5, 83]. As already mentioned, handling extremely corrosive and poisonous anhydrous HF in a laboratory setting is accompanied by serious hazards and experimental difficulties. Molten salts such as 70%HF/pyridine (Olah’s reagent) and commercially available Et3N-3HF [84] are often used to replace anhydrous HF. Other molten salts with the general formula R4NF-nHF (n > 3.5, R = Me, Et, and n-Pr) are useful in electrochemical partial fluorination. These electrolytes are non-viscous liquids that have high conductivity and anodic stability.

Electrochemical fluorination of cyclic ketones and cyclic unsaturated esters in Et3N-5HF is also accomplished to provide ring-opening and ring-expansion fluorinated products, respectively (Schemes 52 and 53) [85, 86].
Scheme 52

Electrochemical fluorination of cyclic ketones in Et3 N-5HF

Scheme 53

Electrochemical fluorination of cyclic unsaturated esters in Et3 N-5HF

Indanone derivatives can be fluorinated by using Et3N-4HF as the electrolytic medium, as shown in Scheme 54 [87].
Scheme 54

Electrochemical fluorination of indanone in Et3 N-4HF

The fluorination of cyclic ethers, esters, lactones, and cyclic and acyclic carbonates can be achieved by anodic oxidation of a large amount of the liquid substrates and a small amount of Et4NF-4HF (only 1.5–1.7 equiv. of F to the ether) at a high current density (150 mA cm−2) (Schemes 5557) [88].
Scheme 55

Electrochemical fluorination of tetrahydrofurane, 1,4-dioxane, and 1,3-dioxolane

Scheme 56

Electrochemical fluorination of γ-lactone and ethylene carbonate

Scheme 57

Electrochemical fluorination of diethyl carbonate and ethyl propionate

Electrochemical fluorination of adamanthanes is also possible. Mono-, di-, tri-, and tetrafluoroadamantanes can be selectively prepared from adamantanes by controlling oxidation potentials, and the fluorine atoms are introduced selectively at the tertiary carbons, as shown in Scheme 58 [89]. Adamantanes bearing functional groups such as ester, cyano, and acetoxymethyl moieties are also selectively fluorinated.
Scheme 58

Electrochemical fluorination of adamanthane in Et3 N-5HF

Notably, a double ionic liquid system is highly effective for electrochemical fluorination of phthalide having high oxidation potential as 2.81 V vs. SCE as follows. Phthalide is efficiently fluorinated electrochemically in a mixture of ionic liquid, 1-ethyl-3-methylimidazolium trifluoromethanesulfonate ([EMIM][OTf]) and Et4NF-5HF (Scheme 59) [90]. The cationic intermediate generated from the phthalide was expected to have a TfO counter anion (activated cation D in Scheme 59), which readily reacted with F to provide the fluorinated phthalide in good yield.
Scheme 59

Electrochemical fluorination of phthalide in a mixed ionic liquid with Et3 N-5HF

Future Direction

Although electrochemical perfluorination has been established and commercialized long time ago, there are some problems like product selectivity and durability of anodes. It is hoped that new electrochemical perfluorination is developed to solve such problems. On the other hand, electrochemical partial fluorination had been unexplored until about 30 years ago. Great progress has been made in this area and various new electrochemical methodologies have been developed for fluorination using various room temperature-molten fluoride salts with and without organic solvents. Highly efficient and selective fluorination of organic compounds using green sustainable methodology is one of the most important goals of modern organofluorine chemistry. It is hoped that electrochemical fluorination will be exploited further and commertialized to produce valuable organofluorine compounds in the near future.

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of ElectrochemistryTokyo Institute of TechnologyMidori-kuJapan