Fluorine/fluoride reaction mechanisms

Extensive work on the interaction of aromatic compounds with xenon difluoride has been carried out in order to investigate the reaction mechanism and the scope of the fluorination depending on the substituents electronic nature.26-59 62 It has been found that benzene and substituted aromatics react with xenon difluoride at room temperature in the presence of hydrogen fluoride to form the typical products of electrophilic fluorination contaminated with low quantities of difluoro-substituted molecules. 

One postulated reaction mechanism for electrochemical fluorination involves an intermediate nickel fluoride, with nickel in the oxidation stage +III/ + IV, as the active fluorination agent. The induction period in which the nickel fluoride layer is formed at the nickel surface can thus be explained. A radical fluorination mechanism has also been postulated, with oxidation of the fluoride anion to the radical, or as discussed below in the ECEC mechanism.15 The mechanism of this process is still a matter for debate. Reference should be made to a report that does not support the postulates of this section.21 For partial electrochemical fluorination, the ECEC mechanism is postulated as follows. In the first step the starting material is oxidized at the anode (E = electrochemical step). 

The fact that functionalization of polymers and small molecules is observed to occur predominately on terminal (methyl) carbon atoms does not imply that the oxyfluorination reaction is truly selective. Although the reaction mechanism has not been studied in detail, it is undoubtedly a free-radical process. Molecular oxygen reacts spontaneously with the fluorocarbon—hydrogen radicals generated by fluorine during the fluorination process. Acid fluorides are retained on terminal carbon atoms because they are stable in 1 atm of elemental fluorine. Hypofluorites, which may be short-lived intermediates of oxygen reactions with methylene radical sites along the carbon chain, are not observed in the functionalized polymers. It is probable that, if they are intermediates, they are cleaved and removed by the excess elemental fluorine. 

In this chapter, recent advances in our understanding of catalytic fluorination under heterogeneous conditions are surveyed from the standpoint of catalyst properties, including developments based on the use of mixed metal fluorides having different structural types, and reaction mechanisms. Much of the newer work has been the result of the need to replace chlorofluorocarbons (CFCs) by alternatives, hydrofluorocarbons (HFCs) or, more controversially, hydrochlorofluorocarbons (HCFCs), following adoption of the Montreal and successor Protocols [2,3]. Where relevant, aspects of catalytic hydrogenolysis, where fluorides have been used as replacement supports in the conventional palladium/carbon catalysts, and isomerization reactions are included. 

Fluorine is produced by electrolysis of molten salts on carbon anodes including KF-21TF at about 100°C, potassium bifluoride at about 250°C, and fluoride salts at about 1000°C. The decomposition potential of molten potassium bifluoride is 1.75 V at 250°C, a value close to that estimated thermodynamically [80]. The kinetics of the anodic process is characterized by a Tafel slope of 0.56 V per decade, j), = 1 x 10 A/cm [81], and by a complex reaction mechanism involving the formation of fluorine atoms on carbon. During the electrolysis, C-F surface compounds on the carbon anode are formed via side reactions. Intercalation compounds such as (CF) contribute to the anodic effect in the electrochemical cell, which can be made less harmful by addition of LiF. 

A study of the reaction of fluorine with SO2 has shown that at temperatures up to 500 °C the reaction rapidly gives sulphuryl fluoride. If the quantity of fluorine is large enough, then SFe is formed, but only slowly, and via the formation of thionyl fluoride, thionyl tetrafluoride, and pentafluorosulphur hypo-fluorite. The fluorination of SO2 by Xep2, in the presence of compounds of the type MX (M = NMe4, Cs, or K X = F or Cl), has been studied. A variety of products were observed (Table 2) and reaction mechanisms were proposed in which the Xep2 functions as a weak Lewis acid. 

Alcoholic hydroxy groups in hydroxyamincs or hydroxyamino acids are replaced by fluorine with sulfur tetrafluoride in anhydrous hydrogen fluoride. The mechanism of this reaction involves simultaneous S>,1 and SN2 pathways30. 

The same authors developed an original method of the synthesis of 1-(1,2,2,2-tetrafluoroethyl)-l,2,4-triazole 85 by treatment of N-(2-chloro-l,l,2-trifluoro)-1,2,4-triazole with tetramethylammonium fluoride [83]. The assumed reaction mechanism consist of several steps. In the first stage elimination of HF and the formation of 2-chloro-l,2-difluoroethylene derivative takes place. Further chlorine atom is replaced by fluorine with the formation of 1,2,2-trifluoroethylene-l,2.4-triazole. Finally addition of HF gave the final product 85. 

An example of cleavage ol the sulfur-oxygen bond in trifluoromethane-sulfonic ester has been reported Tnfluororaethyl triflate reacts with neutral or anionic nucleophiles with elimination of carbonyl difluoride and formation of trifluoromethanesulfonyl fluoride [57] (equation 32) The mechanism of this reaction involves elimination of fluoride ion, which is a chain carrier in the substitution of fluorine for the trifluoromethoxy group... 

Mixtures of anhydrous hydrogen fluoride and tetrahydrofuran are successfully used as fluorinating agents to convert 1,1,2-trifluoro-l-allcen-3-ols, easily prepared from bromotrifluoroethene via lithiation followed by the reaction with aldehydes or ketones, to 1,1,1,2-tetrafluoro-2-alkenes The yields are optimal with a 5 1 ratio of hydrogen fluoride to tetrahydrofuran The fluorination reaction involves a fluonde lon-induced rearrangement (Sf,j2 mechanism) of allylic alcohols [65] (equation 40)... 

Tantalum is severely attacked at ambient temperatures and up to about 100°C in aqueous atmospheric environments in the presence of fluorine and hydrofluoric acids. Flourine, hydrofluoric acid and fluoride salt solutions represent typical aggressive environments in which tantalum corrodes at ambient temperatures. Under exposure to these environments the protective TajOj oxide film is attacked and the metal is transformed from a passive to an active state. The corrosion mechanism of tantalum in these environments is mainly based on dissolution reactions to give fluoro complexes. The composition depends markedly on the conditions. The existence of oxidizing agents such as sulphur trioxide or peroxides in aqueous fluoride environments enhance the corrosion rate of tantalum owing to rapid formation of oxofluoro complexes. 

The Arbuzov reaction has been applied for the synthesis of fluorinated carbohydrates. 1,2 3,4-Di-O-isopropylidene-a-D-galactopyran-ose 6-(N,N-diethyl-P-methylphosphonamidite) was treated with ethyl fluoroacetate, to afford 6-deoxy-6-fluoro-l,2 3,4-di-O-isopropylidene-a-D-galactopyranose in 19% yield.241 The corresponding 6-deoxy-6-fluoride was obtained in 60% yield by treatment of l,2 3,4-di-0-isopropylidene-a-D-galactopyranose 6-(dipropylphosphinite) with hexafluoropropene.242 The mechanism of this reaction has been discussed.243,244 In contrast, treatment of 1,2 -.3,4-di-O-isopropylidene-a-D-galactopyranose 6-(tetraethylphosphorodiamidite) with benzoyl fluoride yielded the corresponding 6-benzoate, not the 6-deoxy-6-flu-oride expected.245... 

Electrochemical fluorination in anhydrous hydrogen fluoride (Simons process) involves electrolysis of organic compounds (ahphatic hydrocarbons, haloalkanes, acid halides, esters, ethers, amines) at nickel electrodes. It leads mostly to perfluori-nated compounds, but is accompanied to a high extent by cleavage and rearrangement reactions. The mechanism of the formation of carbocations according to Eq. (1) and Scheme 1 is assumed... 

So far only a few dozen organofluorine compounds have been isolated from living organisms, for example fluoroacetic acid, 4-fluorothreonine and rw-fluoro-oleic acid [244-246], The reason that nature has not invested in fluorine chemistry could be a combination of low availability of water-dissolved fluoride in the environment due to its tendency to form insoluble fluoride salts, and the low reactivity of water-solvated fluoride ion. However, in 2002, O Hagan and collaborators [247] published the discovery of a biochemical fluorination reaction in a bacterial protein extract from Streptomyces cattleya converting S-adenosyl-L-methionine (SAM) to 5 -fluoro-5 deoxyadenosine (5 -FDA). The same protein extract contained also the necessary enzymatic activity to convert 5 -FDA into fluoroacetic acid. In 2004, the same authors published the crystal structure of the enzyme and demonstrated a nucleophilic mechanism of fluorination [248,249]. 

Synthesis of the thymidine derivative relies on the older two-step insertion of fluorine. Thus, the hydroxyl group in 3 -deoxythymidine benzoate (51-1) is first converted to the mesylate (51-2). Reaction with potassium fluoride in hydrogen fluoride replaces the mesylate by fluorine (51-3). The fact that this reaction, as that above, proceeds with retention of the configuration mles out simple displacement as the mechanism for this transform. The presence of the methyl group at position 5 negates the need for the chlorination step. Saponification then affords the antiviral agent alovudine (51-4) [52]. 

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