Fluorine1

F2

[7782-41-4]  · F2  · Fluorine  · (MW 38.00)

(strong fluorinating agent and oxidizer; substitutes F for H in either radical2 or electrophilic2b,3 reactions; electrophilic substitution of F for other halides;1c adds to multiple bonds;2b,4 oxidatively adds to centers of coordinative unsaturation;5 used in synthesis of other (mostly electrophilic) fluorinating agents;6 with aq MeCN, oxidizes tertiary H to alcohols,7 alcohols to ketones,8 ketones to esters,8 aromatics to phenols or quinones,9 amines to nitro derivatives,10 and alkenes to oxiranes;7,11 cyclotron-produced 18F2 provides 18F-labeled compounds for positron emission tomography12)

Physical Data: mp -219.6 °C; bp -188.2 °C; vapor pressure at 77 K = 280 Torr.

Solubility: slightly sol CFCl3, CF2ClCFCl2, CHCl3, CH2Cl2, MeCN, perfluoroethers, perfluorocarbons; dec H2O giving HF, O2 and trace O3, OF2.13

Form Supplied in: faintly yellow compressed gas in steel cylinders at pressures of 160-400 psi, purity 97-99%; impurities HF, N2, O2, CF4, SF6, SiF4; also in cylinders prediluted with inert gases.

Analysis of Reagent Purity: titration of Cl2 liberated from NaCl, followed by GC for inert components; IR for HF. Rarely performed by user.

Preparative Methods: electrolysis of KF-HF mixtures.14

Purification: HF removed by passage through column of NaF pellets; other impurities removed only by cryogenic distillation.15

Handling, Storage, and Precautions: toxic; strong oxidizer. Pure fluorine should only be used by trained personnel! Prediluted F2 is handled much more easily. Compatible materials: copper, brass, steel, stainless steel, nickel alloys (Monel, Inconel, Hastelloy), fluoropolymers (PTFE, FEP, PFA, Kel-F), dry glass. Vendors and handbooks4a,14a,16 must be consulted for more detailed recommendations! Proper equipment cleaning and passivation are imperative to avoid ignition. Use fume hood, barricade, faceshield, leather gloves. Odor threshold: 20 ppb. TLV: 1 ppm. PEL: 0.1 ppm. IDLH: 25 ppm. Leaks easily detected with paper moistened with aq KI; monitors/detectors available. Use only fluorinated greases and oils for joints, bubblers, valve lubricants. Lubricate pipe threads with PTFE tape; permanent installations should be welded. Scrub effluent with soda lime, activated alumina, or 5-15% aq KOH. (More dilute base gives toxic OF2; KF produced is more soluble than is NaF.) Users of solid scrubbers with vacuum pumps should consider an O2-compatible pump fluid. NaF, aq base, and CaCl2 are useful for workup of reactions producing HF. Caution: Many things will burn in pure fluorine given enough (sometimes insignificant) activation energy; even many materials (PTFE, metals, concrete) not usually considered to be fuels can ignite in F2.

Introduction of Fluorine.

Substitution of Fluorine for Hydrogen.

Perfluorination.

The chief processes for perfluorination of organic compounds are the low-temperature gradient (LaMar) and aerosol fluorination methods. The goal of these is generally complete fluorination and saturation while minimizing fragmentation (eqs 1 and 2)2a,17 although certain functional groups can be preserved (eq 3).18 Perfluorination can also be achieved using inert solvents (eq 4).19

NaF is sometimes added to trap the HF produced as NaHF2. The above reactions are generally radical in character; complete fluorination sometimes requires photochemical polishing to provide larger concentrations of F&bdot; since the organic material becomes increasingly unreactive as fluorine substitution proceeds (see Cobalt(III) Fluoride).

Polymer Surface Modification.

Direct fluorination with F2 is used to convert polymers (e.g. coal-tar pitch)20 to highly fluorinated materials. Fluorination also increases the activity of sulfonic acid catalyst resins in alkylation reactions21 and, when used sparingly, increases the surface energy of polymers, producing improved adhesion.22

Electrophilic Fluorinations.

Despite fluorine's extreme reactivity, its use in selective and electrophilic replacements is not only possible but synthetically useful when mild conditions and solvents such as CFCl3/CHCl3 mixtures are employed. Fluorine excels at replacement of unactivated tertiary hydrogens and complete retention of configuration is observed. High selectivity for tertiary H is due to the higher degree of p character in tertiary C-H bonds over that in primary and secondary bonds,23 and this also influences the relative reactivity of competing tertiary positions (eq 5).2b Nearby electronegative centers, for example, deactivate tertiary H in this reaction. In contrast, LaMar fluorination of alkylcyclohexanes leaves some tertiary H as the only H remaining in the molecule,24 perhaps for steric reasons. Direct electrophilic aromatic substitution is rare although recent improvements have involved the directing effects of Lewis acids.25 Heteroaromatics can also be fluorinated (eq 6).26 Both aliphatic and aromatic substitutions are often facilitated by the use of organometallic derivatives27 in place of the parent molecules (eq 7), and 1,3-diketones can be fluorinated in the form of silyl enol ethers (eq 8).28 Fluorination of fullerenes has been a topic of recent interest.29

Electrophilic Substitution of F for Other Halogens.

While fluoride ion is useful for nucleophilic displacement of other halides, molecular fluorine uses an electrophilic mechanism to achieve this (eq 9).30 Substitution proceeds most effectively when the intermediate carbocation is stabilized. The reactivity of the starting organic halide increases with the atomic weight of the departing species: Cl < Br < I.

Addition to Multiple Bonds.

Alkenes.

Fluorine often adds smoothly in an electrophilic manner to alkenic double bonds, predominantly in syn orientation.2b Fluorine addition has even been applied to conversion of alkene impurities in HFC-134a (CF3CH2F) to more easily removed saturated products.31 Many reactions which are formally replacement of vinylic H by F are addition reactions followed by dehydrofluorination (eq 10).32 Under radical conditions, coupling of intermediate fluorocarbon radicals is often observed. Alkynes react to give tetrafluoro or difluoro products, depending on the conditions.1b

Imines.

Carbon-nitrogen double bonds react to form N-fluoro derivatives; for already highly fluorinated compounds, this is most often done with the aid of a metal fluoride catalyst (eq 11).33 Subsequent dehydrofluorination is often observed if the vicinal proton is relatively acidic.1b

Carbonyls.

Such catalytic pathways are also used to add fluorine across carbonyl groups, forming fluoroxy compounds (hypofluorites) (eq 12).34 Some hypofluorites have found use as electrophilic fluorinating agents in their own right (see, for example, Trifluoromethyl Hypofluorite and Acetyl Hypofluorite).

Oxidative Addition.

Fluorine is capable of oxidizing most elements to their highest valence state. In organic compounds, centers of coordinative unsaturation undergo oxidative addition with little fragmentation if conditions are mild. The sulfur(II) in thiols5a and sulfides, for instance, is transformed to sulfur(VI) in the form of -SF5 or -SF4- groups (eq 13).5b

Preparation of Other Fluorinating Agents.

Most alternative electrophilic fluorinating agents are themselves prepared from elemental fluorine using variations of the reactions above, with extensions to substitution of H on N or O producing N-F or O-F bonds6 (see for example, N-Fluoro-N-t-butyl-p-toluenesulfonamide). Some hypofluorites such as MeOF35 and t-BuOF36 can be formed in situ and used to add RO-F across alkenic double bonds. Fluorination of diselenides can be used similarly37 when conditions are mild enough to avoid oxidation. Oxidative addition is represented by the synthesis of reagents such as Xenon(II) Fluoride, N-Fluoropyridinium Triflate, N-fluoroquinuclidinium salts, and N-fluoro-1,4-diazabicyclo[2.2.2]octane salts.

Oxidations.

Fluorine reacts with aq MeCN to form HOF stabilized by solvent complexation.38 The complex can act as an efficient oxidizing agent and and can be used for 18O labeling.

Tertiary Hydrogen to Hydroxyl.

Fluorine can be used selectively to hydroxylate tertiary hydrogens due to the interaction of the highly electrophilic oxygen atom in the HOF/MeCN complex with the relatively electron-rich tertiary H-C bond (eq 14).7 Experiments with cis- and trans-decalin show that the hydroxylation occurs with full retention of configuration.

Alcohols to Ketones and Ketones to Esters.8

Oxidation of secondary alcohols with stabilized HOF yields ketones (eq 15); primary alcohols are less reactive. Ketones are converted to esters more slowly and with a larger excess of reagent (eq 16).

Aromatics to Phenols and Quinones.9

Aromatics and polynuclear aromatics are oxidized to the respective oxygenated derivatives. The reaction of mesitylene (eq 17) shows that phenols are likely intermediates to quinones. Quinones are quickly prepared in moderate yields (eq 18).

Amines to Nitro Compounds.

Primary aromatic10a and aliphatic10b amines are cleanly converted to nitro compounds without complications from other easily oxidized groups (eq 19).10a Amine salts are not reactive.10b

Alkenes to Oxiranes (Epoxides).7,8,11

Fluorine/aq MeCN readily epoxidizes electron-rich alkenes (eq 20).7 More electron-deficient alkenes require a large excess of reagent and extended reaction time (eq 21).7 Full retention of configuration is characteristic, since the oxides from cis- and trans-stilbene are exclusively cis and trans, respectively.7 The epoxidation occurs preferentially over hydroxyl oxidation, as shown for dihydrocarveol (eq 22).8 Dienes can form bis-epoxides (eq 23),11b or one double bond can react preferentially, given sufficient differences in electron density (eq 24).11b Other popular reagents such as m-Chloroperbenzoic Acid and Trifluoroperacetic Acid failed to react with n-C4F9CH=CH2, which was epoxidized by the F2/MeCN/H2O system in 63% yield.11b


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Stefan P. Kotun

Ohmeda, Murray Hill, NJ, USA



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