Article No : a11_349

Fluorine Compounds, Organic

GU¨ NTER SIEGEMUND, Hoechst Aktiengesellschaft, Frankfurt, Federal Republic of Germany

WERNER SCHWERTFEGER, Hoechst Aktiengesellschaft, Frankfurt, Federal Republic of Germany

ANDREW FEIRING, E. I. DuPont de Nemours & Co., Wilmington, Delaware, United States

BRUCE SMART, E. I. DuPont de Nemours & Co., Wilmington, Delaware, United States

FRED BEHR, Minnesota Mining and Manufacturing Company, St. Paul, Minnesota, United States

HERWARD VOGEL, Minnesota Mining and Manufacturing Company, St. Paul, Minnesota, United States

BLAINE MCKUSICK, E. I. DuPont de Nemours & Co., Wilmington, Delaware, United States

1. Introduction...... 444 8. Fluorinated Carboxylic Acids and 2. Production Processes ...... 445 Fluorinated Alkanesulfonic Acids ...... 470 2.1. Substitution of Hydrogen...... 445 8.1. Fluorinated Carboxylic Acids ...... 470 2.2. Halogen – Fluorine Exchange ...... 446 8.1.1. Fluorinated Acetic Acids ...... 470 2.3. Synthesis from Fluorinated Synthons ... 447 8.1.2. Long-Chain Perfluorocarboxylic Acids .... 470 2.4. Addition of Hydrogen Fluoride to 8.1.3. Fluorinated Dicarboxylic Acids ...... 472 Unsaturated Bonds ...... 447 8.1.4. Tetrafluoroethylene – Perfluorovinyl Ether 2.5. Miscellaneous Methods ...... 447 Copolymers with Carboxylic Acid Groups . . 472 2.6. Purification and Analysis ...... 447 8.2. Fluorinated Alkanesulfonic Acids ...... 472 3. Fluorinated Alkanes...... 448 8.2.1. Perfluoroalkanesulfonic Acids ...... 472 3.1. Fluoroalkanes and Perfluoroalkanes .... 448 8.2.2. Fluorinated Alkanedisulfonic Acids ...... 473 3.2. Chlorofluoroalkanes...... 452 8.2.3. Tetrafluoroethylene – Perfluorovinyl Ether 3.3. Bromofluoroalkanes...... 456 Copolymers with Sulfonic Acid Groups . . . . 474 3.4. Iodofluoroalkanes...... 457 9. Fluorinated Tertiary Amines ...... 474 4. Fluorinated Olefins ...... 458 10. Aromatic Compounds with Fluorinated 4.2. Tetrafluoroethylene ...... 459 Side-Chains ...... 475 4.3. Hexafluoropropene ...... 460 10.1. Properties ...... 475 4.4. 1,1-Difluoroethylene...... 461 10.2. Production ...... 476 4.5. Monofluoroethylene, Monofluoroethylene 461 10.3. Uses ...... 477 4.6. 3,3,3-Trifluoropropene...... 462 11. Ring-Fluorinated Aromatic, Heterocyclic, 4.7. 3,3,3-Trifluoro-2-(trifluoromethyl)- and Polycyclic Compounds ...... 477 prop-1-ene ...... 462 11.1. Mono- and Difluoroaromatic Compounds 478 4.8. Chlorofluoroolefins ...... 462 11.1.1. Properties ...... 478 5. Fluorinated Alcohols ...... 463 11.1.2. Production...... 478 6. Fluorinated Ethers ...... 464 11.1.3. Uses ...... 481 6.1. Perfluoroethers ...... 464 11.2. Highly Fluorinated Aromatic Compounds 481 6.1.1. Low Molecular Mass Perfluoroethers ..... 464 11.3. Perhaloaromatic Compounds...... 482 6.1.2. Perfluorinated Epoxides ...... 464 11.4. Fluorinated Heterocyclic and Polycyclic 6.1.3. High Molecular Mass Perfluoroethers ..... 465 Compounds ...... 483 6.2. Perfluorovinyl Ethers...... 465 11.4.1. Ring-Fluorinated Pyridines...... 483 6.3. Partially Fluorinated Ethers ...... 466 11.4.2. Trifluoromethylpyridines ...... 483 7. Fluorinated Ketones and Aldehydes .... 466 11.4.3. Fluoropyrimidines ...... 483 7.1. Fluoro- and Chlorofluoroacetones ...... 466 11.4.4. Fluorotriazines ...... 483 7.2. Perhaloacetaldehydes...... 468 11.4.5. Polycyclic Fluoroaromatic Compounds.... 484 7.3. Fluorinated 1,3-Diketones ...... 469 12. Economic Aspects ...... 484

2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/14356007.a11_349 444 Fluorine Compounds, Organic Vol. 15

13. Toxicology and Occupational Health .... 484 13.5. Fluorinated Carboxylic Acids ...... 486 13.1. Fluorinated Alkanes...... 485 13.6. Other Classes...... 486 13.2. Fluorinated Olefins ...... 485 References ...... 487 13.3. Fluorinated Alcohols ...... 486 13.4. Fluorinated Ketones...... 486

1. Introduction Fluorine attached to the ring of aromatic com- pounds acts mainly as a para-directing substitu- Organic fluorine compounds are characterized by ent, whereas perfluoroalkyl groups behave as their carbon – fluorine bond. Fluorine can re- meta-directing substituents. place any hydrogen atom in linear or cyclic Naturally, the influence of fluorine is greatest organic molecules because the difference be- in highly fluorinated and perfluorinated com- tween the van der Waals radii for hydrogen pounds. The fact that these compounds have a (0.12 nm) and fluorine (0.14 nm) is small com- high thermal stability and chemical resistance pared to that of other elements (e.g., chlorine and are physiologically inert makes them suitable 0.18 nm). Thus, as in hydrocarbon chemistry, for many applications for which hydrocarbons organic fluorine chemistry deals with a great are not. Properties that are exploited commer- variety of species. When all valences of a carbon cially include high thermal and chemical stabili- chain are satisfied by fluorine, the zig-zag-shaped ty, low surface tension, and good dielectric prop- carbon skeleton is twisted out of its plane in the erties, for example, in fluoropolymers, perfluori- form of a helix. This situation allows the elec- nated oils and inert fluids. tronegative fluorine substituents to envelop the Individual fluorine atoms or perfluoroalkyl carbon skeleton completely and shield it from groups do not change the technical properties chemical (especially nucleophilic) attack. Seve- of a hydrocarbon fundamentally. However, this ral other properties of the carbon – fluorine bond is not the case with physiological properties. A contribute to the fact that highly fluorinated fluorine atom in a bioactive material may sim- alkanes are the most stable organic compounds. ulate a hydrogen atom, and although this does These include low polarizability and high bond not prevent metabolic processes from occur- energies, which increase with increasing substi- ring, the end products may be ineffective or tution by fluorine (bond energies: C – F bond in toxic. Accordingly, such fluorine compounds are important in, for example, pesticides and CH3F, 448 kJ/mol; C – H bond in CH4, 417 kJ/ pharmaceuticals. mol; C – Cl bond in CH3Cl, 326 kJ/mol; and A bibliography of the scientific literature of C – F bond in CF4, 486 kJ/mol). The cumulative negative inductive effect of organofluorine chemistry was published in 1986 the fluorine in perfluoroalkyl groups may reverse [16]; commercial applications of fluorine pro- the polarity of adjacent single bonds (e.g., in ducts are reviewed in [7], [17], and [18]. the pair H3C 3 I and F3C " I) or double bonds dþ d d (e.g.,CH3C H ¼ C H2 and CF3C H Nomenclature. Any organic fluorine com- dþ ¼ C H2). Fluorine substitution changes the re- pound can be named according to the rules of the activity of olefins and carbonyl compounds. International Union for Pure and Applied Chem- Polyfluorinated olefins possess an electron-defi- istry (IUPAC) [19]. However, for highly fluori- cient double bond, which reacts preferentially nated molecules with several carbon atoms, this with nucleophiles. Carboxy groups are affected nomenclature can be confusing. Therefore, the by the presence of an adjacent perfluoroalkyl term ‘‘perfluoro’’ may be used when all hydrogen radical. In carboxylic acids, the acidity is atoms bonded to the carbon skeleton have been markedly increased. In other carbonyl com- replaced by fluorine. The designation of hydro- pounds, the reactivity is increased without any gen atoms belonging to functional groups (e.g., fundamental change in the chemistry of the CHO or COOH), of the functional groups them- compound. Correspondingly, the basicity of selves, and of other substituents is not affected amines is reduced by the introduction of fluorine. [19]. Examples are given in Table 1. Vol. 15 Fluorine Compounds, Organic 445

Table 1. Nomenclature of organic fluorine compounds

Formula CAS IUPAC designation Perfluoro designation registry no.

CF3CF3 [76-16-4] hexafluoroethane perfluoroethane, F-ethane CF3CF2CF2CHO [375-02-0] Heptafluoro-n-butyraldehyde Perfluoro-n-butyraldehyde, F-n-butyraldehyde CF3(CF2)6COOH [335-67-1] Pentadecafluoro-n-octanoic acid Perfluoro-n-octanoic acid, F-n-octanoic acid CF3(CF2)2CHF2 [375-17-7] 1,1,1,2,2,3,3,4,4-Nonafluoro-n-butane 1H-Perfluoro-n-butane, 1-hydryl-F-n-butane CF3(CF2)4CH2OH [423-46-1] 2,2,3,3,4,4,5,5,6,6,6-Undecafluoro-n-hexanol 1H,1H-Perfluoro-n-hexanol, 1,1-dihydroperfluoro-n-hexanol

In the case of highly fluorinated compounds 2. halogen – fluorine exchange with hydrogen with few hydrogen atoms (1 – 4), the perfluoro fluoride, hydrogen fluoride-base complexes, compound can be taken as the parent compound. or metal fluorides The hydrogen atoms are named according to their 3. synthesis of higher molecular mass fluorine number and position; the letter H or the prefix compounds from reactive fluorinated hydryl (hydro) are used for hydrogen. The sym- synthons bol F was approved by the American Chemical 4. addition of fluorine, hydrogen fluoride, or Society as abbreviation for perfluoro [20]. reactive nonmetal fluorides to unsaturated Historical Development. The pioneering bonds work in organofluorine chemistry dates from 1835 to 1940 [21]. Controlled production of Only a few of the many possibilities in each organic fluorine compounds was started in group have been developed commercially, with 1892 by exchanging halogen for fluorine in hy- varying degrees of success. drocarbons, using antimony(III) fluoride. The industrial phase began in 1929 in the United States with the discovery of the nonflammable, 2.1. Substitution of Hydrogen nontoxic refrigerants CCl3F and CCl2F2 [22]. In Germany, commercial production of aromatic Fluorination with Elemental Fluorine [26], fluorine compounds started in 1930. [27]. The action of elemental fluorine on organic The first fluoropolymer, polychlorotrifluor- compounds normally leads to violent, mainly ex- oethylene, was synthesized in 1934 in Germany, plosive, reactions. The substrate fragments into followed by the discovery of polytetrafluoroethy- units with a varying degree of fluorination because lene in 1938 in the United States. During World the heats of formation of the C – F bond (ca. War II, thermally and chemically stable working 460 kJ/mol) and the H – F bond (566 kJ/mol) are materials for the separation of uranium isotopes greater than the heat of formation of the C – C were investigated by the United States Manhat- bond (ca. 348 kJ/mol). tan Project [23]. After World War II, numerous Therefore, direct fluorinations must take place novel applications were discovered. The devel- with strict control of the reaction and removal of opment of new organic fluorine compounds with the heat generated. This may be achieved by novel applications continues undiminished. dilution of the fluorine with inert gases (e.g., N2 or CO2), dilution of the organic substrates with inert solvents [28], intensive mixing, and 2. Production Processes reduction of the temperature to as low as 150 C. The four principal methods for the preparation of Direct fluorination can also be carried out in organic fluorine compounds are as follows [1], the gas phase in a tubular reactor packed with [2], [24], [25]: silver- or gold-plated copper turnings [29]. Spe- cialized methods are based on LaMar fluorina- 1. substitution of hydrogen in hydrocarbons tion [26], aerosol fluorination [30], porous-tube using fluorine, high-valency metal or nonmet- fluorination [31], and jet fluorination [32]; high al fluorides, or electrochemical fluorination product selectivities are achieved at a laboratory 446 Fluorine Compounds, Organic Vol. 15 scale. Commercial operation remains to be halogenated compounds using hydrogen fluoride developed. [42]:

Fluorination with Metal Fluorides [33]. Metal fluorides that can transfer fluorine to or- ganic substrates by changing the oxidative state of the metal, such as cobalt(III) fluoride (CoF3) Whether the process takes place with or with- and silver(II) fluoride (AgF2), serve as fluorinat- out a catalyst depends on the reactivity of the ing agents in an oxidizing fluorination. The spent chlorine atoms to be exchanged. With com- metal fluoride is regenerated with elemental pounds containing several chlorine atoms of fluorine. differing reactivity, selective fluorination can be achieved by selecting suitable process conditions. Fluorinations without a catalyst such as

Fluorination and regeneration can be cyclical, permitting a commercial operation. are carried out in liquid, anhydrous hydrogen Electrochemical Fluorination. The Simons fluoride at 100 – 150 C in pressure vessels process [34], [35] is used commercially for the made of steel, alloy steels, or nickel. The process production of perfluorinated compounds. Solu- can be carried out by batch (e.g., autoclave) or tions of organic compounds (mainly carboxylic continuous methods (autoclaves in series or a acids, sulfonic acids, and tertiary amines) are tubular reactor). In either case, the hydrogen electrolyzed in anhydrous hydrogen fluoride in a chloride that is generated during fluorination is single cell without intermediate formation of free removed from the reactor to maintain the desired fluorine. Fluorination takes place at a nickel anode pressure. by a free-radical mechanism at current densities of Most liquid-phase fluorinations, e.g., of CCl4, 2 10–20mA/cm [36]. Selectivity decreases CHCl3, CCl3CCl3, CCl3CHCl2, or CCl3CH2Cl, sharply as the number of carbons increases. are carried out in the presence of a catalyst [43] to Volatile, hydrogen-containing compounds promote the exchange, which becomes increas- (hydrocarbons and chlorohydrocarbons) can be ingly difficult as fluorination progresses. The electrofluorinated on porous graphite anodes in main catalysts used are antimony(III) and anti- KF-containing hydrogen fluoride in a process mony(V) halides with low volatility. Addition of developed by Phillips Petroleum [37], [38], chlorine oxidizes the antimony to the pentavalent [39] and now referred to as CAVE (Carbon Anode state. Vapor Phase Electrochemical Fluorination), in In addition to the liquid-phase processes, operation at 3 M [40]. The organic compound is many commercially important gas-phase fluor- introduced into the cell through the anode. In the inations employ hydrogen fluoride [43]. The pores of the anode, i.e., at the phase boundary, components in the gas phase are passed through partial or complete exchange of the hydrogen, but a tubular reactor containing the catalyst. The not the chlorine, takes place. To date this process composition of the product can be controlled has been used only on a small scale. within wide limits by varying temperature, pres- sure, residence time, catalyst, and the proportions of the reactants. Various metal fluorides are 2.2. Halogen – Fluorine Exchange suitable catalysts, e.g., aluminum fluoride [44] or basic chromium fluoride [45]. Exchange of chlorine with hydrogen fluo- For further processing of the mixture pro- ride is used in many commercial processes both duced by gas- or liquid-phase fluorination, the for the production of chlorofluoroalkanes and for following criteria should be satisfied [46]: the side-chain fluorination of aromatic and N- heterocyclic compounds [41]. The method in- 1. The hydrogen chloride generated should be volves exchange of chlorine for fluorine in poly- separated in a pure form to permit further use. Vol. 15 Fluorine Compounds, Organic 447

2. Unreacted hydrogen fluoride should be 2.4. Addition of Hydrogen Fluoride to recovered. Unsaturated Bonds 3. Acid residues, water, and other impurities must be removed from the product. Addition of hydrogen fluoride to alkenes and alkynes takes place below 0 C with formation Usually, the hydrogen chloride is separated of mono- or difluoroalkanes; ethylene and acety- from the crude fluorination mixture by fractional lene are exceptions [24]. Ethyl fluoride is pro- distillation. The bulk of the hydrogen fluoride duced from ethylene and hydrogen fluoride at may then be separated from the residue. Further 90 C; catalytic processes have been developed treatment includes washing to remove traces of for the addition of hydrogen fluoride to acetylene acid, drying, and fractional distillation. to produce vinyl fluoride or 1,1-difluoroethane. Unsymmetrical olefins obey Markovnikov’s rule. Exchange of Chlorine with Nonoxidizing Chloroolefins can undergo chlorine – fluorine Metal Fluorides [41]. Alkali fluorides, espe- exchange after addition of hydrogen fluoride. cially potassium fluoride, are often used to Addition of hydrogen fluoride to the electron- exchange chlorine in carboxylic acid chlorides, deficient double bond of perfluoroolefins can be sulfonic acid chlorides, a-chlorocarboxylic acid performed using trialkylamine trishydrofluorides derivatives (esters, amides, and nitriles), ali- at moderate temperatures [49]. phatic monochloro compounds, or activated aromatic chloro compounds (Halex process) [47]. 2.5. Miscellaneous Methods The dry, finely powdered metal fluoride is employed in a solvent-free process at 400 – Substitution of Amino Groups in Aromatic 600 C, e.g., with polychlorinated aromatic com- Compounds [50]. Introduction of one or two pounds, or, in most other cases, in the presence of fluorine atoms into aromatic rings is carried out a solvent. For slow reactions, polar, aprotic sol- commercially by diazotization of aromatic vents are used. amines in anhydrous hydrogen fluoride with solid sodium nitrite and decomposition of the dissolved diazonium salt (see Section 11.1.2). 2.3. Synthesis from Fluorinated Synthons Fluorination with Nonmetal Fluorides. Reactions of nonmetal fluorides with certain sub- The variety of organic fluorine compounds can strates are predominantly restricted to laboratory be greatly increased by the use of easily accessi- operations. Sulfur tetrafluoride and the following ble, low molecular mass fluoroalkanes and ole- compounds can be used for the controlled introduc- fins to synthesize higher molecular mass pro- tion of fluorine into organic compounds: dialkyla- ducts. Halofluoromethanes add to halogenated minosulfur(IV) fluorides (R2NSF3) [51–53], ethylenes to form halogenated fluoropropanes fluoroalkylamines (e.g., 2-chloro-1,1,2-trifluor- [48]. An industrially applied reaction is the ad- oethyldiethylamine or 1,1,2,3,3,3-hexafluoropro- dition of iodopentafluoroethane to tetrafluor- pyldiethylamine), tetra-n-butylammonium fluoride, oethylene yielding a homologous series of trialkylamine trishydrofluorides, nitrosyl fluoride, long-chain 1-iodoperfluoroalkanes (see Section perchloryl fluoride, fluoroxyfluoroalkanes (e.g., 3.4). The pyrolysis of chlorodifluoromethane is CF3OF) [54], xenon difluoride [55], or CH3COOF the industrial source of tetrafluoroethylene, hex- [56]. They are of commercial value for the fluori- afluoropropene, and the corresponding oligo- nation of complex organic compounds such as mers and polymers (see Sections 4.2 and 4.3). pharmaceuticals. These examples illustrate the importance of this synthetic method, especially for the production of organic fluorine compounds containing more 2.6. Purification and Analysis than two carbon atoms where the above-men- tioned fluorination methods fail to give high Impurities are usually removed from organic yields of the desired products. fluorine compounds by fractional distillation, 448 Fluorine Compounds, Organic Vol. 15 fractional crystallization, or chromatographic This system does not allow isomerisms to be methods. This does not apply to fluoropolymers expressed for ethane derivatives; for such cases, a and high-boiling perfluorinated oils, which re- letter (a, b, . . . etc.) is added to isomers as their quire special measures, i.e., the use of extremely asymmetry increases, e.g., pure starting materials. Quantitative determination of fluorine is pos- CF2Cl CCl2F ¼ CFC 113 ðR 113Þ sible in most cases by combustion and subse- quent analysis of the hydrogen fluoride generat- CF3 CCl3 ¼ CFC 113 a ðR 113 aÞ ed. Wet chemical methods are used to determine The compound with the highest degree of fluoride ions [57]. symmetry is not given a letter. Because of the high volatility of organic fluo- A special isomer in the series of propane rine compounds, purity can be readily deter- derivatives is designated by adding two letters mined by gas chromatography. 19F-Nuclear mag- to the numbers derived from the standard rules netic resonance spectroscopy is a valuable tool [60]. The first letter attached to the number refers for determining the structure of organic fluorine to the central carbon atom, coding the total compounds. Structure determinations, even of atomic mass of the two substituents attached mixtures, are often easier using this method than (a ¼ CCl2,b ¼ CFCl, c ¼ CF2,d ¼ CHCl, e ¼ 1 with H-NMR spectra due to the larger chemical CHF, f ¼ CH2). The second appended letter is shifts of 19F-NMR spectra. The 19F signals can be derived from the symmetry rule applied to the integrated and used for quantitative analysis [58]. two terminal carbon atoms combined to an imag- inary ethane unit. This unit is then treated like an ethane derivative with the difference that the 3. Fluorinated Alkanes letter a is given to the most symmetric combina- tion. Examples for the codes of the isomeric The hydrogen atoms of alkanes may be partially propane derivatives C3HCl2F5 are: or totally replaced by fluorine. Partially fluori- nated alkanes are hydrofluorocarbons (HFCs); CF –CF –CHCl HCFC 225 ca fully fluorinated alkanes (perfluoroalkanes) are 3 2 2 CF2Cl–CF2–CHFCl HCFC 225 cb perfluorocarbons (PFCs). In chlorofluorocarbons CF3–CHCl–CF2Cl HCFC 225 da (CFCs) and hydrochlorofluorocarbons (HCFCs), CF3–CHF–CFCl2 HCFC 225 eb. the alkane hydrogens are replaced by both chlo- rine and fluorine. Codes for the butane derivatives contain three A special nomenclature [59] has been intro- letters appended to the numeral (e.g., CF3–CH2– duced to identify smaller chain length fluoroalk- CF2–CH3 is coded as HFC 365 mfc [61]). anes (up to four carbon atoms) used in refriger- ants. It consists of a three-digit number combined with various letters. The first figure of the three- 3.1. Fluoroalkanes and digit number indicates the number of carbon Perfluoroalkanes atoms minus one (for methane derivatives, the figure 0 is omitted); the second figure indicates Properties. Monofluoroalkanes are at- the number of the hydrogen atoms plus one; and tacked by bases and sometimes by heat; however, the third figure indicates the number of fluorine chemical resistance increases with increasing atoms. All other bonds are saturated with chlo- fluorine substitution, especially multiple substi- rine. The letter R before the code number is an tution at the same carbon atom. abbreviation for refrigerant; the letter C indicates Perfluoroalkanes have distinct properties a cyclic compound. The complete number is [62], [63]. Their physical properties differ from called the refrigerant number. The American those of the corresponding hydrocarbons: densi- Society of Heating, Refrigerating, and Air Con- ties and viscosities are higher, whereas surface ditioning Engineers (Atlanta, Georgia) ASH- tensions, refractive indices, and dielectric con- RAE Standard 34 – 78 describes the method of stants are lower. At room temperature perfluor- coding. The abbreviation F is sometimes used oalkanes are attacked only by sodium in liquid and stands for fluorohydrocarbon. ammonia. At 400 – 500 C, they are degraded Vol. 15 Fluorine Compounds, Organic 449

Table 2. Boiling points, melting points, and densities of fluoroalkanes and perfluoroalkanes

q 3 Compound CAS registry Formula Mr Refrigerant Code no. bp, C mp, C d4 , g/cm no. no. (q, C)

Fluoromethane [593-53-3]CH3F 34.03 R 41 HFC 41 78.5 141.8 0.8428 ( 60) Difluoromethane [75-10-5]CH2F2 52.03 R 32 HFC 32 51.7 136 1.100 (20) Trifluoromethane [75-46-7] CHF3 70.02 R 23 HFC 23 82.1 160 1.246 ( 34) Tetrafluoromethane [75-73-0]CF4 88.01 R 14 PFC 14 128 183.6 1.33 ( 80) Fluoroethane [353-36-6]CH3CH2F 48.06 R 161 HFC 161 37.1 143.2 0.8176 ( 37) 1,2-Difluoroethane [624-72-6]CH2FCH2F 66.05 R 152 HFC 152 30.7 0.913 (19) 1,1-Difluoroethane [75-37-6]CH3CHF2 66.05 R 152a HFC 152a 24.7 117 0.966 (19) 1,1,2-Trifluoroethane [430-66-0] CHF2CH2F 84.04 R 143 HFC 143 5.0 84 1,1,1-Trifluoroethane [420-46-2]CH3CF3 84.04 R 143a HFC 143a 47.6 111 0.942 (30) 1,1,2,2-Tetrafluoroethane [359-35-3] CHF2CHF2 102.03 R 134 HFC 134 19.7 89 1,1,1,2-Tetrafluoroethane [811-97-2]CF3CH2F 102.03 R 134a HFC 134a 26.3 101 1.2078 (25) Pentafluoroethane [354-33-6]CF3CHF2 120.03 R 125 HFC 125 48.5 103 1.250 (20) Hexafluoroethane [76-16-4]CF3CF3 138.02 R 116 PFC 116 78.1 100.6 1.607 ( 78) 1,1,2,2,3-Pentafluoropropane [679-86-7] CHF2CF2CH2F 134.05 R 245ca HFC 245ca 26 82 1,1,1,2,2-Pentafluoropropane [1814-88-6]CF3CF2CH3 134.05 R 245cb HFC 245cb 18 1,1,1,3,3-Pentafluoropropane [460-73-1]CF3CH2CHF2 134.05 R 245fa HFC 245fa 15.3 1.320 (25) 1,1,1,2,3,3,3-Heptafluorpropane [431-89-0]CF3CHFCF3 170.03 R 227ea HFC 227ea 16.5 131 1.394 (25) Octafluoropropane [76-19-7]CF3CF2CF3 188.03 R 218 PFC 218 36.7 183 1.350 (20)

Octafluorocyclobutane [115-25-3] 200.04 RC 318 PFCC 318 6.06 40.7 1.5241 (20)

1,1,1,3,3-Pentafluoro-n-butane [406-58-6]CF3CH2CF2CH3 148.07 R 365mfc HFC 365mfc 40.2 1.264 (20) Decafluoro-n-butane [355-25-9]CF3CF2CF2CF3 283.02 R 610 22 128.2 1.517 (20) by alkali metals and silicon dioxide; the former fluoride or metal fluorides such as antimony produce a metal fluoride and carbon, while the fluoride. Monohydroperfluoroalkanes can be ob- latter produces silicon tetrafluoride and carbon tained by adding hydrogen fluoride to perfluor- dioxide. Thermal decomposition starts above oalkenes (e.g., CF3–CHF–CF3, HFC 227 ea) or 800 C (compounds with tertiary carbon atoms by decarboxylation of perfluorocarboxylates in above 600 C) with the formation of saturated the presence of proton donors. The novel com- and unsaturated decomposition products and mercially interesting hydrofluorocarbons are some carbon. In addition to their chemical and produced by processes, that have been developed physical stability, perfluoroalkanes are charac- for the production of chlorofluorocarbons and terized by nonflammability and physiological hydrofluorocarbons and optimized during the last inertness. decades (see Section 3.2). Whereas partially fluorinated alkanes dissolve Higher temperatures and higher hydrogen fluo- in many common solvents, perfluoroalkanes ride : substrate ratios are necessary to achieve have low solubility, which decreases with their complete replacement of all chlorine atoms in the chain length. Only ethers, ketones, esters, chlor- starting chlorocompounds by fluorine. Both liquid- ohydrocarbons, and chlorofluorocarbons have phase halogen exchange in the presence of catalysts the power to dissolve perfluoroalkanes [62]. such as antimony(V) or tin(IV) chlorofluorides and Boiling points, melting points, and densities of vapor phase reactions using solid-phase catalysts fluoroalkanes and perfluoroalkanes are listed in based on chromium are employed. Preferred start- Table 2. For other physical properties of HFCs, ing materials are chloroform for HFC 23 [45], [65], see Table 3. Physical data for liquid perfluoralk- dichloromethane for HFC 32 [66] and 1,1,1-tri- anes are given in Tables 4 and 5. chloroethane for HFC 143 a [67]. The conversion of tetrachloroethylene to HFC 125 [68] and Production. Mono- and difluoroalkanes can trichloroethylene to HFC 134 a [69] involves be produced by addition of hydrogen fluoride to initial HF-addition across the double bond fol- olefins or alkynes (e.g., CF2H–CH3, HFC 152 a). lowed by a series of chlorine – fluorine ex- Another synthetic pathway is the exchange of change reactions. Vapor-phase hydrogenolysis chlorine (or bromine) for fluorine using hydrogen of chlorofluorocarbons and hydrochlorofluoro- 450 Fluorine Compounds, Organic Vol. 15

Table 3. Physical properties of hydrofluorocarbons

Property CH2F2 CHF3 CHF2CH3 CF3CH3 CF3CH2FCF3CHF2 CF3CH2CHF2 CF3CHFCF3 CF3CH2CF2CH3 Critical temperature, C 78.2 26.3 113.3 73.6 101.1 66.3 154.1 101.8 187.7 Critical pressure, MPa 5.80 4.87 4.52 3.83 4.06 3.63 2.93 2.75 Critical density, g/cm3 0.527 0.365 0.434 0.515 0.517 0.582 Heat of evaporation 240.8 326.0 230.0 213.46 177.03 208.96 131.8 at bp, kJ/kg Specific heat, 876 kJ/kg1 K1

Refractive index, nD 1.200 1.442 1.023 1.53 1.407 (25) ( 50) ( 80) ( 30) ( 48.5) Surface tension, N/cm 6.93 9.94 4.60 8.02 3.70 105 105 105 105 105 Vapor pressure (kPa) at 120 C 5.9 100 C 31.5 80 C 113.9 60 C 314.0 40 C 177.3 712.0 141.7 52.0 148.4 32.4 20 C 405.8 1403.0 120.7 316.4 134.0 337.6 19.7 86.7 6.3 0 C 813.4 2504.3 264.2 620.2 293.0 670.6 53.6 196.2 18.8 20 C 1474.6 4184.3 513.4 1104.3 572.0 1204.6 123.8 390.2 46.7 40 C 2477.4 909.7 1831.5 1017.0 2008.1 251.8 702.9 100.9 60 C 3933.4 1501.0 2884.7 1681.0 463.5 1174.7 194.9 80 C 2344.1 2631.0 788.8 1857.2 344.6 100 C 3511.4 3970.0 1261.0 2824.6 567.3 120 C 1920.0 880.2 140 C 1300.2 Lower ignition limit 12.7 none 3.1 7.1 none none none none 3.5 (25 C), vol %, Atmospheric lifetime, a 15.6 40.5 7.4 40 10.8 HGWP* (CFC 11 ¼ 1) 0.15 8.4 0.03 1.0 0.29 0.67 0.69 * HGWP ¼ Halogen Global Warming Potential carbons is also proposed for the production of a fluorine stream [72], [73]. This process is suitable hydrofluorocarbons [70], [71]. for the production of perfluoroalkanes containing Perfluoroalkanes can be produced by a variety of up to 20 carbon atoms. It affords better process routes. Indirect fluorination of hydrocarbons with control and yields than the direct gas-phase fluori- cobalt(III) fluoride or silver(II) fluoride is carried nation using dilute fluorine and a metal catalyst, out in a steel or nickel tube with stirring. The especially for longer-chain compounds [74]. hydrocarbon vapors are passed at 150 – 450 C Fluoroalkanes and perfluoroalkanes can also over the fluorinating agent, which is regenerated in be produced electrochemically by the Phillips

Table 4. Boiling points, melting points, and densities of liquid perfluorocarbons

a 25 3 Compound (also mixtures) CAS registry no. Molecular formula Mr Commercial designation bp, C pour point, C d4 , g/cm

b F-pentanes [678-26-2]C5F12 288 PP50 29 120 1.604 F-methylcyclopentanes C6F12 300 PP1C 48 70 1.707 F-hexanes [355-42-0]C6F14 338 PP1 57 90 1.682 F-methylcyclohexanes C7F14 350 PP2 76 30 1.778 F-decalin (cis/trans) [306-94-5]C10F18 462 PP5/PP6 142 8 1.917 F-perhydrofluorene C13F22 574 PP10 194 40 1.984 F-perhydrophenanthrene [306-91-2]C14F24 624 PP11 215 20 2.03 F-perhydrofluoranthene C16F26 686 PP24 244 0 2.052 F-cyclohexylmethyldecalin C17F30 774 PP25 260 10 2.049 a Flutec notation (BNFL Fluorochemicals) b F ¼ perfluoro Vol. 15 Fluorine Compounds, Organic 451

Table 5. Further physical properties of liquid perfluoroalkanes [64]

Property PP50 PP1C PP1 PP2 PP5/6 PP10 PP11 PP24 PP25

Critical temperature, C 148.7 180.8 177.9 212.8 292.0 357.2 377 388.7 400.4 Critical pressure, MPa 2.05 2.26 1.83 2.02 1.75 1.62 1.46 1.51 1.13 Critical volume, L/kg 1.626 1.567 1.582 1.522 1.521 1.59 1.58 1.606 1.574 Heat of evaporation 90.8 75.8 85.5 85.9 78.7 71 68 65.8 67.9 at bp, kJ/kg Specific heat, kJ/kg1 K1 1.05 0.878 1.09 0.963 1.05 0.92 1.07 0.93 0.957 20 Refractive index, nD 1.283 1.2650 1.2509 1.2781 1.3130 1.3289 1.3348 1.3462 1.3376 Surface tension, N/cm 9.4 105 12.6 105 11.1 105 15.4 105 17.6 105 19.7 105 19 105 22.2 105 Viscosity (dynamic), 0.465 1.049 0.656 1.561 5.10 9.58 28.4 31.5 114.5 mPa s Vapor pressure (kPa) 8.62 3.68 2.94 1.41 0.09 < 0.01 < 0.01 < 0.01 < 0.01 at 25 C

Petroleum process or the electrochemical fluori- spheric level, leading to zero ozone depletion nation of alcohols, amines, carboxylic acids, and potentials (ODP ¼ 0) and to reduced halogen nitriles by the Simons process (see Section 2.1). global warming potentials (HGWPs). However, Tetrafluoromethane (carbon tetrafluoride, depending on the structure of the HFCs this CF4) can be produced by reaction of CCl2F2 or reduced stability can entail an increased flamma- CCl3F and hydrogen fluoride in the gas phase bility and thus make safe handling more difficult. [75] or by direct fluorination of carbon [76]. Therefore, alternatives to the CFCs need to retain Hexafluoroethane (PFC 116) is often obtained the attractive properties of CFCs like low toxici- as a byproduct in the production of CFC 115. ty, nonflammability, good thermodynamic prop- Octafluoropropane (PFC 218) can be produced erties, and accessibility via economically and by direct [77], electrochemical [78], or CoF3- ecologically viable manufacturing processes, but fluorination [79] of commercially available avoid any adverse effect to the environment. hexafluoropropene (see Section 4.3). Octafluor- In refrigeration and air-conditioning systems ocyclobutane is obtained by dimerization of CFC 12 is replaced by HFC 134 a, HCFC 22 by tetrafluoroethylene [80] or by passing 1,2-di- the azeotropic mixtures HFC 507 (HFC 125/ chloro-1,1,2,2-tetrafluoroethane, CClF2CClF2, HFC 143 a 1 : 1) or HFC 410 (HFC 32/HFC 125 over a nickel catalyst at 590 C [81]. 1 : 1) and CFC 13 by HFC 23. HFC 134 a and HFC 227 ea can be used as propellants in medici- Uses. Hydrofluorocarbons have been gaining nal aerosols instead of CFC 114. HFC 245 fa and increasing commercial interest as substitutes for HFC 365 mfc are proposed as blowing agents for chlorofluoro- and hydrochlorofluorocarbons since foams in replacing CFC 11, CFC 113 and governmental regulations banned the worldwide HCFC 141 b [83]. Until now no HFC candidate production and consumption of CFCs by 1996 and for replacement of CFC 11 and CFC 113 as sol- introduced a specific timetable for the phase out of vents, degreasing agents, or cleaning agents for HCFCs [82]. In contrast to CFCs hydrofluorocar- textiles or metal surfaces has been identified. In the bons have no adverse effect on the ozone layer and period 1990 – 1995 159.5 x 103 t of HFC 134 a only a low contribution to global warming (see have been produced [84]. below). The latter effect could be further minimized Gaseous perfluorocarbons (PFC 14, PFC 116, by avoiding leakages in refrigeration and air-con- PFC 218) are used in plasma etching processes in ditioning equipment and by refrigerant recycling. the microelectronic industry [85] and as gaseous In all applications involving considerable emis- dielectrics. Liquid perfluorocarbons [64] serve sions to the atmosphere, e.g., as propellants in as heat-transfer media in transformers and in aerosols (except medicinal aerosols), in open cell capacitors, as lubricants and hydraulic fluids, or foams, or in extruded foams CFCs will be replaced in vapor-phase soldering [86] and vapor-phase by nonhalogenated compounds in the future. sterilization [64]. Due to the presence of hydrogen in the mole- Perfluoroalkanes, e.g., perfluorodecalin [306- cule, the stability of HFCs is reduced. In the 94-5], are used in the production of blood sub- atmosphere they are degraded below the strato- stitutes [87]. 452 Fluorine Compounds, Organic Vol. 15

Trade Names. Hydrofluorocarbons substi- respect to the ozone balance and the greenhouse tuting chlorofluorocarbons and hydrochloro- effect [89], [90] verified the adverse impact on fluorocarbons are marketed worldwide under the stratospheric ozone layer and the significant protected trade names. The individual product contributions to global warming due to the long is characterized by the HFC code number fol- atmospheric lifetimes of the CFCs. In 1987, a lowing the trade name. Some worldwide applied United Nations agreement, called the Montreal trade names are: Protocol – revised in 1992 during the Copenha- gen Intergovernmental Conference – set the deadline for the phase out of CFCs in developed France Rhoˆne-Poulenc Isceon countries. Since 1996 production and consump- Elf Atochem Forane tion of CFCs are prohibited, except as intermedi- Germany ates in the production of fluorine chemicals, Hoechst Reclin especially fluoropolymers. For HCFCs with re- Solvay Solkane United Kingdom duced atmospheric stabilities a timetable has ICI Klea been introduced for their phase out. HCFCs are Italy allowed to be used as drop-in alternatives for Montefluos Algogrene CFCs until suitable HFC substitutes (see Section Japan Asahi Glass Asahiflon 3.1) will have been developed, but no longer than Daikin Daiflon until 2015 to 2030 [82]. United States High molecular mass chlorofluorocarbons, a Allied Signal Genetron small but significant class of CFCs will not be DuPont Suva Great Lakes Chemical FM affected by the ban. 3 M 3M Brand Properties. Chlorofluoroalkanes are char- Perfluorocarbons are offered under trade acterized by high chemical and thermal stabili- names such as Freon C-51–12; Perfluorokero- ties, which increase with their fluorine content. sene FCX-329, FCX-330;Perfluorolube oil FCX- Low flammability (or nonflammability) and low 512, FCX-412 (DuPont); Flutec PP-1, PP-2, PP- toxicity are additional commercial advantages. 3, PP-9, etc. (BNFL Fluorochemicals), Multi- Most of these compounds have a pleasant, weak fluor Inert Fluids (Air Products and Chemicals). odor; some are mild anesthetics [91]. Boiling points, freezing points, and densities of formerly commercially important chloro- 3.2. Chlorofluoroalkanes fluoroalkanes are shown in Table 7; other phys- ical properties are listed in Table 8. Physical For more than 50 years chlorofluorocarbons and properties of some high molecular mass CFCs hydrochlorofluorocarbons have been the most produced from chlorotrifluoroethylene are important organic fluorine compounds commer- given in Table 9. cially. The five products listed in Table 6 have been by far the most important of these with Production. Commercial production of regard to the field of applications and to the chlorofluoroalkanes employs halogen exchange, amount produced [84]. with hydrogen fluoride in the liquid phase in the The results of the investigation on postulated presence of a catalyst. The production scheme for atmospheric changes caused by CFCs [88] with dichlorodifluoromethane shown in Figure 1 is

Table 6. Economically most important organic fluorine compounds

Compound Total production Maximum annual through 1995, 106t production (year), 103 t

Trichlorofluoromethane (R 11, CFC 11) 8.62 382 (1987) Dichlorodifluoromethane (R 12, CFC 12) 11.28 425 (1987) Chlorodifluoromethane (R 22, HCFC 22) 3.85 243 (1995) 1,2,2-Trichloro-1,1,2-trifluoroethane (R 113, CFC 113) 2.97 251 (1989) 1,2-Dichloro-1,1,2,2-tetrafluoroethane (R 114, CFC 114) 0.51 19 (1986) Vol. 15 Fluorine Compounds, Organic 453

Table 7. Boiling points, melting points, and densities of chlorofluoroalkanes

q Compound CAS Formula Mr Refrigerant Code no. bp, mp, d4 , registry no. number C C g/cm3 (q, C)

Trichlorofluoromethane [75-69-4] CCl3F 137.38 R 11 CFC 11 23.7 111 1.490 (20) Dichlorodifluoromethane [75-71-8] CCl2F2 120.93 R 12 CFC 12 29.8 155 1.328 (20) Chlorotrifluoromethane [75-72-9] CClF3 104.47 R 13 CFC 13 81.1 181 0.924 (20) Dichlorofluoromethane [75-43-4] CHCl2F 102.93 R 21 HCFC 21 8.9 135 1.366 (20) Chlorodifluoromethane [75-45-6] CHClF2 86.48 R 22 HCFC 22 40.8 160 1.213 (20) Tetrachloro-1,2-difluoroethane [76-12-0] CCl2FCCl2F 203.85 R 112 CFC 112 92 27.4 1.634 (30) Tetrachloro-1,1-difluoroethane [76-11-9] CClF2CCl3 203.85 R 112 a CFC 112 a 91.5 40.8 1.649 (20) 1,1,2-Trichlorotrifluoroethane [76-13-1] CCl2FCClF2 187.39 R 113 CFC 113 47.7 33 1.582 (20) 1,1,1-Trichlorotrifluoroethane [354-58-5]CF3CCl3 187.39 R 113 a CFC 113 a 45.9 14 1.579 (20) 1,2-Dichlorotetrafluoroethane [76-14-2] CClF2CClF2 170.94 R 114 CFC 114 3.8 94 1.473 (20) 1,1-Dichlorotetrafluoroethane [374-07-2]CF3CCl2F 170.94 R 114 a CFC 114 a 2 56.6 1.478 (21) Chloropentafluoroethane [76-15-3]CF3CClF2 154.48 R 115 CFC 115 38 106 1.291 (25) 1,1,2-Trichloro-2,2-difluoroethane [354-21-2] CClF2CHCl2 169.39 R 122 HCFC 122 71.9 140 1.544 (25) 1,1-Dichlor-2,2,2-trifluoroethane [306-83-2]CF3CHCl2 152.94 R 123 HCFC 123 28.7 107 1.475 (15) 1-Chloro-1,2,2,2-tetrafluoroethane [2837-89-0]CF3CHClF 136.48 R 124 HCFC 124 12 199 1.364(25) 1,2-Dichloro-1,1-difluoroethane [1649-08-7] CClF2CH2Cl 134.94 R 132 b HCFC 132 b 46.8 101.2 1.4163 (20) 1-Chloro-2,2,2-trifluoroethane [75-88-7]CF3CH2Cl 118.49 R 133 a HCFC 133 a 6.9 101 1.389 (0) 1,1-Dichloro-1-fluoroethane [1717-00-6] CCl2FCH3 116.95 R 141 b HCFC 141 b 32 103.5 1.250 (10) 1-Chloro-1,1-difluoroethane [75-68-3] CClF2CH3 100.49 R 142 b HCFC 142 b 9.2 130.8 1.120 (25) 1,1-Dichloro-2,2,3,3,3- [422-56-0]CF3CF2CHCl2 202.9 R 22 5ca HCFC 225 51.1 94 1.550 (25) pentafluoropropane ca

1,3-Dichloro-1,2,2,3,3- [507-55-1] CClF2CF2CHClF 202.9 HCFC 56.1 97 1.560 (25) pentafluoropropane 225 cb typical [93]: of chlorine to convert it to the catalytically active Sb(V) form. CCl4þ2HF!CCl2F2þ2 HCl The crude product is fractionally distilled under pressure (0.6 – 0.8 MPa). The lower- A steam-heated steel autoclave (a) lined with boiling fraction contains some chlorotrifluoro- stainless steel (V2A) serves as the reactor. The methane and most of the dichlorodifluorometh- seals are made from aluminum or copper. The ane (yield 90 % based on carbon tetrachloride, autoclave (capacity 2 – 5 m3) is filled with 80 % based on hydrogen fluoride). The higher- 500 kg of hydrogen fluoride, 1540 kg of carbon boiling fraction consists of trichlorofluoromethane tetrachloride, 220 kg of antimony(III) chloride, (5 – 10 % based on carbon tetrachloride), which and 20 kg of chlorine, and the mixture is heated can be recycled. The distilled product is passed to 100 C. After ca. 2 h and an increase in through a caustic filter (s). Steel bottles, pressure pressure to ca. 3 MPa, the fluorination products vessels, tank cars, and tank trucks are used for with lower boiling points are removed together transport. with the hydrogen chloride that is generated and More recently developed exchange processes some hydrogen fluoride; higher-boiling products are carried out continuously in the gas phase at in the exit gases are condensed and recycled. The 100 – 400 C, using catalysts based on chromi- low-boiling fraction is first washed with water in um [45], aluminum [44], or iron [94]. Starting a tower (e) lined with poly(vinyl chloride) and materials, which include carbon tetrachloride, packed with graphite; it is then washed with chloroform, tetrachloroethylene, and trichloro- caustic in a tower (f) filled with porcelain pack- ethylene, are passed over the catalyst with excess ing. After being washed to neutrality, the product hydrogen fluoride and, where necessary, chlo- is dried in a tower (i) containing concentrated rine. Further processing follows the same prin- sulfuric acid, compressed to a liquid, and fed into ciples as in the liquid-phase process. an intermediate storage tank (m). Each batch In the Montedison chlorofluorination process, takes ca. 24 h to process. The antimony catalyst reaction of C1- and C2-hydrocarbons with chlo- remains in the reactor and is regenerated before rine and hydrogen fluoride takes place in a single each subsequent batch by adding a small amount step in a fluidized-bed reactor. A suitable catalyst 454 Fluorine Compounds, Organic Vol. 15

Table 8. Physical properties of chlorofluoroalkanes [92]

Property CCl3F CCl2F2 CClF3 CHClF2 CCl2FCClF2 CClF2CClF2 CF3CHCl2 CF3CHClF CCl2FCH3 CClF2CH3 Critical temperature, 198.0 112.0 28.8 96.0 214.1 145.7 185 122.2 210.3 137.1 C Critical pressure, 4.40 4.21 3.86 4.94 3.41 3.27 3.79 3.57 4.64 4.12 MPa Critical density, 0.548 0.558 0.581 0.525 0.576 0.578 g/cm3 Heat of evaporation 182.16 166.88 148.50 234.12 145.70 139.42 174.17 167.9 223.15 223.15 at bp, kJ/kg Specific heat at 101.3 kPa, Jkg1 K1 871 854 850 1088 946 971 1017.4 1130 1155.6 1297.9 Refractive index, 1.384 1.285 1.263 1.252 1.355 1.290 1.3322 (15) 1.3600 (10) 26:5 nD Surface tension, 19105 9105 9105 19105 13105 19105 N/cm Solubility in water, g/100 g at 0 C 0.0036 0.0025 0.0019 0.060 0.0036 0.0026 at 30 C 0.013 0.0125 0.0065 0.15 0.013 0.011 0.39 1.71 0.021 0.14 (25 C) (25 C) (25 C) (25 C) Dielectric strength at 101.3 kPa, 23 C, nitrogen ¼ 1 3.1 2.4 1.4 1.3 2.6 (39.2 kPa) 2.8 Dielectric constant liquid at 25 C* 2.5 2.1 2.3 6.6 2.6 2.2 ( 30 C) vapor (t, C) 1.0019 1.0016 1.0013 1.0035 1.0024 (27.5) 1.0021 7.9 (20 C) (26) (29) (29) (25.4) (26.8) Vapor pressure (kPa) at 120 C 6.96 100 C 1.18 33.14 80 C 6.12 109.8 60 C 22.7 282.5 3.6 40 C 5.1 64.3 607 13.0 20 C 15.7 151.0 1146 246 5.08 37.0 0 C 40.2 308.7 1969 500 14.79 87.9 28 20 C 89.0 566.9 3177 917 36.4 182 65 40 C 176 958.5 1549 78.3 340 184 (50 C) 60 C 316 1518.7 2459 151.3 583 80 C 528 2284.7 268.0 935 100 C 830 3297.5 442.2 1423 120 C 1242 2083 140 C 1785 2964 Atmospheric 55 116 15.8 110 220 1.71 7.0 10.8 22.4 lifetime, a ODP 1.00 1.00 0.055 1.07 0.80 0.02 0.022 0.11 0.065 HGWP (CFC11 ¼ 1) 1.00 3.00 0.33 1.6 7.1 0.02 0.11 0.14 0.41 * Except where otherwise stated.

Table 9. Physical data of high molecular mass CFCs with the structure is a combination of aluminum chloride and other Cl(CF CFCl) Cl 2 n metals [95–97]: n ¼ 2345

Mr 304 420.5 537 653.5 bp, C 136 205 255 300 37:8 Density, d4 1.713 1.808 1.865 1.902 Viscosity (dynamic), 1.35 3.4 10.8 48.9 Commercial production of chlorofluoroalk- mPa s (37.8 C) anes is also possible by the electrochemical Vol. 15 Fluorine Compounds, Organic 455

Figure 1. Manufacture of dichlorodifluoromethane (R 12) by fluorination of carbon tetrachloride in the liquid phase a) Autoclave; b) Reflux condenser; c) Separator; d) Pressure valve; e) Wash column (water); f) Wash column (NaOH); g) Pump for NaOH; h) Gasometer; i) Wash column (H2SO4); j) Pump for H2SO4; k) Compressor; l) Condenser; m) Receiver for crude product; n) Distillation pot; o) Dephlegmator; p) Condenser; q) Forerun receiver; r) Tank for pure product; s) Caustic filter

fluorination process developed by Phillips Petro- the area of refrigerants, where R 11, R 12, R 13, leum (see Section 2.1). R 22, R 113, R 114, R 115, and the chlorine-free High molecular mass chlorofluoroalkanes are compounds R 23 and RC 318 were preferred. Of produced by fluorination with chlorine trifluoride the drop-in alternatives to CFCs HCFC 22 is the [98], [99]. most important compound, used as refrigerant Other important processes for production of (annual production in 1995 243 103 t [84]), high molecular mass CFCs are based on the followed by HCFC 141 b (113 103 t in 1995 telomerization of chlorotrifluoroethylene (see [84]) and HCFC 142 b (38 103 t in 1995 [84]) Section 4.8) with carbon tetrachloride [100] or used as blowing agents for closed cell foams. For CFC 113 [101] as telogens. Stabilization and HFCs as alternatives see Section 3.1. end-group fluorination are achieved using cobalt Chlorofluoroalkanes, especially R 11 and trifluoride as fluorinating agent [102], [103]. R 113, were also employed as solvents and de- greasing and cleaning agents for textiles; Specifications. Chlorofluoroalkanes (and HCFC 22, CFC 113, and HCFC 142 b will be also the alternative HCFCs and HFCs) produced important intermediates for the production of on an industrial scale are subject to stringent fluoroolefins also in the future. standards. Impurities must not exceed the fol- Higher molecular mass perchlorofluoroalk- lowing limits (vol %): anes are used as oils, greases, and waxes, as lubricants, hydraulic fluids, damping oils, heat- transfer media, impregnating agents, and plasti- cizers. Oligomers of chlorotrifluoroethylene acids 0 moisture < 0.001 have achieved special importance in this area higher-boiling fractions < 0.05 [104]. other gases 2 Trade Names. Chlorofluoroalkanes were Uses. Up to the ban in the USA in 1978 sold worldwide under protected trade names; the chlorofluoroalkanes had been used mainly as refrigerant numbers describing the chemical aerosol propellants and as spraying and foam composition (see Table 7) are included to specify blowing agents (R 11, R 12, R 114). Further individual compounds. Some of the trade names important applications up to 1996 had been in that were applied worldwide are: 456 Fluorine Compounds, Organic Vol. 15

Halon 1301 denotes CF3Br; Halon 1211 is Australia CF ClBr; and Halon 2402 denotes CF BrCF Br). Australian Fluorine Chemicals Isceon 2 2 2 Czechoslovakia Bromofluorocarbons (BFCs) and hydrobro- Slovek Pro Chemickov Ledon mofluorocarbons (HBFCs) are involved in the Federal Republic of Germany depletion of stratospheric ozone and global Hoechst Frigen warming like the CFCs and HCFCs; however Kali-Chemie Kaltron France the contributions of the bromine-containing Rhoˆne-Poulenc Flugene compounds are distinctly higher. Therefore, the Ugine Kuhlmann Forane 1992 Copenhagen meeting agreed to phase out German Democratic Republic the production of BFCs and HBFCs by 1994, Volkseigener Betrieb Chemiewerk Nunchritz Fridohna Volkseigener Betrieb Fluorwerke Dohna Frigedohn with the exception of Halon for some essential Italy fire-fighting applications. HFC 125 and Montedison Algofrene HCFC 123 (DuPont) or HFC 227 ea (Great Japan Lakes) are announced as alternatives though they Asahi Glass Asahiflon Daikin Kogyo Daiflon are significantly less efficient as fire extinguish- Mitsui Fluorochemicals Flon ing agents than the BFC Halons North America Allied Chemical Genetron Fully halogenated compounds DuPont Freon Properties. Kaiser Chemicals Kaiser with a high fluorine content have excellent ther- Pennwalt Isotron mal stability; they are nonflammable and some Racon Racon (e.g., CF3Br) are physiologically inert [92]. At high Union Carbide Ucon temperature, thermal cleavage of the C – Br bond Soviet Union Khladon into radicals occurs, which is responsible for the Eskimon utility of some of these compounds in extinguish- The Netherlands ing fires (! Fire Extinguishing Agents) [105]. AKZO FCC Their chemical stability is slightly lower than that United Kingdom ICI Arcton of the corresponding chlorofluoroalkanes. Howev- Imperial Smelting Corporation Isceon er, as with the chlorofluoroalkanes, stability in- creases with the fluorine : bromine ratio. Some Trade names of higher molecular mass chloro- compounds have a marked anesthetic effect fluoroalkanes include Florubes (ICI), Fluorolube [91]. Physical properties are listed in Table 10. oils, Fluorolube greases (Hooker Industrial Che- micals Division), Halocarbon oils, greases, and Production. Bromofluoromethanes are ob- waxes (Halocarbon Products), Kel-F oils, greases, tained by bromination of a stream of the appropri- and waxes (3M), and Voltalef (Atochem). ate fluoromethane [106] or chlorofluoromethane [107] at 300 – 600 C. Ethane derivatives can also be obtained by thermal bromination [108] or by 3.3. Bromofluoroalkanes addition of bromine or hydrogen bromide [109] to fluoroolefins. In some cases hydrogen bromide can Bromofluoro compounds of practical importance be used to exchange a chlorine atom in a chloro- are found mainly in the methane and ethane series. fluoroalkane for a bromine atom [110]. Iodine – In the refrigerant (R) numbering system for bromine exchange in a fluoroiodoalkane can be bromofluoroalkanes, the corresponding chloro- effected with bromine [111]. fluoroalkanes are taken as the basic structures (see also Section 3); the substitution of chlorine by Uses. The lower-boiling compounds CBrF3 bromine is expressed by the addition of B1, B2, (R 13B1; Halon 1301) and CBrClF2 (R 12B1; etc. For example, bromotrifluoromethane is de- Halon 1211) had been used as fire extinguishing noted as R 13B1 and 1,2-dibromotetrafluoroethane agents. Producers were Atochem, ICI, and Solvay as R 114B2. In fire-fighting applications the Halon in Europe, DuPont and Great Lakes in the USA numbering system is used, specifying the number and Asahi Glass, Daikin, and Nippon Halon in of carbon, fluorine, chlorine, and bromine atoms in Japan. The total worldwide Halon production was the molecules when reading from left to right (e.g., estimated to be 25 103 t in 1986. Vol. 15 Fluorine Compounds, Organic 457

Table 10. Boiling points, melting points, and densities of bromofluoroalkanes

q 3 Compound CAS Formula Mr Halon no. bp, mp, d 4 , g/m ODP Atmospheric registry no. C C(q,C) R 11 ¼ 1 lifetime,a

Tribromofluoromethane [353-54-8] CBr3F 270.76 1103 106 74.5 2.7648 (20) Dibromodifluoromethane [75-61-6] CBr2F2 209.84 1202 24.5 110 2.3063 (15) Dibromochlorofluoromethane [353-55-9] CBr2ClF 226.30 1112 80 Bromotrifluoromethane [75-63-8] CBrF3 148.93 1301 57.8 168 1.58 (21) 16 67 Bromochlorodifluoromethane [353-59-3] CBrClF2 165.38 1211 4 160.5 1.850 (15) 4 19 Bromodifluoromethane [1511-62-2] CHBrF2 130.92 1201 15.5 145 1.825 (20) 1.4 5.6 1,2-Dibromotetrafluoroethane [124-73-2] CBrF2CBrF2 259.85 2402 47.5 110.4 2.18 (20) 6 1-Bromo-2-chloro-1,1,2- [354-06-3] CHClFCBrF2 197.40 2311 a 51.7 1.864 (20) trifluoroethane

2-Bromo-2-chloro-1,1,1- [151-67-7]CF3CHBrCl 197.40 2311 50.2 1.861 (25) trifluoroethane

Perfluoro-1-bromo-n-octane [423-55-2]is Properties. In contrast to chloro- and bro- physiologically inert and is useful as an X-ray mofluoroalkanes, iodofluoroalkanes readily un- contrast agent, especially for lung examinations dergo chemical reactions [24, Chap. 6], reacting [112]. With its low surface tension it penetrates preferentially by homolytic cleavage of the C – I small spaces and evenly wets healthy lung tissue. bond. . . 2-Bromo-2-chloro-1,1,1-trifluoroethane [151- The radical intermediates CnF2nþ1 and I can 67-7], also known as halothane, has been used add to double bonds; thus, reaction with ethylene worldwide since 1956 as an effective, nonflam- yields 1H,1H,2H,2H-1-iodoperfluoroalkanes, mable inhalation anesthetic (! Anesthetics, which are commercially important intermediates General). It is commonly produced by the ICI [114]: process: CnF2nþ1IþCH2 ¼ CH2!CnF2nþ1CH2CH2I

Control of the reaction between iodofluor- or the Hoechst process [43, pp. 208 – 210]: oalkanes and fluoroolefins, especially tetrafluor- oethylene, can result in oligomerization (telo- merization) of the olefin [115]:

CF3Iþn CF2 ¼ CF2!CF3ðCF2CF2Þ I As alternatives for halothane a series of n fluorinated ethers (containing in addition hydro- gen and chlorine atoms or exclusively hydrogen This reaction is employed commercially and atoms) have been developed, that retain or even is initiated by free radicals, UV irradiation, or surmount the desirable properties of halothane heat [116]. as inhalation anesthetic [113]. However, also Iodofluoroalkanes also form organometallic these compounds have an adverse effect on the compounds, some of which are useful intermedi- ozone layer. ates, e.g., for Grignard reactions [117]. Iodoperfluoroalkanes cannot be used as alky- lating agents and their applications are therefore Trade Names. Fluothane (ICI), Halothane limited. However, derivatives of the FITS-type ‘‘HOECHST’’ (Hoechst). reagent are alkylating agents [118]:

3.4. Iodofluoroalkanes

Iodofluoroalkanes have become important inter- mediates in the commercial production of com- Physical constants of some iodofluoroalkanes pounds containing a perfluorinated moiety. are shown in Table 11. 458 Fluorine Compounds, Organic Vol. 15

Table 11. Boiling points, melting points, and densities of iodoperfluoroalkanes

q 3 Compound CAS registry no. Formula Mr bp, C mp, C d4 , g/cm (q, C)

Trifluoroiodomethane [2314-97-8]CF3I 195.9 22.5 2.3608 ( 32) Pentafluoroiodoethane [354-64-3]CF3CF2I 245.9 12.5 92 2.0850 (20) Perfluoro-1-iodopropane [27636-85-7]CF3(CF2)2I 295.9 41.2 95 2.0626 (20) Perfluoro-2-iodopropane [677-69-0]CF3CFICF3 295.9 38 Perfluoro-1-iodo-n-butane [423-39-2]CF3(CF2)3I 345.9 67 88 2.07 (15) Perfluoro-1-iodo-n-pentane [638-79-9]CF3(CF2)4I 395.9 94.4 50 2.0349 (27.8) Perfluoro-1-iodo-n-hexane [355-43-1]CF3(CF2)5I 445.9 117 45 2.06 (20) Perfluoro-1-iodo-n-heptane [335-58-0]CF3(CF2)6I 495.9 137 – 138 Perfluoro-1-iodo-n-octane [507-63-1]CF3(CF2)7I 545.9 163 20.8 2.008 (25) Perfluoro-1-iodo-n-decane [423-62-1]CF3(CF2)9I 645.9 195 – 200 65.5 1.940 (70) 1,2-Diiodotetrafluoroethane [354-65-4]CF2ICF2I 353.8 112 2.629 (25) 1,4-Diiodooctafluoro-n-butane [375-50-8] I(CF2)4I 453.8 150 9.0 2.4739 (27)

Production. Iodofluoroalkanes can be Properties. The chemical behavior of fluor- produced by heating the silver salts of the per- oolefins [126] is governed by the number of fluorocarboxylic acids with iodine [119] or the vinylic fluorine atoms. In contrast to their hydro- corresponding sodium salts with iodine in di- carbon analogues, fluoroolefins are attacked by methylformamide [120]. Of commercial impor- electrophiles only with difficulty [127], which tance is the production of pentafluoroiodoethane increases with the degree of fluorination. How- (CF3CF2I) by reaction of tetrafluoroethylene with a ever, fluoroolefins react readily with nucleo- mixture of iodine pentafluoride and iodine [121]: philes [128], [129], because as the number of vinylic fluorine atoms increases, the p-electron 5CF2 ¼ CF2þIF5þ2I2!5CF3CF2I system of the double bond is destabilized. Ther- modynamic calculations have shown that the Heptafluoro-2-iodopropane (CF3CFICF3)is strength of the C – C p-bond in tetrafluoroethy- obtained similarly from hexafluoropropene. lene

The higher homologues C F2 þ1I(n ¼ 4 – 12) . . n n CF ¼ CF CF CF are produced commercially by reaction of the lower 2 2 2 2 members with tetrafluoroethylene (telomerization). is only ca. 160 kJ/mol as opposed to 241 kJ/mol a,w-Diiodoperfluoroalkanes are obtained in ethylene [130]. In unsymmetrically substitut- from tetrafluoroethylene and iodine [122]: ed fluoroolefins, the nucleophile attacks the carbon atom that is made strongly positive by the neighboring fluorine atoms and is shielded only weakly (sp2 hybridization). The reactivity of fluoroolefins toward nucleophiles increases Uses. 1-Iodoperfluoroalkanes and as follows: 1 ,1 ,2 ,2 -1-iodoperfluoroalkanes are inter- H H H H CF ¼ CF < CF ¼ CF CF < CF ¼ CðCF Þ mediates in the production of surfactants and 2 2 2 3 2 3 2 textile finishes [123]. Perfluorocarboxylic acids, especially perfluorooctanoic acid, are obtained Fluoroolefins are slightly to highly toxic and from perfluoroiodoalkanes [124], and perfluori- must be handled with care. The toxicity of fluo- nated dicarboxylic acids are obtained from a,w- rinated olefins is apparently proportional to their diiodoperfluoroalkanes [125]. reactivity toward nucleophiles [131]. Perfluoroi- sobutene, CF2¼C(CF3)2 [382-21-8], for exam- ple, is far more toxic than its lower homologues. 4. Fluorinated Olefins Physical properties of commercial fluoro- and chlorofluoroolefins are given in Table 12. The commercial importance of fluoro- and chlor- Fluoroolefins also differ from hydrogen-con- ofluoroolefins lies in the production of fluorinat- taining olefins in their marked tendency to un- ed plastics and inert fluids. dergo cycloaddition [132]. Vol. 15 Fluorine Compounds, Organic 459

Table 12. Physical properties of fluoroolefins and chlorofluoroolefins

Property Tetrafluoro- Hexafluoro- 1,1-Difluoro- Fluoro- Chlorotri- 3,3,3-Tri- ethylene propene ethylene ethylene fluoroethylene fluoro- prop-1-ene [116-14-3][116-15-4][75-38-7][75-02-5][359-29-5][677-21-4]

Mr 100.02 150.02 64.03 46.04 116.47 96.05 bp, C 75.6 29.4 82 72.2 28.36 27 mp, C 142.5 156.2 144 160.5 158.2 q 3 d4 , g/cm (q, C) 1.519 ( 76.3) 1.292 ( 29.4) 0.617 (23.6) 0.775 ( 30) 1.51 ( 40) Critical temperature, C 33.3 86.2 30.1 54.7 105.8 107 Critical pressure, MPa 3.82 2.75 4.29 5.43 3.93 4.14 Critical density, g/cm3 0.58 0.417 0.320 0.55 Heat of evaporation, 16 821 ( 75.6) 20 100 ( 29) 13 189 ( 40) 13 494 ( 20) 20 893 ( 28.4) J/mol (t, C)

Production. Fluoroolefins are produced by (see Section 4.3) and the highly toxic perfluor- dehalogenation of chlorofluoro-, bromofluoro-, oisobutene are formed [139]. or iodofluoroalkanes with zinc and alcohol, by dehydrohalogenation of hydrogen-containing Production. Many commercial processes haloalkanes with alcoholic alkali, or by heating. for the production of tetrafluoroethylene are Other common methods include addition of hy- known, e.g., reaction of tetrafluoromethane in drogen halides to alkynes, decarboxylation of an electric arc [140], dechlorination of CF Cl fluorocarboxylic acid salts, and pyrolysis of 2 CF2Cl with a metal [141], and thermal decom- fluorohydrocarbons [133–135]. position of trifluoroacetic acid [142]:

2CF3COOH!CF2 ¼ CF2þ2HFþ2CO2 4.2. Tetrafluoroethylene The two principal commercial methods are Properties. Tetrafluoroethylene (TFE), per- pyrolysis of trifluoromethane [143]: fluoroethylene, CF2¼CF2, a colorless, odorless gas, is flammable in oxygen, producing tetra- fluoromethane and carbon dioxide. For physical properties, see Table 12. At low temperature in and pyrolysis of chlorodifluoromethane [144]: the presence of oxygen, explosive peroxides are formed [136], [137]. Tetrafluoroethylene must be handled with great care since, even in the absence of oxygen, it can decompose explosively into carbon and tetrafluoromethane under pressure In the second method (Fig. 2), the chlorodi- above 20 C(DH ¼276 kJ/mol at fluoromethane gas is passed at atmospheric or 298 K). If the polymerization to polytetrafluor- reduced pressure through a heated platinum, oethylene (PTFE) (DH ¼172 kJ/mol at silver, or carbon tubular reactor (a). The 28 % 298 K) is uncontrolled, a more strongly exother- conversion obtained under these conditions is mic decomposition reaction can occur. Polymer- low (yield, 83 %), but can be increased to ca. ization inhibitors include dipentene [138-86-3], 65 % with the same yield by adding steam [145]. a-pinene [80-56-8], which are added to liquid In modification of this method, chlorodifluoro- tetrafluoroethylene during purification and stor- methane is treated with superheated steam at ca. age (at 30 C) [138]. In the United States, the 700 C, which results in a conversion rate of transportation of liquid TFE containing stabili- 60 – 80 % and a selectivity of 84 – 93 % [146]. zers is permitted. The pyrolysis gas is washed with water (b) to cool In the gas phase at ca. 300 – 500 C, tetra- it and to remove HCl. After being washed with fluoroethylene dimerizes to perfluorocyclobu- caustic soda (c) and dried with concentrated tane [139]. Above 600 C, hexafluoropropylene sulfuric acid (d), the crude product can be stored 460 Fluorine Compounds, Organic Vol. 15

Figure 2. Flow sheet for tetrafluoroethylene production a) Pyrolysis reactor; b) Quench column (water); c) Wash column (NaOH); d) Drier (conc. H2SO4); e) Intermediate storage tank for crude tetrafluoroethylene; f) Fractionation column for low-boiling constituents; g) Product distillation column; h) Tetrafluoroethylene storage tank; i) Fractionation column in liquid or gaseous form (e). It is a complex Polytetrafluoroethylene [9002-84-0], (PTFE) mixture from which tetrafluoroethylene is sepa- is a homopolymer sold under the trade names rated by distillation in the presence of dipentene Algoflon (Montefluos), Fluon (ICI), Halon (Al- or a similar stabilizer to prevent polymerization. lied Chemical), Hostaflon TFE (Hoechst), Teflon An overhead fraction containing inert gases and PTFE (DuPont), Fluon (Asahi Glass), and Poly- trifluoromethane is obtained in a low-boiling flon TFE (Daikin). Copolymers with fluorinated fractionation column (f) before isolating pure or fluorine-free olefins or vinyl ethers are also TFE (column g). commercially available. The higher-boiling fractions are processed (i) to recover unreacted CHCl2F and to isolate hexafluoropropene, a byproduct. Extractants 4.3. Hexafluoropropene such as methanol are added because of the formation of azeotropes during distillation Properties. Hexafluoropropene (HFP), [147]. Methanol also reacts with the toxic CF3CF¼CF2, a colorless, odorless gas, is non- perfluoroisobutene, (CF3)2C¼CF2,togivean flammable in air at room temperature. For physi- addition product. cal properties, see Table 12. It exhibits no special tendency toward radical homopolymerization Uses. Currently, tetrafluoroethylene is the [149], but like other fluoroolefins, it reacts readi- most important fluoroolefin; it is used mainly for ly with nucleophiles [128], [129]. the production of fluoropolymers (! Fluoropo- Liquid hexafluoropropene has unlimited stor- lymers, Organic). It reacts with perfluoronitro- age life under pressure at room temperature in soalkanes to produce so-called nitroso rubbers steel containers, even without stabilizers. In [148]. Tetrafluoroethylene is also used in the many countries the liquid can be transported in production of low molecular mass compounds steel cylinders or tank cars. Hexafluoropropene is and intermediates, e.g., for the manufacture of toxic (LC50 3000 ppm) and can decompose ther- iodoperfluoroalkanes (see Section 3.4). mally to form highly toxic perfluoroisobutene. Vol. 15 Fluorine Compounds, Organic 461

Production. Hexafluoropropene is pro- Vinylidene fluoride is transported as a liquid duced commercially by temperature-controlled in steel cylinders without stabilizers. pyrolysis of chlorodifluoromethane (cf. produc- tion of tetrafluoroethylene, see Section 4.2) Uses. 1,1-Difluoroethylene is the starting [150]. Hexafluoropropene can also be obtained material for the commercially important homo- from tetrafluoroethylene by heating at normal or polymer poly(vinylidene fluoride) [24937-79-9], reduced pressure, preferably in the presence of an (PVDF) (! Fluoropolymers, Organic, Section inert gas (e.g., CO2) or water vapor [151]: 2.8.).

Trade Names (PVDF). Kynar (Atochem USA), Florafon (Atochem), Solef (Solvay), Neo- flon (Daikin), KF (Kureha Chem.), Vidar Uses. An important application of hexa- (Suddeutsche€ Kalkstickstoffwerke). Worldwide fluoropropene is the production of copolymers, annual production (1988): 7.4 103 t. e.g., with tetrafluoroethylene or 1,1-difluoroethy- The copolymer with hexafluoropropene [116- lene (! Fluoropolymers, Organic, Section 2.3., 15-4] is marketed as Viton (DuPont) and Fluorel ! Fluoropolymers, Organic, Section 3.2.). The (3M). versatile epoxide, hexafluoropropylene oxide [428-59-1] (see Section 6.1.2), can be obtained from hexafluoropropene by oxidation. 4.5. Monofluoroethylene, Monofluoroethylene 4.4. 1,1-Difluoroethylene vinyl fluoride (VF), CH2¼CHF, is a colorless, highly flammable gas; up to 0.2 % of polymeri- vinylidene fluoride (VDF) CH2¼CF2, is a com- mercially important, partially fluorinated olefin. zation inhibitors are added for stabilization dur- It is a colorless, flammable gas that undergoes ing transport and storage. For physical proper- homopolymerization and copolymerization. For ties, see Table 12. physical properties, see Table 12. Production. In the past, vinyl fluoride was Production. Currently, three basic methods produced by dehydrofluorination of 1,1-difluor- are used for the commercial production of vinyl- oethane [75-37-6], obtained in two steps by idene fluoride: addition of hydrogen fluoride to acetylene [24, p. 59 – 66], [156]: 1. Dechlorination of 1,2-dichloro-1,1-difluor- oethane [1649-08-7], R 132 b in the gas phase and on a metal catalyst [142], [152]:

However, with mercury catalysts, vinyl fluo- ride can be produced directly from acetylene and hydrogen fluoride [24, p. 59 – 66], [157]: 2. Dehydrochlorination of 1-chloro-1,1-difluor- oethane [75-68-3], R 142 b [144], [153]:

The dehydrochlorination of 1-chloro-1-fluor- In the presence of steam the temperature can oethane [1615-75-4], CHClFCH3, and 1-chloro- be reduced to 500 – 650 C [154]. 2-fluoroethane [762-50-5], CH2FCH2Cl, are also 3. Dehydrofluorination of 1,1,1-trifluoroethane utilized commercially [158]. [420-46-2], R 143 a [155]: Uses. The main use of monofluoroethylene is in the production of poly(vinyl fluoride) [24981-14-4] (PVF) (! Fluoropolymers, Organic, 462 Fluorine Compounds, Organic Vol. 15

Section 2.8., ! Fluoropolymers, Organic, Section 2.9.).

Trade Names (PVF). Tedlar (DuPont), Dalbon (Diamond Shamrock, USA). Worldwide annual production (1988): 1.6 103 t

Acetic anhydride can be used with hexafluor- 4.6. 3,3,3-Trifluoropropene oacetone instead of ketene. The multistep reac- tion takes place in a single operation in a copper 3,3,3-Trifluoropropene, CF CH¼CH (TFP), is 3 2 reactor above 300 C [167]. Presumably, pro- produced almost exclusively by fluorination and cesses based on the highly toxic perfluoroisobu- dehalogenation of 1,1,1,3-tetrachloropropane tene are designed to remove it as a harmful [ ] (TCP), CCl CH CH Cl. With sodi- 1070-78-6 3 2 2 byproduct of tetrafluoroethylene or hexafluoro- um fluoride at 400 – 475 C, trifluoropropene is propene production. obtained in a single step, involving chlorine – Hexafluoroisobutene is used for the produc- fluorine exchange and dehydrochlorination tion of fluoropolymers. The trade name of the [159]. Using hydrogen fluoride and oxygen, the copolymer [ ] with vinylidene fluo- reaction can be carried out at 300 C over a 34149-71-8 ride is CM-X (Ausimont) [168]. chromium fluoride catalyst [160]. Liquid-phase fluorination of 1,1,1,3-tetrachloropropane with hydrogen fluoride in the presence of an antimony 4.8. Chlorofluoroolefins catalyst yields 1,1,1-trifluoro-3-chloropropane, CF3CH2CH2Cl, which gives 3,3,3-trifluoropro- Among the numerous known chlorofluoroolefins pene when treated with a base [161]. The con- [134], [134], 1,1-dichloro-2,2-difluoroethylene version is effected in a single operation with a [79-35-6] has some importance as a starting mixture of hydrogen fluoride and a tertiary amine material in the production of methoxyflurane [162]. [76-38-0], an inhalation anesthetic. However, chlorotrifluoroethylene is the most important member of this class.

Chlorotrifluoroethylene [359-29-5] A multistep synthesis starts from vinylidene (CTFE), CF2¼CFCl, a colorless, flammable gas, fluoride (CF2¼CH2) [163]. is less reactive than tetrafluoroethylene. For physical properties, see Table 12. Although Uses. The main use of trifluoropropene is in chlorotrifluoroethylene is more stable than tetra- the production of fluorine-containing silicones fluoroethylene, stabilizers such as tributylamine used in hydraulic fluids [159], [164]. are used during transportation and storage in steel cylinders [169]. Chlorotrifluoroethylene is toxic.

4.7. 3,3,3-Trifluoro-2-(trifluoromethyl)- Production. Chlorotrifluoroethylene is pro- prop-1-ene duced commercially by dechlorination of 1,1,2- trichloro-1,2,2-trifluoroethane [76-13-1], (R 113) 3,3,3-Trifluoro-1-(trifluoromethyl)prop-1-ene with zinc in methanol [170]: [382-10-5], hexafluoroisobutene, (HFIB), (CF3)2C¼CH2, is a colorless, toxic gas (4-h LC50 1700 ppm) with a bp of 14.1 C at 101.3 kPa. A number of processes for its production have been An alternative route is dechlorination in the described; the most important use hexafluoroa- gas phase, e.g., on an aluminum fluoride – nickel cetone [165] or perfluoroisobutene [166] as the phosphate catalyst; this catalyst is highly stable starting material. [171]. Vol. 15 Fluorine Compounds, Organic 463

p values of alcohols [178] Uses. Chlorotrifluoroethylene is a starting Table 13. Ka material for homopolymers and copolymers Alcohol R ¼ HR¼ F (PCTFE) (! Fluoropolymers, Organic, Section 2.6., ! Fluoropolymers, Organic, Section 2.7.). CR3CH2OH 15.9 12.8 (CR ) CHOH 17.1 9.3 In addition, chlorotrifluoroethylene is an inter- 3 2 (CR ) COH 19.2 5.4 mediate in the production of the inhalation anes- 3 3 thetic halothane. (2-Chloro-1,1,2-trifluor- oethyl)-diethylamine [357-83-5], ClFHCCF2N trifluoroethanol [75-89-8], bp 73.6 C, and (C2H5)2 (an addition product of chlorotrifluor- 1,1,1,3,3,3-hexafluoro-2-propanol [920-66-1], oethylene with diethylamine), is used as a fluori- bp 58.2 C, have achieved commercial impor- nating agent to replace hydroxyl groups in ster- tance. The former is prepared by catalytic hydro- oids and carbohydrates with fluorine [54], [172]. genation of trifluoroacetamide [179], trifluoroa- Another use of chlorotrifluoroethylene is in tel- cetyl chloride [180], or trifluoroacetic acid esters omerization with carbon tetrachloride or chloro- [181], or by reduction of trifluoroacetic acid with form. The products are stabilized with fluorine or metal hydrides [182]. Similar processes are used CoF3 and are used as inert fluids, hydraulic fluids, to prepare the latter from hexafluoroacetone or lubricants [104], [173]. [183]. Because of their strong tendency to form hydrogen bonds, the fluorinated alcohols form Trade Names (PCTFE). Aclon (Allied- stable complexes with hydrogen bond acceptors Signal), Daiflon (Daikin), Kel-F (3M), Voltalef and are excellent solvents for polar polymers (Atochem). Worldwide annual production [184]. Ethers derived from these alcohols are (1988): 103 t. used as inhalation anesthetics (see Section 6.3). 2-Aryl-1,1,1,3,3,3-hexafluoro-2-propanols are prepared by alkylation of aromatic com- 5. Fluorinated Alcohols [174] pounds with hexafluoroacetone [185]. Tertiary diols, e.g., 1,3-bis(2-hydroxyhexafluoro-2-pro- Primary and secondary alcohols that have fluorine pyl) benzene [802-93-7] are used to prepare and hydroxyl groups on the same carbon atom are fluoroepoxy resins [186]. unstable, and readily lose hydrogen fluoride to form carbonyl compounds. Primary and second- ary perfluoroalkoxides, however, can be prepared in polar solvents under aprotic conditions from carbonyl compounds and a source of ionic fluo- ride [175]; typical counterions are alkali-metal, Long-Chain Fluoroalcohols. The unique tetraalkylammonium, or tris(dialkylamino)sulfo- hydro- and oleophobic properties of long per- nium cations. The perfluoroalkoxides are moder- fluoroalkyl chains lead to many applications of ately nucleophilic and are used in situ to prepare long-chain fluoroalcohols and their derivatives compounds containing perfluoroalkoxy groups as surfactants, antisoilants, and surface-treat- (see Section 6.3). Tris(dialkylamino)sulfonium ment agents [187]. Structures can be repre- perfluoroalkoxides are unusually stable and, in sented by, some cases, have been isolated as crystalline solids [176]. Tertiary perfluoro alcohols, e.g., perfluoro-tert-butanol (1,1,1,3,3,3-hexafluoro-2- where X is typically F, H, or CH3, n is 6 – 12, trifluoromethyl-2-propanol) [2378-02-1] [177] and m is 1 or 2. The most important compounds and alcohols containing CH2 groups between the are the 1H,1H-perfluoroalcohols (X ¼ F, m ¼ fluorinated segment and the OH group are also 1), prepared by reduction of the corresponding stable. Fluorinated alcohols are more acidic than perfluorinated carboxylic acids [188], and the their nonfluorinated analogues because fluorine is 1H,1H,2H,2H-perfluoroalcohols (X ¼ F, m ¼ highly electronegative (see Table 13) [178]. 2); the latter are prepared by treatment of the corresponding 1-iodo-1H,1H,2H,2H-perfluor- Short-Chain Fluoroalcohols. Of the short- oalkanes with oleum [189]. Alcohols of the chain fluorinated alcohols (C2–C4), only 2,2,2- formula H(CF2)nCH2OH, where n is an even 464 Fluorine Compounds, Organic Vol. 15 number, are prepared by telomerization of tet- partially fluorinated or nonfluorinated ethers by rafluoroethylene with methanol [190]. fluorination with cobalt fluoride or elemental For use as soil-repellent finishes, the long- fluorine under carefully controlled conditions chain fluoroalcohols are converted into deriva- [195]. tives to adjust the hydrophobicity, solubility in aqueous and organic solutions, surface retention, Trade Names. Fluorinert liquids (3M) and and stability for each specific application. These Galden fluorinated fluids (Montedison). derivatives include esters, phosphates, carboxy- lates, and polyoxyethylenes. Polymeric alcohols are prepared by esterification with (meth)acry- 6.1.2. Perfluorinated Epoxides loyl chloride, followed by polymerization. In contrast to other perfluorinated cyclic ethers, Trade Names. Teflon, Zepel, and Zonyl ring strain in perfluorinated epoxides results in (DuPont), Scotchgard (3M), and Oleophobal high reactivity, making them versatile precursors (Chemische Fabrik Pfersee, Ciba-Geigy). to other fluorinated compounds [196]. The most important is hexafluoropropylene oxide [428-59- 1] (HFPO), trifluoro(trifluoromethyl)oxirane 6. Fluorinated Ethers [191] [197]. It is prepared from hexafluoropropene by reaction with elemental oxygen [198], by elec- 6.1. Perfluoroethers trochemical oxidation [199], or by reaction with hypochlorites [200] or hydrogen peroxide [201] Perfluorinated ethers are less basic than their in alkaline media. hydrogen-containing analogues [192]. The satu- Hexafluoropropylene oxide (bp 27.4 C) is rated aliphatic and cycloaliphatic perfluoroethers stable at room temperature, but decomposes are noncombustible, and, with the exception of above 150 C to form trifluoroacetyl fluoride and the perfluorinated epoxides, display high chemi- difluorocarbene [202]. In the presence of strong cal and thermal stability. Other properties of the Brønsted or Lewis acids, such as alumina or stable ethers, such as a large difference between aluminum chloride, HFPO undergoes catalytic the melting and boiling points at ambient pres- rearrangement to hexafluoroacetone, constitut- sure, and a low pour point, surface tension, and ing a convenient synthesis of this compound dielectric constant, are the basis of applications [203]. Most significantly, HFPO reacts readily such as dielectric and heat-exchange fluids in, for with nucleophiles. Attack usually occurs at the example, high power transformers. Higher mo- central carbon atom [204], resulting in formation lecular mass perfluoroethers are used as lubri- of an acid fluoride by loss of a fluoride ion from cants and hydraulic fluids in extreme service the intermediate perfluoroalkoxide, which can conditions, i.e., at high temperature and/or in a react further with HFPO to form higher oligo- corrosive environment. mers. Acid fluorides are precursors to the com- mercially important perfluorovinyl ethers and higher molecular mass perfluoroethers. 6.1.1. Low Molecular Mass Perfluoroethers

The low molecular mass perfluoroethers are usu- ally prepared by electrochemical fluorination of aliphatic ethers, alcohols, or carboxylic acids [193]. Typical empirical formulas are C6F12O, C7F14O, and C8F16O; these ethers often consist of where X ¼ nucleophile, e.g., fluoride ion. isomer mixtures. Compound FC-75 [11072-16- Both tetrafluoroethylene oxide [694-17-7] 5] (3M), mostly perfluorobutyltetrahydrofurans, (TFEO), also called tetrafluorooxirane [205], and is a useful solvent that has been explored as an epoxides of longer chain-length perfluoroolefins oxygen-transport agent in artificial blood [194]. [206] are known; however, the former is unstable Perfluorinated ethers can also be prepared from at room temperature and rearranges to form Vol. 15 Fluorine Compounds, Organic 465 trifluoroacetyl fluoride, whereas the latter are alkoxide generated in situ, or of other nucleo- prepared from inaccessible perfluoroolefins. On- philes with HFPO. The resulting acid fluorides ly HFPO has achieved commercial significance are converted to acid salts, which lose carbon because it is used for the synthesis of hexafluor- dioxide and metal fluoride when heated in an oacetone (see Hexafluoroacetone), high molecu- aprotic environment. For example, HFPO is lar mass perfluoroethers, Section 6.1.3, and fluo- treated with cesium trifluoromethoxide (from rinated vinyl ethers (Section 6.2). cesium fluoride and carbonyl fluoride). Hydroly- sis and decarboxylation of the resulting acid fluoride gives perfluoro(methyl vinyl ether) 6.1.3. High Molecular Mass [1187-93-5]. Perfluoroethers

High molecular mass perfluorinated ethers are prepared by fluoride-catalyzed oligomerization of HFPO [207]. The resulting terminal acid fluoride group is removed by hydrolysis and This compound is a comonomer with tetrafluor- decarboxylative fluorination with elemental fluo- oethylene in a perfluorinated elastomer [211]. rine. Chemically inert ethers are produced which Perfluoro(propyl vinyl ether) [ ], have the formula, 1623-05-8 CF3CF2CF2OCF¼CF2, prepared from the dimer of HFPO [212], is copolymerized with tetrafluor- oethylene to a melt-processable perfluoroplastic. Perfluorovinyl ethers containing specific functional groups and usually two or more moles These ethers are obtained in various molecu- of hexafluoropropylene oxide are prepared in a lar mass and viscosity ranges by controlling similar fashion. These compounds have the struc- oligomerization conditions or by partial distilla- ture RO(C F O)CF¼CF ; they are used as func- tion of the oligomeric mixture. In an alternative 3 6 2 tional groups in perfluoroelastomers which can method [208], perfluorinated olefins (e.g., tetra- undergo a crosslinking reaction, i.e., cure-site fluoroethylene or hexafluoropropene) react pho- monomers (R ¼ CF CF CN or pentafluorophe- tochemically with oxygen to form oligomeric 2 2 nyl) [213] and as monomers that provide the ionic perfluoroethers with terminal acid fluoride groups in perfluorinated ion-exchange resins groups and peroxide bonds [209]. These end (R ¼ CF CF SO F, CF CF CF CO CH ,or groups and the unstable peroxide linkages are 2 2 2 2 2 2 2 3 CF CF CO CH ) [214]. Synthesis of the sulfo- eliminated by fluorination. Perfluoroethers with 2 2 2 3 nyl fluoride-substituted vinyl ether is illustrative. molecular masses of ca. 500 – 6000 are used as Reaction of tetrafluoroethylene with sulfur triox- inert fluids, lubricants, and hydraulic fluids in ide gives a sultone, which rearranges to fluoro- applications that require resistance to high tem- sulfonyldifluoroacetyl fluoride. The anion perature or strongly corrosive environments. formed after addition of fluoride ion to this acid fluoride gives a 2 : 1 adduct with HFPO [215]. Krytox (DuPont), Aflunox Trade Names. Pyrolysis of the sodium salt over sodium carbon- (SCM Specialty Chemicals), and Fomblin ate gives the functional monomer [216]. (Montedison).

6.2. Perfluorovinyl Ethers

Perfluorovinyl ethers are comonomers used in the preparation of melt-processable perfluoro- plastics, fluorinated elastomers, and perfluoro- polymers containing functional groups [210] (! Fluoropolymers, Organic, Section 3.3.). The ethers are synthesized by reaction of a fluorinated 466 Fluorine Compounds, Organic Vol. 15

Perfluorovinyl ethers can also be prepared by deiodofluorination of iodine-containing ethers, XRfCF2OCF2CF2I, where X is hydrogen, halo- gen, CO R, CONR ,SOF, or PO(OR) (R ¼ 2 2 2 2 The flammability behavior of the compound is alkyl) and Rf is a perfluoroalkyl group. Initially, an organometallic derivative of the iodide is not significantly better than that of nonfluori- formed by reaction with metals, such as Mg, Cu, nated anesthetics, and it behaves as a mutagen Zn, Sn, or Sb. Heating in the absence of a proton in the Ames test [226]; therefore, the compound source affords the vinyl ethers [217]. is not currently produced commercially. 2-Chloro-1-(difluoromethoxy)-1,1,2-trifluoro- ethane [13838-16-9] [trade name: Ethrane (Ana- 6.3. Partially Fluorinated Ethers quest)], which is nonflammable, is prepared by successive chlorination and fluorination of the Partially fluorinated ethers are synthesized by hydrocarbon ether [227]. 1-Chloro-1-(difluoro- several methods. Fluoroalkyl alkyl or fluoroalkyl methoxy)-2,2,2-trifluoroethane [26675-46-7] aryl ethers are prepared from alkoxides or phen- [trade name: Forane (Anaquest)] is prepared in a oxides and fluoroolefins [218]; for example, similar fashion [228]. Other possible anesthetics 1,1,2,2-tetrafluoro-1-methoxyethane [425-88-7] include 2,2-dichloro-1,1-difluoro-1-methox- is prepared from tetrafluoroethylene and sodium yethane [76-38-0] [229] and 1,1,1,3,3,3-hexa- methoxide – methanol. Higher perfluoroolefins fluoro-2-(fluoromethoxy)propane [28523-86-6] can also be employed [219]. The methyl ethers [230]. are valuable intermediates, which can be con- verted to acid fluorides with sulfur trioxide [220] or other Lewis acids [221]. Primary and second- 7. Fluorinated Ketones and ary perfluorinated alkoxides (see Chap. 5) are not Aldehydes sufficiently nucleophilic to react with fluorinated or nonfluorinated olefins. However, they react The carbonyl groups in partially or perfluorinated with a variety of olefins in the presence of halo- ketones and aldehydes are electron deficient gen to give ethers [222], e.g., owing to the inductive effect of the highly elec- tronegative fluorine atom. Compared with their hydrocarbon counterparts, fluorinated ketones and aldehydes are, consequently, much more reactive toward nucleophilic reagents. Stable Perfluoroalkoxides react with benzyl halides addition compounds with water, alcohols, and to give perfluoroalkyl benzyl ethers [223]. amines are commonly formed. By contrast, fluo- In contrast to the physiological inertness of rinated ketones and aldehydes are relatively un- perfluoroethers, some partially fluorinated ethers reactive toward electrophilic reagents. An ex- act as inhalation anesthetics. Many cyclic and treme case is hexafluoroacetone, which is not acyclic ethers containing varying amounts of protonated by the FSO3H – SbF5 superacid fluorine, hydrogen, and sometimes other halo- [231]. gens have been evaluated as anesthetics in search A wide variety of fluoroalkyl ketones and of the ideal combination of potency, volatility, aldehydes has been synthesized, often by special lack of short- and long-term toxicity, and non- methods that are unique to polyfluorinated com- flammability [224]. Some ethers have achieved pounds [232]. Of the many known examples, a clinical significance (! Anesthetics, General, few fluorinated acetones, aldehydes, and 1,3- Section 2.5.). diketones are of practical importance. The first fluorinated ether anesthetic to be introduced clinically was2,2,2-trifluoro-1-viny- loxyethane [406-90-6] [trade name: Fluromar 7.1. Fluoro- and Chlorofluoroacetones (Anaquest)] [225]. It is prepared by addition of 2 mol of trifluoroethanol to acetylene, followed Several fluoro- and chlorofluoroacetones (propa- by thermolysis: nones) are listed in Table 14. Hexafluoroacetone Vol. 15 Fluorine Compounds, Organic 467

Table 14. Molecular masses and boiling points of fluoro- and chlorofluoropropanones

Name CAS Formula Mr bp, C registry no. (101.3 kPa)

1,1,1-Trifluoro-2-propanone [421-50-1]CF3COCH3 112.05 21.5 – 22.5 1,1,3,3-Tetrafluoro-2-propanone [360-52-1] CHF2COCHF2 130.05 58 1,1,1,3,3,3-Hexafluoro-2-propanone [684-16-2]CF3COCF3 166.03 27.4 1-Chloro-1,1,3,3,3-pentafluoro-2-propanone [79-53-8] CClF2COCF3 182.48 7.8 1,3-Dichloro-1,1,3,3-tetrafluoro-2-propanone [127-21-9] CClF2COCClF2 198.93 45.2 1,1,3-Trichloro-1,3,3-trifluoro-2-propanone [79-52-7] CCl2FCOCClF2 215.38 84.5 1,1,3,3-Tetrachloro-1,3-difluoro-2-propanone [79-51-6] CCl2FCOCCl2F 231.83 123.9 1,1,1,3,3-Pentachloro-3-fluoro-2-propanone [2378-08-7] CCl3COCCl2F 248.28 163.7 1,1,1,3,3,3-Hexachloro-2-propanone [116-16-5] CCl3COCCl3 264.73 203.6

and, to a lesser extent, chloropentafluoroacetone plete exchange of chlorine in hexachloroacetone, and sym-dichlorotetrafluoroacetone are commer- using hydrogen fluoride and a Cr3þ or Cr5þ cially important. Hexafluoroacetone is manufac- catalyst [234], [235], [237]. Their properties and tured by DuPont in the United States and by chemical reactivities are similar to those of hex- Hoechst in the Federal Republic of Germany. afluoroacetone [238]. Like hexafluoroacetone, The two chlorofluoroacetones were made in pi- chloropentafluoroacetone and sym-dichlorotetra- lot-plant quantities by Allied in the 1960s [233], fluoroacetone form stable, acidic hydrates and but their production has been discontinued. hemiacetals, e.g., CClF2COCF3 3H2O[34202- 28-3], bp 105 C, and CClF2COCClF2 2H2O Hexafluoroacetone, 1,1,1,3,3,3-hexafluoro- [34202-29-4], bp 106 C. The hydrates are pow- 2-propanone, is made industrially by the vapor- erful solvents for acetal resins and various polar phase reaction of hexachloroacetone with hydro- polymers [239], [240]. These chlorofluoroace- gen fluoride in the presence of a chromium tones and some of their derivatives possess her- catalyst [234], [235]. The rearrangement of hex- bicidal or fungicidal activity [241–243] and are afluoropropylene oxide induced by Lewis acids useful intermediates for synthesizing repellants [203] is an attractive new route that avoids the for textile fibers [244], [245], specialty polycar- highly toxic sym-dichlorotetrafluoro- and chlor- bonates [246], [247], and inhalation anesthetics opentafluoroacetones. A convenient laboratory [248]. synthesis uses hexafluoropropylene as a starting material [236]: 1,1,1-Trifluoro-2-propanone can be pre- pared in quantitative yield by the acid hydro- lysis of ethyl trifluoroacetoacetate, the ethyl ester of 4,4,4-trifluoro-3-oxobutanoic acid [372-31-6],whichismadebythealkali-pro- moted condensation of ethyl trifluoroacetate with ethyl acetate [249]. 1,1,1-Trifluoro-2-pro- panone is easily made in the laboratory by the Hexafluoroacetone is used mainly for the reaction of trifluoroacetic acid with methyl- manufacture of the solvent hexafluoro-2-propa- magnesium iodide [250]. Its aryl hydrazone nol and high-performance fluoropolymers. For derivatives show nematocidal and acaricidal the properties, chemistry, and uses of hexafluor- activity [251]. oacetone, see ! Acetone. 1,1,3,3-Tetrafluoro-2-propanone is made Chloropentafluoroacetone, 1-chloro- by the acid hydrolysis of the ethyl ester 1,1,3,3,3-pentafluoro-2-propanone [trade name: of 2,2,4,4-tetrafluoro-3-oxobutanoic acid, 5FK (Allied)] and sym-dichlorotetrafluoroace- CHF2COCF2 CO2C2H5 [249]. The ketone is used tone, 1,3-dichloro-1,1,3,3-tetrafluoro-2-propa- as an intermediate in the synthesis of inhalation none (4FK, Allied) can be made by the incom- anesthetics [252], [253]. 468 Fluorine Compounds, Organic Vol. 15

Table 15. Molecular mass and boiling points of perchlorofluoroacetaldehydes

Name Formula Mr CAS registry no. bp, C (101.3 kPa)

Trichloroacetaldehyde CCl3CHO 147.38 [75-87-6] 97.8 Dichlorofluoroacetaldehyde CCl2FCHO 130.93 [63034-44-6]56 Chlorodifluoroacetaldehyde CClF2CHO 114.48 [811-96-1] 17.8 a Trifluoroacetaldehyde CF3CHO 98.03 [75-90-1] 18 to 19 * At 99.7 kPa

7.2. Perhaloacetaldehydes fluoride) to give free trifluoroacetaldehyde. Hydro- lysis of the inhalation anesthetic Halothane, Perchlorfluoroacetaldehydes. Some phys- CF3CHBrCl, by a mixture of 65 % oleum, mercu- ical properties of the perchlorofluoroacetalde- ric oxide, and silver oxide also produces trifluor- hydes are shown in Table 15. Their chemical oacetaldehyde in high yield [257]. reactivities are similar to those of the per- Trifluoroacetaldehyde is commercially avail- chlorofluoroacetones. able as its hydrate or methyl and ethyl hemiace- Chlorodifluoroacetaldehyde and dichloro- tals, which liberate the pure aldehyde in polypho- fluoroacetaldehyde can be prepared by the lithium sphoric acid at 150 – 180 C. A Hoechst process aluminum hydride reduction of the corresponding for the manufacture of its hemiacetals involves methyl chlorofluoroacetates [254], [255]. treating the product from the gas-phase fluorina- tion of chloral with tetraalkoxyl silanes, or with Trifluoroacetaldehyde (fluoral) and some alcohols and silicon tetrachloride. This process of its derivatives have found practical importance avoids the need to isolate or handle free trifluor- as monomers and intermediates for biologically oacetaldehyde [258], [259]. active compounds.

Properties. Trifluoroacetaldehyde is a col- orless gas at ambient temperature and pressure. Like hexafluoroacetone, it reacts with water to form a stable, solid hydrate – 1,1-dihydroxy- 2,2,2-trifluoroethane [421-53-4], CF3CH(OH)2, Uses of Perhaloacetaldehydes. Certain mp 69 – 70 C. It reacts in a manner similar to oximes [260] and hydrazones [251] of trifluor- hexafluoroacetone with alcohols to give stable oacetaldehyde have insecticidal or acaricidal hemiacetals: 2,2,2-trifluoro-1-methoxyethanol activity. Its hemiacetal, 2,2,2-trifluoro-1-meth- [431-46-9], CF3CH(OH)OCH3, bp 96 – oxyethanol, has been used as a starting material 96.5 C; and 2,2,2-trifluoro-1-ethoxyethanol for the preparation of fluoroether inhalation an- [433-27-2], CF3CH(OH)OC2H5, bp 104 – esthetics [261] (see Section 6.3), including iso- 105 C (99.3 kPa). Unlike hexafluoroacetone, it flurane, CF3CHClOCHF2 [262], and its isomer readily homopolymerizes upon cationic, anionic, CF3CHFOCHClF [263], [264]. or free-radical initiation [254], [255]. The stereoregularity of perchlorofluoroacetal- dehyde polymerizations has been an area of Production. Several laboratory syntheses of active research, although no commercial uses of trifluoroacetaldehyde have been developed, in- the polymers have yet appeared. cluding reduction of trifluoroacetic acid and its Trifluoroacetaldehyde can be homopolymer- alkyl esters, trifluoroacetic anhydride, and trifluor- ized to give insoluble crystalline, or soluble, oacetyl chloride [256]. Trifluoroacetaldehyde can amorphous, polyoxymethylene polymers de- be manufactured on a large scale by the reaction of pending upon the polymerization conditions trichloroacetaldehyde (chloral) with hydrogen [254], [255]. This is in contrast with trichloroa- fluoride in the presence of chromium catalysts cetaldehyde which can only be polymerized to [235]. The product is a CF3CHO HF complex, a crystalline, apparently isotactic polymer. bp 38 C (133.3 kPa), which requires treatment Copolymers of perhaloacetaldehydes have been with a hydrogen fluoride acceptor (e.g., sodium prepared [254], [255]. Vol. 15 Fluorine Compounds, Organic 469

7.3. Fluorinated 1,3-Diketones dione [123-54-6], CH3COCH2COCH3 (pKa ¼ 8.9), CF3COCH2COCH3 (pKa ¼ 6.7), and Fluorinated 1,3-diketones in which the two car- CF3COCH2COCF3 (pKa ¼ 4.6) [267]. Fluori- bonyl groups are separated by a methylene or nated 1,3-diketones have a high enolic content, methine group form complexes with a wide typically 92 – 100 %, in comparison with ca. variety of metal ions. This property is the basis 80 % for 1,3-pentanedione. Their enolic protons of their utility in chromatographic analysis of can be readily replaced by metals or metal salts to metals, laser technology, NMR spectroscopy, form 1,3-diketonates of the type and hydrometallurgical separations. The proper- ties, preparation, and uses of fluorinated 1,3- diketones and theirmetal complexes have been extensively reviewed [265–267].

Properties and Production. Some physical properties of the industrially important fluorinat- ed 1,3-diketones are shown in Table 16. These Fluorinated 1,3-diketones form hydrates with compounds are considerably more acidic than water and hemiketals with shorter alcohols. They their nonfluorinated analogues, i.e., 1,3-pentane- are usually obtained by a Claisen condensation of

Table 16. Molecular masses and boiling points of fluorinated 1,3-diketones

Name CAS Formula Mr bp, C (kPa) registry no.

1,1,1-Trifluoro-2,4- [367-57-7]CF3COCH2COCH3 154.09 105 – 107 (101.3) pentanedione

1,1,1,5,5,5-Hexafluoro- [1522-22-1]CF3COCH2COCF3 208.06 70 – 71 (101.3) 2,4-pentanedione

1,1,1-Trifluoro-5,5-di- [22767-90-4]CF3COCH2COC(CH3)3 196.17 138 – 141 (101.3) methyl-2,4-hexanedione

1,1,1,2,2,3,3-Hepta- [17587-22-3]CF3CF2CF2COCH2COC(CH3)3 296.19 46 – 47 (0.67) fluoro-7,7-dimethyl-4,6- octanedione 4,4,4-Trifluoro-1-phenyl- [326-06-7] 216.16 224 (101.3)a 1,3-butanedione

4,4,4-Trifluoro-1-(2-thie- [326-91-0] 222.18 96 – 98 (1.07)b nyl)-1,3-butanedione

3-(Trifluoroacetyl)cam- [51800-98-7] 248.25 100 – 101 (2.13) phor, 1,7,7-trimethyl-3- (trifluoroacetyl)-bicyclo [2.2.1]heptan-2-one

3-(Heptafluorobutyryl) [51800-99-8] 348.26 60 – 70 (0.03) camphor, 3- (2,2,3,3,4,4,4-hepta- fluoro-1-oxo-butyl)-bicy- clo[2.2.1]heptan-2-one

a mp 38 – 40 C. b mp 42 – 43 C. 470 Fluorine Compounds, Organic Vol. 15 a fluorinated carboxylic acid ester with a ketone, acid (2.66), difluoroacetic acid (1.24), and tri- using a strong base such as a sodium alkoxide or fluoroacetic acid (0.23) compared to the pKa of sodium hydride. 4.74 for acetic acid [270].

0 Uses. The 1,3-diketones RCOCH2COR (R ¼ Production. Trifluoroacetic acid has been 0 CF3, n-C3F7 and R ¼ t-C4H9,CF3) that form prepared by the electrochemical fluorination of volatile, thermally and hydrolytically stable com- acetyl chloride or acetic anhydride in anhydrous plexes are useful for liquid or gas chromatographic hydrogen fluoride using the Simons process (Sec- analysis of metals. These diketones, especially tion 2.1) followed by hydrolysis of the resulting 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-octa- trifluoroacetyl fluoride. The yield is excellent nedione are widely used for the extraction of metal (> 90 %) [271], [272]. The Phillips Petroleum ions from aqueous solutions at variable pH [268]. electrochemical process (Section 2.1) employs 4,4,4-Trifluoromethyl- 1-(2-thienyl)-1,3-bu- acetyl fluoride as feed to produce trifluoroacetyl tanedione is especially suited for the analysis of fluoride along with mono and difluoroacetyl fluo- uranium and other radioactive elements. The ride [273]. Sulfur trioxide treatment of CF3CCl3, tetrakis-chelates of 4,4,4-trifluoro-1-phenyl- obtained by isomerization of Freon 113, 1,3-butanedione with rare-earth elements are CF2ClCFCl2, yields CF3COCl [274]. The acid is potential laser materials. purified by hydrolysis of the acyl halide with The paramagnetic lanthanide complexes of alkali, followed by acidification and distillation. heptafluoro-7,7-dimethyl-4,6-octanedione have gained considerable importance as NMR shift Uses. Most uses of fluorinated acetic acids reagents for simplifying the interpretation of are confined to trifluoroacetic acid, its anhydride, complex NMR spectra [269]; the europium com- and its derivative, 1,1,1-trifluoroethanol. Mono- plex is the most widely used. fluoroacetic acid derivatives (salts, esters, amides, and alcohols) are toxic because they are metabolized to fluorocitric acid which inhibits respiration (see Section 13.5) [275]. w-Fluoro

acids of the formula F(CH2)nCOOH, where n is an odd number, are extremely toxic, because of degradation in vivo to monofluoroacetic acid and The chiral-shift reagents derived from 3-hep- finally to fluorocitric acid [275]. Sodium mono- tafluorobutyryl-(þ)- or -()-camphor and 3-tri- fluoroacetate has been used as a rodenticide, but fluoroacetyl-(þ)- or -()-camphor are very use- is now banned. ful for the NMR assay of enantiomeric purity in solution [269]. 8.1.2. Long-Chain Perfluorocarboxylic Acids

Properties. The boiling points and densities of straight-chain perfluorocarboxylic acids are shown in Table 17.

Production. Long-chain perfluorocarbo- 8. Fluorinated Carboxylic Acids and xylic acids are prepared by the Simons electro- Fluorinated Alkanesulfonic Acids chemical fluorination (see Section 2.1.) of the corresponding acyl halide: 8.1. Fluorinated Carboxylic Acids

8.1.1. Fluorinated Acetic Acids The acids are obtained by hydrolysis of the Fluorination increases the strength of acetic acid perfluoroacyl fluoride, followed by distillation. as seen in the pKa values of monofluoroacetic Some carbon – carbon bond scission occurs to Vol. 15 Fluorine Compounds, Organic 471

Table 17. Boiling points and densities of perfluorocarboxylic acids

20 3 Acid CAS registry no. Formula bp, C (kPa) d4 , g/cm

Perfluoroacetic [76-05-1]CF3CO2H 72.4 1.489 Perfluoropropionic [422-64-0]C2F5CO2H 96 1.561 Perfluorobutyric [375-22-4]C3F7CO2H 120 1.651 Perfluorovaleric [2706-90-3]C4F9CO2H 130 Perfluorocaproic [307-24-4]C5F11CO2H 157 1.762 Perfluoroheptanoic [375-85-9]C6F13CO2H 175 1.792 Perfluorocaprylic [335-67-1]C7F15CO2H 189 Perfluorononanoic [375-95-1]C8F17CO2H 110 (2.1) Perfluorocapric [335-76-2]C9F19CO2H 121 (2.0 Perfluoroundecanoic [2058-94-8]C10F21CO2H 245 Perfluorododecanoic [307-55-1]C11F23CO2H 270 form lower homologous acids along with inert Polyfluoroalkoxyacyl fluorides of the type fluorocarbons and cyclic ethers. The acid yield decreases with increasing chain length; for ex- ample, perfluorobutyric acid yields are ca. 36 % compared to ca. 20 % for the industrially impor- are prepared by the addition of perfluoroacyl tant perfluorooctanoic acid [271], [272]. Trifluor- fluorides and hexafluoropropylene oxide cata- oacetic acid is also prepared by the Phillips lyzed by alkali-metal fluorides [281]. Acids, electrochemical method, employing a KF HF salts, or esters are obtained by hydrolysis, neu- molten salt electrolyte [273]. Acids with higher tralization, or esterification, respectively. boiling points are not easily or efficiently pre- Addition reactions of perfluorodiacyl fluor- pared by the Phillips process. ides with hexafluoropropylene oxide [282] give Perfluorocarboxylic acids are also prepared ether-containing diacyl fluorides, such as by nonelectrochemical methods. Treatment of perfluoroalkyl iodides (RfI) with sulfur trioxide [276] or chlorosulfonic acid [277] gives the carboxylic acid in good yield. Another method employs fuming sulfuric acid (oleum) [278]. where n is usually 2 – 4, and at least two units are Another process involves the preparation of per- derived from hexafluoropropylene oxide (i.e., 2) [282]. The addition reaction may occur fluorotetrahydroalkyl iodides, RfCH2CH2I, ob- m tained by the free-radical addition of ethylene to at one or both acyl groups of the starting diacyl perfluoroalkyl iodides, followed by dehydroio- fluoride. Selectivity can be maintained by esteri- dination and oxidation by dichromate [279] or fying one of the acyl fluoride groups. Thus, ozonolysis [280]: CH3OCO(CF2)2COF, prepared by addition of methanol to perfluoro-g-butyrolactone or per- fluorosuccinyl fluoride, reacts with hexafluoro- propylene oxide to give ester acyl fluorides of the formula

This process produces carboxylic acids hav- ing one more carbon atom than the starting perfluoroalkyl iodide, in contrast to the electro- chemical and oleum routes, which produce [283], [284]. The acyl halides are converted to acids containing the same number of carbon acids or salts by hydrolysis or neutralization, atoms as the original acyl halide or telomeric respectively. iodide. In all processes utilizing fluorinated iodine-containing telomers, it is important to Uses. Long-chain perfluoroalkanecarboxylic find uses for the telomers and to recover the acids and their salts are surface-active chemicals expensive iodine. (surfactants), which greatly reduce the surface 472 Fluorine Compounds, Organic Vol. 15 tension (surface energy) of water, aqueous solu- 8.1.4. Tetrafluoroethylene – Perfluorovinyl tions, and organic liquids even at low concentra- Ether Copolymers with Carboxylic Acid tions. These acids (C6–C12) and derivatives are Groups used as wetting, dispersing, emulsifying, and foaming agents. Ion-exchange membranes, used in fuel cells and Ammonium perfluorooctanoate (FC-143, chloralkali production, are copolymers of tetra- 3M) is used as an emulsifier in the polymerization fluoroethylene and perfluorovinyl ethers that of fluorinated monomers, especially tetrafluor- contain esters or other acid precursor groups oethylene. It has exceptional chemical stability [287]. These membranes have excellent thermal and lowers the surface tension of water to ca. and chemical resistance to hot concentrated 3 mN m at 0.5 wt %. In contrast with hydrocar- alkali (up to 40 %). bon emulsifiers, ammonium perfluorooctanoate does not interfere with the emulsion polymeriza- Production. The vinyl ethers are prepared tion of tetrafluoroethylene. by the reaction of hexafluoropropylene oxide and methyl-3-fluorocarbonyl perfluoropropionate Trade Names. Fluorad FC-26, 126, 143 [285], followed by pyrolysis to give:, (3M), Fluorowet CP (Hoechst), RM 350, 370 (Rimar), and Surflon S-111P (Asahi Glass).

Copolymerization with tetrafluoroethylene 8.1.3. Fluorinated Dicarboxylic Acids followed by saponification produces a polymer with terminal carboxylic acid groups. Properties. The boiling points and densities of perfluorodicarboxylic acids are shown in Ta- Flemion (Asahi Glass), Na- ble 18. Trade Names. fion (DuPont), Neosepta (Tokuyama Soda), and Aciplex (Asahi Chemical). Production. a,w-Perfluoroalkanedicarbo- xylic acids are prepared by the electrochemical method, followed by hydrolysis, acidification, 8.2. Fluorinated Alkanesulfonic Acids and extraction. Other methods include the oxi- dation of the appropriate chlorofluoroolefin or 8.2.1. Perfluoroalkanesulfonic Acids perfluoroolefin. Perfluoroglutaric acid is pre- pared from hexachlorocyclopentadiene by halo- Properties. The first member of the series, gen exchange, followed by oxidation and acidi- trifluoromethanesulfonic acid, was reported in fication [285]. Perfluoroadipic acid is prepared 1954 [288]. Perfluoroalkanesulfonic acids are by an analogous method from hexachloroben- among the strongest acids known. Conductivity zene [286]. The cyclic anhydrides from perfluor- measurements in acetic acid show that the acid osuccinic and perfluoroglutaric acid are prepared strength of trifluoromethanesulfonic acid is com- by dehydration of the acids with phosphorus parable to that of fluorosulfonic and perchloric pentoxide. They are used to prepare the corre- acids [289]. Boiling points are listed in Table 19. sponding alcohols by reduction. Because of their ability to lower surface energy,

Table 18. Physical properties of perfluorodicarboxylic acids

Acid CAS registry no. Formula mp, C bp, C (kPa)

Perfluoromalonic [1514-85-8]CF2(CO2H)2 117 – 118 Perfluorosuccinic [377-38-8] (CF2)2(CO2H)2 86 – 87 150 (2.0) Perfluoroglutaric [376-73-8] (CF2)3(CO2H)2 88 134 – 138 (0.4) Perfluoroadipic [336-08-3] (CF2)4(CO2H)2 132 – 134 138 (0.5) Perfluorosuberic [678-45-5] (CF2)6(CO2H)2 154 – 158 Vol. 15 Fluorine Compounds, Organic 473

Table 19. Boiling points of perfluoroalkanesulfonic acids agents [292], [293]. The higher homologues exhibit good surfactant properties; the deriva- Acid Formula CAS registry no. , C (kPa) bp tives of perfluorohexanesulfonyl fluoride are CF3SO3H[1493-13-6] 60 (0.4) employed in fire extinguishing formulations. C F SO H[] 81 (0.29) 2 5 3 354-88-1 Useful derivatives containing the sulfonamido -C F SO H[] 76 – 84 (0.13) n 4 9 3 59933-66-3 group can be prepared by reaction of the sulfonyl n-C5F11SO3H[3872-25-1] 110 (0.67)* n-C6F13SO3H[355-46-4] 95 (0.46) fluoride with a diamine, followed by quaterniza- n-C8F17SO3H[1763-23-1] 133 (0.8) tion with alkylating agents such as methyl iodide * n-C5F11SO3H H2O to give a cationic surfactant. As an example, reaction of perfluorohexanesulfonyl fluoride the longer-chain perfluoroalkanesulfonic acids with 3-dimethylaminopropylamine gives and sulfonyl fluoride derivatives have found utility as surface-active agents and water repel- lents and for antisoiling treatment of textiles and fabrics. The properties related to the low surface energy of the perfluorooctanesulfonyl fluoride, Perfluoroalkanesulfonyl fluor- Production. C8F17SO2F, are utilized in many derivatives. These ides are usually made by the Simons electro- derivatives include alcohols and their acrylate and chemical fluorination process (see Section 2.1), methacrylate esters; they are used as comonomers in which a hydrocarbon sulfonyl fluoride is elec- in polymers that impart oil-, water-, and soil- trolyzed in anhydrous hydrogen fluoride at nickel repellent properties to porous substrates such as electrodes: paper and textiles [294], [295]. A typical reaction sequence for the synthesis of a perfluoroalkane- sulfonamide acrylate monomer is shown below:

The electrochemical yield is excellent for the first member of the series and decreases progres- sively with the increasing length of the carbon chain; the yield for octanesulfonyl fluoride is ca. 40 % [271], [290]. Alkaline hydrolysis of per- fluoroalkanesulfonyl fluorides gives the corre- sponding salts, which when acidified and dis- tilled from concentrated sulfuric acid yield the Perfluoroalkanesulfonamido alcohols are also anhydrous sulfonic acids [288]. used as mold-release agents. Esterification with A nonelectrochemical method for the prepa- phosphoric acid gives phosphate ester salts of the ration of trifluoromethanesulfonic acid deriva- type tives is shown below:

which are useful oil repellents for paper products Alkaline hydrolysis, followed by acidification [296]. of the sulfonate salt, gives the acid [291]. Trade Names. Paper Treatment FC-807, 808 (3M), Textile Treatment Dic-Guard (Dai- Uses. Short-chain perfluoroalkanesulfonyl fluorides are used to prepare sulfonamides, which nippon Ink), and Scotchgard (3M). are employed as plant growth regulators and herbicides. Trifluoromethanesulfonic acid is used as an esterification catalyst (FC-24, 3M), 8.2.2. Fluorinated Alkanedisulfonic Acids and the lithium salt has been investigated as a fuel cell and battery electrolyte (FC-124, 3M). Per- a,w-Perfluoroalkanedisulfonyl fluorides are fluorobutanesulfonate salts are used as antistatic prepared by the electrochemical fluorination of 474 Fluorine Compounds, Organic Vol. 15 hydrocarbon disulfonyl fluorides. The corre- followed by copolymerization with tetrafluor- sponding acids are prepared by alkaline hydro- oethylene gives polymers with fluorosulfonyl lysis of the fluoride and acidification, or by side chains, which are hydrolyzed to sulfonate aqueous permanganate oxidation of the disul- group side-chains [307]. fone, CH3SO2(CF2CF2)nSO2CH3 [297]. Distilla- tion of the acids from phosphorus pentoxide yields the cyclic anhydrides [298]. 9. Fluorinated Tertiary Amines

Physical Properties. Relative to their mo- 8.2.3. Tetrafluoroethylene – Perfluorovinyl lecular mass, perfluoroalkyl-tert-amines, like the Ether Copolymers with Sulfonic Acid perfluoroethers, have low boiling points and low Groups freezing or pour points, as shown in Table 20. Low polarity and weak intermolecular forces are Ion-exchange membranes are prepared by the responsible for other unusually low values for copolymerization of tetrafluoroethylene with properties such as viscosity, solubility, heat of perfluorovinyl ethers containing sulfonyl halide vaporization, refractive index, dielectric con- groups, followed by hydrolysis to yield sulfonic stant, and surface tension [308]. Some perfluor- acids. These membranes have excellent chemical obis(dialkylaminoalkyl) ethers have even lower and thermal properties similar to those of ion- pour points and liquid ranges as broad as 250 C. exchange membranes with terminal carboxylic These ethers exhibit increased internal flexibility acid groups (see Section 8.1.4) [299–301]. through the combined effect of the nitrogen and oxygen atoms [311]. Production. These ethers are prepared by the condensation of hexafluoropropylene oxide Chemical Properties. Perfluorinated tert- with fluorosulfonyldifluoroacetyl fluoride, amines are chemically inert and thermally stable FSO2CF2COF, which is prepared from C2F4 and [308], [312]. The electron-withdrawing nature of SO3, followed by isomerization [302], [303]. the perfluoroalkyl substituents deprives the ni- Condensation of hexafluoropropylene oxide with trogen atom of its basic character and reactivity. g-fluorosulfonylperfluoroalkyl carbonyl fluor- Fluorinated tert-amines do not form salts or ides, FSO2(CF2)nCOF (prepared by electro- complexes with strong acids and are not attacked chemical fluorination of the respective aliphatic by most oxidizing or reducing agents. With sulfone [304], [305]) gives perfluoroether fluor- aluminum chloride they form chlorinated imines osulfonyl acyl fluorides, e.g., [306] [313]. Because of their nonpolar nature, fluori- nated tert-amines are poor solvents and are im- miscible with water and alcohols [308]. Gases such as oxygen, nitrogen, and carbon dioxide have unusually high solubility in perfluorinated Subsequent conversion to the vinyl ether tert-amines. For example, perfluorotributyla- mine dissolves 40 vol % of oxygen at ambient conditions and has been used in artificial blood as an effective oxygen-transport medium [313].

Table 20. Physical properties of fluorinated tert-amines [308–310]

25 Compound CAS registry no. Formula Mr bp, C Pour point, C d4

Perfluorotrimethylamine [432-03-1] N(CF3)3 221 11 Perfluorotriethylamine [359-70-6] N(C2F5)3 371 69 1.74 Perfluorotripropylamine [338-83-0] N(C3F7)3 521 130 52 1.82 Perfluorotributylamine [311-89-7] N(C4F9)3 671 178 50 1.88 Perfluorotriamylamine [338-84-1] N(C5F11)3 821 215 25 1.93 * ** Perfluorotrihexylamine [432-08-6] N(C6F13)3 971 256 33 1.90 * Freezing point. ** 35 d4 Vol. 15 Fluorine Compounds, Organic 475

Production. Electrochemical fluorination The perfluoroalkyl substituents of aromatic com- via the Simons process (see Section 2.1) is the pounds are meta-directing; this influence can, of preferred route to fluorinated tertiary alkyla- cause, be overcome by a stronger ortho-orpara- mines. The hydrogen atoms are completely re- directing substituent. These compounds are usu- placed by fluorine atoms. Perfluorotributyla- ally prepared from iodoperfluoroalkanes and ha- mine, for example, is synthesized as follows:, logenated aromatic compounds in the presence of a copper catalyst [315–317]. Except for the ben- zotrifluorides, aromatic compounds with fluori- nated side-chains have only scientific interest The crude product contains a significant [318]. Araliphatic compounds with one or two amount of perfluorinated isomers and cleavage trifluoromethyl substituents on the benzene ring products because of molecular rearrangement gained commercial importance in the early 1930s during electrolysis; it is purified by fractional for two reasons: 1) the recognition of the advan- distillation and treatment with base. tageous properties of aromatic dyes with CF3 substituents, and 2) the development of an eco- Uses. The combination of unusual physical nomical production process [4]. Since then, their and chemical properties, excellent dielectric importance in the production of dyes, pharma- properties, nonflammability, and lack of toxicity ceuticals, and pesticides has increased. make the perfluorinated tert-amines useful for many fluid applications that involve direct con- tact with sensitive materials [308], [313]. The 10.1. Properties electronic industry relies heavily on these fluids in reliability testing of electronic components, as The physical properties of benzotrifluorides are direct-contact coolants for integrated circuits, shown in Table 21. and as heating media in vapor-phase reflow If no other substituents are present in the soldering. Perfluorinated tributylamine, triamy- benzene ring, the trifluoromethyl group is ther- lamine, and trihexylamine are the main consti- mally stable up to 350 C and resistant to bases tuents of Fluorinert electronic liquids FC-43, FC- up to 130 C. It is inert toward reducing agents 70, and FC-71 (3M). [319], [320] and inhibits oxidation of the benzene Information on the preparation and utility of ring. However, in the presence of aluminum other nitrogen-containing fluoroaliphatic com- chloride the trifluoromethyl group undergoes pounds can be found in the general references chlorolysis to produce a trichloromethyl group [1–15]. [321], and acid hydrolysis forms a carboxy group [322]. Substituents such as amino or hydroxyl groups destabilize the trifluoromethyl group 10. Aromatic Compounds with [323]. Fluorinated Side-Chains The characteristic reaction of benzotrifluor- ides is electrophilic substitution of the benzene The first aromatic compound with a fluorinated ring; chlorination and nitration are commercially side-chain, benzotrifluoride [98-08-8], trifluoro- important. Chlorination of benzotrifluoride at methylbenzene, was synthesized in 1898 [314]. 65 C with FeCl3 as a catalyst yields 83 %

Table 21. Physical properties of benzotrifluorides

q q Compound CAS registry Empirical Mr bp, C d4 (q, C) nD (q, C) number formula

Benzotrifluoride [98-08-8]C7H5F3 146.11 102.03 1.188 (20) 1.4114 (25) 2-Chlorobenzotrifluoride [88-16-4]C7H4ClF3 180.56 152.5 1.367 (20) 1.4550 (20) 4-Chlorobenzotrifluoride [98-56-6]C7H4ClF3 180.56 140 1.35 (15) 1.4444 (25) 2,4-Dichlorobenzotrifluoride [320-60-5]C7H3Cl2F3 215.0 117 – 118 1.377 (20) 1.4802 (20) 1,3-Bis(trifluoromethyl)benzene [402-31-3]C8H4F6 214.11 116.1 1.379 (25) 1.3791 (20) 1,4-Bis(trifluoromethyl)benzene [433-19-2]C8H4F6 214.11 117.1 1.381 (25) 1.3792 (20) 3-Trifluoromethylbenzoyl fluoride [328-99-4]C8H4F4O 192.11 159 – 163 1.4350 (20) 476 Fluorine Compounds, Organic Vol. 15

3-chlorobenzotrifluoride [98-15-7] [324]; chlo- rination of 4-chlorobenzotrifluoride gives 3,4- dichlorobenzotrifluoride [328-84-7]. Nitration of benzotrifluoride results in a 6 : 3 : 91 mixture of 2-nitro- [384-22-5], 4-nitro- [402-54-0], and 3- This reaction can be carried out as a batch nitrobenzotrifluoride [98-46-4] [325]. Other process in autoclaves or continuously in a series commercially important nitrations are the con- of autoclaves [329] (Fig. 3) or tubular reactors version of 2-chlorobenzotrifluoride [88-16-4]to [330]. Typical conditions for the production of 2-chloro-5-nitrobenzotrifluoride [777-37-7] and benzotrifluoride are a temperature of 80 – the conversion of 4-chlorobenzotrifluoride to 110 C, pressure of 1.2 – 1.4 MPa, and a molar yield 99 % 4-chloro-3-nitrobenzotrifluoride ratio of HF : benzotrichloride of 4 : 1. A yield of [121-17-5] or 4-chloro-3,5-dinitrobenzotrifluor- 70 % is obtained within 3–4h[331]. In contin- ide [393-75-9] [326]. These derivatives are re- uous processing, a yield of over 90 % is obtained duced to amines or are further processed. in a nickel flow tube with a residence time of 1 h at 90 – 130 C and at 3 – 5 MPa [332]. Yields are increased by using additives such as hexam- 10.2. Production ethylenetetraamine [333] or by employing chlo- rine – fluorine exchange in the gas phase in the Benzotrifluorides are prepared on a laboratory presence of a transition metal – aluminum oxide scale by the reaction of aromatic compounds with catalyst [334]. Corrosion is reduced by lowering iodotrifluoromethane [315]; by the reaction of the reaction temperature (< 60 C) and adding aromatic carboxylic acids and their derivatives iron or iron compounds [335], [336]. with sulfur tetrafluoride [51–53]; or by chlo- This method is used to produce benzotrifluoride, rine – fluorine exchange in trichloromethyl aro- 2-chlorobenzotrifluoride, 4-chlorobenzotrifluor- matic compounds with metal fluorides [327]. ide, 2,4-dichlorobenzotrifluoride, 1,3-bis(trifluoro- In the commercial process, known since 1931, methyl)benzene, 1,4-bis(trifluoromethyl)benzene, chlorine is exchanged for fluorine with use of 3-(trifluoromethyl)benzoyl fluoride, and 4-(tri- anhydrous hydrogen fluoride in the presence or fluoromethyl)benzoyl fluoride [368-94-5] from the absence of catalyst [328]: corresponding trichloromethyl compounds.

Figure 3. Production of benzotrifluorides in a series of autoclaves [329] a) Reactor; b) Pressure distillation column; c) Separator; d) Product distillation column; e) Product storage tank Vol. 15 Fluorine Compounds, Organic 477

The trifluoromethyl group can also be intro- sant fluoxetine [54910-89-3], the muscle relaxant duced into aromatic compounds by the Friedel – flumetramide [7125-73-7], the appetite depres- Crafts reaction with carbon tetrachloride in the sants fenfluramine [458-24-2] and fludorex presence of hydrogen fluoride [337]. [15221-81-5], and the tranquilizers trifluproma- zine [146-54-3] and fluphenazine [69-23-8]. Bendroflumethiazide [73-48-3] is an effective diuretic and antihypertensive agent.

Pesticides. Benzotrifluorides are also im- portant in the production of pesticides [342]. The key intermediate, 4-chloro-3,5-dinitrobenzotri- fluoride [393-75-9], is obtained by dinitration of 4-chlorobenzotrifluoride. Reaction with second- 10.3. Uses ary amines gives trifluralin [1582-09-8], proflur- alin [26399-36-0], and benfluralin [1861-40-1]. Benzotrifluoride and 4-chlorobenzotrifluoride 4-Chlorobenzotrifluoride and 3,4-dichlo-roben- are key intermediates for the synthesis of dyes, zotrifluoride are intermediates for herbicides pharmaceuticals, and pesticides. with a diphenyl ether structure – fluorodifen [15457-05-3] and acifluorfen [50594-66-6] and Trifluoromethyl aromatic compounds Dyes. the insecticide fluvalinate [69409-94-5]. 3-Ami- were first used in dyes [4] and are still important nobenzotrifluoride [98-16-8] is obtained from intermediates for azo, anthraquinone, and triphe- benzotrifluoride by nitration and hydrogenation. nylmethane dyes. The strongly electronegative It is used to make the selective herbicide fluo- trifluoromethyl group improves color clarity and meturon [2164-17-2] or is used as a component of fastness to light and washing; it also shifts light the herbicide norflurazon [27314-13-2]. absorption to the visible and ultraviolet ranges. Some of these dye intermediates [338] for the production of anthraquinone and azo dyes (Naphtol AS, Hoechst AG) and azo pigments 11. Ring-Fluorinated Aromatic, are still used, especially for polyesters and poly- Heterocyclic, and Polycyclic amides. These compounds include 2-aminoben- Compounds zotrifluoride [88-17-5] for C.I. Pigment Yellow 154 [63661-02-9]; 3-amino-4-chlorobenzotri- The compounds discussed in this chapter contain fluoride [121-50-6] for C.I. Pigment Orange 60 one or more fluorine atoms that are directly [68399-99-5]; 3-(trifluoromethyl)benzoyl fluo- attached to aromatic, heterocyclic, or polycyclic ride for Indanthren Blue CLB [6492-78-0] rings. Unlike chlorination and bromination, (BASF) as well as 2-amino-5-chlorobenzotri- fluorination with elemental fluorine is rarely fluoride [445-03-4], 3,5-bis(trifluoromethyl)ani- employed for their production because its vio- line [328-74-5], and 3-amino-4-ethylsulfonyl- lence produces many side reactions (ring-open- benzotrifluoride [382-85-4]. ing, coupling, polymerization, and charring). Therefore, indirect methods are used, distribut- Pharmaceuticals. The trifluoromethyl sub- ing the reaction enthalpy over several controlla- stituent is highly lipophilic; it increases the lipid ble steps [318]. solubility of pharmaceuticals and thus acceler- Diazonium salts are suitable for introducing ates their absorption and transport in a living up to three fluorine atoms per ring. Chlorine – organism [339], [340]. In some cases, introduc- fluorine exchange (halogen exchange, Halex pro- tion of the CF3 group also increases drug effec- cess) with alkali – metal fluorides is suitable in tiveness and reduces undesirable side effects; cases where activating substituents are present. therefore, benzotrifluorides are used in the Ring-fluorinated aromatic, heterocyclic, and synthesis of many pharmaceuticals [341]. These polycyclic compounds are predominantly used include the analgesics flufenamic acid [530-78- as intermediates for pharmaceuticals, pesti- 9] and niflumic acid [4394-00-7], the antidepres- cides, dyes and other products. The exceptional 478 Fluorine Compounds, Organic Vol. 15 properties of fluorinated cyclic compounds (bio- The reactivity of fluorine in benzene deriva- activity spectrum, effectiveness, and solublity) tives depends on the nature of the other ring justify the higher production costs compared to substituents. Nucleophilic substitution occurs those of fluorine-free compounds. only where activating groups (e.g. nitro) are present in the ortho or para position. In other cases, e.g., with 1-bromo-4-fluorobenzene [460- 11.1. Mono- and Difluoroaromatic 00-4], the carbon – fluorine bond is stronger; Compounds hydrolysis gives 4-fluorophenol [371-41-5] [344], [345]. Research on ring-substituted aromatic fluorine compounds began in 1870. The fluorine atom attached to the benzene ring is strongly electro- 11.1.2. Production negative; it preferentially directs new substitu- ents into the para position and rarely, if ever, into Among the published processes for the produc- the ortho position [343]. Important aspects, es- tion of mono- or difluoroaromatic compounds, pecially for biological applications, are (1) the ring fluorination with dilute fluorine or fluorinat- influence of the strongly electronegative fluorine ing agents such as xenon difluoride [346–349] substituent on adjacent groups, (2) its participa- does not follow a clear course (i.e., without side tion in the resonance system of the aromatic reactions) and has no commercial value. Fluor- compound by returning electron density, and obenzene itself can be prepared by pyrolysis of (3) the simulation of hydrogen or hydroxy sub- chlorodifluoromethane or chlorotrifluoroethy- stituents that is due to the similarity in space lene in the presence of cyclodipentadiene at requirements and has led to the synthesis of a 300 – 800 C [350] and by anodic fluorination series of monofluoro aromatic enzyme inhibitors. of benzene with tetraethylammonium fluoride in The varying lability of the carbon – fluorine acetonitrile [351]. Promising methods are the bond in mono- and difluoro aromatic compounds decarbonylation of benzoyl fluorides in the pres- has been exploited to prepare indicators and ence of tris(triphenylphosphine)rhodium(I) chlo- analytical reagents, especially for biogenic and ride in boiling xylene [352] and the thermal metabolic studies. decarboxylation of aryl fluoroformates [353].

Diazotization. Aromatic compounds con- 11.1.1. Properties taining one or two fluorine substituents are pro- duced commercially by diazotization of aromatic Replacement of aromatic hydrogen by fluorine amines and decomposition of the resulting dia- has only a minor effect on boiling points. Density zonium fluorides [318], [354]. In one process, increases, whereas refractive index and surface aromatic amines are diazotized with dry sodium tension decrease. Physical constants are shown in nitrite in anhydrous hydrogen fluoride at 0 – Table 22. 20 C [355] (see Fig.4).

Table 22. Physical properties of ring-fluorinated aromatic compounds

q q Compound CAS registry Empirical Mr bp, C d4 (q, C) nD (q, C) number formula (101.3 kPa)

Fluorobenzene [462-06-6]C6H5F 96.1 84.7 1.083 (25) 1.4629 (25) 2-Fluorotoluene [95-52-3]C7H7F 110.13 113 – 114 1.003 (21) 1.4727 (20) 3-Fluorotoluene [352-70-5]C7H7F 110.13 115 0.991 (25) 1.4691 (20) 4-Fluorotoluene [352-32-9]C7H7F 110.13 116 0.991 (25) 1.4688 (20) 0 * 4,4 -Difluorodiphenylmethane [457-68-1]C13H10F2 204.22 263.5 1.145 (20) 1.5362 (20) 1,3-Difluorobenzene [372-18-9]C6H4F2 114.09 82 – 83 1.1572 (20) 1.4410 (20) 1,4-Difluorobenzene [540-36-3]C6H4F2 114.09 88 – 89 1.176 (20) 1.4421 (20) * At 100.5 kPa Vol. 15 Fluorine Compounds, Organic 479

Figure 4. Production of fluoroaromatics by the HF diazotization – dediazoniation method [354] a) Diazotation reactor; b) Dediazoniation vessel; c) Condenser; d) Separator; e) Distillation column; f) HF purification column; g) Product storage tank

The temperature is increased to 30 – 120 C, This thermal decomposition must be strictly and the formed diazonium fluorides decompose controlled, especially when nitro substituents are to form fluoroaromatic compounds. A yield of present, to avoid an explosion. Diazonium tetra- over 90 % of mono- and difluorinated com- fluoroborates usually decompose at a higher pounds is obtainable. Yields of ca. 81 % are temperature than the corresponding diazonium reported for batch operations on a 1-t scale. fluorides. The Balz – Schiemann process has In a continuous process the three exothermic rarely been used on a large scale because of the steps are controlled by separation; i.e., hydro- difficulties in handling diazonium tetrafluorobo- fluorination of the aromatic amine, diazotization, rates. However, it is convenient as a laboratory and thermal decomposition [356]. This permits process because it does not require specialized safe operation on a large scale. Diazotization apparatus. A plant of several 100 t/a has been with nitrosyl chloride [357] and nitrosyl fluo- reported [361]. ride – HF complexes [358] is also possible. Pro- A large number of fluoroaromatic compounds blems associated with these processes are hydro- have been produced by using the two diazotiza- gen fluoride recovery and waste gas treatment. tion routes described [327], [362]. Those of In another method (Balz – Schiemann reac- commercial interest include fluorobenzene from tion), water-insoluble diazonium fluoroborates aniline; 2-, 3-, and 4-fluorotoluene from the appro- are prepared by diazotization of aromatic amines priate toluidines; 4,40-difluorodiphenylmethane with sodium nitrite in the presence of 40 % from 4,40-diaminodiphenylmethane; 1,3-difluoro- fluoroboric acid or sodium or ammonium tetra- benzene from m-phenylenediamine; and 1,4-di- fluoroborate in HCl [327], [359]. After filtration fluorobenzene from p-phenylenediamine. the diazonium salts are dried and thermolyzed The reaction sequence of nitration, reduction, [360] (Fig. 5): diazotization, and thermal decomposition can be 480 Fluorine Compounds, Organic Vol. 15

Figure 5. Production of fluoroarmatics by the Balz – Schiemann method a) Stirred diazotization reactor; b) Storage for 50 % HBF4; c) Filter; d) Drier; e) Mixer; f) Dediazoniation reactor; g) Condenser; h) Separation column; i) Product distillation column; k) Product storage tank repeated to introduce up to four fluorine atoms into the benzene ring.

Chlorine – Fluorine Exchange. Of similar commercial importance to diazotization is the replacement of activated chlorine atoms with the aid of alkali-metal fluorides [318], [354]. The usual activating groups are ortho and para nitro, Phase-transfer catalysts are sometimes used cyano, and trifluoromethyl groups [363]. Apro- [364]. The effectiveness of the fluoride source tic – polar solvents are preferred, such as di- decreases in the order CsF > KF > NaF > LiF. methylformamide, dimethylacetamide, dimethyl In commercial batch or semicontinuous sulfoxide, N-methyl-2-pyrrolidone, and tetrahy- operations, the Halex process (Fig. 6), potassium drothiophene-1,1-dioxide (sulfolane). fluoride and the activated chloroaromatic compound

Figure 6. Flow sheet of the Halex process for the manufacture of fluoronitrobenzene [363] a) Reactor; b) Distillation column; c) Condenser; d) Drier; e) Product distillation column; f) Product storage tank; g) Condenser for off-gas Vol. 15 Fluorine Compounds, Organic 481 are thoroughly mixed (1 : 1) with a large volume of benzuron [35367-38-5] (made from 2,6-difluor- an aprotic solvent (dimethyl sulfoxide or sulfolane) obenzonitrile), the herbicides flamprop [58677- and are heated to 150 – 250 C [363], [365]. The 63-3] and fluoronitrofen [13738-63-1], and the reaction is 90 % complete within 48 h. Removal of fungicides nuarimol [63284-71-9] and flurimid KCl and distillation of the product present no [41205-21-4]. difficulty, but efficient solvent recovery is important 4,40-Difluorobenzophenone [345-92-6], a to reduce costs. starting material for aromatic polycondensates, Cost is also reduced by regenerating the potas- is produced by oxidation of 4,40-difluorodiphe- sium fluoride by treating the KCl with HF [366]. nylmethane, which is obtained by diazotization The Halex process has the clear advantage of of the corresponding diamine. 4,40-Difluoroben- readily accessible raw materials, simplicity of a zophenone undergoes polycondensation with hy- single-step procedure, and structural specificity. droquinone, yielding a polyetherether ketone Certain products are accessible in no other way. (PEEK) resin, a thermoplastic. 4-Fluoroaniline The following commercially important inter- [371-40-4], 4-fluorobenzaldehyde [459-57-4], mediates are obtained by the Halex process: 1- and 4-fluorobenzoic acid [456-22-4] are inter- fluoro-2-nitrobenzene [1493-27-2] and 1-fluoro- mediates for liquid crystal polymers [369]. 4-nitrobenzene [350-46-9] from the correspond- Aromatic compounds with reactive fluorine ing chloronitrobenzenes;1-chloro-2-fluoro-5-ni- substituents are used for the characterization of trobenzene [350-30-1] from 1,2-dichloro-4-ni- amino acids (Sanger’s reagent, 1-fluoro-2,4-di- trobenzene;1-chloro-4-fluoro-3-nitrobenzene nitrobenzene [70-34-8]), the immobilization of [345-18-6] from 1,4-dichloro-2-nitrobenzene;1- enzymes (4-fluoro-3-nitrophenylazide [28166- fluoro-2,4-dinitrobenzene [70-34-8]from1- 06-5]), and peptide cross-linkage (1,5-difluoro- chloro-2,4-dinitrobenzene;5-fluoro-2-nitroben- 2,4-dinitrobenzene [327-92-4]). zotrifluoride [393-09-9] from 5-chloro-2-nitro- Aromatic fluorine compounds have been de- benzotrifluoride [118-83-2]; 1,3-difluoro-4-ni- veloped for medical applications, such as 19F- trobenzene [446-35-5] from 1,3-dichloro-4-ni- magnetic resonance imaging (MRI) and in 18F- trobenzene; and 2,6-difluorobenzonitrile [1897- positron emission tomography (PET) [370]. 52-5] from 2,6-dichlorobenzonitrile. These inter- mediates are mostly used for substituted anilines and compounds with carbonyl and carboxy 11.2. Highly Fluorinated Aromatic functions. Compounds

Compounds in which an aromatic ring is substi- 11.1.3. Uses tuted by three to five fluorine atoms have little commercial importance. 1,2,4-Trifluoroben- Fluorobenzene, difluorobenzenes, and their de- zene [367-23-7], bp 88 C, and 1,3,5-trifluoro- rivatives are used widely in the synthesis of benzene [372-38-3], bp 75.5 C, are produced pharmaceuticals and pesticides, and as fine che- by the Balz – Schiemann reaction (see Section micals. Fluoroaromatics have played a special 11.1.2) from 2,4-difluoroaniline [367-25-9]and role in the development of drugs that act on the 3,5-difluoroaniline [372-39-4], respectively. central nervous system [367]. The increase in 1,3,5-Tricyano-2,4,6-trifluorobenzene [3638- lipid solubility due to fluorine atoms facilitates 97-9], mp 148 – 150 C, is used as an interme- the absorption and transport of drugs through the diate for pesticides; it is obtained by chlorine – blood – brain barrier into the central nervous fluorine exchange from 1,3,5-tricyano-2,4,6-tri- system. chlorobenzene [371]. Fluorobenzene derivatives are used in neuro- 1,2,3,5-Tetrafluorobenzene [2367-82-0], bp leptics such as haloperidol [52-86-8], tranquili- 83 C, is obtained by the Balz – Schiemann zers such as fluspirilene [1841-19-6], sedatives reaction from 2,3,5-trifluoroaniline [363-80-4], such as flurazepam [17617-23-1], and antide- and 1,2,4,5-tetrafluorobenzene [327-54-8], bp pressants such as fluroxamin [54739-18-3]. 90 C, from 2,4,5-trifluoroaniline [57491-45- Pesticidal [342] and fungicidal fluorobenzene 9]. 1,2,3,4-Tetrafluorobenzene [551-62-2], bp derivatives [368] include the insecticide diflu- 95 C, pentafluorobenzene [363-72-4], bp 482 Fluorine Compounds, Organic Vol. 15

85 C, and hexafluorobenzene are produced by The CoF2 formed in this reaction is fluorinated the CoF3 method (see Section 11.3). to CoF3 with elemental fluorine, and reused. The The Halex process (Section 11.1.2) is used organic products are heated with an alkali-metal commercially to produce 1,4-dicyano-2,3,5,6- hydroxide to form a mixture of polyfluorocyclo- tetrafluorobenzene [1835-49-0], mp 197 – hexenes and polyfluorocyclohexadienes. These 199 C, from the corresponding tetrachloro de- products are aromatized by passage over iron or rivative [372]. This compound is used as a iron compounds at 400 – 600 C to give hexa- monomer for thermostable polymers. fluorobenzene, pentafluorobenzene, and tetra- fluorobenzenes. Octafluorotoluene [434-64-0] and the three perfluoroxylenes are also obtained 11.3. Perhaloaromatic Compounds by this method. The disadvantages of this process are the Hexafluorobenzene [392-56-3], bp 80.3 C, has technological difficulties and the low utilization been thoroughly investigated [373]. Nucleophilic of fluorine, of which a large part is converted to substitution produces pentafluoroaromatic com- hydrogen fluoride and alkali-metal fluorides. As pounds such as a consequence, aromatic fluorine compounds containing other halogens are currently produced bromopentafluorobenzene [344-04-7], bp by the Halex method (Section 11.1.2). Reaction 135.6 C of hexachlorobenzene [365] with potassium fluo- pentafluorophenol [771-56-2], bp 117 – 118 C ride at 450 C and 1.03 MPa gives a yield of pentafluoroaniline [771-60-8], bp 153 C 21 % hexafluorobenzene together with chloro- pentafluorobenzene [771-61-9], bp 143 C pentafluorobenzene [344-07-0] (20 %), 1,3-di- pentafluorotoluene [771-56-2], bp 117 C chloro-2,4,5,6-tetrafluorobenzene [1198-61-4] pentafluorobenzaldehyde [653-37-2], bp 164 – (14 %), and 1,3,5-trichloro-2,4,6-trifluoroben- 166 C zene [319-88-0] (12 %). pentafluorobenzoic acid [602-94-8], bp 220 C

Production. Hexafluorobenzene was first produced in 1955 by pyrolysis of tribromofluor- The yield of hexafluorobenzene can be in- omethane [353-54-8] in a platinum tube at creased by recycling the other products for fur- 640 C under atmospheric pressure [374]:, ther reaction with potassium fluoride. A yield of 42 % hexafluorobenzene is obtained from chlor- opentafluorobenzene with the more reactive, but more expensive, cesium fluoride [377]. Of greater commercial interest is the pyrolysis Hexachlorobenzene reacts with KF in aprotic of an equimolar mixture of dichlorofluoro- solvents such as dimethylformamide, dimethyl sulfoxide, -methyl-2-pyrrolidone, and sulfo- methane [75-43-40] and chlorofluoromethane N [ ] at 600 – 800 C [375]: lane to give not hexafluorobenzene, but the 593-70-4 above-mentioned mixed products. The reaction temperature is 150 – 250 C and the residence time 5 – 36 h. Detailed discussions of the pro- For many years a commercial multistep pro- cess are given in [363], [365]. cess employed CoF3 as the fluorinating agent [376]. For example, at 150 C benzene gives a Uses. Hexafluorobenzene has been investi- mixture of cyclohexanes containing 8 – 11 fluo- gated as an inhalation anesthetic in veterinary rine atoms. medicine [378] and as a working fluid in Ran- kine-cycle engines for temperatures above 350 C [379]. Derivatives such as pentafluoro- benzaldehyde or pentafluorophenyl dimethylsi- lyl ether are used in the chromatographic analysis of steroids [380] and catecholamines [381], and as intermediates for the production of liquid Vol. 15 Fluorine Compounds, Organic 483 crystal polymers [382]. Pentafluorophenoxy per- mixtures with hexafluorobenzene is used as the fluorovinyl ethers are cross-linking comonomers working fluid in Rankine-cycle engines up to for perfluorinated elastomers [383]. 382 C [379].

11.4. Fluorinated Heterocyclic and 11.4.2. Trifluoromethylpyridines Polycyclic Compounds 2-Trifluoromethyl- [368-48-9], 3-trifluoro- Fluorinated pyridines, pyrimidines, and triazines methyl- [3796-23-4], and 4-trifluoromethylpyr- are heterocycles with commercial importance. idine [3796-24-5] can be obtained by the reaction Only some representative polycyclic fluorine of picolinic, nicotinic, or isonicotinic acid, re- compounds are discussed as examples. spectively, with sulfur tetrafluoride [394]. Com- mercial processes use side-chain chlorination of the methylpyridines followed by chlorine – fluo- 11.4.1. Ring-Fluorinated Pyridines rine exchange with antimony chlorofluorides or anhydrous hydrogen fluoride [395]. 2-Chloro-5- Introduction of fluorine into the pyridine ring trifluoromethylpyridine, bp 190 C, is produced reduces the basicity of the latter [384]. 2-Fluor- commercially from 2-chloro-5-trichloromethyl- opyridine [372-48-5], bp 126 C (100.4 kPa), has pyridine and hydrogen fluoride at 180 – 200 C a labile fluorine substituent. It is produced in 74 % and at a pressure of 3 – 4.5 MPa. It is an inter- yield by reaction of 2-chloropyridine with potas- mediate for the synthesis of the selective herbi- sium bifluoride at 315 C in 4 h [385]. 3-Fluor- cide fluazifop [69335-91-7], [396]. opyridine [372-47-4], bp 105 – 107 C (100.3 kPa), is produced in 50 % yield from 3- aminopyridine using the Balz – Schiemann pro- 11.4.3. Fluoropyrimidines cess (see Diazotization). 4-Fluoropyridine [694- 52-0], bp 108 C (100 kPa) is produced in 54 % Certain fluoropyrimidines have gained commer- yield by diazotization of 4-aminopyridine in an- cial importance [397]. 5-Fluoropyrimidines are hydrous hydrogen fluoride [386]. employed in cancer chemotherapy; their bio- 2,4-Difluoropyridine [34941-90-7], bp 104 – chemistry and pharmacology have been inten- 105 C, is obtained by the Halex process (see sively studied [398]. 5-Fluorouracil [51-21-8]is Chlorine – Fluorine Exchange) from 2,4-di- obtained in a 80 – 92 % yield by the fluorination chloropyridine and potassium fluoride in sulfo- of 2,4-dihydroxypyrimidine with fluorine or tri- lane [387]. 2,6-Difluoropyridine [1513-65-1], bp fluoromethyl hypofluorite [399], [400]. 124.5 C (99.1 kPa), is obtained by the reaction 5-Chloro-2,4,6-trifluoropyrimidine [697-83- of 2,6-dichloropyridine with potassium fluoride 6], bp 114.5 C (100 kPa), is produced commer- in the absence of solvent. The yield is 80 % after cially from 2,4,5,6-tetrachloropyrimidine by 18 h at 400 C [388]. chlorine – fluorine exchange, using sodium fluo- For pentafluoropyridine [700-16-3], bp 83 C, ride at 300 C [401] or anhydrous hydrogen the preferred method is the reaction of pentachlor- fluoride in the liquid phase [402] or gas phase opyridine with KF at 480 – 500 C; the yield is [403]. 83 % [389]. Nucleophilic substitution reactions The 5-chloro-2,4-difluoropyrimidinyl radical have been thoroughly investigated [390]. acts as the reactive group in reactive dyes [397] for cellulose and cotton fibers such as Levafix EA Uses. Fluoropyridines are intermediates for (Bayer) and Drimarene K (Sandoz) and for wool, pesticides. For example, 2-fluoro-4-hydroxypyr- e.g., Verofix (Bayer) and Drimalene (Sandoz). idine [22282-69-5] is a precursor of 2-fluoro-3,5- dihalo-4-hydroxypyridine herbicides [391]; 2- fluoro-6-hydroxypyridine [55758-32-2] is used 11.4.4. Fluorotriazines for insecticides and nematocides [392] and vari- ous derivatives of fluorinated pentahalogenpyr- 2,4,6-Trifluoro-1,3,5-triazine [675-14-9], bp idine herbicides [393]. Pentafluoropyridine in 72.4 C (101.7 kPa), is produced commercially 484 Fluorine Compounds, Organic Vol. 15 from 2,4,6-trichloro-1,3,5-triazine (cyanuric dyes. The main producers in Western Europe are chloride) with either anhydrous hydrogen fluo- Bayer AG, Ciba-Geigy, ICI, and Sandoz. ride [404] or sodium fluoride in sulfolane [405]. Fluorobenzene and its derivatives are pro- It is used to manufacture reactive dyes by reac- duced in Western Europe by AlliedSignal – tion between one or two fluorine substituents Riedel-de-Ha€en (production capacity 1600 t/a), with amino groups of chromophores; the remain- Zeneca (2000 – 2500 t/a), Rhoˆne-Poulenc ing fluorine binds to the fiber [406]. The reactive (1000 t/a), MitEni (1000 t/a) in Europe, DuPont intermediates can be synthesized e.g., from the (1400 t/a), Mallinckrodt (1200 t/a) in the USA corresponding 6-substituted 2,4-dichlorotria- and Asahi Glass (1000 t/a) in Japan. Fluoroni- zines and an alkali-metal fluoride or by reaction trobenzenes and fluoroanilines are produced by of cyanuric fluoride with anilines or phenols in the Halex process by Hoechst, MitEni, Rhoˆne- organic solvents [406], [407]. Like the pyrimi- Poulenc, Asahi Glass, and others. The total ca- dine reactive dyes, the fluorotriazines are used on pacity for fluoroaromatic intermediates is esti- cellulose, polyesters, polyamides, and wool mated to be several thousand tons per year. [397]. See also ! Reactive Dyes. 13. Toxicology and Occupational 11.4.5. Polycyclic Fluoroaromatic Health Compounds With few exceptions, organic fluorine com- Polycyclic fluoroaromatic compounds are pounds are physiologically inert and display used as intermediates for the production of insignificant toxicity. This is a consequence of pharmaceuticals. the chemical stability of the carbon – fluorine 4-Fluoro- [324-74-3] and 4,40-difluorobiphe- bond and the increased stability of hydrogen and nyl [398-23-2] are obtained by diazotization halogen bonds attached to a fluorinated carbon from the corresponding amines in yields of up atom. Low toxicity is an important factor in many to 80 % [408]. Other biphenyl derivatives are applications of these compounds. prepared from fluorobenzenes. The analgesic The difference in toxicity between a chloro or diflunisal [22494-42-4] is produced from 2,4- bromo compound and the corresponding fluoro difluoroaniline [367-25-9] by diazotization and compound is often striking. Thus, carbon tetra- coupling with salicylic acid. The anti-inflamma- chloride [56-23-5] is a powerful liver and kidney tory drugsflurbiprofen [5104-49-4] and fluprofen toxin and a weak carcinogen, as reflected in its [17692-38-5] are prepared from 2-fluoroaniline TLV of 5 ppm. However, the product obtained [348-54-9]. by replacing one chlorine atom with fluorine, The anti-inflammatory drug sulindac [38194- trichlorofluoromethane [75-69-4], has no ad- 50-2] is a monofluorinated indole-3-acetic acid. verse effects on the liver, kidney, or other organs, and no carcinogenic effects on animals exposed to high concentrations for a lifetime; the TLV is 12. Economic Aspects 1000 ppm. Another example is the chemical warfare agent mustard gas, S(CH2CH2Cl)2 The compounds discussed in Chapters 10 and 11 [505-60-2], which is a strong alkylating agent are not produced in large quantities and often and notorious vesicant. The fluoro analog, bis(2- command high prices. 4-Chlorobenzotrifluoride, fluoroethyl) sulfide [373-25-1], is chemically 3,4-dichlorobenzotrifluoride, 3-trifluoromethyl- and physiologically inert, with no vesicant prop- phenyl isocyanate, and benzotrifluoride are pro- erties [409]. duced in the United States by Occidental Chemi- The few highly toxic organofluorine com- cal, in Western Europe by Hoechst, Rhoˆne-Pou- pounds usually have easily replaceable fluorine lenc, MitEni and Dow-Elanco, and in Japan by atoms. Examples are diisopropyl fluoropho- Daikin. The worldwide production capacity is ca. sphate [55-91-4], a potent cholinesterase inhibi- 35 000 – 40 000 t/a. tor, and perfluoroisobutylene [382-21-8], which Heterocyclic fluorine compounds have eco- causes pulmonary edema at low concentrations. nomic importance in the production of reactive Sodium fluoroacetate [62-74-8], a potent roden- Vol. 15 Fluorine Compounds, Organic 485 ticide, is an exception; it does not liberate fluo- ly more toxic, whereas 1,2-dichloro-1,1,2,2-tet- rine, but interferes with metabolism by mimick- rafluoroethane [76-14-2] is slightly less toxic. ing acetic acid. However, for all three a TLV of 1000 ppm is judged to provide an adequate margin of safety. On the other hand, 1,1,1,2-tetrachloro-2,2-di- 13.1. Fluorinated Alkanes fluoroethane [76-11-9] and 1,1,2,2-tetrachloro- 1,2-difluoroethane [76-12-0] cause liver and lung Fluoroalkanes [410], [411]. Perfluoroalk- damage to rats subjected to repeated exposure at anes have very low toxicity. Thus, rats exposed 1000 ppm; therefore, a TLV of 500 ppm is re- to an 80 : 20 mixture of perfluorocyclobutane commended for these compounds. These data [115-25-3] and oxygen for 4 h survived with no indicate that the toxicity of chlorofluorocarbons ill effects. Likewise, no ill effects were seen in tends to increase with the chlorine : fluorine ratio four species of animals exposed to a 10 % con- and the number of carbon atoms. centration in air 6 h/d for 90 d. Partially fluori- Although the toxicity of most chlorofluor- nated alkanes have similarly low toxicity, as oalkanes bearing hydrogen (chlorofluorohydro- shown by similar experiments with difluoro- carbons) is also low, it tends to be higher than that methane [75-10-5] and1,1-difluoroethane [75- of the closely related chlorofluorocarbons. The 37-6]. difference is usually slight, as in the case of 2- chloro-1,1,1,2-tetrafluoroethane [2837-89-0], Chlorofluoroalkanes are more toxic than which is a slightly stronger cardiac sensitizer the corresponding fluoroalkanes; nevertheless, than 1,2-dichloro-1,1,2,2-tetrafluoroethane, but most chlorofluoroalkanes have low toxicity is otherwise similar to it in toxic properties. [410–412]. High concentrations (10 – 50 % in Chlorodifluoromethane [75-45-6] is similar in air) of many of them, like lower concentrations of toxicity to dichlorodifluoromethane in most re- many hydrocarbon and chlorohydrocarbon sol- spects, and has the same TLV of 1000 ppm. At vents, can cause cardiac sensitization, i.e., sen- 50 000 ppm it has a weak carcinogenic effect in sitization of the heart to the body’s adrenalin. male rats, but not at lower concentrations or in This can lead to cardiac arrhythmia (heartbeat mice or female rats; therefore, this is considered irregularity) and sometimes cardiac arrest. of no practical significance [415]. Deaths have been caused by ‘‘aerosol sniffing’’. The toxicity of dichlorofluoromethane [75- The toxicity of dichlorodifluoromethane [75- 43-4] is more like that of chloroform than of 71-8] has been thoroughly investigated. Rats dichlorodifluoromethane or chlorotrifluoro- survived a 6-h exposure to an 80 % mixture with methane [75-72-9], especially with respect to oxygen. Five species of animals continuously injury on repeated exposure; its TLV, 10 ppm, exposed to 810 ppm for 90 d showed no effects is low for a chlorofluoroalkane. except for slight liver damage in guinea pigs. Rats and dogs showed no significant health ef- Bromofluoroalkanes, some of which are fects when fed a diet containing 0.3 % for 2 years. fire extinguishing agents and anesthetics, are Teratogenic and reproductive tests in rats were more toxic than the corresponding chlorofluor- also negative. Repeated exposure caused little or oalkanes, but generally are low in toxicity com- no irritation to rat skin or the rabbit eye. In a pared to other fire extinguishing agents and screening test, dogs injected with adrenalin anesthetics [409], [413]. Trifluorobromo- showed cardiac sensitization on exposure to methane [75-63-8] produced no adverse effects 50 000 ppm in air, but not to 25 000. On the on dogs and rats exposed to 23 000 ppm 6 h/d, basis of animal data and human experience, a 5 d/week, for 18 weeks; its TLV is 1000 ppm TLV of 1000 ppm has been selected to provide [413]. an ample margin of safety against cardiac sensi- tization and other injury [413]. The MAK is also 1000 ppm [414]. 13.2. Fluorinated Olefins Compared to dichlorodifluoromethane, tri- chlorofluoromethane [75-69-4] and 1,1,2-tri- Most fluorinated olefins have halogen atoms of chloro-1,2,2-trifluoroethane [76-13-1] are slight- low reactivity and a correspondingly low-to- 486 Fluorine Compounds, Organic Vol. 15

Table 23. Toxicities of fluorinated olefins* fluoroacetone and three fully halogenated chlor- ofluoroketones indicated moderate acute toxicity Compound CAS Lethal conc., registry no. ppm [416].

Vinyl fluoride [75-02-5] > 800 000 (ALC)** Vinylidene fluoride [75-38-7] > 800 000 (ALC)** Tetrafluoroethylene [116-14-3] 40 000 (LC50) 13.5. Fluorinated Carboxylic Acids Hexafluoropropene [116-15-4] 3 000 (LC50) Chlorotrifluoroethylene [79-38-9] 1 000 (LC50) Fluoroacetic acid [144-49-0] is highly toxic to * Inhalation by rats, 4-h exposure. mammals; its sodium salt is an effective, but ** Approximate lethal concentration. indiscriminate, rodenticide; in rats the LD50 of the salt is only 1.7 mg/kg [413]. In contrast, moderate toxicity [409], [412]. The toxicities of difluoroacetic acid [381-73-7] and perfluoroalk- the five most common members of the class, anoic acids have low acute toxicity. typical in these respects, are shown in Table 23. The unusually high toxicity of fluoroacetic In perfluoroisobutylene and 2,3-dichloro- acid compared to the more highly fluorinated 1,1,1,4,4,4-hexafluoro-2-butene [303-04-8], ha- acids is due to its unique ability to interfere logens are readily displaced by nucleophilic with the citric acid cycle, the oxidation path- reactants; thus, these two compounds exhibit way used for energy production from amino high acute toxicity. Perfluoroisobutene, with a acids, fatty acids, and carbohydrates. Fluoroa- LC50 of 0.5 ppm, acts much like phosgene in cetic acid enters the cycle at the same site as causing death by pulmonary edema. However, acetic acid and is converted to fluorocitric acid perfluoroisobutene is ca. 10 times as toxic as [387-89-1] analogously to the conversion of phosgene, so exposure to it must be carefully acetic acid to citric acid. The fluorocitric acid avoided. Pyrolysis of tetrafluoroethylene or its inhibits aconitase, a key enzyme for the break- polymers above 400 C is one of its sources. down of citric acid, with the result that the citric acid concentration soon rises to lethal levels [417]. 13.3. Fluorinated Alcohols Substances that yield fluoroacetic acid on biochemical oxidation, such as straight-chain, 2-Fluoroethanol [371-62-0] has a high acute even-numbered, w-fluoro alcohols or alkanoic toxicity (LD50 10 mg/kg), a consequence of its acids, are also very toxic. ready biological oxidation to fluoroacetic acid (see Section 13.6). Thus, contact with the skin and inhalation of vapors must be avoided. The di- 13.6. Other Classes and trifluoroethanols ([359-13-7] and [75-89-8], respectively) have relatively low acute toxicity, Simple perfluoroethers, and the oily oligomers of similar to the corresponding acetic acids [412]. hexafluoropropylene oxide with modified end The acute toxicity of 1,1,1,3,3,3-hexafluoro-2- groups, have the low toxicity expected from their propanol [920-66-1] is also low, but the sub- chemical inertness. Hexafluoropropylene oxide stance is a strong skin and eye irritant. itself, a reactive substance, is moderately toxic to rats (4-h LC50, 3700 ppm) [418]. Several partial- ly fluorinated ethers are used as anesthetics, e.g., 13.4. Fluorinated Ketones Enflurane [13838-16-9], F2CHOCF2CHFCl, and Methoxyflurane [76-38-0], CH3OCF2CHCl2. In 90-d inhalation studies in animals, hexafluor- Their toxicity is low compared to that of most oacetone [684-16-2] caused severe damage to anesthetics (! Anesthetics, General). kidneys and other organs at 12 ppm, moderate Perfluorinated tertiary aliphatic amines are damage at 1 ppm, and no damage at 0.1 ppm. inert both chemically and biologically. This is Repeated skin exposure led to testicular damage illustrated by perfluorotripropylamine [338-83- in rats. These data and plant experience led to 0]; in emulsion with perfluorodecalin [306-94-5], selection of a TLV of 0.1 ppm, with a warning it has shown promise as a blood substitute in against skin exposure [413]. Studies of hexa- clinical trials [419]. Vol. 15 Fluorine Compounds, Organic 487

Fluorine substituents usually have little effect 19 R. E. Banks, J. C. Tatlow, J. Fluorine Chem. 33 (1986) on the toxicity of aromatic compounds, whether 285 – 286. monocyclic, polycyclic or heterocyclic [416]. 20 R. E. Banks, J. C. Tatlow, in R. E. Banks, B. E. Smart, J. C. Tatlow (eds.): Organofluorine Chemistry, Principles and Commercial Applications, Plenum Press, New York 1994, p. 1. References 21 R. E. Banks, J. C. Tatlow, J. Fluorine Chem. 33 (1986) 71 – 108. 22 T. Midgley, A. L. Henne, Ind. Eng. Chem. 22 (1930) 542; General References T. Midgley, (1937) 239. 1 , , pp. 1 – 502. Ind. Eng. Chem. 29 Houben-Weyl 5/3 23 H. Goldwhite, (1986) 109. 2 , , 829 – 962. J. Fluorine Chem. 33 Kirk-Othmer 10 24 W. A. Sheppard, C. M. Sharts: 3 R. C. Downing, F. W. Mader, T. W. Tomkowik: Organic Fluorine Chem- , W. A. Benjamin Inc., New York 1969. ‘‘Fluorocarbons’’ in J. J. McKetta, istry Encyclopedia of 25 A. Haas, M. R. C. Gerstenberger, , vol. 23, Marcel Dek- Angew. Chem. 93 Chemical Processing and Design (1981) 659; (1981) 647. ker, New York 1985, pp. 216 – 269. Angew. Chem. Int. Ed. Engl. 20 26 R. J. Lagow, J. L. Margrave, 4 O. Scherer: ‘‘Technische Organische Fluorverbindungen’’ Prog. Inorg. Chem. 26 (1979) 161. in , vol. 14, Springer Verlag, Topics in Current Chem. 27 R. J. Lagow, (1986) 321. Berlin–Heidelberg–NewYork1970,pp.127–234. J. Fluorine Chem. 33 28 W. Bockemuller,€ (1933) 5 R. E. Banks, D. W. A. Sharp, J. C. Tatlow: Justus Liebigs Ann. Chem. 506 Fluorine, The 20; W. T. Miller, (1940) 341. , Elsevier Sequoia, J. Am. Chem. Soc. 62 First Hundred Years (1886 – 1986) 29 G. H. Cady, , (1947) , 290. R. N. Lausanne – New York 1986; et al. Ind. Eng. Chem. 39 J. Fluorine Chem. 33 Haszeldine, F. Smith, 1950, 2689 – 94, (1986) 1 – 399. J. Chem. Soc. 2787 – 89. 6 R. E. Banks (ed.): Organofluorine Chemicals and their 30 J. L. Adcock, K. Horita, E. B. Renk, , Ellis Horwood Ltd., Chichester J. Am. Chem. Soc. Industrial Applications (1981) 371. J. L. Adcock, 1979. 103 J. Fluorine Chem. 33 (1986) 327. 7 R. E. Banks (ed.): Preparation, Properties and Indus- 31 Allied, EP 0 032 210, 1984 (H. R. Nykka, J. B. Hino, R. , Ellis trial Applications of Organofluorine Compounds E. Eibeck, J. I. Braumen); EP-A 0 031 519, 1980 (H. R. Horwood Ltd. & Wiley Halsted Press, New York – Nykko, J. B. Hino, R. E. Eibeck, M. A. Robinson). Brisbane – Chichester – Toronto 1982. 32 E. A. Tyczkowski, L. A. Bigelow, 8 M. Sittig: ‘‘Fluorinated Hydrocarbons and Polymers,’’ J. Am. Chem. Soc. 77 (1955) 3007. A. F. Maxwell, F. E. Detoro, L. A. No. 22, Noyes Develop- Chemical Process Monograph Bigelow, (1960) 5287. ment Corp., Park Ridge N.J. 1966. J. Am. Chem. Soc. 82 33 M. Stacey, J. C. Tatlow in [11], vol. 1, pp. 166 – 188. 9 Process Economics Program (PEP) Report No. 166: 34 T. Abe, S. Nagase in [7], pp. 19 – 43. , SRI International, Menlo Park Fluorinated Polymers 35Y.W.Alsmeyer,W.V.Childs,R.M.Flynn,J.C. Ca. 1983. SchmeltzerinR.E.Banks,B.E.Smart,J.C.Tatlow(eds.): 10 J. H. Simons (ed.): , vols. 1 – 5, Fluorine Chemistry , Principles and Commercial Academic Press, New York 1950–1964. Organofluorine Chemistry Applications, Plenum Press, New York 1994, p. 121. 11 M. Stacey, J. C. Tatlow, A. G. Sharpe (eds.): Advances in 36 G. P. Gambaretto, , (1985) , vols. 1 – 7, Butterworths, London et al. J. Fluorine Chem. 27 Fluorine Chemistry 149. 1960–1973. 37 H. M. Fox, F. N. Ruehlen, W. V. Childs, 12 P. Tarrant (ed.): , vols. 1 – J. Electrochem. Fluorine Chemistry Reviews (1971) 1246. 8, Dekker, New York 1967–1977. Soc. 118 38 Phillips Petroleum Co., US 3 511 760, 1967 (H. M. Fox, 13 R. E. Banks, M. G. Barlow (eds.): Fluorocarbons and F. N. Ruehlen); US 3 686 082, 1970 (F. N. Ruehlen); , vols. 1 – 3, The Chemical Society, Related Chemistry US 3 709 800, 1971 (H. M. Fox); US 3 882 001, 1973 London 1971–1976. (K. L. Mills). 14 H. J. Emeleus, J. C. Tatlow (eds.): . J. Fluorine Chem 39 W. V. Childs in ‘‘Technique of Electroorganic Synthe- Elsevier Sequoia S.A., Lausanne. sis,’’ in A. Weissberger (ed.): , 15 Chemical Abstracts Selects(CAS): Techniques of Chemistry Organofluorine vol. 5, J. Wiley & Sons, New York 1982, ‘‘Chapter 7’’. , American Chemical Society. Chemistry 40 W. V. Childs, L. Christensen, F. W. Klink, C. F. Kolpin in H. Lund, M. M. Baizer (eds.): Organic Electrochem- Specific References , 3rd ed., Marcel Dekker, New York 1981, p. 1103. 16 M. Hudlicky, (1986) 302. istry J. Fluorine Chem. 33 41 A. K. Barbour, L. J. Belf, M. W. Buxton in [11], vol. 3, 17 R. E. Banks (ed.): Organofluorine Chemicals and their pp. 181 – 270. , Ellis Horwood Ltd., Chichester Industrial Applications 42 Kinetic Chemicals Inc., DE 552 919, 1930. 1979. 43 O. Scherer in [4], vol. 14, p. 136. 18 R. E. Banks, B. E. Smart, J. C. Tatlow (eds.): Organo- 44 Hoechst, DE 1 000 798, 1952 (O. Scherer, H. Kuhn,€ E. fluorine Chemistry, Principles and Commercial Appli- Forche). cations, Plenum Press, New York 1994. 488 Fluorine Compounds, Organic Vol. 15

45 Hoechst, GB 1 025 759, 1963 (O. Scherer J. Korinth, P. 85 A. J. Woytek, J. Fluorine Chem. 33 (1986) 331. Frisch). 86 D. S. L. Slinn, S. W. Green in [7], pp. 45 – 82. 46 J. M. Hamilton, Jr. in [11], vol. 3, pp. 117 – 180. 87 M. LeBlanc, J. G. Riess in [7], pp. 83 – 138. 47 L. Dolby-Glover, Chem. Ind. (London) 1986, 518 – 523. 88 M. J. Molina, F. S. Rowland, Nature 249 (1974) 810. 48 O. Paleta in [11], vol. 8, pp. 39 – 71. 89 R. T. Watson, M. A. Geller, R. S. Stolarski, R. F. 49 Hoechst, EU 634 383, 1994 (R. Franz, G. Siegemund). Hampson: Processes That Control Ozone and Other 50 H. Suschitzky in [11], vol. 4, pp. 1 – 30. Climatically Important Trace Gases, NASA Reference 51G.A.Boswell,Jr.,W.C.Ripka,R.M.Scribner,C.W. Publication 1162, NASA, Washington 1986. Tullock in Wm. G. Dauben et al. (eds.): Organic Reactions, 90 J. K. Hammitt, et al.: Product Uses and Market Trends vol. 21, J. Wiley & Sons, New York 1974, pp. 1 – 124. for Potential Ozone Depleting Substances 1985 – 2000, 52 Ch.-L. J. Wang in A. S. Kende et al. (eds.): Organic (R-3386-EPA), Rand Corp., Santa Monica 1986. Reactions, vol. 34, J. Wiley & Sons, New York 1985, 91 E. R. Larsen in [12], vol. 3, p. 1. pp. 319 – 400. 92 Hoechst AG, Frigen, Handbuch fur€ K€alte- und Klima- 53 Y. A. Fialkov, L. M. Yagupolski in I. L. Knunyants, G. technik, 1969. G. Yakobson (eds.): Syntheses of Fluoroorganic Com- 93 BIOS Final Report Nr. 112, I.G. Werke Hoechst (1945). pounds, Springer Verlag, Berlin – Heidelberg – New 94 VEB-Werk Nunchritz, DD 215014, 1983 (I. Lehms, R. York – Tokyo 1985, pp. 233 – 289. Kaden, D. Mross, D. Hass). 54 C. M. Sharts, W. A. Sheppard in [51], pp. 125 – 406. 95 M. Vecchio, Hydrocarbon Process. 49 (1970) 116. 55 R. Filler, Jsr. J. Chem. 17 (1978) 71. 96 M. Vecchio, Hydrocarbon Process. 52 (1973) 97. 56 D. Hebel, O. Lerman, S. Rozen, J. Fluorine Chem. 30 97 Montecatini Edison S.p.A., US 3 442 962, 1966 (M. (1985) 141. Vecchio, L. Lodi). 57 R. Perry, J. Fluorine Chem. 33 (1986) 293. 98 A. J. Rudge, Chem. Ind. (London) 1955, 452 – 461. 58 R. Fields, J. Fluorine Chem. 33 (1986) 287. 99 ICI, GB 633 678, 1947 (H. R. Leech, R. L. Burnett). 59 J. M. Hamilton in [11], p. 125, vol. 3. 100 Occidental Chemical, EP 140 385, 1985 (B. F. Daniels). 60 PCR Research Chemicals Catalogue (1990/91), PCR, 101 Occidental Chemical, US 4 849 556, 1990 (B. F. Da- Inc., Gainesville, FL 1990, p. 176. niels, D. J. Olsen). 61 P. P. Barthelemy, A. Leroy in: Proceedings of the 102 W. T. Miller, Jr., et al., Ind. Eng. Chem. 39 (1947) 333 – UTECH 96 Conference, Den Haag 1996, p. 404. 337. 62 T. J. Brice in [10], vol. 1, p. 423. 103 E. A. Belmore et al., Ind. Eng. Chem. 39 (1947) 338 – 63 T. M. Reed III in [10], vol. 5, p. 133. 342. 64 S. W. Green et al. in [18], p. 89. 104 Occidental Chem. Corp., EP-A 93579, 93580, 1982 (M. 65 Halocarbon, DE 2 644 594, 1975 (L. L. Ferstandig). S. Saran). 66 Allied, US 3 644 545, 1986; ICI, US 2 452 975, 1948. 105 L. Scheichl, VFDB Z. 3 (1954) 37. 67 Dow, GB 805 503, 1958 (R. P. Ruh, R. A. Davis). 106 Hoechst, DE-OS 1 155 104, 1960 (O. Scherer, H. Kuhn,€ 68 ICI, US 4 129 603, 1979 (S. L. Bell). G. Horlein,€ K. H. Grafen); DE-OS 3 046 330, 1980 (H. 69 DuPont, US 3 258 500, 1966. Bock, J. Mintzer, J. Wittmann, J. Russow). 70 C. Gervasutti, L. Marangoni, W. Marra, J. Fluorine 107 Hoechst, DE-OS 1 168 404, 1962 (O. Scherer, H. Kuhn,€ Chem. 19 (1981/82) 1. G. Horlein).€ 71 Asahi Glass, JP Appl. 1–319 443, 1989 (Y. Furutaka, H. 108 ICI, GB 767 779, 1954 (C. W. Suckling, J. Raventos). Aoyama, Y. Homoto). 109 Houben-Weyl, 5/4, 51 – 55, 116 – 117. 72 R. D. Fowler et al., Ind. Eng. Chem. 39 (1947) 292, 319. 110 DuPont, US 2 729 687, 1951 (J. D. Sterling). 73 A. K. Barbour et al., J. Appl. Chem. 2 (1952) 127. 111 Daikin Kogyo KK, JP-Kokai 85 184 033, 1984 74 J. M. Tedder in [11], vol. 2, p. 104. (Y. Furutaka, T. Nakada). 75 DuPont, US 2 458 551, 1947 (A. F. Benning, J. D. Park, 112 Chem. Eng. News 53 (1975) no. 36, 18. S. E. Krahler). 113 D. F. Halpern in R. E. Banks, B. E. Smart, J. C. Tatlow 76 A. J. Woytek in [57], p. 331. (eds.): Organofluorine Chemistry, Principles and Com- 77 Asahi Glass, JP 5 841 829, 1984 (S. Fukui, H. Yoneda). mercial Applications, Plenum Press, New York 1994, 78 Daikin Kogyo, JP 6 077 983, 1985. p. 543. 79 Showa Denka, JP 6 081 134, 1985. 114 DuPont, US 3 145 222, 1961 (N. O. Brace). 80 DuPont, US 2 404 374, 1943 (J. Harmon). 115 R. N. Haszeldine, J. Chem. Soc. 1949, 2856; J. Chem. 81 The National Smelting Comp., DE-OS 1 205 533, 1962 Soc. 1953, 3761. (J. C. Tatlow, P. L. Coe). 116 DuPont, US 3 234 294, 1962 (R. E. Parsons); DE-OS 82 R. L. Powell, J. H. Steven in [18], p. 617. 1 229 506, 1963 (R. E. Parsons). 83 L. Zipfel, W. Krucke,€ K. Borner,€ P. Barthelemy, P. 117 R. E. Banks: Fluorocarbons and their Derivatives, Dournel in: Polyurethanes World Congress 1997,p.176. McDonald Technical & Scientific, London 1970, 84 AFEAS Administrative Organization, Science & Policy pp. 102 – 202. Services, Inc., West Tower - Suite 400, 1333 H Street 118 T. Umemoto et al., J. Fluorine Chem. 31 (1986) 37. NW, Washington 1997. 119 R. N. Haszeldine, J. Chem. Soc. 1951, 584. Vol. 15 Fluorine Compounds, Organic 489

120 D. Paskovich, P. Gaspar, G. S. Hammond, J. Org. Chem. 150 DuPont, DE-OS 1 170 935, 1961 (R. H. Halliwell); Asahi 32 (1967) 833. Glass Co., US 3 459 818, 1966 (H. Ukihashi, M. Hisasue). 121 DuPont, US 3 132 185, 1962 (R. E. Parsons). 151 DuPont, US 2 758 138, 1954 (D. A. Nelson); US 122 C. D. Bedford, K. Baum, J. Org. Chem. 45 (1980) 347. 2 970 176, 1957 (E. H. Ten Eyck, G. P. Larson). NL 123 N. S. Rao, B. E. Baker in R. E. Banks, B. E. Smart, J. C. 7 308 149, 1972 (N. E. West); Daikin, Kogyo KK, GB Tatlow (eds.): Organofluorine Chemistry, Principles 1 016 016, 1963 (H. Niimiya). and Commercial Applications, Plenum Press, New York 152 Allied, US 2 734 090, 1950 (J. D. Calfee, C. B. Miller). 1994, p. 321. 153 Kellogg Co., US 2 774 799, 1954 (M. M. Russel, W. S. 124 Hoechst, EP-A 52285, 1980 (K. v. Werner, A. Gisser). Bernhart). Allied, US 2 628 989, 1951 (C. B. Miller). 125 Daikin Kogyo KK, JP-Kokai 84 048436, 1982 (S. Mis- Hoechst, US 3 183 277, 1961 (O. Scherer, A. Steinmetz, aki, T. Kamifukikoshi, M. Suefuji). H. Kuhn,€ W. Wetzel, K. Grafen). 126 Beilstein I(4), 694.ff 154 Bayer, DE-OS 2044370, 1970 (J. N. Meussdoerfer, 127 B. L. Dyatkin, E. P. Mochalina, I. L. Knunyants in [12] H. Niederprum).€ vol. 3, p. 45. 155 Pennsalt Chem. Corp., US 3 188 356, 1961 (M. 128 R. D. Chambers, R. H. Mobbs in [11] vol. 4, p. 50. Hauptschein, A. H. Fainberg). 129 A. Young in P. Tarrant (ed.): Fluorine Chemistry Re- 156 DuPont, US 2 599 631, 1945 (J. Harmon). views, vol. 1 Dekker, New York 1967 p. 359. J. D. Park, 157 DuPont, US 2 419 010, 1943 (D. D. Coffman, T. A. R. J. McMurtry, J. H. Adams in P. Tarrant (ed.): Fluorine Ford); Dynamit Nobel AG, DE-OS 1 259 329, 1965 (A. Chemistry Reviews, vol. 2 Dekker, New York p. 55. Bluemcke, P. Fischer, W. Krings) DE-OS 1 768 543, 130 H. E. O’Neal, S. W. Benson, J. Phys. Chem. 72 (1968) 1968 (A. Bluemcke, P. Fischer, M. Augenstein, H. J. 1866. Vahlensieck). 131 E. W. Cook, J. S. Pierce, Nature 242 (1973) 337. 158 Montecatini, US 3 200 160, 1962 (D. Sianesi, G. Nelli). 132 W. H. Sharkey in Fluorine Chemistry Reviews, vol. 2, Atlantic Richfield Co., US 3 621 067, 1969 (J. W. pp. 1 – 53. DuPont, US 3 316 312, 1959 (D. I. Hamersma), US 3 642 917, 1969 (J. W. Hamersma). McCane, I. M. Robinson). 159 Dow Corning Corp., US 3 739 036, 1971 (J. A. Vali- 133 A. M. Lovelace, D. A. Rausch, W. Postelnek in: Ali- centi, R. L. Halm, F. O. Stark). phatic Fluorine Compounds, A.C.S. Monograph 138, 160 Central Glass Co., JP-Kokai 84 108726, 1982 (T. Na- Reinhold Publ. Corp., New York 1958, Chap. ‘‘III’’. kasora, H. Nakahara). 134 D. Osteroth: Chemie und Technologie aliphatischer 161 Halocarbon Products Corp., DE-OS 2 644 595, 1975 (L. fluororganischer Verbindungen, Chap. ‘‘IB’’ Ferdinand L. Ferstanding). Enke Verlag, Stuttgart 1964. 162 DuPont, US 4 220 608, 1979 (A. E. Feiring). 135 R. D. Chambers: Fluorine in Organic Chemistry,J. 163 A. E. Feiring, J. Fluorine Chem. 12 (1978) 471. Wiley & Sons, New York – London – Sidney – Tor- 164 Dow Corning Corp., US 3 660 453, 1966 (E. D. Groen- onto 1973, pp. 144 – 148. hof, H. M. Schiefer). 136 A. Pajaczkowski, J. W. Spoors, Chem. Ind. (London) 165 I. L. Knunyants, Y. A. Cheburkov, Otdel. Khim. Nauk 1964, no. 16, 659. 1960, 678. 137 R. Muller,€ H. Fischer, Z. Chem. 7 (1967) 314. 166 Daikin Kogyo KK, JP-Kokai 81 090026, 1979 (S. Mis- 138 DuPont, US 2 407 396, 1943 (M. M. Brubaker); US aki, S. Takamatsu); JP-Kokai 81 138127, 1980 (S. 2 407 405, 1943 (M. A. Deitrich, R. M. Joyce Jr., Takamatsu, S. Misaki). 139 B. Atkinson, V. A. Atkinson, J. Chem. Soc. 1957, 2086. 167 Allied, US 3 894 097, 1974 (N. Vanderkooi, H. J. 140 DuPont, US 3 081 245, 1960 (M. W. Farlow); Dow Huthwaite). Chemical, US 3 133 871, 1963 (W. R. von Trees). 168 A. B. Robertson, S. Chandrasekaran, C. S. Chen, Int. 141 Kinetic Chemicals, US 2 401 897, 1946 (A. F. Benning, SAMPE Tech. Conf. 1986, 18 (Mater. Space-Gathering F. B. Downing, R. J. Plunkett). Momentum), 490 – 9. 142 DuPont, US 2 894 996, 1955 (M. W. Farlow, L. 169 Matheson Gas Data Book, 4th, 5th ed., SupplementsThe Muetterties). Matheson Company, East Rutherford N.J. 1966–1971. 143 Pennsalt Chem. Corp., US 3 009 966, 1960 (M. 170 Kellogg Co., US 2 590 433, 1949 (O. A. Blum); 3M, US Hauptschein, A. H. Fainberg). 3 014 015, 1953 (J. W. Jewell). 144 DuPont, US 2 551 573, 1945 (F. B. Downing, A. F. 171 Phillips Petroleum Co., US 3 789 016, 1966 (L. E. Benning, R. C. McHarness). Gardner). 145 Hoechst, DE-OS 1 073 475, 1958 (O. Scherer, A. Stein- 172 F. Liska, Chem. Listy 66 (1972) 189. E. D. Bergmann, A. metz, H. Kuhn,€ W. Wetzel, K. Grafen). M. Cohen, Isr. J. Chem. 8 (1971) 925. 146 ICI, GB 960 309, 1962 (J. W. Edwards, S. Sherratt, P. A. 173 A. J. Elliot in R. E. Banks, B. E. Smart, J. C. Tatlow (eds.): Small). Organofluorine Chemistry, Principles and Commercial 147 Daikin Kogyo KK, GB 1 027 435, 1963. Applications, Plenum Press, New York 1994, p. 145. 148 M. C. Henry, C. B. Griffis, E. C. Stump in [12] vol. 1, 174 S. K. De, S. R. Palit in J. C. Tatlow, R. D. Peacock, H. H. pp. 1 – 75. Hyman (eds.): Advances in Fluorine Chemistry, vol. 6, 149 DuPont, US 2 958 685, 1957 (H. S. Eleuterio). Butterworths, London 1970, pp. 69 – 81. 490 Fluorine Compounds, Organic Vol. 15

175 J. A. Young, Fluorine Chem. Rev. 1 (1967) 359. M. E. 198 DuPont, FR 1 322 597, 1963 (H. H. Biggs, J. L. War- Redwood, C. J. Willis, Can. J. Chem. 45 (1967) 389. nell). DuPont, US 3 536 733, 1970 (D. P. Carlson). 176 W. B. Farnham et al., J. Amer. Chem. Soc. 107 (1985) Nippon Mektron, JP 57 134 473, 1982. 4565. 199 Hoechst, DE-OS 2 658 328, 1978 (M. Millauer, W. 177 DuPont, US 3 317 616 (V. Weinmayr). R. Filler, R. M. Lindner). M. Millauer, Chem. Ing. Tech. 52 (1980) 53. Shure, J. Org. Chem. 32 (1967) 1217. B. L. Dyatkin, E. 200 Asahi Chemical, EP-OS 64 293, 1982 (M. Ikeda, M. P. Mochalina, I. L. Knunyants, Tetrahedron 21 (1965) Miura, A. Aoshima). Daikin Kogyo, JP 58 39 472, 2991. 1983; JP 58 49 372, 1983. Asahi Chemical, JP 178 R. D. Chambers: Fluorine in Organic Chemistry, Wiley- 59 78 176, 1984. Interscience, New York 1973, pp. 65 – 66. 201 DuPont, US 3 358 003, 1967 (H. S. Eleuterio, R. W. 179 H. Gillman, R. G. Jones, J. Amer. Chem. Soc. 70 (1948) Meschke). Hoechst, DE-OS 2 557 655, 1977 (R. Sulz- 1281. bach, F. Heller). 180 Abbott Laboratories, US 3 970 710, 1976 (S. 202 R. C. Kennedy, J. B. Levy, J. Fluorine Chem. 7 (1974) Wolownik). 101. P. B. Sargeant, J. Amer. Chem. Soc. 91 (1969) 3061. 181 Allied, US 4 072 726, 1978 (H. R. Nychka, R. E. Eibeck, 203 Asahi Glass, JP 58 62 131 A2, 1983; JP 58 62 130 A2, M. A. Robinson, E. S. Jones). 1983. Hoechst, EP-A 54 227, 1982 (P. P. Rammelt, G. 182 D. R. Husted, A. H. Albrecht, J. Amer. Chem. Soc. 74 Siegemund). DuPont, US 4 302 608, 1981 (E. N. (1952) 5422. Squire). DuPont, GB 1 019 788, 1966 (E. P. Moore, 183 I. L. Knunyants, SU 138 604, 1961. Allied, BE A. S. Milian). 3M, US 3 213 134, 1965 (D. E. Morin). 634 368, 1963 (J. Hollander, C. Woolf). 204 R. Watts, P. Tarrant, J. Fluorine Chem. 6 (1975) 481. 184 Hoechst, DE 1 017 782, 1957 (P. Schlack). M. Good- 205 DuPont, US 3 125 599, 1964 (J. L. Warnell). man, I. G. Rosen, M. Safdy, Biopolymers 2 (1964) 503, 206 P. L. Coe, A. Sellers, J. C. Tatlow, J. Fluorine Chem. 23 519, 537. DuPont, US 3 418 337, 1968 (W. J. (1983) 102. DuPont, GB 904 877, 1962.3M, US Middleton). 3 213 134, 1965 (D. E. Morin). E. M. Rokhlin et al., 185 DuPont, US 3 148 220, 1964 (D. C. England). B. S. Dokl. Akad. Nauk SSSR 161 (1965) 1356. Farah, E. E. Gilbert, J. Sibilia, J. Org. Chem. 30 (1965) 207 H. S. Eleuterio, J. Macromol. Sci. Chem. A-6 (1972) 998. 1027. J. T. Hill, J. Macromol. Sci, [A] Chem. 8 (1974) 186 J. R. Griffith, Chemtech. 12 (1982) 290. 499. 187 H. C. Fielding in [6], Chap. 11. 208 D. Sianesi, A. Pasetti, R. Fontanelli, G. C. Bernardi, G. 188 Allied, US 4 273 947, 1981 (M. Novotny). Phillips Caporiccio, Chim. Ind. (Milan) 55 (1973) 221. D. Petroleum Co., US 4 396 784, 1983 (M. M. Johnson, Sianesi, A. Pasetti, C. Corti, Macromol. Chem. 86 G. P. Nowack, P. S. Hudson, B. H. Ashe, Jr.). Hoechst, (1965) 308. D. Sianesi, R. Tontanelli, Macromol. Chem. DE-OS 1 944 381, 1971 (H. Fischer). 102 (1967) 115. 189 DuPont, US 3 283 012, 1966 (R. Day). F. Mares, B. C. 209 A. Faucitano, A. Buttafava, G. Caporiccio, C. T. Viola, J. Oxenrider, J. Fluorine Chem. 8 (1976) 373. Hoechst, Amer. Chem. Soc. 106 (1984) 4172. DE-OS 2 318 677, 1974 (H. Millauer). N. O. Brace, J. 210 B. C. Anderson, L. R. Barton, J. W. Collette, Science 208 Fluorine Chem. 31 (1986) 151. (1980) 807. 190 T. Nguyen, M. Rubinstein, C. Wakselman, Synth. 211 R. E. Uschold, Polym. J. 17 (1985) 253. A. L. Barney, Commun. 13 (1983) 81. Daikin Kogyo Co., US W. J. Keller, N. M. von Gulick, J. Polym. Sci. Part A 1 4 346 250, A 1982 (T. Satokawa, T. Fujii, A. Ohmori, (1970) 1091. Y. Fujita). 212 DuPont, US 3 250 808, 1966 (E. P. Moore, A. S. Milian, 191 A. M. Lovelace, D. A. Rausch, W. Postelnek: Aliphatic Jr., H. S. Eleuterio). DuPont, US 3 291 843, 1966 (C. G. Fluorine Compounds, Reinhold Publ. Co., New York Fritz, S. Selman). Hoechst, US 4 118 421, 1978 (T. 1958, Chap. ‘‘5’’. Martini). 192 A. L. Henne, S. B. Richter, J. Amer. Chem. Soc. 74 213 DuPont, US 4 281 092, 1981 (A. F. Breazeale). DuPont, (1952) 5420. US 3 467 638, 1969 (D. B. Pattison). G. H. Kalb, A. A. 193 T. Abe, S. Nagase in [7], Chap. 1. Khan, R. W. Quarles, A. L. Barney: Advances in Chem- 194 L. C. Clark, F. Becattini, S. Kaplan, Ala. J. Med. Sci. 9 istry Series, 129, Amer. Chem. Soc., Washington, D.C. (1972) 16. E. P. Wesseler, R. Iltis, L. C. Clark, J. 1973. Fluorine Chem. 9 (1977) 137. 214 A. Eisenberg, H. Yeager (eds.): ‘‘Perfluorinated Ionomer 195 G. G. Gerhardt, R. J. Lagow, J. Chem. Soc., Chem. Membranes,’’ ACS Symposium Series, 180, Amer. Commun. 1976, 259. R. D. Chambers, B. Grievson, Chem. Soc., Washington, D.C. 1982. F. G. Drakesmith, R. L. Powell, J. Fluorine Chem. 29 215 DuPont, US 3 301 893, 1967 (R. E. Putnam, W. D. (1985) 323. Nicoll). 196 P. Tarrant, C. G. Allison, K. P. Barthold, E. C. Stump, Jr., 216 DuPont, US 3 282 875 1966 (D. J. Connally, W. F. Fluorine Chem. Rev. 5 (1971) 77. Gresham). W. Grot, Chem. Ing. Tech. 47 (1975) 617. 197 H. Millauer, W. Schwertfeger, G. Siegemund, Angew. 217 Asahi Glass, GB 2 029 827 A, 1979 (M. Yamabe, S. Chem. Int. Ed. Engl. 24 (1985) 161. Kumai, S. Munekata). Vol. 15 Fluorine Compounds, Organic 491

218 D. C. England, L. R. Melby, M. A. Dietrich, R. V. 251 Commonwealth Scientific and Industrial Research Or- Lindsey, Jr., J. Amer. Chem. Soc. 82 (1960) 5116. ganization, JP 54 64 728, 1979 (G. Holan). Chem. Abstr. 219 I. L. Knunyants, A. I. Shchekotiklin, A. V. Fokin, Izv. 91 (1979) 56635 g. Akad. Nauk SSSR, Otd. Khim. Nauk 1953, 282. 252 Baxter, US 3 659 023, 1972 (B. M. Regan). 220 D. C. England, L. Solomon, C. G. Krespan, J. Fluorine 253 Allied, US 3 450 773, 1969 (R. E. A. Dear, E. E. Chem. 3 (1973/1974) 4. Gilbert). 221 D. C. England, J. Org. Chem. 49 (1984) 4007. 254 D. W. Lipp, O. Vogl in T. Saegusa, E. Goethals (eds.): 222 F. W. Evans, M. H. Litt, A.-M. Weidler-Kubanek, F. P. ACS Symposium Series 59, Amer. Chem. Soc., Wa- Avonda, J. Org. Chem. 33 (1968) 1839. shington, D.C. 1977, Chapter ‘‘8’’, pp. 111 – 128. 223 Dow Chemical, US 3 549 711, 1970 (C. I. Merrill, N. L. 255 B. Yamada, R. W. Campbell, O. Vogl, Polym. J. 9 (1977) Madison). 23. 224 W. G. M. Jones in [7], Chap. 5. R. Filler in R. E. Banks 256 Beilstein 1(4), 3133. (ed.): Organofluorine Chemicals and their Industrial 257 CS 183 467, 1980 (A. Posta et al.). Chem. Abstr. 94 Applications, Ellis Horwood Ltd., Chichester 1979, (1981) 156316 j. ‘‘Chap. 6;’’ W. G. M. Jonesin [6], Chap. 7. E. R. 258 Hoechst, DE-OS 2 139 211, 1973 (G. Siegemund). Larsen, Fluorine Chem. Rev. 3 (1969) 1. 259 G. Siegemund, Chem. Ber. 106 (1973) 2960. 225 Air Reduction Co., US 2 870 218, 1959 (P. W. 260 Sumitomo, JP-Kokai 60 64 949, 1985. Townsend). 261 Hoechst, DE-OS 2 656 548, 1978 (G. Siegemund). 226 J. M. Baden, M. Kelley, R. S. Wharton, B. A. Hitt, V. F. 262 Hoechst, DE-OS 2 344 442, 1975 (H. Kuehn, F. Kluge, Simon, R. I. Mazze, Anesthesiology 46 (1977) 346. G. Siegemund). 227 Air Reduction Co., GB 1 138 406, 1969 (R. C. Terrell). 263 Hoechst, DE-OS 2 361 058, 1975 (G. Siegemund, R. 228 Air Reduction Co., US 3 535 425, 1970 (R. C. Terrell). Muschaweck). A. P. Adams, Br. J. Anaesth. 53 (1981) Suppl. 1, 27. 264 Hoechst, DE-OS 2 340 560, 1975 (G. Siegemund, R. 229 Dow Chemical, US 3 264 356, 1966 (E. R. Larsen). Muschaweck). 230 M. J. Halsey, Br. J. Anaesth. 53 (1981) Suppl. 1, 43. 265 K. C. Joshi, J. Indian Chem. Soc. 59 (1982) 1375. 231 G. A. Olah, C. V. Pittman, J. Am. Chem. Soc. 88 (1966) 266 K. C. Joshi, V. N. Pathak, Coord. Chem. Rev. 22 (1977) 3310. 37. 232 Houben-Weyl 7(2C), 2147. 267 P. Mushak, M. T. Glenn, J. Savory, Fluorine Chem. Rev. 233 Chem. Eng. 75 (1968) 22. 6 (1973) 43. 234 Allied, US 3 164 637, 1965 (H. R. Nychka, C. Woolf). 268 K. G. Seeley, W. J. McDowell, L. K. Felker, J. Chem. 235 DuPont, FR 1 372 549, 1964 (F. W. Swamer). Chem. Eng. Data 31 (1986) 136. Abstr. 62 (1965) 6397 a. 269 K. A. Kline, R. E. Sievers, Aldrichimica Acta 10 (1977) 236 M. Van Der Puy, L. G. Anello, Org. Synth. 63 (1985) 54. 154. 270 A. L. Henne, C. J. Fox, J. Am. Chem. Soc. 73 (1955) 237 Allied, FR 1 369 784, 1964 (L. G. Anello, H. R. Nychka, 2323. C. Woolf). Chem. Abstr. 62 (1965) 1570 f. 271 S. Nagase in [12], vol. 1, p. 77. 238 I. Mellan: Ketones, Chemical Publ. Co., New York 272 J. Burdon, J. C. Tatlow in [11], vol. 1, p. 129. 1968, pp. 64 – 68. 273 V. Childs in N. Weinberg, B. Tilak (eds.): Technique in 239 W. J. Middleton, R. V. Lindsey, Jr., J. Am. Chem. Soc. 86 Electroorganic Synthesis, vol. 5, Wiley-Interscience, (1964) 4948. New York 1982, Part 3, p. 341. 240 Allied, US 3 620 666, 1971 (R. W. Lenz, L. Barish, V. L. 274 Kali-Chem, US 3 725 475, 1973 (H. Paucksch, J. Mas- Lyons). sonne, H. Bohm, G. Fernschild). 241 USDA, US 3 998 620, 1976 (A. G. Pittman, W. L. 275 F. L. M. Pattison: Toxic Aliphatic Fluorine Compounds, Wasley). Elsevier, Amsterdam 1959, p. 387. 242 Stauffer Chemical Co., US 3 594 362, 1971 (K. Szabo). 276 M. Hauptschein, J. Am. Chem. Soc. 83 (1961) 2500. 243 Stauffer Chemical Co., NE-A 6 410 536, 1965 (K. 277 Pennwalt, US 3 328 240, 1966 (M. Hauptschein). Szabo, G. P. Willsy, Jr. Chem. Abstr. 63 (1965) 11577 g. 278 Hoechst, US 4 400 325, 1983 (K. von Werner, A. 244 Allied, US 3 177 187, 1965 (J. Hollander, C. Woolf). Gisser). 245 Allied, US 3 177 185, 1965 (J. Hollander, C. Woolf). 279 Daikin Kogyo, US 3 525 758, 1970 (A. Katsushima). 246 Allied, NL-A 6 407 623, 1965 (E. E. Gilbert, J. A. Otto). 280 Asahi Glass, US 4 138 417, 1979 (H. Ukihashi, T. 247 Allied, NL-A 6 407 548, 1965 (E. E. Gilbert, B. C. Hayashi, Y. Takashi et al.). Oxenrider, G. J. Schmitt). 281 DuPont, US 3 250 808, 1966 (E. Moore, A. Milian, E. 248 L. Speers, A. J. Szur, R. C. Terrell, J. Med. Chem. 15 Eleuterio); US 3 322 826, 1967 (E. Moore). (1972) 606. 282 DuPont, GB 1 108 128, 1968. 249 M. Hudlicky: Chemistry of Organic Fluorine Com- 283 S. Kumai, S. Samejima, M. Yamabe, Rep. Res. Lab. pounds, 2nd ed., Ellis Horwood, Chichester 1976, Asahi Glass Co. Ltd. 29 (1979) 105. pp. 353, 712. 284 Asahi Glass, US 4 151 200, 1979 (M. Yamabe, S. 250 [249], p. 714. Kumai). 492 Fluorine Compounds, Organic Vol. 15

285 A. L. Henne, W. J. Zimmersheid, J. Am. Chem. Soc. 69 pp. 45 – 80; M. Le Blanc, J. E. Riess, R. E. Banks (1947) 281. (ed.): Preparation, Properties and Industrial Applica- 286 E. T. McBee, P. A. Wiseman, G. B. Bachman, Ind. Eng. tions of Organofluorine Compounds, Chap. ‘‘3’’, Ellis Chem. 39 (1947) 415. Horwood Ltd. & Wiley Halsted Press, New York – 287 S. Stinson, Chem. Eng. News 1982 (March 15) 22. Brisbane – Chichester – Toronto 1982, pp. 83 – 116. 288 R. N. Hazeldine, J. M. Kidd, J. Chem. Soc. 1954, 4228. 314 F. Swarts, Bull. Cl. Sci. Acad. R. Belg. 35 (1898) 375. 289 T. Gramstad, Tidsskr. Kjemi Bergves. Metall. 19 (1959) 315 Y. Kobayashi, I. Kumadaki, Tetrahedron Lett. 1969, 62. 4095. 290 Bayer, DE-OS 2 201 649, 1973 (P. Voss, H. Nieder- 316 Y. Kobayashi, I. Kumadaki, Chem. Pharm. Bull. 18 pruem, M. Wechsberg). (1970) 2334. 291 R. N. Hazeldine, J. M. Kidd, J. Chem. Soc. 1955, 2901. 317 V. C. R. McLaughlin, J. Thrower, Tetrahedron 25 (1969) 292 Hercules, US 4 505 990, 1985 (S. Dasgupta et al.). 5921. 293 Eastman Kodak, US 4 582 781, 1986 (J. Chen, J. Kelly, 318 J. H. Clark, D. Wails, T. W. Bastock: Aromatic Fluori- J. Plakunov et al.). nation, CRC Press Inc., Boca Raton, FL 1996. 294 3M, US 2 803 656, 1957 (A. Ahlbrecht, H. Brown 319 F. Swarts, Bull. Cl. Sci. Acad. R. Belg. 1920, 399. et al.). 320 Y. Kobayashi, I. Kumadaki, Acc. Chem. Res. 11 (1978) 295 3M, US 2 803 615, 1957 (A. Ahlbrecht, H. Brown, S. 197. Smith et al.). 321 A. L. Henne, M. S. Newman, J. Am. Chem. Soc. 60 296 3M, US 3 094 547, 1963 (R. Heine et al.). (1938) 1697. 297 R. B. Ward, J. Org. Chem. 30 (1965) 3009. 322 R. Filler, H. Novar, Chem. Ind. (London) 1960, 1273. 298 3M, US 4 329 478, 1982 (F. Behr). 323 R. Grinter et al., Tetrahedron Lett. 1968, 3845. 299 DuPont, US 3 301 893, 1967 (R. Putnam, W. Nicoll 324 Hooker Chemical, US 3 234 292, 1966 (St. Robota, E. et al.). A. Belmore). 300 S. Torrey (ed.): Membrane and Ultrafiltration Technol- 325 R. J. Albers, E. C. Kooyman, Rec. Trav. Chim. Pays Bas ogy, Noyes Data Corp., Park Ridge, N.J. 1980, p. 132. 83 (1964) 930. 301 A. Eisenberg, H. Yeager (eds.): Perfluorinated Ionene 326 Montedison, DE-OS 2 746 787, 1976 (M. Bornengo). Membranes, Amer. Chem. Soc., Washington, D.C. 327 G. Schiemann, B. Cornils: Chemie und Technologie 1982. cyclischer Fluorverbindungen, Ferdinand Enke Verlag, 302 DuPont, US 3 282 875, 1964 (D. Connolly, W. Stuttgart 1969, pp. 188 – 193. Gresham). 328 Hoechst (IG Farbenindustrie), DE 575 593, 1931 (P. 303 DuPont, FR 1 406 778, 1963 (R. Putnam, W. Nicoll). Osswald, F. Muller,€ F. Steinh€auser). 304 F. E. Behr, R. J. Koshar: Abstracts Fifth Winter Fluorine 329 Hoechst, DE 2 356 257, 1973 (R. Lademann, H. Lind- Conference, Daytona Beach, Fla. 1981, p. 5. ner, Th. Martini, P. Rammelt). 305 3M, EP 0 058 466, 1982 (F. Behr, R. Koshar et al.). 330 A. K. Barbour et al. in [11], vol. 3, p. 181. 306 Asahi Chemical Industry, GB 2 051 831, 1980 (K. 331 Kinetic Chem. Inc., US 1 967 244, 1932 (L. C. Holt, E. Kimoto, H. Miyauchi, J. Ohmura, M. Ebisawa et al.). Lorenzo). J. H. Brown et al., J. Chem. Soc. Suppl. Issue I, 307 C. Jackson (ed.): ‘‘Modern Chloro-alkali Technology,’’ 1949, 95. 3rd Int. Chlorine Symp. 1982, Horwood, United King- 332 Hoechst, DE 1 618 390, 1967 (O. Scherer, G. Schneider, dom 1983, p. 79. R. H€ahnle). 308 ‘‘Fluorinert Electronic Liquids,’’ Product Manual, 3M 333 Hoechst, DE 1 965 782, 1969 (H. Hermann, H. Co., St. Paul, Minn., 1985. Lindner). 309 R. N. Haszeldine, Research (London) 3 (1950) 430. R. 334 Hooker Chem. Corp., DE-AS 1 543 015, 1965 (St. N. Hazeldine, Chem. Soc. 1951, 102. Robota). 310 3M Co., US 2 616 927, 1952 (E. A. Kauck, J. H. 335 Kali-Chemie, DE-OS 2 161 995, 1971 (H. Bohm,€ J. Simons). Massonne). 311 G. G. I. Moore et al., J. Fluorine Chem. 32 (1986) no. 1, 336 Olin Mathieson Chem. Corp., US 3 136 822, 1961 (L. J. 41. Frainier). 312 H. G. Bryce: ‘‘Industrial and Utilitarian Aspects of 337 Bayer, DE-OS 2 837 499, 1978 (A. Marhold, E. Fluorine Chemistry,’’ in [10], vol. 5, pp. 302 – 346. Klauke). 313 T. Abe, S. Nagase, R. E. Banks (ed.): Preparation, 338 Ullmann, 3rd ed., 7 636 – 639. G. Wolfrum in [6], Properties and Industrial Applications of Organofluor- pp. 208 – 213. ine Compounds, Chap. ‘‘1’’, Ellis Horwood Ltd. & 339 T. Fujita, J. Iwasa, C. Hansch, J. Am. Chem. Soc. 86 Wiley Halsted Press, New York – Brisbane – Chiche- (1964) 5175. ster – Toronto 1982, p. 35; D. S. L. Slinn, S. W. Green, 340 C. Hansch, R. M. Muir, T. Fujita et al., J. Am. Chem. Soc. R. E. Banks (ed.): Preparation, Properties and Indus- 85 (1963) 2817. C. Hansch, J. Fukunaga, CHEMTECH 7 trial Applications of Organofluorine Compounds, (1977) 120. Chap. ‘‘2’’, Ellis Horwood Ltd. & Wiley Halsted Press, 341 R. Filler in [7], pp. 123 – 153. New York – Brisbane – Chichester – Toronto 1982, 342 G. T. Newbold in [2], pp. 169 – 187. Vol. 15 Fluorine Compounds, Organic 493

343 W. A. Sheppard, C. M. Sharts: Organic Fluorine Chem- 370 R. Filler, J. Fluorine Chem. 33 (1986) 361. istry, W. A. Benjamin, New York 1969, pp. 18 – 49. 371 K. Wallenfels, F. Witzler, K. Friedrich, Tetrahedron 23 344 G. G. Yakobson, T. D. Rubina, N. N. Vorozhtsov, Jr., (1967) 1845. Dokl. Akad. Nauk SSSR 141 (1961) 1395. 372 Keishin Matsumoto, JP-Kokai 51 6940, 1974 (S. Fujii, 345 M. M. Boudakian et al., J. Org. Chem. 26 (1961) 4641. K. Inoukai). 346 US Atomic Energy Com., US 3 833 581, 1971 (D. R. 373 Kirk-Othmer, 10, 915. L. S. Kobrina in [12], vol. 7, McKenzie, J. Fajer, R. Snol). pp. 1 – 114. 347 V. Grakauskas, J. Org. Chem. 35 (1970) 723; 34 (1969) 374 Y. Desirant, Bull Cl. Sci. Acad. R. Belg. 41 (1955) 759. 2835. 375 Sperry Rand. Corp., US 3 158 657, 1962 (F. R. Callihan, 348 M. J. Shaw et al., Chem. Eng. News 47 (1969) no. 40, 45; Ch. L. Quatela). J. Am. Chem. Soc. 92 (1970) 6498. 376 M. Stacey, J. C. Tatlow in [11], vol. 1, p. 166. 349 K. Bottenberg, Chem. Ztg. 96 (1972) 84. 377 G. Fuller, J. Chem. Soc. 1965, 6264. 350 Institut Organicheskoi Khimii, Imeni Zelinskogo, DE- 378 L. W. Hall, S. R. K. Jackson, G. M. Massey, Int. Congr. OS 1 618 564, 1967 (O. M. Nefedov, A. A. Ivashenko). Ser. Exerpta Med. 1974, 347. 351 I. N. Rozhkov, A. V. Bukhtiarov, I. L. Knunyants, Iszv. 379 D. R. Miller et al., Intersoc. Energy Convers. Engl. Conf. Akad. Nauk SSSR Ser. Khim. 1972, 1130. Conf. Proc. 7th, (1972) 315. 352 G. A. Olah, P. Kreienbuhl,€ J. Org. Chem. 32 (1967) 380 E. D. Morgan, C. F. Poole, J. Chromatogr. 104 (1975) 1614. 351. 353 K. O. Christe, A. E. Pavlath, J. Org. Chem. 31 (1966) 381 J. C. Lhuguenot, B. F. Maume, J. Chromatogr. Sci. 12 559. (1974) 411. 354 J. S. Moilliet in R. E. Banks, B. E. Smart, J. C. Tatlow 382 M. M. Murza et al., Zh. Org. Khim. 13 (1977) 1046. (eds.): Organofluorine Chemistry, Principles and Com- 383 DuPont, FR 1 555 360, 1969 (D. B. Pattison). mercial Applications, Plenum Press, New York 1994, 384 H. C. Brown, D. McDaniel, J. Am. Chem. Soc. 77 (1955) p. 195. 3752. 355 Hoechst, DE 600 706, 1933 (P. Osswald, O. Scherer). 385 Olin, US 3 296 269, 1967 (M. M. Boudakian). FIAT Final Rep. Nr. 998 I.G. Werke Hoechst (1947) . R. 386 Olin, US 3 703 521, 1972 (M. M. Boudakian). L. Ferm, C. A. v. d. Werf, J. Am. Chem. Soc. 72 (1950) 387 ICI, DE-OS 2 128 540, 1971 (A. Nicolson). 4809. 388 M. M. Boudakian, J. Heterocycl. Chem. 5 (1968) 683. 356 Riedel-de-Haen, DE-OS 3 520 316, 1985 (E. Bege- 389 J. A. Burdon et al., Nature (London) 186 (1960) 231. mann, H. Schmand). 390 G. G. Yakobson, T. D. Petrova, L. S. Kobrina in [7] 357 Harshaw Chemical Company, US 2 563 796, 1951 (W. J. vol. 7, pp. 115 – 223. Shenk, G. R. Pellon). 391 ICI, GB 1 479 721, 1973 (D. W. R. Headford, J. W. 358 Allied, FR 611 545, 1960 (L. G. Anello, C. Woolf). Slater, R. L. Sunley, R. D. Bowden, M. B. Green). 359 H. Suschitzky in [11], vol. 4, p. 1. 392 Dow, DE 2 263 429, 1975 (R. H. Rigterink); US 360 D. T. Flood in A. H. Blatt (ed.): Organic Syntheses, 3 810 902, 1974 (R. H. Rigterink). Collective Volume II, J. Wiley & Sons, New York 1943, 393 ICI, US 4 063 926, 1977 (Sp. Tomlin, J. W. Slater, D. p. 295. Hartley); US 3 850 943, 1974 (R. D. Bowdon, J. W. 361 J. P. Regan: Meeting on Fluoro-organic Compounds in Slater, B. G. White). Industry, Society of Chemical Industry, London 23rd 394 M. S. Raasch, J. Org. Chem. 27 (1962) 1406. January 1986. 395 E. T. McBee, H. B. Hass, E. M. Hodnett, Ind. Eng. Chem. 362 A. E. Pavlath, A. J. Leffler: ‘‘Aromatic Fluorine Com- 2nd ed. 39 (1947) 389. pounds,’’ ACS Monogr. 155 (1962) . 396 Ishihara, DE-OS 2 812 571, 1979 (R. Nishiyama, T. 363 W. Prescott, Chem. & Ind. (London) 1986, 56. Haga, N. Sakashita). 364 Boots Co., DE-OS 2 938 939, 1978 (R. A. North). 397 W. Harms in [6], pp. 188 – 207. 365 L. Dolby-Glover, Chem. & Ind. (London) 1986, 518. 398 Acad. Sci. USSR, DE 2 014 216, 1971 (J. L. Knuny- 366 ISC Chemicals Ltd., GB 1 143 088, 1966 (D. W. ants, L. S. German, N. B. Kazmina). Cottrell). 399 PCR, US 3 954 758, 1976 (P. D. Schuman, P. Tarrant, 367 A. J. Elliott in R. Filler, Y. Kobayashi (eds.): Biome- D. A. Warner, G. Westmoreland); US 4 113 949, 1978 dicinal Aspects of Fluorine Chemistry, Kodansha Ltd., (P. D. Schumann, P. Tarrant, D. A. Warner, G. Tokyo & Elsevier Biomedical, Amsterdam – New Westmoreland). York – Oxford 1982, pp. 55 – 74. 400 D. V. Santi, A. L. Pogolotti, Jr., E. M. Newman, Y. 368 G. C. Finger, F. H. Reed, L. R. Tehon, Illinois State Geol. Wataya in [367], pp. 123 – 142. Survey, Circular No. 199, Urbana (1955) . R. S. Shiley 401 Bayer, FR 1 546 305, 1968 (E. Klauke, H. S. Bien); LU et al., J. Fluorine Chem. 5 (1975) 371. 58 622, 1969 (E. Klauke, H. S. Bien). 369 Thomson-CSF, US 3 979 321, 1976 (A. Couttet, J. C. 402 Bayer, GB 1 158 300, 1966 (E. Klauke, H. S. Bien). Dubois, A. Zaum). American Mikro-System, US 403 Bayer, GB 1 273 914, 1969 (H. U. Alles, E. Klauke, H. 4 018 507, 1977 (N. V. V. Raaghavan). J. P. Van Meter, S. Bien). Eastman Org. Chem. Bull. 45 (1973) 1. 404 Bayer, DE 1 044 091, 1957 (A. Dorlars). 494 Fluorine Compounds, Organic Vol. 15

405 C. W. Tullock, A. D. Coffman, J. Org. Chem. 25 (1960) 417 L. Stryer: Biochemistry, Freeman, San Francisco 1981, 2016. p. 298. 406 Bayer, BE 713 937, 1967 (H. S. Bien, E. Klauke, K. 418 H. Millauer, W. Schwertfeger, G. Siegemund, Angew. Wunderlich); BE 716 013, 1967 (H. S. Bien, E. Klauke, Chem. Int. Ed. Engl. 24 (1985) 161. K. Wunderlich); BE 716 014, 1967 (H. S. Bien, E. 419 R. Frey, H. Beisbarth, K. Stosseck: 5th International Klauke, K. Wunderlich). Symposium on Perfluorochemical Blood Substitutes, 407 Bayer, GB 872 313, 1957 (A. Dorlars). Mainz, Zuckschwerdt Verlag, Mar. 1981, Munich 408 G. Schiemann, E. Bolsted, Chem. Ber. 61 (1928) 1403. 1981, pp. 86 – 90. 409 J. W. Clayton: ‘‘Fluorocarbon Toxicity and Biological Action,’’ in P. Tarrant (ed.): Fluorine Chemistry Re- views, vol. 1, Dekker, New York 1967, pp. 197 – 252. 410 R. R. Montgomery, C. F. Reinhardt: ‘‘Toxicity of Fluo- Further Reading rocarbon Propellants,’’ in P. A. Sanders (ed.): Handbook of Aerosol Technology, 2nd ed., Van Nostrand Reinhold, W. X. Bajzer: Fluorine Compounds, Organic, ‘‘Kirk Othmer New York 1979, pp. 466 – 511. Encyclopedia of Chemical Technology’’, 5th edition, 411 D. M. Aviado: ‘‘Fluorine-Containing Organic Com- John Wiley & Sons, Hoboken, NJ, online DOI: pounds,’’ in G. D. Clayton, F. E. Clayton (eds.): Patty’s 10.1002/0471238961.0914201802011026.a01.pub2. Industrial Hygiene and Toxicology, 3rd ed., vol. 2B, J.-P. Begue, D. Bonnet-Delpon: Bioorganic and Medicinal Wiley-Interscience, New York 1981, pp. 3071 – 3115. Chemistry of Fluorine, John Wiley & Sons, Hoboken, NJ 412 J. W. Clayton: ‘‘TheMammalian Toxicology of Organic 2008. Compounds Containing Fluorine,’’ in F. A. Smith (ed.): W. R. Dolbier: Guide to Fluorine NMR for Organic Chemists, Handbook of Experimental Pharmacology, vol. 20/1, Wiley, Hoboken, NJ 2009. Springer Verlag, New York 1966, pp. 459 – 500. I. Ojima (ed.): Fluorine in Medicinal Chemistry and Chemi- 413 ACGIH (ed.): Documentation of the Threshold Limit cal Biology, Wiley-Blackwell, Chichester 2009. Values (TLV), ACGIH, Cincinnati, Ohio 1986. V. A. Petrov: Fluorinated Heterocyclic Compounds, Wiley, 414 DFG (ed.): Maximum Concentrations at the Workplace Hoboken, NJ 2009. and Biological Tolerance Values for Working Materials, V. A. Soloshonok, K. Mikami, T. Yamazaki, J. T. Welch, J. Verlag Chemie, Weinheim, Germany 1984, Report 20. Honek (eds.): Current Fluoroorganic Chemistry, Ameri- 415 M. H. Litchfield, E. Longstaff, Food Chem. Toxicol. 22 can Chemical Society, Washington, DC 2007. (1984) 465. K. Uneyama: Organofluorine Chemistry, Blackwell, Oxford 416 J. F. Borzelleca, D. Lister, Toxicol. Appl. Pharmacol. 7 2006. (1965) 592.