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Organofluorine chemistry

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Some important fluorocarbons.
A: fluoromethane
B: isoflurane
C: a CFC
D: an HFC
E: triflic acid
F: Teflon
G: PFOS

Organofluorine chemistry describes chemical compounds that contain carbon-fluorine bonds. Organofluorine compounds find diverse applications ranging from refrigerants to pharmaceuticals. In addition to these positive aspects, organofluorine compounds are also pollutants because of contributions to ozone depletion, global warming, and bioaccumulation. The area of organofluorine chemistry often requires special techniques associated with the handling of fluorinating agents.

General properties of organofluorine compounds

(see carbon-fluorine bond)

Like any large class of compounds, organofluorine compounds have diverse properties, reflecting the diversity of their structures, functionality, and molecular weights.

In general, those derivatives that are highly fluorinated are more chemically and thermally stable than the corresponding hydrocarbons. Such species often are more lipophobic. As a consequence of reduced van der Waals interactions, such fluorine-rich species are lubricants and or highly volatile.[1] Gas soluble fluorocarbon liquids have medical applications.

Flurocarbons with few C-F bonds behave similarly to the parent hydrocarbons, but their reactivity can be altered significantly. For example, both uracil and 5-fluorouracil are colourless, high-melting crystalline solids, but the latter is a potent anti-cancer drug. The use of the C-F bond in pharmaceuticals is predicated on this altered reactivity.[2]

Types of organofluorine compounds

Perfluorocarbons

Perfluorocarbons are fluorocarbons that contain only C-C and C-F bonds. Examples include perfluorodecalin and perfluoroisobutylene. They can be very low (perfluorodecalin) or very high (perfluoroisobutylene) in toxicity. Perfluorocarbon liquids readily solubilize oxygen, allowing some such as to find medical applications in liquid breathing and blood substitution. Fluoropolymers can be perfluorinated, e.g. PTFE, or only partially polyfluorinated, e.g. polyvinylidene fluoride ([CH2CF2]n) and polychlorotrifluoroethylene ([CFClCF2]n.

Hydrofluorocarbons

Hydrofluorocarbons are the most common organofluorine compounds. The fluorine content can range from as few as one fluorine per molecule to many. Several drugs and agrichemicals are They were formerly used widely in industry as refrigerants, propellants, and cleaning solvents. Dichlorodifluoromethane and chlorodifluoromethane were widely used refrigerants. CFCs have potent ozone depletion potential due to the homolytic cleavage of the carbon-chlorine bonds; their use is mostly prohibited by the Montreal Protocol. Hydrofluorocarbons (HFCs), such as tetrafluoroethane, contain only hydrogen and fluorine atoms on the carbon chain. They serve as CFC replacements because they do not catalyze ozone depletion.

Chlorofluorocarbons (CFCs) are fluorocarbons and haloalkanes. They were formerly used widely in industry as refrigerants, propellants, and cleaning solvents. Dichlorodifluoromethane and chlorodifluoromethane were widely used refrigerants. CFCs have potent ozone depletion potential due to the homolytic cleavage of the carbon-chlorine bonds; their use is mostly prohibited by the Montreal Protocol. Hydrofluorocarbons (HFCs), such as tetrafluoroethane, contain only hydrogen and fluorine atoms on the carbon chain. They serve as CFC replacements because they do not catalyze ozone depletion.

Applications

Organofluorin chemistry impacts many areas of everyday life and technology. The C-F bond is found in pharmaceuticals, agrichemicals, fluoropolymers, refrigerants, surfactants, anesthetics, oil-repellants, and water-repellants, among other places.

Pharmaceuticals and agrichemicals

The carbon-fluorine bond is commonly found in pharmaceuticals and agrichemicals because it is generally metabolically stable and fluorine acts as a bioisostere of the hydrogen atom. An estimated one fifth of pharmaceuticals contain fluorine, including several of the top drugs.[3] Examples include 5-fluorouracil, fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, and fluconazole.

Fluorosurfactants

Fluorosurfactants have a polyfluorinated "tail" and a hydrophilic "head" and they are potent surfactants because they concentrate at the liquid-air interface due to their lipophobicity.[4] Fluorosurfactants have low surface energies[1] and dramatically lower surface tension[5] The fluorosurfactants perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two of the most studied because of their ubiquity, toxicity, and long residence times in humans and wildlife.

Anesthetics

Many volatile anesthetics are fluorocarbon ethers, such as methoxyflurane, enflurane, isoflurane, sevoflurane and desflurane. Fluorocarbon anesthetics reduce the hazard of flammability with diethyl ether and cyclopropane.

Solvents

HFCs can act as solvents. The HFC 1,1,1,2-tetrafluoroethane is used for extractants of natural products such as taxol, evening primrose oil, and vanillin.[6]

Miscellaneous uses

Lubricants

With a low coefficient of friction, fluid fluoropolymers are used as specialty lubricants. Fluorocarbon-based greases are used in demanding applications. Representative products include Fomblin and Krytox, manufactured by by Solvay Solexis and DuPont, respectively. Certain firearm lubricants such as "Tetra Gun" contain fluorocarbons.

Fire Fighting Foam

Fluorocarbons are used in fire fighting foam because of their chemical and thermal stability, unlike hydrocarbons which undergo combustion.

Chemical reagents

Triflic acid (CF3SO3H) and trifluoroacetic acid (CF3CO2H) are important reagents in organic synthesis. Their strong acidity is attributed to the electronegativity of the trifluoromethyl group that stabilizes the negative charge. The triflate-group (the conjugate base of the triflic acid) is a good leaving group in organic synthesis.

History

Organofluorine chemistry began in the 1800s with the development of organic chemistry as a whole. The first organofluorine compounds were prepared by metathesis reactions using antimony trifluoride as the F- source. The nonflammability and nontoxicity of chlorofluorocarbons CCl3F and CCl2F2 attracted industrial attention in the 1920s. Subsequent major developments were partially a consequence of expertise gained in the production of uranium hexafluoride.Cite error: A <ref> tag is missing the closing </ref> (see the help page). They have been found in microorganisms and plants, but not animals. The most common natural organofluorine compound is fluoroacetic acid, a potent toxin found in a few species of plants. Others include ω-fluoro fatty acids, fluoroacetone, and 2-fluorocitrate which are all believed to be biosynthesized from fluoroacetic acid.

Environmental and Health Concerns

CFC's deplete the ozone layer while perfluorocarbons are potent greenhouse gases. The fluorosurfactants PFOS and PFOA, and other related chemicals, are persistent global contaminants. PFOS is a proposed persistent organic pollutant and may be immunocompromising wildlife.

Chemical properties

The carbon-fluorine bond length is typically about 1.35 Å (1.39 Å in fluoromethane).[7] This is shorter than any other carbon-halogen bond, and shorter than C-N and C-O bonds. Since fluorine is a very electronegative atom (much more so than carbon), the carbon-fluorine bond has a significant dipole moment. The carbon-fluorine bond is stronger than other carbon-halogen bonds. The bond dissociation energy in CH3X is 115 kcal/mol for the carbon-fluorine bond compared to 83.7, 72.1, and 57.6 kcal/mol for bonds between carbon and chlorine, bromine, and iodine, respectively.[8] The strength of the carbon-fluorine bond is also stronger than the carbon-hydrogen bond, which is 104.9 kcal/mol in methane.[8]

As a result of these unique features of the carbon-fluorine bond, an overarching theme in fluorocarbon chemistry is the contrasting set of physical and chemical properties in comparison to the corresponding hydrocarbons. Case studies follow.

Pentakis(trifluoromethyl)cyclopentadiene

Pentakis(trifluoromethyl)cyclopentadiene (C5(CF3)5H) is a strong acid, with a pKa = −2. Its high acidity and robustness is indicated by the fact that this compound is typically purified by distillation from H2SO4. In contrast, C5(CH3)5H requires a strong base such as butyllithium for deprotonation, as is typical for a hydrocarbon.[9] This compound is prepared in a multistep, one-pot reaction of potassium fluoride (KF) with 1,1,2,3,4,4-hexachlorobutadiene.

Hexafluoroacetone and its imine

The molecule hexafluoroacetone ((CF3)2CO), the fluoro-analogue of acetone, has a boiling point of −27 °C compared to +55 °C for acetone itself. This difference illustrates one of the remarkable effects of replacing C-H bonds with C-F bonds. Normally, the replacement of H atoms with heavier halogens results in elevated boiling points due to increased van der Waals interactions between molecules. Further demonstrating the remarkable effects of fluorination, (CF3)2CO forms a stable, distillable hydrate,[10] (CF3)2C(OH)2. Ketones rarely form stable hydrates. Continuing this trend, (CF3)2CO adds ammonia to give (CF3)2C(OH)(NH2) which can be dehydrated with POCl3 to give (CF3)2CNH.[11] Compounds of the type R2C=NH are otherwise quite rare.

Aliphatic vs. Aromatic Fluorocarbons

Aliphatic fluorocarbons tend to segregate from aliphatic hydrocarbons while aromatic fluorocarbons tend to mix with aromatic hydrocarbons. This behavior is evidenced by the following crystal structures.[12][13]

Aliphatic Fluorocarbon-Hydrocarbon Packing (Fluorine atoms are green)
Aromatic Fluorocarbon-Hydrocarbon Packing (Fluorine atoms are green)


Methods for preparation of the C-F bond

Organofluorine compounds are prepared by numerous routes, depending on the degree of fluorination sought. The direct fluorination of hydrocarbons with F2, often highly diluted with N2 is useful for highly fluorinated compounds:

R3CH + F2 → R3CF + HF

Such reactions however are unselective and require care because hydrocarbons can uncontrollably "burn" in F2, analogous to the combustion of hydrocarbon in O2. For this reason, electrophilic fluorination reagents have been developed, for example F-TEDA-BF4.

Metathesis reactions employing alkali metal fluorides are more commonly used.[14].

R3CCl + MF → R3CF + MCl (M = Na, K, Cs)

Many organofluorine compounds are generated from preformed fluorinated reagents. Among the available fluorinated building blocks are CF3X (X = Br, I), C6F5Br, and C3F7I. These species form Grignard reagents that then can be treated with a variety of electrophiles.[15]

ArN2BF4 → ArF + N2 + BF3

Nucleophilic displacement of hydroxyl and carbonyl groups by so-called "deoxofluorination agents". One method of fluoride for oxide exchange in carbonyl compounds is with sulfur tetrafluoride:

RCO2H + SF4 → RCF3 + SO2 + HF

Alternately, organic reagents such as diethylaminosulfur trifluoride (DAST, NEt2SF3) and bis(2-methoxyethyl)aminosulfur trifluoride (deoxo-fluor) are easier to handle and more selective:[17]

bis(2-methoxyethyl)aminosulfur trifluoride reaction

References

  1. ^ a b Cite error: The named reference Lemal2004 was invoked but never defined (see the help page).
  2. ^ G. Siegemund, W. Schwertfeger, A. Feiring, B. Smart, F. Behr, H. Vogel, B. McKusick “Fluorine Compounds, Organic” in “Ullmann’s Encyclopedia of Industrial Chemistry” 2005, Wiley-VCH, Weinheim.
  3. ^ Ann M. Thayer “Fabulous Fluorine” Chemical and Engineering News, June 5, 2006, Volume 84, pp. 15-24. http://pubs.acs.org/cen/coverstory/84/8423cover1.html
  4. ^ Mason Chemical Company: "Fluorosurfactant - Structure / Function" Accessed November 1, 2008.
  5. ^ Jean-Louis Salager: "FIRP Booklet # 300-A: Surfactants-Types and Uses" Universidad de los Andes Laboratory of Formulation, Interfaces Rheology, and Processes. 2002. (Retrieved September 7, 2008).
  6. ^ Fluorocarbons and Sulphur Hexafluoride, maintained by European Fluorocarbons Technical Committee (EFCTC)
  7. ^ O'Hagan D (2008). "Understanding organofluorine chemistry. An introduction to the C-F bond". Chem Soc Rev. 37 (2): 308–19. doi:10.1039/b711844a. PMID 18197347. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ a b Blanksby SJ, Ellison GB (2003). "Bond dissociation energies of organic molecules". Acc. Chem. Res. 36 (4): 255–63. doi:10.1021/ar020230d. PMID 12693923. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ R. D. Chambers, A. J. Roche, J. F.S. Vaughan "Direct syntheses of Pentakis(trifluoromethyl)cyclopentadienide Salts and Related Systems" Canadian Journal of Chemistry volume 74, pages 1925-1929 (1996).
  10. ^ Van Der Puy, M. ; Anello, L. G. "Hexafluoroacetone". Organic Syntheses: 251{{cite journal}}: CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 7.
  11. ^ Middleton, W. J.; Carlson, H. D. "Hexafluoroacetoneimine". Organic Syntheses{{cite journal}}: CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 6, p. 664.
  12. ^ J. Lapasset, J. Moret, M. Melas, A. Collet, M. Viguier, H. Blancou, Z. Kristallogr. 1996, 211, 945. CSD entry TULQOG.
  13. ^ C.E. Smith, P.S. Smith, R.Ll. Thomas, E.G. Robins, J.C. Collings, Chaoyang Dai, A.J. Scott, S. Borwick, A.S. Batsanov, S.W. Watt, S.J. Clark, C. Viney, J.A.K. Howard, W. Clegg, T.B. Marder, J. Mater. Chem. 2004, 14, 413. CSD entry ASIJIV.
  14. ^ See: Gryszkiewicz-Trochimowski and McCombie method
  15. ^ Crombie, A.; Kim, S.-Y.; Hadida, S; Curran, and D. P. (2004). "Synthesis of Tris(2-Perfluorohexylethyl)tin Hydride: A Highly Fluorinated Tin Hydride with Advantageous Features of Easy Purification". Organic Syntheses{{cite journal}}: CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 10, p. 712.
  16. ^ Flood, D. T. "Fluorobenzene". Organic Syntheses; Collected Volumes, vol. 2, p. 295.
  17. ^ Bis(2-methoxyethyl)aminosulfur trifluoride: a new broad-spectrum deoxofluorinating agent with enhanced thermal stability Gauri S. Lal, Guido P. Pez, Reno J. Pesaresi and Frank M. Prozonic Chem. Commun., 1999, 215 - 216, doi:10.1039/a808517j
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