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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
H: fluorouracil
I: Prozac

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. Although the carbon-fluorine bond confers distinctive properties, organofluorine compounds have diverse properties, reflecting the diversity of their structures, functionality, and molecular weights.

Chemical properties of the C-F bond

Main article: carbon-fluorine bond

The carbon-fluorine bond length is typically about 1.35 Å. Since fluorine is more electronegative than carbon, the carbon-fluorine bond has a significant dipole moment. The carbon-fluorine bond is stronger than other carbon-halogen bonds. The carbon-fluorine bond is also stronger than the carbon-hydrogen bond. As a result of these, the physical and chemical properties or organofluorine compounds are distinctive in comparison to the corresponding derivatives of the heavier halides. Compared to aryl chlorides and bromides, aryl fluorides form Grignard reagents only reluctantly. On the other hand, aryl fluorides, e.g. fluoroanilines and fluorophenols, often undergo nucleophilic substitution efficiently.

Types of organofluorine compounds

Organofluorine compounds can be qualitatively classified on the basis of the degree of fluorination.

Hydrofluorocarbons

Hydrofluorocarbons, compounds that contain only one or a few fluorine atoms, are the more common type of organofluorine compounds. 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.[1] Several drugs and agrichemicals contain only one fluorine center or one trifluoromethyl group.

Poly- and perfluorocarbons

Main article: perfluorocarbon

In general, 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. Gas soluble fluorocarbon liquids have medical applications. Fully fluorinated compounds, perfluorocarbons, contain only C-C and C-F bonds. Fluoropolymers can be perfluorinated, e.g. PTFE, or only partially polyfluorinated, e.g. polyvinylidene fluoride ([CH2CF2]n) and polychlorotrifluoroethylene ([CFClCF2]n. Aliphatic fluorocarbons tend to segregate from aliphatic hydrocarbons whereas aromatic fluorocarbons tend to mix with aromatic hydrocarbons. This behavior is evidenced by the following crystal structures.[2][3] Common Chlorofluorocarbons (CFCs) are typically highly fluorinated.

Packing of a mixed aliphatic fluorocarbon-hydrocarbon (Fluorine atoms are green)
Packing of fluoro- and nonfluoroaromatic rings (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 and the nature of the precursors. 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 often unselective and require care because hydrocarbons can uncontrollably "burn" in F2, analogous to the combustion of hydrocarbon in O2. For this reason, alternative fluorination methodologies have been developed. Generally such methods are classified into two classes.

Electrophilic fluorination

Electrophilic fluorination rely on sources of "F+". Often such reagents feature N-F bonds, for example F-TEDA-BF4. Asymmetric fluorination, whereby only one of two possible enantiomeric products are generated from a prochiral substrate, rely on electrophilic fluorination reagents.[4]

Nucleophilic fluorination

The major alternative to electrophilic fluorination is, naturally, nucleophilic fluorination using reagents that are sources of "F-". Metathesis reactions employing alkali metal fluorides are the simplest.[5]

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

The decomposition of aryldiazonium tetrafluoroborates in the Sandmeyer[6] or Schiemann reactions exploit fluoroborates as F- sources.

ArN2BF4 → ArF + N2 + BF3

The so-called "deoxofluorination agents" effect the Nucleophilic displacement of hydroxyl and carbonyl groups. One reagent for fluoride for oxide exchange in carbonyl compounds is 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:[7]

bis(2-methoxyethyl)aminosulfur trifluoride reaction

From fluorinated building blocks

Many organofluorine compounds are generated from reagents that deliver perfluoroalkyl and perfluoroaryl groups. (Trifluoromethyl)trimethylsilane, CF3Si(CH3)3, is used as a source of the trifluoromethyl group, for example.[8] 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. The development of fluorous technologies (see below, under solvents) is leading to the development of reagents for the introduction of "fluorous tails". Sodium fluorodichloroacetate (CAS# 2837-90-3) is used to generate chlorofluorocarbene, for cyclopropanations.

18F-Delivery methods

The usefulness of fluoride-modified glucose and related species in 18F-positron emission tomography has motivated the development of new methods for forming C-F bonds. Because of the short half-life of 18F, these syntheses must be highly efficient, rapid, and easy.[9]

Organofluorine reagents

The development of organofluorine chemistry has contributed many reagents of value beyond and within organofluorine chemistry. Triflic acid (CF3SO3H) and trifluoroacetic acid (CF3CO2H) are useful 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 substitution reactions.

Applications

Organofluorine 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 others.

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.[10] Examples include 5-fluorouracil, fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, and fluconazole. Fluorine-substituted ethers are volatile anesthetics, including the commercial products methoxyflurane, enflurane, isoflurane, sevoflurane and desflurane. Fluorocarbon anesthetics reduce the hazard of flammability with diethyl ether and cyclopropane. Perfluorinated alkanes are used as blood substitutes.

Fluorosurfactants

Fluorosurfactants, which have a polyfluorinated "tail" and a hydrophilic "head", serve surfactants because they concentrate at the liquid-air interface due to their lipophobicity. Fluorosurfactants have low surface energies and dramatically lower surface tension. 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.

Solvents

Fluorinated compounds often display distinct solubility properties. 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 largely prohibited by the Montreal Protocol. Hydrofluorocarbons (HFCs), such as tetrafluoroethane, serve as CFC replacements because they do not catalyze ozone depletion. Oxygen exhibits a high solubility in perfluorocarbon compounds, reflecting again on their lipophilicity. Perfluorodecalin has been demonstrated as a blood substitutes, transporting oxygen from the lungs.

Highly fluorinated substituents, e.g. perfluorohexyl (C6F13) confer distinctive solubility properties to molecules, which facilitates purification of products in organic synthesis.[11] This area, descibed as "fluorous chemistry," exploits the concept of "like-dissolves like" in the sense that fluorine-rich compounds dissolve preferentially in fluorine-rich solvents. This theme has spawned techniques of “fluorous tagging’’ and ‘‘fluorous protection’’. Illustrative of fluorous technology is the use of fluoroalkyl-substituted tin hydrides for reductions, the products being easily separated from the spent tin reagent by extraction using fluorinated solvents.[12]

The solvent 1,1,1,2-tetrafluoroethane has been used for extraction of natural products such as taxol, evening primrose oil, and vanillin. 2,2,2-trifluoroethanol is an oxidation-resistant polar solvent.[13]

Miscellaneous uses

Organofluorine compounds enjoy many niche applications. 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. Capitalizing on their nonflammability, fluorocarbons are used in fire fighting foam. Organofluorine compounds are components of liquid crystal displays. The polymeric analogue of triflic acid, nafion is a solid acid that is potentially useful in fuel cells.

Natural occurrence of organofluorine compounds

In contrast to the existence of many naturally-occurring organic compounds containing the heavier halides, chloride, bromide, and iodide, only a handful of biologically synthesized carbon-fluorine bonds are known.[14] The most common natural organofluorine species is fluoroacetate, a toxin found in a few species of plants. Others include É÷fluorooleic acid, fluoroacetone, nucleocidin (4’-fuoro-5’-O-sulphamoyladenosine), fluorothreonine, and 2-fluorocitrate. Several of these species are probably biosynthesized from fluoroacetaldehyde.

History

Organofluorine chemistry began in the 1800s with the development of organic chemistry as a whole.[15] The first organofluorine compounds were prepared by metathesis reactions using antimony trifluoride as the F- source. The nonflammability and nontoxicity of the chlorofluorocarbons CCl3F and CCl2F2 attracted industrial attention in the 1920s. Subsequent major developments, especially in the US, benefited from expertise gained in the production of uranium hexafluoride.[1] Starting in the late 1940’s, a series of electrophilic fluorinating methodologies were introduced, beginning with CoF3. About this time, electrochemical fluorination became practical. These new methodologies allowed the synthesis of C-F bonds without using elemental fluorine and without relying on metathetical methods. In 1957, the anticancer activity of 5-fluorouracil was described. This report provided one of the first examples of rational design of drugs.[16] This discovery sparked a surge of interest in fluorinated pharmaceuticals and agrichemicals. The discovery of the noble gas compounds, e.g. XeF4, provided a host of new reagents starting in the early 1960’s. In the 1970s, fluorodeoxyglucose was established as a useful reagent in 18F positron emission tomography. In Nobel Prize-winning work, CFC’s were shown to contribute to the depletion of atmospheric ozone. This discovery alerted the world to the negative consequences of organofluorine compounds and motivated the development of new routes to organofluorine compounds. In 2003, the first C-F bond-forming enzyme, fluorinase, was reported.[17]

Environmental and health aspects

In addition to their many beneficial aspects, organofluorine compounds pose significant risks and dangers to health and the environment. CFC's deplete the ozone layer and perfluorocarbons are potent greenhouse gases. Fluorosurfactants, such as PFOS and PFOA, are persistent and global contaminants. Many organofluorine compounds are bioactive and some are quite toxic, such as fluoroacetate and perfluoroisobutene.

References

  1. ^ a b 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.doi:10.1002/14356007.a11 349
  2. ^ J. Lapasset, J. Moret, M. Melas, A. Collet, M. Viguier, H. Blancou, Z. Kristallogr. 1996, 211, 945. CSD entry TULQOG.
  3. ^ 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.
  4. ^ Vincent A. Brunet, David O'Hagan “Catalytic Asymmetric Fluorination Comes of Age” Angewandte Chemie, International Edition 2008, volume 47, 1179-1182. doi:10.1002/anie.200704700
  5. ^ Vogel, A. I.; Leicester, J.; Macey, W. A. T. "n-Hexyl Fluoride". Organic Syntheses{{cite journal}}: CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 4, p. 525.
  6. ^ Flood, D. T. "Fluorobenzene". Organic Syntheses; Collected Volumes, vol. 2, p. 295.
  7. ^ 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, pages 215 - 216. doi:10.1039/a808517j
  8. ^ Pichika Ramaiah, Ramesh Krishnamurti, and G. K. Surya Prakash (1998). "1-trifluoromethyl)-1-cyclohexanol". Organic Syntheses: 232{{cite journal}}: CS1 maint: multiple names: authors list (link).
  9. ^ Le Bars, D. “Fluorine-18 and Medical Imaging: Radiopharmaceuticals for Positron Emission Tomography” Journal of Fluorine Chemistry, 2006 Volume 127, Pages 1488-1493. {{doi:10.1016/j.jfluchem.2006.09.015}}.
  10. ^ 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
  11. ^ J. A. Gladysz, D. P. Curran, I. T. Horváth (Eds.) "Handbook of Fluorous Chemistry", Wiley–VCH, Weinheim, 2004. ISBN 978-3-527-30617-6.
  12. ^ Aimee Crombie, Sun-Young Kim, Sabine Hadida, and Dennis P. Curran. "Synthesis of Tris(2-Perfluorohexylethyl)tin Hydride: A Highly Fluorinated Tin Hydride with Advantagous Features of Easy Purification". Organic Syntheses{{cite journal}}: CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 10, p. 712.
  13. ^ Kabayadi S. Ravikumar, Venkitasamy Kesavan, Benoit Crousse, Danièle Bonnet-Delpon, and Jean-Pierre Bégué (2003). "Mild and Selective Oxidation of Sulfur Compounds in Trifluorethanol: Diphenyl Disulfide and Methyle Phenyl Sulfoxide". Organic Syntheses. 80: 184{{cite journal}}: CS1 maint: multiple names: authors list (link).
  14. ^ David O’Hagan, David B. Harper “Fluorine-Containing Natural Products” Journal of Fluorine Chemistry, 1999, Volume 100, pages 127-133. Error: Bad DOI specified!
  15. ^ William R. Dolbier Jr “Fluorine Chemistry at the Millennium” Journal of Fluorine Chemistry, 2005, Volume 126, pages 157-163. doi:10.1016/j.jfluchem.2004.09.033
  16. ^ C. Heidelberger, N. K. Chaudhuri, P. Danneberg, D. Mooren, L. Griesbach, R. Duschinsky, R. J. Schnitzer, E. Pleven, and J. Schreiner Fluorinated Pyrimidines, A New Class of Tumour-Inhibitory Compounds Nature 1957, volume 179, p. 663-666. doi:10.1038/179663a0
  17. ^ O'Hagan, D.; Schaffrath, C.; Cobb, S. L.; Hamilton, J. T.; Murphy, C. D.; (2002). "Biochemistry: biosynthesis of an organofluorine molecule". Nature. 416: 279. doi:10.1038/416279a. PMID 11907567.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
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