Hexafluorobenzene Explained

Hexafluorobenzene, HFB,, or perfluorobenzene is an organofluorine compound. In this derivative of benzene, all hydrogen atoms have been replaced by fluorine atoms. The technical uses of the compound are limited, although it has some specialized uses in the laboratory owing to distinctive spectroscopic properties.

Geometry of the aromatic ring

Hexafluorobenzene stands somewhat aside in the perhalogenbenzenes. If a perhalogenated benzene ring were to remain planar, then geometric constraints would force adjacent halogens closer than their associated nonbonding radius. Consequently the benzene ring buckles, reducing p-orbital overlap and aromaticity to avoid the steric clash. Perfluorobenzene is an exception: as shown in the following table, two fluorines are small enough to avoid collision, retaining planarity and full aromaticity.[1]

FormulaNameInter-halogen distance (if planar)Nonbonding radius×2Consequent symmetry
C6F6 Hexafluorobenzene 279 270 D6h
C6Cl6 312 360 D3d
C6Br6 327 390 D3d
C6I6 354 430 D3d

Synthesis

The direct synthesis of hexafluorobenzene from benzene and fluorine has not been useful. Instead it is prepared by the reaction of alkali fluorides with halogenated benzene:[2]

C6Cl6 + 6 KF → C6F6 + 6 KClAntimony fluoride instead adds to the ring, breaking aromaticity.

In principle, various halofluoromethanes pyrolyze to hexafluorobenzene, but commercialization was still in the initial stages in 2000.

Reactions

Hexafluorobenzene easily undergoes nucleophilic aromatic substitution. One example is its reaction with sodium hydrosulfide to afford pentafluorothiophenol:[3]

C6F6 + NaSH → C6F5SH + NaF

The further reaction of pentafluorophenyl derivatives has long been puzzling, because the non-fluorine substituent has no effect. The second new substituent is always directed para, to form a 1,4-disubstituted-2,3,5,6-tetrafluorobenzene.

Hexafluorobenzene is thus a comonomer in certain heavily fluorinated heat-resistant polyethers' synthesis.

UV light causes gaseous HFB to isomerize to hexafluoro derivative of Dewar benzene.[4]

Laboratory applications

Hexafluorobenzene has been used as a reporter molecule to investigate tissue oxygenation in vivo. It is exceedingly hydrophobic, but exhibits high gas solubility with ideal liquid gas interactions. Since molecular oxygen is paramagnetic it causes 19F NMR spin lattice relaxation (R1): specifically a linear dependence R1= a + bpO2 has been reported.[5] HFB essentially acts as molecular amplifier, since the solubility of oxygen is greater than in water, but thermodynamics require that the pO2 in the HFB rapidly equilibrates with the surrounding medium. HFB has a single narrow 19F NMR signal and the spin lattice relaxation rate is highly sensitive to changes in pO2, yet minimally responsive to temperature. HFB is typically injected directly into a tissue and 19F NMR may be used to measure local oxygenation. It has been extensively applied to examine changes in tumor oxygenation in response to interventions such as breathing hyperoxic gases or as a consequence of vascular disruption.[6] MRI measurements of HFB based on 19F relaxation have been shown to correlate with radiation response of tumors.[7] HFB has been used as a gold standard for investigating other potential prognostic biomarkers of tumor oxygenation such as BOLD (Blood Oxygen Level Dependent),[8] TOLD (Tissue Oxygen Level Dependent) [9] and MOXI (MR oximetry) [10] A 2013 review of applications has been published.[11]

HFB has been evaluated as standard in fluorine-19 NMR spectroscopy.[12]

Toxicity

Hexafluorobenzene may cause eye and skin irritation, respiratory and digestive tract irritation and can cause central nervous system depression per MSDS.[13] The National Institute for Occupational Safety and Health (NIOSH) lists it in its Registry of Toxic Effects of Chemical Substances as neurotoxicant.

See also

Further reading

Notes and References

  1. Delorme . P. . Denisselle . F. . Lorenzelli . V. . 1967 . Spectre infrarouge et vibrations fondamentales des dérivés hexasubstitués halogénés du benzène . Infrared spectrum and fundamental vibrations of the hexasubstituted halogen derivatives of benzene . Journal de Chimie Physique . French . 64 . 591–600 . 10.1051/jcp/1967640591. 1967JCP....64..591D .
  2. Vorozhtsov . N. N. Jr. . Platonov . V. E. . Yakobson . G. G. . 1963 . Preparation of hexafluorobenzene from hexachlorobenzene . Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science . 12 . 8 . 1389 . 10.1007/BF00847820.
  3. Robson . P. . Stacey . M. . Stephens . R. . Tatlow . J. C. . 1960 . Aromatic polyfluoro-compounds. Part VI. Penta- and 2,3,5,6-tetra-fluorothiophenol . Journal of the Chemical Society . 4 . 4754–4760 . 10.1039/JR9600004754.
  4. 10.1021/ar960057j. Hexafluorobenzene Photochemistry: Wellspring of Fluorocarbon Structures . 2001 . Lemal . David M. . Accounts of Chemical Research . 34 . 8 . 662–671 . 11513574 .
  5. Book: Zhao . D. . Jiang . L. . Mason . R. P. . 2004 . Measuring changes in tumor oxygenation . Conn . P. M. . Imaging in Biological Research, Part B . Methods in Enzymology . 386 . Elsevier . 378–418 . 10.1016/S0076-6879(04)86018-X . 15120262 . 978-0-12-182791-5.
  6. Zhao . D. . Jiang . L. . Hahn . E. W. . Mason . R. P. . 2005 . Tumor physiologic response to combretastatin A4 phosphate assessed by MRI . International Journal of Radiation Oncology, Biology, Physics . 62 . 3 . 872–880 . 10.1016/j.ijrobp.2005.03.009. 15936572 .
  7. Zhao . D. . Constantinescu . A. . Chang . C.-H. . Hahn . E. W. . Mason . R. P. . 2003 . Correlation of tumor oxygen dynamics with radiation response of the Dunning prostate R3327-HI tumor . Radiation Research . 159 . 5 . 621–631 . 10.1667/0033-7587(2003)159[0621:COTODW]2.0.CO;2. 12710873 .
  8. Zhao . D. . Jiang . L. . Hahn . E. W. . Mason . R. P. . 2009 . Comparison of 1H blood oxygen level–dependent (BOLD) and 19F MRI to investigate tumor oxygenation . Magnetic Resonance in Medicine . 62 . 2 . 357–364 . 10.1002/mrm.22020 . free . 4426862 . 19526495.
  9. Hallac . R. R. . Zhou . H. . Pidikiti . R. . Song . K. . Stojadinovic . S. . Zhao . D. . Solberg . T. . Peschke . P. . Mason . R. P. . 2014 . Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response . Magnetic Resonance in Medicine . 71 . 5 . 1863–1873 . 10.1002/mrm.24846 . free . 3883977 . 23813468.
  10. Zhang . Z. . Hallac . R. R. . Peschke . P. . Mason . R. P. . 2014 . A noninvasive tumor oxygenation imaging strategy using magnetic resonance imaging of endogenous blood and tissue water . Magnetic Resonance in Medicine . 71 . 2 . 561–569 . 10.1002/mrm.24691 . free . 3718873 . 23447121.
  11. Yu . J.-X. . Hallac . R. R. . Chiguru . S. . Mason . R. P. . 2013 . New frontiers and developing applications in 19F NMR . Progress in Nuclear Magnetic Resonance Spectroscopy . 70 . 25–49 . 10.1016/j.pnmrs.2012.10.001 . 3613763 . 23540575.
  12. 10.1002/anie.201802620. Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy . 2018 . Rosenau . Carl Philipp . Jelier . Benson J. . Gossert . Alvar D. . Togni . Antonio . Angewandte Chemie International Edition . 57 . 30 . 9528–9533 . 29663671 .
  13. Web site: Material safety data sheet: Hexafluorobenzene, 99% . . n.d. . Fisher Scientific . Thermo Fisher Scientific . 2020-02-08.

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