Hexafluorobenzene

Hexafluorobenzene
Names
	Preferred IUPAC name Hexafluorobenzene
	Other names Perfluorobenzene
Identifiers
CAS Number	392-56-3 ;
3D model (JSmol)	Interactive image;
Abbreviations	HFB
Beilstein Reference	1683438
ChEBI	CHEBI:38589 ;
ChemSpider	13836549 ;
ECHA InfoCard	100.006.252
EC Number	206-876-2;
Gmelin Reference	101976
PubChem CID	9805;
UNII	CMC18T611K ;
CompTox Dashboard (EPA)	DTXSID5043924 ;
	InChI InChI=1S/C6F6/c7-1-2(8)4(10)6(12)5(11)3(1)9 Key: ZQBFAOFFOQMSGJ-UHFFFAOYSA-N ; InChI=1/C6F6/c7-1-2(8)4(10)6(12)5(11)3(1)9 Key: ZQBFAOFFOQMSGJ-UHFFFAOYAJ;
	SMILES Fc1c(F)c(F)c(F)c(F)c1F;
Properties
Chemical formula	C6F6
Molar mass	186.056 g·mol−1
Appearance	Colorless liquid
Density	1.6120 g/cm3
Melting point	5.2 °C (41.4 °F; 278.3 K)
Boiling point	80.3 °C (176.5 °F; 353.4 K)
Refractive index (nD)	1.377
Viscosity	cP (1.200 mPa•s) (20 °C)
Dipole moment	0.00 D (gas)
Hazards
	GHS labelling:
Pictograms
Signal word	Warning
Hazard statements	H225
Precautionary statements	P210, P233, P240, P241, P242, P243
Flash point	10 °C (50 °F; 283 K)
Related compounds
Related compounds	Benzene; Hexachlorobenzene; Polytetrafluoroethylene; Perfluorotoluene
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

Hexafluorobenzene, HFB, C
₆F
₆, 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 In this derivative of benzene, all hydrogen atoms have been replaced by fluorine atoms.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.^[4]

Formula	Name	Inter-halogen distance (if planar)	Nonbonding radius×2	Consequent symmetry
C₆F₆	Hexafluorobenzene	279	270	D_6h
C₆Cl₆	Hexachlorobenzene	312	360	D_3d
C₆Br₆	Hexabromobenzene	327	390	D_3d
C₆I₆	Hexaiodobenzene	354	430	D_3d

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:^[5]

C₆Cl₆ + 6 KF → C₆F₆ + 6 KCl

Antimony fluoride instead adds to the ring, breaking aromaticity.^[6]^: 861

In principle, various halofluoromethanes pyrolyze to hexafluorobenzene, but commercialization was still in the initial stages in 2000.^[7]^: 21^{[needs update]}

Reactions

Hexafluorobenzene easily undergoes nucleophilic aromatic substitution.^[6]^: 866^[7]^: 19–21 One example is its reaction with sodium hydrosulfide to afford pentafluorothiophenol:^[8]

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.^{[citation needed]}

Hexafluorobenzene is thus a comonomer in certain heavily fluorinated heat-resistant polyethers' synthesis.^[9]

UV light causes gaseous HFB to isomerize to hexafluoro derivative of Dewar benzene.^[10]

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.^[11] 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.^[12] MRI measurements of HFB based on 19F relaxation have been shown to correlate with radiation response of tumors.^[13] HFB has been used as a gold standard for investigating other potential prognostic biomarkers of tumor oxygenation such as BOLD (Blood Oxygen Level Dependent),^[14] TOLD (Tissue Oxygen Level Dependent) ^[15] and MOXI (MR oximetry) ^[16] A 2013 review of applications has been published.^[17]

HFB has been evaluated as standard in fluorine-19 NMR spectroscopy.^[18]

Toxicity

Hexafluorobenzene may cause eye and skin irritation, respiratory and digestive tract irritation and can cause central nervous system depression per MSDS.^[19] The National Institute for Occupational Safety and Health (NIOSH) lists it in its Registry of Toxic Effects of Chemical Substances as neurotoxicant.

References

^ Siegemund, Günter; Schwertfeger, Werner; Feiring, Andrew; Smart, Bruce; Behr, Fred; Vogel, Herward; McKusick, Blaine; Kirsch, Peer (2016). "Fluorine compounds, organic". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. p. 44. doi:10.1002/14356007.a11_349.pub2. ISBN 978-3527306732.{{cite encyclopedia}}: CS1 maint: multiple names: authors list (link)
^ "Hexafluorobenzene 99%". Sigma Aldrich.
^ Acros Organics:Catalog of fine Chemicals (1999)
^ 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 (in French). 64: 591–600. Bibcode:1967JCP....64..591D. doi:10.1051/jcp/1967640591.
^ 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. doi:10.1007/BF00847820.
^ ^a ^b Bajzer, William X., "Fluorine compounds, organic", Kirk-Othmer Encyclopedia of Chemical Technology, vol. 11, New York: John Wiley, doi:10.1002/0471238961.0914201802011026.a01.pub2, ISBN 9780471238966
^ ^a ^b Boudakian, Max M., "Fluorinated aromatic compounds", Kirk-Othmer Encyclopedia of Chemical Technology, New York: John Wiley, doi:10.1002/0471238961.0612211502152104.a01, ISBN 9780471238966
^ 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. doi:10.1039/JR9600004754.
^ Cassidy, Patrick E.; Aminabhavi, Tejraj M.; Reddy, V. Sreenivasulu, "Heat-resistant polymers", Kirk-Othmer Encyclopedia of Chemical Technology, New York: John Wiley, p. 18, doi:10.1002/0471238961.0805012003011919.a01, ISBN 9780471238966
^ Lemal, David M. (2001). "Hexafluorobenzene Photochemistry: Wellspring of Fluorocarbon Structures". Accounts of Chemical Research. 34 (8): 662–671. doi:10.1021/ar960057j. PMID 11513574.
^ Zhao, D.; Jiang, L.; Mason, R. P. (2004). "Measuring changes in tumor oxygenation". In Conn, P. M. (ed.). Imaging in Biological Research, Part B. Methods in Enzymology. Vol. 386. Elsevier. pp. 378–418. doi:10.1016/S0076-6879(04)86018-X. ISBN 978-0-12-182791-5. PMID 15120262.
^ 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. doi:10.1016/j.ijrobp.2005.03.009. PMID 15936572.
^ 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. doi:10.1667/0033-7587(2003)159[0621:COTODW]2.0.CO;2. PMID 12710873.
^ 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. doi:10.1002/mrm.22020. PMC 4426862. PMID 19526495.
^ 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. doi:10.1002/mrm.24846. PMC 3883977. PMID 23813468.
^ 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. doi:10.1002/mrm.24691. PMC 3718873. PMID 23447121.
^ 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. doi:10.1016/j.pnmrs.2012.10.001. PMC 3613763. PMID 23540575.
^ Rosenau, Carl Philipp; Jelier, Benson J.; Gossert, Alvar D.; Togni, Antonio (2018). "Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy". Angewandte Chemie International Edition. 57 (30): 9528–9533. doi:10.1002/anie.201802620. PMID 29663671.
^ "Material safety data sheet: Hexafluorobenzene, 99%". Fisher Scientific. Thermo Fisher Scientific. n.d. Retrieved 2020-02-08.