Hexafluorobenzene
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Through Benzene, Hydrogen and Alkali metal
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.
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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:
- C6Cl6 + 6 KF → C6F6 + 6 KCl
Antimony 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:
- 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.
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. 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. MRI measurements of HFB based on 19F relaxation have been shown to correlate with radiation response of tumors. HFB has been used as a gold standard for investigating other potential prognostic biomarkers of tumor oxygenation such as BOLD (Blood Oxygen Level Dependent), TOLD (Tissue Oxygen Level Dependent) and MOXI (MR oximetry) A 2013 review of applications has been published.
HFB has been evaluated as standard in fluorine-19 NMR spectroscopy.
Toxicity
Hexafluorobenzene may cause eye and skin irritation, respiratory and digestive tract irritation and can cause central nervous system depression per MSDS. The National Institute for Occupational Safety and Health (NIOSH) lists it in its Registry of Toxic Effects of Chemical Substances as neurotoxicant.