Hexafluorobenzene


Hexafluorobenzene, HFB,, or perfluorobenzene is an organic, aromatic 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 In this derivative of benzene all hydrogen atoms have been replaced by fluorine atoms.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 is recommended as a solvent in a number of photochemical reactions. In the laboratory hexafluorobenzene is used as
standard in fluorine-19 NMR spectroscopy, solvent and standard in carbon-13 NMR, solvent in proton NMR, solvent when studying some parts in the Infrared and solvent in Ultraviolet–visible spectroscopy, as hexafluorobenzene itself hardly shows any absorbance in the UV region.

Geometry of the aromatic ring

Hexafluorobenzene stands somewhat aside in the perhalogenbenzenes. When counting for bond angles and distances it is possible to calculate the distance between two ortho fluorine atoms. Also the non bonding radius of the halogens is known. The following table presents the results:
FormulaNameCalculated
inter-halogen
distance, aromatic ring assumed planar		Twice nonbonding radiusConsequent symmetry of the benzene
C6F6hexafluorobenzene279270D6h
C6Cl6hexachlorobenzene312360D3d
C6Br6hexabromobenzene327390D3d
C6I6hexaiodobenzene354430D3d

The conclusion of the table is HFB is the only perhalobenzene being planar, the others all are buckled more or less. As a consequence in C6F6 the overlap between the p-orbitals is optimal, while in the others it is less, also giving rise to a lower aromaticity in those compounds.

Synthesis

The direct synthesis of hexafluorobenzene from benzene and fluorine is not possible. The synthetic route proceeds via the reaction of alkali-fluorides with halogenated benzene:

Applications

In the laboratory hexafluorobenzene is used for several purposes:
A substantial part of the chemistry of HFB is related to the position of fluorine in the periodic table. On its position at the end of the first row, fluorine is a halogen. It also is the smallest one, so taking up an electron releases one of the largest amounts of energy of all elements, it is the strongest oxidant, and it has the highest electronegativity. The carbon fluorine bond therefore is highly polarized: the carbon atom has positive charge, fluorine negative. This reasoning holds very much for the electrons in the σ-bonds. Electrons in p-orbitals encounter a totally different situation. The p-orbital at fluorine parallel to the one on the adjacent carbon will face an optimal interaction. Thereby fluorine, unlike the higher halogens, has no extra nodal plane in its orbitals, so size and geometry fit perfectly and no anti-bonding interactions occur. The dipole resulting from the σ-electronegativity will force a partial replacement of electric charge from fluorine towards carbon and the aromatic ring: fluorine behaves as a σ-electronegative, but as a π-electropositive element. This view is supported by the reactions C6F6 exhibits.

Reactions

Most reactions of HFB proceed with displacement of fluoride. One example is its reaction with sodium hydrosulfide to afford pentafluorothiophenol:
The reaction of pentafluorophenyl derivatives has been long puzzling for its mechanism. Independent of the substituent, they all exhibit a para directing effect. The new introduced group too has no effect on the directing behaviour. In all cases, a 1,4-disubstituted-2,3,5,6-tetrafluorobenzene derivative shows up. Finally, the clue is found not in the nature of the non-fluorine substituent, but in the fluorines themselves. The π-electropositive effect introduces electrons into the aromatic ring. The non-fluorine substituent is not capable of doing so. As charge accumulates at the ortho and para positions relative to the donating group, the ortho and para-positions relative to the non-fluorine substituent receive less charge, so are less negative or more positive. Furthermore, the non-fluorine substituent in general is more bulky than fluorine, so its ortho-positions are sterically shielded, leaving the para-position as the sole reaction site for anionic entering groups.

Biomedical 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 : 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, TOLD and MOXI A 2013 review of applications has been published.

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 lists it in its Registry of Toxic Effects of Chemical Substances as neurotoxicant.