Hexafluorobenzene

Geometry of the aromatic ring

Hexafluorobenzene in the perhalogenbenzenes stands somewhat aside. 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:

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:

Fluorine and the aromatic ring

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 (partially) 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 an 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 (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 Dependant), TOLD (Tissue Oxygen Level Dependant) and MOXI (MR oximetry) An extensive review of applications is provided in.