Technical Articles

FLUORINE 101

Fluorine is the most electronegative of all the elements and it has one of the highest ionization potentials, which means that a fluorine substituent has a strong electron-withdrawing affect on chemical bonds. Thus, the C-F bond is more polar than the corresponding C-H bond, although somewhat longer, hence stronger (more ionic). As a result, replacement of H with F in a molecule may lead to polarization with very little change in the overall size of the compound, which can lead to significantly different physical properties and biological activity. The low polarizability of fluorine and relatively small size of the atom also affect electronic and bonding properties, particularly since it has three nonbonding pairs of electrons that may resonate with pi-electron systems.

Many physical and spectroscopic properties are affected by these factors, including boiling point, dielectric constant, surface tension, density, viscosity, critical temperature and UV absorption. The amount of fluorination will also play a role, since partial fluorination leads to net C-C and C-F dipoles in a molecule and more polar behavior than either the non-polar fully fluorinated- or fully hydrogenated-analogues. Thus, changes in physical properties upon replacement of H with F will not be linear, but will be dependent on the degree of substitution as well as the pattern of substitution.

Fluorination can dramatically alter the solvent properties of an organic molecule. Perfluorocarbons (PFCs) typically are much less polar than their hydrocarbon analogues and saturated fluorocarbons are so non-polar that they make poor solvents for anything but other fluorocarbons and some gases. Indeed, much of the developing “fluorous” technology is based upon the poor solubility of heavily fluorinated molecules in standard organic solvents. Again, partial replacement of hydrogen with fluorine can lead to analogues that are more polar than the corresponding hydrocarbon or PFC.

Lipophilicity, which is an important property in biological systems, may be dramatically affected by fluorination, particularly when the fluorine is placed near a heteroatom in the molecule. Whether lipophilicity is increased or decreased is dependent on several factors, including the presence of adjacent atoms or groups with pi electrons (such as heteroatoms, carbonyl groups, and aromatics), as well as how far the site of fluorination is located from the interacting species.

Another significant aspect of fluorine’s influence, particularly for biological systems, is its relatively small size. Fluorine is considered to be roughly equal in size to a hydroxyl group, thus the replacement of an OH group with a fluorine atom in a molecule can lead to major changes in the compound’s reactivity without significantly changing the fundamental size or shape of the molecule.

The acidity of acids, alcohols, amides and most C-H acids increases with the addition of fluorine or fluorinated groups to a molecule. This effect is the result of the strong electron-withdrawing effect of these groups and can be quite large. For the same reasons, the basicity of almost all amines, ethers and carbonyl compounds is reduced by the addition of fluorine or fluorinated groups to the molecule. This property is used in the generation of fluorous media from amines and ethers.

Bond strengths of carbon to other atoms can be increased, sometimes substantially, by fluorination, depending on whether the fluorine is alpha or beta to the C-X bond. This increase leads to greater thermal and oxidative stability for perfluorinated compounds, as well as greater resistance to many common nucleophilic reactions. Partially fluorinated compounds aren’t as thermally stable as their perfluorinated analogues since they decompose by losing HF. Fluorination destabilizes multiple bonds in allenes and acetylenes, but the amount of destabilization for alkenes depends on the number of fluorine atoms attached to the double bond. The presence of fluorine or fluorinated substituents can significantly stabilize or destabilize reactive sites, depending on whether the fluorine species is alpha or beta to the site. Again, this is a reflection of the balance between the inductive and resonance effects exerted by fluorine upon reactive intermediates such as carbocations and carbanions.