Hydrophobicity of fluorine

Yokoyama, H. and Sugiyama, K. (2004) Surface Hydrophobicity of fluorinated block copolymers enhanced by supercritical carbon dioxide annealing. Langmuir, 20,10001-10006. 

Carboxjiates with a fiuorinated alkyl chain ate marketed by the 3M/Industrial Chemical Products Company under the trade name Fluotad surfactants. They also include other functional derivatives of fiuorinated and perfluorinated alkyl chains. Replacement of hydrogens on the hydrophobe by fluorine atoms leads to surfactant molecules of unusually low surface tension. This property imparts excellent leveling effectiveness. 

A C60 derivative with an attached fluorinated chain gave a limiting area of 0.78 nm molecule [266]. It was reported that this film was so mechanically rigid that it pushed the Wilhehny plate out of the water at 11 14 mN m The monolayer spreading of this compound arises from the even greater hydrophobicity of the fluorocarbon chains and their orientation away from the water surface. The LB films with a fluorinated tetrathiafulvalene derivative did not show evidence of charge transfer in their UV spectra. 

This chapter aims to summarize our efforts to investigate the effects of fluorinated amino acid substitutes on the interactions with natural protein environments. In addition to a rather specific example concerning the interactions of small peptides with a proteolytic enzyme, we present a simple polypeptide model that aids for a systematic investigation of the interaction pattern of amino acids that differ in side chain length as well as fluorine content within both a hydrophobic and hydrophilic protein environment. Amino acid side chain fluoiination highly affects polypeptide folding due to steric effects, polarization, and fluorous interactions. 

The a-helical coiled coil-based screening system already provided a wide variety of information about the interactions of fluorinated amino acids within hydrophobic and hydrophilic protein environments. Investigations on the thermal stability as well as the replicase activity have both emphasized the orthogonal properties of fluorinated aliphatic amino acid side chains. The term orthogonal in this context has been chosen by us to demonstrate that they are in fact hydrophobic... 

Being highly hydrophobic but less lipophilic than their hydrocarbon analogs, fluoroalkyl amino acid side chains tend to interact with one another by fluorine-fluorine contacts. Therefore, even one single fluorinated amino acid can direct polypeptide folding due to strong character of fluorine-fluorine interactions (Section 3.3 and 3.4). 

In the case of fluorinated molecules, it is important to differentiate the lipophilic character from the hydrophobic character. Both these characters are in tune for nonfluorinated molecules, but they diverge when the number of fluorine atoms increases in a molecule. It is generally recognized that fluorination induces an increase in the lipophilicity. However, this has only been demonstrated for aromatic compounds, and more specifically when fluorine atoms are in the a position of atoms, or groups bearing n electrons (Table 1.8)." Conversely, the presence of fluorine atoms in an aliphatic molecule provokes a decrease in the lipophilicity, while it can enhance the hydrophobicity. This phenomenon is so important that highly fluorinated molecules are not soluble in organic solvents or in water and constitute a third phase. 

The affinity of a substrate with its biological target is first connected to its complementarity with this macromolecule target. The molecular recognition and affinity depend on all the favorable interactions that exist in the supramolecular assembly formed between the substrate and the macromolecule. If the presence of fluorine atoms enhances the strength or the number of these favorable interactions, the affinity of the fluorinated substrate will be higher than that of the parent compound. The main parameters involved are the steric and conformational effects, the dipolar/hydrophobic interactions, and the hydrogen bonds. 

These effects result from the impact of fluorination on the properties of the peptide at the level of (1) the lipophilicity/hydrophobicity balance and p faJ (2) the conformation, because of the more demanding volume of the fluorinated moiety and (3) the hydrolytic and metabolic stability. 

Highly fluorinated amino acids, such as hexafluoroleucine and hexafluorovaline, enhance the stability of several helical proteins. This enhancement has been attributed to the higher hydrophobicity of the fluorocarbon side chain compared to that of the natural hydrocarbon side chain. 

The dielectric constant is affected in different ways by a number of different mechanisms. Some of these mechanisms are interdependent and so it is difficult to ascertain their individual dependencies on fluorine incorporation. For instance, the increased hydrophobicity caused by fluorination decreases the ambient dielectric constant by elimination of water from the polymer, while the incorporation of fluorine also affects the intrinsic properties of the polymer irrespective of the moisture effect. Most published dielectric data were measured under ambient conditions and thus the distinction between these effects is lost. 

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