Usually organic compounds containing fluorine are considered to be hydrocarbon derivatives. However, highly fluorinated molecules are typically called organofluorine compounds. Most organofluorine molecules can be classified either as fluorocarbon or as perfluorinated compounds. While fluorocarbons exclusively contain carbon and fluorine, perfluorinated compounds are characterized be the replacement of all carbon-hydrogen bonds with carbon-fluorine bonds. Therefore fluorocarbons, in contrast to perfluorinated compounds, do not contain atoms such as nitrogen or oxygen. However, it should be noted that this terminology is not necessarily strictly followed [87].
For the understanding of some of the properties of organofluorine compounds, a discussion of the fundamental unit of these compounds, the carbon-fluorine bond, is required. The C-F-bond is highly polarized due to the high electronegativity of the fluorine. Despite that fact, fluorine is not characterized by a very good hydrogen bond donor ability. This can be reasoned by the fact that the lone pairs of the fluorine, due to the high electronegativity of the atom, do not significantly interact with hydrogen-bonding acceptors [88]. Further, the low polarizability of the fluo-rine atom, respectively the C-F-bond, results in relatively weak London dispersion forces between the molecules, which are scaling with the square of polarizability [87].
In fact, perfluorocarbon compounds were reported as “extremely nonpolar” [89] re-spectively the least polar existing fluids [90]. For example Teflon has a relative permittivity of only 2.1 [91].
As a consequence of the generally very weak interactions of fluorinated com-pounds with other molecules, most organic comcom-pounds are practically insoluble in fluorous fluids [73, 74]. This is also reflected by the fact that fluorinated compounds are not only immiscible with water but also with most organic solvents.
Moreover, the weak intermolecular forces result in a relatively high compress-ibility of the fluids, which reflects the availability of interstitial space [87]. For that reason, respiratory gases such as oxygen and carbon dioxide are generally highly sol-uble in fluorous fluids. In fact, the solubility of oxygen in fluorocarbons is about three to ten times higher than in the parent hydrocarbons [94]. This characteristics makes them highly valuable for the use as blood substitutes or breathing liquids [95–97].
2.4. Emulsions with a fluorous phase
Furthermore, using perfluorinated compounds as a continuous phase, cells can be cultured in aqueous emulsion droplets [50, 92, 93].
In summary, perfluorination of organic compounds generally results in signifi-cantly altered chemical and physical properties. As a result of their weak intermolec-ular interactions, they generally possess an outstanding gas-dissolving capacity and are simultaneously hydro- and lipophobic.
For droplet-based screening applications these properties are highly valuable.
The low solubility of organic molecules in fluorous fluids results in restricted cross-talk between emulsion droplets [20] while the high solubility of respiratory gases is a key for cell survival in droplets [98–101]. Furthermore, while conventional hydrocar-bon compounds may swell the microfluidic core material PDMS, leading to device delamination or channel deformation, fluorinated compounds are highly compati-ble with PDMS [102]. Water-in-fluorinated-oil emulsions are therefore considered to be the most promising systems for the miniaturization of biochemical assays in emulsion droplets [26].
2.4.2 | Phase partitioning into fluorous fluids
Due to the very low polarizability, fluorinated compounds are generally of extremely nonpolar character. Therefore, only molecules with a similar character or in other words, molecules that are fluorophilic enough, are efficiently phase partitioned from a more protic solvent. In fact nonfluorous solutes, with the exception of small gases, are in general virtually insoluble in fluorous solvents [103]. Thus these liquids can be valuable for the selective extraction of molecules covalently modified with fluorous tags [104–110].
Furthermore, it has been shown that specific noncovalent interactions can result in an increased solubility of organic molecules in fluorous liquids [90]. The increased solubility is the result of noncovalent associations of perfluororinated molecules and organic molecules based on hydrogen bonding or ion pairing. Attention has for ex-ample been drawn to fluorous carboxylic acids. They were shown to act as molecular receptor for organic molecules significantly increasing their solubility in fluorous liq-uids. One of the first reports came from Palomo et al. [111]. The authors found a dramatic solubility increase in fluorous solvents for fluorinated urea in the presence of fluorinated carboxylic acids (Fig. 2.7).
In the absence of any other functional groups, carboxylic acids were shown to exist as hydrogen bonded dimers in fluorous fluids [113]. However, it has been demonstrated that hydrogen bonds with the lone pair of nitrogen are more stable than the hydrogen bonds present in cyclic carboxylic acid dimers [114, 115]. As a consequence, most nitrogen H-bond acceptors are more successful at competing for the carboxylic acid H-bonds than the carboxylic acids themselves [112]. This in turn results in the effective extraction of organic molecules comprising Lewis base characteristics as shown for pyridines [103, 112]. In fact, the presence of equimolar amounts of fluorinated carboxylic acids in the fluorous phase leads to an almost complete extraction (up to 99%) of pyridine derivatives from chlorofrom into the fluorous phase [112]. Furthermore, it was demonstrated that the extraction of aniline in similar conditions is much less efficient (5%). This was explained by the fact that pyridyl nitrogen acts as a better hydrogen bond donor than primary amines.
Moreover, it was argued that the highly selective and effective extraction is based on the fact that the substrate-receptor interactions are reinforced in fluorous liquids, as they are considered to be ultimate noncompetitive solvents [103].
In summary, noncovalent interactions significantly improve the extraction of or-ganic molecules into a fluorous phase. The efficiency is strongly dependent on the compatibility of substrate and receptor. Particularly fluorous carboxylic acids have been studied that were shown to form strong hydrogen bonds with nitrogen contain-ing Lewis Bases.
Figure 2.7: Sketch of solubility enhancement of fluorinated urea in a fluorous solvent, in the presence of fluorinated carboxylic acids. Solubility increase was observed for N,N-di(polyfluoroalkyl)ureas due to hydrogen binding with perfluoroalkanoic acid scavengers.
Image taken from reference [111].