Fluorine has become an increasingly important element in biological investigations. The reasons for this are that fluorine does not occur naturally in most biomolecules, that its nucleus has a magnetic moment and a relatively strong nuclear magnetic resonance (NMR) signal, and because the element has unusual electronic properties (specifically, a very large electronegativity). A simple example dramatically illustrates the electronic effect of fluorine on chemical properties: the pK_a of H-H (dihydrogen) acting as an acid is estimated to be about 42 and the pK_a of H-F is 3.2. In other words, substitution of H by F increases acidity by nearly forty orders of magnitude!

When it is synthetically feasible to do so, replacement of a hydrogen in a biological molecule with fluorine provides the potential for both a sensitive physical probe (via NMR) and significant alteration of the molecule’s electronic properties, thus providing a diagnostic tool that can be used in mechanistic investigations. This approach has been widely used in the study of both proteins and small molecules of biological importance. What has made fluorine especially attractive is the notion that its covalent radius is about the same as that of hydrogen. In other words, fluorine, like hydrogen, is small. This in principle eliminates one variable ? size ? from consideration when the effect of fluorine is considered.

David Lemal and Patrick Lindner, scientists at Dartmouth University, have addressed the question of fluorine size both experimentally and theoretically, and have found that, at least in the case of fluorine-fluorine interactions, the sterics effect of fluorine ? the physical consequences of fluorine’s size ? are considerable. This result is consistent with some earlier work by Smart (2) which suggests that the covalent radius of fluorine is not 1.35 A, as previously suggested, but rather 1.47 A. In other words, fluorine is about the same “size” as oxygen.

Lemal and Lindner based their findings on considerable amounts of both experimental equilibrium data and sophisticated theoretical calculations involving fluorinated compounds. The calculations were shown to reproduce some of their experimental findings. Among their theoretical results, they found the E for the following equilibrium:

The large energy change is attributed to relief of the F-F repulsions shown in the leftmost structure.

The Dartmouth scientists conclude that fluorine-fluorine nonbonded repulsions are considerable. In effect, when fluorines are juxtaposed near other fluorines, the fluorines “act as if they are large.” Lemal and Lindner argue that a -CF₃ group is about the same size as an isopropyl group (-CH(CH₃)₂). They also point out, however, that there is more to nonbonded repulsions than size of the electron cloud surrounding a fluorine atom; fluorine, because of its electronegativity, bears considerable negative charge. Consequently, electrostatic repulsion is probably a component of the observed effects.

The “effective size” of a fluorine when it is juxtaposed next to atoms other than another fluorine ? say, hydrogen or carbon ? is not addressed directly by this work. However, there seems to be no doubt that fluorines, energetically speaking, don’t like to be too close to other fluorines, so that the “effective size” of a fluorine in such an environment is perhaps greater than previously thought.

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