The Polar Hydrophobicity of Fluorinated Compounds Justin C. Biffinger, Hong Woo Kim, and Stephen G. DiMagno* [a] Brief Survey of Fluorine Substitution Fluorine substitution is a powerful tool in bioorganic and me- dicinal chemistry. [1±4] The chemical inertness and relatively small size of fluorine [5, 6] coupled with the short C ÀF bond length have made C ÀF substitution attractive for the replace- ment of a number of functional groups, including C ÀOH, C ÀH, and C =O. Fluorine incorporation into biologically active com- pounds can alter drug metabolism [7±12] or enzyme substrate recognition. [13±18] The hydrophobic nature of fluorinated com- pounds is also cited for improved transport across the blood± brain barrier. [19±22] Improved oral bioavailability is seen in some systems where fluorine substitution leads to improved hydro- lytic stability. [21, 23±26] Furthermore, replacement of sensitive or reactive groups with fluorinated substituents has led to mech- anism-based inhibitors for a wide variety of diseases and to chemotherapeutic drugs. [19, 27±31] Review articles appear regular- ly on these subjects ; some recent examples are given in refs. [9, 27, 32±37] . Properties of Fluorinated Compounds Fluorinated compounds, like hydrocarbons, have negative en- tropies of aqueous solvation (at room temperature) due to the tendency of water molecules to ™order∫ around the hydropho- bic portions of the solute, [38±42] although the exact nature of this ™hydrophobic hydration∫ is a matter of considerable con- troversy. [43, 44] Generally, the entropy of binding hydrophobic substrates to protein receptors is large and positive due to the liberation of water by desolvation of the solute. Several strat- egies have been developed to exploit the hydrophobic effect [37, 40±42] for the design of enzyme inhibitors with increased free energies of binding. One germane approach from the group of Whitesides relied on the attachment of a hydropho- bic group to the substrate at a point distant from the specifi- cally recognized portion of the molecule. [45] In this work, the binding of the inhibitors (Scheme 1) to carbonic anhydrase was directly proportional to the total surface area of the hydro- phobic group, irrespective of its (branched or fluorinated) nature, a result indicating that hydrophobic hydration of ap- pended fluorocarbon and hydrocarbon segments enhances the free energy of binding by a similar mechanism. The greater affinities observed for fluoroalkylated compounds were attrib- uted solely to the larger hydrophobic surface areas desolvated upon binding. It should be noted that this general enhance- ment of molecular recognition is expected to be larger if hy- drophilic groups are replaced by fluorocarbon moieties or if the fluorocarbon segment is incorporated into the binding pocket. It is not controversial that fluorocarbon groups are hydro- phobic. [6] However, whether the C ÀF bond can participate in strong polar interactions is a matter of some debate. The C ÀF bond is highly dipolar, as is evidenced by the large dipole mo- ments (m) of fluorinated hydrocarbons (Table 1). A second criti- cal feature of the C ÀF bond is that it is relatively nonpolariza- ble, which accounts, in part, for the extremely low refractive in- dices of fluorocarbons. (C ÀF bonds also reduce overall molecu- lar polarizabilities of organic molecules by increasing the hard- ness of the carbon framework, a fact that helps account for the general increase in lipophilicity (p), [46, 47] of fluorinated aro- matics.) Thus, the C ÀF bond is expected to act as a hard Lewis base. In the gas phase, polar fluorinated hydrocarbons such as flu- oromethane (m = 1.85 debye) act as hydrogen-bond acceptors and form hydrogen bonds that are roughly half the strength of hydrogen bonds formed to water for the same proton donor. [48] Despite this observation, hydrogen bonding to C ÀF dipoles of fluorinated organic molecules is generally not ob- served in polar solvents such as alcohols, amines, or water. [49] The reason for this divergent behavior is clear; the C ÀF bond [a] J. C. Biffinger, H. W. Kim, Prof. S. G. DiMagno Department of Chemistry, University of Nebraska Lincoln, NE 68588-0304 (USA) Fax: (+ 1)402-472-9492 E-mail: sdimagno1@unl.edu Scheme 1. Inhibitors of carbonic anhydrase featuring hydrocarbon and fluoro- carbon tails of varying lengths. Table 1. Physical properties of the C ÀF bond. [77] Compound Dipole mo- ments Compound Refractive b.p. [debye] index [8C] CH 3 F 1.85 perfluorohexane 1.2515 57.1 CH 2 F 2 1.97 hexane 1.3751 69 fluorobenzene 1.70 hexafluorobenzene 1.3777 80.5 benzene 1.5011 80.1 622 ¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI : 10.1002/cbic.200300910 ChemBioChem 2004, 5, 622 ± 627