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   The diverse applications of fluorine in bioorganic and medicinal chemistry The discovery of fluorouracil, fluorocorticoids, and fluoroquinolones has led to expanded interest in and usage of fluorine in chemistry. The first comprehensive reference dedicated to detailing the influence of fluorine on the structural properties of a molecule and on a molecule's biological behavior, Bioorganic and Medicinal Chemistry of Fluorine uses examples of fluorinated drugs to provide a thorough overview of the role of fluorine in pharmaceutical science and development. Covering established drugs as well as innovative and promising ideas, it includes: * An introduction to the structural, physical, and chemical properties of fluorinated compounds and their preparations * An examination of fluorinated analogues of natural products, fluorinated amino acids and peptides, and saccharidic derivatives * A discussion of the inhibition of enzymes by fluorinated compounds * An overview of existing fluorinated pharmaceuticals as well as some in development, categorized according to their therapeutic classes Complete with references for further study, this is the premier resource on fluorine for pharmaceutical and medicinal chemists in academia and industry, researchers in organic chemistry and biochemistry, and advanced students and educators in pharmaceutical and medicinal chemistry, biochemistry, and organic chemistry. Bioorganic and Medicinal Chemistry of FluorineBy Jean-Pierre Bégué Daniele Bonnet-Delpon John Wiley & SonsCopyright © 2008 John Wiley & Sons, Inc.All right reserved. ISBN: 978-0-470-27830-7 Chapter OneGENERAL REMARKS ON STRUCTURAL, PHYSICAL, AND CHEMICAL PROPERTIES OF FLUORINATED COMPOUNDS
This chapter deals with modifications of the physical and chemical properties of an organic molecule, which are induced by the replacement of hydrogen atoms by fluorines. These changes in the physicochemical properties play an important role in the behavior of the molecule when it is put into a biological environment. Compounds with a few fluorine atoms (arbitrarily, from a single F to a [C.sub.2][F.sub.5] group) are called "lightly fluorinated" molecules and are the focus of bioorganic and medicinal chemistry. In these compounds, the presence of fluorine atoms severely modifies their chemical reactivity, but it has only a modest influence on their physical properties. In contrast, the physical characteristics of "highly fluorinated" (perfluorinated) molecules are strongly affected with regard to their "hydrogenated analogues." Despite their important applications in the biomedicinal field (e.g., biocompatible materials and polymers, surfactants, gas carriers), such compounds are only marginally considered in this book. However, some physicochemical aspects of perfluorinated molecules are introduced in this chapter to better comprehend the properties of lightly fluorinated molecules.
1.1 STRUCTURAL EFFECTS Most of the effects induced by the presence of fluorine atoms in a molecule come from both the structure and the fundamental atomic properties of the fluorine atom (Table 1.1). Because of its electronic structure 1[s.sup.2] 2[s.sup.2] 2[p.sup.5], fluorine has very specific properties, as indicated by the extreme values of the atomic parameters given in Table 1.1. The very high ionization potential and the low polarizability of the fluorine atom imply that fluorinated compounds have only weak intermolecular interactions. Thus, perfluoroalkylated compounds have very weak surface energies, dielectric constants, and refracting indexes. The very high electronegativity of fluorine, its small size, the excellent overlap of the 2s or 2p orbitals with the corresponding orbitals of carbon, and the presence of three lone pairs of electrons mean that a fluorine atom borne by a carbon atom is always, on an inductive level, an electron-withdrawing substituent. Bonds are always strongly polarized from the [sp.sup.3] carbon ([[delta].sup.+]) to the fluorine ([[delta].sup.-]). These features associated with the low polarizability of the fluorine atom, implies that the C-F bond has a relatively important ionic character and a stronger energy than the bond between carbon and the other halogens. The dipolar nature of the C-F bond in lightly fluorinated molecules gives a polar character to these molecules. Consequently, their physico-chemical properties can be quite different from those of hydrocarbon compounds and from those of the corresponding perfluorinated compounds. In brief, the effects of fluorination on the molecular properties stem from the combination of the atomic properties of the fluorine atom: strong electronegativity, small size, excellent overlap of the 2s or 2p orbitals with the corresponding orbitals of carbon, and very strong bond with carbon.
1.2 PHYSICAL PROPERTIES 1.2.1 Boiling Point Highly fluorinated molecules have a nonpolar character and an extremely low polarizability, inducing only weak intra- and intermolecular interactions. As a consequence, perfluorocarbons behave almost like ideal liquids: they are very compressible and have very high vapor pressure. For example, the physical properties of perfluorohexane, heptafluorohexane, and hexane are reported in Table 1.2. The effect of the polar character of the hemifluorinated compound (heptafluorohexane) on the dielectric constant value is remarkable. Except in some rare cases, the boiling points of perfluorinated compounds, functionalized or not, are always lower than those of their hydrogenated analogues Table 1.3). Conversely to what is observed with the halogenated analogues, branching has only a minor effect on the boiling point. Indeed, perfluoroisopentane has a boiling point (bp) close to that of n-fluoropentane, while the bpofisopentane is much less than that of n-pentane. The bp of a perfluoroalkane is only 25-30°C higher than that of the rare gas with the same molecular weight. This illustrates the "perfect" fluid character of these compounds, resulting from the low intermolecular interactions. While the boiling points of chloro- and bromomethanes always increase according to the number of halogen atoms, this correlation does not exist in the case of fluoromethanes. The bp increases from [CH.sub.4] to [CH.sub.2][F.sub.2] and then decreases until [CF.sub.4] (Table 1.4). Indeed, a parallelism exists between boiling points and dipolar moments. A partially fluorinated compound will exhibit nonnegligible intermolecular interactions according to the importance of the dipolar moment (Table 1.5). Fluorinated compounds, even the lightly fluorinated ones, have a high vapor pressure with respect to those of their hydrogenated analogues. Fluorinated molecules are often volatile, even when the boiling point is relatively high. Consequently, careful handling of fluorinated compounds is required during isolation to avoid possible accidental inhalation of these toxic substances.
1.2.2 Surface Tension and Activity The surface tension ? measures the molecular forces that oppose the extension of the area of a liquid dropped on a surface. A perfluoroalkane always has a surface tension lower than that of the corresponding alkane (Table 1.6). Perfluoroalkanes are able to wet any kind of surface. Perfluoroamines and -ethers also have low surface tensions (15-16 dyn/[cm.sup.2]). Fluorinated surfactants lower the surface tension of water more strongly than their nonfluorinated analogues. Fluorinated surfactants reduce the superficial pressure of water from 72 to 15-20 dyn/[cm.sup.2] while a nonfluorinated agent only decreases the value to 25-35 dyn/[cm.sup.2] (Table 1.6). Perfluorocarbons bearing a polar hydrophilic head are very active surfactants. Indeed, the presence of fluorine atoms strongly lowers the critical micelle concentration (CMC) of an amphiphilic compound. Moreover, fluorination generally has important effects on micellization phenomena, especially on the size and shape of formed micelles. Hemifluorinated compounds F[([CF.sub.2]).sub.m]-[([CH.sub.2]).sub.n]H often have a particular behavior. Because of their strong polarity, these compounds are able to form micelles in fluorocarbon as well as in hydrocarbon media.
1.2.3 Polarity-Solubility Paradoxically, fluorinated compounds are found among the least polar compounds (perfluorocarbons) as well as among the most polar ones (fluorinated alcohols), according to the empirical scale of Middleton ([P.sub.s]). Some representative examples of fluorinated solvents and related hydrogenated compounds are given in Table 1.7. Perfluorocarbon compounds, almost apolar, are nonmiscible with both water and hydrocarbon compounds. They are able to dissolve only compounds with very low cohesive energies, such as gases and highly fluorinated molecules. This very specific ability of perfluorinated compounds to dissolve gases has found an application in oxygen carrier liquids (short-time blood substitutes). A perfluorocarbon dissolves three times more oxygen than the corresponding hydrocarbon, and ten times more than water. This property can be explained by the presence of large cavities in the liquid and by the weak intermolecular interactions of the medium, and not by specific interactions. Replacing some of the fluorine atoms by hydrogen atoms increases the polarity. Hydrofluorocarbons are more polar than the corresponding perfluorocarbons. They can also be even more polar than their hydrocarbon analogues.
1.2.4 Lipophilicity Lipophilicity is of prime importance in the design of drugs. Indeed, it controls many parameters such as absorption, biological barrier passage (and consequently transport into organs and cells), and also interaction with the macromolecular target (cf. Chapter 3). 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 [pi] 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 confusion between these two characteristics is common in medicinal chemistry. It comes from the usual empirical measurement of the lipophilicity, which is the logarithm of the partition coefficient between 1-octanol and water (log P). This parameter gives a representative overview of a compound absorbed by a lipidic membrane, an essential datum in medicinal chemistry. It is often considered that the higher the log P value is, the more lipophilic the compound is. Actually, the log P value is only a measurement of relative solubility. Considering that the solubility of a fluorinated substance decreases more in water than in octanol, this measurement leads one to think that fluorinated compounds are more "lipophilic." Actually, this represents the relative lack of affinity of fluorinated compounds for both phases. Table 1.8 shows some Hansch-Leo p values for aromatic compounds (p = log [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] for substituted benzenes). Note that the effects of fluorination can be relatively important (e.g., [C.sub.6][[H.sub.5]-[SO.sub.2][CF.sub.3] is ~ 150 times more lipophilic than [C.sub.6][H.sub.5]-S[O.sub.2]C[H.sub.3]). For aliphatic molecules, the data are rarer. Nevertheless, partial fluorination lowers the log P value, conversely to aromatic molecules. For alcohols, the situation is more complex: the log P value is dependent on the position of fluorine atoms and on the chain length (Table 1.9). The log P value strongly depends on the solvent system chosen as a reference (e.g., cyclohexane/water versus octanol/water), since associations and hydrogen bonds are highly depending on the nature of the solvent. This is highlighted in the case of functionalized fluorinated molecules, where fluorination strongly modifies hydrogen bonding (Table 1.10). Trifluoromethyl ketones, which are enzyme inhibitors, constitute an interesting example: the log P value depends on the equilibrium between hydrate, hemiketal, and ketone and the equilibrium is itself less important than the solvent. The solubility of each of these forms also depends on the solvents nature. For these reasons, the observed log P values are often difficult to interpret.
1.3 EFFECTS ON ELECTRONIC PROPERTIES AND REACTIVITY In a molecule, fluorine atoms influence bond energies, electronic distribution, acidity, hydrogen bonds, steric interactions, and the stability of intermediate entities in a transformation. These factors, which have great influence on chemical reactivity, are examined.
1.3.1 Effects of Fluorination on Bond Energies and Reactivity The C-F bond is the strongest bond that a carbon atom can form with another atom. For example, the C-F bond is 25 kcal/mol stronger than the C-Cl bond. Moreover, the strength of the C-F bond increases with the number of fluorine atoms borne by the carbon, conversely to what occurs with the other halogens (Table 1.11). [alpha]-Fluorination does not have much influence on the C-H bonds, but it increases the strength of the C-F,C-O, and C-Cbonds. For example, in the bis(trifluoromethyl) ether C[F.sub.3]-O-C[F.sub.3], the C-O bond is 22 kcal/mol stronger than that of dimethyl ether. The C-C bond of trifluoroethane is more than 10 kcal/mol stronger than that of ethane, and also stronger than that of hexafluoroethane (Table 1.11). Strengthening of the C-F bonds by fluorination explains the great stability of the C[F.sub.3] groups. In contrast, ß-fluorination strongly increases the C-H bond strengths (Table 1.12). The C-H bond in [(C[F.sub.3]).sub.2]C-H is 15 kcal/mol stronger than in [(C[H.sub.3]).sub.2]C-H. However, ß-fluorination has little effect on C-F bonds. This strengthening of C-F, C-H, and C-O bonds, through [alpha]- or ß-fluorination, givesfluoroalkyl compounds a significantly greater chemical, thermal, and enzymatic inertness compared to their nonfluorinated analogues. Highly fluorinated, or perfluorinated, polymers exhibit very high thermal and chemical stabilities, which justify their use in the field of biocompatible materials, volatile anesthetics, and artificial blood. The C-F bond strength renders the aliphatic fluorides much less reactive than the Corresponding chlorides in [S.sub.N]1 or [S.sub.N]2 reactions (from [10.sup.-2] to [10.sup.-6]). Influoroalkenes, the C-F bond is also strong: the more fluorine atoms there are, the stronger the [pi] double bond is. In general, the reactivity of these double bonds decreases with electrophiles while it increases with nucleophiles.
1.3.2 Effects of Fluorination on the Electronic Repartition of a Molecule Due to the inductive effect, fluorine is always an electron-withdrawing substituent. Nevertheless, it can be electron-donating through resonance. Fluoroalkyl groups always behaveas electron-withdrawing substituents. The bond polarization is givenin Figure 1.1. When bonded to an unsaturated carbon atom or to an arene, the fluorine atom exerts an inductive electron-withdrawing effect ([[sigma].sub.I] > 0) and an electron-donating effect through resonance ([[sigma].sub.R] < 0), both being very superior to the effects of the other halogens (Figure 1.1). The values of the Hammet parameters [[sigma].sub.I] and [[sigma].sub.R] of some fluorinated substituents are reported in Table 1.13. The effect of fluorination on the reactivity of the ketone carbonyl group is important. Applications in enzymology are given in Chapters 3 and 7. Nucleophiles such as water, alcohols, and, amines add easily to fluoroaldehydes and fluoroketones, providing stable adducts (e.g., hydrates, hemiketals). Trifluoroacetaldehyde (fluoral) is commercialized only under its stable forms: hydrate and hemiketal. The great electrophilicity of the carbonyl is commonly attributed to an increase in the positive charge of the carbonyl (charge control). However, ab initio calculations on fluoroacetaldehydes have shown that the charge on the carbonyl does not vary significantly, while the length of the C=O bond and the negative charge of the oxygen atom are lowered by the fluorination (Figure 1.2). Different type of computational studies show that the electrophilicity may result from a significant lowering of the carbonyls LUMO (orbital control) (Figure 1.3).
1.3.3 Acidity, Basicity, and Hydrogen Bond 1.3.3.1 Acidity Fluoroalkyl groups are strong electron-withdrawing substituents; consequently, the acidity of neighboring hydrogen atoms is greatly increased (Table 1.14). p[K.sub.a] of carboxylic acids, alcohols, and imides are reported in Table 1.15 and Figure 1.4. In the same manner, fluorination largely lowers the basicity of amines: perfluorinated secondary amines are not able to afford hydrochlorides, and perfluorinated tertiary amines show a behavior close to that of perfluorocarbon compounds. This inertness is essential for their applications (biocompatible emulsions). (Continues...)
Jean-Pierre Begue, PHD, is Emeritus Director of Research at the Centre National de la recherche Scientifique (CNRS) in France. Danièle Bonnet-Delpon, PHD, is Director of Research at CNRS. The authors and their coworkers have developed the chemistry of fluorinated compounds, from organic synthesis to medicinal chemistry. |
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