Fluorine substituent effects (on bioactivity)

doi:10.1016/S0022-1139(01)00375-X

Journal of Fluorine Chemistry

Volume 109, Issue 1, June 2001, Pages 3-11

https://doi.org/10.1016/S0022-1139(01)00375-X Get rights and content

Abstract

The characteristic effects of fluorine and fluoroalkyl substituents on the physico-chemical properties of molecules that are important to biological activity of fluorinated compounds are highlighted. The influence of fluorination on acidity, hydrogen-bonding, and lipophilicity that affect compound absorption and distribution is described. The current perspectives on fluorine steric interactions and the controversial role of hydrogen-bonding involving the CF bond are discussed.

Introduction

Fluorine leaves nobody indifferent; it inflames emotions be that affections or aversions. As a substituent, it is rarely boring, always good for a surprise, but often completely unpredictable [6].

The above quote, although somewhat melodramatic, does capture the reaction of many researchers to the effects of fluorine substitution on chemical and biological activities. With perhaps the exception of fluorine steric interactions, substituent effects on reactive intermediates (carbocations, carbanions, carbenes and free radicals) that underlie the chemical reactivity of fluorinated compounds are now rather well understood and fairly predictable [1], [2], [3], [4], [5]. By contrast, fluorine substituent effects on physical properties important to compound binding, absorption, and transport that can impact biological activity are often less well understood from this author’s experience. This presentation will cover mainly the topics listed below, emphasizing those in italics.

Volatility; lipophilicity; solubility (acidity and basicity); hydrogen-bonding; steric effects.

Section snippets

Atomic physical properties

The unique combination of atomic physical properties of F versus other halogens that underlie its special effects are given in Table 1.

Special properties of F are as follows:

•
high electronegativity;
•
relatively small size;
•
very low polarizability;
•
tightly bound, three non-bonding electron pairs;
•
excellent overlap between F 2s and 2p with corresponding orbitals of other second period elements.

Boiling points, refractive indexes and surface tensions

The pronounced contrasting physical properties of perfluorocarbons versus hydrocarbons (boiling point,

Fluorocarbon solvents and solubility

Organofluorine compounds are amongst both the least and most polar solvents known. Given the widely variable effect of fluorination on polar character and lipophilicity depending upon the site and level of fluorination, it comes as no surprise that organofluorine compounds have solvent properties ranging in extreme from the non-polar perfluoroalkanes to the extraordinarily polar solvent, hexafluoroisopropanol. A quantitative (logarithmic) solvatochromic polarity scale developed by Middleton (

Electronic properties: inductive and resonance effects

The Hammett type substituent parameters for several common fluorinated groups are given in Table 9. The inductive electron withdrawing effects are not surprising given the extreme electronegativity of the fluorine atom, whereas electron donation of fluorine by resonance reflects the attributes of its lone-pair electrons described earlier as the special properties of fluorine. These electronic characteristics make effects of fluorination on acidity and basicity predictable in most cases.

•
Fluorine

Acidity and basicity

Fluorination

•
always increases hydrogen bond acidity;
•
normally increases Bronsted acidity (some carbon acid exceptions);
•
always decreases hydrogen-bond and Bronsted basicities (Table 10).

α^{H},β^{H} : AH + B ⇌ A  H ⋯ B

p K_{a} : AH + H_{2} O ⇌ A^{−} + H_{3} O^{+}

The relative effects of fluorination on amino acid acidity and basicity would appear unusual at first glance where monofluorination has a negligible effect, but trifluorination has a large effect on basicity but only a moderate effect on acidity (Table 11). This trend, however,

Hydrogen-bonding

Although, there is little remaining controversy about the effects of fluorination on acidity, basicity, or functional group hydrogen-bonding, the importance of CF in hydrogen-bonding has been debated intensely over the past decade. Some factors that might either favor or disfavor hydrogen-bonding to FC are listed below, and a summary of the current perspectives on this hydrogen-bonding versus the more conventional type with heteroatoms (O, N) follows. Hydrogen bonds to FC definitely are much

Fluorine steric effects

The final topic covered in this presentation is fluorine steric effects. Although, the incorrect claim that fluorine is nearly the same size as hydrogen is encountered far less often these days, there still remains some confusion about steric size and steric effects of fluorine and fluorinated groups. The old Pauling van der Waals radius values for atoms are obsolete and some commonly accepted values of Bondi [24] or Williams and Houpt [25] which show that fluorine and oxygen are isosteric are

Effects of fluorine on biological activity: two examples

This presentation will conclude with two examples from the recent literature that make use of the particular steric, hydrogen-bonding, and lipophilic properties of fluorine that were described in this review. The first involves the design of an unnatural fluorinated nucleoside (F) that substitutes for thymidine (T) and efficiently codes for adenine in DNA replication [21], [30]. It is claimed [21] that the fluorine atoms act as not only chemical isosteres for the oxygen atoms in the

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ReviewFluorine substituent effects (on bioactivity)