While carbon (C) and hydrogen (H) form the foundation of organic molecules, the rich diversity and specificity of interactions between biological and drug molecules arises from the presence of heteroatoms (N, O, S, P, halides) when they combine with C and H to form various functional groups. One property of many heteroatom containing molecules is a certain acidity or basicity at physiological conditions that can contribute to the reactivity and physiochemical properties of the molecule. Although drug molecules are often designed to have little or no chemical reactivity as administered, once absorbed they are metabolized (i.e., undergo chemical conversions catalyzed by the enzymes of drug metabolism) to give products with new functional groups having enhanced reactivity, potentially leading to adverse side effects. In addition to influencing reactivity, acid/base properties and the charge state of a drug molecule contribute significantly to its relative solubility in water (as found in the interior of cells and in bodily fluids) versus nonpolar media (as found in the lipid membranes of cells). This differential solubility impacts the absorption of the drug and hence the amount that needs to be administered to achieve the desired effect. In this chapter, we review the principal models of acid and base behavior and discuss the relationship of structure and bonding to the acidity of different types of “X–H” bonds (C–H, N–H, O–H, S–H) and the basicity of the lone pairs of electrons on the corresponding “X” atoms (:N, :O, :S).
5.2 Three Theories of Acids and Bases
In the late 1800s, Arrhenius proposed a theory of acids and bases based on observations of “what happens” when a substance is dissolved in pure water. The key observation was that some substances cause an increase in the hydrogen ion concentration, [H+], when dissolved in water and others cause an increase in the hydroxide concentration, [OH-]. On this basis, Arrhenius defined an acid as a compound that dissociates in water to give H+ and an anion (e.g., HCl → H+ + Cl-), and a base as a compound that dissociates in water to give a cation and OH- (e.g., KOH → K+ + OH-). Although the noted changes in [H+] and [OH-] can be a useful description of acid/base behavior for certain systems, the model is limited in the scope of acids/bases and solvents (water only) that can be described.
A more general theory of acids and bases that focuses specifically on “who has the proton” was proposed separately in 1923 by Brønsted in Denmark and by Lowry in England. In this model, the proton never exists in solution as an isolated ion because it is energetically too unstable. Instead it is always covalently bonded to another atom, but can be transferred between lone pairs of electrons on two different atoms. In this proton transfer reaction, the ...