In this work, we show that the apparent pK_a measured by standard titration experiments is an insufficient measure of acidity or basicity of organic functional groups in multiprotic compounds─a frequent aspect of lead optimization in pharmaceutical research. We show that the use of the apparent pK_a in this context may result in costly mistakes. To properly represent the group’s true acidity/basicity, we propose pK₅₀─a single-proton midpoint measure derived from a statistical thermodynamics treatment of multiprotic ionization. We show that pK₅₀, which may be directly measured in specialized NMR titration experiments, is superior in tracking the functional group’s acidity/basicity across congeneric series of related compounds and converges to the well familiar ionization constant in the monoprotic case.

By Robert Fraczkiewicz, Marvin Waldman