In this work, we show that the apparent pKameasured 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 pKain 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.