Efficient p<i>K</i>_a Determination in a Nonaqueous Solvent Using Chemical Shift Imaging

Abstract

p<i>K</i>_a is an important property of a molecule which impacts many fields, such as drug design, catalysis, reactivity, and environmental toxicity. It is often necessary to measure p<i>K</i>_a in nonaqueous media due to the poor solubility of an analyte in water, for example, many compounds of pharmaceutical interest. Although NMR methods to measure p<i>K</i>_a in water are well established, determining p<i>K</i>_a in organic solvents is laborious and problematic. We present an efficient one-shot method to determine the p<i>K</i>_a of an analyte in an organic solvent in a single measurement. Diffusion of an acid into a basic solution of the analyte and a set of pH indicators establishes a pH gradient in the NMR tube. The chemical shift of a pH sensitive resonance of the analyte and the pH of the solution are then determined simultaneously as a function of position along the pH gradient by recording a chemical shift image of the NMR tube. The p<i>K</i>_a of the analyte is then determined using the Henderson-Hasselbalch equation. The method can be implemented in any laboratory with a gradient equipped NMR high-field spectrometer and is demonstrated for a range of pharmaceutical compounds and inorganic phosphazene bases.