Efficient pK(a) Determination in a Nonaqueous Solvent Using Chemical Shift Imaging

[Image: see text] pK(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 pK(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 pK(a) in water are well established, determining pK(a) in organic solvents is laborious and problematic. We present an efficient one-shot method to determine the pK(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 pK(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.