Measurement of the p<i>K</i><sub>a</sub> Values of Organic Molecules in Aqueous–Organic Solvent Mixtures by <sup>1</sup>H NMR without External Calibrants
Matthew Wallace, Nduchi Abiama, Miranda Chipembere
Abstract
High Resolution Image Download MS PowerPoint Slide Aqueous–organic solvent mixtures are commonly used for reactions or analyses, where the components of a system are insoluble in pure water. The acid dissociation constant is an important property to measure in these media as it determines the charge state, solubility, and reactivity of a molecule. While NMR spectroscopy is an established tool for the measurement of p K a in water, its use in aqueous–organic solvents is greatly hindered by the requirement for external calibrants on which a working pH scale is set. Such calibrants include buffer solutions, “anchor” molecules with known p K a values, and pH electrodes that have undergone lengthy calibration procedures in the solvent mixture of interest. However, such calibrations are often inconvenient to perform, while literature p K a data covering the required range may not be available at the solvent composition or the temperature of interest. Here, we present a method to determine p K a in aqueous–organic solvents directly by NMR. We first determine p K a of an organic acid such as 2,6-dihydroxybenzoic acid (2,6-DHB) by measuring its 1 H chemical shift as a function of concentration along a concentration gradient using chemical shift imaging (CSI). Using 2,6-DHB as a reference, we then determine p K a of less acidic molecules in single CSI experiments via the variation of their 1 H chemical shifts along pH gradients. As proof of concept, we determine the p K a values of organic acids and bases up to p K a 10 in 50% (v/v) 1-propanol/water, 50% (v/v) dimethyl sulfoxide/water, and 30% (v/v) acetonitrile/water and obtain good agreement with the literature values.