Determination of pKa in Non-Aqueous Solution using Chemical Shift Imaging

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pKa is a measure of the acidity of a molecule/ion (i.e. the ease with which it loses a proton). It is a widely used parameter in catalysis, pharmacology and chemical synthesis, allowing the prediction of chemical and physical behaviour of species in solution. Reactivity, solubility and the nature of chemical interaction are all governed by the protonation state of a molecule, and thereby its pKa. pKa is usually determined in aqueous solution, but frequently a compound is too insoluble or too reactive to do so. DMSO is commonly used as an alternative, as it is a relatively inert polar aprotic solvent supporting a wide pKa range (up to 35). Water solvates both cations and anions well while DMSO solvates cations well and anions poorly, making meaningful comparisons between pKaDMSO and pKa(aq) difficult. Experimental determination of pKa in DMSO is therefore necessary. Various methods are available to determine pKa, each with its advantages and drawbacks. Non-aqueous pKa measurements add another dimension of difficulty. In the example of potentiometric methods, equipment designed for aqueous measurements often must be adapted to the non-aqueous medium, risking equipment damage and inaccurate results.NMR titration methods are well known in the literature, with a range of NMR active nuclei available including 1H, 13C and 31P. Pure compounds are not necessary (as they must be for conductimetry) and no equipment modification is needed to measure in non-aqueous medium. The conventional NMR titration requires the acquisition of a large series of NMR spectra taken at incrementally changing pH. This is a labour intensive procedure requiring a large sample volume and long instrument times. As an alternative, we have developed a one-shot titration method for determining the pKa of compounds in DMSO solution. Using a set of NMR pH indicators and chemical shift imaging techniques, we can measure the pH of a sample as a function of position along a pH gradient within an NMR tube. From a single measurement we can determine the pKa of an acidic or basic analyte. The pKa of analytes determined using this method are in good agreement with literature values ( 0.1 units) and have been shown to be self-correcting for solution ionic strength.