Measurement of the pKa values of organic molecules in aqueous- organic solvent mixtures by 1H NMR without external calibrants Matthew Wallace, Nduchi Abiama and Miranda Chipembere University of East Anglia, UK Aqueous-organic solvent mixtures are commonly used for reactions or analytical procedures where the components of the system are insoluble in pure water. The acid dissociation constants of organic molecules, K a (usually expressed as the negative logarithm, p K a ) in these solvent mixtures determine the reactivity and charge of the molecules involved and have equivalent importance to their role in aqueous systems. However, there are few convenient methods to measure p K a in aqueous-organic solvent mixtures, while the inclusion of 50% of an organic solvent such as dimethylsulfoxide (DMSO) can change the p K a by more than one unit from its value in aqueous solution. NMR spectroscopy is a powerful tool for the measurement of p K a in aqueous media and we have demonstrated how the combination of pH gradients and 1 H chemical shift imaging (CSI) can provide full titration curves in single NMR experiments. 1,2 Compared to other techniques for aqueous-organic solvents such as conductometry, NMR is tolerant of dilute, impure samples that contain several ionizable molcules. 1 However, the use of NMR is greatly hindered by the requirement for external calibrants on which a pH scale can be based. Such calibrants include buffer solutions, ‘anchor’ molecules with known p K a values, 2 and pH electrodes that have undergone lengthy calibration procedures in the solvent mixture of interest. 3 However, such calibrations are often experimentally inconvenient while literature p K a data may not be available at the required solvent composition, pH range or temperature. Here, we present a method to determine p K a in any aqueous-organic medium by 1 H NMR without external calibration. By creating concentration gradients of 2,6-dihydroxybenzoic acid (2,6-DHB) in aqueous-organic solutions of 1,2,4-triazole, we obtain self-consistent p K a values for both compounds via fundamental equations of dissociation (Scheme 1a). The p K a values of less acidic molecules are then determined relative to these compounds via the variation of their 1 H chemical shifts with pH (Scheme 1b). As proof of concept, we determine the p K a of organic acids and bases up to p K a 10 in 50% (v/v) 1-propanol/water, DMSO/water and 30% (v/v) acetonitrile/water to within 0.4 units of literature values.
Scheme 1. (a) Method to determine pK a values of 2,6-dihydroxybenzoic acid and 1,2,4-triazole in any aqueous-organic solvent mixture by 1 H chemical shift imaging NMR. (b) The pK a of other molecules are then measured relative to 2,6-DHB and triazole, affording good agreement with literature values. References
1. Wallace, D. J. Adams and J. A. Iggo, Anal. Chem. , 2018, 90 , 4160-4166. 2. Schenck, K. Baj, J. A. Iggo and M. Wallace, Anal. Chem. , 2022, 94 , 8115-8119. 3. Deleebeeck, A. Snedden and D. Stoica, Anal. Chim. Acta. X. , 2022, 100085.
P21
© The Author(s), 2023
Made with FlippingBook Learn more on our blog