1H/31P NMR pH indicator series to eliminate the glass electrode in NMR spectroscopic pKa determinations

NMR titration is an efficient method to determine pKa values of multiprotic acids in aqueous solution. While modern 1D/2D NMR techniques yield chemical shifts with increasing precision, the glass electrode-based pH measurement becomes the limiting factor to affect the precision of the resulting dissociation constants. The pH in the NMR tube can also be deduced from the actual chemical shift of an appropriate monoprotic indicator molecule. In the present work, the in situ NMR pH measurement has been extended for the entire pH range 0–12 using indicators with overlapping ranges of dissociation. In the first, calibrating 1H/31P NMR titration, limiting chemical shifts and pK were determined for each indicator. An analysis of error propagation showed that the accuracy and precision of glass electrodes can be achieved at 1.8 < pH < 12 and even exceeded at pH extremes by NMR indicators, respectively. The assembled set of indicators was applied for in situ pH monitoring in the following "electrodeless" 1H/31P NMR titration of a newly synthesized aminophosphinophosphonic acid. Multivariate nonlinear parameter estimation was used to calculate the pK values that were confirmed by potentiometric titrations.