Accurate determination of low pK values by 1H NMR titration

The NMR titration methodology to determine acid dissociation constants in aqueous solutions is extended for pKa values between 0 and 2, where potentiometric titrations are no longer applicable. 1H NMR spectra are acquired for single samples of constant acid concentration (e.g. 0.02 M), controlled ionic strength (I=1 M with HNO3/NaNO3) and varying pH. To avoid biased pH readings due to the acid error of the glass electrode, true, concentration-based pH values are deduced by combination of the charge balance equation with information from 1H NMR chemical shifts of the investigated acid. The method has been tested on histidine (pK1=1.83±0.02) and yielded the dissociation constant of dichloroacetic acid (pK=1.06±0.01) for the first time with good accuracy and precision. Dichloroacetic acid is recommended as an NMR spectroscopical “indicator molecule” for in situ monitoring the pH in strong acidic solutions of other equilibrium systems.