Accurate determination of low pK values by 1H NMR titration

Guidelines for NMR measurements for determination of high and low pKa values (IUPAC Technical Report)

“…For many purposes, all these interactions can be safely ignored, but for NMR-based titrations at high and low p[H] a considerable caution is needed. The use of D 2 O (as the "lock") instead of H 2 O as a solvent, and the addition of uncontrolled "small" amounts of a reference compound like sodium 3-(trimethylsilyl)propane-1-sulfonate (DSS), dimethyl sulfoxide (DMSO), tert-butylalcohol or 1,4-dioxane inside a sample (internally), became common practice for 1 H and 13 C NMR [12,15,16]. In some cases ( 13 C NMR), the added reference compound is itself deuterated (e.g., ( 2 H 6 )DMSO or DSS, deuterated at the CH 2 positions), thus providing the lock signal as well.…”

“…Therefore, it gives a negligible contribution to ionic strength and to solution properties. It is demonstrated to be effective at p[H] 0-1 [12]. At the same time, little is known about the properties of internal references at elevated p[H].…”

Physicochemical Profiling in Drug Research and Development

“…This method has been extended for the measurement of low pK a values (between 0 and 2), where potentiometry is no longer applicable. Since at such low pH a glass electrode has significant acidity error, dichloroacetic acid was proposed as an NMR "indicator molecule" for in situ monitoring of the pH in strong acidic solutions [55]. The pK a values of individual groups of large biopolymers have been reported as measured by NMR technique [65].…”

“…In the recent years, capillary electrophoresis (CE) has proved to be a very powerful pK a determination method, being more sensitive and less sample consuming [11,16]. Some other methods such as NMR/pH titration [55], CD/pH titration [56], and chromatographic technique [57] have also been applied for special cases, but so far have not become routine techniques.…”

Determination of Dissociation Constants of Strychnos Alkaloids from Strychnos nux-vomica L. by Capillary Electrophoresis

“…The dissociation constant can also be used to theoretically predict the behavior of solutes in HPLC [6,7] and electromigration methods [8,9]. Capillary electrophoresis (CE) [10][11][12][13][14][15][16] has been introduced as a new micro-analytical technique for convenient and precise aqueous dissociation constant determination because of its advantages over other commonly used methods such as potentiometry [17][18][19], liquid chromatography (LC) [20][21][22], spectrophotometry [23][24][25][26], and nuclear magnetic resonance spectroscopy (NMR) [27,28]. CE relies on the principle that the solute exhibits an electrophoretic mobility continuum versus pH, which allows calculations independent of solute purity, since impurities can be effectively separated from the solutes of interest.…”