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Multicomponent NMR Titration for Simultaneous Measurement of Relative pKas

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posted on 01.07.1996 by Charles L. Perrin, Miles A. Fabian
An NMR titration method has been developed to simultaneously measure the difference in acid dissociation constants (ΔpKa) of two or more compounds with high precision and accuracy. The ΔpKa between the conjugate acids of the two stereoisomers of 4-tert-butylcyclohexylamine 1 was determined in a single 1H NMR titration experiment. A mixture of the two stereoisomers was titrated with DCl in a 3:1 (v/v) mixture of CD3OD/D2O. From the variations of the H1 chemical shifts the ratio of the acidity constants was determined. The trans stereoisomer 1t was found to be the more basic by 0.121 ± 0.002 pK unit. A repeat titration in DMSO-d6 also found 1t to be the more basic, by 0.217 ± 0.003 pK unit. The ΔpKa between the two stereoisomers of 4-tert-butylcyclohexanecarboxylic acid 2 was determined in both of these solvents using 1H and 13C NMR. Thermodynamic parameters ΔΔH° and ΔΔS° were evaluated from the temperature dependence of ΔpKa. To further demonstrate the utility of this method, the ΔpKas of the conjugate acids of the four stereoisomers of 2-decalylamine 3 were determined in a single 1H NMR titration experiment. The cis,cis stereoisomer (3cc) was found to be the most basic, with the cis,trans (3ct), trans,cis (3tc), and trans,trans (3tt) less basic by 0.012 ± 0.003, 0.037 ± 0.004, and 0.141 ± 0.005 pK unit, respectively. A second four-component titration was also performed with the two 4-tert-butylcyclohexylamines (1) and the two trans-2-decalylamines (3tc, 3tt).