Multicomponent NMR Titration for Simultaneous Measurement of Relative p<i>K</i><sub>a</sub>s

1996-07-01T00:00:00Z (GMT) by Charles L. Perrin Miles A. Fabian
An NMR titration method has been developed to simultaneously measure the difference in acid dissociation constants (Δp<i>K</i><sub>a</sub>) of two or more compounds with high precision and accuracy. The Δp<i>K</i><sub>a</sub> between the conjugate acids of the two stereoisomers of 4-<i>tert</i>-butylcyclohexylamine <b>1</b> was determined in a single <sup>1</sup>H NMR titration experiment. A mixture of the two stereoisomers was titrated with DCl in a 3:1 (v/v) mixture of CD<sub>3</sub>OD/D<sub>2</sub>O. From the variations of the H1 chemical shifts the ratio of the acidity constants was determined. The trans stereoisomer <b>1</b><sub>t</sub> was found to be the more basic by 0.121 ± 0.002 p<i>K</i> unit. A repeat titration in DMSO-<i>d</i><sub>6</sub> also found <b>1</b><sub>t</sub> to be the more basic, by 0.217 ± 0.003 p<i>K</i> unit. The Δp<i>K</i><sub>a</sub> between the two stereoisomers of 4-<i>tert</i>-butylcyclohexanecarboxylic acid <b>2</b> was determined in both of these solvents using <sup>1</sup>H and <sup>13</sup>C NMR. Thermodynamic parameters ΔΔ<i>H</i>° and ΔΔ<i>S</i>° were evaluated from the temperature dependence of Δp<i>K</i><sub>a</sub>. To further demonstrate the utility of this method, the Δp<i>K</i><sub>a</sub>s of the conjugate acids of the four stereoisomers of 2-decalylamine <b>3</b> were determined in a single <sup>1</sup>H NMR titration experiment. The cis,cis stereoisomer (<b>3</b><sub>cc</sub>) was found to be the most basic, with the cis,trans (<b>3</b><sub>ct</sub>), trans,cis (<b>3</b><sub>tc</sub>), and trans,trans (<b>3</b><sub>tt</sub>) less basic by 0.012 ± 0.003, 0.037 ± 0.004, and 0.141 ± 0.005 p<i>K</i> unit, respectively. A second four-component titration was also performed with the two 4-<i>tert</i>-butylcyclohexylamines (<b>1</b>) and the two <i>trans</i>-2-decalylamines (<b>3</b><sub>tc</sub>, <b>3</b><sub>tt</sub>).