MULTICOMPONENT NMR TITRATION FOR SIMULTANEOUS MEASUREMENT OF RELATIVEPK(A)S

An NMR titration method has been developed to simultaneously measure t he difference in acid dissociation constants (Delta pK(a)) of two or m ore compounds with high precision and accuracy, The Delta pK(a) betwee n the conjugate acids of the two stereoisomers of 4-tert-butylcyclohex ylamine 1 was determined in a single H-1 NMR titration experiment, A m ixture of the two stereoisomers was titrated with DCl in a 3:1 (v/v) m ixture of CD3OD/D2O, From the variations of the H1 chemical shifts the ratio of the acidity constants was determined, The trans stereoisomer it was found to be the more basic by 0.121 +/- 0.002 pK unit. A repea t titration in DMSO-d(6) also found It to be the more basic, by 0.217 +/- 0.003 pK unit. The Delta pK(a) between the two stereoisomers of 4- tert-butylcyclo- hexanecarboxylic acid 2 was determined in both of the se solvents using H-1 and C-13 NMR. Thermodynamic parameters Delta Del ta H-0 and Delta Delta S-0 were evaluated from the temperature depende nce of Delta pK(a). To further demonstrate the utility of this method, the Delta pK(a)s of the conjugate acids of the four stereoisomers of 2-decalylamine 3 were determined in a single H-1 NMR titration experim ent. The cis, -cis stereoisomer (3(cc)) was found to be the most basic , with the cis, trans (3(ct)), trans, cis (3(tc)), and trans, trans (3 (tt)) 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 tr ans-2-decalyamines(3(tc), 3(tt)).