Conformational and Acid-Base Equilibria of Captopril in Aqueous Solution

¹H NMR spectra have been measured at 400 MHz and ¹³C spectra at 50.3 MHz for captopril, 1-[2(S )-3-mercapto-2- methyl-1-oxopropyl]-L-proline, In aqueous solution as a function of pH. The NMR spectra Indicate that captopril exists as two Isomers with respect to the conformation across the amide bond. The conformation having the C_α carbon of the proline residue and the C2 carbon of the 2(S)-3-mercapto-2- methyl-1-oxopropyl part trans across the amide bond Is the most abundant, with the actual mole fraction In this form dependent on the protonation states of the carboxylic acid and sulfhydryl groups. The carboxylic acid group of the trans Isomer Is less acidic than that of the cis Isomer by 0.66 pK_A units, and the proportion of captopril In the trans form decreases from 0.86 to 0.58 upon titration of Its carboxylic acid group. These results are Interpreted to Indicate Intramolecular hydrogen bonding between the carbonyl oxygen of the amide group and the carboxylic acid proton In the trans Isomer.