Captopril and its dimer captopril disulfide: comparative structural and conformational studies

The crystal structures of captopril {systematic name: (2S)‐1‐(2S)‐2‐methyl‐3‐sulfanylpropanoyl]pyrrolidine‐2‐carboxylic acid}, C₉H₁₅NO₃S, (1), and its dimer disulfide metabolite, 1,1′‐{disulfanediylbis(2S)‐2‐methyl‐1‐oxopropane‐3,1‐diyl]}bis‐L‐proline, C₁₈H₂₈N₂O₆S₂, (2), were determined by single‐crystal X‐ray diffraction analysis. Compound (1) crystallizes in the orthorhombic space group P2₁2₁2₁, while compound (2) crystallizes in the monoclinic space group P2₁, both with one molecule per asymmetric unit. The molecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five‐membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half‐chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum‐energy conformational search using Monte Carlo methods in the aqueous phase reveals that the optimized conformations of the title compounds differ from those determined crystallographically, which depend on their immediate environment. Intermolecular O—H...O and relatively weak C—H...O interactions seem to be effective in both structures and, together with S—H...O and C—H...S contacts, they create three‐dimensional networks.