Axial and equatorial conformations of penicillins, their sulphoxides and sulphones: the role of N---H···S and C---H···O hydrogen bonds

Abstract

The thiazolidine ring of the penam skeleton exists in two distinct conformations wherein the 3α -CO₂H group is in the axial or equatorial orientation. Crystal structure data have been retrieved from the Cambridge Structural Database (CSD) on 49 penams. These include 30 penicillins, 10 sulphoxides and 9 sulphones. Of the penicillins, 24 are in the axial conformation and 6 are in the equatorial conformation. The 19 sulphoxides and sulphones are exclusively in the equatorial conformation. It is suggested that the axial conformation in penicillins is stabilised by intramolecular N---H···S and C---H···O hydrogen bonds, jointly worth about 3 kcal/mol. Calculations show that the sulphoxides and sulphones do not adopt the axial conformation because of a repulsive C···O interaction between the gem-dimethyl group in the C2 position and the sulphoxide/sulphone O-atom. The pharmocophore groups of the penicillin antibiotics and the sulphoxides/sulphones lie in distinct, well-defined regions and this suggests that the biologically active conformation is the one with the axially oriented 3α -CO₂H group.