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.