The conformation of chloramphenicol in the ordered and disordered phases

Abstract

The conformational behavior of chloramphenicol (CHL) in the solid, liquid and vapor phases is revisited here by means of FTIR spectroscopy and QM methods. In the crystalline phase, both the IR analysis and QM computations discard the conformer proposed by Acharya et al. (Acta Cryst., 1979, B35:1360-1363) and support the one proposed by Chatterjee et al. (J. Cryst. Mol. Struct., 1979, 9:295-304), characterized by an intramolecular OH⋯O hydrogen bond in which the primary hydroxyl group acts as hydrogen bond donor. The conformational behavior of CHL in the liquid and gas phases has been analyzed using QM calculations. The Self-Consistent Reaction Field (SCRF) method with the Onsager solvation model has been used for the initial optimizations in solution, and the lowest energy conformers have been refined using the Solvation Model based on Density (SMD). In solution environment the intramolecular OH⋯O hydrogen bond in CHL is reversed so that the secondary hydroxyl group acts as hydrogen bond donor. In addition, the dichloroacetamide group folds back further over the phenyl ring to form an intramolecular CCl⋯π halogen bond. Two different halogen bonds are actually observed (each one with a different chlorine atom) resulting in two different stable conformers, that can be detected by FTIR spectroscopy due to the conformational sensitivity of the CO group to the conformation of the dichloroacetyl group. Finally, the stability of the conformers with the polarity of the medium is also discussed.

Keywords: Chloramphenicol (CHL); Conformation; Halogen bonding; Hydrogen bonding; Interactions.