Molecular Bases for Anesthetic Agents: Halothane as a Halogen- and Hydrogen-Bond Donor.

Although instrumental for optimizing their pharmacological activity, a molecular understanding of the preferential interactions given by volatile anesthetics is quite poor. This paper confirms the ability of halothane to work as a hydrogen-bond (HB) donor and gives the first experimental proof that halothane also works as a halogen-bond (HaB) donor in the solid state and in solution. A halothane/hexamethylphosphortriamide co-crystal is described and its single-crystal X-ray structure shows short HaBs between bromine, or chlorine, and the phosphoryl oxygen. New UV/Vis absorption bands appear upon addition of diazabicyclooctane and tetra(n-butyl)ammonium iodide to halothane solutions, indicating that nitrogen atoms and anions may mediate the HaB-driven binding processes involving halothane as well. The ability of halothane to work as a bidentate/tridentate tecton by acting as a HaB and HB donor gives an atomic rationale for the eudismic ratio shown by this agent.