Sulfur as an Acceptor to Bromine in Biomolecular Halogen Bonds

The halogen bond (X-bond) has become an important design element in chemistry, including medicinal chemistry and biomolecular engineering. Although oxygen is the most prevalent and best characterized X-bond acceptor in biomolecules, the interaction is seen with nitrogen, sulfur, and aromatic systems as well. In this study, we characterize the structure and thermodynamics of a Br···S X-bond between a 5-bromouracil base and a phosphorothioate in a model DNA junction. The single-crystal structure of the junction shows the geometry of the Br···S to be variable, while calorimetric studies show that the anionic S acceptor is comparable to or slightly more stable than the analogous O acceptor, with a −3.5 kcal/mol difference in ΔΔ H 25 ° C and −0.4 kcal/mol ΔΔ G 25 ° C (including an entropic penalty ΔΔ S 25 ° C of −10 cal/(mol K)). Thus sulfur is shown to be a favorable acceptor for bromine X-bonds, extending the application of this interaction for the design of inhibitors and biological materials.