Theoretical studies on hydrogen bonding in caffeine–theophylline complexes

The intermolecular interactions between caffeine and theophylline have been studied using their geometries, energies and topological features of the electron density with density functional theory (DFT) and MP2 methods implementing the 6-311G (d, p) atomic basis set. Sixteen caffeine–theophylline complexes were found on the potential energy surface involving NH⋯N, NH⋯O, CH⋯N and CH⋯O hydrogen bonds. The complex with conventional NH⋯N hydrogen bond along with a strong CH⋯O bond is found to be the most stable structure at MP2/6-311G (d, p) and B3LYP/6-311G (d, p) level of theories. From atoms in molecule (AIM) analysis an excellent linear correlation is shown to exist between the hydrogen bond length, electron density [ρ(r)] and its Laplacian [∇2ρ(r)] at the bond critical points. The natural bonding orbital analysis on the most stable complex in which NH⋯N and CH⋯O hydrogen bonding interactions are dominant, reveals that imidazole nitrogen of caffeine has offered large amount of lone pairs (0.036) to the contacting σ∗(NH) antibond orbital of theophylline and carbonyl oxygen (amide moiety) of theophylline offers lone pair (0.004) to σ∗(CH) antibond orbital of caffeine.