Cooperative strengthening in paraxanthine- ( H 2 O ) n ( n = 1 - 3 ) complexes: insights from DFT and ab initio computational studies

Solute-solvent interactions play a fundamental role in governing chemical and biological processes, as most biochemical reactions occur in aqueous environments. Water, due to its exceptional hydrogen bonding capability, acts as a key medium influencing molecular structure, stability, and reactivity. In this context, the present study focuses on the computational investigation of paraxanthine, a biologically relevant xanthine derivative, to elucidate its interaction with water molecules. Particular emphasis is placed on identifying the preferred binding sites and the nature of intermolecular interactions in 1:1 paraxanthine-water complexes. Additionally, the study extends to hydrated clusters containing up to three water molecules in order to explore the role of cooperative hydrogen bonding in modulating the stability and interaction patterns of the system.

The geometries and interaction energies of paraxanthine-water complexes were investigated using MP2/6-311++G(d,p) and DFT-D/ $\omega$ B97XD/6-311++G(d,p) levels of theory. Eight stationary points were identified on the 1:1 paraxanthine-water potential energy surface, with most structures exhibiting dual hydrogen bonding motifs and noticeable deviations from ideal linear geometries. Among the various interaction types, including O-H $\cdots$ O, N-H $\cdots$ O, O-H $\cdots$ N, C-H $\cdots$ O, and O-H $\cdots \pi$ , the global minimum structure is stabilized by the combined presence of O-H $\cdots$ O and N-H $\cdots$ O hydrogen bonds. To gain deeper insight into the nature of bonding, quantum theory of atoms in molecules (QTAIM) analysis was employed to characterize bond paths and electron density distribution, while natural bond orbital (NBO) analysis was used to evaluate charge transfer and hyperconjugative interactions. A linear correlation between interaction energy, electron density at bond critical points, and bond length elongation was observed, highlighting the interdependence of these parameters. Weak and non-covalent interactions were further analyzed using the reduced density gradient (RDG) approach. Furthermore, the inclusion of additional water molecules (up to three) enabled the investigation of cooperative hydrogen bonding effects within the paraxanthine-water clusters.