QTAIM, NBO, and NMR studies of hydrogen bonds in capecitabine

Abstract

Intramolecular and Intermolecular hydrogen bonds of capecitabine, a pharmaceutically active substance in the group of fluorinated cytosines, have been investigated by density functional calculations at B3LYP level of theory using some Pople-style basis sets augmented with polarized and diffuse functions. To perform the calculations, one molecule (CAP-M) and three molecules (CAP-T) of capecitabine are modeled by available X-ray crystal analysis in the literature. The topological parameters of the electron density distributions have been analyzed in terms of the quantum theory of atoms in molecules (QTAIM). The calculated hydrogen bond energies, together with the structural parameters, confirm two intramolecular hydrogen bonds, and only one intermolecular hydrogen bond in the trimer or cluster. Calculated ring critical points approve the resonance-assisted hydrogen bonds in the intramolecular hydrogen bonds. Moreover, the natural bond orbital analysis (NBO) has been used to evaluate the nature of hydrogen bonding interactions and charge analysis. The calculated 1H NMR and 17O NMR chemical shifts (CS) are significantly influenced by forming the hydrogen bond bridges. CS values are in excellent agreement with the structural parameters, QTAIM, and NBO results. Molecular electrostatic potential maps confirm the regions of hydrogen bonds donor and hydrogen bonds acceptor of the title molecule.