Deepening bis-(thio)carbohydrazones conformational dynamics and hydrogen bond interactions in a non-protic solvent: DFT, molecular dynamics, NMR, and Raman investigations.

Despite the capability of bis-(thio)carbohydrazones to coordinate metals and the remarkable biological properties of the resulting complexes, no general information is known about their individual behavior in solution. This study is focused on two recently synthesized compounds, a bis-thiocarbohydrazone (bis-TCH) and a bis-carbohydrazone (bis-CH) isolated as sodium salts, that have shown chelating properties toward copper(II) and zinc(II) metal ions along with promising cytotoxic activity. In this work, an integrated theoretical-computational, nuclear magnetic resonance (NMR), and vibrational characterization of both bis-TCH and bis-CH anions in a non-protic solvent (dimethylsulfoxide) is presented to better elucidate their properties. Their protonic NMR spectra underline the presence of cis-trans, EE isomers, characterized by a significant conformational freedom at room temperature. The presence of oxygen or sulfur heteroatoms can tune the molecular conformational dynamics driving a different interaction with the solvent, as highlighted by density functional theory calculations and atomistic molecular dynamics simulations. Our results demonstrate that a quantitative agreement with the NMR and Raman signals is achieved only when an explicit solvent description is included. The insights achieved by this study can contribute to a better understanding of the behavior of bis-carbohydrazones and bis-thiocarbohydrazones in solution, a crucial and mandatory step to improve the design of novel, more potent analogs.