New preparation protocols for coumarin-thiosemicarbazone hybrids: solid state characterization, and in silico/NMR studies of the Z/E isomerization equilibria in solution

Abstract In this work, two improved experimental protocols for the preparation of eight coumarin-thiosemicarbazone hybrids are described. The novel methodologies, based on the use of a microwave-assisted protocol (MW) or a sealed vessel conventionally heated reactor (SVR) are faster, more efficient and render higher yields (average increase in yield = 11% and 16%, respectively). For the solid state characterization, infrared spectra of the obtained compounds were analyzed with the aid of computational tools for signal assignation. In addition, a new crystal structure for the E isomer of compound 2d was obtained and a thorough analysis of the intra and intermolecular interactions was performed by Hirshfeld surface analysis. On the other hand, the hybrids were characterized in DMSO-d6 solution by 1H and 13C-NMR experiments. All of them showed a set of minor signals neither ascribable to the products nor described in the literature. Variable temperature 1H-NMR experiments revealed that a single interconversion equilibrium was operative in the solution, having thermodynamic parameters compatible to those predicted for a Z/E isomerization process by a DFT model. The most stable configuration (E) was further confirmed by DFT, calculating the 13C-NMR chemical shifts for both configurations. The computational model shows that the E configuration is stabilized through the formation of a non-conventional C-H•••O=C intramolecular H-bond between the methyl and carbonyl groups, adopting a conformation less sterically strained. These findings allow to gain insights into the E/Z isomerization equilibria displayed by thiosemicarbazones in solution, a phenomenon usually under described in literature, which seems to be promoted by a balance between weak intramolecular interactions that modulate the relative isomeric stability in solution.