Experimental synthesis and theoretical study of the cyclization of chalcone-derived thiosemicarbazones: Effect of bromine substitution

An experimental and theoretical study was conducted to examine the reactivity and cyclisation of thiosemicarbazones derived from chalcones, with particular emphasis on the effect of bromine substitution. Experimentally, the condensation of chalcones with thiosemicarbazide in an acidic alcoholic medium produced an acyclic thiosemicarbazone from the methyl-substituted chalcone, while the brominated analogue underwent intramolecular cyclisation, highlighting a strong substituent effect. Theoretical calculations using the density functional theory (DFT) method at the B3LYP/6–311 + G(d,p) level were performed to study the influence of bromine addition on the reaction mechanism and to explain the cyclisation observed experimentally. The results showed that substitution with bromine increases electrophilicity and activates the β carbon of the α,β-unsaturated system, thereby promoting cyclisation in the brominated case. Energy and thermodynamic analyses confirmed the greater stability of the brominated cyclised product. In addition, RDG/NCI analyses were performed to better understand the non-covalent interactions, highlighting their role in stabilising the cyclised structure and explaining the experimental selectivity observed.