Exploring the potential of direct electricity-driven synthesis of mesalazine-tetramer and olsalazine, an anti-inflammatory drug.

In this study, the redox behavior of mesalazine (MSZ) was investigated to elucidate its oxidative coupling pathways. Experimental results revealed the existence of two competing coupling pathways, including the formation of dimer and tetramer species. A significant solvent-dependent selectivity was observed, such that aqueous environments favored tetramer formation, while non-aqueous solvents enabled the synthesis of olsalazine (OSZ). The synthesis of the tetramer (TMSZ) is based on the two-electron oxidation of MSZ and the formation of a reactive para-quinoneimine (PQI), which subsequently reacts with MSZ as a nucleophile. TMSZ was synthesized galvanostatically in aqueous solution with good yield and purity under mild, simple, and environmentally friendly conditions. Optimization of effective parameters, including solvent, pH, current density, and electrode material, was performed to increase the yield and purity of TMSZ. The dimer synthesis is based on the one-electron oxidation of MSZ and its related radical (MSZ•) formation in DMF. Radical-radical coupling of these radicals leads to the formation of olsalazine (OSZ). In this work, based on experimental results and theoretical calculations using density functional theory (DFT), a deeper insight into the electronic structures of the intermediates was provided, and the preferred reaction pathways were confirmed. This electrochemical approach offers a controllable and efficient method for OSZ synthesis, reducing operational complexity while enhancing reaction selectivity.