Influence of degraded 1,4-dioxane on the formylation of para-aminobenzoic acid: a pathway to the reactive crystallization of para-formamidobenzoic acid

Abstract

A novel synthesis route using degraded 1,4-dioxane is studied, where the stability of the solvent significantly affects its role in reactive crystallization processes. Over time, hydrogen peroxide present in 1,4-dioxane induces oxidation, forming formic acid, which subsequently reacts with para-aminobenzoic acid (p-ABA) leading to formylation and production of para-formamidobenzoic acid (p-FBA), a valuable intermediate in pharmaceutical synthesis. Fourier transform infrared spectroscopy (FTIR) confirms the degradation of 1,4-dioxane, while powder X-ray diffraction (PXRD) validates the purity of the resulting p-FBA crystals. Single crystal X-ray diffraction (SCXRD) analysis reveals that p-FBA crystallizes in the monoclinic system with the space group Pc. TGA/DSC, NMR and elemental analysis further confirm the reactive crystallization of p-FBA. In contrast, nondegraded 1,4-dioxane facilitates the crystallization of a solvate of p-ABA, with solvent molecules incorporated into its lattice. These findings provide valuable insights into the interplay between solvent stability and crystallization mechanisms, contributing to the broader understanding of organic synthesis pathways, and introduce a new perspective on utilizing degraded solvents in reaction chemistry.