Author response for "Accelerated synthesis of phthalimide derivatives: intrinsic reactivity of diamines towards phthalic anhydride evaluated by paper spray ionization mass spectrometry (PS‐MS)"

RationalePaper spray (PS) is a simple and innovative ambient ionization technique for mass spectrometry (MS) analysis. Under PS‐MS conditions, chemical reactions, which usually occur slowly on a bulk scale, are accelerated. Moreover, the formation of products and transient species can be easily monitored. In this manuscript, reactions between phthalic anhydride and diamines were conducted and monitored using a PS‐MS platform. The reaction products (phthalimides) have many pharmaceutical applications, but their traditional syntheses can take hours under reflux, requiring laborious purification steps.MethodsIn situ reactions were performed by dropping methanolic solutions of phthalic anhydride and diamines on a triangular paper. The analyses were achieved by positioning the triangle tip in front of the mass spectrometer entrance, whereas a metal clip was attached to the triangle base. After adding methanol to the paper, a high voltage was applied across the metal clip, and the mass spectra were acquired.ResultsThe intrinsic reactivity of alkyl and aromatic diamines was evaluated. The carbon chain remarkably influenced the reactivity of aliphatic diamines. For aryl diamines, the ortho isomer was the most reactive. Moreover, for aryl amines with electron‐withdrawing substituents, no reaction was noticed.ConclusionsTaking advantage of the unique characteristics of PS‐MS, it was possible to investigate the intrinsic reactivity of model alkyl (ethylene versus propylene) and aryl (o‐phenylene versus m‐phenylene and p‐phenylene) diamines towards phthalic anhydride. Some crucial parameters that affect the intrinsic reactivity of organic molecules, such as isomerism, intramolecular interaction, and conformation, were easily explored.