Chemical Reactivity Assessment Using Reactive Paper Spray Ionization Mass Spectrometry: The Katritzky Reaction

Paper spray ionization can be used to study organic reactions in solution under ambient conditions by utilizing the rate acceleration that occurs in reactions in small volumes of solution. In this novel approach to performing reactions, reagents are transferred onto a triangular paper surface by drop-casting and charged droplets of the reaction product mixture are released by field evaporation and examined online by mass spectrometry. The increase in the rate of product formation is attributed to solvent evaporation, which increases reagent concentrations, changes the pH, and enhances intermolecular interactions. As a proof of principle, the Katritzky reaction between a pyrylium salt and mono- or diamines, including substituted anilines, was investigated. The influence of electronic and steric effects was evaluated straightforwardly. The carbon chain length of α,ω-diamines was found to control the formation of mono- versus disubstituted products, thus reflecting the strong destabilizing coulombic effects in the shorter carbon-chain systems. Information on the mechanism was provided by the observation of 2H-pyran intermediates and mixed pyridinium-2H-pyran ions. The rates of product formation in the base-assisted Katritzky reaction increase linearly from 0.1 to 10 equivalents of triethylamine. The reactive paper spray technique, owing to its speed and information content, has potential pedagogical value and provides a tool to explore organic reactions and correlate experimental results with current mechanistic understanding.