Mass spectrometry monitoring of organic reactions: a gas-phase study to highlight the reaction mechanism of the Knoevenagel condensation

The creation of carbon–carbon bonds is still highly required topic in organic chemistry for the capacity to give a wide variety of new products of industrial value. The Knoevenagel reaction represents an important reaction to obtain carbon-carbon bonds. [1] Imidazole-based ionic liquids are widely used as catalysts in the Knoevenagel condensation reaction. [2] These catalysts can operate through different reaction paths, through different intermediates. Therefore, the studies of these intermediates can create new research opportunities with respect to the type of catalytic activity, and the precise knowledge of the intermediates involved in the Knoevenagel mechanism is also important to design new specific catalysts. Mass spectrometric techniques were used to capture from the condensed phase the ionic reactants, intermediates, and products of the reaction. The progress reaction was monitored over time with atmospheric pressure (AP) ionization techniques, such as electrospray ionization and AP chemical ionization, coupled to mass spectrometry (ESI-MS and APCI-MS) to check the formation of the reaction products, detect the key intermediates of the process and elucidate the catalyst role in reaction mechanism. [3] Considering the debate existing on the Knoevenagel mechanism, the precise knowledge of the intermediates involved in the reaction is crucial to design task-specific catalysts. To this end, we have exploited the speed and sensitivity of the mass spectrometric techniques to efficiently “fish” from the condensed phase the ionic reactants, intermediates, and products of the reaction and carry them in the gas-phase environment for structural and reactivity investigations. Collision-induced dissociation experiments, performed by an ion-trap mass spectrometer and consisting in subsequent steps of ion isolation and fragmentation, have been employed to characterize intermediates and products of the Knoevenagel condensation. These techniques have long-term contributed to provide mechanistic information about important organic reactions. [4-6] [1] G. Jones, The Knoevenagel Condensation in Organic Reactions, John Wiley, New York, 2011, 15, 204–599. [2] F. Pandolfi, M. Feroci and I. Chiarotto, ChemistrySelect 2018, 3, 4745-4749 [3] L. S. Santos, “Reactive intermediates: MS investigations in solution”, Cap. 3 F. M. Nacthigall and M. N. Eberlin, Organic reactions studies by ESI-MS [4] F.Pepi, A. Ricci, S. Garzoli, A. Troiani, C. Salvitti, B. Di Rienzo, P. Giacomello, Carbohydr. Res. 2015, 413, 145-150. [5] A. Troiani, G. de Petris, F. Pepi, S. Garzoli, C. Salvitti, M. Rosi, A. Ricci, ChemistryOpen 2019, 8, 1190-1198. [6] C. Salvitti, I. Chiarotto, F. Pepi, A. Troiani, ChemPlusChem 2021, 86, 209–223