The Knoevenagel condensation catalyzed by task-specific ionic liquids: a gas-phase study to highlight the reaction mechanism

Ionic liquids (ILs) represent a fascinating class of stable compounds that, owing to their recyclability and ignorable vapour pressure, are commonly used as green solvents in a variety of chemical reactions. The possibility to incorporate suitable functional groups into the cationic or anionic scaffold allows one to implement their catalytic properties and design task-specific derivatives for synthetic applications. In particular, the Knoevenagel condensation between an aldehyde and an activated methylene compound can be considered an archetypal reaction widely used in various fields, such as in pharmaceutical chemistry, for the formation of carbon-carbon bonds. In this regard, some examples are the syntheses of the antimalarial Lumefantrine and a series of tyrosine kinase inhibitors called trifostintins. According to these important implications, the employment of a well-designed basic catalyst can be useful to optimize the selectivity of the process. Likewise, the elucidation of the reaction mechanism is essential to finely design the features of the catalytic system, although it is often hindered by the instability of the elusive intermediates that prevents their isolation and characterization. To this end, the high sensitivity and speed of the electrospray ionization mass spectrometry (ESI-MS) have been exploited in this study to efficiently intercept the ionic reactants, intermediates and products of the Knoevenagel condensation, characterize them by collision-induced dissociation (CID) experiments and highlight the action mechanism of the ionic liquid 1-methyl-3-carboxymethylimidazolium chloride (MAI.Cl) as reaction catalyst.