The curious case of tempo-photocatalysed Knoevenagel condensation: unveiling hidden reaction pathways through ms monitoring

The Knoevenagel condensation is a well-known chemical reaction between compounds with an active methylene group (e.g. malonotrinile, ethyl cyanoacetate) and aldehydes (or ketones) leading to the formation of alpha-(beta) unsaturated condensation products [1]. Due to its broad application in the synthesis of different compounds, such as natural products, pharmaceuticals, and polymers [2], the search for alternative catalysts beyond traditional bases remains an active and growing area of research. In this framework, the expanding demand for greener synthetic methods has encouraged the adoption of water or ionic liquids as alternative solvents [3], as well as the use of nanomaterial catalysts, such as carbon dots (CDs) [4]. The stable 2,2,6,6-tetrametilpiperidin-1-ossil (TEMPO) is a nitroxyl compound commonly used as a free radical scavenger to probe radical-mediated reaction pathways [5]. Owing to its redox properties, TEMPO can also act directly as a catalyst, for example in the dehydrogenation of activated alkanes [6] or in combination with copper salts for the aerobic oxidation of alcohols under green conditions [7]. Moreover, TEMPO was probed as a thermally activated tetramethylpiperidine (TMP) generator for the initiation of thiol-Michael addition polymerizations, laying the foundation for the design of more selective catalysts [8]. In this study, we investigated the photo-generation of TMP from TEMPO catalysed by dicarbonyl compounds with an acidic CH2 carbon acting both as reaction initiator and substrate of the Knoevenagel condensation. The discovery of this catalytic system represents an intriguing case of serendipity, in which the high sensitivity of mass spectrometry used to monitor chemical reactions and detect elusive intermediates enabled the elucidation of an unprecedent catalytic role of TEMPO in the Knoevenagel condensation.