In this work, we investigated the reaction mechanisms between carbon dioxide (CO2) and mefenamic acid (MA) in two distinct environments: (1) a saturated solution in supercritical CO2 (scCO2) and (2) within the nanoconfinement of a nanocrystalline cellulose (NCC) aerogel. Using combined IR spectroscopy and quantum chemical calculations, we demonstrated that in scCO2 bulk solution, the reaction initiates at 190 °C following conformational rearrangement of MA molecules. The dominant reaction pathway involves nucleophilic attack by CO2 on the carbonyl oxygen of the carboxyl-group of MA molecule. Notably, in the NCC aerogel-confined system, reaction products formed at just 100 °C – a significantly lower temperature than in bulk solution. Furthermore, the reaction pathway shifts to favor the participation of the amino-group in nanoconfinement, as opposed to the involvement of the carboxyl-group in bulk solution. Molecular dynamics simulations elucidated the origin of these distinct reaction pathways.
