Unlocking the potential of gas-phase cross-ketonization toward a more sustainable production of valuable asymmetric ketones intermediates

Aromatic ketones are key intermediates in organic synthesis and fundamental building blocks in the production of fine chemicals. They are primarily mass-produced by the Friedel-Crafts (FC) acylation of aromatics, which is cost-effective but has very poor environmental performances. Alternative coupling reactions exists, but their high cost often prevents the large-scale manufacture of the simplest ketones. In this context, the gas-phase cross-ketonization of carboxylic acids/esters is an environmentally friendly reaction that does not require stoichiometric amounts of toxic/corrosive reagents nor noble-metal catalysts, thus representing a promising alternative. In this work, the preparation of the model compound dihydrochalcone (DHC) via the cross-ketonization of ethyl 3-phenylpropionate (E3PP) and ethyl benzoate (EB) was investigated in-depth by varying reaction conditions and catalysts to identify structure-activity relationships, key parameters affecting product selectivity, and shed light on the complex reaction scheme. The catalytic results were fitted with a logistic regression model, which was then used to build response surfaces that indicated more favourable reaction conditions, leading to an improvement in selectivity and productivity (83 % and 0.267 g DHC ⋅g catalyst −1 ⋅h −1 respectively) at 81 % E3PP conversion. The same preparation method was successfully extended to valuable acetophenone, 4-methylacetophenone, propiophenone, valerophenone, and deoxybenzoin. • Valuable ketones are produced by continuous-flow cross-ketonization as an alternative to Friedel-Crafts acylation. • The complex reaction scheme was elucidated by varying the catalysts and reaction conditions in DHC synthesis. • Experimental data were fitted to a logistic model providing a predictive framework to improve process performances. • In optimized conditions DHC was obtained with 83% selectivity and a space-time yield 0.267 g DHC ⋅gc atalyst −1 ⋅h −1 . • Acetophenone, 4-methylacetophenone, propiophenone, valerophenone, and deoxybenzoin were obtained with selectivities 85-95 %.