Greener pharmacy using solvent-free synthesis: Investigation of the mechanism in the case of dibenzophenazine

The mechanism of the solvent-free solid-state dibenzophenazine synthesis by dry co-grinding in a vibratory ball-mill has been investigated. The kinetics of the transformation was followed by HPLC and granulometry evolutions were quantified after co-grinding. The mechanism assumed involves a quinone imine intermediate formed during the first step of the reaction (addition of an amino group to a carbonyle) which is favored by the orbital overlaps between reagents. A water molecule formation occurs during the following step and hydrogen bonds are formed: the water molecule forms a bridge between the reactive centers of the quinone imine, and acts as a catalyst for the completion of the reaction. A push–pull mechanism involving the water bridge is proposed: the energy barrier is reduced by this way. Finally, two thermodynamic drivers favor the dibenzophenazine formation: the increased aromacity number in the product and the stabilization, thanks to water molecules.

Overview of the mechanism of dibenzophenazine synthesis by co-grinding. The water bridge allows a push-pull mechanism lowering the energy barrier to reaction and acts as a geen catalyst.Figure optionsDownload as PowerPoint slideHighlights
► Mechanism investigation of solid-state dibenzophenazine synthesis by co-grinding.
► A complexation occurs between both produced quinone-imine and water molecule.
► The water bridge acts as a green catalyst to reduce the energy barrier to reaction.
► Two energy drivers finalize the reaction: a new aromatic ring and solvatation.