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. (C) 2012 Elsevier B.V. All rights reserved.