Reactivity in Friedel–Crafts aromatic benzylation: the role of the electrophilic reactant

Density functional theory is employed in understanding the reactivity in the TiCl₄ catalyzed Friedel-Crafts benzylation of benzene with substituted benzyl chlorides in nitromethane solvent. A series of ten substituted (in the aromatic ring) benzyl chlorides are characterized by theoretical reactivity indices. The theoretical parameters are juxtaposed to experimental relative rates of benzylation. It is established that the carbon-chlorine ionic bond dissociation energy and the Hirshfeld charge at the chlorine atom for the benzyl chlorides reactants - describe quite satisfactorily the reactivity trends. These results provide further insights into the factors governing reactivity in EAS reactions, which so far have been mostly focused on rate variations induced by changes in the structure of the aromatic substrate. The EAS benzylation investigated is quite unusual since, in contrast to most EAS reactions, the latest experimental kinetic results suggest that the aromatic substrate does not participate in the kinetic equation of the process. To shed more light on this unexpected result, we also conducted a theoretical study on the mechanistic pathway by applying M06-2X density functional computations combined with several basis sets: 6-311+G(d,p), 6-311+G(2df,2p), and def2-TZVPP. Because of the well-known difficulties in evaluating realistic free energy barriers for organic reactions, we tested two solvent models in determining the barrier for the TiCl₄-catalyzed Friedel-Crafts benzylation of benzene by benzyl chloride. Since all methods employed did not provide satisfactory results for the free energy barriers, we used a combination of theoretically estimated enthalpy barriers and the available (from kinetic experiments) entropy contribution. This approach enabled us to verify that indeed the rate of this EAS reaction does not depend on the nature of the aromatic substrate. The computations revealed the structure and relative energies of the critical structures along the mechanistic pathway. Four intermediates were established along the reaction route.