The catalysed electrophilic aromatic bromination of benzenes: insights from density functional theory and biased molecular dynamics simulations.

The catalysed electrophilic aromatic bromination of benzene, anisole and nitrobenzene was investigated using static ωB97X-D/cc-pVTZ calculations in gas phase as well as enhanced umbrella sampling ab initio molecular dynamics simulations in an explicit apolar (CCl4) environment. Whereas the reaction profiles for the bromination of benzene and anisole reveal a classic two-step mechanism with the formation of a short-living Wheland intermediate, an alternative multi-step mechanism involving a 2,5-syn-dibrominated intermediate was retrieved as the only approach towards the kinetically and thermodynamically preferred meta-bromonitrobenzene product. Apolar solvent interactions were shown to stabilize the positively charged intermediate and hence to reduce the activation energy of the rate-determining step. The factors affecting the barrier height of this reaction step and thus regioselectivity of the electrophilic attack were identified using conceptual DFT reactivity indices, aromaticity indices and Wiberg bond indices. In this regard, the para preference of the bromination of anisole could be attributed to both the intrinsic reactivity of the reactant and the less pronounced distortion in aromatic behaviour of the benzene ring during the actual electrophilic attack. Alternatively, our newly proposed mechanism for nitrobenzene showed strong similarity with the previously investigated non-catalysed addition-elimination bromination of arenes bearing electron-withdrawing moieties. Henceforth, the rate-determining dibromination step is fully triggered by the strength of an electrostatic clash between the ipso-carbon of the ring and the nitrogen atom.