Electrophilic aromatic substitution: from isolated reactant approaches to chemical reactivity in solvent

The mechanism and regioselectivity in electrophilic aromatic substitution, a cornerstone reaction in organic chemistry, is described using a range of different computational and interpretational quantum chemical approaches. In a first part, DFT-based reactivity indices, local softness and hardness, are used within an isolated molecule approach to describe the regioselectivity in a series of monosubstituted benzenes through the connection with the classical mechanism of the reaction involving both π and σ (Wheland) complexes between the aromatic compound and the electrophile. Next, ab initio molecular dynamics including solvent effects, applied to aromatic chlorination and sulfonation, are shown to challenge this mechanism in certain conditions. Finally, the mechanistic landscape of the reaction is scrutinized and explained using Valence Bond Theory, and conditions are identified for recovering the Wheland intermediate. It is thus shown that the combination of these diverse computational methods offers a unique insight into the mechanism of this reaction.