The classic SEAr mechanism of electrophilic aromatic substitution (EAS) reactions described in textbooks, monographs, and reviews comprises the obligatory formation of arenium ion intermediates (σ complexes) in a two-stage process. Our findings from several studies of EAS reactions challenge the generality of this mechanistic paradigm. This Account focuses on recent computational and experimental results for three types of EAS reactions: halogenation with molecular chlorine and bromine, nitration by mixed acid (mixture of nitric and sulfuric acids), and sulfonation with SO3. Our combined computational and experimental investigation of the chlorination of anisole with molecular chlorine in CCl4 found that addition-elimination pathways compete with the direct substitution processes. Detailed NMR investigation of the course of experimental anisole chlorination at varying temperatures revealed the formation of addition byproducts. Moreover, in the absence of Lewis acid catalysis, the direct halogenation processes do not involve arenium ion intermediates but instead proceed via concerted single transition states. We also obtained analogous results for the chlorination and bromination of several arenes in nonpolar solvents. We explored by theoretical computations and experimental spectroscopic studies the classic reaction of benzene nitration by mixed acid. The structure of the first intermediate in this process has been a subject of contradicting views. We have reported clear experimental UV/vis spectroscopic evidence for the formation of the first intermediate in this reaction. Our broader theoretical modeling of the process considers the effects of the medium as a bulk solvent but also the specific interactions of a H2SO4 solvent molecule with intermediates and transition states along the reaction path. In harmony with the obtained spectroscopic data, our computational results reveal that the structure of the initial π complex precludes the possibility of electronic charge transfer from the benzene π system to the nitronium unit. In contrast to usual interpretations, our computational results provide compelling evidence that in nonpolar, noncomplexing media and in the absence of catalysts, the mechanism of aromatic sulfonation with sulfur trioxide is concerted and does not involve the conventional σ-complex (Wheland) intermediates. Stable under such conditions, (SO3)2 dimers react with benzene much more readily than monomeric sulfur trioxide. In polar (complexing) media, the reaction follows the classic two-stage SEAr mechanism. Still, the rate-controlling transition state involves two SO3 molecules. The reactivity and regioselectivity in EAS reactions that follow the classic mechanistic scheme are quantified using a theoretically evaluated quantity, the electrophile affinity (Eα), which measures the stabilization energy associated with the formation of arenium ions. Examples of applications are provided.

A comprehensive examination of the mechanism of the uncatalyzed and base-catalyzed aminolysis of phenyl N-phenylcarbamate by theoretical quantum mechanical methods at M06-2X/6-311+G(2d,2p) and B3LYP-D3/6-31G(d,p) levels, combined with an IR spectroscopic study of the reaction, was carried out. Three alternative reaction channels were theoretically characterized: concerted, stepwise via a tetrahedral intermediate, and stepwise involving an isocyanate intermediate. In contrast to dominating views, the theoretical results revealed that the reaction pathway through the isocyanate intermediate (E1cB) is energetically favored. These conclusions were supported by an IR spectroscopic investigation of the interactions of phenyl N-phenylcarbamate with several amines possessing varying basicities and nucleophilicities: n-butylamine, diethylamine, triethylamine, N-methylpyrrolidine, and trimethylamine. The reactivity of substituted phenyl N-phenylcarbamates in the aminolysis reaction was rationalized using theoretical and experimental reactivity indexes: electrostatic potential at nuclei (EPN), Hirshfeld and NBO atomic charges, and Hammett constants. The obtained quantitative relationships between these property descriptors and experimental kinetic constants reported in the literature emphasize the usefulness of theoretical parameters (EPN, atomic charges) in characterizing chemical reactivity.

In the present study, we explore the application of several theoretically estimated indices that characterize the reactivity of a series of phenyl N‐phenylcarbamates in the alkaline hydrolysis reaction. The rate constants (at 25 °C) for the hydrolysis of several derivatives were spectrophotometrically determined. The obtained kinetic data in this study, combined with literature data for other derivatives, were then correlated with theoretically estimated reactivity indices: Hirshfeld and NBO atomic charges, the Parr electrophilicity index (ω), and the electrostatic potential at the carbon and oxygen atoms of the reaction centre (VC, VO). The predictive ability of these quantities is discussed in a comparative context. Copyright © 2011 John Wiley & Sons, Ltd.

Review: 68 refs.