Electrophilic Aromatic Substitution: New Insights into an Old Class of Reactions

Abstract

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.

Solvent and Autocatalytic Effects on the Stabilisation of the σ‐Complex during Electrophilic Aromatic Chlorination

“…The direct substitution mechanism consists of a single concerted reaction step, in which the hydrogen transfer from HCl to Cl 2 and from the aromatic compound to HCl takes place. The addition–elimination mechanism, as proposed by Galabov, Schleyer and co‐workers, involves three steps. The first step is an addition of Cl 2 to the aromatic ring.…”

Electrophilic aromatic substitution over zeolites generates Wheland-type reaction intermediates

“…H-ZSM-5, 12 C-benzene/ethanol and 13 C-benzene/ethanol were purchased from ACS materials, Sigma Aldrich and Cambridge Isotope Laboratories, respectively. Catapal D (alumina) was received from Sasol.…”

“…Furthermore, this reaction is also of academic interest, as the underlying mechanistic principles of S E Ar are currently the subject of debate. According to a few recent studies, the classical Wheland intermediate is not always considered to be an obligatory intermediate during S E Ar [10][11][12][13] . Thus, the objectives of this work are to investigate the S E Ar mechanism at the solid/gas interface of a heterogeneous catalyst, and to resolve the ambiguity about the involvement of Wheland intermediates in zeolite-catalysed S E Ar reactions.…”

Identification of Wheland-type intermediates

“…The electrophilic addition to the aromatic is assumed to give an alkyl cyclohexadienyl cation, also known as a Wheland intermediate or σ-complex (Fig. 1), although an alternative concerted additionelimination pathway without the formation of the intermediate carbocation has been proposed for some cases 8 . As confirmed by Weckhuysen and colleagues for the ethylation of benzene, the active electrophile on zeolites is the ethyl group directly bonded to framework oxygen (that is, the ethoxy group) resulting from the reaction of ethanol or ethylene with the Brønsted acid (Fig.…”