Arenium ions are not obligatory intermediates in electrophilic aromatic substitution

Our computational and experimental investigation of the reaction of anisole with Cl₂ in nonpolar CCl₄ solution challenges two fundamental tenets of the traditional S_EAr (arenium ion) mechanism of aromatic electrophilic substitution. Instead of this direct substitution process, the alternative addition–elimination (AE) pathway is favored energetically. This AE mechanism rationalizes the preferred ortho and para substitution orientation of anisole easily. Moreover, neither the S_EAr nor the AE mechanisms involve the formation of a σ-complex (Wheland-type) intermediate in the rate-controlling stage. Contrary to the conventional interpretations, the substitution (S_EAr) mechanism proceeds concertedly via a single transition state. Experimental NMR investigations of the anisole chlorination reaction course at various temperatures reveal the formation of tetrachloro addition by-products and thus support the computed addition–elimination mechanism of anisole chlorination in nonpolar media. The important autocatalytic effect of the HCl reaction product was confirmed by spectroscopic (UV-visible) investigations and by HCl-augmented computational modeling.Interest in the chemistry of electrophilic aromatic substitution reactions continues because of their widespread application for the production of a great variety of chemicals and materials (1–4). Electrophilic substitution, considered to be the most characteristic reaction of aromatic systems, is typically described in textbooks, monographs, and reviews by the two-stage S_EAr mechanism depicted in Fig. 1 (5–11). Arenium ion (σ-complex) intermediates are often ascribed to Wheland (9) inaccurately, since Pfeiffer and Wizinger (10) laid out the principles of such species for bromination in 1928. Following Brown and Pearsall (11), they are widely believed to have σ-complex structures. Arenium ions (σ-complexes) (9–11) are widely accepted to be obligatory intermediates and are used to rationalize ortho/para vs. meta position orientation preferences (6–11).Open in a separate windowFig. 1.Typical depiction of the arenium ion mechanism for S_EAr reactions.We now reinforce our challenges (12, 13) of this conventional “reaction mechanism paradigm” (14) by a combined computational and experimental study of the facile chlorination of anisole (methoxybenzene) with Cl₂ in CCl₄ solution (15, 16). We find that Fig. 1 is not the favored pathway. Instead, addition reactions of Cl₂ to anisole have the lowest activation energies (Fig. 2). Ready HCl elimination from the initially formed adducts leads to ortho- and para-chloroanisole as the predominate products. This addition–elimination (AE) mechanism (the historical antecedent to Fig. 1) (17–26) predicts the same positional orientation as the usually assumed direct substitution (“S_EAr”) alternative. Instead of this classic S_EAr mechanism (Fig. 1), we find that direct concerted substitution, not involving an arenium ion, σ-complex (“Wheland”) (9–11) intermediate, competes energetically with the AE route. Like some earlier computational studies on aromatic substitution (12, 13, 27, 28) (Rzepa H, www.ch.imperial.ac.uk/rzepa/blog/?p=2423, accessed March 10, 2013), our study finds no such intermediates in the direct substitution of anisole by Cl₂. A concerted mechanism without an arenium ion intermediate was computed at some levels for the related arene nitrosation, but reaction medium and counter ion effects were not considered. Gwaltney et al. (28) reported a single concerted transition state after reoptimizing all saddle points at CCSD(T)/6-31G(d,p) and modeling bulk solvation by the Onsager approximation, and Rzepa (www.ch.imperial.ac.uk/rzepa/blog/?p=2423, accessed March 10, 2013) also found a concerted transition state including a trifluoroacetate counterion. Instead, one-step reactions via single transition states take place (Fig. 2). Our experimental investigations of the chlorination of anisole in CCl₄ solution revealed tetrachloro by-products, which must have arisen by further reaction of intermediate dichloro-adducts. Both our UV-visible (UV-VIS) spectroscopic investigation and our theoretical modeling of this reaction clearly verified the autocatalytic effect of the HCl by-product, in harmony with Andrews and Keefer’s (29, 30) early experimental kinetic studies of the chlorination of arenes, which found that HCl reduces the activation barriers significantly.Open in a separate windowFig. 2.The HCl-catalyzed concerted and addition–elimination pathways of para-chlorination of anisole in nonpolar media.We also applied reliable theoretical methods to model a typical experimental example of the highly investigated S_EAr electrophilic aromatic halogenations, the electrophilic chlorination of anisole by molecular chlorine in simulated CCl₄ solution (15, 16). Although the elucidation of the classic S_EAr mechanism [Fig. 1, involving the initial formation of a π-complex, followed by a transition state leading to a σ-complex (arenium) intermediate in the rate-controlling stage, and, finally, proton loss from the ipso-position leading to the reaction product] is considered to be a triumph of physical organic chemistry (1, 31–37), an alternative addition–elimination pathway leading to substitution products has been discussed since the 19th century (19–26, 38, 39). Nevertheless, it is commonly believed that the classic multistep S_EAr mechanism involving the formation of a σ-complex intermediate in the rate-controlling stage is the only mechanistic route to aromatic substitution products. Our present and previous (12, 13) results challenge the generality of such traditional interpretations. Although the initial stages of the alternative AE route seem unattractive because aromaticity is lost, many arenes are known experimentally to give addition products in considerable amounts (19–26, 38, 39). Thus, de la Mare (21, 25, 38, 39) demonstrated the formation of halogen adduct intermediates. Polybenzenoid hydrocarbons (PBHs) react with halogens to give isolable addition products, which then give substitution products easily by hydrogen halide elimination (23). Our computational investigations of arene bromination with molecular bromine (12) and sulfonation with SO₃ (13) provided clear evidence that the mechanisms of the inherent substitution reactions (i.e., uncatalyzed, gas phase, or weakly solvated) are concerted and do not involve the conventional σ-complex (or any other) intermediates. Moreover, the energetics of the bromination processes document the significance of competition between AE and direct substitution mechanisms leading to the same substitution products. Thus, the computed barrier in a simulated nonpolar (CCl₄) medium is 4 kcal/mol lower for Br₂ addition to benzene (followed by HBr elimination) than that for the direct substitution pathway to bromobenzene (12).Previous theoretical studies of electrophilic aromatic halogenation processes have been based on the classic S_EAr mechanism, involving arenium ion intermediates (Fig. 1). Osamura et al.’s (40) Hartree-Fock computations of the AlCl₃-catalyzed electrophilic aromatic chlorination mechanism found an initial π-complex, a transition state preceding the intermediate σ-complex, and a second transition state leading to final products. Aluminum chloride was important as a Lewis acid catalyst throughout the process. AlCl₃ coordination polarizes Cl₂ and thereby assists its reaction with the arene. Rasokha and Kochi (41) considered the interaction of Br₂ with benzene and toluene in detail in their survey of theoretical and experimental data on the prereactive charge-transfer complexes in electrophilic aromatic substitutions. They argued that the structures and properties of the prereactive complexes provide important mechanistic insights for the S_EAr reactions. Wei et al.’s (42) theoretical study of the iodination of anisole by iodine monochloride at the B3LYP/6-311G* and MP2//B3LYP/6-311G* levels (B3LYP, Becke''s three parameter hybrid functional, using the Lee-Yang-Parr correlation functional; MP2, second order Møller-Plesset perturbation theory computations) found that the highest energy transition state precedes the formation of an intermediate, which they interpreted to be a σ-complex. Instead, the structure of this complex represents a protonated iodobenzene. Volkov et al.’s MP2/LANL2DZ(d)+ study (43) of the chlorination of benzene established that dimers of group 13 metal halides catalyzed the processes more effectively. Optimized geometries of π- and σ-complexes as well as transition structures were reported. Theoretical investigations by Ben-Daniel et al. (44) and by Filimonov et al. (45) of the chlorination of benzene with Cl₂ (and other related processes) reported structural details of transition states purported to lead to the chlorobenzene product. Our reinvestigations revealed errors in major suppositions of both these studies. Our IRC computations show clearly that the transition states in question lead to 1,2 Cl₂–benzene addition products (rather than to chlorobenzene). Zhang and Lund (46) investigated the neat chlorination of toluene by Cl₂ experimentally and theoretically at B3LYP/cc-pVTZ(-f) [cc-pVTZ(-f), correlation consistent polarized triple-zeta without f-functions basis set]. Although we verified their reported geometry of the concerted transition state (figure 6 in ref. 46), our stability check revealed that its wavefunction is unstable. This casts doubt on their conclusions because of the homolysis vs. heterolysis issues. In contrast, all wavefunctions in our paper were checked and all are stable. Most prior theoretical studies of S_EAr halogenations did not consider the connections between transition states, intermediates, and products explicitly, as we have done.Experimental findings not always have been in accord with the prevailing mechanistic assumption for aromatic halogenation: that arenium ion formation is the rate-limiting step. Thus, Olah et al. (47), Kochi and coworkers (48), and Fukuzumi and Kochi (49) have emphasized that substrate and positional selectivity are inconsistent (e.g., low toluene/benzene reactivity ratios but high toluene ortho–para vs. meta regiospecificity) for some electrophiles under certain conditions. This disparity indicates the existence of at least one other mechanistic pathway. It has been suggested that π-complexes may control product formation. Olah et al.’s (47) kinetics of the ferric chloride-catalyzed bromination of benzene and alkyl benzenes provided strong evidence for low substrate selectivity in the rate-determining step, which precedes the formation of a σ-complex intermediate (Fig. 1). High positional selectivity is governed by the transition state associated with the second step of the reaction.However, our earlier study (50) examined the possible participation of π-complexes in the key mechanistic steps of S_EAr bromination reactions in detail but found no link between the energy of formation of these complexes and the overall reactivity. Although there is no doubt that π-complexes form easily (via essentially barrierless processes) in most S_EAr reactions after mixing the electrophile and the aromatic substrate, it is unlikely that these low-energy “bystander” structures influence rates of S_EAr reactions significantly. Thus, the lack of accord between substrate and positional selectivity, established by Olah et al. (47), Kochi and coworkers (48), and Fukuzumi and Kochi (49) may be due to other mechanistic differences. De la Mare and Bolton (21) and de la Mare (51) have stressed the plurality of aromatic substitution mechanisms, depending on the substrate and the conditions.Reactive substrates are known to undergo uncatalyzed aromatic substitution in nonpolar solvents at room temperature. Thus, our computational investigations modeled Watson’s careful experiments on the chlorination of anisole in CCl₄ at 25 °C (15, 16). His low conversion (25%) conditions for chlorophenol permitted more accurate determination of the initial product ratios (and avoided further Cl₂ additions to 4-chloroanisole, which ultimately gave 1,3,4,5,6-pentachloro-4-methoxycyclohexene). After introduction of gaseous Cl₂ into a CCl₄ solution of anisole for 1 h, the products were 4-chloroanisole (76%), 2-chloroanisole (13.6%), 2,6-dichloro anisole (2.1%), 2,4-dichloroanisole (3.0%), and 2,4,6-trichloroanisole (0.4%).Analogous chlorinations of phenol, 2-methylphenol, and 2-chlorophenol in CCl₄ also have been carried out with high conversion rates at the reflux temperature (79 °C) (16). Chlorination of phenol with Cl₂ in CCl₄ has been reported by other groups (52, 53).